Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 20050143429A1
• Filed: 08/18/2004
• Published: 06/30/2005
• Est. Priority Date: 08/23/2002
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Yoshimura, Fumihiko, Rivkin, Alexey, Danishefsky, Samuel J., Dorn, David, Chou, Ting-Chao, Gabarda, Ana E., Dong, Huajin, Wu, Kaida, Moore, Malcolm A.S.
• Granted Patent: US 7,384,964 B2
• Time in Patent Office: Days
• US Class Current: 514/365
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 493/04 Ortho-condensed systems

Abstract

The present invention provides compounds of formula (I): as described generally and in classes and subclasses herein. The present invention additionally provides pharmaceutical compositions comprising compounds of formula (I) and provides methods of treating cancer comprising administering a compound of formula (I).

Claims

1. A compound of the formula:

27. The compound of claim 1 selected from the group consisting of formulae:

28. The compound of claim 1 selected from the group consisting of formulae:

29. The compound of claim 1 selected from the group consisting of formulae:

30. The compound of claim 1 selected from the group consisting of formulae:

31. The compound of claim 1 selected from the group consisting of formulae:

32. The compound of claim 1 selected from the group consisting of formulae:

33. A pharmaceutical composition for the treatment of cancer comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition of claim 33 further comprising Cremophor.

35. The pharmaceutical composition of claim 33 further comprising Cremophor and ethanol.

36. The pharmaceutical composition of claim 33, wherein the compound is suspended in 1:

1 Cremophor/EtOH.

37. The pharmaceutical composition of claim 33 further comprising an additional cytotoxic agent.

38. A pharmaceutical composition for the treatment of cancer comprising:

a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof; and

a pharmaceutically acceptable carrier or diluent,

wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 to about 40 mg compound per kg body weight of a subject.

39. A pharmaceutical composition for the treatment of cancer comprising a compound of claim 1;

and

a pharmaceutically acceptable excipient;

wherein the pharmaceutical composition is suitable for oral administration to a subject.

47. A method of treating cancer comprising:

administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

48. The method of claim 47, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 mg to about 40 mg compound per kg body weight.

49. The method of claim 47, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.1 mg to about 25 mg compound per kg body weight.

2. A compound of the formula:

3. The compound of claim 2, wherein A-B is —

CH═

C(R_B)—

.

4. The compound of claim 2, wherein A-B is

5. The compound of claim 2 wherein R_B is methyl.

6. The compound of claim 2 wherein R_B is —

CF₃.

7. The compound of claim 2, 3, or 4, wherein R₈ is methyl.

8. The compound of claim 2, 3, or 4, wherein R₈ is —

CH₂OH.

9. The compound of claim 2, 3, or 4, wherein R₈ is —

CH₂NH₂.

10. The compound of claim 2, 3, or 4, wherein C-D is

11. The compound of claim 10, wherein Z is NH.

12. The compound of claim 10, wherein Z is CH₂.

13. The compound of claim 10, wherein Z is O.

14. The compound of claim 10, wherein Z is S.

15. The compound of claim 2, 3, or 4, wherein C-D is

16. The compound of claim 15, wherein Z is NH.

17. The compound of claim 15, wherin Z is CH₂.

18. The compound of claim 2, wherein Y is S.

19. The compound of claim 2, wherein Y is O.

20. The compound of claim 2, 3, or 4, wherein C-D is —

C(R_C)₂—

C(R_D)₂—

.

21. The compound of claim 20, wherein each occurrence of R_C and R_D is selected from the group consisting of hydrogen, lower akyl, hydroxyl, halogen, or lower alkoxy.

22. The compound of claim 20, wherein each occurrence of R_C and R_D is selected from the group consisting of hydrogen and methyl.

23. The compound of claim 20, wherein each R_C is methyl and each R_D is hydrogen.

24. The compound of claim 20, wherein each R_C is hydrogen and each R_D is methyl.

25. The compound of claim 20, wherein one R_C is hydrogen and the other R_C is methyl.

26. The compound of claim 20, wherein one R_D is hydrogen and the other R_D is methyl.

40. A pharmaceutical composition for the treatment of cancer comprising a compound of claim 2;

and

a pharmaceutically acceptable excipient;

wherein the pharmaceutical composition is suitable for oral administration to a subject.

41. The pharmaceutical compostion of claim 40, wherein R is —

CH₂OH.

42. The pharmaceutical composition of claim 40, wherein R_B is —

CHF₂, —

CH₂F, or —

CF₃.

43. The pharmaceutical composition of claim 40, wherein C-D is —

CH═

CH—

, wherein the double bond is in the trans configuration.

44. The pharmaceutical composition of claim 40, wherein the compound is of the formula:

formula;

45. The pharmaceutical composition of claim 40, wherein the composition is in solid form.

46. The pharmaceutical composition of claim 40, wherein the composition is in liquid form.

50. A method of treating cancer comprising:

administering orally a therapeutically effective amount of a compound of formula;

to a subject in need thereof.

51. A method of preparing a compound of formula:

52. The method of claim 51, wherein the metal is a transition metal.

53. The method of claim 51, wherein the metal is palladium.

54. The method of claim 51, wherein the reducing agent is selected from the group consisting of LiAlH₄, NaBH₄, and NaBH₃CN.

55. A method of preparing a compound of formula:

56. The method of claim 55, wherein the carbene is CH₂N₂.