JPH01163191A - Novel platinum(ii) complex and remedy for malignant tumor - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R represents 1-17C alkyl). EXAMPLE:5-Acetyl-2,2-dimethyl-1,3-dioxan-4,6-dione-hydroxo(trans-l-1,2- diaminocyclohexane) platinum(II). USE:A remedy for malignant tumor, which is administrated at 0.01-50mg per day.adult body weight. PREPARATION:Dinitrato(1,2-diaminocyclohexane)platinum(II) expressed by formula II is reacted with a 5-acyl-2,2-dimethyl-1,3-dioxane-4,6-dione expressed by formula III in the presence of an alkali hydroxide normally at ordinary temperature under ordinary pressure.

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 cis-dichloro(diammine)platinum (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.

<Problems to be Solved by the Invention> An object of the present invention is to provide a platinum complex that has stronger antitumor activity than CDDP.

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 (hereinafter abbreviated as the compound of the present invention) represented by the following general formula (A) (in which R represents an alkyl group having 1 to 17 carbon atoms) and the above formula FA) is a malignant tumor therapeutic agent containing a novel platinum precious wood as an active ingredient.

In the above formula (^), R represents an alkyl group having 1 to 17 carbon atoms. Specific examples of R include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group,
heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group,
Examples include pentadecyl group, hexadecyl group, and heptadecyl group. R preferably represents a lower alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group.

Ligand of the compound of the present invention is the following formula means a conjugated system shown by

The compound of the present invention can be synthesized according to the reaction formula shown below.

(B) (D) (
A) (C) (D) (A) That is, dinitrato(1,2-diaminocyclohexane)platinum (compound (B)) is converted into 5-acyl-2,2-dimethyl-1, It can be synthesized by reacting with 3-dioxane-4,6-sion (compound (D)). Here, sodium hydroxide or potassium hydroxide can be used as the alkali hydroxide. In addition, the aqueous solution of compound (B) was mixed with Amberlite I
Dihydroxo (1,2
-diaminocyclohexane) platinum (compound (C)) and 5-acyl-2,2-dimethyl-1,3-dioxane-
It can be synthesized by reacting with 4,6-ion (compound (D)).

These reactions are usually carried out at room temperature and pressure by adding 1 equivalent of 5-acyl-2,2-dimethyl-1,
A true color can be obtained by mixing 3-dioxane-4,6-sion.

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

(E) (B) Compound (B) obtained by the above reaction formula contains 1,2-diaminocyclohexane (hereinafter referred to as dach
Pt (trans-1-dac
h) (ONO2)2, Pt (trans-d-dach)
(ONO2)2, Pt(cis-dach)(ONO2)
There are three isomers of 2.

Compound (D), which is another raw material for the compound of the present invention, is J
, An, Chei, Soc,, 75.2044~
2045 (1953) in a pyridine solvent using piperidine as a catalyst.
, 3-dioxane-4,6-dione (Meldrum's acid) with an acid chloride.

The compound of the present invention thus obtained can be used as an active ingredient of an antitumor agent, that is, a 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, sugar-coated tablets, gunpowder, capsules, powders,
It includes lozenges, liquids, whole tablets, injections, etc., and these are manufactured by incorporating pharmaceutically acceptable excipients. 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, buffering agents and the like and 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 from 0.05 to 200 cm, preferably from 0.01 to 50 cm per 10 adult body weights.

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

Example 1 Synthesis of a,5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione A solution of 6.00 g (0,042 mol) of dimedone and 3 drops of piperidine dissolved in 50 cal of pyridine. 3.77 g (0,048 mol) of acetyl chloride was added dropwise to the solution, and the reaction solution was stirred at room temperature for 1 day. 4
00 ml, extracted twice with 80 ml of ethyl acetate, and back-extracted twice with 40 ml of 5% NaCO3 aqueous solution. The extract was made acidic with concentrated hydrochloric acid, and then diluted with 40 ml of ethyl acetate again.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 2.50 g of 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (yield 32%).

The analysis results of the obtained compound were as follows.

Melting point 80-82℃ Elemental analysis value (%) I HNMR (CDC13) δ (ppll)
14.9 (S, IH), 2.67 (S, 3H), 1.7
2 (S, 6H) b, Synthesis of complex Pt (trans-J!-dach) (ONO2) 2 aqueous solution was mixed with anion exchange resin “Diaion 5A-10A” (
100 ml (4
, 2 mmol) to 5-acetyl-2,2-dimethyl-1,
0.78 t (4,
2 mmol) and stirred at room temperature for 3 days.

After removing a small amount of solid matter precipitated during the reaction, the P solution was concentrated under reduced pressure to 16 g and left to cool in a refrigerator overnight. The precipitated crystals were collected in P, dried, washed with ethyl acetate, and dried under reduced pressure to give 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione-hydroxo(trans-1-
1.05 g of platinum (1,2-diaminocyclohexane) (hereinafter abbreviated as the present compound (A1)) was obtained (yield: 49
%).

The IR and NMR spectra of the compound (A1) of the present invention are 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>300°C (210°C blackening) Example 2 CDFT 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 administered intraperitoneally as the test drug. CDDP was used as a comparative drug in this experiment. Each drug is 0.05%”
L12 was used by dissolving or suspending it in en80” solution.
The effectiveness of the antitumor effect of the platinum complex on 10-implanted mice was determined by the T/C value calculated by the following formula and the 30
This was determined by the number of surviving mice on day 0.

The results are shown in Table 1.

Table 1 As is clear from the results shown in Table 1, the compound of the present invention (A
1) was 293% T in the 10 kg/kg administration group.
/C value, and the number of surviving mice on day 300 was 3/6. This can be said to have a stronger antitumor effect than CDDP.

Example 3 An acute toxicity test was conducted on the compound (A1) of the present invention in mice. The compound (A1) of the present invention was administered intraperitoneally to Sβc:ICR mice (male; age 5) as a test drug. The test drug was dissolved or suspended in a 0.05% "Tween 80" solution.

D5or1 was calculated from the mortality rate on day 14 of administration t*.

The results are shown in Table 2.

Table 2 <Effects of the Invention> The compounds of the present invention have strong antitumor activity 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, and FIG. 2 shows the nuclear magnetic resonance absorption spectrum of the same compound.

Claims (2)

[Claims] (1) General formula (A) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) (In the formula, R represents an alkyl group having 1 to 17 carbon atoms. ) A novel platinum(II) complex shown in (2) A novel platinum (II) complex represented by the following general formula (A) ▲Mathematical formulas, chemical formulas, tables, etc.▼(A) (In the formula, R represents an alkyl group having 1 to 17 carbon atoms.) A malignant tumor treatment agent containing as an active ingredient.