Patent GB-783319-A (GB)
Title: Steroid derivatives
IPC: C07J5/00
Filed: 1955-06-09
Abstract: The invention comprises 9a -fluoro-D 4-pregnene - 11b ,17a ,21 - triol - 3,20 - dione, 9a -fluoro-D 1 - pregnene - 17a ,21 - diol - 3,11,20 - trione and the 21-acylates of both compounds, and a process for the preparation of a 21-acylate of 9a  - fluoro - D 4 - pregnene - 3,20 - dione - 11b ,17a ,21-triol by reacting a 21-acylate of 9a -fluoro - D 4 - pregnene - 9b ,11b  - oxido - 17a ,21-diol-3,20-dione with hydrogen fluoride, and the product may then be converted to a 21-acylate of 9a  - fluoro - D 4 - pregnene - 17a ,21 - diol - 3,11,20-trione by oxidation, the corresponding free 21-hydroxy compounds being obtained by hydrolysing the 21-acylates.  The reaction with the hydrogen fluoride may be carried out at a temperature from - 10 DEG  to 10 DEG  C., using e.g. about 4 mols. of hydrogen fluoride, preferably in alcohol-free chloroform.  The oxidation step is preferably carried out with chromium trioxide.  The hydrolysis step may be carried out with an alkali metal or alkaline-earth metal base such as a hydroxide, carbonate or bicarbonate, in an aqueous solvent such as aqueous methanol. Suitable 21-acylates of D 4-pregnene-9b ,11b -oxido - 17a ,21 - diol - 3,20 - dione are the formate, acetate, propionate, butyrate, t.-butylacetate, benzoate, hemisuccinate and phenylacetate. 9a -Fluoro- D 4-pregnene-11b ,17a ,21-triol-3,20-dione 21-t-butylacetate may also be prepared by reacting 9a -fluoro-D 4-pregnene-11b ,17a ,21-triol-3,20-dione with 5-butylacetyl chloride in the presence of an organic base, e.g. anhydrous pyridine with or without dimethylformamide.  A number of detailed examples are given.ALSO:A therapeutic composition comprises 9a -fluoro - D + - pregnene - 11b ,17a ,21 - triol - 3,20-dione 21 - t - butylacetate - (9a  - fluoro - hydrocortisone t-butyl acetate) and a carrier.  The composition may be in the form of a suspension preferably using an isotonic aqueous vehicle containing a surface-active agent, a suspending agent, and a bacteriological preservative.  The suspension may be rendered isotonic by the addition of sodium chloride.  Suitable surface active agents are polyoxyalkylene derivatives of sorbitol anhydride long chain fatty acid esters, e.g. the polyoxyalkylene derivative of sorbitan mono-oleate, and sodium lauryl sulphate, cetyl trimethylammonium bromide and benztrialkonium chloride.  Suitable suspending agents are sodium carboxy methyl cellulose, methyl cellulose, gelatin and sodium alginate.  Suitable bacteriological preservatives are benzyl alcohol and phenol.  Topical compositions may be in the form of aqueous solutions, suspensions or jellies. Suitable ingredients which may be used are vehicles of the water-soluble ointment-base type such as polyethylene glycols; vehicles which act as oils such as the water-immiscible olive oil and petrolatum; water-miscible oils such as anhydrous wool fat, oil in water emulsions such as vanishing creams, water in oil emulsions such as hydrous wool fat, pastes such as a mixture of starch and petrolatum, and collodions; vehicles which act as aqueous mixtures such as aqueous solutions, mixtures of zinc oxide and water, and jellies; and vehicles which act as powders such as the hydrophylic powders especially starch, and hydrophobic powders such as talc and zinc stearate.  The compositions may contain other hormones such as hydrocortisone and hydrocortisone acetate.  In the examples compositions are prepared containing 9a -fluoro-hydrocortisone - t - butylacetate and (a) a polyoxyalkylene derivative of sorbitan mono-oleate, sodium chloride, sodium carboxymethyl cellulose, benzyl alcohol and water; (b) high molecular weight alkyl-dimethyl benzyl ammonium chlorides, sodium phosphate, sodium chloride, sodium citrate, benzyl alcohol, solid polyethylene glycol and water; (c) petrolatum; and (d) zinc stearate, propylene glycol, polyethylene glycol and water.  In composition (a) above, 9a -fluoro-hydrocortisone acetate may replace some of the t-butylacetate.