Patent GB-875570-A (GB)
Title: Improvements in or relating to steroids and the manufacture thereof
IPC: C07J5/00
Filed: 1958-11-25
Abstract: The invention comprises compounds having the formula <FORM:0875570/IV (b)/1> wherein X is C = O or b -CH(OH) an R is hydrogen or the acyl radical of an organic carboxylic acid containing from 1-12 carbon atoms inclusive; compounds having the formula <FORM:0875570/IV (b)/2> wherein Y is halogen and the corresponding D 1 compounds (Group C); compounds having the formula <FORM:0875570/IV (b)/3> and the corresponding D 1 compounds (Group D), the corresponding 9-fluoro, 9-chloro and 9-bromo compounds (Group F); compounds having the formula <FORM:0875570/IV (b)/4> and the corresponding D 1 compounds (Group E), the corresponding 9-fluoro, 9-chloro and 9-bromo compounds (Group G); compounds having the formula <FORM:0875570/IV (b)/5> wherein Y11 is fluorine chlorine or bromine; 2a  - methyl - 6a  - fluoro-11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione 21 - methanesulphonate and 2a -methyl-6a -fluoro-11b ,17a -dihydroxy-21-iodo-4-pregnene-3, 20-dione.  Group A compounds are obtained from the corresponding D 4-pregnenes by fermentive dehydrogenation e.g. by the use of micro organisms such as Septomyxa, Corynebacterium or Fusarium, or by chemical dehydrogenation e.g. by means of selenium dioxide. The 21-OH group if present may be esterified; compounds of Group B are obtained by the dehydration of 2a -methyl-6 - fluoro - 11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione 21-acylate to produce the corresponding 4,9(11) - pregnadiene, followed by treatment of the dehydration product with hypohalous acid in which the halogen is bromine, chlorine or iodine to produce the corresponding 9a -halo-pregnene.  Said 9a -halo-pregnene is epoxidised to give 2a -methyl-6-fluoro - 9b ,11b  - oxido - 17a ,21 - dihydroxy-4-pregnene-3,20-dione 21-acylate which is halogenated to obtain the 2a -methyl-6-fluoro-9a -halo - 11b ,17a ,21 trihydroxy-4-pregnene-3,20-dione 21-acylate. Starting instead with 2-methyl - 6 - fluoro - 11b ,17a ,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acylate by a similar series of reactions the corresponding D 1 compounds (Group C) are obtained; compounds of Group D are obtained by treating a 2a -methyl - 6 - fluoro - 11 - oxygenated-17a ,21-dihydroxy-4-pregnene-3,20-dione with an organic sulphonyl halide to obtain a 21-alkyl or 21-aryl sulphonate of 2a -methyl-6-fluoro-11b ,17a , 21-trihydroxy-4-pregnene-3,20-dione.  Said 21-organic sulphonate is reacted with an iodinating agent to obtain the corresponding 21-iodo steroid which is dehalogenated e.g. with zinc and acetic acid, to produce 2a -methyl-6-fluoro-11b ,17a -dihydroxy-4-pregnene-3,20-dione. The corresponding D 1,4 - pregnadienes may be obtained therefrom by fermentive or chemical dehydrogenation.  Starting instead with 2a -methyl - 6 - fluoro - 9a - halo - 11b ,17a ,21 - trihydroxy-4-pregnene-3,20-dione in which the halogen is fluorine, chlorine or bromine by a similar series of reactions the corresponding 9a -halo compounds (Group F) are obtained; compounds of Group E are obtained by treating a 21-alkyl or aryl sulphonate of 2a -methyl- 6 - fluoro - 11b ,17a ,21 - trihydroxy-4-pregnene-3,20-dione with a fluorinating agent or by fluorinating 2a  - methyl - 6 - fluoro-11b ,17a -dihydroxy-21-iodo 4-pregnene-3,20-dione.  The corresponding D 1,4 - pregnadienes may be obtained therefrom by chemical or fermentive dehydrogenation. Starting instead with 2a -methyl - 6-fluoro-9a -halo-11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione 21 alkyl or aryl sulphonate in which the halogen is fluorine, chlorine or bromine, by a similar series of reactions, the corresponding 9-halo compounds (Group G) are obtained; compounds in Groups A-G bearing in 11-position a keto group may be obtained by employing an 11-keto starting material in the reaction schemes outlined above or by treating the 11-hydroxy group with an oxidising agent e.g. chromic acid.  In the above reaction schemes the 6a  or 6b -epimers may be employed to obtain the appropriate product.  The 6a -epimer may be obtained from the 6b -compound by treatment with an anhydrous acid e.g. hydrochloric acid or by treatment with alkali e.g. sodium or potassium hydroxide. Illustrative products of the invention are 2-methyl-6-fluoro-11b ,17a ,21-trihydroxy - 1,4 pregnadiene-3,20-dione, 2a -methyl - 6,9a  - difluoro - 17a ,21 - dihydroxy-4-pregnene-3,11,20-trione, the corresponding 1,4-pregnadienes, 2a  - methyl-6-fluoro-11b ,17a -dihydroxy-4-pregnene-3,20-dione, 2a -methyl-6,21-difluoro - 11b ,17a - dihydroxy-4-pregnene-3,20-dione and 2a  - methyl 6,9a ,21-trifluoro-17a -hydroxy-4-pregnene-3,11,20-trione. Specifications 724,094, 753,802 and 873,608 are referred to.ALSO:Pharmaceutical compositions comprise (A) 2 - methyl - 6 - fluoro - 11 - oxygenated - 17a ,21-dihydroxy - 1,4 - pregnadiene - 3,20 - diones or the 21-acylates thereof; (B) 2a -methyl-6-fluoro-9a  - halo - 11 - oxygenated - 17a ,21 - dihydroxy-4 - pregnene - 3,20 - diones or the 21 - acylates thereof; (C) 2 - methyl - 6 - fluoro - 9a  - halo-11 - oxygenated - 17a ,21 - dihydroxy - 1,4-pregnadiene - 3,20 - diones or the 21 - acylates thereof; (D) 2a  - methyl - 6 - fluoro - 11 - oxygenated - 17a  - hydroxy - 4 - pregnene - 3,20-diones or the corresponding 1-dehydro-2-methyl compounds; (E) 2a -methyl-6,21-difluoro - 11 - oxygenated - 17a  - hydroxy - 4-pregnene - 3,20 - diones or the corresponding 1-dehydro compounds; (F) 2a -methyl-6-fluoro-9a  - halo - 11 - oxygenated - 17a  - hydroxy - 4-pregnene - 3,20 - diones or the corresponding 1-dehydro compounds; or (G) 2a -methyl-6,21-difluoro - 9a  - halo - 11 - oxygenated - 17a - hydroxy - 4 - pregnene - 3,20 - diones or the corresponding 1-dehydro compounds and a pharmaceutical diluent.  They are employed orally in pills, tablets, capsules, in liquid forms for parenteral use and topically as ointments, creams or lotions with or without coacting antibiotics or germicides. Specifications 724,084, 753,802 and 873,608 are referred to.