Substituted 2,6-diamino-3,5-dicyano-4-aryl-pyridines and their use as adenosine receptor-selective ligands

Abstract

The invention relates to the use of compounds of formula (I) as medicaments, to the novel compounds of formula (I) themselves, and to a method for the production thereof.

1 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1 , R 2  and R 3  independently of one another are (C 1 -C 8 )-alkyl which may be substituted up to three times, independently of one another, by halogen, cyano, hydroxyl, amino, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )-alkynyl, —O—C(O)—R 8 , (C 6 -C 10 )-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S or (C 6 -C 10 )-aryloxy, 
 (C 6 -C 10 )-aryl which may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 )-alkoxy, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 8 )-alkoxy which may be substituted up to three times, independently of one another, by halogen, cyano, hydroxyl, amino, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, —O—C(O)—R 8 , (C 6 -C 10 )-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S or (C 6 -C 10 )-aryloxy,  
 hydrogen, hydroxyl, halogen, nitro, cyano or —NH—C(O)—R 9 ,  
 in which  
 R 8  and R 9  independently of one another represent (C 1 -C 8 )-alkyl which may be substituted by hydroxyl or (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl or (C 6 -C 10 )-aryl which for its part may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 )-alkoxy, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or mono- or di-(C 1 -C 4 )-alkylamino, or  
 
 R 1  and R 2  are attached to adjacent phenyl ring atoms and together with the two ring carbon atoms form a 5- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms from the group consisting of N, O and/or S, which heterocycle may be substituted by (C 1 -C 4 )-alkyl or oxo,  
 R 4  represents hydrogen, (C 1 -C 8 )-alkyl which may be substituted up to three times, independently of one another, by hydroxyl, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- to 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S, or (C 3 -C 8 )-cycloalkyl which for its part may be substituted by hydroxyl or (C 1 -C 6 )-alkyl,  
 R 5  represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or (C 3 -C 7 )-cycloalkyl, or  
 R 4  and R 5  together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated or partially unsaturated heterocycle which may contain one or two further heteroatoms from the group consisting of N, O and/or S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy,  
 R 6  represents (C 3 -C 7 )-cycloalkyl or (C 1 -C 8 )-alkyl, where alkyl may be substituted by (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, (C 6 -C 10 )-alkyl or 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S, where aryl and heteroaryl for their part may be substituted by halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, amino, mono- or di-(C 1 -C 4 )-alkylamino, nitro, cyano or hydroxyl, and  
 R 7  represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or (C 3 -C 7 )-cycloalkyl, or  
 R 6  and R 7  together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated or partially unsaturated heterocycle which may contain one or two further heteroatoms from the group consisting of N, O and/or S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy,  
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof  
 for the prophylaxis and/or treatment of disorders.  
 
     
     
         2 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1 , R 2  and R 3  independently of one another are (C 1 -C 8 )-alkyl which may be substituted up to three times, independently of one another, by halogen, cyano, hydroxyl, amino, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, —O—C(O)—R 8 , (C 6 -C 10 )-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S or (C 6 -C 10 )-aryloxy, 
 (C 6 -C 10 )-aryl which may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 )-alkoxy, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 8 )-alkoxy which may be substituted up to three times, independently of one another, by halogen, cyano, hydroxyl, amino, mono- or di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 3 -C 7 )-cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, —O—C(O)—R 8 , (C 6 -C 10 )-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S or (C 6 -C 10 )-aryloxy,  
 hydrogen, hydroxyl, halogen, nitro, cyano or —NH—C(O)—R 9 ,  
 in which  
 R 8  and R 9  independently of one another represent (C 1 -C 8 )-alkyl which may be substituted by hydroxyl or (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl or (C 6 -C 10 )-aryl which for its part may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 )-alkoxy, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or mono- or di-(C 1 -C 4 )-alkylamino, or  
 
 R 1  and R 2  are attached to adjacent phenyl ring atoms and together with the two ring carbon atoms form a 5- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms from the group consisting of N, O and/or S, which heterocycle may be substituted by (C 1 -C 4 )-alkyl or oxo,  
 R 4  represents hydrogen, (C 1 -C 8 )-alkyl which may be substituted up to three times, independently of one another, by hydroxyl, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 6 -C 10 )-aryl or 5- to 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S, or (C 3 -C 8 )-cycloalkyl which for its part may be substituted by hydroxyl or (C 1 -C 6 )-alkyl,  
 R 5  represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or (C 3 -C 7 )-cycloalkyl, or  
 R 4  and R 5  together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated or partially unsaturated heterocycle which may contain one or two further heteroatoms from the group consisting of N, O and/or S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy,  
 R 6  represents (C 3 -C 7 )-cycloalkyl or (C 1 -C 8 )-alkyl, where alkyl may be substituted by (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, (C 6 -C 10 )-alkyl or 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and/or S, where aryl and heteroaryl for their part may be substituted by halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, amino, mono- or di-(C 1 -C 4 )-alkylamino, nitro, cyano or hydroxyl, and  
 R 7  represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or (C 3 -C 7 )-cycloalkyl, or  
 R 6  and R 7  together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated or partially unsaturated heterocycle which may contain one or two further heteroatoms from the group consisting of N, O and/or S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy,  
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof,  
 except for the following compounds of the formula (I) in which the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined below:  
 R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =2-hydroxyethyl  
 R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =benzyl  
 R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =n-butyl  
 
     
     
         3 . A compound as claimed in  claim 2 , 
 in which    R 1 , R 2  and R 3  independently of one another are hydrogen, hydroxyl, (C 1 -C 6 )-alkyl, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, nitro, (C 1 -C 4 )-alkoxy which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, —O—C(O)—CH 3 , —O—C(O)—C 2 H 5 , (C 3 -C 7 )-cycloalkyl or (C 2 -C 4 )-alkenyl, —NH—C(O)—CH 3  or —NH—C(O)—C 2 H 5 , or    R 1  and R 2  are attached to adjacent phenyl ring atoms and represent a group —O—CH 2 —O— or —O—CH 2 —CH 2 —O—,    R 4  represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by phenyl, pyridyl, (C 1 -C 4 )-alkoxy or mono- or disubstituted by hydroxyl,    R 5  represents hydrogen,    R 6  represents (C 3 -C 7 )-cycloalkyl or (C 1 -C 6 )-alkyl which may be substituted up to two times, independently of one another, by hydroxyl, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, phenyl or 5- or 6-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and/or S, where phenyl and heteroaryl for their part may be substituted by fluorine, chlorine, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, amino, mono- or di-(C 1 -C 4 )-alkylamino, nitro, cyano or hydroxyl, and    R 7  represents hydrogen    or a salt, a hydrate, a hydrate of a salt or a solvate thereof,    except for the following compounds of the formula (I) in which the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined below:    R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =2-hydroxyethyl    R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =benzyl    R 1 =R 2 =R 3 =R 5 =R 7 =H; R 4 =R 6 =n-butyl    
     
     
         4 . A compound as claimed in  claim 2  or  3 ,  
       in which 
 R 1  represents hydrogen, hydroxyl, chlorine, nitro, methyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or —NH—C(O)—CH 3 , where the alkoxy radicals for their part may be substituted by hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, —O—C(O)—CH 3  or cyclopropyl,  
 R 2  and R 3  represent hydrogen,  
 R 4  represents hydrogen, methyl, ethyl, n-propyl or isopropyl, where the alkyl radicals for their part may be substituted by pyridyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or mono- or disubstituted by hydroxyl,  
 R 5  represents hydrogen,  
 R 6  represents methyl, ethyl n-propyl, isopropyl, where the alkyl radicals for their part may be mono- or disubstituted, independently of one another, by cyclopropyl, phenyl which for its part may be substituted by fluorine, trifluoromethyl or methoxy, pyridyl, furyl, thienyl, benzimidazolyl, pyrrolidinonyl, N-methylpyrrolidinonyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-methylimidazolidinonyl, or cyclopropyl and  
 R 7  represents hydrogen  
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof.  
 
     
     
         5 . A process for preparing compounds of the formula (I) as defined in  claim 1 , characterized in that 
 compounds of the formula (II)                          in which    R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 2 ,    are reacted in a solvent with compounds of the formula (III)    R 6 —NH—R 7   (III)    in which    R 6  and R 7  are as defined in  claim 2 .    
     
     
         6 . A compound of the formula (I) as defined in  claim 3  for the prophylaxis and/or treatment of disorders.  
     
     
         7 . A compound of the formula (I) as defined in  claim 4  for the prophylaxis and/or treatment of disorders.  
     
     
         8 . A composition, comprising at least one compounds of the formula (1) as defined in  claim 1  and at least one further auxiliary.  
     
     
         9 . The use of compounds of the formula (I) as defined in  claim 1  for preparing medicaments for the prophylaxis and/or treatment of disorders of the cardiovascular system (cardiovascular disorders).  
     
     
         10 . The use of compounds of the formula (I) as defined in  claim 1  for preparing medicaments for the prophylaxis and/or treatment of diabetes.