Patent GB-776679-A (GB)
Title: Triazine derivatives and compositions containing them
Inventor: CROWTHER ALBERT FREDERICK
IPC: A61K31/00
Filed: 1954-10-22
Abstract: The invention comprises compounds of the general formula <FORM:0776679/IV(b)/1> wherein X and Y, which are the same or different, are chlorine or bromine, and their preparation by any of the four following methods: (1) Reaction of the corresponding dihalogenophenyl biguanide or a salt thereof with formic acid or a salt or ester or other methenylating derivative thereof (e.g. formamide or formamidine), conveniently in a solvent such as methanol, ethanol, 2-ethoxy-ethanol or acetic acid.  Preferably, when a salt of the biguanide is used, the reaction is carried out with formic acid in the presence of a salt of formic or acetic acid.  The biguanide may be generated in situ, for example by synthesis from a dihalogenoaniline salt and dicyandiamide, preferably in a solvent such as acetic acid.  (2) Halogenation of the unsubstituted or mono-halogeno 2-phenylamino-4-amino-1:3:5-triazine.  (3) Reaction with an acid, such as oxalic or hydrochloric acid, preferably in a solvent such as ethanol, of the product obtained from the interaction of a dihalogenophenyl biguanide and a dialkyl oxalate. (4) Decarboxylation by heating of the corresponding 2-(dihalogenophenylamino) - 4 - amino - 1:3:5 - triazine - 6 - carboxylic acid.  The products are useful as diuretics. Examples describe the preparation of 2 - amino - 4 - (21:41-dichloroanilino) - 1:3:5-triazine by each of the above methods, of the corresponding dibromo compound by method (1) and by bromination of 2-phenyl-amino-4-amino-1:3:5-triazine, and of 2-amino-4-(21-bromo-41-chloroanilino) - 1:3:5 - triazine by method (1).  Starting materials.  2:4-Dichlorophenyl biguanide and the corresponding dibromo and 2-bromo-4-chloro compounds are prepared from the appropriately substituted aniline hydrochlorides and dicyandiamide.  2 - Amino - 4 - (21:41 - dichloranilino) - 1:3:5 - triazine - 6 - carboxylic acid is prepared from 2:4-dichlorphenyldiguanide and ethyl oxalate. Specification 676,024 is referred to.ALSO:A diuretic pharmaceutical composition comprises, as active ingredient, one or more of the triazines of the formula <FORM:0776679/VI/1> (wherein X and Y, which are the same or different, are chlorine or bromine), together with suitable pharmaceutical excipients.  The compositions may be in the form of tablets or pills, suitable excipients for the preparation of these being one or more diluents (e.g. calcium carbonate or lactose), one or more disintegrating agents (e.g. maize starch), one or more lubricating agents (e.g. stearic acid or magnesium stearate), and one or more granulating agents or binding agents (e.g. starch paste, gelatin solution or gum acacia).  The tablets or pills may be coated, and the proportion of active ingredients therein preferably lies between 5 and 90 per cent by weight.  The compositions may also be in the form of stable aqueous dispersions, suitable excipients for the preparation of these being one or more suspending or dispersing agents (e.g. neutral hydrophilic colloids such as sodium carboxymethylcellulose), one or more wetting agents (e.g. p polyethyleneoxycetanols), and preferably also one or more preservatives (e.g. an ester of p-hydroxybenzoic acid).  The dispersions may also contain one or more colouring and/or flavouring agents, and the proportion of active ingredients therein preferably lies between 0.5 and 50 per cent by weight. Examples describe the preparation of tablets containing 2 - amino - 4 - (21 : 41 - dichloranilino) - 1 : 3 : 5 - triazine, maize starch, calcium carbonate and magnesium stearate, and of a stable suspension of the above triazine with icing sugar, sodium, carboxymethylcellulose, water, heptadecaethyleneoxycetanol, methyl p - hydroxybenzoate, raspberry flavouring and an edible dyestuff.  Specification 676,024 [Group IV(b)] is referred to.