Novel anticancer conjugates of camptothecin and unsaturated fatty acids

Abstract

The present invention provides novel conjugates of camptothecin compounds and long-chain unsaturated fatty acid. The novel conjugates can be used to treat mammalian cell proliferative diseases such as cancer.

1 . A compound of the following formula or a pharmaceutically acceptable salt thereof:  
         Long chain unsaturated fatty acid-linker-CPT  (Formula I)  
       wherein: 
 the Long-chain unsaturated fatty acid is C 12 -C 22  mono or poly unsaturated fatty acids;  
 the linker is -(alkyl) m -(aryl) n -C(O)— or -(aryl) m -(alkyl) n -C(O)—; wherein: m and n are independently 0-3, and m+n≧1; and  
 CPT is a camptothecin compound with the following general structure (Formula II):  
                     
 wherein: R 1 -R 5  are H, halo, OH, NO 2 , NH 2 , alkyl, O-alkyl, NH-alkyl, N(alkyl) 2 , ester, or amide, and can be the same or different.  
 
     
     
         2 . The compounds of  claim 1 , wherein the long-chain unsaturated fatty acid is palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  
     
     
         3 . The compounds of  claim 2 , wherein the linker is a structure with the following formula (III) and their acid addition salts.  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compounds of  claim 3 , wherein CPT is selected from the group consisting of: camptothecin, 9-aminocamptothecin, 10-hydroxycamptothecin, 7-ethyl-10-hydroxy-camptothecin, 9-N,N-dimethylaminomethyl-10-hydroxycamptothecin, and their acid addition salts.  
     
     
         5 . The compounds of  claim 4 , wherein the compound is  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compounds of  claim 4 , wherein the compound is  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compounds of  claim 4 , wherein the compound is  
       
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition for treating a mammalian cell proliferating disease comprising a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the mammalian cell proliferating disease is cancer.  
     
     
         10 . A method for treating cancers comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to  claim 1.