WO2007080669A1 - Composition medicamenteuse antivirale/anti-inflammatoire - Google Patents

Composition medicamenteuse antivirale/anti-inflammatoire Download PDF

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Publication number
WO2007080669A1
WO2007080669A1 PCT/JP2006/315843 JP2006315843W WO2007080669A1 WO 2007080669 A1 WO2007080669 A1 WO 2007080669A1 JP 2006315843 W JP2006315843 W JP 2006315843W WO 2007080669 A1 WO2007080669 A1 WO 2007080669A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
virus
composition according
gallate
octyl gallate
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PCT/JP2006/315843
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English (en)
Japanese (ja)
Inventor
Tomokazu Higuchi
Masanori Higuchi
Noriyuki Higuchi
Hajime Koyama
Hirofumi Shibata
Tomihiko Higuchi
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Microbiotech Inc.
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Priority claimed from JP2006004252A external-priority patent/JP2006306836A/ja
Application filed by Microbiotech Inc. filed Critical Microbiotech Inc.
Publication of WO2007080669A1 publication Critical patent/WO2007080669A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • Patent Document 1 JP-A-8-26991
  • Patent Document 2 JP-A-9 132532
  • Patent Document 3 Japanese Patent Laid-Open No. 9194358
  • the present invention solves conventional problems, has antibacterial activity, has few side effects, and is effective against emerging viruses.
  • the present invention is characterized by the following in order to solve the above problems.
  • 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.
  • a pharmacologically or pharmaceutically acceptable salt thereof as an antibacterial, antiviral or anti-inflammatory active ingredient.
  • 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.
  • 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.
  • VRE vancomycin-resistant enterococci
  • VRSA vancomycin-resistant Staphylococcus aureus
  • PRSP penicillin-resistant pneumococci
  • EBLSs extended substrate i3-lactamases
  • a pharmaceutical composition which is a disinfectant of bacteria containing drug-resistant bacteria.
  • Ninth A pharmaceutical composition according to any one of the first to eighth aspects, further comprising an action-enhancing ionic component.
  • Tenth A pharmaceutical composition wherein the ion component is a metal ion component.
  • a pharmaceutical composition comprising at least one of a zinc ion component and an iron ion component and having enhanced antibacterial action.
  • Twelfth A pharmaceutical composition according to any one of the ninth to eleventh aspects, wherein the pharmaceutical composition contains a ⁇ -latata antibacterial agent together with an ionic component and has an enhanced antibacterial action object.
  • a twelfth pharmaceutical composition wherein the ionic component is a metal ion component.
  • No. 14 No. 1 containing at least one of a sub-ion component and an iron ion component
  • 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 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.
  • 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 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.
  • R is a chain hydrocarbon group
  • these may be linear or branched and may be saturated or unsaturated.
  • an alkyl group an alkenyl group, or an alkynyl group.
  • 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.
  • 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.
  • 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.
  • substituents include a hydroxyl group, an alkoxyl group, an amino group, a substituted amino group, a mercapto group, and a sulfide group.
  • the hydrocarbon chain R ° is exemplified by an alkylene chain having 16 carbon atoms. These may also have appropriate permissible substituents.
  • R 1 , R 2 and R 3 is other than a hydrogen atom
  • 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.
  • 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.
  • 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.
  • the phenol derivative of the present invention may be a pharmacologically or pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • administration by injection is preferred.
  • 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.
  • Oral administration in various dosage forms is also possible.
  • it is in the form of tablets, capsules, tablets coated with sugar, liquid solutions or suspensions.
  • 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.
  • the pharmaceutical composition of the present invention is usually prepared according to a conventional method and is in a pharmaceutically suitable form.
  • 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.
  • active compounds such as ratatoses, dextrose, saccharose, cellulose, corn starch and potato star
  • compositions are produced by a known method such as mixing, granulating, tableting, sugar coating, or covering method.
  • a suppository intended for rectal application is possible, but the general-purpose dosage form is an injection.
  • dosage forms with different appearances such as liquid preparations, dissolution-type preparations, suspension preparations, etc.
  • 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.
  • 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.
  • the active ingredient can be dissolved in an appropriate medium, sterilized and filtered, and then filled into an appropriate ampoule or vial and sealed.
  • the widely used medium is distilled water for injection, but in the present invention, it is not limited to this.
  • 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.
  • 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.
  • 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.
  • an influenza virus [envelope virus having (single-stranded RNA as a genome) is included in the alkyl gallate as an effective component.
  • HSV_ 1 envelope virus with DNA as a genome
  • VSV vesicular stomatitis virus
  • 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.
  • 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 au
  • the antibacterial and antiviral agents can also be applied in the form of functional foods for preventing bacterial and viral infections.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition of the present invention has a feature that its effect can be enhanced by the addition of an ionic component.
  • ionic components can be called “action-enhancing ionic components”.
  • 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.
  • 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.
  • 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.
  • 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).
  • HSV-1 herpes simplex virus type 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.
  • 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 ⁇ g / ml octyl gallate.
  • 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 ⁇ g / ml.
  • 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.
  • M 0 1 multiplicity of infection
  • 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.
  • 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.
  • HEV-2 monolayer culture cells 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 ⁇ ) 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.
  • MEM serum albumin
  • FIG. 5 shows the results as the degree of carbon number of the alkyl chain of the alkyl gallate.
  • 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.
  • HEp_2 monolayer cultured cells black circles and black triangles in the figure
  • uninfected cells white circles and white triangles in the figure
  • HSV-1 infected with HSV-1 at a rate of 14 PFU per cell.
  • ⁇ 37 ° 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)
  • 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.
  • 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.
  • FIG. 7 illustrates the result
  • 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.
  • VSV vesicular stomatitis virus
  • 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.
  • VS V vesicular stomatitis virus
  • 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.
  • 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.
  • MDCK cells Mesh-Darby canine kidney cells
  • H influenza virus A / HongKong / l / 68
  • FIG. 10 illustrates the result
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • octyl gallate such as octyl gallate
  • gums such as nonyl gallate, decyl gallate, undecyl gallate
  • dodecyl gallate per lg gum is obtained.
  • 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.
  • MIC minimum inhibitory concentration
  • 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.
  • MHA Mueller-Hinton II Agar
  • 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.
  • 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.
  • Enterococcus faeca / is ATCC21212 250 250 250 250 Staphylococcus epideraidis I F03762 250 62.5 250
  • 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.
  • 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 ⁇ .
  • 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.
  • Octyl gallate 0.lmg / ml to 0.5g / ml, ethanol 0 to 82vol% povidone node 0 ⁇ 01 to l% (w / v)
  • Octyl gallate 0. lmg / ml to 0.5g / ml, ethanol 0 to 82vol% Benzalkonium chloride 1-1 OwZv% (Disinfectant 6)
  • 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.
  • 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.

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle composition médicamenteuse caractérisée en ce qu’elle contient, en tant que principe actif antiviral ou anti-inflammatoire, un dérivé du phénol représenté par la formule (1) (où R4 est un substituant représenté par un quelconque élément parmi R, COOR, COOH, OCOR, OR, R0OR, SR et N(R,R); R1, R2, et R3 sont identiques ou différents et chacun représente hydrogène ou un substituant représenté par un quelconque élément parmi OH, OR, OCOR et COR; R représente un groupe de chaînes hydrocarbonées facultativement substitué ou un groupe hydrocarboné cyclique facultativement substitué dans lequel le cycle peut être composé d’atomes comprenant un hétéroatome; et R0 représente une chaîne hydrocarbonée) ou un sel pharmacologiquement acceptable dudit dérivé. La composition médicamenteuse selon l’invention présente peu d’effets indésirables, possède une activité contre de nouveaux virus ainsi qu’une activité inflammatoire dans la stomatite, les plaies, les brûlures, etc.
PCT/JP2006/315843 2006-01-11 2006-08-10 Composition medicamenteuse antivirale/anti-inflammatoire WO2007080669A1 (fr)

Applications Claiming Priority (2)

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JP2006004252A JP2006306836A (ja) 2005-01-11 2006-01-11 抗ウイルス・抗炎症作用薬剤組成物
JP2006-004252 2006-01-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010067869A1 (fr) * 2008-12-12 2010-06-17 国立大学法人広島大学 Agent antiviral et composition antivirale
WO2019087884A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition, composition antibactérienne, composition antivirale, composition anti-norovirus, vaporisateur, et lingette
WO2019087888A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition, composition antimicrobienne, composition antivirale, composition anti-norovirus, pulvérisation et lingette
WO2019087881A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition antivirale, composition anti-norovirus, vaporisateur, et lingette
EP4104829A1 (fr) * 2021-06-17 2022-12-21 Consejo Superior de Investigaciones Científicas (CSIC) Gallate de lauryle à utiliser en tant qu'agent antiviral

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010067869A1 (fr) * 2008-12-12 2010-06-17 国立大学法人広島大学 Agent antiviral et composition antivirale
WO2019087884A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition, composition antibactérienne, composition antivirale, composition anti-norovirus, vaporisateur, et lingette
WO2019087888A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition, composition antimicrobienne, composition antivirale, composition anti-norovirus, pulvérisation et lingette
WO2019087881A1 (fr) * 2017-10-31 2019-05-09 富士フイルム株式会社 Composition antivirale, composition anti-norovirus, vaporisateur, et lingette
JPWO2019087884A1 (ja) * 2017-10-31 2020-11-19 富士フイルム株式会社 組成物、抗菌組成物、抗ウイルス用組成物、抗ノロウイルス用組成物、スプレー、ワイパー
EP4104829A1 (fr) * 2021-06-17 2022-12-21 Consejo Superior de Investigaciones Científicas (CSIC) Gallate de lauryle à utiliser en tant qu'agent antiviral

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