1,3-dihydroimidazole-2-thione derivatives as inhibitors of dopamine-beta-hydroxylase

Abstract

Compounds of formula I and a method for their preparation are described, where R 1 , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4 signifies -alkyl-aryl or alkyl heteroaryl; X signifies CH 2 , oxygen atom or sulphur atom; n is 2 or 3; including the individual (R)- and (S)-enantiomers or mixtures of enantiomers thereof; and including pharmaceutically acceptable salts and esters thereof. The compounds have potentially valuable pharmaceutical properties for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.

1 - 9 . (canceled) 
     
     
         10 . A process for the preparation of the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts or esters of a compound of formula I, 
       
         
           
           
               
               
           
         
         comprising: 
         reacting the individual (R)- or (S)-enantiomers or mixtures of enantiomers of a compound of Formula III 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula IV 
       
         
           
           
               
               
           
         
       
       under reductive alkylation conditions, 
       wherein X signifies CH 2 , oxygen atom or sulphur atom; n is 2 or 3; R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies -alkyl-aryl or -alkyl-heteroaryl; and R 5  signifies aryl or heteroaryl, wherein the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine; the term heteroaryl means heteroaromatic group. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . A process for the preparation of the compound of formula X 
       
         
           
           
               
               
           
         
       
       its (R) or (S) enantiomer, or a mixture of the (R) and (S) enantiomers, or a pharmaceutically acceptable salt or an ester thereof, comprising
 reacting the (R)- or (S)-enantiomer or the mixture of the (R) and (S) enantiomers of 5-(2-aminoethyl)-1-(6,8-difluoro-chroman-3-yl)-1,3-dihydroimidazole-2-thione with benzaldehyde under reductive alkylation reaction conditions. 
 
     
     
         15 . The process according to  claim 14 , wherein the reductive alkylation is performed in the presence of a reducing reagent. 
     
     
         16 . The process according to  claim 15 , wherein the reducing reagent is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst. 
     
     
         17 . The process according to  claim 14 , wherein the treatment takes place in a mixture of methanol and dichloromethane. 
     
     
         18 . The process according to  claim 14 , wherein the process further includes a purification step. 
     
     
         19 - 37 . (canceled) 
     
     
         38 . The process according to  claim 14 , wherein the compound is the (R) enantiomer of the compound of formula X. 
     
     
         39 . The process according to  claim 14 , wherein the compound is the hydrochloride salt of the compound of formula X. 
     
     
         40 . A process for the preparation of the compound of formula Xa 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising
 reacting (R)-5-(2-aminoethyl)-1-(6,8-difluoro-chroman-3-yl)-1,3-dihydroimidazole-2-thione with benzaldehyde under reductive alkylation reaction conditions. 
 
     
     
         41 . The process according to  claim 40 , wherein the reductive alkylation is performed in the presence of a reducing reagent. 
     
     
         42 . The process according to  claim 41 , wherein the reducing reagent is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst. 
     
     
         43 . The process according to  claim 40 , wherein the treatment takes place in a mixture of methanol and dichloromethane. 
     
     
         44 . The process according to  claim 40 , wherein the process further includes a purification step. 
     
     
         45 . The process according to  claim 40 , wherein the compound is the hydrochloride salt of the compound of formula Xa. 
     
     
         46 . The process according to  claim 10 , wherein the reductive alkylation is performed in the presence of a reducing reagent. 
     
     
         47 . The process according to  claim 46 , wherein the reducing reagent is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst. 
     
     
         48 . The process according to  claim 10 , wherein the treatment takes place in a mixture of methanol and dichloromethane. 
     
     
         49 . The process according to  claim 10 , wherein the process further includes a purification step.