GB1018995A - Dibenz-[b,e]-oxepine derivatives - Google Patents

Abstract

The invention comprises compounds of formula <FORM:1018995/C2/1> wherein X and Y are each a hydrogen, chlorine or fluorine atom or an alkyl, alkoxy, alkylthio, trifluoromethyl, acyl or dialkylsulphonamido group, R is hydrogen or a methyl group and R1 is an alkyl, alkenyl or cycloalkyl group, the hydrocarbon and acyl groups having 1 to 4 carbon atoms, acid addition salts thereof, and their preparation (1) by reaction of a compound of formula <FORM:1018995/C2/2> with (a) a 3-substituted-aminopropyl magnesium halide to give a compound of formula <FORM:1018995/C2/3> followed by optional dealkylation and by acidic dehydration, (b) an allyl magnesium halide to give a compound of formula <FORM:1018995/C2/4> followed by dehydration and amination of the double bond, (c) a 3-dialkylamino-propyne-1 in the presence of a condensing agent to give a compound of formula <FORM:1018995/C2/5> followed by hydrogenation of the triple bond and dehydration, (d) acrylonitrile, giving a compound of formula <FORM:1018995/C2/6> followed by reduction of the nitrile group to an aminomethyl group, dehydration and alkylation, or (e) sulphuryl chloride to give a sulphonyl chloride substituent and reacting this with a dialkylamine to give a dialkylsulphonamido substituent, and treating this as in (a) to (d) above, (2) by separation of cis- and transisomers or isomerization, or (3) methylation of separated isomers of the compounds wherein R is hydrogen. Dibenzoxepinones of formula <FORM:1018995/C2/7> are prepared (a) by reaction of a compound of formula <FORM:1018995/C2/8> wherein D is displaceable substituent, e.g. a halogen atom or an organosulphonyl group, and R2 is an alkyl group, with a Y-substituted phenol to give a compound of formula <FORM:1018995/C2/9> followed by hydrolysis to the free acid and cyclization, or (b), where Y is a trifluoromethyl group, reacting 2-bromobenzyl alcohol with, for example, 2 - nitro - 4 - trifluoromethyl - chlorobenzene to give 2-(21-nitro-41-trifluoromethyl-phenoxymethyl) - bromobenzene, removing the nitro group by reduction to and diazotization of the corresponding amine followed by treatment of the diazo compound with hypophosphorous acid or sodium borohydride, replacing the bromine atom by a carboxyl group by treatment with magnesium and carbon dioxide, and cyclizing. Ethyl o - bromomethylbenzoate is prepared by conversion of o-toluic acid to its acid chloride by reaction with thionyl chloride, brominating this to give o-bromomethylbenzyl bromide, and reacting this with ethanol. The compounds of the invention have antidepressant, antiserotonin, antihistaminic, anticholinergic, appetite-stimulating and spasmolytic activity and may be used in pharmaceutical compositions in combination with a carrier, for example in forms suitable for oral or parenteral administration, such as tablets, capsules, or solutions.