Composition for preventing or treating diabetis comprising extract of Acer ginnala Maxim leaf or compounds isolated therefrom as active ingredients

Abstract

The present invention relates to a composition for treating or preventing diabetes comprising an extract of Acerginnala Maxima leaves or a compound isolated therefrom as an active ingredient. Specifically, it can contribute to public health by providing a composition for the prevention or treatment of diabetes through the PTP1B and / or α-glucosidase inhibitory activity of a compound isolated from Acerginnala Maxima leaves.

Description

Technology Field

[0001] The present invention is a tree ( Acer ginnala The present invention relates to a composition for the prevention or treatment of diabetes comprising a Maxim) leaf extract or a compound isolated therefrom as an active ingredient. Background Technology

[0002] The genus Acer consists of approximately 129 species of trees or shrubs that grow primarily in the temperate regions of East Asia, eastern North America, and Europe. In East Asia (Korea, Japan, and China) and North America, many species of this genus are used not only as urban street trees but also for food, beverages, and traditional medicine. For example, the Korean ash tree ( Acer tegmentosum Maxim) has been used in Korea for the treatment of liver disease and traumatic hemorrhage (Bi et al., 2016), and is a native Japanese plant A. maximowiczianum The stem bark was used to treat eye and liver diseases. In Canada A. saccharum Marshall is used to treat cataracts, coughs, shortness of breath, and eye pain, A. rubrum L. and A. spicatum Lam. was used to relieve eye pain. In addition to this, A. negundo L. and A. pensylvanicum L. is used as an emetic and A. pensylvanicumL. has been used to treat bronchitis, the common cold, cough, gonorrhea, renal dysfunction, and hemoptysis. Additionally, the sap of the maple tree has been used as a syrup suitable for diabetic patients (Park et al., 2017). These efficacy of the maple tree is attributed to the physiological activity of various compounds found within the maple tree, such as flavonoids, tannins, diarylheptanoids, phenylpropanoids, terpenoids, phytosterols, and alkaloids, among which flavonoids, tannins, and phenylpropanoids are known to be the most abundant.

[0003] Meanwhile, the zelkova tree ( Acer ginnalaAcer palmatum is a native Korean plant belonging to the genus Acer, also known as the Amur maple, and is distributed in Japan, China, Russia, and North America. In traditional Korean medicine, Acer palmatum has been used to treat eye diseases, wound healing, and diarrhea. It has been reported to exhibit various pharmacological activities due to the presence of phenylpropanoids, gallotannins, flavonoids, and triterpenoids. In particular, galloyl derivatives, which are the main components of Acer palmatum leaf extract, have been reported to exhibit significant antioxidant effects and anti-inflammatory activities, such as inhibiting the overproduction of nitric oxide in LPS-stimulated RAW264.7 cells (Park et al., 2017). In addition, Quercetin-3-O-2'-galloyl-α-L-rhamnopyranoside, an active galloylized flavonol rhamnoside isolated from the leaf extract of *Sinia japonica*, has been reported to be effective in treating skin diseases by inhibiting the activation of proteins related to apoptosis induced by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in HaCaT cells and inhibiting the production of cytokines and chemokines induced by TNF-α stimulation (Kim et al., 2013).

[0004] Park et al. (2017) showed that the leaf extract of Styrax japonica has a potential antidiabetic effect in a mouse model of streptozotocin-induced diabetes. Accordingly, it is necessary to identify the chemical components in the leaves of Styrax japonica that exhibit antidiabetic activity and to elucidate the mechanism of their antidiabetic activity. Prior art literature

[0005] Korean Registered Patent No. 10-1628180, Antimicrobial composition against Salmonella containing a Styrax japonica extract as an active ingredient, Registered June 1, 2016. Korean Registered Patent No. 10-1262671, Composition for treating atopic dermatitis containing a Styrax japonica leaf extract or a flavonol galloyl glycoside compound isolated therefrom as an active ingredient, Registered April 30, 2013. Korean Published Patent No. 10-2017-0091238, Antioxidant composition containing a complex extract of Acer palmatum, Acer palmatum var. japonica, and Styrax japonica, Registered August 9, 2017. Korean Registered Patent No. 10-1261380, Novel gallotannin compound isolated from Styrax japonica leaves and an antioxidant composition containing the same as an active ingredient, Registered April 30, 2013.

[0006] Bi, W., Gao, Y., Shen, J., He, C., Liu, H., Peng, Y., Zhang, C., Xiao, P., 2016. Traditional uses, phytochemistry, and pharmacology of the genus Acer (maple): A review. J. Ethnopharmacol. 189, 31-60. https: / / doi.org / 10.1016 / j.jep.2016.04.021.Park, K.H., Yoon, K.H., Yin, J., Le, T.T., Ahn, H.S., Yoon, S.H., Lee, M.W., 2017. Antioxidative and anti-inflammatory activities of galloyl derivatives and antidiabetic activities of Acer ginnala. Evid. Based Complement Alternat. Med. https: / / doi.org / 10.1155 / 2017 / 6945912.Park, E.J., Kim, J.-Y., Jeong, M.S., Park, K.Y., Park, K.H., Lee, M.W., Joo, S.S., Seo, S.J., 2015. Effect of topical application of quercetin-3-O-(2"-gallate)-α-L-rhamnopyranoside on atopic dermatitis in NC / Nga mice. J. Dermatol. Sci. 77, 166-172. https: / / doi.org / 10.1016 / j.jdermsci.2014.12.005.Yuan, T., Wan, C., Liu, K., Seeram, N.P., 2012. New maplexins F-I and phenolic glycosides from red maple (Acer rubrum) bark. Tetrahedron 68, 959-964. https: / / doi.org / 10.1016 / j.tet.2011.11.062.Wei, J., Huo, X., Yu, Z., Tian, ​​X., Deng, S., Sun, C., Feng, L., Wang, C., Ma, Fitoterapia 121, 129-135. https: / / doi.org / 10.1016 / j.fitote.2017.07.003.Ha, MT, Lee, TH, Kim, CS, Prajapati, R., Kim, JA, Choi, JS, Min, BS, 2022. PTP1B and α-glucosidase inhibitory activities of the chemical constituents from Hedera rhombea fruits: Kinetic analysis and molecular docking simulation. Phytochemistry 197, 113100. https: / / doi.org / 10.1016 / j.phytochem.2022.113100. The problem to be solved

[0007] The objective of the present invention is to provide a composition for the prevention or treatment of diabetes comprising an extract of Styrax japonica leaves or a compound isolated therefrom as an active ingredient. means of solving the problem

[0008] To solve the above problem, the present invention provides a composition for the prevention or treatment of diabetes comprising an extract of Styrax japonica leaves or a compound isolated therefrom as an active ingredient.

[0009] The above-mentioned Styrax leaf extract is Styrax ( Acer ginnalaMaxim) The leaves of a plant can be extracted with an alcohol having 1 (C1) to 4 (C4) carbon atoms or a mixture thereof, preferably an extract using ethanol, and more preferably a 40% aqueous ethanol solution. The solvent extract may further include a step of filtering the extract to remove suspended solid particles. For example, particles may be filtered using cotton, nylon, etc., or ultrafiltration, cryofiltration, centrifugation, etc. may be used, but are not limited thereto.

[0010] The above extract is n -Hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and n - It can be used by fractionating it into an ethyl acetate fraction by sequentially partitioning it with butanol, and the ethyl acetate fraction has a high inhibitory effect on protein-tyrosine phosphatases 1B (PTP1B) and / or α-glucosidase enzymes, so it can be used for the prevention and treatment of diabetes.

[0011] In one aspect of the present invention, the tree ( Acer ginnala Maxim) Leaf extract is the ethanol extract of Styrax leaves. n -Hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and n - It is an ethyl acetate fraction distributed sequentially with butanol.

[0012] The present invention relates to the above-mentioned tree ( Acer ginnala The compound isolated from the Maxim) leaf extract is Acerglucitol A (Acerglucitol A, represented by the following [Chemical Formula 1], Compound 1 ), Acergallate A (Acergallate A, Compound 2 ), Acergallate B (Acergallate B, Compound 3), Acerglycitol B (Acerglycitol B, Compound 4 ), quercetin(quercetin, Compound 5 ), epi -Catechin( epi -catechin, Compound 6 ), Afgelin 3"- O- gallate (afzelin 3"- O -gallate, Compound 7 ), guaijaverin, Compound 8 ), kaempferol 3- O -α-L-arabinopyranoside(kaempferol 3- O -α-L-arabinopyranoside, Compound 9 ), epi -Catechin gallate( epi -catechin gallate, Compound 10 ), 3'- O -Galloyl catechin(3'- O -galloyl quercitrin, Compound 11 ), 3- O -galloyl-3,3',5,5',7-pentahydroxyflaban(3- O -galloyl-3,3',5,5',7-pentahydroxyflavan, Compound 12 ), Kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside(kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside, Compound 13 ), 1- O -3-1-O-3-hydroxyphenyl-5-methoxyphenol-(6'- O -vanilloyl)-β-D-glucopyranoside(1- O -3-hydroxyphenyl-5-methoxyphenol-(6′- O -vanilloyl)- β -D-glucopyranoside, Compound 14 ), quercitrin(quercitrin, Compound 15 ), quercetin-3-O-(2"-galloyl)-α-L-rhamnopyranoside(quercetin-3-O -(2"-galloyl)- α -L-rhamnopyranoside, Compound 16 ), acertannin (2,6-digalloyl-1,5-anhydroglucitol), Compound 17 ) and acetannin (3,6-digalloyl-1,5-anhydroglucitol), compound 18 A composition for the prevention or inhibition of diabetes is provided, characterized by being one or more selected from the group consisting of ).

[0013] [Chemical Formula 1]

[0014]

[0015] The above-mentioned tree ( Acer ginnala The compound isolated from the Maxim) leaf extract is Acerglucitol A (Acerglucitol A, represented by the above [Chemical Formula 1], Compound 1 ), Acergallate A (Acergallate A, Compound 2 ), Acerglycitol B (Acerglycitol B, Compound 4 ), quercetin(quercetin, Compound 5 ), epi -Catechin( epi -catechin, Compound 6 ), Afgelin 3"- O- gallate (afzelin 3"- O -gallate, Compound 7 ), epi -Catechin gallate( epi -catechin gallate, Compound 10 ), 3'- O -Galloyl catechin(3'- O -galloyl quercitrin, Compound 11 ), 3- O -galloyl-3,3',5,5',7-pentahydroxyflaban(3-O -galloyl-3,3',5,5',7-pentahydroxyflavan, Compound 12 ), Kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside(kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside, Compound 13 ), 1- O -3-1-O-3-hydroxyphenyl-5-methoxyphenol-(6'- O -vanilloyl)-β-D-glucopyranoside(1- O -3-hydroxyphenyl-5-methoxyphenol-(6′- O -vanilloyl)- β -D-glucopyranoside, Compound 14 ) and quercetin-3-O-(2"-galloyl)-α-L-rhamnopyranoside (quercetin-3- O -(2"-galloyl)- α -L-rhamnopyranoside, compound 16 It may be 1 or more selected from a group consisting of ).

[0016] The above-mentioned tree ( Acer ginnala The compound isolated from Maxim) leaf extract is the Styrax ( Acer ginnala Ethanol extract of Maxim) leaves n -Hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and n - The ethyl acetate fractions separated by butanol can be obtained through separation by various chromatographs (designed for separation based on size, charge, hydrophobicity, or affinity).

[0017] The above chromatography can be further purified by using various chromatographs such as silica gel column chromatography, thin layer chromatography, and high performance liquid chromatography, and can be obtained by chemical synthesis or other conventional methods.

[0018] In the present invention, diabetes is a disease caused by the abnormal action of insulin. In the present invention, diabetes includes all types of diabetes, such as Type 1 diabetes or Type 2 diabetes. Preferably, the diabetes prevented or treated by the composition of the present invention is Type 2 diabetes.

[0019] In one aspect of the present invention, the composition for the prevention or treatment of diabetes may be carried out by inhibiting protein-tyrosine phosphatases 1B (PTP1B). Protein-tyrosine phosphatases 1B is responsible for blocking the intracellular function of insulin by dephosphorylating tyrosine residues of phosphorylated insulin receptors and proteins involved in insulin signaling. It is also the most important negative regulator of insulin sensitivity and energy balance, and is a receptor phosphatases that cause the inactivation of the regulation of insulin and leptin receptors. Therefore, PTP1B inhibitors are used as effective drugs for the prevention, treatment, and / or improvement of type 2 diabetes.

[0020] The above-mentioned tree ( Acer ginnala Maxim) isolated from leaf extract Compound 1 , 2 , 4~7 , 10~14 and 16It can demonstrate preventive and therapeutic effects for diabetes by inhibiting PTP1B. Among these Compound 1, 10 and 12 Each can exhibit a non-competitive inhibitory effect on PTP1B.

[0021] In one aspect of the present invention, the composition for the prevention or treatment of diabetes may be carried out by inhibiting α-glucosidase. α-glucosidase is a digestive enzyme that converts polysaccharides and disaccharides into monosaccharides in the small intestine and promotes the absorption of carbohydrates. Therefore, an alpha-glucosidase inhibitor can reduce the range of postprandial hyperglycemia by delaying the absorption of complex carbohydrates through inhibition of this action.

[0022] The above-mentioned tree ( Acer ginnala Maxim) isolated from leaf extract Compound 1 , 2 , 4~7 , 10~14 and 16 It can exhibit preventive and therapeutic effects on diabetes by inhibiting α-glucosidase. Among these, Compounds 1, 7, 11, 13 and 16 Each can exhibit a competitive inhibitory effect on α-glucosidase, and Compound 1, 10 and 12 Each can exhibit a non-competitive inhibitory effect on α-glucosidase. Compound 1 It is a mixed inhibitor capable of exhibiting both competitive and non-competitive inhibitory effects against α-glucosidase.

[0023] The above composition for the prevention or treatment of diabetes is the above-mentioned zelkova ( Acer ginnala A pharmaceutical composition for the prevention or treatment of diabetes mellitus may be provided comprising Maxim) leaves or compounds isolated therefrom and pharmaceutically acceptable excipients.

[0024] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects, taking all of the above-mentioned factors into consideration, and this can be easily determined by a person skilled in the art.

[0025] The effective amount of the component having antidiabetic activity in the pharmaceutical composition of the present invention may vary depending on the patient's age, gender, and body weight, and generally, 1 to 5,000 mg per body weight, preferably 100 to 3,000 mg, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, body weight, age, etc., the above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition of the present invention may be administered to a subject through various routes. Any mode of administration is expected, for example, orally, rectally or intravenously, intramuscularly, subcutaneously, intrathecally, or intracerebroventricularly. In the present invention, "administration" means providing a specific substance to a patient by any appropriate method, and the route of administration of the pharmaceutical composition of the present invention may be oral or parenteral through any general route as long as it can reach the target tissue. Additionally, the composition of the present invention may be administered using any device capable of delivering an active ingredient to a target cell. In the present invention, "target" includes, but is not particularly limited, humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and preferably means mammals, more preferably humans.

[0026] The above-mentioned tree ( Acer ginnala Maxim) leaves or compounds isolated therefrom may be added in an amount preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.001 to 30% by weight, based on the total weight of the pharmaceutical composition.

[0027] The above pharmaceutical composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, liquids, and aerosols, as well as external preparations, suppositories, and sterile injectable solutions, according to conventional methods. Carriers, excipients, and diluents that may be included in the above pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulating, the product is prepared using diluents or excipients such as commonly used fillers, fillers, binders, humectants, disintegrants, surfactants, sweeteners, and acidifiers. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid dosage forms are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, or gelatin, with the extract of the *Sophora japonica* leaf or a compound isolated therefrom according to the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as humectants, sweeteners, flavorings, preservatives, and acidifiers, may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, witepsol, macrogol, tween-61, cacao oil, laurin oil, glycerogelatin, etc. may be used.

[0028] The present invention relates to acerglucitol A (Acerglucitol A, represented by the above [Chemical Formula 1], Compound 1 ), Acergallate A (Acergallate A, Compound 2 ), Acerglycitol B (Acerglycitol B, Compound 4 ), quercetin(quercetin, Compound 5 ), epi -Catechin( epi -catechin, Compound 6 ), Afgelin 3"- O- gallate (afzelin 3"- O -gallate, Compound 7 ), epi -Catechin gallate( epi -catechin gallate, Compound 10 ), 3'- O -Galloyl catechin(3'- O -galloyl quercitrin, Compound 11 ), 3- O -galloyl-3,3',5,5',7-pentahydroxyflaban(3- O -galloyl-3,3',5,5',7-pentahydroxyflavan, Compound 12 ), Kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside(kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside, Compound 13 ), 1- O -3-1-O-3-hydroxyphenyl-5-methoxyphenol-(6'- O -vanilloyl)-β-D-glucopyranoside(1- O -3-hydroxyphenyl-5- methoxyphenol-(6′- O -vanilloyl)- β -D-glucopyranoside, Compound 14 ) and quercetin-3-O-(2"-galloyl)-α-L-rhamnopyranoside (quercetin-3- O -(2"-galloyl)- α -L-rhamnopyranoside, Compound 16 A composition for the prevention or treatment of diabetes is provided, characterized by comprising one or more selected from the group consisting of ). The compound is a Styrax japonica ( Acer ginnala Maxim) can be isolated from leaf extract.

[0029] The present invention is a tree ( Acer ginnala A health functional food for the prevention or improvement of diabetes is provided, comprising Maxim) leaf extract or a compound isolated therefrom as an active ingredient.

[0030] In one aspect of the present invention, the ethanol extract of the leaves of the Styrax japonica tree is used. n -Hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and n - It is an ethyl acetate fraction distributed sequentially with butanol.

[0031] The present invention relates to the above-mentioned tree ( Acer ginnala The compound isolated from the Maxim) leaf extract is Acerglucitol A (Acerglucitol A, represented by the above [Chemical Formula 1], Compound 1 ), Acergallate A (Acergallate A, Compound 2 ), Acergallate B (Acergallate B, Compound 3 ), Acerglycitol B (Acerglycitol B, Compound 4 ), quercetin(quercetin, Compound 5 ), epi -Catechin( epi -catechin, Compound 6 ), Afgelin 3"- O- gallate (afzelin 3"- O -gallate, Compound 7 ), guaijaverin, Compound 8 ), kaempferol 3- O -α-L-arabinopyranoside(kaempferol 3- O-α-L-arabinopyranoside, Compound 9 ), epi -Catechin gallate( epi -catechin gallate, Compound 10 ), 3'- O -Galloyl catechin(3'- O -galloyl quercitrin, Compound 11 ), 3- O -galloyl-3,3',5,5',7-pentahydroxyflaban(3- O -galloyl-3,3',5,5',7-pentahydroxyflavan, Compound 12 ), Kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside(kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside, Compound 13 ), 1- O -3-1-O-3-hydroxyphenyl-5-methoxyphenol-(6'- O -vanilloyl)-β-D-glucopyranoside(1- O -3-hydroxyphenyl-5- methoxyphenol-(6′- O -vanilloyl)-β-D-glucopyranoside, Compound 14 ), quercitrin(quercitrin, Compound 15 ), quercetin-3-O-(2"-galloyl)-α-L-rhamnopyranoside(quercetin-3- O -(2"-galloyl)- α -L-rhamnopyranoside, Compound 16 ), acertannin (2,6-digalloyl-1,5-anhydroglucitol), Compound 17 ) and acetannin (3,6-digalloyl-1,5-anhydroglucitol), compound 18A health functional food for the prevention or improvement of diabetes is provided, characterized by being one or more selected from a group consisting of ).

[0032] The present invention provides a health functional food for the prevention or improvement of diabetes comprising the above-mentioned zelkova leaf extract or a compound isolated therefrom and a food-grade acceptable food additive.

[0033] The above health functional food may be provided with an extract of Styrax japonica leaves or a compound isolated therefrom in an amount preferably 0.001 to 50 weight%, more preferably 0.001 to 30 weight%, and most preferably 0.001 to 10 weight% based on the total weight of the food.

[0034] The above-mentioned health functional food includes forms such as tablets, capsules, pills, or liquids, and foods to which the extract of the present invention can be added include, for example, various types of food, beverages, chewing gum, tea, vitamin complexes, health functional food products, etc.

[0035] The present invention relates to acerglucitol A (Acerglucitol A, represented by the following [Chemical Formula 2], Compound 1 ), Acergallate A (Acergallate A, Compound 2 ), Acergallate B (Acergallate B, Compound 3 ) and acerglycitol B (Acerglycitol B, compound 4 Provides one novel compound selected from the group consisting of ).

[0036] [Chemical Formula 2]

[0037] Effects of the invention

[0038] The present invention is a tree ( Acer ginnalaThe present invention relates to a composition for treating or preventing diabetes containing a leaf extract of Maxim) or a compound isolated therefrom as an active ingredient, and specifically, it can contribute to public health by providing a composition for the prevention or treatment of diabetes through the PTP1B and / or α-glucosidase inhibitory activity of a compound isolated from a leaf extract of the Styrax japonica. Brief explanation of the drawing

[0039] FIG. 1 is a Styrax tree according to the present invention ( Acer ginnala These are the chemical structures of compounds 1 to 18 isolated from Maxim) leaf extract. Figure 2 shows the HMBC, COSY, and HMBC correlations of compounds 1 to 4. Figure 3 shows Δδ for MTPA of compound 2. S -R It represents the value. Figure 4 is a graph showing Dixon plots and Lineweaver-Burk plots for the inhibition of PTP1B enzymes by compounds according to the present invention. Dixon plot (AC) and Lineweaver-Burk plot (DF) for the inhibition of PTP1B enzymes by compounds 1 (A and D), 10 (B and E), and 12 (C and F). [I] and [S] represent the inhibitor (μM) and substrate, respectively. p - Represents NPP(mM). FIGS. 5a–5c are graphs showing Dixon plots and Lineweaver-Burk plots for the inhibition of α-glucosidase enzymes by compounds according to the present invention. Dixon plot (AG) and Lineweaver-Burk plot (HO) for the inhibition of α-glucosidase enzymes by compounds 1 (A and H), 7 (B and I), 10 (C and K), 11 (D and L), 12 (E and M), 13 (F and N), and 16 (G and O). [I] and [S] represent the inhibitor (μM) and substrate, respectively.p - Represents NPG(mM). Figures 6a and 6b show docking simulations of the interaction between compounds 1, 10, 12 and compound A (AD) and the allosteric site of PTP1B according to the present invention. FIGS. 7a–7c show docking simulations of interactions between compounds according to the present invention and binding sites of α-glucosidase. Molecular docking models between compounds 1 (A), 7 (C), 11 (E), 13 (G), 16 (H) and acarbose (K) and catalytic sites of α-glucosidase. Molecular docking models between compounds 1 (B), 10 (D), 12 (F) and BIP (I) and catalytic sites of α-glucosidase. Specific details for implementing the invention

[0040] Preferred embodiments of the present invention are described in detail below. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms, and the contents introduced herein are provided to sufficiently convey the concept of the present invention.

[0041] < Examples 1. Styrax leaves Extract preparation and Compound 1 Separation of ~18>

[0042] Shinamu ( Acer ginnala The leaves of Maxim) were collected in June 2020 at Gaesimsa Temple (36°44'48.7"N 126°35'25.4"E) in Seosan-si, Chungcheongnam-do, South Korea, identified by Professor Min Byeong-seon of the College of Pharmacy, Daegu Catholic University, and deposited at the Herbarium of the College of Pharmacy, Daegu Catholic University as a voucher specimen (CUD-2085).

[0043] 5.0 kg of air-dried Styrax japonica leaves were ground into a powder and extracted three times with 40% EtOH (3 x 20 L). After evaporating the 40% EtOH under vacuum, the 40% EtOH extract (0.8 kg) was redissolved in water, and then n - Serially distributed into hexane, CH2Cl2, ethyl acetate, and n-butanol n -Hexane (170.2g), CH2Cl2 (9.1g), EtOAc (150.6g) and n - Butanol (15.2g) and water residue were obtained, respectively.

[0044] The above ethyl acetate fraction (150.6 g) was applied to a silica gel column using sequential elution with CH2Cl2:MeOH (15:1→0:1) to collect nine fractions (E1-E9). Among these, fraction E3 (8.7 g) was chromatographed on a silica gel column eluting with CH2Cl2:MeOH (20:1) to obtain five subfractions E3.1-E3.4. Subfraction E3.4 (250.1 mg) was separated using an RPC-18 CC with MeOH:H2O (1:4) as the mobile phase and [prepared] in a semi-purification Waters HPLC system (50% MeOH in H2O, 5 mL / min, 40 min) Compound 3 (7.0mg, t R = 26.8 min) was obtained. In addition, the above fraction E6 (5.2 g) was divided into 6 subfractions E6.1-E6.6 using silica gel CC CH2Cl2:MeOH (10:1). Among these, the above subfraction E6.2 (123.4 mg) was used with RPC-18 CC (MeOH:H2O, 1:2). Compound 5(5 mg) was obtained. The fraction of E7 (9.9 g) was passed through silica gel CC using CH2Cl2:MeOH (7:1) to obtain 9 subfractions E7.1-E7.8, and among these, subfraction E7.4 (516.3 mg) was separated using silica gel CC using CH2Cl2:MeOH (8:1) and further purified with Sephadex LH-20 CC (MeOH:H2O, 1:2). Compound 2 (5.9mg) and compound 6 (7.0 mg) was obtained. Similarly, in the above subfraction E7.6 (453.8 mg) Compound 7 (32.4 mg) was obtained, and in subfraction E7.7 (1.2 g) Compound 1 (10.1mg), 8 (30.2mg) and 9 (6.9 mg) was obtained. Subsequently, fractions E8 (7.3 g) and E9 (9.2 g) were eluted with gel CC (CH2Cl2:MeOH, 5:1) using silica to divide them into 8 subfractions (E8.1-E8.8) and 16 subfractions (E9.1-E9.16), respectively. For fractions E8.8 (1.2 g), E8.7 (1.3 g), and E8.9 (1.5 g), RPC-18 CC with MeOH:H2O (1:4) was used as the eluent for fraction E8.8. Compound 10 (5.1 mg) and 11 (4.8 mg), in fraction E8.7 Compound 12 (10.2 mg), and in fraction E8.9 Compound 13 (19.5 mg) was collected. Fraction E9.5 (2.1 g) was further fractionated with silica gel CC (CH2Cl2:MeOH, 15:1) and purified with RPC-18 CC (MeOH:H2O, 1:4), then [prepared] on a semi-purification Waters HPLC system (30% MeOH in H2O, 5 mL / min, 50 min) Compound 4 (2.6 mg, tR = 41.0 min) and 14 (3.0 mg, tR = 42.8 min) was obtained. Compound 15 (30.5mg) and16 (30.1 mg) was separated from fraction E9.6 (1.5 g) by RPC-18 CC containing MeOH:H2O (1:2). In addition, the same method as for fraction E8.8 was applied to fractions E9.9 and E9.16 to separate from fractions E9.9 (2.1 g) and E9.16 (2.9 g). Compound 17 (50.4mg) and 18 (50.6 mg) were isolated separately.

[0045] < Examples 2. Determination of the structures of compounds 1–18

[0046] As a result of determining the molecular structures of compounds 1 to 18 obtained from the Styrax japonica leaf extract in Example 1 above using NMR spectroscopy, it was confirmed that compounds 1 to 4 are novel compounds, and compounds 5 to 18 were identified. do 1 The results are shown in Figure 3. For structural determination, optical rotation was measured using a Jasco P-1020 polarimeter (JASCO Corporation, Tokyo, Japan), and IR spectra were recorded using a Bruker IFS-66 / S Fourier Transform (FT)-IR spectrometer. UV spectra were recorded using an Agilent 8453 UV-visible spectrophotometer, and HRESI-MS spectra were recorded using a Micromass QTOF2-MS mass spectrometer. NMR spectra were recorded using a Bruker 500 MHz spectrometer and a Varian Unity Inova 400 MHz spectrometer with TMS as the internal standard.

[0047] Acerglucitol A ( Acerglucitol A, Compound 1)

[0048] Brown amorphous powder: ; [α]+36.0 (c 0.01, MeOH); UV (MeOH) λ max (log ε) 276 (2.71), 217 (0.83) nm; IR (KBr) ν max 3420, 2981, 1698, 1612, 1498 cm -1 . HRESI-MS m / z 459.0905 ([M + Na] + , C 20 H 20 O 11 Calculated value for Na, 459.0903); 1 ¹H NMR (500 MHz, acetone- d 6 ) and 13 13C NMR (125 MHz, acetone- d 6 ) Data, see Table 1.

[0049] Compound 1 It was obtained as a brown amorphous powder. Compound 1 The HRESI-MS value is m / z 459.0905(C 20 H 20 O 11 Sodium addition ion peak [M + Na] at the calculated value for Na (459.0903). + Representing, the chemical formula is C 20 H 20 O 11 It showed that Compound 1 IR absorption of hydroxyl groups (3420 cm⁻¹) -1 ), ester carbonyl (1698 cm -1 ) and aromatic rings (1612 and 1498 cm) -1 ) suggested the existence of Moiety, and 1 H and 13 The C NMR spectrum is δ H / δ C [3.31 (1H, t, J = 10.7 Hz, H a -1) and 4.02 (1H, dd, J = 10.7, 5.5 Hz, H b-1)] / 66.7 (C-1), 3.53 (2H, m, H-4, 5) / 70.8 (C-4) and 78.7 (C-5), 3.76 (1H, m, H-3) / 75.7 (C-3), [4.32 (1H, dd, J = 11.9, 4.8 Hz, H a -6) and 4.51 (1H, m, H b -6)] / 63.7 (C-6), and 4.87 (1H, ddd, J = 10.7, 9.5, 5.5 Hz, H-2) / 72.1 (C-2) exhibited a characteristic signal for a single 1-deoxysugar moiety. The pyranose ring of the 1-deoxysugar unit 1 H- 1 This was further confirmed via the H COSY spectrum, which indicates a spin-coupled sequence from H-1 to H-6 (Fig. 2). Apart from the sugar moiety, the 1D NMR spectrum of Compound 1 is δ H / δ C Two symmetric single signals at 7.09 (2H, s, H-2", 6") / 109.1 (C-2", 6"), δ C Four aromatic quaternary C-atoms at 120.9 (C-1"), 138.0 (C-4"), and 145.2 (C-3"), 5"), δ C Containing one ester carbonyl carbon at 165.9 (C-7") δ H / δ C 6.85 (2H, d, J = 8.8 Hz, H-3′, 5′) / 115.1 (C-3′, 5′) and 7.85 (2H, d, J A single p-hydroxybenzoyl portion consisting of two pairs of symmetric doublet signals at = 8.8 Hz, H-2′, 6′) / 131.8 (C-2′, 6′), and δ C Two aromatic quaternary carbons at 121.3 (C-1′) and 162.0 (C-4′), δ C 165.4 (C-7′) showed one ester carbonyl carbon with one galloyl functional group (Park et al., 2017). O - p -Hydroxybenzoyl and O The γ-galloyl functional group was assigned to C-2 and C-6 of the 1-deoxysugar moiety via ester bonds, which was confirmed by major HMBC correlations from H-2 to C-7′ and H2-6 to C-7", respectively. The planar structure of Compound 1 is HMQC, HMBC, and 1 H- 1 H was further confirmed by the COSY correlation (Fig. 2). H a The strong NOESY correlations of -1 / H-3, H-3 / H-5, and H-2 / H-4 (Fig. 2) provided evidence for the α-direction and β-direction of H-3 / H-5 and H-2 / H-4, respectively, indicating that the 1-deoxysugar residue is 1,5-anhydro-glucitol (Yuan et al., 2012). According to TLC, optical rotation analysis, and comparison with standard samples after acid hydrolysis, the sugar moiety of Compound 1 was identified as 1,5-anhydro-D-glucitol. Therefore, the structure of Compound 1 was determined to be 2-O-(p-hydroxybenzoyl)-6-O-galloyl-1,5-anhydro-D-glucitol (Fig. 1), a previously undescribed compound, and acerglucitol A (acerglucitol A, compound 1 It was named as ). Compounds 1 and 4 (ppm, J of in Hz 1 H (500 MHz) and 13 The C (125 MHz) NMR results are shown in Table 1.

[0050] Compounds 1 a 4 b Position δ H δ C δ H δ C 1 3.31 t, J = 10.7 4.02 dd, J = 10.7, 5.5 66.7 3.20 t, J = 10.93.89 m 69.6 2 4.87 ddd, J = 10.7, 9.5, 5.5 72.1 3.50 ddd, J = 14.4, 8.5, 3.3 70.4 3 3.76 m 75.7 3.32 m 78.4 4 3.53 m 70.8 3.32 m 69.9 5 3.53 m 78.7 3.42 m 78.6 6 4.32 dd, J = 11.9, 4.84.51 m 63.7 4.27 f, J = 12.0, 6.04.50 dd, J = 12.0, 2.0 63.7 1′ - 121.3 126.3 2′ 7.85 d, J = 8.8 131.8 7.21 d, J = 1.9 110.3 3′ 6.85 d, J = 8.8 115.1 - 144.0 4′ - 162.0 - 149.3 5′ 6.85 d, J = 8.8 115.1 6.82 d, J = 8.2 115.1 6′ 7.85 d, J = 8.8 131.8 7.09 dd, J = 8.2, 1.9 122.8 7′ - 165.4 7.64 d, J = 15.9 145.7 8′ - - 6.40 d, J = 15.9 113.9 9′ - - - 167.8 1" - 120.9 - - 2" 7.09 s 109.1 - - 3" - 145.2 - - 4" - 138.0 - - 5" - 145.2 - - 6" 7.09 s 109.1 - - 7" - 165.9 - - 3′-OCH3 - - 3.90 s 55.0

[0051] a is acetone_d Measured at 6

[0053] Acergalate A ( Acergallate A, Compound 2)

[0054] White amorphous powder: [α]+28.0 (c 0.01, MeOH); UV (MeOH) λ max (log ε ) 277 (0.47), 218 (0.94) nm; IR (KBr) ν max 3411, 2980, 1714, 1601, 1500 cm -1 . HRESI-MS m / z 309.0591 ([M + Na] + , C 12 H 14 Calculated value for O8Na, 309.0586); 1 ¹H NMR (400 MHz, CD3OD) and 13 1C NMR (100 MHz, CD3OD) data, see Table 2.

[0055] Compound 2 It was obtained as a white amorphous powder. The molecular formula of compound 2 is m / z 309.0591(C 12 H 14 HRESI-MS [M + Na] at O8Na, calculated value for 309.0586, 309.0586) + Based on the C peak 12 H 14 It was determined to be O8. Its IR absorption is OH (3411 cm⁻¹). -1 ) and C=O (1714 cm - 1 ) indicated the presence of the functional group. Similar to Compound 1, the 1D NMR spectrum of Compound 2 is δ H / δ C 6.99 (2H, s, H-2, 6) / 108.7 (C-2, 6), δ C It showed typical signals indicating a single galloyl moiety at 119.8 (C-1), 138.4 (C-4), 145.0 (C-3, 5), and 166.7 (C-7) of compound 2. 1 H and 13 In the high field of the C NMR spectrum δ C With a signal of one ester carbonyl carbon at 171.8 (C-1′), δ H / δ C [2.47 (1H, dd, J = 15.5, 8.0 Hz, H a -2′) and 2.56 (1H, dd, J = 15.5, 5.0 Hz, H b -2′)] / 38.4 (C-2′) with one methylene group, δ H / δ C 3.59 (3H, s, 1′-OCH3) / 50.8 (1′-OCH3) with one methoxy group, δ H / δ C [4.11 (1H, dd, J = 11.3, 5.0 Hz, H a -4′) and 4.16 (1H, dd, J = 11.3, 5.6 Hz, H b -4′)] / 67.1 (C-4′) one oxygenated methylene group, δ H / δ C 4.25 (1H, dd, J A signal containing a single oxygenated methine group was detected at = 8.0, 5.0 Hz, H-3′) / 66.0 (C-3′). Between H-2′-H-3′-H-4′ 1 H- 1The H COSY correlation and the HMBC correlation from H-2′, H-3′, and 1′-OCH3 to C-1′ indicated the presence of a single methyl 3,4-dihydroxy-butyrate functional group. This moiety was attached to the galloyl moiety via an ester bond due to the HMBC cross-peak between H2-4' (δH 4.16 and 4.11) and C-7 (δC 166.7). Detailed NMR data of Compound 2 (3' S Voice having ) arrangement ( Except for the fact that it is -72.0 Balanophora involucrata It was in very similarity to invonoid D isolated from (Wei et al., 2017), which suggests that they are enantiomers and therefore the absolute configuration of compound 2 is predicted to be (3'R). To definitively confirm the absolute configuration at C-3', a modified Mosher method was used. Thus, compound 2 is pyridine- under the catalysis of 4-(dimethylamino)pyridine d 5 In [location], (R)-MTPA-Cl and (S)-MTPA-Cl reacted to form (S)-MTPA ester and (R)-MTPA ester, respectively. The two isomers 1 Analyzed the H NMR spectrum and Δδ S-R The values ​​were calculated and are shown in Fig. 3. As seen in Fig. 3, the chemical shifts of protons H-2, H-6, and H-4' in the (R)-MTPA ester appeared at a lower field than in the (S)-MTPA ester. In contrast, the chemical shift of H-2' in the (R)-MTPA ester was at a higher field than in the (S)-MTPA ester. Therefore, the absolute configuration at C-3' was determined to be (3'R), consistent with the initial prediction, and consequently, the structure of compound 2, an unexplained galloyl derivative as shown in Fig. 1, was obtained. This is Acergallate A, Compound 2 It was named as ).

[0056] Compounds 2 a 3 b Position δ H δ C δ H δ C 1 - 119.8 - 119.7 2 6.99 s 108.7 6.96 s 108.7 3 - 145.0 - 145.2 4 - 138.4 - 138.6 5 - 145.0 - 145.2 6 6.99 s 108.7 6.96 s 108.7 7 - 166.7 - 166.6 1′ - 171.8 - 171.6 2′ 2.47 f, J = 15.5, 8.02.56 dd, J = 15.5, 5.0 38.4 2.58 f, J = 16.0, 5.4 2.65 dd, J = 16.0, 7.5 36.6 3′ 4.25 dd, J = 8.0, 5.0 66.0 4.09 m 75.6 4′ 4.11 f, J = 11.3, 5.04.16 dd, J = 11.3, 5.6 67.1 4.23 m4.28 f, J = 11.7, 4.1 65.1 1" - - - 171.2 2" - - 4.20 d, J = 3.1 67.4 1′-OCH3 3.59 s 50.8 3.58 s 50.9 1"-OCH3 - - 3.58 s 50.9

[0057] a The data is 400MHz from CD3OD( 1 H) and 100MHz( 13 Measured in C).

[0058] b The data is 500MHz from CD3OD( 1 H) and 125MHz( 13 Measured in C).

[0059] Acergalate B ( Acergallate B, Compound 3)

[0060] White amorphous powder: [α]+23.0 (c 0.01, MeOH); UV (MeOH) λ max (log ε ) 277 (0.47), 218 (0.97) nm; IR (KBr) ν max 3428, 2981, 1709, 1608, 1502 cm -1 . HRESI-MS m / z 381.0797 ([M + Na] + , C 15 H 18 O 10 Calculated value for Na, 381.0798); 1 1H NMR (500 MHz, CD3OD) and 13 13C NMR (125 MHz, CD3OD) data, see Table 2.

[0061] Compound 3 It was obtained as a white amorphous powder with a positive optical rotation [α] +23.0. The chemical formula of Compound 3 was determined by basic HRESI-MS for the sodium adduct ion peak at m / z 381.0797. 15 H 18 O 10 and, C 15 H 18 O 10The calculated value for Na was 381.0798. The IR spectrum of Compound 3 was at 3428 cm⁻¹, respectively. -1 , 1709 cm -1 and 1608 cm -1 Absorption bands of the OH, C=O, and C=C groups were shown. Similar to Compound 2, Compound 3's 1 H and 13 The C NMR spectrum is δ H / δ C 6.96 (2H, s, H-2, 6) / 108.7 (C-2, 6), δ C One galloyl functional group at 119.7 (C-1), 138.6 (C-4), 145.2 (C-3, 5), and 166.6 (C-7), δ H / δ C [2.58 (1H, dd, J = 16.0, 5.4 Hz, H a -2′) and 2.65 (1H, dd, J = 16.0, 7.5 Hz, H b -2′)] / 36.6 (C-2′), 3.58 (3H, s, 1′-OCH3) / 50.9 (1′-OCH3), 4.09 (1H, m, H-3′) / 75.6 (C-3′), [4.23 (1H, m, H a -4′) and 4.28 (1H, dd, J = 11.7, 4.1 Hz, H b -4′)] / 65.1 (C-4′), and δ C At 171.6 (C-1′), a signal belonging to one [methyl 3,4-dihydroxy-butyrate] was observed (Table 2). However, C-3' of compound 3 ( δ C 75.6) is C-3' of compound 2 ( δ CIt moved to a chapter lower than 66.0. Also δ H / δ C One methoxy group at 3.58 (3H, s, 1"-OCH3) / 50.9 (1"-OCH3), δ H / δ C 4.20 (2H, d, J = 3.1, H-2") / 67.4 (C-2"), one oxygenated methylene group and δ C A resonance associated with another working unit containing a single ester carbonyl carbon was observed at 171.2 (C-1"). This moiety is H-2" and 1"-OCH3 Based on the HMBC cross-peak from to C-1', it was determined to be methyl 2-hydroxyacetylate. Furthermore, the HMBC correlations from H2-4′ to C-7 and from H2-2′ to C-3' allowed us to infer that Compound 3 shares a structure similar to Compound 2, except for the substitution at C-3′ of Compound 2 where the methyl 2-hydroxyacetylate moiety forms Compound 3 via an ether bond. By comparing the optical rotation and CD spectra of Compound 3 with those of Compound 2, the absolute stereochemistry of Compound 3 at C-3' was determined to be (3'R), identical to that of Compound 2. As a result, Compound 3 was also determined to be an undisclosed galloyl derivative, Acergallate B, Compound 3 It was named as ).

[0062] Acerglycitol B ( Acerglycitol B, Compound 4)

[0063] White needle type: [α]+30.0 (c 0.01, MeOH); UV (MeOH) λ max (log ε ) 276 (1.88), 218 (0.66) nm; IR (KBr) ν max 3406, 2982, 1702, 1605, 1496 cm -1 . HRESI-MS m / z 363.1055 ([M + Na] + , C 16 H 20 Calculated value for O8Na, 363.1056); 1 1H NMR (500 MHz, CD3OD) and 13 13C NMR (125 MHz, CD3OD) data, see Table 1.

[0064] Compound 4 It was obtained as a white bed. C 16 H 20 The chemical formula of O8 is m / z 363.1055 [M + Na] + It was determined based on the HRESI-MS peak at C 16 H 20 The calculated value for O8Na was 363.1056. The IR and UV spectra were close to those of Compound 1. A detailed analysis of the NMR spectrum of Compound 4 revealed that Compound 4 is similar to Compound 1. δ H / δ C [3.20 (1H, t, J = 10.9 Hz, H a -1) and 3.89 (1H, m, H b -1)] / 69.6 (C-1), 3.32 (2H, m, H-3, 4) / 78.4 (C-3) and 69.9 (C-4), 3.42 (1H, m, H-5) / 78.6 (C-5), 3.50 (1H, ddd, J = 14.4, 8.5, 3.3 Hz, H-2) / 70.4 (C-2), and [4.27 (1H, dd, J = 12.0, 6.0 Hz, Ha -6) and 4.50 (1H, dd, J = 12.0, 2.0 Hz, H b It also includes a single deoxysugar moiety with a typical signal at -6)] / 63.7 (C-6). The remaining 1D NMR data belong to a single (E)-feruloyl moiety, which δ H / δ C 6.82 (d, J = 8.2 Hz, H-5′) / 115.1 (C-5′), 7.09 (dd, J = 8.2, 1.9 Hz, H-6′) / 122.8 (C-6′), and 7.21 (d, J = 1.9 Hz, H-2′) / 110.3 (C-2′), and δ C One ABX spin system at 126.3 (C-1′), 144.0 (C-3′), and 149.3 (C-4′), δ H / δ C 6.40 (d, J = 15.9 Hz, H-8′) / 113.9 (C-8′) and 7.64 (d, J = 15.9 Hz, one trans-disubstituted olefin bond at H-7′) / 145.7 (C-7′), δ H / δ C One methoxy-directing group at 3.90 (s, 3′-OCH3) / 55.0 (3′-OCH3), δ C It has one ester carbonyl carbon at 167.8 (C-9′). This reasoning is HMBC and 1 H- 1 It was further confirmed by H COSY analysis ( Fig. 2). The designation of the O-(E)-feruloyl moiety at C-6 of the 1-deoxysugar moiety was confirmed based on the HMBC correlation from H2-6 to C-9'. Similar to Compound 1, the sugar moiety of Compound 4 is H a It was identified as 1,5-anhydro-glucitol supported by NOESY cross-peaks between -1 / H-5, H-3 / H-5, and H-2 / H-4 (Fig. 2), and was identified as 1,5-anhydro-D-glucitol using the same method as for Compound 1. Therefore, Compound 4 was found to be a previously undescribed 1,5-anhydro-D-glucitol derivative (Fig. 1), and Acerglycitol B (Acerglycitol B, compound 4 It was named as ).

[0065] In addition, by comparing the isolated compounds with their basic spectroscopic data and previous reports, quercetin (quercetin, Compound 5 ), epi -Catechin( epi -catechin, Compound 6 ), Afgelin 3"- O- gallate (afzelin 3"- O -gallate, Compound 7 ), guaijaverin, Compound 8 ), kaempferol 3- O -α-L-arabinopyranoside(kaempferol 3- O -α-L-arabinopyranoside, Compound 9 ), epi -Catechin gallate( epi -catechin gallate, Compound 10 ), 3'- O -Galloyl catechin(3'- O -galloyl quercitrin, Compound 11 ), 3- O -galloyl-3,3',5,5',7-pentahydroxyflaban(3- O -galloyl-3,3',5,5',7-pentahydroxyflavan, Compound 12 ), Kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside(kaempferol-3- O -(2"-galloyl)-α-L-rhamnopyranoside, Compound 13 ), 1- O -3-1-O-3-hydroxyphenyl-5-methoxyphenol-(6'- O -vanilloyl)-β-D-glucopyranoside(1- O -3-hydroxyphenyl-5- methoxyphenol-(6′- O -vanilloyl)-β-D-glucopyranoside, Compound 14 ), quercitrin(quercitrin, Compound 15 ), quercetin-3-O-(2"-galloyl)-α-L-rhamnopyranoside(quercetin-3- O -(2"-galloyl)- α -L-rhamnopyranoside, Compound 16 ), acertannin (2,6-digalloyl-1,5-anhydroglucitol), Compound 17 ), acertannin (3,6-digalloyl-1,5-anhydroglucitol), compound 18 It was confirmed that.... Among these, compounds 7 and 11 were first isolated from *A. ginnala*, and compounds 12 and 14 were first isolated from the genus *Acer*.

[0066] < Examples 3. α-glucosidase of compounds 1–18 and PTP1B Inhibitory activity>

[0067] The antidiabetic activity of compounds 1 to 18 isolated in the above examples was evaluated and is shown in Table 3. PTP1B (Protein Tyrosine Phosphatase 1B) and α-glucosidase inhibition analysis was performed by modifying the method of Ha et al. (2022).

[0068] First, the PTP1B enzyme was prepared by diluting it with 100 mM citric acid buffer to 0.5 units, and then treated with isolated compounds at various concentrations (1–50 μM). The reaction was carried out in a 96-well plate with 2.0 mM as the substrate. p -nitrophenyl phosphate( p It was performed using -NPP in 100 mM citric acid buffer (pH = 6.0) at 37°C. After 20 minutes of reaction, p - Yellow produced under alkaline conditions of NPP p - Nitrophenylene anion was measured at 405 nm. Ursolic acid was used as a positive control.

[0069] α-glucosidase was prepared by dissolving it in 10 mM phosphate buffer to a concentration of 0.1 units, and the isolated compounds were treated at various concentrations (1–50 μM). The reaction was carried out at 37°C in 100 mM phosphate buffer (pH = 6.8) with 2.5 mM as the substrate. p -nitrophenyl α-D-glucopyranoside ( p It was performed in a 96-well plate using -NPG. After 10 minutes of reaction, p The hydrolysis of -NPG produces yellow anions under alkaline conditions. p - Nitrophenol was confirmed by measuring at 405 nm. Acarbose was used as a positive control.

[0070] PTP1B inhibition α-glucosidase inhibition Comp. IC 50 (μM) Inhibition type K i (μM) IC 50 (μM) Inhibition type K i (μM) 1 10.78 ± 0.29 non-competitive 10.7 6.06 ± 0.24 mixed 5.4 2 40.36 ± 0.94 - >50 - - 3 >50 - >50 - - 4 34.96 ± 0.48 - >50 - - 5 4.31 ± 0.15 - 4.29 ± 0.05 - - 6 35.86 ± 0.98 - 15.48 ± 0.94 - - 7 12.11 ± 0.00 - 3.05 ± 0.01 competitive 2.8 8 >50 - >50 - - 9 >50 - >50 - - 10 3.46 ± 0.05 non-competitive 3.4 0.88 ± 0.01 non-competitive 0.87 11 11.91 ± 0.25 - 1.79 ± 0.04 competitive 0.99 12 7.96 ± 0.10 non-competitive 7.8 1.73 ± 0.04 non-competitive 1.60 13 12.65 ± 0.59 - 2.54 ± 0.09 competitive 1.50 14 37.06 ± 0.60 - 27.74 ± 0.89 - - 15 >50 - >50 - - 16 11.97 ± 0.21 - 1.75 ± 0.01 competitive 0.57 17 >50 - >50 - - 18 >50 - >50 - - ursolic acid a 5.10 ± 0.08 - - - - acarbose b - - 141.62 ± 0.86 - -

[0071] a Positive control group for PTP1B inhibition analysis

[0072] b Positive control group for α-glucosidase inhibition analysis

[0074] As shown in Table 3 above, Compounds 1, 5, 6, 7, 10, 11, 12, 13, 14 and 16 It was identified as a dual inhibitor of PTP1B and α-glucosidase. Among these, galloylated flavanol ( Compound 10 and 12 ) showed the strongest inhibitory effect, and IC 50 The values ​​were 3.46 μM and 7.96 μM for PTP1B, and 0.88 μM and 1.73 μM for α-glucosidase, respectively. Compound 10, in which one hydroxyl group is rearranged from C-5' to C-4' of the B ring, showed values ​​similar to Compound 12 and ursolic acid (IC2), a positive control for the PTP1B inhibitor. 50 The activity was greater than that of galloylated flavonol rhamnoside (= 5.10 μM). Compounds 7, 11, 13 and 16 Also, PTP1B(IC 50 : 11.91~12.65μM) and α-glucosidase (IC2) 50 They exhibited very strong inhibitory activity for (1.75 μM–3.05 μM). Further analysis of the relationship between molecular structure and activity revealed that the inhibitory activity of these compounds decreased somewhat when quercetin was converted to kaempferol and the galloyl unit was rearranged from C-3' to C-2' of the rhamnose residue (Fig. 1 and Table 3). The glucitol derivative Compound 1 Likewise, IC50s of 10.78 μM and 6.06 μM for PTP1B and α-glucosidase, respectively. 50 It showed a strong inhibitory effect with the value. Quercetin, a common flavonol found in natural resources ( Compound 5 ) was also found to be a potent inhibitor, with IC50 values ​​of 4.31 μM and 4.29 μM for PTP1B and α-glucosidase, respectively, consistent with previous reports. Furthermore, Compound 6 and 14PTP1B inhibited enzyme activity with IC50 values ​​of 35.86 μM and 37.06 μM, and α-glucosidase with 15.48 μM and 27.74 μM, respectively.

[0075] As mentioned above, the tree ( Acer ginnala Maxim) isolated from leaf extract Compounds 1, 5, 6, 7, 10, 11, 12, 13, 14 and 16 It is acarbose (IC2), an α-glucosidase inhibitor widely used in the treatment of type 2 diabetes. 50 It was confirmed that it exhibits inhibitory activity several times stronger than (= 141.62 μM). In addition, Compound 2 and 4 is PTP1B(IC 50 : showed inhibitory activity at 40.36 μM and 34.96 μM, respectively.

[0076] < Examples 4. PTP1B and α- Glucosidase Inhibitory enzyme kinetics

[0077] To determine the PTP1B and α-glucosidase inhibition types of the compound according to the present invention, the compound with the strongest PTP1B inhibitory activity Compound 1, 10 and 12 and strong α-glucosidase inhibitory activity Compounds 1, 7, 10~13 and 16 It was analyzed using two methods: Lineweaver-Burk plots and Dixon plots.

[0078] The inhibitory effects of PTP1B and α-glucosidase at various concentrations p -NPP ( Compound 1 , 10 and 12 For 0.5 mM, 1 mM, and 2 mM) and p -NPG ( Compound 1, 10 , 12 and 16 About 0.625 mM, 1.25 mM, and 2.5 mM; Compound 7 0.55 mM, 1.1 mM, and 2.2 mM for; Compound 11 0.6 mM, 1.2 mM, and 2.4 mM for; Compound 13 Regarding 0.5 mM, 1 mM, and 2 mM), each was identified, and also each compound was tested at various concentrations (PTP1B inhibition: Compound 1 2.6 μM, 6.1 μM, and 15.0 μM; Compound 10 1.6 μM, 2.5 μM, and 4.0 μM; Compound 12 3.0 μM, 5.0 μM, and 10.5 μM; α-glucosidase inhibitor; Compound 1 6.4 μM, 8.4 μM, and 10.8 μM; Compound 7 is 1.5 μM, 2.5 μM, and 5.5 μM; compound 10 is 2.0 μM, 3.0 μM, and 4.0 μM; Compound 11 Compound 12 was identified at 0.33 μM, 0.75 μM, and 2.5 μM; Compound 13 at 0.75 μM, 1.25 μM, and 3.55 μM; and Compound 16 at 1.21 μM, 1.55 μM, and 2.5 μM, respectively. The results were then analyzed using SigmaPlot 12.0 software (SPCC Inc, Chicago IL, USA) and are shown in Figure 4 (PTP1B enzyme inhibition) and Figures 5a–5c (α-glucosidase enzyme inhibition). The kinetic constant value (Ki) was calculated using a Dixon plot.

[0079] As seen in Fig. 4, Compound 1 For (A and D), K i Non-competitive PTP1B inhibition with a value of 10.7 μM was observed, and as shown in Figure 5 (A and H), it acted as a mixed-type α-glucosidase inhibitor, K i The value was 5.4 μM.

[0080] Compound 10 (Fig. 4B and E, K i = 3.4μM) and 12 (C and F, K in Fig. 4 i In the case of (=7.8μM), non-competitive inhibition was observed in PTP1B, and in α-glucosidase as well. Compound 10 (Fig. 5B and E, K i = 0.87μM) and 12 (E and M, K in Fig. 5 i = 1.60μM) exhibited non-competitive type inhibition.

[0081] one side, Compound 7 (Fig. 5B and I, K i = 2.80 μM), 11 (D and L, K in Fig. 5 i = 0.99 μM) 13 (F and N, K in Fig. 5 i = 1.50 μM) and 16 (G and O, K in Fig. 5 i = 0.57 μM) was a competitive inhibitor for α-glucosidase.

[0082] < Examples 5. PTP1B Molecular Docking Simulation of Inhibition

[0083] Molecular docking simulations of the compound according to the present invention with PTP1B were performed using AutoDock 4.2 software, and the results are shown in Figures 6a and 6b. First, two-dimensional (2D) and three-dimensional (3D) structures of the compound according to the present invention were constructed using ChemBioOffice 12.0. The X-ray crystallographic structures of PTP1B and its reference allosteric inhibitor, compound A [3-(3,5-dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonic acid (4-sulfamoyl-phenyl)-amid, PDB ID: 1T49)] were assigned from the RCSB protein along with α-glucosidase (replaced with isomaltase, PDB ID: 3A4A). The 3D structures of acarbose (CIDs: 41,77) and BIP ((Z)-3-butylidenephthalide, CIDs: 5,352,899) were obtained from PubChem Compound (NCBI). Protein preparation was performed using Discovery Studio Client. In this step, missing disulfide bonds, hydrogen atoms, and amino acid side chains were filled in, water molecules were removed, and hydrogen bonds were optimized. PyRx 0.9.4 virtual screening software was used for restrained minimization until the Root Mean Square Deviation (RMSD) of non-hydrogen atoms converged to 0.30 Å and the energy of the generated compound was minimized. In this invention, this method is intended to place the compound fragments of the invention in triangulation and ensure the optimal configuration of each compound in a binding complex for further analysis. A grid for docking studies was generated to surround all residues of the two target proteins interacting with atoms of the reference inhibitor.The optimal configuration is the one with the lowest docking score (DS) energy (kcal / mol), which is the total energy consumed to form binding interactions between the compound and the selected protein. The interactions of the protein-ligand complex were analyzed by Discovery Studio Client.

[0084] Docking simulations for the PTP1B enzyme and non-competitive PTP1B inhibitors (1, 10, and 12) were successfully performed using Autodock 4.2 in the above method to evaluate the targeted inhibition of PTP1B binding sites. As shown in Figures 6a–6b and Table 4, each compound and reference (alosteric ligand, compound A) were stably located at the allosteric site of PTP1B.

[0085] Comp. Binding energy (kcal / mol) Hydrogen bond interactions Van der Waals interactions Other interactions 1 -7.11 Gln262, Gln266, Arg221, Asp181, Cys215, Ser216, Lys120 Ile219, Gly220, Ala217, Tyr46, Glu115, Trp179, Pro180, Lys116, Gly183, Thr263, Arg24 Gln262 (unfavorable donor-donor), Cys215 (π-Alkyl), Phe182 (Carbon H-bond) 10 -7.02 Lys73, Ser80, Gln102, Leu204, Ser205, His208 Leu71, Ile57, Ile82, Lys103, Gly209, Gln78, Lys73 Arg79 (π-Alkyl), Pro210 (π-Alkyl), Pro206 (π-Alkyl) 12 -7.26 Glu276 Met282, Lys279, Gly277, Phe196, Asn193 Phe280 (π-π T-shaped, Amide-π Stacked), Leu192 (π-π Stacked), Ala189 (π-Alkyl, Carbon H-bond) A a -7.42 Arg79, Lys197 Leu233, Asp236, Gly277, Ala183 Arg199 (π-Alkyl, Carbon H-bond), Phe280 (Alkyl, π-Alkyl, π-π Stacked), Phe196 (π-Alkyl), Glu200 (π-Anion), Lys197 (π-Anion), Leu192 (π-Alkyl), Asn193 (Carbon H-bond).

[0086] a : Reference allosteric ligand for PTP1B

[0087] The above Table 4 As seen in, Compound 1, 10 and 12 It was confirmed that the three types of ligands have a strong affinity for PTP1B. That is, compared with the docking energy of compound A -7.42 kcal / mol Compound 1, 10 and 12 They showed docking energies of -7.11, -7.02, and -7.26 kcal / mol, respectively.

[0088] Compound 1 It has a binding energy of -7.11 kcal / mol, and polar functional groups containing hydroxyl and C=O groups formed 8 hydrogen bonds with the amino acids Gln262, Gln266, Arg221, Asp181, Cys215, Ser216, and Lys120 of PTP1B (Fig. 6A). In addition, PTP1B- Compound 1The complex was more stable through both van der Waals interactions with Ile219, Gly220, Ala217, Tyr46, Glu115, Trp179, Pro180, Lys116, Gly183, Thr263, and Arg24, and hydrophobic interactions with Gln262 (unfavorable donor-donor), Cys215 (π-alkyl), and Phe182 (carbon H-bond).

[0089] Compound 10 It was bound to the allosteric site of PTP1B with a binding energy of -7.26 kcal / mol through 7 H-bonds with Lys73, Ser80, Gln102, Leu204, Ser205, and His208, van der Waals interactions with Leu71, Ile57, Ile82, Lys103, Gly209, Gln78, and Lys73, as well as π-alkyl interactions with Arg79, Pro210, and Pro206 (Fig. 6B).

[0090] Compound 12 The hydroxyl group at the C-3' of the galloyl functional group formed a single hydrogen bond with Glu276 at a distance of 2.76 Å with a bond energy of -7.26 kcal / mol. Compound 12 It was also attached to PTP1B receptor residues Met282, Lys279, Gly277, Phe196, and Asn193 via van der Waals interactions (Fig. 6C). Furthermore, Compound 12 Compound A (Fig. 6D) shared the same binding residues of Phe280 and Leu192 through hydrophobic interactions, thereby further confirming the protein-ligand relationship between Compound 12 and the PTP1B protein. The above molecular docking results are in accordance with the present invention Compound 1, 10 and 12It provides reliable data supporting that it induces PTP1B inhibition. Considering the difficulty in finding inhibitors that target the active site, developing non-competitive inhibitors by targeting the allosteric site of PTP1B as described above can be an effective strategy.

[0091] < Examples 6. Molecular Docking Simulation of α-Glucosidase Inhibition

[0092] Using AutoDock 4.2 software, a molecular docking simulation of the compound according to the present invention with α-glucosidase was performed as in Example 5 above, and the results are shown in Figures 7a to 7c and Table 5.

[0093] Comp. Binding energy (kcal / mol) Hydrogen bond interactions Van der Waals interactions Other interactions 1 -4.03 Arg315, Ser304 Val319, Gly309, His280, Phe303, His305, Ala329, Thr306, Arg359, Ile440, Asn317, Tyr316 Asn307 (Carbon H-bond), Leu313 (π-Alkyl), Pro312 (unfavorable donor-donor), Ser311 (unfavorable donor-donor), Thr310 (unfavorable donor-donor), Phe314 (unfavorable donor-donor), Val308 (unfavorable donor-donor) 1 -3.26 Arg315, Tyr316, Asp352 Ile440, Ser441, Leu219, Val216, Phe178, Thr306, His351, Arg446, Phe159 Glu411 (unfavorable donor-donor), His280 (unfavorable donor-donor), Tyr158 (π-lone pair), Gln279 (unfavorable donor-donor), Phe303 (π-lone pair), Gln353 (unfavorable donor-donor), Asp409 (π-Anion), Arg442 (unfavorable donor-donor), Asp307 (Carbon H-bond) 7 -9.93 Thr274, Ser298, Thr290, Asp341, His295 Arg270, Gly269, Ile262, Leu297, Glu296, Asn259, Cys342, Trp343, Lys16, Glu9, Lys13, Glu271, Glu11 Arg263 (Carbon H-bond, π-Alkyl), Ile272 (Carbon H-bond), Val266 (π-Alkyl), Ala292 (π-σ), Trp15 (Amide-π stacked), Ser291 (π-π T-shaped) 10 -8.23 Tyr158, Arg315, Thr310, Glu277 Asp352, Gln353, His280, Ser311, Phe314, Tyr316, Phe159, Asn415, Gln279, Glu411, Val216, Arg442 Asp307 (π-Anion), Pro312 (π-σ), Arg315 (π-Alkyl), Phe303 (π-π T-shaped) 11 -9.31 Ser298, Thr290, Glu271, Asn259 His295, Glu11, Lys16, Trp343, Asp341, Cys342, Lys13, Ile262, Leu297, Thr274, Glu296, Ile272, Asp268, Gly269 Ala292 (π-σ), Trp15 (Amide-π stacked), Ser291 (π-π T-shaped), Arg263 (π-σ, π-Alkyl), Val266 (π-Alkyl) 12 -9.16 Glu411, Tyr158, Lys156, Ser240, Asp242, Thr310, Asp307, His280 Ser157, Phe314, Ser241, Ser311, Pro312, Phe303, Gln279, Glu277, Asp352, Arg442, Phe159, Phe178 Tyr158 (π-π T-shaped, π-π Stacked), His280 (π-π T-shaped), Arg315 (π-Alkyl), Asp307 (π-Anion) 13 -9.70 Asp307, Thr310, Glu411, Tyr158 Leu313, Tyr316, Phe159, Gly160, Lys156, Ser240, Ser241, Asp242, Arg442, Asp352, Phe303, Gln353, His280 Asn415 (unfavorable donor-donor), Phe314 (π-π T-shaped), Pro312 (Carbon H-bond), Ser311 (Carbon H-bond), Arg315 (Carbon H-bond) 16 -9.37 Ser240, Asp242, Thr310 His280, Ser311, Val308, Lys156, Gly160, Asn415, Ser157, Tyr158, Phe314, Glu411, Asp352, Glu277, Arg442, Phe303 Asp307 (π-Anion), Pro312 (π-Alkyl), Arg315 (π-Alkyl) BIP a -6.38 Arg315, Glu411, Phe159, Asp215, Arg213, Asp69, Glu277, Phe303 Tyr158 (π-π T-shaped), Phe178 (π-Alkyl), Val216 (π-Alkyl), His351 (π-Alkyl), Tyr72 (π-σ), Asp352 (π-Anion), Arg442 (π-Cation) Acarbose b -7.98 Leu313, Asp242, Ser304, Asp307, Thr310 Ser240, Lys156, Phe314, Tyr158, Tyr158, Asn415, Arg315, Tyr316, Phe321, Asp325, Ser304, Ile328, Ala329, Gly309, Val308, Ser311, Asp307 His280 (Carbon H-bond), Pro312 (Carbon H-bond)

[0094] a : Reference allosteric ligand for α-glucosidase

[0095] b : Reference catalytic ligand for α-glucosidase

[0097] The present invention Compounds 1, 7, 10~13 and 16 To investigate the mechanism of binding to this α-glucosidase, these compounds and two reference ligands (BIP-allosteric inhibitor and acarbose-catalyzed inhibitor) were docked to the binding site of α-glucosidase using molecular docking simulations. As shown in Figures 7a–7c and Table 5, Compound 1 It is a mixed inhibitor that was stabilized at both the catalytic and allosteric sites of α-glucosidase. On the other hand Compounds 7, 11, 13 and 16 It is a competitive inhibitor that bound only to the catalytic site, and Compound 10 and 12 It is a non-competitive inhibitor that bound only to the allosteric site of α-glucosidase. Through thorough studies Compound 1It was found that it connects to the catalytic domain of α-glucosidase with a docking energy of -4.03 kcal / mol. In Figures 7A and 7K, the H-bonding with Ser304 and the van der Waals interactions with Gly309, Ala329, and Tyr316 are Compound 1 The catalytic site of α-glucosidase was simultaneously observed in both and acarbose. In addition, Compound 1 of p The H-bond between the C=O in the hydroxybenzoyl ring and Arg315 also played an important role in the interactions of this complex. Meanwhile, the C=O of the galloyl moiety and Compound 1 The OH group of the glucitol moiety formed three H-bonds with Tyr316, Arg315, and Asp352 at the allosteric site of α-glucosidase, exhibiting a docking score of -3.26 kcal / mol. Furthermore, these two complexes were more stable due to different van der Waals and hydrophobic interactions (Figures 7A and 7B, Table 5). The competitive inhibitor Compounds 7, 11, 13 and 16 It also exhibited strong interaction forces at the catalytic site of α-glucosidase with binding energies of -9.93, -9.31, -9.70, and -9.37 kcal / mol, respectively, surpassing acarbose, a reference catalytic inhibitor with a binding energy of -7.98 kcal / mol. These highly hydroxylated compounds Compounds 7, 11, 13 and 16 It also formed H bonds with polar residues of the α-glucosidase catalytic site. Specifically, Compound 7 Five H-bonds were observed between the hydroxyl groups of the galloyl and rhamnose moiety and residues Thr290, Asp341, Thr274, Ser298, and His295 (Fig. 7C). Similarly, as illustrated in Figs. 7E, 7G, and 7H, Compound 11 The hydroxyl group forms five hydrogen bonds with Ser298, Thr290, Glu271, and Asn259, and Compound 13It formed four H-bonds with four residues Asp307, Thr310, Glu411, and Tyr158, and Compound 16 It formed three H-bonds with three residues, Ser240, Asp242, and Thr310. In addition, van der Waals and hydrophobic interactions with nonpolar amino acids also contributed to the stabilization of α-glucosidase and the complex of these compounds (Figure 7, Table 5).

[0098] In particular, similar to Akabos Compound 13 It interacts with Asp307 and Thr310 through H-bonds, with Lys156 and Ser240 through van der Waals interactions, and with Pro312 through carbon H-bonds, and Compound 16 It interacted with Asp242 and Thr310 via H-bonding, with Ser311, Lys156, Tyr158, and Asn415 via van der Waals interactions, and with Pro312 via hydrophobic interactions at the enzyme's active site. On the other hand, the non-competitive inhibitor with docking scores of -8.23 and -9.16 kcal / mol Compound 10 and 12 It was conjugated to the allosteric site of α-glucosidase and exhibited higher binding efficacy than the reference allosteric ligand BIP (-6.38 kcal / mol). Compound 10 and 12 All hydroxyl groups are surrounded by polar amino acids. Compound 10 and 4 H-bonds between the 4 residues Tyr158, Arg315, Thr310 and Glu277 (Fig. 7D), Compound 12 And nine H-bonds were present between the eight residues of α-glucosidase—Glu411, Tyr158, Lys156, Ser240, Asp242, Thr310, Asp307, and His280 (Fig. 7F). In addition, similar to BIP Compound 10 It interacted with Phe159 and Glu411 through van der Waals interactions and Compound 12It also interacted with Phe303, Phe159, and Glu277 through van der Waals interactions, and with Tyr158 through π-π T-type interactions. These molecular docking results were consistent with in vitro test results and allowed for the clarification of the target sites of PTP1B and α-glucosidase of the compound according to the present invention.

[0099] < Jejeye 1. Pharmaceutical Preparations>

[0100] Jejeye 1-1. Preparation of Tablets

[0101] 200 mg of the extract of Styrax japonica or a compound isolated therefrom according to the present invention was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silica. A 10% gelatin solution was added to this mixture, and the mixture was ground and passed through a 14-mesh sieve. This was dried, and the mixture obtained by adding 160 g of potato starch, 50 g of active ingredient, and 5 g of magnesium stearate was made into tablets.

[0102] Jejeye 1-2. Preparation of Injectable Solutions

[0103] 100 mg of the extract of the Styrax japonica or a compound isolated therefrom of the present invention, 0.6 g of sodium chloride, and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20°C for 30 minutes.

[0104] < Jejeye 2. Manufacture of health functional foods

[0105] Jejeye 2-1. Manufacture of Health Functional Foods

[0106] The present invention is prepared by mixing 2g of the extract of the Styrax japonica or a compound isolated therefrom, an appropriate amount of a vitamin mixture, 70µg of vitamin A acetate, 1.0mg of vitamin E, 0.13mg of vitamin B1, 0.15mg of vitamin B2, 0.5mg of vitamin B6, 0.2µg of vitamin B12, 10mg of vitamin C, 10µg of biotin, 1.7mg of nicotinamide, 50µg of folic acid, 0.5mg of calcium pantothenate, an appropriate amount of a mineral mixture, 1.75mg of ferrous sulfate, 0.82mg of zinc oxide, 25.3mg of magnesium carbonate, 15mg of monopotassium phosphate, 55mg of disaccharide phosphate, 90mg of potassium citrate, 100mg of calcium carbonate, and 24.8mg of magnesium chloride to form granules, but it can be prepared by modifying it into various formulations depending on the use. In addition, the composition ratio of the above vitamin and mineral mixture may be arbitrarily modified, and the above ingredients may be mixed and manufactured according to a conventional method for manufacturing health functional foods.

[0107] Jejeye 2-2. Manufacture of Health Functional Beverages

[0108] A beverage was prepared by mixing 1 g of the extract of the Styrax japonica or a compound isolated therefrom of the present invention, 0.1 g of citric acid, 100 g of fructooligosaccharide, and 900 g of purified water, and stirring, heating, filtering, sterilizing, and refrigerating according to a conventional beverage preparation method.

Claims

Claim 1 Shinamu ( Acer ginnala A composition for the prevention or treatment of diabetes mellitus comprising, as an active ingredient, acerglucitol A (Acerglucitol A, Compound 1) represented by the following [Chemical Formula] isolated from Maxim) leaf extract. [Chemical Formula] Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 A composition for the prevention or treatment of diabetes according to claim 1, wherein the acerglucitol A (compound 1) inhibits the enzymatic activity of protein tyrosine phosphatase 1B (protein tyrosine phosphatase 1BPTP1B) or α-glucosidase. Claim 7 delete Claim 8 A composition for the prevention or treatment of diabetes, characterized in that, in claim 1, the acerglucitol A (compound 1) has non-competitive inhibitory activity against protein-tyrosine phosphatases 1B (PTP1B). Claim 9 delete Claim 10 delete Claim 11 A composition for the prevention or treatment of diabetes mellitus according to claim 1, wherein the acerglucitol A (compound 1) has competitive and non-competitive inhibitory activity of α-glucosidase. Claim 12 delete Claim 13 A health functional food for the prevention or improvement of diabetes comprising the composition of any one of claims 1, 6, 8 and 11. Claim 14 Shinamu ( Acer ginnala Acerglucitol A (Compound 1), a novel compound represented by the following [Chemical Formula] isolated from Maxim) leaf extract. [Chemical Formula]

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