Analogs of epothilone

Abstract

Designed epoxide and cyclopropane epothilone analogs with substituted side-chains are disclosed and characterized with respect to their biological activities against a series of human cancer cell lines. Among the several bioactive analogs, the epothilone B analog with a thiomethyl thiazole ring stands out as the most potent.

1 . A compound represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R is a radical selected from the group consisting of the following structures:  
       
         
           
           
               
               
           
         
       
     
     
         2 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 1  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R is a radical selected from the group consisting of the following structures:  
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 8  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 8  represented by the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition containing a therapeutic dose of any one or more of the compounds according to claims  1 - 28  for the treatment of a proliferative disease in a mammal.  
     
     
         12 . A pharmaceutical composition according to  claim 11  where the mammal is a human.  
     
     
         13 . A compound represented by the following structure:  
       
         
           
           
               
               
           
         
       
       wherein X is oxygen or methylene and R is a radical selected from the group consisting of radicals represented by the following structures:  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound according to  claim 13  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound according to  claim 13  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound according to  claim 13  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 13  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound according to  claim 13  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound represented by the following structure:  
       
         
           
           
               
               
           
         
         wherein X oxygen or carbon and R is a radical selected from group consisting of -Me, —Cl, —Br, —SMe, and —CF 3 .  
       
     
     
         20 . A compound according to  claim 19  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound according to  claim 19  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         22 . A compound according to  claim 19  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         23 . A compound according to  claim 19  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         24 . A compound according to  claim 19  represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         25 . A compound represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound represented by the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound represented by the following structure: