Uracil derivatives and antitumor effect potentiator and...

Details Uracil derivatives and antitumor effect potentiator and... Uracil derivatives and antitumor effect potentiator and...

1999-12-09

2001-09-25

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S123000, C544S310000, C544S311000, C544S313000

Reexamination Certificate

active

06294535

ABSTRACT:

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 antitumor activities, such as 5-fluoro-2′-deoxyuridine and 5-trifluoromethyl-2′-deoxyuridine, have already known to have strong in vitro activities [Cancer Research, 18, 335 (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 found in the liver, the small intestine and the like [Cancer Research, 32, 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 satisfactory clinical antitumor effects [Cancer Chemotherapy Reports Part 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 like [Japanese Journal of Cancer and Chemotherapy, 8, 262 (1981)]. 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 [Biochemical Pharmacology, 29, 1059 (1980)], 6-amino-5-chloro-uracil and 3-cyano-2,6-dihydroxypyridine [Japanese Patent Application Laid-Open (Kokai) No. SHO 63-250324], acyclothymidine [Japanese Patent Application 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 a human endogenous angiogenic factor [Nature, 356, 668 (1992)]. 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 activities and is used as an eye drop for herpetic keratitis [Science, 145 (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′):
wherein R
1
represents a chlorine, bromine or iodine atom or a cyano or lower alkyl group; and R
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 which may each be substituted by a lower alkyl group; a group —CH
2
N(R
a
)R
b
in which R
a
and R
b
may be the same or different and each represents a hydrogen atom or a lower alkyl group or R
a
and R
b
may form a pyrrolidine ring together with the nitrogen atom to which R
a
and R
b
are bonded; a group —NH—(CH
2
)
m
—Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group, or a cyano group, and m stands for an integer of from 0 to 3; a group NR
c
(CH
2
)
n
—OH in which R
c
represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group —X—Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido 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, with the proviso that R
1
and R
2
are not a bromine atom and an amino group, respectively, at the same time; or a salt thereof.
With respect to 5-bromo-4-aminomethyluracil which has a bromine atom as R
1
and an amino group as R
2
in the formula (1′), a synthesis process of its hydrochloride salt has been reported [Acta Poloniae Pharmaceutica, 27(4), 329 (1970)], but its inhibitory effects on human-derived thymidine phosphorylase have not been known.
Accordingly, the present invention relates to a pharmaceutical comprising, as an active ingredient, a uracil derivative represented by the following formula (1):
wherein R
1
represents a chlorine, bromine or iodine atom or a cyano or lower alkyl group; and R
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 which may each be substituted by a lower alkyl group; a group —CH
2
N(R
a
)R
b
in which R
a
and R
b
may be the same or different and each represents a hydrogen atom or a lower alkyl group or R
a
and R
b
may form a pyrrolidine ring together with the nitrogen atom to which R
a
and R
b
are bonded; a group —NH—(CH
2
)
m
—Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group, or a cyano group, and m stands for an integer of from 0 to 3; a group NR
c
(CH
2
)
n
—OH in which R
c
represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group —X—Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thiou

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