CCR-3 receptor antagonists

Abstract

The invention provides compounds of Formula (I): wherein R 1 -R 4 have any of the values defined in the specification that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use, and methods and intermediates useful for preparing them.

1 . A compound of Formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is hydrogen or alkyl;  
 R 2  is arylalkyl;  
 R 3  is hydrogen, alkyl, acyl, aryl, or arylalkyl;  
 R 4  is -W-X-Y-Z;  
 W is absent;  
 X is —N(R a )—;  
 Y is arylene; and  
 Z is hydrogen;  
 R a  is hydrogen, alkyl, acyl, aryl, arylalkyl, alkoxycarbonyl, or benzyloxycarbonyl; and  
 each n is 0, 1, or 2;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The compound of  claim 1  wherein R 1  is hydrogen.  
   
   
       3 . The compound of  claim 2  wherein R 2  is phenylalkyl, wherein the phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halo, cyano, nitro, alkoxy, haloalkoxy, hydroxy, amino, acylamino, alkylamino, and dialkylamino.  
   
   
       4 . The compound of  claim 3  wherein R 2  is phenylalkyl, wherein the phenyl is substituted with one, two or three halo substituents.  
   
   
       5 . The compound of  claim 4  wherein R 2  is phenylalkyl, wherein the phenyl is substituted with one halo substituent.  
   
   
       6 . The compound of  claim 5  wherein R 2  is (4-chlorophenyl)alkyl.  
   
   
       7 . The compound of  claim 6  wherein R 2  is 2-(4-chlorophenyl)ethyl, or 3-(4-chlorophenyl)propyl.  
   
   
       8 . The compound of  claim 1  wherein R 3  is hydrogen or methyl.  
   
   
       9 - 17 . (canceled)  
   
   
       18 . The compound of  claim 8  wherein X is —NH—.  
   
   
       19 . (canceled)  
   
   
       20 . The compound of  claim 19 , wherein Y-Z is 3,4,5-trimethoxyphenyl.  
   
   
       21 . The compound of  claim 1  wherein -Y-Z is 4-methylsulfonylphenyl or 3,4,5-trimethoxyphenyl. a 
   
   
       22 - 23 . (canceled)  
   
   
       24 . The compound 
 (±)-trans-1-{2-[3-(4-chlorophenyl)propylamino]-cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea;    (±)-trans-1-(2-{[3-(4-chlorophenyl)propyl]methylamino}-cyclopentyl)-3-(3,4,5-trimethoxyphenyl)urea;    (±)-trans-1-(2-{[2-(4-chlorophenyl)ethyl]-methylamino}-cyclopentyl)-3-(3,4,5-trimethoxyphenyl)urea; or    (±)-trans-1-{2-[2-(4-chlorophenyl)ethylamino]cyclopentyl}-3-(3,4,5-trimethoxyphenyl)urea; 
 or a pharmaceutically acceptable salt thereof.  
   
   
   
       25 . A composition containing a therapeutically effective amount of a compound of Formula (I) as described in  claim 1 , or a salt thereof; and an excipient.  
   
   
       26 . A method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) as described in  claim 1 , or a salt thereof.  
   
   
       27 . The method of  claim 25  wherein the disease is asthma.  
   
   
       28 - 29 . (canceled)  
   
   
       30 . A method for preparing a compound of Formula (I) as described in  claim 1 , wherein R 1  is hydrogen, comprising deprotecting a corresponding compound of Formula (III):  
     
       
         
         
             
             
         
       
     
     wherein Pg is a nitrogen protecting group.  
   
   
       31 - 32 . (canceled)