Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-11-07
2002-10-15
Pryor, Alton N (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S649000, C552S243000
Reexamination Certificate
active
06465522
ABSTRACT:
This application is a 371 of PCT/GB99/104158 files Feb. 9, 1999
The present invention concerns a novel family of anticancer drugs comprising an anthraquinone group linked to an alkylating agent, the agents having potent anticancer activity and displaying potent activity against drug-resistant tumours.
A wide range of chemicals is now available to treat cancers. However, the clinical response to anticancer agents in cancer chemotherapy is ultimately limited by the emergence of drug resistant tumours. For example the utility of the commonly used anticancer drug adriamycin (doxorubicin) is limited by the emergence of adriamycin-resistant tumours. Similarly, the utility of cisplatin, another commonly used anticancer agent, is limited in cancer chemotherapy by the emergence of cisplatin-resistant tumours. Therefore there is a need for new anticancer agents which are active against drug resistant tumours.
The present invention provides novel anticancer drugs that surprisingly display potent activity against tumours, particularly drug resistant tumours. According to the present invention there is provided a molecule comprising an anthraquinone linked to an alkylating agent and having the formula (I):
wherein:
X is a halogen, or a substituted sulfonate group;
in the linker group from the anthraquinone to the amino group, m=1-5;
in the linker group from the anthraquinone to the alkylating agent, n=1-5; and
the amino group —NR
1
R
2
linked to the anthraquinone is primary, secondary or tertiary or is a tertiary group in the N-oxide form having the formula —N(O)R
1
R
2
.
The anthraquinone group of the molecules of the present invention is found in a number of molecules which have anticancer activity, for example adriamycin and mitoxantrone (Islam et al., 1985, J. Med. Chem., 28: 857). In adriamycin the anthraquinone group is present as part of an anthracycline structure. Typically, drugs containing the anthraquinone group show cross-resistance with adriamycin, i.e. anthraquinone analogues usually show poor activity against adriamycin resistant tumours. Thus it is particularly surprising that even though the molecules of the present invention contain the anthraquinone group they exhibit potent activity against adriamycin resistant tumours.
Furthermore, the molecules of the present invention also show activity against cisplatin resistant tumours. The anticancer drug cisplatin is a metallating agent which, in common with antitumour alkylating agents, function as DNA cross-linking agents. It is also normal for tumours to show cross-resistance against agents which function in this manner, and so alkylating agents will usually show poor activity against cisplatin resistant tumours. It is therefore particularly surprising that, despite containing an alkylating group, the molecules of the present invention also display potent activity against cisplatin resistant tumours.
In formula (1), X may be selected from any one of the group of Cl, Br, I, methanesulfonate, benzenesulfonate, and toluenesulfonate (SO
3
CH
3
, SO
3
C
6
H
5
and SO
3
C
6
H
4
CH
3
), and in particular may be Cl. The amino group linked to the anthraquinone may be primary, R1 and R2 being H. Alternatively it may be secondary, R1 being H and R2 being a C1-4 lower alkyl. Alternatively it may be tertiary, R1 and R2 being C1-4 lower alkyls. For example, R
1
and R
2
may be CH
3
. Alternatively, R
1
and/or R
2
may be based on an alkyl chain but having additional functionality. For example, R
1
and/or R
2
may have the formula CH
2
CH
2
OH.
For example, a molecule according to the present invention may be the anthraquinone alkylating agent ZP-281 given by formula (2). It has been found (see below) that this compound is an extremely potent anticancer agent that also shows very potent activity against both adriamycin-resistant tumour cells (e.g. 2780AD cells) and cisplatin-resistant tumour cells (e.g. 2780CP cells).
A key structural feature of compounds of this invention, typified by compound (2), is that they differ from other alkylating anthraquinones in that the alkylating groups are confined to one side-arm only. This is in contrast to compounds of formula (3) and (4) which have alkylating groups in both side-arms. The present inventors have found that the configuration represented in formula (1) where the alkylating functionality resides in only one of the side-arms gives rise to potent cytotoxic agents which evade drug efflux pump mediated resistance, and DNA repair mediated resistance. It is these resistance mechanisms that are commonly associated with anticancer drug treatment failure in the clinic, and the compounds of formula (1), exemplified by compound (2), therefore have utility in the treatment of cancer patients who have relapsed following conventional chemotherapy. The prior art neither discloses nor suggests that anthraquinone alkylating agents should bear alkylating groups on one side-arm only of the anthraquinone.
Due to its drug resistance, a particularly difficult cancer to treat by conventional chemotherapy is ovarian cancer. An important finding with the anthraquinone alkylating agents of the present invention is that they show potent antitumour activity in drug resistant ovarian cancer cell lines such as SKOV-3, CH1cisR, 2780AD, and 2780CP. Thus the molecules of the present invention are particularly valuable for the treatment of ovarian cancer.
Molecules according to the present invention may be for use in the treatment of cancer as an anticancer prodrug. The molecules of the present invention may also be in the form of for example an acid addition salt derived from the reaction of an organic or inorganic acid with the molecule. Such salts may be pharmaceutically acceptable.
Also provided according to the present invention is the use of a molecule according to the present invention in the manufacture of a medicament for the treatment of cancer. Also provided is a method of manufacture of a medicament for the treatment of cancer, characterised in the use of a molecule according to the present invention. Also provided is a method of treatment of cancer, comprising the step of administering to a patient a molecule according to the present invention. Appropriate dosages of the molecules of the present invention may be readily determined using simple dose-response assays.
The invention will be further apparent from the following description, with reference to the several figures of the accompanying drawing, which show, by way of example only, forms of anthraquinone alkylating agents.
REFERENCES:
patent: WO99/40944 (1999-08-01), None
Paniwynk Zennia
Patterson Laurence Hylton
Potter Gerard Andrew
Teesdale-Spittle Paul
De Montford University
Pryor Alton N
Wallenstein & Wagner Ltd.
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