JPH06279475A - New platinum complex - Google Patents

Abstract

PURPOSE:To obtain a new compound, having low toxicity, excellent in antitumor effects and useful as an anticancer agent, etc. CONSTITUTION:This compound is expressed by the formula (A is arsenic or antimony; R is 1-6C alkyl), e.g. cis-(trimethylarsine)oxalatoplatinum(II). Furthermore, the compound expressed by the formula is obtained by thermally reacting, e.g. cis-bis(trimethylarsine)dihydroxoplatinum (II) with oxalic acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel platinum complex.

[0002]

BACKGROUND OF THE INVENTION Some platinum complexes, as represented by cisplatin, have a remarkable antitumor effect, and cisplatin is applied to many cases. However, cisplatin is extremely toxic such as renal toxicity, which is a major obstacle to treatment.

Therefore, it has been desired to develop another novel platinum complex having a remarkable antitumor effect.

[0004]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have synthesized various platinum complexes and conducted extensive studies on their antitumor activity. As a result, they have remarkable antitumor activity. They found a platinum complex and completed the present invention.

That is, the present invention provides the following formula I [In the formula, A represents an arsenic atom or an antimony atom, and R represents a lower (C: 1 to 6) alkyl group. ] The platinum complex represented by this (henceforth the platinum complex of this invention).

Conventionally, platinum complexes other than amine ligands have been treated as organic metals in a non-aqueous solvent, and the invention has pioneered aqueous chemistry of water-soluble arsine and stibine complexes.

The platinum complex of the present invention can be obtained, for example, by the following method.

For example, according to the scheme of FIG. 1, a dihydroxoplatinum complex (I in the figure) obtained by converting a nitrato group into a hydroxyl group using a dinitratoplatinum complex (formula II in the figure) as a raw material.
Obtained by reacting II) with oxalic acid.

Specific examples of the dinitratoplatinum complex include a dinitratoplatinum (II) complex having trimethylarsine and trimethylstibin as ligands, and the same coordination as A and R of the target platinum complex of the present invention. It is preferable to use a dinitratoplatinum (II) complex having a child as a raw material.

For the reaction in step 1, a method capable of converting the nitrato group of the dinitratoplatinum complex into a hydroxyl group may be appropriately selected. For example, bulletin of the chemical society of Japan (Bullet).
in of the Chemical Societ
y of Japan), 64 , 1835 (199).
1), an anion exchange method described in Bulletin of the Chemical Society of Japan, 65, 3386 (1992), that is, contacting with an OH ⁻ type anion exchange resin to remove the nitrato group of the complex. The method of converting into a hydroxyl group can be mentioned.

The reaction of step 2 can be easily carried out by reacting the dihydroxoplatinum complex obtained in step 1 with nitric acid and 1 mol of oxalic acid in an aqueous solution.

Next, the antitumor effect of the platinum complex of the present invention will be shown.

That is, 1 × 10 ⁵ mouse leukemia cells were intraperitoneally transplanted into 6-week-old male CDF ₁ mice, and from the next day, every 4 days, three times a day, the present invention obtained in Examples described later. Was administered intraperitoneally. The survival rate was calculated from the average survival days of the control group to which saline alone was similarly administered. As a result, a life prolonging action was observed, and it was confirmed that it has an excellent antitumor effect.

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 and 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 the adult platinum complex has a weight of 10 to 600 m.
It is considered appropriate to take g in several divided doses per day.

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 addition to the above-mentioned excipients, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc., may be appropriately used in this type of preparation. 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,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

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

[Fluidity promoter] 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, in adults, the weight of the platinum complex of the present invention is 5 to 20 per day.
Intravenous injection up to 0 mg, intravenous drip injection, subcutaneous injection, and intramuscular injection seem to be appropriate.

This parenteral preparation is manufactured by 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 cis-bis (trimethylarsine) dichloroplatinum (I
I) [cis-bis (trimethylarsin
e) dichloroplatinum (II)] 5.
0 g and 2.2 g of silver nitrate were dissolved in 100 ml of distilled water,
The mixture was heated under reflux for about 2 hours. The starting material, cis-bis (trimethylarsine) dichloroplatinum (II), was synthesized by Zeitschricht Anorganitzsche Chemie (Zeits
chrisft f An Anorganische
Chemie) 229 , 237 (1936), cis-bis (triethylarsine) dichloroplatinum (II).
[Cis-bis (triethylsilane) d
The methyl derivative was obtained using trimethylarsine instead of triethylarsine in exactly the same manner as in the synthesis of ichloplatinum (II)]. The reaction solution was filtered and concentrated to 40 to 50 ml by a rotary evaporator to give cis-bis (trimethylarsine) dinitratoplatinum (I) having a nitrato group as a carrier ligand.
I) [cis-bis (trimethylarsin
e) A concentrated solution containing dinitraloplatinum (II)] was obtained. This concentrate is used as Diaion SA
It was passed through a column packed with 160 ml of 10 AOH, and then was made to flow out with distilled water to give cis-bis (trimethylarsine) dihydroxoplatinum (II) [cis-
bis (trimethylarsine) dihyd
roxoplatinum (II)] was obtained. Oxalic acid (1.2 g) was added to the obtained effluent (200 ml), and the mixture was reacted by heating and purified to give cis- (trimethylarsine) oxalatoplatinum (I) having the following physicochemical properties.
I) [cis-bis (trimethylarsin
e) oxalatoplatinum (II)].
2 g (yield: 80%) was obtained.

Structural formula: Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 1694, 1668, 1358 Proton nuclear magnetic resonance spectrum (δ ppm in D
₂ O): 1.62 ¹³ C-nuclear magnetic resonance spectrum (δ ppm in D ₂
O): 11.6, 170.0 Elemental analysis: Calculated value (%): C, 18.37: H, 3.47 Measured value (%): C, 18.32: H, 3.35 Single crystal X Line structure analysis Monoclinic molecular formula: C ₈ H ₂₂ O ₆ PtAs ₂ Molecular weight: Fw = 559.19 Space group: Pa Lattice constant: a = 8.977 (8) Angstrom, b = 10.040 ( 4) Angstrom, c = 9.431 (4) Angstrom, β = 107.84 (5) ° (including two molecules per unit cell) Calculated density: Dx = 2.295 g / cm ⁻³ Measured density : D _m = 2.29 g / cm ⁻³ R value: 0.044 (wR = 0.049) V = 809 (2) (angstrom) ³ 2498 independent reflections were used for structural analysis. A molecular diagram based on the single crystal X-ray structural analysis data of this compound is shown in FIG.

Example 2 As a starting material, cis-bis (trimethylstibine) dichloroplatinum (II) [cis-bis (trimeth)
ylstibine) dichloroplatinu
m (II)] 5.0 g was used, and the same operation as in Example 1 was carried out except that the reaction conditions were ice-cooling.
Cis- (trimethylstibine) oxalatoplatinum (II) [cis-bis (tri) having the following physicochemical properties
methylstibine) oxalatoplat
2.9 g (yield: 56.8%) of inum (II)] was obtained. Starting material cis-bis (trimethylstibine)
Dichloroplatinum (II) was obtained by methyl derivatizing cis-bis (triethylstibine) dichloroplatinum (II) described by Zeitschricht Anorganitsche Chemie.

Structural formula: Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 1698, 1678, 1662, 1362 Proton nuclear magnetic resonance spectrum (δ ppm in D
₂ O): 1.27 ¹³ C-nuclear magnetic resonance spectrum (δ ppm in D ₂
O): -3.4, 169.2 Elemental analysis: Calculated value (%): C, 15.58: H, 2.94 Measured value (%): C, 15.66: H, 2.84 Single crystal X-ray structural analysis Triclinic molecular formula: C ₈ H ₃₀ O ₁₀ PtSb ₂ Molecular weight: Fw = 724.91 Space group: P1 Lattice constant: a = 10.5555 (3) Angstrom, b = 12.920 (3) Angstrom, c = 9.149 (2) Angstrom, α = 109.80 (2) °, β = 115.47 (2) °, γ = 89.69 (2) (two per unit lattice) Density by calculation: Dx = 2.303 g / cm ^-3 Actual density: D _m = 2.29 g / cm ^-3 R value: 0.045 (wR = 0.048) V = 1045.3 ( 5) (angstroms) ³ structure the 4829 independent reflection It was used for the analysis. A molecular diagram based on the single crystal X-ray structural analysis data of this compound is shown in FIG.

Example 3 Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Platinum complex of the present invention obtained in Example 1 10 g Total 100 g The resulting mixture was mixed with and compressed with a tableting machine to obtain 200 mg tablets. 20 mg of the platinum complex of the present invention obtained in Example 1 is contained in each tablet, and 5 to 15 tablets for adults are to be taken in several divided doses per day.

Example 4 Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Platinum complex of the present invention obtained in Example 10 10 g Total 100 g According to the above-mentioned prescription, a part of and was uniformly mixed. After compression molding, the mixture was crushed, and the remaining amount of the mixture was added and mixed, and the mixture was compression molded with a tableting machine to obtain 200 mg tablets. 20 mg of the platinum complex of the present invention obtained in Example 2 was contained in each tablet, and the amount of the adult complex was 5 to 15 per day.
Take the tablet in several doses.

Example 5 Crystalline cellulose 49.5 g 10% Hydroxypropyl cellulose ethanol solution 35 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Platinum complex of the present invention obtained in Example 1 10 g Total 100 g According to the above formulation, and Are evenly mixed, kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and are mixed, and compression-molded by a tableting machine to give 200 mg tablets. Obtained. 20 mg of the platinum complex of the present invention obtained in Example 1 is contained in each tablet, and 5 to 15 tablets for adults are to be taken in several divided doses per day.

Example 6 Corn starch 34.5 g Magnesium stearate 50 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Platinum complex of the present invention obtained in Example 10 10 g Total 100 g After compression molding with a compression molding machine, it was crushed with a crusher and sieved to obtain granules. 1 g of this granule contains 100 mg of the platinum complex of the present invention obtained in Example 2, and 1 to 3 adults a day
Take g in several divided doses.

Example 7 Crystalline Cellulose 55 g 10% Hydroxypropyl Cellulose Ethanol Solution 35 g Platinum Complex of the Invention Obtained in Example 1 10 g Total 100 g After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains 100 mg of the platinum complex of the present invention obtained in Example 1, and 1 day for an adult
Take ~ 3g in divided doses.

Example 7 Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Platinum complex of the present invention obtained in Example 10 10 g Total 100 g
Was filled in a No. 2 capsule. 20 mg of the platinum complex of the present invention obtained in Example 1 is contained in one capsule of this capsule, and 5 to 15 capsules for an adult are taken in several divided doses per day.

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

[Brief description of drawings]

FIG. 1 is a synthetic route of an active ingredient of the platinum complex of the present invention.

FIG. 2 is an Ortep diagram of cis- (trimethylarsine) oxalatoplatinum (II).

FIG. 3 is an ortep diagram of cis- (trimethylstibine) oxalatoplatinum (II).

Claims (1)

[Claims] 1. The following formula I [In the formula, A represents an arsenic atom or an antimony atom, and R represents a lower (C: 1 to 6) alkyl group. ] The platinum complex represented by.