JPH0723307B2 - Anti-cancer drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a wool fatty acid corresponding to a branched saturated aliphatic monocarboxylic acid having 11 to 17 carbon atoms, a wool alcohol, or
The present invention relates to a carcinostatic agent containing these specific ingredients or derivatives as active ingredients.

Although various types of natural fats and oils have been searched for carcinogenic effects, excellent efficacy has not been confirmed. The present inventors have found that a saponified product of wool grease has a strong anti-tumor effect, and achieved the present invention.

That is, the gist of the present invention lies in a carcinostatic agent containing, as an active ingredient, a wool fatty acid corresponding to a branched saturated aliphatic monocarboxylic acid having 11 to 17 carbon atoms, a wool alcohol, or a specific component or derivative thereof. .

The wool fatty acid and the wool alcohol in the present invention mean the acidic component and the alcohol component of the wool grease which is a semi-hair fat.

Wool fatty acids and wool alcohols are prepared by separating each from the product obtained by hydrolyzing wool grease.
For example, dissolve wool grease or concentrated hair-washing waste solution in acetone, add 3 times the amount of quicklime to this, and add 5 atm.
After reacting at 8 ° C. for 8 hours, the acidic component precipitates as a calcium salt. At normal pressure of 55 ° C, the alcohol component is soluble in acetone, and wool alcohol is extracted.

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

Wool fatty acids include C10-31 iso, antiiso, α
-60 or more kinds of carboxylic acids such as hydroxy or linear higher saturated fatty acids and resinous acids are mixed. Wool alcohol includes iso-, anti-iso or linear higher saturated aliphatic alcohols having 16 to 30 carbon atoms, sterols such as cholesterol, triterpene alcohols such as lanosterol, and hydrocarbons, and 30 or more kinds of compounds are mixed.
Both are characterized by having a large amount of iso- and anti-iso higher saturated aliphatic groups.

Specific components of wool fatty acid and wool alcohol having a branched saturated aliphatic group having 11 to 17 carbon atoms are obtained by, for example, molecular distillation.
That is, in a semi-micro pot still under high vacuum of 10 ^-4 mmHg or less, wool fatty acids with a molecular distillation temperature of 75-110 ℃ and 60-95 ℃
The wool alcohol extract is particularly effective. It is preferable to purify them by the urea inclusion body method. That is, when each fraction is dissolved in methanol, urea is added, the mixture is warmed to be dissolved, and then the mixture is allowed to stand for cooling to precipitate crystals. Hydrochloric acid was poured into this filtrate, and hexane and ether were alternately extracted,
It is washed with water, dried with Glauber's salt, and the solvent is distilled off. Chromosorb W / 15% EGSS-X / 178 ℃ gas chromatography and KBr tablet infrared spectrum showed that these were monocarboxylic acids of iso- and anti-iso-branched saturated fatty acids of 11-17 carbon numbers and monovalent Alcohol is the main component. These are iso and anti-isoundecylic acid, hereafter lauric acid, tridecylic acid, myristic acid,
Pentadecyl acid, palmitic acid, margaric acid and their alcohols.

The wool fatty acid derivative in the present invention means the following three kinds. (1) Reduced alcohol: Wool fatty acid is reacted with lithium aluminum hydride to convert a carboxyl group into alcohol. (2) Metal salt: A saturated aqueous solution of wool fatty acid is mixed with a saturated aqueous solution of copper or iron salt in an amount of 2 times mole and spray-dried. Carbonate or hydrogencarbonate of alkali metals such as sodium and potassium acts on wool fatty acid. The calcium salt is obtained in the process of producing the wool fatty acid. In addition, it contains magnesium, zinc, cobalt and selenium salts. (3): Ester: Obtained by esterification of Fischer by allowing a lower saturated aliphatic alcohol such as methyl, ethyl, propyl, isopropyl, or butyl, or sucrose to act under the catalyst of sulfuric acid.

The wool alcohol derivative in the present invention means the following three kinds. (1) Ether: Obtained by Williamson's ether synthesis by allowing a lower saturated aliphatic sodium alkoxide to act on a chloride of wool alcohol. Further, ethylene oxide is allowed to act on wool alcohol in the presence of sulfuric acid to obtain ethylene glycol monoether. (2) Ester: Obtained by reacting wool alcohol with an acid anhydride of a lower fatty acid such as acetic acid, propionic acid or butyric acid in the presence of sulfuric acid.

Injecting the carcinostatic agent of the present invention into an infusion preparation, a surfactant such as Pluronic F68, HCO-60 is added and dispersed by ultrasonic waves, or a liposome or an oil-in-water emulsion,
Preservatives such as methyl p-hydroxybenzoate, stabilizers such as lecithin and linoleic acid, non-aqueous vehicles such as coconut oil, suspending agents such as glucose may be included.
For oral preparation, a capsule suitable for intestinal absorption contains a binder such as gelatin, a stabilizer such as magnesium stearate, an excipient such as lactose, and a disintegrating agent such as potato starch. No, cellulose acetate phthalate, methyl acrylate / methacrylic acid copolymer, etc. can be used to form an enteric film. In addition, it can be formulated as a granule, a sustained-release buried capsule, a suppository, a nebulizer, or a buccal.

The carcinostatic agent of the present invention is administered intravenously, subcutaneously, or by parenteral administration such as infusion, the dose of the active ingredient (adult body weight 1 kg,
(Per day) 10-1500 mg, particularly 50-400 mg is preferable, and in the case of orally administered agents such as capsules, 0.2-50 g, particularly 1-10 g is preferable.

The carcinostatic agent of the present invention is effective not only for ascites cancer and leukemia but also for solid cancer, adenocarcinoma of each tissue, squamous cell carcinoma,
It has a wide range of indications such as undifferentiated cancer and sarcoma. In addition to cancer transplanted animals, it is also effective against cultured malignant cells such as humans, mice, rats, and hamsters, so it has a direct cancer cell-killing effect and no species specificity.
It can be used as a cancer chemotherapy drug for animals. Furthermore, not only direct administration to the site of tumor transplantation, but also remote administration has therapeutic effects. Toxicity LD ₅₀ is 3.4 g / kg by subcutaneous injection in rats, and no side effects are observed even after continuous administration of 800 mg / kg for 10 days.

Test Example 1 Ehrlich ascites tumor cell 1 in the abdominal cavity of 5-week-old mouse ddY
After inoculating 0 ⁶ cells, 24 hours later, 50 mg / ml of each sample was suspended in 0.25% Pluronic F68 / physiological saline, and 10 animals per group, 400 mg / kg /
Injected intraperitoneally for 10 days per day. The control group that received the same solution without the sample had an average survival time of 13.4 days, whereas the wool grease administration group had 24.2 days and the wool fatty acid had 28.0 days.
A day, 30.7 days for wool alcohol, an equal mixture of these
It was 32.5 days, and a significant life-prolonging effect was observed.

Test Example 2 10 ⁶ adenocarcinoma 755 cells were transplanted subcutaneously to the back of 6-week-old mice of the first-generation hybrid of C57BL / 6 and DBA / 2, and 24 hours later, each of them was added to 0.25% HCO-60 / physiological saline. A suspension of the sample in 50 mg / ml was subcutaneously injected at 10 mg / group for 7 days at 300 mg / kg / day. The average tumor weight (g) was 6.4 for the control group, respectively.
Wool fatty acid and wool alcohol administration groups were 4.8 and 5.0, and their molecular distillation temperatures were 75-110 ° C and 60-95 ° C, respectively, and the fractions were 3.7 and 4.1, respectively, and the fractions were purified by the urea inclusion body method. The contents of branched saturated aliphatic compounds were 2.4 and 2.6, which were significant tumor suppressor effects.

Test Example 3 A 6-week-old Wistar rat was walker subcutaneously in the ruminal region
256 sarcoma cells were transplanted 10 ⁶ and 24 hours later, 0.25%
A solution prepared by suspending each sample at 30 mg / ml in HCO-60 / physiological saline was intraperitoneally administered for 10 days at 100 mg / kg / day for 10 animals per group. The average tumor size (mm ² ) on the 20th day was 447 for the control group and 134 for the wool fatty acid administration group, and its reducing alcohol, methyl ester, sucrose ester, ferrous sulfate or cupric chloride, respectively. The administration group of the derivative was 123, 103, 116, 65, 82, and 147, 120, 96, 70, 64 for wool alcohol, its carboxylic acid, acetic acid ester, methyl ether, and ethylene glycol monoether derivatives. Tumor suppressive effect was observed.

Analysis example 1 Molecular distillation temperature of wool fatty acid and wool alcohol 75-
The branched saturated aliphatic-containing fraction obtained by purifying the 110 ° C. and 60-95 ° C. fractions by the urea clathrate method was saturated with KBr tablets, CaF prisms, or infrared spectra at high or low concentrations. There is no absorption band for straight chain aliphatics or alkenes, and branched fatty acids are 1379 cm.
^-1 and an alkane of 2870 cm ^-1 were observed. This fraction was fractionated by gas chromatography at Chromosorb / 15% EGGS-Y / 178 ° C. The standard compound was obtained by reacting isovaleric acid or sec-butyric acid with diazomethane in ether to give a diazoketone with an alcohol with a silver catalyst to increase the number of carbon atoms in the Arund-Eistellt reaction. As a result, a monohydric alcohol was identified in the same manner as the iso (ω1-methyl) and antiiso (ω2-methyl) saturated aliphatic monocarboxylic acids having 11 to 17 carbon atoms.

Test Example 4 Among the components obtained in Analysis Example 1, isopentadecyric acid (13
-Methyl-1-tetradecanoic acid) and antiisotridesilyl alcohol (10-methyl-1-dodecanol)
Was treated with 15 μM for 6 hours, and the colony formation rate of human uterine cancer HeLa S3 cells in Eagle MEM-10% calf serum was 6.2 ×.
It was lowered to 10 ^-3 and 9.4 × 10 ^-3 .

Claims (3)

[Claims] 1. A carcinostatic agent containing, as an active ingredient, a wool fatty acid and / or a wool alcohol corresponding to a branched saturated aliphatic monocarboxylic acid having 11 to 17 carbon atoms. 2. A carcinostatic agent comprising a reducing alcohol, a metal salt, or a lower alkyl ester or sugar ester derivative of wool fatty acid corresponding to a branched saturated aliphatic monocarboxylic acid having 11 to 17 carbon atoms as an active ingredient. 3. A carcinostatic agent comprising an ether or ester derivative of wool alcohol as an active ingredient.