Synthesis of epothilones, intermediates thereto and analogues thereof

• US 6,867,305 B2
• Filed: 03/01/2001
• Issued: 03/15/2005
• Est. Priority Date: 12/03/1996
• Status: Expired due to Fees

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), 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: Stachel, Shawn J., Chappell, Mark D., Wu, Zhical, Lee, Chul Bom, Danishefsky, Samuel J.
• Primary Examiner(s): Saeed, Kamal
• Application Number:
  US09/796,959
• Publication Number:
  US 20020058817A1
• Time in Patent Office: 1,475 Days
• Field of Search: 548/204, 548/236, 548/311.1, 548/110
• 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 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides convergent processes for preparing epothilones, desoxyepothilones, and analogues thereof. The present invention further provides novel compositions and methods for the treatment of cancer and additionally provides methods for the treatment of cancer which has developed a multi-drug phenotype.

Claims

1. A compound having the structure:

wherein M is O;

wherein CY is 4-thiazolyl, imidazolyl, or 4-oxazolyl;

wherein R₂ and R₃ are each independently hydrogen;

substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl;

acyl;

aroyl;

benzoyl;

or Si(R_B)₃, wherein each occurrence of R_B is independently substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl or heteroaryl;

wherein R₄ and R₅ are each independently hydrogen;

or substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted by one or more of hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NRcRo, N-hydroximino, or N-alkoxyimino, wherein R_C and R_D are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl;

wherein R₆ is independently hydrogen;

OR_A;

SR_A;

NR_AR_A;

C(O)OR_A;

C(O)R_A;

CONHR_A;

N₃;

N₂R_A;

halogen;

cyclic acetal;

substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;

wherein each occurrence of R_A is independently hydrogen;

linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;

wherein Z is O, N(OR_E) or N—

NR_FR_G;

wherein R_E, R_F, and R_G are each independently a substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic moiety; and

wherein n is 0, 1, 2, or 3;

wherein said compound is prepared by a method comprising the steps of;

a) providing an alkyl sector having the structure;

wherein Z_A is OP or SP;

wherein P is an oxygen or sulfur protecting group;

wherein Hal is a halogen;

wherein R₆ is independently hydrogen;

OR_A;

SR_A;

NR_AR_A;

C(O)OR_A;

C(O)R_A;

CONHR_A;

N₃;

N₂R_A;

halogen;

cyclic acetal;

substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;

wherein each occurrence of R_A is independently hydrogen;

or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl, which further comprises the steps of;

i) providing a phosphine oxide having the structure;

wherein R₀, R′ and

R″

are independently C_1-8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl, aryl, alkoxy or aryloxy;

ii) condensing the phosphine oxide with a ketone having the structure;

iii) reducing the ester formed instep ii) under suitable conditions to form the compound; and

b) providing an acyl sector having the structure;

wherein Z_B is CO₂R₉ or COSR₉, wherein R₉ is hydrogen or an oxygen or sulfur protecting group, wherein R₂ and R₃ are each independently hydrogen, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl;

linear or branched, substituted or unsubstituted acyl, aroyl or benzoyl;

or Si(R_B)₃, wherein each occurrence of R_B is independently substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl; and

wherein R₄ and R₅ are each independently hydrogen, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR_CR_D, N-hydroxyimino, or N-alkoxyimino, wherein R_C and R_D are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl;

which further comprises;

i) protecting a ketoaldehyde having the structure;

to generate a protected aldehyde and subsequently reacting said protected aldehyde with a compound having a structure;

under suitable conditions to effect condensation to generate an aldol having the structure;

ii) hydrolyzing the protected acetal group to generate a ketoaldehyde having the structure;

iii) reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction, and optionally protecting the C3 alcohol to generate a compound having the structure;

wherein Z_B, and R₂-R₅ are as defined above; and

iv) reacting the acyl sector and the alkyl sector to generate a compound having the structure;

wherein Z_A, Z_B, CY, Z, and R₂-R₆ are as defined above; and

c) subjecting the cyclization precursor to conditions to effect macrocyclization, and optionally subjecting to conditions to effect deprotection to generate the compound.

2. The compound of claim 1, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, CY is 4-thiazolyl, and R₆ is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl,

or (CH₂)_p— OH, wherein p is 1-6, and the compound has the structure;

3. The compound of claim 1, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is hydrogen, and CY is 4-thiazolyl and the compound has the structure:

4. The compound of claim 1, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is methyl, and CY is 4-thiazolyl, wherein the compound has the structure:

5. The compound of claim 1, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is ethyl, and CY is 4-thiazolyl, wherein the compound has the structure:

6. A compound having the structure:

wherein M is O;

wherein CY is 4-thiazolyl, imidazolyl, or 4-oxazolyl;

wherein R₂ and R₃ are each independently hydrogen;

substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl;

acyl;

aroyl;

benzoyl;

or Si(R_B)₃, wherein each occurrence of R_B is independently substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl or heteroaryl;

wherein R₄ and R₅ are each independently hydrogen;

or substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted by one or more of hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR_CR_D, N-hydroximino, or N-alkoxyimino, wherein R_C and R_D are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl;

wherein R₆ is independently hydrogen;

OR_A;

SR_A;

NR_AR_A, C(O)OR_A;

C(O)R_A;

CONHR_A;

N₃;

N₂R_A;

halogen;

cyclic acetal;

substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;

wherein each occurrence of R_A is independently hydrogen;

linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;

wherein Z is O, N(OR_E) or N—

NR_FR_G;

wherein R_E, R_F, and R_G are each independently a substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic moiety; and

wherein n is 0, 1, 2, or 3.

7. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, CY is 4-thiazolyl, and R₆ is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl,

or (CH₂)_p—

OH, wherein p is 1-6, and the compound has the structure;

8. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is hydrogen, and CY is 4-thiazolyl and the compound has the structure:

9. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is methyl, and CY is 4-thiazolyl, wherein the compound has the structure:

10. The compound of claim 6, wherein M is O, R₂ and R₃are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is ethyl, and CY is 4-thiazolyl, wherein the compound has the structure:

11. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, CY is 4-oxazolyl, and R₆ is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl,

or (CH₂)_p—

OH, wherein p is 1-6, and the compound has the structure;

12. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is hydrogen, and CY is 4-oxazolyl and the compound has the structure:

13. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is methyl, and CY is 4-oxazolyl, wherein the compound has the structure:

14. The compound of claim 6, wherein M is O, R₂ and R₃ are hydrogen, R₄ is methyl, R₅ is hydrogen, Z is O, R₆ is ethyl, and CY is 4-thiazolyl, wherein the compound has the structure: