Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 7,750,164 B2
• Filed: 01/11/2007
• Issued: 07/06/2010
• Est. Priority Date: 12/03/1996
• 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: Meng, Dang Fang, Kamenecka, Ted, Sorensen, Erik J, Savin, Kenneth A., Su, Dai-Shi, Balog, Aaron, Danishefsky, Samuel J., Chou, Ting-Chao, Bertinato, Peter
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): Coughlin; Matthew P
• Application Number:
  US11/652,383
• Publication Number:
  US 20080004450A1
• Time in Patent Office: 1,272 Days
• Field of Search: 549/271, 548/204, 548/236
• US Class Current: 548/204
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07C 69/007 Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• 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 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: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype.

Claims

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

2. The method of claim 1, wherein R is acetyl;

R′

is TBS;

R″

is TPS;

R*₂B is derived from 9-BBN; and

Y is (OMe)₂.

4. The method of claim 1, wherein Z is O.

5. The method of claim 1, wherein Z is S.

6. The method of claim 1, wherein R¹ is hydrogen.

7. The method of claim 1, wherein R¹ is methyl.

8. The method of claim 4, wherein R¹ is hydrogen.

9. The method of claim 5, wherein R¹ is methyl.

3. A method of preparing an open-chain aldehyde having the structure:

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

11. The method of claim 10 wherein R′

is TBS and R″

is TPS.

12. The method of claim 10 further comprising the step of treating the protected cyclic alcohol formed in step (a) or (b) with a deprotecting agent under suitable conditions to form a cyclic diol having the structure:

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

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

15. The method of claim 10, wherein R¹ is hydrogen.

16. The method of claim 10, wherein R¹ is methyl.

17. The method of claim 13, wherein R¹ is hydrogen.

18. The method of claim 14, wherein R¹ is methyl.

28. The method of claim 10, wherein in step (b) a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α

-alcohol is obtained.

19. A method of preparing an epothilone having the structure:

20. The method of claim 19, further comprising the steps of:

(i) monoprotecting the cyclic diol having the structure;

21. The method of claim 19, wherein Z is O.

22. The method of claim 19, wherein Z is S.

23. The method of claim 19, wherein R¹ is hydrogen.

24. The method of claim 19, wherein R¹ is methyl.

25. The method of claim 21, wherein R¹ is hydrogen.

26. The method of claim 22, wherein R¹ is methyl.

27. A method comprising the steps of:

(a) cross-coupling a haloolefin having the structure;

29. The method of claim 27, wherein in step (d) a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α

-alcohol is obtained.