Synthesis of epothilones, intermediates thereto and analogues thereof

• US 8,513,429 B2
• Filed: 02/07/2012
• Issued: 08/20/2013
• 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., Rivkin, Alexey, Fumikiko, Yoshimura, Chou, Ting-Chao, Gabarda, Ana E., Dong, Huajin
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US13/367,612
• Publication Number:
  US 20120316348A1
• Time in Patent Office: 560 Days
• Field of Search: None
• US Class Current: 548/110
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 313/00 Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/02 containing two hetero rings
• 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 method of preparing a compound of formula:

3. The method of claim 1, wherein the conditions of a ring closing metathesis reaction include a Grubbs catalyst.

4. The method of claim 1, wherein the Grubbs catalyst is tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) chloride.

5. The method according to claim 1, wherein R_B is selected from —

CH₃ or —

CF₃.

6. The method according to claim 5, wherein X is O.

7. The method according to claim 6, wherein R₁ is —

CH₃.

8. The method according to claim 7, wherein R₂ is a substituted or unsubstituted heteroaryl moiety.

9. The method according to claim 8, wherein R₂ is a substituted heteroaryl moiety.

10. The method according to claim 9, wherein R₂ is selected from a thiazolyl, oxazolyl or isoxazolyl group.

11. The method according to claim 10, wherein R₂ is substituted thiazolyl.

12. The method according to claim 11, wherein the thiazolyl group is substituted with an aliphatic moiety.

13. The method according to claim 12, wherein the thiazolyl group is substituted with a C_1-4 alkyl group.

14. The method according to claim 13, wherein the thiazolyl group is substituted with a methyl group.

15. The method according to claim 10, wherein R₂ is substituted oxazolyl.

16. The method according to claim 15, wherein the oxazolyl group is substituted with an aliphatic moiety.

17. The method according to claim 16, wherein the oxazolyl group is substituted with a C_1-4 alkyl group.

18. The method according to claim 17, wherein the oxazolyl group is substituted with a methyl group.

19. The method according to claim 10, wherein R₂ is substituted isoxazolyl.

20. The method according to claim 19, wherein the isoxazolyl group is substituted with an aliphatic moiety.

21. The method according to claim 20, wherein the isoxazolyl group is substituted with a C_1-4 alkyl group.

22. The method according to claim 21, wherein the isoxazolyl group is substituted with a methyl group.

2. A method of preparing a compound of formula: