Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2003-04-22
Shah, Mukund (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S344000, C544S101000, C514S250000
Reexamination Certificate
active
06552018
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel compound having an antitumor activity, an antitumor agent comprising the compound as an active ingredient, and a method for treating tumors using the antitumor agent.
BACKGROUND ART
Many 5-fluorouracil type drugs (hereinafter abbreviated as 5-FU drugs) have been used as an antitumor agent that can be administered orally, but their mechanism of action is quite the same, and also the effects obtained are not deemed sufficient. Besides, tumors resistant to 5-FU drugs have come out. It has therefore been demanded to develop a new antitumor agent having a different mechanism of action from that of 5-FU drugs which is more efficacious than 5-FU drugs and is effective on 5-FU-resistant tumors as well.
An object of the present invention is to provide a potent antitumor agent which has a novel chemical structure not heretofore reported and exhibits efficacy on 5-FU-resistant tumors as well.
DISCLOSURE OF INVENTION
As a result of extensive study, the inventors of the present invention have found that novel pyrazole derivatives represented by formula (I) hereinafter shown exhibit a powerful antitumor activity even on 5-FU-resistant tumors. It has also been found that the pyrazole derivatives are also effective on P glycoprotein-expressed multiple drug-resistant strains that have been a clinical problem.
The present invention provides a compound represented by formula (I) or a salt thereof;
wherein R
1
and R
2
, which may be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, an aryl group or an alkyl group, in which the alkyl group may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group; R
3
and R
4
, which may be the same or different, each represent a hydrogen atom, a halogen atom, an alkoxy group, an amino group, an alkylamino group, an aryl group or an alkyl group, in which the alkyl group may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group; R
5
represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, in which the alkyl group may be substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group; Q represents an amidino group, a cycloalkyl group, a phenyl group or a monocyclic heterocyclic group except a pyrimidinyl group bonded to the N atom at its 2-position, and the cycloalkyl, phenyl or monocyclic heterocyclic group may have one or more substituents selected from the group consisting of an alkyl group, an alkyl group substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group, a halogen atom, a hydroxy group, an alkoxy group, an alkoxyalkoxy group, an amino group, an alkylamino group, an acylamino group, an alkylaminoalkylamino group, a nitro group, a cyano group, a carbamoyl group, a thiol group, an alkylthio group, an arylthio group, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, an aminosulfonyl group, an alkylaminosulfonyl group, an arylaminosulfonyl group, and an aryl group; G represents a nitrogen-containing saturated heterocyclic structure represented by formula:
wherein X
1
represents a nitrogen atom or CH,
in which structure the ring may have a keto group and may have one or more substituents selected from the group consisting of an alkyl group, analkyl group substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group, a halogen atom, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, and an aryl group; Z represents a phenyl group, a heterocyclic group or a phenyl or heterocyclic group having one or more substituents selected from the group consisting of an alkyl group, an alkyl group substituted with a halogen atom, an amino group, an alkylamino group, a hydroxy group, an alkoxy group, a thiol group or an alkylthio group, a halogen atom, a hydroxy group, an alkoxy group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group, and an aryl group, in which two substituents on the phenyl or heterocyclic group may be connected to each other to form a ring to provide a condensed bicyclic structure as a whole; the substituent on Z and the substituent on G may be connected to each other to form a condensed tricyclic or tetracyclic structure as a whole.
The compound represented by formula (I) includes both cis- and trans-forms attributed to the double bond of the alkenyl moiety.
Terminologies and expressions used in the present invention are explained. The terminology “cis-form” means a configuration having R
3
and R
4
on the same side of the double bond, and the terminology “trans-form” denotes a configuration in which R
3
and R
4
are on the opposite sides of the double bond.
The terminologies “alkyl group”, “alkenyl group” and “alkynyl group” are intended to include straight-chain groups and branched groups and preferably indicate those having 1 to 6 (2 to 6 as to alkenyl and alkynyl groups) carbon atoms.
The “alkoxy group” preferably include those having 1 to 6 carbon atoms.
The term “aryl group” means a monovalent group derived from an aromatic hydrocarbon by removing one hydrogen atom from its nucleus and includes, for example, phenyl, tolyl, biphenyl and naphthyl groups.
In the “aminoalkyl group” as referred to herein, the amino moiety may be bonded to any position of the alkyl moiety, and the alkyl moiety preferably contains 1 to 6 carbon atoms.
The terminology “alkylamino group” is indented to include an amino group substituted with one alkyl group and an amino group substituted with two alkyl groups, which maybe the same or different, in which the alkyl group preferably contains 1 to 6 carbon atoms.
The term “acyl group” means a carbonyl group (—CO—) with a hydrogen atom, an alkyl group or an aryl group bonded thereto, including formyl, acetyl, propanoyl and benzoyl groups. The alkyl group bonded to the carbonyl group preferably contains 1 to 6 carbon atoms, and the aryl group bonded is preferably a phenyl group.
The term “heterocyclic group” designates a group derived from a monocyclic or bicyclic, saturated or unsaturated heterocyclic compound containing in its ring one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the position of the hetero atom(s) being not limited. Monocyclic heterocyclic groups include those derived from monocyclic heterocyclic compounds, such as pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, triazine, pyrazine, piperazine, dioxane, pyran, and morpholine. Bicyclic heterocyclic groups include those derived from bicyclic heterocyclic compounds, such as benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, and chroman.
The terminology “nitrogen-containing saturated heterocyclic group” means a group derived from a saturated heterocyclic compound which contains in its ring one nitrogen atom and may further contain one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples are those derived from such compounds as pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, and homopiperazine.
The expression “two substituents on the phenyl or heterocyclic group may be connected to each other to form a ring to provide a condensed bicyclic structure as a whole” as used in the definition of Z is intended to mean that two substituents on Z are bonded together to form a
Ejima Akio
Naito Hiroyuki
Ohki Hitoshi
Ohsuki Satoru
Daiichi Pharmaceutical Co. Ltd.
Liu Hong
Shah Mukund
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