Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 6,849,651 B2
• Filed: 06/05/2001
• Issued: 02/01/2005
• 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: Savin, Kenneth A, Danishefsky, Samuel J., Chou, Ting-Chao, Meng, Dang Fang, Kamenecka, Ted, Bertinato, Peter, Sorensen, Erik J, Su, Dai-Shi, Balog, Aaron
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US09/874,514
• Publication Number:
  US 20020002194A1
• Time in Patent Office: 1,337 Days
• Field of Search: 514/365, 548/204
• US Class Current: 514/365
• 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 treating cancer in a subject comprising:

administering to the subject in need thereof an average daily dose of a compound having the structure;

wherein R is methyl; and

a pharmaceutically acceptable carrier selected from the group consisting of glycols, oils, and alcohols,

wherein the amount of the compound in the carrier is sufficient for the composition to deliver to the subject between about 0.001 and 0.6 mg compound per kilogram of the subject'"'"'s body weight.

2. The method of claim 1, wherein the average daily dose is within the range of about 0.01 mg to about 0.6 mg compound per kg body weight.

3. The method of claim 1, wherein the step of administering comprises administering individual doses not more frequently than once daily.

4. The method of claim 1, wherein the step of administering comprises interrupting individual dose administrations with at least one day of rest.

5. The method of claim 1, wherein the step of administering comprises interrupting individual dose administrations with at least three days of rest.

6. The method of claim 1, wherein the step of administering comprises administering over a period of at least 6 days.

7. The method of claim 1, wherein the step of administering comprises administering to an animal that has a multidrug resistant tumor.

8. The method of claim 1, wherein the step of administering according to a schedule sufficient to achieve at least about 16% tumor inhibition.

9. A pharmaceutical composition for delivering a therapeutically effective amount of a compound to a mammal, the pharmaceutical composition comprising:

an amount of a compound having the structure;

wherein R is methyl; and

a pharmaceutically acceptable carrier selected from the group consisting of glycols, oils, and alcohols,

wherein the amount of the compound in the carrier is sufficient for the composition to deliver to the mammal between about 0.001 mg and about 0.6 mg compound per kg body weight.

10. The pharmaceutical composition of claim 9, wherein the therapeutically effective amount is an amount sufficient to deliver about 0.01 mg to about 0.6 mg compound per kg body weight.

11. The composition of claim 9, wherein the composition is formulated for parenteral delivery.

12. The composition of claim 9, wherein the composition is formulated for oral delivery.

13. The composition of claim 9, wherein the composition comprises an emulsion.

14. The composition of claim 9, wherein the composition comprises an aqueous suspension.