JPS62132823A - Carcinostatic agent - Google Patents

Abstract

PURPOSE:To provide a carcinostatic agent containing wool fatty acid and/or wool alcohol or their derivatives as active components, effective even against scirrous carcinoma and exhibiting remedying effect by remote administration as well as direct administration. CONSTITUTION:A wool fatty acid, preferably a wool fatty acid corresponding to 11-17C branched-chain saturated aliphatic monocarboxylic acid or reduced alcohol of a wool fatty acid, its metallic salt, ester or their derivatives are used as active components of a carcino-static agent. AS an alternative, a wool alcohol, preferably a wool alcohol corresponding to 11-17C branched-chain saturated aliphatic monohydric alcohol, its carboxylic acid, ether or ester derivative are used as the active components. It has wide application field to the cancer of various tissues or squamous cell carcinoma as well as ascites carcinoma and leukemia. It is free from species specificity and is usable as a medicine and a chemotherapeutic agent for cancer of domestic animals and other animals.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to anticancer agents containing these specific components or derivatives as active ingredients.

Various natural oils and fats have been searched for anticancer activity, but no superior efficacy has been recognized.

The present inventors have discovered that saponified wool grease has a strong anticancer effect, and have accomplished the present invention.

That is, the gist of the present invention resides in an anticancer agent containing wool fatty acid, wool alcohol, or a specific component or derivative thereof as an active ingredient.

In the present invention, wool fatty acid and wool alcohol refer to the acidic component and alcohol component of wool grease, which is wool fat, respectively.

Wool fatty acids and wool alcohol are prepared by separating each from the products obtained by hydrolyzing wool grease.
For example, dissolve wool grease or concentrated hair washing waste liquid in A7Ton, add three times the amount of quicklime, and add 5 atm.
After reacting for 8 hours at 0°C, the acidic components precipitate as calcium salts. Here, at normal pressure of 55@C, 77 tons of alcohol components are soluble, so wool alcohol is extracted.

Next, 3 times the amount of a7ton and 0.2 times the amount of sulfuric acid are added to the calcium salt and reacted at 60'C for 2 hours to decompose the calcium salt with acid. A7ton is distilled off from the filtrate of this product and washed with water to obtain wool fatty acid as a solid.

Wool fatty acids are iso-, antiyne-, meh-hydroxy, or straight-chain higher saturated fatty acids having 10 to 31 carbon atoms;
More than 60 types of carboxylic acids such as resinous acids are mixed. Wool alcohol is a mixture of more than 30 types of compounds, including iso-, anti-iso-, and straight-chain higher saturated aliphatic alcohols with 16-30 carbon atoms, sterols such as cholesterol, triterpene alcohols such as 7-sterols, and hydrocarbons. . All of them are characterized by having large amounts of iso and antiyne higher saturated aliphatic compounds.

The specific components of wool fatty acids and wool alcohols having branched saturated aliphatic groups having 11-17 carbon atoms are obtained, for example, by molecular distillation. That is, oil fractions of wool N fatty acids with a molecular distillation temperature of 75-110''C and wool alcohol with a molecular distillation temperature of 60-95''C in a semi-microbot still under high vacuum of 10-mmHg or less are particularly effective. It is preferable to purify by the urea clathrate method.That is, dissolve each oil fraction in methanol, add urea, warm it to dissolve it, and then leave it to cool.Crystals will precipitate.Hydrochloric acid is poured into this filtrate, and hexane is added. Chromosorb W/15% E
GSS-X/178゛C chromatograph and KB
According to the infrared spectrum of R tablets, both of these are 11
The main components are iso and antiyne saturated fatty acid monocarboxylic acids and monohydric alcohols having -17 carbon atoms.

These are iso- and antiisoundecillic acids, hereinafter also lauric acid, tridecylic acid, myristic acid, bentadecylic acid, palmitic acid, margaric acid, and
These are alcohols.

The wool fatty acid derivative in the present invention means the following three types. (1) Reducing alcohol: Treat wool fatty acid with lithium aluminum hydride to convert carboxyl groups into alcohol. (2) Metal salt: A saturated aqueous solution of copper or iron salt is mixed with 2 times the mole of a saturated solution of wool fatty acid in 7 setone, and the mixture is spray-dried. Carbonate or bicarbonate of alkali metals such as sodium and potassium are applied to wool fatty acids.

Calcium salts are obtained during the process of producing wool fatty acids. Also contains magnesium, zinc, cobalt, and selenium in winter. (3) Ester: Fischer esterification using lower saturated aliphatic alcohols such as methyl, ethyl, propyl, isopropyl, and butyl, or ethylene glyfur, glycerin, ascorbic acid, and sucrose under the catalyst of sulfuric acid. obtain.

The wool alcohol derivative in the present invention means the following three types. (1) A chloride is obtained by reacting phosphorus pentoxide with carboxylic acid diuric alcohol. Dissolve this in dry ether and add magnesium to obtain a Grignard compound.

When this is treated with dry carbon dioxide at low temperature and then reduced with hydrogen, the alcohol is converted to carboxylic acid. (2
) Ether: Obtained by Williamson's ether synthesis by reacting chloride of wool alcohol with sodium alkoxide of a saturated aliphatic base. Ethylene glycol monoether was also obtained by reacting ethylene oxide with wool alcohol in the presence of sulfuric acid. (3) Ester t Obtained by reacting an acid anhydride of a lower fatty acid such as acetic acid, propionic acid or butyric acid with wool alcohol in the presence of sulfuric acid.

To make the anticancer agent of the present invention into a preparation for injection or infusion, add a surfactant such as Pluronic F68 or IC0-60 and disperse it using ultrasound, or form it into liposomes or oil-in-water emulsion, and prepare p-hydroxy Preservatives such as methyl benzoate, stabilizers such as lecithin, sulfuric acid, non-aqueous vehicles such as coconut oil, and suspending agents such as glucose may be included. In addition, for oral preparations, capsules suitable for intestinal absorption include binders such as gelatin, stabilizers such as magnesium stearate, excipients such as lactose,
A disintegrating agent such as potato starch is included, and an enteric coating is formed using cellulose acetate phthalate, menal acrylate/methacrylic acid copolymer, etc. Others, granules,
It can also be formulated as a sustained-release implantable capsule, suppository, nebulizer, or buccal.

The anticancer agent of the present invention is administered parenterally, such as by intravenous, subcutaneous injection, or infusion.
, per day) 10-1500mgvj to 50-400
mg is preferred, and for oral preparations such as capsules, 0.
2-50g, especially 1-10g is preferred.

The anticancer agent of the present invention is effective not only for ascites cancer and leukemia but also for solid cancers, including chewing cancer, squamous cell cancer,
It has a wide range of indications, including undifferentiated cancer and sarcoma. In addition, it is effective not only against cancer-transplanted animals but also against cultured malignant cells of humans, mice, rats, hamsters, etc., so it has a direct cancer cell killing effect and is not species-specific.
It can be used as a cancer chemotherapeutic agent in animals. Furthermore, therapeutic effects have been observed not only by direct administration to the site of epilepsy but also by remote administration. Toxic LD. is 3.4 when subcutaneously injected into rats.
g/kg, and no side effects were observed even after continuous administration of 800 mg/kg for 10 days.

Test Example 1 106 Ehrlich ascites cancer cells were inoculated into lv of 5-week-old ddY mice, and 24 hours later, 50 mg/m I of each sample was suspended in 0.25% Pluronic F68/physiological saline, and 10 cells were added per group. mice were injected intraperitoneally at 400 mg/kg/day for 10 days. The average survival time for the control group administered with the same wave without a sample was 13.4 days, whereas the survival period for the wool grease administration group was 24.2 days, the wool fatty acid survival period was 28.0 days, and the wool fur and coal survival days were 30 days. .7 days, and 32.5 days for these equal mixtures, indicating a significant survival effect.

Test Example 2 106 7-denometry Lucinoma 755 cells were subcutaneously transplanted into the back of a 6-week-old mouse, a first-generation hybrid of C57BL/6 and DB^/2 lines, and 24 hours later, 0.25% lIc0-60/
A suspension of each sample at 50 mg/ml in physiological saline was added to
Groups of 10 animals were injected subcutaneously with 300II at 1 g/kg/day for 7 days. The average drowsy weight (g) was 6.4 for the control group, while the wool fatty acid and wool alcohol administration groups had an average weight of 4.8.
5.0, and their molecular distillation temperatures are 75-110 respectively.
°C, 60-95'C extraction fraction is 3.7.4.1, and the branched saturated aliphatic content obtained by refining the oil fraction by the urea inclusion method is 2.4.2.6. , had a significant Ill/i suppressive effect.

Test Example 3 106 Walker 256 sarcoma cells were subcutaneously transplanted into the supracutaneous region of a 6-week-old Wistar rat, and 24 hours later, each sample was added to 0.25% lIc0-60/physiological saline for 30 minutes.
1 group of 10 animals suspended in 0B/+nl, 100mg/
The drug was administered intra-abdominally for 10 days at a dose of kg/day. The average tumor size (I2) at 20 days was 447 in the control group, 134 in the wool fatty acid treatment group, and 134 in the wool fatty acid administration group, and that of its reducing alcohol, methyl ester, sucrose ester, ferrous sulfate salt, or cupric chloride salt-damaging derivative. The administration group was 123.103.116.65.
82, and 147.120.96.70.64 for wool alcohol, its carboxylic acid, acetate ester, methyl ether, and ethylene glycol monoether derivatives.
A significant phlegmatic suppression effect was observed.

Analysis example 1 Molecular distillation temperature of wool fatty acid and wool alcohol 1 degree each 7
The branched saturated aliphatic-containing fraction obtained by purifying the oil fractions at 5-110°C and 60-95°C using the urea inclusion method can be analyzed by infrared spectroscopy using KBr tablets, CaF prisms, or high or low concentrations. The analysis shows that the absorption bands of saturated straight chain aliphatic and fulcanes are 1379 cm for branched rrR fatty acids and 2870 cm for fulcan.
clI@ was observed. Both parts are chromo soap 715
%E(:GS-Y/178°C gas chromatography. Standard compounds include isovaleric acid or 5ee
- Arndt's diazoketone obtained by reacting butyric acid with diazomethane in ether and reacting alcohol with a silver catalyst.
Each was obtained by sequentially increasing the number of carbon atoms through the Eistert reaction. As a result, monohydric alcohols were identified as well as iso((Lll-methyl) and antiiso(LL+2-methyl) saturated aliphatic monocarboxylic acids having 11 to 17 carbon atoms.

Test Example 4 Among the components obtained in Analysis Example 1, isopentadecylic acid (1
3-Methyl-1-tetradecanoic acid) and antiquity trizosilyl alcohol (10-methyl-1-dodecanol) at 15 μH1 [4-hour treatment with Eagle HEM-10%
The colony formation rate of human uterine cancer IIeLa S3 cells in calf serum was reduced to 6.2 x 1σ' and 9.4 x 10 cells, respectively.

Claims (5)

[Claims] (1) An anticancer agent containing wool fatty acid and/or wool alcohol as an active ingredient. (2) An anticancer agent containing a wool fatty acid corresponding to a branched saturated aliphatic monocarboxylic acid having 11 to 17 carbon atoms as an active ingredient. (3) An anticancer agent containing wool alcohol, which corresponds to a branched saturated aliphatic monohydric alcohol having 11 to 17 carbon atoms, as an active ingredient. (4) An anticancer agent containing a reduced alcohol, metal salt, or ester derivative of wool fatty acid as an active ingredient. (5) An anticancer agent containing a carboxylic acid, ether or ester derivative of wool alcohol as an active ingredient.