Methods of treating fatty liver disease

Patent metadata

Field	Value
Publication number	US-9556155-B2
Application number	US-201414247732-A
Country	US
Kind code	B2
Filing date	Apr 8, 2014
Priority date	May 9, 2006
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

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.

First claim

The invention claimed is:

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:

or a pharmaceutically acceptable salt thereof, wherein R 1 is chosen from substituted and unsubstituted aryl; R 2 is chosen from substituted and unsubstituted alkyl; and R 3 is chosen from substituted and unsubstituted tertiary cyclic amino, wherein the mammal is human.

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 R 2 is substituted by hydroxyl, alkoxy or aryloxy.

16. The method of claim 1 , wherein R 2 is C 2 -C 4 alkyl substituted by optionally substituted alkoxy or optionally substituted aryloxy.

17. The method of claim 16 , wherein R 2 is C 2 alkyl substituted by optionally substituted aryloxy.

18. The method of claim 17 , wherein R 2 is C 2 alkyl substituted by 4-methoxyphenoxy.

19. The method of claim 1 , wherein R 2 comprises at least 7 carbon atoms.

20. The method of claim 1 , wherein R 2 is chosen from substituted and unsubstituted C 7 -C 18 alkyl.

21. The method of claim 20 , wherein R 2 is chosen from substituted and unsubstituted C 7 alkyl.

22. The method of claim 21 , wherein R 2 is 1-(1-hydroxyheptyl) or 1-(6-hydroxyheptyl).

23. The method of claim 20 , wherein R 2 is chosen from substituted and unsubstituted C 8 alkyl.

24. The method of claim 23 , wherein R 2 is 1-(1-hydroxyoctyl) or 1-(7-hydroxyoctyl).

25. The method of claim 1 , wherein R 3 is pyrrolidino, and R 2 is C 2 alkyl.

26. The method of claim 1 , wherein R 3 is pyrrolidino, and R 2 is C 7 alkyl.

27. The method of claim 1 , wherein R 3 is pyrrolidino, and R 2 is C 8 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.

Assignees

• Genzyme Corp

Inventors

• Zhao Hongmei
• Yew Nelson S
• Cheng Seng H
• Jiang Canwen
• Arbeeny Cynthia Marie

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/4245

  Oxadiazoles · CPC title

• A61K31/40 Primary

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title