Thiophene inhibitors of S-nitrosoglutathione reductase
The present invention is directed to novel thiophene inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
1. A compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
X and Y are selected from the group consisting of S or CH, provided that when X is S, Y must be CH and when X is CH, Y must be S;
Ar is selected from the group consisting of phenyl and thiophen-yl;
R 1 is selected from the group consisting of hydrogen, unsubstituted imidazolyl, substituted imidazolyl, carbamoyl, chloro, bromo, fluoro, hydroxy, and methoxy;
R 2 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl;
R 3 is selected from the group consisting of hydrogen, methyl, methoxy, chloro, and fluoro; and
R 4 is selected from the group consisting of CONH 2 , NHSO 2 CH 3 , hydroxy, chloro, and substituted and unsubstituted imidazolyl.
2. The compound of claim 1 wherein Ar is selected from the group consisting of
3. The compound of claim 2 wherein R 1 is
wherein R 5 is selected from the group consisting of hydrogen, methyl and ethyl.
4. The compound of claim 2 wherein ArR 1 R 2 is selected from the group consisting of 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 4-hydroxyphenyl, 4-carbamoylphenyl, and 4-bromophenyl.
5. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, methyl, and methoxy.
6. A compound of claim 1 wherein the compound is a compound of Formula II:
wherein:
Ar is selected from the group consisting of phenyl and thiophen-yl;
R 1 is selected from the group consisting of hydrogen, unsubstituted imidazolyl, substituted imidazolyl, carbamoyl, chloro, bromo, fluoro, hydroxy, and methoxy;
R 2 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl; and
R 3 is selected from the group consisting of hydrogen, methyl, methoxy, chloro, and fluoro; and
R 4 is selected from the group consisting of CONH 2 , NHSO 2 CH 3 , hydroxy, chloro, and substituted and unsubstituted imidazolyl.
7. The compound of claim 6 wherein Ar is selected from the group consisting of
8. The compound of claim 7 wherein R 1 is
wherein R 5 is selected from the group consisting of hydrogen, methyl and ethyl.
9. The compound of claim 7 wherein ArR 1 R 2 is selected from the group consisting of 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 4-hydroxyphenyl, 4-carbamoylphenyl, and 4-bromophenyl.
10. The compound of claim 6 wherein R 3 is selected from the group consisting of hydrogen, methyl, and methoxy.
11. The compound of claim 6 selected from the group consisting of
3-(3-(4-carbamoyl-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)propanoic acid;
3-(3-(4-carbamoylphenyl)-4-(4-chloro-2-methoxyphenyl)thiophen-2-yl)propanoic acid;
3-(3-(4-chloro-2-methoxyphenyl)-4-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid;
3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid;
3-(4-(4-chloro-2-methoxyphenyl)-3-(4-(methylsulfonamido)phenyl)thiophen-2-yl)propanoic acid;
3-(4-(4-carbamoylphenyl)-3-(4-(2-methyl-1H-imidazol-1-yl)phenyl)thiophen-2-yl)propanoic acid;
3-(3-(4-carbamoyl-2-methylphenyl)-4-(4-(2-methyl-1H-imidazol-1-yl)phenyl)thiophen-2-yl)propanoic acid;
3-(3-(4-carbamoylphenyl)-4-(4-(2-methyl-1H-imidazol-1-yl)phenyl)thiophen-2-yl)propanoic acid;
3-(4-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)propanoic acid;
3-(4-(4-chloro-2-methoxyphenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)propanoic acid;
3-(4′-(4-carbamoyl-2-methylphenyl)-5-(2-methyl-1H-imidazol-1-yl)-2,3′-bithiophen-5′-yl)propanoic acid;
3-(5-(2-methyl-1H-imidazol-1-yl)-4′-(2-methyl-4-(methylsulfonamido)phenyl)-2,3′-bithiophen-5′-yl)propanoic acid; and
3-(4-(4-bromophenyl)-3-(4-carbamoyl-2-methylphenyl)thiophen-2-yl)propanoic acid.
12. A compound of claim 1 wherein the compound is a compound of Formula III:
wherein:
Ar is selected from the group consisting of phenyl and thiophen-yl;
R 1 is selected from the group consisting of hydrogen, unsubstituted imidazolyl, substituted imidazolyl, carbamoyl, chloro, bromo, fluoro, hydroxy, and methoxy;
R 2 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl;
R 3 is selected from the group consisting of hydrogen, methyl, methoxy, chloro, and fluoro; and
R 4 is selected from the group consisting of CONH 2 , NHSO 2 CH 3 , hydroxy, chloro, and substituted and unsubstituted imidazolyl.
13. The compound of claim 12 wherein Ar is selected from the group consisting of
14. The compound of claim 13 wherein R 1 is
wherein R 5 is selected from the group consisting of hydrogen, methyl and ethyl.
15. The compound of claim 13 wherein ArR 1 R 2 is selected from the group consisting of 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 4-hydroxyphenyl, 4-carbamoylphenyl, and 4-bromophenyl.
16. The compound of claim 12 wherein R 3 is selected from the group consisting of hydrogen, methyl, and methoxy.
17. The compound of claim 12 selected from the group consisting of 3-(4-(4-carbamoyl-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I according to claim 1 together with a pharmaceutically accepted carrier or excipient.