Patent GB-789703-A (GB)
Title: New phenthiazine derivatives and processes for their preparation
IPC: C07D/
Filed: 1955-11-04
Abstract: The invention comprises the racemic and optically active phenthiazine derivatives of the formula: <FORM:0789703/IV (b)/1> and salts thereof, including their quaternary ammonium derivatives, wherein Y represents a sulphur atom or an > SO2 group, X represents a lower alkyl or lower alkoxy group, containing at most four carbon atoms, preferably in position 3 (Beilstein numbering), R1 is lower alkyl and R2 and R3 both represent lower alkyl groups or one of them represents hydrogen with the other being lower lower alkyl, or R2 and R3 together with the N atom form a mono-nuclear heterocyclic group, e.g. pyrrolidino, piperidino and morpholino. The above compounds are prepared by the following methods: (a) reacting phenthiazine (or its 9; 9 -dioxy derivative) carrying a nuclear X-substituent with a reactive ester Z,CH2,CHR1 CH2,NR2R3 or an acid addition salt thereof, Z being a halogen atom or the residue of a sulphuric or sulphonic ester; (b) condensation of an amine HNR2R3 with a phenthiazine (or 9 : 9-dioxy derivative) carrying a nuclear X-substituent and substituted at position 10 by -CH2,CHR1,CH2Z; (c) alkylation of the corresponding primary or secondary amines, e.g. by methylation with HCHO and hydrogen; (d) reduction of the corresponding compounds wherein the 10-substituent is -CH2 CHR1CONR2R3 or -CH2CHR1CH2N(R2) COR4, (CH2R4 represents R3); (e) reduction in the presence of an amine HNR2R3 of the corresponding phenthiazine derivative wherein the 10-substituent is -CH2CHR1T, (T being -CN or -CHO); (f) cyclization of compounds of the formula: <FORM:0789703/IV (b)/2> in the presence of an alkali condensing agent (e.g. alkali metal hydroxide or carbonate), preferably in a solvent such as dimethyl formamide and in the presence of a dehydrohalogenation catalyst, e.g. copper powder; (g) the dioxophenthiazines are also prepared by oxidation of the corresponding phenthiazines.  The optical isomers may be obtained by resolution of the racemates or by synthesis from optically-active starting materials or intermediates.  The bases have therapeutic activity and are preferably employed as acid addition or quaternary ammonium salts, e.g. hydrohalides, 8-chlorotheophyllinates, and methiodides.  In examples: (1) 3-ethylphenthiazine and sodamide are treated with 1 - dimethylamino - 2 - methyl - 3-chloropropane in xylene to give 3-(31-ethyl-101-phenthiazinyl) - 2 - methyl - 1 - dimethylaminopropane, characterized as the HCl salt; (2) to (7), similarly are prepared the corresponding 31-methyl, 31-methoxy-, 31-n-propyl- and 31-ethoxy derivatives and also 3-(31-ethyl-101-phenthiazinyl) - 2 - ethyl - 1 - dimethylaminopropane, and 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - pyrrolidinopropane; (8) 3 - (31 - methoxy - 101 - phenthiazinyl) - 2-methylpropyl toluene p-sulphonate is autoclaved with ethanol and dimethylamine giving 3 - (31 - methoxy - 101 - phenthiazinyl) 2 - methyl - 1 - dimethylaminopropane, (A); (9) optically active 3-(31-methoxy-101-phenthiazinyl) - 2 - methyl - 1 - aminopropane hydrochloride in methanol and aqueous HCHO is hydrogenated over Pt2O to give laevo-rotatory A; (10) as in (9) using the corresponding optically active 31-ethyl compound characterizing the product as its acid maleate; (11) 3-(31 - methoxy - 101 - phenthiazinyl) - 2 - methyl-1-methylaminopropane is alkylated as in (9) to A; (12) 3-(31-methoxy-101-phenthiazinyl) -2-methyl-1-methyl-formamidopropane is reduced with LiAlH4 in tetrahydrofuran to yield A; (13) as in (12), using optically active starting material; (14) 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide is reduced as in (12) to A, also prepared (15) by hydrogenation over Pd-BaSO4 of 3-(31 - methoxy - 101 - phenthiazinyl) - 2 - methylpropionitrile in methanol containing dimethylamine; (16) oxidation of A in acetic acid containing H2O2 and H2SO4 gives 3-(31-methoxy-91 : 91 - dioxy - 101 - phenthiazinyl) - 2 - methyl-1-dimethylaminopropane, purified via its acid fumarate; (17) to (19) A is converted to its quaternary salt with benzyl bromide, its laevorotatory l-tartrate, and dextro-rotatory d-tartrate from which the optical isomers of the base are isolated; (20) 2-bromo-21-(3-dimethylamino - 2 - methylpropylamino) - 41 - methoxydiphenyl sulphide, dimethylformamide and potassium carbonate and refluxed with copper powder to yield A. The preparation of the following starting materials is described: 1-dimethylamino-2-methyl-3-chloropropane from SOCl2 and 3-dimethylamino - 2 - methylpropan - 1 - ol, itself prepared by reduction of 3-dimethylamino-2-methylpropionaldehyde; 1 - dimethylamino-2-ethyl-3-chloropropane hydrochloride by a similar method; 3-n-propylphenthiazine by Wolff-Kishner reduction of 3-propionylphenthiazine, which is obtained from n-propionyl chloride and 10-acetyl-phenthiazine; 3-ethoxyphenthiazine by cyclization of 3-ethoxydiphenylamine with sulphur; 3 - (31 - methoxy - 101 - phenthiazinyl)-2 - methylpropyl toluene - p - sulphonate by esterification of 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - propanol, prepared by LiAlH4 reduction of methyl 3-(31-methoxy-101 - phenthiazinyl) - 2 - methylpropionate (B), itself obtained from the corresponding nitrile by hydrolysis and treatment with diazomethane; optically active 3-(31-methoxy-101-phenthiazinyl) - 2 - methyl - 1 - aminopropane hydrochloride by LiAlH4 reduction of 3-(31-methoxy - 101 - phenthiazinyl) - 2 - methylpropionitrile, prepared from aqueous ethanolic KCN and 1-(31-methoxy-101-phenthiazinyl)-2-propyl toluene p-sulphonate, which is obtained from 3-methoxyphenthiazine by condensation with L-propylene oxide in presence of lithium, and esterification of the 1-(31-methoxy-101-phenthiazinyl)-isopropanol produced; optically-active 3 - (31 - ethyl - 101 - phenthiazinyl) - 2 - methyl-1-aminopropane is similarly prepared; 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl-1-methylaminopropane is prepared by hydrolysis of 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - 1 - methylformamidopropane, itself prepared from the sodium derivative of 3-methoxyphenthiazine and 1-methylformamido-2-methyl-3-chloropropane, which is obtained from methyl 3-methylamino-2-methylpropionate by reduction with LiAlH4, treatment with formamide, and then SOCl2; optical isomers of methyl-3-methylamino - 2 - methylpropionate are produced by resolution with camphosulphonic acid; 3 - (31 - methoxy - 101 - phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide is prepared from dimethylamine and B; 2 - bromo-21 - (3 - dimethylamino - 2 - methylpropylamino)-41 - methoxydiphenyl sulphide from 2 - bromo-21 - amino - 41 - methoxydiphenyl sulphide and 3 - dimethylamino - 2 - methyl - 1 - chloropropane in the presence of sodamide.  Specifications 608,208, 632,277, 673,005 and 701,741 are referred to.