Nitro and amino substituted heterocycles as topoisomerase I targeting agents

Abstract

The invention provides compounds of formula I: wherein: R 1 -R 5 ,“a” 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 using compounds of formula I.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       one of R 1  and R 2  is nitro or NR a R b ; the other of R 1  and R 2  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, NR a R b , COOR c , or OR d ; and 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 OR d , or R 3  and R 4  taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3-propylenedioxy; or  
       R 1  and R 2  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, NR a R b , COOR c , or OR d or R 1  and R 2  taken together are methylenedioxy, 1,2-ethylenedioxy, or 1,3- propylenedioxy; one of R 3  and R 4  is nitro or NR a R b ; and the other of R 3  and R 4  is hydrogen, (C-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, NR a R b , COOR c , or OR d ;  
       R 5  is (C 1 -C 6 )alkyl substituted with one or more solubilizing groups;  
       X is two hydrogens, =O, =S, or =Nhd e;  
       the bond marked“a” is a single bond or a double bond:  
       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 hydrohgen, (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 - 59 . (canceled)  
     
   
   
       60 . 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.    
   
   
       61 . (canceled)  
   
   
       62 . 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 as described in  claim 1 , effective to provide an antibacterial effect.  
   
   
       63 . (canceled)