Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-08-21
1999-02-09
Wilson, James O.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 49, 514908, 536 2853, 536 2854, 536 2855, A61K 3170, C07H 1906
Patent
active
058694641
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel 2'-deoxy-5-fluorouridine derivatives and pharmaceutically acceptable salts thereof. The compounds of the present invention have a high antitumor activity and are useful as an antitumor agent.
BACKGROUND ART
It is known that 240 -deoxy-5-fluorouridine (FdUrd) significantly inhibits the growth of tumor cells in in vitro tests. But when tested in vivo, FdUrd can not produce a satisfactory therapeutic effect under the influence of pyrimidine nucleoside phosphorylase acting as a decomposition enzyme. For this reason, FdUrd has not been widely used as a anti-cancer agent. Yet, FdUrd has been used for curing specific organic cancers although solely by a continuous administration method (Cancer 57 492-498 (1986), J. Urol. 139 259-262 (1988)). This suggests the possibility that FdUrd might be used as a clinically potent anti-cancer agent if the effective concentration of FdUrd in blood can be retained for a prolonged period. The production of various FdUrd derivatives has been attempted to improve said property (Japanese Unexamined Patent Publications Nos. 113797/1981, 109722/1982, 99499/1983 and 238797/1986). The compounds disclosed in the publications enable effective concentration of FdUrd in blood for a long period. But it was found that the compounds cause side effects such as diarrhea because of the increase of FdUrd concentration in blood beyond its effective concentration in blood, failing to produce a satisfactory clinical effect.
More recently, FdUrd derivatives were reportedly prepared with particular attention directed to the ability of FdUrd to sustain its low concentration in blood (Japanese Unexamined Patent Publications Nos. 106593/1986, 104093/1989 and 199992/1989). The compounds disclosed in the publications achieve an improvement in continuously releasing FdUrd into blood, but sustain the effective concentration of FdUrd in blood to a lesser extent than a continuous administration method because of a low conversion ratio from the compound to FdUrd, failing to give the desired therapeutic index.
DISCLOSURE OF THE INVENTION
The inventor of the present invention conducted extensive research to overcome the foregoing problems and discovered novel 2'-deoxy-5-fluorouridine derivatives having an excellent antitumor activity and a high therapeutic index, namely assuring a high safety. The present invention has been accomplished based on this novel finding.
According to the present invention, there is provided a 2'-deoxy-5-fluorouridine derivative represented by the formula (I) ##STR2## wherein one of R.sub.1 and R.sub.2 is a hydrogen atom or a group easily hydrolyzable in vivo, the other is a benzyl group which may optionally have at least one halogen atom or trifluoromethyl group as a substituent on the phenyl ring, and R.sub.3 is a benzyl group which may optionally have at least one halogen atom as a substituent on the phenyl ring, a phenyl group, a lower alkenyl group or a lower alkyl group which may optionally have at least one substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a di-lower alkylamino group, a furanyl group, a thienyl group and a pyridyl group, or a pharmaceutically acceptable salt thereof.
The compounds of the formula (I) according to the invention have a high antitumor activity and are effective in treating various tumors. The compounds of the invention have the advantages of sustaining a low FdUrd concentration in blood for an extended period, having a low toxicity and assuring a wide safety margin.
Consequently the present invention also provides an antitumor composition comprising an effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Further, the present invention provides a method of treating mammals' tumors, comprising administering to a mammal the compound of the formula (I) or a pharmaceutically acceptable salt thereof.
Fluorine, chlorine, bromine and iodine can be mentioned as examples of
REFERENCES:
patent: 4605645 (1986-08-01), Watanabe et al.
patent: 4864021 (1989-09-01), Fujii
patent: 4946951 (1990-08-01), Tada et al.
patent: 4992534 (1991-02-01), Fujii et al.
Journal of Medicinal Chemistry, vol. 32, No. 1, Jan. 1989, Washington US, pp. 136-139.
Tetrahedron Letters, vol. 26, No. 40, 1985, Oxford GB, pp. 4915-4918.
Journal of Medicinal Chemistry, vol. 31, No. 2, 1988, Washington US, pp. 393-397.
Fukushima Masakazu
Kajitani Makoto
Nomura Makoto
Shimamoto Yuji
Yamashita Jun-ichi
Taiho Pharmaceutical Co. Ltd.
Wilson James O.
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