Amino ceramide-like compounds and therapeutic methods of use

• US 6,569,889 B2
• Filed: 05/31/2001
• Issued: 05/27/2003
• Est. Priority Date: 09/20/1995
• 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: Radin, Norman S., Shayman, James A.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/870,870
• Publication Number:
  US 20010041735A1
• Time in Patent Office: 726 Days
• Field of Search: 514/422, 514/428, 548/526, 548/568
• US Class Current: 514/422
• CPC Class Codes: A61K 31/164 of a carboxylic acid with an aminoalcohol, e.g. ceramides
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Novel 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

where

R₁ is 4-hydroxyphenyl or 3,4-ethylendioxy phenyl;

R₂ is an aliphatic chain having 10 to 18 carbons; and

R₃ is pyrrolidino.

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

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

4. The compound of claim 1, wherein R² is C₁₅H₃₁.

5. The compound of claim 1, wherein the compound is 4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

6. The compound of claim 1, wherein the compound is 3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

7. A method of inhibiting 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, wherein said cancer cells are sensitive to said compound.

8. The method of claim 7, wherein the growth of the cancer cells is inhibited by increasing ceramide levels in the cancer cells to a toxic level.

12. A method of 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, wherein the tumor is sensitive to said compound.

16. A method of 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, wherein said angiogenesis is sensitive to said compound.

9. 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 a compound selected from the group consisting of D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol D-t-4-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, pharmaceutically acceptable salts, and mixtures thereof, wherein said cancer cells are sensitive to said compound composition.

10. The method of claim 9, wherein the compound is D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

11. The method of claim 9, wherein the compound is D-t-4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

13. A method of treating a patient having a drug resistant tumor, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound selected from the group consisting of D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, D-t-4-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, pharmaceutically acceptable salts, and mixtures thereof, wherein the tumor is sensitive to said compound.

14. The method of claim 13, wherein the compound is D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

15. The method of claim 13, wherein the compound is D-t-4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

17. A method of reducing tumor angiogenesis in a patient, comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a compound selected from the group consisting of D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, D-t-4-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol, pharmaceutically acceptable salts, and mixtures thereof, wherein said angiogenesis is sensitive to said compound.

18. The method of claim 17, wherein the compound is D-t 3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.

19. The method of claim 17, wherein the compound is D-t-4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol or pharmaceutically acceptable salts thereof.