Synthesis of 5-Fluorouracil Derivatives Containing an Inhibitor of 5-Fluorouracil Degradation

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概要

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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.

• 公益社団法人日本薬学会の論文
• 1993-09-15

著者

• 木戸 勝

  Second Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 實川 浩一郎

  Fujii Memorial Research Institute Otsuka Pharmaceutical Co. Ltd.

• 小島 裕

  Fujii Memorial Research Institute Otsuka Pharmaceutical Co. Ltd.

• 廣橋 満

  Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd.,

• 山本 栄仁

  Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd.,

• Kido Masaru

  Second Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 廣橋 満

  Fujii Memorial Research Institute Otsuka Pharmaceutical Co. Ltd.

• 山本 栄仁

  Fujii Memorial Research Institute Otsuka Pharmaceutical Co. Ltd.

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