KR880001105B1 - Process for preparing 1-benzil-4-(4-(2-pyrimidinylamino)benjil)-2,3-dioxopiperajine derivatives - Google Patents

Abstract

The title compd. of formula (I) or its salt is prepd. by reacing, 1,1-benzyl-4-[4-(2-pyrimidinyl amino) benzyl -2,3-dioxopiperazine or its reactive deriv. With (II). In the formula, R1=C1-8 alkyl, phenyl or C1-8 acyl gp.; R2=H; X=O or S; Y=activated gp. The novel compd. is useful as an anti-cancer medicine.

Description

Method for preparing 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin derivative

The present invention provides a novel 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3 dioxopiperazine derivative of the following general formula (I) useful as an anticancer agent and salts thereof It is about a method.

Wherein R ¹ is a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R ² is a hydrogen atom or an alkyl group; X is an oxygen or sulfur atom.

The compounds of the present invention are useful as pharmaceuticals and intermediates because of their excellent anticancer activity and low toxicity. It is an object of the present invention to provide a process for preparing the novel 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin derivatives and salts thereof.

Another object of the present invention is a novel 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopipepe which has anticancer activity, low toxicity, and is well absorbed. It is to provide a method for producing a razine derivative and salts thereof.

Another object of the present invention is to provide an anticancer agent containing the novel 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin derivative or a salt thereof. .

Other objects and advantages of the present invention will become apparent from the following description.

In general formula (I), R <^1> is alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; Cycloalkyl groups such as cyclopentyl and cyclohexyl; Aralkyl groups such as benzyl and phenethyl; Alkenyl groups such as vinyl and allyl; Alkadienyl groups, such as 1, 3- butadienyl, 2, 4- hexadienyl, geranyl; Aryl groups such as phenyl and naphthyl; Acyl groups such as acetyl, propionyl, butyryl, pivaloyl, stearoyl, benzoyl, furoyl, tenoyl, pyridylcarbonyl and cyclohexylcarbonyl.

R ¹ mentioned above is a halogen atom such as fluorine, chlorine, bromine or iodine; Hydroxyl group; Carboxyl group; Alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl; Aralkoxycarbonyl groups, such as benzyloxycarbonyl; Aryloxycarbonyl groups such as phenoxycarbonyl; Alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl; Alkenyl groups such as vinyl and allyl; Aralkyl groups such as benzyl and phenethyl; Cycloalkyl groups such as cyclopentyl and cyclohexyl; Cyano group; Mercapto group; Alkylthio groups such as methylthio and ethylthio; Nitro group; Oxo group; Acylamino groups such as acetamido; Alkoxy groups, such as methoxy and ethoxy; Aralkoxy groups, such as benzyloxy; Acyl groups such as propyl, acetyl, propionyl, butyryl and benzoyl; Amino group; Alkylamino groups such as methyl amino, ethylamino, hydroxyethylamino and propylamino; Arylamino groups such as dialkylamino groups such as dimethyl amino, diethylamino, bis (hydroxyethyl) amino and dipropylamino, and anilino; Aralkylamino groups such as benzylamino and phenethyl amino; Heterocyclic groups such as pyridyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazinyl, oxazolyl, furyl, thienyl, pyrrolyl and pyridazinyl; Or a heterocyclic amino group such as pyridylamino, pyrimidinyl amino, or the like.

R ² is a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, butyl, octyl or the like.

In the production of salts of the compounds of general formula (I), any acid or base may be used that produces pharmaceutically harmless salts. Inorganic or organic acid addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, P-roluenesulfonic acid, etc. and inorganic or organic with potassium, sodium, calcium, ammonium, pyridine, collidine, triethylamine, triethanolamine, procaine, etc. Basic salts are particularly preferred. Hydrates of compounds of formula (I) and salts thereof are also included in the present invention.

The anticancer activity and acute toxicity of the representative compounds of the present invention are explained as follows.

a. Minimum Inhibitory Concentration (MIC) for Hela S3 Cells and Ehtlich Cells

Using a microplate with 8 × 12 holes, 0.1 ml of medium (Eagles MEM + 20% calf serum) containing test drug and 0.1 ml of cell-suspension medium (2 × 10 ⁴ cells / ml) Applied to the hole. Continuous 2-fold dilutions (12 steps) ensure the concentration of the test drug is at most 100 μg / ml and at least 0.05 μg / ml. The medium containing the test drug is sterile filtered. After culturing the cells for 4 days, the cells are separated from the medium, washed twice with Hank's salt solution, fixed for 5 minutes with 95% ethanol, and stained for 15 minutes with Giemsa solution. Visually inspect cell growth inhibition. The results are shown in Table 1 below.

TABLE 1

b. Effect on L-1210 Leukemia

L-1210 cells (1 × 10 ⁵ cells / head) were inoculated intravenously into BDF ₁ -crab mice (male, 7 weeks old, 5 in each group), and 24 hours later, test drug was injected for 1 day. Continue oral administration once daily for 7 days. The effect is determined by the mean survival date.

The test drug is used in the form of a solution or suspension in saline or 0.3% carboxymethyl cellulose-containing saline.

Cool T / C from the following equation.

The results are shown in Table 2.

TABLE 2

C. Acute Toxicity

Each test drug is orally administered to ICR-based mice (male, 7 weeks old, and 5 horses each group), and the mice are observed for 7 days.

The test drug is used in the form of a solution or suspension in saline or 0.35% carboxymethyl cellulose-containing saline.

The results are shown in Table 3 below.

TABLE 3

As can be seen from the test results, the compound of the present invention is easily absorbed upon oral administration in vivo, and shows excellent anticancer activity, and its toxicity is low. Therefore, the compounds of the present invention are very useful as anticancer agents.

Recipe (1)

1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine or a reactive derivative thereof is reacted with a compound of the following general formula (II).

Wherein R ¹ is a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R ² is a hydrogen atom or an alkyl group; X is oxygen or sulfur atom; Y is a reactive group.

Recipe (2)

Next, 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin derivative of formula (iII) is reacted with a compound of formula (IV).

Wherein R ² and X are as defined above; R ³ and R ⁴ are substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl groups.

In each preparation, R ¹ , R ² and X have the same meanings as described above, in which R ³ and R ⁴ of formulas (III) and (IV) have the same alkyl, cycloalkyl, aralkyl as for R ¹ , Alkenyl, alkadienyl and aryl groups, and R ³ and R ⁴ may be substituted with the same substituents as the substituents mentioned for R ¹ . As a reactive group represented by Y of general formula (II), Halogen atoms, such as chlorine, bromine, iodine; Arylsulfonyloxy groups such as phenylsulfonyloxy and P-toluenesulfonyloxy; Alkylsulfonyloxy groups, such as methane sulfonyloxy and ethane sulfonyloxy, are mentioned.

, (CH₃)₂[(CH₃)₂CH]Si-, (CH₃O)₃Si-, CH₃(CH₃O)Si-, (CH₃)₂(CH₃O)Si-등의 유기실릴그룹 ; 또는 (CH₃O)₂P-, (C₂H₅O)₂ In each of the above preparations, the reactive derivatives of 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine include alkali metal atoms such as lithium, sodium and potassium. ; (CH ₃ ) ₃ Si-,

, (CH ₃ ) ₂ [(CH ₃ ) ₂ CH] Si-, (CH ₃ O) ₃ Si-, CH ₃ (CH ₃ O) Si-, (CH ₃ ) ₂ (CH ₃ O) Si- Organosilyl group; Or (CH ₃ O) ₂ P-, (C ₂ H ₅ O) ₂

And compounds formed by bonding an organophosphorus group such as to a> NH group. These reactive derivatives can be easily formed by conventional methods and can be used for the next reaction without separation.

1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine and the compound of the following general formula (III) used in the above-mentioned preparation method are represented by the following scheme and preparation method ( Easily obtained according to 1):

Wherein DMF represents N, N-dimethylformamide; AcNH- represents CH ₃ CONH-; R ¹ , R ² , R ⁴ and Y are as described above.

Each manufacturing method is explained concretely as follows. Preparation (1) is carried out in the presence or absence of a solvent which is inert to the reaction. As a solvent used, For example, ether, such as tetrahydrofuran, diethyl ether, dimethoxy ethyl ether, dimethoxyethane, dioxane; Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; Amides such as dimethylformamide and dimethyl acetamide; Nitriles such as acetonitrile and propionitrile; Aromatic hydrocarbons such as benzene, toluene and xylene; Nitroalkanes such as nitromethane and nitroethane; Tertiary amines such as pyridine and quinoline; Sulfoxides such as dimethyl sulfoxide; Phosphoric acid amide, such as hexamethyl phosphate amide, is mentioned. The solvent may also be used in a mixture of two or more.

The reaction temperature and reaction time are not critical but are preferably carried out at 0 to 150 ° C., in which case the reaction is usually completed within 5 minutes to 12 hours.

The compound of formula (II) is at least equimolar with respect to 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine, preferably 1.0 to 1 mole per mole. Use at 1.2 moles.

Preparation (2) is carried out in the presence or absence of a solvent which is inert to the reaction. As a solvent used for reaction, For example, ether, such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Nitroalkanes such as nitromethane and nitroethane; Nitriles such as acetonitrile and propionitrile; Amides such as dimethylformamide and dimethylacetamide; Halogenated hydrocarbons such as methylene chloride and chloroform; Fatty acids such as acetic acid and propionic acid. These solvents can also be used in mixtures of two or more. The reaction temperature and reaction time are not critical but are preferably carried out at 0 to 150 ° C., in which case the reaction is usually completed within 30 minutes to 24 hours.

The compound of formula (IV) may be used in an amount of at least equimolar to the compound of formula (III) to an amount in which the compound of formula (IV) serves as a solvent. Furthermore, as a catalyst, a protic acid of hydrochloric acid, hydrobromic acid, and sulfuric acid; Lewis acids, such as zinc chloride, aluminum chloride, tin chloride, titanium tetrachloride, and boron trifluoride, can be used.

After the preparation (1) or (2) is carried out as described above, the compound of formula (I) can be separated from the reaction mixture in a conventional manner, and purified by column chromatography, recrystallization or the like. Salts of the compound of general formula (I) are inorganic acids, such as hydrochloric acid, hydrobromic acid, a sulfuric acid, phosphoric acid; Organic acids such as P-toluenesulfonic acid and acetic acid; Inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, aqueous ammonia; The reaction may be carried out in a conventional manner using organic bases such as pyridine, collidine, triethylamine, triethanolamine, procaine and the like, and the product may be obtained by separation and purification. In the above-mentioned preparations, when the compounds of the general formulas (II), (III) and (IV) have an active group such as amino, hydroxyl, carbonyl or the like at the non-reactive site, the active group is converted into a known protecting group. Protection, and the process of the present invention can be carried out to obtain a compound having a protecting group, and a compound having a protecting group can be treated by a known method to remove the protecting group, thereby obtaining a compound having a free active group.

The compounds of the present invention obtained as described above are very useful as anticancer agents. Oral preparations such as tablets, syrups, capsules, powders, and granules; It may be formulated into various pharmaceutical forms such as injection preparations such as intramuscular injections, intravenous injections, and drop injections, and may be administered as anticancer agents. The route of administration, dose and frequency of administration are appropriately selected depending on the condition of the patient, but oral administration is preferred. Typically for adults, a total dose of 1 to 4000 mg / kg is administered 1-3 times daily.

The invention is further illustrated by the following examples, which are intended to illustrate the invention and are not intended to limit the invention.

Example 1

(1) Suspend 0.88 g of sodium hydride (purity 60%) in 23 ml of N, N-dimethylformamide (hereinafter referred to as DMF) and 4.5 g of 1-benzyl-2,3-dioxo in the resulting suspension. After piperazine was added, the resulting mixture was stirred at 80 ° C. for 10 minutes and then cooled to 65 ° C. 15 ml of DMF solution containing 4.0 g of 4-acetylaminobenzyl chloride was added dropwise thereto and reacted for 30 minutes at 60 to 65 ° C. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 ml of ethanol was added to the residue, and the precipitated crystals were collected by filtration. The crystals thus obtained are added to 60 ml of 2N hydrochloric acid, and the resulting solution is heated under reflux for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, 4.0 g of sodium hydrogen carbonate was added thereto, and the precipitated crystals were collected by filtration, dried, and then recrystallized from ethyl acetate to have a melting point of 193 to 194 ° C. 4.9 g (90% yield) of 1- (4-aminobenzyl) -4-benzyl-2,3-dioxopiperazin was obtained.

IR (KBr) cm ^-1 : ν _NH 3450, 3350 ν _{c = 0} 1660

Elemental Analysis for C ₁₈ H ₁₉ N ₃ O ₂ (%):

Calculated Value: C69.88, H6.19, N13.58

Found: C69.82, H6.26, N13.52

NMR (d ₆ -DMSO) ppm: 3.34 (4H, s, piperazine ring CH ₂ x 2), 4.38 (2H, s, CH ₂ x 1), 4.53 (2H, s, CH ₂ x 1), 4.99 ( 2H, s, NH ₂ × 1), 6.50 (2H, d, J = 9.0H _z , benzene ring H × 2), 6.93 (2H, d, J = 9.0H _z , benzene ring H × 2), 7.22 ( 5H, s, benzene ring H × 5)

(2) 1.3 g of 1- (4-aminobenzyl) -4-benzyl-2,3-dioxopiperazine was suspended in 3.9 ml of ethylene glycol and 0.57 g of 2-chloropyrimidine was stirred at 140 ° C. And to the resulting suspension. The resulting mixture is reacted for 30 minutes at 140 to 150 ° C. After the reaction is completed, the reaction mixture is cooled to 100 ° C. and 2.42 ml of water is added to the reaction mixture. After the resulting mixture was left to stand, 17 ml of water was added thereto, the resulting mixture was stirred, and the precipitated crystals were collected by filtration, dried, and recrystallized from ethanol to give 0.9 g (yield of 175 to 176 DEG C.) 75%) of 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin.

IR (KBr) cm ^-1 : ν _NH 3320 ν _{c = 0} 1670

Elemental Analysis for C ₂₂ H ₂₁ N ₅ O ₂ (%):

Calculated Value: C 68.20, H 5.46, N 18.08

Found: C 68.24, H 5.38, N 17.89

NMR (d ₆ -DMSO) ppm: 3.42 (4H, bs, piperazine ring CH ₂ x 2), 4.51 (2H, s, CH ₂ x 1), 4.54 (2H, s, CH ₂ x 1), 6.75 ( 1H, t, J = 4.5H _z , pyrimidine ring H × 1), 7.15 (2H, d, J = 8.5H _z , benzene ring H × 2), 7.25 (5H, s, benzene ring H × 5), 7.70 (2H, d, J = 8.5 _z , benzene ring H × 2), 8.40 (2H, d, J = 4.5H _z , pyrimidine ring H × 2), 9.68 (1H, s, NH × 1)

(3) 3 g of 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-di in 20 ml of DMF in a mixture of 372 mg of sodium hydride (50% purity) and 30 ml of DMF. After the solution of oxopiperazine is added dropwise with stirring over 30 minutes, the resulting mixture is allowed to react at 60 to 70 캜 for 1 hour. After the reaction was completed, 1.3 g of pivaloyloxymethyl chloride was added dropwise at the same temperature over 10 minutes. After completion of the dropwise addition, the resulting mixture is reacted at 70 to 80 ° C for 30 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure and the residue thus obtained is extracted with 100 mg of chloroform. The chloroform layer is washed sequentially with 30 ml of water and 40 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (wakogel C-200, eluted with chloroform) and then recrystallized from ethyl acetate-diisophoropyl ether to give 2.5 g (yield 64.3%) having a melting point of 144 to 146 ° C. 1-benzyl-4- {4- [N-pivaloyloxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine of.

IR (KBr) cm ^-1 : ν _{c = 0} 1725, 1670

Elemental Analysis for C ₂₈ H ₃₁ N ₅ O ₄ (%):

Calculated Value: C 67.05, H 6.23, N 13.96

Found: C 66.99, H 6.23, N 13.85

NMR (CDCl ₃ ) ppm: 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 = 5.0 Hz, pyrimidine ring H × 1), 7.23 (4H, s, benzene ring H × 4), 7.25 (5H, s, benzene ring H × 5), 8.33 (2H, d, J = 5.0 Hz, pyrimidine ring H × 2)

Example 2

1 g of 1-benzyl-4- {4- [N-pivaloyloxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine was dissolved in 30 ml of ethyl acetate. , 1 g glycolic acid and 0.02 ml of 1N hydrogen chloride ethanol solution are added, and the resulting mixture is reacted with stirring for 3 hours at room temperature. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue thus obtained is extracted with 100 ml of methylene chloride. The methylene chloride layer is washed with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (wakogel C-200, eluted with chloroform-ethanol) and recrystallized from ethyl acetate-diisophoropropyl ether to give 0.5 g (yield 52.8%) having a melting point of 85 to 90 占 폚. 1-benzyl-4- {4- [N-carboxymethoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazin is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1735, 1665

Elemental Analysis for C ₂₅ H ₂₅ N ₅ O ₅ (%):

Calculated Value: C 63.15, H 5.30, N 14.73

Found: C 63.22, H 5.38, N 14.62

NMR (CDCl ₃ ) ppm: 3.40 (4H, s, piperazine ring CH ₂ x 2), 4.17 (2H, s, CH ₂ x 1), 4.63 (4H, s, CH ₂ x 2), 5.25 (2H, s, CH ₂ x 1), 6.75 (1H, t, J = 5.0 Hz, pyrimidine ring H × 1), 7.22 (5H, s, benzene ring H × 5), 7.28 (4H, s, benzene ring H × 4), 8.34 (2H, d, J = 5.0 Hz, pyrimidine ring H × 2), 9.82 (1H, bs, carboxylic acid H × 1)

Example 3

To 10 ml of ethyl mercaptan, 1.0 g of 1-benzyl-4- {4- [N-pivaloyloxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazin After dissolving and adding 0.01 ml of 5.7N hydrogen chloride dioxane solution dropwise, the resulting mixture is reacted at room temperature for 3 hours. After the reaction is completed, the solvent is removed under reduced pressure, 50 ml of diisopropyl ether is added to the obtained crystals, and the resulting crystals are filtered off. The obtained crystals were recrystallized from isopropyl alcohol to yield 0.8 g (yield 86.8%) of white crystalline 1-benzyl-4- {4- [N-ethylthiomethyl-N- (2-pyrimidy) having a melting point of 144 ° C. Nil) amino] benzyl} -2,3-dioxopiperazine is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1670

Elemental Analysis for C ₂₅ H ₂₇ N ₅ O ₂ S ₁ (%):

Calculated Value: C 65.05, H 5.89, N 15.17

Found: C 65.02, H 5.84, N 15.12

NMR (CDCl ₃ ) ppm: 1.14 (3H, t, CH ₃ x 1), 2.53 (2H, q, CH ₂ x 1), 3.39 (4H, s, piperazine ring CH ₂ x 2), 4.62 (4H, s, CH ₂ x 2), 5.15 (2H, s, CH ₂ x 1), 6.57 (1H, t, pyrimidine ring H × 1), 7.23 to 7.27 (9H, m, benzene ring H × 9), 8.25 (2H, d, pyrimidine ring H × 2)

According to the above method, the following compounds are obtained:

1-benzyl-4- {4- [N-phenylthiomethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine Melting Point: 64 to 65 ° C. (recrystallized from isopropyl alcohol) anger)

IR (KBr) cm ^-1 : ν _{c = 0} 1670

Elemental Analysis for C ₂₉ H ₂₇ N ₅ O ₂ S ₁ (%):

Calculated Value: C 68.34, H 5.34, N 13.74

Found: C 68.36, H 5.32, N 13.71

NMR (CDCl ₃ ) ppm: 3.33 (4H, s, piperazine ring CH ₂ x 2), 4.61 (2H, s, CH ₂ x 1), 4.65 (2H, s, CH ₂ x 1), 5.50 (2H, s, CH ₂ x 1), 6.60 (1H, t, pipemidine ring H × 1), 6.98 to 7.28 (14H, m, benzene ring H × 14), 8.30 (2H, d, pyrimidine ring H × 2 )

Example 4

Dissolve 3.0 g of 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin in 40 ml of DMF, followed by 0.372 g of sodium hydride (52% purity). ) Is added and the resulting mixture is reacted at 80 ° C. for 30 minutes with stirring. The reaction mixture is cooled and 0.72 ml of chloromethylsulfide are added thereto, and the resulting mixture is reacted at 50 to 60 ° C. for 2 hours. After the reaction is completed, the reaction mixture is distilled under reduced pressure, and the obtained residue is extracted with chloroform and washed with water.

The resulting solution is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The obtained crystals were recrystallized from isophorofill alcohol to obtain 3.0 g (yield 86.45%) of white crystalline 1-benzyl-4- {4- [N-methylthiomethyl-N- (2-pyri) having a melting point of 156 占 폚. Midinyl) amino] benzyl} -2,3-dioxopiperazine is obtained.

IR (KBr) cm ^-1 : ν _{c = 0} 1670

Elemental Analysis for C ₂₄ H ₂₅ N ₅ O ₂ S ₁ (%):

Calculated Value: C 64.41, H 5.63, N 15.65

Found: C 64.38, H 5.61, N 15.60

NMR (CDCl ₃ ) ppm: 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 x 1), 6.58 (1H, t, pyrimidine ring H × 1), 7.10 to 7.35 (9H, m, benzene ring H × 9), 8.26 (2H, d, pyrimidine ring H × 2)

According to the above method, the following compounds are obtained.

1-benzyl-4- {4- [N-isopropylthiomethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine Melting Point: 135 ° C. (recrystallized from isopropyl alcohol) )

IR (KBr) cm ^-1 : ν _{c = 0} 1670

Elemental Analysis for C ₂₆ H ₂₉ N ₅ O ₂ S ₁ (%):

Calculated Value: C 65.66, H 6.14, N 14.72

Found: C 65.64, H 6.12, N 14.68

NMR (CDCl ₃ ) ppm: 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 x 2), 5.16 (2H, s, CH ₂ x 1), 6.56 (1H, t, pyrimidine ring H × 1), 7.22 to 7.27 (9H, m, benzene ring H × 9), 8.26 ( 2H, d, pyrimidine ring H × 2)

Example 5

According to Examples 1 and 2, the starting dust is selected to afford the compounds shown in Table 3.

Note: (1) In Table 3, IPA represents isopropyl alcohol, IPE represents diisopropyl ether, AcOEt represents ethyl acetate, and Et ₂ O represents diethyl ether.

(2) In the "Preparation" column, the number (1) or (2) means the number of the recipe described in the specification, the compound mentioned in the line marked "Preparation" number, the method of the embodiment described above with respect to the recipe Are synthesized in the same manner as or in accordance with the methods described in the specification based on the examples.

(3) In the "recrystallization solvent" column, the term "column" means the purification of the product by column chromatography.

TABLE 3

Preparation Example 1

100 mg of 1-benzyl-4- {4- [N-methoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine, 50 mg lactose, 48 mg per capsule This corn starch and 2 mg of magnesium stearate are mixed and then filled into capsules to prepare a capsule.

Preparation Example 2

Per tablet, 250 mg of 1-benzyl-4- {4- [N-ethoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine, 50 mg lactose, 38 mg Corn starch, 10 mg polyvinyl pyrrolidone and 2 mg magnesium stearate are mixed and the resulting mixture is compressed in a conventional manner to prepare tablets.

Claims (11)

Characterized in that 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazin or a reactive derivative thereof is reacted with a compound of formula (II) A process for preparing the compound of formula (I) or a salt thereof.

Wherein R ¹ is C _1-8 alkyl, phenyl or C _1-18 which may be substituted by at least one substituent selected from the group consisting of carboxyl, hydroxyl and bis (hydroxy-C _1-8 alkyl) amino An alkylacyl group: R ² is a hydrogen atom; X is an oxygen or sulfur atom: Y is a reactive group. A process for preparing a compound of formula (V) or a salt thereof, characterized by reacting a compound of formula (III) with a compound of formula (IV)

Wherein R ³ is a C _1-8 alkyl, phenyl group which may be substituted by at least one substituent selected from the group consisting of carboxyl, hydroxyl and bis (hydroxy-C _1-8 alkyl) amino: R ² Is a hydrogen atom; X is an oxygen or sulfur atom: R ⁴ is a C _1-8 alkyl group. The method of claim 1 wherein X is an oxygen atom. The method of claim 3, wherein R ¹ is a C _1-18 acyl group. The method of claim 3, wherein R ¹ is a C _1-8 alkyl group which may be substituted by at least one substituent selected from the group consisting of carboxyl, hydroxyl and bis (hydroxy-C _1-8 alkyl) amino. The compound according to claim 5, wherein 1-benzyl-4- {4- [N-methoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine or a salt thereof How to prepare.

The compound according to claim 5, wherein 1-benzyl-4- {4- [N-ethoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine or a salt thereof How to prepare.

The method of claim 2 wherein X is an oxygen atom. The method of claim 2, wherein R ³ is a C _1-8 alkyl group which may be substituted by at least one substituent selected from the group consisting of carboxyl, hydroxyl and bis (hydroxy-C _1-8 alkyl) amino. 10. The compound of claim 9, wherein 1-benzyl-4- {4- [N-methoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine or a salt thereof How to prepare.

The compound according to claim 9, wherein 1-benzyl-4- {4- [N-ethoxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazin or a salt thereof How to prepare.