Nitro and amino substituted topoisomerase agents

Abstract

The invention provides compounds of formula I: wherein R 1 -R 9 , W, and X have any of the meanings defined in the specification and their pharmaceutically acceptable salts. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I, and therapeutic methods for treating cancer and infections using compounds of formula I.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 one of R 1 , R 2 , R 3 , and R 4  is nitro or NR a R b ;  
 and the remaining R 1 , R 2 , R 3 , and R 4  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, NR a R b , COOR c , OR d ; or R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3-propylenedioxy;  
 R 5  is hydrogen, hydroxy, or fluoro;  
 each R 6 , R 7 , and R 8  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, NR a R b , COOR c , OR d ; or R 6  and R 7 , or R 7  and R 8  taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3-propylenedioxy;  
 R 9  is (C 1 -C 6 )alkyl substituted with one or more solubilizing groups;  
 W is N or CH;  
 X is two hydrogens, ═O, ═S, or ═NR e ;  
 R a  and R b  are each independently hydrogen or (C 1 -C 6 )alkyl, or R a  and R b  together with the nitrogen to which they are attached form a pyrrolidino, piperidino or morpholino ring;  
 each R c  is hydrogen, (C 1 -C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl;  
 each R d  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, aryl, or aryl(C 1 -C 6 )alkyl; and  
 R e  is hydrogen, (C 1 -C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl; 
 or a pharmaceutically acceptable salt thereof.  
 
 
   
   
       2 - 51 . (canceled)  
   
   
       52 . A method of inhibiting cancer cell growth, comprising administering to a mammal afflicted with cancer, an amount of a compound as described in  claim 1 , effective to inhibit the growth of said cancer cells.  
   
   
       53 . (canceled)  
   
   
       54 . A method of producing an antibacterial effect in a mammal in need of such treatment comprising administering to the mammal, an amount of a compound a described in  claim 1 , effective to provide an antibacterial effect.  
   
   
       55 . A method of producing an antifungal effect in a mammal in need of such treatment comprising administering to the mammal, an amount of a compound as described in  claim 1 , effective to provide an antifungal effect.