Patent GB-990857-A (GB)
Title: 1,3-diazaphenothiazines
IPC: C07D239/48
Filed: 1960-06-23
Abstract: The invention comprises 1,3-diazaphenthiazines of the formula <FORM:0990857/C2/1> (wherein R1 and R2 are hydrogen, halogen, alkyl or alkoxy; W is hydrogen, alkyl, amino or hydroxy; and X is hydrogen, halogen, amino, mono- or di-alkylamino, dialkylaminoalkylamino, pyrrolidino, piperidino, morpholino, 4-alkylpiperazino, hydrazino, hydroxy, alkoxy, alkoxyalkoxy, mercapto or alkylthio; the alkyl and alkoxy groups each containing at most 4 carbon atoms); and the preparation of these and other 1,3-diazaphenthiazines by treating with an acidic reagent a compound of the basic structure <FORM:0990857/C2/2> Suitable acidic reagents include phosphorus oxychloride (when it is preferable to acetylate before treatment with this) or, preferably, mineral acids used in aqueous, alcoholic or aqueous/alcoholic solution, desirably at a pH below 2.  In Examples (1) and (2) 2-amino-5-bromo - 4 - hydroxypyrimidine and 2 - aminobenzenethiol give 2 - amino - 5 - (2 - aminophenylthio) - 4 - hydroxypyrimidine, this with acetic anhydride in pyridine gives the 2-acetamido compound, this on cyclization gives a product which is probably 2 - acetamido - 1,3-diazophenthiazine and this on boiling with alcoholic hydrochloric acid gives the 2-amino compound, also prepared in a phosphorylated form (probably 2-phosphoramido-1,3-diazaphenthiazine) by cyclization of the hydroxypyrimidine compound with phosphorus oxychloride, or as the hydrochloride of the free amino form by cyclization with ethanolic hydrochloric acid; (3) 5 - bromouracil and 2 - aminobenzenethiol give 5 - (2 - aminophenylthio) - 2,4 - dihydroxypyrimidine which on cyclization gives 2-hydroxy - 1,3 - diazaphenothiazine; (4), (5), (6), (8), (10), (12), (15), (18) and (19) similarly are prepared 5 - (2 - amino - 4 - chlorophenylthio)-2,4 - dihydroxypyrimidine and 8 - chloro - 2-hydroxy - 1,3 - diazaphenthiazine, 2 - mercapto-1,3 - diazaphenthiazine (also prepared from the 2 - chloro compound and thiourea), 5-(2 - aminophenylthio) - 2 - dimethylamino - 4-hydroxy - 6 - methyl - pyrimidine (by brominating 2 - dimethylamino - 4 - hydroxy - 6 - methyl-pyrimidine to give 5 - bromo - 2 - dimethylamino - 4 - hydroxy - 6 - methylpyrimidine and reacting this with 2-aminobenzenethiol) and 2-dimethylamino - 4 - methyl - 1,3 - diazaphenthiazine hydrochloride, 5 - (2 - amino - 4-chlorophenylthio) - 4 - hydroxy - 2 - (4 - methylpiperazino) - pyrimidine and the corresponding 6 - methyl compound and 8 - chloro - 2 - (4-methylpiperazino) - 1,3 - diazaphenthiazine and the corresponding 4-methyl compound respectively, and the corresponding 2-morpholino and 2 - piperidino compounds, 2 - amino - 5 - (2-aminophenylthio) - 4,6 - dihydroxypyrimidine and 2 - amino - 4 - hydroxy - 1,3 - diazaphenthiazine hydrochloride, and 2,4 - diamino - 5-(2 - aminophenylthio) - 6 - hydroxy - pyrimidine which on cyclization gives a mixture of hydroxy - and aminohydroxy - 1,3 - diazaphenthiazines; (7) 4 - hydroxy - 2 - methylthiopyrimidine and 4 - methylpiperazine give 4-hydroxy - 2 - (4 - methylpiperazino) - pyrimidine, this is brominated to give the 5-bromo hydrobromide and this with 2-aminobenzenethiol gives 2 - (4 - methylpiperazine) - 1,3 - diazaphenthiazine and, as a by-product, 2,21-diamino - diphenylsulphide; (9), (11), (13), (14), and (16) similarly are prepared the corresponding 6 - methyl - pyrimidines and 4-methyldiazaphenthiazines and the corresponding morpholino and piperidino compounds, as free bases or acid-addition salts; (17) 5-bromo-2 - (3 - dimethylaminopropylamino) - 4 - hydroxypyrimidine hydrobromide monohydrate is prepared by bromination and is treated with 2-aminobenzenethiol and the syrupy product cyclized to 2 - (3 - dimethylaminopropylamino)-1,3 - diazaphenthiazine; (20) 4 - amino - 5-bromo - 2 - dimethylamino - 6 - hydroxy - pyrimidine is prepared by bromination and reacted with 2 - aminobenzenethiol to give 4 - amino-5 - (2 - aminophenylthio) - 2 - dimethylamino - 6-hydroxypyrimidine, and this is cyclized to give a mixture of 4-amino-2-dimethylamino-1,3-diazaphenthiazine and the corresponding 4-hydroxy - compound, separated by recrystallization of their hydrochlorides; (21) and (23) to (29) 2-chloro-1,3-diazaphenthiazine is prepared from the 2-hydroxy-compound and phosphorus oxychloride, and is converted to the 2 - methoxy -, 2 - (2 - methoxyethoxy), - 2-hydrazino -, 2 - (3 - dimethylaminopropylamino) - and 2 - (2 - dimethylaminoethylamino)-compounds by reaction with, respectively, sodium methoxide/methanol, 2-methoxyethanol, hydrazine, 3-dimethylaminopropylamine and 2-dimethylamino-ethylamine, an additional product of the second named reaction being 1,3-diazaphenthiazine (also prepared by heating the 2-hydrazine-compound with dilute hydrochloric acid and copper sulphate); (22) 2,8 - dichloro - 1,3 - diazaphenthiazine is prepared by chlorination of the 2-hydroxy-8-chloro - compound; and (30) 2 - amino - 7,8-dimethyl - 1,3 - diazaphenthiazine hydrochloride, 2 - hydroxy - 7,8 - dimethyl - 1,3 - diazaphenthiazine hydrate and 2-chloro-7,8-dimethyl - 1,3 - diazaphenthiazine are prepared by the methods of (2), (3) and (4) and (21) and (22) respectively.  The diazaphenthiazines of the invention are stated to possess anti-bacterial activity and to have a tranquillizing action, and may be made up into pharmaceutical compositions with suitable carriers. These may take the form of tablets, capsules, cachets, ampoules, suppositories, powders, granules, solutions, suspensions, emulsions or ointments, and may contain buffers, flavouring or dispersing agents, preservatives and antioxidants.  Specification 951,431 is referred to.