FR2499569A1 - NOVEL DERIVATIVES OF 1-BENZYL-4- (4- (2-PYRIMIDINYLAMINO) BENZYL) -2,3-DIOXOPIPERAZINES, THEIR SALTS, A PROCESS FOR PREPARING THESE DERIVATIVES AND SALTS AND A CARCINOSTATIC AGENT CONTAINING SAME - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS NEW DERIVATIVES OF 1-BENZYL-4-4- (2-PYRIMIDINYLAMINO) BENZYL-2,3-DIOXOPIPERAZINE. THEY MEET THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A RADICAL ALKYL, CYCLOALKYL, ARALKYL, ALCENYL, ALCADIENYL, ARYL OR ACYL, SUBSTITUTED OR NOT SUBSTITUTED, R IS A HYDROGEN AND RADICAL ALKYL ATOM REPRESENTS AN ATOM OF OXYGEN OR AN ATOM OF SULFUR. USE OF THIS COMPOUND TO PREPARE MEDICINAL PRODUCTS WITH CARCINOSTATIC ACTION FOR ORAL OR PARENTERAL ADMINISTRATION.

Description

The present invention relates to novel 1-benzyl-4- derivatives

  [4- (2-Pyrimidinylamino) benzyl] -2,3-dioxopiperazines and salts thereof, and a process for producing these compounds and a carcinostatic agent containing them. The compounds according to the invention themselves possess an excellent carcinostatic activity and have a low toxicity, so that their use

  is interesting in drugs; they are also useful as inter-

synthesis media.

  The main objects of the invention are to provide: new derivatives of 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl -2,3-dioxopiperazines and their salts;

  derivatives and salts of this type having a carcino-

  static and with low toxicity; derivatives and salts of this type which are well absorbed orally; a process for the preparation of these derivatives and salts; a carcinostatic agent containing these derivatives or salts; and

  - other objectives which will emerge from the description which will

  to follow. The novel derivatives according to the invention, namely the 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine derivatives, have the formula:

O O

t N O CH2-N N-CH - (I)

HC-X-R

  Wherein R represents a substituted or unsubstituted radical selected from alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl and acyl radicals; R is a hydrogen atom or an alkyl radical; and X is an atom

of oxygen or sulfur.

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

cyclohexylcarbonyl or the like.

  The aforementioned radical R1 may carry at least one substituent chosen from halogen atoms, such as fluorine, chlorine, bromine or iodine atoms; a hydroxyl radical; a carboxyl radical; an alkoxycarbonyl radical such as methoxycarbonyl, ethoxycarbonyl, etc .; an aralkoxycarbonyl radical such as benzyloxycarbonyl or the like; an aryloxycarbonyl radical such as phenoxycarbonyl and the like; an alkyl radical such as methylethyl, propyl, isopropyl, butyl, etc .; an alkenyl radical such as vinyl, allyl and the like; an aralkyl radical, such as benzyl, phenethyl and the like; a cycloalkyl radical such as cyclopentyl, cyclohexyl and the like; a cyano radical; a mercapto radical; an alkylthio radical such as methylthio, ethylthio, etc .; a nitro radical; an oxo radical; an acylamino radical such as acetamido and the like; an alkoxy radical such as methoxy, ethoxy and the like; an aralkoxy radical such as benzyloxy and the like; an acyl radical such as formyl, acetyl, propionyl, butyryl, benzoyl, etc .; a radical

  amino; an alkylamino radical such as methylamino, ethylamino, hydroxyethyl-

  amino, propylamino, etc .; a dialkylamino radical, such as dimethylamino,

  thylamino, bis (hydroxyethyl) amino, dipropylamino, etc .; an arylamino radical such as anilino, etc .; an aralkylamino radical such as benzylamino, phenethylamino and the like; heterocyclic radicals 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 analogous substituents.

  R2 represents a hydrogen atom or an alkyl radical such as methyl, ethyl, propyl, butyl, octyl, etc .; The present invention also relates to the salts of the derivatives of

formula (I) defined above.

  To form these salts, any acids or bases may be used as long as the resulting salts are pharmaceutically

  acceptable, although certain salts of mineral acids are particularly preferred.

  organic compounds, such as, for example, the salts obtained with hydrochloric acid

  hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, etc., as well as inorganic or organic base salts, such as, for example, potassium, sodium salts, calcium, ammonium

  and those resulting from the action of pyridine, collidine, triethyl-

  lamine, triethanolamine, procarne, etc. The hydrates of the compounds of formula (I) and hydrates are also encompassed within the scope of the invention.

  salts of the compounds of formula (I).

  Carcinostatic activity and toxicity will be studied below.

  Acute certain representative compounds according to the invention.

  at. Minimum inhibitory concentration (MIC) against cells

HeLa S3 and Ehrlich cells.

  Using microplates having 8x12 cells, 0.1 ml of a culture medium (Eagles MEM + 20% calf serum) containing test drug and 0.1 ml of culture medium were added to each chamber. with cells in suspension (2x104 cells / ml). The concentration of the drug to be tested was 100.4g / ml maximum 0.05 μg / ml minimum, with single-to-double serial dilutions (12 stages). The culture medium containing the test drugs was subjected to sterile filtration. The cells were cultured for four days, after which they were separated from the culture medium, washed twice with Hank's salt solution, and then fixed with 95% ethanol for 5 minutes, the resulting plate being finally treated for 15 minutes with a solution

  from Giemsa. The inhibition of cell growth was determined by the naked eye.

  the. The results obtained appear in Table 1.

Table 1

Table 1 (Continued Table i (Continued)

b. Effect on Leukemia L-1210.

  L-1210 cells (1x105 cells / head) were inoculated intravenously with BDF strain mice. (males, 7 weeks old, each group comprising five mice) and after 24 hours, administered by

  orally the drugs to be tested once a day for 7 days successively

  sive. The effect of the drug was judged by observing the average number of days

survival.

  The drugs to be tested were used as a solution

  or a suspension in a saline solution or in a saline solution

  holding 0.3% carboxymethylcellulose. The ratio between the animals that received the test drug and the control animals (T / C ratio) was calculated by the following equation: Average number of days of survival of the animals that received the test drug T / CxO (=

O O

6 CJO> -F-N CH2-N N-CH2 XO 39 01 78

CH20CH2COOH

O 0

  7 NCC> - -C CH2 NN-CH2- <> 3113 6125

CH20CH2CH (CH3) 2

0 CoCC

8 CO - N-S-2-CCH 2 -N N-CH 2 OH)

CH2OCH2CH2 N (CH2 CH2OH) 21, 1,

  T / C = Mean number of survival days of animals in the control group x100 (%)

  The results obtained appear in Table 2.

TABLE 2

c. Acute toxicity.

  Each of the test drugs was administered once orally to each ICR strain mice (7 week old males,

  each group comprising 5 mice) and the mice were observed for 7 days.

  The drugs were used as a solution or suspension in saline or in saline solution containing 0.3%

  of carboxymethylcellulose. The results appear in Table 3.

  Compose Dose T / C No. (mg / kg / day) (%) 1.

at 135

162

120

220,237

177

220 289

140

177

118

240,177

TABLE 3

  The results above show that compounds according to

  They have properties so good that they are perfectly absorbed into a living body during oral administration, with excellent carcinostatic properties and low toxicity. These compounds

  are therefore very effective as carcinostatic agents.

  We will now describe the production processes of the compounds

according to the invention.

  In order to produce the compounds of formula (I) or their salts according to the invention, it is possible to use the process (1) or process (2) which are described

below.

  Process (1) It consists in making 1-benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine or a reactive derivative thereof with a compound of formula:

Y-CH-X-R

t2 R Compound DL5 No. (mg / kg)

1> 2000

2> 2000

4> 2000

> 2000

7> 2000

  wherein R represents a substituted or unsubstituted radical selected from alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl radicals

  and acyl; R represents a hydrogen atom or an alkyl radical; X represents

  feels an oxygen or sulfur atom; and Y represents a reactive group.

Method (2)

  It consists in reacting a derivative of 1-benzyl-4-L4- (2-pyrimidinyl)

  amino) benzyl3-2,3-dioxopiperazine having the formula:

O O

(N "| eNCH 2 -N N CH 2 2 (III

HC-O-COR 4

  Wherein R is as defined above and R4 represents a substituted or unsubstituted radical selected from alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl and aryl radicals, with a compound of the formula:

H-X-R3

  wherein X is as defined above and R3 is a substituted radical

  killed or unsubstituted selected from alkyl, cycloalkyl, aralkyl radicals,

alkenyl, alkadienyl and aryl.

1 2

  In each of these processes, R, R and X have the same significances.

3 4

  than R and R in formulas (III) and (IV)

  represent the same alkyl, cycloalkyl, aralkyl, alkenyl, alkali,

  dienyl and aryl which have been mentioned in connection with R1; on the other hand, R3 and R may bear the same substituents as those listed in connection with R. As regards the reactive group Y in formula (II), mention may be made of halogen atoms (chlorine, bromine, iodine , etc.), arylsulfonyloxy radicals such as phenylsulfonyloxy, p-toluenesulfonyloxy and the like, as well as radicals

  alkylsulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, etc. -

  In each of the indicated processes, among the reactive derivatives of 3-benzyl-4-4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine, there may be mentioned compounds which are obtained by bonding a metal atom. alkali (lithium, sodium, potassium, etc.), an organic silyl group such as (CH3) 3Si, (CH3) 2Si =, (CH3) 2 [(CH3) 2CH] Si-, (CH30) 3si , CH3 (CH30) 2Si-, (CH3) 2 (CH3O) Si-, or the like; or an organic phosphorus group such as (CH 3 O) 2 P-, (C H 0) P 1 -, L0-R P-C H'O P-, or the like, with the group

2 5 2 L 0 CH 3 O / O,

  -NH. These reactive derivatives can be easily synthesized by a conventional method.

  they can be submitted to subsequent reactions without

  médiaire. 1-Benzyl-4- [4- (2-pyrimidinylamino) benzyl] -2,3-dioxopiperazine and the compounds represented by the formula (III) used in the above production processes can be easily obtained by use of of the following synthetic route: (III) Z

HODO-DH

  ## STR1 ## ## STR2 ## ## STR2 ##

0 O. T

StSHHLNTS aCI S.HIOA

1DH (ú E

HNN- HD

D HOHNVD (Z 00 /

axa / HeN (T o 'f1 -4- C'J o ll

  In the above formulas, DMF denotes N, N-dimethylformamide; AcNH-

  I 2 4 -ess means CH 3 CONH-; R g, R R and Y have the same meanings as above will now be described embodiments of each of

processes of preparation.

  The preparation process (1) is carried out in the presence or absence of an inert solvent with respect to the reaction. Among the solvents

  examples which may be mentioned are ethers such as tetrahydro-

  furan, diethyl ether, dimethoxyethyl ether, dimethoxyethane, dioxane, etc .; halogenated hydrocarbons such as methylene chloride,

  chloroform, 1,2-dichloroethane, etc .; amides such as dimethyl

  formamide, dimethylacetamide, etc .; nitriles such as acetonitrile, propionitrile, etc .; aromatic hydrocarbons such as benzene,

  toluene, xylene, etc .; nitroalkanes such as nitromethane, nitro-

  ethane, etc .; tertiary amines such as pyridine, quinoline,

  etc; sulfoxides such as dimethylsulfoxide, etc .; and phosphorus amides

  such as hexamethylphosphoric amide, etc. The solvents mentioned alone or as mixtures of two or more of them can be used. The reaction temperature and the duration are not critical although a temperature of from 0 to 150 ° C. is preferred and in this case the reaction is

  normally completed in 5 minutes to 12 hours.

  The compound of formula (II) is used in a proportion at least

  equimolar and preferably at 1.0 to 1.2 moles per mole of 1-benzyl-

  4-t4- (2-pyrimidinylamino-benzyl) -2,3-dioxopiperazine The preparation process (2) is carried out in the presence or absence of a solvent which is inert to the reaction. can be chosen, for example, from ethers such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc, the nitroalkanes;

  such as nitromethane, nitroethane, etc .; nitriles such as acetonitrile

  trile, propionitrile, etc .; 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 be used alone or as a mixture of two or more of them. The temperature and the duration of the reaction are not critical, but a temperature of from 0 to 150.degree. C. is preferred.

  In this case, the duration of the reaction is from 30 minutes to 24 hours.

  The compound of formula (IV) can in general be used in at least an equimolar proportion relative to the compound of formula (III), up to a maximum which is such that the compound of formula (IV) can also serve as a solvent. In addition, as a catalyst, it is possible to use protonic acids such as hydrochloric, hydrobromic, sulfuric acid, etc. as well as Lewis acids such as zinc chloride, aluminum chloride or tin chloride, tetrachloride, titanium, boron trifluoride, etc. After the preparation process (1) or (2) carried out as described above, the compound of formula (I) can be isolated from the reaction mixture according to a conventional method and can be purified by a technique such as column chromatography, recrystallization, etc. A salt of the compound of formula (I) can be obtained by carrying out the reaction by a usual method using a mineral acid such as hydrochloric, hydrobromic, sulfuric, phosphoric acid or the like; an organic acid such as p-toluenesulfonic acid, acetic acid or the like; a mineral base such as potassium or sodium hydroxide, potassium or sodium carbonate, sodium or potassium hydrogen carbonate, aqueous ammonia, etc .; or an organic base such as pyridine,

  collidine, triethylamine, triethanolamine, procaine or the like.

  In the processes of preparation which have been mentioned, when the compounds corresponding to formulas (II), (III) and (IV) contain an active group such as an amino, hydroxyl, carbonyl or the like on a site not having to

  react, compounds with a protective

  grouping the active group with a well-known protecting group and then carrying out the process according to the invention; the compound having a free active group can be obtained by treating the compound containing the protecting group by

  a well-known method for releasing said group.

  The compounds according to the invention-obtained in the manner described are very effective as carcinostatic agents. Pharmaceutically acceptable additives are suitably added to this compound and, with the resulting mixture, medicaments may be formed in various forms, for example for oral absorption (tablets, syrups, capsules, granular powders, etc.) or for injection (for example intramuscular injections, intravenous injections, infusions, etc.) and the product thus obtained is used as a carcinostatic drug. The route of administration, the dose and the number of administrations are suitably selected according to the condition. of the patient, although oral administration is preferred. Generally, the compound is administered to an adult at 1 to 4000 mg / kg, in 1 to 3 hours.

taken daily.

  The following examples serve to illustrate the invention without

limit the scope.

EXAMPLE I

  (1) In 23 ml of N, N-dimethylformamide (hereinafter DMF), 0.88 g of sodium hydride (60% purity) are suspended and 4.5 g of sodium hydroxide are added. benzyl-2,3-dioxopiperazine to the resulting suspension, whereupon the mixture is stirred at 80 ° C. for 10 minutes and cooled to 65 ° C. Then 15 ml of a solution in DMF containing 4 ml is added dropwise. 0 g of 4-acetylaminobenzyl chloride and the resulting mixture is reacted for 30 minutes at a temperature of 60-65 ° C. When the reaction is complete, the solvent is distilled off under reduced pressure and 20 ml of ethanol to the residue, after which the precipitated crystals are collected by filtration. The crystals thus obtained are poured into 60 ml of 2N hydrochloric acid and the solution is heated under reflux for 1 hour. After the reaction is complete, the reaction mixture is cooled to room temperature and 4.0 g of sodium hydrogencarbonate are added, then the precipitated crystals are collected by filtration, dried and recrystallized.

  in ethyl acetate to give 4.9 g (90% yield) of 1- (4-aminoethyl)

  benzyl) -4-benzyl-2,3-dioxopiperazine having a melting point of 193194 C.

IR (KBr) cm-: N 3450, 3350

1NH

QC = 0 1660

  Elemental analysis (for C 18 H 19 N 3 O 2) Calcd. (%) C: 69.88, H: 6.19, N: 13.58 Found (%) C: 69.82, H: 6.26, N: 13.52 NMR ( d6-DMSO) values in 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 x 1), 6.50 (2H, d, J = 9, OHz, benzene ring H x 2), 6.93 (2H, d, J = 9, OHz, benzene ring H x 2), 7.22 (5H, benzene ring H x 5) (2) 1.3 g of 1- (4-aminobenzyl) are suspended in 3.9 ml of ethylene glycol. 4-Benzyl-2,3-dioxopiperazine and 0.57 g of 2-chloropyrimidine are added to the suspension with stirring at 140 ° C. This mixture is reacted at 140-150 ° C. for 30 minutes. Once the reaction is complete, the mixture is cooled to 100 ° C. and 2.42 ml of water are added. After leaving the resulting mixture at rest, 17 ml of water are again added and the mixture is stirred and then

  precipitated crystals are collected by filtration, dried and recrystallized

  read in ethanol to obtain 0.9 g (75% yield) of 1-benzyl-4-L4-

  (2-pyrimidinylamino) benzyl] 2,3-dioxopiperazine having a melting point of

-176 C.

IR (KBr) cm-: NH 3320 NH

C = 0 1670

  Elemental analysis (for C22H21N5O2) Calcd. (%) C: 68.20, H: 5.46, N: 18.08 Found (%) C: 68.24, H: 5.38, N: 17.89 RNN ( d6-DMSO) values in ppm: 3.42 (4H, 1s, piperazine CH 2 x 2 nucleus), 4.51 (2H, s, CH 2 x 1), 4.54 (2H, s, CH 2 x 1), 6.75 (1H, t, J = 4.5 Hz, pyrimidine H x 1 nucleus), 7.15 (2H, d, J = 8.5 Hz, benzoinic nucleus H x 2), 7.25 (5H, s). benzoyl nucleus H x 5), 7.70 (2H, d, J = 8.5 Hz, benzenic ring H x 2), 8.40 (2H, d, J = 4.5 Hz, pyrimidine H x 2 nucleus) , 9.68 (1H, s, NH x 1) (3) To a mixture of 372 mg of sodium hydride (50% purity) and

  ml of DMF is added dropwise a solution of 3 g of 1-benzyl-4-ú4-

  (2-pyrimidinylamino) benzyl-2,3-dioxopiperazine in 20 ml of DMF with stirring over 30 minutes, and the resulting mixture is then reacted for 1 hour at

  C. When the reaction is complete, 1.3 g of pivaloyl chloride are added.

  oxymethyl dropwise in 10 minutes while maintaining the temperature at 60-70 C.

  After the addition is complete, the resulting mixture is reacted at 70 ° C. for 30 minutes. After the end of the reaction, the solvent is distilled off under reduced pressure and the residue is extracted with 100 ml of chloroform. The chloroform layer is washed with 30 ml of water and 40 ml of a saturated aqueous solution of sodium chloride, in this order, then dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, purifies the residue by column chromatography ("Wakogel C-200", elution with chloroform) and recrystallized from a mixture of ethyl acetate and diisopropyl ether to thereby obtain 2.5 g (64.3% yield) ) 1-Benzyl-4-t4-tN-pivaloyloxymethyl-N- (2-pyrimidinyl)

  aminolbenzyl S -2,3-dioxopiperazine having a melting point of 144-146 ° C.

  IR (KBr) cm-: C = O 1725, 1670 O = 0 Elemental analysis (for C28H31N5O4) Calcd. (Z) 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 x 3), 3.38 (4H, s, piperazine CH 2 x 2) , 4.65 (4H, s, CH 2 x 2), 5.95 (2H, s, CH 2 x 1), 6.68 (1H, t, J = 5, OHz, pyrimidine H x 1 nucleus), 7 , 23 (4H, benzene ring H x 4), 7.25 (5H, s, benzene ring H x 5), 8.33 (2H, d, J = 5, OHz, pyrimidine ring H x 2)

EXAMPLE 2

  In 30 ml of ethyl acetate, 1 g of 1-benzyl-4- (4-

  N-pivaloyloxymethyl-N- (2-pyrimidinyl) amino] benzyl] -2,3-dioxopiperazine and 1 g of glycolic acid and 0.02 ml of a standard ethanolic solution of hydrochloric acid are added and the mixture is then reacted. resulting at room temperature for 3 hours and with stirring. After the reaction is complete, 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 then 30 ml of a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure and purifies the residue thus obtained by column chromatography ("Wakogel C-200", elution with a mixture of chloroform and ethanol). It is recrystallized from a mixture of ethyl acetate and diisopropyl ether, and

  0.5 g (yield 52.8%) of 1-benzyl-4- (4-N-carboxymethoxymethyl) -N- (2-pyrimidine)

  dinyl) amino] benzyl} -2,3-dioxopiperazine having a melting point of 8590C.

  IR (KBr) cm: C = O 1735, 1665 Elemental analysis (for C25H25N5O5)

25,505)

  Calculated (%) C: 63.15, H: 5.30, N: 14.73 Found (%) C: 63.22, H: 5.38, N: 14.62 NMR (CDCl3) ppm: 3.40 (4H, s, piperazine 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 = 5.3 Hz, H x 1 pyrimidine nucleus), 7.22 (5H, s, benzene ring H x 5), 7.28 (4H, s, benzene ring H x 4), 8.34 (2H, d, J = 5.0 Hz, H 2 x pyrimidine ring), 9.82 (1H, 1s, carboxylic acid H x 1)

EXAMPLE 3

  In 10 ml of ethyl mercaptan, 1.0 g of 1-benzyl

  4- {4-EN-pivaloyloxymethyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine and 0.01 ml of a 5.7N dioxin solution in hydrochloric acid is added and the mixture is then reacted at room temperature. ambient for 3 hours. After the reaction is complete, the solvent is removed under reduced pressure and 50 ml of diisopropyl ether are added to the crystals thus obtained, followed by filtration.

  the resulting crystals. These crystals are recrystallized from isopropyl alcohol

  and gives 0.8 g (86.8% yield) of a white crystalline product which

  is 1-benzyl-4- {4-EN-ethylthiomethyl-N- (2-pyrimidinyl) amino] benzyl}

  dioxopiperazine having a melting point of 144 C.

  IR (KBr) cm: C = O1670 Elemental analysis (for C25H27N5O2S1)

27502S1)

  Calculated (%) C: 65.05, H: 5.89, N: 15.17 Found (%) C: 65.02, H: 5.84, N: 15.12

NMR (CDCl3) values in 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 x 1), 7.23 - 7.27 (9H, m, benzene ring H x 9), 8.25 (2H, d: pyrimidine H x 2 nucleus) By the same method as above, the following compound is obtained:

  1-Benzyl-4- {4- [N-phenylthiomethyl-N- (2-pyrimidinyl) aminolabyl} -

  2,3-dioxopiperazine. Melting point: 64-65 ° C (after recrystallization from isopropyl alcohol). IR (KBr) cm-: C = O 1670

0 = 0

  Elemental analysis (for C29H27N5O2S1) Calcd (%) C: 68.34, H: 5.34, N: 13.74 Found (%) C: 68.36, H: 5.32, N: 13.71 NMR ( CDCl3) values in ppm: 3.33 (4H, s, piperazine CH 2 x 2 nucleus), 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, pyrimidine H x 1 nucleus), 6.98 - 7.28 (14H, m, benzene H x 14 nucleus), 8.30 ( 2H, d, pyrimidine nucleus H x 2)

EXAMPLE 4

  In 40 ml of DMF, 3.0 g of 1-benzyl-4- [4- (2-pyrimidinyl)

  amino) benzyl] 2,3-dioxopiperazine and 0.372 g of sodium hydride (52% purity) is added, and this mixture is then reacted at 80 ° C. for 30 minutes with stirring. The reaction mixture is cooled and 0.72 ml of chloromethyl sulphide is added, and the mixture is then reacted for 2 hours at -60 ° C. When the reaction is complete, the reaction mixture is distilled under reduced pressure and the mixture is extracted. the residue with chloroform, and then washed with water. The solution is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The crystals are recrystallized from isopropyl alcohol to give 3.0 g (86.45% yield).

  a white crystalline product which is 1-benzyl-4- 4- [N-methylthiomethyl-N-

  (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine having a melting point of

156 C.

  IR (KBr) cm -: ν C = O 1670 Elemental analysis (for C24H25N5O2S1) Calcd. (%) C, 64.41, H: 5.63, N: 15.65 Found (%) C, 64.38, H: 5.61, N: 15.60 NMR (CDCl 3) values in ppm: 2.10 (3H, s, CH 3 x 1), 3.40 (4H, s, piperazine ring CH 2 x 2), 4.63 ( 4H, s, CH 2 x 2), 5.15 (2H, s, CH 2 x 1), 6.58 (1H, t, pyrimidine ring H x 1), 7.10-7.35 (9H, m, benzene nucleus H x 9), 8.26 (2H, d, pyrimidine nucleus H x 2) Similarly, the following compound is obtained: 1-benzyl-4- [4- [N-isopropylthiomethyl-N- (2-pyrimidinyl) ) -amino2 benzyl} -2,3-dioxopiperazine; Melting point: 135 ° C. (after recrystallization from isopropyl alcohol). IR (KBr) cm-: C = O 1670 Elemental analysis (for C26H29N5O2S1) Calcd. (%) 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 x 2), 2.97 (1H, q, CH x 1), 3.37 (4H, s). , depiperazine nucleus CH 2 x 2), 4.63 (4H, s, CH 2 x 2), 5.16 (2H, s, CH 2 x 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, pyrimidin H x 2 nucleus)

EXAMPLE 5

  Based on Examples 1 and 2, the materials of

  starting to obtain the compounds listed in Table 3.

  Note: (1) In Table 3, IPA = isopropyl alcohol, IPE = diisopropyl ether, AcOEt = ethyl acetate and Et20 = diethyl ether.

  (2) In the "Process" column, Pro. (1) and Pro. (2) designate respectively

  the processes (1) and (2) discussed above; com-

  posed mentioned on the line in front of the number of the process was synthesized by the same tenchnique as in the example corresponding to this same process,

  or by the technique developed in the description about this

example.

  (3) In the column "Recrystallization solvent", the term

  "Column" means that the product has been purified by chromato-

column spelling.

Table 3

O O

CH2-N N-CH2-Q

CH-X-R1

  R2 R R R2 x m.p. R1 R2 X pf (C) recrystallization Method -CH3 HO 138-140 AcOEt Pro (1), Pro (2) C2H HO 135-138 AcOEt-Et2O Pro (1), 2 2 Pro (2) ) -CEH2CH (CH3) 2 HO 145 AcOEt Pro (1) - C (CH2) CH HO 116 AcOEt Pro (1)

  O .____ __ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _

  CH 2 CHCH 2 OH 75 - 83 CH 2 C -IPE, Pro. (2)

OH _ __ _ _

-CH2CH2N (CH2CH2OH) 2

H oil -1 IR (pure) cm:

MC = O 1.650

  Col o * ne Pro. (2) Pro. (1) o rlO CD "O" O 0%% a

-CH (CH 3) 2 H __O 147 J _A._

PREPARATION EXAMPLE 1

  For each capsule 100 mg of 1-benzyl-4-I 4- [N-methoxy

  methyl-N- (2-pyrimidinyl) aminolbenzyl) -2,3-dioxopiperazine, 50 mg of lactose, 48 mg of corn starch and 2 mg of magnesium stearate, are mixed and filled with the resulting mixture to give get a drug in capsules.

EXAMPLE OF PREPARATION 2

  For each tablet 250 mg of 1-benzyl-4- {4- [N-ethoxy-

  methyl-N- (2-pyrimidinyl) amino] benzyl} -2,3-dioxopiperazine, 50 mg of lactose, 38 mg of corn starch, 10 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate, are mixed and prepared. tablets with this mixture by a

  traditional technique to get a drug in tablets.

Claims (10)

  1. Compound, characterized in that it corresponds to the formula: o o N N CH2-NNCH 2 H-C-X-R1   Wherein R 1 represents an alkadienyl, aryl or acyl radical, substituted hydrogen atom or an alkyl radical or a sulfur atom; alkyl, cycloalkyl, aralkyl, alkenyl, or unsubstituted; R represents one and X represents an oxygen atom   as well as salts of such a compound.   2. Compound according to claim 1, characterized in that R e a hydrogen atom.   3. Compound according to claim 2, characterized in that X es an oxygen atom.   4. Compound according to claim 3, characterized in that R E   a substituted or unsubstituted acyl radical.   5. Compound according to claim 3, characterized in that R e   a substituted or unsubstituted alkyl radical.   6. Compound according to claim 5, characterized in that it is   1-Benzyl-4-4-N-methoxymethyl-N- (2-pyrimidinyl) amino3-benzyl -2,3-   dioxopiperazine of formula: is and _st is co O N & CH 2-N NCH2- C Born | \ C22 tO CH2OCH 3 or a salt of the latter.   7. Compound according to claim 5, characterized in that it is   1-Benzyl-4-4-1N-ethoxymethyl-N- (2-pyrimidinyl) amino3-benzyl} -2,3dioxopi- periper of formula: t 0 0 NOT CNé I - CH 9 -H2-N N-CH2 -o 52CH2CH2CH3 or a salt of the latter.   8. A process for producing a compound as defined in claim 1 or a salt thereof, which comprises [A] reacting 1-benzyl-4-ú4-pyrimidinylamino) benzyl. ] 2,3-dioxopiperazine or a reactive derivative thereof with a compound of formula: Y-CH-X-R! R   wherein Y represents a reactive group, and R, R and X are as defined in claim 1, or LB] reacting a compound of the formula: O O N -o 7-N | CCH2 C 2 HC-OCR   Wherein R represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl radical; and R is as defined in claim 1, with a compound of formula: H-X-R3   in which R represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl radical, and X is as defined in claim I. 9. Process according to claim 8, characterized in that it consists of   reacting 1-benzyl-4-L4- (2-pyrimidinylamino) -benzyl] -2,3-dioxopiperazine   zine or a reactive drift thereof, with a compound of formula: Y-CH-X-R1 R   in which R, R, X and Y have the same meanings as in the 8.   10. Process according to claim 8, characterized in that a compound of formula 0 0 t-- N- - CH2-N N-CH2-- HC-X-R3   Wherein R2, R2 and X are as defined in claim 8, reacting a compound of formula; O 0 (N "t N CH2-N N-CH2-0 HC-OCR4 12 11 R O 2 4   wherein R and R are as defined in claim 8, with a compound of the formula: H-X-R3   wherein R3 and X are as defined in claim 8.   He. Drug especially with carcinostatic action, characterized in that it consists of a compound of formula: O O t 9 N-- CH C2-N N-CH-2X- HC-X-R R2 2? 499 569   in which R! represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadignyl, aryl or acyl radical; R2 is a hydrogen atom or an alkyl radical; and X is an oxygen or sulfur atom, or with a salt of such a compound.   12. Drug composition, characterized in that it comprises   a medicament according to claim 11 in combination with a pharmaceutical vehicle ceutically acceptable.