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.

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Nicotinic acid 1-oxide reacts with acetic anhydride to give as principal product 2-acetylnicotinic acid l-oxide ; 2-hydroxynicotinic acid and 6-hydroxynicotinic acid are by-products. Nicotinic acid l-oxide and propionic anhydride give a neutral diketone (111), together with 2-and 6-hydroxynicotinic acid ; 2-propionylnicotinic acid 1-oxide is formed when reaction times are very short. Isonicotinic acid l-oxide and cinchomeronic acid l-oxide are deoxygenated by acetic anhydride. 3-Picoline l-oxide and acetic anhydride give 3-methyl-2-pyridone, 5-methyl-2-pyridone, and 3-methyl-l-(5-methyl-2-pyridyl) -2-pyridone. Under the same conditions S-hydroxypyridine 1-oxide gives 2,3-dihydroxypyridine as the only product isolated. The mechanisms of these reactions are briefly discussed.ALTHOUGH the rearrangements of pyridine N-oxides have been studied extensively in recent years, there appears to be no record of the behaviour of nicotinic acid 1-oxide towards acetic anhydride. The available evidence relating to the rearrangements of 3-substituted pyridine N-oxides (e.g. , the reaction of nicotinic acid l-oxide with phosphorus pentachloride and phosphorus oxychloride,l and the reaction of 3-picoline 1-oxide with acetic anhydride 2, led us, ab initio, to expect a preponderance of 2-hydroxynicotinic acid in the product. When nicotinic acid I-oxide was boiled with acetic anhydride for six hours N $3cc; ' , , J CHMe 2-acetylnicotinic acid l-oxide (I) (25-30y0), 2-hydroxynicotinic acid (lo%), and 6-hydroxynicotinic acid (3%) were obtained.2-Acetylnicotinic acid l-oxide readily gave the haloform reaction ; the major product * A preliminary account of part of this work has been reported in Clzem. and Ind., 1960, 402.

The 16alpha,17alpha-epoxy-16beta-methylandrostane-17beta-carbothioic acid 2b rearranges in solution at ambient temperature to the 17beta-mercapto-16beta-methylandrostane-17alpha,16alpha-carbolactone 6a, possibly via the spirocyclic alpha-thiolactone 5.

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