GB803440A - Improvements in or relating to estradiol derivatives - Google Patents

Abstract

The invention comprises the hexahydrobenzoates of estradiol of the general formula <FORM:0803440/IV (b)/1> wherein R1 and R2 represent hydrogen or an alkyl or acyl group, R1 and R2 being identical or different, with the proviso that one of R1 and R2 must represent a hexahydrobenzoyl group, and the preparation thereof by condensing in the presence of a condensing agent a hexahydro benzoyl halide, e.g. the chloride or bromide, or hexahydrobenzoyl anhydride with a solution in an inert solvent of a compound of the general formula <FORM:0803440/IV (b)/2> wherein R represents hydrogen or an alkyl or acyl group, and R3 represents hydrogen. In accordance with the above process, the 3-hexahydrobenzoate of estradiol is obtained by reacting substantially equimolecular quantities of hexahydrobenzoyl chloride and estradiol in the presence of an alkali metal hydroxide, the 3,17-dihexahydrobenzoate of estradiol is obtained by reacting more than two mols. of hexahydrobenzoyl chloride with one mol. of estradiol in the presence of an organic tertiary base, e.g. pyridine, 2-methyl-5-ethyl-pyridine or dimethylaniline, the 17-hexahydrobenzoate of 3-benzyloxy-estradiol is prepared by reacting a hexahydrobenzoyl halide with the 3-benzoate of estradiol, e.g. hexahydrobenzoyl chloride in the presence of pyridine may be used, the 3-methoxymethyl ether of 17-hexahydrobenzoyloxyestradiol is prepared by reacting hexahydrobenzoyl chloride with the 3-methoxymethyl ether of estradiol (obtainable by the reduction of 3-methoxymethyl-estrone), and the 17-hexahydrobenzoate of estradiol is prepared by reacting hexahydrobenzoic acid anhydride with estradiol in the presence of p-toluenesulphonic acid, or by selectively hydrolysing the 3,17-dihexahydrobenzoate of estradiol in a water-miscible solvent, e.g. by means of an aqueous solution of an alkali metal hydroxide or carbonate, or by hydrolysing the 3-benzoyl ester or other easily hydrolysable 3-acyloxy ester of the 17 - hexahydrobenzoate of estradiol with an aqueous solution of an alkali metal hydroxide, or by hydrolysing the 3-methoxymethyl ether of the 17-hexahydrobenzoate with hot dilute aqueous mineral acid. A number of detailed examples are given. Starting compound. 3 - Methoxymethyl ether of estradiol is prepared by reacting estrone with monochloro-dimethyl ether to form the 3-methoxymethyl ether of estrone which is then reduced e.g. by means of sodium and alcohol, on alkali metal borohydride or hydrogen in the presence of a catalyst.ALSO:Therapeutic compositions comprise injectable solutions, emulsions or microcrystalline aqueous suspensions of a hexahydrobenzoate of estradiol having the general formula: <FORM:0803440/VI/1> wherein R1 and R2 represent hydrogen or an alkyl or acyl group, R1 and R2 being the same or different with the proviso that either R1 or R2 is a hexahydrobenzoyl group. Suitable diluents are vegetable oils to which a glycol may be added. Olive oil solutions of the 3,17-dihexahydrobenzoate of estradiol and the 3- and the 17-monohexahydrobenzoate of estradiol are referred to. Aluminium monostearate or aluminium 2-ethyl-hexanoate may be added to the oil solutions to form a thixotropic gels.