WO2019240508A1 - Novel compound isolated from acanthopanax sp. fruit extract, and pharmaceutical composition for preventing and treating hypertension, containing same - Google Patents

Novel compound isolated from acanthopanax sp. fruit extract, and pharmaceutical composition for preventing and treating hypertension, containing same Download PDF

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WO2019240508A1
WO2019240508A1 PCT/KR2019/007128 KR2019007128W WO2019240508A1 WO 2019240508 A1 WO2019240508 A1 WO 2019240508A1 KR 2019007128 W KR2019007128 W KR 2019007128W WO 2019240508 A1 WO2019240508 A1 WO 2019240508A1
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compound
formula
blood pressure
present
fruit
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PCT/KR2019/007128
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French (fr)
Korean (ko)
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이대영
김금숙
이영섭
이재원
최두진
이승은
김형돈
서경혜
백남인
정인호
김하늘
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대한민국(농촌진흥청장)
대화제약 주식회사
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Publication of WO2019240508A1 publication Critical patent/WO2019240508A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health

Definitions

  • the present invention relates to a novel compound isolated from the extract of Acanthopanax sp. Fruit and a pharmaceutical composition comprising the same. More particularly, the novel compound of the present invention can effectively suppress blood pressure rise, so It can be usefully used as a preventive and therapeutic pharmaceutical composition or health functional food.
  • Hypertension is a cause of all circulatory disorders, and complications such as cerebral hemorrhage, heart disease, and kidney disease have a high mortality rate. It is estimated that the prevalence rate is 15-20% among the elderly in their 40s. WHO defines high blood pressure as the case where the highest blood pressure is 160 mmHg or more and the minimum blood pressure is 95 mmHg or more. The types of hypertension are divided into essential hypertension, whose cause is unclear, and secondary hypertension caused by the causative disease. It is known to belong. In high blood pressure, only the highest blood pressure is high, and the highest blood pressure and the lowest blood pressure are both high.
  • High blood pressure is often referred to as the latter, and the former, ie only the highest blood pressure, is associated with increased blood flow from the heart and decreased elasticity of the aorta, that is, some type of heart valve disease or hyperthyroidism. , Aortic sclerosis and aortic aneurysms.
  • Inherent hypertension is a relatively low level of inheritance, which is about 60% for children if the parents are hypertensive, about 20% if one of the parents is hypertension, and 5% if the parents are not all hypertension. Hypertension appears.
  • kidney disease acute nephritis, chronic nephritis, pyelonephritis, hydronephrosis, renal artery stenosis, etc.
  • changes in large vessels aortic stenosis, peripheral vascular occlusion
  • endocrine diseases cushing
  • pheochromocytoma essential hyperaldosteroneosis, etc.
  • other gestational addictions such as those found in extreme mental anxiety or nervousness
  • ACE inhibitors are a kind of peptidyl dipeptidase, which catalyzes the production of angiotensin II, known as the most potent booster, and at the same time inhibits the breakdown of bradykinin, the most potent vasodilator. Catalyzes.
  • Ang II a pharmacologically active substance produced by cleaving the His-Leu terminal of Ang I inactive by ACE, increases blood pressure by potent vasoconstrictive action and preserves sodium by stimulating the release of aldosterone in the adrenal cortex. To increase the volume of blood vessels. It is also known that the six amino acids at the C-terminus of the structure of Ang II have most of the information necessary for pharmacological action.
  • ACE inhibitors that inhibit the activity of the ACE will have a consistent hypotensive effect can be used over a wide range for the treatment of hypertension, including patients with essential hypertension.
  • ACE inhibitors not only have a significant antihypertensive effect, but also have good tolerability, and unlike other antihypertensive agents, ACE inhibitors have little side effects due to long-term use, and can be used in patients with high blood pressure such as heart disease, diabetes, asthma, and thus have high utility as antihypertensive agents.
  • Thurman, JM., Schrier, RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney, Am J Med., 114, pp. 588-598, 2003).
  • Plant-derived ACE inhibitory peptides include trypsin hydrolysates of casein, peptides from porcine serum, peptides from digestive digestion of tuna, peptides from vinegar made from rice, residue peptides from sake and by-products, and also Lactobacillus helveticus Peptides produced by hydrolyzing milk proteins by separating extracellular proteases from CP790 (L. helveticus CP790) were studied.
  • ACE inhibitory peptides using Lactobacillus Helveticus CP790 include ⁇ , s1-casein-derived peptides with amino acid sequence Ala-Tyr-Phe-Tyr-Pro-Glu, and ⁇ -casein-derived peptides Arg-Asp- Polypeptides having an amino acid sequence of Met-Pro-Ile-Gln-Aln-Phe have been found (Hong Sang-pil et al., Angiotensin converting enzyme inhibitors and their properties, Food science and Industry, 32 (4), 1998).
  • Acanthopanax senticosus and A. sessiliflorus are Acanthopanax plants belonging to the family Araliaceae. They are deciduous broad-leaved shrubs, 3-4 cm tall, with many branches near the roots. The leaves are regenerated, the mesoderm is 3 ⁇ 5 lobules, ovate.
  • Ogapi plants have excellent pharmacological effects in traditional Chinese medicine, including Dongbobom, herbal medicine composition room, new agricultural herbaceous and herbal herb, and as a tonic, it is effective in treating bronchial asthma, physical strength, musculoskeletal enhancement, neuralgia, diabetes, etc. Recently, it has been scientifically identified to have a blood pressure lowering action, liver function protection, hematopoietic and immune function enhancement, blood cholesterol lowering action, antioxidant activity, anti-allergic action and anti-cancer action. There is an increasing trend of interest and use in many areas, including.
  • Ogapi fruit refers to the fruit of the plant of the genus Ogapi
  • Ogapi fruit is known to have the effect of protecting the liver, improving learning ability, enhancing immunity, anticancer action, lowering cholesterol, treating gastric ulcers.
  • the present inventors have isolated the novel compound from the extract of Ogapi fruit to confirm its ACE inhibitory effect, and completed the present invention.
  • An object of the present invention is to provide a novel compound represented by the following formula (1).
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hypertension disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a blood pressure lowering food composition
  • a blood pressure lowering food composition comprising the compound represented by Formula 1 or a food acceptable salt thereof as an active ingredient.
  • the present invention provides a compound represented by the following formula (1).
  • the compound may be derived from a staghorn fruit.
  • the compound may be for preventing or treating blood pressure diseases.
  • the present invention provides a pharmaceutical composition for preventing or treating hypertension diseases comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may be included in an amount of 0.0001 to 10% by weight based on the total composition.
  • the compound may inhibit the action of angiotensin converting enzyme to inhibit the increase in blood pressure.
  • the present invention provides a food composition for lowering blood pressure, which comprises the compound represented by Formula 1 or a food acceptable salt thereof as an active ingredient.
  • the compound or a salt thereof may be derived from a cactus.
  • the compound may inhibit the action of angiotensin converting enzyme to inhibit the increase in blood pressure.
  • the extracts of the organza fruit may be included in an amount of 0.0001 to 10% by weight based on the total food composition.
  • the present invention provides a method for producing a compound represented by the formula (1).
  • the method for preparing the compound comprises the steps of: (1) concentration of reduced pressure after obtaining the extract by adding C1 to C6 alcohol and water to the fruit of the organ; (2) extracting the concentrated extract under reduced pressure with water and C 1 -C 6 alkyl acetate, and then concentrated under reduced pressure to obtain a primary fraction; (3) partitioning and extracting the primary fractions with water and C1 to C6 alcohols, and then concentrating under reduced pressure to obtain a secondary fraction; And (4) separating and purifying the compound of Formula 1 from the secondary fraction.
  • novel compounds of the present invention can be effectively used as a pharmaceutical composition for preventing and treating hypertension or a food composition for lowering blood pressure because it can effectively suppress blood pressure rise.
  • FIG. 7 is a graph showing the results of ACE inhibitory activity of the novel compounds according to an embodiment of the present invention.
  • the present inventors confirmed the ACE inhibitory effect of the novel compound isolated from the extract of Ogapi fruit, and completed the present invention.
  • Ogapi of the present invention has a nickname such as Ogapi, Oga, Ogamu, etc.
  • Ogapi fruit is also called Ogaza.
  • Ogapi used in the present invention refers to all belonging to the genus Ogapi.
  • the ogapi of the present invention may be any one or more selected from the group consisting of thorn ogapi, Seoul ogapi, island ogapi, ogapi, Jirisan ogapi and incense galpi, more preferably thorn ogapi, Seoul ogapi, island ogapi, ogapi It may be a tree, and even more preferably may be thorny oak, island oak, or oak.
  • Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
  • Acanthopanax senticosus (Rupr. & Maxim.) Harms.
  • Acanthopanax senticosus for. It can be represented by the scientific name of inermis., Seoul Ogapi can be represented by Eleutherococcus seoulensis or Acanthopanax seoulense Nakai, and island ogapi can be represented by Eleutherococcus gracilistylus (WWSm.) SYHu or Acanthopanax koreanum Nakai.
  • Ogapi can be represented as Eleutherococcus sessiliflorus (Rupr.
  • the "blood pressure drop" of the present invention is used to mean that the blood pressure is lowered to the normal blood pressure range for a subject whose blood pressure exceeds the normal blood pressure range (80 mmHg to 120 mmHg).
  • Angiotensin converting enzyme of the present invention is an enzyme that converts angiotensin to angiotensinogen with the help of Lenin, which constricts blood vessels and raises blood pressure.
  • the present invention provides a compound represented by the following formula (1).
  • the compound represented by Chemical Formula 1 may be derived from agapi fruit, and may be used for preventing or treating hypertension diseases.
  • the method for preparing the compound comprises the steps of: (1) concentration of reduced pressure after obtaining the extract by adding C1 to C6 alcohol and water to the fruit of the organ; (2) extracting the concentrated extract under reduced pressure with water and C 1 -C 6 alkyl acetate, and then concentrated under reduced pressure to obtain a primary fraction; (3) partitioning and extracting the primary fractions with water and C1 to C6 alcohols, and then concentrating under reduced pressure to obtain a secondary fraction; And (4) separating and purifying the compound of Formula 1 from the secondary fraction.
  • the primary fraction of step (3) includes an alkyl acetate fraction and a water fraction
  • the novel compound of the present invention may be included in the water fraction. Therefore, the novel compounds of the present invention can be obtained by separating and purifying secondary fractions, preferably water fractions, obtained through step (3).
  • the method of obtaining the extract is not particularly limited as long as it is a method of obtaining an extract from natural products, but preferably, ultrasonic extraction, filtration or reflux extraction may be used.
  • the decompression concentration may be performed using a vacuum decompression concentrator or a vacuum rotary evaporator, but is not limited thereto.
  • the C1 ⁇ C6 alcohol may be used C1 ⁇ C6 alcohol that can be used for the extraction of natural products, preferably, may be methanol, ethanol or n-butanol.
  • the method of separating and purifying the secondary fraction may be generally used a method used for natural product separation, preferably chromatographic methods can be used.
  • the present invention provides a pharmaceutical composition for preventing or treating hypertension diseases, including a salt represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • novel compound according to the present invention and Ogapi fruit extract comprising the same, there is no problem such as toxicity and side effects.
  • the novel compounds are characterized by stabilizing blood pressure by inhibiting angiotensin converting enzyme.
  • Ogapi fruit extract of the present invention by inhibiting ACE (Angiotensin converting enzyme) by effectively inhibiting the increase in blood pressure caused by the action of angiotensin converting enzyme was confirmed that there is a therapeutic effect of lowering blood pressure or hypertension.
  • ACE inhibition of 10 ⁇ M enalapril was about 52%, but the ACE inhibition of 100 ⁇ M novel compound was about 23%, showing that the ACE inhibitory activity was about 44% compared to enalapril.
  • Ogapi fruit extract of the present invention through the blood pressure lowering effect can treat or prevent hypertension or hypertension complications, and the hypertension complications can be coronary artery disease, cerebrovascular disease, kidney dysfunction, heart failure and vision disorders.
  • Compound according to an embodiment of the present invention is characterized in that it comprises 0.0001 to 10 parts by weight, based on 100 parts by weight of the total composition. Preferably it is characterized in that it comprises 0.001 to 7% by weight more preferably 0.01 to 3% by weight.
  • the present invention provides a food pressure lowering food composition
  • a food pressure lowering food composition comprising a compound represented by the following formula (1) or a food acceptable salt thereof as an active ingredient.
  • Examples of the food to which the compound represented by Formula 1 or a food acceptable salt thereof may be added as an active ingredient include, for example, various foods, powders, granules, tablets, capsules, syrups, beverages, gums, teas, Vitamin complexes and health foods. It may also be added to foods or beverages for the purpose of preventing hypertension.
  • the amount of the compound or salt thereof in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, the health beverage composition is added at a ratio of 0.02 to 5g, preferably 0.3 to 1g based on 100ml Can be.
  • the functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound or a salt thereof as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
  • the compounds of the present invention or salts thereof include various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the compounds of the present invention or salts thereof may contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is usually selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the extract of the present invention.
  • a pharmaceutical composition comprising a compound according to the present invention or a salt thereof may be in oral dosage forms, external preparations, suppositories, and sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. Formulated in the form of can be used.
  • Carriers, excipients and diluents that may be included in the composition comprising the extract 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, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. Prepared by mixing sucrose or lactose, gelatin and the like. 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.
  • Preferred dosages of the compounds of the present invention or salts thereof depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art.
  • the compound of the present invention or salt thereof is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 100 mg / kg. 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.
  • the compounds of the present invention or salts thereof can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the present invention should be construed as including the organza fruit, the pulverized product thereof, the processed product thereof, or the extract thereof containing the compound.
  • Solvent fractionation was carried out using n-butanol (2.8 L) and water (3 L) from the extracts obtained from Example 1-2, and the fractions were concentrated to obtain 100 g of n-butanol fraction (ASB).
  • 100 g of the obtained ASB was subjected to silica gel column chromatography (inner diameter 10 x 20 cm, elution ratio of CHCl 3 to MeOH and H 2 O, 9: 3: 1), and each aliquot (200 ml) was subjected to thin layer chromatography (thin).
  • 10 fractions (ASB-1 to ASB-10) were obtained by layer chromatography (TLC).
  • APE-3 fractions were subjected to silica gel column chromatography (inner diameter 4 ⁇ 12 cm, performed at a 9: 3: 1 ratio of CHCl 3, MeOH and H 2 O) to 10 fractions (ASB-3- 1 ⁇ ASB-3-10), and octadecyl column chromatograph (ODS cc), inner diameter 4 ⁇ 10 cm, and 3: 1 of MeOH and H 2 O for 1 g of ASB-3-5 fraction.
  • 15 fractions (ASB-3-5-1 to ASB-3-3-15) were obtained, and among them, 100 mg of ASB-3-5-10 fraction was used for ODS cc and MeOH and H. 2 O at a 5: 1 ratio to give 40 mg of a novel compound.
  • ACE inhibitory activity was analyzed using known methods (lee et al., Statistics and data anlysis method, hyoil press (1998), 253-296). 50 ⁇ l and 100 ⁇ l Hip-His-Leu (Sigma, A3-P4DQ11, USA) were dissolved in 0.2 M boric buffer (pH8.3) and 0.05 M sodium borate buffer containing 0.4 M NaCl, for 1 hour at 37 ° C. Incubated with 150 ⁇ l of ACE. The reaction was left at room temperature for 5 minutes and then 250 ⁇ l of 1N HCL was added to terminate the reaction.
  • the obtained hypuric acid was extracted by adding 1.5 ⁇ l ethyl acetate. After centrifugation at 3000 rpm for 10 minutes, 1 ⁇ l of the upper layer was transferred to a glass tube and dried at 120 ° C. for 30 minutes. It was then cooled in desiccators for 20 minutes. 3 ⁇ l of distilled water was added to the dried sample, followed by stirring for 30 seconds. The absorbance was used at 228 nm spectrophotometer (UV-1650PC, Shimadzu, Kyoto, Japan).
  • the ACE used in this example was treated with 0.2 M boric buffer (pH 8.3) and 0.05 M sodium borate buffer containing 1 .mu.L of 0.4 M NaCl from 1 g rabbit lung acetone powder (Sigma, L0756, USA) at 4 ° C. for one day. The mixture was extracted by centrifugation (4000 rpm, 1 h). Aspirin was used as a positive control in Example 3, ACE inhibitory ability was calculated through the following formula 1.
  • Example 2 The values reported in Example 2 describe the average of three experimental values, and the data were analyzed by ANOVA and Duncan's multi-range test. Statistically, it was interpreted as having statistical significance when P ⁇ 0.05.
  • the concentrations of methoxycecilioside I used in this example were 10, 50 and 100 ⁇ M, respectively, and as shown in FIG. 7, the ACE inhibitory activity of each of the 10 ⁇ M enalapril and 100 ⁇ M novel compounds was 51.69 ⁇ 1.13%. And 22.87 ⁇ 0.34%. It showed about 44% efficacy over 10 ⁇ M enalapril.
  • 10 and 50 ⁇ M of Ogapi fruit extract showed 17.22 ⁇ 0.25% and 18.21 ⁇ 0.78% of ACE inhibitory activity, respectively.
  • Example 1 The structure of the compound obtained in Example 1 was analyzed.
  • Example 1 The compound obtained through Example 1 through the structural analysis was determined to have a chemical structure of the formula (1).
  • the molecular weight was 940 [m] as m / z 939.49322 [MH]-was observed in negative mode using a fast Q-TOF Micro mass detector (Waters, Manchester, UK) for the novel compounds isolated in Examples 1-3. M] + was determined. As a total of 49 signals were observed in the carbon NMR spectrum, it was expected that three molecules of the triterpene structure were bonded and another group of carbon molecules were bound.
  • the anomer carbon of the sugar confirmed the signal of the sugar trimolecule bound to the typical chacinoside [28-O-Glc (inner): ⁇ 95.2, 28-O-Glc (outer): ⁇ 105.0 and 4-O-Rha: ⁇ 102.6].
  • the binding sites were identified by showing the linkages between the respective anomer protons and the oxygen-substituted carbon signals based on the gHMBC spectrum to identify the binding sites of the two molecules of glucopyranose and rhamnose.
  • the methoxy protons ( ⁇ 3.61 ppm) and the carbonyl group [ ⁇ 174.9 (C) were determined based on the gHMBC spectrum to identify the binding sites of the newly generated signals, the methoxy (OCH3) group and the seco-lupan-triretpene skeleton. -3)]
  • the final binding site was confirmed by showing the link with the signal.
  • Compound 1 represented by Chemical Formula 1 is seco-lupane triterpene, (3,4-seco-4 (23), 20, (29)- lupadiene-3,28-dioic acid 3-methyl ester 28-OaL-rhamnopyranosyl (1 ⁇ 4) -bD-glucopyranosyl (1 ⁇ 6) -bD-glucopyranoside was determined and named Methoxysessiloside I It was confirmed that it is a new compound.
  • Example 1 The Ogapi fruit water fraction obtained in Example 1 was subjected to the same procedure as in Example 1-3 to separate and purify the water fraction. As a result, the new compound was not detected.
  • the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
  • tablets are prepared by tableting according to a conventional method for preparing tablets.
  • the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
  • the amount of the above ingredient is prepared per ampoule (2 ml).
  • each component is added and dissolved in purified water, lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle.
  • the solution is prepared by sterilization.
  • composition ratio is a composition suitable for a preferred beverage in a preferred embodiment
  • the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

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Abstract

The present invention relates to a composition containing a novel compound isolated from an Acanthopanax sp. fruit extract. More specifically, a novel compound of the present invention can effectively inhibit blood pressure elevation, caused by the action of an angiotensin converting enzyme (ACE), by inhibiting the ACE, thereby being effectively usable as a pharmaceutical composition and a health functional food for preventing and treating hypertension.

Description

오가피 열매 추출물로부터 분리된 신규 화합물 및 이를 포함하는 고혈압 예방 및 치료용 약학적 조성물Novel compounds isolated from the extracts of Ogapi fruit and pharmaceutical compositions for the prevention and treatment of hypertension comprising the same
본 발명은 오가피 나무 열매(Acanthopanax sp. fruit)추출물로부터 분리된 신규 화합물 및 이를 포함하는 약학적 조성물에 관한 것으로, 보다 상세하게는 본 발명의 신규 화합물은 혈압상승을 효과적으로 억제할 수 있기 때문에 고혈압의 예방 및 치료용 약학적 조성물 또는 건강기능식품으로 유용하게 이용될 수 있다.The present invention relates to a novel compound isolated from the extract of Acanthopanax sp. Fruit and a pharmaceutical composition comprising the same. More particularly, the novel compound of the present invention can effectively suppress blood pressure rise, so It can be usefully used as a preventive and therapeutic pharmaceutical composition or health functional food.
고혈압은 모든 순환기계 질환의 원인이 되는 동시에 뇌출혈, 심장병 및 신장병 등과 합병증으로 나타날 경우에는 치사율이 매우 높은 만성 퇴행성 질환으로 40대 이후의 중노년층에서 유병율이 15-20%로 추정되고 있다. WHO는 최고 혈압이 160 mmHg 이상이고 최저 혈압이 95 mmHg 이상인 경우를 고혈압으로 규정하고 있으며 고혈압의 종류는 원인이 불분명한 본태성 고혈압과 원인질병에 의한 속발성 고혈압으로 나뉘며 80% 이상이 본태성 고혈압에 속하는 것으로 알려져 있다. 고혈압에는 최고혈압만 높은 경우와 최고혈압, 최저혈압 양쪽이 모두 높은 경우가 있다. 보통 고혈압이라고 하는 것은 후자의 경우가 많고 전자, 즉, 최고혈압만이 높은 경우는 심장에서 보내는 혈액량이 많아질 때와 대동맥의 탄력성이 감소되어 있을 때, 즉, 어떤 종류의 심장판막증이거나 갑상선 기능 항진증, 대동맥경화, 대동맥류 등인 경우이다. 본태성 고혈압증에는 유전하부라는 것만이 비교적 확실한 것으로서, 부모가 고혈압증인 경우 자녀들에게는 60% 정도, 부모의 한쪽이 고혈압인 경우에는 20% 정도, 부모가 모두 고혈압이 아닌 경우에는 5% 정도의 비율로 고혈압이 나타난다. 속발성 고혈압의 원인으로는 신장질환(급성신염, 만성신염, 신우염증, 수신증, 신동맥협착 등)에 의한 것, 대혈관의 변화(대동맥협착증, 말초혈관폐색 등)에 의한 것, 내분비성 질환(쿠싱증후군, 갈색세포종, 본태성 고알도스테론증 등)에 의한 것, 기타 임신중독증을 비롯하여 극도의 정신불안이나 긴장상태에서 볼 수 있는 것 등이 알려져 있다(한국 식품 영양과학회, 식품영양학사전, p.82, 1998).Hypertension is a cause of all circulatory disorders, and complications such as cerebral hemorrhage, heart disease, and kidney disease have a high mortality rate. It is estimated that the prevalence rate is 15-20% among the elderly in their 40s. WHO defines high blood pressure as the case where the highest blood pressure is 160 mmHg or more and the minimum blood pressure is 95 mmHg or more. The types of hypertension are divided into essential hypertension, whose cause is unclear, and secondary hypertension caused by the causative disease. It is known to belong. In high blood pressure, only the highest blood pressure is high, and the highest blood pressure and the lowest blood pressure are both high. High blood pressure is often referred to as the latter, and the former, ie only the highest blood pressure, is associated with increased blood flow from the heart and decreased elasticity of the aorta, that is, some type of heart valve disease or hyperthyroidism. , Aortic sclerosis and aortic aneurysms. Inherent hypertension is a relatively low level of inheritance, which is about 60% for children if the parents are hypertensive, about 20% if one of the parents is hypertension, and 5% if the parents are not all hypertension. Hypertension appears. Causes of secondary hypertension include kidney disease (acute nephritis, chronic nephritis, pyelonephritis, hydronephrosis, renal artery stenosis, etc.), changes in large vessels (aortic stenosis, peripheral vascular occlusion), endocrine diseases (cushing) Syndrome, pheochromocytoma, essential hyperaldosteroneosis, etc.), and other gestational addictions, such as those found in extreme mental anxiety or nervousness (Korean Society for Food and Nutrition, Dictionary of Food and Nutrition, p. 82, 1998).
성인병의 하나인 고혈압의 치료를 위해 현재 많은 항고혈압제가 개발되어 사용되고 있으며 작용기전과 작용점에 따라 이뇨제, 교감신경계 작용약물(α,2-아드레날린성 길항제, β-아드레날린성 길항제), 혈관확장제, 칼슘 채널 길항제(calcium channel blockers), 안지오텐신 전환 효소(ACE, angiotensin converting enzyme) 저해제 등으로 분류된다(Mann, SJ., Neurogenic essential hypertension revisited: The case for increased clinical and research attention, American Journal of Hypertension, 16, pp.881-888, 2003; Escobales, N., Crespo, MJ., Oxidative-nitrosative stress in hypertension, Current Vascular Pharmachology, 3, pp.231-246, 2005). Many antihypertensive agents have been developed and used for the treatment of hypertension, which is one of the adult diseases. Diuretics, sympathetic nervous system drugs (α, 2-adrenergic antagonists, β-adrenergic antagonists), vasodilators, calcium Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors (Mann, SJ., Neurogenic essential hypertension revisited: The case for increased clinical and research attention, American Journal of Hypertension, 16, pp. 881-888, 2003; Escobales, N., Crespo, MJ., Oxidative-nitrosative stress in hypertension, Current Vascular Pharmachology, 3, pp. 231-246, 2005).
ACE 저해제는 일종의 펩티딜 디펩티다제(peptidyl dipeptidase)로서 이 효소는 가장 강력한 승압물질로 알려진 안지오텐신 Ⅱ(Ang Ⅱ)의 생성을 촉매화하며 동시에 가장 강력한 혈관확장 물질인 브래디키닌(bradykinin)의 분해를 촉매화 한다. ACE에 의해 불활성인 Ang Ⅰ의 C 말단 His-Leu이 절단되어 생성된 약리적 활성물질인 Ang Ⅱ는 강력한 혈관 수축작용으로 혈압을 상승시키며 부신피질에서 알도스테론의 유리를 자극함으로써 나트륨을 보존시키는 작용을 하여 혈관 내 용적을 증가시킨다. 또한 Ang Ⅱ의 구조 중 C- 말단의 6개의 아미노산이 약리작용에 필수적인 대부분의 정보를 가지고 있다고 알려져 있다. 이러한 ACE의 활성을 저해하는 ACE 저해제는 일관성 있는 혈압강하효과를 나타내게 되므로 본태성 고혈압 환자를 포함한 고혈압 치료를 위해 넓은 영역에 걸쳐 사용될 수 있다. 또한 ACE 저해제는 현저한 혈압강하효과 뿐만 아니라 내약성이 좋고, 다른 항고혈압제와 달리 장기간 사용에 따른 부작용이 적으며, 심장질환, 당뇨, 천식 등이 있는 고혈압 환자에게도 사용할 수 있어 항고혈압제로서의 유용성이 매우 높다(Thurman, JM., Schrier, RW., Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney, Am J Med., 114, pp.588-598, 2003). ACE inhibitors are a kind of peptidyl dipeptidase, which catalyzes the production of angiotensin II, known as the most potent booster, and at the same time inhibits the breakdown of bradykinin, the most potent vasodilator. Catalyzes. Ang Ⅱ, a pharmacologically active substance produced by cleaving the His-Leu terminal of Ang I inactive by ACE, increases blood pressure by potent vasoconstrictive action and preserves sodium by stimulating the release of aldosterone in the adrenal cortex. To increase the volume of blood vessels. It is also known that the six amino acids at the C-terminus of the structure of Ang II have most of the information necessary for pharmacological action. ACE inhibitors that inhibit the activity of the ACE will have a consistent hypotensive effect can be used over a wide range for the treatment of hypertension, including patients with essential hypertension. In addition, ACE inhibitors not only have a significant antihypertensive effect, but also have good tolerability, and unlike other antihypertensive agents, ACE inhibitors have little side effects due to long-term use, and can be used in patients with high blood pressure such as heart disease, diabetes, asthma, and thus have high utility as antihypertensive agents. (Thurman, JM., Schrier, RW., Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney, Am J Med., 114, pp. 588-598, 2003).
현재 ACE 저해제에 대한 많은 연구가 진행되고 있으며, 처음 소개된 ACE 저해제로는 터프로티드(Teprotide)가 있었으나 이는 작용시간이 짧고 혈관주사를 해야 한다는 단점이 있었으므로 이에 따라 캡토프릴 (Captopril)과 에날라프릴(Enalapril) 같은 경구적으로 유용한 ACE 저해제가 개발되어 현재 새롭고 강력한 항 고혈압제로서 사용되고 있다.Currently, many studies on ACE inhibitors have been conducted. The first introduced ACE inhibitors were Tereprotide, which had a short duration of action and had to be vascularized. Therefore, Captopril and E Orally useful ACE inhibitors such as Enalapril have been developed and are currently being used as new and powerful antihypertensive agents.
한편, 화학적인 합성을 통한 유도체의 제조뿐만 아니라 식물 유래의 ACE 저해 펩타이드에 대해서도 많은 연구가 진행되어 왔다. 식물 유래의 ACE 저해 펩타이드로는 카제인의 트립신 가수분해물, 돼지혈청에서 얻은 펩타이드, 참치 내장 소화분해물의 펩타이드, 쌀로 만든 식초의 펩타이드, 청주 및 그 부산물 중 잔기 펩타이드 등이 발견되었으며 또한 락토바실러스 헬베티커스 CP790(L. helveticus CP790)의 세포 외 단백질 분해효소를 분리하여 유단백질을 가수분해함으로써 생성되는 펩타이드가 연구되었다. 락토바실러스 헬베티커스 CP790을 이용한 ACE 저해 펩타이드로는 α, s1-카제인 유래 펩타이드로서 Ala-Tyr-Phe-Tyr-Pro-Glu의 아미노산 배열을 갖는 폴리펩타이드, β-카제인 유래 펩타이드로서 Arg-Asp-Met-Pro-Ile-Gln-Aln-Phe의 아미노산 배열을 갖는 폴리펩타이드 등이 발견된 바 있다(홍상필 외, Angiotensin converting enzyme 저해물질과 특성, Food science and Industry, 32(4), 1998). On the other hand, many studies have been conducted on the production of plant-derived ACE inhibitory peptides as well as the preparation of derivatives through chemical synthesis. Plant-derived ACE inhibitory peptides include trypsin hydrolysates of casein, peptides from porcine serum, peptides from digestive digestion of tuna, peptides from vinegar made from rice, residue peptides from sake and by-products, and also Lactobacillus helveticus Peptides produced by hydrolyzing milk proteins by separating extracellular proteases from CP790 (L. helveticus CP790) were studied. ACE inhibitory peptides using Lactobacillus Helveticus CP790 include α, s1-casein-derived peptides with amino acid sequence Ala-Tyr-Phe-Tyr-Pro-Glu, and β-casein-derived peptides Arg-Asp- Polypeptides having an amino acid sequence of Met-Pro-Ile-Gln-Aln-Phe have been found (Hong Sang-pil et al., Angiotensin converting enzyme inhibitors and their properties, Food science and Industry, 32 (4), 1998).
가시오가피 나무(Acanthopanax senticosus) 및 오가피 나무(A. sessiliflorus)는 두릅나무과(Araliaceae)에 속하는 오가피속(Acanthopanax) 식물로 낙엽활엽 관목으로, 키는 3~4cm이고 뿌리 근처에서 가지가 많이 갈라져 사방으로 퍼지며 잎은 호생하고 장상복엽이며 소엽은 3~5개로 난형이다. Acanthopanax senticosus and A. sessiliflorus are Acanthopanax plants belonging to the family Araliaceae. They are deciduous broad-leaved shrubs, 3-4 cm tall, with many branches near the roots. The leaves are regenerated, the mesoderm is 3 ~ 5 lobules, ovate.
오가피속 식물은 동의보감을 비롯한 한약집성방, 신농본초경 및 본초강목에 이르기까지 고전 한의서에 그 약리 효능이 탁월한 것으로 기재되어, 강장제로서 기관지 천식 치료, 육체력 증진, 근골격 증진, 신경통, 당뇨 등의 효과가 알려져 있으며, 최근에 들어서는 혈압강하작용, 간기능 보호작용, 조혈촉진 및 면역기능 증진작용, 혈중 콜레스테롤 저하작용, 항산화작용, 항알러지작용 및 항암작용 등을 가지는 것으로 과학적으로 규명되어, 건강기능성 식품을 포함한 여러 분야에서 관심과 사용이 증가하는 추세에 있다. Ogapi plants have excellent pharmacological effects in traditional Chinese medicine, including Dongbobom, herbal medicine composition room, new agricultural herbaceous and herbal herb, and as a tonic, it is effective in treating bronchial asthma, physical strength, musculoskeletal enhancement, neuralgia, diabetes, etc. Recently, it has been scientifically identified to have a blood pressure lowering action, liver function protection, hematopoietic and immune function enhancement, blood cholesterol lowering action, antioxidant activity, anti-allergic action and anti-cancer action. There is an increasing trend of interest and use in many areas, including.
그 중 오가피 열매(오가자)는 오가피나무속 식물의 열매를 일컫는 말로, 오가피 열매는 간보호 작용, 학습력 향상, 면역력 증강, 항암 작용, 콜레스테롤 저하, 위궤양 치료 효과가 있는 것으로 알려져 있다.Among them, Ogapi fruit (Ogaza) refers to the fruit of the plant of the genus Ogapi, Ogapi fruit is known to have the effect of protecting the liver, improving learning ability, enhancing immunity, anticancer action, lowering cholesterol, treating gastric ulcers.
본 발명자들은 오가피 열매 추출물로부터 신규 화합물을 분리하여 이의 ACE 저해 효과를 확인하고, 본 발명을 완성하였다.The present inventors have isolated the novel compound from the extract of Ogapi fruit to confirm its ACE inhibitory effect, and completed the present invention.
본 발명은 하기 화학식 1로 표시되는 신규 화합물을 제공하는데 목적이 있다.An object of the present invention is to provide a novel compound represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000001
Figure PCTKR2019007128-appb-I000001
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 약학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 고혈압 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hypertension disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 식품학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 혈압 강하용 식품 조성물을 제공하는 것이다.Still another object of the present invention is to provide a blood pressure lowering food composition comprising the compound represented by Formula 1 or a food acceptable salt thereof as an active ingredient.
상술한 본 발명의 과제를 해결하기 위하여 본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.In order to solve the above problems of the present invention, the present invention provides a compound represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000002
Figure PCTKR2019007128-appb-I000002
본 발명의 일 실시예에 따르면, 상기 화합물은 오가피 열매 유래일 수 있다.According to an embodiment of the present invention, the compound may be derived from a staghorn fruit.
또한, 본 발명의 일 실시예에 따르면, 상기 화합물은 혈압 질환 예방 또는 치료용일 수 있다.In addition, according to an embodiment of the present invention, the compound may be for preventing or treating blood pressure diseases.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 약학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 고혈압 질환 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for preventing or treating hypertension diseases comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 실시예에 따른 고혈압 질환 예방 또는 치료용 약학적 조성물에 따르면, 상기 화합물은 전체 조성물에 대하여, 0.0001 내지 10 중량%로 포함될 수 있다.According to the pharmaceutical composition for preventing or treating hypertension according to an embodiment of the present invention, the compound may be included in an amount of 0.0001 to 10% by weight based on the total composition.
또한, 본 발명의 일 실시예에 따르면, 상기 화합물은 안지오텐신 전환효소의 작용을 저해하여 혈압 상승을 억제시킬 수 있다.In addition, according to an embodiment of the present invention, the compound may inhibit the action of angiotensin converting enzyme to inhibit the increase in blood pressure.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 식품학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 혈압 강하용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for lowering blood pressure, which comprises the compound represented by Formula 1 or a food acceptable salt thereof as an active ingredient.
본 발명의 일 실시예에 따르면, 상기 화합물 또는 그의 염은 오가피 열매 유래일 수 있다.According to an embodiment of the present invention, the compound or a salt thereof may be derived from a cactus.
또한, 본 발명의 일 실시예에 따르면, 상기 화합물은 안지오텐신 전환효소의 작용을 저해하여 혈압 상승을 억제시킬 수 있다.In addition, according to an embodiment of the present invention, the compound may inhibit the action of angiotensin converting enzyme to inhibit the increase in blood pressure.
또한, 본 발명의 일 실시예에 따르면, 상기 오가피 열매 추출물은 전체 식품 조성물에 대하여, 0.0001 내지 10 중량%로 포함될 수 있다.In addition, according to one embodiment of the present invention, the extracts of the organza fruit may be included in an amount of 0.0001 to 10% by weight based on the total food composition.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조 방법을 제공한다.In another aspect, the present invention provides a method for producing a compound represented by the formula (1).
본 발명의 일 실시예에 따르면, 상기 화합물의 제조 방법은 (1) 오가피 열매에 C1~C6 알코올 및 물을 가하여 추출물을 수득한 후 감압농축하는 단계; (2) 감압농축한 추출물을 물과 C1~C6의 알킬아세테이트로 분배 추출한 후 감압농축하여 1차 분획물을 수득하는 단계; (3) 상기 1차 분획물을 다시 물과 C1~C6 알코올로 분배 추출한 후 감압농축하여 2차 분획물을 수득하는 단계; 및 (4) 상기 2차 분획물에서 상기 화학식 1의 화합물을 분리 정제하는 단계;를 포함한다.According to an embodiment of the present invention, the method for preparing the compound comprises the steps of: (1) concentration of reduced pressure after obtaining the extract by adding C1 to C6 alcohol and water to the fruit of the organ; (2) extracting the concentrated extract under reduced pressure with water and C 1 -C 6 alkyl acetate, and then concentrated under reduced pressure to obtain a primary fraction; (3) partitioning and extracting the primary fractions with water and C1 to C6 alcohols, and then concentrating under reduced pressure to obtain a secondary fraction; And (4) separating and purifying the compound of Formula 1 from the secondary fraction.
상술한 바와 같이, 본 발명의 신규 화합물은 혈압상승을 효과적으로 억제할 수 있기 때문에 고혈압의 예방 및 치료용 약학 조성물 또는 혈압 강하용 식품 조성물로 유용하게 이용될 수 있다.As described above, the novel compounds of the present invention can be effectively used as a pharmaceutical composition for preventing and treating hypertension or a food composition for lowering blood pressure because it can effectively suppress blood pressure rise.
도 1은 본 발명의 일 실시예에 따른 신규 화합물의 Proton NMR 데이터이다.1 is Proton NMR data of a novel compound according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따른 신규 화합물의 Carbon NMR 데이터이다.2 is Carbon NMR data of a novel compound according to an embodiment of the present invention.
도 3은 본 발명의 일 실시예에 따른 신규 화합물의 Carbon-DEPT NMR 데이터이다.3 is Carbon-DEPT NMR data of a novel compound according to an embodiment of the present invention.
도 4는 본 발명의 일 실시예에 따른 신규 화합물의 2D-HMBC NMR 데이터이다.4 is 2D-HMBC NMR data of a novel compound according to an embodiment of the present invention.
도 5는 본 발명의 일 실시예에 따른 신규 화합물의 UPLC-TOF NMR 데이터이다.5 is UPLC-TOF NMR data of a novel compound according to an embodiment of the present invention.
도 6은 본 발명의 일 실시예에 따른 신규 화합물의 UPLC-TOF NMR 데이터이다.6 is UPLC-TOF NMR data of a novel compound according to an embodiment of the present invention.
도 7은 본 발명의 일 실시예에 따른 신규 화합물의 ACE 억제 활성 결과를 나타낸 그래프이다.7 is a graph showing the results of ACE inhibitory activity of the novel compounds according to an embodiment of the present invention.
이하, 첨부한 도면을 참고로 하여 본 발명의 실시예에 대하여 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 상세히 설명한다. 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.
본 발명자들은 오가피 열매 추출물로부터 분리된 신규 화합물의 ACE 저해 효과를 확인하고, 본 발명을 완성하였다  The present inventors confirmed the ACE inhibitory effect of the novel compound isolated from the extract of Ogapi fruit, and completed the present invention.
본 발명의 “오가피”는 오가피, 오가, 오가목 등의 이명을 가지며, “오가피 열매”는 오가자라고 불리기도 한다. 본원 발명에서 사용되는 오가피는 오가피속에 속하는 것을 모두 이르는 말이다."Ogapi" of the present invention has a nickname such as Ogapi, Oga, Ogamu, etc., "Ogapi fruit" is also called Ogaza. Ogapi used in the present invention refers to all belonging to the genus Ogapi.
바람직하게 본 발명의 오가피는 가시오가피, 서울오가피, 섬오가피나무, 오가피나무, 지리산 오가피 및 향갈피로 이루어지는 군에서 선택되는 어느 하나 이상일 수 있으며, 더욱 바람직하게는 가시오가피, 서울오가피, 섬오가피나무, 오가피나무일 수 있으며, 보다 더욱 바람직하게는 가시오가피, 섬오가피나무, 오가피나무일 수 있다.  Preferably the ogapi of the present invention may be any one or more selected from the group consisting of thorn ogapi, Seoul ogapi, island ogapi, ogapi, Jirisan ogapi and incense galpi, more preferably thorn ogapi, Seoul ogapi, island ogapi, ogapi It may be a tree, and even more preferably may be thorny oak, island oak, or oak.
가시오가피는 Eleutherococcus senticosus (Rupr. & Maxim.)Maxim., Acanthopanax senticosus(Rupr.&Maxim.) Harms. 또는 Acanthopanax senticosus for. inermis.의 학명으로 나타낼 수 있고, 서울오가피는 Eleutherococcus seoulensis 또는 Acanthopanax seoulense Nakai로 나타낼 수 있으며, 섬오가피나무는 Eleutherococcus gracilistylus (W.W.Sm.) S.Y.Hu 또는 Acanthopanax koreanum Nakai로 나타낼 수 있다. 또한 오가피나무는 Eleutherococcus sessiliflorus (Rupr. et Maxim.) S. Y. Hu 또는 Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem.로 나타낼 수 있으며, 지리산오가피는 Eleutherococcus divaricatus var. chiisanensis (Nakai) C.H.Kim & B.Y.Sun 또는 Acanthopanax chiisanensis Nakai로 나타낼 수 있고, 향가피는 Periploca sepium Bunge의 학명으로 나타낼 수 있다. Prickly Pear Eleutherococcus senticosus (Rupr. & Maxim.) Maxim., Acanthopanax senticosus (Rupr. & Maxim.) Harms. Or Acanthopanax senticosus for. It can be represented by the scientific name of inermis., Seoul Ogapi can be represented by Eleutherococcus seoulensis or Acanthopanax seoulense Nakai, and island ogapi can be represented by Eleutherococcus gracilistylus (WWSm.) SYHu or Acanthopanax koreanum Nakai. Also, Ogapi can be represented as Eleutherococcus sessiliflorus (Rupr. Et Maxim.) SY Hu or Acanthopanax sessiliflorus (Rupr. Et Maxim.) Seem . chiisanensis (Nakai) CHKim & BYSun or Acanthopanax chiisanensis Nakai. Perfume can be represented by the scientific name of Periploca sepium Bunge.
본 발명의 “혈압 강하” 는 혈압이 정상 혈압범위(80mmHg 내지 120mmHg)를 초과하는 대상에 대하여 혈압을 정상 혈압 범위로 낮춘다는 의미로 사용된다.The "blood pressure drop" of the present invention is used to mean that the blood pressure is lowered to the normal blood pressure range for a subject whose blood pressure exceeds the normal blood pressure range (80 mmHg to 120 mmHg).
본 발명의 “안지오텐신 전환효소”는 레닌의 도움으로 안지오텐신을 안지오텐시노겐으로 전환하는 효소로 혈관을 수축시키고, 혈압을 상승시키는 작용을 한다."Angiotensin converting enzyme" of the present invention is an enzyme that converts angiotensin to angiotensinogen with the help of Lenin, which constricts blood vessels and raises blood pressure.
본 발명은 하기 화학식 1로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000003
Figure PCTKR2019007128-appb-I000003
본 발명의 일 실시예에 따르면, 상기 화학식 1로 표시되는 화합물은 오가피 열매에서 유래된 것일 수 있으며, 고혈압 질환 예방 또는 치료용으로 사용될 수 있다.According to an embodiment of the present invention, the compound represented by Chemical Formula 1 may be derived from agapi fruit, and may be used for preventing or treating hypertension diseases.
다음으로, 본 발명에 따른 상기 화학식1로 표시되는 화합물의 제조 방법을 설명한다. Next, a method for preparing the compound represented by Chemical Formula 1 according to the present invention will be described.
본 발명의 일 실시예에 따르면, 상기 화합물의 제조 방법은 (1) 오가피 열매에 C1~C6 알코올 및 물을 가하여 추출물을 수득한 후 감압농축하는 단계; (2) 감압농축한 추출물을 물과 C1~C6의 알킬아세테이트로 분배 추출한 후 감압농축하여 1차 분획물을 수득하는 단계; (3) 상기 1차 분획물을 다시 물과 C1~C6 알코올로 분배 추출한 후 감압농축하여 2차 분획물을 수득하는 단계; 및 (4) 상기 2차 분획물에서 하기 화학식 1의 화합물을 분리 정제하는 단계;를 포함할 수 있다.According to an embodiment of the present invention, the method for preparing the compound comprises the steps of: (1) concentration of reduced pressure after obtaining the extract by adding C1 to C6 alcohol and water to the fruit of the organ; (2) extracting the concentrated extract under reduced pressure with water and C 1 -C 6 alkyl acetate, and then concentrated under reduced pressure to obtain a primary fraction; (3) partitioning and extracting the primary fractions with water and C1 to C6 alcohols, and then concentrating under reduced pressure to obtain a secondary fraction; And (4) separating and purifying the compound of Formula 1 from the secondary fraction.
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000004
Figure PCTKR2019007128-appb-I000004
구체적으로, 상기 (3) 단계의 1차 분획물은 알킬아세테이트 분획물과 물 분획물을 포함하며, 본 발명의 신규 화합물은 상기 물 분획물에 포함되어 있을 수 있다. 따라서, 본 발명의 신규 화합물은 상기 (3)단계를 통해 수득된 2차 분획물, 바람직하게는 물 분획물을 분리 정제하여 수득 될 수 있다. Specifically, the primary fraction of step (3) includes an alkyl acetate fraction and a water fraction, the novel compound of the present invention may be included in the water fraction. Therefore, the novel compounds of the present invention can be obtained by separating and purifying secondary fractions, preferably water fractions, obtained through step (3).
상기 추출물을 수득하는 방법으로는 통상적으로 천연물에서 추출물을 수득하는 방법이라면 특별히 제한되지 않으나, 바람직하게는 초음파 추출법, 여과법 또는 환류 추출법을 사용할 수 있다.The method of obtaining the extract is not particularly limited as long as it is a method of obtaining an extract from natural products, but preferably, ultrasonic extraction, filtration or reflux extraction may be used.
또한, 상기 감압농축은 진공감압농축기 또는 진공회전증발기를 이용하여 수행될 수 있으나, 이에 한정되지는 않는다.In addition, the decompression concentration may be performed using a vacuum decompression concentrator or a vacuum rotary evaporator, but is not limited thereto.
또한, 상기 C1~C6 알코올은 통상적으로 천연물 추출에 사용될 수 있는 C1~C6 알코올을 사용할 수 있으나, 바람직하게는 메탄올, 에탄올 또는 n-부탄올일 수 있다.In addition, the C1 ~ C6 alcohol may be used C1 ~ C6 alcohol that can be used for the extraction of natural products, preferably, may be methanol, ethanol or n-butanol.
또한, 상기 2차 분획물을 분리 정제하는 방법은 통상적으로 천연물 분리에 사용되는 방법을 사용할 수 있으며, 바람직하게는 크로마토그래피법을 사용할 수 있다.In addition, the method of separating and purifying the secondary fraction may be generally used a method used for natural product separation, preferably chromatographic methods can be used.
또한, 본 발명은 하기 화학식 1로 표시되는 또는 약학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 고혈압 질환 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition for preventing or treating hypertension diseases, including a salt represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000005
Figure PCTKR2019007128-appb-I000005
또한, 본 발명에 따른 신규 화합물 및 이를 포함하는 오가피 열매 추출물은 독성 및 부작용 등의 문제가 없다.In addition, the novel compound according to the present invention and Ogapi fruit extract comprising the same, there is no problem such as toxicity and side effects.
상기 신규 화합물은 안지오텐신 전환효소를 저해하여 혈압을 안정시키는 것을 특징으로 한다. 본 발명의 오가피 열매 추출물은 ACE(안지오텐신 전환효소)를 저해함으로써 안지오텐신 전환효소의 작용으로 발생하는 혈압상승을 효과적으로 억제하여 혈압 강하 또는 고혈압의 치료 효과가 있음을 확인하였다. 도7에 나타난 바와 같이, 10 μM 에날라프릴의 ACE 저해능은 약 52%였지만, 100 μM 신규 화합물의 ACE 저해능은 약 23%로 에날라프릴 대비 약 44%의 ACE 저해능을 보인다는 것을 확인하였다.The novel compounds are characterized by stabilizing blood pressure by inhibiting angiotensin converting enzyme. Ogapi fruit extract of the present invention by inhibiting ACE (Angiotensin converting enzyme) by effectively inhibiting the increase in blood pressure caused by the action of angiotensin converting enzyme was confirmed that there is a therapeutic effect of lowering blood pressure or hypertension. As shown in FIG. 7, the ACE inhibition of 10 μM enalapril was about 52%, but the ACE inhibition of 100 μM novel compound was about 23%, showing that the ACE inhibitory activity was about 44% compared to enalapril.
상기 혈압 강하 효과를 통해 본 발명의 오가피 열매 추출물은 고혈압 또는 고혈압 합병증을 치료 또는 예방할 수 있으며, 상기 고혈압 합병증으로는 관상 동맥 질환, 뇌혈관 질환, 신장 기능장애, 심부전증 및 시력 장애일 수 있다.Ogapi fruit extract of the present invention through the blood pressure lowering effect can treat or prevent hypertension or hypertension complications, and the hypertension complications can be coronary artery disease, cerebrovascular disease, kidney dysfunction, heart failure and vision disorders.
본 발명의 일 실시예에 따른 화합물은 전체 조성물 100중량부에 대하여, 0.0001 내지 10 중량부로 포함하는 것을 특징으로 한다. 바람직하게는 0.001 내지 7 중량% 더욱 바람직하게는 0.01 내지 3 중량%로 포함하는 것을 특징으로 한다.Compound according to an embodiment of the present invention is characterized in that it comprises 0.0001 to 10 parts by weight, based on 100 parts by weight of the total composition. Preferably it is characterized in that it comprises 0.001 to 7% by weight more preferably 0.01 to 3% by weight.
다음으로, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 식품학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 혈압 강하용 식품 조성물을 제공한다. Next, the present invention provides a food pressure lowering food composition comprising a compound represented by the following formula (1) or a food acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000006
Figure PCTKR2019007128-appb-I000006
상기 화학식 1로 표시되는 화합물 또는 식품학적으로 허용 가능한 그의 염을 유효성분으로 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 분말, 과립, 정제, 캡슐, 시럽제, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다. 또한, 고혈압 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. Examples of the food to which the compound represented by Formula 1 or a food acceptable salt thereof may be added as an active ingredient include, for example, various foods, powders, granules, tablets, capsules, syrups, beverages, gums, teas, Vitamin complexes and health foods. It may also be added to foods or beverages for the purpose of preventing hypertension.
이 때, 식품 또는 음료 중의 상기 화합물 또는 그의 염의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.At this time, the amount of the compound or salt thereof in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, the health beverage composition is added at a ratio of 0.02 to 5g, preferably 0.3 to 1g based on 100ml Can be.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물 또는 그의 염을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound or a salt thereof as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Can be. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 화합물 또는 그의 염은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 화합물 또는 그의 염은 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 추출물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the compounds of the present invention or salts thereof include various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compounds of the present invention or salts thereof may contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is usually selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the extract of the present invention.
본 발명에 따른 화합물 또는 그의 염을 포함하는 약학조성물은, 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. 추출물을 포함하는 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, 메틸히드록시 벤조에이트, 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 상기 화합물 또는 그의 염에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 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(propylene glycol), 폴리에틸렌 글리콜, 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. A pharmaceutical composition comprising a compound according to the present invention or a salt thereof may be in oral dosage forms, external preparations, suppositories, and sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. Formulated in the form of can be used. Carriers, excipients and diluents that may be included in the composition comprising the extract 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, methyl hydroxy benzoate, propyl hydroxy benzoate, 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 form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. Prepared by mixing sucrose or lactose, gelatin and the like. 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 화합물 또는 그의 염의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물 또는 그의 염은 1일 0.0001 내지 100mg/kg으로, 바람직하게는 0.001 내지 100mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Preferred dosages of the compounds of the present invention or salts thereof depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention or salt thereof is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 100 mg / kg. 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 화합물 또는 그의 염은 쥐, 생쥐, 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(intracerebroventricular) 주사에 의해 투여될 수 있다.The compounds of the present invention or salts thereof can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
또한, 본 발명은 상기 화합물을 함유하는 오가피 열매, 이의 분쇄물, 이의 가공물, 또는 이들의 추출물을 포함하는 것으로 해석해야 됨이 마땅하다.In addition, the present invention should be construed as including the organza fruit, the pulverized product thereof, the processed product thereof, or the extract thereof containing the compound.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
(실시예 1)(Example 1)
1) 오가피 열매의 준비1) Preparation of Ogapi Fruit
오가피(Acanthopanax sessilifloruss) 열매는 2015년 10월 정선군 농업기술센터내 정선명주로부터 제공받았으며, 우석 대학교 약학과 김대근 교수님 및 경희대학교 약학과 육창수 명예교수님 으로부터 확인되었다. 오가피 열매 표본(NIHHS15-13)은 농촌진흥청 국립원예특작과학원 인삼특작부에 보관되어 있다.The fruit of Acanthopanax sessilifloruss was provided by Jeong, Seong-Myung-ju in ChungSeon-Gun Agricultural Technology Center in October 2015, and was confirmed by Professor Kim Dae-Geun of Woosuk University and Emeritus Professor Yuk Chang-Soo of KyungHee University. Ogapi fruit specimens (NIHHS15-13) are stored in the Ginseng Specialty Division, National Institute of Horticultural & Herbal Science, Rural Development Administration.
2) 오가피 열매 추출물의 준비2) Preparation of Ogapi Fruit Extract
공기 중에 건조된 오가피 열매 10kg을 분말화 하고, 70% 에탄올 수용액 36L와 혼합하여 24시간동안 상온에서 추출하였다. 추출물을 여과하고, 남은 것을 동일한 방법으로 2회 더 추출하였다.10 kg of dried dried orange fruit in air was powdered and mixed with 36 L of 70% ethanol aqueous solution and extracted at room temperature for 24 hours. The extract was filtered and the remaining one was extracted twice more in the same way.
3) 오가피 열매 추출물로부터 신규 화합물 분리3) Separation of Novel Compounds from the Extracts of Ogapi Fruit
실시예 1-2에서 얻은 오가피 추출물로부터 n-부탄올(2.8L)와 물(3L)을 이용하여 용매분획을 실시하였으며, 분획을 농축한 후 n-부탄올 분획물(ASB) 100g을 얻었다. 얻어진 ASB 100g을 실리카겔 컬럼 크로마토그래피 (내경 10 × 20 cm, 용출용매 CHCl3와 MeOH 및 H2O 의 비율 9:3:1로 실시)를 실시하였고, 각 분취액(200 ml)을 박층 크로마토그래피(thin layer chromatography, TLC)로 확인하여 10개의 분획물(ASB-1 ~ ASB-10)을 얻었다. 그 중, APE-3 분획물 5g 에 대하여 실리카겔 컬럼 크로마토 그래피(내경 4 × 12 cm, CHCl3, MeOH와 H20의 9:3:1 비율로 실시)를 실시하여 10개의 분획물(ASB-3-1 ~ ASB-3-10)로 나누었고, ASB-3-5 분획물 1g에 대해 옥타데실 실리카겔 컬럼 크로마토 그래피(octadecyl column chromatograph(ODS c.c), 내경 4 × 10 cm, MeOH와 H2O의 3:1 비율로 실시)를 실시하여 15개의 분획물(ASB-3-5-1 ~ ASB-3-3-15)을 얻었으며, 이 중에서 ASB-3-5-10 분획물 100mg에 대해 ODS c.c 및 MeOH와 H2O의 5:1비율로 실시)를 실시하여 신규화합물 40mg을 수득하였다.Solvent fractionation was carried out using n-butanol (2.8 L) and water (3 L) from the extracts obtained from Example 1-2, and the fractions were concentrated to obtain 100 g of n-butanol fraction (ASB). 100 g of the obtained ASB was subjected to silica gel column chromatography (inner diameter 10 x 20 cm, elution ratio of CHCl 3 to MeOH and H 2 O, 9: 3: 1), and each aliquot (200 ml) was subjected to thin layer chromatography (thin). 10 fractions (ASB-1 to ASB-10) were obtained by layer chromatography (TLC). Among them, 5 g of APE-3 fractions were subjected to silica gel column chromatography (inner diameter 4 × 12 cm, performed at a 9: 3: 1 ratio of CHCl 3, MeOH and H 2 O) to 10 fractions (ASB-3- 1 ~ ASB-3-10), and octadecyl column chromatograph (ODS cc), inner diameter 4 × 10 cm, and 3: 1 of MeOH and H 2 O for 1 g of ASB-3-5 fraction. 15 fractions (ASB-3-5-1 to ASB-3-3-15) were obtained, and among them, 100 mg of ASB-3-5-10 fraction was used for ODS cc and MeOH and H. 2 O at a 5: 1 ratio to give 40 mg of a novel compound.
(실시예 2) 안지오텐신 전환효소(ACE) 저해 활성 평가Example 2 Evaluation of Angiotensin Converting Enzyme (ACE) Inhibitory Activity
ACE 저해 활성 평가는 공지된 방법(lee et al., statistics and data anlysis method, hyoil press(1998), 253-296)을 사용하여 분석하였다. 시료 50 ㎕ 와 100 ㎕ Hip-His-Leu(시그마, A3-P4DQ11, USA)를 0.4M NaCl 포함하는 0.2M 보릭 버퍼(pH8.3)와 0.05M 나트륨 보레이트 버퍼에 용해시키고, 37℃에서 1시간 동안 ACE 150 ㎕와 함께 배양하였다. 반응물을 실온에서 5분간 방치한 후, 250 ㎕의 1N HCL을 첨가하여 반응을 종료시켰다. Evaluation of ACE inhibitory activity was analyzed using known methods (lee et al., Statistics and data anlysis method, hyoil press (1998), 253-296). 50 μl and 100 μl Hip-His-Leu (Sigma, A3-P4DQ11, USA) were dissolved in 0.2 M boric buffer (pH8.3) and 0.05 M sodium borate buffer containing 0.4 M NaCl, for 1 hour at 37 ° C. Incubated with 150 μl of ACE. The reaction was left at room temperature for 5 minutes and then 250 μl of 1N HCL was added to terminate the reaction.
수득된 히퓨릭 산(hippuric acid)은 1.5 ㎕ 에틸 아세테이트를 첨가하여 추출하였다. 3000 rpm에서 10분간 원심분리를 한 후, 상층 1 ㎕를 유리 튜브로 옮겨 120 ℃에서 30분 동안 건조시켰다. 그리고 20분간 데시케이터(desiccators)에서 냉각시켰다. 건조된 샘플에 증류수 3 ㎕를 첨가한 후, 골고루 30초간 교반하였다. 흡광도는 228nm에서 분광 광도계(UV-1650PC, Shimadzu, Kyoto, Japan)를 사용하였다. 본 실시예에서 사용된 ACE는 1g 토끼 폐 아세톤 분말(Sigma, L0756, USA)로부터 0.4M NaCl 10 ㎕를 포함하는 0.2M 보릭 버퍼(pH 8.3)와 0.05M 나트륨 보레이트 버퍼를 4 ℃에서 하룻동안 처리하고, 원심분리(4000rpm, 1h)하여 추출하였다. 아스피린은 본 실시예 3에서 양성 대조군으로 사용되었으며, ACE 억제능은 하기 계산식 1을 통해 계산되었다.The obtained hypuric acid was extracted by adding 1.5 μl ethyl acetate. After centrifugation at 3000 rpm for 10 minutes, 1 μl of the upper layer was transferred to a glass tube and dried at 120 ° C. for 30 minutes. It was then cooled in desiccators for 20 minutes. 3 μl of distilled water was added to the dried sample, followed by stirring for 30 seconds. The absorbance was used at 228 nm spectrophotometer (UV-1650PC, Shimadzu, Kyoto, Japan). The ACE used in this example was treated with 0.2 M boric buffer (pH 8.3) and 0.05 M sodium borate buffer containing 1 .mu.L of 0.4 M NaCl from 1 g rabbit lung acetone powder (Sigma, L0756, USA) at 4 ° C. for one day. The mixture was extracted by centrifugation (4000 rpm, 1 h). Aspirin was used as a positive control in Example 3, ACE inhibitory ability was calculated through the following formula 1.
[계산식 1][Calculation 1]
Figure PCTKR2019007128-appb-I000007
Figure PCTKR2019007128-appb-I000007
*Sa: 샘플 흡광도, Sb: 샘플 blank 흡광도, Ca: 대조군 흡광도, Cb: 대조군 blank 흡광도* Sa: sample absorbance, Sb: sample blank absorbance, Ca: control absorbance, Cb: control blank absorbance
실시예 2에서 보고된 상기 값은 3회 실험된 실험값의 평균을 기재한 것이며, 데이터는 ANOVA와 Duncan의 다중 범위 시험으로 분석하였다. 통계적으로 P<0.05일 때 통계적 유의성을 갖는 것으로 해석하였다.The values reported in Example 2 describe the average of three experimental values, and the data were analyzed by ANOVA and Duncan's multi-range test. Statistically, it was interpreted as having statistical significance when P <0.05.
본 실시예에서 사용된 메톡시세실리오사이드 I의 농도는 각각 10, 50 및 100 μM이었으며, 도 7에 나타난 바와 같이, 10 μM 에날라프릴과 100 μM 신규 화합물 각각의 ACE 저해능은 51.69±1.13% 및 22.87±0.34%로 측정되었다. 10 μM 에날라프릴 대비 약 44%의 효능을 나타내었다. 그 외에도 오가피 열매 추출물 10 및 50 μM에서 각각 17.22±0.25% 및 18.21±0.78%의 ACE 저해능을 보였다. The concentrations of methoxycecilioside I used in this example were 10, 50 and 100 μM, respectively, and as shown in FIG. 7, the ACE inhibitory activity of each of the 10 μM enalapril and 100 μM novel compounds was 51.69 ± 1.13%. And 22.87 ± 0.34%. It showed about 44% efficacy over 10 μM enalapril. In addition, 10 and 50 μM of Ogapi fruit extract showed 17.22 ± 0.25% and 18.21 ± 0.78% of ACE inhibitory activity, respectively.
결과적으로, 오가피 열매 추출물로부터 ACE 저해 활성을 가지는 신규 화합물을 분리해 내었으며, ACE 저해 활성을 통해 혈압 안정 효과를 얻을 수 있다. As a result, a novel compound having ACE inhibitory activity was isolated from the extract of Ogapi fruit, and blood pressure stabilizing effect can be obtained through ACE inhibitory activity.
(실시예 3) 화합물의 구조 분석Example 3 Structure Analysis of a Compound
실시예 1에서 수득된 화합물의 구조를 분석하였다. The structure of the compound obtained in Example 1 was analyzed.
NMR(Nuclear Magnetic Resonance)은 400 MHz FT-NMR 스펙트로미터(Varian Inova AS 400, Palo Alto, CA)로 측정하였고, 질량값은 Waters ACQUITY UPLCTM system (Waters Corp., MA, USA)을 사용하여 측정함으로써 구조 분석을 실시하였다.NMR (Nuclear Magnetic Resonance) was measured with a 400 MHz FT-NMR spectrometer (Varian Inova AS 400, Palo Alto, Calif.), And the mass value was measured using a Waters ACQUITY UPLC ™ system (Waters Corp., MA, USA). Thus, structural analysis was performed.
상기 구조 분석을 통해 실시예 1을 통해 수득된 화합물은 하기 화학식 1의 화학구조를 갖는다고 결정하였다.The compound obtained through Example 1 through the structural analysis was determined to have a chemical structure of the formula (1).
[화학식 1][Formula 1]
Figure PCTKR2019007128-appb-I000008
Figure PCTKR2019007128-appb-I000008
실시예 1-3에서 분리된 신규화합물에 대해 빠른 Q-TOF Micro mass detector (Waters, Manchester, UK)를 사용해 네거티브 (negative)모드에서 m/z 939.49322 [M-H]-가 관측됨에 따라 분자량은 940[M]+로 결정하였다. 탄소 NMR 스펙트럼에서 총 49개의 시그널이 관측됨에 따라, 트리테르펜(triterpene) 구조의 당 세 분자가 결합하고 다른 그룹의 탄소분자가 결합되어 있음을 예상하였다. 저자장 영역에서 2개의 카르보닐기[δ 174.9(C-3), 176.9(C-28)] 및 2개의 이소프로페닐기[148.1(C-4), 150.8(C-20), 110.1(C-29), 113.6(C-23), 23.7(C-24), 19.4(C-30)]가 관측됨에 따라, 2개의 이소프로페닐기가 결합된 세코-루판-트리레트펜(seco-lupane-triterpene)의 골격을 확인하였다. 고자장 영역에서 5개의 메틴 카본(methine carbon)이 관측되었다. 당의 아노머 카본(anomer carbon)은 전형적인 차시노사이드에 결합되어 있는 당 3분자의 시그널을 확인하였다 [28-O-Glc(inner): δ 95.2, 28-O-Glc(outer): δ 105.0 및 4-O-Rha: δ102.6]. 또한 글루코피라노오스 두분자 및 람노즈의 결합 부위를 확인하기 위하여 gHMBC 스펙트럼을 토대로, 각각의 아노머 프로톤과 산소가 치환된 탄소 시그널과의 연결고리를 보여줌으로써 결합부위를 확인하였다. 당의 아노머 프로톤 시그널[δ 6.34, d, J=8.2 Hz (H-1')]이 카르보닐 카본[δ 176.9 (C-28)]에 연결됨에 따라, C-28번에 β-결합되었음을 확인하였고, 더욱이 아노머 카본[δ 95.2 (C-1')]이 고자장으로 약 5 ppm 정도 이동함을 확인할 수 있었다. 또한, 카르보닐 카본[δ 174.9 (C-3)]이 메틸렌 프로톤 시그널들과의 연결고리가 확인됨에 따라 트리테르펜의 A-링(A-ring)이 개환되어 있는 것을 확인하였다. 또한 새롭게 생성된 시그널인 메톡시(OCH3) 그룹 및 세코-루판-트리레트펜 골격의 결합 부위를 확인하기 위하여 gHMBC 스펙트럼을 토대로, 메톡시 프로톤(δ3.61 ppm)과 카르보닐기[δ174.9(C-3)] 시그널과의 연결고리를 보여줌으로써 최종 결합부위를 확인하였다. 위 결과를 종합하여 구조 동정한 결과, 상기 화학식 1로 표시되는 화합물 1은 세코-루판 트리테르펜(seco-lupane triterpene)인, (3,4-seco-4(23),20,(29)-lupadiene-3,28-dioic acid 3-methyl ester 28-O-a-L-rhamnopyranosyl(1→4)-b-D-glucopyranosyl(1→6)-b-D-glucopyranoside로 결정하였고, 메톡시세실로사이드 I(Methoxysessiloside I)로 명명하였으며, 신규 화합물임을 확인하였다.The molecular weight was 940 [m] as m / z 939.49322 [MH]-was observed in negative mode using a fast Q-TOF Micro mass detector (Waters, Manchester, UK) for the novel compounds isolated in Examples 1-3. M] + was determined. As a total of 49 signals were observed in the carbon NMR spectrum, it was expected that three molecules of the triterpene structure were bonded and another group of carbon molecules were bound. Two carbonyl groups [δ 174.9 (C-3), 176.9 (C-28)] and two isopropenyl groups [148.1 (C-4), 150.8 (C-20), 110.1 (C-29) , 113.6 (C-23), 23.7 (C-24), and 19.4 (C-30)] were observed, as compared to the seco-lupane-triterpene of two isopropenyl groups. The skeleton was confirmed. Five methine carbons were observed in the high magnetic field. The anomer carbon of the sugar confirmed the signal of the sugar trimolecule bound to the typical chacinoside [28-O-Glc (inner): δ 95.2, 28-O-Glc (outer): δ 105.0 and 4-O-Rha: δ 102.6]. In addition, the binding sites were identified by showing the linkages between the respective anomer protons and the oxygen-substituted carbon signals based on the gHMBC spectrum to identify the binding sites of the two molecules of glucopyranose and rhamnose. Confirmation of β-bonding at C-28 as the sugar anomer proton signal [δ 6.34, d, J = 8.2 Hz (H-1 ′)] was linked to carbonyl carbon [δ 176.9 (C-28)] In addition, it was confirmed that the anomer carbon [δ 95.2 (C-1 ′)] moved about 5 ppm to the high magnetic field. In addition, as the carbonyl carbon [δ 174.9 (C-3)] was identified as a link to the methylene proton signals, it was confirmed that the A-ring of the triterpene was opened. In addition, the methoxy protons (δ3.61 ppm) and the carbonyl group [δ174.9 (C) were determined based on the gHMBC spectrum to identify the binding sites of the newly generated signals, the methoxy (OCH3) group and the seco-lupan-triretpene skeleton. -3)] The final binding site was confirmed by showing the link with the signal. As a result of the structural identification by combining the above results, Compound 1 represented by Chemical Formula 1 is seco-lupane triterpene, (3,4-seco-4 (23), 20, (29)- lupadiene-3,28-dioic acid 3-methyl ester 28-OaL-rhamnopyranosyl (1 → 4) -bD-glucopyranosyl (1 → 6) -bD-glucopyranoside was determined and named Methoxysessiloside I It was confirmed that it is a new compound.
(비교예 1)(Comparative Example 1)
상기 실시예 1에서 얻어진 오가피 열매 물 분획물에 대하여 실시예 1-3과 동일하게 실시하여 물 분획물을 분리하고 정제하였다. 그 결과 상기 신규화합물이 검출되지 않았다.The Ogapi fruit water fraction obtained in Example 1 was subjected to the same procedure as in Example 1-3 to separate and purify the water fraction. As a result, the new compound was not detected.
본 발명에 따른 화합물(메톡시세실로사이드 I)을 포함하는 약학 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Examples of the preparation of a pharmaceutical composition comprising a compound according to the present invention (methoxy ceciloside I) will be described, but the present invention is not intended to be limiting but merely illustrative.
제제예 1. 산제의 제조Formulation Example 1 Preparation of Powder
메톡시세실로사이드 I 20 mgMethoxyceciloside I 20 mg
유당 100 mg Lactose 100 mg
탈크 10 mg Talc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
메톡시세실로사이드 I 10 mgMethoxyceciloside I 10 mg
옥수수전분 100 mg Corn starch 100 mg
유당 100 mg Lactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조Formulation Example 3 Preparation of Capsule
메톡시세실로사이드 I 10 mgMethoxyceciloside I 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
메톡시세실로사이드 I 10 mgMethoxyceciloside I 10 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4·12H2O 26 mgNa 2 HPO 4 12 H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
메톡시세실로사이드 I 20 mgMethoxyceciloside I 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to the conventional method for preparing a liquid, each component is added and dissolved in purified water, lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. The solution is prepared by sterilization.
제제예 6. 건강 음료의 제조Formulation Example 6 Preparation of Healthy Drink
메톡시세실로사이드 I 100 ㎎ Methoxyceciloside I 100 mg
비타민 C 15 g15 g of vitamin C
비타민 E (분말) 100 g100 g of vitamin E (powder)
젖산철 19.75 gIron lactate 19.75 g
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinamide 3.5 g
비타민 A 0.2 g0.2 g of vitamin A
비타민 B1 0.25 g0.25 g of vitamin B1
비타민 B2 0.3 g0.3 g of vitamin B2
물 적량Water quantity
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강 음료 조성물 제조에 사용한다.After mixing the above components according to a conventional healthy beverage production method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilized and then refrigerated and stored in the present invention For the manufacture of healthy beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

Claims (11)

  1. 하기 화학식 1로 표시되는 화합물:Compound represented by the following formula (1):
    [화학식 1][Formula 1]
    Figure PCTKR2019007128-appb-I000009
    Figure PCTKR2019007128-appb-I000009
  2. 제1항에 있어서, The method of claim 1,
    상기 화합물은 오가피 열매 유래인 화합물.The compound is a compound derived from Ogapi fruit.
  3. 제1항에 있어서, The method of claim 1,
    상기 화합물은 고혈압 질환 예방 또는 치료용인 화합물.The compound is a compound for preventing or treating hypertension disease.
  4. 하기 화학식 1로 표시되는 화합물 또는 약학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 고혈압 질환 예방 또는 치료용 약학적 조성물:A pharmaceutical composition for preventing or treating hypertension diseases comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Formula 1]
    Figure PCTKR2019007128-appb-I000010
    Figure PCTKR2019007128-appb-I000010
  5. 제4항에 있어서,The method of claim 4, wherein
    상기 화합물은 전체 조성물에 대하여, 0.0001 내지 10 중량%로 포함되는 고혈압 질환 예방 또는 치료용 약학적 조성물. The compound is 0.0001 to 10% by weight relative to the total composition of the pharmaceutical composition for preventing or treating hypertension diseases.
  6. 제4항에 있어서,The method of claim 4, wherein
    상기 화합물은 안지오텐신 전환효소의 작용을 저해하여 혈압 상승을 억제시키는 고혈압 질환 예방 또는 치료용 약학적 조성물. The compound is a pharmaceutical composition for preventing or treating hypertension diseases by inhibiting the action of angiotensin converting enzyme to inhibit blood pressure rise.
  7. 하기 화학식 1로 표시되는 화합물 또는 식품학적으로 허용 가능한 그의 염을 유효성분으로 포함하는 혈압 강하용 식품 조성물:A blood pressure lowering food composition comprising the compound represented by Formula 1 or a food acceptable salt thereof as an active ingredient:
    [화학식 1] [Formula 1]
    Figure PCTKR2019007128-appb-I000011
    Figure PCTKR2019007128-appb-I000011
  8. 제7항에 있어서,The method of claim 7, wherein
    상기 화합물 또는 그의 염이 오가피 열매 유래인 혈압 강하용 식품 조성물.A blood pressure lowering food composition wherein the compound or a salt thereof is derived from a staghorn fruit.
  9. 제7항에 있어서,The method of claim 7, wherein
    상기 화합물은 안지오텐신 전환효소의 작용을 저해하여 혈압 상승을 억제시키는 혈압 강하용 식품 조성물.The compound inhibits the action of angiotensin converting enzyme to inhibit blood pressure lowering food composition.
  10. 제7항에 있어서,The method of claim 7, wherein
    상기 오가피 열매 추출물은 전체 식품 조성물에 대하여, 0.0001 내지 10 중량%로 포함되는 혈압 강하용 식품 조성물.The organo fruit extract is a blood pressure lowering food composition comprising 0.0001 to 10% by weight relative to the total food composition.
  11. (1) 오가피 열매에 C1~C6 알코올 및 물을 가하여 추출물을 수득한 후 감압농축하는 단계;(1) adding C1 ~ C6 alcohol and water to the fruit of Ogapi to obtain an extract, and then concentrating under reduced pressure;
    (2) 감압농축한 추출물을 물과 C1~C6의 알킬아세테이트로 분배 추출한 후 감압농축하여 1차 분획물을 수득하는 단계;(2) extracting the concentrated extract under reduced pressure with water and C 1 -C 6 alkyl acetate, and then concentrated under reduced pressure to obtain a primary fraction;
    (3) 상기 1차 분획물을 다시 물과 C1~C6 알코올로 분배 추출한 후 감압농축하여 2차 분획물을 수득하는 단계; 및(3) partitioning and extracting the primary fractions with water and C1 to C6 alcohols, and then concentrating under reduced pressure to obtain a secondary fraction; And
    (4) 상기 2차 분획물에서 하기 화학식 1의 화합물을 분리 정제하는 단계;(4) separating and purifying the compound of Formula 1 from the secondary fraction;
    를 포함하는 하기 화학식 1로 표시되는 화합물의 제조방법:Method for preparing a compound represented by the following formula (1) comprising:
    [화학식 1][Formula 1]
    Figure PCTKR2019007128-appb-I000012
    Figure PCTKR2019007128-appb-I000012
PCT/KR2019/007128 2018-06-14 2019-06-13 Novel compound isolated from acanthopanax sp. fruit extract, and pharmaceutical composition for preventing and treating hypertension, containing same WO2019240508A1 (en)

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