JPH059191A - Novel platinum complex and antitumor agent containing the complex as an active ingredient - Google Patents

Abstract

(57) [Summary] [Objective] The present invention has lower toxicity than conventional platinum complexes,
The purpose is to provide a drug having a higher antitumor effect. [Structure] The present invention is a novel platinum complex [bis (glycolate) diaminocyclohexaneplatinum (II)] having the structure shown in FIG. 1 and an antitumor agent comprising the complex as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a platinum complex having antitumor activity and useful as a drug such as an antitumor agent.

[0002]

2. Description of the Related Art Some platinum complexes, as represented by cisplatin, have a remarkable antitumor effect, and cisplatin is applied to many cases.

[0003]

However, cisplatin is extremely toxic such as renal toxicity, which is a major obstacle to the treatment.

Therefore, it has been desired to develop a drug having a lower anti-tumor effect than that of the conventional platinum complex.

In order to solve the above problems, the present inventors have
As a result of synthesizing various platinum complexes and conducting intensive studies on their antitumor activity and their side effects, a platinum complex having lower toxicity and higher antitumor activity than conventional platinum complexes was found, and the present invention was completed. I arrived.

That is, the present invention provides the following formula I A platinum complex represented by the formula I (hereinafter referred to as the platinum complex of the present invention) and an antitumor agent containing the complex as an active ingredient.

The platinum complex of the present invention uses, for example, a dinitratoplatinum complex having 1,2-cyclohexanediamine as a carrier ligand, which is brought into contact with an OH ^- type anion exchange resin to remove the nitrato group of the complex. It can be obtained by converting into a hydroxyl group and reacting with glycolic acid.

A specific example of the dinitratoplatinum complex is dinitrato (diaminocyclohexane) platinum (II). Where dinitrato (diaminocyclohexane) platinum (I
I) is dinitrato- (1R, 2R)-(diaminocyclohexane)
There is a trans form represented by platinum (II) and dinitrato- (1S, 2S)-(diaminocyclohexane) platinum (II) and a cis form represented by dinitrato-cis- (diaminocyclohexane) platinum (II). In the present invention, all isomers synthesized corresponding to the raw materials, and further, a mixture in which each isomer is mixed at an arbitrary ratio is included.

As a specific example of the OH ^- type anion exchange resin, Diaion SA10AOH (manufactured by Mitsubishi Kasei Co., Ltd.) and the like can be used.

As the method of contacting, any method such as a batch method or a column method may be used as long as the resin and the platinum complex are in contact with each other, and the column method is preferable in view of efficiency.

To act glycolic acid, glycolic acid may be added to the reaction solution and mixed. After mixing, the solvent is distilled off by using a rotary evaporator or the like in warm water of about 70 ° C. Crystals of the platinum complex of the invention are deposited.

For further purification, recrystallization may be carried out using a suitable solvent such as water.

The platinum complex of the present invention can also be used as a pharmaceutically acceptable salt or hydrate.

The structure of the platinum complex of the present invention was confirmed by elemental analysis, infrared absorption spectrum and single crystal X-ray structural analysis.

Next, the antitumor effect of the platinum complex of the present invention will be described with reference to experimental examples.

Experimental Example 1 Mouse fibroblast 3T3 and its Kirsten-sarcoma virus transformant
ransformant) cells DT, mouse leukemia cells L1210, human cervical cancer cells HeLa, human bladder cancer cells T24 and human breast cancer cells MCF7 are each suspended in Eagle medium or RPMI1640 medium containing 10% fetal bovine serum, and coaster (Costar) 3596
Plate 3 × 10 ³ cells / well at 100 μl per well, and after overnight culture, the platinum complex or cisplatin of the present invention.
10 μl of physiological saline solution of various concentrations of (CDDP) was added. In addition, only saline was used as a control.

This is placed in a carbon dioxide incubator 37
After culturing at 48 ° C for 48 hours, the cell growth was confirmed by
hiazol-2-yl) -2,5-diphenyltetrazolium bromide] method
[J. Immunol. Method 65 , 55, 1983)]. The absorbance at each concentration after culturing for 48 hours is A, the absorbance of the control after culturing for 48 hours is B, the absorbance before addition of the platinum complex of the present invention or CDDP is C, and the proliferation reaction rate D at each concentration is as follows. The concentration of the platinum complex or CDDP of the present invention and the concentration of the platinum complex or CDDP of the present invention (IC ₅₀ value, unit: μg / ml), which is 50% of the control, was determined from the curve of the concentration of the platinum complex or CDDP of the present invention and the proliferation reaction rate.

[0018]

The results are shown in Table 1.

As is clear from Table 1, it was found that the platinum complex of the present invention has a cancer cell growth inhibitory activity comparable to or stronger than that of CDDP.

Experimental Example 2 1 × 10 ⁵ L1210 cells were intraperitoneally transplanted into a 6-week-old BDF ₁ female mouse, and the physiological saline solution of the platinum complex of the present invention was intraperitoneally administered for 3 days from the day after transplantation. Was administered. The dose is 0.3, 1.
The dose was 0, 3.0, 6.0, 10.0 and 15.0 mg / kg / day, and 6 animals were used per group. In addition, physiological saline was administered to 12 animals in the control group.

Daily general symptoms and life and death were observed up to 25 days after L1210 cell transplantation, and the average survival days, survival rate, etc. were determined.

The effect of the antitumor effect is determined by the following formula from the average survival time after L1210 transplantation of the platinum complex administration group of the present invention and the control administration group, as expressed by the following equation: Seek and done by this.

[0024]

The number of survivors after 25 days, the average number of surviving days, ILS (%), etc. at each dose are shown in Table 2, and the 30% life-prolonging dose (IL
S ₃₀ ), maximum life-sustaining dose (ILSmax), therapeutic index, etc. are shown in Table 3.

[0026]

[0027] However, in Table 3, the complete cure number indicates the number of mice used.

From the above results, the platinum complex of the present invention was confirmed to have excellent antitumor activity. In addition, side effects such as nephrotoxicity did not occur in this experiment.

That is, the platinum complex of the present invention exhibits an excellent antitumor effect and is useful as an antitumor agent.

Next, the dose and formulation of the platinum complex of the present invention will be described.

The platinum complex of the present invention can be administered to animals or humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but usually 10 to 600 mg of the platinum complex of the present invention is administered to an adult several times daily. It seems appropriate to take them separately.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used in a conventional manner.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Flowability Accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The platinum complex of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

In order to exert a desired effect as a parenteral agent, it depends on the age, body weight and degree of disease of the patient.
Usually 5 to 200 mg / day as the weight of the platinum complex of the present invention in adults.
Intravenous injection, intravenous drip infusion, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 1R, 2 having cyclohexanediamine as a carrier ligand
8.6 g of R-diaminocyclohexanedinitratoplatinum (II) was heated and dissolved in 100 ml of distilled water to dissolve Diaion SA10AOH in 16 ml.
It was passed through a column packed with 0 mg, and further discharged with distilled water. Glycolic acid (4.5 g) was added to the effluent to dissolve it, and the mixture was allowed to stand for 5 minutes and then concentrated by a rotary evaporator to obtain 8.2 g of crystalline powder. The crystalline powder was filtered on a glass frit to give crude crystals. Further, recrystallization was performed using water. This is represented by the following formula II from the following physicochemical properties (1R, 2R) -bis (glycolate) diaminocyclohexane platinum (II) dihydrate [(1R, 2R) -bis (glycolate diam
inocyclohexaneplatinum (II) dihydrate].

[0046] Formula II

Solubility 54.6 / H ₂ O ₁ cm ³ Elemental analysis: C ₁₀ H ₂₄ N ₂ O ₈ Pt Calculated value (%): C, 24.24: H, 4.88: N, 5.66 Measured value (%): C, 24.17: H , 4.63: N, 5.65 Single crystal X-ray structural analysis Triclinic system, molecular weight Fw = 495.4 Lattice constant a = 9.536 (2) angstrom, b = 12.161 (3) angstrom, c = 7.671 (3) angstrom, α = 106.47 (2) °, β = 110.93 (2) °, γ = 68.56 (2) ° Space group P1 Z value 2 Calculated density Dx = 2.135g / cm ³ Measurement reflection number 5546 (total number), 3219 (use I> 3.00) σ) R value 0.062 (Rw = 0.084) The molecular diagram based on the single crystal X-ray structural analysis data of this compound is shown in FIG.

Example 2 According to the above prescription, the ingredients (1) to (4) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each). 20 mg of the compound obtained in Example 1 is contained in one tablet, and 5 to 15 tablets for adults are to be taken in divided doses.

Example 3 According to the above prescription, a part of and was uniformly mixed, compression-molded, then crushed, and the remaining amount of was added and mixed, and compression-molded by a tableting machine to obtain a tablet of 200 mg. . 20 mg of the compound obtained in Example 1 was added to each tablet.
It contains 5 to 15 tablets for adults in several divided doses a day.

Example 4 According to the above recipe, and mix evenly,
The mixture was kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and were mixed and compression-molded by a tableting machine to obtain a tablet of 200 mg. In this one tablet,
20 mg of the compound obtained in Example 1 is contained and
Take ~ 15 tablets in several doses.

Example 5 According to the above prescription, were uniformly mixed, compression-molded by a compression molding machine, crushed by a crusher, and sieved to obtain a granule. 1 g of this granule contains the compound 100 obtained in Example 1.
Contain 1 mg, and take 1 to 3 g for adults in several divided doses.

Example 6 According to the above recipe, was mixed uniformly and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains the compound 1 obtained in Example 1.
It contains 00mg, and 1 to 3g for adults should be taken in several divided doses.

Example 7 Mix evenly according to the above recipe and add 200 mg to 2
No. capsules were filled. One capsule of this capsule contains 20 mg of the compound obtained in Example 1, and adult 1
Take 5 to 15 capsules several times daily.

Example 8 According to the above formulation, was dissolved in and, and a solution of and was added and emulsified to obtain an injection.

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[Procedure amendment]

[Submission date] April 22, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Brief description of the drawing

[Correction method] Added

[Correction content]

[Brief description of drawings]

FIG. 1 is a molecular diagram based on single crystal X-ray structural analysis data of a platinum complex of the present invention.

Claims (2)

[Claims] 1. The following formula I A platinum complex represented by the formula I. 2. The following formula I An antitumor agent comprising a platinum complex represented by the formula I as an active ingredient.