Amino ceramide-like compounds and therapeutic methods of use

• US 7,335,681 B2
• Filed: 09/15/2006
• Issued: 02/26/2008
• Est. Priority Date: 01/10/2001
• Status: Expired due to Term

• Current Assignee: 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: Shayman, James A.
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): Coppins; Janet L.
• Application Number:
  US11/522,063
• Publication Number:
  US 20070072916A1
• Time in Patent Office: 529 Days
• Field of Search: 514/408, 514/428, 514/210.1, 514/315, 546/233, 548/568, 548/579, 548/237.8, 544/162
• US Class Current: 514/428
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring

Abstract

Novel prodrugs of amino ceramide-like compounds are provided which inhibit glucosyl ceramide (GlcCer) formation by inhibiting the enzyme GlcCer synthase, thereby lowering the level of glycosphingolipids. The compounds of the present invention have improved GlcCer synthase inhibition activity and are therefore highly useful in therapeutic methods for treating various conditions and diseases associated with altered glycosphingolipid levels.

Claims

1. A compound represented by the formula:

2. The compound of claim 1 wherein R¹ is 4-hydroxyphenyl.

3. The compound of claim 1 wherein R¹ is 3,4-ethylenedioxyphenyl.

4. The compound of claim 1 wherein hydrolyzable groups represented R⁴ is selected from the group consisting of an acetyl, —

CO(CH₂)CH₃ and

5. A method for treating a patient having Gaucher'"'"'s disease, Tay Sachs disease, Fabry'"'"'s disease. Sandhoff disease or GM1 gangliosidosis, comprising the step of administering to the patient a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salts thereof.

6. A compound selected from the group consisting of the formula:

7. The compound of claim 6 wherein R¹ is 4-hydroxyphenyl.

8. The compound of claim 6 wherein R¹ is 3,4-ethylenedioxyphenyl.

9. The compound of claim 6 wherein hydrolyzable groups represented R⁴ and R⁶ are independently selected from the group consisting of an acetyl, —

CO(CH₂)CH₃ and

10. A method for treating a patient having Gaucher'"'"'s disease, Tay Sachs disease, Fabry'"'"'s disease. Sandhoff disease or GM1 gangliosidosis, comprising the step of administering to the patient a therapeutically effective amount of the compound of claim 6 or pharmaceutically acceptable salts thereof.

11. A compound selected from the group consisting of the formulas:

12. A method for treating a patient having Gaucher'"'"'s disease, Tay Sachs disease, Fabry'"'"'s disease. Sandhoff disease or GM1 gangliosidosis, comprising the step of administering to the patient a therapeutically effective amount of a compound selected from the group consisting of the formulas: