Arginine mimetics as factor Xa inhibitors

Abstract

The invention relates generally to a novel type of arginine mimetics which are inhibitors of factor X a ; to pharmaceutical compositions which comprise these mimetics; and to the use of these arginine mimetics for producing compositions for antithrombotic therapy.

1 . A process for preparing a compound in accordance with the following structural formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  comprises a linker L 1 , which is directly bonded to the phenylalanine analog and which is selected from a bond, a group R X  having a chain length of from 1 to 10 atoms, —CO—, —CO—NH—, —COO—, —CS—, —CS—NH—, —COS—, —CO—CH 2 —NH— or a natural or unnatural amino acid, and a substituted or unsubstituted, saturated or unsaturated, group R 4 ;  
 R 2  comprises a linker L 2 , which is bonded directly to the phenylalanine analog, and which is selected from —OR 5 —, —NH—R 5 —, —NH—NH—R 5 — or —CH 2 —R 5 -where R 5  can be a substituted or unsubstituted, saturated or unsaturated, carbocyclic, heterocyclic or noncyclic alkyl radical or a group R X , and a substituted or unsubstituted, saturated or unsaturated group R 7 ; and  
 R 3  is a basic substituent at the 3 or 4 position of the aromatic ring of the phenylalanine radical and the aromatic ring is optionally substituted by additional substituents R Y , in particular polar substituents and/or basic substituents and/or basic substituents, with z being=0 to 4, said process comprising:  
 a) adding R 4 —NCO, R 4 —NCS, X—CO—R 4 , X-SO 2 -R 4 , X—CO—NH—R 4  or X—COOR 4  to D- or L-phenylalanine which, at the 3 or 4 position, possesses the basic substituent R 3 , or a precursor of R 3 ;  
 b) optionally converting the precursor of R 3  into the substituent R 3 ; and  
 c) optionally adding YR 5  to the reaction product of step b).  
 
     
     
         2 . The process as claimed in  claim 1 , in which X is ═Cl or active ester.  
     
     
         3 . The process as claimed in  claim 1 , in which X—CO—R 4 , X—SO 2 —R 4 , X—CO—NH—R 4  or X—COOR 4  is added in the form of its respective acid anhydride.  
     
     
         4 . The process as claimed in  claim 1 , in which, if R 3  is an amidino radical, D- or L-(3-or 4-cyano) phenylalanine is used in step a) and, in step b), the cyano group is converted into the amidino radical by adding hydroxylalamine hydrochloride and subsequently performing catalytic hydrogenation.  
     
     
         5 . The process as claimed in  claim 1 , in which Y is OH when R 2 ═OR 5  and HOR 5  is optionally added in the presence of acid or DCC or Y is H 2 N when R 2 ═NHR 5  and H 2 NR 5  is optionally added in the presence of condensing reagents which are customarily used in peptide synthesis.  
     
     
         6 . The use of a compound in accordance with the following structural formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  comprises a linker L 1 , which is directly bonded to the phenylalanine analog and which is selected from a bond, a group R X  having a chain length of from 1 to 10 atoms, —CO—, —CO—NH—, —COO—, —CS—, —CS—NH—, —COS—, —CO—CH 2 —NH— or a natural or unnatural amino acid, and a substituted or unsubstituted, saturated or unsaturated, group R 4 ;  
 R 2  comprises a linker L 2 , which is bonded directly to the phenylalanine analog, and which is selected from —OR 5 —, —NH—R 5 —, —NH—NH—R 5 — or —CH 2 —R 5 -where R 5  can be a substituted or unsubstituted, saturated or unsaturated, carbocyclic, heterocyclic or noncyclic alkyl radical or a group R X , and a substituted or unsubstituted, saturated or unsaturated group R 7 ; and  
 R 3  is a basic substituent at the 3 or 4 position of the aromatic ring of the phenylalanine radical and the aromatic ring is optionally substituted by additional substituents R Y , in particular polar substituents and/or basic substituents and/or basic substituents, with z being =0 to 4, for producing a composition for anticoagulatory therapy.  
 
     
     
         7 . The use of a compound in accordance with the following structural formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  comprises a linker L 1 , which is directly bonded to the phenylalanine analog and which is selected from a bond, a group R X  having a chain length of from 1 to 10 atoms, —CO—, —CO—NH—, —COO—, —CS—, —CS—NH—, —COS—, —CO—CH 2 —NH— or a natural or unnatural amino acid, and a substituted or unsubstituted, saturated or unsaturated, group R 4 ;  
 R 2  comprises a linker L 2 , which is bonded directly to the phenylalanine analog, and which is selected from —OR 5 —, —NH—R 5 —, —NH—NH—R 5 — or —CH 2 —R 5 -where R 5  can be a substituted or unsubstituted, saturated or unsaturated, carbocyclic, heterocyclic or noncyclic alkyl radical or a group R X , and a substituted or unsubstituted, saturated or unsaturated group R 7 ; and  
 R 3  is a basic substituent at the 3 or 4 position of the aromatic ring of the phenylalanine radical and the aromatic ring is optionally substituted by additional substituents R Y , in particular polar substituents and/or basic substituents and/or basic substituents, with z being =0 to 4,  
 for producing an antitumor composition.  
 
     
     
         8 . The use of a compound in accordance with the following structural formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  comprises a linker L 1 , which is directly bonded to the phenylalanine analog and which is selected from a bond, a group R X  having a chain length of from 1 to 10 atoms, —CO—, —CO—NH—, —COO—, —CS—, —CS—NH—, —COS—, —CO—CH 2 —NH— or a natural or unnatural amino acid, and a substituted or unsubstituted, saturated or unsaturated, group R 4 ;  
 R 2  comprises a linker L 2 , which is bonded directly to the phenylalanine analog, and which is selected from —OR 5 —, —NH—R 5 —, —NH—NH—R 5 — or —CH 2 —R 5 -where R 5  can be a substituted or unsubstituted, saturated or unsaturated, carbocyclic, heterocyclic or noncyclic alkyl radical or a group R X , and a substituted or unsubstituted, saturated or unsaturated group R 7 ; and  
 R 3  is a basic substituent at the 3 or 4 position of the aromatic ring of the phenylalanine radical and the aromatic ring is optionally substituted by additional substituents R Y , in particular polar substituents and/or basic substituents and/or basic substituents, with z being =0 to 4, as a diagnostic agent.