Salt forms of poorly soluble probucol esters and ethers

• US 6,960,683 B2
• Filed: 07/14/2003
• Issued: 11/01/2005
• Est. Priority Date: 07/12/2002
• Status: Expired due to Fees

• Current Assignee: Salutria Pharmaceuticals, LLC
• Original Assignee: Atherogenics, Inc.
• Inventors: Meng, Charles Q.
• Primary Examiner(s): Richter, Johann R.
• Assistant Examiner(s): Puttlitz, Karl J.
• Application Number:
  US10/619,268
• Publication Number:
  US 20040082807A1
• Time in Patent Office: 841 Days
• Field of Search: 562/512, 562/405, 562/426, 562/427, 564/463, 564/503, 568/700, 568/715, 568/716, 568/717, 568/780, 568/784, 568/817, 568/816, 568/822, 568/823, 514/553, 514/579, 514/706, 514/724, 514/732, 514/738
• US Class Current: 562/427
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/225 Polycarboxylic acids
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 323/20 : with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring

Abstract

Organic amine salts of compounds of the formula:
and their pharmaceutically acceptable salts, and uses in medical therapy are provided.

Claims

1. A meglumine salt represented by the formula:

wherein;

R₁ and R₂ are independently hydrogen or alkyl or taken together to form a carbonyl; and

Y is (CH₂)_0-5; and

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5.

30. A method for the treatment of an inflammatory disorder, comprising administering to a host in need thereof an effective treatment amount of the salt of claim 1.

31. The method of claim 30, wherein the inflammatory disorder is arthritis.

32. The method of claim 30, wherein the inflammatory disorder is rheumatoid arthritis.

33. The method of claim 30, wherein the inflammatory disorder is osteoarthritis.

34. The method of claim 30, wherein the inflammatory disorder is asthma.

35. The method of claim 30, wherein the inflammatory disorder is multiple sclerosis.

36. The method of claim 30, wherein the inflammatory disorder is psoriasis.

37. A method for the treatment of a cardiovascular disorder, comprising administering to a host in need thereof an effective treatment amount of the salt of claim 1.

38. The method of claim 37, wherein the cardiovascular disorder is atherosclerosis.

39. The method of claim 37, wherein the cardiovascular disorder is postangioplasty restenosis.

40. The method of claim 37, wherein the cardiovascular disorder is coronary artery disease.

41. The method of claim 37, wherein the cardiovascular disorder is small artery disease.

42. The method of claim 37, wherein the cardiovascular disorder is angina.

43. A method for inhibiting expression of VCAM-1, comprising administering to a host in need thereof an effective treatment amount of the salt of claim 1.

44. A method of treating an immune response, comprising administering to a host in need thereof an effective treatment amount of the salt of claim 1.

45. The method of claim 44, wherein the immune response is solid organ transplant rejection.

2. A meglumine salt represented by the formula:

wherein;

Y is (CH₂)_1-5.

3. The salt of claim 2, wherein Y is (CH₂).

4. The salt of claim 2 wherein Y is (CH₂)₂.

5. The salt of claim 2 wherein Y is (CH₂)₃.

6. The salt of claim 2 wherein Y is (CH₂)₄.

7. The salt of claim 2 wherein Y is (CH₂)₅.

8. A meglumine salt represented by the formula:

wherein;

Y is (CH₂)_0-5.

9. The salt of claim 8, wherein Y is (CH₂)₀.

10. The salt of claim 8 wherein Y is (CH₂).

11. The salt of claim 8 wherein Y is (CH₂)₂.

12. The salt of claim 8 wherein Y is (CH₂)₃.

13. The salt of claim 8 wherein Y is (CH₂)₄.

14. The salt of claim 8 wherein Y is (CH₂)₅.

15. A meglumine salt selected from the group consisting of:

butanedioic acid, mono [4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]ester, meglumine salt;

acetic acid, [4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methyl-ethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-, meglumine salt; and

butanoic acid, 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)4-hydroxyphenyl]thio]-1-methyl-ethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-, meglumine salt.

16. A pharmaceutical composition comprising a meglumine salt represented by the formula:

wherein;

R₁ and R₂ are independently hydrogen or alkyl or taken together to form a carbonyl; and

Y is (CH₂)_0-5;

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a meglumine salt represented by the formula:

wherein;

Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, wherein Y is (CH₂).

19. The pharmaceutical composition of claim 17 wherein Y is (CH₂)₂.

20. The pharmaceutical composition of claim 17 wherein Y is (CH₂)₃.

21. The pharmaceutical composition of claim 17 wherein Y is (CH₂)₄.

22. The pharmaceutical composition of claim 17 wherein Y is (CH₂)₅.

23. A pharmaceutical composition comprising a meglumine salt represented by the formula:

wherein;

Y is (CH₂)_0-5;

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein Y is (CH₂)₀.

25. The pharmaceutical composition of claim 23 wherein Y is (CH₂).

26. The pharmaceutical composition of claim 23 wherein Y is (CH₂)₁.

27. The pharmaceutical composition of claim 23 wherein Y is (CH₂)₃.

28. The pharmaceutical composition of claim 23 wherein Y is (CH₂)₄.

29. The pharmaceutical composition of claim 23 wherein Y is (CH₂)₅.

46. An organic amine salt represented by the formula:

wherein;

R₁ and R₂ are independently hydrogen or alkyl or taken together to form a carbonyl; and

Y is (CH₂)_0-5;

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5.

49. A method for the treatment of an inflammatory disorder, comprising administering to a host in need thereof an effective treatment amount of the salt of any one of claims 46-48.

50. A method for the treatment of a cardiovascular disorder, comprising administering to a host in need thereof an effective treatment amount of the salt of any one of claims 46-48.

51. A method for inhibiting expression of VCAM-1, comprising administering to a host in need thereof an effective treatment amount of the salt of any one of claims 46-48.

52. A method of treating an immune response, comprising administering to a host in need thereof an effective treatment amount of the salt of any one of claims 46-48.

47. An organic amine salt represented by the formula:

wherein;

Y is (CH₂)_1-5.

48. An organic amine salt represented by the formula:

wherein;

Y is (CH₂)_0-5.

53. A pharmaceutical composition represented by the formula:

wherein;

R₁ and R₂ are independently hydrogen or alkyl or taken together to form a carbonyl; and

Y is (CH₂)_0-5;

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.

56. A method for the treatment of an inflammatory disorder, comprising administering to a host in need thereof an effective treatment amount of the composition of any one of claims 53-55.

57. A method for the treatment of a cardiovascular disorder, comprising administering to a host in need thereof an effective treatment amount of the composition of any one of claims 53-55.

58. A method for inhibiting expression of VCAM-1, comprising administering to a host in need thereof an effective treatment amount of the composition of any one of claims 53-55.

59. A method of treating an immune response, comprising administering to a host in need thereof an effective treatment amount of the composition of any one of claims 53-55.

54. A pharmaceutical composition represented by the formula:

wherein;

Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.

55. A pharmaceutical composition represented by the formula:

wherein;

Y is (CH₂)_0-5;

when R₁ and R₂ taken together form a carbonyl, Y is (CH₂)_1-5;

together with a pharmaceutically acceptable carrier.