Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-10
2001-10-23
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S118000, C546S256000, C514S303000, C514S333000, C514S256000, C514S253010, C514S235500, C544S333000, C544S360000, C544S131000
Reexamination Certificate
active
06306853
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 1,4-dihydropyridine derivative having an action for overcoming resistance to an anti-cancer drug or an action for increasing the effect of an anti-cancer drug or a drug for overcoming resistance to an anti-cancer drug or a drug for increasing the effect of an anti-cancer drug having the derivative or its pharmacologically acceptable salt or hydrate as an effective ingredient.
BACKGROUND ART
Many compounds are already known as 1,4-dihydropyridine derivatives. The majority of these known 1,4-dihydropyridine derivatives have a pharmacological activity with respect to the circulatory system. For other pharmacological activities, there have been just a few reports for those having an anti-inflammatory action, liver protecting action, etc.
On the other hand, “acquired resistance ”, where the effect of the anti-cancer drug is lost during the treatment, is becoming a problem in the chemotherapy of cancers. Multidrug resistance which exhibited against a variety of anti-cancer drugs is becoming an important problem. As a method for overcoming this multidrug resistance, it has been reported that combined administration of an anti-cancer drug and some calcium antagonists (1,4-dihydropyridine compounds such as nicardipine) is effective (Cancer Res., 41, 1967-1972 (1981),
Cancer and Chemotherapy,
vol. 15, 2848 (1988)).
Further, Japanese Unexamined Patent Publication (Kokai) No. 2-40383, Japanese Unexamined Patent Publication (Kokai) No. 2-240081, describe a 1,4-dihydropyridine compound having a dioxene ring or a dithiene ring at its 4-position, Japanese Unexamined Patent Publication (Kokai) No. 5-117235 and Japanese Unexamined Patent Publication (Kokai) No. 2-138221 describes a 1,4-dihydropyridine compound having an aromatic group such as a phenyl group bonded at its 4-position, and WO96/04268, WO97/28125, WO97/28152 describe a 1,4-dihydropyridine compound having, an alkyl group etc., bonded at its 4-position, as those having an action for overcoming resistance to an anti-cancer drug.
However, the inventions described in the above references (i.e.,
Cancer Res.,
41, 1967-1972 (1981) and
Cancer and Chemotherapy,
vol. 15, 2848 (1988)) use calcium antagonists for overcoming resistance to anti-cancer drugs and have the defect that they are not necessarily practical in terms of side effects. That is, calcium channel blockers inherently have a powerful action and act on the heart, blood vessels, etc. even in very small amounts, and therefore, if large amounts of these drugs are used, there is the problem that inconvenient effects are to be caused on the heart and circulatory system.
Further, among the 1,4-dihydropyridines described in the above references, Japanese Unexamined Patent Publication (Kokai) No. 2-40383, Japanese Unexamined Patent Publication (Kokai) No. 2-240081, WO96/04268, WO97/28125, WO97/28152 etc., there are preferable compounds having an action to increase the effect of anti-cancer drugs or an action for overcoming the resistance to an anti-cancer drug and further have almost no calcium channel blocking action. However, the chemical structures of the 1,4-dihydropyridine compounds described in these publications are clearly different from those of the present invention.
DISCLOSURE OF THE INVENTION
Therefore, an object of the present invention is to provide a novel 1,4-dihydropyridine derivative having an activity for overcoming resistance to an anti-cancer drug or an activity for increasing the effect of an anti-cancer drug.
In accordance with the present invention, there is provided a 1,4-dihydropyridine derivative having the formula (I):
wherein R
1
represents a substituted or unsubstituted phenyl or pyridyl group, R
2
represents a C
1
to C
5
lower alkyl group, R
3
represents a substituted or unsubstituted C
1
to C
8
alkyl, alkenyl or alkynyl group, or substituted or unsubstituted C
3
to C
7
cycloalkyl or cycloalkenyl group, R
4
represents —A—R
5
, wherein A represents a C
3
to C
5
alkynylene group having one triple bond, and R
5
represents a substituted or unsubstituted pyridyl, quinolyl, isoquinolyl or pyrymidyl group.
In accordance with the present invention, there is also provided a drug, particularly a drug for overcoming resistance to an anti-cancer drug or a drug for increasing the effect of an anti-cancer drug containing the 1,4-dihydropyridine derivative or its pharmacologically acceptable salt or hydrate.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors synthesized 1,4-dihydropyridine derivatives having various substituents and screened a broad range of these compounds for combined effects with anti-cancer drugs. As a result, we found a novel compound, that is, a 1,4-dihydropyridine derivative having the formula (I) has the action for remarkably increasing the sensitivity of cancer calls to an anti-cancer drug, in particular, the sensitivity of acquiring resistant cancer cells to an anti-cancer drug (i.e., the action for overcoming resistance to anti-cancer drug). Further, we found that such compounds exhibit an effect for prolonging the survival days of a cancerous animal by the combined administration of an anti-cancer drug and further that there are almost no action for the calcium channel, and the toxicities are low, and thus the present invention has been completed.
The present invention will now be explained in further detail.
In the 1,4-dihydropyridine derivative having the formula (I), as R
1
, a substituted or unsubstituted phenyl or heterocyclic group such as a pyridyl group may be mentioned. Preferably, a phenyl or pyridyl group, which may be substituted with a group selected from the group consisting of a 5- or 6-membered heterocyclic group, including a condensed heterocyclic group, having at least one nitrogen or sulfur atom and optionally substituted at the ring thereof, with a C
1
to C
3
lower alkyl group, trifluoromethyl group or halogen atom; a C
1
to C
3
lower alkylthio group; a C
1
to C
3
lower alkyloxy group; a C
1
to C
3
lower alkyl group; a two-substituted amino group; and a halogen atom may be mentioned. More preferably, a pyridyl group, or a phenyl group substituted with one heterocyclic group selected from the group consisting of imidazopyridine, piperadine, imidazole, morpholine, indole, benzimidazole, indazole, thiophene, and 1H-benzotriazole, provided that these heterocyclic groups may be substituted with a C
1
to C
3
lower alkyl group or trifluoromethyl, especially (2-substituted imidazo[4,5-c]pyridin-1-yl)phenyl group substituted, at the 2-position of the imidazo[4,5-c]pyridine, with a C
1
to C
3
lower alkyl or trifluoromethyl group, or a (1-imidazolyl)phenyl group may be mentioned.
Typically, R
1
is a 3-pyridyl, 4-(2-methylimidazo[4,5-b]pyridin-1-yl)phenyl,4-(2isopropylimidazo[4,5-c]pyridin-1-yl)phenyl,3-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl,3-(2-isopropylimidazo[4,5-c]pyridin-1-yl)phenyl,3-(2-trifluoromethylimidazo[4,5-c]pyridin-1-yl)phenyl, 4-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl,4-(4-methylpiperadin-1-yl)phenyl, 4methtylthiphenyl,4-(1H-benzotriazol-1-yl)phenyl,4-(benzoimidazoyl-1-yl)phenyl,4-(1-imidazolyl)phenyl,3-(1-imidazolyl)phenyl,4-morpholinophenyl,4-(1-indazolyl)phenyl,4-(3-thienyl)phenyl,3-(3-thienyl)phenyl, 4-(1-indolyl)phenyl, etc. may be mentioned.
As R
2
, a C
1
to C
5
lower alkyl group, preferably, methyl or ethyl, may be mentioned.
As R
3
, a substituted or unsubstituted C
1
to C
8
alkyl, alkenyl or alkynyl group or a substituted or unsubstituted C
3
to C
7
cycloalkyl group, or cycloalkenyl group. Preferably a C
1
to C
6
alkyl or alkenyl group; a C
1
to C
4
lower alkyl group or C
2
to C
3
lower alkenyl group substituted with a phenyl group, thienyl group, furyl group, cyclohexyl group, naphthyl group, indanyl group, 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene-yl group, 5H-dibenzo[a,d]cycloheptene-yl group or 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-yl group, provid
Gomi Noriaki
Kiue Akira
Omori Hiromasa
Tanabe Hirokazu
Tasaka Shigeyuki
Christie Parker & Hale LLP
Liu Hong
Nikken Chemicals Co., Ltd.
Shah Mukund J.
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