Patent GB-814512-A (GB)
Title: New phenthiazine derivatives and their preparation
IPC: C07D/
Filed: 1957-07-15
Abstract: The invention comprises phenothiazine derivatives of the general formula <FORM:0814512/IV (b)/1> and their acid addition and quaternary ammonium salts (wherein X is S or SO; R1 and R2 are the same or different and either each is an alkyl group containing not more than five carbon atoms, or one of R1 and R2 is such an alkyl group and the other is hydrogen, or R1 and R2 with the adjacent nitrogen atom form a heterocyclic group; A is a straight or branched chain divalent aliphatic hydrocarbon group containing two to five carbon atoms, unsubstituted or substituted by <FORM:0814512/IV (b)/2> wherein B is a single bond or a methylene group, the nitrogen atoms of the phenothiazine nucleus and <FORM:0814512/IV (b)/3> being separated by at least two carbon atoms), and their preparation by the following processes: (1) reacting a 3-dimethylsulphamoylphenothiazine (II): <FORM:0814512/IV (b)/4> with the compound (III): <FORM:0814512/IV (b)/5> (wherein Y is the acid residue of a reactive ester, e.g. a halogen atom or a sulphuric or sulphonic ester residue) in the form of the base or of a salt thereof; (2) thermally decarboxylating above 100 DEG  C. an aminoalkyl phenothiazine-10-carboxylate (IV): <FORM:0814512/IV (b)/6> (3) reacting an amine HNR1R2 with a reactive ester (V): <FORM:0814512/IV (b)/7> (4) alkylating the corresponding primary or secondary amines; (5) when X is a sulphur atom reducing, e.g. by catalytic hydrogenation, a phenothiazine (VI): <FORM:0814512/IV (b)/8> (wherein A1 is such that A1-CH2- represents A); (6) cyclizing a compound (VII): <FORM:0814512/IV (b)/9> (wherein one of R3 and R4 is hydrogen and the other is a dimethylsulphamoyl group, and Hal is a halogen atom) in the presence of a basic condensing agent; (7) when <FORM:0814512/IV (b)/100> is a 4-acyloxyalkylpiperazino group, acylating the corresponding 4-hydroxyalkylpiperazino derivatives; and (8) when X is SO, oxidizing the corresponding compounds in which X is sulphur. When the group -A- is an asymmetric branched chain, isomerization may take place during the reactions involved in methods (1) and (2) above, and when the chain A contains an asymmetric carbon atom the compounds (I) may exist in optically active forms.  The phenothiazines of the invention are preferably employed in the form of acid addition salts or quaternary ammonium derivatives.  Examples describe the preparation of the following compounds by the methods indicated: 3-dimethylsulphamoyl - 10 - (3 - dimethylamino - 2 - methylpropyl) phenothiazine (1) and (6), as its hydrochloride and picrate; 3-dimethylsulphamoyl - 10 - (3 - dimethylaminopropyl) phenothiazine (1), (4) and (5), as its acid oxalate and methanesulphonate; 3 - dimethylsulphamoyl - 10 - (3 - 41 - methyl - 11 - piperazinylpropyl) phenothiazine, (1) and (2), and its diacid fumarate; 3-dimethylsulphamoyl-10-(3-41 - ethyl - 11 - piperazinylpropyl) phenothiazine, (1); 3 - dimethylsulphamoyl - 10 - (2 - dimethylaminopropyl) phenothiazine, (1), as its hydrochloride; 3 - dimethylsulphamoyl - 10 - (3 - 11-pyrrolidinopropyl) - phenothiazine, (1), as its hydrochloride; 3 - dimethylsulphamoyl - 10 - (3-morpholinopropyl) phenothiazine, (1), as its oxalate; 3 - dimethylsulphamoyl - 10 - (3 - 41-methyl - 11 - piperazinyl - 2 - methylpropyl) phenothiazine, (1); 3-dimethylsulphamoyl-10-(3 - 41 - hydroxyethyl - 11 - piperazinylpropyl) phenothiazine, (3), as its dimethanesulphonate; 3 - dimethylsulphamoyl - 10 - (3 - methylaminopropyl) phenothiazine, (3), as its hydrochloride; 3 - dimethylsulphamoyl - 10 - [3 - (4 - 31 - hydroxypropyl - 1 - piperazinyl) propyl] phenothiazine, (3); 3-dimethylsulphamoyl-10 - (3 - 41 - acetoxyethyl - 11 - piperazinylpropyl) phenothiazine, (7), as its di-acid maleate; 3 - dimethylsulphamoyl - 10 - (2 : 3 - bis - dimethylaminopropyl) phenothiazine, (2), and 3 - dimethylsulphamoyl - 9 - oxy - 10 - (3 - 41-methyl - 11 - piperazinylpropyl) phenothiazine, (8), (two dimorphic forms).  3 - Dimethylsulphamoylphenothiazine is obtained by cyclizing 2-bromo-21-amino-41-dimethylsulphamoyldiphenyl sulphide, itself prepared by iron/acetic acid reduction of 2-bromo-21 - nitro - 41 - dimethylsulphamoyldiphenyl sulphide, obtained in turn by a Sandmeyer reaction on 2 - amino - 21 - nitro - 41 - dimethylsulphamoyldiphenyl sulphide.  3 - Dimethylsulphamoyl - 10 - (3 - toluene - p-sulphonyloxypropyl) phenothiazine is obtained by condensing p-toluenesulphonyl chloride in pyridine with 3 - dimethylsulphamoyl - 10 - (3-hydroxypropyl) phenothiazine, itself prepared by the acid hydrolysis of 3-dimethylsulphamoyl-10 - (3 - tetrahydropyranyloxypropyl) phenothiazine, obtained in turn by reacting 3-tetrahydropyranyloxy - 1 - chloropropane with 3-dimethylsulphamoylphenothiazine in the presence of sodamide.  3 - (4 - Methyl - 1 - piperazinyl) propyl 3 - dimethylsulphamoylphenothiazine - 10 - carboxylate (and its di-acid maleate) is obtained by condensing 3 - (4 - methyl - 1 - piperazinyl) propanol with 3 - dimethylsulphamoylphenothiazine - 10 - carbonyl chloride, prepared in turn by the action of phosgene on 3-dimethylsulphamoylphenothiazine.  1 : 3 - bis - Dimethylamino - 2 - propyl - 3 - dimethylsulphamoylphenothiazine - 10 - carboxylate (and its dihydrochloride) is obtained by condensing 1 : 3 - bis - dimethylamino - 2 - propanol with 3 - dimethylsulphamoylphenothiazine-10-carbonyl chloride.  2 - Bromo - 21 - (3 - dimethylamino - 2 - methylpropyl) amino - 41 - dimethylsulphamoyldiphenyl sulphide is prepared by condensing 3-dimethylamino - 2 - methyl - 1 - chloropropane with 2-bromo - 21 - amino - 41 - dimethylsulphamoyldiphenyl sulphide in the presence of sodamide.  3 - Dimethylsulphamoyl - 10 - (2 - cyanoethyl)-phenothiazine (prepared by condensing acrylonitrile with 3 - dimethylsulphamoyl - phenothiazine) is hydrogenated in ethanol in the presence of Raney nickel and ammonia to give 3-dimethylsulphamoyl - 10 - (3 - aminopropyl)-phenothiazine, purified via its oxalate. Specification 813,025 is referred to.