CN1069490A - Urea derivatives - Google Patents
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- CN1069490A CN1069490A CN 92109284 CN92109284A CN1069490A CN 1069490 A CN1069490 A CN 1069490A CN 92109284 CN92109284 CN 92109284 CN 92109284 A CN92109284 A CN 92109284A CN 1069490 A CN1069490 A CN 1069490A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- 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
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
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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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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Abstract
As above to lead to novel urea derivatives or its salt that formula I is represented, have the effect of k-receptor activation, be useful as the central analgesic agent.
Description
The present invention relates to have the pharmaceutically useful urea derivatives and the salt thereof of analgesic activity etc.
To treatment of pain, using anodyne is to begin to use step by step from weak drugs with function clinically, and final the use pretended the medication morphine.As everyone knows, morphine can form dependency.
In recent years, because the opiate receptor progress of research has disclosed numerous hypotypes such as μ, κ, δ, σ.The effect of strong analgesics such as morphine is to activate μ-acceptor and present analgesic activity.The shortcoming of this receptor stimulant is to show dependency.The medicine no dependence of selectively activate κ-acceptor is just become the central analgesic agent by expectation.
So far, European patent No.261 for example, 842 have put down in writing κ-receptor agonism 2-aminoethyl derivative.
In of the generality record of this communique, mentioned some carbamide compound, but this carbamide compound there is no any concrete announcement extensive compound.
The result that present inventors concentrate on studies confirm to show the strong analgesic activities that can be equal to mutually with morphine and no dependence, selectivity κ-receptor stimulant that toxicity is low again, is the medicine that can reach clinical purpose, thereby has finished the present invention.
The compounds of this invention is obviously to distinguish, do not have the pretend medication dependency of confirming, the compound that toxicity is low again such as morphine with above-mentioned known compound on chemical structure.And, still show good oral absorption and have the compounds of lasting, good κ-receptor agonist activity.
The present invention relates to the urea derivatives and the salt thereof of the novelty represented with following general formula.
Group is expressed as follows in the formula:
R
1, R
2: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
1With R
2Together, form cyclic group jointly with nitrogen-atoms;
R
3, R
4: hydrogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
3With R
4All-in-one-piece low-grade alkylidene, rudimentary alkylene group, or formula
The group of expression, (in the formula, X is Sauerstoffatom or sulphur atom, and n is 1 to 5 integer);
R
5: can substituted carbocylic radical, or can be substituted and the heterocyclic radical that contains 1-2 Sauerstoffatom and/or sulphur atom of phenyl ring condensation;
R
6: can substituted phenyl
X: Sauerstoffatom or sulphur atom.
Yet, when X is Sauerstoffatom, R
3, R
4For connecting together, substituent low-grade alkylidene, rudimentary alkylene group or formula can be arranged
The group of expression.(following same)
Fig. 1 is for comparing the persistence of the analgesic effect of The compounds of this invention (compound of embodiment 21) and control compound (European patent No.261, the compound of 842 embodiment 1) with the acetic acid twisting method.
The compounds of this invention :-zero-, control compound :--
（20mg/kg） （1mg/kg）
Further describe The compounds of this invention below.
Being defined in when not limiting especially in advance of this specification sheets formula of, so-called " rudimentary " is meant carbonatoms 1-6 straight or branched carbochain.
Therefore, " low alkyl group ", can enumerate particularly such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl, tert-butyl, amyl group, isopentyl, neo-pentyl, uncle-amyl group, the 1-methyl butyl, the 2-methyl butyl, 1, the 2-dimethyl propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl etc., preferable is methyl, ethyl, propyl group, sec.-propyl, butyl etc.
" low-grade alkenyl " is carbonatoms 2-6 straight or branched alkenyl, can be particularly: vinyl, allyl group, the 1-propenyl, pseudoallyl, the 1-butylene base, crotyl, the 3-butenyl, 2-methyl isophthalic acid-propenyl, the 2-methacrylic, 1-methyl isophthalic acid-propenyl, the 1-methacrylic, 1,1-dimethyl vinyl, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, the 3-methyl-1-butene base, 3-methyl-2-butene base, 3-methyl-3-butenyl, the 2-methyl-1-butene thiazolinyl, 2-methyl-2-butene base, 2-methyl-3-butenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, 1-methyl-3-butenyl, 1, the 1-dimethyl-allyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1,1-dimethyl-1-butylene base, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 1-methyl-1-pentene thiazolinyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 4-methyl-pentenyl, 4-methyl-3-pentenyl etc., preferable is vinyl, allyl group, the 1-propenyl, 1-butylene base etc.
" low-grade alkynyl " can have carbonatoms is the individual straight or branched alkynyl of 2-6: ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-proyl, pentenyl, 3-pentynyl, 4-pentynyl, 3-methyl isophthalic acid-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base etc., preferable is ethynyl, 1-proyl, ethyl acetylene base etc.
" low-grade alkylidene " can have carbonatoms is the individual straight or branched carbochain of 2-6, can enumerate particularly: ethylidene, propylidene, butylidene, 2-methyl-propylidene, 1-ethyl-ethylidene, pentamethylene, 1,2-diethyl-ethylidene etc.
" rudimentary alkylene group " can have carbonatoms is the straight or branched carbochain of 2-6, particularly as: vinylidene, propenylidene, crotonylidene, 1-methyl-vinylidene, 2-methyl-propenylidene etc.
" cycloalkyl " can have carbonatoms is that 3-8 is individual, as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
R
1With R
2The nitrogenous saturated heterocyclyls of 5-7 unit such as pyrrolidyl, piperidino, piperazinyl, morpholinyl, thio-morpholinyl can be arranged etc. " connect together, form the group of ring jointly with nitrogen-atoms ".
" carbocylic radical " can be just like phenyl, naphthyl, indenyl, fluorenyl, indanyl, diphenylene, anthryl, phenanthryl etc.
" contain 1-2 Sauerstoffatom and/or sulphur atom with the heterocyclic radical phenyl ring condensation " can enumerate following representative groups:
Can be substituted on the phenyl ring of these " carbocylic radicals " or " heterocyclic radical ", substituting group has halogen atom; hydroxyl; low alkyl group; low-grade alkenyl; lower alkoxy; rudimentary alkenyloxy; low-grade alkyl thio group; the low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; low alkyl group sulfinyl oxygen base; the low alkyl group sulfonyloxy; the low alkyl group sulfoamido; nitro; amino; cyano group; trifluoromethyl; rudimentary amide group; carboxyl; elementary alkoxy carbonyl; aryl; aralkyl; formamyl; alkylsulfonyl; the lower alkyl alcohol radical; the lower acyl methylamino-; one or the amino that replaces of dialkyl group; one or the aminocarboxyl that replaces of dialkyl group; one or the amino-sulfonyl that replaces of dialkyl group etc.
Wherein, " halogen atom " is fluorine atom, chlorine atom, bromine atoms and iodine atom; " lower alkoxy " is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy, tert.-butoxy, pentyloxy (n-amylether base), isopentyloxy, uncle-pentyloxy, neopentyl oxygen, 2-methyl butoxy, 1,2-dimethyl propoxy-, 1-ethyl propoxy-, hexyloxy etc.; " rudimentary alkenyloxy " is the straight or branched alkenyloxy of 2-6 carbon atom, and the hydrogen atom that can be hydroxyl (OH yl) is particularly replaced the group of gained by above-mentioned low-grade alkenyl;
And " low-grade alkyl thio group " can be the hydrogen atom of sulfydryl (SH yl) particularly by the group of above-mentioned low alkyl group replacement gained, for example, and methyl thio group, ethylenebis dithiocarbamate base, propyl dithiocarbamate base, butyl thio group, isobutyl-thio group, amyl group thio group etc.; " low alkyl group sulfinyl (oxygen) base " can be methyl sulfinyl (oxygen) base, ethyl sulfinyl (oxygen) base, propyl group sulfinyl (oxygen) base, sec.-propyl sulfinyl (oxygen) base, butyl sulfinyl (oxygen) base, isobutyl-sulfinyl (oxygen) base, sec-butyl sulfinyl (oxygen) base, tertiary butyl sulfinyl (oxygen) base, amyl group sulfinyl (oxygen) base, hexyl sulfinyl (oxygen) base etc.; " low alkyl group sulphonyl (oxygen) base " can be sulfonyloxy methyl (oxygen) base, ethyl sulphonyl (oxygen) base, sulfonyl propyl (oxygen) base, sec.-propyl sulphonyl (oxygen) base, butyl sulphonyl (oxygen) base, isobutyl-sulphonyl (oxygen) base, sec-butyl sulphonyl (oxygen) base, tertiary butyl sulphonyl (oxygen) base, amyl group sulphonyl (oxygen) base, hexyl sulphonyl (oxygen) base etc.;
" low alkyl group sulfoamido " can be sulfonyloxy methyl amido, ethyl sulfonamide base, sulfonyl propyl amido, sec.-propyl sulfoamido, butyl sulfonamide base, isobutyl-sulfoamido, sec-butyl sulfoamido, tertiary butyl sulfoamido, amyl group sulfoamido etc.; " rudimentary amide group " can be acetamido, propionamido-, amide-based small, valeryl amido, isovaleryl amido etc.; " lower acyl " can be ethanoyl, propionyl, butyryl radicals, pentanoyl, isovaleryl etc.; " lower acyl methylamino-" can be acetyl methylamino-, propionyl methylamino-, butyryl methylamino-, valeryl methylamino-, isovaleryl methylamino-etc.;
And " elementary alkoxy carbonyl " can be methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl etc.; Alkyl among " one or the amino that replaces of dialkyl group ", " one or the aminocarboxyl that replaces of dialkyl group " or " one or the amino-sulfonyl that replaces of dialkyl group " can be above-mentioned low alkyl group; " aryl " can be phenyl, naphthyl etc.; " aralkyl " can be benzyl, styroyl, diphenyl-methyl, trityl etc.
The substituting group of these groups can be 1 to n on the optional position of the phenyl ring of " carbocylic radical " or " heterocyclic radical ", is preferably 1 to 3 substituting group.
R
6Commutable substituting group can be enumerated the substituting group on above-mentioned carbocylic radical or the heterocyclic radical on the phenyl of expression, and preferable is nitro, amino, hydroxyl, halogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, trifluoromethyl, cyano group, lower alkoxy etc.
In the The compounds of this invention, preferable compound is R
1, R
2For low alkyl group or both connect together, form the nitrogenous heterocyclic group of saturated mono ring type jointly with nitrogen-atoms; R
3, R
4Be hydrogen atom, low alkyl group; R
3With R
4Be integral, for low-grade alkylidene or with
The group of expression; R
5For the carbocylic radical that can be replaced by halogen atom, trifluoromethyl, low alkyl group, lower alkoxy, lower alkoxycarbonyl, low-grade alkyl thio group, low alkyl group alkylsulfonyl, low alkyl group sulfonyloxy, rudimentary amide group, low alkyl group sulfahydantoin, nitro, amino, cyano group, aryl or contain 1 to 2 heterocyclic radical with the Sauerstoffatom of phenyl ring condensation; R
6For can be by nitro or amino phenyl compound or its salt that replaces.That better is following compound or its salt: R
1, R
2Be integral, form the group of ring jointly with nitrogen-atoms; R
3, R
4Be hydrogen atom, low alkyl group or be low-grade alkylidene identical or differently with being integral; R
5Be the phenyl or 3 that replaces with low alkyl group, halogen atom, trifluoromethyl, 4-methylenedioxyphenyl; R
6Be phenyl.
In the The compounds of this invention (I), there is optical isomer, diastereo-isomerism based on unsymmetrical carbon.Along with the difference of substituting group kind, also there are geometrical isomer, tautomer etc.According to different situations, also there be hydrate, the solvate of various isomer.The whole compounds such as the monomer of separating and composition thereof that contain these isomer in the The compounds of this invention.And stereoisomer form is in logical formula I preferably, substituent R
6Residing carbon atom is (S) coordinate compound.
In the The compounds of this invention (I), there is optical isomer, has geometrical isomer again owing to substituent kind is different based on unsymmetrical carbon.In the The compounds of this invention, contain monomer of separating of these isomer and composition thereof.
The compounds of this invention (I) forms salt, and such salt can be enumerated and organic acid acid salt such as mineral acid such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid and methyl, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, Citric Acid, tartrate, carbonic acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, L-glutamic acid.Wherein salt is the salt that forms with hydrochloric acid, oxalic acid, toxilic acid, fumaric acid etc. preferably.And, can be the salt that forms with alkaline-earth metal such as basic metal, magnesium such as sodium, potassium with substituent kind difference, with the salt of organic basess formation such as ammonia, Trimethylamine 99.
Can utilize with its basic framework and substituent feature, prepare The compounds of this invention (I) with various synthesis methods.Below list its representational method for making.
Method for making 1
(in the formula, R
1, R
2, R
3, R
5, R
6And the X definition as above).
(compound represented of amine that I a) can be represented by logical formula II and logical formula III reacts and is prepared The compounds of this invention.
This reaction mixes compound (II) in inert solvent to be carried out with reaction isocyanic ester of corresponding amount or lsothiocyanates.Inert solvent can be such as N, dinethylformamide, N,N-DIMETHYLACETAMIDE, tetrachloroethane, methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, Methylal(dimethoxymethane), glycol dimethyl ether, ethyl acetate, benzene, acetonitrile, methyl-sulphoxide etc. and mixed solvent thereof, these solvents carry out appropriate selection by the method for using.
In addition, this is reflected at room temperature so that be easy to carry out under the cooling.
Method for making 2
(in the formula, Y is above-mentioned halogen atom, R
1, R
2, R
3, R
5And R
6Definition as above.）
React by leading to the amine that amine that formula II represents and logical formula IV represent and the carbonyl diurethane halogenide of general formula (V) expression, (I a) can to prepare The compounds of this invention.
This reaction is in above-mentioned inert solvent,, so that heat down compound (IV) and the compound (V) of compound (II) with the reaction corresponding amount is reacted in room temperature.
Method for making 3
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6And the X definition as above.）
The amine that the amine that logical formula II is represented and logical formula IV are represented and lead to carbonic acid gas or the dithiocarbonic anhydride that formula VI represents and react, (I a) can to prepare The compounds of this invention.
This reaction is in above-mentioned inert solvent, preferably under heating, compound (IV) and the compound (VI) of compound (II) with the reaction corresponding amount is reacted.
Method for making 4
(in the formula, R
1, R
2, R
3, R
5And R
6Definition as above.R
7Be above-mentioned low alkyl group.）
The amine that logical formula II is represented reacts with the amino acid ester that general formula (VII) is represented, can prepare The compounds of this invention (I c).This reaction be compound (VII) with compound (II) and reaction corresponding amount in the presence of Lewis acid, in above-mentioned inert solvent, preferably under heating, carry out.
Method for making 5
(in the formula, Z is halogen atom or alkylsulfonyl.R
1, R
2, R
3, R
5And R
6Definition as above.）
This method for making is in logical formula I, R
4Method for making for the purpose product of low alkyl group, low-grade alkenyl, low-grade alkynyl and cycloalkyl.
The reaction of this method for making is the replacement(metathesis)reaction of being undertaken by the halogenide of formula (VIII) expression or sulphonate, to react the starting compound of corresponding amount in suitable inert solvent, in the presence of alkali such as sodium hydride, under cooling off so that under the room temperature, can under heating, react usually according to different situations.
Method for making 6
(in the formula, A is the alkylidene group of 2-6 carbonatoms, the alkylene group of a 2-6 carbonatoms; R
1, R
2, R
5, R
6And Z is for as defined above.）
This method for making is R in logical formula I
3, R
4The method for making of compound of formed alkylidene group or alkylene group group fuses.
This reaction is should be ω with compound shown in the general formula (I d) and reaction pair, and ω '-dihalo (or disulfonyl base) alkane (or alkene) reacts to be finished.Reaction conditions is identical with method for making 5.
Method for making 7
(in the formula, X, Y, R
1, R
2, R
5, R
6And A is following defined.）
Phosgene (thiophosgene) that the amine of general formula (X) expression and general formula (XI) are represented or carbonyl dimidazoles (CDI) or thiocarbonyldiimidazole react, and can prepare The compounds of this invention (I e).
This reaction be as above compound with compound (X) and reaction corresponding amount in above-mentioned inert solvent, in ice-cooled or room temperature so that carry out under the heating.
Method for making 8
(in the formula, R
1, R
2, R
3, R
4, R
5, R
6And Ar is for as defined above.）
As the another kind of method of preparation thiourea derivative purpose compound, be the method that urea derivatives is changed into thiourea derivative.
By urea derivatives (I c) is warm altogether with thiophosphoric anhydride or Lawesson ' s reagent, can easily carry out this transformationreation.
Method for making 9
This method for making is the compound reduction with general formula (I g) expression, the method for compound shown in the logical formula I of preparation.Be to reduce with lithium aluminium hydride, borane-tetrahydrofuran (THF) coordination compound, solvent is ether, tetrahydrofuran (THF), benzene etc.
As above prepared The compounds of this invention with free form or carry out salify by well-established law and handle and to obtain its salt, separates again, and is refining.
Separate, refining adopt extract, concentrate, common chemical operation such as distillation, crystallization, filtration, recrystallization, various chromatographys.With suitable starting compound, or, racemoid can be changed into isomer pure on the stereochemistry with general racemization partition method [for example, introduce the diastereomeric salt that forms with general opticity acid (tartrate etc.), tear method etc. open] with the light credit.
The compounds of this invention (I) oral absorption is good, has activation κ-receptor active all good on selectivity and persistence simultaneously.And because extremely low to the avidity of other opiate receptor, the dependency of the morphine that forms based on μ-acceptor etc. is seldom revealed in expection, and the unplessantness displeasure that produces based on sigma-receptor, side effects such as illusion.
Thereby The compounds of this invention is useful as the central analgesic agent of the continuous action of no dependence.And, in the The compounds of this invention (I), except that analgesic activities, also contain the compound of pharmacological actions such as showing anti-inflammatory effect, diuretic properties, neurocyte protection effect.Such compound also is useful as anti-inflammatory agent, diuretic(s), nerve cell-protective agents.The pharmacologically active of The compounds of this invention is confirmed with following test method.
1. mouse folder tail test
Method by Gao Ben etc. is carried out (Japan J.Pharmacol., 16:287,1966).
The male ICR mouse of the about 25g of body weight (SLC), every group is adopted 10-12 only.The clip that is adjusted into 500g with pressure is clamped the initial part (anus side) of mouse tail, and the reaction of gnaw root of the tail portion and the clip that cause thus as index, is judged analgesic effect.Use this method in advance, reject the mouse that in 2 seconds, does not show the reaction of gnawing.Tested compound is dissolved in physiological saline, do subcutaneous injection or oral administration and after, the analgesic effect when measuring 15 minutes and 30 minutes.Judging criterion is as follows.
Analgesia (+) fully: also do not produce the reaction of gnawing more than 6 seconds behind the folder clip.In order to prevent tissue injury, be limited to for 15 seconds with clip.
Part analgesia (±): 2-6 gnaws second behind the folder clip.
Do not ease pain (-): gnawed with interior in 2 seconds.
Calculating shows complete analgesic number of animals/use number of animals under each consumption, obtain ED with プ ロ PVC Star ト method
50
2. receptor affinity test
A. the preparation of meninx sample
By the thick P of preparation
2The general method of part prepares the meninx sample.
With the Hartley about body weight 350g is that male marmot (SLC) is removed postcerebellar full brain make homogenate in the ice-cooled 0.32M sucrose solution of 10 times of volumes, then, and under 900 * g centrifugal 10 minutes.With supernatant liquor in 11,500 * g centrifugal 20 minutes, the particle suspension of gained was in 0.05M Tris damping fluid (pH7.4).Then, in 11,500 * g centrifugal 20 minutes, with the particle resuspending in 0.05M Tris damping fluid (pH7.4).With its in 37 ℃ cultivate 30 minutes after, in 11,500 * g centrifugal 20 minutes.The particle suspension that obtains like this in 0.05M Tris damping fluid (pH7.4), is stored in-80 ℃.Melt during use, use for experiment.
B. with the combining of κ-acceptor
Press Gillan ﹠amp; Kosterlitz method (Br.J.Pharmacol., 77:461,1982) is carried out receptor binding assays.
With H
3The U-69563 of the 5nM of mark measures the combination and the tested compound antagonism bonded activity of meninx sample therewith as aglucon.Non-specific combination is by adding excessive (10 μ M) Dynorphin(1-17 far away) and measure.
With meninx sample and mark, non-marked aglucon and tested compound in 0.5ml 0.05M Tris damping fluid (pH7.4), after cultivating 30 minutes under 37 ℃, add the ice-cold 0.05M Tris damping fluid (pH7.4) of 5ml, under reduced pressure use Whatman GF/B filter paper filtering, wash three times.Be combined in the radioactivity of the mark aglucon on the filter paper with liquid flashing counter measuring.Calculate Ki(nM by 50% antagonism mark aglucon bonded concentration) value, draw the avidity of The compounds of this invention to κ-acceptor.
C. with the combining of μ-acceptor
Also undertaken with the test that combines of μ-acceptor by the method for above-mentioned κ-receptors bind experiment.Aglucon uses H
3The 3nM DAGO([D-Ala of mark
2, Gly-01
5] enk).
D. with the combining of sigma-receptor
About sigma-receptor in conjunction with test, be that the cultivation temperature and time with above-mentioned κ-receptor binding assays changes 25 ℃, 45 minutes into.Aglucon uses H
3The 3nM DTG(1 of mark, 3-xylyl guanidine).
Compile above experimental result, be listed in the table below.The result clearly illustrates that The compounds of this invention is compared with Srm-Rhotaard or comparative compound, and analgesic activities is identical or higher, and shows good kappa selective.
(-) of record-anti--2-(3 among chemical compounds I: the US 4,145,435, the 4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidyl) cyclohexyl] the ethanamide maleate
3. persistence test
The acetic acid twisting method
The male ICR mouse of body weight 27-31g, every group of 6-9 only.Examined compound give acetic acid before 50 minutes, 110 minutes or 170 minutes per os give.The control group per os gives distilled water, replaces tested compound.Every 10g body weight abdominal injection 0.6%w/v acetum 0.1ml.Calculate to give with acetic acid after occur within 5-15 minute 10 minutes turn round the body number of times.Turn round the body inhibiting rate by what following formula was obtained every mouse, calculate the mean value and the standard error of each group.Wilcoxon U-Test is adopted in the test of significance of administration group.The results are shown in Figure 1.
Inhibiting rate (%)=(1-(being examined the measured value of medicine individuality)/(the average measurement value of control group)) * 100
Find out significantly from the result, comparative compound oral administration and demonstrate the significant analgesia role tendency that disappears after 180 minutes, in contrast, The compounds of this invention demonstrates lasting analgesic effect.
4. autonomic movement flow measurement test
Body weight 28-35g male 6 the week age ICR mouse, 25 every group.Measure device (ANIMEX III A with the laboratory animal amount of exercise; The SHIMADZU corporate system) measures before the amount of exercise, subcutaneously give tested compound.The control group tested compound subcutaneous injection of physiologic saline for substitute that contains 10%DMSO.Autonomic movement amount behind the tested compound of mensuration injection in 10 minutes of 10-20 minute.
Value after the mensuration is obtained the autonomic movement inhibiting rate of each administration group by following formula, calculates the mean value and the standard error of each group.By the dosage and the autonomic movement inhibiting rate of tested compound, calculate 50% with プ ロ PVC Star ト method and suppress consumption (ID again
50).
Inhibiting rate (%)=(1-(the average measurement value of tested medicine group)/(the average measurement value of control group)) * 100
The result:
Embodiment No. ID
50(mg/kg. s.c.)
32 0.23
53 0.28
Comparative compound 0.012
The compound of comparative compound: EP 261,842 embodiment 1
By this experiment, point out tested compound mouse to be had or not the power of sedative effect and sedative effect.
Show that from above result The compounds of this invention is compared with comparative compound, little to the autonomic movement restraining effect.
Contain The compounds of this invention (I) or its salt preparation as effective constituent more than a kind or 2 kinds, with common formulations employed carrier, vehicle, other additive or the like, make tablet, lozenge, powder, granula subtilis, granule, capsule, pill, oral solution (comprising syrup), injection, suppository etc., per os or non-per os ground throw with.
The carrier that preparation is used, vehicle etc. can be solid or the liquid pharmaceutical material of non-toxicity.As an example, can enumerate such as lactose, Magnesium Stearate, starch, talcum powder, gelatin, agar, pectin, gum arabic, sweet oil, sesame oil, cocoa butter, ethylene glycol etc. and other material commonly used.
The clinical throwing of The compounds of this invention and amount consider medication disease of patient, body weight, year make, in addition suitably adjustment after the sex, route of administration etc., usually oral dosage is per day for adults 0.1-200mg, be 0.5-50mg preferably, quiet injecting amount is per day for adults 0.01-100mg, be 0.1-10mg preferably, once throw with or divide throw for 2-4 time and.
The compounds of this invention and preparation method thereof more than has been described, below has been described in more detail with embodiment.
Contain new compound in the starting compound of the present invention, its method for making example that sees reference.
In the mark of expression physicochemical property, IR is an infrared absorption spectrum; MS is a mass spectrum; Mp is a fusing point; Anal. be the ultimate analysis value, and
1H NMR is a nuclear magnetic resonance spectrum.
Reference example 1
At 10.0g(S)-the 200ml ethyl acetate solution of 2-phenyl-2-benzyloxy carbonyl amide group-N,N-dimethylacetamide in, add 10% palladium charcoal 1.0g, contact reduction at normal temperatures and pressures.Behind the elimination catalyzer, concentrating under reduced pressure gets (S)-2-phenyl-2-amino-N,N-dimethylacetamide 5.56g, and its physico-chemical property is as follows:
Physico-chemical property
MS（FAB）：179（M
++1）
IR（KBr）cm
-1：3488，1642
1H NMR(CDCl
3, the TMS internal standard)
δ：2.04（2H，s），2.85（3H，s），2.99（3H，s），4.72（1H，s），7.33（5H，s）
Reference example 2
At 7.08g triethylamine and 11.3g3, in the 100ml dichloromethane solution of 4-dichlorphenamide bulk powder, under-10 ℃, drip tri-methyl-chlorosilane 8.9ml, stir after 30 minutes, under-10 ℃, add メ Le De ラ system acid 7.99g, stirring is 3 hours under the room temperature.Behind the concentrating under reduced pressure solvent, in residue, add chloroform, after cleaning with 1N hydrochloric acid, use the anhydrous magnesium sulfate drying organic layer.
Elimination sal epsom, concentrating under reduced pressure filtrate with silica gel column chromatography (chloroform/methanol=10/1) purification residue, gets N-(3, the 4-dichlorophenyl) carbamyl acetate 8.23g.Its physico-chemical property is as follows.
1H NMR(DMSO-d
6, the TMS internal standard)
δ：3.38（2H，s），7.35-7.65（2H，m），
7.98（1H，d，J＝2Hz），10.42（1H，s），12.70（1H，brs）
Reference example 3
At 5.34g(S)-2-phenyl-2-amino-N, N-N,N-DIMETHYLACETAMIDE, 8.12g N-(3, the 4-dichlorophenyl) in the 200ml dichloromethane solution of carbamyl acetate and 4.45g1-hydroxybenzotriazole, add N down in-5 ℃, N '-dicyclohexyl carbodiimide 6.74g stirred 26 hours under room temperature.
Behind the elimination insolubles, add ethyl acetate, elimination insolubles once more.After washing ethyl acetate layer with 1N hydrochloric acid, 1N aqueous sodium hydroxide washes, use anhydrous magnesium sulfate drying.Elimination sal epsom, concentrating under reduced pressure, residue is purified with silica gel column chromatography (chloroform/methanol=100/1), get (S)-N-(3, the 4-dichlorophenyl)-and N '-(1-phenyl-2-oxygen-2-dimethylin) ethyl Malonamide 11.35g, be colorless amorphous substance, its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：408，410（M
++1）
IR（KBr）cm
-1：3320，1648，1596，1532，1480
1H NMR(CDCl
3, the TMS internal standard)
δ：2.91（3H，s），2.99（3H，s），3.37（2H，dd，J＝27，17Hz），
5.83（1H，d，J＝7Hz），7.25-7.40（7H，m），
7.77（1H，d，J＝2Hz），7.95（1H，d，J＝7Hz），
9.95（1H，s）
Reference example 4
In 100ml 1M borane-THF solution, add 5.00g(S)-N-(3, the 4-dichlorophenyl)-N '-(1-phenyl-2-oxygen-2-dimethylin) ethyl Malonamide, reflux 7.5 hours.Add 35ml methyl alcohol, reflux 30 minutes adds 35ml concentrated hydrochloric acid reflux.
The concentrating under reduced pressure solvent behind the clean residue of ether, adds the 1N aqueous sodium hydroxide solution, uses ethyl acetate extraction.Behind the anhydrous magnesium sulfate drying ethyl acetate layer, elimination sal epsom, filtrate decompression concentrates.Residue is purified through silica gel column chromatography (chloroform/methanol=20/1), gets (S)-N-(3, the 4-dichlorophenyl)-N '-(1-phenyl-2-dimethylamino ethyl) propylene diamine 3.05g, be yellow oil, its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：366，368（M
++1）
IR（Neat）cm
-1：3448，3328，1604，1500，1476，1350，1154
1H NMR(CDCl
3, the TMS internal standard)
δ：1.6-2.3（2H，m），1.99（1H，brs），
2.28（6H，s），2.4-2.7（2H，m），
3.0-3.2（2H，m），3.5-3.8（2H，m），
4.54（1H，brs），6.37（1H，dd，J＝9.2Hz），
6.60（1H，d，J＝3Hz），7.14（1H，d，J＝9Hz），
7.2-7.4（1H，m），7.31（5H，s）.
Reference example 5
N at sodium hydroxide (60%) 0.71g, in the dinethylformamide 50ml suspension liquid, add the 1-(5-benzofuryl)-2-oxygen-pyrimidine alkane 3.25g, after stirring 1.5 hours under 45 ℃, dropping 2-(1-pyrrolidyl carbonyl in 30 minutes) N of bromotoluene 4.53g, dinethylformamide 10ml solution.Stir after 2.5 hours under the room temperature, in reaction solution impouring frozen water, use ethyl acetate extraction.Organic layer is through washing, behind the anhydrous magnesium sulfate drying, elimination sal epsom, concentrating under reduced pressure filtrate.Residue is purified with silica gel column chromatography, gets the 1-(5-benzofuryl)-2-oxygen-3-[2-oxygen-1-phenyl-2-(1-pyrrolidyl) ethyl-pyrimidine alkane 3.23g, be yellow oil.Its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：404（M
++1）
333，305
IR（Neat）cm
-1：1636，1438，1206
1H NMR(CDCl
3, the TMS internal standard)
δ：1.70-1.95（5H，m），2.13-2.19（1H，m），
2.87-3.02（2H，m），3.46-3.85（6H，m），
6.50（1H，s），6.73（1H，s），7.22-7.62（9H，m）
Reference example 6
With (S)-α-(1-pyrrolidyl carbonyl) benzylamine 6.90g and N-(4-nitrophenyl) acrylamide 7.40g in 50ml methyl alcohol, stir a night down in 115 ℃.The concentrating under reduced pressure reaction solution, residue obtained through silica gel column chromatography (chloroform/methanol=49/1) purification, get (S)-1-oxygen-N-(4-nitrophenyl)-N '-[α-(1-pyrrolidyl carbonyl) benzyl]-1,3-propylene diamine 10.02g is yellow oil.Its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：397（M
++1），298
1H-NMR(CDCl
3, the TMS internal standard)
δ：1.73-1.96（4H，m），2.51-2.69（2H，m），
2.80（1H，brs），2.88-3.12（3H，m），
3.44-3.62（3H，m），4.44（1H，s），
7.33-7.44（5H，m），7.67（2H，d，J＝8.8Hz），
8.13（2H，d，J＝9.3Hz），11.41（1H，s）
Reference example 7
At room temperature, in 30 minutes, in 80ml 1M borane-THF solution, drip 8.70g(S)-1-oxygen-N-(4-nitrophenyl)-N '-[α-(1-pyrrolidyl carbonyl) benzyl]-1, the 60ml tetrahydrofuran solution of 3-propylene diamine, reflux is 6 hours then.Add methyl alcohol 100ml in reaction solution, reflux added 1N hydrochloric acid 100ml after 1 hour, and reheat refluxed 1 hour.Behind the concentrating under reduced pressure solvent, add the 1N aqueous sodium hydroxide solution, use chloroform extraction, washing.Behind the anhydrous magnesium sulfate drying organic layer, elimination sal epsom, concentrating under reduced pressure filtrate.Residue is purified through silica gel column chromatography (chloroform/methanol=49/1), gets (S)-N-(4-nitrophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1,3-propylene diamine 7.05g is yellow oil.Its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：369，（M
++1），174
1H NMR(CDCl
3, the TMS internal standard)
δ：1.72-1.86（6H，m），
3.00（1H，dd，J＝12.2，3.4Hz），
2.42-2.92（9H，m），3.12-3.35（2H，m），
3.68（1H，dd.J＝12.4，3.4Hz）
5.98（1H，brs），6.45（2H，d，J＝9.3Hz），
7.21-7.35（5H，m），8.05（2H，d，J＝8.8Hz）
Reference example 8
In the 30.0g vitriol oil, under room temperature, drip the 4.5ml concentrated nitric acid, at room temperature stirred 1 hour.With mixing acid be added in the vitriol oil 60.0g solution of (S)-α-(1-pyrrolidyl carbonyl) benzylamine 12.1g down in ice-cooled, stirred 30 minutes down in ice-cooled.In reaction solution impouring frozen water, hydro-oxidation sodium is used ethyl acetate extraction.Ethyl acetate layer with anhydrous magnesium sulfate drying after, elimination sal epsom, filtrate decompression concentrates.Residue is purified through silica gel column chromatography (chlorine note/methyl alcohol=40/1), gets (S)-3-nitro-α-(1-pyrrolidyl carbonyl) benzylamine 6.41g, is greenish orange look oily matter, and its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：250（M
++1）
IR（Neat）cm
-1：3400，1644，1534，1448，1354
1H-NMR(CDCl
3, the TMS internal standard)
δ：1.76-2.04（4H，m），2.60（2H，brs），
3.05-3.12（1H，m），3.40-3.52（1H，m），
3.53-3.64（2H，m），4.78（1H，brs），
7.55（1H，t，J＝7.9Hz），7.77（1H，d，J＝7.3Hz），
8.16（1H，d，J＝7.9Hz），8.25（1H，d，J＝1.2Hz）
Reference example 9
With anhydrous succinic acid 5.00g, 3, the 50ml benzole soln reflux that 4-dichlorphenamide bulk powder 8.00g, phosphatase 11 drip 3 hours.Add 2 of phosphoric acid and benzene 50ml, reheat refluxed 5.5 hours, the crystallization that leaching is separated out ,-N-(3, the 4-dichlorophenyl) succinamic acid 10.6g, its physico-chemical property is as follows.
Physico-chemical property
MS（EI）：261，263（M
+）
IR（KBr）cm
-1：3308，1708，1668
1H-NMR(DMSO-d
6, the TMS internal standard)
δ：2.56（4H，s），7.26-8.00（3H，m），10.24（1H，brs），
11.5（1H，brs）.
Reference example 10
Under ice-cooled, at (S)-α-(1-pyrrolidyl carbonyl) benzylamine 6.13g, N-3,4-dichlorophenyl) in the methylene dichloride 200ml solution of succinamic acid 8.65g, I-hydroxybenzotriazole 4.45g, add N, N '-dicyclohexylcarbodiimide 6.74g stirred 3 hours under room temperature.Behind the elimination insolubles, concentrating under reduced pressure adds ethyl acetate in residue, the elimination insolubles.Ethyl acetate layer is used anhydrous magnesium sulfate drying after cleaning successively with 1N hydrochloric acid, 1N sodium hydroxide.Elimination sal epsom, filtrate decompression concentrates, residue is purified through silica gel column chromatography (chloroform/methanol=50/1), gets (S)-N-(3, the 4-dichlorophenyl)-N '-[α-(1-pyrrolidyl carbonyl) benzyl] succinic diamide 10.5g, be faint yellow oily thing.Its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：449
IR（Neat）cm
-1：3432，3320，1634，1594，1532，1478
1The H-NMR(TMS internal standard)
δ：1.73-1.93（4H，m），2.55-2.75（4H，m），
3.00-3.07（1H，m），3.37-3.58（3H，m），
5.69（1H，d，J＝6.8Hz），7.22-7.40（7H，m），
7.48（1H，d，J＝6.8Hz），9.20（1H，brs）
Reference example 11
In 100ml 1M first boric acid-THF solution, add (S)-N-(3, the 4-dichlorophenyl)-N '-[α-(1-pyrrolidyl carbonyl) benzyl] succinic diamide 5.39g, reflux 8 hours.Add 35ml methyl alcohol in reaction solution, reflux added concentrated hydrochloric acid 35ml after 1 hour, reflux 1 hour.The solvent concentrating under reduced pressure.Add the 1N aqueous sodium hydroxide solution, use chloroform extraction.Chloroform layer with anhydrous magnesium sulfate drying after, elimination sal epsom, filtrate decompression concentrates, residue is purified through silica gel column chromatography (chloroform/methanol=20/1), get (S)-N-(3, the 4-dichlorophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1,4-succinyl-diamines 4.45g is faint yellow oily thing.Its physico-chemical property is as follows.
Physico-chemical property
MS（FAB）：406，408（M
++1）
IR（Neat）cm
-1：3448，3324，1608，1476，1324，1134
1H-NMR(CDCl
3, the TMS internal standard)
δ：1.52-1.73（4H，m），1.75-1.85（4H，m），
2.28（1H，dd，J＝12.0，3.2Hz），2.42-2.58（4H，m），
2.59-2.68（2H，m），2.85（1H，t，J＝11.5Hz），
2.96-3.07（2H，m），3.68-3.74（1H，m），
6.38（1H，dd，J＝8.8，2.9Hz），
6.61（1H，d，J＝2.9Hz），7.14（1H，d，J＝8.8Hz），
7.23-7.38（5H，m）
Embodiment 1
With (S)-1-[(2-methylamino--2-phenyl) ethyl] tetramethyleneimine 1.50g and isothiocyanic acid 2-chlorobenzene ester 1.30g be at 15ml 1, in the 2-ethylene dichloride, under room temperature, stir a night.The reaction solution concentrating under reduced pressure, residue is purified through silica gel column chromatography (chloroform/methanol=49/1), gets (S)-1-(2-chloro-phenyl-)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide 1.88g, be faint yellow oily thing.
With (S)-1-(2-chloro-phenyl-)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] after thiocarbamide 1.88g handles with 4N hydrogenchloride-ethyl acetate solution 2ml, gained crystallization recrystallization from alcohol-ether, get (S)-1-(2-chloro-phenyl-)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide salt hydrochlorate 1.90g, be colourless acicular crystal.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 2
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-chlorobenzene ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-(4-chloro-phenyl-)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 3
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-methyl phenyl ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-methyl-3-(4-aminomethyl phenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 4
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-bromobenzene ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-(4-bromophenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 5
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 3-chlorobenzene ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-(3-chloro-phenyl-)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 6
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-methoxy phenyl ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-(4-methoxyphenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 7
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-nitro phenyl ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-methyl-3-(4-nitrophenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 8
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanate 1-naphthyl ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-methyl-3-(1-naphthyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 9
With the isothiocyanic acid 2-chlorobenzene ester of record among the isothiocyanic acid 4-fluorobenzene ester replacement embodiment 1, handle similarly to Example 1, get (S)-1-(4-fluorophenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 10
With the isothiocyanic acid 2-chlorobenzene ester of record among the thiocarbanil replacement embodiment 1, handle similarly to Example 1, get (S)-1-methyl-3-phenyl-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 11
With isothiocyanic acid 3,4-dimethyl phenyl ester replaces the isothiocyanic acid 2-chlorobenzene ester of record among the embodiment 1, handle similarly to Example 1, get (S)-1-(3, the 4-3,5-dimethylphenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 12
The isothiocyanic acid 2-chlorobenzene ester that replaces record among the embodiment 1 with isothiocyanic acid 4-methyl phenyl ester, reach with (S)-N, N, N '-trimethylammonium-2-phenylethylenediamine replaces (S)-1-[(2-methylamino--2-phenyl) ethyl] tetramethyleneimine, handle similarly to Example 1, get (S)-1-(2-dimethylamino-1-styroyl)-1-methyl-3-(4-aminomethyl phenyl) the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 13
A) with (S)-1-[(2-methylamino--2-phenyl) ethyl] tetramethyleneimine 0.61g and isothiocyanic acid 3,4-methylenedioxy group phenyl ester 0.55g stirred 1 day under room temperature in the 10ml sym.-tetrachloroethane.The reaction solution concentrating under reduced pressure, residue obtained through silica gel column chromatography (chloroform/methanol=49/1) purification, get (S)-1-methyl-3-(3,4-methylenedioxy group phenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide 1.01g, be filbert oily thing.
B) with (S)-1-methyl-3-(3,4-methylenedioxy group phenyl)-and 1-[1-phenyl-2-(1-pyrrolidyl) ethyl] after thiocarbamide 1.01g handles with 4N hydrogenchloride-ethyl acetate solution, gained crystallization recrystallization from water-ethanol, get (S)-1-methyl-3-(3,4-methylenedioxy group phenyl)-and 1-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide salt hydrochlorate 0.52g, be colourless needle crystal.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 14
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 5-indane ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(5-indanyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physics and chemistry see the following form.
Embodiment 15
With the isothiocyanic acid 3 of record among the isothiocyanic acid 2-naphthalene ester replacement embodiment 13,4-methylenedioxy group phenyl ester is handled similarly to Example 13, gets (S)-1-methyl-3-(2-naphthyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 16
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 2-methyl phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-methyl-3-(2-aminomethyl phenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 17
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 3-methyl phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-methyl-3-(3-aminomethyl phenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 18
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-ethyl phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(4-ethylphenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 19
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-propyl group phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, (S)-1-methyl isophthalic acid-[1-phenyl-2-(1-pyrrolidyl) ethyl]-3-(4-propyl group phenyl) the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 20
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-butyl phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(4-butyl phenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide maleate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 21
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-secondary butyl phenenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get the 1-(4-secondary butyl phenenyl)-the 3-methyl-3-[(1S)-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 22
With isothiocyanic acid 3,4-dimethoxy phenyl ester replaces the isothiocyanic acid 3 of record among the embodiment 13, and 4-methylenedioxy group phenyl ester is handled similarly to Example 13, get (S)-1-(3, the 4-Dimethoxyphenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 23
With isothiocyanic acid 3,4,5-trimethoxy phenyl ester replaces the isothiocyanic acid 3 of record among the embodiment 13,4-methylenedioxy group phenyl ester, handle similarly to Example 13, (S)-1-methyl isophthalic acid-[1-phenyl-2-(1-pyrrolidyl) ethyl]-3-(3,4,5-trimethoxyphenyl) the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 24
With isothiocyanic acid 3, the 4-Dichlorfop replaces the isothiocyanic acid 3 of record among the embodiment 13, and 4-methylenedioxy group phenyl ester is handled similarly to Example 13, get (S)-1-(3, the 4-dichlorophenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 25
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-cyanobenzene ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(4-cyano-phenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 26
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-tertiary butyl phenyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(4-tert-butyl-phenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide maleate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 27
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 5-benzofuranyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(5-benzofuryl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 28
With isothiocyanic acid 2,3-dihydro-5-benzofuranyl ester replaces the isothiocyanic acid 3 of record among the embodiment 13,4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(2,3-dihydro-5-benzofuryl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 29
The isothiocyanic acid 3 that replaces record among the embodiment 13 with isothiocyanic acid 4-benzofuranyl ester, 4-methylenedioxy group phenyl ester, handle similarly to Example 13, get (S)-1-(4-benzofuryl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 30
With the isothiocyanic acid 3 of record among the isothiocyanic acid 2-fluorenes ester replacement embodiment 13,4-methylenedioxy group phenyl ester is handled similarly to Example 13, gets (S)-1-(2-fluorenyl)-3-methyl-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] the thiocarbamide salt hydrochlorate.Its chemical structure and physico-chemical property see the following form.
Embodiment 31
At 1.0g(S)-N-(3, the 4-dichlorophenyl)-the 15ml dichloromethane solution of N '-(1-phenyl-2-dimethyl aminoethyl) propylene diamine and 0.8ml triethylamine in, add the 280mg triphosgene, under room temperature, stirred 3 hours.Add the 270mg triphosgene again, after stirring 2 hours under the room temperature, in reaction solution, add the 1N aqueous sodium hydroxide solution, use chloroform extraction.Organic layer with anhydrous magnesium sulfate drying after, elimination sal epsom, concentrating under reduced pressure.Residue is purified through silica gel column chromatography (chloroform/methanol=50/1), gets (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-(1-phenyl-2-dimethyl aminoethyl) pyrimidine alkane 0.86g, be faint yellow oily thing.
With 0.86g(S)-1-(3, the 4-dichlorophenyl)-and 2-oxygen-3-(1-phenyl-2-dimethyl aminoethyl) pyrimidine alkane is dissolved in ethanol, add the 254mg toxilic acid, concentrating under reduced pressure, the gained crystallization is recrystallization from ethanol, ether, get (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-(1-phenyl-2-dimethyl aminoethyl) pyrimidine alkane maleate 659mg.
The chemical structural formula and the physico-chemical property of this compound see the following form.
Embodiment 32
Under ice-cooled, 85ml N at 0.36g sodium hydride (60%), in the dinethylformamide suspension liquid, drip (S)-1-(3,4-dichlorophenyl)-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] N of urea 3.46g, dinethylformamide 3ml solution, after stirring 30 minutes under 5 ℃, drip 1, the N of 3-dibromopropane 2.00g, dinethylformamide 5ml solution through 30 fens clock times.At room temperature stirred 1.5 hours, 60 ℃ were stirred after 1 hour, added sodium hydride (60%) 0.36g down ice-cooled, at room temperature stirred 5 days.With reaction solution impouring frozen water, use ethyl acetate extraction, saturated sodium-chloride washing, anhydrous magnesium sulfate drying.Elimination sal epsom, filtrate decompression concentrates, residue is purified through silica gel column chromatography (chloroform/methanol=24/1), gets (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 0.46g, be faint yellow oily thing.
With (S)-1-(3,4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 0.46g is dissolved in the 5ml ethanol, add the 0.13g fumaric acid after, the concentrating under reduced pressure solvent.Residue obtainedly use the acetonitrile crystallization, recrystallization from acetonitrile again, (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate 0.41g, be colourless crystallization.The chemical structural formula and the physico-chemical property of this compound see the following form.
Embodiment 33
In 5 minutes, in the 8ml of 68mg lithium aluminium hydride tetrahydrofuran (THF) suspension, Dropwise 5 00mg 1-(5-benzofuryl)-and 2-oxygen-3-[2-oxygen-1-phenyl-2-(1-pyrrolidyl) ethyl] the 8ml tetrahydrofuran solution of pyrimidine alkane, at room temperature stirred 1.5 hours.In reaction solution, add saturated sodium bicarbonate solution, the elimination insolubles, filtrate decompression concentrates.Add 20ml water in the residue, use ethyl acetate extraction, anhydrous magnesium sulfate drying.Elimination sal epsom, filtrate decompression concentrates, residue obtainedly purify through silica gel column chromatography (chloroform/methanol=29/1), gained crystallization recrystallization from ethyl acetate-hexane, get the 1-(5-benzofuryl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 181mg, be colourless needle crystal.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 34
Use the 1-(4-benzofuryl)-2-oxygen-3-[2-oxygen-1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane replaces the 1-(5-benzofuryl of record among the embodiment 33)-2-oxygen-3-[2-oxygen-1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane, similarly handle with embodiment 33, handle with fumaric acid then, get the 1-(4-benzofuryl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 35
Under ice-cooled, at 6.50g(S)-the N-(4-nitrophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, in the 65ml dichloromethane solution of 3-propylene diamine and 11.60g triethylamine, add the 1.91g triphosgene, stir and add the 1.50g triphosgene again after 40 minutes, under room temperature, stirred 1 hour.In reaction solution, add saturated sodium bicarbonate aqueous solution 100ml, use chloroform extraction, washing, anhydrous magnesium sulfate drying.Behind the elimination sal epsom, concentrating under reduced pressure filtrate, residue is purified through silica gel column chromatography (chloroform/methanol=49/1), gets the 1-(4-nitrophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 4.85g, be yellow oil.With the 1.20g1-(4-nitrophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane is dissolved in the 20ml ethanol, add 0.27g oxalic acid after, the concentrating under reduced pressure solvent.Gained crystallization recrystallization from alcohol-water gets the 1-(4-nitrophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt 0.75g, be faint yellow needle crystal.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 36
With (S)-N-(4-ethylphenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-ethylphenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 37
With (S)-N-(4-aminomethyl phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-aminomethyl phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 38
With (S)-N-(4-methylsulfonyl phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1; the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1; the 3-propylene diamine; similarly handle with embodiment 35, get (S)-1-(4-methylsulfonyl phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt ethanol compound.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 39
With (S)-N-(4-methylsulfonyl phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1; the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1; the 3-propylene diamine; similarly handle with embodiment 35, get (S)-1-(4-mesyloxy phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt ethanol compound.Its chemical structural formula and physico-chemical property see the following form.
With (S)-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-N '-(2,3,4-trifluorophenyl-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine is similarly handled with embodiment 35, gets (S)-2-oxygen-1-[1-phenyl-2-(1-pyrrolidyl) ethyl]-3-(2,3, the 4-trifluorophenyl) pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 41
With (S)-N-(4-methoxycarbonyl phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-methoxycarbonyl phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 42
With (S)-N-(1-naphthyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-naphthyl-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 43
With (S)-N-(3-nitrophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3-nitrophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 44
With (S)-N-(2-naphthyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(2-naphthyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 45
With (S)-N-(4-chloro-phenyl-)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-chloro-phenyl-)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 46
With (S)-N-(3, the 4-difluorophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3, the 4-difluorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 47
With (S)-N-(3, the 4-dimethoxy)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3, the 4-Dimethoxyphenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 48
With (S)-N-(4-fluorophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-fluorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 49
With (S)-N-(4-p-methoxy-phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-p-methoxy-phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 50
With (S)-N-(4-iodophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-iodophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 51
With (S)-N-(4-methyl thio-phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-methyl thio-phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt ethanol compound.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 52
With (S)-N-(4-phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-2-oxygen-1-(4-phenyl)-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 53
With (S)-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-N '-(4-trifluoromethyl)-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-2-oxygen-1-[1-phenyl-2-(1-pyrrolidyl) ethyl]-the 3-(4-trifluoromethyl) pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 54
With (S)-N-(3, the 4-3,5-dimethylphenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3, the 4-3,5-dimethylphenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 55
With (S)-N-(3,4-methylenedioxy group phenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3,4-methylenedioxy group phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 56
With (S)-N-(4-bromophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(4-bromophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 57
With (S)-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-N '-(4-propyl group phenyl)-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, (S)-2-oxygen-[1-phenyl-2-(1-pyrrolidyl) ethyl]-3-(4-propyl group phenyl) pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 58
Use the N-(4-secondary butyl phenenyl)-N '-[(1S)-and 1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get the 1-(4-secondary butyl phenenyl)-2-oxygen-3-[(1S)-1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 59
With (S)-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-N '-(3,4, the 5-trichlorophenyl)-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine is similarly handled with embodiment 35, gets (S)-2-oxygen-1-[1-phenyl-2-(1-pyrrolidyl) ethyl]-3-(3,4, the 5-trichlorophenyl) pyrimidine dodecin salt.Its chemical structural formula and physico-chemical property see the following form.
With (S)-N-(3, the 4-dichlorophenyl)-N '-[the 1-(3-nitrophenyl)-the 2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3, the 4-dichlorophenyl)-the 3-[1-(3-nitrophenyl)-the 2-(1-pyrrolidyl) ethyl]-2-oxygen pyrimidine alkane fumarate.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 61
Under-20 ℃, in the 50ml of 1.4g lithium aluminium hydride tetrahydrofuran (THF) suspension liquid, add 6.9g(S)-the N-(5-benzofuryl)-1-oxygen-N '-[α-(1-pyrrolidyl carbonyl) benzyl]-1, the 40ml tetrahydrofuran solution of 3-propylene diamine at room temperature stirred 2 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution, 1N aqueous sodium hydroxide solution, behind the elimination insolubles, use chloroform extraction filtrate, chloroform layer with anhydrous magnesium sulfate drying after, elimination sal epsom, concentrating under reduced pressure filtrate.Residue is made silica gel column chromatography (chloroform/methanol=40/1), gets rough (S)-N-(5-benzofuryl)-1-oxygen-N '-[α-(1-pyrrolidyl benzyl)]-1,3-propylene diamine 2.1g is faint yellow oily thing.This material does not add processing and is directly used in following reaction.
Under ice-cooled, at rough (the S)-N-(5-benzofuryl of 2.1g)-1-oxygen-N '-[α-(1-pyrrolidyl) benzyl]-1, in the 20ml chloroformic solution of 3-propylene diamine 2.1g and 1.6ml triethylamine, add triphosgene 1.28g, under room temperature, stirred 2 hours.In reaction solution, add triethylamine 1.6ml, add triphosgene 1.28g down ice-cooled then, at room temperature stirred 2 hours.In reaction solution, add the 1N aqueous sodium hydroxide solution, use chloroform extraction.Chloroform layer with anhydrous magnesium sulfate drying after, elimination sal epsom, filtrate decompression concentrates.Residue is purified through silica gel column chromatography (chloroform/methanol=40/1), gets (S)-3-(5-benzofuryl)-2,4-dioxy-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 0.53g, be colourless crystallization.
The chemical structural formula and the physico-chemical property of this compound see the following form.
Embodiment 62
Under ice-cooled, at 1.10g(S)-N-(3, the 4-dichlorophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, in the 15ml dichloromethane solution of 4-butanediamine and 0.8ml triethylamine, add the 280mg triphosgene, at room temperature stirred 3 hours.In the ice-cooled 280mg triphosgene that adds down, under room temperature, stirred 3 hours again.In reaction solution, add the 1N aqueous sodium hydroxide solution, use chloroform extraction.Organic layer with anhydrous magnesium sulfate drying after, elimination sal epsom, concentrating under reduced pressure.Residue is purified through silica gel column chromatography (chloroform/methanol=40/1), gets (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-diaza
Alkane 1.19g is faint yellow oily thing.
With 1.19g(S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-diaza
Alkane is dissolved in the ethanol, behind the adding fumaric acid 300mg, and concentrating under reduced pressure, gained crystallization recrystallization from alcohol-ether gets (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-diaza
Alkane fumarate 479mg.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 63
With (S)-N-(3, the 4-dichlorophenyl)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 2-quadrol replaces (S)-N-(4-nitrophenyl of record among the embodiment 35)-N '-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1, the 3-propylene diamine, similarly handle with embodiment 35, get (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] imidazolidine hydrochloride.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 64
With 5.30g(S)-the 1-(4-nitrophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane in 50ml ethanol liquid, in the presence of 0.80g10% palladium carbon powder, carry out normal temperature and pressure contact reduction.Behind the elimination palladium carbon powder, filtrate decompression is concentrated, residue is purified through silica gel column chromatography (chloroform/methanol=19/1), gets (S)-1-(4-aminophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 2.77g, be yellow amorphous substance.
With 0.64g(S)-the 1-(4-aminophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane is dissolved in the 10ml ethanol, add fumaric acid 0.20g after, the concentrating under reduced pressure solvent.Residue obtained with behind the acetonitrile crystallization, recrystallization from acetonitrile-ethanol gets (S)-1-(4-aminophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate 0.41g, be yellow crystal.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 65
At 3.25g(S)-1-(3, the 4-dichlorophenyl)-the 3-[1-(3-nitrophenyl)-the 2-(1-pyrrolidyl) ethyl]-the 30ml methanol solution of 2-oxygen-pyrimidine alkane in, the 30ml aqueous solution that adds 3.42g ammonium chloride, then at the ice-cooled 4.18g zinc powder that adds down, at room temperature stirred 2 hours after 3 hours in ice-cooled stirring down.
Behind the elimination insolubles, filtrate decompression is concentrated, add the 1N aqueous sodium hydroxide solution, use chloroform extraction.Chloroform layer with anhydrous magnesium sulfate drying after, elimination sal epsom, filtrate decompression concentrates.Residue is purified through silica gel column chromatography (chloroform/methanol=10/1), gets (S)-1-[1-(3-aminophenyl)-the 2-(1-pyrrolidyl) ethyl]-3-(3, the 4-dichlorophenyl)-2-oxygen-pyrimidine alkane 500mg, be faint yellow oily thing.
With (S)-1-[1-(3-aminophenyl)-the 2-(1-pyrrolidyl) ethyl]-3-(3, the 4-dichlorophenyl)-2-oxygen-pyrimidine alkane 422mg is dissolved in the methyl alcohol, after adding 87mg oxalic acid, concentrating under reduced pressure, gained crystallization recrystallization from acetonitrile, get (S)-1-[1-(3-aminophenyl)-the 2-(1-pyrrolidyl) ethyl]-3-(3, the 4-dichlorophenyl)-2-oxygen-pyrimidine dodecin salt 263mg.
The chemical structural formula and the physico-chemical property of this compound see the following form.
Embodiment 66
With 1.60g(S)-the 1-(4-aminophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane is dissolved in the 3ml concentrated hydrochloric acid, under the cooling of ice-methyl alcohol, drips the 8ml aqueous solution of 0.36g Sodium Nitrite in 5 minutes.In-5 ℃ down stir 15 minutes after, with saturated sodium bicarbonate aqueous solution the pH of reaction solution is adjusted into 8, in ice-cooled down, in 15 minutes, be added drop-wise in the water-ethyl acetate mixed solution of 1.02g cuprous chloride and 2.28g potassium cyanide.
Behind the restir 15 minutes, under room temperature, stirred 2.5 hours, separate organic layer.After the saturated sodium-chloride washing, use anhydrous magnesium sulfate drying.Behind the elimination sal epsom, concentrating under reduced pressure filtrate.Residue obtained through silica gel column chromatography (chloroform/methanol=49/1) purification, get (S)-1-(4-cyano-phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 1.41g, be red oil.
With (S)-1-(4-cyano-phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 1.41g is dissolved in the 30ml ethanol, add oxalic acid 0.33g after, the concentrating under reduced pressure solvent.Residue obtained in acetonitrile-ether behind the crystallization, recrystallization from acetonitrile, (S)-1-(4-cyano-phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine dodecin salt 0.58g, be the incarnadine crystallization.
The chemical structural formula and the physico-chemical property of this compound see the following form.
Embodiment 67
At 0.85g(S)-the 1-(4-aminophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] in the 8ml pyridine solution of pyrimidine alkane,, stirred 1.7 hours in the ice-cooled 0.2ml methylsulfonyl chloride that adds down.Behind the reaction solution concentrating under reduced pressure, add 30ml chloroform and 30ml saturated sodium bicarbonate aqueous solution, vigorous stirring then.After separating organic layer, use anhydrous magnesium sulfate drying.Elimination sal epsom, filtrate decompression concentrates, residue is through silica gel column chromatography (chloroform/methanol=49:1) purify gets (S)-1-(4-methylsulfonyl amido phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 0.83g, be yellow oil.
With (S)-1-(4-methylsulfonyl amido phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane 0.83g is dissolved in the 15ml ethanol, adds fumaric acid 0.22g.The crystallization that leaching is separated out, recrystallization from alcohol-water gets (S)-1-(4-methylsulfonyl amido phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane fumarate 0.51g, be faint yellow crystallization.Its chemical structural formula and physico-chemical property see the following form.
Embodiment 68
With the methylsulfonyl chloride of record among the Acetyl Chloride 98Min. replacement embodiment 67, similarly handle with embodiment 67, get (S)-1-(4-acetamido phenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine heptane hydrochloride salt hydrate.Its chemical structural formula and physico-chemical property see the following form.
The prescription example
Enumerate the medicine prescription example of The compounds of this invention below.
(1) tablet
The compound of embodiment 13 (following table is shown compd A) 5.0mg
Lactose 106.4mg
W-Gum 43.0mg
Hydroxypropylcellulose 5.0mg
Magnesium Stearate 0.6mg
160.0mg/ sheet
Compound A-45 .0g, lactose 106.4g and W-Gum 43g are mixed, add hydroxypropylcellulose 10% aqueous solution 43ml therein, granulate with nodulizer.Add Magnesium Stearate 0.6g in the particle after granulation, be pressed into the sheet (1000) of 160mg.
The compound of embodiment 32 (following table is shown compd B) 1.0mg
Lactose 106.4mg
W-Gum 48.0mg
Hydroxypropylcellulose 4.0mg
Magnesium Stearate 0.6mg
160.0mg/ sheet
Compound B-11 .0g, lactose 106.4g and W-Gum 48g are mixed, add hydroxypropylcellulose 10% aqueous solution 40ml therein, granulate with nodulizer.Add Magnesium Stearate 0.6g in the particle after granulation, be pressed into the sheet (1000) of 160mg.
(2) powder
Compd A 5.0mg
Mannitol 770.0mg
W-Gum 195.0mg
Polyvinylpyrrolidine 30.0mg
1000.0mg
Compound A-45 .0g, mannitol 770g and W-Gum 195.0g are mixed, add 10% polyvinylpyrrolidine aqueous solution 300ml, granulate, make powder (1kg) with nodulizer.
Compd B 1.0mg
Mannitol 770.0mg
W-Gum 191.0mg
Polyvinylpyrrolidine 30.0mg
1000.0mg
Compound B-11 .0g, mannitol 770g and W-Gum 191.0g are mixed, add 10% polyvinylpyrrolidine aqueous solution 300ml, granulate, make powder (1kg) with nodulizer.
(3) capsule
Compd A 5.0mg
W-Gum 195.0mg
Calcium stearate 1.0mg
200.0mg
Compound A-45 .0g, rice starch 195.0g, calcium stearate 1g are mixed, and each filling 200mg in No. 3 capsules makes capsule (1000 capsules).
Compd B 1.0mg
W-Gum 191.0mg
Calcium stearate 1.0mg
200.0mg
Compound B-11 .0g, W-Gum 191.0g, calcium stearate 1g are mixed, and each filling 200mg in No. 3 capsules makes capsule (1000 capsules).
(4) quiet notes injection
Compd A 0.2mg
Sodium-chlor 9mg
Distilled water for injection adds to 1.0ml
Compd A 200mg, sodium-chlor 9g are dissolved in distilled water for injection, and are adjusted to 1000ml.This solution filters each filling 1ml of back in ampoule, makes injection.When filling, be full of the space of ampoule with nitrogen.
Then, in autoclave with ampoule heat sterilization (1000 ampoule).
Compd B 0.2mg
Sodium-chlor 9mg
Distilled water for injection adds to 1.0ml
Compd B 200mg, sodium-chlor 9g are dissolved in distilled water for injection, and are adjusted to 1000ml.This solution filters each filling 1ml of back in ampoule, makes injection.When filling, be full of the space of ampoule with nitrogen.
Then, in autoclave with ampoule heat sterilization (1000 ampoule).
Claims (16)
1, novel urea derivatives or its salt of representing with following general formula,
It is characterized in that, wherein
R
1, R
2: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
1With R
2Together, form cyclic group jointly with nitrogen-atoms;
R
3, R
4: hydrogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
3With R
4All-in-one-piece low-grade alkylidene, rudimentary alkylene group, or formula
The group of expression, in the formula, X is Sauerstoffatom or sulphur atom, n is 1 to 5 integer;
R
5: can substituted carbocylic radical, or can be substituted and the heterocyclic radical that contains 1-2 Sauerstoffatom and/or sulphur atom of phenyl ring condensation;
R
6Can substituted phenyl
X: Sauerstoffatom or sulphur atom
But, when X is Sauerstoffatom,
R
3, R
4For what connect together substituent low-grade alkylidene, rudimentary alkylene group or formula arranged
The group of expression.
2, by the described compound or its salt of claim 1, it is characterized in that wherein X is a Sauerstoffatom; R
3, R
4Be all-in-one-piece low-grade alkylidene, rudimentary alkylene group or formula
The group of expression.
3, by the described compound or its salt of claim 1, it is characterized in that wherein X is a sulphur atom.
4, by the described compound or its salt of claim 1, it is characterized in that, wherein R
5Substituting group be halogen atom; hydroxyl; low alkyl group; low-grade alkenyl; lower alkoxy; rudimentary alkenyloxy; low-grade alkyl thio group; the low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; low alkyl group sulfinyl oxygen base; the low alkyl group sulfonyloxy; the low alkyl group sulfoamido; nitro; amino; cyano group; trifluoromethyl; rudimentary amide group; carboxyl; lower alkoxycarbonyl; aryl; aralkyl; formamyl; sulfo group; the lower alkyl alcohol radical; the lower acyl methylamino-; one or the amino that replaces of dialkyl group; one or the aminocarboxyl that replaces of dialkyl group; one or the amino-sulfonyl that replaces of dialkyl group.
5, by the described compound or its salt of claim 1, it is characterized in that, wherein R
1, R
2For low alkyl group or both connect together, with the common nitrogenous heterocyclic group of saturated monocycle that forms of nitrogen-atoms; R
3, R
4Be hydrogen atom, low alkyl group, R
3With R
4All-in-one-piece low-grade alkylidene or formula
The group of expression; R
5For the carbocylic radical that can be replaced by halogen atom, trifluoromethyl, low alkyl group, lower alkoxy, lower alkoxycarbonyl, low-grade alkyl thio group, low alkyl group alkylsulfonyl, low alkyl group sulfonyloxy, rudimentary amide group, low alkyl group sulfoamido, nitro, amino, cyano group, aryl or with the heterocyclic radical that contains 1-2 Sauerstoffatom of phenyl ring condensation; R
6For can be by nitro or the amino phenyl that replaces.
6, compound or its salt as claimed in claim 1 is characterized in that, wherein R
1, R
2For being integral, form the group of ring jointly with nitrogen-atoms; R
3, R
4Identical or differently for hydrogen atom, low alkyl group or fuse substituent low-grade alkylidene arranged; R
5Be the phenyl or 3 that low alkyl group, halogen atom, trifluoromethyl replace, 4-methylenedioxy group phenyl; R
6Be phenyl.
7, by the described compound or its salt of claim 2, it is characterized in that, wherein R
1, R
2Fuse, become pyrrolidyl jointly with nitrogen-atoms; R
3, R
4Be integral and be propylidene; R
5Phenyl for halogen atom or trifluoromethyl replacement; R
6Be phenyl.
8, by the described compound or its salt of claim 3, it is characterized in that, wherein R
1, R
2Be integral, become pyrrolidyl jointly with nitrogen-atoms; R
3, R
4Be hydrogen atom or low alkyl group unequally; R
5Be the phenyl or 1 that low alkyl group replaces, 3-methylenedioxy group phenyl; R
6Be phenyl.
9, (S)-1-(3, the 4-dichlorophenyl)-2-oxygen-3-[1-phenyl-2-(1-pyrrolidyl) ethyl] pyrimidine alkane or its salt
10, ethyl (S)-2-oxygen-1-[1-phenyl-2-(1-pyrrolidyl)]-the 3-(4-trifluoromethyl) pyrimidine alkane or its salt
11, (S)-1-methyl-3-(3,4-methylenedioxy group phenyl)-1-[1-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide or its salt
12,1-(4-secondary butyl phenenyl)-the 3-methyl-3-[(1S)-phenyl-2-(1-pyrrolidyl) ethyl] thiocarbamide or its salt
13, the novel urea derivatives of representing with following general formula or the preparation method of its salt
Wherein
R
1, R
2: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
1With R
2Form cyclic group jointly with nitrogen-atoms together;
R
3, R
4: hydrogen atom, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, or R
3With R
4Be integral, can have substituent low-grade alkylidene, rudimentary alkylene group, or formula
The group of expression, in the formula, X is Sauerstoffatom or sulphur atom, n is 1 to 5 integer;
R
5: can substituted carbocylic radical, or can be substituted and the heterocyclic radical that contains 1-2 Sauerstoffatom and/or sulphur atom of phenyl ring condensation;
R
6Can substituted phenyl
X: Sauerstoffatom or sulphur atom
But, when X is Sauerstoffatom, R
3, R
4For what connect together substituent low-grade alkylidene, rudimentary alkylene group or formula arranged
The group of expression
Method feature is:
1) logical formula II
Represented amine compound and logical formula III
Represented compound reacts;
2) lead to amine compound and the logical formula IV that formula II is represented
Represented compound and general formula (V)
Y is a halogen atom in the formula, and the compound of expression reacts;
3) compound represented of the amine compound represented of logical formula II and logical formula IV and lead to formula VI
The carbonic acid gas or the dithiocarbonic anhydride of expression react;
4) in the compound that logical formula I is represented, the preparation of the compound of following general formula (I b) expression
Be to lead to amine compound and the general formula (VII) that formula II is represented
R
5-NHCOOR
7（Ⅶ）
The carbamate of expression reacts;
5) in the compound that logical formula I is represented, the preparation of the compound of following general formula (I c) expression
Be compound and general formula (VIII) with general formula (I b) expression
Z is halogen atom or alkylsulfonyl in the formula, and the compound of expression reacts;
6) in the compound that logical formula I is represented, the preparation of the compound of following general formula (I e) expression
A is the alkylidene group or the alkylene group of 2-6 carbonatoms in the formula, is with general formula (I d)
The compound and the general formula (IX) of expression
The compound of expression reacts, or general formula (X)
The compound and the general formula (XI) of expression
The halogenide or the phosphinylidyne diimidazole of expression react;
7) in the compound that logical formula I is represented, the preparation of the compound of following general formula (I f) expression
Be that the compound that above-mentioned general formula (I c) is represented is reacted with thiophosphoric anhydride or Lawesson ' s reagent
8) with general formula (I g)
The compound of expression reduces the method that is constituted.
14, by the described compound or its salt of claim 1, and with pharmacy on the medical composition formed of the carrier that allows.
15, with the κ-receptor stimulant of the described compound or its salt of claim 1 as effective constituent.
16, with the central analgesic agent of the described compound or its salt of claim 1 as effective constituent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP223280/91 | 1991-08-08 | ||
| JP22328091 | 1991-08-08 | ||
| JP30995291 | 1991-10-29 | ||
| JP309952/91 | 1991-10-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1069490A true CN1069490A (en) | 1993-03-03 |
Family
ID=26525374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92109284 Pending CN1069490A (en) | 1991-08-08 | 1992-08-07 | Urea derivatives |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1069490A (en) |
| AU (1) | AU2390892A (en) |
| WO (1) | WO1993003011A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485714A (en) * | 2011-10-09 | 2012-06-06 | 连云港盛和生物科技有限公司 | Method for synthesis of sorafenib through carbonylation |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5684041A (en) * | 1996-02-01 | 1997-11-04 | The Procter & Gamble Company | Dihydrobenzofuran and related compounds useful as anti-inflammatory agents |
| AU6747098A (en) * | 1997-04-11 | 1998-11-11 | Otsuka Chemical Co. Ltd. | Benzene derivatives, benzofuran derivatives, and processes for producing these |
| CA2514267C (en) | 2003-02-04 | 2011-05-17 | F. Hoffmann-La Roche Ag | Malonamide derivatives as gamma-secretase inhibitors |
| EP1621539A1 (en) * | 2004-07-27 | 2006-02-01 | Aventis Pharma S.A. | Heterocycle -substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors |
| EP2109604A1 (en) | 2007-02-02 | 2009-10-21 | F. Hoffmann-Roche AG | 6-oxo-6,7-dihydro-5h-dibenzo[b,d]azepin-7-yl derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8600263D0 (en) * | 1985-01-22 | 1986-02-12 | Ici America Inc | Peptide derivatives |
| IE902295A1 (en) * | 1989-07-07 | 1991-01-16 | Abbott Lab | Amino acid analog cck antagonists |
-
1992
- 1992-08-04 AU AU23908/92A patent/AU2390892A/en not_active Abandoned
- 1992-08-04 WO PCT/JP1992/000993 patent/WO1993003011A1/en active Application Filing
- 1992-08-07 CN CN 92109284 patent/CN1069490A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485714A (en) * | 2011-10-09 | 2012-06-06 | 连云港盛和生物科技有限公司 | Method for synthesis of sorafenib through carbonylation |
| CN102485714B (en) * | 2011-10-09 | 2013-07-24 | 连云港盛和生物科技有限公司 | Method for synthesis of sorafenib through carbonylation |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2390892A (en) | 1993-03-02 |
| WO1993003011A1 (en) | 1993-02-18 |
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