Patent GB-848881-A (GB)
Title: Improvements in or relating to hormone compositions and the preparation thereof
Filed: 1956-12-10
Abstract: 17a -acyloxyprogesterones are made by esterifying 17a -hydroxyprogesterones with an appropriate acid, including monocarboxylic, hydroxy-substituted and di-basic carboxylic acids. The esters may be prepared by dissolving 17a -hydroxyprogesterone in a mixture of the appropriate acid and its anhydride with p toluene sulphonic acid.  In alternative methods exemplified for preparing 17a -hydroxyprogesterone cyclopentylpropionate, (6), (a) 17a -hydroxy-progesterone in a methylene chloride / methanol mixture is treated with pyrrolidine to give the pyrrolidinyl enamine which is dissolved in methylene chloride and treated with gaseous HCl to give the hydrochloride.  To this is added cyclopentylpropionic acid and cyclopentylpropionyl chloride with p toluene sulphonic acid monohydrate and reacted to give the acyl compound which is purified on a "Florisil" (Registered Trade Mark) column; or (b) 3b , 17a -dihydroxy-5-ene-20-one-3-acetate is esterified with cyclopentylpropionyl chloride to give 3b , 17a -dihydroxy - 5 - ene - 20 - one - 3 - acetone - 17 - cyclopentylpropionate which is treated by methanolic HCl to hydrolyse one-3-acyl group and followed by an Oppenauer oxidation to give 17a -hydroxyprogesterone cyclopentylpropionate.  Sodium 17a -hydroxyprogesterone hemi-succinate is prepared (4a) by treating the hemi-succinate with sodium hydroxide.  Specifications 784,659, 794,482 and 815,517 are referred to.ALSO:A therapeutic composition for oral administration which produces a progestational effect in humans and animals comprises a 17a -acyloxyprogesterone and a pharmaceutical diluent, or an animal feed mix.  The active ingredients are derived from 17a -hydroxy progesterone by esterification with a suitable acid preferably an organic carboxylic acid containing 1 to 12 carbon atoms.  Suitable esters are the formate, acetate, propionate, butyrate, iso-butyrate, valerate, enanthate, caproate, caprylate, benzoate cyclopentylpropionate, phenylacetate, phenylpropionate, tri-methylacetate, t-butylacetate, cyclopentylcarboxylate, ethylbutyrate, o-toluate, dodecanoate, cyclohexylacetate, stearate, hydroxystearate, palmitate, gluconate, glucuronate, saccharate, sorbate, ethoxyacetate, furoate, furylacrylate, t-butylphenoxyacetate, p-chlorophenoxyacetate, succinate, glutarate, diglycalate, b -methylglutarate or b ,b -dimethylglutarate and the sodium, potassium, calcium, magnesium and amine salts thereof.  Other active ingredients may include other coactive hormonal substances e.g. estrogenic substances such as estradiol &c., or androgenic substances e.g. 17-methyltestosterone &c., analgesics e.g. aspirin, acetyl-p-aminophenol &c., sedatives such as barbiturates, reserpine &c., anti-spasmodics e.g. belladonna, hyoxyamine &c., carticosteroids e.g. carbisone, hydrocortisone, prednisone &c., vitamins e.g. vitamin A, C, D, K and members of the B series, and antibiotics e.g. penicillin, tetracyclines &c.  The compositions which are preferably in dosage unit form e.g. tablets, capsules, pills, cachets or pellets, and may also take the form of solutions, syrups, suspensions, emulsions, or elixirs.  When prepared in tablet form, different active ingredients may be incorporated in different laminae of which the tablet may be made up, each section may be separated by an enteric coating.  The compositions preferably contain from 5-200 mgms of the 17a -acyloxyprogesterone per unit dosage form. Specifications 784,659, 794,482 and 815,517 are referred to.