ANTIBACTERIAL AGENTS AND PROCESS FOR THEIR PREPARATION

摘要

1,244,026. Kasugamycin derivatives; imidates. BRISTOL-MYERS CO. 1 Nov., 1968 [1 Nov., 1967], No. 51855/68. Headings C2A and C2C. Novel derivatives of the antibiotic kasugamycin having the formula wherein R is hydrogen or C 1-10 alkyi and non- toxic pharmaceutically acceptable acid addition salts thereof may be prepared by (A) reacting kasugamycin, or a pharmaceutically acceptable non-toxic salt thereof with an appropriate [3- diketone in a solvent system consisting of water or an aqueous solution of an inert organic solvent at a pH below 7.5 to produce a novel first intermediate product of the formula wherein Z is the ketonic residue of a Schiff base derived from a #-diketone having the formula in which R1, R2 , R3 and R4 are alike or different and each is hydrogen or C 1-10 alkyl; (B) reacting the first intermediate product with an aqueous solution of an alkaline earth metal hydroxide, with heating, to produce a novel second intermediate having the formula wherein Z is as defined above; (C) reacting the second intermediate compound with an imidate ester of the formula in which R and R5 are hydrogen or C 1-10 alkyl, or with a mineral acid salt thereof, in a C 1-10 aliphatic alcohol, at a pH of 6.5 to 8.0 to produce a novel third intermediate compound of the formula wherein R is hydrogen or C 1-10 alkyl and Z is as defined above; and (D) reacting an aqueous solution of the third intermediate with bromine water or nitrous acid at 0‹ to 40‹ C. Step (A) may be conducted at pH 6 to 7 in aqueous methanol, step (B) in an aqueous solution of barium or calcium hydroxide and step (C) at pH 7À0 to 7À4 in methanol or ethanol. The hydrochloride, hydrobromide, hydroiodide, C 1-10 alkyl sulphate, C 1-10 alkyl and aryl sulphonate, phosphate, sulphate, maleate, fumarate, succinate, tartrate, citrate and amine salts are referred to. The compounds may be purified by crystallization and chromatography. Pharmaceutical compositions having antibacterial activity for topical, oral or parenteral administration comprise compounds of Formula I or a pharmaceutically acceptable non-toxic acid addition salt thereof and a diluent or carrier. Methyl acetimidate, propionimidate and butyr. imidate hydrochlorides are prepared by reacting acetonitrile, propionitrile or butyronitrile respectively with methanol and hydrogen chloride. Isobutyl formimidate hydrochloride is prepared by the reaction of formamide and isobutylchloroformate.