WO2021241666A1

WO2021241666A1 - Antiviral agent

Info

Publication number: WO2021241666A1
Application number: PCT/JP2021/020127
Authority: WO
Inventors: 修松田; えり子扇谷; 政春新屋
Original assignee: 京都府公立大学法人
Priority date: 2020-05-29
Filing date: 2021-05-27
Publication date: 2021-12-02
Also published as: JPWO2021241666A1

Abstract

The present invention addresses the problem of providing an antiviral agent, particularly an anti-coronavirus agent for a coronavirus such as SARS-CoV-2. The problem is solved by an antiviral agent comprising at least one selected from the group consisting of (A-components) resveratrol, resveratrol derivatives, resveratrol multimers, derivatives of resveratrol multimers, or sirtuin activators, (B-components) extracts of a plant of the genus Orychophragmus, (C-components) barrigenol or glycosides thereof, (D-components) apigenin or glycosides thereof, (E-components) extracts of a plant of the genus Bellis, (F-components) extracts of a plant of the genus Ilex, (G-components) ulsoric acid or glycosides thereof, (H-components) coumaric acid or glycosides thereof, (I-components) 2-phenylethanol or glycosides thereof, (J-components) tamarixetin or glycosides thereof, and (K-components) sarmentol or glycosides thereof.

Description

Antiviral agent

The present invention relates to an antiviral agent or the like.

Coronavirus is a species of virus belonging to the subfamily Coronaviridae of the Coronaviridae family, and is a plus-strand RNA virus that infects humans and animals and causes respiratory, gastrointestinal, or neurological disorders. Coronaviruses can emerge from carriers and cause large-scale infectious diseases in humans. Examples of coronaviruses include SARS coronavirus 1 (SARS-CoV-1), which was prevalent in 2002 and 2003, and Middle East respiratory syndrome coronavirus (MERS-CoV). Recently, a worldwide epidemic of SARS coronavirus 2 (SARS-CoV-2) has occurred, and since the treatment technology has not been established, serious damage continues in various fields such as medical treatment and economy.

An object of the present invention is to provide an antiviral agent, particularly an antiviral agent against a coronavirus such as SARS-CoV-2.

As a result of diligent research in view of the above problems, the present inventor (component A) resveratrol, resveratrol derivative, resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator, ( B component) Oaraseito plant extract, (C component) Varigenol or its glycoside, (D component) Apigenin or its glycoside, (E component) Hinagiku plant extract, (F component) Mochinoki plant extract (G component) ursoleic acid or its glycoside, (H component) kumalic acid or its glycoside, (I component) 2-phenylethanol or its glycoside, (J component) tamarixetine or its glycoside , And an antiviral agent containing at least one selected from the group consisting of (K component) salmenthol or a glycoside thereof, it has been found that the above-mentioned problems can be solved. The present inventor has completed the present invention as a result of further research based on this finding. That is, the present invention includes the following aspects.

Item 1. (Component A) Resveratrol, resveratrol derivative, resveratrol multimer, resveratrol multimer derivative, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(D component) Apigenin or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(H component) Coumaric acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
An antiviral agent containing at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.

Item 2. Item 2. The antiviral agent according to Item 1, wherein the virus is a coronavirus.

Item 3. Item 2. The antiviral agent according to Item 1 or 2, wherein the virus is SARS-CoV-2.

Item 4. (Ingredient A) Resveratrol tetramer,
(B component) Shokatsusai extract,
(C component) A1-varigenol,
(D component) Apigenin,
(E component) Daisy flower extract,
(F component) Yerba mate extract,
(G component) Matesaponin 3,
(H component) p-coumaric acid,
(Component I) 2-Phenylethyl-β-D-Glucopyranoside,
(J component) Tamarixetin 7-O-β-D-glucopyranoside, and (K component) Sesmoside E2 or Sesmoside E3
Item 6. The antiviral agent according to any one of Items 1 to 3, which contains at least one selected from the group consisting of.

Item 5. Item 2. The antiviral agent according to any one of Items 1 to 4, which is used for application to a living body.

Item 6. Item 5. The antiviral agent according to Item 5, which is a medicine, cosmetics, disinfectant or cleaning agent.

Item 7. Item 5. The antiviral agent according to Item 5 or 6, which is a preventive or therapeutic agent for COVID-19.

Item 8. Item 2. The antiviral agent according to any one of Items 1 to 4, which is used for applying to articles.

Item 9. Item 8. The antiviral agent according to Item 8, which is a disinfectant or a cleaning agent.

The present invention also includes the following aspects.

Item 1. (Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
An antiviral agent containing at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.

Item 4. (Ingredient A) Resveratrol tetramer,
(B component) Shokatsusai extract,
(C component) A1-varigenol,
(E component) Daisy flower extract,
(F component) Yerba mate extract,
(G component) Matesaponin 3,
(Component I) 2-Phenylethyl-β-D-Glucopyranoside,
(J component) Tamarixetin 7-O-β-D-glucopyranoside, and (K component) Sesmoside E2 or Sesmoside E3
Item 6. The antiviral agent according to any one of Items 1 to 3, which contains at least one selected from the group consisting of.

Item 5. Item 2. The antiviral agent according to any one of Items 1 to 4, which contains at least one selected from the group consisting of Hopeaphenol, Isohopeaphenol, and derivatives thereof.

Item 6. Item 2. The antiviral agent according to any one of Items 1 to 5, which is used for application to a living body.

Item 7. Item 6. The antiviral agent according to Item 6, which is a food composition, a food additive, a medicine, a cosmetic, a disinfectant or a cleaning agent.

Item 8. Item 6. The antiviral agent according to Item 6 or 7, which is a preventive or therapeutic agent for COVID-19.

Item 9. Item 2. The antiviral agent according to any one of Items 1 to 5, which is used for applying to articles.

Item 10. Item 9. The antiviral agent according to Item 9, which is a disinfectant or a cleaning agent.

Item 11. An antiviral food composition containing at least one selected from the group consisting of Hopeaphenol, Isohopeaphenol, and derivatives thereof.

Item 12. (Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
An antiviral method comprising applying to a living body or an article at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.

Item 13. For use as an antiviral agent,
(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
A preparation containing at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.

Item 14. (Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
Use for the production of at least one antiviral agent selected from the group consisting of (component J) tamalixetin or its glycosides and (component K) salmenthol or its glycosides.

Item 15. (Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
Use as an antiviral agent of at least one selected from the group consisting of (J component) tamalixetin or its glycoside, and (K component) salmenthol or its glycoside.

According to the present invention, it is possible to provide an antiviral agent, particularly an antiviral agent against a coronavirus such as SARS-CoV-2.

The test results of Test Example 2 when hopeaphenol and isohopeaphenol are used as samples are shown. The vertical axis shows the virus inhibition rate based on CPE. The horizontal axis shows the sample name and the concentration of the sample in the virus solution. The test result of Test Example 2 when the methanol extract of daisy flower was used as a sample is shown. The vertical axis shows the virus inhibition rate based on CPE. The horizontal axis shows the sample name and the concentration of the sample in the virus solution.

In the present specification, the expressions "contains" and "contains" include the concepts of "contains", "contains", "substantially consists" and "consists only".

The present invention, in one aspect thereof, is an antiviral agent (the present specification) containing at least one selected from the group consisting of A to K components (sometimes referred to as an "active ingredient" in the present specification). In the book, it may be referred to as "the pharmaceutical product of the present invention"). This will be described below.

1. 1. Active ingredient 1-1. Component A Component A is a resveratrol, a resveratrol derivative, a resveratrol multimer, a derivative of the resveratrol multimer, or a sirtuin activator.

The resveratrol derivative is not particularly limited, and known derivatives can be used without limitation. The resveratrol derivative is not particularly limited, but for example, a cis type, a hydroxyl group on the benzene ring (for example, 1 to 2 or one hydroxyl group) is another group (for example, a hydrogen atom, an alkoxy group, an alkyl group, an amino group, etc. Derivatives substituted with carboxy groups, etc., hydrogen atoms on the benzene ring (eg, 1-2 or 1 hydrogen atom) are substituted (eg, hydroxyl groups, alkoxy groups, alkyl groups, amino groups, carboxy groups, etc.) Derivatives, derivatives formed by condensing a benzene ring with another ring, etc., and one or more modifications (for example, 1 to 3, 1 to 2, or 1) in these derivatives are combined. Derivatives and the like.

The resveratrol multimer is a compound having a plurality of skeletons of resveratrol or a derivative thereof, and is not particularly limited as long as it is. Resveratrol multimers include, for example, resveratrol dimer (eg Amurensin A and H, Ampelopsin A, B, D, and F, Balanocarpol, Cyphostemmin A and B, δ-viniferin, ε-viniferin, Gnetin A and C, Leachinol F, Malibatol A, Pallidol, Parthenocissin A, Quadrangularin A, Restrytisol A, B, and C, Vitisinol D), resveratrol trimer (α-viniferin, Ampelopsin C, Amurensin C, D and G, Hopeanolin , Malaysian A, Miyabenol C, Resviniferin A and B, trans-diptoindonesin B), resveratrol tetramer (Ampelopsin H, Amurensin K, Caraphenol B, Carasinol B, Flexuosol A, Hopeaphenol, Isohopeaphenol, Kobophenol A Vaticanol B and C, Vaticaphenol A, Vitisin A, B and C, β-viniferin (cyclic resveratrol tetramer)), resveratrol pentamer (Amurensin E and F), resveratrol hexamer (Chunganenol), γ- Examples include viniferin and Valeriaphenol A.

The derivative of resveratrol multimer is the same as that of resveratrol derivative.

The sirtuin activator is not particularly limited, but for example, the above-mentioned components can be used. In addition to these, as sirtuin activators, for example, Resveratrol, Quercetin, Butein, SRT1720, SRT1460, SRT2183, STAC-5, STAC-9, STAC-10, Piceatannol, SRT2104, 1,4-DHP derivative, UBCS039 , SRT2379, SRT3025, β-nicotinamide mononucleotide (NMN) and the like.

As the component A, a plant extract containing the above components can also be used.

As the component A, a resveratrol multimer is preferable, a resveratrol tetramer is more preferable, and Hopephenol and Isohopeaphenol are particularly preferable.

As resveratrol and its multimers, those obtained according to a known production method can be used, or commercially available products can be used. Resveratrol and its multimers can be obtained, for example, by extraction and purification from various plants (eg grapes, shorea roxburghii). Specifically, for example, it can be obtained according to or in accordance with the previously reported (Bioorganic & Medicinal Chemistry 20 (2012) 832-840).

The component A may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the component A, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.01 μM or more, preferably 0.1 μM or more, more preferably 1 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-2. Component B Component B is an extract of the genus Orychophragmus.

The Orychophragmus genus plant extract is not particularly limited as long as it is obtained by extracting from the Orychophragmus genus plant.

Examples of plants of the genus Orychophragmus include Orychophragmus violaceu, Orychophragmus limprichtianus, Orychophragmus ziguiensis and the like. Among these, Shokatsusai is particularly preferable.

It is preferable to cut the plants of the genus Orychophragmus to be extracted as necessary.

The extraction solvent is not particularly limited. Examples of the extraction solvent include water; alcohols such as methanol, ethanol, propanol and butanol; alkyl acetates such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; and supercritical carbon dioxide. Among these, alcohol (especially methanol) and the like are preferable. The extraction solvent may be one kind alone or a combination of two or more kinds.

The temperature of the solvent at the time of extraction is not particularly limited, but is preferably 50 to 100 ° C, preferably 60 to 100 ° C. The extraction time varies depending on the extraction method, solvent, temperature, etc., and is not particularly limited.

The B component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the B component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content (in terms of dry weight of the extract) is such that, for example, the concentration at the time of use (concentration in blood or tissue after ingestion or administration) is, for example, 0.1 mg / mL or more, preferably 1 mg / mL or more. More preferably, the content may be 5 mg / mL or more (the upper limit is not particularly limited, but for example, 1 g / mL, 100 mg / mL, 10 mg / mL).

1-3. C component C component is varigenol or a glycoside thereof.

Examples of barrigenol include A1-varigenol and R1-varigenol.

The varigenol glycoside is not particularly limited as long as it is a compound in which varigenol is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6.

As the C component, a plant extract containing the above component can also be used.

The C component is preferably varigenol, and particularly preferably A1-varigenol.

As the varigenol and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Varigenol and its glycosides can be obtained, for example, by extracting and purifying from various plants (eg, tea flowers). Specifically, it can be obtained, for example, according to or in accordance with the previously reported (Chem.Pharm.Bull.60 (5) 674-680 (2012)).

The C component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the C component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-4. D component D component is apigenin or its glycoside.

The apigenin glycoside is not particularly limited as long as it is a compound in which apigenin is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6.

As the D component, a plant extract containing the above component can also be used.

The D component is particularly preferably apigenin.

As apigenin and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Apigenin and its glycosides can be obtained, for example, by extraction and purification from various plants (eg, daisy flowers). Specifically, for example, it can be obtained by a method according to or similar to the previously reported (Chem.Pharm.Bull.56 (4) 559-568 (2008)).

The D component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the D component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-5. E component E component is a plant extract of the genus Bellis.

The daisy plant extract is not particularly limited as long as it is obtained by extracting from a daisy plant.

Bellis perennis (daisy flower), Bellis annua, Bellis bernardii, Bellis caerulescens, Bellis cordifolia, Bellis dubia, Bellis hyrcanica, Bellis longifolia, Bellis microcephala, Bellis, etc. .. Among these, daisy flowers are particularly preferable.

It is preferable to cut the daisy plants used for extraction as necessary.

The extraction method is not particularly limited, but for example, the previously reported method (Chem.Pharm.Bull.56 (4) 559-568 (2008)) can be adopted.

The E component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the E component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content (in terms of dry weight of the extract) is such that, for example, the concentration at the time of use (concentration in blood or tissue after ingestion or administration) is, for example, 0.1 mg / mL or more, preferably 1 mg / mL or more. More preferably, the content may be 5 mg / mL or more (the upper limit is not particularly limited, but for example, 1 g / mL, 100 mg / mL, 10 mg / mL).

1-6. F component F component is an extract of a plant belonging to the genus Ilex.

The extract of the genus Ilex is not particularly limited as long as it is obtained by extracting from the genus Ilex.

Examples of Holly plants include Ilex paraguariensis (Yerba mate), Ilex abscondita, Ilex ambigua, Ilex amelanchier, Ilex amygdalina, Ilex anonoides, Ilex aquifolium, Ilex arisanensis, Ilex arnhemensis, Ilex asphrella. Among these, Yerba mate is particularly preferable.

It is preferable to cut the plants of the genus Ilex used for extraction as necessary.

The extraction solvent is not particularly limited. Examples of the extraction solvent include water; alcohols such as methanol, ethanol, propanol and butanol; alkyl acetates such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; and supercritical carbon dioxide. Among these, alcohol (particularly butanol) and the like are preferable. The extraction solvent may be one kind alone or a combination of two or more kinds.

The extraction method is not particularly limited, but for example, the previously reported method (Chem.Pharm.Bull. 57 (3) 257-261 (2009)) can be adopted.

The F component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains an F component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content (in terms of dry weight of the extract) is such that, for example, the concentration at the time of use (concentration in blood or tissue after ingestion or administration) is, for example, 0.05 mg / mL or more, preferably 0.5 mg / mL or more. More preferably, the content may be 2 mg / mL or more (the upper limit is not particularly limited, but for example, 1 g / mL, 100 mg / mL, 10 mg / mL).

1-7. G component G component is ursolic acid or its glycoside.

The ursolic acid glycoside is not particularly limited as long as it is a compound in which ursolic acid is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6. Specific examples of the ursolic acid glycoside include matesaponin 3.

As the G component, a plant extract containing the above component can also be used.

The G component is preferably a ursolic acid glycoside, and particularly preferably matesaponin 3.

As ursolic acid and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Ursolic acid and its glycosides can be obtained, for example, by extraction and purification from various plants (eg, Yerba mate). Specifically, it can be obtained, for example, according to or in accordance with the previously reported (Chem.Pharm.Bull. 57 (3) 257-261 (2009)).

The G component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the G component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-8. H component The H component is coumaric acid or a glycoside thereof.

Examples of coumaric acid include p-coumaric acid, m-coumaric acid, o-coumaric acid and the like.

The coumaric acid glycoside is not particularly limited as long as it is a compound in which coumaric acid is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6.

As the H component, a plant extract containing the above component can also be used.

The H component preferably includes coumaric acid, and particularly preferably p-coumaric acid.

As coumaric acid and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Coumaric acid and its glycosides can be obtained, for example, by extracting and purifying from various plants.

The H component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the H component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-9. Component I Component component I is 2-phenylethanol or its glycoside.

The 2-phenylethanol glycoside is not particularly limited as long as it is a compound in which 2-phenylethanol is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6. Specific examples of the 2-phenylethanol glycoside include 2-phenylethyl-β-D-glucopyranoside.

As the I component, a plant extract containing the above component can also be used.

The I component preferably includes 2-phenylethanol glycoside, and particularly preferably 2-phenylethyl-β-D-glucopyranoside.

As 2-phenylethanol and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. 2-Phenylethanol and its glycosides can be obtained, for example, by extraction and purification from various plants (for example, Sedum sarmentosum). Specifically, for example, it can be obtained according to or in accordance with the previously reported (HETEROCYCLES, Vol. 71, No. 7, 2007, pp1565-1576).

The I component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the I component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-10. J component J component is tamalixetin or its glycoside,
The tamalixetin glycoside is not particularly limited as long as it is a compound in which tamalixetin is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6. Specific examples of the tamalixetin glycoside include tamalixetin 7-O-β-D-glucopyranoside.

As the J component, a plant extract containing the above component can also be used.

Examples of the J component preferably include tamalixetin glycosides, and particularly preferably tamalixetin 7-O-β-D-glucopyranoside.

As tamalixetin and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Tamarixetin and its glycosides can be obtained, for example, by extracting and purifying from various plants (for example, Sedum sarmentosum). Specifically, for example, it can be obtained according to or in accordance with the previously reported (HETEROCYCLES, Vol. 71, No. 7, 2007, pp1565-1576).

The J component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the J component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

1-11. K component The K component is not particularly limited as long as salmenthol or its glycoside salmenthol glycoside is a compound in which salmenthol is used as an aglycone and a sugar is linked to the aglycone (usually, a glycosidic bond). .. Examples of the sugar include glucose, arabinose, pyranose, raffinose, rutinose, apiose, rhamnose, rutinose, primeberose, gentiobiose, jigitoxose, galactose, xylose and the like, and examples thereof include sugars formed by linking a plurality of these. The number of monosaccharide residues constituting the sugar is, for example, 1 to 8 and 1 to 6. Specific examples of the salmenthol glycoside include sesmoside E2 and sezmoside E3.

As the K component, a plant extract containing the above component can also be used.

Examples of the K component preferably include salmenthol glycosides, and particularly preferably sesmoside E2 and sesmoside E3.

As salmenthol and its glycoside, those obtained according to a known production method can be used, or commercially available products can be used. Salmenthol and its glycosides can be obtained, for example, by extraction and purification from various plants (eg, Sedum sarmentosum). Specifically, for example, it can be obtained according to or in accordance with a previously reported report (Chem. Pharm. Bull. 55 (3) 435-441 (2007)).

The K component may be one type alone or a combination of two or more types.

When the pharmaceutical product of the present invention contains the K component, the content thereof is not particularly limited as long as it can exert an antiviral effect on the virus. The content thereof is, for example, a concentration at the time of use (concentration in blood or tissue after ingestion or administration) of, for example, 0.05 μM or more, preferably 0.5 μM or more, more preferably 5 μM or more (the upper limit is not particularly limited). However, the content may be 100 mM, 10 mM, 1 mM, 100 μM).

2. Use The target virus of the pharmaceutical product of the present invention is not particularly limited. Examples of viruses include influenza virus (for example, type A, type B, etc.), ruin virus, Ebola virus, corona virus, measles virus, varicella / herpes zoster virus, mumps virus, arbovirus, RS virus, SARS virus, hepatitis virus (for example). For example, hepatitis B virus, hepatitis C virus, etc.), yellow fever virus, AIDS virus, mad dog disease virus, hunter virus, dengue virus, nipavirus, lissavirus and other enveloped viruses (viruses with envelope); adenovirus, norovirus, rotavirus. , Human papillomavirus, poliovirus, enterovirus, coxsackie virus, human parvovirus, encephalomyelitis virus, poliovirus, rhinovirus and other non-enveloped viruses (viruses without envelope) and the like. Of these, coronavirus is particularly preferred.

Coronavirus is a virus belonging to the subfamily Orthocoronavirus. Examples of the coronavirus include alpha coronavirus genus, beta coronavirus genus, gamma coronavirus genus, delta coronavirus genus, and the like, and among these, beta coronavirus genus is preferable. Examples of the beta coronavirus genus include SARS-related coronavirus (SARSr-CoV), broad coronavirus HKU1, and MERS coronavirus, and among these, SARSr-CoV is preferable. Examples of SARSr-CoV include SARS-CoV-2 and SARS-CoV-1, and among these, SARS-CoV-2 is preferable. The pharmaceutical product of the present invention can be particularly preferably used for SARS-CoV-2.

According to the pharmaceutical product of the present invention, it can exert an antiviral effect against a virus. Specific examples of the antiviral action include a virus infection suppressing action, a virus-induced cell death suppressing action, a virus inactivating action, and a virus resistance-inducing action. In addition, due to this action, it can also be used as a prophylactic or therapeutic agent for viral infections (preferably coronavirus infections, particularly COVID-19).

The pharmaceutical product of the present invention can be widely used in various fields requiring antiviral properties. The pharmaceutical product of the present invention can be used in various fields such as industry, cleaning, medical treatment, food, and daily necessities. The use of the pharmaceutical product of the present invention is mainly divided into a use applied to a living body and a use applied to an article described later.

2-1. Applications for living organisms Applications for living organisms include, for example, pharmaceuticals, cosmetics, food compositions (including health foods, health enhancers, dietary supplements (supplements, etc.)), food additives, disinfectants, and cleaning agents. And so on. The application target in this case is not particularly limited, and examples thereof include various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.

By applying the pharmaceutical product of the present invention to a living body, it is possible to exert an antiviral effect at a site where the active ingredient comes into contact.

The form of the pharmaceutical product of the present invention is not particularly limited, and the form usually used in each use can be taken depending on the use of the pharmaceutical product of the present invention.

As for the form, when the use is pharmaceutical, for example, injection, drip, mouthwash, patch (tape such as plaster, ointment (reservoir type, matrix type, etc.), pap, patch, micro). Needles, etc.), ointments, external solutions (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc., creams, gels, eye drops, eye ointments, nasal drops, suppositories, etc. Pharmaceutical form suitable for parenteral ingestion of semi-solid preparations for rectal, enema, etc .; tablets (including medially disintegrating orally disintegrating tablets, chewable tablets, effervescent tablets, troches, jelly-like drops, etc.), rounds, granules, etc. Formulation form suitable for oral ingestion of agents, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, syrups), jelly, etc. (oral formulation) Can be mentioned.

Examples of the form include liquids, gels, creams, ointments, sprays, sticks, etc. when the use is cosmetics.

In terms of form, when the application is a food composition, liquid, gel or solid foods such as juices, soft drinks, tea, soups, soy milk and other beverages, salad oils, dressings, yogurts, jellies, puddings, sprinkles, etc. Examples include milk powder for childcare, cake mixes, dairy products (eg, powder, liquid, gel, solid, etc.), bread, confectionery (eg, cookies, etc.). When the application is a food additive, a health enhancer, a dietary supplement (supplement, etc.), it includes, for example, tablets (intraoral disintegrating tablets, chewable tablets, effervescent tablets, troches, jelly-like drops, etc.). ), Rounds, granules, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including suspensions and syrups), jelly and the like.

In terms of form, when the application is a disinfectant or cleaning agent, for example, a liquid (solution, emulsion, suspension, spray, etc.), a semi-solid (gel, cream, paste, etc.), a solid (tablet, particulate agent, etc.) It can take any form such as a capsule, a film, a kneaded product, a molten solid, a waxy solid, an elastic solid, etc.). For example, when applied to the oral cavity, more specifically, dentifrice (dentifrice, liquid dentifrice, liquid dentifrice, powdered dentifrice, etc.), mouthwash, coating agent, patch, mouth refreshing agent, food ( For example, chewing gum, confectionery, candy, toothpaste, film, troche, etc.). Further, when applied to the nasal cavity, more specifically, a spray-type nasal drop or the like can be mentioned. When applied to the skin, soaps, body soaps, shampoos, conditioners, sprays and the like can be mentioned.

The pharmaceutical product of the present invention may further contain other components, if necessary. The other components are not particularly limited as long as they are components that can be blended in, for example, pharmaceuticals, cosmetics, disinfectants, cleaning agents, etc., but for example, bases, carriers, solvents, dispersants, emulsifiers, buffers, etc. Examples include stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, chelating agents and the like.

The buffering agent is not particularly limited, and an appropriate buffering agent that is acceptable can be adopted depending on the intended use. Preferred examples include a phosphate buffer solution and an acetic acid buffer solution.

The content of the active ingredient in the pharmaceutical product of the present invention depends on the type, use, mode of use, application target, state of application target, etc. of the active ingredient, and is not limited, but is, for example, 0.000001 to 100% by weight. It can be preferably 0.01 to 50% by weight.

The application amount (for example, administration, ingestion, inoculation, etc.) of the pharmaceutical product of the present invention is not particularly limited as long as it is an effective amount that exerts a desired effect, and is usually 0.1 to 0.1 per day as the weight of the active ingredient. 1000 mg / kg body weight. The above dose is preferably administered once a day or divided into 2 to 3 times, and may be appropriately increased or decreased depending on the age, pathological condition, and symptom.

2-2. Applications applied to articles Examples of applications applied to articles include disinfectants, cleaning agents, and the like. The application target in this case is not particularly limited, and examples thereof include industrial products and raw materials thereof used in various fields.

Specific examples of goods include OA equipment, home appliances, air conditioning equipment, vacuum cleaners, desks, chairs, sofas, benches, windows, leather, handles, seats, automatic ticket gates, automatic ticket vending machines, vending machines, doors, fences. , Handrails, tableware, cooking utensils, packaging film, packaging bags, bottles, bottles, packaging packs, sinks, toilet bowls, stationery, books, shelves, toothbrushes, mirrors, air conditioning filters, masks, coats, jackets, trousers, skirts, shirts, Knit shirts, blouses, sweaters, cardigans, nightwear, underwear, underwear, omelets, supporters, socks, tights, stockings, hats, scarves, mufflers, scarves, stalls, gloves, clothing linings, clothing cores, clothing Batting, work clothes, uniforms, clothing such as school uniforms, curtains, ami doors, duvets, duvet cotton, duvet covers, pillowcases, sheets, mats, carpets, towels, handkerchiefs, wall cloths, band aids, bandages, etc. Can be mentioned.

By applying the pharmaceutical product of the present invention to an article, it is possible to exert an antiviral effect at a site where the active ingredient comes into contact. The site where the active ingredient comes into contact is not limited to the site on the article, but also includes the site in the living body when the article is applied to a living body or the like.

The dosage form of the pharmaceutical product of the present invention is not particularly limited and can be appropriately selected according to its intended use. Examples of the dosage form include liquids such as liquids, emulsions, suspensions, dispersants, sprays and aerosols; solid or semi-solids such as wettable powders, powders, granules, fine granules and flowables. Be done.

The pharmaceutical product of the present invention may further contain other components, if necessary. The other components are not particularly limited as long as they are components that can be blended in, for example, cleaning agents and disinfectants for articles, but are not particularly limited, and are, for example, bases, carriers, solvents, dispersants, emulsifiers, buffers, and stabilizers. , Excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, chelating agents and the like.

The content of the active ingredient in the pharmaceutical product of the present invention depends on the type, use, mode of use, application target, state of application target, etc. of the active ingredient, and is not limited, but is, for example, 0.000001 to 100% by weight. It can be preferably 0.001 to 50% by weight.

Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited to these examples.

Test example 1. Antiviral activity evaluation test 1
(A component) hopeaphenol (10 μM) and isohopeaphenol (10 μM), (B component) Shokatsusai methanol extract (10 μg / mL), (C component) A1-varigenol (10 μM), (D component) apigenin (10 μM), ( E component) Daisy flower methanol extract (10 μg / mL), (F component) Jerba mate butanol extract (10 μg / mL), (G component) matesaponin 3 (10 μM), (H component) p-kumalic acid (component E) 10 μM), (I component) 2-phenylethyl-β-D-glucopyranoside (10 μM), (J component) tamarixetine 7-O-β-D-glucopyranoside (10 μM), and (K component) sesmoside E2 (10 μM) and The antiviral effect of Sesmoside E3 (10 μM) against SARS-CoV-2 infection was evaluated) (all concentrations are final concentrations).

Specifically, after the virus and the test sample are mixed and incubated for a certain period of time, the mixed solution is added to the cell culture well to culture the cells, and after the culture is completed, live cell staining is performed to control (without virus addition). Similarly, when CPE was not observed, it was judged to have an antiviral effect. Three steps the amount of virus (10 ^2, 10 ^3, or 10 ⁴ TCID ₅₀ / 100μL) to be varied and tested, 10 ^2, 10 ^3, and 10 ⁴ TCID ₅₀ / there antiviral effect in all cases of 100 [mu] L and a case where it is determined and evaluated as "+++", the case where it is determined that there is the case where only the antiviral effect of 10 ² and 10 ³ TCID _50/100 [mu] L was evaluated as "++", 10 ² TCID ₅₀ / When it was judged that there was an antiviral effect only in the case of 100 μL, it was evaluated as “+”.

The details of the test protocol are as follows.
Day -1
Vero E6 / TMPRSS2 cells were seeded on a 96-well plate ^{at 5.0 x 10 4 cells / 100 μL.} The medium is DMEM medium supplemented with 0.5% fetal bovine serum. Incubated for 24 hours at 37 ° C., 5% CO ₂ / 95% air.
Day 0
In 96 well plates (1.2 [mu] L already added samples), virus solution (10 ^2, 10 ^3, or 10 ⁴ TCID _50/100 [mu] L) was added 120μL and allowed to stand at room temperature for 5 minutes. The culture supernatant was discarded from the 96-well plate in which the cells were seeded and cultured on the previous day (Day -1), and 100 μL of the sample / virus mixture obtained above was added. The cells were cultured at 37 ° C. and 5% CO ₂ / 95% air for 72 hours.
Day 3
100 μL of glutaraldehyde solution (25% W / V) was added to the cells (96-well plate), and the cells were allowed to stand at room temperature for 30 minutes. The culture solution and glutaraldehyde mixture were discarded, and the wells were washed with tap water. It was allowed to stand at room temperature and dried. 100 μL of 1% crystal violet stain was added to the fixed cells (96-well plate), and the cells were allowed to stand at room temperature for 30 minutes. The stain was discarded and the wells were washed with tap water. After allowing to stand at room temperature and drying, the plate was photographed and the presence or absence of staining was observed.

The methanol extract of (component B) Orychophragmus violaceus is obtained by hot-extracting 1.0 kg of fresh Orychophragmus violaceus with methanol (heating and refluxing for 2 hours x 3 times) and distilling off the solvent under reduced pressure. I used the one. (Component E) The methanol extract of daisy flower used was obtained according to the method previously reported (Chem.Pharm.Bull.56 (4) 559-568 (2008)). (F component) The butanol extract of Yerba mate used was obtained according to the method previously reported (Chem.Pharm.Bull. 57 (3) 257-261 (2009)).

The results are shown in Table 1.

Test example 2. Evaluation test of antiviral effect 2
For (A component) hopeaphenol (10 μM, 1 μM, 0.1 μM) and isohopeaphenol (10 μM, 1 μM, 0.1 μM), and (E component) daisy flower methanol extract (10 μg / mL, 1 μg / mL, 0.1 μg / mL) The antiviral effect on SARS-CoV-2 was evaluated (all concentrations are final concentrations).

Specifically, in addition to the same method as in Test Example 1 (Pre-infection protocol: a method of reacting a sample with a virus before infecting cells), Post-infection protocol: after infecting cells with a virus and culturing. , The test was carried out by the method of adding a sample. The test was performed by Quadruplication. Virus infection scores were given for each of the four Quadruplication wells as shown in Table 2. After that, the average value of the four wells was calculated.

The CPE suppression rate was calculated as follows.

Also, as a control, a well to which only the test sample was added without infecting the virus was prepared by Quadruplication. If cell death was observed in these, it was considered that there was a possibility of cell damage due to DMSO, which is the solvent of the sample, and therefore the test sample at the relevant concentration was judged to be "undeterminable".

Pre-infection protocol uses those 10 ² TCID ₅₀ / 100μL as a virus solution, the culture time in the Day 0 except that the 96 hours, the same as in Test Example 1.

The Post-infection protocol is the same as in Test Example 1 except that Day 0 is the protocol shown below.
Day 0
Day (Day -1) to VeroE6 / TMPRSS2 cells were seeded Discard the culture supernatant from the 96 well plate and culturing was started, the virus solution (10 ² TCID ₅₀ / 100μL) was 100 [mu] L added. Incubated for 30 minutes at 37 ° C., 5% CO _{2 / 95% air.} 1 μL of the sample was added and _{cultured at 37 ° C. under 5% CO 2} / 95% air for 96 hours.

The results are shown in Figures 1 and 2.

Claims

(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
An antiviral agent containing at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.
The antiviral agent according to claim 1, wherein the virus is a coronavirus.
The antiviral agent according to claim 1 or 2, wherein the virus is SARS-CoV-2.
(Ingredient A) Resveratrol tetramer,
(B component) Shokatsusai extract,
(C component) A1-varigenol,
(E component) Daisy flower extract,
(F component) Yerba mate extract,
(G component) Matesaponin 3,
(Component I) 2-Phenylethyl-β-D-Glucopyranoside,
(J component) Tamarixetin 7-O-β-D-glucopyranoside, and (K component) Sesmoside E2 or Sesmoside E3
The antiviral agent according to any one of claims 1 to 3, which contains at least one selected from the group consisting of.
The antiviral agent according to any one of claims 1 to 4, which contains at least one selected from the group consisting of Hopeaphenol, Isohopeaphenol, and derivatives thereof.
The antiviral agent according to any one of claims 1 to 5, which is used for application to a living body.
The antiviral agent according to claim 6, which is a food composition, a food additive, a medicine, a cosmetic, a disinfectant or a cleaning agent.
The antiviral agent according to claim 6 or 7, which is a prophylactic or therapeutic agent for COVID-19.
The antiviral agent according to any one of claims 1 to 5, which is used for application to an article.
The antiviral agent according to claim 9, which is a disinfectant or a cleaning agent.
An antiviral food composition containing at least one selected from the group consisting of Hopeaphenol, Isohopeaphenol, and derivatives thereof.
(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
An antiviral method comprising applying to a living body or an article at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.
For use as an antiviral agent,
(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
A preparation containing at least one selected from the group consisting of (component J) tamalixetin or a glycoside thereof, and (component K) salmenthol or a glycoside thereof.
(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
Use for the production of at least one antiviral agent selected from the group consisting of (component J) tamalixetin or its glycosides and (component K) salmenthol or its glycosides.
(Component A) Resveratrol multimer, derivative of resveratrol multimer, or sirtuin activator,
(B component) Orychophragmus genus plant extract,
(C component) Varigenol or its glycoside,
(E component) Bellis plant extract,
(F component) Ilex plant extract,
(G component) Ursolic acid or its glycoside,
(Component I) 2-Phenylethanol or its glycoside,
Use as an antiviral agent of at least one selected from the group consisting of (J component) tamalixetin or its glycoside, and (K component) salmenthol or its glycoside.