JPS6176497A - Platinum complex - Google Patents

Abstract

NEW MATERIAL:1,1-Cyclobutanecarboxylato( 2-aminomethylpyrrolidine )platinum(II). USE:A carcinostatic agent, having improved antitumor activity, low toxicity, and high water solubility. PREPARATION:For example, platinum(II) potassium chloride is reacted with 2-aminomethylpyrrolidine in water solvent at room temperature for 1 day to give dichloro(2-aminomethylpyrrolidine)platinum(II), which is then reacted with 2mol based on the compound of silver nitrate under sunproofing conditions at room temperature for 3 days to give dinitrato(2-aminomethylpyrrolidine) platinum(II), which is reacted with sodium 1,1-cyclobutanedicarboxylate at room temperature for 4 days.

Description

[Detailed description of the invention] ・-1 The novel platinum complex of the present invention is useful as an anticancer agent.

Discovery of antitumor activity of cisplatin (CDDP) by Rosenberg et al. (Nature, L., 385)
Since 1969), research on platinum complexes with antitumor activity has been actively carried out (Special Publication No. 59-55
99. JP-A-57-77894, etc.).

Although conventional platinum complexes such as cisplatin (CDDP) have a wide antitumor spectrum, they have fatal nephrotoxicity, which limits the total dose and applicable cases. has been done.

Furthermore, it is generally said that platinum complexes bind to plasma proteins and become inactive.

The present inventors have conducted various studies in order to find a platinum complex having better antitumor activity and less toxicity, and have synthesized the compound of the present invention by the following means to solve the problems.

6. The present inventors reacted platinum(II)potassium chloride with 2-aminomethylpyrrolidine to obtain dichloro(2-amythetatylpyrrolidine)platinum(II).
This was then reacted with silver nitrate to form dinitrate (
2-Aminomethylpyrrolidine)platinum(II) and then reacted with 1,1-cyclobutanedicarboxylic acid disodium salt to produce 1,1-cyclobutanedihydrupoxylat(2-aminomethylpyrrolidine)platinum(II). was synthesized to solve the above problems.

1. The compound of the present invention thus obtained has excellent antitumor activity, low toxicity, and high water solubility, making it extremely useful as a medicine.

Actual JL Example” - Platinum (II) Botium Chloride 4.15g
(0.01 mol) was dissolved in 100 ml of water, and after removing some insoluble materials by filtration, 2-aminomethylpyrrolidine was added. A solution of OOg (0.0 f mol) in 10 ml of water is added and stirred at room temperature for 1 day. The generated solid was collected by filtration, washed with water, and dried under reduced pressure at 60°C for 3 hours.
Pale yellow dichloro(2-aminomethylpyrrolidine)platinum(II) 3. OOg (82% yield) was obtained. Melting point 255-270°C (decomposition).

This 3. OOg (0,0082 mol) in 300 m of water
1, add 2.78 g (0.0IE14 mol) of silver nitrate, and stir at room temperature for 3 days in the dark. The precipitated white precipitate of silver chloride was filtered through a Millipore filter (0.22 μm
), and a 0.5% aqueous sodium chloride solution is added to the filtrate to precipitate and remove unreacted silver nitrate as silver chloride. The obtained filtrate is added with mol) at 40° C. or below, and reacted at room temperature for 4 days. The precipitated white crystalline solid was collected by filtration, washed with water, and dried under reduced pressure at 60°C for 3 hours to obtain 1.86 g of 1,1-cyclobutane dilupoxylate (2-aminomethylpyrrolidine) platinum (II) (yield 5).
2%). Melting point 235-255°C (decomposed).

Elemental analysis value Molecular formula CoH+sN 204 P t as CHN Theoretical value (%) 30.20 4.15 6.40
Actual value (%) 30.00 4.11 6.61
Colon 2Ei in for carclnoma
Vivo antitumor test A 1-2 mm triangular Co1on was subcutaneously placed in the flank of a 6-week-old CDF1/Crj male mouse.
26 carclnoma tumor pieces were transplanted, and 4 days later, mice bearing tumors of approximately the same size (group 1, 5 to 6
A predetermined amount of the drug was intraperitoneally administered to the mice (1), and 10 days later (14 days after tumor implantation), the tumor weight was measured to determine the growth inhibition rate (GIR%).

GIR (%)=-needle"-X 100 (%) where,
C and T represent the average tumor weights of the control group and drug-treated group, respectively.

The results are shown in Table 1. Note that the known compound CDDP (cisplatin) was used as a comparative drug.

Table 1, Co1on 2Ei carcjnoma
Compounds with antitumor activity against Dose Growth inhibition rate (GIR%) Comparison of binding properties with plasma proteins in vitro The drug solution was added to the plasma obtained from SD rats at a volume ratio of 19:1 (Pt amount 5 μg/ml). In addition, 37℃ under light shielding
It was then incubated. After a predetermined period of time, the reaction solution was sampled and coated with a molecular sieve membrane (Amicon Cen
trlflov PMS (manufactured by Amicon) was centrifugally filtered. Pt (non-protein bound Pt) in the filtrate was quantified using an atomic absorption spectrometer.

The results are shown in Table 2.

Table 2. Binding rate with plasma protein (%) Compound of the present invention 2 9 14
38CDDP 1B 62 8
Table 1 of Example 2 shows that the compound of the present invention has antitumor activity superior to CDDP and has a wider therapeutic range.

Furthermore, it is said that platinum complexes combine with plasma proteins and become inactive, but from Table 2 of Example 3, the compounds of the present invention
It has been found that its binding to plasma proteins is clearly weaker than that of DDP, making it useful as an anticancer agent.

Claims (1)

[Claims] formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A novel platinum(II) complex represented by