Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
The present invention is directed to novel substituted bicyclic aromatic compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
1. The compound of Formula 1:
wherein
R 1 is selected from the group consisting of H, F, and Cl;
R 2a and R 2b are independently selected from the group consisting of H, F, Cl, Br, Me, OCH 3 , and cyano;
R 2c is selected from the group consisting of H, F, Cl, Br, Me, and OCH 3;
X is selected from the group consisting of
A is selected from the group consisting of
R 3 is selected from the group consisting of F, Cl, Br, CH 3 , CF 3 , OCH 3 ,cyano, N(CH 3 ) 2 , and morpholino;
n is selected from the group consisting of 0, 1, and 2;
R 4 is selected from the group consisting of H, F, Cl, Br, CH 3 , CF 3 , OCH 3 , cyano, N(CH 3 ) 2 , and morpholino;
with the proviso that when X is
and A is COOH, then at least one of R 1 , R 2a , R 2b , R 2c , and R 4 is not hydrogen, or n must be >0, and R 3 when meta to naphthalene, cannot be CH 3 .
2. The compound of claim 1 wherein X is
3. The compound of claim 2 wherein R 2c is hydrogen.
4. The compound of claim 2 where R 2b is hydrogen.
5. The compound of claim 1 wherein the compound is a compound of Formula 2
6. The compound of claim 5 wherein
R 1 is selected from the group consisting of H and F;
R 2a is selected from the group consisting of H, F, Cl, Br, and cyano;
R 2b is selected from the group consisting of H, F, and Cl;
R 2c is H; and
R 4 is selected from the group consisting of H, F, Cl, and cyano.
7. The compound of claim 5 wherein Ri is selected from the group consisting of F and Cl.
8. The compound of claim 5 wherein R 2a is selected from the group consisting of F, Cl, Br, Me, OCH 3 , and cyano.
9. The compound of claim 5 wherein R 2b is selected from the group consisting of F, Cl, Br, Me, OCH 3 , and cyano.
10. The compound of claim 5 wherein R 2c is selected from the group consisting of F, Cl, Br, Me, and OCH 3 .
11. The compound of claim 5 wherein R 4 is selected from the group consisting of F, Cl, Br, CH 3 , CF 3 , OCH 3 , cyano, N(CH 3 ) 2 , and morpholino.
12. The compound of claim 1 wherein the compound is a compound of Formula 3
13. The compound of claim 12 wherein X is
14. The compound of claim 13 where A is COOH.
15. The compound of claim 12 wherein the compound is a compound of Formula 4
16. The compound of claim 15 wherein R 2c is H.
17. The compound of claim 15 wherein R 2b is H.
18. The compound of claim 15 wherein
R 1 is selected from the group consisting of H and F;
R 2b is selected from the group consisting of H, F, and Cl;
R 2c is H; and
R 4 is selected from the group consisting of H, F, Cl, and cyano.
19. The compound of claim 1 wherein the compound is a compound of Formula 5
20. The compound of claim 19 wherein X is
21. The compound of claim 20 wherein A is COOH.
22. The compound of claim 19 wherein the compound is a compound of Formula 6
23. The compound of claim 22 wherein R 2c is H.
24. The compound of claim 22 wherein R 2b is H.
25. The compound of claim 22 wherein
R 2a is selected from the group consisting of H, F, Cl, Br, and cyano;
R 2b is selected from the group consisting of H, F, and Cl;
R 2c is H; and
R 4 is selected from the group consisting of H, F, Cl, and cyano.
26. The compound of claim 1 wherein the compound is selected from the group consisting of
3-chloro-4-(6-hydroxynaphthalen-2-yl)benzoic acid;
3-fluoro-4-(6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxynaphthalen-2-yl)-3-methoxybenzoic acid;
3-(dimethylamino)-4-(6-hydroxynaphthalen-2-yl)benzoic acid;
3-cyano-4-(6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxynaphthalen-2-yl)-3-morpholinobenzoic acid;
4-(1-bromo-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxy-1-methylnaphthalen-2-yl)benzoic acid;
4-(1-cyano-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxy-3-methoxynaphthalen-2-yl)benzoic acid;
4-(1-chloro-6-hydroxynaphthalen-2-yl)benzoic acid;
6-(4-(1H-tetrazol-5-yl)phenyl)naphthalen-2-ol;
5-(6-hydroxynaphthalen-2-yl)picolinic acid;
6-(6-hydroxynaphthalen-2-yl)nicotinic acid;
5-(6-hydroxynaphthalen-2-yl)pyrazine-2-carboxylic acid;
6-(6-hydroxynaphthalen-2-yl)pyridazine-3-carboxylic acid;
5-(6-hydroxynaphthalen-2-yl)pyrimidine-2-carboxylic acid;
6-(1H-benzo[d][1,2,3]triazol-6-yl)naphthalen-2-ol;
4-(6-hydroxynaphthalen-2-yl)-3-(trifluoromethyl)benzoic acid;
3-chloro-4-(3-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(3-chloro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(3-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxy-1-methoxynaphthalen-2-yl)benzoic acid;
4-(1-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(6-hydroxy-3-methylnaphthalen-2-yl)benzoic acid;
4-(1-cyano-5-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(1-cyano-6-hydroxynaphthalen-2-yl)-3-fluorobenzoic acid;
3-chloro-4-(5-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
4-(5-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid;
3-fluoro-4-(5-fluoro-6-hydroxynaphthalen-2-yl)benzoic acid; and
4-(5 -fluoro-6-hydroxynaphthalen-2-yl)-3 -methylbenzoic acid.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.
28. A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of Formula 1 as defined in claim 1 to a patient in need thereof, wherein the disease or condition is selected from asthma, COPD or inflammatory bowel disease (IBD).
29. A method of making a pharmaceutical composition comprising combining a compound of Formula 1 as defined in claim 1 with a pharmaceutically acceptable carrier or excipient.