Patent GB-832214-A (GB)
Title: 1,4,6-pregnatrienes
IPC: C07J5/00
Filed: 1956-06-07
Abstract: The invention comprises 1,4,6-pregnatrienes of the formula <FORM:0832214/IV (b)/1> wherein R is H, OH or OAc (Ac being a carboxylic acyl group), X is =O, <FORM:0832214/IV (b)/2> (a  or b ) or <FORM:0832214/IV (b)/3> (a  or b ), Y is =O, <FORM:0832214/IV (b)/4> or <FORM:0832214/IV (b)/5> Z is H or a (OH), W is H, F, Cl or Br, providing that when W is H, R also is H, and Ac is a carboxylic acyl group.  The compounds are obtained by (1) dibrominating a D 4-pregnene and removing 2 mols. of HBr; monobrominating a D 4-pregnene, dehydrobrominating and introducing a D 1 double bond into the D 4,6-pregnadiene by biochemical means; (2) brominating a D 1,4-pregnadiene and dehydrobrominating to give the 1,4,6-pregnatriene; alternatively the 6-position may be hydroxylated and/or esterified and the elements of water or acid eliminated; (3) introducing a D 1 double bond into a D 4,6-pregnadiene by the action of Corynebacterium simplex or C. Loagii or B. Sphaericus.  Further substituents, e.g. 21-hydroxy or acyloxy, 11-keto, hydroxy or acyloxy, and 9-fluoro-, chloro- or bromo-atoms may be introduced either into 1,4,6-pregnatrienes or at a suitable intermediate stage. Examples describe the preparation of 1,4,6 - pregnatriene - 17a ,21 - diol - 3,11,20 - trione and the 21-acetate and 3-semicarbazone thereof, 1,4,6 - pregnatriene - 11b ,17a ,21 - triol - 3,20-dione and the 11-formate and 21-acetate thereof, 1,4,6 - pregnatriene - 11a ,17a ,21 - triol - 3,20-dione and the 11-acetate and 21-acetate thereof, 9a  - fluoro - 1,4,6 - pregnatriene - 11b ,17a ,21-triol-3,20-dione and the 21-acetate thereof, 9a  - fluoro - 1,4,6 - pregnatriene - 17a ,21,diol-3,11,20-trione and the 21-acetate thereof, 9b ,11b -oxido-1,4,6-pregnatriene-17a ,21-diol-3,20-dione and the 21-formate 21-acetate, 21 - propionate, and 21 - p - toluenesulphonate thereof, 9b ,11b  - oxido - 1,4,6 - pregnatriene - 17a  - ol - 3,20 - dione, 9b ,11b  - oxido - 1,4,6 - pregnatriene - 17a ,20b ,21 - triol - 3 - one and the 21-acetate thereof, 9b ,11b -oxido-1,4,6-pregnatriene - 17a ,20b  - dione - 3 - one, 9a  - bromoand 9a -chloro - 1,4,6 - pregnatriene - 11b ,17a ,21 - triol - 3,20 - dione 21 - acetate, 9a  - bromo- and 9a  - chloro - 1,4,6 - pregnatriene - 17a ,21 - diol - 3,11,20-trione 21-acetate.  Other 21-esters mentioned are butyrates, valerates, hemisuccinates, tartrates, benzoates, salicylates, phthalates and esters of glycollic acid, cyclopentyl and cyclohexylcarboxylic acids, cyclohexylpropionic acids, phenyl acetic acid, trimethylacetic acid, butoxybutyric acid, ethoxy caproic acid, phenylthioacetic acid, caproic acid, toluic acid, ethoxybenzoic acid, p-chlorophenoxyacetic acid, 2,4,5 - trichlorophenoxyacetic acid, 5 - chloro - furoic acid, 4-bromophenoxyacetic acid, 4-methylphenoxyacetic acid, 4-methoxyphenoxy-acetic acid, 5 - t - butylfuroic acid, furoic acid and phenoxypropionic acid.  Specification 786,019 is referred to.ALSO:A therapeutic composition comprises a 1,4,6-pregnatriene having the formula <FORM:0832214/VI/1> wherein R is H, OH or OAC (AC being a carboxylic acyl group), X is: O, <FORM:0832214/VI/2> (a  or b ) or <FORM:0832214/VI/3> (a  or b ) Y is: O, <FORM:0832214/VI/4> or <FORM:0832214/VI/5> , Z is H or a .OH, W is H, F, Cl or Br providing that when W is hydrogen R also is hydrogen, and a pharmaceutically acceptable carrier.  Examples describe (1) a cream containing 9-fluoro-1,4,6-pregnatriene - 11b ,17a ,21 - triol - 3,20 - dione, tetracycline hydrochloride and neomycin sulphate; (2) analgesic tablets containing 9-fluoro - 1,4,6 - pregnatriene - 17a ,21 - diol - 3,11,20-trione, acetophenetidin, caffeine, and acetylsalicylic acid; (3) a suspension for intraarticular injection containing 9-fluoro-1,4,6-pregnatriene - 17a ,21 - diol - 3,11,20 - trione; (4) an infusion for intravenous use containing 9 - fluoro - 1,4,6 - 17a ,21 - diol - 3,11,20 - trione; (5) an ophthalmic ointment containing 9-fluoro-1,4,6 - 11b ,17a ,21 - triol - 3,20 - dione which may also contain tetracycline hydrochloride; (6) an ophthalinic suspension containing 9-fluoro - 1,4,6 - pregnatriene - 11b ,17a ,21 - triol-3,20-dione; (7) a nasal spray and a cream containing 9-fluoro-1,4,6-pregnatriene-11b ,17a ,21-triol-3,20-dione; (8) a cream containing 9-fluoro - 1,4,6 - pregnatriene - 11b ,17a ,21 - triol-3,20-dione and neomycin sulphate; (9) an aqueous suspension containing 9-fluoro-1,4,6-pregnatriene - 17a ,21 - diol - 3,11,20 - trione; (10) an oil suspension containing 9-fluoro-1,4,6-pregnatriene - 17a ,21 - diol - 3,11,20 - trione 21-acetate; (11) an ophthalmic suspension containing 9 - fluoro - 1,4,6 - pregnatriene-11b ,17a ,21 - triol - 3,20 - dione, sodium sulphacetamide and which may also contain neomycin sulphate; (12) an ophthalmic ointment containing 9 - fluoro - 1,4,6 - pregnatriene - 11b ,17a ,21 - triol - 3,20 - dione and sodium sulphacetamide; (13) tablet containing 9-fluoro - 1,4,6 - pregnatriene - 17a ,21 - diol-3,11,20-trione.  Specification 786,019 is referred to.