Patent GB-813861-A (GB)
Title: Improvements in or relating to 10-(aminoalkyl)-trifluoro-methyl phenothiazine derivatives
IPC: C07D279/28
Filed: 1956-11-15
Abstract: The invention comprises phenthiazine derivatives of the formula <FORM:0813861/IV (b)/1> and salts thereof with non-toxic organic and inorganic acids (in which formula Z is -S- or -SO-, Y is -CF3, R is hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxyl (containing one to four carbon atoms), A is a divalent aliphatic hydrocarbon chain containing two to six carbon atoms, R1 and R2 are lower alkyl, hydrogen, or when taken together with the nitrogen atom form a five, six or sevenmembered ring, e.g. pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino or azepidino.  Specified salts include those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methane sulphonic, ethane sulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycollic, p-aminobenzoic, glutamic, benzene sulphonic, theophylline acetic, hydrohalic, nitric, sulphuric, sulphamic, and phosphoric acids and with 8-halotheophyllines.  The compounds are prepared by the standard methods for formation of 10-substituted phenthiazines, e.g. by condensation of the trifluoromethylphenthiazine with, for example, a reactive t-aminoalkyl ester, acrylonitrile, or phthalimidoalkyl halide, followed by modification of the terminal cyano, carboxy, tosylate formyl or other group of the alkyl chain of the phenthiazine produced; alternatively 2-halo-x - trifluoromethyl - 21 - dialkylaminoalkylaminodiphenylamines may be cyclized by means of a copper catalyst.  Oxidation, preferably with 30 per cent H2O2 or conc. HNO3, gives the corresponding 5-mono-oxide derivatives, whilst exhaustive oxidation gives the N : 5 : 5-trioxides, from which the 5 : 5-dioxides are obtained by reduction of the N-oxide group with sodium hydrosulphite.  In examples: (1) 2-trifluoromethylphenthiazine in benzene is treated with sodamide and condensed with 3-chloro-1-dimethylaminopropane to give 10 - (31 - dimethylaminopropyl) - 2 - trifluoromethylphenthiazine, characterized as its hydrochloride, citrate, oxalate and (16) its 8-chlorotheophyllinate; (2) oxidation of the oxalate with H2O2 in aqueous ethanol gives the corresponding 5-oxide isolated as its hydrochloride, and using excess H2O2 a 5-dioxide-N-oxide which is reduced with sodium hydrosulphite to 10 - (31 - dimethylaminopropyl) - 2 - trifluoromethylphenthiazine-5-dioxide; (3) to (8) similarly are prepared 8-chloro-10-(31-dimethylaminopropyl) - 2 - trifluoromethylphenthiazine, 8 - chloro - 10 - (21 - N - pyrrolidinyl - 11 and 21 - ethylethyl) - 2 - trifluoromethylphenthiazine (from 2-chloro-1-pyrrolidinylbutane), 8-methoxy - 10 - [31 - (411 - methyl - 111 - piperazinyl)-propyl] - 2 - trifluoromethylphenthiazine pamoate, 8 - ethoxy - 10 - (31 - dimethylaminopropyl) - 2 - trifluoromethylphenthiazine, 10 - [31 - (411 - methyl - 111 - piperazinyl) - propyl] - 2-trifluoromethylphenthiazine and its dimaleate, and using NaOH, 8-methyl-10-(31-N-piperidylpropyl) - 2 - trifluoromethylphenthiazine; (9) 10 - (31 - hydroxypropyl) - 2 - trifluoromethylphenthiazine p-toluene sulphonate is autoclaved with methanol and methylamine, giving 10-(31-methylaminopropyl) - 2 - trifluoromethylphenthiazine as its HCl salt; (10)-(13), (19)-(25), (27), (29)-(31) and (34)-(36), as in (1), using sodamide, NaOH, KNH2 or LiNH2, are prepared the following 2-trifluoromethylphenthiazines: 10-(61-dimethylaminohexyl)-, 10-(21-N-morpholinylethyl)- and its acid maleate, 8-bromo - 10 - (dimethylaminoisopropyl)- and its bismethylene salicylate, 8-trifluoromethyl-10-(31 - dimethylaminopropyl) -, 10 - (21,21 - dimethyl - 31 - dimethylaminopropyl) -, 10 - (31 - dimethylamino - 21 - methylpropyl) - and its HCl salt, 10 - (31 - dimethylaminopropyl) - 7 - methyl -, 10 - (31 - N - morpholinylpropyl) -, 10 - (41 - dimethylaminobutyl) -, 8 - fluoro - 10 - (31 - dimethylaminopropyl) - as its pamoate and citrate, 7 - chloro - 10 - (31 - dimethylaminopropyl)- as its pamoate, 10-(31-N-pyrrolidinylpropyl)-, its acetate and HBr salt, 6-chloro-10-(31-dimethylaminopropyl)-, its maleate, 10-[31-(N-thiomorpholinyl) - propyl] -, 8 - butyl - 10 - [31 - (411 - methyl - 111 - piperazinyl) propyl]-5 - oxido -, 10 - (31 - diethylaminopropyl) - 6 - methyl -, 10 - (21 - pyrrolidinylmethyl - butyl)-, and 10 - (31 - hexahydroazepinylpropyl)-and likewise (28) and (32) 10 - (31 - dimethylaminopropyl)- and 10-(31-diethylaminopropyl) - 4 - trifluoromethylphenthiazine; (14)-10 - (21 - chloroethyl) - 2 - trifluoromethylphenthiazine prepared from 2-trifluoromethylphenthiazine and ethylene oxide, and reaction with thionyl chloride, is refluxed with piperazine and isoamyl alcohol, giving 10-(21-piperazinyl-ethyl)-2-trifluoromethylphenthiazine and then its dimaleate; (15) treatment of the last-named base with ethyl p-toluene sulphonate, sodium carbonate and aqueous methanol gives 10-[21-(411 - ethyl - 111 - piperazinyl) ethyl] - 2 - trifluoromethylphenthiazine as its di-HCl salt and also its difumarate; (17) 10-(21-cyanoethyl)-2-trifluoromethylphenthiazine (prepared from acrylonitrile and the phenthiazine under alkaline conditions) is reduced with LiAlH4 to 10-(31-aminopropyl) - 2 - trifluoromethylphenthiazine hydrochloride and alkylated with n-butyl bromide to the 10-(31-dibutylaminopropyl) derivative; (18) alkylation of the base of (14) with formic acid-formaldehyde gives 10-[21-(411-methyl - 111 - piperazinyl) - ethyl] - 2 - trifluoromethylphenthiazine; (26) 10 - (31 - chloro - 21 - methylpropyl) - 2 - trifluoromethylphenthiazine (from 1 - bromo - 3 - chloro - 2 - methylpropane and the fluorophenthiazine) is refluxed with N-methyl-piperazine in methanol, giving 10-[21-methyl - 31 - (411 - methyl - 111 - piperazinyl) propyl] - 2 - trifluoromethyl phenthiazine and its dimaleate; (33) the 3-amino propyl compound of (17) is refluxed with butyl bis-(b -chloroethyl) amine in butanol, then with tributylamine, giving 10-[31-(411-butyl-111-piperazinyl) propyl] - 2 - trifluoromethylphenthiazine.  2 - and 4 - Trifluoromethylphenthiazines are prepared by the Bernthsen thionation of 3-trifluoromethyldiphenylamine; similarly are obtained 8 - methoxy -, 8 - ethoxy -, 8 - methyl -, 8-bromo-, 7-methyl-, 8-fluoro-, 7-chloro-, and 8 - butyl - 2 - trifluoromethylphenthiazines and also 4 - trifluoromethylphenthiazine; 8 - chloro-2 - trifluoromethylphenthiazine is prepared by the Smiles rearrangement of 4-chloro-2-formamido-21 - nitro - 51 - trifluoromethyldiphenyl sulphide; similarly are obtained 8-trifluoromethyl-6-chloro-, and 6-methyl-2-trifluoromethylphenthiazines.  1 - Chloro - 3 - dimethylamino - 2 - methylpropane is prepared by reverse addition of HBr to methallyl chloride and selective action of the resulting 1-bromo-3-chloro-2-methylpropane with dimethylamine.  8 - Butyl - 2 - trifluoromethylphenthiazine - 5 - oxide is obtained by H2O2 oxidation of the corresponding phenthiazine.  1 - Chloro - 2 - (pyrrolidinylmethyl) - butane is prepared by a Mannich reaction on butyraldehyde, reduction of the Mannich base and halogenation of the amino alcohol.  3 - Chloro - 1 - hexahydroazepinylpropane is prepared by condensation of 3-bromo-1-chloropane and hexamethyleneimine.