Catechin derivative, antiviral agent, disinfectant, and cleanser

Abstract

To provide a novel catechin derivative having excellent stability at room temperature and excellent solubility in water or ethanol, and to provide an antiviral agent, disinfectant, and cleanser containing the catechin derivative.SOLUTION: Provided is a catechin derivative represented by gly-EGCG(3')-C16 obtained by the following reaction formula, in which a catechin skeleton such as epigallocatechin gallate (EGCG) and a saturated or unsaturated C8-24 acyl group are chemically bonded via a sugar chain such as glucose.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to catechin derivatives, antiviral agents, disinfectants, and cleaning agents. [Background technology]

[0002] Various measures are being taken to prevent the spread of viral contamination, such as hand disinfection and environmental disinfection.

[0003] For example, the virus that causes COVID-19 is an enveloped virus. It is known that drugs such as alcohol (ethanol, isopropanol, etc.) and invert soap are effective against such viruses, and alcohol preparations such as rubbing alcohol are widely used. On the other hand, non-enveloped viruses such as norovirus have strong resistance to drugs such as alcohol (ethanol, isopropanol, etc.) and invert soap.

[0004] In recent years, various alcohol preparations have been commercially available that contain additional ingredients to alcohol, which is safe for the human body and easy to handle, to enhance the inactivation effect against non-enveloped viruses such as norovirus (Non-Patent Document 1).

[0005] Among the above-mentioned alcohol preparations, there are some that contain plant-derived virus inactivating substances added. For example, Patent Document 1 discloses that a composition is prepared by mixing an extract of a tannin-containing plant of the Diospyros genus with ethanol, and that the use of this composition can inactivate norovirus and the like.

[0006] Furthermore, for example, Patent Document 2 describes a norovirus killing agent containing a specified amount of proanthocyanidins from grape seed extract.

[0007] In addition, catechins contained in green tea and the like are also known to have an antiviral effect, and attempts have been made to use catechin derivatives as antiviral agents. For example, Patent Document 3 discloses a method for producing an acylated derivative of epigallocatechin gallate (EGCG) by performing an enzymatic reaction with lipase using epigallocatechin gallate and an acyl group donor as substrates, and acylation of epigallocatechin gallate. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2008 / 153077 [Patent Document 2] JP 2013-47196 A [Patent Document 3] International Publication No. 2007 / 105280 [Non-patent literature]

[0009] [Non-Patent Document 1] National Institute of Health Sciences, Food Sanitation Control Division: FY2015 Survey Report on Inactivation Conditions for Norovirus, https: / / www.mhlw.go.jp / file / 06-Seisakujouhou-11130500-Shokuhinanzenbu / 0000125854.pdf Summary of the Invention [Problem to be solved by the invention]

[0010] For example, an acylated derivative of epigallocatechin gallate (EGCG) can be produced according to the method described in Patent Document 3. However, the present inventors have conducted studies and found that the acylated derivative of epigallocatechin gallate (EGCG) obtained by the method of Patent Document 3 is very unstable (decomposes in a short period of time) in a room temperature (25° C.) environment, and further has low solubility in water or ethanol, making it difficult to put it into practical use as an antiviral agent.

[0011] The main object of the present disclosure is to provide a novel catechin derivative. Another object of the present disclosure is to provide a novel catechin derivative having excellent stability in a room temperature environment and excellent solubility in water or ethanol. Another object of the present disclosure is to provide an antiviral agent, a disinfectant, and a cleaning agent using the novel catechin derivative. [Means for solving the problem]

[0012] As a result of intensive research to solve the above problems, the present inventors have found that a novel catechin derivative can be obtained by chemically bonding a catechin skeleton and an acyl group via a sugar chain. The present inventors have also found that the catechin derivative has excellent stability in a room temperature environment and excellent solubility in water or ethanol. The present inventors have also found that the catechin derivative can be used as an antiviral agent, a disinfectant, and a cleaning agent. The present disclosure is an invention that was completed based on these findings and through further research.

[0013] That is, the present disclosure provides the inventions of the following aspects. Item 1. A catechin skeleton R represented by the following general formula (1): 1 and the acyl group R 3 However, glycan R 2 is a catechin derivative chemically bonded via R 1 -R 2 -R 3 (1) The catechin skeleton R 1 is at least one selected from the group consisting of an epigallocatechin gallate (EGCG) moiety, a gallocatechin gallate (GCG) moiety, an epicatechin gallate (ECG) moiety, a catechin gallate (CG) moiety, an epigallocatechin (EGC) moiety, a gallocatechin (GC) moiety, an epicatechin (EC) moiety, and a +catechin (+C) moiety; The sugar chain R 2is at least one selected from the group consisting of a glucose portion, a galactose portion, a xylose portion, a mannose portion, a lyxose portion, an arabinose portion, a maltose portion, a xylobiose portion, an isomaltose portion, a cellobiose portion, a gentiobiose portion, a lactose portion, a sucrose portion, a nigerose portion, a turanose portion, a raffinose portion, a gentianose portion, and a melezitose portion; The acyl group R 3 is a saturated or unsaturated acyl group having 8 to 24 carbon atoms, The catechin skeleton R 1 and one of the phenolic hydroxyl groups of the glycan R 2 One of the hydroxyl groups is dehydrated and condensed, The sugar chain R 2 and the acyl group R 3 A catechin derivative in which the and form an ester bond. Item 2. The catechin skeleton R 1 is an epigallocatechin gallate (EGCG) moiety, and the glycan R 2 is a glucose moiety. Item 3. An antiviral agent comprising the catechin derivative according to item 1 or 2. Item 4. The antiviral agent according to any one of Items 1 to 3, further comprising ethanol. Item 5. The antiviral agent according to any one of Items 1 to 3, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof. Item 6. A disinfectant comprising the catechin derivative according to any one of items 1 to 3. Item 7. The disinfectant according to Item 6, further comprising ethanol. Item 8. The disinfectant according to Item 6 or 7, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof. Item 9. A cleaning agent comprising the catechin derivative according to any one of items 1 to 3. Item 10. The cleaning agent according to Item 9, further comprising ethanol. Item 11. The cleaning agent according to Item 9 or 10, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof. Effect of the Invention

[0014] According to the present disclosure, a novel catechin derivative can be provided. In addition, according to the present disclosure, a novel catechin derivative having excellent stability in a room temperature environment and excellent solubility in water or ethanol can be provided. Furthermore, according to the present disclosure, an antiviral agent, a disinfectant, and a cleaning agent using the novel catechin derivative can be provided. [Brief description of the drawings]

[0015] [Figure 1] 1 is a graph showing the relationship between the residual rate (%) of catechin derivatives and the number of days elapsed in a 25° C. environment, in which the stability in a room temperature environment was evaluated for each of Example 1 and Comparative Examples 1 to 3. [Diagram 2] 1 is a graph showing evaluation of the antiviral effect (logarithmic reduction value Log10TCID50 / 0.1 mL) of each of the catechin derivatives obtained in Examples 1 to 3 and Comparative Examples 1 to 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] In this specification, a numerical value connected with "~" means a numerical range including the numerical values ​​before and after "~" as the lower limit and upper limit. When multiple lower limit values ​​and multiple upper limit values ​​are listed separately, any lower limit value and upper limit value can be selected and connected with "~".

[0017] 1. Catechin derivatives The catechin derivative of the present disclosure has a catechin skeleton R represented by the following general formula (1): 1 and the acyl group R 3 However, glycan R 2 It is a catechin derivative chemically bonded via R 1 -R2 -R 3 (1)

[0018] In the general formula (1), the catechin skeleton R 1 is at least one selected from the group consisting of an epigallocatechin gallate (EGCG) moiety, a gallocatechin gallate (GCG) moiety, an epicatechin gallate (ECG) moiety, a catechin gallate (CG) moiety, an epigallocatechin (EGC) moiety, a gallocatechin (GC) moiety, an epicatechin (EC) moiety, and a +catechin (+C) moiety. 1 Among these, it is preferable that the moiety is an epigallocatechin gallate (EGCG).

[0019] In addition, in the general formula (1), the sugar chain R 2 is at least one selected from the group consisting of a glucose portion, a galactose portion, a xylose portion, a mannose portion, a lyxose portion, an arabinose portion, a maltose portion, a xylobiose portion, an isomaltose portion, a cellobiose portion, a gentiobiose portion, a lactose portion, a sucrose portion, a nigerose portion, a turanose portion, a raffinose portion, a gentianose portion, and a melezitose portion. 2 Among these, it is preferable that the moiety is a glucose moiety.

[0020] In addition, in the general formula (1), the acyl group R 3 is a saturated or unsaturated acyl group having 8 to 24 carbon atoms. 3 is preferably a saturated or unsaturated acyl group having 12 to 20 carbon atoms, more preferably a saturated or unsaturated acyl group having 16 to 18 carbon atoms. 3 In the above formula, the saturated or unsaturated acyl group having 8 to 24 carbon atoms can be referred to as, for example, a saturated or unsaturated fatty acid or fatty acid ester residue having 8 to 24 carbon atoms. The carbon chain of the fatty acid or fatty acid ester residue may be either linear or branched.

[0021] In the general formula (1), the catechin skeleton R1 and one of the phenolic hydroxyl groups of the glycan R 2 In other words, the catechin skeleton R 1 and Glycan R 2 The chemical bond with can be formed by dehydration condensation of catechins and sugar. 1 and one of the hydroxyl groups (phenolic hydroxyl groups) of the catechins (i.e., at least one selected from the group consisting of epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), epicatechin gallate (ECG), catechin gallate (CG), epigallocatechin (EGC), gallocatechin (GC), epicatechin (EC) and +catechin (+C)) that form the glycan R 2 (i.e., at least one selected from the group consisting of glucose, galactose, xylose, mannose, lyxose, arabinose, maltose, xylobiose, isomaltose, cellobiose, gentiobiose, lactose, sucrose, nigerose, turanose, raffinose, gentianose, and melezitose) forms the catechin skeleton R 1 and Glycan R 2 The catechin skeleton R can form a chemical bond, the -O- bond. 1 and Glycan R 2 The structure in which these are chemically bonded is the catechin skeleton R 1 and glycan R 2 These can be referred to as catechin-sugar dehydration condensation moieties.

[0022] In the catechin derivative represented by the general formula (1), the catechin skeleton R 1 is an epigallocatechin gallate (EGCG) moiety, at least one hydroxyl group position selected from the 7-position of the A ring, the 3'-position of the B ring, the 4'-position of the B ring, the 3"-position of the D ring, and the 4"-position of the D ring of the epigallocatechin gallate (EGCG) is a catechin skeleton R 1 and Glycan R 2 It is preferable that the sugar chain R 2When there is a glucose moiety, at least the 1st hydroxyl group of glucose is in the catechin skeleton R 1 and Glycan R 2 In the catechin derivative represented by the general formula (1), the catechin skeleton R 1 is the epigallocatechin gallate (EGCG) moiety, and glycan R 2 is a glucose moiety, it is preferable that the epigallocatechin gallate (EGCG) moiety and the glucose moiety are chemically bonded to each other at the position of the hydroxyl group at the 3'-position of the B ring or the 3"-position of the D ring of epigallocatechin gallate (EGCG) and the position of the 1-position hydroxyl group of glucose.

[0023] The catechin derivative of the present disclosure may be only one type of compound included in the catechin derivative represented by general formula (1), or may be a mixture of two or more types. When the catechin derivative of the present disclosure is produced, for example, by the production method described below, it is usually produced as a mixture of two or more types. Even when it is a mixture of two or more types, the catechin derivative of the present disclosure has a catechin skeleton R 1 is the epigallocatechin gallate (EGCG) moiety, and glycan R 2 It is preferable that the catechin derivative contains a glucose moiety, and it is more preferable that the catechin derivative contains a catechin derivative in which the epigallocatechin gallate (EGCG) moiety and the glucose moiety are chemically bonded at the hydroxyl group position of the B ring 3' or the D ring 3" of epigallocatechin gallate (EGCG) and the hydroxyl group position 1 of glucose.

[0024] In the general formula (1), the sugar chain R 2 Another hydroxyl group (catechin skeleton R 1 (hydroxyl group different from the hydroxyl group formed by dehydration condensation with acyl group R 3 and form an ester bond. 2 and the acyl group R 3 The chemical bond (ester bond) of the catechin skeleton R 1 and Glycan R 2The catechins-saccharide dehydration condensation product can be formed by an acylation reaction between a catechins-saccharide dehydration condensation product having a chemical bond with a saturated or unsaturated fatty acid having 8 to 24 carbon atoms, or an acylation reaction between a saturated or unsaturated fatty acid ester having 8 to 24 carbon atoms.

[0025] Catechin-saccharide dehydration condensation product sugar chain R 2 If there is a glucose moiety, at least the 6-hydroxyl group of the glucose is substituted with the glycan R 2 and the acyl group R 3 In the catechin derivative represented by the general formula (1), the catechin skeleton R 1 is the epigallocatechin gallate (EGCG) moiety, and glycan R 2 is a glucose moiety, the epigallocatechin gallate (EGCG) moiety and the glucose moiety are chemically bonded at the hydroxyl group position of the B ring 3' or D ring 3" of epigallocatechin gallate (EGCG) and the hydroxyl group position of the 1st position of glucose, and the glucose moiety and the acyl group R 3 is preferably chemically bonded.

[0026] As described above, when the catechin derivative of the present disclosure is produced by the production method described below, it is usually produced as a mixture of two or more types. Even when it is a mixture of two or more types, the catechin derivative of the present disclosure has a catechin skeleton R 1 is the epigallocatechin gallate (EGCG) moiety, and glycan R 2 It is preferable that the catechin derivative contains a glucose moiety, and the epigallocatechin gallate (EGCG) moiety and the glucose moiety are chemically bonded at the 3'- or 3"-hydroxyl position of the epigallocatechin gallate (EGCG) and the 1-hydroxyl position of the glucose, and the glucose moiety and the acyl group R are chemically bonded at the 6-hydroxyl position of the glucose. 3 It is more preferable that the catechin derivative contains a catechin derivative having a chemical bond thereto.

[0027] As described above, in the catechin derivative of the present disclosure, the catechin skeleton R 1 and Glycan R2 The chemical bond with the catechin can be formed by dehydration condensation of the catechin and the sugar. 2 and the acyl group R 3 The chemical bond (ester bond) of the catechin skeleton R 1 and Glycan R 2 The catechins-saccharide dehydration condensation product can be formed by an acylation reaction between a catechins-saccharide dehydration condensation product having a chemical bond with a saturated or unsaturated fatty acid having 8 to 24 carbon atoms, or an acylation reaction between a saturated or unsaturated fatty acid ester having 8 to 24 carbon atoms.

[0028] The method for producing the catechin derivatives of the present disclosure is not particularly limited, and the derivatives can be suitably produced, for example, by a production method including the following steps 1 and 2.

[0029] (Step 1) A step of dehydrating and condensing catechins and sugar to obtain a catechin-sugar dehydration condensation product (Step 2) A step of acylation of the hydroxyl group of the sugar portion of the catechin-sugar dehydration condensation product to obtain a catechin derivative.

[0030] In step 1, the catechins used as the substrate are at least one selected from the group consisting of epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), epicatechin gallate (ECG), catechin gallate (CG), epigallocatechin (EGC), gallocatechin (GC), epicatechin (EC) and +catechin (+C), or a mixture of multiple catechins extracted from natural green tea. The sugar used as the substrate may be at least one type selected from the group consisting of amylose, starch, maltodextrin, cyclodextrin, partial starch hydrolysates such as maltooligosaccharides, glucose, galactose, xylose, mannose, lyxose, arabinose, maltose, maltotriose, maltotetraose, xylobiose, isomaltose, cellobiose, gentiobiose, lactose, sucrose, nigerose, turanose, raffinose, gentianose, and melezitose, as long as it is capable of saccharifying catechins.

[0031] The dehydration condensation reaction in step 1 can be carried out by a known glycosylation reaction. Specifically, the glycosylation reaction of catechins can be carried out by an enzyme reaction, and known enzymes can be used. Commercially available enzymes that can be used in the glycosylation reaction of catechins include, for example, cyclodextrin glucanotransferase (Toruzyme 3.0L: Novozymes), (Contizyme: Amano Enzyme), (CGT-SL: Amano Enzyme), α-glycosidase (EC 3.2.1.20), α-amylase (EC 3.2.1.1), and sucrose phosphorylase (EC 2.4.1.7).

[0032] Step 1 can be carried out by glucosylating catechins and sugars as substrates in a solvent using an enzyme. The solvent can be any solvent capable of glycosylating catechins, and examples of the solvent include water, methanol, ethanol, isopropanol, acetonitrile, acetone, dimethylformamide, and dimethylsulfoxide. The reaction temperature can be about 40°C to 80°C, preferably 45°C to 60°C, and the reaction time can be about 0.5 hours to 24 hours, preferably 1 hour to 3 hours.

[0033] The product (catechins-sugar dehydrated condensate) obtained in step 1 can be purified by preparative HPLC or a porous synthetic resin. The porous synthetic resin is a synthetic resin such as a non-ionic styrene-divinylbenzene polymer, a phenol-formaldehyde resin, an acrylate resin, or a methacrylate resin that is porous and has a wide adsorption surface area. For example, a known purification method such as commercially available Amberlite XAD-1, Amberlite XAD-2, Amberlite XAD-4, Amberlite XAD-7, Amberlite XAD-8, Amberlite XAD-11, Amberlite XAD-12, Diaion HP-10, Diaion HP-20, Diaion HP-30, Diaion HP-40, Diaion HP-50, Sepabeads SP-70, or Sepabeads SP-700 can be used. In addition, the product obtained in step 1 can be analyzed by known analytical methods such as HPLC, FT-IR, 1H-NMR, 13C-NMR, various 2D-NMR (COSY, HMBC, HMQC), and various mass spectrometry.

[0034] The acylation in step 2 can be carried out by a known acylation reaction. Specifically, the acylation reaction of the catechins-sugar dehydration condensate can be carried out by an enzymatic reaction or a general chemical reaction. In the case of an enzymatic reaction, lipase can be used as the enzyme. Commercially available lipases are not particularly limited, but examples thereof include lipase (Novozym435: Novozymes), (LipozymeTL IM: Novozymes), and (LipozymeRM IM: Novozymes). In the case of a general chemical reaction, for example, a method is available in which, under dehydration conditions, a carboxylic anhydride is reacted with a glycosylated catechin in an organic solvent such as pyridine, dimethyl sulfoxide, or dimethylformamide, and, if necessary, a catalyst such as p-toluenesulfonic acid is coexistent, or a carboxylic acid is reacted with a glycosylated catechin in the presence of a catalyst such as concentrated sulfuric acid. From the viewpoint of drug safety and environmental load, it is preferable to use an enzymatic reaction.

[0035] The acylation in step 2 can be carried out by an esterification reaction between at least one selected from the group consisting of saturated or unsaturated fatty acids having 8 to 24 carbon atoms and saturated or unsaturated fatty acid esters having 8 to 24 carbon atoms and a hydroxyl group of the sugar moiety of the catechins-sugar dehydration condensate. Specific examples of the acyl donor include fatty acids such as caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, ricinoleic acid, arachidic acid, arachidonic acid, petroselinic acid, vaccenic acid, linoleic acid, linolenic acid, eleostearic acid, licanic acid, parinaric acid, behenic acid, and lignoceric acid, or fatty acid esters derived from these fatty acids. As for the fatty acid esters, fatty acid esters in which the ester moiety of these fatty acids is a vinyl group, a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, or the like can be mentioned.

[0036] Step 2 can be carried out by using a catechin-sugar dehydration condensate and at least one selected from the group consisting of saturated or unsaturated fatty acids having 8 to 24 carbon atoms and saturated or unsaturated fatty acid esters having 8 to 24 carbon atoms as substrates, and carrying out an acylation reaction in a solvent using an enzyme. Examples of the solvent that can be used include acetonitrile, acetone, diethyl ether, tert-butanol, tert-amyl alcohol, sec-butanol, n-butanol, isopropanol, ethyl acetate, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, tetrahydrofuran, and pyridine. If necessary, moisture in the solvent can be removed using a drying agent such as a molecular sieve. The reaction temperature can be about 40 to 80°C, preferably about 50 to 60°C, and the reaction time can be about 2 to 96 hours, preferably about 10 to 24 hours.

[0037] The product obtained in step 2 (the catechin derivative represented by general formula (1)) can be purified by known purification methods such as silica gel chromatography and preparative HPLC. The product obtained in step 2 can be analyzed by known analytical methods such as HPLC, FT-IR, 1H-NMR, 13C-NMR, various 2D-NMR (HH-COSY, HMBC, HMQC), and various mass spectrometry.

[0038] In the method for producing a catechin derivative according to the present disclosure, step 1 may be omitted. Specifically, a catechin derivative can also be produced by a method including the following steps 1A and 2.

[0039] (Step 1A) A catechin skeleton R represented by the following general formula (1A) 1 and Glycan R 2 A process for preparing a catechin-sugar dehydration condensate in which R 1 -R 2 (1A) (Step 2) A step of acylating the hydroxyl group of the sugar moiety of the catechin-sugar dehydration condensate to obtain the catechin derivative.

[0040] In step 1A, a catechin skeleton R represented by the general formula (A) is 1 and Glycan R 2 As the catechins-saccharide dehydration condensation product in which the catechins and saccharides are chemically bonded, for example, the product obtained through the above-mentioned step 1 may be used, or a commercially available product may be used. An example of the commercially available product is Inoveol (registered trademark) EGCG (Givaudan).

[0041] Step 2 is the same as described above.

[0042] 2. Antiviral agents, disinfectants, and cleaning agents The antiviral agent, disinfectant, and cleaning agent of the present disclosure (hereinafter, these may be collectively referred to as "antiviral agent, etc. of the present disclosure") are antiviral agents, disinfectants, and cleaning agents, respectively, containing the catechin derivative represented by the above-mentioned general formula (1). Details of the catechin derivative represented by general formula (1) are as described above. Among the catechin derivatives represented by general formula (1) contained in the antiviral agent, etc. of the present disclosure, the preferred catechin derivatives are also the catechin derivatives that were preferred in the section "1. Catechin derivatives".

[0043] In the antiviral agent etc. of the present disclosure, the higher the content of the catechin derivative represented by the general formula (1), the higher the antiviral effect. It is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, and even more preferably 0.05% by mass or more. In consideration of economical viewpoints and solubility, it is preferably 1.0% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.2% by mass or less, and preferred ranges include about 0.001 to 1.0% by mass, about 0.001 to 0.5% by mass, about 0.001 to 0.2% by mass, about 0.01 to 1.0% by mass, about 0.01 to 0.5% by mass, about 0.01 to 0.2% by mass, about 0.05 to 1.0% by mass, about 0.05 to 0.5% by mass, and about 0.05 to 0.2% by mass.

[0044] The catechin derivatives contained in the antiviral agent etc. of the present disclosure may be one type or two or more types. In addition, the antiviral agent etc. of the present disclosure may further contain a catechin derivative different from the catechin derivative represented by general formula (1) in addition to the catechin derivative represented by general formula (1).

[0045] The antiviral agent etc. of the present disclosure may further contain water, a polar organic solvent, etc., in addition to the catechin derivative represented by general formula (1). As the polar organic solvent, dimethyl sulfoxide or a lower alcohol such as ethanol or isopropanol is preferred, and ethanol is more preferred in terms of enhancing the antiviral effect, disinfection effect, or cleaning effect. In the antiviral agent etc. of the present disclosure, the content of ethanol is preferably 30% by mass or more, and preferably 80% by mass or less.

[0046] The pH of the antiviral agent of the present disclosure can be adjusted by a known pH adjuster or buffer solution, so long as it does not inhibit the effects of the present disclosure. That is, the antiviral agent of the present disclosure may contain additives such as a pH adjuster or buffer solution. Examples of pH adjusters include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; organic acids and salts thereof such as citric acid, acetic acid, malic acid, lactic acid, fumaric acid, succinic acid, tartaric acid, gluconic acid, phosphoric acid, benzoic acid, ascorbic acid, erythorbic acid, sorbic acid, adipic acid, cinnamic acid, itaconic acid, ferulic acid, and phytic acid; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and carbonates such as potassium carbonate and sodium bicarbonate. Examples of buffer solutions include citrate buffer solutions, phosphate buffer solutions, citrate phosphate buffer solutions, lactic acid buffer solutions, and carbonate bicarbonate buffer solutions. When the antiviral agent of the present disclosure contains a pH adjuster or buffer solution, each of these may be only one type or two or more types.

[0047] The antiviral agent and the like of the present disclosure may contain additives other than pH adjusters and buffer solutions. The other additives are not particularly limited, and additives that can be used in known antiviral agents, disinfectants, or cleaning agents can also be used in the present disclosure. Examples of additives include antioxidants and moisturizing agents. Only one type of additive may be used, or two or more types may be mixed and used. In addition, when the antiviral agent and the like of the present disclosure contains additives, the concentration thereof is not particularly limited as long as it does not inhibit the effects of the invention of the present disclosure, and each may be, for example, about 0.001 to 4.0 mass%.

[0048] Examples of antioxidants include L-ascorbic acid, L-ascorbic acid palmitate, L-ascorbic acid phosphate magnesium salt, L-ascorbic acid 2-glucoside, L-sodium ascorbate, D-ascorbic acid, sodium D-ascorbate, L-cysteine, N-acetyl L-cysteine, cystine, glutathione (oxidized form), glutathione (reduced form), L-ergothioneine, thioctic acid, ferulic acid, edetate, propyl gallate, tocopherol, tocotrienol, dibutylhydroxytoluene, butylhydroxyanisole, sodium sulfite, potassium sulfite, potassium pyrosulfite, sulfur dioxide, coffee bean extract (chlorogenic acid), green tea extract (catechins), rosemary extract, bayberry extract, amla extract, and yeast extract.

[0049] Moisturizing agents include polyhydric alcohols such as sorbitol, glycerin, polyglycerin, propylene glycol, and 1,3-butylene glycol; NMF components such as serine, glycine, and pyrrolidone carboxylic acid; hyaluronic acid; and collagen.

[0050] The antiviral agent etc. of the present disclosure may contain general antiviral components such as acyclovir, and general antibacterial components such as phenoxyethanol, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, and isopropylmethylphenol, within the scope that does not impair the characteristics of the present disclosure.

[0051] In addition, glycerin fatty acid ester may be added to enhance the disinfecting power against general bacteria. Examples of glycerin fatty acid ester include glycerin monocaprate, glycerin monolaurate, glycerin monomyristate, glycerin monopalmitate, glycerin monostearate, glycerin monoisostearate, glycerin monooleate, and glycerin monobehenate; glycerin difatty acid ester such as glycerin distearate, glycerin diisostearate, and glycerin dioleate; and monoglyceride derivatives such as acetate monoglyceride, citrate monoglyceride, succinate monoglyceride, diacetyltartarate monoglyceride, and lactate monoglyceride. In the present disclosure, one or more of these may be selected and used. In terms of enhancing the disinfecting power against general bacteria, it is preferable to use glycerin monofatty acid esters of fatty acids having 8 to 12 carbon atoms, such as glycerin monocaprylic acid ester, glycerin monocapric acid ester, and glycerin monolauric acid ester.

[0052] Furthermore, surfactants other than the above glycerin fatty acid esters can be added to the antiviral agent etc. of the present disclosure for the purpose of imparting cleaning properties and foaming properties, within a range that does not affect the effects of the present disclosure or the stability of the composition. Examples of such surfactants that can be used include cationic surfactants such as primary to tertiary fatty amine salts, quaternary ammonium salts, and 2-alkyl-1-alkyl-1-hydroxyethyl imidazolinium salts; alkyl betaine types such as N,N-dimethyl-N-alkyl-N-carboxymethyl ammonium betaine; amino carboxylic acid types such as N,N-dialkyl amino alkylene carboxylic acid; alkyl sulfo betaine types such as N,N,N-trialkyl-N-sulfo alkylene ammonium betaine; imidazoline type amphoteric surfactants such as 2-alkyl-1-hydroxyethyl-1-carboxymethyl imidazolinium betaine; and fatty acid ester type nonionic surfactants such as sucrose fatty acid esters. Furthermore, for the purposes of increasing foaming, improving the stability of the formulation, flavoring, etc., water-soluble polymers such as gum arabic, carrageenan, sodium carboxymethylcellulose, hydroxycellulose, sodium polyacrylate, etc.; sequestering agents such as sodium ethylenediaminetetraacetate, tripolyphosphate, hexametaphosphate, etc.; inorganic salts such as sodium chloride, potassium chloride, sodium sulfate, etc.; flavorings, etc. may be added.

[0053] The antiviral agents etc. disclosed herein exhibit excellent antiviral, disinfecting, or cleaning effects against viruses belonging to the Norovirus genus, but may also exhibit good antiviral, disinfecting, or cleaning effects against non-enveloped viruses other than Norovirus, such as other Caliciviridae viruses, Picornaviridae viruses, Parvoviridae viruses, Papillomavirdae viruses, Polyomaviridae viruses, and Adenoviridae viruses.

[0054] In the present disclosure, the "antiviral effect" refers to an effect of removing or reducing the infectivity or proliferation ability of the virus. Therefore, it is not necessary for the antiviral agent to have a denaturing or destructive effect on virus particles or nucleic acids, but it is sufficient for the agent to reduce or inhibit the infectivity or proliferation ability of the virus in the host cell through adsorption to the surface of the virus or the host cell, binding to the viral enzyme, or the like.

[0055] The antiviral agent, etc. of the present disclosure can be widely used for disinfection, sterilization and cleaning of facilities such as hospital rooms, living rooms, kitchens, bathrooms, washrooms, toilets, etc., sterilization and disinfection of furniture such as tables, chairs, bedding, etc., instruments, devices, and equipment such as tableware, cooking utensils, and medical supplies, and sterilization and disinfection of hands and fingers, and other purposes for sterilization, disinfection, and cleaning of places where viruses may be present or objects that may be contaminated with viruses.

[0056] The antiviral agent etc. of the present disclosure may be used in an amount sufficient to thoroughly wet the surface of the object to be disinfected or cleaned. The time during which the antiviral agent etc. of the present disclosure acts on the object to be disinfected or cleaned may be short, and sufficient antiviral effect, disinfection effect, or cleaning effect can be obtained in 1 to 5 minutes. EXAMPLES

[0057] The present disclosure will be described in more detail below with reference to examples. In the following, "%" means "% by mass" unless otherwise specified.

[0058] <Synthesis of catechin derivatives> Example 1 The catechin derivative (gly-EGCG(3')-C16) represented by the following formula was synthesized by the following procedure.

[0059] In the glycosylation reaction of EGCG, EGCG (Green Tea Extract 90% EGCG: Vidya Japan) (18.4 mg) and starch (Fujifilm Wako Pure Chemical Industries, Ltd.) (34 mg) were added to a reaction vessel as substrates, and a dehydration condensation reaction was carried out using cyclodextrin glucanotransferase (Toruzyme 3.0L: Novozymes) (0.06 mL) as an enzyme and ion-exchanged water as a solvent to obtain glycosylated catechins (catechin-sugar dehydration condensation products). The reaction conditions were 55°C, 2 hours, and shaking at 150 rpm. Purification was performed by preparative HPLC, and analysis was performed by HPLC and 1H-NMR.

[0060] Next, the obtained glycosylated catechins (catechins-sugar dehydration condensate) were subjected to an esterification reaction with a fatty acid ester (vinyl palmitate) to obtain a catechin derivative (gly-EGCG(3')-C16) represented by the following formula. In the esterification reaction, the glycosylated catechins (11.8 mg) and vinyl palmitate (Tokyo Chemical Industry Co., Ltd.) (57 mg) were added to a reactor as substrates, lipase (LipozymeTL IM: Novozymes) was added as an enzyme, and acetonitrile was used as a solvent. The reaction conditions were 55°C, 20 hours, and shaking at 150 rpm. Purification was performed by preparative HPLC, and analysis was performed using HPLC, 1H-NMR, 13C-NMR, HMBC, HMQC, and HH-COSY.

[0061] [ka]

[0062] Example 2 The catechin derivative (gly-EGCG(3")-C16) represented by the following formula was synthesized by the following procedure.

[0063] The glycosylation reaction was carried out under the same conditions as in Example 1, purification was carried out using preparative HPLC, and analysis was carried out using HPLC and 1H-NMR.

[0064] Next, the obtained glycosylated catechins (catechin-sugar dehydration condensation products) were subjected to an esterification reaction under the same conditions as in Example 1 to obtain a catechin derivative represented by the following formula (gly-EGCG(3″)-C16). Purification was performed using preparative HPLC, and analysis was performed using HPLC, 1H-NMR, 13C-NMR, HMBC, HMQC, and HH-COSY.

[0065] [ka]

[0066] Example 3 The catechin derivative (gly-EGCG(3')-C18) represented by the following formula was synthesized by the following procedure.

[0067] The glycosylation reaction was carried out under the same conditions as in Example 1, purification was carried out using preparative HPLC, and analysis was carried out using HPLC and 1H-NMR.

[0068] Next, the obtained glycosylated catechins (catechins-sugar dehydration condensate) were subjected to an esterification reaction with a fatty acid ester (vinyl stearate) to obtain a catechin derivative (gly-EGCG(3')-C18) represented by the following formula. In the esterification reaction, glycosylated catechins and vinyl stearate (Tokyo Chemical Industry Co., Ltd.) were used as substrates, lipase (LipozymeTL IM: Novozymes) was used as an enzyme, and acetonitrile was used as a solvent. The reaction conditions were 55°C, 20 hours, and shaking at 150 rpm. Purification was performed by preparative HPLC, and analysis was performed by HPLC, 1H-NMR, 13C-NMR, HMBC, HMQC, and HH-COSY.

[0069] [ka]

[0070] Comparative Example 1 Based on the description in Patent Document 3 (WO 2007 / 105280), a catechin derivative (EGCG-C16) represented by the following formula was synthesized by the following procedure. [ka]

[0071] Comparative Example 2 Epigallocatechin gallate (EGCG), which was used as the substrate in Example 1, was used.

[0072] Comparative Example 3 The glycosylated catechins (gly-EGCG(3')) synthesized in Example 1 were used.

[0073] [Stability at room temperature (25℃)] The stability of Example 1 and Comparative Examples 1 to 3 in a room temperature environment (25°C) was evaluated by the following procedure. The results are shown in Table 1 and the graph in Figure 1. As a method for preparing the samples used in the stability evaluation, Example 1 and Comparative Examples 1 to 3 were each dissolved in a mixed solvent to a concentration of 0.1% by the following procedure. First, each sample was dissolved in dimethyl sulfoxide, and then dissolved in ion-exchanged water, and the weight ratio of the mixed solvent was set to 9:1 between ion-exchanged water and dimethyl sulfoxide. This solution was placed in a 1.5 mL glass vial for HPLC autosampler, and stored in an incubator (TVN680TA) manufactured by ADVANTEC in an environment of 25°C for 56 days, and the stability of the components was evaluated by HPLC from the remaining rate of the area of ​​the peak of interest. As an analysis condition using HPLC, an Agilent LC1220InfinityII with a UV detector was used, and (column) Inertsil was used. Analysis was performed using a WP300 C4, 4.6 x 150 mm 5 μm (GL Sciences), (eluent) A solution: 0.1% acetic acid aqueous solution, B solution: 0.1% acetic acid + acetonitrile, (flow rate) 1.0 mL / min (elution program) 0-11 min: B solution 16%, 11-12 min: B solution 100%, 12-15 min: B solution 16%, (column oven) 40°C, (wavelength) 280 nm. The remaining rate of the components was calculated using the following formula, using the peak area (mAU·s) of the corresponding peak of each sample before storage and the peak area of ​​the same component on the 56th day of storage, rounded to the nearest decimal place. (Component remaining rate%) = (peak area on the 56th day of storage) ÷ (peak area before storage) × 100 As an evaluation criterion, if 50% or more of each of the catechin derivative components blended remained on the 56th day of storage, it was rated as "suitable: ◯", and if the remaining rate of each of the catechin derivative components blended on the 56th day of storage was less than 50%, it was rated as "unsuitable: ×".

[0074] [Table 1]

[0075] [Discoloration resistance] The discoloration resistance of Example 1 and Comparative Examples 1 to 3 was evaluated by the following procedure. The results are shown in Table 2. The appearance of the sample used for stability in the room temperature environment (25°C) after 56 days of storage was visually confirmed to evaluate the presence or absence of coloration. As the evaluation criteria, if no coloration was observed in the liquid with the naked eye, it was evaluated as "satisfactory: ◯", and if coloration was observed, it was evaluated as "unsuitable: x".

[0076] [Table 2]

[0077] [Solubility in aqueous ethanol solution] The solubility in an aqueous ethanol solution of each of Examples 1 to 3 and Comparative Examples 1 to 3 was evaluated by the following procedure. The results are shown in Table 3. Each of Examples 1 to 3 and Comparative Examples 1 to 3 was dissolved in a 50% aqueous ethanol solution to a concentration of 0.1%, and the presence or absence of dissolution was confirmed by visual inspection. As the evaluation criteria, if complete dissolution was observed by visual inspection, it was evaluated as "suitable: ◯", and if turbidity or residual dissolution was observed in the liquid, it was evaluated as "unsuitable: ×".

[0078] [Table 3]

[0079] [Antiviral effect] The antiviral effect of each of Examples 1 to 3 and Comparative Examples 1 to 3 was evaluated by the following procedure. The results are shown in Table 4 and the graph in FIG. 2. Each of the samples obtained in Examples 1 to 3 and Comparative Examples 1 to 3 was dissolved in 450 μL of a mixed solution of 100 μL of dimethyl sulfoxide and 350 μL of phosphate buffered saline (PBS) to a concentration of 0.1%. These solutions were placed in 1.5 mL microtubes and stored in an incubator (TVN680TA) manufactured by ADVANTEC in an environment of 40° C. for 7 days to prepare sample solutions for evaluation. Using the above sample solutions, the inactivation effect of feline calicivirus was evaluated by the following procedure.

[0080] (a) The test virus solution was the FCV-F9 strain, which was diluted with phosphate-buffered saline (PBS) to obtain a log 10 TCID 50 A suspension prepared so that the concentration was 6.0 to 8.0 / mL was used. (b) The above virus solution and each sample solution were mixed in a volume ratio of 1:9 and suspended at 25°C for 60 seconds. The suspension was then added to D-MEM (2% fetal bovine serum solution = F2) in a volume ratio of 1:9 and suspended to stop the reaction. (c) 100 μL of the above suspension was added to the diluent D-MEM (F0) to dilute it 10-fold, and this procedure was further repeated to prepare a 10-fold serial dilution series. (d) Feline kidney cells (CRFK cells) were adjusted to 2 x 10^5 cells / mL in D-MEM (F0), 0.1 mL was dispensed into each well of a 96-well plate, and cultured at 37°C, 5% CO2 for more than 3 hours to allow the cells to attach to the plate. (e) 100 μL of the diluted solution in (c) was dispensed into each well in (d) and cultured at 37°C and 5% CO2 for 4 days. The presence or absence of CPE was observed and the infectivity titer was calculated by the Reed-Muench method.

[0081] The evaluation standard was the difference in the infectivity of PBS and each sample solution as the feline calicivirus inactivation effect, which was 3 log 10 TCID 50 If the log reduction is 0.1mL or more, it is marked as "Good" and if it is 3log 10 TCID 50 If the log reduction value was less than 0.1 mL, it was judged as "unsuitable: ×".

[0082] [Table 4]

Claims

1. A catechin skeleton R represented by the following general formula (1): 1 and an acyl group R 3 And, glycan R 2 is a catechin derivative chemically bonded via R 1 -R 2 -R 3 (1) The catechin skeleton R 1 is at least one selected from the group consisting of an epigallocatechin gallate (EGCG) moiety, a gallocatechin gallate (GCG) moiety, an epicatechin gallate (ECG) moiety, a catechin gallate (CG) moiety, an epigallocatechin (EGC) moiety, a gallocatechin (GC) moiety, an epicatechin (EC) moiety, and a +catechin (+C) moiety; The sugar chain R 2 is at least one selected from the group consisting of a glucose portion, a galactose portion, a xylose portion, a mannose portion, a lyxose portion, an arabinose portion, a maltose portion, a xylobiose portion, an isomaltose portion, a cellobiose portion, a gentiobiose portion, a lactose portion, a sucrose portion, a nigerose portion, a turanose portion, a raffinose portion, a gentianose portion, and a melezitose portion; The acyl group R 3 is a saturated or unsaturated acyl group having from 8 to 24 carbon atoms, The catechin skeleton R 1 and one of the phenolic hydroxyl groups of the sugar chain R 2 and one of the hydroxyl groups is dehydrated and condensed, The sugar chain R 2 and the acyl group R 3 A catechin derivative in which the and form an ester bond.

2. The catechin skeleton R 1 is an epigallocatechin gallate (EGCG) moiety, and the glycan R 2 The catechin derivative according to claim 1 , wherein is a glucose moiety.

3. An antiviral agent comprising the catechin derivative according to claim 1 or 2.

4. The antiviral agent of claim 3 further comprising ethanol.

5. The antiviral agent according to claim 3, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof.

6. A disinfectant comprising the catechin derivative according to claim 1 or 2.

7. The disinfectant of claim 6 further comprising ethanol.

8. The disinfectant according to claim 6 or 7, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof.

9. A cleaning agent comprising the catechin derivative according to claim 1 or 2.

10. 10. The cleaning agent of claim 9 further comprising ethanol.

11. The cleaning agent according to claim 9, further comprising at least one selected from the group consisting of citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and salts thereof.

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