JPH0827174A - Anti-tumor platinum (iv) complex of cyclohexanediamine derivative - Google Patents

Abstract

PURPOSE:To provide a new platinum (IV) complex of a specific cyclohexanediamine derivative, having advanced anti-tumor activities, highly soluble in lipids and useful as an anti-tumor agent, etc., intending to be simply administered per oral. CONSTITUTION:This new anti-tumor platinum (IV) complex of cyclohexadiamine derivative is expressed by formula I {formula II is 1,2-cycloalkane(5-8C)diamine [stereo-configuration is cis (R, S-), trans-d (1S, 2S-), trans-l (1R, 2R-)], 2- aminomethylcyclohexylamine expressed by formula IV [stereo-configulation is cis-l (R, R-), cis-d (S, S-), trans-l (R, S-) or trans-d (S, R-)], 1,1- diaminomethylcyclohexane expressed by formula V, o-phenylenediamine or an alkylenediamine; formula VI is a ligand capable of forming a 5 or 6 membered ring coordinated to platinum (IV) through o,o-coordination; M is a metal; R1 is an alkyl, etc., and R2 is an alkyl subordinating to the metal M}.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor cyclohexanediamine derivative platinum (IV) complex used as an anticancer agent.

[0002]

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

[0003]

However, while conventional platinum anti-cancer agents are administered intravenously and place a heavy burden on patients, 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, an object of the present invention is to provide an antitumor cyclohexanediamine derivative platinum (IV) complex having further antitumor activity and aiming for easier oral administration.

[0004]

In order to solve the above-mentioned problems, the antitumor cyclohexanediamine derivative platinum (IV) complex of the present invention has the general formula: ## STR1 ## , 2-cycloalkane (C ₅ -C ₈ ) diamine (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-1 (R, S-) or trans-d (S, R-). ), 1, 1 shown in Chemical formula 5
It is a kind selected from diaminomethylcyclohexane, O-phenylenediamine, ethylenediamine or propylenediamine. Further, Chemical formula 6 is a ligand that forms an O, O-coordinated 5- or 6-membered ring on platinum (IV), M is a metal, and R is
₁ is an aliphatic alkyl or aromatic alkyl, and R ₂ is an alkyl group belonging to M. ) Is represented by. The ligand is one selected from oxalate represented by Chemical formula 7, 1,1-cyclobutanedicarboxylate represented by Chemical formula 8, malonate represented by Chemical formula 9, glycolate represented by Chemical formula 10, and derivatives thereof. Preferably there is. The above-mentioned derivative represents an aliphatic alkyl or an aromatic alkyl in which R is a C _{1 to} C ₁₀ aliphatic cyclic alkyl in Chemical formula 11 or Chemical formula 12. The metal is preferably any metal that forms an organometallic compound. As the arbitrary metal, Fe, Ti, Si, Cu, A
It is preferably one selected from g, Au, Bi and Zn.

[0005]

The antitumor cyclohexanediamine derivative platinum (IV) complex of the present invention has high lipophilicity and excellent antitumor effect.

[0006]

Embodiments of the present invention will be described below.

[0007]

Example 1 Pt (oxalato) [OCOC ₆ H _{4
OSi (CH 3) 2 {C} (CH 3) 3} ] ₂ (l-da
ch) Synthesis of compound 13. First, Pt (oxalato) (O
H) ₂ (l-dach) -modified 14 To 1.00 g of (2.32 mmol), 2.17 g (9.28 mmol) of P- (t-butyldimethylsilyloxy) benzoic anhydride and 20 ml of dimethylformamide were added, and at a temperature of 70 ° C. I made it react all day and night. Then, the solvent was distilled off, and Pt (ox
alato) [OCOC ₆ H ₄ OSi (CH ₃ ) ₂ {C
(CH ₃ ) ₃ }] ₂ (l-dach) 1.13 g (yield 54
%) Was obtained.

[0008]

[Chemical 13]

[0009]

[Chemical 14]

[0010]

Example 2 Pt (oxalato) (OCOC₆H_Four
OH)₂Synthesis of (l-dach). First, obtain in Example 1
Pt (oxalato) [OCOC₆H_FourOSi (C
H ₃)₂{C (CH₃)₃}]₂(L-dach) 1.00
20 mmol of water and 1 part of P-toluenesulfonic acid in g (1.11 mmol)
Add 211 mg (1.11 mmol) of hydrate for 3 hours at 80 ℃
It was made to react. Then, the solvent was distilled off and recrystallized (methanol
-Ether) to Pt (oxalato) [OCOC
₆H_FourOH)₂(1-dach) 0.60 g (yield 80%)
Obtained.

[0011]

Example 3 Pt (oxalato) [OCOC ₆ H ₄
Synthesis of _{OTi (C 5 H 5) 2} Cl ] ₂ (l-dach) of 15. First, Pt (oxalato) obtained in Example 2
[OCOC ₆ H ₄ OH) ₂ (l-dach) 1.00 g (1.
81 mmol) in 4 ml of water and 73 mg of solid sodium hydroxide (1.81 mm)
ol) was added and stirred until uniform. Then add 20 ml of methylene chloride and immediately add 900 mg of titanocene dichloride.
(3.62 mmol) was added and reacted for 20 minutes. Next, the organic layer is washed with water, and the solvent is distilled off, whereby Pt (oxalato)
_{[OCOC 6 H 4 OTi (C 5} H 5) 2 Cl ] ₂ (l-
Dach) was obtained (0.93 g, yield 47%).

[0012]

[Chemical 15]

The analytical data of the compounds synthesized in Examples 1 to 3 are shown in Tables 1 and 2.

[0014]

[Table 1]

[0015]

[Table 2]

In each table, the compound numbers refer to Examples 1 to 1.
Corresponds to 3 compounds.

Here, the compounds synthesized in Examples 1 to 3 were examined for their antitumor properties against L1210, an experimental tumor of mice. CD12 and L1210 (the number of transplanted cells per mouse was 10 ⁵ per mouse) were intraperitoneally transplanted to CDF, and then from the next day to the 1st, 5th and 9th days, each of the above compounds was used as a drug. It was intraperitoneally administered at the dose shown in. The effect judgment is
The average survival time T / C (%) was calculated (average survival time of drug administration group / average survival time of control group × 100). For L1210, mean survival time T / C of 125% or more was effective, and the results are shown in Table 1. A group consists of 6 animals. The number in parentheses in the table indicates the number of cured mice in one group.

[0015]

[Table 3]

From Table 3, it can be seen that each compound exhibits antitumor properties.

[0017]

As described above, according to the antitumor cyclohexanediamine derivative platinum (IV) complex of the present invention,
Since it has an excellent antitumor effect and high lipophilicity, it is very effective for the treatment of various organ tumors such as brain tumors.

Claims (5)

[Claims] 1. A 1,2-cycloalkane (C ₅ -C ₈ ) diamine represented by the general formula 1, wherein 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-1 (R, S-) or trans-d (S, R-). ), 1, 1 shown in Chemical formula 5
It is a kind selected from diaminomethylcyclohexane, O-phenylenediamine, ethylenediamine or propylenediamine. Further, Chemical formula 6 is a ligand that forms an O or O-coordinated 5- or 6-membered ring on platinum (IV), M is a metal, R ₁ is an aliphatic alkyl or aromatic alkyl, and R ₂ is M Is an alkyl group belonging to ) The antitumor cyclohexanediamine derivative platinum (IV) complex represented by Embedded image Embedded image Embedded image [Chemical 4] Embedded image [Chemical 6] 2. The oxalate represented by Chemical Formula 7, the 1,1-cyclobutanedicarboxylate represented by Chemical Formula 8, or the malonate represented by Chemical Formula 9, the glycolate represented by Chemical Formula 10, and a derivative thereof. The antitumor cyclohexanediamine derivative platinum (IV) complex according to claim 1, wherein the platinum (IV) complex is one selected. [Chemical 7] Embedded image [Chemical 9] [Chemical 10] 3. The compound represented by Chemical formula 11 or Chemical formula 12
Is represented by an aliphatic alkyl or aromatic alkyl containing a C ₁ -C ₁₀ aliphatic cyclic alkyl, and the antitumor cyclohexanediamine derivative platinum (IV) complex according to claim 2. [Chemical 11] [Chemical 12] 4. The metal according to claim 1, 2 or 3, wherein the metal is any metal forming an organometallic compound.
Antitumor cyclohexanediamine derivative described Platinum (IV)
Complex. 5. The arbitrary metal is Fe, Ti, Si,
The antitumor cyclohexanediamine derivative platinum (IV) complex according to claim 4, which is a kind selected from Cu, Ag, Au, Bi or Zn.