Nova Patents
IL138113A

Synthesis of epothilones, intermediates thereto and analogues thereof

Abstract

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof, useful in the treatment of cancer and cancer which has developed a multidrug-resistant phenotype. Also provided are intermediates useful for preparing said epothilones.

Term

No projected expiry on record.

  1. Priority
  2. Filed
  3. Published
  4. Today

39 claims: 6 independent, 33 dependent

  1. 1
    138113/2 WO 99/43653 PCT/US99/04008 -142- The claims defining the invention are as follows:1. A method of preparing a desoxyepothilone having the structure: 10 15 wherein R, R* and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR,R?, N-hydroximino, or N-alkoxyimino, wherein R, and R, are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein R" is -CY«=CX-, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furany|, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-l ,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein Y is H or linear or branched chain alkyl;wherein Z is O, N(ORj) or N-NR«R„ wherein RJ( R, and R, are independently H or a linear or branched alkyl;and wherein π is 0,1,2, or 3;which comprises treating an epothilone having a structure: 20 wherein R, Ro, R„ Rj, Rj, R,, Rs, R', R", X, Y, Z and n are defined as for the desoxyepothilone/ under suitable conditions so as to deoxygenate the epothilone, and thereby to provide the desoxyepothilone.
  2. 8
    9. A method of preparing a desoxyepothilone having the structure:4 5 6 7 8 9 10 11 12 13 14 15 16 17 wherein R, Ro, and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldedyde, linear or branched alkyl or cyclic acetal, fluorine, NR(R2, N-hydroximino, or N-alkoxyimino, wherein Rt and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein R" is -CY«CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-t,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-l ,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein Y is H or linear or branched chain alkyl;'and wherein Z is O, N(ORj) or N-NR,RS where R„ R< and R} are independently H or a linear or branched alkyl;and wherein n is 0,1 or 2 which comprises treating a protected desoxyepothilone having the structure: O “ORb 18 138113/2 WO 99/43653 PCT/US99/04008 19 20 21 22 23 24 25 26 27 1 1 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 10 -146- whereln RA is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trlalkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;and wherein Ra is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsllyl) alkyloxycarbonyl, benzyl, trlalkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarysilyt, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;under suitable conditions to form the desoxyepothilone.
  3. 12
    13. A method of preparing a protected desoxyepothilone having the structure:wherein R, Ro, and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR,R„ N-hydroximino, or N-alkoxyimino, wherein R, and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein R" is -CY«CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-l,3-oxazolinyl, 3-indolyl or 138113/2 WO.99/43653 PCT/US99/04008 -147- 11 12 13 14 15 16 17 18 19 20 21 6-indoiyl;wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyi, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein Y is H or linear or branched chain aJkyJ;wherein n is 2 or 3;wherein RA fc a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, triaJkylsiiyi, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyi or benzoyl;and wherein R0 is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkyloxycarbonyl, benzyl, trialkylsiiyl, dialkylarylsilyf, alkyldiaryisilyl, . triarysilyl, a linear or branched acyl, substituted or unsubstituted aroyi or benzoyl;which comprises cydocondensing a hydroxy acid desoxyepothilone precursor having the structure: 22 23 24 25 wherein R, Ro, Ra. Rb. R’« R" are defined as above and n Is 0,1 or 2;under suitable conditions to form the protected desoxyepothilone. 14'. 15. The method of claim 13 wherein R"is 2-methyI-1,3-thiazoHnyl. The method of ciaim 13 wherein RA is TES and Ra is Troc.
  4. 15
    18. A method of preparing a hydroxy acid desoxyepothilone precursor having the structure:4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 wherein R, Ro, and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR,R2, N-hydroximino, or N-alkoxyimino, wherein R, and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein R" is -CY = CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyI, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein Y is H or linear or branched chain alkyl;wherein n is 2 or 3;wherein RA is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;wherein Re is hydrogen, t-butyloxycarbonyl, amyloxycarbony I, (trialkylsilyl) alkyloxycarbonyl, (dialkylarylsilyl)alkyloxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarysilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;which comprises selectively etherifying and hydrolyzing a hydroxy ester desoxyepothilone precursor having the structure: I 138113/2 PCT/US99/04008 WO 99/43653 -14 9- 23 24 25 26 27 1 1 1 2 3 4 1 2 wherein R, Ro, RB, Rc, R', R" and n are defined as above;and wherein Rc is tertiary-alkyl;under suitable conditions to form the hydroxy acid desoxyepothilone precursor.
  5. 25
    29. A method of preparing a hydroxy ketoester desoxyepothilone precursor having the structure:wherein P is H;wherein R, Ro, and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR,R}, N-hydroximino, or N-alkoxyimino, wherein R, and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein R" is -CY = CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;wherein Y is H or linear or branched chain alkyl;wherein n is 2 or 3;wherein Re is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl). alkyloxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarysilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;and wherein Rc is tertiary-alkyl;which comprises deprotecting a protected ketoester desoxyepothilone precursor having the structure: 138113/2 PCT/US99/04008 WO 99/43653 -152- 20 21 22 23 24 25 26 27 wherein R, R<„ R^ RB, Rc, R'( R" and n are defined as above;and wherein P is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl or triarylsilyl;under suitable conditions to form the hydroxy ketoester desoxyepothilone precursor.
  6. 38
    43. A method of preparing a terminal vinyl enol ether ester having the structure:138113/2 PCT/US99/04008 WO 99/43653 1 2 3 4 5 6 7 8 9 10 11 12 -155- wherein R<, and R' are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR,R2, N-hydroximino, or N-alkoxyimino, wherein R, and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;wherein m is 0, 1 or 2;wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialky.lsilyl)alkyl-oxycarbonyl, (dialkylarylsilyl)alky-loxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarysilyI, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;wherein Rc is tertiary-alkyl;and wherein Ro is linear or branched alkyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarysilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;which comprises: (a) treating a keto enol ester having the structure: COjRc ORd 13 14 15 under suitable conditions to form an enolate enol ester having the structure: COjRc ORd 16 17 18 19 wherein M is Li, Na or K;and (b) coupling the enolate enol ester with a vinyl aldehyde having the structure: 20 21 22 wherein m, and R<, and R' are as defined above;under suitable conditions to form the terminal vinyl enol ether ester.
Independent claims6