JPS6366319B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, R ¹ is an alkyl, aryl or acyl group optionally substituted with a hydroxyl group, carboxyl group or bis(hydroxyalkyl)amino group; R ² is a hydrogen atom, and X is an oxygen atom or a sulfur atom. show. ] The present invention relates to 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivatives and salts thereof, their production methods, and anticancer agents containing them. The purpose is to provide a compound that has excellent anticancer activity and low toxicity, and is useful as a medicine or an intermediate thereof. The present invention will be explained in more detail below. Examples of the alkyl group in R ¹ of the general formula [] include methyl, ethyl, propyl, butyl, pentyl,
groups such as hexyl, heptyl or octyl;
Aryl groups include, for example, phenyl or naphthyl; acyl groups include, for example, acetyl, propionyl, butyryl, pivaloyl, stearoyl, benzoyl, furoyl, thenoyl,
Groups such as pyridylcarbonyl or cyclohexylcarbonyl may be mentioned. And R ¹ mentioned above
may be substituted with one or more groups such as a hydroxyl group; a carboxyl group; or a bis(hydroxyalkyl)amino group such as bis(hydroxymethyl)amino and bis(hydroxyethyl)amino. Further, as the salt of the compound represented by the general formula [], any salt acceptable as a pharmaceutical may be used, including acid and base addition salts thereof. Preferred acid addition salts are salts with inorganic or organic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid or p-toluelsulfonic acid. Further, as base addition salts, for example, salts with inorganic bases such as potassium sodium, calcium, and ammonium, and organic bases such as pyridine, collidine, triethylamine, triethanolamine, and procaine are preferable. Furthermore, hydrates of the compound represented by the general formula [] and its salt are also included in the present invention. Next, the antitumor effects and acute toxicity of representative compounds in the present invention will be explained. a Using a microplate with a minimum inhibitory concentration (MIC value) of 8 x 12 for HeLaS3 cells and Ehrlich cells, add 0.1 ml of culture solution containing drug (EaglesMEM + 20% fetal bovine serum) and 0.1 ml of cell suspension culture solution per chamber. (2×10 ⁴ cells/
ml). The drug concentration was 2-fold diluted (12 serial dilutions) with the highest concentration being 100 μg/ml, and the lowest concentration was 0.05 μg/ml. All drug samples were over-sterilized. After culturing for 4 days, discard the culture solution and wash twice with Hank's salt solution to remove 95%
Fix cells with ethanol (5 minutes) and Giemsa
The cells were stained with a solution (for 15 minutes) and then visually determined. The results are shown in Table-1. In the structural formula in the table, Me is a methyl group, Et
represents an ethyl group.

【table】

[Table] b Effect on murine leukemia L1210 L1210 ascites cancer cells 1×10 ⁵ cells/head were intravenously transplanted into 7-week-old mice (BDF ₁ strain, male, 5 mice per group), and 24 hours later, the cells were administered. The reagent was orally administered once a day for 7 days, and the efficacy was determined from the average survival days. The test drug was used after being dissolved or suspended in physiological saline or 0.3% carboxycellulose physiological saline. T/C was determined using the following formula. T/C=average survival days of test drug administration group/average survival days of untreated group×100 (%) The results are shown in Table 2.

【table】

[Table] c Acute toxicity The test drug was orally administered once to 7-week-old mice (ICR strain, male, 5 mice per group) and observed for 7 days. The test drugs were used after being dissolved or suspended in physiological saline or 0.3% carboxymethyl cellulose physiological saline. The results are shown in Table-3.

[In the formula, R ⁴ represents an alkyl or aryl group which may be substituted with a hydroxyl group, a carboxyl group, or a bis(hydroxyalkyl)amino group, and X has the meaning described above. ]

By reacting the compound represented by the general formula [In the formula, R ² , R ⁴ and X have the meanings described above. ] A method for producing a 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and a salt thereof. (3) General formula [In the formula, R ¹ , R ² and X have the meanings described above. ] A compound represented by or its reactive derivative and the general formula [In the formula, Y represents a reactive group. ] The compound represented by is reacted to form 1-benzyl-4-[4-
(2-pyrimidinylamino)benzyl]-2,3
- A method for producing a dioxopiperazine derivative and a salt thereof. (4) General formula [In the formula, R ¹ , R ² and X have the meanings described above. ] A compound represented by or its reactive derivative and the general formula [In the formula, Y represents a reactive group. ] By reacting the compound represented by the general formula []
A method for producing a 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and a salt thereof. In each of ^the above-mentioned production methods, ^{R 1} , ^{R 2 and} Alkyl or aryl groups as described; cycloalkyl groups such as cyclopentyl, cyclohexyl; aralkyl groups such as benzyl, phenethyl; alkenyl groups such as vinyl, allyl; Examples include alkadienyl groups. and R ³ or R ⁴ as mentioned above
is a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom; hydroxyl group; carboxyl group; alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl; aralkyloxycarbonyl group such as benzyloxycarbonyl; phenoxycarbonyl Aryloxycarbonyl groups such as; alkyl groups such as methyl, ethyl, propyl, isopropyl or butyl; alkenyl groups such as vinyl or allyl; aralkyl groups such as benzyl or phenethyl;
Cycloalkyl groups such as cyclopentyl or cyclohexyl; cyano groups; mercapto groups; alkylthio groups such as methylthio or ethylthio; nitro groups; oxo groups; acylamino groups such as acetamido; alkoxy groups such as methoxy or ethoxy; aralkyl such as benzyloxy groups Oxy group; acyl group such as formyl, acetyl, propionyl, butyryl or benzoyl; amino group; alkylamino group such as methylamino, ethylamino, hydroxyethylamino, propylamino; dimethylamino, diethylamino, bis(hydroxyethyl)amino or dialkylamino groups such as dipropylamino; arylamino groups such as anilino; aralkylamino groups such as benzylamino and phenethylamino; pyridyl,
It may be substituted with one or more groups such as a heterocyclic group such as pyrimidinyl, imidazolyl, thiazolyl, pyrazinyl, oxazolyl, furyl, thienyl, pyrrolyl or pyridazinyl; or a heterocyclic amino group such as pyridylamino or pyrimidinylamino. In addition, reactive groups for Y in the compounds represented by the general formulas [], [] and [] include, for example, halogen atoms such as chlorine atom, bromine atom or iodine atom, p-toluenesulfonyloxy or phenylsulfonyloxy, etc. and an alkylsulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy. In addition, in the above-mentioned production method, 1-benzyl-
4-[4-(2-pyrimidinylamino)benzyl]
Examples of reactive derivatives of -2,3-dioxopiperazine or compounds represented by the general formulas [] and [] include alkali metal atoms such as lithium, sodium or potassium;
(CH ₃ ) ₃ Si−, (CH ₃ ) ₂ Si, (CH ₃ ) ₂ [(CH ₃ ) ₂ CH]
An organic silyl group such as Si-, ( _CH3O ) _3Si- , _CH3 ( _{CH3O2 )} Si- or ( _CH3 ) ₂ ( _CH3O )Si-, or ( _CH3O ) _2P- , (C ₂ H ₅ O) ₂ P−,

【formula】

[Formula] or

Examples include compounds in which an organic phosphorus group such as [Formula] is bonded to an NH group that is a reactive site. These reactive derivatives can be easily synthesized by conventional methods and may be subjected to subsequent reactions without being isolated. In addition, 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine and compounds of the general formulas [], [] and [] used in each of the above production methods are, for example, as follows. can be easily obtained according to the reaction route and each production method described above. [In the above formula, R ¹ , R ² , X and Y have the meanings described above. DMF is dimethylformamide,
AcNH- indicates _CH3CONH- . ] Next, embodiments of each manufacturing method will be described. Production methods (1), (3) and (4) are similarly carried out in the presence or absence of a solvent inert to the reaction. Solvents used in this reaction include, for example, ethers such as tetrahydrofuran, diethyl ether, dimethoxyethyl ether, dimethoxyethane or dioxane, halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and dimethylformamide. or amides such as dimethylacetamide, nitriles such as acetonitrile or propionitrile, aromatic hydrocarbons such as benzene, toluene or xylene, nitroalkanes such as nitromethane or nitroethane, tertiary amines such as pyridine or quinoline, Examples include sulfoxides such as dimethyl sulfoxide, and phosphoric acid amides such as hexamethylphosphoricamide. Two or more of the above solvents can also be used in combination. The reaction temperature and reaction time are not particularly limited, but it is preferably carried out at 0°C to 150°C, and at this time,
The reaction is usually completed in 5 minutes to 12 hours. The compounds represented by the general formulas [], [] and [] are 1-benzyl-4-[4-(2-
pyrimidinylamino)benzyl]-2,3-dioxopiperazine or general formula [] or []
It is usually used in an amount of equivalent mole or more, preferably 1.0 to 1.2 mole, per the compound represented by. In production method (4), inorganic and organic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, or pyridine may be used as deoxidizing agents. Production method (2) is carried out in the presence or absence of a solvent inert to the reaction. Examples of the solvent used in this reaction include tetrahydrofuran,
Ethers such as diethyl ether, dioxane or dimethoxyethane, aromatic hydrocarbons such as benzene, toluene or xylene, nitroalkanes such as nitromethane or nitroethane, nitriles such as acetonitrile or propionitrile, dimethylformamide or dimethylacetamide, etc. Examples include amides of , halogenated hydrocarbons such as methylene chloride or chloroform, fatty acids such as acetic acid or propionic acid, and two or more of these may be used as a mixed solvent. The reaction temperature and reaction time are not particularly limited, but it is preferably carried out at 0°C to 150°C, and at this time, the reaction is usually carried out for 30 minutes to 24 minutes.
It will be completed in time. The compound represented by the general formula [] can be used in an amount usually equal to or more than the molar amount of the compound represented by the general formula []. Further, as a catalyst, protic acids such as hydrogen chloride, hydrogen bromide and sulfuric acid, or Lewis acids such as zinc chloride, aluminum chloride, tin chloride, titanium tetrachloride, and boron trifluoride may be used. After carrying out the above-mentioned reaction, the compound represented by the general formula [] is isolated from the reaction mixture according to a conventional method, and can be purified by performing operations such as column chromatography and recrystallization.
Furthermore, to obtain an acid addition salt of the compound represented by the general formula [], a conventional method can be used using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or an organic acid such as p-toluenesulfonic acid or acetic acid. It can be obtained by reaction, isolation and purification according to the following. To obtain base addition salts, inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or aqueous ammonia, or pyridine, collidine, triethylamine, triethanolamine or procaine may be used. It can be obtained by reacting with an organic base according to a conventional method. In addition, in each of the above manufacturing methods, the general formula [], [], [], []
If the compound represented by and [ ] has an active group such as an amino group, hydroxyl group or carboxyl group in the non-reactive site, it is protected with a known protecting group and the method of the present invention is carried out.
A compound having a protecting group can be obtained, and by treating this by a method known per se to remove the protecting group, a compound having a free group can be obtained. The compound of the present invention obtained as described above is extremely useful as an anticancer agent, and can be used in oral formulations (powders, capsules, tablets, syrups, granules, etc.) and injectable formulations by appropriately using additives commonly used in pharmaceuticals. It is used as an anti-cancer agent in the form of anti-cancer agents, injectables, intravenous injections, drips, etc. administration method,
Although the dosage and frequency of administration are appropriately selected depending on the patient's symptoms, oral administration is particularly preferred, and for adults, 100 to 200 mg may be administered 1 to 3 times per day. Next, the present invention will be explained by giving examples and formulation examples. Example 1 (1) 0.88g of sodium hydride (purity 60%),
N,N-dimethylformamide (DMF)
) Suspend in 23 ml of 1-benzyl-
Add 4.5g of 2,3-dioxopiperazine and 80℃
Stir for 10 minutes. Then, cool to 65℃ and 4-
Contains 4.0g of acetylaminobenzyl chloride
Add 15 ml of DMF solution dropwise and react at 60-65°C for 30 minutes. After the reaction is complete, the solvent is distilled off under reduced pressure, 20 ml of ethanol is added, and the precipitated crystals are collected. Add the obtained crystals to 60 ml of 2N hydrochloric acid.
Heat to reflux for an hour. After the reaction is complete, cool to room temperature, add 4.0 g of sodium hydrogen carbonate, dry the precipitated crystals, and recrystallize from ethyl acetate to obtain 1-(4-aminobenzyl)-4-benzyl, which has a melting point of 193-194°C. 4.9 g (yield 90%) of -2,3-dioxopiperazine is obtained. IR (KBr) cm ^-1 : ν _NH 3450, 3350 ν _C=0 1660 Elemental analysis value (C ₁₈ H ₁₉ N ₃ O ₂ ) Calculated value (%) C; 69.88H; 6.19N; 13.58 Actual value (%) C; 69.82H; 6.26N; 13.52 NMR ( _d6 -DMSO) ppm value; 3.34 (4H, s, piperazine ring CH ₂ × 2) 4.38 (2H, s, CH ₂ × 1) 4.53 (2H, s, CH ₂ × 1) 4.99 (2H, s, NH ₂ × 1) 6.50 (2H, d, J = 9.0Hz benzene ring H × 2) 6.93 (2H, d, J = 9.0Hz benzene ring H × 2) 7.22 (5H , s, benzene ring H x 5) (2) 1-(4-aminobenzyl)-4-benzyl-
1.3 g of 2,3-dioxopiperazine is suspended in 3.9 ml of ethylene glycol, and 0.57 g of 2-chloropyrimidine is added while stirring at 140°C. 140
Carry out the reaction at ~150 °C for 30 min. After the reaction is complete, cool to 100°C and add 2.42ml of water. After cooling, add water again.
Add 17ml, stir, and collect the precipitated crystals.
After drying, if recrystallized from ethanol, the melting point
1-Benzyl-4-[4-(2
-pyrimidinylamino)benzyl]-2,3-
0.9 g (yield 75%) of dioxopiperazine is obtained. IR (KBr) cm ^-1 ; ν _NH 3320 ν _C=0 1670 Elemental analysis value (C ₂₂ H ₂₁ N ₅ O ₂ ) Calculated value (%) C; 68.20H; 5.46N; 18.08 Actual value (%) C; 68.24H; 5.38N; 17.89 NMR ( _d6 -DMSO) ppm value; 3.42 (4H, bs, piperazine ring _CH2 × 2) 4.51 (2H, s, _CH2 × 1) 4.54 (2H, s, _CH2 × 1) 6.75 (1H, t, J = 4.5Hz, pyrimidine ring H x
1) 7.15 (2H, d, J = 8.5Hz, benzene ring H x
2) 7.25 (5H, s, benzene ring H x 5) 7.70 (2H, d, J = 8.5Hz, benzene ring H x
2) 8.40 (2H, d, J = 4.5Hz, pyrimidine ring H x
2) 9.68 (1H, s, NH x 1) (3) 372 mg of sodium hydride (purity 50%)
Mix 30 ml of DMF and, under stirring, 1-benzyl-
Contains 3 g of 4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine
Add 20ml of DMF solution dropwise over 30 minutes at 60-70℃.
Let it react for 1 hour. After the reaction is completed, 1.3 g of pivaloyloxymethyl chloride is added dropwise over 10 minutes at the same temperature. After completing the dropwise addition, react at 70 to 80°C for 30 minutes. After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is extracted with 100 ml of chloroform. The chloroform layer was washed with 30 ml of water and then with 40 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (Wako Gel C
1-benzyl-4-
{4-[N-pivaloyloxymethyl-N-(2
-pyrimidinyl)amino]benzyl}-2,3
- Obtain 2.5 g of dioxopiperazine (yield 64.3%). IR (KBr) cm ^-1 ; ν _C=0 1725, 1670 Elemental analysis value (C ₂₈ H ₃₁ N ₅ O ₄ ) Calculated value (%) C; 67.05H; 6.23 N; 13.96 Actual value (%) C; 66.99 H; 6.23N; 13.85 NMR (CDCl ₃ ) ppm value; 1.17 (9H, s, CH ₃ × 3) 3.38 (4H, s, piperazine ring CH ₂ × 2) 4.65 (4H, s, CH ₂ × 2) 5.95 (2H, s, CH ₂ × 1) 6.68 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.23 (4H, s, benzene ring H x 4) 7.25 (5H, s, benzene ring H x 5) 8.33 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) The following compound is obtained in the same manner. Γ1-benzyl-4-{4-[N-methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}
-2,3-dioxopiperazine melting point: 138-140℃ (recrystallized from ethyl acetate) IR (KBr) cm ^-1 ; ν _C=0 1665 Elemental analysis value (C ₂₄ H ₂₅ N ₅ O ₃ ) Calculated value ( %) C; 66.80H; 5.84N; 16.23 Actual value (%) C; 67.10H; 5.82N; 16.14 NMR ( _CDCl3 ) ppm value; 3.38 (7H, s, CH3 _× 1, piperazine ring _CH2 ×
2) 4.62 (4H, s, CH ₂ × 2) 5.29 (2H, s, CH ₂ × 1) 6.60 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.23 (4H, s, benzene ring H x 4) 7.26 (5H, s, benzene ring H x 5) 8.26 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) Γ1-benzyl-4-{4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}
-2,3-dioxopiperazine Melting point: 135-138℃ (recrystallized from ethyl acetate-diethyl ether) IR (KBr) cm ^-1 ; ν _C=0 1665 Elemental analysis value (C ₂₅ H ₂₇ N ₅ O ₃ ) Calculated value (%) C; 67.40H; 6.11N; 15.72 Actual value (%) C; 67.32H; 6.12N; 15.59 NMR ( _CDCl3 ) ppm value; 1.16 (3H, t, J = 7.0Hz, _-CH3 ×1) 4.38 (4H, s, piperazine ring CH ₂ ×2) 3.60 (2H, q, J=7.0Hz, CH ₂ ×1) 4.62 (4H, s, CH ₂ ×2) 5.35 (2H, s, CH ₂ × 1) 6.57 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.23 (4H, s, benzene ring H x 4) 7.26 (5H, s, benzene ring H x 5) 8.26 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) Γ1-Benzyl-4-{4-[N-isobutoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 145°C (recrystallized from ethyl acetate) IR ( KBr) cm ^-1 ; ν _C=0 1660 NMR (CDCl ₃ ) ppm value; 0.88 (6H, d, J=6.5Hz, -CH ₃ × 2) 1.85 (1H, m, CH × 1) 3.33 (2H, d, J=6.5Hz, CH ₂ ×1) 3.40 (4H, s, piperazine ring CH ₂ ×2) 4.65 (4H, s, CH ₂ ×2) 5.38 (2H, s, CH ₂ ×1) 6.63 (1H , t, J=5.0Hz, pyrimidine ring H×
1) 7.25 (4H, s, benzene ring H x 4) 7.29 (5H, s, benzene ring H x 5) 8.27 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) Γ1-benzyl-4-{4-[N-stearoyloxymethyl-N-(2-pyrimidinyl)amino]
Benzyl}-2,3-dioxopiperazine Melting point: 116℃ (recrystallized from ethyl acetate) IR (KBr) cm ^-1 ; ν _C=0 1735, 1660 Elemental analysis value (C ₄₁ H ₅₇ N ₅ O ₄ ) Calculation Value (%) C; 72.00H; 8.40N; 10.24 Actual value (%) C; 71.14H; 8.61N; 10.23 Γ1-benzyl-4-{4-[N-isopropyloxymethyl-N-(2-pyrimidinyl) amino〕
Benzyl}-2,3-dioxopiperazine (recrystallized from isopropyl alcohol) Melting point: 147℃ IR (KBr) cm ^-1 ; ν _C=O 1670 Elemental analysis value (C ₂₆ H ₂₉ N ₅ O ₃ ) Calculated value ( %) C; 67.95H; _{6.36N ;} 15.24 Actual value (%) , piperazine ring CH ₂ × 2), 3.54-4.04 (1H, m, CH × 1), 4.63 (4H, s, CH ₂ × 2), 5.37 (2H, s, CH ₂ × 1), 6.59 (1H, t, pyrimidine ring H x 1), 7.23 (5H, s, benzene ring H x 5), 7.28 (4H, s, benzene ring H x 4), 8.27 (2H, d, pyrimidine ring H x 2), Γ1- Benzyl-4-{4-[N-methylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 156°C (recrystallized from isopropyl alcohol) IR (KBr) cm ^-1 ;ν _C=O 1670 Elemental analysis value (C ₂₄ H ₂₅ N ₅ O ₂ S ₁ ) Calculated value (%) C; 64.41H; 5.63N; 15.65 Actual value (%) C; 64.38H; 5.61N; 15.60 NMR (CDCl ₃ ) ppm value; 2.10 (3H, s, CH ₃ × 1), 3.40 (4H, s, piperazine ring CH ₂ × 2), 4.63 (4H, s, CH ₂ × 2), 5.15 (2H, s , CH ₂ × 1), 6.58 (1H, t, pyrimidine ring H × 1), 7.10-7.35 (9H, m, benzene ring H × 9), 8.26 (2H, d, pyrimidine ring H × 2) Γ1-benzyl -4-{4-[N-isopropylthiomethyl-N-(2-pyrimidinyl)amino]
Benzyl}-2,3-dioxopiperazine Melting point: 135℃ (recrystallized from isopropyl alcohol) IR (KBr) cm ^-1 ; ν _C=O 1670 Elemental analysis value (C ₂₆ H ₂₉ N ₅ O ₂ S ₁ ) Calculation Value (%) C; 65.66H; 6.14N; 14.72 Actual value (%) C; 65.64H; 6.12N; 14.68 NMR (CDCl ₃ ) ppm value; 1.25 (6H, d, CH ₃ × 2), 2.97 (1H , q, CH × 1), 3.37 (4H, s, piperazine ring CH ₂ × 2), 4.63 (4H, s, CH ₂ × 2), 5.16 (2H, s, CH ₂ × 1), 6.56 (1H, t, pyrimidine ring H x 1), 7.22-7.27 (9H, m, benzene ring H x 9), 8.26 (2H, d, pyrimidine ring H x 2) Example 2 1 obtained in Example 1-(3) -benzyl-4-{4-
Dissolve 1 g of [N-pivaloyloxymethyl-N-(2-pyrimidinyl)]aminobenzyl}-2,3-dioxopiperazine in 20 ml of ethanol, and dissolve N-
Add 0.02 ml of hydrogen chloride-ethanol solution and react at room temperature for 2 hours with stirring. After the reaction, the solvent was distilled off under reduced pressure, and the obtained white crystals were recrystallized from ethyl acetate-diethyl ether to give 1-benzyl-4- as shown in Example 1.
0.7 g (yield 79%) of {4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine is obtained. The physical properties of this product were consistent with those obtained in Example 1. The following compound is obtained in the same manner. Γ1-Benzyl-4-{4-[N-ethylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 144°C (recrystallized from isopropyl alcohol) IR (KBr) cm ^-1 ; ν _C=O 1670 Elemental analysis value (C ₂₅ H ₂₇ N ₅ O ₂ S ₁ ) Calculated value (%) C; 65.05H; 5.89N; 15.17 Actual value (%) C; 65.02H; 5.84N ; 15.12 NMR (CDCl ₃ ) ppm value; 1.14 (3H, t, CH ₂ × 1), 2.53 (2H, q, CH ₂ × 1), 3.39 (4H, s, piperazine ring CH ₂ × 2), 4.62 ( 4H, s, CH ₂ × 2), 5.15 (2H, s, CH ₂ × 1), 6.57 (1H, t, pyrimidine ring H × 1), 7.23-7.27 (9H, m, benzene ring H × 9), 8.25 (2H, d, pyrimidine ring H x 2) Γ1-benzyl-4-{4-[N-phenylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 64-65℃ (recrystallized from isopropyl alcohol) IR (KBr) cm ^-1 ; ν _C=O 1670 Elemental analysis value (C ₂₉ H ₂₇ N ₅ O ₂ S ₁ ) Calculated value (%) C; 68.34H; 5.34 N; 13.74 Actual value (%) C; 68.36H; 5.32N; 13.71 NMR (CDCl ₃ ) ppm value; 3.33 (4H, s, piperazine ring CH ₂ × 2), 4.61 (2H, s, CH ₂ × 1) , 4.65 (2H, s, CH ₂ × 1), 5.50 (2H, s, CH ₂ × 1), 6.60 (1H, t, pyrimidine ring H × 1), 6.98-7.28 (14H, m, benzene ring H × 14), 8.30 (2H, d, pyrimidine ring H x 2) Example 3 1-benzyl-4-{4- obtained in Example 1-(3)
1 g of [N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine is dissolved in 30 ml of ethyl acetate, followed by 1 g of glycolic acid and 0.02 ml of N-hydrogen chloride-ethanol solution. ml and reacted at room temperature for 3 hours with stirring. After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is extracted with 100 ml of methylene chloride. Add 30ml of water to the methylene chloride layer and then add saturated saline.
After washing with 30ml, drying with anhydrous magnesium sulfate,
The solvent is removed under reduced pressure. The resulting residue was purified by column chromatography (Wako Gel C-200, chloroform-ethanol elution) and crystallized from ethyl acetate-isopropyl ether to give 1-benzyl- 4-{4
-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine 0.5 g (yield 52.8%) is obtained. IR (KBr) cm ^-1 ; ν _C=0 1735, 1665 Elemental analysis value (C ₂₅ H ₂₅ N ₅ O ₅ ) Calculated value (%) C; 63.15H; 5.30 N; 14.73 Actual value (%) C; 63.22 H; 5.38N; 14.62 NMR (CDCl ₃ ) ppm value 3.40 (4H, s, piperazine ring CH ₂ × 2) 4.17 (2H, s, CH ₂ × 1) 4.63 (4H, s, CH ₂ × 2) 5.25 ( 2H, s, CH ₂ × 1) 6.75 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.22 (5H, s, benzene ring H x 5) 7.28 (4H, s, benzene ring H x 4) 8.34 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) 9.82 (1H, bs, carboxylic acid H x 1) Example 4 1-benzyl-4-{4- obtained in Example 1-(3)
2 g of [N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine was dissolved in 20 ml of DMF, and then 20 ml of glycerin and 0.02 ml of N-hydrogen chloride-ethanol solution were added. , react under stirring at room temperature for 10 hours. After the reaction, the solvent was distilled off under reduced pressure, 50 ml of water was added to the resulting residue, and 100 ml of methylene chloride was added.
Extract twice. The methylene chloride layer is washed with 30 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (Wako Gel C-200, chloroform-ethanol elution) and crystallized from methylene chloride-diisopropyl ether, giving a melting point of 75-83.
1-benzyl-4-{4-[N-(2,3
-dihydroxy-1-propyl)oxymethyl-N-(2-pyrimidinyl)amino]benzyl}-
2,3-dioxopiperazine 1.8g (yield 92%)
get. IR (KBr) cm ^-1 ; ν _C=0 1665 NMR (CDCl ₃ −D ₂ O) ppm value; 3.24 to 3.87 (5H, m, CH ₂ × 2, CH × 1) 3.38 (4H, s, piperazine ring CH ₂ ×2) 4.60 (4H, s, CH ₂ ×2) 5.34 (2H, s, CH ₂ ×1) 6.62 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.18-7.32 (9H, bs, benzene ring H x 9) 8.28 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) Example 5 1-benzyl-4-{4- obtained in Example 1-(3)
2.4 g of [N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine was dissolved in 30 ml of acetic acid and 10 ml of triethanolamine, and the mixture was stirred at room temperature for 1 day. Make it react. After the reaction is complete, acetic acid is distilled off under reduced pressure, 100 ml of ice water is added to the resulting residue, the pH is adjusted to 7.5 with sodium bicarbonate, and the mixture is extracted twice with 100 ml of chloroform. Add 100% water to the chloroform layer.
ml and 100 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (Wako Gel C-200, chloroform-ethanol elution) to obtain 1-benzyl-4- as a colorless oil.
{4-{N-β-[N,N-bis(β-hydroxyethyl)amino]ethoxymethyl-N-(2-pyrimidinyl)amino}benzyl}-2,3-dioxopiperazine 1.3 g (yield 49.6%). IR (neat) cm ^-1 ; ν _C=0 1650 NMR (CDCl ₃ −D ₂ O) ppm value; 2.5 to 2.86 (6H, m, CH ₂ × 3) 3.27 to 3.72 (6H, m, CH ₂ × 3 ) 3.41 (4H, s, piperazine ring CH ₂ × 2) 4.64 (4H, s, CH ₂ × 2) 5.37 (2H, s, CH ₂ × 1) 6.67 (1H, t, J = 5.0Hz, pyrimidine ring H ×
1) 7.26 (5H, s, benzene ring H x 5) 7.30 (4H, s, benzene ring H x 4) 8.31 (2H, d, J = 5.0Hz, pyrimidine ring H x
2) Formulation Example 1 1-Benzyl-4-{4-[N-methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-
2,3-dioxopiperazine 100mg, lactose 50mg,
48 mg of corn starch and 2 mg of magnesium stearate are mixed per capsule and filled into capsules to obtain capsules. Formulation example 2 1-benzyl-4-{4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-
2,3-dioxopiperazine 250mg, lactose 50mg,
38 mg of corn starch, 10 mg of polyvinyl pyrrolidone and 2 mg of magnesium stearate are mixed per tablet to obtain a tablet.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is an alkyl, aryl or acyl group optionally substituted with a hydroxyl group, carboxyl group or bis(hydroxyalkyl)amino group, R ² is a hydrogen atom, and X is an oxygen atom or a sulfur atom. show. ] A 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and a salt thereof. 2. The 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and its salt according to claim 1, wherein X is an oxygen atom. 3. The ¹ -benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and its salt according to claim 2, wherein R1 is an acyl group. 4. 1-benzyl-4-[4-(2-pyrimidinyl) according to claim 2, wherein R ¹ is an alkyl group optionally substituted with a hydroxyl group, a carboxyl group, or a bis(hydroxyalkyl)amino group. amino)benzyl]-2,3-dioxopiperazine derivatives and salts thereof. 5 1-benzyl-4-{4-[N-methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}
The compound according to claim 4, which is -2,3-dioxopiperazine and a salt thereof. 6 1-benzyl-4-{4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}
The compound according to claim 4, which is -2,3-dioxopiperazine and a salt thereof. 7 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine or a reactive derivative thereof, and the general formula [In the formula, R ¹ is an alkyl, aryl or acyl group optionally substituted with a hydroxyl group, carboxyl group or bis(hydroxyalkyl)amino group, R ² is a hydrogen atom, and X is an oxygen atom or a sulfur atom. , Y indicates reactivity. ] A general formula characterized by reacting a compound represented by [In the formula, R ¹ , R ² and X have the meanings described above.] ] A method for producing a 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and a salt thereof. 8 General formula [In the formula, R ² is a hydrogen atom, R ³ is an alkyl, cycloalkyl, with or without a substituent,
Indicates an aralkyl, alkenyl, alkadienyl or aryl group. ] and ^a compound represented by the general formula H-X-R ⁴ [wherein, Indicates a good alkyl or aryl group. ] A general formula characterized by reacting a compound represented by [In the formula, R ² , R ⁴ and X have the meanings described above.] ] A method for producing a 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative and a salt thereof. 9 General formula [In the formula, R ¹ is an alkyl, aryl or acyl group optionally substituted with a hydroxyl group, carboxyl group or bis(hydroxyalkyl)amino group, R ² is a hydrogen atom, and X is an oxygen atom or a sulfur atom. show. ] An anticancer agent containing a 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative or a salt thereof. 10. An anticancer agent containing the 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivative or a salt thereof according to claim 9 in an oral dosage form.