Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors

• US 20050009872A1
• Filed: 08/12/2004
• Published: 01/13/2005
• 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 7,265,228 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• 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.

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. The method of claim 15 further comprising the step of debenzylating the —

NHCH(—

CH₂OH)R₅ group of the amine compound, thereby forming a sphingosine-like compound represented by the following structural formula;

19. The method of claim 18 wherein the amine compound is debenzylated by hydrogenation.

20. The method of claim 19 wherein the amine compound is debenzylated by hydrogenation under a hydrogen atmosphere with a catalytic amount of a hydrogenation catalyst.

21. The method of claim 18 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:

22. The method of claim 21 wherein the sphingosine-like compound is acylated with R₇COX, wherein is X —

Cl or N-hydroxysuccinimidyl and R is a C1-C30 straight chained alkyl or alkenyl group.

23. The method of claim 9 wherein the cyclic starting material is prepared by reacting at least two equivalents of an aldehyde compound R₁CHO with a cyclic lactone, wherein the cyclic lactone is represented by the following structural formula:

24. A method of preparing an amine compound represented by the following structural formula:

25. The method of claim 24 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.

26. The method of claim 25 wherein R₅ is a phenyl group.

27. The method of claim 26 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.

28. The method of claim 27 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 pyrrolindinyl group.

29. The method of claim 28 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.

30. The method of claim 24, further comprising the step of debenzylating the —

NHCH(—

CH₂OH)R₅ group of the amine compound to form a sphingosine-like compound represented by the following structural formula;

31. The method of claim 30 wherein the amine compound is debenzylated by hydrogenation.

32. The method of claim 31 wherein the amine compound is debenzylated by hydrogenation under a hydrogen atmosphere with a catalytic amount of Pd(OH)₂.

33. The method of claim 30 further comprising the step of acylating the primary amine group in the sphingosine-like compound, thereby forming a ceramide-like compound represented by the following structural formula:

34. The method of claim 33 wherein the sphingosine-like compound is acylated with R₇COX, wherein is X is a —

Cl or an N-hydroxysuccinimidyl group and R₇ is a C1-C30 straight chained alkyl or alkenyl group.

35. A method of preparing a sphingosine-like compound represented by the following structural formula:

36. The method of claim 35 wherein the amine compound is debenzylated by hydrogenation.

37. The method of claim 36 wherein the amine compound is debenzylated by hydrogenation under a hydrogen atmosphere with a catalytic amount of Pd(OH)₂.

38. The method of claim 35 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:

39. The method of claim 38 wherein the sphingosine-like compound is acylated with R₇COX, wherein is X is —

Cl or N-hydroxysuccinimidyl and R₇ is a C1-C30 straight chained alkyl or alkenyl group.

40. A method of preparing a ceramide-like compound represented by the following structural formula:

41. The method of claim 40 wherein R₇ is a C10-C16 alkyl group.

42. The method of claim 41 wherein R₁ is a phenyl group substituted with —

OCH₂O—

, —

OCH₂CH₂O—

, halo, —

O(lower alkyl), lower alkyl thiol, —

OH, —

O(phenyl), —

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

43. The method of claim 42 wherein R₁ is

44. The method of claim 40 wherein R₁ is para-hydroxyphenyl or