Amino ceramide--like compounds and therapeutic methods of use

• US 5,916,911 A
• Filed: 09/05/1996
• Issued: 06/29/1999
• 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: Shayman, James A., Radin, Norman S.
• Primary Examiner(s): Goldberg, Jerome D.
• Application Number:
  US08/708,574
• Time in Patent Office: 1,027 Days
• Field of Search: 514/408, 514/428
• US Class Current: 514/428
• 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 31/445 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

Abstract

Novel amino 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 method for inhibiting the growth of cancer cells in a mammal, wherein said cancer cells are sensitive to the compounds below, comprising the step of administering to the mammal a therapeutically effective amount of a compound selected from the group consisting of compounds of the formula:

##STR5## where R₁ is an aromatic structure, an alicyclic structure, a branched aliphatic structure or a linear aliphatic group having 5 to 15 carbons;

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

R₃ is pyrrolidino;

and functional homologues, isomers and pharmaceutically acceptable salts thereof.

2. The method of claim 1, where the growth of the cancer cells is inhibited by increasing ceramide levels in the cancer cells to a toxic level.

3. The method of claim 1, where R₁ is a phenyl group.

4. The method of claim 1, where R₁ is p-methoxyphenyl.

5. The method of claim 1, where R₂ is C₁₅ H₃₁.

6. The method of claim 1, where the compound is 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol and pharmaceutically acceptable salts thereof.

7. A method for treating a patient having a drug resistant tumor sensitive to the compounds below, comprising the step of administering to the patient a therapeutically effective amount of a compound selected from the group consisting of compounds of the formula:

##STR6## where R₁ is an aromatic structure, an alicyclic structure, a branched aliphatic structure or a linear aliphatic group having 5 to 15 carbons;

R₂ is an aliphatic chain having 9 to 18 carbons; and

R₃ is pyrrolidino;

and functional homologues, isomers and pharmaceutically acceptable salts thereof.

8. The method of claim 7, where R₁ is a phenyl group.

9. The method of claim 7, where R₁ is p-methoxyphenyl.

10. The method of claim 7, where R₂ is C₁₅ H₃₁.

11. The method of claim 7, where the compound is 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol and pharmaceutically acceptable salts thereof.

12. A method for reducing tumor angiogenesis in a patient, wherein said angiogenesis is sensitive to the compounds below, comprising the step of administering to the patient a therapeutically effective amount of a compound selected from the group consisting of compounds of the formula:

##STR7## where R₁ is an aromatic structure, an alicyclic structure, a branched aliphatic structure or a linear aliphatic group having 5 to 15 carbons;

R₂ is an aliphatic chain having 9 to 18 carbons; and

R₃ is pyrrolidino;

and functional homologues, isomers and pharmaceutically acceptable salts thereof.

13. The method of claim 12, where R₁ is a phenyl group.

14. The method of claim 12, where R₁ is p-methoxyphenyl.

15. The method of claim 12, where R₂ is C₁₅ H₃₁.

16. The method of claim 12, where the compound is 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol and pharmaceutically acceptable salts thereof.