Patent GB-877730-A (GB)
Title: Aliphatic acyl esters of oleandomycin
IPC: C07H17/08
Filed: 1958-05-28
Abstract: The invention relates to acyl esters of oleandomycin having the formula <FORM:0877730/IV (b)/1> wherein R1, R2 and R3 are hydrogen or an acyl moiety derived from an aliphatic hydrocarbon monocarboxylic acid having from 2 to 6 (preferably 2 or 3) carbon atoms, at least one of said groups being an acyl moiety.  Examples are 1,2,3-triacetyl-, 2,3-diacetyl, 1,3-diacetyl-, 3-monoacetyl-, 2-monoacetyl-, 1-monoacetyl-, 1,2,3 - tripropionyl-, 2,3-dipropionyl-, 1,2,3-tributyryl-, 1,2,3-trivaleryl- and 1,2,3 - tricaproyl - oleandomycin.  1,23 - triacyl oleandomycin is prepared by contacting oleandomycin under substantially anhydrous conditions with the corresponding lower aliphatic hydrocarbon monocarboxylic acid anhydride in the presence of an organic base, p  preferably a tertiary amine, at a temperature in the range 0 to 50 DEG C. for 5 to 48 hours, the acylating agent being present in such amount that its volume is at least twice the weight of the oleandomycin and the said organic base is present in an amount that is at least 5% by weight that of the acylating agent.  The oleandomycin may be used as the base or chloroform adduct.  In the case of the acid addition salts, the base is first liberated from the salt by the addition of an alkali metal hydroxide.  The 2,3-diacyl ester is produced from the 1,2,3-triacyl ester by contacting the latter with 3 to 5 parts by weight of a watermiscible primary alkanol having 1 to 4 C atoms at a temperature within the range 15 to 45 DEG C. for 24 hours to 3 weeks. The 3-monoacyl ester is prepared by heating an aqueous lower alkanolic solution of the corresponding 1,2,3-triacyl ester at a temperature of 45 to 60 DEG C. for 0.5 to 2.0 hours at pH 10 to 11, the alkanol having from 1 to 3 C atoms and the ratio by volume of the alkanol to water being 2:3.  The 1,3-diacyl ester is prepared by treating the 3-monoacyl ester in an inert organic solvent under substantially anhydrous conditions with at least an equivalent in moles of the desired acyl chloride having from 2 to 3 carbon atoms in the presence of a basic agent at a temperature of 0 to 50 DEG C. from 1 to 5 hours, said basic agent being present in sufficient amount to neutralise the liberated hydrogen chloride.  The 2-position may be deacylated by treating the 1,2,3-triacyl ester or the 2,3-diacyl ester with methanol and potassium hydroxide. The monoacyl esters may be obtained from the di- or tri-esters by treating the ester in an aqueous solvent with an alkali metal or alkaline earth metal hydroxide.  Acylation in the 1-position may be obtained by treatment with an acyl chloride in organic solvent in the presence of a base e.g. alkali metal hydroxide.  The esters are non-toxic, tasteless, and stable in aqueous media.  They are also urinary antiseptics and may be used in various formulations (see Group VI).  Specification 779,257 is referred to.ALSO:A pharmaceutical composition comprises a carrier and an acylester of oleandomycin of formula <FORM:0877730/VI/1> wherein R1, R2 and R3 are hydrogen or an acyl moiety derived from an aliphatic hydrocarbon monocarboxylic acid having 2 or 3 carbon atoms, at least one being an acyl moiety (see Group IV (b)).  The oleandomycin acyl esters are non-toxic, tasteless, stable in aqueous media and are urinary antiseptics. They are administered orally or parenterally and may be put up as capsules, tablets, syrups, emulsions, aqueous or oily suspensions and elixirs.  Triacetyloleandomycin may be injected in a 10% aqueous solution of glutamic acid hydrochloride. 3-Monoacetyloleandomycin may be injected in aqueous ascorbic acid solution, in diethyl carbonate, dimethylformamide or oil.  Other esters are the 2,3-diacetyl-1,3-diacetyl-, 1 - monoacetyl, 2 - monoacetyl-, 1,2,3 - tripropionyl, 1,2,3 - tributyryl, 1,2,3 - trivaleryl and 1,2,3-tricapropyl esters of oleandomycin. Specification 779,257 also is referred to.