Ureido and thioureido derivatives of 4-amino-2(5H)-furanones and 4-amino-2(5H)-thiophenones as antitumor agents

Abstract

Subject of the present invention are compounds of general formula (I), wherein A is oxygen or sulfur; X is oxygen or sulfur, R1 and R2 are independently hydrogen or an alkyl group with from 1 to 6 carbon atoms; R is selected from alkyl, cycloalkyl, alkylsulphinyl, alkylsulphonyl, hydroxyalkyl, napthtyl, phenyl group which can be unsubsituted or substituted; or R is a 5- or 6-membered heterocycle containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which can be optionally benzocondensed, the pure steroisomers or mixtures thereof as well as salts thereof with pharmaceutically acceptable acids or bases, for the use as medicaments, in particular as antitumor agents.

1 . Compounds of the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is oxygen or sulfur;  
 X is oxygen or sulfur;  
 R1 and R2 are independently hydrogen or an alkyl group with from 1 to 6 carbon atoms;  
 R is selected from: (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulphinyl, (C 1 -C 4 )alkylsulphonyl, (C 1 -C 4 )hydroxyalkyl, naphthyl, phenyl, phenyl substituted by from 1 to 3 groups selected from: (C 1 -C 4 )alkyl; chlorine, bromine, iodine or fluorine; (C 1 -C 4 )perfluoroalkyl; hydroxy; (C 1 -C 4 )alkoxy; amino; mono- or di-(C 1 -C 4 )alkylamino; aminosulphonyl; (C 1 -C 4 )alkylsulphonamido: phenyl- or tolyl-sulphonamido; carboxy; (C 1 -C 4 )alkoxycarbonyl; amidocarbonyl or (C 1 -C 4 )alkylamidocarbonyl; carboxaldehyde; (C 1 -C 4 )alkylcarbonyl; nitro; phenylthio; cyanomethyl, and optionally substituted phenyloxy or optionally substituted phenyl-(C 1 -C 4 )-alkyl or R is a 5- or 6-membered aromatic or non-aromatic heterocycle containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which can be optionally benzocondensed,  
 the pure stereoisomers or mixtures thereof as well as salts thereof with pharmaceutically acceptable acids or bases, with the proviso, that when A is oxygen and X is oxygen, R is not (C 1 -C 10 ) alkyl, for the use as medicaments.  
 
     
     
         2 . The compounds of  claim 1  for the use as antitumor agents.  
     
     
         3 . Compounds of the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is oxygen or sulfur;  
 X is oxygen or sulfur;  
 R1 and R2 are independently hydrogen or an alkyl group with from 1 to 6 carbon atoms;  
 R is selected from: (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulphinyl, (C 1 -C 4 )alkylsulphonyl, (C 1 -C 4 )hydroxyalkyl, naphthyl, phenyl, phenyl substituted by from 1 to 3 groups selected from: (C 1 -C 4 )alkyl; chlorine, bromine, iodine or fluorine; (C 1 -C 4 )perfluoroalkyl; hydroxy; (C 1 -C 4 )alkoxy; amino; mono- or di-(C 1 -C 4 )alkylamino; aminosulphonyl; (C 1 -C 4 )alkylsulphonamido; phenyl- or tolyl-sulphonamido; carboxy; (C 1 -C 4 )alkoxycarbonyl; amidocarbonyl or (C 1 -C 4 )alkylamidocarbonyl; carboxaldehyde; (C 1 -C 4 )alkylcarbonyl; nitro; phenylthio; cyanomethyl, and optionally substituted phenyloxy or optionally substituted phenyl-(C 1 -C 4 )-alkyl or R is a 5- or 6-membered aromatic or non-aromatic heterocycle containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which can be optionally benzocondensed,  
 the pure stereoisomers or mixtures thereof as well as salts thereof with pharmaceutically acceptable acids or bases, with the proviso that, when A is oxygen and X is oxygen, R is not unsubstituted phenyl or (C 1 -C 10 ) alkyl.  
 
     
     
         4 . Compounds according to  claim 3 , in which X is oxygen, R1 and R2 are hydrogen and R is a substituted phenyl group.  
     
     
         5 . Compounds according to  claim 4 , wherein said compounds are: 
 4-[N-(4-chlorophenyl)aminocarbonylamino]-2(5H)-furanone;    4-[N-(4-ethyl-3-chlorophenyl)aminocarbonylamino]-2(5H)-furanone.    
     
     
         6 . Pharmaceutical compositions containing a pharmaceutically effective amount of one or more compounds of formula (I) as depicted in  claim 1 , in admixture with pharmaceutically acceptable eccipients.  
     
     
         7 . The use of the compounds of formula (I) as depicted in  claim 1  for the preparation of a medicament having antitumor activity.  
     
     
         8 . A process for the preparation of the compounds according to  claims 1  to  5 , which comprises reacting a compound of formula (VII),  
       
         
           
           
               
               
           
         
       
       wherein A is oxygen or sulfur and R 1  and R 2  have the meanings mentioned above, with an urea or thiourea of formula (III):  
       
         
           
           
               
               
           
         
       
       in which R and X have the meanings mentioned above, in a solvent at reflux.