AU8024082A - Dioxopiperazine derivatives - Google Patents

Description

~NSTRUMrIONS 4I a) If- Cofnlention (a) f- fvt application insert "Convention"' AUSTR~ALIA

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Delete one APPLICATION FOR A STANDARD[Itki

Insert FULL nWe(c) TOYAMA CHEMICAL CO., LTD. name(s) of applicant(s)

~~88240/82; Insert FULL Of 2-5, 3-chomne, Nishishinjuki, u-j'k-u address(es) of Toyko 160, Japan applicant(s)

De-

Delete one hereby apply for the grant of a Standard/AIM Patent for an invention entitled QjqIsert TITLE (M "NOVEL 1-BENZYL-4- E4- (2-PYRIMIDINYLAMINO) -2,3- ofrinvention

+kfl~I SAME AND CARO INOSTATIC AGENT CONTAINING THE SAME" 4,g ert "complete" which is described in the accompatiiyng complete specification. LR ,"Provisional" "petty patent" o0

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Details of basic application(s)

Insert numhp., country and Application No. Country Filing Date ~"fiang date for 4 4

0 e/or EACH basic application 15837/81 Japan 6February, 1981

VT u ifi F~eSSTAMP 70o VA". C

00 18 MAIL OFFIC-L-!:;

.0bouM m

Address for Service: PILLIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia 3000 Insert DATE oi signing Dated 26th January, 1982. ()Signature of applicant(s) (For body corporate see headnote*) ~PHILLIPS ORMONDE AND FITZPATRICK Attorneys for Corporate seal if any TOYAMA CHEMICAL CO., LTD.

bmap Note: No legalization or other witness required

WD. PHILLIPS ORMONDE AND FITZPATRICK I Patent and Trade Mark Attorneys A 367 Collins Street -4 Melbourne, Australia STUART TAYLOR

(12) AUSTRALIAN PATENT ABSTRACT (19)j AU (11) AU-A -80 240/82

(54) DIOXOPIPERAZINE DERIVATIVES (71) TOYAMA CHEMICAL CO., LTD. (21) 80 240/82 (22) 5.2.82 (24) 6.2.81 (31) 56-15837 (32) 6.2.81 (33) JP (43) 12/08/82 3 (51) CO7D 403/12 A61K 31/505 (72) TAKAKO HORI ET AL (74) PO (57) Carcinostatic agent. Claim 1. A compound represented by the formula,

0 0

-CH2- N N-CH-

H-C-X-R 2 R

wherein R 1 represents a substituted or unsubstituted

alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or

acyl group; R 2 represents a hydrogen atom or an alkyl

group; and X represents an oxygen atom or a sulfur atom,

or a salt thereof.

ND ;2 34

AUSTRALIA

Patents Act

COMPLETE SPECIFICATION (ORIGINAL)

Class Int. Class Application Number: OO 0/ Lodged:

Complete Specification Lodged: Accepted: Published: PAority:

Related Art:

APPLICANT'S REF.: A6370-09 TOYAMA Name(s) of Applicant(s): TOYAMA CHEMICAL CO., LTD.

Address(es) or Applicant(s): 2-5, 3-chome, Nishishinjuku, Shinjuku-ku, Tokyo 160, Japan

Actual Inventor(s): TAKAKO HORI, CHOSAKU YOSHIDA, YASUO KIBA, RYUKO TAKENO, JOJI NAKANO, JUN NITTA, SUMIKO KISHIMOTO, SHOHACHI MURAKAMI, HISATSUGU TSUDA, ISAMU SAIKAWA

Address for Service is: PHILLIPS, ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367. Collins Street Melbourne, Australia, 3000 Complate Specification for the intT' EN ZYL-4 -E 4- (2-PYRIMIDINYLAMINO) BENZYL-2, 3- DIOXOPIPERAZINE DERIVATIVES, SALTS THEREOF, PROCESS FOR PRODUCING THE SAME AND CARCINOSTATIC AGENT CONTAINING THE SAME"

The following statement is a full description of this invention, including the best method of performing it known to applicant(s): WD.

1 This invention relates to novel l-benzyl-4-[4-

(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine deriva-

tives and salts thereof, to a process for producing the

same, and to a carcinostatic agent containing the same.

The compounds of this invention are per se

e:cellent in carcinostatic activity, low in toxicity,

useful as medicines, and useful also as intermediates.

An object of this invention is to provide

novel l-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-

dioxopiperazine derivatives and salts thereof.

Another object of this invention is to provide

novel l-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-

dioxopiperazine derivatives which have a carcinostatic

activity and are low in toxicity, and salts thereof.

A further object of this invention is to provide

novel l-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-

dioxopiperazine derivatives or salts thereof which are

well orally absorbable.

A still further object of this invention is to

provide a process for producing novel l-benzyl-4-[4-(2-

pyrimidinylamino)benzyl]-2,3-dioxopiperazine derivatives,

or salts thereof.

A still further object of this invention is

to provide a carcinostatic agent containing novel

1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-

STUART TAYLOR

1 dioxopiperazine derivatives, or salts thereof.

Other objects and advantages of this invention

will be apparent from the following description. l-benzyl-4-[4- According to this invention, there is provided azine deriva- 5 a novel l-benzyl-4- (2-pyrimidinylamino)benzyl] -2,3- producing the dioxopiperazine derivative represented by the formula Ling the same. or a salt thereof: are per se

.n toxicity,

Ltermediates.

-o provide NC-1 HC-X-R 1 -o =nyl]-2,3-

:eof. wherein R represents a substituted or unsubstituted i is to provide alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or nzyl]-2,3- 2 10 acyl group; R represents a hydrogen atom or an alkyl -arcnostatic group; and X represents an oxygen atom or a sulfur atom. :s thereof. In the formula R1 is an alkyl group, such Lon is to provide as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 3nzyl]-2,3- octyl, or the like; a cycloalkyl group, such as cyclo- aof wlich are pentyl, cyclohexyl, or the like; an aralkyl group, such

as benzylr phenethyl, or the like; an alkenyl group, invention is to such as vinyl, allyl, or the like; an alkadienyl group, nzyl-4-v4-(2- or the such as 1,3-butadienyl, 2,4-hexadienyl, geranyl, ine derivatives, like; an aryl group, such as phenyl, naphthyl, or the

20 like; and an acyl group, such as acetyl, propionyl, invention is butyri1Z2, pivaloyl, stearoyl, benzoyl, furoyl, thenoyl, rg novel pyridylcarbonyl, cyclohexylcarbonyl, or the like. -2,3-

-3

1 In the above formulas, DMF means N,N-dimethyl- 1 2 4 formamide; AcNH- means CH 3 CONH-; R R R and

1 The above-mentioned R1 may be substituted by f. at least one substituent selected from the group is invention consisting of halogen atoms such as fluorine, chorine, ion. bromine, iodine, and the like; hydroxyl group; carboxyl is provided group; alkoxycarbonyl groups such as methoxycarbonyl, nzyl]-2,3- ethoxycarbonyl, and the like; aralkoxycarbonyl groups a formula such as benzyloxycarbonyl and the like; aryloxycarbonyl

groups such as phenoxycarbonyl and the like; alkyl

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, phenethyl, and

the like; cycloalkyl groups such as cyclopentyl, cyclo-

hexyl, and the like; cyano group; mercapto group;

stituted alkylthio groups such as methylthio, ethylthio, and the

!nyl, aryl or 15 like; nitro group; oxo group; acylamino groups such as

7an alkyl acetamido and the like; alkoxy groups such as methoxy,

sulfur atom. ethoxy, and the like; aralkoxy groups such -s henzyloxv

group, such and the like; acyl groups such as formyl, acetyl,

cyl, heptyl, propionyl, butyryl, benzoyl, and the like; amino group;

i as cyclo-' 20 alkylamino groups such as methylamino, ethylamino,

group, such hydroxyethylamino, propylamino, and the like; dialkyl-

l group, amino groups such as dimet'iylamino, diethylamino,

Lenyl group, bis(hydroxyethyl)amino, dipropylamino, and the like;

inyl, or the arylamino groups such as anilino and the like; aralkyl-

41, or the 25 amino groups such as benzylamino, phenethylamino and the

Dpionyl, like; heterocyclic groups such as pyridyl, pyrimidinyl,

1, thenoyl, imidazolyl, thiazolyl, pyrazinyl, oxiizolyl, furyl,

like. thienyl, pyrrolyl, pyridazinyl, and the like; and

-4

1 is used in a quantity at least equimolar to, preferably thy1- of 1.0 to 1.2 moles per mole of, l-benzyl-4-[4-(2- R and

,ubstituted by

ie group 1 heterocyclic amino groups such as pyridylamino,

xine, chlorine, pyrimidinylamino, etc.; and the like.

R is a hydrogen atom or an alkyl group such Iroup; carboxyl as methyl, ethyl, propyl, butyl, octyl, or the like. Loxycarbonyl, 5 For the formation of the salts of the compounds -bonyl groups represented by the formula any acids or bases may ryloxycarbonyl be used so long as the resulting salts are pharmaceutical- .ke; alkyl ly acceptable, though inorganic or organic acidic selts )propyl, butyl, such as salts with hydrogen chloride, hydrogen bromide, r, allyl, and 10 sulfuric acid, phosphoric acid, p-toluenesulfonic acid, phenethyl, and and the like and inorganic or organic basic salts suuh )pentyl, cyclo- as salts with potassium, sodium, calcium, ammonium, :o group; pyridine, collidine, triethylamine, triethanolamine, Tlthio, and the procaine, and the like are particularly preferred. rroups such as 15 Hydrates of the compounds represented by the formula (I) -has methoxy, and hydrates of the salts of the compounds of the !h =s be-zyloxv formula are also included in this invention. acetyl, The carcinostatic activity and acute toxicity amino group; of the representative compounds of this invention are hylamino, 20 explained below. ike; dialkyl- a. Minimum inhibitory concentration (MIC) against .ylamino, HeLa S3 cells and Ehrlich cells Ld the like; Using microplate of 8x12 wells, to each like; aralkyl- chamber were added 0.1 ml of a culture medium (Eagles Lylamino and the MEM 20% calf serum) ccntaining a test drug and pyrimidinyl, 0.1 ml of a cell-suspended culture medium (2x104 1, furyl, cells/ml). The concentration of the test drug was 100 ike; and ig/ml at the highest, and 0.05 ug/ml at the lowest,

to, preferably 1 chloride, titanium tetrachloride, boron trifluoride, and

the like.

After the above production process or

1 with serial twofold dilutions (12 steps). The test

drug-containing culture medium was subjected to sterile

filtration. The cells were cultured for 4 days, after

'which the cells were separated from the culture medium,

washed twice with Hank's salt solution, then fixed with

ethanol for 5 min, and thereafter stained with the

Giemsa solution for 15 min. The inhibition of cell

growth was judged with unaided eye. The results obtained

are shown in Table 1.

6

i ii i I cont'd

7

1 min, and then cooled to 65 0 C. Thereinto was dropped

ml of a DMF solution containing 4.0 g of 4-acetylamino-

benzyl chloride, and the resulting mixture was subjected

Table 1 (cont'd)

O 0

6 )--CH 2 -N N-CH 0) 0.39 0.78

CH 2 OCH 2 COOH

0 0

7 CH 2 -N N-CH 2 3.13 6.25

CH2OCH 2 CH(CH 3 )2

o 0

8 0 -CH 2 -N N-CH2 12.5 12.5

CH2OCH 2 CH 2 N(CH 2 H 22OH) 2

1 b. Effect on L-1210 Leukemia

L-1210 cells (1x105 cells/head) were

inoculated intravenously into BDFl-strain mice (male,

7 weeks old, each group consisting of 5 mice), and after

24 hours, test drugs were orally administered once a

day for 7 succesive days. The effect thereof was judged

from the mean survival days.

The test drugs were used in the form of a

solution or suspension in a saline solution or a 0.3%

carboxymethyl cellulose-containing saline solution.

T/C was calculated by the following equation:

8

benzene ring H x 7.22 (5H, s, benzene ring

H x 1.3 g In 3.9 ml of ethylene glycol was suspended I t 4 Y'.nA

Mean survival days in group to T/C which test drug was administered X 100(% Mean survival days of control group

The results obtained are shown in Table 2.

Table 2

Compound Dose T/C No. (mg/kg/day)

135 1 100 162

110 120 2 220 237

110 177 4 220 289

140

130 177

120 118 7 240 177

1 c. Acute Toxicity

Each of the test drugs was administered

orally once ICR-strain mice (male, 7 weeks old, each

group consisting of 5 mice), and the mice were observed

for 7 days.

The test drugs were used in the form of a

solution or suspension in a saline solution or a 0.3%

carboxymethyl cellulose-containing saline solution. The

results obtained are shown in Table 3.

-9-

7.70 (2H, d, J=8.5Hz, benzene ring H x 2),

8.40 (2H, d, J=4.5Hz, pyrimidine ring H x 2),

9.68 (1H, s, NH x 1) II

Table 3

Compound LD 5 0 No. (mg/kg)

1 2000

2 2000

4 2000

2000

7 2000

1 As is clear from the above test results, the

compounds of this invention have such excellent pro-

perties that they are well absorbed in a living body

when orally administered to exhibit excellent

carcinostatic activities, and have low toxicities.

Therefore, they are very useful as carcinostatic agents.

An explanation is made below of processes for

producing the compounds of this invention.

The compounds of the formula or salts

thereof of the present invention are produced according

to the process or described below.

Process (1)

A process comprising reacting l-benzyl-4-[4-

(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine or a

reactive derivative thereof with a compound represented

by the formula:

10

Elementary analysis (for C 2 8 H 3 1 N 5 0 4 Calcd. C: 67.05, H: 6.23, N: 13.96

Found C: 66.99, H: 6.23, N: 13.85 7MRfl IC'ThC'1 \I ,ralT1 c

Y-CH-X-R 1 (I I)

1 wherein R1 represents a substituted or unsubstituted

alkyl, cycloalky, aralkyl, alkenyl, alkadienyl, aryl,

or acyl group; R2 represents a hydrogen atom or an

alkyl group; X represents an oxygen atomn or a sulfur

atom; and Y represents a reactive group.

Process (2)

A process comprising reacting a l-benzyl-4-

[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine

derivative represented by the formula, esults, the 0 0 lent pro- (IT) ving body S- N CH 2 -N N-GB 2

nt HC-O-COR cities.

tatic agents. 10 wherein R2 has the same meaning as defined above, and )rocesses for R represents a substituted or unsubstituted alkyl,

cycloalkyl, aralkyl, alkenyl, alkadienyl, or aryl group, or salts with a compound represented by the formula: -ed according

H-iX-R (IV)

wherein X has the same meaning as defined above, and benzyl-4-[ 4- 15 4rzP represents a substituted or unsubstituted alkyl, azine or a cycloa4kyl, aralkyl, alkenyl, alkadienyl, or aryl group. d represented 1 2 and X have the In each of the urocesses, R ,R

11

1 recrystallized from e4lhyl acetate-diisopropyl ether, to

obtain 0.5 g (yield 52.8%) of 1-benzyl-4-{4-[N-carboxy- S:13.96 methoxymethyl-N-(2-pyrimidinyl)aminolbenzyl}-2,3- 13.85 dioxopiperazine having a melting point of 85 900 C.

3 4 1 same meanings as defined above, and R and R in the

formulas (III) and (IV) include the same alkyl, cyclo-

alkyl, aralkyl, alkenyl, alkadienyl and aryl groups

mentioned for R and R 3 and R may be substituted 1 As the by the same substituents as mentioned for R

reactive group for in the formula there may be

mentioned halogen such as chlorine, bromine,

iodine, and the like; arylsulfonyloxy groups such as

phenylsulfonyloxy, p-toluenesulfonyloxy, and the like;

and alkylsulfonyloxy groups such as methanesulfonyloxy,

ethanesulfonyloxy, and the like.

In each of the above-mentioned production

processes, the reactive derivatives of l-benzyl-4-[4-

(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine include

compounds formed by bonding an alkali metal atom such as

lithium, sodium, potassium, or the like; an organic

silyl group such as (CH 3 3 Si-, (C 3 2SiZ,

(CH3) 2[(CH) 2 CH] Si (CH O) Si-, CH 3 (CH 3 0) 2 Si-

(CH 3 )2 (CH3O)Si-.. or the like; or an organic phosphorus

group such as (CH3 0) 2 (C2 H5 0)2 P-

CHP-, or the like, to the >-NH group. CH 3 lo Co

These reactive derivatives can easily be synthesized

according to a conventional method, and may be subjected

without isolation to the subsequent reaction.

The l-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-

2,3-dioxopiperazine and the compounds represented by

O

1 the formula-,(III) used in the above-mentioned production d R in the processes can easily be obtained through the following alkyl, cyclo- reaction routes and according to the process ryl groups

bstituted 1. i R. As the

there may be

bromine,

)ups such as

and the like; Ki Lnesulfonyloxy,

production

-benzyl-4- [4-

razine include

:al atom such as

an organic

-r

ric phospshorus

the >NH group.

synthesized

may be subjected

tion.

ylamino)benzyll-

presented by

13

zed from isopropyl CH 2 x 6.60 (1H, t, pyrimidine ring H x 1),

f white crystalline 6.98 7.28 (14H, m, benzene ring H x 14), 8.30

yrimidinyl)amino]- (2H, d, pyrimidine ring H x 2)

lting point of

Reaction Routes 1) NaH/DMF

0 0 2) AcNH--& CH 2 Cl 0 0 HN CH NCH (-CH2 -N NH 3) HCI

CN Cl 0 0 N

N -NH CH 2-N\-j N-CH 2

Y-CHOCOR4 12

N N N 4 I-C-OCOR

(III) applicant(s): WD.

S C .me S S o e 0~ .0 0. *5O CCC e.g C

Reaction Routes 1) NaH/DMF

2) AcNH O-CH 2 cl 0

O-CH -N 2 NH 3) HC1 H~ IT CH2-N

C N N '4

C N N

Note: In Table 3, IPA isopropyl alcohol,

CH 2 C 0 0

S0 SS N 055S

CHC1CO 04 22

2 CH2 N CUH -N

4 HC-OCOR

1 2I

icohol,

1 In the above formulas, DMF means N,N-dimethyl- 1 2 4 formamide; AcNH- means CH3CONH-; 3 R R R and i Y have the same.meanings as defined above.

Embodiments of each production process are

described below.

The production process is carried out

in the presence or absence of a solvent inert

to the reaction. The solvent used in the reaction

includes, for example, ethers such as tetrahydrofuran,

diethyl ether, dimethoxyethyl ether, dimethoxyethane,

dioxane, and the like; halogenated hydrocarbons such

as methylene chloride, chloroform, 1,2-dichloroethaner

and the like; amides such as dimethylformamide, dimethyl-

acetamide, and the like; nitriles such as acetonitrile,

propionitrile, and the like; aromatic hydrocarbons such

as benzene, toluene, xylene, and the like; nitroalkanes

such as nitromethane, nitroethane, and the like;

tertiary amines such as pyridine, quinoline, and the

like; sulfoxides such as dimethylsulfoxide and the like;

and phosphoric amides such as hexamethylphosphoric amide

and the like. The above-mentioned solvents may be used

also in admixture of two or more.

The reaction temperature and the reaction time

are not critical, though the reaction is preferably

effected at 00 to 150 0 C, and in this case, the reaction

Sis ustally completed in 5 minutes to 12 hours.

The compound represented by the formula (II)

1 is used in a quantity at least equimolar to, preferably

of 1.0 to 1.2 moles per mole of, l-benzyl-4-[4-(2-

pyrimidinylamino)benzyl]-2,3-dioxopiperazine.

The prodction process is carried out in

the presence or absence of a solvent inert to the

reaction. The solvent used in the reaction includes,

for example, ethers such as tetrahydrofuran, diethyl

ethes, dioxane, dimethoxyethane, and the like; aromatic

hydrocarbons such as benzene, toluene, xylene, and the

like; nitroalkanes such as nitromethane, nitroethane,

and the like; nitriles such as acetonitrile, propio-

nitrile, and the like; amides such as dimAthylformamide,

dimethylacetamide, and the like; halogenated hydro-

c, carbons such as methylene chloride, chloroform, and-the

like; and fatty acids suct as acetic acid, propionic

acid, and the like. These solvents may be used also in

admixture of two or more. The reaction temperature and

the reaction time are not critical, though the reaction

is preferably effected at 00 to 150 0 C, in this case,

the reaction is usually completed in 30 minutes to 24

hours.

The compound represented by the formula (IV)

may usually be used in an amount at least equimolar to

the compound represented by the formula (III) to such

an amount that the compound of the formula (IV) can also

serve as a solvent. Moreover, as the catalyst, there

may be used protonic acids such as hydrogen chloride,

hydrogen bromide, sulfuric acid, and the like; and Lewis

acids such as zinc chloride, aluminum chloride, tin 16

J,~1

1 chloride, titanium tetrachloride, boron trifluoride, and

the like.

After the above production process or

is carried out in the manner described above, the

compound represented by the formula can be isolated

from the reaction mixture according to a conventional

method, and purified by procedures such as column

chromatography, recrystallization, and the like. A salt

of the compound represented by the formula can be

obtained by effecting the reaction according to a con-

ventional method using an inorganic acid such as

hydrochloric acid, hydrobromic acid, sulfuric acid,

phosphoric acid, or the like; an organic acid such as

p-toluenesulfonic acid, acetic acid, or the like; an

inorganic base such as potassium hydroxide, sodium

hydroxide, potassium carbonate, sodium carbonate, sodium

hydrogen carbonate, potassium hydrogen carbonate,

aqueous ammonia, or the like; or an organic base such

as pyridine, collidine, triethylamine, triethanolamine,

procaine, or the like, and then isolating and purifying

the reaction product. In the above-mentioned production

processes, when the compounds represented by the

formulas (III) and (IV) have an active group such

as amino, hydroxyl, carbonyl, or the like in the

unreactive site, compounds having a protecting group

can be obtained by protecting the active group with a

well-known protecting group, and then carrying out the rifluoride, and 1 active group can be obtained by treating the compound having a protecting group by a well-known method to :ess or release the protecting group. ad above, the K The compound of this invention obtained as an be isolated mentioned above is very useful as a carcinostatic agent. conventional Pharmaceutically acceptable additives are appropriately as column added to the compound and the resulting mixture can be he like. A salt formulated into various drug forms such as oral pre- la can be parations, for example tablets, syrup, capsules, powder, ding to a con- 10 granules and the like, and injections, for example, such as intramuscular injection, intravenous injection, drip furic acid, infusion. and the like, and then applied as a carcino- acid such as static agent. The administration route, the dosage and the like; an the number of administrations are properly selected de, sodium 15 depending upon the conditions of a patient, though oral arbonate, sodium In usual, in the case of an administration is preferred. arbonate, adult, the compound is administered once to thrice a day nic base such in a total dosage of 1 to 4,000 mg/kg. riethanolamine, This invention is further explained below ig and purifying referring to Examples, which are merely by way of illust- ioned production ration and not by way of limitation. id by the

:tive group such Example 1 ce in the In 23 ml of N,N-dimethylformamide (referred to ecting group hereinafter as DMF) was suspended 0.88 g of sodium a group with a 25 hydride (purity and 4.5 g of l-benzyl-2,3-dioxo- arrying out the piperazine was added to the resulting suspension, after id havina a free which the resulting mixture was stirred at 800 C for

1 min, and then cooled to 650 C. Thereinto was dropped

ml of a DMF solution containing 4.0 g of 4-acetylamino-

benzyl chloride, and the resulting mixture was subjected

'to reaction at 60 65°C for 30 min. After the completion

of the reaction, the solvent was removed by distillation

under reduced pressure, and 20 ml of ethanol was added

to the residue, after which the crystals precipitated

were collected by filtration. The crystals thus obtained

were added to 60 ml of 2N hydrochloric acid, and the

resulting solution was heated under reflux for one hour.

After the completion of the reaction, the reaction

mixture was cooled to room temperature, and thereto

was added 4.0 g of sodium hydrogen carbonate, after which

the crystals precipitated were collected by filtration,

dried, and then recrystallized from ethyl acetate, to

obtain 4.9 g (yield 90%) of 1-(4-aminobenzyl)-4-benzyl-

2,3-dioxopiperazine having a melting point of 193

194 0 C.

IR (KBr) cm -1 vNH 3450, 3350

C=O 1660

Elementary analysis (for C 1 8 H 9N 3 0 2

Calcd. C: 69.88, H: 6.19, N: 13.58

Found C: 69.82, H: 6.26, N: 13.52

NMR (d6 -DMSO) ppm values:

3.34 (4H, s, piperazine ring CH 2 x 4.38

(2H, s, CH 2 x 4.53 (2H, s, CH 2 x 1),

4.99 (2H, s, NH 2 x 6.50 (2H, d,

benzene ring H x 6.93 (2H, d,

1 benzene ring H x 7.22 (5H, s, benzene ring

H x

In 3.9 ml of ethylene glycol was suspended 1.3 g

of 1-(4-aminobenzyl)-4-benzyl-2,3-dioxopiperazine, and

0.57 g of 2-chloropyrimidine was added to the resulting

suspension with stirring at 140 0 C. The resulting mixture

was subjected to reaction at 140 150 0 C for 30 min.

After the completion of the reaction, the reaction

mixture was cooled to 100 0 C, and 2.42 ml of water was

added to the reaction mixture. After allowing the

resulting mixture to stand, 17 ml of water was added

again thereto, and the resulting mixture was stirred,

after which the crystals precipitated were collected by

filtration, dried.and then recrystallized from ethanol,

to obtain 0.9 g (yield 75%) of l-benzyl-4-[4-(2-

pyrimidinylamino)benzyl]-2,3-dioxopiperazine having a 0 melting point of 175 176 C. -i IR (KBr) cm-: VNH 3320

VC=0 1670

Elementary analysis (for C 2 2 H 2 1 N 5 0 2

Calcd. C: 68.20, H: 5.46, N: 18.08

Found C: 68.24, H: 5.38, N: 17.89

NMR (d 6 -DMSO) ppm values:

3.42 (4H, bs, piperazine ring CH 2 x 2),

4.51 (2H, s, CH 2 x 4.54 (2H, s, CH 2 x 1),

6.75 (1H, t, J=4.5Hz, pyrimidine ring H x 1),

7.15 (2H, d, J=8.5Hz, benzene ring H x 2),

7.25 (5H, s, benzene ring H x

1 7.70 (2H, d, J=8.5Hz, benzene ring H x 2),

8.40 (2H, d, J=4.5Hz, pyrimidine ring H x 2),

9.68 (1H, s, NH x 1)

To a mixture of 372 mg of sodium hydride (purity

50%) and 30 ml of DMF was added dropwise a solution of

3 g of l-benzyl-4-4--(2-pyrimidinylamino)benzyl]-2,3-

dioxopiperazine in 20 ml of DMF with stirring over

min, after which the resulting mixture was subjected to

reaction at 60 70°C for one hour. After the completion

of the reaction, 1.3 g of pivaloyloxymethyl chloride was

dropped thereinto over 10 min at the same temperature.

After the completion of the dropwise addition, the

resulting mixture was subjected to reaction at 70 80 C

for 30 min. After the completion of the reaction,-the

solvent was removed by distillation under reduced

pressure, and the residue thus obtained was extracted

with 100 ml of chloroform. The chloroform layer was

washed with 30 ml of water and 40 ml of saturated aqueous

sodium chloride solution in this order, and dried over

anhydrous magnesium sulfate, after which the solvent was

removed by distillation under reduced pressure. The

residue thus obtained.was purified by a column chromato-

graphy (Wakogel C-200, eluted with chloroform), and then

recrystallized from ethyl acetate-diisopropyl ether, to

obtain 2.5 g (yield 64.3%) of l-benzyl-4-{4-[N-

pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-

dioxopiperazine having a melting point of 144 1460C.

IR (KBr) cm-: -1 v 1725, 1670

21

above; or reacting have the same meanings as defined formula, a compound represented by the

.ng H x 2), Elementary analysis (for C2 8 H 3 1 N 504)

ring H k 2) Calcd. C: 67.05, H: 6.23, N: 13.96

Found C: 66.99, H: 6.23, N: 13.85

i hydride (purity NMR (CDCl3 ppm values:

Lsolution of 1.17 (9H, s, CH3 x 3.38 (4H, s, piperazine

)enzyl]-2,3- ring CH2 x 4.65 (4H, s, CH2 x 5.95

'ing over 30 (2H, s, CH2 x 6.68 (1H, t,

subjected to pyrimidine ring H x 7.23 (41, s, benzene

the completion ring H x 7.25 (5H, s, benzene ring H x

rl chloride was 8.33 (2H, d, J=5.OHz, pyrimidine ring H x 2) I I

temperature.

-ion, the Exa2,le 2

)n at 7'0 80'C In 30 ml of ethyl acetate was dissolved 1 g

-eaction, the of l-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-

reduced amino]benzyl}-2,3-dioxopiperazine, and 1 g of glycolic

is extracted 15 acid and 0.02 ml of N hydrogen chloride--ethanol solution

i layer was were added, after which the resulting mixture was subject-

iturated aqueous ed to reaction at room temperature for 3 hours with

id dried over stirring. After the completion of the reaction, the

:he solvent was solvent was removed by distillation under reduced

The 20 pressure, and the residue thus obtained was extracted

)lumn chromato- with 100 ml of methylene chloride. The methylene chloride

orm), and then layer was washed with 30 ml of water and then 30 ml of

3pyl ether, to saturated aqueous sodium chloride solution, and dried

over anhydrous magnesium sulfate, after which the solvent

enzyll-2,3-. 25 was removed by distillation under reduced pressure. The

144 1460C. residue thus obtained was purified by column chromatography

(Wakogel C-200, eluted with chloroform-ethanol), and

22

I

or reacting 0 0

NfCH N N-H

1 recrystallized from e 4 hyl acetate-diisopropyl ether, to

obtain 0.5 g (yield 52.8%) of l-benzyl-4-{4-[N-carboxy-

methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-

dioxopiperazine having a melting point of 85 90 0 C. -1 IR (KBr) cm: C= 1735, 1665

Elementary analysis (for C 2 5 H 2 5N 5 0 5

Calcd. C: 63.15, H: 5.30, N: 14.73

Found C: 63.22, H: 5.38, N: 14.62

NMR (CDCl3 ppm values:

3.40 (4H, s, piperazine ring CH 2 x 4.17

(2H, s, CH 2 x 4.63 (4H, s, CH 2 x 5.25

(2H, s, CH 2 x 6.75 (1H, t,

pyrimidine ring H x 7.22 (5H, s, benzene

ring H x 7.28 (4H, s, benzene ring H-x 4),

8.34 (2H, d, J=5.0Hz, pyrimidine ring H x 2),

9.82 (1H, bs, carboxylic acid H x 1)

Example 3

In 10 ml of ethyl mercaptan was dissolved 1.0 g

of l-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-

maino3]benzyl}-2,3-dioxopiperazine, and 0.01 ml of 5.7N

hydrogen chloride-dioxane solution was added thereto,

after which the resulting mixture was subjected to

reaction at room temperature for 3 hours. After

the completion of the reaction, the solvent was

removed under reduced pressure, and 50 ml of diiso-

propyl ether was added to the crystals thus obtained,

after which the resulting crystals were filtered. The

1 crystals thus obtained were recrystallized from isopropyl

alcohol to obtain 0.8 g (yield 86.8%) of white crystalline

l-benzyl-4-{4-[N-ethylthiomethyl-N-(2-pyrimidinyl)amino]-

benzyl}-2,3-dioxopiperazine having a melting point of

144 0 C. -11 IR (KBr) cm v 1670

Elementary analysis (for C25H27N0S)

Calcd. C: 65.05, H: 5.89, N: 15.17

Found C: 65.02, H: 5.84, N: 15.12

NMR (CDCl3 ppm values:

1.14 (3H, t, CH 3 x 2.53 (2H, q, CH 2 x 1),

3.39 (4H, s, piperazine ring CH 2 x 4.62 (4H,

s, CH 2 x 5.15 (2H, s, CH 2 x 6.57 (1H, t,

pyrimidine ring H x 7.23 7.27 (9H, .m,

S. 15 benzene ring H x 8.25 (2H, d, pyrimidine

ring H x 2)

In the same manner as above, the following compound

was obtained:

l-Benzyl-4-{4-[N-phenylthiomethyl-N- (2-

pyrimidinyl)aminolbenzyl}-2,3-dioxopiperazine

Melting point: 64 650 C (recrystallized from

isopropyl alcohol) -1 IR (KBr) cm v 1670

Elementary analysis (for C 2 9 H 2 7N 5 0 2 S1)

Calcd. C: 68.34, H: 5.34, N: 13.74

Found C: 68.36, H: 5,32, N: 13.71

NMR (CDC1 3 ppm values:

3.33 (4H, s, piperazine ring CH2 x 4.61 (2H,

s, CH 2 x 1i, 4.65 (2H, s, CH 2 x 5.50 (2H, s, 24

L1 11 II: zed from isopropyl CH 2 x 6.60 (1H, t, pyrimidine ring H x 1), f white crystalline 6.98 7.28 (14H, m, benzene ring H x 14), 8.30 yrimidinyl)aminol- (2H, d, pyrimidine ring H x 2) Iting point of

Example 4

In 40 ml of DMF was dissolved 3.0 g of 1-

2N 15 benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxo-

N: 15.12 piperazine, and 0.372 g of sodium hydride (purity 52%) N: 15. 12 was added thereto, after which the resulting mixture was

subjected to reaction at 8000 for 30 min with stirring. (2H, q, CE 2 x 1), 10 ThE, reaction mixture was then cooled, and 0.72 ml of CH x 4.62 (4H, choromethylmethylsul'ide was added thereto, after which 2 x 6.57 (i1H, t, the resulting mixture was subjected to reaction at 7.27 (9H, m, 50 600 for 2 hours. After the completion of the d, pyrimidine reaction, the reaction mixture was distilled under

reduced pressure and the residue thus obtained was following compound extracted with chloroform and then washed with water.

T1 ,--'solution thus obtained was dried over anhydrous ethyl-N-(2- magnesium sulfate, and the solvent was then removed by erazine distillation under reduced pressure. The crystals thus tallized from 20 obtained were recrystallized from isopropyl alcohol to

obtain 3.0 g (yield 86.45%) of white crystalline 1-

benzyl-4-{4-[N-methylthiomethyl-N- (2-pyrimidinyl) aino]-

io 2 s1) benzyl}-2,3-dioxopiperazine having a melting point of 14, N: 13.74 1560C. 32, N: 13.71 IR (KBr) cm 1670

Elementary analysis (for C 2 4 H 2 5 N 5 0 2 S 1 TCH 2 x 4.61 (2H, Calqa. C: 64.41, H: 5.63, N: 15.65 12 x 5.50 (2H, s,

1 Found C: 64.38, 5.61, N: 15.60

NMR (CDC13 ppm values:

2.10 (3H, s, CH 3 x 3.40 (4H, s, piperazine

ring CH 2 x 4.63 (4H, s, CH2 x 5.15

(2H, s, CH 2 x 6.58 (1H, t, pyrimidine ring

H x 7.10 7.35 (9H, m, benzene ring H x 9),

8.26 (2H, d, pyrimidine ring H x 2)

In the same manner as above, the following compound

was obtained:

l-Benzyl-4-{4-[N-isopropylthiomethyl-N-(2-

pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine Melting point: 135 0 C (recrystallized from isopropyl

alcohol) -1 IR (KBr) cm Cv 1670 C=O Elementary analysis (for C 2 6 H29N 5 0 2 S 1

Calcd. C: 65.66, H: 6.14, N: 14.72

Found C: 65.64, H: 6.12, N: 14.68

NMR (CDCl3 ppm values:

1.25 (6H, d, CH 3 x 2.97 (1H, q, CH x 1),

3.37 (4H, s, piperazine ring CH 2 x 4.63 (4H,

s, CH 2 x 5.16 (2H, s, CH 2 x 6.56 (1H, t,

pyrimidine ring H x 7.22 7.27 (9H, m,

benzene ring H x 8.26 (2H, d, pyrimidine ring

H x 2)

Example

Based on Examples 1 and 2, any starting

materials were selected to obtain the compounds shown in

Table 3.

1 Note: In Table 3, IPA isopropyl alcohol,

IPE diisopropyl ether, AcOEt ethyl acetate and Et 2 0

diethyl ether.

In the "Process" columns, the word "Pro."

number refers to the process number stated in the

description of the specification, and the compound

referred to in the line in which the "Pro." number appears

was synthesized in the same manner as in the Example

mentioned hereinbefore concerning the said process, or

according to the method described in the specification

based on said Example.

In the "Recrystallization Solvent" column,

the term "Column" means that the product was purified by

column chromatography.

Table 3

0 0

NN CH 2-N NC

CH-X-R 1 R2 2 M.P. (OC) Recrystalliza- Process

-CH3 H 0 138 140 AcOEt Pro. -C H5 H 0 135 138 AcOEt-Et 0 Pro. 2 Pro. (2)

-CH 2 CH (CH3 2 H 0 145 AcOEt Pro. (1)

-C(CH 2 1 6 CH 3 H 0 116 AcOEt Pro. (1) 11

-CH 2 CHCH 2 OH H 5-8 H2 Cl2-IEPo (2

OH___

-CH 2 CH 2 N(CH 2 CH 2 OH) 2 HRn 0cm t Column Pro. (2)

-CH (CH 3 2 H j0147 IPA Pro. (1)

SIa S 0 S C SO gOOSe0 C S 0 0 0* S 4501 OS C b5S S Oe@ S 550 See.. S I 0S* S SOS C *SS S

Table 3

0

C>- N& CH 2 -N N-H2

CH-X-R' 12 R

R R2 x M. P. C)

-CH 3 H 0 138 140

C2H5 H 0 135 -138

-CH 2C (CH32H 0 145

-C(CH 2 1 6 CH 3 H 0 116

-CH 2 CHCH 2 OH H 0 75 -83

OH

H 0 oil -1 -CH2 C CH 2IR(neat) 2 O)N(C cm -CHCH 2 (vHCH=O) 1650

H 0 147 -CH(CH 3 2

C S C C C C C C C C OCCS Sum CC S S 0 C C COSSO C@ C C C 6 6 CCC C 6 e.g 5OS C *CS C CCC C S

Table 3

0 0

NCH 2 -N N-CH 2 -K

CH-X-R'

R2 Recrystalliza- Process tion Solvent

H 0 138 140 AcOEt Pro. Pro. H 0 135 138 AcOEt-Et 0 Pro.

H 0 145 AcOEt Pro. (1) H 0 116 AcOEt Pro. (1)

H 0 75 83 CH 2 C1 2 IPE Pro.(2

H 0 oil IR(neat) cm Column Pro. (2) XC=0 1650

I 147 IPA Pro. (1)

1 Preparation Example 1

Per one capsule, 100 mg of l-benzyl-4-{4-[N-

methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxo-

piperazine, 50 mg of milk sugar, 48 mg of corn starch

and 2 mg of magnesium stearate were mixed, and capsules

were filled with the resulting mixture, to obtain a

capsule drug.

Preparation Example 2

Per one tablet, 250 mg of l-benzyl-4-{4--[N-

ethoxymethyl-N-(2-pyrimidinyl)aminolbenzyl}-2,3-

dioxopiperazine, 50 mg of milk sugar, 38 mg of corn starch,

mg of polyvinyl pyrrolidone and 2 mg of magnesium

stearate were mixed, and the resulting mixture was formed

into tablets in the conventional manner to obtain a tablet

drug.

=yl- -iox-

myl-4,-d4- [-I

corn starch

1, and capsules

:o obtain a

izyl-4-{4-F[N-

rl}1-2,3-

mg of corn starch,

Df magnesium

Lxture was-formed

:o obtain a

Claims (1)

The claims defining the invention are as follows:

1. A compound represented by the formula,

0 0

CH2 H -CH 2 2

H-C-X-R 2 R

wherein R represents a substituted or unsubstituted

alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or 2 acyl group; R represents a hydrogen atom or an alkyl

group; and X represents an oxygen atom or a sulfur atom,

or a salt thereof.

2. The compound according to Claim 1, wherein R 2

is a hydrogen atom.

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

an oxygen atom.

4. The compound according to Claim 3, wherein R 1

is a substituted or unsubstituted acyl group.

The compound according to Claim 3, wherein R is

a substituted or unsubstituted alkyl group.

6. The compound of Claim 5, which is l-benzyl-

4-{4-[N-methoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-

dioxopiperazine of the formula,

0 0

-N CH2 -N N-CH-

CH 2 OCH 3

or a salt thereof.

lows: 7. The compound of Claim 5, which is l-benzyl-4-

mula, {4-[N-ethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-

dioxopiperazine of the formula,

0 0

C- N -N -CH2-N N-CH 2

CH 2 OCH CH 2 3

Lbstituted or a salt thereof.

.enyl, aryl or 8. A process for producing a compound represented

)r an alkyl by the formula,

L sulfur atom, 0 0 -C- I N- N C L, wherein R

H-C-X-R

2, wherein X is

wherein R1 represents a substituted or unsubstituted 3, wherein alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl Jp. 2 or acyl group; R represents a hydrogen atom or a:a alkyl 1 3, wherein R is group; and X represents an oxygen atom or a sulfur atom,

or a salt thereof, which comprises reacting l-benzyl- s l-benzyl- 4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine or no]benzyll-2,3- a reactive derivative thereof with a ccmpound represented

by the formula,

1 Y-CH-X-R

wherein Y represents a reactive group, and R, R and X have the same meanings as defined above; or reacting a compound represented by the formula,

0 0

N- CH2-N N-CH29

HC-OCR 4 12 11 R 0

4 wherein R represents a substituted or unsubstituted

alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl

group; and R 2 has the same meaning as definted above, with

a compound represented by the formula:

H-X-R 3

wherein R 3 represents a substituted or unsubstituted

alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl or aryl

group; and X has the same meaning as defined above.

9. A process according to Claim 8, which comprises

reacting l-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-

dioxopiperazine or a reactive derivative thereof, with

a compound represented by the formula,

Y-CH-X-R1 12 R

wherein R R X and Y have the same meanings as defined

in Claim 8.

A process according to Claim 8, wherein a

compound represented by the formula,

HC-X-R

2 3 wherein R 2 R and X have the same meanings as defined in

Claim 8, is produced by reacting a compound represented

by the formula,

0 0

c -N N CH2-N N-CH a HC-OCR- 12 R 0

2 4 wherein R 2 and R have the same meanings as defined in

Claim 8, with a compound represented by the formula,

H-X-R 3

wherein R 3 and X have the same meanings as defined in

Claim 8.

11. A carcinostatic agent comprising a compound

represented by the formula,

O 0

N-4 CH 2 -CH2

1 1

R

33

i- wherein R 1 represents a substituted or unsubstituted alkyl, cycloalkyl, aralkyl, alkenyl, alkadienyl, aryl or acyl group; R2 represents a hydrogen atom or an alkyl group; and X represents an oxygen atom or a sulfur atom, or a salt thereof.

lings as defined in

>ound represented

DATED: 26th January, 1982.

PHILLIPS ORMONDE AND FITZPATRICK Attorneys for LTD, o ao TOYAMA CHEMICAL CO., LTD. A

gs as defined in

y the formula,

s as defined in

sing a compound isubstituted idienyl, aryl or ui or an alkyl r a sulfur atom,