Patent GB-797179-A (GB)
Title: Improvements in or relating to phenthiazine derivatives
Filed: 1956-09-10
Abstract: The invention comprises compounds of the formula <FORM:0797179/IV (b)/1> (wherein A represents a single bond or a divalent hydrocarbon group containing from 1 to 3 carbon atoms, the groupings -N(R)2 are the same or different and represent either dialkyl amino groups in which the alkyl groups contain not more than 4 carbon atoms, or heterocyclic groups, e.g. pyrrolidino, piperidino, morpholino, piperazino, or 4-alkylpiperazino; the benzene rings of the phenthiazine nucleus may be substituted by halogen atoms, or alkyl or alkoxy groups containing at most four carbon atoms), their addition salts formed with mineral or organic acids, 8-halogeno-xanthine salts, theophylline acetates, and quaternary ammonium derivatives. Preferred addition salts include hydrohalides, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, oxalates, methane sulphonates, and ethane disulphonates, and preferred quaternary salts are formed with methyl or ethyl chloride, bromide, or iodide, or with allyl or benzyl chloride or bromide.  The compounds are prepared: (a) by reaction of a diamino-alcohol HO.A.CH : (CH2NR2)2 with a reactive derivative (particularly an ester or halide) of a phenthiazine-10-carboxylic acid, preferably in the presence of a condensing agent such as an alkali metal carbonate or hydroxide or a tertiary amine; (b) by condensation of a secondary amine HN(R)2 with a phenthiazine of formula <FORM:0797179/IV (b)/2> in which X and Y each represent a residue of a reactive ester, such as a halogen atom or a sulphuric or sulphonic ester group, or one of them may instead represent the group -N(R)2; (c) by reaction of a chlorocarbonate of a diamino - alcohol of formula Cl.COO.A.CH : (CH2.NR2)2 with a phenthiazine; or (d) for the production of compounds in which R is alkyl, by alkylation of the corresponding compound bearing a primary amino group or groups.  In examples: (1) phenthiazine-10-carbonyl chloride and 1,3 - bis - (dimethylamino) - 2 - propanol are heated in toluene, the mixture extracted with acid, extracts made alkaline and 1,3 - bis - (dimethylamino) - 2 - propyl phenthiazine-10-carboxylate isolated by ether extraction and characterised as its dihydrochloride and its mono-methiodide; similarly are prepared the following esters of phenthiazine 10-carboxylic acid: 1,3-di-piperidino-2-propyl and its dimethiodide salt, 2,2-bis-(dimethylaminomethyl)-ethyl, and its dimethiodide, 1,3-bis-(diethylamino) - 2 - propyl, 1,3 - bis - (di - n - butylamino)-2-propyl as its dihydrochloride, 1,3 - bis - (2 - methylpiperidino) - 2 - propyl, and likewise 1,3 - bis - (dimethylamino) - 2 - propyl 3 - chlorophenthiazine - 10 - carboxylate, 1,3-bis - (dimethylamino) - 2 - propyl 3 - methylphenthiazine - 10 - carboxylate, and 1,3 - bis - (4 - methyl - piperazinyl) - 2 - propyl 3 - methoxyphenthiazine-10-carboxylate. Starting materials.  1,3 - bis - (Dimethylamino) - 2 - propanol, 1,3 - dipiperidino - 2 - propanol, 1,3 - bis - (di - n - butylamino) - 2 - propanol and 1,3 - bis - (2 - methylpiperidino) - 2 - propanol are prepared by the action of the appropriate amine, e.g. dimethylamine, on epichlorhydrin.