Studies on Antitumor Agents. V. Syntheses and Antitumor Activities of 5-Fluorouracil Derivatives

Abstract

Six types of 5-fluorouracil (5-FU) derivatives were synthesized; namely, 2,4-di-O-substituted, 2-O-substituted, 4-O-substituted, 1,3-disubstituted, 1-substituted and 3-substituted compounds. After oral administration of these compounds to rats, the blood levels of 5-FU were determined. Among O-substituted derivatives, a 4-O-substituted derivative was most easily activated to 5-FU and 2-O-substituted derivatives were next most easily activated. Among N-substituted derivatives, acyl and sulfonyl derivatives showed the highest 5-FU releasing abilities and 1-alkoxymethyl substituted derivatives showed low ability. N-Alkyl substituted derivatives were not activated to 5-FU. Several compounds which gave higher blood levels of 5-FU than that obtained with 1-(tetrahydro-2-furyl)-5-fiuorouracil (Thf-FU), as well as same related compounds, were selected and their antitumor activities were examined. The 2-O-substituted derivatives, 2-butoxy-5-fluoro-4(1H)-pyrimidone (11) and 2-benzyloxy-5-fluoro-4(1H)-pyrimidone (19), were as effective as Thf-FU. The activities of 2,4-di-O-substituted derivatives, 2,4-dibutoxy-5-fluoropyrimidine (1) and 2,4-dibenzyloxy-5-fluoropyrimidine (6), against Ehrlich carcinoma and against sarcoma 180, respectively, were the same as those of Thf-FU. The 1-substituted derivatives, 1-ethoxymethyl-5-fluorouracil (49) and 1-(1-ethoxy-1-phenylmethyl)-5-fluorouracil (50), were found to be as effective as Thf-FU. © 1982, The Pharmaceutical Society of Japan. All rights reserved.