JPS6312447B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a sugar nitrosourea derivative represented by the following formula (), 3-[3-(2-chloroethyl)-
3-nitrosouride]-3-deoxy-1,
2:5,6-di-O-isopropylidene-α-D
-Relating to a novel antitumor agent characterized by containing allofuranose as an active ingredient. Many sugar nitrosourea derivatives have been known to have antitumor and antileukemia effects, but
In general, many of the compounds themselves are unstable and difficult to formulate, and moreover, they have many problems as pharmaceuticals, such as having side effects that are greater than their effects, and none are always satisfactory. As a result of intensive research to solve these problems, the present inventors first invented a D-allose nitrosourea derivative of the formula ( No.). In this prior invention, a compound of formula (), 3
―[3-(2-chloroethyl)ureido]-3-
Deoxy-1,2:5,6-di-O-isopropylidene-α-D-allofuranose is treated with a nitrosating agent in the presence of an acid, and simultaneously hydrolyzed to nitrosate to remove the isopropylidene group and directly A compound of formula () was prepared. The present invention is based on the discovery that the compound of formula (), which is obtained by nitrosation of the compound of formula () in an acid-free solvent and in which the isopropylidene group is not removed, is an excellent antitumor agent. It is. The compound of formula () according to the present invention is a novel compound isolated for the first time by the present inventors. It can be produced by nitrosation with In addition, as another manufacturing method, for example, 3- of the formula ()
Amino-3-deoxy-1,2:5,6-di-O
-Isopropylidene-α-D-allofuranose (Carbohydr.Res. Vol. 6, p. 276, 1968) and ()
P-nitrophenyl-N-(2-chloroethyl)-N-nitrosocarbamate of the formula [Pharmaceutical Journal No. 94
Vol. 8, pp. 1032-1037 (1974)] in tetrahydrofuran to produce the compound of formula (). The manufacturing method and antitumor effect of the compound according to the present invention will be explained in detail below. Production example 1 3-[3-(2-chloroethyl)ureido]-
Dissolve 3 g of 3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-allofuranose in 50 ml of chloroform, and add nitrogen sesquioxide ether solution while stirring on ice until the color does not disappear. .
Next, after stirring for 15 minutes under cooling, the mixture is concentrated under reduced pressure at a temperature below 40°C. The obtained syrup was crystallized from isopropyl alcohol and further recrystallized from ethanol to give 3-[3-(2-chloroethyl)-3-nitrosouride]-3-deoxy-1,2:5,6
2.7 g (yield: 83%) of -di-O-isopropylidene-α-D-allofuranose was obtained. mp 94-95゜[α] _D = 75.7 (C = 1, chloroform) Elemental analysis value C ₁₅ H ₂₄ N ₃ O ₇ Cl (molecular weight 393.638) Actual value: C 45.68, H 6.12, N 10.65, Cl 9.03 Calculation Values: C 45.77, H 6.10, N 10.67, Cl 9.01 NMR spectrum (CDCl ₃ -TMS) δ 7.3 1H d (NH) 5.95 1H d (C-1) 4.8 1H t (C-2) 3.6 2H t (NCH ₂ ) 1.25~1.5 12H s×4

[Formula] IR spectrum (cm ^-1 ) 1710 (C=0) 1530 (NH) 1500 (N-NO) Production example 2 3-amino-3-deoxy-1,2:5,6-
Di-O-isopropylidene-α-D-allofuranose 2.6g (10mMol) in tetrahydrofuran 2.0
ml, P-nitrophenyl-N-(2-
Chloroethyl)-N-nitrosocarbamate 3.0
g (11.6 mmol) in 30 ml of tetrahydrofuran under stirring at room temperature. After completion of the dropwise addition, stir at room temperature for 7 to 15 hours, then concentrate under reduced pressure at below 40°C, dissolve the resulting syrup in chloroform, wash with saturated sodium bicarbonate and water in that order, and dry over anhydrous sodium sulfate. . Next, after filtering out the desiccant,
Concentration under reduced pressure at below 40°C, and the resulting syrup was crystallized from isopropyl alcohol and further recrystallized from ethanol to give 3-[3-(2-chloroethyl)-3-nitrosouride]-3-deoxy-
3-1,2: 2.0 g of 5,6-di-O-isopropylidene-α-D-allofuranose (yield 51%)
Obtained. Compared with that obtained by the method of Production Example 1, the various properties are the same. Next, a test example will be shown to explain the antitumor effect of the compound [ ] according to the present invention. Test Example 1 (Anti-leukemia effect test) A CDF ₁ mouse, male, 6 weeks old, weighing 22±1 g was used as a test animal. In the intraperitoneal administration test, there were 7 mice per group, and in the oral administration test, there were 5 mice per group. Leukemia L-1210 nodules (1×10 ⁵ cells/mouse) were intraperitoneally transplanted into mice, and 24 hours later, the compound [] was suspended in a 0.5% CMC aqueous solution and administered intraperitoneally or orally to mice. We investigated the median survival days of mice (the number of days required for the death of the 4th mouse when there are 7 mice in a group and the death of the 3rd mouse when there are 5 mice in a group, hereinafter referred to as MSD) and the number of mice that survived for 60 days. The survival rate (hereinafter abbreviated as ILS) was calculated using the group to which no drug was administered as a control. ILS (%) = MSD of drug administration group - MSD of control/MSD of control x 100 The results of this test are shown in Table 1.

【table】

[Table] Test Example 2 (Anti-Lewis Lung Cancer Effect Test) As test animals, 5 BDF ₁ mice, male, 6 weeks old, weighing 22±1 g, were used in each group. Lewis lung cancer cells (5×10 ⁵ /mouse) were subcutaneously transplanted, and 24 hours later, the compound () was suspended in a 0.5% CMC aqueous solution and orally administered. The median survival number of mice and the number of mice that survived for 60 days were investigated, and the effect of the drug of the present invention was evaluated in the same manner as in Test Example 1. The results of this test are shown in Table 2.

[Table] Test Example 3 (Anti-lung autotumor efficacy test) Ethylnitrosourea 100mg/Kg was intraperitoneally administered to DDY mice on the 15th to 16th day after pregnancy, and when the offspring reached 5 weeks of age. Compound (2) was orally administered to 7 male rats in each group twice a week for 3 weeks. The mice were dissected at 9 weeks, the lung surface was observed under a stereoscopic microscope, and the number of tumors and tumor area were measured. The results of this test are shown in Table 3.

[Table] As is clear from the above test results, the compound () according to the present invention exerts a strong antitumor effect against leukemia, Lewis lung cancer, and mouse lung autologous tumor, and shows that the compound () according to the present invention exerts a strong antitumor effect on leukemia, Lewis lung cancer, and mouse lung autologous tumor, and that it exerts a strong antitumor effect on mixed-race animals affected by these tumors. extended survival time and suppressed tumor cell proliferation. In addition, the acute toxicity of the compound () according to the present invention
LD ₅₀ is 89mg/Kg for intraperitoneal administration and 310 for oral administration.
mg/Kg (All DDY male mice weigh 20~
22.5g was used. ). In addition, the compound itself is stable over time, with almost no decomposition observed for several months when stored at 30°C.
It is easy to formulate it as a drug.

Claims (1)

[Claims] 1 3-[3-(2-chloroethyl)-3-nitrosouride]-3-deoxy-1,2:5,6
An antitumor agent characterized by containing -di-O-isopropylidene-α-D-allofuranose as an active ingredient.