Patent GB-789811-A (GB)
Title: New phenthiazine derivatives and processes for their preparation
Inventor: JACOB ROBERT MICHEL
IPC: C07D/
Filed: 1954-11-29
Abstract: The invention comprises racemic and optically active phenthiazine derivatives of the general formula <FORM:0789811/IV (b)/1> and their salts and quaternary ammonium derivatives (wherein X represents a sulphur atom or an SO or SO2 group, and R1 and R2 are the same or different and each represents a hydrogen atom or an alkyl group containing not more than four carbon atoms or together with the N atom represent a mononuclear heterocyclic group, e.g. pyrrolidino, piperidino and morpholino); also processed for their preparation (a) by interaction of phenthiazine (or its > SO or > SO2 analogues) with a halogenoamine of formula Hal-A-NR3R4 or an acid addition salt thereof (A is either the branched chain -CH2.CH(CH3).CH2- or a group convertible thereinto by reduction, R3 and R4 either represent R1 and R2 or groups convertible thereto), and if necessary subsequently transforming any "convertible" groups by reduction; (b) by condensing a phenthiazine (or the > SO or > SO2 analogue) substituted at position 10 by the group -A.Y with an amine HNR3R4 (Y is the residue of a reactive ester, e.g. a halogen atom or a sulphuric or sulphonic ester group, A, R3 and R4 are as above defined), thereafter reducing any "convertible" groups if present; (c) by alkylation of the corresponding primary or secondary amines, e.g. methylation with HCHO and hydrogen; (d) by reduction of corresponding compounds wherein either the 10-substituent is -CH2.CH(CH3).CO.NR3R4 or -CH2.CH(CH3).CH2.N(R3)CO.R5, (-CH2R5 represents R4); (e) by reduction of corresponding compounds wherein the 10-substituent is -CH2.CH(CH3).CN in the presence or absence of a primary or secondary amine depending whether a primary, secondary or tertiary amine is required; (f) by cyclization of compounds of formula <FORM:0789811/IV (b)/2> in the presence of an alkali condensing agent (e.g. alkali metal hydroxide or carbonate), preferably in a solvent such as formamide or acetamide and in the presence of a dehydrohalogenation catalyst, e.g. copper powder; and (g) of the oxophenthiazines (X is <SO or <SO2) by oxidation of the corresponding phenthiazine derivative.  The novel compounds may also be prepared by reduction of compounds wherein the 10 - substituent is -CH2.CH(CH3).CHO in the presence of an amine HNR3R4, and in the case of the phenthiazine compounds by cyclization with sulphur in the presence of iodine of an N-substituted diphenylamine, the N-substituent being -A.NR3R4, with subsequent reduction of "convertible" groups if necessary.  The optically active isomers may be obtained by resolution of the racemates or by synthesis from optically active starting materials or intermediates.  The bases have therapeutic activity, particularly as antihistaminics and spasmolytics, and are preferably employed as acid addition salts or quaternary ammonium salts, e.g. hydrohalides, 8-chlorotheophyllinates, and methiodides.  In examples: (1) phenthiazine and sodamide are refluxed in xylene with 1-chloro - 2 - methyl - 3 - dimethylaminopropane, mixture treated with water and N-methane sulphonic acid, then with NaOH and 3-(10-phenthiazinyl) - 2 - methyl - 1 - dimethylaminopropane (A) isolated with ether and characterized as its hydrochloride; (2) to (4), as in (1), using different halo-amines the following are produced : 3-(10-phenthiazinyl)-2-methyl-1-diethylamino-, 1-piperidino-, and 1-(11-pyrrolidinyl)-propane (characterized as its hemioxalate); (5) racemic 3-(10-phenthiazinyl)-2-methyl-1-aminopropane in acetic acid containing formalin is hydrogenated in presence of Pd-charcoal, giving A; (6) 3-(10-phenthiazinyl)-2-methylpropyl toluene-p-sulphonate is heated in a sealed tube with dimethylamine in propanol giving A characterized as the acid maleate; (7) and (8), as in (5) using l- and d-isomers of 3-(10 phenthiazinyl) - 2 - methyl - 1 - aminopropane respectively and Adams catalyst for hydrogenation, giving optically active forms of A as the acid maleate salts; (9) as in (6) using monomethylamine to give 3-(10-phenthiazinyl)-2-methyl-1-methylaminopropane and its HCl salt; (10) as in (6) using monoethylamine; (11) 3-(10-phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide in ether is refluxed with LiAlH4 and mixture decomposed to give A; (12) oxidation at 15 DEG  C. of A with H2O2 in H2SO4 and glacial acetic acid gives 3-(9-oxy-10-phenthiazinyl) - 2 - methyl - 1 - dimethylaminopropane and its acid maleate; (13) oxidation as in (12) but at 60 DEG  C. yields 3-(9 : 9-dioxy-10-phenthiazinyl) - 2 - methyl - 1 - dimethylaminopropane and its HCl; (14) A is converted to its quaternary salt with ethyl iodide; (15) racemic 3-(10-phenthiazinyl)-2-methylpropionitrile in methanol and dimethylamine is hydrogenated over Pd-BaSO4 to give A; (16) 2-bromo-21-(3 - dimethylamino - 2 - methylpropylamino) diphenyl sulphide, dimethyl formamide, potassium carbonate and copper powder are heated under reflux, mixture cooled, filtered and the crude A obtained by pouring into water purified via the neutral tartrate. The preparation of the following starting materials is described: 1-chloro-2-methyl-3-3-diethylaminopropane from methyl 3-diethylamino-2-methylpropionate by reduction with LiAlH4 to 3-diethylamino-2-methylpropan-1-ol and then treatment with SOCl2; 1-chloro-2-methyl-3-piperidinopropane similarly obtained from methyl 3-piperidino-2-methylpropionate via 3 - piperidino - 2 - methylpropan - 1 - ol; 1 - chloro - 2 - methyl - 3 - (11 - pyrrolidinyl) propane from methyl 3-(11-pyrrolidinyl)-2-methylpropionate via 3-(11-pyrrolidinyl)-2-methylpropan-1-ol; racemic 3-(10-phenthiazinyl)-2-methyl1-aminopropane by hydrogenation with Raney Ni in ammonia of 3-(10-phenthiazinyl)-2-methylpropionitrile (B), itself prepared by the action of ethanolic KCN on 101-phenthiazinyl-isopropyl toluene p-sulphonate obtained from p-toluene sulphonyl chloride and 1-(10-phenthiazinyl) propan - 2 - ol; 3 - (10 - phenthiazinyl) - 2 - methylpropyl toluene p-sulphonate by the action of p-toluene sulphonyl chloride on 3-(10-phenthiazinyl) - 2 - methylpropan - 1 - ol, which is prepared by LiAlH4 reduction of methyl 3-(10-phenthiazinyl) - 2 - methylpropionate, itself obtained from B by hydrolysis and esterification with diazomethane; laevo - 3 - (10 - phenthiazinyl) - 2 - methyl - 1 - aminopropane by hydrogenation with lithium hydride in tetrahydrofuran of laevo-B, which is prepared from laevo 1-bromopropan-2-ol and phenthiazine; the dextro - 3 - (10 - phenthiazinyl) - 2 - methyl - 1 - aminopropane is similarly prepared; 3-(10-phenthiazinyl) - 2 - methyl - N : N - dimethylpropionamide is obtained from dimethylamine and the acid chloride corresponding to B; 2-bromo-21-(3 - dimethylamino - 2 - methylpropylamino) - diphenyl sulphide is prepared by condensing 2-bromo-21-amino-diphenyl 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.