Chromone Inhibitors of S-Nitrosoglutathione Reductase
The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
1 . A method of treatment of a disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein the disease or condition is a disease where there is risk of apoptosis occurring
wherein
R 1 is selected from the group consisting of CF 3 , CF 2 H, CF 2 CH 3 , CF 2 CH 2 CH 3 , isopropyl, isobutyl, cyclopentyl, CH 2 OCH 3 , SCH 3 , benzyl, thiophen-2-yl, and thiophen-3-yl;
R 2 is selected from H, F, Cl, methoxy, and cyano; and
R 3 is selected from H, F, Cl, and methoxy.
2 . The method of claim 1 wherein R 1 is selected from the group consisting of CF 3 , CF 2 H, and CF 2 CH 3 ; and R 2 is hydrogen.
3 . The method of claim 1 wherein R 1 is selected from the group consisting of CF 3 , isopropyl, and isobutyl; and R 2 and R 3 are both hydrogen.
4 . The method of claim 1 wherein R 1 is selected from the group consisting of CF 3 , isopropyl, isobutyl, CF 2 H, CF 2 CH 3 , and CF 2 CH 2 CH 3 ; and R 2 and R 3 are both hydrogen.
5 . The method of claim 1 wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of
4-(2-(difluoromethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-2-(methoxymethyl)-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-2-isopropyl-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(2-cyclopentyl-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(2-benzyl-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-4-oxo-2-(thiophen-2-yl)-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-4-oxo-2-(thiophen-3-yl)-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-2-isobutyl-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-2-(methylthio)-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(6-chloro-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
4-(6-fluoro-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
2-fluoro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
3-chloro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
4-(2-(1,1-difluoroethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-6-methoxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
2-chloro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid;
4-(2-(1,1-difluoropropyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid;
4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)-3-methoxybenzoic acid; and
4-(6-cyano-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid.
6 . The method of claim 1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically accepted carrier or excipient.
7 . The method of claim 1 wherein said disease or condition is liver injury.
8 . The method of claim 7 wherein the liver injury is ischemic.
9 . The method of claim 7 wherein the liver injury is alcoholic.
10 . The method of claim 1 wherein the said disease or condition is selected from heart failure, atherosclerosis, degenerative neurologic disorders, and arthritis.