Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
The present invention is directed to novel quinoline compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
1. The method of preparing a compound of Formula 1c, or a salt thereof,
the method comprising the step of coupling a compound of Formula 1a
with a compound Formula 1b
wherein:
m is selected from the group consisting of 0 and 1;
R 1 is independently selected from the group consisting of chloro, fluoro, bromo, cyano, and methoxy;
R 2b and R 2c are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 ;
R A and R B are independently selected from the group consisting of H and Me;
R C and R D are independently or together a group that can by hydrolyzed to hydroxyl;
n is selected from the group consisting of 0 and 1; and
R 3 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 .
2. The method of claim 1 wherein m is 0.
3. The method of claim 1 wherein R C and R D are both OH or R C and R D together with the boron atom to which they are bound form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group.
4. The method of claim 1 wherein R C and R D are both OH.
5. The method of claim 1 wherein R A is Me.
6. The method of claim 1 wherein R B is Me.
7. The method of claim 1 wherein R A and R B are both H.
8. The method of claim 1 wherein the method comprises a demethylation step using BBr 3 , AlCl 3 , or Na2S.
9. The method of claim 6 wherein the method comprises an ester hydrolysis step using LiOH or NaOH.
10. The method of claim 1 wherein the coupling step uses PdCl 2 (dppf) or Pd(PPh 3 ) 4 .
11. The method of claim 1 wherein the compound 1c is selected from the group consisting of
4-(6-hydroxy-3-methylquinolin-2-yl)benzoic acid;
4-(6-hydroxyquinolin-2-yl)benzoic acid;
3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid;
4-(3-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-chloro-3-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(3-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
3-(dimethylamino)-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid;
4-(3-chloro-6-hydroxyquinolin-2-yl)-3-fluorobenzoic acid;
4-(6-hydroxyquinolin-2-yl)-3-(trifluoromethyl)benzoic acid;
4-(6-hydroxy-3-(trifluoromethyl)quinolin-2-yl)benzoic acid;
3-chloro-4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
3-fluoro-4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(5-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(5-bromo-6-hydroxyquinolin-2-yl)benzoic acid;
3-bromo-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-(dimethylamino)-6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-fluoro-6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid;
3-cyano-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(3-cyano-6-hydroxyquinolin-2-yl)benzoic acid;
4-(5-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(8-fluoro-6-hydroxyquinolin-2-yl)benzoic acid; and
3-fluoro-4-(5-fluoro-6-hydroxyquinolin-2-yl)benzoic acid.
12. The method of claim 1 wherein the compound 1c is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid.
13. The method of claim 1 wherein the compound 1c is 3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid.
14. The method of claim 1 wherein the compound 1c is 4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid.