Novel benzamidine derivatives having anti-inflammatory and immunosuppressive activity

Abstract

Compounds which can be represented by the general formula (I) indicated below: and in which: A is selected independently from the carboxamide group, the thiocarboxamide group, and the carbonyl group, R 1 is selected from an alkyl group having from 1 to 3 carbon atoms and the amino group, unsubstituted or substituted with the nitro group or the methyl group, R 2 is selected independently from hydrogen, an alkyl group having from 1 to 4 carbon atoms, the methoxy, ethoxy, propoxy group, a mono-, bi- or tricyclic cycloalkane residue having from 5 to 12 carbon atoms, the adamantyl group, an aryl, naphthyl or heterocyclic group, unsubstituted or substituted with methyl, methoxy, hydroxy, amino or halogen groups, R 3 and R 4 are selected independently from hydrogen and an alkyl group having from 1 to 3 carbon atoms, R 5 represents one or two substituents independently selected from hydrogen and the methyl, methoxyl and hydroxyl groups, n is a whole number from 0 to 6, and the amidine group is in the para or meta position relative to the “-A-NH—” group.

1 . A compound of formula (I) below:  
       
         
           
           
               
               
           
         
         wherein 
 A is selected independently from a carboxamide group, a thiocarboxamide group, and a carbonyl group;  
 R 1  is selected from an alkyl group having from 1 to 3 carbon atoms and an amino group substituted with a nitro group when A is the thiocarboxamide group;  
 R 1  is selected from an alkyl group having from 1 to 3 carbon atoms when A is selected independently from a carboxamide group and a carbonyl group;  
 R 2  is selected independently from hydrogen, an alkyl group having from 1 to 4 carbon atoms, a methoxy group, an ethoxy group, or a propoxy group, a mono-, bi- or tricyclic cycloalkane group having from 5 to 12 carbon atoms, an adamantyl group, and an aryl, naphthyl or heterocyclic group, unsubstituted or substituted with a methyl group, a methoxy group, a hydroxy group, an amino group or a halogen group;  
 R 3  and R 4  are selected independently from hydrogen and an alkyl group having from 1 to 3 carbon atoms;  
 R 5  represents one or two substituents independently selected from hydrogen and a methyl group, a methoxyl group and a hydroxyl group;  
 n is a whole number from 0 to 6; and  
 an amidine group is in the para or meta position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof.  
 
       
     
     
         2 . The compound of according to  claim 1 , wherein A is a thiocarboxamide group; R 1  is an alkyl group having from 1 to 3 carbon atoms; R 2  is a methyl group or a mono-, bi- or tricyclic cycloalkane group having from 5 to 12 carbon atoms; R 3 , R 4  and R 5  are hydrogen; n is a whole number between 0 and 6; and the amidine group is in the para position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . The compound according to  claim 1  wherein A is selected independently from a carboxamide group and a carbonyl group; R 1  is an alkyl group having from 1 to 3 carbon atoms; R 2  is a methyl group or a mono-, bi- or tricyclic cycloalkane group having from 5 to 12 carbon atoms; R 3 , R 4  and R 5  are hydrogen; n is a whole number between 0 and 6; and the amidine group is in the para position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The compound according to  claim 1  wherein A is a thiocarboxamide group; R 1  is selected from an amino group substituted with a nitro group; R 2  is a methyl group or a mono-, bi- or tricyclic cycloalkane group having from 5 to 12 carbon atoms; R 3 , R 4  and R 5  are hydrogen; n is a whole number between 0 and 6; and the amidine group is in the para position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The compound according to  claim 1  wherein A is a thiocarboxamide group; R 1  is an alkyl group having from 1 to 3 carbon atoms; R 2  is selected from an aryl group, unsubstituted or substituted with halogen groups; R 3 , R 4  and R 5  are hydrogen; n is a whole number between 0 and 6, and the amidine group is in the para position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The compound according to  claim 1  wherein A is a thiocarboxamide group; R 1  is selected independently from a methyl group, or a nitro-amino group; R 2 , R 3 , R 4  and R 5  are hydrogen; n is 5; and the amidine group is in the para position relative to the -A-NH— group.  
     
     
         7 . A pharmaceutical preparation comprising a compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier.  
     
     
         8 . The pharmaceutical preparation according to  claim 7  further comprising pharmaceutically-acceptable inactive ingredients selected from the group consisting of vehicles, binders, flavourings, sweeteners, disaggregants, preservatives, humectants and mixtures thereof, ingredients which facilitate rectal, transdermal or transmucosal absorption, and ingredients that permit the controlled release of the active ingredient over time.  
     
     
         9 . A method for the preparation of a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein 
 A is selected independently from a carboxamide group, a thiocarboxamide group, and a carbonyl group;  
 R 1  is selected from an alkyl group having from 1 to 3 carbon atoms and an amino group substituted with a nitro group or a methyl group;  
 R 2  is selected independently from hydrogen, an alkyl group having from 1 to 4 carbon atoms, a methoxy group, an ethoxy group, or a propoxy group, a mono-, bi- or tricyclic cycloalkane group having from 5 to 12 carbon atoms, an adamantyl group, and an aryl, naphthyl or heterocyclic group, unsubstituted or substituted with a methyl group, a methoxy group, a hydroxy group, an amino group or a halogen group;  
 R 3  and R 4  are selected independently from hydrogen and an alkyl group having from 1 to 3 carbon atoms;  
 R 5  represents one or two substituents independently selected from hydrogen and a methyl group, a methoxyl group and a hydroxyl group;  
 n is a whole number from 0 to 6; and  
 an amidine group is in the para or meta position relative to the -A-NH— group, or a pharmaceutically acceptable salt thereof which comprises the steps of:  
 
         a) reacting a 1,3 or 1,4-phenylenediamine of formula (IV)  
         
           
             
             
                 
                 
             
           
         
         in which R 5  has the meaning given above, with the isothiocyanate of formula (V A), with the acyl chloride of formula (V B), or with the isocyanate of formula (V C),  
         
           
             
             
                 
                 
             
           
         
         in which R 2 , R 3 , and n have the meanings given above, with an excess of phenylenediamine, in a neutral solvent and at a temperature of between 4° C. and the reflux temperature of the solvent used, to give the corresponding anilines of formula (III)  
         
           
             
             
                 
                 
             
           
         
         in which R 2 , R 3 , R 4 , A and n have the meanings given above, and in which the amine group is in the meta or para position relative to the chain adjacent to the -A-NH— group;  
         b) reacting the anilines of formula (III) with an appropriate imidate hydrochloride of formula (II)  
         
           
             
             
                 
                 
             
           
         
         in which R 1  has the meaning given above, in the presence of an excess of formula (II) and of the corresponding stoichiometric quantity of a tertiary base, in an inert anhydrous solvent, at a temperature of between 4° C. and the boiling point of the solvent to give the corresponding derivatives of formula (I)  
         
           
             
             
                 
                 
             
           
         
         in which A, R 1 , R 2 , R 3 , R 4 , R 5  and n have the meanings given above and in which the amidine group is in the para or meta position relative to the -A-NH— group, recovering the compound of formula (I) or a pharmaceutically-acceptable salt thereof from the reaction mass and purifying;  
         c) alternatively, if R 1  is NH—NO 2 , the corresponding compound of formula (I) in which A is the thiocarboxamide group and R 2 , R 3 , R 4 , R 5  and n have the meanings given above is prepared by reacting the anilines of formula (III) with N-methyl-N-nitroso-N′-nitroguanidine.