Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents

Abstract

According to the invention, there is provided a method of manufacturing a medicament for use in the treatment of cancer or viral infections which comprises obtaining a cancer treating effective amount of a compound of formula (I), and combining the compound of formula (I) with at least one pharmaceutically acceptable excipient, and wherein the cancer treating effective amount of a compound of formula I is an acryloyl substituted distamycin derivative in which n, R 1 and R 2 , R 3 , B, are defined herein or a pharmaceutically acceptable salt thereof to produce a medicament for use in the treatment of cancer or viral infections.

1 . An acryloyl substituted distamycin derivative of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 2, 3 or 4;  
 R 1  and R 2  are selected, each independently, from: hydrogen, halogen, and C 1 -C 4  alkyl;  
 R 3  is hydrogen or halogen;  
 B is selected from:  
                     
 wherein R 4 , R 5 , R 6 , R 7 , and R 8  are, each independently, hydrogen or C 1 -C 4  alkyl, with the proviso that at least one of R 4 , R 5  and R 6  is C 1 -C 4  alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound as defined in  claim 1 , wherein: 
 n is 3 or 4;    R 1  and R 2  are hydrogen;    R 3  is chlorine or bromine;    B is selected from:                          wherein R 4 , R 5 , R 6 , R 7 , and R 8  are, each independently, hydrogen or methyl, with the proviso that at least one of R 4 , R 5  and R 6  is methyl.    
     
     
         3 . A compound as defined in  claim 1 , selected from: 
 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propioncyanamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propioncyanamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N,N′-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N,N′-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamidoxime;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamidoxime;    2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) ethylguanidine;    2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) ethylguanidine;    2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) ethylguanidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionitrile;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionitrile;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamide;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamide;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamide;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-α-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methyl-amidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethyl-amidine;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine; and    3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(α-chloroacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;    and the pharmaceutically acceptable salts thereof.    
     
     
         4 . A process for producing a compound as defined in  claim 1 , which process comprises: 
 (a) reacting a compound of formula:                          wherein:    n is 2, 3 or 4;    m is 0 or 1;    B is selected from:                           wherein R 4 , R 5 , R 6 , R 7 , and R 8  are, each independently, hydrogen or C 1 -C 4  alkyl, with the proviso that at least one of R 4 , R 5  and R 6  is C 1 -C 4  alkyl;    with a compound of formula:                          wherein: R 1  and R 2  are selected, each independently, from: hydrogen, halogen, and C 1 -C 4  alkyl; R 3  is hydrogen or halogen; X is hydroxy or a leaving group; and m has the above reported meanings;    or:    (b) when B is equal to —C≡N, reacting a compound of formula:                           wherein n, R 1 , R 2 , and R 3  are as defined above; with succinic anhydride, and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.    
     
     
         5 . A compound as defined in any one of  claims 1  to  3 , for use in a method of treating the human or animal body by therapy.  
     
     
         6 . A compound as claimed in  claim 5  for use as an antineoplastic agent.  
     
     
         7 . A compound as claimed in  claim 5  for use as an antiviral agent.  
     
     
         8 . Use of a compound as defined in any one of  claims 1  to  3 , in the manufacture of a medicament for use in the treatment of cancer.  
     
     
         9 . Use of a compound as defined in any one of  claims 1  to  3 , in the manufacture of a medicament for use in the treatment of viral infection.  
     
     
         10 . A pharmaceutical composition, which comprises an effective amount of a compound as defined in any one of  claims 1  to  3  as an active principle, in association with one or more pharmaceutically acceptable carriers and/or diluents.