Patent GB-841998-A (GB)
Title: Steroid compounds
IPC: C07J5/00
Filed: 1957-11-11
Abstract: The invention comprises 16,20-diketo-17 a -hydroxy steroids of the pregnane series having at ring D the formula:  <FORM:0841998/IV(b)/1> and the preparation thereof by treating D 16-20-keto-steroids of the pregnane series having at ring D the formula <FORM:0841998/IV(b)/2> with a catalytic amount of a metal oxide e.g., osmium tetroxide, chormium trioxide or tungsten trioxide and a peroxide compound e.g. hydrogen peroxide, alkyl peroxides such as t-butyl hydroperoxide, and peracids such as peracetic, pobenzoic and perphthalic acids, and by oxidising the required 16a , 17a -dihydroxy-20-keto-steroids e.g with chromium trioxide, sodium dichromate, N-brom-succininide or N-bromacetamide.  The preferred 16,20-diketo-17 a -hydroxy-steroids have at ring D the formula <FORM:0841998/IV(b)/3> wherein R represents a methyl, methylol or esterified methylol group, or have the general formula <FORM:0841998/IV(b)/4> wherein ring A contains double bonds in the 1:2 and/or 4:5 positions, R1 is a hydroxy or esterified hydroxy group e.g. derived from an organic carboxylic acid including dicarboxylic acids and inorganic acids such as sulphuric and phosphoric acids X represents a keto, hydroxy or acyloxy group, and each Y represents hydrogen or a halogen atom such as chlorine or fluorine, with the proviso that at least one Y represents a hydrogen atom.  The steroid starting compounds may be substituted by keto, hydroxy esterified hydroxy, chlorine, bromine and/or methyl groups on the nuclear or 21-carbon atoms, and may contain additional double bonds in the 1-, 4-and 9(11)-positions.  Additional double bonds in the 9(11)-position or in positions conjugated with a carbonyl group are inert under the reaction conditions, but double bonds in other positions should preferably be protected.  When the reactant contains a 21-hydroxy group, it is preferable to esterify the hydroxy group before the reaction is carried out in which case the final product is a 21-ester.  Suitable esterifying units are inorganic acids such as sulphuric or phosphoric acid, and the usual organic carboxylic acids a number of which are specified including oxalic, succinic, tricarballylic b ,b -dimethylglutaric and phthalic acids.  The specification refers to a large number of D 1-, and D 4-pregnene and D 1,4- pregnadienes that may be prepared by the above process including compounds containing 9 a -chloro and -fluoro substituents. Functional groups such as 1:2 and/or 4:5 double bonds, 11-oxygenated, 9-halo substituents, 21-hydroxy and 21-ester may be introduced into the 16-keto-17 a -hydroxy compounds by known reactions.  Thus a 21-ester group may be hydrolysed to a 21-hydroxy group, a 21-hydroxy group may be esterified, and a 4-pregnene may be converted to a 1,4-pregnadiene by the dehydrogenating activity produced by growing the micro-organisms Bacillus sphaericus.  In the examples D 4-pregnene-11b , 17a , 21 - triol - 3,16,20 - trione, D 4-pregnene-17a ,21 - diol - 3,11,16,20 - tetrone, 9a  - fluoro-D 4 - pregnene - 11b ,17 a ,21-triol - 3,16,20-trione, D 1,4-pregnadiene-11,b 17 a ,21-triol-3, 16,20, - trione, 9a -fluoro- D 1,4-pregnadiene 17a ,21 - diol - 3,11,16,20-tetrone, 9a  - fluoro (and chloro) - D 114 - pregnadiene - 11b ,17 a ,21-triol - 3,16,20 - trione, 12 a -fluoro - D 1,4 - pregnadiene - 11b ,17 a ,21 - triol - 3,16,20 - trione, 12a  - fluoro - D 1,4 - pregnadiene - 17 a ,21-diol - 3,11,16,20 - tetrone, 12a  - chloro - D 4 pregnene - 17 a ,21 - diol - 3,11,16,20 - tetrone and 12a  - fluoro - D 4 - pregnene -11b ,17 a , 21 - triol - 3,16,20 - trione and 21-esters thereof are prepared.  9a  - Fluoro - D 4,16 - pregnadiene - 11b , 21 - diol - 3,20 - dione 21 - acetate is prepared by treating 9a -fluoro- D 4-pregnene-11b , 17a , 21-triol-3, 20-dione 21-acetate with semicarboxide hydrochloride to form the corresponding 3,20-disemicarbazone, refluxing the dicenicarbazone with acetic anhydride and acetic acid to form the 3,20-disemicarbazone of 9-a  - fluoro - D 4,16 - pregnadiene - 11b ,21 - diol - 3,20 - dione 21-acetate, and treating this compound with pyruric acid.  9a -Fluoro - D 4,16 - pregnadiene - 21 - ol - 3, 11,20 - trione 21 - acetate is prepared from 9a  - fluoro - D 4 - pregnene - 17 a ,21 - diol-3, 11,20 - trione 21 - acetate by conversion to the corresponding 3,20-disemicabazone, and the 3,20 - disemicarbazone of 9 a  - fluoro - D 1,16 - pregnadien - 21 - ol - 3,11,20 - trione 21 - acetate by the method of the previous paragraph.  9a  - Fluoro - D 1,4,16 - pregnatriene - 11b , 21 - diol - 3,20 - dione 21 - acetate is prepared from 9 a  - fluoro - D 1,4 - pregnadiene - 11b , 17 a ,21 - triol - 3,20 - dione 21 - acetate by conversion to the corresponding 3,20 - disemicarbazone and the 3,20 - disemicarbazone of 9 a  - fluoro - D 1,4,16 - pregnatriene - 11b , 21-diol-3,20-dione 21-acetate as above.ALSO:A pharmaceutical preparation contains as the active ingredient a 16,20-diketo-17a -hydroxy steroid of the pregnane series having at ring D the partial structural formula <FORM:0841998/VI/1> and a pharmaceutical carrier.  The preferred active ingredients have at ring D the partial structural formula <FORM:0841998/VI/2> wherein R is a methyl, methylol or esterified methylol group, and may belong to the D  1- or D  4- pregnene or D 1,4 - pregnadiene series.  Other substituents that may be present are 9- and 12- halo substituents such as the chloro and fluoro substituents, 11-keto and hydroxy groups, and 21-hydroxy and ester groups.  The composition may be in the form of a tablet, capsule, lotion, cream or ointment.  Examples are given of a tablet containing q a -fluoro-D  114-pregnadiene-11b , 17a , 21-triol-3, 16, 20-trione 21-acetate, lactose, corn starch, sucrose, acacia and magnesium stearate; and a topical ointment containing 9a -fluoro-D 1,4-pregnoliene-11b , 17a , 21-triol-3, 16, 20-trione 21-acetate, 1, 2-propylene glycol, polymerised ethylene glycol, zinc stearate and water.