WO2016167385A1 - Composition-ii for preventing or treating alzheimer's disease, comprising lycopodiella cernua extract or compound isolated therefrom - Google Patents
Composition-ii for preventing or treating alzheimer's disease, comprising lycopodiella cernua extract or compound isolated therefrom Download PDFInfo
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- WO2016167385A1 WO2016167385A1 PCT/KR2015/003790 KR2015003790W WO2016167385A1 WO 2016167385 A1 WO2016167385 A1 WO 2016167385A1 KR 2015003790 W KR2015003790 W KR 2015003790W WO 2016167385 A1 WO2016167385 A1 WO 2016167385A1
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- 0 CC(c1c(*2)cc(C)cc1O)C(O)=C2c1cc(OC)c(*)cc1 Chemical compound CC(c1c(*2)cc(C)cc1O)C(O)=C2c1cc(OC)c(*)cc1 0.000 description 10
- SHDTXQNLDCQHKE-UHFFFAOYSA-N Cc(cc(C(C(CO)O)O)cc1)c1O Chemical compound Cc(cc(C(C(CO)O)O)cc1)c1O SHDTXQNLDCQHKE-UHFFFAOYSA-N 0.000 description 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/11—Pteridophyta or Filicophyta (ferns)
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- the present invention relates to a composition for the prophylaxis or treatment of Alzheimer's disease comprising an extract of Lycopodiella cernua or a compound isolated therefrom.
- Alzheimer's disease is the most common type of senile neurological disease, which is the most common degenerative brain disease causing dementia, a brain disease causing memory, thinking and behavioral problems.
- Dementia is a general term that means severe loss of memory and other intellectual skills that interfere with daily life.
- Alzheimer's disease is estimated to account for 60-80% of cases of dementia. In the United States, more than five million people have Alzheimer's disease, and the number of Americans with Alzheimer's disease and other dementia is expected to grow each year as the proportion of people age 65 and older in the United States continues to grow.
- Acetylcholine is one of the neurotransmitters and is found mostly in the area where neurons and skeletal muscle meet.
- acetylcholine secreted from the nerve terminal is inactivated by decomposing into choline and acetic acid by acetylcholinesterase (AChE) after the transmission of the stimulus, the choline is an enzyme according to the action of cholineacetylase (cholinacetylase) Synthetically synthesized to form acetylcholine.
- Acetylcholinesterase inhibitors support signaling between neurons by preventing and maintaining high levels of acetylcholine, an important chemical messenger for memory and learning.
- butyrylcholinesterase breaks down acetylcholine in the brain and plays a role in choline delivery. Therefore, the inhibition of the acetylcholinesterase and butyrylcholinesterase increases the concentration of acetylcholine in the synaptic gap, enhances neurotransmission of acetylcholine, and improves defects.
- acetylcholinesterase inhibitors which cannot completely prevent the progression of the disease, and alleviate or slow down some pathological symptoms. Only effect.
- Drugs of this class include donepezil, rivastingmine, galantamine, and tacrine.
- acetylcholinesterase is the most pharmacological action point in the world, it is possible to develop drugs and functional materials of acetylcholinesterase inhibitor with few side effects and excellent effects using various natural products. There is a need.
- ⁇ -secretase 1 acts on the amyloid- ⁇ -precursor protein (APP) to generate ⁇ -amyloid fragments.
- APP amyloid- ⁇ -precursor protein
- ⁇ -amyloid since the accumulation of ⁇ -amyloid is known as a major cause of Alzheimer's disease, the development of a substance for the inhibitory activity of ⁇ -secretase may be helpful in the treatment of Alzheimer's disease by preventing the cleavage of the ⁇ -amyloid precursor protein. have.
- ⁇ -secretase inhibitor x-ray crystallography x-ray crystallography
- x-ray crystallography revealed a clear structure, a variety of inhibitors can be easily developed, but there is no efficacy and still available as a therapeutic agent to be. Therefore, the development of new ⁇ -secretase inhibitors could be of great help in the treatment of Alzheimer's disease.
- the Lycopodiella cernua is a river of vascular plants that make spores, belonging to the family of cypresses and similar plants. It is widely spread around the world, and consists of four genera and about 1,000 species. Plants in this river are small in size and can grow upright or even grow on other plants. The stem is divided into two branches and pruned. The differentiation of roots, stems, and leaves is distinct, and photosynthesis is possible. The spore sac runs on a special leaf called the spores, which gather together to form a cone-shaped spores. It is an evergreen perennial plant, which inhabits Jeju, Jeonnam, Hambuk, Hamnam, and Gangwon.
- Korean Laid-Open Patent Publication No. 2011-0118145 suggested that lycopoduim clavatum extract or a compound isolated therefrom is effective in treating cancer, and the anti-memory loss effect of vegetable base isolated from lychee (Chuong, NN et al., 2014), anticholinesterase activity (Konrath, EL et al., 2013) of vegetable bases isolated from South American pine family has been disclosed.
- the compounds isolated from the pine tree of the present invention have an inhibitory effect of acetylcholinesterase or butyrylcholinesterase or ⁇ -secretase 1.
- the present invention relates to a composition for the prophylaxis or treatment of Alzheimer's disease comprising an extract of Lycopodiella cernua or a compound isolated therefrom. More specifically, lambnagin (Compound 1), quercetin 3,3'- dimethyl ether (Compound 2), guaiacylglycerol (Compound 3), apigenin (Compound 4), isomorphoside (Compound 1) 5), Bahia genin -4'- O - (2 '', 6 '' - di-p -O- - Kumar in one) - ⁇ -D- gluconic nose Llano side (compound 6), spring Basin -4- O - ⁇ - D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O - ⁇ - D- gluconic nose Llano side) 1'-benzofuran propionic acid (
- the travertine extract is characterized in that the extract is extracted with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohol, acetone, n-hexane, dichloromethane and ethyl acetate.
- the present invention is isolated from the Lycopodiella cernua ( Lycopodiella cernua ) of Rhamnajin (Compound 1), Quercetin 3,3'- dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4) ), Isoshaphtoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) - ⁇ -D-glucopyranoside (compound 6) ), Bombacin-4- O- ⁇ - D -glucopyranoside (Compound 7), (7 R , 8 S ) -7,8-dihydro-8-hydroxymethyl-7- (3-methoxy Phenyl-4- O- ⁇ -D-glucopyranoside) -1'-benzofuran propionic acid (Compound 8), apigenin-4'- O- (6 '' -O - p
- the compound is characterized by inhibiting at least one enzyme activity selected from the group consisting of acetylcholinesterase, butyrylcholinesterase and ⁇ -secretase 1.
- the present invention is the lambnagin (Compound 1), quercetin 3,3'- dimethyl ether (Compound 2), guaiacylglycerol (Compound 3), apigenin (Compound 4) of the formula 1 isolated from the trachea Isomorphoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) - ⁇ -D-glucopyranoside (compound 6), Basin spring -4- O - ⁇ - D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl- 4- O- ⁇ -D-glucopyranoside) -1'-benzofuranpropionic acid (Compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) - ⁇ -D 1 type selected from the group
- the present invention comprises the steps of preparing the extract of the Songseok River with Lycopodiella cernua in water, C1 to C4 lower alcohol or a mixed solvent thereof; Fractionating the travertine extract using n-hexane and ethyl acetate in sequence and re-fractionating the water layer residue with dichloromethane; And chromatographing the water layer except for the re-distilled dichloromethane to lambnazin of the formula (compound 1), quercetin 3,3'-dimethyl ether (compound 2), guaiacylglycerol (compound 3), apigenin ( Compound 4), isomorphoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) - ⁇ -D-glucopyranoside ( compound 6), spring Basin -4- O - ⁇ - D - gluconic nose Llano side (compound 1), quer
- the present invention also provides (7 R, 8 S) is a novel compound, having the following chemical structure 7,8-dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O - ⁇ -D -Glucopyranoside) -1'-benzofuran propionic acid.
- the present invention relates to a composition for the prevention or treatment of Alzheimer's disease comprising the compound of formula (I) isolated from the Lycopodiella cernua .
- the travertine extract may be obtained by extracting the travertine with water, a lower alcohol of C1 to C4 or a mixed solvent thereof, and the lower alcohol of C1 to C4 may use methanol, ethanol, propanol, isopropanol, butanol, and the like. have.
- the extract may be fractions re-fractionated with an organic solvent, n-hexane, ethyl acetate and dichloromethane may be used as the organic solvent.
- the compound separated from the travertine can be obtained by fractionating the water layer extract of the travertine, and the chromatography is silica gel column chromatography, HP-20 column chromatography. , RP-18 column chromatography, LH-20 column chromatography, high-performance liquid chromatography, and the like.
- the compound of the present invention may be synthesized according to a conventional method in the art, and may be prepared as a pharmaceutically acceptable salt.
- the present invention also provides a pharmaceutical composition for the prevention or treatment of Alzheimer's disease comprising at least one compound selected from the group of compounds of the formula (1) isolated from the extract of the trachea.
- Pharmaceutical compositions comprising the extracts or compounds are formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. Can be used.
- Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, or the like in the extract or compound of the present invention. Or it is prepared by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
- Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
- the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- the dosage of the pharmaceutical composition comprising the extract of the pine needles of the present invention or a compound isolated therefrom is determined by the age, sex, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the It will depend on your judgment. Dosage determination based on these factors is within the level of skill in the art and generally dosages range from 0.01 mg / kg / day to approximately 2000 mg / kg / day. More preferred dosage is 1 mg / kg / day to 500 mg / kg / day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
- compositions comprising the extract of the pine needles of the present invention or a compound isolated therefrom can be administered to mammals such as rats, livestock, humans and the like by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections.
- the extract of the present invention or a compound isolated therefrom has little toxicity and side effects, and thus is a drug that can be used safely even for prolonged administration for the purpose of prevention.
- the present invention provides a health functional food for preventing or improving Alzheimer's disease comprising at least one compound selected from the group of the compound of formula 1 isolated from the pineapple extract or the above-mentioned do.
- the extract or compound may be added as 0.001 to 100% by weight to the health functional food of the present invention.
- the health functional food of the present invention includes the form of tablets, capsules, pills, or liquids, and the food to which the extract or compound of the present invention may be added, for example, various foods, beverages, gums, teas, Vitamin complexes.
- the present invention relates to a composition for the prevention or treatment of Alzheimer's disease, including the extract of the Songseok River or a compound isolated therefrom, wherein the extract of the Songseok River or the compound isolated therefrom is an acetylcholinesterase, butyrylcholinesterase and ⁇ -ce Excellent inhibitory effect of Cretease 1 can be usefully used as a composition for the prevention or treatment of Alzheimer's disease.
- Figure 1 is a novel compound of (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O - ⁇ -D- gluconic nose pyrano of the invention side) is an illustration showing a 1'-benzofuran propionic acid 1 H- 1 H COSY (bold lines ) and the 1 H- 13 C HMBC correlation (arrow) on.
- Lycopodium cernua used in the present invention was obtained in Lumdongzhou, Vietnam in April 2012, extracting and filtering the reflux of the Songsong River (3 kg) with methanol (2 L ⁇ 3 times), and filtering the filtrate. Distillation under reduced pressure gave 280 g of methanol extract. Then, the methanol extract was suspended in water (2 L) and sequentially partitioned into n-hexane (2 L ⁇ 3 times) and ethyl acetate (2 L ⁇ 3 times), and the n-hexane fraction (48 g) and ethyl acetate fraction (175.5). g) and finally a fraction (55 g) containing the water layer residue.
- the fraction containing the water layer residue was suspended with 5% [v / v] hydrochloric acid, and then fractionated with dichloromethane to obtain a dichloromethane fraction (1.9 g).
- the aqueous layers of the fractions with dichloromethane to pH11-12 with 0.1N sodium hydroxide, and then fractionated with dichloromethane.
- the organic layer was collected, dried over sodium sulfate, and evaporated to obtain a crude alkaloid fraction.
- the residue containing the water layer was anionic HP- according to the concentration gradient elution condition of aqueous methanol solution (0 ⁇ 100% [v / v]). Fractionation by 20 column chromatography gave 12 fractions (W1-W12).
- Fraction W6 (1.05 g) was fractionated by silica gel column chromatography (column size: 3.0 ⁇ 50 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.2 [v: v: v]).
- W6.1-W6.9 Nine small fractions (W6.1-W6.9) were obtained.
- W6.2 25 mg in the small fractions afforded Compound 4 (6.2 mg) through filtration.
- the small fraction W6.9 (167 mg) was fractionated by Sephadex LH-20 column chromatography (column size: 2.0 ⁇ 120 cm) according to isocratic elution conditions of methanol: water (1: 1 [v: v]).
- Compound 5 (7 mg) and compound 6 (10.3 mg) were obtained.
- W8 (1.52 g) in the fractions was purified by silica gel column chromatography (column size: 3.0 ⁇ 60 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.1 [v: v: v]). To obtain eight small fractions (W8.1-W8.8). W8.6 (125 mg) in the small fractions was separated by Sephadex LH-20 column chromatography (column size: 2.0 ⁇ 60 cm) according to isocratic elution conditions of methanol: water (1: 1 [v: v]). Fractionation gave compound 7 (3 mg).
- Fraction W9 (1.36 g) was purified by silica gel column chromatography (column size: 3.0 ⁇ 60 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.1 [v: v: v]). Small fractions (W9.1-W9.7) were isolated. W9.4 (45 mg) in the small fractions was separated by Sephadex LH-20 column chromatography (column size: 1.5 ⁇ 120 cm) according to isocratic elution conditions of methanol: water (2: 1 [v: v]). Fractionation gave compound 9 (6.7 mg).
- quercetin 3,3'-dimethyl ether quercetin 3,3'-dimethyl ether
- Example 2-8 (7 R ,8 S ) -7,8-dihydro-8-hydroxymethyl-7- (3-methoxyphenyl-4- O - ⁇ -D-glucopyranoside) -1'-benzofuran propionic acid (compound 8)
- the compound isolated from the extract of the pine tree of the present invention has an inhibitory activity of acetylcholinesterase or butyrylcholinesterase, which can be usefully used as a prophylactic and therapeutic agent for Alzheimer's disease Can be.
- Example 5-2 Long-term and tissue toxicity experiments in experimental and control groups
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Abstract
The present invention relates to a composition for preventing or treating Alzheimer's disease comprising lycopodiella cernua extract or a compound isolated therefrom. The lycopodiella cernua extract or the compound isolated therefrom has an excellent effect of inhibiting acetylcholinesterase, butyrylcholinesterase, and β-secretase 1, and thus can be effectively used as a composition for preventing or treating Alzheimer's disease.
Description
본 발명은 석송강(Lycopodiella cernua) 추출물 또는 이로부터 분리된 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prophylaxis or treatment of Alzheimer's disease comprising an extract of Lycopodiella cernua or a compound isolated therefrom.
생명과학 및 의학의 급속한 발전으로 인간의 평균수명이 늘어나고, 장노년 인구의 비중이 점차 늘어남에 따라 새로운 사회적 문제들이 부각되고 있다. 특히 뇌졸증(stroke), 알츠하이머병(Alzheimer disease, AD), 파킨슨병(Parkinson disease, PD) 등의 노인성 신경계 질환들은 치명적인 신경계의 기능장애로 나타나며, 현재까지는 이를 막을 수 있는 효과적인 방법이 없어 삶의 질 저하 및 막대한 의료비의 지출 등으로 인해 주변 가족에게 상당한 정신적인 부담을 주고 있다.The rapid development of life sciences and medicine has led to an increase in the average life span of humans and the growing proportion of elderly people. In particular, senile neurological diseases such as stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) appear as lethal dysfunction of the nervous system, and until now there is no effective way to prevent them. Degradation and huge medical expenses are putting a strain on the families around them.
특히, 노인성 신경계 질환 중 가장 흔하게 나타나고 있는 것이 알츠하이머병이며, 이는 치매를 일으키는 가장 흔한 퇴행성 뇌질환으로 기억력, 사고력 및 행동상의 문제를 야기하는 뇌 질병이다. 치매는 일상생활을 방해할 정도로 심각한 기억력 및 기타 지적 능력의 상실을 의미하는 일반 용어로 알츠하이머병은 치매 사례의 60~80%를 차지하는 것으로 추정된다. 미국의 경우, 5백만 명 이상이 알츠하이머병에 걸렸으며 미국 내 65세 이상의 인구 비율이 계속 증가함에 따라 알츠하이머병 및 기타 치매에 걸린 미국인의 수는 매년 커질 것으로 예상된다. In particular, Alzheimer's disease is the most common type of senile neurological disease, which is the most common degenerative brain disease causing dementia, a brain disease causing memory, thinking and behavioral problems. Dementia is a general term that means severe loss of memory and other intellectual skills that interfere with daily life. Alzheimer's disease is estimated to account for 60-80% of cases of dementia. In the United States, more than five million people have Alzheimer's disease, and the number of Americans with Alzheimer's disease and other dementia is expected to grow each year as the proportion of people age 65 and older in the United States continues to grow.
알츠하이머병의 발병 기전과 원인에 대해서는 아직까지 정확히 알려져 있지 않으며, 현재까지는 신경전달물질인 아세틸콜린(acetylcholine)의 합성 감소, β-아밀로이드(beta-amyloid)의 침착, 타우 단백질(tau protein)의 과인산화로 인한 신경 세포의 손상이 주된 원인으로 알려져 있다(이은희 et. al., 2008).The pathogenesis and cause of Alzheimer's disease are not yet known. To date, the synthesis of the neurotransmitter acetylcholine, the reduction of β-amyloid, the tau protein superphosphate Nerve cell damage due to anger is known to be a major cause (Lee Eun-hee et. Al., 2008).
아세틸콜린은 신경전달물질의 하나이며, 대부분 신경세포인 뉴런과 골격근이 만나는 부분에서 발견된다. 또한, 신경말단에서 분비된 아세틸콜린은 자극의 전달이 끝나면 아세틸콜린에스테라아제(acetylcholinesterase, AChE)에 의해 콜린과 아세트산으로 분해되어 불활성화 되며, 상기 콜린은 콜린아세틸라아제(cholinacetylase)의 작용에 따라 효소적으로 합성되어 다시 아세틸콜린이 된다. 아세틸콜린에스테라아제 억제제는 기억 및 학습을 위한 중요한 화학전령인 아세틸콜린의 분해를 막고 이의 수준을 높게 유지하여 신경세포 사이의 신호전달을 지원한다. 또한, 최근 연구에서는 부티릴콜린에스테라아제(butyrylcholinesterase, BChE)가 뇌에서 아세틸콜린을 분해시키며 콜린 전달에 일정 역할을 한다고 밝혀졌다. 따라서 상기 아세틸콜린에스테라아제 및 부티릴콜린에스테라아제의 억제는 시냅스 간극의 아세틸콜린 농도를 증가시켜 아세틸콜린의 신경전달을 강화시키고, 결손을 개선시켜준다. Acetylcholine is one of the neurotransmitters and is found mostly in the area where neurons and skeletal muscle meet. In addition, acetylcholine secreted from the nerve terminal is inactivated by decomposing into choline and acetic acid by acetylcholinesterase (AChE) after the transmission of the stimulus, the choline is an enzyme according to the action of cholineacetylase (cholinacetylase) Synthetically synthesized to form acetylcholine. Acetylcholinesterase inhibitors support signaling between neurons by preventing and maintaining high levels of acetylcholine, an important chemical messenger for memory and learning. Recent studies have also shown that butyrylcholinesterase (BChE) breaks down acetylcholine in the brain and plays a role in choline delivery. Therefore, the inhibition of the acetylcholinesterase and butyrylcholinesterase increases the concentration of acetylcholine in the synaptic gap, enhances neurotransmission of acetylcholine, and improves defects.
현재까지 알츠하이머병의 근본적인 치료방법은 개발되지 않았지만, 각국에서 사용되고 있는 치료제로는 아세틸콜린에스테라아제 억제제가 대부분이며 이는 병의 진행을 완전히 막을 수 없고, 약간의 병리적 증상을 완화시키거나 진행 정도를 늦추는 효과만 있다. 이 계열의 약물로는 도네페질(donepezil), 리바스티그민(rivastingmine), 갈란타민(galantamine), 타크린(tacrine) 등이 있다. 치료제의 개발과정에 있어, 전 세계적으로 아세틸콜린에스테라아제가 가장 많이 약리작용점으로 채택되고 있는 연구 추세에 따라, 여러 천연물을 이용하여 부작용이 적고 그 효과가 우수한 아세틸콜린에스테라아제 억제제의 약제 및 기능성 소재를 개발할 필요가 있다.To date, the basic treatment for Alzheimer's disease has not been developed, but most of the therapeutic agents used in countries are acetylcholinesterase inhibitors, which cannot completely prevent the progression of the disease, and alleviate or slow down some pathological symptoms. Only effect. Drugs of this class include donepezil, rivastingmine, galantamine, and tacrine. In the development of therapeutics, according to the research trend that acetylcholinesterase is the most pharmacological action point in the world, it is possible to develop drugs and functional materials of acetylcholinesterase inhibitor with few side effects and excellent effects using various natural products. There is a need.
또한, β-세크레타제 1(β-secretase 1)은 β-아밀로이드의 전구체 단백질(amyloid-β-precursor protein, APP)에 작용하여 β-아밀로이드 조각을 생성하는 역할을 한다. 또한, β-아밀로이드의 축적이 알츠하이머병을 일으키는 주된 원인으로 알려져 있으므로, β-세크레타제의 억제활성에 대한 물질 개발은 β-아밀로이드 전구체 단백질이 절단되지 못하도록 하여 알츠하이머병의 치료에 도움이 될 수 있다. 또한, β-세크라타제 억제제의 경우 x-선 결정기술(x-ray crystallography)로 명확한 구조가 밝혀져 있어 다양한 억제제들이 용이하게 개발될 수 있으나, 효능이 있고 치료제로써 사용가능 한 것은 아직까지 없는 상황이다. 따라서 새로운 β-세크라타제 억제제의 개발은 알츠하이머병의 치료에 큰 도움을 줄 수 있을 것이다.In addition, β-secretase 1 acts on the amyloid-β-precursor protein (APP) to generate β-amyloid fragments. In addition, since the accumulation of β-amyloid is known as a major cause of Alzheimer's disease, the development of a substance for the inhibitory activity of β-secretase may be helpful in the treatment of Alzheimer's disease by preventing the cleavage of the β-amyloid precursor protein. have. In addition, in the case of β-secretase inhibitor x-ray crystallography (x-ray crystallography) revealed a clear structure, a variety of inhibitors can be easily developed, but there is no efficacy and still available as a therapeutic agent to be. Therefore, the development of new β-secretase inhibitors could be of great help in the treatment of Alzheimer's disease.
석송강(Lycopodiella cernua)은 포자를 만드는 관다발식물의 한 강으로 석송류와 이와 비슷한 식물이 속한다. 세계적으로 널리 퍼져있으며 4속, 약 1,000여 종으로 이루어져 있다. 이 강의 식물은 크기가 작고, 곧추서거나 기기도 하여 다른 식물 위에서 자라기도 한다. 줄기는 2갈래로 갈라지고 가지치기를 한다. 뿌리·줄기·잎의 분화가 뚜렷하며 광합성을 할 수 있다. 포자낭을 포자엽이라고 하는 특수한 잎에 달리는데 이 포자엽이 모여 원추 모양의 포자수를 만든다. 상록성 다년초로서 제주, 전남, 함북, 함남, 강원 등지에 서식하며 국외로는 일본, 타이완, 중국, 쿠릴, 유럽, 아프리카 등 북반구의 온대에서 열대지역의 고산까지 분포한다.The Lycopodiella cernua is a river of vascular plants that make spores, belonging to the family of cypresses and similar plants. It is widely spread around the world, and consists of four genera and about 1,000 species. Plants in this river are small in size and can grow upright or even grow on other plants. The stem is divided into two branches and pruned. The differentiation of roots, stems, and leaves is distinct, and photosynthesis is possible. The spore sac runs on a special leaf called the spores, which gather together to form a cone-shaped spores. It is an evergreen perennial plant, which inhabits Jeju, Jeonnam, Hambuk, Hamnam, and Gangwon.
중국에서는 석송을 전통적으로 류마티즘과 백일해, 간염, 신장 결석, 타박상 등의 치료제로 이용하였으며(Zhang, X. C. et. al., 2004; Xiao, P. G., 2002), 베트남에서는 중추 신경계 치료를 위한 민간요법에 사용되기도 하였다. 또한, 한국공개특허 제2011-0118145호에는 석송(lycopoduim clavatum) 추출물 또는 이로부터 분리된 화합물이 암 치료에 효과가 있음을 제시하였으며, 석송으로부터 분리된 식물성염기의 항기억상실 효과(Chuong, N. N. et al., 2014), 남미 석송과에서 분리된 식물성염기의 항콜린에스테라아제 활성(Konrath, E. L. et al., 2013) 등의 다양한 효과가 개시된바 있다. 그러나 본 발명의 석송강으로부터 분리된 화합물들이 아세틸콜린에스테라아제 또는 부티릴콜린에스테라아제 또는 β-세크레타제 1의 억제 효과가 있음은 아직 알려지지 않은 상황이다.In China, travertine has traditionally been used to treat rheumatism, whooping cough, hepatitis, kidney stones and bruises (Zhang, XC et. Al., 2004; Xiao, PG, 2002). It was also used. In addition, Korean Laid-Open Patent Publication No. 2011-0118145 suggested that lycopoduim clavatum extract or a compound isolated therefrom is effective in treating cancer, and the anti-memory loss effect of vegetable base isolated from lychee (Chuong, NN et al., 2014), anticholinesterase activity (Konrath, EL et al., 2013) of vegetable bases isolated from South American pine family has been disclosed. However, it is not yet known that the compounds isolated from the pine tree of the present invention have an inhibitory effect of acetylcholinesterase or butyrylcholinesterase or β-secretase 1.
본 발명의 목적은 석송강 추출물 또는 이로부터 분리된 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 조성물을 제공하는 데 있다.It is an object of the present invention to provide a composition for the prevention or treatment of Alzheimer's disease, including the extract of the pine needles or a compound isolated therefrom.
본 발명은 석송강(Lycopodiella cernua) 추출물 또는 이로부터 분리된 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이다. 보다 자세하게는, 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 석송강(Lycopodiella cernua) 추출물을 함유하는 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prophylaxis or treatment of Alzheimer's disease comprising an extract of Lycopodiella cernua or a compound isolated therefrom. More specifically, lambnagin (Compound 1), quercetin 3,3'- dimethyl ether (Compound 2), guaiacylglycerol (Compound 3), apigenin (Compound 4), isomorphoside (Compound 1) 5), Bahia genin -4'- O - (2 '', 6 '' - di-p -O- - Kumar in one) -β-D- gluconic nose Llano side (compound 6), spring Basin -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β- D- gluconic nose Llano side) 1'-benzofuran propionic acid (compound 8), Bahia genin -4'- O - (6 '' - O - p - in one) -β-D- gluconic nose Llano side Kumar ( Compound 9), a stone comprising at least one compound selected from the group consisting of dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (compound 10) and sharposide (compound 11) Songjiang (Lycopodiella cernua) composition for preventing or treating Alzheimer's disease comprising the extract Relate to.
[화학식 1][Formula 1]
상기 석송강 추출물은 석송강을 물, C1 내지 C4의 저급 알코올, 아세톤, n-헥산, 디클로로메탄 및 에틸아세테이트로 이루어진 군에서 선택되는 1종 이상의 용매로 추출한 추출물인 것을 특징으로 한다.The travertine extract is characterized in that the extract is extracted with at least one solvent selected from the group consisting of water, C1 to C4 lower alcohol, acetone, n-hexane, dichloromethane and ethyl acetate.
본 발명은 석송강(Lycopodiella cernua)으로부터 분리된 상기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이다.The present invention is isolated from the Lycopodiella cernua ( Lycopodiella cernua ) of Rhamnajin (Compound 1), Quercetin 3,3'- dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4) ), Isoshaphtoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (compound 6) ), Bombacin-4- O- β- D -glucopyranoside (Compound 7), (7 R , 8 S ) -7,8-dihydro-8-hydroxymethyl-7- (3-methoxy Phenyl-4- O- β-D-glucopyranoside) -1'-benzofuran propionic acid (Compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) -β Selected from the group consisting of -D-glucopyranoside (Compound 9), dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (Compound 10) and shaftoside (Compound 11) A composition for the prevention or treatment of Alzheimer's disease comprising at least one compound A.
상기 화합물은 아세틸콜린에스테라아제(acetylcholinesterase), 부티릴콜린에스테라아제(butyrylcholinesterase) 및 β-세크레타제 1(β-secretase 1)로 이루어진 군에서 선택되는 1종 이상의 효소 활성을 억제하는 것을 특징으로 한다.The compound is characterized by inhibiting at least one enzyme activity selected from the group consisting of acetylcholinesterase, butyrylcholinesterase and β-secretase 1.
또한, 본 발명은 석송강으로부터 분리된 상기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 석송강(Lycopodiella cernua) 추출물을 함유하는 것을 특징으로 하는 알츠하이머병의 예방 또는 개선용 건강기능식품에 관한 것이다.In addition, the present invention is the lambnagin (Compound 1), quercetin 3,3'- dimethyl ether (Compound 2), guaiacylglycerol (Compound 3), apigenin (Compound 4) of the formula 1 isolated from the trachea Isomorphoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (compound 6), Basin spring -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl- 4- O- β-D-glucopyranoside) -1'-benzofuranpropionic acid (Compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) -β-D 1 type selected from the group consisting of -glucopyranoside (Compound 9), dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (Compound 10) and sharposide (Compound 11) of lycopodiopsida (Lycopodiella cernua) Alzheimer's disease comprising the extract containing the above compound It relates to a dietary supplement for a room or improvement.
또 다른 일면에 있어서, 본 발명은 석송강(Lycopodiella cernua)을 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 석송강 추출물을 제조하는 단계; 상기 석송강 추출물을 n-헥산 및 에틸아세테이트를 이용하여 순차적으로 분획한 후 물층 잔사를 디클로로메탄으로 재분획하는 단계; 및 상기 재분획된 디클로로메탄을 제외한 물층을 크로마토그래피로 상기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 분리하는 방법에 관한 것이다.In yet another aspect, the present invention comprises the steps of preparing the extract of the Songseok River with Lycopodiella cernua in water, C1 to C4 lower alcohol or a mixed solvent thereof; Fractionating the travertine extract using n-hexane and ethyl acetate in sequence and re-fractionating the water layer residue with dichloromethane; And chromatographing the water layer except for the re-distilled dichloromethane to lambnazin of the formula (compound 1), quercetin 3,3'-dimethyl ether (compound 2), guaiacylglycerol (compound 3), apigenin ( Compound 4), isomorphoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside ( compound 6), spring Basin -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3 Methoxyphenyl-4- O- β-D-glucopyranoside) -1'-benzofuranpropionic acid (compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) In the group consisting of -β-D-glucopyranoside (Compound 9), dihydrodihydroconiferyl alcohol-4- O -β-D-glucopyranoside (Compound 10) and shaftoside (Compound 11) A method for separating one or more compounds selected.
본 발명은 또한, 하기 화학구조를 갖는 신규 화합물인 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 제공한다.The present invention also provides (7 R, 8 S) is a novel compound, having the following chemical structure 7,8-dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D -Glucopyranoside) -1'-benzofuran propionic acid.
이하 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 석송강(Lycopodiella cernua)으로부터 분리된 상기 화학식 1의 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prevention or treatment of Alzheimer's disease comprising the compound of formula (I) isolated from the Lycopodiella cernua .
상기 석송강 추출물은 석송강을 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 추출하여 얻을 수 있으며, 상기 C1 내지 C4의 저급 알코올로는 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올 등을 이용할 수 있다. 또한, 상기 석송강 추출물은 유기용매로 재분획한 분획물일 수 있으며, 상기 유기용매로는 n-헥산, 에틸아세테이트 및 디클로로메탄을 이용할 수 있다.The travertine extract may be obtained by extracting the travertine with water, a lower alcohol of C1 to C4 or a mixed solvent thereof, and the lower alcohol of C1 to C4 may use methanol, ethanol, propanol, isopropanol, butanol, and the like. have. In addition, the extract may be fractions re-fractionated with an organic solvent, n-hexane, ethyl acetate and dichloromethane may be used as the organic solvent.
상기 석송강으로부터 분리된 화합물은 석송강의 물층 추출물을 크로마토그래피로 분획하여 얻을 수 있으며, 상기 크로마토그래피는 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), HP-20 컬럼 크로마토그래피(HP-20 column chromatography), RP-18 컬럼 크로마토그래피(RP-18 column chromatography), LH-20 컬럼 크로마토그래피(LH-20 column chromatography), 고성능 액체 크로마토그래피 (High-performance liquid chromatography) 등에서 선택하여 사용할 수 있다.The compound separated from the travertine can be obtained by fractionating the water layer extract of the travertine, and the chromatography is silica gel column chromatography, HP-20 column chromatography. , RP-18 column chromatography, LH-20 column chromatography, high-performance liquid chromatography, and the like.
한편, 본 발명의 화합물은 당해 기술 분야에서 통상적인 방법에 따라 합성될 수 있으며, 약학적으로 허용 가능한 염으로 제조될 수도 있다.Meanwhile, the compound of the present invention may be synthesized according to a conventional method in the art, and may be prepared as a pharmaceutically acceptable salt.
또한, 본 발명은 석송강 추출물 또는 이로부터 분리된 상기 화학식 1의 화합물 군에서 선택되는 1종 이상의 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 약학 조성물을 제공한다. 상기 추출물 또는 화합물을 포함하는 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 상기 추출물 또는 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The present invention also provides a pharmaceutical composition for the prevention or treatment of Alzheimer's disease comprising at least one compound selected from the group of compounds of the formula (1) isolated from the extract of the trachea. Pharmaceutical compositions comprising the extracts or compounds are formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. Can be used. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, or the like in the extract or compound of the present invention. Or it is prepared by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 석송강 추출물 또는 이로부터 분리된 화합물을 포함하는 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition comprising the extract of the pine needles of the present invention or a compound isolated therefrom is determined by the age, sex, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the It will depend on your judgment. Dosage determination based on these factors is within the level of skill in the art and generally dosages range from 0.01 mg / kg / day to approximately 2000 mg / kg / day. More preferred dosage is 1 mg / kg / day to 500 mg / kg / day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
본 발명의 석송강 추출물 또는 이로부터 분리된 화합물을 포함하는 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 본 발명의 추출물 또는 이로부터 분리된 화합물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.Pharmaceutical compositions comprising the extract of the pine needles of the present invention or a compound isolated therefrom can be administered to mammals such as rats, livestock, humans and the like by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections. The extract of the present invention or a compound isolated therefrom has little toxicity and side effects, and thus is a drug that can be used safely even for prolonged administration for the purpose of prevention.
또한, 본 발명은 석송강 추출물 또는 이로부터 분리된 상기 화학식 1의 화합물 군에서 선택되는 1종 이상의 화합물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 알츠하이머병의 예방 또는 개선용 건강기능식품을 제공한다. 상기 추출물 또는 화합물은 본 발명의 건강기능식품에 0.001~100 중량%로 하여 첨가될 수 있다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 추출물 또는 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다.In another aspect, the present invention provides a health functional food for preventing or improving Alzheimer's disease comprising at least one compound selected from the group of the compound of formula 1 isolated from the pineapple extract or the above-mentioned do. The extract or compound may be added as 0.001 to 100% by weight to the health functional food of the present invention. The health functional food of the present invention includes the form of tablets, capsules, pills, or liquids, and the food to which the extract or compound of the present invention may be added, for example, various foods, beverages, gums, teas, Vitamin complexes.
본 발명은 석송강 추출물 또는 이로부터 분리된 화합물을 포함하는 알츠하이머병의 예방 또는 치료용 조성물에 관한 것이며, 상기 석송강 추출물 또는 이로부터 분리된 화합물은 아세틸콜린에스테라아제, 부티릴콜린에스테라아제 및 β-세크레타제 1의 억제 효과가 우수하여 알츠하이머병의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.The present invention relates to a composition for the prevention or treatment of Alzheimer's disease, including the extract of the Songseok River or a compound isolated therefrom, wherein the extract of the Songseok River or the compound isolated therefrom is an acetylcholinesterase, butyrylcholinesterase and β-ce Excellent inhibitory effect of Cretease 1 can be usefully used as a composition for the prevention or treatment of Alzheimer's disease.
도 1은 본 발명의 신규 화합물인 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산에 대한 1H-1H COSY(bold lines) 및 1H-13C HMBC 상관관계(arrow)를 나타내는 그림이다.Figure 1 is a novel compound of (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose pyrano of the invention side) is an illustration showing a 1'-benzofuran propionic acid 1 H- 1 H COSY (bold lines ) and the 1 H- 13 C HMBC correlation (arrow) on.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the information provided herein is to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.
본 발명에서 사용된 석송강(Lycopodium cernua)은 2012년 4월에 베트남의 럼동성에서 얻었으며, 석송강(3㎏)을 메탄올(2ℓ×3회)로 환류 추출 및 여과하고, 상기 여과물을 감압 증류하여 메탄올 추출물 280g을 얻었다. 이후, 상기 메탄올 추출물을 물(2ℓ)에 현탁하여 n-헥산(2ℓ×3회) 및 에틸아세테이트(2ℓ×3회)로 순차적으로 분획하여, n-헥산 분획물(48g) 및 에틸아세테이트 분획물(175.5g)과 마지막으로 물층 잔사를 포함하는 분획물(55g)을 얻었다. Lycopodium cernua used in the present invention was obtained in Lumdong Province, Vietnam in April 2012, extracting and filtering the reflux of the Songsong River (3 kg) with methanol (2 L × 3 times), and filtering the filtrate. Distillation under reduced pressure gave 280 g of methanol extract. Then, the methanol extract was suspended in water (2 L) and sequentially partitioned into n-hexane (2 L × 3 times) and ethyl acetate (2 L × 3 times), and the n-hexane fraction (48 g) and ethyl acetate fraction (175.5). g) and finally a fraction (55 g) containing the water layer residue.
이후, 상기 물층 잔사를 포함하는 분획물을 5%[v/v] 염산으로 현탁한 뒤, 디클로로메탄으로 분획하여 디클로로메탄 분획물(1.9g)을 얻었다. 또한, 상기 디클로로메탄으로 분획한 것 중 물층(aqueous layers)을 0.1N의 수산화나트륨으로 pH11-12가 되게 하고, 다시 디클로로메탄으로 분획하였다. 이의 유기 층을 모아 황산나트륨으로 건조하고 증발시켜 크루드한 알칼로이드 분획물을 얻었으며, 물층을 포함하는 잔사를 메탄올 수용액(0 → 100%[v/v])의 농도구배 용출 조건에 따른 이음이온 HP-20 컬럼 크로마토그래피로 분획하여 12개의 분획물(W1-W12)을 얻었다. 상기 분획물 중에서 W3(1.24g)을 디클로로메탄:메탄올:물(4:1:0.2[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:3.5×50㎝)로 분획하여 13개의 소분획물(W3.1-W3.13)을 얻었다.Thereafter, the fraction containing the water layer residue was suspended with 5% [v / v] hydrochloric acid, and then fractionated with dichloromethane to obtain a dichloromethane fraction (1.9 g). In addition, the aqueous layers of the fractions with dichloromethane to pH11-12 with 0.1N sodium hydroxide, and then fractionated with dichloromethane. The organic layer was collected, dried over sodium sulfate, and evaporated to obtain a crude alkaloid fraction. The residue containing the water layer was anionic HP- according to the concentration gradient elution condition of aqueous methanol solution (0 → 100% [v / v]). Fractionation by 20 column chromatography gave 12 fractions (W1-W12). W3 (1.24 g) in the fractions was purified by silica gel column chromatography (column size: 3.5 × 50 cm) according to isocratic elution conditions of dichloromethane: methanol: water (4: 1: 0.2 [v: v: v]). Fractionation gave 13 small fractions (W3.1-W3.13).
상기 소분획물 중 W3.4(115㎎)을 디클로로메탄:메탄올:물(5:1:0.1[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:1.5×25㎝)로 분획하여 화합물 3(8.8㎎)을 얻었다. 또한, 소분획물 W3.6(65㎎)은 디클로로메탄:메탄올:물(4:1:0.2[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:1.5×25㎝)로 분획하여 화합물 1(28.7㎎)을 얻었다. 소분획물 W3.8(36㎎)은 20%[v/v] 아세토나이트릴 수용액의 등용매 용출조건에 다른 RP-C18 실리카겔 컬럼 크래마토그래피로 분리하여 화합물 2(7.7㎎)를 얻었다.W3.4 (115 mg) in the small fractions was subjected to silica gel column chromatography (column size: 1.5 × 25) according to isocratic elution conditions of dichloromethane: methanol: water (5: 1: 0.1 [v: v: v]). Fractions) to give compound 3 (8.8 mg). The small fraction W3.6 (65 mg) was purified by silica gel column chromatography (column size: 1.5 × 25) according to isocratic elution conditions of dichloromethane: methanol: water (4: 1: 0.2 [v: v: v]). Fractions) to give compound 1 (28.7 mg). Small fraction W3.8 (36 mg) was prepared by RP-C18 according to the isocratic elution conditions of 20% [v / v] acetonitrile aqueous solution. Compound 2 (7.7 mg) was obtained by silica gel column chromatography.
분획물 W6(1.05g)은 디클로로메탄:메탄올:물(3:1:0.2[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:3.0×50㎝)로 분획하여 9개의 소분획물(W6.1-W6.9)을 얻었다. 상기 소분획물 중 W6.2(25㎎)는 여과를 통해 화합물 4(6.2㎎)를 얻었다. 소분획물 W6.9(167㎎)는 메탄올:물(1:1[v:v])의 등용매 용출조건에 따른 세파덱스 LH-20 컬럼 크로마토그래피(컬럼크기:2.0×120㎝)로 분획하여 화합물 5(7㎎) 및 화합물 6(10.3㎎)을 얻었다.Fraction W6 (1.05 g) was fractionated by silica gel column chromatography (column size: 3.0 × 50 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.2 [v: v: v]). Nine small fractions (W6.1-W6.9) were obtained. W6.2 (25 mg) in the small fractions afforded Compound 4 (6.2 mg) through filtration. The small fraction W6.9 (167 mg) was fractionated by Sephadex LH-20 column chromatography (column size: 2.0 × 120 cm) according to isocratic elution conditions of methanol: water (1: 1 [v: v]). Compound 5 (7 mg) and compound 6 (10.3 mg) were obtained.
분획물 중 W8(1.52g)을 디클로로메탄:메탄올:물(3:1:0.1[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:3.0×60㎝)로 분획하여 8개의 소분획물(W8.1-W8.8)을 얻었다. 상기 소분획물 중 W8.6(125㎎)을 메탄올:물(1:1[v:v])의 등용매 용출조건에 따른 세파덱스 LH-20 컬럼 크로마토그래피(컬럼크기:2.0×60㎝)로 분획하여 화합물 7(3㎎)을 얻었다. 또한, 소분획물 W8.8(150㎎)은 메탄올:물(1:1[v:v])의 등용매 용출조건에 따른 세파덱스 LH-20 컬럼 크로마토그래피(컬럼크기:1.5×120㎝)로 화합물 8(12.3㎎)을 분리하였다.W8 (1.52 g) in the fractions was purified by silica gel column chromatography (column size: 3.0 × 60 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.1 [v: v: v]). To obtain eight small fractions (W8.1-W8.8). W8.6 (125 mg) in the small fractions was separated by Sephadex LH-20 column chromatography (column size: 2.0 × 60 cm) according to isocratic elution conditions of methanol: water (1: 1 [v: v]). Fractionation gave compound 7 (3 mg). The small fraction W8.8 (150 mg) was subjected to Sephadex LH-20 column chromatography (column size: 1.5 × 120 cm) according to isocratic elution conditions of methanol: water (1: 1 [v: v]). Compound 8 (12.3 mg) was isolated.
분획물 W9(1.36g)은 디클로로메탄:메탄올:물(3:1:0.1[v:v:v])의 등용매 용출조건에 따른 실리카겔 컬럼 크로마토그래피(컬럼크기:3.0×60㎝)로 7개의 소분획물(W9.1-W9.7)을 분리하였다. 상기 소분획물 중 W9.4(45㎎)을 메탄올:물(2:1[v:v])의 등용매 용출조건에 따른 세파덱스 LH-20 컬럼 크로마토그래피(컬럼크기:1.5×120㎝)로 분획하여 화합물 9(6.7㎎)를 얻었다. 또한, 소분획물 W9.7(65.7㎎)을 메탄올:물(2:1[v:v])의 등용매 용출조건에 따른 세파덱스 LH-20 컬럼 크로마토그래피(컬럼크기:1.5×120㎝)로 분획하여 화합물 10(14.1㎎)과 화합물 11(10.5㎎)을 얻었다.Fraction W9 (1.36 g) was purified by silica gel column chromatography (column size: 3.0 × 60 cm) according to isocratic elution conditions of dichloromethane: methanol: water (3: 1: 0.1 [v: v: v]). Small fractions (W9.1-W9.7) were isolated. W9.4 (45 mg) in the small fractions was separated by Sephadex LH-20 column chromatography (column size: 1.5 × 120 cm) according to isocratic elution conditions of methanol: water (2: 1 [v: v]). Fractionation gave compound 9 (6.7 mg). In addition, small fraction W9.7 (65.7 mg) was purified by Sephadex LH-20 column chromatography (column size: 1.5 × 120 cm) according to isocratic elution conditions of methanol: water (2: 1 [v: v]). Fractionation gave compound 10 (14.1 mg) and compound 11 (10.5 mg).
<실시예 2. 석송강으로부터 분리된 화합물의 물리화학적 구조 확인><Example 2. Identification of Physicochemical Structure of Compound Isolated from Limestone Steel>
실시예 2-1. 람나진(화합물 1)Example 2-1. Ramnazin (Compound 1)
rhamnazin;rhamnazin;
노르스름한 분말;Yellowish powder;
IR (KBr)νmax 3545, 3400, 1658, 1130, 1117㎝-1;IR (KBr) v max 3545, 3400, 1658, 1130, 1117 cm -1 ;
1H NMR 및 13C NMR 데이터는 하기 표 1 및 표 2 참조; 1 H NMR and 13 C NMR data see Table 1 and Table 2 below;
EI-MS [M]+ 330.2 m/z, C17H14O7.EI-MS [M] + 330.2 m / z, C 17 H 14 O 7 .
실시예 2-2. 케르세틴 3,3'-디메틸 에테르(화합물 2)Example 2-2. Quercetin 3,3'-dimethyl ether (Compound 2)
quercetin 3,3'-dimethyl ether;quercetin 3,3'-dimethyl ether;
노르스름한 분말;Yellowish powder;
1H NMR 및 13C NMR 데이터는 하기 표 1 및 표 2 참조; 1 H NMR and 13 C NMR data see Table 1 and Table 2 below;
EI-MS [M]+ 330.2 m/z, C17H14O7.EI-MS [M] + 330.2 m / z, C 17 H 14 O 7 .
실시예 2-3. 구아이아실글리세롤(화합물 3)Example 2-3. Guaiacylglycerol (Compound 3)
guaiacylglycerol;guaiacylglycerol;
백색 분말;White powder;
1H NMR 및 13C NMR 데이터는 하기 표 1 및 표 2 참조; 1 H NMR and 13 C NMR data see Table 1 and Table 2 below;
EI-MS [M]+ 214.2 m/z, C10H14O5.EI-MS [M] + 214.2 m / z, C 10 H 14 O 5 .
실시예 2-4. 아피게닌(화합물 4)Example 2-4. Apigenin (Compound 4)
apigenin;apigenin;
노르스름한 분말; Yellowish powder;
1H NMR 및 13C NMR 데이터는 하기 표 1 및 표 2 참조; 1 H NMR and 13 C NMR data see Table 1 and Table 2 below;
EI-MS [M]+ 270.0 m/z, C15H10O5.EI-MS [M] + 270.0 m / z , C 15 H 10 O 5 .
실시예 2-5. 이소샤프토사이드(화합물 5)Example 2-5. Isomorphoside (Compound 5)
isoschaftoside;isoschaftoside;
노르스름한 분말;Yellowish powder;
1H NMR 및 13C NMR 데이터는 하기 표 3 참조; 1 H NMR and 13 C NMR data see Table 3 below;
EI-MS [M]+ 564.4 m/z, C26H28O14.EI-MS [M] + 564.4 m / z, C 26 H 28 O 14 .
실시예 2-6. 아피게닌-4'-Example 2-6. Apigenin-4'-
OO
-(2'',6''-디-O--(2 '', 6 ''-D-O-
pp
-쿠마로일)-β-D-글루코피라노사이드(화합물 6)-Coumaryl) -β-D-glucopyranoside (Compound 6)
apigenin-4'-O-(2'',6''-di-O-p-coumaroyl)-β-D-glucopyranoside;apigenin-4'- O- (2 '', 6 ''-di- O - p- coumaroyl) -β-D-glucopyranoside;
백색 무정형 분말;White amorphous powder;
1H NMR 및 13C NMR 데이터는 하기 표 4 참조; 1 H NMR and 13 C NMR data see Table 4 below;
ESI-MS [M+H] 579.1 m/z, C30H27O12.ESI-MS [M + H] 579.1 m / z, C 30 H 27 O 12 .
실시예 2-7. 봄바신-4-Example 2-7. Bombasin-4-
OO
-β--β-
DD
-글루코피라노사이드(화합물 7)Glucopyranoside (Compound 7)
bombasin-4-O-β-D-glucopyranoside;bombasin-4- O- β- D- glucopyranoside;
백색 무정형 분말;White amorphous powder;
UV (MeOH): 231 (4.23), 283 (4.17) ㎚;UV (MeOH): 231 (4.23), 283 (4.17) nm;
IR (KBr): 3367, 2920, 1651, 1601, 1514, 1464, 1427, 1265, 1223, 1159, 1126 ㎝-1;IR (KBr): 3367, 2920, 1651, 1601, 1514, 1464, 1427, 1265, 1223, 1159, 1126 cm -1 ;
1H NMR 및 13C NMR 데이터는 하기 표 4 참조; 1 H NMR and 13 C NMR data see Table 4 below;
EI-MS [M]+506.18 m/z, C25H30O11.EI-MS [M] + 506.18 m / z, C 25 H 30 O 11 .
실시예 2-8. (7Example 2-8. (7
RR
,8,8
SS
)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-) -7,8-dihydro-8-hydroxymethyl-7- (3-methoxyphenyl-4-
OO
-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8)-β-D-glucopyranoside) -1'-benzofuran propionic acid (compound 8)
(7R,8S)-7,8-dihydro-8-hydroxymethyl-7-(3-methoxyphenyl-4-O-β-D-glucopyranoside)-1'-benzofuranpropanoic acid("lycocernuaside A"라고도 함)(7R, 8S) -7,8-dihydro-8-hydroxymethyl-7- (3-methoxyphenyl-4-O-β-D-glucopyranoside) -1'-benzofuranpropanoic acid (also called "lycocernuaside A")
백색 무정형 분말;White amorphous powder;
IR (KBr) νmax 3379, 2941, 2834, 1638, 1600, 1515, 1453, 1274, 1032 ㎝-1;IR (KBr) ν max 3379, 2941, 2834, 1638, 1600, 1515, 1453, 1274, 1032 cm -1 ;
UV (MeOH) λmax (logε) 281 (2.50), 230 (3.12) ㎚;UV (MeOH) λ max (log ε ) 281 (2.50), 230 (3.12) nm;
ECD (c 0.030 mM, MeOH): △ε
278 -2.38, △ε
232 -1.42, △ε
216 +1.30;ECD ( c 0.030 mM, MeOH): Δ ε 278 -2.38, Δ ε 232 -1.42, Δ ε 216 +1.30;
1H NMR 및 13C NMR 데이터는 하기 표 5 참조; 1 H NMR and 13 C NMR data see Table 5 below;
HR-FAB-MS m/z 559.1794 [M+Na]+ (calcd for C26H32O12Na, 559.1791).HR-FAB-MS m / z 559.1794 [M + Na] + (calcd for C 26 H 32 O 12 Na, 559.1791).
실시예 2-9. 아피게닌-4'-Example 2-9. Apigenin-4'-
OO
-(6''--(6 ''-
OO
--
pp
-쿠마로일)-β-D-글루코피라노사이드 (화합물 9)-Coumaryl) -β-D-glucopyranoside (Compound 9)
apigenin-4'-O-(6''-O-p-coumaroyl)-β-D-glucopyranoside;apigenin-4'- O- (6 '' -O - p- coumaroyl) -β-D-glucopyranoside;
백색 무정형 분말;White amorphous powder;
1H NMR 및 13C NMR 데이터는 하기 표 6 참조; 1 H NMR and 13 C NMR data see Table 6 below;
ESI-MS [M+H] 579.1 m/z, C30H27O12.ESI-MS [M + H] 579.1 m / z, C 30 H 27 O 12 .
실시예 2-10. 디히드로디히드로코니페릴알코올-4-Example 2-10. Dihydrodihydroconiferyl Alcohol-4-
OO
-β-D-글루코피라노사이드(화합물 10)-β-D-glucopyranoside (Compound 10)
dihydrodehydroconiferyl alcohol-4-O-β-D-glucopyranoside;dihydrodehydroconiferyl alcohol-4- O- β-D-glucopyranoside;
무색의 고무;Colorless rubber;
IR (KBr)νmax 3380, 2945, 2834, 1600, 1517, 1462, 1270, 1035 ㎝-1;IR (KBr) v max 3380, 2945, 2834, 1600, 1517, 1462, 1270, 1035 cm -1 ;
UV (MeOH)λmax (logε) 280 (2.35), 232 (3.0) ㎚;UV (MeOH) λ max (logε) 280 (2.35), 232 (3.0) nm;
1H NMR 및 13C NMR 데이터는 하기 표 6 참조; 1 H NMR and 13 C NMR data see Table 6 below;
EI-MS m/z 552 [M]+(calcd for C26H34O11, 552).EI-MS m / z 552 [M] + (calcd for C 26 H 34 O 11, 552).
실시예 2-11. 샤프토사이드(화합물 11)Example 2-11. Sharptoside (Compound 11)
schaftoside;schaftoside;
노르스름한 분말;Yellowish powder;
1H NMR 및 13C NMR 데이터는 하기 표 3 참조; 1 H NMR and 13 C NMR data see Table 3 below;
EI-MS [M]+ 564.4 m/z, C26H28O14.EI-MS [M] + 564.4 m / z, C 26 H 28 O 14 .
표 1
Table 1
화합물1 | 화합물2 | 화합물3 | 화합물4 | |
Position | δH(ppm)a | δH(ppm)a | δH(ppm)b | δH(ppm)a |
1 | 4.43 (1H, d, J = 6.4 ㎐) | |||
2 | 3.59 (1H, m, H-2) | |||
3 | 3.41 (1H, dd, J = 11.2, 4.0 ㎐, H-3a); 3.27 (1H, m, H-3b) | 6.68 (1H, s) | ||
4 | ||||
5 | ||||
6 | 6.77 (1H, s, J = 2.0 ㎐) | 6.75 (1H, s, J = 2.0 ㎐) | 6.54 (1H, s, J = 2.0 ㎐) | |
7 | ||||
8 | 6.38 (1H, s, J = 2.0 ㎐) | 6.40 (1H, s, J = 2.0 ㎐) | 6.25 (1H, s, J = 2.0 ㎐) | |
9 | ||||
10 | ||||
1' | ||||
2' | 7.68 (1H, d, J = 2.0 ㎐) | 7.70 (1H, d, J = 2.0 ㎐) | 6.91 (1H, d, J = 1.2 H) | 7.98 (1H, d, J = 8.7 ㎐) |
3' | 7.20 (1H, d, J = 8.7 ㎐) | |||
4' | ||||
5' | 6.92 (1H, s, J = 8.0 ㎐) | 6.92 (1H, s, J = 8.0 ㎐) | 6.69 (1H, d, J = 8.0 ㎐) | 7.20 (1H, d, J = 8.7 ㎐) |
6' | 7.62 (1H, dd, J = 8.0, 2.0 ㎐) | 7.62 (1H, dd, J = 8.0, 2.0 ㎐) | 6.73 (1H, dd, J = 8.0, 1.2 ㎐) | 7.98 (1H, d, J = 8.7 ㎐) |
7-MeO | 3.86 (3H, s) | |||
3-MeO | 3.80 (3H, s) | |||
3'-MeO | 3.87 (3H, s) | 3.85 (3H, s) | 3.78 (3H, s) | |
5-OH | 12.05 (1H, s) | 12.14 (1H, s) | ||
a : 1H NMR(400 ㎒ in DMSO-d6) spectroscopy data; b : 1H NMR(400 ㎒ in MeOD-d4) spectroscopy data. |
Compound 1 | Compound 2 | Compound 3 | Compound 4 | |
Position | δ H (ppm) a | δ H (ppm) a | δ H (ppm) b | δ H (ppm) a |
One | 4.43 (1H, doublet, J = 6.4 μs) | |||
2 | 3.59 (1H, m, H-2) | |||
3 | 3.41 (1H, doublet of doublets, J = 11.2, 4.0 Hz, H-3a); 3.27 (1H, m, H-3b) | 6.68 (1 H, s) | ||
4 | ||||
5 | ||||
6 | 6.77 (1H, s, J = 2.0 μs) | 6.75 (1H, s, J = 2.0 μs) | 6.54 (1H, s, J = 2.0 μs) | |
7 | ||||
8 | 6.38 (1H, s, J = 2.0 μs) | 6.40 (1H, s, J = 2.0 μs) | 6.25 (1H, s, J = 2.0 μs) | |
9 | ||||
10 | ||||
One' | ||||
2' | 7.68 (1H, doublet, J = 2.0 μs) | 7.70 (1H, doublet, J = 2.0 μs) | 6.91 (1H, doublet, J = 1.2 H) | 7.98 (1H, doublet, J = 8.7 μs) |
3 ' | 7.20 (1H, doublet, J = 8.7 μs) | |||
4' | ||||
5 ' | 6.92 (1H, s, J = 8.0 μs) | 6.92 (1H, s, J = 8.0 μs) | 6.69 (1H, doublet, J = 8.0 μs) | 7.20 (1H, doublet, J = 8.7 μs) |
6 ' | 7.62 (1H, doublet of doublets, J = 8.0, 2.0 μs) | 7.62 (1H, doublet of doublets, J = 8.0, 2.0 μs) | 6.73 (1H, doublet of doublets, J = 8.0, 1.2 μs) | 7.98 (1H, doublet, J = 8.7 μs) |
7-MeO | 3.86 (3H, s) | |||
3-MeO | 3.80 (3H, s) | |||
3'-MeO | 3.87 (3H, s) | 3.85 (3H, s) | 3.78 (3H, s) | |
5-OH | 12.05 (1H, s) | 12.14 (1 H, s) | ||
a: 1 H NMR (400 MHz in DMSO-d 6 ) spectroscopy data; b: 1 H NMR (400 MHz in MeOD-d 4 ) spectroscopy data. |
표 2
TABLE 2
화합물1 | 화합물2 | 화합물3 | 화합물4 | |
Position | δC(ppm)a | δC(ppm)a | δC(ppm)b | δC(ppm)a |
1 | 75.6 | |||
2 | 156.3 | 156.5 | 77.7 | 164.2 |
3 | 133.6 | 136.5 | 64.3 | 105 |
4 | 177.7 | 178.2 | 182.5 | |
5 | 160.8 | 161.2 | 158.7 | |
6 | 97.9 | 97.3 | 94.7 | |
7 | 165.2 | 164.4 | 164.8 | |
8 | 92.4 | 92.6 | 99.6 | |
9 | 157 | 157.7 | 163.2 | |
10 | 105 | 106.2 | 105.2 | |
1' | 120.7 | 122.5 | 134.9 | 126 |
2' | 112.6 | 112.4 | 111.6 | 128.9 |
3' | 149.6 | 150.5 | 147.2 | 117.5 |
4' | 147.2 | 147.7 | 149 | 161 |
5' | 115.4 | 115.6 | 116 | 117.5 |
6' | 122.9 | 121.4 | 120.8 | 128.9 |
7-MeO | 55.4 | |||
3-MeO | 55.2 | |||
3'-MeO | 55.7 | 56.1 | 56.4 | |
5-OH | ||||
a : 13C-NMR(100 ㎒ in DMSO-d6) spectroscopy data; b : 13C-NMR(100 ㎒ in MeOD-d4) spectroscopy data. |
Compound 1 | Compound 2 | Compound 3 | Compound 4 | |
Position | δ C (ppm) a | δ C (ppm) a | δ C (ppm) b | δ C (ppm) a |
One | 75.6 | |||
2 | 156.3 | 156.5 | 77.7 | 164.2 |
3 | 133.6 | 136.5 | 64.3 | 105 |
4 | 177.7 | 178.2 | 182.5 | |
5 | 160.8 | 161.2 | 158.7 | |
6 | 97.9 | 97.3 | 94.7 | |
7 | 165.2 | 164.4 | 164.8 | |
8 | 92.4 | 92.6 | 99.6 | |
9 | 157 | 157.7 | 163.2 | |
10 | 105 | 106.2 | 105.2 | |
One' | 120.7 | 122.5 | 134.9 | 126 |
2' | 112.6 | 112.4 | 111.6 | 128.9 |
3 ' | 149.6 | 150.5 | 147.2 | 117.5 |
4' | 147.2 | 147.7 | 149 | 161 |
5 ' | 115.4 | 115.6 | 116 | 117.5 |
6 ' | 122.9 | 121.4 | 120.8 | 128.9 |
7-MeO | 55.4 | |||
3-MeO | 55.2 | |||
3'-MeO | 55.7 | 56.1 | 56.4 | |
5-OH | ||||
a: 13 C-NMR (100 MHz in DMSO-d 6 ) spectroscopy data; b: 13 C-NMR (100 MHz in MeOD-d 4 ) spectroscopy data. |
표 3
TABLE 3
화합물5 | 화합물11 | ||||
Position | δH(ppm)a | δC(ppm)b | Position | δH(ppm)c | δC(ppm)d |
2 | 165.2 | 2 | 166.6 | ||
3 | 6.63 (1H, s) | 105.5 | 3 | 6.41 (1H, s) | 105.5 |
4 | 183.5 | 4 | 184.1 | ||
5 | 156.8 | 5 | 157.4 | ||
6 | 106.8 | 6 | 108.3 | ||
7 | 163.2 | 7 | 163 | ||
8 | 103.8 | 8 | 103.7 | ||
9 | 163.2 | 9 | 162.7 | ||
10 | 109.6 | 10 | 105.7 | ||
1' | 123.5 | 1' | 123.3 | ||
2' | 8.32 (1H, d, J = 8.8 ㎐) | 129.7 | 2' | 7.80 (1H, d, J = 8.0 ㎐) | 129.6 |
3' | 7.27 (1H, d, J = 8.8 ㎐) | 117.5 | 3' | 7.74 (1H, d, J = 8.0 ㎐) | 117.1 |
4' | 160.5 | 4' | 160.1 | ||
5' | 7.27 (1H, d, J = 8.8 ㎐) | 117.5 | 5' | 7.74 (1H, d, J = 8.0 ㎐) | 117.1 |
6' | 8.32 (1H, d, J = 8.8 ㎐) | 129.7 | 6' | 7.80 (1H, d, J = 8.0 ㎐) | 129.6 |
8-Glc | 6-Glc | ||||
1'' | 5.86 (1H, d, J = 9.6 ㎐) | 75.7 | 1'' | 4.93 (1H, d, J = 9.6 ㎐) | 75.5 |
2'' | 4.68 (1H, m) | 81.4 | 2'' | 3.75 (1H, m) | 82.6 |
3'' | 4.39 (1H, m) | 76.7 | 3'' | 3.72 (1H, m) | 80.3 |
4'' | 4.28 (1H, m) | 71.9 | 4'' | 3.49 (1H, m) | 71.5 |
5'' | 4.50 (1H, m) | 72.8 | 5'' | 3.60 (1H, m) | 72.4 |
6'' | 4.57~4.28 (1H, m) | 63.4 | 6'' | 3.32 (1H, m), 3.84 (1H, m) | 63.2 |
6-Rha | 8-Rha | ||||
1''' | 5.66 (1H, d, J = 9.6 ㎐) | 84 | 1''' | 4.63 (1H, d, J = 9.6 ㎐) | 82.9 |
2''' | 4.67 (1H, m) | 76.2 | 2''' | 3.90 (1H, m) | 76.6 |
3''' | 4.48 (1H, m) | 73.4 | 3''' | 3.75 (1H, m) | 73.2 |
4''' | 4.37 (1H, m) | 71.4 | 4''' | 3.42 (1H, m) | 71.2 |
5''' | 4.33 (1H, m) | 72.2 | 5''' | 3.80 (1H, m) | 71.7 |
a : 1H NMR(400 ㎒ in Pyridine-d 5)spectroscopy data; b : 13C-NMR(100 ㎒ in Pyridine-d 5)spectroscopy data; c : 1H NMR (400 ㎒ in DMSO-d 6) spectroscopy data; d : 13C-NMR (100 ㎒ in DMSO-d 6) spectroscopy data. |
Compound 5 | Compound 11 | ||||
Position | δ H (ppm) a | δ C (ppm) b | Position | δ H (ppm) c | δ C (ppm) d |
2 | 165.2 | 2 | 166.6 | ||
3 | 6.63 (1 H, s) | 105.5 | 3 | 6.41 (1 H, s) | 105.5 |
4 | 183.5 | 4 | 184.1 | ||
5 | 156.8 | 5 | 157.4 | ||
6 | 106.8 | 6 | 108.3 | ||
7 | 163.2 | 7 | 163 | ||
8 | 103.8 | 8 | 103.7 | ||
9 | 163.2 | 9 | 162.7 | ||
10 | 109.6 | 10 | 105.7 | ||
One' | 123.5 | One' | 123.3 | ||
2' | 8.32 (1H, doublet, J = 8.8 μs) | 129.7 | 2' | 7.80 (1H, doublet, J = 8.0 μs) | 129.6 |
3 ' | 7.27 (1H, doublet, J = 8.8 μs) | 117.5 | 3 ' | 7.74 (1H, doublet, J = 8.0 μs) | 117.1 |
4' | 160.5 | 4' | 160.1 | ||
5 ' | 7.27 (1H, doublet, J = 8.8 μs) | 117.5 | 5 ' | 7.74 (1H, doublet, J = 8.0 μs) | 117.1 |
6 ' | 8.32 (1H, doublet, J = 8.8 μs) | 129.7 | 6 ' | 7.80 (1H, doublet, J = 8.0 μs) | 129.6 |
8-Glc | 6-Glc | ||||
One'' | 5.86 (1H, doublet, J = 9.6 kPa) | 75.7 | One'' | 4.93 (1H, doublet, J = 9.6 kPa) | 75.5 |
2'' | 4.68 (1H, m) | 81.4 | 2'' | 3.75 (1 H, m) | 82.6 |
3 '' | 4.39 (1 H, m) | 76.7 | 3 '' | 3.72 (1H, m) | 80.3 |
4'' | 4.28 (1 H, m) | 71.9 | 4'' | 3.49 (1H, m) | 71.5 |
5 '' | 4.50 (1 H, m) | 72.8 | 5 '' | 3.60 (1H, m) | 72.4 |
6 '' | 4.57-4.28 (1H, m) | 63.4 | 6 '' | 3.32 (1H, m), 3.84 (1H, m) | 63.2 |
6-Rha | 8-Rha | ||||
One''' | 5.66 (1H, doublet, J = 9.6 kPa) | 84 | One''' | 4.63 (1H, doublet, J = 9.6 kPa) | 82.9 |
2''' | 4.67 (1 H, m) | 76.2 | 2''' | 3.90 (1H, m) | 76.6 |
3 ''' | 4.48 (1 H, m) | 73.4 | 3 ''' | 3.75 (1 H, m) | 73.2 |
4''' | 4.37 (1 H, m) | 71.4 | 4''' | 3.42 (1 H, m) | 71.2 |
5 ''' | 4.33 (1 H, m) | 72.2 | 5 ''' | 3.80 (1 H, m) | 71.7 |
a: 1 H NMR (400 MHz in Pyridine- d 5 ) spectroscopy data; b: 13 C-NMR (100 MHz in Pyridine- d 5 ) spectroscopy data; c: 1 H NMR (400 MHz in DMSO- d 6 ) spectroscopy data; d: 13 C-NMR (100 MHz in DMSO- d 6 ) spectroscopy data. |
표 4
Table 4
화합물 6 | 화합물 7 | |||
Position | δH(ppm)a | δC(ppm)b | δH(ppm)c | δC(ppm)d |
1 | 130.8 | |||
2 | 163.8 | 7.33 (1H, d, J = 2.0 ㎐) | 111.9 | |
3 | 6.71 (1H, s) | 105.7 | 150.6 | |
4 | 182.6 | 148.4 | ||
5 | 158.3 | 7.19(1H, dd, J=2.0, 8.5㎐) | 116.6 | |
6 | 6.53 (1H, s, J = 2.0㎐) | 94.5 | 7.59 (1H, d, J = 8.5㎐) | 119.5 |
7 | 165.1 | 6.16 (1H, d, J = 6.5㎐) | 89.3 | |
8 | 6.27 (1H, s, J = 2.0㎐) | 100.2 | 3.96 (1H, m) | 54.2 |
9 | 163.7 | 4.27 (2H, m) | 64 | |
10 | 105.1 | |||
1' | 124.6 | 7.78 (1H, brs) | 120.1 | |
2' | 7.90(1H, d, J = 8.7㎐) | 129.1 | 132.6 | |
3' | 7.18 (1H, d, J = 8.7㎐) | 117.5 | 7.92 (1H, brs) | 113.6 |
4' | 161.3 | 137.6 | ||
5' | 7.18 (1H, d, J = 8.7㎐) | 117.4 | 147 | |
6' | 7.90 (1H, d, J = 8.7㎐) | 129.1 | 145.2 | |
7' | 196.7 | |||
8' | 2.58 (3H, s) | 26.5 | ||
9' | ||||
1'' | 5.42 (1H, d, J = 8.1㎐) | 99.8 | 5.69 (1H, d, J = 7.0㎐) | 102.7 |
2'' | 5.15 (1H, dd, J=9.4, 8.1㎐) | 74.2 | 4.36 (1H, m) | 75 |
3'' | 3.80 (1H, t, J = 9.0㎐) | 73.9 | 4.37 (1H, m) | 78.6 |
4'' | 3.70 (1H, t, J = 9.0㎐) | 77.3 | 4.32 (1H, m) | 71.4 |
5'' | 3.78 (1H, m) | 74.6 | 4.13 (1H, m) | 79 |
6'' | 3.83 (1H, dd, J=12.1, 2.0㎐); 3.74 (1H, dd, J=12.1, 5.5㎐) | 66.4 | 4.55 (1H, dd, J = 2.0, 12.0㎐); 4.37 (1H, m) | 62.5 |
1''' | 126.7 | |||
2''' | 7.54 (1H, d, J = 8.5㎐) | 131.2 | ||
3''' | 6.68 (1H, d, J = 8.5㎐) | 116.5 | ||
4''' | 160.8 | |||
5''' | 6.68 (1H, d, J = 8.5㎐) | 115.4 | ||
6''' | 7.54 (1H, d, J = 8.5㎐) | 130.5 | ||
7''' | 7.66 (1H, d, J = 15.0㎐) | 146 | ||
8''' | 6.37 (1H, d, J = 15.0㎐) | 114.8 | ||
9''' | 166.7 | |||
1'''' | 125.8 | |||
2'''' | 7.53 (1H, d, J = 8.5㎐) | 131.1 | ||
3'''' | 6.86 (1H, d, J = 8.5㎐) | 116.6 | ||
4'''' | 160.5 | |||
5'''' | 6.86 (1H, d, J = 8.5㎐) | 116.6 | ||
6'''' | 7.53 (1H, d, J = 8.5㎐) | 131.1 | ||
7'''' | 7.60 (1H, d, J = 15.0㎐) | 145.6 | ||
8'''' | 6.39 (1H, d, J = 15.0㎐) | 114.7 | ||
9'''' | 167.8 | |||
3-OMe | 3.86 (3H, s) | 56.2 | ||
6'-OMe | 3.69 (3H, s) | 56.2 | ||
a : 1H NMR(400 ㎒ in DMSO-d 6) spectroscopy data; b : 13C-NMR(100 ㎒ in DMSO-d 6) spectroscopy data; c : 1H NMR(400 ㎒ in MeOD-d 4) spectroscopy data; d : 13C-NMR(100 ㎒ in MeOD-d 4) spectroscopy data. |
Compound 6 | Compound 7 | |||
Position | δ H (ppm) a | δ C (ppm) b | δ H (ppm) c | δ C (ppm) d |
One | 130.8 | |||
2 | 163.8 | 7.33 (1H, doublet, J = 2.0 μs) | 111.9 | |
3 | 6.71 (1 H, s) | 105.7 | 150.6 | |
4 | 182.6 | 148.4 | ||
5 | 158.3 | 7.19 (1H, doublet of doublets, J = 2.0, 8.5 Hz) | 116.6 | |
6 | 6.53 (1H, s, J = 2.0 μs) | 94.5 | 7.59 (1H, doublet, J = 8.5 μs) | 119.5 |
7 | 165.1 | 6.16 (1H, doublet, J = 6.5 μs) | 89.3 | |
8 | 6.27 (1H, s, J = 2.0 μs) | 100.2 | 3.96 (1H, m) | 54.2 |
9 | 163.7 | 4.27 (2H, m) | 64 | |
10 | 105.1 | |||
One' | 124.6 | 7.78 (1 H, brs) | 120.1 | |
2' | 7.90 (1H, doublet, J = 8.7 μs) | 129.1 | 132.6 | |
3 ' | 7.18 (1H, doublet, J = 8.7 μs) | 117.5 | 7.92 (1 H, brs) | 113.6 |
4' | 161.3 | 137.6 | ||
5 ' | 7.18 (1H, doublet, J = 8.7 μs) | 117.4 | 147 | |
6 ' | 7.90 (1H, doublet, J = 8.7 μs) | 129.1 | 145.2 | |
7 ' | 196.7 | |||
8' | 2.58 (3H, s) | 26.5 | ||
9 ' | ||||
One'' | 5.42 (1H, doublet, J = 8.1 μs) | 99.8 | 5.69 (1H, doublet, J = 7.0 μs) | 102.7 |
2'' | 5.15 (1H, doublet of doublets, J = 9.4, 8.1 Hz) | 74.2 | 4.36 (1H, m) | 75 |
3 '' | 3.80 (1H, t, J = 9.0 μs) | 73.9 | 4.37 (1 H, m) | 78.6 |
4'' | 3.70 (1H, t, J = 9.0 μs) | 77.3 | 4.32 (1H, m) | 71.4 |
5 '' | 3.78 (1 H, m) | 74.6 | 4.13 (1 H, m) | 79 |
6 '' | 3.83 (1H, doublet of doublets, J = 12.1, 2.0 Hz); 3.74 (1H, doublet of doublets, J = 12.1, 5.5 Hz) | 66.4 | 4.55 (1H, doublet of doublets, J = 2.0, 12.0 μs); 4.37 (1 H, m) | 62.5 |
One''' | 126.7 | |||
2''' | 7.54 (1H, d, J = 8.5 μs) | 131.2 | ||
3 ''' | 6.68 (1H, doublet, J = 8.5 μs) | 116.5 | ||
4''' | 160.8 | |||
5 ''' | 6.68 (1H, doublet, J = 8.5 μs) | 115.4 | ||
6 ''' | 7.54 (1H, d, J = 8.5 μs) | 130.5 | ||
7 ''' | 7.66 (1H, doublet, J = 15.0 μs) | 146 | ||
8''' | 6.37 (1H, doublet, J = 15.0 μs) | 114.8 | ||
9 ''' | 166.7 | |||
One'''' | 125.8 | |||
2'''' | 7.53 (1H, doublet, J = 8.5 μs) | 131.1 | ||
3 '' | 6.86 (1H, doublet, J = 8.5 μs) | 116.6 | ||
4'''' | 160.5 | |||
5 '' | 6.86 (1H, doublet, J = 8.5 μs) | 116.6 | ||
6 '''' | 7.53 (1H, doublet, J = 8.5 μs) | 131.1 | ||
7 '''' | 7.60 (1H, doublet, J = 15.0 μs) | 145.6 | ||
8'''' | 6.39 (1H, doublet, J = 15.0 μs) | 114.7 | ||
9 '''' | 167.8 | |||
3-OMe | 3.86 (3H, s) | 56.2 | ||
6'-OMe | 3.69 (3H, s) | 56.2 | ||
a: 1 H NMR (400 MHz in DMSO- d 6 ) spectroscopy data; b: 13 C-NMR (100 MHz in DMSO- d 6 ) spectroscopy data; c: 1 H NMR (400 MHz in MeOD- d 4 ) spectroscopy data; d: 13 C-NMR (100 MHz in MeOD- d 4 ) spectroscopy data. |
표 5
Table 5
화합물 8 | ||
Position | δ H (ppm, J in ㎐) a | δ C (ppm) b |
1 | 129.6 | |
2 | 7.06, brs | 111.2 |
3 | 150.9 | |
4 | 147.5 | |
5 | 7.17, d (8.0) | 118.1 |
6 | 6.96, brd (8.0) | 119.4 |
7 | 5.55, d (6.0) | 88.4 |
8 | 3.51, m | 55.5 |
9 | 3.88, m; 3.78, m | 65.2 |
1' | 136.1 | |
2' | 6.80, brs | 114.1 |
3' | 138.5 | |
4' | 147.7 | |
5' | 145.2 | |
6' | 6.76, brs | 117.8 |
7' | 2.84, t (7.6) | 32.3 |
8' | 2.53, t (7.6) | 38.1 |
9' | 178.1 | |
1'' | 4.89, d (7.6) | 102.8 |
2'' | 3.53, m | 74.8 |
3'' | 3.51, m | 77.8 |
4'' | 3.43, m | 71.3 |
5'' | 3.45, m | 79.4 |
6'' | 3.72, dd (3.5, 12.0); 3.89, m | 62.4 |
3-OMe | 3.88, s | 56.7 |
5'-OMe | 3.85, s | 56.8 |
a : 1H NMR (500 ㎒ in Methanol-d 4,d values) spectroscopic data; b: 13C NMR (125 ㎒ in Methanol-d 4,d values) spectroscopic data. |
Compound 8 | ||
Position | δ H (ppm, J in ㎐) a | δ C (ppm) b |
One | 129.6 | |
2 | 7.06, brs | 111.2 |
3 | 150.9 | |
4 | 147.5 | |
5 | 7.17, d (8.0) | 118.1 |
6 | 6.96, brd (8.0) | 119.4 |
7 | 5.55, d (6.0) | 88.4 |
8 | 3.51, m | 55.5 |
9 | 3.88, m; 3.78, m | 65.2 |
One' | 136.1 | |
2' | 6.80, brs | 114.1 |
3 ' | 138.5 | |
4' | 147.7 | |
5 ' | 145.2 | |
6 ' | 6.76, brs | 117.8 |
7 ' | 2.84, t (7.6) | 32.3 |
8' | 2.53, t (7.6) | 38.1 |
9 ' | 178.1 | |
One'' | 4.89, d (7.6) | 102.8 |
2'' | 3.53, m | 74.8 |
3 '' | 3.51, m | 77.8 |
4'' | 3.43, m | 71.3 |
5 '' | 3.45, m | 79.4 |
6 '' | 3.72, dd (3.5, 12.0); 3.89, m | 62.4 |
3-OMe | 3.88, s | 56.7 |
5'-OMe | 3.85, s | 56.8 |
a: 1 H NMR (500 MHz in Methanol- d 4 , d values) spectroscopic data; b: 13 C NMR (125 MHz in Methanol- d 4 , d values) spectroscopic data. |
표 6
Table 6
화합물9 | 화합물10 | |||
Position | δH(ppm)a | δC(ppm)b | δH(ppm)c | δC(ppm)d |
1 | 129.4 | |||
2 | 164.2 | 7.01 (1H, brs) | 111.3 | |
3 | 6.68 (1H, s) | 105 | 150.7 | |
4 | 182.5 | 147.4 | ||
5 | 158.7 | 6.87 (1H, d, J = 8.5㎐) | 117.9 | |
6 | 6.54 (1H, s, J = 2.0㎐) | 94.7 | 6.99 (1H, dd, J = 1.5, 8.5㎐) | 119.2 |
7 | 164.8 | 5.61 (1H, d, 6.0㎐) | 88.3 | |
8 | 6.25 (1H, s, J = 2.0㎐) | 99.6 | 3.55 (1H, m) | 55.4 |
9 | 163.2 | 3.91 (1H, m); 3.82 (1H, m) | 64.9 | |
10 | 105.2 | |||
1' | 126 | 6.79 (1H, brs) | 120.3 | |
2' | 7.98 (1H, d, J = 8.7㎐) | 128.9 | 132.7 | |
3' | 7.20 (1H, d, J = 8.7㎐) | 117.5 | 7.20 (1H, brs) | 114.9 |
4' | 161 | 138.2 | ||
5' | 7.20 (1H, d, J = 8.7㎐) | 117.5 | 147.3 | |
6' | 7.98 (1H, d, J = 8.7㎐) | 128.9 | 145 | |
7' | 2.69 (2H, t, J = 7.5㎐) | 32.6 | ||
8' | 1.88 (2H, m) | 36 | ||
9' | 3.63 (2H, t,J = 6.5㎐) | 62.3 | ||
1'' | 5.39 (1H, d, J = 8.1㎐) | 99.4 | 4.95 (1H, d, J = 7.0㎐) | 102.6 |
2'' | 5.17 (1H, dd, J=9.4, 8.1㎐) | 74.1 | 3.53 (1H, m) | 74.7 |
3'' | 3.82 (1H, t, J = 9.0㎐) | 75.6 | 3.45 (1H, m) | 77.6 |
4'' | 3.61 (1H, t, J = 9.0㎐) | 71.2 | 3.46 (1H, m) | 71.1 |
5'' | 3.71 (1H, m) | 78.1 | 3.52 (1H, m) | 77.9 |
6'' | 3.96 (1H, dd, J = 12.1, 2.0㎐); 3.76 (1H, dd, J = 12.1, 5.8㎐) | 62.2 | 3.74 (1H, dd, J = 3.5, 12.0㎐); 3.94 (1H, m) | 62 |
1''' | 126.8 | |||
2''' | 7.54 (1H, d, J = 8.5㎐) | 130.9 | ||
3''' | 6.68 (1H, d, J = 8.5㎐) | 116.5 | ||
4''' | 160.5 | |||
5''' | 6.68 (1H, d, J = 8.5㎐) | 116.5 | ||
6''' | 7.54 (1H, d, J = 8.5㎐) | 130.9 | ||
7''' | 7.66 (1H, d, J = 15.0㎐) | 145.5 | ||
8''' | 6.37 (1H, d, J = 15.0㎐) | 115.2 | ||
9''' | 166.5 | |||
3-OMe | 3.90 (3H, s) | 56.5 | ||
6'-OMe | 3.94 (3H, s) | 56.6 | ||
a : 1H NMR(400 ㎒ in DMSO-d 6) spectroscopy data; b : 13C NMR(100 ㎒ in DMSO-d 6) spectroscopy data; c : 1H NMR(400 ㎒ in MeOD-d 4) spectroscopy data; d : 13C NMR(100 ㎒ in MeOD-d 4) spectroscopy data. |
Compound 9 | Compound 10 | |||
Position | δ H (ppm) a | δ C (ppm) b | δ H (ppm) c | δ C (ppm) d |
One | 129.4 | |||
2 | 164.2 | 7.01 (1H, broad singlet) | 111.3 | |
3 | 6.68 (1 H, s) | 105 | 150.7 | |
4 | 182.5 | 147.4 | ||
5 | 158.7 | 6.87 (1H, doublet, J = 8.5 μs) | 117.9 | |
6 | 6.54 (1H, s, J = 2.0 μs) | 94.7 | 6.99 (1H, doublet of doublets, J = 1.5, 8.5 Hz) | 119.2 |
7 | 164.8 | 5.61 (1H, d, 6.0 Hz) | 88.3 | |
8 | 6.25 (1H, s, J = 2.0 μs) | 99.6 | 3.55 (1H, m) | 55.4 |
9 | 163.2 | 3.91 (1 H, m); 3.82 (1 H, m) | 64.9 | |
10 | 105.2 | |||
One' | 126 | 6.79 (1H, brs) | 120.3 | |
2' | 7.98 (1H, doublet, J = 8.7 μs) | 128.9 | 132.7 | |
3 ' | 7.20 (1H, doublet, J = 8.7 μs) | 117.5 | 7.20 (1H, brs) | 114.9 |
4' | 161 | 138.2 | ||
5 ' | 7.20 (1H, doublet, J = 8.7 μs) | 117.5 | 147.3 | |
6 ' | 7.98 (1H, doublet, J = 8.7 μs) | 128.9 | 145 | |
7 ' | 2.69 (2H, t, J = 7.5 μs) | 32.6 | ||
8' | 1.88 (2H, m) | 36 | ||
9 ' | 3.63 (2H, t, J = 6.5 μs) | 62.3 | ||
One'' | 5.39 (1H, doublet, J = 8.1 μs) | 99.4 | 4.95 (1H, doublet, J = 7.0 μs) | 102.6 |
2'' | 5.17 (1H, doublet of doublets, J = 9.4, 8.1 Hz) | 74.1 | 3.53 (1 H, m) | 74.7 |
3 '' | 3.82 (1H, t, J = 9.0 μs) | 75.6 | 3.45 (1H, m) | 77.6 |
4'' | 3.61 (1H, t, J = 9.0 μs) | 71.2 | 3.46 (1H, m) | 71.1 |
5 '' | 3.71 (1 H, m) | 78.1 | 3.52 (1 H, m) | 77.9 |
6 '' | 3.96 (1H, doublet of doublets, J = 12.1, 2.0 μs); 3.76 (1H, doublet of doublets, J = 12.1, 5.8 Hz) | 62.2 | 3.74 (1H, doublet of doublets, J = 3.5, 12.0 μs); 3.94 (1 H, m) | 62 |
One''' | 126.8 | |||
2''' | 7.54 (1H, d, J = 8.5 μs) | 130.9 | ||
3 ''' | 6.68 (1H, doublet, J = 8.5 μs) | 116.5 | ||
4''' | 160.5 | |||
5 ''' | 6.68 (1H, doublet, J = 8.5 μs) | 116.5 | ||
6 ''' | 7.54 (1H, d, J = 8.5 μs) | 130.9 | ||
7 ''' | 7.66 (1H, doublet, J = 15.0 μs) | 145.5 | ||
8''' | 6.37 (1H, doublet, J = 15.0 μs) | 115.2 | ||
9 ''' | 166.5 | |||
3-OMe | 3.90 (3H, s) | 56.5 | ||
6'-OMe | 3.94 (3H, s) | 56.6 | ||
a: 1 H NMR (400 MHz in DMSO- d 6 ) spectroscopy data; b: 13 C NMR (100 MHz in DMSO- d 6 ) spectroscopy data; c: 1 H NMR (400 MHz in MeOD- d 4 ) spectroscopy data; d: 13 C NMR (100 MHz in MeOD- d 4 ) spectroscopy data. |
<실시예 3. 아세틸콜린에스테라아제 및 부티릴콜린에스테라아제의 억제활성 측정>Example 3 Determination of Inhibitory Activity of Acetylcholinesterase and Butyrylcholinesterase
콜린에스테라아제에 의해 아세틸콜린 또는 부티릴아세틸콜린이 가수분해되면 노란색의 5'-티오-2-나이트로벤조에이트 음이온(5'-thio-2-nitrobenzoat anion)을 형성하게 되므로 412㎚에서 흡광도 변화를 통해 효소 활성을 측정하였다.Hydrolysis of acetylcholine or butyrylacetylcholine by cholinesterase results in the formation of a yellow 5'-thio-2-nitrobenzoate anion (5'-thio-2-nitrobenzoate anion). The enzyme activity was measured through.
96웰 플레이트(96wells microplates)에 140㎕의 인산나트륨 완충용액(sodium phosphate buffer, pH8.0)과 최종 농도가 100μM인 본 발명의 각 화합물 20㎕, 아세틸콜린에스테라아제 또는 부티릴콜린에스테라아제 (5units/㎖) 20㎕, 10㎕의 DTNB(dithiobisnitrobenzoate), 10㎕의 아세틸콜린 또는 부티릴콜린을 더하여 상온에서 15분 동안 반응하였다. 양성대조군으로는 베르베린(berberine)을 이용하였으며, 반응 후 형성된 5'-티오-2-나이트로벤조에이트 음이온을 흡광도 측정기(VERSA max, Molecular Devices, USA)로 412㎚에서 확인하여 하기 표 7에 IC50(the half maximal inhibitory concentration)으로 나타내었다.140 µl of sodium phosphate buffer (pH 8.0) and 20 µl of each compound of the present invention with a final concentration of 100 µM, acetylcholinesterase or butyrylcholinesterase (5 units / ml) in 96 wells microplates 20 µl, 10 µl of dithiobisnitrobenzoate (DTNB), 10 µl of acetylcholine or butyrylcholine were added and reacted at room temperature for 15 minutes. As a positive control group, berberine was used, and the 5'-thio-2-nitrobenzoate anion formed after the reaction was confirmed at 412 nm with an absorbance meter (VERSA max, Molecular Devices, USA). 50 (the half maximal inhibitory concentration).
표 7
TABLE 7
조건 | 아세틸콜린에스테라아제 억제활성 (IC50) | 부티릴콜린에스테라아제 억제활성 (IC50) |
화합물 1 | 8.69±0.49μM | > 30μM |
화합물 2 | 8.78±0.97μM | 13.04±0.99μM |
화합물 3 | 1.56±0.22μM | > 30μM |
화합물 4 | 7.29±0.23μM | 15.78±0.95μM |
화합물 5 | 0.23±0.17μM | 3.08±0.26μM |
화합물 6 | 1.24±0.31μM | 3.11±0.77μM |
화합물 7 | 11.25±0.99μM | 12.23±0.89μM |
화합물 8 | 15.22±0.89μM | 24.09±0.33μM |
화합물 9 | 2.78±0.42μM | 7.15±0.19μM |
화합물 10 | 11.93±0.96μM | 7.02±0.29μM |
화합물 11 | 1.70±0.22μM | 0.62±0.47μM |
베르베린 | 0.71±0.11μM | 7.08±0.01μM |
Condition | Acetylcholinesterase inhibitory activity (IC 50 ) | Butyrylcholinesterase Inhibitory Activity (IC 50 ) |
Compound 1 | 8.69 ± 0.49μM | > 30 μM |
Compound 2 | 8.78 ± 0.97μM | 13.04 ± 0.99 μM |
Compound 3 | 1.56 ± 0.22μM | > 30 μM |
Compound 4 | 7.29 ± 0.23μM | 15.78 ± 0.95 μM |
Compound 5 | 0.23 ± 0.17μM | 3.08 ± 0.26μM |
Compound 6 | 1.24 ± 0.31μM | 3.11 ± 0.77μM |
Compound 7 | 11.25 ± 0.99μM | 12.23 ± 0.89μM |
Compound 8 | 15.22 ± 0.89μM | 24.09 ± 0.33μM |
Compound 9 | 2.78 ± 0.42μM | 7.15 ± 0.19μM |
Compound 10 | 11.93 ± 0.96μM | 7.02 ± 0.29μM |
Compound 11 | 1.70 ± 0.22μM | 0.62 ± 0.47μM |
Berberine | 0.71 ± 0.11μM | 7.08 ± 0.01μM |
상기 표 7의 결과를 참고하면, 본 발명의 석송강 추출물로부터 분리된 화합물이 아세틸콜린에스테라아제 또는 부티릴콜린에스테라아제의 억제활성을 가지는 것으로 확인되어 알츠하이머병의 예방 및 치료제로서 유용하게 사용될 수 있음을 알 수 있다.Referring to the results of Table 7, it was confirmed that the compound isolated from the extract of the pine tree of the present invention has an inhibitory activity of acetylcholinesterase or butyrylcholinesterase, which can be usefully used as a prophylactic and therapeutic agent for Alzheimer's disease Can be.
<실시예 4. β-세크레타제 1의 억제활성 측정>Example 4 Determination of Inhibitory Activity of β-Secretase 1
β-세크레타제 1에 의해 기질이 잘리면 형광이 나타나는데 이를 BACE1 FRET 어세이 키트(β-Secretase, human recombinant, PanVera Co. USA)로 측정하여 효소의 활성을 확인하였다. Fluorescence was generated when the substrate was cut by β-secretase 1, and the enzyme activity was confirmed by measuring it with a BACE1 FRET assay kit (β-Secretase, human recombinant, PanVera Co. USA).
각 10㎕의 50mM 아세트산나트륨(pH4.5), β-세크레타제 1 및 기질(750nM Rh-EVNLDAEFK-Quencher)에 100μM의 각 화합물을 10㎕씩 더하여 25℃에서 60분 동안 어두운 곳에서 반응시켰다. 양성대조군으로 케르세틴을 사용하였으며, 반응 결과를 확인하기 위해 여기 파장 545㎚ 및 발광 파장 585㎚에서 형광을 측정하고, 하기 표 8에 IC50(the half maximal inhibitory concentration)으로 나타내었다.To each 10 μl of 50 mM sodium acetate (pH4.5), β-secretase 1 and the substrate (750 nM Rh-EVNLDAEFK-Quencher), 10 μl of each compound was added and reacted in the dark at 25 ° C. for 60 minutes. . Quercetin was used as a positive control, here measuring fluorescence at the wavelength and emission wavelength 545㎚ 585㎚ to determine the reaction results, it is shown to the IC 50 (the half maximal inhibitory concentration ) in Table VIII.
표 8
Table 8
조건 | β-세크레타제 1 억제활성 (IC50) |
화합물 1 | 5.59±0.33μM |
화합물 3 | 7.33±1.77μM |
화합물 10 | 26.86±1.94μM |
화합물 11 | 2.16±0.37μM |
케르세틴 | 6.76±0.63μM |
Condition | β-secretase 1 inhibitory activity (IC 50 ) |
Compound 1 | 5.59 ± 0.33μM |
Compound 3 | 7.33 ± 1.77μM |
Compound 10 | 26.86 ± 1.94μM |
Compound 11 | 2.16 ± 0.37μM |
Quercetin | 6.76 ± 0.63μM |
표 8의 결과를 살펴보면, 본 발명의 석송강 추출물로부터 분리된 화합물이 β-세크레타제 1의 활성을 억제하는 것으로 확인되어, 알츠하이머병에 대한 치료 효과가 우수함을 확인할 수 있다.Looking at the results of Table 8, it was confirmed that the compound isolated from the extract of the pine tree of the present invention inhibits the activity of β-secretase 1, it can be confirmed that the therapeutic effect for Alzheimer's disease is excellent.
<실시예 5. 독성실험> Example 5. Toxicity Test
실시예 5-1. 급성독성 Example 5-1. Acute Toxicity
본 발명의 석송강 추출물 또는 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 1)을 단기간에 과량을 섭취하였을 때 급성적(24시간 이내)으로 동물 체내에 미치는 독성을 조사하고, 치사율을 결정하기 위하여 본 실험을 수행하였다. 일반적인 마우스인 ICR 마우스를 20마리를 준비하였고, 각 군별로 10마리씩 배정하였다. 대조군에는 30% PEG-400만을 투여하고, 실험군은 본 발명의 추출물 또는 화합물 1을 1.0g/㎏의 농도로 각각 경구 투여하였다. 투여 24시간 후에 각각의 치사율을 조사한 결과, 대조군과 상기 추출물 또는 화합물 1을 투여한 실험군에서는 모두 생존하였다.Of the present invention lycopodiopsida extract or (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) This experiment was carried out to investigate the toxicity of acutely (within 24 hours) to the body of an animal when a large amount of -1'-benzofuran propionic acid (Compound 1) was ingested and to determine the lethality. Twenty ICR mice, which are common mice, were prepared, and 10 were assigned to each group. Only 30% PEG-400 was administered to the control group, and the experimental group orally administered the extract or compound 1 of the present invention at a concentration of 1.0 g / kg, respectively. Each mortality rate was examined 24 hours after administration, and both the control group and the experimental group administered with the extract or Compound 1 survived.
실시예 5-2. 실험군 및 대조군의 장기 및 조직 독성 실험Example 5-2. Long-term and tissue toxicity experiments in experimental and control groups
장기 독성 실험은 C57BL/6J 생쥐를 대상으로 동물의 각 장기(조직)에 미치는 영향을 조사하기 위하여 본 발명의 석송강 추출물 또는 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 1.0g/㎏의 농도로 투여한 실험군과 용매만을 투여한 대조군의 동물들로부터 8주 후 혈액을 채취하여 GPT(glutamate-pyruvate transferase) 및 BUN(blood urea nitrogen)의 혈액 내 농도를 Select E(vital scientific NV, Netherland) 기기를 이용하여 측정하였다. 그 결과, 간독성과 관계있는 것으로 알려진 GPT와 신장독성과 관계있는 것으로 알려진 BUN의 경우, 대조군과 비교하여 실험군은 별다른 차이를 보이지 않았다. 또한, 각 동물로부터 간과 신장을 절취하여 통상적인 조직절편 제작과정을 거쳐 광학현미경으로 조직학적 관찰을 시행하였으나 특이한 이상은 관찰되지 않았다.Long-term toxicity experiments lycopodiopsida extract or (7 R, 8 S) of the present invention to investigate the effect of each organ (tissue) of the animals intended for C57BL / 6J mice, 7,8-dihydro-8-hydroxy Of the experimental group in which oxymethyl-7- (3-methoxyphenyl-4- O- β-D-glucopyranoside) -1'-benzofuran propionic acid was administered at a concentration of 1.0 g / kg and the control group in which only the solvent was administered Blood was collected after 8 weeks from the animals, and blood concentrations of glutamate-pyruvate transferase (GPT) and blood urea nitrogen (BUN) were measured using a Select E (vital scientific NV, Netherland) instrument. As a result, in the case of GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to nephrotoxicity, there was no difference in the experimental group compared to the control group. In addition, liver and kidneys were excised from each animal, and histological observations were performed by optical microscopy through a conventional tissue fabrication process. No abnormalities were observed.
<제제예 1. 약학적 제제>Preparation Example 1. Pharmaceutical Formulations
제제예 1-1. 정제의 제조Formulation Example 1-1. Manufacture of tablets
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산 200g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' 200 g of benzofuran propionic acid was mixed with 175.9 g lactose, 180 g potato starch and 32 g colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.
제제예 1-2. 주사제의 제조Formulation Example 1-2. Preparation of Injectables
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' 1 g of benzofuran propionic acid, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.
<제제예 2. 식품 제조>Preparation Example 2 Food Preparation
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Preparation of Cooking Seasonings
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 조리용 양념에 1 중량%로 첨가하여 건강 증진용 조리용 양념을 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' Benzofuran propionic acid was added to the cooking seasoning at 1% by weight to prepare a cooking seasoning for health promotion.
제제예 2-2. 밀가루 식품의 제조Formulation Example 2-2. Manufacture of Flour Food
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 밀가루에 0.1 중량%로 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' Benzofuran propionic acid was added to the flour at 0.1% by weight, and the mixture was used to prepare bread, cake, cookies, crackers and noodles to prepare foods for health promotion.
제제예 2-3. 스프 및 육즙(gravies)의 제조Formulation Example 2-3. Preparation of soups and gravy
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 스프 및 육즙에 0.1 중량%로 첨가하여 건강 증진용 수프 및 육즙을 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' Benzofuran propionic acid was added to the soup and broth in 0.1% by weight to prepare soup and broth for health promotion.
제제예 2-4. 유제품(dairy products)의 제조Formulation Example 2-4. Manufacture of dairy products
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산을 우유에 0.1 중량%로 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' Benzofuran propionic acid was added to the milk at 0.1% by weight, and the milk was used to prepare various dairy products such as butter and ice cream.
제제예 2-5. 야채주스 제조Formulation Example 2-5. Vegetable Juice Manufacturing
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산 0.5g을 토마토주스 또는 당근주스 1,000㎖에 가하여 건강 증진용 야채주스를 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' 0.5 g of benzofuran propionic acid was added to 1,000 ml of tomato juice or carrot juice to prepare vegetable juice for health promotion.
제제예 2-6. 과일주스 제조Formulation Example 2-6. Fruit juice manufacturing
본 발명의 (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산 0.1g을 사과주스 또는 포도주스 1,000㎖에 가하여 건강 증진용 과일주스를 제조하였다.Of the present invention (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Llano side) 1' 0.1 g of benzofuran propionic acid was added to 1,000 ml of apple juice or wine to prepare fruit juice for health promotion.
Claims (10)
- 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 석송강(Lycopodiella cernua) 추출물을 함유하는 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물.Ramnazin (Compound 1), Quercetin 3,3'-dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4), Isomorphoside (Compound 5), Api Genenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (Compound 6), bombacin-4- O- β- D - glue nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Ranoside) -1′-benzofuranpropionic acid (compound 8), apigenin-4′- O- (6 '' -O - p -coumaroyl) -β-D-glucopyranoside (compound 9), Lycopodiella cernua comprising at least one compound selected from the group consisting of dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (compound 10) and sharposide (compound 11) A composition for the prevention or treatment of Alzheimer's disease, characterized in that it contains an extract.[화학식 1][Formula 1]
- 제1항에 있어서,The method of claim 1,상기 석송강 추출물은 석송강을 물, C1 내지 C4의 저급 알코올, 아세톤, n-헥산, 디클로로메탄 및 에틸아세테이트로 이루어진 군에서 선택되는 1종 이상의 용매로 추출한 추출물인 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물.Said Songseok River extract is an extract of Alkheimer's disease, characterized in that the extract of the Songseok River with water, C1 to C4 lower alcohol, acetone, n-hexane, dichloromethane and ethylacetate selected from the group consisting of one or more solvents Or a therapeutic composition.
- 석송강(Lycopodiella cernua)으로부터 분리된 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물.Rhamnazin (Compound 1), Quercetin 3,3'-dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4), Iso isolated from Lycopodiella cernua Shaptoside (Compound 5), Apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (Compound 6), spring Basin -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4 O- β-D-glucopyranoside) -1'-benzofuranpropionic acid (compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) -β-D- At least one member selected from the group consisting of glucopyranoside (compound 9), dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (compound 10) and sharposide (compound 11) A composition for preventing or treating Alzheimer's disease, comprising a compound.[화학식 1][Formula 1]
- 제1항 또는 제3항에 있어서, The method according to claim 1 or 3,상기 화합물은 아세틸콜린에스테라아제(acetylcholinesterase), 부티릴콜린에스테라아제(butyrylcholinesterase) 및 β-세크레타제 1(β-secretase 1)로 이루어진 군에서 선택되는 1종 이상의 효소 활성을 억제하는 것을 특징으로 하는 알츠하이머병의 예방 또는 치료용 조성물.Alzheimer's disease, characterized in that the compound inhibits at least one enzyme activity selected from the group consisting of acetylcholinesterase, butyrylcholinesterase and β-secretase 1 (β-secretase 1) Composition for the prevention or treatment of
- 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 석송강(Lycopodiella cernua) 추출물을 함유하는 것을 특징으로 하는 알츠하이머병의 예방 또는 개선용 건강기능식품.Ramnazin (Compound 1), Quercetin 3,3'-dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4), Isomorphoside (Compound 5), Api Genenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (Compound 6), bombacin-4- O- β- D - glue nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4- O -β-D- gluconic nose Ranoside) -1′-benzofuranpropionic acid (compound 8), apigenin-4′- O- (6 '' -O - p -coumaroyl) -β-D-glucopyranoside (compound 9), Lycopodiella cernua comprising at least one compound selected from the group consisting of dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (compound 10) and sharposide (compound 11) Health functional food for the prevention or improvement of Alzheimer's disease, characterized in that it contains an extract.[화학식 1][Formula 1]
- 제5항에 있어서,The method of claim 5,상기 석송강 추출물은 석송강을 물, C1 내지 C4의 저급 알코올, 아세톤, n-헥산, 디클로로메탄 및 에틸아세테이트로 이루어진 군에서 선택되는 1종 이상의 용매로 추출한 추출물인 것을 특징으로 하는 알츠하이머병의 예방 또는 개선용 건강기능식품.Said Songseok River extract is an extract of Alkheimer's disease, characterized in that the extract of the Songseok River with water, C1 to C4 lower alcohol, acetone, n-hexane, dichloromethane and ethylacetate selected from the group consisting of one or more solvents Or dietary supplements for improvement.
- 석송강(Lycopodiella cernua)으로부터 분리된 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 포함하는 것을 특징으로 하는 알츠하이머병의 예방 또는 개선용 건강기능식품.Rhamnazin (Compound 1), Quercetin 3,3'-dimethyl ether (Compound 2), Guaiacylglycerol (Compound 3), Apigenin (Compound 4), Iso isolated from Lycopodiella cernua Shaptoside (Compound 5), Apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside (Compound 6), spring Basin -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3-methoxyphenyl -4 O- β-D-glucopyranoside) -1'-benzofuranpropionic acid (compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) -β-D- At least one member selected from the group consisting of glucopyranoside (compound 9), dihydrodihydroconiferyl alcohol-4- O- β-D-glucopyranoside (compound 10) and sharposide (compound 11) Health functional food for the prevention or improvement of Alzheimer's disease comprising a compound.[화학식 1][Formula 1]
- 제5항 또는 제7항에 있어서, The method according to claim 5 or 7,상기 화합물은 아세틸콜린에스테라아제(acetylcholinesterase), 부티릴콜린에스테라아제(butyrylcholinesterase) 및 β-세크레타제 1(β-secretase 1)로 이루어진 군에서 선택되는 1종 이상의 효소 활성을 억제하는 것을 특징으로 하는 알츠하이머병의 예방 또는 개선용 건강기능식품.Alzheimer's disease, characterized in that the compound inhibits at least one enzyme activity selected from the group consisting of acetylcholinesterase, butyrylcholinesterase and β-secretase 1 (β-secretase 1) Functional foods for the prevention or improvement of
- 석송강(Lycopodiella cernua)을 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 석송강 추출물을 제조하는 단계; 상기 석송강 추출물을 n-헥산 및 에틸아세테이트를 이용하여 순차적으로 분획한 후 물층 잔사를 디클로로메탄으로 재분획하는 단계; 및 상기 재분획된 디클로로메탄을 제외한 물층을 크로마토그래피로 하기 화학식 1의 람나진(화합물 1), 케르세틴 3,3'-디메틸 에테르(화합물 2), 구아이아실글리세롤(화합물 3), 아피게닌(화합물 4), 이소샤프토사이드(화합물 5), 아피게닌-4'-O-(2'',6''-디-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 6), 봄바신-4-O-β-D-글루코피라노사이드(화합물 7), (7R,8S)-7,8-디히드로-8-히드록시메틸-7-(3-메톡시페닐-4-O-β-D-글루코피라노사이드)-1'-벤조푸란프로피온산(화합물 8), 아피게닌-4'-O-(6''-O-p-쿠마로일)-β-D-글루코피라노사이드(화합물 9), 디히드로디히드로코니페릴알코올-4-O-β-D-글루코피라노사이드(화합물 10) 및 샤프토사이드(화합물 11)로 이루어진 군에서 선택되는 1종 이상의 화합물을 분리하는 방법. Preparing an extract of S. limpidus ( Lycopodiella cernua ) with water, C1 to C4 lower alcohol or a mixed solvent thereof; Fractionating the travertine extract using n-hexane and ethyl acetate in sequence and re-fractionating the water layer residue with dichloromethane; And chromatographing the water layer except for the re-distilled dichloromethane with lambnazin (Compound 1), quercetin 3,3'-dimethyl ether (Compound 2), guaiacylglycerol (Compound 3), and apigenin (Formula 1). Compound 4), isomorphoside (compound 5), apigenin-4'- O- (2 '', 6 ''-di-O- p -coumaroyl) -β-D-glucopyranoside ( compound 6), spring Basin -4- O -β- D - gluconic nose Llano side (compound 7), (7 R, 8 S) -7,8- dihydro-8-hydroxy-7- (3 Methoxyphenyl-4- O- β-D-glucopyranoside) -1'-benzofuranpropionic acid (compound 8), apigenin-4'- O- (6 '' -O - p -coumaroyl) In the group consisting of -β-D-glucopyranoside (Compound 9), dihydrodihydroconiferyl alcohol-4- O -β-D-glucopyranoside (Compound 10) and shaftoside (Compound 11) A method of separating one or more compounds selected.[화학식 1][Formula 1]
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