Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17 beta-carbothioates and -17 beta-carboselenoates.

The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)- 11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoate analogues. Anti-inflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha- (propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.

Structure-activity relationships of topically active steroids: the selection of fluticasone propionate.

Although corticosteroids have long been known to be effective in the treatment of respiratory diseases, the wide range of unwanted side-effects with the systemic compounds prompted the development of safe, topically active analogues. Of these analogues, betamethasone 17-valerate, beclomethasone 17,21-dipropionate, budesonide, flunisolide and triamcinolone acetonide have been developed as aerosols for use in asthma and rhinitis with a great deal of success and very little detectable systemic activity. In attempts to avoid these minimal side-effects, further analogues were prepared. The steroid 17-carboxylates were extremely active topically when esterified, while the parent acids were inactive. Thus, it was possible that enzymic hydrolysis of the ester function would lead to systemic deactivation. The 17-carboxylate series was superseded by the corresponding carbothioates, particularly fluticasone propionate which showed unusually high topical anti-inflammatory activity in rodents but was almost inactive after oral administration. This lack of oral activity is attributed to hepatic first-pass metabolism to the corresponding 17-carboxylic acid, which is virtually inactive.

Synthesis and biological activity of some cardiotonic compounds related to gitoxigenin.

The four diastereomeric 3,16-diacetates 6, 9, 10 and 11 were prepared from gitoxin 1 by the routes shown in Schemes 1 and 2 and tested for inotropic activity in the isolated guinea-pig atrial preparation. In line with earlier findings in the digitoxigenin series, derivatives with a 3 alpha-acetoxy function, viz 9 and 10, possessed high biological activity.

Synthesis and biological activity of some cardiotonic compounds related to digitoxigenin.

3 beta-Amino compounds with 17 beta-(3-furyl) and (4-pyridazinyl) ring systems were prepared from digitoxigenin 1b and found to have similar cardiotonic properties to the analogous 3 beta-hydroxy compounds when tested in the isolated guinea-pig atrial preparation. Derivatives with 3 alpha-acetoxy functions were found to have higher than expected activities. Particularly potent was the pyridazine N1-oxide 19. All isocardenolides and the unsaturated anhydride 18 were devoid of activity.

Synthesis and biological activity of some 3-amino compounds related to digoxigenin.

3 alpha-Amino 1a and 3 beta-amino 1b analogues of digoxigenin 14 and their 12 beta-acetate derivatives 2a and 2b were prepared and tested for inotropic activity in the isolated guinea-pig atrial preparation. The 3 alpha-amino compounds were inactive whereas the 3 beta-amino compounds showed comparable activity to their 3 beta-hydroxy counterparts. The replacement of the 17 beta-butenolide ring by other ring systems was investigated. Compounds with a 3'-furyl ring, 9b and 16 were found to possess appreciable activity. A compound with a 4'-pyridazinyl ring 13b exhibited weak activity, whereas the isomeric butenolide compound 11b proved inactive. N-monomethylation of the amine 2b reduced activity and N-dimethylation abolished activity. Acetylation of the 12 beta-hydroxyl function gave less active compounds.

A new series of steroidal antidysrhythmic agents.

With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.

Steroidal anaesthetics: synthesis of 3alpha-hydroxy-5alpha-pregnane-11,20-dione-(21-14C) and 3alpha,21-dihydroxy-5alpha-pregnane-11,20-dione-(21-14C) 21-acetate.

3alpha-Hydroxy-5alpha-pregnane-11,20-dione-[21-14C] and 3alpha,21-dihydroxy-5alpha-pregnane-11,20-dione-[21-14C] 21-acetate were prepared from a common radio-labelled intermediate, 21-diazo-3alpha-hydroxy-5alpha-pregnane-11,20-dione-[21-14C] 3-nitrate, obtained by the reaction of 17beta-chlorocarbonyl-3alpha-hydroxy-5alpha-androstan-11-one 3-nitrate with diazomethane-[14C].