Fused imidazolium derivatives

Details Fused imidazolium derivatives Fused imidazolium derivatives

2002-07-01

2004-05-11

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S302100, C546S273100, C514S338000, C514S255050, C544S405000

Reexamination Certificate

active

06734203

ABSTRACT:

TECHNICAL FIELD
This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof.
BACKGROUND OF THE INVENTION
As imidazolium derivatives fused with aryl or heteroaryl ring and having anti-tumor activity, only the 4,9-dioxonaphtho[2,3-d]imidazolium compounds (KP-1, KP-3 and the like) of the following formula have so far been disclosed in
Khim. Pharm. Zh
., 32(6), 10-11 (1998).
(In the formula, Et and Me respectively represent ethyl and methyl, the same shall apply hereinafter.)
J. Med. Chem
., 7(3), 362-364 (1964) discloses a compound having an antimicrobial action in which R
1
and R
2
of the general formula (I) of the present invention, which will be described later, are both lower alkyl, or one is -lower alkylene-(an aryl which may have one or more substituents) and the other is —CH
3
, —(CH
2
)
3
CH
3
or -phenyl group, or one is -lower alkylene-CO— (an aryl which may have one or more substituents) and the other is —CH
2
CH(CH
3
)
2
or —(CH
2
)
3
CH
3
, but there is no disclosure on its anti-tumor activity.
Also, 4,9-dioxonaphtho[2,3-d]imidazolium derivatives in which R
1
and R
2
of the general formula (I) of the present invention are both lower alkyl groups are disclosed in
J. Org. Chem. USSR
, 1, 1479-85 (1965), JP-A-3-258765 and JP-A-6-59371 and the like. However, there is no disclosure on the medicinal use of these compounds.
British Patent No. 1314881 discloses 1,4-dihydro-1,4-dioxonaphthalene derivatives useful as a herbicide, and JP-B-54-25085 discloses isoquinoline-5,8-dione derivatives useful as a herbicide, respectively. Also, several 1,4-dihydro-1,4-dioxonaphthalene derivatives are commonly known by
Zh. Org. Khim
., 22(8), 1736-42 (1986),
J. Gen. Chem. USSR
, 36, 649-652 (1966) and reagent catalogs [Sigma Aldrich Library of Rare Chemicals Structure Index, with update (Aldrich Chemical Company, Inc.) and the like]. However, all of these documents do not disclose on the medicinal use of these compounds.
Imidazole derivatives fused with aryl ring are disclosed in WO 97/30022
, J. Med. Chem
., 39(7), 1447-1451 (1996) and
J. Med. Chem
., 7(3), 362-364 (1964).
DISCLOSURE OF THE INVENTION
Creation of an anticancer agent which exhibits excellent anti-tumor activity and also has low toxicity is still in great demand.
The present inventors have conducted intensive studies on anticancer agents having less side effects and found as a result of the efforts that novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized by being substituted at the 1- and/or 3-position with substituted alkyl group etc., exhibit excellent anti-tumor activity and low toxicity, thus they can be useful as anticancer agents having wide margins of safety. In addition, by finding a 2-acylamino-3-amino-1,4-quinone derivative and a fused imidazole derivative useful as their synthetic intermediates and further finding that this synthetic intermediate 2-acylamino-3-amino-1,4-quinone derivative itself also shows low toxicity and excellent anti-tumor activity, the invention has been accomplished.
That is, the invention relates to a fused imidazolium derivative represented by the following general formula (I) and a pharmaceutical composition, particularly an anticancer agent, which comprises this fused imidazolium derivative and a pharmaceutically acceptable carrier.
(Symbols in the formula have the following meanings;
R
1
and R
2
: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R
1
and R
2
is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),
group B: —OR
a
, —SR
a
, -prodrug-formed OH, —O-lower alkylene-OR
a
, —O-lower alkylene —O-lower alkylene-OR
a
, —O-lower alkylene-NR
a
R
b
, —O-lower alkylene-O-lower alkylene-NR
a
R
b
, —O-lower alkylene-NR
c
-lower alkylene-NR
a
R
b
, —OCO—NR
a
R
b
, —SOR
a
, —SO
2
R
a
, —SO
2
NR
a
R
b
, —NR
a
—SO
2
R
b
, —NR
a
R
b
, —NR
c
-lower alkylene-NR
a
R
b
, —N(-lower alkylene-NR
a
R
b
)
2
, -RinD, —NO
2
, —CN, -halogen, —CO
2
R
a
, —COO
−
, —CONR
a
R
b
, —CONR
a
—O—R
b
, —NR
a
—COR
b
, —NR
a
—CO—NR
b
R
c
, —OCOR
a
and —CO—R
a
,
R
a
, R
b
and R
c
: the same or different from one another and each represents —H, -lower alkyl, -lower alkylene-RinD or -RinD,
RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),
R
3
: —H or -(lower alkyl which may have one or more substituents), or R
2
and R
3
may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR
4
(R
4
: —H or -lower alkyl),
ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, and
X
−
: counter anion, with the proviso that X
−
does not exist when the substituent —COO
−
of the group B forms intramolecular salt with imidazolium cation,
with the proviso that compounds having the following combinations of R
1
and R
2
are excluded:
(1) one is -lower alkylene-(aryl which may have one or more substituents) and the other is —CH
3
, —(CH
2
)
3
CH
3
or -phenyl,
(2) one is -lower alkylene-CO-(aryl which may have one or more substituents) and the other is —CH
2
CH(CH
3
)
2
or —(CH
2
)
3
CH
3
, or
(3) R
1
and R
2
are both -benzyl, —(CH
2
)
2
OC
2
H
5
or —(CH
2
)
2
O—COCH
3
; the same shall apply hereinafter.)
Also, the invention relates to a 2-acylamino-3-amino-1,4-quinone derivative represented by the following general formula (II) or a salt thereof, which is a synthetic intermediate of the above general formula (I) and has excellent anti-tumor activity by itself too, and to a pharmaceutical composition, particularly an anticancer agent, which contains this compound or a salt thereof and a pharmaceutically acceptable carrier.
(Symbols in the formula have the following meanings;
R
1
and R
2
: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R
1
and R
2
is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),
group B: —OR
a
, —SR
a
, -prodrug-formed OH, —O-lower alkylene-OR
a
, —O-lower alkylene-O-lower alkylene-OR
a
, —O-lower alkylene-NR
a
R
b
, —O-lower alkylene-O-lower alkylene-NR
a
R
b
, —O-lower alkylene-NR
c
-lower alkylene-NR
a
R
b
, —OCO—NR
a
R
b
, —SOR
a
, —SO
2
R
a
, —SO
2
NR
a
R
b
, —NR
a
—SO
2
R
b
, —NR
a
R
b
, —NR
c
-lower alkylene-NR
a
R
b
, —N(-lower alkylene-NR
a
R
b
)
2
, -RinD, —NO
2
, —CN, -halogen, —CO
2
R
a
, —CONR
a
R
b
, —CONR
a
R
b
, —CONR
a
—O—R
b
, —NR
a
—COR
b
, —NR
a
—CO—NR
b
R
c
, —OCOR
a
and —CO—R
a
,
R
a
, R
b
and R
c
: the same or different from one another and each represents —H, -lower alky

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