SYNTHESIS OF UDP-GLUCOSE: N-ACYLSPHINGOSINE GLUCOSYL TRANSFERASE INHIBITORS

• US 20150148534A1
• Filed: 06/26/2014
• Published: 05/28/2015
• Est. Priority Date: 07/16/2001
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Hirth, Bradford H., Siegel, Craig
• Granted Patent: US 9,546,161 B2
• Time in Patent Office: Days
• US Class Current: 544/105
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

Disclosed is a novel enantiomeric synthesis ceramide-like inhibitors of UDP-glucose: N-acylsphingosine glucosyltransferase. Also disclosed are novel intermediates formed during the synthesis.

Claims

1-6. -6. (canceled)

7. A compound represented by the following structural formula:

8. The compound of claim 7 wherein R₅ is phenyl.

9. A method of preparing an acyclic compound represented by the following structural formula:

10. The method of claim 9 wherein:

R₁ and R₅ are independently, a substituted or unsubstituted phenyl group; and

R₂ and R₃ are independently —

H, an unsubstituted C1-C5 alkyl group or, taken together with the nitrogen atom to which they are bonded, are an unsubstituted C3-C10 non-aromatic heterocyclic ring.

11. The method of claim 10 wherein R₅ is a phenyl group.

12. The method of claim 11 wherein R₂ and R₃ taken together with the nitrogen atom to which they are bonded, are pyrrolidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, piperidinyl or N-phenylpiperazinyl.

13. The method of claim 12 wherein R₁ is a substituted or unsubstituted phenyl group and R₂ and R₃ taken together with the nitrogen atom to which they are bonded, are a pyrrolidinyl group.

14. The method of claim 13 wherein the phenyl group represented by R₁ is substituted with —

OCH₂O—

, —

OCH₂CH₂O—

, halo, —

O(lower alkyl), lower alkyl thiol, —

OH, —

O(phenyl), —

OCH₂(phenyl), lower alkyl, amino, lower alkyl amino or lower dialkyl amino.

15. The method of claim 9 further comprising the step of reacting the acyclic compound with an amide reducing agent, thereby forming an amine compound represented by the following structural formula:

16. The method of claim 15 wherein the amide reducing agent is lithium aluminum hydride.

17. The method of claim 15 wherein the amide reducing agent is borane tetrahydrofuran.

18-23. -23. (canceled)