JPH08113583A - Antineoplastic platinum(iv) complex - Google Patents

Abstract

PURPOSE: To obtain a new platinum(IV) complex intended for oral administration and useful as e.g. a malignant tumor therepeutic agent composed of an 1,2- cycloalkanediamine, 2-aminomethylcyclohexylamine, etc., and platinum. CONSTITUTION: This new antineoplastic platinum(IV) complex is expressed by formula I [formula II represents a 5-7C 1,2-cycloalkanediamine of formula III ((n) is 1-4) (the stereostructure is cis (R, S-), trans-d(1S, 2S-) or trans-L(1R, 2R-)), 2-aminomethylcyclohexylamine of formula IV (the stereostructure is cis-L (R, R-), cis-d(S, S-). trans-L(R, S-) or trans-d(S, R-)), 1,1-diaminomethylcyclohexane of formula V, O-phenylenediamine, etc.; formula VI represents a ligand forming a 5-6 membered ring with O,O-configuration to the platinum(IV); X is an aliphatic alkyl such as a 1-10C alicyclic alkyl, or an aromatic alkyl].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor platinum (IV) complex used as an anticancer agent and a therapeutic agent for malignant tumor containing the platinum (IV) complex as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, cisdichloroammineplatinum (II) complex (general name cisplatin) and carboplatin have been used as platinum anticancer drug mainly in ovarian cancer, bladder cancer, lung cancer and head and neck cancer.

[0003]

However, while conventional platinum anti-cancer agents are administered intravenously, they impose a heavy burden on patients, while they are also active against tumors of organs other than the ovary and testes (eg brain tumors). It is desired to develop a platinum anticancer drug. Therefore, the present invention has further antitumor activity,
It is another object of the present invention to provide an antitumor platinum (IV) complex intended for simple oral administration and a therapeutic agent for malignant tumor containing the platinum (IV) complex as an active ingredient.

[0004]

In order to solve the above-mentioned problems, the antitumor platinum (IV) complex of the present invention has the general formula:
(In the formula, 1,2-cycloalkane (C ₅ -C ₇ ) diamine represented by Chemical formula 2 is a cis (R, S
-), Trans-d (1S, 2S-) or trans-l
(1R, 2R-). ), 2-aminomethylcyclohexylamine represented by Chemical formula 4 (steric structure is cis-l
(R, R-), cis-d (S, S-), trans-1
(R, S) or trans-d (S, R-). ),
It is any one kind of diamine selected from 1,1-diaminomethylcyclohexane, O-phenylenediamine, ethylenediamine or propylenediamine represented by Chemical formula 5. Further, Chemical Formula 6 is a ligand that forms an O, O-coordinated 5- or 6-membered ring on platinum (IV), and X is an aliphatic alkyl or aromatic compound containing a C ₁ -C ₁₀ aliphatic cyclic alkyl. Group alkyl. ) Is represented by. As the diamine, 1,2-cyclohexanediamine represented by Chemical formula 7 (hereinafter referred to as dach) is particularly preferable. The ligand is selected from oxalate represented by Chemical formula 8, 1,1-cyclobutanedicarboxylate represented by Chemical formula 9, malonate represented by Chemical formula 10, glycolate represented by Chemical formula 11, and derivatives of each. It is preferably one type. The above-mentioned derivative is represented by Chemical Formula 12 or Chemical Formula 13, wherein R is C ₁ to
It is represented by aliphatic alkyl or aromatic alkyl including C ₁₀ aliphatic cyclic alkyl.

[0005]

The antitumor platinum (IV) complex of the present invention has high lipophilicity, and when used as a main component of a drug, it can be orally administered and is excellent in antitumor action.

[0006]

EXAMPLES Examples of the present invention will be described in detail below.

[0007]

Example 1 Pt (oxalato) (OSO ₂ p-C
Synthesis of ₆ H ₄ CH ₃ ) ₂ (l-dach)

[0008]

[Chemical 14]

First, Pt (oxalato) (OH) ₂
700 mg (1.62 mmol) of (l-dach) -modified 15 was suspended in 7 ml of water, and p-toluenesulfonic acid monohydrate 3.08
What melt | dissolved g (16.2 mmol) in 7 ml of water was added, and after stirring at room temperature for 8 hours, it was made to react at the temperature of 70 degreeC for 1.5 hours.

[0010]

[Chemical 15]

Then, water was distilled off, and acetone was added for recrystallization, and Pt (oxalato) (OSO ₂ p-C ₆
H ₄ CH ₃₎ to give the _{2 (l-dach) · 3H} 2 O 700mg (58% yield).

The infrared absorption analysis result of the above compound is 3063 cm.
^-1 (NH) and 1754 cm ^-1 (C = O). The analytical data of the above compounds are shown in Table 1.

[0013]

[Table 1]

Further, the above compounds were tested for their antitumor activity against an experimental mouse tumor, L1210. After CD12, L1210 (the number of transplanted cells per mouse was 10 ⁵ cells) was intraperitoneally transplanted to CDF and mice, the above compounds were used as drugs in Table 2 from the next day on the 1st, 5th and 9th days. The indicated dose was administered intraperitoneally. Efficacy judgment is mean survival time T / C (%)
(Mean survival days of drug administration group / Average survival days of control group x
100) For L1210, the mean survival time T / C of 125% or more was effective, and the results are shown in Table 2. A group consists of 6 animals. The number in parentheses in the table indicates the number of cured mice in one group.

[0015]

[Table 2]

From Table 2, it can be seen that the compounds according to the present invention show antitumor properties.

[0017]

Industrial Applicability As described above, the antitumor platinum (IV) complex of the present invention has excellent antitumor activity and high lipophilicity, and therefore can be used for treating various tumors such as brain tumors. It is possible to provide a very effective therapeutic agent for malignant tumor.

Claims (5)

[Claims] 1. A 1,2-cycloalkane (C ₅ -C ₇ ) diamine represented by the general formula 1 in which the chemical formula 2 is the chemical formula 3 (the steric structure is cis (R, S-), trans-d (1S, 2S
-) Or trans-1 (1R, 2R-). ), 2-aminomethylcyclohexylamine represented by Chemical formula 4 (steric structure is cis-1 (R, R-), cis-d (S, S
-), Trans-l (R, S) or trans-d (S,
R-). ), And 1, 1-diaminomethylcyclohexane, O-phenylenediamine, ethylenediamine, or propylenediamine represented by Chemical formula 5 above. In addition, chemical formula 6 is platinum (IV) with O, O
A ligand forming a coordinated 5- or 6-membered ring, X
Are aliphatic alkyls or aromatic alkyls, including C ₁ -C ₁₀ aliphatic cyclic alkyls. ) The antitumor platinum (IV) complex represented by the formula Embedded image Embedded image Embedded image [Chemical 4] Embedded image [Chemical 6] 2. The diamine represented by Chemical Formula 1, 2,
The antitumor platinum (IV) complex according to claim 1, which is cyclohexanediamine. [Chemical 7] 3. The oxalate represented by Chemical Formula 8, the 1,1-cyclobutanedicarboxylate represented by Chemical Formula 9, or the malonate represented by Chemical Formula 10, the glycolate represented by Chemical Formula 11, and derivatives thereof, wherein the ligand is The antitumor platinum (IV) complex according to claim 1 or 2, which is one selected from the group consisting of: Embedded image [Chemical 9] [Chemical 10] [Chemical 11] 4. The compound represented by Chemical Formula 12 or Chemical Formula 13 is R
4. The antitumor platinum (IV) according to claim 3, wherein is an aliphatic alkyl containing a C ₁ -C ₁₀ aliphatic cyclic alkyl or an aromatic alkyl. [Chemical 12] [Chemical 13] 5. A therapeutic agent for malignant tumor, which comprises an antitumor platinum (IV) complex represented by Chemical formula 1 as an active ingredient.