WO2009151173A1

WO2009151173A1 - Pharmaceutical compositions for prevention and treatment of viral diseases containing rhodiola extracts, fractions, the isolated flavonoid compounds therefrom, derivatives compounds thereof or the pharmaceutically acceptable salts as an active ingredient

Info

Publication number: WO2009151173A1
Application number: PCT/KR2008/003415
Authority: WO
Inventors: Woo Song Lee; Byung Dae Yoon; Hyo Kon Chun; Hyung Jae Jeong; Hyung Jun Kwon; Jang Hoon Kim; Ki Hun Park
Original assignee: Korea Research Institute Of Bioscience And Biotechnology
Priority date: 2008-06-12
Filing date: 2008-06-17
Publication date: 2009-12-17

Abstract

Disclosed is a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient a Rhodlo La extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound. Having excellent inhibitory activity against neuraminidase, the active ingredient is useful in the prevention and treatment of viral diseases and the suppression of virus proliferation. Thus, the compositions can be applied for use in the prevention and treatment of viral diseases and as prophylaxis against influenza virus.

Description

[DESCRIPTION] [invention Title]

PHARMACEUTICAL COMPOSITIONS FOR PREVENTION AND

TREATMENT OF VIRAL DISEASES CONTAINING RHODIOLA EXTRACTS, FRATIONS, THE ISOLATED FLAVONOID COMPOUNDS THEREFROM,

DERIVATIVES COMPOUNDS THEREOF OR THE PHARMACEUTICALLY

ACCEPTABLE SALTS AS AN ACTIVE INGREDIENT

[Technical Field]

The present invention relates to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient, a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the extract or the fraction, or a pharmaceutically acceptable salt of the flavonoid.

[Background Art]

The influenza virus is a highly infective agent causing acute pulmonary diseases. In more serious cases, influenza causes pneumonia, which can be particularly fatal in young children, the elderly, and patients with cardiopulmonary diseases. In addition, influenza spreads around the world in seasonal epidemics, killing in addition numerous people in pandemic years (Hien, T. T. et al. N. Eng. J. Med., 350, 1179, 2004) . The influenza virus is an RNA virus of the family Orthomyxoviridae, which comprises Influenzavirus A, Influenzavi rus B, Influenzavirus C, and the other two genera. Of these, influenzavirus A and B are responsible for the epidemic spread of influenza. Influenzavi cus A, B and C are very similar in structure. The influenza virus contains eight pieces of segmented RNA, with hemagglutinin (HA) and neuraminidase (NA) on the outside thereof, which serve as surface antigens. Hemagglutinin, the name of which comes from the protein' s ability to cause red blood cells to clump together in vitro, is a homotrimeric integral membrane glycoprotein, which consists of a head and a tail. The head part, responsible for most antigenic variations, contains binding sites for sialic acid residues on the surface of target cells, mediating the binding of the virus to target cells and the subsequent entry of the viral genome into the target cell (Chandrasekaran, A. et al. Nature biotechnology 26, 107, 2008) . Meanwhile, neuraminidase NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Influenza neuraminidase, existing as a mushroom-shape projection on the surface of the influenza virus, is a tetrameric glycoprotein having a head with an active site topped thereon. The neuraminidase cleaves the α-ketosidic bond linking a terminal neuraminic-acid residue to the adjacent oligosaccharide moiety, being essential for movement of the virus to and from sites of infection in the respiratory tract (a. Mark, V. T. Nature review 6_r 967, 2007. b. Huberman, K. et al . Virology 214, 294, 1995) .

Both the surface glycoproteins HA and NA of influenza viruses frequently undergo variation within the same subtype, resulting in the emergence of new antigen mutants each year. When influenza viruses reassort, they may acquire new antigens. The novel Influenza will spread uncontrollably, causing a pandemic, exemplified by the recently generated avian influenza found in chickens, turkeys, ducks and wild birds sweeping over Asia. Upon its outbreak in a population of chickens, avian influenza was reported to show a morbidity of at least 80% and thus, has become one of the factors that most greatly threatens and damages the poultry industry. Now, poultry influenza viruses are said to be a threat to all of mankind as well as to the poultry industry because, although initiated in birds, they can be transferred to humans (Gubareva, L. V. et al. Lancet. 355, 2000) .

With the aim of treating viral diseases, significant notice has been given to inhibitory actions relating to viral adsorption to epithelial cells, viral intrusion into cells, transcription and replication of viral genomes, viral protein expression, and progeny virus release from cells, which are al.l now targets of antiviral drugs. For the treatment of influenza, scientists have mapped strategies for inhibiting its attachment onto epithelial cells, penetration into cells, transcription, replication, translation, and progeny release from cells, all of which have become the targets of anti-influenza virus agents.

Under the strategies, antiviral agents have been developed, and there are four drugs Amantadine, Rimantadine, Zanamivir and Oseltamivir that have been approved by the FDA for use in the treatment of influenza. Amantadine and Rimantadine show antiviral activity by blocking the M2 ion channel which is essential for viral proliferation, thereby interfering with viral uncoating inside cells. Both the M2 inhibitors are, however, effective only against influenza virus A and are associated with several toxic effects in the digestive system and the autonomic nervous system, and with the rapid emergence of drug-resistant variants during the 40 years of its use (Bantia, S. et al. Antiviral Research 69, 39, 2006) . Since 1989, the new drugs Zanamivir and Oseltamivir have been used for the treatment and prophylaxis of influenza virus A and influenza virus B because they act as inhibitors of neuraminidase which plays an important role in viral proliferation and is stably present in both influenza viruses A and B (Zhang, J. et al. Bioorg. Med. Chem. Lett. 16, 3009, 2006) .

Zanamivir shows high antiviral activity, but suffers from the disadvantage of low bioavailability and fast renal excretion (Ryan, D. M. et al . Antimicrob . Agents Chemother. , 39, 2583, 1995) while nausea and vomiting were reported more frequently among adults receiving Oseltamivir .

As mentioned above, the antiviral drugs administered to this time must be applied with extreme caution because they are reported to produce significant adverse side effects. Additionally, vaccination may be useless in preventing the infection and proliferation of influenza viruses if a virus type of a vaccine is different from that of the epidemic influenza virus. For these reasons, there is an imperative need for an antiviral agent that has high inhibitory activity against influenza viruses and can be generally utilized without adverse side- effects .

Rhodiola is a perennial herbaceous plant in the Crassulaceae family that grows in cold regions. Thus far, 96 kinds of the plant have been reported with 50% thereof found in China. This plant inhibits highlands at an altitude from 1,700 to 2,300 meters, which highlands are dry and of low-temperature in years with large diurnal ranges, and the plant is exposed to intense UV light.

Recently, Rhodiola has also been called highland ginseng because it is found to have the function of invigoration and detoxification like ginseng and acanthopanax (Kim, Joo-Cheol, Ahn, Sang-Deuk, Lee, Myoung-Rye, Colorful Illustrated Guide to Resource Plants of Mt. Baek Doo, Academybook, Seoul, p.324) . Rhodiola can be used for food and medicine. In folk remedies, Rhodiola has been used as a sedative, an antipyretic and an astringent. In herbal medicine, Rhodiola is used as a tonic particularly for senile cardiac failure and impotence. It is also prescribed as a powder or decoction for the treatment of diabetes, anemia, cholesystitis, fatigue and nervous prostration and for postpartum care (Zucker, L. M., et al . J. Lipid Res. 13, 234, 1972) . Many ingredients can be isolated from the roots and stems of Rhodiola, including Flavonoids (Ming, D. S., et al. Phytother. Res. 19, 740, 2005), monoterpenoids (Ma, G. et al. Chem. Pharm. Bull. 54, 1229, 2006), phenylpropanoid and phenylethanol derivatives (Tolonen, A. et al. Chem. Pharm. Bull. 51, 467, 2003), and aliphatic glycoside (Nakamura, S. et al . Chem. Pharm. Bull. 55, 1505, 2007) .

With regard to extracts from Rhodiola, reference can be made to Korean Patent No. 10-0179087, entitled "Composition for Lowering Blood Alcohol Concentration Comprising Rhodiola schalinesis Extract", Koren Patent No. 10-0179088, entitled "Composition Containing Rhodiola sachalinesis Extract for Prophylaxis and Treatment of Diabetes Mellitus", Korean Patent No. 10-0265385, entitled "Extract of Rhodiola sp . for Preventing and Treating Circulatory Diseases", Korean Patent No.10- 0316790, entitled "Composition for Preventing Liver Fibrosis Comprising Extract from Rhodiola sachalinensis A. Bor", Korean Patent No. 10-0386809, entitled "Immunopotentiating Composition Containing Extract of Rhodiola root", and Korean Patent No. 10-0445404 entitled "Whitening Composition Containing Rhodiola sachalinensis a. bor Extract." Nowhere is mentioned the use of Rhodiola extracts in the treatment and prophylaxis of viral diseases, especially influenza, in Lhe prior art.

Leading to the present invention, intensive and thorough research into the prevention and treatment of viral diseases, conducted by the present inventors, resulted in the finding that extracts from Rhodiola , fractions derived from the extracts, Clavonoid compounds isolated from the fractions, and pharmaceutically acceptable salts of the flavonoids have high inhibitory activity against neuraminidase.

[Disclosure] [Technical Problem]

It is therefore an object of the present invention to provide a pharmaceutical composition for the prevention and treatment of viral diseases or an antiviral composition for inhibiting influenza virus activity.

It is another object of the present invention to provide a health food composition for the prevention of viral diseases.

[Technical Solution]

In order to accomplish the above objects, the present invention provides a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound. Also, the present invention provides an anti-viral composition for use as prophylaxis against influenza virus, comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound.

Further, the present invention provides a health food composition for the prevention of viral diseases, comprising as an active ingredient a Rhodiola extract, a Rhodiola fraction, a flavonoid compound isolated from the Rhodiola extract or fraction, or a pharmaceutically acceptable salt of the flavonoid compound.

[Advantageous Effects] Having excellent inhibitory activity against neuraminidase, the Rhodio La extract, the Rhodiola fraction, the flavonoid compounds isolated from the Rhodiola extract or fraction, or the pharmaceutically acceptable salts of the flavonoid compounds is useful in the prevention and treatment of viral diseases and the suppression of virus proliferation. Therefore, the compositions comprising as an active ingredient the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds isolated from the Rhodiola extract or fraction, or the pharmaceutically acceptable salts of the flavonoid compound in accordance with the present invention can be applied for use in the prevention and treatment of viral diseases and as prophylaxis against influenza virus.

[Best Mode]

In accordance with an aspect thereof, the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising an extract from Rhodiola as an active ingredient.

Rhodiola from which an extract useful in the present invention can be obtained may be a cultured or a commercially available variety. As long as it may be used to produce a useful extract therefrom, any Rhodiola is applicable for purposes of the present invention. A Rhodiola extract may be prepared by a typical extraction method known in the art, such as ultrasonication, filtration or reflux extraction. Preferably, an extract may be obtained from dried Rhodiola and water, a Ci-C₃ alcohol or a mixture thereof, more preferably with a Ci-C₃ alcohol, and most preferably with methanol or ethanol . For example, dried Rhodiola roots are finely sectioned and immersed in a lower alcohol of Ci~C₃ or a mixture thereof at room temperature for a predetermined period of time, followed by filtration to afford an alcohol extract. Preferably, extraction is performed for one week in the alcohol. Concentration or lyophilization may be further conducted. In accordance with another aspect thereof, the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising a Rhodiola fraction as an active ingredient . The Rhodiola fraction may be preferably obtained during sequential fractionation with hexane, chloroform and ethylacetate in that order from a suspension of the Rhodiola extract in water.

In accordance with a further aspect thereof, the present invention pertains to a pharmaceutical composition for the prevention and treatment of viral diseases, comprising as an active ingredient at least one selected from a group consisting of kaempferol, represented by the following chemical formula 1, kaempferol-3-O-glucoside, represented by the following chemical formula 2, kaempferol-3-O-rutinoside, represented by the folJ owing chemical formula 3, herbacetin, represented by the foJ lowing chemical formula 4, rhodiolinm, represented by the following chemical formula 5, rhodionin, represented by the following chemical formula 6, rhodiosin, represented by the following chemical formula 7, herbacetin-3, 8-0- diglucoside, represented by the following chemical formula 8, and pharmaceutically acceptable salts thereof. [Chemical Formula 1]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5[

[Chemical Formula 6^'

[Chemical Formula 7]

[Chemical Formula 8]

The compounds of chemical formula 1 to 8 may be separated from the Rhodiola extract or the Rhodiola fraction, may be purchased from commercial manufacturers thereof, or may be chemically synthesized. Among them, the compounds ot chemical formulas 1, 5, 6 and 7 are known as representative active ingredients of Rhodiola, and can be isolated as described below.

In accordance with still a further aspect thereof, the present invention is concerned with a method for preparing compounds of chemical formulas 1, 5, 6 and 7, comprising :

Forming an extract from Rhodiola with water, a Ci-C₃ alcohol, or a mixture thereof (Step 1);

Separating an active fraction from the extract of Step 1 sequentially with hexane, chloroform and ethyl acetate in that order (Step 2); and

Isolating the compounds of chemical formulas 1, 5, 6 and 7 through column chromatography (Step 3) .

In Step 1, Rhodiola is extracted with water, a C_X~C₃ alcohol or a mixture thereof to give a Rhodiola extract.

For use in this extraction, a lower alcohol such as methanol, ethanol, propanol or butanol may be taken, with preference for methanol and ethanol, the latter being more preferred. In more detail, dried Rhodiola roots are finely sectioned to a predetermined size and extracted with a suitable volume of water, an alcohol, or a mixture thereof in an extraction vessel lor three weeks, followed by filtration and then concentration in a vacuum to afford a Rhodiola extract.

Step 2 is to fraction the Rhodiola extract in the sequential order of hexane, chloroform and ethyl acetate to give an active fraction.

In Step 3, the active fraction is subjected to column chromatography to yield the flavonoid compounds of chemical formula 1, 5, 6 and 7.

Preferably, the ethyl acetate fraction thus obtained in Step 2 is submitted to two rounds of fractionation using silica gel column chromatography eluting with mixtures of chloroform and methanol, followed by open column chromatography. For example, the two rounds of silica gel column chromatography eluting with a mixture of various ratios of chloroform and methanol (e.g., 9:1) afford fractions showing high inhibitory activity against neuraminidase from which the f] avonoids can be then isolated by open column chromatography on sephadex LH-20 eluting with a mixture of 1:1 chloroform : methanol (v/v) .

According to results from an assay for inhibitory activity against neuraminidase, the ethanol extract of Rhodiola showed 0.58 μg/mL of IC50 value, and the ethyl acetate fraction showed 1.17 μg/mL. The Hot water extract also showed 1.01 μg/mL (see Table 3) .

In addition, the compounds isolated from the Rhodiola extract and the Rhodiola fraction, and derivatives thereof were found to show high inhibitory effects on neuraminidase (see Table 2), implying that they have excellent anti-influenza activity.

With the identification of excellent inhibitory activity against neuraminidase, the Rhodiola extract, the

Rhodiola fraction, flavonoid compounds separated from

Rhodiola, and derivatives of the flavonoids in accordance with the present invention may be used as active ingredients of a pharmaceutical composition for the prevention and treatment of viral diseases or in an antiviral composition.

It should be understood that in addition to the compounds of chemical formulas 1 to 8 and pharmaceutically acceptable salts thereof, solvates, hydrates and racemates that can be prepared therefrom are included within the scope of the present invention.

The flavonoid compounds of the present invention, represented by chemical formulas 1 to 8, may be used in the form of pharmaceutically acceptable salts. For example, the derivative represented by chemical formula 1 in accordance with the present invention may be in the form of pharmaceutically acceptable salts. Within the range of these salts are included acid addition salts formed with pharmaceutically acceptable free acids. Useful as the free acids are inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic acids, aliphatic and aromatic sulfonic acids. Examples of such non-toxic bases include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprilate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 , 4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylene benzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene~l-su] fonate, naphthalene-2- sulfonate and mandelate.

The acid addition salts of the compounds according to the present invention may be prepared using a conventional method, for example, by dissolving the compound of chemical formula 1 in excess acid in water and precipitating the resulting salt in a water-miscible organic solvent, e.g., methanol., ethanol , acetone or acetonitrile .

Alternatively, the compounds of chemical formulas 1 to 8 may be heated along with the same amount of acid or alcohol in water, followed by evaporating the mixture and drying or suction filtering the precipitate to prepare acid addition salts thereof.

Also, metal salts formed with bases may fall within the range of pharmaceutically acceptable salts of the compounds of the present invention. Examples of the metal salts useful in the present invention include al kali metal salts and alkaline earth metal salts. For example, the compound of the present invention may be dissolved in excess alkali metal hydroxide or alkaline earth metal hydroxide in water, and after the removal of non- dissolved compound salts through filtration, the filtrate thus obtained may be dried to afford the pharmaceutically acceptable salts of the compound of the present invention. Suitable for use in pharmaceutics are sodium, potassium or calcium salts. Corresponding silver salts may be obtained by reacting the alkali metal or alkaJine earth metal salts with suitable silver salt (e.g., silver nitrate ) .

For clinical practice, the composition in accordance with the present invention may be used in oral or non- oral forms. It is usually formulated in combination with a diluent or an excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant , a surfactant, etc. Solid preparations intended for oral administration of the compound of the present invention may take the form of tablets, pills, powders, granules, capsules, and the like. In these solid agents, the Rhodiola extract, the Rhodlola fraction, the flavonoids compounds or the pharmaceutically acceptable salts are formulated in combination with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, a lubricant such as magnesium stearate, talc, or the like may also be added. Liquid preparations intended for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like. In addition to a simple diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics, preservatives, and the like may be contained in the liquid preparations. Also, the compound of the present invention may be administered via a non-oral route. For this, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophil izates, suppositories, and the like may be used. Injectable propylene glycol, polyethylene glycol, vegetable oiJ s such as olive oil, and esters such as ethyl oleate may be suitable for non- aqueous solvents and suspensions. The basic materials of suppositories include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, and glycerogelatin .

According to purposes, the pharmaceutical composition of the present invention may be administered non-orally (i.e., intravenously, subcutaneously, intraperitoneally, or topically) or orally. The active ingredient according to the present invention may be administered in a single dose or in multiple doses per day at a daily dose ranging from 0.1 to 500 mg/kg of body weight, preferably from 1 to 100 mg/kg of body weight, and most preferably from 0.5 to 10 mg/kg of body weight. The effective dosage of the active ingredient in accordance with the present invention depends on various factors, including the patient's weight, age, gender, state of health, diet, the L Lme ol administration, route of administration, excretion rate, severity of diseases, etc.

The compounds of the present invention were proven safe with an oral lethal dose (LD_J50) of at least 1,000 mg/kg as measured by an acute oral toxicity assay in rats .

In accordance with still another aspect thereof, the present invention is concerned with a health food composition for the prevention and treatment of viral diseases, comprising as an active ingredient the Rhodiola extract, the Rhodiola fraction, the flavonoid compound isolated from the extract or fraction, or a pharmaceutically acceptable salt of the flavonoid. The viral diseases may be caused by influenza viruses .

With the aim of alleviating viral diseases, the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola, or the pharmaceutically acceptable salts of the flavonoids according to the present invention may be added to health food. As a food additive, at least one of the active ingredients according to the present invention may be properly used alone or in combination with other food ingredients according to a conventional method. The amount of the active ingredient according to the present invention may vary depending on the purpose thereof (prevention, health improvement or therapeutic treatment) . Generally, when used for the preparation of foods or beverages, the active ingredient according to the present invention may be added in an amount of 0.01 to 20 weight % based on the total weight of the health food and preferably in an amount of 0.1 to 5 weight % . In the case where the active ingredient is applied to health foods which are designed to be taken habitually, its content may be below the above-mentioned range. However, the extract has no problems of being harmful to the body and thus can be used in an amount exceeding the ranges specified.

No particular limitations are imposed on the kind of foods to which the active ingredient, e.g., the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola, or the pharmaceutically acceptable salts of the compounds can be applied. Examples of the foods include meat, sausages, bread, chocolate, candies, snacks, confectionaries , pizza, ramen and other noodles, dairy products including ice creams, soups, beverages, teas, drinks, alcoholic beverages, vitamin tablets, etc. and are not limited thereto. All usually accepted health foods may contain the active ingredient according to the present invention. The health food composition of the present invention may further contain various fragrant or natural carbohydrates. Examples of such naturaJ carbohydrates include monosaccharides, such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Also, sweeteners, e.g., natural sweeteners such as thaumatin and a stevia extract, or synthetic sweeteners such as saccharin and aspartame, may be added to the health food to which the active ingredient of the present invention is applied. The natural carbohydrate may be used in an amount of about 0.01 ~ 0.04 weight parts based on 100 weight parts of the composition of the present invention, and preferably in an amount of about 0.02 ~ 0.03 weight parts.

In addition, the health food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH modifiers, stabilizers, antiseptics, glycerin, alcohols, and carbonating agents used in carbonated beverages. Moreover, the composition of the present invention can contain fruit flesh for preparing natural fruit juices, fruit beverages and vegetable beverages. These ingredients may be used individually or in combination. The ratio of these additives is not important, but is generally selected Ln a range of 0.01 to 0.1 weight parts per 100 weight parts of the composition of the present invention.

In accordance with yet another aspect thereof, the present invention pertains to an antiviral composition, particularly against influenza viruses. In accordance with yet still a further aspect thereof, the present invention pertains to a method for preventing and treating a viral disease, comprising administering at least one selected from among the Rhodiola extract, the Rhodiola fraction, the flavonoid compounds of Rhodiola and the pharmaceutically acceptable salts thereof according to the present invention at a therapeutically effective dose to a subject in need thereof .

The viral disease may be caused by influenza virus, particularly by Influenza virus A, B or C. The subject in need of administration wi th the active ingredient of the present invention may suffer from chills, fever, sore throat, bronchitis, or pneumonia, and may be birds afflicted with avian influenza. [Mode for Invention}

A better understanding ol the present invention may be obtained through the foil owing examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.

EXAMPLE 1 : Preparation of Rhodiola. Extract

1.0 kg of dried Rhodiola (Korea Rhodiola rosea Association) roots was extracted with 10 L of 100 % ethanol (EtOH) at room temperature for one week, followed by filtration through a filter and concentration to give an ethanol extract (380 g) . In addition, 200 g of

Rhodiola was extracted with 3 L of water by stirring it for 6 hours at 70 ^°C , to give an hot water extract (90 g)

EXAMPLE 2 : Preparation of Rhod±ola Fraction

After being suspended in 1000 mL of water, the ethanol extract obtained in Example 1 was fractioned sequentially with n-hexane, chloroform and ethyl acetate in that order to afford 11 g of an n-hexane-soJ uble fraction, 14 g of a chloroform (CHCl₃) -soluble fraction and 59 g of an ethyl acetate (ELOΛc) -soluble fraction, respectively. EXAMPLE 3: Isolation and Structural Identification of Flavonoid Compounds

59 g of the ethyl acetate-soluble fraction obtained in Example 2 was subjected to two rounds of silica gel column chromatography eluting with a mixture of chloroform and methanol, followed by purification through column chromatography on sephadex. First, the ethyl acetate-soJ uble fraction was developed in silica gel column chromatography (silica gel: Merck, Art 9385, column size : φ7 x 40 cm) eluting with 1.5 L of a mixture of 9:3, 7:1, 5:1, 3:1 or 1:1 chloroform : methanol (v/v) or 1.5 L of 100% methanol to give three fractions, named Fraction 1, 2 and 3.

Then, Fraction 1 (7.6 g, with chloroform : methanol = 9:1 and 7:1) was further divided into four sub- fractions, named Sub-Fraction 1-1, 1-2, 1-3 and 1-4, respectively, by column chromatography on silica gel eluting with 500 mL of a mixture of 20:1, 15:1, 10:1 or 7:1 chloroform : methanol. From Sub-Fraction 1-3 (3.7 g, with chloroform : methanol = 10:1 ~ 7:1), the kaempferol compound of chemical formula 1 and the rhodiolinin compound of chemical formula 5 were isolated through column chromatography on sephadex LH-20 column (GE Heathcare Co, Sweden, CHCl₃/MeOH --= 1:1) and Lichroprep RP- 18 (40 -63 μm, Merck) .

Separately, Fraction 2 (25 g, chloroform : methanol

= 5:1 and 3:1) was submitted to a second round of silica gel column chromatography eluting with 500 ml of a mixture of 9:1, 5:1, 3:1 or 1:1 chloroform : methanol

(v/v) , or 500 ml of 100 % methanol to give five fractions, named Sub-Fraction 2-1, 2-2, 2-3, 2-4 and 2-5, respectively. Likewise, Sub-Fraction 2-3 (6.56 g, chloroform : methanol = 5:1 to 3:1) was further separated through column chromatography on sephadex LH-20 column

(GE Heathcare Co, Sweden, CHCl₃/MeOJI = 1:1) and Lichroprep

RP-18 (40-63 μm, Merck) into rhodionin of chemical formula 6 and rhodiosin of chemical formula 7. The structural analysis of the four compounds was achieved by a VG high resolution GC/MS spectrometer (Election Ionization MS, Autospec-Ul tima, Micromass, UK) for determining molecular weights and molecular formulas, a polarimeter (DIP-181 digital polarimeter, Jasco, Japan) for measuring optical rotation, and an NMR spectrophotometer (AMX 500, Bruker, Germany) for ¹H NMR, ¹³C NMR, HOMO-COSY, HMQC (^-Detected heteronuclear Multiple-Quantum Coherence) , HMBC (Heteronuclear Multiple-Bond Coherence) , DEPT (Distortionless Enhancement by Polarization) spectra. From these spectrophotometric data, molecular structures of the compounds were determined.

Comparative analysis between the instrumental data and those of literature identified the compounds as kaempferol of chemical formula 1 (18mg; Lee, M. W., Lee, Y. A., Park, H. M., Toh, S. H., Lee, F',. J., Jang, H. D., Kim, Y. H., Arch. Farm. Res. 23, 455, 2002), rhodioldnin of chemical formula 5 (24mg; Yu W. S., Chen X. M., Li H., Yang L., Planta Med. 59, 80, 1993), rhodionin of chemical formula 6 (92mg; Lee, M. W., Lee, Y. A., Park, H. M., Toh, S. H., Lee, E. J., Jang, II. D., Kim, Y. H., Arch. Farm. Res. 23, 455, 2002), and rhodiosin of chemical formula 7 (89mg/ Yu W. S., Chen X. M., Li H., Yang L., Planta Med. 591, 80, 1993) . Detailed analysis data are given, below.

Kaempferol [Chemical Formula 1]

1) Property: yellow crystal 2) Mw: 286.0477 3) Molecular Formula : C₁₅Il₁₀Oe

4) ¹H NMR (500 MHz, CD₃OD) δ 8.06 (d, J = 8.90 Hz, 2H, H-2 ', 6 ') , 6.88 (d, J = 9.15 Hz, 2H, H-3 ' , 5 ' ) , 6.37 (d, J = 2.2 Hz, IH, H-8) , 6.16 (d, J = 2.0 Hz, IH, H-6) . 5) ¹³C NMR (125 MHz, CD₃OD) δ 177.4 (C-4) , 165.6 (C-7) ,

162.5 (C-5) , 160.5 (C-4 ' ) , 158.2 (C-9) , 148.0 (C-2) , 137.1 (C- 3) , 130.7 (C-2 ', 6 ' ) , 123.7 (C-I ' ) , 116.3 (C-3 ' , 5 ' ) , 104.5 (C- 10) , 99.3 (C-6) , 94.5 (C-8) .

Rhodiolinin

[Chemical Formula 5]

1) Property: green crystal

2) Optical rotation: [α]_D ²⁵ -57.5 ° (c = 0.6, Acetone) 3) Mw: 480.1056

4) Molecular formula: C₂5H20O₁0

5) ¹H NMR (500 MHz, CD₃OD) δ 8.16 (d, J = 8.60 Hz, 2H, H-2 ' , 6 ' ) , 7.02 (d, J = 1.40 Hz, IH, H-2") , 6.92 (dd, J = 1.75 Hz, 8.05 Hz, IH, H-6") , 6.90 (d, J = 8.9 Hz, 2H, H-3 ', 5 ' ) , 6.85 (d, J = 8.0 Hz, IH, H-5") , 6.24 (s, IH, H-

6) , 5.05 (d, J = 8.0 Hz, IH, H-7") , 4.06 (m, IH, H-8") , 3.88 (s, 3H, -OCH₃) , 3.85 (m, IH, H-9") , 3.53 (dd, J = 3.70 Hz, 12.6 Hz, IH, H-9") .

6) ¹³C NMR (125 MHz, CD₃OD) δ 177.4 (C-A) , 160.7 (C- 4 ') , 154.1 (C-5) , 150.5 (07) , 149.2 (C-3") , 148.5 (C-4") , 148.1 (C-2) , 145.5 (C-9) , 137. b (O3) , 140.0 (C-2 ' , 6 ' ) ,

128.7 (C-I") , 126.2 (O8) , 123.7 (C-I ' ) , 121.8 (C-5", 6" ) , 116.3 (O3 ', 5 ' ) , 112.1 (02") , 105.5 (C-IO) , 99.2 (C-6) , 79.7 (C-8") , 78.9 (C-7") , 61.9 (C-9) , 56.5 (-OCH₃) .

Rhodionin

[Chemical Formula 6]

1) Property: green crystal

2) Optical rotation: [α] _D ²⁵ -78.5 ° ( c = 0.7, Acetone)

3) Mw: 448.1006

4) Molecular formula: C₂₁H₂₀O₁₁

5) ¹H NMR (500 MHz, CD₃OD) δ 8.20 (d, J = 8.8 Hz, 2H, H-2 ', 6' ) , 6.90 (d, J = 8.6 Hz, 2Ii, H-3 ' , 5' ) , 6.64 (s, IH, H-6) , 5.53 (d, J = 1.4 Hz, 311, H-I") , 4.14 (q, J -= 1.7 Hz, IH, H-2) , 3.98 (dd, J =3.4 Hz, 9.45 Hz, IH, H-5") , 3.72-3.67 (m, IH, H-3") , 3.49 (t, J = 9.57 Hz, IH, H-4") , 1.27 (d, J = 6.3 Hz, 3H, -CII₃) . 6) ¹³C NMR (125 MHz, CD₃OD) δ 176.4 (C-4) , 159.4 (C- 4 ') , 152.4 (C-5) , 150. KC-7) , 147.4 (C-2) , 144.8 (C-9) , 135.9 (C-3) , 129.7 (C-2 ', 6' ) , 127.1 (C-8) , 122.4 (C-I ' ) , 114.9 (C-3 \ 5 ' ) , 104.7 (C-IO) , 99.6 (C-I") , 97.9 (C-β) ,

72.4 (C-3") , 70.7 (C-4") , 70.4 (C-2") , 69.8 (C-5") , 16.7 (C- 6", -CH₃) .

Rhodiosin

[Chemical Formula 7 ]

1) Property: green crystal

2) Optical rotation: [α]_D ²⁵ -42.8 °(c = 0.3, Acetone)

3) Mw: 610.1534

4) Molecular formula: C₂₇H₃oOi₆ 5) ¹H NMR (CDCl₃, 500 MHz) δ 8.20 (d, J = 8.85 Hz,

2H, H-2 ' , 6' ) , 6.91 (d, J = 9.15 Hz, 2H, H-3 ', 5 ' ) , 6.64 (s, IH, H-6) , 5.56 (s, IH, H-I") , 4.67 (d, J = 7.45 Hz, IH, H-I) , 4.42 (d, J = 1.15 Hz, IH) , 4.16 (dd, J = 3.30 Hz, 9.30 Hz, IH) , 3.90 (d, J = 11 .45 Hz, IH) , 3.75 (m, 2H) , 3.67 (t, J = 9.45 Hz, IH) , 3.42 (m, IH) , 3.37 (m,

2H) , 3.35 (m, IH) , 1.28 (d, J = 6.0 Hz, 3H, -CH₃) . 6) ¹³C NMR (CDCl₃, 125 MHz) ό 177.7 (C-4), 160.7 (C- 4'), 153.6(C-5), 150.9(C-I), 148.7(C-2), 145.9(C-9), 137.2(C-3), 131.0 (C-2 ' , 6') , 128.5(C-8), 123.8(C-I'), 116.3 (C-3', 5') , 106.1(C-I), 105.7(C-IO), 100.5(C-6), 99.1(C-I"), 82.3(C-3"), 77.8(C-5), 11.1 (C-2) , 75.4(C-3), 72.4(C-4"), 71.2(C-4), 71.0(C-2"), 70.8(C-5"), 62.4(C-6), 18.1 (C-6", -CH₃) .

EXAMPLE 4 : Preparation of Derivatives

Derivatives of the compounds isolated in Example 3 were purchased from Sigma Aldrich. These are represented kaempferol-3-O-glucoside of chemical formula 2, kaempferol-3-0-rutinoside of chemicaL formula 3, herbacetin of chemical formula 4, and herbacetin-3, 8-0- diglucoside of chemical formula 8.

EXPERIMENTAL EXAMPLE 1: Assay of Rhodiola. Extract and Fraction for Inhibitory Activity against Neuraminidase

The inhibitory activities against influenza virus neuraminidase of the Rhodiola extract of Example 1 and the Rhodiola fractions of Example 2 were determined using a modification of the Markus et al . method (Anal. Biochem. 250, 176, 1997) . Λs a substrate for neuraminidase (concentration, 0.1 ~ 0.11 ϋ, from Vibrio cholera, Sigma), synthetic 2 ' - (4-methylumbelliferyl ) -α-D- W-acetylneuraminic acid sodium salt (Sigma) was used. The extract of Example 1 and the fractions of Example 2 were individually diluted in methanol. To 510 μL of a 50 mM sodium acetate solution (pH=5.0) were added 15 μL of one of the dilutions, along with 60 μL of the substrate 2 '-(4- methyl umbeJ 1 iferyl ) -α-D-N- acetylneuraminic acid (final concentration, U2.5 μM) , followed by the addition of 15 μL of neuraminidase (final concentration, 2.5 rnU/mL) . An enzymatic reaction was performed at 37⁰C for 10 min. Fluorescence spectra for absorption at 365 nm and emission at 450 nm were analyzed to determine inhibitory activity against neuraminidase. The results are summarized in Table 1, below.

TABLE 1

Inhibitory Activity of Inventive Extract and Fraction against Neuraminidase

As seen in Table 1, most extracts and fractions showed high inhibitory activities against neuraminidase, with the highest inhibitory activity exhibited by the ethanol extract.

EXPERIMENTA EXAMPLE 2: Assay for Flavonoids Isolated from Rhodiola Extract against Neuraminidase

The four compounds isolated and identified in Example 3 were assayed for inhibitory activity against neuraminidase in a similar manner to that of Experimental Example 1.

Results are summarized in Table 2, below.

TABLE 2

Inhibitory Activity of Inventive Compounds against

Neuraminidase

As is apparent from the data of Table 2, the compounds of the present invention, kaempferol, kaempferol-3-0~glucoside, kaempferol-3-O-rutinoside , herbacetin, rhodiolinin, rhodionin, rhodiosin and herbacetin-3 , 8-O-diglucoside can act as excellent neuraminidase inhibitors with low TC₅₀ values.

Taken together, the data obtained in Examples and Experimental Examples demonstrate that the active ingredients according to the present invention, that is, the Rhodiola extract, the Rhodlola fractions, the flavonoid compounds of Rhodiola, and the pharmaceutically acceptable salts of the flavonoids can be useful in the prevention and treatment of viral diseases and in virus suppression, particularly, influenza virus activity.

EXPERIMENTAL EXAMPLE 3: Assay for Acute Toxicity

An assay of the compounds in accordance with the present invention was performed for acute toxicity in mice .

24 SPF (specific pathogen free) C57BL/6J mice, 12 male and 12 female, each 6 weeks old, were divided into four groups of three (females or males only in each group) and bred in an animal lab set at a temperature of 22+3°C and RH 55+10% under a light condition of 12L/12D. They were acclimated to their new environment for one week before use and allowed to freely approach feedstuff (for mice and rats, CJ Corporation, Korea) and water, which were provided after steri.1 izat i on.

Each of the compounds prepared in Examples 3 and 4 was dissolved at a concentration of 50 mg/mL Ln 0.5% Tween 80 and the solution was orally administered to mice weighing 20 g at a dose of 0.04 ml, (100 mg/kg) , 0.2 mL(500 mg/kg) and 0.4 mL (1,000 mg/kg) . Administration was performed once. For seven days after administration, the mice were observed for abnormal changes in body, clinical symptoms and death. That is, they were monitored for changes in body and death at 1, 4, 8 and 12 hours after the administration and once or more times on the forenoon and the afternoon each from Day 1 to Day 7 after the administration. Neither particular clinical symptoms nor death of animals were observed. In addition, no acute toxicity was observed in body weight change, haematological tests, serobiochemi ca L tests, or autopsy examination .

These results demonstrate thai the compounds tested do not induce toxicity up to a dose of 1,000 mg/kg in mice, and are proven safe with an LD₅₀ of ] , 000 mg/kg or more upon oral administration.

Below, a description will be gj vcn of pharmaceutical dosage forms or health foods comprising the Rhodiola extract, the Rhodiola fraction, the f1 avonoid compounds or pharmaceutically acceptable salts thereof.

FORMULATION EXAMPLE 1 : Preparation of Pharmaceutical Preparation

1-1. Preparation of Powder

Rhodiola Extract, Fraction, P¹I avonoid Cpd. Or Salt:

2 g

Lactose: 2 g The above ingredients were mixed and loaded into an airtight sac to produce a powder agent.

1-2. Preparation of Tablet

Rhodiola Extract, Fraction, Fl avonoid Cpd. Or Salt: 100 mg

Corn Starch: 100 mg

Lactose: 100 mg

Mg Stearate: ? mg

These ingredients were mixed and prepared into tablets using a typical tablettLng method. 1-3. Preparation of Capsule

Rhodiola Extract, Fraction, FJ avonoid Cpd. Or Salt:

100 mg Corn Starch: 100 mg

Lactose: 100 mg

Mg Stearate: 2 mg

These ingredients were mixed and Loaded into gelatin capsules according to a typical method to produce capsules .

1-4. Preparation of Injection

Rhodiola Extract, Fraction, Fl avonoid Cpd. Or Salt: lOμg/ml DiI. HCl BP: added to form pH 3.5

NaCl BP injection: up to ImI

The Rhodiola extract, fraction, flavonoid compound or salt according to the present invention was dissolved in a suitable volume of an NaCl BP injection, and the solution was adjusted to a pH of 3.5 with diluted HCl BP and to a desired volume with an NaCl BP injection, followed by sufficient mixing. The solution was loaded into transparent 5 m.L type I ampules, which were hermetically sealed by melting, followed by autoclaving at 120⁰C for 15 min to prepare LnjectJons.

Formulation Example 2 : Preparation of Health Food

2-1. Preparation of seasoning

A health-improving seasoning was prepared to contain the Rhodiola extract, fraction, flavonoid compound or salt according to the present invention in an amount of 0.2 ~ 10 wt%.

2-2. Preparation of tomato ketchup and sauce. Health-improving tomato ketchup or sauce was prepared by adding the Rhodiola extract, fraction, flavonoid compound or salt according to the present invention in an amount of 0.2 ~ 1.0 wt% to typical tomato ketchup or sauce.

2-3. Preparation of CJour-basod food

To flour was added 0.1 ~ 5.0 wt% of the Rhodiola extract, fraction, flavonoid compound or salt according to the present invention and the flour mixture was used to make breads, cakes, cookies and noodles.

2-4. Preparation of soups and gravies The Rhodiola extract, fraction, flavonoid compound or salt according to the present invention was added in an amount of 0.1 ~ 1.0 wt% to typical soups or gravies to prepare health-improving soups or gravies for consumption with meat processed products or noodles.

2-5. Preparation of ground beet

The Rhodiola extract, fraction, f3 avonoid compound or salt according to the present invention was added in an amount of 10 wt% to typicai ground beel to prepare health-improving ground beef.

2-6. Preparation of dairy products

To milk was added 0.1 ~ 1.0 wt% of the Rhodiola extract, fraction, flavonoid compound or salt according to the present invention and the milk was used to prepare various dairy products such as butter and Lee cream.

2-7. Preparation of zen iood

Unmilled rice, barley, glutinous rice, and unshelled adlay were pregelatinized using a typical method, dried and roasted before grinding into powder with a particle size of 60 meshes.

Black soybean, black sesame and wild sesame were steamed according to a typical method, dried and roasted before grinding into powder with a particle size of 60 meshes .

The Rhodiola extract, fraction, frlavonoid compound or salt according to the present invention was concentrated in a vacuum using a vacuum concentrator and dried in a convection oven, followed by grinding into powder with a particle size of: 60 meshes.

The powders made of the grains, the seeds, and the Rhodiola extract, fraction, fJ avonoid compound or salt according to the present invention were formulated at the following ratios to yield a zen food.

Grains (unmilled rice 30 wt%, unshelled adlay 15 wt%, barley 20 wt%) ,

Seeds (wild sesame 7 wt%, black soybean 8 wt%, black sesame 7 wt% ) ,

Dry powder of the extract according to the present invention (3 wt%),

Ganoderma lucidum (0.5 wt%), Foxglove (0.5 wt%)

2-8. Preparation of a carbonated beverage

A mixture containing 5 ~ 10% of sugar, 0.05 ~ 0.3% of citric acid, 0.005 ~ 0.02% of caramel and 0.1 ~ 1% of vitamin C was admixed with 79 ~ 94% of pure water to give syrup which was then sterilized at 85 ~ 98°C for 20 ~ 180 sec. The sterilized syrup was mixed at a ratio of 1:4 with cold water, followed by injecting 0.5 ~ 0.82% of carbon dioxide to afford a carbonated beverage containing the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention.

2-9. Preparation of health beverage

Liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) were homogeneously formulated, along with the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention and the formulation was subjected to pasteurization and loaded into a bottle, such as a glass bottle, a PET bottle, etc.

2-10. Preparation of vegetable juice

5 g of the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention was added to 1,000 mL of typical tomato or carrot juice to give a health-improving vegetable juice.

2-11. Preparation of fruit juice

1 g of the Rhodiola extract, fraction, fiavonoid compound or salt according to the present invention was added to 1,000 mL of typical apple or grape juice to give a health-improving frui t jui ce

Claims

[CLAIMS]

[Claim l]

A pharmaceutical composition for prevention and treatment of a viral disease, comprising a Rhodiola extract as an active ingredient.

[Claim 2]

The pharmaceutical composition according to claim 1, wherein the Rhodiola extract, is obtained by extracting Rhodiola with water, a Ci-C₃ alcohol or a mixture thereof.

[Claim 3]

The pharmaceuticai composition according to claim 2, wherein the alcohol is methanol or cLhanoJ .

[Claim 4]

The pharmaceutical composition according to claim 2, wherein the alcohol is ethanol .

[Claim 5]

A pharmaceutical composition ϊor prevention and treatment of a viral disease, comprising a Rhodiola fraction as an active ingredient, said Rhodiol a fraction being obtained by fractionating the Rhodi ola extract of claim 2.

[Claim 6]

The pharmaceutical composition according to claim 5, wherein the Rhodlola fraction is obtained by fractionating a suspension of the Rhodiola extract in water sequentially with hexane, chloroform and ethyl acetate .

[Claim 7]

A pharmaceutical composition for prevention and treatment of a viral disease, comprising as an active ingredient at least one selected from a group consisting of kaempferol, represented by the following chemical formula 1, kaempferol-3-O-glucosie, represented by the following chemical formula 2, kaempfetrol-3-O-rutinoside, represented by the following chemical formula 3, herbacetin, represented by the following chemical formula 4, rhodiolinin, represented by the following chemical formula 5, rhodionin, represented by the following chemical formula 6, rhodiosin, represented by the following chemical formula 7, herbacetin-3, 8-0- diglucoside, represented by the following chemical formula 8, and pharmaceutically acceptable salts thereof. [Chemical Formula 1]

[Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula

[Claim 8]

The pharmaceutical composition according to claim 7, wherein the compounds of chemical formulas 1, 5, 6 and 7 are isolated from Rhodiola .

[Claim 9]

The pharmaceutical composition according to claim 8, wherein the compounds of chemical formulas 1, 5, 6 and 7 are prepared by: forming an extract from Rhodiola with water, a Ci~C₄₃ alcohol, or a mixture thereof (Step 1 ) ; separating an active fraction from the extract of Step 1 sequentially with hexane, chloroform and ethyl acetate in that order (Step 2); and isolating the compounds of chemical formulas 1, 5, 6 and 7 through column chromatography (Step 3) .

[Claim 10] The pharmaceutical composition according to claim 9, wherein the alcohol is methanol or ethanol .

[Claim ll]

The pharmaceutical composition according to claim 9, wherein the fraction of Step 2 is an ethyl acetate fraction .

[Claim 12]

The pharmaceutical composition according to one of claims 1 to 11, wherein the viral disease Ls caused by an influenza virus.

[Claim 13]

The pharmaceutical composition according to claim 12, having inhibitory activity against neuraminidase.

[Claim 14]

A health food composition for prevention of a viral disease, comprising at least one selected from among the Rhodiola extract, the Rhodiola faction, the compounds isolated from the fraction, or the pharmaceutical Iy acceptable salts of the compounds, as defined in one of claims 1 to 11, as an active ingredient.

[Claim 15]

The health food composition according to claim 14, wherein the viraL diseases Ls caused by an influenza virus .

[Claim 16]

An anti-viral composi tion for use as prophylaxis against influenza virus, comprising at Least one selected from among the Rhodiola extract, the Rhodiola fraction, the compounds isolated from the fraction, or the pharmaceutically acceptable salts of the compounds, as defined as in one of claims 1 to 11, as an active ingredient .

[Claim 17] A method for preventing or treating viral diseases, comprising administering at least one selected from among the Rhodiola extract, the Rhodiola fraction, the compounds isolated from the fraction, or the pharmaceutically acceptable saJts of the compounds, as defined in one of claims 1 to 11, at a therapeutically effective dose to a subject in need thereof.