JPH01128991A - Novel platinum (ii) complex and remedy for malignant tumor - Google Patents

Abstract

NEW MATERIAL:The compound of formula I. USE:A remedy for malignant tumors. PREPARATION:Coumarinic acid of formula III is allowed to react with an aqueous solution of dihydroxodiaminocyclohexane Pt(II) to give the compound of formula I. The compound of formula II is obtained by allowing K2ptcl4 to react with a compound of formula IV to give a compound of formula V, then allowing the product to react with silver nitrate into the compound of formula VI, then passing the product through an OH-type anion-exchange resin.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention includes 1. The present invention relates to a novel platinum (II) complex and a therapeutic agent for malignant tumors containing the same as an active ingredient.

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

On the other hand, especially DLF (dose limiting f
Various studies have been conducted to improve the nephrotoxicity of cis-diammine-1,1-cyclobutane dihydroboxylate platinum (■) (hereinafter referred to as CBD).
Second generation platinum complexes such as platinum (abbreviated as CA) and cis-diammine-0,0'-glycolate platinum (n) have been developed (JP-A-56-154493, 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. For this reason,
The development of platinum complexes with strong antitumor effects and low toxicity is desired.

An object of the present invention is to provide a novel platinum(n) complex that satisfies both the requirements of having strong antitumor activity and having low toxicity, and furthermore, to provide a therapeutic agent for malignant tumors that satisfies both of the above conditions. Our goal is to provide the following.

[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) (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 coumaric acid (B) and dihydro, xodiaminocyclohexane platinum (n) (C) (hereinafter, diaminocyclohexane will be abbreviated as dach).

(C) (B) (A) That is, it can be synthesized by reacting an aqueous solution of dihydroxodach platinum (II) (C) with coumaric acid (B). The reaction is usually carried out at room temperature and pressure.
This can be carried out by mixing dihydroxodach platinum (n) (C) and coumaric acid (B) in an aqueous solution. Although the compound (A) obtained by reacting in an aqueous solution may contain water as an aco complex, the aco complex is also included in the scope of the compounds of the present invention.

Dihydroxodach platinum (
n) (C) is a compound represented by the above formula (C),
(Pt(trans-!:l-dach)(OH)2)
There are three isomers: (Pt(trans-d-dach)(OH)2) and (Pt(cis-dach)(OH)2).

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

(D) (D) + 2AgNO3-11 (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 route. Its dosage forms include tablets, sugar-coated tablets, gunpowders, capsules, powders, lozenges, liquids, skewers, injections, etc., which are manufactured by incorporating pharmaceutically acceptable excipients (exclρent). be done. 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, saline, sterile water, glycerin, coloring agents, seasonings, and concentrates. agents, stabilizers, isotonic agents, buffering agents, 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 is 0.005 to 200 cm, preferably 0.01 to 50 cm per 18 adult body weight.

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

Example 1 (Pt ()-lance-fl-dach> (OH
)2) 2.12 g of coumaric acid was added to 40 ml (7.5 mmol) of an aqueous solution, and the mixture was stirred overnight at room temperature. 50 more
The mixture was stirred at ℃ for 1 hour, and after cooling, the precipitate was collected.

In order to remove unreacted raw materials, washing with water and ethanol were repeated, followed by drying under reduced pressure at 40°C to obtain a pale yellow powder of bis(2-pyrone-5-carboxylad)-(trans-f).
2.43 g of a monohydrate of platinum (II) complex (hereinafter referred to as the compound of the present invention (A1)) was obtained.

The 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 280-285℃ (decomposition) Elemental analysis value (%
) Example 2 CDF1 mice (male, 6 weeks old, 6 to 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 intraperitoneally administered as a test drug three times in total on the 1st, 5th, and 9th days, with the transplant day being set as day 0. CBDCA and CDDP were used as comparative drugs in this experiment. Each drug was used after being dissolved or suspended in a 0.05% "Tween 80" solution. The antitumor effect of the platinum complex on LL210-implanted mice was evaluated based on the T/C value determined by the following formula and the number of mice surviving on day 30.

Mean survival of control animals The results are shown in Table 1.

As is clear from the results shown in Margin Table 1 below, the compound of the present invention (A
1) showed a T/C value of 200% or more in the 100 μ/kg and 200 μ/kg administration groups. This is C
It can be said that the antitumor effect is equivalent to or greater than that of DDP.

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 (A1) of the present invention was administered intraperitoneally to SΩC; ICR mice (male, 5 weeks @) as a test drug. The test drug was 0.05%”Twee
The LD5o value was calculated from the mortality rate on day 14 after administration.

The results are shown in Table 2.

Table 2 As is clear from the results shown in Table 2, the present invention metal product (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.