WO2007080669A1

WO2007080669A1 - Antiviral/antiinflammatory drug composition

Info

Publication number: WO2007080669A1
Application number: PCT/JP2006/315843
Authority: WO
Inventors: Tomokazu Higuchi; Masanori Higuchi; Noriyuki Higuchi; Hajime Koyama; Hirofumi Shibata; Tomihiko Higuchi
Original assignee: Microbiotech Inc.
Priority date: 2006-01-11
Filing date: 2006-08-10
Publication date: 2007-07-19

Abstract

A novel drug composition characterized by containing a phenol derivative represented by the formula (1) (wherein R4 is a substituent represented by any of R, COOR, COOH, OCOR, OR, R0OR, SR, and N(R,R); R1, R2, and R3 are the same or different and each represents hydrogen or a substituent represented by any of OH, OR, OCOR, and COR; R represents an optionally substituted chain hydrocarbon group or an optionally substituted cyclic hydrocarbon group in which the ring may be constituted of atoms including a heteroatom; and R0 represents a hydrocarbon chain) or a pharmacologically or pharmaceutically acceptable salt of the derivative as an antiviral or antiinflammatory active ingredient. The drug composition is reduced in side effect, has activity against new viruses, and further has inflammatory activity for stomatitis, wounds, burn, etc.

Description

Specification

Antiviral and anti-inflammatory drug composition

Technical field

[0001] The present invention relates to a pharmaceutical composition having antibacterial, antiviral or anti-inflammatory activity useful as a pharmaceutical or agrochemical. More specifically, the present invention relates to a novel pharmaceutical composition useful as a pharmaceutical or agrochemical, comprising a phenol derivative as an active ingredient, an antibacterial and antiviral antiseptic agent, a prescription for the treatment of stomatitis, wounds and burns, and the like. It is about.

Background art

[0002] The power of many antiviral agents known to date These conventional antiviral agents mainly consist of structural analogs of nucleobases and inhibitors of proteases, and have various serious side effects. There are problems such as the emergence of resistant viruses. In addition, no effective antiviral agent against emerging viruses such as SARS has been developed. Therefore, there is an urgent need to develop new antiviral agents that have few side effects and are effective against emerging viruses such as SARS. In addition, there are currently no drugs with immediate effects on stomatitis, wounds and burns, and the development of such drugs has been desired.

[0003] Furthermore, many antibacterial agents against various pathogenic bacteria have been developed in the past. However, the development of new antibacterial agents has been urgent because of the emergence of resistant bacteria.

[0004] Under such circumstances, although the antibiotic activity of phenol derivatives has been attracting attention in the past (for example, Patent Documents 1 and 2), since the substance is not always clear, the invention of the present application. As a result, the present inventors have already proposed an anti-MRSA active pharmaceutical composition containing a polyvalent phenolate derivative as a result (for example, Patent Document 3).

Patent Document 1: JP-A-8-26991

Patent Document 2: JP-A-9 132532

Patent Document 3: Japanese Patent Laid-Open No. 9194358

Disclosure of the invention Problems to be solved by the invention

[0005] Based on the background as described above, the present invention solves conventional problems, has antibacterial activity, has few side effects, and is effective against emerging viruses. However, it is an object to provide a novel, pharmaceutical composition that has activity and has anti-inflammatory properties against stomatitis, wounds, burns, and the like.

[0006] The present invention is characterized by the following in order to solve the above problems.

[0007] First:

[0008] [Chemical 1]

[0009] (In the formula, R ⁴ is any substituent represented by R, COOR, COOH, OCOR, OR, R0OR, SR, N (R, R);

R ³ is, independently of each other, any one of the substituents represented by a hydrogen atom, OH, OR, OCOR, or COR, and R is a chain that may have a substituent. A ring is formed through a hydrocarbon group or a heteroatom, and the ring may be a cyclic hydrocarbon group, and R ° represents a hydrocarbon chain. Or a pharmacologically or pharmaceutically acceptable salt thereof as an antibacterial, antiviral or anti-inflammatory active ingredient.

[0010] Second: The above pharmaceutical composition, which is a pharmaceutical or agrochemical, wherein the virus to be inactivated is an animal or plant virus having DNA and RNA.

[0011] Third: Viruses targeted for inactivation are box virus, herpes virus, adenowinoles, panolebowinores, baculowinores, piconorenowinoles, togawinores, retrowinoles, orthomyxovirus, paramyxovirus, rhabdo Virus, reovirus, coronawinores, SARS coronavirus, AIDS virus (HIV_ 1), influenza virus, taba The above-mentioned pharmaceutical composition, which is a comosa mosaic virus, a potyvirus, a comovirus, or a kaurimovirus.

[0012] Brother 4 Vibrio parahaemolyticus, Campylobacter jejuni / coli, Clos tridium perrnngens, Yersinia enterocolitica, Vibrio cholerae, Vivrio mimicus, Vibrio fluvialis, Aeromonas hydrophila, Aeromonas sobria, Plesiomonas shigelloides, Clostr idium botulinum pneumonia Mycobacterium tuberculosis,

Drugs that are Penicillinase-producing Staphylococcus aureus, vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA), penicillin-resistant pneumococci (PRSP), or extended substrate i3-lactamases (ESBLSs) Composition.

[0013] Fifth: The above pharmaceutical composition which is a disinfectant.

[0014] Sixth: A pharmaceutical composition which is a disinfectant of bacteria containing drug-resistant bacteria.

[0015] Seventh: Functional foods and other pharmaceutical compositions for the prevention or improvement of bacterial infections containing drug-resistant bacteria.

[0016] Eighth: The above pharmaceutical composition which is a prescription for treatment of stomatitis, wound or burn.

[0017] Ninth: A pharmaceutical composition according to any one of the first to eighth aspects, further comprising an action-enhancing ionic component.

[0018] Tenth: A pharmaceutical composition wherein the ion component is a metal ion component.

[0019] Eleventh: A pharmaceutical composition comprising at least one of a zinc ion component and an iron ion component and having enhanced antibacterial action.

[0020] Twelfth: A pharmaceutical composition according to any one of the ninth to eleventh aspects, wherein the pharmaceutical composition contains a β-latata antibacterial agent together with an ionic component and has an enhanced antibacterial action object.

[0021] Thirteenth: A twelfth pharmaceutical composition, wherein the ionic component is a metal ion component.

[0022] No. 14: No. 1 containing at least one of a sub-ion component and an iron ion component

13 pharmaceutical compositions. Brief Description of Drawings

[0023] FIG. 1 is a graph illustrating the effect of octyl gallate on the survival rate of HSV-1.

FIG. 2 is a diagram illustrating the effect of octyl gallate on the proliferation of HSV — 1 in Vero cells.

FIG. 3 is a diagram illustrating the effect of octyl gallate on the proliferation of HSV-1 in human cells HEp — 2 cells.

FIG. 4 shows the effect of octyl gallate on the proliferation of VSV in HEp-2 cells.

FIG. 5 is a graph illustrating the effect of alkyl chain length on the inhibition of simple herpesvirus type 1 (HSV-1) growth by gallic acid alkyl esters.

FIG. 6 is a diagram illustrating the effect of octyl gallate on cell death induced by HSV-1 infection.

[FIG. 7] FIG. 7 is a single-stage growth curve of HSV-1 in the presence of octyl gallate.

FIG. 8 is a diagram illustrating the inhibitory effect of octyl gallate on VSV proliferation.

FIG. 9 is a diagram illustrating the direct action of octyl gallate on virus particles.

FIG. 10 is a graph showing an example of the antiviral effect of octyl gallate on poliovirus growth.

BEST MODE FOR CARRYING OUT THE INVENTION

[0024] The pharmaceutical composition of the present invention contains the polyvalent phenol derivative represented by the above formula as an active ingredient exhibiting antibacterial, antiviral or anti-inflammatory activity. R4, as described above, is any substituent represented by R, COOR, COOH, OCOR, OR, R0OR, SR, N (R, R), R ¹ , R ² , R ³ are Each is the same or different, and is a hydrogen atom, any one of the substituents represented by OH, or OR, and R is a chained hydrocarbon group which may have a substituent. Alternatively, it represents a cyclic hydrocarbon group which may form a ring via a hetero atom, and R ° represents a hydrocarbon chain. [0025] When R is a chain hydrocarbon group, these may be linear or branched and may be saturated or unsaturated. For example, an alkyl group, an alkenyl group, or an alkynyl group. Specifically, for example, an alkyl group may be a straight or branched chain, for example, methinole, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl. , N_octyl, n-noel, n-decyl, n-undecyl, n-lauryl, isobutyl, and isoamyl groups.

[0026] In the case where R is a cyclic hydrocarbon group, these include a hetero atom such as an oxygen atom (O), a nitrogen atom (N), a sulfur atom (S) which may be monocyclic or polycyclic. A ring may be formed through this.

[0027] Regarding the hydrocarbon group R, the carbon number is considered to be in the range of 24 or less, more preferably in the range of 5 15. These hydrocarbon groups R may have appropriate permissible substituents. For example, an oxygen atom (◯) or an oxygen-containing group, a nitrogen atom (N) or a nitrogen-containing group, a sulfur atom ( Examples are S) or sulfur group deviation. Examples of these substituents include a hydroxyl group, an alkoxyl group, an amino group, a substituted amino group, a mercapto group, and a sulfide group.

[0028] The hydrocarbon chain R ° is exemplified by an alkylene chain having 16 carbon atoms. These may also have appropriate permissible substituents.

More preferably, in the present invention, in the above formula, at least one of R ¹ , R ² and R ³ is other than a hydrogen atom, and R ⁴ has a carboxyl group or a carboxyl group. Or an alkyl group having an ester, acyloxy group, alkoxy group or alkoxy group of these carboxyl groups.

[0030] The phenol derivative of the present invention is typically gallate, for example, and specific examples thereof are as follows. Ethyl gallate, n_propinoregalate, n-butinoregalate, n-pentinoregalate, n_hexinoregalate, n ptylgallate, n-octylgallate, n-nonylgallate, n-decylgallate, n_undecylgallate, n_lauryl Mention may be made of gallate, isobutyl gallate, isoamyl gallate, force techin gallate, gallocatechin gallate and epicatechin gallate. Preferably, methinoregalate, ethinoregalate, n-propinoregalate, n-butinore Examples thereof include gallate, n-pentyl gallate, n-octino gallate, n-nonyl gallate, n-decino gallate, isobutyl gallate, isoamino gallate, 1,2,3-trihydroxy-5-decyl benzene and the like.

[0031] The phenol derivative of the present invention may be a pharmacologically or pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include commonly used pharmaceutically acceptable salts such as sodium, potassium, calcium and the like, and amine salts such as pro-yne and dibenzylamine, and acid addition salts such as hydrochloride. means. It can also be formulated with other active pharmaceutical ingredients.

[0032] In the pharmaceutical composition comprising the phenol derivative of the present invention or a group thereof as an active ingredient for antibacterial, antiviral and anti-inflammatory effects, its administration form is parenteral administration and oral administration in the same manner as usual antibiotics. Administration or topical administration may be mentioned. In general, administration by injection is preferred. In this case, the injection is prepared by a conventional method, and the case where the injection is dissolved in an appropriate vehicle such as sterilized distilled water or physiological saline is also included.

[0033] Oral administration in various dosage forms is also possible. For example, it is in the form of tablets, capsules, tablets coated with sugar, liquid solutions or suspensions.

[0034] The dose of the active ingredient used in the prevention 'treatment can vary depending on the age, body weight, patient symptoms and administration route. For example, when administered to an adult, 10 mg per administration Administer ~ 3 g (per kg body weight) 1 to 3 times daily. The best therapeutic effect should be achieved by changing these doses and administration routes.

[0035] The pharmaceutical composition of the present invention is usually prepared according to a conventional method and is in a pharmaceutically suitable form. For example, solid oral forms can be combined with active compounds, diluents such as ratatoses, dextrose, saccharose, cellulose, corn starch and potato starch, silica, tanolec, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycol Lubricants, starch, gum arabic, gelatin, binders such as methyl cellulose, carboxymethyl cellulose, polybulurpyrrolidine, disintegrants such as starch, alginic acid, alginate, sodium starch glycolate, foaming agents, dyes, sweeteners, for example Wetting agents such as lecithin, polysorbate, lauryl sulfate, and It may also contain pharmaceutically inactive substances generally used in non-toxic and pharmaceutical formulations.

[0036] These pharmaceutical compositions are produced by a known method such as mixing, granulating, tableting, sugar coating, or covering method.

[0037] In the case of parenteral administration, a suppository intended for rectal application is possible, but the general-purpose dosage form is an injection. For injections, there are dosage forms with different appearances such as liquid preparations, dissolution-type preparations, suspension preparations, etc. Basically, the active ingredient is sterilized by an appropriate method and then directly put in a container. It is considered the same in terms of sealing.

[0038] As the simplest formulation method, there is a method in which an active active ingredient is sterilized by an appropriate method, and then separately or physically mixed, and then a predetermined amount is divided into divided formulations. . When selecting a liquid form, the active ingredient can be dissolved in an appropriate medium, sterilized and filtered, and then filled into an appropriate ampoule or vial and sealed.

[0039] In this case, the widely used medium is distilled water for injection, but in the present invention, it is not limited to this. Also, if necessary, preservatives such as painkillers with local anesthetics such as pro-in hydrochloride, xylocaine hydrochloride, benzyl alcohol and phenol, benzylanolol, phenol, methinole, or propylbataben, and chlorobutanol, Buffers such as acid, acetic acid and sodium phosphate, solubilizers such as ethanol, propylene glycol and arginine hydrochloride, stabilizers such as L-cysteine, L-methionine and L-histidine, and isotonic agents It is also possible to add other additives.

[0040] The pharmaceutical composition of the present invention can be prepared as an antibacterial or antiviral agent. These are preferably considered to contain polyphenolic derivatives at a concentration of about 0.:! To 10 (wt)%. For example, it can be used for scissors, scalpels, catheters and other instruments, disinfection of patient effluents, skin, mucous membranes and wounds.

[0041] In this case, the viruses to be inactivated are all animal and plant viruses having DNA and RNA, such as box virus, herpes virus, adenovirus, panorebowinores, baculovirus. Winores, Piconore Nawinoles, Toga Winores, Retro Winores, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Reovirus, Corona Winore , SARS coronavirus, AIDS virus (HIV-1), influenza virus, tabaco mosaic virus, potyvirus, comovirus, kaurimovirus.

[0042] For example, as illustrated in the examples described later, according to the pharmaceutical composition of the present invention, an influenza virus [envelope virus having (single-stranded RNA as a genome) is included in the alkyl gallate as an effective component. ] And HSV_ 1 (envelope virus with DNA as a genome), as well as vesicular stomatitis virus (VSV) [non-enveloped virus with (single-stranded RNA as a genome)] and poliovirus [(ten) -stranded RNA as a genome. It has been found that it has antiviral activity against non-envelope viruses possessed by the present invention, and from this fact, according to the present invention, it is possible to suppress a wide range of virus growth.

[0043] In addition, pathogenic bacteria as antibacterial targets are Bacillus cereus, Bacillus subtilis, Enterococc us faecalis, Staphylococcus epedermidis, Acinetobacter calcoaceticus, Escherichia c oli, Pseudomonas aeruginosa, Proteus mirbilis, Salmonella Enterella parahaemolyticus, Campylobacter jejuni / coli, Clostridium perrrmgens, Yersinia enterocolitica, Vibrio cholerae, Vivrio mimicus, Vi ono fluvialis, Aeromonas hydrophila, Aeromonas sobria, Plesiomonas shigelloides, C lostridium botulinum, Mycoe pneumum tuberculosis, Penicillina ¹ ~~ production Raw Staphylococcus aureus, vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), or extended substrate specificity — lactamase (ESBLSs ), Is shown as a representative example.

[0044] The antibacterial and antiviral agents can also be applied in the form of functional foods for preventing bacterial and viral infections.

[0045] There are no particular restrictions on the form when used as a food or drink, for example, drinks 1J, solids, jelly-like foods, etc. The solids include powders, granules, tablets and capsules as preparations. What was processed into any form is included. Also, the polyphenol derivative is added to udon, buckwheat noodles, cookies, biscuits, candy, bread, cakes, gums and other foods, and soft drinks, lactic acid beverages and other various beverages. You can also. [0046] The phenol derivatives and salts thereof of the present invention can be synthesized by an appropriate method using known compounds as raw materials or intermediates. You may obtain it as a commercial product.

[0047] Furthermore, the pharmaceutical composition of the present invention has a feature that its effect can be enhanced by the addition of an ionic component. Such ionic components can be called “action-enhancing ionic components”.

[0048] Such an ionic component may be any inorganic or organic ionic component, and among them, a metal ionic component is considered suitable. These metal ion components are prepared by adding them as metal compounds. For example, polyvalent metal ions such as zinc, iron and manganese.

[0049] Actually, in the present invention, for example, the antibacterial action can be remarkably increased by, for example, zinc ions and iron ions, and when a ratatametic antibacterial agent is also used, a greater enhancing effect can be obtained.

[0050] In the following, an example will be shown and described in more detail. Of course, the invention is not limited by the following examples.

Example

[0051] <Synthesis example> Synthesis of n_octyl gallate

Octanol (2 ml) and DCC (1.2 g) were added to an anhydrous THF (20 ml) solution of commercially available galley Hi. Og) and stirred at room temperature for 5 hours under N atmosphere. The obtained reaction solution was concentrated under reduced pressure, 5% aqueous citrate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO and dried over MgSO. After filtration through filter paper, the solvent of the filtrate was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel chromatography “CHC1-methanol” (

99: 1) ”and recrystallization with n-hexane-CHC1 to obtain octyl gallate.

For subjects who developed stomatitis (a white rash with a diameter of 7 mm) on the upper lip and had difficulty eating due to pain, an octyl gallate solution (20% ethanol and 80% saline) was added to the affected area. Octyl gallate 150 μg / ml) When applied twice (around 9 am and around 5 pm), the first application alleviated the pain, and on the second day the rash disappeared and was completely cured.

[0052] A subject who developed stomatitis (a white rash with a diameter of 4 mm and 6 mm in diameter) on the back side of the tongue and the left side of the lower lip was immersed in an octyl gallate solution (same as above) in a club.

When applied twice a day (around 10 am and around 4 pm), the first application reduced the pain, and on the second day the rash disappeared and was completely cured.

From the above, it was confirmed that the octyl gallate solution was highly effective for stomatitis. Octyl gallate is known to have anti-inflammatory effects, and the cause of stomatitis is not single, but simple recurrent infection with herpesvirus (recurrent stomatitis) (Medical Dictionary, Nanzan-do) This suggests that octyl gallate has anti-herpesvirus activity.

Example 2>

Example 1 suggests that octyl gallate has an anti-herpesvirus activity, so it is effective against herpes simplex virus type 1 (HSV-1; a pathogen of cold sores, a virus that possesses DNA). When the virus activity was examined, the following test results were obtained.

[0054] 1) Figure 1 illustrates the effect of octyl gallate on the survival rate of HSV-1, where HSV-1 was incubated on ice with various concentrations of octyl gallate for 10 minutes, and then This is the result of infecting Vero cells, counting the number of plaques, and determining the virus inactivation rate. From FIG. 1, it can be seen that octyl gallate completely inactivated HSV-1 directly at a concentration of 80 / ig / ml.

[0055] 2) FIG. 2 is a diagram illustrating the effect of octyl gallate on the proliferation of HSV-1 in Vero cells. Monolayer Vero cells grown to confluence were infected with HSV-1 at a multiplicity of infection (M0I) of 12, and cells infected with the virus were treated overnight in media containing the indicated concentrations of octyl gallate. Incubated at ° C, total virus count (◯) and extracellular virus count (△) are measured separately. Figure 2 shows that HSV_1 proliferation in Vero cells (established cells derived from kidney cells of African green monkeys) was suppressed to 1/1000 or less in the presence of 4 µg / ml octyl gallate.

[0056] 3) Figure 3 shows octyl galley in the proliferation of HSV-1 in human cells HEp_2 cells. It is the figure which illustrated the effect of G. Confluent monolayer HEp-2 cells were infected with HSV-1 at a multiplicity of infection (MOI) of 12, and the rest is the same as in Figure 2. HSV-1 proliferation in human HEp2 cells was suppressed to less than 1 / 10,000 at a concentration of 8 μg / ml.

[0057] 4) FIG. 4 shows the effect of octyl gallate on the proliferation of VSV in HEp_2 cells. Confluent monolayer HEp_ 2 cells were infected with 3 at a multiplicity of infection (M 0 1) of 12, and the culture time was 17 hours. The O in the figure indicates the total amount of virus. The others are the same as in FIG. The growth of VSV (vesicular stomatitis virus, RNA-bearing virus) in Vero cells was also suppressed in the same way as HSV_1.

[0058] From these test results, it was clarified that octyl gallate has anti-herpesvirus activity as expected. Furthermore, it was revealed that octyl gallate has antiviral activity against VSV, an RNA virus.

[0059] Octyl gallate was found to have strong antiviral activity against DNA and RNA viruses. Note that no decrease in cell number due to octyl gallate at the concentrations used was observed.

After infecting HEV-2 monolayer culture cells with HSV-1 at a rate of 14 PFU per cell, culture medium containing 0.1% gallic acid or its various alkyl esters: alkyl gallate (15 μΜ) The cells were cultured for about 24 hours at 37 ° C in serum albumin (MEM). The infected cells were freeze-thawed twice with the culture medium, and the total progeny virus was released into the freeze-thaw solution, and then the amount of progeny virus was quantified. For the amount of progeny virus in the presence of each reagent, the relative production was calculated based on the amount of progeny virus produced without the reagent.

[0060] FIG. 5 shows the results as the degree of carbon number of the alkyl chain of the alkyl gallate.

[0061] FIG. 5 shows that the antiviral activity against HSV-1 is strongest when dodecyl gallate having 12 carbon atoms in the alkyl chain is used.

Example 4> The effect of octyl gallate on cell death induced by HSV-1 infection was evaluated. [0062] FIG. 6 illustrates the results.

[0063] Prepare HEp_2 monolayer cultured cells (black circles and black triangles in the figure) and uninfected cells (white circles and white triangles in the figure) infected with HSV-1 at a rate of 14 PFU per cell. Μ37 ° C in culture medium (0.1% urine serum albumin card MEM) with Ota tilgarate (white triangles, black triangles in the figure) or non-additives (white circles and black triangles in the figure) In culture. Samples were taken at regular intervals, and the number of live cells and dead cells were quantified using trypan blue, and the ratio of dead cells in each sample was calculated. The horizontal axis in the figure shows the time since infection of HEp_2 cells with HSV-1.

[0064] From FIG. 6, octyl gallate significantly promotes cell death induced by HSV-1 infection. It should also be noted that octyl gallate at the concentration used does not show significant cytotoxicity.

Inhibition of intracellular virus growth and virus release from cells was evaluated for HSV-1 growth in the presence of octyl gallate.

FIG. 7 illustrates the result.

[0066] HEp—2 cell monolayer culture cells were infected with HSV—1 at a rate of 14 cells per cell, then cultured with 15 / M octyl gallate added (black circle, black triangle) or non-added (white circle, white triangle) The cells were cultured at 37 ° C in a liquid (0.1% ushi serum albumin capsule MEM). Samples were taken at regular intervals to determine the amount of all progeny virus (white circles, black circles) and the amount of virus released into the culture medium (white triangles, black triangles). From FIG. 7, it is clear that octyl gallate suppresses both the growth of virus in cells and the release of virus from cells.

Example 6>

The inhibitory effect of octyl gallate on the growth of vesicular stomatitis virus (VSV) was evaluated. That is, after infecting HEp_2 monolayers with VSV at a rate of 17 PFU per cell, they were cultured at 37 ° C in a medium containing 0.1% octyl gallate at various concentrations (0.1% urine serum albumin-added MEM). After approximately 17 hours of incubation, the progeny that are released into the culture broth The amount of Nores was quantified. For the amount of progeny virus at each concentration, the relative production was calculated based on the amount of progeny virus produced without the reagent.

The results are shown in FIG.

[0068] From Fig. 8, the force that is an enveloped virus similar to HSV-1 is also the vesicular stomatitis virus (VS V) that has RNA as a genomic nucleic acid and increases in a completely different growth mode from HSV-1. It can be seen that octyl gallate exhibits significant antiviral activity.

Example 7>

The direct effect of octyl gallate on virus particles was evaluated. Figure 9 shows the results.

[0069] That is, octyl gallate is added to a virus solution containing a certain amount of HSV-1 (◯) or VSV (A) (final concentration 60 x gZml) and kept warm in ice water. Take a sample at regular intervals and immediately dilute to determine the remaining virus titer (PFU; plaque-forming unit) using the plaque method. The relative titer relative to the virus titer prior to reagent addition was calculated.

[0070] FIG. 9 shows that octyl gallate also has a direct virus inactivation action against HSV-1 and VSV. However, this virus inactivation requires a higher concentration of octyl gallate than when it exhibits an anti-viral effect on infected cells.

Inhibition of growth of influenza virus A / Hong Kong / l / 68 (H N) in MDCK cells by octyl gallate was evaluated.

[0071] That is, MDCK cells (Madin-Darby canine kidney cells) are seeded in a 24-well plate (400 μ 1 / well) and made confluent, followed by influenza virus A / HongKong / l / 68 (H

N) (lOPFUZwell) 37. C, 5% CO incubator for 1 hour. Next

, 1% grayed Norekosu to the culture medium (DMEM medium containing Okuchirugareto of different concentrations of the infected cells, 0.2 ^_0/0 Ushichi,? Blue Anorebumin, 0. 5 o / o gentamicin ^sulfate, 0. 00025 ο / _{ο in} Trypsin, 0.03% gnoretamine, 7% Meyron (Otsuka Pharmaceutical) 6%, 250 zg / ml amphotericin B (nakalai tesque) 0.5%) 34.5. C, cultured in a 5% CO incubator for 3 days. The cultured virus solution (100 μ1) was diluted 10-fold, and virus particles were measured by the plaque method. The results are shown in Table 1.

[0073] [Table 1]

[0074] From Table 1, it was found that octyl gallate completely suppressed the growth of influenza virus A / Hong Kong / 1/68 (H3N2) in MDCK cells at a concentration of 6 μgZ ml.

[0075] The antiviral effect of octyl gallate on poliovirus growth was evaluated.

[0076] That is, after infecting a monolayer culture cell of HEp-2 cells with poliovirus type 1 Sabin strain [non-enveloped virus having (+) chain RNA as a genome] at a rate of 10 cells per cell, The cells were cultured at 35.5 ° C. for about 22 hours in a culture medium containing 0.1% octyl gallate (MEM supplemented with 0.1% ushi serum albumin). Infected cells were frozen and thawed twice with the culture medium, and the amount of virus in the frozen thaw solution was quantified.

FIG. 10 illustrates the result.

[0078] FIG. 10 shows that octyl gallate inhibits poliovirus type 1 proliferation in HEp_2 cells, indicating that octyl gallate has anti-winole activity against poliovirus type 1. .

From the above examples, octyl gallate was presumed to have an anti-inflammatory action. Therefore, when the therapeutic effect on wounds / burns was examined on 20 subjects, it was confirmed that it exhibited a rapid effect. It was.

The following various dosage forms were prepared as octyl gallate-containing anti-inflammatory and antiviral agents.

[0079] (tablets) Octyl gallate 100 g, hydroxypropyl cellulose 80 g, light anhydrous caic acid 20 g, lactose 50 g, crystalline cellulose 50 g, and talc 50 g were tableted with a diameter of 9 mm and a weight of 200 mg by a conventional method.

[0080] (Capsule)

Talented chinenoregalate 100g, crystalline senorelose 100g? 150g sucrose and 20g light caustic anhydride were used as a force psenore by a conventional method.

[0081] (Granule)

200 g of octinoregalate, 200 g of lactose, 300 g of hydroxypropylcellulose, and 15 g of Tanorec were granulated by a conventional method.

[0082] (Cream)

Octyl gallate 0.2 g, cholesteryl isostearate lg, polyether-modified silicone 1.5 g, cyclic silicone 20 g, methylphenylpolysiloxane 2 g, methylpolysiloxane 2 g, magnesium sulfate 0.5 g, 55% ethanol 5 g, carboxy Methyl chitin 0.5g and purified water (remaining amount) were mixed to prepare a cream.

[0083] (ointment)

Octyl gallate 0.5 g, cholesteryl isostearate 3 g, liquid paraffin 10 g, a-toferonol 0. lg, glycerinole: n-thenole lg, ku "lyserin 10 g, and white fuselin 2 g were combined to form an ointment.

[0084] (Injection)

Octyl gallate 15 mg and glucose lOO mg were dissolved in 5 ml of distilled water for injection and sterilized by heating to obtain an injection.

[0085] (Lotion)

Octyl gallate lg, glycerin monostearate lg, ethanolanol 15 g, propylene glycolate 4 g, isopropino renole. A lotion was obtained by mixing 3 g of noremitate, 0.5 g of lanolin, 0.5 g of ceramide, 0.5 g of noraxyoxy shoulder, 0 lg of methyl fragrate, 5 g of vitamin CO., Fragrance, small amount of pigment, 72 g of purified water.

In Example 11, instead of octyl gallate, other than those represented by the above general formula [Chemical Formula 1] Various compounds such as nonyl gallate, decyl gallate, undecyl gallate, and dodecino regaleate were mixed to obtain tablets, capsules, creams, ointments, injections, and lotions.

<Example 13> Functional food

As functional foods effective for the prevention or treatment of colds caused by stomatitis and influenza virus, compounds such as octyl gallate such as octyl gallate such as gums, such as nonyl gallate, decyl gallate, undecyl gallate, A gum with 0.05 to 0.3 mg dodecyl gallate per lg gum is obtained.

<Example 14> Antiviral toothpaste

As toothpaste effective for the prevention or treatment of cold caused by stomatitis or influenza virus, commercially available toothpaste and the like, such as octyl gallate, a compound represented by the above general formula [Dig 1], such as nonyl gallate, decyl gallate, undecyl gallate, Toothpaste with dodecyl gallate mixed with 0.05mg of toothpaste per lg 0.05.0-0. 3mg.

<Example 15> Antibacterial activity of various gallates by agar plate dilution method

MIC (minimum inhibitory concentration) was measured according to the agar plate dilution method defined by the Japanese Society of Chemotherapy. As a culture medium for sensitivity measurement, CAMHA in which Ca ion 50 mg / l, Mg ion 25 mg / l and 2% NaCl was added to Mueller-Hinton II Agar (MHA) was used. The bacterial solution that has been cultured at 37 ° C for 1 hour is diluted with physiological saline to 10 ⁶ CFU / ml, and inoculated on a plate for sensitivity measurement using a microplanter (Sakuma Seisakusho), and cultured at 37 ° C for 24 hours. Later, the MIC was determined. The results are shown in Table 2 and Table 3.

[0086] As shown in the table, the carbon number powers of the anolequinole chain 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 2, 16 are gallate, Methyl gallate, ethyl gallate, propyl gallate, hexinoregalate, octinoregalate, noninoregalate, decinoregallate, undecinoregalate, lauryl gallate, cetylgallate.

From the results in this table, it can be seen that octyl gallate, nonyl gallate, decyl gallate, and undecyl gallate have strong antibacterial activity against any fungus.

[0088] [Table 2] Carbon number of alkyl chain 5 6 7 8 9 10 1 1 12 6

(] Gram-positive bacteria

Bacillus subtilis IF03134 250 125 250

Enterococcus faeca / is ATCC21212 250 250 250 Staphylococcus epideraidis I F03762 250 62.5 250

S. pyogenes IID Cock 500 1000> 000

S. pyogenes ATCC19165 125 250> 000

S. pneumoniae IID553 62.5 62.5 62.5

S. pneumoniae 62.5 62.5 62.5

S. pneumoniae 4201 62.5 62.5 ΐ ί

S. pneumoniae 4203 250 1000 10

S. pneumoniae 4204 62.5 62.5 1 2∑5

S. pneumoniae 4205 31,3 31.3 l 2i 5

S. pneumoniae 4207 125 125 12; 5

S. pneumoniae 421 1 31.3 31.3 31.3

S. pneumoniae 4213 62,5 62.5 31.3

£ faecaiis 0497P 250

£ faecah's (VanB) 250

E faecium 0677P 250

E. faecium (VanA) 125

E galiinanim (VanCD 250

E- cesselHlavus (VanC2 / C3) 250

(2) Gram- negative bacteria

We evaluated the antibacterial effect of alkylgallate on MRSA, MSSA, and VISA by zinc ion and iron ion. As an experimental method, MIC values were measured according to the plate agar dilution method defined by the Japanese Society of Chemotherapy. Zinc ions were added as zinc ions. Also, iron ions were used with FeCl 3 and 6H 2 O added. The incubation time was 24 hours at 37 ° C.

[0091] Table 4 shows the results.

[0092] [Table 4] octyl gallate ICC i g mL) none Zn 0.1 mM Zn 0.5 mM Zn 1.0 mM Fe 0.1 mM Fe 0.5 mM Fe I .OmM

MRSA

MRSA1 31.25 15.63 15.63 ND 15.63 7.81 7.81

MRSA2 31.25 15.63 7.81 3.91 7.81 3.91 3.91 RSA3 31.25 15.63 15.63 3.91 7.81 3.91 3.91 RSA4 31.25 15.63 1 5.63 3.91 7.81 7.81 7.81

MRSA5 31.25 15.63 7.81 3.91 7.81 3.91 3.91

MRSA6 31.25 1 5.63 1 5.63 7.81 7.81 7.81 3.91

MRSA7 31.25 1 5.63 1 5.63 3.91 7.81 3.91 3.91

MRSA8 15.63 15.63 7.81 1.95 3.91 3.91 3.91

MRSA9 15.63 7.81 7.81 3.91 3.91 7.81 3.91 RSA10 31.25 7.81 3.91 ND 7.81 7.81 3.91

MRSA12 31.25 31.25 15.63 7.81 1 5.63 7.81 3.91

MRSA13 31.25 1 5.63 7.81 3.91 7.81 F.81 3.91

MRSA1 6 31.25 31.25 3.91 1.95 3.91 3.91 3.91

MRSA17 31.25 15,63 F.81 3.91 7,81 7.81 3.91

M SA18 31.25 15.63 15.63 3.91 7.81 F.8 ΐ 7,81

M SA19 31.25 15.63 7.81 3.91 15.63 7.81 3.91

MRSA20 31.25 31.25 7.81 1.95 7.81 7.81 3.91 RSA21 31.25 31.25 15.63 1.95 7.81 7.81 7.81

MRSA22 31.25 31.25 15.63 1.95 7.81 7.81 7.81

MRSA COL 1 5.63 15.63 7.81 to 0.977 7.81 7.81 3.91

VISA Mu3 31.25 15.63 3.91 ND 7.81 3.91 3.91

MSSA

1003 31.25 15.63 7.81 7.81 7.81 3.91 3.91

1010 31.25 15.63 7.81 3.91 7.81 3,91 3.91

1020 31.25 31.25 15.63 3.91 15.63 7.81 7.81

1023 ND ND ND ND ND ND ND

1029 15.63 15.63 7.81 ND 7.81 3.91 3.91

1032 31.25 31.25 15.63 7.81 15.63 7.81 7.81

ATCC6538 31.25 15.63 15.63 1.95 7.81 7.81 7.81

RN4220 15.63 3,91 3.91 ND 7.81 3.91 3.91

ND: not determined [0093] Table 4 shows that zinc ions and iron ions have an effect of enhancing the antibacterial action of octyl gallate against MRSA, MSSA, and VISA in a concentration-dependent manner. The effect of enhancing the antibacterial action of octyl gallate by such ions was also observed in various alkyl gallates having 1 to 12 carbon atoms in other alkyl chains.

We further evaluated the effect of octyl gallate to enhance the sensitivity of MRSA, MSSA and VISA to oxacillin by zinc and iron ions.

[0094] As an experimental method, MIC values were measured according to the plate agar dilution method defined by the Japanese Society of Chemotherapy. Zinc ions were added as zinc ions. The iron ions were added with FeCl and 6H ○.

[0095] Table 5 shows the results.

[0096] [Table 5]

oxacillin MIC (/ mL)

octyl gallate 1.56 fi g / mL none n 0.5m Fe 0.5mf

MRS A

MRSA2 64 64 8 2

MRS A3 64 4 8 0.125

MRSA4 128 128 64 64

MRSA5 128 64 ND 8

MRSA6 128 32 8 2

MRSA7〉 128 128 32 8

MRSA8 123 32 4 ND

MRSA9〉 128 128 32 1 28

M SA10 64 32 4 2 RSA12> 128 64 64 1

MRSA13 128 64 32 2

SA16 0.5 1 ND 0.5 SA17 128 64 32 32

MRSA18〉 128 128 64 128

MRSA19 128 64 64 8

MRSA20 16 2 1 0.5

MRSA21 32 16 2 2

MRSA22 32 16 2 8

MRS A COL〉 128 128 8 64

VISAMu3> 128> 128 32> 128 SSA

MSSA1003 0.25 0.25 0.5 ND SSA1010 0.25 0.25 0.5 0.125 SSA1020 1 2 2 2

MSSA1029 2 4 0.5 0.25

MSSA1032 0.125 0.125 0.5 0.125

ATCC 6538 0.063 0.063 0.125 0.063 N4220 0.063 0.125 0.25 0.125

ND: not determined From Table 5, it was revealed that zinc ions and iron ions further enhance the enhancement of MRSA, MSSA, VI SA sensitivity to oxacillin by octyl gallate. Oxacillin is a type of latatum antibacterial drug, and ions and iron ions are octyl gallate of other beta-latatabacterial drugs (penicillin G, methicillin, cefapirin, panipenem, cefotaxime). It was also confirmed that the enhancement of susceptibility due to antibacterial activity was further enhanced. It is judged.

<Example 18> Use of octyl gallate as a dental antibacterial agent: 1

An ointment containing lmg octyl gallate per lg of white petrolatum to a subject with caries, applied to the lesion twice a week, only to prevent the caries from expanding X-ray taken 6 months later As a result, it was revealed that calcium was deposited on the dentin of the lesion. Therefore, this ointment is expected to be a breakthrough treatment for caries.

Example 19 Use of octyl gallate as a dental antibacterial agent: 2

Applying ointment containing lmg octyl gallate per lg white petrolatum to subjects with alveolar pyorrhea is effective in removing bad breath as well as improving the lesion. Therefore, it is expected that octyl gallate can be used as a treatment for alveolar pyorrhea and as an oral disinfectant, mouthwash, and bad breath remover. <Example 20>

As disinfectants containing octyl gallate, the following various compositions were prepared. (Disinfectant 1)

Octinoregalate 0.1 mg / ml to 0.5 g / ml, ethanol 20-82 vol%

(Disinfectant 2)

Octyl gallate 0.lmg / ml to 0.5g / ml, ethanol 0 to 82vol% povidone node 0 · 01 to l% (w / v)

(Disinfectant 3)

Octyl gallate 0 · lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Potassium permanganate 0.01 to 0.1%

(Disinfectant 4)

Octyl gallate 0.1 mg / ml to 0.5 g / ml, ethanol 0 to 82 vol% Isopropanol 5 to 70 vol%

(Disinfectant 5)

Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Benzalkonium chloride 1-1 OwZv% (Disinfectant 6)

Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Talesol

5 ~ 50vol%

(Disinfectant 7)

Octyl gallate 0.1 mg / ml to 0.5 g / ml, ethanol 0 to 82 vol% Chlorhexidine dalconate 0.1 to 0.5 w / v%

(Disinfectant 8)

Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% phenol

5 ~ 90vol%

(Disinfectant 9)

Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Mercurochrome 0 :! ~ 2vol%

(Disinfectant 10)

Octyl gallate 0.1 mg / ml to 0.5 g / ml, ethanol 0 to 82 vol% formaldehyde nodehydride 5 to 40 vol%

(Disinfectant 11)

Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Atalinore 0. 01 to 0.2vol%

(Disinfectant 12)

Octyl gallate 0.1 mg / ml to 0.5 g / ml, ethanol 0 to 82 vol% Sodium hypochlorite:! To 12 vol%

Industrial applicability

According to the present invention as described above, a pharmaceutical composition having antibacterial activity, high antiviral activity against various viruses with few side effects, and useful as a medicine or agricultural chemical is provided. In addition, an antiviral action against stomatitis, a wound, a burn, etc., or a pharmaceutical composition having an immediate effect of an anti-inflammatory action is realized.

Claims

Claim [1]

[Chemical 1]

(Wherein R ⁴ is any substituent represented by R, COOR, COOH, OCOR, OR, R ° OR, SR, N (R, R),

Are the same or different and each is a hydrogen atom, 0H, 〇R, OCOR, or COR, and any substituent represented by ROR, R may have a substituent, a chain A ring is formed through a hydrocarbon group or a heteroatom, and the ring may be a cyclic hydrocarbon group, and R ° represents a hydrocarbon chain. )

And a pharmacologically or pharmaceutically acceptable salt thereof as an antibacterial, antiviral or anti-inflammatory active ingredient.

[2] The pharmaceutical composition according to claim 1, wherein the virus is a pharmaceutical or agrochemical, and the virus to be inactivated is an animal or plant virus having DNA and RNA.

[3] The viruses to be inactivated are box virus, herpes virus, adenovirus, parvovirus, butarovirus, piconal virus, togavirus, retrovirus, orthomyxovirus, paramyxovirus, rhabdovirus, reovirus. 3. The pharmaceutical composition according to claim 2, which is coronavirus, SARS coronavirus, AIDS virus (HIV-1), influenza virus, tobacco mosaic virus, potyvirus, comovirus or kaurimovirus.

[4] Pathogenic fungi as anti-male elephant, Bacillus cereus, Bacillus subtilis, Enterococcus faeca lis, Staphylococcus epedermidis, Acinetobacter calcoaceticus, Escherichia coli, Pse udomonas aeruginosa, Proteus mirbilis, Salmonella Enteritidis, Salmonella Typhi, Sal monella Typhimurium, Vibrio parahaemolyticus, Campylobacter jejuni / coli, Clostri dium perfringens, Yersinia enterocolitica, Vibrio cholerae, Vibrio cholerae, Viorio mimicus Clostridi um botulinum, Mycoplasma pneumoniae, Hemophilus influenzae, Klebsiella pneumon iae, Legionella pneumophila, Mycobacterium tuberculosis 2. The pharmaceutical composition according to claim 1, which is a cocci (PRSP) or a substrate-specific extended β-ratatase (ESBLSs).

5. The pharmaceutical composition according to claim 1, which is a disinfectant.

6. The pharmaceutical composition according to claim 1, which is a disinfectant for bacteria containing drug-resistant bacteria.

[7] The pharmaceutical composition according to claim 1, for preventing or ameliorating a bacterial infection including drug-resistant bacteria.

8. The pharmaceutical composition according to claim 1, which is a prescription for treatment of stomatitis, wound or burn.

[9] The pharmaceutical composition according to any one of claims 1 to 8, further comprising an action-enhancing ion component.

10. The pharmaceutical composition according to claim 9, wherein the ionic component is a metal ion component.

[11] The pharmaceutical composition according to claim 10, wherein at least one of a zinc ion component and an iron ion component is contained, and the antibacterial action is enhanced.

[12] The pharmaceutical composition according to any one of claims 9 to 11, wherein the pharmaceutical composition contains a ratatum antibacterial agent together with an ionic component, and has an enhanced antibacterial action.

13. The pharmaceutical composition according to claim 12, wherein the ionic component is a metal ion component.

[14] The pharmaceutical composition according to [13], wherein at least a zinc ion component and an iron ion component are contained or misaligned.