Mercaptoimidazoles as ccr2 receptor antagonists

Abstract

The present invention relates to a compound of formula (I) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R 1 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxyC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, aryl or heteroaryl; each R 2 independently represents halo, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, cyano, aminocarbonyl, amino, mono- or di(C 1-4 alkyl)amino, nitro, aryl or aryloxy; R 3 represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b or C(═O)—R 8 ; R 4 represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b or C(═O)—R 8 ; or R 3 and R 4 taken together may form a bivalent radical of formula —C(═O)—NH—NH—C(═O)—; n is 1, 2, 3, 4 or 5; provided that at least one of R 3 or R 4 is other than hydrogen; and that if R 3 represents C(═O)—OH, C(═O)—O—C 1-6 alkyl or C(═O)—O—C 2-6 alkenyl, then R 4 is other than hydrogen; and that if R 3 represents CH 2 OH and R 1 and R 5 represents hydrogen, then R 4 is other than hydrogen; and that if R 3 represents C(═O)—NH—C 1-4 alkyl-NH 2 and R 1 and R 5 represents hydrogen, then R 4 is other than hydrogen; and that if R 3 represents and R 1 and R 5 represents hydrogen, then R 4 is other than hydrogen having CCR2 receptor antagonistic properties. The invention also relates to processes for preparing the compounds of formula (1) and pharmaceutical compositions comprising them.

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       11 . The method for treating diseases mediated through activation of the CCR2 receptor comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
 R 1  represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxyC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, aryl or heteroaryl; 
 each R 2  independently represents halo, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, cyano, aminocarbonyl, amino, mono- or di(C 1-4 alkyl)amino, nitro, aryl or aryloxy; 
 R 3  represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b  or C(═O)—R 5 ; 
 R 4  represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b  or C(═O)—R 8 ; 
 or R 3  and R 4  taken together may form a bivalent radical of formula —C(═O)—NH—NH—C(═O)—; 
 R 6  represents hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, mono- or di(C 1-4 alkyl)aminocarbonylC 1-6 alkyl, aryl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl; wherein pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl may optionally be substituted with C 1-4 alkyl; 
 R 7a  and R 7b  each independently represent hydrogen, C 1-6 alkyl, amino, mono- or di(C 1-4 alkyl)amino, arylNH—, aminoC 1-6 alkyl, mono- or di(C 1-4 alkyl)amino C 1-6 alkyl, C 1-6 alkylcarbonylamino, aminocarbonylamino, C 1-6 alkyloxy, —NH—C(O)—H or hydroxyC 1-6 alkyl; or 
 R 7a  and R 7b  taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or piperazinyl substituted with C 1-6 alkyl; 
 R 8  represents hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, polyhaloC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, mono- or di(C 1-4 alkyl)aminocarbonylC 1-6 alkyl or aryl; 
 R 5  represents hydrogen or C 1-6 alkyl; 
 n is 1, 2, 3, 4 or 5; 
 aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, cyano, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, amino, mono- or di(C 1-4 alkyl)amino, phenyloxy or nitro; 
 heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, cyano, aminocarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, amino, mono- or di(C 1-4 alkyl)amino or nitro; 
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 that at least one of R 3  or R 4  is other than hydrogen. 
 
   
   
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       13 . The method according to  claim 11  wherein the disease is an inflammatory disease. 
   
   
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