Pyridopyranoazepine derivatives, their preparation and their therapeutic application
View Patent ↗The invention relates to pyridopyranoazepine derivatives, to pharmaceutical compositions containing them, to process for preparing them, and to the method of use thereof in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors.
1. A process for preparation of compound in the form of pure geometrical or optical isomers or a mixture of such isomers, of formula (I)
in which
R 1 is a hydrogen atom, a (C 1 -C 4 )alkyl group, a phenyl (C 1 -C 4 )alkyl group, a phenylhydroxy (C 1 -C 4 ) alkyl group, a furanyl(C 1 -C 4 )alkyl group, or a furanylhydroxy(C 1 -C 4 )alkyl group,
R 2 is either a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, nitro, acetyl, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy group or a group of general formula NR 4 R 5 in which R 4 is a hydrogen atom or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkanoyl group and R 5 is a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 4 and R 5 form, with the nitrogen atom which carries them, a C 4 -C 7 ring, or a phenyl or naphthyl group optionally substituted by a halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, acetyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or methylenedioxy group linked in the 2 and 3 positions of the phenyl ring, and
R 3 is a hydrogen or halogen atom or a (C 1 -C 4 )alkyl group,
in the state of a base or an addition salt to an acid wherein a compound of general formula (IV)
in which R 2 and R 3 are as defined above is subjected to a dehydration in acid medium followed by a rearrangement at high temperature, to obtain a compound of general formula (Ia)
in which, if desired, the substituents R 2 and R 3 are modified into other R 2 or R 3 substituents and/or a substituent R 1 such as defined above is introduced to afford compounds of Formula I.
2. A method for the treatment or prevention of pain which comprises administering to a patient in need of such treatment an effective amount of a compound in the form of pure geometrical or optical isomers or a mixture of such isomers, of formula (I)
in which
R 1 is a hydrogen atom, a (C 1 -C 4 )alkyl group, a phenyl(C 1 -C 4 )alkyl group, a phenylhydroxy(C 1 -C 4 )alkyl group, a furanyl(C 1 -C 4 )alkyl group, or a furanylhydroxy(C 1 -C 4 )alkyl group,
R 2 is either a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, nitro, acetyl, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy group or a group of general formula NR 4 R 5 in which R 4 is a hydrogen atom or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkanoyl group and R 5 is a hydrogen atom or a (C 1 -C 4 )alkyl group, or else R 4 and R 5 form, with the nitrogen atom which carries them, a C 4 -C 7 ring, or a phenyl or naphthyl group optionally substituted by a halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, acetyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or methylenedioxy group linked in the 2 and 3 positions of the phenyl ring, and
R 3 is a hydrogen or halogen atom or a (C 1 -C 4 )alkyl group,
in the state of a base or an addition salt to an acid.
3. A method according to claim 2 wherein R 1 is hydrogen, methyl, ethyl, phenylmethyl, phenyl CH(OH)—, furanyl CH(OH); R 2 is hydrogen, bromo, phenyl, phenyl substituted by methyl, trifluoromethoxy, trifluoromethyl, nitro, acetyl, methylenedioxy, fluoro, naphthyl, chloro or cyano; and R 3 is hydrogen or bromo.
4. A method according to claim 3 wherein R 1 is hydrogen, methyl, ethyl, phenylmethyl, phenyl CH(OH), 3-furanyl CH(OH)-; R 2 is hydrogen, bromo, phenyl, 4-methylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3-nitrophenyl, 3-acetylphenol, 3,4-methylene dioxyphenyl, 3,5-ditrifluoromethylphenyl, 4-fluorophenyl, 4-biphenyl, 2-naphthyl, chloro, or cyano; and R3 is hydrogen or bromo.
5. A method according to claim 4 wherein the compound is (5a S, 10aR)-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido [2′,3′:5,6]pyrano[2,3-d]azepine or an addition salt to an acid thereof.
6. A method according to claim 5 wherein the compound is (5a S, 10aR)-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido [2′,3′:5,6]pyrano[2,3-d]azepine hydrochloride (2:1).