C5ar antagonists

Abstract

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of C5a receptors.

1 .- 14 . (canceled) 
     
     
         15 . The method of  claim 40 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 .- 31 . (canceled) 
     
     
         32 . A method for treating a mammal suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal an effective amount of a compound 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 each R 1  is independently selected from the group consisting of halogen, —CN, —R c , —NR a R b  and —OR a , and wherein each R a  and R b  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl, and wherein the aliphatic and cyclic portions of R a , R b  and R c  are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R 1  substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; 
 R 2  is a member selected from the group consisting of H and F; 
 p is 1; and 
 R 3  is X 4 R j , wherein X 4  is C 1-3  alkylene, and R j  is pyrrolidinyl substituted with CF 3 . 
 
     
     
         33 - 39 . (canceled) 
     
     
         40 . A method of assaying a compound for C5a-receptor (C5aR) antagonistic activity, said method comprising
 (a) contacting the compound with cells expressing C5aR and a radiolabeled C5a to form a reaction mixture;   (b) aspirating the reaction mixture onto a GF/B glass filter pre-soaked in a polyethyleneimine solution;   (c) measuring the amount radioactivity remaining on the GF/B glass filter,
 wherein said method comprises performing steps (a)-(c) with a positive control sample having the formula 
   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 each R 1  is independently selected from the group consisting of halogen, —CN, —R c , —NR a R b  and —OR a , and wherein each R a  and R b  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl, and wherein the aliphatic and cyclic portions of R a , R b  and R c  are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R 1  substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; 
 R 2  is a member selected from the group consisting of H and F; 
 p is 1; and 
 R 3  is X 4 R′, wherein X 4  is C 1-3  alkylene, and R j  is pyrrolidinyl substituted with CF 3 . 
 
     
     
         41 . The method of  claim 40 , wherein said cells expressing C5aR are 2 U937 cells or isolated human neutrophils. 
     
     
         42 . The method of  claim 40 , wherein said radiolabeled C5a is  125 I labeled C5a. 
     
     
         43 . The method of  claim 40 , wherein said reaction mixture comprises an assay buffer comprising 20 mM HEPES, 140 mM NaCl, 1 mM CaCl 2 , 5 mM MgCl 2 , pH 7.1. 
     
     
         44 . The method of  claim 40 , wherein said measuring comprises adding scintillation fluid to the aspirated GF/C glass filter. 
     
     
         45 . The method of  claim 40 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . The method of  claim 40 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.