Aldose reductase inhibitors and methods of use thereof

11498,925

17/086699

November 02, 2020

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.

The Trustees of Columbia University in the City of New York (New York, NY, US)

THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK (New York, NY, US)

1. A method for inhibiting aldose reductase activity in a subject, comprising administering to a subject who has retinopathy, nephropathy, or cardiomyopathy, a therapeutically effective amount of a compound of Formula (I) [chemical expression included] 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 [chemical expression included] 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; 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.

2. The method of claim 1 , wherein Z is [chemical expression included] 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 [chemical expression included] 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 retinopathy, nephropathy, or cardiomyopathy, a therapeutically effective amount of a compound of Formula (I) [chemical expression included] 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 [chemical expression included] 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 [chemical expression included] or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 6 , where the compound of Formula I is [chemical expression included] or a pharmaceutically acceptable salt or solvate thereof.

22. The method of claim 6 , where the compound of Formula I is [chemical expression included] or a pharmaceutically acceptable salt or solvate thereof.

23. The method of claim 6 , where the compound of Formula I is [chemical expression included] or a pharmaceutically acceptable salt or solvate thereof.

24. A method for preparing a compound of Formula (I) [chemical expression included] 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 or [chemical expression included] 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; comprising reacting Compound (1): [chemical expression included] with: (i) Compound (2): [chemical expression included] (ii) Compound (3): [chemical expression included] or (iii) Compound (4): [chemical expression included] wherein each Q is a halogen.

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