GB2094296A - Dioxopiperazine derivatives - Google Patents

Abstract

1-Benzyl-4-[4-(2-pyrimidinylamino)benzyl]- 2,3-dioxopiperazine derivatives represented by the formula: <IMAGE> wherein R<1> is optionally substituted hydrocarbyl or acyl, R<2> is H or alkyl and X is O or S, and salts thereof have an excellent carcinostatic activity but a low toxicity. Therefore, said compounds are useful as medicines and also as intermediates.

Description

SPECIFICATION Novel I -benzyl-4-(4-(2-pyrimidinylamino)benzyl-2,3-dioxopiperazine derivatives, salts thereof, process for producing the same and carcinostatic agent containing the same This invention relates to novel 1 -benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2, 3-dioxopiperazine derivatives and salts thereof, to a process for producing the same, and to a carcinostatic agent containing the same.

The compounds of this invention are per se excellent in carcinostatic activity, low in toxicity, useful as medicines, and useful also as intermediates.

An object of this invention is to provide novel 1-benzyl-4-[4-(2-pyrimidinylaminoubenzyl]-2,3- dioxopiperazine derivatives and salts thereof.

Another object of this invention is to provide novel 1-benzyl-4-(4-(2-pyrimidinylamino)benzylj- 2,3-dioxopiperazine derivatives which have a carcinostatic activity and are low in toxicity, and salts thereof.

A further object of this invention is to provide novel 1-benzyl-4-(4-(2-pyrimidinylamino)benzyl) 2,3-dioxopiperazine derivatives or salts thereof which are well orally absorbable.

A still further object of this invention is to provide a process for producing novel 1-benzyl-4 [4-(2-pyri midinylamino)benzyl]-2, 3-dioxopiperazi ne derivatives, or salts thereof.

A still further object of this invention is to provide a carcinostatic agent containing novel 1benzyl-4-[4-(2-pyri mid inylam ino)benzyl]-2, 3-dioxopiperazine derivatives, or salts thereof.

Other objects and advantages of this invention will be apparent from the following description.

According to this invention, there is provided a novel 1-benzyl-4-[4(2-pyrimidinylamino)ben zyl]-2,3-dioxopiperazine derivatives represented by the formula (I) or a salt thereof:

wherein R' represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R2 represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom.

In the formula (I), R1 is an alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or the like; a cycloalkyl group, such as cyclopentyl, cyclohexyl, or the like; an aralkyl group, such as benzyl, phenethyl, or the like; an alkenyl group, such as vinyl, allyl, or the like; an alkadienyl group, such as 1,3-butadienyl, 2,4-hexadienyl, geranyl, or the like; an aryl group, such as phenyl, naphthyl, or the like; and an acyl group, such as acetyl, propionyl, butyryl, pivaloyl, stearoyl, benzoyl, furoyl, thenoyl, pyridylcarbonyl, cyclohexylcarbonyl, or the like.

The above-mentioned R' may be substituted by at least one substituent selected from the group consisting of halogen atoms such as fluorine, chlorine, bromine, iodine, and the like; hydroxyl group; carboxyl group; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and the like; aralkoxycarbonyl groups such as benzyloxycarbonyl and the like; aryloxycarbonyl groups such as phenoxycarbonyl and the like; alkyl groups such as methyl, ethyl, popyl, isopropyl, butyl, and the like; alkenyl groups such as vinyl, allyl, and the like; aralkyl groups such as benzyl, phenethyl, and the like; cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like; cyano group; mercapto group; alkylthio groups such as methylthio, ethylthio, and the like; nitro group; oxo group; acylamino groups such as acetamido and the like; alkoxy groups such as methoxy, ethoxy, and the like; aralkoxy groups such as benzyloxy and the like; acyl groups such as formyl, acetyl, propionyl, butyryl, benzoyl, and the like; amino group; alkylamino groups such as methylamino, ethylamino, hydroxyethylamino, propylamino, and the like; dialkylamino groups such as dimethylamino, diethylamino, bis(hydroxyethyl)amino, dipropylamino, and the like; arylamino groups such as anilino and the like; aralkylamino groups such as benzylamino, phenethylamino and the like; heterocyclic groups such as pyridyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazinyl, oxazolyl, furyl, thienyl, pyrrolyl, pyridazinyl, and the like; and heterocyclic amino groups such as pyridylamino, pyrimidinylamino, etc.; and the like.

R2 is a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, butyl, octyl, or the like.

For the formation of the salts of the compounds represented by the formula (I), any acids or bases may be used so long as the resulting salts are pharmaceutically acceptable, though inorganic acidic salts such as salts with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and the like and inorganic or organic basic salts such as salts with potassium, sodium, calcium, ammonium, pyridine, collidine, triethylamine, triethanolamine, procaine, and the like are particularly preferred. Hydrates of the compounds represented by the formula (l) and hydrates of the salts of the compounds of the formula (I) are also included in this invention.

The carcinostatic activity and acute toxicity of the representative compounds of this invention are explained below.

a. Minimum inhibitory concentration (MIC) against HeLA S3 cells and Ehrlich cells Using microplate of 8 X 12 wells, to each chamber were added 0.1 ml of a culture medium (Eagles MEW + 20% calf serum) containing a test drug and 0.1 ml of a cell-suspended culture medium (2 x 104 cells/ml). The concentration of the test drug was 100 ygtml at the highest, and 0.05 ,ugtml at the lowest, with serial twofold dilutions (12 steps). The test drug-containing culture medium was subjected to sterile filtration. The cells were cultured for 4 days, after which the cells were separated from the culture medium, washed twice with Hank's salt solution, then fixed with 95% ethanol for 5 min, and thereafter stained with the Giemsa solution for 15 min.

The inhibition of celi growth was judged with unaided eye. The results obtained are shown in Table 1.

Table 1

MIC (ug/m1) No. Compound HeLa Ehrlich 040 1 (0, FN CH2-N 0.39 0.39 CH2OCC (CH3) 3 II 0 2 EONN N 4 1.56 1. 56 v CH20C2H5 m 3 1 N - Cn2-Nx oN CH2 0.39 CH2OC (CH2) 16CH3 4 (-ON N > CH2-N 1.56 4 l . 56 3 13 CH2OCH3 5 QoNNYN e 2 2 4 3.13 3.13 CH2OCH2CHCH2OH OH - cont'd Table 1 (cont'd)

0 0 X CH2-N N-CH2 4 0.39 ; 0.78 CH20CH2COOH 7 CO )no CH2-N N-CII24 3,13 6 . 6.25 CH2OCH2CH (CH3)2 8 NCH2CH2 12.5 12.5 C}I2OCH2CH2N (CH2CH2OH) b. Effect on L-1210 Leukemia L-1210 cells (1 X 105 cells/head) were inoculated intravenously into BDF1-strain mice (male, 7 weeks old, each group consisting of 5 mice), and after 24 hours, test drugs were orally administered once a day for 7 successive days. The effect thereof was judged from the means survival days.

The test drugs were used in the form of a solution or suspension in a saline solution or a 0.3% carboxymethyl cellulose-containing saline solution. T/C was calculated by the following equation: Mean survival days in group to which test drug was administered T/C = x 100(%) Mean survival days of control group The results obtained are shown in Table 2.

Table 2 Compound Dose T/C No. (mg/kg/day) (%) 1 50 135 100 162 2 110 120 220 237 4 110 177 220 289 5 65 140 130 177 7 120 118 240 177 c. Acute Toxicity Each of the test drugs was administered orally once ICR-strain mice (male, 7 weeks old, each group consisting of 5 mice), and the mice were observed for 7 days.

The test drugs were used in the form of a solution or suspension in a saline solution or a 0.3% carboxymethyl cellulose-containing saline solution. The results obtained are shown in Table 3.

Table 3 Compound LD50 No. (mg/kg) 1 2000 2 > 2000 4 > 2000 5 > 2000 7 > 2000 As is clear from the above test results, the compounds of this invention have such excellent properties that they are well absorbed in a living body when orally administered to exhibit excellent carcinostatic activities, and have low toxicities. Therefore, they are very useful as carcinostatic agents.

An explanation is made below of processes for producing the compounds of this invention.

The compounds of the formula (I) or salts thereof of the present invention are produced according to the process (1) or (2) described below.

Process (1) A process comprising reacting 1 -benzyl-4-[4-(2-pyrimidinylamino)benzyl] 3dioxopipera- zine or a reactive derivative thereof with a compound represented by the formula:

wherein R' represents a substantial or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl, or acyl group; R2 represents a hydrogen atom or an alkyl group; X represents an oxygen atom or a sulfur atom; and Y represents a reactive group.

Process (2) A process comprising reacting a 1 -benzyl-4-[4-(2-pyrimidinylamino)benzyl] 3-dioxopiperazine derivative represented by the formula,

wherein R2 has the same meaning as defined above, and R4 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group, with a compound represented by the formula: H-X-R3 (IV) wherein X has the same meaning as defined above, and R3 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group.

In each of the processes, R1, R2 and X have the same meanings as defined above, and R3 and R4 in the formulas (III) and (IV) include the same alkyl, cyclo-alkyl, aralkyl, alkenyl, alkadienyl and aryl groups mentioned for Rt, and R3 and R4 may be substituted by the same substituents as mentioned for R1. As the reactive group for Y in the formula (II), there may be mentioned halogen atoms such as chlorine, bromine, iodine, and the like; arylsulfonyloxy groups such as phenylsulfonyloxy, p-toluenesulfonyloxy, and the like; and alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, and the like.

In each of the above-mentioned production processes, the reactive derivatives of 1-benzyl-4 [4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine include compounds formed by bonding an alkali metal atom such as lithium, sodium, potassium, or the like; an organic silyl group such as (CH3)3Si-,

(CH3)2[(CH3)2CH]Si-, (CH30)3Si-, CH3(CH3O)2Si-, (CH3)2(CH30)Si-, or the like; or an organic phosphorus group such as (CH3O)2P-, (C2H50)2P-,

or the like, to the

group.

These reactive derivatives can easily be synthesized according to a conventional method, and may be subjected without isolation to the subsequent reaction.

The 1-benzyl-4-[-4-(2-pyrimidinylamino)benzyl]-2,3-dioXopiperazine and the compounds represented by the formula (III) used in the above-mentioned production processes can easily be obtained through the following reaction routes and according to the process (1):

In the above formulas, DMF means N,N-dimethylformamide; AcNH-means CH3CONH-; R1, R2, R4 and Y have the same meanings as defined above.

Embodiments of each production process are described below.

The production process (1) is carried out in the presence or absence of a solvent inert to the raction. The solvent used in the reaction includes, for example, ethers such as tetrahydrofuran, diethyl ether, dimethoxyethyl ether, dimthoxyethane, dioxane and the like; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and the like; am ides such as dimethylformamide, dimethyl-acetamide, and the like; nitriles such as acetonitrile, propionitrile, and the like; aromatic hydrocarbons such as benzene, toluene xylene, and the like; nitroalkanes such as nitromethane, nitroethane, and the like; tertiary amines such as pyridine, quinoline, and the like; sulfoxides such as dimethylsulfoxide and the like; and phosphoric amides such as hexamethylphosphoric amide and the like.The above-mentioned solvents may be used also in admixture of two or more.

The reaction temperature and the reaction time are not critical, though the reaction is preferably effected at 0 to 150 C, and in this case, the reaction is usually completed in 5 minutes to 1 2 hours.

The compound represented by the formula (II) is used in a quantity at least equimolar to, preferably of 1.0 to 1.2 moles per mole of, 1-benzyl-4[4-(2-pyrimidinylamino)benzyl]-2,3- dioxopiperazine.

The production process (2) is carried out in the presence or absence of a solvent inert to the reaction. The solvent used in the reaction includes, for example, ethers such as terahydrofuran, diethyl ether, dioxane, dimethoxyethane, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; nitroalkanes such as nitromethane, nitroethane, and the like; nitriles such as acetonitrile, propionitrile, and the like; am ides such as dimethylformamide, dimethylacetamide, and the like; halogenated hydrocarbons such as methylene chloride, chloroform, and the like; and fatty acids such as acetic acid, propionic acid, and the like. These solvents may be used also in admixture of two or more.The reaction temperature and the reaction time are not critical, though the reaction is preferably effected at 0 to 150"C, in this case, the reaction is usually completed in 30 minutes to 24 hours.

The compound represented by the formula (IV) may usually be used in an amount at least equimolar to the compound represented by the formula (III) to such an amount that the compound of the formula (IV) can also serve as a solvent. Moreover, as the catalyst, there may be used protonic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and the like; and Lewis acids such as zinc chloride, aluminum chloride, tin chloride, titanium tetrachloride, boron trifluoride, and the like.

After the above production process (1) or (2) is carried out in the manner described above, the compound represented by the formula (I) can be isolated from the reaction mixture according to a conventional method, and purified by procedures such as column chromatography, recrystallization, and the like.A salt of the compound represented by the formula (I) can be obtained by effecting the reaction according to a conventional method using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like; an organic acid such as p-toluenesulfonic acid, acetic acid, or the like; an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, aqueous ammonia, or the like; or an organic base such as pyridine, collidine, triethylamine, triethanolamine, procaine, or the like, and then isolating and purifying the reaction product.In the above-mentioned production processes, when the compounds represented by the formulas (if), (III) and (IV) have an active group such as amino, hydroxyl, carbonyl, or the like in the unreactive site, compounds having a protecting group can be obtained by protecting the active group with a well-known protecting group, and then carrying out the process of this invention, and a compound having a free active group can be obtained by treating the compound having a protecting group by a well-known method to release the protecting group.

The compound of this invention obtained as mentioned above is very useful as a carcinostatic agent. Pharmaceuticaliy acceptable additives are appropriately added to the compound and the resulting mixture can be formulated into various drug forms such as oral preparations, for example tablets, syrup, capsules, powder, granules and the like, and injections, for example, intramuscular injection, intravenous injection, drip infusion, and the like, and then applied as a carcinostatic agent. The administration route, the dosage and the number of administrations are properly selected depending upon the conditions of a patient, though oral administration is preferred. In usual, in the case of an adult, the compound is administered once to thrice a day in a total dosage of 1 to 4,000 mg/kg.

This invention is further explained below referring to Examples, which are merely by way of illustration and not by way of limitation.

Example 1 (1) In 23 ml of N,N-dimethylformamide (referred to hereinafter as DMF) was suspended 0.88 g of sodium hydride (purity 60%), and 4.5 g of 1-benzyl-2,3-dioxopiperazine was added to the resulting suspension, after which the resulting mixture was stirred at 80"C for 10 min, and then cooled to 65 C. Thereinto was dropped 15 ml of a DMF solution containing 4.0 g of 4acetylamino-benzyl chloride, and the resulting mixture was subjected to reaction at 60-65"C for 30 min. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and 20 ml of ethanol was added to the residue, after which the crystals precipitated were collected by filtration.The crystals thus obtained were added to 60 ml of 2N hydrochloric acid, and the resulting solution was heated under reflux for one hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and thereto was added 4.0 g of sodium hydrogen carbonate, after which the crystals precipitated were collected by filtration, dried, and then recrystallized from ethyl acetate, to obtain 4.9 g (yield 90%) of 1-(4-aminobenzyl)-4-benzyl-2,3-dioxopiperazine having a melting point of 193-194"C.

IR (KBr) cm-': VNH 3450, 3350 vc=O 1660 Elementary analysis (for C,8H1gN302) Calcd. (%) C: 69.88, H: 6.19, N: 13.58 Found (%) C: 69.82, H: 6.26, N: 13.52 NMR (ds-DMSO) ppm values: 3.34 (4H, s, piperazine ring CH2 X 2), 4.38 (2H, s, CH2 X 1), 4.53 (2H, s, CH2 X 1), 4.99 (2H, s, NH2 X 1), 6.50 (2H, d, J = 9.0Hz, benzene ring H X 2), 6.93 (2H, d, J = 9.0Hz, benzene ring H X 2), 7.22 (5H, s, benzene ring H X 5) (2) In 3.9 ml of ethylene glycol was suspended 1.3 g of 1-(4-aminobenzyl)-4-benzyl-2,3- dioxopiperazine, and 0.57 g of 2-chloropyrimidine was added to the resulting suspension with stirring at 140 C. The resulting mixture was subjected to reaction at 140-150"C for 30 min.

After the completion of the reaction, the reaction mixture was cooled to 100"C, and 2.42 ml of water was added to the reaction mixture. Afer allowing the resulting mixture to stand, 17 ml of water was added again thereto, and the resulting mixture was stirred, after which the crystals precipitated were collected by filtration, dried and then recrystallized from ethanol, to obtain 0.9 g (yield 75%) of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine having a melting point of 175-176"C.

IR (KBr) cm-': VNH 3320 vc=O 1670 Elementary analysis (for C22H2,N502) Calcd. (%) C: 68.20, H: 5.46, N: 18.08 Found (%) C: 68.24, H: 5.38, N: 17.89 NMR (d6-DMSO) ppm values: 3.42 (4H, bs, piperazine ring CH2 X 2), 4.51 (2H, s, CH2X 1), 4.54 (2H, s, CH2 X1), 6.75 (1 H, 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) To a mixture of 372 mg of sodium hydride (purity 50%) and 30 ml of DMF was added dropwise a solution of 3 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine in 20 ml of DMF with stirring over 30 min, after which the resulting mixture was subjected to reaction at 60-70"C for one hour. After the completion of the reaction, 1.3 g of pivaloyloxymethyl chloride was dropped thereinto over 10 min at the same temperature. After the completion of the dropwise addition, the resulting mixture was subjected to reaction at 70-80"C for 30 min. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 1 00 ml of chloroform. The chloroform layer was washed with 30 ml of water and 40 ml of saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by a column chromatography (Wakogel C-200, eluted with chloroform), and then recrystallized from ethyl acetate-diisopropyl ether, to obain 2.5 g (yield 64.3%) of 1-benzyl-4 {4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 144-146 C.

IR (KBr) cm-1: Yc=o 1725, 1670 Elementary analysis (for C2BH3iN5O4) Calcd. (%) C: 67.05, H: 6.23, N: 13.96 Found (%) C: 66.99, H: 6.23, N: 13.85 NMR (CDCl3) ppm values:: 1.17 (9H, s, CH3 X 3), 3.38 (4H, s, piperazine ring CH2 x 2), 4.65 (4H, s, CH2 x 2), 5.95 (2H, s, CH2 x 1), 6.68 (1 H, t, J = 5.0Hz, pyrimidine ring H X 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) Example 2 In 30 ml of ethyl acetate was dissolved 1 g of l-benzyl-4- (4-[N-pivaloyloxymethyl-N-(2- pyrimidinyl)-aminolbenzyl) -2, 3-dioxopiperazine, and 1 g of glycolic acid and 0.02 ml of N hydrogen chloride ethanol solution were added, after which the resulting mixture was subjected to reaction at room temperature for 3 hours with stirring. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of methylene chloride.The methylene chloride layer was washed with 30 ml of water and then 30 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, after which the- solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (Wakogel C-200, eluted with chloroform-ethanol), and recrystallized from ethyl acetate-diisopropyl ether, to obtain 0.5 g (yield 52.8%) of 1 -benzyl-4- (4-[N-carboxy-methoxymethyl-N-(2-pyrimidinyl)ami- no]benzyl}-2,3-dioxopiperazine having a melting point of 85-90 C.

IR (KBr) cm-': vc=O 1735, 1665 Elementary analysis (for C25H2sN5Os) Calcd. (%) C: 63.15, H: 5.30, N: 14.73 Found (%) C: 63.22, H: 5.38, N: 14.62 NMR (CDCI3) ppm values: 3.40 (4H, s, piperazine ring CH2 X 2), 4.17 (2H, s, CH2 X 1), 4.63 (4H, s, CH2 X 2), 5.25 (2H, s, CH2 X 1), 6.75 (1 H, t, J = 5.0Hz, pyrimidine ring H X 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 (1 H, bs, carboxylic acid H X 1) Example 3 In 10 ml of ethyl mercaptan was dissolved 1.0 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2pyrimidinyl)-amino]benzyl}-2,3-dioxopiperazine, and 0.01 of 5.7N hydrogen chloride-dioxane solution was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 3 hours. After the completion of the reaction, the solvent was removed under reduced pressure, and 50 ml of diisopropyl ether was added to the crystals thus obtained, after which the resulting crystals were filtered. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 0.8 g (yield 86.8%) of white crystalline 1-benzyl-4-{4-[N-ethylthiomethyl-N-(2-pyrimidinyl)amino]-benzyl}-2,3-dioxopiperazine having a melting point of 144 C.

IR (KBr) cm-': vc= @ 1670 Elementary analysis (for C25H27N502S,) Calcd. (%) C: 65.05, H: 5.89, N: 15.17 Found (%) C: 65.02, H: 5.84, N: 15.12 NMR (CDCl3) ppm values: 1.14 (3H, t, CH3 X 1), 2.53 (2H, q, CH2 X 1), 3.39 (4H, s, piperazine ring CH2 X 2), 4.62 (4H, s, CH2 X 2), 5.15 (2H, s, CH2 X 1), 6.57 (1H, t, pyrimidine ring H X 1), 7.23-7.27 (9H, m, benzene ring H X 9), 8.25 (2H, d, pyrimidine ring H X 2) In the same manner as above, the following compound was obtained: 1-Benzyl-4-{4-[N-phenylthlomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 64-65 C (recrystallized from isopropyl alcohol) IR (KBr) cm-': y,=, 1670 Elementary analysis (for C29H27N502S,) Calcd. (%) C: 68.34, H: 5.34, N: 13.74 Found (%) C: 68.36, H: 5.32, N: 13.71 NMR (CDCl3) ppm values: 3.33 (4H, s, piperazine ring CH2 X 2), 4.61 (2H, s, CH2 X 1), 4.65 (2H, s, CH2 X 1), 5.50 (2H, s, CH2 X 1), 6.60 (1H, t, pyrimidine ring H x 1), 6.98-7.28 (14H, m, benzene ring H X 14), 8.30 (2H, d, pyrimidine ring H X 2) Example 4 In 40 ml of DMF was dissolved 3.0 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3- dioxopiperazine, and 0.372 g of sodium hydride (purity 52%) was added thereto, after which the resulting mixture was subjected to reaction at 80 C for 30 min with stirring. The reaction mixture was then cooled, and 0.72 ml of chloromethylmethylsulfide was added thereto, after which the resulting mixture was subjected to reaction at 50-60 C for 2 hours.After the completion of the reaction, the reaction mixture was distilled under reduced pressure and the residue thus obtained was extracted with chloroform and then washed with water. The solution thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 3.0 g (yield 86.45%) of white crystalline 1-benzyl-4-f4(N methylthiomethyl-N-(2-pyrimidinyl)amino]-benzyl}-2,3-dioxopiperazine having a melting point of 1 56 C.

IR (KBr) cm-1 : #c=o 1670 Elementary analysis (for C24H25N502S,) Calcd. (%) C: 64.41, H: 5.63, N: 15.65 Found (%) C: 64.38, H: 5.61, N: 15.60 NMR (CDCl3) ppm values: 2.10 (3H, s, CH3 X 1), 3.40 (4H, s, piperazine ring CH2 x 2), 4.63 (4H, s, CH2 x 2), 5.15 (2H, s, CH2 X 1), 6.58 (1 H, t, pyrimidine ring H X 1), 7.10-7.35 (9H, m, benzene ring H X 9), 8.26 (2H, d, pyrimidine ring H x 2) In the same manner as above, the following compound was obtained: 1 -Benzyl-4- (4-CN-isopropylthiomethyl-N-(2-pyri midinyl)amino]benzyl) -2, 3-dioxopiperazine Melting point: 1 35 C (recrystallized from isopropyl alcohol) IR (KBr) cm-1: vc=O 1670 Elementary analysis (for C26H29N502S1) Calcd. (%) C: 65.66, H: 6.14, N: 14.72 Found (%) C: 65.64, H: 6.12, N: 14.68 NMR (CDCl3) ppm values: 1.25 (6H, d, CH3 X 2), 2.97 (1H, q, CH x 1), 3.37 (4H, s, piperazine ring CH2 x 2), 4.63 (4H, s, CH2 X 2), 5.16 (2H, s, CH2 X 1), 6.56 (1 H, 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 5 Based on Examples 1 and 2, any starting materials were selected to obtain the compounds shown in Table 3.

Note: (1) In Table 3, IPA = isopropyl alcohol, IPE = diisopropyl ether, AcOEt = ethyl acetate and Et2O = diethyl ether.

(2) In the "Process" columns, the word "Pro." number refers to the process number stated in the description of the specification, and the compound referred to in the line in which the "Pro." number appears was synthesized in the same manner as in the Example mentioned hereinbefore concerning the said process, or according to the method described in the specification based on said Example.

(3) In the "Recrystallization Solvent" column, the term "Column" means that the product was purified by column chromatography.

Table 3

R R X m.p. ( C) Recrystalliza- Process tion Solvent -CH3 H O 138 - 140 AcOEt Pro. (1), Pro. (2) -C2H5 H O 135 - 138 AcOEt-Et2O Pro. (1), Pro. (2) -CH2CH(CH3)2 H O 145 AcOEt Pro. (1) # H O 116 AcOEt Pro. (1) # H O 75 - 83 CH2Cl2-IPE Pro. (2) -CH2CH2N(CH2CH2OH)2 H O oil IR(neat) cm-1 : Column Pro. (2) #C=O 1650 -CH(CH3)2 H O 147 IPA Pro. (1) Preparation Example 1 Per one capsule, 100 mg of 1 -benzyl-4- (4-EN-methoxymethyl-N-(2-pyri midinyl)aminojbenzyl) - 2,3-dioxo-piperazine, 50 mg of milk sugar, 48 mg of corn starch and 2 mg of magnesium stearate were mixed, and capsules were filled with the resulting mixture, to obtain a capsule drug.

Preparation Example 2 Per one tablet, 250 mg of 1-benzyl-4-{4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3dioxopiperazine, 50 mg of milk sugar, 38 mg of corn sterch, 10 mg of polyvinyl pyrrolidone and 2 mg of magnesium stearate were mixed, and the resulting mixture was formed into tablets in the conventional manner to obtain a tablet drug.

Claims (12)

1. A compound represented by the formula,

wherein R' represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R2 represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof.

2. The compound according to Claim 1, wherein R2 is a hydrogen atom.

3. The compound according to Claim 2, wherein X is an oxygen atom.

4. The compound according to Claim 3, wherein R1 is a substituted or unsubstituted acyl group.

5. The compound according to Claim 3, wherein R' is a substituted or unsubstituted alkyl group.

6. The compound of Claim 5, which is 1-benzyl-4-{4-[N-methoxymethyl-N-(2-pyrimidinyl)am- ino]benzylj-2,3-dioxopiperazine of the formula,

or a salt thereof.

7. The compound of Claim 5, which is 1-benzyl-4-f4-[N-ethoxymethyl-N-(2-pyrimidinyl)ami- nojbenzyl) -2, 3-dioxopiperazine of the formula,

or a salt thereof.

8. A process for producing a compound represented by the formula,

wherein R1 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R2 represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof, which comprises (A] reacting 1-benzyl-4-[4-(2- pyrimidinylamino)benzyl]-2,3-dioxopiperazine or a reactive derivative thereof with a compound represented by the formula,

wherein Y represents a reactive group, and R1, R2 and X have the same meanings as defined above; or [B] reacting a compound represented by the formula,

wherein R4 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl group; and R2 has the same meaning as defined above, with a compound represented by the formula: H-X-R3 wherein R3 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl group; and X has the same meaning as defined above.

9. A process according to Claim 8, which comprises reacting 1-benzyl-4-[4-(2-pyrimidinylam ino)benzyl]-2,3-dioxopiperazine or a reactive derivative thereof, with a compound represented by the formula,

wherein R', R2, X and Y have the same meanings as defined in Claim 8.

1 0. A process according to Claim 8, wherein a compound represented by the formula,

wherein R2, R3 and X have the same meanings as defined in Claim 8, is produced by reacting a compound represented by the formula,

wherein R2 and R4 have the same meanings as defined in Claim 8, with a compound represented by the formula, H-X-R3 wherein R3 and X have the same meanings as defined in Claim 8.

11. A carcinostatic agent comprising a compound represented by the formula,

wherein R1 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R2 represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof.

12. A carcinostatic agent and/or a process of producing a carcinostatic agent substantially as described in any one of the specific examptes hereinbefore set forth.