Pyrazole derivatives and salts thereof

Details Pyrazole derivatives and salts thereof Pyrazole derivatives and salts thereof

2001-01-24

2003-06-03

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S123000, C544S238000, C544S295000, C544S296000, C544S321000, C544S324000, C544S331000

Reexamination Certificate

active

06573377

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel compound having a chemical structure which is different from those of the conventionally used antitumor agents, to an antitumor agent which contains the compound as its active ingredient and to a highly effective antitumor agent capable of showing its efficacy even against 5-FU drug resistant tumors.
BACKGROUND ART
Though a number of 5-FU drugs are currently used as antitumor agents which can be orally administered, it cannot be said that their effects are sufficient, and there are tumors which show resistance against 5-FU drugs, so that concern has been directed toward the development of a drug which has more higher effects and shows its efficacy even against 5-FU drug resistant tumors. In this connection, antitumor effects of pyrazole derivatives related to this invention are described in JP-A-9-48776 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”) and WO 98/32739. This invention is to provide pyrazole derivatives having a novel structure in which a condensed tricyclic heterocyclic ring is substituted, and this invention is also to provide novel compounds in which novel substituents are introduced into the pyrimidinyl group of JP-A-9-48776 and the cycloalkyl group, phenyl group, monocyclic heterocyclic ring group and the like of WO 98/32739.
It is to provide a highly effective antitumor agent which has a novel chemical structure different from that of the conventional antitumor agents and shows its efficacy even against 5-FU drug resistant tumors.
DISCLOSURE OF THE INVENTION
As a result of intensive investigations, the present inventors have found that a pyrazole derivative having a novel structure shows its efficacy even against 5-FU drug resistant tumors and has strong antitumor effects.
This invention has been accomplished by founding that this compound also exerts its effect upon P-glycoprotein expression multi-drug resistant strains which are causing clinical problems.
This invention relates to a compound represented by formula (I):
[in the formula,
R
1
represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R
2
represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group, an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R
3
represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R
4
represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl 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, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
Q represents an amidino group, a cycloalkyl group, a phenyl group or a monocyclic heterocyclic ring group, wherein these amidino group, cycloalkyl group, phenyl group and monocyclic heterocyclic ring group may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, an alkoxylalkoxyl 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; and
G represents a condensed tricyclic heterocyclic ring, wherein the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl 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, the condensed tricyclic heterocyclic ring may have an epoxy group, and the condensed tricyclic heterocyclic ring may also have a carbonyl, group as a constituent element of the ring] or a salt thereof (with the proviso that, in this compound and a salt thereof, a compound [in which G is a condensed tricyclic heterocyclic ring, and a saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or saturated heterocyclic ring having no substituent (excluding a case in which Q is a pyrimidinyl group and binds at the 2-position)] and a salt thereof are excluded).
This invention also provides a compound represented by formula (Ia):
[in the formula,
R
1
, R
2
, R
3
, R
4
, R
5
and Q are as defined in the foregoing, and
G
1
represents a condensed tricyclic heterocyclic group wherein the condensed tricyclic heterocyclic group comprises a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring, wherein
the nitrogen-containing heterocyclic ring constituting the condense tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl 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, and the nitrogen containing heterocyclic ring may contain a carbonyl group as a constituent element of the ring,
the saturated or unsaturated hydrocarbon ring or heterocyclic ring constituting the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), an halogen atom, a hydroxyl group, an alkoxyl group, 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, it may have an epoxy group between ring-forming two atoms, and the saturated or unsaturated hydrocarbon ring or heterocyclic ring may contain a carbonyl group as a constituent element of the ring, and
the benzene ring constituting the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group

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