Trinuclear cationic platinum complexes having antitumor activity

Details Trinuclear cationic platinum complexes having antitumor activity Trinuclear cationic platinum complexes having antitumor activity

1997-07-25

2000-01-04

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Heavy metal containing

556136, C07F 1500

Patent

active

060111666

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to platinum complexes having antitumour activity, processes for the preparation thereof and pharmaceutical compositions containing them.


TECHNOLOGICAL BACKGROUND

The use of platinum complexes such as cisplatin and carboplatin in cancer chemotherapy is well established in the art. A number of platinum complexes, such as cisplatin, are used to treat testicular, ovarian, head and neck and small-cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumour becoming refractory to treatment by the agent.
It is generally believed that platinum complexes such as cisplatin manifest their biological activity through covalent interaction with DNA. In particular, cisplatin induces the formation of a range of adducts on DNA including monodentate adducts, bidentate adducts, such as GG or AG and GNG intrastrand crosslinks [Reedijk et al., Structure and Bonding, (1987) 67, 53-89]. To a lesser extent, cisplatin also results in interstrand GG crosslinks and DNA-protein crosslinks [Rahmouni et al., Biochemistry, (1987) 26, 7229-7234]. These DNA lesions result in conformational changes which are reflected in bending and local unwinding of the DNA. These DNA lesions have been reported to inhibit the activity of various DNA polymerases [Vallan et al., Nucl. Acids Res., (1988) 16, 4407-4418; Pinto et al., Proc. Natl. Acad. Sci., (1985) 82, 4616-4619; Gralla et al., Cancer Res., (1987) 47, 5092-5096].
The interstrand crosslinks between two neighbouring guanine bases have also been shown to inhibit RNA polymerase function [Lemaire et al., Proc. Natl. Acad. Sci., (1991) 88, 1982-1985]. Accordingly, the cytotoxic effects of cisplatin are most likely attributable to the combined effects of these DNA lesions, rather than the result of any one specific lesion event.
Mono(platinum) and bis(platinum) complexes respectively containing one or two platinum atoms are known in the art (U.S. Pat. Nos. 4,225,529, 4,250,189, 4,533,502, 4565,884, 4,571,335 and 4,797,393). For example, mono(platinum) complexes include monomeric chloramine square-planar Pt(II) compounds which are four coordinate. The relative number of chloride and ammonia groups in such compounds may vary and these compounds may therefore be described by the general formula:
Thus, the structure of these compounds may vary from [Pt(NH.sub.3).sub.4 ].sup.2+ where m=0 to PtCl.sub.4.sup.2- where m=4. Since Cl is more substitution labile in comparison to ammonia, the complexes [PtCl.sub.2 (NH.sub.3).sub.2 ] and [PtCl(NH.sub.3).sub.3 ]Cl are considered bifunctional and monofunctional, respectively, wherein the "bis" and "mono" prefixes refers to the number of leaving ligands. The charge of the complexes is obtained by considering that the Pt(II) cation has a formal charge of +2 and thus requires a negative charge of -2 for charge neutralization. For example, when m=0, neutralization is provided by the presence of two chloride anions outside the coordination sphere.
The formation of the bond between platinum and ammonia, which is a neutral ligand, may be described as electron-pair donation from NH.sub.3 to the empty orbitals on the Pt(II) atom. Thus, no electron sharing between the Pt and NH.sub.3 group takes place. Because of this absence of electron sharing, the number of neutral ligands does not affect the overall charge in the Pt coordination sphere. Thus [Pt(NH.sub.3).sub.4 ].sup.2+ is formally a 2+ cation requiring non-co-ordinating anion or anions, or counter-ions, having a net negative charge of 2- for neutralization of the complex. For example, neutralization can be provided by two mononegatively charged anions (e.g., NO.sub.3.sup.+, Cl.sup.-, PF.sub.6.sup.-, BF.sub.4.sup.- and mono-carboxylates having the general formula RCOO.sup.-) or a single dinegatively charged anion (e.g., SO.sub.4.sup.2-, dicarboxylates having the general formula [R(COO).sub.2 ].sup.2-). Therefore, for the same principles, [PtCl.sub.2 (NH.sub.3)

REFERENCES:
patent: 5380897 (1995-01-01), Hoeschele
International Publication No. WO 95/26968, published Oct. 12, 1995.

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