Heterocyclic cytotoxic agents

Details Heterocyclic cytotoxic agents Heterocyclic cytotoxic agents

2000-09-29

2002-11-26

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S285000, C514S280000, C514S248000, C544S233000, C546S048000, C546S061000, C546S070000

Reexamination Certificate

active

06486167

ABSTRACT:

BACKGROUND OF THE INVENTION
DNA-topoisomerases are enzymes which are present in the nuclei of cells where they catalyze the breaking and rejoining of DNA strands, which control the topological state of DNA. Recent studies also suggest that topoisomerases are also involved in regulating template supercoiling during RNA transcription. There are two major classes of mammalian topoisomerases. DNA-topoisomerase-1 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.
The exceptional topoisomerase poisoning observed with coralyne, nitidine, 5,6-dihydro-8-desmethylcoralyne and related analogs prompted several recent studies on those structural features which are associated with their ability to act specifically as poisons of topoisomerase I or topoisomerase II (Gatto et al.,
Cancer Res.
1996, 56, 2795-2800; Wang et al.,
Chem. Res. Toxicol.
1996, 9, 75-83; Wang et al.,
Chem. Res. Toxicol.,
1993, 6, 813-818). A common feature associated with all three of these agents is the presence of a 3-phenylisoquinolinium moiety within their structure.
Despite the observation that several of these compounds had similar potency to camptothecin as a topoisomerase I poison or similar potency to VM-26 as a topoisomerase II poison, they possessed only modest cytotoxic activity. The absence of a more direct correlation with their potency as topoisomerase poisons was attributed, in part, to the likelihood that these agents are not likely to be absorbed as effectively into cells as either camptothecin or VM-26. The presence of the quaternary ammonium group most likely impedes cellular uptake. It has been speculated that agents such as coralyne and nitidine may need to undergo hydrolysis to permit effective transport, with subsequent dehydration or cyclodehydration to reform the quaternary ammonium parent compound. This may explain the relatively poor antitumor activity observed in vivo with agents such as coralyne or nitidine.
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 show inhibitory activity against topoisomerase I and/or topoisomerase II, and compounds that are effective cytotoxic agents against cancer cells, including drug-resistant cancer cells. Accordingly, the invention provides a compound of the invention which is a compound of formula I:
wherein
R
1
, R
2
, and R
3
are each individually hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, COOR
k
, OR
m
, or halo; or R
1
and R
2
taken together are methylenedioxy and R
3
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, COOR
k
, OR
m
, or halo; or R
2
and R
3
taken together are methylenedioxy and R
1
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, COOR
k
, OR
m
, or halo;
R
4
is oxy, (C
1
-C
6
)alkyl, or is absent;
R
5
is hydrogen, hydroxy, or (C
1
-C
6
)alkyl;
R
6
, R
7
and R
8
are each individually hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, COOR
k
, OR
m
, or halo; or R
6
and R
7
taken together are methylenedioxy and R
8
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, COOR
k
, OR
m
, or halo; or R
7
and R
8
taken together are methylenedioxy and R
6
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, nitro, hydroxy, NR
g
R
h
, C(═O)R
k
, COOR
k
, OR
m
, or halo;
each bond represented by ————— is individually present or absent;
X is C(R
a
)(R
b
) or NR
c
;
Y is C(R
d
)(R
e
) or NR
f
;
if present, R
a
and R
b
are each independently hydrogen or (C
1
-C
6
)alkyl if the bond between the 11- and 12-positions represented by ————— is absent; or R
a
is hydrogen or (C
1
-C
6
)alkyl and R
b
is absent if the bond between the 11- and 12-positions represented by ————— is present;
if present, R
c
and R
f
are each independently hydrogen or (C
1
-C
6
)alkyl if the bond between the 11- and 12-positions represented by ————— is absent; or R
c
and R
f
are each independently (C
1
-C
6
)alkyl or absent if the bond between the 11- and 12-positions represented by ————— is present;
if present, R
d
and R
e
are each independently hydrogen or (C
1
-C
6
)alkyl if the bond between the 11- and 12-positions represented by ————— is absent; or R
d
is hydrogen or (C
1
-C
6
)alkyl and R
e
is absent if the bond between the 11- and 12-positions represented by ————— is present;
each R
g
and R
h
is independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, aryl, aryl(C
1
-C
6
)alkyl, aryloxy, or aryl(C
1
-C
6
)alkoxy; or R
g
and R
h
together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;
each R
k
is independently hydrogen, or (C
1
-C
6
)alkyl; and
each R
m
is independently (C
1
-C
6
)alkanoyl, aryl, or aryl(C
1
-C
6
)alkyl;
wherein any (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, or (C
1
-C
6
)alkoxy of R
1
, R
2
, R
3
, R
6
, R
7
, R
8
, or R
k
is optionally substituted on carbon with 1, 2, or 3 substituents independently selected from hydroxy, halo, NR
n
R
p
, (C
3
-C
6
)cycloalkyl, or (C
1
-C
6
)alkoxy; wherein each R
n
and R
p
is independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, or (C
1
-C
6
)alkanoyl; or R
n
and R
p
together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;
wherein any aryl is optionally be substituted with 1, 2, or 3 substituents independently selected from hydroxy, halo, nitro, trifluoromethyl, trifluoromethoxy, carboxy, amino, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, and (C
1
-C
6
)alkoxy;
provided that at least one of R
2
and R
8
is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro; or at least one of R
2
and R
8
forms part of a methylenedioxy; and
provided that R
1
-R
3
and R
6
-R
8
are not all hydrogen;
or a pharmaceutically acceptable salt thereof.
The invention also

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