JP7772626B2 - anti-influenza virus agent - Google Patents

Description

The present invention relates to an anti-influenza virus agent.

Influenza is a respiratory tract infection caused by the influenza virus. Human influenza viruses that cause human influenza are single-stranded RNA viruses of the Orthomyxovirus genus, and are classified into types A, B, and C based on the antigenicity of the nucleoprotein (NP). Of these, types A and B cause major epidemics every year, mainly in winter, and it is known that in Japan, they affect an estimated 10 million or more people annually.
Influenza viruses of types A and B are further classified into subtypes based on differences in antigenicity of hemagglutinin (HA) and neuraminidase (NA), which are viral surface proteins.

Influenza viruses cause acute respiratory infections, and their clinical symptoms are characterized by systemic symptoms such as sudden onset of fever, headache, joint pain, and general fatigue, along with various respiratory symptoms associated with colds such as runny nose and cough, and a high fever of 38°C or higher. Healthy people usually recover within one to two weeks, but infants, the elderly, patients with chronic respiratory, circulatory, or renal diseases, and patients with metabolic diseases such as diabetes or weakened immune systems often develop secondary bacterial infections or pneumonia, leading to death in many cases.

Currently, vaccination is considered the basic preventative measure against influenza. The only approved anti-influenza drugs other than vaccines are amantadine, which inhibits the function of the M2 protein ion channel, and the neuraminidase inhibitors oseltamivir and zanamivir.

On the other hand, it has been reported that epigallocatechin gallate (EGCg) and theaflavin digallate, polyphenols found in tea, have the effect of inhibiting infection with influenza viruses (Patent Document 1). Furthermore, Patent Documents 2 and 3 disclose that catechin derivatives without a hydroxyl group on the A ring have anti-influenza virus activity, and Non-Patent Document 1 discloses that catechin derivatives with an alkylated hydroxyl group at the 3-position have anti-influenza virus activity.

Japanese Patent Application Publication No. 3-101623 JP 2008-156324 A JP 2010-53066 A

Shuichi Mori et al., Bioorg Med Chem Lett. 2008 Jul 15;18(14):4249-52.

The present invention relates to providing an anti-influenza virus agent that inactivates influenza viruses and suppresses influenza virus infection of cells.

The present inventors have discovered that an EGCg derivative represented by the following formula (I), which is a metabolite of EGCg, has the effect of inactivating influenza viruses and suppressing influenza virus infection and proliferation in host cells, making it useful as an anti-influenza virus agent.

That is, the present invention relates to the following 1) to 4).
1) An anti-influenza virus agent containing, as an active ingredient, an EGCg derivative represented by the following formula (I):
2) A preventive or ameliorating agent for influenza virus infection, comprising an EGCg derivative represented by the following formula (I) as an active ingredient:
3) An anti-influenza virus food containing, as an active ingredient, an EGCg derivative represented by the following formula (I):
4) A food for preventing or ameliorating influenza virus infections, which contains as an active ingredient an EGCg derivative represented by the following formula (I):

[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]

The anti-influenza virus agent of the present invention makes it possible to prevent or ameliorate influenza virus infection. Furthermore, the anti-influenza virus agent of the present invention can inactivate influenza viruses attached to hard and soft surfaces in the living environment, thereby preventing or reducing the spread of influenza virus infection.

NP protein amount in influenza virus-infected cells. 6: Compound 6, 10: Compound 10, 12: Compound 12, 14: Compound 14. HA titer in influenza virus-infected cells. 6: Compound 6, 12: Compound 12.

In the anti-influenza virus agent of the present invention, the influenza virus may be any of types A, B, and C, but types A or B are preferred, and type A is more preferred. Furthermore, the subtype, which is determined by differences in the antigenicity of the viral surface proteins hemagglutinin (HA) and neuraminidase (NA), is not particularly limited. For example, in type A, there are 15 types of HA and 9 types of NA subtypes, and any of these is acceptable. Type A influenza viruses that have been prevalent to date include types H1N1, H2N2, and H3N2, with type H1N1 being more preferred.

In formula (I), alkali metal atoms represented by M include potassium and sodium. Alkaline earth metal atoms represented by M include magnesium and calcium. M is preferably an alkali metal atom, more preferably sodium.

The EGCg derivative represented by formula (I) of the present invention (also referred to as the "EGCg derivative of the present invention") is a sulfate conjugate and glucuronide conjugate of EGCg, and is known to be a metabolite when EGCg is ingested. Such an EGCg derivative can be chemically synthesized from epigallocatechin by the steps shown below, and specifically, can be produced using the method described in the Examples below.

[In the formula, R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium), Bn represents a benzyl group, Allyl represents an allyl group, GluA represents a glucuronosyl group, and TCE represents a 2,2,2-trichloroethyl group.]

That is, the phenolic hydroxyl group of epigallocatechin (i) is benzylated to form benzylated epigallocatechin (ii), which is then condensed with benzylated gallic acid allyl ether (iii) to form an allylated epigallocatechin gallate compound (iv), and then the allyl group is eliminated to obtain benzylated epigallocatechin gallate (v).
Next, the hydroxyl group at the 3" position of the benzylated epigallocatechin gallate (v) is sulfated with TCE using a TCE sulfation reagent (2,2,2-trichloroethoxy-sulfuryl-1,2-dimethylimidazolium triflate; SDIS) to obtain benzylated epigallocatechin gallate TCE sulfate (vi). Furthermore, the hydroxyl group at the 3" position of the benzylated epigallocatechin gallate (v) is glucuronidated using a glucuronic acid donor such as methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-glucuronate to obtain benzylated epigallocatechin gallate glucuronide (vii).
Then, these are subjected to a deprotection reaction to remove the protecting group, whereby the EGCg derivative (I) of the present invention can be obtained.

As shown in the Examples described below, when influenza virus is treated with the EGCg derivative of the present invention or EGCg for 30 minutes and then infected into Madin-Darby canine kidney cells (MDCK cells), the EGCg derivative of the present invention inactivates the influenza virus and suppresses the infection and proliferation of influenza virus in MDCK cells at a concentration at which EGCg does not exert its effect.
Therefore, the EGCg derivatives of the present invention can serve as anti-influenza virus agents that inactivate influenza viruses and suppress the infection and proliferation of influenza viruses in host cells, or as agents for preventing or ameliorating influenza virus infections. Alternatively, the EGCg derivatives of the present invention can be used to produce anti-influenza virus agents or agents for preventing or ameliorating influenza virus infections.
Furthermore, the EGCg derivatives of the present invention can be used to inactivate influenza viruses, suppress the infection and proliferation of influenza viruses in host cells, or prevent or ameliorate influenza virus infection. For example, by administering or ingesting the EGCg derivatives of the present invention to a subject, the proliferation of influenza viruses can be suppressed and influenza virus infection can be prevented or ameliorated, and by contacting a subject with the EGCg derivatives of the present invention, influenza viruses can be inactivated.
Here, the use may be therapeutic or non-therapeutic. "Non-therapeutic" is a concept that does not include medical procedures, i.e., a concept that does not include methods of surgery, therapy, or diagnosis on humans, and more specifically, a concept that does not include methods of surgery, therapy, or diagnosis on humans by a physician or a person under the direction of a physician.

Here, "anti-influenza virus" means inactivating influenza viruses, preventing or suppressing infection of host cells, and further preventing or suppressing proliferation in those cells.
The anti-influenza virus activity can be evaluated, for example, by measuring the HA titer or NP protein amount of influenza virus in host cells infected with the influenza virus. Here, the host cells are not particularly limited and include, for example, monkey kidney cells, human fetal cells, MDCK cells and their transgenic strains, hCK cells, and AX4 cells, with MDCK cells being preferred.
Furthermore, "influenza virus infection" refers to an acute respiratory disease caused by infection with an influenza virus. Symptoms include systemic symptoms such as sudden fever, headache, joint pain, and general fatigue, as well as various respiratory symptoms associated with colds, such as runny nose and cough, and a high fever (e.g., 38°C or higher), but are not limited to these symptoms in the present invention.

In the present invention, "prevention" refers to preventing, suppressing, or delaying influenza virus infection in an individual, or reducing the risk of onset. Furthermore, "amelioration" refers to the improvement of symptoms caused by influenza virus infection, the prevention or delay of worsening symptoms, or the reversal, prevention, or delay of the progression of symptoms, and is intended to include "treatment."

The anti-influenza virus agent or agent for preventing or ameliorating influenza virus infection of the present invention may be in the form of using the EGCg derivative of the present invention alone, or may be in the form of a composition containing the same (for example, a pharmaceutical composition, a food composition, a germicidal disinfectant composition, a sanitary product composition, etc.). That is, the anti-influenza virus agent or agent for preventing or ameliorating influenza virus infection of the present invention can be a pharmaceutical, quasi-drug, or food (i.e., anti-influenza virus food, food for preventing or ameliorating influenza virus infection) that exhibits an anti-influenza virus effect or an effect of preventing or ameliorating influenza virus infection, a germicidal disinfectant composition or a sanitary product composition that exhibits an anti-influenza virus effect, or a material or formulation to be incorporated into these.
In addition, anti-influenza virus foods and foods for preventing or ameliorating influenza virus infections include not only general foods and beverages, but also foods labeled as such, functional foods, foods for the sick, foods for specified health uses, foods with functional claims, and supplements, as needed.

The above-mentioned pharmaceuticals (including quasi-drugs) can be administered in any form, either orally or parenterally. Depending on the administration form, the pharmaceuticals can be prepared by conventional pharmaceutical means by adding, as appropriate, to the active ingredient of the present invention, solid or liquid pharmaceutical non-toxic carriers suitable for various administration forms, such as stabilizers, wetting agents, emulsifiers, binders, isotonicity agents, and excipients. Examples of pharmaceutical composition forms include solid formulations such as tablets, granules, powders, and capsules; liquid formulations such as solutions, suspensions, and emulsions; oral preparations such as sublingual tablets and lozenges; nasal drops, sprays, dusting powders, and freeze-dried formulations.

The above foods can be prepared in various dosage forms suitable for eating or drinking, such as fine granules, tablets, granules, powders, capsules, syrups, liquids, and pastes. The types of foods are not limited, but examples include bread, noodles, pasta, jelly foods, various snacks, cakes, confectionery, ice cream, soups, dairy products, frozen foods, instant foods, other processed foods, seasonings, supplements, and various beverages (fruit juices, carbonated drinks, teas, coffee, dairy drinks, alcoholic drinks, soft drinks, etc.). Viscous beverages, candies, lozenges, chewing gum, and other forms that remain in the mouth for a long time, and supplements and other forms that remain in the digestive tract for a long time are preferred.

Such pharmaceuticals, quasi-drugs, and foods may contain bactericides, anti-inflammatory agents, water-soluble vitamins, plant extracts, and other medicinal ingredients, as appropriate, as long as they do not impair the effects of the present invention.

The germicidal disinfectant composition may contain antibacterial substances such as hypochlorous acid, hydrogen peroxide, and silver ion compounds, cationic antibacterial agents (e.g., benzethonium chloride), disinfectants (e.g., triclosan and isopropylmethylphenol), ethanol, surfactants, etc., and is prepared by appropriately blending additives such as chelating agents, humectants, lubricants, builders, buffers, abrasives, electrolytes, bleaches, fragrances, dyes, foam control agents, corrosion inhibitors, essential oils, thickeners, pigments, gloss enhancers, enzymes, detergents, solvents, dispersants, polymers, silicones, and hydrotropes. The germicidal disinfectant composition may be in the form of, but is not limited to, a liquid, emulsion, cream, lotion, paste, gel, sheet (supported by a substrate), aerosol, spray, oil, gel, or other form.

Examples of the hygiene product compositions include lotions, creams, shampoos, hair conditioners, hand soaps, body shampoos, facial cleansers, bath additives, foams, antiperspirants, deodorants, anti-armpit odor agents, and oral hygiene products (mouthwashes, toothpastes, mouth fresheners, mouthwashes, etc.).
The composition can be prepared by a conventional method by appropriately combining carriers acceptable for use in cosmetics and the like (e.g., diluents, dispersants, buffers, pH adjusters, dispersants, emulsifiers, surfactants, preservatives, stabilizers, antioxidants, colorants, moisturizers, thickeners, disinfectants, fragrances, etc.).

In embodiments in which the anti-influenza virus agent or agent for preventing or ameliorating influenza virus infection of the present invention is used as a composition, the content of the active ingredient can be determined appropriately depending on the form of the composition. For example, the content of the active ingredient relative to the total amount of the composition is preferably 0.005% by mass or more, more preferably 0.008% by mass or more, and even more preferably 0.01% by mass or more. It is also preferably 10% by mass or less, more preferably 8% by mass or less, and even more preferably 5% by mass or less. Alternatively, the content of the active ingredient relative to the total amount of the composition is preferably 0.005 to 10% by mass, more preferably 0.008 to 8% by mass, and even more preferably 0.01 to 5% by mass.

When the anti-influenza virus agent or the agent for preventing or ameliorating influenza virus infection of the present invention is used as a pharmaceutical, quasi-drug, or food, the subjects to which it is administered or ingested are preferably mammals, including non-human mammals, but preferably humans. Preferred subjects for administration or ingestion include humans wishing to prevent influenza virus infection and humans wishing to improve symptoms of influenza virus infection (fever, dry cough, fatigue, sputum, shortness of breath, sore throat, headache, diarrhea, etc.).
In this case, the amount administered or ingested can be determined appropriately based on the individual's condition, body weight, sex, age, activity of the material, administration route, administration schedule, formulation, or other factors. For example, per adult (body weight 60 kg), the amount of the EGCg derivative of the present invention is preferably 20 mg/day or more, more preferably 100 mg/day or more. Also, the amount is preferably 3000 mg/day or less, more preferably 1000 mg/day or less, and more preferably 800 mg/day. Alternatively, the amount administered or ingested is preferably 20 to 3000 mg/day, more preferably 100 to 1000 mg/day, of the EGCg derivative of the present invention per adult (body weight 60 kg).
The active ingredient can be taken or administered once or several times a day, or at any period and interval.

Furthermore, by using the anti-influenza virus agent of the present invention as a germicidal disinfectant composition or a sanitary product composition, it becomes possible to inactivate influenza viruses that are contaminated with the skin or mucous membranes of animals or that are attached to the hard or soft surfaces of inanimate objects. Examples of the surfaces of inanimate objects include hard surfaces in homes and business facilities, such as counters, sinks, restrooms, toilets, bathtubs, shower basins, floors, windows, doorknobs, walls, sewer outlets, and pipes; hard surfaces of various appliances, tools, and miscellaneous items, such as kitchenware, furniture, telephones, and toys; and soft surfaces, such as textile products (carpets, area rugs, curtains, fabric furniture, clothing, and the like).
The composition is used by contacting it with the object to be treated, and the manner of application is not particularly limited, and may be any of a method in which the composition is directly applied to the object to be treated, a method in which the composition is atomized and sprayed or scattered using an atomizing device such as a pump spray, an aerosol, a pressurized liquid atomizing spray, or a pressurized air atomizing spray device, or a method in which the surface of the object to be treated is wiped with a sheet, gauze, towel, wet towel, tissue, wet tissue, or the like impregnated with the composition.
The concentration of EGCg when treating the treatment target is 100 ppm or more, preferably 150 ppm or more, and more preferably 200 ppm or more, from the viewpoint of inactivating influenza viruses.

In relation to the above-described embodiment, the present invention further discloses the following aspects.
<1> An anti-influenza virus agent containing, as an active ingredient, an epigallocatechin gallate derivative represented by the following formula (I):
<2> A preventive or ameliorating agent for influenza virus infection, comprising an epigallocatechin gallate derivative represented by the following formula (I) as an active ingredient:
<3> An anti-influenza virus food containing, as an active ingredient, an epigallocatechin gallate derivative represented by the following formula (I):
<4> A food for preventing or ameliorating influenza virus infections, comprising as an active ingredient an epigallocatechin gallate derivative represented by the following formula (I):

<5> Use of an epigallocatechin gallate derivative represented by the following formula (I) for producing an anti-influenza virus agent.
<6> Use of an epigallocatechin gallate derivative represented by the following formula (I) for producing an agent for preventing or ameliorating influenza virus infection.
<7> Use of an epigallocatechin gallate derivative represented by the following formula (I) for producing an anti-influenza virus food.
<8> Use of an epigallocatechin gallate derivative represented by the following formula (I) for producing a food for preventing or ameliorating influenza virus infection.

<9> An epigallocatechin gallate derivative represented by the following formula (I) for use in inactivating or suppressing infection with influenza viruses:
<10> An epigallocatechin gallate derivative represented by the following formula (I) for use in preventing or ameliorating influenza virus infection:

<11> Non-therapeutic use of an epigallocatechin gallate derivative represented by the following formula (I) for inactivating or suppressing infection with influenza virus:
<12> Non-therapeutic use of an epigallocatechin gallate derivative represented by the following formula (I) for preventing or ameliorating influenza virus infection:

<13> A method for inactivating or suppressing infection with influenza viruses, comprising administering an effective amount of an epigallocatechin gallate derivative represented by the following formula (I) to a subject in need thereof:
<14> A method for preventing or ameliorating influenza virus infection, comprising administering or ingesting an effective amount of an epigallocatechin gallate derivative represented by the following formula (I) to a subject in need thereof:

<15> In <1> or <5>, the anti-influenza virus agent is a germicidal disinfectant composition or a hygiene product composition.

[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]

Reference Example 1 Production of Compound A3 Compound A3 was synthesized from a gallic acid ester by the following steps: The following reagents and solvents, except for epigallocatechin gallate, were obtained from Tokyo Chemical Industry Co., Ltd., Kanto Chemical Co., Ltd., Sigma-Aldrich, and Fujifilm Wako Pure Chemical Industries, Ltd., and epigallocatechin gallate was obtained from Sun-shine Chemical.

(1) Preparation of Methyl 4-(allyloxy)-3,5-dihydroxybenzoate (Compound A2) Under an argon atmosphere, methyl gallate (Compound A1) (1.00 g, 5.43 mmol) was added to a round-bottom flask, followed by the addition of acetonitrile (50 mL) and stirring to obtain a pale yellow solution. Subsequently, N,N-diisopropylethylamine (1.07 mL, 5.97 mmol), allyl bromide (2.31 mL, 27 mmol), and allyl iodide (catalytic amount) were added sequentially while cooling in an ice bath. The temperature was then raised to room temperature and stirred for 72 hours. After stirring, the mixture was diluted with ethyl acetate (100 mL), and 1 mol/L hydrochloric acid was added while cooling in an ice bath to acidify the reaction solution, thereby terminating the reaction. Subsequently, the mixture was extracted three times with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate (3:1, v/v)) to obtain the target compound A2.

Compound A2: white solid (yield: 91%)
^1H -NMR (600MHz, acetone- _d6 ) δ 7.08 (s, 2H), 6.06-6.13 (m, 1H), 5.29 (ddt, J=17, 1.6, 1.6Hz, 1H), 5.29 ( ddt, J=10, 1.8, 1.2Hz, 1H), 5.15 (ddd, J=6, 1.5, 1.2Hz, 1H), 3.80 (s, 3H).
¹³ C-NMR (150 MHz, CDCl ₃ ) δ 166.88, 151.37, 138.64, 135.26, 126.38, 118.44, 109.69, 73.89, 52.15.

(2) Preparation of 4-(Allyloxy)-3,5-bis(benzyloxy)benzoic acid (Compound A3) Under an argon atmosphere, Compound A2 (4.90 g, 22 mmol) and tetrabutylammonium iodide (8.00 g, 22 mmol) were added to a 200 mL round-bottom flask, followed by the addition of tetrahydrofuran (50 mL) and stirring to obtain a clear solution. Subsequently, 60% by mass sodium hydride (2.64 g, 66 mmol) and benzyl bromide (13 mL, 109 mmol) were added sequentially while cooling in an ice bath. The mixture was then heated to 50°C and stirred for 8 hours. Subsequently, ethanol (32 mL), water (16 mL), and a 7 mol/L aqueous sodium hydroxide solution (16 mL) were added, followed by heating to 60°C and stirring for 18 hours. After stirring, 1 mol/L hydrochloric acid was added under ice bath cooling to acidify the reaction solution and terminate the reaction. The solvent was distilled off under reduced pressure using an evaporator to obtain a white solid, which was filtered, washed with water, and eluted with acetone. The solvent was then distilled off under reduced pressure using an evaporator to obtain Compound A3 (6.90 g, 17 mmol, 81% yield) as a white solid from the resulting residue.

Compound A3:
^1H -NMR (600MHz, DMSO-d ₆ )δ 7.46-7.47 (m, 4H), 7.39-7.41 (m, 4H), 7.32-7.36 (m, 4H), 5.95-6.01 (m, 1H), 5.28 (ddt, J=1 7, 1.7, 1.7Hz, 1H), 5.17 (s, 4H), 5.14 (ddt, J=10, 1.2Hz, 1H), 4.54 (ddd, J=5.6, 1.2Hz, 1H).

Reference Example 2 Production of Compound A5 Compound A5 was synthesized from gallic acid ester according to the following steps.

(1) Preparation of Methyl 4,5-bis(benzyloxy)-3-hydroxybenzoate (Compound A4) Under an argon atmosphere, methyl gallate (Compound A1) (5 g, 27 mmol) was added to a 500 mL round-bottom flask, followed by the addition of acetonitrile (250 mL) and stirring to obtain a pale yellow solution. Subsequently, N,N-diisopropylethylamine (9.5 mL, 57 mmol) and benzyl bromide (13 mL, 114 mmol) were added sequentially while cooling in an ice bath. The temperature was then raised to room temperature and stirred for 96 hours. After stirring, the mixture was diluted with ethyl acetate (250 mL), and 1 mol/L hydrochloric acid was added while cooling in an ice bath to acidify the reaction solution, thereby terminating the reaction. Subsequently, the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (5:1, v/v)) to obtain Compound A4 (4.8 g, 13 mmol, 49%) as a white amorphous substance.

Compound A4:
^1H -NMR (600MHz, acetone- _d6 ) δ 7.54-7.56 (m, 2H), 7.34-7.44 (m, 5H), 7.28-7.30 (m, 4H), 7.20 (d, J=1.9Hz, 1H), 5.22 (s, 2H), 5.13 (s, 2H), 3.83 (s, 3H).

(2) Preparation of 3-(Allyloxy)-4,5-bis(benzyloxy)benzoic acid (Compound A5) Under an argon atmosphere, Compound A4 (260 mg, 0.71 mmol) and tetrabutylammonium iodide (230 mg, 0.71 mmol) were added to a 200 mL round-bottom flask, followed by the addition of tetrahydrofuran (20 mL) and stirring to obtain a clear solution. Subsequently, 60% by mass sodium hydride (85 mg, 2.1 mmol) and allyl bromide (121 μL, 1.4 mmol) were added sequentially while cooling in an ice bath. The mixture was then heated to 50°C and stirred for 9 hours. At this time, ethanol (20 mL), water (13 mL), and a 7 mol/L aqueous sodium hydroxide solution (7 mL) were added, followed by heating to 60°C and stirring for 9 hours. After stirring, 1 mol/L hydrochloric acid was added under ice bath cooling to acidify the reaction solution and terminate the reaction. The solvent was distilled off under reduced pressure using an evaporator to obtain a white solid, which was filtered, washed with water, and eluted with acetone. The solvent was then distilled off under reduced pressure using an evaporator. Compound A5 (383 mg, 0.53 mmol, 76% yield) was obtained as a white solid from the resulting residue.

Compound A5:
¹ H-NMR (600 MHz, CD ₃ CN) δ 7.18-7.43 (m, 12H), 5.99-6.05 (m, 1H), 5.36 (ddt, J=17, 1.8Hz, 1H), 5.10 (dd t, J=6.6, 1.5Hz, 1H), 5.11 (s, 2H), 5.02 (s, 2H), 4.56 (ddd, J=17, 1.8Hz, 1H).

Reference Example 3 Production of 2,2,2-trichloroethoxy-sulfuryl-1,2-dimethylimidazolium triflate (Compound B4) Compound B4 was synthesized from 2,2,2-trichloroethanol according to the following steps.

(1) Preparation of 2,2,2-Trichloroethyl sulfurochloridate (Compound B2) Under an argon atmosphere, 2,2,2-trichloroethanol (Compound B1) (5.9 mL, 61 mmol) and pyridine (4.97 mL, 61 mmol) were added to a 300 mL round-bottom flask, followed by the addition of diethyl ether (100 mL) and stirring to obtain a clear solution. Subsequently, sulfuryl chloride (5 mL, 61 mmol) was added dropwise over 1 hour while the reaction vessel was cooled to -78°C. The mixture was then warmed to room temperature and stirred for 3 hours. After stirring, the resulting white solid was washed twice with 20 mL of diethyl ether, and the solvent was removed from the filtrate by vacuum distillation using an evaporator at 25°C. Compound B2 (12.0 g, 48 mmol, 79% yield) was obtained as a clear liquid from the resulting residue.

(2) Preparation of 2',2',2'-Trichloroethyl 2-methyl-1H-imidazole-1-sulfonate (Compound B3) Under an argon atmosphere, 2-methylimidazole (18.2 g, 172 mmol) was added to a 300 mL round-bottom flask, followed by the addition of tetrahydrofuran (50 mL) and stirring to obtain a clear solution. Subsequently, Compound B2 (12.0 g, 48 mmol) diluted with tetrahydrofuran (50 mL) was added dropwise over 1 hour while cooling in an ice bath. The mixture was then warmed to room temperature and stirred for 1 hour. After stirring, the resulting white solid was washed twice with 20 mL of tetrahydrofuran, and the solvent in the filtrate was distilled under reduced pressure using an evaporator at 25°C. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)) to obtain Compound B3 (9.70 g, 32 mmol, 68%) as a clear liquid.

(3) Preparation of 2,3-Dimethyl-1-((2',2',2'-trichloroethoxy)sulfonyl)-1H-imidazolium-3-ium trifluoromethanesulfonate (Compound B4) Under an argon atmosphere, Compound B3 (9.70 g, 32 mmol) was placed in a 300 mL round-bottom flask, and then diethyl ether (100 mL) was added and stirred to obtain a clear solution. Subsequently, methyl trifluoromethanesulfonate (3.8 mL, 33 mmol) was added dropwise while cooling in an ice bath, and the mixture was stirred for 3 hours. Thereafter, the mixture was cooled to -20°C. The obtained white solid was washed with cooled diethyl ether to obtain Compound B4 (12.9 g, 27 mmol, 85%) as a white solid.

Production Example 1 Production of 3"-sulfated epigallocatechin gallate 3"-sulfated epigallocatechin gallate (Compound 6) was synthesized from (-)-epigallocatechin (EGC) by the following steps.

(1) Preparation of (2R,3R)-5,7-Bis(benzyloXy)-2-(3',4',5'-tris(benZyloxy)phenyl)chroman-3-ol (Compound 2) Under an argon atmosphere, 60% by mass sodium hydride (336 mg, 8.4 mmol) was added to a 100 mL round-bottomed ?ask, followed by the addition of N,N-dimethylformamide (8 mL) and stirring to obtain a suspension. Subsequently, a solution prepared from (-)-epigallocatechin (Compound 1) (500 mg, 1.6 mmol), benzyl bromide (13 mL, 109 mmol), and N,N-dimethylformamide (8 mL) was added dropWise While cooled at -50°C, the mixture Was then warmed to room temperature and stirred for 48 hours. After stirring, the reaction Was quenched by adding 1 mol/L hydrochloric acid While cooling in an ice bath to acidify the reaction solution. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (4:1, v/v)) to give compound 2 (710 mg, 4.78 mmol, yield 57%) as a white amorphous substance.

Compound 2:
^1H -NMR (600MHz, acetone- _d6 ) δ 7.26-7.52 (m, 25H), 7.04 (s, 2H), 6.36 (d, J=2.2Hz, 1H), 6.23 (d, J=2.2Hz, 1H) 5.14 (s, 4H), 5.12 (d, J=2.8Hz, 2H), 5.08 (s, 2H), 5.03 (s, 2H), 5.01 (m, 1H), 4.31-4.33 (m, 1H), 2.86-2.96 (m, 2H).

(2)<(2R,3R)-5,7-Bis(benzyloxy)-2-(3',4',5'-tris(benzyloxy)phenyl)chroman-3-yl Production of 5”-(allyloxy)-3”,4”-bis(benzyloxy)benzoate> (compound 3) Under an argon atmosphere, compound 2 (258 g, 0.34 mmol), the allyl ether gallate ester (compound A5) (200 g, 0.51 mmol) prepared in Reference Example 2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg, 1.00 mmol), and N,N-dimethyl-4-aminopyridine (63 mg, 0.34 mmol) were added to a round-bottom flask, followed by the addition of acetonitrile (10 mL) and stirring to obtain a pale yellow solution. The mixture was then stirred at room temperature for 1 hour. After stirring, the mixture was diluted with ethyl acetate (20 mL), and 1 mol/L hydrochloric acid was added under ice bath cooling to acidify the reaction solution, thereby terminating the reaction. The mixture was then extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (4:1, v/v)) to obtain target compound 3.

Compound 3: White amorphous (yield: 100%)
¹ H-NMR (600 MHz, CDCl ₃ ) δ 7.20-7.42 (m, 37H), 6.74 (s, 2H), 6.36 (d, J=2.2Hz, 1H), 6.32 (d, J= 2.2Hz, 1H), 5.89-5.95 (m, 1H), 5.65-5.66 (m, 1H), 5.30 (ddt, J=17, 1.4Hz, 1H), 5.19 (ddt, J=10, 1.3Hz, 1H), 5.14 (m, 1H), 4.83-5.04 (m , 12H), 4.72 (d, J=11Hz, 2H), 4.48-4.49 (m, 2H), 3.04-3.13 (m, 2H).

(3)<(2R,3R)-5,7-Bis(benzyloxy)-2-(3',4',5'-tris(benzyloxy)phenyl)chroman-3-yl Production of 3”,4”-bis(benzyloxy)-5”-hydroxybenzoate (compound 4) Under an argon atmosphere, compound 3 (390 mg, 0.34 mmol) was added to a round-bottom flask, followed by the addition of tetrahydrofuran (10 mL) and stirring to obtain a clear solution. Subsequently, morpholine (61 μL, 0.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (40 mg, 34 μmol) were added, and the mixture was stirred for 45 minutes. After stirring, the mixture was diluted with ethyl acetate (20 mL), and 1 mol/L hydrochloric acid was added under ice bath cooling to acidify the reaction solution, thereby terminating the reaction. Subsequently, the mixture was extracted three times with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (3:1, v/v)) to obtain the target compound 4.

Compound 4: White amorphous (yield: 53%)
¹ H-NMR (600 MHz, CDCl ₃ ) δ 7.17-7.44 (m, 37H), 6.79 (s, 2H), 6.34 (d, J=2.3Hz, 1H), 6.30 (d, J=2.2Hz, 1H), 5.60-5 .61 (m, 1H), 5.14 (m, 1H), 4.93-5.08 (m, 12H), 4.81 (d, J=11Hz, 2H), 3.06-3.16 (m, 2H).

(4) (2R,3R)-5,7-Bis(benzyloxy)-2-(3',4',5'-tris(benzyloxy)phenyl)chroman-3-yl 4”,5”-bis(benzyloxy)-3”-(((2,2,2-trichloroethoxy)sulfonyl)oxy)benzoate> Production of (Compound 5) Under an argon atmosphere, compound 4 (190 mg, 0.17 mmol) and the trichloroethyl sulfonating reagent (B4) (398 mg, 0.87 mmol) prepared in Reference Example 3 were added to a round-bottom flask, followed by the addition of dichloromethane (10 mL) and stirring to obtain a clear solution. Subsequently, 1,2-dimethylimidazole (84 mg, 0.87 mmol) was added and the mixture was stirred overnight. After stirring, the mixture was diluted with ethyl acetate (20 mL) and the reaction was stopped by adding water. Subsequently, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure using an evaporator. The resulting residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (4:1, v/v)) to obtain the target compound 5 (white amorphous) (yield: 69%).

(5) Preparation of 3"-sulfated epigallocatechin gallate (Ammonium 3"-((((2R,3R)-5,7-dihydroxy-2-(3',4',5'-trihydroxyphenyl)chroman-3-yl)oxy)carbonyl)-4",5"-dihydroxyphenyl sulfate; Compound 6) Compound 5 (50 mg, 38 μmol), palladium carbon (5 mg), and ammonium formate (24 mg, 380 μmol) were placed in a round-bottom flask under an argon atmosphere, and then tetrahydrofuran-methanol (4 mL, 3:1, v/v) was added and the mixture was stirred to obtain a suspension. Subsequently, the atmosphere in the resulting suspension was replaced with hydrogen and then stirred for 18 hours. After stirring, the insoluble matter was filtered off and washed with tetrahydrofuran-methanol (8 mL, 3:1, v/v) and water (2 mL). Subsequently, the filtrate was evaporated under reduced pressure using an evaporator. The resulting residue was purified by preparative HPLC to obtain target compound 6 as a white solid.
[Filling conditions]
Preparative column: L-column ODS, size 20 mm x 259 mm 5 μm
Eluent: A (10 mM ammonium formate water), B (acetonitrile)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280 nm
Gradient condition B (%): 3 → 20% (5 min), 20 → 30% (10 min), 30 → 97% (3 min), 97 → 3% (0.1 min), 3% (2 min)
Fractionation time: 8.0-9.6 minutes

Compound 6: White solid (78% yield)
¹ H-NMR (600 MHz, D ₂ O:MeOH (=200:1)) δ 7.44 (d, J = 1.4Hz, 1H), 7.20 (d, J = 1.5Hz, 1H), 6.54 (s, 2H), 6.11 (d, J = 1.9Hz, 1H), 6.06 (d, J = 1.5Hz) , 1H), 5.53-5.53 (m, 1H), 5.06-5.06 (m, 1H), 3.00 (dd, J=17.6, 3.9, Hz, 1H), 2.89 (d, J=17.3Hz, 1H).
^13C -NMR (150MHz, _D2O :MeOH (=200:1)) δ 167.14, 156.14, 156.03, 155.94, 145.81, 145.78, 143.36, 139.54, 132.73, 120.73, 117.17, 115.21, 107.12, 99.73, 96.70, 95.87, 77.81, 69.88, 25.55.
HRMS calcd. for C ₂₂ H ₁₉ O ₁₄ S ⁺ [M+H] ⁺ :539.0496;found:539.0483

Production Example 2 Production of 4"-sulfated epigallocatechin gallate In the following steps, compound 2 was synthesized from (-)-epigallocatechin (EGC) in the same manner as in Production Example 1(1). This compound was then subjected to a condensation reaction with the allyl ether gallate ester (compound A3) produced in Reference Example 1 in the same manner as in Production Example 1(2) to obtain compound 7. The allyl group was then removed in the same manner as in Production Example 1(3) to obtain compound 8, which was then converted to trichloroethyl sulfate in the same manner as in Production Example 1(4) to obtain compound 9, which was then subjected to a deprotection reaction in the same manner as in Production Example 1(5) to synthesize 4"-sulfated epigallocatechin gallate (compound 10).

4"-sulfated epigallocatechin gallate (Ammonium 4"-((((2R,3R)-5,7-dihydroxy-2-(3',4',5'-trihydroxyphenyl)chroman-3-yl)oxy)carbonyl)-3",5"-dihydroxyphenyl sulfate; Compound 10):
White solid (52%)
¹ H-NMR (600 MHz, D ₂ O:MeOH (=200:1)) δ 6.93 (s, 2H), 6.51 (s, 2H), 6.09 (d, J = 2.1Hz, 1H), 6.06 (d, J = 1.9Hz, 1H), 5.56-5.56 (m, 1H), 5.04-5.04 (m, 1H), 3.00 (dd, J=17.9, 5.2, Hz, 1H), 2.89 (d, J=17.2Hz, 1H).
^13C -NMR (150MHz, _D2O :MeOH (=200:1)) δ 167.07, 156.15, 156.03, 155.90, 150.69, 145.85, 132.76, 132.42, 130. 31, 128.31, 110.57, 107.03, 99.73, 96.70, 95.84, 77.73, 70.06, 25.46.
HRMS calcd. for C ₂₂ H ₁₈ O ₁₄ SNa ⁺ [M+Na] ⁺ :561.0315;found:561.0315

Production Example 3: Production of 3"-glucuronidated epigallocatechin gallate Compound 4, synthesized from (-)-epigallocatechin (EGC), was glucuronidated in the same manner as in Production Example 1 to obtain compound 11, which was then subjected to a deprotection reaction in the same manner as in Production Example 1(5) to synthesize 3"-glucuronidated epigallocatechin gallate (compound 12).

(1) Under an argon atmosphere, compound 4 (1 equivalent), 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-methyl glucuronate (5 equivalents), and molecular sieves 4Å (5 parts by mass) were placed in a 50 mL round-bottom flask. Anhydrous dichloromethane (0.2 M diluted) was added and stirred to obtain a clear solution. Subsequently, trifluoroborane-ether complex (5 equivalents) was added at 0°C, and the mixture was warmed to room temperature and stirred for 24 hours. After the reaction, the mixture was diluted with ethyl acetate (20 mL) and then quenched by adding water. Subsequently, the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure using an evaporator. The resulting residue was crudely purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)), yielding a white amorphous mixture.

(2) Preparation of 3"-glucuronidated epigallocatechin gallate ((2''R,3''R,4''R,5''S,6''R)-6''-(5''-((((2R,3R)-5,7-Dihydroxy-2-(3',4',5'-trihydroxyphenyl)chroman-3-yl)oxy)carbonyl)-2'',3''-dihydroxyphenoxy)-3''',4''',5'''-trihydroxytetrahydro-2H-pyran-2'''-carboxylic acid; Compound 12) The mixture obtained in (1) was placed in a 100 mL round-bottom flask, and tetrahydrofuran-ethanol-purified water solution (2:2:1, 50-fold diluted) was added and stirred to obtain a clear solution. Subsequently, 1N aqueous sodium hydroxide solution (1-fold diluted) was added at room temperature, and the mixture was stirred for 30 minutes. After the reaction, Amberlyst® 15(H) and acetic acid were added to acidify the reaction solution, thereby terminating the reaction. Subsequently, the mixture was filtered, and the solvent was removed from the obtained filtrate by vacuum distillation using an evaporator. To the resulting residue, a tetrahydrofuran-methanol-acetic acid solution (30:10:2, 52-fold diluted) was added under an argon atmosphere, and the mixture was stirred to obtain a clear liquid. Subsequently, palladium carbon (0.2 parts by mass) was added at room temperature, the atmosphere in the flask was replaced with hydrogen, and the mixture was vigorously stirred for 5 hours. After the reaction, the palladium carbon was filtered and washed with a tetrahydrofuran-methanol solution, and the solvent was removed from the obtained organic layer by vacuum distillation using an evaporator. The resulting residue was purified by preparative HPLC, yielding compound 12 as a white solid.

[Filling conditions]
Preparative column: L-column ODS, size 20 mm x 259 mm 5 μm
Eluent: A (0.1% formic acid water), B (methanol)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280 nm
Gradient condition B (%): 3 → 20% (5 min), 20 → 30% (10 min), 30 → 97 (0.1 min), 97% (2.9 min), 97 → 3% (2 min)
Collection time: 8-9 minutes

Compound 12:
White solid (3-step yield: 19%)
^1H NMR (600MHz, _D2O (1% acetic acid)) δ6.93 (s, 2H), 6.52 (s, 2H) 6.10 (d, J=2.1Hz, 1H), 6.07 (d, J= 1.8Hz, 1H), 5.55-5.55 (m, 1H), 5.07-5.07 (m, 1H), 4.97 (d, J = 7.8Hz , 1H), 3.65 (dd, = 5.0, 4.1Hz, 1H), 3.58 (dd, = 9.6, 8.2Hz, 1H), 3.51- 3.49 (m, 2H), 3.01 (dd, J = 18.3, 4.9, Hz, 1H), 2.89 (d, J = 17.2Hz, 1H)
¹³ C-NMR (150 MHz, D ₂ O (1% acetone-d ₆ )) δ165.78, 165.76, 154.75, 154.73, 148.52, 144.41, 135.76, 131.33, 128.90, 125.61, 109.10 , 105.61, 102.49, 98.30, 95.27, 94.42, 76.30, 75.82, 74.47, 72.32, 70.89, 68.57, 67.26, 24.03
HRMS calcd. for C ₂₈ H ₂₇ O ₁₇ ⁺ [M+H]+:635.1248;found:635.1261.

Production Example 4 Production of 4"-Glucuronidated Epigallocatechin Gallate Compound 8, synthesized from (-)-epigallocatechin (EGC) in the same manner as in Production Example 2, was glucuronidated in the same manner as in Production Example 3(1) to obtain Compound 13, which was then subjected to a deprotection reaction in the same manner as in Production Example 3(2) to synthesize 4"-glucuronidated epigallocatechin gallate (Compound 14).

4"-Glucuronidated epigallocatechin gallate ((2''R,3''R,4''R,5''S,6''R)-6''-(4''-((((2R,3R)-5,7-Dihydroxy-2-(3',4',5'-trihydroxyphenyl)chroman-3-yl)oxy)carbonyl)-2'',6''-dihydroxyphenoxy)-3''',4''',5'''-trihydroxytetrahydro-2H-pyran-2'''-carboxylic acid; Compound 14)
White solid (3-step yield 61%)
^1H NMR (600MHz, _D2O (1% acetic acid)) δ6.93 (s, 2H), 6.52 (s, 2H) 6.10 (d, J=2.1Hz, 1H), 6.07 (d, J= 1.8Hz, 1H), 5.55-5.55 (m, 1H), 5.07-5.07 (m, 1H), 4.97 (d, J = 7.8Hz , 1H), 3.65 (dd, = 5.0, 4.1Hz, 1H), 3.58 (dd, = 9.6, 8.2Hz, 1H), 3.51- 3.49 (m, 2H), 3.01 (dd, J = 18.3, 4.9, Hz, 1H), 2.89 (d, J = 17.2Hz, 1H)
¹³ C-NMR (150 MHz, D ₂ O (1% acetic acid) δ165.78, 165.76, 154.75, 154.73, 148.52, 144.41, 135.76, 131.33, 128.90, 125.61, 109.1 0,105.61,102.49,98.30,95.27,94.42,76.30,75.82,74.47,72.32,70.89,68.57,67.26,24.03
HRMS calcd. for _C28H27O17 ⁺ _[ M+H] ₊ ^: 635.1248;found:635.1261.

Test Example 1: Evaluation of antiviral activity of EGCg and EGCg derivatives (1) MDCK cells (obtained from ATCC; CCL-34) were cultured in Eagle's minimum essential medium (MEM; Invitrogen Co.) supplemented with 5% (v/v) fetal bovine serum (Sigma, St. Louis) heat-inactivated at 65°C for 30 minutes, and 50 μg/mL of gentamicin sulfate (Invitrogen Co.). The cells were grown to confluence in a 96-well plate and used in this test.

(2) 125 μL of 20 μM EGCg, the EGCg derivatives synthesized in Production Examples 1 to 4 (3′-sulfated epigallocatechin gallate (Compound 6), 3′-glucuronidated epigallocatechin gallate (Compound 12)), 4′-sulfated epigallocatechin gallate (Compound 10), and 4′-glucuronidated epigallocatechin gallate (Compound 14)) were prepared, and 125 μL of 2,000 TCID/mL influenza virus (A/Puerto Rico/8/34, H1N1 experimental strain) was added thereto and shaken at 300 rpm for 1 minute. The mixture was then incubated at 37°C in ₅ % CO for 30 minutes (compound concentration: 10 μM, virus dose: 250 TCID/250 μL). The MDCK cells prepared in the 96-well plate were then washed with PBS and infected with 100 μL/well. The test was performed in duplicate. Thirty minutes after infection, 100 μL of virus culture medium (serum-free medium, acetylated trypsin 2 mg/mL, gentamicin sulfate 50 μg/mL) was added, and the cells were cultured for 24 hours. The culture supernatant was collected, and the cells were fixed with methanol (FUJIFILM Wako Pure Chemical). The influenza virus HA titer of the collected culture supernatant was measured using the HA assay described below.
The fixed cells were reacted with a primary antibody: mouse monoclonal anti-influenza NP antibody (Invitrogen) and a secondary antibody: HRP-linked goat anti-mouse IgG antibody (FUJIFILM Wako Pure Chemical), and then reacted with HRP using a DEPDA reaction to stain the viral NP protein blue.
<HA Assay>
Using a U-bottom 96-well plate, 50 μL of influenza virus culture supernatant was serially diluted in 2-fold increments from 2 to 1024 to prepare a dilution series. 50 μL of PBS containing 0.7 v/v% guinea pig red blood cells was added thereto, and the mixture was allowed to stand at 4°C for 2 hours. After that, red blood cell agglutination was confirmed, and the dilution concentration at which agglutination was observed was taken as the HA titer.

(3) Results The results of staining NP protein are shown in Figure 1. All viruses reacted with each compound were infectious, and viral NP protein was detected. However, while EGCg, which has been reported to have antiviral activity, showed a decrease in NP protein detection, the EGCg derivatives of the present invention (compounds 6 and 12) showed a significant inhibition of NP protein detection. 4"-sulfated epigallocatechin gallate (compound 10) and 4"-glucuronidated epigallocatechin gallate (compound 14) showed almost no inhibition of NP protein detection.
Furthermore, according to the HA assay, EGCg at the evaluation concentration, which has been reported to have antiviral activity and has been observed to reduce the detection of NP protein, did not show a decrease in HA titer or reduce the amount of virus, but the HA titer was significantly reduced in the culture supernatant of the virus reacted with the EGCg derivatives of the present invention (compounds 6 and 12), which have been observed to significantly suppress the detection of NP protein, and a decrease in the amount of virus was observed. In particular, the amount of virus detected with compound 12 was below the detection limit (N.D.; not detected) (Figure 2).
From the above results, it was confirmed that the EGCg derivatives of the present invention have superior anti-influenza virus activity compared to EGCg.

Claims (5)

The following formula (I):
[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]
An anti-influenza virus agent containing, as an active ingredient, an epigallocatechin gallate derivative represented by the formula: The following formula (I):
[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]
An agent for preventing or ameliorating influenza virus infections, comprising as an active ingredient an epigallocatechin gallate derivative represented by the formula: The following formula (I):
[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]
An anti-influenza virus food containing, as an active ingredient, an epigallocatechin gallate derivative represented by the formula: The following formula (I):
[wherein R represents a glucuronosyl group or —SO ₃ M (wherein M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium)]
A food for preventing or ameliorating influenza virus infections, which contains as an active ingredient an epigallocatechin gallate derivative represented by the formula: The anti-influenza virus agent according to claim 1, which is a bactericidal disinfectant composition or a sanitary product composition.