Process for the Preparation of 4-(Benzimidazolylmethylamino)-Benzamides and the Salts Thereof

Abstract

The invention relates to a process for preparing an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without isolating the intermediate product of the hydrogenation beforehand; as well as a process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) the product thus obtained is hydrogenated, and (c) i) optionally the amidino group is carbonylated and ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.

1 . Process for preparing an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that 
 (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid and    (b) the product thus obtained is hydrogenated.    
   
   
       2 . The process as recited in  claim 1  further comprising carbonylating the amidino group without first isolating the product of hydrogenation.  
   
   
       3 . Process according to  claim 1  for preparing an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  denotes a C 1-6 -alkyl or C 3-7 -cycloalkyl group,  
 R 2    
 (i) denotes a C 1-6 -alkyl group, a C 3-7 -cycloalkyl group optionally substituted by a C 1-3 -alkyl group, while the C 1-3 -alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group, or  
 (ii) denotes an R 21 NR 22  group, wherein 
 R 21  denotes a C 1-6  alkyl group which may be substituted by a carboxy, C 1-6  alkoxycarbonyl, benzyloxycarbonyl, C 1-3 -alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, a C 2-4 -alkyl group substituted by a hydroxy, phenyl-C 1-3 -alkoxy, carboxy-C 1-3 -alkylamino, C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino, N-(C 1-3 -alkyl)-carboxy-C 1-3 -alkylamino or N-(C 1-3 -alkyl)-C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino group, while in the above-mentioned groups the carbon atom in the α position to the adjacent nitrogen atom cannot be substituted, or  
 a piperidinyl group optionally substituted by a C 1-3 -alkyl group, and R 22  denotes a hydrogen atom, a C 1-6 -alkyl group, a C 3-7 -cycloalkyl group optionally substituted by a C 1-3 -alkyl group, or a C 3-6 -alkenyl or C 3-6 -alkynyl group, while the unsaturated moiety may not be linked directly to the nitrogen atom of the R 21 NR 22  group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl or C 1-3 -alkoxy group, or a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group optionally substituted by a C 1-3 -alkyl group, or R 21  and R 22  together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group optionally substituted by a carboxy or C 1-4 -alkoxycarbonyl group, to which additionally a phenyl ring may be fused, and  
 
 R 3  denotes a hydrogen atom, a C 1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C 1-3 -alkoxycarbonyl, benzoyl, p-C 1-3 -alkyl-benzoyl or pyridinoyl group, while the ethoxy moiety in the 2 position of the above-mentioned C 1-9 -alkoxycarbonyl group may additionally be substituted by a C 1-3 -alkylsulphonyl or 2-(C 1-3 -alkoxy)-ethyl group, while in step (a) a phenyldiamine of formula (II)  
                     
  wherein R 1  and R 2  have the meanings given for formula (I),  
 is reacted with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, the resulting product of formula (III)  
                     
  wherein R 1  and R 2  have the meanings given for formula (I),  
 is hydrogenated in step (b)i), and subsequently, without any prior isolation of the hydrogenation product, the compound of formula (I) thus obtained wherein R 3  denotes hydrogen is optionally reacted in step (b)ii) with a compound of formula (IV) 
   R 3 —X  (IV) 
  wherein R 3  has the meaning given for formula (I), and  
 X denotes a suitable leaving group.  
 
   
   
       4 . Process according to  claim 3 , for preparing a compound of formula (I), wherein 
 R 1  denotes a C 1-3 -alkyl group,    R 2  denotes an R 21 NR 22  group, wherein 
 R 2  denotes a C 1-3  alkyl group which may be substituted by a carboxy, C 1-3  alkoxycarbonyl, and  
 R 22  denotes a hydrogen atom, a C 1-3 -alkyl group, a pyridinyl group optionally substituted by a C 1-3 -alkyl group, and  
   R 3  denotes a hydrogen atom or a C 1-8 -alkoxycarbonyl group.    
   
   
       5 . Process according to  claim 4 , for preparing the compound of formula (I), wherein 
 R 1  denotes a methyl group,    R 2  denotes an R 21 NR 22  group, wherein 
 R 21  denotes an ethyl group which is substituted by an ethoxycarbonyl group, and  
 R 22  denotes a pyridin-2-yl group, and  
   R 3  denotes an n-hexyloxycarbonyl group.    
   
   
       6 . Process according to  claim 3 , characterised in that the compound of formula (I) thus obtained is subsequently converted into a physiologically acceptable salt.  
   
   
       7 . Process according to  claim 6 , characterised in that the physiologically acceptable salt is the methanesulphonate.  
   
   
       8 . Process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein 
 (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid,    (b) the product thus obtained is hydrogenated, and    (c) the amidino group is carbonylated.    
   
   
       9 . The process according to  claim 8  further comprising isolating the desired salt without prior isolation of the product of the carbonylation  
   
   
       10 . Process according to  claim 8  for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 3  are defined as in  claim 3 , comprising the following steps: 
 (a) reacting a phenyldiamine of formula (II)  
                     
  wherein R 1  and R 2  have the meanings given for formula (I),  
 with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid,  
 (b) hydrogenating the product of formula (III) thus obtained  
                     
  wherein R 1  and R 2  have the meanings given for formula (I), and  
 (c) i) reacting the compound of formula (I) thus obtained, wherein R 3  denotes hydrogen, with a compound of formula (IV) 
   R 3 —X  (IV) 
  wherein R 3  has the meaning given for formula (I) and  
 X denotes a suitable leaving group, and 
 ii) precipitating the desired salt of the compound of formula (I) thus obtained, without previously isolating the carbonylation product.  
 
 
   
   
       11 . Process according to  claim 10 , for preparing a salt of a compound of formula (I), wherein 
 R 1  denotes a C 1-3 -alkyl group,    R 2  denotes an R 21 NR 22  group, wherein 
 R 21  denotes a C 1-3  alkyl group which may be substituted by a carboxy, C 1-3  alkoxycarbonyl, and  
 R 22  denotes a hydrogen atom, a C 1-3 -alkyl group, a pyridinyl group optionally substituted by a C 1-3 -alkyl group, and  
   R 3  denotes a hydrogen atom or a C 1-8 -alkoxycarbonyl group.    
   
   
       12 . Process according to  claim 11 , for preparing a salt of the compound of formula (I), wherein 
 R 1  denotes a methyl group,    R 2  denotes an R 21 NR 22  group, wherein 
 R 21  denotes an ethyl group which is substituted by an ethoxycarbonyl group, and  
 R 22  denotes a pyridin-2-yl group,  
   R 3  denotes an n-hexyloxycarbonyl group and    the counter-ion is methanesulphonate.    
   
   
       13 . Process according to  claim 8 , characterised in that the condensation of step (a) is carried out in the presence of an inert diluent and a water-binding agent.  
   
   
       14 . Process according to  claim 8 , characterised in that the hydrogenation of step (b) or (b)i) is carried out in the presence of an inert diluent and a hydrogenation catalyst.  
   
   
       15 . Process according to  claim 8 , characterised in that in order to prepare 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline is reacted with a 2-haloacetic acid ester in the presence of a weak base, and the 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid ester obtained is saponified.  
   
   
       16 . Process according to  claim 8 , characterised in that in order to prepare 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline, 4-aminophenyl-amidoxime is reacted with a dialkyl carbonate in the presence of a base.