JPH02258789A - New platinum complex and antitumor agent containing the same platinum complex as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (Ph represents phenyl). USE:An antitumor agent. PREPARATION:N-Phenylacetamide is added to cis-dichlorodiammineplatinum (II) and the resultant mixture is adjusted to a weak acidic pH using an alkaline aqueous solution (preferably sodium hydroxide at a concentration of 0.5M) and reacted for 1-5hr preferably at 60-80 deg.C. After finishing the reaction, the resultant product is cooled and precipitated.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention is directed to anti-III! This article relates to platinum complexes that have tumor activity and are useful as pharmaceuticals such as antitumor agents.

[Prior Art and Problems] Currently, various drugs are used clinically as antitumor agents. However, these drugs are by no means satisfactory due to problems such as efficacy and side effects. Therefore, the development of more useful antitumor agents has been desired.

[Means for solving the problem] The present inventor has conducted research to solve the above problem,
As a result of extensive research, a novel platinum complex with high antitumor effects was discovered, and the present invention was completed.

That is, the present invention provides a platinum complex represented by the following formula f (where Ph represents a phenyl group) and anti-II! It is an anticancer drug.

The novel platinum complex of the present invention (hereinafter referred to as the compound of the present invention) can be obtained, for example, as follows.

That is, N- to cis-dichlorodiammine platinum (U)
Add phenylacetamide and adjust pH with alkaline aqueous solution.
The mixture was adjusted to be slightly acidic and allowed to react for 1 to 5 hours. After the reaction is completed, the target substance can be obtained by cooling and precipitation.

Specific examples of the alkaline aqueous solution include sodium hydroxide, potassium hydroxide, etc., but sodium hydroxide is preferred, and the a degree is preferably about 0.5M.

The reaction temperature may be room temperature, but taking into account yield, reaction time, etc., it is appropriate to heat the reaction to 60 to 80°C.

Although the compounds of the present invention are thought to exhibit their effects in the form of ions, they usually exist in the form of salts. Therefore, it goes without saying that the compounds of the present invention include pharmacologically acceptable salts such as nitrates and hydrochlorides.

Next, the fact that the compound of the present invention has an antitumor effect will be explained with reference to experimental examples.

Experimental Example 1 Antitumor test against murine leukemia P-388 cells>
Three 1XIO mouse leukemia P-388 cells were intraperitoneally transplanted into a 6-week-old male CDF mouse, and the compound obtained in Example 1 below was intraperitoneally administered three times every four days starting from the next day. Similarly, a group to which only physiological saline was administered was used as a control group.

To evaluate the antitumor effect, the survival rate (T/C value) was calculated from the average survival days of the compound-administered group and the control group obtained in Example I below, as expressed by the following formula.

T/C values (%) at the trough dosage are shown in Table 1.

Also, ICs of the compounds of the present invention. was 0.68u9/J.

From the above results, the compound of the present invention was found to have excellent antitumor activity. Furthermore, no side effects such as nephrotoxicity were observed in this experiment.

That is, the compound of the present invention exhibits excellent antitumor activity,
It is useful as an antitumor agent.

Acute toxicity tests of the compounds of the present invention were conducted using TCR mice, and when administered intraperitoneally, the LDso was 200.
It was 'i in 1g/.

Next, the dosage and formulation of the compound of the present invention will be explained.

The compounds of the present invention can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as appropriate, and examples include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and drops. It will be done.

In order to exert the desired effect as an IID agent, although it varies depending on the age, body size, and severity of the disease of the patient, it is normal for an adult to take 1 to 60,019 lbs. of the compound of the present invention in divided doses several times a day. It seems appropriate to take it.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the prescribed excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, etc. may be used in this type of preparation. reactor. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethylcellulose, Calcium C ximedylcellulose, carboxymethylcellulose, low substituted hydroxypropylcellulose.

[Surfactant] Sodium lauryl sulfate, soybean gintin, 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 promoters: light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the invention can also be administered as suspensions, emulsions, syrups, elixirs,
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, the compound of the present invention should be administered intravenously in an amount of 5 to 200 mg per day for adults, although this will vary depending on the age, weight, and severity of the disease. , intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited in any way by this.

Example 1 0.3aM cis-dihydroxydiammineplatinum(II)
(cis PL(NHs)e(OHz)y)0 in aqueous solution
, 3xH of N-phenylacetamide was added as an aqueous solution at 80 °C, and p
I-I was set to 4.3, and the reaction was carried out for 3 hours at gO.

When the solution turned blue-green, it was left to cool at room temperature, and the green precipitate formed was filtered. This precipitate has the following physical and chemical properties: [PL=(NHs)s(CsHsNO)4](Oil)
Tetra-μmN-phenylacetamidatotetrakis(cis-diammine)platinum (PlatinumN-phenylacetamt) represented by the structure z(NHs)s
de blue).

Elemental analysis calculation value (%): C: 22.97. H:3.47N:L
2.12 Actual value (%): C:I 9.56. H:3.12N:I
O, 78 Infrared absorption spectrum ν2; a'□'=2380.9
, 1607.1.1392.8 Ultraviolet absorption spectrum λ
,,. xNR: Proton nuclear magnetic resonance spectrum (δ pp+* in CDC1,) 2.84 (s), 5.99 (broad) This compound was also diamagnetic.

Example 2 ■Corn starch 529 ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 5g ■Light anhydrous silicic acid 0.551■Magnesium stearate 0.59■Example 17" Compound obtained
2 g total 1001 According to the above recipe, ■ to ■ were mixed uniformly and compression molded using a key press to obtain a portion of tablets 20019.

These tablets contain 4 kg of the compound obtained in Example 2, and are taken by adults in 3 to 50 tablets a day in several doses.

Example 3 ■Crystalline cellulose 92.5g ■Magnesium stearate 059 ■Carboquine methylcellulose calcium 5? ■ Compound obtained in Example 1 22 total 1009 According to the above recipe, ■, ■, and part of ■ are uniformly mixed, compressed and molded, crushed, and the remaining amounts of ■ and ■ are added and mixed, and the keys are pressed. A portion of the mixture was compression molded using a machine to obtain 200 M9 tablets.

This tablet contains the compound 4. obtained in Example 1. -9, and adults should take 3 to 50 tablets a day in several doses.

Example 4 ■ Crystalline cellulose 42.59 ■ 10% hydroxypropyl cellulose ethanol solution 509 ■ Carboxymethylcellulose calcium 59 ■ Magnesium stearate 0.59 ■ Compound obtained in Example 1 29 Total 1009 ■, ■ and ■ according to the above recipe After homogeneously mixing, neutering by a conventional method, granulating with an extrusion granulator, drying and crushing, mix ■ and ■, compression mold with a tablet machine, and make a portion of 200 K9. tablets were obtained.

These tablets contain the compound 4R9 obtained in Example 1, and are taken by adults in 3 to 50 tablets a day in several doses.

Example 5 ■Corn starch 939 ■Magnenium stearate 059 ■Calcium carboxymethyl cellulose 59 ■Light anhydrous silicic acid 059 ■Compound obtained in Example 1 1 g Total 1009 Mix ■~■ uniformly according to the above recipe and compression mold. After compression molding in a machine, it was crushed in a crusher and sieved to obtain granules.

This granule 12 contains the compound 10xy obtained in Example 1, and is administered to adults 101 to 209 in several doses.

Example 6 ■Crystalline cellulose 699 ■10% hydroxypropyl cellulose ethanol solution 30g ■Compound obtained in Example 1 19 Total 100g According to Kitaki's recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, it was dried and sieved to obtain Necklace 1.

1 g of this drug contains 10 m2 of the compound obtained in Example I, and is taken by adults in 1 to 209 doses per day in several doses.

Example 7 ■Corn starch 97.59■Light silicic anhydride 0.59■Compound obtained in Example 1
2g Total 100g Mix ■～■ evenly according to the above recipe, 200R9
was filled into a No. 2 capsule.

One capsule contains 4.5% of the compound obtained in Example 1. Contains my, and adults should take 3 to 50 capsules a day in several doses.

Example 9 ■Appropriate amount of distilled water for injection■Grapes! 200 Compound obtained in R9■9■ 100 xei total amount
5) After dissolving ① and ② in distilled water for injection, they were poured into an ampoule of 5- and autoclaved at 121°C for 15 minutes to obtain an injection.

Claims (2)

[Claims] (1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (However, Ph represents a phenyl group.) A novel platinum complex represented by (2) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (However, Ph represents a phenyl group.) An antitumor agent containing a novel platinum complex as an active ingredient.