Solubilized topoisomerase poison agents

Abstract

The invention provides compounds of formula I: wherein A, B, W, Y, Z, and R 1 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 - 76 . (canceled)  
   
   
       77 . A method for modulating topoisomerase activity in a mammal, comprising administering to the mammal an amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 A and B are independently N or CH;  
 W is N or CH;  
 R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl, or R 3  and R 4  together are ═O, ═S, ═NH or ═N—R 2 ;  
 Y and Z are independently hydroxy, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy, substituted (C 1 -C 6 )alkanoyloxy, —O—P(═O)(OH) 2 , or —O—C(═O)NR c R d ; or Y and Z together with the ring carbon atoms to which they are attached form an alkylenedioxy ring with from 5 to 7 ring atoms;  
 R 1  is a —(C 1 -C 6 )alkyl substituted with one or more solubilizing groups;  
 R 2  is (C 1 -C 6 )alkyl or substituted (C 1 -C 6 )alkyl; and  
 R c  and R d  are each independently (C 1 -C 6 )alkyl or substituted-(C 1 -C 6 )alkyl; or R c  and R d  together with the nitrogen to which they are attached form a N′-{(C 1 -C 6 )alkyl}piperazino, pyrrolidino, or piperidino ring, which ring can optionally be substituted with one or more aryl, heteroaryl, or heterocycle;  
 or a pharmaceutically acceptable salt thereof;  
 effective to produce a topoisomerase-modulating effect:  
 
   
   
       78 . The method of  claim 77 , wherein the administration of the compound of formula I inhibits the activity of a topoisomerase.  
   
   
       79 . The method of  claim 78 , wherein the administration of the compound of formula I inhibits the activity of topoisomerase I and/or topoisomerase II.  
   
   
       80 . The method of  claim 79 , wherein the administration of the compound of formula I inhibits the activity of topoisomerase I.  
   
   
       81 . The method of  claim 79 , wherein the administration of the compound of formula I inhibits the activity of topoisomerase II.  
   
   
       82 . A method for producing an antiviral effect in a mammal, comprising administering to the mammal an amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 A and B are independently N or CH;  
 W is N or CH;  
 R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl, or R 3  and R 4  together are ═O, ═S, ═NH or ═N—R 2 ;  
 Y and Z are independently hydroxy, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy, substituted (C 1 -C 6 )alkanoyloxy, —O—P(═O)(OH) 2 , or —O—C(═O)NR c R d ; or Y and Z together with the ring carbon atoms to which they are attached form an alkylenedioxy ring with from 5 to 7 ring atoms;  
 R 1  is a —(C 1 -C 6 )alkyl substituted with one or more solubilizing groups;  
 R 2  is (C 1 -C 6 )alkyl or substituted (C 1 -C 6 )alkyl; and  
 R c  and R d  are each independently (C 1 -C 6 )alkyl or substituted (C 1 -C 6 )alkyl; or R c  and R d  together with the nitrogen to which they are attached form a N′-{(C 1 -C 6 )alkyl}piperazino, pyrrolidino, or piperidino ring, which ring can optionally be substituted with one or more aryl, heteroaryl, or heterocycle;  
 or a pharmaceutically acceptable salt thereof;  
 effective to produce an antiviral effect in the mammal.  
 
   
   
       83 . A method for producing an antipsoritic, antiprotozoal, and/or antihelmetic effect in a mammal, comprising administering to the mammal an effective amount of a compound of formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 A and B are independently N or CH;  
 W is N or CH;  
 R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl, or R 3  and R 4  together are ═O, ═S, ═NH or ═N—R 2 ;  
 Y and Z are independently hydroxy, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyloxy, substituted (C 1 -C 6 )alkanoyloxy, —O—P(═O)(OH) 2 , or —O—C(═O)NR c R d ; or Y and Z together with the ring carbon atoms to which they are attached form an alkylenedioxy ring with from 5 to 7 ring atoms;  
 R 1  is a —(C 1 -C 6 )alkyl substituted with one or more solubilizing groups;  
 R 2  is (C 1 -C 6 )alkyl or substituted (C 1 -C 6 )alkyl; and  
 R c  and R d  are each independently (C 1 -C 6 )alkyl or substituted (C 1 -C 6 )alkyl; or R c  and R d  together with the nitrogen to which they are attached form a N′—{(C 1 -C 6 )alkyl}piperazino, pyrrolidino, or piperidino ring, which ring can optionally be substituted with one or more aryl, heteroaryl, or heterocycle;  
 or a pharmaceutically acceptable salt thereof  
 
   
   
       84 . The method of  claim 83 , wherein the the administration of the compound of formula I produces an antipsoritic effect.  
   
   
       85 . The method of  claim 83 , wherein the the administration of the compound of formula I produces an antiprotozoal effect.  
   
   
       86 . The method of  claim 83 , wherein the the administration of the compound of formula I produces an antihelmetic effect.  
   
   
       87 . The method of  claim 77 , wherein the the compound of formula I is 13-{2-(dimethylamino)-ethyl}-2,3-dimethoxy-13H-8,10-dioxa-5,6,13-triaza-cyclopenta[b]chrysen-12-one or a pharmaceutically acceptable salt thereof.  
   
   
       88 . The method of  claim 77 , wherein the the compound of formula I is 13-{2-(dimethylamino)-ethyl}-2,3-dimethoxy-13H-8,10-dioxa-6,13-diaza-cyclopenta[b]chrysen-12-one or a pharmaceutically acceptable salt thereof.  
   
   
       89 . The method of  claim 77 , wherein the the compound of formula I is a compound of formula II  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       90 . The method of  claim 77 , wherein the the compound of formula I is a compound of formula III  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       91 . The method of  claim 77 , wherein the the compound of formula I is a compound of formula IV  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.