IP Library › Granted Patent US 9,283,213

Granted Patent B2

US 9,283,213 · App. 14/598,202 · Granted Mar 15, 2016

Dihydropyridin-2(1H)-one compounds as

Inventors: Xicheng Sun (Broomfield, CO); Jian Qiu (Longmont, CO)

Assignee: Nivalis Therapeutics, Inc.

A61K31/4412 A61K31/444 A61K31/4436 A61K31/4439 C07D211/86 C07D211/88 C07D401/04 C07D401/14 C07D409/04 C07D409/14

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,283,213
App. No.: 14/598,202
Granted: Mar 15, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention is directed to novel dihydropyridin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors and/or Neurokinin-3 (NK3) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of making and using the same.

Claims (69)

1. A method of treatment of a disease or condition wherein the disease or condition is selected from the group consisting of pulmonary disorders, inflammatory bowel disease, schizophrenia, psychosis, anxiety, and depression, which comprises administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof

wherein

X 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, and substituted pyridin-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 0, S, and NRS;

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 method 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 method 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 method 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 method 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 method 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-1-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 method 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 method of claim 1 wherein Z is O.

9. The method of claim 1 wherein the compound is 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-tetrahydropyridin-4-yl)benzoic acid.

10. The method of claim 1 wherein the disease or condition is a pulmonary disorder.

11. The method of claim 10 wherein the pulmonary disorder is selected from the group consisting of asthma, cystic fibrosis, and chronic obstructive pulmonary disorder (COPD).

12. The method of claim 1 wherein the disease or condition is inflammatory bowel disease (IBD).

13. The method of claim 1 wherein the disease or condition is selected from the group consisting of anxiety, depression, psychosis and schizophrenia.

14. A method of inhibiting S-nitrosoglutathione reductase (GSNOR) in a subject, said method comprising administering to the subject a pharmacologically effective amount of a pharmaceutical composition comprising the compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the compound of formula I is the S enantiomer.

16. The method of claim 14 wherein the compound is selected from the group consisting of