Amino ceramide-like compounds and therapeutic methods of use

• US 6,255,336 B1
• Filed: 07/09/1999
• Issued: 07/03/2001
• 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): Raymond, Richard L.
• Application Number:
  US09/350,768
• Time in Patent Office: 725 Days
• Field of Search: 514/428, 514/422, 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 wherein the compound is D-t-3′

,4′

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

2. A compound wherein the compound is D-t-4′

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

3. A composition comprising a carrier and 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 thereof and mixtures thereof.

4. The composition of claim 3, wherein the compound is D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol.

5. The composition of claim 3, wherein the compound is a pharmaceutically acceptable salt of D-t-3′

,4′

-ethylenedioxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol.

6. The composition of claim 3, wherein the compound is D-t-4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol.

7. The composition of claim 3, wherein the compound is a pharmaceutically acceptable salt of D-t-4′

-hydroxy-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol.

8. 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 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 thereof and mixtures thereof.

9. The method of claim 8, wherein the patient is diagnosed as having Gaucher disease.

10. The method of claim 8, wherein the patient is diagnosed as having Tay-Sachs disease.

11. The method of claim 8, wherein the patient is diagnosed as having Fabry disease.