Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Patent
1990-11-05
1992-04-14
Shen, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
556 40, 556137, A61K 3128, C07F 1500
Patent
active
051048957
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to platinum(II) complexes useful as anti-tumour agents, to a method for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
It is well known the wide interest on platinum(II) and Platinum(IV) complexes as anti-tumour agents.
The anti-tumour activity of four platinum compounds in animal models was first reported in 1969 (B. Rosemberg et al., Nature 222, 385, 1969). This followed the observation that filamentous growth occurred when cultures of E. Coli were subjected to an electric field and the realization that certain cis-diamino-platinum complexes were the cause of this effect (B. Rosenberg et al., Nature, 205, 965, 1965).
The anti-tumour activity of said platinum(II) complexes has been demonstrated in several animal models. These compounds inhibit tumors such as ascitic leukaemia, Walker-256 carcinosarcoma, mammary tumors induced by dimethylbenzanthracene and B-16 ascitic melanoma. It is estimated that over 2,000 analogues of the original platinum compounds have been synthetized and tested throughout the world since that time.
For a review see P.C. Hydes and M.J.H. Russell, Cancer and metastasis reviews, 7, 67, 1988. Among these compounds, cis-diammino-dichloro-platinum (cDDP, cisplatin) has been the most studied one, and nowadays it has entered clinical practice after approval for the treatment of testicular and ovarian cancer in 1978.
Also other platinum(II) complexes have been studied successfully on animal models (see for example "Platinum, Gold and other metal chemotherapeutic agents", S. J. Lippard Ed., ACS Symp. Series, 209, Washington D.C., 1983).
The antitumour activity of cisplatin has been well-documented in patients affected with various tumours, being particularly effective in the treatment of genito-urinary tumours, of neck and head tumours. Further clinical observations confirm efficacy of cisplatin in several human tumors, when administered in combination with other chemotherapeutic agents.
Due to important gastrointestinal and renal side-effects, haematologic and neurologic complications (ototoxicity) following cisplatin use, there is a increasing demand for novel platinum compounds provided with a better therapeutical index, and devoid of cross resistance with cisplatin.
Subsequent selection and evaluation processes resulted in the approval of carboplatin for use in the treatment of ovarian and small cell lung cancer in 1986. Carboplatin is reported to be less nephrotoxic than cis-platin.
Cisplatin and carboplatin (albeit at higher dose levels) show a similar spectrum of activity as other platinum compounds under clinical investigation.
At present time, the major requirement for a new drug is that it exerts a wider spectrum of clinical activity. In spite of all these efforts the results are not always encouraging both due to considerable toxicity and unfavourable lypophilic and hydrophilic properties of many of new platinum(II) complexes (see for example J. Clin. Hematol. Oncol. 12, 29, 1982). Poor solubility and stability in aqueous vehicles used for administration to patients represent one of the most serious obstacles for the clinical use of new compounds.
To overcome these difficulties, platinum(II) complexes endowed with additional basic or acid groups in neutral ligands and/or in leaving groups have been synthetized and screened The additional (basic and acid) functional groups were thought to be particularly suitable for achieving solubilization after salificaticn of the complexes with an appropriate counter-ion at the moment of dissolution in aqueous media.
Examples of said compounds are for ex.: cis-diamino-2-amino-malonate-platinum(II) complexes (Gandolfi O., U.S. Pat. No. 4,614,811, 1986); bis-platinum(II) complexes disclosed in U.S. Pat. No. 4,565,884 wherein the central polyfunctionalized leaving group is provided with an additional acid group; aromatic dicarboxylato derivatives of diamino-cyclopentane platinum(II) containing SO.sub.3 H and CO.sub.2 H groups in the aromatic ring (D.C. Craciunescu
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Menta Ernesto
Pasini Alessandro
Spinelli Silvano
Tognella Sergio
Zunino Franco
Boehringer Mannheim Italia S.p.A.
Shen Cecilia
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