Sulpur derivatives containing a retroamide bond as inhibitors of endothelin-converting enzymes

Abstract

The following products: [S—R + , S + )] N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[phenylmethoxy) carbonyl] amino]-1H-indole-3-propanamide, 2′-cyano-alpha-[[[1-mercaptomethyl)-2-phenylethyl] amino] carbonyl] (1,2′-biphenyl)-4-propanoic acid, (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide, said products being in all possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with pharmaceutically acceptable mineral and organic bases of said products of formula (I) having an inhibitory activity on enothelin-converting enzymes.

1 ) Use, for the preparation of medicaments intended for the treatment of pathologies requiring an inhibition of the endothelin-converting enzyme, of the products of formula (I) :  
       
         
           
           
               
               
           
         
       
       in which : 
 R 1  represents an phenyl or biphenyl radical optionally substituted by one or more radicals chosen from halogen atoms, the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy and the dioxol radical,  
 n1 and n2, identical or different, represent the integer 0 or 1,  
 R 2  represents a hydrogen atom or a methyl radical substituted by a phenyl, phenylthio or indolyl radical and optionally by a second phenyl radical, these phenyl, phenylthio and indolyl radicals being optionally substituted by one or more radicals chosen from halogen atoms, and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy, thienyl, naphthyl and phenyl, these three last radicals being themselves optionally substituted by one or more radicals chosen from halogen atoms, the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,  
 A represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical, or an alkyl radical, containing up to 10 carbon atoms and substituted by a radical chosen from the following radicals: free, salified, esterified or amidified carboxy, the optionally protected hydroxyl, alkoxy containing up to 4 carbon atoms, phenoxy, phenyl, naphthyl, thienyl, indolyl and pyridyl, these radicals being optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,  
 {circle over (1)} and {circle over (2)} indicating, if appropriate, the asymmetric centres of the products or formula (I),  
 said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I).  
 
     
     
         2 ) Use as defined in  claim 1 , in which R 1 , R 2 , and n 2  have the meanings indicated in  claim 1 , 
 n1 represents the integer 1,    and A represent the free, salified, esterified ou amidified carboxy radical or an alkyl radical, containing at most 10 carbon atoms and substituted by a radical chosen from the free, salified, esterified ou amidified carboxy radicals, optionally protected hydroxyl radicals, alkoxy radical containing at most 4 carbon atoms, and phenoxy radical, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I).    
     
     
         3 ) Use as defined in  claim 1  or  2 , in which 
 R 1  represents a phenyl or biphenyl radical, optionally substituted by a halogen atom, or by a hydroxyl radical optionally in the form of of the trifluoromethylsulphonyloxy radical,  
 n1 represents the integer 1, n2 represents the integer 0,  
 R 2  represents a hydrogen atom or a methyl radical substituted by a phenyl radical, itself optionally substituted by a thienyl or phenyl radical itself optionally substituted by a cyano radical,  
 A represents the free, salified, esterified ou amidified carboxy radical or an alkyl radical, containing at most 10 carbon atoms substituted by a phenoxy radical,  
 said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts or with mineral and organic bases of said products of formula (I).  
 
     
     
         4 ) Use as defined in  claim 1 , of products the names of which follow: 
 [S—(R * ,S * )] N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl] amino]-1H-indole-3-propanamide,    2′-cyano-alpha-[[[1- (mercaptomethyl)-2-phenylethyl] amino]carbonyl] (1,1′-biphenyl)-4-propanoic acid,    (R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide,    said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic bases of said products of formula (I).    
     
     
         5 ) Preparation process for the products of formula (I) for use as defined in  claim 1 , characterized in that a product of formula (II);  
       
         
           
           
               
               
           
         
       
       in which n1 has the meaning indicated in  claim 1  and R′ 1  has the meaning indicated in claim I for R 1  in which the optional reactive functions are optionally protected, is subjected either to the action of a compound of formula (III):  
       
         
           
           
               
               
           
         
       
       in which R′ 2  has the meaning indicated in  claim 1  for R 2  in which the optional reactive functions are optionally protected, and R represents an alkyl or arylalkyl radical, in order to obtain the product of formula (IV):  
       
         
           
           
               
               
           
         
       
       in which n1, R′ 1 , R′ 2  and R have the meanings indicated above, or to the action of an acid halide of formula (V):  
       
         
           
           
               
               
           
         
       
       in which n2 has the meaning indicated in  claim 1 , Hal represents a halogen atom, R′ 2  has the meaning indicated above and A′ has the meaning indicated in  claim 1  for A in which the optional reactive functions are optionally protected, such as in particular A′ does not represent a free carboxy radical, in order to obtain a product of formula (VI):  
       
         
           
           
               
               
           
         
       
       in which n1, n2, R′ 1 , R′ 2  and A′ have the meanings indicated above,  
       which products of formula (IV) and (VI), in order to obtain products of formula (I) or to convert the products of formula (I) into other products of formula (I), can be treated, if desired and if necessary, to one or more or the following reactions, in any order: 
 a saponification reaction of the ester function into an acid function,  
 a conversion reaction of the cyano function into an acid or tetrazolyl function,  
 a conversion reaction of the alkoxy function into the hydroxyl function,  
 an esterification, salification or amidification reaction of the acid function,  
 a reaction which releases the thiol function from the radical  
                     
 an elimination reaction of the protective groups which can be carried by the protected reactive functions,  
 a salification reaction by a mineral or organic acid or base in order to obtain the corresponding salt,  
 said products of formula (I) thus obtained being in all possible racemic, enantiomeric and diastereoisomeric isomer forms.  
 
     
     
         6 ) The following products: 
 [S—R * ,S * )] N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl] amino]-1H-indole-3-propanamide,    2′-cyano-alpha- [[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl] (1,1′-biphenyl)-4-propanoic acid,    (R)N-(1-mercaptomethyl)-2-phenylethyl) -11-phenoxy-undecanamide,    said products being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with pharmaceutically acceptable mineral and organic bases of said products of formula (I).    
     
     
         7 ) The pharmaceutical compositions containing, as active ingredient, at least one of the products as defined in claim  6 .  
     
     
         8 ) Use of the products of formula (IV) and (VI) as defined in  claim 5 , for the preparation of an inhibiting agent of the endothelin-converting enzyme.  
     
     
         9 ) Use of the products of formula (I) aA defined in  claims 1  to  4  and  8  for the preparation of pharmaceutical compositions intended for the treatment, by inhibition of endothelin-converting enzyme, of illnesses such as hypertension induced by endothlin, vascular spasms, the effects of a cerebral haemorrhage, renal insufficiencies, myocardial infarction, cardiac insufficiency, as well as in the prevention of post-angioplasty recurrence or stenosis and cardiac and vascular fibrosis.