Patent GB-825312-A (GB)
Title: Substituted phenoxazine derivatives
IPC: C07D265/38
Filed: 1957-08-01
Abstract: The invention comprises substituted phenoxazines of the general formula <FORM:0825312/IV (b)/1> wherein Y represents chlorine, bromine, trifluoromethyl or methyl and R represents <FORM:0825312/IV (b)/2> where R1 and R2 represent alkyl groups containing 1 to 5 carbon atoms and R3 is hydrogen or methyl, and non-toxic salts thereof including salts derived from inorganic and organic acids and from 8-halo-theophyllines, and the preparation thereof by hydrolysing a substituted 2-amino-21-methoxydiphenyl ether of the general formula <FORM:0825312/IV (b)/3> wherein Y and Z represent chlorine, bromine, trifluoromethyl, methyl or hydrogen, one of Y and Z being hydrogen, to form the corresponding substituted 2-amino-21-hydroxy-diphenyl ether, cyclizing this compound by heating with a mineral acid to form a 2-substituted phenoxazine of the general formula <FORM:0825312/IV (b)/4> wherein Y represents chlorine, bromine, trifluoromethyl or methyl, and then alkylating this compound with the required reactive dialkylaminoalkyl ester, e.g. a dialkylaminoalkyl halide or arylsulphonate, preferably in the presence of an acid binding agent. The hydrolysis step may be carried out by heating in the presence of 48% hydrobromic or by heating with hydrochloric acid in a closed system, in both cases the temperature is maintained in the range of about 120 DEG  to about 140 DEG  C., and the cyclization step may be carried out by heating with a mineral acid, e.g. sulphuric acid, or a hydrohalic acid such as hydrobromic or hydrochloric acid, preferably in a closed system, at a temperature from about 180 DEG  to about 220 DEG  C.  In the examples substituted phenoxazines of the above general formula are prepared containing 2-chloro, bromo, trifluoromethyl and methyl substituents and 10-(31-dimethylaminopropyl), (31-diethylaminopropyl) and (21-methyl-31-dimethylaminopropyl) substituents, the intermediates formed being 2 - amino - 4 - chloro-(bromo, trifluoromethyl and methyl) - 21 - hydroxy-diphenylether, and 2-chloro-(bromo, trifluoromethyl and methyl)-phenoxazine.  2 - Amino - 21 - methoxy - diphenyl ethers of the general formula <FORM:0825312/IV (b)/5> wherein one of Y and Z is bromine, chlorine, trifluoromethyl or methyl and the other is hydrogen, are prepared by reacting the required Y - substituted - 2 - nitrochloro - benzene with the required Z - substituted - 1 - hydroxy - 2-methoxy-benzene to form a 21-methoxy-2-nitro-diphenylether of the general formula <FORM:0825312/IV (b)/6> wherein Y and Z have the above significance and reducing this compound e.g. with Raney nickel-hydrazine hydrate or with hydrogen in the presence of platinum oxide.  3 - Dimethylaminopropyl - 1 - p - toluene-sulphonate p-toluene-sulphonic acid salt is prepared by reacting p-toluenesulphonyl chloride with 1 - dimethylamino - 3 - hydroxypropane to form the required free base and then forming the salt with p-toluene sulphonic acid.ALSO:A pharmaceutical composition contains a solid or liquid carrier and, as the active ingredient, a phenoxazine of the general formula <FORM:0825312/VI/1> wherein Y represents chlorine, bromine, trifluoromethyl or methyl, and R represents <FORM:0825312/VI/2> R1 and R2 being alkyl groups containing 1 to 5 carbon atoms and R3 represents hydrogen or methyl, or a non-toxic salt thereof including a salt derived from an inorganic or organic acid or from an 8-halo-theophylline.  Suitable solid carriers mentioned are lactose, cornstarch, mannitol, talc, magnesium stearate and starch, and suitable liquid carriers are soy bean or peanut oil-particularly when the composition is incorporated in a gelatine capsule, and water.