Patent GB-721171-A (GB)
Title: Derivatives of ª‰- and ª†- carbolines
IPC: C07D471/04
Filed: 1952-04-30
Abstract: The invention comprises 1 : 2 : 3 : 4-tetrahydro-b - and -g -carbolines of the general formula.  <FORM:0721171/IV (b)/1> (wherein X represents hydrogen or halogen, R represents an alkyl, alkylaminoalkyl, alkylmercaptoalkyl, aralkyl or mononuclear aryl radical, or an aromatic mononuclear heterocyclic radical attached directly or by an alkylene bridge, R1 and R11 are identical or different and each represent hydrogen or an alkyl radical of 1-4 carbon atoms, and m and n are integers the sum of which is 3), and the manufacture thereof by the following methods: (a) reacting the corresponding compounds containing an alkali metal in place of the radical R with an alkyl, alkylaminoalkyl, aryl or aralkyl halide on a reactive ester of the alcohol or phenol corresponding to the radical R; (b) for the tetrahydro-g -carbolines (n=1, m=2), reacting an N : N-substituted phenylhydrazine with a salt of an N-alkylpiperidone-4 in mineral acid solution (with or without isolation of the intermediate phenylhydrazones); (c) for the tetrahydro-b -carbolines (n=2, m=1), condensing a tryptamine, substituted at the indole nitrogen, with formaldehyde or acetaldehyde to effect ring closure, followed, if desired, by alkylation at the 2-nitrogen atom (e.g. by the action of formaldehyde and formic acid).  Some of the products are useful as antihistaminic agents, preferably in the form of their salts with common mineral or simple organic acids.  In examples: (1) N - phenyl - N - benzylhydrazine hydrochloride and N - methylpiperidone - 4 hydrochloride are boiled together in alcoholic hydrochloric acid to produce 2-methyl-5-benzyl-1 : 2 : 3 : 4-tetrahydro-g -carboline, isolated as hydrochloride or liberated therefrom by the action of alkali; the same compound, isolated as its sulphate or naphthalene-1 : 5-disulphonate, is also obtainable by adding methylimino-diethyl-dipropionate to a solution of sodium ethylate in alcohol, distilling of the alcohol in vacuo, boiling the residue with dilute sulphuric acid until evolution of CO2 ceases and boiling the product with N-phenyl-N-benzylhydrazine and sulphuric acid; (2) N : N-diphenylhydrazine is converted as in the first part of (1) to 2-methyl-5 - phenyl - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline; (3) 2-methyl-1 : 2 : 3 : 4-tetrahydro-g -carboline (obtainable from phenylhydrazine hydrochloride and N-methylpiperidone-4 hydrochloride) is refluxed with sodamide in xylene and the resulting sodium derivative is refluxed with dimethylaminoethyl chloride in xylene to give 2 - methyl - 5 - dimethylaminoethyl - 1 : 2 : 3 : 4 - tetrahydro-g -carboline, the maleate of which is described; (4) N-p-chlorobenzyl-N-p-chlorophenylhydrazine methanesulphonate is reacted as in the first part of (1) to form 2-methyl-8-chloro - 5 - p - chlorobenzyl - 1 : 2 : 3 : 4 - tetrahydro-g -carboline, isolated as hydrochloride or methanesulphonate; (5) N-2-pyridyl-N-phenylhydrazine hydrochloride similarly yields 2-methyl - 5 - (21 - pyridyl) - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline; (6) N - n - butyl - N - phenylhydrazine similarly gives 2-methyl-5-n-butyl - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline, the maleate of which is described; (7) 1-methyl-1 : 2 : 3 : 4 - tetrahydro - b  - carboline is methylated with formaldehyde and formic acid and the resulting 1 : 2-dimethyl compound is treated as in (3) to produce 1 : 2-dimethyl-9-dimethylaminoethyl - 1 : 2 : 3 : 4 - tetrahydro - b  - carboline, the naphthalene-1 : 5-disulphonate of which is described; (8) 1-benzyltryptamine (from N-benzyl - N - phenylhydrazine and g  - aminobutyraldehyde diethylacetal) is heated with acetaldehyde in dilute hydrochloric acid to form 1 - methyl - 9 - benzyl - 1 : 2 : 3 : 4 - tetrahydro - b  - carboline; (9) the product of (8) is methylated in the 2-position with formaldehyde and formic acid; the picrate of the product is described; (10) N - p - chlorobenzyl - N - phenylhydrazine is reacted as in the first part of (1) to form 2 - methyl - 5 - p - chlorobenzyl - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline; (11) 2 - methyl - 8 - chloro - 9 - p - methoxybenzyl - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline is similarly prepared; (12) N-ethylmercaptoethyl-N-phenylhydrazine similarly yields 2-methyl-9-b -ethylmercaptoethyl - 1 : 2 : 3 : 4 - tetrahydro - g  - carboline, the maleate of which is described; (13) N - a  - pyridylmethyl - N - phenylhydrazine similarly gives 2 - methyl - 5 - a  - pyridylmethyl-1 : 2 : 3 : 4 - tetrahydro - g  - carboline as hydrochloride.  N : N - Disubstituted hydrazines are prepared by reducing the Schiff's bases from p-chloroaniline and p-chlorobenzaldehyde, aniline and p-chlorobenzaldehyde, p-chloroaniline and anisaldehyde, and aniline and a -formylpyridine, treating the products with nitrous acid and reducing the nitroso group so introduced.  N - 2 - pyridyl - and N - ethylmercaptoethyl - N - phenylhydrazine are produced by the last two of the foregoing steps from, respectively, 2-phenylaminopyridine (from aniline and 2-bromopyridine) and ethylmercaptoethylaniline (from aniline and b -chlorodiethyl sulphide).