2-acylaminopropoanol-type glucosylceramide synthase inhibitors

• US 8,304,447 B2
• Filed: 05/30/2008
• Issued: 11/06/2012
• Est. Priority Date: 05/31/2007
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Siegel, Craig, Bastos, Cecilia M., Harris, David J., Dios, Angeles, Lee, Edward, Silva, Richard, Cuff, Lisa M., Levine, Mikaela, Celatka, Cassandra A., Vinick, Frederic, Jozefiak, Thomas H., Xiang, Yibin, Kane, John, Liao, Junkai
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US12/601,871
• Publication Number:
  US 20100256216A1
• Time in Patent Office: 1,621 Days
• Field of Search: 514/408, 514/422, 548/400, 548/526
• US Class Current: 514/408
• 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: C07D 295/125 with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 411/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher'"'"'s; or Fabry'"'"'s disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1, wherein the compound is represented by the following structural formula:

3. The compound of claim 2, wherein the compound is represented by the following structural formula:

4. The compound of claim 2, wherein the compound is represented by the following structural formula:

5. The compound of claim 1, wherein the compound is represented by the following structural formula:

6. The compound of claim 5, wherein the compound is represented by the following structural formula:

7. The compound of claim 1, wherein the compound is represented by the following structural formula:

8. The compound of claim 7, wherein the compound is represented by the following structural formula:

9. The compound of claim 7, wherein the compound is represented by the following structural formula:

10. The compound of claim 7, wherein the compound is represented by the following structural formula:

11. The compound of claim 7, wherein the compound is represented by the following structural formula:

12. The compound of claim 1, wherein the compound is represented by the following structural formula:

13. The compound of claim 12, wherein the compound is represented by the following structural formula:

14. The compound of claim 12, wherein the compound is represented by the following structural formula:

20. The compound of claim 1, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof.

15. A compound represented by the following structural formula:

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by the following structural formula:

17. A method of treating a subject having Tay-Sachs, Gaucher'"'"'s or Fabry'"'"'s disease, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

18. A compound represented by the following structural formula:

19. The compound of claim 18, wherein the compound is a (1R,2R) stereoisomer, or a pharmaceutically acceptable salt thereof.