CN1272105A - Compound containing six-membered rings, processes for their preparation, and their use as medicaments - Google Patents
Compound containing six-membered rings, processes for their preparation, and their use as medicaments Download PDFInfo
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- CN1272105A CN1272105A CN98809320A CN98809320A CN1272105A CN 1272105 A CN1272105 A CN 1272105A CN 98809320 A CN98809320 A CN 98809320A CN 98809320 A CN98809320 A CN 98809320A CN 1272105 A CN1272105 A CN 1272105A
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- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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Abstract
Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidase activity are also described.
Description
The cross reference of related application
The U.S.Provisional Serial 60/059,308 that the application is submitted on the 17th based on 08/938,644 and 1997 year September of U.S. Patent Application Serial Number that 60/060,195,1997 years Septembers of U.S.Provisional Serial that September in 1997 is submitted on the 26th are submitted on the 26th.
The U.S. Patent Application Serial Number 08/653 that the application was also submitted with March 24th, 1996, 034 is related, the latter is the U.S. Patent Application Serial Number 08/606 submitted for 26th for 2 months for 1996, 624 part continuation application, and U.S. Patent Application Serial Number 08/606, 624 be the U.S. Patent Application Serial Number 08/580 submitted December 29 nineteen ninety-five, 567 part continuation application, U.S. Patent Application Serial Number 08/580, 567 be the U.S. Patent Application Serial Number 08/476 submitted June 6 nineteen ninety-five, 946 part continuation application, U.S. Patent Application Serial Number 08/476, 946 be the U.S. Patent Application Serial Number 08/395 submitted nineteen ninety-five 2 month 27, 245 part continuation application, all these applications are incorporated herein entirety for reference.The U.S. Patent Application Serial Number 08/917,640 that the application was submitted on the 22nd with August in 1997 is related, latter describes the method for preparing carbocyclic compound, particularly prepares GS 4104, phosphatic method, and be incorporated herein entirety for reference.
Invention field
Neuraminidase (being also known as sialidase, acylneuraminate base hydrolase, and EC3.2.1.18) is animal and enzyme common in many microorganisms.It is a kind of glycosylhydrolase (glycohydrolase), from glycoprotein, and glycolipid decomposes the sialic acid that end α -one glycosidic bonds connect with oligosaccharides.Many microorganisms containing neuraminidase are pathogenic to the mankind and other animals (including poultry, horse, pig and sea dog).These pathogenic organisms include influenza virus.
Neuraminidase and influenza virus it is pathogenic relevant.It is considered to help freshly synthesized virion from infected cell to deviate from, and helps virus to be moved in respiratory mucus (by its hydrolytic enzyme activities).
Description of Related Art
Von Itzstein, M. et al. are in " natural (Nature) ", 363 (6428)：The Theoretical Design of the sialidase base inhibitor of influenza virus duplication is disclosed in 418-423 (1993).
Colman, et al. P.M. in International Patent Publication No. WO92/06691 (international application no PCT/AU90/00501, on April 30th, 1992 is open) in, von Itzstein, et al. L.M. in the 204A1 (European Patent Application No.s 92309648.6 of European Patent Publication No 0539, on April 28th, 1993 is open) in, and von Itzstein, et al. L.M. in International Patent Publication No. WO91/16320 (international application no PCT/AU91/00161, on October 31st, 1991 is open) in disclose the compound combined with neuraminidase, and claim that it has interior resisting virus activity.
Goal of the invention
Present invention is primarily aimed at the suppression of the suppression, particularly influenza virus of virus.Specific object is to suppress glycolytic ferment such as neuraminidase, the selective depression of particularly viral or bacillary neuraminidase.
Another object of the present invention is to provide neuraminidase inhibitor, it has suppression to urination speed, nose or pulmonary secretions can be entered from body circulation, with being enough therapeutically effective oral bioavailability rate, with efficient, clinically acceptable toxicity profile (profiles), and other required pharmacological properties.
Another object is the synthetic method for providing improved relatively inexpensive neuraminidase inhibitor.
Another object is to provide the improved method for applying known and new neuronal propylhomoserin enzyme inhibitor.
A further object is used to prepare polymer to provide, surfactant or immunogene and for other commercial runs and the composition of product.
Above-mentioned these purposes and other purposes are readily able to be understood by those of ordinary skill after integrally the present invention is considered.
Summary of the invention
The invention provides the compound or composition with formula (I) or (II)Wherein A1For-C (J1)=,-N=or-N (O)=；A2For-C (J1)2- ,-N (J1)-,-N (O) (J1)-,-S- ,-S (O)-,-S (O)2- or-O-；E1For-(CR1R1)m1W1；G1For N3,-CN ,-OH ,-OR6a,-NO2, or-(CR1R1)m1W2；T1For-NR1W3, H ,-R3,-R5, heterocycle, or and U1Or G1The group with following structure is formed together：
U1For H ,-R3Or-X1W6；J1With J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3；J2With J2aIt independently is H or R1；R1It independently is H or C1-C12Alkyl；R2It independently is R3Or R4, wherein each R4Independently with 0 to 3 R3Substituent group；R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b)(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2),
-N(R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) ,=N (R6b) or W5；R4It independently is C1-C12Alkyl, C2-C12Alkenyl, or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0 to 3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene, any alkylidene, alkylene group or alkynylene are by 0 to 3 R3Group is replaced；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides；W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides can be converted into alkaline heteroatomic group；W3For W4Or W5；W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Substituent group；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(H)(R6b)) ,-C (NR6b)((N(R6b)2) ,-C (N (H) (N (R6b)2) ,-C (S) N (R6b)2, or-C (O) R2；X1For a key ,-O- ,-N (H)-,-N (W6)-,-N (OH)-,-N (OW6)-,-N (NH2)-,-N (N (H) (W6))-,-N (N (W6)2)-,-N (H) N (W6)-,-S- ,-SO-, or-SO2-；With each m1 independently 0 to 2 integer；But condition is to exclude WO91/16320 the 23rd rows of page 3 to the following compounds described in the 6th row of page 5, wherein：(a)A1For-CH=or-N=and A2For-CH2-；(b)E1For COOH, P (O) (OH)2, SOOH, SO3H, or
(c)G1For CN, N (H) R20, N3, SR20, OR20, guanidine radicals ,-N (H) CN
(d)T1For-NHR20；(e)R20For H；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the analog that its halogen replaces；Pi-allyl or unsubstituted aryl, or by halogen, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；(f)J1For H and J1aFor H, F, Cl, Br or CN；(g)J2For H and J2aFor H, CN or N3；(h)U1For CH2YR20a, CHYR20aCH2YR20a, or CHYR20aCHYR20aCH2YR20a；(i)R20aFor H or C1-C4Acyl group；(j) Y is O, S, H or NH；(k) 0 to 2 YR20aFor H, and (l) U1Each Y portion is identical or different in group, and when Y is H, R20aFor covalent bond, and if condition is G1For N3Then U1It is not -CH2OCH2Ph, and its pharmaceutically acceptable salt and solvate；And its salt, solvate, the enantiomer and the diastereomer of purifying of fractionation.
WO92/06691 the 26th rows of page 9 are also excluded to the formula II below compound described in the 5th row of page 11, wherein：(a)A2For O；(b)E1For COOH, P (O) (OH)2, NO2, SOOH, SO3H, tetrazolium, CH2CHO, CHO, CH (CHO)2Or wherein E1For COOH, P (O) (OH)2, SOOH or SO3H, its ethyl, methyl or pivaloyl base ester；(c)G1For hydrogen, N (R20a)2, SR20aOr OR20a；(d)T1For-NHC (O) R20b, wherein R20bThe C replaced for unsubstituted or halogen1-C6Line style or cyclic alkyl, or SR20a, OR20a, COOH or its alkyl/aryl ester, NO2, C (R20a)3, CH2COOH
Or its alkyl/aryl ester, CH2NO2Or CH2NHR20b；(e)R20aFor hydrogen；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the analog that its halogen replaces；Or unsubstituted aryl or by halogen, pi-allyl, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；(f)J1For H and J1aFor H, OR20a, F, Cl, Br, CN, NHR20a, SR20aOr CH2X, wherein X are NHR20a, halogen or OR20a；(g)J2For H or J2aFor hydrogen, N (R20a)2, SR20aOr OR20a；(h)U1For CH2YR20a, CHYR20aCH2YR20aOr CHYR20aCHYR20aCH2YR20a, wherein Y is O, S or H, and U1In each Y portion it is identical or different, and R20aCovalent bond is represented when Y is hydrogen；And its pharmacologically acceptable salt or derivatives thereof.
Another embodiment of the present invention is related to following formula: compound：
Wherein E1For-(CR1R1)m1W1；G1For N3,-CN ,-OH ,-OR6a,-NO2, or-(CR1R1)m1W2；T1For-NR1W3, heterocycle, or and U1Or G1The group with following structure is formed together：U1For H or-X1W6And if-X1W6, then U1For side chain；J1With J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3；J2With J2aIt independently is H or R1；R1It independently is H or C1-C12Alkyl；R2It independently is R3Or R4, wherein each R4Independently with 0 to 3 R3Substituent group；
R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2) ,-N (R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) or=N (R6b)；R4It independently is C1-C12Alkyl, C2-C12Alkenyl, or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0 to 3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene, any alkylidene, alkylene group, alkynylene are by 0 to 3 R3Group is replaced；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides；W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides；W3For W4Or W5；W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Group is replaced；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(R6b)2) ,-C (S) N (R6b)2Or-C (O) R2；X1For a key ,-O- ,-N (H)-,-N (W6)-,-N (OH)-,-N (OW6)-,-N (NH2)-,
-N(N(H)(W6))-,-N (N (W6)2)-,-N (H) N (W6)-,-S- ,-SO-, or-SO2-；With each m1 independently 0 to 2 integer；And its salt, solvate, the enantiomer and the diastereomer of purifying of fractionation.
Another embodiment of the present invention is related to the compound of following formula：
Wherein E1For-(CR1R1)m1W1；G1For N3,-CN ,-OH ,-OR6a,-NO2, or-(CR1R1)m1W2；T1For-NR1W3, heterocycle, or and U1Or G1The group with following structure is formed together：
U1For H or-X1W6；J1For J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3；J2With J2aIt independently is H or R1；R1It independently is H or C1-C12Alkyl；R2It independently is R3Or R4, wherein each R4Independently by 0 to 3 R3Group is replaced；R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2),
-N(R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) or=N (R6b)；R4It independently is C1-C12Alkyl, C2-C12Alkenyl, or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0 to 3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene, any alkylidene, alkylene group, alkynylene are by 0 to 3 R3Group is replaced；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides；W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides；W3For W4Or W5；W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Group is replaced；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(R6b)2) ,-C (S) N (R6b)2, or-C (O) R2；X1For-O- ,-N (H)-,-N (W6)-,-N (OH)-,-N (OW6)-,-N (NH2)-,-N (N (H) (W6))-,-N (N (W6)2)-,-N (H) N (W6)-,-S- ,-SO-, or-SO2-；With each m1 independently 0 to 2 integer；And its salt, solvate, the enantiomer and the diastereomer of purifying of fractionation.
Another embodiment of the present invention is related to the compound of following formula；Wherein
E1For-CO2R1；G1For-NH2,-N (H) (R5) or-N (H) (C (N (H)) (NH2))；T1For-N (H) (C (O) CH3)；U1For-OR60；R1For H or the alkyl with 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom；And R60For the branched-alkyl with 3,4,5,6,7,8,9,10,11 or 12 carbon atoms；And its salt, solvate, the enantiomer and the diastereomer of purifying of fractionation.
Another embodiment of the present invention is related to formula (VII) or (VIII) compound：
Wherein E1For-(CR1R1)m1W1；G1For N3,-CN ,-OH ,-OR6a,-NO2, or-(CR1R1)m1W2；T1For-NR1W3, heterocycle, or and G1The group with following structure is formed togetherU1For-X1W6；J1With J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3；J1With J2aIt independently is H or R1；R1It independently is H or C1-C12Alkyl；R2It independently is R3Or R4, wherein each R4Independently by 0 to 3 R3Group is replaced；R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1),
-C(O)N(R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2) ,-N (R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) or=N (R6b)；R4It independently is C1-C12Alkyl, C2-C12Alkenyl, or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0 to 3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene, any alkylidene, alkylene group or alkynylene are by 0 to 3 R3Group is replaced；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides；W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides；W3For W4Or W5；W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Group is replaced；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(R6b)2) ,-C (NR6b)(N(H)(R6b)) ,-C (N (H) (N (R6b)2) ,-C (S) N (R6b)2, or C (O) R2；X1For a key ,-O- ,-N (H)-,-N (W6)-,-S- ,-SO-, or-SO2-；With each m1 independently 0 to 2 integer；But condition is to exclude wherein U1For H or-CH2CH(OH)CH2(OH) compound；And its salt, solvate, the enantiomer and the diastereomer of purifying of fractionation.
The compounds of this invention or composition for additionally comprising pharmaceutically acceptable carrier are provided in another embodiment of the present invention.
In another embodiment of the present invention, the activity of neuraminidase is suppressed comprising method the step of may containing the sample of neuraminidase with the compounds of this invention or compositions-treated with one.
Another embodiment of the present invention provides the method for suppressing neuraminidase activity, and it includes allowing the step of may being contacted containing the sample of neuraminidase with the present composition.
Another embodiment of the present invention infects to treat or prevent virus in host, the particularly method of influenza virus infection, it includes the WO91/16320 that the data sender effective dose is applied to via the approach beyond local application to respiratory tract, WO92/06691 or United States Patent (USP) 5, antiviral activity compound described in 360,817.
There is provided the novel synthetic method of the compounds of this invention in other embodiments.There is provided the method using the compound of formula 281 in a this embodiment, wherein the method includes using formula R5-X1- H compounds handle compound 281, form the compound of formula 281.1：Wherein X1With R5As defined above；R51For the stable protection group of acid of carboxylic acid；And R54For aziridine activated group.
Method using following formula: compound is provided in another embodiment
Wherein the method is included with cinchoninic acid is handled together with (geminal) dialkoxyalkane or together with dialkoxy cycloalkane and acid, to form following formula: compound：Compound 274 is handled with metal alkoxide and alkanol, form following formula: compound：Compound 275 is handled with sulfonic acid halide and amine, following formula: compound is formed：Compound 276 is handled with dehydrating agent, is then handled again with acid with alkanol, following formula: compound is formed：
Wherein R50For 1,2- glycerol protection bases；R51For the stable protection group of acid of carboxylic acid；And R52For hydroxy activated group.The simple declaration of accompanying drawing
Fig. 1 and Fig. 2 illustrates the arterial oxygen saturation (SaO by the influenza-A mouse infected2), following compounds treatment of the mouse through various i.p. dosage：GG167 (GG167), it is that known influenza emits virus compound (Fig. 1), the compounds of this invention 203 (Fig. 2)：Respectively use respectively with square in the test compound and saline control group of 50,10,2 and 0.5mpk (mg/kg/ days), figure, it is real
Heart circle, triangle, rhombus is represented with open circle.In all figures, compared with saline control group,*P ＜ 0.05,**P ＜ 0.01.
Fig. 3-5 compares the SaO in the mouse that influenza A infects2Level, its ribavirin (triangle) respectively through p.o. dosage, compound 203 (square) is treated with GG167 (solid rim), and saline control group is open circle.Fig. 3：Compound 203 and GG167 is respectively 150mpk, and ribavirin is 100mpk；Fig. 4：Compound 203 and GG167 is respectively 50mpk, and ribavirin is 32mpk；Fig. 5：Compound 203 and GG167 is respectively 10mpk, and ribavirin is 10mpk.
Fig. 6-8 illustrates the SaO by the influenza-A mouse infected2Level, its compound 262 (circle) respectively through low p.o. dosage and 260 (solid squares) and GG167 (triangle) are handled；Saline control group is open circle, and is uninfected by control group for square hollow.Fig. 6：Each test compound is mpk；Fig. 7：Each test compound is 1mpk；Fig. 8：Each test compound is 0.1mpk.Describe invention composition in detail
The compounds of this invention excludes hitherto known compound.But as other following embodiments it can be seen, be antiviral purpose and using only knowing in the past for prepare antiviral compound produce and known compound as intermediate also within the scope of the present invention.In the U.S., this paper compound or composition exclude the compound expected under 35USC § 102 or the obvious compound under 35USC § 103.Especially, following claims eliminate WO91/16320, WO 92/06691, United States Patent (USP) 5360817 or Chandler, et al. M. " J.Chem.Soc.Perkin Trans.1 ", 1995,1189-1197 expected or compounds that do not have novelty.
But include to fall in one embodiment of this invention in WO91/16320, WO92/06691, or the compound in the range of the upperseat concept of United States Patent (USP) 5360817, but it has the Formulas I a that (a) ' 320 are applied, (b) it is used for the carbon of group " A ", and (c) ' 320 and the R of ' 691 applications in ' 320 applying5For "-CH2YR6,-CHYR6CH2YR6Or-CHYR6CHYR6CH2YR6", wherein YR6Can not for OH or protection OH (wherein the protection group in human gi-tract under conditions of hydrolyzable produce free OH), i.e., this compound is in the gastrointestinal tract
To hydrolysis-stable.Therefore the compound that the embodiment is excluded is typically wherein R5For acetyl group or other C1-C4Carbonic acyl radical (carbacyl) ' 320 or ' 691 application compound.
The method for determining stability of the compound in alternative gastrointestinal secretion thing is known.The so-called compound stablized in the gastrointestinal tract refers to：It is de-protected by blocking group less than about 50mol% after being cultivated 1 hour in the intestinal juice or gastric juice of 37 DEG C of replacements.Such compound is suitable for use in the embodiment above.It should be noted that the compound stablized in the gastrointestinal tract is not offered as it and can not hydrolyzed in vivo.Generally, prodrug is stable in digestive system, but in gastrovascular cavity, in liver or other metabolic organs, or intracellular can significantly be hydrolyzed into female medicine (parental drug) general.
It should be understood that other the of the invention embodiments being detailed below are contemplated using in fact in WO91/16320, the specifically disclosed compound of institute in WO92/06691 or United States Patent (USP) 5360817, including those wherein YR6The compound for the hydroxyl protected for free hydroxyl group or by facile hydrolysis group (such as acetyl group).But in this instance, these compounds are used by novel method of administration.
In another embodiment, this paper compound excludes following compound, wherein：(a)E1For-CO2H ,-P (O) (OH)2,-NO2,-SO2H ,-SO3H, tetrazole radical ,-CH2CHO ,-CHO, or-CH (CHO)2；(b)G1For-CN, N3,-NHR20, NR20,-OR20, guanidine radicals, SR20,-N (R20) → O ,-N (R20)(OR20) ,-N (H) (R20)N(R20)2, unsubstituted pyrimidine radicals, or unsubstituted (pyrimidine radicals) methyl；(c)T1For-NHR20,-NO2；And R20For H；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the congener that its halogen replaces；Pi-allyl or unsubstituted aryl, or through halogen, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；(d) each J1For H；X (e)1For a key ,-CH2- or-CH2CH2-；In this instance, W6It is not H, W7Or-CH2W7, wherein W7For H ,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1, or-SR6a。
WO92/06691 the 26th rows of page 9 are also excluded to the formula II below compound described in the 5th row of page 11, wherein：(a)A2For O；(b)E1For COOH, P (O) (OH)2, NO2, SOOH, SO3H, tetrazolium, CH2CHO, CHO, CH (CHO)2
Or wherein E1For COOH, P (O) (OH)2, SOOH or SO3H, its ethyl, methyl or pivaloyl base ester；(c)G1For hydrogen, N (R20a)2, SR20aOr OR20a；(d)T1For-NHC (O) R20b, wherein R20bThe C replaced for unsubstituted or halogen1-C6Line style or cyclic alkyl, or SR20a, OR20a, COOH or its alkyl/aryl ester, NO2, C (R20a)3, CH2COOH or its alkyl/aryl ester, CH2NO2Or CH2NHR20b；(e)R20aFor hydrogen；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the analog that its halogen replaces；Or unsubstituted aryl or by halogen, pi-allyl, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；(f)J1For H and J1aFor H, OR20a, F, Cl, Br, CN, NHR20a, SR20aOr CH2X, wherein X are NHR20a, halogen or OR20a；(g)J2For H or J2aFor hydrogen, N (R20a)2, SR20aOr OR20a；(h)U1For CH2YR20a, CHYR20aCH2YR20aOr CHYR20aCHYR20aCH2YR20a, wherein Y is O, S or H, and U1In each Y portion it is identical or different, and R20aCovalent bond is represented when Y is hydrogen；And its pharmacologically acceptable salt or derivatives thereof.
In another embodiment, the compounds of this invention is wherein U1It is not -CH2OH ,-CH2OAc or-CH2OCH2Those of Ph.
In another embodiment, the compounds of this invention is wherein E1It is not -CH2OH ,-CH2OTMS, or-CHO those.
In another embodiment, the compounds of this invention is wherein U1It is not connected to via carbon atom bonding on nuclear ring directly, or U1Do not replaced by hydroxyl or hydroxy ester, particularly U1It is not polyhydroxyalkanes, particularly-CH (OH) CH (OH) CH2Those of OH.In another embodiment, U1For branched group R as described below5, or with least one group R5Substituted carbocyclic ring.
In other embodiments, the present invention excludes following formula: compound：
Wherein：
1. in formula (V)：A2For-O- or-CH2-；E1For-CO2H；G1For-N (H) (C (NH) (NH2))；T1For-N (H) (Ac)；And U1With following formula：2. in formula (V)：A2For-O- or-CH2-；E1For-CO2H；G1For-NH2；T1For-N (H) (Ac)；And U1For-CH2OH；3. in formula (V)：A2For-CH2-；E1For-CH2OH or-CH2OTMS；G1For-N3；T1For-N (H) (Ac)；And U1For-CH2OCH2Ph；4. in formula (V)：A2For-CH2-；E1For-CO2H or-CO2CH3；G1For-N3；T1For-N (H) (Ac)；And U1For-CH2OH；5. in formula (V)：A2For-CH2-；
E1For-CO2H ,-CHO, or-CH2OH；G1For-N3：T1For-N (H) (Ac)；And U1For-CH2OCH2Ph；6. in formula (VI)：A2For-CH2-；E1For-CO2H；G1For-OCH3；T1For-NH2；And U1For-CH2OH；With 7. in formula (VI)：A2For-CH2-；E1For-CO2H；G1For-OCH3；T1For-N (H) (Ac)；And U1For-CH2OAc。
When compound described herein by same group (for example, " R1" or " R6c) when replacing more than once, it should be understood that the group be may be the same or different, i.e., each group is independently selected.
" heterocycle " includes herein, limits as an example but not, Paquette, Leo A.；" contemporary heterocyclic chemistry principle (Principles of Modern HeterocyclicChemistry) " (W.A.Benjamin, New York, 1968), particularly the 1st, 3,4,6,7 and 9 chapter；" heterocyclic compound chemistry (The Chemistry of HeterocyclicCompounds), A series of Monographs " (John Wiley＆Sons, New York, 1950 so far), the particularly the 13rd, 14, volume 16,19 and 28；And " JACS (J.Am.Chem.Soc.) ", 82：5566 (1960) heterocycle.
The example of heterocycle includes, and limits as an example but not, pyridine radicals, thiazolyl, tetrahydro-thienyl, thio-oxidizing tetrahydro-thienyl, pyrimidine radicals, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, tetrazole radical, benzofuranyl, thianaphthenyl, indyl, indolinyl (indolenyl), quinolyl, isoquinolyl, benzimidazolyl, piperidyl, 4- piperazines
Pyridine ketone group, pyrrolidinyl, 2-Pyrrolidone base, pyrrolinyl, tetrahydrofuran base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, octahydro isoquinolyl, azocine base, triazine radical, 6H-1, 2, 5- thiadiazine bases, 2H, 6H-1, 5, 2- dithiazine bases, thienyl, thianthrene group, pyranose, isobenzofuran-base, benzopyranyl, xanthyl, benzene oxathiin base (phenoxathiinyl), 2H- pyrrole radicals, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizine base, isoindolyl, 3H- indyls, 1H- indazolyls, purine radicals, 4H- quinolizine bases, 2, 3- phthalazinyls, 1, 5- phthalazinyls, quinoxalinyl, quinazolyl, 1, 2- phthalazinyls, pteridyl, 4aH- carbazyls, carbazyl, B-carboline base, phenanthridinyl, acridinyl, pyrimidine radicals, phenanthroline, phenazinyl, phenothiazinyl, furazanyl, phenoxazine group, isochroman base, dihydro pyranyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, the peaceful ring group of quinoline, morpholinyl, oxazole alkyl, BTA base, benzoisoxazole base, hydroxyindole base, benzoxazole quinoline base and isatinoyl (isatinoyl).
Not limit as an example, the bonded heterocycle of carbon is connected to 2,3,4,5 or 6 of pyridine, the 3 of pyridazine, 4,5, or 6, the 2 of pyrimidine, 4,5 or 6,2,3,5 or 6 of pyrazine, the 2 of furans, tetrahydrofuran, thio-furan, thiophene, pyrroles or nafoxidine, 3,4, or 5 Wei , oxazoles, the 2 of imidazoles or thiazole, 4, or 5 , isoxazoles, the 3 of pyrazoles or isothiazole, 4 or 5,2 or 3 of aziridine, 2,3 or 4 of azetidine, the 2,3,4,5 of quinoline, 6,7 or 8, the 1,3 of isoquinolin, 4,5,6,7 or 8.More particularly, the bonded heterocycle of carbon includes 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 5- pyridine radicals, 6- pyridine radicals, 3- pyridazinyls, 4- pyridazinyls, 5- pyridazinyls, 6- pyridazinyls, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, 6- pyrimidine radicals, 2- pyrazinyls, 3- pyrazinyls, 5- pyrazinyls, 6- pyrazinyls, 2- thiazolyls, 4- thiazolyls or 5- thiazolyls.
Not limit as an example, the bonded heterocycle of nitrogen is connected to aziridine, azetidine, pyrroles, pyrrolidines, 2- pyrrolins, 3- pyrrolins, imidazoles, imidazolidine, 2- imidazolines, 3- imidazolines, pyrazoles, pyrazoline, 2- pyrazolines, 3- pyrazolines, piperidines, piperazine, indoles, indoline, 1 of 1H- indazoles, 2 of benzazine or isodihydroazaindole, 4 of morpholine, 9 of carbazole or B-carboline.More particularly, the bonded heterocycle of nitrogen includes 1- aziridinyls, 1- azetidinyls (azetedyl), 1- pyrrole radicals, 1- imidazole radicals, 1- pyrazolyls and 1- piperazines
Piperidinyl.
" alkyl " used herein, unless otherwise specified, refers to and contains just, secondary, the C of uncle or ring carbon atom1-C12Alkyl.Example has methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), 1- propyl group (n-Pr, n-propyl ,-CH2CH2CH3), 2- propyl group (i-Pr, isopropyl ,-CH (CH3)2), 1- butyl (n-Bu, normal-butyl ,-CH2CH2CH2CH3), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH2CH(CH3)2), 2- butyl (s-Bu, sec-butyl ,-CH (CH3)CH2CH3), 2- methyl-2-propyls (t-Bu, the tert-butyl group ,-C (CH3)3), 1- amyl group (n-pentyl ,-CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), 1- hexyls (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3).The group 2-5,7,9 and 100-399 of the example of alkyl such as table 2.
The present composition includes the compound of one of following formula：
In typical embodiments, compound of formula I is selected.
J1With J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3, typically R1Or F, it is more typically H or F, more preferably H.
J2With J2aIt independently is H or R1, typically H.
A1For-C (J1)=, or-N=, typically-C (J1)=, is more typically-CH=.
A2For-C (J1)2- ,-N (J1)-,-N (O) (J1)-,-N (O)=,-S- ,-S (O)-,-S (O)2-
Or-O-, typically-C (J1)2- ,-N (J1)-,-S- or-O-, is more typically-C (J1)2-, or-O-, it is more typically-CH2- or-O-, it is more typically-CH2-。
E1For-(CR1R1)m1W1。
Typically, R1For H or C1-C12Alkyl, usually H or C1-C4Or C5-C10Alkyl, is more typically H or the alkyl with 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom, is more typically H or selected from methyl, ethyl, the C of n-propyl and isopropyl1-C3Alkyl.Most typically R1For H.
M1 is 0 to 2 integer, typically 0 or 1, most typically about 0.
M2 is 0 to 1 integer.
M3 is 1 to 3 integer.
W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides, acidic hydrogen herein refers to the group that anion or correspondence salt or solvate are produced with a hydrogen atom that can be removed by alkali.The acidity and alkaline General Principle of organic substance are known, and define W with this1, no longer it is described in detail herein.But Streitwieser, A. and Heathcock are referred to, C.H.；Organic chemistry introduction (Introduction to OrganicChemistry), the second edition (Macmillan, New York, 1981), the 60-64 pages.Generally, the pK values that acidic-group of the invention has are smaller than water, and usually less than pK=10, preferably more than pK=8, preferably lower than pK=6.They include tetrazolium and carbon, sulphur, the typically acid of phosphorus and nitrogen, carboxylic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid and phosphonic acids, and these acids R6cAcid amides and R6bEster (R6aWith R6cIt is defined as below).W1Example have-CO2H ,-CO2R6a,-OSO3H ,-SO3H ,-SO2H ,-OPO3H2,-PO3(R6a)2,-PO3H2,-PO3(H)(R6a) and-OPO3(R6a)2, E1Typically W1, W1Typically-CO2H ,-CO2R6a,-CO2R4Or CO2R1, most typically about CO2R14, wherein R14For just or the secondary C in end1-C6Alkyl.
W1Also can for protection acidic-group, it refers to have been used in herein is usually used in protection acidic-group and below will be in R in the art6aThe above-mentioned acidic-group of one of group of lower explanation protection.More typically, the W of protection1For-CO2R1,-SO3R1,-S (O) OR1,-P (O) (OR1)2,-C (O) NHSO2R4, or-SO2NHC(O)-R4, wherein R1And R4It is as defined above.
More typically, E1Selected from-C (O) O (CH2)bCH((CH2)cCH3)2, wherein b=0 to 4, c=0 to 4, b+c=1 is to 4, or selected from following groups：
Group E1Example be listed in table 3a into 3b.
G1For N3,-CN ,-OH, OR6a,-NO2Or-(CR1R1)m1W2, wherein R1It is as defined above with m1.Usual G1For-(CR1R1)m1W2。
W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides.W2Alkaline hetero atom is generally comprised, it refers to not for carbon and generally (there can be above-mentioned W by acidic hydrogen herein1Acid range) protonation atom.The general principle such as Streitwieser and Heathcock (as above recited) of alkalescence are described, and the meaning for making the alkaline word of hetero atom one that there is the art those of ordinary skill to understand.Generally, the alkaline heteroatomic correspondence protonated form used in the compounds of this invention has above-mentioned W1Scope pK values.Alkaline hetero atom includes hetero atom common in organic compound, and it, which has, does not share, not bonded, the electronics pair of n-type etc..Unrestricted as an example, typical alkalescence hetero atom includes alcohol, amine, amidine, guanidine, the oxygen of sulfide etc., nitrogen and sulphur atom, usually amine, amidine and guanidine.Usual W2For amino or aminoalkyl (typically rudimentary, i.e. C1-C6Alkyl), for example, aminomethyl, aminoethyl or aminopropyl；Amidino groups or Amidinylalkyl, such as amidinomethyl, amidinoethyl or amidino groups propyl group；Or guanidine radicals or guanidine alkyl, such as guanidine methyl, guanidine ethyl or guanidine propyl group (in each case, alkyl is used to this alkali subtituent bridging to carbocyclic ring).More typically, W2For amino, amidino groups, guanidine radicals, heterocycle, the heterocycle through 1 or 2 amino or guanidine radicals (being typically 1) substitution, or replace through amino or guanidine radicals
C2-C3Alkyl, or through amino and the C selected from hydroxyl and second substituent group of amino2-C3Alkyl.W can be used as2Heterocycle typically comprise and contain 1 or 2 hetero atom in 5 or 6 yuan of rings containing N or S, its middle ring.Such heterocycle is generally substituted on ring carbon atom.It can be saturation or unsaturation and can be via low alkyl group (m1=1 or 2) or-NR1- be bonded on core cyclohexene.More typically, W2For-NHR1,-C (NH) (NH2) ,-NR1-C(NR1)(NR1R3) ,-NH-C (NH) (NHR3) ,-NH-C (NH) (NHR1) ,-NH-C (NH) NH2,-CH (CH2NHR1)(CH2OH) ,-CH (CH2NHR1)(CH2NHR1) ,-CH (NHR1) ,-(CR1R1)m2-CH(NHR1)R1,-CH (OH)-(CR1R1)m2-CH(NHR1)R1, or-CH (NHR1)-(CR1R1)m2-CH(OH)R1,-(CR1R1)m2-S-C(NH)NH2,-N=C (NHR1)(R3) ,-N=C (SR1)N(R1)2,-N (R1)C(NH)N(R1) C=N, or-N=C (NHR1)(R1)；Wherein each m2 is usually O, usual R1For H, R3For C (O) N (R1)2。
W2Can be arbitrarily the alkaline hetero atom protected, it refers to herein has used R6bSuch as the above-mentioned alkaline hetero atom of one of group commonly used in the art protection.Such group is specified in Greene as described below (recited herein).Limit as an example but not, such group includes acid amides, carbamate, amido-acetal, imines; enamine, N- alkyl or N- arylphosphinyls, N- alkyl or N- aryl sulfonyl kias or sulfonyl, N- alkyl or N- arylsilyl groups; thioether, thioesters, disulphide, sulfinyl etc..In certain embodiments, R6bProtection group can be in disconnecting under physiological condition, and typically it disconnects in vivo, wherein, such as alkaline hetero atom is with organic acid or for example naturally occurring amino acid of amino acid or hereinafter to group R6aDescribed polypeptide formation acid amides.
Typically, G1Selected from following：
Group G1Other example is listed in Table 4 below.
T1For-NR1W3,-R3,-R5Or heterocycle, or and U1Or G1The group with following structure is formed together：Wherein R6bIt is defined as below, R1With W3It is as defined above.Typically, T1For-NR1、W3Or heterocycle.Usual T1Selected from following：
Group T1Example be listed in Table 5 below.
W3For W4Or W5, wherein W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5。W3Typically-C (O) R5Or W5。
R2It independently is the R being defined as below3Or R4, condition is each R4Independently by 0 to 3 R3Group is replaced；R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2) ,-N (R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) ,=N (R6b) or W5。
R3Typically F, Cl ,-CN, N3, NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-NR1C(O)R1,-N (R6b)C(O)R1,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2Or=O.More typically, comprising R6bGroup R3Including-C (O) N (R6b)2Or-C (O) N (R6b)(R1).More typically, R3For F, Cl ,-CN, N3,-OR1,-N (R1)2,-SR1,-C (O) OR1,-OC (O) R1, or=O.More typically, R3For F ,-OR1,-N (R1)2Or=O.
In this application, "=O " represent with the bonded oxygen atom of double bond (oxo), "=S ", "=N (R6b) " and "=N (R1) " represent sulphur and nitrogen analog.
R4For C1-C12Alkyl, C2-C12Alkynyl or C2-C12Alkenyl.Typically, alkyl R4
With 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom, alkenyl and alkynyl R4With 2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms.R4Usually alkyl (as defined above).Work as R4During for alkenyl, usually vinyl (- CH=CH2), 1- propyl- 1- alkenyls (- CH=CHCH3), 1- propyl- 2- alkenyls (- CH2CH=CH2), 2- propyl- 1- alkenyls (- C (=CH2)(CH3)), 1- but-1-ene bases (- CH=CHCH2CH3), 1- but-2-ene bases (- CH2CH=CHCH3), 1- butyl- 3- alkenyls (- CH2CH2CH=CH2), 2- methyl isophthalic acids -propyl- 1- alkenyls (- CH=C (CH3)2), 2- methyl isophthalic acids -propyl- 2- alkenyls (- CH2C (=CH2)(CH3)), 2- but-1-enes base (- C (=CH2)CH2CH3), 2- but-2-enes base (- C (CH3)=CHCH3), 2- butyl- 3- alkenyls (- CH (CH3) CH=CH2), amyl- 1- the alkenyls (- CH=CHCH of 1-2CH2CH3), amyl- 2- the alkenyls (- CHCH=CHCH of 1-2CH3), amyl- 3- the alkenyls (- CHCH of 1-2CH=CHCH3), amyl- 4- the alkenyls (- CHCH of 1-2CH2CH=CH2), amyl- 1- alkenyls (- the C (=CH of 2-2)CH2CH2CH3), the amyl- 2- alkenyls (- C (CH of 2-3)=CH2CH2CH3), the amyl- 3- alkenyls (- CH (CH of 2-3) CH=CHCH3), the amyl- 4- alkenyls (- CH (CH of 2-3)CH2CH=CH2) or 3- methyl isophthalic acids-but-2-ene base (- CH2CH=C (CH3)2).More typically, R4Alkenyl has 2,3 or 4 carbon atoms.Work as R4During for alkynyl, typically acetenyl (- C ≡ CH), 1- propyl- 1- alkynyls (- C ≡ CCH3), 1- Propargyls (- CH2C ≡ CH), 1- butyl- 1- alkynyls (- C ≡ CCH2CH3), 1- butyl- 2- alkynyls (- CH2C≡CCH3), 1- butyl- 3- alkynyls (- CH2CH2C ≡ CH), 2- butyl- 3- alkynyls (- CH (CH3) C ≡ CH), the amyl- 1- alkynyls of 1- (- C ≡ CCH2CH2CH3), amyl- 2- the alkynyls (- CH of 1-2C≡CCH2CH3), amyl- 3- the alkynyls (- CH of 1-2CH2C≡CCH3) or amyl- 4- the alkynyls (- CH of 1-2CH2CH2C≡CH).More typically, R4Alkynyl has 2,3 or 4 carbon atoms.
R5For R4(as defined above), or through 0 to 3 R3The R of substituent group4.Typically, R5For the C through 0 to 3 fluorine atom substitution1-C4Alkyl.
R5aIt independently is through 0 to 3 R3The C of substituent group1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene.Such as R4Defined in, R5aFor the alkylidene with 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom；Alkylene group or alkynylene with 2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms.Each typical R4Group is typical R5aGroup, condition is the R4A hydrogen atom is removed and formed the open valency (open valence) of carbon atom in group, passes through second key of the carbon atom and R5aIt is connected.
R14For just or the secondary C in end1-C6Alkyl.
W5For carbocyclic ring or heterocycle, condition is each W5Independently by 0 to 3 R2Group is replaced.W5Carbocyclic ring and T1And W5Heterocycle is stable chemical constitution.These structures can in the reactant mixture from -78 DEG C to 200 DEG C with it is measurable go out yield separate, and with measurable purity.Each W5Independently by 0 to 3 R2Group is replaced.Typically, T1With W5For containing monocyclic or bicyclic carbocyclic or miscellaneous ring filling, insatiable hunger and/or aromatic ring.More typically, T1Or W5With 3 to 10 annular atoms, more typically, 3 to 7 annular atoms, and typically 3 to 6 annular atoms.T1With W5Ring be saturation when containing 3 annular atoms；To be saturation or monounsaturated when containing 4 annular atoms；It is saturation when containing 5 annular atoms, single insatiable hunger and/or two undersaturated；It is saturation when containing 6 annular atoms, monounsaturated, two is undersaturated, or is aromatics.W5The degree of unsaturation of ring includes inside and outside degree of unsaturation, and its China and foreign countries' degree of unsaturation combines an annular atom.
Work as W5During for carbocyclic ring, monocyclic or 7 to 12 carbon atoms two rings of typically 3 to 7 carbon.More typically, W5Monocycle carbocyclic ring has 3 to 6 annular atoms, more preferably 5 or 6 annular atoms.W5Bicyclic carbocycle typically has 7 to 12 annular atoms, and they line up two rings (4,5), (5,5), and (5,6) or (6,6) system is more typically 9 or 10 annular atoms for lining up two rings (5,6) or (6,6) system.Example includes cyclopropyl, cyclobutyl, cyclopenta, the amyl- 1- alkenyls of 1- rings, the amyl- 2- alkenyls of 1- rings, the amyl- 3- alkenyls of 1- rings, cyclohexyl, 1- hexamethylene -1- alkenyls, 1- hexamethylene -2- alkenyls, 1- hexamethylene -3- alkenyls, phenyl, spiryl and naphthyl.
T1Or W5Heterocycle typically has 3 to 7 ring memberses, and (2 to 6 carbon atoms are with 1 to 3 selected from N, O, P, S hetero atom) it is monocyclic, or (4 to 9 carbon atoms and 1 to 3 are selected from N, O with 7 to 10 ring memberses, P, S hetero atom) two rings.More typically, T1With W5Heterocyclic monocycles have 3 to 6 annular atoms (2 to 5 carbon atoms are selected from N, O, S hetero atom with 1 to 2), more typically 5 or 6 annular atoms (3 to 5 carbon atoms and 1 to 2 hetero atom selected from N and S).T1With W5The ring of heterocycle two has 7 to 10 annular atoms (6 to 9 carbon atoms are with 1 to 2 selected from N, O, S hetero atom), they line up two rings (4,5), (5,5), (5,6) or (6,6) system, more typically 9 to 10 annular atoms (8 to 9 carbon atoms and 1 to 2 hetero atom for being selected from N and S), they line up two rings (5,6) or (6,6) system.
Typically, T1With W5Heterocycle is selected from：Pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, cyanuro , oxazolyls, imidazole radicals, thiazolyl , isoxazolyls, pyrazolyl, isothiazolyl, furyl, thio-furan base, thienyl or pyrrole radicals.
More typically, T1With W5Heterocycle comes bonded via its carbon atom or nitrogen-atoms.More typically, T1Heterocycle is bonded in the cyclohexene ring of the present composition by its nitrogen-atoms with stable covalent bond, W5Heterocycle is bonded in the cyclohexene ring of the present composition by its carbon or nitrogen-atoms with stable covalent bond.Stable covalent bond refers to above-mentioned chemically stable structure.W5Arbitrarily selected from following：
U1For H or-X1W6, but typically the latter.
X1For a key ,-O- ,-N (H) ,-N (W6)-,-N (OH)-,-N (OW6)-,-N (NH2) ,-N (N (H) (W6))-,-N (N (W6)2)-,-N (H) N (W6)-,-S- ,-SO-, or-SO2-；Typically, X1For-root key ,-O- ,-N (H)-,-N (R5)-,-N (OH)-,-N (OR5)-,-N (NH2)-,-N (N (H) (R5))-,-N (N (R5)2)-,-N (H) N (R5)-,-S- ,-SO-, or-SO2-, more typically X1For a key ,-O- ,-NR1- ,-N (OR1)-,-N (NR1R1)-,-S- ,-SO-, or-SO2-.Usual X1For-O- ,-NH- ,-S- ,-SO-, or-SO2-；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(R6b)2) ,-C (NR6b)(N(H)(R6b)) ,-C (N (H) (N (R6b)2) ,-C (S) N (R6b)2, or-C (O) R2, W6Typically-R5,-W5, or-R5aW5；In certain embodiments, W6For R1,-C (O)-R1,-CHR1W7,-CH (R1)aW7,-CH (W7)2, (wherein work as W7During for monovalence, a is 0 or 1, but works as W70) or-C (O) W it is then during for divalence7.In certain embodiments, W6For-CHR1W7Or-C (O) W7, or W6For
-(CH2)m1CH((CH2)m3R3)2,-(CH2)m1C((CH2)m3R3)3；-(CH2)m1CH((CH2)m3R5aW5)2；-(CH2)m1CH((CH2)m3R3)((CH2)m3R5aW5)；-(CH2)m1C((CH2)m3R3)2(CH2)m3R5aW5), (CH2)m1C((CH2)m3R5aW5)3Or-(CH2)m1C((CH2)m3R3)((CH2)m3R5aW5)2；Wherein m3 is 1 to 3 integer.
W7For R3Or R5, but typically by 0 to 3 R3The C of substituent group1-C12Alkyl, the latter is typically chosen from-NR1(R6b) ,-N (R6b)2,-OR6a, or SR6a.More typically, W7For-OR1, or through OR1Substituted C3-C12Alkyl.
Generally, U1For R1O- ,-OCHR1W7,
U1The example of group is listed in Table 2 below.
One embodiment of this invention includes following formula: compound：
Wherein E2For E1, but be typically chosen from：
Wherein G2For G1, but be typically chosen from：
Wherein T2For R4Or R5.Usual T2For the C replaced by 0 to 3 fluorine atom1-C2Alkyl.
U2To be one of following：Wherein R7For H ,-CH3,-CH2CH3,-CH2CH2CH3,-OCH3,-OAc (- O-C (O) CH3) ,-OH ,-NH2, or-SH, typically H ,-CH3Or-CH2CH3。
Group R6aWith R6bAnd insignificant functional group, therefore can be extensively varied.When not being H, its function is the intermediate as female medicine, it is not intended that it does not have bioactivity.On the contrary, female medicine is is changed into prodrug by the major function of these groups, so that the prodrug converts and disengages female medicine in vivo.Because the more female medicine of active prodrugs is easily absorbed, in fact, in vivo, efficiency generally more female medicine of prodrug is height.When not being hydrogen, R6aWith R6bIt can be removed in external (in the example of chemical intermediate) or in vivo (in the example of prodrug).When as chemical intermediate, function (pro-functionality) product before gained, for example, alcohol, if be not particularly critical for physiology is acceptable, although be typically preferable with the harmless person of pharmacology.
R6aFor H or into ether or into the group of ester." into the group of ether " refers to can form the group of stable covalent bond between parent molecule and following formula group：
Wherein VaFor tetrad, C and Si are generally selected from；VbFor triad, B, Al, N and P, more preferably N and P are generally selected from；VcFor bivalent, O, S and Se, more preferably S are generally selected from；V1To be bonded to V to stablize covalent single bonda, VbOr VcGroup, typically V1For W6Group, more preferably H, R2, W5Or-R5aW5, preferably H or R2；V2To be bonded to V to stablize double covalent bondsaOr VbGroup, condition is V2Can not be=O ,=S or=N-, V2Typically=C (V1)2, wherein V1As described above；V3To be bonded to V to stablize covalent three keyaGroup, typically V3For ≡ C (V1), wherein V1As described above.
" into the group of ester " refers to can form the group of stable covalent bond between parent molecule and following formula group：Wherein Va, VbWith V1As described above；VdFor pentavalent atom, P and N are typically chosen from；VeFor hexad, typically S；V4To be bonded to V to stablize double covalent bondsa, Vb, VdOr VeGroup, condition is at least one V4For=O ,=S or=N-V1, when not for=O ,=S or=N- when, typically=C (V1)2, wherein V1As described above.
The protection group of-OH functional groups (whether hydroxyl, acid or other functional groups) for " into ether or into the group of ester " embodiment.
Into ether or into the group of ester, particularly good person is can be used as protection group person in synthetic reaction scheme described herein.However, as one skilled in the art is to understand, some hydroxyls are not into ether or the group into ester with sulfydryl (thio) protection group, and are included in following R6cAcid amides in.R6cHydroxyl or sulfydryl can be protected, so that parent molecule hydrolysis generation hydroxyl or sulfydryl.
When playing into ester, typically, R6aAny acidic-group is bonded to (for example, unrestricted as an example ,-CO2H or-C (S) OH groups), so as to form-CO2R6a.For example, R6aCan
Derive many ester groups from WO95/07920.
R6aExample include：C3-C12Heterocycle (as described above) or C6-C12Aryl.These aryl are in a arbitrary manner to be polycyclic or monocyclic.Example has phenyl, spiryl, 2- and 3- pyrrole radicals, 2- and 3- thienyls, 2- and 4- imidazole radicals, 2-, 4- and 5- oxazolyls, 3- and 4- isoxazolyls, 2-, 4- and 5- thiazolyl, 3-, 4- and 5- isothiazolyls, 3- and 4- pyrazolyls, 1-, 2-, 3- and 4- pyridine radicals, and 1-, 2-, 4- and 5- pyrimidine radicals, the C replaced through following groups3-C12Heterocycle or C6-C12Aryl：Halogen, R1, R1-O-C1-C12Alkylidene, C1-C12Alkoxy, CN, NO2, OH, carboxyl, carboxyl ester, mercaptan, thioesters, C1-C12Haloalkyl (1-6 halogen atom), C2-C12Alkenyl or C2-C12Alkynyl.Such group includes 2-, 3- and 4- alkoxyphenyl radical (C1-C12Alkyl), 2-, 3- and 4- anisyls, 2-, 3- and 4- ethoxyphenyls, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4- and 3, 5- diethoxy phenyl, 2- and 3- carbethoxyl group -4- hydroxyphenyls, 2 with 3- ethyoxyl -5- hydroxyphenyls, 2- and 3- ethyoxyl -6- hydroxyphenyls, 2- and 3- ethyoxyl -4- hydroxyphenyls, 2-, 3- and 4-O- acetylphenyls, 2-, 3- and 4- dimethylamino phenyls, 2-, 3- and 4- methyl mercapto phenyl, 2-, 3- and 4- halogenophenyls (including, 2-, 3- and 4- fluorophenyls and 2-, 3- and 4- chlorphenyls), 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4- and 3, 5- xylyls, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4- and 3, the carboxyethyl phenyls of 5- bis-, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4- and 3, 5- dimethoxy phenyls, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4- and 3, 5- dihalogenated phenyls (including 2, 4- difluorophenyls and 3, 5- difluorophenyls), 2-, 3- and 4- haloalkylphenyls (1 to 5 halogen atom, C1-C12Alkyl, including 4- trifluoromethyls), 2-, 3- and 4- cyano-phenyls, 2-, 3- and 4- nitrobenzophenones, 2-, 3- and 4- haloalkyls benzyl (1 to 5 halogen atom, C1-C12Alkyl, including 4- trifluoromethyl benzyls and 2-, 3- and 4- trichloromethyls phenyl and 2-, 3- and 4- trichloromethyls phenyl), 4-N- methyl piperidine bases, 3-N- methyl-piperidyls, 1- ethyl piperazidine bases, benzyl, alkylated salicylamide base phenyl (C1-C4Alkyl, including 2-, 3- and 4- ethyl salicyls phenyl), 2-, 3- and 4- acetylphenyls, 1,8- dihydroxy naphthyl (- C10H6- OH) and fragrant oxygen ethyl (C6-C9Aryl (including benzene oxygen ethyl)), 2,2 '-dihydroxy xenyl, 2-, 3- and 4-N, N- dialkylamino phenol ,-C6H4-CH2-N(CH3)2, trimethoxy benzyl, three ethoxybenzyls, 2- Alkylpyridyls (C1-C4Alkane
Base)；
The C of 2- carboxyl phenyls4-C8Ester；And C1-C4Alkylidene-C3-C6Aryl (including benzyl ,-CH2- pyrrole radicals ,-CH2- thienyl ,-CH2- imidazole radicals ,-CH2- oxazolyls ,-CH2- isoxazolyls ,-CH2- thiazolyl ,-CH2- isothiazolyl ,-CH2- pyrazolyl ,-CH2- pyridine radicals and-CH2- pyrimidine radicals), its aryl moiety is replaced by 3 to 5 halogen atoms or 1 to 2 selected from following atom or group：Halogen, C1-C12Alkoxy (including methoxyl group and ethyoxyl), cyano group, nitro, OH, C1-C12Haloalkyl (1 to 6 halogen atom；Including-CH2-CCl3), C1-C12Alkyl (including methyl and ethyl), C2-C12Alkenyl or C2-C12Alkynyl；Alkoxyl oxygen alkyl ethyl (C1-C6Alkyl, including-CH2-CH2-O-CH3(methoxyethyl))；The alkyl (- CH replaced by the substituent (particularly OH) of above-mentioned aryl or 1 to 3 halogen atom3,-CH (CH3)2,-C (CH3)3,-CH2CH3,-(CH2)2CH3,-(CH2)3CH3,-(CH2)4CH3,-(CH2)5CH3,-CH2CH2F ,-CH2CH2Cl ,-CH2CF3, and-CH2CCl3)；；- N-2- propylmorpholin generations, 2,3- dihydro -6- hydroxyl indenes, sesamol, catechol monoesters,-CH2-C(O)-N(R1)2,-CH2-S(O)(R1) ,-CH2-S(O)2(R1) ,-CH2-CH(OC(O)CH2R1)-CH2(OC(O)CH2R1), cholesteryl, enolpyruvate (HOOC-C (=CH2) -), glycerine；The monose of 5 or 6 carbon, disaccharide or oligosaccharides (3 to 9 monosaccharide residues)；Triglycerides, such as via the glyceryl oxygen atom of the triglycerides be bonded to this paper parent compound acyl groups α-D- β-diglyceride (wherein constitute lipid glyceride aliphatic acid be usually naturally occurring saturation or unsaturation C6-26, C6-18Or C6-10Aliphatic acid, such as linoleic acid, laurate, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, the aliphatic acid such as leukotrienes)；Phosphatide, carboxyl is connected to via the phosphoric acid ester bond of the phosphatide；Phthalidyl (Clayton et al., anti-microbial agents and chemotherapy, 5 (6)：Shown in 670-671 [1974] Fig. 1)；Cyclic carbonate, such as (5-Rd- 2- oxos -1,3- dioxole (dioxolen) -4- bases)
Methyl esters (Sakamoto et al., chemicals publication (Chem.Pharm.Bull.), 32 (6) 2241-2248 [1984]), wherein RdFor R1, R4Or aryl；And
The hydroxyl of the compounds of this invention is any through group III disclosed in WO94/21604, and one of IV or V, or isopropyl are replaced.
As another embodiment, Table A lists R6aThe example of ester part, it can be connected to via oxygen key such as-C (O) O- and-P (O) (O-)2Group, also lists several R in addition6cAmidate, it is directly bonded to-C (O)-or-P (O)2.Structure 1 to 5,8 to 10 and 16,17,19 to 22 ester is by by the compound with free hydroxyl group and corresponding halide (chloride or acyl chlorides etc.) and N, N- dicyclohexyl-N- morpholine carboxylic carbonamidines (carboxamidine) (or other alkali, such as DBU, triethylamine, CsCO3, N, N- dimethylanilines etc.) react and synthesize in DMF (or other solvents, such as acetonitrile or 1-METHYLPYRROLIDONE).Work as W1During for phosphonate ester, structure 5 to 7,11,12,21 are reacted by alcohol or alkoxide (or corresponding amine, in such as example of compound 13,14 and 15) with 23 to 26 ester and synthesized with monochloro phosphonate ester or dichloro phosphonate ester (or other activation phosphonate ester).
Table A 1.-CH2-C(O)-N(R1)2 10.-CH2-O-C(O)-C(CH3)32.-CH2-S(O)(R1) 11.-CH2-CCl33.-CH2-S(O)2(R1) 12.-C6H54.-CH2-O-C(O)-CH2-C6H5 13.-NH-CH2-C(O)O-CH2CH35.3- cholesteryl 14.-N (CH3)-CH2-C(O)O-CH2CH36.3- pyridine radicals 15.-NHR17.N- ethyl morpholines are for 16.-CH2-O-C(O)-C10H158.-CH2-O-C(O)-C6H5 17.-CH2-O-C(O)-CH(CH3)29.-CH2-O-C(O)-CH2CH3 18.-CH2-C#H(OC(O)CH2R1)-CH2--(OC(O)CH2R1) #- chiral centres are (R), (S) or racemate
Other esters being applicable herein are described in EP 632 048.
R6aAlso comprising the preceding functional group for forming " dibasic acid esters " (double ester), for example
When as prodrug, selected ester is preferably previously used for antibiotic medicine person, particularly cyclic carbonate, dibasic acid esters, or phthalidyl ester, aryl ester or Arrcostab.
It should be noted that R6a, R6cWith R6bGroup can arbitrarily be used for preventing the side reaction in synthesis step with the group of protection, so it can be used as protection group (PRT) in synthesis.Determine which group is to be protected and property of PRT it is usual must depending on confrontation to be protected reactive chemistry (for example, acid,
Alkalescence, oxidisability, reproducibility or other conditions) and synthesize the direction to be carried out and determine.If there are the multiple PRT to replace in compound, the PRT groups need not, and be not usually, identical.In general, PRT will be used for protecting carboxyl, hydroxyl or amino.Deprotection draws the order of free group depending on direction and reaction condition that synthesis is carried out, and any order that can be determined with those skilled in the art occurs.
Very many R6aHydroxyl protecting group and R6cAcid amides formation group and corresponding chemical disconnect reaction and are described in " blocking group in organic chemistry "; Theodora W.Greene (John Wiley＆Sons, Inc., New York; 1991, ISBN 0-471-62301-6) (" Greene ").Also Kocienski, Philip J. are referred to；" blocking group " (Georg Thieme VerlagStuttgart, New York, 1994), it is integrally incorporated herein incorporated by reference.Particularly the 1st chapter, blocking group：Summary, the 1-20 pages, the 2nd chapter, hydroxy-protective group, the 21-94 pages, the 3rd chapter, diol protecting group, the 95-117 pages, the 4th chapter, carboxy protective group, the 118-154 pages, the 5th chapter, carboxy protecting group, the 155-184 pages.For R6aCarboxylic acid, phosphonic acids, phosphonate ester, sulfonic acid and W1Other protection groups of acid refer to following Greene.Such group includes, unrestricted as an example, ester, acid amides, hydrazides etc..
In certain embodiments, through R6aThe acidic-group of protection is the ester of the acidic-group, and R6aFor the residue of hydroxyl functional group.In other embodiments, R6cAmino-compound is used to protect acid functional group.Suitable hydroxyl or functional group's residue containing amino are as described above, or be found in WO95/07920.Particularly useful is amino acid, amino-acid ester, polypeptide or fragrant and mellow residue.The amino acid residue of typical amino acid, polypeptide and carboxyl esterification is described in 11-18 pages of WO95/07920 with related content, being used as group L1Or L2.WO95/07920 instructs the amidate of phosphonic acids, it should be understood that these amidates are formed with any acidic-group described herein and amino acid residue shown in WO95/07920.
For protecting W1The typical R of acid functional groups6aEster is also described in WO95/07920, also, it is to be understood that can also be formed and phosphonate ester identical ester disclosed in use ' 920 with this paper acidic-group.Typical ester group is at least defined in the 89-93 pages of WO95/07920 (in R31Or R35Under), in the table of page 105, and the 21-23 pages (R).Particularly good person is the ester of following groups：The aryl being unsubstituted, such as phenyl or aralkyl (such as benzyl), or the aryl or alkaryl replaced through hydroxyl, halogen, alkoxy, carboxyl and/or Arrcostab carboxyl, particularly phenyl, adjacent ethoxy benzene
Base, or C1-C4Arrcostab carboxyl phenyl (salicylic acid C1-C12Arrcostab).
The acidic-group W of protection1, when particularly with WO95/07920 ester or acid amides, can be used as oral prodrugs.But W1Acidic-group might not obtain to be protected and can just allow the compounds of this invention to be orally efficiently used.When with by blocking group the compounds of this invention (particularly amino acid amide compound or the aryl ester that is substituted and is unsubstituted) whole body or oral administration when, it can be hydrolyzed fracture in vivo and draw free acid.
One or more acid hydroxy groups can be protected.If more than one acid hydroxy group is protected, identical or different protection group can be used, for example, ester can be identical or different, or the amidate and ester mixed can be used.
Typical R6aHydroxyl protecting group is described in Greene (the 14-118 pages), including ether (methyl)；Methyl ether (the methoxyl methyl being substituted, first sulfidomethyl, tertiary fourth sulfidomethyl, (phenyldimethylsilyl) methoxyl methyl, benzyloxymethyl, to methoxyl group benzyloxymethyl, (4- methoxyphenoxies) methyl, o-methoxyphenol methyl, tertiary fourth oxygen methyl, 4- amylene epoxide methyl, silanyloxymethyl, 2- methoxyl group ethoxymethyls, 2, 2, 2- tri-chloroethoxy methyl, two (2- chloroethoxies) methyl, 2- (trimethyl silyl) ethoxymethyl, THP trtrahydropyranyl, 3- bromine THP trtrahydropyranyls, tetrahydrochysene thiopyranyl, 1- methoxycyclohexyls, 4- methoxyl group THP trtrahydropyranyls, 4- methoxyl group tetrahydrochysene thiopyranyls, 4- methoxyl group tetrahydrochysene thiopyranyls S, the oxygen bridges of S- bis- (dioxido), 1- ((the chloro- 4- methyl of 2-) phenyl) -4- methoxy piperide -4- bases, 35, 1, 4- dioxane -2- bases, tetrahydrofuran base, tetrahydrochysene thio-furan base, 2, 3, 3a, 4, 5, 6, 7, 7a- octahydros -7, 8, 8- trimethyls -4, 7- methylenebenzofuran -2- bases))；Substituted ethylether (1- ethoxyethyls, 1- (2- chloroethenes oxygen) ethyl, 1- methyl isophthalic acids-methoxyethyl, 1- methyl isophthalic acids-benzyloxyethyl, 1- methyl isophthalic acids-benzyloxy -2- fluoro ethyls, 2,2,2- trichloroethyls, 2- trimethylsilyethyls, 2- (phenylselenyl) ethyl, the tert-butyl group, pi-allyl, rubigan, p-methoxyphenyl, 2,4- dinitrophenyls, benzyl)；The benzylic ether being substituted is (to methoxybenzyl, 3,4- veratryls, adjacent nitro benzyl, to nitrobenzyl, to halogeno-benzyl, 2,6- dichloro benzyls, to cyanobenzyls, to phenylbenzyl, 2- and 4- picolyls, 3- methyl -2- picolyl N- oxygen bridges, benzhydryl, p, p '-dinitro benzhydryl, 5- dibenzocycloheptyls, trityl, Alpha-Naphthyl benzhydryl, p-methoxyphenyl benzhydryl, two (p-methoxyphenyl) benzyls, three (p-methoxyphenyl) methyl, 4- (4 '-Bromophenacyl methoxies
Base) phenyl benzhydryl, 4, 4 ', 4 "-three (4, 5- dichloro phthalimidos phenyl) methyl, 4, 4 ', 4 "-three (levulinic acyl-oxygen phenyl) methyl, 4, 4 ', 4 ",-three (benzoxy phenyl) methyl, 3- (imidazoles -1- ylmethyls) two (4 ', 4 '-dimethoxy phenyl) methyl, 1, 1- bis- (4- anisyls) -1 '-pyrenylmethy, 9- anthryls, 9- (9- phenyl) xanthyl, 9- (oxo of 9- phenyl -10 one) anthryl, 1, 3- benzo dithiane -2- bases, benzisothia oxazolyl S, the oxygen bridges of S- bis-)；Silyl ether (trimethyl silyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethyl isopropyl silyl, ethylhexyl dimethyl silicyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silicyl, three paraxylene base silicyls, triphenyl-silyl, diphenylmethylsilane base, tert-butyl group butylmethoxyphenylsilyl)；Ester (formic acid esters, benzoyl formiate, acetic acid esters, chloracetate, dichloroacetic acid ester, trichloroacetic esters, trifluoro-acetate, methoxyacetic acid ester, triphenylmethoxy acetic acid esters, phenoxyacetic acid ester, parachlorophen-oxyacetic acid ester, to polyphenyl yl acetate, 3- phenylpropionic acid esters, LA ester (levulinate), 4,4- (ethylene is thio) valerate, pivalate, adamantate, crotonates, 4- methoxyl group crotonates, benzoic ether, p-phenyl benzoic acid ester, 2,4,6- trimethylbenzoic acid esters；Carbonic ester (methyl, 9- fluorenyl methyls, ethyl, 2; 2,2- trifluoroethyls, 2- (trimethyl silyl) ethyl, 2- (phenyl sulfonyl) ethyl; 2- (triphenyl phosphorus base) ethyl, isobutyl group, vinyl, pi-allyl; p-nitrophenyl, benzyl, to methoxybenzyl, 3; 4- veratryls, adjacent nitro benzyl, to nitrobenzyl; S- benzyl sulfocarbonates, 4- ethyoxyl -1- naphthyls, dithiocarbonic acids methyl esters)；Group (the 2- iodobenzoic acid esters being broken with help; 4- azido butyrates; 4- nitro-4-methyl valerates; adjacent (two bromomethyls) benzoic ether; 2- formylbenzene sulfonates; carbonic acid 2- (methylthiomethoxy) ethyl ester, 4- (methyl mercapto methoxyl methyl) butyrate, 2- (methylthiomethoxy) benzoic ether)；Other esters (2, the chloro- 4- methylphenoxyacetates of 6- bis-, 2, the chloro- 4- (1 of 6- bis-, 1, 3, 3- tetramethyl butyls) phenoxyacetic acid ester, 2, 4- bis- (1, 1- dimethyl propyls) phenoxyacetic acid ester, chloro diphenyl acetic acid ester, isobutyrate, monosuccinic acid ester, (E) -2- methyl-2-butenes acid esters (tigliate), adjacent (methoxycarbonyl group) benzoic ether, to polyphenyl formic acid esters, α-naphthoic acid ester, nitrate, alkyl N, N, N ', N '-tetramethyl phosphorodiamidite, N- carbanilates, borate, dimethyl disulfide phosphino-, 2, 4- dinitrophenyl sulfenic acids ester)；And sulphonic acid ester (sulfuric ester, methanesulfonates, benzyl sulphur
Acid esters, tosylate).
More typically, R6aHydroxyl protecting group includes the methyl ether being substituted, the benzylic ether being substituted, silyl ether, and the esters including sulphonic acid ester, preferably trialkylsilyl ethers, tosylate and acetic acid esters.
Typical 1,2- glycerol protections base (so, usual this two OH base and R6aProtection group merges) as described in Greene at the 118-142 pages, including cyclic acetal and ketal (methylene, ethylidene, 1- t butylethylidenes; 1- phenyl-ethylenes, (4- anisyls) ethylidene, 2,2; 2- trichloroethylidenes, acetone solvate (isopropylidene), cyclopentylene; cyclohexylidene, cycloheptylidene, benzal; to benzylidene, 2,4- dimethoxybenzylidenegroup groups; 3,4- dimethoxybenzylidenegroup groups, 2- nitrobenzals)；Cyclic ortho ester (methoxymethylene, ethoxymeyhylene, dimethoxymethylene, 1- methoxyethlyens, 1- ethoxyethylidenes, 1,2- dimethoxyethylidene, α-benzylidene, 1- (N, N- dimethylamino) ethidene derivant, α-(N, N- dimethylaminos) benzylidene derivatives, 2- oxacyclopentylidenes)；Silyl derivative (di-t-butyl silylene, 1,3- (1,1,3, the sub- siloxy group of 3- tetra isopropyls two), and the subunit of four tert-butoxy disiloxane -1,3- bis-), cyclic carbonate, cycliborate (Boronate), ethyl-boron dihydroxide ester and phenyl boronate.
More typically, 1,2- glycerol protections base includes those shown in table B, more preferably epoxides, acetone solvate, cyclic ketal and aryl acetal.
Table B
Wherein R9For C1-C6Alkyl.
R6bFor H, the residue of amino protecting group or carboxylated compound, particularly H ,-C (O) R4, amino acid, polypeptide, or be not -C (O) R4, the protection group of amino acid or polypeptide.Form acid amides
R6bSuch as group G1Shown in.Work as R6bDuring for amino acid or polypeptide, its structure is R15NHCH(R16) C (O)-, wherein R15For H, amino acid or polypeptid residue, or R5, and R16It is defined as below.
R16The C replaced for low alkyl group or through following groups1-C6Low alkyl group：Amino, carboxyl, acid amides, carboxyl ester, hydroxyl, C6-C7Aryl, guanidine radicals, imidazole radicals, indyl, sulfydryl, sulfoxide and/or alkyl phosphate.R16Also it can merge to form proline residue (R with the α-N of amino acid16=-(CH2)3-).But R16The usually side base of naturally occurring amino acid, such as H ,-CH3,-CH (CH3)2,-CH2-CH(CH3)2,-CHCH3-CH2-CH3,-CH2-C6H5,-CH2CH2-S-CH3,-CH2OH ,-CH (OH)-CH3,-CH2- SH ,-CH2-C6H4OH ,-CH2-CO-NH2,-CH2-CH2CONH2,-CH2- COOH ,-CH2-CH2- COOH ,-(CH2)4-NH2With-(CH2)3-NH-C(NH2)-NH2。R16Also 1- guanidine radicals propyl- 3- bases, benzyl, 4- acrinyls, imidazol-4 yl, indol-3-yl, anisyl and ethoxyphenyl are included.
When most of, R6bFor carboxylic acid residues, but also can be with any Greene in the typical amino protecting group described in the 315-385 pages.They include carbamate (methyl, ethyl, 9- fluorenyl methyls, 9- (2- sulfo groups) fluorenyl methyl, 9- (2,7- dibromo) fluorenyl methyl, 2,7- di-t-butyls-(9- (10,10- dioxos -10,10,10, the thio xanthyl of 1O- tetrahydrochysenes)), methyl, 4- methoxyphenacyls)；The ethyl (2 being substituted, 2, 2- trichloroethyls, 2- trimethylsilyethyls, 2- phenylethyls, 1- (1- adamantyls) -1- Methylethyls, 1, 1- dimethyl -2- halogenated ethyls, 1, 1- dimethyl -2, 2- dibromoethyls, 1, 1- dimethyl -2, 2, 2- trichloroethyls, 1- methyl isophthalic acids-(4- xenyls) ethyl, 1- (3, 5- di-tert-butyl-phenyls) -1- Methylethyls, 2- (2 '-and 4 '-pyridine radicals) ethyl, 2- (N, N- dicyclohexyls carboxamido) ethyl, the tert-butyl group, 1- adamantyls, vinyl, pi-allyl, 1- isopropylallyls, cinnamyl, 4- nitrocinnamyl bases, 8- quinolyls, N- hydroxy piperidine bases, alkane disulfide group, benzyl, to methoxybenzyl, to nitrobenzyl, to bromobenzyl, p-chlorobenzyl, 2, 4- dichloro benzyls, 4- methanesulfinyl benzyls, 9- anthrylmethyls, diphenyl methyl)；Group (2-methylmercaptoethyl, 2- methysulfonylethyls, 2- (p-toluenesulfonyl) ethyl being broken with help; (2 (1,3- dithiane base)) methyl, 4- methyl mercapto phenyl; 2,4- dimethylthiophenyls, 2- phosphorus base ethyls; 2- triphenylphosphonioisopropyls, 1,1- dimethyl -2- cyanoethyls; between it is chloro- to acyloxybenzyl; to (dihydroxy boryl) benzyl, 5- benzoisoxazole methyl, 2- (three
Methyl fluoride) -6- chromones ylmethyl)；Light degradable group (m-nitro base, 3,5- dimethoxy-benzyls, adjacent nitro benzyl, 3,4- dimethoxy -6- nitrobenzyls, phenyl (O-Nitrophenylfluorone) methyl)；Urea-Type Derivatives (phenothiazinyl-(10)-carbonyl, N '-tolysulfonyl amino carbonyl, N '-phenylaminothiocarbonyl)；Other carbamate (tertiary pentyls, S- benzyl thiocarbamates, to cyanobenzyls, cyclobutyl, cyclohexyl, cyclopenta, Cvclopropvlmethvl, to decyloxy benzyl, diisopropyl methyl, 2, 2- dimethoxycarbonyl vinyl, neighbour (N, N- dimethyl carboxamido) benzyl, 1, 1- dimethyl -3- (N, N- dimethyl carboxamido) propyl group, 1, 1- alkynyl dimethyls, two (2- pyridine radicals) methyl, 2- furyl methyls, 2- iodine ethyls, isobornyl, isobutyl group, different nicotinoyl base, to (p-methoxyphenyl azo group) benzyl, 1- methyl-cyclobutyls, 1- methylcyclohexyls, 1- methyl isophthalic acids-Cvclopropvlmethvl, 1- methyl isophthalic acids-(3, 5- dimethoxy phenyls) ethyl, 1- methyl isophthalic acids-(to phenylazo phenyl) ethyl, 1- methyl isophthalic acids-phenethyl, 1- methyl isophthalic acids-(4- pyridine radicals) ethyl, phenyl, to (phenylazo) benzyl, 2, 4, 6- tri-tert phenyl, 4- (trimethylammonium) benzyl, 2, 4, 6- trimethyl benzyls)；Acid amides (N- formoxyls, N- acetyl group, N- chloracetyls, N- tribromo-acetyl bases; N-TFA base, N- phenyl acetyls, N-3- PHENYLPROPIONYLs, N- picoline acyl groups; N-3- pyridylcarboxamides, N- benzoyl phenylalanyls, N- benzoyls, N- is to Phenylbenzoyl)；Acid amides (the N- ortho-nitrophenyl acetyl group being broken with help, N- o-nitrophenoxyacetyls, N- acetoacetyls, (the thio benzyloxycarbonyl aminos of N '-two) acetyl group, N-3- (p-hydroxybenzene) propiono, N-3- (O-Nitrophenylfluorone) propiono, N-2- methyl -2- (ortho-nitrophenyl epoxide) propiono, N-2- methyl -2- (adjacent phenylazo phenoxyl) propiono, N-4- chlorobutyryls, N-3- methyl-3-nitro bytyries, N- adjacent nitro cinnamoyls, N- acetyl group methionine, N- o-nitrobenzoyls, N- neighbour's (benzoyloxymethyl) benzoyls, 4, 5- diphenyl -3- oxazoline -2- ketone)；Cyclic Imide Derivatives (N- phthalimides, N- dithiasuccinoyls, N-2,3- diphenyl maleoyls; N-2,5- dimethyl pyrrole, N-1,1; 4,4- tetramethyl xylene silylation aza-cyclopentane addition products, 1, the 3- dimethyl -1 of 5- substitutions; 3,5,-Trianacyclohexane -2- ketone; 1,3- dibenzyl -1,3 of 5- substitutions; 5- Trianacyclohexane -2- ketone, 3, the 5- dinitro -4- pyriconyls of 1- substitutions)；N- alkyl and N- arylamines (N- methyl, N- pi-allyls, N- (2- (trimethyl silyl) ethyoxyl) methyl, N-3- second monomethacryloxypropyls, N- (1- isopropyl -4- nitro -2- oxo -3- pyrrolin -3- bases), quaternary ammonium salt,
N- benzyls, N- bis- (4- methoxyphenyls) methyl, N-5- dibenzocycloheptyls, N- trityl groups, N- (4- methoxyphenyls) diphenyl methyl, N-9- phenylfluorenyls, N-2, the chloro- 9- fluorenes methylene of 7- bis-, N- ferrocenyl methyl, N-2- picolyl amine N '-oxide), imine derivative (N-1, 1- dimethylthiomethylenes, N- benzals, N- is to benzylidene, N- diphenylmethylenes, N- ((2- pyridine radicals) meter Ji) methylene, N- (N ', N '-dimethylamino) methylene, N, N '-isopropylidene, N- is to nitrobenzal, N- salicylidenes, N-5- chlorine salicylidenes, N- (the chloro- 2- hydroxyphenyls of 5-) phenylmethylene, N- cyclohexylidenes)；Enamine derivates (N- (5,5- dimethyl -3- oxo -1- cyclohexenyl groups))；N- metal derivatives (N- borane derivatives, N- diphenyl-borinic acids (borinic acid) derivative, N- (phenyl (pentacarbonyl chromium or tungsten)) carbene base, N- copper or N- chelates of zinc)；N-N derivatives (N- nitros, N- nitrosos, N- oxides)；N-P derivatives (N- two phenenyl phosphinyls, N- dimethyl sulphur-based phosphinyls, N- hexichol sulfenyl phosphinyls, N- dialkyl phosphoryls, N- dibenzyl phosphoryls, N- diphenylphosphoryls)；N-Si derivatives；N-S derivatives；N- sulfinyl derivatives (N- phenylsulfinyl bases, N- ortho-nitrophenyl sulfinyls, N-2; 4- dinitro benzene sulfinyls, N- pentachlorobenzene sulfinyls, N-2- nitro -4- methoxybenzene sulfinyls; N- trityl group sulfinyls, N-3- nitropyridines sulfinyl)；And N- sulfonyl-derivatives (N- p-toluenesulfonyls, N- benzenesulfonyls, N-2, 3, 6- trimethyl -4- MethOxybenzenesulfonyls, N-2, 4, 6- trimethoxybenzenesulfonyls, N-2, 6- dimethyl -4- MethOxybenzenesulfonyls, N- pentamethylbenzene sulfonyls, N-2, 3, 5, 6- tetramethyl -4- MethOxybenzenesulfonyls, N-4- MethOxybenzenesulfonyls, N-2, 4, 6- trimethylphenysulfonyls, N-2, 6- dimethoxy-4 's-Methyl benzenesulfonyl base, N-2, 2, 5, 7, 8- pentamethyl benzodihydropyran -6- sulfonyls, N- mesyls, N- β-trimethyl silyl ethylsulfonyl, N-9- anthracene sulfonyls, N-4- (4 ', 8 '-dimethoxy menaphthyl) benzenesulfonyl, N- benzylsulphonyls, N- trifluoromethyl sulfonyls, N- phenacyls sulfonyl).
More typically, the amino of protection includes carbamate and acid amides, more preferably-NHC (O) R1Or-N=CR1N(R1)2.Another protection group, may also act as G1The prodrug of position, particularly for amino or-NH (R5), it is：
With reference to for example, Alexander, J. et al.；Pharmaceutical chemistry magazine (J.Med.Chem.) 1996,39,480-486.
R6cFor H or the residue containing amino-compound (particularly amino acid, polypeptide), protection group ,-NHSO2R4, NHC (O) R4,-N (R4)2, NH2Or-NH (R4) H, thus, W1Carboxyl or phosphonate group and above-mentioned amine react to form acid amides, such as in-C (O) R6c,-P (O) (R6c)2Or-P (O) (OH) (R6c) in.Usual R6cWith R17C(O)CH(R16) NH- structure, wherein R17For OH, OR6a, OR5, amino acid or polypeptid residue.
Amino acid is low molecular weight compound, less than about 1000MW, and comprising at least one amino or imino group, and at least one carboxyl.This usual amino acid is present in nature, i.e. can be in biological substance such as bacterium or other microorganisms, plant, is detected in animal or people.Suitable amino acid is typically a-amino acid, i.e., one amino or imino nitrogen atom are separated by the carbon atom of a monosubstituted or unsubstituted alpha -carbon atom and a carboxyl in compound.Preferably is hydrophobic residue, such as single-or di-alkyl or aryl amino acid, cycloalkylamino acid etc..These residues contribute to cell permeability by improving the distribution coefficient of female medicine.Typically, this residue and without sulfydryl or guanidino substituent.
Native amino acid residues are the residue particularly naturally found in its protein in plant, animal or microorganism.Polypeptide is typically made up of the naturally occurring amino acid residue of this class substantially.These amino acid are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, oxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxy-proline.
Work as R6bWith R6cDuring for single amino acid residue or polypeptide, it is generally in R3, W6, W1And/or W2Upper substitution, but preferably only in W1Or W2Upper substitution.These conjugates pass through the carboxyl and W in the amino acid (or carbon teminal amino acid of such as polypeptide)2Between formed amido link and formed.Similarly, also can be in W1Conjugate is formed between the amino of amino acid or polypeptide.Generally, only one of which position amino acid amide as described herein in parent molecule, but introduce amino acid also within the scope of the present invention in more than one position.Usual W1Carboxyl amino acid amide.Generally, the terminal amino group or carboxyl of the alpha-amido of this amino acid or α-carboxyl or polypeptide are connected to the functional group of parent compound, i.e., the carboxyl or amino on amino acid side chain are generally not used to be formed and parent compound
Between amido link (although these groups may need to be protected when conjugate is synthesized, as described below).
Contain carboxylic side-chain on amino acid or polypeptide, it should be understood that the carboxyl can be protected arbitrarily, for example, using R6a, use R5Esterification, or use R6cAmidatioon.Similarly, amino side chain R16R can arbitrarily be used6bProtect or use R5Substitution.
Ester or amido link that these and side-chain amino group or carboxyl are formed, such as the ester or amido link that are formed with parent molecule, arbitrarily can be hydrolyzed under the conditions of inner or in vitro acidity (pH ＜ 3) or alkaline (pH ＞ 10).In addition, they are basicly stable in human gi-tract, but can be by enzyme hydrolysis in blood or intracellular environment.These esters or amino acid or polypeptide amide compound also can be used as intermediate when prepared by the parent molecule containing free amine group or carboxyl.The free acid or alkali of parent compound easily can be made up of ester of the present invention or amino acid or many peptide conjugates via routine hydrolysis.
When amino acid residue contains one or more chiral centres, any D, L, meso, Soviet Union or red (if appropriate) racemate, crystallization isomeric compound (scalemates) or its mixture can be used.Generally, if the non-enzymatically hydrolyse of intermediate to be made (such as the chemical intermediate that this acid amides is used as to free acid or unhindered amina), D isomers is useful.On the other hand, L isomers is more generally applicable, because it can be urged or non-enzymatically hydrolyse through enzyme, and more effectively can be shifted in the gastrointestinal tract by amino acid or dipeptides transfer system.
(its residue is with R for Suitable amino acids6bWith R6cRepresent) example include it is following：Glycine；Aminopolycanboxylic acid, for example, aspartic acid, beta-hydroxy aspartic acid, glutamic acid, beta-hydroxyglutamic acid, Beta-methyl aspartic acid, Beta-methyl glutamic acid, β, beta-dimethyl aspartic acid, γ-Hydroxy GIutaminic Acid, β, γ-dihydroxy glutamic acid, beta-phenyl glutamic acid, γ-methyleneglutaric acid, 3- aminoadipic acids, 2- diaminopimelic acids, 2- amino suberic acid and 2- amino decanedioic acid；Amino acid amide, such as glutamine and asparagine；Polyamino-or polynary monocarboxylic acid, such as arginine, lysine, beta-amino alanine, gamma-amino butyrin, ornithine, citrulling, homoarginine, Homocitrulline, oxylysine, allohydroxylysine and diaminobutyric acid；Other alkaline amino acid residues, such as histidine；Diamino dicarboxylic acid, e.g., α, α '-diaminosuccinic acid, α, α '-diaminourea glutaric acid, α, α '-diaminourea adipic acid, α, α '-diaminopimelic acid, α, α '-diaminourea-beta-hydroxy heptan
Diacid, α, α '-diaminourea suberic acid, α, α '-diaminourea azelaic acid, with α, α '-diaminourea decanedioic acid；Imino acid, such as proline, hydroxy-proline, other hydroxyproline, γ-methylproline, piperidines -2- formic acid, 5- hydroxy piperidine -2- formic acid, with AzeOH；Single-or dialkyl group (preferably C1-C8Side chain or straight chain) amino acid, such as alanine, valine, leucine, allylglycine, butyrin, norvaline, nor-leucine, propylhomoserin in heptan (heptyline), Alpha-Methyl serine, alpha-amido-Alpha-Methyl-γ-hydroxypentanoic acid, alpha-amido-Alpha-Methyl-δ-hydroxypentanoic acid, alpha-amido-Alpha-Methyl-ε-hydroxycaproic acid, isovaline, Alpha-Methyl glutamic acid, α-aminoacid, alpha-amido diethacetic acid, alpha-amido diisopropyl acetic acid, alpha-amido diη-propyl acetic acid, alpha-amido diisobutyl acetic acid, alpha-amido di-n-butylacetic acid, alpha-amido ethylisopropyl guanidine-acetic acid, alpha-amido n-propyl acetic acid, alpha-amido diisoamyl acetic acid, Alpha-Methyl aspartic acid, Alpha-Methyl glutamic acid, 1- amino-cyclopropane -1- carboxylic acids, isoleucine, alloisoleucine, Terleu, Beta-methyl tryptophan, with pantonine-ethyl-β-phenylpropionic acid；Beta-phenyl seryl-；Aliphatic pantonine-carboxylic acid, e.g., serine, beta-hydroxy leucine, beta-hydroxy nor-leucine, beta-hydroxy norvaline, with pantonine-hydroxy stearic acid；Alpha-amido, α-, γ-, δ-or ε-carboxylic acid, e.g., homoserine, γ-hydroxynorvaline, δ-hydroxynorvaline, with ε-hydroxyl nor-leucine residue；Canavanine and canaline；γ-hydroxyl ornithine；2- hexose propylhomoserins, such as D- glucose propylhomoserin or D- galactolipin propylhomoserins；Pantonine-mercaptan, such as penicillamine, β-mercaptan norvaline or β-mercaptan butyrin；The amino acid residue of other sulfur-bearings includes cysteine；The mercaptan ether of homocystine, beta-phenyl methionine, methionine, SACS, 2- mercaptan histidines, cystathionie, and cysteine or homocysteine；Phenylalanine, tryptophan and cyclosubstituted a-amino acid, e.g., phenyl-or cyclohexyl amino acids, alpha aminophenylacetic acid, alpha-amido cyclohexyl-acetic acid and pantonine-cyclohexylpropionic acid；Containing aryl, low alkyl group, hydroxyl, guanidine radicals, oxyalkyl ether, nitro, the phenylalanine congener of the phenyl of sulphur or halogen substitution and derivative (for example, tyrosine, methyl-tyrosine is chloro- with neighbour,
To chloro-, 3,4- bis- is chloro-, o-, m- or p- methyl -, 2,4,6- trimethyls, 2- ethyoxyl -5- nitros -, 2- hydroxyl -5- nitros-with to nitro-phenyl alanine)；Furyl-, thienyl-, pyridine radicals-, pyrimidine radicals-, purine radicals-or naphthyl-alanine；And tryptophan analog and derivative, including kynurenin, 3-hydroxykynurenine, 2- hydroxytryptophans and 4- carboxyl tryptophans；The amino acid of alpha-amido substitution, including methyl amimoacetic acid (sarcosine), N- benzyl glycines, N- methylalanines, N- benzyl alanine, N- methyl phenylalanines, N- benzyl phenyl alanine, N- methylvalines and N- benzyl valines；Alpha-hydroxy and the Alpha-hydroxy amino acid of substitution include serine, threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptide is the polymer of amino acid, and the carboxyl of one of amino acid monomer is bonded together with the amino of another amino acid monomer or imino group with amido link.Polypeptide includes dipeptides, low molecular weight polypeptide (about 1500-5000MW) and protein.Protein can arbitrarily comprising 3,5,10,50,75,100 or more residues, and preferably with the mankind, animal, the protein of plant or microorganism has substantially similar sequence.It includes enzyme (e.g., hydroperoxides are dark) and immunogene (such as KLH), or antibody, or produces because of confrontation any kind of protein of immune response.The property of these polypeptides can be widely varied with identification feature.
Polypeptide amide compound can be used as immunogene and the antibody of the create antagonism polypeptide (if the simultaneously non-immunogenic in the animal body of medication) or the epitope on confrontation the compounds of this invention remainder.
The antibody that can be bound on the parent compound of non-peptidyl linker can be used to isolate the parent compound from mixture, for example, in diagnosis or when prepared by parent compound.The conjugate of parent compound and polypeptide generally can have more immunogenicity in species than the polypeptide, so making the polypeptide more immunogenicity, promote its antibody that creates antagonism.So, the polypeptide or protein may not necessarily be immunogenicity in the animal (for example, rabbit, mouse, horse and rat) commonly used to produce antibody, as long as and final conjugation product is immunogenicity in this at least one animal.Contain peptide solution enzymatic breaking position on any peptide bond between first and second residue of neighbouring acidic heteroatom of this polypeptide.This fracture position is laterally attacked by enzyme identification structure, for example, specific residue sequence is recognized by peptide solution enzyme.
It is known for the peptide solution enzyme that cuts off many peptide conjugates of the invention, particularly including carboxypeptidase.Carboxypeptidase decomposes polypeptide by removing carbon teminal residue, and in many examples, has specificity to particular carbon terminal sequence.This fermentoid is generally known with its matrix demand.For example, dipeptides (having specific a pair of residues and free carboxyl end group) is covalently bond on the phosphorus of compounds herein or carbon atom with its alpha-amido.In W1For in the example of phosphonate ester, it is contemplated that this peptide will be cut off by appropriate peptide solution enzyme, leave near-end (proximal) amino acid residue carboxyl and self-catalysis cut off phosphono amine key.
Suitable two peptidyl (with its single-letter representation) is AA,AR,AN,AD,AC,AE,AQ,AG,AH,AI,AL,AK,AM,AF,AP,AS,AT,AW,AY,AV,RA,RR,RN,RD,RC,RE,RQ,RG,RH,RI,RL,RK,RM,RF,RP,RS,RT,RW,RY,RV,NA,NR,NN,ND,NC,NE,NQ,NG,NH,NI,NL,NK,NM,NF,NP,NS,NT,NW,NY,NV,DA,DR,DN,DD,DC,DE,DQ,DG,DH,DI,DL,DK,DM,DF,DP,DS,DT,DW,DY,DV,CA,CR,CN,CD,CC,CE,CQ,CG,CH,CI,CL,CK,CM,CF,CP,CS,CT,CW,CY,CV,EA,ER,EN,ED,EC,EE,EQ,EG,EH,EI,EL,EK,EM,EF,EP,ES,ET,EW,EY,EV,QA,QR,QN,QD,QC,QE,QQ,QG,QH,QI,QL,QK,QM,QF,QP,QS,QT,QW,QY,QV,GA,GR,GN,GD,GC,GE,GQ,GG,GH,GI,GL,GK,GM,GF,GP,GS,GT,GW,GY,GV,HA,HR,HN,HD,HC,HE,HQ,HG,HH,HI,HL,HK,HM,HF,HP,HS,HT,HW,HY,HV,IA,IR,IN,ID,IC,IE,IQ,IG,IH,II,IL,IK,IM,IF,IP,IS,IT,IW,IY,IV,LA,LR,LN,LD,LC,LE,LQ,LG,LH,LI,LL,LK,LM,LF,LP,LS,LT,LW,LY,LV,KA,KR,KN,KD,KC,KE,KQ,KG,KH,KI,KL,KK,KM,KF,KP,KS,KT,KW,KY,KV,MA,MR,MN,MD,MC,ME,MQ,MG,MH,MI,ML,MK,MM,MF,MP,MS,MT,MW,MY,MV,FA,FR,FN,FD,FC,FE,FQ,FG,FH,FI,FL,FK,FM,FF,FP,FS,FT,FW,FY,FV,PA,PR,PN,PD,PC,PE,PQ,PG,PH,PI,PL,PK,PM,PF,PP,PS,PT,PW,PY,PV,SA,SR,SN,SD,SC,SE,SQ,SG,SH,SI,SL,SK,SM,SF,SP,SS,ST,SW,SY,SV,TA,TR,TN,TD,TC,TE,TQ,TG,TH,TI,TL,TK,TM,TF,TP,TS,TT,TW,TY,TV,WA,WR,WN,WD,WC,WE,WQ,WG,WH,WI,WL,WK,WM,WF,WP,WS,WT,WW,WY,WV,YA,YR,YN,YD,YC,YE,YQ,YG,YH,YI,YL,YK,YM,YF,YP,YS,YT,YW,YY,YV,VA,VR,VN,VD,VC,VE,VQ,VG,VH,VI,VL,VK,VM,VF,VP,VS,VT,VW,VY and VV.
Tripeptide residue also can be used as R6bOr R6c.Work as W1During for phosphonate ester, (wherein X4 is any amino acid residue to sequence-X4-pro-X5-, X5 is amino acid residue, the carboxyl ester of proline, or hydrogen) X4 can be cut into by luminal (luminal) carboxypeptidase, it carries free carboxy, and it is expected that self-catalysis phosphono amine key can be cut off.X5 carboxyl is arbitrarily esterified through benzyl.
The species of dipeptides or tripeptides is selected according to known transfer property and/or on the sensitiveness (it can influence the transfer to intestinal mucosa or other cellular morphologies) of peptase.It is sub transfer medium (Bai, the J.P.F., " drug research (Pharm Res.) " 9 of the peptide transfer found in the brush boundary film of intestinal mucosa cells to lack alpha-amino dipeptides or tripeptides：969-978(1992)).The peptide for being adapted to transfer can be used for strengthening the bioavailability of the amide compound.With one or the dipeptides or tripeptides of many D configurations amino acid is also suitable for peptide transfer and available in amide compound of the present invention.D amino acids are also used to reduction dipeptides or tripeptides by the possibility of protease hydrolytic, and the protease is common for brush border, for example aminopeptidase N (EC3.4.11.2).In addition, the relative challenge of protease hydrolytic that also can be according to dipeptides or tripeptides to being found in enteric cavity and select it.For example, the bad matrix that the tripeptides or polypeptide that lack asp and/or glu are aminopeptidase A (EC3.4.11.7)；The dipeptides or tripeptides of lack amino acid residue are the bad matrix of phthalein chain restriction endonuclease 24,11 (EC3.4.24.11) on the nitrogen end side of hydrophobic amino acid (leu, tyr, phe, val, trp)；The bad matrix that the peptides that penultimate position lacks pro residues at free carboxy end are carboxypeptidase P (EC3.4.17).Also it can be selected using similar consideration more difficult or be easier to the peptide that is hydrolyzed by cytosol, kidney, liver, serum or other peptases.It is such a to be difficult cut-off polypeptide amide compound for immunogene or can be used to be bound on protein is made immunogene.
Another embodiment of the present invention is related to formula (VII) or the composition of (VIII)：Wherein E1, G1, T1, U1, J1, J1a, J2With J2aIt is as defined above, but unlike：T1For-NR1W3, heterocycle, or and G1The group with following structure is formed together
X1For a key ,-O- ,-N (H)-,-N (R5)-,-S- ,-SO-, or-SO2-；But condition is to exclude U1For H or-CH2CH(OH)CH2(OH) compound；
And its salt, solvate, the enantiomer of fractionation and purified diastereomer.
Formula (I)-(VI) as detailed above typical or general embodiment is also formula (VII) and the typical embodiments of (VIII).
Many formulas (VII) and (VIII) compound (wherein U1For H or-CH2CH(OH)CH2(OH) synthesis) sees Nishimura, Y. et al.；Antibiotic magazine (J.Antibiotics), 1993,46 (2), 300；46 (12), 1883；And Nat.Prod.Lett.1992,1 (1), 39.By U of the present invention1The method that group is connected is as described in this article.Stereoisomer
The compounds of this invention is rich in (enriched) or the optical isomer split on any or all asymmetric atom.For example, obvious chiral centre is in chiral isomer or racemic mixture in explanation.Racemic mixture or non-enantiomer mixture, and be separated or each optical isomer (being matched substantially free of its enantiomer or diastereomer) for synthesizing within the scope of the present invention.
Isomers or pure isomers rich in enantiomer are prepared using the one or more in the method being set forth below.These methods are approx listed with its preferred sequence, i.e., can generally use the stereotaxis of chiral precursor to synthesize before the chromatographic resolution before spontaneous crystallization.
Stereotaxis synthesis is described in embodiment.The use of such method is easily when suitable chiral raw material can be obtained and selected reactions steps will not produce undesirable racemization in chiral site.One advantage of stereotaxis synthesis is will not to produce the unwanted enantiomer that must be removed from final product, thus will not reduce whole synthetic yield.Typically, those skilled in the art, which will be appreciated that, use which type of raw material and reaction condition to obtain the required isomers or pure isomer rich in enantiomer to be synthesized by stereotaxis.If being considered as to occur the racemization do not expected in stereospecific method, only need to obtain required product using one of following separation method.
If suitable stereotaxis synthesis can not be with conventional experiment from empirically being designed or determined, those skilled in the art will turn to other methods.A kind of conventional method is the chromatographic resolution enantiomer on chiral chromatographic resin.These resins are seated in the commonly referred to as post of Pirkle posts and can be commercially.The post contains chiral stationary phase.Racemic modification is placed in solution and is loaded on post, is then separated by HPLC.For example, see Proceedings
International symposium collections of thesis of the Chromatographic Society- on chiral separation, in September, 1987 3-4 days.Can be used for screening the example of the chiral column of optimal separation technology includes Diacel Chriacel OD, Regis Pirkle Covalent Dphenylglycine, RegisPirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, ServaChiral D-DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck cellulosic triacetate posts, Astec Cyclobond I-Beta or Regis PirkleCovalent D-Naphthylalanine.These not all posts all may be effective to each racemic mixture.It may require a certain amount of conventional screening to determine maximally effective stationary phase however, those skilled in the art understand.When using the post, it is generally desirable to using the embodiment of the compounds of this invention, wherein electric charge is not neutralized, and for example wherein acid functional groups such as carboxyl is not esterified or amidatioon.
Another method is related to chiral auxiliary is converted into diastereomer by the enantiomer in mixture, then by conventional column chromatography for separation conjugated body.This is very suitable method, particularly when the embodiment contains free carboxy, amino or hydroxyl with the chiral auxiliary forming salt or covalent bond.Amino acid, organic acid or the organic sulfonic acid of chiral purity can be employed as chiral auxiliary, and they are known in the art.It can form the salt with the analog assistant, or they covalently (but reversibly) can be bonded on functional group.For example, pure D or L amino acid can for amidatioon embodiment of the present invention carboxyl, then separated by chromatographing.
It is another method with potential value that enzyme, which is split,.In such method, the covalence derivative of the enantiomer in racemic mixture is prepared, usually lower alkyl esters (lower alkyl esters of such as carboxyl), the derivative is then subjected to enzyme cracking, typically hydrolyzed.In order to successfully carry out this method, it is necessary to which the enzyme of stereotaxis cracking is capable of in selection, so usually require to carry out several enzymes conventional screening.To cracking ester, then esterase, phosphate and lipase can be selected, and determine its activity to the derivative.Typical esterase comes from liver, pancreas or other animal organs, and including Pig Liver Esterase.
If mixture of enantiomers is separated with the crystal form of agglomerate, i.e. enantiomer-pure from solution or melt, then the crystal can be separated mechanically, so as to produce the preparation rich in enantiomer.But this method for it is extensive prepare it is unactual and for real racemic compound and valueless.
Asymmetric syntheses is the technology of another acquisition enantiomer enrichment.For example, making chiral protecting groups and radical reaction to be protected, and reactant mixture is balanced.If the reaction is enantiomer orientation, product will be enriched in the enantiomer.
Other methods of enantiomer separation mixture can as an example but be not intended to limit at " enantiomer; racemic modification and fractionation ", Jean Jacques, Andre Collet and Samuel H.Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4) in find.Particularly, part 2, the fractionation of mixture of enantiomers, the 217-435 pages；Specifically in Section 4, split by direct crystallization, the 217-251 pages, Section 5, the formation and separation of diastereomer, the 251-369 pages, Section 6 crystallizes the asymmetric transformation of induction, the 369-378 pages, and Section 7, the test situation and technology of fractionation, the 378-435 pages；Further saved in 5.1.4, the fractionation of alcohol, alcohol is to the conversion into salt derivative, the 263-266 pages, 5.2.3 is saved, alcohol, the covalence derivative of mercaptan and phenol, the 332-335 pages, 5.1.1 is saved, the fractionation of acid, the 257-259 pages, 5.1.2 is saved, the fractionation of alkali, the 259-260 pages, 5.1.3 is saved, the fractionation of amino acid, the 261-263 pages, 5.2.1 is saved, the covalence derivative of acid, page 329, 5.2.2 is saved, the covalence derivative of amine, the 330-331 pages, 5.2.4 is saved, aldehyde, the covalence derivative of ketone and sulfoxide, the 335-339 pages and 5.2.7 section, the chromatographic property of covalent diastereomeric, the 348-354 pages, they are referred to as the example of those skilled in the art.
The spatial chemistry example of the compounds of this invention shows as in following table C.Table C
Formula (I)
Formula (I)
| E1 | J1a | J1b | U1 | T1 | G1 |
| - | - | α | β | α | α |
| - | - | β | α | α | α |
| - | - | α | β | β | α |
| - | - | α | β | α | β |
| - | - | β | α | β | α |
| - | - | β | α | α | β |
| - | - | α | β | β | β |
| - | - | β | α | β | β |
| E1 | J1a | J1b | J2 | U1 | T1 | G1 |
| - | α | β | α | β | α | α |
| - | β | α | α | β | α | α |
| - | α | β | β | α | α | α |
| - | α | β | α | β | β | α |
| - | α | β | α | β | α | β |
| - | β | α | β | α | α | α |
| - | β | α | α | β | β | α |
| - | β | α | α | β | α | β |
| - | α | β | β | α | β | α |
| - | α | β | β | α | α | β |
| - | α | β | α | β | β | β |
| - | β | α | β | α | β | α |
| - | β | α | β | β | α | β |
| - | β | α | α | β | β | β |
| - | α | β | β | α | β | β |
| - | β | α | β | α | β | β |
The compounds of this invention also can be in dynamic isomer in some examples.For example, imidazoles, guanidine, amidine can be in alkene-amine dynamic isomer with tetrazolium system, and all possible dynamic isomer is within the scope of the present invention.Example compound
The example of compound, it is unrestricted as an example, listed with forms mode (table 6).Generally, each compound is expressed as the core (core is represented with capitalization) being substituted, and each substituent is then sequentially represented with lowercase or numeral.Table 1a and 1b is the table of each core, and its main difference part is the property of unsaturated position and ring substituents on the ring of each core.Each core gives a digital code in table 1a and 1b, and this code name is the 1st word of each compound name.Similarly, table 2a-av, 3a-b, 4a-c and 5a-d list selected Q1, Q2, Q3, Q4Substituent, similarly, uses letter or number code name.Therefore, each compound named will be expressed as：One capitalization represents the core in table 1a-1b, is then to represent Q1The numeral of substituent, represents Q2The lowercase of substituent, represents Q3The numeral of substituent, represents Q4The lowercase of substituent.So A.49.a.4.i the structure 8 in reaction scheme 1 is expressed as.It should be understood that Q1-Q4Not group or atom, are related representation.
Table 1a
Table 1b
Table 2a
Table 2b
Table 2c
Table 2d
Table 2e
Table 2f
Table 2g
Table 2h
Table 2i
Table 2j
Table 2k
Table 2l
Table 2m
Table 2n
Table 2o
Table 2p
Table 2q
Table 2r
Table 2s
Table 2t
Table 2u
Table 2v
Table 2w
Table 2x
Table 2y
Table 2z
Table 2aa
Table 2ab
Table 2ac
Table 2ad
Table 2ae
Table 2af
Table 2ag
Table 2ah
Table 2ai
Table 3a
Table 3b
Table 4a
Table 4b
Table 4c
Table 5a
Table 5b
Table 5c
The example compound of table 6 is A.17.a.4.i；A.17.a.4.v；A.17.a.6.i；A.17.a.6.v；A.17.a.11.i；A.17.a.11.v；A.17.a.14.i；A.17.a.14.v；A.17.a.15.i；A.17.a.15.v；A.17.a.18.i；A.17.a.18.v；A.17.a.25.i；A.17.a.25.v；A.17.e.4.i；A.17.e.4.v；A.17.e.6.i；A.17.e.6.v；A.17.e.11.i；A.17.e.11.v；A.17.e.14.i；A.17.e.14.v；A.17.e.15.i；A.17.e.15.v；A.17.e.18.i；A.17.e.18.v；A.17.e.25.i；A.17.e.25.v；A.17.g.4.i；A.17.g.4.v；A.17.g.6.i；A.17.g.6.v；A.17.g.11.i；A.17.g.11.v；A.17.g.14.i；A.17.g.14.v；A.17.g.15.i；A.17.g.15.v；A.17.g.18.i；A.17.g.18.v；A.17.g.25.i；A.17.g.25.v；A.17.l.4.i；A.17.l.4.v；A.17.l.6.i；A.17.l.6.v；A.17.l.11.i；A.17.l.11.v；A.17.l.14.i；A.17.l.14.v；A.17.l.15.i；A.17.l.15.v；A.17.l.18.i；A.17.l.18.v；A.17.l.25.i；A.17.l.25.v；A.17.m.4.i；A.17.m.4.v；A.17.m.6.i；A.17.m.6.v；A.17.m.11.i；A.17.m.11.v；A.17.m.14.i；A.17.m.14.v；A.17.m.15.i；A.17.m.15.v；A.17.m.18.i；A.17.m.18.v；A.17.m.25.i；A.17.m.25.v；A.17.o.4.i；A.17.o.4.v；A.17.o.6.i；A.17.o.6.v；A.17.o.11.i；A.17.o.11.v；A.17.o.14.i；A.17.o.14.v；A.17.o.15.i；A.17.o.15.v；A.17.o.18.i；A.17.o.18.v；A.17.o.25.i；A.17.o.25.v；A.33.a.4.i；A.33.a.4.v；A.33.a.6.i；A.33.a.6.v；A.33.a.11.i；A.33.a.11.v；A.33.a.14.i；A.33.a.14.v；A.33.a.15.i；A.33.a.15.v；A.33.a.18.i；A.33.a.18.v；A.33.a.25.i；A.33.a.25.v；A.33.e.4.i；A.33.e.4.v；A.33.e.6.i；A.33.e.6.v；A.33.e.11.i；A.33.e.11.v；A.33.e.14.i；A.33.e.14.v；A.33.e.15.i；A.33.e.15.v；A.33.e.18.i；A.33.e.18.v；A.33.e.25.i；A.33.e.25.v；A.33.g.4.i；A.33.g.4.v；A.33.g.6.i；A.33.g.6.v；A.33.g.11.i；A.33.g.11.v；A.33.g.14.i；A.33.g.14.v；A.33.g.15.i；A.33.g.15.v；A.33.g.18.i；A.33.g.18.v；A.33.g.25.i；A.33.g.25.v；A.33.l.4.i；A.33.l.4.v；A.33.l.6.i；A.33.l.6.v；A.33.l.11.i；A.33.l.11.v；A.33.l.14.i；A.33.l.14.v；A.33.l.15.i；A.33.l.15.v；A.33.l.18.i；A.33.l.18.v；A.33.l.25.i；A.33.l.25.v；A.33.m.4.i；A.33.m.4.v；A.33.m.6.i；A.33.m.6.v；A.33.m.11.i；A.33.m.11.v；A.33.m.14.i；A.33.m.14.v；A.33.m.15.i；A.33.m.15.v；A.33.m.18.i；A.33.m.18.v；A.33.m.25.i；A.33.m.25.v；A.33.o.4.i；A.33.o.4.v；A.33.o.6.i；A.33.o.6.v；A.33.o.11.i；A.33.o.11.v；A.33.o.14.i；A.33.o.14.v；A.33.o.15.i；A.33.o.15.v；A.33.o.18.i；A.33.o.18.v；A.33.o.2.5.i；A.33.o.25.v；A.49.a.4.i；A.49.a.4.v；A.49.a.6.i；A.49.a.6.v；A.49.a.11.i；A.49.a.11.v；A.49.a.14.i；A.49.a.14.v；A.49.a.15.i；A.49.a.15.v；A.49.a.18.i；A.49.a.18.v；A.49.a.25.i；A.49.a.25.v；A.49.e.4.i；A.49.e.4.v；A.49.e.6.i；A.49.e.6.v；A.49.e.11.i；A.49.e.11.v；A.49.e.14.i；A.49.e.14.v；A.49.e.15.i；A.49.e.15.v；A.49.e.18.i；A.49.e.18.v；A.49.e.25.i；A.49.e.25.v；A.49.g.4.i；A.49.g.4.v；A.49.g.6.i；A.49.g.6.v；A.49.g.11.i；A.49.g.11.v；A.49.g.14.i；A.49.g.14.v；A.49.g.15.i；A.49.g.15.v；A.49.g.18.i；A.49.g.18.v；A.49.g.25.i；A.49.g.25.v；A.49.l.4.i；A.49.l.4.v；A.49.l.6.i；A.49.l.6.v；A.49.l.11.i；A.49.l.11.v；A.49.l.14.i；A.49.l.14.v；A.49.l.15.i；A.49.l.15.v；A.49.l.18.i；A.49.l.18.v；A.49.l.25.i；A.49.l.25.v；A.49.m.4.i；A.49.m.4.v；A.49.m.6.i；A.49.m.6.v；A.49.m.11.i；A.49.m.11.v；A.49.m.14.i；A.49.m.14.v；A.49.m.15.i；A.49.m.15.v；A.49.m.18.i；A.49.m.18.v；A.49.m.25.i；A.49.m.25.v；A.49.o.4.i；A.49.o.4.v；A.49.o.6.i；A.49.o.6.v；A.49.o.11.i；A.49.o.11.v；A.49.o.14.i；A.49.o.14.v；A.49.o.15.i；A.49.o.15.v；A.49.o.18.i；A.49.o.18.v；A.49.o.25.i；A.49.o.25.v；B.17.a.4.i；B.17.a.4.v；B.17.a.6.i；B.17.a.6.v；B.17.a.11.i；B.17.a.11.v；B.17.a.14.i；B.17.a.14.v；B.17.a.15.i；B.17.a.15.v；B.17.a.18.i；B.17.a.18.v；B.17.a.25.i；B.17.a.25.v；B.17.e.4.i；B.17.e.4.v；B.17.e.6.i；B.17.e.6.v；B.17.e.11.i；B.17.e.11.v；B.17.e.14.i；B.17.e.14.v；B.17.e.15.i；B.17.e.15.v；B.17.e.18.i；
B.17.e.18.v；B.17.e.25.i；B.17.e.25.v；B.17.g.4.i；B.17.g.4.v；B.17.g.6.i；B.17.g.6.v；B.17.g.11.i；B.17.g.11.v；B.17.g.14.i；B.17.g.14.v；B.17.g.15.i；B.17.g.15.v；B.17.g.18.i；B.17.g.18.v；B.17.g.25.i；B.17.g.25.v；B.17.l.4.i；B.17.l.4.v；B.17.l.6.i；B.17.l.6.v；B.17.l.11.i；B.17.l.11.v；B.17.l.14.i；B.17.l.14.v；B.17.l.15.i；B.17.l.15.v；B.17.l.18.i；B.17.l.18.v；B.17.l.25.i；B.17.l.25.v；B.17.m.4.i；B.17.m.4.v；B.17.m.6.i；B.17.m.6.v；B.17.m.11.i；B.17.m.11.v；B.17.m.14.i；B.17.m.14.v；B.17.m.15.i；B.17.m.15.v；B.17.m.18.i；B.17.m.18.v；B.17.m.25.i；B.17.m.25.v；B.17.o.4.i；B.17.o.4.v；B.17.o.6.i；B.17.o.6.v；B.17.o.11.i；B.17.o.11.v；B.17.o.14.i；B.17.o.14.v；B.17.o.15.i；B.17.o.15.v；B.17.o.18.i；B.17.o.18.v；B.17.o.25.i；B.17.o.25.v；B.33.a.4.i；B.33.a.4.v；B.33.a.6.i；B.33.a.6.v；B.33.a.11.i；B.33.a.11.v；B.33.a.14.i；B.33.a.14.v；B.33.a.15.i；B.33.a.15.v；B.33.a.18.i；B.33.a.18.v；B.33.a.25.i；B.33.a.25.v；B.33.e.4.i；B.33.e.4.v；B.33.e.6.i；B.33.e.6.v；B.33.e.11.i；B.33.e.11.v；B.33.e.14.i；B.33.e.14.v；B.33.e.15.i；B.33.e.15.v；B.33.e.18.i；B.33.e.18.v；B.33.e.25.i；B.33.e.25.v；B.33.g.4.i；B.33.g.4.v；B.33.g.6.i；B.33.g.6.v；B.33.g.11.i；B.33.g.11.v；B.33.g.14.i；B.33.g.14.v；B.33.g.15.i；B.33.g.15.v；B.33.g.18.i；B.33.g.18.v；B.33.g.25.i；B.33.g.25.v；B.33.l.4.i；B.33.l.4.v；B.33.l.6.i；B.33.l.6.v；B.33.l.11.i；B.33.l.11.v；B.33.l.14.i；B.33.l.14.v；B.33.l.15.i；B.33.l.15.v；B.33.l.18.i；B.33.l.18.v；B.33.l.25.i；B.33.l.25.v；B.33.m.4.i；B.33.m.4.v；B.33.m.6.i；B.33.m.6.v；B.33.m.11.i；B.33.m.11.v；B.33.m.14.i；B.33.m.14.v；B.33.m.15.i；B.33.m.15.v；B.33.m.18.i；B.33.m.18.v；B.33.m.25.i；B.33.m.25.v；B.33.o.4.i；B.33.o.4.v；B.33.o.6.i；B.33.o.6.v；B.33.o.11.i；B.33.o.11.v；B.33.o.14.i；B.33.o.14.v；B.33.o.15.i；B.33.o.15.v；B.33.o.18.i；B.33.o.18.v；B.33.o.25.i；B.33.o.25.v；B.49.a.4.i；B.49.a.4.v；B.49.a.6.i；B.49.a.6.v；B.49.a.11.i；B.49.a.11.v；B.49.a.14.i；B.49.a.14.v；B.49.a.15.i；B.49.a.15.v；B.49.a.18.i；B.49.a.18.v；B.49.a.25.i；B.49.a.25.v；B.49.e.4.i；B.49.e.4.v；B.49.e.6.i；B.49.e.6.v；B.49.e.11.i；B.49.e.11.v；B.49.e.14.i；B.49.e.14.v；B.49.e.15.i；B.49.e.15.v；B.49.e.18.i；B.49.e.18.v；B.49.e.25.i；B.49.e.25.v；B.49.g.4.i；B.49.g.4.v；B.49.g.6.i；B.49.g.6.v；B.49.g.11.i；B.49.g.11.v；B.49.g.14.i；B.49.g.14.v；B.49.g.15.i；B.49.g.15.v；B.49.g.18.i；B.49.g.18.v；B.49.g.25.i；B.49.g.25.v；B.49.l.4.i；B.49.l.4.v；B.49.l.6.i；B.49.l.6.v；B.49.l.11.i；B.49.l.11.v；B.49.l.14.i；B.49.l.14.v；B.49.l.15.i；B.49.l.15.v；B.49.l.18.i；B.49.l.18.v；B.49.l.25.i；B.49.l.25.v；B.49.m.4.i；B.49.m.4.v；B.49.m.6.i；B.49.m.6.v；B.49.m.11.i；B.49.m.11.v；B.49.m.14.i；B.49.m.14.v；B.49.m.15.i；B.49.m.15.v；B.49.m.18.i；B.49.m.18.v；B.49.m.25.i；B.49.m.25.v；B.49.o.4.i；B.49.o.4.v；B.49.o.6.i；B.49.o.6.v；B.49.o.11.i；B.49.o.11.v；B.49.o.14.i；B.49.o.14.v；B.49.o.15.i；B.49.o.15.v；B.49.o.18.i；B.49.o.18.v；B.49.o.25.i；B.49.o.25.v；E.17.a.4.i；E.17.a.4.v；E.17.a.6.i；E.17.a.6.v；E.17.a.11.i；E.17.a.11.v；E.17.a.14.i；E.17.a.14.v；E.17.a.15.i；E.17.a.15.v；E.17.a.18.i；E.17.a.18.v；E.17.a.25.i；E.17.a.25.v；E.17.e.4.i；E.17.e.4.v；E.17.e.6.i；E.17.e.6.v；E.17.e.11.i；E.17.e.11.v；E.17.e.14.i；E.17.e.14.v；E.17.e.15.i；E.17.e.15.v；E.17.e.18.i；E.17.e.18.v；E.17.e.25.i；E.17.e.25.v；E.17.g.4.i；E.17.g.4.v；E.17.g.6.i；E.17.g.6.v；E.17.g.11.i；E.17.g.11.v；E.17.g.14.i；E.17.g.14.v；E.17.g.15.i；E.17.g.15.v；E.17.g.18.i；E.17.g.18.v；E.17.g.25.i；E.17.g.25.v；E.17.l.4.i；E.17.l.4.v；E.17.l.6.i；E.17.l.6.v；E.17.l.11.i；E.17.l.11.v；E.17.l.14.i；E.17.l.14.v；E.17.l.15.i；E.17.l.15.v；E.17.l.18.i；E.17.l.18.v；E.17.l.25.i；E.17.l.25.v；E.17.m.4.i；E.17.m.4.v；E.17.m.6.i；E.17.m.6.v；E.17.m.11.i；E.17.m.11.v；E.17.m.14.i；E.17.m.14.v；E.17.m.15.i；E.17.m.15.v；E.17.m.18.i；E.17.m.18.v；E.17.m.25.i；E.17.m.25.v；E.17.o.4.i；E.17.o.4.v；E.17.o.6.i；E.17.o.6.v；E.17.o.11.i；E.17.o.11.v；E.17.o.14.i；E.17.o.14.v；E.17.o.15.i；E.17.o.15.v；
E.17.o.18.i；E.17.o.18.v；E.17.o.25.i；E.17.o.25.v；E.33.a.4.i；E.33.a.4.v；E.33.a.6.i；E.33.a.6.v；E.33.a.11.i；E.33.a.11.v；E.33.a.14.i；E.33.a.14.v；E.33.a.15.i；E.33.a.15.v；E.33.a.18.i；E.33.a.18.v；E.33.a.25.i；E.33.a.25.v；E.33.e.4.i；E.33.e.4.v；E.33.e.6.i；E.33.e.6.v；E.33.e.11.i；E.33.e.11.v；E.33.e.14.i；E.33.e.14.v；E.33.e.15.i；E.33.e.15.v；E.33.e.18.i；E.33.e.18.v；E.33.e.25.i；E.33.e.25.v；E.33.g.4.i；E.33.g.4.v；E.33.g.6.i；E.33.g.6.v；E.33.g.11.i；E.33.g.11.v；E.33.g.14.i；E.33.g.14.v；E.33.g.15.i；E.33.g.15.v；E.33.g.18.i；E.33.g.18.v；E.33.g.25.i；E.33.g.25.v；E.33.l.4.i；E.33.l.4.v；E.33.l.6.i；E.33.l.6.v；E.33.l.11.i；E.33.l.11.v；E.33.l.14.i；E.33.l.14.v；E.33.l.15.i；E.33.l.15.v；E.33.l.18.i；E.33.l.18.v；E.33.l.25.i；E.33.l.25.v；E.33.m.4.i；E.33.m.4.v；E.33.m.6.i；E.33.m.6.v；E.33.m.11.i；E.33.m.11.v；E.33.m.14.i；E.33.m.14.v；E.33.m.15.i；E.33.m.15.v；E.33.m.18.i；E.33.m.18.v；E.33.m.25.i；E.33.m.25.v；E.33.o.4.i；E.33.o.4.v；E.33.o.6.i；E.33.o.6.v；E.33.o.11.i；E.33.o.11.v；E.33.o.14.i；E.33.o.14.v；E.33.o.15.i；E.33.o.15.v；E.33.o.18.i；E.33.o.18.v；E.33.o.25.i；E.33.o.25.v；E.49.a.4.i；E.49.a.4.v；E.49.a.6.i；E.49.a.6.v；E.49.a.11.i；E.49.a. 11.v；E.49.a.14.i；E.49.a.14.v；E.49.a.15.i；E.49.a.15.v；E.49.a.18.i；E.49.a.18.v；E.49.a.25.i；E.49.a.25.v；E.49.e.4.i；E.49.e.4.v；E.49.e.6.i；E.49.e.6.v；E.49.e.11.i；E.49.e. 11.v；E.49.e.14.i；E.49.e.14.v；E.49.e.15.i；E.49.e.15.v；E.49.e.18.i；E.49.e.18.v；E.49.e.25.i；E.49.e.25.v；E.49.g.4.i；E.49.g.4.v；E.49.g.6.i；E.49.g.6.v；E.49.g.11.i；E.49.g.11.v；E.49.g.14.i；E.49.g.14.v；E.49.g.15.i；E.49.g.15.v；E.49.g.18.i；E.49.g.18.v；E.49.g.25.i；E.49.g.25.v；E.49.l.4.i；E.49.l.4.v；E.49.l.6.i；E.49.l.6.v；E.49.l.11.i；E.49.l.11.v；E.49.l.14.i；E.49.l.14.v；E.49.l.15.i；E.49.l.15.v；E.49.l.18.i；E.49.l.18.v；E.49.l.25.i；E.49.l.25.v；E.49.m.4.i；E.49.m.4.v；E.49.m.6.i；E.49.m.6.v；E.49.m.11.i；E.49.m.11.v；E.49.m.14.i；E.49.m.14.v；E.49.m.15.i；E.49.m.15.v；E.49.m.18.i；E.49.m.18.v；E.49.m.25.i；E.49.m.25.v；E.49.o.4.i；E.49.o.4.v；E.49.o.6.i；E.49.o.6.v；E.49.o.11.i；E.49.o.11.v；E.49.o.14.i；E.49.o.14.v；E.49.o.15.i；E.49.o.15.v；E.49.o.18.i；E.49.o.18.v；E.49.o.25.i； E.49.o.25.v；H.17.a.4.i；H.17.a.4.v；H.17.a.6.i；H.17.a.6.v；H.17.a.11.i；H.17.a.11.v；H.17.a.14.i；H.17.a.14.v；H.17.a.15.i；H.17.a.15.v；H.17.a.18.i；H.17.a.18.v；H.17.a.25.i；H.17.a.25.v；H.17.e.4.i；H.17.e.4.v；H.17.e.6.i；H.17.e.6.v；H.17.e.11.i；H.17.e.11.v；H.17.e.14.i；H.17.e.14.v；H.17.e.15.i；H.17.e.15.v；H.17.e.18.i；H.17.e.18.v；H.17.e.25.i；H.17.e.25.v；H.17.g.4.i；H.17.g.4.v；H.17.g.6.i；H.17.g.6.v；H.17.g.11.i；H.17.g.11.v；H.17.g.14.i；H.17.g.14.v；H.17.g.15.i；H.17.g.15.v；H.17.g.18.i；H.17.g.18.v；H.17.g.25.i；H.17.g.25.v；H.17.l.4.i；H.17.l.4.v；H.17.l.6.i；H.17.l.6.v；H.17.l.11.i；H.17.l.11.v；H.17.l.14.i；H.17.l.14.v；H.17.l.15.i；H.17.l.15.v；H.17.l.18.i；H.17.l.18.v；H.17.l.25.i；H.17.l.25.v；H.17.m.4.i；H.17.m.4.v；H.17.m.6.i；H.17.m. 6.v；H.17.m.11.i；H.17.m.11.v；H.17.m.14.i；H.17.m.14.v；H.17.m.15.i；H.17.m.15.v；H.17.m.18.i；H.17.m.18.v；H.17.m.25.i；H.17.m.25.v；H.17.o.4.i；H.17.o.4.v；H.17.o.6.i；H.17.o.6.v；H.17.o.11.i；H.17.o.11.v；H.17.o.14.i；H.17.o.14.v；H.17.o.15.i；H.17.o.15.v；H.17.o.18.i；H.17.o.18.v；H.17.o.25.i；H.17.o.25.v；H.33.a.4.i；H.33.a.4.v；H.33.a.6.i；H.33.a.6.v；H.33.a.11.i；H.33.a.11.v；H.33.a.14.i；H.33.a.14.v；H.33.a.15.i；H.33.a.15.v；H.33.a.18.i；H.33.a.18.v；H.33.a.25.i；H.33.a.25.v；H.33.e.4.i；H.33.e.4.v；H.33.e.6.i；H.33.e.6.v；H.33.e.11.i；H.33.e.11.v；H.33.e.14.i；H.33.e.14.v；H.33.e.15.i；H.33.e.15.v；H.33.e.18.i；H.33.e.18.v；H.33.e.25.i；H.33.e.25.v；H.33.g.4.i；H.33.g.4.v；H.33.g.6.i；H.33.g.6.v；H.33.g.11.i；H.33.g.11.v；H.33.g.14.i；H.33.g.14.v；H.33.g.15.i；H.33.g.15.v；H.33.g.18.i；H.33.g.18.v；H.33.g.25.i；H.33.g.25.v；H.33.l.4.i；H.33.l.4.v；H.33.l.6.i；H.33.l.6.v；H.33.l.11.i；H.33.l.11.v；H.33.l.14.i；H.33.l.14.v；H.33.l.15.i；H.33.l.15.v；H.33.l.18.i；
H.33.l.18.v；H.33.l.25.i；H.33.l.25.v；H.33.m.4.i；H.33.m.4.v；H.33.m.6.i；H.33.m.6.v；H.33.m.11.i；H.33.m.11.v；H.33.m.14.i；H.33.m.14.v；H.33.m.15.i；H.33.m.15.v；H.33.m.18.i；H.33.m.18.v；H.33.m.25.i；H.33.m.25.v；H.33.o.4.i；H.33.o.4.v；H.33.o.6.i；H.33.o.6.v；H.33.o.11.i；H.33.o.11.v；H.33.o.14.i；H.33.o.14.v；H.33.o.15.i；H.33.o.15.v；H.33.o.18.i；H.33.o.18.v；H.33.o.25.i；H.33.o.25.v；H.49.a.4.i；H.49.a.4.v；H.49.a.6.i；H.49.a.6.v；H.49.a.11.i；H.49.a.11.v；H.49.a.14.i；H.49.a.14.v；H.49.a.15.i；H.49.a.15.v；H.49.a.18.i；H.49.a.18.v；H.49.a.25.i；H.49.a.25.v；H.49.e.4.i；H.49.e.4.v；H.49.e.6.i；H.49.e.6.v；H.49.e.11.i；H.49.e.11.v；H.49.e.14.i；H.49.e.14.v；H.49.e.15.i；H.49.e.15.v；H.49.e.18.i；H.49.e.18.v；H.49.e.25.i；H.49.e.25.v；H.49.g.4.i；H.49.g.4.v；H.49.g.6.i；H.49.g.6.v；H.49.g.11.i；H.49.g.11.v；H.49.g.14.i；H.49.g.14.v；H.49.g.15.i；H.49.g.15.v；H.49.g.18.i；H.49.g.18.v；H.49.g.25.i；H.49.g.25.v；H.49.l.4.i；H.49.l.4.v；H.49.l.6.i；H.49.l.6.v；H.49.l.11.i；H.49.l.11.v；H.49.l.14.i；H.49.l.14.v；H.49.l.15.i；H.49.l.15.v；H.49.l.18.i；H.49.l.18.v；H.49.l.25.i；H.49.l.25.v；H.49.m.4.i；H.49.m.4.v；H.49.m.6.i；H.49.m.6.v；H.49.m.11.i；H.49.m.11.v；H.49.m.14.i；H.49.m.14.v；H.49.m.15.i；H.49.m.15.v；H.49.m.18.i；H.49.m.18.v；H.49.m.25.i；H.49.m.25.v；H.49.o.4.i；H.49.o.4.v；H.49.o.6.i；H.49.o.6.v；H.49.o.11.i；H.49.o.11.v；H.49.o.14.i；H.49.o.14.v；H.49.o.15.i；H.49.o.15.v；H.49.o.18.i；H.49.o.18.v；H.49.o.25.i；H.49.o.25.v；I.17.a.4.i；I.17.a.4.v；I.17.a.6.i；I.17.a.6.v；I.17.a.11.i；I.17.a.11.v；I.17.a.14.i；I.17.a.14.v；I.17.a.15.i；I.17.a.15.v；I.17.a.18.i；I.17.a.18.v；I.17.a.25.i；I.17.a.25.v；I.17.e.4.i；I.17.e.4.v；I.17.e.6.i；I.17.e.6.v；I.17.e.11.i；I.17.e.11.v；I.17.e.14.i；I.17.e.14.v；I.17.e.15.i；I.17.e.15.v；I.17.e.18.i；I.17.e.18.v；I.17.e.25.i；I.17.e.25.v；I.17.g.4.i；I.17.g.4.v；I.17.g.6.i；I.17.g.6.v；I.17.g.11.i；I.17.g.11.v；I.17.g.14.i；I.17.g.14.v；I.17.g.15.i；I.17.g.15.v；I.17.g.18.i；I.17.g.18.v；I.17.g.25.i；I.17.g.25.v；I.17.l.4.i；I.17.l.4.v；I.17.l.6.i；I.17.l.6.v；I.17.l.11.i；I.17.l.11.v；I.17.l.14.i；I.17.l.14.v；I.17.l.15.i；I.17.l.15.v；I.17.l.18.i；I.17.l.18.v；I.17.l.25.i；I.17.l.25.v；I.17.m.4.i；I.17.m.4.v；I.17.m.6.i；I.17.m.6.v；I.17.m.11.i；I.17.m.11.v；I.17.m.14.i；I.17.m.14.v；I.17.m.15.i；I.17.m.15.v；I.17.m.18.i；I.17.m.18.v；I.17.m.25.i；I.17.m.25.v；I.17.o.4.i；I.17.o.4.v；I.17.o.6.i；I.17.o.6.v；I.17.o.11.i；I.17.o.11.v；I.17.o.14.i；I.17.o.14.v；I.17.o.15.i；I.17.o.15.v；I.17.o.18.i；I.17.o.18.v；I.17.o.25.i；I.17.o.25.v；I.33.a.4.i；I.33.a.4.v；I.33.a.6.i；I.33.a.6.v；I.33.a.11.i；I.33.a.11.v；I.33.a.14.i；I.33.a.14.v；I.33.a.15.i；I.33.a.15.v；I.33.a.18.i；I.33.a.18.v；I.33.a.25.i；I.33.a.25.v；I.33.e.4.i；I.33.e.4.v；I.33.e.6.i；I.33.e.6.v；I.33.e.11.i；I.33.e.11.v；I.33.e.14.i；I.33.e.14.v；I.33.e.15.i；I.33.e.15.v；I.33.e.18.i；I.33.e.18.v；I.33.e.25.i；I.33.e.25.v；I.33.g.4.i；I.33.g.4.v；I.33.g.6.i；I.33.g.6.v；I.33.g.11.i；I.33.g.11.v；I.33.g.14.i；I.33.g.14.v；I.33.g.15.i；I.33.g.15.v；I.33.g.18.i；I.33.g.18.v；I.33.g.25.i；I.33.g.25.v；I.33.l.4.i；I.33.l.4.v；I.33.l.6.i；I.33.I.6.v；I.33.l.11.i；I.33.l.11.v；I.33.l.14.i；I.33.l.14.v；I.33.l.15.i；I.33.l.15.v；I.33.l.18.i；I.33.l.18.v；I.33.l.25.i；I.33.l.25.v；I.33.m.4.i；I.33.m.4.v；I.33.m.6.i；I.33.m.6.v；I.33.m.11.i；I.33.m.11.v；I.33.m.14.i；I.33.m.14.v；I.33.m.15.i；I.33.m.15.v；I.33.m.18.i；I.33.m.18.v；I.33.m.25.i；I.33.m.25.v；I.33.o.4.i；I.33.o.4.v；I.33.o.6.i；I.33.o.6.v；I.33.o.11.i；I.33.o.11.v；I.33.o.14.i；I.33.o.14.v；I.33.o.15.i；I.33.o.15.v；I.33.o.18.i；I.33.o.18.v；I.33.o.25.i；I.33.o.25.v；I.49.a.4.i；I.49.a.4.v；I.49.a.6.i；I.49.a.6.v；I.49.a. 11.i；I.49.a.11.v；I.49.a.14.i；I.49.a.14.v；I.49.a.15.i；I.49.a.15.v；I.49.a.18.i；I.49.a.18.v；I.49.a.25.i；I.49.a.25.v；I.49.e.4.i；I.49.e.4.v；I.49.e.6.i；I.49.e.6.v；I.49.e.11.i；I.49.e.11.v；I.49.e.14.i；I.49.e.14.v；I.49.e.15.i；I.49.e.15.v；I.49.e.18.i；I.49.e.18.v；I.49.e.25.i；I.49.e.25.v；I.49.g.4.i；I.49.g.4.v；
I.49.g.6.i；I.49.g.6.v；I.49.g.11.i；I.49.g.11.v；I.49.g.14.i；I.49.g.14.v；I.49.g.15.i；I.49.g.15.v；I.49.g.18.i；I.49.g.18.v；I.49.g.25.i；I.49.g.25.v；I.49.l.4.i；I.49.l.4.v；I.49.l.6.i；I.49.l.6.v；I.49.l.11.i；I.49.l.11.v；I.49.l.14.i；I.49.l.14.v；I.49.l.15.i；I.49.l.15.v；I.49.l.18.i；I.49.l.18.v；I.49.l.25.i；I.49.l.25.v；I.49.m.4.i；I.49.m.4.v；I.49.m.6.i；I.49.m.6.v；I.49.m.11.i；I.49.m.11.v；I.49.m.14.i；I.49.m.14.v；I.49.m.15.i；I.49.m.15.v；I.49.m.18.i；I.49.m.18.v；I.49.m.25.i；I.49.m.25.v；I.49.o.4.i；I.49.o.4.v；I.49.o.6.i；I.49.o.6.v；I.49.o.11.i；I.49.o.11.v；I.49.o.14.i；I.49.o.14.v；I.49.o.15.i；I.49.o.15.v；I.49.o.18.i；I.49.o.18.v；I.49.o.25.i；I.49.o.25.v；L.17.a.4.i；L.17.a.4.v；L.17.a.6.i；L.17.a.6.v；L.17.a.11.i；L.17.a.11.v；L.17.a.14.i；L.17.a.14.v；L.17.a.15.i；L.17.a.15.v；L.17.a.18.i；L.17.a.18.v；L.17.a.25.i；L.17.a.25.v；L.17.e.4.i；L.17.e.4.v；L.17.e.6.i；L.17.e.6.v；L.17.e.11.i；L.17.e.11.v；L.17.e.14.i；L.17.e.14.v；L.17.e.15.i；L.17.e.15.v；L.17.e.18.i；L.17.e.18.v；L.17.e.25.i；L.17.e.25.v；L.17.g.4.i；L.17.g.4.v；L.17.g.6.i；L.17.g.6.v；L.17.g.11.i；L.17.g.11.v；L.17.g.14.i；L.17.g.14.v；L.17.g.15.i；L.17.g.15.v；L.17.g.18.i；L.17.g.18.v；L.17.g.25.i；L.17.g.25.v；L.17.l.4.i；L.17.l.4.v；L.17.l.6.i；L.17.l.6.v；L.17.l.11.i；L.17.l.11.v；L.17.l.14.i；L.17.l.14.v；L.17.l.15.i；L.17.l.15.v；L.17.l.18.i；L.17.l.18.v；L.17.l.25.i；L.17.l.25.v；L.17.m.4.i；L.17.m.4.v；L.17.m.6.i；L.17.m.6.v；L.17.m.11.i；L.17.m.11.v；L.17.m.14.i；L.17.m.14.v；L.17.m.15.i；L.17.m.15.v；L.17.m.18.i；L.17.m.18.v；L.17.m.25.i；L.17.m.25.v；L.17.o.4.i；L.17.o.4.v；L17.o.6.i；L.17.o.6.v；L.17.o.11.i；L.17.o.11.v；L.17.o.14.i；L.17.o.14.v；L.17.o.15.i；L.17.o.15.v；L.17.o.18.i；L.17.o.18.v；L.17.o.25.i；L.17.o.25.v；L.33.a.4.i；L.33.a.4.v；L.33.a.6.i；L.33.a.6.v；L.33.a.11.i；L.33.a.11.v；L.33.a.14.i；L.33.a.14.v；L.33.a.15.i；L.33.a.15.v；L.33.a.18.i；L.33.a.18.v；L.33.a.25.i；L.33.a.25.v；L.33.e.4.i；L.33.e.4.v；L.33.e.6.i；L.33.e.6.v；L.33.e.11.i；L.33.e.11.v；L.33.e.14.i；L.33.e.14.v；L.33.e.15.i；L.33.e.15.v；L.33.e.18.i；L.33.e.18.v；L.33.e.25.i；L.33.e.25.v；L.33.g.4.i；L.33.g.4.v；L.33.g.6.i；L.33.g.6.v；L.33.g.11.i；L.33.g.11.v；L.33.g.14.i；L.33.g.14.v；L.33.g.15.i；L.33.g.15.v；L.33.g.18.i；L.33.g.18.v；L.33.g.25.i；L.33.g.25.v；L.33.l.4.i；L.33.l.4.v；L.33.l.6.i；L.33.l.6.v；L.33.l.11.i；L.33.l.11.v；L.33.l.14.i；L.33.l.14.v；L.33.l.15.i；L.33.l.15.v；L.33.l.18.i；L.33.l.18.v；L.33.l.25.i；L.33.l.25.v；L.33.m.4.i；L.33.m.4.v；L.33.m.6.i；L.33.m.6.v；L.33.m.11.i；L.33.m.11.v；L.33.m.14.i；L.33.m.14.v；L.33.m.15.i；L.33.m.15.v；L.33.m.18.i；L.33.m.18.v；L.33.m.25.i；L.33.m.25.v；L.33.o.4.i；L.33.o.4.v；L.33.o.6.i；L.33.o.6.v；L.33.o.11.i；L.33.o.11.v；L.33.o.14.i；L.33.o.14.v；L.33.o.15.i；L.33.o.15.v；L.33.o.18.i；L.33.o.18.v；L.33.o.25.i；L.33.o.25.v；L.49.a.4.i；L.49.a.4.v；L.49.a.6.i；L.49.a.6.v；L.49.a.11.i；L.49.a.11.v；L.49.a.14.i；L.49.a.14.v；L.49.a.15.i；L.49.a.15.v；L.49.a.18.i；L.49.a.18.v；L.49.a.25.i；L.49.a.25.v；L.49.e.4.i；L.49.e.4.v；L.49.e.6.i；L.49.e.6.v；L.49.e.11.i；L.49.e.11.v；L.49.e.14.i；L.49.e.14.v；L.49.e.15.i；L.49.e.15.v；L.49.e.18.i；L.49.e.18.v；L.49.e.25.i；L.49.e.25.v；L.49.g.4.i；L.49.g.4.v；L.49.g.6.i；L.49.g.6.v；L.49.g.11.i；L.49.g.11.v；L.49.g.14.i；L.49.g.14.v；L.49.g.15.i；L.49.g.15.v；L.49.g.18.i；L.49.g.18.v；L.49.g.25.i；L.49.g.25.v；L.49.l.4.i；L.49.l.4.v；L.49.l.6.i；L.49.l.6.v；L.49.l.11.i；L.49.l.11.v；L.49.l.14.i；L.49.l.14.v；L.49.l.15.i；L.49.l.15.v；L.49.l.18.i；L.49.l.18.v；L.49.l.25.i；L.49.l.25.v；L.49.m.4.i；L.49.m.4.v；L.49.m.6.i；L.49.m.6.v；L.49.m.11.i；L.49.m.11.v；L.49.m.14.i；L.49.m.14.v；L.49.m.15.i；L.49.m.15.v；L.49.m.18.i；L.49.m.18.v；L.49.m.25.i；L.49.m.25.v；L.49.o.4.i；L.49.o.4.v；L.49.o.6.i；L.49.o.6.v；L.49.o.11.i；L.49.o.11.v；L.49.o.14.i；L.49.o.14.v；L.49.o.15.i；L.49.o.15.v；L.49.o.18.i；L.49.o.18.v；L.49.o.25.i；L.49.o.25.v；B.93.a.4.i；B.93.a.4.v；B.93.a.6.i；B.93.a.6.v；B.93.a.11.i；B.93.a.11.v；B.93.a.14.i；B.93.a.14.v；B.93.a.15.i；B.93.a.15.v；B.93.a.18.i；
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A.98.a.41.bk；A.98.a.42.i；A.98.a.42.o；A.98.a.42.bh；A.98.a.42.bi；A.98.a.42.bj；A.98.a.42.bk；A.98.a.43.i；A.98.a.43.o；A.98.a.43.bh；A.98.a.43.bi；A.98.a.43.bj；A.98.a.43.bk；A.2.a.4.i；A.3.a.4.i；A.4.a.4.i；A.5.a.4.i；A.6.a.4.i；A.7.a.4.i；A.9.a.4.i；A.10.a.4.i；A.15.a.4.i；A.100.a.4.i；A.101.a.4.i；A.102.a.4.i；A.103.a.4.i；A.104.a.4.i；A.105.a.4.i；A.106.a.4.i；A.107.a.4.i；A.108.a.4.i；A.109.a.4.i；A.110.a.4.i；A.111.a.4.i；A.112.a.4.i；A.113.a.4.i；A.114.a.4.i；A.115.a.4.i；A.116.a.4.i；A.117.a.4.i；A.118.a.4.i；A.119.a.4.i；A.120.a.4.i；A.121.a.4.i；A.122.a.4.i；A.123.a.4.i；A.124.a.4.i；A.125.a.4.i；A.126.a.4.i；A.127.a.4.i；A.128.a.4.i；A.129.a.4.i；A.130.a.4.i；A.131.a.4.i；A.132.a.4.i；A.133.a.4.i；A.134.a.4.i；A.135.a.4.i；A.136.a.4.i；A.137.a.4.i；A.138.a.4.i；A.139.a.4.i；A.140.a.4.i；A.141.a.4.i；A.142.a.4.i；A.143.a.4.i；A.144.a.4.i；A.145.a.4.i；A.146.a.4.i；A.147.a.4.i；A.148.a.4.i；A.149.a.4.i；A.150.a.4.i；A.151.a.4.i；A.152.a.4.i；A.153.a.4.i；A.154.a.4.i；A.155.a.4.i；A.156.a.4.i；A.157.a.4.i；A.158.a.4.i；A.159.a.4.i；A.160.a.4.i；A.161.a.4.i；A.162.a.4.i；A.163.a.4.i；A.164.a.4.i；A.165.a.4.i；A.166.a.4.i；A.167.a.4.i；A.168.a.4.i；A.169.a.4.i；A.170.a.4.i；A.171.a.4.i；A.172.a.4.i；A.173.a.4.i；A.174.a.4.i；A.175.a.4.i；A.176.a.4.i；A.177.a.4.i；A.178.a.4.i；A.179.a.4.i；A.180.a.4.i；A.181.a.4.i；A.182.a.4.i；A.183.a.4.i；A.184.a.4.i；A.185.a.4.i；A.186.a.4.i；A.187.a.4.i；A.188.a.4.i；A.189.a.4.i；A.190.a.4.i；A.191.a.4.i；A.192.a.4.i；A.193.a.4.i；A.194.a.4.i；A.195.a.4.i；A.196.a.4.i；A.197.a.4.i；A.198.a.4.i；A.199.a.4.i；A.200.a.4.i；A.201.a.4.i；A.202.a.4.i；A.203.a.4.i；A.204.a.4.i；A.205.a.4.i；A.206.a.4.i；A.207.a.4.i；A.208.a.4.i；A.209.a.4.i；A.210.a.4.i；A.211.a.4.i；A.212.a.4.i；A.213.a.4.i；A.214.a.4.i；A.215.a.4.i；A.216.a.4.i；A.217.a.4.i；A.218.a.4.i；A.219.a.4.i；A.220.a.4.i；A.221.a.4.i；A.222.a.4.i；A.223.a.4.i；A.224.a.4.i；A.225.a.4.i；A.226.a.4.i；A.227.a.4.i；A.228.a.4.i；A.229.a.4.i；A.230.a.4.i；A.231.a.4.i；A.232.a.4.i；A.233.a.4.i；A.234.a.4.i；A.235.a.4.i；A.236.a.4.i；A.237.a.4.i；A.238.a.4.i；A.239.a.4.i；A.240.a.4.i；A.241.a.4.i；A.242.a.4.i；A.243.a.4.i；A.244.a.4.i；A.245.a.4.i；A.246.a.4.i；A.247.a.4.i；A.248.a.4.i；A.249.a.4.i；A.250.a.4.i；A.251.a.4.i；A.252.a.4.i；A.253.a.4.i；A.254.a.4.i；A.255.a.4.i；A.256.a.4.i；A.257.a.4.i；A.258.a.4.i；A.259.a.4.i；A.260.a.4.i；A.261.a.4.i；A.262.a.4.i；A.263.a.4.i；A.264.a.4.i；A.265.a.4.i；A.266.a.4.i；A.267.a.4.i；A.268.a.4.i；A.269.a.4.i；A.270.a.4.i；A.271.a.4.i；A.272.a.4.i；A.273.a.4.i；A.274.a.4.i；A.275.a.4.i；A.276.a.4.i；A.277.a.4.i；A.278.a.4.i；A.279.a.4.i；A.280.a.4.i；A.281.a.4.i；A.282.a.4.i；A.283.a.4.i；A.284.a.4.i；A.285.a.4.i；A.286.a.4.i；A.287.a.4.i；A.288.a.4.i；A.289.a.4.i；A.290.a.4.i；A.291.a.4.i；A.292.a.4.i；A.293.a.4.i；A.294.a.4.i；A.295.a.4.i；A.296.a.4.i；A.297.a.4.i；A.298.a.4.i；A.299.a.4.i；A.300.a.4.i；A.301.a.4.i；A.302.a.4.i；A.303.a.4.i；A.304.a.4.i；A.305.a.4.i；A.306.a.4.i；A.307.a.4.i；A.308.a.4.i；A.309.a.4.i；A.310.a.4.i；A.311.a.4.i；A.312.a.4.i；A.313.a.4.i；A.314.a.4.i；A.315.a.4.i；A.316.a.4.i；A.317.a.4.i；A.318.a.4.i；A.319.a.4.i；A.320.a.4.i；A.321.a.4.i；A.323.a.4.i；A.324.a.4.i；A.325.a.4.i；A.326.a.4.i；A.327.a.4.i；A.328.a.4.i；A.329.a.4.i；A.330.a.4.i；A.331.a.4.i；A.332.a.4.i；A.333.a.4.i；A.334.a.4.i；A.335.a.4.i；A.336.a.4.i；A.337.a.4.i；A.338.a.4.i；A.339.a.4.i；A.340.a.4.i；A.341.a.4.i；A.342.a.4.i；A.343.a.4.i；A.344.a.4.i；A.345.a.4.i；A.346.a.4.i；A.347.a.4.i；A.348.a.4.i；A.349.a.4.i；A.350.a.4.i；A.351.a.4.i；A.352.a.4.i；A.353.a.4.i；A.354.a.4.i；A.355.a.4.i；A.356.a.4.i；A.357.a.4.i；A.358.a.4.i；A.359.a.4.i；A.360.a.4.i；A.361.a.4.i；A.362.a.4.i；A.363.a.4.i；
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A.360.a.11.i；A.361.a.11.i；A.362.a.11.i；A.363.a.11.i；A.364.a.11.i；A.365.a.11.i；A.366.a.11.i；A.367.a.11.i；A.368.a.11.i；A.369.a.11.i；A.370.a.11.i；A.371.a.11.i；A.372.a.11.i；A.373.a.11.i；A.374.a.11.i；A.375.a.11.i；A.376.a.11.i；A.377.a.11.i；A.378.a.11.i；A.379.a.11.i；A.380.a.11.i；A.381.a.11.i；A.382.a.11.i；A.383.a.11.i；A.384.a.11.i；A.385.a.11.i；A.386.a.11.i；A.387.a.11.i；A.388.a.11.i；A.389.a.11.i；A.390.a.11.i；A.391.a.11.i；A.392.a.11.i；A.393.a.11.i；A.394.a.11.i；A.395.a.11.i；A.396.a.11.i；A.397.a.11.i；A.398.a.11.i；A.399.a.11.i；A.400.a.11.i；A.401.a.11.i；A.402.a.11.i；A.403.a.11.i；A.404.a.11.i；A.405.a.11.i；A.406.a.11.i；A.407.a.11.i；A.408.a.11.i；A.409.a.11.i；A.410.a.11.i；A.411.a.11.i；A.412.a.11.i；A.413.a.11.i；A.414.a.11.i；A.415.a.11.i；A.416.a.11.i；A.417.a.11.i；A.418.a.11.i；A.419.a.11.i；A.420.a.11.i；A.421.a.11.i；A.422.a.11.i；A.423.a.11.i；A.424.a.11.i；A.425.a.11.i；A.426.a.11.i；A.427.a.11.i；A.428.a.11.i；A.429.a.11.i；A.430.a.11.i；A.431.a.11.i；A.432.a.11.i；A.433.a.11.i；A.434.a.11.i；A.435.a.11.i；A.436.a.11.i；A.437.a.11.i；A.438.a.11.i；A.439.a.11.i；A.440.a.11.i；A.441.a.11.i；A.442.a.11.i；A.443.a.11.i；A.444.a.11.i；A.445.a.11.i；A.446.a.11.i；A.447.a.11.i；A.448.a.11.i；A.449.a.11.i；A.450.a.11.i；A.451.a.11.i；A.452.a.11.i；A.453.a.11.i；A.454.a.11.i；A.455.a.11.i；A.456.a.11.i；A.457.a.11.i；A.458.a.11.i；A.459.a.11.i；A.460.a.11.i；A.461.a.11.i；A.462.a.11.i；A.463.a.11.i；A.464.a.11.i；A.465.a.11.i；A.466.a.11.i；A.467.a.11.i；A.468.a.11.i；A.469.a.11.i；A.470.a.11.i；A.471.a.11.i；A.472.a.11.i；A.473.a.11.i；A.474.a.11.i；A.475.a.11.i；A.476.a.11.i；A.477.a.11.i；A.478.a.11.i；A.479.a.11.i；A.480.a.11.i；A.481.a.11.i；A.482.a.11.i；A.483.a.11.i；A.484.a.11.i；A.485.a.11.i；A.486.a.11.i；A.487.a.11.i；A.488.a.11.i；A.489.a.11.i；A.490.a.11.i；A.491.a.11.i；A.492.a.11.i；A.493.a.11.i；A.494.a.11.i；A.495.a.11.i；A.496.a.11.i；A.497.a.11.i；A.498.a.11.i；A.499.a.11.i；A.500.a.11.i；A.501.a.11.i；A.502.a.11.i；A.503.a.11.i；A.504.a.11.i；A.505.a.11.i；A.506.a.11.i；A.507.a.11.i；A.508.a.11.i；A.509.a.11.i；A.510.a.11.i；A.511.a.11.i；A.512.a.11.i；A.512.a.11.i；A.513.a.11.i；A.514.a.11.i；A.515.a.11.i；A.516.a.11.i；A.517.a.11.i；A.518.a.11.i；A.519.a.11.i；A.520.a.11.i；A.521.a.11.i；A.522.a.11.i；A.523.a.11.i；A.524.a.11.i；A.525.a.11.i；A.526.a.11.i；A.527.a.11.i；A.528.a.11.i；A.529.a.11.i；A.530.a.11.i；A.531.a.11.i；A.532.a.11.i；A.533.a.11.i；A.534.a.11.i；A.535.a.11.i；A.536.a.11.i；A.537.a.11.i；A.538.a.11.i；A.539.a.11.i；A.540.a.11.i；A.541.a.11.i；A.542.a.11.i；A.543.a.11.i；A.544.a.11.i；A.545.a.11.i；A.546.a.11.i；A.547.a.11.i；A.548.a.11.i；A.549.a.11.i；A.550.a.11.i；A.551.a.11.i；A.552.a.11.i；A.553.a.11.i；A.554.a.11.i；A.555.a.11.i；A.556.a.11.i；A.557.a.11.i；A.558.a.11.i；A.559.a.11.i；A.560.a.11.i；A.561.a.11.i；A.562.a.11.i；A.563.a.11.i；A.564.a.11.i；A.565.a.11.i；A.566.a.11.i；A.567.a.11.i；A.568.a.11.i；A.569.a.11.i；A.570.a.11.i；A.571.a.11.i；A.572.a.11.i；A.573.a.11.i；A.574.a.11.i；A.575.a.11.i；A.576.a.11.i；A.577.a.11.i；A.578.a.11.i；A.579.a.11.i；A.580.a.11.i；A.581.a.11.i；A.582.a.11.i；A.583.a.11.i；A.584.a.11.i；A.585.a.11.i；A.586.a.11.i；A.587.a.11.i；A.588.a.11.i；A.589.a.11.i；A.590.a.11.i；A.591.a.11.i；A.592.a.11.i；A.593.a.11.i；A.594.a.11.i；A.595.a.11.i；A.596.a.11.i；A.597.a.11.i；A.598.a.11.i；A.599.a.11.i；A.600.a.11.i；A.601.a.11.i；A.602.a.11.i；A.603.a.11.i；A.604.a.11.i；A.605.a.11.i；A.606.a.11.i；A.607.a.11.i；A.608.a.11.i；A.609.a.11.i；A.610.a.11.i；A.611.a.11.i；A.612.a.11.i；A.613.a.11.i；A.614.a.11.i；A.615.a.11.i；A.616.a.11.i；A.617.a.11.i；A.618.a.11.i；A.619.a.11.i；A.620.a.11.i；A.621.a.11.i；A.622.a.11.i；A.623.a.11.i；A.624.a.11.i；A.625.a.11.i；A.626.a.11.i；A.627.a.11.i；A.628.a.11.i；A.629.a.11.i；A.630.a.11.i；A.631.a.11.i；A.632.a.11.i；A.633.a.11.i；A.634.a.11.i；A.635.a.11.i；A.636.a.11.i；A.637.a.11.i；A.638.a.11.i；A.639.a.11.i；A.640.a.11.i；
A.641.a.11.i；A.642.a.11.i；A.643.a.11.i；A.644.a.11.i；A.645.a.11.i；A.646.a.11.i；A.647.a.11.i；A.648.a.11.i；A.649.a.11.i；A.650.a.11.i；A.651.a.11.i；A.652.a.11.i；A.653.a.11.i；A.654.a.11.i；A.655.a.11.i；A.656.a.11.i；A.657.a.11.i；A.658.a.11.i；A.659.a.11.i；A.660.a.11.i；A.2.b.4.i；A.3.b.4.i；A.4.b.4.i；A.5.b.4.i；A.6.b.4.i；A.7.b.4.i；A.9.b.4.i；A.10.b.4.i；A.15.b.4.i；A.100.b.4.i；A.101.b.4.i；A.102.b.4.i；A.103.b.4.i；A.104.b.4.i；A.105.b.4.i；A.106.b.4.i；A.107.b.4.i；A.108.b.4.i；A.109.b.4.i；A.110.b.4.i；A.111.b.4.i；A.112.b.4.i；A.113.b.4.i；A.114.b.4.i；A.115.b.4.i；A.116.b.4.i；A.117.b.4.i；A.118.b.4.i；A.119.b.4.i；A.120.b.4.i；A.121.b.4.i；A.122.b.4.i；A.123.b.4.i；A.124.b.4.i；A.125.b.4.i；A.126.b.4.i；A.127.b.4.i；A.128.b.4.i；A.129.b.4.i；A.130.b.4.i；A.131.b.4.i；A.132.b.4.i；A.133.b.4.i；A.134.b.4.i；A.135.b.4.i；A.136.b.4.i；A.137.b.4.i；A.138.b.4.i；A.139.b.4.i；A.140.b.4.i；A.141.b.4.i；A.142.b.4.i；A.143.b.4.i；A.144.b.4.i；A.145.b.4.i；A.146.b.4.i；A.147.b.4.i；A.148.b.4.i；A.149.b.4.i；A.150.b.4.i；A.151.b.4.i；A.152.b.4.i；A.153.b.4.i；A.154.b.4.i；A.155.b.4.i；A.156.b.4.i；A.157.b.4.i；A.158.b.4.i；A.159.b.4.i；A.160.b.4.i；A.161.b.4.i；A.162.b.4.i；A.163.b.4.i；A.164.b.4.i；A.165.b.4.i；A.166.b.4.i；A.167.b.4.i；A.168.b.4.i；A.169.b.4.i；A.170.b.4.i；A.171.b.4.i；A.172.b.4.i；A.173.b.4.i；A.174.b.4.i；A.175.b.4.i；A.176.b.4.i；A.177.b.4.i；A.178.b.4.i；A.179.b.4.i；A.180.b.4.i；A.181.b.4.i；A.182.b.4.i；A.183.b.4.i；A.184.b.4.i；A.185.b.4.i；A.186.b.4.i；A.187.b.4.i；A.188.b.4.i；A.189.b.4.i；A.190.b.4.i；A.191.b.4.i；A.192.b.4.i；A.193.b.4.i；A.194.b.4.i；A.195.b.4.i；A.196.b.4.i；A.197.b.4.i；A.198.b.4.i；A.199.b.4.i；A.200.b.4.i；A.201.b.4.i；A.202.b.4.i；A.203.b.4.i；A.204.b.4.i；A.205.b.4.i；A.206.b.4.i；A.207.b.4.i；A.208.b.4.i；A.209.b.4.i；A.210.b.4.i；A.211.b.4.i；A.212.b.4.i；A.213.b.4.i；A.214.b.4.i；A.215.b.4.i；A.216.b.4.i；A.217.b.4.i；A.218.b.4.i；A.219.b.4.i；A.220.b.4.i；A.221.b.4.i；A.222.b.4.i；A.223.b.4.i；A.224.b.4.i；A.225.b.4.i；A.226.b.4.i；A.227.b.4.i；A.228.b.4.i；A.229.b.4.i；A.230.b.4.i；A.231.b.4.i；A.232.b.4.i；A.233.b.4.i；A.234.b.4.i；A.235.b.4.i；A.236.b.4.i；A.237.b.4.i；A.238.b.4.i；A.239.b.4.i；A.240.b.4.i；A.241.b.4.i；A.242.b.4.i；A.243.b.4.i；A.244.b.4.i；A.245.b.4.i；A.246.b.4.i；A.247.b.4.i；A.248.b.4.i；A.249.b.4.i；A.250.b.4.i；A.251.b.4.i；A.252.b.4.i；A.253.b.4.i；A.254.b.4.i；A.255.b.4.i；A.256.b.4.i；A.257.b.4.i；A.258.b.4.i；A.259.b.4.i；A.260.b.4.i；A.261.b.4.i；A.262.b.4.i；A.263.b.4.i；A.264.b.4.i；A.265.b.4.i；A.266.b.4.i；A.267.b.4.i；A.268.b.4.i；A.269.b.4.i；A.270.b.4.i；A.271.b.4.i；A.272.b.4.i；A.273.b.4.i；A.274.b.4.i；A.275.b.4.i；A.276.b.4.i；A.277.b.4.i；A.278.b.4.i；A.279.b.4.i；A.280.b.4.i；A.281.b.4.i；A.282.b.4.i；A.283.b.4.i；A.284.b.4.i；A.285.b.4.i；A.286.b.4.i；A.287.b.4.i；A.288.b.4.i；A.289.b.4.i；A.290.b.4.i；A.291.b.4.i；A.292.b.4.i；A.293.b.4.i；A.294.b.4.i；A.295.b.4.i；A.296.b.4.i；A.297.b.4.i；A.298.b.4.i；A.299.b.4.i；A.300.b.4.i；A.301.b.4.i；A.302.b.4.i；A.303.b.4.i；A.304.b.4.i；A.305.b.4.i；A.306.b.4.i；A.307.b.4.i；A.308.b.4.i；A.309.b.4.i；A.310.b.4.i；A.311.b.4.i；A.312.b.4.i；A.313.b.4.i；A.314.b.4.i；A.315.b.4.i；A.316.b.4.i；A.317.b.4.i；A.318.b.4.i；A.319.b.4.i；A.320.b.4.i；A.321.b.4.i；A.323.b.4.i；A.324.b.4.i；A.325.b.4.i；A.326.b.4.i；A.327.b.4.i；A.328.b.4.i；A.329.b.4.i；A.330.b.4.i；A.331.b.4.i；A.332.b.4.i；A.333.b.4.i；A.334.b.4.i；A.335.b.4.i；A.336.b.4.i；A.337.b.4.i；A.338.b.4.i；A.339.b.4.i；A.340.b.4.i；A.341.b.4.i；A.342.b.4.i；A.343.b.4.i；A.344.b.4.i；A.345.b.4.i；A.346.b.4.i；A.347.b.4.i；A.348.b.4.i；A.349.b.4.i；A.350.b.4.i；A.351.b.4.i；A.352.b.4.i；A.353.b.4.i；A.354.b.4.i；A.355.b.4.i；
A.356.b.4.i；A.357.b.4.i；A.358.b.4.i；A.359.b.4.i；A.360.b.4.i；A.361.b.4.i；A.362.b.4.i；A.363.b.4.i；A.364.b.4.i；A.365.b.4.i；A.366.b.4.i；A.367.b.4.i；A.368.b.4.i；A.369.b.4.i；A.370.b.4.i；A.371.b.4.i；A.372.b.4.i；A.373.b.4.i；A.374.b.4.i；A.375.b.4.i；A.376.b.4.i；A.377.b.4.i；A.378.b.4.i；A.379.b.4.i；A.380.b.4.i；A.381.b.4.i；A.382.b.4.i；A.383.b.4.i；A.384.b.4.i；A.385.b.4.i；A.386.b.4.i；A.387.b.4.i；A.388.b.4.i；A.389.b.4.i；A.390.b.4.i；A.391.b.4.i；A.392.b.4.i；A.393.b.4.i；A.394.b.4.i；A.395.b.4.i；A.396.b.4.i；A.397.b.4.i；A.398.b.4.i；A.399.b.4.i；A.400.b.4.i；A.401.b.4.i；A.402.b.4.i；A.403.b.4.i；A.404.b.4.i；A.405.b.4.i；A.406.b.4.i；A.407.b.4.i；A.408.b.4.i；A.409.b.4.i；A.410.b.4.i；A.411.b.4.i；A.412.b.4.i；A.413.b.4.i；A.414.b.4.i；A.415.b.4.i；A.416.b.4.i；A.417.b.4.i；A.418.b.4.i；A.419.b.4.i；A.420.b.4.i；A.421.b.4.i；A.422.b.4.i；A.423.b.4.i；A.424.b.4.i；A.425.b.4.i；A.426.b.4.i；A.427.b.4.i；A.428.b.4.i；A.429.b.4.i；A.430.b.4.i；A.431.b.4.i；A.432.b.4.i；A.433.b.4.i；A.434.b.4.i；A.435.b.4.i；A.436.b.4.i；A.437.b.4.i；A.438.b.4.i；A.439.b.4.i；A.440.b.4.i；A.441.b.4.i；A.442.b.4.i；A.443.b.4.i；A.444.b.4.i；A.445.b.4.i；A.446.b.4.i；A.447.b.4.i；A.448.b.4.i；A.449.b.4.i；A.450.b.4.i；A.451.b.4.i；A.452.b.4.i；A.453.b.4.i；A.454.b.4.i；A.455.b.4.i；A.456.b.4.i；A.457.b.4.i；A.458.b.4.i；A.459.b.4.i；A.460.b.4.i；A.461.b.4.i；A.462.b.4.i；A.463.b.4.i；A.464.b.4.i；A.465.b.4.i；A.466.b.4.i；A.467.b.4.i；A.468.b.4.i；A.469.b.4.i；A.470.b.4.i；A.471.b.4.i；A.472.b.4.i；A.473.b.4.i；A.474.b.4.i；A.475.b.4.i；A.476.b.4.i；A.477.b.4.i；A.478.b.4.i；A.479.b.4.i；A.480.b.4.i；A.481.b.4.i；A.482.b.4.i；A.483.b.4.i；A.484.b.4.i；A.485.b.4.i；A.486.b.4.i；A.487.b.4.i；A.488.b.4.i；A.489.b.4.i；A.490.b.4.i；A.491.b.4.i；A.492.b.4.i；A.493.b.4.i；A.494.b.4.i；A.495.b.4.i；A.496.b.4.i；A.497.b.4.i；A.498.b.4.i；A.499.b.4.i；A.500.b.4.i；A.501.b.4.i；A.502.b.4.i；A.503.b.4.i；A.504.b.4.i；A.505.b.4.i；A.506.b.4.i；A.507.b.4.i；A.508.b.4.i；A.509.b.4.i；A.510.b.4.i；A.511.b.4.i；A.512.b.4.i；A.512.b.4.i；A.513.b.4.i；A.514.b.4.i；A.515.b.4.i；A.516.b.4.i；A.517.b.4.i；A.518.b.4.i；A.519.b.4.i；A.520.b.4.i；A.521.b.4.i；A.522.b.4.i；A.523.b.4.i；A.524.b.4.i；A.525.b.4.i；A.526.b.4.i；A.527.b.4.i；A.528.b.4.i；A.529.b.4.i；A.530.b.4.i；A.531.b.4.i；A.532.b.4.i；A.533.b.4.i；A.534.b.4.i；A.535.b.4.i；A.536.b.4.i；A.537.b.4.i；A.538.b.4.i；A.539.b.4.i；A.540.b.4.i；A.541.b.4.i；A.542.b.4.i；A.543.b.4.i；A.544.b.4.i；A.545.b.4.i；A.546.b.4.i；A.547.b.4.i；A.548.b.4.i；A.549.b.4.i；A.550.b.4.i；A.551.b.4.i；A.552.b.4.i；A.553.b.4.i；A.554.b.4.i；A.555.b.4.i；A.556.b.4.i；A.557.b.4.i；A.558.b.4.i；A.559.b.4.i；A.560.b.4.i；A.561.b.4.i；A.562.b.4.i；A.563.b.4.i；A.564.b.4.i；A.565.b.4.i；A.566.b.4.i；A.567.b.4.i；A.568.b.4.i；A.569.b.4.i；A.570.b.4.i；A.571.b.4.i；A.572.b.4.i；A.573.b.4.i；A.574.b.4.i；A.575.b.4.i；A.576.b.4.i；A.577.b.4.i；A.578.b.4.i；A.579.b.4.i；A.580.b.4.i；A.581.b.4.i；A.582.b.4.i；A.583.b.4.i；A.584.b.4.i；A.585.b.4.i；A.586.b.4.i；A.587.b.4.i；A.588.b.4.i；A.589.b.4.i；A.590.b.4.i；A.591.b.4.i；A.592.b.4.i；A.593.b.4.i；A.594.b.4.i；A.595.b.4.i；A.596.b.4.i；A.597.b.4.i；A.598.b.4.i；A.599.b.4.i；A.600.b.4.i；A.601.b.4.i；A.602.b.4.i；A.603.b.4.i；A.604.b.4.i；A.605.b.4.i；A.606.b.4.i；A.607.b.4.i；A.608.b.4.i；A.609.b.4.i；A.610.b.4.i；A.611.b.4.i；A.612.b.4.i；A.613.b.4.i；A.614.b.4.i；A.615.b.4.i；A.616.b.4.i；A.617.b.4.i；A.618.b.4.i；A.619.b.4.i；A.620.b.4.i；A.621.b.4.i；A.622.b.4.i；A.623.b.4.i；A.624.b.4.i；A.625.b.4.i；A.626.b.4.i；A.627.b.4.i；A.628.b.4.i；A.629.b.4.i；A.630.b.4.i；A.631.b.4.i；A.632.b.4.i；A.633.b.4.i；A.634.b.4.i；A.635.b.4.i；A.636.b.4.i；
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A.352.b.11.i；A.353.b.11.i；A.354.b.11.i；A.355.b.11.i；A.356.b.11.i；A.357.b.11.i；A.358.b.11.i；A.359.b.11.i；A.360.b.11.i；A.361.b.11.i；A.362.b.11.i；A.363.b.11.i；A.364.b.11.i；A.365.b.11.i；A.366.b.11.i；A.367.b.11.i；A.368.b.11.i；A.369.b.11.i；A.370.b.11.i；A.371.b.11.i；A.372.b.11.i；A.373.b.11.i；A.374.b.11.i；A.375.b.11.i；A.376.b.11.i；A.377.b.11.i；A.378.b.11.i；A.379.b.11.i；A.380.b.11.i；A.381.b.11.i；A.382.b.11.i；A.383.b.11.i；A.384.b.11.i；A.385.b.11.i；A.386.b.11.i；A.387.b.11.i；A.388.b.11.i；A.389.b.11.i；A.390.b.11.i；A.391.b.11.i；A.392.b.11.i；A.393.b.11.i；A.394.b.11.i；A.395.b.11.i；A.396.b.11.i；A.397.b.11.i；A.398.b.11.i；A.399.b.11.i；A.400.b.11.i；A.401.b.11.i；A.402.b.11.i；A.403.b.11.i；A.404.b.11.i；A.405.b.11.i；A.406.b.11.i；A.407.b.11.i；A.408.b.11.i；A.409.b.11.i；A.410.b.11.i；A.411.b.11.i；A.412.b.11.i；A.413.b.11.i；A.414.b.11.i；A.415.b.11.i；A.416.b.11.i；A.417.b.11.i；A.418.b.11.i；A.419.b.11.i；A.420.b.11.i；A.421.b.11.i；A.422.b.11.i；A.423.b.11.i；A.424.b.11.i；A.425.b.11.i；A.426.b.11.i；A.427.b.11.i；A.428.b.11.i；A.429.b.11.i；A.430.b.11.i；A.431.b.11.i；A.432.b.11.i；A.433.b.11.i；A.434.b.11.i；A.435.b.11.i；A.436.b.11.i；A.437.b.11.i；A.438.b.11.i；A.439.b.11.i；A.440.b.11.i；A.441.b.11.i；A.442.b.11.i；A.443.b.11.i；A.444.b.11.i；A.445.b.11.i；A.446.b.11.i；A.447.b.11.i；A.448.b.11.i；A.449.b.11.i；A.450.b.11.i；A.451.b.11.i；A.452.b.11.i；A.453.b.11.i；A.454.b.11.i；A.455.b.11.i；A.456.b.11.i；A.457.b.11.i；A.458.b.11.i；A.459.b.11.i；A.460.b.11.i；A.461.b.11.i；A.462.b.11.i；A.463.b.11.i；A.464.b.11.i；A.465.b.11.i；A.466.b.11.i；A.467.b.11.i；A.468.b.11.i；A.469.b.11.i；A.470.b.11.i；A.471.b.11.i；A.472.b.11.i；A.473.b.11.i；A.474.b.11.i；A.475.b.11.i；A.476.b.11.i；A.477.b.11.i；A.478.b.11.i；A.479.b.11.i；A.480.b.11.i；A.481.b.11.i；A.482.b.11.i；A.483.b.11.i；A.484.b.11.i；A.485.b.11.i；A.486.b.11.i；A.487.b.11.i；A.488.b.11.i；A.489.b.11.i；A.490.b.11.i；A.491.b.11.i；A.492.b.11.i；A.493.b.11.i；A.494.b.11.i；A.495.b.11.i；A.496.b.11.i；A.497.b.11.i；A.498.b.11.i；A.499.b.11.i；A.500.b.11.i；A.501.b.11.i；A.502.b.11.i；A.503.b.11.i；A.504.b.11.i；A.505.b.11.i；A.506.b.11.i；A.507.b.11.i；A.508.b.11.i；A.509.b.11.i；A.510.b.11.i；A.511.b.11.i；A.512.b.11.i；A.512.b.11.i；A.513.b.11.i；A.514.b.11.i；A.515.b.11.i；A.516.b.11.i；A.517.b.11.i；A.518.b.11.i；A.519.b.11.i；A.520.b.11.i；A.521.b.11.i；A.522.b.11.i；A.523.b.11.i；A.524.b.11.i；A.525.b.11.i；A.526.b.11.i；A.527.b.11.i；A.528.b.11.i；A.529.b.11.i；A.530.b.11.i；A.531.b.11.i；A.532.b.11.i；A.533.b.11.i；A.534.b.11.i；A.535.b.11.i；A.536.b.11.i；A.537.b.11.i；A.538.b.11.i；A.539.b.11.i；A.540.b.11.i；A.541.b.11.i；A.542.b.11.i；A.543.b.11.i；A.544.b.11.i；A.545.b.11.i；A.546.b.11.i；A.547.b.11.i；A.548.b.11.i；A.549.b.11.i；A.550.b.11.i；A.551.b.11.i；A.552.b.11.i；A.553.b.11.i；A.554.b.11.i；A.555.b.11.i；A.556.b.11.i；A.557.b.11.i；A.558.b.11.i；A.559.b.11.i；A.560.b.11.i；A.561.b.11.i；A.562.b.11.i；A.563.b.11.i；A.564.b.11.i；A.565.b.11.i；A.566.b.11.i；A.567.b.11.i；A.568.b.11.i；A.569.b.11.i；A.570.b.11.i；A.571.b.11.i；A.572.b.11.i；A.573.b.11.i；A.574.b.11.i；A.575.b.11.i；A.576.b.11.i；A.577.b.11.i；A.578.b.11.i；A.579.b.11.i；A.580.b.11.i；A.581.b.11.i；A.582.b.11.i；A.583.b.11.i；A.584.b.11.i；A.585.b.11.i；A.586.b.11.i；A.587.b.11.i；A.588.b.11.i；A.589.b.11.i；A.590.b.11.i；A.591.b.11.i；A.592.b.11.i；A.593.b.11.i；A.594.b.11.i；A.595.b.11.i；A.596.b.11.i；A.597.b.11.i；A.598.b.11.i；A.599.b.11.i；A.600.b.11.i；A.601.b.11.i；A.602.b.11.i；A.603.b.11.i；A.604.b.11.i；A.605.b.11.i；A.606.b.11.i；A.607.b.11.i；A.608.b.11.i；A.609.b.11.i；A.610.b.11.i；A.611.b.11.i；A.612.b.11.i；A.613.b.11.i；A.614.b.11.i；A.615.b.11.i；A.616.b.11.i；A.617.b.11.i；A.618.b.11.i；A.619.b.11.i；A.620.b.11.i；A.621.b.11.i；A.622.b.11.i；A.623.b.11.i；A.624.b.11.i；A.625.b.11.i；A.626.b.11.i；A.627.b.11.i；A.628.b.11.i；A.629.b.11.i；A.630.b.11.i；A.631.b.11.i；A.632.b.11.i；
A.633.b.11.i；A.634.b.11.i；A.635.b.11.i；A.636.b.11.i；A.637.b.11.i；A.638.b.11.i；A.639.b.11.i；A.640.b.11.i；A.641.b.11.i；A.642.b.11.i；A.643.b.11.i；A.644.b.11.i；A.645.b.11.i；A.646.b.11.i；A.647.b.11.i；A.648.b.11.i；A.649.b.11.i；A.650.b.11.i；A.651.b.11.i；A.652.b.11.i；A.653.b.11.i；A.654.b.11.i；A.655.b.11.i；A.656.b.11.i；A.657.b.11.i；A.658.b.11.i；A.659.b.11.i；A.660.b.11.i；A.2.x.4.i；A.3.x.4.i；A.4.x.4.i；A.5.x.4.i；A.6.x.4.i；A.7.x.4.i；A.9.x.4.i；A.10.x.4.i；A.15.x.4.i；A.100.x.4.i；A.101.x.4.i；A.102.x.4.i；A.103.x.4.i；A.104.x.4.i；A.105.x.4.i；A.106.x.4.i；A.107.x.4.i；A.108.x.4.i；A.109.x.4.i；A.110.x.4.i；A.111.x.4.i；A.112.x.4.i；A.113.x.4.i；A.114.x.4.i；A.115.x.4.i；A.116.x.4.i；A.117.x.4.i；A.118.x.4.i；A.119.x.4.i；A.120.x.4.i；A.121.x.4.i；A.122.x.4.i；A.123.x.4.i；A.124.x.4.i；A.125.x.4.i；A.126.x.4.i；A.127.x.4.i；A.128.x.4.i；A.129.x.4.i；A.130.x.4.i；A.131.x.4.i；A.132.x.4.i；A.133.x.4.i；A.134.x.4.i；A.135.x.4.i；A.136.x.4.i；A.137.x.4.i；A.138.x.4.i；A.139.x.4.i；A.140.x.4.i；A.141.x.4.i；A.142.x.4.i；A.143.x.4.i；A.144.x.4.i；A.145.x.4.i；A.146.x.4.i；A.147.x.4.i；A.148.x.4.i；A.149.x.4.i；A.150.x.4.i；A.151.x.4.i；A.152.x.4.i；A.153.x.4.i；A.154.x.4.i；A.155.x.4.i；A.156.x.4.i；A.157.x.4.i；A.158.x.4.i；A.159.x.4.i；A.160.x.4.i；A.161.x.4.i；A.162.x.4.i；A.163.x.4.i；A.164.x.4.i；A.165.x.4.i；A.166.x.4.i；A.167.x.4.i；A.168.x.4.i；A.169.x.4.i；A.170.x.4.i；A.171.x.4.i；A.172.x.4.i；A.173.x.4.i；A.174.x.4.i；A.175.x.4.i；A.176.x.4.i；A.177.x.4.i；A.178.x.4.i；A.179.x.4.i；A.180.x.4.i；A.181.x.4.i；A.182.x.4.i；A.183.x.4.i；A.184.x.4.i；A.185.x.4.i；A.186.x.4.i；A.187.x.4.i；A.188.x.4.i；A.189.x.4.i；A.190.x.4.i；A.191.x.4.i；A.192.x.4.i；A.193.x.4.i；A.194.x.4.i；A.195.x.4.i；A.196.x.4.i；A.197.x.4.i；A.198.x.4.i；A.199.x.4.i；A.200.x.4.i；A.201.x.4.i；A.202.x.4.i；A.203.x.4.i；A.204.x.4.i；A.205.x.4.i；A.206.x.4.i；A.207.x.4.i；A.208.x.4.i；A.209.x.4.i；A.210.x.4.i；A.211.x.4.i；A.212.x.4.i；A.213.x.4.i；A.214.x.4.i；A.215.x.4.i；A.216.x.4.i；A.217.x.4.i；A.218.x.4.i；A.219.x.4.i；A.220.x.4.i；A.221.x.4.i；A.222.x.4.i；A.223.x.4.i；A.224.x.4.i；A.225.x.4.i；A.226.x.4.i；A.227.x.4.i；A.228.x.4.i；A.229.x.4.i；A.230.x.4.i；A.231.x.4.i；A.232.x.4.i；A.233.x.4.i；A.234.x.4.i；A.235.x.4.i；A.236.x.4.i；A.237.x.4.i；A.238.x.4.i；A.239.x.4.i；A.240.x.4.i；A.241.x.4.i；A.242.x.4.i；A.243.x.4.i；A.244.x.4.i；A.245.x.4.i；A.246.x.4.i；A.247.x.4.i；A.248.x.4.i；A.249.x.4.i；A.250.x.4.i；A.251.x.4.i；A.252.x.4.i；A.253.x.4.i；A.254.x.4.i；A.255.x.4.i；A.256.x.4.i；A.257.x.4.i；A.258.x.4.i；A.259.x.4.i；A.260.x.4.i；A.261.x.4.i；A.262.x.4.i；A.263.x.4.i；A.264.x.4.i；A.265.x.4.i；A.266.x.4.i；A.267.x.4.i；A.268.x.4.i；A.269.x.4.i；A.270.x.4.i；A.271.x.4.i；A.272.x.4.i；A.273.x.4.i；A.274.x.4.i；A.275.x.4.i；A.276.x.4.i；A.277.x.4.i；A.278.x.4.i；A.279.x.4.i；A.280.x.4.i；A.281.x.4.i；A.282.x.4.i；A.283.x.4.i；A.284.x.4.i；A.285.x.4.i；A.286.x.4.i；A.287.x.4.i；A.288.x.4.i；A.289.x.4.i；A.290.x.4.i；A.291.x.4.i；A.292.x.4.i；A.293.x.4.i；A.294.x.4.i；A.295.x.4.i；A.296.x.4.i；A.297.x.4.i；A.298.x.4.i；A.299.x.4.i；A.300.x.4.i；A.301.x.4.i；A.302.x.4.i；A.303.x.4.i；A.304.x.4.i；A.305.x.4.i；A.306.x.4.i；A.307.x.4.i；A.308.x.4.i；A.309.x.4.i；A.310.x.4.i；A.311.x.4.i；A.312.x.4.i；A.313.x.4.i；A.314.x.4.i；A.315.x.4.i；A.316.x.4.i；A.317.x.4.i；A.318.x.4.i；A.319.x.4.i；A.320.x.4.i；A.321.x.4.i；A.323.x.4.i；A.324.x.4.i；A.325.x.4.i；A.326.x.4.i；A.327.x.4.i；A.328.x.4.i；A.329.x.4.i；A.330.x.4.i；A.331.x.4.i；A.332.x.4.i；A.333.x.4.i；A.334.x.4.i；A.335.x.4.i；A.336.x.4.i；A.337.x.4.i；A.338.x.4.i；A.339.x.4.i；A.340.x.4.i；A.341.x.4.i；A.342.x.4.i；A.343.x.4.i；A.344.x.4.i；A.345.x.4.i；A.346.x.4.i；A.347.x.4.i；
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A.624.x.11.i；A.625.x.11.i；A.626.x.11.i；A.627.x.11.i；A.628.x.11.i；A.629.x.11.i；A.630.x.11.i；A.631.x.11.i；A.632.x.11.i；A.633.x.11.i；A.634.x.11.i；A.635.x.11.i；A.636.x.11.i；A.637.x.11.i；A.638.x.11.i；A.639.x.11.i；A.640.x.11.i；A.641.x.11.i；A.642.x.11.i；A.643.x.11.i；A.644.x.11.i；A.645.x.11.i；A.646.x.11.i；A.647.x.11.i；A.648.x.11.i；A.649.x.11.i；A.650.x.11.i；A.651.x.11.i；A.652.x.11.i；A.653.x.11.i；A.654.x.11.i；A.655.x.11.i；A.656.x.11.i；A.657.x.11.i；A.658.x.11.i；A.659.x.11.i；A.660.x.11.i；A.2.y.4.i；A.3.y.4.i；A.4.y.4.i；A.5.y.4.i；A.6.y.4.i；A.7.y.4.i；A.9.y.4.i；A.10.y.4.i；A.15.y.4.i；A.100.y.4.i；A.101.y.4.i；A.102.y.4.i；A.103.y.4.i；A.104.y.4.i；A.105.y.4.i；A.106.y.4.i；A.107.y.4.i；A.108.y.4.i；A.109.y.4.i；A.110.y.4.i；A.111.y.4.i；A.112.y.4.i；A.113.y.4.i；A.114.y.4.i；A.115.y.4.i；A.116.y.4.i；A.117.y.4.i；A.118.y.4.i；A.119.y.4.i；A.120.y.4.i；A.121.y.4.i；A.122.y.4.i；A.123.y.4.i；A.124.y.4.i；A.125.y.4.i；A.126.y.4.i；A.127.y.4.i；A.128.y.4.i；A.129.y.4.i；A.130.y.4.i；A.131.y.4.i；A.132.y.4.i；A.133.y.4.i；A.134.y.4.i；A.135.y.4.i；A.136.y.4.i；A.137.y.4.i；A.138.y.4.i；A.139.y.4.i；A.140.y.4.i；A.141.y.4.i；A.142.y.4.i；A.143.y.4.i；A.144.y.4.i；A.145.y.4.i；A.146.y.4.i；A.147.y.4.i；A.148.y.4.i；A.149.y.4.i；A.150.y.4.i；A.151.y.4.i；A.152.y.4.i；A.153.y.4.i；A.154.y.4.i；A.155.y.4.i；A.156.y.4.i；A.157.y.4.i；A.158.y.4.i；A.159.y.4.i；A.160.y.4.i；A.161.y.4.i；A.162.y.4.i；A.163.y.4.i；A.164.y.4.i；A.165.y.4.i；A.166.y.4.i；A.167.y.4.i；A.168.y.4.i；A.169.y.4.i；A.170.y.4.i；A.171.y.4.i；A.172.y.4.i；A.173.y.4.i；A.174.y.4.i；A.175.y.4.i；A.176.y.4.i；A.177.y.4.i；A.178.y.4.i；A.179.y.4.i；A.180.y.4.i；A.181.y.4.i；A.182.y.4.i；A.183.y.4.i；A.184.y.4.i；A.185.y.4.i；A.186.y.4.i；A.187.y.4.i；A.188.y.4.i；A.189.y.4.i；A.190.y.4.i；A.191.y.4.i；A.192.y.4.i；A.193.y.4.i；A.194.y.4.i；A.195.y.4.i；A.196.y.4.i；A.197.y.4.i；A.198.y.4.i；A.199.y.4.i；A.200.y.4.i；A.201.y.4.i；A.202.y.4.i；A.203.y.4.i；A.204.y.4.i；A.205.y.4.i；A.206.y.4.i；A.207.y.4.i；A.208.y.4.i；A.209.y.4.i；A.210.y.4.i；A.211.y.4.i；A.212.y.4.i；A.213.y.4.i；A.214.y.4.i；A.215.y.4.i；A.216.y.4.i；A.217.y.4.i；A.218.y.4.i；A.219.y.4.i；A.220.y.4.i；A.221.y.4.i；A.222.y.4.i；A.223.y.4.i；A.224.y.4.i；A.225.y.4.i；A.226.y.4.i；A.227.y.4.i；A.228.y.4.i；A.229.y.4.i；A.230.y.4.i；A.231.y.4.i；A.232.y.4.i；A.233.y.4.i；A.234.y.4.i；A.235.y.4.i；A.236.y.4.i；A.237.y.4.i；A.238.y.4.i；A.239.y.4.i；A.240.y.4.i；A.241.y.4.i；A.242.y.4.i；A.243.y.4.i；A.244.y.4.i；A.245.y.4.i；A.246.y.4.i；A.247.y.4.i；A.248.y.4.i；A.249.y.4.i；A.250.y.4.i；A.251.y.4.i；A.252.y.4.i；A.253.y.4.i；A.254.y.4.i；A.255.y.4.i；A.256.y.4.i；A.257.y.4.i；A.258.y.4.i；A.259.y.4.i；A.260.y.4.i；A.261.y.4.i；A.262.y.4.i；A.263.y.4.i；A.264.y.4.i；A.265.y.4.i；A.266.y.4.i；A.267.y.4.i；A.268.y.4.i；A.269.y.4.i；A.270.y.4.i；A.271.y.4.i；A.272.y.4.i；A.273.y.4.i；A.274.y.4.i；A.275.y.4.i；A.276.y.4.i；A.277.y.4.i；A.278.y.4.i；A.279.y.4.i；A.280.y.4.i；A.281.y.4.i；A.282.y.4.i；A.283.y.4.i；A.284.y.4.i；A.285.y.4.i；A.286.y.4.i；A.287.y.4.i；A.288.y.4.i；A.289.y.4.i；A.290.y.4.i；A.291.y.4.i；A.292.y.4.i；A.293.y.4.i；A.294.y.4.i；A.295.y.4.i；A.296.y.4.i；A.297.y.4.i；A.298.y.4.i；A.299.y.4.i；A.300.y.4.i；A.301.y.4.i；A.302.y.4.i；A.303.y.4.i；A.304.y.4.i；A.305.y.4.i；A.306.y.4.i；A.307.y.4.i；A.308.y.4.i；A.309.y.4.i；A.310.y.4.i；A.311.y.4.i；A.312.y.4.i；A.313.y.4.i；A.314.y.4.i；A.315.y.4.i；A.316.y.4.i；A.317.y.4.i；A.318.y.4.i；A.319.y.4.i；A.320.y.4.i；A.321.y.4.i；A.323.y.4.i；A.324.y.4.i；A.325.y.4.i；A.326.y.4.i；A.327.y.4.i；A.328.y.4.i；A.329.y.4.i；A.330.y.4.i；A.331.y.4.i；A.332.y.4.i；A.333.y.4.i；A.334.y.4.i；A.335.y.4.i；A.336.y.4.i；A.337.y.4.i；A.338.y.4.i；A.339.y.4.i；
A.340.y.4.i；A.341.y.4.i；A.342.y.4.i；A.343.y.4.i；A.344.y.4.i；A.345.y.4.i；A.346.y.4.i；A.347.y.4.i；A.348.y.4.i；A.349.y.4.i；A.350.y.4.i；A.351.y.4.i；A.352.y.4.i；A.353.y.4.i；A.354.y.4.i；A.355.y.4.i；A.356.y.4.i；A.357.y.4.i；A.358.y.4.i；A.359.y.4.i；A.360.y.4.i；A.361.y.4.i；A.362.y.4.i；A.363.y.4.i；A.364.y.4.i；A.365.y.4.i；A.366.y.4.i；A.367.y.4.i；A.368.y.4.i；A.369.y.4.i；A.370.y.4.i；A.371.y.4.i；A.372.y.4.i；A.373.y.4.i；A.374.y.4.i；A.375.y.4.i；A.376.y.4.i；A.377.y.4.i；A.378.y.4.i；A.379.y.4.i；A.380.y.4.i；A.381.y.4.i；A.382.y.4.i；A.383.y.4.i；A.384.y.4.i；A.385.y.4.i；A.386.y.4.i；A.387.y.4.i；A.388.y.4.i；A.389.y.4.i；A.390.y.4.i；A.391.y.4.i；A.392.y.4.i；A.393.y.4.i；A.394.y.4.i；A.395.y.4.i；A.396.y.4.i；A.397.y.4.i；A.398.y.4.i；A.399.y.4.i；A.400.y.4.i；A.401.y.4.i；A.402.y.4.i；A.403.y.4.i；A.404.y.4.i；A.405.y.4.i；A.406.y.4.i；A.407.y.4.i；A.408.y.4.i；A.409.y.4.i；A.410.y.4.i；A.411.y.4.i；A.412.y.4.i；A.413.y.4.i；A.414.y.4.i；A.415.y.4.i；A.416.y.4.i；A.417.y.4.i；A.418.y.4.i；A.419.y.4.i；A.420.y.4.i；A.421.y.4.i；A.422.y.4.i；A.423.y.4.i；A.424.y.4.i；A.425.y.4.i；A.426.y.4.i；A.427.y.4.i；A.428.y.4.i；A.429.y.4.i；A.430.y.4.i；A.431.y.4.i；A.432.y.4.i；A.433.y.4.i；A.434.y.4.i；A.435.y.4.i；A.436.y.4.i；A.437.y.4.i；A.438.y.4.i；A.439.y.4.i；A.440.y.4.i；A.441.y.4.i；A.442.y.4.i；A.443.y.4.i；A.444.y.4.i；A.445.y.4.i；A.446.y.4.i；A.447.y.4.i；A.448.y.4.i；A.449.y.4.i；A.450.y.4.i；A.451.y.4.i；A.452.y.4.i；A.453.y.4.i；A.454.y.4.i；A.455.y.4.i；A.456.y.4.i；A.457.y.4.i；A.458.y.4.i；A.459.y.4.i；A.460.y.4.i；A.461.y.4.i；A.462.y.4.i；A.463.y.4.i；A.464.y.4.i；A.465.y.4.i；A.466.y.4.i；A.467.y.4.i；A.468.y.4.i；A.469.y.4.i；A.470.y.4.i；A.471.y.4.i；A.472.y.4.i；A.473.y.4.i；A.474.y.4.i；A.475.y.4.i；A.476.y.4.i；A.477.y.4.i；A.478.y.4.i；A.479.y.4.i；A.480.y.4.i；A.481.y.4.i；A.482.y.4.i；A.483.y.4.i；A.484.y.4.i；A.485.y.4.i；A.486.y.4.i；A.487.y.4.i；A.488.y.4.i；A.489.y.4.i；A.490.y.4.i；A.491.y.4.i；A.492.y.4.i；A.493.y.4.i；A.494.y.4.i；A.495.y.4.i；A.496.y.4.i；A.497.y.4.i；A.498.y.4.i；A.499.y.4.i；A.500.y.4.i；A.501.y.4.i；A.502.y.4.i；A.503.y.4.i；A.504.y.4.i；A.505.y.4.i；A.506.y.4.i；A.507.y.4.i；A.508.y.4.i；A.509.y.4.i；A.510.y.4.i；A.511.y.4.i；A.512.y.4.i；A.512.y.4.i；A.513.y.4.i；A.514.y.4.i；A.515.y.4.i；A.516.y.4.i；A.517.y.4.i；A.518.y.4.i；A.519.y.4.i；A.520.y.4.i；A.521.y.4.i；A.522.y.4.i；A.523.y.4.i；A.524.y.4.i；A.525.y.4.i；A.526.y.4.i；A.527.y.4.i；A.528.y.4.i；A.529.y.4.i；A.530.y.4.i；A.531.y.4.i；A.532.y.4.i；A.533.y.4.i；A.534.y.4.i；A.535.y.4.i；A.536.y.4.i；A.537.y.4.i；A.538.y.4.i；A.539.y.4.i；A.540.y.4.i；A.541.y.4.i；A.542.y.4.i；A.543.y.4.i；A.544.y.4.i；A.545.y.4.i；A.546.y.4.i；A.547.y.4.i；A.548.y.4.i；A.549.y.4.i；A.550.y.4.i；A.551.y.4.i；A.552.y.4.i；A.553.y.4.i；A.554.y.4.i；A.555.y.4.i；A.556.y.4.i；A.557.y.4.i；A.558.y.4.i；A.559.y.4.i；A.560.y.4.i；A.561.y.4.i；A.562.y.4.i；A.563.y.4.i；A.564.y.4.i；A.565.y.4.i；A.566.y.4.i；A.567.y.4.i；A.568.y.4.i；A.569.y.4.i；A.570.y.4.i；A.571.y.4.i；A.572.y.4.i；A.573.y.4.i；A.574.y.4.i；A.575.y.4.i；A.576.y.4.i；A.577.y.4.i；A.578.y.4.i；A.579.y.4.i；A.580.y.4.i；A.581.y.4.i；A.582.y.4.i；A.583.y.4.i；A.584.y.4.i；A.585.y.4.i；A.586.y.4.i；A.587.y.4.i；A.588.y.4.i；A.589.y.4.i；A.590.y.4.i；A.591.y.4.i；A.592.y.4.i；A.593.y.4.i；A.594.y.4.i；A.595.y.4.i；A.596.y.4.i；A.597.y.4.i；A.598.y.4.i；A.599.y.4.i；A.600.y.4.i；A.601.y.4.i；A.602.y.4.i；A.603.y.4.i；A.604.y.4.i；A.605.y.4.i；A.606.y.4.i；A.607.y.4.i；A.608.y.4.i；A.609.y.4.i；A.610.y.4.i；A.611.y.4.i；A.612.y.4.i；A.613.y.4.i；A.614.y.4.i；A.615.y.4.i；A.616.y.4.i；A.617.y.4.i；A.618.y.4.i；A.619.y.4.i；A.620.y.4.i；
A.621.y.4.i；A.622.y.4.i；A.623.y.4.i；A.624.y.4.i；A.625.y.4.i；A.626.y.4.i；A.627.y.4.i；A.628.y.4.i；A.629.y.4.i；A.630.y.4.i；A.631.y.4.i；A.632.y.4.i；A.633.y.4.i；A.634.y.4.i；A.635.y.4.i；A.636.y.4.i；A.637.y.4.i；A.638.y.4.i；A.639.y.4.i；A.640.y.4.i；A.641.y.4.i；A.642.y.4.i；A.643.y.4.i；A.644.y.4.i；A.645.y.4.i；A.646.y.4.i；A.647.y.4.i；A.648.y.4.i；A.649.y.4.i；A.650.y.4.i；A.651.y.4.i；A.652.y.4.i；A.653.y.4.i；A.654.y.4.i；A.655.y.4.i；A.656.y.4.i；A.657.y.4.i；A.658.y.4.i；A.659.y.4.i；A.660.y.4.i；A.2.y.11.i；A.3.y.11.i；A.4.y.11.i；A.5.y.11.i；A.6.y.11.i；A.7.y.11.i；A.9.y.11.i；A.10.y.11.i；A.15.y.11.i；A.100.y.11.i；A.101.y.11.i；A.102.y.11.i；A.103.y.11.i；A.104.y.11.i；A.105.y.11.i；A.106.y.11.i；A.107.y.11.i；A.108.y.11.i；A.109.y.11.i；A.110.y.11.i；A.111.y.11.i；A.112.y.11.i；A.113.y.11.i；A.114.y.11.i；A.115.y.11.i；A.116.y.11.i；A.117.y.11.i；A.118.y.11.i；A.119.y.11.i；A.120.y.11.i；A.121.y.11.i；A.122.y.11.i；A.123.y.11.i；A.124.y.11.i；A.125.y.11.i；A.126.y.11.i；A.127.y.11.i；A.128.y.11.i；A.129.y.11.i；A.130.y.11.i；A.131.y.11.i；A.132.y.11.i；A.133.y.11.i；A.134.y.11.i；A.135.y.11.i；A.136.y.11.i；A.137.y.11.i；A.138.y.11.i；A.139.y.11.i；A.140.y.11.i；A.141.y.11.i；A.142.y.11.i；A.143.y.11.i；A.144.y.11.i；A.145.y.11.i；A.146.y.11.i；A.147.y.11.i；A.148.y.11.i；A.149.y.11.i；A.150.y.11.i；A.151.y.11.i；A.152.y.11.i；A.153.y.11.i；A.154.y.11.i；A.155.y.11.i；A.156.y.11.i；A.157.y.11.i；A.158.y.11.i；A.159.y.11.i；A.160.y.11.i；A.161.y.11.i；A.162.y.11.i；A.163.y.11.i；A.164.y.11.i；A.165.y.11.i；A.166.y.11.i；A.167.y.11.i；A.168.y.11.i；A.169.y.11.i；A.170.y.11.i；A.171.y.11.i；A.172.y.11.i；A.173.y.11.i；A.174.y.11.i；A.175.y.11.i；A.176.y.11.i；A.177.y.11.i；A.178.y.11.i；A.179.y.11.i；A.180.y.11.i；A.181.y.11.i；A.182.y.11.i；A.183.y.11.i；A.184.y.11.i；A.185.y.11.i；A.186.y.11.i；A.187.y.11.i；A.188.y.11.i；A.189.y.11.i；A.190.y.11.i；A.191.y.11.i；A.192.y.11.i；A.193.y.11.i；A.194.y.11.i；A.195.y.11.i；A.196.y.11.i；A.197.y.11.i；A.198.y.11.i；A.199.y.11.i；A.200.y.11.i；A.201.y.11.i；A.202.y.11.i；A.203.y.11.i；A.204.y.11.i；A.205.y.11.i；A.206.y.11.i；A.207.y.11.i；A.208.y.11.i；A.209.y.11.i；A.210.y.11.i；A.211.y.11.i；A.212.y.11.i；A.213.y.11.i；A.214.y.11.i；A.215.y.11.i；A.216.y.11.i；A.217.y.11.i；A.218.y.11.i；A.219.y.11.i；A.220.y.11.i；A.221.y.11.i；A.222.y.11.i；A.223.y.11.i；A.224.y.11.i；A.225.y.11.i；A.226.y.11.i；A.227.y.11.i；A.228.y.11.i；A.229.y.11.i；A.230.y.11.i；A.231.y.11.i；A.232.y.11.i；A.233.y.11.i；A.234.y.11.i；A.235.y.11.i；A.236.y.11.i；A.237.y.11.i；A.238.y.11.i；A.239.y.11.i；A.240.y.11.i；A.241.y.11.i；A.242.y.11.i；A.243.y.11.i；A.244.y.11.i；A.245.y.11.i；A.246.y.11.i；A.247.y.11.i；A.248.y.11.i；A.249.y.11.i；A.250.y.11.i；A.251.y.11.i；A.252.y.11.i；A.253.y.11.i；A.254.y.11.i；A.255.y.11.i；A.256.y.11.i；A.257.y.11.i；A.258.y.11.i；A.259.y.11.i；A.260.y.11.i；A.261.y.11.i；A.262.y.11.i；A.263.y.11.i；A.264.y.11.i；A.265.y.11.i；A.266.y.11.i；A.267.y.11.i；A.268.y.11.i；A.269.y.11.i；A.270.y.11.i；A.271.y.11.i；A.272.y.11.i；A.273.y.11.i；A.274.y.11.i；A.275.y.11.i；A.276.y.11.i；A.277.y.11.i；A.278.y.11.i；A.279.y.11.i；A.280.y.11.i；A.281.y.11.i；A.282.y.11.i；A.283.y.11.i；A.284.y.11.i；A.285.y.11.i；A.286.y.11.i；A.287.y.11.i；A.288.y.11.i；A.289.y.11.i；A.290.y.11.i；A.291.y.11.i；A.292.y.11.i；A.293.y.11.i；A.294.y.11.i；A.295.y.11.i；A.296.y.11.i；A.297.y.11.i；A.298.y.11.i；A.299.y.11.i；A.300.y.11.i；A.301.y.11.i；A.302.y.11.i；A.303.y.11.i；A.304.y.11.i；A.305.y.11.i；A.306.y.11.i；A.307.y.11.i；A.308.y.11.i；A.309.y.11.i；A.310.y.11.i；A.311.y.11.i；A.312.y.11.i；A.313.y.11.i；A.314.y.11.i；A.315.y.11.i；A.316.y.11.i；A.317.y.11.i；A.318.y.11.i；A.319.y.11.i；A.320.y.11.i；A.321.y.11.i；A.323.y.11.i；A.324.y.11.i；A.325.y.11.i；A.326.y.11.i；A.327.y.11.i；A.328.y.11.i；A.329.y.11.i；A.330.y.11.i；A.331.y.11.i；A.332.y.11.i；A.333.y.11.i；A.334.y.11.i；A.335.y.11.i；
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A.328.z.11.i；A.329.z.11.i；A.330.z.11.i；A.331.z.11.i；A.332.z.11.i；A.333.z.11.i；A.334.z.11.i；A.335.z.11.i；A.336.z.11.i；A.337.z.11.i；A.338.z.11.i；A.339.z.11.i；A.340.z.11.i；A.341.z.11.i；A.342.z.11.i；A.343.z.11.i；A.344.z.11.i；A.345.z.11.i；A.346.z.11.i；A.347.z.11.i；A.348.z.11.i；A.349.z.11.i；A.350.z.11.i；A.351.z.11.i；A.352.z.11.i；A.353.z.11.i；A.354.z.11.i；A.355.z.11.i；A.356.z.11.i；A.357.z.11.i；A.358.z.11.i；A.359.z.11.i；A.360.z.11.i；A.361.z.11.i；A.362.z.11.i；A.363.z.11.i；A.364.z.11.i；A.365.z.11.i；A.366.z.11.i；A.367.z.11.i；A.368.z.11.i；A.369.z.11.i；A.370.z.11.i；A.371.z.11.i；A.372.z.11.i；A.373.z.11.i；A.374.z.11.i；A.375.z.11.i；A.376.z.11.i；A.377.z.11.i；A.378.z.11.i；A.379.z.11.i；A.380.z.11.i；A.381.z.11.i；A.382.z.11.i；A.383.z.11.i；A.384.z.11.i；A.385.z.11.i；A.386.z.11.i；A.387.z.11.i；A.388.z.11.i；A.389.z.11.i；A.390.z.11.i；A.391.z.11.i；A.392.z.11.i；A.393.z.11.i；A.394.z.11.i；A.395.z.11.i；A.396.z.11.i；A.397.z.11.i；A.398.z.11.i；A.399.z.11.i；A.400.z.11.i；A.401.z.11.i；A.402.z.11.i；A.403.z.11.i；A.404.z.11.i；A.405.z.11.i；A.406.z.11.i；A.407.z.11.i；A.408.z.11.i；A.409.z.11.i；A.410.z.11.i；A.411.z.11.i；A.412.z.11.i；A.413.z.11.i；A.414.z.11.i；A.415.z.11.i；A.416.z.11.i；A.417.z.11.i；A.418.z.11.i；A.419.z.11.i；A.420.z.11.i；A.421.z.11.i；A.422.z.11.i；A.423.z.11.i；A.424.z.11.i；A.425.z.11.i；A.426.z.11.i；A.427.z.11.i；A.428.z.11.i；A.429.z.11.i；A.430.z.11.i；A.431.z.11.i；A.432.z.11.i；A.433.z.11.i；A.434.z.11.i；A.435.z.11.i；A.436.z.11.i；A.437.z.11.i；A.438.z.11.i；A.439.z.11.i；A.440.z.11.i；A.441.z.11.i；A.442.z.11.i；A.443.z.11.i；A.444.z.11.i；A.445.z.11.i；A.446.z.11.i；A.447.z.11.i；A.448.z.11.i；A.449.z.11.i；A.450.z.11.i；A.451.z.11.i；A.452.z.11.i；A.453.z.11.i；A.454.z.11.i；A.455.z.11.i；A.456.z.11.i；A.457.z.11.i；A.458.z.11.i；A.459.z.11.i；A.460.z.11.i；A.461.z.11.i；A.462.z.11.i；A.463.z.11.i；A.464.z.11.i；A.465.z.11.i；A.466.z.11.i；A.467.z.11.i；A.468.z.11.i；A.469.z.11.i；A.470.z.11.i；A.471.z.11.i；A.472.z.11.i；A.473.z.11.i；A.474.z.11.i；A.475.z.11.i；A.476.z.11.i；A.477.z.11.i；A.478.z.11.i；A.479.z.11.i；A.480.z.11.i；A.481.z.11.i；A.482.z.11.i；A.483.z.11.i；A.484.z.11.i；A.485.z.11.i；A.486.z.11.i；A.487.z.11.i；A.488.z.11.i；A.489.z.11.i；A.490.z.11.i；A.491.z.11.i；A.492.z.11.i；A.493.z.11.i；A.494.z.11.i；A.495.z.11.i；A.496.z.11.i；A.497.z.11.i；A.498.z.11.i；A.499.z.11.i；A.500.z.11.i；A.501.z.11.i；A.502.z.11.i；A.503.z.11.i；A.504.z.11.i；A.505.z.11.i；A.506.z.11.i；A.507.z.11.i；A.508.z.11.i；A.509.z.11.i；A.510.z.11.i；A.511.z.11.i；A.512.z.11.i；A.512.z.11.i；A.513.z.11.i；A.514.z.11.i；A.515.z.11.i；A.516.z.11.i；A.517.z.11.i；A.518.z.11.i；A.519.z.11.i；A.520.z.11.i；A.521.z.11.i；A.522.z.11.i；A.523.z.11.i；A.524.z.11.i；A.525.z.11.i；A.526.z.11.i；A.527.z.11.i；A.528.z.11.i；A.529.z.11.i；A.530.z.11.i；A.531.z.11.i；A.532.z.11.i；A.533.z.11.i；A.534.z.11.i；A.535.z.11.i；A.536.z.11.i；A.537.z.11.i；A.538.z.11.i；A.539.z.11.i；A.540.z.11.i；A.541.z.11.i；A.542.z.11.i；A.543.z.11.i；A.544.z.11.i；A.545.z.11.i；A.546.z.11.i；A.547.z.11.i；A.548.z.11.i；A.549.z.11.i；A.550.z.11.i；A.551.z.11.i；A.552.z.11.i；A.553.z.11.i；A.554.z.11.i；A.555.z.11.i；A.556.z.11.i；A.557.z.11.i；A.558.z.11.i；A.559.z.11.i；A.560.z.11.i；A.561.z.11.i；A.562.z.11.i；A.563.z.11.i；A.564.z.11.i；A.565.z.11.i；A.566.z.11.i；A.567.z.11.i；A.568.z.11.i；A.569.z.11.i；A.570.z.11.i；A.571.z.11.i；A.572.z.11.i；A.573.z.11.i；A.574.z.11.i；A.575.z.11.i；A.576.z.11.i；A.577.z.11.i；A.578.z.11.i；A.579.z.11.i；A.580.z.11.i；A.581.z.11.i；A.582.z.11.i；A.583.z.11.i；A.584.z.11.i；A.585.z.11.i；A.586.z.11.i；A.587.z.11.i；A.588.z.11.i；A.589.z.11.i；A.590.z.11.i；A.591.z.11.i；A.592.z.11.i；A.593.z.11.i；A.594.z.11.i；A.595.z.11.i；A.596.z.11.i；A.597.z.11.i；A.598.z.11.i；A.599.z.11.i；A.600.z.11.i；A.601.z.11.i；A.602.z.11.i；A.603.z.11.i；A.604.z.11.i；A.605.z.11.i；A.606.z.11.i；A.607.z.11.i；A.608.z.11.i；
A.609.z.11.i；A.610.z.11.i；A.611.z.11.i；A.612.z.11.i；A.613.z.11.i；A.614.z.11.i；A.615.z.11.i；A.616.z.11.i；A.617.z.11.i；A.618.z.11.i；A.619.z.11.i；A.620.z.11.i；A.621.z.11.i；A.622.z.11.i；A.623.z.11.i；A.624.z.11.i；A.625.z.11.i；A.626.z.11.i；A.627.z.11.i；A.628.z.11.i；A.629.z.11.i；A.630.z.11.i；A.631.z.11.i；A.632.z.11.i；A.633.z.11.i；A.634.z.11.i；A.635.z.11.i；A.636.z.11.i；A.637.z.11.i；A.638.z.11.i；A.639.z.11.i；A.640.z.11.i；A.641.z.11.i；A.642.z.11.i；A.643.z.11.i；A.644.z.11.i；A.645.z.11.i；A.646.z.11.i；A.647.z.11.i；A.648.z.11.i；A.649.z.11.i；A.650.z.11.i；A.651.z.11.i；A.652.z.11.i；A.653.z.11.i；A.654.z.11.i；A.655.z.11.i；A.656.z.11.i；A.657.z.11.i；A.658.z.11.i；A.659.z.11.i；A.660.z.11.i；A.2.A.4.i；A.3.A.4.i；A.4.A.4.i；A.5.A.4.i；A.6.A.4.i；A.7.A.4.i；A.9.A.4.i；A.10.A.4.i；A.15.A.4.i；A.100.A.4.i；A.101.A.4.i；A.102.A.4.i；A.103.A.4.i；A.104.A.4.i；A.105.A.4.i；A.106.A.4.i；A.107.A.4.i；A.108.A.4.i；A.109.A.4.i；A.110.A.4.i；A.111.A.4.i；A.112.A.4.i；A.113.A.4.i；A.114.A.4.i；A.115.A.4.i；A.116.A.4.i；A.117.A.4.i；A.118.A.4.i；A.119.A.4.i；A.120.A.4.i；A.121.A.4.i；A.122.A.4.i；A.123.A.4.i；A.124.A.4.i；A.125.A.4.i；A.126.A.4.i；A.127.A.4.i；A.128.A.4.i；A.129.A.4.i；A.130.A.4.i；A.131.A.4.i；A.132.A.4.i；A.133.A.4.i；A.134.A.4.i；A.135.A.4.i；A.136.A.4.i；A.137.A.4.i；A.138.A.4.i；A.139.A.4.i；A.140.A.4.i；A.141.A.4.i；A.142.A.4.i；A.143.A.4.i；A.144.A.4.i；A.145.A.4.i；A.146.A.4.i；A.147.A.4.i；A.148.A.4.i；A.149.A.4.i；A.150.A.4.i；A.151.A.4.i；A.152.A.4.i；A.153.A.4.i；A.154.A.4.i；A.155.A.4.i；A.156.A.4.i；A.157.A.4.i；A.158.A.4.i；A.159.A.4.i；A.160.A.4.i；A.161.A.4.i；A.162.A.4.i；A.163.A.4.i；A.164.A.4.i；A.165.A.4.i；A.166.A.4.i；A.167.A.4.i；A.168.A.4.i；A.169.A.4.i；A.170.A.4.i；A.171.A.4.i；A.172.A.4.i；A.173.A.4.i；A.174.A.4.i；A.175.A.4.i；A.176.A.4.i；A.177.A.4.i；A.178.A.4.i；A.179.A.4.i；A.180.A.4.i；A.181.A.4.i；A.182.A.4.i；A.183.A.4.i；A.184.A.4.i；A.185.A.4.i；A.186.A.4.i；A.187.A.4.i；A.188.A.4.i；A.189.A.4.i；A.190.A.4.i；A.191.A.4.i；A.192.A.4.i；A.193.A.4.i；A.194.A.4.i；A.195.A.4.i；A.196.A.4.i；A.197.A.4.i；A.198.A.4.i；A.199.A.4.i；A.200.A.4.i；A.201.A.4.i；A.202.A.4.i；A.203.A.4.i；A.204.A.4.i；A.205.A.4.i；A.206.A.4.i；A.207.A.4.i；A.208.A.4.i；A.209.A.4.i；A.210.A.4.i；A.211.A.4.i；A.212.A.4.i；A.213.A.4.i；A.214.A.4.i；A.215.A.4.i；A.216.A.4.i；A.217.A.4.i；A.218.A.4.i；A.219.A.4.i；A.220.A.4.i；A.221.A.4.i；A.222.A.4.i；A.223.A.4.i；A.224.A.4.i；A.225.A.4.i；A.226.A.4.i；A.227.A.4.i；A.228.A.4.i；A.229.A.4.i；A.230.A.4.i；A.231.A.4.i；A.232.A.4.i；A.233.A.4.i；A.234.A.4.i；A.235.A.4.i；A.236.A.4.i；A.237.A.4.i；A.238.A.4.i；A.239.A.4.i；A.240.A.4.i；A.241.A.4.i；A.242.A.4.i；A.243.A.4.i；A.244.A.4.i；A.245.A.4.i；A.246.A.4.i；A.247.A.4.i；A.248.A.4.i；A.249.A.4.i；A.250.A.4.i；A.251.A.4.i；A.252.A.4.i；A.253.A.4.i；A.254.A.4.i；A.255.A.4.i；A.256.A.4.i；A.257.A.4.i；A.258.A.4.i；A.259.A.4.i；A.260.A.4.i；A.261.A.4.i；A.262.A.4.i；A.263.A.4.i；A.264.A.4.i；A.265.A.4.i；A.266.A.4.i；A.267.A.4.i；A.268.A.4.i；A.269.A.4.i；A.270.A.4.i；A.271.A.4.i；A.272.A.4.i；A.273.A.4.i；A.274.A.4.i；A.275.A.4.i；A.276.A.4.i；A.277.A.4.i；A.278.A.4.i；A.279.A.4.i；A.280.A.4.i；A.281.A.4.i；A.282.A.4.i；A.283.A.4.i；A.284.A.4.i；A.285.A.4.i；A.286.A.4.i；A.287.A.4.i；A.288.A.4.i；A.289.A.4.i；A.290.A.4.i；A.291.A.4.i；A.292.A.4.i；A.293.A.4.i；A.294.A.4.i；A.295.A.4.i；A.296.A.4.i；A.297.A.4.i；A.298.A.4.i；A.299.A.4.i；A.300.A.4.i；A.301.A.4.i；A.302.A.4.i；A.303.A.4.i；A.304.A.4.i；A.305.A.4.i；A.306.A.4.i；A.307.A.4.i；A.308.A.4.i；A.309.A.4.i；A.310.A.4.i；A.311.A.4.i；A.312.A.4.i；A.313.A.4.i；A.314.A.4.i；A.315.A.4.i；A.316.A.4.i；A.317.A.4.i；A.318.A.4.i；A.319.A.4.i；A.320.A.4.i；A.321.A.4.i；
A.323.A.4.i；A.324.A.4.i；A.325.A.4.i；A.326.A.4.i；A.327.A.4.i；A.328.A.4.i；A.329.A.4.i；A.330.A.4.i；A.331.A.4.i；A.332.A.4.i；A.333.A.4.i；A.334.A.4.i；A.335.A.4.i；A.336.A.4.i；A.337.A.4.i；A.338.A.4.i；A.339.A.4.i；A.340.A.4.i；A.341.A.4.i；A.342.A.4.i；A.343.A.4.i；A.344.A.4.i；A.345.A.4.i；A.346.A.4.i；A.347.A.4.i；A.348.A.4.i；A.349.A.4.i；A.350.A.4.i；A.351.A.4.i；A.352.A.4.i；A.353.A.4.i；A.354.A.4.i；A.355.A.4.i；A.356.A.4.i；A.357.A.4.i；A.358.A.4.i；A.359.A.4.i；A.360.A.4.i；A.361.A.4.i；A.362.A.4.i；A.363.A.4.i；A.364.A.4.i；A.365.A.4.i；A.366.A.4.i；A.367.A.4.i；A.368.A.4.i；A.369.A.4.i；A.370.A.4.i；A.371.A.4.i；A.372.A.4.i；A.373.A.4.i；A.374.A.4.i；A.375.A.4.i；A.376.A.4.i；A.377.A.4.i；A.378.A.4.i；A.379.A.4.i；A.380.A.4.i；A.381.A.4.i；A.382.A.4.i；A.383.A.4.i；A.384.A.4.i；A.385.A.4.i；A.386.A.4.i；A.387.A.4.i；A.388.A.4.i；A.389.A.4.i；A.390.A.4.i；A.391.A.4.i；A.392.A.4.i；A.393.A.4.i；A.394.A.4.i；A.395.A.4.i；A.396.A.4.i；A.397.A.4.i；A.398.A.4.i；A.399.A.4.i；A.400.A.4.i；A.401.A.4.i；A.402.A.4.i；A.403.A.4.i；A.404.A.4.i；A.405.A.4.i；A.406.A.4.i；A.407.A.4.i；A.408.A.4.i；A.409.A.4.i；A.410.A.4.i；A.411.A.4.i；A.412.A.4.i；A.413.A.4.i；A.414.A.4.i；A.415.A.4.i；A.416.A.4.i；A.417.A.4.i；A.418.A.4.i；A.419.A.4.i；A.420.A.4.i；A.421.A.4.i；A.422.A.4.i；A.423.A.4.i；A.424.A.4.i；A.425.A.4.i；A.426.A.4.i；A.427.A.4.i；A.428.A.4.i；A.429.A.4.i；A.430.A.4.i；A.431.A.4.i；A.432.A.4.i；A.433.A.4.i；A.434.A.4.i；A.435.A.4.i；A.436.A.4.i；A.437.A.4.i；A.438.A.4.i；A.439.A.4.i；A.440.A.4.i；A.441.A.4.i；A.442.A.4.i；A.443.A.4.i；A.444.A.4.i；A.445.A.4.i；A.446.A.4.i；A.447.A.4.i；A.448.A.4.i；A.449.A.4.i；A.450.A.4.i；A.451.A.4.i；A.452.A.4.i；A.453.A.4.i；A.454.A.4.i；A.455.A.4.i；A.456.A.4.i；A.457.A.4.i；A.458.A.4.i；A.459.A.4.i；A.460.A.4.i；A.461.A.4.i；A.462.A.4.i；A.463.A.4.i；A.464.A.4.i；A.465.A.4.i；A.466.A.4.i；A.467.A.4.i；A.468.A.4.i；A.469.A.4.i；A.470.A.4.i；A.471.A.4.i；A.472.A.4.i；A.473.A.4.i；A.474.A.4.i；A.475.A.4.i；A.476.A.4.i；A.477.A.4.i；A.478.A.4.i；A.479.A.4.i；A.480.A.4.i；A.481.A.4.i；A.482.A.4.i；A.483.A.4.i；A.484.A.4.i；A.485.A.4.i；A.486.A.4.i；A.487.A.4.i；A.488.A.4.i；A.489.A.4.i；A.490.A.4.i；A.491.A.4.i；A.492.A.4.i；A.493.A.4.i；A.494.A.4.i；A.495.A.4.i；A.496.A.4.i；A.497.A.4.i；A.498.A.4.i；A.499.A.4.i；A.500.A.4.i；A.501.A.4.i；A.502.A.4.i；A.503.A.4.i；A.504.A.4.i；A.505.A.4.i；A.506.A.4.i；A.507.A.4.i；A.508.A.4.i；A.509.A.4.i；A.510.A.4.i；A.511.A.4.i；A.512.A.4.i；A.512.A.4.i；A.513.A.4.i；A.514.A.4.i；A.515.A.4.i；A.516.A.4.i；A.517.A.4.i；A.518.A.4.i；A.519.A.4.i；A.520.A.4.i；A.521.A.4.i；A.522.A.4.i；A.523.A.4.i；A.524.A.4.i；A.525.A.4.i；A.526.A.4.i；A.527.A.4.i；A.528.A.4.i；A.529.A.4.i；A.530.A.4.i；A.531.A.4.i；A.532.A.4.i；A.533.A.4.i；A.534.A.4.i；A.535.A.4.i；A.536.A.4.i；A.537.A.4.i；A.538.A.4.i；A.539.A.4.i；A.540.A.4.i；A.541.A.4.i；A.542.A.4.i；A.543.A.4.i；A.544.A.4.i；A.545.A.4.i；A.546.A.4.i；A.547.A.4.i；A.548.A.4.i；A.549.A.4.i；A.550.A.4.i；A.551.A.4.i；A.552.A.4.i；A.553.A.4.i；A.554.A.4.i；A.555.A.4.i；A.556.A.4.i；A.557.A.4.i；A.558.A.4.i；A.559.A.4.i；A.560.A.4.i；A.561.A.4.i；A.562.A.4.i；A.563.A.4.i；A.564.A.4.i；A.565.A.4.i；A.566.A.4.i；A.567.A.4.i；A.568.A.4.i；A.569.A.4.i；A.570.A.4.i；A.571.A.4.i；A.572.A.4.i；A.573.A.4.i；A.574.A.4.i；A.575.A.4.i；A.576.A.4.i；A.577.A.4.i；A.578.A.4.i；A.579.A.4.i；A.580.A.4.i；A.581.A.4.i；A.582.A.4.i；A.583.A.4.i；A.584.A.4.i；A.585.A.4.i；A.586.A.4.i；A.587.A.4.i；A.588.A.4.i；A.589.A.4.i；A.590.A.4.i；A.591.A.4.i；A.592.A.4.i；A.593.A.4.i；A.594.A.4.i；A.595.A.4.i；A.596.A.4.i；A.597.A.4.i；A.598.A.4.i；A.599.A.4.i；A.600.A.4.i；A.601.A.4.i；A.602.A.4.i；A.603.A.4.i；
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A.280.A.11.i；A.281.A.11.i；A.282.A.11.i；A.283.A.11.i；A.284.A.11.i；A.285.A.11.i；A.286.A.11.i；A.287.A.11.i；A.288.A.11.i；A.289.A.11.i；A.290.A.11.i；A.291.A.11.i；A.292.A.11.i；A.293.A.11.i；A.294.A.11.i；A.295.A.11.i；A.296.A.11.i；A.297.A.11.i；A.298.A.11.i；A.299.A.11.i；A.300.A.11.i；A.301.A.11.i；A.302.A.11.i；A.303.A.11.i；A.304.A.11.i；A.305.A.11.i；A.306.A.11.i；A.307.A.11.i；A.308.A.11.i；A.309.A.11.i；A.310.A.11.i；A.311.A.11.i；A.312.A.11.i；A.313.A.11.i；A.314.A.11.i；A.315.A.11.i；A.316.A.11.i；A.317.A.11.i；A.318.A.11.i；A.319.A.11.i；A.320.A.11.i；A.321.A.11.i；A.323.A.11.i；A.324.A.11.i；A.325.A.11.i；A.326.A.11.i；A.327.A.11.i；A.328.A.11.i；A.329.A.11.i；A.330.A.11.i；A.331.A.11.i；A.332.A.11.i；A.333.A.11.i；A.334.A.11.i；A.335.A.11.i；A.336.A.11.i；A.337.A.11.i；A.338.A.11.i；A.339.A.11.i；A.340.A.11.i；A.341.A.11.i；A.342.A.11.i；A.343.A.11.i；A.344.A.11.i；A.345.A.11.i；A.346.A.11.i；A.347.A.11.i；A.348.A.11.i；A.349.A.11.i；A.350.A.11.i；A.351.A.11.i；A.352.A.11.i；A.353.A.11.i；A.354.A.11.i；A.355.A.11.i；A.356.A.11.i；A.357.A.11.i；A.358.A.11.i；A.359.A.11.i；A.360.A.11.i；A.361.A.11.i；A.362.A.11.i；A.363.A.11.i；A.364.A.11.i；A.365.A.11.i；A.366.A.11.i；A.367.A.11.i；A.368.A.11.i；A.369.A.11.i；A.370.A.11.i；A.371.A.11.i；A.372.A.11.i；A.373.A.11.i；A.374.A.11.i；A.375.A.11.i；A.376.A.11.i；A.377.A.11.i；A.378.A.11.i；A.379.A.11.i；A.380.A.11.i；A.381.A.11.i；A.382.A.11.i；A.383.A.11.i；A.384.A.11.i；A.385.A.11.i；A.386.A.11.i；A.387.A.11.i；A.388.A.11.i；A.389.A.11.i；A.390.A.11.i；A.391.A.11.i；A.392.A.11.i；A.393.A.11.i；A.394.A.11.i；A.395.A.11.i；A.396.A.11.i；A.397.A.11.i；A.398.A.11.i；A.399.A.11.i；A.400.A.11.i；A.401.A.11.i；A.402.A.11.i；A.403.A.11.i；A.404.A.11.i；A.405.A.11.i；A.406.A.11.i；A.407.A.11.i；A.408.A.11.i；A.409.A.11.i；A.410.A.11.i；A.411.A.11.i；A.412.A.11.i；A.413.A.11.i；A.414.A.11.i；A.415.A.11.i；A.416.A.11.i；A.417.A.11.i；A.418.A.11.i；A.419.A.11.i；A.420.A.11.i；A.421.A.11.i；A.422.A.11.i；A.423.A.11.i；A.424.A.11.i；A.425.A.11.i；A.426.A.11.i；A.427.A.11.i；A.428.A.11.i；A.429.A.11.i；A.430.A.11.i；A.431.A.11.i；A.432.A.11.i；A.433.A.11.i；A.434.A.11.i；A.435.A.11.i；A.436.A.11.i；A.437.A.11.i；A.438.A.11.i；A.439.A.11.i；A.440.A.11.i；A.441.A.11.i；A.442.A.11.i；A.443.A.11.i；A.444.A.11.i；A.445.A.11.i；A.446.A.11.i；A.447.A.11.i；A.448.A.11.i；A.449.A.11.i；A.450.A.11.i；A.451.A.11.i；A.452.A.11.i；A.453.A.11.i；A.454.A.11.i；A.455.A.11.i；A.456.A.11.i；A.457.A.11.i；A.458.A.11.i；A.459.A.11.i；A.460.A.11.i；A.461.A.11.i；A.462.A.11.i；A.463.A.11.i；A.464.A.11.i；A.465.A.11.i；A.466.A.11.i；A.467.A.11.i；A.468.A.11.i；A.469.A.11.i；A.470.A.11.i；A.471.A.11.i；A.472.A.11.i；A.473.A.11.i；A.474.A.11.i；A.475.A.11.i；A.476.A.11.i；A.477.A.11.i；A.478.A.11.i；A.479.A.11.i；A.480.A.11.i；A.481.A.11.i；A.482.A.11.i；A.483.A.11.i；A.484.A.11.i；A.485.A.11.i；A.486.A.11.i；A.487.A.11.i；A.488.A.11.i；A.489.A.11.i；A.490.A.11.i；A.491.A.11.i；A.492.A.11.i；A.493.A.11.i；A.494.A.11.i；A.495.A.11.i；A.496.A.11.i；A.497.A.11.i；A.498.A.11.i；A.499.A.11.i；A.500.A.11.i；A.501.A.11.i；A.502.A.11.i；A.503.A.11.i；A.504.A.11.i；A.505.A.11.i；A.506.A.11.i；A.507.A.11.i；A.508.A.11.i；A.509.A.11.i；A.510.A.11.i；A.511.A.11.i；A.512.A.11.i；A.512.A.11.i；A.513.A.11.i；A.514.A.11.i；
A.515.A.11.i；A.516.A.11.i；A.517.A.11.i；A.518.A.11.i；A.519.A.11.i；A.520.A.11.i；A.521.A.11.i；A.522.A.11.i；A.523.A.11.i；A.524.A.11.i；A.525.A.11.i；A.526.A.11.i；A.527.A.11.i；A.528.A.11.i；A.529.A.11.i；A.530.A.11.i；A.531.A.11.i；A.532.A.11.i；A.533.A.11.i；A.534.A.11.i；A.535.A.11.i；A.536.A.11.i；A.537.A.11.i；A.538.A.11.i；A.539.A.11.i；A.540.A.11.i；A.541.A.11.i；A.542.A.11.i；A.543.A.11.i；A.544.A.11.i；A.545.A.11.i；A.546.A.11.i；A.547.A.11.i；A.548.A.11.i；A.549.A.11.i；A.550.A.11.i；A.551.A.11.i；A.552.A.11.i；A.553.A.11.i；A.554.A.11.i；A.555.A.11.i；A.556.A.11.i；A.557.A.11.i；A.558.A.11.i；A.559.A.11.i；A.560.A.11.i；A.561.A.11.i；A.562.A.11.i；A.563.A.11.i；A.564.A.11.i；A.565.A.11.i；A.566.A.11.i；A.567.A.11.i；A.568.A.11.i；A.569.A.11.i；A.570.A.11.i；A.571.A.11.i；A.572.A.11.i；A.573.A.11.i；A.574.A.11.i；A.575.A.11.i；A.576.A.11.i；A.577.A.11.i；A.578.A.11.i；A.579.A.11.i；A.580.A.11.i；A.581.A.11.i；A.582.A.11.i；A.583.A.11.i；A.584.A.11.i；A.585.A.11.i；A.586.A.11.i；A.587.A.11.i；A.588.A.11.i；A.589.A.11.i；A.590.A.11.i；A.591.A.11.i；A.592.A.11.i；A.593.A.11.i；A.594.A.11.i；A.595.A.11.i；A.596.A.11.i；A.597.A.11.i；A.598.A.11.i；A.599.A.11.i；A.600.A.11.i；A.601.A.11.i；A.602.A.11.i；A.603.A.11.i；A.604.A.11.i；A.605.A.11.i；A.606.A.11.i；A.607.A.11.i；A.608.A.11.i；A.609.A.11.i；A.610.A.11.i；A.611.A.11.i；A.612.A.11.i；A.613.A.11.i；A.614.A.11.i；A.615.A.11.i；A.616.A.11.i；A.617.A.11.i；A.618.A.11.i；A.619.A.11.i；A.620.A.11.i；A.621.A.11.i；A.622.A.11.i；A.623.A.11.i；A.624.A.11.i；A.625.A.11.i；A.626.A.11.i；A.627.A.11.i；A.628.A.11.i；A.629.A.11.i；A.630.A.11.i；A.631.A.11.i；A.632.A.11.i；A.633.A.11.i；A.634.A.11.i；A.635.A.11.i；A.636.A.11.i；A.637.A.11.i；A.638.A.11.i；A.639.A.11.i；A.640.A.11.i；A.641.A.11.i；A.642.A.11.i；A.643.A.11.i；A.644.A.11.i；A.645.A.11.i；A.646.A.11.i；A.647.A.11.i；A.648.A.11.i；A.649.A.11.i；A.650.A.11.i；A.651.A.11.i；A.652.A.11.i；A.653.A.11.i；A.654.A.11.i；A.655.A.11.i；A.656.A.11.i；A.657.A.11.i；A.658.A.11.i；A.659.A.11.i；A.660.A.11.i；A.2.B.4.i；A.3.B.4.i；A.4.B.4.i；A.5.B.4.i；A.6.B.4.i；A.7.B.4.i；A.9.B.4.i；A.10.B.4.i；A.15.B.4.i；A.100.B.4.i；A.101.B.4.i；A.102.B.4.i；A.103.B.4.i；A.104.B.4.i；A.105.B.4.i；A.106.B.4.i；A.107.B.4.i；A.108.B.4.i；A.109.B.4.i；A.110.B.4.i；A.111.B.4.i；A.112.B.4.i；A.113.B.4.i；A.114.B.4.i；A.115.B.4.i；A.116.B.4.i；A.117.B.4.i；A.118.B.4.i；A.119.B.4.i；A.120.B.4.i；A.121.B.4.i；A.122.B.4.i；A.123.B.4.i；A.124.B.4.i；A.125.B.4.i；A.126.B.4.i；A.127.B.4.i；A.128.B.4.i；A.129.B.4.i；A.130.B.4.i；A.131.B.4.i；A.132.B.4.i；A.133.B.4.i；A.134.B.4.i；A.135.B.4.i；A.136.B.4.i；A.137.B.4.i；A.138.B.4.i；A.139.B.4.i；A.140.B.4.i；A.141.B.4.i；A.142.B.4.i；A.143.B.4.i；A.144.B.4.i；A.145.B.4.i；A.146.B.4.i；A.147.B.4.i；A.148.B.4.i；A.149.B.4.i；A.150.B.4.i；A.151.B.4.i；A.152.B.4.i；A.153.B.4.i；A.154.B.4.i；A.155.B.4.i；A.156.B.4.i；A.157.B.4.i；A.158.B.4.i；A.159.B.4.i；A.160.B.4.i；A.161.B.4.i；A.162.B.4.i；A.163.B.4.i；A.164.B.4.i；A.165.B.4.i；A.166.B.4.i；A.167.B.4.i；A.168.B.4.i；A.169.B.4.i；A.170.B.4.i；A.171.B.4.i；A.172.B.4.i；A.173.B.4.i；A.174.B.4.i；A.175.B.4.i；A.176.B.4.i；A.177.B.4.i；A.178.B.4.i；A.179.B.4.i；A.180.B.4.i；A.181.B.4.i；A.182.B.4.i；A.183.B.4.i；A.184.B.4.i；A.185.B.4.i；A.186.B.4.i；A.187.B.4.i；A.188.B.4.i；A.189.B.4.i；A.190.B.4.i；A.191.B.4.i；A.192.B.4.i；A.193.B.4.i；A.194.B.4.i；A.195.B.4.i；A.196.B.4.i；A.197.B.4.i；A.198.B.4.i；A.199.B.4.i；
A.200.B.4.i；A.201.B.4.i；A.202.B.4.i；A.203.B.4.i；A.204.B.4.i；A.205.B.4.i；A.206.B.4.i；A.207.B.4.i；A.208.B.4.i；A.209.B.4.i；A.210.B.4.i；A.211.B.4.i；A.212.B.4.i；A.213.B.4.i；A.214.B.4.i；A.215.B.4.i；A.216.B.4.i；A.217.B.4.i；A.218.B.4.i；A.219.B.4.i；A.220.B.4.i；A.221.B.4.i；A.222.B.4.i；A.223.B.4.i；A.224.B.4.i；A.225.B.4.i；A.226.B.4.i；A.227.B.4.i；A.228.B.4.i；A.229.B.4.i；A.230.B.4.i；A.231.B.4.i；A.232.B.4.i；A.233.B.4.i；A.234.B.4.i；A.235.B.4.i；A.236.B.4.i；A.237.B.4.i；A.238.B.4.i；A.239.B.4.i；A.240.B.4.i；A.241.B.4.i；A.242.B.4.i；A.243.B.4.i；A.244.B.4.i；A.245.B.4.i；A.246.B.4.i；A.247.B.4.i；A.248.B.4.i；A.249.B.4.i；A.250.B.4.i；A.251.B.4.i；A.252.B.4.i；A.253.B.4.i；A.254.B.4.i；A.255.B.4.i；A.256.B.4.i；A.257.B.4.i；A.258.B.4.i；A.259.B.4.i；A.260.B.4.i；A.261.B.4.i；A.262.B.4.i；A.263.B.4.i；A.264.B.4.i；A.265.B.4.i；A.266.B.4.i；A.267.B.4.i；A.268.B.4.i；A.269.B.4.i；A.270.B.4.i；A.271.B.4.i；A.272.B.4.i；A.273.B.4.i；A.274.B.4.i；A.275.B.4.i；A.276.B.4.i；A.277.B.4.i；A.278.B.4.i；A.279.B.4.i；A.280.B.4.i；A.281.B.4.i；A.282.B.4.i；A.283.B.4.i；A.284.B.4.i；A.285.B.4.i；A.286.B.4.i；A.287.B.4.i；A.288.B.4.i；A.289.B.4.i；A.290.B.4.i；A.291.B.4.i；A.292.B.4.i；A.293.B.4.i；A.294.B.4.i；A.295.B.4.i；A.296.B.4.i；A.297.B.4.i；A.298.B.4.i；A.299.B.4.i；A.300.B.4.i；A.301.B.4.i；A.302.B.4.i；A.303.B.4.i；A.304.B.4.i；A.305.B.4.i；A.306.B.4.i；A.307.B.4.i；A.308.B.4.i；A.309.B.4.i；A.310.B.4.i；A.311.B.4.i；A.312.B.4.i；A.313.B.4.i；A.314.B.4.i；A.315.B.4.i；A.316.B.4.i；A.317.B.4.i；A.318.B.4.i；A.319.B.4.i；A.320.B.4.i；A.321.B.4.i；A.323.B.4.i；A.324.B.4.i；A.325.B.4.i；A.326.B.4.i；A.327.B.4.i；A.328.B.4.i；A.329.B.4.i；A.330.B.4.i；A.331.B.4.i；A.332.B.4.i；A.333.B.4.i；A.334.B.4.i；A.335.B.4.i；A.336.B.4.i；A.337.B.4.i；A.338.B.4.i；A.339.B.4.i；A.340.B.4.i；A.341.B.4.i；A.342.B.4.i；A.343.B.4.i；A.344.B.4.i；A.345.B.4.i；A.346.B.4.i；A.347.B.4.i；A.348.B.4.i；A.349.B.4.i；A.350.B.4.i；A.351.B.4.i；A.352.B.4.i；A.353.B.4.i；A.354.B.4.i；A.355.B.4.i；A.356.B.4.i；A.357.B.4.i；A.358.B.4.i；A.359.B.4.i；A.360.B.4.i；A.361.B.4.i；A.362.B.4.i；A.363.B.4.i；A.364.B.4.i；A.365.B.4.i；A.366.B.4.i；A.367.B.4.i；A.368.B.4.i；A.369.B.4.i；A.370.B.4.i；A.371.B.4.i；A.372.B.4.i；A.373.B.4.i；A.374.B.4.i；A.375.B.4.i；A.376.B.4.i；A.377.B.4.i；A.378.B.4.i；A.379.B.4.i；A.380.B.4.i；A.381.B.4.i；A.382.B.4.i；A.383.B.4.i；A.384.B.4.i；A.385.B.4.i；A.386.B.4.i；A.387.B.4.i；A.388.B.4.i；A.389.B.4.i；A.390.B.4.i；A.391.B.4.i；A.392.B.4.i；A.393.B.4.i；A.394.B.4.i；A.395.B.4.i；A.396.B.4.i；A.397.B.4.i；A.398.B.4.i；A.399.B.4.i；A.400.B.4.i；A.401.B.4.i；A.402.B.4.i；A.403.B.4.i；A.404.B.4.i；A.405.B.4.i；A.406.B.4.i；A.407.B.4.i；A.408.B.4.i；A.409.B.4.i；A.410.B.4.i；A.411.B.4.i；A.412.B.4.i；A.413.B.4.i；A.414.B.4.i；A.415.B.4.i；A.416.B.4.i；A.417.B.4.i；A.418.B.4.i；A.419.B.4.i；A.420.B.4.i；A.421.B.4.i；A.422.B.4.i；A.423.B.4.i；A.424.B.4.i；A.425.B.4.i；A.426.B.4.i；A.427.B.4.i；A.428.B.4.i；A.429.B.4.i；A.430.B.4.i；A.431.B.4.i；A.432.B.4.i；A.433.B.4.i；A.434.B.4.i；A.435.B.4.i；A.436.B.4.i；A.437.B.4.i；A.438.B.4.i；A.439.B.4.i；A.440.B.4.i；A.441.B.4.i；A.442.B.4.i；A.443.B.4.i；A.444.B.4.i；A.445.B.4.i；A.446.B.4.i；A.447.B.4.i；A.448.B.4.i；A.449.B.4.i；A.450.B.4.i；A.451.B.4.i；A.452.B.4.i；A.453.B.4.i；A.454.B.4.i；A.455.B.4.i；A.456.B.4.i；A.457.B.4.i；A.458.B.4.i；A.459.B.4.i；A.460.B.4.i；A.461.B.4.i；A.462.B.4.i；A.463.B.4.i；A.464.B.4.i；A.465.B.4.i；A.466.B.4.i；A.467.B.4.i；A.468.B.4.i；A.469.B.4.i；A.470.B.4.i；A.471.B.4.i；A.472.B.4.i；A.473.B.4.i；A.474.B.4.i；A.475.B.4.i；A.476.B.4.i；A.477.B.4.i；A.478.B.4.i；A.479.B.4.i；A.480.B.4.i；A.481.B.4.i；A.482.B.4.i；
A.483.B.4.i；A.484.B.4.i；A.485.B.4.i；A.486.B.4.i；A.487.B.4.i；A.488.B.4.i；A.489.B.4.i；A.490.B.4.i；A.491.B.4.i；A.492.B.4.i；A.493.B.4.i；A.494.B.4.i；A.495.B.4.i；A.496.B.4.i；A.497.B.4.i；A.498.B.4.i；A.499.B.4.i；A.500.B.4.i；A.501.B.4.i；A.502.B.4.i；A.503.B.4.i；A.504.B.4.i；A.505.B.4.i；A.506.B.4.i；A.507.B.4.i；A.508.B.4.i；A.509.B.4.i；A.510.B.4.i；A.511.B.4.i；A.512.B.4.i；A.512.B.4.i；A.513.B.4.i；A.514.B.4.i；A.515.B.4.i；A.516.B.4.i；A.517.B.4.i；A.518.B.4.i；A.519.B.4.i；A.520.B.4.i；A.521.B.4.i；A.522.B.4.i；A.523.B.4.i；A.524.B.4.i；A.525.B.4.i；A.526.B.4.i；A.527.B.4.i；A.528.B.4.i；A.529.B.4.i；A.530.B.4.i；A.531.B.4.i；A.532.B.4.i；A.533.B.4.i；A.534.B.4.i；A.535.B.4.i；A.536.B.4.i；A.537.B.4.i；A.538.B.4.i；A.539.B.4.i；A.540.B.4.i；A.541.B.4.i；A.542.B.4.i；A.543.B.4.i；A.544.B.4.i；A.545.B.4.i；A.546.B.4.i；A.547.B.4.i；A.548.B.4.i；A.549.B.4.i；A.550.B.4.i；A.551.B.4.i；A.552.B.4.i；A.553.B.4.i；A.554.B.4.i；A.555.B.4.i；A.556.B.4.i；A.557.B.4.i；A.558.B.4.i；A.559.B.4.i；A.560.B.4.i；A.561.B.4.i；A.562.B.4.i；A.563.B.4.i；A.564.B.4.i；A.565.B.4.i；A.566.B.4.i；A.567.B.4.i；A.568.B.4.i；A.569.B.4.i；A.570.B.4.i；A.571.B.4.i；A.572.B.4.i；A.573.B.4.i；A.574.B.4.i；A.575.B.4.i；A.576.B.4.i；A.577.B.4.i；A.578.B.4.i；A.579.B.4.i；A.580.B.4.i；A.581.B.4.i；A.582.B.4.i；A.583.B.4.i；A.584.B.4.i；A.585.B.4.i；A.586.B.4.i；A.587.B.4.i；A.588.B.4.i；A.589.B.4.i；A.590.B.4.i；A.591.B.4.i；A.592.B.4.i；A.593.B.4.i；A.594.B.4.i；A.595.B.4.i；A.596.B.4.i；A.597.B.4.i；A.598.B.4.i；A.599.B.4.i；A.600.B.4.i；A.601.B.4.i；A.602.B.4.i；A.603.B.4.i；A.604.B.4.i；A.605.B.4.i；A.606.B.4.i；A.607.B.4.i；A.608.B.4.i；A.609.B.4.i；A.610.B.4.i；A.611.B.4.i；A.612.B.4.i；A.613.B.4.i；A.614.B.4.i；A.615.B.4.i；A.616.B.4.i；A.617.B.4.i；A.618.B.4.i；A.619.B.4.i；A.620.B.4.i；A.621.B.4.i；A.622.B.4.i；A.623.B.4.i；A.624.B.4.i；A.625.B.4.i；A.626.B.4.i；A.627.B.4.i；A.628.B.4.i；A.629.B.4.i；A.630.B.4.i；A.631.B.4.i；A.632.B.4.i；A.633.B.4.i；A.634.B.4.i；A.635.B.4.i；A.636.B.4.i；A.637.B.4.i；A.638.B.4.i；A.639.B.4.i；A.640.B.4.i；A.641.B.4.i；A.642.B.4.i；A.643.B.4.i；A.644.B.4.i；A.645.B.4.i；A.646.B.4.i；A.647.B.4.i；A.648.B.4.i；A.649.B.4.i；A.650.B.4.i；A.651.B.4.i；A.652.B.4.i；A.653.B.4.i；A.654.B.4.i；A.655.B.4.i；A.656.B.4.i；A.657.B.4.i；A.658.B.4.i；A.659.B.4.i；A.660.B.4.i；A.2.B.11.i；A.3.B.11.i；A.4.B.11.i；A.5.B.11.i；A.6.B.11.i；A.7.B.11.i；A.9.B.11.i；A.10.B.11.i；A.15.B.11.i；A.100.B.11.i；A.101.B.11.i；A.102.B.11.i；A.103.B.11.i；A.104.B.11.i；A.105.B.11.i；A.106.B.11.i；A.107.B.11.i；A.108.B.11.i；A.109.B.11.i；A.110.B.11.i；A.111.B.11.i；A.112.B.11.i；A.113.B.11.i；A.114.B.11.i；A.115.B.11.i；A.116.B.11.i；A.117.B.11.i；A.118.B.11.i；A.119.B.11.i；A.120.B.11.i；A.121.B.11.i；A.122.B.11.i；A.123.B.11.i；A.124.B.11.i；A.125.B.11.i；A.126.B.11.i；A.127.B.11.i；A.128.B.11.i；A.129.B.11.i；A.130.B.11.i；A.131.B.11.i；A.132.B.11.i；A.133.B.11.i；A.134.B.11.i；A.135.B.11.i；A.136.B.11.i；A.137.B.11.i；A.138.B.11.i；A.139.B.11.i；A.140.B.11.i；A.141.B.11.i；A.142.B.11.i；A.143.B.11.i；A.144.B.11.i；A.145.B.11.i；A.146.B.11.i；A.147.B.11.i；A.148.B.11.i；A.149.B.11.i；A.150.B.11.i；A.151.B.11.i；A.152.B.11.i；A.153.B.11.i；A.154.B.11.i；A.155.B.11.i；A.156.B.11.i；A.157.B.11.i；A.158.B.11.i；A.159.B.11.i；A.160.B.11.i；A.161.B.11.i；A.162.B.11.i；A.163.B.11.i；A.164.B.11.i；A.165.B.11.i；A.166.B.11.i；A.167.B.11.i；A.168.B.11.i；A.169.B.11.i；A.170.B.11.i；A.171.B.11.i；A.172.B.11.i；A.173.B.11.i；A.174.B.11.i；A.175.B.11.i；A.176.B.11.i；A.177.B.11.i；A.178.B.11.i；A.179.B.11.i；A.180.B.11.i；A.181.B.11.i；A.182.B.11.i；A.183.B.11.i；A.184.B.11.i；A.185.B.11.i；A.186.B.11.i；A.187.B.11.i；A.188.B.11.i；A.189.B.11.i；A.190.B.11.i；A.191.B.11.i；A.192.B.11.i；A.193.B.11.i；A.194.B.11.i；
A.195.B.11.i；A.196.B.11.i；A.197.B.11.i；A.198.B.11.i；A.199.B.11.i；A.200.B.11.i；A.201.B.11.i；A.202.B.11.i；A.203.B.11.i；A.204.B.11.i；A.205.B.11.i；A.206.B.11.i；A.207.B.11.i；A.208.B.11.i；A.209.B.11.i；A.210.B.11.i；A.211.B.11.i；A.212.B.11.i；A.213.B.11.i；A.214.B.11.i；A.215.B.11.i；A.216.B.11.i；A.217.B.11.i；A.218.B.11.i；A.219.B.11.i；A.220.B.11.i；A.221.B.11.i；A.222.B.11.i；A.223.B.11.i；A.224.B.11.i；A.225.B.11.i；A.226.B.11.i；A.227.B.11.i；A.228.B.11.i；A.229.B.11.i；A.230.B.11.i；A.231.B.11.i；A.232.B.11.i；A.233.B.11.i；A.234.B.11.i；A.235.B.11.i；A.236.B.11.i；A.237.B.11.i；A.238.B.11.i；A.239.B.11.i；A.240.B.11.i；A.241.B.11.i；A.242.B.11.i；A.243.B.11.i；A.244.B.11.i；A.245.B.11.i；A.246.B.11.i；A.247.B.11.i；A.248.B.11.i；A.249.B.11.i；A.250.B.11.i；A.251.B.11.i；A.252.B.11.i；A.253.B.11.i；A.254.B.11.i；A.255.B.11.i；A.256.B.11.i；A.257.B.11.i；A.258.B.11.i；A.259.B.11.i；A.260.B.11.i；A.261.B.11.i；A.262.B.11.i；A.263.B.11.i；A.264.B.11.i；A.265.B.11.i；A.266.B.11.i；A.267.B.11.i；A.268.B.11.i；A.269.B.11.i；A.270.B.11.i；A.271.B.11.i；A.272.B.11.i；A.273.B.11.i；A.274.B.11.i；A.275.B.11.i；A.276.B.11.i；A.277.B.11.i；A.278.B.11.i；A.279.B.11.i；A.280.B.11.i；A.281.B.11.i；A.282.B.11.i；A.283.B.11.i；A.284.B.11.i；A.285.B.11.i；A.286.B.11.i；A.287.B.11.i；A.288.B.11.i；A.289.B.11.i；A.290.B.11.i；A.291.B.11.i；A.292.B.11.i；A.293.B.11.i；A.294.B.11.i；A.295.B.11.i；A.296.B.11.i；A.297.B.11.i；A.298.B.11.i；A.299.B.11.i；A.300.B.11.i；A.301.B.11.i；A.302.B.11.i；A.303.B.11.i；A.304.B.11.i；A.305.B.11.i；A.306.B.11.i；A.307.B.11.i；A.308.B.11.i；A.309.B.11.i；A.310.B.11.i；A.311.B.11.i；A.312.B.11.i；A.313.B.11.i；A.314.B.11.i；A.315.B.11.i；A.316.B.11.i；A.317.B.11.i；A.318.B.11.i；A.319.B.11.i；A.320.B.11.i；A.321.B.11.i；A.323.B.11.i；A.324.B.11.i；A.325.B.11.i；A.326.B.11.i；A.327.B.11.i；A.328.B.11.i；A.329.B.11.i；A.330.B.11.i；A.331.B.11.i；A.332.B.11.i；A.333.B.11.i；A.334.B.11.i；A.335.B.11.i；A.336.B.11.i；A.337.B.11.i；A.338.B.11.i；A.339.B.11.i；A.340.B.11.i；A.341.B.11.i；A.342.B.11.i；A.343.B.11.i；A.344.B.11.i；A.345.B.11.i；A.346.B.11.i；A.347.B.11.i；A.348.B.11.i；A.349.B.11.i；A.350.B.11.i；A.351.B.11.i；A.352.B.11.i；A.353.B.11.i；A.354.B.11.i；A.355.B.11.i；A.356.B.11.i；A.357.B.11.i；A.358.B.11.i；A.359.B.11.i；A.360.B.11.i；A.361.B.11.i；A.362.B.11.i；A.363.B.11.i；A.364.B.11.i；A.365.B.11.i；A.366.B.11.i；A.367.B.11.i；A.368.B.11.i；A.369.B.11.i；A.370.B.11.i；A.371.B.11.i；A.372.B.11.i；A.373.B.11.i；A.374.B.11.i；A.375.B.11.i；A.376.B.11.i；A.377.B.11.i；A.378.B.11.i；A.379.B.11.i；A.380.B.11.i；A.381.B.11.i；A.382.B.11.i；A.383.B.11.i；A.384.B.11.i；A.385.B.11.i；A.386.B.11.i；A.387.B.11.i；A.388.B.11.i；A.389.B.11.i；A.390.B.11.i；A.391.B.11.i；A.392.B.11.i；A.393.B.11.i；A.394.B.11.i；A.395.B.11.i；A.396.B.11.i；A.397.B.11.i；A.398.B.11.i；A.399.B.11.i；A.400.B.11.i；A.401.B.11.i；A.402.B.11.i；A.403.B.11.i；A.404.B.11.i；A.405.B.11.i；A.406.B.11.i；A.407.B.11.i；A.408.B.11.i；A.409.B.11.i；A.410.B.11.i；A.411.B.11.i；A.412.B.11.i；A.413.B.11.i；A.414.B.11.i；A.415.B.11.i；A.416.B.11.i；A.417.B.11.i；A.418.B.11.i；A.419.B.11.i；A.420.B.11.i；A.421.B.11.i；A.422.B.11.i；A.423.B.11.i；A.424.B.11.i；A.425.B.11.i；A.426.B.11.i；A.427.B.11.i；A.428.B.11.i；A.429.B.11.i；A.430.B.11.i；A.431.B.11.i；A.432.B.11.i；A.433.B.11.i；A.434.B.11.i；A.435.B.11.i；A.436.B.11.i；A.437.B.11.i；A.438.B.11.i；A.439.B.11.i；A.440.B.11.i；A.441.B.11.i；A.442.B.11.i；A.443.B.11.i；A.444.B.11.i；A.445.B.11.i；A.446.B.11.i；A.447.B.11.i；A.448.B.11.i；A.449.B.11.i；A.450.B.11.i；A.451.B.11.i；A.452.B.11.i；A.453.B.11.i；A.454.B.11.i；A.455.B.11.i；A.456.B.11.i；A.457.B.11.i；A.458.B.11.i；A.459.B.11.i；A.460.B.11.i；A.461.B.11.i；A.462.B.11.i；A.463.B.11.i；A.464.B.11.i；A.465.B.11.i；A.466.B.11.i；A.467.B.11.i；A.468.B.11.i；A.469.B.11.i；A.470.B.11.i；A.471.B.11.i；A.472.B.11.i；A.473.B.11.i；A.474.B.11.i；A.475.B.11.i；A.476.B.11.i；A.477.B.11.i；
A.478.B.11.i；A.479.B.11.i；A.480.B.11.i；A.481.B.11.i；A.482.B.11.i；A.483.B.11.i；A.484.B.11.i；A.485.B.11.i；A.486.B.11.i；A.487.B.11.i；A.488.B.11.i；A.489.B.11.i；A.490.B.11.i；A.491.B.11.i；A.492.B.11.i；A.493.B.11.i；A.494.B.11.i；A.495.B.11.i；A.496.B.11.i；A.497.B.11.i；A.498.B.11.i；A.499.B.11.i；A.500.B.11.i；A.501.B.11.i；A.502.B.11.i；A.503.B.11.i；A.504.B.11.i；A.505.B.11.i；A.506.B.11.i；A.507.B.11.i；A.508.B.11.i；A.509.B.11.i；A.510.B.11.i；A.511.B.11.i；A.512.B.11.i；A.512.B.11.i；A.513.B.11.i；A.514.B.11.i；A.515.B.11.i；A.516.B.11.i；A.517.B.11.i；A.518.B.11.i；A.519.B.11.i；A.520.B.11.i；A.521.B.11.i；A.522.B.11.i；A.523.B.11.i；A.524.B.11.i；A.525.B.11.i；A.526.B.11.i；A.527.B.11.i；A.528.B.11.i；A.529.B.11.i；A.530.B.11.i；A.531.B.11.i；A.532.B.11.i；A.533.B.11.i；A.534.B.11.i；A.535.B.11.i；A.536.B.11.i；A.537.B.11.i；A.538.B.11.i；A.539.B.11.i；A.540.B.11.i；A.541.B.11.i；A.542.B.11.i；A.543.B.11.i；A.544.B.11.i；A.545.B.11.i；A.546.B.11.i；A.547.B.11.i；A.548.B.11.i；A.549.B.11.i；A.550.B.11.i；A.551.B.11.i；A.552.B.11.i；A.553.B.11.i；A.554.B.11.i；A.555.B.11.i；A.556.B.11.i；A.557.B.11.i；A.558.B.11.i；A.559.B.11.i；A.560.B.11.i；A.561.B.11.i；A.562.B.11.i；A.563.B.11.i；A.564.B.11.i；A.565.B.11.i；A.566.B.11.i；A.567.B.11.i；A.568.B.11.i；A.569.B.11.i；A.570.B.11.i；A.571.B.11.i；A.572.B.11.i；A.573.B.11.i；A.574.B.11.i；A.575.B.11.i；A.576.B.11.i；A.577.B.11.i；A.578.B.11.i；A.579.B.11.i；A.580.B.11.i；A.581.B.11.i；A.582.B.11.i；A.583.B.11.i；A.584.B.11.i；A.585.B.11.i；A.586.B.11.i；A.587.B.11.i；A.588.B.11.i；A.589.B.11.i；A.590.B.11.i；A.591.B.11.i；A.592.B.11.i；A.593.B.11.i；A.594.B.11.i；A.595.B.11.i；A.596.B.11.i；A.597.B.11.i；A.598.B.11.i；A.599.B.11.i；A.600.B.11.i；A.601.B.11.i；A.602.B.11.i；A.603.B.11.i；A.604.B.11.i；A.605.B.11.i；A.606.B.11.i；A.607.B.11.i；A.608.B.11.i；A.609.B.11.i；A.610.B.11.i；A.611.B.11.i；A.612.B.11.i；A.613.B.11.i；A.614.B.11.i；A.615.B.11.i；A.616.B.11.i；A.617.B.11.i；A.618.B.11.i；A.619.B.11.i；A.620.B.11.i；A.621.B.11.i；A.622.B.11.i；A.623.B.11.i；A.624.B.11.i；A.625.B.11.i；A.626.B.11.i；A.627.B.11.i；A.628.B.11.i；A.629.B.11.i；A.630.B.11.i；A.631.B.11.i；A.632.B.11.i；A.633.B.11.i；A.634.B.11.i；A.635.B.11.i；A.636.B.11.i；A.637.B.11.i；A.638.B.11.i；A.639.B.11.i；A.640.B.11.i；A.641.B.11.i；A.642.B.11.i；A.643.B.11.i；A.644.B.11.i；A.645.B.11.i；A.646.B.11.i；A.647.B.11.i；A.648.B.11.i；A.649.B.11.i；A.650.B.11.i；A.651.B.11.i；A.652.B.11.i；A.653.B.11.i；A.654.B.11.i；A.655.B.11.i；A.656.B.11.i；A.657.B.11.i；A.658.B.11.i；A.659.B.11.i；A.660.B.11.i；A.2.C.4.i；A.3.C.4.i；A.4.C.4.i；A.5.C.4.i；A.6.C.4.i；A.7.C.4.i；A.9.C.4.i；A.10.C.4.i；A.15.C.4.i；A.100.C.4.i；A.101.C.4.i；A.102.C.4.i；A.103.C.4.i；A.104.C.4.i；A.105.C.4.i；A.106.C.4.i；A.107.C.4.i；A.108.C.4.i；A.109.C.4.i；A.110.C.4.i；A.111.C.4.i；A.112.C.4.i；A.113.C.4.i；A.114.C.4.i；A.115.C.4.i；A.116.C.4.i；A.117.C.4.i；A.118.C.4.i；A.119.C.4.i；A.120.C.4.i；A.121.C.4.i；A.122.C.4.i；A.123.C.4.i；A.124.C.4.i；A.125.C.4.i；A.126.C.4.i；A.127.C.4.i；A.128.C.4.i；A.129.C.4.i；A.130.C.4.i；A.131.C.4.i；A.132.C.4.i；A.133.C.4.i；A.134.C.4.i；A.135.C.4.i；A.136.C.4.i；A.137.C.4.i；A.138.C.4.i；A.139.C.4.i；A.140.C.4.i；A.141.C.4.i；A.142.C.4.i；A.143.C.4.i；A.144.C.4.i；A.145.C.4.i；A.146.C.4.i；A.147.C.4.i；A.148.C.4.i；A.149.C.4.i；A.150.C.4.i；A.151.C.4.i；A.152.C.4.i；A.153.C.4.i；A.154.C.4.i；A.155.C.4.i；A.156.C.4.i；A.157.C.4.i；A.158.C.4.i；A.159.C.4.i；A.160.C.4.i；A.161.C.4.i；A.162.C.4.i；A.163.C.4.i；A.164.C.4.i；A.165.C.4.i；A.166.C.4.i；A.167.C.4.i；A.168.C.4.i；A.169.C.4.i；A.170.C.4.i；A.171.C.4.i；A.172.C.4.i；A.173.C.4.i；A.174.C.4.i；A.175.C.4.i；A.176.C.4.i；A.177.C.4.i；A.178.C.4.i；A.179.C.4.i；A.180.C.4.i；A.181.C.4.i；A.182.C.4.i；A.183.C.4.i；A.184.C.4.i；A.185.C.4.i；A.186.C.4.i；A.187.C.4.i；A.188.C.4.i；A.189.C.4.i；
A.190.C.4.i；A.191.C.4.i；A.192.C.4.i；A.193.C.4.i；A.194.C.4.i；A.195.C.4.i；A.196.C.4.i；A.197.C.4.i；A.198.C.4.i；A.199.C.4.i；A.200.C.4.i；A.201.C.4.i；A.202.C.4.i；A.203.C.4.i；A.204.C.4.i；A.205.C.4.i；A.206.C.4.i；A.207.C.4.i；A.208.C.4.i；A.209.C.4.i；A.210.C.4.i；A.211.C.4.i；A.212.C.4.i；A.213.C.4.i；A.214.C.4.i；A.215.C.4.i；A.216.C.4.i；A.217.C.4.i；A.218.C.4.i；A.219.C.4.i；A.220.C.4.i；A.221.C.4.i；A.222.C.4.i；A.223.C.4.i；A.224.C.4.i；A.225.C.4.i；A.226.C.4.i；A.227.C.4.i；A.228.C.4.i；A.229.C.4.i；A.230.C.4.i；A.231.C.4.i；A.232.C.4.i；A.233.C.4.i；A.234.C.4.i；A.235.C.4.i；A.236.C.4.i；A.237.C.4.i；A.238.C.4.i；A.239.C.4.i；A.240.C.4.i；A.241.C.4.i；A.242.C.4.i；A.243.C.4.i；A.244.C.4.i；A.245.C.4.i；A.246.C.4.i；A.247.C.4.i；A.248.C.4.i；A.249.C.4.i；A.250.C.4.i；A.251.C.4.i；A.252.C.4.i；A.253.C.4.i；A.254.C.4.i；A.255.C.4.i；A.256.C.4.i；A.257.C.4.i；A.258.C.4.i；A.259.C.4.i；A.260.C.4.i；A.261.C.4.i；A.262.C.4.i；A.263.C.4.i；A.264.C.4.i；A.265.C.4.i；A.266.C.4.i；A.267.C.4.i；A.268.C.4.i；A.269.C.4.i；A.270.C.4.i；A.271.C.4.i；A.272.C.4.i；A.273.C.4.i；A.274.C.4.i；A.275.C.4.i；A.276.C.4.i；A.277.C.4.i；A.278.C.4.i；A.279.C.4.i；A.280.C.4.i；A.281.C.4.i；A.282.C.4.i；A.283.C.4.i；A.284.C.4.i；A.285.C.4.i；A.286.C.4.i；A.287.C.4.i；A.288.C.4.i；A.289.C.4.i；A.290.C.4.i；A.291.C.4.i；A.292.C.4.i；A.293.C.4.i；A.294.C.4.i；A.295.C.4.i；A.296.C.4.i；A.297.C.4.i；A.298.C.4.i；A.299.C.4.i；A.300.C.4.i；A.301.C.4.i；A.302.C.4.i；A.303.C.4.i；A.304.C.4.i；A.305.C.4.i；A.306.C.4.i；A.307.C.4.i；A.308.C.4.i；A.309.C.4.i；A.310.C.4.i；A.311.C.4.i；A.312.C.4.i；A.313.C.4.i；A.314.C.4.i；A.315.C.4.i；A.316.C.4.i；A.317.C.4.i；A.318.C.4.i；A.319.C.4.i；A.320.C.4.i；A.321.C.4.i；A.323.C.4.i；A.324.C.4.i；A.325.C.4.i；A.326.C.4.i；A.327.C.4.i；A.328.C.4.i；A.329.C.4.i；A.330.C.4.i；A.331.C.4.i；A.332.C.4.i；A.333.C.4.i；A.334.C.4.i；A.335.C.4.i；A.336.C.4.i；A.337.C.4.i；A.338.C.4.i；A.339.C.4.i；A.340.C.4.i；A.341.C.4.i；A.342.C.4.i；A.343.C.4.i；A.344.C.4.i；A.345.C.4.i；A.346.C.4.i；A.347.C.4.i；A.348.C.4.i；A.349.C.4.i；A.350.C.4.i；A.351.C.4.i；A.352.C.4.i；A.353.C.4.i；A.354.C.4.i；A.355.C.4.i；A.356.C.4.i；A.357.C.4.i；A.358.C.4.i；A.359.C.4.i；A.360.C.4.i；A.361.C.4.i；A.362.C.4.i；A.363.C.4.i；A.364.C.4.i；A.365.C.4.i；A.366.C.4.i；A.367.C.4.i；A.368.C.4.i；A.369.C.4.i；A.370.C.4.i；A.371.C.4.i；A.372.C.4.i；A.373.C.4.i；A.374.C.4.i；A.375.C.4.i；A.376.C.4.i；A.377.C.4.i；A.378.C.4.i；A.379.C.4.i；A.380.C.4.i；A.381.C.4.i；A.382.C.4.i；A.383.C.4.i；A.384.C.4.i；A.385.C.4.i；A.386.C.4.i；A.387.C.4.i；A.388.C.4.i；A.389.C.4.i；A.390.C.4.i；A.391.C.4.i；A.392.C.4.i；A.393.C.4.i；A.394.C.4.i；A.395.C.4.i；A.396.C.4.i；A.397.C.4.i；A.398.C.4.i；A.399.C.4.i；A.400.C.4.i；A.401.C.4.i；A.402.C.4.i；A.403.C.4.i；A.404.C.4.i；A.405.C.4.i；A.406.C.4.i；A.407.C.4.i；A.408.C.4.i；A.409.C.4.i；A.410.C.4.i；A.411.C.4.i；A.412.C.4.i；A.413.C.4.i；A.414.C.4.i；A.415.C.4.i；A.416.C.4.i；A.417.C.4.i；A.418.C.4.i；A.419.C.4.i；A.420.C.4.i；A.421.C.4.i；A.422.C.4.i；A.423.C.4.i；A.424.C.4.i；A.425.C.4.i；A.426.C.4.i；A.427.C.4.i；A.428.C.4.i；A.429.C.4.i；A.430.C.4.i；A.431.C.4.i；A.432.C.4.i；A.433.C.4.i；A.434.C.4.i；A.435.C.4.i；A.436.C.4.i；A.437.C.4.i；A.438.C.4.i；A.439.C.4.i；A.440.C.4.i；A.441.C.4.i；A.442.C.4.i；A.443.C.4.i；A.444.C.4.i；A.445.C.4.i；A.446.C.4.i；A.447.C.4.i；A.448.C.4.i；A.449.C.4.i；A.450.C.4.i；A.451.C.4.i；A.452.C.4.i；A.453.C.4.i；A.454.C.4.i；A.455.C.4.i；A.456.C.4.i；A.457.C.4.i；A.458.C.4.i；A.459.C.4.i；A.460.C.4.i；A.461.C.4.i；A.462.C.4.i；A.463.C.4.i；A.464.C.4.i；A.465.C.4.i；A.466.C.4.i；A.467.C.4.i；A.468.C.4.i；A.469.C.4.i；A.470.C.4.i；A.471.C.4.i；A.472.C.4.i；
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A.468.C.11.i；A.469.C.11.i；A.470.C.11.i；A.471.C.11.i；A.472.C.11.i；A.473.C.11.i；A.474.C.11.i；A.475.C.11.i；A.476.C.11.i；A.477.C.11.i；A.478.C.11.i；A.479.C.11.i；A.480.C.11.i；A.481.C.11.i；A.482.C.11.i；A.483.C.11.i；A.484.C.11.i；A.485.C.11.i；A.486.C.11.i；A.487.C.11.i；A.488.C.11.i；A.489.C.11.i；A.490.C.11.i；A.491.C.11.i；A.492.C.11.i；A.493.C.11.i；A.494.C.11.i；A.495.C.11.i；A.496.C.11.i；A.497.C.11.i；A.498.C.11.i；A.499.C.11.i；A.500.C.11.i；A.501.C.11.i；A.502.C.11.i；A.503.C.11.i；A.504.C.11.i；A.505.C.11.i；A.506.C.11.i；A.507.C.11.i；A.508.C.11.i；A.509.C.11.i；A.510.C.11.i；A.511.C.11.i；A.512.C.11.i；A.512.C.11.i；A.513.C.11.i；A.514.C.11.i；A.515.C.11.i；A.516.C.11.i；A.517.C.11.i；A.518.C.11.i；A.519.C.11.i；A.520.C.11.i；A.521.C.11.i；A.522.C.11.i；A.523.C.11.i；A.524.C.11.i；A.525.C.11.i；A.526.C.11.i；A.527.C.11.i；A.528.C.11.i；A.529.C.11.i；A.530.C.11.i；A.531.C.11.i；A.532.C.11.i；A.533.C.11.i；A.534.C.11.i；A.535.C.11.i；A.536.C.11.i；A.537.C.11.i；A.538.C.11.i；A.539.C.11.i；A.540.C.11.i；A.541.C.11.i；A.542.C.11.i；A.543.C.11.i；A.544.C.11.i；A.545.C.11.i；A.546.C.11.i；A.547.C.11.i；A.548.C.11.i；A.549.C.11.i；A.550.C.11.i；A.551.C.11.i；A.552.C.11.i；A.553.C.11.i；A.554.C.11.i；A.555.C.11.i；A.556.C.11.i；A.557.C.11.i；A.558.C.11.i；A.559.C.11.i；A.560.C.11.i；A.561.C.11.i；A.562.C.11.i；A.563.C.11.i；A.564.C.11.i；A.565.C.11.i；A.566.C.11.i；A.567.C.11.i；A.568.C.11.i；A.569.C.11.i；A.570.C.11.i；A.571.C.11.i；A.572.C.11.i；A.573.C.11.i；A.574.C.11.i；A.575.C.11.i；A.576.C.11.i；A.577.C.11.i；A.578.C.11.i；A.579.C.11.i；A.580.C.11.i；A.581.C.11.i；A.582.C.11.i；A.583.C.11.i；A.584.C.11.i；A.585.C.11.i；A.586.C.11.i；A.587.C.11.i；A.588.C.11.i；A.589.C.11.i；A.590.C.11.i；A.591.C.11.i；A.592.C.11.i；A.593.C.11.i；A.594.C.11.i；A.595.C.11.i；A.596.C.11.i；A.597.C.11.i；A.598.C.11.i；A.599.C.11.i；A.600.C.11.i；A.601.C.11.i；A.602.C.11.i；A.603.C.11.i；A.604.C.11.i；A.605.C.11.i；A.606.C.11.i；A.607.C.11.i；A.608.C.11.i；A.609.C.11.i；A.610.C.11.i；A.611.C.11.i；A.612.C.11.i；A.613.C.11.i；A.614.C.11.i；A.615.C.11.i；A.616.C.11.i；A.617.C.11.i；A.618.C.11.i；A.619.C.11.i；A.620.C.11.i；A.621.C.11.i；A.622.C.11.i；A.623.C.11.i；A.624.C.11.i；A.625.C.11.i；A.626.C.11.i；A.627.C.11.i；A.628.C.11.i；A.629.C.11.i；A.630.C.11.i；A.631.C.11.i；A.632.C.11.i；A.633.C.11.i；A.634.C.11.i；A.635.C.11.i；A.636.C.11.i；A.637.C.11.i；A.638.C.11.i；A.639.C.11.i；A.640.C.11.i；A.641.C.11.i；A.642.C.11.i；A.643.C.11.i；A.644.C.11.i；A.645.C.11.i；A.646.C.11.i；A.647.C.11.i；A.648.C.11.i；A.649.C.11.i；A.650.C.11.i；A.651.C.11.i；A.652.C.11.i；A.653.C.11.i；A.654.C.11.i；A.655.C.11.i；A.656.C.11.i；A.657.C.11.i；A.658.C.11.i；A.659.C.11.i；A.660.C.11.i；A.2.D.4.i；A.3.D.4.i；A.4.D.4.i；A.5.D.4.i；A.6.D.4.i；A.7.D.4.i；A.9.D.4.i；A.10.D.4.i；A.15.D.4.i；A.100.D.4.i；A.101.D.4.i；A.102.D.4.i；A.103.D.4.i；A.104.D.4.i；A.105.D.4.i；A.106.D.4.i；A.107.D.4.i；A.108.D.4.i；A.109.D.4.i；A.110.D.4.i；A.111.D.4.i；A.112.D.4.i；A.113.D.4.i；A.114.D.4.i；A.115.D.4.i；A.116.D.4.i；A.117.D.4.i；A.118.D.4.i；A.119.D.4.i；A.120.D.4.i；A.121.D.4.i；A.122.D.4.i；A.123.D.4.i；A.124.D.4.i；A.125.D.4.i；A.126.D.4.i；A.127.D.4.i；A.128.D.4.i；A.129.D.4.i；A.130.D.4.i；A.131.D.4.i；A.132.D.4.i；A.133.D.4.i；A.134.D.4.i；A.135.D.4.i；A.136.D.4.i；A.137.D.4.i；A.138.D.4.i；A.139.D.4.i；A.140.D.4.i；A.141.D.4.i；A.142.D.4.i；A.143.D.4.i；A.144.D.4.i；A.145.D.4.i；A.146.D.4.i；A.147.D.4.i；A.148.D.4.i；A.149.D.4.i；A.150.D.4.i；A.151.D.4.i；A.152.D.4.i；A.153.D.4.i；A.154.D.4.i；A.155.D.4.i；A.156.D.4.i；A.157.D.4.i；A.158.D.4.i；A.159.D.4.i；A.160.D.4.i；A.161.D.4.i；A.162.D.4.i；A.163.D.4.i；A.164.D.4.i；A.165.D.4.i；A.166.D.4.i；A.167.D.4.i；A.168.D.4.i；A.169.D.4.i；A.170.D.4.i；A.171.D.4.i；A.172.D.4.i；A.173.D.4.i；A.174.D.4.i；A.175.D.4.i；A.176.D.4.i；A.177.D.4.i；A.178.D.4.i；A.179.D.4.i；A.180.D.4.i；
A.181.D.4.i；A.182.D.4.i；A.183.D.4.i；A.184.D.4.i；A.185.D.4.i；A.186.D.4.i；A.187.D.4.i；A.188.D.4.i；A.189.D.4.i；A.190.D.4.i；A.191.D.4.i；A.192.D.4.i；A.193.D.4.i；A.194.D.4.i；A.195.D.4.i；A.196.D.4.i；A.197.D.4.i；A.198.D.4.i；A.199.D.4.i；A.200.D.4.i；A.201.D.4.i；A.202.D.4.i；A.203.D.4.i；A.204.D.4.i；A.205.D.4.i；A.206.D.4.i；A.207.D.4.i；A.208.D.4.i；A.209.D.4.i；A.210.D.4.i；A.211.D.4.i；A.212.D.4.i；A.213.D.4.i；A.214.D.4.i；A.215.D.4.i；A.216.D.4.i；A.217.D.4.i；A.218.D.4.i；A.219.D.4.i；A.220.D.4.i；A.221.D.4.i；A.222.D.4.i；A.223.D.4.i；A.224.D.4.i；A.225.D.4.i；A.226.D.4.i；A.227.D.4.i；A.228.D.4.i；A.229.D.4.i；A.230.D.4.i；A.231.D.4.i；A.232.D.4.i；A.233.D.4.i；A.234.D.4.i；A.235.D.4.i；A.236.D.4.i；A.237.D.4.i；A.238.D.4.i；A.239.D.4.i；A.240.D.4.i；A.241.D.4.i；A.242.D.4.i；A.243.D.4.i；A.244.D.4.i；A.245.D.4.i；A.246.D.4.i；A.247.D.4.i；A.248.D.4.i；A.249.D.4.i；A.250.D.4.i；A.251.D.4.i；A.252.D.4.i；A.253.D.4.i；A.254.D.4.i；A.255.D.4.i；A.256.D.4.i；A.257.D.4.i；A.258.D.4.i；A.259.D.4.i；A.260.D.4.i；A.261.D.4.i；A.262.D.4.i；A.263.D.4.i；A.264.D.4.i；A.265.D.4.i；A.266.D.4.i；A.267.D.4.i；A.268.D.4.i；A.269.D.4.i；A.270.D.4.i；A.271.D.4.i；A.272.D.4.i；A.273.D.4.i；A.274.D.4.i；A.275.D.4.i；A.276.D.4.i；A.277.D.4.i；A.278.D.4.i；A.279.D.4.i；A.280.D.4.i；A.281.D.4.i；A.282.D.4.i；A.283.D.4.i；A.284.D.4.i；A.285.D.4.i；A.286.D.4.i；A.287.D.4.i；A.288.D.4.i；A.289.D.4.i；A.290.D.4.i；A.291.D.4.i；A.292.D.4.i；A.293.D.4.i；A.294.D.4.i；A.295.D.4.i；A.296.D.4.i；A.297.D.4.i；A.298.D.4.i；A.299.D.4.i；A.300.D.4.i；A.301.D.4.i；A.302.D.4.i；A.303.D.4.i；A.304.D.4.i；A.305.D.4.i；A.306.D.4.i；A.307.D.4.i；A.308.D.4.i；A.309.D.4.i；A.310.D.4.i；A.311.D.4.i；A.312.D.4.i；A.313.D.4.i；A.314.D.4.i；A.315.D.4.i；A.316.D.4.i；A.317.D.4.i；A.318.D.4.i；A.319.D.4.i；A.320.D.4.i；A.321.D.4.i；A.323.D.4.i；A.324.D.4.i；A.325.D.4.i；A.326.D.4.i；A.327.D.4.i；A.328.D.4.i；A.329.D.4.i；A.330.D.4.i；A.331.D.4.i；A.332.D.4.i；A.333.D.4.i；A.334.D.4.i；A.335.D.4.i；A.336.D.4.i；A.337.D.4.i；A.338.D.4.i；A.339.D.4.i；A.340.D.4.i；A.341.D.4.i；A.342.D.4.i；A.343.D.4.i；A.344.D.4.i；A.345.D.4.i；A.346.D.4.i；A.347.D.4.i；A.348.D.4.i；A.349.D.4.i；A.350.D.4.i；A.351.D.4.i；A.352.D.4.i；A.353.D.4.i；A.354.D.4.i；A.355.D.4.i；A.356.D.4.i；A.357.D.4.i；A.358.D.4.i；A.359.D.4.i；A.360.D.4.i；A.361.D.4.i；A.362.D.4.i；A.363.D.4.i；A.364.D.4.i；A.365.D.4.i；A.366.D.4.i；A.367.D.4.i；A.368.D.4.i；A.369.D.4.i；A.370.D.4.i；A.371.D.4.i；A.372.D.4.i；A.373.D.4.i；A.374.D.4.i；A.375.D.4.i；A.376.D.4.i；A.377.D.4.i；A.378.D.4.i；A.379.D.4.i；A.380.D.4.i；A.381.D.4.i；A.382.D.4.i；A.383.D.4.i；A.384.D.4.i；A.385.D.4.i；A.386.D.4.i；A.387.D.4.i；A.388.D.4.i；A.389.D.4.i；A.390.D.4.i；A.391.D.4.i；A.392.D.4.i；A.393.D.4.i；A.394.D.4.i；A.395.D.4.i；A.396.D.4.i；A.397.D.4.i；A.398.D.4.i；A.399.D.4.i；A.400.D.4.i；A.401.D.4.i；A.402.D.4.i；A.403.D.4.i；A.404.D.4.i；A.405.D.4.i；A.406.D.4.i；A.407.D.4.i；A.408.D.4.i；A.409.D.4.i；A.410.D.4.i；A.411.D.4.i；A.412.D.4.i；A.413.D.4.i；A.414.D.4.i；A.415.D.4.i；A.416.D.4.i；A.417.D.4.i；A.418.D.4.i；A.419.D.4.i；A.420.D.4.i；A.421.D.4.i；A.422.D.4.i；A.423.D.4.i；A.424.D.4.i；A.425.D.4.i；A.426.D.4.i；A.427.D.4.i；A.428.D.4.i；A.429.D.4.i；A.430.D.4.i；A.431.D.4.i；A.432.D.4.i；A.433.D.4.i；A.434.D.4.i；A.435.D.4.i；A.436.D.4.i；A.437.D.4.i；A.438.D.4.i；A.439.D.4.i；A.440.D.4.i；A.441.D.4.i；A.442.D.4.i；A.443.D.4.i；A.444.D.4.i；A.445.D.4.i；A.446.D.4.i；A.447.D.4.i；A.448.D.4.i；A.449.D.4.i；A.450.D.4.i；A.451.D.4.i；A.452.D.4.i；A.453.D.4.i；A.454.D.4.i；A.455.D.4.i；A.456.D.4.i；A.457.D.4.i；A.458.D.4.i；A.459.D.4.i；A.460.D.4.i；A.461.D.4.i；A.462.D.4.i；A.463.D.4.i；
A.464.D.4.i；A.465.D.4.i；A.466.D.4.i；A.467.D.4.i；A.468.D.4.i；A.469.D.4.i；A.470.D.4.i；A.471.D.4.i；A.472.D.4.i；A.473.D.4.i；A.474.D.4.i；A.475.D.4.i；A.476.D.4.i；A.477.D.4.i；A.478.D.4.i；A.479.D.4.i；A.480.D.4.i；A.481.D.4.i；A.482.D.4.i；A.483.D.4.i；A.484.D.4.i；A.485.D.4.i；A.486.D.4.i；A.487.D.4.i；A.488.D.4.i；A.489.D.4.i；A.490.D.4.i；A.491.D.4.i；A.492.D.4.i；A.493.D.4.i；A.494.D.4.i；A.495.D.4.i；A.496.D.4.i；A.497.D.4.i；A.498.D.4.i；A.499.D.4.i；A.500.D.4.i；A.501.D.4.i；A.502.D.4.i；A.503.D.4.i；A.504.D.4.i；A.505.D.4.i；A.506.D.4.i；A.507.D.4.i；A.508.D.4.i；A.509.D.4.i；A.510.D.4.i；A.511.D.4.i；A.512.D.4.i；A.512.D.4.i；A.513.D.4.i；A.514.D.4.i；A.515.D.4.i；A.516.D.4.i；A.517.D.4.i；A.518.D.4.i；A.519.D.4.i；A.520.D.4.i；A.521.D.4.i；A.522.D.4.i；A.523.D.4.i；A.524.D.4.i；A.525.D.4.i；A.526.D.4.i；A.527.D.4.i；A.528.D.4.i；A.529.D.4.i；A.530.D.4.i；A.531.D.4.i；A.532.D.4.i；A.533.D.4.i；A.534.D.4.i；A.535.D.4.i；A.536.D.4.i；A.537.D.4.i；A.538.D.4.i；A.539.D.4.i；A.540.D.4.i；A.541.D.4.i；A.542.D.4.i；A.543.D.4.i；A.544.D.4.i；A.545.D.4.i；A.546.D.4.i；A.547.D.4.i；A.548.D.4.i；A.549.D.4.i；A.550.D.4.i；A.551.D.4.i；A.552.D.4.i；A.553.D.4.i；A.554.D.4.i；A.555.D.4.i；A.556.D.4.i；A.557.D.4.i；A.558.D.4.i；A.559.D.4.i；A.560.D.4.i；A.561.D.4.i；A.562.D.4.i；A.563.D.4.i；A.564.D.4.i；A.565.D.4.i；A.566.D.4.i；A.567.D.4.i；A.568.D.4.i；A.569.D.4.i；A.570.D.4.i；A.571.D.4.i；A.572.D.4.i；A.573.D.4.i；A.574.D.4.i；A.575.D.4.i；A.576.D.4.i；A.577.D.4.i；A.578.D.4.i；A.579.D.4.i；A.580.D.4.i；A.581.D.4.i；A.582.D.4.i；A.583.D.4.i；A.584.D.4.i；A.585.D.4.i；A.586.D.4.i；A.587.D.4.i；A.588.D.4.i；A.589.D.4.i；A.590.D.4.i；A.591.D.4.i；A.592.D.4.i；A.593.D.4.i；A.594.D.4.i；A.595.D.4.i；A.596.D.4.i；A.597.D.4.i；A.598.D.4.i；A.599.D.4.i；A.600.D.4.i；A.601.D.4.i；A.602.D.4.i；A.603.D.4.i；A.604.D.4.i；A.605.D.4.i；A.606.D.4.i；A.607.D.4.i；A.608.D.4.i；A.609.D.4.i；A.610.D.4.i；A.611.D.4.i；A.612.D.4.i；A.613.D.4.i；A.614.D.4.i；A.615.D.4.i；A.616.D.4.i；A.617.D.4.i；A.618.D.4.i；A.619.D.4.i；A.620.D.4.i；A.621.D.4.i；A.622.D.4.i；A.623.D.4.i；A.624.D.4.i；A.625.D.4.i；A.626.D.4.i；A.627.D.4.i；A.628.D.4.i；A.629.D.4.i；A.630.D.4.i；A.631.D.4.i；A.632.D.4.i；A.635.D.4.i；A.634.D.4.i；A.635.D.4.i；A.636.D.4.i；A.637.D.4.i；A.638.D.4.i；A.639.D.4.i；A.640.D.4.i；A.641.D.4.i；A.642.D.4.i；A.643.D.4.i；A.644.D.4.i；A.645.D.4.i；A.646.D.4.i；A.647.D.4.i；A.648.D.4.i；A.649.D.4.i；A.650.D.4.i；A.651.D.4.i；A.652.D.4.i；A.653.D.4.i；A.654.D.4.i；A.655.D.4.i；A.656.D.4.i；A.657.D.4.i；A.658.D.4.i；A.659.D.4.i；A.660.D.4.i；A.2.D.11.i；A.3.D.11.i；A.4.D.11.i；A.5.D.11.i；A.6.D.11.i；A.7.D.11.i；A.9.D.11.i；A.10.D.11.i；A.15.D.11.i；A.100.D.11.i；A.101.D.11.i；A.102.D.11.i；A.103.D.11.i；A.104.D.11.i；A.105.D.11.i；A.106.D.11.i；A.107.D.11.i；A.108.D.11.i；A.109.D.11.i；A.110.D.11.i；A.111.D.11.i；A.112.D.11.i；A.113.D.11.i；A.114.D.11.i；A.115.D.11.i；A.116.D.11.i；A.117.D.11.i；A.118.D.11.i；A.119.D.11.i；A.120.D.11.i；A.121.D.11.i；A.122.D.11.i；A.123.D.11.i；A.124.D.11.i；A.125.D.11.i；A.126.D.11.i；A.127.D.11.i；A.128.D.11.i；A.129.D.11.i；A.130.D.11.i；A.131.D.11.i；A.132.D.11.i；A.133.D.11.i；A.134.D.11.i；A.135.D.11.i；A.136.D.11.i；A.137.D.11.i；A.138.D.11.i；A.139.D.11.i；A.140.D.11.i；A.141.D.11.i；A.142.D.11.i；A.143.D.11.i；A.144.D.11.i；A.145.D.11.i；A.146.D.11.i；A.147.D.11.i；A.148.D.11.i；A.149.D.11.i；A.150.D.11.i；A.151.D.11.i；A.152.D.11.i；A.153.D.11.i；A.154.D.11.i；A.155.D.11.i；A.156.D.11.i；A.157.D.11.i；A.158.D.11.i；A.159.D.11.i；A.160.D.11.i；A.161.D.11.i；A.162.D.11.i；A.163.D.11.i；A.164.D.11.i；A.165.D.11.i；A.166.D.11.i；A.167.D.11.i；A.168.D.11.i；A.169.D.11.i；A.170.D.11.i；A.171.D.11.i；A.172.D.11.i；A.173.D.11.i；A.174.D.11.i；A.175.D.11.i；
A.176.D.11.i；A.177.D.11.i；A.178.D.11.i；A.179.D.11.i；A.180.D.11.i；A.181.D.11.i；A.182.D.11.i；A.183.D.11.i；A.184.D.11.i；A.185.D.11.i；A.186.D.11.i；A.187.D.11.i；A.188.D.11.i；A.189.D.11.i；A.190.D.11.i；A.191.D.11.i；A.192.D.11.i；A.193.D.11.i；A.194.D.11.i；A.195.D.11.i；A.196.D.11.i；A.197.D.11.i；A.198.D.11.i；A.199.D.11.i；A.200.D.11.i；A.201.D.11.i；A.202.D.11.i；A.203.D.11.i；A.204.D.11.i；A.205.D.11.i；A.206.D.11.i；A.207.D.11.i；A.208.D.11.i；A.209.D.11.i；A.210.D.11.i；A.211.D.11.i；A.212.D.11.i；A.213.D.11.i；A.214.D.11.i；A.215.D.11.i；A.216.D.11.i；A.217.D.11.i；A.218.D.11.i；A.219.D.11.i；A.220.D.11.i；A.221.D.11.i；A.222.D.11.i；A.223.D.11.i；A.224.D.11.i；A.225.D.11.i；A.226.D.11.i；A.227.D.11.i；A.228.D.11.i；A.229.D.11.i；A.230.D.11.i；A.231.D.11.i；A.232.D.11.i；A.233.D.11.i；A.234.D.11.i；A.235.D.11.i；A.236.D.11.i；A.237.D.11.i；A.238.D.11.i；A.239.D.11.i；A.240.D.11.i；A.241.D.11.i；A.242.D.11.i；A.243.D.11.i；A.244.D.11.i；A.245.D.11.i；A.246.D.11.i；A.247.D.11.i；A.248.D.11.i；A.249.D.11.i；A.250.D.11.i；A.251.D.11.i；A.252.D.11.i；A.253.D.11.i；A.254.D.11.i；A.255.D.11.i；A.256.D.11.i；A.257.D.11.i；A.258.D.11.i；A.259.D.11.i；A.260.D.11.i；A.261.D.11.i；A.262.D.11.i；A.263.D.11.i；A.264.D.11.i；A.265.D.11.i；A.266.D.11.i；A.267.D.11.i；A.268.D.11.i；A.269.D.11.i；A.270.D.11.i；A.271.D.11.i；A.272.D.11.i；A.273.D.11.i；A.274.D.11.i；A.275.D.11.i；A.276.D.11.i；A.277.D.11.i；A.278.D.11.i；A.279.D.11.i；A.280.D.11.i；A.281.D.11.i；A.282.D.11.i；A.283.D.11.i；A.284.D.11.i；A.285.D.11.i；A.286.D.11.i；A.287.D.11.i；A.288.D.11.i；A.289.D.11.i；A.290.D.11.i；A.291.D.11.i；A.292.D.11.i；A.293.D.11.i；A.294.D.11.i；A.295.D.11.i；A.296.D.11.i；A.297.D.11.i；A.298.D.11.i；A.299.D.11.i；A.300.D.11.i；A.301.D.11.i；A.302.D.11.i；A.303.D.11.i；A.304.D.11.i；A.305.D.11.i；A.306.D.11.i；A.307.D.11.i；A.308.D.11.i；A.309.D.11.i；A.310.D.11.i；A.311.D.11.i；A.312.D.11.i；A.313.D.11.i；A.314.D.11.i；A.315.D.11.i；A.316.D.11.i；A.317.D.11.i；A.318.D.11.i；A.319.D.11.i；A.320.D.11.i；A.321.D.11.i；A.323.D.11.i；A.324.D.11.i；A.325.D.11.i；A.326.D.11.i；A.327.D.11.i；A.328.D.11.i；A.329.D.11.i；A.330.D.11.i；A.331.D.11.i；A.332.D.11.i；A.333.D.11.i；A.334.D.11.i；A.335.D.11.i；A.336.D.11.i；A.337.D.11.i；A.338.D.11.i；A.339.D.11.i；A.340.D.11.i；A.341.D.11.i；A.342.D.11.i；A.343.D.11.i；A.344.D.11.i；A.345.D.11.i；A.346.D.11.i；A.347.D.11.i；A.348.D.11.i；A.349.D.11.i；A.350.D.11.i；A.351.D.11.i；A.352.D.11.i；A.353.D.11.i；A.354.D.11.i；A.355.D.11.i；A.356.D.11.i；A.357.D.11.i；A.358.D.11.i；A.359.D.11.i；A.360.D.11.i；A.361.D.11.i；A.362.D.11.i；A.363.D.11.i；A.364.D.11.i；A.365.D.11.i；A.366.D.11.i；A.367.D.11.i；A.368.D.11.i；A.369.D.11.i；A.370.D.11.i；A.371.D.11.i；A.372.D.11.i；A.373.D.11.i；A.374.D.11.i；A.375.D.11.i；A.376.D.11.i；A.377.D.11.i；A.378.D.11.i；A.379.D.11.i；A.380.D.11.i；A.381.D.11.i；A.382.D.11.i；A.383.D.11.i；A.384.D.11.i；A.385.D.11.i；A.386.D.11.i；A.387.D.11.i；A.388.D.11.i；A.389.D.11.i；A.390.D.11.i；A.391.D.11.i；A.392.D.11.i；A.393.D.11.i；A.394.D.11.i；A.395.D.11.i；A.396.D.11.i；A.397.D.11.i；A.398.D.11.i；A.399.D.11.i；A.400.D.11.i；A.401.D.11.i；A.402.D.11.i；A.403.D.11.i；A.404.D.11.i；A.405.D.11.i；A.406.D.11.i；A.407.D.11.i；A.408.D.11.i；A.409.D.11.i；A.410.D.11.i；A.411.D.11.i；A.412.D.11.i；A.413.D.11.i；A.414.D.11.i；A.415.D.11.i；A.416.D.11.i；A.417.D.11.i；A.418.D.11.i；A.419.D.11.i；A.420.D.11.i；A.421.D.11.i；A.422.D.11.i；A.423.D.11.i；A.424.D.11.i；A.425.D.11.i；A.426.D.11.i；A.427.D.11.i；A.428.D.11.i；A.429.D.11.i；A.430.D.11.i；A.431.D.11.i；A.432.D.11.i；A.433.D.11.i；A.434.D.11.i；A.435.D.11.i；A.436.D.11.i；A.437.D.11.i；A.438.D.11.i；A.439.D.11.i；A.440.D.11.i；A.441.D.11.i；A.442.D.11.i；A.443.D.11.i；A.444.D.11.i；A.445.D.11.i；A.446.D.11.i；A.447.D.11.i；A.448.D.11.i；A.449.D.11.i；A.450.D.11.i；A.451.D.11.i；A.452.D.11.i；A.453.D.11.i；A.454.D.11.i；A.455.D.11.i；A.456.D.11.i；A.457.D.11.i；A.458.D.11.i；
A.459.D.11.i；A.460.D.11.i；A.461.D.11.i；A.462.D.11.i；A.463.D.11.i；A.464.D.11.i；A.465.D.11.i；A.466.D.11.i；A.467.D.11.i；A.468.D.11.i；A.469.D.11.i；A.470.D.11.i；A.471.D.11.i；A.472.D.11.i；A.473.D.11.i；A.474.D.11.i；A.475.D.11.i；A.476.D.11.i；A.477.D.11.i；A.478.D.11.i；A.479.D.11.i；A.480.D.11.i；A.481.D.11.i；A.482.D.11.i；A.483.D.11.i；A.484.D.11.i；A.485.D.11.i；A.486.D.11.i；A.487.D.11.i；A.488.D.11.i；A.489.D.11.i；A.490.D.11.i；A.491.D.11.i；A.492.D.11.i；A.493.D.11.i；A.494.D.11.i；A.495.D.11.i；A.496.D.11.i；A.497.D.11.i；A.498.D.11.i；A.499.D.11.i；A.500.D.11.i；A.501.D.11.i；A.502.D.11.i；A.503.D.11.i；A.504.D.11.i；A.505.D.11.i；A.506.D.11.i；A.507.D.11.i；A.508.D.11.i；A.509.D.11.i；A.510.D.11.i；A.511.D.11.i；A.512.D.11.i；A.512.D.11.i；A.513.D.11.i；A.514.D.11.i；A.515.D.11.i；A.516.D.11.i；A.517.D.11.i；A.518.D.11.i；A.519.D.11.i；A.520.D.11.i；A.521.D.11.i；A.522.D.11.i；A.523.D.11.i；A.524.D.11.i；A.525.D.11.i；A.526.D.11.i；A.527.D.11.i；A.528.D.11.i；A.529.D.11.i；A.530.D.11.i；A.531.D.11.i；A.532.D.11.i；A.533.D.11.i；A.534.D.11.i；A.535.D.11.i；A.536.D.11.i；A.537.D.11.i；A.538.D.11.i；A.539.D.11.i；A.540.D.11.i；A.541.D.11.i；A.542.D.11.i；A.543.D.11.i；A.544.D.11.i；A.545.D.11.i；A.546.D.11.i；A.547.D.11.i；A.548.D.11.i；A.549.D.11.i；A.550.D.11.i；A.551.D.11.i；A.552.D.11.i；A.553.D.11.i；A.554.D.11.i；A.555.D.11.i；A.556.D.11.i；A.557.D.11.i；A.558.D.11.i；A.559.D.11.i；A.560.D.11.i；A.561.D.11.i；A.562.D.11.i；A.563.D.11.i；A.564.D.11.i；A.565.D.11.i；A.566.D.11.i；A.567.D.11.i；A.568.D.11.i；A.569.D.11.i；A.570.D.11.i；A.571.D.11.i；A.572.D.11.i；A.573.D.11.i；A.574.D.11.i；A.575.D.11.i；A.576.D.11.i；A.577.D.11.i；A.578.D.11.i；A.579.D.11.i；A.580.D.11.i；A.581.D.11.i；A.582.D.11.i；A.583.D.11.i；A.584.D.11.i；A.585.D.11.i；A.586.D.11.i；A.587.D.11.i；A.588.D.11.i；A.589.D.11.i；A.590.D.11.i；A.591.D.11.i；A.592.D.11.i；A.593.D.11.i；A.594.D.11.i；A.595.D.11.i；A.596.D.11.i；A.597.D.11.i；A.598.D.11.i；A.599.D.11.i；A.600.D.11.i；A.601.D.11.i；A.602.D.11.i；A.603.D.11.i；A.604.D.11.i；A.605.D.11.i；A.606.D.11.i；A.607.D.11.i；A.608.D.11.i；A.609.D.11.i；A.610.D.11.i；A.611.D.11.i；A.612.D.11.i；A.613.D.11.i；A.614.D.11.i；A.615.D.11.i；A.616.D.11.i；A.617.D.11.i；A.618.D.11.i；A.619.D.11.i；A.620.D.11.i；A.621.D.11.i；A.622.D.11.i；A.623.D.11.i；A.624.D.11.i；A.625.D.11.i；A.626.D.11.i；A.627.D.11.i；A.628.D.11.i；A.629.D.11.i；A.630.D.11.i；A.631.D.11.i；A.632.D.11.i；A.633.D.11.i；A.634.D.11.i；A.635.D.11.i；A.636.D.11.i；A.637.D.11.i；A.638.D.11.i；A.639.D.11.i；A.640.D.11.i；A.641.D.11.i；A.642.D.11.i；A.643.D.11.i；A.644.D.11.i；A.645.D.11.i；A.646.D.11.i；A.647.D.11.i；A.648.D.11.i；A.649.D.11.i；A.650.D.11.i；A.651.D.11.i；A.652.D.11.i；A.653.D.11.i；A.654.D.11.i；A.655.D.11.i；A.656.D.11.i；A.657.D.11.i；A.658.D.11.i；A.659.D.11.i；A.660.D.11.i；A.2.E.4.i；A.3.E.4.i；A.4.E.4.i；A.5.E.4.i；A.6.E.4.i；A.7.E.4.i；A.9.E.4.i；A.10.E.4.i；A.15.E.4.i；A.100.E.4.i；A.101.E.4.i；A.102.E.4.i；A.103.E.4.i；A.104.E.4.i；A.105.E.4.i；A.106.E.4.i；A.107.E.4.i；A.108.E.4.i；A.109.E.4.i；A.110.E.4.i；A.111.E.4.i；A.112.E.4.i；A.113.E.4.i；A.114.E.4.i；A.115.E.4.i；A.116.E.4.i；A.117.E.4.i；A.118.E.4.i；A.119.E.4.i；A.120.E.4.i；A.121.E.4.i；A.122.E.4.i；A.123.E.4.i；A.124.E.4.i；A.125.E.4.i；A.126.E.4.i；A.127.E.4.i；A.128.E.4.i；A.129.E.4.i；A.130.E.4.i；A.131.E.4.i；A.132.E.4.i；A.133.E.4.i；A.134.E.4.i；A.135.E.4.i；A.136.E.4.i；A.137.E.4.i；A.138.E.4.i；A.139.E.4.i；A.140.E.4.i；A.141.E.4.i；A.142.E.4.i；A.143.E.4.i；A.144.E.4.i；A.145.E.4.i；A.146.E.4.i；A.147.E.4.i；A.148.E.4.i；A.149.E.4.i；A.150.E.4.i；A.151.E.4.i；A.152.E.4.i；A.153.E.4.i；A.154.E.4.i；A.155.E.4.i；A.156.E.4.i；A.157.E.4.i；A.158.E.4.i；A.159.E.4.i；A.160.E.4.i；A.161.E.4.i；A.162.E.4.i；A.163.E.4.i；A.164.E.4.i；A.165.E.4.i；A.166.E.4.i；A.167.E.4.i；A.168.E.4.i；A.169.E.4.i；A.170.E.4.i；A.171.E.4.i；
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A.450.E.11.i；A.451.E.11.i；A.452.E.11.i；A.453.E.11.i；A.454.E.11.i；A.455.E.11.i；A.456.E.11.i；A.457.E.11.i；A.458.E.11.i；A.459.E.11.i；A.460.E.11.i；A.461.E.11.i；A.462.E.11.i；A.463.E.11.i；A.464.E.11.i；A.465.E.11.i；A.466.E.11.i；A.467.E.11.i；A.468.E.11.i；A.469.E.11.i；A.470.E.11.i；A.471.E.11.i；A.472.E.11.i；A.473.E.11.i；A.474.E.11.i；A.475.E.11.i；A.476.E.11.i；A.477.E.11.i；A.478.E.11.i；A.479.E.11.i；A.480.E.11.i；A.481.E.11.i；A.482.E.11.i；A.483.E.11.i；A.484.E.11.i；A.485.E.11.i；A.486.E.11.i；A.487.E.11.i；A.488.E.11.i；A.489.E.11.i；A.490.E.11.i；A.491.E.11.i；A.492.E.11.i；A.493.E.11.i；A.494.E.11.i；A.495.E.11.i；A.496.E.11.i；A.497.E.11.i；A.498.E.11.i；A.499.E.11.i；A.500.E.11.i；A.501.E.11.i；A.502.E.11.i；A.503.E.11.i；A.504.E.11.i；A.505.E.11.i；A.506.E.11.i；A.507.E.11.i；A.508.E.11.i；A.509.E.11.i；A.510.E.11.i；A.511.E.11.i；A.512.E.11.i；A.512.E.11.i；A.513.E.11.i；A.514.E.11.i；A.515.E.11.i；A.516.E.11.i；A.517.E.11.i；A.518.E.11.i；A.519.E.11.i；A.520.E.11.i；A.521.E.11.i；A.522.E.11.i；A.523.E.11.i；A.524.E.11.i；A.525.E.11.i；A.526.E.11.i；A.527.E.11.i；A.528.E.11.i；A.529.E.11.i；A.530.E.11.i；A.531.E.11.i；A.532.E.11.i；A.533.E.11.i；A.534.E.11.i；A.535.E.11.i；A.536.E.11.i；A.537.E.11.i；A.538.E.11.i；A.539.E.11.i；A.540.E.11.i；A.541.E.11.i；A.542.E.11.i；A.543.E.11.i；A.544.E.11.i；A.545.E.11.i；A.546.E.11.i；A.547.E.11.i；A.548.E.11.i；A.549.E.11.i；A.550.E.11.i；A.551.E.11.i；A.552.E.11.i；A.553.E.11.i；A.554.E.11.i；A.555.E.11.i；A.556.E.11.i；A.557.E.11.i；A.558.E.11.i；A.559.E.11.i；A.560.E.11.i；A.561.E.11.i；A.562.E.11.i；A.563.E.11.i；A.564.E.11.i；A.565.E.11.i；A.566.E.11.i；A.567.E.11.i；A.568.E.11.i；A.569.E.11.i；A.570.E.11.i；A.571.E.11.i；A.572.E.11.i；A.573.E.11.i；A.574.E.11.i；A.575.E.11.i；A.576.E.11.i；A.577.E.11.i；A.578.E.11.i；A.579.E.11.i；A.580.E.11.i；A.581.E.11.i；A.582.E.11.i；A.583.E.11.i；A.584.E.11.i；A.585.E.11.i；A.586.E.11.i；A.587.E.11.i；A.588.E.11.i；A.589.E.11.i；A.590.E.11.i；A.591.E.11.i；A.592.E.11.i；A.593.E.11.i；A.594.E.11.i；A.595.E.11.i；A.596.E.11.i；A.597.E.11.i；A.598.E.11.i；A.599.E.11.i；A.600.E.11.i；A.601.E.11.i；A.602.E.11.i；A.603.E.11.i；A.604.E.11.i；A.605.E.11.i；A.606.E.11.i；A.607.E.11.i；A.608.E.11.i；A.609.E.11.i；A.610.E.11.i；A.611.E.11.i；A.612.E.11.i；A.613.E.11.i；A.614.E.11.i；A.615.E.11.i；A.616.E.11.i；A.617.E.11.i；A.618.E.11.i；A.619.E.11.i；A.620.E.11.i；A.621.E.11.i；A.622.E.11.i；A.623.E.11.i；A.624.E.11.i；A.625.E.11.i；A.626.E.11.i；A.627.E.11.i；A.628.E.11.i；A.629.E.11.i；A.630.E.11.i；A.631.E.11.i；A.632.E.11.i；A.633.E.11.i；A.634.E.11.i；A.635.E.11.i；A.636.E.11.i；A.637.E.11.i；A.638.E.11.i；A.639.E.11.i；A.640.E.11.i；A.641.E.11.i；A.642.E.11.i；A.643.E.11.i；A.644.E.11.i；A.645.E.11.i；A.646.E.11.i；A.647.E.11.i；A.648.E.11.i；A.649.E.11.i；A.650.E.11.i；A.651.E.11.i；A.652.E.11.i；A.653.E.11.i；A.654.E.11.i；A.655.E.11.i；A.656.E.11.i；A.657.E.11.i；A.658.E.11.i；A.659.E.11.i；A.660.E.11.i；A.2.F.4.i；A.3.F.4.i；A.4.F.4.i；A.5.F.4.i；A.6.F.4.i；A.7.F.4.i；A.9.F.4.i；A.10.F.4.i；A.15.F.4.i；A.100.F.4.i；A.101.F.4.i；A.102.F.4.i；A.103.F.4.i；A.104.F.4.i；A.105.F.4.i；A.106.F.4.i；A.107.F.4.i；A.108.F.4.i；A.109.F.4.i；A.110.F.4.i；A.111.F.4.i；A.112.F.4.i；A.113.F.4.i；A.114.F.4.i；A.115.F.4.i；A.116.F.4.i；A.117.F.4.i；A.118.F.4.i；A.119.F.4.i；A.120.F.4.i；A.121.F.4.i；A.122.F.4.i；A.123.F.4.i；A.124.F.4.i；A.125.F.4.i；A.126.F.4.i；A.127.F.4.i；A.128.F.4.i；A.129.F.4.i；A.130.F.4.i；A.131.F.4.i；A.132.F.4.i；A.133.F.4.i；A.134.F.4.i；A.135.F.4.i；A.136.F.4.i；A.137.F.4.i；A.138.F.4.i；A.139.F.4.i；A.140.F.4.i；A.141.F.4.i；A.142.F.4.i；A.143.F.4.i；A.144.F.4.i；A.145.F.4.i；A.146.F.4.i；A.147.F.4.i；A.148.F.4.i；A.149.F.4.i；A.150.F.4.i；A.151.F.4.i；A.152.F.4.i；A.153.F.4.i；A.154.F.4.i；A.155.F.4.i；A.156.F.4.i；A.157.F.4.i；A.158.F.4.i；A.159.F.4.i；A.160.F.4.i；A.161.F.4.i；A.162.F.4.i；
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A.158.F.11.i；A.159.F.11.i；A.160.F.11.i；A.161.F.11.i；A.162.F.11.i；A.163.F.11.i；A.164.F.11.i；A.165.F.11.i；A.166.F.11.i；A.167.F.11.i；A.168.F.11.i；A.169.F.11.i；A.170.F.11.i；A.171.F.11.i；A.172.F.11.i；A.173.F.11.i；A.174.F.11.i；A.175.F.11.i；A.176.F.11.i；A.177.F.11.i；A.178.F.11.i；A.179.F.11.i；A.180.F.11.i；A.181.F.11.i；A.182.F.11.i；A.183.F.11.i；A.184.F.11.i；A.185.F.11.i；A.186.F.11.i；A.187.F.11.i；A.188.F.11.i；A.189.F.11.i；A.190.F.11.i；A.191.F.11.i；A.192.F.11.i；A.193.F.11.i；A.194.F.11.i；A.195.F.11.i；A.196.F.11.i；A.197.F.11.i；A.198.F.11.i；A.199.F.11.i；A.200.F.11.i；A.201.F.11.i；A.202.F.11.i；A.203.F.11.i；A.204.F.11.i；A.205.F.11.i；A.206.F.11.i；A.207.F.11.i；A.208.F.11.i；A.209.F.11.i；A.210.F.11.i；A.211.F.11.i；A.212.F.11.i；A.213.F.11.i；A.214.F.11.i；A.215.F.11.i；A.216.F.11.i；A.217.F.11.i；A.218.F.11.i；A.219.F.11.i；A.220.F.11.i；A.221.F.11.i；A.222.F.11.i；A.223.F.11.i；A.224.F.11.i；A.225.F.11.i；A.226.F.11.i；A.227.F.11.i；A.228.F.11.i；A.229.F.11.i；A.230.F.11.i；A.231.F.11.i；A.232.F.11.i；A.233.F.11.i；A.234.F.11.i；A.235.F.11.i；A.236.F.11.i；A.237.F.11.i；A.238.F.11.i；A.239.F.11.i；A.240.F.11.i；A.241.F.11.i；A.242.F.11.i；A.243.F.11.i；A.244.F.11.i；A.245.F.11.i；A.246.F.11.i；A.247.F.11.i；A.248.F.11.i；A.249.F.11.i；A.250.F.11.i；A.251.F.11.i；A.252.F.11.i；A.253.F.11.i；A.254.F.11.i；A.255.F.11.i；A.256.F.11.i；A.257.F.11.i；A.258.F.11.i；A.259.F.11.i；A.260.F.11.i；A.261.F.11.i；A.262.F.11.i；A.263.F.11.i；A.264.F.11.i；A.265.F.11.i；A.266.F.11.i；A.267.F.11.i；A.268.F.11.i；A.269.F.11.i；A.270.F.11.i；A.271.F.11.i；A.272.F.11.i；A.273.F.11.i；A.274.F.11.i；A.275.F.11.i；A.276.F.11.i；A.277.F.11.i；A.278.F.11.i；A.279.F.11.i；A.280.F.11.i；A.281.F.11.i；A.282.F.11.i；A.283.F.11.i；A.284.F.11.i；A.285.F.11.i；A.286.F.11.i；A.287.F.11.i；A.288.F.11.i；A.289.F.11.i；A.290.F.11.i；A.291.F.11.i；A.292.F.11.i；A.293.F.11.i；A.294.F.11.i；A.295.F.11.i；A.296.F.11.i；A.297.F.11.i；A.298.F.11.i；A.299.F.11.i；A.300.F.11.i；A.301.F.11.i；A.302.F.11.i；A.303.F.11.i；A.304.F.11.i；A.305.F.11.i；A.306.F.11.i；A.307.F.11.i；A.308.F.11.i；A.309.F.11.i；A.310.F.11.i；A.311.F.11.i；A.312.F.11.i；A.313.F.11.i；A.314.F.11.i；A.315.F.11.i；A.316.F.11.i；A.317.F.11.i；A.318.F.11.i；A.319.F.11.i；A.320.F.11.i；A.321.F.11.i；A.323.F.11.i；A.324.F.11.i；A.325.F.11.i；A.326.F.11.i；A.327.F.11.i；A.328.F.11.i；A.329.F.11.i；A.330.F.11.i；A.331.F.11.i；A.332.F.11.i；A.333.F.11.i；A.334.F.11.i；A.335.F.11.i；A.336.F.11.i；A.337.F.11.i；A.338.F.11.i；A.339.F.11.i；A.340.F.11.i；A.341.F.11.i；A.342.F.11.i；A.343.F.11.i；A.344.F.11.i；A.345.F.11.i；A.346.F.11.i；A.347.F.11.i；A.348.F.11.i；A.349.F.11.i；A.350.F.11.i；A.351.F.11.i；A.352.F.11.i；A.353.F.11.i；A.354.F.11.i；A.355.F.11.i；A.356.F.11.i；A.357.F.11.i；A.358.F.11.i；A.359.F.11.i；A.360.F.11.i；A.361.F.11.i；A.362.F.11.i；A.363.F.11.i；A.364.F.11.i；A.365.F.11.i；A.366.F.11.i；A.367.F.11.i；A.368.F.11.i；A.369.F.11.i；A.370.F.11.i；A.371.F.11.i；A.372.F.11.i；A.373.F.11.i；A.374.F.11.i；A.375.F.11.i；A.376.F.11.i；A.377.F.11.i；A.378.F.11.i；A.379.F.11.i；A.380.F.11.i；A.381.F.11.i；A.382.F.11.i；A.383.F.11.i；A.384.F.11.i；A.385.F.11.i；A.386.F.11.i；A.387.F.11.i；A.388.F.11.i；A.389.F.11.i；A.390.F.11.i；A.391.F.11.i；A.392.F.11.i；A.393.F.11.i；A.394.F.11.i；A.395.F.11.i；A.396.F.11.i；A.397.F.11.i；A.398.F.11.i；A.399.F.11.i；A.400.F.11.i；A.401.F.11.i；A.402.F.11.i；A.403.F.11.i；A.404.F.11.i；A.405.F.11.i；A.406.F.11.i；A.407.F.11.i；A.408.F.11.i；A.409.F.11.i；A.410.F.11.i；A.411.F.11.i；A.412.F.11.i；A.413.F.11.i；A.414.F.11.i；A.415.F.11.i；A.416.F.11.i；A.417.F.11.i；A.418.F.11.i；A.419.F.11.i；A.420.F.11.i；A.421.F.11.i；A.422.F.11.i；A.423.F.11.i；A.424.F.11.i；A.425.F.11.i；A.426.F.11.i；A.427.F.11.i；A.428.F.11.i；A.429.F.11.i；A.430.F.11.i；A.431.F.11.i；A.432.F.11.i；A.433.F.11.i；A.434.F.11.i；A.435.F.11.i；A.436.F.11.i；A.437.F.11.i；A.438.F.11.i；A.439.F.11.i；A.440.F.11.i；
A.441.F.11.i；A.442.F.11.i；A.443.F.11.i；A.444.F.11.i；A.445.F.11.i；A.446.F.11.i；A.447.F.11.i；A.448.F.11.i；A.449.F.11.i；A.450.F.11.i；A.451.F.11.i；A.452.F.11.i；A.453.F.11.i；A.454.F.11.i；A.455.F.11.i；A.456.F.11.i；A.457.F.11.i；A.458.F.11.i；A.459.F.11.i；A.460.F.11.i；A.461.F.11.i；A.462.F.11.i；A.463.F.11.i；A.464.F.11.i；A.465.F.11.i；A.466.F.11.i；A.467.F.11.i；A.468.F.11.i；A.469.F.11.i；A.470.F.11.i；A.471.F.11.i；A.472.F.11.i；A.473.F.11.i；A.474.F.11.i；A.475.F.11.i；A.476.F.11.i；A.477.F.11.i；A.478.F.11.i；A.479.F.11.i；A.480.F.11.i；A.481.F.11.i；A.482.F.11.i；A.483.F.11.i；A.484.F.11.i；A.485.F.11.i；A.486.F.11.i；A.487.F.11.i；A.488.F.11.i；A.489.F.11.i；A.490.F.11.i；A.491.F.11.i；A.492.F.11.i；A.493.F.11.i；A.494.F.11.i；A.495.F.11.i；A.496.F.11.i；A.497.F.11.i；A.498.F.11.i；A.499.F.11.i；A.500.F.11.i；A.501.F.11.i；A.502.F.11.i；A.503.F.11.i；A.504.F.11.i；A.505.F.11.i；A.506.F.11.i；A.507.F.11.i；A.508.F.11.i；A.509.F.11.i；A.510.F.11.i；A.511.F.11.i；A.512.F.11.i；A.512.F.11.i；A.513.F.11.i；A.514.F.11.i；A.515.F.11.i；A.516.F.11.i；A.517.F.11.i；A.518.F.11.i；A.519.F.11.i；A.520.F.11.i；A.521.F.11.i；A.522.F.11.i；A.523.F.11.i；A.524.F.11.i；A.525.F.11.i；A.526.F.11.i；A.527.F.11.i；A.528.F.11.i；A.529.F.11.i；A.530.F.11.i；A.531.F.11.i；A.532.F.11.i；A.533.F.11.i；A.534.F.11.i；A.535.F.11.i；A.536.F.11.i；A.537.F.11.i；A.538.F.11.i；A.539.F.11.i；A.540.F.11.i；A.541.F.11.i；A.542.F.11.i；A.543.F.11.i；A.544.F.11.i；A.545.F.11.i；A.546.F.11.i；A.547.F.11.i；A.548.F.11.i；A.549.F.11.i；A.550.F.11.i；A.551.F.11.i；A.552.F.11.i；A.553.F.11.i；A.554.F.11.i；A.555.F.11.i；A.556.F.11.i；A.557.F.11.i；A.558.F.11.i；A.559.F.11.i；A.560.F.11.i；A.561.F.11.i；A.562.F.11.i；A.563.F.11.i；A.564.F.11.i；A.565.F.11.i；A.566.F.11.i；A.567.F.11.i；A.568.F.11.i；A.569.F.11.i；A.570.F.11.i；A.571.F.11.i；A.572.F.11.i；A.573.F.11.i；A.574.F.11.i；A.575.F.11.i；A.576.F.11.i；A.577.F.11.i；A.578.F.11.i；A.579.F.11.i；A.580.F.11.i；A.581.F.11.i；A.582.F.11.i；A.583.F.11.i；A.584.F.11.i；A.585.F.11.i；A.586.F.11.i；A.587.F.11.i；A.588.F.11.i；A.589.F.11.i；A.590.F.11.i；A.591.F.11.i；A.592.F.11.i；A.593.F.11.i；A.594.F.11.i；A.595.F.11.i；A.596.F.11.i；A.597.F.11.i；A.598.F.11.i；A.599.F.11.i；A.600.F.11.i；A.601.F.11.i；A.602.F.11.i；A.603.F.11.i；A.604.F.11.i；A.605.F.11.i；A.606.F.11.i；A.607.F.11.i；A.608.F.11.i；A.609.F.11.i；A.610.F.11.i；A.611.F.11.i；A.612.F.11.i；A.613.F.11.i；A.614.F.11.i；A.615.F.11.i；A.616.F.11.i；A.617.F.11.i；A.618.F.11.i；A.619.F.11.i；A.620.F.11.i；A.621.F.11.i；A.622.F.11.i；A.623.F.11.i；A.624.F.11.i；A.625.F.11.i；A.626.F.11.i；A.627.F.11.i；A.628.F.11.i；A.629.F.11.i；A.630.F.11.i；A.631.F.11.i；A.632.F.11.i；A.633.F.11.i；A.634.F.11.i；A.635.F.11.i；A.636.F.11.i；A.637.F.11.i；A.638.F.11.i；A.639.F.11.i；A.640.F.11.i；A.641.F.11.i；A.642.F.11.i；A.643.F.11.i；A.644.F.11.i；A.645.F.11.i；A.646.F.11.i；A.647.F.11.i；A.648.F.11.i；A.649.F.11.i；A.650.F.11.i；A.651.F.11.i；A.652.F.11.i；A.653.F.11.i；A.654.F.11.i；A.655.F.11.i；A.656.F.11.i；A.657.F.11.i；A.658.F.11.i；A.659.F.11.i；A.660.F.11.i；A.2.a.44.i；A.3.a.44.i；A.4.a.44.i；A.5.a.44.i；A.9.a.44.i；A.100.a.44.i；A.101.a.44.i；A.102.a.44.i；A.103.a.44.i；A.104.a.44.i；A.105.a.44.i；A.106.a.44.i；A.107.a.44.i；A.108.a.44.i；A.109.a.44.i；A.110.a.44.i；A.111.a.44.i；A.112.a.44.i；A.113.a.44.i；A.114.a.44.i；A.115.a.44.i；A.116.a.44.i；A.117.a.44.i；A.118.a.44.i；A.119.a.44.i；A.120.a.44.i；A.121.a.44.i；A.122.a.44.i；A.123.a.44.i；A.124.a.44.i；A.125.a.44.i；A.126.a.44.i；A.127.a.44.i；A.128.a.44.i；A.129.a.44.i；A.130.a.44.i；A.131.a.44.i；A.132.a.44.i；A.133.a.44.i；A.134.a.44.i；A.135.a.44.i；A.136.a.44.i；A.137.a.44.i；A.138.a.44.i；A.139.a.44.i；A.140.a.44.i；A.141.a.44.i；A.142.a.44.i；A.143.a.44.i；A.144.a.44.i；A.145.a.44.i；A.146.a.44.i；A.147.a.44.i；A.148.a.44.i；A.149.a.44.i；A.150.a.44.i；A.151.a.44.i；A.152.a.44.i；A.153.a.44.i；A.154.a.44.i；A.155.a.44.i；A.156.a.44.i；
A.157.a.44.i；A.158.a.44.i；A.159.a.44.i；A.160.a.44.i；A.161.a.44.i；A.162.a.44.i；A.163.a.44.i；A.164.a.44.i；A.165.a.44.i；A.166.a.44.i；A.167.a.44.i；A.168.a.44.i；A.169.a.44.i；A.170.a.44.i；A.171.a.44.i；A.172.a.44.i；A.173.a.44.i；A.174.a.44.i；A.175.a.44.i；A.176.a.44.i；A.177.a.44.i；A.178.a.44.i；A.179.a.44.i；A.180.a.44.i；A.181.a.44.i；A.182.a.44.i；A.183.a.44.i；A.184.a.44.i；A.185.a.44.i；A.186.a.44.i；A.187.a.44.i；A.188.a.44.i；A.189.a.44.i；A.190.a.44.i；A.191.a.44.i；A.192.a.44.i；A.193.a.44.i；A.194.a.44.i；A.195.a.44.i；A.196.a.44.i；A.197.a.44.i；A.198.a.44.i；A.199.a.44.i；A.200.a.44.i；A.201.a.44.i；A.202.a.44.i；A.203.a.44.i；A.204.a.44.i；A.205.a.44.i；A.206.a.44.i；A.207.a.44.i；A.208.a.44.i；A.209.a.44.i；A.210.a.44.i；A.211.a.44.i；A.212.a.44.i；A.213.a.44.i；A.214.a.44.i；A.215.a.44.i；A.216.a.44.i；A.217.a.44.i；A.218.a.44.i；A.219.a.44.i；A.220.a.44.i；A.221.a.44.i；A.222.a.44.i；A.223.a.44.i；A.224.a.44.i；A.225.a.44.i；A.226.a.44.i；A.227.a.44.i；A.228.a.44.i；A.229.a.44.i；A.230.a.44.i；A.231.a.44.i；A.232.a.44.i；A.233.a.44.i；A.234.a.44.i；A.235.a.44.i；A.236.a.44.i；A.237.a.44.i；A.238.a.44.i；A.239.a.44.i；A.240.a.44.i；A.241.a.44.i；A.242.a.44.i；A.243.a.44.i；A.244.a.44.i；A.245.a.44.i；A.246.a.44.i；A.247.a.44.i；A.248.a.44.i；A.249.a.44.i；A.250.a.44.i；A.251.a.44.i；A.252.a.44.i；A.253.a.44.i；A.254.a.44.i；A.255.a.44.i；A.256.a.44.i；A.257.a.44.i；A.258.a.44.i；A.259.a.44.i；A.260.a.44.i；A.261.a.44.i；A.262.a.44.i；A.263.a.44.i；A.264.a.44.i；A.265.a.44.i；A.266.a.44.i；A.267.a.44.i；A.268.a.44.i；A.269.a.44.i；A.270.a.44.i；A.271.a.44.i；A.272.a.44.i；A.273.a.44.i；A.274.a.44.i；A.275.a.44.i；A.276.a.44.i；A.277.a.44.i；A.278.a.44.i；A.279.a.44.i；A.280.a.44.i；A.281.a.44.i；A.282.a.44.i；A.283.a.44.i；A.284.a.44.i；A.285.a.44.i；A.286.a.44.i；A.287.a.44.i；A.288.a.44.i；A.289.a.44.i；A.290.a.44.i；A.291.a.44.i；A.292.a.44.i；A.293.a.44.i；A.294.a.44.i；A.295.a.44.i；A.296.a.44.i；A.297.a.44.i；A.298.a.44.i；A.299.a.44.i；A.300.a.44.i；A.301.a.44.i；A.302.a.44.i；A.303.a.44.i；A.304.a.44.i；A.305.a.44.i；A.306.a.44.i；A.307.a.44.i；A.308.a.44.i；A.309.a.44.i；A.310.a.44.i；A.311.a.44.i；A.312.a.44.i；A.313.a.44.i；A.314.a.44.i；A.315.a.44.i；A.316.a.44.i；A.317.a.44.i；A.318.a.44.i；A.319.a.44.i；A.320.a.44.i；A.321.a.44.i；A.322.a.44.i；A.323.a.44.i；A.324.a.44.i；A.325.a.44.i；A.326.a.44.i；A.327.a.44.i；A.328.a.44.i；A.329.a.44.i；A.330.a.44.i；A.331.a.44.i；A.332.a.44.i；A.333.a.44.i；A.334.a.44.i；A.335.a.44.i；A.336.a.44.i；A.337.a.44.i；A.338.a.44.i；A.339.a.44.i；A.340.a.44.i；A.341.a.44.i；A.342.a.44.i；A.343.a.44.i；A.344.a.44.i；A.345.a.44.i；A.346.a.44.i；A.347.a.44.i；A.348.a.44.i；A.349.a.44.i；A.350.a.44.i；A.351.a.44.i；A.352.a.44.i；A.353.a.44.i；A.354.a.44.i；A.355.a.44.i；A.356.a.44.i；A.357.a.44.i；A.358.a.44.i；B.2.a.44.i；B.3.a.44.i；B.4.a.44.i；B.5.a.44.i；B.9.a.44.i；B.100.a.44.i；B.101.a.44.i；B.102.a.44.i；B.103.a.44.i；B.104.a.44.i；B.105.a.44.i；B.106.a.44.i；B.107.a.44.i；B.108.a.44.i；B.109.a.44.i；B.110.a.44.i；B.111.a.44.i；B.112.a.44.i；B.113.a.44.i；B.114.a.44.i；B.115.a.44.i；B.116.a.44.i；B.117.a.44.i；B.118.a.44.i；B.119.a.44.i；B.120.a.44.i；B.121.a.44.i；B.122.a.44.i；B.123.a.44.i；B.124.a.44.i；B.125.a.44.i；B.126.a.44.i；B.127.a.44.i；B.128.a.44.i；B.129.a.44.i；B.130.a.44.i；B.131.a.44.i；B.132.a.44.i；B.133.a.44.i；B.134.a.44.i；B.135.a.44.i；B.136.a.44.i；B.137.a.44.i；B.138.a.44.i；B.139.a.44.i；B.140.a.44.i；B.141.a.44.i；B.142.a.44.i；B.143.a.44.i；B.144.a.44.i；B.145.a.44.i；B.146.a.44.i；B.147.a.44.i；B.148.a.44.i；B.149.a.44.i；B.150.a.44.i；B.151.a.44.i；B.152.a.44.i；B.153.a.44.i；B.154.a.44.i；B.155.a.44.i；B.156.a.44.i；B.157.a.44.i；B.158.a.44.i；B.159.a.44.i；B.160.a.44.i；B.161.a.44.i；B.162.a.44.i；B.163.a.44.i；B.164.a.44.i；B.165.a.44.i；B.166.a.44.i；B.167.a.44.i；B.168.a.44.i；B.169.a.44.i；B.170.a.44.i；B.171.a.44.i；B.172.a.44.i；B.173.a.44.i；B.174.a.44.i；B.175.a.44.i；
B.176.a.44.i；B.177.a.44.i；B.178.a.44.i；B.179.a.44.i；B.180.a.44.i；B.181.a.44.i；B.182.a.44.i；B.183.a.44.i；B.184.a.44.i；B.185.a.44.i；B.186.a.44.i；B.187.a.44.i；B.188.a.44.i；B.189.a.44.i；B.190.a.44.i；B.191.a.44.i；B.192.a.44.i；B.193.a.44.i；B.194.a.44.i；B.195.a.44.i；B.196.a.44.i；B.197.a.44.i；B.198.a.44.i；B.199.a.44.i；B.200.a.44.i；B.201.a.44.i；B.202.a.44.i；B.203.a.44.i；B.204.a.44.i；B.205.a.44.i；B.206.a.44.i；B.207.a.44.i；B.208.a.44.i；B.209.a.44.i；B.210.a.44.i；B.211.a.44.i；B.212.a.44.i；B.213.a.44.i；B.214.a.44.i；B.215.a.44.i；B.216.a.44.i；B.217.a.44.i；B.218.a.44.i；B.219.a.44.i；B.220.a.44.i；B.221.a.44.i；B.222.a.44.i；B.223.a.44.i；B.224.a.44.i；B.225.a.44.i；B.226.a.44.i；B.227.a.44.i；B.228.a.44.i；B.229.a.44.i；B.230.a.44.i；B.231.a.44.i；B.232.a.44.i；B.233.a.44.i；B.234.a.44.i；B.235.a.44.i；B.236.a.44.i；B.237.a.44.i；B.238.a.44.i；B.239.a.44.i；B.240.a.44.i；B.241.a.44.i；B.242.a.44.i；B.243.a.44.i；B.244.a.44.i；B.245.a.44.i；B.246.a.44.i；B.247.a.44.i；B.248.a.44.i；B.249.a.44.i；B.250.a.44.i；B.251.a.44.i；B.252.a.44.i；B.253.a.44.i；B.254.a.44.i；B.255.a.44.i；B.256.a.44.i；B.257.a.44.i；B.258.a.44.i；B.259.a.44.i；B.260.a.44.i；B.261.a.44.i；B.262.a.44.i；B.263.a.44.i；B.264.a.44.i；B.265.a.44.i；B.266.a.44.i；B.267.a.44.i；B.268.a.44.i；B.269.a.44.i；B.270.a.44.i；B.271.a.44.i；B.272.a.44.i；B.273.a.44.i；B.274.a.44.i；B.275.a.44.i；B.276.a.44.i；B.277.a.44.i；B.278.a.44.i；B.279.a.44.i；B.280.a.44.i；B.281.a.44.i；B.282.a.44.i；B.283.a.44.i；B.284.a.44.i；B.285.a.44.i；B.286.a.44.i；B.287.a.44.i；B.288.a.44.i；B.289.a.44.i；B.290.a.44.i；B.291.a.44.i；B.292.a.44.i；B.293.a.44.i；B.294.a.44.i；B.295.a.44.i；B.296.a.44.i；B.297.a.44.i；B.298.a.44.i；B.299.a.44.i；B.300.a.44.i；B.301.a.44.i；B.302.a.44.i；B.303.a.44.i；B.304.a.44.i；B.305.a.44.i；B.306.a.44.i；B.307.a.44.i；B.308.a.44.i；B.309.a.44.i；B.310.a.44.i；B.311.a.44.i；B.312.a.44.i；B.313.a.44.i；B.314.a.44.i；B.315.a.44.i；B.316.a.44.i；B.317.a.44.i；B.318.a.44.i；B.319.a.44.i；B.320.a.44.i；B.321.a.44.i；B.322.a.44.i；B.323.a.44.i；B.324.a.44.i；B.325.a.44.i；B.326.a.44.i；B.327.a.44.i；B.328.a.44.i；B.329.a.44.i；B.330.a.44.i；B.331.a.44.i；B.332.a.44.i；B.333.a.44.i；B.334.a.44.i；B.335.a.44.i；B.336.a.44.i；B.337.a.44.i；B.338.a.44.i；B.339.a.44.i；B.340.a.44.i；B.341.a.44.i；B.342.a.44.i；B.343.a.44.i；B.344.a.44.i；B.345.a.44.i；B.346.a.44.i；B.347.a.44.i；B.348.a.44.i；B.349.a.44.i；B.350.a.44.i；B.351.a.44.i；B.352.a.44.i；B.353.a.44.i；B.354.a.44.i；B.355.a.44.iB.356.a.44.i；B.357.a.44.i；B.358.a.44.i；E.2.a.44.i；E.3.a.44.i；E.4.a.44.i；E.5.a.44.i；E.9.a.44.i；E.100.a.44.i；E.101.a.44.i；E.102.a.44.i；E.103.a.44.i；E.104.a.44.i；E.105.a.44.i；E.106.a.44.i；E.107.a.44.i；E.108.a.44.i；E.109.a.44.i；E.110.a.44.i；E.111.a.44.i；E.112.a.44.i；E.113.a.44.i；E.114.a.44.i；E.115.a.44.i；E.116.a.44.i；E.117.a.44.i；E.118.a.44.i；E.119.a.44.i；E.120.a.44.i；E.121.a.44.i；E.122.a.44.i；E.123.a.44.i；E.124.a.44.i；E.125.a.44.i；E.126.a.44.i；E.127.a.44.i；E.128.a.44.i；E.129.a.44.i；E.130.a.44.i；E.131.a.44.i；E.132.a.44.i；E.133.a.44.i；E.134.a.44.i；E.135.a.44.i；E.136.a.44.i；E.137.a.44.i；E.138.a.44.i；E.139.a.44.i；E.140.a.44.i；E.141.a.44.i；E.142.a.44.i；E.143.a.44.i；E.144.a.44.i；E.145.a.44.i；E.146.a.44.i；E.147.a.44.i；E.148.a.44.i；E.149.a.44.i；E.150.a.44.i；E.151.a.44.i；E.152.a.44.i；E.153.a.44.i；E.154.a.44.i；E.155.a.44.i；E.156.a.44.i；E.157.a.44.i；E.158.a.44.i；E.159.a.44.i；E.160.a.44.i；E.161.a.44.i；E.162.a.44.i；E.163.a.44.i；E.164.a.44.i；E.165.a.44.i；E.166.a.44.i；E.167.a.44.i；E.168.a.44.i；E.169.a.44.i；E.170.a.44.i；E.171.a.44.i；E.172.a.44.i；E.173.a.44.i；E.174.a.44.i；E.175.a.44.i；E.176.a.44.i；E.177.a.44.i；E.178.a.44.i；E.179.a.44.i；E.180.a.44.i；E.181.a.44.i；E.182.a.44.i；E.183.a.44.i；E.184.a.44.i；E.185.a.44.i；E.186.a.44.i；E.187.a.44.i；E.188.a.44.i；E.189.a.44.i；E.190.a.44.i；E.191.a.44.i；E.192.a.44.i；E.193.a.44.i；E.194.a.44.i；
E.195.a.44.i；E.196.a.44.i；E.197.a.44.i；E.198.a.44.i；E.199.a.44.i；E.200.a.44.i；E.201.a.44.i；E.202.a.44.i；E.203.a.44.i；E.204.a.44.i；E.205.a.44.i；E.206.a.44.i；E.207.a.44.i；E.208.a.44.i；E.209.a.44.i；E.210.a.44.i；E.211.a.44.i；E.212.a.44.i；E.213.a.44.i；E.214.a.44.i；E.215.a.44.i；E.216.a.44.i；E.217.a.44.i；E.218.a.44.i；E.219.a.44.i；E.220.a.44.i；E.221.a.44.i；E.222.a.44.i；E.223.a.44.i；E.224.a.44.i；E.225.a.44.i；E.226.a.44.i；E.227.a.44.i；E.228.a.44.i；E.229.a.44.i；E.230.a.44.i；E.231.a.44.i；E.232.a.44.i；E.233.a.44.i；E.234.a.44.i；E.235.a.44.i；E.236.a.44.i；E.237.a.44.i；E.238.a.44.i；E.239.a.44.i；E.240.a.44.i；E.241.a.44.i；E.242.a.44.i；E.243.a.44.i；E.244.a.44.i；E.245.a.44.i；E.246.a.44.i；E.247.a.44.i；E.248.a.44.i；E.249.a.44.i；E.250.a.44.i；E.251.a.44.i；E.252.a.44.i；E.253.a.44.i；E.254.a.44.i；E.255.a.44.i；E.256.a.44.i；E.257.a.44.i；E.258.a.44.i；E.259.a.44.i；E.260.a.44.i；E.261.a.44.i；E.262.a.44.i；E.263.a.44.i；E.264.a.44.i；E.265.a.44.i；E.266.a.44.i；E.267.a.44.i；E.268.a.44.i；E.269.a.44.i；E.270.a.44.i；E.271.a.44.i；E.272.a.44.i；E.273.a.44.i；E.274.a.44.i；E.275.a.44.i；E.276.a.44.i；E.277.a.44.i；E.278.a.44.i；E.279.a.44.i；E.280.a.44.i；E.281.a.44.i；E.282.a.44.i；E.283.a.44.i；E.284.a.44.i；E.285.a.44.i；E.286.a.44.i；E.287.a.44.i；E.288.a.44.i；E.289.a.44.i；E.290.a.44.i；E.291.a.44.i；E.292.a.44.i；E.293.a.44.i；E.294.a.44.i；E.295.a.44.i；E.296.a.44.i；E.297.a.44.i；E.298.a.44.i；E.299.a.44.i；E.300.a.44.i；E.301.a.44.i；E.302.a.44.i；E.303.a.44.i；E.304.a.44.i；E.305.a.44.i；E.306.a.44.i；E.307.a.44.i；E.308.a.44.i；E.309.a.44.i；E.310.a.44.i；E.311.a.44.i；E.312.a.44.i；E.313.a.44.i；E.314.a.44.i；E.315.a.44.i；E.316.a.44.i；E.317.a.44.i；E.318.a.44.i；E.319.a.44.i；E.320.a.44.i；E.321.a.44.i；E.322.a.44.i；E.323.a.44.i；E.324.a.44.i；E.325.a.44.i；E.326.a.44.i；E.327.a.44.i；E.328.a.44.i；E.329.a.44.i；E.330.a.44.i；E.331.a.44.i；E.332.a.44.i；E.333.a.44.i；E.334.a.44.i；E.335.a.44.i；E.336.a.44.i；E.337.a.44.i；E.338.a.44.i；E.339.a.44.i；E.340.a.44.i；E.341.a.44.i；E.342.a.44.i；E.343.a.44.i；E.344.a.44.i；E.345.a.44.i；E.346.a.44.i；E.347.a.44.i；E.348.a.44.i；E.349.a.44.i；E.350.a.44.i；E.351.a.44.i；E.352.a.44.i；E.353.a.44.i；E.354.a.44.i；E.355.a.44.i；E.356.a.44.i；E.357.a.44.i；E.358.a.44.i；B.2.a.4.i；B.3.a.4.i；B.4.a.4.i；B.5.a.4.i；B.9.a.4.i；B.100.a.4.i；B.101.a.4.i；B.102.a.4.i；B.103.a.4.i；B.104.a.4.i；B.105.a.4.i；B.106.a.4.i；B.107.a.4.i；B.108.a.4.i；B.109.a.4.i；B.110.a.4.i；B.111.a.4.i；B.112.a.4.i；B.113.a.4.i；B.114.a.4.i；B.115.a.4.i；B.116.a.4.i；B.117.a.4.i；B.118.a.4.i；B.119.a.4.i；B.120.a.4.i；B.121.a.4.i；B.122.a.4.i；B.123.a.4.i；B.124.a.4.i；B.125.a.4.i；B.126.a.4.i；B.127.a.4.i；B.128.a.4.i；B.129.a.4.i；B.130.a.4.i；B.131.a.4.i；B.132.a.4.i；B.133.a.4.i；B.134.a.4.i；B.135.a.4.i；B.136.a.4.i；B.137.a.4.i；B.138.a.4.i；B.139.a.4.i；B.140.a.4.i；B.141.a.4.i；B.142.a.4.i；B.143.a.4.i；B.144.a.4.i；B.145.a.4.i；B.146.a.4.i；B.147.a.4.i；B.148.a.4.i；B.149.a.4.i；B.150.a.4.i；B.151.a.4.i；B.152.a.4.i；B.153.a.4.i；B.154.a.4.i；B.155.a.4.i；B.156.a.4.i；B.157.a.4.i；B.158.a.4.i；B.159.a.4.i；B.160.a.4.i；B.161.a.4.i；B.162.a.4.i；B.163.a.4.i；B.164.a.4.i；B.165.a.4.i；B.166.a.4.i；B.167.a.4.i；B.168.a.4.i；B.169.a.4.i；B.170.a.4.i；B.171.a.4.i；B.172.a.4.i；B.173.a.4.i；B.174.a.4.i；B.175.a.4.i；B.176.a.4.i；B.177.a.4.i；B.178.a.4.i；B.179.a.4.i；B.180.a.4.i；B.181.a.4.i；B.182.a.4.i；B.183.a.4.i；B.184.a.4.i；B.185.a.4.i；B.186.a.4.i；B.187.a.4.i；B.188.a.4.i；B.189.a.4.i；B.190.a.4.i；B.191.a.4.i；B.192.a.4.i；B.193.a.4.i；B.194.a.4.i；B.195.a.4.i；B.196.a.4.i；B.197.a.4.i；B.198.a.4.i；B.199.a.4.i；B.200.a.4.i；B.201.a.4.i；B.202.a.4.i；B.203.a.4.i；B.204.a.4.i；B.205.a.4.i；B.206.a.4.i；B.207.a.4.i；B.208.a.4.i；B.209.a.4.i；B.210.a.4.i；B.211.a.4.i；B.212.a.4.i；B.213.a.4.i；B.214.a.4.i；B.215.a.4.i；B.216.a.4.i；B.217.a.4.i；B.218.a.4.i；B.219.a.4.i；B.220.a.4.i；B.221.a.4.i；B.222.a.4.i；B.223.a.4.i；B.224.a.4.i；B.225.a.4.i；B.226.a.4.i；B.227.a.4.i；B.228.a.4.i；B.229.a.4.i；B.230.a.4.i；B.231.a.4.i；B.232.a.4.i；
B.233.a.4.i；B.234.a.4.i；B.235.a.4.i；B.236.a.4.i；B.237.a.4.i；B.238.a.4.i；B.239.a.4.i；B.240.a.4.i；B.241.a.4.i；B.242.a.4.i；B.243.a.4.i；B.244.a.4.i；B.245.a.4.i；B.246.a.4.i；B.247.a.4.i；B.248.a.4.i；B.249.a.4.i；B.250.a.4.i；B.251.a.4.i；B.252.a.4.i；B.253.a.4.i；B.254.a.4.i；B.255.a.4.i；B.256.a.4.i；B.257.a.4.i；B.258.a.4.i；B.259.a.4.i；B.260.a.4.i；B.261.a.4.i；B.262.a.4.i；B.263.a.4.i；B.264.a.4.i；B.265.a.4.i；B.266.a.4.i；B.267.a.4.i；B.268.a.4.i；B.269.a.4.i；B.270.a.4.i；B.271.a.4.i；B.272.a.4.i；B.273.a.4.i；B.274.a.4.i；B.275.a.4.i；B.276.a.4.i；B.277.a.4.i；B.278.a.4.i；B.279.a.4.i；B.280.a.4.i；B.281.a.4.i；B.282.a.4.i；B.283.a.4.i；B.284.a.4.i；B.285.a.4.i；B.286.a.4.i；B.287.a.4.i；B.288.a.4.i；B.289.a.4.i；B.290.a.4.i；B.291.a.4.i；B.292.a.4.i；B.293.a.4.i；B.294.a.4.i；B.295.a.4.i；B.296.a.4.i；B.297.a.4.i；B.298.a.4.i；B.299.a.4.i；B.300.a.4.i；B.301.a.4.i；B.302.a.4.i；B.303.a.4.i；B.304.a.4.i；B.305.a.4.i；B.306.a.4.i；B.307.a.4.i；B.308.a.4.i；B.309.a.4.i；B.310.a.4.i；B.311.a.4.i；B.312.a.4.i；B.313.a.4.i；B.314.a.4.i；B.315.a.4.i；B.316.a.4.i；B.317.a.4.i；B.318.a.4.i；B.319.a.4.i；B.320.a.4.i；B.321.a.4.i；B.322.a.4.i；B.323.a.4.i；B.324.a.4.i；B.325.a.4.i；B.326.a.4.i；B.327.a.4.i；B.328.a.4.i；B.329.a.4.i；B.330.a.4.i；B.331.a.4.i；B.332.a.4.i；B.333.a.4.i；B.334.a.4.i；B.335.a.4.i；B.336.a.4.i；B.337.a.4.i；B.338.a.4.i；B.339.a.4.i；B.340.a.4.i；B.341.a.4.i；B.342.a.4.i；B.343.a.4.i；B.344.a.4.i；B.345.a.4.i；B.346.a.4.i；B.347.a.4.i；B.348.a.4.i；B.349.a.4.i；B.350.a.4.i；B.351.a.4.i；B.352.a.4.i；B.353.a.4.i；B.354.a.4.i；B.355.a.4.i；B.356.a.4.i；B.357.a.4.i；B.358.a.4.i；E.2.a.4.i；E.3.a.4.i；E.4.a.4.i；E.5.a.4.i；E.9.a.4.z；E.100.a.4.i；E.101.a.4.i；E.102.a.4.i；E.103.a.4.i；E.104.a.4.i；E.105.a.4.i；E.106.a.4.i；E.107.a.4.i；E.108.a.4.i；E.109.a.4.i；E.110.a.4.i；E.111.a.4.i；E.112.a.4.i；E.113.a.4.i；E.114.a.4.i；E.115.a.4.i；E.116.a.4.i；E.117.a.4.i；E.118.a.4.i；E.119.a.4.i；E.120.a.4.i；E.121.a.4.i；E.122.a.4.i；E.123.a.4.i；E.124.a.4.i；E.125.a.4.i；E.126.a.4.i；E.127.a.4.i；E.128.a.4.i；E.129.a.4.i；E.130.a.4.i；E.131.a.4.i；E.132.a.4.i；E.133.a.4.i；E.134.a.4.i；E.135.a.4.i；E.136.a.4.i；E.137.a.4.i；E.138.a.4.i；E.139.a.4.i；E.140.a.4.i；E.141.a.4.i；E.142.a.4.i；E.143.a.4.i；E.144.a.4.i；E.145.a.4.i；E.146.a.4.i；E.147.a.4.i；E.148.a.4.i；E.149.a.4.i；E.150.a.4.i；E.151.a.4.i；E.152.a.4.i；E.153.a.4.i；E.154.a.4.i；E.155.a.4.i；E.156.a.4.i；E.157.a.4.i；E.158.a.4.i；E.159.a.4.i；E.160.a.4.i；E.161.a.4.i；E.162.a.4.i；E.163.a.4.i；E.164.a.4.i；E.165.a.4.i；E.166.a.4.i；E.167.a.4.i；E.168.a.4.i；E.169.a.4.i；E.170.a.4.i；E.171.a.4.i；E.172.a.4.i；E.173.a.4.i；E.174.a.4.i；E.175.a.4.i；E.176.a.4.i；E.177.a.4.i；E.178.a.4.i；E.179.a.4.i；E.180.a.4.i；E.181.a.4.i；E.182.a.4.i；E.183.a.4.i；E.184.a.4.i；E.185.a.4.i；E.186.a.4.i；E.187.a.4.i；E.188.a.4.i；E.189.a.4.i；E.190.a.4.i；E.191.a.4.i；E.192.a.4.i；E.193.a.4.i；E.194.a.4.i；E.195.a.4.i；E.196.a.4.i；E.197.a.4.i；E.198.a.4.i；E.199.a.4.i；E.200.a.4.i；E.201.a.4.i；E.202.a.4.i；E.203.a.4.i；E.204.a.4.i；E.205.a.4.i；E.206.a.4.i；E.207.a.4.i；E.208.a.4.i；E.209.a.4.i；E.210.a.4.i；E.211.a.4.i；E.212.a.4.i；E.213.a.4.i；E.214.a.4.i；E.215.a.4.i；E.216.a.4.i；E.217.a.4.i；E.218.a.4.i；E.219.a.4.i；E.220.a.4.i；E.221.a.4.i；E.222.a.4.i；E.223.a.4.i；E.224.a.4.i；E.225.a.4.i；E.226.a.4.i；E.227.a.4.i；E.228.a.4.i；E.229.a.4.i；E.230.a.4.i；E.231.a.4.i；E.232.a.4.i；E.233.a.4.i；E.234.a.4.i；E.235.a.4.i；E.236.a.4.i；E.237.a.4.i；E.238.a.4.i；E.239.a.4.i；E.240.a.4.i；E.241.a.4.i；E.242.a.4.i；E.243.a.4.i；E.244.a.4.i；E.245.a.4.i；E.246.a.4.i；E.247.a.4.i；E.248.a.4.i；E.249.a.4.i；E.250.a.4.i；E.251.a.4.i；E.252.a.4.i；E.253.a.4.i；E.254.a.4.i；E.255.a.4.i；E.256.a.4.i；E.257.a.4.i；E.258.a.4.i；E.259.a.4.i；E.260.a.4.i；E.261.a.4.i；E.262.a.4.i；E.263.a.4.i；E.264.a.4.i；E.265.a.4.i；E.266.a.4.i；E.267.a.4.i；E.268.a.4.i；E.269.a.4.i；E.270.a.4.i；E.271.a.4.i；E.272.a.4.i；E.273.a.4.i；E.274.a.4.i；E.275.a.4.i；E.276.a.4.i；E.277.a.4.i；E.278.a.4.i；E.279.a.4.i；E.280.a.4.i；E.281.a.4.i；E.282.a.4.i；E.283.a.4.i；E.284.a.4.i；E.285.a.4.i；E.286.a.4.i；E.287.a.4.i；E.288.a.4.i；E.289.a.4.i；E.290.a.4.i；E.291.a.4.i；E.292.a.4.i；E.293.a.4.i；E.294.a.4.i；E.295.a.4.i；E.296.a.4.i；E.297.a.4.i；E.298.a.4.i；
E.299.a.4.i；E.300.a.4.i；E.301.a.4.i；E.302.a.4.i；E.303.a.4.i；E.304.a.4.i；E.305.a.4.i；E.306.a.4.i；E.307.a.4.i；E.308.a.4.i；E.309.a.4.i；E.310.a.4.i；E.311.a.4.i；E.312.a.4.i；E.313.a.4.i；E.314.a.4.i；E.315.a.4.i；E.316.a.4.i；E.317.a.4.i；E.318.a.4.i；E.319.a.4.i；E.320.a.4.i；E.321.a.4.i；E.322.a.4.i；E.323.a.4.i；E.324.a.4.i；E.325.a.4.i；E.326.a.4.i；E.327.a.4.i；E.328.a.4.i；E.329.a.4.i；E.330.a.4.i；E.331.a.4.i；E.332.a.4.i；E.333.a.4.i；E.334.a.4.i；E.335.a.4.i；E.336.a.4.i；E.337.a.4.i；E.338.a.4.i；E.339.a.4.i；E.340.a.4.i；E.341.a.4.i；E.342.a.4.i；E.343.a.4.i；E.344.a.4.i；E.345.a.4.i；E.346.a.4.i；E.347.a.4.i；E.348.a.4.i；E.349.a.4.i；E.350.a.4.i；E.351.a.4.i；E.352.a.4.i；E.353.a.4.i；E.354.a.4.i；E.355.a.4.i；E.356.a.4.i；E.357.a.4.i；E.358.a.4.i；B.2.a.11.i； B.3.a.11.i； B.4.a.11.i；B.5.a.11.i；B.9.a.11.i；B.100.a.11.i；B.101.a.11.i；B.102.a.11.i；B.103.a.11.i；B.104.a.11.i；B.105.a.11.i；B.106.a.11.i；B.107.a.11.i；B.108.a.11.i；B.109.a.11.i；B.110.a.11.i；B.111.a.11.i；B.112.a.11.i；B.113.a.11.i；B.114.a.11.i；B.115.a.11.i；B.116.a.11.i；B.117.a.11.i；B.118.a.11.i；B.119.a.11.i；B.120.a.11.i；B.121.a.11.i；B.122.a.11.i；B.123.a.11.i；B.124.a.11.i；B.125.a.11.i；B.126.a.11.i；B.127.a.11.i；B.128.a.11.i；B.129.a.11.i；B.130.a.11.i；B.131.a.11.i；B.132.a.11.i；B.133.a.11.i；B.134.a.11.i；B.135.a.11.i；B.136.a.11.i；B.137.a.11.i；B.138.a.11.i；B.139.a.11.i；B.140.a.11.i；B.141.a.11.i；B.142.a.11.i；B.143.a.11.i；B.144.a.11.i；B.145.a.11.i；B.146.a.11.i；B.147.a.11.i；B.148.a.11.i；B.149.a.11.i；B.150.a.11.i；B.151.a.11.i；B.152.a.11.i；B.153.a.11.i；B.154.a.11.i；B.155.a.11.i；B.156.a.11.i；B.157.a.11.i；B.158.a.11.i；B.159.a.11.i；B.160.a.11.i；B.161.a.11.i；B.162.a.11.i；B.163.a.11.i；B.164.a.11.i；B.165.a.11.i；B.166.a.11.i；B.167.a.11.i；B.168.a.11.i；B.169.a.11.i；B.170.a.11.i；B.171.a.11.i；B.172.a.11.i；B.173.a.11.i；B.174.a.11.i；B.175.a.11.i；B.176.a.11.i；B.177.a.11.i；B.178.a.11.i；B.179.a.11.i；B.180.a.11.i；B.181.a.11.i；B.182.a.11.i；B.183.a.11.i；B.184.a.11.i；B.185.a.11.i；B.186.a.11.i；B.187.a.11.i；B.188.a.11.i；B.189.a.11.i；B.190.a.11.i；B.191.a.11.i；B.192.a.11.i；B.193.a.11.i；B.194.a.11.i；B.195.a.11.i；B.196.a.11.i；B.197.a.11.i；B.198.a.11.i；B.199.a.11.i；B.200.a.11.i；B.201.a.11.i；B.202.a.11.i；B.203.a.11.i；B.204.a.11.i；B.205.a.11.i；B.206.a.11.i；B.207.a.11.i；B.208.a.11.i；B.209.a.11.i；B.210.a.11.i；B.211.a.11.i；B.212.a.11.i；B.213.a.11.i；B.214.a.11.i；B.215.a.11.i；B.216.a.11.i；B.217.a.11.i；B.218.a.11.i；B.219.a.11.i；B.220.a.11.i；B.221.a.11.i；B.222.a.11.i；B.223.a.11.i；B.224.a.11.i；B.225.a.11.i；B.226.a.11.i；B.227.a.11.i；B.228.a.11.i；B.229.a.11.i；B.230.a.11.i；B.231.a.11.i；B.232.a.11.i；B.233.a.11.i；B.234.a.11.i；B.235.a.11.i；B.236.a.11.i；B.237.a.11.i；B.238.a.11.i；B.239.a.11.i；B.240.a.11.i；B.241.a.11.i；B.242.a.11.i；B.243.a.11.i；B.244.a.11.i；B.245.a.11.i；B.246.a.11.i；B.247.a.11.i；B.248.a.11.i；B.249.a.11.i；B.250.a.11.i；B.251.a.11.i；B.252.a.11.i；B.253.a.11.i；B.254.a.11.i；B.255.a.11.i；B.256.a.11.i；B.257.a.11.i；B.258.a.11.i；B.259.a.11.i；B.260.a.11.i；B.261.a.11.i；B.262.a.11.i；B.263.a.11.i；B.264.a.11.i；B.265.a.11.i；B.266.a.11.i；B.267.a.11.i；B.268.a.11.i；B.269.a.11.i；B.270.a.11.i；B.271.a.11.i；B.272.a.11.i；B.273.a.11.i；B.274.a.11.i；B.275.a.11.i；B.276.a.11.i；B.277.a.11.i；B.278.a.11.i；B.279.a.11.i；B.280.a.11.i；B.281.a.11.i；B.282.a.11.i；B.283.a.11.i；B.284.a.11.i；B.285.a.11.i；B.286.a.11.i；B.287.a.11.i；B.288.a.11.i；B.289.a.11.i；B.290.a.11.i；B.291.a.11.i；B.292.a.11.i；B.293.a.11.i；B.294.a.11.i；B.295.a.11.i；B.296.a.11.i；B.297.a.11.i；B.298.a.11.i；B.299.a.11.i；B.300.a.11.i；B.301.a.11.i；B.302.a.11.i；B.303.a.11.i；B.304.a.11.i；B.305.a.11.i；B.306.a.11.i；B.307.a.11.i；B.308.a.11.i；B.309.a.11.i；B.310.a.11.i；B.311.a.11.i；B.312.a.11.i；B.313.a.11.i；B.314.a.11.i；B.315.a.11.i；B.316.a.11.i；B.317.a.11.i；B.318.a.11.i；B.319.a.11.i；B.320.a.11.i；B.321.a.11.i；B.322.a.11.i；B.323.a.11.i；B.324.a.11.i；B.325.a.11.i；
B.326.a.11.i；B.327.a.11.i；B.328.a.11.i；B.329.a.11.i；B.330.a.11.i；B.331.a.11.i；B.332.a.11.i；B.333.a.11.i；B.334.a.11.i；B.335.a.11.i；B.336.a.11.i；B.337.a.11.i；B.338.a.11.i；B.339.a.11.i；B.340.a.11.i；B.341.a.11.i；B.342.a.11.i；B.343.a.11.i；B.344.a.11.i；B.345.a.11.i；B.346.a.11.i；B.347.a.11.i；B.348.a.11.i；B.349.a.11.i；B.350.a.11.i；B.351.a.11.i；B.352.a.11.i；B.353.a.11.i；B.354.a.11.i；B.355.a.11.i；B.356.a.11.i；B.357.a.11.i；B.358.a.11.i；E.2.a.11.i；E.3.a.11.i；E.4.a.11.i；E.5.a.11.i；E.9.a.11.i；E.100.a.11.i；E.101.a.11.i；E.102.a.11.i；E.103.a.11.i；E.104.a.11.i；E.105.a.11.i；E.106.a.11.i；E.107.a.11.i；E.108.a.11.i；E.109.a.11.i；E.110.a.11.i；E.111.a.11.i；E.112.a.11.i；E.113.a.11.i；E.114.a.11.i；E.115.a.11.i；E.116.a.11.i；E.117.a.11.i；E.118.a.11.i；E.119.a.11.i；E.120.a.11.i；E.121.a.11.i；E.122.a.11.i；E.123.a.11.i；E.124.a.11.i；E.125.a.11.i；E.126.a.11.i；E.127.a.11.i；E.128.a.11.i；E.129.a.11.i；E.130.a.11.i；E.131.a.11.i；E.132.a.11.i；E.133.a.11.i；E.134.a.11.i；E.135.a.11.i；E.136.a.11.i；E.137.a.11.i；E.138.a.11.i；E.139.a.11.i；E.140.a.11.i；E.141.a.11.i；E.142.a.11.i；E.143.a.11.i；E.144.a.11.i；E.145.a.11.i；E.146.a.11.i；E.147.a.11.i；E.148.a.11.i；E.149.a.11.i；E.150.a.11.i；E.151.a.11.i；E.152.a.11.i；E.153.a.11.i；E.154.a.11.i；E.155.a.11.i；E.156.a.11.i；E.157.a.11.i；E.158.a.11.i；E.159.a.11.i；E.160.a.11.i；E.161.a.11.i；E.162.a.11.i；E.163.a.11.i；E.164.a.11.i；E.165.a.11.i；E.166.a.11.i；E.167.a.11.i；E.168.a.11.i；E.169.a.11.i；E.170.a.11.i；E.171.a.11.i；E.172.a.11.i；E.173.a.11.i；E.174.a.11.i；E.175.a.11.i；E.176.a.11.i；E.177.a.11.i；E.178.a.11.i；E.179.a.11.i；E.180.a.11.i；E.181.a.11.i；E.182.a.11.i；E.183.a.11.i；E.184.a.11.i；E.185.a.11.i；E.186.a.11.i；E.187.a.11.i；E.188.a.11.i；E.189.a.11.i；E.190.a.11.i；E.191.a.11.i；E.192.a.11.i；E.193.a.11.i；E.194.a.11.i；E.195.a.11.i；E.196.a.11.i；E.197.a.11.i；E.198.a.11.i；E.199.a.11.i；E.200.a.11.i；E.201.a.11.i；E.202.a.11.i；E.203.a.11.i；E.204.a.11.i；E.205.a.11.i；E.206.a.11.i；E.207.a.11.i；E.208.a.11.i；E.209.a.11.i；E.210.a.11.i；E.211.a.11.i；E.212.a.11.i；E.213.a.11.i；E.214.a.11.i；E.215.a.11.i；E.216.a.11.i；E.217.a.11.i；E.218.a.11.i；E.219.a.11.i；E.220.a.11.i；E.221.a.11.i；E.222.a.11.i；E.223.a.11.i；E.224.a.11.i；E.225.a.11.i；E.226.a.11.i；E.227.a.11.i；E.228.a.11.i；E.229.a.11.i；E.230.a.11.i；E.231.a.11.i；E.232.a.11.i；E.233.a.11.i；E.234.a.11.i；E.235.a.11.i；E.236.a.11.i；E.237.a.11.i；E.238.a.11.i；E.239.a.11.i；E.240.a.11.i；E.241.a.11.i；E.242.a.11.i；E.243.a.11.i；E.244.a.11.i；E.245.a.11.i；E.246.a.11.i；E.247.a.11.i；E.248.a.11.i；E.249.a.11.i；E.250.a.11.i；E.251.a.11.i；E.252.a.11.i；E.253.a.11.i；E.254.a.11.i；E.255.a.11.i；E.256.a.11.i；E.257.a.11.i；E.258.a.11.i；E.259.a.11.i；E.260.a.11.i；E.261.a.11.i；E.262.a.11.i；E.263.a.11.i；E.264.a.11.i；E.265.a.11.i；E.266.a.11.i；E.267.a.11.i；E.268.a.11.i；E.269.a.11.i；E.270.a.11.i；E.271.a.11.i；E.272.a.11.i；E.273.a.11.i；E.274.a.11.i；E.275.a.11.i；E.276.a.11.i；E.277.a.11.i；E.278.a.11.i；E.279.a.11.i；E.280.a.11.i；E.281.a.11.i；E.282.a.11.i；E.283.a.11.i；E.284.a.11.i；E.285.a.11.i；E.286.a.11.i；E.287.a.11.i；E.288.a.11.i；E.289.a.11.i；E.290.a.11.i；E.291.a.11.i；E.292.a.11.i；E.293.a.11.i；E.294.a.11.i；E.295.a.11.i；E.296.a.11.i；E.297.a.11.i；E.298.a.11.i；E.299.a.11.i；E.300.a.11.i；E.301.a.11.i；E.302.a.11.i；E.303.a.11.i；E.304.a.11.i；E.305.a.11.i；E.306.a.11.i；E.307.a.11.i；E.308.a.11.i；E.309.a.11.i；E.310.a.11.i；E.311.a.11.i；E.312.a.11.i；E.313.a.11.i；E.314.a.11.i；E.315.a.11.i；E.316.a.11.i；E.317.a.11.i；E.318.a.11.i；E.319.a.11.i；E.320.a.11.i；E.321.a.11.i；E.322.a.11.i；E.323.a.11.i；E.324.a.11.i；E.325.a.11.i；E.326.a.11.i；E.327.a.11.i；E.328.a.11.i；E.329.a.11.i；E.330.a.11.i；E.331.a.11.i；E.332.a.11.i；E.333.a.11.i；E.334.a.11.i；E.335.a.11.i；E.336.a.11.i；E.337.a.11.i；E.338.a.11.i；E.339.a.11.i；E.340.a.11.i；E.341.a.11.i；E.342.a.11.i；E.343.a.11.i；E.344.a.11.i；
E.345.a.11.i；E.346.a.11.i；E.347.a.11.i；E.348.a.11.i；E.349.a.11.i；E.350.a.11.i；E.351.a.11.i；E.352.a.11.i；E.353.a.11.i；E.354.a.11.i；E.355.a.11.i；E.356.a.11.i；E.357.a.11.i；E.358.a.11.i；A.661.a.4.i；A.662.a.4.i；A.663.a.4.i；A.664.a.4.i；A.665.a.4.i；B.661.a.4.i；B.662.a.4.i；B.663.a.4.i；B.664.a.4.i；B.665.a.4.i；C.661.a.4.i；C.662.a.4.i；C.663.a.4.i；C.664.a.4.i；C.665.a.4.i；A.661.a.11.i；A.662.a.11.i；A.663.a.11.i；A.664.a.11.i；A.665.a.11.i；B.661.a.11.i；B.662.a.11.i；B.663.a.11.i；B.664.a.11.i；B.665.a.11.i；C.661.a.11.i；C.662.a.11.i；C.663.a.11.i；C.664.a.11.i；C.665.a.11.i；A.661.a.44.i；A.662.a.44.i；A.663.a.44.i；A.664.a.44.i；A.665.a.44.i；B.661.a.44.i；B.662.a.44.i；B.663.a.44.i；B.664.a.44.i；B.665.a.44.i；C.661.a.44.i；C.662.a.44.i；C.663.a.44.i；C.664.a.44.i；C.665.a.44.i；A.666.a.4.i；A.666.a.11.i；A.666.a.44.i；A.666.b.4.i；A.666.b.11.i；A.666.b.44.i；A.666.x.4.i；A.666.x.11.i；A.666.x.44.i；A.666.y.4.i；A.666.y.11.i；A.666.y.44.i；A.666.z.4.i；A.666.z.11.i；A.666.z.44.i；A.666.A.4.i；A.666.A.11.i；A.666.A.44.i；A.666.B.4.i；A.666.B.11.i；A.666.B.44.i；A.666.C.4.i；A.666.C.11.i；A.666.C.44.i；A.666.D.4.i；A.666.D.11.i；A.666.D.44.i；A.666.E.4.i；A.666.E.11.i；A.666.E.44.i；A.666.F.4.i；A.666.F.11.i；A.666.F.44.i；B.666.a.4.i；B.666.a.11.i；B.666.a.44.i；B.666.b.4.i；B.666.b.11.i；B.666.b.44.i；B.666.x.4.i；B.666.x.11.i；B.666.x.44.i；B.666.y.4.i；B.666.y.11.i；B.666.y.44.i；B.666.z.4.i；B.666.z.11.i；B.666.z.44.i；B.666.B.4.i；B.666.B.11.i；B.666.B.44.i；B.666.B.4.i；B.666.B.11.i；B.666.B.44.i；B.666.C.4.i；B.666.C.11.i；B.666.C.44.i；B.666.D.4.i；B.666.D.11.i；B.666.D.44.i；B.666.E.4.i；B.666.E.11.i；B.666.E.44.i；B.666.F.4.i；B.666.F.11.i；B.666.F.44.i；E.666.a.4.i；E.666.a.11.i；E.666.a.44.i；E.666.b.4.i；E.666.b.11.i；E.666.b.44.i；E.666.x.4.i；E.666.x.11.i；E.666.x.44.i；E.666.y.4.i；E.666.y.11.i；E.666.y.44.i；E.666.z.4.i；E.666.z.11.i；E.666.z.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.B.4.i；E.666.B.11.i；E.666.B.44.i；E.666.C.4.i；E.666.C.11.i；E.666.C.44.i；E.666.D.4.i；E.666.D.11.i；E.666.D.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.F.4.i；E.666.F.11.i；E.666.F.44.i；A.2.a.46.i；A.3.a.46.i；A.4.a.46.i；A.5.a.46.i；A.7.a.46.i；A.9.a.46.i；A.100.a.46.i；A.101.a.46.i；A.102.a.46.i；A.103.a.46.i；A.104.a.46.i；A.105.a.46.i；A.106.a.46.i；A.107.a.46.i；A.108.a.46.i；A.109.a.46.i；A.110.a.46.i；A.111.a.46.i；A.112.a.46.i；A.113.a.46.i；A.114.a.46.i；A.115.a.46.i；A.116.a.46.i；A.117.a.46.i；A.118.a.46.i；A.119.a.46.i；A.120.a.46.i；A.121.a.46.i；A.122.a.46.i；A.123.a.46.i；A.124.a.46.i；A.125.a.46.i；A.126.a.46.i；A.127.a.46.i；A.128.a.46.i；A.129.a.46.i；A.130.a.46.i；A.131.a.46.i；A.132.a.46.i；A.133.a.46.i；A.134.a.46.i；A.135.a.46.i；A.136.a.46.i；A.137.a.46.i；A.138.a.46.i；A.139.a.46.i；A.140.a.46.i；A.141.a.46.i；A.2.a.47.i；A.3.a.47.i；A.4.a.47.i；A.5.a.47.i；A.7.a.47.i；A.9.a.47.i；A.100.a.47.i；A.101.a.47.i；A.102.a.47.i；A.103.a.47.i；A.104.a.47.i；A.105.a.47.i；A.106.a.47.i；A.107.a.47.i；A.108.a.47.i；A.109.a.47.i；A.110.a.47.i；A.111.a.47.i；A.112.a.47.i；A.113.a.47.i；A.114.a.47.i；A.115.a.47.i；A.116.a.47.i；A.117.a.47.i；A.118.a.47.i；A.119.a.47.i；A.120.a.47.i；A.121.a.47.i；A.122.a.47.i；A.123.a.47.i；A.124.a.47.i；A.125.a.47.i；A.126.a.47.i；A.127.a.47.i；A.128.a.47.i；A.129.a.47.i；A.130.a.47.i；A.131.a.47.i；A.132.a.47.i；A.133.a.47.i；A.134.a.47.i；A.135.a.47.i；A.136.a.47.iA.137.a.47.i；A.138.a.47.i；A.139.a.47.i；A.140.a.47.i；A.141.a.47.i；A.2.a.48.i；A.3.a.48.i；A.4.a.48.i；A.5.a.48.i；A.7.a.48.i；A.9.a.48.i；A.100.a.48.i；A.101.a.48.i；A.102.a.48.i；A.103.a.48.i；A.104.a.48.i；A.105.a.48.i；A.106.a.48.i；A.107.a.48.i；A.108.a.48.i；A.109.a.48.i；A.110.a.48.i；A.111.a.48.i；A.112.a.48.i；A.113.a.48.i；A.114.a.48.i；A.115.a.48.i；A.116.a.48.i；A.117.a.48.i；A.118.a.48.i；A.119.a.48.i；A.120.a.48.i；A.121.a.48.i；A.122.a.48.i；A.123.a.48.i；A.124.a.48.i；A.125.a.48.i；
A.126.a.48.i；A.127.a.48.i；A.128.a.48.i；A.129.a.48.i；A.130.a.48.i；A.131.a.48.i；A.132.a.48.i；A.133.a.48.i；A.134.a.48.i；A.135.a.48.i；A.136.a.48.i；A.137.a.48.i；A.138.a.48.i；A.139.a.48.i；A.140.a.48.i；A.141.a.48.i；A.2.a.49.i；A.3.a.49.i；A.4.a.49.i；A.5.a.49.i；A.7.a.49.i；A.9.a.49.i；A.100.a.49.i；A.101.a.49.i；A.102.a.49.i；A.103.a.49.i；A.104.a.49.i；A.105.a.49.i；A.106.a.49.i；A.107.a.49.i；A.108.a.49.i；A.109.a.49.i；A.110.a.49.i；A.111.a.49.i；A.112.a.49.i；A.113.a.49.i；A.114.a.49.i；A.115.a.49.i；A.116.a.49.i；A.117.a.49.i；A.118.a.49.i；A.119.a.49.i；A.120.a.49.i；A.121.a.49.i；A.122.a.49.i；A.123.a.49.i；A.124.a.49.i；A.125.a.49.i；A.126.a.49.i；A.127.a.49.i；A.128.a.49.i；A.129.a.49.i；A.130.a.49.i；A.131.a.49.i；A.132.a.49.i；A.133.a.49.i；A.134.a.49.i；A.135.a.49.i；A.136.a.49.i；A.137.a.49.i；A.138.a.49.i；A.139.a.49.i；A.140.a.49.i；A.141.a.49.i；A.2.a.50.i；A.3.a.50.i；A.4.a.50.i；A.5.a.50.i；A.7.a.50.i；A.9.a.50.i；A.100.a.50.i；A.101.a.50.i；A.102.a.50.i；A.103.a.50.i；A.104.a.50.i；A.105.a.50.i；A.106.a.50.i；A.107.a.50.i；A.108.a.50.i；A.109.a.50.i；A.110.a.50.i；A.111.a.50.i；A.112.a.50.i；A.113.a.50.i；A.114.a.50.i；A.115.a.50.i；A.116.a.50.i；A.117.a.50.i；A.118.a.50.i；A.119.a.50.i；A.120.a.50.i；A.121.a.50.i；A.122.a.50.i；A.123.a.50.i；A.124.a.50.i；A.125.a.50.i；A.126.a.50.i；A.127.a.50.i；A.128.a.50.i；A.129.a.50.i；A.130.a.50.i；A.131.a.50.i；A.132.a.50.i；A.133.a.50.i；A.134.a.50.i；A.135.a.50.i；A.136.a.50.i；A.137.a.50.i；A.138.a.50.i；A.139.a.50.i；A.140.a.50.i；A.141.a.50.i；A.2.a.51.i；A.3.a.51.i；A.4.a.51.i；A.5.a.51.i；A.7.a.51.i；A.9.a.51.i；A.100.a.51.i；A.101.a.51.i；A.102.a.51.i；A.103.a.51.i；A.104.a.51.i；A.105.a.51.i；A.106.a.51.i；A.107.a.51.i；A.108.a.51.i；A.109.a.51.i；A.110.a.51.i；A.111.a.51.i；A.112.a.51.i；A.113.a.51.i；A.114.a.51.i；A.115.a.51.i；A.116.a.51.i；A.117.a.51.i；A.118.a.51.i；A.119.a.51.i；A.120.a.51.i；A.121.a.51.i；A.122.a.51.i；A.123.a.51.i；A.124.a.51.i；A.125.a.51.i；A.126.a.51.i；A.127.a.51.i；A.128.a.51.i；A.129.a.51.i；A.130.a.51.i；A.131.a.51.i；A.132.a.51.i；A.133.a.51.i；A.134.a.51.i；A.135.a.51.i；A.136.a.51.i；A.137.a.51.i；A.138.a.51.i；A.139.a.51.i；A.140.a.51.i；A.141.a.51.i；A.2.b.46.i；A.3.b.46.i；A.4.b.46.i；A.5.b.46.i；A.7.b.46.i；A.9.b.46.i；A.100.b.46.i；A.101.b.46.i；A.102.b.46.i；A.103.b.46.i；A.104.b.46.i；A.105.b.46.i；A.106.b.46.i；A.107.b.46.i；A.108.b.46.i；A.109.b.46.i；A.110.b.46.i；A.111.b.46.i；A.112.b.46.i；A.113.b.46.i；A.114.b.46.i；A.115.b.46.i；A.116.b.46.i；A.117.b.46.i；A.118.b.46.i；A.119.b.46.i；A.120.b.46.i；A.121.b.46.i；A.122.b.46.i；A.123.b.46.i；A.124.b.46.i；A.125.b.46.i；A.126.b.46.i；A.127.b.46.i；A.128.b.46.i；A.129.b.46.i；A.130.b.46.i；A.131.b.46.i；A.132.b.46.i；A.133.b.46.i；A.134.b.46.i；A.135.b.46.i；A.136.b.46.i；A.137.b.46.i；A.138.b.46.i；A.139.b.46.i；A.140.b.46.i；A.141.b.46.i；A.2.b.47.i；A.3.b.47.i；A.4.b.47.i；A.5.b.47.i；A.7.b.47.i；A.9.b.47.i；A.100.b.47.i；A.101.b.47.i；A.102.b.47.i；A.103.b.47.i；A.104.b.47.i；A.105.b.47.i；A.106.b.47.i；A.107.b.47.i；A.108.b.47.i；A.109.b.47.i；A.110.b.47.i；A.111.b.47.i；A.112.b.47.i；A.113.b.47.i；A.114.b.47.i；A.115.b.47.i；A.116.b.47.i；A.117.b.47.i；A.118.b.47.i；A.119.b.47.i；A.120.b.47.i；A.121.b.47.i；A.122.b.47.i；A.123.b.47.i；A.124.b.47.i；A.125.b.47.i；A.126.b.47.i；A.127.b.47.i；A.128.b.47.i；A.129.b.47.i；A.130.b.47.i；A.131.b.47.i；A.132.b.47.i；A.133.b.47.i；A.134.b.47.i；A.135.b.47.i；A.136.b.47.iA.137.b.47.i；A.138.b.47.i；A.139.b.47.i；A.140.b.47.i；A.141.b.47.i；A.2.b.48.i；A.3.b.48.i；A.4.b.48.i；A.5.b.48.i；A.7.b.48.i；A.9.b.48.i；A.100.b.48.i；A.101.b.48.i；A.102.b.48.i；A.103.b.48.i；A.104.b.48.i；A.105.b.48.i；A.106.b.48.i；A.107.b.48.i；A.108.b.48.i；A.109.b.48.i；A.110.b.48.i；A.111.b.48.i；A.112.b.48.i；A.113.b.48.i；A.114.b.48.i；A.115.b.48.i；A.116.b.48.i；A.117.b.48.i；A.118.b.48.i；A.119.b.48.i；A.120.b.48.i；A.121.b.48.i；A.122.b.48.i；A.123.b.48.i；A.124.b.48.i；A.125.b.48.i；
A.126.b.48.i；A.127.b.48.i；A.128.b.48.i；A.129.b.48.i；A.130.b.48.i；A.131.b.48.i；A.132.b.48.i；A.133.b.48.i；A.134.b.48.i；A.135.b.48.i；A.136.b.48.i；A.137.b.48.i；A.138.b.48.i；A.139.b.48.i；A.140.b.48.i；A.141.b.48.i；A.2.b.49.i；A.3.b.49.i；A.4.b.49.i；A.5.b.49.i；A.7.b.49.i；A.9.b.49.i；A.100.b.49.i；A.101.b.49.i；A.102.b.49.i；A.103.b.49.i；A.104.b.49.i；A.105.b.49.i；A.106.b.49.i；A.107.b.49.i；A.108.b.49.i；A.109.b.49.i；A.110.b.49.i；A.111.b.49.i；A.112.b.49.i；A.113.b.49.i；A.114.b.49.i；A.115.b.49.i；A.116.b.49.i；A.117.b.49.i；A.118.b.49.i；A.119.b.49.i；A.120.b.49.i；A.121.b.49.i；A.122.b.49.i；A.123.b.49.i；A.124.b.49.i；A.125.b.49.i；A.126.b.49.i；A.127.b.49.i；A.128.b.49.i；A.129.b.49.i；A.130.b.49.i；A.131.b.49.i；A.132.b.49.i；A.133.b.49.i；A.134.b.49.i；A.135.b.49.i；A.136.b.49.i；A.137.b.49.i；A.138.b.49.i；A.139.b.49.i；A.140.b.49.i；A.141.b.49.i；A.2.b.50.i；A.3.b.50.i；A.4.b.50.i；A.5.b.50.i；A.7.b.50.i；A.9.b.50.i；A.100.b.50.i；A.101.b.50.i；A.102.b.50.i；A.103.b.50.i；A.104.b.50.i；A.105.b.50.i；A.106.b.50.i；A.107.b.50.i；A.108.b.50.i；A.109.b.50.i；A.110.b.50.i；A.111.b.50.i；A.112.b.50.i；A.113.b.50.i；A.114.b.50.i；A.115.b.50.i；A.116.b.50.i；A.117.b.50.i；A.118.b.50.i；A.119.b.50.i；A.120.b.50.i；A.121.b.50.i；A.122.b.50.i；A.123.b.50.i；A.124.b.50.i；A.125.b.50.i；A.126.b.50.i；A.127.b.50.i；A.128.b.50.i；A.129.b.50.i；A.130.b.50.i；A.131.b.50.i；A.132.b.50.i；A.133.b.50.i；A.134.b.50.i；A.135.b.50.i；A.136.b.50.i；A.137.b.50.i；A.138.b.50.i；A.139.b.50.i；A.140.b.50.i；A.141.b.50.i；A.2.b.51.i；A.3.b.51.i；A.4.b.51.i；A.5.b.51.i；A.7.b.51.i；A.9.b.51.i；A.100.b.51.i；A.101.b.51.i；A.102.b.51.i；A.103.b.51.i；A.104.b.51.i；A.105.b.51.i；A.106.b.51.i；A.107.b.51.i；A.108.b.51.i；A.109.b.51.i；A.110.b.51.i；A.111.b.51.i；A.112.b.51.i；A.113.b.51.i；A.114.b.51.i；A.115.b.51.i；A.116.b.51.i；A.117.b.51.i；A.118.b.51.i；A.119.b.51.i；A.120.b.51.i；A.121.b.51.i；A.122.b.51.i；A.123.b.51.i；A.124.b.51.i；A.125.b.51.i；A.126.b.51.i；A.127.b.51.i；A.128.b.51.i；A.129.b.51.i；A.130.b.51.i；A.131.b.51.i；A.132.b.51.i；A.133.b.51.i；A.134.b.51.i；A.135.b.51.i；A.136.b.51.i；A.137.b.51.i；A.138.b.51.i；A.139.b.51.i；A.140.b.51.i；A.141.b.51.i；A.2.x.46.i；A.3.x.46.i；A.4.x.46.i；A.5.x.46.i；A.7.x.46.i；A.9.x.46.i；A.100.x.46.i；A.101.x.46.i；A.102.x.46.i；A.103.x.46.i；A.104.x.46.i；A.105.x.46.i；A.106.x.46.i；A.107.x.46.i；A.108.x.46.i；A.109.x.46.i；A.110.x.46.i；A.111.x.46.i；A.112.x.46.i；A.113.x.46.i；A.114.x.46.i；A.115.x.46.i；A.116.x.46.i；A.117.x.46.i；A.118.x.46.i；A.119.x.46.i；A.120.x.46.i；A.121.x.46.i；A.122.x.46.i；A.123.x.46.i；A.124.x.46.i；A.125.x.46.i；A.126.x.46.i；A.127.x.46.i；A.128.x.46.i；A.129.x.46.i；A.130.x.46.i；A.131.x.46.i；A.132.x.46.i；A.133.x.46.i；A.134.x.46.i；A.135.x.46.i；A.136.x.46.i；A.137.x.46.i；A.138.x.46.i；A.139.x.46.i；A.140.x.46.i；A.141.x.46.i；A.2.x.47.i；A.3.x.47.i；A.4.x.47.i；A.5.x.47.i；A.7.x.47.i；A.9.x.47.i；A.100.x.47.i；A.101.x.47.i；A.102.x.47.i；A.103.x.47.i；A.104.x.47.i；A.105.x.47.i；A.106.x.47.i；A.107.x.47.i；A.108.x.47.i；A.109.x.47.i；A.110.x.47.i；A.111.x.47.i；A.112.x.47.i；A.113.x.47.i；A.114.x.47.i；A.115.x.47.i；A.116.x.47.i；A.117.x.47.i；A.118.x.47.i；A.119.x.47.i；A.120.x.47.i；A.121.x.47.i；A.122.x.47.i；A.123.x.47.i；A.124.x.47.i；A.125.x.47.i；A.126.x.47.i；A.127.x.47.i；A.128.x.47.i；A.129.x.47.i；A.130.x.47.i；A.131.x.47.i；A.132.x.47.i；A.133.x.47.i；A.134.x.47.i；A.135.x.47.i；A.136.x.47.i；A.137.x.47.i；A.138.x.47.i；A.139.x.47.i；A.140.x.47.i；A.141.x.47.i；A.2.x.48.i；A.3.x.48.i；A.4.x.48.i；A.5.x.48.i；A.7.x.48.i；A.9.x.48.i；A.100.x.48.i；A.101.x.48.i；A.102.x.48.i；A.103.x.48.i；A.104.x.48.i；A.105.x.48.i；A.106.x.48.i；A.107.x.48.i；A.108.x.48.i；A.109.x.48.i；A.110.x.48.i；A.111.x.48.i；A.112.x.48.i；A.113.x.48.i；A.114.x.48.i；A.115.x.48.i；A.116.x.48.i；A.117.x.48.i；A.118.x.48.i；A.119.x.48.i；A.120.x.48.i；A.121.x.48.i；A.122.x.48.i；A.123.x.48.i；A.124.x.48.i；A.125.x.48.i；
A.126.x.48.i；A.127.x.48.i；A.128.x.48.i；A.129.x.48.i；A.130.x.48.i；A.131.x.48.i；A.132.x.48.i；A.133.x.48.i；A.134.x.48.i；A.135.x.48.i；A.136.x.48.i；A.137.x.48.i；A.138.x.48.i；A.139.x.48.i；A.140.x.48.i；A.141.x.48.i；A.2.x.49.i；A.3.x.49.i；A.4.x.49.i；A.5.x.49.i；A.7.x.49.i；A.9.x.49.i；A.100.x.49.i；A.101.x.49.i；A.102.x.49.i；A.103.x.49.i；A.104.x.49.i；A.105.x.49.i；A.106.x.49.i；A.107.x.49.i；A.108.x.49.i；A.109.x.49.i；A.110.x.49.i；A.111.x.49.i；A.112.x.49.i；A.113.x.49.i；A.114.x.49.i；A.115.x.49.i；A.116.x.49.i；A.117.x.49.i；A.118.x.49.i；A.119.x.49.i；A.120.x.49.i；A.121.x.49.i；A.122.x.49.i；A.123.x.49.i；A.124.x.49.i；A.125.x.49.i；A.126.x.49.i；A.127.x.49.i；A.128.x.49.i；A.129.x.49.i；A.130.x.49.i；A.131.x.49.i；A.132.x.49.i；A.133.x.49.i；A.134.x.49.i；A.135.x.49.i；A.136.x.49.i；A.137.x.49.i；A.138.x.49.i；A.139.x.49.i；A.140.x.49.i；A.141.x.49.i；A.2.x.50.i；A.3.x.50.i；A.4.x.50.i；A.5.x.50.i；A.7.x.50.i；A.9.x.50.i；A.100.x.50.i；A.101.x.50.i；A.102.x.50.i；A.103.x.50.i；A.104.x.50.i；A.105.x.50.i；A.106.x.50.i；A.107.x.50.i；A.108.x.50.i；A.109.x.50.i；A.110.x.50.i；A.111.x.50.i；A.112.x.50.i；A.113.x.50.i；A.114.x.50.i；A.115.x.50.i；A.116.x.50.i；A.117.x.50.i；A.118.x.50.i；A.119.x.50.i；A.120.x.50.i；A.121.x.50.i；A.122.x.50.i；A.123.x.50.i；A.124.x.50.i；A.125.x.50.i；A.126.x.50.i；A.127.x.50.i；A.128.x.50.i；A.129.x.50.i；A.130.x.50.i；A.131.x.50.i；A.132.x.50.i；A.133.x.50.i；A.134.x.50.i；A.135.x.50.i；A.136.x.50.i；A.137.x.50.i；A.138.x.50.i；A.139.x.50.i；A.140.x.50.i；A.141.x.50.i；A.2.x.51.i；A.3.x.51.i；A.4.x.51.i；A.5.x.51.i；A.7.x.51.i；A.9.x.51.i；A.100.x.51.i；A.101.x.51.i；A.102.x.51.i；A.103.x.51.i；A.104.x.51.i；A.105.x.51.i；A.106.x.51.i；A.107.x.51.i；A.108.x.51.i；A.109.x.51.i；A.110.x.51.i；A.111.x.51.i；A.112.x.51.i；A.113.x.51.i；A.114.x.51.i；A.115.x.51.i；A.116.x.51.i；A.117.x.51.i；A.118.x.51.i；A.119.x.51.i；A.120.x.51.i；A.121.x.51.i；A.122.x.51.i；A.123.x.51.i；A.124.x.51.i；A.125.x.51.i；A.126.x.51.i；A.127.x.51.i；A.128.x.51.i；A.129.x.51.i；A.130.x.51.i；A.131.x.51.i；A.132.x.51.i；A.133.x.51.i；A.134.x.51.i；A.135.x.51.i；A.136.x.51.i；A.137.x.51.i；A.138.x.51.i；A.139.x.51.i；A.140.x.51.i；A.141.x.51.i；A.2.y.46.i；A.3.y.46.i；A.4.y.46.i；A.5.y.46.i；A.7.y.46.i；A.9.y.46.i；A.100.y.46.i；A.101.y.46.i；A.102.y.46.i；A.103.y.46.i；A.104.y.46.i；A.105.y.46.i；A.106.y.46.i；A.107.y.46.i；A.108.y.46.i；A.109.y.46.i；A.110.y.46.i；A.111.y.46.i；A.112.y.46.i；A.113.y.46.i；A.114.y.46.i；A.115.y.46.i；A.116.y.46.i；A.117.y.46.i；A.118.y.46.i；A.119.y.46.i；A.120.y.46.i；A.121.y.46.i；A.122.y.46.i；A.123.y.46.i；A.124.y.46.i；A.125.y.46.i；A.126.y.46.i；A.127.y.46.i；A.128.y.46.i；A.129.y.46.i；A.130.y.46.i；A.131.y.46.i；A.132.y.46.i；A.133.y.46.i；A.134.y.46.i；A.135.y.46.i；A.136.y.46.i；A.137.y.46.i；A.138.y.46.i；A.139.y.46.i；A.140.y.46.i；A.141.y.46.i；A.2.y.47.i；A.3.y.47.i；A.4.y.47.i；A.5.y.47.i；A.7.y.47.i；A.9.y.47.i；A.100.y.47.i；A.101.y.47.i；A.102.y.47.i；A.103.y.47.i；A.104.y.47.i；A.105.y.47.i；A.106.y.47.i；A.107.y.47.i；A.108.y.47.i；A.109.y.47.i；A.110.y.47.i；A.111.y.47.i；A.112.y.47.i；A.113.y.47.i；A.114.y.47.i；A.115.y.47.i；A.116.y.47.i；A.117.y.47.i；A.118.y.47.i；A.119.y.47.i；A.120.y.47.i；A.121.y.47.i；A.122.y.47.i；A.123.y.47.i；A.124.y.47.i；A.125.y.47.i；A.126.y.47.i；A.127.y.47.i；A.128.y.47.i；A.129.y.47.i；A.130.y.47.i；A.131.y.47.i；A.132.y.47.i；A.133.y.47.i；A.134.y.47.i；A.135.y.47.i；A.136.y.47.i；A.137.y.47.i；A.138.y.47.i；A.139.y.47.i；A.140.y.47.i；A.141.y.47.i；A.2.y.48.i；A.3.y.48.i；A.4.y.48.i；A.5.y.48.i；A.7.y.48.i；A.9.y.48.i；A.100.y.48.i；A.101.y.48.i；A.102.y.48.i；A.103.y.48.i；A.104.y.48.i；A.105.y.48.i；A.106.y.48.i；A.107.y.48.i；A.108.y.48.i；A.109.y.48.i；A.110.y.48.i；A.111.y.48.i；A.112.y.48.i；A.113.y.48.i；A.114.y.48.i；A.115.y.48.i；A.116.y.48.i；A.117.y.48.i；A.118.y.48.i；A.119.y.48.i；A.120.y.48.i；A.121.y.48.i；A.122.y.48.i；A.123.y.48.i；A.124.y.48.i；A.125.y.48.i；
A.126.y.48.i；A.127.y.48.i；A.128.y.48.i；A.129.y.48.i；A.130.y.48.i；A.131.y.48.i；A.132.y.48.i；A.133.y.48.i；A.134.y.48.i；A.135.y.48.i；A.136.y.48.i；A.137.y.48.i；A.138.y.48.i；A.139.y.48.i；A.140.y.48.i；A.141.y.48.i；A.2.y.49.i；A.3.y.49.i；A.4.y.49.i；A.5.y.49.i；A.7.y.49.i；A.9.y.49.i；A.100.y.49.i；A.101.y.49.i；A.102.y.49.i；A.103.y.49.i；A.104.y.49.i；A.105.y.49.i；A.106.y.49.i；A.107.y.49.i；A.108.y.49.i；A.109.y.49.i；A.110.y.49.i；A.111.y.49.i；A.112.y.49.i；A.113.y.49.i；A.114.y.49.i；A.115.y.49.i；A.116.y.49.i；A.117.y.49.i；A.118.y.49.i；A.119.y.49.i；A.120.y.49.i；A.121.y.49.i；A.122.y.49.i；A.123.y.49.i；A.124.y.49.i；A.125.y.49.i；A.126.y.49.i；A.127.y.49.i；A.128.y.49.i；A.129.y.49.i；A.130.y.49.i；A.131.y.49.i；A.132.y.49.i；A.133.y.49.i；A.134.y.49.i；A.135.y.49.i；A.136.y.49.i；A.137.y.49.i；A.138.y.49.i；A.139.y.49.i；A.140.y.49.i；A.141.y.49.i；A.2.y.50.i；A.3.y.50.i；A.4.y.50.i；A.5.y.50.i；A.7.y.50.i；A.9.y.50.i；A.100.y.50.i；A.101.y.50.i；A.102.y.50.i；A.103.y.50.i；A.104.y.50.i；A.105.y.50.i；A.106.y.50.i；A.107.y.50.i；A.108.y.50.i；A.109.y.50.i；A.110.y.50.i；A.111.y.50.i；A.112.y.50.i；A.113.y.50.i；A.114.y.50.i；A.115.y.50.i；A.116.y.50.i；A.117.y.50.i；A.118.y.50.i；A.119.y.50.i；A.120.y.50.i；A.121.y.50.i；A.122.y.50.i；A.123.y.50.i；A.124.y.50.i；A.125.y.50.i；A.126.y.50.i；A.127.y.50.i；A.128.y.50.i；A.129.y.50.i；A.130.y.50.i；A.131.y.50.i；A.132.y.50.i；A.133.y.50.i；A.134.y.50.i；A.135.y.50.i；A.136.y.50.i；A.137.y.50.i；A.138.y.50.i；A.139.y.50.i；A.140.y.50.i；A.141.y.50.i；A.2.y.51.i；A.3.y.51.i；A.4.y31.i；A.5.y.51.i；A.7.y.51.i；A.9.y.51.i；A.100.y.51.i；A.101.y.51.i；A.102.y.51.i；A.103.y.51.i；A.104.y.51.i；A.105.y.51.i；A.106.y.51.i；A.107.y.51.i；A.108.y.51.i；A.109.y.51.i；A.110.y.51.i；A.111.y.51.i；A.112.y.51.i；A.113.y.51.i；A.114.y.51.i；A.115.y.51.i；A.116.y.51.i；A.117.y.51.i；A.118.y.51.i；A.119.y.51.i；A.120.y.51.i；A.121.y.51.i；A.122.y.51.i；A.123.y.51.i；A.124.y.51.i；A.125.y.51.i；A.126.y.51.i；A.127.y.51.i；A.128.y.51.i；A.129.y.51.i；A.130.y.51.i；A.131.y.51.i；A.132.y.51.i；A.133.y.51.i；A.134.y.51.i；A.135.y.51.i；A.136.y.51.i；A.137.y.51.i；A.138.y.51.i；A.139.y.51.i；A.140.y.51.i；A.141.y.51.i；A.2.z.46.i；A.3.z.46.i；A.4.z.46.i；A.5.z.46.i；A.7.z.46.i；A.9.z.46.i；A.100.z.46.i；A.101.z.46.i；A.102.z.46.i；A.103.z.46.i；A.104.z.46.i；A.105.z.46.i；A.106.z.46.i；A.107.z.46.i；A.108.z.46.i；A.109.z.46.i；A.110.z.46.i；A.111.z.46.i；A.112.z.46.i；A.113.z.46.i；A.114.z.46.i；A.115.z.46.i；A.116.z.46.i；A.117.z.46.i；A.118.z.46.i；A.119.z.46.i；A.120.z.46.i；A.121.z.46.i；A.122.z.46.i；A.123.z.46.i；A.124.z.46.i；A.125.z.46.i；A.126.z.46.i；A.127.z.46.i；A.128.z.46.i；A.129.z.46.i；A.130.z.46.i；A.131.z.46.i；A.132.z.46.i；A.133.z.46.i；A.134.z.46.i；A.135.z.46.i；A.136.z.46.i；A.137.z.46.i；A.138.z.46.i；A.139.z.46.i；A.140.z.46.i；A.141.z.46.i；A.2.z.47.i；A.3.z.47.i；A.4.z.47.i；A.5.z.47.i；A.7.z.47.i；A.9.z.47.i；A.100.z.47.i；A.101.z.47.i；A.102.z.47.i；A.103.z.47.i；A.104.z.47.i；A.105.z.47.i；A.106.z.47.i；A.107.z.47.i；A.108.z.47.i；A.109.z.47.i；A.110.z.47.i；A.111.z.47.i；A.112.z.47.i；A.113.z.47.i；A.114.z.47.i；A.115.z.47.i；A.116.z.47.i；A.117.z.47.i；A.118.z.47.i；A.119.z.47.i；A.120.z.47.i；A.121.z.47.i；A.122.z.47.i；A.123.z.47.i；A.124.z.47.i；A.125.z.47.i；A.126.z.47.i；A.127.z.47.i；A.128.z.47.i；A.129.z.47.i；A.130.z.47.i；A.131.z.47.i；A.132.z.47.i；A.133.z.47.i；A.134.z.47.i；A.135.z.47.i；A.136.z.47.i；A.137.z.47.i；A.138.z.47.i；A.139.z.47.i；A.140.z.47.i；A.141.z.47.i；A.2.z.48.i；A.3.z.48.i；A.4.z.48.i；A.5.z.48.i；A.7.z.48.i；A.9.z.48.i；A.100.z.48.i；A.101.z.48.i；A.102.z.48.i；A.103.z.48.i；A.104.z.48.i；A.105.z.48.i；A.106.z.48.i；A.107.z.48.i；A.108.z.48.i；A.109.z.48.i；A.110.z.48.i；A.111.z.48.i；A.112.z.48.i；A.113.z.48.i；A.114.z.48.i；A.115.z.48.i；A.116.z.48.i；A.117.z.48.i；A.118.z.48.i；A.119.z.48.i；A.120.z.48.i；A.121.z.48.i；A.122.z.48.i；A.123.z.48.i；A.124.z.48.i；A.125.z.48.i；
A.126.z.48.i；A.127.z.48.i；A.128.z.48.i；A.129.z.48.i；A.130.z.48.i；A.131.z.48.i；A.132.z.48.i；A.133.z.48.i；A.134.z.48.i；A.135.z.48.i；A.136.z.48.i；A.137.z.48.i；A.138.z.48.i；A.139.z.48.i；A.140.z.48.i；A.141.z.48.i；A.2.z.49.i；A.3.z.49.i；A.4.z.49.i；A.5.z.49.i；A.7.z.49.i；A.9.z.49.i；A.100.z.49.i；A.101.z.49.i；A.102.z.49.i；A.103.z.49.i；A.104.z.49.i；A.105.z.49.i；A.106.z.49.i；A.107.z.49.i；A.108.z.49.i；A.109.z.49.i；A.110.z.49.i；A.111.z.49.i；A.112.z.49.i；A.113.z.49.i；A.114.z.49.i；A.115.z.49.i；A.116.z.49.i；A.117.z.49.i；A.118.z.49.i；A.119.z.49.i；A.120.z.49.i；A.121.z.49.i；A.122.z.49.i；A.123.z.49.i；A.124.z.49.i；A.125.z.49.i；A.126.z.49.i；A.127.z.49.i；A.128.z.49.i；A.129.z.49.i；A.130.z.49.i；A.131.z.49.i；A.132.z.49.i；A.133.z.49.i；A.134.z.49.i；A.135.z.49.i；A.136.z.49.i；A.137.z.49.i；A.138.z.49.i；A.139.z.49.i；A.140.z.49.i；A.141.z.49.i；A.2.z.50.i；A.3.z.50.i；A.4.z.50.i；A.5.z.50.i；A.7.z.50.i；A.9.z.50.i；A.100.z.50.i；A.101.z.50.i；A.102.z.50.i；A.103.z.50.i；A.104.z.50.i；A.105.z.50.i；A.106.z.50.i；A.107.z.50.i；A.108.z.50.i；A.109.z.50.i；A.110.z.50.i；A.111.z.50.i；A.112.z.50.i；A.113.z.50.i；A.114.z.50.i；A.115.z.50.i；A.116.z.50.i；A.117.z.50.i；A.118.z.50.i；A.119.z.50.i；A.120.z.50.i；A.121.z.50.i；A.122.z.50.i；A.123.z.50.i；A.124.z.50.i；A.125.z.50.i；A.126.z.50.i；A.127.z.50.i；A.128.z.50.i；A.129.z.50.i；A.130.z.50.i；A.131.z.50.i；A.132.z.50.i；A.133.z.50.i；A.134.z.50.i；A.135.z.50.i；A.136.z.50.i；A.137.z.50.i；A.138.z.50.i；A.139.z.50.i；A.140.z.50.i；A.141.z.50.i；A.2.z.51.i；A.3.z.51.i；A.4.z.51.i；A.5.z.51.i；A.7.z.51.i；A.9.z.51.i；A.100.z.51.i；A.101.z.51.i；A.102.z.51.i；A.103.z.51.i；A.104.z.51.i；A.105.z.51.i；A.106.z.51.i；A.107.z.51.i；A.108.z.51.i；A.109.z.51.i；A.110.z.51.i；A.111.z.51.i；A.112.z.51.i；A.113.z.51.i；A.114.z.51.i；A.115.z.51.i；A.116.z.51.i；A.117.z.51.i；A.118.z.51.i；A.119.z.51.i；A.120.z.51.i；A.121.z.51.i；A.122.z.51.i；A.123.z.51.i；A.124.z.51.i；A.125.z.51.i；A.126.z.51.i；A.127.z.51.i；A.128.z.51.i；A.129.z.51.i；A.130.z.51.i；A.131.z.51.i；A.132.z.51.i；A.133.z.51.i；A.134.z.51.i；A.135.z.51.i；A.136.z.51.i；A.137.z.51.i；A.138.z.51.i；A.139.z.51.i；A.140.z.51.i；A.141.z.51.i；A.2.A.46.i；A.3.A.46.i；A.4.A.46.i；A.5.A.46.i；A.7.A.46.i；A.9.A.46.i；A.100.A.46.i；A.101.A.46.i；A.102.A.46.i；A.103.A.46.i；A.104.A.46.i；A.105.A.46.i；A.106.A.46.i；A.107.A.46.i；A.108.A.46.i；A.109.A.46.i；A.110.A.46.i；A.111.A.46.i；A.112.A.46.i；A.113.A.46.i；A.114.A.46.i；A.115.A.46.i；A.116.A.46.i；A.117.A.46.i；A.118.A.46.i；A.119.A.46.i；A.120.A.46.i；A.121.A.46.i；A.122.A.46.i；A.123.A.46.i；A.124.A.46.i；A.125.A.46.i；A.126.A.46.i；A.127.A.46.i；A.128.A.46.i；A.129.A.46.i；A.130.A.46.i；A.131.A.46.i；A.132.A.46.i；A.133.A.46.i；A.134.A.46.i；A.135.A.46.i；A.136.A.46.i；A.137.A.46.i；A.138.A.46.i；A.139.A.46.i；A.140.A.46.i；A.141.A.46.i；A.2.A.47.i；A.3.A.47.i；A.4.A.47.i；A.5.A.47.i；A.7.A.47.i；A.9.A.47.i；A.100.A.47.i；A.101.A.47.i；A.102.A.47.i；A.103.A.47.i；A.104.A.47.i；A.105.A.47.i；A.106.A.47.i；A.107.A.47.i；A.108.A.47.i；A.109.A.47.i；A.110.A.47.i；A.111.A.47.i；A.112.A.47.i；A.113.A.47.i；A.114.A.47.i；A.115.A.47.i；A.116.A.47.i；A.117.A.47.i；A.118.A.47.i；A.119.A.47.i；A.120.A.47.i；A.121.A.47.i；A.122.A.47.i；A.123.A.47.i；A.124.A.47.i；A.125.A.47.i；A.126.A.47.i；A.127.A.47.i；A.128.A.47.i；A.129.A.47.i；A.130.A.47.i；A.131.A.47.i；A.132.A.47.i；A.133.A.47.i；A.134.A.47.i；A.135.A.47.i；A.136.A.47.i；A.137.A.47.i；A.138.A.47.i；A.139.A.47.i；A.140.A.47.i；A.141.A.47.i；A.2.A.48.i；A.3.A.48.i；A.4.A.48.i；A.5.A.48.i；A.7.A.48.i；A.9.A.48.i；A.100.A.48.i；A.101.A.48.i；A.102.A.48.i；A.103.A.48.i；A.104.A.48.i；A.105.A.48.i；A.106.A.48.i；A.107.A.48.i；
A.108.A.48.i；A.109.A.48.i；A.110.A.48.i；A.111.A.48.i；A.112.A.48.i；A.113.A.48.i；A.114.A.48.i；A.115.A.48.i；A.116.A.48.i；A.117.A.48.i；A.118.A.48.i；A.119.A.48.i；A.120.A.48.i；A.121.A.48.i；A.122.A.48.i；A.123.A.48.i；A.124.A.48.i；A.125.A.48.i；A.126.A.48.i；A.127.A.48.i；A.128.A.48.i；A.129.A.48.i；A.130.A.48.i；A.131.A.48.i；A.132.A.48.i；A.133.A.48.i；A.134.A.48.i；A.135.A.48.i；A.136.A.48.i；A.137.A.48.i；A.138.A.48.i；A.139.A.48.i；A.140.A.48.i；A.141.A.48.i；A.2.A.49.i；A.3.A.49.i；A.4.A.49.i；A.5.A.49.i；A.7.A.49.i；A.9.A.49.i；A.100.A.49.i；A.101.A.49.i；A.102.A.49.i；A.103.A.49.i；A.104.A.49.i；A.105.A.49.i；A.106.A.49.i；A.107.A.49.i；A.108.A.49.i；A.109.A.49.i；A.110.A.49.i；A.111.A.49.i；A.112.A.49.i；A.113.A.49.i；A.114.A.49.i；A.115.A.49.i；A.116.A.49.i；A.117.A.49.i；A.118.A.49.i；A.119.A.49.i；A.120.A.49.i；A.121.A.49.i；A.122.A.49.i；A.123.A.49.i；A.124.A.49.i；A.125.A.49.i；A.126.A.49.i；A.127.A.49.i；A.128.A.49.i；A.129.A.49.i；A.130.A.49.i；A.131.A.49.i；A.132.A.49.i；A.133.A.49.i；A.134.A.49.i；A.135.A.49.i；A.136.A.49.i；A.137.A.49.i；A.138.A.49.i；A.139.A.49.i；A.140.A.49.i；A.141.A.49.i；A.2.A.50.i；A.3.A.50.i；A.4.A.50.i；A.5.A.50.i；A.7.A.50.i；A.9.A.50.i；A.100.A.50.i；A.101.A.50.i；A.102.A.50.i；A.103.A.50.i；A.104.A.50.i；A.105.A.50.i；A.106.A.50.i；A.107.A.50.i；A.108.A.50.i；A.109.A.50.i；A.110.A.50.i；A.111.A.50.i；A.112.A.50.i；A.113.A.50.i；A.114.A.50.i；A.115.A.50.i；A.116.A.50.i；A.117.A.50.i；A.118.A.50.i；A.119.A.50.i；A.120.A.50.i；A.121.A.50.i；A.122.A.50.i；A.123.A.50.i；A.124.A.50.i；A.125.A.50.i；A.126.A.50.i；A.127.A.50.i；A.128.A.50.i；A.129.A.50.i；A.130.A.50.i；A.131.A.50.i；A.132.A.50.i；A.133.A.50.i；A.134.A.50.i；A.135.A.50.i；A.136.A.50.i；A.137.A.50.i；A.138.A.50.i；A.139.A.50.i；A.140.A.50.iA.141.A.50.i；A.2.A.51.i；A.3.A.51.i；A.4.A.51.i；A.5.A.51.i；A.7.A.51.i；A.9.A.51.i；A.100.A.51.i；A.101.A.51.i；A.102.A.51.i；A.103.A.51.i；A.104.A.51.i；A.105.A.51.i；A.106.A.51.i；A.107.A.51.i；A.108.A.51.i；A.109.A.51.i；A.110.A.51.i；A.111.A.51.i；A.112.A.51.i；A.113.A.51.i；A.114.A.51.i；A.115.A.51.i；A.116.A.51.i；A.117.A.51.i；A.118.A.51.i；A.119.A.51.i；A.120.A.51.i；A.121.A.51.i；A.122.A.51.i；A.123.A.51.i；A.124.A.51.i；A.125.A.51.i；A.126.A.51.i；A.127.A.51.i；A.128.A.51.i；A.129.A.51.i；A.130.A.51.i；A.131.A.51.i；A.132.A.51.i；A.133.A.51.i；A.134.A.51.i；A.135.A.51.i；A.136.A.51.i；A.137.A.51.i；A.138.A.51.i；A.139.A.51.i；A.140.A.51.i；A.141.A.51.i；A.2.B.46.i；A.3.B.46.i；A.4.B.46.i；A.5.B.46.i；A.7.B.46.i；A.9.B.46.i；A.100.B.46.i；A.101.B.46.i；A.102.B.46.i；A.103.B.46.i；A.104.B.46.i；A.105.B.46.i；A.106.B.46.i；A.107.B.46.i；A.108.B.46.i；A.109.B.46.i；A.110.B.46.i；A.111.B.46.i；A.112.B.46.i；A.113.B.46.i；A.114.B.46.i；A.115.B.46.i；A.116.B.46.i；A.117.B.46.i；A.118.B.46.i；A.119.B.46.i；A.120.B.46.i；A.121.B.46.i；A.122.B.46.i；A.123.B.46.i；A.124.B.46.i；A.125.B.46.i；A.126.B.46.i；A.127.B.46.i；A.128.B.46.i；A.129.B.46.i；A.130.B.46.i；A.131.B.46.i；A.132.B.46.i；A.133.B.46.i；A.134.B.46.i；A.135.B.46.i；A.136.B.46.i；A.137.B.46.i；A.138.B.46.i；A.139.B.46.i；A.140.B.46.i；A.141.B.46.i；A.2.B.47.i；A.3.B.47.i；A.4.B.47.i；A.5.B.47.i；A.7.B.47.i；A.9.B.47.i；A.100.B.47.i；A.101.B.47.i；A.102.B.47.i；A.103.B.47.i；A.104.B.47.i；A.105.B.47.i；A.106.B.47.i；A.107.B.47.i；A.108.B.47.i；A.109.B.47.i；A.110.B.47.i；A.111.B.47.i；A.112.B.47.i；A.113.B.47.i；A.114.B.47.i；A.115.B.47.i；A.116.B.47.i；A.117.B.47.i；A.118.B.47.i；A.119.B.47.i；A.120.B.47.i；A.121.B.47.i；
A.122.B.47.i；A.123.B.47.i；A.124.B.47.i；A.125.B.47.i；A.126.B.47.i；A.127.B.47.i；A.128.B.47.i；A.129.B.47.i；A.130.B.47.i；A.131.B.47.i；A.132.B.47.i；A.133.B.47.i；A.134.B.47.i；A.135.B.47.i；A.136.B.47.i；A.137.B.47.i；A.138.B.47.i；A.139.B.47.i；A.140.B.47.i；A.141.B.47.i；A.2.B.48.i；A.3.B.48.i；A.4.B.48.i；A.5.B.48.i；A.7.B.48.i；A.9.B.48.i； A.100.B.48.i；A.101.B.48.i；A.102.B.48.i；A.103.B.48.i；A.104.B.48.i；A.105.B.48.i；A.106.B.48.i；A.107.B.48.i；A.108.B.48.i；A.109.B.48.i；A.110.B.48.i；A.111.B.48.i；A.112.B.48.i；A.113.B.48.i；A.114.B.48.i；A.115.B.48.i；A.116.B.48.i；A.117.B.48.i；A.118.B.48.i；A.119.B.48.i；A.120.B.48.i；A.121.B.48.i；A.122.B.48.i；A.123.B.48.i；A.124.B.48.i；A.125.B.48.i；A.126.B.48.i；A.127.B.48.i；A.128.B.48.i；A.129.B.48.i；A.130.B.48.i；A.131.B.48.i；A.132.B.48.i；A.133.B.48.i；A.134.B.48.i；A.135.B.48.i；A.136.B.48.i；A.137.B.48.i；A.138.B.48.i；A.139.B.48.i；A.140.B.48.i；A.141.B.48.i；A.2.B.49.i；A.3.B.49.i；A.4.B.49.i；A.5.B.49.i；A.7.B.49.i；A.9.B.49.i；A.100.B.49.i；A.101.B.49.i；A.102.B.49.i；A.103.B.49.i；A.104.B.49.i；A.105.B.49.i；A.106.B.49.i；A.107.B.49.i；A.108.B.49.i；A.109.B.49.i；A.110.B.49.i；A.111.B.49.i；A.112.B.49.i；A.113.B.49.i；A.114.B.49.i；A.115.B.49.i；A.116.B.49.i；A.117.B.49.i；A.118.B.49.i；A.119.B.49.i；A.120.B.49.i；A.121.B.49.i；A.122.B.49.i；A.123.B.49.i；A.124.B.49.i；A.125.B.49.i；A.126.B.49.i；A.127.B.49.i；A.128.B.49.i；A.129.B.49.i；A.130.B.49.i；A.131.B.49.i；A.132.B.49.i；A.133.B.49.i；A.134.B.49.i；A.135.B.49.i；A.136.B.49.i；A.137.B.49.i；A.138.B.49.i；A.139.B.49.i；A.140.B.49.i；A.141.B.49.i；A.2.B.50.i；A.3.B.50.i；A.4.B.50.i；A.5.B.50.i；A.7.B.50.i；A.9.B.50.i；A.100.B.50.i；A.101.B.50.i；A.102.B.50.i；A.103.B.50.i；A.104.B.50.i；A.105.B.50.i；A.106.B.50.i；A.107.B.50.i；A.108.B.50.i；A.109.B.50.i；A.110.B.50.i；A.111.B.50.i；A.112.B.50.i；A.113.B.50.i；A.114.B.50.i；A.115.B.50.i；A.116.B.50.i；A.117.B.50.i；A.118.B.50.i；A.119.B.50.i；A.120.B.50.i；A.121.B.50.i；A.122.B.50.i；A.123.B.50.i；A.124.B.50.i；A.125.B.50.i；A.126.B.50.i；A.127.B.50.i；A.128.B.50.i；A.129.B.50.i；A.130.B.50.i；A.131.B.50.i；A.132.B.50.i；A.133.B.50.i；A.134.B.50.i；A.135.B.50.i；A.136.B.50.i；A.137.B.50.i；A.138.B.50.i；A.139.B.50.i；A.140.B.50.i；A.141.B.50.i；A.2.B.51.i；A.3.B.51.i；A.4.B.51.i；A.5.B.51.i；A.7.B.51.i；A.9.B.51.i；A.100.B.51.i；A.101.B.51.i；A.102.B.51.i；A.103.B.51.i；A.104.B.51.i；A.105.B.51.i；A.106.B.51.i；A.107.B.51.i；A.108.B.51.i；A.109.B.51.i；A.110.B.51.i；A.111.B.51.i；A.112.B.51.i；A.113.B.51.i；A.114.B.51.i；A.115.B.51.i；A.116.B.51.i；A.117.B.51.i；A.118.B.51.i；A.119.B.51.i；A.120.B.51.i；A.121.B.51.i；A.122.B.51.i；A.123.B.51.i；A.124.B.51.i；A.125.B.51.i；A.126.B.51.i；A.127.B.51.i；A.128.B.51.i；A.129.B.51.i；A.130.B.51.i；A.131.B.51.i；A.132.B.51.i；A.133.B.51.i；A.134.B.51.i；A.135.B.51.i；A.136.B.51.i；A.137.B.51.i；A.138.B.51.i；A.139.B.51.i；A.140.B.51.i；A.141.B.51.i；A.2.C.46.i；A.3.C.46.i；A.4.C.46.i；A.5.C.46.i；A.7.C.46.i；A.9.C.46.i；A.100.C.46.i；A.101.C.46.i；A.102.C.46.i；A.103.C.46.i；A.104.C.46.i；A.105.C.46.i；A.106.C.46.i；A.107.C.46.i；A.108.C.46.i；A.109.C.46.i；A.110.C.46.i；A.111.C.46.i；A.112.C.46.i；A.113.C.46.i；A.114.C.46.i；A.115.C.46.i；A.116.C.46.i；A.117.C.46.i；A.118.C.46.i；A.119.C.46.i；A.120.C.46.i；A.121.C.46.i；A.122.C.46.i；A.123.C.46.i；A.124.C.46.i；A.125.C.46.i；A.126.C.46.i；A.127.C.46.i；A.128.C.46.i；A.129.C.46.i；A.130.C.46.i；A.131.C.46.i；A.132.C.46.i；A.133.C.46.i；A.134.C.46.i；A.135.C.46.i；A.136.C.46.i；A.137.C.46.i；A.138.C.46.i；A.139.C.46.i；A.140.C.46.i；A.141.C.46.i；A.2.C.47.i；A.3.C.47.i；A.4.C.47.i；A.5.C.47.i；A.7.C.47.i；A.9.C.47.i；A.100.C.47.i；A.101.C.47.i；A.102.C.47.i；A.103.C.47.i；A.104.C.47.i；A.105.C.47.i；A.106.C.47.i；A.107.C.47.i；A.108.C.47.i；A.109.C.47.i；A.110.C.47.i；A.111.C.47.i；A.112.C.47.i；A.113.C.47.i；A.114.C.47.i；A.115.C.47.i；
A.116.C.47.i；A.117.C.47.i；A.118.C.47.i；A.119.C.47.i；A.120.C.47.i；A.121.C.47.i；A.122.C.47.i；A.123.C.47.i；A.124.C.47.i；A.125.C.47.i；A.126.C.47.i；A.127.C.47.i；A.128.C.47.i；A.129.C.47.i；A.130.C.47.i；A.131.C.47.i；A.132.C.47.i；A.133.C.47.i；A.134.C.47.i；A.135.C.47.i；A.136.C.47.i；A.137.C.47.i；A.138.C.47.i；A.139.C.47.i；A.140.C.47.i；A.141.C.47.i；A.2.C.48.i；A.3.C.48.i；A.4.C.48.i；A.5.C.48.i；A.7.C.48.i；A.9.C.48.i；A.100.C.48.i；A.101.C.48.i；A.102.C.48.i；A.103.C.48.i；A.104.C.48.i；A.105.C.48.i；A.106.C.48.i；A.107.C.48.i；A.108.C.48.i；A.109.C.48.i；A.110.C.48.i；A.111.C.48.i；A.112.C.48.i；A.113.C.48.i；A.114.C.48.i；A.115.C.48.i；A.116.C.48.i；A.117.C.48.i；A.118.C.48.i；A.119.C.48.i；A.120.C.48.i；A.121.C.48.i；A.122.C.48.i；A.123.C.48.i；A.124.C.48.i；A.125.C.48.i；A.126.C.48.i；A.127.C.48.i；A.128.C.48.i；A.129.C.48.i；A.130.C.48.i；A.131.C.48.i；A.132.C.48.i；A.133.C.48.i；A.134.C.48.i；A.135.C.48.i；A.136.C.48.i；A.137.C.48.i；A.138.C.48.i；A.139.C.48.i；A.140.C.48.i；A.141.C.48.i；A.2.C.49.i；A.3.C.49.i；A.4.C.49.i；A.5.C.49.i；A.7.C.49.i；A.9.C.49.i；A.100.C.49.i；A.101.C.49.i；A.102.C.49.i；A.103.C.49.i；A.104.C.49.i；A.105.C.49.i；A.106.C.49.i；A.107.C.49.i；A.108.C.49.i；A.109.C.49.i；A.110.C.49.i；A.111.C.49.i；A.112.C.49.i；A.113.C.49.i；A.114.C.49.i；A.115.C.49.i；A.116.C.49.i；A.117.C.49.i；A.118.C.49.i；A.119.C.49.i；A.120.C.49.i；A.121.C.49.i；A.122.C.49.i；A.123.C.49.i；A.124.C.49.i；A.125.C.49.i；A.126.C.49.i；A.127.C.49.i；A.128.C.49.i；A.129.C.49.i；A.130.C.49.i；A.131.C.49.i；A.132.C.49.i；A.133.C.49.i；A.134.C.49.i；A.135.C.49.i；A.136.C.49.i；A.137.C.49.i；A.138.C.49.i；A.139.C.49.i；A.140.C.49.i；A.141.C.49.i；A.2.C.50.i；A.3.C.50.i；A.4.C.50.i；A.5.C.50.i；A.7.C.50.i；A.9.C.50.i；A.100.C.50.i；A.101.C.50.i；A.102.C.50.i；A.103.C.50.i；A.104.C.50.i；A.105.C.50.i；A.106.C.50.i；A.107.C.50.i；A.108.C.50.i；A.109.C.50.i；A.110.C.50.i；A.111.C.50.i；A.112.C.50.i；A.113.C.50.i；A.114.C.50.i；A.115.C.50.i；A.116.C.50.i；A.117.C.50.i；A.118.C.50.i；A.119.C.50.i；A.120.C.50.i；A.121.C.50.i；A.122.C.50.i；A.123.C.50.i；A.124.C.50.i；A.125.C.50.i；A.126.C.50.i；A.127.C.50.i；A.128.C.50.i；A.129.C.50.i；A.130.C.50.i；A.131.C.50.i；A.132.C.50.i；A.133.C.50.i；A.134.C.50.i；A.135.C.50.i；A.136.C.50.i；A.137.C.50.i；A.138.C.50.i；A.139.C.50.i；A.140.C.50.i；A.141.C.50.i；A.2.C.51.i；A.3.C.51.i；A.4.C.51.i；A.5.C.51.i；A.7.C.51.i；A.9.C.51.i；A.100.C.51.i；A.101.C.51.i；A.102.C.51.i；A.103.C.51.i；A.104.C.51.i；A.105.C.51.i；A.106.C.51.i；A.107.C.51.i；A.108.C.51.i；A.109.C.51.i；A.110.C.51.i；A.111.C.51.i；A.112.C.51.i；A.113.C.51.i；A.114.C.51.i；A.115.C.51.i；A.116.C.51.i；A.117.C.51.i；A.118.C.51.i；A.119.C.51.i；A.120.C.51.i；A.121.C.51.i；A.122.C.51.i；A.123.C.51.i；A.124.C.51.i；A.125.C.51.i；A.126.C.51.i；A.127.C.51.i；A.128.C.51.i；A.129.C.51.i；A.130.C.51.i；A.131.C.51.i；A.132.C.51.i；A.133.C.51.i；A.134.C.51.i；A.135.C.51.i；A.136.C.51.i；A.137.C.51.i；A.138.C.51.i；A.139.C.51.i；A.140.C.51.i；A.141.C.51.i；A.2.D.46.i；A.3.D.46.i；A.4.D.46.i；A.5.D.46.i；A.7.D.46.i；A.9.D.46.i；A.100.D.46.i；A.101.D.46.i；A.102.D.46.i；A.103.D.46.i；A.104.D.46.i；A.105.D.46.i；A.106.D.46.i；A.107.D.46.i；A.108.D.46.i；A.109.D.46.i；A.110.D.46.i；A.111.D.46.i；A.112.D.46.i；A.113.D.46.i；A.114.D.46.i；A.115.D.46.i；A.116.D.46.i；A.117.D.46.i；A.118.D.46.i；A.119.D.46.i；A.120.D.46.i；A.121.D.46.i；A.122.D.46.i；A.123.D.46.i；A.124.D.46.i；A.125.D.46.i；A.126.D.46.i；A.127.D.46.i；A.128.D.46.i；A.129.D.46.i；A.130.D.46.i；A.131.D.46.i；A.132.D.46.i；A.133.D.46.i；A.134.D.46.i；A.135.D.46.i；A.136.D.46.i；A.137.D.46.i；A.138.D.46.i；A.139.D.46.i；A.140.D.46.i；A.141.D.46.i；A.2.D.47.i；A.3.D.47.i；A.4.D.47.i；A.5.D.47.i；A.7.D.47.i；A.9.D.47.i；A.100.D.47.i；A.101.D.47.i；A.102.D.47.i；A.103.D.47.i；A.104.D.47.i；A.105.D.47.i；A.106.D.47.i；A.107.D.47.i；A.108.D.47.i；A.109.D.47.i；
A.110.D.47.i；A.111.D.47.i；A.112.D.47.i；A.113.D.47.i；A.114.D.47.i；A.115.D.47.i；A.116.D.47.i；A.117.D.47.i；A.118.D.47.i；A.119.D.47.i；A.120.D.47.i；A.121.D.47.i；A.122.D.47.i；A.123.D.47.i；A.124.D.47.i；A.125.D.47.i；A.126.D.47.i；A.127.D.47.i；A.128.D.47.i；A.129.D.47.i；A.130.D.47.i；A.131.D.47.i；A.132.D.47.i；A.133.D.47.i；A.134.D.47.i；A.135.D.47.i；A.136.D.47.i；A.137.D.47.i；A.138.D.47.i；A.139.D.47.i；A.140.D.47.i；A.141.D.47.i；A.2.D.48.i；A.3.D.48.i；A.4.D.48.i；A.5.D.48.i；A.7.D.48.i；A.9.D.48.i；A.100.D.48.i；A.101.D.48.i；A.102.D.48.i；A.103.D.48.i；A.104.D.48.i；A.105.D.48.i；A.106.D.48.i；A.107.D.48.i；A.108.D.48.i；A.109.D.48.i；A.110.D.48.i；A.111.D.48.i；A.112.D.48.i；A.113.D.48.i；A.114.D.48.i；A.115.D.48.i；A.116.D.48.i；A.117.D.48.i；A.118.D.48.i；A.119.D.48.i；A.120.D.48.i；A.121.D.48.i；A.122.D.48.i；A.123.D.48.i；A.124.D.48.i；A.125.D.48.i；A.126.D.48.i；A.127.D.48.i；A.128.D.48.i；A.129.D.48.i；A.130.D.48.i；A.131.D.48.i；A.132.D.48.i；A.133.D.48.i；A.134.D.48.i；A.135.D.48.i；A.136.D.48.i；A.137.D.48.i；A.138.D.48.i；A.139.D.48.i；A.140.D.48.i；A.141.D.48.i；A.2.D.49.i；A.3.D.49.i；A.4.D.49.i；A.5.D.49.i；A.7.D.49.i；A.9.D.49.i；A.100.D.49.i；A.101.D.49.i；A.102.D.49.i；A.103.D.49.i；A.104.D.49.i；A.105.D.49.i；A.106.D.49.i；A.107.D.49.i；A.108.D.49.i；A.109.D.49.i；A.110.D.49.i；A.111.D.49.i；A.112.D.49.i；A.113.D.49.i；A.114.D.49.i；A.115.D.49.i；A.116.D.49.i；A.117.D.49.i；A.118.D.49.i；A.119.D.49.i；A.120.D.49.i；A.121.D.49.i；A.122.D.49.i；A.123.D.49.i；A.124.D.49.i；A.125.D.49.i；A.126.D.49.i；A.127.D.49.i；A.128.D.49.i；A.129.D.49.i；A.130.D.49.i；A.131.D.49.i；A.132.D.49.i；A.133.D.49.i；A.134.D.49.i；A.135.D.49.i；A.136.D.49.i；A.137.D.49.i；A.138.D.49.i；A.139.D.49.i；A.140.D.49.i；A.141.D.49.i；A.2.D.50.i；A.3.D.50.i；A.4.D.50.i；A.5.D.50.i；A.7.D.50.i；A.9.D.50.i；A.100.D.50.i；A.101.D.50.i；A.102.D.50.i；A.103.D.50.i；A.104.D.50.i；A.105.D.50.i；A.106.D.50.i；A.107.D.50.i；A.108.D.50.i；A.109.D.50.i；A.110.D.50.i；A.111.D.50.i；A.112.D.50.i；A.113.D.50.i；A.114.D.50.i；A.115.D.50.i；A.116.D.50.i；A.117.D.50.i；A.118.D.50.i；A.119.D.50.i；A.120.D.50.i；A.121.D.50.i；A.122.D.50.i；A.123.D.50.i；A.124.D.50.i；A.125.D.50.i；A.126.D.50.i；A.127.D.50.i；A.128.D.50.i；A.129.D.50.i；A.130.D.50.i；A.131.D.50.i；A.132.D.50.i；A.133.D.50.i；A.134.D.50.i；A.135.D.50.i；A.136.D.50.i；A.137.D.50.i；A.138.D.50.i；A.139.D.50.i；A.140.D.50.i；A.141.D.50.i；A.2.D.51.i；A.3.D.51.i；A.4.D.51.i；A.5.D.51.i；A.7.D.51.i；A.9.D.51.i；A.100.D.51.i；A.101.D.51.i；A.102.D.51.i；A.103.D.51.i；A.104.D.51.i；A.105.D.51.i；A.106.D.51.i；A.107.D.51.i；A.108.D.51.i；A.109.D.51.i；A.110.D.51.i；A.111.D.51.i；A.112.D.51.i；A.113.D.51.i；A.114.D.51.i；A.115.D.51.i；A.116.D.51.i；A.117.D.51.i；A.118.D.51.i；A.119.D.51.i；A.120.D.51.i；A.121.D.51.i；A.122.D.51.i；A.123.D.51.i；A.124.D.51.i；A.125.D.51.i；A.126.D.51.i；A.127.D.51.i；A.128.D.51.i；A.129.D.51.i；A.130.D.51.i；A.131.D.51.i；A.132.D.51.i；A.133.D.51.i；A.134.D.51.i；A.135.D.51.i；A.136.D.51.i；A.137.D.51.i；A.138.D.51.i；A.139.D.51.i；A.140.D.51.i；A.141.D.51.i；A.2.E.46.i；A.3.E.46.i；A.4.E.46.i；A.5.E.46.i；A.7.E.46.i；A.9.E.46.i；A.100.E.46.i；A.101.E.46.i；A.102.E.46.i；A.103.E.46.i；A.104.E.46.i；A.105.E.46.i；A.106.E.46.i；A.107.E.46.i；A.108.E.46.i；A.109.E.46.i；A.110.E.46.i；A.111.E.46.i；A.112.E.46.i；A.113.E.46.i；A.114.E.46.i；A.115.E.46.i；A.116.E.46.i；A.117.E.46.i；A.118.E.46.i；A.119.E.46.i；A.120.E.46.i；A.121.E.46.i；A.122.E.46.i；A.123.E.46.i；A.124.E.46.i；A.125.E.46.i；A.126.E.46.i；A.127.E.46.i；A.128.E.46.i；A.129.E.46.i；A.130.E.46.i；A.131.E.46.i；A.132.E.46.i；A.133.E.46.i；A.134.E.46.i；A.135.E.46.i；A.136.E.46.i；A.137.E.46.i；A.138.E.46.i；A.139.E.46.i；A.140.E.46.i；A.141.E.46.i；A.2.E.47.i；A.3.E.47.i；A.4.E.47.i；A.5.E.47.i；A.7.E.47.i；A.9.E.47.i；A.100.E.47.i；A.101.E.47.i；A.102.E.47.i；A.103.E.47.i；A.104.E.47.i；A.105.E.47.i；
A.106.E.47.i；A.107.E.47.i；A.108.E.47.i；A.109.E.47.i；A.110.E.47.i；A.111.E.47.i；A.112.E.47.i；A.113.E.47.i；A.114.E.47.i；A.115.E.47.i；A.116.E.47.i；A.117.E.47.i；A.118.E.47.i；A.119.E.47.i；A.120.E.47.i；A.121.E.47.i；A.122.E.47.i；A.123.E.47.i；A.124.E.47.i；A.125.E.47.i；A.126.E.47.i；A.127.E.47.i；A.128.E.47.i；A.129.E.47.i；A.130.E.47.i；A.131.E.47.i；A.132.E.47.i；A.133.E.47.i；A.134.E.47.i；A.135.E.47.i；A.136.E.47.i；A.137.E.47.i；A.138.E.47.i；A.139.E.47.i；A.140.E.47.i；A.141.E.47.i；A.2.E.48.i；A.3.E.48.i；A.4.E.48.i；A.5.E.48.i；A.7.E.48.i；A.9.E.48.i；A.100.E.48.i；A.101.E.48.i；A.102.E.48.i；A.103.E.48.i；A.104.E.48.i；A.105.E.48.i；A.106.E.48.i；A.107.E.48.i；A.108.E.48.i；A.109.E.48.i；A.110.E.48.i；A.111.E.48.i；A.112.E.48.i；A.113.E.48.i；A.114.E.48.i；A.115.E.48.i；A.116.E.48.i；A.117.E.48.i；A.118.E.48.i；A.119.E.48.i；A.120.E.48.i；A.121.E.48.i；A.122.E.48.i；A.123.E.48.i；A.124.E.48.i；A.125.E.48.i；A.126.E.48.i；A.127.E.48.i；A.128.E.48.i；A.129.E.48.i；A.130.E.48.i；A.131.E.48.i；A.132.E.48.i；A.133.E.48.i；A.134.E.48.i；A.135.E.48.i；A.136.E.48.iA.137.E.48.i；A.138.E.48.i；A.139.E.48.i；A.140.E.48.i；A.141.E.48.i；A.2.E.49.i；A.3.E.49.i；A.4.E.49.i；A.5.E.49.i；A.7.E.49.i；A.9.E.49.i；A.100.E.49.i；A.101.E.49.i；A.102.E.49.i；A.103.E.49.i；A.104.E.49.i；A.105.E.49.i；A.106.E.49.i；A.107.E.49.i；A.108.E.49.i；A.109.E.49.i；A.110.E.49.i；A.111.E.49.i；A.112.E.49.i；A.113.E.49.i；A.114.E.49.i；A.115.E.49.i；A.116.E.49.i；A.117.E.49.i；A.118.E.49.i；A.119.E.49.i；A.120.E.49.i；A.121.E.49.i；A.122.E.49.i；A.123.E.49.i；A.124.E.49.i；A.125.E.49.i；A.126.E.49.i；A.127.E.49.i；A.128.E.49.i；A.129.E.49.i；A.130.E.49.i；A.131.E.49.i；A.132.E.49.i；A.133.E.49.i；A.134.E.49.i；A.135.E.49.i；A.136.E.49.i；A.137.E.49.i；A.138.E.49.i；A.139.E.49.i；A.140.E.49.i；A.141.E.49.i；A.2.E.50.i；A.3.E.50.i；A.4.E.50.i；A.5.E.50.i；A.7.E.50.i；A.9.E.50.i；A.100.E.50.i；A.101.E.50.i；A.102.E.50.i；A.103.E.50.i；A.104.E.50.i； A.105.E.50.i；A.106.E.50.i；A.107.E.50.i；A.108.E.50.i；A.109.E.50.i；A.110.E.50.i；A.111.E.50.i；A.112.E.50.i；A.113.E.50.i；A.114.E.50.i；A.115.E.50.i；A.116.E.50.i；A.117.E.50.i；A.118.E.50.i；A.119.E.50.i；A.120.E.50.i；A.121.E.50.i；A.122.E.50.i；A.123.E.50.i；A.124.E.50.i；A.125.E.50.i；A.126.E.50.i；A.127.E.50.i；A.128.E.50.i；A.129.E.50.i；A.130.E.50.i；A.131.E.50.i；A.132.E.50.i；A.133.E.50.i；A.134.E.50.i；A.135.E.50.i；A.136.E.50.i；A.137.E.50.i；A.138.E.50.i；A.139.E.50.i；A.140.E.50.i；A.141.E.50.i；A.2.E.51.i；A.3.E.51.i；A.4.E.51.i；A.5.E.51.i；A.7.E.51.i；A.9.E.51.i；A.100.E.51.i；A.101.E.51.i；A.102.E.51.i；A.103.E.51.i；A.104.E.51.i；A.105.E.51.i；A.106.E.51.i；A.107.E.51.i；A.108.E.51.i；A.109.E.51.i；A.110.E.51.i；A.111.E.51.i；A.112.E.51.i；A.113.E.51.i；A.114.E.51.i；A.115.E.51.i；A.116.E.51.i；A.117.E.51.i；A.118.E.51.i；A.119.E.51.i；A.120.E.51.i；A.121.E.51.i；A.122.E.51.i；A.123.E.51.i；A.124.E.51.i；A.125.E.51.i；A.126.E.51.i；A.127.E.51.i；A.128.E.51.i；A.129.E.51.i；A.130.E.51.i；A.131.E.51.i；A.132.E.51.i；A.133.E.51.i；A.134.E.51.i；A.135.E.51.i；A.136.E.51.i；A.137.E.51.i；A.138.E.51.i；A.139.E.51.i；A.140.E.51.i；A.141.E.51.i；A.2.F.46.i；A.3.F.46.i；A.4.F.46.i；A.5.F.46.i；A.7.F.46.i；A.9.F.46.i；A.100.F.46.i；A.101.F.46.i；A.102.F.46.i；A.103.F.46.i；A.104.F.46.i；A.105.F.46.i；A.106.F.46.i；A.107.F.46.i；A.108.F.46.i；A.109.F.46.i；A.110.F.46.i；A.111.F.46.i；A.112.F.46.i；A.113.F.46.i；A.114.F.46.i；A.115.F.46.i；A.116.F.46.i；A.117.F.46.i；A.118.F.46.i；A.119.F.46.i；A.120.F.46.i；A.121.F.46.i；A.122.F.46.i；A.123.F.46.i；A.124.F.46.i；A.125.F.46.i；A.126.F.46.i；A.127.F.46.i；A.128.F.46.i；A.129.F.46.i；A.130.F.46.i；A.131.F.46.i；A.132.F.46.i；A.133.F.46.i；A.134.F.46.i；A.135.F.46.i；A.136.F.46.i；A.137.F.46.i；A.138.F.46.i；A.139.F.46.i；A.140.F.46.i；A.141.F.46.i；A.2.F.47.i；A.3.F.47.i；A.4.F.47.i；A.5.F.47.i；A.7.F.47.i；A.9.F.47.i；A.100.F.47.i；A.101.F.47.i；
A.102.F.47.i；A.103.F.47.i；A.104.F.47.i；A.105.F.47.i；A.106.F.47.i；A.107.F.47.i；A.108.F.47.i；A.109.F.47.i；A.110.F.47.i；A.111.F.47.i；A.112.F.47.i；A.113.F.47.i；A.114.F.47.i；A.115.F.47.i；A.116.F.47.i；A.117.F.47.i；A.118.F.47.i；A.119.F.47.i；A.120.F.47.i；A.121.F.47.i；A.122.F.47.i；A.123.F.47.i；A.124.F.47.i；A.125.F.47.i；A.126.F.47.i；A.127.F.47.i；A.128.F.47.i；A.129.F.47.i；A.130.F.47.i；A.131.F.47.i；A.132.F.47.i；A.133.F.47.i；A.134.F.47.i；A.135.F.47.i；A.136.F.47.i；A.137.F.47.i；A.138.F.47.i；A.139.F.47.i；A.140.F.47.i；A.141.F.47.i；A.2.F.48.i；A.3.F.48.i；A.4.F.48.i；A.5.F.48.i；A.7.F.48.i；A.9.F.48.i；A.100.F.48.i；A.101.F.48.i；A.102.F.48.i；A.103.F.48.i；A.104.F.48.i；A.105.F.48.i；A.106.F.48.i；A.107.F.48.i；A.108.F.48.i；A.109.F.48.i；A.110.F.48.i；A.111.F.48.i；A.112.F.48.i；A.113.F.48.i；A.114.F.48.i；A.115.F.48.i；A.116.F.48.i；A.117.F.48.i；A.118.F.48.i；A.119.F.48.i；A.120.F.48.i；A.121.F.48.i；A.122.F.48.i；A.123.F.48.i；A.124.F.48.i；A.125.F.48.i；A.126.F.48.i；A.127.F.48.i；A.128.F.48.i；A.129.F.48.i；A.130.F.48.i；A.131.F.48.i；A.132.F.48.i；A.133.F.48.i；A.134.F.48.i；A.135.F.48.i；A.136.F.48.i；A.137.F.48.i；A.138.F.48.i；A.139.F.48.i；A.140.F.48.i；A.141.F.48.i；A.2.F.49.i；A.3.F.49.i；A.4.F.49.i；A.5.F.49.i；A.7.F.49.i；A.9.F.49.i；A.100.F.49.i；A.101.F.49.i；A.102.F.49.i；A.103.F.49.i；A.104.F.49.i；A.105.F.49.i；A.106.F.49.i；A.107.F.49.i；A.108.F.49.i；A.109.F.49.i；A.110.F.49.i；A.111.F.49.i；A.112.F.49.i；A.113.F.49.i；A.114.F.49.i；A.115.F.49.i；A.116.F.49.i；A.117.F.49.i；A.118.F.49.i；A.119.F.49.i；A.120.F.49.i；A.121.F.49.i；A.122.F.49.i；A.123.F.49.i；A.124.F.49.i；A.125.F.49.i；A.126.F.49.i；A.127.F.49.i；A.128.F.49.i；A.129.F.49.i；A.130.F.49.i；A.131.F.49.i；A.132.F.49.i；A.133.F.49.i；A.134.F.49.i；A.135.F.49.i；A.136.F.49.i；A.137.F.49.i；A.138.F.49.i；A.139.F.49.i；A.140.F.49.i；A.141.F.49.i；A.2.F.50.i；A.3.F.50.i；A.4.F.50.i；A.5.F.50.i；A.7.F.50.i；A.9.F.50.i；A.100.F.50.i；A.101.F.50.i；A.102.F.50.i；A.103.F.50.i；A.104.F.50.i；A.105.F.50.i；A.106.F.50.i；A.107.F.50.i；A.108.F.50.i；A.109.F.50.i；A.110.F.50.i；A.111.F.50.i；A.112.F.50.i；A.113.F.50.i；A.114.F.50.i；A.115.F.50.i；A.116.F.50.i；A.117.F.50.i；A.118.F.50.i；A.119.F.50.i；A.120.F.50.i；A.121.F.50.i；A.122.F.50.i；A.123.F.50.i；A.124.F.50.i；A.125.F.50.i；A.126.F.50.i；A.127.F.50.i；A.128.F.50.i；A.129.F.50.i；A.130.F.50.i；A.131.F.50.i；A.132.F.50.i；A.133.F.50.i；A.134.F.50.i；A.135.F.50.i；A.136.F.50.i；A.137.F.50.i；A.138.F.50.i；A.139.F.50.i；A.140.F.50.i；A.141.F.50.i；A.2.F.51.i；A.3.F.51.i；A.4.F.51.i；A.5.F.51.i；A.7.F.51.i；A.9.F.51.i；A.100.F.51.i；A.101.F.51.i；A.102.F.51.i；A.103.F.51.i；A.104.F.51.i；A.105.F.51.i；A.106.F.51.i；A.107.F.51.i；A.108.F.51.i；A.109.F.51.i；A.110.F.51.i；A.111.F.51.i；A.112.F.51.i；A.113.F.51.i；A.114.F.51.i；A.115.F.51.i；A.116.F.51.i；A.117.F.51.i；A.118.F.51.i；A.119.F.51.i；A.120.F.51.i；A.121.F.51.i；A.122.F.51.i；A.123.F.51.i；A.124.F.51.i；A.125.F.51.i；A.126.F.51.i；A.127.F.51.i；A.128.F.51.i；A.129.F.51.i；A.130.F.51.i；A.131.F.51.i；A.132.F.51.i；A.133.F.51.i；A.134.F.51.i；A.135.F.51.i；A.136.F.51.i；A.137.F.51.i；A.138.F.51.i；A.139.F.51.i；A.140.F.51.i；A.141.F.51.i；
Salt and hydrate
The present composition arbitrarily salt containing compounds herein, particularly pharmaceutically acceptable non-toxic salt, it contains for example, Na+, Li+, K+, Ca++With Mg++.Such salt also may include that those derive from the appropriate cation of mixing (such as alkali metal ion, alkaline-earth metal ions or ammonium ion and quaternary ammonium ion) and (are typically W with acid anion moiety1Carboxylic acid) salt.If desired water soluble salt is then preferably monovalent salt.
Typically, reacted with metal hydroxides and the compounds of this invention and metal salt is made.The example for the metal salt being made in this way is containing Li+, Na+With K+Salt.Appropriate metallic compound, which is added, from the solution of more readily soluble salt is precipitated out less soluble metal salt.
In addition, also can be by adding acid to alkaline center (preferably G1Amine) or to acidic-group (such as E1) and forming salt, for example, some organic acids and inorganic acid (e.g., HCl, HBr, H2SO4, H3PO4) or organic sulfonic acid.Finally, it is to be understood that the compounds of this invention that confectionery composition includes can be in not dissociate, or in zwitterionic form, or in the example of hydrate, it is mixed with the water of stoichiometry.
Also include it is within the scope of the invention that the salt of parent compound and one or more amino acid.Any of above amino acid is applicable, and especially as the naturally occurring amino acid of protein component, but this amino acid preferably carries the amino acid of the side chain containing alkalescence or acidic-group, such as, lysine, arginine or glutamic acid, or the amino acid with neutral group, such as, glycine, serine, threonine, alanine, isoleucine or leucine.The suppression method of neuraminidase
Another aspect of the present invention is related to the method for suppressing neuraminidase activity, and it includes handling the step of may containing the sample of neuraminidase with the compounds of this invention.
The present composition is used as the inhibitor of neuraminidase, the intermediate of such inhibitor or with following purposes.The inhibitor is bound to the position on neuraminidase surface or in hole (position has the structure that only neuraminidase just has).The combination of composition and neuraminidase has different degrees of invertibity.The compound of those substantial Irreversible bindings is the desirable material for the inventive method.In a typical implementation, composition is with less than 10-4M, is more typically less than 10-6M, more typically 10-8M attachment coefficient combination neuraminidase.Once after mark, the composition of this substantial Irreversible binding can be used as detecting the probe of neuraminidase.Therefore, the present invention relates to the nerve that detection may be in the sample containing neuraminidase
The method of propylhomoserin enzyme, it comprises the following steps：The sample of neuraminidase may be contained with the compositions-treated containing the compounds of this invention for being bonded to label (label)；Observe the effect of sample to label activity.Appropriate label is well known to diagnosis circle, including stable free radical, fluorogen, radio isotope, enzyme, chemiluminescent groups and chromophore.Compounds herein is marked in conventional manner with functional group (such as hydroxyl or amino).
In the present invention, may contain the sample of neuraminidase includes natural or artificial material, such as live body；Tissue or cell culture；Biosample, such as biomaterial sample (blood, serum, urine, celiolymph, tear, phlegm, saliva, tissue sample etc.)；Laboratory sample；Food, water or air sample；Bioproduct specimen, such as cell extraction thing, particularly recombinant cell (it can synthesize required glycoprotein) etc..Typically, possible sample is containing that can produce the organism of neuraminidase, typically pathogenic organisms, for example, viral.Sample can be contained in any aqueous medium with organic solvent/aqueous mixtures.Sample includes organism living, such as such as mankind or manmade materials, cell culture.
Process step of the present invention includes adding to the present composition in sample, or the precursor of said composition is added in sample.This addition step includes any of above application process.
If desired, any method (including direct and indirect neuraminidase activity detection method) observation can be used using the activity of the neuraminidase after composition.Quantitative, the qualitative neuraminidase activity detection method with sxemiquantitative can use.Typically, using any of above-mentioned screening method, but any other method can be also used, for example, to the observation method of live physiological property.
Organism containing neuraminidase includes bacterium (comma bacillus, C.perfringens, streptococcus pneumonia and Arthrobacter sialophilus) and virus (particularly orthomyxovirus or paramyxoviridae, such as influenza virus A and B, parainfluenza virus, mumps virus, ewcastle disease virus, poultry plague virus, with sendai virus).The inhibitory action for the neuraminidase activity for occurring or finding in these organisms is in the object of the invention.The virology of influenza virus is as " described in Fundamental Virology " (Raven Press, NewYork, 1986) the 24th chapter.The compounds of this invention can be used for the such infection for treating or preventing animals or humans, and the example of said animal has duck, rodent or pig.
However, when screening can suppress the compound of influenza virus, should keep enzyme analysis result firmly in mind might not be consistent with cell culture analytical result, such as Chandler et al., ibid,
Table 1 shown in.So main screening technique should be used as using plaque reduction assay.The screening of neuraminidase inhibitor
With conventional any inhibitory activity of the technology screening present composition to neuraminidase for being used for assessing enzymatic activity.Herein, typically first screening composition is used to suppress neuraminidase in vitro, and the composition with inhibitory activity screens its activity in vivo again.External Ki (inhibition constant) is below about 5 × 10-6M, preferably below about 1 × 10-7M, preferably than about 5 × 10-8M, composition it is preferable to vivo applications.
Useful in-vitro screening has been described, therefore is repeated no more herein.Von Itzstein, M. et al.；" nature ", 363 (6428)：Page full section of the 2nd column the 3rd of 418-423 (1933), particularly the 420th illustrates Potier M. et al. to the 1st section of the column of page 421 the 2nd；" Analyt.Biochem. ", 94：A kind of suitable analyzed in vitro in 287-296 (1979), the analysis is Chong, A.K.J. et al.；" Biochem.Biophys.Acta ", 1077：65-71 (1991) is improved, in addition, Colman, P.M. et al. WO92/06691 (international application no PCT/AU90/00501 is disclosed on April 30th, 1992) the 13rd row to the 16th rows of page 35 of page 34 illustrate another useful in-vitro screening method.
Internal screening method has also been described, with reference to von Itzstein, M. et al.；As described above, particularly page 421 full section of the 2nd column the 1st be to the 1st section of the column of page 423 the 2nd, and Colman, P.M. et al.；As described above, the 1-38 rows of page 36, which illustrate suitable internal screening method.Pharmaceutical preparation and method of administration
The compounds of this invention is allocated with conventional carrier and excipient, and the carrier puts into practice selected with excipient by.Tablet will include excipient, glidant, filler, adhesive etc..Sterile form is made in aqueous compositions, and if being intended to parenteral in use, typically isotonic.All formulas arbitrarily contain excipient, as described in " handbook of pharmaceutical excipients (Handbook of PharmaceuticalExcipients) " (1986).Excipient includes ascorbic acid and other antioxidants, such as EDTA etc chelating agent, such as carbohydrate, dextrin, hydroxy alkyl cellulose, hydroxyalky methyl celluloses, stearic acid etc..The pH of these formulas is about 3 to 11, but typically about 7 to 10.
One or more compounds (referred to herein as active component) of the present invention are suitable for symptom to be treated
Approach be administered.Suitable route includes oral, per rectum, intranasal, local (including cheek with sublingual), Via vagina and parenteral (including subcutaneous, intramuscular, intravenous, intracutaneous, intrathecal and Epidural cavity) etc..There are different preferably approach depending on the situation by medicine person.The advantage of the compounds of this invention is its oral bio availability, it is possible to oral administration, without via intrapulmonary or intra-nasal route.Unexpectedly (particularly in view of Bamford, M.J., " enzyme level magazine ", 10：1-6 (1995) and especially the 15th page, the first full section), WO91/16320, the influenza of WO92/06691 and United States Patent (USP) 5360817, which emits compound, successfully oral or intraperitoneal to be administered.The embodiment that sees below 161.
Although can be used alone active component, preferably used with pharmaceutical preparation.Invention formulation, for animals or people uses, and includes at least one active component, and one or more acceptable carriers and arbitrary other treatment composition as defined above.The carrier must be " acceptable ", you can compatible with the other compositions of preparation and to harmless by medicine person.
Preparation includes those of suitable foregoing method of administration, and it is in unit dosage forms to be preferably, its available any known method of pharmaceutical industry is made.Generally, these technologies and preparation can be learnt by Remington ' s PharmaceuticalSciences (Mack Publishing Co., Easton, PA).These methods include merging the step of active component is with carrier (constituting one or more auxiliary elements).Generally by it is uniform and be sufficiently mixed active component and liquid-carrier or solid carrier fine powder or the two, then, if desired, be molded this product and preparation of preparation.
Scattered unit, such as capsule is made suitable for oral preparation in the present invention, cachet or tablet (its respectively the active component containing scheduled volume)；Powder or particle；Solution or suspension (in liquid, aqueous or on-aqueous liquid)；Oil-in-water liq emulsion or water-in-oil liquid emulsion.Active component can be in bolus, electuary or paste.
Tablet is arbitrarily mixed with one or more auxiliary elements by suppressing or being molded.Compressed tablets is formed as follows：In suitable machine, compacting is in the active component (e.g., powder or particle) of free-flowing form, and is arbitrarily mixed with adhesive, lubricant, inert diluent, preservative, surfactant or dispersant.Molded tablet is then that the mixture of the active component in appropriate machine, humidified by powdered and through inert liquid diluent is molded.These tablets can arbitrarily be coated or indentation, and be arbitrarily modulated into and can slowly release or control to release active component therein.In one embodiment, the acidolysis of medicine is avoided by using casing.
For eye or other outside organizations (such as, mouth or skin) infection when, preferably used with topical ointment or creme, its contain such as 0.075 to 20%w/w active component (active principle included be 0.1% to 20%, and be 0.1%w/w increasing amounts, such as 0.6%w/w, 0.7%w/w etc.), preferably 0.2 to 15%w/w, preferably 0.5 to 10%w/w.When being modulated into ointment, this active component can be used in combination with paraffin or the miscible ointment bases of water.In addition, this active component also can be modulated into creme with oil-in-water cream base.
If desired, the aqueous phase of cream base can be included, for example, at least 30%w/w polyhydroxy-alcohols, there is the alcohol of two or more hydroxyls, for example, propane diols, butane -1,3- glycol, mannitol, D-sorbite, glycerine and polyethylene glycol (including PEG 400) and its mixture.Local prescription, which preferably contains, can strengthen compound of the active component via absorption or the infiltration of skin or other affected areas.Such example for wearing skin penetration enhancers includes dimethyl sulfoxide (DMSO) and related analogs.
The oil phase of emulsion of the present invention can be made up of known way with principal component.Although this mutually can only include emulsifying agent, at least one emulsifying agent and fat or the mixture of oil (or fat and both oil) are preferably included.Preferred hydrophilic emulsifying agent is used in combination with lipophilic emulsifier (being used as stabilizer).Further preferably include oil and both fat.So-called emulsifying wax is constituted with or without the emulsifying agent of stabilizer, and wax constitutes so-called emulsifying ointment base with oil and fat, it forms the oily dispersed phase of creme.
Include Tween 69, Span 80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl monostearate and NaLS suitable for the emulsifying agent and emulsion stabilizer of inventive formulation.
The oil or fat that this formula is applicable regard required cosmetic property and selected.Creme preferably non-greasy, the product that does not dye and can wash off, and with d spiss without being leaked out from pipe or in other containers.Straight or branched can be used, unitary or binary alkyl ester, such as two different adipate esters, different cetyl stearate, coconut fatty acid propylene glycol diesters, isopropyl myristic acid ester, Ceraphyl 140, isopropyl cetylate, butyl stearate, 2- ethyl hexyl palmitats or the mixture of branched ester (such as Crodaol CAP), latter three are preferable ester.Depending on required property, it individually or can merge and use.It can also use high-melting fat, such as White soft paraffin and/or atoleine or other mineral oil in addition.
Being adapted to the local formula used in eye also includes eye drops, and wherein active component is dissolved in or is suspended in suitable carrier, particularly in its aqueous solvent.The concentration of active component preferably 0.5 to 20%w/w, more preferably 0.5 to 10%, preferably about 1.5%.
Being adapted to the local formula being used in mouth includes：Lozenge, it includes being contained in the active component in flavoured base, and the matrix is usually sucrose, Arabic gum and bassora gum；Pastille, it includes being contained in inert base such as gelatin and glycerine, or sucrose and the active component in Arabic gum；And mouth-wash, it includes the active component being contained in appropriate liquid carrier.
Rectum, which is used, matches somebody with somebody and can include such as cocoa butter or salicylate in suppository form, mixed applicable matrix.
(including particle diameter is in 0.1 to 500 micrometer range, and in cumulative combination, for example for such as 0.1 to 500 micron for intrapulmonary or the nose particle diameter that has of formula, 0.5,1,30 micron, 35 microns etc.), it quickly sucks via nasal passage or is sucked via mouth and reach alveolar sac.Suitable formula includes the aqueous or oily solution of active component.It is adapted to can be made according to a conventional method aerosol or matching somebody with somebody for dry powder administration, and can be together applied with other therapeutic agents (such as following compounds for being previously used for treating or preventing influenza A or B infection).
For vagina administration with can make pessary, cotton wool, creme, gel, paste, foam or spray composition form, it is in addition to containing active component, also containing being known in the art as appropriate carrier.
Formula for parenteral includes aqueous with non-aqueous aseptic parenteral solution, and it can contain antioxidant, buffer substance, antibacterial substance and can make this formula with being in isotonic solute by medicine person blood；Aqueous and non-aqueous sterile suspensions, it can contain suspending agent and thickener.
These formulas are presented in unit dose or multi-dose container, for example, sealedly ampoule and bottle, and can be stored under lyophilisation condition, and sterile liquid carrier need to be being added again using preceding, for example, water for injection.Jury parenteral solution is made up with suspension of sterile aforementioned powder, particle or tablet.Preferable single dose unit formulation is those containing daily dose or day time dosage unit (as described above) or the active component of its appropriate partial amount.
It should be understood that except the composition particularly pointed out above, inventive formulation can be comprising other reagents for being usually used in the formula, and they need to consider the type of the formula, for example, formula of oral just can contain flavor enhancement.
The present invention also provides veterinary composition, and it includes at least one above-mentioned active component and Veterinary carriers.
Veterinary carriers are the materials for administration said composition, can be solid, liquid or gaseous matter, and are that inertia or animal doctor circle are acceptable, and can be compatible with the active component.These veterinary compositions can be oral, and parenteral or other desired approach are administered.
The compounds of this invention, which can be used for providing, contains one or more the compounds of this invention as the medical ingredients (controlled release ingredients) of active component control release, wherein the release of active component is by control and adjusts without frequent drug administration, or improves the pharmacokinetics or toxicity properties of the active component.
The effective dose of active component is at least depending on following factors：The essence of symptom to be treated, toxicity, compound is used to prevent (relatively low-dose) or therapeutic activity influenza infection, application process, and pharmaceutical formulation, and it can be studied to make by doctor according to routine dose amendment.Expectable dosage is about 0.0001 to 100mg/kg body weight/days, preferably about 0.01 to 10mg/kg body weight/days, preferably about 0.01 to 5mg/kg body weight/days, preferably about 0.05 to 0.5mg/kg body weight/days.For example, integrally weighing about 70kg adult when with suction medication, daily dosage is 1mg to 1000mg, and preferably 5mg can be taken to 500mg with single or multiple dosage.
Typical dosage includes 5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,110,115,120,125,130,135,140,145,150,157,200,225,250,275,300,325,350,375,400,425,450,475,500,550,600,650,700,750,800,850,900,950 and 1000mgGS4104, phosphate, once or twice daily；More typically 20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,110,115,120,125,130,135,140,145,150,157,200mgGS4104, phosphate, once or twice daily；More typically 20,50,75,100,150 and 200mgGS4104, phosphate, once or twice daily；More typically 75 or 150mgGS4101, phosphate, once or twice daily.
Inventive compound can be also used in combination with other active components.This combination according to symptom to be treated, the pharmacological properties of cross-reactive and combination between composition and determine.For example, when the virus infection, particularly influenza infection for being used to treat respiratory system, the present composition can
With antivirotic (e.g., amantadine (amantidine), Rimantadine and ribavirin), mucolytic agent, expectorant, bronchodilator, antibiotic, antipyretic or anodyne, which merge, to be used.Generally, antibiotic, antipyretic is together applied with anodyne with the compounds of this invention.The metabolite of the compounds of this invention
The interior metabolism product of compounds herein also within the scope of the present invention, as long as such product is novel and non-obvious for prior art.Such product can be reduced by such as oxidation using compound, hydrolysis, amidatioon, and esterification etc. is obtained, and process is urged mainly due to enzyme.Therefore the present invention includes the novel and non-obvious compound being made by the following method：The compounds of this invention is set to contact a period of time with mammal and its metabolite can be produced.Typically, by first preparing through radioactive label (e.g., C14Or H3) the compounds of this invention, by detectable dosage (such as, generally greater than about 0.5mg/kg) compound parenteral administration to animal (such as, rat, mouse, cavy, monkey) or people, after metabolism is enough time for occurring (typically about 30 seconds to 30 hours), from urine, its converted product is isolated in blood or other biological sample.These products are easily separated (other are then isolated using the antibody for the epitope that can be remained in conjugated metabolite) because being labeled.In a usual manner, such as MS or NMR analyses are determined the structure of metabolite.Generally, the analysis of metabolite is carried out with conventional drug metabolism research mode well known in the art.This converted product, as long as its elsewhere is not found in vivo, even if itself does not have neuraminic acid enzyme inhibition activity, the diagnostic analysis also treated available for the compounds of this invention.Other purposes of the compounds of this invention
The compounds of this invention, or its bioactive substance produced via internal hydrolysis or metabolism can be used as immunogene or be used for and protein conjugation, prepare and may specifically bind to the protein as the composition of immunogenic composition, the antibody of the compound or its metabolite, aforementioned metabolic products still retain the epitope (antibody binding position) of immunogenicity identification.So this immunogenic composition can be used as intermediate when prepared by the antibody (for the diagnosis of the compound or its novel metabolite, method or the analysis such as quality control).Antibody of this compound available for other non-immunogenic polypeptides that create antagonism, at this moment, these compounds use haptens position as, stimulate the immune response with the cross reaction of non-modified conjugated protein.
Preferable hydrolysate includes the production after the above-mentioned acidity through protection is hydrolyzed with basic group
Thing.As described above, acidity or alkaline amide (e.g., albumin is fixed on the hemocyanin of keyhole) containing immunogenic polypeptide are usually as immunogene.The immunological cross activity with the compounds of this invention that above-mentioned metabolite can retain significance degree.So antibody of the present invention can be bound to the compounds of this invention without protection, without being bound to the compound through protection；In addition, when there is metabolite, the antibody can be bound to compound and/or metabolite through protection, without being bound to the compounds of this invention through protection, or specifically can all it be combined with one of them or three.This antibody is expected will substantially will not be with natural materials cross reaction.The cross reactivity of essence refers to the reactivity under the conditions of the particular analysis to specific analyte (it is enough to disturb analysis result).
The immunogene of the present invention includes providing the compounds of this invention of epitope, and it is combined with immunogenic substance.Herein, this combines the mixture for representing covalent bond and forming immunogenic conjugate (when appropriate) or Non-covalent binding material, or its combination.Immunogenic substance includes auxiliary substance, such as Freund auxiliary substances, such as immunogenic protein, virus, bacterium, yeast, Plants and Animals polypeptide, especially it is affixed to the hemocyanin of keyhole, seralbumin, bovine thyroglobulin or soybean trypsin inhibitor and immunogenic polysaccharide.Typically, compound with required epitope structure is by (being usually two functional groups) the crosslinking agent Covalent conjugation of multiple functional radical to immunogenic polypeptide or polysaccharide.The method for preparing haptens immunogene is common in itself, it was used for haptens being conjugated the method to immunogenic polypeptide etc. before any and is also applied for this, it is considered to the possibility of functional group's (it can be used for being crosslinked) and the production antibody special to the epitope (opposite with immunogenic substance) on parent or hydrolysate.
Typically, the polypeptide is conjugated to position of the compounds of this invention away from epitope to be identified.
This conjugate is made in conventional manner.For example, crosslinking agent such as n-hydroxysuccinimide can be used, succinic anhydride or alkyl-N=C=N- alkyl prepare conjugate of the present invention.This conjugate includes the compounds of this invention, and it is with a key or C1-C100(preferably C1-C25, more preferably C1-C10) linker is connected in immunogenic substance.This conjugate is isolated from starting material with accessory substance with methods such as chromatograms, is then sterile filtered, bottling storage.
The compounds of this invention is crosslinked by any one or more following groups, for example, U1Hydroxyl
Base, E1Carboxyl, U1, E1, G1Or T1Carbon atom (substitution H)；G1Amido.Such compound also includes the acid amides of polypeptide, and wherein this polypeptide serves as above-mentioned R6cOr R6bGroup.
Typically, make animal to this immunogenic conjugate or derivative and the antiserum being made in a usual manner or monoclonal antibody in immune.
The compounds of this invention can be used for the structural intergrity for keeping glycoprotein in recombinant cell culture thing, i.e. it is added in the fermentate of glycoprotein generation and suppresses the fracture of the neuraminic acid enzymatic of this required glycoprotein.This point carried out in heterologous host cell protein be re-combined into it is particularly useful because the cell can be degraded the carbohydrate portions of the protein synthesized.
The compounds of this invention is polyfunctional.It can be used as the special monomer of class during Macroscopic single crystal.Unrestricted as an example, the polymer that the compounds of this invention is made includes polyamide and polyester.
The compounds of this invention is used as the monomer that the polymer with unique side functional group is made, and it can be used for homopolymer, or as the comonomer with the monomer copolymerization in the range of non-invention.The compounds of this invention have into the purposes of homopolymer：In molecular sieve (polyamide), fabric, fiber, film, article shaped etc. is used as cation-exchanger (polyester or polyamide), wherein acid functional group E when preparing1, by U1In hydroxy esterification, therefore pendant basic base G1Just it can be combined with acid functional groups, for example, the acid functional groups in the polypeptide to be purified.Polyamide is by E1With G1It is crosslinked and is formed, and U1Can be freely as hydrophily or hydrophobic group (depending on selected U with neighbouring part on ring1Depending on).The method that polymer is made by the compounds of this invention is known per se.
The compounds of this invention can act also as the unique multifunctional surfactant of a class.Particularly work as U1Without hydrophilic, and it is such as alkyl or alkoxy, this compound has the property of difunctional surface's activating agent.Themselves there is useful interfacial activity, surface coating is emulsion modified, rheological characteristic modification and surface wettability property.
When with specific structure and simultaneous with polarity and during nonpolar moiety, chemical combination of the present invention can be used as the unique consisting of phase-transferring agent of a class.Unrestricted as an example, the compounds of this invention can be used in phase transfer catalysis (PTC) and liquid liquid ion extractuin (LIX).
The compounds of this invention is in group U1, E1, G1With T1In can arbitrarily include asymmetric carbon atom, now it can be that a class in the synthesis or fractionation for other optically active substances is unique chiral
Adjuvant.For example, the racemic mixture of carboxylic acid can split into its enantiomer with laxative remedy：1) with the compounds of this invention (wherein U1For asymmetric hydroxyl alkane or aminoalkyl) form the mixture of diastereomeric ester or acid amides；2) this diastereomer is separated；3) ester structure is hydrolyzed.Racemic alcohol then uses E1Acidic group formation ester and separate.In addition, this method is also used for splitting the compounds of this invention in itself, if replacing racemic starting material using the optically active acid or alcohol.
The compounds of this invention can prepare affinity absorption base, for the immobilized enzyme of process control, or during immunological assay reagents, as linker or interval base.Compound herein includes multiple functional groups, is used as the position of the expected material of crosslinking.For example, traditionally by affinity reagents, such as hormone, peptide, antibody, medicine etc. is bonded on insoluble matrix.Be then used in a known manner from preparation into insoluble reagent, diagnosis sample or other the combination companions of the affinity reagents is not absorbed in pure mixture.Similarly, immobilized enzyme is then used for carrying out catalyzed conversion, and can simply reclaim enzyme.When preparing diagnostic reagent, difunctional's compound is commonly used to which analyte is connected with detectable group.
Many functional groups can be used for being crosslinked in the compounds of this invention.Such as E1Carboxylic acid or phosphonate group can be intended to cross-linking reagent alcohol or amine form ester or acid amides respectively.Suitable position is through OH, NHR1, SH, azido (if desired can be in crosslinking pre reduction into amino), CN, NO2, amino, guanidine radicals, the substituted G such as halogen1Position.When being reacted with crosslinking agent to prevent difunctional's compound of the present invention from polymerizeing, reactive group can be given suitably protecting.Usual this paper compound is bound to first via carboxylic acid or phosphonic acids and combined with upper hydroxyl or amino, then again with T1Or G1Combine and used with covalent bond with other.For example, first combines the carboxylic esterification with the compounds of this invention with (e.g., steroid hormone), then this conjugate is with G1Hydroxyl is cross-linked to the Sepaharose (agarose trade name) through cyanogen bromide-activated, can so obtain immobilization steroids.Other chemical conjugates are known.With reference to such as Maggio, " Enzyme-Immunoassay " (CRC, page 1988,71-135) and reference recited herein.
As described above, present invention treatment useful compound (wherein W1Or G1Hydroxyl, carboxyl or amino are protected) oral or slow release formulation can be made.In these purposes, protection based on (for example, hydrolysis or oxidation) is removed in vivo, to generate free carboxy, amino or hydroxyl.Depending on the substrate specificity of ester or acid amides according to esterase and/or carboxypeptidase suitable for this purposes, enzyme expection in precursor hydrolysis acts on the cell carried out can be found., can be to being permitted if this enzyme is specific unknown
Many the compounds of this invention are screened, until finding expected substrate specificity.This can be learnt by the outward appearance or antiviral activity of free cpds.The acid amides or ester of the compounds of this invention are generally selected with following two principle：(i) it is not hydrolyzed or slowly hydrolyzes in upper enteron aisle, (ii) enteron aisle and cell permeable, and (iii) is hydrolyzed in cytoplasm and/or systemic circulation.The cell of particular organization (easily by influenza infection), such as pulmonary branches tunica mucosa tracheae are preferably used in screening analysis.Analytic approach known in the art be can be used to determine vivo biodistribution availability, including intestinal lumen stability, and cell permeability, liver homogenate stability is analyzed with plasma stability.But, even if ester, acid amides or other derivatives through protection do not get transformed into free carboxy, amino or hydroxyl in vivo, and it is still useful chemical intermediate.Manufacture the exemplary method of the compounds of this invention
The invention further relates to manufacture the method for the present composition.Said composition is made up of any applicable technology of organic synthesis.Many such a technologies are, it is known that many is then specified in this area：" methodology of organic synthesis summary " (John Wiley＆Sons, New York), Vol.1, Ian T.Harrison and Shuyen Harrison, 1971；Vol 2, Ina T.Harrison and Shuyen Harrison, 1974；Vol.3, Louis S.Hegedus and Leroy Wade, 1977；Vol.4, Leroy G.Wade, jr., 1980；Vol.5, Leroy G.Wade, Jr., 1984；And Vol.6, Michael B.Smith；And March., J., " Advanced Organic Chemistry; the third edition " (John Wiley＆Sons, New York, 1985), " comprehensive organic synthesis; the selectivity in modern organic chemistry, strategy and efficiency (ComprehensiveOrganic Synthesis.Selectivity, Strategy＆Efficiency in ModernOrganic Chemistry. ", volume 9, Barry M.Trost chief editors (Pergamon Press, New York, print for 1993).
The many exemplary method following articles for preparing the present composition are contained, and it is used for the essence for illustrating that these prepare method, not for the scope of limitation methods availalbe.
Generally, reaction condition such as temperature, reaction time, solvent, process step etc. is well known in the art for pending specific reaction.The reference (including the data wherein quoted from) of citation includes the detailed description of these conditions.Typically, temperature is -100 DEG C to 200 DEG C, and solvent is non-proton or proton solvent, and the reaction time is 10 seconds to 10 days.Processing is mainly made up of the following steps：Any unreacted reagent is interrupted, water/organic layer system (extraction) is then allocated in,
Separate the layer containing product.
Oxidation is typically carried out with reduction reaction at a temperature of close to room temperature (about 20 DEG C), but when using metal hydride reduction, temperature is generally reduced to 0 DEG C to -100 DEG C, reduction is generally aprotic with solvent, and can be then protic or aprotic to oxidation.The reaction time is adjusted with up to expected conversion ratio.
Condensation reaction is generally carried out at a temperature of close to room temperature, but for non-equilibrium, the condensation of dynamics Controlling, the temperature (0 DEG C to -100 DEG C) of generally available reduction.Solvent can be protic (common in balanced reaction) or aprotic (common in dynamics Controlling reaction).
The synthetic technology of standard, is such as azeotroped off byproduct of reaction and common for this area using anhydrous response condition (e.g., inert gas environment), and it just can be used as applicable.
Prepare shown in a kind of following reaction scheme 1 of exemplary method of the compounds of this invention.It is described in detail in following " experiment " parts.
Reaction scheme 1
The improvement of reaction scheme 1 changes to form other particular instantiation in reaction scheme 2-4.Reaction scheme 2
Reaction scheme 2
Worked together by Utimoto with it, " Tet Lett ", 31：The step of 6379 (1990), is by aziridine 5 with Yb (CN)3Catalytic addition TMSCN and change into amino nitrile 9.
Nitrile 9 is changed into correspondence amidine 10 and completed using the step procedure of standard three：i)H2S, ii) CH3I, iii) NH4OAc.In " pharmaceutical chemistry magazine ", 36：A typical transformation can be found in 1811 (1993).
Nitrile 9 is with " modern synthesis ", the second edition, H.O.House, Benjamin/CummingsPublishing Co., and any methods availalbe is reduced into amino methyl compound 11 described in 1972.
Amino methyl compound 11 presses " Tet Lett " through the N,-Boc-1H- pyrazoles -1- carboxylics carbonamidines of N '-two, and 36：299 (1995) methods describeds handle and changed into the guanidine compound 12 of two-Boc protections.
Reaction scheme 3Reaction scheme 3
Aziridine 5 draws 13 with the open loop of alpha-cyano tert-butyl acetate.This type aziridine ring-opening reaction refers to " Tet Lett ", 23：5021(1982).Optionally t-butyl ester portion is hydrolyzed in acid condition, then decarboxylation, draw nitrile 14.
Aminoethyl derivative 15 is reduced into 14 to complete in the conversion identical mode with 9 to 11.Then by the N of amine 15,-Boc-1H- pyrazoles -1- carboxylics the carbonamidines of N '-two press " Tet Lett ", and 36：299 (1995) methods describeds change into guanidine derivative 16.
Nitrile 14 changes into correspondence amidine 17 with the identical step of the conversion with above-mentioned 9 to 10.
Reaction scheme 4
Reaction scheme 4
Epoxy radicals alcohol 1 is protected into (PG=protection groups), for example, uses MOMCl.Typical condition is referred to " blocking group in organic synthesis ", the second edition, T.W.Greene and P.G.M.Wuts, John Wiley＆Sons, New York, NY, 1991.
Epoxides 19 is then by Sharpless and its work together " Journal of Organic Chemistry ", 50：The step of 1557 (1985), uses NaN3/NH4Cl open loops turn into amino alcohol 20.
N- acetyl group aziridine 21 is reduced into 20 to complete with following three step reactions：1) MsCl/ triethylamines；2)H2/Pd；3) AcCl/ pyridines.Such conversion refers to " Angew.Chem.Int.Ed. Engl. ", 35：599(1994).
Aziridine 21 uses NaN in 65 DEG C in DMF3/NH4Cl is by " J.Chem.Soc.PerkinTrans I ", 801 (1976) open loop changes into azido acid amides 22.
With " blocking group in organic synthesis ", the second edition, T.W.Greene and P.G.M.Wuts, John Wiley＆Sons, New York, NY, 1991 methods described remove 22 MOM protection groups.Gained alcohol is directly translated into aziridine 24 in pyridine with TsCl.Such conversion refers to " Angew.Chem.Int.Ed.Engl. ", 33：599(1994).
Then aziridine 24 and ROH, RNH are allowed2, RSH or organic metal (metal-R) reaction draw corresponding p-Coumaric acid 25,26,27 and 27.1 respectively.Such aziridine open loop is referred to, " Tet Lett " 23：5021 (1982) and " Angew.Chem.Int.Ed.Engl. ", 33：599(1994).Reaction scheme 5
The another kind of compound of the present invention is made by reaction scheme 5a and 5b method.With Shing.T.K.M. et al. " tetrahedron ", 47 (26)：Cinchoninic acid is changed into 28 by the method for 4571 (1991).In TEA/CH2Cl2It is middle carried out with MsCl Mesylation draw 29,29 in DMF with NaN3Reaction draws 30.30 in CH2Cl2In with TFA reaction draw 31,31 in TEA/CH2Cl2It is middle to draw 32 with MsCl Mesylations.33 are drawn with triphen phosphine reaction in water, it is sequentially using CH 1) in pyridine3C(O)Cl；2) NaN in DMF3；And 3) the NaH processing in THF changes into 35.Many compounds such as 36 are drawn with various nucleopilic reagent alkylations 35 known in the art.Such as 36 compound conversion cost is invented into the method for other concrete examples as described above.
Reaction scheme 5a
Reaction scheme 5b
Reaction scheme 6Reaction scheme 6
The method of the another kind of compound such as reaction scheme 6 of the present invention is made.The alcohol 22 (PG=methoxymethyl ethers) of protection is at such as " blocking group in organic synthesis ", the second edition, is deprotected under T.W.Greene and standard conditions described in P.G.M.Wuts, John Wiley＆Sons, New York, NY, 1991.Alcohol 51 changes into acetic acid esters 52 with acetic anhydride and pyridine at the standard conditions.The TMSOTf or BF of acetic acid esters 523·OEt2Handle get Chu oxazolines 53.Such conversion can refer to " Liebigs Ann.Chem. ", 129 (1991) and " carbohydrate compound research ", 181 (1993) respectively.The other Zhuanization oxazoline 53 as described below of alcohol 51 that can also allow：Corresponding methanesulfonates or p-methyl benzenesulfonic acid ester 23 is first changed into, then Huanization oxazoline at the standard conditions, such as " Journal of Organic Chemistry ", 50：1126 (1985) and " chemistry meeting will ", 1385 (1970) are described.Oxazoline 53 and ROH, RR ' NH or RSH (wherein R and R ' and above-mentioned W6Definition be consistent) reaction draw corresponding p-Coumaric acid 54,55 and 56 respectively.Such conversion refers to " Journal of Organic Chemistry ", 49：4889 (1984) and " Chem.Rev. ", 71：483(1971).Reaction scheme 7-63
Other exemplary methods for preparing the compounds of this invention see below and show reaction scheme 7-63.In " experiment " part of the detailed description of these methods below.Reaction scheme 7a
Reaction scheme 7b
Reaction scheme 7c
Reaction scheme 8
Reaction scheme 9
Reaction scheme 10
Reaction scheme 11
Reaction scheme 12
Reaction scheme 13
Reaction scheme 14
Reaction scheme 15a
Reaction scheme 15b
Reaction scheme 16
Reaction scheme 17
Reaction scheme 18Reaction scheme 19
Reaction scheme 20
Reaction scheme 21
Reaction scheme 22
Reaction scheme 23
Reaction scheme 24
Reaction scheme 25
Reaction scheme 26Reaction scheme 27
Reaction scheme 28Reaction scheme 29
Reaction scheme 30
Reaction scheme 31
Reaction scheme 32
Reaction scheme 33
Reaction scheme 34
Reaction scheme 35
Reaction scheme 36
Reaction scheme 37
Reaction scheme 38
Reaction scheme 39
Reaction scheme 40
Reaction scheme 40.1
The other particular instantiation with the method using the present composition is prepared in reaction scheme 36-40.1.One aspect of the present invention is related to the method for preparing the compounds of this invention of method A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V or W (individually or being mutually combined) comprising reaction scheme 36-40.1.The concrete example of the illustration method A-W exemplary methods of table 27.Each concrete example is the single method using element method A-W (alone or in combination).In table 27 each method concrete example with branch "；" separate.Correspond to one of method A-W if concrete example is single letter, if more than one letter, carried out corresponding to each method and according to shown order.
Another aspect of the present invention is directed to use with the method for shikimic acid prepare compound 270 (as shown in A in reaction scheme 36),Use the method for the prepare compound 271 of compound 270 (as shown in B in reaction scheme 36),Use the method for the prepare compound 272 of compound 271 (as shown in C in reaction scheme 36),Use the method for the prepare compound 273 of compound 272 (as shown in D in reaction scheme 36),Use the method for cinchoninic acid prepare compound 274 (as shown in E in reaction scheme 37),Use the method for the prepare compound 275 of compound 274 (as shown in F in reaction scheme 37),Use the method for the prepare compound 276 of compound 275 (as shown in G in reaction scheme 37),Use the method for the prepare compound 272 of compound 276 (as shown in H in reaction scheme 37),Use the method for the prepare compound 277 of compound 273 (as shown in I in reaction scheme 38),Use the method for the prepare compound 278 of compound 277 (as shown in J in reaction scheme 38),Use the method for the prepare compound 279 of compound 278 (as shown in K in reaction scheme 38),Use the method for the prepare compound 280 of compound 279 (as shown in L in reaction scheme 38),Use the method for the prepare compound 281 of compound 280 (as shown in M in reaction scheme 38),Use the method for the prepare compound 282 of compound 281 (as shown in N in reaction scheme 39),Use the method for the prepare compound 283 of compound 282 (as shown in O in reaction scheme 39),Use the method for the prepare compound 284 of compound 283 (as shown in P in reaction scheme 39),Use the method for the prepare compound 285 of compound 283 (as shown in Q in reaction scheme 40),Use the method for the prepare compound 286 of compound 285 (as shown in R in reaction scheme 40),Use the method for the prepare compound 288 of compound 287 (as shown in S in reaction scheme 40.1),Use the method for the prepare compound 289 of compound 288 (as shown in T in reaction scheme 40.1),Using the method for the prepare compound 290 of compound 289 (as instead
Answer in scheme 40.1 shown in U), using the method (as shown in V in reaction scheme 40.1) of the prepare compound 291 of compound 290, use the method for the prepare compound 292 of compound 291 (as shown in W in reaction scheme 40.1).
Described in the general content following article and embodiment of these exemplary methods.Each product in following methods is arbitrarily separated before for next method, is isolated and/or is purified.
" processing " word abutment, is mixed, and reaction is allowed to react, and is brought into contact with and other generally in the art represent the processed term for changing into one or more other chemical bodies of one or more chemical bodies.So " with compound 2 handle compound 1 " with it is following synonymous：" make compound 1 with compound 2 react ", " compound 1 is contacted with compound 2 ", " compound 1 is reacted with compound 2 " and other organic syntheses are general to represent the use compound 2 of compound 1 " processing " or words and expressions with compound 2 " reaction ".
" processing " represents the reasonable and general fashion for reacting organic chemistry material.Unless otherwise indicated, normal concentration (0.01M to 10M, preferably 0.1M to 1M) is referred to, (- 100 DEG C to 250 DEG C, preferably -78 DEG C to 150 DEG C, more preferably -78 DEG C to 100 DEG C of temperature, preferably 0 DEG C to 100 DEG C), reaction vessel (preferably glass, plastics, metal), solvent, pressure, atmosphere is (during to oxygen and the insensitive reaction of water, preferably air, the reaction to oxygen and water sensitive is then nitrogen or argon) etc..Understanding to similar reaction known to organic synthesis field can be used to select to give the condition and device in method used in " processing ".Especially, the general personnel for being familiar with organic synthesis technology are expected successfully carry out the condition and device of the chemical reaction of methods described based on knowledge-chosen known in the art.Method A, reaction scheme 36
With following methods shikimic acid prepare compound 270.
Cis -4,5- functionalized with glycols base of shikimic acid can be by the way that selective protection is both this and makes it different from the carboxylic acid group on carbon 1.Typically, cis -4, the 5- functionalized with glycols bases are protected with cyclic ketal, the carboxylic acid group is protected with ester.
R50For 1, the 2- glycerol protection bases that easily acid is decomposed, as illustrated in Greene cited hereinabove works, the typically ketal of cyclic ketal or acetal, more preferably cyclohexanone or acetone.R51For the carboxylic acid protecting group that acid is stable, as illustrated in Gereene cited hereinabove works, typically line style, branch or ring-type C1-C12Alkyl, alkenyl or alkynyl,
Group 2-7,9-10,15 or 100-660 as shown in table 2, more preferably line style or branch C1-C8Alkyl, preferably group 2-5 as shown in table 2,9 or 100-358, line style or branch C1-C6Alkyl, group 2-5 as shown in table 2,9 or 100-141, but preferably R51It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, or the tert-butyl group.
Make thick grass acid reaction and make its carboxylic acid by group R51Protection, cis -4,5- glycol is by group R50Protection.Typically; shikimic acid alcohol (such as methanol; ethanol, normal propyl alcohol or isopropanol) and acid catalyst (such as inorganic acid or sulfonic acid, such as methanesulfonic acid; benzene sulfonic acid or toluenesulfonic acid) processing; then protected with the dialkyl group ketal or acetal of ketone or aldehyde, such as 2,2-dimethoxypropane or 1; 1- dimethoxycyclohexanes, and carried out in the presence of correspondence ketone or aldehyde (such as acetone or cyclohexanone).Arbitrarily, with dialkyl group ketal or ketal before processing, alcohol is separated with the product that acid catalyst is handled, isolates and/or purifies.In addition, shikimic acid CH2N2Processing.
Typically, this method includes shikimic acid alkanol and sulfonic acid and handled, and is then handled with together with-dialkoxy alkane or together with-dialkoxy cycloalkanes with alkane ketone or cyclanone to generate compound 270.More typically, the method includes handling shikimic acid with sulfonic acid with alkanol；Evaporation excess alkanol obtains residue；To handle the residue together with-dialkoxy alkane or together with-dialkoxy cycloalkanes and alkane ketone or cyclanone to generate compound 270.More typically include handling shikimic acid with p-methyl benzenesulfonic acid with methanol；Evaporation excessive methanol draws residue, with 2,2-dimethoxypropane and the acetone treatment residue to generate compound 270.
The demonstration concrete example of the method such as embodiment 55.Method B, reaction scheme 36
With following methods prepare compound 271 of compound 270.
Make the hydroxy activated of position 3, typically, to displacement reaction activation, more typically, the reaction activation of epoxide ring is formed to the displacement of the alcohol of position 4.
R52Base is activated for alcohol, typically, displacement reaction activation base more typically, the activation base for forming epoxide ring reaction is replaced by the alcohol of position 4.Such group includes those used in the typical case of this area, such as sulphonic acid ester, more preferably methanesulfonates, benzene sulfonate, or tosylate.In a concrete example, R52Merge (i.e.-OR with O52) it is leaving group commonly used in the art.
Typically, this method includes handling compound 270 to generate compound 271 with carboxylic acid halides.More typically, the method is included in suitable solvent is handled compound 270 and is formed with sulfonic acid halide
Compound 271.More typically, the method is included in suitable solvent, for example amine, and optionally in the presence of cosolvent (for example, alkyl halide), handles compound 270 with sulfonic acid halide and form compound 271.Preferably, the method is included in triethylamine/dichloromethane is handled compound 270 and is formed compound 271 with mesyl chloride.
The demonstration particular instantiation following article embodiment 56 of the method.Method C, reaction scheme 36
Compound 271 is used for prepare compound 272 in following methods.
Remove the sour decomposable asymmetric choice net protection group (R of the hydroxyl of position 4 and 550).Typically, R is removed50Shi Jiben is not except lixiviating decomposable asymmetric choice net carboxylic acid protecting group is (for example, R51) or hydroxy activated base (for example, R52).More typically, R50It is broken in acid condition.
Typically, the method includes handling compound 271 with proton solvent, more typically, is carried out in the presence of above-mentioned acid catalyst.It is preferred that the method includes handling compound 271 with above-mentioned alkanol and acid catalyst.It is preferred that the method includes being handled compound 271 with methanol and p-methyl benzenesulfonic acid and compound 272 being made.
Shown in the demonstration concrete example following article embodiment 57 of the method.Method D, reaction scheme 36
Compound 272 is used for prepare compound 273 in following methods.
Activated hydroxyl groups on the position 3 of compound 272 are replaced by the hydroxyl on the position 4 of compound 272 and turn into epoxides 273.Typically, this displacement reaction is with appropriate base catalysis, the preferably amine base such as DBU or DBN etc.
Typically, the method is included with base catalyst (arbitrarily in the presence of suitable solvent) processing compound 272.More typically, in polarity, compound 272 is handled with amine base in aprotic solvent (such as ether or THF).More typically, the method is included in THF is handled compound 272 and compound 273 is made with DBU.
Shown in the demonstration concrete example following article embodiment 58 of the method.Method E, reaction scheme 37
Cinchoninic acid is used for that compound 274 is made in following methods.
Cis -4,5- functionalized with glycols bases of cinchoninic acid are different from the carboxylic acid on carbon 1 by selective protection.Typically, this cis -4,5- functionalized with glycols base is protected with cyclic ketal, carboxylic acid
Functional group then forms lactone with the hydroxyl protection on position 3.
R50As described above.
Typically, the method include with together with-dialkoxy alkane or together with-dialkoxy cycloalkanes (as described above) with alkane ketone or cyclanone are (as described above) handles cinchoninic acid, arbitrarily carried out in the presence of acid catalyst (as described above), so as to form compound 274.More typically, the method is included with together with-dialkoxy alkane or together with-dialkoxy cycloalkanes, alkane ketone or cyclanone, and acid catalyst forms compound 274 to handle cinchoninic acid.More typically, the method includes using 2,2-dimethoxypropane, and acetone handles cinchoninic acid with p-methyl benzenesulfonic acid and forms compound 274.
Shown in the demonstration concrete example following article embodiment 101 of the method.Method F, reaction scheme 37
Compound 274 is used for prepare compound 275 in following methods.
By lactone open loop into compound 275.Typically, lactone open loop is formed and is carboxylic acid through protection in position 1 and is free hydroxyl group in position 3.More typically, it is R that lactone open loop forming position 1 is made in the basic conditions51The carboxylic acid of protection, position 3 is then free hydroxyl group.
R51As described above.
Typically, with suitable alkali process compound 274 in suitable proton solvent.More typically, compound 274 is handled in alkanol (as described above) with metal alkoxide alkali (such as sodium, potassium, lithium alkoxide).More typically, compound 274 is handled with NaOMe in MeOH and forms compound 275.
Shown in the demonstration concrete example following article embodiment 102 of the method.Method G, reaction scheme 37
Compound 275 is used for prepare compound 276 in following methods.
Make the hydroxy activated of position 3, typically, to displacement reaction activation, more typically, the reaction activation of epoxide ring is formed to the displacement of the alcohol of position 4.
R52Base is activated for alcohol, typically, the activation base of reaction is replaced, more typically, the activation base for forming epoxide ring reaction is replaced by the alcohol of position 4.Such group includes those used in the typical case of this area, such as sulphonic acid ester, more preferably methanesulfonates, benzene sulfonate, or tosylate.In a concrete example, R52Merge (that is ,-OR with O52) it is leaving group commonly used in the art.
Typically, this method includes handling compound 275 to generate compound 276 with carboxylic acid halides.More typically, the method is included in suitable solvent is handled compound 275 and is formed compound 276 with sulfonic acid halide.More typically, the method is included in suitable solvent, for example amine, and optionally in the presence of cosolvent (for example, alkyl halide), handles compound 275 with sulfonic acid halide and form compound 276.Preferably, the method is included in pyridine/dichloromethane is handled compound 275 and is formed compound 276 with paratoluensulfonyl chloride.
Shown in the demonstration concrete example following article embodiment 103 of the method.Method H, reaction scheme 37
Compound 276 is used for prepare compound 272 in following methods.
The hydroxyl of position 1 is eliminated, the protection group of cis -4,5- glycol is removed.The hydroxyl for eliminating position 1 forms ethylene linkage between position 1 and 6, and removes cis -4, and cis -4, the 5- glycol is regenerated after 5- glycerol protection bases.
Typically, the method includes using appropriate dehydrating agent, such as inorganic acid (HCl, H2SO4) or SO2Cl2Handle compound 276.More typically, compound 276 uses SO2Cl2Processing, is then handled, and arbitrarily carry out in presence of an acid catalyst with alkanol.More typically, compound 276 uses SO in suitable polarity aprotic solvent (e.g., amine)2Cl2Handle and form alkene；The alkene is handled with alkanol (as described above) and acid catalyst (as described above) and forms compound 272.More typically, compound 276 is in pyridine/CH2Cl2In, use SO at a temperature of -100 DEG C to 0 DEG C (preferably -100 DEG C to -10 DEG C, preferably -78 DEG C)2Cl2Handle and form alkene；Handle the alkene to form compound 272 with methanol and p-methyl benzenesulfonic acid.
Shown in the demonstration concrete example following article embodiment 104 of the method.Method I, reaction scheme 38
Compound 273 is used for prepare compound 277 in following methods.
The hydroxyl of position 5 is protected.Typically, this protection group is sour decomposable asymmetric choice net hydroxyl protecting group.More typically, this protection group will not be transferred to adjacent hydroxyl.
R53For sour decomposable asymmetric choice net hydroxyl protecting group, as described in Greene cited hereinabove works.More typically, R53Ether, best R can be broken for acid53For methoxy (MOM, CH3-O-CH2-)。
Typically, the method includes using hydroxyl protecting group reagent (as described in Greene) processingization
Compound 273.More typically, the method includes compound 273 in suitable solvent (e.g., polar aprotic solvent) with alkyl halide or alkene (such as methoxyl methyl chlorine (the MOM chlorides, CH for being substituted or being unsubstituted3-O-CH2Cl) handle.More typically, the method, which is included in amine solvent, makes the MOM chloride treatments of compound 273.More typically, the method, which is included in diisopropylethylamine, makes the MOM chloride treatments of compound 273.
Shown in the demonstration concrete example following article embodiment 59 of the method.Method J, reaction scheme 38
Compound 277 is used for prepare compound 278 in following methods.
By the epoxy ring-opening formation azide of position 3 and 4.More typically, the epoxy ring-opening formation 3- azido -4- hydroxy compounds 278 of position 3 and 4 is made.
Typically, the method, which is included in suitable solvent, uses nitrine salt treatment compound 277.More typically, the method includes making compound 277 be handled with gentle alkali (such as ammonium halide) with sodium azide in polar aprotic solvent (such as alkanol or water).Now typically, the method includes making compound 277 be processed into compound 278 with sodium azide and ammonium chloride in water/methanol solution.
Shown in the demonstration concrete example following article embodiment 60 of the method.Method K, reaction scheme 38
Compound 278 is used for prepare compound 279 in following methods.
Hydroxyl of the compound 278 in 4 positions is set to be replaced to form aziridine cpd 279 by 3- azidos.
Typically, the method is included with hydroxy activated base (as described above), organic phosphine and alkali process compound 278.More typically, the method includes with sulfonic acid halide processing compound 278 (as described above) forming activated hydroxyl groups compound, again with trialkyl phosphine or triaryl phosphine (such as, triphenyl phasphine) the activated hydroxyl groups compound is handled with shape into phosphonium salt, then the Phosphonium salt forming compound 279 is handled with alkali (such as amine).More typically, the method includes handling compound 278 to form activated hydroxyl groups compound with mesyl chloride, then handles the activated hydroxyl groups compound shape into phosphonium salt with triphenyl phasphine, with triethylamine and the water process Phosphonium salt forming compound 279.
Shown in the demonstration concrete example following article embodiment 61 and 62 of the method.Method L, reaction scheme 38
Compound 279 is used for prepare compound 280 in following methods.
Aziridine cpd 279 uses azide open loop into nitrine amine 280.
Typically, the method is included in suitable solvent with nitrine salt treatment compound 279.More typically, the method includes making compound 279 be handled with gentle alkali (such as ammonium halide) with sodium azide in polar aprotic solvent (such as ether, amine, acid amides).More typically, the method is included in DMF solution is made compound 280 with sodium azide and ammonium chloride processing compound 279.
Shown in the demonstration concrete example following article embodiment 63 of the method.Method M, reaction scheme 38
Compound 280 is used for prepare compound 281 in following methods.
The protection hydroxyl of 5 positions is replaced by the amine of position 4 and forms aziridine 281.Typically, aziridine 281 is more preferably replaced by sour decomposable asymmetric choice net substituent group by aziridine activation base.
R54For sour decomposable asymmetric choice net group, typically sour decomposable asymmetric choice net amine protecting group (as described in above-mentioned Greene works).More typically, R54Base is activated for aziridine, the group that aziridine carries out acid catalysis open loop can be more preferably activated.Typically, group R54Including unrestricted as an example, the C of line style or branch1-C12, 1- oxos-alkane -1- bases, wherein moieties be C1-C11Line style or branched alkyl groups (e.g., CH3(CH2)zC (O)-, z is 0 to 10 integer, i.e. acetyl group (CH3C (O) -) etc.), methyl (e.g., the trityl (Ph being substituted3C-), or be abbreviated as Tr), or carbamate, such as BOC or Cbz or sulphonic acid ester (e.g., alkyl sulfonate esters (such as sulfonic acid methyl ester)).More typically, R54Group includes trityl and C1-C81- oxos-alkane -1- bases, more preferably with 1,2,3,4,5 or 6 carbon atom, preferably with 2 or 3 carbon atoms.
Typically, the method includes spending protective agent processing compound 280 removing group R53, R54Generation reagent (as described in Greene, R54- halide, such as chloroacetic chloride or Tr-Cl, or R54-O-R54, such as acetic anhydride) and hydroxy activated base (such as method B, described in reaction scheme 36 those).More typically, the method includes handling compound 280 with polar aprotic solvent, is arbitrarily carried out in the presence of above-mentioned acid catalyst, to form the first intermediate；First intermediate is handled in polar aprotic solvent (for example, amine) and form the second intermediate with Tr-Cl；And handle second intermediate compound 281 is made in polar aprotic solvent (e.g., amine) middle sulfonic acid halide (e.g., mesyl chloride or paratoluensulfonyl chloride).More typically, the method includes being handled compound 280 with methanol with HCl and being formed the first intermediate, with Tr-Cl and triethylamine
First intermediate is handled, the second intermediate is formed, second intermediate is handled with mesyl chloride and triethylamine, compound 281 is made.
Shown in the demonstration concrete example following article embodiment 64 of the method.Method N, reaction scheme 39
Compound 281 is used for prepare compound 282 in following methods.
After the open loop of aziridine 281, institute is into amine R55Substituent group and form compound 282.Typically, aziridine 281 is by acid catalysis ring-opening reaction and open loop, and institute is then acylated into amine.
R55For above-mentioned W3.Typically, R55For-C (O) R5.More typically, R55For-C (O) R1, more preferable R55For-C (O) CH3。
R56For above-mentioned U1.Typically, R56For W6- O-, W6- S-, or W6-N(H)-.More typically, R56For R5- O-, R5- S- or R5- N (H)-, more preferably, R56For R5- O-, best R56For R1-O-。
Typically, the method includes making compound 281 with acid catalyst and such as formula W6-X1- H compound processing (wherein X1It is as defined above) form amine intermediate；It uses formula W3-X1-W3, W3-X10Compound processing (wherein X10For leaving group) form compound 282.Acid catalyst preferably lewis acid commonly used in the art, such as BF3·Et2O, TiCl3, TMSOTf, SmI2(THF)2, LiClO4, Mg (ClO4)2, Ln (OTf)3(wherein Ln=Yb, Gd, Nd), Ti (Oi-Pr)4, AlCl3, AlBr3, BeCl2, CdCl2, ZnCl2, BF3, BCl3, BBr3, GaCl3, GaBr3, TiCl4, TiBr4, ZrCl4, SnCl4, SnBr4, SbCl5, SbCl3, BiCl3, FeCl3, UCl4, ScCl3, YCl3, LaCl3, CeCl3, PrCl3, NdCl3, SmCl3, EuCl3, GdCl3, TbCl3, LuCl3, DyCl3, HoCl3, ErCl3, TmCl3, YbCl3, ZnI2, Al (OPri)3, Al (acac)3, ZnBr2, or SnCl4.Typically, X1For-O- ,-S-, or-N (H)-.X10Typically halogen, for example, Cl, Br or I.More typically, the method includes using R5- OH, R5- SH or R5-NH2Compound and BF3·Et2The O processing formation intermediates of compound 281, then handle with alkane acid anhydrides this intermediate formation compound 282.More typically, the method includes using R5- OH compounds and BF3·Et2The O processing formation intermediates of compound 281, compound 282 is formed with this intermediate of the acetic anhydride process for being substituted or being unsubstituted.R5The example of-OH compounds includes 2-7,9-10,15 and 660 (wherein Q in table 21For-OH) described in those, that shown in other example those (including its CAS accession number) as shown in table 25 below and table 26 below
A bit (including its CAS accession number and Aldrich chemical companies production code member).More typical R5The example of-OH compounds is 2-5 in table 2,9 and 100-141 (wherein Q1For-OH) described in those.
In method N, another concrete example of reaction scheme 39, R55For H.
Typically, the method includes using acid catalyst and R56-X1- H compounds (wherein X1It is as defined above) handle compound 281 and form amine intermediate, to form compound 282.Acid catalyst and X1It is as defined above.More typically, the method includes using R5- OH, R5- SH or R5-NH2Compound and BF3·Et2O handles compound 281 and forms compound 282.More typically, the method includes using R5- OH compounds and BF3·Et2O handles compound 281 and forms compound 282.R5The example of-OH compounds is as described above.
Shown in the demonstration concrete example following article embodiment 65,86,92 and 95 of the method.Method O, reaction scheme 39
Compound 282 is used for prepare compound 283 in following methods.
Azide 282 is reduced into amino-compound 283.
Typically, the method includes being handled compound 282 with reducing agent and being formed compound 283.More typically, the method is included with hydrogen and catalyst (such as Pt/C, or Lindlar catalyst) or reducing agent (e.g., above-mentioned trialkyl phosphine or triaryl phosphine) processing compound 282.More typically, the method is included in water/THF forms compound 283 with three stupid phosphine processing compounds 282.
Shown in the demonstration concrete example following article embodiment 87,93 and 96 of the method.Method P, reaction scheme 39
Compound 283 is used for prepare compound 284 in following methods.
Remove carboxylic acid protecting group.
Typically, the method is included with alkali process compound 283.More typically, the method is included in suitable solvent (such as non-proton transfering polarity solvent) with metal hydroxides processing compound 283.More typically, the method is included in THF so that potassium hydroxide aqueous solution handles compound 283 and compound 284 is made.
Shown in the demonstration concrete example following article embodiment 88,94 and 97 of the method.Method O, reaction scheme 40
Compound 283 is used for prepare compound 285 in following methods.
Amine is converted to the guanidine through protection.
R57For guanidine protection group generally in the art, such as BOC or Me.
Typically, the method includes handling compound 283 with guanidinated reagent (as commonly used in the art).The example of guanidinated reagent includes two-BOC thiocarbamide amino imino methanesulfonic acids (Kim et al.；" Tet Lett ", 29 (26)：3183-3186 (1988) and 1- guanylpyrazoles (Bernatowicz et al.；" Tet Lett ", 34 (21)：3389-3392(1993).More typically, the method is included with two-BOC thiocarbamide acid treatments compounds 283.More typically, the method two-BOC thiocarbamides acid and HgCl2Handle the formation compound 285 of compound 283.
Shown in the demonstration concrete example following article embodiment 67 of the method.Method R, reaction scheme 40
Compound 285 is used for prepare compound 286 in following methods.
Remove carboxylic acid protecting group and guanidine protection group.
Typically, the method includes, with alkali process compound 285, acid treatment then being used as described above.More typically, the method includes forming intermediate with metal hydroxides alkali processing compound 285 (as described above), then forms compound 286 with acid treatment.More typically, this compound includes forming intermediate with potassium hydroxide aqueous solution and THF processing compounds 285, then handles this intermediate formation compound 286 with TFA.Method S, reaction scheme 40.1
Compound 287 is used for prepare compound 288 in following methods.
The E of compound 287 and 2881, J1With J2As described above.Typically, E1For-CO2R51(as described above), J1For H, F or methyl, more preferably H.Typically, J1For H or line style or branch C1-C6Alkyl, more preferably H, methyl, ethyl, n-propyl or isopropyl, more preferably H.
R60With R61To be formed for that can react in compound 288 through R63The group of the aziridine ring of (being defined as below) substitution.Typically, R60With R61One of be primary or secondary amine, or the group of primary or secondary amine can be changed into.R60With R61Such group include, unrestricted as an example ,-NH2,-N (H) (R6b) ,-N (R6b)2,-NH (R1) ,-N (R1)(R6b) and-N3。R60With R61Another the group to form aziridine can be preferably replaced by primary or secondary amine, including, unrestricted as an example ,-OH ,-OR6a, Br, Cl and I.Typically, R60With R61In anti-configuration.More typically, R60For primary or secondary amine, or the group of primary or secondary amine, R can be changed into61For can be by primary or secondary amine
Displacement forms the group of aziridine, more preferably, R50For β-azido or β-NH2, R61For α-OH, α-O- mesyls, or α-O- p-toluenesulfonyls.
R62Explanation in method U below, reaction scheme 40.1.
The method includes the processing formation compound 288 of compound 287.It makes R typically via processing compound 28760Replace R61And complete.More typically, the processed activation R of compound 28761, make it by R60Displacement.More typically, processing compound 287 makes R61Activation and by R60Displacement, and R60Then it is activated into replaceable R61.If R60With R61The two is activated, then can simultaneously carry out or sequentially be activated.If sequentially carrying out, it can complete in any order, typically, R61Activation in R60Activation before.
Typically, R is made61To R60Displacement activation be performed as follows, with hydroxy activated reagent (such as mesyl chloride or toluene sulfochloride) handle compound 287.Make R60To displacement R61Activation is typically by following completion：The formation primary or secondary amine of compound 287 is handled, then with the alkali process amine.It is unrestricted as an example, turn into the reducing agent and alkali process compound 287 of amine with reducible azide.
In the concrete example of the method one, compound 287 uses R61Activating reagent and R60Activating reagent is treated as compound 288.In another concrete example, compound 287 uses R61Activating reagent and R60Activating reagent is treated as compound 288 in suitable solvent.In another concrete example, compound 287 uses R61Activating reagent, R60Activating reagent and alkali process turn into compound 288.In another concrete example, compound 287 uses R in suitable solvent61Activating reagent, R60Activating reagent and alkali process turn into compound 288.In another concrete example, (the wherein R of compound 28760For azide) use R61Activating reagent handles with azide go back original reagent and compound 288 is made.In another concrete example, (the wherein R of compound 28760For azide) R is used in suitable solvent61Activating reagent and azide go back original reagent handle and compound 288 are made.In another concrete example, (the wherein R of compound 28760For azide) use R61Activating reagent, azide go back original reagent and alkali process and compound 288 is made.In another concrete example, (the wherein R of compound 28760For azide) R is used in suitable solvent61Activating reagent and azide go back original reagent and alkali process and compound 288 is made.In another concrete example, (the wherein R of compound 28760For azide, R61For hydroxyl) hydroxy activated reagent is used, azide go back original reagent is processed into compound 288.In another concrete example, (the wherein R of compound 28760For azide,
R61For hydroxyl) hydroxy activated reagent is used in suitable solvent, azide go back original reagent is processed into compound 288.In another concrete example, (the wherein R of compound 28760For azide, R61For hydroxyl) use hydroxy activated reagent, azide go back original reagent and alkali process are into compound 288.In another concrete example, (the wherein R of compound 28760For azide, R61For hydroxyl) in suitable solvent with hydroxy activating reagent, azide reducing agent and alkali process are into compound 288.
The demonstration concrete example of the method such as above method K, shown in reaction scheme 38.Method T, reaction scheme 40.1
Compound 288 is used for that compound 289 is made in following methods.
R64Typically H, R6bOr H or R can be changed into6bGroup.More typically, R64For H. R65Typically G1Or G can be changed into1Group, preferably R65For-N3,-CN or-(CR1R2)m1W2, best R65For-N3,-NH2,-N (H) (R6b) ,-N (R6b)2,-CH2N3Or-CH2CN。
Typically, compound 288 is processed into amine 289.More typically, compound 288 nucleopilic reagent (preferably nitrogen nucleophile, such as R65, R65Cationic salts, or R65Protonation congener, it is unrestricted as an example, for example, NH3, kazoe (such as NaN3, KN3Deng), HCN, the salt of cyanide salt (e.g., NaCN, KCN etc.) or cyanoalkyl is (for example, (CH2CN)-, such as NaCH2CN, KCH2CN etc.) processing.More typically, the nitrine salt treatment of compound 288.Can be again arbitrarily using alkali (preferably gentle alkali, for example, ammonium halide) and solvent (preferably polar aprotic solvent (e.g., ether, amine or acid amides).
In a concrete example, compound 288 is handled with nucleopilic reagent.In another concrete example, compound 288 is handled with nucleopilic reagent in suitable solvent and compound 289 is made.In another concrete example, compound 288 uses nucleopilic reagent and alkali process into compound 289.In another concrete example, compound 288 uses nucleopilic reagent and alkali process into compound 289 in suitable solvent.In another concrete example, compound 288 is processed into compound 289 with nitrogen nucleophile.In another concrete example, compound 288 is processed into compound 289 in suitable solvent with nitrogen nucleophile.In another concrete example, compound 288 uses nitrogen nucleophile and alkali process into compound 289.In another concrete example, compound 288 uses nitrogen nucleophile and alkali process into compound 289 in suitable solvent.In another concrete example, compound 288 is processed into compound 289 with kazoe.In another concrete example, compound 288 is processed into suitable solvent with kazoe
Compound 289.In another concrete example, compound 288 uses kazoe and alkali process into compound 289.In another concrete example, compound 288 uses kazoe and alkali process into compound 289 in suitable solvent.
The demonstration particular instantiation of the method is in method L above, reaction scheme 38.Method U, reaction scheme 40.1
Compound 289 is used for that compound 290 is made in following methods.
R62To be formed for that can be reacted with amine in compound 290 through R66The group of the aziridine ring of (being defined as below) substitution.Typically, R62For the group to form aziridine can be replaced by primary or secondary amine.Such group includes, unrestricted as an example ,-OR53,-OH ,-OR6a, Br, Cl and I.Typically, R62Nitrogen with position 4 is in anti-configuration.Preferably, R62For-OR53。
R64For H or R6b, typically sour decomposable asymmetric choice net protection group, such as R54。
R66For H, R6bOr R54。
The method includes the processing formation compound 290 of compound 289.Typically, this makes its R by handling compound 28962Replaced and carried out by the amine of position 4.More typically, processing compound 289 makes the amine of position 4 activate and replace R62.More preferably, processing compound 289 replaces R with the amine of activated positions 462, and R62It is activated and is replaced by the amine of position 4.If R62It is activated, then can be simultaneously or sequentially activated with the amine of position 4.If sequentially being activated, it can carry out in any order, preferable R62Activation before the activation of the amine of position 4.
Make R62Displacement activation in the amine of position 4 is generally performed as follows, compound 289 is handled with hydroxy activating reagent (such as method B, described in reaction scheme 36 those).Arbitrarily make R62Deprotect before activation.Make on position 4 amine to displacement R62Activation is generally performed as follows, and processing compound 289 forms primary or secondary amine, then handles the amine with acid catalyst (such as method N, described in reaction scheme 39 those).
Typically, R is worked as62For-OR53, and R66For R56When, the method includes with deprotection agent treatment compound 289 removing R53, R54Produce reagent as described in Greene (R54- halide, such as chloroacetic chloride or Tr-Cl, or R54-O-R54, such as acetic anhydride) and hydroxy activated group (such as method B, described in reaction scheme 36 those).More typically, the method includes handling compound 289 with polar aprotic solvent, is carried out arbitrarily in the presence of above-mentioned acid catalyst, to form the first intermediate；Handled with Tr-Cl in polar aprotic solvent (for example, amine)
First intermediate and form the second intermediate；Handle second intermediate compound 290 is made then at polar aprotic solvent (e.g., amine) middle sulfonic acid halide (e.g., mesyl chloride or toluoyl sulphur chlorine).More typically, the method includes being handled compound 289 with methanol with HCl and being formed the first intermediate, and it forms the second intermediate with Tr-Cl with triethylamine processing, and compound 290 is made with mesyl chloride and triethylamine processing in it.
In a concrete example, compound 289 is processed into compound 290 with acid catalyst.In another concrete example, compound 289 is processed into compound 290 in suitable solvent with acidic catalyst.In another concrete example, compound 289 is processed into compound 290 with hydroxy activated reagent and acid catalyst.In another concrete example, compound 289 is processed into compound 290 in suitable solvent with hydroxy activated reagent and acid catalyst.In another concrete example, compound 289 deprotects reagent with hydroxyl, and hydroxy activated reagent is processed into compound 290 with acid catalyst.In another concrete example, compound 289 deprotects reagent in suitable solvent with hydroxyl, and hydroxy activated reagent is processed into compound 290 with acid catalyst.
The particular instantiation of the method is in above method M, reaction scheme 38.Method V, reaction scheme 40.1
Compound 290 is used for prepare compound 291 in following methods.
Aziridine 290 is processed into compound 291.Typically, aziridine 290 is then acylated by acid catalysis ring-opening reaction and open loop, and institute into amine.
R68It independently is H, R6b, R1Or R55(as described above).Typically, R55For-C (O) R5.Typically one R68For H or R6b, another is then W3。
R67For U1(as described above).Typically, R67For W6- O-, W6- S-, or W6- N (H)-, more preferable R67For R5- O-, R5- S- or R5-N(H)-。
Typically, the method is included with acid catalyst and W6-X1- H compounds (wherein X1It is as defined above) handle compound 290 and form amine intermediate；Again with W3-X1-W3Or W3-X10Compound (wherein X10For leaving group) handle the amine intermediate and form compound 291.W6-X1The processing of-H compounds and acid catalyst can be with W3-X1-W3Or W3-X10The processing of compound while or carry out before it.Acid catalyst is typically method N, described in reaction scheme 39 in one kind.More typically, the method includes using R5- OH, R5- SH, or R5-NH2Compound and acid catalyst processing compound 290；Again with alkane acid anhydrides processing intermediate formation compound 291.
One concrete example includes using W6-X1- H compounds handle compound 290 to form compound 291 with acid catalyst.Another concrete example is that W is used in suitable solvent6-X1Compound 291 is made with acid catalyst processing compound 290 in-H compounds.Another concrete example is to use W6-X1- H compounds, acid catalyst and W3-X1-W3Or W3-X10Compound 291 is made in compound processing chemical combination 290.Another concrete example is that W is used in suitable solvent6-X1- H compounds, acid catalyst and W3-X1-W3Or W3-W10Compound 291 is made in compound processing compound 290.
The concrete example of the method such as above method N, reaction scheme 39.Method W, reaction scheme 40.1
Compound 291 is used for prepare compound 292 in following methods.
Compound 291 is processed into compound 292.Typically R65It is converted into G1。U1For R67A concrete example, T1For-N (R68)2A concrete example.It is prepared by such as above method V, reaction scheme 40.1.
In a concrete example, R65Deprotected, be alkylated, it is guanidinated, aoxidize or be reduced into G1.Any kind of above-mentioned processing can be sequentially or simultaneously carried out with any.It is unrestricted as an example, work as R65During for azido, this method concrete example includes method O, OQ, OQR and OP.Typically, alkylating reagent is commonly used in the art, is included, it is unrestricted as an example, alkyl halide (e.g., methyl iodide, methyl bromide, ethyl iodide, bromic ether, n-propyl iodide, positive propyl bromo, isopropyl iodide, isopropyl bromide) and alkylene oxide (such as oxirane or expoxy propane).Base catalyst specifically described herein can be arbitrarily used in alkylation step.
One concrete example includes making (the wherein R of compound 29165For azido) compound 292 is processed into reducing agent.Another concrete example includes making (the wherein R of compound 29165For azido) compound 292 is processed into reducing agent in suitable solvent.Another concrete example includes making (the wherein R of compound 29165For amino) compound 292 is processed into alkylating reagent.Another concrete example includes making (the wherein R of compound 29165For amino) compound 292 is processed into alkylating reagent in suitable solvent.Another concrete example includes making (the wherein R of compound 29165For azido) it is processed into compound 292 with reducing agent and alkylating reagent.Another concrete example includes making (the wherein R of compound 29165For azido) with reducing agent and alkylating reagent it is processed into compound 292 in suitable solvent.Another concrete example includes making (the wherein R of compound 29165For amino) it is processed into compound 292 with alkylating reagent and base catalyst.Another concrete example includes making (the wherein R of compound 29165For amino) in suitable solvent
It is middle to be processed into compound 292 with alkylating reagent and base catalyst.Another concrete example includes making (the wherein R of compound 29165For azido) reducing agent is used, alkylating reagent is processed into compound 292 with base catalyst.Another concrete example includes making (the wherein R of compound 29165For azido) in suitable solvent with reducing agent, alkylating reagent is processed into compound 292 with base catalyst.
The demonstration concrete example of this method is provided with the method O of scheme 39 above.
The example concrete example following article embodiment 68 and 69 of the method.Table 25- formulas R5- OH example compound (CAS No.) C4 fluorinated alcohols (R*, R*)-(±) fluoro- fluoro- 2- butanol (the 18804-31-4) (R of 2- butanol (124536-12-5) (R) -3- fluoro- n-butyl alcohol (120406-57-7) 3- fluoro- n-butyl alcohol (19808-95-8) 4- of fluoro- 2- butanol (139755-61-6) 1- of -3-*, S*) fluoro- 2- butanol (the 6228-94-0) (R of -3-*, R*) the fluoro- 2- methyl isophthalic acids of -3- fluoro- 2- butanol (6133-82-0) 2- fluoro- n-butyl alcohol (4459-24-9) 2--fluoro- 2- amylalcohols (18804-35-8) of fluoro- 1- amylalcohols (123650-81-7) (the R) -2- of fluoro- 2- methyl-2-propanols (353-80-0) the C5 fluorinated alcohols 2- of propyl alcohol (3109-99-7) 3- fluoro- 2- butanol (1813-13-4) 4- fluoro- n-butyl alcohol (372-93-0) 1- fluoro- 2- amylalcohols (19808-94-7) 5- of fluoro- 3- amylalcohols (30390-84-2) 4- of fluoro- 3- methyl-1-butanols (104715-25-5) 1- of fluoro- fluoro- 3- methyl-1-butanols (113942-98-6) 4- of 3- methyl-1-butanols (113943-11-6) (S) -2-
Fluoro- 1- amylalcohols (592-80-3) C6 fluorinated alcohols (R- (R of fluoro- 3- methyl -2- butanol (1998-77-2) 5- of fluoro- 2-methyl-1-butene alcohol (4456-02-4) 3- of fluoro- 2- methyl -2- butanol (7284-96-0) 2- of 3-*, S*)) fluoro- 3- methyl-1-pentenes alcohol (168749-88-0) 1- fluoro- 2 of -2-, fluoro- fluoro- 4- methyl-1-pentenes alcohol (157988-30-2) (S- (R of 2,3- dimethyl-1-butanols (161082-89-9) (R) -2- of 3- dimethyl -2- butanol (161082-90-2) 2-*, R*)) fluoro- 3- methyl-1-pentenes alcohol (the 151717-18-9) (R of -2-*, S*) fluoro- 3- methyl-1-pentenes alcohol (151657-14-6) (the S) -2- fluoro- 3 of -2-, fluoro- 4- methyl -2- amylalcohols (19031-69-7) 1- fluoro- 3 of 3- dimethyl-1-butanols (141022-94-8) (M) -2- fluoro- 3- methyl -2- amylalcohols (19808-90-3) 4- of fluoro- 3- hexanols (19808-92-5) 4- of fluoro- 2- methyl -2- amylalcohols (21871-78-3) 5- of fluoro- 3- hexanols (30390-85-3) 5- of fluoro- 2- methyl -3- amylalcohols (69429-53-4) 1- of fluoro- 2- methyl -2- amylalcohols (69429-54-5) 2- of fluoro- 3- methyl-1-pentenes alcohol (112754-22-0) 3- of fluoro- fluoro- 1- hexanols (127608-47-3) 3- of 2- methyl-1-pentenes alcohol (137505-57-8) (S) -2-, fluoro- 1- hexanols (1786-48-7) 3- fluoro- 2 of fluoro- 4- methyl-1-pentenes alcohol (4455-95-2) 2- of fluoro- 2- methyl-1-pentenes alcohol (4456-03-5) 2- of 3- dimethyl -2- butanol (4604-66-4) 2-, the fluoro- 1- hexanols (373-32-0) of 3- dimethyl -2- butanol (661-63-2) 6-
The fluoro- 5- methyl isophthalic acids-hexanols of C7 fluorinated alcohols 5-, (, 168268-63-1, ), (, R, ), the fluoro- 2- methyl -2- hexanols of -1-, (, 153683-63-7, ), (, S, ), the fluoro- 1-heptanols of -3-, (, 141716-56-5, ), (, S, ), the fluoro- 2- methyl isophthalic acids - hexanols of -2-, (, 132354-09-7, ), (, R, ), the fluoro- 1-heptanols of -3-, (, 120406-54-4, ), (, S, ), the fluoro- 1-heptanols of -2-, (, 110500-31-7, ), the fluoro- 3- enanthol of 1-, (, 30390-86-4, ), the fluoro- 2- enanthol of 7-, (, 18804-38-1, ), 2- ethyls -2-, (, methyl fluoride, ), - n-butyl alcohol, (, 14800-35-2, ), 2-, (, methyl fluoride, ), -2- methyl-1-pentene alcohol, (, 13674-80-1, ), the fluoro- 5- methyl isophthalic acids-hexanols of 2-, (, 4455-97-4, ), the fluoro- 1-heptanols of 2-, (, 1786-49-8, ), the fluoro- 1-heptanols of 7-, (, 408-16-2, ), C8 fluorinated alcohols, (, M, ), the fluoro- 2- methyl isophthalic acids - enanthol of -2-, (, 137505-55-6, ), the fluoro- 6- methyl isophthalic acids-enanthol of 6-, (, 135124-57-1, ), the fluoro- sec-n-octyl alcohols of 1-, (, 127296-11-1, ), (, R, ), the fluoro- 1- octanols of -2-, (, 118205-91-7, ), (, ±, ), the fluoro- 2- methyl isophthalic acids - enanthol of -2-, (, 117169-40-1, ), (, S, ), the fluoro- 1- octanols of -2-, (, 110500-32-8, ), (, S, ), the fluoro- sec-n-octyl alcohols of -1-, (, 110270-44-5, ), (, R, ), the fluoro- sec-n-octyl alcohols of -1-, (, 110270-42-3, ), (, ±, ), the fluoro- sec-n-octyl alcohols of -1-, (, 110229-70-4, ), the fluoro- 4- methyl -3- enanthol of 2-, (, 87777-41-1, ), the fluoro- 6- methyl isophthalic acids-enanthol of 2-, (, 4455-99-6, ), the fluoro- 1- octanols of 2-, (, 4455-93-0, ),
Fluoro- 2,6- dimethyl-2-heptanols (160981-64-6) (S) -3- fluoro- 1 nonyl alcohol (160706-24-1) (R- (R of fluoro- 1- octanols (408-27-5) the C9 chlorhydrins 6- of 8-*, R*)) fluoro- 2- nonyl alcohols (137909-46-7) (R- (R of -3-*, S*)) fluoro- 2- nonyl alcohols (137639-20-4) (S- (R of fluoro- 2- nonyl alcohols (137909-45-6) 3- of -3-*, R*)) fluoro- 2- nonyl alcohols (137639-19-1) (S- (R of -3-*, S*)) the fluoro- 2- methyl isophthalic acids of -3- fluoro- 2- nonyl alcohols (137639-18-0) (±) -3- fluoro- 1 nonyl alcohol (134056-76-1) 2- fluoro- 1 nonyl alcohol (123650-79-3) 2--fluoro- fluoro- 3- nonyl alcohols (30390-87-5) 2- fluoro- 2 of 2- nonyl alcohols (111423-41-7) (S) -2- fluoro- 1 nonyl alcohol (110500-33-9) 1- of octanol (120400-89-7) (R) -2- fluoro- 1 nonyl alcohol (118243-18-8) (S) -1-, fluoro- fluoro- 3- decyl alcohol (145438-91-1) (R- (R of 1- decyl alcohol (167686-45-5) (P) -10- of 6- dimethyl -3- enanthol (684-74-2) 9- fluoro- 1 nonyl alcohol (463-24-1) C10 fluorinated alcohols 4-*, R*)) the fluoro- fluoro- 2- decyl alcohol (119105-15-6) of 2- decyl alcohol (119105-16-7) (S) -1- of the fluoro- 5- methyl isophthalic acids of -3--fluoro- 1- decyl alcohol (127608-48-4) (R) -1- of fluoro- 2- decyl alcohol (130876-22-1) (the S) -2- of fluoro- 2- decyl alcohol (139750-57-5) 1- of nonyl alcohol (144088-79-9) (P) -10-
Fluoro- 5- decyl alcohol (106533-31-7) 4- fluoro- 2 of fluoro- 1- decyl alcohol (110500-35-1) 1- of 2-, 2, 5, the fluoro- 2- methyl isophthalic acids of fluoro- 1- decyl alcohol (334-64-5) the C11 fluorinated alcohols 10- of 5- tetramethyl -3- hexanols (24212-87-1) 10--fluoro- 1- tip-nips (110500-34-0) 8- fluoro- 5 of decyl alcohol (139750-53-1) 2-, the fluoro- 2- methyl isophthalic acids of fluoro- 1- tip-nips (463-36-5) the C12 fluorinated alcohols 11- of fluoro- 2- tip-nips (101803-63-8) 11- of 8- dimethyl -5- nonyl alcohols (110318-90-6) 11--tip-nip (139750-52-0) 1- fluoro- dodecanol (132547-33-2) (R*, S*) fluoro- 6- dodecanols (the 130888-52-7) (R of -7-*, R*) the fluoro- fluoro- 2- amyl groups of 6- dodecanols (130876-18-5) (S) -2- fluoro- DODECANOL, 1- (127608-49-5) 12--enanthol (the 120400-91-1) (R of -7-*, S*)-(±) fluoro- 6- dodecanols (the 119174-39-9) (R of -7-*, R*)-(±) -7- fluoro- 6- dodecanols (119174-38-8) 2- fluoro- DODECANOL, 1- (110500-36-2) 11- fluoro- 2- methyl -2- dodecanols (101803-67-2) 1- fluoro- DODECANOL, 1- (100278-87-3) 12- fluoro- DODECANOL, 1- (353-31-1) C4 nitroalcohols (R) -4- nitro -2- butanol (129520-34-9) (S) -4- nitro -2- butanol (120293-74-5)
4- nitros-n-butyl alcohol ion radical (1-) (83051-13-2) (R*, S*) -3- nitro -2- butanol (82978-02-7) (R*, R*) -3-The nitro - 2 - butanol ( 82978-01-6 ) 4-The nitro - 1 - butanol ( 75694-90-5 ) ( ± ) -4-The nitro - 2 - butanol ( 72959-86-5 ) 4-The nitro - 2 - butanol ( 55265-82-2 ) ,1- nitro - methyl - 2 - propanol ( 22916-75-2 ) 3- nitro - methyl - 2 - propanol ( 22916-74-1 ) 2-Methyl - 3 - nitro - 1 - propanol ( 21527-52-6 ) 3-The nitro - 2 - butanol ( 6270-16-2 ) 2 - methyl - 1 - nitro - 2 - propanol (5447-98-3) 2 - acid type - The nitro - 1 - butanol (4167-97-9) 1 - The nitro - 2 - butanol (3156-74-9) 2 - The nitro - 1 - butanol (609-31-4) 2 - methyl - 2 - nitro - 1 - propanol (76-39-1) C5 nitro alcohols (R) - 3 - methyl - 3 - The nitro - 2 - butanol (154278-27-0) 3 - methyl - 1 - The nitro - 1 - butanol (20-153977-9) (+) - 1 - nitro - 3 - amyl alcohol (144179-64-6) (S) 1 - nitro - 3 - amyl alcohol (144139-35-5) (R) 1 - nitro - 3 - amyl alcohol (34-144139-4) (R) - 3 - methyl-1-The nitro - 2 - butanol ( 141434-98-2 ) ( ± ) - 3 - methyl-1-The nitro - 2 - butanol ( 141377-55-1 ) ( R*, R*) -3- nitro -2- amylalcohols (138751-72-1) (R*, S*) -3- nitro -2- amylalcohols (138751-71-0) (R*, R*) -2- nitro -3- amylalcohols (138668-26-5) (R*, S*) -2- nitro -3- amylalcohols (138668-19-6) 3- nitro -1- amylalcohols (135462-98-5)
, (, R, ), -5- nitro -2- amylalcohols, (, 129520-35-0, ), (, S, ), -5- nitro -2- amylalcohols, (, 120293-75-6, ), 4- nitro -1- amylalcohols, (, 116435-64-4, ), (, ±, ), -3- methyl-3-nitro -2- butanol, (, 114613-30-8, ), (, S, ), -3- methyl-3-nitro -2- butanol, (, 109849-50-5, ), 3- methyl -4- nitro -2- butanol, (, 96597-30-7, ), (, ±, ), -5- nitro -2- amylalcohols, (, 78174-81-9, ), 2- methyl -2- nitros - n-butyl alcohol, (, 77392-55-3, ), 3- methyl -2- nitros - n-butyl alcohol, (, 77392-54-2, ), 3- methyl -4- nitros - n-butyl alcohol, (, 75694-89-2, ), 2- methyl -4- nitro -2- butanol, (, 72183-50-7, ), 3- methyl-3-nitros-n-butyl alcohol, (, 65102-50-3, ), 5- nitro -2- amylalcohols, (, 54045-33-9, ), 2- methyl -3- acids - nitro -2- butanol, (, 22916-79-6, ), 2- methyl isophthalic acid - acid - nitro -2- butanol, (, 22916-78-5, ), 2- methyl-3-nitro -2- butanol, (, 22916-77-4, ), 2- methyl isophthalic acids - nitro -2- butanol, (, 22916-76-3, ), 5- nitro -1- amylalcohols, (, 21823-27-8, ), 2- methyl-3-nitros-n-butyl alcohol, (, 21527-53-7, ), 2- nitro -3- amylalcohols, (, 20575-40-0, ), 3- methyl-3-nitro -2- butanol, (, 20575-38-6, ), 3- nitro -2- amylalcohols, (, 5447-99-4, ), 2- nitro -1- amylalcohols, (, 2899-90-3, ), 3- methyl isophthalic acids - nitro -2- butanol, (, 2224-38-6, ), 1- nitro -2- amylalcohols, (, 2224-37-5, ), C6 nitroalcohols, (, -, ), -4- methyl isophthalic acids - nitro -2- amylalcohols, (, 158072-33-4, ), 3-, (, nitre methyl, ), -3- amylalcohols, (, 156544-56-8, ),
(R*, R*) -3- methyl -2- nitro -3- amylalcohols (148319-17-9) (R*, S*) -3- methyl -2- nitro -3- amylalcohols (148319-16-8) 6- nitro -2- hexanols (146353-95-9) (±) -6- nitro -3- hexanols (144179-63-5) (S) -6- nitro -3- hexanols (144139-33-3) (R) -6- nitro -3- hexanols (144139-32-2) 3- nitro -2- hexanols (127143-52-6) 5- nitro -2- hexanols (110364-37-9) 4- methyl isophthalic acids-nitro -2- amylalcohols (102014-44-8) (R*, S*) -2- methyl -4- nitro -3- amylalcohols (82945-29-7) (R*, R*) -2- methyl -4- nitro -3- amylalcohols (82945-20-8) 2- methyl-5-nitro -2- amylalcohols (79928-61-3) 2,3- dimethyl -1- nitro -2- butanol (68454-59-1) 2- methyl-3-nitro -2- amylalcohols (59906-62-6) 3,3- dimethyl -1- nitro -2- butanol (58054-88-9) 2,3- dimethyl -3- nitro -2- butanol (51483-61-5) 2- methyl isophthalic acids-nitro -2- amylalcohols (49746-26-1) 3,3- dimethyl -2- nitros-n-butyl alcohol (37477-66-0) 6- nitro -1- hexanols (31968-54-4) 2- methyl-3-nitro -1- amylalcohols (21527-55-9) 2,3- dimethyl -3- nitros-n-butyl alcohol (21527-54-8) 2- methyl -4- nitro -3- amylalcohols (20570-70-1) 2- methyl -2- nitro -3- amylalcohols (20570-67-6) 2- nitro -3- hexanols (5448-00-0) 4- nitro -3- hexanols (5342-71-2) 4- methyl -4- nitro -1- amylalcohols (5215-92-9) 1- nitro -2- hexanols (2224-40-0) C7 nitroalcohols
1- nitro -4- enanthol (167696-66-4) (R) -1- nitro -4- enanthol (146608-19-7) 7- nitros -1-heptanol (133088-94-5) (R*, S*) -3- nitro -2- enanthol (127143-73-1) (R*, R*) -3- nitro -2- enanthol (127143-72-0) (R*, S*) -2- nitro -3- enanthol (127143-71-9) (R*, R*) -2- nitro -3- enanthol (127143-70-8) (R*, S*) -2- methyl-5-nitro -3- hexanols (103077-95-8) (R*, R*, ), -2- methyl-5-nitro -3- hexanols, , (, 103077-87-8, ), 3- ethyl -4- nitro -1- amylalcohols, , (, 92454-38-1, ), 3- ethyl -2- nitro -3- amylalcohols, , (, 77922-54-4, ), 2- nitro -3- amylalcohols, , (, 61097-77-6, ), 2- methyl isophthalic acids - nitro -3- hexanols, , (, 35469-17-1, ), 2- methyl -4- nitro -3- hexanols, , (, 20570-71-2, ), 2- methyl -2- nitro -3- hexanols, , (, 20570-69-8, ), 5- methyl-5-nitro -2- hexanols, , (, 7251-87-8, ), 1- nitro -2- enanthol, , (, 6302-74-5, ), 3- nitro -4- enanthol, , (, 5462-04-4, ), 4- nitro -3- enanthol, , (, 5342-70-1, ), C8 nitroalcohols, , (, ±, ), -1- nitro -3- octanols, , (, 141956-93-6, ), 1- nitro -4- octanols, , (, 167642-45-7, ), , , (, S, ), -1- nitro -4- octanols, , (, 167642-18-4, ), 6- methyl -6- nitro -2- enanthol, , (, 142991-77-3, ), , , (, R*, S*) -2- nitro -3- octyl groups (135764-74-8) (R*, R*) -2- nitro -3- octyl groups (135764-73-7) 5- nitro -4- octanols (132272-46-9) (R*, R*) -3- nitro -4- octanols (130711-79-4)
(R*, S*) -3- nitro -4- octanols (130711-78-3) 4- ethyls -2- nitro -3- hexanols (126939-74-0) 2- nitro -3- octanols (126939-73-9) 1- nitro -3- octanols (126495-48-5) (R*, R*)-(±) -3- nitro -4- octanols (118869-22-0) (R*, S*)-(±) -3- nitro -4- octanols (118869-21-9) 3- nitros-sec-n-octyl alcohol (127143-53-7) (R*, S*) -2- methyl-5-nitro -3- enanthol (103078-03-1) (R*, R*) -2- methyl-5-nitro -3- enanthol (103077-90-3) 8- nitro -1- octanol (101972-90-1) (±) -2- nitro -1- octanols (96039-95-1) 3, 4- dimethyl -1- nitro -2- hexanols (64592-02-5) 3- (nitre methyl) -4- enanthol (35469-20-6) 2, 5- dimethyl -1- nitro -3- hexanols (35469-19-3) 2- methyl isophthalic acids-nitro -3- enanthol (35469-18-2) 2, 4, , 4- trimethyl -1- nitro -2- amylalcohols (35223-67-7) 2, 5- dimethyl -4- nitro -3- hexanols (22482-65-1) 2- nitro -1- octanols (2882-67-9) 1- nitros-sec-n-octyl alcohol (2224-39-7) C9 nitroalcohols 4- nitro -3- nonyl alcohols (160487-89-8) (R*, R*) -3- ethyls -2- nitro -3- enanthol (148319-18-0) 2,6- dimethyl -6- nitro -2- enanthol (117030-50-9) (R*, S*) -2- nitro -4- nonyl alcohols (103077-93-6) (R*, R*) -2- nitro -4- nonyl alcohols (103077-85-6) 2- nitro -3- nonyl alcohols (99706-65-7) 9- nitros -1 nonyl alcohol (81541-84-6) 2- methyl isophthalic acids-nitro -3- octanols (53711-06-1)
4- nitro -5- nonyl alcohols (34566-13-7) 2- methyl -3- (nitre methyl) -3- enanthol (5582-88-7) 1- nitro -2- nonyl alcohols (4013-87-0) C10 nitroalcohols 2- nitro -4- decyl alcohol (141956-94-7) (R*, S*) -3- nitro -4- decyl alcohol (135764-76-0) (R*, R*) -3- nitro -4- decyl alcohol (135764-75-9) 5,5- dimethyl -4- (2- nitre ethyl) -1- hexanols (133088-96-7) (R*, R*)-(±) -3- nitro -4- decyl alcohol (118869-20-8) (R*, S*)-(±) -3- nitro -4- decyl alcohol (118869-19-5) 5- nitro -2- decyl alcohol (112882-29-8) 3- nitro -4- decyl alcohol (93297-82-6) 4,6,6- trimethyl -1- nitro -2- enanthol (85996-72-1) 2- methyl -2- nitro -3- nonyl alcohols (80379-17-5) 1- nitro -2- decyl alcohol (65299-35-6) 2,2,4,4- tetramethyl -3- (nitre methyl) -3- amylalcohols (58293-26-8) C11 nitroalcohols 11- nitro -5- tip-nips (167696-69-7) (R*, R*) -2- nitro -3- tip-nips (144434-56-0) (R*, S*) -2- nitro -3- tip-nips (144434-55-9) 2- nitro -3- tip-nips (143464-92-0) 2,2- dimethyl -4- nitro -3- nonyl alcohols (126939-76-2) 4,8- dimethyl -2- nitros -1 nonyl alcohol (118304-30-6) 11- nitro -1- tip-nips (81541-83-5) C12 nitroalcohol 2- methyl -2- nitro -3- tip-nips (126939-75-1)
2- nitros-DODECANOL, 1- (62322-32-1) 1- nitro -2- dodecanols (62322-31-0) 2- nitro -3- dodecanols (82981-40-6) 12- nitro -1- lauryl alcohols (81541-78-8) table 26- formulas R5The OH bromo- 1- propyl alcohol 627, 189 1671691 of example compound (CAS No./A1drich No.) 3-, The chloro- 3- of 2- propyl alcohol 96, the chloro- 2 of of 3- bis- of 231 184489, 2- dimethyl -1- propyl alcohol 13, 401, 564 1893162, (the chloromethyl) -1- of 2- bis- propyl alcohol 5, 355, 544 2076911, 3 - two fluorine - 2 - propanol 453134 1769232-2264242-5271385 (in a harvard) ethanol (butyl amine) ethanol (1684912-102818 (diisopropyl amino) ethanol 96800 1687263 - methyl - 3 - butene - 1-763326 1294022 - methyl - 3 - alcohol butene - 115184 1368163 - methyl - 2-2 - alcohol butene - 1-556821 1623534 - hexene alcohol - 1-928927 2376045 - hexene alcohol - 821410, 230324, shun - 2-1 - alcohol - alcohol 928949 224707 anti - hexene - 1 - hexene - 1-3 alcohol 928972 224715 anti - 2 - hexene - 1 - alcohol, 928950, 132667 (+ / -) - 6 - methyl - 5 - heptene - 2 - alcohol 4630062 195871 dihydrogen geranyl enol 18479588 196428, Trans- 2, 4- hexadiene -1- alcohol 17, 102, 646 1830592, 4- dimethyl -2, The 1633333- butyne-1-ols 927, 742 130850 of 80, 192, the The isethionic acid of 3- pentyne-1-alcohols 10 of 569 238767 geraniol of 6- heptadiene -1- alcohol 106241, 229, 104 208698, Sodium salt 1, 562, 001 220078 (propane sulfonic acid of 4- (2- ethoxys) -1- piperazinyls 16, 052, 065 163740) HEPES, The 1308693- methyl cyclohexanols 591, of 75277393 of the 2338891- methylcyclopropanemethanols of sodium salt of 231 1397343, 2, 746, 147 6, 077, 721 233811 (+/-)-alantol of 2365942- methylcyclopropanemethanols, 18, 383, 590 194654 cyclobutanemethanol, 4, 415, 821 767055 1872751- acetenyls cyclopentanol of 1879173- cyclopenta -1- propyl alcohol 17356193, 3, 5, The 1906244- cyclohexyl of the 5- tetramethyl-rings hexanol 2650400- (1S of 4, 441, 570 197408 dihydrocarveol of n-butyl alcohol 619, 012 218421, 2R, (the 1S of 5S)-(+)-menthol 15, 356, 704 224464, 2S, (the 1S of 5R)-(+)-neomenthol 2, 216, 526 235180, 2R, (S) - (-) -562, 743 218383 α of terpinen-4-ols of perilla alcohol 536, 594 218391-terpineol 98, 555 218375 (the is are +/-)-trans- p- Meng-6- alkene-2 of 5S)-(+)-isomenthol 23, 283, 978 242195 (+/-) -3- cyclohexene-Menthol 72, 581, 329 162167 (+)-P- Meng-1- alkene-9- alcohol 13, 835, 308 183741, 1395131- ethyl -4- the hydroxy piperidines 3, 518, 830 224634 of 32, 226, 643 247774 cycloheptane methanol of 8- glycol, 4, 448, 753 138657 tetrahydrofurfuryl alcohol, 97, 994 185396 (S) - (+) -2- pyrrolidine carbinols, the 3- hydroxyl piperidine hydrochloric acid salts of 23356969 1865111- methyl -2- pyrrolidines ethanol 67004642, , , , 64051792, 174416, (, it is are are +/-, ), -2- piperidine carbinols, , , , 3433372, 1552253- piperidine carbinols, , , , , , 4606659, 1552331- methyl -2- piperidine carbinols, , , , 20845345, 1552411- methyl -3- piperidine carbinols, , , , 7583531, 1461452- piperidine ethanols, , , , , , 1484840, 1315204- hydroxy piperidines, , , , , , 5382161, 1287754- methyl isophthalic acids-piperazine propyl alcohol, , , , 5317339, 238716 outer-norborneols, , , , , , 497370, , in 179590-norborneol, , , , , , 497369, , 1864575- ENB -2- methanol, , , , 95125, , 248533, (, it is are are +/-, ), -3- methyl -2- norbornane methanol, 6968758, 130575, (, 1S, ), - interior-, (, -, ), - borneol, , , , 464459, , 139114, (, 1R, ), - interior-, (, +, ), - fenchol, , , , 2217029, the ring of 1964449- ethyls two, (, 3.3.1, ), nonyl- 9- alcohol, , 21951333, 193895, (, it is are are +/-, ), - isopinocampheol, , , , , 51152115, 183229, (, S, ), - along verbenol, , , , 18881044, 247065, (, 1R, 2R, 3R, The 1884171- adamantanols 768, 956 1303463 of (1R)-(-) of 5S)-(-)-isopinocampheol 25, 465, 650 221902-myrtenol 515004, 2274202- methyl-5-nitro -1- imidazole radicals the ethanol 443, of 707379 of the 2312902- adamantanols of 5- dimethyl -1- adamantanols of 481 226742, 700, 2287964- methyl -5- imidazolemethanols hydrochloride of 1538261- adamantane the methanol 770718 of the 1842091- Adamantane ethanols of 572 13781674, 6240115 1881153- furancarbinols 4, 412, 913 196398 furfuryl alcohol, 98000 1859302- (3- thienyls) ethanol 38585625 4-, of the 1906752- of 32673419 of 2199084- methyl-5-thiazoles ethanol of (methylol) the imidazole hydrochloride 137008, the 1529861- of 103, 1844461- benzyl -4- hydroxy piperidines of 1286432- hydroxyl -6- the picolines 3279763 of the 1287404- pyridylcarbinols of 742 6968725, 586958 1516293- pyridylcarbinol N- oxides of (2- ethoxys) pyridine 4727724, (4- chlorphenyls) -1- cyclopentanemethanols 80, 866, 791 188697, (4S, 5S) - (-) of 1876666- (4- chlorphenyls) -4 of of -2- methyl -5- phenyl -2- oxazoline -4- methanol 53732415, The chloro- α of 1295264- of 38, 958, the 1383392- naphthyl ethyl alcohols of 826 773999 1834582- isopropyl-phenols of 243728N- (2- ethoxys) phthalimide 3891074, 1485070 1881071- naphthyl ethyl alcohols of 5- dihydros -2- (2- hydroxyls butyl) -3 (2H) - pyridazinone 88697, the 1423284- fluorobenzene ethanol of the fluoro- 1408563- of of The 1625152- methyl isophthalic acids of 403418 of 5468973 of of 1327053- phenyl-1-propanols of α - methylbenzylalcohol 122974 (4- the anisyls) -1- propyl alcohol of the 1305594- of alpha-alpha-dimethyl phenethyl alcohol 5406188, 7589277 1541724- methoxybenzenes ethanol, 702, 238 154, the 1625072- fluorophenyl methanols of trans- 2- methyl-3- phenyl-2- propylene-1- alcohol 1504558 of the 1558882- ethoxylanilines of 180 456473, of the 122985 of the 1568763- fluorophenyl methanols 446515- α of phenyl-2- propyl alcohol 100, 867 170275- (chloromethyl) -2, The 1784032- phenyl-1-propanols 1, 123, the 4- chlorophenethylols of 859 17817 of 4- dichloros methanol 13692143, , , , , , , 1875883, 1834234- bromophenethyl alcohols, , , , , , , 4654391, 1834314- nitre benzyl carbinols, , , , , , , 100276, , 1834662- nitre benzyl carbinols, , , , , , , 15121843, 183474 β-ethyl benzyl carbinol, , , , , , 2035941, 1834824- phenyl-n-butyl alcohol, , , , , , 3360416, 1847562- methoxybenzene ethanol, , , , , , 7417187, 1879253- methoxybenzene ethanol, , , , , , 5020417, 1879333- phenyl-n-butyl alcohol, , , , , , 2722363, 1879762- methyl benzyl carbinols, , , , , , 19819988, 1881233- methyl benzyl carbinols, , , , , , 1875894, 1881314- methyl benzyl carbinols, , , , , , 699025, , 1881585- phenyl -1- amylalcohols, , , , , , 10521912, 1882204-, (, 4- anisyls, ), - n-butyl alcohol, , , , 22135508, 1882394-, (, 4- nitrobenzophenones, ), - n-butyl alcohol, , , , 79524202, 1887513, of (the +/-)-α of 20017678 of the 1889721- phenyl-2- propyl alcohol of 3- diphenyl-1- propyl alcohol 14, 898, 874 189235-ethyl benzyl carbinol 701, 702 1901361, 1935182- chlorophenethylols 19, 819, 955 193844 (the is are +/-) -1- phenyl -2- amylalcohols 705, of 29338496 of 5182445 of of the 1907563- chlorophenethylols of 1- diphenyl -2- propyl alcohol 737 1952862, 1965684- ethyoxyl -3- methoxybenzenes the ethanol 77, 891, 293 1975993 of 2- diphenyl ethanol 1883325, The 1976533- (3 of 4- dimethoxy-benzenes ethanol 7417212, 4- dimethoxy phenyls) 3, 929, 473 34743889 1987652- fluorobenzene ethanol of 1976882- (4- bromobenzenes epoxide) ethanol of -1- propyl alcohol, 50919067 2287883- (trifluoromethyl) benzyl carbinol 455, 016 230359 2327771- (2- the anisyls) -2- propyl alcohol 15 of The table 27- methods A-R of 2- (thiophenyl) ethanol 699127, 541, 261 233773 method concrete example example Reaction scheme 41
Reaction scheme 41
The amine 301 that amine 300 (intermediate of embodiment 52 can be purified arbitrarily using preceding) draws single Boc protections is handled with Boc acid anhydrides.This conversion refers to Greene, T.W. " blocking group in organic synthesis ", the second edition (John Wiley ＆ Sons, New York, 1991), the 327-328 pages.
Methyl esters 301 is with DIBAL in low-temperature reduction into corresponding primary allyl alcohol 302.This conversion such as Garner, P. and Park, J.M., " Journal of Organic Chemistry ", 52：2361 (1987) are described.
Primary alconol 302 is protected paired methoxybenzyl ether derivant 303 with the processing of 4- methoxybenzyls chlorine in the basic conditions.This conversion such as Horita, K. et al., " tetrahedron ", 42：3021 (1986) are described.
303 MOM and Boc protection group is by using TFA/CH2Cl2Handle and remove, amino alcohol 304 is made.This conversion is such as Greene, T.W., " blocking group in organic synthesis ", and the second edition (John Wiley ＆ Sons, New York, 1991) is described.
304 change into the two step programs completion that the aziridine 305 of correspondence trityl as protecting group is reacted with following kettles：1) TrCl/TEA, 2) MsCl/TEA.This conversion is as described above.
Then such as following derivatives 307 that aziridine 305 is changed into correspondence Boc protections：First trityl is removed with HCl/ acetone and obtain 306, this conversion such as Hanson, R.W and Law, H.D. " chemistry meeting will ", 7285 (1965) are described, then handle aziridine 306 with Boc acid anhydrides and change into correspondence Boc derivatives 307, this conversion such as Fitremann, J. et al., " Tet Lett ", 35：1201 (1994) are described.
Pi-allyl aziridine 307 is with the organic cuprate of high price in BF3·Et2In the presence of O under low temperature in allylic positions optionally open loop and draw open loop adduct 308.This open loop such as Hudlicky, T. et al. " Synlett. " 1125 (1995) are described.
With two step programs：1)TFA/CH2Cl2；2)Ac2The Boc amine 308 protected is changed into N- acetyl derivatives 309 by O/ pyridines.This conversion refers to Greene, T.W., " blocking group in organic synthesis ", the 327-328 page and the 351-352 pages of the second edition (John Wiley ＆ Sons, New York, 1991).
Benzylic ether 309 is deprotected with DDQ in room temperature, primary allyl alcohol 310 is obtained.This conversion such as Horita, K. et al. " tetrahedron ", 42：3021 (1986) are described.
Alcohol 310 is oxidized with kettle reaction and changes into methyl esters 311, uses MnO2/ AcOH/MeOH/NaCN carries out Corey oxidations and completed.This conversion such as Corey, E.J. et al. " JACS ", 90：5616 (1968) are described.
Nitrine base ester 311 is in two step response procedures：1)Ph3P/H2O/THF：2) KOH/THF changes into amino acid 312.This conversion is as described above.Reaction scheme 42
Reaction scheme 42
By the known (Sutherland of fluoroacetate 320; et al. J.K. " chemistry can will; chemical publication (J.Chem.Soc.Chem.Commun.) " 464 (1993)) free alcohol is deprotected into, then change into correspondence methanesulfonates 321 with two steps：1)NaOMe；2)MsCl/TEA.This conversion is such as Greene, T.W., " blocking group in organic synthesis ", and the second edition (John Wiley ＆Sons, New York, 1991) is described.
321 deprotection are drawn into glycol 322 in acid condition, it is cyclized into epoxy alcohol 323 in the basic conditions.This conversion is as previously described.
323 aziridine 324 for being converted into N- trityl as protecting group are completed by following orders：1)MOMCl/TEA；2)NaN3/NH4Cl；3)MsCl/TEA；4)PPh3/TEA/H2O；5)NaN3/NH4Cl；6)HCl/MeOH；7) i) TrCl, ii) MsCl/TEA.This order is as described above.
Then with suitable alcohol under the conditions of lewis acid by the open loop of aziridine 324, then use Ac2The processing of O/ pyridines draws acetylate 325.This conversion is as described above.
Ester 325 is converted to corresponding amino acid 326, via following two steps programs 1) PPh3/H2O/THF；2)KOH/THF.This conversion is as described above.
United States Patent (USP) 5214165, the particularly row of the 9th column 61 illustrate the preparation of 6 α and 6 β fluoro shikimic acids to " description and the embodiment " of the row of the 18th column 26 (label is as described therein).These fluoric compounds are suitable for use in using in the compounds of this invention preparation method of shikimic acid as starting material.
Answer scheme 43 in side
Reaction scheme 43
Beta-unsaturated esters 330 (are made up of acetonide alcohol with standard acetylation process; such as Campbell; M.M. et al., " synthesis ", 179 (1993) are described) (for organic cuprate since then, (R ' is J to wherein R ' with suitable organic cuprate1a) be transferred to the ligand in compound) react, institute draws 331 into intermediate with PhSeCl captures, then uses 30%H2O2Processing draws alpha, beta-unsaturated esters 332.This conversion refers to Hayashi, Y. et al., " Journal of Organic Chemistry ", 47：3428(1982).
Then with two step programs 1) NaOMe/MeOH；2) acetic acid esters 332 is changed into corresponding methanesulfonates 333 by MsCl/TEA.This conversion as described above, and refers to Greene, T.W., " blocking group in organic synthesis ", the second edition (John Wiley ＆ Sons, New York, 1991).
Then with two step programs 1) p-TsOH/MeOH/ Δs；2) acetonide 333 is changed into epoxy radicals alcohol 334 by DBU/THF.This conversion is as described above.
Epoxides 334 changes into N- trityls aziridine 3351 with following programs) MOMCl/TEA；2)NaN3/NH4Cl；3)MsCl/TEA；4)PPh3/TEA/H2O；5)NaN3/NH4Cl；6)HCl/MeOH；7) i) TrCl, ii) MsCl/TEA.This program is as described above.
Then with suitable alcohol under the conditions of lewis acid by the open loop of aziridine 335, then use Ac2The processing of O/ pyridines draws acetylate 336.This conversion is as described above.
Nitrine base ester 336 is converted to corresponding amino acid 337, via following two steps programs 1) PPh3/H2O/THF；2)KOH/THF.This conversion is as described above.
Reference reaction scheme 44 and 45 in embodiment.
Reaction scheme 44
Reaction scheme 45
Reaction scheme 46
Reaction scheme 47
Reaction scheme 48
Reaction scheme 49
Reaction scheme 50
Reaction scheme 51
Reaction scheme 52
Reaction scheme 53
Reaction scheme 54
Reaction scheme 55
Reaction scheme 56
Reaction scheme 57
Reaction scheme 58
Reaction scheme 59Reaction scheme 60
Reaction scheme 61
Reaction scheme 62
Reaction scheme 63Reaction scheme 64
Change the starting material of example to form different E1Group was described in detail already, repeated no more herein.Referring to Fleet, G.W.J. et al., " J.Chem.Soc.Perkin Trans.I ", 905-908 (1984), F1eet, G.W.J. et al.；" chemistry meeting will, chemical publication ", 849-850 (1983), Yee, Ying K. et al.；" pharmaceutical chemistry magazine ", 33,2437-2451 (1990)；Olson, R.E. et al.：" biological organic and pharmaceutical chemistry bulletin (Bioorganic ＆ Medicinal Chemistry Letters) ", 4 (18), 2229-2234 (1994)；Santella, J.B.III et al.；" biological organic and pharmaceutical chemistry bulletin ", 4 (18), 2235-2240 (1994)；Judd, D.B. et al.；" pharmaceutical chemistry magazine ", 37,3108-3120 (1994) and Lombaert, S.De et al.；" biological organic and pharmaceutical chemistry bulletin ", 5 (2), 151-154 (1994).
The E of carboxylic acid compound of the present invention1Sulfur analogs are made up of either standard technology, unrestricted as an example, and carboxylic acid is reduced into alcohol with standard method, then alcohol is changed into halide or sulphonic acid ester with standard method, and sulphidisation product reacts into compound and NaSH in institute.Such reaction is loaded in Patai, " thiol chemistry " (John Wiley, New York, 1974), particularly pt.2, the 721-735 pages.
The improvement of above-mentioned each reaction scheme can obtain the various congeners of above-mentioned particular example compound.The works of the suitable organic synthesis method of described above can be applied to these improvement.
It is preferably that reaction product is separated from each other and/or isolate from starting material in above-mentioned each reaction scheme.The expection product of each step or series of steps is separated and/or purified with technology commonly used in the art and (collectively referred to hereinafter as separated) to the required uniformity.Typically, this separation is related to multiphase extraction, is crystallized from solvent or solvent mixture, distillation, distillation or chromatographic isolation.Chromatographic isolation can be carried out with a variety of methods, for example, size is repelled or ion-exchange chromatography, it is high, in, low pressure liquid phase chromatography, on a small scale with preparative thin layer or thick layer chromatography, and small-scale thin layer and flash chromatography.
Another kind of partition method, which is related to, uses agent treatment mixture, and the reagent is chosen to be bound to expected product, unreacted starting material, byproduct of reaction etc. or separates it.Such reagent includes adsorbent or absorbent, such as activated carbon, molecular sieve, Ion Exchange Medium etc..In addition, in the example of alkaline matter, the reagent can be acid, and in the example of acidic materials, it can be alkali, or it can be bonding agent, such as antibody, conjugated protein, selectivity chelator, such as crown ether,
Liquid liquid ion extractuin agent (LIX) etc..
The selection of suitable partition method is depending on the essence for participating in material.For example, boiling point and molecular weight when distillation is with distillation, during chromatographic isolation whether polarized functional group, the stability of material in acid and alkaline medium etc. when multiphase is extracted.One skilled in the art can reach expected separating resulting using optimal skill.
All the above document is incorporated herein entirety in its citation position with patent citation and referred to.The paragraph or number of pages that above-mentioned works is especially quoted from are then clearly to be used as reference its described.The present invention has described in detail and has manufactured one skilled in the art and use the subject matter of following claims., it will be clear that to some improvement of the method and composition of claims below still within the scope of the invention with spirit.Casing is protected
Another embodiment of the present invention is related to the casing forms of protection of the compounds of this invention.Term " casing protection " used herein refers to the compound of the protection present invention to avoid making a part of intestines and stomach, and typically on the gastrointestinal tract, particularly stomach and oesophagus are exposed to compound of the invention.Can so mucosa tissue be protected in order to avoid being exposed to the compounds of this invention, this exposure can have a negative impact such as nausea；Or the compounds of this invention is not exposed to a part of or many parts intestines and stomach, typically condition present on the gastrointestinal tract.
Limit as an example and not, such casing forms of protection includes the tablet of the formulation that casing is coated, such as casing cladding, the granule of casing cladding, the bead of casing cladding, the particle of casing cladding, the microparticle of casing cladding and the capsule of casing cladding.In preferred embodiments, the compounds of this invention is placed in suitable formulation such as tablet, granule and capsule and the formulation is coated with pharmaceutically acceptable casing.In other preferred embodiments, the compounds of this invention is made into the granule of casing protection, particle; microparticle, ball, microballoon or colloid; and the granule of casing protection; particle, microparticle, ball; microballoon or colloid are made into pharmaceutically acceptable formulation; such as tablet, granule, capsule or suspension.
One aspect of the present invention is related to the compounds of this invention formulation of casing cladding, so that the pharmaceutical composition being made up of the about 0.1-1000mg active components of therapeutically effective amount and optional pharmaceutically acceptable excipient is delivered medicine in the intestines of people or other mammals, preferred small intestine.
Term " formulation " used herein includes pharmaceutically acceptable formulation.Many formulations are well known in the art, such as herein cited tablet, coated tablet, capsule, hard shell capsules, Perle, particle, microparticle, ball, microballoon, colloid, the sustained release agent of microencapsulation, semi-solid, suppository or granule.
Term " pharmaceutically acceptable excipient " used herein includes any physiologically inert and pharmacologically inactive material known to a person skilled in the art, and it is compatible to the physics and chemical characteristic for the compound that the present invention is selected.These excipient are described herein.Excipient can be with, but need not be protected there is provided casing.
Term used herein " unit dose " has common implication, refers to the compound of the present invention with following amounts single administration or delivering medicine to treated main body.It should be understood that being given dosage is treated or prevented with a unit dose, or given with the multiple of two or more unit doses, until adding the desired amount of compound altogether within preset time.
For constituent parts dosage, the composition of oral dosage unit forms of the invention preferably uses about 1-1000mg, typically about 10-500mg, more typically about 50-300mg, more typically the 75mg compound.Actual amount becomes with selected reactive compound.
In a typical implementation; casing protective agent is applied in the formulation containing compound or not into the compound of formulation; the protective agent prevents from inducing the exposure of nausea; contact or compound contact with mouth, oesophagus or stomach; but the compound is discharged in proximal part of the formulation by lower gastrointestinal tract for absorption; or in some embodiments, substantially only in colon.
Change the relative scale of protective agent and the compounds of this invention to reach optimal absorption according to selected compound.The protectant maximum or minimum (percetage by weight) of casing is unimportant.Typically, the embodiment of casing protection contains the enteric coating below about 50% weight.More typically about 1% weight is to about 25%, more typically about 1% weight to about 15% weight, more preferably about 1% weight to about 10% weight.
Many handbooks describe casing and protect and can be used for the correlation technique for preparing the composition of casing protection of the present invention.Such handbook includes：" theory and practice of industrial medicine ", the 3rd edition, Lea＆ Febiger, Philadelphia, 1986 (ISBN 0-8121-0977-5)；Lehmann, K.；" practice process that Laquer is coated ", Eudragit, 1989；Lieberman；
Lachman, L.；Schwartz, " pharmaceutical dosage form；Tablet ", 1990, Dekker (ISBN：0-8247-8289-5)；Lee, Ping I.Editor Good, WilliamR.Editor, " slow release method：Medicinal application ", ACS Symposium Ser.Vol.348 (ISBN：0-608-03871-7)；Wilson；Billie E.；Shannon, Margret T., " Rapid Dose Calculation：Method for simplifying ", 1996, Appleton ＆ Lange (ISBN：0-8385-9297-x)；Liebeman, Herbert A.Editor Rieger, Martin M., " pharmaceutical dosage form-dispersion ", 1996, Dekker (ISBN：0-8247-9 387-0)；" basic experiment of pharmaceutical dosage form ", 1995, World Health (ISBN：92-4-154418-x)；Karsa, D.R. are edited；Stephenson, R.A. are edited, " the excipient and delivery systme of pharmaceutical preparation：Proceedings of the " the British Association forChemical Specialties of Formulate ' 94 " Symposium ", 1995, CRC Pr (ISBN：0-85404-715-8)；Ansel, Howard C.；Popovich, Nicholas G.；Allen, LloydV., " pharmaceutical dosage form and drug delivery system, the 6th edition ", 1994, William ＆ Wilkins (ISBN：0-683-01930-9)；“The Sourcebook for Innovative DrugDelivery：Device and drug manufacturer, products ＆ services provider, information source ", 1987, Canon Comns (ISBN：0-9618649-0-7)；Chiellini, E., Giusti, G., Migliaresi, C., NicDlas, L. are compiled, " the polymer II in medicine：Bio-pharmaceutical and medicinal application ", 1986, Plenum (ISBN：0-306-42390-1)；" medicinal aerosol：Drug delivery system in transformation ", 1994, Technomic (ISBN：0-87762-971-4)；Avis；Lieberman, L.；Lachman, " pharmaceutical dosage form：Parenteral, expands second edition；Revised edition ", 1992, Dekker (ISBN：0-8247-9020-0)；Laffer, U., Bachmann, I., Metzger, U. are compiled, " implantable drug delivery system ", 1991, S.Karger (ISBN：3-8055-5434-6)；Borchardt, Ronald T., Repta, ArnoldJ., Stella, Valentino J. are compiled, and " are directly administered：Multidisciplinary method ", 1985, Humana (ISBN：0-89603-089-x)；Anderson, James M. are compiled, " drug delivery system progress 5：The recent progress international symposium of 5th drug delivery system, salt lake city, the U.S., 25-28 days 2 months 1991 ", Elsevier (ISBN：0-444-88664-8)；Turco, Salvatore J.；King, Robert E., " sterile formulation：It is prepared and clinical practice ", 1987, Williams ＆ Wilkins (ISBN：0-8121-1067-6)；Tomlinson, E., Davis,
S.S. compile, " locus specificity is administered：Cell biology, medicine and pharmaceutical progress ", 1986, Wiley (ISBN：0-471-91236-0)；Hess, H. are compiled, " pharmaceutical dosage form and its application ", 1986, Hogrefe ＆ Huber Pubs (ISBN：3-456-81422-4)；Avis；Lieberman；Lachman, " pharmaceutical dosage form, volume 2 ", 1986, Dekker (ISBN：0-8247-7085-4)；Carstensen, Jens T., " solid and the medicine of solid dosage forms ", 1977, Wiley (ISBN：0-471-13726-x)；Robinson, Joseph R. are compiled, " opthalmological delivery systme ", 1980, Am Pharm Assn (ISBN：0-917330-32-3)；Ansel, Howard C., " pharmaceutical dosage form introduction, the 4th edition ", 1985, Williams ＆Wilkins (ISBN：0-8121-0956-2)；" high-tech drug delivery system ", 1984, IntlRes Dev (ISBN：0-88694-622-0)；Swarbrick, James, " the current idea of pharmaceutical science：Formulation is designed and bioavailability ", 1985, Lea ＆ Febiger (ISBN：0-318-79917-0)；Sprowls, Joseph B. are compiled, " prescription pharmacy：Formulation and pharmaceutical adjuvants, second edition ", 1970, Lippincott (ISBN：0-397-52050-6)；And polderman, J. are compiled, " formula of formulation and preparation：37th F.I.P. pharmaceutical science international conference, Hague, Holland, in September, 1977 ", Elsevier (ISBN：0-444-80033-6).
Specific embodiment：
In another embodiment, the present composition is the Tabules that casing is coated.In this embodiment, stiff sheet agent is made by common method in preparation, and routinely technology coats the tablet with casing.
In preferred embodiments, the compounds of this invention is the powder form that casing is coated.In this embodiment, preparation is filled with hard or soft shell capsule or in its equivalent, and routinely technology coats the capsule with casing.
In one embodiment, the present composition is the liquid suspension form for the compounds of this invention particle that casing is coated.In this embodiment, the liquid suspension of the inhibitor is filled with hard or soft shell capsule or in its equivalent, and routinely technology coats the capsule with casing.
As the replacement of foregoing embodiments, casing protection reagent or component is made in capsule or other dose containers in itself, or it is integral with the container.
In another embodiment, casing protective agent is used to the compounds of this invention delivering medicine to colon.The drug delivery system is tablet, by up of three layers：1) core containing reactive compound of the present invention；
2) polymer can be lost by surrounding the non-swelling property of the core (combination of the core with that can lose polymeric layer is referred to as " Double substrate micro tablet ")；With 3) impose on the casing on Double substrate micro tablet.The composition and function of the drug delivery system each component by target of colon are specified in United States Patent (USP) 5,482,718, and the latter is integrally incorporated herein herein incorporated by reference, and the particularly specific row of the 2nd column the 29th that introduces is to the row of the 4th column the 12nd.
Another embodiment of the present invention is related to the emulsion of casing protection, and suspension, tablet, coated tablet, hard shell capsules, Perle, microencapsulation body, sustained release preparation, liquid is semi-solid, the aerosol dosage forms of suppository and the compounds of this invention." industrial medicinal theory and put into practice ", the 3rd edition, these standard dosage forms are described in detail in lower column position in Lea Febiger, Philadelphia, 1986 (ISB N0-8121-0977-5)：Emulsion and liquid suspension dosage form (pp.100-122), tablet (pp.293-345), coated tablet (pp.346-373), hard shell capsules (pp.374-397), Perle (pp.398-411), microencapsulation thing (pp.412-430), slow release formulation (pp.430-456), liquid (pp.457-478), drug suspension (pp.479-501), emulsion (pp.502-533), semi-solid (pp.534-563), suppository (pp.564-587), and medicinal aerosol (pp.589-618).
Other embodiments include the sustained release agent that the casing of the compounds of this invention is protected, control release formulation, particle; microencapsulation thing, microparticle, multiple particle; colloid, nasal dosage form, inhalant; oral mucosa agent; colon formulation, skin formulation, transdermal dosage form; ophthalmically acceptable formulation, topical formulations and special livestock formulation.Each formulation is described in detail in " medicine and the pharmaceutical science " that James Swarbrick are edited, Marcel Dekker, New York.
Material：
PH is usually less than about 5.5 in traditional casing protective agent polymer used herein or its mixture polymer insoluble under being included in pH below about 5.5, stomach, but the polymer is solvable in pH about 5.5 or more than 5.5, and pH is typically about 5.5 or more than 5.5 in small intestine and large intestine.Known United States Patent (USP) method can be used to measure the specific protectant validity of casing.
Include Cellacefate available for the example casing protection polymer in the embodiment; methyl acrylate-methacrylic acid copolymer; cellulose acetate succinate; HPMCP, poly- acetate phthalate vinyl acetate and Eudragit S100.Another example is anionic carboxylic copolymer, and it is based on methacrylic acid and methacrylate, commercially available with Eudragit (r).Representative instance includes acetic acid
Phthalate, cellulose (" CAP "), Cellulose acetotrimellitate, HPMCP (" HPMCP "), hydroxypropyl methyl cellulose phthalic acid succinate, poly- acetate phthalate vinyl acetate (" PVAP "), methacrylic acid and methacrylate.More typical protective agent is selected from PVAP and/or HPMCP, particularly PVAP.PVAP is with trade mark Sureteric (r), it is known that being manufactured by Colorcon, Inc..
Casing protection materials can be imposed in formulation with or without Conventional plasticizers such as acetylated glycerides under propane diols, glycerine, glyceryl triacetate, polyethylene glycol, triethyl citrate, ATBC, diethyl phthalate or dibutyl phthalate with means known in the art.
The example embodiment of casing protection：
Embodiment 1：The GS4104 capsules of casing protection
In the example embodiment, GS4104 (compound 262, embodiment 116, phos-phate forms, 131.4mg/ capsules, are equivalent to 100mg free alkalis) in No. 4 White-opalescent hard gelatin capsule shells, (capsule is constituted with Croscarmellose sodium (2.6mg/ capsules)：Gelatin NF, titanium dioxide USP) simultaneously casing coats the capsule for middle mixing.
Following casing cladding formula is imposed on capsule by means known in the art.Composition %w/w prepares A：The water 15.5 of 0.5 alcohol USP of the ester of hydroxypropyl methyl cellulose phthalic acid 5.0 (" HPMCP ") glyceryl triacetate 7.9 prepares B：The alcohol USP 72.75 of 0.05 lemon triethyl of HPMCP 10.0 titanium dioxide, 0.2 dimethicones 1.0
Water 16.00 prepares C：The denatured alcohol 44.9 of Cellacefate (" CAP) 8.5 diethyl phthalate, 1.5 titanium dioxide, 0.2 acetone 44.9 prepares D：The denatured alcohol 47.1 of 0.8 dichloromethane of poly- acetate phthalate vinyl esters (" PVAP ") 5.0 acetylated glycerides 47.1 prepares E：Methacrylic acid or methacrylate 8.0 (Eudragit (r) S or L, Rohm Pharma, GMBH, Wetterstadt, West Germany's manufacture) acetone 46.0 absolute alcohol, 46.0 plasticizer are appropriate
Typically enteric polymer (with or without plasticizer) is dissolved under each formula in the solvent, forms suspension/solution.Optionally, opacifying agent such as titanium dioxide is added.Sprayed under certain condition with suspension/solution with the coating in suitable vessel the formulation, so that casing protective layer is located in formulation and insoluble or destroy the formulation.For the protection of suitable casing, enteric polymer layer accounts for the about 1-50% weight of final coated dosage form, typically 1-15% weight, and more typically 5-10% weight is useful.
Embodiment 2：The tablet of casing protection
In another example embodiment, the big envelope tablet cores in enteric coating.Optionally employ priming coat (Subcoating).
Tablet cores：
The tablet cores of the present invention can be formed as follows：(a) mixed active composition and pharmaceutically acceptable excipient, the excipient and for form of mixtures and comprising such as diluent, adhesive, disintegrant choose any one kind of them or a variety of compositions selected from compression aid, flavor enhancement, flavoring agent, sweetener, dyestuff, pigment, buffer system and preservative；(b) with lubricator lubricate the mixture and (c) and the lubricated mixture of gained is compressed into required tablet using various pressed-disc techniques known in the art.Terms used herein " tablet " is intended to include compression or the shaped pharmaceutical form formula of all shape and size.
Include lactose or microcrystalline cellulose available for the diluent in the embodiment.
Typical adhesive available for the embodiment includes but is not limited to polyvinylpyrrolidone (povidone).Polyvinylpyrrolidone can be obtained with trade name " Avicel " from ISP companies.
Disintegrant can be one of several modified starches, or modified cellulosic polymer.Typically, using croscarmellose sodium.A type Croscarmellose sodium NF can be bought with trade name " Ac-di-Sol ".
Typical lubricant includes magnesium stearate, stearic acid, hydrogenated vegetable oil or talcum.
Flavor enhancement include Remington pharmaceutical sciences, the 18th edition, Mack PublishingCompany, described in 1990, pp.1288-1300 those.
Typical sweetener includes saccharin, A Siba sugar, or edible monose or polysaccharide, such as glucose or sucrose.
Dyestuff and pigment include " handbook of pharmaceutical excipients ", pp.81-90, those described in 1986 (AmericanPharmaceutical Association ＆ the Pharmaceutical Society of GreatBritain).
Typical preservative includes nipagin, nipasol, hexadecylpyridinium chloride and its salt, sorbic acid and its salt, thiomersalate or Benasept.
Enteric coating：
Eudragit L-30-D (r) (methacrylic acid copolymer, Rohm Pharma GmbH, Weiterstadt, West Germany) are a kind of suitable enteric polymers.The ratio between free carboxy and ester group that Eudragit L-30-D (r) have are about 1: 1 and can freely dissolved in pH5.5 and more than 5.5.Generally, Eudragit L-30-D (r) contents in enteric coating are bigger, then active component discharges closer to lower gastrointestinal tract.The lower gastrointestinal tract position of casing release compound can be by this area
Those of skill in the art are adjusted by the composition and thickness of control enteric coating used.
A kind of plasticizer is typically comprised, as described above those.
Other additives such as talcum or silica can be used as subtracting thick dose improving coated technique.
Priming coat：
The stability enhancing priming coat in tablet cores is optionally employed so that the interaction between the compounds of this invention and casing is minimum.This also allows using the thick casing film of single 10-300 microns without influenceing product stability.The priming coat inhibitory activity composition is from tablet cores move to casing, so as to improve useful life and product stability, but the once coating breaks down of outside, and priming coat dissolves rapidly in intestinal juice.
Include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Hydroxypropyl ethyl cellulose or PVP available for the typical basecoat polymers in the embodiment.
Embodiment general rule
The following example reference reaction scheme.
Some embodiments are carried out for several times, and in the embodiment repeated, reaction condition (such as time, temperature, concentration etc.) and yield are in normal experimental error.If repeating experiment with notable improvement, sign has dramatically different result person.If embodiment also indicates it using different starting materials.When using " correspondence " congener of compound in the embodiment repeated, such as " correspondingly ethyl ester ", it refers to that another group (in this example, usually methyl esters) is changed to shown group.For example, " the corresponding ethyl ester of compound 1 " refers to
Embodiment 1
Epoxy alcohol 1：From shikimic acid with McGowan and Berchtold, " Journal of Organic Chemistry " is made the step of 46,2381 (1981).
Embodiment 2
Epoxy radicals allyl ether 2：Ethanol thallium (I) (1.01mL) is once added into anhydrous benzene (50mL) solution of epoxy alcohol 1 (2.37g, 14.08mmol).Reactant mixture is concentrated in vacuo after 2 hours, residue is dissolved in acetonitrile.Allyl iodide (3.0mL) is added, this mixture is stirred in dark 16 hours.Solid is filtered out with Celite pad, with chloroform.After vacuum concentration, carry out flash chromatography separation (40%EtOAc hexane solution) and draw 1.24g (42%) 2, it is light thick oil.1H NMR (300MHz, CDCl3)：δ 6.75 (1H, m) 6.10-5.90 (1H, m ,-CH=, pi-allyl)；5.40-5.15 (2H, m ,=CH2, pi-allyl)；4.47-4.43 (1H, m), 4.30-4.15 (2H, m ,-CH2-, pi-allyl)；3.73 (3H, s)；3.55-3.50 (1H, m)；3.45-3.40 (1H, m)；(3.15-3.00 1H, dm, J=19.5Hz)；2.50-2.35 (1H, dm, J=2.7,19.5Hz).Embodiment 3
Azido alcohol 3：Make epoxides 2 (1.17g, 5.57mmo1), sodium azide (1.82g) is with ammonium chloride (658mg) in MeOH/H2Backflow 18 hours in O (8: 1) (35mL).Then the concentrated reaction mixture in vacuum, makes residue distribution in ether and water.Organic layer is dried with after salt water washing.Be concentrated in vacuo 3, its for light color oil, 1.3g (92%), without purifying just can be used directly.1H NMR (300MHz, CDCl3)：δ 6.95-6.85 (1H, m)；6.00-5.85 (1H, m ,-CH=, pi-allyl)；5.35-5.25 (2H, m ,=CH2, pi-allyl)；4.25-4.10 (2H, m ,-CH2-, pi-allyl)；4.12 (1H, bt, J=4.2Hz)；3.95-3.75 (2H, m), 3.77 (3H, s)；(2.85 1H, dd, J=5.3,18.3Hz)；2.71 (1H, bs)；2.26 (1H, dd, J=7.2,18,3Hz).Embodiment 4
Aziridine 4：CH is dissolved in toward alcohol 3 (637mg, 2.52mmol)2Cl2In (20mL) and be cooled in 0 DEG C of solution add DMAP (several crystal) with triethylamine (442 μ L).Then MsCl (287 μ L) is added again, is made to react on 0 DEG C and is stirred 2 hours.Volatile matter is removed, residue is allocated in ether and water.Organic layer saturated bicarbonate, salt solution is done after being washed out with water
It is dry.Vacuum concentration draws 881mg crude mesylates.1H NMR (300MHz, CDCl3)：δ 6.87-6.84 (1H, s)；6.00-5.85 (1H, m ,-CH2=, pi-allyl)；5.40-5.25 (2H, m ,=CH2, pi-allyl)；(4.72 1H, dd, J=3.9,8.5Hz)；4.32 (1H, bt, J=3.9Hz)；4.30-4.15 (2H, m ,-CH2-, pi-allyl)；3.77 (3H, s)；3.14 (3H, s)；2.95 (1H, dd, J=5.7,18.6Hz)；2.38 (1H, dd, J=6.7,18.6Hz).
This crude mesylate is dissolved in anhydrous THF (20mL), and uses Ph3P (727mg) processing.It is stirred at room temperature after 3 hours, addition water (15mL) and solid NaHCO3(1.35g), is stayed overnight then at this mixture is stirred at room temperature.Then reactant mixture is concentrated in vacuo, residue is then distributed between EtOAc, saturated bicarbonate and salt solution.Organic layer is isolated, MgSO is used4Dry.After vacuum concentration, residue flash chromatography, which is separated, draws aziridine 4,170mg (33%), and it is light yellow oil.1H NMR (300MHz, CDCl3)：δ 6.82-6.80 (1H, m)；6.04-5.85 (1H, m ,-CH=, pi-allyl)；5.35-5.20 (2H, m ,=CH2, pi-allyl)；(4.39 1H, bd, J=2.4Hz)；4.20-4.05 (2H, m ,-CH2-, pi-allyl)；3.73 (3H, s)；(2.90-2.80 1H, bd, J=18.9Hz)；2.65-2.40 (2H, m).Embodiment 5
N- acetyl group aziridine 5：Aziridine 4 (170mg, 0.814mmol) is dissolved in CH2Cl2(2ml) is with pyridine (4ml), being cooled to 0 DEG C.Then addition chloroacetic chloride (87 μ l), is stirred 1 hour in 0 DEG C.Volatile matter is removed in vacuum, by residue distribution in ethyl acetate, saturated bicarbonate and salt solution.Organic layer is isolated, MgSO is used4Dry.Concentration draws rough 5,196mg (96%), just can be used directly without purifying.1H NMR (300MHz, CDCl3)δ：6.88-6.86 (1H, m)；6.00-5.85 (1H, m ,-CH=, pi-allyl)；5.40-5.20 (2H, m ,=CH2, pi-allyl)；；4.45-4.40 (1H, m)；4.16 (2H, d, J=6.0Hz ,-CH2-, pi-allyl)；3.76 (3H, s)；3.00-2.95 (2H, m)；2.65 (1H, bd, J=18.5HZ)；2.14 (3H, s).Embodiment 6
Azido allyl ether 6：By aziridine 5 (219mg, 0.873mmol), sodium azide
(426mg) in dry DMF (7mL), is heated overnight in 65 DEG C under a nitrogen with ammonium chloride (444mg).Reactant mixture is poured into saturated bicarbonate/salt solution, ether extracted several times are used.Combined ether layer, is dried with after salt water washing.Flash chromatography separation (only with EtOAc) is carried out after concentration and draws azido amine 77mg (35%), CH is dissolved in2Cl2(1mL) is with pyridine (1mL), being cooled to 0 DEG C.Chloroacetic chloride (38 μ L) is added, solid NaHCO is added after 45 minutes3, volatile matter is removed in vacuum.By residue distribution in EtOAc and salt solution.Organic layer MgSO4It is concentrated in vacuo after drying.Flash chromatography separates 6 (99%) that 90mg is drawn (only with EtOAc).1H NMR (500MHz, CDCl3)；δ 6.86 (1H, bt, J=2.2Hz)；5.95-5.82 (1H, m, CH=, pi-allyl)；5.68 (1H, bd, J=7.3Hz)；5.35-5.20 (2H, m ,=CH2, pi-allyl)；4.58-4.52 (1H, m)；4.22-4.10 (2H, m)；4.04 (1H, dd, J=5.9,12.5Hz)；3.77 (3H, s)；3.54-3.52 (1H, m)；2.89 (1H, dd, J=5.9,17.6Hz)；2.32-2.22 (1H, m)；2.06 (3H, s).Embodiment 7
Azido glycol 7：Acetone (3mL) and addition N-methylmorpholine-N- oxides (39mg) and OsO in the solution in water (258 μ L) are dissolved in toward alkene 6 (90mg, 0.306mmol)4(73 μ L, 2.5%w/w t-butanol solution).Then this reactant mixture is stirred at room temperature 3 days.Solid sodium bisulfite is added, after stirring 20 minutes, is filtered with Celite pad.Washed with enough acetone.After vacuum concentration, flash chromatography separation (10%MeOH/CH is carried out2Cl2) draw glycol 7,50mg (50%).1H NMR (300MHz, CD3CN)：δ 6.80-6.70 (1H, m)；4.20-4.15 (1H, bm)；3.95-3.80 (1H, m)；3.80-3.25 (6H, m)；3.70 (3H, s)；3.10 (1H, bs)；2.85 (1H, bs)；2.85-2.75 (1H, m)；2.30-2.15 (1H, m)；2.16 (1H, bs)；1.92 (3H, s).Embodiment 8
Amino acid glycol 8：At room temperature solution of the glycol 7 (23mg, 0.07mmol) in THF (1mL) is handled with the KOH aqueous solution (223L, 0.40M).After stirring 1.5 hours, reactant mixture is acidified to pH=4 with Amberlite IR-120 (sun) ion exchange resin.Resin is filtered out, is washed with MeOH.Crude is drawn after vacuum concentration, ethanol is dissolved in
In (1.5mL).Lindlar catalyst (20mg) is added into this solution, stirring 20 hours in atmosphere of hydrogen (1atm, via balloon).Reactant mixture is filtered by Celite pad, is washed with hot ethanol with washing.Ethanol removed in vacuo, draws the mixture of expected amino acid 8 and starting azide 7, it is white powder after the freeze-drying of gained water layer.Compound 8：1H NMR (500MHz, D2O)：δ 6.5 (1H, s)；4.24-4.30 (2H, m)；4.25-4.18 (1H, m)；3.90-3.55 (5H is combined m)；2.96-2.90 (1H, m)；2.58-2.50 (1H is combined m)；2.12 (3H, s).Embodiment 9
Compound 62：By cinchoninic acid (60g), ring ethyl ketone (160mL) is flowed back 14 hours with suspension of the toluenesulfonic acid (600mg) in benzene (450mL) with Dean-Stark devices.Reactant mixture is cooled to after room temperature, pours into saturation NaHCO3Solution (150mL).Water layer CH2Cl2Extraction 3 times.Merge organic layer, with water (2 times), (1 time) washing of salt solution, Na2SO4Concentrated after drying, draw white solid, (75g, 95%) is recrystallized from ether；1H NMR(CDCl3)：δ 4.73 (dd, J=6.1,2.5Hz, 1H)；4.47 (ddd, J=7.0,7.0,3.0Hz, 1H)；4.30 (ddd, J=5.4,2.6,1.4Hz, 1H), 2.96 (s, 1H), 2.66 (d, J=11.7Hz, 1H), 2.40-2.15 (m, 3H), 1.72-1.40 (m, 10H).Embodiment 10
Compound 63：Once sodium methoxide (2.7g, 500mmol) is added into solution of the lactone 62 (12.7g, 50mmol) in methanol (300mL).This mixture is stirred at room temperature 3 hours, is stirred for 10 minutes after interrupting reaction with acetic acid (3mL).Reactant mixture is poured into saturation NH4In Cl solution (300mL), CH is used2Cl2Extraction three times.Merge organic layer, cleaned with salt solution once, MgSO4Dry.Glycol (11.5g, 80%) and starting material (1.2g, 10%) are drawn with flash column chromatography (hexane/EtOAc=1/1 to 1/2) purifying；1H NMR(CDCl3)：δ 4.47 (ddd, J=7.4,5.8,3.5Hz, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.81 (s, 3H), 3.45 (s, 1H), 2.47 (d, J=3.3Hz, 1H), 2.27 (m, 2H), 2.10 (dd, J=11.8,4.3Hz, 1H), 1.92-1.26 (m, 10H).
Embodiment 11
Compound 64：PCC (3.3g, 15.6mmol) is once added into glycol 63 (1.100g, 3.9mmol), molecular sieve (3A, 2.2g) is with pyridine (1.1g) in CH2Cl2In mixture in (15mL).This mixture is stirred at room temperature 26 hours, then diluted with ether (30mL).This suspension is filtered through a Celite pad, washed with ether (2 × 20mL).Combined ether layer, with using MgSO after salt water washing (2x)4Dry.After concentration ketone (0.690g, 67%) is drawn through flash column chromatography (hexane/EtOAc=3/1) purifying；1H NMR(CDCl3)：δ 6.84 (d, J=2.8Hz, 1H), 4.69 (ddd, J=6.4,4.9,1.6Hz, 1H), 4.30 (d, J=5.0Hz, 1H), 3.86 (s, 3H), 3.45 (d, J=22.3Hz, 1H), 2.86 (m, 1H), 1.69-1.34 (m, 10H).Embodiment 12
Compound 28：In in 0,30 minute by NaBH4In MeOH (12mL) solution for adding ketone 64 (0.630g, 2.4mmol).This mixture is stirred for 1.5 hours in 0, with 15mL saturations NH4Cl solution interrupts reaction.This solution CH2Cl2Extraction three times, merges organic extract, uses MgSO4Dry.Alcohol (0.614g, 97%) is drawn with flash column chromatography (hexane/EtOAc=2/1) purifying：1H NMR(CDCl3)：δ 6.94 (d, J=0.5Hz, 1H), 4.64 (ddd, J=9.8,6.7,3.2Hz, 1H), 4.55 (dd, J=7.1,4.2Hz, 1H), 4.06 (m, 1H), 3.77 (s, 3H), 3.04 (dd, J=16.5,2.1Hz, 1H), 2.73 (d, J=10.2Hz, 1H), 1.94 (m, 1H), 1.65-1.29 (m, 10H).Embodiment 13
Compound 66：Alcohol 28 (2.93g, 10.9mmol) and toluenesulfonic acid (1.5g) are dissolved in acetone (75mL), this mixture is stirred at room temperature 15 hours.Interrupted and reacted with water (30mL), use dense NH3-H2O alkalizes to pH=9.Acetone is removed under reduced pressure, aqueous phase then uses CH2Cl2Extraction 3 times.Merge organic extract, washed once with salt, Na2SO4Dry.Expected product is drawn after concentration：1H NMR(CDCl3)：δ 7.01 (m, 1H), 4.73 (m, 1H), 4.42 (m, 1H), 3.97 (m, 1H), 3.76 (s, 3H), 2.71-2.27 (m, 2H), 2.02 (s, 3H), 1.98 (s, 3H).
Embodiment 14
Compound 67：Pyridine (4.4mL, 54.5mmol) is added to alcohol 66 (10.9mmol) CH when 0 DEG C2Cl2In (60mL) solution, trimethyl-aceyl chloride (2.7mL, 21.8mmol) is then added again.Mixture is warmed to room temperature and stirred 14 hours, then uses CH2Cl2Dilution, through washing twice, after salt solution washed once, uses MgSO4Dry.Flash column chromatography (hexane/EtOAc=9/1) draws diester (2.320g, 68%) after purification：1H NMR(CDCl3)：δ 6.72 (m, 1H), 5.04 (m, 1H), 4.76 (m, 1H), 4.40 (m, 1H), 3.77 (s, 3H), 2.72-2.49 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.23 (s, 9H).Embodiment 15
Compound 68：Diester 67 (2.32g, 2.3mmol) is dissolved in acetone/water (1/1,100mL) and heated 16 hours in 55 DEG C.Solvent is removed, adds water (2 × 50mL) and evaporates.Together concentrated with toluene (2 × 50mL) and draw glycol, direct use need not be further purified：1H NMR(CDCl3)：δ 6.83 (m, 1H), 5.06 (m, 1H), 4.42 (m, 1H), 4.09 (m, 1H), 3.77 (s, 3H), 2.68-2.41 (m, 2H), 1.22 (s, 9H).Embodiment 16
Compound 69：Triethylamine (0.83mL, 6.0mmol) is added in glycol 68 (0.410g, 1.5mmol) THF (8mL) solution in 0 DEG C, be then slowly added thionyl chloride (0.33mL, 4.5mmol).Mixture is warmed to room temperature and stirred 3 hours.Use CHCl3It is washed with water after dilution three times, salt solution washed once, MgSO4Dry.Flash column chromatography (hexane/EtOAc=5/1) purifying draws outer/inner mixture (0.430g, 90%)；1H NMR(CDCl3)：δ 6.89-6.85 (m, 1H), 6.48-4.84 (m, 3H), 3.80,3.78 (s, 3H), 2.90-2.60 (m, 2H), 1.25,1.19 (s, 9H).Embodiment 17
Compound 70：By sulfone 69 (0.400g, 1.3mmol) and sodium azide (0.410g,
6.29mmol) stirred 20 hours in DMF (10mL) mixture.Then ethyl acetate diluted reaction mixture is used, saturation NH is used4Cl solution, water and salt water washing, MgSO4Dry.Concentration draws azide (0.338g, 90%)：1H NMR(CDCl3)：δ 6.78 (m, 1H), 5.32 (m, 1H), 4.20 (m, 1H), 3.89 (m, 1H), 3.78 (s, 3H), 3.00-2.60 (m, 2H), 1.21 (s, 9H).Embodiment 18
Compound 71：Triethylamine (0.4mL, 2.9mmol) is added to alcohol 70 (0.338g, 1.1mmol) CH in 0 DEG C2Cl2In (11mL) solution, mesyl chloride (0.18mL, 2.3mmol) is then slowly added to.This mixture is stirred 3 minutes in 0 DEG C, CH is used2Cl2Dilution, organic layer is washed with water secondary, then uses salt water washing, MgSO4Dry.Flash column chromatography (hexane/EtOAc=3/1) purifies to obtain expecting compound (0.380g, 82%)；1H NMR(CDCl3)：δ 6.82 (m, 1H), 5.44 (m, 1H), 4.76 (dd, J=7.3,1.4Hz, 1H), 4.48 (m, 1H), 3.80 (s, 3H), 3.11 (s, 3H), 2.82-2.61 (m, 2H), 1.21 (s, 9H).Embodiment 19
Compound 72：The mixture of azide 71 (0.380g, 0.94mmol) and triphenyl phasphine (0.271g, 1.04mmol) in THF (19mL) is stirred 2 hours.Reaction water (1.9mL) is interrupted with triethylamine (0.39mL, 2.82mmol), is stirred for 14 hours.Removal of solvent under reduced pressure, mixture is directly used in next step.Pyridine (0.68mL, 8.4mmol) is added into said mixture in CH in 0 DEG C2Cl2In the solution of (20mL), acyl chlorides (0.30mL, 4.2mmol) is then slowly added to.This mixture is stirred 5 minutes in 0 DEG C, diluted with ethyl acetate.Mixture is washed twice with water, and salt solution washed once, and uses MgSO4Dry.Flash column chromatography (hexane/EtOAc=3/1) draws aziridine (0.205g, 83%) after purification：1H NMR(CDCl3)：δ 7.19 (m, 1H), 5.58 (m, 1H), 3.77 (s, 3H), 3.14 (m, 2H), 2.85 (dd, J=7.0,1.6Hz, 1H), 2.34 (m, 1H), 2.16 (s, 3H), 1.14 (s, 9H).Embodiment 20
Compound 73：By aziridine 72 (0.200g, 0.68mmol), sodium azide (0.221g,
3.4mmol) it is stirred at room temperature 14 hours with mixture of the ammonium chloride (0.146g, 2.7mmol) in DMF (10mL).Then, this mixture is diluted with ethyl acetate, be washed with water five times, salt solution uses MgSO after washed once4Dry.Flash column chromatography (hexane/EtOAc=2/1) draws expected product and deacetylation amine (0.139g) after purification.This mixture is dissolved in acetic anhydride (2mL) and stirred 2 hours.Excessive acid anhydrides is removed under reduced pressure, expected product (149mg) is drawn：1H NMR(CDCl3)：δ 6.76 (m, 1H), 5.53 (d, J=8.5Hz, 1H), 5.05 (m, 1H), 4.31 (m, 1H), 4.08 (m, 1H), 3.79 (s, 3H), 2.91 (m, 1H), 2.51 (m, 1H), 1.99 (s, 3H), 1.20 (s, 9H).Embodiment 21
Compound 74：By KOH MeOH/H2O solution (0.5M, 4.4mL, 2.2mmol) is added in ester 73 (149mg, 0.44mmol), and this mixture is stirred 3 hours at room temperature, 0 DEG C is subsequently cooled to, and pH=3-4 is acidified to Amberlite (acidity).Mixture is filtered, after being washed with MeOH, and concentration draws carboxylic acid, and it is white solid (73mg, 69%)：1H NMR(CD3OD)：δ 6.62 (m, 1H), 4.15 (m, 1H), 3.95-3.72 (m, 2H), 2.84 (dd, J=6.7,1.4Hz, 1H), 2.23 (m, 1H), 1.99 (s, 3H).Embodiment 22
Compound 75：By azide 74 (8mg) and Pd-C (Lindlar) (15mg) in ethanol (2mL)) in mixture stir under hydrogen 16 hours.Mixture is filtered with diatomite, hot MeOH-H is used2O (1/1) is washed.Concentration draws solid.This solid is soluble in water, C-8 posts one short are passed through, are washed with water, concentration draws white solid (6mg)：1H NMR(D2O)：6.28 (m, 1H), 4.06-3.85 (m, 3H), 2.83 (dd, J=17.7,5.4Hz, 1H), 2.35 (m, 1H), 2.06 (s, 3H).Embodiment 23
Compound 76：Carboxylic acid 74 (68mg, 0.28mmol) and diphenyl diazomethane (61mg, 0.31mmol) are dissolved in ethanol (12mL) and stirred 16 hours.Reaction acetic acid (0.5mL) is interrupted, and is stirred for 10 minutes.Removal of solvent under reduced pressure, flash column chromatography (EtOAc) purifying
Ester output (56mg, 50%) is obtained afterwards；1H NMR(CD3OD)：δ 7.36-7.23 (m, 10H), 6.88 (s, 1H), 6.76 (s, 1H), 4.21 (m, 1H), 3.93-3.79 (m, 2H), 2.89 (dd, J=17.7,5.0Hz, 1H), 2.34 (m, 1H), 2.00 (s, 3H).Embodiment 24
Compound 77：Pyridine (40 μ L, 0.5mmol) is added to alcohol 76 (20mg, 0.05mmol) CH2Cl2In (1mL) solution, acetic anhydride (24 μ L, 0.25mmol) is subsequently added into.This mixture is stirred 24 hours, removal of solvent under reduced pressure and reagent.Flash column chromatography (hexane/EtOAc=1/2) purifying draws diester (20mg, 91%)：1H NMR(CDCl3)：δ 7.40-7.27 (m, 10t), 6.95 (s, 1H), 6.87 (m, 1H), 5.60 (m, 1H), 5.12 (ddd, J=16.4,10.2,5.9Hz, 1H), 4.28 (dd, J=20.0,9.4Hz, 1H), 4.15 (m, 1H), 2.93 (dd, J=17.8,5.2Hz, 1H), 2.57 (m, 1H), 2.09 (s, 3H), 2.01 (s, 3H).Embodiment 25
Compound 78：By diester 77 (20mg, 0.045mmol), anisole (50 μ L, 0.45mmol) is with TFA (1mL) in CH2Cl2Mixture in (1mL) is stirred 20 minutes.Removal of solvent under reduced pressure and reagent.Flash column chromatography (EtOAc to EtOAc/AcOH=100/1) purifying draws carboxylic acid (6mg)：1H NMR(CDCl3)：δ 6.85 (m, 1H), 5.54 (m, 1H), 5.12 (m, 1H), 4.31-4.03 (m, 2H), 2.89 (m, 1H), 2.60-2.41 (m, 1H), 2.11 (s, 3H), 2.03 (s, 3H).Embodiment 26
Compound 79：By azide 78 (6mg, 0.02mmol) and Pd-C (Lindlar) (15mg) in EtOH/H2Mixture in O (2.2mL, 10/1) is stirred 3 hours under hydrogen.Mixture is filtered with Celite pad, uses hot MeOH/H2O (1/1) is washed.Evaporation draws white solid, is dissolved in water, passes through C-8 posts.Boil off water and draw white powder (3mg)：1H NMR(D2O)：6.32 (m, 1H), 5.06 (m, 1H), 4.06 (t, J=10.4Hz, 1H), 3.84 (m, 1H), 2.83 (m, 1H), 2.42 (m, 1H), 2.06 (s, 3H),
2.00 (s, 3H).Embodiment 27
Compound 80：DCC (35mg, 0.172mmol) is added into alcohol 76 (35mg, 0.086mmol), Boc- glycine (30mg, 0.172mmol) is with catalytic amount DMAP in CH2Cl2In solution in (1mL).This mixture is stirred 30 minutes, filters and uses CHCl3Washing.Gained CHCl3Solution is washed with water secondary.Concentration draws white solid.Flash column chromatography (hexane/EtOAc=1/2) purifying draws product (30mg)：1H NMR(CDCl3)：δ 7.39-7.26 (m, 10H), 6.95 (s, 1H), 6.86 (m, 1H), 5.77 (m, 1H), 5.27 (m, 1H), 4.99 (m, 1H), 4.18-4.01 (m, 2H), 3.94-3.84 (m, 2H), 2.96 (dd, J=7.8,5.9Hz, 1H), 2.57 (m, 1H), 2.02 (s, 3H), 1.45 (s, 9H).Embodiment 28
Compound 81：By diester 80 (30mg, 0.05mmol), anisole (150 μ L) is with TFA (1mL) in CH2Cl2Mixture in (1mL) is stirred 3 hours.Boil off solvent and reagent.This mixture is soluble in water, use CHCl3Washing three times.White solid (15mg) is drawn after aqueous phase evaporation：1H NMR(CD3OD)：δ 6.73 (m, 1H), 5.25-5.15 (m, 1H), 4.35 (m, 1H), 4.17 (m, 1H), 3.82 (m, 2H), 2.93 (dd, J=17.7,5.6Hz, 1H), 2.42 (m, 1H), 1.97 (s, 3H).Embodiment 29
Compound 82：By azide 81 (15mg, 0.05mmol) and Pd-C (Lindlar) (30mg) in EtOH/H2Mixture in O (4mL, 1/1) is stirred 3 hours under hydrogen.Reactant mixture is filtered with Celite pad, uses hot MeOH/H2O (1/1) is washed.Concentration draws vitreous solid, is dissolved in water, passes through C-8 posts.Boil off and amino acid is drawn after water：1H NMR(D2O)：6.68 (m, 1H), 5.28 (m, 1H), 4.29 (m, 1H), 4.08-3.79 (m, 3H), 2.85 (m, 1H), 2.41 (m, 1H), 2.04 (s, 3H).
Embodiment 30
Two-Boc guanidinomethies esters 92：Such as Kim and Qian, " Tet Lett " 34-7677 (1993) described step process.By mercury chloride (46mg, 0.170mmol) once add the (42mg of amine 91,0.154mmol), in two-Boc thiocarbamides (43mg, 0.155mmol) and 0 DEG C of solution of the triethylamine (72 μ L) in dry DMF (310 μ L).After 30 minutes, reactant mixture is warmed to room temperature, and is stirred for 2.5 hours.Reactant mixture is filtered with Celite pad, concentration, draws 70mg (89%) 92 with flash column chromatography (100% ethyl acetate) purifying, it is colourless foam.1H NMR(CDCl3, 300MHz)：δ 11.37 (s, 1H)；8.60 (d, 1H, J=7.8Hz)；6.83 (t, 1H, J=2.1Hz)；6.63 (d, 1H, J=8.4Hz)；4.76 (d, 1H, J=7.0Hz)；4.71 (d, 1H, J=7.0Hz)；(4.45-4.10 compound m, 2H)；3.76 (s, 3H)；3.39 (s, 3H)；2.84 (dd, 1H, J=5.4,17.4Hz)；2.45-2.30 (m, 1H)；1.92 (s, 3H)；1.49 (s, 18H).Embodiment 31
Two-Boc guanidine radicals carboxylic acids 93：The KOH aqueous solution (350 μ L, 0.476M) is added in THF (3mL) solution (being cooled to 0 DEG C) toward ester 92 (70mg, 0.136mmol).Then reactant mixture is warmed to room temperature and stirred 2 hours, then pH=4.5 is acidified to Amberlite IR-120 (just) acidic resins.Resin is filtered out, with ethanol and water washing.Vacuum concentration draws 66mg (97%) carboxylic acid 93, and it is white solid.1H NMR(CDCl3, 300MHz)：δ 11.40 (br s, 1H)；8.67 (d, 1H, J=7.8Hz)；6.89 (s, 1H)；6.69 (br d, 1H, J=8.4Hz)；4.77 (d, 1H, J=7.2Hz)；(4.70 d, 1H, J=7.2Hz)；4.40-4.15 (m, 2H)；3.39 (s, 3H)；2.84 (dd, 1H, J=4.8,17.1Hz)；2.45-2.30 (m, 1H)；1.95 (s, 3H)；1.49 (s, 9H)；1.48 (s, 9H).Embodiment 32
Guanidine carboxylic acid TFA salt 94：Toward two-Boc guanidine radicals carboxylic acids 93 (23mg, 0.046mmol) in CH2Cl2The pure trifluoroacetic acid (500 μ L) of addition in the solution (being cooled to 0 DEG C) of (1mL).Reactant mixture is warmed to room temperature after 30 minutes, is stirred for 1.25 hours.Volatile matter, residue H is removed in vacuum2Evaporation for several times, obtains light orange solid to O jointly.Use anti-phase C18Chromatogram,
With H2O makees eluant, eluent, purifies the residue, merges the fraction containing expected product, and freeze-drying draws 15mg 93, and it is white powder.1H NMR(D2O, 500MHz)：6.82 (t, 1H, J=2.0Hz)；4.51-4.47 (m, 1H)；3.93 (dd, 1H, J=9.0,11.2Hz)；(3.87-3.80 apparent ddd, 1H)；2.88 (m, 1H)；(2.48-2.45 compound M)；2.07 (s, 3H).13C NMR(D2O)：176.1；170.0；157.1；139.2；129.5；69.4；56.2；50.9；30.3；22.2.Embodiment 33
102 synthesis：Ethanol (1mL) solution of azido allyl ether 6 (24mg, 0.082mmol) is handled 1.5 hours in Lindlar catalyst (30mg) with hydrogen (1atm).Reactant mixture is filtered with Celite pad, is washed with hot ethanol.Vacuum concentration draws pale solid, is dissolved in THF (1.5mL), with the KOH aqueous solution (246 μ L, 0.50M) handle, stir 2 hours at room temperature, be then acidified to pH=4.0 with Amberlite IR-120 (just) acidic resins, ethanol and H are used after filtering2O is washed.Vacuum concentration obtains orange solids, is used C18Column chromatography (H2O is eluted) purifying.Merge the fraction containing product, freeze-drying draws the 102 of 21 and the mixture of fully saturated compound 103, and it is white powder.Compound 1021H NMR datas：1H NMR(D2O, 500MHz)：7.85 (s, 1H)；4.29 (br d, 1H, J=9.2Hz)；4.16 (dd, 1H, J=11.6,11.6Hz)；3.78-3.72 (m, 2H)；3.62 (apparent ddd, 1H)；2.95 (apparent dd, 1H)；2.58-2.52 (m, 1H)；2.11 (s, 3H)；1.58 (q, 2H, J=7.3Hz)；0.91 (t, 3H, J=7.3Hz).Embodiment 34
115 synthesis：By (the 10.7mg of amino acid/11 14, water (1.3mL) solution 0.038mmol) is cooled to 0 DEG C, adjusted with 1.0M NaOH to pH=9.0, then benzyl carboximide (formimideate) hydrochloride (26mg is once added, 0.153mmol), kept stirring reactant mixture 3 hours in 0-5 DEG C while pH=8.5 to 9.0 with 1.0M NaOH.Then reactant mixture is concentrated in vacuo, residue is through C18Post is eluted with water.Merge the fraction containing product, freeze-drying draws carbonamidine carboxylic acid 115 (10mg), and it is white powder.1H NMR(D2O, 300MHz, isomer mixture)：7.83(s
, 1H)；(6.46 (s) ＆6.43 (s)；Sum is 1H)；4.83 (d, 1H, J=7.3Hz)；(4.73 d, 1H, J=7.3Hz)；4.50-4.35 (m, 1H)；4.10-4.05 (m, 1H)；(4.04-3.95 (m) ＆3.80-3.65 (m), sum is 1H)；3.39 (s, 3H)；2.90-2.75 (m, 1H)；2.55-2.30 (m, 1H)；(2.03 (s) and 2.01 (s), sum is 3H).Embodiment 35
Compound 123：In pyridine (40mL) solution that toluene sulfochloride (4.3g, 22.6mmol) is added to alcohol 63 (5.842g, 20.5mmol) and DMAP (200mg).This mixture is stirred 40 hours at room temperature, and pyridine is removed under reduced pressure.Interrupted and reacted with water, extracted three times with EtOAc.Merge organic extract liquid, with water and salt water washing, MgSO4After drying, flash column chromatography (hexane/EtOAc=2/1) purifying draws p-methyl benzenesulfonic acid ester (8.04g, 89%)：1H NMR(CDCl3)：δ 7.84 (d, J=8.3Hz, 2H), 7.33 (d, J=8.1Hz, 2H), 4.78 (m, 1H), 4.43 (m, 1H), 4.06 (m, 1H), 3.79 (s, 3H), 2.44 (s, 3H), 2.43-1.92 (m, 4H), 1.61-1.22 (m, 10H).Embodiment 36
Compound 124：By POCl3(100 μ L, 1.1mmol) is added in alcohol 123 (440mg, 1.0mmol) pyridine (3mL) solution.This mixture is stirred 12 hours at room temperature, saturation NH is used4Cl solution interrupts reaction.Aqueous phase with ether extract three times, combined ether layer, be washed with water it is secondary, 2NHCl solution washing it is secondary, use MgSO after salt water washing4Dry.Flash column chromatography (hexane/EtOAc=2/1) draws the mixture (350mg, 83%, 2/1) of expected product 124 and some impurity after purification.Embodiment 37
Compound 1：By mesyl chloride (330 μ L, 4.23mmol) add to the acetonide (877mg of -10 DEG C of known methyl shikimate, 3.85mmol, " Tet Lett ", 26-21 (1985)) dichloromethane (15mL) solution in, then triethylamine (640 μ L, 4.62mmol) is added dropwise.This solution is stirred 1 hour in -10 DEG C, is then stirred 2 hours in 0 DEG C, now adds mesyl chloride (30 μ L), triethylamine (64 μ L).After 1 hour, cold water is added,
Organic phase is separated, (MgSO is dried after washing4), re-evaporation.Crude product purified by silica gel chromatographic isolation (1/1 hexane/ethyl acetate) draws oily methanesulfonates 130 (1.1g, 93%).Methanesulfonates 130 (990mg, 3.2mmol) is dissolved in tetrahydrofuran (5 μ L), handled with 1MHCl (5mL).This solution is stirred 19 hours at room temperature, is diluted and is stirred for 7 hours with 5mL water.Evaporate organic solvent and draw oily residue, be extracted with ethyl acetate.Merge and (MgSO is dried after organic extract, salt water washing4), then evaporate.Plus CH2Cl2Into crude residue, the white solid separated out is filtered, CH is used2Cl2Glycol 131 (323mg, 38%) is drawn after washing.This glycol 131 (260mg, 0.98mmol) is cooled to 0 DEG C in THF (5mL) partial suspended liquid, addition DBU (154 μ L, 1.03mmol), this solution is stirred 3 hours in 0 DEG C, then warms to room temperature stirring 5 hours.Solvent is boiled off, by crude residue distribution in ethyl acetate (40mL) and 5% citric acid (20mL).Organic phase salt water washing, aqueous phase is stripped with ethyl acetate (15mL), merges organic extract, dries (MgSO4) evaporate afterwards, epoxides (117mg, 70%) is drawn, it is white solid, its1H NMR spectras are consistent with structure made from literature method 1.Embodiment 38
Alcohol 51：Trifluoroacetic acid (8mL) is added to the CH of 0 DEG C of the alcohol (PG=methoxyl methyls) (342mg, 1.15mmol) through protection2Cl2In (10mL) solution.Evaporated after the solution behind at 0 DEG C 5 minutes, is stirred at room temperature 1 hour.Raw product purifies on silica gel (ethyl acetate) and draws oily alcohol 51 (237mg, 82%)：1H NMR (300MHz, CDCl3)：δ 2.11 (s, 3H), 2.45 (m, 1H), 2.97 (dd, 1H, J=3.8,18.8), 3.66 (m, 2H), 3.78 (s, 3H), 4.40 (br s, 1H), 5.22 (br s, 1H), 6.19 (brs, 1H), 6.82 (m, 1H).Embodiment 39
Methyl ether 150：Add NaH (60% dispersion oils, 8mg, 0.20mmol) to (46mg of alcohol 51,0.18mmol) with methyl iodide (56 μ L, in THF (0.7mL) solution 0.90mmol), after 0 DEG C is stirred 2.5 hours, then add second part of NaH (2mg).Stir 1 hour, stir 4 hours at room temperature in 0, be cooled to 0 DEG C, 5% citric acid of addition (0.5mL).
Mixture is extracted with ethyl acetate (4 × 2mL), merges organic extract, dries (MgSO4) evaporate afterwards.Crude residue (ethyl acetate) on silica gel draws solid-like methyl ether 150 (12mg, 25%) after purification：1H NMR (300MHz, CDCl3)：δ 2.07 (s, 3H), 2.23-2.34 (m, 1H), 2.89 (apparent ddd, 1H), 3.43 (s, 3H), 3.58 (m, 1H), 3.78 (s, 3H), 4.13 (m, 1H), 4.40 (m, 1H), 5.73 (d, 1H, J=7.6), 6.89 (m, 1H).Embodiment 40
Amino acid/11 51：The Ph that polymer is carried3P (75mg, 3mmol P/g resins) adds to methyl ether 150 (12mg, 0.45mmol) THF (1mL)/H2In O (100 μ L) solution.This mixture is stirred 19 hours at room temperature.Resin is filtered out, is washed with THF for several times, merging filtrate and cleaning solution, evaporation draws 8mg crude residues, is dissolved in THF (0.5mL), 0.5M KOH (132 μ L)/water (250 μ L) is added.This solution is stirred 1.25 hours at room temperature, pH is adjusted to 3-4 with the ion exchange resin of IR 120, resin is filtered out and is together stirred with 1MHCl, after filtering, resin similarly is handled with 1MHCl again, until there is no amine (being predicted with ninhydrin) in acidic cleaning liquid.Merge resin cleaning solution, residue C-18 reverse phase silica gels are purified and (are eluted with water) after evaporation, freeze-drying draws amino acid/11 51 (1.8mg, 15%), and it is white solid：1H NMR (300MHz, D2O)：2.09 (S, 3H), 2.48-2.59 (apparent qt, 1H), 2.94 (dd, 1H, J=5.7,17.4), 3.61 (m, 1H), 4.14-4.26 (m, 2H), 6.86 (br s, 1H).Embodiment 41
Amino acid allyl ether 153：The PPh that polystyrene is carried3(50mg) adds to azide 6 (16mg, 0.054mmol) THF (0.5mL)/H2In O (35 μ L) solution.This reactant mixture is stirred 24 hours at room temperature, filtered with sintered glass funnel, hot methanol washing.Vacuum concentration draws rough amino ester, is dissolved in THF (1.0mL), is handled with the KOH aqueous solution (220 μ L, 0.5M).After stirring 2 hours at room temperature, AmberliteIR-120 (just) acidic resins are added, until pH value of solution=4.5.Resin is filtered out, with ethanol and H2O is washed.Vacuum concentration draws light orange solid, uses anti-phase C18Chromatogram (H2O is eluted) purifying.
Merge the fraction containing expected product, freeze-drying draws the amino acid of white powder.1H NMR(D2O, 300MHz)：6.51 (br t, 1H)；6.05-5.80 (m, 1H ,-CH=, pi-allyl)；5.36-5.24 (m, 2H ,=CH2, pi-allyl)；4.35-4.25 (m, 1H)；4.25-4.05 (m, 2H ,-CH2-, pi-allyl)；4.02-3.95 (m, 1H)；3.81-3.70 (m, 1H)；(2.86-2.77 apparent dd, 1H)；(2.35-2.24 compound m, 1H)；2.09 (s, 3H).Embodiment 42
Epoxides 161：In dichloromethane (15mL) solution of alkene 160 (532mg, 1.61mmol obtained by embodiment 14, are filtered crude mesylate through silica gel using preceding with 30%EtOAc/ hexanes) that MCPBA (690mg) is added to 0 DEG C.This mixture is warmed to room temperature and is stirred overnight.Solvent is removed under vacuum, then is diluted with ethyl acetate.Organic layer is with aqueous solution of sodium bisulfite, saturated sodium bicarbonate, salt water washing, MgSO4Dry, be concentrated in vacuo, residue then draws light oily 161 (437mg, 78%) with flash column chromatography (30% hexane/ethyl acetate) purifying.1H NMR(CDCl3, 300MHz)：(1: 1 non-enantiomer mixture) (4.75 (dd, J=3.9,8.2Hz) ＆4.71 (dd, J=3.9,8.4Hz), sum are 1H)；4.37 (m, 1H)；4.25-4.00 (m, 2H)；3.78 (s, 3H)；(3.68 (dd, J=5.7,11.7Hz) and 3.51 (dd, J=6.6,11.7Hz), sum are 1H)；(3.17 (s) ＆3.16 (s), sum is 3H)；(2.99 (m) ＆2.93 (m), sum is 1H)；(2.83 (t, J=4.1Hz) and 2.82 (t, J=4.5Hz), sum are 1H)；2.70-2.60 (m, 1H)；2.45-2.30 (m, 1H).Embodiment 43
Glycol 162：By epoxides 161 (437mg, 1.23mmol) in contain 5 drop 70%HClO4THF (20mL)/H2Gentle reflux 1 hour in O (10mL).Add solid NaHCO3, vacuum concentrated mixture.Residue is dissolved in EtOAc, dried after salt solution cleaning.Vacuum concentration draws rough glycol 162, and it is light oily (quantitative yield).Next reaction is directly used in without purifying.Embodiment 44
Aldehyde 163：Worked together by Vo-Quang with it, " synthesis ", 68 (1988) step carries out the oxidation of glycol 162.By NaIO4(4.4mL, the 0.65M aqueous solution) adds to silica gel (4.3g) in dichloromethane (30mL) slurry.EtOAc (5mL)/CH of rough glycol 162 (520mg) is added again2Cl2(15mL) solution.Solid is filtered out after 1 hour, is washed with 20% hexane/EtOAc.Oily residue is concentrated to give, EtOAc is dissolved in, MgSO is used4Dry.Vacuum concentration draws light oily aldehyde 163, and it is directly used in next reaction.1H NMR(CDCl3, 300MHz)：9.69 (s, 1H)；6.98 (m, 1H)；4.72 (dd, 1H, J=3.7,9.1Hz)；4.53 (d, 1H, J=18.3Hz)；4.45 (d, 1H, J=18.3Hz)；4.31 (m, 1H)；4.26-4.18 (m, 1H)；3.79 (s, 3H)；3.19 (s, 3H)；3.05 (dd, 1H, J=5.7,18.6Hz)；2.20-2.45 (m, 1H).Embodiment 45
Alcohol 164：Crude aldehyde 163 is worked together by Borch with it, " JACS ", 93-2897 (1971) described step, with NaCNBH3Processing, flash chromatography separation (40% hexane/EtOAc) draws 269mg (65%) alcohol 164：1H NMR(CDCl3, 300MHz)：6.91 (m, 1H)；4.75 (dd, 1H, J=3.9,8.7Hz)；4.34 (br t, 1H, J=4.1Hz)；4.25-4.15 (m, 1H)；3.85-3.70 (m, 4H)；3.77 (s, 3H)；3.16 (s, 3H)；2.95 (dd, 1H, J=5.7,18.6Hz)；2.37 (dd, 1H, J=7.1,18.6Hz)；2.26 (br s, 1H).Embodiment 46
Aziridine 165：With conventional process (AcCl, pyridine, dichloromethane, DMAP catalyst) by alcohol 164 (208mg, 0.62mmol) acetylation, acetic acid esters (241mg, 100%) is drawn.Crude acetic acid ester (202mg, 0.54mmol) is used into Ph in THF (12mL) at room temperature3P (155mg) is handled 2 hours.Then H is added2O (1.1mL) and triethylamine (224 μ L), solution is stirred overnight.Concentrated reaction mixture, by residue distribution between ethyl acetate and saturated bicarbonate/salt solution.Organic layer is dried, is concentrated in vacuo, purification by flash chromatography (10%MeOH/EtOAc) draws white solid aziridine 165 (125mg, 90%).1H NMR(CDCl3, 300MHz)：6.80 (m, 1H)；4.44 (br s, 1H)；4.23 (t, 2H,
J=4.8Hz)；3.82-3.65 (m, 2H)；3.74 (s, 3H)；2.85 (br d, 1H, J=19.2Hz)；2.65-2.40 (m, 3H)；2.09 (s, 3H)；1.25 (br s, 1H).Embodiment 47
N-Boc aziridine 166：Boc acid anhydrides (113mg, 0.52mmol) is added in aziridine 165 (125mg, 0.49mmol), triethylamine (70 μ L), solution of the DMAP (catalytic amount) in dichloromethane (7mL).Concentrated after 1 hour, residue flash chromatography (40%EtOAc/ hexanes) purifying draws 154mg (88%) light color oily N-Boc aziridine 166.1H NMR(CDCl3, 300MHz)：6.82 (m, 1H)；4.47 (brm, 1H)；4.23 (t, 2H, J=4.7Hz)；3.81 (t, 2H, J=4.7Hz)；3.75 (s, 3H)；3.00 (brd, 1H, J=18.0Hz)；2.90-2.85 (m, 2H)；2.65-2.55 (m, 1H)；2.10 (s, 3H)；1.44 (s, 9H).Embodiment 48
Nitrine ester 167：By aziridine 166 (154mg, 0.43mmol), sodium azide (216mg) is heated 18 hours with ammonium chloride (223mg) in DMF (5mL) in 100 DEG C.After reactant mixture cooling, distribution is in ether and salt solution.Ether layer water after salt washing with drying (MgSO4).Concentration draws crude residue, and it is at room temperature in CH2Cl2It is middle with 40%TFA processing.It is concentrated in vacuo after 2 hours and draws light oil, it (is eluted) by short column of silica gel with EtOAc.(AcCl, pyridine, dichloromethane, DMAP catalyst) acylate in a usual manner, flash chromatography separation (5%MeOH/ chloroforms) draws nitrine ester 167, and it is light yellow oil, 16mg (three steps totally 11%).1H NMR(CDCl3, 300MHz)：6.85 (m, 1H)；5.80 (brd, 1H, J=7.8Hz)；4.55 (m, 1H)；4.25-4.10 (m, 3H)；3.90-3.85 (m, 2H)；3.78 (s, 3H)；3.55 (m, 1H)；2.90 (dd, 1H, J=5.4,17.0Hz)；2.45-2.25 (m, 1H)；2.10 (s, 3H)；2.05 (s, 3H).Embodiment 49
Amino acid/11 68：The KOH aqueous solution (208 μ L, 0.0476M) is added into 0 DEG C of ester 167 (16mg, 0.47mmol) in THF (1mL) solution.Then reactant mixture is warmed
To room temperature and stir 2 hours, then with Amberlite IR-120 (just) acidic resins acidified reaction mixtures to pH=4.0.Resin is filtered out, with ethanol and H2O is washed.Vacuum concentration draws the nitrine carboxylic acid of 14mg (100%) white solid, it is dissolved in ethanol (2mL), worked together according to Corey with it, " synthesis ", 590 (1975) step is handled 16 hours on Lindlar catalyst (15mg) with hydrogen (1atm).Reactant mixture is filtered with Celite pad, with hot ethanol and water washing.Light orange solid is drawn after vacuum concentration, C is used18Column chromatography (H2O is eluted) purifying, merge the fraction containing product, freeze-drying draws 9.8mg white powders 168.1HNMR(D2O, 500MHz)：6.53 (br s, 1H)；4.28 (brM, 1H)；4.08 (dd, 1H, J=11.0,11.0Hz)；(3.80-3.65 compound m, 4H)；3.44 (m, 1H)；2.84 (apparent dd, 1H)；(2.46-2.39 compound m, 1H)；2.08 (s, 3H).Embodiment 50
Epoxy MOM ethers 19 (PG=methoxyl methyls)：Worked together according to Mordini with it, (74%) is made from epoxy radicals alcohol 1 in " Journal of Organic Chemistry ", 59-4784 (1994) step.1H NMR(CDCl3, 300MHz)：6.73 (m, 1H)；4.87 (s, 2H)；4.59 (t, 1H, J=2.4Hz)；3.76 (s, 3H)；3.57 (m, 1H)；3.50-3.40 (m, 1H)；3.48 (s, 3H)；3.10 (d, J=19.5Hz)；2.45 (m, 1H).Embodiment 51
Aziridine 170：(gross production rate 77%) is made from epoxides 19 (pG=methoxyl methyls) in general step according to embodiment 3 and 4.1H NMR(CDCl3, 300MHz)：6.85 (m, 1H)；4.78 (s, 2H)；4.54 (m, 1H)；3.73 (s, 3H)；3.41 (s, 3H)；2.87 (d, 1H, J=18.9Hz)；2.70-2.45 (m, 3H).Embodiment 52
Nitrine ester 22 (PG=methoxyl methyls)：By aziridine 170 (329mg, 1.54mmol), NaN3(446mg) and NH4Cl (151mg) is heated 18 hours in DMF (20mL) in 65 DEG C.After reactant mixture cooling, distribution is in ether and salt solution.(MgSO is dried after ether layer water, salt water washing4).Vacuum concentration draws the rough nitrine amine of light oily, is dissolved in CH2Cl2
In (15mL), handled with pyridine (4mL) and AcCl (150 μ L).Flash chromatography separation draws 350mg (76%) nitrine ester 22 (pG=methoxyl methyls), light color oil after residue processing.1H NMR(CDCl3, 300MHz)：6.78 (s, 1H)；6.39 (br d, 1H, J=7.8Hz)；4.72 (d, 1H, J=6.9Hz)；4.66 (d, 1H, J=6.9Hz)；4.53 (br d, 1H, J=8.4Hz)；4.00-3.90 (m, 1H)；3.80-3.65 (m, 1H)；3.75 (s, 3H)；3.37 (s, 3H)；2.85 (dd, 1H, J=5.4,17.7Hz)；2.35-2.20 (m, 1H)；2.04 (s, 3H).Embodiment 53
Amino acid/11 14：Worked together by Corey with it, " synthesis ", the step of 590 (1975), azide 22 (PG=methoxyl methyls) (39mg, 0.131mmol) is used into hydrogen (1atm) processing 2.5 hours in ethanol on Lindlar catalyst (39mg).Reactant mixture is filtered through Celite pad, and concentration draws the rough amine of light colored foam shape, 33mg (92%) after being washed with hot ethanol.This amine is handled in THF (1mL) with the KOH aqueous solution (380 μ L, 0.476M), pH=4.0 is acidified to Amberlite IR-120 (just) acidic resins after 1 hour.Then resin is filtered out, concentration draws pale solid after washing, through C18Column chromatography (H2O is eluted) purifying, the fraction containing product is collected, freeze-drying draws 20mg white powders 114.1H NMR(D2O, 300MHz)：6.65 (s, 1H)；4.87 (d, 1H, J=7.5Hz)；4.76 (d, 1H, J=7.5Hz)；4.47 (br d, 1H, J=8.7Hz)；4.16 (dd, 1H, J=11.4,11.4Hz)；3.70-3.55 (m, 1H)；3.43 (s, 3H)；2.95 (dd, 1H, J=5.7,17.4Hz)；2.60-2.45 (m, 1H)；(2.11 s, 3H).Embodiment 54
Amino acid/11 71：By 40%TFA/CH2Cl2(1mL is first cooled to 0 DEG C before addition) is added in solid amino acid 114 (4mg, 0.015mmol).This reactant mixture is stirred 1.5 hours at room temperature, white foam is obtained after concentration.With H2O is co-evaporated for several times, is freeze-dried to obtain 5.5mg white solids 117, it is tfa salt.1H NMR(D2O, 300MHz)：6.85 (m, 1H)；4.45 (m, 1H)；4.05 (dd, 1H, J=11.4,11.4Hz)；3.65-3.55 (m, 1H)；3.00-2.90 (m, 1H)；2.60-2.45 (m, 1H)；2.09
(s, 3H).Embodiment 55
Acetonide 180：In methanol (300mL) suspension that p-methyl benzenesulfonic acid (274mg, 1.44mmol, 1mol%) is added to shikimic acid (25g, 144mmol, Aldrich), this mixture is heated to reflux 2 hours.More p-methyl benzenesulfonic acid (1mol%) are added again, and backflow is evaporated after 26 hours.Rough methyl esters (28.17g) is suspended in acetone, handled with dimethoxy propane (35mL, 288mmol), is evaporated after stirring 6 hours at room temperature.This raw product is dissolved in ethyl acetate (400mL), saturation NaHCO is used3(3 × 125mL) is washed with saturation NaCl.Organic phase dries (MgSO4), filtering evaporates to obtain crude acetone compound 180 (~29.4g), it can be used directly：1H NMR(CDCl3)：6.91 (t, 1H, J=1.1), 4.74 (t, 1H, J=4.8), 4.11 (t, 1H, J=6.9), 3.90 (m, 1H)；2.79 (dd, 1H, J=4.5,17.4), 2.25 (m, 2H), 1.44 (s, 3H), 1.40 (s, 3H).Embodiment 56
Methanesulfonates 130：Triethylamine (29.5mL, 212mmol) is added to the CH of 0 DEG C of acetonide 180 (29.4,141mmol)2Cl2In (250mL) solution, mesyl chloride (13.6mL, 176mmol) was then added during 10 minutes.Reactant mixture is stirred 1 hour in 0 DEG C, icy water (250mL) is added, is transferred to after separatory funnel, organic phase water, 5% citric acid (300mL), saturation NaHCO3(300mL) is washed, and dries (MgSO4) evaporate after filtering.Crude product filters (being eluted with ethyl acetate) with sintered glass funnel (a bit of silica gel is housed).Evaporation filtrate draws methanesulfonates 130 (39.5g, 91%), and it is toughening oil, and is directly used in next step：1H NMR(CDCl3)：6.96 (m, 1H), 4.80 (m, 2H), 4.28 (dd, 1H, J=6.6,7.5), 3.90 (s, 3H), 3.12 (s, 3H), 3.01 (dd, 1H, J=5,17.7), 2.56-2.46 (m, 1H).Embodiment 57
Glycol 131：In methanol (500mL) solution that p-methyl benzenesulfonic acid (1.11g, 5.85mmol, 5mol%) is added to methanesulfonates 130 (35.85g, 117mmol), this solution is returned
Stream evaporates after 1.5 hours.Residue is re-dissolved in after methanol (500mL), is flowed back 4 hours.Evaporation solvent, raw oil is developed with ether (250mL).In after 0 DEG C of crystallised overnight, solid is filtered out, with cold ether, drying draws glycol 131 (24.76g), and it is white solid.After filtrate boils off, residue draws 1.55g again from methanol/ether crystallization.It there are 26.3g (85%) glycol 131：1H NMR(CD3OD)：6.83 (m, 1H), 4.86 (m, 1H), 4.37 (t, 1H, J=4.2), 3.87 (dd, 1H, J=4.2,8.4), 3.75 (s, 3H), 3.13 (s, 3H), 2.98-2.90 (m, 1H), 2.53-2.43 (m, 1H).Embodiment 58
Epoxy radicals alcohol 1：In 0 DEG C by the (20.78g of glycol 131, tetrahydrofuran (400mL) suspension 78mmol) uses 1, the processing of the carbon -7- alkene (11.7mL, 78mmol) of 8- diazabicylos (5.4.0) 11, is stirred at room temperature 9 hours to complete reaction.Crude residue is dissolved in CH after evaporation2Cl2In (200mL), and washed with saturation NaCl (300mL).Aqueous phase CH2Cl2Extract (2 × 200mL).Merge organic extract liquid, dry (MgSO4) evaporate after filtering.Crude product purified by silica gel (ethyl acetate) purifying obtains white solid epoxy radicals alcohol 1 (12g, 90%), its1H NMR spectras are consistent with reported in literature：McGowan, D.A.：Berchtold, G.A., " Journal of Organic Chemistry ", 46：2381(1981).Embodiment 59
Methoxyl methyl ether 19 (PG=methoxyl methyls)：N, N '-diisopropylethylamine (12.3mL, 70.5mmol) are added into epoxy radicals alcohol 1 (4g, 23.5mmol) CH2Cl2In (100mL) solution, then add Chloromethyl methyl ether (3.6mL, 47mmol are drawn by technical grade distillation).After this solution is flowed back 3.5 hours, solvent is boiled off, residue is then distributed in ethyl acetate (200mL) and water (200mL).Aqueous phase is extracted with ethyl acetate (100mL), is merged organic extract liquid, is washed with saturation NaCl (100mL), dries (MgSO4) after filtering, evaporation draws 4.9g solid residues, and its purity is directly suitable for next step：Mp62-65 DEG C (rough)；Mp64-66 DEG C (ether/hexane)；1H NMR(CDCl3)：6.73 (m, 1H), 4.87 (s, 2H), 4.59 (m, 1H), 3.75 (s, 3H), 3.57 (m, 1H), 3.48 (overlapping with m s, 4H), 3.07 (dd, 1H, J=1.2,19.8), 2.47 (dq, 1H
J=2.7,19.5).The ethyl ester congener of compound 19：
Diisopropylethylamine (34.0mL, 0.13mmol) is added to the CH of the corresponding ethyl ester (12.0g, 0.065mol) of the compound 1 of room temperature2Cl2In (277mL) solution, Chloromethyl methyl ether (10.0mL, 0.19mol) is then added.By this reactant mixture gentle reflux 2 hours, it is concentrated in vacuo after cooling, reallocation is in EtOAc and water.Separate organic layer, sequentially with dilute HCl, saturated bicarbonate, salt water washing, MgSO4It is evaporated in vacuo after drying.Then the corresponding ethyl ester that flash chromatography separation (silica gel, 50% hexane/EtOAc) draws 13.3g (90%) colourless liquids compound 22 is carried out.1H NMR (300MHz, CDCl3)：δ 6.73-6.71 (m, 1H)；4.87 (s, 2H)；4.61-4.57 (m, 1H)；4.21 (q, 2H, J=7.2Hz)；3.60-3.55 (m, 1H)；3.50-3.45 (m, 1H)；3.48 (s, 3H)；3.12-3.05 (m, 1H)；2.52-2.42 (m, 1H)；1.29 (t, 3H, J=7.2Hz).Embodiment 60
Alcohol 181：Sodium azide (7.44g, 114.5mmol) and ammonium chloride (2.69g, 50.4mmol) are added to methoxyl methyl ether 22 (PG=methoxyl methyls) (4.9g, 22.9mmol) 8/1-MeOH/H2In O (175mL, v/v) solution, mixture is flowed back 15 hours.With water (75mL) dilution with the molten salt split out, concentrate this solution to remove methanol.Gained is diluted with water to 200mL containing the aqueous phase for separating out oily residue, is extracted with ethyl acetate (3 × 100mL).Merge organic extract liquid, washed with saturation NaCl (100mL), dry (MgSO4) filter afterwards, and concentrate.Rough thing silica gel (1/1- hexane/ethyl acetates) purifying draws alcohol 181 (5.09g, 86%), and it is light yellow oil.Alcohol 181 can be directly used for next step without repurity and carry out follow-up preparation.1H NMR(CDCl3)：6.86 (m, 1H), 4.79 (s, 2H), 4.31 (brt, 1H, J=4.2), 3.90-3.75,3.77 (overlapping with m s, 5H), 3.43 (s, 1H), 2.92 (d, 1H, J=6.6), 2.87 (dd, 1H, J=5.4,18.6), 2.21-2.30 (m, 1H).Embodiment 61
Methanesulfonates 184：Triethylamine (4.4mL, 31.5mmol) and mesyl chloride (2.14mL, 27.7mmol) are sequentially added to the CH of 0 DEG C of alcohol 181 (6.47g, 25.2mmol)2Cl2In (100mL) solution.Reactant mixture is stirred 5 minutes in 0 DEG C, then warms to room temperature and is stirred for 15 minutes.After evaporation, by residue distribution in ethyl acetate (200mL) and water (100mL), organic phase water (100mL), saturation NaHCO3(100mL), saturation NaCl (100mL) washings.Water lotion is extracted with ethyl acetate once, uses identical NaHCO3/ NaCl solution washs the ethyl acetate.Merge organic extract liquid, dry (MgSO4) evaporate after filtering.The purity of crude product is suitable to be used directly in next step：1H NMR(CDCl3)：6.85 (m, 1H), 4.82 (d, 1H, J=6.9), 4.73 (d, 1H, J=6.9), 4.67 (dd, 1H, J=3.9,9.0), 4.53 (brt, 1H, J=4.2), 3.78 (s, 3H), 3.41 (s, 3H), 3.15 (s, 3H), 2.98 (dd, 1H, J=6.0,18.6), 2.37 (m, 1H)；13C NMR(CDCl3)：165.6,134.3,129.6,96.5,78.4,69.6,55.8,55.7,52.1,38.2,29.1.Embodiment 62
Aziridine 170：In 0 DEG C by Ph3P (8.2g, 31mmol) is added in methanesulfonates 184 (8.56g, 25mmol) THF (150mL) solution, adds 1/3 amount in cooling first, is removed interior by remaining Ph at 10-15 minutes after ice bath3P is added.Ph3After P additions completely, stir 3 hours at room temperature, white depositions are had therebetween and are formed.Triethylamine (5.2mL, 37.5mmol) and water (10mL) are added into this suspension, this mixture is stirred at room temperature 12 hours.Concentration removes THF, and residue is distributed in CH2Cl (200mL) and saturation NaCl2In (200mL).Aqueous phase CH2Cl2Extracted several times, merge organic extract liquid, dry (MgSO4), filtering, evaporation draws crude product, draws oily aziridine 170 (4.18g, 78%) with silica gel (10%MeOH/EtOAc) purifying, it typically contains the triphenyl phasphine oxide impurity of trace：1H NMR(CDCl3)：6.81 (m, 1H), 4.78 (s, 2H), 4.54 (m, 1H), 3.73 (s, 3H), 3.41 (s, 3H), 2.87 (apparent dd, 1H), 2.64 (brs, 1H), 2.56-2.47 (m, 2H), NH signals are not obvious；13C NMR(CDCl3)：166.9,132.5,128.0,95.9,69.5,55.2,51.6,31.1,27.7,24.1.
Embodiment 63
Amine 182：By aziridine 170 (3.2g, 15mmol) DMF (30mL) solution in several minutes of applying vacuum on rotary evaporator (40 DEG C) so that the solution deaerates.Then addition sodium azide (4.9g, 75mmol) and ammonium chloride (1.6g, 30mmol), this mixture are heated in 65-70 DEG C 21 hours.It is cooled to after room temperature, is filtered after being diluted with ethyl acetate (~100mL).Filtrate is evaporated, by residue distribution in ether (100mL) and saturation NaCl (100mL).Organic phase washed once with saturation NaCl (100mL) again, dry (MgSO4), evaporated after filtering.Water lotion be extracted with ethyl acetate and ibid after method processing can again extra crude product.Crude product purified by silica gel (5%MeOH/CH2Cl2) purifying draws oily amine 182 (2.95g), it contains a small amount of triphen phosphorous oxides impurity from previous step：1H NMR(CDCl3)：6.82 (t, 1H, J=2.3), 4.81 (d, 1H, J=7.2), 4.77 (d, 1H, J=6.9), 4.09-4.04 (m, 1H), 3.76 (s, 3H), 3.47 and 3.44 (overlap with m s, 4H), 2.94-2.86 (m, 2H), 2.36-2.24 (m, 1H)13C NMR(CDCl3)：165.9,137.3,128.2,96.5,79.3,61.5,55.7,55.6,51.9,29.5.Embodiment 64
N- trityls aziridine 183：Amine 182 (2.59g, 10.2mmol) is dissolved in 5%HCl/MeOH (30mL), this solution is stirred 3 hours at room temperature.5%HCl/MeOH (10mL) is added again and is stirred 1 hour, boils off and 2.52gHCl salt is obtained after solvent, high vacuum, it is brown solid.Toward the CH of this 0 DEG C of HCl salt2Cl2Triethylamine (3.55mL, 25.5mmol) is added in (50mL) suspension, solid trityl chloride (5.55g, 12.8mmol) is then once added.This mixture is stirred 1 hour in 0 DEG C, stirring 2 hours is warmed to room temperature after many, it is cooled to 0 DEG C, add triethylamine (3.6mL, 25.5mmol), then mesyl chloride (0.97mL, 12.5mmol) is added, institute's resulting mixture is stirred 1 hour in 0 DEG C, then at stirring 22 hours at room temperature.After evaporation, by residue distribution in ether (200mL) and water (200mL).Organic phase is washed with water (200mL), merges aqueous phase, then extracted with ether (200mL).Merge organic extract liquid, washed with water (100mL) with saturation NaCl (200mL), dry (MgSO4), evaporated after filtering.Crude product is in silica gel (1/1 hexane/CH2Cl2) on purifying draw white foam N- trityls aziridine 183 (3.84g, 86%).1H NMR(CDCl3)：7.4-7.23
(m, 16H), 4.32 (m, 1H), 3.81 (s, 3H), 3.06 (dt, 1H, J=1.8,17.1), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J=5.0).Embodiment 65
Compound 190：By N- trityls aziridine 183 (100mg, 0.23mmol), the solution of cyclohexanol (2mL) and BFEE (42 μ L, 0.35mmol) is heated 1.25 hours in 70 DEG C, then evaporated.Residue is dissolved in pyridine (2mL), with acetic anhydride (100 μ L, 1.15mmol) and catalytic amount DMAP processing.Evaporated after stirring 3 hours at room temperature, by residue distribution in ethyl acetate and 5% citric acid.Aqueous phase is extracted with ethyl acetate, and merges organic extract liquid, uses saturation NaHCO3Washed with saturation NaCl.Organic phase dries (MgSO4) evaporate after filtering.Crude product purified by silica gel (1/1- hexane/ethyl acetates) purifying draws solid chemical compound 190 (53mg, 69%)：Mp105-107 DEG C (ethyl acetate/hexane)；1H NMR(CDCl3)：6.78 (m, 1H), 6.11 (dd, 1H, J=7.4), 4.61 (m, 1H), 4.32-4.23 (m, 1H), 3.76 (s, 3H), 3.44-3.28 (m, 2H), 2.85 (dd, 1H, J=5.7,17.6), 2.28-2.17 (m, 1H), 2.04 (s, 3H), 1.88-1.19 (m, 10H).Embodiment 66
Compound 191：Triphenyl phasphine (57mg, 0.22mmol) and water (270uL) are added in compound 190 (49mg, 0.15mmol) THF solution, the solution is then heated in 50 DEG C 10 hours.Residue is dissolved in ethyl acetate after evaporation, (Na is dried2SO4) evaporate after filtering.Crude product (1/1-MeOH/EtOAc) purifying on silica gel draws pale-yellow solid amine (46mg).1.039N KOH solutions (217 μ L) and water (200 μ L) are added in THF (1.5mL) solution of this amine, 0 DEG C is cooled to after stirring 1 hour at room temperature, pH6-6.5 is acidified into IR120 ion exchange resin.Resin is filtered out, after being washed with methanol, filtrate is evaporated.Solid residue is then dissolved in water, is passed to C-18 reverse phase silica gels post (4 × 1cm), is eluted with water and later with 2.5% acetonitrile/water.Merge product section, evaporation, residue is dissolved in water, and freeze-drying draws white solid amino acid/11 91 (28mg)：1H NMR(D2O)：6.47 (brs, 1H), 4.80 (brd, 1H), 4.00 (dd, 1H, J=8.9,11.6), 3.59-3.50 (m, 2H), 2.87 (dd, 1H, J=5.5,17.2), 2.06 (s, 3H), 1.90-1.15
(serial m, 10H)；C15H24N2O4·H2O elementary analysis calculated values：C, 57.31；H, 8.34；N, 8.91.Measured value：C, 57.38；H, 8.09；N, 8.77.Embodiment 67
Two-Boc guanidine radicals esters 201：By Kim and Qian, " Tet Lett ", 34：The step of 7677 (1993), is handled.By HgCl2(593mg, 2.18mmol) once adds 0 DEG C of amine 200 (529mg, 1.97mmol are made with the method for embodiment 109), two-Boc thiocarbamides (561mg, 2.02mmol) and Et3In N (930 μ L) dry DMF (5.0mL) solution.This heterogeneous reaction mixture is stirred 45 minutes in 0 DEG C, then at being stirred at room temperature 15 minutes, is then diluted, is filtered with Celite pad with EtOAc.After vacuum concentration, residue draws the light oilies 201 of 904mg (90%) in Flash chromatography on silica gel separation (10% hexane/ethyl acetate).1H NMR(CDCl3, 300MHz)：11.39 (s, 1H)；(8.63 d, 1H, J=7.8Hz)；6.89 (t, 1H, J=2.4Hz)；6.46 (d, 1H, J=8.7Hz)；4.43-4.32 (m, 1H)；4.27-4.17 (m, 1H)；4.13-4.06 (m, 1H)；3.77 (s, 3H)；3.67-3.59 (m, 1H)；2.83 (dd, 1H, J=5.1,17.7Hz)；2.45-2.33 (m, 1H)；1.95 (s, 3H)；1.65-1.50 (m, 2H)；1.45 (s, 18H)；0.90 (t, 3H, J=7.5Hz).Embodiment 68
Carboxylic acid 202：In THF (10mL) solution that the KOH aqueous solution (3.45mL, 1.039N) is added to methyl esters 201 (904mg, 1.77mmol).This reactant mixture is stirred at room temperature 17 hours, 0 DEG C is cooled to, with Amberlite IR-120 (H+) acidic resins are acidified to pH4.0.Resin is filtered out, is washed with water with methanol, vacuum concentration draws light colored foam shape free acid, next reaction is directly used in without purifying.Embodiment 69
Guanidine carboxylic acid 203：Pure trifluoroacetic acid (25mL) is added to the CH of 0 DEG C of two-Boc guanidino-acids 202 (from the previous raw product for reacting and obtaining)2Cl2In the solution of (40mL), this reactant mixture is stirred 1 hour in 0 DEG C, is then stirred at room temperature 2 hours.It is concentrated in vacuo
Go out light orange solid, use C18Reverse-phase chromatography (being eluted with water) is purified.The fraction containing expected product is collected, freeze-drying draws the trifluoroacetate of 495mg (68%, 2 steps) guanidine carboxylic acid 203.1H NMR(D2O, 300MHz)：6.66 (s, 1H)；4.29 (bd, 1H, J=9.0Hz)；4.01 (dd, 1H, J=10.8,10.8Hz)；3.87-3.79 (m, 1H)；3.76-3.67 (m, 1H)；3.60-3.50 (m, 1H)；2.83 (dd, 1H, J=5.1,17.4Hz)；2.47-2.36 (m, 1H), 2.06 (s, 3H)；1.65-1.50 (m, 2H)；0.90 (t, 3H, J=7.2Hz).C15H23O6N4F3Elementary analysis calculated value：C, 43.69；H, 5.62；N, 13.59.Measured value：C, 43.29；H, 5.90；N, 13.78.Embodiment 70
Carbonamidine carboxylic acid 204：Water (500 μ L) solution of amino acid/11 02 (25mg, 0.10mmol are made by the method for embodiment 110) is adjusted into pH to 8.5 when 0-5 DEG C with 0.1N NaOH.Once benzyl carboximide hydrochloride (45mg, 0.26mmol) is added, the pH for maintaining this reactant mixture stirs it 3 hours in 0-5 DEG C while being 8.5-9.0 (using 1.0N NaOH).Then it is concentrated in vacuo, C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 4.0mg (13%) carbonamidines carboxylic acid 204.1H NMR(D2O, 300MHz)：7.85 (s, 1H)；(6.53 bd, 1H, J=7.8Hz)；4.32-4.25 (bm, 1H)；4.10-3.97 (m, 1H)；3.76-3.67 (m, 2H)；3.57-3.49 (m, 1H)；2.86-2.81 (m, 1H)；2.55-2.40 (m, 1H)；2.04 (s, 1H)；1.65-1.50 (m, 2H)；0.90 (t, 3H, J=7.4Hz).Embodiment 71
Amino acid 206：The KOH aqueous solution (481 μ L, 1.039N) is added in THF (1.0mL) solution of amino methyl 205 (84mg, 0.331mmol are made by embodiment 107).This reactant mixture is stirred at room temperature 2.5 hours, with Amberlite IR-120 (H+) acidic resins are acidified to pH6.5.Resin is filtered out, is washed with water with methanol, the amino acid for drawing white solid is concentrated in vacuo, it is through C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 59mg (74%) amino acid 206.1H NMR(CD3OD, 300MHz)：6.60 (bd, 1H, J=1.8Hz)；4.01-3.95 (m, 1H)；3.71-3.60
(m, 2H)；3.50-3.42 (m, 1H)；3.05-2.85 (m, 2H)；2.39-2.28 (m, 1H)；1.70-1.55 (m, 2H)；0.95 (t, 3H, J=7.5Hz).Embodiment 72
Trifluoroacetamide 207：It is degassed after adding Et under argon gas toward amino acid 206 (59mg, 0.246mmol) in absolute methanol (1.0mL) solution3N (35 μ L), then trifluoro-acetate (35 μ L) is added, it was stirred to 1 week at room temperature and concentrated.By1H NMR analyses show that reaction has 40% completion.Rough reaction product is re-dissolved in absolute methanol (1.0mL), trifluoro-acetate (1.0mL) and Et3In N (0.5mL), and it is stirred at room temperature 5 days.Then in vacuum concentration, it is re-dissolved in 50%THF/H2In O (2.0mL), with Amberlite IR-120 (H+) acidic resins are acidified to pH4, filter, concentration draws rough trifluoroacetamide carboxylic acid, and it can be directly used for next reaction without purifying.Embodiment 73
Amino acid 208：Solution by azide 207 (as the rough thing obtained by previous reaction) in THF (2.0mL) and water (160 μ L) is handled with the triphenyl phasphine (225mg) of carrying on polymer at room temperature, after stirring 20 hours, polymer is filtered out, is washed with methanol.Vacuum concentration draws pale solid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 6.5mg (9%) trifluoroacetamide amino acid 208.1H NMR(D2O, 300MHz)：6.59 (bs, 1H)；4.40-4.30 (m, 1H)；4.26 (t, 1H, J=10.1Hz)；3.80-3.66 (m, 2H)；3.56-3.47 (m, 1H)；2.96 (bdd, 1H, J=5.4,17.7Hz)；2.58-2.45 (m, 1H)；1.62-1.50 (m, 2H)；0.89 (t, 3H, J=7.5Hz).Embodiment 74
Methanesulfomide methyl esters 209：Mesyl chloride (19 μ L) is added to 0 DEG C of amine 205 (58mg, 0.23mmol are made by embodiment 107), Et3N (97 μ L) and catalytic amount DMAP (several crystal) is in CH2Cl2In solution in (1.0mL).Reactant mixture is warmed to room temperature and is stirred for 1 hour after 30 minutes, is concentrated in vacuo, residue is in silica gel (50% hexane/acetic acid
Ethyl ester) on flash chromatography separation draw 61mg (79%) sulfonamide 209.1H NMR(CDCl3, 300MHz)：(6.87 t, 1H, J=2.3Hz)；(5.08 d, 1H, J=7.5Hz)；4.03-3.90 (m, 1H)；3.78 (s, 3H)；3.75-3.45 (m, 4H)；3.14 (s, 3H)；2.95 (dd, 1H, J=5.2,17.3Hz)；2.42-2.30 (m, 1H)；1.75-1.55 (m, 2H)；0.95 (t, 3H, J=7.5Hz).Embodiment 75
Amino ester 210：By (the 61mg of azide 209,0.183mmol) handled at room temperature with the triphenyl phasphine (170mg) of carrying on polymer in the solution of THF (2.0mL) and water (118 μ L), stirring filters out polymer after 17.5 hours, is washed with methanol.After vacuum concentration, residue carries out flash chromatography separation with short silicagel column (100% methanol) and draws 45mg (80%) light colored foam shape amino ester 210.1H NMR(CDCl3, 300MHz)：6.85 (s, 1H)；(3.94 bd, 1H, J=7.8Hz)；3.77 (s, 3H)；3.74-3.60 (m, 2H)；3.55-3.45 (m, 1H)；3.25-3.15 (m, 1H)；(3.11 s, 3H)；2.94-2.85 (m, 1H)；(2.85 bs, 2H)；2.22-2.10 (m, 1H)；1.70-1.56 (m, 2H)；0.94 (t, 3H, J=7.5Hz).Embodiment 76
Amino acid 211：Methyl esters 210 (21mg, 0.069mmol) THF (200 μ L) solution is handled with the KOH aqueous solution (135 μ L, 1.039N), reactant mixture is stirred 40 minutes at room temperature, with Amberlite IR-120 (H+) acidic resins are neutralized to pH7.0, filter out resin, are washed with water with methanol, the amino acid for drawing pale solid shape is concentrated in vacuo, C is used18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 3.5mg (17%) amino acid 211.1H NMR(D2O, 300MHz)：6.60 (d, 1H, J=1.8Hz)；4.30-4.20 (m, 1H)；3.84-3.75 (m, 1H)；3.68-3.58 (m, 1H)；3.60-3.40 (m, 2H)；3.20 (s, 3H)；2.96-2.88 (m, 1H)；2.55-2.45 (m, 1H)；1.72-1.59 (m, 2H)；0.93 (t, 3H, J=7.4Hz).Embodiment 77
Two-Boc guanidine radicals esters 212：By Kim and Qian, " Tet Lett " 34：7677 (1993) steps are handled.By HgCl2(30mg, 0.11mmol) once adds 0 DEG C of amine 210 (31mg, 0.101mmol), two-Boc thiocarbamides (28.5mg, 0.103Mmol) and Et3In N (47 μ L) dry DMF (203 μ L) solution.This heterogeneous reaction mixture is stirred 30 minutes at 0 DEG C, is stirred for 30 minutes, is then diluted with EtOAc, then filtered with Celite pad at room temperature.It is concentrated in vacuo, residue flash chromatography separation on silica gel (40% hexane/ethyl acetate) draws the light oilies 212 of 49mg (89%).1H NMR(CDCl3, 300MHz)：11.47 (s, 1H)；8.66 (d, 1H, J=8.4Hz)；6.87 (s, 1H)；6.01 (bs, 1H)；4.50-4.35 (m, 1H)；4.04 (bd, 1H, J=8.4Hz)；3.76 (s, 3H)；3.70-3.60 (m, 1H)；3.53-3.45 (m, 2H)；3.02 (s, 3H)；2.85 (dd, 1H, J=5.3,17.3Hz)；2.42-2.30 (m, 1H)；1.66-1.55 (m, 2H)；1.49 (s, 9H)；1.48 (s, 9H)；0.93 (t, 3H, J=7.3Hz).Embodiment 78
Carboxylic acid 213：The KOH aqueous solution (260 μ L, 1.039N) is added in methyl esters 212 (49mg, 0.090mmol) THF (1.0mL) solution.This reactant mixture is stirred 16 hours at room temperature, is cooled to 0 DEG C, with Amberlite IR-120 (H+) acidic resins are acidified into pH4.0.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws light colored foam shape free acid, and it is used directly in next reaction without purifying.Embodiment 79
Guanidine carboxylic acid 214：Pure trifluoroacetic acid (2.0mL) is added to the CH of 0 DEG C of two-Boc guanidino-acids 213 (the rough thing for deriving from previous reaction)2Cl2In (2.0mL) solution.This reactant mixture is stirred 1 hour at 0 DEG C, then at stirring 1 hour at room temperature.Vacuum concentration draws light orange solid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 10mg (25%, 2 steps) guanidine carboxylic acid 214.1H NMR(D2O, 300MHz)：6.60 (bs, 1H)；4.22 (bd, 1H, J=9.0Hz)；3.82-3.66 (m, 2H)；3.65-3.54 (m, 1H)；3.43 (bt, 1H, J=9.9Hz)；3.15 (s, 3H)；2.82 (dd, 1H, J=5.0,17.5Hz)；2.48-2.30 (m, 1H)；1.71-1.58 (m, 2H)；
0.93 (t, 3H, J=7.3Hz).Embodiment 80
Propionamide methyl esters 215：Propionyl chloride (96 μ L, 1.1mmol) is added into 0 DEG C of amine 205 (178mg, 0.70mmol are made by embodiment 107) and the CH of pyridine (1.5mL)2Cl2In (2.0mL) solution, in concentrated reaction mixture after 0-30 minutes, then make its distribution in ethyl acetate and salt solution.Organic layer is separated, sequentially with saturated sodium bicarbonate, salt water washing dries (MgSO4) be concentrated in vacuo afterwards, residue separates to obtain 186mg (86%) pale-yellow solid propionamide methyl esters 215 in flash chromatography on silica gel (40% hexane/EtOAc).1H NMR(CDCl3, 300MHz)：6.86 (t, 1H, J=2.3Hz)；5.72 (bd, 1H, J=7.8Hz)；4.52-4.49 (m, 1H)；4.25-4.15 (m, 1H)；(3.77 s, 3H)；(3.65-3.38 compound m, 3H)；2.87 (dd, 1H, J=5.7,17.7Hz)；(2.28 q, 2H, J=7.5Hz)；2.25-2.20 (m, 1H)；1.65-1.50 (m, 2H)；1.19 (t, 3H, J=7.5Hz).0.92 (t, 3H, J=7.5Hz).Embodiment 81
Amino methyl 216：By (the 186mg of azide 215,0.60mmol) handled at room temperature with the triphenyl phasphine (560mg) of carrying on polymer in the solution of THF (5.0mL) and water (400 μ L), after stirring 21 hours, polymer is filtered out, is washed with methanol.Vacuum concentration draws rough amino ester 216, and it can be used directly in next reaction without purifying.Embodiment 82
Amino acid 217：By THF (500 μ L) the solution KOH aqueous solution (the 866 μ L of methyl esters 216 (the rough thing for deriving from previous reaction), 1.039N) processing, this reactant mixture was stirred at room temperature after 3 hours, with Amberlite IR-120 (H+) acidic resins are neutralized to pH7.0.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws pale solid shape amino acid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 49mg (31%, 2 steps) amino acid 217.1H NMR(D2O, 300MHz)：6.54 (s, 1H)；4.25 (bd, 1H, J=8.7Hz)；4.13 (dd, 1H, J=9.0,11.3Hz)；3.74-3.60
(m, 1H)；3.61-3.40 (m, 2H)；2.85 (dd, 1H, J=5.9,17.1Hz)；2.55-2.40 (m, 1H)；2.35 (q, 2H, J=7.5Hz)；1.65-1.45 (m, 2H)；1.13 (t, 3H, J=7.5Hz)；0.88 (t, 3H, J=7.5Hz).Embodiment 83
(monomethyl) two-Boc guanidine radicals ester 218：At room temperature, by 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (38mg) and Et3N (56 μ L) is added in dry DMF (1.0mL) solution of amine 200 (51mg, 0.19mmol) and-Boc thiocarbamides (36mg, 0.19mmol) of monomethyl two, at room temperature by HgCl after 1.5 hours2(about 75mg, excessive) is once added.This heterogeneous reaction mixture is stirred 45 minutes, after ethyl acetate dilution, filtered with Celite pad.Filtrate is diluted with extra ethyl acetate again, through dilute HCl, saturated sodium bicarbonate, after salt water washing, dries (MgSO4), it is concentrated in vacuo.Residue flash chromatography separation on silica gel (10%MeOH/EtOAc) draws-Boc guanidine radicals ester 218 of 13mg (16%) colourless foam (monomethyl) two.1H NMR(CDCl3, 300MHz)：6.84 (s, 1H)；6.20 (bd, 1H, J=5.1Hz)；5.45 (bs, 1H)；4.25-4.40 (bm, 1H)；4.20-4.05 (bm, 2H)；3.76 (s, 3H)；3.60-3.50 (m, 1H)；3.43-3.30 (m, 1H)；2.90 (dd, 1H, J=5.4,17.7Hz)；2.77 (d, 3H, J=4.8Hz)；2.35-2.25 (m, 1H)；1.96 (s, 3H)；1.60-1.50 (m, 2H)；1.47 (s, 9H)；0.91 (t, 3H, J=7.2Hz).Embodiment 84
(monomethyl) two-Boc guanidino-acids 219：By the KOH aqueous solution (60 μ L, 1.039N) add to (13mg of methyl esters 218, in THF (500 μ L) solution 0.031mmol), this reactant mixture is stirred 1 hour at room temperature, then gentle reflux 1 hour, it is cooled to after 0 DEG C, with Amberlite IR-120 (H+) acidic resins are acidified to pH6.0.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws free acid 219, and it is used directly in next reaction without pure.Embodiment 85
(monomethyl) guanidine radicals amino acid 220：Pure trifluoroacetic acid (1.0mL) is added to 0 DEG C
The CH of (monomethyl) two-Boc guanidino-acids 219 (the rough thing for deriving from previous reaction)2Cl2In (1.0mL) solution.This reactant mixture is stirred 1 hour at 0 DEG C, then stirred 1 hour at room temperature.Vacuum concentration draws pale solid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 4.4mg (33%, 2 steps) guanidine carboxylic acid 220.1H NMR(D2O, 300MHz)：6.52 (bs, 1H)；4.27 (bd, 1H, J=8.4Hz)；4.01 (dd, 1H, J=9.2,10.3Hz)；3.86-3.75 (m, 1H)；3.75-3.67 (m, 1H)；3.60-3.49 (m, 1H)；2.85 (s, 3H)；2.80 (dd, 1H, J=5.1,17.7Hz)；2.47-2.37 (m, 1H)；2.04 (s, 3H)；1.64-1.50 (m, 2H)；0.90 (t, 3H, J=7.2Hz).Embodiment 86
(R)-methyl-prop base ester 221：In argon gas and at room temperature, by BF in stirring3·Et2O (63 μ L, 0.51mmol) is added in (R)-(-) -2- butanol (1.2mL) solution of N- trityls aziridine 183 (150mg, 0.341mmol).By this light coloured solution after 70 DEG C are heated 2 hours, it is concentrated in vacuo, obtain brown residue, it is dissolved in anhydrous pyridine (2.0mL), handled at 0 DEG C with acetic anhydride (225 μ L) with catalytic amount DMAP (several crystal), reactant mixture is warmed to room temperature and stirred 2 hours, is concentrated in vacuo, distribution is in ethyl acetate and salt solution.Organic layer is separated, sequentially with dilute HCl, saturated sodium bicarbonate, salt is washed, dry (MgSO4) be concentrated in vacuo afterwards.Residue flash chromatography separation on silica gel (50% hexane/ethyl acetate) draws 75mg (72%) pale solid shapes (R)-methyl-prop base ester 221.1H NMR(CDCl3, 300MHz)：6.79 (t, 1H, J=2.2Hz)；6.14 (d, 1H, J=7.3Hz)；(4.55 bd, 1H, J=8.7Hz)；4.33-4.23 (m, 1H)；3.77 (s, 3H)；3.56-3.45 (m, 1H)；3.40-3.27 (m, 1H)；2.85 (dd, 1H, J=5.5,17.5Hz)；2.30-2.15 (m, 1H)；2.04 (s, 3H)；1.59-1.40 (m, 2H)；1.10 (d, 3H, J=6.0Hz)；0.91 (t, 3H, J=7.4Hz).Embodiment 87
(R)-methylpropylamino ester 222：By Ph3P (95mg, 0.36mmol) once adds the THF (3.0mL) of azide 221 (75mg, 0.24mmol) and water (432 μ L)
In solution.This pale yellow solution is heated 10 hours in 50 DEG C, is concentrated in vacuo after cooling and draws pale solid.66mg (97%) pale solid shape amino ester 222 is drawn with silica gel (50%MeOH/EtOAc) purification by flash chromatography.Embodiment 88
Amino acid 223：Methyl esters 222 (34mg, 0.12mmol) THF (1.0mL) solution is handled with the KOH aqueous solution (175 μ L, 1.039N).Reactant mixture was stirred after 3 hours at room temperature, with Amberlite IR-120 (H+) acidic resins are acidified into pH6.0, filter out resin, are washed with water with methanol, vacuum concentration draws pale solid shape amino acid, uses C18Reverse-phase chromatography (being eluted with water) is purified.The fraction containing expected product is collected, freeze-drying draws 11.5mg (36%) amino acid 223.1H NMR(D2O, 300MHz)：6.52 (bs, 1H)；4.28 (bd, 1H, J=8.7Hz)；4.04 (dd, 1H, J=8.8,11.5Hz)；3.74-3.65 (m, 1H)；3.50-3.60 (m, 1H)；2.90 (dd, 1H, J=5.5,17.2Hz)；2.50-2.40 (m, 1H)；2.10 (s, 3H)；1.60-1.45 (m, 2H)；1.14 (d, 3H, J=6.2Hz)；0.91 (t, 3H, J=7.4Hz).Embodiment 89
Two Boc guanidine radicals esters 224：By Kim and Qian, " Tet Lett ", 34-7677 (1993) step is handled.By HgCl2(34mg, 0.125mmol) once adds 0 DEG C of amine 222 (32mg, 0.113mmol), two-Boc thiocarbamides (32mg, 0.115mmol) and Et3In N (53 μ L) dry DMF (350 μ L) solution.This heterogeneous reaction mixture is stirred 45 minutes in 0 DEG C, then at stirring 1 hour at room temperature, then diluted with EtOAc, then filtered with Celite pad.It is concentrated in vacuo, residue flash chromatography separation on silica gel (20% hexane/ethyl acetate) draws 57mg (96%) colourless foam 224.1H NMR(CDCl3, 300MHz)：11.40 (s, 1H)；8.65 (d, 1H, J=7.8hz)；6.82 (s, 1H)；6.36 (d, 1H, J=8.7Hz)；4.46-4.34 (m, 1H)；4.20-4.10 (m, 1H)；4.10-3.95 (m, 1H)；3.76 (s, 3H)；2.79 (dd, 1H, J=5.4,17.7Hz)；2.47-2.35 (m, 1H)；1.93 (s, 3H)；1.60-1.45 (m, 2H)；1.49 (s, 18H)；1.13 (d, 3H, J=6.0Hz)；0.91 (t, 3H, J=7.5Hz).
Embodiment 90
Carboxylic acid 225：The KOH aqueous solution (212 μ L, 1.039N) is added in methyl esters 224 (57mg, 0.11mmol) THF (1.5mL) solution.This reactant mixture is stirred at room temperature 16 hours, 0 DEG C is cooled to, with Amberlite IR-120 (H+) acidic resins are acidified into pH4.0.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws light colored foam shape free acid, and it can be used directly in next reaction without purifying.Embodiment 91
Guanidine carboxylic acid 226：Pure trifluoroacetic acid (4.0mL) is added to the CH of 0 DEG C of two-Boc guanidino-acids 225 (the rough thing for deriving from previous reaction)2Cl2In (4.0mL) solution.This reactant mixture is stirred 1 hour in 0 DEG C, then at being stirred at room temperature 2 hours；Vacuum concentration obtains light orange solid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 18.4mg (40%, 2 steps) guanidine carboxylic acid 226.1H NMR(D2O, 300MHz)：6.47 (s, 1H)；4.28 (bd, 1H, J=8.4Hz)；3.93-3.74 (m, 2H)；3.72-3.63 (m, 1H)；2.78 (dd, 1H, J=4.8,17.4Hz)；2.43-2.32 (m, 1H)；1.58-1.45 (m, 2H)；1.13 (d, 3H, J=6.0Hz)；0.90 (t, 3H, J=7.4Hz).Embodiment 92
(diethyl) methyl ether ester 227：In hydrogen and at room temperature, by BF in stirring3·Et2O (6.27mL, 51mmol) is added in 3- amylalcohols (230mL) solution of N- trityls aziridine 183 (15g, 34mmol).This light coloured solution is heated 1.75 hours at 70-75 DEG C, vacuum concentration draws brown residue, it is dissolved in again in anhydrous pyridine (2.0mL), handled with acetic anhydride (16mL, 170mmol) and catalytic amount DMAP (200mg).Reactant mixture is stirred at room temperature 18 hours, distributed after vacuum concentration in ethyl acetate and 1MHCl.Organic layer is separated, sequentially with saturated sodium bicarbonate, salt water washing dries (MgSO4) be concentrated in vacuo afterwards.Residue on silica gel (50% hexane/ethyl acetate) flash chromatography separation draw 7.66g (diethyl) methyl ether ester, from ethyl acetate/hexane recrystallization draw colourless needles 227 (7.25g,
66%).1H NMR(CDCl3, 300MHz)：6.79 (t, 1H, J=2.1Hz)；5.92 (d, 1H, J=7.5Hz)；4.58 (bd, 1H, J=8.7Hz)；4.35-4.2 (m, 1H)；3.77 (s, 3H)；3.36-3.25 (m, 2H)；2.85 (dd, 1H, J=5.7,17.4Hz)；2.29-2.18 (m, 1H)；2.04 (s, 3H)；1.60-1.45 (m, 4H)；0.91 (t, 3H, J=3.7Hz)；0.90 (t, 3H, J=7.3Hz).Embodiment 93
(diethyl) methyl ether amino ester 228：By Ph3P (1.21g, 4.6mmol) is once added in the solution of azide 227 (1g, 3.1mmol) and water (5.6mL) in THF (30mL).Then this pale yellow solution is heated 10 hours in 50 DEG C, be concentrated in vacuo after cooling.By aqueous oily residue distribution in EtOAc and saturation NaCl.Organic phase dries (MgSO4), evaporated after filtering.The shallow white solid amino esters 228 of 830mg (90%) are drawn with the separation of silica gel (50% methanol/ethyl acetate) flash chromatography.1H NMR(CDCl3, 300MHz)：6.78 (t, 1H, J=2.1Hz)；5.68 (bd, 1H, J=7.8Hz)；4.21-4.18 (m, 1H)；3.75 (s, 3H)；3.54-3.45 (m, 1H)；3.37-3.15 (m, 2H)；2.74 (dd, 1H, J=5.1,17.7Hz)；2.20-2.07 (m, 1H)；2.03 (s, 3H)；1.69 (bs, 2H ,-NH2)；1.57-1.44 (m, 4H)；0.90 (t, 3H, J=7.5Hz)；0.89 (t, 3H, J=7.5Hz).Embodiment 94
Amino acid 229：THF (15mL) solution of methyl esters 228 (830mg, 2.8mmol) is handled with the KOH aqueous solution (4mL, 1.039N).This reactant mixture is stirred at room temperature 40 minutes, pH5.5-6.0 is acidified into Dowex 50WX8 acidic resins.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws pale solid shape amino acid, uses C18Reverse-phase chromatography (uses water, followed by 5%CH3CN/ water elutions) purifying, the fraction containing expected product is collected, freeze-drying draws 600mg (75%) amino acid 229.1H NMR(D2, 300MHz)：6.50 (t, 1H, J=2.1Hz)；4.30-4.26 (m, 1H)；4.03 (dd, 1H, J=9.0,11.7Hz)；3.58-3.48 (m, 2H)；2.88 (dd, 1H, J=5.4,16.8Hz)；2.53-2.41 (m, 1H)；1.62-1.40 (m, 4H)；0.90 (t, 3H, J=7.5Hz)；0.85 (t,
3H, J=7.5Hz).Embodiment 95
Tertiary pentyl ether-ether 230：In argon gas and at room temperature, by BF in stirring3·Et2O (43 μ L, 0.35mmol) is added in tert-pentyl alcohol (2.5mL) solution of N- trityls aziridine 183 (104mg, 0.24mmol).This light coloured solution is heated 3 hours at 75 DEG C, vacuum concentration draws brown residue, is dissolved in anhydrous pyridine (2.0mL), handled with acetic anhydride (250 μ L) and catalytic amount DMAP (several crystal).Reactant mixture is stirred at room temperature 1.5 hours, after vacuum concentration, distribution is in ethyl acetate and salt solution.Organic layer is separated, sequentially with dilute HCl, saturated sodium bicarbonate, salt water washing dries (MgSO4) be concentrated in vacuo afterwards.Residue draws 27mg (35%) light orange oily tertiary pentyl ether-ether 230 in flash chromatography separation on silica gel (50% hexane/ethyl acetate).1H NMR(CDCl3, 300MHz)：6.72 (t, 1H, J=2.1Hz)；5.83 (d, 1H, J=7.2Hz)；4.71 (bd, 1H, J=8.1Hz)；4.45-4.35 (m, 1H)；3.75 (s, 3H)；3.27-3.17 (m, 1H)；2.84 (dd, 1H, J=5.7,17.4Hz)；2.27-2.15 (m, 1H)；2.05 (s, 3H)；1.57-1.47 (m, 2H)；1.19 (s, 3H)；1.15 (s, 3H)；0.90 (t, 3H, J=7.5Hz).Embodiment 96
Tert-amyl ether amino ester 231：By Ph3P (35mg, 0.133mmol) is once added in the solution of azide 230 (27mg, 0.083mmol) and water (160 μ L) in THF (1.5mL).This light orange solution is heated 10 hours in 50 DEG C, is concentrated in vacuo after cooling and draws pale solid.Flash chromatography separation draws the light oily amino esters 231 of 20mg (82%) on silica gel (50%MeOH/EtOAc).Embodiment 97
Amino acid 232：Methyl esters 231 (20mg, 0.068mmol) THF (1.0mL) solution is handled with the KOH aqueous solution (131 μ L, 1.039N).This reactant mixture is stirred 2.5 hours at room temperature, then with Amberlite IR-120 (H+) acidic resins are acidified to pH5.0.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws pale solid shape amino acid, and it is used
C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 8.6mg (45%) amino acid 232.1H NMR(D2O, 300MHz)：6.47 (bs, 1H)；4.42 (bd, 1H, J=8.1Hz)；3.97 (dd, 1H, J=8.4,11.4Hz)；3.65-3.54 (m, 1H)；2.88 (dd, 1H, J=5.5,17.3Hz)；2.51-2.39 (m, 1H)；2.08 (s, 3H)；1.61-1.46 (m, 2H)；1.23 (s, 3H)；1.18 (s, 3H)；0.86 (t, 3H, J=7.5Hz).Embodiment 98
N-propyl thioether ester 233：In argon gas and at room temperature, by BF in stirring3·Et2O (130 μ L, 1.06mmol) is added in 1- propanethiols (8.0mL) solution of N- trityls aziridine 183 (300mg, 0.68mmol).This light coloured solution is heated 45 minutes in 65 DEG C, distributed after concentration in ethyl acetate and salt solution.Organic layer is separated, with saturated sodium bicarbonate, salt water washing dries (MgSO4) be concentrated in vacuo afterwards.Residue draws the light oily n-propyl thioether esters 233 of 134mg (73%) in flash chromatography separation on silica gel (30% hexane/ethyl acetate).1H NMR(CDCl3, 300MHz)：6.87 (t, 1H, J=2.4Hz).3.77 (s, 3H)；3.48-3.38 (m, 1H)；3.22-3.18 (m, 1H)；2.93 (dd, 1H, J=5.4,17.4Hz)；(2.80 t, 1H, J=9.9Hz)；2.51 (t, 2H, J=7.2Hz)；2.32-2.20 (m, 1H)；1.96 (bs, 2H ,-NH2)；1.69-1.56 (m, 2H)；(2.00 t, 3H, J=7.2Hz).Embodiment 99
N-propyl thioether nitrine base ester 234：In pyridine (1.5mL) solution for the amine 233 (134mg, 0.50mmol) that pure chloroacetic chloride (60 μ L, 0.84mmol) is added into 0 DEG C.Reactant mixture after one hour of the stirring, is warmed to room temperature and is stirred for 15 minutes.Distributed after reactant mixture concentration in ethyl acetate and salt solution, sequentially with dilute HCl, water, saturated sodium bicarbonate, salt water washing dries (MgSO4) be concentrated in vacuo afterwards.The separation of residue silica gel (30% hexane/ethyl acetate) flash chromatography draws 162mg (100%) pale-yellow solid n-propyl thioether nitrine base ester 234.1H NMR(CDCl3, 300MHz)：6.90 (t, 1H, J=2.7Hz)；(5.87 bd, 1H, J=7.8Hz)；4.07-3.98 (m, 1H)；3.77 (s, 3H)；3.65-
3.55 (m, 1H)；2.95-2.85 (m, 1H)；2.60-2.45 (m, 2H)；2.30-2.18 (m, 1H)；2.08 (s, 3H)；1.65-1.53 (m, 2H)；0.98 (t, 3H, J=7.2Hz).Embodiment 100
N-propyl thioamido ester 235：By azide 234 (130mg, 0.416mmol) ethyl acetate (10mL) solution at room temperature with Lindlar catalyst (150mg) hydrogenation (1atm) 18 hours.Then catalyst is filtered out with Celite pad, after being washed with hot ethyl acetate and methanol, be concentrated in vacuo, orange residue draws 62mg (53%) n-propyl thioamido ester 235 through flash chromatography separation.1H NMR(CDCl3, 300MHz)：6.88 (t, 1H, J=2.7Hz)；5.67 (bd, 1H, J=8.7Hz)；3.76 (s, 3H)；3.75-3.65 (m, 1H)；3.45-3.35 (bm, 1H)；3.05-2.95 (m, 1H)；2.87-2.78 (m, 1H)；2.56-2.40 (m, 2H)；2.18-2.05 (m, 1H)；2.09 (s, 3H)；1.65-1.50 (m, 2H)；1.53 (bs, 2H ,-NH2)；0.98 (t, 3H, J=7.2Hz).Embodiment 101
Compound 240：By cinchoninic acid (103g), 2,2-dimethoxypropane (200mL) is stirred 4 days at room temperature with suspension of the toluenesulfonic acid (850mg) in acetone (700mL).Removal of solvent under reduced pressure and excess reagent.Flash column chromatography (hexane/EtOAc=2/1-1.5/1) purifying draws lactone 240 (84g, 73%)：1H NMR(CDCl3)：4.72 (dd, J=2.4,6.1Hz, 1H), 4.50 (m, 1H), 4.31 (m, 1H), 2.67 (m, 2H), 2.4-2.2 (m, 3H)；2.52 (s, 3H), 1.33 (s, 3H).If by reaction backflow 4 hours, water process purifying (distribution is in ethyl acetate/water) made crude product recrystallize out lactone 240 (yield 71%) from ethyl acetate/hexane.Embodiment 102
Compound 241：In methanol (1200mL) solution that sodium methoxide (4.37M, 46.5mL, 203mmol) is once added to lactone 240 (43.5g, 203mmol).This mixture is stirred 3 hours at room temperature, is interrupted and reacted with acetic acid (11.62mL).Methanol is removed under reduced pressure.
Mixture is diluted with water, and is extracted three times with EtOAc.Merge organic phase, once, salt solution dries (MgSO after washed once for washing4).Flash column chromatography (hexane/EtOAc=1/1 to 1/4) purifying draws glycol (43.4g, 87%)：1H NMR(CDCl3) 4.48 (m, 1H), 4.13 (m, 1H), 3.99 (t, J=6.4Hz, 1H)；3.82 (s, 3H), 3.34 (s, 1H), 2.26 (d, J=3.8Hz, 2H), 2.08 (m, 1H), 1.91 (m, 1H), 1.54 (s, 3H), 1.38 (s, 3H).If in addition, lactone 240 is handled in ethanol with catalytic amount caustic alcohol (1mol%), crude product draws correspondence ethyl ester (67%) after ethyl acetate/hexane recrystallization.Residue derived from mother liquor (being made up of starting material with product) is handled again with same reaction conditions, and additional product is drawn after recrystallization.Gross production rate is 83%.Embodiment 103
Compound 242：In pyridine (230mL) solution that paratoluensulfonyl chloride (27.7g, 145mmol) is added to glycol 241 (29.8g, 121mmol) and 4- (N, N- dimethylamino) pyridines (500mg).This mixture is stirred 3 days at room temperature, pyridine is removed under reduced pressure.Mixture is diluted with water, is extracted three times with EtOAc.Merge organic phase, be washed with water secondary, salt solution washed once, dry (MgSO4) concentrate afterwards.Flash column chromatography (hexane/EtOAc=2/1-1/1) purifying draws p-methyl benzenesulfonic acid ester 242 (44.6g, 92%).1H NMR(CDCl3)：7.84 (d, J=8.4Hz, 2H), 7.33 (d, J=8.1Hz, 2H), 4.76 (m, 1H), 4.42 (m, 1H), 4.05 (dd, J=5.5,7.5Hz, 1H), 3.80 (s, 3H), 2.44 (s, 3H), 2.35 (m, 1H), 2.24 (m, 2H), 1.96 (m, 1H), 1.26 (s, 3H), 1.14 (s, 3H).The corresponding ethyl ester of compound 241 is in 0 DEG C in CH2Cl2Middle use mesyl chloride is handled with triethylamine, and mesylate derivatives (quantitative yield) are drawn after water process.This methanesulfonates need not be further purified and just can be used directly.Embodiment 104
Compound 243：Toward the CH of p-methyl benzenesulfonic acid ester 242 (44.6g, 111.5mmol)2Cl2(450mL) solution adds pyridine (89mL) at -78 DEG C, is then slowly added SO2Cl2(26.7mL, 335mmol).By this mixture after -78 DEG C are stirred 5 hours, it is stirred for 12 hours after methanol (45mL), warm mixture to room temperature is added dropwise.Add after ether, use
Water washing mixture three times, salt solution washed once, and dry (MgSO4) concentrate afterwards, draw oily intermediate (44.8g).In MeOH (500mL) solution that TsOH (1.06g, 5.6mmol) is added to this intermediate (44.8g, 111.5mmol), flow back 4 hours.Reactant mixture is cooled to after room temperature, and methanol is removed under reduced pressure.The fresh methanol (500mL) of addition, this mixture is flowed back 4 hours again, is cooled to after room temperature, methanol is removed under reduced pressure.Flash column chromatography (hexane/EtOAc=3/1-1/3) draws the mixture (26.8g) of two isomers after purification.Pure expection product 243 (20.5g, 54%) is drawn from EtOAc/ hexanes recrystallization：1H NMR(CDCl3)：7.82 (d, J=8.3Hz, 2H), 7.37 (d, J=8.3Hz, 2H), 6.84 (m, 1H), 4.82 (dd, J=5.8,7.4Hz, 1H), 4.50 (m, 1H), 3.90 (dd, J=4.4,8.2Hz, 1H), 3.74 (s, 3H), 2.79 (dd, J=5.5,18.2Hz, 1H), 2.42 (dd, J=6.6,18.2Hz, 1H).
Corresponding methanesulfonates-ethyl ester derivative of compound 242 is similarly handled as described.Acetonide protecting group is removed with acetic acid treatment in refluxing ethanol, glycol (39% yield) can be drawn from this crude reaction mixture ether Direct precipitation.Embodiment 105
Compound 1：In THF (300mL) solution for the glycol 243 (20.0g, 58.5mmol) that DBU (8.75mL, 58.5mmol) is added to 0 DEG C.This reactant mixture is warmed to room temperature and stirred 12 hours.Removal of solvent under reduced pressure (THF).Flash column chromatography (hexane/EtOAc=1/3) purifying draws epoxides 1 (9.72g, 100%)：1H NMR(CDCl3)：6.72 (m, 1H), 4.56 (td, J=2.6,10.7Hz, 1H), 3.76 (s, 3H), 3.56 (m, 2H), 3.0 (d, J=21Hz, 1H), 2.50 (d, J=20Hz, 1H), 2.11 (d, 10.9Hz, 1H).
Handle the corresponding methanesulfonates of compound 243 in the same manner as described.Ethyl ester derivative, epoxides is drawn with almost quantitative yield.Embodiment 106
Aziridine 244：Absolute ethyl alcohol (8.0mL) solution of allyl ether 4 (223mg, 1.07mmol) and Lindlar catalyst (200mg) is handled 50 minutes with hydrogen (1atm) at room temperature.Then catalyst is filtered out with Celite pad, is washed with hot methanol.Vacuum concentration is drawn
About 230mg pale yellowish oil 244, it, which need not be further purified, just can be used in next reaction.Embodiment 107
Azido amine 205：By rough aziridine 244 (230mg), sodium azide (309mg, 4.75mmol) under argon gas, is heated 16 hours with solution of the ammonium chloride (105mg, 1.96mmol) in dry DMF (10mL) in 70 DEG C.Solid is filtered to remove after cooling with sintered glass funnel, is then distributed in ethyl acetate and salt solution.Organic layer is separated, MgSO is used4Dry.It is concentrated in vacuo, residue is in the isolated 154mg of flash chromatography on silica gel (10% hexane/ethyl acetate) (57%, 2 steps) 205, and it is yellow thick oil, and its purity is enough to be used directly in next reaction.Embodiment 108
N- acetyl group azide 245：Chloroacetic chloride (70 μ L, 0.98mmol) is added into 0 DEG C of amine 205 (154mg, 0.61mmol) and the CH of pyridine (1.3mL)2Cl2In (4.0mL) solution.At 0 DEG C after 1.5 hours, concentrated reaction mixture is simultaneously distributed in ethyl acetate and salt solution.Organic layer is separated, sequentially with saturated sodium bicarbonate, salt water washing uses MgSO4It is concentrated in vacuo after drying, residue is in the isolated 167mg of flash chromatography (93%) light yellow solid 245 on silica gel (ethyl acetate).Embodiment 109
Amino ester 200：Triphenyl phasphine (1.7g, 6.48mmol) fraction is added in 245 (1.78g, 6.01mmol) THF (40mL) and the solution of water (1.5mL), reactant mixture stirred at room temperature 42.5 hours.Volatile matter is removed in vacuum, by crude solid absorption on silica gel, 1.24g (77%) pale solid 200 is drawn with purification by flash chromatography on silica gel (100% ethyl acetate, followed by 100% methanol).Embodiment 110
Amino acid/11 02：In THF (4.0mL) solution for the methyl esters 200 (368mg, 1.37mmol) that the NaOH aqueous solution (1.37mL, 1.0N) is added to 0 DEG C, by reactant mixture in 0 DEG C
Stirring 10 minutes, is stirred at room temperature after 1.5 hours, with Amberlite IR-120 (H+) acidic resins are acidified into pH7.0-7.5.Resin is filtered out, is washed with water with methanol.Vacuum concentration draws white solid amino acid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 290mg (83%) amino acid/11 02.Embodiment 111
Amine hydrochlorate 250：Amine 228 (15.6mg, 0.05mmol) is handled and evaporated with 0.1NHCl.Residue is dissolved in water, with a short C18Reverse phase silica gel post is filtered.Freeze-drying obtains solid-like hydrochloride 250 (12mg)：1H NMR(D2O)：6.86 (s, 1H), 4.35 (brd, J=9.0), 4.06 (dd, 1H, J=9.0,11.6), 3.79 (s, 3H), 3.65-352 (m, 2H), 2.97 (dd, 1H, J=5.5,17.2), 2.58-2.47 (m, 1H), 2.08 (s, 3H), 1.61-1.41 (m, 4H), 0.88 (t, 3H, J=7.4), 0.84 (t, 3H, J=7.4).Embodiment 112
Two-Boc- guanidines 251：By HgCl2(125mg, 0.46mmol) adds to 0 DEG C of amine 228 (126mg, 0.42mmol), N, in DMF (4mL) solution of the tertbutyloxycarbonyls of N '-two thiocarbamide (127mg, 0.46mmol) and triethylamine (123 μ L, 0.88mmol).This mixture is stirred 30 minutes at 0 DEG C, stirred 1.5 hours at room temperature.Filtered after being diluted with ethyl acetate through diatomite.Solvent is boiled off, residue distribution is in ethyl acetate and water.Organic phase dries (MgSO after being washed with saturation NaCl4), boil off solvent after filtering.This crude product draws the-Boc guanidines -251 (155mg, 69%) of solid-like two in purifying on silica gel (2/1,1/1 hexane/ethyl acetate).1H NMR(CDCl3)：11.40 (s, 1H), 8.66 (d, 1H, J=7.9), 6.8 (s, 1H), 6.22 (d, 1H, J=8.9), 4.43-4.34 (m, 1H), 4.19-4.08 (m, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.35 (m, 1H), 2.79 (dd, 1H, J=5.4,17.7), 2.47-2.36 (m, 1H), 1.92 (s, 3H), 1.50,1.49 (2s, 18H), 0.89 (m, 6H).Embodiment 113
Guanidino-acid 252：1.039N KOH solutions (337 μ L) and water (674 μ L) are added in THF (3mL) solution of two-Boc guanidines 251 (150mg, 0.28mmol).This mixture is stirred 3 hours, then adds 1.039N KOH solutions (67 μ L) and is stirred for 2 hours.Reactant mixture is filtered to remove a small amount of dark precipitate thing.Filtrate is cooled to 0 DEG C, pH4.5-5.0 is acidified into IR-120 ion exchange resin.Resin is filtered out, is washed with methanol.Filtrate is evaporated, residue is dissolved in CH2Cl2(3mL) and 0 DEG C is cooled to, then it is handled with trifluoroacetic acid (3mL), stirred 10 minutes in 0 DEG C, then at being stirred at room temperature 2.5 hours.Solvent is boiled off, residue is dissolved in water, chromatographic isolation (first with water, then being eluted with 5% acetonitrile/water) is carried out with C-18 reverse phase silica gels short column (3 × 1.5cm).Merge the fraction containing product, evaporation after residue is dissolved in water, is freeze-dried and draws white solid guanidino-acid 252 (97mg, 79%).Embodiment 114
Azido acid 260：The KOH aqueous solution (1.60mL, 1.039N) is added in methyl esters 227 (268mg, 0.83mmol) THF (7.0mL) solution at room temperature.Stir 19 hours at room temperature, with Amberlite IR-120 (H+) acidic resins are acidified to pH4.0, filter out resin, are washed with water with ethanol, vacuum concentration draws the rough azido acid 260 of light orange foam shape, and it, which need not be further purified, is just used in next reaction.Embodiment 115
Azidoethyl ester 261：DCC (172mg, 0.83mmol) is once added into carboxylic acid 260 (the rough thing from previous reaction, it is assumed that be 0.83mmol), ethanol (150 μ L) and catalytic amount DMAP CH at room temperature2Cl2In (6.0mL) solution.There is sediment to be formed after several minutes, be stirred for after 1 hour, filter, use CH2Cl2Washing.Pale solid is drawn after vacuum concentration, 272mg (96%, there is a small amount of DCU impurity) white solid 261 is drawn after being separated with silica gel (50% hexane/ethyl acetate) flash chromatography.When DCC is changed into Diisopropylcarbodiimide, 261 yield is 93%, but there is chromatogram purification when using DCC and remove the urea impurity existed.Embodiment 116
Amino-ethyl ester 262：In THF (17mL)/water (1.6mL) solution that triphenyl phasphine (342mg, 1.30mmol) is once added to 261 (272g, 0.80mmol).Then reactant mixture is heated 10 hours in 50 DEG C, is concentrated in vacuo after cooling and draws shallow white solid.This crude solid draws 242mg (96%) pale solid amino-ethyl ester 262 with silica gel (50% methanol/ethyl acetate) purification by flash chromatography.It is dissolved in 3NHCl, freeze-drying draws corresponding water-soluble HCl salt.1H NMR(D2O, 300MHz)：6.84 (s, 1H)；4.36-4.30 (brM, 1H)；4.24 (q, 2H, J=7.2Hz)；4.05 (dd, 1H, J=9.0,11.7Hz)；3.63-3.50 (m, 2H)；2.95 (dd, 1H, J=5.7,17.1Hz)；2.57-2.45 (m, 1H)；1.60-1.39 (m, 4H)；1.27 (t, 3H, J=7.2Hz)；0.89-0.80 (m, 6H).Embodiment 117
Two-Boc guanidinos esters 263：By Kim and Qian, " Tet Lett ", 34：The step of 7677 (1993), is handled.By HgCl2(69mg, 0.25mmol) once adds to 0 DEG C of amine 262 (72mg, 0.23mmol), two-Boc thiocarbamides (66mg, 0.24mmol) and Et3In N (108 μ L) dry DMF (600 μ L) solution.This heterogeneous reactant mixture is stirred 1 hour in 0 DEG C, then at being stirred at room temperature 15 minutes, is then diluted, is filtered with Celite pad with EtOAc.After vacuum concentration, residue provides 113mg (89%) colourless foam 263 in flash chromatography separation on silica gel (20% hexane/ethyl acetate).1H NMR(CDCl3, 300MHz)：11.41 (s, 1H)；8.65 (d, 1H, J=8.1Hz)；6.83 (s, 1H)；6.22 (d, 1H, J=9.0Hz)；4.46-4.34 (m, 1H)；4.21 (q, 2H, J=6.9Hz)；4.22-4.10 (m, 1H)：4.04-4.00 (m, 1H)；(3.36 quintet, 1H, J=5.7Hz)；2.78 (dd, 1H, J=5.4,17.7Hz)；2.46-2.35 (m, 1H)；1.94 (s, 3H)；1.60-1.40 (m, 4H)；1.49 (s, 9H)；1.50 (s, 9H)；1.30 (t, 3H, J=6.9Hz)；0.93-0.84 (m, 6H).Embodiment 118
Guanidino ester 264：The CH of two-Boc guanidinos esters 263 (113mg, 0.20mmol)2Cl2(5.0mL) solution is cooled to after 0 DEG C, pure trifluoroacetic acid (5.0mL) is added, by this
Reactant mixture is stirred 30 minutes in 0 DEG C, is stirred at room temperature 1.5 hours.Vacuum concentration draws light orange solid, uses C18Reverse-phase chromatography (being eluted with water) is purified, and collects the fraction containing expected product, and freeze-drying draws 63mg (66%) white solid guanidino ester 264.1H NMR(D2O, 300MHz)：6.82 (s, 1H)；4.35-4.31 (m, 1H)；4.24 (q, 2H, J=7.1Hz)；3.95-3.87 (m, 1H)；3.85-3.76 (m, 1H)；3.57-3.49 (m, 1H)；2.87 (dd, 1H, J=5.1,17.7Hz)；2.46-2.34 (m, 1H)；2.20 (s, 3H)；1.60-1.38 (m, 4H)；1.28 (t, 3H, J=7.1Hz)；0.90-0.80 (m, 6H).Embodiment 119
Enzyme inhibition：Using above-mentioned external activity screening method, measure it is following activity (+10-100 μm, ++ 1-10 μm, +++ 1.0 μm of ＜).
Embodiment 120
| Compound | IC50 |
| 102/103(2∶1) | +++ |
| 8 | ++ |
| A.17.a.4.i | ++ |
| 114 | ++ |
| A.1.a.4.i | ++ |
| 79 | + |
| 82/75(1.2∶1) | + |
| 94 | +++ |
| A.100.a.11.i | +++ |
| A.101.a.11.i | +++ |
| A.113.a.4.i | +++ |
Respectively by compound A.113.b.4.i with A.113.x.4.i being cultivated in enzyme analysis buffer and determining activity as described in embodiment 119.The activity of the two 100 μm of ＞.Before such as embodiment 119 is tested, each compound is respectively placed in rat plasma and cultivated, and the activity of the two is A.113.a.4.i similar with compound.
Embodiment 121
Utah State University antiviral study Dr.Robert Sidwell supervision under studied, with comparative compound 203 (embodiment 69), GG167 emits A activity with ribavirin influenza of (i.p. or p.o. route of administration) in Mice Body.GG167 and the compound that ribavirin is that known influenza emits virus.
Mouse：Male 13-15g derives from SimonsenLaboratories (Gilroy, CA) without specified pathogen BALB/c mouse.Quarantined using first 24 hours, be placed in Wayne Lab Blox and originally water environment.Once contain 0.006% terramycin (Pfizer, NewYork, NY) in infection, drinking water to control possible secondary bacterial infections.
Virus：Influenza virus A/NWS/33 (H1N1) derives from K.W.Cochran, University of Michigan (Ann Arbor, MI).Allow Madin Darby dogs nephrocyte (mdck cell) fusion individual layer infection after, in 37 DEG C in 5%CO2Middle culture, after 3 to 5 days when viral cytopathic effect reaches 90-100%, collects cell and virus base is made.By its envelope bottle and -80 DEG C are stored in, until when using.
Compound：Compound 203 and GG167 is dissolved in sterile saline to be studied.Arterial oxygen saturation (SaO2) determine：SaO is determined with the pulsed oximeters (Ohmeda, Lonisville, OH) of Ohmeda Biox 37402.Using aural sound, the probe is placed at animal thigh, and selection is determined at a slow speed.Every animal read reading after 30 second stationary phase.Influence of the influenza virus to artery saturation degree is determined with this instrument by Sidwell et al., anti-microbial agents and chemotherapy, 36：473-476 (1992) explanation.
The experimental design orally studied：11 mouse turn into one group, make the virus of the lethal dose of its intranasal infection about 95%, and receive the test compound of various dosage.203 and GG167 agent
Measure as 50,10,2 and 0.5mg/kg/ days.I.p treatments (two times/day) totally 5 days are carried out after virus infects in advance within 4 hours.Taken at the 3rd day to the 10th day 8 it is infected and so that the mouse of each dosage treatment and 16 be infected and control group with brine treatment, analyze its SaO2Value, records the death toll of these animals totally 21 days daily.Remaining 3 animals and 6 control groups with brine treatment were killed at the 6th day in every group, were taken out lung, were weighed, with the given fraction of the degree of lung darkviolet (0=is normal, and 4=100% lungs are impacted).Because 203 dosage does not find toxicity when being 300mg/kg/ days, and reported in literature shows that GG167 does not also have toxicity, so no in research carry out toxicity control.The experimental design of Intraperitoneal medication research：11 mouse are one group, make the virus of the lethal dose of its intranasal infection about 95%, and are 250,50 with dosage or ribavirin treatment that the 203 or GG167 or dosage of 10mg/kg/ days is 100,32 or 10mg/kg/ days.Oral gavage (p.o.) treatment (two times/day) totally 5 days is carried out after virus infects in advance within 4 hours.8 animals recorded death toll daily by indwelling 21 days in each group, and SaO was determined at the 3rd day to the 10th day2Value.The mouse of remaining 3 infection was killed at the 6th day in every group, takes out lung, weighs, with the given fraction of the degree of dark purple (plum) color of lung (0=is normal, and 4=100% lungs are impacted).15 infected mouse only use brine treatment, and indwelling 21 days simultaneously as above determines SaO2, take 6 mouse infected and with brine treatment again in addition, progress lung analysis killed at the 6th day.3 Normal group indwellings 21 days, with above-mentioned carry out SaO2Determine, separately take 3 intact animals, killed in the 6th day, lung is weighed and scored.
The experimental design of low dose oral research：8 mouse are one group, the virus of the lethal dose of its intranasal infection about 90%, and receive the test compound of various dosage.The dosage of each compound is 10,1 and 0.1mg/kg/ days.(two times/day) of p.o. treatments totally 5 days are carried out after virus infects in advance within 4 hours.At the 3-11 days, 8 infected and the mouse with each dosage treatment and 16 control groups infected and with brine treatment are taken, its SaO is analyzed2Value, records the death toll of these animals totally 21 days daily.
Statistical estimation：The increase for assessing survival number is corrected with least-square analysis and Yates.With the increase of t- check analyses mean survival time and SaO2Difference, lung weight and Pneumovirinae titer.Lung score difference analyzes (ranked sum analysis) to assess with total number of grades.In all examples, research drug therapy and the difference of brine treatment control group.
I.p. the result of experiment is administered to be summarized in Table I and Fig. 1 and 2.In this model, two compounds are significantly inhibited in high dose, and 203 also had notable survival in dosage for the treatment of 10mg/kg/ days.Two compounds significantly inhibited SaO in 50mg/kg/ days dosage2Reduction, and GG167 even 2mg/kg/ days, can also suppress above-mentioned reduction in 10mg/kg/ days dosage.Lung fractional data shows identical trend, and wherein GG167 is effective in multiple dosage.In lung weight it can be seen that some come and go, from receive maximum dose level GG167 mouse take out lung compared with brine treatment control group have higher average weight.
The result of p.o administration experiments is summarized in Table II, daily SaO2Value is then shown in Fig. 3-5.In this model, the oral medication popularity common cold virus of three kinds of medicines can prevent death, reduction lung fraction and the lung weight related to infection infected with significantly inhibiting, and can suppress SaO2Reduction.
P.o. low dosage result of study is summarized in Table III and Fig. 6-8.In this experiment, infection to have in 16 brine treatment animals mean survival time in 14 death, this group to be 9.6 days.Three kinds of compounds on viral infection are respectively provided with the depression effect of some degree, and 262 (Ethyl ester prodrugs) are most effective in each dosage, and this can prevent SaO by survival number, mean survival time2Reduction is verified.
Table III shows the average SaO of all analysis times2%.Every earning in a day of each compound is illustrated in Fig. 6 to 8.Fig. 6 represents the SaO of each compound maximum concentration2Data；Fig. 7 represents numerical value during each compound median dose, and Fig. 8 then compares SaO during each compound low dosage2Value.
Table III represents to induce experiment when three compounds are oral influenza A (H1N1) viruses infected with active function with Fig. 6-8, most effective with 262.It not can determine that whether 262 improvement anti-virus ability is not accompanied by higher animal toxicity, but because speculating that its more efficient power is the result because higher oral bio availability, high animal toxicity would be impossible to occur.
Table I .203 and GG167 i.paThe effect for delivering medicine to the mouse of influenza A (H1N1) virus infection compares
Infection, the average SaO of therapeutic compounds dosage survival number Average Survival2 cAverage lung parameterd
Mg/kg/ days/the sum timeb(my god) % fractions weight (mg) 203 50 8/8**＞ 21.0** 87.2** 0.7* 173*
10 3/8* 10.8 84.7 2.5 217
2 0/7 12.6 84.4 2.0 203
0.5 0/8 11.1 85.2* 2.0 230GG167 50 8/8**＞ 21.0** 87.6** 0.7* 230
10 7/8* 15.0 87.5** 1.7 170*
2 1/8 12.6 86.0** 1.3 213
0.5 0/8 12.3 84.5 2.3 227 salt solution -0,/16 11.0 82.9 2.0 220 Table II .203, GG167 is administered orally with ribavirinaThe effect to mouse influenza A (H1N1) virus infection compares afterwards
Infection, the average SaO of therapeutic compounds dosage survival number Average Survival2 cAverage lung parameterd
Mg/kg/ days/the sum timeb(my god) % fractions weight (mg) 203 250 8/8**＞ 21.0** 87.9* 0.8** 160**
50 8/8**＞ 21.0** 87.9* 1.3* 200
10 4/8* 12.8* 87.7* 1.3* 240GG167 250 8/8**＞ 21.0** 88.6* 0.3** 163**
50 8/8**＞ 21.0** 88.0* 1.5* 187*
10 5/7* 10.5 85.2 1.5*250 triazoles 100 8/8**＞ 21.0** 88.2* 0.3** 140**Nucleosides 32 6/8* 13.0 88.0* 0.8** 163**
10 3/8 11.0 86.4 2.2 267 salt solution -1,/16 10.9 84.5 2.4 203
Table III .260,262 are administered orally with GG167aAfterwards to the average SaO of effect comparative compound dosage survival number % Average Survivals of mouse influenza A (H1N1) virus infection2 c
Mg/kg/ days/sum survivor's timeb(my god) %260 10 6/8** 75** 13.5** 87.6**
1 3/5 38 11.8 86.8
0.1 0/8 0 10.0 84.3262 10 8/8*** 100***＞ 21.0** 88.1**
1 7/8*** 88*** 14.0** 87.4*
0.1 2/8 25 11.1** 85.7GG167 10 5/8* 63* 12.3** 86.9
1 2/8 25 11.7** 85.7
Table I-the III of 0.1 0/8 0 9.8 83.5 salt solution -2,/16 13 9.6 83.8 virus of footnote a 4 hours carried out after infecting in advance 5 days b at the 21st day or before the average value d that determines for the 3-10 days of dead animal c in the 6th day measure relative to brine treatment control group*P ＜ 0.05,**P ＜ 0.01,***P ＜ 0.001
Unexpectedly, it is shown above in this model, it is effective to reducing the death rate of influenza infection mouse when practical therapeutic dose that oral or i.p. gives GG167, although this conclusion (anti-microbial agents and the chemotherapy, 38 (10) of point with Ryan et al.：2270-2275) [1994] are different, Ryan thinks " GG167 Intraperitoneal medications are in the relatively low activity in vivo in mouse; although there is good biological availability; be due to that it is rapidly eliminated from blood plasma; so not easily penetrate into respiratory secretions, along with can not penetrate into resting on cell interior ... ... similarly, oral poorly efficient power is probably due to; in addition to above-mentioned other factors, low oral bio availability " (p.2274).These observations and Von Izstein et al. WO91/16320, WO92/06691 and United States Patent (USP) 5360817 (it covers or be related to specific GG167 researchs) one
Cause.These patent documents give GG167 in the way of not instructing or advise beyond intranasal.But, intranasal administration is not only inconvenient but also not cheap in some cases.If have more feasible path give GG167 and its related compound (such as WO91/16320, WO92/06691 with shown in United States Patent (USP) 5360817) will be highly beneficial.
So one embodiment of this invention is related to a kind of method for treating or preventing host's influenza virus infection, including the path via non local medication to respiratory system, the formula (X) of the data sender effective dose or the antiviral activity compound of (Y) are given
A is oxygen, carbon or sulphur wherein in formula (x), and A is nitrogen or carbon in formula (y)；R1For COOH, P (O) (OH)2, NO2, SOOH, SO3H, tetrazolium, CH2CHO, CHO or CH (CHO)2, R2For H, OR6, F, Cl, Br, CN, NHR6, SR6, or CH2X, wherein X are NHR6, halogen or OR6, and R6For hydrogen；C1-C4Acyl group；Line style or ring-type C1-C6Alkyl or its congener replaced through halogen；Pi-allyl；The aryl being unsubstituted or the aryl replaced through following groups：Halogen, OH groups, NO2Group, NH2Group or COOH group；R3With R3' identical or different and independently be hydrogen, CN, NHR6, N3, SR6,=N-OR6, OR6, guanidine radicals,R4For NHR6, SR6, OR6, COOR6, NO2, C (R6)3, CH2COOR6, CH2NO2Or CH2NHR6, and R5For CH2YR6, CHYR6CH2YR6Or CHYR6CHYR6CH2YR6, wherein Y be O, S, NH or
H, and R5Each Y is partly identical or inequality in group, and its pharmaceutically acceptable salt or derivative, and condition is that (i) works as R in formula (x)3Or R3' it is OR6Or hydrogen, and A be oxygen or sulphur when, the compound can not have simultaneously (a) be hydrogen R2It is the R of NH- acyl group (b)4, and (ii) is when Y is hydrogen, R6For covalent bond, and (i) works as R in formula (y)3Or R3' it is CR6Or hydrogen, and A be nitrogen when, the compound can not have simultaneously (a) be hydrogen R2It is the R of NH- acyl group (b)4, and (ii) is when Y is hydrogen, R6For covalent bond.
Formula (x) is with (y) compound in WO91/16320 the 23rd rows of page 3 to the 1st row of page 7, WO92/06691 in United States Patent (USP) 5360819 with being described in more detail, in the publication, (x) is denoted as I and Ia with (y).
For up to this paper purposes, the path via " non local to be administered to respiratory tract " is not precluded from buccal or sublingual administration, and be not excluded for oral, sporadic oesophagus absorbs during buccal or sublingual administration, as long as the folder, mouthful, sublingual or oesophagus, which absorbs, to be not intended to pulmonary administration or the similar situation such as sucks by nasal cavity.
Generally, compound is with article shaped, and slurry or solution are administered.
In typical embodiments of the present invention, compound is GG167, and host is the animal (such as ferret or people) of non-muroid, and administration routes are oral, and the purpose for the treatment of and prevention is the reduction death rate.The prodrug of formula (X) or (Y) compound can be arbitrarily used, but as shown in above, and be not required to so make to reach oral antiviral effect.It is used as the prodrug of GG167 disclosed compounds associated therewith, the ester of any the compounds of this invention herein, acid amides or other prodrugs can be used in combination with the analog (e.g., carboxyl ester or acid amides) of formula (X) or (Y) compound.
When GG167 compounds associated therewith are with oral or during through other non-nose route of administration, its treatment effective dose can be determined by general doctor according to the medication instruction of the compounds of this invention.It is topmost to be thought of as administration routes and host type.Generally, it is intravenous to oral Titration, can subcutaneously being applied if medication to larger animal according to conventional pharmacology scale up principle.The general technology for being defined as this field of therapeutic activity dosage, but generally this dosage is roughly the same with used in the compounds of this invention.Embodiment 122
Each reaction is carried out by reaction scheme 50 shown in table 50, and the reaction carried out is represented with " ".Unless otherwise indicated in table 50, step AA, AB and AC are carried out by embodiment 92,93 and 94 respectively, and step AD is combined and carried out with 113 by embodiment 112.
Reaction scheme 50
Table 50
The (Continued) of table 50
The (Continued) of table 50
Table 50 (note) a) azide reduction before ester hydrolysis b) Ph3P carries out azide reduction and c) carries out the Ph that ester hydrolysis d) is carried with polymer with the KOH aqueous solution/MeOH at room temperature3P carries out azide reduction and e) is separated into HCl salt f) Ph at room temperature3P MeOH/THF/H2O carries out azide reduction g) non-enantiomer mixture, and Major Diastereomer, which is indicated, h) uses Me3P carries out azide reduction and i) isolates C- alkylates in 55 DEG C of open loop j) for carrying out aziridine
K) alcohol l) diastereomeric mixtures are not evaporated before acylated, embodiment 123 is separated by chromatogram/recrystallization
Trifluoroacetamide 340：Pyridine (4 μ L, 0.51mmol) and TFAA (TFAA) (52 μ L, 0.37mmol) are added to the CH of 0 DEG C of amine 228 (100mg, 34mmol)2Cl2In (3.5mL) solution, it is stirred for 45 minutes, adds extra TFAA (0.5 equivalent) again therebetween.After 15 minutes, it is evaporated under reduced pressure, residue distribution is in ethyl acetate and 1MHCl.Organic phase saturation NaHCO3, saturation NaCl washings, dry (MgSO4) evaporate after filtering.Residue draws trifluoroacetamide 340 (105mg, 78%) in chromatographic isolation on silica gel (2/1- hexane/ethyl acetates)：1HNMR(CDCl3)：8.64 (d, 1H, J=7.7), 6.81 (s, 1H), 6.48 (d, 1H, J=8.2), 4.25-4.07 (m, 3H), 3.75 (s, 3H), 3.37 (m, 1H), 2.76 (dd, 1H, J=4.5,18.7), 2.54 (m, 1H), 1.93 (s, 3H)
1.48 (m, 4H), 0.86 (m, 6H).Embodiment 124
N- methyl trifluoros acetamide 341：In DMF (2mL) solution for the trifluoroacetamide 340 (90mg, 0.23mmol) that sodium hydride (10mg, 60% dispersion oil, 0.25mmol) is added to 0 DEG C.Methyl iodide (71 μ L, 1.15mmol) is added after 0-15 minutes, it is stirred 2 hours in 0 DEG C, stirred 1 hour at room temperature.Acetic acid (28 μ L) is added, solution is evaporated.By residue distribution in ethyl acetate and water.Organic phase is washed with saturation NaCl, dries (MgSO4) evaporate after filtering.Residue draws colourless glass N- methyl trifluoros acetamide 341 (81mg, 87%) in chromatographic isolation on silica gel (1/1- hexane/ethyl acetates)：1H NMR(CDCl3)：6.80 (s, 1H), 6.26 (d, 1H, J=9.9), 4.67 (m, 1H), 4.32 (m, 1H), 4.11 (m, 1H), 3.78 (s, 3H), 3.32 (m, 1H), 3.07 (br s, 3H), 2.60 (m, 2H), 1.91 (s, 3H), 1.48 (m, 4H), 0.87 (m, 6H).Embodiment 125
N- methyl amines 342：By 1.04N KOH (48 μ L, 0.50mmol) add to (81mg of N- methyl trifluoros acetamide 341, in THF (3mL) solution 0.20mmol), this mixture is stirred 14 hours at room temperature, it is about 4 to be acidified to pH with IR-120 ion exchange resin.Resin is filtered out, is washed with THF, filtrate is evaporated.Evaporation, residue is eluted with water by C-18 reverse phase silica gels post (1.5 × 2.5cm) after residue is dissolved in 10%TFA/ water (5mL).Product fraction is collected, freeze-drying draws white solid N- methyl amines 342 (46mg, 56%)：1H NMR(D2O)：6.80 (s, 1H), 4.31 (br d, 1H, J=8.8), 4.09 (dd, 1H, J=8.9,11.6), 3.53 (m, 2H), 2.98 (dd, 1H, J=5.4,16.9), 2.73 (s, 3H), 2.52-2.41 (m, 1H), 2.07 (s, 3H), 1.61-1.39 (m, 4H), 0.84 (m, 6H).Embodiment 126
Compound 346：Toward the 8/1-MeOH/H of epoxides 345 (13.32g, 58.4mmol)2Sodium azide (19.0g, 292.0mmol) and ammonium chloride are added in O (440mL, v/v) solution
(2.69g, 129.3mmol), this mixture is flowed back 15 hours.It is concentrated under reduced pressure after cooling, distribution is in EtOAc and water.Organic layer sequentially uses saturated bicarbonate, salt water washing.Dry (MgSO4) be concentrated in vacuo afterwards.Flash chromatography separation draws 11.81g (75%) toughening oil azido alcohol 346 on silica gel (30% EtOAc/ hexanes).1H NMR (300MHz, CDCl3)：δ 6.90-6.86 (m, 1H)；4.80 (s, 2H)；4.32 (bt, 1H, J=4.2Hz)；4.22 (q, 2H, J=7.2Hz)；(3.90-3.74 overlapping m, 2H)；3.44 (s, 3H)；2.90 (d, 1H：J=6.9Hz)；2.94-2.82 (m, 1H)；2.35-2.21 (m, 1H)；1.30 (t, 3H, J=7.2Hz).Embodiment 127
Compound 347：Through syringe toward DIBAL (5.1ml, 1.0M toluene solution) is added dropwise in solution of the ethyl ester 346 (420mg, 1.55mmol) in anhydrous THF (8.0ml) (being cooled to -78 DEG C).Glassy yellow reactant mixture is stirred 1.25 hours at -78 DEG C, is then slowly added into MeOH (1.2ml) and is slowly hydrolyzed.Volatile matter is removed under reduced pressure and by residue distribution between EtOAc and cold dilute HCl.Separate organic layer and be stripped water layer with EtOAc.Merge organic layer and use saturated bicarbonate, salt water washing successively, use MgSO4Dry.It is concentrated in vacuo, then separates (20% hexane/EtOAc) in Flash chromatography on silica gel, obtain 127mg (36%) glycol 347, it is colorless viscous oil.1H NMR (300MHz, CDCl3)：δ 5.83-5.82 (m, 1H)；4.78 (s, 2H)；4.21 (bt, 1H, J=4.4Hz)；4.06 (bs, 2H)；(3.85-3.65 overlapping M, 2H)：3.43 (s, 3H)；3.18 (d, 1H, J=8.1Hz)；2.51 (dd, 1H, J=5.5,17.7Hz)；2.07-1.90 (m, 1H)；1.92 (bs, 1H).Embodiment 128
Methyl ester 600：From D- (-)-cinchoninic acid with Frost, J.W. et al., " Journal of Organic Chemistry " is made the step of 61,3897 (1996), gross production rate is 51%.Embodiment 129
Ketone 601：Toward (the 15.0g of glycol 600,46.9mmol), pyridine (13.7ml), dichloromethane (200mL) slurry of diatomite (volume is equal to PCC) is added portionwise in PCC (40.5g, 187.9mmol) and reactant mixture is stirred at room temperature 21 hours.Add 2- propyl alcohol
Destroy excessive PCC.It is further stirred for after 30 minutes using ether diluted reaction mixture, filtration over celite pad is simultaneously washed with ethyl acetate.Then organic layer is washed by short column of silica gel and with ethyl acetate.Yellow solid is concentrated under reduced pressure to give, 10.9g (74%) ketone 601, crystalline powder are recrystallized to give with methanol/ethyl acetate/hexane.HRMS(FAB)：C14H22O8(MLi+) calculated value：325.11474, measured value：325.1471.Embodiment 130
Alkene 602：N-BuLi (26.0mL1.61M hexane solutions) is added dropwise into slurry (being cooled to 0 DEG C) of the butyl triphenyl phosphonium bromide (16.6g, 41.6mmol) in anhydrous THF (150mL).Mixture is warmed to room temperature after being stirred 20 minutes at 0 DEG C, stirring 5 minutes is simultaneously cooled to 0 DEG C.The solution of 601 solution (6.0g, 18.9mmol) in anhydrous THF is added into the bright orange solution through sleeve pipe.Reactant mixture is warmed to room temperature, stirring 10 minutes, then gentle reflux 2.5 hours.Reactant mixture is cooled down, saturated sodium bicarbonate is added and is diluted with ethyl acetate.Organic layer is separated, is dried with salt water washing and with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography separation (30% hexane/ethyl acetate) is then carried out on silica gel, obtains the sticky light color oil of 5.5g (81%), it is made up of 4: 1 mixtures of olefin isomer.Embodiment 131
Triethylsilyl ether 603：To 602 (5.5g, 15.37mmol) being cooled in 0 DEG C of solution in dichloromethane (125ml) adds 2,6- lutidines (3.6ml), is then added dropwise trifluoromethanesulfonic acid triethylsilyl ester (5.35ml, 23.66mmol).Reactant mixture is slowly warmed to room temperature and stirred 15 hours.Fugitive constituent is removed under reduced pressure and crude residue is allocated between ether and water.Organic layer watery hydrochloric acid, saturated sodium bicarbonate, salt water washing is simultaneously dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography separation (20% ethyl acetate/hexane) is then carried out on silica gel, the 603 of 6.78g (93%) is obtained, is flowable liquid.Embodiment 132
Butylcyclohexyl acetate 604：To alkene 603 (6.78g, 14.34mmol) ethanol (140ml)
10%Pd/C (5.0g) is added in de gassed solution.Then reactant mixture is stirred at room temperature 22 hours under hydrogen (1 atmospheric pressure, via a balloon).Washed by reactant mixture filtration over celite pad and with the methanol of heat.It is concentrated under reduced pressure, flash column chromatography (10% ethyl acetate/hexane) is then carried out on silica gel, 5.44g (80%) 604 is obtained, is colourless shape grease.Embodiment 133
Alcohol 605：Tributyl ammonium fluoride (17.1ml, 1.0MTHF solution) is added dropwise in 604 (5.44g, 11.46mmol) THF (50ml) solution at room temperature.After 45 minutes, most of THF is removed under reduced pressure and by crude reaction product distribution between ether and water.With saturated ammonium chloride, water, salt water washing organic layer is dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (20% ethyl acetate/hexane) is then carried out on silica gel, 3.18g (77%) 605 is obtained, is colorless viscous grease.Embodiment 134
Alkene 606：Sulfonic acid chloride (1.07ml, 13.32mmol) is added dropwise through syringe into alcohol 605 (3.18g, 8.82ml) pyridine (39ml) and dichloromethane (35ml) solution (being cooled to -78 DEG C).Then reactant mixture is slowly warmed to -40 DEG C through 30 minutes, and maintains -40 DEG C to -30 DEG C 30 minutes.Reactant mixture is cooled to -78 DEG C again and methanol (1.0ml) is added.Then reactant mixture is slowly warmed to room temperature through 3 hours, diluted with ether.Organic layer uses water successively, and watery hydrochloric acid, water, saturated sodium bicarbonate, salt water washing is simultaneously dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (25% ethyl acetate/hexane) is then carried out on silica gel, 2.73g (90%) 606 is obtained, is colorless viscous grease, it is polluted by~3% isomery cyclohexene carboxylate ester.Embodiment 135
Glycol 607：606 (2.73g, 7.97mmol) dichloromethane (58ml) solution is handled 14 hours with 40% trifluoroacetic acid (37ml) at room temperature.Volatile matter is removed under reduced pressure and by residue distribution between ether and water.Organic layer saturated sodium bicarbonate, water and salt solution are carefully washed, and are dried with magnesium sulfate.Be concentrated under reduced pressure, then on silica gel carry out flash column chromatography (10% oneself
Alkane/ethyl acetate), 1.36g (75%) 607 is obtained, is sticky oil thing.Embodiment 136
Methanesulfonates 608 and 609：Mesyl chloride (360 μ l, 4.64mmol) is added dropwise into dichloromethane (25ml) solution (being cooled to -78 DEG C) of glycol 607 (1.06g, 4.64mmol) and triethylamine (1.31ml).Reactant mixture is stirred 1 hour at -78 DEG C, then slowly 0 DEG C was warmed to through 1 hour.After being kept for 1 hour at such a temperature, reactant mixture ether is diluted and water is used, saturated sodium bicarbonate, salt water washing is dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (20% ethyl acetate/hexane) is then carried out on silica gel, 1.23g (87%) 608 and 609 is obtained, the inseparable mixture for being 6: 1.Embodiment 137
Epoxides 610：DBU (601 μ l, 4.02mmol) is added into anhydrous THF (20ml) solution (being cooled to 0 DEG C) of 608 and 609 6: 1 mixtures (1.23g, 4.02mmol).Remove ice bath and reactant mixture is stirred at room temperature 18 hours.Reactant mixture ether is diluted and uses water, and salt water washing is dried with magnesium sulfate.It is concentrated under reduced pressure, then flash column chromatography (20% ethyl acetate/hexane) is carried out on silica gel, 490mg (58%) pure epoxies compound 610 is obtained, is mobility liquid and 100mg (13%) benzoic acid methyl -3- butyl esters 611, is grease.C12H18O3Analytically calculated value：C, 68.55；H, 8.63.Measured value：C, 68.29；H, 8.52.Embodiment 138
Azido alcohol 612 and 613：By 610 (490mg, 2.33mmol), methanol/water (8: 1,17.0ml) the solution gentle reflux of sodium azide (764mg, 11.75mmol) and ammonium chloride (281mg, 5.25mmol) 15 hours.The reactant mixture of cooling is concentrated under reduced pressure and distributed between ether and water.Dried with salt water washing organic layer and with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (20% ethyl acetate/hexane) is then carried out on silica gel, 562mg (95%) 612 and 613 is obtained, the inseparable mixture for being 2: 1.
Embodiment 139
Azido methanesulfonates 614 and 615：To 612 and 613 (642mg, 2.54mmol), mesyl chloride (232 μ l, 3.0mmol) is added dropwise in the DMAP of triethylamine (1.8ml) and catalytic amount dichloromethane (15ml) solution (being cooled to 0 DEG C).Reactant mixture is stirred 1.5 hours at 0 DEG C, is then stirred at room temperature 30 minutes.With ether diluted reaction mixture and water is used, watery hydrochloric acid, saturated sodium bicarbonate, salt water washing is dried with magnesium sulfate.It is concentrated under reduced pressure, obtains yellow liquid, by the liquid by short column of silica gel (25% ethyl acetate/hexane), obtains 840mg (100%) 614 and 615, be inseparable mixture.Embodiment 140
Aziridine 616：Triphenylphosphine (750mg) is added portionwise in 614 and 615 (840mg, 2.53mmol) anhydrous THF (20ml) solution at room temperature.Triethylamine (550 μ l) and water (5.5ml) are added after 2.5 hours, reactant mixture is stirred at room temperature 16 hours.Fugitive constituent is removed under reduced pressure, residue is diluted with ethyl acetate.Organic layer water, saturated sodium bicarbonate, salt water washing is dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (5% methanol/ethyl acetate) is then carried out on silica gel, 375mg (71%) 616 is obtained, is sticky oil thing.Embodiment 141
Azido amine 617：By 616 (354mg, 1.7mmol), dry DMF (8.0ml) solution of sodium azide (550mg, 8.54mmol) and ammonium chloride (182mg, 3.4mmol) is heated 17 hours at 80 DEG C.Most of DMF is removed under reduced pressure, by residue distribution between ether and water.Organic layer water, salt water washing, is dried with magnesium sulfate.It is concentrated under reduced pressure, obtains yellow liquid, by it by short column of silica gel (ethyl acetate), obtain 380mg (86%) 617, be yellow liquid, is directly used in next step reaction.Embodiment 142
N- acetyl group azide 618：The anhydrous pyridine (3.0ml) and dichloromethane (7.0ml) solution of crude product amine 617 (380mg, 1.51mmol) are handled with chloroacetic chloride (173 μ l, 2.4mmol) at 0 DEG C.After 40 minutes, reactant mixture is warmed to room temperature and stirred 5 minutes.It is removed under reduced pressure
Fugitive constituent, by residue distribution between ether and water.Organic layer watery hydrochloric acid, saturated sodium bicarbonate, salt water washing is dried with magnesium sulfate.It is concentrated under reduced pressure, flash column chromatography (20% hexane/ethyl acetate) is then carried out on silica gel, 349mg pale solids are obtained, it is recrystallized with ethyl acetate and hexane, 304mg (68%) 618 is obtained, is colorless needles.Embodiment 143
N- acetyl-aminos ester 619：The water (1.8ml) and THF (15ml) solution of 618 (292mg, 0.99mmol) and triphenylphosphine (393mg, 1.5mmol) are heated 10 hours at 50 DEG C.Reactant mixture is evaporated to dryness, is added in silicagel column and is eluted with 40% methanol/ethyl acetate, obtain 250mg (93%) 619, be light color colloidal solid.Embodiment 144
Amino acid 620：619 (142mg, 0.53mmol) of potassium hydroxide aqueous solution (770 μ l, 1.039M solution) processing THF (2.0ml) solution is used at room temperature 3.5 hours, then with Amberlite IR-120 (H+) ion exchange resin is acidified to pH=3.0.Reactant mixture is filtered, then resin is washed with water and methanol.It is concentrated under reduced pressure, obtains pale solid, is used C8Reversed-phase column chromatography is purified, and is eluted with water.Collect the fraction containing required product and evaporation obtains 87mg (65%) 620, be colourless powder.
Embodiment 145
Azidopropyl ester 265：At room temperature by Diisopropylcarbodiimide (31 μ l, 0.19mmol) it is added dropwise to (the 55mg of carboxylic acid 260,0.8mmol), in the DMAP of 1- propyl alcohol (67 μ l, 0.89mmol) and catalytic amount dichloromethane (1.0ml) solution.After stirring 1 hour, reactant mixture is concentrated and (50% hexane/ethyl acetate) is purified by flash chromatography on silica gel, 53mg (85%) 265 is obtained, is colorless crystalline solid.
Embodiment 146
Aminopropan base ester 266：In THF (4.0ml) and water (300 μ l) solution that triphenylphosphine (65mg, 0.25mmol) is once added to 265 (53mg, 0.15mmol).Then will reaction
Mixture is heated 10 hours at 50 DEG C, is cooled down and is concentrated in vacuo and obtains shallow white solid.The crude solid is obtained into light oil in Flash chromatography on silica gel chromatography (50% methanol/ethyl acetate) purifying, it is evaporated from 3N hydrochloric acid and obtains solid, by solid C18Reversed-phase column chromatography is purified, and is eluted with water.The fraction containing required product is collected, it is lyophilized to obtain 41mg (75%) 266, it is colourless powder.
Embodiment 147
Sulfide 700 prepares (Robert H.Rich, BrianM.Lawrence, Paul A.Bartlett, " Journal of Organic Chemistry ", 59,693-694 (1994) by shikimic acid according to the method for document.
Embodiment 148
Sulfoxide 701：Into -45 DEG C of solution of sulfide 700 (16.0g, 32.7mmol) dichloromethane (750ml) through 0.5 hour be added dropwise metachloroperbenzoic acid (8.5g, 57-86%) dichloromethane (250ml) solution.Reactant mixture is stirred 1 hour at -40 DEG C, is then stirred at room temperature 0.5 hour.Reactant mixture is evaporated, solid starts to be precipitated out, then diluted with hexane.It is filtered to remove solid and evaporates filtrate.Residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate, is dried with magnesium sulfate, filters and evaporates.The purification of crude product by the chromatography (ethyl acetate/hexane) on silica gel, obtaining sulfoxide 701, (14.2g, 86%, non-enantiomer mixture, ratio is 2.2: is colorless solid 1).
Embodiment 149
Vinyl chloride 702：Sulfoxide 701 (14g, 27.7mmol) is flowed back 50 minutes in dimethylbenzene (180ml).Reactant mixture is to room temperature and evaporates for cooling.Residue obtains vinyl chloride 702 (7.6g, 79%), grease through chromatography.
Embodiment 150
Triol 703：Sodium methoxide (0.3ml, 25%, 1.3mmol) is added into solution at room temperature of the vinyl chloride 702 (7.3g, 20.9mmol) in absolute methanol (80ml).Reaction mixing is stirred at room temperature
Thing 1 hour, is then terminated with hydrochloric acid/methanol (1.0ml, 1.4M, 1.4mmol).Reactant mixture is evaporated and residue is handled with ethyl acetate/hexane, triol 703 (4.6g, 99%) is obtained, is colorless solid.C8H11ClO51/14/Na/Cl analytically calculated value：C, 42.36；H, 4.89；Cl, 16.75.Measured value：C, 42.29；H, 4.90；Cl, 16.56.
Embodiment 151
Acetone solvate 704：By triol 703 (4.6g, 20.7mmol), the mixture of 2,2-dimethoxypropane (4.0ml, 32.5mmol) and acetone (50ml) is stirred at room temperature 1.5 hours.Reactant mixture is evaporated, fresh 2,2-dimethoxypropane (1.5ml, 12.2mmol) and acetone (30ml) is added.Reactant mixture is further stirred for 1.5 hours.Reactant mixture is evaporated and crude product is filtered into short column of silica gel.Evaporation filtrate obtains acetone solvate 704 (5.4g, 99%), grease, C11H15ClO5·1/4H2O analytically calculated value：C, 49.45；H, 5.85；Cl, 13.27.Measured value：C, 49.67；H, 5.82；Cl, 13.60.
Embodiment 152
Methanesulfonates 705：Triethylamine (2.23ml, 16mmol) is added into 0 DEG C of solution of the acetone solvate 704 (2.63g, 10.0mmol) in dichloromethane (30ml), mesyl chloride (1.16ml, 15mmol) is then added.Reactant mixture is stirred 1 hour at 0 DEG C, then evaporated.By residue distribution between ethyl acetate and water.Aqueous phase is extracted with ethyl acetate.The organic phase of merging is dried with magnesium sulfate, is filtered and is evaporated.Crude product is filtered by short column of silica gel.Evaporation filtrate obtains methanesulfonates 705 (3.4g, 100%) grease.
Embodiment 153
3- amyl groups ketal 706：The mixture of methanesulfonates 705 (3.4g, 10.0mmol) and perchloric acid (30mg, 70%, 0.2mmol) in propione (40ml) is stirred 2 hours at 45 DEG C.Reactant mixture is evaporated and fresh propione (40ml) is added.Reactant mixture is further stirred for 0.5 hour, then evaporated.Crude product is filtered by short column of silica gel.Evaporation filtrate obtains 3- amyl groups ketal 706 (3.7g, 100%) grease.
Embodiment 154
Methanesulfonic acid ester alcohol 707：To (the 1.68g of ketal 706, borane-methyl sulfide complex (0.7ml 4.55mmol) is added in -5 DEG C of solution in dichloromethane (20ml), 10M, 7.0mmol), then trifluoromethanesulfonic acid trimethyl silyl ester (0.82ml, 4.6mmol) is added.Reactant mixture is stirred 1 hour at 0 DEG C, saturated sodium bicarbonate is then very slowly added (for 5 initial drops, 1 drop/10 minutes, 1ml).Gained mixture is filtered by short column of silica gel.Residue is simultaneously carried out chromatography (ethyl acetate/hexane) on silica gel and purified by evaporation filtrate, obtains mixture (1.2g, 71%, 8/9=3/2) grease of region isomer (regio-isomer) 707 and 708.
Embodiment 155
Epoxides 709：707 and 708 mixture (1.95g, 5.2mmol) and saleratus (1.0g, 10mmol) are mixed in methanol (15ml) and water (10ml).Reactant mixture is stirred at 5 DEG C 1 hour, then evaporate to remove methanol.Remaining mixture is extracted with ethyl acetate.The extract of merging is dried with magnesium sulfate, is filtered and is evaporated.Residue obtains epoxides 709 (0.88g, 61%) grease through chromatography.
Embodiment 156
Azide alcohol 710：By (the 0.95g of epoxides 709,3.46mmol), the mixture of sodium azide (0.65g, 10mmol) and ammonium chloride (0.4g, 7.5mmol) in methanol (40ml) and water (10ml) is stirred 18 hours at 65 DEG C.Reactant mixture is diluted with water and evaporated to remove methanol, be then extracted with ethyl acetate.Organic extract liquid is dried with magnesium sulfate, filters and evaporates.The crystallization of crude product hexane/ethyl acetate is obtained into azide alcohol 710 (0.8g, 73%) colorless solid.C13H20ClN3O4Analytically calculated value：C, 49.14；H, 6.34；N, 13.22；Cl, 11.16.Measured value：C, 49.14；H, 6.47；N, 13.21；Cl, 11.38.Embodiment 157
Azide methanesulfonates 711：Triethylamine (1.1ml, 8.0mmol) is added into 0 DEG C of solution of the azide alcohol 710 (1.0g, 3.15mmol) in dichloromethane (20ml), is then added
Methanesulfonic acid chlorine (0.5ml, 6.5mmol).Gained mixture is stirred 0.5 hour at 0 DEG C, is then stirred at room temperature other 0.5 hour.Two are added to reactant mixture to drip, and are then diluted and are filtered by short column of silica gel with hexane.Filtrate evaporation obtains azide methanesulfonates 711 (1.27g, 100%) grease.
Embodiment 158
Triazobenzene ethyl ester 800：To 260 (63mg, 0.2mmol), phenethyl alcohol (26 μ l, 0.22mmol) and DMAP (7.8mg) add Diisopropylcarbodiimide (34 μ l, 0.22mmol) at room temperature in the solution in 1/1- dichloromethane/THF (2ml).After stirring 4 hours, residue is simultaneously chromatographed (1/1- hexane/ethyl acetates) and obtains 800 (60mg) grease by evaporation solvent on silica gel, and it contains the phenethyl ester of trace.The material is directly used in next step without further purification.
Embodiment 159
Aminophenethyl ester 801：Triphenylphosphine (55mg, 0.21mmol) is once added in solution of 800 (60mg, the 0.14mmol) in THF (2ml) and water (252 μ l).Then heating response mixture 10 hours at 50 DEG C, cool down and evaporate.Residue is purified by silica gel column chromatography (1/1- ethyl acetate/methanols), 53mg grease is obtained, is dissolved in 0.1N hydrochloric acid (1ml) and evaporates.Residue is soluble in water and pass through C18Reverse phase silica gel post, 801 (41mg, 69%), white solid are obtained after freezing.
Embodiment 160
Azido butyl ester 802：At room temperature to 260 (60mg, 019mmol), Diisopropylcarbodiimide (33 μ l, 0.21mmol) is added in the solution of n-butanol (87 μ l, 0.95mmol) and DMAP (4mg) in 2/1- dichloromethane/THF (3ml).Evaporation solvent and residue is chromatographed into (1/1- hexane/ethyl acetates) on silica gel obtain 802 (48mg, 68%) grease after stirring 2 hours.
Embodiment 161
Aminobutyl ester 803：By triphenylphosphine (51mg, 0.19mmol) once add 802 (48mg, 0.13mmol) in the solution in THF (1.5ml) and water (234 μ l), then reactant mixture is heated 10 hours at 50 DEG C, cools down and evaporates.Residue is dissolved in ethyl acetate, is dried (sodium sulphate), is filtered and evaporate.Residue is purified with silica gel chromatography (1/1- ethyl acetate/methanols), 38mg grease is obtained, is dissolved in 0.1N hydrochloric acid (2ml) and evaporates.Residue is soluble in water and pass through C18Reverse phase silica gel post, 803 (23mg, 47%), white solid are obtained after freezing.Embodiment 162
1- phenyl -3- amylalcohols 804：Solution of the hydrocinnamaldehyde (6.71g, 50mmol) in ether (50ml) is added into 0 DEG C of solution of the ethylmagnesium bromide (75mmol) in ether (325ml).The solution is stirred 1 hour and warmed to room temperature, reaction solution is poured into frozen water (1000ml) and mixture is acidified to pH=3 with concentrated hydrochloric acid.Separate each layer and extract aqueous phase with ether.The organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, is filtered and is evaporated.Crude product is distilled under high vacuum (bp90-93 DEG C) and obtains 804 (5.3g, 64%) colorless oils.Embodiment 163
1,5- diphenyl -3- amylalcohols 805：Solution of the hydrocinnamaldehyde (3.0g, 22.5mmol) in ether (30ml) is added into 0 DEG C of solution of the phenethyl magnesium bromide (25ml, 0.9M THF solution) in ether (100ml).The solution is stirred 5 minutes and stirring 1 hour is warmed to room temperature, reaction solution is poured into frozen water (200ml), and mixture is acidified to pH=3 with concentrated hydrochloric acid.Separate each layer and extract aqueous phase with ether.The organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, is filtered and is evaporated.(4/1- hexane/ethyl acetates) is chromatographed on silica gel and obtains light yellow oil (3.74g), it solidifies during cooling.805 (1.35g, 25%) white spicules are recrystallized to give with hexane.Embodiment 164
1,3- diphenyl -2- propyl alcohol 806：To 1,3- diphenyl acetones
Sodium borohydride (3.07g, 81.2mmol) is added in the 0 DEG C of solution of (17.08g, 81.2mmol) in ethanol (100ml) and is stirred the mixture for 2 hours.With 1N hydrochloric acid acidizing reactions mixture to pH=3 and ethanol evaporation.Reactant mixture is diluted with water and aqueous phase is extracted with ethyl acetate several times.The organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, is filtered and is evaporated and obtains 806 (17g, 99%) pale yellow oils.Embodiment 165
Ether 807：BF is added into 183 (200mg, 0.46mmol) and 804 (1ml) solution3·OEt2(85 μ l, 0.69mmol) and the solution is heated 1.25 hours at 75-80 DEG C.It is cooled to after room temperature and dilutes reactant mixture with the pyridine (5ml) for being cooled to 0 DEG C, is handled with acetic anhydride (1.25ml) and DMAP (50mg).The reactant mixture is stirred 15 minutes at 0 DEG C, is then stirred at room temperature 14 hours.Evaporation solvent simultaneously distributes residue between ethyl acetate and 1N hydrochloric acid, and organic phase uses 1N salt acid elutions again.The aqueous phase of merging is extracted with ethyl acetate, and the organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, is filtered and is evaporated.Residue chromatographs (1/1- hexane/ethyl acetates) on silica gel and obtains 807 (116mg, 63%), is non-enantiomer mixture, it is chromatographed again (2/1- hexane/ethyl acetates).Merge the fraction containing the diastereomer most eluted soon and obtain 807a (44mg) solid, it is recrystallized with hexane/ethyl acetate：mp131-133℃.More slowly the diastereomer eluted is obtained in solid form, and it is recrystallized with hexane/ethyl acetate.Obtain 807b (41mg) spicule；mp111-112℃.
Embodiment 166
It is handled to obtain amino ester 808a and 808b similar to the processing of the method for embodiment 93, obtains amino acid 809a and 809b by nitrine base ester 807a and 807b triphenylphosphine with potassium hydroxide aqueous solution as described in embodiment 94.
Embodiment 167
Ether 810：Pass through mild heat formation 183 (200mg, 0.46mmol) and 805 (750mg, 3.1mmol, mp43-45 DEG C) solution.BF is added into the solution3·OEt2(85 μ l, 0.69mmol)
And heat the solution 1.5 hours at 70-75 DEG C.It is cooled to after room temperature and dilutes reactant mixture with the pyridine (2ml) for being cooled to 0 DEG C, with the DMAP processing of acetic anhydride (660 μ l, 7.0mmol) and catalytic amount.Reactant mixture is stirred a few minutes at 0 DEG C, is then stirred at room temperature 16 hours.Evaporation solvent simultaneously distributes residue between ethyl acetate and 1N hydrochloric acid, again with 1N salt acid elution organic phases.The aqueous phase cleaning solution of merging is extracted with ethyl acetate, and by the organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, filters and evaporate.Residue is chromatographed into (1/1- hexane/ethyl acetates) on silica gel and obtains solid residue, (hexane/ethyl acetate) is recrystallized and obtains 810 (63mg, 28%) spicules：mpl39-140℃.
Embodiment 168
Nitrine base ester 810, to be obtained amino ester 811 similar to the processing of the method for embodiment 93, it as described in embodiment 94 handle with potassium hydroxide aqueous solution obtains amino acid 812 with triphenylphosphine.
Embodiment 169
Ether 813：BF is added into 183 (100mg, 0.23mmol) and 806 (1ml) solution3·OEt2(42 μ l, 0.35mmol) and the solution is heated 1.25 hours at 70-75 DEG C.It is cooled to after room temperature and dilutes reactant mixture with the pyridine (5ml) for being cooled to 0 DEG C, with the DMAP processing of acetic anhydride (680 μ l, 7.2mmol) and catalytic amount.Reactant mixture is stirred a few minutes at 0 DEG C, is then stirred at room temperature 15 hours.Evaporation solvent simultaneously distributes residue between ethyl acetate and 1N hydrochloric acid, again with 1N salt acid elution organic phases.The aqueous phase cleaning solution of merging is extracted with ethyl acetate, and by the organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, filters and evaporate.Residue is chromatographed into (1/1- hexane/ethyl acetates) on silica gel and obtains solid residue, (hexane/ethyl acetate) is recrystallized and obtains 813 (57mg, 55%) light yellow solids：Mp132-133 DEG C (spicule is obtained by hexane/ethyl acetate).
Embodiment 170
Nitrine base ester 813, to be obtained amino ester 817 similar to the processing of the method for embodiment 93, it as described in embodiment 94 handle with potassium hydroxide aqueous solution obtains amino acid 815 with triphenylphosphine.
Embodiment 171
N-Boc aziridine 817：To 816 (700mg, 3.1mmol, prepared in a similar manner as described in cinchonic acid such as methyl ester derivative 170) DMAP (10%mol) of solution and catalytic amount of the di-tert-butyl dicarbonic acid ester (1.0g, 4.6mmol) in dichloromethane (5ml) is added in solution in dichloromethane (10ml).Evaporation solvent is stirred at room temperature after 45 minutes and residue is directly purified into (3/1- hexane/ethyl acetates) by silica gel column chromatography and obtains 817 (880mg, 87%) grease.
Embodiment 172
Alcohol 818：Ammonium formate (1.59g, 25.2mmol) is added into solution of 817 (826mg, the 2.52mmol) in DMF (20ml) and heats the mixture 1 hour at 130 DEG C.After second of addition ammonium formate (1.59g, 25.2mmol), reactant mixture is heated 1.5 hours and evaporated.Residue is distributed between ethyl acetate and saturated sodium bicarbonate.By organic phase salt water washing, dried with magnesium sulfate, filter and evaporate.Residue silica gel chromatography (1/2- hexane/ethyl acetates) purification is obtained into 818 (556mg, 64%), light yellow solid.
Embodiment 173
Ethyl acetate 819：DMAP (20mg, 0.16mmol) and acetic anhydride (216 μ l, 2.3mmol) are added into solution of 818 (500mg, the 1.45mmol) in pyridine (10ml).The solution is stirred at room temperature 1 hour and evaporated.Residue is obtained into 819 (557mg, 94%) solids by silica gel chromatography (1/1- hexane/ethyl acetates) purification.
Embodiment 174
N- trityls aziridine 820：Solution of 819 (459mg, the 1.18mmol) in 1.24M hydrochloric ethyl acetates solution (20ml) is stirred at room temperature 2.5 hours.Evaporation solvent obtains white
Solid, it is stood overnight under a high vacuum.Trityl chloride (346mg, 1.25mmol) and triethylamine (354 μ l, 2.54mmol) are added into dichloromethane (10ml) solution (0 DEG C) of the solid (315mg).Stir the solution 1.75 hours, triethylamine (354 μ l, 2.54mmol) and mesyl chloride (10 μ l, 1.36mmol) are added therebetween.The reactant mixture is stirred 1.5 hours and warmed to room temperature at 0 DEG C, is stirred 5 hours.Evaporation solvent simultaneously distributes residue between ether and water.Organic phase is washed with water and extracts the aqueous phase cleaning solution of merging with ether.The organic extract liquid of merging salt water washing, is dried with magnesium sulfate, is filtered and is evaporated.Residue silica gel chromatography (dichloromethane) purification obtains 820 (440mg, 83%), white foam.Embodiment 175
Amyl ether 821：BF is added into solution of 820 (100mg, the 0.21mmol) in 3- amylalcohols (2ml)3·OEt2(39 μ l, 0.32mmol) and the solution is heated 1.5 hours at 70-75 DEG C.Residue is simultaneously dissolved in pyridine (2ml) by evaporation solvent, with acetic anhydride (100 μ l, 1.05mmol) and DMAP processing.Reactant mixture is stirred at room temperature 14 hours.Evaporation solvent simultaneously distributes residue between ethyl acetate and 1N hydrochloric acid.Aqueous phase cleaning solution is extracted with ethyl acetate, and by the organic extract liquid saturated sodium bicarbonate of merging, salt water washing is dried with magnesium sulfate, filters and evaporate.Residue is chromatographed into (1/1- ethyl acetate/dichloromethanes) on silica gel and obtains 821 (46mg, 62%) solids.Embodiment 176
Carboxylic acid 822：1N potassium hydroxide (260 μ l, 0.27mmol) is added into solution of 821 (42mg, the 0.12mmol) in THF (2ml) and mixture is stirred at room temperature 5.5 hours.The solution is acidified with Amberlite IR120 ion exchange resin (pH=3) and by the resin filter, washed with THF.Evaporation solvent obtains residue, is dissolved in water and in C8Chromatograph, be eluted with water on reverse phase silica gel.Evaporate water and evaporate residue from methanol and obtain 822 (29mg, 85%) solids.
Embodiment 177
Methyl ether 823：BF is added into solution of 816 (200mg, the 0.88mmol) in methanol (5ml)3·OEt2(120 μ l, 0.97mmol).The solution is flowed back two hours, evaporates and simultaneously residue is dissolved in pyridine (4ml), handled with acetic anhydride (41 μ l, 4.4mmol).It is stirred at room temperature after 1 hour, evaporation solvent simultaneously distributes residue between ethyl acetate and 5% citric acid.Organic phase saturated sodium bicarbonate, salt water washing, is dried with magnesium sulfate, is filtered and is evaporated.Residue is purified with silica gel chromatography (10% ethanol/methylene), obtains 823 (76mg, 29%) white solids.
Embodiment 178
Carboxylic acid 824：Solution of 823 (33mg, the 0.11mmol) in 2.5M hydrochloric ethyl acetates solution (2ml) is stirred at room temperature 2.5 hours and evaporated.Residue is dissolved in THF (2ml), and is handled with 1N potassium hydroxide (154 μ l, 0.16mmol) and water (300 μ l).Reactant mixture is stirred at room temperature 6 hours, and is acidified with Dowex 50WX8 ion exchange resin.Filter resin and evaporate filtrate and obtain residue, be dissolved in water and in C19Reversed-phase silica gel chromatography.After lyophilized 824 (24mg, 95%) are isolated with white solid forms.
Embodiment 179
Methyl ether 825：BF is added into solution of 820 (80mg, the 0.17mmol) in methanol (2ml)3·OEt2(32 μ l, 0.26mmol).The solution is flowed back 2 hours, evaporates and residue is dissolved in pyridine (2ml).The DMAP of acetic anhydride (80 μ l, 0.85mmol) and catalytic amount is added into the solution.After stirring 14 hours, residue is simultaneously chromatographed (ethyl acetate) by evaporation solvent on silica gel, obtains 825 (46mg, 90%) white solids.
Embodiment 180
Carboxylic acid 826：1N potassium hydroxide (433 μ l, 0.45mmol) is added into solution of 825 (46mg, the 0.15mmol) in THF (2ml) and the mixture is stirred at room temperature 5 hours.The solution is acidified with Dowex 50WX8 ion exchange resin, resin is filtered and is washed with methanol.Evaporation solvent obtains residue, is dissolved in water and by C18Reverse phase silica gel post, is eluted with water.Evaporation solvent obtains 826 (33mg, 96%) white solids.
Embodiment 181
Methyl ether 827：BF is added into solution of 816 (612mg, the 0.27mmol) in methanol (25ml)3·OEt2(370 μ l, 3.0mmol).The solution is flowed back 2 hours, evaporate and residue is dissolved in dichloromethane (5ml) and with di-tert-butyl dicarbonic acid ester (880mg, dichloromethane (3ml) solution 4.1mmol) and triethylamine (570 μ l, 4.1mmol) processing.It is stirred at room temperature after 5 hours, evaporation solvent simultaneously distributes residue between ethyl acetate and water.Organic phase water, salt water washing, is dried with magnesium sulfate, is filtered and is evaporated.Residue obtains 827 (630mg, 65%) grease with silica gel chromatography (2/1- hexane/ethyl acetates).
Embodiment 182
N- trityls aziridine 828：Solution of 827 (574mg, the 1.6mmol) in 2.5M hydrochloric ethyl acetates solution (20ml) is stirred at room temperature 5 hours.Evaporation solvent obtains white solid (400mg).Trityl chloride (490mg, 1.6mmol) and triethylamine (278 μ l, 3.6mmol) are added into solution (0 DEG C) of the solid in dichloromethane (5ml).Stir the solution 2 hours, triethylamine (278 μ l, 3.6mmol) and mesyl chloride (136 μ l, 1.76mmol) are added therebetween.The reactant mixture is stirred 1 hour and warmed to room temperature at 0 DEG C, is stirred 4 hours.Evaporation solvent simultaneously distributes residue between ether and water.Organic phase is washed with water and extracts the aqueous phase cleaning solution of merging with ether.The organic extract liquid of merging salt water washing, is dried with magnesium sulfate, is filtered and is evaporated.Residue silica gel chromatography (dichloromethane) purification obtains 828 (170mg, 25%), white foam.Embodiment 183
Double methyl ethers 829：BF is added into solution of 828 (60mg, the 0.14mmol) in methanol (2ml)3·OEt2(26 μ l, 0.21mmol).The solution is flowed back 1 hour, residue is simultaneously dissolved in pyridine (1ml) by evaporation solvent, handled with acetic anhydride (66 μ l, 0.7mmol).Reactant mixture is stirred at room temperature 18 hours.Evaporation solvent simultaneously distributes residue between ethyl acetate and 1N hydrochloric acid.By organic phase saturated sodium bicarbonate, salt water washing is dried with magnesium sulfate, filters and evaporate.Residue is chromatographed into (10% methyl esters/dichloromethane) on silica gel to obtain
829 (13mg, 34%) white solids.Embodiment 184
Carboxylic acid 830：1N potassium hydroxide (649 μ l, 5.072mmol) is added into solution of 829 (13mg, the 0.048mmol) in THF (1ml) and mixture is stirred at room temperature 48 hours.The solution is acidified with Dowex 50WX8 ion exchange resin and by the resin filter, washed with methanol.Evaporation solvent obtains residue, is dissolved in water and in C18Chromatographed on reverse phase silica gel.830 (8mg, 68%) white solids are obtained after lyophilized.
Embodiment 185
Lactone 900：By cinchoninic acid (20kg, 104mmol, [α]D- 43.7 ° (c=1.12, water)；Merck Index the 11st edition, 8071：[α]D- 42 ° to -44 ° (water)), the solution of 2,2-dimethoxypropane (38.0kg, 365mol) and p-methyl benzenesulfonic acid monohydrate (0.2mg, 1.05mol) in acetone (80kg) is heated at reflux 2 hours.Add ethanol solution (0.34kg, the 1.05mol) terminating reaction of 21% caustic alcohol and be evaporated in vacuo, most of solvent.By residue distribution between ethyl acetate (108kg) and water (30kg).Aqueous layer with ethyl acetate (13kg) is stripped and washs the organic layer of merging with 5% sodium bicarbonate aqueous solution (14kg).The most of ethyl acetate of vacuum distillation, obtains light yellow solid residue 900, it is directly used in next step.
Embodiment 186
Hydroxy ester 901：Solution of the crude product lactone 900 (coming from 104mol (-)-cinchoninic acid) in absolute ethyl alcohol (70kg) is handled with the ethanol solution (0.34kg, 1.05mmol) of 20% caustic alcohol.At room temperature after 2 hours, add acetic acid (0.072kg, 1.2mol) and distill solvent in vacuo.Add ethyl acetate (36kg) and continue distillation to close to drying.Brown solid residue (being made up of about 5: 1 901: 900 mixtures) is dissolved in ethyl acetate (9kg) driving to flow down, and adds hexane (9kg).White crystalline solid is formed during cooling, be separated by filtration obtain 901: 900 about 6.5: 1 mixtures (19.0kg, 70% yield).Embodiment 187
Methyl ester 902：By hydroxy ester 901 and about 6.5: 1 mixture (18.7kg of lactone 900, about 72mol) solution in dichloromethane (77kg) is cooled to 0-10 DEG C and with mesyl chloride (8.23kg, 71.8mol) processing, it is then slowly added into triethylamine (10.1kg, 100mol).It it is possible to additionally incorporate mesyl chloride (0.84kg, 7.3mol).Water (10kg) and 3% hydrochloric acid (11kg) are added after 1 hour.Separate each layer and wash organic layer with water (9kg), then vacuum distillation obtains semi-solid residue, and it is made up of about 6.5: 1 mixtures of methylsulfonyl base ester 902 and mesyl lactone 903.Residue is dissolved in ethyl acetate (11kg) and -10 DEG C to -20 DEG C, holding 2 hours are cooled to.Methanesulfonic acid base lactone 903 is crystallized and is isolated by filtration, and is washed with cold ethyl acetate (11kg).Concentration filtrate obtains methylsulfonyl base ester 902, is orange resin (24.5kg, 84.3% yield).Embodiment 188
Mesyl acetone solvate 904：By (the 10.3kg of methylsulfonyl base ester 902; 30.4mol) with pyridine (10.4kg; 183mol) solution in dichloromethane (63kg) is cooled to -20 DEG C to -30 DEG C and with sulfonic acid chloride (6.22kg, 46mol) batch processing.After exothermic reaction is disappeared, gained slurry is terminated with the ethanol (2.4kg) for being warmed to 0 DEG C and successively with 16% sulfuric acid (35kg), water (15kg) and 5% sodium bicarbonate aqueous solution (1kg) washing.The organic layer in vacuo for containing 904: 905: 906 about 4: 1: 1 mixtures concentrates and adds ethyl acetate (14kg).By using pyrrolidines (2.27kg, 31.9mol) with tetrakis triphenylphosphine palladium (0) (0.0704kg, ethyl acetate solution 0.061mol) is handled at room temperature 5 hours, then washed with 16% sulfuric acid (48kg) and be selectively removed allylic mesylate 905.Organic layer filtration silicagel pad (11kg) is simultaneously eluted with ethyl acetate (42kg).It is concentrated in vacuo filtrate and obtains sticky orange oil, it is made up of 904: 906 about 4: 1 mixtures.Residue is dissolved in ethyl acetate (5.3kg) under reflux and hexane (5.3kg) is added.Mesyl acetone solvate 904 is crystallized and is separated by filtration during cooling, is washed with 14% ethyl acetate/hexane (2.1kg).After vacuum drying, 904 (4.28kg, 43.4% yields), mp102-3 DEG C are obtained with yellow needles.Embodiment 189
Amyl group ketal 907：By acetone solvate 904 (8.9kg, 27.8mol), propione
The solution of (24kg, 279mol) and 70% perchloric acid (0.056kg, 0.39mol) is stirred 18 hours, fugitive constituent is evaporated in vacuo at room temperature and as the progress of distillation is gradually added into fresh propione (30kg, 348mol).To filter reactant mixture, and add toluene (18kg), successively with 6% sodium acid carbonate the aqueous solution (19kg), water (18kg) and salt solution (24kg) wash resulting solution.Organic layer in vacuo is concentrated and as the progress of distillation is gradually added into toluene (28kg).When multiple distillation, the orange of residual is made up of amyl group ketal 907 (9.7kg, 100% yield) and toluene (about 2kg).Embodiment 190
Amyl ether 908：By (the 8.6kg of ketal 907,25mol) solution in dichloromethane (90kg) is cooled to -30 DEG C to -20 DEG C and with borane-methyl sulfide complex (2.1kg, 27.5mol) handled with trifluoromethanesulfonic acid trimethyl silyl ester (7.2kg, 32.5mol).After 1 hour, 10% sodium bicarbonate aqueous solution (40kg) is slowly added to.Mixture is warmed to room temperature and stirred 12 hours.Filtering organic layer is simultaneously concentrated in vacuo, and is obtained 908: 909 about 8: 1 mixtures, is grey waxy solid (7.8kg, 90% yield).
Embodiment 191
Epoxides 910：Solution of about 8: 1 mixtures (7.8kg, 22.3mol) of the amyl ether 908: 909 of isomery in ethanol (26kg) is handled with saleratus (3.52kg, 35mol) water (22kg) solution.After being heated 2 hours at 55 DEG C -65 DEG C, cool down the solution and extracted 2 times with hexane (31kg, then 22kg).Unreacted 909 remain in hydrous ethanol layer.Filter the hexane extract merged and vacuum concentration obtains epoxides 910, be flocculent white crystalline solid (3.8kg, 60% yield), mp=54-6 DEG C.
Embodiment 192
Hydroxy azide 911：By (the 548g of epoxides 910,2.0mol), the mixture of sodium azide (156g, 2.4mol) and ammonium chloride (128.4g, 2.4mol) in water (0.265 liter) and ethanol (1.065 liters) is heated 8 hours in 70-75 DEG C.Add sodium bicarbonate aqueous solution (0.42 liter, 8% solution) and ethanol is evaporated in vacuo.With (1 liter) aqueous remnants of extraction of ethyl acetate
Thing simultaneously washs extract with water (0.5 liter).Water lotion (0.5 liter) back extraction of ethyl acetate.The organic extract liquid of merging is washed with salt solution (0.5 liter), with anhydrous sodium sulfate drying, is filtered and is concentrated in vacuo, and obtains about 10: 1 mixtures (608g, 102% yield) of the hydroxy azide 911: 912 of isomery, dark brown oil.
Embodiment 193
Aziridine 913：About 10: 1 mixtures (608g, 2.0mol) of hydroxy azide 911: 912 are sent out three times from anhydrous acetonitrile (3 × 0.3 liters) vacuum co evaporation, are then dissolved in anhydrous acetonitrile (1 liter).Solution of the anhydrous triphenylphosphine (483g, 1.84mol) in anhydrous tetrahydro furan (0.1 liter) and anhydrous acetonitrile (0.92 liter) was added dropwise in 2 hours.It is heated at reflux the mixture 6 hours, is then concentrated in vacuo and obtains golden pastel, it is by aziridine 913, the triphenylphosphine composition of triphenylphosphine oxide and trace.The pastel (0.35 liter) development of ether.It is filtered to remove most of insoluble triphenylphosphine oxide and is washed with ether (1.5 liters).It is concentrated in vacuo filtrate and obtains dark brown oil, is dissolved in 20% methanol aqueous solution and with the extraction three times of (3 × 1 liters) of hexane, to remove triphenylphosphine.With (0.5 liter) back extraction hexane extract of 20% methanol aqueous solution and the aqueous methanol layer of merging is concentrated in vacuo.By residue, vacuum co evaporation is sent out twice from anhydrous acetonitrile (2 × 0.5 liters).Dark brown oil is obtained, it is made up of nitrogen pyridine 913 (490g, 96.8% yield) and triphenylphosphine oxide (about 108g), is directly used in next step.
Embodiment 194
Acetamido azide 915：By (the 490g of aziridine 913,1.93mol) with triphenylphosphine oxide (about 108g), sodium azide (151g, 2.33mol) with ammonium chloride (125g, 2.33mol) mixture in dimethylformamide (1.3 liters) is heated 5 hours at 80-85 DEG C, add sodium acid carbonate (32.8g, 0.39mol) and water (0.66 liter).Amino azide 914 is isolated from reactant mixture by using the extraction 6 times of (6 × 1 liters) of hexane.The hexane extract of merging is concentrated in vacuo to about 4.5 liters of cumulative volume and adds dichloromethane (1. 04 liters).Sodium bicarbonate aqueous solution (4.2 liters, 8% solution, 3.88mol) is added, acetic anhydride (198g, 1.94mol) is then added.It is stirred at room temperature after 1 hour, discards water layer.Be concentrated in vacuo organic phase ad pond om be 1.74kg simultaneously
Under reflux with (0.209 liter) dissolving of ethyl acetate.Acetamido azide 95 is crystallized and is isolated by filtration during cooling.Washed with cold 15% ethyl acetate isohexane solution (1 liter) and pure 915 are obtained after vacuum drying at room temperature, be beige crystals (361g, 55% yield), mp126-132 DEG C.
Embodiment 195
Acetamido amine 916：The mixture of azide 915 (549g, 1.62mol) and Lindlar catalyst (50g) in absolute ethyl alcohol (3.25 liters) is stirred 8 hours, while hydrogen (1 atmospheric pressure) bubbling is passed through into the mixture.Filtration over celite is simultaneously concentrated in vacuo filtrate and obtains 916, for the foam (496g, 98% yield) solidified when placing.
Embodiment 196
916 phosphate：Reflux solution of the acetamido amine 916 (5.02g, 16.1mmol) in acetone (75ml) is handled with 85% phosphoric acid (1.85g, 16.1mmol) absolute ethyl alcohol (25%) solution.Immediately begin to crystallization, and be cooled to 0 DEG C keep 12 hours after precipitation is collected by filtration, obtain 916H3PO4, it is colourless long spicule (4.94g, 75% yield；[α]D- 39.9 ° (c=1, water)), mp203-4 DEG C.
Embodiment 197
916 hydrochloride：Solution of the acetamido amine 916 (2.8g, 8.96mmol) in absolute ethyl alcohol (9ml) is handled with 2.08M ethanol solution hydrochlorides (8.6ml, 17.9mmol).It is evaporated in vacuo most of ethanol and stirs oily residue ethyl acetate (20ml) until forming solid together.Hexane (20ml) is gradually added into the mixture of stirring.The solid is collected by filtration after 1 hour at room temperature, is washed and is dried in vacuo with ether.916HCl is obtained, is pale solid (2.54g, 81% yield) [α]D- 43 ° (c=0.4, water)), mp206 DEG C.
Embodiment 198
Aziridine 712：Triphenylphosphine (1.0g, 3.8mmol) is added in four times into solution at room temperature of the azide methanesulfonates 711 (1.27g, 3.15mmol) in anhydrous THF (10ml).Instead
Answer mixture to be stirred at room temperature 3.5 hours, be subsequently cooled to 0 DEG C, and add triethylamine (0.53ml, 3.8mmol) and water (0.5ml).Gained mixture is stirred at room temperature 3 hours, is then stirred at 45 DEG C other 3 hours.Reactant mixture is evaporated and distributes residue between ethyl acetate and water.Aqueous phase is extracted with ethyl acetate.The extract of merging salt water washing, is dried with magnesium sulfate, is filtered and is evaporated.Residue is chromatographed, and is handled with ethyl acetate/hexane (to remove most triphenylphosphine oxides), obtains required aziridine 712 (0.56g, 65% there is also about 15% three epoxide phosphine oxides).Embodiment 199
N- acetyl group azide 713：By aziridine 712 (0.56g, 17mmol), the mixture of sodium azide (0.65g, 10.0mmol) and ammonium chloride (0.4g, 7.5mmol) in DMF (5mL) is stirred 18 hours at 65 DEG C.With hexane (20mL) diluted reaction mixture and filter short column of silica gel (being eluted with ethyl acetate/hexane).Evaporate filtrate.Residue is dissolved in pyridine (5.0ml), acetic anhydride (1.0mL) is added.Gained reactant mixture is stirred at room temperature 14 hours, then evaporates.Residue is dissolved in ethyl acetate and with saturated sodium bicarbonate and salt water washing.Organic phase (magnesium sulfate) is dried, filters and evaporates.Residue by chromatography and obtains N- acetyl group azide 713 (20mg, 3.3%) from ethyl acetate/hexane crystallization, is solid.1H NMR (300MHz, CDCl3)：5.68 (d, 1H, J=7.9)；4.31 (d, 1H, J=5.2)；4.09 (m, 1H)；3.94 (m, 1H)；3.83 (s, 3H)；3.65 (m, 1H)；2.82 (ddd, 1H, J=0.9,5.2,17.7)；2.55 (ddd, 1H, J=1.5,7.3,17.7)；2.06 (s, 3H)；1.62 (m, 4H), 0.96 (m, 6H).
All above document and patent citation are incorporated herein entirety in its citation position and referred to.The paragraph or number of pages that above-mentioned works is especially quoted from are then clearly to be used as reference its described.The present invention has described in detail and has manufactured one skilled in the art and use the subject matter of following claims., it will be clear that to some improvement of the method and composition of claims below still within the scope of the invention with spirit.
Claims (10)
1. a kind of composition, the diastereomer of compound and its salt, solvate comprising formula (I) or (II), the enantiomer split and purification：
Wherein A1For-C (J1)=,-N=or-N (O)=；A2For-C (J1)2- ,-N (J1)-,-N (O) (J1)-,-S- ,-S (O)-,-S (O)2- or-O-；E1For-(CR1R1)m1W1；G1For N3,-CN ,-OH ,-OR6a,-NO2Or-(CR1R1)m1W2；T1For-NR1W3, H ,-R3,-R5, heterocycle, or and U1Or G1The group with following structure is formed together
U1For H ,-R3Or-X1W6；J1And J1aIt independently is R1, Br, Cl, F, I, CN, NO2Or N3；J2And J2aIt independently is H or R1；R1It independently is H or C1-C12Alkyl, R2It independently is R3Or R4, wherein each R4Independently with 0-3 R3Substituent group；R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2),
-N(R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2) ,-N (R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) ,=N (R6b) or W5；R4It independently is C1-C12Alkyl, C2-C12Alkenyl, or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0 to 3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group, or C2-C12Alkynylene, any alkylidene, alkylene group or alkynylene are by 0 to 3 R3Group is replaced；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W1For the group containing acidic hydrogen, the acidic-group of protection, or the R containing acid hydrogen group6cAcid amides；W2For the alkaline heteroatomic group containing alkaline hetero atom or protection, or the alkaline heteroatomic R6bAcid amides；W3For W4Or W5；W4For R5Or-C (O) R5,-C (O) W5,-SO2R5Or-SO2W5；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Substituent group；W6For-R5,-W5,-R5aW5,-C (O) OR6a,-C (O) R6c,-C (O) N (R6b)2,-C (NR6b)(N(H)(R6b)) ,-C (NR6b)(N(R6b)2) ,-C (N (H) (N (R6b)2) ,-C (S) N (R6b)2, or-C (O) R2；X1For a key ,-O- ,-N (H)-,-N (W6)-,-N (OH)-,-N (OW6)-,-N (NH2)-,-N (N (H) (W6))-,-N (N (W6)2)-,-N (H) N (W6)-,-S- ,-SO-, or-SO2-；With each m1 independently 0 to 2 integer；But condition is to exclude following compounds, wherein：(a)A1For-CH=or-N=and A2For-CH2-；(b)E1For COOH, P (O) (OH)2, SOOH, SO3H, or tetrazolium；(c)G1For CN, N (H) R20, N3, SR20, OR20, guanidine radicals ,-N (H) CN
(d)T1For-NHR20；(e)R20For H；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the analog that its halogen replaces；Pi-allyl or unsubstituted aryl, or by halogen, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；(f)J1For H and J1aFor H, F, Cl, Br or CN；(g)J2For H and J2aFor H, CN or N3；(h)U1For CH2YR20a, CHYR20aCH2YR20a, or CHYR20aCHYR20aCH2YR20a；(i)R20aFor H or C1-C4Acyl group；(j) Y is O, S, H or NH；(k) 0 to 2 YR20aFor H, and (l) U1Each Y portion is identical or different in group, and when Y is H, R20aFor covalent bond, and if condition is G1For N3, then U1It is not -CH2OCH2Ph, and its pharmaceutically acceptable salt and solvate；Formula II compound is also excluded, wherein：(a)A2For O；(b)E1For COOH, P (O) (OH)2, NO2, SOOH, SO3H, tetrazolium, CH2CHO, CHO, CH (CHO)2Or wherein E1For COOH, P (O) (OH)2, SOOH or SO3H, its ethyl, methyl or pivaloyl base ester；(c)G1For hydrogen, N (R20a)2, SR20aOr OR20a；(d)T1For-NHC (O) R20b, wherein R20bThe C replaced for unsubstituted or halogen1-C6Line style or cyclic alkyl, or SR20a, OR20a, COOH or its alkyl/aryl ester, NO2, C (R20a)3, CH2COOH or its alkyl/aryl ester, CH2NO2Or CH2NHR20b；(e)R20aFor hydrogen；C1-C4Acyl group；C1-C6Line style or cyclic alkyl, or the analog that its halogen replaces；Or unsubstituted aryl or by halogen, pi-allyl, OH groups, NO2Group, NH2Group or the aryl of COOH group substitution；
(f)J1For H and J1aFor H, OR20a, F, Cl, Br, CN, NHR20a, SR20aOr CH2X, wherein X are NHR20a, halogen or OR20a；(g)J2For H or J2aFor hydrogen, N (R20a)2, SR20aOr OR20a；(h)U1For CH2YR20a, CHYR20aCH2YR20aOr CHYR20aCHYR20aCH2YR20a, wherein Y is O, S or H, and U1In each Y portion it is identical or different, and R20aCovalent bond is represented when Y is hydrogen；And its pharmacologically acceptable salt or derivatives thereof.
2. a kind of composition, includes compound according to claim 1 and casing protective agent.
3. a kind of composition, the compound for the claim 1 protected comprising casing.
4. a kind of composition, includes casing protective agent and following formula: compound：
Wherein E1For-CO2H ,-CO2R5,-CO2R5aW5Or-CO2W5；G1For-N (R11)2,-N (R11)C(N(R11))(N(R11)2) or-C (R11)2-N(R11)2；T1For-NH (C (O) CH3) ,-NH (C (O) CH2F) ,-NH (C (O) CHF2) or-NH (C (O) CF3)；U1For-OR4,-SR4, NHR4Or N (R4)2；Each R1It independently is H or C1-C12Alkyl；Each R2It independently is R3Or R4, wherein each R4Independently with 0-3 R3Substituent group；Each R3It independently is F, Cl, Br, I ,-CN, N3,-NO2,-OR6a,-OR1,-N (R1)2,-N (R1)(R6b) ,-N (R6b)2,-SR1,-SR6a,-S (O) R1,-S (O)2R1,-S (O) OR1,-S (O) OR6a,-S (O)2OR1,-S (O)2OR6a,-C (O) OR1,-C (O) R6c,-C (O) OR6a,-OC (O) R1,-N (R1)(C(O)R1) ,-N (R6b)(C(O)R1) ,-N (R1)(C(O)OR1) ,-N (R6b)(C(O)OR1) ,-C (O) N (R1)2,-C (O) N (R6b)(R1) ,-C (O) N (R6b)2,-C (NR1)(N(R1)2) ,-C (N (R6b))(N(R1)2) ,-C (N (R1))(N(R1)(R6b)) ,-C (N (R6b))(N(R1)(R6b)) ,-C (N (R1))(N(R6b)2) ,-C (N (R6b))(N(R6b)2) ,-N (R1)C(N(R1))(N(R1)2) ,-N (R1)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)2),
-N(R6b)C(N(R6b))(N(R1)2) ,-N (R6b)C(N(R1))(N(R1)(R6b)) ,-N (R1)C(N(R6b))(N(R1)(R6b)) ,-N (R1)C(N(R1))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R1)(R6b)) ,-N (R6b)C(N(R1))(N(R6b)2) ,-N (R1)C(N(R6b))(N(R6b)2) ,-N (R6b)C(N(R6b))(N(R6b)2) ,=O ,=S ,=N (R1) ,=N (R6b) or W5；R4It independently is C1-C12Alkyl, C2-C12Alkenyl or C2-C12Alkynyl；R5It independently is R4, wherein each R4By 0-3 R3Group is replaced；R5aIt independently is C1-C12Alkylidene, C2-C12Alkylene group or C2-C12Alkynylene, any alkylidene, alkylene group or alkynylene are with 0-3 R3Substituent group；R6aIt independently is H or into ether or into the group of ester；R6bIt independently is H, amino protecting group or carboxylated compound residue；R6cIt independently is H or the residue containing amino-compound；W5For carbocyclic ring or heterocycle, wherein W5Independently by 0 to 3 R2Group is replaced；And R11It independently is H or R5。
5. the composition of the compound comprising claim 4, wherein E1For C (O) OCH2CH3；G1For NH2；T1For NH (C (O) CH3)；And U1For OCH (CH2CH3)2。
6. a kind of composition, the following formula: compound protected comprising casing：
7. composition according to claim 6, includes following formula: compound
With a kind of casing.
8. it is a kind of suppress neuraminidase active method, including make may the sample containing neuraminidase with comprising claim 1 casing protect composition composition contact the step of.
9. method according to claim 8, wherein neuraminidase are internal influenza neuraminidases.
10. a kind of method for the influenza infection for treating or preventing host, including it is applied to the composition of the protection compound of the casing comprising claim 1 of the data sender effective dose.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5930897P | 1997-09-17 | 1997-09-17 | |
| US60/059,308 | 1997-09-17 | ||
| US6019597P | 1997-09-26 | 1997-09-26 | |
| US93864497A | 1997-09-26 | 1997-09-26 | |
| US60/060,195 | 1997-09-26 | ||
| US08/938,644 | 1997-09-26 |
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| Publication Number | Publication Date |
|---|---|
| CN1272105A true CN1272105A (en) | 2000-11-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98809320A Pending CN1272105A (en) | 1997-09-17 | 1998-09-15 | Compound containing six-membered rings, processes for their preparation, and their use as medicaments |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1015417A1 (en) |
| JP (1) | JP2001516739A (en) |
| KR (1) | KR20010024123A (en) |
| CN (1) | CN1272105A (en) |
| AR (1) | AR013960A1 (en) |
| AU (1) | AU747702B2 (en) |
| BR (1) | BR9812649A (en) |
| CA (1) | CA2303323A1 (en) |
| EA (1) | EA003989B1 (en) |
| ID (1) | ID25516A (en) |
| IL (1) | IL134691A0 (en) |
| IN (1) | IN190983B (en) |
| NZ (1) | NZ502988A (en) |
| TR (1) | TR200000723T2 (en) |
| WO (1) | WO1999014185A1 (en) |
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| CN102659615A (en) * | 2012-05-09 | 2012-09-12 | 中国药科大学 | Derivatives of oseltamivir, and method and medical application thereof |
| CN108047076A (en) * | 2017-12-26 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir enantiomter |
| CN110194728A (en) * | 2019-06-19 | 2019-09-03 | 湖南华腾制药有限公司 | Oseltamivir phosphate intermediate is continuously synthesizing to method |
| WO2022022448A1 (en) * | 2020-07-29 | 2022-02-03 | 广州市恒诺康医药科技有限公司 | Neuraminidase inhibitor compound, and pharmaceutical composition and use thereof |
| CN116375595A (en) * | 2023-03-31 | 2023-07-04 | 重庆医药高等专科学校 | A kind of preparation method and refining method of oseltamivir phosphate |
| CN116666669A (en) * | 2023-07-25 | 2023-08-29 | 四川大学 | Ir cluster supported by VN and its preparation method and its use in catalyst |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9813480A (en) * | 1997-12-17 | 2000-10-10 | Biocryst Pharm Inc | Substituted cyclopentane neuraminidase inhibitor compounds, composition and methods of inhibiting influenza virus neuraminidase and treatment of influenza virus infection |
| US6455571B1 (en) | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
| US6518305B1 (en) | 1998-04-23 | 2003-02-11 | Abbott Laboratories | Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases |
| EP1059283B1 (en) * | 1999-06-11 | 2003-05-28 | F. Hoffmann-La Roche Ag | Process for preparing neuraminidase inhibitor ro-64-0796 |
| AU7608100A (en) * | 1999-10-19 | 2001-04-30 | Abbott Laboratories | 1-cyclohexene-1-carboxylic acid and 1-cyclohexene-1-carboxylates as neuraminidase inhibitors |
| US6593314B1 (en) | 1999-10-19 | 2003-07-15 | Abbott Laboratories | Neuraminidase inhibitors |
| JP2001131144A (en) * | 1999-11-02 | 2001-05-15 | Sagami Chem Res Center | Method for producing 7-azabicyclo [4.1.0] hept-3-en-3-carboxylic acid esters |
| US6403824B2 (en) * | 2000-02-22 | 2002-06-11 | Hoffmann-La Roche Inc. | Process for the preparation for 4,5-diamino shikimic acid derivatives |
| WO2001080892A1 (en) * | 2000-04-25 | 2001-11-01 | Sankyo Company, Limited | Preventives for influenza |
| WO2002092555A1 (en) * | 2001-05-11 | 2002-11-21 | Sankyo Company, Limited | Sialic acid derivatives |
| US7122684B2 (en) | 2003-03-13 | 2006-10-17 | Roche Colorado Corporation | Process for preparing 1,2-diamino compounds |
| JP2009522227A (en) * | 2005-12-28 | 2009-06-11 | エフ．ホフマン−ラ ロシュ アーゲー | Epoxide intermediates in the synthesis of Tamiflu |
| US8334319B2 (en) * | 2008-01-04 | 2012-12-18 | Roche Palo Alto Llc | Polymorphic forms of oseltamivir phosphate |
| CN102597120B (en) * | 2009-11-11 | 2015-05-27 | 3M创新有限公司 | Polymeric compositions and method of making and articles thereof |
| DE102011117128A1 (en) | 2011-10-28 | 2013-05-02 | Christian-Albrechts-Universität Zu Kiel | Compounds for the treatment of influenza |
| RU2469020C1 (en) * | 2011-11-08 | 2012-12-10 | Александр Васильевич Иващенко | (3r,4r,5s)-4-acylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acids, their esters and method for using |
| RU2520836C1 (en) * | 2013-02-27 | 2014-06-27 | Александр Васильевич Иващенко | (3r,4r,5s)-4-amino-5-(2,2-difluoroacetylamino)-3-(1-ethylpropoxy)-cyclohex-1-enecarboxylic acid and its ethers, method of obtaining and applying thereof |
| RU2633085C2 (en) * | 2014-05-20 | 2017-10-11 | Российская Федерация, от имени которой выступает Федеральное государственное казенное учреждение "Войсковая часть 68240" | Antiviral drug as capsules and method for its preparation |
| CN105439884A (en) * | 2015-10-27 | 2016-03-30 | 沈阳药科大学 | Oseltamivir preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SK282950B6 (en) * | 1990-04-24 | 2003-01-09 | Biota Scientific Management Pty Ltd | Alpha-D-neuraminic acid derivatives, processes for their preparation, their use, and pharmaceutical compositions based thereon |
| WO1992006691A1 (en) * | 1990-10-19 | 1992-04-30 | Biota Scientific Management Pty. Ltd. | Anti-viral compounds that bind the active site of influenza neuramidase and display in vivo activity against orthomyxovirus and paramyxovirus |
| AU720933B2 (en) * | 1995-02-27 | 2000-06-15 | Gilead Sciences, Inc. | Novel selective inhibitors of viral or bacterial neuraminidases |
| US5763483A (en) * | 1995-12-29 | 1998-06-09 | Gilead Sciences, Inc. | Carbocyclic compounds |
| NZ507106A (en) * | 1996-08-23 | 2003-01-31 | Gilead Sciences Inc | Preparation of cyclohexene carboxylate derivatives |
-
1998
- 1998-09-15 IL IL13469198A patent/IL134691A0/en not_active IP Right Cessation
- 1998-09-15 JP JP2000511738A patent/JP2001516739A/en not_active Withdrawn
- 1998-09-15 WO PCT/US1998/019355 patent/WO1999014185A1/en not_active Application Discontinuation
- 1998-09-15 KR KR1020007002880A patent/KR20010024123A/en not_active Application Discontinuation
- 1998-09-15 EP EP98949356A patent/EP1015417A1/en not_active Ceased
- 1998-09-15 BR BR9812649-0A patent/BR9812649A/en not_active Application Discontinuation
- 1998-09-15 CN CN98809320A patent/CN1272105A/en active Pending
- 1998-09-15 NZ NZ502988A patent/NZ502988A/en not_active IP Right Cessation
- 1998-09-15 TR TR2000/00723T patent/TR200000723T2/en unknown
- 1998-09-15 CA CA002303323A patent/CA2303323A1/en not_active Abandoned
- 1998-09-15 AU AU95694/98A patent/AU747702B2/en not_active Expired
- 1998-09-15 EA EA200000332A patent/EA003989B1/en not_active IP Right Cessation
- 1998-09-15 ID IDW20000543A patent/ID25516A/en unknown
- 1998-09-17 AR ARP980104638A patent/AR013960A1/en unknown
- 1998-09-17 IN IN2791DE1998 patent/IN190983B/en unknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102659615A (en) * | 2012-05-09 | 2012-09-12 | 中国药科大学 | Derivatives of oseltamivir, and method and medical application thereof |
| CN102659615B (en) * | 2012-05-09 | 2014-05-07 | 中国药科大学 | Derivatives of oseltamivir, and preparation method and medical application thereof |
| CN108047076A (en) * | 2017-12-26 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir enantiomter |
| CN108047076B (en) * | 2017-12-26 | 2020-05-08 | 杭州新博思生物医药有限公司 | Preparation method of oseltamivir enantiomer |
| CN110194728A (en) * | 2019-06-19 | 2019-09-03 | 湖南华腾制药有限公司 | Oseltamivir phosphate intermediate is continuously synthesizing to method |
| CN110194728B (en) * | 2019-06-19 | 2021-04-30 | 湖南华腾制药有限公司 | Continuous synthesis method of oseltamivir phosphate intermediate |
| WO2022022448A1 (en) * | 2020-07-29 | 2022-02-03 | 广州市恒诺康医药科技有限公司 | Neuraminidase inhibitor compound, and pharmaceutical composition and use thereof |
| CN116375595A (en) * | 2023-03-31 | 2023-07-04 | 重庆医药高等专科学校 | A kind of preparation method and refining method of oseltamivir phosphate |
| CN116666669A (en) * | 2023-07-25 | 2023-08-29 | 四川大学 | Ir cluster supported by VN and its preparation method and its use in catalyst |
| CN116666669B (en) * | 2023-07-25 | 2023-10-03 | 四川大学 | VN-supported Ir clusters, their preparation methods and their use in catalysts |
Also Published As
| Publication number | Publication date |
|---|---|
| IN190983B (en) | 2003-09-06 |
| BR9812649A (en) | 2000-08-22 |
| JP2001516739A (en) | 2001-10-02 |
| AU747702B2 (en) | 2002-05-16 |
| EA200000332A1 (en) | 2000-10-30 |
| ID25516A (en) | 2000-10-05 |
| AU9569498A (en) | 1999-04-05 |
| WO1999014185A1 (en) | 1999-03-25 |
| EP1015417A1 (en) | 2000-07-05 |
| EA003989B1 (en) | 2003-12-25 |
| KR20010024123A (en) | 2001-03-26 |
| NZ502988A (en) | 2002-08-28 |
| AR013960A1 (en) | 2001-01-31 |
| TR200000723T2 (en) | 2001-06-21 |
| IL134691A0 (en) | 2001-04-30 |
| CA2303323A1 (en) | 1999-03-25 |
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