Prodrugs and conjugates of 2,4-dinitrophenol, and compositions and methods thereof

Abstract

The present invention provides novel 2, 4-dinitrophenol (DNP) derivatives and prodrugs thereof as modulators of mitochondrial function. The invention also provides pharmaceutical compositions comprising the compounds of the invention and their use in the treatment of various diseases and disorders associated or associated with mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, liver disease, heart failure or renal failure, neurodegenerative disease, and aging-related diseases, e.g., kidney failure, kidney failure, heart failure, kidney failure, and kidney failure). , including but not limited to sarcopenia, osteoporosis, etc.).

Description

a a π π π δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ μ δ μ μ μ μ

Claims

1. A compound having structural formula (I) or (II): Or its pharmaceutically acceptable form or isotopic derivative, wherein n is 1, 2, 3 or 4; and R X For R X1 R X2 Or R X3 , where R X1 The radical is selected from the following groups: CH2C(=O)OR 3 CH2C(=O)SR 3 C(=O)NR 4 R 5 OR 6 SR 6 NR 7 R 8 NR 9 C(=O)R 10 OC(=O)R 11 ,SC(=O)R 12 OC(=O)OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 ,SC(=O)NR 14 R 15 NR 9 C(=O)NR 14 R 15 OC(=O)SR 3 ,SC(=O)SR 3 NR 9 C(=O)SR 3 Halogens, CN, H and C 1-6 Alkyl; and R X2 The groups are selected from the following: ； And R X3 The groups are selected from the following: ； And R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 and R 15 Each of them: Independently selected from H and C 1-6 Alkyl, 3- to 8-membered carbocyclic or heterocyclic, optionally surrounded by 1-6 R... A Replace, or R 4 and R 5 R 7 and R 8 、or R 14 and R 15 Together with the N atoms they are bonded to, they form 3- to 8-membered heterocycles, optionally bound by 1-6 R atoms. A replace; Each R A Independently selected from: D, halogen, R, OR, and NRR'; and each of R and R' is independently H or C. 1-6 Alkyl group, optionally surrounded by 1-4 atoms selected from D, halogen, C 1-6 The alkoxy and amino groups are substituted; or R and R' together with the N atom to which they are bonded form 3- to 6-membered heterocycles, optionally substituted with 1-4 groups selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

2. The compound according to claim 1, wherein the compound has structural formula (I).

3. The compound according to claim 1, wherein the compound has structural formula (II).

4. The compound according to any one of claims 1 to 3, wherein R X For R X1 .

5. The compound according to claim 4, wherein R X1 CH2C(=O)OR 3 Or OC(=O)R 11 .

6. The compound according to claim 4, wherein R X1 For C(=O)NR 4 R 5 or NR 9 C(=O)R 10 .

7. The compound according to claim 4, wherein R X1 CH2C(=O)SR 3 Or SC(=O)R 12 .

8. The compound according to claim 4, wherein R X1 For OC (=O) OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 , SC(=O)NR 14 R 15 、NR 9 C(=O)NR 14 R 15 、OC(=O)SR 3 、SC(=O)SR 3 或NR 9 C(=O)SR 3 。 9. The compound according to claim 4, wherein R X1 OR 6 or SR 6 .

10. The compound according to claim 4, wherein R X1 For NR 7 R 8 .

11. The compound according to claim 4, wherein R X1 Halogen, CN or C 1-3 alkyl.

12. The compound according to any one of claims 1 to 3, wherein R X For R X2 .

13. The compound according to claim 12, wherein R X2 for: 。 14. The compound according to claim 12, wherein R X2 for: 。 15. The compound according to claim 12, wherein R X2 for: 。 16. The compound according to claim 12, wherein R X2 for: 。 17. The compound according to any one of claims 1 to 3, wherein R X For R X3 .

18. The compound according to any one of claims 1 to 17, wherein each of R and R', if present, is independently H or C. 1-3 alkyl.

19. A compound having structural formula (III) or (IV): ； Or a pharmaceutically acceptable form or isotopic derivative thereof, wherein n is 1, 2, 3 or 4; Y is selected from single bond, NR, S, CRR', and O; R Y It is selected from the following groups: H, halogen, CN, R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR; And each of R and R' is independently H or C. 1-6 Alkyl groups, or R and R', together with the N atoms to which they are bonded, form 3- to 6-membered heterocycles, wherein the alkyl group or heterocycle is optionally surrounded by 1-4 atoms selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

20. The compound according to claim 19, wherein the compound has structural formula (III).

21. The compound according to claim 19, wherein the compound has structural formula (IV).

22. The compound according to any one of claims 19 to 21, wherein Y is O.

23. The compound according to claim 22, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

24. The compound according to any one of claims 19 to 21, wherein Y is S.

25. The compound according to claim 24, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

26. The compound according to any one of claims 19 to 21, wherein Y is NR.

27. The compound according to claim 26, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

28. The compound according to any one of claims 19 to 21, wherein Y is CH2.

29. The compound according to claim 28, wherein R Y Selected from halogens, CN, R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

30. The compound according to any one of claims 19 to 21, wherein Y is a single bond.

31. A compound selected from Table 1A.

32. A compound selected from Table 1B.

33. A coupling compound formed from the compound according to any one of claims 1 to 31 and a bioactive portion characterized by anti-ROS and / or anti-inflammatory activity.

34. The coupling compound according to claim 33, wherein the bioactive moiety is selected from: 。 35. The compound according to any one of claims 1 to 34, wherein the compound has one or more deuterium atoms in place of one or more hydrogen atoms.

36. The compound according to claim 35, wherein the compound has a deuterium atom in place of a hydrogen atom.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36.

38. A unit dosage form comprising the pharmaceutical composition according to claim 37.

39. The unit dosage form according to claim 38, wherein the unit dosage form is a tablet.

40. The unit dosage form according to claim 38, wherein the unit dosage form is a capsule.

41. A method of treating or alleviating a disease or symptom, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 36.

42. The method of claim 41, wherein the disease or condition is related to the mitochondrial function of the subject.

43. The method of claim 41, wherein the disease or condition is related to one or more mitochondrial functional defects.

44. The method of claim 41, wherein the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

45. The method of claim 41, wherein the disease or condition is obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or renal failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic disease associated with increased reactive oxygen species (ROS), Friedreich ataxia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) or related diseases or conditions.

46. ​​A method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 36.

47. The method according to any one of claims 41 to 46, wherein the administration is by oral administration.

48. Use of the compound according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient, carrier or diluent in the preparation of a medicament for treating a disease or condition.

49. Use of the compound according to any one of claims 1 to 36 for treating diseases or conditions.

50. The use according to claim 48 or 49, wherein the disease or condition is related to one or more mitochondrial functional defects.

51. The use according to claim 48 or 49, wherein the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

52. The use according to claim 48 or 49, wherein the disease or condition is selected from obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or renal failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic diseases associated with increased reactive oxygen species (ROS), Friedreich ataxia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or related diseases or conditions.

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