Aldose reductase inhibitors and methods of use thereof
View Patent ↗The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.
1. A method for inhibiting aldose reductase activity in a subject, comprising administering to a subject who has neuropathy a therapeutically effective amount of a compound of Formula (I)
wherein,
R 1 is CO 2 R 2 ;
R 2 is H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;
X 1 is H or halogen;
X 2 is H or halogen;
Y is a bond, C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;
Z is
A 1 is NR 7 , O, S or CH 2 ;
A 2 is N or CH;
A 3 is NR 7 , O, or S;
R 3 through R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkylsulfonyl;
R 7 is hydrogen, C 1 -C 4 alkyl, or C(O)O—(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. The method of claim 1 , wherein
Z is
or a pharmaceutically acceptable salt or solvate thereof.
3. The method of claim 2 , wherein
R 2 is hydrogen or (C 1 -C 6 )-alkyl;
Y is C═O;
A 1 is NR 7 , O, or S;
A 2 is N;
R 3 through R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkylsulfonyl; and
R 7 is hydrogen, C 1 -C 4 alkyl, or C(O)O—(C 1 -C 4 )-alkyl; or a pharmaceutically acceptable salt or solvate thereof.
4. The method of claim 1 , wherein
Z is
or a pharmaceutically acceptable salt or solvate thereof.
5. The method of claim 4 , wherein
R 2 is hydrogen or (C 1 -C 6 )-alkyl;
Y is C═O;
R 3 through R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkylsulfonyl; and
R 7 is hydrogen, C 1 -C 4 alkyl, or C(O)O—(C 1 -C 4 )-alkyl; or a pharmaceutically acceptable salt or solvate thereof.
6. A method for inhibiting aldose reductase activity in a subject, comprising administering to a subject who has neuropathy a therapeutically effective amount of a compound of Formula (I)
wherein,
R 1 is CO 2 R 2 ;
R 2 is H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl, or (C 1 -C 6 )-aminoalkyl;
X 1 is H;
X 2 is H;
Y is C═O;
Z is
A 1 is S;
A 2 is N; and
R 3 through R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, or (C 1 -C 4 )-alkylsulfonyl;
or a pharmaceutically acceptable salt or solvate thereof.
7. The method of claim 6 , wherein R 2 is (C 1 -C 6 )-alkyl.
8. The method of claim 7 , wherein R 3 through R 6 are independently hydrogen, halogen, or haloalkyl.
9. The method of claim 6 , wherein R 2 is (C 1 -C 6 )-hydroxyalkyl.
10. The method of claim 9 , wherein R 3 through R 6 are independently hydrogen, halogen, or haloalkyl.
11. The method of claim 6 , wherein R 2 is (C 1 -C 6 )-aminoalkyl.
12. The method of claim 11 , wherein R 3 through R 6 are independently hydrogen, halogen, or haloalkyl.
13. The method of claim 6 , wherein R 2 is H.
14. The method of claim 13 , wherein R 3 through R 6 are independently hydrogen, halogen, or haloalkyl.
15. The method of claim 6 , wherein R 3 , R 5 , and R 6 are each hydrogen; and R 4 is hydrogen, halogen, or haloalkyl.
16. The method of claim 7 , wherein R 3 , R 5 , and R 6 are each hydrogen; and R 4 is hydrogen, halogen, or haloalkyl.
17. The method of claim 9 , wherein R 3 , R 5 , and R 6 are each hydrogen; and R 4 is hydrogen, halogen, or haloalkyl.
18. The method of claim 11 , wherein R 3 , R 5 , and R 6 are each hydrogen; and R 4 is hydrogen, halogen, or haloalkyl.
19. The method of claim 13 , wherein R 3 , R 5 , and R 6 are each hydrogen; and R 4 is hydrogen, halogen, or haloalkyl.
20. The method of claim 6 , where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.
21. The method of claim 6 , where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.
22. The method of claim 6 , where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.
23. The method of claim 6 , where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.