JPH0136809B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anticancer agent containing 3-O-alkyl or alkenyl-D-glucose as an active ingredient. The present inventors investigated the pharmacological effects of various O-alkyl-D-glucoses, and found that 3-O-alkyl or alkenyl-D-glucose
- It was discovered that glucose has a specifically strong anticancer effect, and the present invention was completed. That is, the present invention is based on the following formula () (wherein R represents an alkyl or alkenyl group having 1 to 30 carbon atoms) An anticancer agent containing 3-O-alkyl or alkenyl-D-glucose as an active ingredient is provided. The 3-O-alkyl or alkenyl-D-glucose of the present invention is a known compound or a compound easily produced by a known method. Regarding such compounds, there are already examples of
Tr.−Mezhdunar.Kongr.Pouerkhn.−Akt,
Veshchestuam, 7th1976 (Pub.1977), 1217~
1223 (Ger). and Nats.Kom.SSSR Pouerkhn.−
Akh. Veshchestuam: Moscow, USSR. discloses 3-O-lauryl-D-glucose as a surfactant, and also 3-O-lauryl-D-glucose having 1 to 4 carbon atoms.
-Alkyl-D-glucose and 3-O-allyl-D-glucose are also known. However, their anticancer effects were completely unknown. The anticancer effect of the 3-O-alkyl or alkenyl-D-glucose () of the present invention is specific; for example, in the case of the O-alkyl form at the 1-position, the effect is about 1/10 weaker. The 3-O-alkyl or alkenyl-D-glucose () of the present invention can be produced, for example, according to the following reaction formula. (In the formula, R is the same as above) That is, 3-O-alkyl or alkenyl-D-1,2:5,6-di-isopropylidene-α-D-glucofuranose () in the presence of an acid catalyst, It is easily obtained by refluxing in an aqueous solution. As the acid catalyst, mineral acids such as sulfuric acid and hydrochloric acid and acidic ion exchange resins such as Amberlite IR-120 and CG-120 are used. The reaction is completed by refluxing for 30 minutes to 50 hours. From the reaction product thus obtained, the compound ()
If the target product is poorly soluble in water, it can be obtained by suctioning it directly or by extracting it with an organic solvent such as ether. If you use
After neutralizing with an appropriate alkali, water is distilled off under reduced pressure. If the target substance is water-soluble and an ion exchange resin is used as an acid catalyst, the liquid is concentrated under reduced pressure after passing through the ion exchange resin. This is done by each. The crude crystals of the compound () obtained as described above can be further treated with a solvent such as alcohols such as methanol, ethanol, n-propanol, and isopropanol, ketones such as acetone, methyl ethyl ketone, water, etc., or a combination thereof. By recrystallizing, pure 3-O-alkyl or alkenyl-D-glucose crystals can be obtained. 3-0-alkyl or alkenyl-1,2:5,6-di-0 which is the starting material for the compound of the present invention
Among -isopropylidene-α-D-glucofuranose (), the alkyl and allyl forms having 1, 2, 3, 4, and 12 carbon atoms are known compounds, but the others are new compounds. These compounds can be prepared by dissolving 1,2:5,6-di-0-isopropylidene-α-D-glucofuranose in a suitable solvent and adding 1 to 2 equivalents of a strong base such as sodium hydride. It can be easily produced by reacting ~2 equivalents of alkyl or alkenyl halide at 0 to 80°C for 0.5 to 10 hours.
Solvents include benzene, toluene, dioxane,
Tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, etc. can be used, and dimethyl sulfoxide is particularly preferred. Next, among the compounds of the present invention thus obtained, representative ones are listed in Table 1, and the results of tests on their anticancer activity and acute toxicity are shown.

【table】

[Table] (1) Anti-cell effect on Leukemia L-5178Y The anti-cancer effect was investigated using Leukemia L-5178Y as tumor cells. Contains 10% fetal bovine serum
1 x ¹⁰⁵ L-5178Y cells in RPMI1640 medium
After adding a sample at a predetermined concentration, the cells were cultured at 37° C. in a 5% carbon dioxide incubator for 48 hours. After the culture was completed, the number of cells was counted and the cell proliferation rate of the experimental group compared to the control was determined. This value was plotted on log probability paper and IC ₅₀ was calculated from it. The results are shown in Table 2.

【table】

[Table] (2) Anticancer effect on P388 ¹⁰⁵ P388 cells were transplanted into the abdominal cavity of 6 BDF ₁ female mice per group, and 24 hours later, they were placed in physiological saline. The suspended test compound was intraperitoneally administered once a day at 30 mg/Kg for 5 consecutive days. The ILS (%) was determined from the number of days each mouse survived after cancer cell transplantation, and the anticancer activity was examined based on its survival prolonging effect. The results are shown in Table 3.

[Table] (3) Acute Toxicity Typical compounds used in the anticancer agent of the present invention were dissolved or suspended in physiological saline, administered intraperitoneally to 5 male mice per group, and kept for observation for 7 days.
As a result, all mice survived at a dose of 500 mg/Kg, and no abnormalities were observed. Therefore, as shown in Table 4, the LD ₅₀ of any compound is
It is more than 500mg/Kg and has extremely low toxicity.

【table】

[Table] Next, the administration method and dosage of the anticancer agent of the present invention thus obtained are shown. Administration methods include oral administration in the form of tablets, capsules, granules, syrups, etc., subcutaneous, intramuscular, intratumor, or intravenous administration as an injection, or infusion by mixing with infusions, etc., or suppositories. Parenteral administration is also possible. The dosage varies depending on the route of administration, and is usually 1.0 to 200 mg/Kg for oral administration and 0.5 to 100 mg/Kg for parenteral administration for adults. Oral preparations can be manufactured according to conventional manufacturing methods. Namely, excipients such as starch, lactose, and mannitol, binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose, disintegrants such as crystalline cellulose and calcium carboxymethyl cellulose, lubricants such as talc and magnesium stearate, and light anhydrous silica. Tablets, capsules, granules, etc. can be manufactured by appropriately combining and formulating fluidity improvers such as acids. When used as a parenteral preparation in the form of an aqueous solution such as an injection, the compound of the present invention, such as Compound No. 6, is dissolved in water, physiological saline, etc., and thus the injection and the like can be prepared by a conventional method. Suppositories can be prepared by dispersing the compound of the present invention in a commonly used base such as cacao butter, synthetic oil, etc. by a conventional method and then solidifying the compound. Next, the present invention will be further explained with reference examples and examples. Reference example 1 Synthesis of 3-O-lauryl-D-glucose: 3-0-lauryl-1,2:5,6-di-0-
Isopropylidene-α-D-glucofuranose
Suspend 2.07g in 40ml of water and add Amberlite CG.
-120 (treated with 1N hydrochloric acid) 1.51g added, 24
Reflux for an hour. After cooling, suction and rinse with water. The residue is dissolved in methanol, filtered and the liquid is concentrated to crystallize. Recrystallization from isopropyl alcohol yields 1.03 g of colorless needle crystals. (yield 61.2
%) Example 1 (Tablet) 3-O-octadecyl-D-glucose (Compound No. 13) 100mg D-mannitol 150mg Crystalline cellulose 50mg Potato starch 28mg Carboxymethyl cellulose calcium 16mg Talc 4mg Magnesium stearate 2mg Total amount 350mg The above ingredients Then, prepare one tablet using a conventional method. Example 2 (Capsule) 3-O-lauryl-D-glucose (Compound No. 9) 25 mg Crystalline cellulose 17 mg Light anhydrous silicic acid 7 mg Magnesium stearate 1 mg Lactose 130 mg Total amount 180 mg The above ingredients were taken and granulated by a conventional method. and fill it into one No. 3 capsule. Example 3 (Injection) 50 mg of 3-O-octyl-D-glucose (compound number 6) is dissolved in physiological saline to make a total volume of 2 ml. After sterilizing the product using a membrane filter in a conventional manner, it is filled into a glass ampoule and fused to make an injection. Example 4 (Emulsifier for infusion) 3-O-lauryl-D-glucose (Compound No. 9) 0.5 g Refined soybean oil 100 g Refined egg yolk lecithin 12 g Glycerin for injection 25 g The total volume is brought to 1 with distilled water for injection. The osmotic pressure ratio of this product to physiological saline is approximately 1. Example 5 (Suppositories) 3-O-hexadecyl-D-glucose (Compound No. 12) 50 mg Cocoa butter 1150 mg Total amount 1200 mg The above ingredients were taken, and after melting and stirring by a conventional method,
Let the mold harden to make one suppository. Test Example 1 Different hydroxyl groups of sugars were substituted with the same alkyl group, and the anticancer effect on Leukemia L-5178Y was investigated. The test method is the same as the above test method for the same cells. The results are shown in Table 5.

[Table] From these results, it is clear that the anticancer effect of the alkyl substituted product at the 3-position is specific.

Claims (1)

[Claims] 1st-order equation () (In the formula, R represents an alkyl or alkenyl group having 1 to 30 carbon atoms.) An anticancer agent containing 3-O-alkyl or alkenyl-D-glucose as an active ingredient.