Patent GB-800889-A (GB)
Title: Steroids
IPC: C07J75/00
Filed: 1956-06-22
Abstract: The invention comprises a compound of the formula: <FORM:0800889/IV (b)/1> wherein St is a 17-(3-keto- D 4-androstenyl) radical which may have hydroxy, oxo, halo and methyl substituents and a D 1-double bond, R is the radical of a dicarboxylic inner anhydride, and Z is a basic amine containing a water-solubilizing group and the preparation thereof which comprises reacting a compound having the formula: <FORM:0800889/IV (b)/2> wherein St is as defined above, with a dicarboxylic inner anhydride having the formula: <FORM:0800889/IV (b)/3> wherein R is as defined above to form an acid ester having the formula: <FORM:0800889/IV (b)/4> wherein St and R are as defined above, and reacting the resulting acid ester with a basic amine containing a water-solubilizing group.  The esterification may be effected in an organic base, e.g. pyridine or lutidine and the acidester thus obtained neutralized with a base amine in a volatile water-miscible solvent, e.g. acetone, tetrahydrofuran, dioxane, 2-propanol and ethanol.  The solvent is removed by vacuum distillation.  The dicarboxylic inner anhydrides employed may be derived from succinic, itaconic, aspartic, maleic, citraconic, aconitic, tricarballylic, phthalic, pyromellitic, naphthalic, diglycolic, iminodiacetic, cimhomeronic, quinolinic, glutaric acids and many others.  Examples describe the preparation of the N-methyl glucamine, galactamine, procaine, ephedrine, epinephrine, phenylephrine, monoethanolammonium, diethanolammonium, triethanolammonium, N - butylmonoethanolammonium ethyldiethanolammonium, phenylmonoethanolammonium, p - tertiaryamylphenyldiethanolammonium, 2 - amine - 1 - butanol, tris - (hydroxymethyl) aminomethane, 2 - amino - 2 - ethyl - 1,3 - propanediol, and 2-amino-2-methyl-1-propanol salts of hydrocortisone 21-hemisuccinate, and the corresponding salts of the hemisuccinates of D 1-cortisone, D 1 - hydrocortisone, 2 - methylhydrocortisone, 9,a -fluoro and 9,a -chlorohydrocortisone and cortisone, 9,a -fluoro and 9,a -chloro- D 1-hydrocortisone and cortisone and of corticosterone. Specifications 794,483, 794,484 and 794,485 are referred to.ALSO:Therapeutic compositions comprise a compound having the formula <FORM:0800889/VI/1> wherein St is a 17-(3-keto- D 4-adrenosteryl radical which may have hydroxy, oxo, halo and methyl substituents and a D 1-double bond, R is the radical of a dicarboxylic inner anhydride and Z is a basic amine containing a water-solubilizing group.  Solutions for topical use comprise a phosphate buffer, sodium chloride, sodium ethylmercurithiosalicylate, chlorobutanol, benzyl alcohol and water.  An ointment for topical use comprises white petrolatum, mineral oil and woolfat.  Dusting powders incorporate lactose.  Water-soluble ointments comprise "Carbowaxes" or higher molecular weight polyethylene glycols. Compositions may take the form of suppositories, bougies, vaginal creams, ointments, dental cones for administration to body cavities and comprise cocoa-butter.  For oral administration the compositions may take the form of tablets, lozenges, gelatine capsules, granules, aqueous solutions and dry mixes. Effervescent tablets comprise a tartaric acid-citric acid-sodium bicarbonate base.  In an elixir, alcohol is present.  Solutions for injection, comprise gelatine or oxypolygelatine. Water-soluble compositions may comprise penicillin G, penicillin O, procaine penicillin, N,N1-dibenzylethylenediamine dipenicillin, bacitracin, tetracycline, chlortetracycline, oxytetracycline, chloramphenicol, streptomycin, dihydrostreptomycin, erythromycin, circulin, endomycin, tyrothricin, granicidin, sorbic acid, nitrofurazone, chloroazodin, hexachlorophene, undecylenic acid, propionic acid, sodium and/or zinc caprylate, lower alkyl p-hydroxybenzoates, sodium sulphacetamide, sulphisoxazole diethanolamine, 4 - aminomethylbenzenesulphonamide hydrochloride, sulphadiazine, sulphamerazine and sulphamethazine.  Compositions for oral or parenteral use may comprise thiamine, riboflavin, pyridoxine, ascorbic acid, pantothenic acid, menadione, nicotinamide, and Vitamin B12.  Specifications 794,483, 794,484 and 794,485 are referred to.