Patent GB-793850-A (GB)
Title: Derivatives of aldosterone, a new active substance from adrenal glands and process of making them
IPC: C07J5/00
Filed: 1954-08-25
Abstract: The invention comprises esters, ethers, enol esters, enol ethers, acetals, the corresponding thio derivatives, and enamines of aldosterone, which itself has the formula <FORM:0793850/IV (b)/1> Specified esterifying acids include formic, acetic, chloracetic, trifluoracetic, propionic, butyric, valeric, trimethylacetic, diethylacetic, caproic, oenanthic, caprylic, palmitic, crotonic, undecanoic, undecylenic, oxalic, succinic, pimelic, maleic, lactic, carbamic, alkoxycarboxylic, b -cyclopentylpropionic, hexahydrobenzoic, benzoic, phenylacetic, cyclohexylacetic, phenylpropionic, trimethylgallic, phthalic, furane-2-carboxylic, isonicotinic, methane sulphonic, p-toluene sulphonic, sulphuric, hydrohalic and phosphoric acids; specified ether, enol ether and enamine residues include methyl, ethyl, ethylene, benzyl, di- and tri-phenylmethyl, tetrahydropyranyl, pyrrolidine, piperidine, glucose, galactose, and maltose residues.  The compounds are prepared from aldosterone by conventional methods, e.g. esters may be prepared from the above-mentioned acids, their anhydrides, halides, or ketenes; the ethers and acetals are obtainable by use of reactive esters of the corresponding alcohols, the alcohols themselves, or silicon tetra-alkyls; thio-acetals and thio-enol ethers are obtainable by treatment with mercapto compounds in the presence of acid catalysts, and 11 : 18-oxygen-sulphur acetals then produced by reaction with heavy metal derivatives forming mercaptides followed by H2S.  Other processes, e.g. trans-esterification, selective esterification and partial hydrolysis by chemical or enzymic means are mentioned.  In examples: (1) aldosterone or a monoacetate is treated with acetic anhydride and pyridine at 0 DEG  and then 25 DEG C., yielding aldosterone diacetate after chromatography on alumina or silica gel, the di-isobutyrate and dibenzoate are likewise prepared; subsequent hydrolysis with potassium bicarbonate in aqueous methanol yields aldosterone; (2) aldosterone is acetylated at 20 DEG  C. with acetic anhydride and pyridine giving the 21-monoacetate; the 21-propionate, trimethylacetate, cyclopentylpropionate, benzoate and phenylacetate can be similarly prepared; (3) treatment of the 21-acetate with benzoyl chloride in pyridine gives the 21-acetate-18-benzoate, and likewise the 21-acetate-18-valerate and acetate-trimethylacetate; (14) partial hydrolysis of aldosterone diacetate with aqueous ether or acetone yields aldosterone 18-monoacetate, and likewise the 18-propionate and benzoate; (5) subsequent treatment with trimethylacetyl chloride in pyridine gives the 21-trimethylacetate-18-acetate; other mixed esters of the 21-hydroxy-18-acetate which can be prepared are the valerate, benzoate, oenanthate, undecylenate and cyclopentylpropionate; (6) aldosterone is left to stand in dilute HCl, yielding the 18 : 11,21-acetal of the formula <FORM:0793850/IV (b)/2> which (7) with acetic anhydride and H2SO4 gives aldosterone diacetate; and (8) with ethylene glycol and p-toluene sulphonic acid yields the 3-ethylene ketal of the acetal; this compound (9) with zinc chloride, methyl mercaptan and CCl4 yields D 5-3-ethylenedioxy-11b ,21-dihydroxy - 20 - oxo - pregnene - 18 - one - dimethylthioacetal which with mercury chloride and then H2S yields the 11-oxygen-18-methylthio-acetal of D 5-3-ethylenedioxy-11b , 21-dihydroxy - 18,20 - dioxo - pregnene; this is reconverted to aldosterone by acetic acid cleavage of the 3-ketal group and treatment with mercury chloride and cadmium carbonate in acetone, the steps carried out in either order; (10) aldosterone is benzoylated at 20 DEG  C. to yield a monobenzoate; and (11) treated with trimethylacetyl chloride and pyridine to furnish the 21-trimethylacetate.  Specification 786,562 is referred to.ALSO:Pharmaceutical preparations suitable for external, parenteral, or topical application comprise esters, ethers, enol esters, enol ethers, acetals, the corresponding thio derivatives, and enamines of aldosterone in combination with an inert carrier. Specified carriers include water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, cholesterol, polyalkylene glycols, white petroleum jelly, and the compositions may further contain preservatives, stabilizing, wetting or emulsifying agents, salts which vary the osmotic pressure, buffer substances or other therapeutic agents. Specified compositions contain: (1) aldosterone diacetate in sesame oil; (2) aldosterone diacetate in aqueous suspension containing sodium carboxymethyl cellulose, sodium chloride, sodium phosphates, mercury sodium thiosalicylate and sorbitan-monolaurate ethylene oxide ether; (3) aldosterone 21-mono-acetate in tablets incorporating lactose, gelatine, starch, talc and magnesium stearate; (4) aldosterone diacetate in linguets containing lactose, stearin, talc, sugar and "Sapamine KW" (Registered Trade Mark).  Specification 786,562 is referred to.