Bridged bicyclic amine derivatives useful as CCR-3 receptor antagonists

Abstract

Compounds having the formula (I), Ar—F-(E)-(CR 3 R 4 )—(CHR 5 ) m -(T)-(Q)-Ar 1 , are useful as CCR-3 receptor antagonists, wherein T is a bridged heterocyclyl group having one N atom and a bridge of one to two bridgehead carbon atoms; Ar and Ar 1 are aryl or heteroaryl; F is alkylene, alkenylene, or a bond; E is —C(═O)N(R 10 )—, —SO 2 N(R 10 )—, —N(R 11 )C(═O)N(R 10 O)—, —N(R 11 )SO 2 N(R 10 )—, —N(R 11 )C(═S)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 11 )SO 2 —, —N(R 12 )C(═O)CH(R 13 )—, or CH(R 13 )C(═O)N(R 12 )—; Q is —C(═O)— or C 1-2 alkylene; and R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , and R 13 are defined as set forth in the specification.

1 - 18 . (canceled)  
   
   
       19 . A method of treatment of a disease in a mammal treatable by administration of a CCR-3 antagonist, comprising administering to the mammal a therapeutically effective amount of a compound of the formula  
       Ar—(F)-(E)-(CR 3 R 4 )—(CHR 5 ) m -(T)-(Q)-Ar 1 ,  
     wherein 
 T is  
                     
 where R 6  is taken together with one of R 7  and R 8  to form a bridge of one to two carbon atoms, and the other of R 7  and R 8  is selected from hydrogen and R 9 ;  
 Ar and Ar 1  are, independently of each other, aryl or heteroaryl;  
 F is alkylene, alkenylene, or a bond;  
 E is selected from —C(═O)N(R 10 )—, —SO 2 N(R 10 )—, —N(R 11 )C(═O)N(R 10 )—, —N(R 11 )SO 2 N(R 10 )—, —N(R 11 )C(═S)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 11 )SO 2 —, —N(R 12 )C(═O)CH(R 13 )—, and CH(R 13 )C(═O)N(R 12 )—, where:  
  R 10 , R 11 , R 12 , and R 13  are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(═O)-Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;  
  or alternatively, R 12  and R 13  may be taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form a heterocyclyl or heteroaryl ring optionally substituted with up to two groups selected from R 14 ;  
 R 3  and R 4  are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, -(alkylene)-C(═O)-Z 1 , or -(alkylene)-C(O)Z 1 , where Z 1  is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy,  
 R 5  is hydrogen or alkyl;  
 Q is —C(═O)— or C 1-2 alkylene,  
 R 9  is attached to any available carbon atom of ring T and is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, or a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy;  
 R 14  is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, and a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy;  
 m is 0 or 1 and  
 n is 0 to 4;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       20 . The method of  claim 19 , wherein the disease is asthma.  
   
   
       21 . The method of  claim 19 , wherein: 
 Ar and Ar 1  are both optionally substituted phenyl;    F is a bond;    E is selected from —C(═O)N(R 10 )—, —N(R 11 )C(═O)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 12 )C(═O)CH(R 13 )—, and CH(R 13 )C(═O)N(R 12 )—, where:     R 10 , R 11 , R 12  , and R 13  are, independently of each other, hydrogen or alkyl; or alternatively, R 12  and R 13  may be taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form a heterocyclyl or heteroaryl ring optionally substituted with up to two groups selected from R 14 ;    R 3  and R 4  are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, heteroalkyl, or -(alkylene)-C(═O)-Z 1 , where Z 1  is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;    Q is —CH 2 —;    R 9  and R 14  are independently selected from methyl, ethyl, hydroxy, methoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy; and    n is 0 to 2.    
   
   
       22 . The method of  claim 19 , wherein T is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and R 9  is attached to any available carbon atom of ring T and is selected from lower alkyl and hydroxy, and n is 0 to 2.  
   
   
       23 . The method of  claim 19 , wherein: 
 Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, —COR 15 , —SO 2 R 17 , methylenedioxy, hydroxy, halo, acylamino, amino, mono- or disubstituted amino, —CONR 15 R 16 , -(alkylene)-CONR 15 R 16 , —COOR 15 , -(alkylene)-COOR 15  and —NR 16 SO 2 R 17 ;    R 15  and R 16  are each independently hydrogen or alkyl; and    R 17  is alkyl, amino or mono or disubstituted amino.    
   
   
       24 . The method of  claim 23 , wherein: Ar is selected from phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methylsulfonylphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,4,5-trimethoxyphenyl.  
   
   
       25 . The method of  claim 19 , wherein F is a bond.  
   
   
       26 . The method of  claim 19 , wherein E is —C(═O)N(R 10 )—, —N(R 10 )C(═O)N(R 11 )—, or N(R 12 )C(═O)CH(R 13 )—, where R 10  and R 11  are hydrogen or lower alkyl, and R 12  and R 13  are taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form  
     
       
         
         
             
             
         
       
     
     where R 18  and R 19  are selected from hydrogen and lower alkyl.  
   
   
       27 . The method of  claim 26 , wherein E is  
     
       
         
         
             
             
         
       
     
     and m is 0.  
   
   
       28 . The method of  claim 19 , wherein: 
 R 3  is hydrogen; and    R 4  is hydrogen, methyl, ethyl, 1-methylethyl, isopropyl, 1-hydroxyethyl or 2-hydroxyethyl.    
   
   
       29 . The method of  claim 19 , wherein R 3  is hydrogen; and R 4  is 1-methylethyl.  
   
   
       30 . The method of  claim 19 , wherein T is  
     
       
         
         
             
             
         
       
     
   
   
       31 . The method of  claim 19 , wherein Q is —CH 2 —.  
   
   
       32 . The method of  claim 19 , wherein: 
 Ar 1  is a phenyl ring optionally substituted with one, two or three substituent selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- or disubstituted amino.    
   
   
       33 . The method of  claim 19 , wherein Ar 1  is 4-chlorophenyl or 3,4-dichlorophenyl.