Platinum (II) complex and agent for treating malignant tumor

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

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514186, 549 3, 549206, 549210, 549450, 549451, 549452, A61K 3324, A61K 3128, C07F 1500

Patent

active

053025873

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel platinum complex and to an agent for treating malignant tumor containing the same as an effective component.


BACKGROUND ART

A number of organic acid platinum (II) complexes wherein the ligand component is 1,2-diaminocyclohexane have been reported. However, many of them have low solubility so that they cannot be intravenously administered (e.g., cyclobutane-1,1-dicarboxylate disclosed in Japanese Laid Open Patent Application (Kokai) No. 60-10952) while the intravenous administration is the administration route of platinum complexes or, in the alternative, their stabilities in aqueous solutions are low although their solubilities are large (e.g., trimellitate disclosed by P. J. Andrulis et al., Proceedings of the Fifth International Symposium and Other Metal Compounds in Cancer Chemotherapy, p.450 (1987)).
On the other hand, there is a problem in seeking a platinum complex with anti-tumor activity that an impurity contaminated in the synthesized platinum complex often shows anti-tumor activity. Therefore, it is necessary to appropriately purify the platinum complex. Recently, James D. Hoeschele and N. Farrel reported examples wherein the anti-tumor activity of a platinum complex disappeared after an appropriate purification of the platinum complex in Inorg. Chem., 27, 4106-4113 (1988). That is, they reported that among the 1,2-diaminocyclohexane Pt(II) complexes which were reported to be water-soluble and to have high anti-tumor activities, some complexes lost their anti-tumor activities after purification. Thus, they emphasized the importance of obtaining a sample with a high purity for the evaluation of the anti-tumor activities.
The present inventors previously discovered that the platinum (II) complexes containing 1 mole of 1,2-diaminocyclohexane and 2 moles of 3-acetyl-6-methyltetrahydropyran-2,4-dione or its analogue have anti-tumor activities (EP 337,459). However, it turned out that these complexes do not show anti-tumor activities when they are highly purified. Thus, it is important for an industrial preparation that the synthesized complex can be purified easily and the complex with a high purity can be obtained easily.
The object of the present invention is to provide a novel platinum (II) complex with a strong anti-tumor activity, which may easily be purified, which has a solubility that enables intravenous administration, and which is stable in aqueous solution.


DISCLOSURE OF THE INVENTION

The present invention provides a novel platinum (II) complex represented by the following formula (A): ##STR2## wherein R.sub.1 represents C.sub.1 -C.sub.5 lower hydrocarbon group, R.sub.2 and R.sub.3 represents hydrogen atom or C.sub.1 -C.sub.3 lower hydrocarbon group, the configuration of 1,2-diaminocyclohexane being cis, trans-l- or trans-d- as well as an agent for treating malignant tumor comprising the complex as an effective component.


BEST MODE FOR CARRYING OUT THE INVENTION

The lower hydrocarbon group employed in the present invention is preferably alkyl group and alkenyl group such as methyl, ethyl, propyl, butyl, pentyl, vinyl, isopropyl, allyl and isopropenyl. Among these, methyl is especially preferred.
The moiety represented by the formula ##STR3## bonded to platinum in the complex of the formula (A) exhibits the tautomerism represented by the equation of ##STR4## and chelates the platinum. The moiety ##STR5## exhibits the tautomerism represented by the equation of ##STR6##
The present inventors discovered that a complex can be synthesized, in which one molecule of a deprotonated derivative of a five-membered ring compound (B) of the formula: ##STR7## compound (B) exhibits the tautomerism presented by the equation of ##STR8## chelates the platinum (II) and another one molecule of the deprotonated derivative of the compound (B) in the form of an anion is attached thereto so as to form a complex. This complex is highly soluble in water and stable in aqueous solution, and has high anti-tumor activity.
The compound that may be synthesi

REFERENCES:
patent: 4783452 (1988-11-01), Haines et al.
patent: 4912100 (1990-03-01), Ohno
patent: 4980347 (1990-12-01), Ohno
patent: 5011959 (1991-04-01), Khokhar et al.
patent: 5034552 (1991-07-01), Keppler et al.
Staquet et al, Cancer Treatment Reports vol. 67, No. 9, 1983, p. 753.

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