Patent GB-800635-A (GB)
Title: New derivatives of phenthiazine and processes for their production
Inventor: HORCLOIS RAYMOND JACQUES
Filed: 1954-11-09
Abstract: The invention comprises compounds of the formula: <FORM:0800635/IV (b)/1> and their salts and quaternary derivatives, wherein X represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy or lower acyl group, A represents a trivalent aliphatic hydrocarbon chain containing three carbon atoms each of which is linked to a different nitrogen atom and the groups R are methyl or ethyl groups (the word "lower" meaning that the group in question contains not more than four carbon atoms).  Such compounds are obtained by (a) reacting a phenthiazine (appropriately substituted by the radical X) with a bis-(dialkylamino) - halogenopropane, especially a 1 : 3-bis - (dialkylamino) - 2 - chloropropane, wherein the alkyl groups are methyl or ethyl groups, or an acid addition salt thereof; (b) condensation of dimethylamine or diethylamine with a phenthiazine derivative of the formula: <FORM:0800635/IV (b)/2> (wherein A1 either represents the hydrocarbon chain A or a group convertible into the chain A by reduction, Z represents the residue of a reactive ester, such as a halogen atom or a sulphonic or sulphuric ester residue, Z1 is either the same as Z or represents an -N(R)2 group) and, where A1 is other than A, reduction of the grouping A1 into the aliphatic chain A; (c) cyclisation, preferably in a solvent in the form of a substituted amide of a lower aliphatic acid (such as formamides or acetamides) in the presence of a condensing agent (e.g. alkali metal hydroxide or carbonate) and, if desired, in the presence of a catalyst such as copper powder, of a derivative of the formula: <FORM:0800635/IV (b)/3> (wherein Hal represents a halogen atom, A1 either represents the hydrocarbon chain A or a group convertible into A by reduction) and, where A1 is other than A, reduction of the grouping A1 into the aliphatic hydrocarbon chain A.  In method (a) suitable condensing agents are alkali metals or derivatives thereof, such as a hydride, amide, hydroxide, alcoholate or metal alkyl or aryl.  The condensation yields a mixture of isomers, containing as substituents in the 10-position the groups -CH2-CH(NR2) -CH2-N(R)2 and -CH[CH2-N(R)2]2 respectively, which can be separated by fractional crystallization of their dihydrochlorides. The products can be used therapeutically as their acid addition salts, such as hydrohalides or 8-chlorotheophyllinates or as quaternary ammonium salts.  In examples: (1) phenthiazine and 1 : 3 - bis - (dimethylamino) - 2 - chloropropane are reacted in toluene in the presence of sodamide to give a mixture of 10-[2 : 3-bis-(dimethylamino) - 1 - propyl] - phenthiazine and a minor proportion of 10-[1 : 3-bis-(dimethylamino) - 2 - propyl] - phenthiazine; (2) similarly obtained is a mixture of 10-[2 : 3-bis-(diethylamino) - 1 - propyl] - phenthiazine and 10 - [1 : 3 - bis - (diethylamino) - 2 - propyl]-phenthiazine; (3) and (4) the mixed bases of examples (2) and (1) respectively are separated by fractional crystallization of their hydrochlorides; (5) 1-(10-phenthiazinyl)-2-chloro-3-dimethylaminopropane hydrochloride (from the reaction of thionyl chloride on 1-(10-phenthiazinyl) - 2 - hydroxy - 3 - dimethylaminopropane) is heated in a sealed tube with dimethylamine to give 10-[2 : 3-bis-(dimethylamino)-1-propyl]-phenthiazine.  Similarly obtained is 3-acetyl - 10 - [2 : 3 - bis - (dimethylamino) - 1-propyl]-phenthiazine, characterized as its neutral fumarate; (6) 3-methoxyphenthiazine and 1 : 3 - bis - (dimethylamino) - 2 - chloropropane are reacted in xylene in the presence of sodamide to give a mixture of 3-methoxy-10-[2 : 3-bis-(dimethylamino) - 1 - propyl) phenthiazine and a minor proportion of 3-methoxy-10-[1 : 3-bis-(dimethylamino) - 2 - propyl] phenthiazine.  Similarly prepared are (7) a mixture of 3-methyl - 10 - [2 : 3 - bis (dimethylamino) - 1-propyl] phenthiazine and 3-methyl-10-[1 : 3-bis-(dimethylamino) - 2 - propyl] - phenthiazine; (8) a mixture of 3-chloro-10-[2 : 3-bis-(dimethylamino) - 1 - propyl] - phenthiazine and 3-chloro - 10 - [1 : 3 - bis - (dimethylamino) - 2-propyl]-phenthiazine; (9) a mixture of 1-chloro10 - [2 : 3 - bis - (dimethylamino) - 1 - propyl]-phenthiazine and 1 - chloro - 10 - [1 : 3 - bis-(dimethylamino) - 2 - propyl] phenthiazine. In further examples: (10) 10 - [2 : 3 - bis-(dimethylamino) - 1 - propyl] phenthiazine monoethiodide; and (11) 10-[2 : 3-bis (dimethylamino) - 1 - propyl] phenthiazine dimethiodide are prepared by quaternation of the base; (12) 10 - [2 : 3 - bis - (dimethylamino) 1 - propyl]-phenthiazine is prepared by refluxing a mixture of 21 - [2 : 3 - bis - (dimethylamino) propyl] amino - 2 - bromodiphenyl sulphide, dimethylformamide, potassium carbonate and copper powder.  21 - [2 : 3 - bis - (Dimethylamino) propyl] amino - 2 - bromodiphenyl sulphide is prepared by reacting 2-bromo-21-aminodiphenyl sulphide and 1 : 3-bis-(dimethylamino) 2-chloropropane in xylene in the presence of sodamide.