JPS63303987A - Novel platinum (ii) complex and remedy for therioma - Google Patents

Abstract

NEW MATERIAL:m-Hydroxybenzonate-hydroxo ( trans-l-diaminocyclohexane ) platinum (II) complex expressed by formula I. USE:A remedy for therioma. PREPARATION:A m-hydroxybenzoic acid expressed by formula II is reacted with an aqueous solution of dihydroxodiaminocyclohexane-platinum (II) expressed by formula III preferably at 50-80 deg.C under normal pressure.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> 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 cisdiaminedichloroplatinum (■) (hereinafter abbreviated as CDDP). That is, this is because CDDP has shown remarkable efficacy against genital diseases such as ovarian cancer and testicular disease, which were previously difficult to treat with chemotherapeutic agents. However, CD
DP has serious side effects such as nephrotoxicity and bone marrow toxicity.
This has become a problem in clinical use.

On the other hand, especially D L F (dose limiting
In order to improve the nephrotoxicity that has become a factor of 0,0'-
Second-generation platinum complexes such as glycolate platinum (II) were 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. For this reason,
It is desired to develop platinum complexes that have strong antitumor effects and low toxicity.

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 low toxicity, and to provide a therapeutic agent for malignant tumors that roughly satisfies both of these conditions. It is about providing.

Means to solve 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 referred to as the compound of the present invention)) and a novel platinum (II) complex represented by the above formula (A>).
It is a malignant tumor therapeutic agent that contains a complex as an active ingredient.

The compound of the present invention comprises m-hydroxybenzoic acid (B) and dihydroxodiaminocyclohexane platinum (II) (C) (
Hereinafter, diaminocyclohexane is abbreviated as dach).

(C) (B) (A> That is, it can be synthesized by reacting an aqueous solution of dihydroxodach platinum (II> (C) with m-hydroxybenzoic acid (B). The reaction is usually carried out at room temperature to
The reaction can be carried out by mixing dihydroxodach platinum (II>(C) and m-hydroxybenzoic acid (B) in an aqueous solution and heating at 100°C, preferably 50 to 80°C, under normal pressure.The reaction can be carried out in an aqueous solution. Compound (A>
may contain water as an aco complex, but the aco complex is also included within the scope of the compounds of the present invention.

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

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

(D) (D)+2AciNO3→ (E) +2ACICff (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, tablets, capsules, powders, lozenges, solutions, suppositories, injections, etc., which may be formulated with pharmaceutically acceptable excipients (eXC1pient). Manufactured. Examples of excipients include the following. Lactose, sucrose, glucose, sorbitol, mannitol, potato starch, amylopectin, various other starches/v, 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 bases, ethanol, propylene glycol, physiological saline, sterile water, glycerin, colorants, seasonings, thickeners, stabilizers, isotonic agent,
buffering agents and other pharmaceutically acceptable excipients.

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

The dosage of the therapeutic agent of the present invention mainly depends on the symptoms, but is 0.1OO5 to 200 mg per adult body weight per day,
It is preferably 0.01 to 50 Irtg.

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

Example 1 21.46 g of m-hydroxybenzoic 1F was added to 200 Irdl (10.5 mmol) of an aqueous solution of (Pi<trans-fl-dach)(OH)2, and the mixture was stirred overnight at room temperature. The mixture was roughly stirred at 80° C. for 4 hours, and after cooling, the precipitated crystals were collected by filtration. In order to remove unreacted raw materials, water washing and ethyl acetate washing were repeated, and drying was carried out under reduced pressure at 40°C to obtain a grayish brown powder of m-hydroxybenzonatohydroxo(trans-fl-dach)platinum (II > gf1). 2.99g of monohydrate (A1) was obtained.

The IRSNMR of this complex is shown in FIGS. 1 and 2, and the melting point and elemental analysis values are shown below (Pt was determined by atomic absorption spectrometry).

Melting point 241-251°C (decomposition) Elemental analysis value (%) Example 2 CDF1 mice (male, 6 weeks old, 6-10 mice per group)
10,105 L1 mouse leukemia cells passaged in DBA/2 mice were intraperitoneally transplanted. Taking the transplant date as day 0,
The test drug was intraperitoneally administered three times in total on the 1st, 5th, and 9th days. 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 11210-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.

Average survival days of treated animals T/C (%) = x100 Average survival days of control animals The results are shown in Table 1.

As is clear from the results shown in Table 1, the compound of the present invention (A
1) TZ co07 in the 100 m'j/ni'j administration group.
6JA top (7) T/G 1lfl smaller, 80
In each case, 2/6 mice survived at the eye and mouth.

This can clearly be said to be a stronger antitumor effect than CDDP, (T), or CBDCΔ.

Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. SD, c: The test drug was intraperitoneally administered to ICR mice (male: 5 weeks old). The test drug was dissolved or suspended in a 0.05% Tween 80" solution.

D5oiFIi was estimated 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 compounds of the present invention have strong antitumor activity and low toxicity, making them effective as therapeutic agents for malignant tumors.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1, and FIG. 2 shows a nuclear magnetic resonance absorption spectrum of the same compound.

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.