Heterocyclic topoisomerase poisons

Details Heterocyclic topoisomerase poisons Heterocyclic topoisomerase poisons

2000-01-14

2001-04-24

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...

C548S305400

Reexamination Certificate

active

06221892

ABSTRACT:

BACKGROUND OF THE INVENTION
DNA-topoisomerases are enzymes present in the nuclei of cells where they catalyze the breaking and rejoining of DNA strands, controlling the topological state of DNA. Recent studies also suggest that topoisomerases are involved in regulating template supercoiling during RNA transcription. There are two major classes of mammalian topoisomerases. DNA-topoisomerase-I catalyzes changes in the topological state of duplex DNA by performing transient single-strand breakage-union cycles. In contrast, mammalian topoisomerase II alters the topology of DNA by causing a transient enzyme bridged double-strand break, followed by strand passing and resealing. Mammalian topoisomerase II has been further classified as Type II &agr; and Type II &bgr;. The antitumor activity associated with agents which are topoisomerase poisons is associated with their ability to stabilize the enzyme-DNA cleavable complex. This drug-induced stabilization of the enzyme-DNA cleavable complex effectively converts the enzyme into a cellular poison.
Several antitumor agents in clinical use have potent activity as mammalian topoisomerase II poisons. These include adriamycin, actinomycin D, daunomycin, VP-16, and VM-26 (teniposide or epipodophyllotoxin).
In contrast to the number of clinical and experimental drugs which act as topoisomerase II poisons, there are currently only a limited number of agents which have been identified as topoisomerase I poisons. Camptothecin and its structurally-related analogs are among the most extensively studied topoisomerase I poisons. Recently, bi- and terbenzimidazoles (Chen et al.,
Cancer Res.
1993, 53, 1332-1335; Sun et al.,
J. Med. Chem.
1995, 38, 3638-3644; Kim et al.,
J. Med. Chem.
1996, 39, 992-998), certain benzo[c]phenanthridine and protoberberine alkaloids and their synthetic analogs (Makhey et al.,
Med. Chem. Res.
1995, 5, 1-12; Janin et al.,
J. Med. Chem
1975, 18, 708-713; Makhey et al.,
Bioorg. & Med. Chem.
1996, 4, 781-791), as well as the fungal metabolites, bulgarein (Fujii et al.,
J. Biol. Chem.
1993, 268, 13160-13165) and saintopin (Yamashita et al.,
Biochemistry
1991, 30, 5838-5845) and indolocarbazoles (Yamashita et al.,
Biochemistry
1992, 31, 12069-12075) have been identified as topoisomerase I poisons.
Presently, a need exists for novel anti-cancer agents, for anti-cancer agents that exhibit improved activity, and for anti-cancer agents that exhibit fewer side-effects or improved selectivity compared to existing agents.
SUMMARY OF THE INVENTION
The present invention provides compounds that exhibit inhibitory activity against topoisomerase I, and compounds that are effective cytotoxic agents against cancer cells, including drug-resistant cancer cells. Accordingly there is provided a compound of the invention which is a compound of formula I:
wherein
R
1
and R
2
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkanoyloxy, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl; or R
1
and R
2
taken together are methylenedioxy; or R
1
and R
2
taken together are benzo;
R
3
, R
4
, and R
5
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
2
-C
6
)alkanoyloxy, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, and heteroaryl(C
1
-C
6
)alkyl;
R
6
and R
7
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, or (C
1
-C
6
)alkanoyloxy;
R
8
is hydroxy, halo, nitro, cyano, mercapto, carboxy, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, —NR
a
R
b
, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkanoyloxy, aryloxy, or heteroaryloxy; or R
8
is (C
1
-C
6
)alkyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, nitro, cyano, mercapto, carboxy, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, —NR
a
R
b
, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkanoyloxy, aryloxy, and heteroaryloxy; and
each of R
a
and R
b
is independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, heteroaryl(C
1
-C
6
)alkyl, arylcarbonyl, or heteroarylcarbonyl; or R
a
and R
b
together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino.
wherein any aryl, heteroaryl, or benzo of R
1
-R
5
, R
8
, R
a
, and R
b
may optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, and (C
1
-C
6
)alkanoyloxy;
or a pharmaceutically acceptable salt thereof
The invention also provides a compound of the invention which is a compound of formula I:
wherein
R
1
and R
2
are each independently (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkanoyloxy, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl; or R
1
and R
2
taken together are methylenedioxy;
R
3
, R
4
, and R
5
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
2
-C
6
)alkanoyloxy, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, and heteroaryl(C
1
-C
6
)alkyl;
R
6
and R
7
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, or (C
1
-C
6
)alkanoyloxy; and
R
8
is hydrogen, (C
1
-C
6
)alkyl, aryl, or heteroaryl;
wherein any aryl or heteroaryl of R
1
-R
5
and R
8
may optionally be substituted by 1, 2, or 3 substituents independently selected from the group consisting of (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, and (C
1
-C
6
)alkanoyloxy;
or a pharmaceutically acceptable salt thereof
The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
The invention also provides a therapeutic method comprising inhibiting cancer cells by administering to a mammal (e.g. a human) in need of such therapy, an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, effective to inhibit said cancer cells.
The invention also provides a method comprising inhibiting cancer cells by

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