Patent GB-1012618-A (GB)
Title: Indolylalkyl piperidines and preparation thereof
IPC: C07D401/06
Filed: 1962-06-22
Abstract: The invention comprises compounds of the general formula <FORM:1012618/C2/1> and their acid acid addition and quaternary ammonium salts including addition compounds with acidic ion-exchange resins (see Division C3), wherein n is 1 or 2, R1 represents a hydrogen or halogen atom, or a hydroxy, alkoxy, methylenedioxy, alkylmercapto, alkylsulphonyl or benzyloxy group, R2 represents a hydrogen atom or an alkyl or monocarbocyclic-aryl-alkyl group; R3 represents a hydrogen atom, an alkyl group or a monocarbocyclic aryl group, R4 represents a hydrogen atom or one to five alkyl radicals, R5 represents a hydroxy, hydroxy-alkyl, alkanoyloxy, monocarbocyclic aroyloxy, alkanoyloxyalkyl, monocarbocyclic aroyloxyalkyl, cycloalkyl-alkyl, carbo-alkoxy, unsubstituted-carbamyl, N-alkylcarbamyl, N-alkenylcarbamyl, N,N-dialkylcarbamyl, N,N-dialkenylcarbamyl, hydrazido, N-alkyl-hydrazido, N-alkylidenehydrazono, aminomethyl, N-alkylaminomethyl, N-alkenyl amino-methyl, N,N-dialkylaminomethyl, N,N-dialkenylaminomethyl, N-alkylamino, N,N-dialkylamino, N,N-dialkenylamino or alkanoylamino group and Alk represents a C2-7 alkyline residue interposing from 2 to 6 carbon atoms between the indolyl group and the nitrogen atom of the piperidine ring (the term "monocarbocyclic aryl" includes phenyl and phenyl substituted by the groups of R1), and the preparation thereof by reacting in the presence of an acid acceptor a compound of the formula <FORM:1012618/C2/2> with an appropriately substituted piperidine or by reducing, with an alkali metal aluminium hydride, a compound of the formula <FORM:1012618/C2/3> wherein Alk1 is a C1-6 alkylene residue interposing from 1 to 5 carbon atoms between the inoldyle group and the carbonyl group, and R51 is an oxo or C1-6 alkanoyl-amno group or a group defined by R5 or by reacting in the presence of an acid catalyst an R1-substituted phenylhydrazine with a compound of the formula <FORM:1012618/C2/4> Compounds of the invention wherein Alk is 1,2-ethylene and linked to the 3-position of the indole ring, R2 is a hydrogen atom, and R5 is an hydroxy, hydroxylower alkyl, cycloalkyl-lower-alkyl, aminomethyl, N-lower-alkylaminomethyl, N-lower-alkenylaminomethyl, N,N-di-lower-alkylaminomethyl, N,N-di-lower-alkenyl aminomethyl, N-lower-alkylamino or N,N-di-lower-alkylamino are prepared by reducing the corresponding 1-(3-indolyl-glyoxalyl)piperidine with an alkali metal aluminium hydride.  Compounds of the invention wherein R5 is an hydrazido group are prepared by reacting a compound where R5 is a carbo-alkoxy group with hydrazine and this group is in turn converted into an alkylidine hydrazono group by reaction with an aldehyde or ketone and thence into an N-lower-alkylhydrazido group by reduction.  Compounds where R5 is a 4-hydroxy group may also be prepared by reducing a 4-piperidone analogue of any of the intermediates.  Indolylalkanoylpiperidines used as starting materials are prepared by forming the mixed anhydride from an indolylalkanoic acid and an alkyl haloformate and reacting this with an appropriate piperidine.  Indolyalkylhalides are prepared by reducing an indolylalkanoic acid with an alkali metal aluminium hydride to the alcohol and forming the halide.  Indolylglyoxalyl piperidines are prepared by reacting an indole with a glyoxalyl halide.  In all the intermediates containing R5 as a hydrazido, alkylidene hydrazono, or alkylhydrazido the said groups are introduced by the reactions set out above. 1-(3-Acetylpropyl)-4-(2-hydroxyethyl)piperidine is prepared from 4-(2-hydroxyethyl)piperidine and 1-chloro-4-pentanone.ALSO:Pharmaceutical compositions, having hypotensive, sedative, anti-inflammatory, monoamine oxidase inhibitory, cororary dilatory, adrenolytic, tranquillizing and anti-bacterial activity, contain compound of the general formula <FORM:1012618/A5-A6/1> or their acid addition or quaternary ammonium salts or addition compounds with anionic exchange resins, where n is 1 or 2, R1 is a hydrogen or halogen atom, or a hydroxy, alkoxy, methylene dioxy, alkylmercapto, alkylsulphonyl or benzyloxy group; R2 is a hydrogen atom or an alkyl or monocarbocyclic aryl-alkyl group; R3 is a hydrogen atom or an alkyl or a monocarbocyclic aryl group; R4 is a hydrogen atom or a C1-5 alkyl group; R5 is a hydroxy, hydroxy alkyl, alkanoyloxy, monocarbocyclic aroyloxy, alkanoyloxy-alkyl, monocarbocyclic aroyloxyalkyl, cyclo alkyl-alkyl, carboalkoxy, carbamyl, alkyl-, alkenyl-, dialkyl- or dialkenyl-carbamyl, hydrazido, alkyl-hydrazido, alkylidene hydrazono, amino methyl, alkyl-, dialkyl-, dialkenyl-, dialkenylamino methyl, alkyl-, dialkyl-, dialkenyl-, and alkanoylamino groups and Alk is a C2-7 alkylene residue interposing from 2 to 6 carbon atoms between the indolyl group and the H atom of the piperidine ring (the term mono carbocyclic aryl includes phenyl optionally substituted by the groups deified by R1) and, when used as hypotensive agents, may also contain reserpine.