Imidazoline receptor binding compounds

Abstract

Pentamidine and analogs thereof have activity as imidazoline receptor binding compounds. A method of binding the imidazoline receptor, comprises contacting a bis-benzene to said imidazoline receptor in an amount effective to bind to said receptor, wherein said bis-benzene contains at least one amidine group (e.g., one or two). The contacting step may be carried out in vivo or in vitro. Contacting may be carried out with individual active compounds or with libraries of active compounds.

We claim:  
     
         1 . A method of binding the imidazoline receptor, comprising: 
 contacting a bis-benzene to said imidazoline receptor in an amount effective to bind to said receptor, wherein said bis-benzene contains at least one amidine group.    
     
     
         2 . A method according to  claim 1 , wherein said contacting step is carried out in vitro.  
     
     
         3 . A method according to  claim 1 , wherein said contacting step is carried out in vitro with cells that express said imidazoline receptor.  
     
     
         4 . A method according to  claim 1 , wherein said contacting step is carried out in vitro with a cell-free preparation comprising said imidazoline receptor.  
     
     
         5 . A method according to  claim 1 , wherein said contacting step is carried out in vivo.  
     
     
         6 . A method according to  claim 1 , wherein said contacting step is carried out in vivo by administering said compound to a subject afflicted with a disease state which is alleviable by treatment with a compound having high selectivity and affinity for the imidazoline receptor site.  
     
     
         7 . A method according to  claim 1 , wherein said bis-benzene has the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and compounds of formula (i):  
                     
 subject to the proviso that at least one of A and B is a compound of formula (i);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cyloalkyl, aryl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl; or two R 1  group on the same amidine group together represent —(CH 2 )m- wherein m is 2, 3, or 4;  
 R 3  is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;  
 n is from 2 to 6; and  
 X is O, NH, or S;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         8 . A method according to  claim 7 , wherein R 1 , R 2  and R 3  are H; wherein X is O; and wherein n is 5.  
     
     
         9 . A method according to  claim 1 , wherein said bis-benzene has the formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and compounds of formula (i):  
                     
 subject to the proviso that at least one of A and B is a compound of formula (i);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cyloalkyl, aryl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl; or two RI group on the same amidine group together represent —(CH 2 )m- wherein m is 2, 3, or 4;  
 R 3  is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;  
 X is linear or branched, saturated or unsaturated C1-C12 alkyl containing up to 4 double bonds; or X is a heterocyclic aromatic group selected from the group consisting of:  
                     
 wherein  
 R 6 , R 7 , and R 8  are each independently selected from the group consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, or oxyarylalkyl;  
 R 9  is hydrogen, loweralkyl, hydroxy, aminoalkyl or alkylaminoalkyl;  
 or the pharmaceutically acceptable salts thereof.  
 
     
     
         10 . A method according to  claim 1 , wherein said bis-benzene has the formula III:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and substituents of formula (i):  
                     
 subject to the proviso that at least one of A and B is a substituent of formula (i);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cyloalkyl, aryl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl; or two R 1  groups on the same amidine group together represent —(CH 2 )m- wherein m is 2, 3, or 4;  
 R 3  is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;  
 or two R 1  groups on the same amidine group together represent  
                     
 wherein R 5  is  
                     
 n is an integer from 0 to 2; and  
 A is a heterocyclic aromatic group selected from the group consisting of:  
                     
 wherein  
 R 6 , R 7 , and R 8  are each independently selected from the group consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, or oxyarylalkyl;  
 R 9  is hydrogen, loweralkyl, hydroxy, aminoalkyl or alkylaminoalkyl;  
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         11 . A method according to  claim 1 , wherein said bis-benzamidine has the formula IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and substituents of formula (i):  
                     
 subject to the proviso that at least one of A and B is a substituent of formula (i);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cyloalkyl, aryl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl; or two R 1  group on the same amidine group together represent —(CH 2 )m—wherein m is 2, 3, or 4;  
 R 3  is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;  
 or two R 1  groups on the same amidine group together represent  
                     
 wherein R 5  is  
                     
 and the pharmaceutically acceptable salts thereof.  
 
     
     
         12 . A method according to  claim 1 , said bis-benzene having the formula (V): B  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and substituents of formula (ii):  
                     
 subject to the proviso that at least one of A and B is a substituent of formula (ii);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, aryl, alkylaryl, aminoalkyl, aminoaryl, halogen, oxyalkyl, oxyaryl, or oxyarylalkyl;  
 R 3  and R 4  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkylaryl, aryl, oxyaryl, aminoalkyl, aminoaryl, or halogen; and  
 each R 5  is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl or two R 5  groups together represent C 2  to C 10  alkyl, hydroxyalkyl, or alkylene; and  
 R 6  is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, or alkylaryl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         13 . A method according to  claim 1 , wherein said bis-benzene has the formula VI:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, nitro, amino, aminoalkyl, halo, hydroxy, carboxy, and substituents of formula (i):  
                     
 subject to the proviso that at least one of A and B is a substituent of formula (i);  
 R 1  and R 2  are each independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cyloalkyl, aryl, hydroxyalkyl, aminoalkyl and alkylaminoalkyl; or two R 1  group on the same amidine group together represent —(CH 2 )m- wherein m is 2, 3, or 4;  
 R 3  is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, aryl, aminoalkyl, alkylaminoalkyl or halogen;  
 or two R 1  groups on the same amidine group together represent  
                     
 wherein R 5  is  
                     
 X is O, S or NH;  
 n is an integer from 1 to 8;  
 and the pharmaceutically acceptable salts thereof  
 
     
     
         14 . A method of identifying imidazoline receptor binding agents, comprising the steps of: 
 providing a library of bis-benzene compounds, said bis-benzene compound containing at least one amidine group; and    screening said library for compounds that bind to said imidazoline receptor.    
     
     
         15 . A method according to  claim 14 , wherein said library is a combinatorial library.  
     
     
         16 . A method according to  claim 14 , wherein said bis-benzene compounds are immobilized on a solid support.