JPH0450312B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel 1,2-bis-3,5-dioxopiperazinylethane derivative having antitumor activity. [Prior Art] In 1970, Clayton et al. reported antitumor activity. Subsequently, research was carried out in search of derivatives of this type with higher activity and lower toxicity, and in 1980, a dioxopiperazine compound represented by the following formula was developed at the Shanghai Drug Research Institute. Bis[N-morpholinomethyl-1,2-bis(3,5-dioxopiperazinyl)]ethane (hereinafter referred to as bimoran). Vimoran exhibits a broad antitumor spectrum, and is said to have low toxicity and a high therapeutic index. These conventionally known bisdioxopiperazine derivatives are non-specific proteinase inhibitors, have antimitotic inhibitory effects, and are thought to inhibit cancer cell metastasis by blocking blood vessel formation around cancer. Although it has been reported, its toxicity and antitumor activity are still unsatisfactory. [Means for solving the problem] Therefore, the present inventors synthesized various derivatives based on the chemical structure of vimoran and compared their antitumor activity and toxicity. We have discovered that a substance with the introduced structure has superior antitumor activity and toxicity compared to Vimoran,
The present invention has now been completed. The compound according to the present invention has the following general formula: (In the formula, R ₁ and R ₂ each represent a hydrogen atom or a lower alkyl group. However, at least one of R ₁ and R ₂ is a lower alkyl group.) The compound according to the present invention has an antimitotic inhibitory effect and can be used as an agent for preventing cancer metastasis or an anticancer agent by inhibiting blood vessel formation around a tumor where cell proliferation is active. The compound according to the present invention can be produced by the following method. general formula (wherein R ₁ and R ₂ have the above definitions)
The alkylmorpholino derivative represented by the above, formalin, and 1,2-bis(3,5-dioxopiperal)-ethane are heated and stirred in a mixed solvent using dimethylformamide, ethanol, and the like. The reaction formula in this case is shown below. [Examples, Test Examples] Example 1 1,2-bis-[N-(2-methylmorpholino)-methyl-3,5-dioxopiperazinyl]-
Ethane 1,2-bis- in 44.6 ml of dimethylformamide
(3,5-dioxopiperazinyl)ethane 3.77g
and 7.4 ml of formalin were suspended, and 6.77 g of 2-methylmorpholine was added little by little while stirring. After heating and stirring in an oil bath (bath temperature 85°C) for 2 hours, the reaction mixture turned into a light brown transparent solution. Excess reaction reagent and dimethylformamide were distilled off under reduced pressure, left to cool overnight, and the resulting white crystals were washed with 100 ml of ethanol and 200 ml of acetone and dried under reduced pressure to obtain the title compound as white crystals (3.87 g). . Melting point 138.0℃ Elemental analysis (C ₂₂ H ₃₆ N ₆ O ₆ ) Calculated value C; 54.98 H; 7.55 N; 17.49 Actual value C; 54.50 H; 7.22 N; 17.91 IR (νcm ^-1 ) 2960, 2850, 1735, 1690 ,1300,
1160 Example 2 1,2-bis-[N-(2,6-dimethylmorpholino)-methyl-3,5-dioxopiperazinyl]
-Ethane 100ml dimethylformamide and 30ml ethanol
5.08 g of 1,2-bis-(3,5-dioxopiperazinyl)-ethane and 7.4 ml of formalin were suspended in a mixed solution of 2,6-dimethylmorpholine.
9.12 g was added little by little with stirring. After the addition was completed, the mixture was heated and stirred for 2 hours in an oil bath (bath temperature: 80°C). Unreacted crystals were removed by filtration under reduced pressure, and the liquid was distilled under reduced pressure to remove excess reaction reagents ethanol and dimethylformamide. Excluded. After standing overnight, the resulting crystals were thoroughly washed with 200 ml of ethanol and then with 300 ml of acetone and dried under reduced pressure to obtain the title compound as white crystals (7.39 g). Melting point 168.0℃ Elemental analysis (C ₂₄ H ₄₀ N ₆ O ₆ ) Calculated value C; 56.67 H; 7.97 N; 16.53 Actual value C; 56.90 H; 7.84 N; 16.24 IR (νcm ^-1 ) 2975, 2870, 1735, 1690 ,1300,
1160 Example 3 1,2-bis-[N-(2-ethylmorpholino)
-Methyl-3,5-dioxopiperazinyl]-ethane Add 2.54 g of 1,2-bis-(3,5-dioxopiperazinyl)-ethane and 5 ml of formalin to a mixture of 50 ml of dimethylformamide and 15 ml of ethanol. was suspended, and 3.46 g of 2-ethylmorpholine was added little by little while stirring. Immediately after the addition was completed, the mixture was heated and stirred in an oil bath (bath temperature: 70°C), and after 2 hours, unreacted crystals were removed under reduced pressure. The resulting pale brown solution was subjected to reduced pressure to remove excess solvent and the like and left overnight to form crystals. Ethanol these crystals.
After thorough washing with 100 ml and 200 ml of acetone and drying under reduced pressure, the title compound was obtained as white crystals (1.27 g). Melting point 166.5℃ Elemental analysis (C ₂₄ H ₄₀ N ₆ O ₆ ) Calculated value C; 56.67 H; 7.93 N; 16.53 Actual value C; 56.47 H; 7.63 N; 16.79 IR (νcm ^-1 ) 2975, 2825, 1730, 1690 ,1300,
1125 Example 4 1,2-bis-[N-(2,6-diethylmorpholino)-methyl-3,5-dioxopiperazinyl]
-Ethane 165ml dimethylformamide and 20ml ethanol
4.19 g of 1,2-bis(3,5-dioxopiperazinyl)-ethane and 10 ml of formalin were suspended in the mixture, and 7.16 g of 2,6-diethylmorpholine was added little by little to this while stirring. added. After the addition was completed, the mixture was heated and stirred in an oil bath (bath temperature: 80°C) for 2 hours. The resulting pale brown and transparent reaction mixture was filtered, and the liquid was distilled under reduced pressure to remove excess reaction reagents and
Ethanol and dimethylformamide were distilled off. Crystals formed when the distillation residue was left overnight. After collecting the crystals, they were thoroughly washed with a small amount of ethanol and acetone and dried under reduced pressure to obtain 0.96 g of the title compound as white crystals. moreover,
When the liquid was left to stand overnight, white crystals were formed, which were collected and washed with a small amount of acetone to obtain 4.87 g of crystals. Melting point 139.0-140.5℃ Elemental analysis (C ₂₈ H ₄₈ N ₆ O ₆ ) Calculated value C; 59.55 H; 8.57 N; 14.88 Actual value C; 59.83 H; 8.57 N; 14.90 IR (νcm ^-1 ) 2960, 2825, 1720 , 1660, 1300,
1160, 1120 Test Example: Antitumor effect against S-180 solid cancer ICR male mice weighing approximately 20-25 g (10
Sarcoma 180 tumor cells (1×10 ⁶ cells/mouse) were subcutaneously implanted into the mice. 24 hours after transplantation, 20 mg/Kg of each sample listed in Table 1 was suspended in 0.5% CMC saline and orally administered. For each test case, the same amount of each sample was then administered daily for 10 days. Sarcoma 180 after transplantation 21
Kill mice on day 1 and measure tumor weight, 0.5%
The ratio to the tumor weight of the control group administered only with CMC saline was calculated and defined as the tumor inhibition rate (%). (Table 1)

[Table] Acute toxicity Each sample listed in Table 2 was orally administered to ICR mice (body weight 20-25 g), and Litchfield and
LD50 was determined by Wilcoxon's method.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₂ each represent a hydrogen atom or a lower alkyl group. However, R ₁ and R ₂
At least one of them is a lower alkyl group) A 1,2-bis-3,5-dioxopiperazinylethane derivative represented by: 2 R ₁ and R ₂ are each selected from the group consisting of a hydrogen atom, a methyl group, and an ethyl group (provided that
1,2-bis-3,5-dioxopiperazinylethane derivative according to claim 1 (except when R ₁ and R ₂ are both hydrogen).