Patent GB-872991-A (GB)
Title: Water-soluble tetracycline derivatives and process for their manufacture
IPC: C07D/
Filed: 1957-10-03
Abstract: The invention relates to water-soluble derivatives of tetracycline, chlortetracycline and oxytetracycline of general formula <FORM:0872991/IV (b)/1> in which R1 is hydrogen, 1 to 8 C alkyl, cycloalkyl, hydroxyalkyl or diethylaminoethyl; R2 is hydrogen, 1 to 8 C alkyl, cycloalkyl or hydroxyalkyl; or <FORM:0872991/IV (b)/2> is the radical of a heterocyclic amine; R3 is hydrogen or chlorine; R4 is hydrogen or when R3 is hydrogen or hydroxyl; and also the aminomethylation products of anhydrotetracycline in which the aminomethyl group corresponds to <FORM:0872991/IV (b)/3> where R1 and R2 have the meanings given above; and physiologically tolerable acid addition salts thereof.  The compounds are produced by the aminomethylation of the appropriate tetracycline or anhydro-tetracycline which may be in the form of the base or a salt with an inorganic or organic acid or with an inorganic or organic base.  Aminomethylation is by means of formaldehyde and an amine. Specified amines are ammonia or primary or secondary aliphatic or heterocyclic amines, e.g. methylamine, ethyl amine, n-butylamine, cyclohexylamine, octadecylamine, dimethylamine, diethylamine, di-n-butylamine, di-isobutylamine, di-isohexylamine, N-methyloctadecylamine, ethanolamine, diethanolamine, diethylaminoethylamine, di-(diethylaminoethyl)amine, piperidine, pyrrolidine, morpholine, piperazine and N-methylpiperazine.  The amines may be used as the free bases or as salts thereof with inorganic or organic acids. The free aminomethylated tetracyclines are obtained by reacting the free tetracyclines with the free amine bases.  Suitable solvents for the aminomethylation are water, and aqueous or non-aqueous organic solvents, e.g. alcohols such as methanol, ethyl acetate, tetrahydrofuran dioxane, pyridine, glacial acetic acid, dimethylformamide, methylene chloride, chloroform and benzene.  Alternatively, there may be used a substance capable of yielding formaldehyde under the conditions of aminomethylation, e.g. chloromethyl ether.  Examples disclose the preparation of (1) piperidinomethyl-tetracycline acetate, (2) morpholinomethyl-tetracycline hydrochloride, (3) pyrrolidinomethyl oxytetracycline formate, (4) N-methylpiperazine -methyl-chlorotetracycline diacetate, (5) piperidinomethyl anhydrotetracycline acetate, (6) ethanolaminomethyl tetracycline acetate, (7) diethanolaminomethyl tetracycline ascorbate, (8) N-(diethylamino ethyl)-aminomethyl tetracycline diacetate, (9) piperidinomethyl tetracycline penicillin G, (10) pyrrolidino methyl tetracycline pantothenate, (11) diethylaminomethyl tetracycline, (12) aminomethyl tetracycline, (13) piperdinomethyl oxytetracycline acetate, (14) pyrrolidinomethyl tetracycline. Specifications 768.735 and 793,558 are referred to.ALSO:Injections or oral preparations comprise aqueous solutions of aminomethylation products of tetracycline, chlorotetracycline and oxytetracycline of general formula <FORM:0872991/VI/1> in which R1 is hydrogen, 1 to 8 C. alkyl, cycloalkyl, hydroxyalkyl or diethylaminoethyl; R2 is hydrogen, 1 to 8 C. alkyl, cycloalkyl or hydroxyalkyl; <FORM:0872991/VI/2> is the radical of a heterocyclic amine; R3 is hydrogen or chlorine and R4 is hydrogen or where R3 is hydrogen, R4 is hydrogen or hydroxyl; and also the aminomethylation products of anhydrotetracycline in which the aminomethyl group corresponds to <FORM:0872991/VI/3> where R1 and R2 have the meaning given above; or a physiologically tolerable acid addition salt thereof (see Group IV (b)).  Typical salts are the carbonate, hydrochloride, sulphate, phosphate, acetate, palmitate, oleate, lactate, tartarate, citrate, gluconate, ascorbate, pantothenate and penicillinate. Specifications 768,735 and 793,558 are referred to.