Patent GB-783289-A (GB)
Title: New phenthiazine derivatives and processes for their preparation
Inventor: HORCLOIS RAYMOND JACQUES
IPC: C07D279/18
Filed: 1954-11-12
Abstract: The invention comprises phenthiazine derivatives containing the structure: <FORM:0783289/IV (a)/1> wherein X represents a hydrogen or halogen atom or a lower alkyl or lower alkoxy group (i.e. containing not more than 6 carbon atoms) and Y represents a sulphur atom or an SO2 group; A and B each represent a divalent straight or branched chain aliphatic hydrocarbon group containing 2 to 4 carbon atoms, R1 and R2 are alike or different and either each represents a hydrogen atom or a lower alkyl or a cycloalkyl group or R1 and R2 together with the nitrogen atom to which they are attached collectively represent a mononuclear heterocyclic radical and R3 represents a hydrogen atom or a lower alkyl or benzyl group.  Such compounds are obtained by the interaction of a compound of the structure: <FORM:0783289/IV (a)/2> with a compound Q, the group P and the compound Q being such that Q will react with the compound of said structure to introduce or form at the 10-position of the ring a substituent grouping of the structure: <FORM:0783289/IV (a)/3> wherein A1 and B1 each represent a divalent straight or branched aliphatic hydrocarbon group containing 2 to 4 carbon atoms or a divalent group which may be converted thereto by reduction, and where either or both of the starting materials contain one or more convertible groups, reduction of the convertible group(s) into the desired final group(s).  More specific embodiments are (a) the reaction of an ester of the formula: <FORM:0783289/IV (a)/4> with a phenthiazine derivative of the formula: <FORM:0783289/IV (a)/5> (b) the action of a diamine of the formula: <FORM:0783289/IV (a)/6> upon a phenthiazine derivative of the formula: <FORM:0783289/IV (a)/7> (c) the action of a base of the general formula HNR1R2 upon a phenthiazine derivative of the formula: <FORM:0783289/IV (a)/8> wherein Z is the acid residue of a reactive ester When A or B are branched chains, the products can be obtained in optically active form by resolution of the racemic mixture or by employing optically active starting compounds.  "Convertible groups" are, for example, -A2-CO, -CO-B2- and -CO-B3CO-, wherein A2 and B2 are divalent hydrocarbon radicals of 1 to 3 carbon atoms and B3 represents a divalent hydrocarbon group containing 1 or 2 carbon atoms.  Reduction may be effected with lithium aluminium hydride. The products may be quaternated or converted to addition salts with e.g. hydrochloric acid or 8-chlorotheophylline.  In examples: (1) 10-(2-chloroethyl) phenthiazine is heated with 1-ethylamino-2-diethylaminoethane to give 1-(10-phenthiazinyl)-3 - aza - 3 - ethyl - 5 - diethylaminopentane; (2) 1 - (10 - phenthiazinyl) - 4 - aza - 4 - ethyl-6 - diethylaminohexane (as its dimaleate); and (3) 1 - (3 - chloro - 10 - phenthiazinyl) - 3 - aza-3 - ethyl - 5 - diethylaminopentane maleate are prepared similarly; (4) 3-chlorophenthiazine and 1 - (N - 3 - chloropropyl - N - ethyl)-amino-2-diethylaminoethane are reacted in the presence of sodamide to give 1-(3-chloro-10-phenthiazinyl) - 4 - aza - 4 - ethyl - 6 - diethylaminohexane (as dimaleate).  By analogous methods to (4) are prepared: (5) 1-(10-phenthiazinyl) - 3 - aza - 3 - ethyl - 5 - diethylaminopentane; (6) 1-(3-methyl-10-phenthiazinyl)-4-ethyl - 4 - aza - 6 - diethylaminohexane; (7) 1-(9 - dioxy - 10 - phenthiazinyl) - 4 - ethyl - 4-aza - 6 - diethylaminohexane; (8) 1 - (10-phenthiazinyl) - 3 - aza - 6 - (1 - pyrrolidinyl) hexane (and dimaleate); (10) 1-(10-phenthiazinyl) - 3 - aza - 5 - (1 - ethyl - 4 - piperazinyl) pentane trihydrochloride.  In further examples: (9) 10-(2-hydroxy-1-propyl)-phenthiazine toluene - p - sulphonate and 1 - ethylamino - 2 - diethylaminoethane are reacted to give 1-(10-phenthiazinyl) - 2 - methyl - 3 - aza - 3 - ethyl-5-diethylaminopentane hydrochloride; (11) 10-(2 - 21 - chloroethylaminoethyl) phenthiazine hydrochloride is heated with piperidine to give 1 - (10 - phenthiazinyl) - 3 - aza - 5 - piperidinopentane (and dimaleate); (12) 1-(10-phenthiazinyl) - 2 - methyl - 3 - aza - 3 - ethyl 5-piperidinopentane dihydrochloride; and (13) 1-(10 - phenthiazinyl) - 4 - benzyl - 4 - aza - 6-morpholinohexane dihydrochloride are prepared similarly to (11); (14) 1-(3-chloro-10-phenthiazinyl) - 4 - piperidinoacetyl - 4 - azapentane is reduced with lithium aluminium hydride to 1 - (3 - chloro - 10 - phenthiazinyl)-4 - methyl - 4 - aza - 6 - piperidinohexane; (15) 1 - (3 - chloro - 10 - phenthiazinyl) - 4-methyl - 4 - aza - 6 - cyclohexylaminohexane is obtained similarly; (16) 1-(10-phenthiazinyl)-3 - ethyl - 3 - aza - 5 - diethylaminopentane is converted to the dimethiodide; (17) 1-(10-phenthiazinyl) - 3 - ethyl - 3 - aza - 5 - diethylaminopentane diethiodide; and (18) 1-(10-phenthiazinyl) - 2 - methyl - 3:6:6 - triethyl-3 - aza - 6 - azaniumoctane iodide are obtained similarly; (19) 3-(3-methoxy-10-phenthiazinyl) propyl toluene-p-sulphonate and 1-ethylamino-2-diethylaminoethane are refluxed in propanol to give 1 - (3 - methoxy - 10 - phenthiazinyl) - 4-aza - 4 - ethyl - 6 - diethylaminohexane which is converted to the picrate.  Starting materials.  1 - (N - 3 - chloropropyl-N - ethyl) - amino - 2 - diethylaminoethane is obtained by reacting 1-chloro-3-bromopropane with 1-ethylamino-2-diethylaminoethane.  1 - (N - 2 - Chloroethyl (or propyl - N - ethyl) amino - 2 - diethylaminodihydrochloride is obtained by treating 1-(N-2-hydroxyethyl (or propyl - N - ethyl) amino - 2 - diethylaminoethane with hydrogen chloride and thionyl chloride.  1 - (N - 3 - Hydroxypropyl - N - ethyl) amino-2-diethylaminoethane is obtained by heating 1-ethyl - amino - 2 - diethylaminoethane with 3-chloropropan - 1 - ol and aqueous sodium iodide.  1 - (3 - 21 - hydroxyethylaminopropyl)pyrrolidine is obtained from 1-(3-chloropropyl) pyrrolidine and ethanolamine in the presence of sodium ethoxide.  10 - (2 - 21 - Chloroethylaminoethyl)phenthiazine hydrochloride is obtained by treating the corresponding hydroxy compound with hydrogen chloride and thionyl chloride.  1 - (3 - Chloro - 10 - phenthiazinyl) - 4 - piperidinoacetyl - 4 - azapentane is obtained by heating with piperidine 1-(3-chloro-10-phenthiazinyl4 - chloroacetyl - 4 - azapentane, in turn obtained from 3-chloro-10-(3-methylaminopropyl) phenthiazine and chloroacetyl chloride.  1 - (3 - Chloro - 10 - phenthiazinyl) - 4 - cyclohexylaminoacetyl - 4 - azapentane is prepared by boiling 1-(3-chloro-10-phenthiazinyl)-4-chloracetyl-4-azapentane with cyclohexyl amine.