GB968497A - New steroids and methods of their preparation - Google Patents

Abstract

The invention comprises steroids of the general formula: <FORM:0968497/C1/1> and the D 1-, D 6- and D 1,6- derivatives thereof, wherein R1 represents hydrogen or a free or esterified hydroxyl group, R2 represents hydrogen or an aliphatic acyl group containing up to 8 carbon atoms, R3 represents a -H, b -OH or H,H or keto, R4 represents hydrogen, methyl, chlorine or fluorine, X represents chlorine or fluorine, and Y represents hydrogen or fluorine, and the preparation thereof by reacting the corresponding 16a , 17a -oxido-16b -CH2X compound in which X represents chlorine or fluorine with a strong inorganic acid such as perchloric, hydrobromic, hydrochloric, hydriodic, hydrofluoric or sulphuric acid, in the presence of water and an inert organic solvent miscible with water. Steroids of the above general formula may be converted to other steroids falling within the scope of the same general formula by any one or more of the following methods:-(a) a double bond may be introduced at the 1,2-position chemically, for example, with selenium dioxide or 2,3-dichloro-5,6-di-cyano-benzoquinone, or microbiologically using Bacillus sphaericus var. fusiformis, Corynebacterium simplex, and Fusarium solani; (b) a double bond may be introduced at the 6,7-position by reaction with chloranil; (c) a 21-acyloxy group may be hydrolyzed to a 21-hydroxy group (this hydrolysis may take place during any of the microbiological processes referred to); (d) a 21-hydroxy may be esterified, for example, with mono- and di-carboxylic acids (in the latter case a free carboxyl group may be treated with an alkali metal or alkaline earth metal hydroxide to form a salt) or with phosphoric and sulphuric acids; (e) a 21-acyloxy (and hydroxy) group may be formed by treating a 21-unsubstituted compound with iodine to form a 21-iodo compound and then with an alkali metal acylate to form the 21-acyloxy compound which may then be hydrolyzed to a 21-hydroxy group, (f) an 11b -hydroxy group can be introduced into a compound of the above general formula wherein R3 and Y are hydrogen by microbiologically oxidizing with a suitable microorganism such as fungi of the genus Curvularia, Stachylidium and Streptomyces; (g) an 11-keto group can be introduced by microbiologically 11a -hydroxylating with a suitable microorganism such as fungi of the genus Absidia, Cunninghamella, Fusarium, Mucor, Penicillium and Rhizopus, and oxidizing the resulting 11a -hydroxy compound or the previously mentioned 11b -hydroxy compound; (h) a 17a -hydroxy group may be acylated by acylating using a method for esterifying a tertiary hydroxy group; and (i) the 9a -fluoro compounds of the general formula above by dehydrating an 11-hydroxy compound of the above formula wherein Y represents hydrogen to form a 9,11-dehydro compound, for example, by first forming an 11-tosylate, converting the dehydro compound to a 9b ,11b -oxido compound through the 9a -bromo-11b -hydroxy compound, and treating this compound with hydrogen fluoride. Alternatively, any of the processes set out under (a) to (i) above may be applied to the above 16a ,17a -oxido-16b -CH2X reactant before the reaction with the strong inorganic acid. Therapeutic compositions having gestanenic or antiphlogistic activity and which may be in the form of pills, tablets, dragees, suppositories, emulsions, suspensions, or injectable solutions contain as the active ingredient steroids of the above general formula. Specification 960,737 is referred to.