5-a-pregnano-[3,2-c]pyrazole compounds

摘要

Novel steroids of the formulae (in which R1 is hydrogen, b -halogen, b -hydroxy, b -formyloxy or keto, being b -halogen only when X is halogen; R2 is hydrogen, fluorine or methyl; R3 is hydrogen, a -fluorine or a - or b -methyl; R4 is hydrogen, fluorine, iodine, hydroxy, carboxylic acyloxy, dihydrogen phosphate or alkali metal salts thereof or methylsulphonyloxy; R5 is hydrogen, acyl, carbamyl, C1- 6 alkyl, C7- 10 aralkyl, cycloalkyl, b -hydroxyethyl, naphthyl, 2- or 3-thienyl, C6- 9 aryl, halophenyl, C1- 6 alkoxy-phenyl, nitrophenyl, pyridyl, pyridyloxide or pyrimidinyl; and X is hydrogen or halogen) and acid-addition salts thereof are prepared by reducing appropriate 17a ,21-dihydroxy-4-pregnene-3,20-diones to the 5a -pregnane compounds, converting these before or after reduction to the corresponding 17a ,20 : 20,21-bismethylenedioxy derivatives, oxidizing if desired an 11b -ol to an 11-one, treating with an alkyl formate and sodium hydride in an inert atmosphere to give the 2-hydroxymethylene derivatives, reacting these or the 2-alkoxymethylene derivatives prepared therefrom by standard methods with hydrazine or the appropriately substituted hydrazine to give [3,2-c]-pyrazoles, and removing the 17-side chain protecting group. The nature of the product, i.e. whether it is a 11- or 21-substituted pyrazole, when a substituted hydrazine is used depends on the nature of the substitution and on whether a 2-hydroxymethylene or 2-alkoxymethylene steroid is used. The isomers may be separated by chromatography. N-alkyl-pyrazoles may also be prepared by direct N-alkylation. Products containing an 11-keto group may be reduced to the 11b -ols. Products are the 21-ols or acylates thereof derived from the acid used to remove the protecting group. 21-acyl and N-acyl groups may be removed by treatment with sodium methoxide in methanol, or N-acyl groups selectively removed by treatment with acetic acid. Acylation of the N-substituted 21-ols or 21-acylates gives N,21-diacylates. The 21-ols are converted to 21-mesylates, 21-iodo and -fluoro compounds, 21-dihydrogen phosphates and their alkali metal salts and 21-unsubstituted compounds by standard procedures, N-unsubstituted compounds being converted to N-carbamoyl derivatives during these processes and the carbamoyl group being subsequently removed. The 17a , 21-epoxy compounds formed together with the required 21-fluoro compounds when the 21-mesylates are heated with an alkali metal fluoride may be removed by chromatography. 6a ,9a ,16a - Trifluoro - 11b ,17a ,21 trihydroxy-4-pregnene-3,20-dione is prepared by reacting the 3-enol ethyl ether of methyl 3,11-keto-4,17(20)-pregnadien-21-oate (prepared from the free 3-ketone and ethyl orthoformate) with perchloryl fluoride to give methyl 6#x-fluoro-3,11-diketo-4,17(20) - pregnadien - 21 - oate, reacting this first with pyrrolidine and p-toluenesulphonic acid, then with lithium aluminium hydride, then with sodium acetate and acetic acid in methanol, and lastly with acetic anhydride in pyridine to give 21-acetoxy-6a -fluoro-11b -hydroxy - 4,17(20) - pregnadien - 3 - one, heating this with selenium dioxide to give 21-acetoxy-6a - fluoro - 11b ,16a - dihydroxy - 4,17(20)-pregnadien-3-one, reacting this with thionyl chloride to give 21-acetoxy-20-chloro-6a -fluoro-11b - hydroxy - 4,16 - pregnadien - 3 - one, converting this to 20,21-epoxy-6a -fluoro-11b -hydroxy - 4,16 - pregnadien - 3 - one, reacting this with HF and then acetic anhydride to give 21 - acetoxy - 6a ,16a - difluoro - 11b - hydroxy-4,17(20) - pregnadien - 3 - one, converting this to 21 - acetoxy - 6a ,16a - difluoro - 11b ,17a - dihydroxy - 4 - pregnene - 3,20 - dione, dehydrating this to 21 - acetoxy - 6a ,16a - difluoro - 17a -hydroxy - 4,9(11) - pregnadiene - 3,20 - dione, reacting this with N-bromosuccinimide to give 21 - acetoxy - 9a - bromo - 6a ,16a - difluoro-11b ,17a - dihydroxy - 4 - pregnene - 3,20 - dione, converting this to 21-acetoxy-9b ,11b -epoxy-6a , 16a - difluoro - 17a - hydroxy - 4 - pregnene - 3,20-dione, reacting this with HF to give the 21-acetate of the required product, and hydrolysing this. 9a ,11b - Dichloro - 17a ,21 - dihydroxy - 4-pregnene - 3,20 - dione compounds are prepared by halogenation and hydrolysis of the corresponding D 9(11)-21-acetates, prepared by dehydration of the 11b ,17a ,21-triols and then acetylation. The [3,2-c]pyrazolo-steroids of the invention, with the exception of the 21-iodo compounds, the 21-mesylates and the N-acyl derivatives, which are anti-inflammatory agents, may be made up into pharmaceutical compositions for topical use with suitable carriers.