5-Fluorouracil is known as the compound having antitumor activity and to speak of its mode of action, it takes in vivo a metabolic pathway to 5-fluorouridinemonophosphate, then to 5-fluorouridinediphosphate, and further to 5-fluoro-2'-deoxyuridinemonophosphate, which inhibits thymidylate synthetase activity, thus providing the antitumor effect. Said 5-fluoro-2'-deoxyuridinemonophosphate is metabolizable further into 5-fluoro-2'-deoxyuridine.
The last-mentioned 5-fluoro-2'-deoxyuridine, one of said metabolites, is also known as the compound having an antitumor activity. However, it has been reported that, though 5-fluoro-2'-deoxyuridine shows a strong antitumor activity in vitro, it fails to exercise enough antitumor effect in experiments conducted in vivo on tumor-bearing animals (Cancer Research, 19, 494 (1959); Proc. Soc. Exp. Biol., N.Y., 97, 470 (1958); Proc. Soc. Exp. Biol., N.Y., 104, 127 (1960); Ann., N.Y. Acad. Sci., 76, 576 (1958)).
This is attributed to the fact that, in in vivo, the half-life period of 5-fluoro-2'-deoxyuridine is extremely short, so there is not enough time for 5-fluoro-2'-deoxyuridine to be in contact with the tumor cells (Cancer Research, 32, 1045 (1972); Clin. Pharmacol. Ther., 5, 581 (1964); Cancer Research, 38, 3479 (1978); Bull. Cancer (Paris), 66, 67 (1979); Bull. Cancer (Paris), 66, 75 (1979); Europ. J. Cancer, 16, 1087 (1980)).
Studies have hitherto been made by many specialists on 5-fluoro-2'-deoxyuridine in order to overcome the disadvantage mentioned above.
For example, 3-acyl-5-fluoro-2'-deoxyuridines (Japanese Patent Application Laid-open No. 163586/'79) and 3-acyl-3',5'-di-0-acetyl-5-fluoro-2'-deoxyuridines (Japanese Patent Application Laid-open Nos. 113797/'81 and 113795/'81) are known. These compounds, however, have not had their antitumor effect improved sufficiently enough and there is still a drawback in terms of their safety (therapeutic index).
It has also been reported that 3',5'-diacyl-5-fluoro-2'-deoxyuridines which have their 3'- and 5'-positions acylated with alkanoyl groups have antitumor activity (Biochemical Pharmacology, 14, 1605 (1965)). According to this report, 3',5'-diacyl-5-fluoro-2'-deoxyuridines have their antitumor activity tested always at doses ranging from 10 to 40 mg/kg/day, i.e., doses at which its parental compound 5-fluoro-2'-deoxyuridine showed antitumor activity. However, it has not yet been ascertained whether it has a significantly high level of antitumor activity and therapeutic index comparable to that of 5-fluoro-2'-deoxyuridine.
It is reported in the Cancer Chemother. Pharmacol., (1981) 6: 19.about.23, that, of the 3',5'-diacyl-5-fluoro-2'-deoxyuridine family whose 3'- and 5'-positions are acylated with an alkanoyl group, 3',5'-diacyl-5-fluoro-2'-deoxyuridine which has its 3'- and 5'-positions acylated with an acetyl (C.sub.2), propanoyl (C.sub.3), butyryl (C.sub.4), hexanoyl (C.sub.6), or palmitoyl (C.sub.16) group exhibits an antitumor effect at a lower dose as compared with 5-fluoro-2'-deoxyuridine. With regard to the therapeutic index, however, these 3',5'-diacyl-5-fluoro-2'-deoxyuridines show an improvement by only 2 to 3 times that of 5-fluoro-2'-deoxyuridine.
USPTO Backgrounds
USPTO Backgrounds