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WO2014010748A1 - Dérivé de cyclopropane présentant une activité inhibitrice de bace1 - Google Patents

Dérivé de cyclopropane présentant une activité inhibitrice de bace1 Download PDF

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Publication number
WO2014010748A1
WO2014010748A1 PCT/JP2013/069231 JP2013069231W WO2014010748A1 WO 2014010748 A1 WO2014010748 A1 WO 2014010748A1 JP 2013069231 W JP2013069231 W JP 2013069231W WO 2014010748 A1 WO2014010748 A1 WO 2014010748A1
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substituted
unsubstituted
compound
alkyl
ring
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PCT/JP2013/069231
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English (en)
Inventor
Satoshi Shuto
Shuji Yonezawa
Kazunari Hattori
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Shionogi & Co., Ltd.
National University Corporation Hokkaido University
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Publication of WO2014010748A1 publication Critical patent/WO2014010748A1/fr

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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a compound which has an effect of inhibiting amyloid- production and is useful as a ⁇ therapeutic or preventing agent for diseases induced by production, secretion and/or deposition of amyloid- ⁇ proteins.
  • amyloid- ⁇ proteins which widely accumulate outside neurons to form insoluble plaques (senile plaques) are observed. These senile plaques are thought to kill neurons and cause the onset of Alzheimer's disease.
  • agents promoting degradation of amyloid- ⁇ proteins and amyloid- ⁇ vaccines have been studied.
  • Secretases are enzymes which cleave a protein called amyloid- ⁇ precursor protein (APP) within a cell and generate an amyloid- ⁇ protein.
  • An enzyme involving production of the N-terminal of amyloid- ⁇ proteins is called as ⁇ -secretase (beta-site APP-cleaving enzyme 1, BACE1) . It is considered that production of amyloid- ⁇ proteins may be suppressed by inhibiting this enzyme, and thus a substance with such an effect can serve as a therapeutic or preventing agent for Alzheimer's disease.
  • Patent Document 1 discloses compounds having a similar structure, to that of the compound of the ' present invention and these compounds can be a therapeutic agent for Alzheimer's disease or Alzheimer-related symptoms. However, the document specifically discloses different structures in its basic skeleton from that of the present invention.
  • Non-Patent Document 1 Compounds having a similar structure to that of the compounds of the present invention are disclosed in Patent Document 2 and Non-Patent Document 1 as an inhibitor of Na/H exchanger (NHE) , in Non-Patent Document 2 as an inhibitor of the receptor tyrosine kinases Tie-2, in Non-Patent Document 3 as a positive allosteric modulator of the metabotropic glutamate receptor subtype 4, and in Patent Document 3 and Patent Document 4 as a modulator of histamine H4 receptor.
  • Non-Patent Document 4 discloses a process for the production of a compound having similar structure to that of the compound of the invention. However, BACEl inhibitor activity is not suggested in any way.
  • the present invention provides a compound which has an effect of inhibiting amyloid- ⁇ production, in particular a BACE1 inhibitory effect, and is useful as a therapeutic or preventing agent for diseases induced by production, secretion or deposition of amyloid- ⁇ proteins.
  • the present invention provides for examples as follows: [0010]
  • a compound of the Formula (II), or a- pharmaceutically acceptable salt thereof : .
  • Ring A is aromatic carbocycle or aromatic heterocycle;
  • -X- is -N ( R 4 ) - , -0- or -S-;
  • R 4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio, carboxy or substituted or unsubstituted amino;
  • r is 1 or 2;
  • R 15 is hydrogen, or substituted or unsubstituted alkyl; each R 16 is independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
  • each R 17 is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl ;
  • either two R 16 and/or two R 17 on the different carbon atoms are optionally taken together to form a single bond when r is 2;
  • R 11 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
  • R 12 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio; R and R are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio;
  • R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 2]
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
  • R za and R z are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclylalkoxy or substituted or unsubstituted
  • heterocyclyloxycarbonyl or R za and R zb , taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle ;
  • R 3 , R 3b , R 3c , R 3d , R 3e and R 3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • substituted or unsubstituted alkynylthio substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
  • alkynyloxycarbonyl substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubsti
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 3a and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • R 3c and R 3d taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle;
  • Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle
  • Y 3 and Y 4 are each independently -C (R 5 ) (R 6 )-, -N(R 7 )-, -S-, -SO-, -SO 2 - or -0-;
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted a kyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
  • alkoxycarbonyl substituted or unsubstituted .
  • alkylsulfinyl substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl, or substituted or unsubstituted heterocyclylsulfonyl ;
  • n 1, 2 or 3;
  • each R 8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
  • Ph is phenyl
  • Ring A is aromatic carbocycle or aromatic heterocycle;
  • -X- is -N ( R 4 ) - , -0- or -S-;
  • R 4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio,. carboxy, or substituted or unsubstituted amino;
  • a dashed line indicates the presence or absence of a bond
  • R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 5]
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
  • R za and R zb are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclylalkoxy or substituted or unsubstituted
  • heterocyclyloxycarbonyl or R za and R zb , taken together with the carbon atom to which, they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle;
  • R 3 , R 3b , R 3c , R 3d , R 3e and R 3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • substituted or unsubstituted alkynylthio substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
  • alkynyloxycarbonyl substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, " substituted or unsub
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heter.ocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 3 and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • R 0 and R taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle
  • Y 3 and Y 4 are each independently -C (R 5 ) (R 6 ) -, -N (R 7 ) -, -S-, -SO-, -S0 2 - or -0-;
  • R 5 and R 6 are each independently hydrogen,, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • n 1, 2 or 3 ;
  • each R 8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
  • unsubstituted alkoxycarbonyl a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclylalkyl , substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl , substituted or
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
  • R 3a , R 3b , R 3c and R 3d are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted
  • heterocyclylalkoxy substituted or unsubstituted alkylthio, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted amino, substituted or
  • R 3a and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle.
  • Ring A is benzene ring or pyridine ring.
  • R 8 is a group of the formula:
  • Ring B is aromatic carbocycle or aromatic heterocycle; m is 0 , 1 or 2 ;
  • R 9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl ; and
  • Ak is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and each of the other R , when n is 2 or 3, is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclylalkyl , or
  • ring-constituting atom at any one of ⁇ -, ⁇ -, ⁇ - or ⁇ -position is nitrogen atom when Ring A is pyridine ring.
  • Ring B is benzene ring, or 5- or 6-membered aromatic heterocycle .
  • a pharmaceutical composition comprising a compound according to any one of the above (1) to (12) or a
  • a method for treatment and/or prevention of disease caused by BACEl comprising administering the compound according to any one of the above ( 1 ) to (12) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the compounds of the invention are useful as an agent for treating or preventing disease induced by production, secretion or deposition of amyloid ⁇ protein such as Alzheimer's disease.
  • aromatic carbocycle refers to monocyclic or condensed aromatic carbocycle, and examples include benzene ring, napthalene ring, anthracene ring, preferably benzene ring.
  • aromatic heterocycle refers to include tomonocyclic or condensed aromatic heterocycle, and examples include pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, isothiazole ring, isoxazol ring, oxazole ring, thiazole ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole ring, oxadiazole ring, thiadiazol ring, indolizine ring, isoindole ring, indole ring, indazole ring, purine ring, quinolizine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinolone ring, quinazoline ring, cinnoline ring, pteridin ring, carba
  • ring acridine ring, dibenzofuran ring, benzoxazolone ring, benzoxazinone ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazol ring, benzofuran ring, benzothiophene ring, Dibenzothiophene ring, benzodioxolan ring etc ., preferably pyridinium ring, furan ring, thiophene ring.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl includes C1-C15, preferably C1-C10, more, preferably C1-C6, and further, preferably C1-C3 straight or branched alkyl. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl .
  • alkylsulfonylamino , “alkylsulfonyl alkylamino”
  • alkylsulfonylimino "alkylsulfinyl amino", “alkylsulfinyl alkylamino", “alkylsulfinylimino” , “alkyl sulfamoyl”, “alkylsulfinyl” , “carbocyclylalkyl “ , “carbocyclylalkoxy” , “carbocyclylalkoxycarbonyl” , “carbocyclylalkylamino” , v"carbocyclylalkyl carbamoyl", “heterocyclyalkyl",
  • heterocyclylalkoxycarbonyl and “heterocyclyalkyl carbamoyl” is defined above for “alkyl”.
  • substituted or unsubstituted alkyl refers to the above “alkyl” substituted or unsubstituted with one or more groups selected from the substituent group a.
  • the substituent group a herein consists of halogens, hydroxy, alkoxy, halogeno alkyl , halogeno alkoxy, hydroxy alkoxy, alkoxy alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkyl carbamoyl, hydroxyalkyl carbamoyl, sulfamoyl, alkyl sulfamoyl, alkylsulfinyl , alkylsulfonylamino, alkylsulfonyl alkylamino, alkylsulfonylimino, alkylsulfinyl amino, alkylsulfinyl alkylamino, alkylsulfinylimino, cyano, nitro, carbocycl
  • substituent group in "substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl” , “substituted or unsubstituted alkylthio", “substituted or unsubstituted alkylsulfonyl” and “substituted or unsubstituted alkylsulfinyl" may be one or more groups selected from the . substituent group ex.
  • halogeno alkyl includes trifluoromethyl, fluoro methyl , trichloro methyl , and the like.
  • halogeno alkoxy includes trifuoro methoxy, fluoro methoxy, . trichloro methoxy, and the like.
  • alkenyl refers to include C2-C15, preferably C2-C10, more, preferably C2-C6, and further, preferably C2-C4 straight or branched alkenyl having one or more double bonds at any position. Specific examples thereof include vinyl, allyl, propenyl, isopropenyl, butenyl, .
  • alkenyl moiety in “alkenyloxy” , “alkenyl oxycarbonyl” , “alkenyl- carbonyl”, “alkoxy alkenyloxy”, “alkenylthio” , “alkenylamino” , “alkenyl sulphonyl” and “alkenyl sulfinyl” is defined above for “alkenyl”.
  • alkynyl refers to include C2-C10, preferably C2-C8, and more, preferably C3-C6 straight or branched alkynyl having one or more triple bonds at any position Specific examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl . These groups may further have a double bond at any position. [0040]
  • alkynyl moiety in “alkoxy alkynyl”, “alkynyloxy”, “alkynyl oxycarbonyl " , “alkynyl carbonyl”, “alkoxy alkynyloxy”, “alkynylthio” , “alkynyl sulfinyl”, “alkynyl sulphonyl” and “alkynyl amino” is defined above for “alkynyl”.
  • acyl refers to include formyl, C1-C10 alkylcarbonyl, C2-C10 alkenyl carbonyl, C2-C10 alkynyl carbonyl, carbocyclylcarbonyl and heterocyclic carbonyl. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,.
  • hexanoyl acryloyl, propioloyl, methacryloyl , crotonoyl, benzoyl, cyclohexanecarbonyl , pyridinium carbonyl, furan carbonyl , thiophene carbonyl, benzothiazol carbonyl, pyrazine carbonyl, piperidine carbonyl and thiomorpholino .
  • carbocyclic group includes cycloalkyl, cycloalkenyl , aryl and fused non-aromatic carbocyclic groups . [0044] .
  • cycloalkyl includes C3-C10, preferably C3-C8 , and more, preferably C4-C8 carbocyclic groups . Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl . [0045]
  • cycloalkenyl includes those having one or more double bonds at any position in the ring of the cycloalkyl. Specific examples thereof include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl , cycloheptynyl , cyclooctynyl and cyclohexadienyl .
  • aryl includes phenyl, naphthyl, anthryl and phenanthryl . Phenyl is particularly preferable among these.
  • fused non-aromatic carbocyclic group includes non-aromatic groups formed by fusion of two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl”. Specific examples thereof include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
  • non-aromatic carbocycle is the same as that of the "cycloalkyl” , “cycloalkenyl” and “fused non-aromatic carbocyclic group". Specific examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane , cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
  • Carbocyclylsulfinyl is defined above for “carbocyclic group” .
  • heterocyclic group includes heterocyclic groups having one or more hetero atoms arbitrarily selected from oxygen atom, sulphur atom and nitrogen atom in the ring. Specific examples thereof include .5- or 6-membered heteroaryls such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl , thiazolyl, and thiadiazolyl ;
  • non-aromatic heterocyclic groups such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathioranyl , azetidinyl, thianyl, thiazolidinyl , pyrrolidinyl , pyrrolinyl, imidazolidinyl , imidazolinyl , pyrazolidinyl , pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl , thiomorpholino, dihydropyridyl , tetrahydropyridyl , tetrahydrofuryl , tetrahydropyranyl , dihydrothiazolyl , tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl , hexahydro
  • bicyclic heterocyclic groups such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl , quinolyl, isoquinolyl, cinnolinyl, phthalazinyl , quinazolinyl , naphthyridinyl , quinoxalinyl , purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl , benzoxadiazolyl , benzoisothiazolyl , benzothiazolyl , benzothiadiazolyl , benzofuryl, isobenzofuryl , benzothienyl , benzotriazolyl, thienopyridyl , thienopyrrolyl , thienopyrazolyl , thi
  • chromanyl chromenyl, octahydrochromenyl , dihydrobenzodioxinyl , dihydrobenzooxedinyl , dihydrobenzodioxepinyl and dihydrothienodioxinyl ; and fused tricyclic heterocyclic groups such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl , phenoxathiinyl , phenoxazinyl , dibenzofuryl , imidazoquinolyl and tetrahydrocarbazolyl .
  • Preferable among these are 5- or 6-membered heteroaryls or non-aromatic heterocyclic groups.
  • heterocyclylsulphonyl , “heterocyclylcarbamoyl” , “heterocyclyloxycarbonyl “ , “heterocyclylalkylamino” , “heterocyclylalkoxycarbonyl” and “heterocyclyalkyl carbamoyl” is defined above for “heterocyclic group”.
  • heterocycle moiety in "non-aromatic heterocycle” is the same as that in the above “non-aromatic heterocyclic group” .
  • Specific examples thereof include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidin, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine , pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydro pyridinium, tetrahydro pyridinium, tetrahydrofuran, tetrahydro pyran, dihydro thiazole, tetrahydro thiazole, tetrahydro isothiazole, dihydro oxazine, hexahydro azepine, tetrahydro diazepine, te
  • the bond (s) in the above “heterocyclic group” may be positioned in any ring.
  • heteroaryl includes aromatic heterocyclic groups which are included in the “heterocyclic group”.
  • alkylene includes C1-C10, preferably C1-C6, and more, preferably C1-C3 straight or branched divalent carbon chains. Specific examples thereof include methylene, dimethylene, .trimethylene, tetramethylene and methyl trimethylene.
  • alkenylene includes C2-C10, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a double bond at any position. Specific examples thereof include vinylene, propenylene, butenylene, butadienylene , methyl propenylene, pentenylene and hexenylene.
  • alkynylene includes C2-C10, more, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a triple bond at any position and optionally further having a double bond. Specific examples thereof include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • the compound of formula (I) includes pharmaceutically acceptable salts thereof.
  • examples thereof include salts with alkaline metals (e.g. lithium, sodium and potassium) , alkaline earth metals (e.g. magnesium and calcium), transition metals (e.g., zinc), ammonium, organic bases and amino acids, and salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids (e.g.
  • acetic acid trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and ethanesulfonic acid) .
  • Specifically preferable are hydrochloric acid, phosphoric acid, tartaric acid and methanesulfonic acid. These salts may be formed by a conventional method.
  • the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate) and/or crystal polymorphism. Such solvates and crystal polymorphism is encompassed by the present invention.
  • any number of solvent (e.g., water) molecules may be conjugated with one molecule of the compound of formula (I) and (II) .
  • the compound of formula (I) and (II) or a pharmaceutically acceptable salt thereof by allowing it to stand in the atmosphere, may absorb moisture leading to attachment of adsorbed water or formation of a hydrate.
  • the compound of formula (I) and (II) of a pharmaceutically acceptable salt thereof may form crystal polymorphism by recrystallization thereof.
  • the compounds of formula (I) and (II) are not limited to a specific isomer, and include any possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers , optical isomers and rotamers ) and racemic mixtures .
  • compounds of formula (I) wherein R 2a is hydrogen include the following tautomers .
  • a compound of formula (I), wherein -X- is -N(H)-, and R 3a and R 3b are taken together with the carbon atom to which they are attached to form a carbonyl group includes the following tautomers.
  • the compound of formula (I) and (II) has an asymmetric carbon atom(s), and thus, includes the following optical isomers. [Chemical Formula 20]
  • An optical isomer of the compound of formula (I) and (II) may be obtained by conventional technique known in the art, such as chiral chromatography, and formation of diastereomer salt using an optical active acid or base.
  • one or more hydrogen, carbon or other atoms of acompound of formula (I) and (II) may be replaced by an isotope of the hydrogen, carbon or other atoms.
  • Compounds of formula (I) and (II) include all radiolabeled forms of compounds of formula (I) and (II) .
  • Such "radiolabeled, " “radiolabeled form” , and the like of a compound of formula (I) and (II) is useful as a research and/or diagnostic to ol in metabolism pharmacokinetic studies and in binding assays, and also as a medicament.
  • isotopes that can be incorporated into a compound of formula (I) and (II) of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 123 I and 36 C1.
  • Radiolabeled compounds of the invention can be prepared by methods well known in the art.
  • tritiated compounds of. formula (I) or (II) can be prepared by introducing tritium into the particular compound of formula (I) or (II) , for example, by catalytic dehalogenation with tritium.
  • This method may include reacting a suitably halogen-substituted precursor of a compound of formula (I) or (II) with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base.
  • a suitable catalyst such as Pd/C
  • Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences , Vol. 1, Labeled Compounds (Part A) Chapter 6 (1987) .
  • 14 C-labeled compounds can be prepared by employing starting materials having a. 14 C carbon.
  • ring A in formula (I) or (II) includes benzene ring or pyridine ring.
  • R 2a and R 2b in formula (I) or (II) include respectively hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl--, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl .
  • R 2a and R 2 may be both hydrogen.
  • R za and R zb are taken together with the carbon atom to which they are attached to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle.
  • R 3a and R 3b in formula (I) or (II) can be taken together with the carbon atom to which they are attached to form a carbonyl group.
  • R 3a and R 3b are taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 3c and R 3d are taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 8 can be represented by the formula:
  • each variable is as defined above, and R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring.
  • R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring.
  • m 1 is 0 or 1
  • the other variables are as defined above.
  • R 8 can be represented by the formula
  • each variable is as defined above, and R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring, and
  • R 8 can be halogens, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl .
  • R 8 can be represented by the formula [Chemical Formula 37]
  • Ring B is aromatic carbocycle or aromatic heterocycle
  • n is an integer of 0 to 2;
  • R 9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1- .
  • R 8 can be represented by the formula [Chemical Formula 38]
  • ring B, m, R 9 are as defined above, Ak is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C3 alkenylene or substituted or unsubstituted C1-C3 alkynylene.
  • Ak can be G2 alkylene, C2 alkenylene or C2 alkynylene .
  • ring B can be benzene ring, napthalene ring, or 5 or .6-membered aromatic heterocycle.
  • R 1 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 1 is specifically, for example, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 1 is more particularly, for example, C1-C3 unsubstituted alkyl.
  • Me is methyl; ) in formula (I) or (II), [Chemical Formula 64]
  • each R 9 in the above 5) is independently [Chemical Formula 71]
  • n in the above 5) is 0, 1 or 2.
  • the present compound of the formula (I) or (II) can be prepared by the following method .
  • any substituent group that interferes with the reaction e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy
  • wedge-shaped solid or dashed lines are used to denote absolute configuration, and bold solid or dashed lines are used to denote relative configuration.
  • Lactone 3 can be prepared according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem. ) 1996, 61, 915-923, using epichlorohydrin 1 as a starting material.
  • a base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide
  • the mixture is reacted at a temperature from-10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs .
  • An acid such as hydrochloric acid is added to neutralize, and the solvent is removed.
  • An alkylsilyl halide is added to react at a temperature from-10 to 50°C, preferably 0 to 2°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs.
  • a base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide
  • a solvent e.g., methanol, ethanol, water
  • the solution is neutralized with an acid such as hydrochloric acid to obtain compound 4.
  • Compound 5 can be prepared by isomerizing compound 4 according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem.) 2003, 68, 9255-9262. [0105]
  • Compound 6 can be prepared by oxidation of compound 5 using sodium periodate and ruthenium chloride, using potassium permaganate under alkaline condition, by Jones oxidation, under condition using PCC, PDC, ruthenium tetroxide and TEMPO, or using sodium hypochlorite, sodium chlorite and TEMPO.
  • An optically active compound 6 can be prepared using an optically active epichlorohydrin 1.
  • Carboxylic acid 6, 10a (1R,2R) or 10b (1S,2S) obtained above can be reacted with CDI to convert to an active ester. Then, salt of malonic acid halfester, magnesium chloride and triethylamine are added, and the mixture is reacted at 0 to 100°C, preferably 25 to 80°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound 11.
  • compound la can be prepared by treating compound 11 with guanidine to form amino pyrimidone ring.
  • compounds of the present invention may be prepared by forming aminooxazine ring or aminothiazine ring according to the procedure described below.
  • An ester compound such as ethyl propionate is reacted in the presence of a. base, such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate.
  • a. base such as lithium diisopropylamide
  • a solvent e.g., toluene, dichloromethane, THF
  • a titanium agent such as chlorotitanium triisopropoxide, and compound a, which can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound b.
  • Compound b is reacted with a Grignard reagent commercially available or prepared by known method such as methylmagnesium bromide, or an reducing agent such as borane,. sodium borohydride, and lithium aluminum hydride, in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof at -80 to 80°G, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, to obtain compound c.
  • a Grignard reagent commercially available or prepared by known method such as methylmagnesium bromide, or an reducing agent such as borane,. sodium borohydride, and lithium aluminum hydride
  • Compound c is reacted in a solvent (e.g., dioxane, methanol, dichl-o omethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound d.
  • a solvent e.g., dioxane, methanol, dichl-o omethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound d is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) , in a solvent (e . g . , ⁇ dioxane , THF, toluene, acetone) or a mixed solvent thereof at -30 to 50 °C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound e.
  • a solvent e . g . , ⁇ dioxane , THF, toluene, acetone
  • Compound e is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide), at 0 to 200°C, preferably 40 to 150°C for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound lb.
  • an alkylating agent e.g., methyl iodide, diethyl sulfate, benzyl bromide
  • a solvent e.g., methanol, ethanol, dimethylformamide, THF
  • an base e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydrox
  • Compound a which can be prepared by known method, is added to a Grignard reagent such as allylmagnesium bromide, in a solvent (e.g., toluene, dichloromethane , THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound f .
  • a solvent e.g., toluene, dichloromethane , THF
  • Step 2 Compound f is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound g.
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound g is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate ) , in a solvent (e.g., dichloromethane, dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30to50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound h.
  • a solvent e.g., dichloromethane, dioxane, THF, toluene, acetone
  • Compound h is reacted with a hologenium ion source (e.g. , iodine, bromine, N-bromo succinimide (NBS)), in a solvent such as dichloromethane, at -20 to 40°C, preferably 0 to 20°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by the reaction with a base (e.g., pyrrolidine, piperidine, piperazine, morpholine) at 20 to 100°C, preferably 40 to 80°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ic.
  • a hologenium ion source e.g. , iodine, bromine, N-bromo succinimide (NBS)
  • a solvent such as dichloromethane
  • a base e.g., pyrrolidine, piperidine, piperazine, morpholine
  • a carbonyl compound such as diethyl ketone is reacted in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate.
  • a titanium agent such as chlorotitanium triisopropoxide, and compound a, which. can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
  • Compound i is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound j ⁇ .
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound j is reacted with an isocyanate having .
  • a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate), in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound k.
  • Compound k is reacted with an acid such as cone, sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound [0130]
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Y a is Y 1 or Y 3
  • Y b is Y 2 or Y 4
  • a dashed line indicates the presence or absence of a bond
  • Compound a which can be prepared by known method, is reacted with an enolate obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound 1.
  • a solvent e.g., toluene, dichloromethane, THF
  • a mixed solvent thereof e.g., toluene, dichloromethane, THF
  • Compound 1 is reacted in a solvent (e.g., dioxane, methanol, dichloromethane) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound m.
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound m is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound le.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone .
  • sulfuric acid and cone, nitric acid at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12
  • Compound le wherein a dashed line indicates the absence of a bond can be prepared from compound le wherein either dashed line indicates the presence of a bond, using conventional method such as a method of hydrogenation .
  • Compound a which can be prepared by known method, is reacted with an enolate which was obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30 °C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound n.
  • a solvent e.g., toluene, dichloromethane, THF
  • a mixed solvent thereof e.g., toluene, dichloromethane, THF
  • Compound n is reacted with a Grignard reagent commercially available or prepared by known method (e.g., methylmagnesium bromide) in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof, at -80 to 80°C, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, followed by the reaction in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound o.
  • a solvent e.g., dioxane, THF, ether, toluene
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound o is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e . g ., benzoyl isocyanate) in a solvent (e . g ., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p.
  • a solvent e . g ., dioxane, THF, toluene, acetone
  • an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to
  • Step 4 To compound p in a solvent (e . g . , dichloromethane, THF, toluene) are added oxalyl chloride or thionyl chloride and a catalytic quantity of N, N-dimethylformamide, or is added a chlorinating agent such as l-chloro-2-trimethylpropenylamine, and the mixture is reacted at 0 to 100°C, preferably 10 to 50°C, for 0.5 to 72 hrs, preferably 0.5 to 6 hrs, to obtain compound If.
  • a solvent e . g . , dichloromethane, THF, toluene
  • Compound a is added to a Grignard reagent (e.g., phenylmagnesium bromide having optionally protected hydroxy group at ortho position) or a lithium agent (e.g., pyridyl lithium having optionally protected hydroxy group at ortho position) in a solvent (e.g., toluene, diethylether, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, and the protecting group is removed by known method to obtain compound q. .
  • a Grignard reagent e.g., phenylmagnesium bromide having optionally protected hydroxy group at ortho position
  • a lithium agent e.g., pyridyl lithium having optionally protected hydroxy group at ortho position
  • solvent e.g., toluene, diethylether, THF
  • Compound q is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic.acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound r .
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic.acid, sulfuric acid, trifluoroacetic acid
  • Compound r is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound s.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • Compound s is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide) at 0. to 200°C, preferably 40 to 150°C, for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound Ig.
  • an alkylating agent e.g., methyl iodide, diethyl sulfate, benzyl bromide
  • a solvent e.g., methanol, ethanol, dimethylformamide, THF
  • an base e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide
  • compounds of the invention can be prepared by forming amino thiazine ring according to the procedure as described in Journal of Hetero cyclic Chemistry, 14, 717-723 (1977) .
  • a solvent e.g. , ' dichloromethane, THF, toluene
  • a chlorinating agent such as l-chloro-2-trimethylpropenylamine
  • Compound a which can be prepared by known method, is added to an enolate obtained by the reaction with corresponding alkyl ketone (e.g., 3-methyl -2-butanone) , in the presence of a base, such as lithium diisopropylamide , potassium hexamethyldisilazide, ' in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
  • a base such as lithium diisopropylamide , potassium hexamethyldisilazide
  • a solvent e.g., toluene, dichloromethane, THF
  • Compound i is reacted with an acid such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, at 0 to 60°C, preferably 0 to 30°C, for 0.1 to 24 hrs, preferably 0.5 to 12 hrs, to obtain compound ii.
  • an acid such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid
  • Compound ii is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound Ii.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Compound j is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 70°C, preferably -20 to 50°C for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 1 to 12 hrs, preferably 1 to 6 hrs, to obtain compound Ij..
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Compound m is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid to react at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ik.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone .
  • sulfuric acid and cone nitric acid to react at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24
  • Compound o is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate ) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone, sulfuric acid and cone .
  • nitric acid at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p .
  • a solvent e.g., dichloromethane, THF, toluene
  • Compound II wherein a dashed line indicates the absence of a bond can be prepared from compound II wherein either dashed line indicates the presence of a bond, using a conventional method such as a method of hydrogenation .
  • R is a group such as optionally substituted alkyl, optionally substituted hydrocarbon ring, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • Compound I wherein R is hydrogen is reacted with an acylating agent having a substituent group corresponding to the desired compound, such as benzoyl chloride, 2-furoyl chloride, and acetic anhydride, in the presence or absence of a solvent such as THF and dichloromethane, in the presence or absence of a base such as pyridine and triethylamine, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs reactions, or the above compound I is reacted with a carboxylic acid having a substituent group corresponding to the desired compound, such as amino acid, and -glycol acid, in a solvent such .
  • NHR U is optionally substituted amino
  • NR 20 COR ,2 ' 1 L is optionally substituted acylamino, optionally substituted ureido, or carboxy amino having a substitutent group on oxygen atom, and the other variables are as defined above.
  • Compound I wherein Ring A is optionally substituted with amino is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoylchloride,.
  • a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoylchloride,.
  • NHR is optionally substituted amino
  • R z 22 is alkyl
  • R is a group, such as optionally substituted alkyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • G is a group such as optionally substituted alkenyl, optionally substituted alkynyl, . optionally substituted alkoxycarbonyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • R 24 is hydrogen or optionally substituted alkyl
  • R 25 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted carbocyclic group or optionally substituted heterocyclic group, and the other variables are as defined above.
  • Compound I is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, and isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc.
  • a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, and isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc.
  • the substituent group may be protected in advance for coupling reaction, and the protective group may be removed at a desirable step.
  • the compound is reacted at -30 to 100 °C, preferably 0 to 90°G for 0.5 to 12 hrs in a solvent such as methanol, ethanol, ether, THF, 1,4-dioxane, dichloromethane , ethyl acetate, containing hydrogen chloride, trifluoroacetic acid etc., or trifluoroacetic acid in the absence of a solvent, or according to the method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) to obtain compound Is.
  • a solvent such as methanol, ethanol, ether, THF, 1,4-dioxane, dichloromethane , ethyl acetate, containing hydrogen chloride, trifluoroacetic acid etc., or trifluoroacetic acid in the absence of a solvent, or according to the method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) to
  • LI is methanesulfonyl or toluenesulfonyl , etc. , and the other variables are as defined above.
  • a solvent such as ether, and THF
  • Compound 15 is reacted with sodium borohydride, lithium triethylborohydride or lithium aluminum hydride, etc. in a solvent such as ether, and THF, at -30 to 50°C, preferably 0 to 25°C, for 0.5 to 5 hrs, to obtain compound 16.
  • Compound 12 is reacted with compound 17 in a solvent such as THF, and toluene, at -80 to 150°C, preferably -30 to 100°C, for 0.5 to 24 hrs, to obtain compound 18.
  • a solvent such as THF, and toluene
  • Compound 18 is reacted with hydrogen gas in a solvent such as methanol, ethanol, ether, THF, ethyl acetate, acetic acid, and a mixed solvent thereof, in the presence of a metal catalyst at 0 to reflux temperature, preferably 0 to 40°C, for 0.5 to 72 hrs, preferably 1 to 12 hrs, . to obtain compound 19.
  • a solvent such as methanol, ethanol, ether, THF, ethyl acetate, acetic acid, and a mixed solvent thereof
  • Compound 12 is reacted with compound 20 in a solvent such as dichloromethane, in the presence of a reducing agent such as sodium cyanoborohydride , sodium triacetoxyborohydride, at -30 to 100°C, preferably 0 to 25°C, for 0.5 to 24 hrs to obtain compound 21.
  • a reducing agent such as sodium cyanoborohydride , sodium triacetoxyborohydride
  • Cyclopropane intermediate 24 and 25 are prepared according to the method as described in J. Med. Chem. , 2006, 49, 5587-5596.
  • Compound 26 is reacted with compound 27 in a solvent such as THF, DMF, and D SO, in the presence of sodium hydride, potassium carbonate, cesium carbonate, etc. at 0 to 120°C, preferably 0 to 50 °C, for 0.5 to 24 hrs to obtain compound 28.
  • a solvent such as THF, DMF, and D SO
  • PI is a carboxy protecting group and the other variables are as defined above.
  • An optically active from of compound (I) or (II) can be prepared by using an optical activate starting material, obtaining an optical activate intermediate by asymmetric synthesis in appropriate step, or optically resoluting. an intermediate of each racemate and a final product in an appropriate step.
  • Procedures of the optical resolution include a method of separating an optical isomer using an optically active column; kinetic optical resolution utilizing an enzymatic reaction and the like; crystallization resolution of a diastereomer by salt formation using a chiral acid or a chiral base; preferential crystallization method and the like.
  • compound 4 obtained in Step 2 can be subjected to cyclization reaction to form amino pyrimidone ring, followed by isomerization reaction by Barton decarboxylation to obtain cis-form stereoselectively .
  • the compound of the invention is useful in disease induced by the production / secretion or deposition of amyloid ⁇ protein, and are effective in treatment and/or .
  • prevention and symptom improvement of diseases such as dementia of the Alzheimer' s type (e.g. , Alzheimer ' s disease, senile dementia of Alzheimer type ) , Down's syndrome, memory impairment, prion disease (e.g., Creutzfeldt-Jakob disease) , mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other type of degenerative dementia, mixed dementia with Alzheimer's and vascular type, dementia, with Parkinson's Disease, dementia with progressive supranuclear palsy, dementia with Cortico-basal degeneration, Alzheimer ' s disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's Disease, amyloid angiopathy.
  • dementia of the Alzheimer' s type e.g. , Alzheimer
  • treating Alzheimer's disease includes prevention of aggravation of MCI and prevention of familial Alzheimer's disease.
  • a pharmaceutical composition for treating Alzheimer's disease includes a pharmaceutical composition for prevention of aggravation of MCI and prevention of familial Alzheimer's disease.
  • the present compound Since the present compound has high inhibitory activity on BACEl, and/or has high selectivity on other enzymes, it can be a medicament with reduced side effect. Further, since the compound has high effect of reducing amyloid ⁇ production in a cell system, particularly, has high effect of reducing amyloid ⁇ production in .brain, it can be an excellent medicament. In addition, by converting the compound into aft optically active compound having suitable stereochemistry, the compound can be a medicament having a wider safety margin on the side effect.
  • the present compound also has advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, clearance is good, brain transference is high, a half-life is long, non-protein binding rate is high, hERGchannel inhibition is low, CYP inhibition is low, CYP MBI (mechanism-based inhibition) is low, and/or an Ames test is negative. [0181]
  • the compound of the invention can be administrated in combination with other pharmaceutical agents such as other therapeutic drugs for .
  • Alzheimer's disease e.g., acetylcholinesterase and the like.
  • the compound of the invention can be administered in combination with anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine.
  • anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine.
  • the compound of the invention When the compound of the invention is administered to a human, it can be administered orally as powders, granules, tablets, capsules, pills, solutions, or the like, or parenterally as injectables, suppositories, transdermal absorbable agents, inhalations, or the like.
  • the compound of the invention can be formulated into pharmaceutical, preparations by adding pharmaceutical additives such as excipients, binders, wetting agents , disintegrating agents , lubricants and the like, which are suitable for mulations and an effective amount of the compound.
  • the dose is varied depending on state of disease, an administration route, and an age and a weight of a patient, and is usually 0.1 pg to 1 g/day, preferably 0.01 to 200 mg/day when orally administered to an adult, and is usually 1 ]iq to 10 g/day, preferably 0.1 to 2 g/day when parenterally administered.
  • RT in the tables means retention time (minute) in LC/MS: liguid chromatography / Mass spectroscopy measured under the following condition.
  • UV detection wavelength 254 nm
  • ethanol 120ml
  • lOmol/L aqueous potassium hydroxide 40ml
  • the solvent was removed to half its original volume under reduced pressure, and the solution was poured into a mixture of cooled cone, hydrochloric acid (60ml) and water (60ml).
  • the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over sodium sulfate. Sodium sulfate was removed, and the solution was concentrated under reduced pressure.
  • the aqueous layer was acidified with 6mol/L hydrochloric acid, and the solution was extracted with ethyl acetate.
  • the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residual solid was washed with hexane to yield compound all (16.2g, 56.8mmol, 87%) as a greyish brown solid.
  • Triisopropoxy titanium (IV) chloride (3.72ml, 15.6mmol) in THF (6ml) was added over 10 min, and the mixture was stirred at - 70°C for 20 min.
  • Compound a21 (977mg, 3.71mmol) in THF (4ml) was. added over 5 min, and the reaction mixture was stirred at - 70°C for 1 hr and added dropwise to ammonium chloride (1.19g) in water (4ml) under ice-cooling.
  • ethyl acetate (10ml) and celite (2g) To the reaction mixture were added ethyl acetate (10ml) and celite (2g) , the mixture was stirred at room.temperature for 10 min. The resultant insoluble solids were filtered off over celite, and water was added to the filtrate.
  • compound a28 was obtained as a colorless liquid.

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Abstract

La présente invention concerne des compositions de formules (I) et (II) : dans lesquelles chaque variable est telle que définie dans la description, leurs sels et solvates pharmaceutiquement acceptables, ainsi que l'utilisation de tels composés comme inhibiteur de BACE1. Les composés de l'invention sont utiles comme agent de traitement d'une maladie induite par la production, la sécrétion et/ou un dépôt de protéine β amyloïde.
PCT/JP2013/069231 2012-07-10 2013-07-09 Dérivé de cyclopropane présentant une activité inhibitrice de bace1 WO2014010748A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
WO2020017569A1 (fr) 2018-07-17 2020-01-23 日本ケミファ株式会社 Inhibiteur du canal calcique de type t
WO2020203609A1 (fr) 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation de bloqueur des canaux calciques de type t servant au traitement du prurit
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001027107A2 (fr) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company Inhibiteurs heterocycliques d'echange sodium / protons et procedes a cet effet
WO2006041404A1 (fr) * 2004-10-15 2006-04-20 Astrazeneca Ab Composes amino substitues et utilisation de ces compose
WO2009068512A1 (fr) * 2007-11-30 2009-06-04 Palau Pharma, S. A. Dérivés de 2-aminopyrimidine en tant qu'antagonistes d'histamine h4
WO2012156284A1 (fr) * 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines en tant qu'inhibiteurs de bace1 et/ou de bace2

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001027107A2 (fr) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company Inhibiteurs heterocycliques d'echange sodium / protons et procedes a cet effet
WO2006041404A1 (fr) * 2004-10-15 2006-04-20 Astrazeneca Ab Composes amino substitues et utilisation de ces compose
WO2009068512A1 (fr) * 2007-11-30 2009-06-04 Palau Pharma, S. A. Dérivés de 2-aminopyrimidine en tant qu'antagonistes d'histamine h4
WO2012156284A1 (fr) * 2011-05-16 2012-11-22 F. Hoffmann-La Roche Ag 1,3-oxazines en tant qu'inhibiteurs de bace1 et/ou de bace2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHUJ I YONEZAWA ET AL.: "Conformational Restriction Approach to beta-Secretase(BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 20, 25 October 2012 (2012-10-25), pages 8838 - 8858 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
KR20160141849A (ko) 2014-04-11 2016-12-09 시오노기세이야쿠가부시키가이샤 Bace1 저해 작용을 갖는 디하이드로티아진 및 디하이드로옥사진 유도체
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
WO2020017569A1 (fr) 2018-07-17 2020-01-23 日本ケミファ株式会社 Inhibiteur du canal calcique de type t
WO2020203609A1 (fr) 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation de bloqueur des canaux calciques de type t servant au traitement du prurit

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