Synthesis of UDP-glucose: N -acylsphingosine glucosyltransferase inhibitors

• US 8,138,353 B2
• Filed: 07/06/2010
• Issued: 03/20/2012
• Est. Priority Date: 07/16/2001
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Hirth, Bradford H., Siegel, Craig
• Primary Examiner(s): Anderson, Rebecca
• Application Number:
  US12/830,962
• Publication Number:
  US 20110003987A1
• Time in Patent Office: 623 Days
• Field of Search: 548/526
• US Class Current: 548/526
• 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. A compound represented by the following structural formula:

2. The compound of claim 1 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.

3. The compound of claim 2 wherein R₅ is a phenyl group.

4. The compound of claim 3 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.

5. A compound represented by the following structural formula:

6. The compound of claim 5 wherein the phenyl group represented by R₁ is substituted with —

OCH₂O—

, —

OCH₂CH₂O—

, halo, —

O(lower alkyl), —

OH, lower alkyl thiol, —

O(phenyl), —

OCH₂(phenyl), —

O—

CH₂—

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