US 2007/0167440 A1Published application

Novel pyrrolidine compound and a process for preparing the same

AssigneeMitsubishi Tanabe Pharma Corporation

InventorsYasunori Moritani, Shigeru Furukubu, Yasunori Tsuboi, Chieko Okagaki, Akira Oku, Naomitsu Hirano

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Abstract

The present invention relates to a novel pyrrolidine compound, which has a potent antagonistic activity against central cannabinoid (CB1) receptor, having the formula [I]: wherein each of R1 and R2 is (A) optionally substituted aryl (or heteroaryl) group, or (B) both of the groups combine to form a group of the formula: one of R3 and R4 is hydrogen and another is hydrogen, hydroxyl, hydroxyalkyl, etc., or both of R3 and R4 combine to form oxo group, R5 is hydrogen or alkyl, Y is single bond, oxygen atom or a group of the formula: —N(R7)—, R6 is optionally substituted hydrocarbon group or optionally substituted cyclic group, R7 is alkyl or alkyloxycarbonylalkyl, provided that R6 is not 4-amino-5-chloro-2-methoxyphenyl group when Y is single bond and one of the R3 and R4 is hydrogen and another is hydroxymethyl, or a pharmaceutically acceptable salt thereof.

Claims40

Dependent claims

A compound of the formula [I]:

wherein each of R1 and R2 is (A) independently an aryl (or heteroaryl) group optionally substituted by the same or different one to three group(s) selected from (1) a halogen atom, (2) cyano group, (3) an alkyl group optionally substituted by one to three groups selected from a halogen atom and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or di-alkylamino group, a pyrrolidinyl group and a morpholino group, (5) an amino group optionally substituted by a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or di-alkylamino-alkyl group, (6) a carbatnoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group,(11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13)) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group, or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:
one of R3 and R4 is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R3 and R4 combine each other to form an oxo group, R5 is a hydrogen atom or an alkyl group, Y is a single bond, an oxygen atom or a group of the formula:
—N(R7)—, R6 is (1) a straight or branched chain hydrocarbon group optionally having a substituent(s) and optionally containing one or more double or triple bond in the molecule or (2) a cyclic group optionally having a substituent(s) and optionally containing one or more heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, R7 is an alkyl group or an alkyloxycarbonylalkyl group, provided that R6 is not 4-amino-5-chloro-2-methoxyphenyl group when Y is a single bond and one of the R3 and R4 is hydrogen atom and another is hydroxymethyl group, or a pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of:

1-[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-[(4-chlorobenzoyl)amino]pyrrolidine;
1-[bis-(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-isopropoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[(4-chlorophenyl)[4-[N-methyl-N-(2-methoxyethyl)amino]phenyl]methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine;
1-[bis-(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
1-[(2-chlorophenyl)(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine;
1-[bis-(4-chlorophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-morpholino-4-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]amino]-pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[(4-cyanobenzoyl)amino]pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-cyanobenzoyl)amino]pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(2-fluoro-4-cyanobenzoyl)amino]-pyrrolidine;
(3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-morpholino-4-[(4-chlorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-isopropyloxyphenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[3-fluoro-4-(trifluoro-methyl)benzolyl]amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine;
(3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine:
(3R)-1-[[(S)-4-cyanophenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine:
(3R)-1-[[(S)-4-cyanophenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-methoxypyridin-3-yl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-methoxypyridin-3-yl)methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[2-fluoro-4-(trifluoromethyl)phenyl)]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(4-chlorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(4-chlorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-chlorobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-chlorobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-chlorophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-chloro-2-fluorophenyl)]methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-chlorophenyl)methyl]-3-[[5-(trifluoromethyl)-2-thenoyl]amino]-pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-methylthiophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(S)-(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)amino]-pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-ethoxypyridin-3-yl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2,2-difluoroethoxy)-pyridin-3-yl]methyl]-3-[(2-fluoro-4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-ethoxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2,2-difluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2-methoxyethoxy)-pyridin-3-yl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-cyano-2-fluorobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-chlorophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-chlorophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(2-isopropyloxypyrimidin-5-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(2-isopropyloxypyrimidin-5-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(6-isopropyloxymethylpyridin-3-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(6-cyanonicotinoyl)-amino]pyrrolidine;
(3R)-1-[(4-chlorophenyl)(6-methoxymethylpyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(6-methoxymethylpyridin-3-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-methoxymethylpyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2-fluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-ethoxybenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-methylthiobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(5-bromo-2-thenoyl)amino]-pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine;
(3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine;
(3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-ethoxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-ethoxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(1-fluoromethyl-2-fluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-dimethylamino-carbonyloxybenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-dimethylaminocarbonyl-oxybenzoyl)amino]pyrrolidine;
(3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine;
(3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]-pyrrolidine;
(3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-dimethylaminocarbonyloxyphenyl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-dimethylaminocarbonyloxyphenyl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(4-dimethylaminocarbonyloxyphenyl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine;
(3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;
and
(3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine;
or a pharmaceutically acceptable salt thereof.

142 more elements

A process for preparing a compound of the formula [I]:

wherein each of R1 and R2 is (A) independently an aryl (or heteroaryl) group optionally substituted by the same or different one to three group(s) selected from (1) a halogen atom, (2) cyano group, (3) an alkyl group optionally substituted by one to three groups selected from a halogen atom and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or di-alkylamino group, a pyrrolidinyl group and a morpholino group, (5) an amino group optionally substituted by a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or di-alkylamino-alkyl group, (6) a carbamoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group,(11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13)) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group, or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:
one of R3 and R4 is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R3 and R4 combine each other to form an oxo group, R5 is a hydrogen atom or an alkyl group, Y is a single bond, an oxygen atom or a group of the formula:
—N(R7)—, R6 is (1) a straight or branched chain hydrocarbon group optionally having a substituent(s) and optionally containing one or more double or triple bond in the molecule or (2) a cyclic group optionally having a substituent(s) and optionally containing one or more heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, R7 is an alkyl group or an alkyloxycarbonylalkyl group, provided that R6 is not 4-amino-5-chloro-2-methoxyphenyl group when Y is a single bond and one of the R3 and R4 is hydrogen atom and another is hydroxymethyl group, which comprises a step of reacting a compound of the formula [II]:
wherein the symbols are the same as defined above with a compound of the formula [III]:
R6—Y—COOR0 [III]
wherein R0 is a hydrogen atom, an alkyl group or a benzyl group and other symbols are the same as defined above or a salt thereof.

3 more elements

A process for preparing a compound of the formula [I]:

wherein each of R1 and R2 is (A) independently an aryl (or heteroaryl) group optionally substituted by the same or different one to three group(s) selected from (1) a halogen atom, (2) cyano group,
(3) an alkyl group optionally substituted by one to three groups selected from a halogen atom and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or di-alkylamino group, a pyrrolidinyl group and a morpholino group, (5) an amino group optionally substituted by a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or di-alkylamino-alkyl group, (6) a carbamoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group,(11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13)) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group, or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:
one of R3 and R4 is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R3 and R4 combine each other to form an oxo group, R5 is a hydrogen atom or an alkyl group, Y is a single bond, an oxygen atom or a group of the formula:
—N(R7)—, R6 is (1) a straight or branched chain hydrocarbon group optionally having a substituent(s) and optionally containing one or more double or triple bond in the molecule or (2) a cyclic group optionally having a substituent(s) and optionally containing one or more heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, R7 is an alkyl group or an alkyloxycarbonylalkyl group, provided that R6 is not 4-amino-5-chloro-2-methoxyphenyl group when Y is a single bond and one of the R3 and R4 is hydrogen atom and another is hydroxymethyl group, which comprises a step of reacting a compound of the formula [IV]:
wherein X is a reactive residue and other symbols are the same as defined above with a compound of the formula [V]:
wherein the symbols are the same as defined above.

3 more elements

A process for preparing a compound of the formula [I-a]:

wherein each of R1 and R2 is (A) independently an aryl (or heteroaryl) group optionally substituted by the same or different one to three group(s) selected from (1) a halogen atom, (2) cyano group, (3) an alkyl group optionally substituted by one to three groups selected from a halogen atom and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or di-alkylamino group, a pyrrolidinyl group and a morpholino group, (5) an amino group optionally substituted by a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or di-alkylamino-alkyl group, (6) a carbamoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group,(11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13)) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group, or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:
either one of R3 and R4 is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R3 and R4 combine each other to form an oxo group, R5 is a hydrogen atom or an alkyl group, each of R8 and R9 is independently a group selected from an alkyl group, an arylalkyl group, an alkyloxy-carbonylalkyl group and an aryl group optionally substituted by a halogen atom, or both of the groups combine each other together with an adjacent nitrogen atom to form a heterocyclic group (said heterocyclic group being optionally fused to a benzene ring and optionally substituted by a halogenoaryl group), which comprises a step of reacting a compound of the formula [II]:
wherein the symbols are the same as defined above with a compound of the formula [VI]:
(R8)(R9)NH [VI]
wherein the symbols are the same as defined above in the presence of a compound of the formula [VII]:
wherein W1 and W2 are the same or different and a removing group.

3 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/579,950Filed 27 May 2005
Priority: JP 2004-16005928 May 2004
Published: 19 Jul 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 207/14
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,…:…
A61P 25/00
Drugs for disorders of the nervous system
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links