2,4-substituted pyrrolidine derivatives-CCR-3 receptor antagonists

Abstract

This invention relates to certain 2,4-substituted pyrrolidine derivatives that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

What is claimed:  
     
         1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, acyl, heteroalkyl, —CONR 3 R 4  (where R 3  and R 4  are independently hydrogen or alkyl), —COOR 5  (where R 5  is hydrogen, alkyl or heteroalkyl), or —SO 2 R 6  where R 6  is alkyl;  
 alk 1  is an alkylene chain of 1 to 6 carbon atoms;  
 X is —NHCO— or —CONH—;  
 Y is an alkylene chain of 1 to 3 carbon atoms or an alkylene chain of 2 or 3 carbon atoms wherein one of the carbon atoms is replaced by a heteroatom selected from the group consisting of —O—, —NR b — [where R b  is hydrogen, alkyl, acyl, —CONR 7 R 8  (where R 7  and R 8  are independently hydrogen or alkyl), —COOR 9  (where R 9  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] and —S(O)n- wherein n is 0 to 2;  
 Ar 1  is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar 2  group, with a group selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;  
 Ar 2  is aryl;  
 alk 2  is an alkylene group of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NR c — [where R c  is hydrogen, alkyl, acyl, —CONR 10 R 11  (where R 10  and R 11  are independently hydrogen or alkyl), —COOR 12  (where R 12  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or —S(O)nl- wherein nl is 0 to 2;  
 Ar 3  is cycloalkyl, aryl or heteroaryl; or  
 a pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound represented by Formula (Ia):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, acyl, heteroalkyl, —CONR 3 R 4  (where R 3  and R 4  are independently hydrogen or alkyl), —COOR 5  (where R 5  is hydrogen, alkyl or heteroalkyl), or —SO 2 R 6  where R 6  is alkyl;  
 alk 1  is an alkylene chain of 1 to 6 carbon atoms;  
 X is —NHCO— or —CONH—;  
 Y is —O—(CH 2 )—, —O—(CH 2 ) 2 —, —O—(CHCH 3 )—, —NR b —(CH 2 )—, —NR b —(CH 2 ) 2 —, —NR b —(CHCH 3 )— [where R b  is hydrogen, alkyl, acyl, —CONR 7 R 8  (where R 7  and R 8  are independently hydrogen or alkyl), —COOR 9  (where R 9  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)], —S(O)n-(CH 2 )—, —S(O)n-(CH 2 ) 2 —, or —S(O)n-(CHCH 3 )— where n is 0 to 2;  
 Ar 1  is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar 2  group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;  
 Ar 2  is aryl;  
 alk 2  is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NR c — [where R c  is hydrogen, alkyl, acyl, —CONR 10 R 11  (where R 10  and R 11  are independently hydrogen or alkyl), —COOR 12  (where R 12  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or —S(O)nl- wherein nl is 0 to 2;  
 Ar 3  is cycloalkyl, aryl or heteroaryl; or  
 a pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 2  wherein R 1  is hydrogen, alkyl, acyl, or —SO 2 R a  where R a  is alkyl.  
     
     
         4 . The compound of  claim 4  wherein R 1  is hydrogen, methyl, acetyl, —COCH 2 CO 2 H, —COCH 2 CO 2 CH 3 , or —CO 2 -tert-butyl.  
     
     
         5 . The compound of  claim 2  wherein Y is —SCH 2 —, —OCH 2 — or —NHCH 2 —.  
     
     
         6 . The compound of  claim 5  wherein X is —CONH—.  
     
     
         7 . The compound of  claim 6  wherein Y is —SCH 2 —.  
     
     
         8 . The compound of  claim 6  wherein Y is —OCH 2 —.  
     
     
         9 . The compound of  claim 8  wherein alk 1  and alk 2  are independently an alkylene chain of 1 or 2 carbon atoms.  
     
     
         10 . The compound of  claim 2  wherein Ar 1  is a heteroaryl group.  
     
     
         11 . The compound of  claim 3  wherein Ar 1  is pyrimidin-2-yl.  
     
     
         12 . The compound of  claim 11  wherein Y is —SCH 2 — or —OCH 2 —.  
     
     
         13 . The compound of  claim 12  wherein Ar 2  is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, or halo.  
     
     
         14 . The compound of  claim 13  wherein Ar 2  is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl.  
     
     
         15 . The compound of  claim 12  wherein alk 2  is —CH 2 — and Ar 3  is aryl.  
     
     
         16 . The compound of  claim 15  wherein Ar 3  is 3,4-dichlorophenyl.  
     
     
         17 . A compound represented by Formula (Ib):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, acyl, heteroalkyl, —CONR 3 R 4  (where R 3  and R 4  are independently hydrogen or alkyl), —COOR 5  (where R 5  is hydrogen, alkyl or heteroalkyl), or —SO 2 R 6  where R 6  is alkyl;  
 alk 1  is an alkylene chain of 1 to 6 carbon atoms;  
 X is —NHCO— or —CONH—;  
 Y is: 
 (i) —(CH 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CHCH 3 )—, —(CHCH 3 )—(CH 2 )—, or —(CH 2 )—(CHCH 3 )—; or  
 (iii) —(CH 2 )—O—, —(CH 2 ) 2 —O—, —(CHCH 3 )—O—, —(CH 2 )—NR b —, —(CH 2 ) 2 —NR b —, or —(CHCH 3 )—NR b — [where R b  is hydrogen, alkyl, acyl, —CONR 7 R 8  (where R 7  and R 8  are independently hydrogen or alkyl), —COOR 9  (where R 9  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] when X is —CONH—;  
 
 Ar 1  is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar 2  group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;  
 Ar 2  is aryl;  
 alk 2  is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NR c — [where R c  is hydrogen, alkyl, acyl, —CONR 10 R 11  (where R 10  and R 11  are independently hydrogen or alkyl), —COOR 12  (where R 12  is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or —S(O)nl- wherein nl is 0 to 2;  
 Ar 3  is cycloalkyl, aryl or heteroaryl; or  
 a pharmaceutically acceptable salts thereof.  
 
     
     
         18 . The compound of  claim 17  wherein Ar 1  is a heteroaryl group and Ar 2  is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, or halo.  
     
     
         19 . The compound of  claim 18  wherein Ar 1  is pyrimidin-2-yl and Ar 2  is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl.  
     
     
         20 . The compound of  claim 19  wherein X is —CONH— and R 1  is —COCH 2 CO 2 H, —COCH 2 CO 2 CH 3 , or —CO 2 -tert-butyl.  
     
     
         21 . The compound of  claim 20  wherein Y and alk 1  are independently methylene or ethylene, alk 2  is methylene and Ar 3  is 3,4-dichlorophenyl.  
     
     
         22 . An intermediate of the Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 11  is hydrogen or alkoxy;  
 R 12  is alkoxy;  
 R 13  is hydrogen or alkyl.  
 
     
     
         23 . The intermediate of  claim 22  wherein R 11  and R 12  are alkoxy.  
     
     
         24 . The intermediate of  claim 22  wherein R 11  and R 12  are methoxy and are at the 3 and 4 position of the phenyl ring.  
     
     
         25 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims  1 - 21  and a pharmaceutically acceptable excipient.  
     
     
         26 . A method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of claims  1 - 21  and a pharmaceutically acceptable excipient.  
     
     
         27 . The method of  claim 26  wherein the disease is asthma.  
     
     
         28 . A process for preparing a compound as claimed in  claim 1 , which process comprises: 
 coupling a compound having a formula  7 ,                          wherein Pro is a protective group, and alk 2  and Ar 3  are as defined in  claim 1;     with a compound of formula  8 :    Ar 1 —Ar 2 —Y—CO 2 H    8     wherein Ar 1 , Ar 2  and Y are as described in  claim 1;     removal of the protecting group to provide a compound of Formula (I)                          wherein R 1  is hydrogen, and Ar 1 , Ar 2 , alk 2  and Ar 3  are as defined in  claim 1;  and    conversion to compounds of Formula (I) wherein R 1  is acyl or sulfonyl with an acid halide of general formula R 1 C(O)Hal or a sulfonyl halide of general formula R 1 SO 2 Hal, wherein Hal is a halo group.    
     
     
         29 . A process for preparing a compound as claimed in  claim 1 , which process comprises 
 reduction of the cyano group of a compound having a formula  10 :                          wherein Pro is a protective group, and alk 2  and Ar 3  are as defined in  claim 1;     coupling with a compound of Formula  8 :    Ar 1 —Ar 2 —Y—CO 2 H    8     wherein Ar 1 , Ar 2  and Y are as described in  claim 1;     removal of the protecting group to provide a compound of Formula (I):                          wherein R 1  is hydrogen, and Ar 1 , Ar 2 , alk 2  and Ar 3  are as defined in  claim 1 , and    conversion to compounds of Formula (I) wherein R 1  is an acyl or sulfonyl group with an acid halide R 1 C(O)Hal or a sulfonyl halide R 1 SO 2 Hal, wherein Hal is a halo group.    
     
     
         30 . A process for preparing a compound as claimed in  claim 1 , which process comprises coupling a compound having a formula  15a  or  15b   
       
         
           
           
               
               
           
         
         wherein R 1  is alkyl, and alk2 and Ar3 are as defined in  claim 1 , with a compound of formula  8   
         Ar 1 —Ar 2 —Y—CO 2 H    8   
         wherein Ar 1 , Ar 2  and Y are as described in  claim 1  to provide a compound of Formula (Ia) or (Ib)  
         
           
             
             
                 
                 
             
           
         
         wherein R 1  is alkyl , Ar 1 , Ar 2 , alk 2  and Ar 3  are as defined in  claim 1 .  
       
     
     
         31 . A process for preparing a compound as claimed in  claim 1 , which process comprises 
 mesylating a compound having a formula  16 ,                          wherein R 1  is alkyl, and alk 2  and Ar 3  are as defined in  claim 1;     converting to a cyanide followed by reduction, and    coupling with a compound of formula  8     Ar 1 —Ar 2 —Y—CO 2 H    8     wherein Ar 1 , Ar 2  and Y are as described in  claim 1 , to provide a compound of Formula (I)                          wherein R 1  is alkyl, and Ar 1 , Ar 2 , alk 2 , Ar 3 , and Y are as described in  claim 1.