Patent GB-847844-A (GB)
Title: Steroids
IPC: C07J5/00
Filed: 1957-05-29
Abstract: The invention comprises pregnane compounds of the general formulae: <FORM:0847844/IV(b)/1> and <FORM:0847844/IV(b)/2> wherein R represents hydrogen or an acyl group, R1 represents hydroxy or keto group, X represents a chlorine or fluorine and R is a group convertible to keto by acid hydrolysis or an acid-catalysed ketal interchange reaction, a process that comprises converting a 3-keto-\se4-steroid of the general formula:  <FORM:0847844/IV(b)/3> wherein X has the above circumference and R11 represents an acyl group, to the corresponding 3R*-\se5-steroid, reacting the latter compound with hydrogen cyanide e.g., using liquid hydrogen cyanide in the presence of a small amount of tertiary amine such as triethylamine, to produce the corresponding 3R*-20-cyanohydrin-\se5-steroid, dehydrating the cyanohydric to form the corresponding 3R*-20-cyano-\se5, 17pregnadiene, e.g., with phosphorus oxychloride in an excess of a tertiary amine, and oxidising this compound to form a compound of the general formula: <FORM:0847844/IV(b)/4> wherein R* and X have the above significance and R11 represents an acyl group, e.g., with alkalimetal permanganates such as potassium permanganate, with the optional further step of subjecting this product to acid hydrolysis or to an acid-catalysed ketal interchange reaction to produce the corresponding 3, 11, 20-triketo-12a -(chloro- or fluoro)-17a -hydroxy-21-acyloxy-D 4-pregnene and, if required, saponifying this product to form the corresponding free 21-hydroxy compound, and a process that comprises reacting 3, 11, 20-triketo-12a -(chloro or fluoro)-17a , 21-dihydroxy-D 4-pregnene which may be prepared by the above process with a nitrogenous ketone-reagent, e.g., senicarbazide, to protect the 3- and 20-keto groups, reducing the resulting 3, 20-di (protected keto)-17a , 21-dihydroxy-11-keto-D 4-pregnene, p  e.g. with lithium borohydride, to form a 3,20-di (protected keto)-11b , 17a , 21-trihydroxy-4-pregnene, and acylating and acid hydrolysing the latter compound e.g. with acetic an hydride and aqueous acid respectively, to form a 3, 20-diketo-11b , 17a -dihydroxy-21-acyloxy-D 4-pregnene.  Th3 invention also includes a process for preparing D 1,4-21-hydroxy-pregnadienes by dehydrogenating the D 4-pregnenes prepared by the above processes by the dehydrogenation activity produced in a medium fermented by Bacillus sphaericus, and the D 1,4-21-hydroxy-pregn?dienes may then be acylated to form the corresponding 21-acylates; the D 1,4-pregnadienes may also be prepared by the process detailed above using D 1,4-premudiene reactants instead of the D 4-pregnene reactants.  The group convertible to keto by acid hydrolysis, i.e., the group R*, may be a cyclic or non-cyclic ketal, hemithioketal, thioketal or enol ether group-in the latter case an additional double bond will be present in the 3(4)-position, the preferred protecting groups being the ethylenedioxy or propylenedioxy group.  A number of detailed examples are given.  3-Keto-D 4-steroids of the general formula:  <FORM:0847844/IV(b)/5> wherein X and R11 have the above significance, are prepared by acetylating 12a -bromo-4-pregnene-21-ol-3, 11, 20-trione, reacting the resulting 21-acetate with semi-carbazide to form 12a -bromo-4-pregnen-21-ol-3, 11, 20-trione, 3, 20-bis-semicarbazone-21-acetate, reducing this compound with lithium borohydride to form 12a -bromo-4-pregnen-11b , 21-diol-3, 20-dione 3, 20-bis-semicarbazone, hydrolysing, this compound to form 12a -bromo-4-pregnene-11b , 21-diol-3, 20-dione, reacting this compound with a base to form 11b , 12b -oxido-4-pregnen-21-ol-3, 20-dione, acylating this compound to form the corresponding 21-acylate, treating the 11b , 12b -oxido-4-pregnen-21-ol or the 21-acylate thereof with hydrochloric or hydrofluoric acid, to form the corresponding 12a -halo-4-pregnene-11b , 21-diol-3, 20-dione and 21-acylates thereof, and finally oxidising the 11b -hydroxy group to an 11-keto group.  Specifications 835,909, 845,116 and 846,909 are referred to.ALSO:A pharmaceutical composition comprises a steroid compound of any of the general formulae: <FORM:0847844/VI/1> wherein R represents hydrogen or an acyl group, R1 represents a keto or hydroxy group, X represents a fluorine or chlorine atom, and Rx is a group convertible to a keto group by acid hydrolysis or an acid-catalysed ketal interchange reaction such as a cyclic or non-cyclic ketal, henithioketal, mioketal or erol ether group, and a pharmaceutical carrier.  The composition may be in the form of a powder, tablet, capsule, ointment, gel solution, suspension or dispersion.  Suitable liquid diluents for injectable solutions are sterile water or oils. Liquid compositions may also contain suspending agents such as sodium carboxymethylcellulose, methyl cellulose or gelatin, and solubilising or dispersing agents such as lecithin.  Solid preparations suitable for topical and oral administration may include petrolatum, carbowax, polyglycol, starch, sugar or talc.