Methods of treating fatty liver disease

• US 9,556,155 B2
• Filed: 04/08/2014
• Issued: 01/31/2017
• Est. Priority Date: 05/09/2006
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Zhao, Hongmei, Yew, Nelson S., Cheng, Seng H., Jiang, Canwen, Arbeeny, Cynthia Marie
• Primary Examiner(s): Wang, Shengjun
• Application Number:
  US14/247,732
• Publication Number:
  US 20150051261A1
• Time in Patent Office: 1,029 Days
• Field of Search: 514/422, 514/408
• US Class Current: 1/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• 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: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The disclosure provides methods for treating fatty liver disease and associated conditions by inhibiting the synthesis of glucosphingolipids, as exemplified by the use of glucosylceramide synthase substrate analogs.

Claims

1. A method of treating a fatty liver disease by inhibiting glucosphingolipid synthesis in a mammal in need of the treatment, comprising administering to the mammal an effective amount of a compound of formula I:

2. The method of claim 1, wherein the mammal is diagnosed with fatty liver disease.

3. The method of claim 2, wherein the mammal is diagnosed with nonalcoholic steatohepatitis, hepatic fibrosis, or hepatic cirrhosis.

4. The method of claim 1, wherein the mammal is at risk for developing fatty liver disease.

5. The method of claim 1, wherein the treatment results in one or more of the following:

a. a reduction in serum levels of at least one hepatic enzyme chosen from alanine aminotransferase, aspartate aminotransferase, γ

-glutamyltransferase, and alkaline phosphatase; and

b. a decrease in hepatic lipid deposits.

6. The method of claim 1, wherein the glucosphingolipid whose synthesis is inhibited is chosen from glucosylceramide, gangliosides, globo-series glucosphingolipids, neolacto-series glucosphingolipids, isoglobo-series glucosphingolipids, and muco-series glucosphingolipids.

7. The method of claim 6, wherein the glucosphingolipid is a ganglioside.

8. The method of claim 7, wherein the ganglioside is an a-series ganglioside, a b-series ganglioside, a c-series ganglioside, or an o-series ganglioside.

9. The method of claim 8, wherein the ganglioside is an a-series ganglioside.

10. The method of claim 9, wherein the a-series ganglioside is the ganglioside GM3.

11. The method of claim 10, wherein the ganglioside GM3 synthesis is inhibited by inhibiting activity or expression of one of more GM3 synthesis enzymes selected from the group consisting of (a) glucosylceramide synthase, (b) lactosylceramide synthase, and (c) GM3 synthase.

12. The method of claim 11, wherein the ganglioside GM3 synthesis is inhibited by administering to the mammal a therapeutically effective amount of a composition comprising an inhibitor of glucosylceramide synthase enzymatic activity.

13. The method of claim 12, wherein the composition is administered orally.

14. The method of claim 13, wherein the inhibitor of glucosylceramide synthase enzymatic activity is a substrate analog of a glucosylceramide synthase.

15. The method of claim 1, wherein R₂ is substituted by hydroxyl, alkoxy or aryloxy.

16. The method of claim 1, wherein R₂ is C₂-C₄ alkyl substituted by optionally substituted alkoxy or optionally substituted aryloxy.

17. The method of claim 16, wherein R₂ is C₂ alkyl substituted by optionally substituted aryloxy.

18. The method of claim 17, wherein R₂ is C₂ alkyl substituted by 4-methoxyphenoxy.

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

20. The method of claim 1, wherein R₂ is chosen from substituted and unsubstituted C₇-C₁₈ alkyl.

21. The method of claim 20, wherein R₂ is chosen from substituted and unsubstituted C₇ alkyl.

22. The method of claim 21, wherein R₂ is 1-(1-hydroxyheptyl) or 1-(6-hydroxyheptyl).

23. The method of claim 20, wherein R₂ is chosen from substituted and unsubstituted C₈ alkyl.

24. The method of claim 23, wherein R₂ is 1-(1-hydroxyoctyl) or 1-(7-hydroxyoctyl).

25. The method of claim 1, wherein R₃ is pyrrolidino, and R₂ is C₂ alkyl.

26. The method of claim 1, wherein R₃ is pyrrolidino, and R₂ is C₇ alkyl.

27. The method of claim 1, wherein R₃ is pyrrolidino, and R₂ is C₈ alkyl.

28. The method of claim 1, wherein the compound of Formula I is 1-(1,4-benzodioxan-6-yl)-2-nonanoylamino-3-pyrrolidino-1-propanol or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the compound of Formula I is 1(R)-(1,4-benzodioxan-6-yl)-2(R)-nonanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof.

30. The method of claim 1, wherein the compound of Formula I is 1-(1,4-benzodioxan-6-yl)-2-(4-methoxyphenoxy)propanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the compound of Formula I is 1(R)-(1,4-benzodioxan-6-yl)-2(R)-(4-methoxyphenoxy)propanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof.

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

33. The method of claim 32, wherein the pharmaceutically acceptable salt is tartrate.

34. The method of claim 1, further comprising administering to the subject at least one compound selected from the group consisting of an α

-glucosidase inhibitor, a biguanide, insulin, a meglitinide, a sulfonylurea, a thiazolidinedione, an antioxidant, a lipid-lowering agent, a weight-loss agent, a cytoprotective agent, an alpha-2 adrenergic agonist, an anticonvulsant, a barbiturate, a benzodiazepine, a beta-adrenergic blocker, disulfiram, an opioid antagonist, a phenothiazine, and a serotonin reuptake inhibitor.