Patent GB-744773-A (GB)
Title: Indole derivatives
IPC: C07D209/14
Filed: 1953-03-30
Abstract: The invention comprises a (5-benzyloxy-3-indole)-alkylamine having the formula <FORM:0744773/IV(a)/1> wherein X is phenyl, halophenyl, lower alkoxyphenyl, or lower alkylphenyl, Y is hydrogen, phenyl, halophenyl, lower alkoxyphenyl or lower alkylphenyl, R1 and R2 are alike or different and represent hydrogen or alkyl, n is 0 or 1, and R3 and R4 are alike or different and represent hydrogen, alkyl, cycloalkyl, aralkyl or phenyl, at least one of R3 and R4 being other than hydrogen, or wherein R3 and R4 together with the - N = form a 5 or 6 atom monoheterocyclic amino radical, or an acid addition salt or quaternary ammonium salt thereof, the terms "lower alkyl" and "lower alkoxy" denoting radicals containing 1 to 8 carbon atoms. The invention also includes a process for the preparation of (benzyloxy-3-indole)-alkylamines which comprises reducing the carbonyl group of a (benzyloxy-3-indole)-alkanoylamide to a methylene group.  Heterocyclic radicals which -NR3R4 can represent include piperidyl, morpholyl, pyrrolidyl and thiomorpholyl radicals. Suitable reducing agents are lithium aluminium hydride, lithium borohydride, sodium and alcohol, or hydrogen with a catalyst, preferably platinum.  Suitable media for the catalytic reduction are tetrahydrofuran, ether, isopropyl ether, morpholine and dioxane, the reduction usually being effected at the boiling point of the solvent though temperatures from about 0 DEG  to 100 DEG  C. are suitable. The products may be isolated from the reaction mixture as the free base, the salt with an acid such as hydrochloric, hydrobromic, sulphuric, acetic, tartaric or citric, or as quaternary ammonium salts such as the methochloride, ethobromide and benzyl chloride. The starting materials may be prepared by the series of reactions set out in Specifications 720,584, 728,013, 744,765 and 744,772.  The products are suitable starting materials for the production of (hydroxy-3-indole)-alkylamines, such as 5-hydroxytryptamine (serotonin) by the method of Specification 744,774.  The description includes a preparation of a -3-(5-benzyloxyindole)-N-benzyl-N-methylacetamide by the method of example 1 of Specification 744,772.  In example (1) 5-benzyloxy - 3 - [2 - (N - benzyl - N - methylamino)ethyl] - indole is prepared by reduction with lithium aluminium hydride of a -3-(5-benzyloxyindole) - N - benzyl - N - methylacetamide, and is converted to the hydrochloride or other salts. 5-Benzyloxy-3-(2-aminoethyl)-indole and its salts are prepared similarly.  In an analogous manner are prepared (2) 5 - benzyloxy - 3 - [2 - (N.N - dibenzyl amino) - ethyl]indole; and (3) its hydrochloride; (4) 5 - benzyloxy - 3 - [2 - (N,N-dimethylamino) - ethyl] - indole; (5) 5 - benzyloxy - 3 - [2 - (1 - piperidino) - ethyl] - indole (a  - 3 - (5 - benzyloxyindole) - acetopiperidide, for use as starting material, is obtained by the method of example (11) of Specification 744,772.  A list is given of similar compounds containing 2 - piperidino - ethyl, 1 - methyl - 2 - piperidinoethyl, 2 - morpholinoethyl, 2 - pyrrolidinoethyl, 2 - (4 - thiomorpholino) - ethyl, 3 - piperidino - propyl, and 1 - ethyl - 3 - (1 - piperidino)-propyl groups, in some cases with 2-ethyl groups, which are prepared similarly; (6) 5-(p,p1 - dimethylbenzhydryloxy) - 3 - [1 - methyl-3 - (N,N - dibenzylamino) - propyl] - indole (the reduction being effected with lithium borohydride).  A list of similar 5-alkylbenzyloxy-3-indole)-alkanoylamides, containing p-methylethyl and propyl substituents and N-substituents selected from isopropyl, benzyl and phenyl radicals; (7) 2-ethyl-5-(p,p1-dichlorobenzhydryloxy) - 3 - [2 - (N - methyl - N - benzylamino) - ethyl] - indole (the reduction being effected with sodium and alcohol).  Similar (5-halobenzyloxy - 3 - indole) - alkylamines are mentioned containing p-bromo and p-iodo substituents and N-substituents selected from methyl, cyclohexyl, benzyl and isopropyl radicals; (8) 5 - (p,p1 - dimethoxybenzhydryloxy) - 3 - [3 - (N,N - dibenzylamino) - propyl]-indole, and similar (5 - alkoxybenzyloxy - 3-indole)-alkylamines containing p-methoxy and ethoxy groups and N-substituents selected from cyclohexyl, benzyl and ethyl radicals; (9) 5-benzyloxy - 3 - [3 - (N,N - diethylamino) - propyl] - indole and similar compounds containing N-substituents selected from methyl isopropyl and benzyl radicals; (10) 5-benzhydryloxy - 3 - [2 - (N - benzylamino) - ethyl] - indole and similar compounds containing substituted ethyl-indole groups and N-substituents selected from ethyl, cyclopentyl, methyl and phenyl radicals; (11) 5 - benzyloxy - 3 - [2 - (N,N - dibutylamino) - ethyl] - indole and similar compounds containing 2 - (N - benzylamino)-ethyl, 2 - (N,N - dicyclohexylamino) - ethyl, 2-(N - cyclohexylamino) - ethyl, 2 - (N - methylamino) - ethyl, 3 - (N - methyl - N - benzylamino) - propyl, and 1 - methyl - 3 - (N - benzylamino) - propyl radicals; (12) 5 - benzyloxy-3 - [2 - (N - benzyl - N - phenethylamino) - ethyl indole; and (12) 2 - methyl - 5 - benzyloxy - 3-[2 - (N,N - dibenzylamino) - ethyl] - indole.