JPH0311091A - Novel platinum (ii) complex and remedy for malignant tumor - Google Patents

Abstract

NEW MATERIAL:The compound containing spiculisporato-(trans-l-1,2- diaminocyclohexane)platinum expressed by formula I. USE:A remedy for malignant tumor. PREPARATION:The objective compound can be produced by reacting dinitrato(1,2-diaminocyclohexane)platinum(II) or sulfato(1,2-diaminocyclohexane)platinum(II) of formula II [R<1> is (NO3)2 or SO4] with spiculisporic acid of formula III in the presence of an alkali metal or alkaline-earth metal hydroxide (preferably sodium hydroxide, potassium hydroxide or barium hydroxide) or reacting dihydroxo(1,2-diaminocyclohexane)platinum(II) of formula IV with the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel platinum 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 cyssujikukou (jiangmin) 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. Since then, research on platinum complexes having antitumor activity has been actively conducted (for example, Japanese Patent Application Laid-Open No. 70246/1983).

<Problems to be Solved by the Invention> However, conventional platinum complexes such as CDDP have serious side effects such as nephrotoxicity and bone marrow toxicity, which is a problem in clinical use. Therefore, the development of platinum compounds with low toxicity is desired.

An object of the present invention is to provide a novel platinum-containing compound that satisfies both the requirements of having strong antitumor activity and having low toxicity.
The aim is to provide therapeutic agents.

Means to solve problems〉 The above object is achieved by the present invention as described below.

That is, the present invention provides a malignant tumor therapeutic agent containing a novel platinum complex represented by the following formula (A) (hereinafter referred to as the compound of the present invention) and a novel platinum complex represented by the above formula (A) as active ingredients. be.

Further, the present invention provides (a) the following formula (B) (wherein (R1) is (NO3)2 or (s).

4) A platinum compound represented by ) is reacted with a compound represented by the following formula (C) in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide, or (b) a platinum compound represented by the following formula (C) This is a malignant tumor therapeutic agent containing as an active ingredient a platinum complex obtained by reacting the platinum compound represented by (0) with the compound represented by the above formula (C).

The compounds of the present invention are dinitrato(1,2-diaminocyclohexane)platinum (compound (Bl)) or sulfato(1,2-diaminocyclohexane)platinum (compound (Bl)).
B2)) in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide with a spicrispole acidic compound (C)) or by reacting dihydroquine (1,2-diaminocyclohexane) platinum <It can be synthesized by reacting compound (D) and compound (C).

Here, as the alkali metal hydroxide or alkaline earth metal hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are preferably used, and the compound (
Normally, the monovalent alkali metal hydroxide is used in an amount twice the amount of C), and the divalent alkali metal hydroxide is used in an amount of 1 times the amount used.

Here, compound (C) and an alkali metal hydroxide may be reacted in advance to obtain an alkali metal salt of spicrisporic acid, and this may be reacted with compound (B1) or (B2).

Compound (D) is usually compound (B1) or (B2)
Anion exchange resin (O
It is obtained by passing it through a column packed with H type).

(B) (C) (A) The reaction is usually carried out by adding the compound (B1
), (B2) or compound (C) against compound (D)
This can be carried out by mixing in an aqueous solution. Although the compound of the present invention thus obtained may contain water as an aco complex, the aco complex is also included within the scope of the compound of the present invention.

Dinitrato(1,2-diaminocyclohexane)platinum (compound (Bl)), which is a raw material for the compound of the present invention, can be synthesized, for example, by the following method.

(D) (E) (A) (Bl) Compound (B2) can be synthesized by using Ag2SO4 instead of AgNO3 in the above reaction formula.

Compounds (B1), (B2), CD obtained by the above reaction formula
), Pt (trans-dach) (N03), Pt (trans-d-dach) (NO3), Pt (cis- da
ch) (NO3)2, Pt (trans-1-dach) (SO4), Pt (trans-d
-dach) (304), Pt (cis-dach) (
Three isomers of SO4), Pt lance-Jj-da
ch) (OH)2, Pt (trans-d-dach)
Three isomers exist, (OH)2 and Pt(cis-dach)(OH)2.

The compound of the present invention thus obtained can be used as an antitumor agent, that is, an active ingredient of a malignant tumor therapeutic agent.

When administering a therapeutic agent containing an effective amount of the compound of the present invention in a clinical setting, it is administered by oral or parenteral routes. The dosage forms include tablets, dragees, powders, capsules, powders, lozenges, solutions, tablets, 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 (such as 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, and thickening agents. , stabilizers, silvering agents, buffering agents, etc. 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 0.005 to 200 mg, preferably 0.01 to 50 mg per adult body weight per day.

<Example> Hereinafter, the present invention will be explained in more detail by giving examples.

Example 1 [Pt (trans-1-dach)(N20)2(N0
3) To 50 ml (3.75 mmol) of a 2:l aqueous solution, 150 ml (150 ml aqueous sodium hydroxide solution of 1.261 r spicrysporic acid<3.75 mmol) was added dropwise at room temperature. After stirring at room temperature for 4 days, the precipitate was collected. After repeated washing with water and drying under reduced pressure at 40°C, a trihydrate of subiclisborate (trans-1-dach) platinum-containing compound (hereinafter abbreviated as the compound of the present invention (A1)) in the form of a light yellow powder was obtained. 2.02g was obtained.

The infrared absorption spectrum (IR) of the compound (A1) of the present invention is shown in Figure 1, and the melting point and elemental analysis values are shown below (pt is not determined by atomic absorption spectrometry) Melting point: 210-215°C
(Decomposition) Elemental analysis value (%) (C23H4ON206 Pt
・As 2H20) Example 2 CDFT mice (male, 6 appropriate ages, 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 administered intraperitoneally as a test drug, and CDDP was used as a comparative drug in this experiment. Each drug is 0.05%”
It was used by dissolving or suspending it in en 80” solution.L1
The antitumor effect of the platinum compound on 210-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.

Table 1 The results are shown in Table 1.

From the results shown in Table 1, the compound (A1) of the present invention has a
■/kg administration group showed a T/C value of 200%. It can be said that this showed a remarkable antitumor effect on mice transplanted with L1210.

Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control.

Sλ, c: IcR mice (male; the compound of the present invention (A1) was intraperitoneally administered once every 5 weeks as a test drug. The test drug was dissolved or suspended in a 0.05% IITween 80" solution. Based on the mortality rate 14 days after administration, L
The s o value was calculated.

The results are shown in Table 2.

Table 2 <Effects of the invention> The compound of the present invention has anti-! It has tumor activity and low toxicity, making it useful as a therapeutic agent for malignant tumors.

[Brief explanation of the drawing]

FIG. 1 shows the infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1. Patent Application Daito Co., Ltd. As is clear from the results shown in Table 2, the compound of the present invention (A
1) has lower toxicity than CDDP.

Claims (3)

[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 tumor comprising the novel platinum (II) complex according to claim 1 as an active ingredient. (3) (A) The following formula (B) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(B) (In the formula, (R^1) is (NO_3)_2 or (SO_
4) is shown. ) in the presence of an alkali metal hydroxide or alkaline earth metal hydroxide, a platinum (II) compound represented by the following formula (C
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(C) React the compounds shown in (C) or (B) The following formula (D) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・... (D) A malignant tumor therapeutic agent containing as an active ingredient a platinum (II) complex obtained by reacting the platinum (II) compound represented by the formula (D) with the compound represented by the above formula (C).