Patent EA-004957-B1 (EA)
Title: Novel branched substituted amino derivatives of 3-amino-1-phenyl-1h[1,2,4]triazol, methods for producing them and pharmaceutical compositions containing them
Inventor: GESLIN MICHEL
IPC: A61P25/00
Filed: 2000-12-14
Abstract: 1. A compound of formula: in which: R1 and R2 represent, each independently of the other, a halogen atom; a (C1-C5)alkyl; a (C1-C5)alkoxy; a nitro, trifluoromethyl or cyano group; an NRaRb amino group in which Ra and Rb represent, each independently of the other, a hydrogen, a (C1-C3)alkyl or a CO(C1-C3)alkyl; or an S-R group in which R represents a hydrogen atom or a (C1-C5)alkyl, it being possible for the sulphur atom to be monooxidized or dioxidized; R3 represents hydrogen or is as defined above for R1; R4 represents hydrogen; a halogen; a (C1-C5)alkyl; a (C3-C5)cycloalkyl; a (C3-C5)cycloalkyl(C1-C2)alkyl; or an Rc-X-(C1-C2)alkyl group in which Rc represents hydrogen or a (C1-C3)alkyl and X represents O, S, SO or SO2; R5 represents a (C1-C5)alkyl, an alkynyl with 3 to 5 carbon atoms or an alkenyl with 3 to 5 carbon atoms; a (C3-C5)cycloalkyl(C1-C3)alkyl; or a (C1-C3)alkyl-X-(C0-C3)alkyl in which X represents O, S, SO or SO2; R6 represents a phenyl group substituted by one or more Z radical, one of the is at least position 2, and Z represents halogen; a nitro, trifluoromethyl or cyano group; a (C1-C5)alkyl; a (C1-C5)alkyl-X- or (C1-C3)alkyl-X-(C1-C2)alkyl where X represents O, S, SO or SO2; a hydroxy(C1-C3)alkyl; a CORd or COORd in which Rd represents (C1-C3)alkyl or (C3-C5)cycloalkyl; or R6 represents a -CHR7R8, in which R7 represents (C3-C5)cycloalkyl; R7 represents a phenyl group which can be substituted in the 3-, 4- and 5-positions by one or more Z' radicals, with Z' representing a halogen; a nitro, trifluoromethyl or cyano group; a (C1-C5)alkyl; a (C1-C5)alkyl-X- or (C1-C3)alkyl-X-(C1-C2)alkyl where X represents O, S, SO or SO2; a hydroxy(C1-C3)alkyl; a CORd or COORd in which Rd is as defined above; a methylenedioxy or an ethylenedioxy; or R7 represents pyridyl group optionally substituted by an NRaRb amino group as defined above or Z' radical as defined above; R8 represents a (C1-C6)alkyl; (C3-C5)cycloalkyl; (C3-C5)cycloalkyl(C1-C3)alkyl; (C1-C3)alkyl-X-(C1-C3)alkyl where X represents O, S, SO or SO2; (C3-C5)cycloalkyl(C1-C2)alkyl-X-(C1-C3)alkyl where X represents O, S, SO or SO2; or a pharmaceutically acceptable addition salt, hydrate and/or solvate thereof. 2. A compound according to claim 1, in which: R1 and R2 represent, each independently of the other, a halogen atom; a (C1-C5)alkyl; a (C1-C5)alkoxy; a trifluoromethyl or an S-R group in which R represents a (C1-C5)alkyl; R3 represents hydrogen or a (C1-C5)alkyl; R4 represents a (C1-C5)alkyl; a (C3-C5)cycloalkyl or an Ra-X-(C1-C2)alkyl group in which Ra represents a (C1-C3)alkyl and X represents O; R5 represents a (C1-C5)alkyl or an alkynyl with 3 to 5 carbon atoms; R6 represents -CHR7R8, in which R7 represents a phenyl group which can be substituted in the 3-, 4- and 5-positions by one or more Z' radicals, with Z' representing a halogen; a (C1-C5)alkyl; a (C1-C5)alkyl-X- or (C1-C3)alkyl-X-(C1-C2)alkyl where X represents O; or a methylenedioxy group; R8 represents a (C1-C6)alkyl (C3-C5)cycloalkyl(C1-C3)alkyl; or (C1-C3)alkyl-X-(C1-C2)alkyl where X represents O; or a pharmaceutically acceptable addition salt, hydrate and/or solvate thereof. 3. A compound according to claim 1 or 2 in which R5 represents a propyl or propargyl group. 4. A compound according to any one of claims 1-3 in the enantiomeric form. 5. A compound according to claim 1 chosen from: 5-Cyclopropyl-N-[2-cyclopropyl-1-(4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[2-Cyclopropyl-1-(4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-5-(methoxymethyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[2Cyclopropyl-1-(4-fluorophenyl)ethyl]-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[2-cyclopropyl-1-(4-fluorophenyl)ethyl]-5-methyl-N-(2-propynyl)-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[2-cyclopropyl-1-(4-fluorophenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-5-cyclopropyl-N-[2-cyclopropyl-1-(4-fluorophenyl)ethyl]-N-(2-propynyl)-1H-1,2,4-triazol-3-amine hydrochloride, 5-Cyclopropyl-N-[2-cyclopropyl-1-(4-fluorophenyl)ethyl]-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-propyl-1H-1,2,4-triazol-3-amine hydrobromide, 5-Cyclopropyl-N-(2-cyclopropyl-1-phenylethyl)-1-(2,4-dichlorophenyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-5-cyclopropyl-N-(2cyclopropyl-1-phenylethyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-5-cyclopropyl-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-5-cyclopropyl-N-(2-cyclopropyl-1-phenylethyl)-N-(2-propynyl)-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-5-cyclopropyl-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-N-(2-propynyl)-1H-1,2,4-triazol-3-amine hydrobromide, 5-Cyclopropyl-N-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-1-(2,4-dichlorophenyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 5-Cyclopropyl-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-1-(2,4-dimethylphenyl)-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-2-Cyclopropyl-1-(4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-ethyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-(1S)-2-Cyclopropyl-1-(4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-5-ethyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propynyl)-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(4-fluorophenyl)ethyl]-5-ethyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-1-(2,4-dichlorophenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(4-methylphenyl)ethyl[-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-2-Cyclopropyl-1-(4-methylphenyl)ethyl]-1-(2,4-dichlorophenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(4-fluorophenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-[2-Chloro-4-(trifluoromethyl)phenyl]-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-1-(1,3-Benzodioxol-5-yl)-2-cyclopropylethyl]-1-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-1-(1,3-Benzodioxol-5-yl)-2-cyclopropylethyl]-1-(2,4-dichlorophenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-{(1S)-2-cyclopropyl-1-[(4-methoxymethyl)phenyl]ethyl}-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxyphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-phenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, N-[(1S)-2-Cyclopropyl-1-phenyl)ethyl]-1-(2,4-dichlorophenyl)-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-[2Chloro-4-(methylsulphonyl)phenyl]-N-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride, 1-(2-Chloro-4-methoxyphenyl)-N-[(1S)-2-cyclopropyl-1-(4-fluorophenyl)ethyl]-5-methyl-N-propyl-1H-1,2,4-triazol-3-amine hydrochloride or a corresponding base, other pharmaceutically acceptable addition salt, solvate and/or hydrate thereof. 6. A method for producing compounds of formula (I) according to claim 1, characterized in that the compound of formula: in which R1, R2, R3, R5 and R6 are as defined for (I) reacts with the compound of formula R4COX (where X is halogen) to obtain the compound of formula (I). 7. A method for producing compounds of formula (I) according to claim 1, characterized in that the compound of formula (VIII): in which R1, R2, R3, R4 and R6 are as defined for (I) alkylates with the compound of formula R5X (where X is halogen) to obtain the compound of formula (I). 8. A method for producing compounds of formula (I) according to claim 1 and compounds of formula (VIII), characterized in that the compounds of formula (VI) or (X): in which R4, R5 and R6 are as defined for (I) reacts with the compound of formula (III): in which R1, R2 and R3 are as defined for (I) to obtain correspondingly the compounds of formula (I) or formula (VIII). 9. A pharmaceutical composition which comprises, as active principle, a compound according to any one of claims 1-5 in combination with one or more appropriate excipients. 10. Use of the compounds according to any one of claims 1-5 in manufacturing medicaments for treating and/or preventing corticotropin releasing factor (CRF) dependant diseases.