80474-24-4Relevant academic research and scientific papers
Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17β- carbothioates and -17β-carboselenoates
Phillipps,Bailey,Bain,Borella,Buckton,Clark,Doherty,English,Fazakerley,Laing,Lane-Allman,Robinson,Sandford,Sharratt,Steeples,Stonehouse,Williamson
, p. 3717 - 3729 (2007/10/02)
The preparation and topical antiinflammatory potencies of a series of halomethyl 17α-(acyloxy)-11β-hydroxy-3-oxoandrosta-1,4-diene-17β- carbothioates, carrying combinations of 6α-fluoro, 9α-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 17β-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 17α-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17β- 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 17α-propionyloxy group. S-Fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta- 1,4-diene-17β-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.
ANDROSTANE CARBOTHIOATES
-
, (2008/06/13)
Compounds of the formula wherein R1 represents a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group, R2 represents a group COR6 where R6 is a C 1-3 alkyl group or OR2 and R3 together form a 16alpha,17alpha-isopropylidenedioxy group; R3 represents a hydrogen atom, a methyl group (which may be in either the alpha- or beta -configuration) or a methylene group; R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and symbol represents a single or double bond have good anti-inflammatory activity, particularly on topical applications. The compounds of formula I are prepared by esterification, halogenation, reduction, deprotection and reaction at a 9,11-double bond to form a 9alpha-halo-11 beta-hydroxy grouping. Pharmaceutical compositions containing the compounds of formula I and methods for the use of the compounds are described and claimed
