JPS61152660A - Bis-dioxopiperazine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are H or lower alkyl, provided that both R1 and R2 are not lower alkyl at the same time; R3 is H or group of formula II; (a) when both R1 and R2 are H and R3 is group of formula II, then R4 is (CH2)nR5 or group of formula III-IV, etc.; R5 is lower alkoxy, phenylthio, etc.; R6 and R7 are H or lower alkyl, or R6 is phenyl, etc.; R8 is H, lower alkylcarbonyl, etc.; R9 is lower alkoxy, NH2, etc.; (b) when both R1 and R2 are lower alkyl and R3 is group of formula II, then R4 is lower alkyl, phenyl, lower alkoxy, etc.; and (c) when R3 is H, then R4 is the groups of R4 in the case (b) except for lower alkyl] and its non-toxic salt. EXAMPLE:1,2-bis[4-[ 2-(N-Methoxycarbonyl)aminoacetoxymethyl ]- 3,5-dioxopipe razin-1-yl]ethane. USE:An antitumor agent suitable for drug preparation. PREPARATION:The compound of formula I can be prepared by condensing the compound of formula V with the compound of formula R4COOH in the presence of a condensation agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a compound of the general formula (I) [wherein R1 and R1 are both a hydrogen atom or a lower alkyl group].

However, it cannot be a lower alkyl group at the same time.

R1 is a hydrogen atom or has the formula -CH, -0-C-R.

It is the basis of

R4 is a) R and R1 are both hydrogen atoms, and R1 is of the formula -CH
, -0-C-R,: R7 or a substituted or unsubstituted heterocyclic group (wherein R2 is a lower alkoxy group, a substituted or unsubstituted phenylthio group, a substituted or unsubstituted biphenyl group, A substituted or unsubstituted heterocyclic group or a lower alkylcarbonyl group, R6 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group, R1 is a hydrogen atom or a lower alkyl group, R1 is a hydrogen atom, Lower alkylcarbonyl group, lower alkoxycarbonyl group, or tosyl group, R6 is lower alkoxy group, amino group, methanesulfonyl group, or substituted or unsubstituted phenyl group, RIll is 07-1. a substituted benzyl group or a substituted or unsubstituted phenyl group, n represents 1 or 2] b) Either R or R1 is a lower alkyl group and R
When 1 is a group of formula -CH, -〇-C-R4: lower alkyl group, substituted or unsubstituted phenyl group, lower alkoxy group, substituted or unsubstituted benzyloxy group, or substituted or unsubstituted phenoxy group c) When R is a hydrogen atom: Represents a substituted or unsubstituted phenyl group, lower alkoxy group, substituted or unsubstituted benzyloxy group, or substituted or unsubstituted phenoxy group] This invention relates to derivatives or non-toxic salts thereof.

[Conventional technology]

Various bis-dioxopiperazine derivatives have been reported to date, but there are only 1 compounds with anti-cancer activity.
．． 2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)ethane [Proceedings of the 8th International Conference on Pharmacology, p. 441, 1981] and 1,2-bis(4-
Morpholinomethyl-3,5-dioxopiperazine-1-
, il) propane (Japanese Unexamined Patent Publication No. 59-190976) is known.

[Problem that the invention seeks to solve]

However, these compounds have had problems in formulation because they are unstable in protic polar solvents such as water and lower alcohols.

[Means for solving problems]

The present inventors conducted research on sudioxopiverazine derivatives, which are advantageous in terms of formulation, and found that the compound represented by the general formula (I) has excellent anti-NG action and stability in protic polar solvents, which is advantageous in terms of formulation. The present invention was completed based on the finding that

The compound of the present invention is represented by the above general formula [1], and the meanings and examples of words used to define each symbol in this formula will be explained below.

"Lower" means a group having 1 to 6 carbon atoms unless otherwise specified.

Examples of "lower alkyl groups" include methyl, ethyl,
n-propyl, 1so-propyl, ■-butyl, 1s
Straight chain or branched chain alkyl groups such as o-butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned.

r Ct~1. Examples of the "alkyl group" include linear or branched alkyl groups such as n-heptyl, 2-methylhexyl, n-octyl, 2-ethylhexyl, n-nonyl, and n-decyl.

Examples of the "lower alkoxy group" include methoxy, ethoxy, n-propoxy, 1so-propoxy, n-butoxy, 1so-butoxy, tCrt-butoxy, n-pentyloxy, n-hexyloxy, and the like.

[Lower alkylcarbonyl group] is a carbonyl group substituted with the above-mentioned lower alkyl group, such as acetyl,
Examples include propionyl, butyryl, 1so-butyryl, valeryl, 1so-valeryl, piparoyl, and the like.

"Lower alkoxycarbonyl group" is a carbonyl group substituted with the lower alkoxy group, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1so-propoxycarbonyl, n-butoxycarbonyl, 1so-butoxycarbonyl, tert
-butoxycarbonyl and the like.

The "heterocyclic group" is a 5-membered ring group containing an oxygen atom or a sulfur atom, such as 2- or 3-furyl, 2- or 3-chenyl, and the like.

In addition, when the phenyl group, biphenyl group, phenylthio group, benzyl group, benzyloxy group, phenoxy group, or heterocyclic group has a substituent, examples of the substituent include halogen atoms such as fluorine, chlorine, and bromine, methyl, and ethyl. Examples of alkyl groups, carboxyl groups, and phenoxy groups such as methoxy and ethoxy include nitro groups.

Examples of the compounds of the present invention include the following two compounds.

・1,2-bis(4-β-7cetylprobionyloxymethyl-3.5-dioxopiperazin-1-yl)ethane ・1,2-bis(4-p-biphenylacetoxymethyl=3.5- dioxopiperazin-1-yl)ethane 1
．． 2-bis(4-furylacetoxymethyl-3,5-dioxopiperazin-1-yl)ethane/1,2-bis(
4-Thhenylacetoxymethyl-3,5-thioxopiperazin-1-yl)ethane, 1,2-bis[4-(2-
Aminoacetoxymethyl)-3゜5-dioxopiperazin-1-yl]ethane trifluoroacetate 1,2-bis[4-(2-(N-methoxycarbonyl)aminoacetoxymethyl]-3,5- dioxopiperazin-1-yl]ethane・1,2-bis[4-(2-(N-tert-butoxycarbonyl)aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]ethane・1. 2-bis[4-[2-(N-p-toluenesulfonylcoaminoacetoxymethyl]-3,5-dioxopiperazin-1-yl]ethane, 1,2-bis(4-(N-acetyl-α) -alanyloxymethyl)-3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-(N-acetyl-N-methyl-α)
-7-ranyloxymethyl)-3,5-dioxopiperazin-1-yl]ethane 1,2-bis(4-(2-amino-2-phenylacetoxymethyl)-3,5-dioxopiperazine- 1-yl]ethane trifluoroacetate 1,2-bis[+-C2-(N-methoxycarbonyl)amino-2-phenylacetoxymethyl]-3,5-
dioxopiperazin-1-yl]ethane-1,2-bis[4-(2-(N-tCrt-butoxycarbonyl)amino-2-phenylacetoxymethyl]-3,5-dioxopiperazin-1-yl) Ethane 1,2-bis(4
-methoxyacetoxymethyl-3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-p-fluorophenylthioacetoxymethyl-3,5-dioxopiperazin-1-yl)ethane 1 ,2-bis(4-p-bromophenylthioacetoxymethyl-3,5-dioxopiperazin-1-yl)ethane-1,2-bis(4-O-methoxybenzoyloxymethyl-3,5-dioxo piperazin-1-yl)ethaneel, 2-bis(4-p-aminobenzoyloxymethyl-3,5-dioxopiperazin-1-yl)ethane/1,2-bis(4-p-methanesulfonylaminobenzoyl) Oxymethyl-3,5-dioxopiperazine-1
-yl)ethane 1,2-bis(4-p-phenylbenzoyloxymethyl-3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-furoyloxymethyl-oxopiperazine- 1-yl)ethane-1,2-bis(4-(4-carboxy)furoyloxymethyl-3,5-dioxopiperazin-1-yl)ethane/1,2-bis(4-thenoyloxymethyl -3.5-
dioxopiperazin-1-yl)ethane・1,2-bis(4-(2-ethylhexyloxycarbonyloxymethyl)-3,5-dioxopiperazine-
1-yl]ethaneΦ1.2-bis(4-p-nitrobenzyloxycarbonyloxymethyl-3.5-dioxopiperazine-1-
yl]ethane・1,2-bis(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane・1,2-bis(4-acetoxymethyl-3.5-dioxopiperazine- 1-yl)propaneψ1,2-bis(4-piparoyloxymethyl-3.5
-thioxobiperazin-1-yl)propane 1,2-
Bis(4-benzoyloxymethyl-3,5-thioxobiperazin-1-yl)propane 1,2-bis(4-
o-chlorobenzoyloxymethyl-3.5-dioxopiperazin-1-yl)propane/1.2-bis[4-methoxycarbonyloxymethyl-3.5-dioxopiperazin-1-yl)propane/1. 2-bis(4-jso-butoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane, 1,2-bis(4-p-nitrobenzyloxycarbonyloxymethyl-3,5-dioxo piperazine-1-
yl) propane φ1.2-bis(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane@1-(4-o-chlorobenzoyloxymethyl-3,
5-dioxopiperazin-1-yl)-2-(3.5-
dioxopiperazin-l-yl)ethane l-(4-iso-butoxycarbonyloxymethyl-3.5-dioxopiperazin-1-yl)-2-(3
．． 5-thioxobiperazin-1-yl)ethane/l-(
4-o-chlorobenzoyloxymethyl-3.5-dioxopiperazin-1-yl)-2-(3.5-dioxopiperazin-1-yl)propane 1-(3.5-dioxopiperazin-1-yl) 1-yl)-2-(4-〇-chlorobenzoyloxymethyl-3,5-dioxopiperazine-
1-yl)propane/l-(4-iso-butoxycarbonyloxymethyl-3,5-dioxopiperazine-1
-yl)-2-(3,5-dioxopiperazin-1-yl)propane-1-(3,5-dioxopiperazine-1
-yl)-2-(4-iso-butoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane 111-(4-p-nitrobenzyloxycarbonyloxymethyl-3,5-dioxopiperazine) -1-
yl)-2-(3,5-dioxopiperazin-1-yl)propane 1-(3,5-dioxopiperazin-1-yl)-2
-(4-p-nitrobenzylcarbonyloxymethyl-
3,5-dioxopiperazin-1-yl)propane@1-(4-phenoxycarbonyloxymethyl-3゜5-dioxopiperazin-1-yl)-2-(3,5-
dioxopiperazin-1-yl)propane 1-(3,
5-Dioxopiperazin-1-yl)-2-(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane The compound (I) of the present invention has an asymmetric carbon in its molecule. When it has atoms, it includes optical isomers and mixtures thereof.

Further, the compound of the present invention may take the form of an acid addition salt as a pharmacologically acceptable non-toxic salt, and the salt in this case includes hydrochloride, oxalate, p-toluenesulfonate,
Examples include vinegar ai, trifluoro chuchu salt, and the like.

Compound (I) of the present invention can be produced by the method shown below.

(^) In the presence of the MA mixture, the compound represented by the general formula ■ c (in the formula, R1 and R1 are the same as the definitions in the surface) and the general formula ■ R9-C0OH...■ (in the formula, R4 is The compound (+
) is manufactured.

Examples of the condensing agent include 1-methyl-2-chloropyridinium iodide, 2-chloro-3-ethylbenzoxazolium tetrafluoroporate, and dicyclohexylcarbodiimide.

In this condensation reaction, R1 is of the formula -cu or -o-a-u for 1 mole of the compound of general formula (2).

In the case of the group, use at least 2 moles each of the compound of the general formula (1) and the condensing agent, and when R1 is a hydrogen atom, use 0.8 to 1.2 moles each of the compound of the general formula (1) and the condensing agent.0 reaction temperature. The reaction can be carried out at -30 to 100°C, preferably from 0°C to room temperature.The reaction time varies depending on the reaction temperature, etc., but 1 to 24 hours is appropriate.As the reaction solvent, an aprotic Solvents such as N,N-dimethylformamide (DMF), acetonitrile, chloroform,
Dichloromethane and the like can be used alone or in combination.

In the above reaction, it is preferable to use dimethylaminopyridine as a catalyst.

(8) Compound (I) is produced by reacting the compound of general formula (1) with a reactive derivative of the compound of general formula (2), ie, a chloride or a hot hydrate.

In this reaction, the acid halide, haze anhydride or halogenated formate of the compound of general formula 0 is added to 1 mol of the compound of general formula
When R1 is a hydrogen atom, at least 2 moles are used, and when R1 is a hydrogen atom, 0.8-1.2 moles are used. The reaction temperature is -10~
The reaction can be carried out at 120°C, preferably in the range of 0 to 80'0, and the reaction time varies depending on the reaction temperature, etc.
As the reaction solvent for which 4 hours is appropriate, aprotic polar solvents such as DMF, acetonitrile, chloroform, dichloromethane, ethyl cupcake, pyridine, lutidine, picoline, etc. can be used alone or in combination.

The above reaction is preferably carried out in the presence of a base such as pyridine or triethylamine.

Furthermore, a compound represented by the general formula (1) (in which R1 and R are the same as defined above) is reacted with sodium hydride, and then a compound represented by the general formula (0) is reacted with sodium hydride.
Compound (I) can also be produced by reacting a halogenated methyl ester of the compound.

When producing the compound (+) of the present invention, the functional group of compound 0 is protected by a conventional method if necessary.

Also, acid addition salts of the compound (I) of the present invention, such as hydrochloride,
Shu salt-resistant, toluenesulfone salt-resistant, acetate, trifluoroacetate, etc. can be produced by conventional methods.

The compound of general formula (1), which is the starting material for the above production method, is a known compound and is described in British Patent No. 1,234,935. Further, the compound of general formula 0, which is a starting material, is a new compound and can be easily produced by reacting compound 0 with formaldehyde.

[For production]

Next, the anti-II compound of the present invention obtained by the above production method
I Explain the tumor action.

Anti-II of the compounds of the present invention! The tumor effect was confirmed by the survival rate for P388 leukemia rt*m in mice in the following pharmacological test.

P388 Leukemia ■! In the survival test for cancer, 10 animals in the control group and 7 animals in the administration group were tested using CDF, #! Mouse (6
Weeks of age, weight 25±2j), 1.0X 10 P388 leukemia 1 in the peritoneal cavity! Tumor cells were each transplanted, and a predetermined amount of the test compound was intraperitoneally administered twice on the next day and on the 5th day. The effectiveness of the test compound is determined by its survival rate (Rate).
of Increase in Life 5pan)
It was calculated using the following formula.

T: Median survival days of the administration group C: Median survival days of the control group The results are shown in Tables 1-1 and 1-2 above. - Table 1-1 Nawate leukemia I! Table 1-2 Results of life prolonging test for P388 leukemia H tumor The compound of the present invention shows the results of the life prolonging test for P388 leukemia H tumor. Since it showed an excellent survival rate against tumor cells, it is clear that it has anti-111m activity and is useful as an anti-111m agent for animals and humans.

Next, the administration method, dosage form, and dosage when the bis-dioxopiperazine derivative of the present invention is applied to the human body will be explained.

The compound of the present invention can be administered orally or parenterally, and dosage forms for oral administration include tablets, coatings, etc.
Powders, granules, capsules, syrups, etc. can be used, and as dosage forms for parenteral administration, injections (including lyophilized injections that are dissolved before use), skewers, etc. can be used. These dosage forms (a) contain pharmaceutically acceptable excipients, binders,
Lubricants, disintegrants, suspending agents, emulsifiers, preservatives, stabilizers and dispersants, such as lactose, sucrose, starch, dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, distilled water or It is performed using physiological saline.

Although the dosage varies depending on the patient's symptoms, age, body weight, etc., the daily dose for adults can be 50 to 3000 ms, preferably 500 to 100 OIIIJI, divided into 1 to 3 doses.

[Manufacturing examples and examples]

Next, production examples and examples will be shown to explain the present invention in more detail, but the present invention is not limited thereto.

Production example 1.2-bis(4-hydroxymethyl-3
,5-dioxopiperazin-1-yl)-ethane 2.0 g (7,9 mmof) of 1,2-bis(3,5-dioxopiperazin-1-yl)-ethane was added with DMF
After adding 10mM and heating and stirring at 130' (:!) for 10 minutes, 2 d of a 37% aqueous formaldehyde solution was added.
Another 130'C! The mixture was heated and stirred for 1.5 hours. After the reaction was completed, the reaction mixture was left in a refrigerator overnight, and the resulting solid was collected in an oven. This was washed with ethyl acetate and dried under reduced pressure to obtain 1.6 Jl (yield: 64.7%) of the title compound.

Melting point: 170-172°C (recrystallized from dioxane) Elemental analysis: C, H, J40. Theoretical value (%)
: C45,86H5,77N 17.83 actual measurement value (
%): C45,83H5,73N 17.73 Example 11,2-bis[4-(2-(N-methoxycarbonyl)aminoacetoxymethyl)-3,5-dioxopiperazin-1-yl]ethane N- Methoxycarbonyl-2-aminoacetyl chloride 0.68g (4.5mmol) and pyridine (0-3aQ
) -DMF (I011Q) mixture, -10
1,2-bis(4-hydroxymethyl-3,5-
dioxopiperazin-1-yl)ethane0JOn(ka■
After stirring for 1.5 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. 10% extract
After washing with sulfuric acid and then water, it was dehydrated with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent from the extract under reduced pressure was purified by silica gel column chromatography (chloroform:methanol ratio 9:1, Rff direct -0.3) to obtain the title compound 0-25JI (yield 24 %) was obtained.

Melting point = 184-188°C Infrared absorption spectrum (KBr) an-“: 1760.
1700 (C-0) Nuclear magnetic resonance spectrum (D5od,) J ppm
: 2.65 (4M, s), 1.55 (6H, s
) 3.59 (8H, s), 3.73 (4H, d,
J=6Hz) 5.66(4H,s), 7.56(
2H, t, J=6Hz) The following compound was produced in the same manner as in Example 1 from the corresponding starting materials.

・1,2-bis[4-[2-(N-p-toluenesulfonyl)aminoacetoxymethyl]-3,5-dioxopiperazin-1-yl]ethane (yield 12%) Melting point = 66
~70°C Infrared absorption spectrum (KBr) an-': 174
0.1690 (C-0) 1330.1150 (-5O,-) Nuclear magnetic resonance spectrum CDMSO-d, ) a pprn:2
．． 37 (6B, s), 2.64 (4H, s)3
．． 57 (8H, s), 3.66 (4) 1, d
, J=6Hz) 5.58 (4H, s), 7.37
(4H, d, J=81h)7.65(4)1,
d, J = 8Hz) 8.16 (2H, t, J = 6
Hz) Example 21.2-bis[4-C2-(N-ter
t-Butoxycarbonyl)aminoacetoxymethyl]-3,5-dioxopiperazin-1-yl]ethane 1,2-bis[4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane 2-36s (7,5+
+unol), N-tert-butoxycarbonylglycine 2.6371 (I5 mmol), 4-N,
A dichloromethane (I5mQ) solution of 109g (I5+n+nol) of dicyclohexylcarbodiimide was gradually added to a mixture of 0.15j N-dimethylaminopyridine and 40taQ dichloromethane under water cooling, and the mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 hours. The reaction mixture was filtered. The filtrate was condensed with S under reduced pressure and the resulting residue was subjected to silica gel column chromatography (ethyl acetate, Rf(fi-
0,6) to obtain 81 g of the title compound L (yield 60%).
I got it.

Melting point: 161-164°C Infrared absorption spectrum (KBr) C1l+-”: 174
0.1700 (C=0) Nuclear Magnetic Resonance Spectrum (D5o-d,) a pptn: 1.38 (I
8) 1, s), 2.65 (4H, 5) 3-58
(8H, s), 3.65 (4H, d, J=6H
z) 5.65 (4H, s), 7.23 (2) 1,
t, J=6Hz) The following compound was prepared in the same manner as in Example 2 from the corresponding starting materials.

・1.2-bis[4-((S)-2-(N-tert-
butoxycarbonyl)amino-2-phenylacetoxymethyl]-3,5-dioxopiperazin-1-yl]ethane Melting point: 55-60°C Infrared absorption spectrum (KBr) an -”: 1760
．． 1700 (C-0) Nuclear magnetic resonance spectrum (CDCQ,) θppm: 1.
43 (I8H, s), 2.54 (4H, 5) 3-4
6 (8H, s), 5.33 (2H, d, J=8
Hz) 5.56 (2H, d, J-8Hz), 5
．． 87(41(,s)7.37(IOH,m) ・1.2-bis[4-((R)-2-(N-tert-
Butoxycarbonyl)amino-2-phenylacetoxymethyl)-3,5-dioxopiperazin-1-yl]ethane (yield 5B 59%) Melting point near 2-74°C Infrared absorption spectrum (KBr) cs -': 176
0.1700 (C wing 0) +1. (a % Resonance spectrum (CDC11,) J
spt: 1.42 (I8B, s), 2-52
(4B, s) 3.43 (8H, s), 5.31
(2B, d, J=8Hz) 5.53 (2H, d
, J=8Hz), 5-83 (4H, s) 7.3
1 (IOH, shoe) ・1,2-bis(4-(N-7 cetyl-N-methyl~D
.

L-α-alanyloxymethyl)-3-5-dioxopiperazin-1-yl]ethane (colorless oil, yield 64%)
) Infrared absorption spectrum (liquid film) cm-': 1740.16
90 (C 0) Nuclear Magnetic Resonance Spectrum (CDCQ,) tpp praise: 1.3
6(6)1, d, J=711z), 2.
09 (6B, s) 2.71 (4H, s), L9
5 (611, s).

3-56 (8H, s), 5.09-5.18 (2H, m
) 5.74-5.84 (4H, +a) ・1.2-bis[4-(N-7 Cetyl-D, L-α-7
ranyloxymethyl)-3,5-dioxopiperazine-
1-yl]ethane (yield 9%) Melting point: 175-179°C (decomposition) Infrared absorption spectrum (KBr) φ゛°: 1740.16
95 (C 0) Nuclear magnetic resonance spectrum (DMSO-d, ) δppm
:1.21 (6M, d, J=7Hz), 1.8
2 (6H, s) 2.65 (4H, s) , 3.34 (
88, s) 3.59 (4H, s), 117 (4H,
m) 5.63 (41, m), 8.29 (2H, d
, J=7Hz)ff Example 31.2-bis[4-(2-
12-bis[4-(2-(N -t
ert-butoxycarbonyl)aminoacetoxymethyl]-3,5-dioxopiperazin-1-yl]ethane 0
．． Add 75g (Immol) to trifluoro vinegar under water cooling.
11111 and stirred for 30 minutes. After evaporating the solvent from the reaction mixture under reduced pressure, ether was added to the residue, and the resulting precipitate was filtered. The precipitate was washed with ether and dried to obtain 0.78 Jl (100% yield) of the title compound.

Melting point = 68~72℃ Infrared absorption spectrum (KBr)! :1m-' :17
60.1690 (C-0) Nuclear magnetic resonance spectrum (DMSO-d,) a PPI
I:2J8(4)1, s), 3.63(8H,
s) 3.84 (4H, s), 5.76 (4fl,
s) 8.35 (6H, s) The following compound was produced in the same manner as in Example 3 from the corresponding starting materials.

・1.2-bis[4-((R)-2-amino-2-phenylacetoxymethyl)-3,5-dioxopiperazin-1-yl]ethane trifluoroacetic acid salt (yield 94%)
) Melting point: 100-105°C Infrared absorption spectrum (KBr) am -': 1760
．． 1700 (C 0) Nuclear magnetic resonance spectrum (D5 o-d,) δppm:
2.50 (4H, s), 3.51 (88, s)5.
33 (2) 1, s), 5.76 (4H, s) 7
．． 43 (IOH, m), 8.95 (6H, s) Example 41.2-bis(4-(2-furylacetoxymethyl)-3,5-dioxopiperazin-1-yl]ethane 1.2- Bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane 1.59 g (5 mmo
l), 2-71J Le Vinegar 1 ¥31.26 Jl (I011
111101), 4-N, N-dimethylaminopyridine 60111711 Add 2.03 J of dicyclohexylcarbodiimide to a mixture of 20 parts of dichloromethane under water cooling.
l (I011111101) of dichloromethane (I5a
dl > solution was added slowly and after stirring at 0°C for 30 minutes and at room temperature for 16 hours, the reaction mixture was heated. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate, Rf value -〇, 5) to obtain 1.0 Hg (yield 37%) of the title compound.

Melting point = 143-146°C Infrared absorption spectrum (KBr) cx -': 1750
．． 1700 (C-0) Nuclear magnetic resonance spectrum (CDcQ#) a ppm+
: 2.68 (4H, s), 3.53 (8B,
s) 3.70 (4H, s), 5.83 (4H, s)
6.2-7.4 (6H, m) The following compounds were produced in the same manner as in Example 4 from the corresponding starting materials.

・1,2-bisC4-(2-thhenylacetoxymethyl)-3,5-dioxopiperazin-1-yl)ethane (
Yield 39%) Melting point = 154-156°C Infrared absorption spectrum (KBr) an -': 175
0.1700 (C snow 0) Nuclear magnetic resonance spectrum (CDCQ,) δppm: 2.6
6 (4H, s), 1.53 (88, s) 3.85 (
4H, s), 5-83 (4H, s) 6.9-7.2
(614, 1) ・1.2-bis(4-p-biphenylacetoxymethyl=3,5-dioxopiperazin-1-yl)ethane (yield 68%) Melting point: 153-155-5°C Infrared absorption Spectrum (KBr) an-': 175
5.1705 (C=O) nuclear magnetic resonance spectrum (CDCQ,) δppm: 2.57 (41, s),
3.47 (8H, s) 3.67 (4H, s), 5
．． 82 (41, s) 7.30-7.58 (I8B,
m) Example 5 1,2-bis(4-o-methoxybenzoyloxymethyl-3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazine) -1-yl) ethane 3-14 g (I0+u
+ol).

O-methoxybenzoin #3-35g (22mmol),
4-N, N-dimethylaminopyridine (L20g
, and dichloromethane 60-, dicyclohexylcarbodiimide 4.12 g (20 mmol) under water cooling.
was added gradually. After further stirring at room temperature for 6 hours, the reaction mixture was filtered, and the quenched solution was washed with water and dried.

The solvent was distilled off from the quenching liquid under reduced pressure, and the resulting residue was recrystallized from ethylene glycol monomethyl ether to obtain the title compound 1.
8171 (yield 31%) was obtained.

Melting point: 163-164℃ Elemental analysis value, theoretical value as C,, H,, N, O,
%): C57,73H5,19N 9.62 Actual value (%): C57-77H5,30N 9.48 Nuclear magnetic resonance spectrum (CDOl,) a PPII:2
．． 70 (4H, s), 3-55 (8H, s) 3.8
8 (6H, s), 5-99 (4H, s) 6.91~
6.97 (4H, m) 7.43-7.50 (2H, m), 7.72-7.
75 (2H, n+) The following compound was prepared in the same manner as in Example 5 from the corresponding starting materials.

・1.2-bisC4-(2-thenoyloxymethyl)-
3,5-Dioxopiperazin-1-yl]ethane (yield 43%) Melting point: 150-151°C Elemental analysis (a: C,, H,, N4! Theoretical value (%) as 3,0.): C4!L42 H4,15N 1
0-48 actual value (%): C4'lJ, 66 H4
,29N 10.61 nuclear magnetic resonance spectrum (CDC1
1,) a pptn: 2.71 (4H, s),
3.57 (8H, 5) 6-00 (4H, s) 7.08 (2H, dd, J=5) 1z-4Hz) 7
．． 57 (2H, dd, J=5Hz・IHz) 7.7
9 (2H, dd, J=4Hz・IHz)・1.2-
Bis(4-(2-furoyloxymethyl)-3,5-dioxopiperazin-1-yl)ethane (yield 42%) Melting point: 166-167°C Elemental analysis (fA2C,,)1. ,?1,0...-Jl
-Theoretical value for H and O [%]: C51,66H4,
53N 10.96 Actual value (%): C51,79
H4,41N 10°89 nuclear magnetic resonance spectrum (CD
CQ, ) jppm: 2.71 (4H, s), 3.5
7 (81, s) 6.00 (4H, 5) 6-50 (2H, dd, J=3-6Hz・1-6Hz
)7-20(2B, dd, J-3,6Hz・0
．． 7Hz) 7-58 (2H, dd, J=1-6Hz・
0.7Hz)・1,2-bis(4-p-bromophenylthioacetoxymethyl-3,5-dioxopiperazine-
1-yl)ethane (yield 44%) Melting point ゛138-139℃ Elemental analysis m: C* @ BI @ Na St
Theory as O* B r * (m (%): C4
3-53H3-65N 7.25 Actual value (%): C
43,661 (3-82N 7.21 Nuclear Magnetic Resonance Spectrum 7L/ (CDCQ,)J ppw+:2.65r4
H, s), 3-49 (8H, s) 3.59 (4H,
s), 5.79 (4H, s) 7.27 (4H, dd
, J=8Hz・2H2)7.42(4H,dd,
J=8Hz・2Hz)・1,2-bis(4-p-fluorophenylthioacetoxymethyl-3,5-dioxopiperazin-1-yl)ethane (yield 48%) Melting point: 103-104°C Infrared Absorption spectrum (KBr) tx-:1740.1
690 (C-0) Nuclear magnetic resonance spectrum (CDCQ m) J Pp+n
:2-66 (4H, s), 3.50 (8H, s) 1.5
3 (41, s), 5.78 (48, s) 6.97~
7.04 (48, decoy) 7.40-7.47 (4H, m) ・1.2-bis(4-β-7cetylpropionyloxymethyl-3,5-dioxopiperazin-1-yl)ethane (Yield 52%) Melting point = 93-94°C Elemental analysis m: cmH,,N4G,, +H, O (theoretical value c%): C5G, 86 H6,01N 10
．． 78 actual survey (%): C50-78H5,75N
10.70 Nuclear magnetic resonance spectrum (CDcQ,) jpp
m: 2.16 (6H, s), L5G ~ 2-70 (8
1, m) 2.70 (41, s), L52 (811,
s) 5.72 (4H, s) Example 6 1,2-bis(4-p-aminobenzoyloxymethyl-3,5-dioxopiperazin-1-yl)-ethane 1,2-bis(4- 0.63 g of hydroxymethyl-3,5-dioxopiperazin-1-yl)-ethane (2,0
pfimol) in pyridine (I0ml) solution.
-Benzyloxycarbonylaminobenzoic acid chloride 1
．． 27 g (4,4a+mol) of pyridine (I2a+Q
) The solution was added gradually under water cooling and stirred at 0°C for 1 hour and then at room temperature for 16 hours. The solvent was removed from the reaction mixture under reduced pressure, water (50d) was added to the residue, and chloroform (I
50IIQX2), and the extract was mixed with 10% sulfuric acid, water,
The mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and then with water, and then dried. The residue obtained by removing the solvent from the extract was purified by silica gel column chromatography [ethyl acetate] to obtain the benzyloxycarbonyl derivative 1.2 of the title compound.
7Jl (yield 77.4%) was obtained.This compound 1-27
tt with vinegar and ethyl-ethanol mixed solvent [mixing ratio 1:
1) Dissolved in 160III, 10% palladium-
13 g of carbon (L) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol - 95:5). Purification and then recrystallization from ether gave the title compound 0.3971 (yield: 45
-7%).

Melting point: 196-199°C Infrared absorption spectrum (KBr) am -': 169
5.1600 (C-0) nuclear magnetic resonance spectrum (DMSO-d,) δppm:
2.68 (4H, s), 3J2 (8H, 5)
5-77 (4H, s), 6.55 (4H, d
, J=9Hz)7-57 (4H,d, J=9
Hz) 0.88 g of the title compound obtained as above (I-
Methanesulfonyl chloride 0-25td C3,2ram was added to a solution of pyridine (6 mmol) in pyridine (20 dl) under water cooling.
The solvent was distilled off under reduced pressure from the reaction mixture, which was stirred for 1 hour at 0°C and then for 2 hours at room temperature.
The extract was washed with 10% sulfuric acid, water, a saturated aqueous sodium hydrogen solution, and water in this order, and dried. The solvent was distilled off from this extract, and the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain 1,2-bis(
43 g of 4-p-methanesulfonylaminobenzoyloxymethyl-3,5-dioxopiperazin-1-yl)-ethane O-(yield 38%) was obtained.

Melting point: 95-105°C Infrared absorption spectrum (KBr) tx-': 170
0, 1600 (C-0) nuclear magnetic resonance spectrum (DMSO-d,) app tone = 2.68 (4H, s)
, 3.10 (6B, 5)3J3 (8H, s
), 5-85 (411, s) 7.28 (48,
d, J-9Hz>7.86 (4H, d, J=
9Hz) Example 7 1,2-bis(4-(3-furoyloxymethyl)-3,5-dioxopiperazin-1-yl)ethane 1.30 g (I0mlIol) of 3-furoylchloride and pyridine (I5adl) Add 1,2-bis[
4-hydroxymethyl-3,5-dioxopiperazine-
Add 1.57 g (5 mmol) of 1-yl)ethane and
After stirring at °C for 30 minutes and at room temperature for 4 hours, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with 10% sulfuric acid and then with water, and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off from the extract under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (rh
ea ethyl, Rf (fa -0,5) Niterite purification to obtain 1.80n (yield 72%) of the title compound.

Melting point = 179-182°C Infrared absorption spectrum (KBr) am -': 174
0, 1700 (C-0) nuclear magnetic resonance spectrum (CDOl,) J ppm: 2.70 (411, s)
, 3.56 (811, s) 5.96 (4H, s) ,
L7-8.0 (61, m) The following compound was produced in the same manner as in Example 7 from the corresponding starting materials.

・1.2-bis(<-2-phenylbenzoyloxymethyl-3,5-dioxopiperazin-1-yl)ethane [yield 51%] Melting point: 2194-197°C (recrystallized from ethylene glycol monomethyl ether) ) Infrared absorption spectrum (KBr) am −': 175
5, 1710 (C-0) nuclear magnetic resonance spectrum (CDCQ,) tppm: 2-72 (4) 1, s
), 3.58 (8)1, s)6.06 (4
H, s) 7.38~7.48・7.58=7.64・8.04~
8-07(I8H,m)A Example 81.2-bis[4-C
3-(4-carboxy)furoyloxymethyl]-3,
1.37 g (5.0 mmol) of 5-dioxopiperazin-1-yl]ethane 3-(4-benzyloxycarbonyl]furoyl chloride in pyridine (I0td
l) 0.78 g (2.5 mmof) of 1,2-bis[4-hydroxymethyl-35-dioxopiperazin-1-yl)ethane was added to the solution at -10°C for 1 hour, and the mixture was further heated at room temperature. After stirring for 18 hours, the solvent was distilled off from the reaction mixture under reduced pressure, and the residue was extracted with chloroform. The extract was washed with 10% sulfur and then water, and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off from the extract under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate, Rfl-0,7) to obtain 85 g of benzyl ester L of the title compound (yield: 97%).

0.45 g (0.6 mmol) of this benzyl ester
was dissolved in 30 ml of ethyl acetate/methanol mixed solvent (mixing ratio 1:1), 0-1 mQ of Gijo and 10% palladium-carbon o, osg were added, and the mixture was heated to 18 ml at room temperature under a hydrogen atmosphere.
Stir for hours. After removing the insoluble matter from the reaction mixture and dissolving it in 1all DMF and separating the catalyst, 300 g of ether was added to the furnace solution and the precipitated crystals were collected to give the title compound 0.08 JI (yield 22 %) was obtained.

Melting point: 203-206°C (decomposition) Infrared absorption spectrum (KBr) am -': 174Q
, 1700 (C-0) nuclear magnetic resonance spectrum (DMSO-d,) a ppm: 2.68 (4H, s
), 3J1 (8H, s) 5.80 (4H, s),
8.3-g-4 (4H, m) 12.93 (2B, Broad S) Example 91.2-bis(4-(2-ethylhexyloxycarbonyloxymethyl)-3,5-dioxopiperazine -1-yl]ethane 1.26 g (4.0 m
2-ethylhexyl 1.9371 (I011111
After gradually adding 01) and stirring at room temperature for 12 hours, the reaction mixture was added to 10 HmQ of water and extracted with chloroform. The extract was washed with water, 5% sulfur haze, and water in this order, and then dehydrated with anhydrous magnesium sulfate. The extract was then concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate, Rfliii-0,72) to obtain the title compound 2.1511 (yield: $86%).

Melting point: 58-61'0 Infrared absorption spectrum (KBr) am -': 174
0, 1700 (C-0) nuclear magnetic resonance spectrum (CDα,) θppm: 0.85-0.91 (I2H
, m) , 1.27-1.38r16H, m) 1.5
6-1.64 (2H, m), 2-67 (4H, s)
3.52 (8H, s), 4.06-4.09 (4H
, m) 5.81 (4H, s) The following compound was produced in the same manner as in Example 9 from the corresponding starting materials.

・1,2-bis[4-p-nitrobenzyloxycarbonyloxymethyl-3,5-dioxopiperazine-1-
) Ethane (yield $49%) Melting point: 158-160.5°C Infrared absorption spectrum (KBr) an -': 1750
, 1700 (C-0) nuclear magnetic resonance spectrum (
CDCQ,)J ppm:2.68r4H,s),
3.53 (8H, s) 5.27 (48, s), 5-
85 (4H, s) 7.53 (4H, d, J=8.6
1(z)8.23 (4H, d, J=8.6Hz)・
1.2-Bis(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane (yield 60%) Melting point: 138 to 140°C Infrared absorption spectrum (KBr) an -' :1750
, 1700 (C-0) nuclear magnetic resonance spectrum (
CDCIl, ) J ppm: 2.69 (4H, s),
3.56 (8H, s) 5.92 (4) 1, s)
, 7-16~7.41(IOH, m)・1,2-bis(4-methoxyacetoxymethyl-3,5-thioxopiperazin-1-yl)ethane (yield 74%) Melting point: 117~120 °C Infrared absorption spectrum (KBr) as-“:1740
, 1700 (C-0) nuclear magnetic resonance spectrum (C
DCQ, ) J ppm: 2.71 (4H, s), 3
．． 42 (8H, s) 3.55 (6H, s), 4-0
3 (411, s) 5.83 (4B, s) Example 10 72 g of dl-1,2-bis(4-acetoxymethyl-3,5-dioxopiperazin-1-yl)propane 64% sodium hydride L Paraffin was removed by washing with dry ether under a nitrogen stream, and after the ether was distilled off, dry DMF 10d was added. A solution of 2.1471 (8 mmol) of U-bis(3,5-dioxopiperazin-1-yl)propane in dry DMF (401IQ) was added dropwise to this mixture under a nitrogen atmosphere, and the mixture was heated at room temperature for 1 hour.
The mixture was then stirred at 50°C for 30 minutes. Furthermore, 1.73 g (I6 mmol) of chloromethyl acetate was added to dry DMF (3 n
Q) After adding the solution dropwise and stirring overnight at room temperature, the reaction mixture was added to water and extracted with chloroform. The extract was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The yellow oil obtained was purified by silica gel column chromatography (ethyl acetate:acetone -9:1, Rf value -0.78) to obtain a pale yellow oil. 0-44 g (yield 13%) of the title compound was obtained.

Infrared absorption spectrum [liquid film] Cal-''.

1740, 1700 (C-0) nuclear magnetic resonance spectrum (CDCQ,) J ppm: 1.06 (3■,
d, J=6Hz), 2.04(6H,s)2
．． 40~2.48 (IB, m), 2-64~2
．． 72 (LH, m) 2.98-3.06 (IH, m)
, 3-51 to 3-57 (81, m) 5.74 (4H,
s) The following compounds were prepared in the same manner as in Example 10 from the corresponding starting materials.

・dffi-1,2-bis(4-piparoyloxymethyl-3゜5-dioxopiperazin-1-yl)propane (yield 60%) Infrared absorption spectrum (liquid film) aa-": 1740, 1
700 (C00) Nuclear magnetic resonance spectrum (CDC)
Q,) appm: 1.05 (31, d, J=7Hz
), 1.17 (I8H, s) 2.41 (LH, dd
, J=6Hz・13Hz)2.62(IM, dd
, J=7Hz・13Hz)2.97(I)1,
m), 3.53 (4H, s) 3.56 (4H, s)
, 5-75(2H,5)5-76(231,s) ・di1.2-bis(4-benzoyloxymethyl-3
゜5-dioxopiperazin-1-yl)propane (yield 34%) Infrared absorption spectrum (liquid film) 3-': 1725, 1703 (C bulk 0) nuclear magnetic resonance spectrum 7L/ (CDCQ,) 6 ppm , :1-0
4 (3H, d, J-6-6Hz) 2.38-2.4
6 (IH, m), 2-63 to 2.71 (IH, n)
2.97-3.05 (IH, m), 3.55 (4H
, s) 3.58 (4H, s) , 6.00 (2H, s
)6.01 (2H, s) 7.37~7.42・7.51~7.56・7.95~
7J8 (IOH, m) Example 11 di-1,2-
BisC4-methoxycarbonyloxymethyl-3,5-
dioxopiperazin-1-yl)propane dQ-1,2-bis(3,5-dioxopiperazine-1
D to propane 1-60JI (6111of)
After adding M F 12- and stirring at 80°C for 10 minutes, 1.6 d of a 37% aqueous formaldehyde solution was gradually added, and the mixture was further stirred at 80°C for 1.5 hours. The solvent was distilled off under reduced pressure from the reaction mixture. Dry benzene 3 is added to the residue obtained by
After adding 0.0 ml of water, water was removed azeotropically to obtain a pale yellow oil.

A solution of this oil in pyridine (I0mQ) was heated to -20°C.
1.13 g (I2 mmol)
) was gradually added and stirred for 30 minutes and further at room temperature for 3 hours, the reaction mixture was added to water 50IIIQ and extracted with chloroform. The extract was dehydrated with water, 5% sulfur haze, water, saturated aqueous potassium carbonate solution, water in this order, and anhydrous magnesium sulfate. The solvent was distilled off from the extract under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate, R
fm -0,67) to give the title compound 1-29 as a pale yellow oil. g (yield 48%) was obtained.

Infrared absorption spectrum (liquid [) am-": 1730, 1
690 (C-0) nuclear magnetic resonance spectrum (CDC)
Q,) tppm: 1.03 (3H, d, J=6-6
Hz) 2.36 to 2-45 (IH-, m), 2-5
8-2-67 (IB, m) 2.93-3.02 (I)
I, m), 3-49~3.54 (811, ■)
3.80(31(,s), 3-81(3H,s)5
．． 80 (2H, s), 181 (2H, s) Example 1
The following compounds were prepared from the corresponding starting materials in the same manner as in Example 1.

・dx-1,2-bis(4-iso-butoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane (oil, yield 17%) Infrared absorption spectrum (liquid film) aa- ':1730,1
690 (C-0) nuclear magnetic resonance spectrum (CDC)
Q,) a ppm: 0.92 (68, s), 0
．． 94 (6H, s) 1.03 (38, d, J=6
-6H2) 1.91 to 1.98 (IB, m),
2.35-2.43 (IH, m) 2.58-2.66 (
IH, m), 2.92-3.01 (IH, m)3.
50-3.54 (8H, m) 3.93 (4H, d, J = 6-6Hz) 54O (2
H, s), 5.81(2H, s)・dQ-1,2-
Bis(4-p-nitrobenzyloxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane (yield 13%) Melting point: 49-53°C (glassy) 99-110°C (decomposed) Infrared absorption spectrum (KBr) am-: 1740,
1690 (Cl0) nuclear magnetic resonance spectrum ((:
DCQ@) + tPpH: 1.03 (3B, d,
J-6,6Hz) 2.36-2.43 (I1, a+)
, 2.59~2.67 (IH, o+) 2.94^3-
02 (IH, Fan), 3.48-3.56 (8H, n
+) 5.26 (48, s), 5.845 (2B,
s) 5.849 (2H, s), 7.53 (4H, d
, J = 8.9Hz) 8-225 (4B , d , J
=8.9Hz)-dQ-1,'l-bis(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)propane (yield 10%) Melting point: 56-58°C Infrared absorption Spectrum (KBr) C11-“:176
0, 1700 (C-0) nuclear magnetic resonance spectrum)
li (CDCQ, Mppm: 1.06r3H, d
, J=6-6Hz) 2.40-2.48 (I1, m)
, 2.62-2.71 (IH, m) 2.98-3.0
6(I)l, m), 3-55~3.59(8M
, +a) 5.92 (2H, s) , 5J3 (211
, s) 7.17-7-41 (IOH, m) dQ-1,2-bis(4-G-chlorobenzoyloxymethyl-3,5-dioxopiperazin-1-yl)propane (yield 21 %) Melting point = 52-54℃ Infrared absorption spectrum (Br)an-": 1730 (
Shoulder), 1690 (C-0) Nuclear Magnetic Resonance Sheet')
g) Lt (CDCQ,) J ppm: 1.05 (3H
, d, J=6.6Hz) 2.40-2.49(I
H, m), 2-62 to 2.73 (IH, m) 2-9
5-3.04 (IB, a+), 3.48-3.
58 (8H, m) 6.01 (2H, s), 6-02
(2B, 5) 7-25~7.47'7.76~7
．． ,80(8H,m) Methyl chloroformate 1-13Jl(
I21111101) Orioogiso phenyl 0.94g
The following compound was produced in the same manner as in Example 11 except that (6 mmol) was used.

@dffi-1-(4-phenoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)-2-
(3,5-dioxopiperazin-1-yl)propane or 1-(3,5-dioxopiperazin-1-yl)-2
-[4-phenoxycarbonyloxymethyl-3,5-
dioxopiperazin-1-yl)propane (yield 11
%) Melting point = 85-88°C Infrared absorption spectrum (KBr)al-': 1750
, 1695 (C-0) Nuclear Magnetic Resonance Spec') /
L/ CCDCl1. )6pprr+H1.03(3H
, d, J=6.6Hz) 2.38-2.46(I
H, m), 2.63-2-71 (IH, 11)2.
98-3.06 (IH, n+), 3.42 (4H,
s) 3.52 (4H, s), 5.91 (2H, s)
7.16-7.41 (IOH, m) 8.24-8-29 (IB, Broad S) Example 1
2 1-(4-o-chlorobenzoyloxymethyl-
3,5-dioxopiperazin-1-yl)-2-(3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazine-1- ) Ethane 1.57 Jl (511
m+01), 0-chlorobenzoyl chloride 0.8871 (5111101) was added to a mixture of pyridine 15- under water cooling.
was gradually added and stirred at room temperature for 12 hours, the reaction mixture was added to water and extracted with chloroform. The extract was washed with water, 5% sulfuric acid, water, potassium carbonate aqueous solution, and water in this order, and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off from the extract under reduced pressure to obtain a solid, which was washed with a small amount of chloroform to obtain 0.45 g (yield 21%) of the title compound.

Melting point = 178-180°C Infrared absorption spectrum (KBr) am-“: 1738
(shoulder), 1708 (C=O) nuclear magnetic resonance spectrum (CDC11,) θppm: 2.71 (4H, s)
, 3-44 (4H, s) 3.57 (4H, s) ,
6-03 (2H, s) 7.27-7.45・7.78
~7.90 (4H, m) Example 13 1-(4-js
o-Butoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)-2-(3,5-dioxopiperazin-1-yl)ethane 1,2-bis(4-hydroxymethyl-3,5 -dioxopiperazin-1-yl]ethane 2.42 g (7.7 m
mol) and 10 d of pyridine were gradually added with 0.95 s (7 ml of) of isobutyl chloroformis under water cooling, and after stirring at room temperature for 3 hours, the reaction mixture was added to water and extracted with chloroform. The extract was mixed with water, 5% sulfuric acid, water,
After washing with an aqueous potassium carbonate solution and water in that order, it was dehydrated with anhydrous magnesium sulfate. The solvent was distilled off from the extract under reduced pressure, and the resulting oil was subjected to silica gel column chromatography [
Purification was performed using ethyl acetate (Rf value -0.51) to obtain 0-43 g (yield 14.4%) of the title compound.

Melting point: 123-126°C Infrared absorption spectrum (KBr) polarization -1:1730, 1
700 (C-0) nuclear magnetic resonance spectrum (CDC)
t,) j ppm: 0.94 (61, d, J=6
-6Hz) 1.95 to 2.05 (LH, m), 2.
70 (4H, s) 3.43 (4M, s), 3-
54 (4H, s) 3.94 (2H, d, J=6-9
Hz) 5.81 (2H, s), 8-41 (IH, s
) [Effects of the Invention] As described above, the bis-dioxopiperazine derivative represented by the general formula (+) or its non-toxic salt of the present invention is a novel compound unknown in the literature, and has excellent anti-111 activity. It is a novel compound that can be used industrially, and is useful as an antitumor agent.

Claims (1)

[Claims] 1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 and R_2 are both hydrogen atoms or lower alkyl groups. However, it cannot be a lower alkyl group at the same time. R_3 is a hydrogen atom or a group of the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R_4 is a) R_1 and R_2 are both hydrogen atoms, and R_3 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ For the group: Formula - (CH_2)_n-R_■, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲Mathematical formulas, chemical formulas, tables, etc.▼, -OR_1_0 Or a substituted or unsubstituted heterocyclic group (in the formula, R_5 is a lower alkoxy group, a substituted or unsubstituted phenylthio group, a substituted or unsubstituted biphenyl group) , a substituted or unsubstituted heterocyclic group or a lower alkylcarbonyl group, R_6 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group, R_7 is a hydrogen atom or a lower alkyl group, R_8 is a hydrogen atom , lower alkylcarbonyl group, lower alkoxycarbonyl group, or tosyl group, R_9 is lower alkoxy group, amino group, methanesulfonyl group, or substituted or unsubstituted phenyl group, R_1_0 is C_7_ to_1_0 alkyl group, substituted or unsubstituted Substituted benzyl group or substituted or unsubstituted phenyl group, n represents 1 or 2) b) Either R_1 or R_2 is a lower alkyl group and R_3 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the case of the group: lower alkyl group, substituted or unsubstituted phenyl group, lower alkoxy group, substituted or unsubstituted benzyloxy group, or substituted or unsubstituted phenoxy group c) When R_■ is a hydrogen atom: Substituted or represents an unsubstituted phenyl group, a lower alkoxy group, a substituted or unsubstituted benzyloxy group, or a substituted or unsubstituted phenoxy group] or a non-toxic salt thereof.