Method of lowering blood glucose

• US 9,532,976 B2
• Filed: 08/20/2014
• Issued: 01/03/2017
• Est. Priority Date: 11/10/2004
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Cheng, Seng H., Yew, Nelson S., Scheule, Ronald K., Zhao, Hongmei
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US14/464,432
• Publication Number:
  US 20150190373A1
• Time in Patent Office: 867 Days
• Field of Search: 514/422, 514/428, 514/866
• US Class Current: 1/1
• 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 lowering blood glucose in a subject in need thereof, 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.

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 or L-threo isomer.

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

19. 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.

20. 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.

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

,4′

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

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

,4′

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

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

24. The method of claim 23, wherein the substituted phenyl group is (3′

,4′

-ethylenedioxy)phenyl.

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

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

27. The method of claim 26, wherein R₂ is a C₇-C₁₈ alkyl group.

28. The method of claim 27, wherein the alkyl group is a C₇ alkyl group.

29. The method of claim 26, wherein R₂ is a C₈ alkyl group.

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

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

32. 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.

33. 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.