Patent GB-776176-A (GB)
Title: Improvements in or relating to biguanides
IPC: C07D295/215
Filed: 1954-09-09
Abstract: Biguanides and acid addition salts of the formula RC(:NH).C(:NH)NH2, where R represents a nuclear nitrogen atom in a substituted morpholine, thiomorpholine or unsubstituted or substituted piperazine group are prepared by (a) reacting dicyandiamide with a heterocyclic amine containing said group or with an acid addition salt of such an amine, or (b) reacting guanyl - S - alkyl - iso -thiocarbamide or guanylthiocarbamide with a heterocyclic amine containing said group or with an acid addition salt of such an amine and subjecting the product to treatment with a sulphur-precipitating material such as copper or mercury oxides or (c) reacting a dicyandiamide containing the radical R with ammonia or an acid addition salt of ammonia.  Acid addition salts produced can be converted to other acid addition salts by metathesis.  The production of compounds of the above formula where R is a nitrogen atom in the unsubstituted morpholino ring, for use in therapeutic compositions (see Group VI) is also described.  In examples: (1) to (4) N1,N1-anhydrobis-(b -oxy-ethyl)-biguanide is prepared (as its hydrochloride or sulphate) by (1) and (2) heating morpholine and dicyandiamide in the presence of hydrochloric acid, (3) reacting morpholine and guanyl-S-ethyl isothiocarbamide, (4) reacting morpholine-guanylthiocarbamide with mercury oxide; (5) N1,N1-anhydrobis-(b -oxyethyl) biguanide-HCl is converted to the nitrate by reaction with silver nitrate; (6) morpholine, dicyandiamide and copper sulphate solution are reacted and the product, after purification, is converted to N1,N1-anhydro-bis-(b -oxyethyl) biguanide acetate; (7) the product of (1) after treatment with an anion-exchange resin is converted to the maleate; (8) 2-methylmorpholine neutralized with hydrochloric acid is reacted with dicyandiamide to give N1,N1-anhydro-(b -oxyethyl - b 1 - oxypropyl) biguanide HCl; (9) N1,N1-anhydrobis-(b -oxypropyl)-biguanide-HCl is prepared similarly; (10) 2-phenylmorpholine neutralized with hydrochloric acid is reacted with dicyandiamide to give N1,N1-anhydro-(b -oxyethyl - b 1 - oxy - b 1 - phenylethyl) biguanide-HCl; (11) diethylene-bis-biguanide HCl is prepared by heating piperazine hydrochloride and dicyandiamide; (12) N-phenylpiperazine and dicyandiamide are heated in the presence of hydrochloric acid to give N1,N1-(b -phenyliminodiethyl) biguanide-HCl; (13) thiomorpholine and dicyandiamide are reacted in the presence of hydrochloric acid to give N1,N1-thiodiethylbiguanide-HCl.  It is stated that by analogous methods there may be prepared compounds of the above general formula in which the atom R is part of an imidazole, triazole, tetrazole, dioxazole, isoxazine, benzpyrazole, benzimidazole, benzisotriazole, benzisoxazine or phenthiazine group.  Specification 556,150, [Group IV], is referred to.ALSO:A therapeutic composition active against viruses such as influenza and canine distemper comprises a therapeutically acceptable carrier and a compound of the general formula RC (: NH) NH . C (: NH) NH2 where R represents a nitrogen atom in an unsubstituted or substituted heterocyclic ring which contains at least one hetero atom in addition to the said nitrogen atom or an acid addition salt of such a compound.  R may, for example, form part of a morphaline, methyl- or dimethylmorpholine, thiomorpholine, piperazine, imidazole, triazole, tetrazole, dioxazole, isoxazine, benzpyrazole, benzimidazole, benzisotriazole, benzisoxazine, or phenthiazine.  The preparation of some of such compounds is described (see Group IV (b)). Specification 556,150 [Group IV] is referred to.