IT8247729A1 - Piperazine derivatives, their production process, and carcinostatic agents containing them - Google Patents

Description

Dear tion

The present invention relates to novel derivatives of L-benzyl-4-[4-(2-pyrithiadinylamino)-benzyl-3-' 2,3-dioxopiperazine and their salts, to a process for producing them and to a carcinostatic agent containing them.

The compounds of the present invention are in themselves excellent in carcinostatic activity, have low toxicity, are useful as drugs and are also useful as intermediates.

It is an object of the present invention to provide novel derivatives of l-bensyl-4-[4^2-pyrimidinyl-amino)-benzyl~2,3~dioxopiperazine and their salts.

It is another object of the present invention to provide novel derivatives of 1-beazyl-4-[4-(2-pyrimidinyl-amino)-benzyl]-2,3-dioxopiperazine which have carcinostatic activity and have low toxicity, and their salts.

It is another object of the present invention to provide novel derivatives of l-benzyl-4-[4-(2-p?rimidinylamino)-benzyl]-2,3-dioxopiperazine or their salts which are well absorbable orally.

It is yet another object of the present invention to provide a process for producing novel derivatives of 1-benzyl-4-[4-(2-pyrimidinilamino)-benzyl]-2,3-dioxopiperazine or salts thereof.

It is yet another object of the present invention to provide a carcinostatic agent containing novel derivatives of l-benzyl-4-[4-(2-pyrimidinyl-amino)-benzyl]-2, 3-dioxopiperazine or salts thereof.

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

According to the present invention, a novel derivative of l-benzyl-4[4(2-pyrimidinylamino)-benzyl]-2,3-dioxopiperazine represented by the formula (I) or a salt thereof is provided:

or 0

O-rO N-CH

HC-X-R

where R 1 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; -2

R represents a hydrogen atom or an alkyl group and X represents an oxygen atom or a sulfur atom.

In formula (I), R^<" >? 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 benziyl, renethyl or the like; an alkenyl group such as vinyl, allyl or the like; an alkadienyl group such as 1,5-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 ?<x >may be replaced by at least one substituent selected from the group consisting of halogen atoms such as chlorine, chlorine, bromine, iodine, and the like; a hydroxyl group; a carboxylic group; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and the like; aralkoxycarbonyl groups such as benzyloxycarboxyl and the like; aryloxycarbonyl groups such as phenoxycarbonyl and the like; ethyl groups such as methyl, ethyl, propyl, isopropyl, butyl, and the like; alkenyl groups such as vinyl, allyl, and the like; aralkyl groups such as benzyl, phenyl, and the like; cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like; cyanogroup; merehaptogroup; alkylthiogroups such as methio, ethylthio, and the like; nitrogroup; oxogroup; acylamino groups such as acetamido and the like; alkoxy groups such as methoxy, ethoxy and silyl; acyloxy groups such as benzyloxy and the like; acyl groups such as formyl, acetyl, propionyl, butyryl, beazoyl and the like; amino groups, alkylamino groups such as methylamino, ethylamino, hydroxyethylamino, propylamino and the like; dialkylamino groups such as dimethylamino, diethylamino, bis-(hydroxyethyl)amino, dipropylamino and the like; arylamine groups such as anilino and the like; aralkylamino groups such as benzylamino, phenethylamino and the like; cyclic heterogroups such as pyridyl, pyrimidinyl, imidazolyl, tyrozolyl, pyrazyl, oxazolyl, furyl, thienyl, pyrrolyl, pyridazinyl and the like; and heterocyclic aminogroups such as pyridylalanine, pyriminilamino, etc.; and

<? >similar.

p

R? a hydrogen atom with an alkyl group such as methyl, ethyl, propyl, botyl, octyl? similar.

For the formation of salts of compounds represented by formula (I) any acid or base may be used as long as the resulting salts are readily acceptable, although particularly preferred are inorganic or organic acid salts such as salts with hydrochloric acid, hydrobromic acid, 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, collidines, triethylamines, triethanolamine, procaine, and the like. Also included in the present invention are hydrates of the compounds represented by formula (I) and hydrates of the salts of the compounds of formula (I).

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

a) Minimum inhibitory concentration (MIC)

against HeLa S3 cells and Ehrlich cells Using an 8 x 12 pan microdish, 0.1 ml of a culture medium (Eagles MEM 20# bovine serum) containing a test drug and 0.1 ml of a culture medium containing a test drug are added to each chamber. culture with suspended cells (2 x 10^<" >cells/ml). The concentration of the test drug is 100 pg/ml at the highest dilution and 0.05 ??/? at the lowest dilution with serial 2-fold dilutions (12 steps). The culture medium containing the test drug is subjected to sterile filtration. The cells are cultured for 4 days after which they are separated from the culture medium, washed twice with Hanks' salt solution, then fixed with 95% ethanol for 5 minutes and then stained with Giemsa's solution for 15 minutes. Inhibition of cell growth is judged by the naked eye. The results obtained are shown in Table 1.

Table 1

MIC (μg/ml) NO. Compound

HeLa Ehrlich

0 0

/ ? N / v ^ ^ / v

1 1 \2/ <CH2">\_^ 0.39 0.39<N_CH2 >A2/

CH2OCC(CH3) 3

0

0 . 0

/-N / - v ^ ^ / - v

2 (oy- -\Oj~ CH2-N _ N-CH2 -\OJ 1.56 1.56

CH2OC2H5

0 0

/ ? N / \ ^ ^ / V

3 \0^<~ >j \2/ <CH>2<"N>N-V<N"CH>2 <?>\0/ 0.39 0.39

<CH>2?jf<(CH>2<)>16<CH>3

0

Table 1 (continued)

<_ >?

1.56 3.13

CH2OCH3

0 0

/-N > ? v ^ f r<~>\

\?/ | \2/ <CH>2<_N>V-/ 3.13 3.13<N_CH>^ <2 ?>\Oy CH2OCH2CHCH2OH

OH

o. 0

/ ? N / v ^ ^ / V

\2/ <CH>2<_N>W<N_CH>2 \2/ 0.39 0.78

CH2OCH2COOH

0 ^0

)? CH2-N _ /N-CH2-<5) 3.13 6.25

CH2OCH2CH (CH3) 2

0 0

)? <N~<>(^Oy~<CH>2~<?>\ _ N-CH2 -<5) 12.5 12.5

CH2OCH2CH2N (CH2CH2OH) 2

b. Effect on leukemia L-1210

L-1210 cells (1 x 10^ cells/head) were inoculated intravenously into BDF-^ strain mice (males, age 7 weeks, each group consisting of

from 5 mice and, after 24 hours, test compounds are administered orally once daily for 7

days later. Their effect is judged

from the average survival days.

The drugs under test are used in the form of

a solution or suspension in a saline solution

or a saline solution containing carboxymethylcell_

lulose at 0.5%? T/C is calculated by the following

equation:

Average survival days in a group at

m /n_ which one? The test drug was administered

<~ >Mean survival days of control group_ xl00(%)

The results obtained are shown in table 2.

Table 2

Compound Dose T/C

No. (mg/kg/gipm o) (%)

50 135

1

100 162

110 120

2

220 237

110 177

4

220 289

65 140

5

130 177

120 118

7

240 177

c. Acute toxicity

Each of the test drugs is administered orally once to ICR strain mice (males, and at seven weeks, each group consisting of 5 mice) and the mice are kept under observation for 7 days.

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

Table 5

Compound <LD>50

No. (mg/kg)

1 > 2000

2 > 2000

4 > 2000

5 > 2000

7 > 2000

As is clear from the above test results, the compounds of the present invention have such excellent properties that they are well adsorbed by a living organism when administered orally so as to exhibit excellent carcinostatic activities and have low toxicity. Therefore, they are very useful as carcinostatic agents.

An explanation of processes for producing the compounds of the present invention is given below.

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

Procedure (1)

A process comprising reacting l-benzyl-4-[4-(2-pyrimidinyl-aminino)-benzyl?-2,3-dioxopiperazine or a reactive derivative thereof with a compound represented by the formula:

Y-CH-X-R

I <1>

(II)

R

where RI represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group;

2

R represents a hydrogen atom or an alkyl group; X represents an oxygen atom or a sulfur atom; and Y represents a reactive group. Procedure (2)

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

0 0

^ <N cu>2<~>\ _ /<N-CH>2 (III)

HC-O-COR<4>

R'2

p

where R has the same meaning as defined above 4

and R represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group, with a compound represented by the formula:

H-X-R<5 >(IV)

where X has the same meaning as defined above and R^ represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl group.

In each of the processes R1, R2 and X have 7, li.

the same meanings defined above and R^ and R^ in formulas (III) and (IV) include the same alkyl, cycloalkyl, aralkyl, alkenyl, cycloalkyl, alkadienyl and aryl groups mentioned for R^ and R^ ii.

and R can be replaced by the same substituents mentioned for R. As reactive group for Y in formula (II), halogen atoms such as chlorine, bromine, iodine and the like may be mentioned; 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-pyrimidinyl-amino)-hexyl]-2,5-dioxopiperazine include compounds formed by linking an alkali metal atom such as lithium, sodium, potassium, or the like; an organic silica group such as (CH^^Si-, (CH^gSi^ , (GH3)2E(ca5)2CH]si-, (GH5O)5S?-, CH5(CH5O)2S?-, (GE3)2(CH3O)S?~, or the like; or an organic phosphoric group such as (CH^O^P-, (CgH^COgP-? O-^ .r -P-, or the like? 0 0^

to the y&H group.

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

1-Benzyl-4-[4-(2-pirimidinilamino)-benzil]-2,3-dioxopiperazine and compounds represented by the formula (III) used in the above-mentioned production processes can be easily obtained by the following reaction routes and according to procedure (I):

Reaction pathways

1) NaH/DMF

0 2) AcNH CH?C1

CH~~N NH H2N-Q ^ CH2- vN rN-3) HCl >-o

THERE

0 0 <CH>2<~>\_ /<N~CH>2<">^3

? ? Y-CHOCOR

R12

0

-OCOR

(III)

In the above formulas, DHF means N,N-dimethylformamide; AcNH means CEjCONH; R\ R<*>% L\.

R and Y have the same meanings as defined above. Executions of each manufacturing process are described below.

The production process (1) is carried out in the presence or absence of an inert solvent for the reaction. The solvent used in the reaction includes, for example, ethers such as tetrahydrofuran, diethyl ether, dimethoxyethyl ether, dimethoxyethane, dioxane and the like; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like; amides such as dimethylformamide, dimethylacetamide 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 dimethyl sulfoxide and the like; and phosphoric amides such as hexaethyl phosphoric amide and the like. The above-mentioned solvents can also be used in mixtures of two or more.

The reaction temperature

and the reaction time are not critical although the reaction is preferably carried out at Q? up to 150?C and, in this case, the reaction is usually complete in 5 minutes up to 12 hours. The compound represented by formula (II) is used in an amount at least equimolar and preferably 1.0 to 1.2 moles per mole of l-benzyl-^-[4-(2-pyrimidinylamino)-benzyl]-2,3-dioxopiperazioa.

The production process (2) is carried out in the presence or absence of an inert solvent for the reaction. The solvent used in the reaction includes, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; nitroalkanes such as nitroethane, nitroethane and the like; nitriles such as acetonitrile, propionitrile and the like; amides such as dimethylformamide, dimethylacetamid 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 can also be used in mixtures of two or more solvents. The reaction temperature and reaction time are not critical although the reaction is usually carried out in a controlled manner. preferably carried out at 0 to 150?C; in this case, the reaction is usually completed in 30 minutes to 24 hours.

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

After the production process (1) or (2) above has been carried out in the manner described above, the compound represented by formula (I) may 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 formula (I) may be obtained by carrying out 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 phosphate, sodium 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 formulas (II), (III), and (IV) have an active group such as an amino, hydroxyl, carbonyl, or syn group in the unreactive position, 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 the present 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 liberate the protecting group. The compound of the present invention obtained as stated above is It is very useful as a carcinostatic agent. Pharmaceutically acceptable additives are added as appropriate to the compound and the resulting mixture can be formulated into various drug forms such as oxalate preparations, e.g., tablets, syrup, capsules, powder, granules and vials and injections, e.g., intramuscular injection, intravenous injection, drip infusion and the like and then applied as carcinostatic agents. The manner of administration, dosage and number of administrations are chosen appropriately depending on a patient's condition, although oral administration is preferred. Usually, in the case of an adult, the compound is administered once to three times daily in a total dosage of 1 to 4000 mg/kg.

The present invention is further explained below with reference to examples, which are merely for illustration and in no way limiting.

Example 1

(1) In 23 ml of N^-dimethylformamide (hereinafter referred to as DHF) are suspended 0.88 g of sodium hydride (60% purity), and to the resulting suspension are added 4.5 g of 1-benzyl-2,3-dioxopiperazine, after which the resulting mixture is stirred at 80°C for 10 minutes and then cooled to 65°C. Then 15 ml of a DM? solution containing 4.0 g of 4-acetylaminobenzyl chloride are dropped, and the resulting mixture is reacted at 65°C for 30 minutes. After completion of the reaction, the solvent is removed by distillation under reduced pressure and 20 ml of ethanol is added to the residue, after which the precipitated crystals are collected by filtration. The crystals thus obtained are added to 60 ml of 2 L hydrochloric acid and the resulting solution is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is cooled to room temperature and 4.0 g of sodium hydrogen carbonate is added, after which the precipitated crystals are collected by filtration, dried and then recrystallized from ethyl acetate to yield 4.9 g (90% yield) of 1-(4-aminobenzyl)-4-benzyl-2,5-dioxoperazine having a melting point of 195-1990-2000°C.

IR (KBr) cm<-1>: Vra 3450, 3350

VC=0166O

Elemental analysis: (for <C>18<H>19<N>5?2<)>

calculated (%) G:<' >69.88, H: 6.19, E:13.58 found (%)".<' ? >C: 69.82, H: 6.26, N:15.52

NHR (dg-DHSO) ppm values:

(4?, s, piperazine ring CH^ x 2), 4.J8 (2H, s, GH2 xl) 4.53 (2H* s, CH^ x 1), 4.99 (2H, s, ???^ xl), 6.50 (2H , d, J=9.0 Hz, benzene ring E x 2), 6.93 (2K, d, J-9.0 Hz, benzene ring H x 2), 7.22 (5H, a, benzene ring H x 5).

(2) 1,3 ml of 1,(4-aminobenzyl)-4-behzyl-2,5'-dioxopiperazine is suspended in 5.9 ml of ethylene glycol and to the resulting suspension 0.57 ml of 2-chloropyrimidine is added with stirring at 140°C. The resulting mixture is reacted at 140-150°C for 50 minutes. After completion of the reaction, the reaction mixture is cooled to 100°C and 2.42 ml of water is added to the reaction mixture. After allowing the reaction mixture to stand, 17 ml of water is added again and the resulting mixture is stirred after which the precipitated crystals are collected by filtration, dried and then re-esterified by ethanol to give 0.9 ml (75% yield). l-benzyl-4[4-(2-pirimi dini1amino)-ben zi1]-2,3-dioxopipera ziaa has a melting point of 175-1?6?C.

?E (KBr) ca<'>V , <'>"??m 3320

V -O <16>??

Elementary analysis (for

calculated (%) C:68.20, H: 5.46, N:18.03 found (%) G:68.24, H: 5.38, ??:17.89

IME (dg-DMSO) ppm values;

3.42 (4E, bs, piperazine ring CH^ x 2), 4.51 (2H, s, CH2 x 1), 4.54 (2H, s, CH2

H x 1), 7.15 (2H, d, J-8.5 Hz, benzene ring H x 2), 7.25 (5H,.s, benzene ring Hx5), 7.70 (2H, d5 J=8.5 Hz, benzene ring H x 2), 8.40 (2H, d, J=4.5 ??? p?rimidine ring H x 2), 9.68 (IH, s, NH x 1).

(5) To a mixture of 572 mg of sodium hydride (50% purity) and 50 ml of DHF, a solution of 56 g of l-benzyl-4-[4-*(2-p-rimidinil-amino)-bensyl]-275-dioxopipeiazine in 20 ml of BKF is added dropwise with stirring within 30 minutes after which the resulting mixture is reacted at 60-70°C for one hour. After completion of the reaction, 1.5 g of pivaloyloxymethylchloride is added dropwise within 10 minutes at the same temperature. After completion of the dropwise addition, the resulting mixture is reacted at 70-80°C for 10 minutes. After completion of the reaction, the solvent is removed by distillation under reduced pressure and the residue is then evaporated. The resulting chloroform is extracted with 100 ml of chloroform. The chloroform layer is washed with 50 ml of water and 40 ml of saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate after which the solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column electrophoresis (Wakogel C-200, eluted with chloroform) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 2.5 g (64.3% yield) of

1~ben zi1-4~14-[N-pivaioyl s?imeti?-N--(2-pyrimidini1)?-amino]-benzyl-2,3~dioxopiperazine having a melting point of 144-146?C.

IH (KBr) cnf<1>: ^??()1725, 1670

Elementary analysis (for <G>2a<H>31<H>5?4<)>

calculated (%) C: 67*05, B: o,23, ??: 15,96 found (%) C: 66,99, H: 6,25, N: 15,85

NMR (CDClj) ppm values

1.17 (9H, s, CH^ x 5), 5.3<8 >(4H, s, pipe ring, razine CH2 x 2), 4.65 (4H, s, CH2 x 2), 5.95 (2H, s, CHp x 1), 6.68 (1H, t, J*=5.0 Bz, pyrimidine ring H x 1), 7.25 (4H, s, benzene ring H x 4)s 7.25 (5H, s, benzene ring H X 5), 8.35 (2H, d, J=5.0 Bz, pyrimidine ring

B x 2).

Example 2

1 g of l-benzyl-4-(4-[N--pivaloyl--O3SimetiH&-(2^pyrimidine)-amino]-benzyl]-2,3-dioxopiperazine is dissolved in 30 ml of ethyl acetate and 1 g of glycolic acid and 0.02 ml of ethanolic hydrogen chloride solution 1N are added after which the resulting mixture is subjected to reaction alone at room temperature for 5 hours, stirring. After completion of the reaction, the solvent is removed by distillation 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

50 ml of saturated aqueous sodium chloride solution is added and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (Wakogel C-200, eluted with chloroform-ethanol) and recrystallized from ethyl acetate-diisopropyl ether to obtain 0.5 g (52.8% yield) of 1-benzyl-4-4-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)-amino]-benzyl}-2,3-dioxopiperazine having a melting point of 85-90°C.

IR (KBr) dm<"1>: ??;01755, 1665

Elemental analysis for Cg^H^ N^Q,,)

calculated (%) C: 65.15, H: 5.30, ,N: 14.73 found C: 65.22, H: 5.38, Ni 14.62

NMR (CDCl,) ppm values:

5.40 (4H, s, piperzine ring CH2 x 2), 4.17 (2H, s, CH2 x 1), 4.63 (4H, 3, <? x 2), 5.25 (2H, CH2X 1), 6.?5 (1H, t, J*5.0 Ha, ane? lo ?i pyrimidine H x 1), 7.22 (5H, s, benzene ring H x 5), 7.23 (4H, s, benzene ring ? x 4), 8.34 (2H, d, J=5.0 Hz, pyrimidine ring H x 2), 9.82 (1H,.,b?, carboxylic acid ? x 1).

Example 3

1.0 g of 1-benzyl-4-(4-CN-pivaloyloxymethyl-N(2-pyrimidine)-aminobenzidine)-2,3-dioxopiperazine is dissolved in 10 ml of ethyl mercaptan and 0.01 ml of 5.7 H dioxane-hydrogen chloride solution is added, after which the resulting mixture is subjected to reaction at room temperature for 3 hours. After completion of the reaction, the solvent is removed under reduced pressure and 50 ml of diisopropyl ether is added to the resulting crystals, after which the resulting crystals are filtered. The resulting crystals are recrystallized from isopropyl alcohol to obtain 0.8 g (86.8% yield) of 1-benzyl-2,3-dioxopyl ether. {4-CN-ethylthiomethyl-H-(2-pyrimidinyl)-amino]-benzyl<'>? -2,3-dioxopiperasin is a white crystalline substance having a melting point of 144?C. IR (KBr) crT<1>: \>C=016??

Elemental analysis (for C^H^r^ OgS^)

calculated <(>%) C: 65.05, H: 5.89, N: 15.17

found (%) Ci 65.02, H: 5.84, Ni 15.12

NKR (CDGl^) ppin values:

1.14 (5H, t, CK5 x 1), 2.55 (2H, q, G3? xl), 5.39 (4K, s, piperazin ring GH2 x 2), 4.62 (4H, s, Cflg jc 2), 5.15 C2H, s, CH2 x 1), 6.57 (1H, t, pyrimidine ring H x 1), 7.25-7.27 (9H, a, benzene ring H x 9), 8.25

(2H, d, pyrimidine ring H x 2)?

In the same manner as above, the following compound is obtained: l-benz?l-4-{4~[N~phenylthiomethyl-N~(2-pigifflidiniI)-amiro3-benz?l}-2 d?oxopiperazine, melting point: 64-65?C (re-rystallized from isopropyl alcohol)

IR (KBr) cui<"1>: .\>0as01670

Elementary analysis (for 829?27^5?2<S>1^

calculated (%) 0: 68.54, H: 5.34, N: 13.74 found (%) ' ?; ,C:,69.36, H: 5.32, N: 13.71

NMR (CUCI,,) ppm values:

3.53 (4H, s, piperazine ring CH2 x 2),

! (

4.61 (2H, s, GH2 X 1), 4.65 (2H, s, CH2 x 1), 5.50 (2H, s, GH2 x 1), 6.60 (1H, t, pyrimidine ring H x 1), 6.98 - 7.28 (14H, m benzene ring H x 1:4), 8.50 (2H, d, pyrimidine ring H x 2).

Example 4

3.0 g of 1-oenzyl-4-[4-(2-pyrimidithiamino)-benzil3-2,3-dioxopiperazine] is dissolved in 40 ml of BMF and 0.3-2 g of sodium hydride (32% purity) is added, after which the resulting mixture is reacted at 80°C for 30 minutes with stirring. The reaction mixture is then cooled and 0.72 ml of chloromethylmethylsulfide is added, after which the resulting mixture is reacted at 50-50°C for 2 hours. After completion of the reaction, the reaction mixture is distilled under reduced pressure and the resulting residue is extracted with chloroform and then washed with water. The resulting solution is then The resulting solution is dried over anhydrous magnesium sulfate and the solvent is then removed by distillation under reduced pressure. The crystals thus obtained are recrystallized from isopropyl alcohol to yield 5.0 g (86.45% strength) of 1-bensyl-4-{^?CH-methylthiomeci(2-pyrimidinyl)-amino]-henzyl}-2,3-dioxopiperacetic acid having a melting point of 156?C.

IH (KBr) cnT<1 >: \>? ? O V 16?0<a>

elemental analysis (for <C>24?5<N>5??P

calculated (%) C ; 64.41 , H: 5.65, N: 15.65 found (%) C; 64 ,38, H: 5.61, ??; 15.60

HKH (GDCl^) values d? ppm:

2.10 (3H, s, 0H3 x 1), 3.40 (4S, s, piperazine ring CH^ x 2), 4.63 (4H, s, OH2 * 2), 5*15 (2H, s, CH2 x 1), 6.58 (1H, t, pyrimidine ring, ma Hxl), 7.10-7.55 (9H, m, benzene ring Hx9), 8.26 (2H, d, pyrimidine ring H x 2)r

In the same manner as above, the following compound is obtained:

l~benz?l-4- ?4-[N-isopropylthioiaethyl*-N-(2-pyrime?di<i_ nyl)-amino] -benzyl } -2,3-dioxopiperazine.

melting point: 135?C (recrystallized from isopropyl alcohol).

IH (KBr) cm<"1 >: ^C=Q 1670

Elementary analysis (for <C>26<K>29^5?2<S>1^

calculated (%) G ; 65.66, Hi 6.14, N: 14.72 found (%) C : 65.64, H: 6.12, N: 14.68

33MH (GDClj) ppm value:

1.25 (SH, d, CH7 x 2), 2.97 (IH, q, CH x 1), 3.57 (4H, s, piperazine ring CH2 l),

7.22-7.27 (9H, m, benzene ring H x 9), 8.26 (2H, d, pyrimidine ring d x 2).

Example 5

Based on Examples 1 and 2, any starting material is chosen to obtain the compounds shown in Table 5.

Note: (1) In Table 3, IPA = isopropyl alcohol,

IPE = diisopre?pilie ether, AcOEfc = ethyl acetate and Sto0 = d?ethyl ether.

(2) In the columns ?Procedure??* the term "Pro" number refers to the procedure number indicated in the description of the report and the compound cited in the line in which the "Pro" number appears is summarised in the same manner as in the example mentioned above regarding the said procedure or according to the method described in the description based on the said example.

(3) In the column "Recrystallization solvent" the term "column" means that the product has been purified by column chromatography.

Table 3

0 0

O j-O <CH>2-<?>W<N~CH2?>Q

CH-X-R<1>

R<1 >R<2 >X m.f. (?C) Solvent for re-stabilization process

-CH3 H 0 138 - 140 AcOEt Pro. (1)r Pro. 12) Pro. (1), <"C>2<H>5 H 0 135 - 138 Ac0Et-Et20 Pro. (2) -CH2CH(CH3) 2 H 0 145 AcOEt Pro. (1)

H 0 116 AcOEt Pro. (1) The <2 16 3>

0

-CH_CHCH9OH H 0 75 - 83 CH2CI2-IPE Pro. (2) <4 >\

OH

H 0 oil

-CH2CH2N (CH2CH2OH)2 IR(net)<cra : >Column Pro. (2) "c=o <1650>

-CH(CH3)2 H 0 147 IPA Pro. (1) Preparation example 1:

For one capsule, 100 mg of l-benzyl-4-^-[N-methoxymethyl-N-^-pyrimidini^ -aminol-benzyl?}-2,3-dioxopiperazine, 50 mg of lactose, 48 mg of corn starch and 2 mg of magnesium stearate are mixed and capsules are filled with the resulting mixture to obtain a capsule drug - Preparation example 2:

For one tablet, 250 mg of 1-benzil-4-4-[N-ethoxymethyl-N-(2-pyrimidinyl)-amino]-benzyl}-2,3-dihydroxybenzoylpiperazine, 50 mg of lactose, 58 mg of corn starch, 10 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate are mixed and the resulting mixture is made into tablets in the usual manner to obtain a tablet drug.

-

Claims (6)

1. Compound represented by the formula: O O O-YO H-C-X-R R2 where R<">*" represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; p R <? >represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof. 2. Compound according to claim 1, wherein _R2 is a hydrogen atom. 3 Compound according to claim 2, wherein X is an oxygen atom. 4. A compound according to claim 2, wherein R^ is a substituted or unsubstituted acyl group. 5- 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)-aminobenzyl}-2,3-dioxopiperazine of the formula: c y<~ >|CH -2oOCH3 -o od one of its salts. ?. Compound of claim 5, which is 1-benzyl-4-^4-[N-e toxi-me tyl-N-(2-pyrimidinyl)-amino]-benzyl3-2,3-dioxopiperazino<* >of the formula: or 0 :-0-"v??.-0 CH2OCH2CH3 or a salt of it. 8. Procedure for producing a compound represented by the formula: 0-??0- CH~- VN YN-CH, -O H-C-X-R R^2 where R^ represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, al_ group 2 chenyl, alkadienyl, aryl or acyl; R represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof, which comprises the steps of (A) reacting 1-benzyl-4-[4-(2-pyrimidinyl-amino)-benzyl]-2,3-dioxopiperazine or a reactive derivative thereof with a compound represented by the formula Y-CH-X-R<1> J2 where Y represents a reactive group and R1, R2 and X have the same meanings as defined above; or (B) react a compound represented by the formula: O rO <CV>\Z/-<CH>2-0 HC-OCR \ 0 II R 0 4. where R represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, al_ group 2 chenylic, alkadienyl or aryl; and R has the same meaning as defined above, with a compound represented by the formula: H-X-R<5> where R^ represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group; and X has the same meaning as defined above. 9. The process of claim 8, which comprises reacting l-benzyl-4-[4-(2-pyrimidinylamino)-benzyl]-2,5-dioxopiperazine or a reactive derivative thereof, with a compound represented by the formula: Y-CH-X-R R* wherein R1, R2, X and Y have the same meanings as defined in claim 8. 10. Process according to claim 8, wherein a compound represented by the formula: 0 or 0 -??0 - CH_- VN YN-CH. HC-X-R<' ,>-o I, R wherein R2, R3 and X have the same meanings as defined in claim 8, is produced by reacting a compound represented by the formula: | -O -<? >?2-}^CCH2 HC-OCR<4> 12 I! R 0 wherein R? and R4 have the same meanings as defined in claim 8 with a compound represented by the formula: H-X-R<5 > X wherein and X have the same meanings as defined in claim 8. 11. A carcinostatic agent comprising a compound represented by the formula C?-jO -'-.-v-.O HC-X-R<1> the 2 R where R"^ represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R<1>^ represents a hydrogen atom or an alkyl group and X represents an oxygen atom or a sulfur atom, or a salt thereof, p.p. TOYAMA CHEMICAL CO., LTD., S0C??T? }TM f ( - Z?f - of ethanolic solution of hydrogen chloride ?.5?dopo-?sst vtriig &* ve* of C?-.O the resulting mixture is subjected to reflux at room temperature for 3 hours, stirring. After completion of the reaction, the solvent is removed by distillation 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 saturated aqueous sodium chloride solution is dried over anhydrous magnesium sulfate, the solvent being removed by distillation under reduced pressure. The residue thus obtained is purified by column chromatography (Wakogel C-200, eluted with chloroform-ethanol) and recrystallized from ethyl acetate-β-isopropyl ether to obtain 0.5 g (52.8% yield) of 1-Lensyl-4-|4-[N-carboxymethoxymethyl-α-(2-pyrimidine)-aminoα-benzyl}-2,3-dioxyl-5-piperazine having a melting point of 85-90°C. IH (KBr) cm<?1>: 1735, 1665 Elementary analysis for <C>25? 5^5^5^ calculated (%) 0 : 63.15, H: 5.30, .U: 14?.75 found (ago) C: 63.22, H: 5.38, ??:14?.62 HMR (CBC17)) ppm values: 3.40 (4EL s, piperazine ring CHp x 2),