Heterocyclic hydrazones as novel anti-cancer agents

Abstract

The invention relates to novel 2-benzimidazoyl-, 2-benzoxazolyl- and 2-benzothiazolyl hydrazones that are derived from 2-formylpyridine, 2-acylpyridines, acetyldiazines and acetyl(iso)quinolines. The invention also relates to a novel method for producing 2-benzimidazolyl-, 2-benzoxazolyl- and 2-benzothiazolyl hydrazones and to their use as useful anti-cancer therapeutic agents. The novel compounds are also active against multidrug-resistant cancer cells.

1 . A compound of the general formula:  
     
       
         
         
             
             
         
       
     
     wherein Het  
     
       
         
         
             
             
         
       
       and wherein R H, CH 3 , OCH 3 , OH, Cl, Br, F, CF 3 , NO 2 , NH 2 , NHCOCH 3 , N(CH 3 ) 2 , phenyl, CN, C═NH(NH 2 ), C═S(NH 2 ), C═NH(NHOH), COOH or COOR 4 , wherein R 4 =an aliphatic residue or a phenyl group, or CONR 5 R 6 , wherein R 5  and R 6  are H, an aliphatic substituent or a phenyl group,  
       R 1 ═H, methyl, ethyl, propyl, iso-propyl, butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl, and  
       X═O or S  
       with the proviso that if Het  
       
         
           
           
               
               
           
         
       
       wherein R═H,  
       in case X═S: R 1  is not H, methyl, phenyl or 2-pyridyl,  
       in case X═O: R 1  is not methyl,  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S: R 1  is not methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S: R 1  is not H or methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S and R 1 =methyl: R is not H or methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S and R 1 =methyl: R is not methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S and R 1 =methyl: R is not H;  
       as well as with the proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S and R 1 ═H: R in position 6 is not methyl;  
       as well as the pharmaceutically acceptable salts thereof.  
     
   
   
       2 . A compound according to  claim 1 , namely  
     
       
         
         
             
             
         
       
     
     wherein R 1 ═H, methyl, ethyl, propyl, iso-propyl, butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl, and X═O or S,  
     with the proviso that 
 if X═S: R 1  is not H, methyl, phenyl or 2-pyridyl;  
 if X═O: R 1  is not methyl,  
 as well as the pharmaceutically acceptable salts thereof.  
 
   
   
       3 . A compound according to  claim 1 , namely  
     
       
         
         
             
             
         
       
     
     wherein Het= 
     
       
         
         
             
             
         
       
     
     R═H or CH 3 , X═O or S,  
     with the proviso that if Het  
     
       
         
         
             
             
         
       
     
     : R is  
     not H, with the further proviso that if Het  
     
       
         
         
             
             
         
       
     
     X is not S; with the further proviso that if  
     Het  
     
       
         
         
             
             
         
       
     
     X is not S;  
     with the further proviso that if Het  
     
       
         
         
             
             
         
       
       in case X═S: R is not H or methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case X═S: R is not methyl;  
       with the further proviso that if Het  
       
         
           
           
               
               
           
         
       
       in case of X═S: R is not H;  
       as well as the pharmaceutically acceptable salts thereof.  
     
   
   
       4 . A method of preparing a compound of the general formula  
     
       
         
         
             
             
         
       
     
     wherein Het= 
     
       
         
         
             
             
         
       
       and wherein R═H, CH 3 , OCH 3 , OH, Cl, Br, F, CF 3 , NO 2 , NH 2 , NHCOCH 3 , N(CH 3 ) 2 , phenyl, CN, C═NH(NH 2 ), C═S(NH 2 ), C═NH(NHOH), COOH or COOR 4 , wherein R 4  is an aliphatic residue or a phenyl group, or CONR 5 R 6 , wherein R 5  and R 6  are H, an aliphatic substituent or a phenyl group,  
       R 1 ═H, methyl, ethyl, propyl, iso-propyl, butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl, or 2-pyridyl, and X═O or S, with the proviso that if X═S and Het=pyridinyl, then R 1  is not H or methyl, characterised in that a ketone of the general formula (III)  
       
         
           
           
               
               
           
         
       
       wherein Het and R 1  are as defined above, is reacted with a hydrazine of the general formula (II)  
       
         
           
           
               
               
           
         
       
       wherein X is as defined above in the general formula.  
     
   
   
       5 . A method according to  claim 4 , characterised in that the reaction is carried out in methanol or ethanol.  
   
   
       6 . A method according to  claim 4  or  5 , characterised in that the reaction is carried out in the presence of a catalytic amount of an acid selected from the group consisting of acetic acid, hydrochloric acid or sulphuric acid.  
   
   
       7 . A method of treating a patient for cancer comprising, administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       8 . A method of treating a tumor in a patient comprising, administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       9 . A method of treating bladder cancer, breast cancer, colon cancer, stomach cancer, lung cancer, melanoma, cancer of the ovaries, prostate cancer, renal cancer, or cancer of the uterus in a patient comprising, administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof.  
   
   
       10 . A method of treating a patient for cancer comprising, administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula:  
     
       
         
         
             
             
         
       
     
     wherein Het= 
     
       
         
         
             
             
         
       
       and wherein R═H, CH 3 , OCH 3 , OH, Cl, Br, F, CF 3 , NO 2 , NH 2 , NHCOCH 3 , N(CH 3 ) 2 , phenyl, CN, C═NH(NH 2 ), C═S(NH 2 ), C═NH(NHOH), COOH or COOR 4 , wherein R 4 =an aliphatic residue or a phenyl group, or CONR 5 R 6 , wherein R 5  and R 6  are H, an aliphatic substituent or a phenyl group,  
       R 1 ═H, methyl, ethyl, propyl, iso-propyl, butyl, tert.-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl, and  
       X═NH or N—R 2 , wherein R 2 =methyl, ethyl, propyl, sec.-propyl, butyl, tert.-butyl, allyl, cyclopropyl, phenyl, benzyl, CH 2 —CH 2 —O—CH 3  or CH 2 —CH 2 -n(CH 3 ) 2 ,  
       with the proviso that if  
       
         
           
           
               
               
           
         
       
       Het=, wherein R═H,  
       in case X═N: R 1  is not H,  
       in case X═NH: R 1  is not methyl,  
       in case X═N—R 2  with R 2 ═CH 3 : R 1  is not methyl;  
       as well as the pharmaceutically acceptable salts thereof.  
     
   
   
       11 . A method of treating a tumor in a patient comprising, administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 10 , or a pharmaceutically acceptable salt thereof.  
   
   
       12 . A method of treating bladder cancer, breast cancer, colon cancer, stomach cancer, lung cancer, melanoma, cancer of the ovaries, prostate cancer, renal cancer, or cancer of the uterus in a patient comprising, administering to a patient in need thereof a therapeutically effective amount of a compound as defined in  claim 10 , or a pharmaceutically acceptable salt thereof.