Combination therapies of Thiazolidinedione analogues

• US 20090143441A1
• Filed: 09/16/2008
• Published: 06/04/2009
• Est. Priority Date: 03/16/2006
• Status: Abandoned Application

• Current Assignee: Metabolic Solution Development Company
• Original Assignee: Metabolic Solution Development Company
• Inventors: Colca, Gerard R.
• Application Number:
  US12/283,801
• Publication Number:
  US 20090143441A1
• Time in Patent Office: Days
• US Class Current: 514/342
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to thiazolidinedione analogues that are useful for treating inflammatory disease.

Claims

1. A method of treating inflammatory disease comprising administering to a patient a pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;

R₃ is hydrogen, halo, or optionally substituted aliphatic; and

Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

6. The method of claim 1, wherein R₁ is an optionally substituted C_1-6 aliphatic.

7. The method of claim 1, wherein R₁ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

8. The method of claim 1, wherein R₁ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

9. The method of claim 1, wherein R₁ is a hydrogen.

10. The method of claim 1, wherein R₂ is hydrogen, hydroxy, or oxo.

11. The method of claim 1, wherein R₂ is an optionally substituted C_1-6 aliphatic.

12. The method of claim 1, wherein R₂ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

13. The method of claim 1, wherein R₂ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy.

14. The method of claim 1, wherein R₂ is methyl or ethyl, each of which is substituted with hydroxy.

15. The method of claim 1, wherein R₃ is hydrogen or halo.

16. The method of claim 1, wherein R₃ is an optionally substituted C_1-6 aliphatic.

17. The method of claim 1, wherein R₃ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

18. The method of claim 1, wherein R₃ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

19. The method of claim 1, wherein ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

20. The method of claim 1, wherein ring A is furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiaziole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl, each of which is substituted with —

CH₂—

R₁, at any chemically feasible position.

21. The method of claim 1, wherein ring A is a pyridine-yl that is substituted with —

CH₂—

R₁, at any chemically feasible position.

22. The method of claim 1, wherein ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl, each of which is substituted with —

CH₂—

R₁, at any chemically feasible position.

23. The method of claim 1, wherein ring A is a pyridine-2-yl or pyridine-3-yl, each of which is substituted with —

CH₂—

R₁, at any chemically feasible position.

24. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

25. The method of claim 1, wherein the glucocorticoid agonist is hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or combinations thereof.

26. The method of claim 1, wherein the pharmaceutical composition further comprises an NSAID.

54. The method of claim 1, wherein the compound of formula I is selected from

Compound No. 1 Compound No. 2 Compound No. 3 Compound No. 4 Compound No. 5 Compound No. 6 Compound No. 7 Compound No. 8 Compound No. 9 Compound No. 10 Compound No. 11 Compound No. 12 Compound No. 13

2. A method of treating inflammatory disease comprising administering to a patient a pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy;

R₃ is hydrogen, halo, or aliphatic optionally substituted with hydroxy; and

Ring A is a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

3. A method of treating inflammatory disease comprising administering to a patient a pharmaceutically acceptable dose of a pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

4. A method of treating inflammatory disease comprising administering to a patient a pharmaceutically acceptable dose of a pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

5. A method of treating inflammatory disease comprising administering to a patient a pharmaceutically acceptable dose of a pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

27. A pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;

R₃ is hydrogen, halo, or optionally substituted aliphatic; and

Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

32. The pharmaceutical composition of claim 27, wherein R₁ is an optionally substituted C_1-6 aliphatic.

33. The pharmaceutical composition of claim 27, wherein R₁ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

34. The pharmaceutical composition of claim 27, wherein R₁ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

35. The pharmaceutical composition of claim 27, wherein R₁ is a hydrogen.

36. The pharmaceutical composition of claim 27, wherein R₂ is hydrogen, hydroxy, or oxo.

37. The pharmaceutical composition of claim 27, wherein R₂ is an optionally substituted C_1-6 aliphatic.

38. The pharmaceutical composition of claim 27, wherein R₂ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

39. The pharmaceutical composition of claim 27, wherein R₂ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy.

40. The pharmaceutical composition of claim 27, wherein R₂ is methyl or ethyl, each of which is substituted with hydroxy.

41. The pharmaceutical composition of claim 27, wherein R₃ is hydrogen or halo.

42. The pharmaceutical composition of claim 27, wherein R₃ is an optionally substituted C_1-6 aliphatic.

43. The pharmaceutical composition of claim 27, wherein R₃ is an optionally substituted straight or branched C_1-6 alkyl, an optionally substituted straight or branched C_2-6 alkenyl, or an optionally substituted straight or branched C_2-6 alkynyl.

44. The pharmaceutical composition of claim 27, wherein R₃ is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

45. The pharmaceutical composition of claim 27, wherein ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

46. The pharmaceutical composition of claim 27, wherein In other examples, ring A is a furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiaziole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl, each of which is substituted with —

CH₂—

R₁ at any chemically feasible position.

47. The pharmaceutical composition of claim 27, wherein ring A is a pyridine-yl that is substituted with —

CH₂—

R₁, at any chemically feasible position.

48. The pharmaceutical composition of claim 27, wherein ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl, each of which is substituted with —

CH₂—

R₁, at any chemically feasible position.

49. The pharmaceutical composition of claim 27, wherein ring A is a pyridine-2-yl or pyridine-3-yl, each of which is substituted with —

CH₂—

R₁, at any chemically feasible position.

50. The pharmaceutical composition of claim 27, wherein the glucocorticoid agonist further comprises hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or combinations thereof.

51. The pharmaceutical composition of claim 27, further comprising a NSAID.

53. A method of treating or reducing the severity of inflammatory disease comprising administering a compound as described in claim 27 to a mammal.

28. A pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy;

R₃ is hydrogen, halo, or optionally substituted aliphatic; and

Ring A is an optionally substituted monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —

CH₂—

R₁, at any chemically feasible position on ring A.

29. A pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

30. A pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxy, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

31. A pharmaceutical composition comprising a glucocorticoid agonist and a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen or an optionally substituted aliphatic;

R₂ is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and

R₃ is hydrogen, halo, or optionally substituted aliphatic.

52. A pharmaceutical composition comprising a glucocorticoid agonist and compound selected from

Compound No. 1 Compound No. 2 Compound No. 3 Compound No. 4 Compound No. 5 Compound No. 6 Compound No. 7 Compound No. 8 Compound No. 9 Compound No. 10 Compound No. 11 Compound No. 12 and Compound No. 13