JPH07267864A - Hypothermic agent - Google Patents

Abstract

PURPOSE:To obtain a hypothermic agent containing a new compound originated from a crude drug as an active component, having hypothermic action and little side effect, excellent in stability and useful as an antipyretic, etc. CONSTITUTION:This hypothermic agent contains a compound of formula I (gal expresses galactose; glc expresses glucose), formula II or formula III as an active component. Compounds of formula I to formula III are obtained by extracting a crude drug of Anemarrhenae rhizoma, Anemarrhenae asphodeloides Bunge of the plant producing Anemarrhenae rhizoma or a plant belonging to the same family with a solvent, e.g. hexane, removing the solvent from the obtained extract and fractionating the residue by chromatography under appropriate conditions with an eluent, e.g. hexane.

Description

Detailed Description of the Invention [Industrial applications]

The present invention relates to a compound having a hypothermic effect and useful as a drug such as an antipyretic agent. Specifically, Timosaponin A-II, which is a saponin contained in Chinese herbs, etc.
I, Thymone, a xanthone derivative (mangiferin)
Alternatively, it is a hypothermic agent containing linoleic acid as an active ingredient.

[0002]

2. Description of the Related Art Many antipyretic drugs act nonspecifically and rapidly develop their effects, and are therefore widely used for so-called daily diseases such as acute febrile diseases.

Typical antipyretics currently in use are pyrinic and nonpyrrine, and the nonpyrrine are classified into salicylic acid agents, aniline and indole.

However, with the pyrin antipyretic drug, side effects such as shock due to the cold medicine ampoule, gastrointestinal disorders such as nausea and vomiting, and hypersensitivity symptoms such as anaphylaxis have been observed.
A wide range of side effects such as gastrointestinal disorders, hypersensitivity and thrombocytopenia have been reported for non-pyrine antipyretics.

New antipyretic drugs have been introduced one after another up to the present, but at present, few have established safety, especially safety for children.

[0006]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found a compound having a hypothermic effect, which has few side effects and is highly safe.
The present invention has been completed.

That is, the present invention is as follows.

(1) The following formula I (In the formula, gal represents galactose and glc represents glucose.)
A hypothermic agent containing a compound represented by

(2) The following formula II A hypothermic agent containing a compound represented by

(3) The following formula III A hypothermic agent containing a compound represented by

Hereinafter, the compounds represented by the formulas I, II and III are collectively referred to as a compound of the formula.

The compound of the formula is contained in the crude drug known as "Chinese medicine" and can be isolated, for example, as follows.

[0013] That is, the herb of Chinese medicine, its original plant, or the same genus plant, is extracted with at least one solvent selected from hexane, diethyl ether, petroleum ether, ethyl acetate, chloroform, acetone, methanol, ethanol and water. Then, the residue obtained by removing the solvent from the obtained extract, hexane, diethyl ether, petroleum ether, ethyl acetate, chloroform, acetone, methanol, ethanol, acetonitrile, tetrahydrofuran, at least one solvent selected from water. As an elution solvent, Diaion HP-20, a porous polymer such as MCI gel CHP20P, Sephadex such as Sephadex LH-20, reversed phase silica gel, silica gel, polyamide, column chromatography using a carrier such as cellulose or Celite or High speed liquid For chromatography (HPLC)
The compound of the formula can be obtained by fractionating once or several times while confirming the target component by thin layer chromatography or high performance liquid chromatography.

If necessary, it may be purified by recrystallization using a suitable solvent such as methanol, dioxane, acetone, n-hexane, ethyl acetate or petroleum ether.

Next, specific examples of the production of the compound of the formula will be shown below.

Specific Example 1 9.1 kg of Chimbo (Shibata Co., Ltd.) was finely chopped, cold soaked in methanol overnight, and reflux extraction was carried out for 6 hours to obtain 4.0 kg of a methanol extract. Precipitating while concentrating this methanol extract (600 g)
Then, this precipitate was collected by filtration and fractionated into two, a mother liquor and a precipitate.
By repeating recrystallization of 150 g of the precipitate with methanol: dioxane = 1: 1, the literature [Tosio Kawasaki, Tatsuo Yamag
uchi, and Nobuo Itakura, YAKUGAKU ZASSHI, 83 (9) 892
-896 (1963)] described in Timosaponin A-III
2.8g was obtained.

Example 2 9.1 kg of Chimbo (Shibata Co., Ltd.) was finely chopped, soaked in methanol overnight, and then reflux extracted for 6 hours to obtain 4.0 kg of a methanol extract. Precipitating while concentrating this methanol extract (600 g)
Then, this precipitate was collected by filtration and fractionated into two, a mother liquor and a precipitate.
3.3 kg of the filtrate was added to water, 5 times with Diaion HP20.
Elution was performed with 0% methanol and methanol, respectively, and the mixture was fractionated into three. Of the three fractions, 252 g of 50% methanol eluate extract was recrystallized with methanol: water = 2: 1 to obtain a mixture of the literature [Naotaka Morita, Mineo Simizu, and
Masako Fukuta, YAKUGAKU ZASSHI, 85 (4) 374-375 (196
5)] Mangiferin (also known as thymonin)
Obtained 59.5 g.

Specific Example 3 9.1 kg of Chimbo (Shibata Co., Ltd.) was finely chopped, cold soaked in methanol overnight, and reflux extraction was performed for 6 hours to obtain 4.0 kg of a methanol extract. Precipitating while concentrating this methanol extract (600 g)
Then, this precipitate was collected by filtration and fractionated into two, a mother liquor and a precipitate.
3.3 kg of the filtrate was added to water, 5 times with Diaion HP20.
Elution was performed with 0% methanol and methanol, respectively, and the mixture was fractionated into three. Silica gel using 10 g of methanol eluate extract 689 g out of these three fractions, by repeating each column chromatogram of CIG column, etc., 20 mg linoleic acid (linoleic acid) described in the Merck Index (MERCK INDEX) Obtained.

[0019] Incidentally, the herb of Chinese medicine is one of those frequently used as a constituent herbal medicine of Kampo medicine.
It is used for Jiin Shiho-to, Ji-in Furu-to, Soju-Nin-to, Shin-Seisei-to, and Byora-kajinjin-to.

Seifu-san is a skin disease, Ji-in Shiho-to, Ji-in Furu-tou are cough and tan, Soju-nin-to is sleepless, Shin-Sei-sei-to is nasal stuffiness, and Shiratora-Kinseng-to is Used for those with thirst and hot flashes. In addition, antibacterial action, antipyretic action and the like are known as the pharmacological action of the extract of Botanical herbs.

However, it has not been clarified as to what causes the antipyretic action of Byakko-kainjin-to and the extract of Chimbo as a constituent crude drug thereof, and it has not been clarified that the compound of the formula has a hypothermic action. It has been made clear by the present inventors for the first time.

The compounds of the formula may be used alone or as a mixture of two or more thereof, and they have an excellent hypothermic effect as compared with the case of using the extract of Chichibu.

Next, the compound of the formula has a hypothermic effect,
Usefulness as a drug such as an antipyretic agent will be described with reference to experimental examples.

Experimental Example 1 Four-week-old male ddY mice (1 group, 5 mice) were used. To measure the body temperature of the mouse, after the mouse became stable, the tail was lifted to expose the anus, a small amount of olive oil was applied to the tip of the element, and the element was placed in the rectum along the body axis up to about 1.5 cm (during measurement). The element was moved according to the movement of the mouse so that the depth of the element was constant).

Sufficient time was taken until the scale of the thermistor became constant, the scale was read, the body temperature was measured several times every 30 minutes, and the measurement was taken until the body temperature became constant.

After measuring the body temperature prior to administration of the compound of formula
The compound of formula was suspended in 0.5% carboxymethylcellulose (CMC) saline solution and 50 mg / kg was injected intraperitoneally.

After administration of the compound of the formula, the measurement was carried out every 30 minutes for 2 hours and thereafter every 1 hour until the body temperature was recovered.

The results are shown in Table 1.

[Table 1]

As is clear from Table 1, it was confirmed that the compound of the formula has a hypothermic effect.

In addition, when an acute toxicity test was carried out using male ICR mice, the compounds obtained in Examples 1, 2 and 3 showed no deaths after oral administration of 1 g / kg. It was confirmed that the safety was high.

As described above in detail, the compound of the formula has a hypothermic effect and is highly safe, so that it is useful as a drug such as an antipyretic agent.

Next, the dose and formulation of the compound of formula will be explained.

The compounds of formula can be administered to animals and humans either neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of a patient, but usually 50 mg to 5 g as the weight of the compound of formula is divided into several times a day in adults. All doses seem appropriate.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used in a conventional manner.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Flowability Accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the formula can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents. .

In order to exert a desired effect as a parenteral agent, it depends on the age, weight and degree of disease of the patient.
Usually, it is considered that intravenous injection, intravenous infusion, subcutaneous injection, and intramuscular injection of 5 to 50 mg per day as the weight of the compound in an adult are considered appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the formulation examples of the present invention will be described.

[Formulation Example 1]

According to the above formulation, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each).

One of these tablets was prepared by using the compound 2 obtained in Example 1.
It contains 0mg, and adults take 3-10 tablets daily in several divided doses.

[Formulation Example 2] Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound obtained in Example 2 10 g Total 100 g

According to the above formulation, a part of and was uniformly mixed, compression-molded, crushed, and the remaining amount of was added and mixed, and compression-molded with a tableting machine to give one tablet.
0 mg tablets were obtained.

Compound (1) obtained in Example 2 was added to each tablet.
It contains 0mg, and adults take 3-10 tablets daily in several divided doses.

[Formulation Example 3] Crystalline cellulose 79.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound 10 g obtained in Example 3 Total 145 g

According to the above formulation, and were uniformly mixed, and the mixture was kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and then mixed, and compressed by a tableting machine. It was molded to obtain a tablet of 200 mg each.

Compound 1 obtained in Example 3 was added to one tablet.
It contains 0mg, and adults take 3-10 tablets daily in several divided doses.

[Formulation Example 4]

According to the above recipe, the components (1) to (4) are uniformly mixed, compression molded with a compression molding machine, and crushed with a crusher,
Sieve to obtain granules.

The compound 1 obtained in Example 1 was added to 1 g of this granule.
It contains 00mg, and takes 1 to 2g daily for adults in several divided doses.

[Formulation Example 5] Crystalline cellulose 86.5 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound obtained in Example 2 10 g Total 131.5 g

According to the above-mentioned recipe, the ingredients (1) to (4) were mixed uniformly and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules.

1 g of this granule contains the compound 1 obtained in Example 2.
It contains 00mg, and takes 1 to 2g daily for adults in several divided doses.

[Formulation Example 6] Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 3 10 g Total 100 g

According to the above formulation, were mixed uniformly and 200 mg was filled in No. 2 capsule.

One capsule of this capsule contains 20 mg of the compound obtained in Example 3, and 3 to 10 capsules per day for adults are to be taken in several divided doses.

[Formulation Example 7] Distilled water for injection 89.5 g Soybean oil 5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound obtained in Example 1 1 g Total amount 100 g

According to the above-mentioned formulation, was dissolved in and, and a solution of and was added thereto to emulsify to obtain an injection.

Claims (3)

[Claims] 1. The following formula I (In the formula, gal represents galactose and glc represents glucose.)
A hypothermic agent containing a compound represented by 2. The following formula II A hypothermic agent containing a compound represented by 3. The following formula III A hypothermic agent containing a compound represented by