Synthesis of epothilones, intermediates thereto and analogues thereof

• US 20020058286A1
• Filed: 03/01/2001
• Published: 05/16/2002
• Est. Priority Date: 02/24/1999
• Status: Abandoned Application

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Stachel, Shawn J., Wu, Zhicai, Danishefsky, Samuel J., Chou, Ting-Chao, Chappell, Mark D., Lee, Chul Bom
• Application Number:
  US09/797,027
• Publication Number:
  US 20020058286A1
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The present invention provides convergent processes for preparing epothilones, desoxyepothilones, and analogues thereof. The present invention further provides novel compositions and methods for the treatment of cancer and additionally provides methods for the treatment of cancer which has developed a multi-drug phenotype.

Claims

1. A compound having the structure:

2. The compound of claim 1, wherein M is O.

3. The compound of claim 1, wherein R₆ is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl,

4. The compound of claim 1, wherein R₆ is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.

5. The compound of claim 4, wherein R₆ is ethyl, n-propyl, n-butyl, n-hexyl,

8. The compound of claim 1, wherein CY is 4-thiazolyl or 4-oxazolyl;

R₁ is OR_A and R_A is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic aliphatic or heteroaliphatic, or substituted or unsubstituted aryl or heteroaryl;

W is —

CH₂—

; and

m is 1.

9. The compound of claim 1, wherein CY is 4-thiazolyl or 4-oxazolyl, W is (C═

O), m is 1, and R₁ is hydrogen.

10. The compound of claim 1, wherein R₂ and R₃ are each hydrogen;

R₄ is methyl and R₅ is hydrogen; and

Z is O.

11. The compound of claim 1, wherein the compound has the structure:

12. The compound of claim 1, wherein the compound has the structure:

13. The compound of claim 1, wherein the compound has the structure:

14. The compound of claim 1, wherein the compound has the structure:

15. The compound of claim 1, wherein the compound has the structure:

16. The compound of claim 15, wherein R₆ is methyl and the compound has the structure:

17. The compound of claim 1, wherein the compound has the structure:

18. The compound of claim 1, wherein the compound has the structure:

19. The compound of claim 1, wherein the compound has the structure:

20. A composition comprising:

a polymeric backbone; and

two or more compounds of claim 1, wherein the two or more compounds of claim 1 are the same or different, whereby said two or more compounds are linked to the polymeric backbone directly or through a linker, and wherein the two or more compounds are linked through the 12-position, the 20- position or the 21-position of the compound.

21. The composition of claim 20, wherein the polymeric backbone is a dendrimer, a peptide, or a biodegradable polymer.

22. A dimeric desoxyepothilone having the structure:

23. The compound of claim 22, wherein EPO has the structure:

24. The compound of claim 23, wherein R₆ is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.

25. The compound of claim 23, wherein X is methylene, Y is O, and Z is (CO).

26. The compound of claim 23, wherein X is methylene, Y is NH, and Z is absent.

27. The compound of claim 23, wherein X is (C═

O), Y is O or NH, and Z is absent.

28. A pharmaceutical composition for treating cancer comprising

a compound of claim 1;

and

a pharmaceutically suitable carrier or diluent.

29. A method of treating cancer in a subject suffering therefrom comprising:

administering to the subject a therapeutically effective amount of a compound of claim 1.

30. The method of claim 29, wherein the cancer is a solid tumor.

31. The method of claim 29, wherein the cancer is breast cancer.

32. The composition of claim 28, further comprising an amount of a cytotoxic agent.

33. The composition of claim 28, wherein the cytotoxic agent is an anticancer agent.

34. The composition of claim 33, wherein the anticancer agent is adriamycin, vinblastin or paclitaxel.

35. The composition of claim 28, wherein the effective amount of the compound is between about 0.01 mg/kg to about 50 mg/kg of body weight.

37. The method of claim 36, wherein the step of hydroxylating comprises reacting the haloketone using asymmetric catalyst in the presence of OsO₄ and AD-mix-α

to effect asymmetric dihydroxylation, to generate a compound having the structure;

38. The method of claim 36, wherein the step of hydroxylating comprises reacting the haloketone in the presence of OsO₄ and AD-mix-β

to effect asymmetric dihydroxylation, to generate a compound having the structure;

40. The method of claim 39, wherein the substituted organometallic reagent is a Grignard reagent.

36. A method of preparing a compound having the structure:

39. A method of preparing a compound having the structure:

41. A method of preparing a compound having the structure:

42. The method of claim 41, wherein R₁ is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.

43. The method of claim 41, wherein R₁ is substituted or unsubstituted 4-thiazolyl.

44. A method of preparing a compound having the structure:

45. The method of claim 44, wherein R₁ is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-fliranyl, 4-furanyl, 2-pyridyl, 3-pyridy, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.

46. The method of claim 44, wherein R₁ is substituted or unsubstituted 4-thiazolyl.

49. The method of claim 48, wherein the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde under stoichiometric conditions with a chiral titanium enolate.

50. The method of claim 48, wherein the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde with a catalytic reagent.

51. The method of claim 50, wherein the catalytic reagent employed is the Carreira catalyst.

52. The method of claim 50, wherein the catalytic reagent employed is Mikami'"'"'s chiral aldol catalyst.

47. A method of preparing a compound having the structure:

48. A method for preparing a compound having the structure:

53. A method for preparing a compound having the structure:

54. The method of claim 53, wherein the method includes a step of deprotection to generate a compound wherein R₂ and R₃ are hydrogen.

55. The method of claim 53, wherein R₁ is —

CY═

CHX or hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-faranyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl, wherein X is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.

56. The method of claim 53, wherein the aliphatic, heteroaliphatic, aryl or heteroaryl group is further substituted with a photoactivatable group or with one or more of hydroxy, thio, amino, substituted amino, aldehyde, carboxylic acid, alkenyl, iminio, or diazo.

57. The method of claim 53, wherein M is O, R₁ is —

CY═

CHX, wherein Y is methyl and X is 4-thiazolyl substituted at the 2-position by —

(C═

O)H, —

(CH₂)_nOH, or —

(CH₂)NR_AR_A and wherein n is 0-5.

58. The method of claim 53, wherein R₇-R₁₁ are each independently selected from the group consisting of hydrogen, linear or branched alkyl, alkoxyalkyl, aryloxyalkyl, or Si(R_B)₃, wherein each occurrence of R_B is independently branched or unbranched, substituted or unsubstituted aliphatic or heteroaliphatic, or substituted or unsubstituted aryl or heteroaryl.

59. The method of claim 53, wherein the step of subjecting said first and second sectors to suitable conditions comprises subjecting said sectors to conditions to effect Suzuki coupling.

60. The method of claim 53, wherein the step of providing the precursor further comprises:

providing a first sector having the structure;

 

wherein R₁, R₆, and Z_A are as defined above;

providing a second sector having the structure;

 

wherein R₂, R₃, R₄, and R₅ are as defined above, and wherein Z_B is CO₂R₉ or COSR₉;

wherein the step of providing a second sector further comprises;

protecting a ketoaldehyde having the structure;

 

to generate a protected aldehyde and subsequently reacting said protected aldehyde with a compound having a structure;

 

under suitable conditions to effect condensation to generate an aldol having the structure;

 

hydrolyzing the protected acetal group to generate a ketoaldehyde having the structure;

 

reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction, and optionally protecting the C3 alcohol to generate the second sector having the structure;

 

wherein Z_B, and R₂-R₅ are as defined above;

reacting said first and second sectors under suitable conditions to effect coupling to generate the precursor.

61. The method of claim 60,

wherein R₁ is CY═

CHX, wherein Y is hydrogen or alkyl, and wherein X is 4-thiazolyl substituted at the 2-position by linear or branched alkyl or substituted by —

(CH₂)_nOH, wherein n is 0-5; and

wherein R₆ is hydrogen, hydroxy, thio, amino, or halogen, or is substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, thioalkyl, arylthio, carboxy, carboxaldehyde, cyclic acetal, alkylamino, arylamino, hydroxyimino, or alkoxyimino.

62. The method of claim 60, wherein Z_A is N₃, optionally further comprising a step of reacting the azide under suitable conditions to generate a protected amine.

63. The method of claim 60, optionally further comprising a step of deprotecting the precursor compound to generate a free hydroxy acid precursor, or an amino acid precursor.