著者

廣橋 満 木戸 勝 山本 栄仁 小島 裕 實川 浩一郎 藤井 節郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.41, no.9, pp.1498-1506, 1993-09-15 (Released:2008-03-31)

参考文献数

23

被引用文献数

6 10

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The reactivities of 5-fluorouracil (5-FUra) degradation inhibitors, 2, 4- (2) and 2, 6-dihydroxypyridines (3), were investigated. Acylation of 2 and 2, 4-bis(trimethylsilyloxy)pyridines with equimolar amounts of acid chlorides preferentially occurred at the 4-OH and 2-OH positions, respectively, and the structure of monobenzoylated 5-chloro-2, 4-dihydroxypyridine (2b) was determined as 4-benzoyloxy-5-chloro-2-pyridone (5b) by X-ray crystallo-graphic analysis. Compounds 2 and 3, as well as the N-2-tetrahydrofuryl (11), N-alkyl (12), and N-carbamoyl (14) derivatives of 2, exhibit dynamic keto-enol tautomerism. The acyl derivatives of these pyridines are labile and are thought to be active esters. Monoacyl ester derivatives of these pyridines were combined with 5-FUra analogs to develop novel antitumor agents containing an inhibitor of 5-FUra degradation. One of them, 3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil (BOF-A2) (22b), was the most effective and is currently undergoing late phase-II clinical trials.