Methods of Treating Fatty Liver Disease

• US 20090105125A1
• Filed: 05/09/2007
• Published: 04/23/2009
• Est. Priority Date: 05/09/2006
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Arbeeny, Cynthia Marie, Cheng, Seng H., Yew, Nelson S., Zhao, Hongmei, Jiang, Canwen
• Granted Patent: US 8,716,327 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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, comprising inhibiting glucosphingolipid synthesis in a mammal in need of the treatment.

3. The method of claim 1, wherein the mammal is diagnosed with nonalcoholic steatohepatitis, hepatic fibrosis, or hepatic cirrhosis.

5. The method of claim 1, wherein the mammal is human.

16. The method of claim 1, wherein the mammal is administered an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted alky;

R₂ is chosen from substituted and unsubstituted alkyl; and

R₃ is chosen from substituted and unsubstituted tertiary cyclic amino.

18. The method of claim 16, wherein R₁ is chosen from substituted and unsubstituted phenyl.

19. The method of claim 18, wherein R₁ is 1,4-benzodioxan-6-yl.

25. The method of claim 16, wherein R₂ is chosen from substituted and unsubstituted C₇-C₁₈ alkyl.

26. The method of claim 25, wherein R₂ is chosen from substituted and unsubstituted C₇ or C₈ alkyl.

27. The method of claim 26, wherein R₂ is 1-(1-hydroxyheptyl), 1-(6-hydroxyheptyl), 1-(1-hydroxyoctyl) or 1-(7-hydroxyoctyl).

30. The method of claim 16, wherein R₃ is pyrrolidine.

32. The method of claim 30, wherein R₃ is pyrrolidino, and R₂ is C₇ or C₈ alkyl.

34. The method of claim 16, wherein R₁ is chosen from substituted and unsubstituted phenyl;

R₂ is chosen from substituted and unsubstituted alkyl; and

R₃ is chosen from tertiary cyclic amino.

37. The method of claim 16, wherein the compound of Formula I is 1-(1,4-benzodioxan-6-yl) -2-octanoylamino-3-pyrrolidino-1-propanol or a pharmaceutically acceptable salt thereof .

38. The method of claim 37, wherein the compound of Formula I is 1 (R)-(1,4-benzodioxan-6-yl)-2(R)-octanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof.

42. The method of claim 16, wherein the pharmaceutically acceptable salt is tartrate.

43. 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.

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