JPH0348665A - (r)-1,2-bisdioxopiperazinepropane derivative - Google Patents

Abstract

NEW MATERIAL:A (R)-1,2-bisdioxopiperazinepropane derivative shown by formula I [R' is lower alkyl; Ar is phenyl which may be replaced with 1-3 halogen atoms; (R) in the formula shows possession of absolute coordination of R with respect to asymmetric carbon]. EXAMPLE:(R)-1,2-Bis[4-(R)-(2-acetoxy-2-phenylacetoxymethyl)-3,5-dioxop iperazine-1- yl]propane. USE:Having carcinostatic action, useful as a drug and being orally administnative. PREPARATION:A compound shown by formula II is reacted with formaldehyde or paraformaldehyde and further a prepared formyl derivative shown by formula II is not isolated and reacted with a reactive derivative of a compound shown by formula III in the presence of a condensation agent to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound (11) having excellent anticancer activity.

Japanese Patent Application Publication No. 1986-97963 and Japanese Patent Publication No. 1987-281
No. 870 0 +1) In the formula, R' represents a lower alkyl group, and Ar represents a phenyl group which may be substituted with 1 to 3 halogen atoms. This shows that it has an absolute coordination of

Lower alkyl in R' is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-
Butyl is given.

Examples of the halogen atom as a substituent in Ar include fluorine, chlorine, and bromine.

Preferred compounds having formula (1) are those in which R' is methyl, ethyl, propyl, isopropyl and Ar is phenyl or 4-chlorophenyl.

The compound having formula (1) has isomers based on mandic acid derivatives. The present invention relates to these isomers.

-i The compound having formula (1) is synthesized as follows.

The compound represented by the formula is reacted with formaldehyde or paraformaldehyde, without further isolating the formyl compound of (2) obtained [wherein R' and Ar have the same meanings as described above] When reactive derivatives of compounds having the formula, such as acid chlorides, acid anhydrides, etc., are reacted in the presence of a condensing agent by the method shown in Jikai No. 62-281870, -formula) [wherein R', A compound having the same meaning as described above is obtained.

The survival time of mice intraperitoneally administered with compound (11) was approximately 3 times that of mice in the untreated control group (R, L, Geran
Evaluation methods such as Cancer Chamother R
ept, 4+ part 3.1-52 (1972)) survived. Compound 11) also showed P388 by oral administration.
It showed antitumor activity against white blood cells.

The compound (11) of the present invention can be administered orally, and dosage forms for oral administration include tablets, coatings, powders, granules, capsules, and syrups.

The dosage varies depending on the patient's symptoms, age, body weight, etc., but the daily dose for adults is 50 to 3,000 μ, preferably 500 to 1,000 μ, which can be administered in 1 to 3 divided doses.

Next, the present invention will be explained with reference to examples and reference examples, but the scope of the present invention is not limited to the examples.

Propane(R)-1,2-bis(3,5-dioxopiperazine-
1-yl) propane 6.00 g (22,3 mmoj
dimethylformamide formaldehyde 6,00 g (20 0.0
+u+offi) and stirred at 90°C for 1.5 hours. After cooling, 7 tons (300 n/liter) was added, the insoluble matter was removed in the oven, and the solvent was distilled off under reduced pressure. Ethyl acetate (600 mf) was added to the resulting caramel-like residue, and heated extraction (steam bath) was carried out. The insoluble matter was removed in an oven, the solvent was distilled off under reduced pressure, and the crude methylol compound obtained was dissolved in dry pyridine (100 mf
), 10.62 g of (R) 2-acetoxy-2-phenylacetyl chloride under -20'C
(50.0 mmof) was added dropwise, and the mixture was stirred for 2 hours at 0 to 5" CI, and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate (200 ml), and the mixture was cooled. Wash with 5% KtlSO4 (200mj2) and cold 10% brine (200 mj2) in this order, and dry the organic layer over anhydrous magnesium sulfate.The desiccant is removed from the oven and the solvent is distilled off under reduced pressure. The residue was purified by silica gel Rover column chromatography (column: Merck Art 10402, developer: cyclohexane/ethyl acetate = 1/2) to obtain a candy-like oil, which was dissolved in benzene and freeze-dried to yield [α)o 18 .1° (C=-
2.0.

Colorless powder target compound showing CI (J!s) 6.80
g (45.0%) was obtained.

Infrared absorption spectrum (KBr) aII publication = 1748.
1700 (C=0) nuclear magnetic resonance spectrum (CDC13), δppn+
:0.98 (3H, d, J=6.0), 1.92~3
．． 08 (2H+LH, m).

2.16 (3HX2.s), 3.45 (2HX2.s
), 3.48 (211X2゜s), 5.86 (2H
X2. s) + 5.90 (IH, s), 5.91 (L
H,s).

7.22-7.60 (5H
0,0mmof), the ite reaction is sult, [α] o
0.3' (C= 2. Oo, CtlCI!
, 3) 6.52 g (43
, 2%).

Nuclear magnetic resonance spectrum (CDCl i), δpp
m: 0.98 (3H, d, J=6.0), 1.92
~3.08(211-)-Ill, m).

2.16 (3HX2.s), 3.45 (211X2.s)
s), 3.48 (211X2゜s), 5.86 (2
tlX2. s), 5.90(LH,s), 5.9H
111, s).

7.22-7.60 (511X2.m) Propane Perzin-1-yl Propane Example 1. Similarly, (R)-12-bis(3,5-dioxopiperazin-1-yl)propane 6.00g (2
2,3n+n+ojri, paraformaldehyde 6.0
Hg (200,0 mmo7 and (S)-2-acetoki(R)-1,2-diaminopropane-N,N,N'
, N'-tetraacetic amide 61.2 g (0,19
9 mol) of ethyl carbamate (183.6 g (2
,064mof) and stirred for 24 hours at 160-165"C. After cooling, isopropyl ether (500m
Add j2) and leave overnight.

When the precipitated crystals are taken out in a furnace and reconsolidated with water, m, p, 194196
°C (decomposition), [α) o 11.1' (C-5,
20.2 g (38.0%) of the desired product was obtained as colorless, granular crystals exhibiting 0.0, dimethylformamide).

Nuclear magnetic resonance spectrum i (DMSO) δ (J=IIZ
), 90MIIZ; 0.9H311,d, J・6.0
), 2.16-2.76(2[1,l11), 2.
83-3.33 (111, m), 3.35 (211X
2. s), 3.38 (211X2.s).

11.03(ill,s), 11.10(ltl,s
) Wash with nyl acetylchloride monohydrochloric acid (200mf) and 10% saline (200n+42) in this order, and dry the organic layer over anhydrous magnesium sulfate. When the desiccant is removed from the oven and the solvent is distilled off under reduced pressure, the resulting crystals are reconsolidated with a mixture of isopropyl ether and n-hexane to obtain [α) D 41.6° (C = 1. Q
, EtOH), 29.2 g (94.1%) of compound (2) was obtained as a colorless powder with no m, p, 73-74°C.

This was dissolved in 300 ml of dry methylene chloride, and while cooling to 5°C, 31.3 g of phosphorus pentachloride was added, followed by stirring at the same temperature for 1 hour. The solvent of the reaction solution and the by-product phosphorus oxychloride were distilled off under reduced pressure to obtain 32.0 g of the title compound as a colorless liquid.
(100%) obtained.

The title compound was directly used in Example 1 without purification.
It was used to synthesize the target compound shown in .

Claims (1)

[Claims] A compound having the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1). In the formula, R' represents a lower alkyl group, and Ar represents a phenyl group which may be substituted with 1 to 3 halogen atoms, where (R) has an absolute coordination of R with respect to the asymmetric carbon. Show that.