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US RE41,990 E1Granted
Synthesis of epothilones, intermediates thereto, analogues and uses thereof
AssigneeSloan-Kettering Institute for Cancer Research
InventorsSamuel J. Danishefsky, Peter Bertinato, Dai-Shi Su, Dongfang Meng, Ting-Chao Chou, Ted Kamenecka, Erik J. Sorensen, Aaron Balog, Kenneth A. Savin
Life of this patent
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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.
Claims93
A purified compound having the a structure:
- or a compound having the structure:
- wherein R1, R2, and R3 are each independently H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independendy H, phenyl, benzyl, linear or branched chain alkyl;
- R″ is —CY═CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;
- Z is O, N(OR6) or N—NR7R8, wherein R6, R7 and R8 are independently H or a linear or branched chain alkyl or alkoxy;
- and
- n is 0, 1, 2, or 3;
- wherein when the compound is of the formula:
- R1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH2OH, (CH2)3OH, or
5 more elements
A purified compound having the structure:
- wherein R1 is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independently H, phenyl, benzyl, linear or branched chain alkyl,
- wherein R1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH2OH, (CH2)3OH, or
A pharmaceutical composition comprising:
- a compound having a structure:
- or a compound having a structure:
- wherein R1, R2, and R3 are each independantly H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independently H, phenyl, benzyl, linear or branched chain alkyl;
- R″ is —CY═CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;
- Z is O, N(OR6) or N—NR7R8, wherein R6, R7 and R8 are independently H or a linear or branched chain alkyl or alkoxy;
- and
- n is 0, 1, 2, or 3;
- and
- wherein when the compound is of the formula:
- R1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH2OH, (CH2)3OH, or
- and
- a pharmaceutically acceptable carrier,
- said composition optionally further comprising a cytotoxic agent.
10 more elements
A pharmaceutical composition comprising:
- a compound having the structure:
- wherein R1 is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independently H, phenyl, benzyl, linear or branched chain alkyl,
- wherein R1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH2OH, (CH2)3OH, or
- and
- a pharmaceutically acceptable carrier,
- said composition optionally further comprising a cytotoxic agent.
3 more elements
A method of treating cancer in a subject comprising:
- administering to the subject a therapeutically effective amount of a compound having the structure:
- or a compound having the structure:
- wherein R1, R2, and R3 are each independently H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independently H, phenyl, benzyl, linear or branched chain alkyl;
- R″ is —CY═CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;
- Z is O, N(OR6) or N—NR7R8, wherein R6, R7 and R8 are independently H or a linear or branched chain alkyl or alkoxy;
- and
- n is 0, 1, 2, or 3,
- said method optionally further comprising administering a cytotoxic agent.
5 more elements
A method for treating cancer in a subject comprising:
- administering to a subject a therapeutically effective amount of a compound having the structure:
- wherein R1 is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR4R5, N-hydroximino, or N-alkoxyimino, wherein R4 and R5 are independently H, phenyl, benzyl, linear or branched chain alkyl,
- said method optionally further comprising administering a cytotoxic agent.
Dependencies are inferred from the claim text.