Trinuclear cationic platinum complexes having antitumor activity

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

1996-09-27

1998-04-28

Nazario-Gonzalez, Porfirio

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

556137, C07F 1500, A61K 3128

Patent

active

057444978

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATION

This application was filed under 35 U.S.C. .sctn. 371 as a request for U.S. examination of International application No. PCT/EP95/01074 filed Mar. 22, 1995.
The present invention relates to platinum-complexes having anti-tumour activity, processes for the preparation thereof and pharmaceutical compositions ontaining them.


TEXHNOLOGICAL BACKGROUND

The use of platinum complexes such as cisplatin and carboplatin in cancer chemotherapy is well stablished in the art. A number of platinum complexes, such as cis-platin, 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 tumor 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 GG or AG, and GNG 53-89!. To a lesser extent, cisplatin also results in interstrand GG (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 et al., Proc. Natl. Acad. Sci., (1985) 82, 4616-4619; and Gralla et al., Cancer Res., (1987) 47, 5092-5096!. The interstrand crosslink between two neighboring guanine bases has also been shown to inhibit RNA polymerase Accordingly, the cytotoxic effects of cisplatin are most likely attributable to the combined effects of these DNA lesion, 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, 4,565,884, 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: !.sup.2+ where m=0 to PtCl.sub.4.sup.2- where m=4. Since Cl is more bifunctional and monofunctional respectively, wherein the "bi" 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 formally a 2+ cation requiring non-coordinating 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 monocarboxylates 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-. neutral complex.
These considerations can be applied not only to ammonia, but to neutral ligands such as primary or secondary amines as well.
It is noted that anionic ligands such as Cl.sup.- may be either coordinately bound (i.e., forming a Pt--Cl bond) or may act as a counter-anion without any need for covalent bond formation. The exact form that anions such as Cl.sup.- are comprised in a given platinum complex depends both on the

REFERENCES:
patent: 5049686 (1991-09-01), Hoeschele
patent: 5380897 (1995-01-01), Hoeschele et al.
Chemical Abstracts, vol. 119, No. 21, 22 Nov. 1993.
Biochemistry, vol. 29, No. 41, 1990, pp. 9522-9531.
Chemical Abstracts, vol. 118, No. 24, Jun. 14, 1993.
WO,A, 91 03482, Published Mar. 21, 1991.

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