- GLUCOCORTICOID RECEPTOR AGONIST AND IMMUNOCONJUGATES THEREOF
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Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, pharmaceutical compositiosn including the same, and methods of using the same.
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- METHOD FOR PREPARING FLUTICASONE FUROATE
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Method for preparing fluticasone furoate (6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(2-furoyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester) by directly subjecting a compound of Formula III and a complex of a fluoromethylating reagent in presence of an organic base to a replacement reaction to obtain the target compound. Generation of impurities in a process via Compound IV is avoided; the method is simple with mild reaction conditions, suitable for industrial production, and yields products with purity of 98% by HPLC.
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Page/Page column 0027-0028
(2013/10/22)
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- 17.BETA- (ALPHA-HYDROXY) -ESTERS OF ANDROSTANES AS INTERMEDIATES FOR THE PREPARATION FOR THE PREPARATION OF 17Β-FLUORINATED-ANDROSTANE ESTERS
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Process for the preparation of polyhalogenated steroids, in particular of androstanic fluoro derivatives corticosteroids by means of the formation of new androstanic S-hydroxy alkyl or aralkyl-17-carbothioate intermediates.
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- Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17β- carbothioates and -17β-carboselenoates
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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.
- Phillipps,Bailey,Bain,Borella,Buckton,Clark,Doherty,English,Fazakerley,Laing,Lane-Allman,Robinson,Sandford,Sharratt,Steeples,Stonehouse,Williamson
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p. 3717 - 3729
(2007/10/02)
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- Androstane carbothioic acids
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Androstane carbothioic acids of the formula: STR1 wherein R1 represents a hydrogen atom, a hydroxy group in the α-configuration, a methyl group which may be in either the α- or β-configuration, or a methylene group; R2 represents a hydroxy or protected hydroxy group in either the α- or β-configuration or an oxo group; R3 represents a hydrogen, bromine, chlorine or fluorine atom; or R2 and R3 together represent a carbon-carbon bond or an epoxy group in the β-configuration; R4 represents a hydrogen or fluorine atom; and the symbol represents a single or double bond and the salts thereof are useful as intermediates in the preparation of anti-inflammatory androstane 17β-carbothioate esters. The compounds of formula I are prepared by reaction of a reactive derivative of a 17β-carboxylic acid corresponding to the compound of formula I with hydrogen sulphide or a sulphide or hydrosulphide salt.
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