Imidazole compounds and their therapeutic applications

Abstract

A compound selected from the group consisting of a compound of the formula wherein the substituents are defined as in the specification having antagonist properties to histamine H 3 -receptors.

We claim:  
     
       1. A method of inducing antagonist activity of H 3  histamine receptors in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound selected from the group consisting of a compound of the formula                    
       in which A is a hydrocarbon chain containing 1 to 6 carbon atoms uninterrupted or interrupted by a heteroatom selected from the group consisting of —S—, —O— and —NH—, X is selected from the group consisting of oxygen, sulfur, —NH—, —NHCO—, —N(alkyl)CO—, NHCONH—, —NH—CS—NH—, —NHCS—, —O—CO—, —CO—O—, —OCONH—, —OCON(alkyl)—, —OCONH—CO—, —CONH—, —CON(alkyl)—, —SO—, —CO—, —CHOH— and —NR—C(═NR″)—NR′, R and R′ are hydrogen or lower alkyl and R″ is selected from the group consisting of hydrogen, cyano and COY 1 , Y 1  is alkoxy, B is selected from the group consisting of —(CH 2 ) n —, n is an integer from 0 to 5, a branched alkylene of 2 to 8 carbon atoms uninterrupted or interrupted by at least one oxygen or sulfur, and —(CH 2 ) n′ —O— and —(CH 2 ) n′ —S— where n′ is an integer of 1 or 2, Y is selected from the group consisting of alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, bicycloalkyl, cycloalkenyl, aryl 5- or 6-membered heterocycle selected from the group consisting of pyridyl, N-oxide-pyridyl, pyrimidinyl and pyrazinyl unsubstituted or substituted with at least one member of the group consisting of —NO 2 , —CF 3 , —CH 3 , —NH 2 , halogen, —COOCH 3 , imidazolyl and thiazolyl and a bicyclic formed by a heterocycle as defined above to which a phenyl ring is fused, with the proviso that 
         a )  when X represents —NH—, then the substituents are not the chain A the — ( CH   2 ) 2   — group, the chain B the — ( CH   2 ) 2   —O— group or the group — ( CH   2 ) n   —S— and Y the phenyl or p - chlorophenyl group,    
         b )  when X represents the —NHCO— group, then the substituents are not the chain A the — ( CH   2 ) 2   — group and Y the methyl group  ( formula IB )  or the chain B and Y  ( formula IA )  represent a straight alkylene chain — ( CH   2 ) n   —, n being between  1  and  4 , the —CH   2   —O— or —CH   2   —S—CH   2   — groups and a phenyl group, or also the —CH   2   —CH   2   — or —CH   2   —S—CH   2   — groups and the diphenyl group, or also the — ( CH   2 ) 3   — or —CH   2   —S—CH   2   — groups and the pyridyl group, or also the —CH   2   —CH   2   — or —CH   2   —S— groups and the diphenyl group, or else the — ( CH   2 ) 3   — group and the imidazolyl or cyclohexyl group,    
         c )  when X represents —NHCO—, the substituents are not the chain A the —CH   2   —CH ( CH   3 )—  group, the chain B the — ( CH   2 ) 3   — group and Y the phenyl group,    
         d )  when X represents —NHCSNH— or —NHCONH—, the substituents are not the chain A the — ( CH   2 ) 2   — group, the chain B the — ( CH   2 ) 2   — group and Y the phenyl group,  and a pharmaceutically acceptable salt, a hydrate, a hydrated salt, the polymorphic crystalline structures or the tautomeric forms thereof sufficient to induce said antagonist activity.  
     
     
       2. The method of claim  1  wherein the active compound has the formula                    
       wherein A is a hydrocarbon of 2 to 6 carbon atoms, X is oxygen and Y is phenyl unsubstituted or substituted by at least one member of the group consisting of halogen, lower alkyl, —CF 3 , —CN, —COCH 3 , —COOR, —COR, —COOH, —NO 2  and                    
       R is lower alkyl and R 2  and R 3  are hydrogen or lower alkyl and a pharmaceutically acceptable salt, a hydrate, a hydrated salt, the polymorphic crystalline structures or the tautomeric forms thereof. 
     
     
       3. The method of claim  2  wherein A is ethylene or propylene. 
     
     
       4. The method of claim  1  where the compound used is a compound selected from the group consisting of a compound of the formula                    
       wherein A is a hydrocarbon of 1 to 6 carbon atoms optionally interrupted by a heteroatom selected from the group consisting of oxygen, sulfur and —NH—, X is selected from the group consisting of —OCO—, —COO—, —OCONH—, —OCON(alkyl)— and —OCONH—CO—, B is selected from the group consisting of —(CH 2 ) n —, n is an integer from 0 to 5, a branched alkylene of 2 to 8 carbon atoms optionally interrupted by at least one oxygen or sulfur, —(CH 2 ) n′ —O— and —(CH 2 ) n′ —S— where n′ is an integer of 1 or 2, Y is selected from the group consisting of alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, bicycloalkyl, cycloalkenyl, aryl, 5- or 6-membered heterocycle selected from the group consisting of pyridyl, N-oxide-pyridyl, pyrimidinyl and pyrazinyl optionally substituted with at least one member of the group consisting of —NO 2 , —CF 3 , —CH 3 , —NH 2 , halogen, —COOCH 3 , imidazolyl and thiazolyl and a bicyclic formed by a heterocycle as defined above to which a phenyl ring is fused and a pharmaceutically acceptable salt, a hydrate, a hydrated salt, the polymorphic crystalline structures or the tautomeric forms thereof.  
     
     
       5. The method of claim  1  where the compound used is a compound selected from the group consisting of a compound of the formula                    
       wherein A is a hydrocarbon of 1 to 6 carbon atoms optionally interrupted by a heteroatom selected from the group consisting of oxygen, sulfur and —NH—, X is selected from the group consisting of sulfur, oxygen, —N(alkyl)CO—, —NHCS—, —CON(alkyl)—, —SO— and —CHOH—, B is selected from the group consisting of —(CH 2 ) n —, n is an integer from 0 to 5, a branched alkylene of 2 to 8 carbon atoms optionally interrupted by at least one oxygen or sulfur, —(CH 2 ) n′ —O— and —(CH 2 ) n′ —S— where n′ is an integer of 1 or 2, Y is selected from the group consisting of alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, bicycloalkyl, cycloalkenyl, aryl 5- or 6-membered heterocycle selected from the group consisting of pyridyl, N-oxide-pyridyl, pyrimidinyl and pyrazinyl optionally substituted with at least one member of the group consisting of —NO 2 , —CF 3 , —CH 3 , —NH 2 , halogen, —COOCH 3 , imidazolyl and thiazolyl and a bicyclic formed by a heterocycle as defined above to which a phenyl ring is fused and a pharmaceutically acceptable salt, a hydrate, a hydrated salt, the polymorphic crystalline structures or the tautomeric forms thereof.  
     
     
       6. The method of claim  1  wherein the compound used is a compound selected from the group consisting of a compound of the formula                    
       wherein A is a hydrocarbon of 1 to 6 carbon atoms optionally interrupted by a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, X is                    
       R and R′ are hydrogen or lower alkyl, R″ is selected from the group consisting of hydrogen, cyano and —COY 1 , Y 1  is alkoxy, B is selected from the group consisting of —(CH 2 ) n —, n is an integer from 0 to 5, a branched alkylene of 2 to 8 carbon atoms optionally interrupted by at least one oxygen or sulfur, —(CH 2 ) n′ —O— and —(CH 2 ) n′ —S— where n′ is an integer of 1 or 2, Y is selected from the group consisting of cycloalkyl of 3 to 6 carbon atoms, bicycloalkyl, cycloalkenyl, pyrimidinyl and pyrazinyl optionally substituted with at least one member of the group consisting of —NO 2 , —CF 3 , —CH 3 , —NH 2 , halogen and —COOCH 3  and a pharmaceutically acceptable salt, a hydrate, a hydrated salt, the polymorphic crystalling structures or the tautomeric forms thereof. 
     
     
       7. The method of claim  1  wherein A is —(CH 2 ) n — and n is an integer from 0 to 6. 
     
     
       8. The method of claim  7  wherein A is alkylene substituted with at least one methyl or ethyl. 
     
     
       9. The method of claim  1  wherein Y is selected from the group consisting of cyclopentyl, cyclohexyl and bicycloalkyl. 
     
     
       10. The method of claim  1  wherein Y is phenyl substituted with at least one member of the group consisting of halogen, lower alkyl, —CF 3 , —CN, —COCH 3 , —COOR 1 , —COR, —COOH, —NO 2  and                    
       R is alkyl and R 2  and R 3  are individually hydrogen or lower alkyl. 
     
     
       11. The method of claim  1  wherein Y is benzothiazolyl. 
     
     
       12. The method of claim  1  wherein A is a saturated hydrocarbon chain interrupted by a sulfur. 
     
     
       13. The method of claim  1 , characterized in that the compounds are chosen from: 
       N-((1H-Imidazol-4-yl)methyl)-5-phenylpentanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-phenylpropanamide,  
       N-(3-(1H-Imidazol-4-yl)-propyl)-3-cyclohexylpropanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-2-(4-chlorophenoxy)acetamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide,  
       N-(3-(1H-Imidazol-4-yl)propyl-4-cyclohexylbutanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-4-methylpentanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3,3-diphenylpropanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-(bicyclo[2.2.1]hept-2-yl)propanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)hexanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)heptanamide  
       N-(3-(1H-Imidazol-4-yl)propyl)octanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-cyclopenten-1-yl)propanamide,  
       (R,S)-(±)-N-(3-(1H-Imidazol-4-yl)propyl-3-phenylbutanamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-pyrazinyl)propanamide,  
       N-(4-(1H-Imidazol-4-yl)butyl)-2-cyclopentylacetamide,  
       N-(4-(1H-Imidazol-4-yl)butyl)-3-cyclopentylpropanamide,  
       (E)-N-(3-(1H-Imidazol-4-yl)allyl)-3-cyclopentylpropanamide,  
       N-(3-Phenylpropyl)-3-(1H-imidazol-4-yl)propanamide,  
       N-(2-(1H-Imidazol-4-yl)ethyl)-4-cyclohexylbutanethioamide,  
       N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanethioamide,  
       N-Benzyl-N′-(3-(1H-imidazol-4-yl)propyl)urea,  
       3-(1H-Imidazol-4-yl)propyl ester of 3-cyclopentylpropanoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of benzoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 4-iodobenzoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 3-iodobenzoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 3-iodo-4-methylbenzoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 3-(4-iodophenyl)propanoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 4-amino-3,5-diiodobenzoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 4-(4-iodophenyl)butanoic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 2-(4-iodophenyl)acetic acid,  
       3-(1H-Imidazol-4-yl)propyl ester of 4-phenylbutanoic acid,  
       3-(1H-Imidazol-4-yl)propyl N-benzylcarbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(cyclohexylmethyl)carbamate,  
       3-Cyclohexylpropyl 3-(1H-imidazol-4-yl)propyl ether,  
       3-(3,4-Difluorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,  
       3-(4-Bromophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,  
       3-(3-Trifluoromethylphenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,  
       1-Naphthylmethyl 3-(1H-imidazol-4-yl)propyl ether,  
       (4-Iodophenyl)methyl 3-(1H-imidazol-4-yl)propyl ether,  
       4-Phenylbutyl 3-(1H-imidazol-4-yl)propyl ether,  
       (Z)-N-(1H-Imidazol-4-yl)allyl)-3-cyclohexylpropanamide,  
       (R,S)-(±)-N-(3-(1H-Imidazol-4-yl)butyl)-3-cyclohexylpropanamide,  
       3-Phenylpropyl 3-(1H-imidazol-4-yl)propyl ether,  
       3-Phenylpropyl 3-(1H-imidazol-4-yl)propyl sulphide,  
       4-[(4-Nitrobenzylthio)methyl]-1H-imidazole,  
       3-Phenylpropyl 3-(1H-imidazol- 4 yl)propyl sulphoxide,  
       1-(1H-Imidazol-4-yl)-7-phenylheptan-4-one,  
       1-(1H-Imidazol-4-yl)-7-phenylheptan-4-ol,  
       N-Cyano-N′-[3-(1H-imidazol-4-yl)propyl]-N″-cyclohexylmethylguanidine,  
       N-Ethoxycarbonyl-N′-[3-(1H-imidazol-4-yl)propyl]-N″-cyclohexylmethylguanidine,  
       N-(1,1-Dimethylethoxycarbonyl)-N′-[3-(1H-imidazol-4-yl)propyl]-N″-cyclohexylmethylguanidine,  
       N-[3-(1H-Imidazol-4-yl)propyl]-N′-cyclohexlmethylguanidine,  
       3-(1H-Imidazol-4-yl)propyl N-benzoylcarbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(cyclobutylmethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(cyclopropylmethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl (R)-(+)-N-(1-phenylethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl (S)-(−)-N-(1-phenylethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-cyclohexylcarbamate,  
       3-(1H-Imidazol-4-yl)propyl N-phenylcarbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-methylphenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-trifluoromethylphenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(3-trifluoromethylphenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(2-trifluoromethylphenyl)carbamate,  
       2-(1H-Imidazol-4-yl)ethyl N-(2-phenylethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-nitrobenzyl)carbamate,  
       3-(1H-Imidazol-4yl)propyl N-(4-aminobenzyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(3-nitrophenyl)carbamate,  
       N-[2-(1H-Imidazol-4-yl)ethyl]-N-methyl-4-cyclohexylbutanamide,  
       3-Cyclohexylpropyl ester 3-(1H-imidazol-4-yl)propanoic acid,  
       3-(1H-Imidazol-4-yl)propyl N-(2-nitrophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-fluorophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(2-phenylethyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-fluorobenzyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-chlorophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-chlorobenzyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(3-iodophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(2-iodophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-iodophenyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(3-phenylpropyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-(4-trifluoromethylbenzyl)carbamate,  
       3-(1H-Imidazol-4-yl)propyl N-benzyl-N-methylcarbamate,  
       3-(1H-Imidazol-4-yl)propyl N-benzyl-N-isopropylcarbamate,  
       3-(4-Chlorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,  
       (4-Chlorophenyl)methyl 3-(1H-imidazol-4-yl)propyl ether,  
       Cyclohexylmethyl (1H-imidazol-4-yl)methyl ether,  
       3-(4-Fluorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,  
       p-Nitrophenyl trans-3-(1H-imidazol-4-yl)-2-propenoate,  
       2-{[2-(1H-Imidazol-4yl)ethyl]amino}pyrimidine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}benzothiazole,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}pyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-3-nitropyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-5-nitropyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}thiazole,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}pyrazine,  
       2-{[2-(1H-Imidazol-4yl)ethyl]amino}-3,6-dimethylpyrazine,  
       1-{[2-(1H-Imidazol-4-yl)ethyl]amino}-4-nitrobenzene,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-5-trifluoromethylpyridine,  
       4-{[2-(1H-Imidazol-4-yl)ethyl]amino}-2-chloropyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-5-carbomethoxypyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-4-nitropyridine-N-oxide,  
       2-{[3-(1H-Imidazol-4-yl)propyl]amino}-5-nitropyridine,  
       2-{2-[(1H-Imidazol-4-yl)methylthio]ethylamino}-5-nitropyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]amino}-5-aminopyridine,  
       2-[(1H-Imidazol-4-yl)methylthio]-5-nitropyridine,  
       2-{2-[1H-Imidazol-4-yl]ethylthio}-5-nitropyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]thio}pyridine,  
       2-{[2-(1H-Imidazol-4-yl)ethyl]thio}-1H-imidazol,  
       4-[2-(4-Nitrophenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Carbomethoxyphenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Cyanophenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Acetylphenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Ethoxycarbonylphenoxy)ethyl]-1H-imidazole,  
       4-[2-(3-Nitrophenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Methoxyphenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Propylphenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Bromophenoxy)ethyl]-1H-imidazole,  
       4-[2-(3,5-Dichlorophenoxy)ethyl]-1H-imidazole,  
       4-[2-(2,3,4,5,6-Pentafluorophenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Ethylphenoxy)ethyl]-1H-imidazole,  
       4-[2-(3-Cyanophenoxy)ethyl]-1H-imidazole,  
       4-[2-(2-Cyanophenoxy)ethyl]-1H-imidazole,  
       4-[2-(2-Naphthyloxy)ethyl]-1H-imidazole,  
       4-[2-(4-Trifluoromethylphenoxy)ethyl]-1H-imidazole, and  
       4-[2-(1-Naphthyloxy)ethyl]-1H-imidazole,  
       4-[2-(4-Benzoylphenoxy)ethyl]-1H-imidazole,  
       4-[2-(4-Nitrophenylthio)ethyl]-1H-imidazole,  
       4-[3-(4-Cyanophenoxy)propyl]-1H-imidazole,  
       4-[3-(4-Trifluoromethylphenoxy)propyl]-1H-imidazole.