Back to results
US 2002/0058286 A1Published application
Synthesis of epothilones, intermediates thereto and analogues thereof
OwnerSamuel J. Danishefsky, Shawn J. Stachel +4inventors
InventorsSamuel J. Danishefsky, Shawn J. Stachel, Chul Bom Lee, Mark D. Chappell, Ting-Chao Chou, Zhicai Wu
Life of this patent
Estimating the term…
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.
Claims61
A compound having the structure:
- 154
- wherein M is NH or O;
- wherein CY is an aryl or heteroaryl moiety;
- wherein q is 1-5;
- wherein each occurrence of W is independently absent;
- —NH—;
- C═O;
- C═S;
- —O—;
- —S—;
- or C(V)2;
- wherein each occurrence of V is independently hydrogen;
- halogen;
- —OH;
- —SH;
- amino;
- or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl;
- wherein each occurrence of m is independently 1-5;
- wherein the bond W—R1 represents a single bond or a double bond;
- wherein each occurrence of R1 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N3;
- N2;
- N2RA;
- halogen;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- polymer;
- carbohydrate;
- photoaffinity label;
- or radiolabel;
- wherein each occurrence of RA is independently hydrogen;
- linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- nitrogen protecting group;
- carbon protecting group;
- oxygen protecting group;
- sulfur protecting group;
- polymer;
- carbohydrate;
- photoaffinity label;
- or radiolabel;
- wherein R2 and R3 are each independently hydrogen;
- substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
- acyl;
- aroyl;
- benzoyl;
- or Si(RB)3, wherein each occurrence of RB 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 6ne or more of hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NRCRD, N-hydroximino, or N-alkoxyimino, wherein RC and RD are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl;
- wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N2;
- N2RA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- nitrogen protecting group;
- carbon protecting group;
- oxygen protecting group;
- sulfur protecting group;
- linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- polymer;
- carbohydrate;
- photoaffinity label;
- or radiolabel;
- wherein Z is O, N(ORE) or N—NRFRG;
- wherein RE, RF, and RG are each independently a substituted or unsubstituted, linear or branched, cyclic or acyclic aliphatic moiety;
- and
- wherein n is 0, 1, 2, or 3.
76 more elements
A method of preparing a compound having the structure:
- 168
- wherein P is an oxygen protecting group;
- wherein Hal is a halogen;
- and wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N3;
- N2RA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- nitrogen protecting group;
- oxygen protecting group;
- sulfur protecting group;
- or carbon protecting group;
- polymer;
- carbohydrate;
- photoaffinity label;
- or radiolabel, which method comprises the steps of:
- a) providing a haloketone having the structure:
- 169
- b) subjecting said haloketone to conditions to generate enol ethers and subsequently hydroxylating under suitable conditions to prepare a hydroxyketone having the structure:
- 170
- c) protecting the hydroxyketone under suitable conditions to form the compound:
- 171
28 more elements
A method of preparing a compound having the structure:
- 174
- wherein P is an oxygen protecting group;
- wherein Hal is a halogen;
- and wherein R6 is hydrogen, hydroxy, thio, amino, or halogen, or is substituted or unsubstituted, cyclic or acyclic linear or branched aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, thioalkyl, arylthio, carboxy, carboxaldehyde, cyclic acetal, alkylamino, arylamino, hydroxyimino, or alkoxyimino comprising the steps of
- a) preparing a glycolimide having the structure:
- 175
- b) treating the glycolimide with a substituted hydroxylamine selected from the group consisting of N,O-(linear or branched chain C1-8 alkyl,aryl)hydroxylamine, N,O-di-(linear or branched chain C1-8)alkylhydroxylamine and N,O-aryl,arylhydroxylamine under suitable conditions to form an amide having the structure:
- 176
- wherein R′ and R″ are each independently linear or branched chain C1-8 alkyl or aryl;
- and
- c) reacting the amide with a substituted organometallic reagent under suitable conditions to form the compound.
8 more elements
A method of preparing a compound having the structure:
- 177
- wherein R1 is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic;
- wherein ZA is OP, SP, or NHP;
- wherein P is an oxygen, nitrogen or sulfur protecting group;
- wherein Hal is a halogen;
- wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N2;
- NRA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- nitrogen protecting group;
- sulfur protecting group;
- oxygen protecting group;
- carbon protecting group;
- or polymer;
- which comprises the steps of:
- a) preparing a phosphine oxide having the structure:
- 178
- wherein R′ and R″ are independently C1-8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl;
- alkoxy or aryloxy;
- b) condensing the phosphine oxide with a ketone having the structure:
- 179
- c) optionally subjecting said compound to inversion or optionally reducing the ester formed under suitable conditions to form the compound.
29 more elements
A method of preparing a compound having the structure:
- 180
- wherein R1 is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic;
- wherein ZA is N3 or NHP;
- wherein P is a nitrogen protecting group;
- wherein Hal is a halogen;
- wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N2;
- NRA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- which comprises the steps of:
- a) preparing a phosphine oxide having the structure:
- 181
- wherein R′ and R″ are independently C1-8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl, alkoxy or aryloxy;
- b) condensing the phosphine oxide with a ketone having the structure:
- 182
- c) reacting the compound formed in step b) under suitable conditions to effect inversion to generate an azide, and optionally further treating the azide to generate a protected amine.
23 more elements
A method of preparing a compound having the structure:
- 183
- wherein P is a nitrogen protecting group;
- wherein Hal is a halogen;
- wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N3;
- N2RA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- which comprises the steps of:
- a) preparing a phosphine oxide having the structure:
- 184
- wherein R0, R′ and R″ are independently C1-8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl, alkoxy or aryloxy;
- b) condensing the phosphine oxide with a ketone having the structure:
- 185
- c) reducing the ester formed in step b) under suitable conditions to form the compound.
21 more elements
A method for preparing a compound having the structure:
- 186
- wherein ZB 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(RB)3, wherein each occurrence of RB 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, NRCRD, N-hydroxyimino, or N-alkoxyimino, wherein RC and RD are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl;
- said method comprising:
- protecting a ketoaldehyde having the structure:
- 187
- to generate a protected aldehyde and subsequently reacting said protected aldehyde with a compound having a structure:
- 188
- under suitable conditions to effect condensation to generate an aldol having the structure:
- 189
- hydrolyzing the protected acetal group to generate a ketoaldehyde having the structure:
- 190
- 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:
- 191
- wherein ZB, and R2-R5 are as defined above.
14 more elements
A method for preparing a compound having the structure:
- 192
- wherein R1 is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic, or is —CY═CHX, wherein X is hydrogen, or is substituted or unsubstituted linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substituted aliphatic or aryl substituted heteroaliphatic and wherein Y is hydrogen, or linear or branched chain alkyl;
- 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(RB)3, wherein each occurrence of RB is independently substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl;
- 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, NRCRD, N-hydroximino, or N-alkoxyimino, wherein RC and RD are each independently H, phenyl, benzyl, linear or branched chain alkyl;
- wherein R6 is independently hydrogen;
- ORA;
- SRA;
- NRARA;
- C(O)ORA;
- C(O)RA;
- CONHRA;
- N3;
- N2RA;
- halogen;
- cyclic acetal;
- substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl;
- wherein each occurrence of RA is independently hydrogen;
- or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl;
- nitrogen protecting group;
- oxygen protecting group;
- sulfur protecting group;
- carbon protecting group;
- or polymer;
- wherein M is NH or O;
- and wherein n is 0, 1, 2 or 3;
- which method comprises:
- providing a precursor having the structure:
- 193
- wherein R1-R6 are as defined above;
- ZA is OR7, NHR8, or N3, and ZB is CO2R9 or COSR9 wherein each occurrence of R7, R8, R9, R10, or R11 is independently hydrogen, an oxygen protecting group or a nitrogen protecting group;
- and wherein the step of providing the precursor further comprises:
- reacting a first compound having the structure
- 194
- under suitable conditions with a second compound having the structure:
- 195
- to effect coupling to generate the precursor;
- and
- subjecting said precursor to suitable conditions to effect macrocyclization and optionally deprotection to generate the desired compound.
37 more elements
Dependencies are inferred from the claim text.