GB2147578A

GB2147578A - Novel organic platinum complex and process for the preparation thereof

Info

Publication number: GB2147578A
Application number: GB08326755A
Authority: GB
Inventors: Kenji Tsujihara; Tamio Morikawa; Mikio Takeda; Yoshihisa Arai
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Seiyaku Co Ltd
Priority date: 1983-10-06
Filing date: 1983-10-06
Publication date: 1985-05-15
Also published as: GB8326755D0

Abstract

A novel organic platinum complex of the formula: <IMAGE> wherein Y<1> and Y<2> are each a group of the formula: NH2COCOO-, or Y<1> and Y<2> combine to form a group of the formula: -O-CO-CH(R)-CO-O-, and R is a lower alkyl group or hydroxyl group, and a process for the preparation thereof. The compound [I] has an excellent anti-tumor activity and is useful as an anti-tumor agent.

Description

SPECIFICATION Novel organic platinum complex and process for the preparation thereof The present invention relates to a novel organic platinum complex and a process for the preparation thereof. More particularly, it relates to a novel organic platinum complex of the formula;

wherein Y' and Y2 are each a group of the formula: NH2COCOO-, or Y' and Y2 combine to form a group of the formula: -O-CO-CH(R)-CO-O-, and R is a lower alkyl or hydroxyl group, and a process for the prepartion of the organic platinum complex.

The organic platinum complexes of formula [I] of the present invention have an excellent antitumor activity and are useful as anti-tumor agents.

There have hitherto been prepared many organic platinum complexes wherein various diamines are used as a ligand, and the anti-tumor activity of these compounds has also been studied (cf. Rosenberg et al, Nature, 222, 385 (1969), etc.). However, these known compounds have toxicity to the kidney and the organ of hearing [cf. A.W. Prestayko, Cancer and Chemotherapy, 3, 133(1981)].

As a result of extensive study by the present inventors, it has been found that certain organic platinum complexes containing 2-aminomethylpyridine as a ligand have excellent anti-tumor activity without increasing the toxicity as compared with the known components of the preceding paragraph.

In the present specification, the term "a lower alkyl group" denotes an alkyl group having 1 to 4 carbon atoms.

The organic platinum complexes of formula (I] of the present invention can be prepared for example by reacting a compound of the formula:

with a compound of the formula: NH2cocooM [Ill] wherein M is an alkali metal or M-O-CO-CH(R)-CO-O-M [lV] wherein R is a lower alkyl group or hydroxyl group and M is as defined above.

The above process is preferably carried out by dissolving the compound of formula [Il] in a solvent, adding thereto a compound of formula [Ill] or formula [lV] and stirring the mixture. An example of a compound of formula [III] is sodium oxamidate, and examples of compounds of formula [IV] are disodium 2-methylmalonate, disodium 2-ethylmalonate, and disodium 2hydroxymalonate.The solvent is preferably water, The compound of formula [III] is preferably used in an amount of about 2.0 to about 2.5 moles to 1 mole of the compound of formula [il], and the compound of formula [IV] is preferably used in an amount of about 1.0 to about 1.5 moles to 1 mole of the compound of formula [Il]. The reaction is usually carried out at room temperature.

The desired compound of formula [I] prepared by the above process can be isolated from the reaction mixture by a conventional method, for example, by filtering the resulting precipitate. If required, prior to said filtration the reaction mixture may be concentrated.

The starting compound of formula [II] can be prepared by reacting a compound of the formula: K2Pt(ll)X4 or Na2Pt(ll)X4 (wherein X is a halogen atom) with a compound of the formula:

to give an organic platinum complex of the formula:

wherein X is as defined above, and reacting this compound with silver nitrate.

The organic platinum complexes of formula l] of the present invention show potent antitumor activity against various tumor cells such as, for example, Ehrlich carcinoma, sarcoma 180, leukemia L-1210, Lewis lung carcinoma, Yoshida sarcoma, and rat ascites hepatoma. It may be useful to prolong the survival time of warm-blood animals, including humans, afflicted with tumors and/or minimize the growth of tumors in said animals.For example, according to the experiments on anti-leukemia L-1 210 activity (wherein the test compound was intraperitoneally administered for 5 days to mice grafted intraperitoneally with leukemia L-1 210 cells), cisdioxamato (2-aminomethylpyridine) platinum (Il) showed 1LS30: 1.65 mg/kg/day (1LS30 means a dose per day which causes 30% prolongation of the average survival days compared between the medicated mice and control mice, i.e. a non-medicted group of mice grafted with the tumor cells).Moreover, according to the experiment on activity against Ehrlich ascites carcinoma (wherein the test compound was intraperitoneally administered for 5 days to mice grafted with Ehrlich ascites carcinoma, and the amount of the ascites carcinoma was measured 7 days after the administration of the test compound), cis-dioxamato (2-amino-methylpyridine) platinum (II), cis-(2-methylmalonato) (2-aminomethylpyridine) platinum (it), and cis-(2-hydroxy-malonato) (2aminomethylpyridine) platinum (II) all showed M.E.D.: 6.25 mg/kg/day (M.E.D. means a minimum effective dose per day which causes 100% inhibition of Ehrlich ascites carcinoma).

The compound of the present invention is also useful for the treatment of various other tumors such as, for example, prostate tumor, orchis tumor, ovary tumor, malignant lymphoma, leukemia, and breast cancer. The compounds of the present invention show potent anti-tumor activity and have a low toxicity, and hence, can be used as anti-tumor agents with high safety index.

The organic platinum complexes of formula [I] of the present invention can be used for pharmaceutical use in the form of a pharmaceutical preparation suitable for either oral or parentereal administration, preferably for parentereal administration. The compounds of formula I] may also be used in conjunction or admixture with a pharmaceutical excipient. The excipient selected should be one which does not react with the compounds of formula [I]. Suitable excipients are, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum and vegetable oils. Other known medicinal excipients may be employed. The pharmaceutical preparation may be in solid dosage form such as, for example, a tablet, a coated tablet, a pill or a capsule; or in liquid dosage form such as, for example, a solution, a suspension or an emulsion. Further, for parentereal administration, the compounds of formula [I] of the present invention can also be used in the form of an injection or a suppository, preferably an injection. For injection, they are used in the form of an isotonic solution, which is prepared by admixing a compound of formula [I] with an isotonic agent such as, for example, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, o; mannose. The pharmaceutical preparation may be sterilized and/or may contain auxiliaries such as for example, preserving and stabilizing agents. The dose of the compound of formula [I] for pharmaceutical use depends on the route of administration; the age, weight and condition of the host; and the particular disease to be treated.In general, it may be used for pharmaceutical use at a dose of about 20 to 1000 mg/m2, especially 50 to 500 mg/m2, per day.

Practical and presently-preferred embodiments of the present invention are illustratively shown in the following Examples.

Example 1 Cis-dinitrato (2-aminomethylpyridine) platinum (Il) (0.43 g) is dissolved in water (40 ml) with heating. After cooling, sodium oxamidate (0.24 9) is dissolved therein with stirring, and the mixture is allowed to stand at room temperature overnight. The reaction mixture is filtered to remove a small amount of undissolved materials, and the filtrate is concentrated under reduced pressure to 5 ml in volume. The concentrated mixture is cooled and allowed to stand, and the precipitated crystals are separated by filtration, washed with a small amount of cooled water and dried togive cis-dioxamato (2-aminomethylpyridine) platinum (Il) (0.28 g) as a pale yellow powder.

Elementary analysis for CloH12N4o6pt Found (%): C, 24.97; H, 2.56; N, 11.75 Calcd.(%): C, 25.05; H, 2.51; N, 11.69 Nujol IRv max (cm): The IR spectrum of the above compound is shown in the accompanying Fig. 1.

Example 2 Cis-dinitrato(2-aminomethylpyridine) platinum (Il) (0.43 g) is dissolved in water (40 ml) with heating. After cooling an aqueous solution of disodium 2-methylmalonate (0.178 9 in 5 ml H20) is added, and the mixture is allowed to stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure to 10 ml in volume, and the precipitated crystals are separated by filtration, washed with water and dried to give cis-(2-methyl-malonato) (2-aminomethylpyridine) platinum (oil) (0.35 g) as a colourless powder.

Elementary analysis for C10H,2N204Pt: Found (%): C, 28.60; H, 2.82; N, 6.72 Calcd.(%): C, 28.64; H, 2.86; N, 6.68 Nujol IRv max (cm1): The IR spectrum of the above compound is shown in the accompanying Fig. 2.

Example 3 In the same manner as described in Example 2, cis-dinitrato (2-aminomethylpyridine) platinum (Il) (0.43 g) and disodium 2-hydroxymalonate (0.18 g) are treated to give cis-(2-hydroxymalonato) (2-aminomethyl-pyridine) platinum (Il) (0.35 g), as a colourless powder.

Elementary analysis for CgH10H205Pt: Found (%): C, 25.71; H, 2.36; N, 6.54 Calcd.(%): C, 25.65; H, 2.38; N, 6.65 Nujol IRv max (cm1): The IR spectrum of the above compound is shown in the accompanying Fig. 3.

Example 4 In the same manner as described in Example 2, cis-dinitrato(2-aminomethylpyridine) platinum (Il) (0.43 g) and disodium 2-ethylmalonate (0.1 94 g) are treated to give cis-(2-ethylmalonato) (2-amino-methylpyridine) platinum (Il) (0.34 g), as a colourless powder.

Elementary analysis for C11H14N204Pt: Found (%): C, 30.48; H, 3.23; N, 6.47 Calcd.(%): C, 30.35; H, 3.20; N, 6.38 Nujol IRv max (cm1): The IR spectrum of the above compound is shown in the accompanying Fig. 4.

Claims

1. An Organic platinum complex of the formula:

wherein Y1 and Y2 are each a group of the formula: NH2COCOO-, or Y' and Y2 combine to form a group of the formula: -O-CO-CH(R)-CO-O-, and R is a lower alkyl or hydroxyi group.

2. Organic platinum complexes of the formula given in claim 1, substantially as herein described with reference to and as illustrated in any of the Examples.

3. A process for preparing an organic platinum complex of the formula:

wherein Y, and Y2 are each a group of the formula: NH2COCOO-, or Y and y2 combine to form a group of the formula: -O-CO-CH(R)-CO-O-, and R is a lower alkyl or hydroxyl group. which comprises reacting a compound of the formula:

with a compound of the formula: NH2COCOOM (wherein M is an alkali metal) or M-O-CO-CH(R) CO-O-M (wherein R is a lower alkyl group or hydroxy group, M is as defined above).

4. A process according to claim 3, which comprises dissolving a compound of formula [II] in a solvent, adding thereto a compound of formula [III] or formula [IV] and stirring the mixture.

5. A process according to claim 4, wherein the solvent is water.

6. A process according to claim 3, 4 or 5, wherein the compound of formula 1111] is used in an amount of about 2.0 to about 2.5 moles per mole of the compound of formula ll].

7. A process according to claim 3, 4 or 5 wherein the compound of formula lV] is used in an amount of about 1.0 to about 1.5 moles per mole of the compound of ormula ll].

8. A process for preparing an organic platinum complex of the formula given in claim 1, substantially as herein described, with reference to and as illustrated in any of the Examples.

9. Organic platinum complexes of the formula given in claim 1, for use as anti-tumor agents.