Dihydropyridin-2(1H)-one compound as S-nirtosoglutathione reductase inhibitors and neurokinin-3 receptor antagonists

1. The compound of formula I or pharmaceutically acceptable salts thereof:

wherein

X is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, prazin-yl, substituted pyrazin-yl, pyridin-yl, and substituted piridin-yl, cyclohexyl, substituted cyclohexyl;

Y is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, substituted pyridin-yl, furan-yl, substituted furan-yl, benzo[d][1,3]dioxol-yl, substituted benzo[d][1,3]dioxol-yl, imidazol-yl, substituted imidazol-yl, naphthalen-yl, substituted naphthalen-yl, pyrrol-yl, substituted pyrrol-yl, pyrazol-yl, substituted pyrazol-yl, tetrahydrofuran-yl, substituted tetrahydrofuran-yl, cyclopentyl, substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl;

Z is selected from the group consisting of O, S, and NR 7 ;

R 1 and R 2 and R 7 are independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl;

R 3 is selected from the group consisting of hydrogen, nitro, cyano, carboxyl, carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C 1 -C 6 alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl;

R 4 is selected from the group consisting of hydroxyl, carboxyl, and tetrazol-5-yl;

R 5 is selected from the group consisting of hydrogen, hydroxyl, carboxy, chloro, fluoro, cyano, —O(CH 2 ) 1-6 NMe 2 , C 1 -C 6 alkyl, —O(CH 2 ) 1-6 OCH 3 , —O(CH 2 ) 1-6 OH, acetyl, CF 3 , and C 1 -C 6 alkoxy; and

R 6 is selected from the group consisting of hydrogen and hydroxyl.

2. The compound of claim 1 wherein R 1 , R 2 and R 7 are independently selected from the group consisting of hydrogen and methyl;

R 5 is selected from the group consisting of hydrogen, hydroxyl, carboxyl, chloro, fluoro, cyano, —O(CH 2 ) 2 NMe 2 , C 1 -C 6 alkyl, —O(CH 2 ) 2 OCH 3 , —O(CH 2 ) 2 OH, acetyl, CF 3 , methoxy, ethoxy, isopropoxy, and n-propoxy; and

R 6 is hydrogen.

3. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, nitro, and hydroxyl; and R 5 is selected from the group consisting of hydrogen, ethoxy, fluoro, and —O(CH 2 ) 2 OH.

4. The compound of claim 1 wherein X is selected from the group consisting of phenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, 2-fluorophenyl, p-tolyl, m-tolyl, biphenyl-4-yl, 4-methoxyphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-bromophenyl, o-tolyl, 4-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,4-difluorophenyl, 4-cyanophenyl, 3-carbamoylphenyl, pyrazin-2-yl, biphenyl-3-yl, 2-cyanophenyl, pyridin-4-yl, and pyridin-3-yl, 4-(dimethylamino)phenyl, 3-fluorophenyl, 3-ethylphenyl, and cyclohexyl.

5. The compound of claim 1 wherein X is selected from the group consisting of phenyl, thiophen-2-yl, thiophen-3-yl, and pyridin-3-yl.

6. The compound of claim 1 wherein Y is selected from the group consisting of phenyl, 3-methoxyphenyl, p-tolyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 3-fluorophenyl, 4-bromophenyl, biphenyl-4-yl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl, 2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl, 4-morpholinophenyl, 4-aminophenyl, pyridin-2-yl, benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, pyridin-3-yl, pyridin-4-yl, 4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl, 1-methyl-1H-imidazol-4-yl, naphthalen-l-yl, methyl phenylcarbamate, and naphthalen-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl, 1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl, 4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl, pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl, tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl and cyclohexyl-.

7. The compound of claim 1 wherein Y is selected from the group consisting of phenyl, pyridin-3-yl, 1-methyl-1H-pyrazol-4-yl, and cyclohexyl.

8. The compound of claim 1 wherein Z is O.

9. The compound of claim 1 selected from the group consisting of 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyridin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyridin-2(1H)-one;

4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyridin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyridin-2(1H)-one;

4-(4-(2H-tetrazol-5-yl)phenyl)-6(1-methyl- 1H-pyrazol-4-yl)-5- (thiophen-3 -yl)-3 ,4-dihydropyridin-2(1H)-one;

2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

2-hydroxy-4-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

4-(4-(2H-tetrazol-5-yl)phenyl)-6(1-methyl- 1H-pyrazol-4-yl)-5-phenyl-3 ,4-dihydropyridin-2(1H)-one;

2-hydroxy-4- (6-(1-methyl- 1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3 -yl)- 1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

2-fluoro-6-hydroxy-4- (6- (1-methyl- 1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)- 1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

4-(6-cyclohexyl-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyridin-4-yl)-2-fluoro-6-hydroxybenzoic acid;

4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyridin-2(1H)-one;

2-fluoro-6-hydroxy-4-(1-methyl-2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyridin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyridin-2(1H)-one; and

2-fluoro-6-hydroxy-4- (6- (1-methyl- 1H-pyrazol-4-yl)-2-oxo-5-(thiophen-2-yl)- 1,2,3,4-tetrahydrop yridin-4-yl)benzoic acid.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.