Chemokine receptor antagonists and methods of use therefor

Abstract

Disclosed is a method of treating a subject with a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to the subject a therapeutically effective amount of a compound represented by the following structural formula: and physiologically acceptable salts thereof. Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to one or more carbocyclic aromatic rings and/or heteroaromatic rings, wherein each ring in Z is independently substituted or unsubstituted; Y is a covalent bond, —O— or —CO—; n is an integer from one to about five; X is a covalent bond or —CO—; and M is >NR 2 , >CR 1 R 2 ; R 1 is —H, —OH, an aliphatic group, —O—(aliphatic group), —SH or —S—(aliphatic group); R 2 is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group, a substituted benzylic group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

What is claimed:  
     
         1 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
         and physiologically acceptable salts thereof, wherein: 
 Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to one or more carbo cyclic aromatic rings and/or heteroaromatic rings, wherein each ring in Z is independently substituted or unsubstituted;  
 Y is a covalent bond, —O— or —CO—;  
 n is-an integer from one to about five;  
 X is a covalent bond or —CO—; and  
 M is >NR 2  or >CR 1 R 2 ;  
 R 1  is —H, —OH, an aliphatic group, —O—(aliphatic group), —SH or —S—(aliphatic group);  
 R 2  is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group, a substituted benzylic group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.  
 
       
     
     
         2 . The method of  claim 1  wherein X and Y are each a covalent bond.  
     
     
         3 . The method of  claim 2  wherein Z is represented by the following structural formula:  
       
         
           
           
               
               
           
         
         wherein: 
 Ring A and Ring B are independently substituted or unsubstituted; and  
 Ring C is a substituted or unsubstituted C 7  Or C 8  nonarmatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring connected by a single covalent bond to the group represented by the following structural formula:  
                     
 
       
     
     
         4 . The method of  claim 3  wherein Z is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein: 
 X 1  is a chemical bond, —S—, —CH 2 — or —CH 2 S—; and  
 W is —H or an electron withdrawing group.  
 
       
     
     
         5 . The method of  claim 4  wherein Z is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5  wherein W is —H or —CN.  
     
     
         7 . The method of  claim 6  wherein R 1  is —OH.  
     
     
         8 . The method of  claim 7  wherein M is >C(OH)R 2  and n is three.  
     
     
         9 . The method of  claim 8  wherein R 2  is a substituted or unsubstituted aromatic group.  
     
     
         10 . The method of  claim 1  wherein X is a covalent bond and Y is —CO—.  
     
     
         11 . The method of  claim 2  wherein: 
 Z is represented by a structural formula selected from:  
                     
 wherein: 
 X 1  is a chemical bond, —S—, —CH 2 — or —CH 2 S—;  
 W is —H, —CN, alkylsulfonyl, carboxamido or carboxyalkyl;  
 n is an integer from 2-5;  
 Ring A is substituted with R 8  and R 9 , wherein R 8  and R 9  are independently —H, a halogen, alkoxy or alkyl, or, taken together with ring A, form a naphthyl group;  
 M is >N(alkanoyl), >N(aroyl), >N(aralkoyl), >N(alkyl), >N(aralkyl), >N(cycloalkyl), >C(OH) (aryl) or >CH(heteroaryl).  
 
 
     
     
         12 . The method of  claim 1  wherein the compound is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 2  wherein Z is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein Rings A, B and C are independently substituted or unsubstituted.  
       
     
     
         14 . A compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
         and physiologically acceptable salts thereof, wherein: 
 Z is one or more heteroaromatic rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, wherein each ring in Z is independently substituted or unsubstituted;  
 n is an integer from one to about five;  
 M is >NR 2  or >CR 1 R 2 ;  
 R 1  is —H, —OH, an aliphatic group, —O—(aliphatic group), —SH or —S—(aliphatic group);  
 R 2  is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group, a substituted benzylic group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.  
 
       
     
     
         15 . A compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       and physiologically acceptable salts thereof, wherein: 
 M is >NR 2  or >CR 1 R 2 ;  
 R 1  is —H, —OH, an aliphatic group, —O—(aliphatic group), —SH or —S—(aliphatic group);  
 R 2  is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group, a substituted benzylic group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;  
 n is an integer from one to about five;  
 Z is represented by the following structural formula:  
                     
 W is an electron withdrawing group; and  
 at least one of Ring A or Ring B is substituted.  
 
     
     
         16 . The compound of  claim 15  wherein W is —CN.  
     
     
         17 . The compound of  claim 16  wherein R 1  is —OH.  
     
     
         18 . The compound of  claim 17  wherein M is >C(OH)R 2  and n is three.  
     
     
         19 . The compound of  claim 18  wherein R 2  is a substituted or unsubstituted aromatic group.  
     
     
         20 . The compound of  claim 15  wherein: 
 W is —H, —CN, alkylsulfonyl, carboxamido or carboxyalkyl;  
 n is an integer from 2-5;  
 Ring A is substituted with R 8  and R 9 , wherein R 8  and R 9  are independently a halogen, alkoxy or alkyl, or, taken together with ring A, form a naphthyl group; and  
 M is >N(alkanoyl), >N(aroyl), >N(aralkoyl), >N(alkyl), >N(aralkyl), >N(cycloalkyl), >C(OH)(aryl) or >CH(heteroaryl).