Patent GB-780193-A (GB)
Title: Phenthiazine derivatives and processes for the preparation
Inventor: HORCLOIS RAYMOND JACQUES
IPC: F28F3/12
Filed: 1954-04-27
Abstract: The invention comprises compounds of the formula: <FORM:0780193/IV (a)/1> including not only the bases corresponding to this formula but also the corresponding acid addition and quaternary ammonium salts and addition compounds, wherein A represents a divalent saturated aliphatic hydrocarbon radical with a straight or branched chain containing from 2 to 6 carbon atoms, R1 represents a hydrogen atom or a lower alkyl or an aryl or araliphatic group, Y and Y1 are respectively a hydrogen or halogen atom or a lower alkyl, alkoxy or aryl or aryloxy group, the phenthiazine ring may carry one or more substituents additional to Y and Y1 and one or more of the carbon atoms of the piperazine ring may carry a substituent in the form of a methyl group, the word "lower" applied to an alkyl group meaning one containing not more than 6 carbon atoms.  Such compounds are obtained by reacting a phenthiazine compound having a structure represented by the formula: <FORM:0780193/IV (a)/2> with a compound Q, the group P and the compound Q being such that Q will react with the compound of the said formula to introduce or form at the 10-position of the ring a substituent grouping of the structure: <FORM:0780193/IV (a)/3> A1 representing a divalent saturated aliphatic straight or branched chain hydrocarbon radical containing 2 to 6 carbon atoms or a divalent grouping which is convertible thereto by reduction and R2 representing a hydrogen atom or a lower alkyl, aryl, or araliphatic group or a group convertible thereinto and, where either or both of the said starting materials contain one or more "convertible" groups, transformation of the convertible groups into the desired final atom and/or group.  Specific embodiments are (1) reaction of a phenthiazine of the formula: <FORM:0780193/IV (a)/4> with a piperazine derivative of the formula: <FORM:0780193/IV (a)/5> (X representing the residue of a reactive ester, e.g. a halogen atom or a sulphuric or sulphonic ester radical); (2) interaction of a phenthiazine of the formula: <FORM:0780193/IV (a)/6> with a piperazine derivative of the general formula: <FORM:0780193/IV (a)/7> (3) where the piperazine ring contains no substituent on a carbon atom interaction of a compound of the general formula: <FORM:0780193/IV (a)/8> with an amine of the formula R2NH2.  Such reactions may be effected in the presence of an alkaline condensing agent such as an alkali metal or the hydroxide, amide, hydride or alcoholate thereof.  By the statement that R2 is a group "convertible" into R1 is meant the following possibilities: (I) (for products where R1 is other than hydrogen): (a) intermediates where R2 is hydrogen (convertible into the product by alkylation; (b) intermediates in which R2 is a group -CO-R3, and R3 is an alkyl, aralkyl or aryl group (convertible by reduction into corresponding compounds where R1 is an alkyl or aralkyl group).  (II) Products where R1 represents a hydrogen atom: intermediates contain in the 4-position of the piperazine ring (a) -CH2C6H5, convertible by reduction (debenzylation); (b) -C6H5, convertible by nitrosation and fission; (c) -COOR4 where R4 represents a hydrocarbon group, convertible by hydrolysis; (d) -CO-N(R5)2 where R5 represents any convenient radical such as a hydrocarbon group, convertible by hydrolysis. Further intermediates are compounds of the formul : <FORM:0780193/IV (a)/9> and <FORM:0780193/IV (a)/100> conversion being effected by reduction, e.g. with lithium, A2 being an aliphatic hydrocarbon radical containing 1 to 5 carbon atoms.  An alternative method of preparation comprises the cyclization of a diphenyl sulphide derivative of the formula: <FORM:0780193/IV (a)/111> preferably in solvent comprising an N-substituted amide of a fatty acid containing not more than 3 carbon atoms in the presence of an alkaline condensation catalyst and if desired in the presence of a dehydrohalogenation catalyst such as copper powder, followed, where appropriate, by the conversion of A1 into A and of R2 into R1.  The products have anti-epileptic and anti-emetic properties.  In examples there are prepared by the different methods outlined compounds of the first formula above in which: A is selected from ethylene, trimethylene, 2-phenylallyl and tetramethylene; R1 represents variously hydrogen or methyl, ethyl, propyl, butyl, phenyl or 2-phenylallyl; Y and/or Y1 (when other than hydrogen) represent 1- or 3-chloro, 3-methyl, 3-ethyl, 3-methoxy or 2 : 3 or 2 : 5-dimethyl substituents.  Salts prepared are those with hydrochloric, picric, maleic, theophylline acetic and theobromine acetic acids, and the 8-chlorotheophyllinate.  Methyl iodide and ethyl iodide are used as quaternizing agents.  Starting compounds. 1-(2-Chloroethyl)-4-benzyloxycarbonylpiperazine is obtained by reacting thionyl chloride with 1-(2-hydroxyethyl)-4-benzyloxycarbonylpiperazine hydrochloride which is obtained by condensing ethylene oxide with 1-benzyloxycarbonylpiperazine in methanol.  1 - (2 - Chloroethyl) - 4 - methylpiperazine is obtained from thionyl chloride and 1-(2-hydroxyethyl) - 4 - methylpiperazine.  3 - (3 - Chloro-10 - phenthiazinyl)propyl p - toluenesulphonate is obtained from 3-(3-chloro-10-phenthiazinyl) propanol and p-toluenesulphonyl chloride.  1-(2-Phenylallyl) - 4 - (3 - chloropropyl)piperazine is prepared by reacting 1-chloro-3-bromopropane with 2-phenylallylpiperazine in ether.  1 - (4 - Bromobutyl) - 4 - ethylpiperazine is obtained from thionyl bromide and 1-(4-hydroxybutyl) - 4 - ethylpiperazine.  1 - (2 - Chloroethyl) - 4 - butylpiperazine is obtained similarly.  1 - (2 - Hydroxyethyl) - 4 - butylpiperazine is prepared by heating 1-(2-hydroxyethyl)piperazine with butyl-p-toluenesulphonate and treating the product with sodium hydroxide.  1 - (3 - Chloropropyl) - 4 - methylpiperazine is prepared by reacting 1-chloro-3-bromopropane with 1-methylpiperazine. Similarly obtained are 1 - (3 - chloropropyl) - 4 - ethyl - or butylpiperazines.  2 : 3 - Dimethylphenthiazine is prepared by reacting sulphur with 3 : 4-dimethyldiphenylamine in the presence of iodine. 10-(2-41-Propionyl - 11 - piperazinylethyl)phenthiazine is obtained from propionyl chloride and 10-(2-11-piperazinylethyl)phenthiazine. Similarly obtained is 3 - chloro - 10 - (3 - 41 - acetyl - 11-piperazinylpropyl)phenthiazine. From 10-(2-chloroethyl)phenthiazine and the corresponding carbamylpiperazines are prepared 10-(2-41diethylcarbamyl, 41 - dimethylcarbamyl, 41 - carbamyl, or 41 - phenylcarbamyl - 11 - piperazinylethyl)phenthiazines. 2-Bromo-21-(3-41-methyl-11 - piperazinylpropylamino) - 41 - chlorodiphenyl sulphide is obtained by reacting 1-(3-chloropropyl) - 4 - methylpiperazine with 2-bromo - 21 - amino - 41 - chlorodiphenyl sulphide in xylene in the presence of sodamide.  Specifications 632,277, 641,452 and 716,206 are referred to.