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 alleviating the symptoms or complications of pulmonary disorders 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
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. A method of alleviating the symptoms or complications of inflammatory disorders 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
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.
8. The method of claim 7 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.
9. The method of claim 7 wherein R 1 is selected from the group consisting of CF 3 , isopropyl, and isobutyl; and R 2 and R 3 are both hydrogen.
10. The method of claim 7 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.
11. The method of claim 7 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.
12. The method of claim 7 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.