Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 6,972,335 B2
• Filed: 12/04/2001
• Issued: 12/06/2005
• 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: Danishefsky, Samuel J., Meng, Dongfang, Chou, Ting-Chao, Kamenecka, Ted, Bertinato, Peter, Sorensen, Erik J, Savin, Kenneth A., Su, Dai-Shi, Balog, Aaron
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/004,571
• Publication Number:
  US 20050033059A1
• Time in Patent Office: 1,463 Days
• Field of Search: 548/202
• US Class Current: 548/202
• 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 an epothilone precursor having the structure:

wherein R₁ is hydrogen or methyl;

wherein X is O, or a hydrogen and OR″

, each singly bonded to carbon; and

wherein R₀, R′ and

R″

are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises

(a) coupling a compound having the structure;

wherein R is an acetyl, with an aldehyde having the structure;

wherein Y is oxygen, under suitable conditions to form an aldol intermediate and optionally protecting the aldol intermediate under suitable conditions to form an acyclic epothilone precursor having the structure;

(b) subjecting the acyclic epothilone precursor to conditions leading to intramolecular olefin metathesis to form the epothilone precursor.

2. The method of claim 1 wherein the conditions leading to intramolecular olefin metathesis require the presence of an organometallic catalyst.

3. The method of claim 1 wherein the catalyst is a Ru or Mo complex.

6. The method of claim 1, wherein step (a) comprises using a non-nucleophilic base.

7. The method of claim 6, wherein the non-nucleophilic base is lithium diethylamide or lithium diisopropylamide.

8. The method of claim 1, wherein step (a) is performed at subambient temperatures.

9. The method of claim 1, wherein step (a) is performed at about −

78°

C.

10. The method of claim 2, wherein the catalyst is Grubbs'"'"'s catalyst.

4. A method of preparing a protected epothilone having the structure:

wherein R₁ is hydroaen or methyl; and

R′ and

R″

are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl-arylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises;

(a) monoprotecting a cyclic dial having the structure;

 

under suitable conditions to form a cyclic alcohol having the structure;

 

and

(b) oxidizing the cyclic alcohol formed in step (a) under suitable conditions to form the protected epothilone.

5. The method of claim 4 wherein R′

and R″

are TBS.

11. The method of claim 4, wherein step (a) is performed in the presence of a base.

12. The method of claim 11, wherein the base is 2,6-lutidine.

13. The method of claim 4, wherein step (a) is performed in an inert organic solvent.

14. The method of claim 13, wherein the solvent is dichloromethane.

15. The method of claim 4, wherein step (a) is performed at subambient temperatures.

16. The method of claim 4, wherein step (a) is performed at about −

30°

C.

17. The method of claim 4, wherein step (b) is performed using Dess-Martin periodinane in an inert organic solvent.

18. The method of claim 17, wherein the solvent is dichloromethane.

19. The method of claim 4, wherein step (b) is performed at 20-25°

C.