Method for extending half-life of theanine in vivo

Abstract

To provide a method for extending a half-life of theanine in vivo.SOLUTION: The present invention provides use of a theanine glycoside-based compound in manufacture of a product for extending a half-life of theanine in vivo. The theanine glycoside-based compound has a structure shown by a following formula (where R represents a moiety shown in the following figure, and n represents 1-4).SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present invention belongs to the field of biomedical technology, and specifically relates to a method for extending the in vivo half-life of theanine. [Background technology]

[0002] Theanine is an important non-protein amino acid found in tea, accounting for approximately 0.5-2% of the dry weight of tea. Theanine has a short half-life in the body, and its blood concentration generally peaks about 0.5-1 hour after oral ingestion, then begins to decline, returning to the initial concentration 8-12 hours later. Recent related studies have shown that theanine has anti-inflammatory effects, oxidative damage reduction effects, sedative effects and antidepressant effects (previous literature: Untargeted and targeted mass spectrometry reveal the effects of theanine on the central and peripheral metabolomics of chronic unpredictable mild stress-induced depression in juvenile rats. Journal of Pharmaceutical Analysis. 2023,13. It has been found to have many beneficial functions, such as improving learning and memory (see previous literature: "Effect of Theanine on the Learning and Memory Ability of Mice", Lin Xueling, Food Science, 2004, 25, 218-219), improving sleep (see previous literature: "Experimental Study on the Improvement of Theanine on Mouse Sleeping Situation", Food Science, 2009, 30, 214-216), lowering blood pressure (i.e., maintaining blood pressure at a healthy level; previous literature: "Progress in the Pharmacological Research of Theanine", Ruan Xuelian, Special Review of Chinese Tea), and assisting in tumor suppression. However, due to its short half-life, current oral theanine products require multiple consecutive administrations to maintain effective blood concentrations, limiting the further application of theanine. There have been no relevant reports on methods to extend the half-life of theanine in vivo. Therefore, it is of great importance to develop a safe and efficient method to extend the half-life of theanine and extend the half-life of theanine in vivo. Summary of the Invention

[0003] In order to solve the above problems, the present invention provides a method for extending the half-life of theanine in vivo. This method is expected to have a future because the raw materials are cheap and easy to obtain, the reaction conditions are mild, and the yield is high. In the present invention, theanine is modified with monosaccharide to obtain theanine glycoside compound, which can effectively improve the stability of drugs, improve the drug absorption in the body, extend the half-life of drugs, improve the bioavailability of drugs, and improve the therapeutic effect.

[0004] The first object of the present invention is to provide a use of theanine glycoside-based compound in the manufacture of a product for extending the half-life of theanine in vivo. The structure of the said theanine glycoside-based compound is represented by the following formula: JPEG2024177073000002.jpg20170In the formula, R is JPEG2024177073000003.jpg25170, where n is 1-4.

[0005] In one embodiment of the present invention, the main metabolite of the theanine glycoside compound in the blood and brain is theanine.

[0006] In one embodiment of the present invention, the theanine glycoside compound can improve the absorption of theanine in the body and extend its half-life in the blood and brain.

[0007] In one embodiment of the present invention, the product may be an anti-inflammatory product, an oxidative damage relieving product, an anti-depressant product, a product for improving learning and memory ability, a product for improving sleep, a product for lowering blood pressure, a product for maintaining healthy blood pressure levels, a tumor suppression aid product, and the like.

[0008] In one embodiment of the invention, the product may be a drug, a supplement, a special dietary supplement, a food product, or the like.

[0009] In one embodiment of the invention, the product is a blood pressure lowering agent, a supplement to improve memory, or a sleep aid supplement, an antidepressant supplement.

[0010] In one embodiment of the invention, the product may be an oral product.

[0011] In one embodiment of the invention, the product may be a liquid product, a solid product or a semi-solid product.

[0012] In one embodiment of the present invention, when the product containing the theanine glycoside compound according to the present invention is a pharmaceutical composition, its form may be any one of solutions, suspensions, powders, solid molded products, etc., and is not particularly limited. Alternatively, it may be provided in the form of capsules, tablets, powders, granules, beverages, etc. Also, it may be used in combination with other drugs.

[0013] In one embodiment of the present invention, the method for producing the product of the present invention includes, but is not limited to, a method for mixing the powder of the theanine glycoside compound with other raw materials; a method for dissolving the theanine glycoside compound and other raw materials in a solvent to form a mixture; and a method for mixing the theanine glycoside compound with other raw materials. The mixture is frozen and dried, spray-dried, or other general production methods for food and pharmaceutical products are used. For example, a product can be obtained by mixing ingredients such as the theanine glycoside compound with known excipients, carriers, adhesives, stabilizers, etc.

[0014] A second object of the present invention is to provide a product for extending the half-life of theanine in vivo, the product comprising a theanine glycoside compound, the structure of which is represented by the following formula: JPEG2024177073000004.jpg19170In the formula, R is JPEG2024177073000005.jpg24170, where n is 1-4. The theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

[0015] In one embodiment of the present invention, the product may be an anti-inflammatory product, an oxidative damage relieving product, an anti-depressant product, a product for improving learning and memory ability, a product for improving sleep, a product for lowering blood pressure, a product for maintaining healthy blood pressure levels, a tumor suppression aid product, and the like.

[0016] The third object of the present invention is to provide a sustained release drug, which comprises a theanine glycoside compound, the structure of which is represented by the following formula: JPEG2024177073000006.jpg19170In the formula, R is JPEG2024177073000007.jpg24170, where n is 1-4. The theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

[0017] The fourth object of the present invention is to provide a supplement for improving memory, which comprises a theanine glycoside compound, the structure of which is represented by the following formula: JPEG2024177073000008.jpg19170In the formula, R is JPEG2024177073000009.jpg24170, where n is 1-4. The theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

[0018] The fifth object of the present invention is to provide an antihypertensive agent. The supplement contains a theanine glycoside compound. The structure of the theanine glycoside compound is represented by the following formula: JPEG2024177073000010.jpg19170In the formula, R is JPEG2024177073000011.jpg24170, where n is 1-4. The theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

[0019] The sixth object of the present invention is to provide a use of theanine glycoside compound in the manufacture of supplements for improving memory and antihypertensive agents. The structure of theanine glycoside compound is represented by the following formula: JPEG2024177073000012.jpg19170In the formula, R is JPEG2024177073000013.jpg24170, where n is 1-4. In one embodiment of the invention, the use improves memory and lowers blood pressure by extending the in vivo half-life of theanine with theanine glycoside-based compounds.

[0020] In one embodiment of the invention, in said use, R is specifically Selected from JPEG2024177073000014.jpg25170.

[0021] A seventh object of the present invention is to provide a theanine glycoside compound having the following structure: JPEG2024177073000015.jpg19170R is Selected from JPEG2024177073000016.jpg24170. In one embodiment of the present invention, the theanine glycoside compound is prepared by amminating the amino group of theanine with a monosaccharide, wherein the monosaccharide is selected from galactose and ribose.

[0022] In one embodiment of the invention, the amination modification is (1) protecting the amino group of L-theanine as a substrate to obtain intermediate 1, then esterifying intermediate 1 with an alcohol compound to obtain intermediate 2, and deprotecting the amino group of intermediate 2 under the action of an oxidation reagent to obtain intermediate 3; (2) protecting and oxidizing a monosaccharide as a substrate to obtain intermediate 4; (3) using the obtained intermediate 3 and intermediate 4 as substrates, a reductive amination reaction is carried out under the action of a catalyst to obtain intermediate 5, and then the hydroxy group of intermediate 5 is deprotected with an acidic reagent to obtain intermediate 6, which is then reduced by hydrogenation to obtain the target product, theanine glycoside-based compound; Includes.

[0023] In one embodiment of the present invention, in step (1), the reaction process of protecting an amino group comprises: The method comprises dissolving L-theanine, an amino group protecting reagent, and a base reagent in a mixture of tetrahydrofuran and water, and reacting them at room temperature with stirring to obtain intermediate 1.

[0024] In one embodiment of the present invention, in the process of amino group protection described in step (1), the amino group protecting reagent is BocO (di-tert-butyl dicarbonate), and the molar ratio of L-theanine to the amino group protecting reagent is 1:(1-1.5).

[0025] In one embodiment of the present invention, in the process of amino group protection described in step (1), the basic reagent is Na2CO3, K2CO3, and the molar ratio of L-theanine to the basic reagent is 1:(2-3).

[0026] In one embodiment of the present invention, in the process of protecting amino groups described in step (1), the volume ratio of tetrahydrofuran to water in the mixed system is 1:1, and the concentration of L-theanine in the mixed system is 20-30 mg / mL, specifically, it may be 25 mg / mL.

[0027] In one embodiment of the present invention, the reaction process of esterification in step (1) is as follows: The obtained intermediate 1 and an alcohol compound are dissolved in a solvent, dichloromethane (DCM), and an esterification reaction is carried out under the action of 1-ethyl-3(3-dimethylpropylamine)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP) with stirring at room temperature to obtain intermediate 2.

[0028] In one embodiment of the present invention, in the esterification process described in step (1), the alcohol-based compound is benzyl alcohol, and the molar ratio of intermediate 1 to the alcohol-based compound is 1:(1-1.5).

[0029] In one embodiment of the present invention, in the esterification process described in step (1), the molar ratio of intermediate 1 to EDCI is 1:1.5.

[0030] In one embodiment of the present invention, in the esterification process described in step (1), the molar ratio of intermediate 1 to DMAP is 1:0.1.

[0031] In one embodiment of the present invention, in the esterification process described in step (1), the concentration of intermediate 1 relative to DCM is 20-30 mg / mL, and may specifically be 25 mg / mL.

[0032] In one embodiment of the present invention, the process of amino group deprotection described in step (1) comprises: Intermediate 2, HCl / dioxane solution and DCM are mixed and stirred at room temperature to give intermediate 3.

[0033] In one embodiment of the present invention, the reaction process of step (2) comprises: The procedure involves dissolving a monosaccharide in dichloromethane (DCM) and stirring with a mixture of DMSO (dimethylsulfoxide) and oxalyl chloride (COCl)2 as the oxidation system at -50 to -70 °C under N2 atmosphere for 10-40 min to obtain intermediate 4.

[0034] In one embodiment of the present invention, the process for preparing the oxidation system includes dispersing DMSO in DCM to obtain a DMSO dispersion, dispersing (COCl)2 in DCM pre-cooled to -50°C to -70°C to obtain a (COCl)2 dispersion, and then adding the DMSO dispersion dropwise to the (COCl)2 dispersion at -50°C to -70°C in a N2 atmosphere to obtain the oxidation system.

[0035] In one embodiment of the present invention, in the oxidation system, the molar ratio of DMSO to (COCl)2 is 2:1, the concentration of the DMSO dispersion is 0.5-1.0 g / mL, specifically, it may be 0.75 g / mL, and the concentration of the (COCl)2 dispersion is 0.05-0.1 g / mL.

[0036] In one embodiment of the present invention, the molar ratio of monosaccharide to (COCl)2 is 1:0.5-1:5. It may also be 1:(1-2).

[0037] In one embodiment of the present invention, in the reductive amination described in step (3), the molar ratio of intermediate 3 to intermediate 4 is 1:(0.8-1.5).

[0038] In one embodiment of the present invention, in the reductive amination in step (3), the catalyst is NaBH(COOCH3)3.

[0039] In one embodiment of the present invention, the reductive amination described in step (3) is carried out in a solvent DCM, and the concentration of intermediate 3 relative to DCM is 20-30 mg / mL.

[0040] In one embodiment of the present invention, the temperature of the reductive amination reaction in step (3) is -50°C to -70°C, the reaction time is 1 hour, and the reaction atmosphere is nitrogen gas.

[0041] In one embodiment of the present invention, in the deprotection of the hydroxy group in step (3), the acidic reagent is an HCl solution. The concentration of the HCl solution is 5 mol / L.

[0042] In one embodiment of the present invention, the specific process of deprotecting hydroxyl group in step (3) is to mix HCl solution with THF, then add intermediate 5, and react with stirring, where the volume ratio of HCl solution to THF is 1:1.

[0043] In one embodiment of the present invention, the hydrogenation reduction in step (3) is performed by dissolving the palladium carbon catalyst and intermediate 6 in methanol, introducing hydrogen gas, and stirring overnight at room temperature under H2 atmosphere.

[0044] In one embodiment of the present invention, the amount of palladium on carbon catalyst used relative to intermediate 6 in the hydrogenation reduction process is 10 wt %.

[0045] In one embodiment of the present invention, the main metabolite of the theanine glycoside compound in the blood and brain is theanine.

[0046] In one embodiment of the present invention, the theanine glycoside compound can improve the absorption of theanine in the body and extend its half-life in the blood and brain.

[0047] The eighth object of the present invention is to provide a method for extending the in vivo half-life of theanine, which comprises amminating the amino groups of theanine using a monosaccharide, wherein the monosaccharide is: JPEG2024177073000017.jpg25170, where n is 1-4.

[0048] In one embodiment of the present invention, the structure of the theanine glycoside compound is represented by the following formula: JPEG2024177073000018.jpg20170In the formula, R is JPEG2024177073000019.jpg24170, where n is 1-4. In one embodiment of the invention, the monosaccharide is specifically selected from fructose, galactose, ribose.

[0049] In one embodiment of the present invention, R is specifically Selected from JPEG2024177073000020.jpg24170. Effect of the Invention

[0050] In the present invention, theanine glycoside is modified with a specific monosaccharide to extend the in vivo half-life of theanine, which can be used to prepare sustained-release drugs, extend the duration of drug action, reduce the number of doses, and improve patient compliance. The modified theanine glycoside compound has a wide range of potential applications in scientific research and clinical practice, and has high commercial value. Theanine itself has many beneficial functions, such as anti-inflammatory, oxidative damage relief, sedative and antidepressant, improved learning and memory ability, improved sleep, lowered blood pressure, tumor suppression assistance, etc. In the present invention, theanine glycoside is prepared by modifying it with a specific monosaccharide, and the in vivo half-life of theanine is extended, which can be applied to the manufacture of products that extend the in vivo half-life of theanine, and the above-mentioned beneficial functions of theanine itself can be better exerted. [Brief description of the drawings]

[0051] [Figure 1] 1 is a 1H NMR spectrum of 1-deoxy-1-L-theanine-D-fructopyranose obtained in Example 1. [Diagram 2] 1H NMR spectrum of 1-deoxy-1-L-theanine-D-galactopyranose obtained in Example 2. [Diagram 3] 1H NMR spectrum of 1-deoxy-1-L-theanine-D-ribopyranose obtained in Example 3. [Figure 4] 1 shows liquid chromatographs and corresponding mass spectra of in vivo metabolites of theanine glycosid derivatives in Example 4. [Diagram 5] FIG. 1 is a diagram comparing the contents of theanine obtained by metabolism of each theanine glycoside derivative in the blood and the brain in Example 4. [Figure 6] FIG. 13 is a graph showing the change in blood concentration of theanine produced after forced oral administration of theanine glycoside in Example 5. [Figure 7] FIG. 1 shows the results of metabolic dynamics in blood of theanine and different theanine glycosides in Example 5. [Figure 8]FIG. 13 is a graph showing changes in the concentration of theanine in the brain produced after forced oral administration of theanine glycoside in Example 6. [Figure 9] FIG. 1 shows the results of metabolic dynamics in the brain of theanine and different theanine glycosides in Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] Example 1: Method for extending the in vivo half-life of theanine Synthesis of 1-deoxy-1-L-theanine-D-fructopyranose based on theanine JPEG2024177073000021.jpg85170JPEG2024177073000022.jpg69170

[0053] Preparation of intermediate 1 At room temperature, L-theanine (10.0 g, 57.4 mmol) was added to a mixture of 200 mL of THF and 200 mL of H2O, and Na2CO3 (18.25 g, 172.2 mmol) and Boc2O (13.8 g, 63.2 mmol) were added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was diluted with 300 mL of water, then washed with 3 volumes of ethyl acetate (300 mL x 3), the organic layer was collected, and the remaining aqueous layer was acidified to pH = 3 with saturated citric acid, and then extracted with ethyl acetate (300 mL x 3), the organic phases were collected and combined, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain intermediate 1 (12.6 g, yield: 80%) as a colorless oil. LCMS: C 12 H 22 The theoretical m / z value for N2O5 is 274.32, and the measured value is 275.1.

[0054] Preparation of intermediate 2 Intermediate 1 (12.6 g, 45.9 mmol) and benzyl alcohol (5.46 g, 50.5 mmol) were added to 500 mL of DCM, and EDCI (13.2 g, 68.8 mmol) and DMAP (560 mg, 4.59 mmol) were further added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was washed with 200 mL of H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain a white solid compound, intermediate 2 (9.66 g, 57.7% yield). LCMS: C 19 H 28 The theoretical m / z value of N2O5 is 364.44, and the measured value is 365.0.

[0055] Preparation of intermediate 3 Intermediate 2 (9.66 g, 26.5 mmol) and 4 mol / L HCl / dioxane solution (66 mL, 265 mmol) were added to 100 mL of DCM and stirred at room temperature overnight to give a mixture. The mixture was concentrated in vacuo to give Intermediate 3 (10.45 g, crude) as a yellow oil. No further purification was required. LCMS: 14 H 20 The theoretical m / z value for N2O3 is 264.33, and the measured value is 265.3.

[0056] Preparation of intermediate 4a DMSO (9.0 g, 115.2 mmol) was added to 12 mL of DCM to obtain a DMSO dispersion. (COCl)2 (7.3 g, 57.6 mmol) was added to 100 mL of DCM solution precooled to -60°C, and after uniform mixing, a (COCl)2 dispersion was obtained. The DMSO dispersion was added dropwise to the (COCl)2 dispersion in a N2 atmosphere at -60°C, and the mixture was stirred for 20 min to obtain an oxidation system. Fructose (15.0 g, 83.3 mmol) was dissolved in DCM (66 mL) under N2 atmosphere at -60°C, added dropwise to the oxidation system, and stirred for 30 min. Triethylamine (32 mL, 0.23 mmol) was added dropwise to the mixture solution under N2 and -60°C conditions, stirred for 10 min, slowly warmed to room temperature, and allowed to stand overnight. The mixture was washed with H2O (100 mL), 1 mol / L pre-cooled HCl (200 mL), and brine (150 mL), and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give intermediate 4a (8.06 g, crude oil) as a brown oil. No purification was required. LCMS: C 12 H 18 The theoretical m / z of O6 is 258.11, and the measured value is 258.21.

[0057] Preparation of intermediate 5a by reductive amination Intermediate 3 (7.95 g, 26.7 mmol) and intermediate 4a (10.24 g, 26.0 mmol) were added to 300 mL of DCM, followed by NaBH(COOCH3)3 (17 g, 80.1 mmol) and stirring at room temperature overnight to form a mixture. Then, the mixture was washed with H2O (200 mL), the organic phase was collected, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain the crude product. The crude product was further purified by silica gel chromatography (n-hexane:ethyl acetate = 1:1 to 0:1) to obtain intermediate 5a (10.0 g, two-step yield: 51%) as a yellow oil. LCMS: C 26 H 38 The theoretical m / z value for N2O8 is 506.60, and the measured value is 507.8.

[0058] Preparation of intermediate 6a by deprotection of the hydroxy group of intermediate 5a Intermediate 5a (2.0 g, 3.95 mmol) was added to a mixture of 5 mol / L HCl solution (8 mL, 40 mmol) and THF (8 mL), and the solution was stirred at 30° C. for 2 days. The mixture was then diluted with water (16 mL) and the aqueous layer was washed with diethyl ether (20 mL×2) and ethyl acetate (20 mL×2). The pH of the aqueous layer was adjusted with NaHCO3 (3.4 g, 4.0 mmol), and then washed with ethyl acetate (20 mL×2). The aqueous layer was collected and concentrated, and the residue was purified by chromatography on silica gel (DCM:MeOH:2%NH3 / MeOH=10:1:1) to give intermediate 6a (210 mg, yield: 12%) as a yellow oil. LCMS: C 20 H 30 The theoretical m / z value for N2O8 is 426.46, and the measured value is 427.5.

[0059] Preparation of the desired product 1-deoxy-1-L-theanine-D-fructopyranose by hydrogenation reduction of intermediate 6a Intermediate 6a (300 mg, 0.67 mmol) and palladium carbon catalyst (10%, 50 mg) were dissolved in methanol (5 mL) and stirred at room temperature in an H2 atmosphere (hydrogen balloon) for 5 hours and then allowed to stand overnight to give a mixture. The mixture was filtered through diatomaceous earth, washed with MeOH, and the filtrate was concentrated in vacuo to give the white solid product theanine glycoside (200 mg, yield: 84%). Structural characterization of 1-deoxy-1-L-theanine-D-fructopyranose HNMR(400MHz,CDCl3):δ4.32(s,OH),4.77(s,OH),4.74(s,OH),4.51(s,OH),12.39(s,OH),8.01(s,NH),5.52(s,NH),5.85(d,C H),3.88(dd,CH),3.6(t,CH),3.7(t,CH),2.94(dd,CH2),3.40(t,CH),3.11(q,CH2),2.05(t,CH2),1.92(m,CH2),0.99(t,CH3).

[0060] Example 2: Method for extending the in vivo half-life of theanine Synthesis of 1-deoxy-1-L-theanine-D-galactopyranose based on theanine JPEG2024177073000023.jpg163170

[0061] Preparation of intermediate 1 At room temperature, L-theanine (10.0 g, 57.4 mmol) was added to a mixture of 200 mL of THF and 200 mL of H2O, and Na2CO3 (18.25 g, 172.2 mmol) and Boc2O (13.8 g, 63.2 mmol) were added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was diluted with 300 mL of water, washed with 3 volumes of ethyl acetate (300 mL x 3), the organic layer was collected, the remaining aqueous layer was acidified to pH = 3 with saturated citric acid, and then extracted with ethyl acetate (300 mL x 3), the organic phase was collected and combined, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain intermediate 1 (12.6 g, yield: 80%) as a colorless oil. LCMS: C 12 H 22 The theoretical m / z value for N2O5 is 274.32, and the measured value is 275.1.

[0062] Preparation of intermediate 2 Intermediate 1 (12.6 g, 45.9 mmol) and benzyl alcohol (5.46 g, 50.5 mmol) were added to 500 mL of DCM, and EDCI (13.2 g, 68.8 mmol) and DMAP (560 mg, 4.59 mmol) were further added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was washed with 200 mL of H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain a white solid compound, intermediate 2 (9.66 g, yield 57.7%). LCMS:C 19 H 28 The theoretical m / z value of N2O5 is 364.44, and the measured value is 365.0.

[0063] Preparation of intermediate 3 Intermediate 2 (9.66 g, 26.5 mmol) and 4 mol / L HCl / dioxane solution (66 mL, 265 mmol) were added to 100 mL of DCM and stirred at room temperature overnight to give a mixture. The mixture was concentrated in vacuo to give intermediate 3 (10.45 g, crude oil) as a yellow oil. No further purification was required. LCMS:C 14 H 20 The theoretical m / z value for N2O3 is 264.33, and the measured value is 265.3.

[0064] Preparation of intermediate 4b DMSO (9.0 g, 115.2 mmol) was added to 12 mL of DCM to obtain a DMSO dispersion. (COCl)2 (7.3 g, 57.6 mmol) was added to 100 mL of DCM solution precooled to -60°C, and after uniform mixing, a (COCl)2 dispersion was obtained. The DMSO dispersion was added dropwise to the (COCl)2 dispersion in a N2 atmosphere at -60°C, and stirred for 20 min to obtain an oxidation system. Galactose (10.0 g, 55.5 mmol) was dissolved in DCM (66 mL) under N2 atmosphere at -60°C and added dropwise to the mixture and stirred for 30 min. Triethylamine (32 mL, 0.23 mmol) was added dropwise to the mixture under N2 and -60°C conditions and stirred for 10 min, slowly warmed to room temperature and allowed to stand overnight. The mixture was washed with H2O (100 mL), 1 mol / L pre-cooled HCl (200 mL) and brine (150 mL), respectively, and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give intermediate 4b (7.88 g, crude oil) as a brown oil. No purification was required. LCMS: C 12 H 18 The theoretical m / z of O6 is 258.11, and the measured value is 258.20.

[0065] Preparation of intermediate 5b by reductive amination Intermediate 3 (7.95 g, 26.7 mmol) and intermediate 4b (10.24 g, 26.0 mmol) were added to 300 mL of DCM, followed by the addition of NaBH(COOCH3)3 (17 g, 80.1 mmol) and stirring at room temperature overnight to form a mixture. The mixture was then washed with H2O (200 mL), the organic phase was collected, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain the crude product. The crude product was further purified by silica gel chromatography (n-hexane:ethyl acetate = 1:1 to 0:1) to obtain intermediate 5b (9.82 g, two-step yield: 49.5%) as a yellow oil. LCMS:C 26 H 38 The theoretical m / z value for N2O8 is 506.60, and the measured value is 507.8.

[0066] Preparation of intermediate 6b by deprotection of the hydroxy group of intermediate 5b Intermediate 5b (2.0 g, 3.95 mmol) was added to a mixture of 5 mol / L HCl solution (8 mL, 40 mmol) and THF (8 mL), and the solution was stirred at 30° C. for 2 days. The mixture was then diluted with water (16 mL) and the aqueous layer was washed with diethyl ether (20 mL×2) and ethyl acetate (20 mL×2). The pH of the aqueous layer was adjusted with NaHCO3 (3.4 g, 4.0 mmol), and then washed with ethyl acetate (20 mL×2). The aqueous layer was collected and concentrated, and the residue was purified by chromatography on silica gel (DCM:MeOH:2%NH3 / MeOH=10:1:1) to give intermediate 6b (180 mg, yield: 11%) as a yellow oil. LCMS:C 20 H 30 The theoretical m / z value for N2O8 is 426.46, and the measured value is 427.5.

[0067] Preparation of the desired product 1-deoxy-1-L-theanine-D-galactopyranose by hydrogenolysis of intermediate 6b Intermediate 6b (300 mg, 0.67 mmol) and palladium on carbon catalyst (10%, 50 mg) were dissolved in methanol (5 mL) and stirred at room temperature under H2 atmosphere (hydrogen balloon) for 5 h and then allowed to stand overnight to give a mixture. The mixture was filtered through diatomaceous earth, washed with MeOH, and the filtrate was concentrated in vacuo to give the white solid product theanine glycoside (177 mg, yield: 79.5%).

[0068] Structural characterization of 1-deoxy-1-L-theanine-D-galactopyranose HNMR(400MHz,CDCl3):δ4.32(s,OH),4.77(s,OH),4.88(s,OH),4.51(s,OH),12.39(s,OH),8.01(s,NH),5.52(s,NH),5.70(m,CH),3.55(m,C H),3.70(m,CH),3.60(m,CH),3.70(m,CH),2.79,2.53500(dd,CH2),3.40(dd,CH),3.11(q,CH2),2.05(t,CH2),1.92(dd,CH2),0.99(t,CH3).

[0069] Example 3: Method for extending the in vivo half-life of theanine Synthesis of 1-deoxy-1-L-theanine-D-ribopyranose based on theanine JPEG2024177073000024.jpg169170

[0070] Preparation of intermediate 1 At room temperature, L-theanine (10.0 g, 57.4 mmol) was added to a mixture of 200 mL of THF and 200 mL of H2O, and Na2CO3 (18.25 g, 172.2 mmol) and Boc2O (13.8 g, 63.2 mmol) were added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was diluted with 300 mL of water, then washed with 3 volumes of ethyl acetate (300 mL x 3), the organic layer was collected, the remaining aqueous layer was acidified to pH = 3 with saturated citric acid, and then extracted with ethyl acetate (300 mL x 3), the organic phase was collected and combined, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain intermediate 1 (12.6 g, yield: 80%) as a colorless oil. LCMS: C12 H 22 The theoretical m / z value for N2O5 is 274.32, and the measured value is 275.1.

[0071] Preparation of intermediate 2 Intermediate 1 (12.6 g, 45.9 mmol) and benzyl alcohol (5.46 g, 50.5 mmol) were added to 500 mL of DCM, and EDCI (13.2 g, 68.8 mmol) and DMAP (560 mg, 4.59 mmol) were further added, and the mixture was stirred at room temperature overnight to obtain a mixture. The mixture was washed with 200 mL of H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain a white solid compound, intermediate 2 (9.66 g, yield 57.7%). LCMS: C 19 H 28 The theoretical m / z value of N2O5 is 364.44, and the measured value is 365.0.

[0072] Preparation of intermediate 3 To 100 mL of LDCM was added intermediate 2 (9.66 g, 26.5 mmol) and 4 mol / L HCl / dioxane solution (66 mL, 265 mmol) and stirred at room temperature overnight to give a mixture. The mixture was concentrated in vacuo to give intermediate 3 (10.45 g, crude) as a yellow oil. No further purification was required. LCMS: C 14 H 20 The theoretical m / z value for N2O3 is 264.33, and the measured value is 265.3.

[0073] Preparation of intermediate 4c DMSO (9.0 g, 115.2 mmol) was added to 12 mL of DCM to obtain a DMSO dispersion. (COCl)2 (7.3 g, 57.6 mmol) was added to 100 mL of DCM solution precooled to -60°C, and after uniform mixing, a (COCl)2 dispersion was obtained. The DMSO dispersion was added dropwise to the (COCl)2 dispersion in a N2 atmosphere at -60°C, and stirred for 20 min to obtain an oxidation system. Ribose (15.0 g, 99.9 mmol) was dissolved in DCM (66 mL) under N2 atmosphere at -60°C and added dropwise to the mixture and stirred for 30 min. Triethylamine (32 mL, 0.23 mmol) was added dropwise to the mixture under N2 and -60°C conditions and stirred for 10 min, slowly warmed to room temperature and allowed to stand overnight. The mixture was washed with H2O (100 mL), 1 mol / L pre-cooled HCl (200 mL) and brine (150 mL), respectively, and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give intermediate 4c (7.55 g, crude oil) as a brown oil. No purification was required. LCMS: C8H 12 The theoretical m / z value of O5 is 188.07, and the measured value is 188.15.

[0074] Preparation of intermediate 5c by reductive amination Intermediate 3 (7.95 g, 26.7 mmol) and intermediate 4c (14.46 g, 26.0 mmol) were added to 300 mL of DCM, followed by the addition of NaBH(COOCH3)3 (17 g, 80.1 mmol) and stirring at room temperature overnight to form a mixture. The mixture was then washed with H2O (200 mL), the organic phase was collected, the organic layer was dried over anhydrous Na2SO4, and concentrated in vacuum to obtain the crude product. The crude product was further purified by silica gel chromatography (n-hexane:ethyl acetate = 1:1 to 0:1) to obtain intermediate 5c (9.66 g, 2-step yield: 48.7%) as a yellow oil. LCMS: C 22 H 32 The theoretical m / z value for N2O7 is 436.22, and the measured value is 436.32.

[0075] Preparation of intermediate 6c by deprotection of the hydroxy group of intermediate 5c Intermediate 5c (2.0 g, 3.95 mmol) was added to a mixture of 5 mol / L HCl solution (8 mL, 40 mmol) and THF (8 mL), and the solution was stirred at 30° C. for 2 days. The mixture was then diluted with water (16 mL) and the aqueous layer was washed with diethyl ether (20 mL×2) and ethyl acetate (20 mL×2). The pH of the aqueous layer was adjusted with NaHCO3 (3.4 g, 4.0 mmol), and the aqueous layer was washed with ethyl acetate (20 mL×2). The aqueous layer was collected and concentrated, and the residue was purified by chromatography on silica gel (DCM:MeOH:2%NH3 / MeOH=10:1:1) to give intermediate 6c (178 mg, yield: 10.8%) as a yellow oil. LCMS: C 19 H 28 The theoretical m / z value for N2O7 is 396.44, and the measured value is 396.22.

[0076] Preparation of the desired product 1-deoxy-1-L-theanine-D-ribopyranose by hydrogenolysis of intermediate 6c Intermediate 6c (300 mg, 0.67 mmol) and palladium on carbon catalyst (10%, 50 mg) were dissolved in methanol (5 mL) and stirred at room temperature under H2 atmosphere (hydrogen balloon) for 5 h and then allowed to stand overnight to give a mixture. The mixture was filtered through diatomaceous earth, washed with MeOH, and the filtrate was concentrated in vacuo to give the white solid product theanine glycoside (191 mg, yield: 80.2%).

[0077] Structural characterization of 1-deoxy-1-L-theanine-D-ribopyranose HNMR(400MHz,CDCl3):δ4.22(s,OH),4.37(s,OH),4.51(s,OH),12.39(s,OH),8.01(s,NH),5.52(s,NH),5.85(d,CH),3.70(d d,CH),3.95(t,CH),4.51(t,CH),2.79,2.53(dd,CH2),3.40(t,CH),3.11(q,CH2),2.05(t,CH2),1.92(m,CH2),0.99(t,CH3).

[0078] Example 4: Examination of in vivo metabolites of theanine glycoside derivatives 1-Deoxy-1-L-theanine-D-fructopyranose was designated theanine glycoside 1, 1-deoxy-1-L-theanine-D-galactopyranose was designated theanine glycoside 2, and 1-deoxy-1-L-theanine-D-ribopyranose was designated theanine glycoside 3.

[0079] 1. Test animals: C57BL / 6J mice, male, body weight (20±2) g

[0080] 2. Dosing and Sample Collection Mice were administered theanine glycoside (n=6) by oral gavage. They were not fed for 12 hours before administration, and water was allowed to be consumed ad libitum. After oral gavage, the mice could be provided with water. The dose of oral gavage was 500mg / kg. After 1h administration, the eyes of six mice in each group were removed and 0.5mL of blood was collected, and the mice were killed by cervical dislocation, dissected to remove their brain tissue, and the blood samples were centrifuged at 3000g for 15min, and the supernatant of the blood samples was separated and stored at -80℃ for later examination.

[0081] 3. Instrument conditions and blood sample measurement Instrument: SCIEX Triple Quad(R) 5500 LC-MS / MS Sample processing 100 μL of blood sample and 20 mg of brain tissue were each mixed with 1.5 mL of 70% aqueous methanol, vortexed for 30 s, sonicated in an ice-water bath for 10 min, and incubated at -20°C for 20 min to precipitate proteins. The samples were briefly centrifuged for 15 s (twice), the supernatants were removed, evaporated at 4°C using a vacuum concentrator, redissolved in 200 μL of methanol, and centrifuged at 4°C at 12,000 g for 15 min. 100 μL of the supernatant was taken for LC-MS / MS analysis.

[0082] 4. Experimental Results The liquid chromatograph and the corresponding mass spectrum are shown in Figure 4. The content of theanine obtained by metabolism of each theanine glycosid derivative in the blood and brain is shown in Figure 5. As a result, the main metabolite in the blood and brain of the theanine glycosid derivatives forcefully administered to mice was theanine.

[0083] Example 5: Pharmacokinetics of theanine produced by metabolism of theanine glycoside derivatives in blood 1-Deoxy-1-L-theanine-D-fructopyranose was designated theanine glycoside 1, 1-deoxy-1-L-theanine-D-galactopyranose was designated theanine glycoside 2, and 1-deoxy-1-L-theanine-D-ribopyranose was designated theanine glycoside 3.

[0084] 1. Experimental animals: SD rats, male, weight (180±20)g

[0085] 2. Dosing and Sample Collection Rats were administered the theanine or theanine glycoside by gavage (n=6). They were randomly divided into two groups, the theanine group and the theanine glycoside group. They were not fed for 12 hours before administration, but were allowed to drink water ad libitum. After gavage, the rats were allowed to drink water. The dose for gavage was 500mg / kg. Blood was collected from the orbit of six rats in each group before administration and 1, 2, 4, 8, and 12 hours after administration. 0.5mL of blood was collected, and the blood samples were centrifuged at 3000g for 15 minutes, and the supernatant of the blood samples was separated and stored at -80℃.

[0086] 3. Instrument Conditions and Blood Sample Measurement Instrument: SCIEX Triple Quad(R) 5500 LC-MS / MS Preparation of standard curve 100μL of blank plasma from rats was added to 1.5mL of 70% aqueous methanol solution, mixed with a vortex for 30s, sonicated in an ice-water bath for 10min, left to stand at -20℃ for 20min to precipitate proteins, briefly centrifuged for 15s (twice), the supernatant was removed, evaporated at 4℃ using a vacuum concentrator, redissolved in 200μL methanol, and 200μL of standard stepwise solution of the test compound and 10μL of internal standard (DL-4-chlorobenzamide) were added in order to prepare blood samples of the test compound corresponding to plasma concentrations of 0.1, 1, 10, 100, 1000, and 10000μM, and LC-MS / MS analysis was performed. The test substance concentration (x) was taken as the abscissa, and the peak area ratio (y) between the test substance and the internal standard was taken as the ordinate, and a linear regression equation, i.e., a standard curve, was obtained by regression calculation using the weighted least squares method. The linear range of the test compound in rat plasma was calculated to be 0.1-10000 μM by the LC-MS / MS method based on the standard curve. Blood sample processing 100 μL of rat blood sample was mixed with 1.5 mL of 70% aqueous methanol, vortexed for 30 s, sonicated in an ice-water bath for 10 min, incubated at -20°C for 20 min to precipitate proteins, briefly centrifuged for 15 s (twice), the supernatant was removed, evaporated at 4°C using a vacuum concentrator, redissolved in 200 μL methanol, centrifuged at 4°C at 12,000 g for 15 min, and 100 μL of the supernatant was taken for LC-MS / MS analysis. The half-life T is calculated using the following formula: 1 / 2 was calculated.

number

[0087] 4. Experimental Results The blood concentration changes of theanine produced after oral gavage of theanine glycoside are shown in Figure 6. The corresponding pharmacokinetic results are shown in Table 1 and Figure 7.

[0088] Table 1: Blood half-life results for theanine and different theanine glycosides JPEG2024177073000026.jpg29170

[0089] Example 6: Pharmacokinetic measurement of theanine produced by metabolism of theanine glycoside derivatives in the brain 1-Deoxy-1-L-theanine-D-fructopyranose was designated theanine glycoside 1, 1-deoxy-1-L-theanine-D-galactopyranose was designated theanine glycoside 2, and 1-deoxy-1-L-theanine-D-ribopyranose was designated theanine glycoside 3.

[0090] 1. Experimental animals: C57BL / 6J mice, male, weight (20±2)g

[0091] 2. Dosing and Sample Collection Mice were administered the theanine or theanine glycoside by gavage (n=6). They were randomly divided into two groups, the theanine group and the theanine glycoside group. They were not fed for 12 hours before administration, but were allowed to drink water ad libitum. After gavage, the mice were allowed to drink water. The dose for gavage was 500mg / kg. Six mice from each group were killed by cervical dislocation before administration and 1, 2, 4, 8, and 12 hours after administration. They were dissected and their brain tissues were extracted and stored at -80℃ for later examination.

[0092] 3. Apparatus Conditions and Brain Tissue Measurement Instrument: SCIEX Triple Quad(R) 5500 LC-MS / MS Preparation of standard curve 20 mg of mouse brain tissue was placed in 1.5 mL of 70% aqueous methanol, mixed with a vortex for 30 s, sonicated in an ice-water bath for 10 min, and left to stand at -20 ° C for 20 min to precipitate proteins, then briefly centrifuged for 15 s (twice), the supernatant was removed, evaporated at 4 ° C using a vacuum concentrator, and redissolved in 200 μL methanol, and 200 μL of the standard step solution of the test compound and 10 μL of the internal standard (DL-4-chlorobenzamide) were added in order to prepare brain tissue samples of the test compound corresponding to brain tissue concentrations of 0.1, 1, 10, 100, 1000, and 10000 μM, and LC-MS / MS analysis was performed. The test substance concentration (x) was taken as the abscissa, and the peak area ratio (y) between the test substance and the internal standard was taken as the ordinate, and a linear regression equation, i.e., a standard curve, was obtained by regression calculation using the weighted least squares method. The linear range of the test compound in mouse plasma was calculated to be 0.1-10000 μM by the LC-MS / MS method based on the standard curve. Processing of brain tissue samples Brain tissue mass (20±2mg) was precisely weighed and placed in a 2mL EP tube, 70% methanol aqueous solution was added at 20mg / 1.5mL, homogenized at low temperature of 4℃ using a freeze grinder, mixed by vortexing for 30s, sonicated in an ice-water bath for 10min, incubated at -20℃ for 20min to precipitate proteins, briefly centrifuged for 15s (twice), the supernatant was removed, evaporated at 4℃ using a vacuum concentrator, redissolved in 200μL methanol, centrifuged at 4℃ and 12000g for 15min, and 100μL of the supernatant was taken for LC-MS / MS analysis.

[0093] 4. Experimental Results The changes in theanine concentration in the brain after oral gavage of theanine glycoside are shown in Figure 8. The corresponding metabolic results are shown in Table 2 and Figure 9.

[0094] Table 2: Half-life results in the brain for theanine and different theanine glycosides JPEG2024177073000027.jpg30170

[0095] Example 7: Use of theanine glycosides in the manufacture of products that extend the in vivo half-life of theanine A use of a theanine glycoside compound in the manufacture of a product for extending the in vivo half-life of theanine, the structure of the theanine glycoside compound being represented by the following formula: JPEG2024177073000028.jpg19170In the formula, R is JPEG2024177073000029.jpg24170, where n is 1-4.

[0096] The products may be based on any disclosed known formulation or product containing theanine, and may substitute any one or more of the theanine glycoside compounds listed above in place of some or all of the theanine.

[0097] The main metabolite of the theanine glycoside compound in the blood and brain is theanine, which can improve the absorption of theanine in the body and extend its half-life in the blood and brain.

[0098] Alternatively, the product may be a learning and memory improving product, a sleep improving product, a blood pressure lowering product, a product for maintaining healthy blood pressure levels, a tumor suppression aid product, and the like.

[0099] In this embodiment, the theanine glycoside compound can be used in place of a part or all of theanine in any existing product. It may be, but is not limited to, an improved version of a published product. The product of this embodiment can exert the desired effect because it has been discovered for the first time that the theanine glycoside compound in the product has the function of extending the half-life of theanine in the blood and brain, and it has been discovered that theanine has the corresponding functions of the disclosed product (e.g., anti-inflammation, mitigation of oxidative damage, sedation and antidepressant, improvement of learning and memory ability, improvement of sleep, lowering blood pressure, assisting in tumor suppression, etc.).

[0100] Example 8: Products that extend the in vivo half-life of theanine prepared using theanine glycoside compounds This embodiment provides the use of a theanine glycoside-based compound in the manufacture of a product for extending the half-life of theanine in vivo. The product for extending the half-life of theanine in vivo is a sleep-promoting composition comprising a theanine glycoside-based compound. The structure of the theanine glycoside-based compound is represented by the following formula: JPEG2024177073000030.jpg19170In the formula, R is JPEG2024177073000031.jpg24170, where n is 1-4.

[0101] Optionally, the theanine glycoside compound may be one or more of 1-deoxy-1-L-theanine-D-fructopyranose, 1-deoxy-1-L-theanine-D-galactopyranose, and 1-deoxy-1-L-theanine-D-ribopyranose.

[0102] Currently, the use of theanine in the manufacture of food or medicine for promoting sleep in subjects with sleep disorders has already been reported (CN100374108C (sleep-promoting composition)). In this embodiment, the theanine glycoside compound can be used in place of part or all of the theanine in the existing food or medicine for promoting sleep in subjects with sleep disorders, and there is no need to make other improvements to the existing food or medicine.

[0103] This embodiment provides a sleep-promoting composition that contains the theanine glycoside compound or is based on an existing sleep-promoting composition and further contains a food or medicine suitable for subjects with sleep disorders.

[0104] The sleep-promoting composition of this embodiment (hereinafter, "composition") can be used to alleviate or improve various sleep disorders caused by various factors in daily life. The composition of this embodiment can exert the desired effects based on the function of the theanine glycoside compound in the composition to extend the half-life of theanine in the blood and brain, which was discovered for the first time, and the sleep-promoting effect of theanine that has already been discovered.

[0105] The content of the theanine glycoside compound in the composition of the embodiment is not particularly limited and may be appropriately adjusted as necessary. For example, the content of the theanine glycoside compound in the composition is preferably 5-100% by weight, particularly preferably 50-100% by weight.

[0106] The composition of this embodiment may further contain various minerals. The composition containing minerals is particularly preferably a composition that has the effect of replenishing essential elements and trace essential elements that are easily deficient in the living body. The content of the minerals in the composition is preferably 0.0001 to 99.9% by weight, more preferably 0.01 to 99.9% by weight. Examples of the minerals include metals or salts thereof that are necessary for maintaining and regulating the stability of the living body, such as iron, magnesium, copper, zinc, selenium, calcium, potassium, manganese, chromium, iodine, molybdenum, nickel, and vanadium. These substances may be used alone or in combination of two or more.

[0107] The composition may further contain natural drugs, medicinal herbs, amino acids, vitamins, etc. The natural drugs contained are not particularly limited, but are preferably Ganoderma lucidum, Rehmannia stalk, and jujube, which are effective in calming the nerves. Furthermore, the medicinal herbs are not particularly limited, and include, for example, fennel, ginseng seeds, cloves, coriander, oak, cinnamon, juniper, ginger, sweet orange, pine needles, basil, patchouli, bitter orange, small fennel, black pepper, laurel, peppermint, bergamot, mandarin orange, myrrh, lemongrass leaves, rosemary, grapefruit, lignum cedrum, fragrant sage, musk herb, tea plant, purple leaves, herbs, hyssop, eucalyptus, lime, lemon, ylang-ylang tree, and cucumber. Examples of herbs include rudamone, sage, jasmine, geranium, sweet chrysanthemum, Bulgarian rose, rose, frankincense, lavender, sandalwood, neroli oil, verbena, vetiver, oregano, rosewood, wild willow, St. John's malt, and tuna, among which, peppermint, bergamot, ylang-ylang tree, geranium, sweet chrysanthemum, lavender, St. John's malt, and tuna, which have sedative and relaxing effects, are preferred. The form of these herbs may be, for example, an extract, essential oil, herbal tea, etc., and is not particularly limited. The amino acid is also not particularly limited, and may be, for example, glutamine, glutamic acid, tryptophan, alanine, arginine, aspartic acid, threonine, serine, gamma-aminobutyric acid, aminoethanesulfonic acid, thiotaurine, and hypotaurine. Vitamins include, but are not limited to, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, niacin, lipoic acid, pantothenic acid, biotin, coenzyme Q, prostaglandin, and derivatives of these vitamins.Further, other ingredients include, for example, aloe vera, royal jelly, melatonin, placenta, propolis, isoflavones, soy lecithin, egg yolk lecithin, egg butter, chondroitin, cocoa mass, collagen, vinegar, chlorella, spirulina, ginkgo leaves, green tea, Eucommia tea, Yellow Queen tea, Oolong tea, mulberry leaves, sweet tea, unsaturated fatty acids, sugars such as oligosaccharides; fungi such as bifidobacteria and sake koji; mushrooms such as agaricus; lingonberries, prunes, grapes, oligosaccharides, etc. Examples of such substances include fruits such as Japanese apricots and citrus fruits; seeds such as peanuts, almonds, sesame and chili peppers; vegetables such as green chili peppers, red chili peppers, scallions, pumpkins, bitter melons, carrots, burdock, hemp leaves, garlic, shiso, wasabi, tomatoes, leeks, vegetable leaves, tubers and beans; seaweed such as wakame seaweed; fish; meat of animals, birds and whales; and grains. These substances or their extracts, dried products, crude products, refined products, processed products, brewed products and the like can be appropriately selected as necessary. Furthermore, as one embodiment of this embodiment, a food or medicine containing the composition of this embodiment, suitable for daily use, and applicable to subjects with sleep disorders is provided. Such food or medicine is not particularly limited as long as it is a composition containing the theanine glycoside compound of the present invention. In addition, the "subject" in this embodiment refers to, for example, mammals, specifically, humans, pigs, cows, dogs, cats, horses, etc., and is particularly preferably humans.

[0108] Examples of foods containing the theanine glycoside compound of this embodiment include the following foods.

[0109] Examples of foods include solid foods; liquid foods such as soft drinks, mineral water, high-end drinks, and alcoholic drinks. The liquid foods listed here are not particularly limited, and are preferably green tea, oolong tea, black tea, herbal tea, and other teas, concentrated fruit juice, concentrated reconstituted fruit juice, pure fresh fruit juice, complex fruit juice, fruit juice with added pulp, fruit juice-containing drinks, fruit and vegetable complex juice, vegetable juice, mineral water, carbonated drinks, soft drinks, milk, milk drinks, sake, beer, wine, cocktails, shochu, whiskey, and the like. Furthermore, the solid foods are also not particularly limited, and are preferably soy products, soybean processed products, jellies, lactic acid, cold sweets, sugar, chocolate, gum, crackers, snacks, cookies, bread, and the like.

[0110] Furthermore, the pharmaceutical of this embodiment is not particularly limited as long as it contains theanine glycoside compound. For example, its form may be any one of solution, suspension, powder, solid molding, etc. Its dosage form may be tablet, capsule, powder, granule, drink, etc. Furthermore, it may be used in combination with other pharmaceuticals.

[0111] Example 9: Sleep aid supplement containing theanine glycoside compound This embodiment provides a supplement that calms the mind, quiets the spirit, and promotes sleep. The optimal mass ratio of each component in the formula is 8-12 parts lily powder, 8-12 parts theanine glycoside compound, 8-12 parts jujube seed extract, 8-12 parts ganoderma lucidum extract, 8-12 parts mulberry powder, 8-12 parts lotus seed powder, 3-7 parts poria extract, 3-7 parts yam extract, 3-7 parts ginkgo leaf extract, 3-7 parts L-tryptophan, 2-5 parts oryzanol, 10.2-0.8 parts vitamin B, 0.2-0.8 parts vitamin B6, 0.1-0.4 parts vitamin B12, and 0.005-0.015 parts folic acid. The final dosage form is a powder.

[0112] The theanine glycoside compound has the following structure: JPEG2024177073000032.jpg20170In the formula, R is JPEG2024177073000033.jpg24170, where n is 1-4.

[0113] Optionally, the theanine glycoside compound may be one or more of 1-deoxy-1-L-theanine-D-fructopyranose, 1-deoxy-1-L-theanine-D-galactopyranose, and 1-deoxy-1-L-theanine-D-ribopyranose.

[0114] Optionally, the optimal weight ratio of each component in the formula is 10 parts lily powder, 10 parts theanine glycoside compound, 10 parts jujube seed extract, 10 parts ganoderma lucidum extract, 10 parts mulberry bark powder, 10 parts lotus seed powder, 5 parts poria extract, 5 parts yam extract, 5 parts ginkgo leaf extract, 5 parts L-tryptophan, 3.5 parts oryzanol, 10.5 parts vitamin B, 60.5 parts vitamin B, 120.25 parts vitamin B, and 0.01 parts folic acid.

[0115] Example 10: Sustained release drug containing theanine glycoside compound This embodiment provides a sustained release drug comprising a theanine glycoside compound, the structure of which is represented by the following formula: JPEG2024177073000034.jpg19170In the formula, R is JPEG2024177073000035.jpg24170, where n is 1-4. Optionally, the theanine glycoside compound may be one or more of 1-deoxy-1-L-theanine-D-fructopyranose, 1-deoxy-1-L-theanine-D-galactopyranose, and 1-deoxy-1-L-theanine-D-ribopyranose. Alternatively, the form may be any one of a solution, a suspension, a powder, a solid molded product, etc., and is not particularly limited. Alternatively, they may be provided in the form of capsules, tablets, powders, granules, beverages, etc. Furthermore, they may be used in combination with other supplements.

[0116] Example 11: Supplement for improving memory containing theanine glycoside compound This embodiment provides a supplement for improving memory, which contains a theanine glycoside compound, the structure of which is represented by the following formula: JPEG2024177073000036.jpg19170In the formula, R is JPEG2024177073000037.jpg24170, where n is 1-4. Optionally, the theanine glycoside compound may be one or more of 1-deoxy-1-L-theanine-D-fructopyranose, 1-deoxy-1-L-theanine-D-galactopyranose, and 1-deoxy-1-L-theanine-D-ribopyranose. Alternatively, the form may be any one of a solution, a suspension, a powder, a solid molded product, etc., and is not particularly limited. Alternatively, they may be provided in the form of capsules, tablets, powders, granules, beverages, etc. Furthermore, they may be used in combination with other supplements.

[0117] Example 12: Hypoglycemic drug containing theanine glycoside compound In this embodiment, the weight parts are The present invention provides an antihypertensive agent comprising 10-22 parts of Phellodendron Bark, 6-11 parts of Rhubarb, 22-36 parts of Xanthomonas Root, 11-21 parts of Forsythia Fruit, 8-22 parts of Magnolia Root, 10-18 parts of Moutan Cortex, 30-50 parts of Pueraria Root, and 1-20 parts of theanine glycoside compound. Here, the structure of theanine glycoside compound is represented by the following formula. JPEG2024177073000038.jpg19170In the formula, R is JPEG2024177073000039.jpg24170, where n is 1-4. Optionally, the theanine glycoside compound may be one or more of 1-deoxy-1-L-theanine-D-fructopyranose, 1-deoxy-1-L-theanine-D-galactopyranose, and 1-deoxy-1-L-theanine-D-ribopyranose. Optionally, the antihypertensive agent contains, by weight, 16 parts Phellodendron Bark, 8.5 parts Rhubarb, 29 parts Xanthomonas Root, 16 parts Forsythia Fruit, 15 parts Magnolia Root, 14 parts Moutan Cortex, 40 parts Pueraria Root, and 12 parts of theanine glycoside compound.

[0118] The above embodiments do not limit the scope of the present invention, and the steps described do not limit the order of execution. Those skilled in the art can make obvious improvements to the present invention based on existing common knowledge, which are also included in the scope of protection defined by the claims of the present invention.

Claims

1. 1. Use of a theanine glycoside compound in the manufacture of a product for extending the in vivo half-life of theanine, comprising: The structure of the theanine glycoside compound is as follows: (Wherein, R is and n is 1-4. The use, characterized in that it is represented by:

2. A product that extends the half-life of theanine in vivo, The product contains a theanine glycoside-based compound, the structure of which is represented by the following formula: (Wherein, R is and n is 1-4. and the theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

3. A sustained release drug, The sustained release drug includes a theanine glycoside compound, the structure of which is represented by the following formula: (Wherein, R is and n is 1-4. and the theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

4. A supplement for improving memory, comprising: The supplement contains a theanine glycoside compound, and the structure of the theanine glycoside compound is represented by the following formula: (Wherein, R is and n is 1-4. and the theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

5. An antihypertensive agent, The antihypertensive agent includes a theanine glycoside compound, the structure of which is represented by the following formula: (Wherein, R is and n is 1-4. and the theanine glycoside compound is not 1-deoxy-1-L-theanine-D-fructopyranose.

6. 2. Use of theanine glycoside compound in the manufacture of a supplement for improving memory and a blood pressure lowering agent, The structure of the theanine glycoside compound is as follows: (Wherein, R is and n is 1-4. The use, characterized in that it is represented by:

7. Specifically, R is 7. The use according to claim 6, characterized in that it is selected from:

8. Below formula: (Wherein, R is is selected from. Theanine glycoside compound having the structure represented by the formula:

9. The compound according to claim 8, wherein the theanine glycoside compound is prepared by amminating the amino group of theanine using a monosaccharide, wherein the monosaccharide is selected from the group consisting of galactose and ribose.

10. The amination modification is (1) protecting the amino group of L-theanine as a substrate to obtain intermediate 1, then esterifying intermediate 1 with an alcohol compound to obtain intermediate 2, and deprotecting the amino group of intermediate 2 under the action of an oxidation reagent to obtain intermediate 3; (2) protecting the hydroxyl group of a monosaccharide as a substrate and oxidizing it to obtain intermediate 4; (3) using the obtained intermediate 3 and intermediate 4 as substrates, a reductive amination reaction is carried out under the action of a catalyst to obtain intermediate 5, and then the hydroxy group of intermediate 5 is deprotected with an acidic reagent to obtain intermediate 6, which is then reduced by hydrogenation to obtain the target product, theanine glycoside compound; The compound according to claim 8, characterized in that it comprises:

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