NL8200451A - 1-BENZYL-4-4- (2-PYRIMIDINYLAMINO) BENZYL-2,3-DIOXOPIPERAZINE DERIVATIVES, SALTS AND METHODS FOR PREPARING THESE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

* 1-benzyl-4 - / - - - (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine derivatives, salts thereof and processes for the preparation of these derivatives and pharmaceutical preparations containing them.

The invention relates to new 1-benzy 2-pyrimi-dinylamino} -benzyl-2,3-dioxopiperazine derivatives and salts thereof and to processes for the preparation of these derivatives and of pharmaceutical preparations having a carcinostatic action containing them.

The compounds according to the invention have an excellent carcinostatic effect, a low toxicity per se and are useful as medicines and also as intermediates.

An object of this invention is to provide new 1-benzyl-2-i + - (2-pyrimidinylamino) benzyl-2,3-dioxopiperaz inederivative and salts thereof.

Another object of this invention is to provide novel 1-benzyl-k- / H- (2-pyrimidinylamino) benzyl-7-15 2,3-dioxopiperazine derivatives with carcinostatic activity and low toxicity, as well as their salts.

Yet another goal. of this invention is to provide novel 1-benzyl - ^ - / - ^ - (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine derivatives and their salts which are orally well absorbed.

Yet another object of this invention is to provide a process for the preparation of new 1-benzyl-1-k- (2-pyrimidinylamino) benzyl-7, 2,3-dioxopiperazine derivatives and their salts.

Finally, yet another object of this invention is to provide a careinostatic agent containing new 1-benzyl-h - / - * - {2-pyrimidinylamino) benzyl7-2,3-dioxopiperaz inederi and, and / or the salts of which contains.

Other objects and advantages of this invention will be explained in the following description.

8200451. i - 2 -

According to the invention, new 1-benzyl-H - / "* U- (2-pyrimidinylamino) benzyl-7, 2,3-dioxopiperazine derivatives of the formula 1, or a salt thereof, are provided in which R is an unsubstituted or substituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group, Rg represents a hydrogen atom or an alkyl group and X represents an oxygen or sulfur atom.

In this formula 1, an alkyl group such as a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group, or a corresponding group, is a cycloalkyl group, such as a cyclopentyl or cyclohexyl group, or a corresponding group, an aralkyl group, such as a benzyl or phenethyl group, or a corresponding group, an alkenyl group, such as a vinyl or allyl group, or a corresponding group, an alkadienyl group, such as a 1,3-butadienyl, 2,2U- hexadienyl-15 or geranyl group, or a corresponding group, an aryl group, such as a phenyl or naphthyl group, or a corresponding group, or an acyl group, such as an acetyl, propionyl, butyryl, pivaloyl, stearoyl, benzoyl, furoyl, thenoyl, pyridyl carbonyl or cyclohexyl carbonyl group, or a corresponding group.

The aforementioned substituent R 4 may be substituted by at least one substituent selected from the group consisting of halogen atoms, such as fluorine, chlorine, bromine, iodine, etc., the hydroxyl group, carboxyl group, alkoxycarbonyl groups, such as the methoxycarbonyl and ethoxycarbonyl group, etc. aralkoxycarbonyl groups, such as benzyloxycarbonyl, etc., aryloxy-carbonyl groups, such as phenoxycarbonyl, etc., alkyl groups, such as methyl, ethyl, propyl, isopropyl, outyl, etc., alkenyl groups, such as vinyl, allyl, etc., aralkyl groups, such as benzyl, phenethyl, etc. , cycloalkyl groups, such as cyclopentyl, cyclohexyl, etc., the cyano group, mercapto group, alkylthio groups, such as methylthio, ethylthio etc., the nitro group, oxo group, acylamino groups, such as acetamido, etc., alkoxy groups, such as benzyloxy, etc. ., acyl groups, such as formyl, acetyl, propionyl, butyryl, benzoyl, etc., the amino group, 8200451 * -3-alkylamino groups, such as methylamino, ethylamino h ydroxyethyl-amino, propylamino etc., dialkylamino groups, such as dimethyl amino, diethylamino, bis (hydroxyethyl) amino, dipropylamino etc., arylamino groups, such as anilino etc., aralkylamino groups, such as benzylamino, phenethylamino etc., heterocyclic groups such as pyridyl, pyrimid , imidazolyl, thiazolyl, pyrazinyl, oxazolyl, furyl, thienyl, pyrrolyl, pyridazinyl etc. and heterocyclic amino groups such as pyridylamino, pyrimidinylamino etc. and corresponding compounds.

10 represents a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, butyl, octyl, etc.

Any acid or base can be used for the preparation of salts of the compounds of formula 1, as long as the resulting salts are pharmaceutically acceptable, although inorganic and organic salts, such as with hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, p-toluenesulfonic acid etc. and inorganic and organic salts such as salts with potassium, sodium, calcium, ammonium, pyridine, collidine, triethylamine, triethanolamine, procaine etc. are particularly recommended. Hydrates of the compounds of formula 1 and hydrates of salts of the compounds of formula 1 are also included in this invention.

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

a) The minimum concentration with an inhibitory activity (MIC) against HeLa S3 cells and Ehrlich cells.

A microplate of 8 x 12 containers was used, with 0.1 ml of a culture fluid (Eagles MEM + 20% calf serum / containing a drug to be tested and 0.1 ml of a culture fluid in which cells were suspended (2x10 ^) were added to each chamber. cell / ml).

The concentration of the investigational drug was at most 100 µg / ml and at least 0.05 µg / ml, with a series of 35 two-fold dilutions (12 steps). The culture fluid containing 8200451 V ♦ - It - the drug to be tested was filtered sterile. The cells were grown for k days, after which the cells were separated from the culture fluid, washed twice with a solution of Hank's salt, then fixed for 5 min with 95 # 's ethanol and then stained with a 15 min.

Giemsa solution. Cell growth inhibition was assessed with the naked eye. The results obtained are shown in Table A.

Table A

no. Compound of formula MIC (fs / ™ 1)

HeLa Ehrlich 1 k 0.39 0.39 2 5 1.56 1.56 3 6 0.39 0.39 15 U 7 1.56 3.13 5 8 3.13 3.13 6 9 0.39 0, 78 7 10 3.13 6.25 8 11 12.5 12.5 20 b) Effect on L-1210 leukemia.

L-1210 cells (1x10 ^ cell ley / cup) were inoculated intravenously onto mice of the BDF ^ strain (males, 7 weeks old, each group consisting of 5 mice) and after 2b hours, the drugs to be tested were once daily 25 Orally administered for 7 consecutive days. The effect of this was assessed on the basis of the average number of survival days.

The drugs to be tested were used in the form of a solution or suspension in a salt solution or a 0.3 # 's carboxymethyl cellulose containing saline. The ratio T / C was calculated with the following equation: 8200451 - 5 - the mean number of survival days in the group to which the drug under investigation was administered T / C = x 100 ($) the average number of survival days in the control group

The results obtained are shown in Table B. Table B

compound no. dose (mg / kg / day) T / C (%) 1 50 135 100 162 2 110 120 220 237 k 110 177 220 289 5 65 140 130 177 T 120 118 2k0 177 c) acute toxicity.

Each of the drugs to be tested was administered orally once to mice of the ICR strain (males, 7 weeks old, each group consisting of 5 mice), after which the mice were absorbed for 7 days.

The drugs to be tested were used in the form of a solution or suspension in a saline or saline solution containing 0.3% carboxymethyl cellulose,

The results obtained are shown in Table C.

8200451 »- 6 -

Table C

compound no. LD ^ Q (mg / kg) 1> 2000 2> 2000 5 b> 2000 5> 2000 7> 2000

As can be seen from the above results, the compounds of the invention have such excellent properties as they are well absorbed by a living organism when administered orally, have excellent carcinostatic properties and have low toxicity. They are therefore very useful as carcinostatic agents.

The compounds of the invention of the formula I and the salts thereof can be obtained according to the methods (1) and (2) described below.

Method (1).

This process involves the reaction of 1-benzyl-lt-20 / -1 * - (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine or a reactive derivative thereof with a compound of formula 2, wherein an unsubstituted or substituted alkyl- , cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group, Rg represents a hydrogen atom or an alkyl group, X represents an oxygen atom or a sulfur atom and Y represents a reactive group.

Method (2).

This process comprises the reaction of a 1-benzyl-1 + - / "U- (2-pyrimidinylamino) benzyl-7, 2,3-dioxopiperazine derivative of formula 3, wherein Rg has the same meaning as given above and R8 is a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group, with a compound of formula HXR ^ wherein X has the meaning previously defined and R ^ represents an unsubstituted or substituted 8200451-7 alkyl, cycloalkyl , aralkyl, alkenyl, alkadienyl or aryl group.

In each of these processes, Rg and X have the same meanings as defined above and 5 and R ^ in formulas 3 and HXR ^ include the same alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl and aryl groups listed for R ^, while R 2 and R 2 may be substituted by the same substituents as stated for R 2, As the reactive group for Y in formula 2, halogen atoms such as chlorine, bromine, iodine, etc., arylsulfonyloxy groups such as phenylsulfonyloxy, p-toluene-sulfonyloxy etc. and alkylsulfonyloxy groups such as methanesulfonyloxy, ethylene sulfonyloxy, etc. are mentioned.

In any of the aforementioned preparation methods, the reactive derivatives of 1-benzyl-W "4-15 (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine compounds formed by bonding an alkali metal atom, such as lithium, sodium, potassium, etc., an organic silyl group such as (CH ^ Si-, (CH ^ Si ^, (CH ^ rtCH ^ CHZsi-, (CH ^ Si-, CH ^ iCH ^ O ^ Si-, (03 ^) 2 (0 ^ 0) 81-, etc. or an organic phosphorus-20 group, such as (CH-OjgF-, (CglLOjgP-, r0ss Γ ° Ν P-, P-, / P- etc.), to the> NH group.

Lo 'CH ^ O ^ Vo' '

These reactive derivatives can be easily synthesized by a conventional method and can be subjected to the subsequent reaction without separation.

The 1-benzyl - - - - * - (2-pyrimidinylamino) benzyl-7,2,3-dioxopiperazine and the compounds represented by the formula 3 used in the above-described preparation methods can easily be used according to the reaction scheme shown on the formula sheet 30 and according to method (1) are obtained. In this reaction scheme, DMF: N denotes 3-dimethylformamide and AcNH-: CH 2 CONH- and the substituents R 1, R 8, R 1, and Y have the previously defined meanings.

Embodiments of each preparation method are given below.

8200451 * * - 8 -

Process (1) is carried out in the presence or absence of a solvent which is inert in the reaction. Examples of solvents used in the reaction are: ethers, such as tetrahydrofuran, diethyl ether, dimethoxyethyl-5 ether, dimethoxyethane, dioxane, etc., halogenated hydrocarbons, such as methylene chloride, chloroform, 1,2-dichloroethane, etc., amides, such as dimethylformamide, dimethylacetamide etc, nitriles, such as acetonitrile, propionitrile, etc., aromatic hydrocarbons, such as benzene, toluene, xylene, etc., nitroalkanes, such as nitro-10 methane, nitroethane, etc., tertiary amines, such as pyridine, quinoline, etc., sulfoxides, such as dimethyl sulfoxide etc., and phosphoramides, such as hexamethylphosphoric amide, etc. The aforementioned solvents may also be a mixture of two or more solvents.

The reaction temperature and reaction time are not critical, although the reaction is preferably carried out at a temperature between 0 and 150 ° C, in which case the reaction will usually be completed between 5 minutes and 12 hours.

The compounds represented by formula II are used in an amount which is at least equimolar to, preferably between 1.0 and 1.2 mole per mole, 1-benzyl-U- / h- (2-pyrimidinylamino) benzyl7- 2,3-dioxopiperazine.

Process (2) is also carried out in the presence or absence of a solvent which is inert in the reaction. Examples of solvents used in the reaction are: ethers such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane etc., aromatic hydrocarbons such as benzene, toluene, xylene etc., nitroalkanes such as nitromethane, nitroethane etc., nitriles such as acetonitrile, propionitrile etc. .30 amides, such as dimethylformamide, dimethylacetamide, etc., halogenated hydrocarbons, such as methylene chloride, chloroform, etc., and fatty acids, such as acetic acid, propionic acid, etc.

These solvents can also be a mixture of 2 or more solvents. The reaction temperature and the reaction time are again not critical, although the reaction is preferably carried out at a temperature between 0 and 150 ° C, in which case the reaction is usually completed between 30 minutes and 2 hours.

The compounds represented by formula H-X-R ^ are usually used in an amount at least equimolar to the compound represented by formula 3, in that the compound of formula H-X-R ^ can also function as a solvent. In addition, as the catalyst, protonic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, etc., and Lewis acids, such as zinc chloride, aluminum chloride, tin chloride, titanium tetrachloride, boron trifluoride, etc., can be used.

After the above-described processes (1) or (2) have been carried out in the manner outlined above, the compound of formula 1 can be separated from the reaction mixture by a conventional method and purified by methods such as column chromatography, recrystallization, etc. . A salt of the compound of formula 1 can be obtained by the reaction according to a conventional method using an inorganic acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, etc., an organic acid such as p-toluenesulfonic acid, acetic acid etc. ., an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and ammonia etc. or an organic base such as pyridine, collidine, triethylamine, triethanolamine, procaine etc. and then separating the reaction product and purify. In the preparation methods described above, if the compounds of formulas 2, 3 and HXR 2 have an active group, such as amino, hydroxyl, carboxyl, etc., on the non-reactive side, compounds with a protecting group can be obtained by the active protecting a group with a known protecting group and then carrying out the method according to the invention. A compound with a free active group can be obtained by treating the compound with a protecting group according to a known 8200451-10 method to cleave the protecting group.

The compounds of the invention, which can be obtained in the manner described above, are very useful as a carcinostatic agent. Suitably, pharmaceutically acceptable additives are added to the compounds and the resulting mixture can be processed into various drug forms, such as oral preparations, for example, tablets, syrups, capsules, powders, granules, etc., and injectable preparations, for example, for intramuscular injection, intra venous injection, drip, etc., and then administered as a carcinostatic agent. The mode of administration, the dose and the number of administrations are chosen and depend on the condition of the patient, although oral administration is preferred. Generally, in adults, the compound will be administered 1 to 3 times a day in a total dose of 1,000 mg / kg daily.

Example I

(1) 0.88 g of sodium hydride (purity 60%) was suspended in 23 ml of N, N-dimethyl-20 formamide (hereinafter referred to as DMF) and H, 5 g of 1-benzyl-2 was added to the resulting suspension. , 3-dioxopiperazine, after which the resulting mixture was stirred at 80 ° C for 10 min and then cooled to 65 ° C. 15 ml of a DMF solution containing 0.0 g of H-acetylaminobenzyl chloride was dropped into this mixture and the resulting mixture was allowed to react for 30 min at 60-65 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure and 20 ml of ethanol were added to the residue, after which the precipitated crystals were filtered off. 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 0.0 g of sodium hydrogen carbonate was added thereto, the precipitated crystals were filtered off, dried and then recrystallized from 8200451-11 - from ethyl acetate. There were thus obtained 4.9 g (90%) of 1- (4-amino-benzyl) -4-benzyl-2,3-dioxopiperazine having a melting point of (193-194 ° C).

IR (KBr) cm 1: 3450, 3350 5 uc = 0 1660

Elemental Analysis (for C 12 g H N N Og) calculated C 69.88 Jf; H 6.19% i N 13.58% found C 69.82% \ H 6.26% \ N 13.52% NMR (dg-DMSO) ppm values: 10 3.34 (4H, s, piperazine ring CHg x 2), 4.38 (2H, s, 0¾ x 1), 4.53 (2H, s, CH2 x 1), 4.99 (2H, s, UHg x 1), 6.50 (2H, d, J = 9.0 Hz, benzene ring H x 2), 6.93 (2H, d, J “9.0 Hz, benzene ring H x 2), 7.22 (5H, s, benzene ring H x 5) 15 (2) 1.3 g of 1- (4-aminobenzyl) -4- * benzyl-2,3-dioxopiperazine were suspended in 3.9 ml of ethylene glycol and 0.57 g of 2-chloropyrimidine was added to the resulting suspension under stirring and at 140 ° C to. The resulting mixture was then allowed to react at 140-150 ° C for 30 min. At the end of the reaction, the reaction mixture was cooled to 100 ° C and 2.42 ml of water was added to the reaction mixture. After the resulting mixture was allowed to stand, 17 ml of water was again added and the resulting mixture was stirred, after which the precipitated crystals were filtered, dried and then recrystallized from ethanol. There was thus obtained 0.9 g (75% yield) of 1-benzyl-4- / 4- (2-pyrimidinylamino) benzyl-7, 2,3-dioxopiperazine, m.p. 175-176 ° C.

IR (KBr) cm "1: υ ^ Η 3320 υο = ο 1 ^ ° 30 Elemental analysis for ^ 22 ^ 21 ^ 5 ^ 2 ^ calculated: C 68.20% \ H 5.46% \ N 18.08% found : C 68.24 H 5.38% \ N 17.89% NMR (dg-DMSO) ppm values: 3.42 (4h, bs, piperazination C 1 x 2), 35 '4.51 (2H, s, x 1), 4.54 (2H, s, 0¾ x 1), 8200451 - 12 - 6.75 (1H, t, J = 1 +, 5Hz, pyrimidine ring Hx 1), 7.15 (2H, d, J = 8.5 Hz, benzene ring Hx 2), 7.25 (5H, s, benzene ring H x 5), 7.70 (2H, d, J = 8.5Hz, benzene ring H x 2), 5 8.1 + 0 (2Η, d, J = 1 +, 5 Hz, pyrimidine ring H x 2), 9.68 (1 Η, s, NH x 1) (3) It was added dropwise with stirring and for 30 min to a mixture of 372 mg sodium hydride (purity 50%) and 30 ml of DMF add a solution of 3 g of 1-benzyl-1 + - / 1 + - (2-10 pyrimidinylamino) benzyl7-2,3-dioxopiperazine in 20 ml of DMF and the resulting mixture is stirred for an hour reacted at a temperature between 60 and 70 ° C. After completion of the reaction, 1.3 g of pivaloyloxymethyl chloride were added dropwise for 10 minutes and at the same temperature. The resulting mixture is reacted for 30 minutes at a temperature between 70 and 80 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue thus obtained was extracted with 100 ml of chloroform.

The chloroform layer was washed with 30 ml of water and then 1 + 0 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (Wakogel C-200, elution with chloroform) and then recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2.5 g (yield 61 +, 3%) 1-Denzyl-1 + - {1 + - / "N-pivaloyl-oxymethyl-N - (" 2-pyrimdinyl) aaino-benzyl] -2,3-dioxopiperazine having a melting point of 11 + 1 + - 11 + 6 ° C.

IR (KBr) cm 1: i> c = Q 1725, 1670 Elemental analysis (for CggH ^ ^ N ^ O ^) calculated. C 67.05 Η 6.23% \ N 13.96% found: C 66 .99% \ H 6.23% \ N 13.85% NMR (CDClg) ppm values: 1.17 (9H, s, CH ^ x 3) ;, 3.38 (1 + H, s, piperazine-35 ring CH2 x 2), U, 65 (^ H, s, CH2 x 2), 5.95 8200451 - 13 - (2H, s, CH2 x 1), 6.68 (1H, t, J = 5.0Hz , pyrimidine ring H x 1), 7.23 (^ H, s, benzene ring H x U), 7> 25 (5H, s, benzene ring H x 5), 3.33 (2H, d, J = 5, 0Hz, pyrimidine ring H x 2)

Example II

1 g of 1-benzyl-1 + - [U - / - N-piyaloyloxymethyl-I'i- (2-pyrimidinyl) -amino-benzyl] -2,3-dioxopiperazine was dissolved in 30 ml of ethyl acetate and 1 g of glycolic acid and 0p2 were added thereto. ml of an N solution of hydrogen chloride in ethanol and the resulting mixture was reacted with stirring for 3 hours. At the end of the reaction, the solvent was distilled off 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 a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained in this way was purified by column chromatography (Wakogel C-200; elution with a mixture of chloroform and ethanol) and recrystallized from a mixture of ethyl acetate and diisopropyl ether. There was thus obtained 0.5 g (yield 52.8%) 1-benzyl-1 - {k- / ~ N-carboxymethoxymethyl-N-pyrimidinyl) amino7-benzyl] -2,3-dioxopiperazine, m.p. 85- 90 ° C.

IR (KBr) cm -1: i> c_0 1735, 1665 25 Elemental analysis (for C ^ H ^ N ^ Ot-) calculated: C 63.15% \ H 5.30%, N 14.73% * found : * C 63.22; #; H 5.38 N 1 ^, 62% NMR (CDCl ^) ppm values: 3.0 ^ 0 (UH, s, piperazine CHg x 2), U, 17 30 (2H, s , CH2 x 1), M3 (^ H, s, CH2 x 2), 5.25 (2H, s, CH2 X 1), 6.75 (1H, t, J = 5.0 Hz, pyrimidine ring H x 1 ), 7.22 (5H, s, benzene ring H x 5), 7.28 (kï, s, benzene ring H xk)> 8.3 ^ (2H, d, J = 5.0Hz, pyrimidine ring H x 2), 35 9.82 (1H, bs, carboxylic acid H x 1) 8200451 - 11 * -

Example III

* 1.0 g of 1-benzyl - ^ - [i + - / “N-pivaloyloxy-methyl-N- (2-pyrimidinyl) -amino-benzyl-2,3-dioxopiperazine were dissolved in 10 ml of ethyl mercaptan and 0, Add 1 ml of a 5.7 N solution of hydrogen chloride in dioxane and the resulting mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 50 ml of diisopropyl ether were added to the crystals thus obtained, after which these crystals were filtered off. The crystals thus obtained were recrystallized from isopropyl alcohol to give 0.8 g (yield 86.8 l) of white crystalline 1-benzyl-H-ethylthiomethyl-N- (2-pyrimidinyl) amino7-benzyl-2,3-dioxopiperazine obtained a melting point of 11 * -U ° C, 15 IR (KBr) cm -1: 1670

Elemental analysis (for C 1 -H-Ncr, S 1) 25 5 2 1 calculated: C 65.05 ï; H 5.89 N 15.17% found: C 65.02% \ H 5.8U% \ II 15.12% NMR (CDCL 3) ppm values: 20 1.1¾ (3H, t, CH 3 x 1), 2.53 (2H, *, CHg x 1), 3.39 (1 * H, s, piperazine ring CHg x 2), i *, o2 (Uh, s, CH2 x 2), 5.15 (2H, s .0¾ x 1), 6.57 (1Hf t, pyrimidine ring H x 1), 7.23 - 7.27 (9H, m, benzene ring H x 9), 8.25 (2H, d, pyrimidine 25 ring H x 2)

In the same manner as described above, the following compound was obtained: 1-benzyl-U- {U - / N-phenylthiomethyl-N- (2-pyrimidinyl) amino7-benzyl-2,3-dioxopiperazine 30 mp: 6U-65 ° C (recrystallized from isopropyl alcohol) IR (KBr) cm 1: uc-1670 elemental analysis (for ^ 9 ^ 27 ^ 5 ^ 2 ^ 1) calculated: C 68.3b% \ H 5.3b N 13.7¾% C 68, 36%, H 5.32%, N 13.71% 35 NMR (CDCl 3) ppm values: 8200451 - 15 - 3.33 (i * H, s, piperazine ring CH 2 x 2), U, 61 (2H, s, CH2 x 1), U, 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 (1UH, m, benzene ring H x 1 ^), 8.30 (2H, d, pyrimidine ring H x 2)

Example IV

3.0 g of 1-benzyl-1 * - / - 1t- (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine were dissolved in 1 * 0 ml of DMF and 0.372 g of sodium hydride (purity 52%) were then added. The resulting mixture was allowed to react with stirring at 80 ° C for 30 min. The reaction mixture was then cooled and 0.72 ml of chloromethylmethyl sulfide was added thereto, and the resulting mixture was allowed to react for 2 hours at a temperature between 50 and 60 ° C. After completion of the reaction, the reaction mixture was distilled under reduced pressure and the residue thus obtained was extracted with chloroform and then solid with water. The solution thus obtained was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The crystals 20 thus obtained were recrystallized from isopropyl alcohol to yield 3.0 g (yield 86.1 * 5%) of white crystalline 1-benzyl-1 * - [i * - / ~ N-methylthiomethyl-N- (2- pyrimidinyl) amino7-benzyl} -2,3-dioxopiperazine having a melting point of 150 ° C.

IR (KBr) cm-1: 1670 25 elemental analysis (for calculated C 61 *, 1 * 1% \ H 5.63 N 15.65% found C 61 *, 38% \ H 5.61% \ N 15.60 % NMR (CDCl ^) ppm values: 2.10 (3H, s, CH ^ x 1), 3.1 * 0 (1 * H, s, piperazine-30 ring CHg x 2), 1 +, 63 (1 * H, s, CHg x 2), 5.15 (2H, s, CHg x 1), 6.58 (1H, 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)

The following compound was prepared in the same manner as described above: 8200451 - 16 - 1-benzyl - ^ - {U- / ~ N-isopropylthiometbyl-N - {2-pyrimidinyl) amino7-benzyl] -2,3-dioxopiperazine melting point : 135 ° C (recrystallized from isopropyl alcohol) 5 IR (KBr) cm -1: u ^ _q 1670 elemental analysis (for C26H29N5 ° 2S 1> calculated: C 65.66% \ H 6.1U%, N 72% found: C 65.6U% \ H 6.12% \ N 1U, 68% NMR (CDCl ^) ppm values: 10 1.25 (6η, d, CI ^ x 2), 2.97 (1H, q, CH x 1), 3.37 (^ H, s, piperazine CHg x 2), ^, 63 (^ H, s, x 2), 5.16 (2H, s, CI ^ x 1), 6., : 56 (1H, t, pyrimidine ring Hx 1), 7.22 - 7.27 (9H, m, benzene ring H x 9), 8.26 (2H, d, pyrimidine ring 15 H x 2)

Example V

Based on Examples I and II, the appropriate starting materials were selected to obtain the compounds listed in Table C below.

Note: (1) in Table C, IPA = isopropyl alcohol.

IPE = diisopropyl ether, AcOEt = ethyl acetate and Et2O = diethyl ether.

(2) In the "method 1" column denotes "Pro" and the method number mentioned in the description / compound 25 to which in the line mentioning the "Pro number" was synthesized in the same manner as in the above example which relates on this method or according to the method described in the description based on this example.

(3) In the column under "recrystallization solvent", the term "column" refers to the fact that the product was purified by column chromatography.

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* T w ^ 3 nT * ^ W

O o o 0 = 0 O o o 8200451 - 18 -

Preparation example 1.

Per capsule, 100 mg of 1-benzyl-U- {U- / ~ N-methoxymethyl-N- (2-pyrimidinyl) amino7-benzyl] -2,3-dioxopiperazine, 50 mg of milk sugar, U8 mg of corn starch and 2 mg of magnesium stearate 5 were mixed and capsules were filled with the mixture thus obtained, whereby a drug was obtained in a capsule.

Preparation example 2.

250 mg of 1-benzyl - [- (i * - / ”N-ethoxymethyl-N- (2-pyrimidinyl) amino-benzyl] -2,3-dioxopiperazine, 50 mg of milk sugar, 38 mg of corn starch, 10 mg of polyvinylpyrrolidone were mixed per tablet and 2 mg of magnesium stearate and the mixture thus obtained were formed into tablets in a conventional manner, whereby a drug in tablet form was obtained.

8200451

Claims (11)

1. Compounds of formula 1, wherein an unsubstituted or substituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group, Rg represents a hydrogen atom or an alkyl group and X represents an oxygen or sulfur atom, or a salt thereof. Compounds according to claim 1, wherein Rg represents a hydrogen atom. Compounds according to claim 2, wherein X 10 represents an oxygen atom. h. Compounds according to claim 3, wherein R 1 represents an unsubstituted or substituted acyl group. Compounds according to claim 3, wherein represents an unsubstituted or substituted alkyl group. 6, A compound according to claim 5, 1-benzyl-4-fU- / "N-methoxymethyl-N- (2-pyrimidinyl) amino7-benzyl] -2,3-dioxopiperazine of formula 7, or a salt thereof. A compound according to claim 5, 1-benzyl-U- {1- / N-et-boxymethyl-N- (2-pyrimidinyl) amino7-benzyl] -2,3-dioxo-20 piperazine of formula 12, or a salt thereof . 8. Process for preparing an aromatic compound, characterized in that a compound of formula 1, wherein R 1 is an unsubstituted or substituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group , Rg represents a hydrogen atom or an alkyl group and X represents an oxygen or a sulfur atom, or a salt thereof, prepared by reacting a) 1-benzyl-2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine or a reactive derivative thereof with a compound of formula 2, wherein Y represents a reactive group and R 1, R 9 and X have the meanings indicated above, or b) a compound of formula 3, wherein R 1 is an unsubstituted or substituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl group and Rg has a meaning defined above to react with a compound of 8200451> - 20 - formula HXR ^ j in which R ^ is an unsubstituted or substituted alkyl, cycloalkyl -, aralkyl, alkenyl, alkadienyl or arylg call and X has a previously defined meaning. 9. Process according to claim 8, characterized in that 1-benzyl-k - / - - (2-pyrimidinylamino) benzyl7-2,3-dioxopiperazine or a reactive derivative thereof is reacted with a compound of formula 2, wherein, R, X, and Y have the meanings set forth in claim 8. 10. Process according to claim 8, characterized in that a compound of formula 13, in which Rg, Rl and X have the meanings stated in claim 8, is prepared by a compound of formula 3, in which Rl and R ^ have the meanings mentioned in claim 8 to react with a compound of formula HXR ^, wherein R 1 and X have the meanings indicated in claim 8. 11. Therapeutic preparation with carcinostatic properties, which preparation comprises one or more compounds of the formula 1. wherein R 1 is an unsubstituted or substituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl, or acyl group, R 1 represents a hydrogen atom or an alkyl group and X represents an oxygen or sulfur atom, and / or a salt thereof. 12. A method of preparing or manufacturing a therapeutic composition having a carcinostatic action, characterized in that one or more compounds of the formula 1, as defined in claim 11, and / or a salt thereof, are used in such a use. appropriate dosage form. 13. Methods as described in the description and / or examples. 30 1U. Therapeutic preparations formed by using a method according to claim 12 or 13. r 8200451