Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-14
2003-08-19
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S710000, C514S711000, C514S712000, C514S713000, C514S513000, C514S532000, C514S544000, C514S570000, C514S679000, C514S709000, C514S602000, C514S472000, C514S618000, C514S438000, C514S616000, C514S269000, C514S277000, C514S274000, C514S252100, C514S351000, C514S311000, C514S354000, C514S355000, C514S237800, C514S238200, C514S460000, C514S451000, C514S452000, C514S467000, C514S400000, C514S465000, C514S255010, C560S125000, C568S039000, C568S047000, C568S029000, C562S026000, C562S512000, C546S232000, C546S
Reexamination Certificate
active
06608061
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel bisaryl compound and a medicament for treatment of cancer which comprises said compound or a known bisaryl compound as an active ingredient.
BACKGROUND ART
In the cell proliferation process, DNA replication process is regulated by a family of enzymes relating to nucleic acid synthesis. Among these enzymes, it has been reported that ribonucleotide reductase (occasionally referred to as “RNR” hereinafter in this specification) is a particularly important enzyme involved in the biosynthesis of dNTPs, which are precursors of DNA (Ann. Rev. Biochem, 57, pp.349-374).
In cancer cells, endless cell proliferation continues due to over-expression of certain families of enzymes and the like, which leads to death of the host. It has been reported that RNR is over-expressed in cancer cells to maintain high ability of cell proliferation of cancer cells (Cancer Research, 43, pp.3466-3492). Moreover, there has also been reported a possibility that malignant alteration of cancer is caused with accompanying expression of RNR (Proc. Natl. Acad. Sci. USA, 93, pp.14036-14040). Therefore, an agent selectively inhibiting RNR is expected to be able to exert highly selective toxicity to cancer cells, and accordingly, expected to be useful as a medicament for cancer treatment that selectively inhibits the proliferation of cancer cells.
Hydroxyurea has been known as a compound exhibiting antitumor activity by inhibiting RNR, and the compound is used clinically as an anti-leukemia agent. However, the drug only has weak inhibitory activity, and therefore a high blood concentration need to be maintained for a long period of time to successfully inhibit RNR. In addition, the drug causes strong side effects such as bone marrow toxicity, and hence is not a satisfactory therapeutic agent. For these reasons, it has been desired to develop an RNR inhibitor which has potent RNR inhibitory activity as well as reduced side effects including bone marrow toxicity, and has a wide range of effective dosage.
As low molecular RNR inhibitors, there have so far been reported polyhydroxybenzoic acid derivatives (Published Japanese translation of PCT international publication (Kohyo) No. 60-501409/1985), alkoxyphenol compounds (Mol. Pharmacol., 45, pp.792-796), thiosemicarbazone derivatives (Biochem. Pharmacol., 48, pp.335-344), bipyridyl derivatives (Cancer Research, 53, pp.19-26) and the like. However, RNR inhibitory activity and anticancer activity of bisaryl derivatives have not been reported. As for usefulness of bisaryl compounds composed of aryl groups linked by means of plural sulfur atoms as anticancer agents, derivatives comprising aromatic benzenesulfonamide groups as the bisaryl moieties (Japanese Patent Publication (Kokoku) No. 42-10857/1967) have been reported, and the synthesis of an anthramycin dimer has also been reported (Tetrahedron Lett., 129, p.5105). It has also been known that certain bisaryl compounds have antiviral activity (Japanese Patent Unexamined Publication (Kokai) No. 5-501860/1993).
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel bisphenol compound useful as an active ingredient of a medicament.
Another object of the present invention is to provide an medicament for treatment of cancer which comprises a bisphenol compound having inhibitory activity against RNR as an active ingredient.
A still further object of the present invention is to provide a novel bisaryl compound useful as an active ingredient of a medicament.
The inventors of the present invention found that the compounds of the present invention represented by the following formula have inhibitory activity against RNR and anticancer activity, and thus they are useful as an active ingredient of a medicament for treatment of cancer. The present invention was achieved on the basis of these findings.
The present invention provides a medicament for treatment of cancer which comprises a compound represented by the following general formula (I):
Ar
1
—S—R
1
—S—Ar
2
or a physiologically acceptable salt thereof,
wherein R
1
represents a nonmetal bridging group, Ar
1
and Ar
2
independently represent a group selected from the group consisting of an aryl group which has, on its ring, one or more hydroxyl groups optionally substituted with a monovalent group (the aryl group may have one to three substituents other than a hydroxyl group on its ring), and a heteroaryl group which has, on its ring, one or more hydroxyl groups optionally substituted with a monovalent group (the heteroaryl group may have one to three substituents other than a hydroxyl group on its ring).
Preferred embodiments of the aforementioned invention provided are as follows:
the above medicament for treatment of cancer which comprises a compound represented by the aforementioned general formula (I) or a physiologically acceptable salt thereof, wherein R
1
is represented by the general formula (II):
—R
2
—N(R
4
)—R
3
— (II)
wherein R
2
and R
3
independently represent a divalent group, R
4
represents a monovalent group, and R
4
may bind to R
2
or R
3
to form a cyclic structure; the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R
1
is represented by the general formula (III):
—R
5
—X
1
—R
6
— (III)
wherein R
5
and R
6
independently represent a single bond or a divalent group not containing a nitrogen atom, X
1
represents an oxygen atom, S(O)
k
wherein k represents an integer of from 0 to 2, or [(R
9
X
2
)
m
(R
10
X
3
)
n
(R
11
X
4
)
p
]
q
wherein R
9
, R
10
, and R
11
independently represent a single bond or a divalent group not containing a nitrogen atom, and wherein any groups selected from R
5
, R
6
, R
9
, R
10
and R
11
may bind together to form a cyclic structure, X
2
, X
3
and X
4
independently represent an oxygen atom, S(O)
r
wherein r represents an integer of from 0 to 2, or a single bond, and m, n, p and q independently represent an integer of from 1 to 3;
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R
1
is 2,6-pyridinediyldimethyl group (the pyridinediyldimethyl group may have one to three substituents other than a hydrogen atom on its ring);
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R
2
and R
3
are the same divalent groups, and R
4
is a C
1-4
alkyl group which may have one to three substituents other than a hydrogen atom;
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R
2
and R
3
are the same divalent groups, R
4
is represented as COR
25
wherein R
25
represents a hydrogen atom, a C
1-4
alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aralkyl group, or NR
26
R
27
wherein R
26
and R
27
each represent a hydrogen atom, a C
1-4
alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, or an aralkyl group, and said alkyl group, aryl group, heteroaryl group, heterocyclic group, and aralkyl group including those for R
26
and R
27
may have one to three substituents other than a hydrogen atom; and
the above medicament for treatment of cancer which comprises the aforementioned compound or a physiologically acceptable salt thereof, wherein R
1
is represented as R
1A
—R
1B
CO—R
1C
—R
1D
—R
1C
—COR
1B
—R
1A
wherein R
1A
represents a C
1-4
lower alkylene group, R
1B
represents NH or a methylene group, R
1C
represents a single bond or a methylene group, R
1D
represent a divalent bridging cyclic hydrocarbon group, a monocyclic hydrocarbon group, or a heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, and heterocyclic group may have one to three substituents other than a hydrogen atom.
According to further preferred embodiments of the aforementioned each in
Asanuma Naoki
Ikeda Shun-ichi
Inaba Tadashi
Kanda Yuko
Kawamoto Hiroshi
Huang Evelyn Mei
Kyoma Hakko Kogyo Co., Ltd.
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