Platinum complex and anti-tumor agent comprising said complex as

Details Platinum complex and anti-tumor agent comprising said complex as Platinum complex and anti-tumor agent comprising said complex as

1991-10-15

1993-05-25

Prescott, Arthur C.

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

Organic compounds

Heavy metal containing

C07F 1500

Patent

active

052141748

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel platinum complex having an anti-tumor activity and which is valuable as a medicine such as an anti-tumor agent.


BACKGROUND ART

Some platinum complexes represented by cisplatin have a remarkable anti-tumor effect, and cisplatin has been applied to various cases. Nevertheless, the toxicity, such as the kidney toxicity, of cysplatin is very strong, and this strong toxicity is an obstacle to a medical treatment. Accordingly, the development of a medicine having a toxicity lower than those of conventional platinum complexes, and a higher anti-tumor effect, is required.


DISCLOSURE OF THE INVENTION

With a view to solving this problem, the present inventors synthesized various platinum complexes and examined the anti-tumor effects thereof, and as the result, the inventors found a platinum complex having a toxicity lower than those of the conventional platinum complexes, and a higher anti-tumor activity, and the present invention was completed based on this finding.
More specifically, in accordance with the present invention, there are provided a novel platinum complex represented by the following formula I or a steric isomer thereof (hereinafter referred to as "the compound of the present invention"): ##STR2## and an anti-tumor agent comprising this complex as an active ingredient.
Furthermore, there is provided a method of remedying a tumor with the compound of the present invention.


BEST MODE OF CARRYING OUT THE INVENTION

The steric isomer of the compound of the formula I includes compounds represented by the following formulae ##STR3##
The compound of the present invention can be prepared, for example, according to the following procedures.
A dinitrato platinum complex having 1,2-cyclooctanediamine as a carrier ligand is used as the starting material, and this complex is brought into contact with an OH.sup.- anion exchange resin, to convert the nitro group of the complex to a hydroxyl group. The intended complex is obtained by reacting the above complex with oxalic acid, and recrystallization can be carried out by using an appropriate solvent such as water, according to need.
Furthermore, after the termination of the reaction, a filtration can be carried out by using an adsorbent such as active carbon, according to need, whereby a more refined crystal can be obtained.
As a specific example of the dinitrato platinum complex, there can be mentioned dinitrato(diaminocyclooctane)platinum (II).
As the dinitrato(diaminocyclooctane)platinum (II), there are known dinitrato-(1R,2R)-diaminocyclooctane platinum (II) and dinitrato-(1S,2S)-diaminocyclooctane platinum (II) as the trans-form, and dinitrato-cis-diaminocyclooctane platinum (II) as the cis-form. The present invention includes all of the corresponding isomers prepared from these starting materials and mixtures comprising these isomers at optional ratios.
As a specific example of the OH.sup.- type anion exchange resin, there can be mentioned Diaion SA10AOH (supplied by Mitsubishi Kasei).
As the contact method, any method whereby the platinum complex is brought into contact with the resin, for example, the batch methods and column methods, can be adopted, but in view of the operation efficiency, a column method is preferably adopted.
For the reaction with oxalic acid, there is preferably adopted a method in which oxalic acid dihydrate is dissolved in an amount slightly smaller than the chemical equivalent to the starting platinum complex, and the solution is allowed to stand for about 12 to about 36 hours. After termination of the reaction, the aqueous solution is concentrated or a precipitation is effected by addition of a solvent such as methanol, and the precipitated crystal is recovered by filtration and dried to obtain the intended complex.
The structure of the compound of the present invention has been confirmed by elementary analysis, infrared absorption spectrum analysis and the like.
The anti-tumor effect of the compound of the present invention will now be described with reference to the f

REFERENCES:
patent: 4169846 (1979-10-01), Kindani et al.
patent: 4359425 (1982-11-01), Totani et al.
patent: 4739087 (1988-04-01), Speer et al.
patent: 4921984 (1990-05-01), Nowatari et al.
Pasini et al, "New Cisplatin Analogues . . . ", Angewandte Chemie, International Ed. English, vol. 26, No. 7, Jul. 1987, pp. 615-624.
Chemical Abstracts, vol. 87, 1977, p. 11, abstract No. 87:15694z, Hall et al, "Analogs of sulfato 1,2-diaminocyclohexane platinum (II) (SHP)".
Chemical Abstracts, vol. 94, 1981, p. 42, abstract No. 94:167604c, Speer et al, "Preclinical evaluation of some cisplatin analogs as potential antitumor agents".

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