Amino ceramide - like compounds and therapeutic methods of use

• US 20020156107A1
• Filed: 01/10/2002
• Published: 10/24/2002
• Est. Priority Date: 01/10/2001
• Status: Active Grant

• 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., Radin, Norman S.
• Granted Patent: US 7,148,251 B2
• Time in Patent Office: Days
• US Class Current: 514/343
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain

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 selected from the group consisting of the formula:

2. The compound of claim 1 wherein R₃ is pyrrolidino.

3. The compound of claim 1 wherein R₄ is selected from the group consisting of an acetyl, —

CO(CH₂)_nCH₃ wherein n is at least 1 and

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

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

6. A method for inhibiting the growth of cancer cells in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising the compound of claim 1 and pharmaceutically acceptable salts thereof.

7. A method for treating a patient having sphingolipidosis by reducing glycosphingolipid synthesis comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 1 and pharmaceutically acceptable salts thereof.

8. A method for treating a patient having a microbial or viral infection comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 1 and pharmaceutically acceptable salts thereof.

9. 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 1 and pharmaceutically acceptable salts thereof.

10. 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 1 and pharmaceutically acceptable salts thereof.

11. A vaccination method comprising the steps of:

a). removing cancer cells sensitive to the compounds below from a patient;

b). treating the cancer cells in vitro with an effective amount of a composition comprising the compound of claim 1 and pharmaceutically acceptable salts thereof.

13. The compound of claim 12 wherein R₃ is pyrrolidino.

14. The compound of claim 12 wherein R₄ is selected from the group consisting of an acetyl, —

CO(CH₂)_nCH₃ wherein n is at least 1 and

15. The compound of claim 12 wherein R₆ is selected from the group consisting of an acetyl, —

CO(CH₂)_nCH₃ wherein n is at least 1 and

16. The compound of claim 12 wherein R₁ is 4-hydroxyphenyl.

17. The compound of claim 12 wherein R₁ is 3,4-ethylenedioxy.

18. A method for inhibiting the growth of cancer cells in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising the compound of claim 12 and pharmaceutically acceptable salts thereof.

19. A method for treating a patient having sphingolipidosis by reducing glycosphingolipid synthesis comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 12 and pharmaceutically acceptable salts thereof.

20. A method for treating a patient having a microbial or viral infection comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 12 and pharmaceutically acceptable salts thereof.

21. 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 12 and pharmaceutically acceptable salts thereof.

22. 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 12 and pharmaceutically acceptable salts thereof.

23. A vaccination method comprising the steps of:

a). removing cancer cells sensitive to the compounds below from a patient;

b). treating the cancer cells in vitro with an effective amount of a composition comprising the compound of claim 12 and pharmaceutically acceptable salts thereof.

25. The compound of claim 24 wherein R₃ is pyrrolidino.

26. A method for inhibiting the growth of cancer cells in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising the compound of claim 24 and pharmaceutically acceptable salts thereof.

27. A method for treating a patient having sphingolipidosis by reducing glycosphingolipid synthesis comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 24 and pharmaceutically acceptable salts thereof.

28. A method for treating a patient having a microbial or viral infection comprising the step of administering to the patient a therapeutically effective amount of a composition comprising the compound of claim 24 and pharmaceutically acceptable salts thereof.

29. 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 24 and pharmaceutically acceptable salts thereof.

30. 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 24 and pharmaceutically acceptable salts thereof.

31. A vaccination method comprising the steps of:

a). removing cancer cells sensitive to the compounds below from a patient;

b). treating the cancer cells in vitro with an effective amount of a composition comprising the compound of claim 24 and pharmaceutically acceptable salts thereof.

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

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