JP2000344675A - Prophylactic agent for alcohol damage, and food containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic agent capable of suppressing the absorption of ingested alcohol or metabolite thereof into the interior of the body, and preventing or reducing organ derangement and/or nervous disorder by including a pulverized product of a plant belonging to the family Lauraceae, or an essence extracted from the plant with a lipophilic solvent. SOLUTION: This prophylactic agent contains a pulverized product of one portion of a plant belonging to the family Lauraceae (preferably a leaf of laurel), or an essence extracted from the portion of the plant with a lipophilic solvent. The pulverized product or the extracted essence preferably contains sesquiterpenes having α-substituted γ-butyrolactone group of the formula (R1 is methyl or methylene), and a derivative thereof. For example, a bark (cassia) of Cinnamomum cassia and a plant belonging to the same genus, and a root of Lindera strychnifolia can be used as the portion of the plant belonging to the family Lauraceae except the laurel. The prophylactic agent can also contain one portion of a saponin-containing plant or an essence extracted therefrom with the lipophilic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention can prevent various diseases caused by alcohol itself or its metabolites and alleviate their symptoms by suppressing the absorption of ingested alcohol into the body. And a prophylactic agent for alcohol disorders having a low frequency of side effects.

[0002]

2. Description of the Related Art Alcohol taken orally as an alcoholic beverage or alcohol-containing food contains stomach, duodenum,
After being absorbed through the digestive tract mainly composed of the small intestine, it is transported to the whole body through blood. Most of the alcohol absorbed into the body (usually about 90% of the total) is metabolized in the liver; first, alcohol dehydrogenase (ADH)
Co-acts with the coenzyme nicotinamide adenine dinucleotide phosphate reduced product (NADPH) and nicotinamide adenine dinucleotide (NAD), thereby producing oxidized harmful acetaldehyde. Next, the produced acetaldehyde is oxidized to acetic acid by the action of aldehyde dehydrogenase (ALDH) and NAD, and finally converted to water and carbon dioxide, and excreted with the exhaled breath.

[0003] The rate of absorption of alcohol into the body is extremely faster than nutrients such as starch, proteins and lipids. The alcohol diffuses into the tissues of the whole body through the blood, and at the same time exerts the action of expanding capillaries. In addition, flushing of the face and upper arm is caused. Alcohol, which has diffused through the blood into tissues throughout the body, quickly passes through the blood-brain barrier and reaches the cerebral cortex, resulting in changes in emotions and emotions, ie, intoxication. It is thought that the onset of drunkenness is complicatedly related to the direct action of alcohol, the balance with its metabolites, acetaldehyde and electrolytes, and biogenic amines. Above all, acetaldehyde, which is highly toxic and pharmacological to the human body, is also a cause of hangover, discomfort and headache.

[0004] Excessive alcohol consumption can result in a number of organ disorders, for example: (1) Gastrointestinal ulcers in the upper gastrointestinal tract (eg, stomach and duodenum): This is the most typical example of organ damage due to excessive intake of alcohol, mucosal invasion, and decreased mucus secretion ability that is a protective factor And decreased gastric mucosal blood flow. (2) Liver damage and promotion of worsening of liver damage: Acetaldehyde produced by metabolism of alcohol causes damage to mitochondria and microtubules in liver cells, and is an inflammatory factor by acetaldehyde acting on Kupffer cells and monocytes. Production of active oxygen and nitric oxide is promoted. (3) Cirrhosis: Caused by the fact that cytokines produced from Kupffer cells and monocytes promote the production of type IV collagen from Ito cells and sinusoidal endothelial cells. (4) Hyperlipidemia and fatty liver: The accumulation of NADH produced simultaneously with the action of alcohol dehydrogenase inhibits the metabolic pathway of lipids by xanthine oxidase.

[0005] As an example of a therapeutic agent for the above-mentioned organ disorders, for the treatment of gastrointestinal ulcer (1), H2 blockers such as cimetidine ("Cimetidine"), a proton pump inhibitor omeprazole, a mucosal protective agent Ceteraxate and sucralfate, as well as anticholinergic agents, can cause side effects such as a decrease in the number of granulocytes and platelets in blood and an increase in GOT and / or GPT test values. As an anti-ulcer agent using a natural product having fewer side effects as compared with the synthetic drug, a formulation containing dehydrocostus lactone derived from crude drug Mokko (Kiko) and polyethylene glycol (JP-A-7-13)
No. 8157) has been studied.

As a therapeutic agent for liver damage (2) to (4), various agents such as an acetaldehyde trapping agent, a toxicity reducing agent and a metabolism promoting agent have been reported. Examples thereof include D-penicillamine and L-methionine, as well as clofibrate and γ-linolenic acid, all of which are synthetic preparations and can also induce various side effects.

[0007] On the other hand, excessive consumption of alcohol not only causes organ damage as described above, but also causes neuropathy such as alcohol dependence, poisoning and even alcohol psychosis due to the above-mentioned intoxication. is there. Alcohol inhibitors prescribed for alcohol dependent patients include, for example, disulfiram. When administered before alcohol consumption, such alcohol inhibitors can inhibit acetaldehyde dehydrogenase and accumulate acetaldehyde to induce headache and mood discomfort, thereby preventing excessive intake of alcohol. It does not have the effect of suppressing alcohol absorption.

[0008] Formulations capable of exhibiting the action of inhibiting the absorption of alcohol into the body are those used to reduce adverse effects on living organisms due to the toxicity of both alcohol itself and acetaldehyde. Examples of such preparations include tea saponin and / or quillaja saponin-containing alcohol absorption inhibitors for the purpose of suppressing alcohol absorption into the body and lowering blood alcohol concentration (Japanese Patent Laid-Open No. 4-145028). Bulletin);
Oleanolic acid extracted from carrot, senega, mukuroji, and horse chestnut,
Presenegenin, hederagenin (hede
ragenin) and / or protoescienin (protoaesc)
alcohol-suppressing agent containing a glycoside having genin) as a sapogenin (JP-A-7-53385).

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to prevent the ingestion of alcohol itself or its metabolites from being absorbed into the body to prevent organ damage and / or neuropathy, or to prevent various diseases thereof. It is an object of the present invention to provide an alcohol disorder preventive agent for alleviating symptoms, which has a lower frequency of side effects and can exert its effect with a smaller dose.

[0010]

The Lauraceae laurel (Laurus nobilis) is a plant widely cultivated in sunny and fertile soils, especially from Asia Minor to Mediterranean countries. Laurel leaves are commonly known by names such as laurel, laurier or bay leaf and are used as culinary herbs and spices, especially bouquet garni. In Western countries, it is used as a folk remedy for preservatives, excitement, digestive function, and aromatic stomach, as well as a bath preparation, a hair growth agent, and an external preparation for rheumatic pain relief Have been.
Laurel leaves with pinene and borneol
rneol) and other monoterpenoids; costunolide, dehydrocostus lactone (deh)
ydrocostuslactone), β-eudesmall (β-eudesm)
ol) and the like, and the inclusion of lignans, flavonoids, phenylpropanoids is known from various prior art documents. Also, from a pharmacological point of view, natural extracts from laurel seeds inhibit ethanol-induced ulcers in rats [Afifi FV
Authors, J. Ethnopharmacol., 58 , pp. 9-14 (19
1997)] and that extract from bay leaves can suppress sugar absorption in rabbits [Gurman EG et al., Fizi
ol Zh SSSR Im IM Sechenova, 78 , 109th-11th
6 pages] have been reported.

The present inventors have studied the effect of suppressing the absorption of alcohol on rodents by using ground leaves of laurel leaves, a plant of the camphoraceae family, and found that a fat-soluble solvent extract (particularly methanol Or ethanol extract)
Further, it has been found that all of the further fat-soluble fractions from the extract contain sesquiterpenes having a γ-lactone ring, and that these sesquiterpenes can exhibit alcohol absorption inhibitory activity.

The inventors of the present invention also performed similar evaluations on pulverized products of one part of other camphoraceous plants, Cinnamomam cassia, Dendai yak and Kromoji, and their fat-soluble solvent extracts. It has also been found that an absorption suppressing effect can be exhibited. Traditionally,
Saponin-containing plants are known as natural products that exhibit an alcohol absorption inhibitory effect, but it has not been reported that saponins have been isolated from the camphoraceous plants such as laurel, and saponins are usually Since it exhibits high water solubility and is insoluble in fat-soluble solvents, it was confirmed in one site of the camphoraceous plant that there was an ingredient other than saponins that was effective in suppressing alcohol absorption.

The present inventors have further studied and found that, when the sesquiterpenes are in the form of sesquiterpenes having an α-substituted γ-butyrolactone group and derivatives thereof, higher alcohol absorption is obtained. The present inventors have found a new finding that they exhibit an inhibitory action, and have achieved the present invention.

That is, a first aspect of the present invention is a prophylactic agent for alcohol damage, comprising a pulverized product of a part of a camphor tree plant (particularly preferably a bay leaf) or a fat-soluble solvent extract thereof. Particularly preferably, the fat-soluble solvent extraction extract can exhibit an alcohol absorption suppressing action,
sesquiterpenes having an α-substituted γ-butyrolactone group and derivatives thereof. The agent for preventing an alcohol disorder according to the second aspect of the present invention comprises, as one site of a plant of the camphor tree family other than laurel, for example, Cinnamomum cassia and the bark of its congener plant (ie, calyx), and roots of Tendai yak. Or using a substance selected from the stem of kuromoji, and crushing it or a fat-soluble solvent-extracted extract thereof, or any of sesquiterpenes having an α-substituted γ-butyrolactone group or derivatives thereof contained therein. It is characterized in that it is contained in such a form. As a third aspect, the present invention provides, as a third aspect, a saponin-containing plant extract or a fat-soluble solvent extract obtained from a saponin-containing plant or a fat-soluble solvent extract together with a pulverized material from one part of the plant of the family Camphoraceae or an extract of the fat-soluble solvent extract thereof. The present invention also provides a preventive agent for alcohol damage containing a crude saponin fraction of an extract or an isolated and purified product thereof. Further, the present invention provides, as a further aspect, a food containing the alcohol disorder preventive agent.

[0015]

The alcohol disorder preventive agent of the present invention can be taken before drinking alcohol or ingesting alcohol-containing foods.
Alcohol absorption from the gastrointestinal tract is suppressed, thereby suppressing an increase in blood alcohol concentration, gastrointestinal disorders such as ulcers and cancers caused by it, and liver diseases (eg, alcoholic hepatitis, fatty liver, liver cancer) , Diabetes, hyperlipidemia, and also the onset of alcoholism or addiction. The prophylactic agent for alcohol disorders of the present invention is safer because it is derived from natural products and has a significantly lower frequency of side effects as compared to synthetic drugs usually used in clinical practice. In addition, since the ability to develop a drug effect, that is, the effect of suppressing absorption of alcohol into the body is extremely high, the effect is exhibited with a smaller dose. The alcohol disorder preventive agent of the present invention contains an effective part of a conventionally known saponin-containing plant or an extract obtained therefrom, a fraction of the extract or a purified product isolated therefrom, thereby absorbing alcohol into the body. The inhibitory action can be further enhanced. Since the present invention can be provided as a food containing the alcohol disorder preventive agent, a patient can easily ingest it orally.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The preventive agent for alcohol damage according to the present invention contains a pulverized product of one part of a camphor tree plant or a fat-soluble solvent extract obtained therefrom.
Particularly preferably, the alcohol damage preventive agent of the present invention is isolated and purified from the fat-soluble extract, having the formula:

Embedded image (In the formula, R ₁ represents a methyl group or a methylene group.)
And sesquiterpenes having an α-substituted γ-butyrolactone group and derivatives thereof. The derivative has the formula:

Embedded image (In the formula, R ₁ represents a methyl group or a methylene group.)
May have an α-substituted γ-butyrolactone reduced group represented by

In a first embodiment of the present invention, laurel leaves are used as a part of a camphor tree plant.

The sesquiterpenes having an α-substituted γ-butyrolactone group and derivatives thereof can be obtained, for example, by the following procedure. First, crushed dried leaves of laurel are dried in an organic fat-soluble solvent (particularly, methanol or ethanol), preferably at 10 to 30 ° C. for 24 to 24 hours.
After 36 hours of cold immersion extraction, the solvent is evaporated to obtain a fat-soluble solvent extract. Solvent evaporation is particularly preferably 45
Under a reduced pressure (particularly 90 to 180 mm
Hg or less). Next, the obtained fat-soluble solvent extract was separated into an ethyl acetate layer and an aqueous layer using an ethyl acetate / water mixture at a volume ratio of 1: 1. The ethyl acetate layer was separated with hexane / ethyl acetate (= 30/1 to 0/100
(v / v)) The mixture is subjected to a normal phase silica gel column chromatography method using a mixed solvent as a carrier. The fraction containing the active ingredient is subjected to a column chromatography method, and then further subjected to high performance liquid chromatography (H
PLC) method to obtain the desired α-substituted γ
Sesquiterpenes having a butyrolactone group are isolated and
Can be purified.

In the present invention, in the column chromatography method, a Chromatorex ODS column is preferably used, and a methanol-based solvent, particularly a mixed solvent of methanol / water = 60/40 to 100/0 (v / v) is preferably used as a carrier. use. Further, in the subsequent HPLC method, a C18 column is preferably used, and a methanol-based solvent, specifically, methanol / water =
A mixed solvent system of 50/50 to 80/20 (v / v) is preferably used.

Α-isolated and purified by the above-described method
Specific examples of sesquiterpenes having a substituted γ-butyrolactone group include costunolide (1), santamarin (2), dehydrocostus lactone (3), elemantine (4), zalzanine C (5), and spirafolone. Ride (6), Magnolia Ride (7), Zarzanine D
(8), Reynosine (9), 3-α-acetoxyeudesma-1,4 (15), 11 (13) -triene-12,6-α-olide (1
0), 3-oxyeudesm-6βH-1,4,11-triene-6,13
-Olide (11) and the like. The chemical formulas of these species are shown below.

Embedded image

In the present invention, the above-mentioned sesquiterpenes having an α-substituted γ-butyrolactone group may be used in the form of a derivative obtained by further conversion. Since the alcohol disorder preventive agent of the present invention exhibits a higher alcohol absorption inhibitory action, for example, a derivative of dehydrocostulactone (3), in particular, a reduced form (3b) or (3b) having a γ-lactone ring or an acetal ring The form 3c) is particularly preferably exemplified. In Scheme I below:
2 shows the preparation of a derivative from dehydrocostus lactone (3).

Embedded image

In Scheme I above, 11α-methyl-6,
The 12-diol derivative (3a) is obtained by treating dehydrocostus lactone (3) with lithium aluminum hydride (LiAlH ₄ ) at 0 ° C. in a tetrahydrofuran solvent. Alternatively, mockolactone (3) can be obtained by reducing dehydrocostulactone (3) with sodium borohydride (NaBH ₄ ) at 0 ° C. in a methanol solvent, and then subjecting it to chromatography.
b), 11α-methyl-lactol mixture (3c, α-form and β-form)
1: 1) and the 11α-methyl-12-methylene derivative (3d) can be isolated. However, in the above scheme I, 11α-methyl-6,12-diol derivative (3a) (uncyclized lactone) and 11α-methyl-12
-All the methylene derivatives (3d) (deketone reduced products)
Since it does not have a characteristic functional group (γ-lactone ring group or acetal ring group) in the present invention, it is not included in the preferred derivatives of the present invention.

The preventive agent for alcohol disorders according to the present invention is characterized in that, in the case of an adult, at least two portions of a plant of the camphor tree (for example, crushed laurel leaves) are administered per dose.
50 mg, preferably in an amount of 500 to 2,500 mg, more preferably, the fat-soluble solvent extract obtained by the above procedure, at least 50 mg, preferably 100 to 500 mg per dose for adults. In the amount of In the preventive agent for alcohol disorders of the present invention, when the sesquiterpenes having the α-substituted γ-butyrolactone group and derivatives thereof are characteristic components, in the case of an adult, at least 5 mg per dose, Preferably it is used in an amount of 25-50 mg.

In the second embodiment of the present invention, one part of the camphor tree plant to be used is not limited to the leaves of the above-mentioned laurel tree, and may be, for example, the bark of Cinnamomam cassia and its congener plants (ie, calyx). ), The roots of Tendai yak, the stems of kuromoji, and the like. In the present invention, when one part of any plant is used, it is more preferably used in the form of its pulverized product, its fat-soluble solvent extract, its fraction, or its isolated and purified product.

Here, Cain (Cinnamomi cortex)
It is the bark of Cinnamomum cassia and is cultivated in China and Vietnam. Caffeine, which contains silicic aldehyde and has a unique flavor, is used as a raw material for spices and confectionery. Keihi is also listed in the Japanese Pharmacopoeia and is widely used in the prescription of aromatic stomachic and Chinese herbal medicine.

Tendai yak (Lindera strychnifoli)
a) is a plant whose main production area is Tiantai, Zhejiang Province in China, and its roots are usually dried and used. Since Tendai yak contains essential oils, it is used in Chinese medicine as an aromatic stomachic, an analgesic, and a sedative. In the present invention, the root portion is used.

The black name (Lindera umbellata) is known in Chinese names as sycamore or angiosperm, and in Chinese medicine, its root bark or bark is used as a remedy for gastrointestinal catarrh, gastric ulcer, beriberi and edema. In addition, when a branch is broken, a peculiar fragrance is emitted. Therefore, the branch is used as a fragrance such as soap. In the present invention, a stem site is used.

The above camphoraceous plants are those generally distributed in the crude drug market.
Similarly, one part of the plant is also an example, and the present invention is not limited thereto. In the present invention, the relevant part of the plant is used in the form of finely pulverized by a pulverizing means usually used in the art. Alternatively, an extract can be prepared and used using the same extraction solvent and method as described for the bay leaves.

The preventive agent for alcohol disorders according to the present invention comprises an effective lipid-soluble solvent extract obtained from one site of camphoraceous plant, based on the total weight of the preparation, in the case of an adult, at least 50 mg, preferably at least 50 mg per dose. Is 100-500
It may be contained in mg amounts.

The prophylactic agent for alcohol disorders of the present invention further enhances the effect of suppressing alcohol absorption by further increasing buds and bark of thaliana, aralia, roots of ginseng,
One part of a saponin-containing plant selected from the roots of Senega, the skin of skull, the seeds of horse chestnut, or a fat-soluble solvent-extracted extract obtained therefrom or a crude saponin fraction thereof or an isolated and purified product thereof may be contained. .

[0031] Thonburi is a fruit of the rhododendron (Kochia scoparia) native to Europe, and is mainly cultivated in Akita Prefecture in China and Japan.
It is marketed as food with the touch of “field caviar”. Thonburi (pea seeds) contains saponin, a triterpene glycoside such as momodin Ic, and the dried product is used in China as a crude drug called diphtheria (Kochiae fructus).

[0032] Taraxacum (Arallia elta SEEM) is a plant of the araliaceae family, and its buds are mainly used for food in Japan. It contains saponins such as elatoside I. In the present invention, bud portions are used, but bark and root bark may be included if desired.

[0033] Panax phizome is
It is a crude drug obtained by processing the rhizome of Panax japonicus, a plant belonging to the family Ukogi, and contains chikusetsu saponins. It is cultivated in Fukui Prefecture, Nagano Prefecture, Yamagata Prefecture, etc., and is used as a stomachic drug in the Japanese Pharmacopoeia. In the present invention, the root portion is used.

[0034] Senega is a plant belonging to the family Scarabaeidae, and is generally Senega (Polygala senega Linne) or Hirohasenega (P.
olygala senega Linne var. latifoloa Torrery et Gla
y) means the root. It is cultivated in North America as a raw material for expectorants and in Hokkaido and Hyogo Prefecture in Japan, and is also distributed in Senega Syrup of the Japanese Pharmacopoeia. presen
sene, a triterpene saponin with igenin as genin
Contains gin- etc. In the present invention, a root portion is used.

Sapindus mukurossi is a plant belonging to the family Sapindaceae and is also known as Japanese Soapnut Tree. It contains sapinin sapindosides with hederagenin as aglycone and is used as expectorant.
In the present invention, the peel is used.

Horse chestnut (Aesculus hippocastan)
um) contains saponins such as escin-Ia and is used as a raw material for anti-inflammatory drugs in Europe.
In the present invention, the seed is used.

When one part of the saponin-containing plant is used as it is, it is preferably used after being sufficiently dried and then finely pulverized by a pulverizing means usually used in the art.

Next, a method for extracting an extract or a fraction thereof from one part of the saponin-containing plant and a method for isolating and purifying the extract will be described below.

The ground material of the saponin-containing plant is treated with an organic solvent,
Most preferably, reflux extraction is performed in methanol at a temperature of 70 to 90 ° C. for 3 to 9 hours, and then the solvent is distilled off under reduced pressure (about 180 mmHg) to obtain a fat-soluble solvent extract. This is dispersed in water, washed with ethyl acetate, and then a fraction containing crude saponins is obtained with n-butanol. Subsequently, the desired saponin fraction can be isolated and purified by fractionating this fraction by reverse-phase silica gel column chromatography (carrier; methanol / water = 30/70 (v / v)).

The preventive agent for alcohol disorders of the present invention may contain the saponin-containing plant pulverized product in an amount of at least 200 mg, preferably 500 to 1,000 mg per dose. Alternatively, in the case of an adult, the extract or the crude saponin fraction obtained from the pulverized product or the isolated and purified product thereof may be contained in an amount of 5 to 200 mg, preferably 25 to 100 mg per dose. .

The prophylactic agent for alcohol disorders of the present invention comprises tablets,
It can be administered in the form of granules, fine granules, capsules and the like.

The dose of the alcohol disorder prophylactic agent of the present invention may vary depending on age, symptoms, etc. For example, the effective dose for adults is 50 to 1,000 m per dose.
g, preferably 50-500 mg, before meals
It is preferable to take it about 30 minutes three times a day.

Furthermore, the present invention provides, in a second aspect, a food containing the above alcohol disorder preventive agent. The type of food that can be added is not particularly limited. However, since the plant has a unique flavor, it is preferably added to, for example, beverages such as drinks and highly sweet foods such as candy. The addition amount of the alcohol disorder preventive agent in such foods and drinks, depending on the type of the target food, may be added in a range that does not impair the original taste of the food, usually for the target food,
It may be added in the range of 0.01 to 1% by weight.

[0044]

The present invention will be described in more detail with reference to the following examples, but the present invention is not unduly limited to these examples.

All of the compounds isolated and purified in the preparation examples and examples in the present specification are carbon 13 ( ¹³ C) and hydrogen ( ¹ H) nuclear magnetic resonance, mass spectrometry, infrared and ultraviolet absorption spectra and application. The luminous intensity was measured, and the measured values were compared with literature values for identification, thereby confirming each chemical structure.

Preparation Example 1 5 kg of dried leaves of bay laurel were finely chopped, and 1.5-5.0 kg of methanol was added thereto, followed by cold immersion extraction at 25 ° C. for 36 hours. Then it was filtered. Filtrate at 45 ° C
Methanol was completely distilled off under reduced pressure (180 mmHg or less) at the following temperature to obtain 999 g of a methanol extract.

Preparation Example 2 69 g of an ethanol extract was obtained in the same manner as described above, except that 1 kg of dried leaves of bay laurel was used and ethanol was used as a solvent.

Preparation Example 3 366 g of the methanol-extracted extract obtained in Preparation Example 1 was partitioned using a mixed solution of ethyl acetate / water (= 1/1 (v / v)), and the obtained ethyl acetate fraction was subjected to partitioning. Column chromatography was carried out through a silica gel column using a hexane / ethyl acetate (= 30/1 to 1/1 (v / v)) mixed carrier, and the ethyl acetate fraction was further fractionated to obtain 11 fractions. . Among them, fractions # 4 and # 7, which are sesquiterpenes-containing fractions
Was further purified by HPLC.

The above fraction # 4 (23.3 g) was
Using a hromatorex ODS column [Fuji Silysia Co., carrier; methanol / water (= 70/30 (v / v))]
Reversed phase column chromatography was performed. The eluted crude fraction was then subjected to Nacalai Tesque HPLC
By purifying using [Cosmosil 5C18 column, carrier; methanol / water (= 65/35 (v / v))], as sesquiterpenes having a γ-lactone ring,
Costunolide (1) (yield: 767 mg) was isolated and purified.

Preparation Example 4 Fraction # 4 containing sesquiterpenes obtained in Preparation Example 3
(23.3 g) was prepared separately from Chromatorex O
Reversed phase column chromatography was performed using a DS column [Fuji Silysia Co., carrier; methanol / water (= 80/20 (v / v))]. The eluted crude fraction was then purified by Nacalai Tesque HPLC [Cosmosil
5C18 column, carrier; methanol / water (= 80
/ 20 (v / v))] to give costunolide (1) (yield: 12 mg) and dehydrocostulactone as sesquiterpenes having a γ-lactone ring.
(3) (yield: 34.1 mg), elemantine (4) (yield:
17.4 mg), spirafolide (6) (yield: 89.8)
mg) were isolated and purified.

Preparation Example 5 Fraction # 7 containing the active substance obtained in Preparation Example 3 (3.
76 g) was added to a Chromatorex ODS column [Fuji Silysia Co., Ltd., carrier; methanol / water (= 80/20 (v /
v))], reverse phase column chromatography was performed. Next, the obtained crude fraction was subjected to HPLC [Cosmosil 75C18-OPN column manufactured by Nacalai Tesque, carrier; methanol / water (= 50 / 50-65)].
/ 35 (v / v))] to give santaquiterins as sesquiterpenes having a γ-lactone ring.
(2) (yield: 521.8 mg), zalzanine C (5) (yield: 62.5 mg) and magnolialide (7) (yield:
47.4 mg) was isolated and purified.

Preparation Example 6 Here, using the dehydrocostus lactone (3) obtained in Preparation Example 4 above, four kinds of reductants as derivatives thereof were prepared according to Scheme I described above. A solution of 150 mg (0.65 mmol) of dehydrocostulactone (3) in tetrahydrofuran (5.0 ml) was treated with 62 mg of lithium aluminum hydride (LiAlH ₄ ), and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was quenched by addition of aqueous saturated ether and then 4N aqueous KOH,
The whole was extracted with ethyl acetate. The ethyl acetate extract was washed with brine. Then, it was dried with MgSO ₄ powder and filtered. The solvent was removed from the filtrate under reduced pressure, the residue was recovered, and HPLC [YMC Pack ODS-A 4.
6 × 250 mm (methanol-water volume ratio = 70: 30)] to obtain the 11α-methyl-6,12-diol derivative (3a) (the symbol and chemical structure given after the compound name are the same as those described in Scheme I above). (66 mg, 46% yield).

Further, dehydrocostus lactone (3) 6
00 mg (2.6 mmol) of methanol (10.0 m
L) The solution was washed with sodium borohydride (NaBH ₄ ) 10
Treated with 0 mg, the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was quenched with acetone and extracted with ethyl acetate.
After washing the ethyl acetate extract with brine and dried over MgSO ₄ powders. Removal of the solvent from the filtrate under reduced pressure gave a residue. HPLC [YMC Pack ODS]
-A 4.6 x 250 mm inner diameter (methanol-water volume ratio = 7
5:25)], and mockolactone (3b) (106
mg, 18% yield), 11α-methyl-lactol mixture (3
c) (489 mg, 70% yield) and 11α-methyl-12-
Each methylene derivative (3d) (53 mg, yield 9%) was isolated (for both the sign and the chemical structure added after the compound name, refer to the above-mentioned scheme I).

The isolated and purified compounds (3a) to (3d) were subjected to carbon 13 ( ¹³ C) and hydrogen ( ¹ H) nuclear magnetic resonance, mass spectrometry, infrared and ultraviolet absorption spectra under the following equipment and conditions. And the degree of illuminance were measured, respectively, and the measured values were compared with the literature values to identify them, and each chemical structure was confirmed: ¹³ C-NMR spectrum = JNM-LA500 using tetramethylsilane as an internal standard
(125 MHz) spectrometer; ¹ H-NMR spectrum = J
NM-LA500 (500 MHz) spectrometer; EI-MS and high resolution MS = JOEL JMS-GCCMATE mass spectrometer; FAB-MS and high resolution MS = JOE
L JMS-SX 102A mass spectrometer; IR spectrometer =
Shimadzu FTIR-8100 spectrometer; and specific light intensity = HORIBA SEPA-300 digital polarimeter (L = 5 cm).
The following experimental conditions were used for various chromatography for isolation and purification. (1) Normal phase silica gel column chromatography = silica gel BW-200 (Fuji Silysia Chemical Limited, 150 to 350 mesh). (2) TLC = silica gel 60F ₂₅₄ (Merck, 0.25
mm) (normal phase) or silica gel RP-18 60F ₂₅₄
T precoated with (Merck, 0.25 mm) (reverse phase)
LD plate. (3) Reverse phase HPTLC = silica gel RP-18 60WF
TLD plate precoated with _254S (Merck, 0.25 mm) (normal phase). TLC was detected by 1% Ce (S
O ₄₎ was sprayed with ₂ -10% sulfuric acid, it was carried out by heating.

Preparation Example 7 3 L of methanol was added to 1 kg of pulverized cinnamon from Vietnam, and extraction was carried out at 15 to 25 ° C. for 36 hours with occasional stirring, followed by filtration. The obtained filtrate was completely distilled off at a temperature of 45 ° C. or lower under reduced pressure (180 mmHg or lower) to obtain a methanol extract of caulis (yield: 172 g).

Preparation Example 8 A methanol extract of Tendai yak (yield: 27 g) was obtained in the same procedure as in Preparation Example 6, except that 1 kg of dried and ground root of Tendai yak was used.

Preparation 9 Except that 1 kg of dried and ground croaked stem was used,
By a procedure similar to that of Preparation Example 6 above, a methanol extract of Kromoji (yield: 38 g) was obtained.

Preparation Example 10 1.5 kg of methanol was added to 1 kg of ground material (1 kg) of ground flea (difushi).
After adding 5.0 kg, the mixture was extracted with heating at 80 to 90 ° C. for 3 hours, cooled, and filtered. The obtained filtrate was completely distilled at a temperature of 45 ° C. or less under reduced pressure (180 mmHg or less) to obtain a methanol extract of Thonburi (yield: 121.0 g). This extract was dispersed in water, washed with ethyl acetate, and extracted with n-butanol to obtain a saponin fraction (yield: 20.1 g).

Preparation Example 11 The same procedure as in Preparation Example 9 described above was carried out except that 1 kg of a dried and coarsely cut bark of the arachis bark was used to obtain a methanol extract of bark of the aragan tree (yield: 34.0 g). This extract was dispersed in water, washed with ethyl acetate, and n-
Extracted with butanol and saponin fraction (yield:
0.7 g).

Example 1 The extract of laurel leaves obtained by the above-mentioned Preparation Examples 1 and 2 was extracted with methanol and ethanol, and the ethyl acetate or water fraction of the methanol extract and the isolated and purified γ-lactone ring were obtained. Using sesquiterpenes (costunolide (1) and dehydrocostus lactone (3)), the effect of inhibiting alcohol absorption was tested according to the following method. Aqueous suspension samples (A and A ') of 0.5% gum arabic of the methanol and ethanol extracts obtained in Preparation Examples 1 and 2, each of the ethyl acetate fraction or the water fraction obtained in Preparation Example 3 above Aqueous suspension samples of 0.5% gum arabic (B) and (B '), and a 0.5% gum arabic suspension sample of costunolide (1) isolated in Preparation Example 3 (C) An aqueous suspension sample (C ′) of 0.5% gum arabic of dehydrocostulactone (3) obtained in Preparation Example 4 was prepared. These are 1
Male Wistar rats (body weight 110) fasted for 8 to 20 hours
To 150 g; 5 mice per group)
Oral administration in an amount of g body weight. The dose for each sample is summarized below.

Sample (A): 125, 250 and 500 mg / kg body weight Sample (A '): 125 and 250 mg / kg body weight Sample (B): 125 and 250 mg / kg body weight Sample (B'): 125 and 250 mg / kg Body weight Sample (C): 25 and 50 mg / kg body weight Sample (C '): 25 and 50 mg / kg body weight

As a control group, a group of rats (body weight 110 to 150 g; 5 rats per group) to which none of the above samples was administered under the same conditions was prepared.

Thirty minutes after administration of the sample,
A v / v% ethanol solution was orally administered at a rate of 5 mL / kg body weight. 0.5 hours later, 1 hour later and 2 hours later.
After a time, the rats to which the sample was administered and the rats in the control group were lightly anesthetized with ether, and then blood was collected from the fundus vein. The collected blood was immediately cooled on ice, and 0.33N perchloric acid was added to remove proteins. Then, after centrifuging it, the ethanol concentration in the supernatant was measured using F kit (ethanol) manufactured by Boehringer Mannheim. The experimental results were expressed as the mean value and the standard error, and Dunnett's multiple comparison test was used to test for a significant difference from the control group. Table 1 shows the results.

[0064]

[Table 1] In the table, in the test sample column, (A) was an aqueous suspension sample of 0.5% gum arabic of the methanol-extracted extract obtained in Preparation Example 1, and (A ′) was obtained in Preparation Example 2. (B) is a 0.5% aqueous gum arabic gum suspension sample of the ethyl acetate fraction obtained in Preparation Example 3; B ′) is an aqueous suspension sample of 0.5% gum arabic of the water fraction obtained in Preparation Example 3, and (C) is a 0.1% aqueous solution of Costunolide (1) isolated in Preparation Example 3. 5% represents an aqueous suspension sample of gum arabic and (C ′) represents an aqueous suspension sample of 0.5% gum arabic of dehydrocostulactone (3) isolated in Preparation Example 4. , And the suffixes “ ^* ” and “ ^** "represents a significant difference from the control tested by Dunnett's multiple comparison test: p was less than 0.05 or 0.01.

From the results shown in Table 1 above, costunolide and dehydrocostus lactone isolated as sesquiterpenes having a γ-lactone ring according to the present invention, as well as extracts and fractions containing these, have a high alcohol absorption inhibitory effect. It turns out that it expresses.

Example 2 In this example, the dehydrocostus lactones obtained in Preparation Examples 4 and 6 and their derivatives (four kinds of reduced forms) were prepared.
Was used to examine the effect of suppressing the increase in blood ethanol in ethanol-added rats. Animals and Materials: Wistar male rats (body weight 80-130 g) 4-6 weeks old were obtained from Kiwa Experimental Animals Co., Ltd. (Wakayama, Japan) and bred in a room air-conditioned at 23 ± 2 ° C. Standard laboratory chow (MF, Oriental yeast, Tokyo, Japan) and tap water were provided ad libitum. 20-22 before the experiment
He was fasted for hours but given unlimited water. Preparation of test sample: dehydrocostus lactone obtained in Preparation Examples 4 and 6 and its derivative (reduced form 4
Seed) was suspended in a 5% gum arabic solution to prepare a test sample. The test sample was 5 mL / kg for the Wistar male rats fasted for 20 to 22 hours.
Oral administration was performed in a body weight amount. The dose for each sample is summarized below. Dehydrocostus lactone (3): 25, 50 mg / kg
body weight. 11α-methyl-6,12-diol derivative (3a): 50 mg / k
g weight. Moccolactone (3b): 25, 50 mg / kg body weight. 11α-methyl-lactol mixture (3c): 25, 50 mg /
kg body weight. 11α-methyl-12-methylene derivative (3d): 50 mg / kg
body weight.

As a control group, rats under the same conditions (body weight 80 to 130 g; 5 rats per group, except that 11α-methyl-12-
In the test for the methylene derivative (3d), a sample to which none of the above samples was administered was prepared.

Thirty minutes after the test sample was orally administered to rats, ethanol (20 v / v%, 5 mL /
kg body weight) was orally administered. 0.5 from ethanol administration
At 1, 1 and 2 hours, blood samples were taken from the orbital venous plexus of the rats. The blood was immediately mixed with 10 volumes of ice-cold 0.33N perchloric acid and then centrifuged (4 ° C, 3000 rpm, 10 minutes). The ethanol concentration in the blood of the centrifuged supernatant was measured by an enzyme method (F-kit (registered trademark) ethanol, manufactured by Boehringer Mannheim). The results are summarized in Table 2.

[Table 2] In the test sample column of Table 2, (3) is a suspension sample of dehydrocostulactone in a 5% gum arabic solution, and (3a) is 5% of a 11α-methyl-6,12-diol derivative.
(3b) a suspension sample of mockolactone in a 5% gum arabic solution, (3b)
c) is a suspension sample of the 11α-methyl-lactol mixture in a 5% gum arabic solution, and (3d) is 11α-methyl-12
-Represents a suspension sample of the methylene derivative (3d) in a 5% gum arabic solution, and the sign “ ^** ” at the end of the blood alcohol concentration result indicates a significant difference from the control tested by Dunnett's multiple comparison test. Difference: represents that p was less than 0.01.

From the results shown in Table 2 above, it can be seen that all of dehydrocostus lactone (3) and its derivatives exhibit a high blood alcohol concentration increase inhibitory activity. In particular,
Moccolactone (3b) (ie, exomethylene reduced form) and 11α-methyl-lactol mixture (3c) (ie,
Ketone group reductant) has shown favorable results. In the results in Table 2, the uncyclized lactone, 11α-methyl-6,12
-The diol derivative (3a) has clearly lost its activity of suppressing blood alcohol concentration elevation, and the 11α-methyl-12-methylene derivative (3d) (ie, deketone reduced form) has the above activity, It is not statistically significant. That is, in order to express the activity of suppressing increase in blood alcohol concentration, the presence of a γ-lactone ring or an acetal ring in the structure is essential, and the presence of a methyl group or a methylene group in the ring is preferable. I understand.

Example 3 Aqueous suspension samples of 0.5% gum arabic of the methanol extract of cauliflower, tendai yak and kuromoji obtained in Preparation Examples 7 to 9 were prepared respectively. Using these samples, the effect of suppressing alcohol absorption was tested in the same manner as in Example 1 except that the blood alcohol concentration 0.5 hours after the administration of the samples was measured.
Table 3 shows the results.

[0071]

[Table 3] From the results in Table 3 above, it can be seen that the methanol extract obtained from the plants of the camphor tree family exhibits an alcohol absorption suppressing action.

In the following Examples 4 and 5, the methanol extract obtained in the above Preparation Example 1 was added to the above Extraction Example 10
By adding the saponin fractions from the saponin-containing plants obtained in Steps 11 and 11, the effect of enhancing the effect of suppressing alcohol absorption was examined.

Example 4 Aqueous suspension sample of 0.5% gum arabic of methanol extract from laurel leaves obtained in Preparation Example 1 (A), 0% of saponin fraction of Thonburi obtained in Preparation Example 10 An aqueous suspension sample of 0.5% gum arabic (a
Example 1 except that an aqueous suspension sample (a-2) of 0.5% each of gum extract and methanol extract from laurel leaves and saponin fraction of Thonburi were used as test samples. The effect of suppressing alcohol absorption was tested in the same manner as described above. Table 4 shows the results.

Example 5 Each alcohol injury was carried out in the same manner as in Example 4 except that the saponin fraction of the bark of the agaric tree obtained in Preparation Example 11 was used instead of the saponin fraction of Thonburi obtained in Preparation Example 10. Test samples (A), (b-1) and (b-2) were prepared as prophylactic agents, and their alcohol absorption inhibitory effects were tested. Table 4 shows the results.

[0075]

[Table 4]

In the results shown in Table 4 above, the sample (A) containing only the methanol extract from bay leaves was used.
Or, as compared to the samples (a-1) and (b-1) containing only the saponin fraction of the saponin-containing plant, the samples (a-2) and (b-) containing both of them are compared.
2) shows a stronger alcohol absorption suppressing action. That is, it can be seen that the addition of the saponin fraction of the saponin-containing plant to the methanol extract from laurel leaves exerts an excellent synergistic effect.

The following Examples 6 to 9 include the above Preparation Examples 1 to
9. The alcohol absorption inhibitor obtained in 9 and, if necessary, the alcohol absorption inhibitor and Preparation Examples 10 and 11
2 shows examples of foods blended with each saponin fraction from the saponin-containing plant obtained in step 1.

Example 6 Water was added to 100 parts by weight of the extract of Tablet Preparation Example 2 and 148 parts by weight of lactose, mixed, extruded into granules by a granulator, dried, and mixed with 2 parts by weight of magnesium stearate. And
One tablet was weighed to 300 mg using a tableting machine. In one tablet, the content of the extract of Preparation Example 2 was 40 mg.

Example 7: Granules The water was added to 100 parts by weight of the extract of Preparation Example 7, 296 parts by weight of lactose and 4 parts by weight of dextrin, mixed, extruded to form granules by a granulator, and dried, and 2 g Attached to stick packaging. In one packet, the content of the extract of Preparation Example 7 was 500
mg.

Example 8: Composition of a drink composition Compounding amount 25 mg of the extract of Preparation Example 2 25 mg of the extract from the skin obtained in Preparation Example 10 Saponin fraction Liquid sugar 10 g Citric acid 1.2 g Vitamin C the amount total 100mL of a 1g perfume 0.1mL purified water total volume of 100mL

According to the above formulation ratio, each component was dissolved in purified water to make a total volume of 100 mL, filled in a 100 mL brown bottle, and sterilized by heating at 98 ° C. for 30 minutes. The extract and the extract of Preparation Example 10 had a saponin fraction content of 25 mg for each drink.

Example 9: Composition of Candy Blending Amount 0.5 g of the extract of Preparation Example 2 0.5 g of the extract from the agaric tree obtained in Preparation Example 11 Saponin fraction Granular sugar 51.2 g 47.6 g of starch syrup (anhydrous) Citric acid 0.5 g Lemon flavor 0.5 g Total 100 g

According to a conventional method, granulated sugar and starch syrup are dissolved by heating, boiled down to 120 ° C., cooled to 95 ° C., all the remaining components are added, and the mixture is uniformly mixed.
Manufactured candy. One candy contained 10 mg of the saponin fraction of the extract of Preparation Example 2 and 10 mg of the extract of Preparation Example 11, respectively.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/00 A61P 39/00 39/00 A23G 3/00 101 // A23G 3/00 101 A23L 2/00 F (72) Inventor Toshiaki Uemura 1-1-30 Tamazo, Chuo-ku, Osaka City, Osaka Prefecture Inside Morishita Jintan Co., Ltd. (72) Inventor Masayuki Yoshikawa 3-18-9 Ao Shinke, Minoh-shi, Osaka F-term (reference) 4B014 GB06 GG18 GL03 GP27 4B017 LC03 LG20 LP01 4B018 LB01 LB08 MD48 ME14 MF01 4C086 AA01 BA03 MA01 MA52 NA14 ZA02 4C088 AB12 AB17 AB18 AB33 AC05 BA07 BA10 BA32 CA03 MA52 NA14 ZA02

Claims (8)

[Claims] 1. A preventive agent for alcohol damage containing a ground portion of a camphor tree plant or a fat-soluble solvent extract thereof. 2. The method according to claim 1, wherein one part of the camphoraceous plant is laurel leaf. 3. A crushed material of one part of a camphoraceous plant or a fat-soluble solvent-extracted extract thereof is represented by the following formula: (In the formula, R ₁ represents a methyl group or a methylene group.)
The preventive agent for alcohol damage according to claim 1 or 2, comprising a sesquiterpene having an α-substituted γ-butyrolactone group represented by the formula: or a derivative thereof. 4. The derivative is of the formula: (In the formula, R ₁ represents a methyl group or a methylene group.)
The agent for preventing alcohol damage according to claim 3, which has an α-substituted γ-butyrolactone reduced group represented by the formula: 5. The method according to claim 1, wherein one part of the camphor tree plant is selected from the bark of Cinnamomum cassia, the root of Tendai yak or the stem of Kuromoji. 6. The method according to claim 1, further comprising a portion of a saponin-containing plant or a fat-soluble solvent extract obtained therefrom, a crude saponin fraction of the fat-soluble solvent extract, or an isolated and purified product thereof. An agent for preventing alcohol disorders according to the above. 7. One part of the saponin-containing plant is at least one kind selected from sprouts and bark of aralia, roots of ginseng, roots of Senega, pericarp of sap, and seeds of horse chestnut. 6. The preventive agent for alcohol disorder according to 6. 8. A food containing the alcohol disorder preventive agent according to any one of claims 1 to 7.