Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors

• US 7,265,228 B2
• Filed: 08/12/2004
• Issued: 09/04/2007
• 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 L
• Application Number:
  US10/916,824
• Publication Number:
  US 20050009872A1
• Time in Patent Office: 1,118 Days
• Field of Search: 548/526, 548/568, 548/569
• 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 method of preparing a sphingosine-like compound represented by the following structural formula:

2. The method of claim 1 wherein the amine compound is debenzylated by hydrogenation.

3. The method of claim 2 wherein the amine compound is debenzylated by hydrogenation under a hydrogen atmosphere with a catalytic amount of Pd(OH)₂.

4. The method of claim 1 further comprising the step of acylating the primary amine group of the sphingosine-like compound, thereby forming a ceramide-like compound represented by the following structural formula:

5. The method of claim 4 wherein the sphingosine-like compound is acylated with R₇COX, wherein is X is —

Cl or N-hydroxysuccinimidyl.

6. The method of claim 1, wherein the sphingosine-like compound has an enantiomeric excess of at least 10%.

7. The method of claim 1, wherein the sphingosine-like compound has an enantiomeric excess of at least 90%.

8. The method of claim 1, wherein the sphingosine-like compound has an enantiomeric excess of at least 98%.

9. The method of claim 1, wherein R2 and R3 taken together with the nitrogen atom to which they are bound are pyrrolidinyl.

10. The method of claim 9, wherein R5 is a substituted or unsubstituted phenyl group.

11. The method of claim 10, wherein R1 is a phenyl group substituted in the meta/para positions with —

OCH₂O—

, —

OCH₂CH₂O—

or in the para position with halo, lower alkyl thiol, —

OH, —

O(phenyl), —

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

O(lower alkyl).

12. The method of claim 10, wherein R1 is a phenyl group substituted in the meta/para positions with —

OCH₂O—

or —

OCH₂CH₂O—

.

13. The method of claim 10, wherein R1 is a phenyl group substituted in the meta/para positions with —

OCH₂CH₂O—

.

14. The method of claim 5, wherein R1 is a phenyl substituted in the mela/para positions with —

OCH₂O—

or —

OCH₂CH₂O—

or in the para position with halo, CH₃O—

, CH₃CH₂O—

, CH₃CH₂CH₂O—

, CH₃(CH₃)CHO—

, CH₃—

, CH₃CH₂—

, CH₃CH₂CH₂—

, CH₃(CH₃)CH—

, —

OH or —

OCH₂(phenyl); and

R₇ is CH₃(CH₂)_n-or CH₃(CH₂)_n-2CH═

CH—

, wherein n is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.

15. The method of claim 14, wherein n of R7 is 7 or 8.

16. The method of claim 15, wherein R1 is a phenyl substituted with —

OCH₂CH₂O—

.