GB814000A — Steroid compounds and the preparation thereof

USPTO Abstract

The invention comprises D 1,4,6-androstatrien-3,17 - dione, D 1,9(11) - Compound S, a 21-ester thereof with a monocarboxylic acid, a 21-acid ester thereof with a polycarboxylic acid, or a salt of such an acid ester, 14-hydroxy- D 1-cortisone, 14 - hydroxy - D 1 - hydrocortisone, 21-esters thereof with a monocarboxylic acid, 21-acid esters thereof with a polycarboxylic acid and salts of said acid esters and a process according to the parent Specification for the preparation of a 3-keto- D 1,4-steroid compound by contacting a 3-keto- D 4-steroid compound with the oxidizing activity of an organism of the genus Mycobacterium, characterized by the fact that the steroid starting material is an 11-oxygenated 3-keto- D 1-steroid compound or one of the following other 3-keto- D 4-steroid compounds: nortestosterone, 17a - hydroxyprogesterone, D 4,6 - androstadien - 3,17 - dione, 16 - dehydroprogesterone and D 9(11) - compound S. As the micro-organism there may be used Mycobacterium species 607, M. berolinense, M. lacticola, M. thamnopheos, M. smegmatis, and M. phlei. Starting compounds mentioned are hydrocortisone, cortisone, D 4-pregnadiene-11b , 21 - diol-3,20 - dione, nortestosterone, 17a -hydroxyprogesterone, 1 - ketoprogesterone, 9a -fluorohydrocortisone, 14a - hydroxy - hydrocortisone, 1 - epihydrocortisone, D 4,6 - andostadien - 3,17 - dione, 11b ,17a - dihydroxyprogesterone, D 14 - dehydro - Compound S, 16-dehydroprogesterone, and D 9,11 - dehydro-Compound S. The 21-hydroxy group may be esterified by means of acetic anhydride or the acid halides of propanoic, butanoic, hexanoic, heptanoic, octanoic, nonanoic, decanoic, o-toluic, benzoic, 1-ethyl cyclohexane carboxylic, cyclohexane carboxylic, 1-methyl cyclopropane carboxylic acids, maleic anhydride, glutaric anhydride, phthalic anhydride, phthaloyl chloride, malic acid, citric acid, tartaric acid, succinic anhydride and pyromellitic acid. The acid esters may be converted to ammonium or alkali metal salts. Examples describe the production of D 1-hydrocortisone, D 1 - cortisone, D 1 - 14a - hydroxy - hydrocortisone, D 1 - 14a - hydroxycortisone, D 1,4 - pregnadiene - 11a ,21 - diol-3,20 - dione D 1 - 9a - fluoro - compound F, D 1,4,6 - androstatriene - 3,17 - dione, D 1 - 11b , 17a - dihydroxyprogesteron, D 1,14 - compound S, D 1 - 19 - nortestosterone, D 1,16 - progesterone, D 1 - 11 - keto - progesterone, D 1,9(11)-compound S, D 1 - 14a ,15a - epoxido - Compound S, D 1 - 14a ,15a - epoxido - Compound F, D 1-hydrocortisone acetate, formate, propionate, phthalate and succinate, &c.ALSO:The invention comprises a therapeutic composition comprising one of the following compounds: D 1-cortisone, D 1-hydrocortisone, 14-hydroxy - D 1 - cortisone, 14 - hydroxy - D 1 - hydrocortisone, D 1,4,6 - androstatriene - 3,17 - dione, D 1,9(11)-compound S, 21-esters thereof with a monocarboxylic acid, 21-acid esters thereof with a polycarboxylic acid, and salts of said acid esters, incorporated with a pharmaceutical carrier, or in the case of a salt of an acid ester, in sterile aqueous solution. Excipients such as starch and milk sugar may be used to prepare tablets for oral administration. Elixirs containing flavouring and sweetening agents may also be used. Solutions for injection are made isotonic with saline or glucose. Examples describe (1) a tablet for oral usage comprising D 1-hydrocortisone, calcium phosphate, milk sugar, potato starch, magnesium stearate, and magnesium trisilicate; (2) a topical ointment comprising D 1-hydrocortisone acetate, sodium lauryl sulphate, propylene glycol, stearyl alcohol, cetyl alcohol, cholesterol, white petrolatum, mineral oil, water, methyl paraben, and propyl paraben; (3) a solution for intra-articular injection comprising D 1-hydrocortisone acetate, sodium chloride, sodium carboxymethylcellulose, methocel, "Tween" (Registered Trade Mark), methyl paraben, propyl paraben and water; (4) an ophthalmic suspension comprising D 1-hydrocortisone acetate, sodium carboxymethylcellulose, polyvinyl pyrrolidone, benzyl alcohol polysorbate and water. In the above compositions the D 1-hydrocortisone may be replaced by D 1-cortisone or the corresponding 14-hydroxy compounds.