Patent GB-723267-A (GB)
Title: New penicillin compounds and method of making same
IPC: A61K31/43
Filed: 1952-06-30
Abstract: A penicillin-streptomycin compound of high activity against M tuberculosis consists of an addition compound of a penicillin salt of a dialkylaminoalkyl ester of o - iodo - p - amino benzoic acid or o-hydroxy-p-aminobenzoic acid and a salt of one or more of the following streptomycin antibiotics: streptomycin, dihydrostreptomycin, hydroxy streptomycin, hydroxydihydrostreptomycin and mannosido streptomycin.  It is prepared by mixing equimolecular amounts of the penicillin and streptomycin salts in aqueous suspension, preferably with heating to 60-65 DEG  C., and freeze drying.  The compound may also contain excess of one or other of the reactants.  The penicillin is a penicillin such as G, F, dihydro F, X, K or O, or a mixture thereof.  Specified salts of streptomycin are the hydrochloride, sulphate and phosphate.  The penicillin salt of the dialkylaminoalkyl ester of o-iodo p-aminobenzoic acid or o-hydroxy-p-amino benzoic acid is prepared by (a) reacting the ester and penicillin in an organic solvent such as alkyl acetates of 2 to 9 carbon atoms, e.g. butyl or amyl acetate, ether and chloroform; (b) reacting water-soluble salts in aqueous solution, e.g. the ammonium, potassium, sodium, calcium and organic base salts of penicillin with the hydrochloride, hydrobromide, sulphate, nitrate or formate of the ester; (c) reacting a penicillin salt with a salt of the N-glucosides of the esters in aqueous solution; (d) reacting penicillin di-isopropyl ether with the ester in organic solution.  The dialkylaminoalkyl esters may be prepared by (a) reacting o-iodo-p-nitrobenzoyl chloride and diethylamino ethanol in benzene solution and then reducing catalytically with hydrogen; (b) reacting the sodium salt of o-iodo-p-nitrobenzoic acid with diethylamino ethyl halide, e.g. chloride or bromide and reducing the nitro group.  A preferred method is to produce the sodium salt and to carry out the reduction in a boiling solution of metallic sodium in anhydrous isopropyl alcohol or other aliphatic alcohol such as methanol, ethanol, butanol and amyl alcohols.  The alkyl may be methyl, ethyl, propyl, isopropyl, butyl or amyl, e.g. diethylaminoethyl. The N-glucoside of the dialkylaminoalkyl esters is prepared, e.g. by refluxing the dialkylaminoalkyl ester in ethanol with glucose and ammonium chloride.  Instead of glucose there may be used galactose, fructose, mannose, rhamnose and ribose.  The penicillinstreptomycin addition compound is used medicinally in aqueous or oil suspension (see Group VI).ALSO:A penicillin-streptomycin addition compound of high activity against M. tuberculosis is produced by combining a penicillin salt of a dialkylaminoalkyl ester of oiodo p-amino-benzoic acid, or o-hydroxy-pamino-benzoic acid, with a streptomycin salt (see Group IV(b)), is injected suspended in a liquid medium such as water, with or without the further addition of buffers such as sodium citrate or phosphate.  The streptomycin may be in the form of dihydrostreptomycin, hydroxystreptomycin, hydroxy dihydrostreptomycin or mannosido streptomycin.  The penicillin salts of the said dialkylaminoalkyl esters may be injected per se in (a) water (b) saline (c) oil e.g. cottonseed oil, peanut oil, sesame oil or (d) emulsion form.  The iodo compounds are suitable for combining penicillin therapy with sulphonamide therapy.