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A number of N-acyl and N-(alkoxycarbonyl)-5-fluorouracil derivatives possessing, for example, benzoyl, o-toluyl, acetyl, propionyl, heptanoyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl groups as N1 and/or N3 substituents were synthesized, and their antitumor activities were evaluated. The synthesis was achieved by a direct and two-step acylation of 5-fluorouracil and by selective N1-deacetylation of N1-acetyl-N3-substituted-5-fluorouracil under appropriate reaction conditions. Several N3-benzoyl- and N3-o-toluyl-5-fluorouracil derivates and showed significant activity against experimental tumor, and N1-acetyl-N3-o-toluyl-5-fluorouracil was found to be most promising among them. Further investigation revealed 12 to retain higher activity toward various tumors, with lower toxicity and good blood level, than either 1 or FT-207, even for oral administration.

Die Acylierung von 5‐Fluoruracil (I) mit Acetylchlorid ergibt ein untrennbares Gemisch der Verbindungen (II) und (III).

N,N-Dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]- benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M1) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M1 and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean Cmax (1.13 micrograms mL-1) of M1 after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean Cmax (3.38 micrograms mL-1) after 3 h in plasma. The mean AUC of M1 and indomethacin in plasma were 5.45 micrograms h mL-1 and 22.49 micrograms h mL-1, respectively. The mean tmax, Cmax and AUC of M1 in PMNs were 1 h, 11.1 ng (41 pmol)/10(8) cells and 58.6 ng (164 pmol) h/10(8) cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15.4 ng (57 pmol)/10(8) cells and 95.2 ng (266 pmol) h/10(8) cells, respectively. The PMNs/plasma ratio of M1 was about 2.8 times that of indomethacin. These results indicate that the association of M1, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.

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