KR101784261B1 - Composition containing prenylated naphthoquinone or pharmaceutically acceptable salts thereof as an active ingredient for anti-virus - Google Patents

Abstract

The present invention relates to an antiviral composition comprising a prenylated naphthoquinone compound or a pharmaceutically acceptable salt thereof as an active ingredient. More particularly, the present invention relates to an antiviral composition comprising a rhinacanthin C N (Rhinacanthin N), a health functional food, an external composition for skin, and a quasi-drug composition.

Description

[0001] The present invention relates to an antiviral composition comprising a prenylated naphthoquinone compound or a pharmaceutically acceptable salt thereof as an active ingredient,

The present invention relates to an antiviral composition comprising a prenylated naphthoquinone compound or a pharmaceutically acceptable salt thereof, and more particularly to an antiviral composition comprising a rhinacanthin C or Rhinacanthin N A pharmaceutical composition for antivirals, a health functional food, a composition for external application for skin, and a composition for quasi-drug.

Enterovirus (Enterovirus) is taxonomically belongs to the blood or cor bayireoseugwa (Picornaviridae), there are about 68 kinds of serotypes known to date. Greatly depending on the serotype polio virus (Poliovirus), coxsackie virus A (Coxsackievirus A), coxsackie virus B; consists of (Coxsackievirus B CVB), echo virus (Echovirus) and other human enterovirus (EV) including (Mayo , M. and Pringle, CR J Gen Virol 79: 649 ~ 657, 1998; Pringle, CR Arch Virol 144:.. 2065 ~ 2070, 1999).

Enteroviruses mainly invade infant and childhood during the summer season and may cause serious infections depending on the immunological characteristics of the infected person. Enteroviruses are transmitted through the digestive tract and then primarily proliferate in the laryngopharynx or small intestine lymph nodes and then migrate to each organ of the body (Melnick, J. L, In Fields virology, 3rd, 655-712, 1996) . Clinical symptoms vary from mild symptoms such as colds to severe paralysis. A typical symptom caused by enterovirus is aseptic meningitis, which occurs mainly during the summer, but sporadically occurs in spring or late autumn, or even in the winter, and there is a risk of infection throughout the year. In addition, the main generation ages can occur in children and the elderly and infants, or in accordance with the spirit, if (Kok, PW et al, Bull World Health Organ 70:... 93 ~ 103, 1992; Yerly, S. et al, J Clin Microbiol. 34 : 199-201, 1996).

Coxsackievirus B3 (CVB3), an enterovirus, is an antigenic virus that causes a variety of diseases, ranging from mild to severe cases with no distinct symptoms due to a wide spectrum of infections, and also from infants to children and adults Infection cases were reported. Clinically, not only gastrointestinal problems but also hepatitis, encephalitis, acute heart failure to aseptic meningitis can occur. It is reported that 20 to 30% of cardiomyopathy-related diseases are related to CVB3. Symptoms of meningitis caused by coxsack virus first appear through cold symptoms such as fever and headache as well as cough rhinorrhea. Especially, And diarrhea are known to cause.

Human rhinovirus 1B (HRV1B) is also a typical pathogenic antigen virus belonging to enterovirus. HRV1B is a respiratory pathway, which is a respiratory disease like a common cold in healthy individuals without respiratory disease, but it causes severe symptoms in the lower respiratory tract in patients with chronic respiratory diseases such as asthma This has been reported. In addition, HRV1B infected with asthma patients may be a major cause of treatment difficulties due to increased susceptibility to seizures by asthma.

Development of antiviral agents is continuously required to overcome problems such as the emergence of resistant viruses, side effects of drugs, and high production costs (Jassim, SA and Naji, MA, J Appl Microbiol. 95 (3): 412-427 ). As an attempt to solve the above problem, there has been a growing interest in research on the discovery and development of antiviral substances based on medicinal plants, mainly in Asia and Europe (Briskin, DP Plant Physiol. 124 2): 507-514 , 2000; Williams, JE Altern Med Rev. 6 (6): 567-579, 2001). Of these, jasmine ( Rhinacanthus nasutus ) is one of the medicinal plants inhabited in Southeast Asia, and it is known that the extract extracted from the extract contains a prednized naphthoquinone derivative as an active ingredient. It is known that linacantin C and linacantin N, which are one of the above-mentioned prenylated naphthoquinone derivatives, exhibit anti-allergic activity, anti-viral activity against some viruses, antiproliferative activity and the like. Specifically, it has been reported that linacantin C and linacantin D isolated from jasmine extract have inhibitory activity against human cytomegalovirus (CMV) (Sendl, Anna, et al., Journal of natural products, 59.8 1996): 808-811.), Only a few are studies, and no antiviral effects of linacantin C and linacantin N on CVB3 and HRV1B have been reported.

As a result of efforts to develop an effective antiviral composition, the present inventors have found that linacantin C and linacantin N significantly inhibit the cytopathic effect (CPE) caused by viruses in CVB3 or HRV1B infected cells, The present inventors have completed the present invention by confirming that the linacantin C or linacantin N of the present invention can be used as an active ingredient of an antiviral composition.

Thus, the inventors of the present invention completed the present invention by confirming that linacantin C and linacantin N significantly inhibited CPE caused by virus in CVB3 or HRV1B-infected cells and increased cell viability.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for antiviral treatment.

Still another object of the present invention is to provide a health functional food for antivirus.

It is still another object of the present invention to provide a composition for external application for skin for antivirals.

Still another object of the present invention is to provide a quasi-drug composition for antivirals.

In order to achieve the above object, the present invention provides a pharmaceutical composition for antiviral therapy, which contains, as an active ingredient, a prenylated naphthoquinone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof to provide:

[Chemical Formula 1]

.

.

(From here,

Wherein R ₁ is selected from the group consisting of geranyl, fanesyl, geranylgeranyl, geranylfanesyl, fanesylfanesyl or derivatives thereof;

; 또는

; or

이다.

to be.

Wherein each of R < _{2 >} or R < ₃ > is independently H or a group selected from C1-C4 alkyl.

Further, the present invention provides a health functional food containing the prednized naphthoquinone compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a composition for external application for skin for antivirals, which comprises as an active ingredient a prenylated naphthoquinone compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof.

Further, the present invention provides a quasi-drug composition containing the predrnized naphthoquinone compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

According to a preferred embodiment of the present invention, R1 of the formula (1)

(n=0~5);

(n = 0 to 5);

;

;

; 또는

; or

로부터 선택되는 어느 하나일 수 있다.

. ≪ / RTI >

According to a preferred embodiment of the present invention, the prenylated naphthoquinone may be either one or both of a linacantin C represented by the following formula 2 or a linacantin N represented by the following formula 3:

(2)

; 또는

; or

(3)

.

.

According to another preferred embodiment of the present invention, the virus may be either CVB3 or HRV1B.

Accordingly, the present invention provides an antiviral composition comprising a prenylated naphthoquinone compound or a pharmaceutically acceptable salt thereof.

Since the linacantin C and the linacantin N of the present invention can significantly inhibit the CPE caused by the virus in the cells infected with CVB3 or HRV1B and increase the survival rate of the cells, the linacantin C or linacantin N of the present invention Is effective as an active ingredient of a pharmaceutical composition for viral, a health functional food, a composition for external application for skin and a composition for quasi-drug.

Figure 1 shows the cell viability according to the treatment concentration of the naphthoquinone compound that is predilinated in CVB3 infected cells and CVB3 non-infected cells.
2 shows the cell viability according to the treatment concentration of the naphthoquinone compound that is prenylated in HRV1B infected cells and HRV1B non-infected cells.

Hereinafter, the present invention will be described in detail.

As described above, the development of an anti-CVB3 virus agent and an anti-HRV1B virus agent in the development of an effective antiviral agent has been continuously demanded. However, the research on this is only a partial study, Have not been reported.

Since the linacantin C and the linacantin N of the present invention can significantly inhibit the CPE caused by the virus in the cells infected with CVB3 or HRV1B and increase the survival rate of the cells, the linacantin C or linacantin N of the present invention Is effective as an active ingredient of a pharmaceutical composition for viral, a health functional food, a composition for external application for skin and a composition for quasi-drug.

Accordingly, the present invention provides a pharmaceutical composition for antiviral use, which comprises, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

.

.

(From here,

Wherein R ₁ is selected from the group consisting of geranyl, fanesyl, geranylgeranyl, geranylfanesyl, fanesylfanesyl or derivatives thereof;

; 또는

; or

이다.

to be.

Wherein each of R < _{2 >} or R < ₃ > is independently H or a group selected from C1-C4 alkyl.

The geranyl, panesyl, geranyl-geranyl, geranyl-panesyl, panesyl-panesyl or derivatives thereof of R1 in the formula (1) of the present invention are prenyl- In the structure in which the groups are repeated, the double bond in the structure may be changed into a single bond. In addition, deformation such as hydroxylation or carbonyl may be additionally observed in the skeleton of C5n.

Specifically, R < 1 >

(n=0~5);

(n = 0 to 5);

;

;

; 또는

; or

로부터 선택되는 어느 하나인 것이 바람직하나, 이에 한정되지 않는다.

, But it is not limited thereto.

The prenylated naphthoquinone of the present invention is preferably, but not limited to, linacantin C represented by the following formula (2) or linacantin N represented by the following formula (3)

(2)

; 또는

; or

(3)

.

.

The prenylated naphthoquinone of the present invention may be one isolated from the extract of R. nasutus or a fraction thereof, but is not limited thereto, and any of those derived from other substances or synthesized can be used.

The virus of the present invention is preferably an enterovirus, and more specifically, it is preferably any one of CVB3 and HRV1B, but is not limited thereto.

When the virus of the present invention is CVB3, the prenylated naphthoquinone of the present invention is preferably contained at a concentration of 0.02 to 2.00 g / ml. When the virus of the present invention is HRV1B, the prenylated naphthoquinone Is preferably contained at a concentration of 0.2 to 1.0 占 퐂 / ml, but is not limited thereto.

In a specific example of the present invention, the inventors of the present invention have examined the degree of CPE caused by viruses by treating a napthoquinone compound that has been prenylated on a vero cell infected with CVB3. As a result, the present inventors have found that linacantin C (RNR- The therapeutic index (TI) was 1666.67 and 34.72, respectively. Linacantin C and Linacantin N were found to inhibit CVB3-mediated lesion of cervical N cell line (RNR-5) Viral effect significantly (Figure 1 and Table 1) without reducing growth.

The present inventors also examined the degree of CPE caused by the virus by treating a naphthoquinone compound that was prenylated with HRV1B-infected hereloma cells (HeLa cells). As a result, it was found that Linacantin C and Linacantin N inhibited HRV1B- Inhibited the cell survival rate, and confirmed that TI was 103.38 and 124.33, respectively, and that linacanthin C and linacantin N significantly exhibited anti-viral effects without decreasing cell growth (Fig. 2 and Table 2).

Therefore, the linacantin C and linacantin N of the present invention can significantly inhibit the CPE caused by the virus in CVB3 or HRV1B infected cells and increase the survival rate of the cells. Therefore, the linacantin C or linacantin N Can be usefully used as an active ingredient of a pharmaceutical composition for antiviral use.

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of the formula (1) in an excess amount of an acid aqueous solution, and mixing the salt with a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. By heating the same amount of the compound of formula (I) and an acid or alcohol in water, and then evaporating and drying the mixture, or by filtering the precipitated salt by suction filtration.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

The compound of formula (I) of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, Or by adding an aqueous acid solution of an inorganic acid, followed by precipitation or crystallization. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be formulated into various oral or parenteral dosage forms But the present invention is not limited thereto.

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (E.g., silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycols), such as, for example, water, rosin, sucrose, mannitol, sorbitol, cellulose and / or glycine. The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

The pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, intramuscular injection, As shown in FIG. In this case, in order to formulate the composition for parenteral administration, the compound of the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dose of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. In general, when referring to an adult patient weighing 60 kg, And may be 0.01 to 500 mg / day, preferably 0.01 to 500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.

Further, the present invention provides an antiviral health functional food containing, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

.

.

(From here,

Wherein R ₁ is selected from the group consisting of geranyl, fanesyl, geranylgeranyl, geranylfanesyl, fanesylfanesyl or derivatives thereof;

; 또는

; or

이다.

to be.

Wherein each of R < _{2 >} or R < ₃ > is independently H or a group selected from C1-C4 alkyl.

The geranyl, panesyl, geranyl-geranyl, geranyl-panesyl, panesyl-panesyl or derivatives thereof of R1 in the formula (1) of the present invention are prenyl- In the structure in which the groups are repeated, the double bond in the structure may be changed into a single bond. In addition, deformation such as hydroxylation or carbonyl may be additionally observed in the skeleton of C5n.

Specifically, R < 1 >

(n=0~5);

(n = 0 to 5);

;

;

; 또는

; or

 , But it is not limited thereto.

The prenylated naphthoquinone of the present invention is preferably, but not limited to, linacantin C represented by the following formula (2) or linacantin N represented by the following formula (3)

(2)

; 및

; And

(3)

.

.

The prenylated naphthoquinone of the present invention may be one isolated from the extract of R. nasutus or a fraction thereof, but is not limited thereto, and any of those derived from other substances or synthesized can be used.

The virus of the present invention is preferably an enterovirus, and more specifically, it is preferably any one of CVB3 and HRV1B, but is not limited thereto.

When the virus of the present invention is CVB3, the prenylated naphthoquinone of the present invention is preferably contained at a concentration of 0.02 to 2.00 g / ml. When the virus of the present invention is HRV1B, the prenylated naphthoquinone Is preferably contained at a concentration of 0.2 to 1.0 占 퐂 / ml, but is not limited thereto.

Since the linacantin C and the linacantin N of the present invention can significantly inhibit the CPE caused by the virus in the CVB3 or HRV1B infected cells and increase the survival rate of the cells, the linacantin C or linacantin N of the present invention exhibits anti It can be usefully used as an active ingredient of a health functional food for viruses.

The food composition according to the present invention can be prepared in various forms according to a conventional method known in the art. Common foods include but are not limited to beverages (including alcoholic beverages), fruits and processed foods (eg, canned fruits, jam, maamalade, etc.), fish, meat and processed foods (Eg butter, chewing), edible vegetable oil, margarine (such as corn oil, etc.), breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasonings (for example, soybean paste, soy sauce, sauce, etc.). The nutritional supplement may be prepared by adding the compound of formula (I) of the present invention to capsules, tablets, rings and the like. The health functional food is not limited to this. For example, the compound of formula (I) of the present invention itself may be prepared in the form of tea, juice, and drink to be liquefied, granulated, encapsulated And powdered. In order to use the compound of formula (I) of the present invention in the form of a food additive, it may be prepared in the form of powder or concentrate. In addition, the compound of formula (I) of the present invention may be mixed with known active ingredients known to have antiviral effects to prepare a composition.

When the compound of the formula (1) of the present invention is used as a health drink, the health beverage composition may contain various flavors or natural carbohydrates as an additional ingredient like ordinary beverages. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose, sucrose; Polysaccharides such as dextrin, cyclodextrin; Xylitol, sorbitol, erythritol, and the like. Sweeteners include natural sweeteners such as tau Martin and stevia extract; Synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the composition of the present invention.

In addition, the compound of formula (I) of the present invention may be contained as an active ingredient of an antiviral health functional food. The amount thereof is not particularly limited to an amount effective for achieving antiviral action, Is preferably 0.01 to 100% by weight. The food composition of the present invention may be prepared by mixing together the compound of formula (I) together with other active ingredients known to have antiviral effect.

In addition to the above, the health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acid, protective colloid thickener, pH adjusting agent, Glycerin, an alcohol or a carbonating agent, and the like. In addition, the health food of the present invention may contain natural fruit juice, fruit juice drink, or pulp for the production of vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention also provides an antiviral dermatological composition comprising as an active ingredient a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

.

.

(From here,

Wherein R ₁ is selected from the group consisting of geranyl, fanesyl, geranylgeranyl, geranylfanesyl, fanesylfanesyl or derivatives thereof;

; 또는

; or

이다.

to be.

Wherein each of R < _{2 >} or R < ₃ > is independently H or a group selected from C1-C4 alkyl.

The geranyl, panesyl, geranyl-geranyl, geranyl-panesyl, panesyl-panesyl or derivatives thereof of R1 in the formula (1) of the present invention are prenyl- In the structure in which the groups are repeated, the double bond in the structure may be changed into a single bond. In addition, deformation such as hydroxylation or carbonyl may be additionally observed in the skeleton of C5n.

Specifically, R < 1 >

(n=0~5);

(n = 0 to 5);

;

;

; 또는

; or

로부터 선택되는 어느 하나인 것이 바람직하나, 이에 한정되지 않는다.

, But it is not limited thereto.

The prenylated naphthoquinone of the present invention is preferably, but not limited to, linacantin C represented by the following formula (2) or linacantin N represented by the following formula (3)

(2)

; 및

; And

(3)

.

.

The prenylated naphthoquinone of the present invention may be one isolated from the extract of R. nasutus or a fraction thereof, but is not limited thereto, and any of those derived from other substances or synthesized can be used.

The virus of the present invention is preferably an enterovirus, and more specifically, it is preferably any one of CVB3 and HRV1B, but is not limited thereto.

When the virus of the present invention is CVB3, the prenylated naphthoquinone of the present invention is preferably contained at a concentration of 0.02 to 2.00 g / ml. When the virus of the present invention is HRV1B, the prenylated naphthoquinone Is preferably contained at a concentration of 0.2 to 1.0 占 퐂 / ml, but is not limited thereto.

Since the linacantin C and the linacantin N of the present invention can significantly inhibit the CPE caused by the virus in the CVB3 or HRV1B infected cells and increase the survival rate of the cells, the linacantin C or linacantin N of the present invention exhibits anti It can be usefully used as an active ingredient of a composition for external application to skin for viruses.

The compound of formula (I) of the present invention is preferably used as a raw material for cosmetics, pharmaceutical ointments or animal pharmaceuticals.

That is, the antiviral dermatological composition containing the compound of formula (I) of the present invention as an active ingredient may be prepared as a solution, a suspension, a spray, a patch, a pad, a cream, an ointment or a gel.

The solution may contain, in addition to the active compound, conventional excipients such as solvents, solubilizers and emulsifiers such as water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, Glycerin, natural corn stover oil, olive oil, castor oil, almond oil and sesame oil, glycerol, glycerol formal alcohol, tetramethyluronium hexafluorophosphate, Fatty acid esters of sorbitan, furfuryl alcohol, polyethylene glycol and sorbitan, or mixtures of these substances, and may contain methyl or propyl-p-hydroxybenzoate or sorbic acid as a preservative.

In addition to the active compound, the suspending agent may contain conventional excipients such as liquid diluents (e.g., water, ethyl alcohol and propylene glycol, polyethylene glycol), and suspending agents (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan Esters, cellulose derivatives and preservatives for hydrogenation), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, injectable esters such as ethyl oleate, or mixtures of these substances.

The ointments, creams and gels may contain conventional excipients such as animal and vegetable fats, wax paraffin, starch, targacans, cellulose derivatives, May contain a mixture of substances.

In addition, the administration method can be generally applied to the affected part, and the preferable administration method can be selected according to the formulation.

The daily dose of the composition of the present invention is determined depending on the subject to be administered, the method of administration, and symptoms, but it is generally preferred that the compound of the formula 1 contained in the composition is administered in an amount of 0.01 to 100 占 퐂 / ml. However, the above dosage needs to be changed, and in particular, it is necessary to change the composition specificity and body weight of the object to be treated, the kind and depth of disease, The nature of the formulation, the nature of the drug administration, and the duration or interval of administration.

In order to effectively treat viral diseases, it is important to select a suitable external preparation type. In order to treat a viral disease, the compound of Chemical Formula 1 may be appropriately diluted and applied directly to the skin. In the present invention, an anti-viral therapeutic agent can be effectively applied to the affected part.

The ointment of the present invention is prepared by compounding the above-described viral disease therapeutic agent with an inorganic substance and then coating it with a liposoluble base. The inorganic material is preferably a material having excellent antimicrobial activity, anti-inflammatory effect, epidermal regeneration effect, etc. Specific examples thereof include zinc oxide, zinc carbonate, iron oxide and the like.

Further, it is preferable to further use a ceramic carrier capable of safely impregnating a therapeutic agent for viral diseases of the present invention which is a water-soluble substance. As the ceramic carrier, zeolite, talc, gypsum, mortar and mixtures thereof are preferably used. Such a ceramic carrier is excellent in the impregnation property of the water-soluble component, so that the water-soluble component can be smoothly supplied to the skin.

The present invention also provides a quasi-drug composition for antivirals comprising, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

.

.

(From here,

Wherein R ₁ is selected from the group consisting of geranyl, fanesyl, geranylgeranyl, geranylfanesyl, fanesylfanesyl or derivatives thereof;

; 또는

; or

이다.

to be.

Wherein each of R < _{2 >} or R < ₃ > is independently H or a group selected from C1-C4 alkyl.

The geranyl, panesyl, geranyl-geranyl, geranyl-panesyl, panesyl-panesyl or derivatives thereof of R1 in the formula (1) of the present invention are prenyl- In the structure in which the groups are repeated, the double bond in the structure may be changed into a single bond. In addition, deformation such as hydroxylation or carbonyl may be additionally observed in the skeleton of C5n.

Specifically, R < 1 >

(n=0~5);

(n = 0 to 5);

;

;

; 또는

; or

로부터 선택되는 어느 하나인 것이 바람직하나, 이에 한정되지 않는다.

, But it is not limited thereto.

The prenylated naphthoquinone of the present invention is preferably, but not limited to, linacantin C represented by the following formula (2) or linacantin N represented by the following formula (3)

(2)

; 또는

; or

(3)

.

.

The prenylated naphthoquinone of the present invention may be one isolated from the extract of R. nasutus or a fraction thereof, but is not limited thereto, and any of those derived from other substances or synthesized can be used.

The virus of the present invention is preferably an enterovirus, and more specifically, it is preferably any one of CVB3 and HRV1B, but is not limited thereto.

When the virus of the present invention is CVB3, the prenylated naphthoquinone of the present invention is preferably contained at a concentration of 0.02 to 2.00 g / ml. When the virus of the present invention is HRV1B, the prenylated naphthoquinone Is preferably contained at a concentration of 0.2 to 1.0 占 퐂 / ml, but is not limited thereto.

Since the linacantin C and the linacantin N of the present invention can significantly inhibit the CPE caused by the virus in the CVB3 or HRV1B infected cells and increase the survival rate of the cells, the linacantin C or linacantin N of the present invention exhibits anti It can be usefully used as an active ingredient of a quasi-drug composition for viruses.

When the compound of the formula (1) of the present invention is used as an active ingredient of the quasi-drug composition, the compound of the formula (1) having an antiviral activity may be directly added or used together with other quasi-drugs or quasi-drugs, And the like. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use.

The antiviral quasi-drug composition of the present invention is not particularly limited in its formulation, and may be variously formulated in the form of quasi-drugs known in the art to exhibit antiviral activity against a virus infected with a cell. The formulated quasi-drugs include shampoo, foam cleansing, body shower, hand cleaner, detergent soap, soap, toothpaste, tooth whitening agent, bathing agent, disinfectant cleaner, gagrin, wet tissue, mask, ointment agent, patch or filter filler, Includes all quasi-drugs in the sense.

In addition, the composition for antiviral use for antivirals in each formulation can be arbitrarily selected and mixed with other components in accordance with the formulation of the other quasi-drugs, the purpose of use, and the like. The amount of the active ingredient to be mixed may be appropriately determined depending on the purpose of use, and may include, for example, customary adjuvants such as thickeners, stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.

The content of the composition is preferably 0.0001 to 10% by weight based on the total weight of the composition. If it is more than 10% by weight, the color and stability of the composition are poor. When the composition is less than 0.0001% by weight, . The quasi-drug composition containing the compound of formula (I) of the present invention as an active ingredient has little toxicity and side effects to cells as confirmed by the treatment index, and thus can be usefully used as a quasi-drug product.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Prenylated Naphthoquinone ( prenylated naphthoquinone ) Of anti-coxsackievirus B3 ( Coxsackievirus  B3, CVB3)

In order to confirm the antiviral activity of the prenylated naftoride, the effects of linacantin C (RNR-2) and linacantin N (RNR-5) on CPE inhibition caused by CVB3 were investigated using Sulforhodamine B , SRB) method was performed.

Specifically, 2 × 10 ⁴ vero cells (American Type Culture Collection (ATCC)) per well were placed in a 96 well culture plate (BD Biosciences, San Jose, CA, USA) (Gibco, Germany) containing 1% antibiotic-antiserum solution and incubated for 24 hours at 37 ° C. On the next day of inoculation, After removing the medium and washing once with phosphate buffered saline (PBS), BERO cells were infected with CVB3 by replacing with medium containing CVB3 (KCDC, KCDC). 0.016, 0.08, 0.4, 2, 10 or 50 μg of RNR-2, RNR-5, RNR-9 or RNR- / Ml, and cultured for 2 days. Each well was treated with SRB (Sigma-Aldrich, USA), and VERSAmax Micro plate reader was confirmed that the degree of cell survival by measuring the absorbance at wavelength 540 ㎚ using (Molecular Devices, Palo Alto, CA, USA). At this time, the baseline absorbance was set to 620 ㎚.

The relative cell viability (%) of CVB3-infected cells was calculated according to the maximum survival rate of CVB3-uninfected cells after normalization to the cell viability in CVB3-uninfected normal control cells. To confirm cytotoxicity, the cytotoxic concentration (CC ₅₀ ) of RNR-2 or RNR-5 was determined to be 50% of the cell survival rate in CVB3-uninfected Vero cells treated with RNR compounds. In order to demonstrate the virus-induced cytopathic effect for confirming the antiviral effect, the inhibitory concentration (IC ₅₀ ) of the RNR compound was determined to be 50% of the survival rate of the CVB3-infected Bero cell treated with the RNR compound . The same procedure was repeated three times in all the experiments and the average value was shown in the results.

As a result, as shown in the following Table 1 and FIG. 1, RNR compounds exhibited a CC ₅₀ value of _more than 50 μg / ml in the CVB3-infected bero cells, showing no significant cytotoxicity, (Fig. 1 and Table 1), it was found that when RNR-2 or RNR-5 was treated, the cell viability was increased as the treatment concentration was increased and the cell viability was significantly increased as compared with the RNR compound untreated CVB3- . IC ₅₀ values for CVB3 were 0.03 ± 0.01 μg / ml for RNR-2 and 1.44 ± 0.23 μg / ml for RNR-5.

Comparison of Drug Effects of RNR Compounds on CVB3 in Vero Cells compound CC ₅₀ ([mu] g / ml) IC ₅₀ ([mu] g / ml) TI RNR-2 > 50 0.03 ± 0.01 1666.67 RNR-5 > 50 1.44 ± 0.23   34.72 RNR-9 > 50 1.50 + 0.07   33.33 RNR-11 > 50 0.82 + 0.40   60.98

Therapeutic index (TI) = CC ₅₀ / IC ₅₀

Prenylated Naphthoquinone ( prenylated naphthoquinone ) Anti-human Linovirus  1B (Human rhinovirus 1B, HRV1B ) Active confirmation

In order to confirm the antiviral activity of the prenylated naftoride, RNR compounds RNR-2 and RNR-5 confirmed the activity of inhibiting cytopathies caused by HRV1B.

Specifically, 96-well Hera cells, 2 × 10 ⁴ per well in a culture plate (HeLa cell; American Cell Line Bank (American Type Culture Collection; the ATCC) FBS and 1% antibiotics and inoculated into MEM medium containing an antifungal agent solution, The culture medium for each well was washed once with PBS solution, and the medium was replaced with a medium containing HRV1B (American Type Culture Collection, Manassas, VA, USA) The cells were then infected with HRV1 B. Then, the infected cells were treated with the RNR compound in the same manner as in <Example 1>, and the cell viability was confirmed by the SRB method.

As a result, as shown in the following Table 2 and FIG. 2, RNR-2 and RNR-5 compounds exhibited significant cytotoxicity with a CC ₅₀ value of about 30 μg / ml in the non-HRV1B- (Table 2). In addition, the cell survival rate was significantly increased in the RNR-2 or RNR-5 treated group compared to the cell survival rate of the HRV1B-infected Hera cells not treated with RNR, and the IC ₅₀ value for HRV1B was 0.29 ± 0.02 占 퐂 / ml, and that RNR-5 showed 0.24 占 0.01 占 퐂 / ml (Table 2 and Fig. 2).

Comparison of Drug Effects of RNR Compounds on HRV1B in Hera Cells compound CC ₅₀ ([mu] g / ml) IC ₅₀ ([mu] g / ml) TI RNR-2 29.98 0.29 + 0.02 103.38 RNR-5 29.98 0.24 ± 0.01 124.33 RNR-9 > 50 0.97 + 0.13  51.54 RNR-11 > 50 5.35 ± 0.21   9.34

Therapeutic index (TI) = CC ₅₀ / IC ₅₀

Claims (12)

A pharmaceutical composition for antiviral therapy, which comprises, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof,
Wherein the virus is any one or both of Coxsackievirus B3, CVB3 and Human rhinovirus 1B, HRV1B.
[Chemical Formula 1]

.
(Wherein R &lt; ₁ &gt;

,

,

, or

. &Lt; / RTI &gt;
delete 2. The antiviral composition according to claim 1, wherein the prenylated naphthoquinone is either one or both of a linacantin C represented by the following formula (2) or a linacantin N represented by the following formula (3) Pharmaceutical composition:
(2)

; And
(3)

.
delete A health functional food for antivirals, which comprises, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
Wherein said virus is any one or both of coxsackievirus B3 (CVB3) and human lynovirus 1B (HRV1B)
[Chemical Formula 1]

.
(Wherein R &lt; ₁ &gt;

,

,

, or

. &Lt; / RTI &gt;
delete 6. The antiviral composition according to claim 5, wherein the prenylated naphthoquinone is either one or both of a linacantin C represented by the following formula (2) or a linacantin N represented by the following formula (3) Functional foods for health:
(2)

; And
(3)

.
delete 1. An antiviral dermatological topical composition for antiviral comprising, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof,
Wherein said virus is any one or both of cocksaki virus B3 (CVB3) and human lynovirus 1B (HRV1B).
[Chemical Formula 1]

.
(Wherein R &lt; ₁ &gt;

,

,

, or

. &Lt; / RTI &gt;
delete 1. A quasi-drug composition for antivirals comprising, as an active ingredient, a prenylated naphthoquinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof,
Wherein the virus is any one or both of coxsackievirus B3 (CVB3) and human lynovirus 1B (HRV1B).
[Chemical Formula 1]

.
(Wherein R &lt; ₁ &gt;

,

,

, or

. &Lt; / RTI &gt; delete

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