JPS6312476B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to D-altropyranoside derivatives represented by the formula [], namely methyl-4,6-O-benzylidene-3-[3-(2-chloroethyl)-3-
This invention relates to [nitrosourade]-3-deoxy-α-D-altropyranoside and an antitumor agent containing the same as an active ingredient. Many sugar nitrosourea derivatives have been known to have antitumor and antileukemia effects, but
Many of the compounds themselves are unstable and difficult to formulate, and many have toxicity and side effects that are greater than their effectiveness, causing many problems as pharmaceuticals, and none of them are necessarily satisfactory. In order to solve these problems, the present inventors synthesized a large number of compounds and, as a result of intensive research, found that D-allose nitrosourea derivatives, 3-[3-(2-chloroethyl)- He invented 3-nitrosouride]-3-deoxy-D-allose and filed a patent application (Japanese Patent Application No. 36,200/1983). The present inventors further advanced their research and completed the present invention by creating a compound with extremely high antitumor activity and low toxicity. The compound of the present invention is a compound of formula [], methyl-
4,6-O-benzylidene-3-[3-(2-chloroethyl)ureido]-3-deoxy-α-D
-It can be produced by nitrosating altropyranoside with nitrogen sesquioxide in an organic solvent such as chloroform, acetone, or ether. The compound of formula [] is methyl-3-amino-
4,6-O-benzylidene-3-deoxy-α-
D-Altropyranoside [J.Chem.Soc.5288
(1963). ] can be easily produced by reacting it with 2-chloroethyl isocyanate in an organic solvent such as acetone or alcohol. Hereinafter, the manufacturing method and antitumor effect of the compound of the present invention will be explained in detail. Example Methyl 4,6-O-benzylidene-3-[3-
Dissolve 1.0 g of (2-chloroethyl)ureido]-3-deoxy-α-D-altropyranoside in 20 ml of chloroform, cool it to 0-5°C, and then add an ether solution of nitrogen sesquioxide until the reaction mixture turns green. After stirring for 30 minutes, concentrate under reduced pressure at room temperature. Add 10 ml of 2-propanol to the concentrated residue and filter the precipitated powder. This product was dried under reduced pressure to produce a pale yellow methyl 4,6-O-benzylidene-3-
0.8 g of [3-(2-chloroethyl)-3-nitrosouride]-3-deoxy-α-D-altropyranoside was obtained. Yield 74% Melting point 130-131℃ Specific optical rotation [α] ²² _D 84.6 (C=1, CHCl ₃ ) Elemental analysis value C ₁₇ H ₂₂ N ₃ O ₇ Cl C% H% N% Calculated value 49.09 5.33 10.11 Actual value 49.21 5.39 10.02 IR spectrum (KBr) 3480cm ^-1 (ν _OH ), 3370cm ^-1 (ν _NH ) 1710cm ^-1 (ν _C=O ), 1490cm ^-1 (ν _NO ) NMR spectrum (CDCl ₃ -TMS) δ 3.50 (3H, s, CH ₃ ) δ 4.80 (1H, s, H-1) δ 5.73 (1H, s, CH Ph) δ 7.50 (5H, s, CH Ph ) δ 8.30 (1H, d, NH, J _NH,3 =9 Hz) Next, the method for producing the raw material compound [] used for producing the compound of the present invention will be specifically explained using reference examples. Reference example Methyl 3-amino-4,6-O-benzylidene-3-deoxy-α-D-altropyranoside
Dissolve 2.0g in 30ml of anhydrous methanol and heat to 0-5℃.
After cooling to , 1.0 ml of 2-chloroethyl isocyanate was added while stirring, and after stirring for 30 minutes,
Concentrate under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography (Wako, c300, 50g;
Effluent solvent chloroform-methanol 95:5v/v)
methyl 4,6-O-benzylidene-3
―[3-(2-chloroethyl)ureido]-3-
1.8 g of deoxy-α-D-altropyranoside is obtained. Yield 65% Specific rotation [α] ²² _D 48.8 (C=1, CHCl ₃ ) Elemental analysis value C ₁₇ H ₂₃ N ₂ O ₆ Cl C% H% N% Calculated value 52.78 5.99 7.25 Actual value 52.57 5.91 7.05 IR Spectrum 3350cm ^-1 (ν _OH,NH ), 1640cm ^-1 (ν _C=0 ) NMR spectrum (CDCl ₃ -TMS) δ 3.40 (3H, s, CH ₃ ) δ 3.45 (4H, bs, CH ₂ CH ₂ ) δ 4.70 (1H, s, H-1) δ 5.10 (1H, bs, OH) δ 5.60 (1H, s, CH Ph) δ 6.05 (2H, m, NH) δ 7.50 (5H, s, Ph) Next A test example is shown below to explain the antitumor effect of the compound of 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 fourth mouse to die when there are 7 mice in a group, and the number of days required for the third mouse to die when there are 5 mice in a group, hereinafter abbreviated 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] 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. The compound [ ] 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 strong antitumor effects against leukemia, Lewis lung cancer, and mouse lung autologous tumors, and has a strong antitumor effect on leukemia, Lewis lung cancer, and mouse lung autologous tumors. It extended the survival period of blood animals and suppressed the proliferation of tumor cells. In addition, the acute toxicity of the compound [] according to the present invention
LD ₅₀ is 192mg/Kg for intraperitoneal administration and 500 for oral administration.
mg/Kg (all DDY male mice, weight 20~
22.5g was used).

Claims (1)

[Claims] 1. A D-altropyranoside derivative represented by the formula []. 2. An antitumor agent comprising a D-altropyranoside derivative represented by the formula [] as an active ingredient.