Imidazole derivatives

Abstract

The invention relates to imidazole derivatives which have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The invention also relates to a pharmaceutically-suitable acid-addition salt of the above compound. The invention further relates to a composition comprising an imidazole derivative as described above, or a pharmaceutically-suitable acid-addition salt thereof, and to processes for preparing such compounds.

1 . A compound according to formula I, 
     
       
         
         
             
             
         
       
     
     wherein
 R is selected from the group consisting of hydrogen, lower alkyl and amino; 
 X is selected from the group consisting of —CH 2 —, —CH(lower alkoxy)-, —CH(OH)—, and —NH—; 
 Y is selected from the group consisting of —CH 2 , —CH(lower alkyl)-, —CH(lower alkoxy)-, —O—, —S—, —S(O)—, —S(O) 2 —, —CH(phenyl)- and —C(lower alkyl) 2 -; and 
 Ar is selected from the group consisting of phenyl, napthtyl and benzofuranyl, said phenyl, mapthyl, or benzofuranyl being unsubstituted or substituted by one or more substituents, each substituent being independently selected from the group consisting of lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy, lower alkoxy substituted by halogen, hydroxy, amino, di-alkylamino, morpholinyl, phenyl, benzyl and O-benzyl; 
 or a pharmaceutically-suitable acid-addition salt thereof; 
 with the provisio that, wherein, when X is —NH—, Y is selected from the group consisting of —CH 2 , —CH(lower alkyl)-, —CH(lower alkoxy)-, —CH(phenyl)- or —C(lower alkyl) 2 -; and 
 the further proviso that said compound is not 
 5-phenethyl-1H-imidazole, 
 5-(2-phenyl-propyl)-1H-imidazole, 
 1-(1H-imidazol-4-yl)-2-phenyl-ethanol, 
 5-(2,2-diphenyl-ethyl)-1H-imidazole, 
 4-(2-m-tolyl-ethyl)-1H-imidazole, 
 4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole, 
 4-(biphenyl-2-yloxymethyl)-1H-imidazole, 
 5-(2-methyl-2-phenyl-propyl)-1H-imidazole, 
 4-(2-chloro-phenoxymethyl)-1H-imidazole, 
 4-(2-fluoro-phenoxymethyl)-1H-imidazole, 
 4-o-tolyloxymethyl-1H-imidazole, 
 4-(3-chloro-phenoxymethyl)-1H-imidazole, 
 4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or 
 5-methyl-4-phenylsulfanylmethyl-1H-imidazole. 
 
   
   
       2 . A compound according to  claim 1 , wherein X and Y are both —CH 2 —. 
   
   
       3 . A compound according to  claim 2 , selected from the group consisting of:
 4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole;   4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole;   4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole;   4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole;   4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;   4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole;   4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole;   4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       4 . A compound according to  claim 1 , wherein X is —CH 2 — and Y is —CH(lower alkyl). 
   
   
       5 . A compound according to  claim 4 , selected from the group consisting of:
 4-(2-phenyl-butyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       6 . A compound according to  claim 1 , wherein X is —CH 2 — and Y is —O—. 
   
   
       7 . A compound according to  claim 6 , selected from the group consisting of:
 4-(2,3-dichloro-phenoxymethyl)-1H-imidazole;   4-(2,3-difluoro-phenoxymethyl)-1H-imidazole;   4-(3,4-dichloro-phenoxymethyl)-1H-imidazole;   4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole;   5-(benzofuran-6-yloxymethyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       8 . A compound according to  claim 1 , wherein X is —CH 2 — and Y is —S—. 
   
   
       9 . A compound according to  claim 8 , selected from the group consisting of:
 5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole;   4-(4-chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole;   4-(naphthalen-2-ylsulfanylmethyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       10 . A composition comprising a compound according to  claim 1  and a therapeutically-inert carrier. 
   
   
       11 . A process for the preparation of a compound of formula I, 
     
       
         
         
             
             
         
       
     
     comprising deprotecting a compound according to formula II, 
     
       
         
         
             
             
         
       
     
     wherein, in the above formulas,
 R is selected from the group consisting of hydrogen, lower alkyl and amino; 
 X is selected from the group consisting of —CH 2 —, —CH(lower alkoxy)-, —CH(OH)—, and —NH—; 
 Y is selected from the group consisting of —CH 2 , —CH(lower alkyl)-, —CH(lower alkoxy)-, —O—, —S—, —S(O)—, —S(O) 2 —, —CH(phenyl)- and —C(lower alkyl) 2 -; and 
 Ar is selected from the group consisting of phenyl, napthtyl and benzofuranyl, said phenyl, mapthyl, or benzofuranyl being unsubstituted or substituted by one or more substituents, each substituent being independently selected from the group consisting of lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy, lower alkoxy substituted by halogen, hydroxy, amino, di-alkylamino, morpholinyl, phenyl, benzyl and O-benzyl; with the provisio that, wherein, when X is —NH—, Y is selected from the group consisting of —CH 2 , —CH(lower alkyl)-, —CH(lower alkoxy)-, —CH(phenyl)- or —C(lower alkyl) 2 -. 
 
   
   
       12 . A compound according to  claim 2  wherein said compound is selected from the group consisting of:
 4-[2-(2-ethyl-phenyl)-ethyl]-1H-imidazole;   4-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;   {2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine;   4-{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-morpholine;   4-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-imidazole;   2-methyl-5-phenethyl-1H-imidazole;   5-phenethyl-1H-imidazol-2-ylamine; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       13 . A compound according to  claim 3  wherein said compound is selected from the group consisting of:
 4-(3-methyl-2-phenyl-butyl)-1H-imidazole;   4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       14 . A compound according to  claim 6  wherein said compound is selected from the group consisting of:
 4-(2-Ethyl-phenoxymethyl)-1H-imidazole;   4-(2-Isopropyl-phenoxymethyl)-1H-imidazole;   4-(2-Trifluoromethyl-phenoxymethyl)-1H-imidazole;   4-(2-Benzyl-phenoxymethyl)-1H-imidazole;   4-(2-Methoxy-phenoxymethyl)-1H-imidazole;   4-(2-Isopropoxy-phenoxymethyl)-1H-imidazole;   4-(2-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;   4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole;   2-(1H-Imidazol-4-ylmethoxy)-phenol;   4-(3-Trifluoromethyl-phenoxymethyl)-1H-imidazole;   4-(3-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;   [3-(1H-Imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine;   4-[-(1H-Imidazol-4-ylmethoxy)-phenyl]-morpholine;   4-(2,6-Diethyl-phenoxymethyl)-1H-imidazole;   4-(3,4-Difluoro-phenoxymethyl)-1H-imidazole;   4-(3-Chloro-5-fluoro-phenoxymethyl)-1H-imidazole;   5-(4-Bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       15 . A compound according to  claim 1  wherein X is —CH 2 — and Y is —S(O)—, said compound selected from the group consisting of:
 4-benzenesulfinylmethyl-5-methyl-1H-imidazole;   5-(2,3-dichloro-benzenesulfinylmethyl)-1-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       16 . A compound according to  claim 1  wherein X is —CH 2 — and Y is —S(O) 2 —, said compound selected from the group consisting of:
 5-(2,3-dichloro-benzenesulfonylmethyl)-1-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       17 . A compound according to  claim 1  wherein X is —NH— and Y is —CH 2 —, said compound selected from the group consisting of:
 Benzyl-(1H-imidazol-4-yl)-amine; and   pharmaceutically-suitable acid-addition salts thereof.   
   
   
       18 . A compound according to  claim 1  wherein X is —CH(lower alkoxy)- and Y is —CH 2 —, said compound selected from the group consisting of:
 4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole; and   pharmaceutically-suitable acid-addition salts thereof.