SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF ANTIINFLAMMATORY CORTICOSTEROID ANALOGS, HALOMETHYL ANDROSTANE-17-BETA-CARBOTHIOATES AND ANDROSTANE-17-BETA-CARBOSELENOATES

被引：35

作者：

PHILLIPPS, GH ^{[1
]}

BAILEY, EJ ^{[1
]}

BAIN, BM ^{[1
]}

BORELLA, RA ^{[1
]}

BUCKTON, JB ^{[1
]}

CLARK, JC ^{[1
]}

DOHERTY, AE ^{[1
]}

ENGLISH, AF ^{[1
]}

FAZAKERLEY, H ^{[1
]}

LAING, SB ^{[1
]}

LANEALLMAN, E ^{[1
]}

ROBINSON, JD ^{[1
]}

SANDFORD, PE ^{[1
]}

SHARRATT, PJ ^{[1
]}

STEEPLES, IP ^{[1
]}

STONEHOUSE, RD ^{[1
]}

WILLIAMSON, C ^{[1
]}

机构：

[1] GLAXO RES & DEV LTD,DEPT EXTERNAL SCI AFFAIRS,GREENFORD UB6 0HE,MIDDX,ENGLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1994年 / 37卷 / 22期

关键词：

D O I：

10.1021/jm00048a008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-carboselenoat analogues. Antiinflammatory 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.

引用

页码：3717 / 3729

页数：13

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