Compounds and methods for modulating CXCR3 function

Abstract

Compounds and compositions are provided that bind to the CXCR3 chemokine receptor and which are useful for treating diseases associated with CXCR3 activity, such as multiple sclerosis.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 the subscript n is an integer of from 0 to 4;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
 R 1  is a member selected from the group consisting of substituted or unsubstituted (C 5 -C 15 )alkyl;  
 R 2  is a member selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl;  
 each R 3  is an aryl substituent;  
 X is a member selected from the group consisting of CH and N;  
 Y is a member selected from the group consisting of substituted or unsubstituted (C 2 -C 8 )alkylene and substituted or unsubstituted (C 2 -C 8 )heteroalkylene; and  
 Z is —NR 4 R 5 , 
 wherein R 4  and R 5  are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
 
   
   
       2 . A compound in accordance with  claim 1 , wherein X is N.  
   
   
       3 . A compound in accordance with  claim 1 , wherein X is N, and Ar is substituted phenyl.  
   
   
       4 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, and R 1  is a (C 8 -C 14 )acyl group.  
   
   
       5 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, and R 2  is unsubstituted (C 1 -C 4 )alkyl.  
   
   
       6 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, and Y is (C 2 -C 5 )alkylene.  
   
   
       7 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, Y is (C 2 -C 5 )alkylene, and Z is dimethylamino.  
   
   
       8 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, Y is (C 2 -C 5 )alkylene, Z is dimethylamino, and n is 0.  
   
   
       9 . A compound in accordance with  claim 1 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is methyl, Y is ethylene, Z is dimethylamino, and n is 0.  
   
   
       10 . A compound in accordance with  claim 9 , wherein said substituted phenyl is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, and 4-bromophenyl.  
   
   
       11 . A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 the subscript n is an integer of from 0 to 4;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
 R 1  is a member selected from the group consisting of substituted or unsubstituted (C 5 -C 15 )alkyl;  
 R 2  is a member selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl;  
 each R 3  is an aryl substituent;  
 X is a member selected from the group consisting of CH and N;  
 Y is a member selected from the group consisting of substituted or unsubstituted (C 2 -C 8 )alkylene and substituted or unsubstituted (C 2 -C 8 )heteroalkylene; and  
 Z is —NR 4 R 5 , 
 wherein R 4  and R 5  are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
 
   
   
       12 . A composition in accordance with  claim 11 , wherein X is N.  
   
   
       13 . A composition in accordance with  claim 11 , wherein X is N, and Ar is substituted phenyl.  
   
   
       14 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, and R 1  is a (C 8 -C 14 )acyl group.  
   
   
       15 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, and R 2  is unsubstituted (C 1 -C 4 )alkyl.  
   
   
       16 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, and Y is (C 2 -C 5 )alkylene.  
   
   
       17 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, Y is (C 2 -C 5 )alkylene, and Z is dimethylamino.  
   
   
       18 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is unsubstituted (C 1 -C 4 )alkyl, Y is (C 2 -C 5 )alkylene, Z is dimethylamino, and n is 0.  
   
   
       19 . A composition in accordance with  claim 11 , wherein X is N, Ar is substituted phenyl, R 1  is a (C 8 -C 14 )acyl group, R 2  is methyl, Y is ethylene, Z is dimethylamino, and n is 0.  
   
   
       20 . A composition in accordance with  claim 19 , wherein said substituted phenyl is selected from the group consisting of 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, and 4-bromophenyl.  
   
   
       21 . A method of modulating CXCR3 function, said method comprising contacting a CXCR3 protein or truncated form thereof with a CXCR3-modulating amount of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 the subscript n is an integer of from 0 to 4;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
 R 1  is a member selected from the group consisting of substituted or unsubstituted (C 5 -C 15 )alkyl;  
 R 2  is a member selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl;  
 each R 3  is an aryl substituent;  
 X is a member selected from the group consisting of CH and N;  
 Y is a member selected from the group consisting of substituted or unsubstituted (C 2 -C 8 )alkylene and substituted or unsubstituted (C 2 -C 8 )heteroalkylene; and  
 Z is —NR 4 R 5 , 
 wherein R 4  and R 5  are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.  
 
 
   
   
       22 . A method of treating a CXCR3-mediated condition or disease in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 the subscript n is an integer of from 0 to 4;  
 Ar is a member selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;  
 R 1  is a member selected from the group consisting of substituted or unsubstituted (C 5 -C 15 )alkyl;  
 R is a member selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl;  
 each R 3  is an aryl substituent;  
 X is a member selected from the group consisting of CH and N;  
 Y is a member selected from the group consisting of substituted or unsubstituted (C 2 -C 8 )alkylene and substituted or unsubstituted (C 2 -C 8 )heteroalkylene; and  
 Z is —NR 4 R 5 , 
 wherein R 4  and R 5  are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl.  
 
 
   
   
       23 . A method in accordance with  claim 22 , wherein said CXCR3-mediated condition or disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis, cancer and HIV infection.  
   
   
       24 . A method in accordance with  claim 22 , wherein said CXCR3-mediated condition or disease is multiple sclerosis.  
   
   
       25 . A method in accordance with  claim 22 , wherein said administration is oral or intravenous.  
   
   
       26 . A method in accordance with  claim 22 , wherein said subject is selected from the group consisting of human, rat, dog, cow, horse, and mouse.  
   
   
       27 . A method in accordance with  claim 22 , wherein said subject is human.  
   
   
       28 . A method in accordance with  claim 22 , wherein n is 0, Ar is substituted phenyl, R 1  is unsubstituted (CS—C 15 )acyl, R 2  is unsubstituted (C 1 -C 4 )alkyl, X is N, Y is unsubstituted (C 2 -C 4 )alkylene, and Z is selected from the group consisting of methylamino, dimethylamino, ethylamino and diethylamino.  
   
   
       29 . A method in accordance with  claim 22 , wherein said CXCR3-mediated disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis, cancer and HIV infection; n is 0, Ar is substituted phenyl, R 1  is unsubstituted (C 5 -C 15 )acyl, R 2  is unsubstituted (C 1 -C 4 )alkyl, X is N, Y is unsubstituted (C 2 -C 4 )alkylene, and Z is selected from the group consisting of methylamino, dimethylamino, ethylamino and diethylamino.