Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors

• US 20070203223A1
• Filed: 02/05/2007
• Published: 08/30/2007
• Est. Priority Date: 07/16/2001
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi ), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Siegel, Craig, Shayman, James, Harris, David, Nelson, Carol, Copeland, Diane
• Granted Patent: US 7,615,573 B2
• Time in Patent Office: Days
• US Class Current: 514/422
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• 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 498/04 Ortho-condensed systems

Abstract

Disclosed is a novel enantiomeric synthesis ceramide-like inhibitors of UDP-glucose: N-acylsphingosine glucosyltransferase. Also disclosed are novel intermediates formed during the synthesis.

Claims

1. A method of inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

2. The method of claim 1, wherein the compound has an enantiometric excess of at least 25%.

3. The method of claim 1, wherein the compound has an enantiometric excess of at least 50%.

4. The method of claim 1, wherein the compound has an enantiometric excess of at least 90%.

5. The method of claim 1, wherein the compound has an enantiometric excess of at least 99%.

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

7. The method of claim 6, wherein the compound has an enantiometric excess of at least 25%.

8. The method of claim 6, wherein the compound has an enantiometric excess of at least 50%.

9. The method of claim 6, wherein the compound has an enantiometric excess of at least 90%.

10. The method of claim 6, wherein the compound has an enantiometric excess of at least 99%.

11. A method of inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following structural formula:

12. The method of claim 11, wherein the compound has an enantiometric excess of at least 25%.

13. The method of claim 11, wherein the compound has an enantiometric excess of at least 50%.

14. The method of claim 11, wherein the compound has an enantiometric excess of at least 90%.

15. The method of claim 11, wherein the compound has an enantiometric excess of at least 99%.

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

17. The method of claim 16, wherein the compound has an enantiometric excess of at least 25%.

18. The method of claim 16, wherein the compound has an enantiometric excess of at least 50%.

19. The method of claim 16, wherein the compound has an enantiometric excess of at least 90%.

20. The method of claim 16, wherein the compound has an enantiometric excess of at least 99%.