Methods of Treating Diabetes Mellitus

• US 20080161379A1
• Filed: 11/11/2005
• Published: 07/03/2008
• Est. Priority Date: 11/10/2004
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Cheng, Seng H., Yew, Nelson S., Scheule, Ronald K., Zhao, Hongmei
• Granted Patent: US 8,003,617 B2
• Time in Patent Office: Days
• US Class Current: 514/422
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

The invention provides methods of treating a diabetic subject comprising administering a glucosylceramide synthase inhibitor to the subject.

Claims

1. A method of treating a subject having type 2 diabetes, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula Ib, or a pharmaceutically acceptable salt thereof,

2. The method of claim 1, wherein R₁ is an optionally substituted aromatic ring.

3. The method of claim 2, wherein R₁ is an optionally substituted phenyl group.

4. The method of claim 3, wherein R₁ is a phenyl group;

R₂ is an alkyl group; and

R₃ is a tertiary cyclic amine, and where the tertiary cyclic amine is not a morpholine group.

5. The method of claim 3, wherein R₁ is a substituted phenyl group.

6. The method of claim 5, wherein R₁ is (3′

,4′

-ethylenedioxy)phenyl.

7. The method of claim 1, wherein R₃ is pyrrolidine.

8. The method of claim 1, wherein R₂ comprises at least 7 carbon atoms.

9. The method of claim 8, wherein R₂ is an optionally substituted C₇-C₁₈ alkyl group.

10. The method of claim 9, wherein R₂ is an optionally substituted C₇ alkyl group.

11. The method of claim 10, wherein R₂ is chosen from 1-(1-hydroxyheptyl) and 1-(6-hydroxyheptyl).

12. The method of claim 9, wherein R₂ is an optionally substituted C₈ alkyl group.

13. The method of claim 12, wherein R₂ is chosen from 1-(1-hydroxyoctyl) and 1-(7-hydroxyoctyl).

14. The method of claim 1, wherein the compound of Formula Ib is in the form of a free base.

15. The method of claim 1, wherein the compound of Formula Ib is in the form of a pharmaceutically acceptable salt.

16. The method of claim 15, wherein the pharmaceutically acceptable salt is chosen from citrate, tartrate, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate).

17. The method of claim 1, wherein the compound of Formula Ib is a D-threo isomer.

18. The method of claim 1, wherein the compound of Formula Ib is an L-threo isomer.

19. The method of claim 1, wherein the compound of Formula Ib is an L-erythro isomer.

20. The method of claim 1, wherein the compound of Formula Ib is a D-erythro isomer.

21. The method of claim 1, wherein the compound of Formula Ib is a tartrate salt, and wherein R₁ is D-threo-(3′

,4′

-ethylenedioxy)phenyl, R₃ is pyrrolidine, and R₂ is a C₇ alkyl group.

22. The method of claim 1, wherein the compound of Formula Ib is a tartrate salt, and wherein R₁ is D-threo-(3′

,4′

-ethylenedioxy)phenyl, R₃ is pyrrolidine, and R₂ is a C₈ alkyl group.

23. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient.

24. The method of claim 1, wherein the compound of Formula Ib is administered orally.

25. The method of claim 1, wherein administration of the compound of Formula Ib to the subject decreases blood glucose levels in the subject compared to a subject not treated with the compound.

26. The method of claim 1, wherein administration of the compound of Formula Ib to the subject increases blood insulin levels in the subject compared to a subject not treated with the compound.

27. The method of claim 1, further comprising administering to the subject at least one compound chosen from a sulfonylurea, a metformin, an α

-glucosidase inhibitor, troglitazone, glyburide, nateglinide, thiazolidinedione and repaglinide.

28. The method of claim 1, wherein the compound of Formula Ib is 1-(3′

,4′

-ethylenedioxy)phenyl-2-nonanoylamino-3-pyrrolidino-1-propanol.

29. The method of claim 1, wherein the compound of Formula Ib is 1-(3′

,4′

-ethylenedioxy)phenyl-2-octanoylamino-3-pyrrolidino-1-propanol.

30. The method of claim 4, wherein R₁ is a substituted phenyl group.

31. The method of claim 30, wherein the substituted phenyl group is (3′

,4′

-ethylenedioxy)phenyl.

32. The method of claim 4, wherein R₃ is pyrrolidine.

33. The method of claim 4, wherein R₂ comprises at least 7 carbon atoms.

34. The method of claim 33, wherein R₂ is a C₇-C₁₈ alkyl group.

35. The method of claim 34, wherein the alkyl group is a C₇ alkyl group.

36. The method of claim 33, wherein R₂ is a C₈ alkyl group.

37. The method of claim 4, wherein the compound is in the form of a free base.

38. The method of claim 4, wherein the compound is in the form of a pharmaceutically acceptable salt.

39. The method of claim 38, wherein the salt is chosen from citrate, tartrate hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate).

40. The method of claim 4, wherein the compound is a D-threo isomer.

41. The method of claim 4, wherein the compound is a L-threo isomer.

42. The method of claim 4, wherein the compound is a L-erythro isomer.

43. The method of claim 4, wherein the compound is a L-erythro isomer.

44. The method of claim 4, wherein the compound is a tartrate salt and wherein R₁ is D-threo-(3′

,4′

-ethylenedioxy)phenyl, R₃ is pyrrolidine, and is a C₇ alkyl group.

45. The method of claim 4, wherein the compound is a tartrate salt, and wherein the R₁ is D-threo-(3′

,4′

-ethylenedioxy)phenyl, R₃ is pyrrolidine, and R₂ is a C₈ alkyl group.

46. The method of claim 4, wherein the composition further comprises a pharmaceutically acceptable excipient.

47. The method of claim 4, wherein the compound is administered orally.

48. The method of claim 4, wherein administration of the compound to the subject decreases blood glucose levels in the subject compared to a subject not treated with the compound.

49. The method of claim 4, wherein administration of the compound to the subject increases blood insulin levels in the subject compared to a subject not treated with the compound.

50. The method of claim 4, further comprising administering to the subject at least one compound chosen from a sulfonylurea, a metformin, an α

-glucosidase inhibitor, troglitazone, glyburide, nateglinide, thiazolidinedione and repaglinide.

51. A method of lowering blood glucose in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ib,

52. A method of improving glucose tolerance in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula Ib,

53. A method of decreasing plasma TNF-α

in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula Ib,

54. A method of decreasing glycated hemoglobin levels in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula Ib,

55. A method of treating a subject having renal hypertrophy or hyperplasia associated with diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula Ib,

56. Use of a compound of Formula Ib