Patent GB-176038-A (GB)
Title: Manufacture of new therapeutically active acridine derivatives
IPC: C07D219/10
Filed: 1920-10-14
Abstract: Acridine derivatives of therapeutic value containing in the 9-position the group -NRR1 (where R & R1 represent hydrogen or residues which are not aryl groups) are obtained by treating by known methods an acridine derivative containing in the 9-position an atom or group capable of being exchanged for, or convertible into, the -NRR1 group.  Other substituents such as halogen, -NH2, -NO2, alkyl, or alkyloxy, may be present.  The process may be carried out by the action of ammonia or an amine on a 9-halogen acridine or a 9-RO-acridine (R=alkyl, aralkyl, or aryl) in the presence of a catalyst such as a copper salt; or by reducing a 9-hydrazinoacridine; or by decomposing the acid azide of a 9-acridine carboxylic acid (whereby isocyanates, ureas, or urethanes may be formed as intermediate products); or by treating acridine-9-carboxylic amide with hypohalogenite; amino-9-amino-acridines may be obtained by reducing the corresponding nitro-9-amino-acridines.  According to examples:-2-ethoxy-9-chloroacridine is heated with ethanolamine, 4-amino-antipyrine, diethylamine, piperidine, or b -(p-oxyphenyl)-ethylamine; the product from the latter compound yields a soluble salt with glycollic acid; 9-chloroacridine is heated with alcoholic ammonia; 9-ethoxy-acridine is heated with alcoholic ammonia or ethylamine; 9-phenylhydrazinoacridine hydrochloride is reduced with zinc dust, iron, aluminium, tin, or stannous chloride and acid in the presence of alcohol; 9-amino-acridine is nitrated and the dinitro-body reduced to a triamino-acridine; 3-nitro-9-chloro-acridine Illegible data heated with alcoholic ammonia and the 3-nitro-9-amino-acridine reduced to 3 : 9-diamino-acridine; 3-nitro-7-ethoxy-9-chloro-acridine treated with ammonia gives 3-nitro-7-ethoxy-9-aminoacridine which may be reduced to 3 : 9 : 7-diaminoethyacridine; the azide of acridine-9-carboxylic acid is digested with water and boiled with dilute sulphuric acid; acridine-9-carboxylic azide, or its 2-chloro-derivative is heated with alcohol, the urethane (C13H8N) NH,COOC2H5, or (C13H8NCl) NH.COOC2H5, crystallizing on cooling and giving the corresponding amine on boiling with dilute sulphuric acid; acridine-9-carboxylic amide is ground up with potassium hypobromite solution.  Acridone is formed as a by-product in some of the above reactions. 9-Chloroacridines, for example 2-ethoxy-9-chloroacridines are obtained from the corresponding acridones or arylanthranilic acids by heating with phosphorus oxychloride or pentachloride.  9-RO-acridines (R=alkyl, aralkyl, or aryl) are obtained from 9-halogen acridines and alkali alcoholates or phenolates; 9-ethoxy- and 2 : 9-diethoxy-acridines are mentioned.  9-Hydrazinoacridines are obtained from 9-halogen acridines and hydrazines, for example hydrazine or phenylhydrazine; 9-phenylhydrazino-, 9-hydrazino-, and 2-ethoxy-9-phenylhydrazinoacridines are mentioned, also hydrazino-9 : 9-bisacridine C13H8N.NH.NH.C13H8N.  3-Nitro-9-chloroacridine is obtained by condensing 2 : 4-chlornitrobenzoic acid with aniline to form 5-nitro-diphenylamine-2-carboxylic acid, eliminating water, and treating the 3-nitroacridone with phosphorus pentachloride. 3-Nitro-7-ethoxy-9-chloroacridine is obtained similarly from 2 : 4-chlornitrobenzoic acid and p-phenetidine.  Hydrazide of acridine-9-carboxylic acid or its 2-chlor derivative is produced by esterifying the acid and boiling with hydrazine; treatment with sodium nitrite in acetic acid yields the corresponding azide. 2-Chloro-9-acridinecarboxylic acid is obtained by treating o-chlorbenzaldehyde with MgCH3I, oxidizing the o-chlorphenylethylalcohol to o-chloracetophenone, condensing this with p-chloraniline and converting the resulting 2-chlor-9-methylacridine to the corresponding aldehyde and acid. Amides of acridine-9-carboxylic acids are prepared from the acid chlorides in the usual manner.