JPH01165594A - Novel platinum(ii)complex and remedy for malignant tumor - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I. USE:A remedy for malignant tumor having low toxicity. PREPARATION:N-(4-Carboxylphenyl)maleimide expressed by formula II is reacted with dihydroxodiaminocyclohexane platinum (II) expressed by formula III, normally under ordinary temperature and ordinary pressure in an aqueous solution to provide the compound expressed by formula I. Furthermore, the compound expressed by formula III which is a starting raw material is produced by heating N-(4-carboxyphenyl)maleimide in an acetic anhydride solvent in the presence of sodium acetate. The compound expressed by formula III is produced by reacting a compound expressed by the formula K2PtCl4 with a compound expressed by formula IV, reacting the resultant compound expressed by formula V with AgNO3 and then treating the resultant compound expressed by formula VI with a OH type anion exchange resin.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel platinum (n) complex and a therapeutic agent for malignant tumors containing the complex as an active ingredient.

[Prior Art] Chemotherapy for malignant tumors has made dramatic progress in recent years with the application of cis-dichloro(diammine)platinum (■) (hereinafter abbreviated as CDDP). That is, this is because CDDP has shown remarkable effects on ovarian cancer and genital muscles such as testicular muscles, which were previously difficult to treat with chemotherapeutic agents. However, CD
DP has serious side effects such as nephrotoxicity and bone marrow toxicity, which poses problems in clinical use.

On the other hand, especially DLF (dose Imitingra
In order to improve the nephrotoxicity of cis-1,1-cyclobutanedicarboxylate (diammine) platinum (■) (hereinafter referred to as CBDCA
Second generation platinum complexes such as cis-0,0'-glycolate (diammine) platinum (n) have been developed (Japanese Patent Application Laid-Open No. 154493/1983, etc.).

[Problems to be Solved by the Invention] However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as that of CDDP.

Therefore, it is desired to develop platinum complexes that have strong antitumor effects and low toxicity.

The purpose of the present invention is to provide a novel platinum (If) complex that satisfies both the requirements of having strong antitumor activity and low toxicity, and further to provide a therapeutic agent for malignant tumors that satisfies both of these conditions. It is about providing.

[Means for solving problems] The above object is achieved by the present invention as described below.

That is, the present invention provides a novel platinum (n) complex represented by the following formula (A) υ (hereinafter abbreviated as the compound of the present invention) and a novel platinum (II) complex represented by the above formula (A).
This is a malignant tumor therapeutic agent that contains a complex as an active ingredient.

The compound of the present invention can be synthesized from N-(4-carboxylphenyl)maleimide (B) and dihydroxodiaminocyclohexane platinum (II) (C) (hereinafter, diaminocyclohexane is abbreviated as dach).

(C) (B)υ (person) That is, an aqueous solution of dihydroxodach platinum (n) (C) and N-(4-carboxyphenyl)maleimide (
It can be synthesized by reacting B). The reaction was carried out at room temperature and under normal pressure with dihydroxodach platinum (n).
This can be carried out by mixing (C) and N-(4-carboxyphenyl)maleimide (B) in an aqueous solution. The compound (A>) obtained by reacting in an aqueous solution may contain water as an aco complex, but the aco complex is also included in the scope of the compounds of the present invention.

N-(4-carboxyphenyl)maleimide represented by the above formula (B) can be easily obtained by heating N-(4-carboxyphenyl)maleamide in an acetic anhydride solvent in the presence of sodium acetate.

In addition, dihydroxodach platinum (n) (C), which is the other raw material for the compound of the present invention, is a compound represented by the above formula (C), (Pt(trans-Q-dach)(
OH)2), (Pt() lance-d-dach)(OH
)2) and (pt(cis-dach)(OH)2).

Dihydroxodach platinum (n) (C) can be synthesized by the following method.

(D) (D) + 2AgN03- (E) (C) When a therapeutic agent containing an effective amount of the compound of the present invention is administered clinically, it is administered by oral or parenteral routes. The dosage forms include tablets, dragees, powders, capsules, powders, lozenges, solutions, suppositories, injections, etc., which may be formulated with pharmaceutically acceptable excipients. Manufactured. Examples of excipients include the following. Lactose, sucrose, glucose, sorbitol, mannitol, potato starch, amylopectin, various other starches, cellulose derivatives (e.g. carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, magnesium stearate, polyvinyl alcohol, calcium stearate,
Polyethylene glycol wax, gum arabic, talc, titanium dioxide, vegetable oils such as olive oil, peanut oil, and sesame oil, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterile water, glycerin, coloring agents, seasonings. , thickeners, stabilizers, isotonic agents, buffers, etc., and other pharmaceutically acceptable excipients.

The therapeutic agent of the present invention may contain the compound of the present invention in an amount of 0.001 to 85% by weight, preferably 0.005 to 60% by weight.

The dosage of the therapeutic agent of the present invention mainly depends on the symptoms, but it is 0.05 to 200 cm, preferably 0.01 to 50 cm per 18-year-old adult body weight.

[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples.

Reference Example I Synthesis of N-(4-carboxyphenyl)maleimide 2.71 g of N-(4-carboxyphenyl)maleamide
and 11.58 g of sodium acetate anhydride to 50 ml of acetic anhydride.
and stirred at 75°C for 20 minutes.

After cooling, 400011 drops of water were added under water cooling to remove the precipitate;
After the number of houses, after repeated washing with water, drying under reduced pressure at 40℃,
11 g of -(4-carboxyphenyl)maleimide 2 was obtained.

Melting point 239.2-239.7°C Example I N-(4-carboxyphenyl)maleimide 1°67g
(Pt (trans-4-d
ach)(OH)2) aqueous solution (10 ml (3°75 mmol)) was added dropwise. After stirring overnight at room temperature, insoluble matter was removed, and washing with water and ethanol were repeated. After drying under reduced pressure at 40°C, a light yellow powder of bis(N-(4-carboxyphenyl)maleimido]-(trans=(1-d
ach) 2.46 g of a dihydrate of platinum (II) complex (hereinafter referred to as the compound of the present invention (A1)) was obtained.

The infrared absorption spectrum (IR>) of this complex is shown in FIG. 1, and the melting point and elemental analysis values are shown below (pt was determined by atomic absorption spectrometry).

Melting point 273-278°C (decomposition) Elemental analysis value (%) (as C28H26N408Pt・2H2o) Example 2 CDF1 mice (male, 6 weeks old, 6-10 mice per group used)
105 L1210 mouse leukemia cells passaged in DBA/2 mice were intraperitoneally transplanted. The compound of the present invention (
A1) was administered intraperitoneally as a test drug. CBDCA and CDDP were used as comparative drugs in this experiment. Each drug has 0
．． It was used by dissolving or suspending it in 05% "Tween 80" solution. The antitumor effect of the platinum complex on L1210-implanted mice was evaluated based on the T/C value determined by the following formula and the number of surviving mice on the 300th day.

The results are shown in Table 1.

Table 1 From the results shown in Table 1, the compound (A1) of the present invention has 25 m
The T/C value was 331% in the g/kg administration group, and 3
The number of surviving mice on day 0 was also 4/6. This can be said to have shown an antitumor effect greater than that of CDDP and CBDCA.

Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. The compound of the present invention (A1) was administered intraperitoneally to SQc:ICR mice (male, 5 weeks old) as a test drug. The test drug was 0.05% “Twe
The D5o value was calculated from the mortality rate 14 days after administration.

The results are shown in Table 2.

Table 2 As is clear from the results shown in Table 2, the compound of the present invention (A
1) has lower toxicity than CDDP.

[Effects of the Invention] The compound of the present invention has strong antitumor activity and low toxicity, and is effective as a therapeutic agent for malignant tumors.

[Brief explanation of the drawing]

FIG. 1 shows an infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1.

Claims (2)

[Claims] (1) The following formula (A) ▲There are mathematical formulas, chemical formulas, tables, etc.▼…(A) A novel platinum(II) complex shown in (2) A therapeutic agent for malignant tumors containing a novel platinum (II) complex represented by the following formula (A) ▲Mathematical formulas, chemical formulas, tables, etc.▼...(A) as an active ingredient.