Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-26
2001-07-03
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S295000, C544S296000, C544S310000, C544S311000
Reexamination Certificate
active
06255314
ABSTRACT:
TECHNICAL FIELD
This invention relates to a cancerous metastasis inhibitor which contains a uracil derivative having thymidine phosphorylase inhibiting activity.
BACKGROUND ART
Cancer treatments have achieved an innovative level of progress in recent years and, especially, an improvement in the success rate of primary carcinoma removal by surgery or radiotherapy has significantly contributed to the progress in cancer treatments. Nonetheless, there are not but a few cases of death by relapse due to metastases of cancers in spite of complete removal of primary carcinomas. A limitation is therefore imposed on the complete prevention of advances of cancers by surgery or radiotherapy.
There is accordingly a growing recognition that the prevention of metastasis of a cancer is an important theme to be achieved for the treatment of the cancer, and clinical tests of cancerous metastasis inhibitors are now under way in the United States, Great Britain, etc.
As a mechanism of hematogenous metastasis of a cancer, the metastasis is assumed to take place through a process which comprises (1) growth of carcinoma cells in a primary carcinoma lesion, (2) development of blood vessels, (3) infiltration of developed blood vessels by malignant carcinoma cells, followed by their penetration into the blood vessels, (4) circulation through the body, (5) arrival at and bonding to a target site, (6) infiltration to the outside of the blood vessels, (7) growth in a target organ, and (8) formation of a metastasized lesion.
As a cancerous metastasis inhibitor, it is generally desirable not only to prevent metastasis of carcinoma cells beforehand but also to prevent proliferation and metastasis of a small metastasized lesion already formed. Those currently available as chemotherapeutic agents for cancers (antitumor agents) on the market are used as drugs effective for the phase (1) in that they exhibit direct growth inhibition and cytocidal activity against carcinoma cells while bringing about size reductions of tumors. They are however not satisfactory drugs as cancerous metastasis inhibitors in that they cause various side effects led by myelotoxicity and exhibit substantially no activity against the other metastasis phases.
Accordingly, drugs of such a new type as having less side effects and permitting long-term administration in view of the process of metastasis are highly valued as cancerous metastasis inhibitors. Clinically, there is also a demand for such drugs.
The blood vessel development phase (2) has therefore been attracting interests as an important target phase for the inhibition of metastasis in recent years in that, except for the growth of a cancer, it takes place only in special cases such as wound healing, resulting in active developments of angiogenesis-inhibiting drugs as metastasis inhibitors.
Various factors are considered to take part in angiogenesis. Platelet-derived endothelial cell growth factor (PD-ECGF) [Nature, 338, 557-562 (1989)], one of such factors, has been reported to be genetically identical human thymidine phosphorylase in recent years [Nature, 356, 668 (1992)]. Thymidine phosphorylase is an enzyme essential for the metabolism of thymidine, and its development in various tissues (livers, lungs, small intestines, large intestines, placentas, etc.) of human and diverse animals has been confirmed. It has also been reported that in a malignant tumor, its development is promoted in the tumored part compared with its adjacent normal tissue [Biochimica et Biophysica Acta, 1034, 107-113 (1992)] and that this thymidine phosphorylase is also developed very often in clinical samples of human tumors and its development is in a positive correlation with the number of blood vessels in a tumor [Cancer Letters, 95, 57-62 (1995)]. As is appreciated from the foregoing, thymidine phosphorylase/PD-ECGF is considered to have close connection with angiogenesis associated with the growth of a tumor. For the induction of angiogenesis by thymidine phosphorylase, its enzymatic activity has been proven to be indispensable, thereby indicating the possibility of suppression of angiogenesis by inhibiting the enzymatic activity [Cancer Research, 55, 1687-1690 (1995)]. Reported as thymidine phosphorylase inhibitors to date include 6-amino-5-bromo-uracil and 6-aminothimine [Biochemical Pharmacology, 29, 1059 (1980)], 6-amino-5-chlorouracil and 3-cyano-2,6-dihydroxypyridine [JP Kokai 63-250324], and acyclothymidine [J P Kokai 5-213761]. Their inhibitory effects are however not sufficient, and it is the current circumstances that no metastasis inhibitor has been found yet for the suppression of angiogenesis induced by thymidine phosphorylase.
Accordingly, an object of the present invention is to provide a cancerous metastasis inhibitor having excellent inhibitory activity against thymidine phosphorylase.
DISCLOSURE OF THE INVENTION
With the foregoing circumstances in view, the present inventors have proceeded with an investigation from various viewpoints about pharmacological effects of uracil derivatives of a specific type which have heretofore been known to have neither angiogenesis inhibiting effects nor cancererous metastasis inhibiting effects. As a result, these compounds have been found to have extremely good thymidine phosphorylase inhibiting activity and, based on this activity, angiogenesis and cancerous metastasis inhibiting activities, leading to the completion of the present invention.
Accordingly, the present invention relates to a cancerous metastasis inhibitor 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 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; or a salt thereof.
The present invention is also concerned with a cancerous metastasis inhibitor composition comprising the uracil derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Further, the present invention pertains to use of the uracil derivative (1) or the salt thereof for the production of a cancerous metastasis inhibitor.
The present invention also relates to a method for the inhibition of metastasis of a cancer, which comprises administering to a patient an effective amount of the uracil derivative (1) or the salt thereof.
BEST MODE FOR CARRYING OUT
Emura Tomohiro
Miyadera Kazutaka
Wierzba Konstanty
Yamada Yuji
Balasubramanian Venkataraman
Raymond Richard L.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Taiho Charmaceutical Co., Ltd.
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