JP2013194052A - New tetrahydrobiphenyl - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful for prevention and treatment of neurological disease, enabling the intake or administration while adopting a normal dietary form by utilizing a safe plant having nerve growth factor (NGF)-like actions required for the neurological disease such as cerebral ischemia, Alzheimer's disease, Parkinson's disease and Huntington's disease, and used as a food.SOLUTION: Safe and new tetrahydrobiphenyl represented by formula (1) and contained in Java ginger of a Zingiberaceae plant of Indonesian product, and having neurite extension activity and nitrogen monoxide synthase inhibitory action is produced, and utilized for a food material, a composition and food and drink containing the same as an active ingredient.

Description

The present invention relates to a novel tetrahydrobiphenyl having both a neurite outgrowth extending action and a nitric oxide synthase inhibitory action. That is, the present invention relates to a novel tetrahydrobiphenyl that can be expected to prevent and / or treat neurological diseases such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease not only by the neurite outgrowth extending action but also by the nitric oxide synthase inhibitory action.

With the progress of an aging society, senile dementia (dementia) has been increasing and has become a social problem. Alzheimer's disease and cerebrovascular dementia are known as senile dementia, but Alzheimer's disease is limited, although treatment with acetylcholinesterase inhibitors has been attempted, and its etiology is unknown and progressive. There is still no effective treatment. Therefore, nerve cell nutrition / nerve growth factor (hereinafter referred to as NGF) is required for nerve cell growth, process formation and activity maintenance. Therefore, NGF production promoter or NGF is used for prevention, improvement and treatment of dementia. There is a strong demand for the development of active substances. Furthermore, the development of nitric oxide synthase inhibitors is also desired for the prevention, amelioration and treatment of Alzheimer's disease and Parkinson's disease resulting from accumulation of nitrotyrosine-containing proteins by overproduction of nitric oxide.

This NGF is a neurotrophic factor that acts on the myeltobasal cholinergic neurons in the forebrain basal cortex as a group of neurons that cause significant loss, particularly in Alzheimer's disease, and therefore has been attempted to be used directly in the treatment of Alzheimer's disease. However, since it is a high molecular weight protein and cannot pass through the blood-brain barrier, it is administered intraventricularly and has many problems. Therefore, various applications relating to the nerve cell activation action have been made. Examples of plant-derived examples used for food include soybean isoflavones (Patent Document 1), mugwort, kumazasa (Patent Document 2), polyalkoxyflavonoids derived from Citrus plants (Patent Document 3), and mushroom extracts (Patent Document 4). ), Triterpenoids contained in persimmon (Patent Document 5), tricycloiricinone (Patent Document 6) contained in Shikimidae plants, rosemary and sage-derived caffeic acid and carnosic acid (Patent Document 7), citrus peel Fermentation compositions (Patent Document 8) and plants such as horsetail (Patent Document 9) are disclosed.

Pyrido [2,3-c] furazane-1-oxide derivatives are disclosed as neuronal nitric oxide synthase inhibitors that improve diseases and symptoms such as cerebrovascular disorders, Parkinson's disease, pain and obesity (patents) Reference 10). It is also selective for the treatment of diseases of the central nervous system, dementia such as Alzheimer's disease, HIV-dementia, amyotrophic lateral sclerosis and similar sclerosis, cerebral ischemia and other neurodegenerative diseases. An imidazole derivative of a nitric oxide synthase (hereinafter referred to as NOS) inhibitor is also disclosed (Patent Document 11).

Parkinson's disease is partly due to accumulation of nitrotyrosine-containing proteins caused by increased production of nitric oxide (hereinafter referred to as NO) due to overexpression of neuronal NOS in neurons, but NOS inhibitors show neuroprotective effects Therefore, it is reported to be useful for treatment (Non-patent Documents 2 and 3). In Alzheimer's patients, a large number of nNOS-activated astrocytes are found around beta-amyloid fibrils (nerve fiber concentrates) deposited in the hippocampus and entorhinal cortex, and increased NO production is involved in the development of Alzheimer's disease It is reported that this is happening (Non-Patent Document 4).

Gingerol, curcumin, curcumen, etc. are known as components of ginger family plants often used in Japan (Non-patent Document 5), but platelet activating factor antagonism (patent) It is disclosed that the substituted cyclohexene compound which shows literature 12) and the chemokine expression inhibitory effect (patent documents 13 and 14) is contained. However, these prior arts do not describe nerve cells, and Patent Documents 15 and 16 disclose prevention and treatment of neurological diseases with substituted cyclohexene compounds that are components of Java ginger. There is no description about.

JP 2001-511117 A JP-A-10-276719 JP 2002-60340 A JP 2005-15362 A Japanese Patent Application Laid-Open No. 9-100295 JP 2005-139153 A JP 2007-230945 A Japanese Patent Application Laid-Open No. 2011-1248 JP 2011-207814 A Japanese Patent Laid-Open No. 10-81622 Japanese National Patent Publication No. 11-515008 JP 2001-192339 A JP 2003-306438 A JP 2004-269450 A JP 2010-90053 A JP 2011-6324 A

Biochemistry Dictionary 3rd edition (supervised by Kazutomo Imabori and Tamio Yamakawa), 711 pages, Tokyo Chemical Doujin (1998) Ann. Neurol. 44, S110-S114 (1998) Nitric Oxide, 4, 534-539 (2000) Exp. Neurol. 165, 12-26 (2000) Food Pharmacy Handbook (Isao Kitagawa, Masayuki Yoshikawa), 54, 122 pages, Kodansha (2005)

In view of the above problems, the present invention can be ingested or taken or applied or applied while taking a normal meal form by using a safe plant component used as a food, and is cerebral ischemia, Alzheimer's disease. The object is to provide a novel tetrahydrobiphenyl useful for the prevention, amelioration and treatment of neurological diseases such as Parkinson's disease and Huntington's disease.

As a result of continual research to solve the above-mentioned problems, the present inventors have found that a novel tetrahydro which is a component of the Indonesian name Bangle (scientific name Zingiber purpurium Roxb., Hereinafter referred to as Java ginger) of the ginger family ginger from Indonesia. The present inventors have found that biphenyl exhibits not only a neurite outgrowth extending action but also an NO production inhibitory action, and has completed the present invention. That is, the present invention provides a novel tetrahydro effective for the prevention, improvement and treatment of neurological diseases such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and the like by neuronal cell extension and neuronal cell death protecting actions and NOS inhibitory actions. The present invention relates to food materials, compositions and foods and drinks containing biphenyl and novel tetrahydrobiphenyl as active ingredients.

According to the present invention, the novel tetrahydrobiphenyl contained in Java ginger, which is often eaten in Southeast Asia, is safe and has both excellent neurite outgrowth action and NOS inhibition action, so that nerve cell growth, protrusion formation and activity In addition to stimulating cerebral ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease, the prevention and improvement of cerebral ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease And can contribute to treatment. In addition, food compositions, compositions and foods and drinks containing novel tetrahydrobiphenyls having such actions, as well as foods and drinks and plant extracts using Java ginger, and health compositions including agents for preventing, improving and treating neurological diseases It can contribute to the prevention, improvement or treatment of neurological diseases in daily life by ingesting, taking, applying or sticking things.

FIG. 1 is a photograph showing the neurite outgrowth effect of control, NGF (2 ng / mL) and novel tetrahydrobiphenyl 1A (1, 10 μM). Example 4

The novel tetrahydrobiphenyl represented by the following formula (1) referred to in the present invention (hereinafter referred to as novel tetrahydrobiphenyl (1)) can be produced by separating and purifying an extract obtained by solvent extraction of the extract. It is a possible substance. For the extraction, a Java ginger rhizome is suitable, but not only ginger family plants but also plants containing novel tetrahydrobiphenyl (1) can be used. The lottery can be used either dry or undried. For separation and purification, silica gel, porous polymer, reverse phase column chromatography or gel filtration chromatography can be used.

In the novel tetrahydrobiphenyl (1), the double bond of the substituent side chain at the 2-position of the tetrahydrobiphenyl ring in the structural formula is all E-type.

A suitable Java ginger used in the present invention is a plant belonging to the genus Ginger, which grows in the tropical / subtropical region, and Bangle (also known as Bengle, scientific name Zingiber purpurum Roxb., Indonesian name Bangle, Bengle). And / or pontok ginger (scientific name Zingiber cassumunar Roxb., Indonesian name Bangle, Bengle) is widely cultivated in Southeast Asia and eaten as jamu (folk medicine) in Indonesia. In the present invention, the whole plant can be used, but it is preferable to use a rhizome, and it can be used either dry or undried.

The food material referred to in the present invention is a material to be blended when manufacturing a processed food using various food materials, and the Java ginger itself and the extract (extract) containing the novel tetrahydrobiphenyl (1). Extract, concentrate, semi-solid concentrate, solid concentrate and the like, and other food materials and food additives can be blended as necessary.

The composition according to the present invention includes a novel tetrahydrobiphenyl (1) as an active ingredient, a processed food preparation that is easy to use for food processing, and a health composition and a medical composition for prevention, improvement, and treatment of neurological diseases. In other words, the health composition can be a health food and a food for specified health use, and the medical composition can be a medicine and a quasi-drug. The blending amount of the novel tetrahydrobiphenyl (1) is in the range of 0.001 to 10%, preferably in the range of 0.005 to 5%. To do. The drug product can be in the form of powder (powder), granule, tablet, capsule, liquid, semi-solid, transdermal absorption, etc. depending on the intended use. Forming agent, binder, suspending agent, thickening gelling agent, disintegrating agent, lubricant, inclusion agent, surfactant, emulsifier, base for semi-solid agent, sweetener, acidulant, fortifier, Seasonings, quality improvers, etc. can be blended.

Excipients include water-soluble saccharides such as glucose, lactose, dextrin, oligosaccharide, polysaccharides such as starch, flour, crystalline cellulose, organic solvents such as methanol, ethanol, 2-propanol, propylene glycol, butylene glycol, and acetone. , Inorganic substances such as sodium chloride, calcium sulfate, calcium carbonate, calcium phosphate, potassium phosphate, sodium bicarbonate, and water. Examples of the binder include pregelatinized starch, gum arabic, gelatin, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, and the like. Examples of lake materials include pregelatinized starch, gum arabic, gelatin, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and sodium alginate. Disintegrants include agar, starch, crystalline cellulose, carboxymethylcellulose calcium, and lubricants include magnesium stearate, hydrogenated vegetable oil, talc, and silicon dioxide. To aid solubilization, absorption (intestinal tract, mucous membrane, skin, etc.) absorption and taste masking, inclusion agents such as α-, β- and γ-cyclodextrins, branched (or branched) cyclodextrins, glycerin fatty acid esters, Use surfactants (emulsifiers) such as polyglycerin fatty acid ester, propylene glycol fatty acid ester, sodium alkyl sulfate, sucrose fatty acid ester, sorbitan fatty acid ester, lecithin, saponin, yucca extract, gnemonoside A, melinjo extract Can do. In semi-solid preparations, bases such as vegetable oil, animal oil, hydrogenated oil, beeswax, macrogol, liquid paraffin, sodium carboxymethylcellulose, macrogol fatty acid ester, stearic acid, gelatin, stearyl alcohol, hydrolanolin, and cetanol can be used. . If necessary, a moisturizing agent / quality improving agent such as gum arabic, glycerin, D-sorbitol, propylene glycol, and simple syrup can be blended.

Quasi-drugs including cosmetics can be prepared by combining the above materials and blending a fragrance as necessary. In the case of adhesive transdermal absorbents, cloth, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polyamide, aluminum sheet, etc. are listed as base materials, and vinyl acetate, silicone as adhesives Resins, polyisoprene rubber, polyisobutylene rubber, acrylic rubber, natural rubber, olive oil, liquid paraffin, polybutene, rosin, calcium stearate, anti-rash agent, etc., and release materials such as polyethylene, polypropylene, polyvinyl chloride, polyester, poly Examples include vinylidene chloride, silicone resin, and fluorine resin.

In order to adjust the taste of foods and drinks that are health compositions, sweeteners such as glucose, fructose, sucrose, lactose, maltose, erythritol, sorbitol, maltitol, xylitol, stevioside, rubusoside, corn syrup, lactose, citric acid, Tartaric acid, malic acid, succinic acid, acidulants such as lactic acid, seasonings such as amino acids can be added, vitamins, nicotinic acid amide, calcium pantothenate and other reinforcing agents, calcium salts, coloring agents, swelling agents , Flavoring agents, preservatives and the like, which are used as general food and beverage ingredients, can be appropriately mixed and manufactured.

Examples of foods and drinks for prevention, improvement and treatment of neurological diseases include soft drinks, juices, coffee, tea, liqueurs, milk, whey drinks, lactic acid bacteria drinks, yogurt, candy, caramel, chewing gum, Chocolate, gummi, ice cream, pudding, egg products, sheep crab, water sheep crab, rice cake, rice cake, dumpling, rice cracker, crepe, okonomiyaki, bread, cookies, noodles, hamburger, water paste product, tempura, sprinkle, fermented food, etc. .

If necessary, not only tomatoes, onions, carrots, broccoli, cabbage, kidney beans, pumpkins, lettuce, red peppers, celery, spinach, apples, lemons, acerola, mandarin and other fruits and extracts, as well as tomorrow leaves, Amacha, Achacharu, Aloe, Ginkgo biloba, Oolong tea, Turmeric, Vulture, Ozokogi, Ezoukogi, Psyllium, Oyster, Oyster, Camellia, Chamomile, Karin, Garcinia, Kawahara decision, Chrysanthemum, Gardenia, Mulberry, Black tea, Red pea Cedar, Comfrey, Kelp, Cherry, Saffron, Shiitake, Perilla, Ginger, Ginger, Sugina, Swangi, Sekisho, Sendangsa, Sembli, Buckwheat, Tamarin, Taranoki, Dandelion, Chicory, Tochu, Natsume, Elderberry, Rattus Hub, Bangle, Matsuba, So-called herbal medicines and health teas such as te, barley tea, megsurinoki, eucalyptus, mugwort, rahan fruit, green tea, rooibos, ganoderma, galangal, gymnema, guava leaf, geno shoko, brown rice, burdock, dokudami, banaba, loquat leaves, safflower An extract of the above may be added and blended. Furthermore, dairy products such as milk and cream, and soy products such as soy milk and tofu can be added.

The health composition of the present invention is used for the prevention and improvement of neurological diseases such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. due to the neurite outgrowth-promoting action, neuronal cell death protecting action and NOS inhibitory action. The dose (administration) when used as a product varies depending on the purpose of use and the situation of the user (sex, age, weight, degree of obesity, overall health, etc.). Tetrahydrobiphenyl (1) can be taken in the range of 0.1 to 100 mg / kg body weight in terms of weight. Since the plant of the raw material is a regular diet, taking over 100 mg / kg body weight has no problem. The same applies to animals.

The food / beverage products said by this invention are the food / beverage products which mix | blended the said food material and manufactured using the novel tetrahydrobiphenyl (1) containing foodstuff preparation.

If necessary, a solid material obtained by cutting an undried plant containing the novel tetrahydrobiphenyl (1), a paste obtained by pulverizing the undried plant with a wet pulverizer, a freeze dryer or drying Solid materials obtained by drying with a machine, further crushing them, or crushing or powdered products obtained by crushing dried plants with a crusher or crusher, dried or undried plants with a cutter or slicer The sliced material obtained by cutting can be used as a health composition as it is or after being heat-processed or extracted.

In addition, various ingredients normally used in animal feeds are appropriately blended according to the purpose to form powders, granules, pastes, capsules, syrups, solids, gels, liquids, suspensions, emulsions, etc. Can be used as animal feed such as livestock feed, cat food, pet food such as dog food and rabbit food.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.

Example 1 (Production of powder) 5 kg of dried Java ginger was pulverized with a pulverizer to obtain 4.7 kg of Java ginger powder.

Implementation ceremony 2 (Manufacture of extracts)
A cut product of 5 kg of Java ginger was immersed in 40 L of methanol for 2 weeks, and the extract was concentrated under reduced pressure to dryness to obtain 350 g of Java ginger extract.

Implementation ceremony 3 (production of novel tetrahydrobiphenyl (1))
25 g of Java ginger jelly in Implementation 2 was distributed between ethyl acetate and water, and the ethyl acetate layer was evaporated under reduced pressure to obtain 24.78 g. It was fractionated into 11 fractions by silica gel chromatography (hexane: ethyl acetate = 3: 2). Fraction 10 (1.33345 g) was fractionated into 7 fractions by silica gel chromatography (methylene chloride: ethyl acetate = 9: 1), and fraction 5 (190.9 mg) was separated using Sephadex LH-20 (methanol). It was fractionated into 4 fractions. Fraction 1 (90.1 mg) was fractionated into 6 fractions by silica gel chromatography (toluene: methanol = 19: 1), and fraction 2 (34.3 mg) was HPLC (Cosmosil πNAP, methanol: water = 9: 17.5 mg of solid novel tetrahydrobiphenyl (1) was obtained by purification in 1). The structure of the novel tetrahydrobiphenyl was analyzed by analyzing the following instrumental analysis data: (R) -2,2-bis [(E) -3- (4-hydroxy-3-methoxyphenyl) -1-oxo-2-propenyl] -3 ', 4'-dimethoxy-1,2,3,4-tetrahydro-1,1'-biphenyl was determined.

Instrumental analysis data of novel tetrahydrobiphenyl (1), [α] _D +71.3 (c0.1, 28 ° C., methanol); IR (ATR, cm ⁻¹ ), 3389 (OH), 1658 (C═O), 1579 (aromatic ring); HR-EIMS experimental value m / z: 609.1819 [M + K] ⁺ , calculated value: 609.1819 (C ₃₄ H ₃₄ O ₈ K
39); PMR (600 MHz, heavy benzene, δ): 2.07 (1H, dddd, J = 18.1, 12.3, 5.6, 2.7 Hz), 2.17 (1H, dt, J = 18, 1, 5.3 Hz), 2.73 (1H, brdd, J = 14.5, 5.6 Hz), 2.81 (1H, ddd, J = 14.5, 12.3, 5.6 Hz) , 2.90 (3H, s), 2.96 (3H, s), 3.29 (3H, s), 3.32 (3H, s), 5.04 (1H, brd, J = 3.7 Hz) ), 5.80 (1H, m), 6.07 (1H, m), 6.46 (1H, d, J = 1.8 Hz), 6.52 (1H, d, J = 8.4 Hz), 6.59 (1H, d, J = 1.8 Hz), 6.73 (4H, dd, J = 8.2, 1.8 Hz), 6.9 (1H, d, J = 2.1 Hz), 6 .98 1H, dd, J = 8.4, 1.8 Hz), 7.08 (1H, d, J = 15.5 Hz), 7.11 (1H, d, J = 15.4 Hz), 7.62 (1H , D, J = 15.5 Hz), 8.03 (1H, d, J = 15.4 Hz); CMR (150 MHz, heavy benzene, δ): 22.8, 23.2, 43.8, 55.1 , 55.2, 55.3, 55.4, 69.7, 110.6, 111.1, 111.9, 115.2, 119.1, 121.1, 122.8, 122.9, 123 .8, 125.3, 127.1, 127.2, 129.9, 132.5, 143.4, 144.7, 146.9, 148.9, 149.0, 149.3, 195.2 , 196.1

Example 4 (neurite outgrowth action)
Rat adrenal medulla brown cell PC12 was cultured in rat-tailed collagen-coated culture flask in DMEM medium containing 10% HS, 5% FBS and 1% penicillin-streptomachine, humidity 95%, carbon dioxide 5%, 37 ° C. After culturing in an incubator under the environment, PC12 cells were isolated. The cells (8000 cells / mL) were seeded in each well of a collagen-coated 24-well plate and cultured in a DMEM medium containing 10% HS, 5% FBS, and 1% penicillin-strept machine for 24 hours in an incubator under the same environment. Thereafter, the sample was replaced with a DMEM medium containing 2% HS, 1% FBS, and 1% penicillin-streptmachine containing the sample. After culturing in the same environment for 96 hours, the cells were fixed with 4% paraformaldehyde, stained with 0.5% methylene blue, and the cell morphology was observed under a microscope to confirm the extension of the protrusion and photographed. The novel tetrahydrobiphenyl (1) of Example 3 was dissolved in 50% ethanol and then diluted 100 times with a medium. NGF 2 ng / mL was used as a positive control.

The test results are shown in FIG. As shown in the figure, no neurite outgrowth was observed in the control, whereas the novel tetrahydrobiphenyl (1) of the present invention clearly showed neurite outgrowth from 1 μM compared to the positive control, and 10 μM the protuberance was elongated longer. Marked neurite outgrowth activity.

Example 5 (NO production inhibitory action)
The rat brain was homogenized with 50 mM Tris buffer (adjusted to pH 7.4 with 1 M hydrochloric acid) containing 5 volumes of 1 mM EDTA, and then centrifuged at 1,000 × g for 10 minutes to obtain a supernatant. Centrifugation was performed at 1,000 × g for 60 minutes. The obtained supernatant was used as a crude NOS enzyme solution. This enzyme solution, 1 mM L-arginine, 3 mM DTT, 0.3 mM NADPH, 4 μM tetrahydrobiopterin, 0.1 mM phenylmethylsulfonyl fluoride, 5 μg / mL aprotinin, 5 μg / mL chymostatin, 4 μg / mL leupeptin, 5 μg / The DMSO solution of NG-monomethyl-L-arginine of the novel tetrahydrobiphenyl (1) of Example 3 or the positive control compound was added to 20 mM Tris buffer solution (adjusted to pH 7.4 with 1 M hydrochloric acid) containing mL pupestatin at 37 ° C. After incubating with NO and reacting the produced NO with the Gries reagent kit, the absorbance at 540 nm was measured and quantified. As a result, the IC ₅₀ (50% inhibitory concentration) of the positive control compound was 57 μM, whereas the novel tetrahydrobiphenyl (1) of the present invention showed a good activity of 11 μM.

Example 6 (Production of powder)
0.015 g of the novel tetrahydrobiphenyl (1) of Example 3 is dissolved in 0.2 mL of ethanol, 0.85 g of Avicel (Asahi Kasei) and 2 g of dextrin (Max 1000, Matsutani Chemical) are mixed well in a mortar to obtain 3 g of powder. Manufactured.

Example 7 (Production of hard capsule)
After mixing 0.01 g of magnesium stearate with 3 g of the powder of Example 6, gelatin capsules were filled to produce hard capsules.

Example 8 (Manufacture of tablets)
100 g of Java ginger extract of Example 2, 100 g of dextrin (Max 1000, manufactured by Matsutani Chemical Co., Ltd.), 200 g of lactose and 2 g of magnesium stearate were mixed, and this mixture was tableted with a single tableting machine, and the diameter was 8 mm and the weight was 200 mg. Tablets (containing 99 mg of Bangle Extract) were produced.

Example 9 (Manufacture of hard capsules)
100 g of Java ginger extract of Example 2, 30 g of corn starch, 20 g of avicel and 10 g of calcium monohydrogen phosphate were mixed, and the mixture was filled into gelatin capsules to produce hard capsules.

Example 10 (Manufacture of candy)
A candy was prepared by blending 1 part of Java ginger extract of Example 2, 280 parts of granulated sugar, 210 parts of starch syrup, 5 parts of citric acid, 1 part of perfume and 1 part of pigment. The taste of this candy was good.

Example 11 (Manufacture of juice)
1 part of Java ginger extract of Example 2, 25 parts of frozen concentrated Unshu mandarin orange juice, 55 parts of fructose glucose liquid sugar, 1 part of citric acid, 0.1 part of L-ascorbic acid, 1 part of fragrance, 0.5 part of pigment and water A juice was prepared by blending 400 parts. This juice had no change in the flavor and color of tangerines.

Example 12 (Production of chewing gum)
Chewing gum was prepared by blending 1 part of Java Ginger Extract of Example 2, 300 parts of chewing gum base, 800 parts of sucrose, 300 parts of starch syrup, softening agent 60, 13 parts of perfume and 1 part of pigment. The taste of this chewing gum was good.

Example 13 (Production of chocolate)
A chocolate was produced by blending 1 part of the Java ginger extract of Example 2, 220 parts of chocolate, 75 parts of sucrose, 100 parts of cacao butter and 100 parts of whole milk powder. The blended bangle extract did not affect the flavor and color of the chocolate and was delicious.

Example 14 (Manufacture of cookies)
1 part of Java ginger powder of Example 1, 2.3 parts of soft flour, 1.6 parts of whole egg, 1.9 parts of margarine, 2.5 parts of super white sugar, 0.02 part of baking powder and 0.73 part of water are blended. Made cookies. The cookies were tasty and tasted good.

Example 15 (Manufacture of oysters)
Japanese oyster powder was prepared by blending 1 part of the Java ginger powder of Example 1, 5 parts of koji powder, 0.1 part of salt and 6 parts of water. This oyster had a good flavor and a good taste.

Example 16 (Production of crepes)
A crepe was prepared by blending 1 part of Java ginger powder of Example 1, 2 parts of soft flour, 1 part of whole egg, 1 part of milk, 0.05 part of salt, an appropriate amount of vanilla essence and 2 parts of water. The crepe had good flavor and taste.

Example 17 (Paste Production)
The mixture was pulverized with a pulverizer while adding 2 kg of water to 8 kg of Java ginger, and further finely powdered with an ultrasonic crusher to obtain 10 kg of Java ginger paste.

Example 18 (Manufacture of juice)
Juice was produced by adding 2 parts of water to 1 part of the Java ginger paste of Example 17 and mixing. The juice was tasty and delicious.

Example 19 (Manufacture of sprinkles)
A solution prepared by dissolving 1 part of Java ginger extract of Example 2 in 3 parts of ethanol, 5 parts of sucrose, 5 parts of salt, 29 parts of pregelatinized starch, 10 parts of dried whole egg powder and 50 parts of upper fresh powder, mixed with water 17 mL was added to obtain a kneaded product, which was fined with an extruded granulator, dried, and then added with appropriate amounts of powdered laver and roasted sesame seeds to produce a sprinkle. This sprinkle had good flavor and taste.

Example 20 (Production of transdermal absorption preparation)
A solution obtained by dissolving 0.015 g of novel tetrahydrobiphenyl (1) obtained in the same manner as in Example 3 in 0.1 mL of ethanol and 0.4 g of isopropyl myristate, 0.48 g of polyisobutylene and alicyclic petroleum oil The mixture was added to a solution of 0.12 g of hexane in 0.5 mL of hexane and stirred and mixed, and then dried on a release liner to form a paste layer. This plaster layer was bonded to the polyester nonwoven fabric laminated with the polyester film to produce a transdermal absorption preparation.

Example 21 (Manufacture of solid dog food)
Example 1 Java ginger powder 1 part, meat meal 2.4 parts, chicken extract 0.35 parts, vegetable oil 0.3 parts, carbohydrate 1.2 parts, calcium carbonate 0.03 parts, salt 0.01 parts, A dog food was prepared by blending 0.05 part of a complex vitamin preparation and 0.6 part of water.

According to the present invention, the novel tetrahydrobiphenyl (1) of the present invention obtained from Java ginger, which is often eaten in Southeast Asia, is safe and has both neurite outgrowth action and nitric oxide synthase inhibitory action. Not only is growth, protrusion formation and activity activated, but regulation of excessive NO levels suppresses the accumulation of nitrotyrosine-containing proteins and protects nerve cells to prevent cerebral ischemia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. Useful for prevention, amelioration and treatment of neurological diseases. In addition, the food material, composition and food of the present invention containing the novel tetrahydrobiphenyl (1) having such an action as an active ingredient, foods and drinks and plant extracts using Java ginger, and health compositions comprising them Is useful as an agent for the prevention, amelioration, and treatment of such neurological diseases, which can be ingested, taken, applied, or affixed in the form of a normal meal in daily life. The use of a health composition containing the novel tetrahydrobiphenyl (1) of the present invention as a feed for animals such as pets and livestock is also burdensome for breeders against neurosis, which has been increasing due to the aging of pets in recent years. Is reduced and convenient.

Claims (4)

Novel tetrahydrobiphenyl represented by the following formula (1)
A food material comprising a novel tetrahydrobiphenyl represented by the following formula (1)
A composition comprising a novel tetrahydrobiphenyl represented by the following formula (1):
A food or drink comprising a novel tetrahydrobiphenyl represented by the following formula (1):