Amino ceramide-like compounds and therapeutic methods of use

• US 6,916,802 B2
• Filed: 05/05/2004
• Issued: 07/12/2005
• Est. Priority Date: 04/29/2002
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi ), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Genzyme Corporation (Sanofi ), Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Siegel, Craig, Harris, David J., Shayman, James A., Nelson, Carol A., Copeland, Diane P.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US10/839,497
• Publication Number:
  US 20050049235A1
• Time in Patent Office: 433 Days
• Field of Search: 544/148, 544/168, 546/197, 546/233, 548/528, 548/568, 548/590, 514/210.01, 514/233.8, 514/237.8, 514/315, 514/321, 514/331, 514/422, 514/428
• US Class Current: 514/210.01
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• 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 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 31/04 Antibacterial agents
• 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: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 317/54 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 321/10 condensed with carbocyclic rings or ring systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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

Claims

1. A compound of formula I:

a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein

R¹ is a phenyl, a substituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel;

R² is an alkyl group 6, 7, or 8 carbons long; and

R³ is a pyrrolidine, azetidine, morpholine or piperidine, in which the nitrogen atom is attached to the kernel.

2. The compound of claim 1, wherein R¹ is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl.

3. A method for inhibiting the growth of cancer cells in a patient, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of any of claim 1 or 2, wherein said cancer cells are sensitive to said compound.

4. A method for treating a patient having a drug resistant tumor, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of any of claim 1 or 2, wherein the cells of the tumor are sensitive to said compound.

5. A method for reducing tumor angiogenesis in a patient, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of any of claim 1 or 2, wherein said angiogenesis is sensitive to said compound.

6. A method for treating a patient having a glyxosphingolipidosis disorder, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of any of claim 1 or 2, wherein the glycosphingolipidos disorder is associated with the presence of glucosylceramide.

7. The method of claim 6, wherein said glycosphingolipidos disorder is selected from the group consisting of Gaucher disease, Fabry disease, TaySachs, Sandhoff disease, and GM1 gangliosidosis.

8. A compound of formula I:

or a stereoisomer, pharmaceutically acceptable salt, or a mixture thereof, wherein

R¹ is a substituted or unsubstituted phenyl group, a branched aliphatic group, or a 7-15 carbons long alkyl chain or a 7-15 carbons long alkenyl chain with a double bond next to the kernel;

R² is an alkyl group 6, 7, or 8 carbons long; and

R³ is pyrrolidine, in which the nitrogen atom is attached to the kernel.

9. The compound of claim 8, wherein R¹ is a phenyl group substituted with a functional group selected from the group consisting of a p-methoxy, hydroxyl, methylenedioxy, ethylenedioxy, trimethylenedioxy and cyclohexyl.

10. A method for inhibiting the growth of cancer cells in a patient, comprising the step of administering to the patient a therapeutically effective amount of the compound of claim 8, wherein said cancer cells are sensitive to said compound.

11. A method for treating a patient having a drug resistant tumor, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 8, wherein the cells of the tumor are sensitive to said compound.

12. A method for reducing tumor angiogenesis in a patient, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 8, wherein said angiogenesis is sensitive to said compound.

13. A method for treating a patient having a glycosphingolipidosis disorder, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 8, wherein the glycosphingolipidosis disorder is associated with the presence of glucosylceramide.

14. The method of claim 13, wherein said glycosphingolipidosis disorder is selected from the group consisting of Gaucher disease, Fabry disease, TaySachs, Sandhoff disease, and GM1 gangliosidosis.