JPH02311488A - New platinum complex and antitumor agent containing the same platinum complex as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R represents formulae II or III; Ph represents phenyl). EXAMPLE:[1,2-Bis(diphenylphosphino)ethane](1R,2R-cyclohexanediamine)pa lladium (II) nitrate. USE:An antitumor agent. PREPARATION:A cyclohexanediamine palladium (II) nitrate [Pd(NO3)2(R,R-dach)] or 1,2-bis(diphenylphosphino)ethanepalladium (II) chloride [PdCl2(DPPE)] is dissolved or dispersed in water and 1,2-bis-(diphenylphosphino)ethane or ethylenediamine is then added and reacted for 30min to 5hr. After completing the reaction, the resultant product is cooled and precipitated.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a metal complex that has antitumor activity, can be used as an antitumor agent in cancer treatment, and is useful as a pharmaceutical.

[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 effectiveness and side effects.

In addition, metal complexes with various ligands have recently been synthesized,
Its antitumor activity is actively being investigated.

However, even metal complexes that have antitumor activity often lose their value as pharmaceuticals because of their poor solubility in water.

Therefore, it has been desired to develop a more useful antitumor agent with good solubility in water.

[Means for solving the problem] The present inventor has conducted research to solve the above problem,
As a result of extensive research, we discovered a novel metal complex that has an antitumor effect and has good water solubility in a palladium complex containing diphosphines and diamines as mixed ligands, and completed the present invention. reached.

That is, the present invention provides a novel metal complex represented by the following formula 1 (wherein R represents and Ph represents a phenyl group) and an anti-l! ! It is an anticancer drug.

The novel metal complex of the present invention (hereinafter referred to as the compound of the present invention) can be obtained by reacting diamines and diphenylphosphines in a water-acetone solution.

To explain in detail, cyclohexanediamine palladium(II) nidorate [Pd(NOa)*(R,Rd
ach)]or]! , 2-bisdiphenylphosphino)ethane i′ Palladium (■) chloride [PdCl , (DPPE
) is dissolved or suspended in water, 1,2-bis-(diphenylphosphino)ethane or ethylenediamine is added, and the mixture is reacted for 30 minutes to 5 hours. After the reaction is completed, the compound of the present invention can be obtained by cooling and settling.

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

After the reaction is completed, the compound of the present invention can be obtained by filtration, and can be appropriately recrystallized using a recrystallization solvent such as acetone.

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 also 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 by giving experimental examples.

Experimental Example 1 - Antitumor test against murine leukemia P-388 cells>
1X10' mouse leukemia P-388 cells were intraperitoneally transplanted into a 6-week-old male CD I mouse, and the compound obtained in Example 1 below was intraperitoneally administered three times every 4 days starting from the next day. Similarly, a control group was administered with only normal saline.

To evaluate the antitumor effect, the survival rate (T 2 /Cl ratio) was determined 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.

Table 1 shows the T/C value (%) for each dose.

Experimental Example 2 Mouse metastatic lymphoid cells P 388 leukem
2×JO' ia were transplanted, and 4 days later, the compound obtained in the example was administered at 16 degrees each, and the cells were left in contact for 2 hours and 24 hours. IC5o was examined by counting the number of cells on the 6th. The results are shown in Table 2.

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.

In addition, when an acute toxicity test of the compound of the present invention was conducted using ICR mice, it was found that when administered intraperitoneally, [,D5G
was 9 on +00 jI97.

Therefore, the compounds of the present invention exhibit excellent antitumor effects and are useful as antitumor agents.

Furthermore, the compound of the present invention has a solubility in water of 100Q.
/-, and for example, cisplatin is much higher than 1m9/-. This is very advantageous for pharmaceuticals used as antitumor agents.

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 necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to exert the desired effect as an oral agent, it is necessary to administer 1 to 600 *ti of the compound of the present invention in several doses per day for an adult, although this will vary depending on the age, weight, and severity of the disease. It seems appropriate to take this drug.

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 excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

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

[Disintegrant] Starch, hydroxypropyl starch, carboxydimethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low substituted hydroxypropylcellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant cortalc, algae, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] 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,
Each of these heel dosage forms may contain a flavoring agent and a coloring agent.

In order to exert the desired effect as a parenteral agent, the compound of the present invention is usually administered intravenously in an amount of 5 to 200 m9 per day for adults, although it varies depending on the age, body weight, and severity of the disease of the patient. , intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and diluents generally include 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. Can be used. 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.
However, the present invention is not limited thereby.

Example 1 1, +6. M cyclohexanediamine palladium (n
)-tray h CPd(NOs)-(R,R-dach
)] 1,2-bis(diphenylhosephino)ethane (DP
PE) 462M was added and stirred at room temperature. After stirring for 1 hour, the mixture was evaporated to dryness under reduced pressure. Pour the residue into 30% water. After filtration, the filtrate was concentrated to 5II11 and the resulting precipitate was collected by filtration. White crystals were obtained by recrystallizing this precipitate using water. Due to the physical and chemical properties shown below, this white crystal is represented by the structure [Pd(R,R-dach)(DPP
E)](NOJt, i.e., white, 2-bis(diphenylphosphino)ethane](IR,2R-cyclohexanoamine)palladium(II) nidolate
o) ethane] (IR, 2R-cyclohexa
palladium([1)ni
It was decided that

elemental analysis Calculated values (%); C: 50.55, H: 5.53.

N: 7.15 Actual value (%): C: 50.42. H: 5.17°N:
7.15 Infrared absorption spectrum ν 22Hcyyt-': 32
00.3050,2930,2850゜1580.14
35,1390,980 UV absorption spectrum λ2A2'nm: 304 (ε=7400).

260 (ε=21200) 31p nuclear magnetic resonance spectrum (6ppm in DtO
):63.48 Example 2 0.35. MI, 2-bis(diphenylphosphino) x
Tanhara Shi'ymu (It) RiO! J F 20 O19
[PdCIz(DPPE)] in 100 d1. : Suspended and added to a solution of an equivalent amount of ethylenediamine dissolved in 5I11 of water. After stirring at room temperature for 30 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to 10-. White crystals were obtained by freeze-drying the concentrate and recrystallizing the resulting residue using acetone. Due to the physical and chemical properties shown below, this white crystal has the structure [Pd(en)(DPPE)](NO
z)! - i.e., [1,2-bis(diphenylphosphino)equunco(ethylenediamine)palladium ([1
) Nidorate ([1,2-bis(diphenylp)
hosphio)ethane] (IR, 2R-eth
ylenediaaine) palladium (Il
)niLraLe).

Elemental analysis calculated value (%); C: 47.57. H: 4.85°N:
7.93 Actual value (%): C: 47.47. H:4.54.

N: 7.95 Infrared absorption spectrum ν2'::cm-':320
0,3100,2950.15B0゜1430.138
0.990 Ultraviolet absorption spectrum λ wma2”n1ll'30
8 (ε=5960).

258 (ε=17600) ″IP nuclear magnetic resonance spectrum (δ ppIIIin D
tO): 63.9.1 Example 3 ■Corn starch 529 ■Crystalline cellulose 409 ■Carboxymethyl cellulose calcium 59 ■Light anhydrous silicic acid 0.59 ■Magnesium stearate 0.596 1. Takamu
2 total 1009 According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain a portion of 200719 tablets.

This tablet-tablet has an example! Contains 41g of the compound obtained in 1.Adults should take 3 to 50!1 doses per day in several doses.

Example 4 ■ Crystalline cellulose 92.59 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 59 Hypolyte obtained in Example 2 29 Total 1009 Parts of ■, ■, and ■ were uniformly mixed according to the above recipe, After compression molding, the mixture was pulverized, the remaining amounts of ■ and ■ were added and mixed, and compression molded using a key press to obtain a portion of tablets 200319.

Two portions of these tablets contain the compound 4 obtained in Example 2, and are taken by adults in doses of 3 to 50 Fi divided into several doses per day.

Example 5 ~ ■ Crystalline cellulose 42.59 ■ ■ 0% hydroxypropyl cellulose ethanol solution 509 ■ Carboxymethylcellulose calcium 59 ■ Magnesium stearate 0.59 ■ Compound obtained in Example I 29 Total l 009 According to the above recipe ■, ■ and ■ are mixed uniformly, and the mixture is wetted using a conventional method, granulated using an extrusion granulator, dried and crushed, then ■ and ■ are mixed, and a portion of 200 ! 19 tablets were obtained.

This tablet-tablet has an example! It contains Compound 419 obtained in 2009, and adults should take 3 to 50 tablets a day in several doses.

Example 6 ■ Corn starch 939 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 59 ■ Light anhydrous silicic acid 0.5 g ■ Compound obtained in Example 2 19 Total 1009 Mix ■ ~ ■ uniformly according to the above recipe 11 After compression molding using a compression molding machine, the mixture was crushed using a crusher and sieved to obtain granules.

This granule 19 contains Compound 1 (ly) obtained in Example 2, and is taken by adults in 1 to 209 doses divided into several doses per day.

Example 7 ■ Crystalline cellulose 699 ■ 10% hydroxypropyl cellulose ethanol solution 309 3 Compounds treated in Example 11 19 total 1
00g According to the above recipe, ① to ② were uniformly mixed and then suspended. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains the compound 10R9 obtained in Example 1, and is taken by adults in 1 to 209 doses per day in several doses.

Example 8 ■Woon starch 97.59 ■Light silicic acid anhydride 0.593 Characteristics obtained in Example 2
2g total 1009 Mix ■~■ uniformly according to the above recipe, 20014
9 was filled into a No. 2 capsule.

This capsule contains 4-xg of the compound obtained in Example 1, and adults should take 3 to 50 capsules a day in several doses.

Example! O ■ Distilled water for injection Appropriate amount ■ Glucose 200 jI9 ■ Compound obtained in Example 1 10019 total 1
5d After dissolving (1) and (2) in distilled water for injection, they were poured into an ampoule (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.▼ (In the formula, R represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and Ph is a phenyl group. A novel metal complex represented by (2) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and Ph is a phenyl group. An antitumor agent containing a novel metal complex as an active ingredient.