JPH0236144A - Novel platinum (ii) complex and remedy for malignant tumor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel platinum complex and a therapeutic agent for treating malignant 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 cis-dichloro(diammine)platinum (hereinafter abbreviated as CDDP). In other words, CDDP showed remarkable effects on genital muscles such as ovarian cancer and testicular cancer, which were previously difficult to treat with chemotherapy drugs.However, CDDP has serious side effects such as nephrotoxicity and bone marrow toxicity. This is a problem in clinical use.

On the other hand, especially D L F (dose limiting
In order to improve nephrotoxicity, which has become a factor of
Second generation platinum complexes of cis-0,0゛-glycolate (diammine) platinum (abbreviated as A) and cis-0,0゛-glycolate (diammine) platinum have been developed (Japanese Patent Application Laid-Open No. 154493/1983, etc.).

<Problem to be solved by the invention> However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as that of CDDP.
There is a desire to develop a platinum B form that has strong antitumor effects and low toxicity.

An object of the present invention is to provide a novel platinum 0 complex that satisfies both conditions 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 in.

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 complex represented by the following formula (A) (hereinafter referred to as the compound of the present invention) and a malignant tumor therapeutic agent containing a novel platinum complex represented by the above formula (A) as active ingredients. be. The present invention also provides a method for converting a platinum compound represented by the following formula (B) (in the formula, (R1) represents (NO3) or (SO4)) into an alkali metal hydroxide or an alkaline earth metal compound. In the presence of hydroxide, the following formula (C) HOC-CH=CHCH=CHCH3...(C)
A malignant tumor containing as an active ingredient a platinum complex obtained by reacting a compound represented by (b) the following formula CD) or a platinum compound represented by the following formula (CD) and a compound represented by the above formula (C). It is a therapeutic agent.

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, a sorbic acid compound (C
)) or by reacting with dihydroxo(1,2diaminocyclohexane)platinum (compound (D
)) and compound (C). I can do two things.

Here, as the alkali metal hydroxide or alkaline earth metal hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are preferably used, and the compound f
Usually 0.7 to 1.3 times the mole of c), preferably 1
Use twice the mole.

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

The compound of the present invention can also be prepared by passing an aqueous solution of compound (B1) or (B2) through a column packed with an anion exchange fat (OH type) such as 11 Amberlite I RA-400'' and ``Diaion 5A-1OA''. It can be synthesized by reacting the obtained dihydroxo(1,2-diaminocyclohexane)platinum (compound (D)) with compound (C).

(B) (C) (A> The reaction is usually carried out at room temperature to 100°C under normal pressure.
), (B2) or compound 11 for compound (0)! I
This can be carried out by mixing (C) in an aqueous solution and heating. The compound of the present invention obtained by reacting in an aqueous solution may contain water as an aco complex, but 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) (B1) Compound (B2) can be synthesized by using Ag25O in place of AgNO3 in the above reaction formula.

Compounds (B1), (B2), (D
), Pt (trans-d-dach) (NO3), Pt (trans-d-dach) (NO3), Pt (cis −
dach)(NO3)2, Pt(trans-1-dach)(SO4), Pt(trans-1-dach)(SO4), Pt(trans-1-dach)(SO4)
d-dach) (SO+), Pt (cis-dac
h) Three isomers of (SO4), Pt(trans-Ji
-dach) (OH)2, Pt (trans-d-da
ch)(OH)2 and Pt(cis-dach)(OH
) There are three isomers of 2.

The compound of the present invention thus obtained can be used as an active ingredient of an antitumor agent, that is, an agent for treating malignant tumors.

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. Its formulation includes tablets, dragees, powders, capsules, powders, lozenges, solutions, suppositories, injections, etc., which are formulated with pharmaceutically acceptable excipients (8XCipient). 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, and thickening agents. , 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 is 0.005 to 200 square meters, preferably 0.01 to 50 square meters 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) 2) Sodium hydroxide aqueous solution 50 [01
(15.2 mmol) was slowly added dropwise at room temperature. After stirring at room temperature overnight and further stirring at 50°C for 1 hour, a lot of the precipitate was collected. After repeated washing with water and drying under reduced pressure at 40°C, the monohydrate of bis-(2-propenyl acrylate)-(trans-1-dach) platinum complex in the form of a light yellow powder was prepared. 3.27 g of A1) was obtained.

The infrared absorption spectrum (IR) of the compound of the present invention (AI) is shown in Figure 1, and the melting point and elemental analysis values are shown below (Pt
was determined by atomic absorption spectrometry).

Melting point 215-221'C (decomposition) elemental analysis value (%
) (C+aH2aN20+Pt/Example 2 CDFI mice (male, 6'fA age, 6 to 10 mice per group) were intraperitoneally transplanted with 105 murine leukemia cells L1210 passaged in DBA/2 mice.The day of transplantation was set to 0. The compound of the present invention (
A1) was administered intraperitoneally as a test drug. BDCA and CDDP were used as comparative drugs. Each drug was dissolved or suspended in a 0.05% Tween 80" solution. LL210 The antitumor effect of the platinum complex on transplanted 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 265%, and 1/6 of the mice survived on day 30. It can be said that this clearly showed a stronger antitumor effect than CDDP and (BDCA).

Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. S1c: IcR mouse (
The compound (A1) of the present invention was administered intraperitoneally to a male (5 retractions) as a test drug.

The test drug was dissolved or suspended in a 0.05% "Tween 80" solution. L from the mortality rate 14 days after administration
Ds. The value was calculated.

The results are shown in Table 2.

Compound (A1) has lower toxicity than CDDP.

<Effects of the Invention> The compounds of the present invention have strong antitumor activity, are weakly malignant, and are effective as therapeutic agents 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.

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).