Patent PT-97210-A (PT)
Title: Process for the preparation of substituted isoindole, isoquinoline and azepine derivatives and pharmaceutical compositions
Inventor: DEBERNARDIS JOHN F
IPC: A61P25/26
Filed: 1991-03-28
Abstract: This invention relates to a process for the preparation of compounds of formula: <IMAGE> in which R1 is hydrogen or C1-C6 alkyl, R2 is C1-C6 alkyl substituted with a C7-C16 heterocyclic or aralkyl group, in which the aryl group is not substituted or substituted with one to three members, other than hydrogen, selected independently of each other from the group comprising halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, amine and C1-C6 alkylamine, R3, R4, R5 and R6 are selected independently of each other from the group comprising hydrogen, C1-C6 alkoxy, C1-C6 alkyl, halogen or C1-C6 haloalkyl, or any two of R3, R4, R5 and R6 taken together forming a methylene dioxy group, and R7 is hydrogen, methyl or ethyl, which comprises the steps of: adding a cyanide to a tetralone of formula 1 <IMAGE> acid-catalysed removal of water from the resultant cyanhydrin, conjugated addition of a 2-lithium-2- substituted-1,3-dithiane to the resulting α, β- unsaturated nitrile, conversion of the dithiane compound to the corresponding ketal of formula 5 <IMAGE> reduction of the nitrile group to yield the aminomethyl- ketal compound, hydrolysis of the ketal acetone, spontaneous intramolecular formation of the imine, reduction of the resulting imine and alkylation of the nitrogen atom in the ring, or the addition of a cyanide to a tetralone of formula 1, the acid-catalysed removal of water from the resultant cyanhydrin, solvolysis of the resulting α, β- unsaturated nitrile of formula 2 <IMAGE> to the corresponding resultant α, β-unsaturated ester, conjugated addition of a substituted nitromethane anion to the resultant α, β-unsaturated ester, selective reduction of the nitro group, spontaneous intramolecular cyclization, to form a lactam of formula 15 <IMAGE> reduction of the resultant lactam to a cyclic amine, (benzo-iso-indoline) and alkylation of the nitrogen atom of the ring, or addition of a cyanide to a tetralone of formula 1, acid- catalysed removal of water from the resultant cyanhydrin, conjugated addition of an acetate anion to the resulting α, β-unsaturated nitrile, selective reduction of the nitrile group to yield the amino methyl intermediary, spontaneous intramolecular cyclization of the aminomethyl intermediary to form a lactam of formula 22 <IMAGE> alkylation of the nitrogen atom of the lactam ring, alkylation of the carbonyl carbon atom, elimination of water from the resultant hydroxy adduct and reduction of the resulting cyclic imine, or condensation of a tetralone with an acrylic acid ester to yield an adduct of formula 24 <IMAGE> addition of cyanide to the ketone, elimination of water from the resultant cyanhydrin, selective reduction of the cyanide group to yield the aminomethyl intermediary, spontaneous cyclization of the aminomethyl intermediary, alkylation of the nitrogen atom of the resultant lactam ring, alkylation of the carbonyl carbon atom, elimination of water from the resultant hydroxy adduct and reduction of the resulting cyclic imine. The invention also relates to the process of preparing pharmaceutical compositions useful in the treatment of emotional disturbances which include one of the compounds prepared according to the invention as an active ingredient.