Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 7,384,964 B2
• Filed: 08/18/2004
• Issued: 06/10/2008
• Est. Priority Date: 08/23/2002
• Status: Expired due to Fees

• 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: Danishefsky, Samuel J., Dorn, David, Chou, Ting-Chao, Gabarda, Ana E., Dong, Huajin, Yoshimura, Fumihiko, Rivkin, Alexey, Moore, Malcolm A. S., Wu, Kaida
• Primary Examiner(s): Anderson; Rebecca
• Assistant Examiner(s): Barker; Michael P.
• Application Number:
  US10/921,109
• Publication Number:
  US 20050143429A1
• Time in Patent Office: 1,392 Days
• Field of Search: 548/202, 548/159, 548/235, 548/217, 548/203, 514/365, 514/374, 514/367, 514/375
• 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:

10. The compound of claim 1, 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 1, 2, 3, or 4, wherein C-D is

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

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

20. The compound of claim 1, 2, 3, or 4, wherein C-D is —

C(R_C)₂—

C(R_D)₂—

.

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

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

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

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

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

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

27. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

28. The pharmaceutical composition of claim 27 further comprising polyethoxylated castor oil.

29. The pharmaceutical composition of claim 27 further comprising polyethoxylated castor oil and ethanol.

30. The pharmaceutical composition of claim 27, wherein the compound is suspended in 1:

1 polyethoxylated castor oil/EtOH.

31. The pharmaceutical composition of claim 27 further comprising a cytotoxic agent.

32. A pharmaceutical composition 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.

33. A pharmaceutical composition comprising a compound of claim 1;

and

a pharmaceutically acceptable excipient;

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

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.

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

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

34. A pharmaceutical composition comprising a compound of claim 2;

and

a pharmaceutically acceptable excipient;

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

35. The pharmaceutical composition of claim 34, wherein R₈ is —

CH₂OH.

36. The pharmaceutical composition of claim 34, wherein R_B is —

CHF₂, —

CH₂F, or —

CF₃.

37. The pharmaceutical composition of claim 34, wherein C-D is —

CH═

CH—

, wherein the double bond is in the trans configuration.

38. The pharmaceutical composition of claim 34, wherein the compound is of the formula:

39. The pharmaceutical composition of claim 34, wherein the composition is in solid form.

40. The pharmaceutical composition of claim 34, wherein the composition is in liquid form.

41. A method of preparing a compound of formula:

42. The method of claim 41, wherein the carbene is CH₂N₂.