Uracil derivatives, and antitumor effect potentiator and antitum

Details Uracil derivatives, and antitumor effect potentiator and antitum Uracil derivatives, and antitumor effect potentiator and antitum

1996-11-21

1998-04-28

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514359, 544255, 544309, A01N 4354, A01N 4364, C07D23900, C07D23902

Patent

active

057444757

DESCRIPTION:

BRIEF SUMMARY
This is a 371 application of PCT/JP 96/00828 filed on Mar. 28, 1996.


TECHNICAL FIELD

This invention relates to novel uracil derivatives having excellent inhibitory effects on human-derived thymidine phosphorylase, and also to antitumor effect potentiators and antitumor agents containing same.


BACKGROUND ART

Unnatural pyrimidine nucleosides showing anti-tumor activities, such as 5-fluoro-2'-deoxyuridine and 5-trifluoromethyl-2'-deoxyuridine, have (1958); 22, 815 (1962); 28, 2529 (1968); Proceedings of the Society for Experimental Biology and Medicine, 97, 470 (1958)!.
However, these compounds are known to be promptly decomposed and inactivated in vitro by pyrimidine nucleoside phosphorylase which are 247 (1972); Japanese Journal of Cancer and Chemotherapy 8, 262 (1981); 8, 1548 (1981)!, so that none of them have been found to bring about 1, 55, 205 (1971); Physicians' Desk Reference, 32, 1387 (1978)!.
With a view to preventing the inactivation, research have hence been conducted to develop inhibitors for pyrimidine nucleoside phosphorylase, and some strong inhibitors have been reported. Incidentally, there are two types of pyrimidine nucleoside phosphorylases, that is, uridine phosphorylase and thymidine phosphorylase. It has been reported that uridine phosphorylase is a primary enzyme in selenodonts such as mice and rats while thymidine phosphorylase is a principal enzyme in human and the Potentiating the antitumor effects in human therefore requires an inhibitor for thymidine phosphorylase rather than an inhibitor for uridine phosphorylase.
However, a great majority of inhibitors which have been reported to date selectively exhibit inhibitory activities against uridine phosphorylase and show practically no activities against thymidine phosphorylase. Reported to date as exceptions, in other words, as inhibitors for thymidine phosphorylase are 6-amino-5-bromouracil and 6-aminothymine Laid-Open (Kokai) No. HEI 5-213761!, and the like. Their inhibitory activities are however not sufficient.
Further, human thymidine phosphorylase has recently been found to be the same as PD-ECGF (Platelet Derived Endothelial Cell Growth Factor) which is Accordingly, a thymidine phosphorylase inhibitor can inhibit angiogenesis which is closely associated with malignancy of pathomas such as solid tumors, rheumatism and diabetic retinopathy, and is useful as a therapeutic for these diseases.
In addition, 5-trifluoromethyl-2'-deoxyuridine also has antiviral (3632), 585 (1964); American Journal of Ophthalmology, 73, 932 (1972)!. Phosphorylase inhibitors are also expected to have utility as enhancers for antiviral activities and effects.
An object of the present invention is therefore to provide a novel compound which has excellent inhibitory effects on human-derived thymidine phosphorylase and is useful as an antitumor effect potentiator and an antitumor agent.
With the foregoing circumstances in view, the present inventors have proceeded with extensive research. As a result, it has been found that a uracil derivative represented by the below-described formula (1) has excellent inhibitor effects on human-derived thymidine phosphorylase, leading to the completion of the present invention.


DISCLOSURE OF THE INVENTION

This invention relates to a uracil derivative represented by the following formula (1'): ##STR2## wherein R.sup.1 represents a chlorine, bromine or iodine atom or a cyano or lower alkyl group; and R.sup.2 represents a 4-8 membered heterocyclic group having 1-3 nitrogen atoms, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; a (lower alkyl)amidino group; an amino group, one or both of the hydrogen atoms on the nitrogen atom of

REFERENCES:
patent: 4820712 (1989-04-01), Ottenheijim
Wamhoff et al., "Heterocyclic .beta.-Enamino Esters . . . ", Chemical Abstract, vol. 87 (1977), p. 544, Abs #68271r.
Kinoshita et al., "Pyrimidine Derivatives . . . ", Journal of Heterocyclic Chemistry, vol. 29 (1992), No. 4, pp. 741-747.

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