JPS6230792A - Novel platinum complex - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X and Y are Cl or together represent formula II; m is 1 when X and Y are Cl, and 0 in the other cases). EXAMPLE:cis-Dichloro-trans-dihydroxy(2-aminomethylazetidine)platinum (IV). USE:A carcinostatic agent having antitumor activity, low toxicity and high water- solubility. PREPARATION:For example, platinum (II) potassium chloride is reacted with 2-aminomethylazetidine to give cis-dichloro(2-aminomethylazetidine)platinum (II), which is then reacted with hydrogen peroxide. The 2-aminomethylazetidine is preferably obtained by a well-known method for reducing 2- carboxyamidoazetidine with lithium aluminum hydride in tetrahydrofuran (THF).

Description

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

Discovery of the antitumor activity of cisplatin (CDDP) by Rosenberg et al. [Nature, ff1.385
(1989)], research on platinum complexes with antitumor activity has been actively conducted (Special Publication No. 59-5
599. JP-A-57-77694, etc.).

Ni0 (゛.

Although conventional platinum complexes such as cisplatin (CDDP) exhibit a wide antitumor spectrum, they exhibit fatal nephrotoxicity, which limits the total dosage and applicable cases.

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.

-q, the present inventors reacted platinum (■) potassium chloride with 2-aminomethylazetidine to form cis-dichloro(2-aminemethylazetidine) platinum (■).
and then reacting this with hydrogen peroxide to synthesize cis-dichloro-trans-dihydroxy(2-aminomethylazetidine)platinum (IV).

Furthermore, platinum(n)potassium chloride and 2-
By reacting with aminomethylazetidine, dichloro(2-
aminomethylazetidine)platinum (If), which was then reacted with silver nitrate to form dinitrato(2-aminomethylazetidine)platinum (n), and then 1,
By reacting with 1-cyclobutanedicarboxylic acid disodium salt, 1,1-cyclobutanedicarboxylate (2-aminomethylazetidine)platinum CU) was synthesized to solve the above problems.

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

Fruit "L Example" - Platinum (n) Potassium Chloride 4.15g (0
, 01 mol) in 80 ml of water, and after removing some insoluble matter by filtration, 2-aminomethylazetin:/”0
．． A solution of 86 g (0.01 mol) dissolved in 10 ml of water is added and stirred at room temperature for 4 hours. The generated solid was collected by filtration, washed with water, and dried under pressure at 60°C for 3 hours to obtain 2.64 g (yield 75%) of white cis-dichloro(2-aminomethylazetidine)platinum(II). . Melting point 215
~235°C (decomposed).

This 1.78 g (0,005 mol) is suspended in 3 ml of water, and 181% of 31% hydrogen peroxide solution is added while stirring at room temperature, followed by reaction at the same temperature for 30 minutes and then at 80° C. for 1 hour. After filtering the generated solid in a refrigerator and washing it with water, it was dried under pressure at 60°C for 3 hours to obtain a light brown 7-su-dichloro-trans-nohydro-7(2-aminomethylazetidine) platinum (■) compound. No. 1) 1.18g (yield 60%)
I got it. Melting point 200-220°C (decomposition).

Elemental analysis value CHN as molecular formula C4H12C1□N202Pt Theoretical value (%) 12.44 3.13 7.25
Actual value (%) 12.61 3.16 7.13
￥) Production method of 2-aminomethylazetidine J, He t
e rocyc 1 ic Chem, , 1l
2 obtained by the method described in lr 795 (1973)
-Carboxamide azetidine was reduced with lithium aluminum hydride in tetrahydrofuran to give 2-amine methyl azetidine.

Ltane ■ Yuplatinum (n) Botacium Chloride 4.15g (0
, 01 mol) in 100 ml of water, and after removing some insoluble matter by filtration, 2-aminomethylazetin 7*)
A solution of 86 g (0.01 mol) of C.o. in 10 ml of water is added and stirred at room temperature for 4 hours. The generated solid was collected by filtration, washed with water, and dried under pressure at 60°C for 3 hours to obtain 2.6t4g (yield 75%) of white dichloro(2-aminomethylazetidine)platinum (If). Melting point 21
5-235°C (decomposition).

This 1.0 Og (0,0028 mol) was added to 350,111 mol of water.
0.90 g (0,0053 mol) of silver nitrate was added, and the mixture was stirred at room temperature for 3 days while shielded from light. The precipitated white precipitate of silver chloride is removed using 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 concentrated under reduced pressure to 20 ml at 40° C. or below, and 0.53 g (0,0028 mol) of 1,1-cyclobutanedicarboxylic acid disodium salt is added thereto, and the mixture is reacted at room temperature for 1 day. The precipitated white crystalline solid was collected by filtration,
After washing with water, dry burning at 60°C for 3 hours under reduced pressure, 0.85 g of 1,1-cyclobutane dilupoxylate (2-aminomethylazetidine) platinum (n) (compound No. 2) (yield 7).
2%). Melting point 220-245°C (decomposition).

Elemental analysis value Molecular formula C+oH16N204 P CHN as t Theoretical value (%) 28.36 3.81 6.62
Actual value (%) 28.33 3.77 6.59
In for ``Mitsu'' L Masu Co1on 2G carcinon+a
vlvo anti-tumor test 6 week old CD F I/Cr
j Inject 1-2 ml of Co1on 2G carcinoma subcutaneously into the flank of a male mouse. ! Four days after tumor fragments were transplanted, a predetermined amount of the drug was intraperitoneally administered to mice (1 group, 5 to 6 mice) bearing tumors of approximately the same size, and 10 days later (14 days after tumor transplantation). On day 1), tumor weight was measured and growth inhibition rate (GIR%) was determined.

GIR (%) = Yuzo'-X100 (%) Here, C and T represent the average m tumor weights of the control group and drug administration 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 26carcinoma
Antitumor active compound Dose (mg/kg)
Growth inhibition rate (GIR%) The compound of the present invention has excellent antitumor activity, low toxicity, and high water solubility, making it a promising candidate as an anticancer agent.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X and Y are each Cl or together ▲ Numerical formula,
There are chemical formulas, tables, etc. ▼, m indicates 1 when X and Y are each Cl, and 0 in other cases. ) A novel platinum complex represented by