Synthesis of epothilones, intermediates thereto, analogues and uses thereof

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.

1 - 58 . (canceled) 
     
     
         59 . A method of stabilizing microtubules in a subject, the method comprising steps of: 
       administering to a subject in need thereof a composition comprising a compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino; 
 R 4  and R 5  are independently H, phenyl, benzyl, linear or branched chain alkyl; according to an administration schedule that delivers to the subject a dose that corresponds to an average daily dose in a mouse that is within the range of 0.001-35 mg/kg. 
 
     
     
         60 . The method of  claim 59 , wherein the administration schedule that delivers to the subject a dose that corresponds to an average daily dose in a mouse that is within the range of 0.001-25 mg/kg. 
     
     
         61 . The method of  claim 59 , wherein the administration schedule that delivers to the subject a dose that corresponds to an average daily dose in a mouse that is within the range of 0.001-10 mg/kg. 
     
     
         62 . The method of  claim 59 , wherein the administration schedule that delivers to the subject a dose that corresponds to an average daily dose in a mouse that is within the range of 0.001-1.0 mg/kg. 
     
     
         63 . The method of  claim 59 , wherein in the compound R 1  is H. 
     
     
         64 . The method of  claim 59 , wherein in the compound R 1  is methyl. 
     
     
         65 . The method of  claim 59 , wherein in the compound R 1  is ethyl. 
     
     
         66 . The method of  claim 59 , wherein in the compound R 1  is propyl. 
     
     
         67 . The method of  claim 59 , wherein in the compound R 1  is substituted or unsubstituted, linear or branched chain alkyl. 
     
     
         68 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl, substituted by hydroxy, fluorine, cyclic acetal, or NR 4 R 5 , wherein R 4  and R 5  are independently H, phenyl, benzyl, or linear or branched chain alkyl. 
     
     
         69 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl substituted by fluorine. 
     
     
         70 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl substituted by hydroxy. 
     
     
         71 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl substituted by NR 4 R 5 , wherein R 4  and R 5  are independently H, phenyl, benzyl, or linear or branched chain alkyl. 
     
     
         72 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl substituted by cyclic acetal. 
     
     
         73 . The method of  claim 72 , wherein in the compound R 1  is 2-(1,3-dioxolanyl)methyl. 
     
     
         74 . The method of  claim 59 , wherein in the compound R 1  is linear or branched chain alkyl substituted by a substituted carboxy group. 
     
     
         75 . The method of  claim 59 , wherein the composition further comprises a pharmaceutically acceptable carrier selected from the group consisting of glycols, oils, and alcohols.