Substituted 2, 6-Diamino-3, 5-Dicyano-4-Aryl-Pyridines And Their Use As Adenosine-Receptor-Selective Ligands

Abstract

The present invention relates to substituted 2,6-diamino-3,5-dicyano-4-arylpyridines of the formula (I) wherein the definitions of substituent groups R 1 -R 7 are as provided in the specification and claims, to a pharmaceutical composition containing such a compound, to a process for preparation of such materials, and to their use as medicaments for the treatment of cardiovascular disorders and diabetes.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R 3  represents (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, 
 
 
         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 )aryl 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 thereof. 
       
     
     
         2 . The compound of  claim 1   in which   R 3  represents (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 )-alkyl amino, (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, 
   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 )aryl 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 thereof.   
     
     
         3 . The compound of  claim 1 ,
 in which   R 3  represents 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 ,   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 thereof.   
     
     
         4 . (canceled) 
     
     
         5 . A process for preparing a compound of  claim 1 , comprising:
 reacting a compound of the formula (II)   
       
         
           
           
               
               
           
         
         in which 
         R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 2 , 
         in a solvent with a compound of the formula (III)
   R 6 —NH—R 7   (III)
 
 
         in which 
         R 6  and R 7  are as defined in  claim 1 . 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . A pharmaceutical composition, comprising at least one compound of  claim 1  and at least one pharmacologically acceptable auxiliary. 
     
     
         9 . A method for the prophylaxis and/or treatment of a cardiovascular disorder selected from coronary heart disease, hypertension, restenosis after balloon dilation of peripheral blood vessels, arteriosclerosis, tachycardia, arrhythmias, peripheral vascular disorders and cardiovascular disorders, stable and unstable angina pectoris and atrial fibrillation, myocardial infarction, stroke, and transitory ischemic attacks, comprising administering to a subject in need thereof an effective amount of a compound  claim 1 . 
     
     
         10 . A method for the prophylaxis and/or treatment of diabetes comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .