Heterocyclic cytotoxic agents

Abstract

The invention provides compounds of formula I: wherein R 1 -R 8 and A-G 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: 
 A is N or CR 3 ;  
 B is N or CR s ;  
 D is NR e  or CR a R b ;  
 E is NR f  or CR c R d ;  
 F is N or CR t ;  
 G is N or CR 6 ;  
 R 1 , R 2  and R 3  are each individually hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, COOR k , OR m , or halo; or R 1  and R 2  taken together are methylenedioxy and R 3  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 2  and R 3  taken together are methylenedioxy and R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo;  
 R 6 , R 7  and R 8  are each individually hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 6  and R 7  taken together are methylenedioxy and R 8  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -Cd)cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 7  and R 5  taken together are methylenedioxy and R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , C(═O)R k , COOR k , OR m , or halo;  
 each bond represented by ----- is individually present or absent;  
 R a  and R b  are each independently hydrogen or (C 1 -C 6 )alkyl if the bond between the 11- and 12-positions represented by ----- is absent; or R a  is hydrogen or (C 1 -C 6 )alkyl and R b  is absent if the bond between the 11- and 12-positions represented by ----- is present;  
 R c  and R d  are each independently hydrogen or (C 1 -C 6 )alkyl if the bond between the 11- and 12-positions represented by ----- is absent; or R a  is hydrogen or (C 1 -C 6 )alkyl and R d  is absent if the bond between the 11- and 12-positions represented by ----- is present;  
 R e  is hydrogen or (C 1 -C 6 )alkyl if the bond between the 5- and 6-positions represented by ----- is absent; or R b  is absent if the bond between the 5- and 6-positions represented by ----- is present;  
 R f  is hydrogen or (C 1 -C 6 )alkyl if the bond between the 5- and 6-positions represented by ----- is absent; or R f  is absent if the bond between the 5- and 6-positions represented by ----- is present;  
 each R g  and R h  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, aryloxy, or aryl(C 1 -C 6 )alkoxy; or R g  and R h  together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;  
 each R k  is independently hydrogen, or (C 1 -C 6 )alkyl; and  
 each R m  is independently (C 1 -C 6 )alkanoyl, aryl, or aryl(C 1 -C 6 )alkyl;  
 each R s  and R t  is independently hydrogen, methyl, nitro, hydroxy, amino, or halo;  
 wherein any (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkoxy of R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , or R k  is optionally substituted on carbon with 1, 2, or 3 substituents independently selected from hydroxy, halo, NR n R p , (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkoxy; wherein each R n  and R p  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkanoyl; or R n  and R p  together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;  
 wherein any aryl is optionally be substituted with 1, 2, or 3 substituents independently selected from hydroxy, halo, nitro, trifluoromethyl, trifluoromethoxy, carboxy, amino, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy;  
 provided no more than two of A-G comprise nitrogen; and  
 provided the compound of formula (I) is not 2,3,8,9-tetramethoxy-5,6-diazachrysene or 2,3-8,9-bismethylenedioxy-5,6-diazacrysene; and  
 provided the compound of formula (I) is not a compound of formula (I) wherein D is NR e , when A CR 3 ; B is Cs; E is CR c R d ; F is CR t ; and G is CR 6 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1  wherein R 3  is hydrogen.  
     
     
         3 . The compound of  claim 1  wherein R 1 , R 2  and R 3  are each individually hydrogen, or (C 1 -C 6 )alkoxy; or R 1  and R 2  taken together are methylenedioxy and R 3  is hydrogen or (C 1 -C 6 )alkoxy.  
     
     
         4 . The compound of  claim 1  wherein R 7  or R is (C 1 -C 6 )alkoxy; or R 7  and R 8  taken together are methylenedioxy.  
     
     
         5 . The compound of  claim 1  wherein R 7  and R 8  taken together are methylenedioxy.  
     
     
         6 . The compound of  claim 1  wherein R 2  is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro.  
     
     
         7 . The compound of  claim 1  wherein R 8  is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro.  
     
     
         8 . The compound of  claim 1  wherein the bonds represented by ----- are both present.  
     
     
         9 . The compound of  claim 1  wherein wherein R 1  is (C 1 -C 6 )alkoxy, nitro, hydroxy, or halo; or R 1  and R 2  taken together are methylenedioxy.  
     
     
         10 . The compound of  claim 1  wherein R 2  is (C 1 -C 6 )alkoxy, nitro, hydroxy, or halo; or a pharmaceutically acceptable salt thereof.  
     
     
         11 . The compound of  claim 1  wherein R 3  is (C 1 -C 6 )alkoxy, nitro, hydroxy, or halo; or R 2  and R 3  taken together are methylenedioxy.  
     
     
         12 . The compound of  claim 1  wherein R 8  is (C 1 -C 6 )alkoxy, nitro, hydroxy or halo; or R 7  and R, taken together are methylenedioxy.  
     
     
         13 . The compound of  claim 1  wherein R 7  is (C 1 -C 6 )alkoxy, nitro, hydroxy, or halo.  
     
     
         14 . The compound of  claim 1  wherein R 6  is (C 1 -C 6 )alkoxy, nitro, hydroxy, or halo; or R 6  and R 7  taken together are methylenedioxy.  
     
     
         15 . The compound of  claim 1  which is a compound of formulae II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         16 . The compound of  claim 1  which is a compound of formulae III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         17 . The compound of  claim 1  which is a compound of formulae V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The compound of  claim 1  which is a compound of formulae VI:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The compound of  claim 1  which is a compound of formulae VII:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         20 . The compound of  claim 1  which is a compound of formulae VIII:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         21 . The compound of  claim 1  which is a compound of formulae DC:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         22 . The compound of  claim 1  which is a compound of formulae X:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         23 . The compound 2,3-Dimethoxyibenzo[ch]cinnoline (6); 2,3-Dimethoxy-8,9-methylenedioxy-dibenzo[c,h]cinnoline (14); 2,3,8-Trimethoxydibenzo[c,h]cinnoline (60); 2,3,9-Trimethoxydibenzo[ch]cinnoline (61); 9-Benzyloxy-2,3,8-trimethoxydibenzo[ch]cinnoline (42); 2-Methoxy-8,9-methylenedioxydibenzo[c,h]cinnoline (43); or 3-Methoxy-8,9-methylenedioxydibenzo[c,h]cinnoline (44); or a pharmaceutically acceptable salt thereof.  
     
     
         24 . The compound 2,3-Dimethoxy-8,9-methylenedioxy-dibenzo[c,h]cinnoline (14); or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The compound of  claim 1  wherein R 1 -R 3  and R 6 -R 8  are not each hydrogen.  
     
     
         26 . The compound of  claim 1  wherein one of R 2  and R 8  is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro; or at least one of R 2  and R 8  forms part of a methylenedioxy;  
     
     
         27 . The compound of  claim 1  which is not 9-hydroxy-2,3,8-trimethoxydibenzo[c,h]cinnoline.  
     
     
         28 . A pharmaceutical composition comprising a effective amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is N or CR 3 ;  
 B is N or CR g ;  
 D is NR e  or CR a R b ;  
 E is NR f  or CR c R d ;  
 F is N or CR t ;  
 G is N or CR 6 ;  
 R 1 , R 2  and R 3  are each individually hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 1  and R 2  taken together are methylenedioxy and R 3  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 2  and R 3  taken together are methylenedioxy and R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo;  
 R 6 , R 7  and R 8  are each individually hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 6  and R 7  taken together are methylenedioxy and R g  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , COOR k , OR m , or halo; or R 7  and R 8  taken together are methylenedioxy and R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, nitro, hydroxy, NR g R h , C(═O)R k , COOR k , OR m , or halo;  
 each bond represented by ----- is individually present or absent;  
 R a  and R b  are each independently hydrogen or (C 1 -C 6 )alkyl if the bond between the 11- and 12-positions represented by ----- is absent; or R a  is hydrogen or (C 1 -C 6 )alkyl and R b  is absent if the bond between the 11- and 12-positions represented by ----- is present;  
 R c  and R d  are each independently hydrogen or (C 1 -C 6 )alkyl if the bond between the 11- and 12-positions represented by ----- is absent; or R a  is hydrogen or (C 1 -C 6 )alkyl and R d  is absent if the bond between the 11- and 12-positions represented by ----- is present;  
 R e  is hydrogen or (C 1 -C 6 )alkyl if the bond between the 5- and 6-positions represented by ----- is absent; or R a  is absent if the bond between the 5- and 6-positions represented by ----- is present;  
 R f  is hydrogen or (C 1 -C 6 )alkyl if the bond between the 5- and 6-positions represented by ----- is absent; or R f  is absent if the bond between the 5- and 6-positions represented by ----- is present;  
 each R g  and R h  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, aryloxy, or aryl(C 1 -C 6 )alkoxy; or R g  and R h  together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;  
 each R k  is independently hydrogen, or (C 1 -C 6 )alkyl;  
 each R m  is independently (C 1 -C 6 )alkanoyl, aryl, or aryl(C 1 -C 6 )alkyl; and  
 each R s  and R t  is independently hydrogen, methyl, nitro, hydroxy, amino, or halo;  
 wherein any (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkoxy of R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , or R k  is optionally substituted on carbon with 1, 2, or 3 substituents independently selected from hydroxy, halo, NR n R p , (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkoxy; wherein each R n  and R p  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )alkanoyl; or R n  and R p  together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;  
 wherein any aryl is optionally be substituted with 1, 2, or 3 substituents independently selected from hydroxy, halo, nitro, trifluoromethyl, trifluoromethoxy, carboxy, amino, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy;  
 provided no more than two of A-G comprise nitrogen;  
 provided R 1 -R 3  and R 6 -R 8  are not each hydrogen;  
 provided the compound is not 9-hydroxy-2,3,8-trimethoxy-dibenzo[c,h]cinnoline; and  
 provided the compound of formula (I) is not a compound of formula (1) wherein D is NR e ; when A CR 3 ; B is CR s ; E is CR c R d ; F is CR t ; and G is CR 6 ;  
 or a pharmaceutically acceptable salt thereof; in combination with a pharmaceutically acceptable diluent or carrier.  
 
     
     
         29 . A pharmaceutical composition comprising a compound as described in  claim 1  in combination with a pharmaceutically acceptable diluent or carrier.  
     
     
         30 . 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.  
     
     
         31 . A method comprising inhibiting cancer cell growth by contacting said cancer cell in vitro or in vivo with an amount of a compound as described in  claim 1 , effective to inhibit the growth of said cancer cell.  
     
     
         32 . 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.  
     
     
         33 . 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.