WO2010061497A1 - Anti-influenza virus agent - Google Patents

Anti-influenza virus agent Download PDF

Info

Publication number
WO2010061497A1
WO2010061497A1 PCT/JP2009/003937 JP2009003937W WO2010061497A1 WO 2010061497 A1 WO2010061497 A1 WO 2010061497A1 JP 2009003937 W JP2009003937 W JP 2009003937W WO 2010061497 A1 WO2010061497 A1 WO 2010061497A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen atom
group
hydroxy group
influenza virus
lower alkoxy
Prior art date
Application number
PCT/JP2009/003937
Other languages
French (fr)
Japanese (ja)
Inventor
憲 安川
昌彦 黒川
寛美 清水
理英 澤村
Original Assignee
学校法人日本大学
学校法人高梁学園
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人日本大学, 学校法人高梁学園 filed Critical 学校法人日本大学
Priority to JP2010540295A priority Critical patent/JPWO2010061497A1/en
Publication of WO2010061497A1 publication Critical patent/WO2010061497A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/26—Polyhydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C49/217—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
    • C07C49/248—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to an anti-influenza virus agent, particularly an anti-influenza virus agent containing a plant-derived component as an active ingredient.
  • Influenza is a type of acute infection caused by influenza virus, and when it develops, it causes high fever, muscle pain, etc., and symptoms similar to those of a cold may occur. In rare cases, death may occur due to acute encephalopathy or secondary infection. It is one of the most important diseases in medicine because of its epidemic nature.
  • anti-influenza drugs As anti-influenza drugs, anti-influenza virus agents that suppress the growth of influenza virus are effective, and three types of amantadine, zanamivir, and oseltamivir are currently in practical use. However, there are problems such as the appearance of drug-resistant viruses and side effects.
  • Ryokyo a herbal medicine derived from the rhizome of Ginger family Ryokyo, has long been known to have antiemetic effects.
  • Ryokyo contains 1,8-cineole, methyl cinnamate, eugenol, pinene, and kadinene as essential oil components, and is known to contain galangol as a pungent component.
  • Ryoko has been reported to have an antiviral effect (Patent Document 1), but herpes virus, poliovirus, blister virus and the like are described as the target virus, but it is effective against influenza virus. There is no description of whether or not.
  • An object of the present invention is to search for a new anti-influenza virus agent from plant-derived components.
  • the present invention has the general formula (1)
  • X represents C ⁇ O or CH—OH
  • R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group
  • R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group.
  • a broken line indicates that the bond may be a double bond
  • the anti-influenza virus agent which uses the diphenyl heptanoid represented by these as an active ingredient is provided.
  • the present invention also provides a composition for preventing and / or treating influenza comprising a diphenylheptanoid represented by formula (1) and a pharmaceutically acceptable carrier.
  • the present invention also provides use of diphenylheptanoid represented by the formula (1) for producing an anti-influenza virus agent.
  • this invention provides the prevention and / or treatment method of influenza which administers the effective amount of the diphenylheptanoid represented by Formula (1).
  • the present invention also provides a diphenylheptanoid represented by the formula (1) for preventing and / or treating influenza.
  • the anti-influenza virus agent of the present invention strongly suppresses the growth of influenza viruses, particularly type A viruses, it is useful for the prevention and treatment of influenza.
  • the compound of formula (1) which is an active ingredient of the anti-influenza virus agent of the present invention, does not show an inhibitory action against herpes simplex virus type 1. The usefulness of the compound (1) as an excellent anti-influenza virus agent was completely unexpected from the action of Ryoko itself.
  • the active ingredient of the anti-influenza virus agent of the present invention is a compound represented by the general formula (1).
  • X represents C ⁇ O or CH—OH.
  • R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group.
  • the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group, and among these, a methoxy group is particularly preferable.
  • R 2 to R 4 are the same or different and each represents a hydrogen atom, a hydroxy group or a lower alkoxy group.
  • the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group, and among these, a methoxy group is particularly preferable.
  • R 2 is particularly preferably a hydrogen atom.
  • R 3 is particularly preferably a hydrogen atom or a hydroxy group.
  • R 4 is particularly preferably a hydrogen atom or a methoxy group.
  • R 1 is preferably a hydrogen atom.
  • the compound of formula (1) may be a mixture of optically active substances or an optically active substance.
  • preferred compounds are the compounds of the following formulas (1a) to (1l), of which the formulas (1a), (1b), (1f), (1g), (1h) ), (1i), (1j), (1k) and (1l) are preferred, and compounds of formula (1b), (1g), (1h), (1i) and (1l) are particularly preferred.
  • the compound represented by the general formula (1) is extracted from, for example, Ryokyo or by chemical synthesis (Jacobs, PM, and Soroway, AH, Synthesis of 3,5-dialkyl-1, 2-dioxolanes, J. Org. Chem., 39 (23), 3427-3429).
  • the extraction solvent include lower alcohols such as methanol, ethanol, n-propanol, isopropanol, and aqueous media and ethers thereof. These may be used alone or in combination. Preferred is methanol, ethanol or ether. Ethyl acetate and acetone are also preferable extraction solvents.
  • the compound according to the present invention can be obtained by separation and purification from the above extract.
  • the compound of the general formula (1) has an excellent growth inhibitory activity against influenza virus. Moreover, there is a large difference between the anti-influenza virus action and cytotoxicity of the compound of general formula (1), and the compound of general formula (1) is also highly safe. Therefore, the compound of the general formula (1) or the Ryokyo extract containing these compounds is useful as an influenza preventive / therapeutic agent for mammals including humans and a composition for preventing or treating influenza.
  • influenza virus targeted for the anti-influenza virus agent and influenza preventive / treating composition of the present invention includes both types A and B, and is particularly useful against influenza virus type A.
  • an influenza preventive / therapeutic agent or influenza preventive / therapeutic composition When an influenza preventive / therapeutic agent or influenza preventive / therapeutic composition is used, the compound of formula (1) or the above extract is mixed with an excipient, a binder, a lubricant, a disintegrant, a coating agent, an emulsifier, a suspension.
  • One or more pharmaceutically acceptable carriers such as turbidizers, solvents, stabilizers, absorption aids, ointment bases, thickeners, surfactants, preservatives, dyes, fragrances and the like are added as appropriate.
  • a preparation for oral administration a dosage form of a preparation for parenteral administration such as injection administration, rectal administration, external use, intranasal administration, gargle and the like can be obtained.
  • Preparations for oral administration include granules, tablets, dragees, capsules, pills, liquids, emulsions, suspensions, etc .; preparations for injection administration include intravenous injection, intramuscular injection, subcutaneous injection, infusion Preparations for injection and the like; As preparations for rectal administration, suppository soft capsules and the like are preferable.
  • preparations for external use liquids, gels, creams, ointments, lotions and the like; as preparations for intranasal administration, nasal drops, nasal cleansing agents and the like; Oropharyngeal agents, gargles and the like are preferred.
  • the preparation for intranasal administration or gargle is preferably used, for example, in the form of a solution, granule, powder, etc., diluted or dissolved as appropriate at the time of use.
  • the anti-influenza virus agent and the composition for preventing / treating influenza of the present invention can be administered to mammals including humans as a preparation as described above.
  • the anti-influenza virus agent and the composition for preventing / treating influenza of the present invention are preferably administered as the compound of the formula (1) at about 1 to 500 mg / kg once to 4 times per day.
  • the content of the compound of the formula (1) in the preparation It is preferably used in an amount of 001 to 5% by mass, preferably 0.001 to 1% by mass, divided into 1 to several times a day.
  • composition for preventing / treating influenza can be used as food, feed and cosmetics.
  • the form is not particularly limited and may be, for example, solid, semi-solid, gel or liquid.
  • beverages such as tea, jelly, candy, chocolate, chewing gum, etc. can be mentioned.
  • tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule It may be a form or the like.
  • feed include forms such as mash, pellets, and flakes, and can be used for livestock, poultry, small animals, and the like.
  • cosmetics can be used as external preparations for skin, cleaning agents, etc., and can be provided in various dosage forms such as lotions, emulsions, gels, creams, solids, powders, granules, etc., depending on the method of use. .
  • the content of the compound of formula (1) or the extract in the composition for preventing or treating influenza varies depending on the form, use, etc., but is generally 0.001 to 5% by mass, particularly 0.001 to 1% by mass. Is preferred.
  • Example 1 Hereinafter, an example of a method for separating and purifying various diphenylheptanoid compounds from Ryoko will be described with reference to FIG.
  • the methanol extract of Ryokyo was first subjected to solvent fractionation with ethyl acetate-water (1: 1) to obtain an ethyl acetate fraction (collected amount: 25.7 g) and an aqueous layer.
  • Fractions were fractionated (fractions 4-1 to 4-10).
  • Fr. 4-3 (recovery amount: 52.3 mg) was obtained by fractionating 5 into fractions (fraction 4-3-1) using silica gel-CC [silica gel use amount: 100 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. Fractionated to 4-3-5). Fr. 4-3-4 (recovered amount: 44.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5S) -1,7-diphenyl-5-methoxy-3-heptanone (compound 1i; recovered amount: 42 mg). )
  • Fr. 4-5 (recovered amount: 62 mg) was obtained by fractionating 5 (fractions 4-5-1 to 4-4) with silica gel-CC [silica gel use amount: 100 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. -5-5).
  • Fr. 4-5-4 (Recovery amount: 41 mg) was obtained by repeating preparative ODS-HPLC to give 7- (4 ′′ -hydroxy-3 ′′ -methoxyphenyl) -1-phenyl-4E-hepten-3-one ( Compound 1b; recovery amount: 36 mg) was obtained.
  • Fr. 4-7 (recovered amount: 313 mg) was obtained by adding 3 fractions (fractions 4-7-1 to 4) to silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. It was fractionated into -7-3).
  • Fr. 4-7-2 (recovery amount: 275 mg) was obtained by repeating preparative ODS-HPLC to obtain (5R) -7- (4 ′′ -hydroxy-3 ′′ -methoxyphenyl) -5-methoxy-1-phenyl- 3-Heptanone (Compound 1c; recovery amount: 270 mg) was obtained.
  • Fr. 4-8 (recovered amount: 112 mg) was obtained by fractionating 5 into fractions (fractions 4-8-1 to 4-4) using silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. It was fractionated into -8-5).
  • Fr. 4-8-2 (recovery amount: 100.8 mg) was obtained by repeating preparative ODS-HPLC to give 5-hydroxy-7- (4 ′′ -hydroxy-3 ′′ -methoxyphenyl) -1-phenyl-3- Heptanone (Compound 1a; recovery amount: 97 mg) was obtained.
  • Fr. 4-9 (recovered amount: 331 mg) was obtained by adding 6 fractions (fractions 4-9-1 to 4) to silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (3: 1)]. -9-6).
  • Fr. 4-9-2 (recovered amount: 170.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5R) -1,7-diphenyl-5-hydroxy-3-heptanone (compound 1f; recovered amount: 155 0.6 mg) was obtained. Next, Fr.
  • Fr. 4-10 (recovered amount: 398 mg) was obtained from 8 fractions (fractions 4-10-1 to 4) by silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (3: 1)]. Fractionated to -10-8). Fractionated to -10-8). Fractionated to -10-2). Fr. 4-10-2 (recovery amount: 17.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5S) -7- (4 ′′ -hydroxyphenyl) -5-methoxy-1-phenyl-3-heptanone.
  • Example 2 (anti-influenza virus activity) (Method) (1) Inhibition of influenza virus growth
  • MTT 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide
  • MEM medium containing 0.1% bovine albumin serum
  • final concentration of DMSO was 0.5% or less, and was a concentration that did not cause toxicity to cells.
  • Influenza virus (A / H1N1 / PR8 / 34 strain) was diluted with a phosphate buffer solution containing 1% bovine albumin serum and used as a virus solution.
  • MDCK canine kidney cell-derived cells were used as the cells.
  • MEM medium MEM medium containing 10% fetal bovine serum
  • each of the maintenance media was added at 50 ⁇ l / well in the presence or absence of diallyl heptanoids diluted at each concentration (virus infection control) and cultured at 37 ° C. After 4 days, 10 ⁇ l / well of MTT-phosphate buffer solution (7.5 mg / mL) was added and incubated at 37 ° C. After 4 hours, 100 ⁇ l / well of a 20% sodium dodecyl sulfate / 50% N, N-dimethylformamide mixture was added, and the absorbance at 540 nm was measured.
  • the compound of the formula (1) has an excellent influenza virus growth inhibitory action and has low cytotoxicity.
  • Example 3 Compounds (1b) and (1h) were examined for anti-herpesvirus activity.
  • Method (1) Inhibition of herpesvirus growth Evaluation was made using the plaque reduction method. Details are described below. After diallyl heptanoids are dissolved in DMSO, they are added to a methylcellulose-containing maintenance medium (2% bovine serum-containing MEM medium), and the final concentration (1b) is 0.1, 1, 3, 10, 30 ⁇ g / mL, (1 h ) Was 0.1, 1, 3, 10, 50, 80 ⁇ g / mL. The final concentration of DMSO was set to 0.1% or less so as not to cause toxicity to cells.
  • a methylcellulose-containing maintenance medium 2% bovine serum-containing MEM medium
  • herpes simplex virus type 1 7401H strain
  • Vero African green monkey kidney-derived cells
  • Vero African green monkey kidney-derived cells
  • 5 ⁇ 10 5 Vero cells / dish were cultured in a growth medium (MEM medium containing 8% bovine serum) in a 60 mm dish. After 4 days of culture, the growth medium was removed, the cells were washed with a phosphate buffer solution, and 200 ⁇ l of virus solution (corresponding to 100 pfu / dish) was added to each dish and incubated at 37 ° C.
  • the cells were washed with a phosphate buffer solution, each containing 5 mL / dish of methylcellulose-containing maintenance medium in the presence or absence of diallyl heptanoids diluted at each concentration (virus infection control).
  • the cells were cultured at 37 ° C. After 4 days, 5 mL of 5% formalin solution was added to fix the cells. After standing overnight, the formalin solution was washed off, and 0.03% methylene blue staining solution was added to each 5 mL / dish for staining. The staining solution was washed away, air-dried, and plaques were counted. (2) Cytotoxicity Cytotoxicity was evaluated visually. Details are described below.
  • Example 4 Compound (1b) was examined for anti-influenza virus activity against influenza virus-infected mice.
  • (Method) (1) Body weight change and survival days of influenza virus infected mice Compound (1b) was dissolved in dimethyl sulfoxide (DMSO) and then diluted by adding purified water for injection, final concentrations of 30 mg / 0.2 mL, 100 mg / 0.2 mL It was. The final concentration of DMSO was set to 1% or less so as not to cause toxicity to mice.
  • Influenza virus (A / H1N1 / PR8 / 34 strain) was diluted with a phosphate buffer solution and used as a virus solution (500 PFU). As the mice, female BALB / cN mice (6 weeks old, 20-22 g) were used.
  • Influenza virus infection in mice was performed by injecting the virus solution nasally into mice under anesthesia.
  • the compound (1b) diluted to each concentration was orally administered once every 4 hours before the infection day (Day 0), once within 2 hours after the infection, and once after another 4 hours.
  • administration was performed 3 times a day until 5 days after infection.
  • the non-administration group was administered to mice using purified water for injection in the same manner as the administration group. Body weight was measured every morning before administration until 8 days after infection. In addition, the number of surviving virus-infected mice was counted after 5, 6, 7, 9, and 11 days after infection.
  • mice Three to six days after virus infection (Days 3 and 6), the lungs of the mice were washed with a phosphate buffer solution, and the virus titer of influenza virus contained in the lung washings was evaluated.
  • the virus titer was evaluated using the plaque reduction method. Details are described below.
  • MDCK cells of 2 ⁇ 10 5 cells / dish in a 60 mm dish were cultured in a growth medium (MEM medium containing 10% fetal bovine serum). After 4 days of culture, the growth medium was removed, the cells were washed with a phosphate buffer solution, diluted with a phosphate buffer solution containing 1% bovine albumin serum, and 200 ⁇ l of a lung wash solution serially diluted to 10 7 times in each dish.
  • MEM medium containing 10% fetal bovine serum

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Disclosed is a novel anti-influenza virus agent comprising a diphenylheptanoid represented by general formula (1) [wherein X represents C=O or CH-OH; R1 represents a hydrogen atom, a hydroxy group, or a lower alkoxy group; R2 to R4 independently represent a hydrogen atom, a hydroxy group, or a lower alkoxy group; and the dashed line means that the bond may be a double bond] as an active ingredient.

Description

抗インフルエンザウイルス剤Anti-influenza virus agent
　本発明は、抗インフルエンザウイルス剤、特に植物由来の成分を有効成分とする抗インフルエンザウイルス剤に関する。 The present invention relates to an anti-influenza virus agent, particularly an anti-influenza virus agent containing a plant-derived component as an active ingredient.
　インフルエンザは、インフルエンザウイルスによる急性感染症の一種であり、発症すると高熱、筋肉痛などを伴い風邪と同様な症状があらわれ、まれに急性脳症や二次感染により死亡することもある。流行性であることから、被害が大きく、医学上最も重要視されている疾患の一つである。 Influenza is a type of acute infection caused by influenza virus, and when it develops, it causes high fever, muscle pain, etc., and symptoms similar to those of a cold may occur. In rare cases, death may occur due to acute encephalopathy or secondary infection. It is one of the most important diseases in medicine because of its epidemic nature.
　インフルエンザの治療薬としては、インフルエンザウイルスの増殖を抑制する、抗インフルエンザウイルス剤が有効であり、現在、アマンタジン、ザナミビル、オセルタミビルの３種類が実用化されている。しかし、すでに薬剤耐性ウイルスが発現する、副作用がある等の問題がある。 As anti-influenza drugs, anti-influenza virus agents that suppress the growth of influenza virus are effective, and three types of amantadine, zanamivir, and oseltamivir are currently in practical use. However, there are problems such as the appearance of drug-resistant viruses and side effects.
　一方、植物は古来より医薬品資源として注目されており、これまでにも様々な医薬品あるいは医薬品素材が植物中から見出されている。ショウガ科コウリョウキョウの根茎由来の生薬である良姜（リョウキョウ）には、古くから鎮吐作用があることが知られている。また、リョウキョウには、精油成分として１，８－シネオール、メチルシンナメート、オイゲノール、ピネン、カディネンなどが含まれており、また辛味成分としてガランゴールなどが含まれていることが知られている。またリョウキョウには、抗ウイルス作用を有することが報告されている（特許文献１）が、その対象となるウイルスとしてヘルペスウイルス、ポリオウイルス、水疱ウイルス等が記載されているが、インフルエンザウイルスに有効か否かの記載はない。 On the other hand, plants have attracted attention as a pharmaceutical resource since ancient times, and various pharmaceuticals or pharmaceutical materials have been found in plants. Ryokyo, a herbal medicine derived from the rhizome of Ginger family Ryokyo, has long been known to have antiemetic effects. In addition, Ryokyo contains 1,8-cineole, methyl cinnamate, eugenol, pinene, and kadinene as essential oil components, and is known to contain galangol as a pungent component. . In addition, Ryoko has been reported to have an antiviral effect (Patent Document 1), but herpes virus, poliovirus, blister virus and the like are described as the target virus, but it is effective against influenza virus. There is no description of whether or not.
特開平６－２５００３号公報Japanese Patent Laid-Open No. 6-25003
　本発明の課題は、植物由来成分から新たな抗インフルエンザウイルス剤を探索することにある。 An object of the present invention is to search for a new anti-influenza virus agent from plant-derived components.
　そこで本発明者は、リョウキョウの抽出物及びその類縁体を対象として抗インフルエンザウイルス活性を指標にスクリーニングしたところ、後記式（１）で表されるジフェニルヘプタノイド類がヘルペスウイルスに対して全く作用しないにもかかわらず、インフルエンザウイルスに対しては強力な増殖抑制作用を有し、かつ細胞毒性が低いことから抗インフルエンザウイルス剤として有用であることを見出し、本発明を完成した。 Therefore, when the present inventor screened Ryokyo extract and its analogs using anti-influenza virus activity as an index, diphenylheptanoids represented by the following formula (1) have no effect on herpes virus. In spite of this, the present inventors have found that it is useful as an anti-influenza virus agent because it has a strong growth inhibitory action against influenza virus and has low cytotoxicity, and has completed the present invention.
　すなわち、本発明は、一般式（１） That is, the present invention has the general formula (1)
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
（式中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示し；Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ｒ２～Ｒ４は同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示し；破線部は、当該結合が二重結合であってもよいことを示す）
で表されるジフェニルヘプタノイドを有効成分とする抗インフルエンザウイルス剤を提供するものである。
　また、本発明は、式（１）で表されるジフェニルヘプタノイド、並びに薬学的に許容される担体を含有してなるインフルエンザの予防及び／又は治療用組成物を提供するものである。
　また、本発明は、式（１）で表されるジフェニルヘプタノイドの抗インフルエンザウイルス剤製造のための使用を提供するものである。
　また、本発明は、式（１）で表されるジフェニルヘプタノイドの有効量を投与するインフルエンザの予防及び／又は治療方法を提供するものである。
　また、本発明はインフルエンザの予防及び／又は治療のための式（１）で表されるジフェニルヘプタノイドを提供するものである。 Wherein X represents C═O or CH—OH; R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group; R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group. A broken line indicates that the bond may be a double bond)
The anti-influenza virus agent which uses the diphenyl heptanoid represented by these as an active ingredient is provided.
The present invention also provides a composition for preventing and / or treating influenza comprising a diphenylheptanoid represented by formula (1) and a pharmaceutically acceptable carrier.
The present invention also provides use of diphenylheptanoid represented by the formula (1) for producing an anti-influenza virus agent.
Moreover, this invention provides the prevention and / or treatment method of influenza which administers the effective amount of the diphenylheptanoid represented by Formula (1).
The present invention also provides a diphenylheptanoid represented by the formula (1) for preventing and / or treating influenza.
　本発明の抗インフルエンザウイルス剤は、インフルエンザウイルス、特にＡ型ウイルスの増殖を強く抑制するので、インフルエンザの予防・治療に有用である。また、リョウキョウ自体に抗ヘルペスウイルス作用はあるが、本発明の抗インフルエンザウイルス剤の有効成分である式（１）の化合物は単純ヘルペスウイルス１型に対する抑制作用を示さないことから、式（１）の化合物が優れた抗インフルエンザウイルス剤として有用であることは、リョウキョウ自体の作用からは全く予想外であった。 Since the anti-influenza virus agent of the present invention strongly suppresses the growth of influenza viruses, particularly type A viruses, it is useful for the prevention and treatment of influenza. In addition, although Ryokyo itself has an anti-herpesvirus action, the compound of formula (1), which is an active ingredient of the anti-influenza virus agent of the present invention, does not show an inhibitory action against herpes simplex virus type 1. The usefulness of the compound (1) as an excellent anti-influenza virus agent was completely unexpected from the action of Ryoko itself.
本発明化合物の抽出方法の概略を示す図である。It is a figure which shows the outline of the extraction method of this invention compound. インフルエンザウイルス感染マウスの体重変化に対する化合物（１ｂ)の影響を示す図である。It is a figure which shows the influence of the compound (1b) with respect to the body weight change of an influenza virus infection mouse | mouth. インフルエンザウイルス感染マウスの生存日数に対する化合物（１ｂ)の影響を示す図である。It is a figure which shows the influence of the compound (1b) with respect to the survival days of an influenza virus infection mouse | mouth.
　本発明の抗インフルエンザウイルス剤の有効成分は、前記一般式（１）で表される化合物である。式（１）中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示す。Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示す。ここで低級アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基等の炭素数１～６のアルコキシ基が挙げられ、このうちメトキシ基が特に好ましい。 The active ingredient of the anti-influenza virus agent of the present invention is a compound represented by the general formula (1). In the formula (1), X represents C═O or CH—OH. R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group. Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group, and among these, a methoxy group is particularly preferable.
　Ｒ２～Ｒ４は、同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示す。ここで低級アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基等の炭素数１～６のアルコキシ基が挙げられ、このうちメトキシ基が特に好ましい。またＲ２としては水素原子が特に好ましい。Ｒ３としては水素原子又はヒドロキシ基が特に好ましい。Ｒ４としては水素原子又はメトキシ基が特に好ましい。 R 2 to R 4 are the same or different and each represents a hydrogen atom, a hydroxy group or a lower alkoxy group. Examples of the lower alkoxy group include alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group, and among these, a methoxy group is particularly preferable. R 2 is particularly preferably a hydrogen atom. R 3 is particularly preferably a hydrogen atom or a hydroxy group. R 4 is particularly preferably a hydrogen atom or a methoxy group.
　式（１）中の破線部は、当該結合が二重結合であってもよいことを示す。この結合が二重結合であるとき、Ｒ１は水素原子であるのが好ましい。 The broken line part in Formula (1) shows that the said bond may be a double bond. When this bond is a double bond, R 1 is preferably a hydrogen atom.
　一般式（１）の化合物には不斉炭素原子が存在する場合がある。その場合には、式（１）の化合物は、光学活性体の混合物であってもよく、光学活性体であってもよい。 There may be an asymmetric carbon atom in the compound of the general formula (1). In that case, the compound of formula (1) may be a mixture of optically active substances or an optically active substance.
　一般式（１）の化合物のうち、好ましい化合物は次の式（１ａ）～（１ｌ）の化合物であり、このうちさらに式（１ａ）、（１ｂ）、（１ｆ）、（１ｇ）、（１ｈ）、（１ｉ）、（１ｊ）、（１ｋ）及び（１ｌ）の化合物が好ましく、特に式（１ｂ）、（１ｇ）、（１ｈ）、（１ｉ）及び（１ｌ）の化合物が好ましい。 Among the compounds of the general formula (1), preferred compounds are the compounds of the following formulas (1a) to (1l), of which the formulas (1a), (1b), (1f), (1g), (1h) ), (1i), (1j), (1k) and (1l) are preferred, and compounds of formula (1b), (1g), (1h), (1i) and (1l) are particularly preferred.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　一般式（１）で表される化合物は、例えばリョウキョウから抽出することにより、又は化学合成（Ｊａｃｏｂｓ，Ｐ．Ｍ．，ａｎｄ　Ｓｏｌｏｗａｙ，Ａ．Ｈ．，Ｓｙｎｔｈｅｓｉｓ　ｏｆ　３，５－ｄｉａｌｋｙｌ－１，２－ｄｉｏｘｏｌａｎｅｓ，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，３９（２３），３４２７－３４２９）により製造することができる。例えば、抽出溶媒としては、低級アルコール、例えば、メタノール、エタノール、ｎ－プロパノール、イソプロパノール及びこれらの水性媒体やエーテルを挙げることができる。これらは単独で用いても良いし、混合しても良い。好ましくは、メタノール、エタノール又はエーテルである。また、酢酸エチルやアセトンなども好ましい抽出溶媒である。本発明に係る化合物は、上記抽出物から分離精製することで得られる。 The compound represented by the general formula (1) is extracted from, for example, Ryokyo or by chemical synthesis (Jacobs, PM, and Soroway, AH, Synthesis of 3,5-dialkyl-1, 2-dioxolanes, J. Org. Chem., 39 (23), 3427-3429). For example, examples of the extraction solvent include lower alcohols such as methanol, ethanol, n-propanol, isopropanol, and aqueous media and ethers thereof. These may be used alone or in combination. Preferred is methanol, ethanol or ether. Ethyl acetate and acetone are also preferable extraction solvents. The compound according to the present invention can be obtained by separation and purification from the above extract.
　後記実施例から明らかなように、一般式（１）の化合物は、インフルエンザウイルスに対して優れた増殖抑制活性を有する。また、一般式（１）の化合物の抗インフルエンザウイルス作用と細胞毒性との間には大きな差があり、一般式（１）の化合物は安全性も高い。従って、一般式（１）の化合物、あるいはこれらの化合物を含有するリョウキョウ抽出物は、ヒトを含む哺乳動物のインフルエンザ予防・治療薬、インフルエンザ予防・治療用組成物として有用である。 As will be apparent from Examples below, the compound of the general formula (1) has an excellent growth inhibitory activity against influenza virus. Moreover, there is a large difference between the anti-influenza virus action and cytotoxicity of the compound of general formula (1), and the compound of general formula (1) is also highly safe. Therefore, the compound of the general formula (1) or the Ryokyo extract containing these compounds is useful as an influenza preventive / therapeutic agent for mammals including humans and a composition for preventing or treating influenza.
　本発明の抗インフルエンザウイルス剤、インフルエンザ予防・治療用組成物の対象となるインフルエンザウイルスには、Ａ型及びＢ型のいずれも含まれるが、特にインフルエンザウイルスＡ型に対して有用である。 The influenza virus targeted for the anti-influenza virus agent and influenza preventive / treating composition of the present invention includes both types A and B, and is particularly useful against influenza virus type A.
　インフルエンザ予防・治療薬、インフルエンザ予防・治療用組成物とする場合、式（１）の化合物、あるいは前記抽出物に、賦形剤、結合剤、滑沢剤、崩壊剤、被覆剤、乳化剤、懸濁化剤、溶剤、安定化剤、吸収助剤、軟膏基剤、増粘剤、界面活性剤、保存剤、色素、香料等の１以上の薬学的に許容される担体を適宜添加し、常法により経口投与用の製剤；注射投与用、直腸内投与用、外用、鼻腔内投与用、含嗽用等の非経口投与用の製剤の剤形とすることができる。 When an influenza preventive / therapeutic agent or influenza preventive / therapeutic composition is used, the compound of formula (1) or the above extract is mixed with an excipient, a binder, a lubricant, a disintegrant, a coating agent, an emulsifier, a suspension. One or more pharmaceutically acceptable carriers such as turbidizers, solvents, stabilizers, absorption aids, ointment bases, thickeners, surfactants, preservatives, dyes, fragrances and the like are added as appropriate. According to the method, a preparation for oral administration; a dosage form of a preparation for parenteral administration such as injection administration, rectal administration, external use, intranasal administration, gargle and the like can be obtained.
　経口投与用の製剤としては、顆粒、錠剤、糖衣錠、カプセル剤、丸剤、液剤、乳剤、懸濁剤等が；注射投与用の製剤としては、静脈内注射、筋肉内注射、皮下注射、点滴注射用の製剤等が；直腸内投与用の製剤としては、坐薬軟カプセル等が好ましい。 Preparations for oral administration include granules, tablets, dragees, capsules, pills, liquids, emulsions, suspensions, etc .; preparations for injection administration include intravenous injection, intramuscular injection, subcutaneous injection, infusion Preparations for injection and the like; As preparations for rectal administration, suppository soft capsules and the like are preferable.
　また、外用の製剤としては、液剤、ゲル剤、クリーム剤、軟膏剤、ローション剤等が；鼻腔内投与用の製剤としては、点鼻剤、鼻洗浄剤等が；含嗽用の製剤としては、口腔咽頭剤、含嗽剤等が好ましい。鼻腔内投与用又は含嗽用の製剤は、例えば、液剤、顆粒剤、散剤等の形態で、使用時に適宜希釈又は溶解して用いるのが好ましい。 In addition, as preparations for external use, liquids, gels, creams, ointments, lotions and the like; as preparations for intranasal administration, nasal drops, nasal cleansing agents and the like; Oropharyngeal agents, gargles and the like are preferred. The preparation for intranasal administration or gargle is preferably used, for example, in the form of a solution, granule, powder, etc., diluted or dissolved as appropriate at the time of use.
　本発明の抗インフルエンザウイルス剤、インフルエンザ予防・治療用組成物は、上記の如き製剤として、ヒトを含む哺乳動物に投与することができる。 The anti-influenza virus agent and the composition for preventing / treating influenza of the present invention can be administered to mammals including humans as a preparation as described above.
　本発明の抗インフルエンザウイルス剤、インフルエンザ予防・治療用組成物は、式（１）の化合物として、１日当り約１～５００ｍｇ／ｋｇを１～４回投与するのが好ましい。
　また、本発明の抗インフルエンザウイルス剤、インフルエンザ予防・治療用組成物を外用、鼻腔内投与用又は含嗽用の製剤とする場合、該製剤中の式（１）の化合物の含有量を、０．００１～５質量％、好ましくは０．００１～１質量％として、一日１～数回に分けて使用するのが好ましい。 The anti-influenza virus agent and the composition for preventing / treating influenza of the present invention are preferably administered as the compound of the formula (1) at about 1 to 500 mg / kg once to 4 times per day.
In addition, when the anti-influenza virus agent and influenza prevention / treatment composition of the present invention is used as a preparation for external use, intranasal administration or gargle, the content of the compound of the formula (1) in the preparation It is preferably used in an amount of 001 to 5% by mass, preferably 0.001 to 1% by mass, divided into 1 to several times a day.

　また、インフルエンザ予防・治療用組成物は、食品、飼料、化粧料としても使用できる。その形態は、特に制限されず、例えば固形、半固形、ゲル状又は液状等であり得る。例えば、食品では、茶等の飲料、ゼリー、あめ、チョコレート、チューインガム等の形態が挙げられ、上記の製剤と同様、錠剤形態、丸剤形態、カプセル形態、液剤形態、シロップ形態、粉末形態、顆粒形態等であってもよい。飼料では、マッシュ、ペレット、フレーク等の形態が挙げられ、家畜、家禽、小動物等に用いることができる。また、化粧料では、皮膚外用剤、洗浄剤等とすることができ、使用方法に応じて、ローション、乳液、ゲル、クリーム、固形、粉末、顆粒等の種々の剤形で提供することができる。　
In addition, the composition for preventing / treating influenza can be used as food, feed and cosmetics. The form is not particularly limited and may be, for example, solid, semi-solid, gel or liquid. For example, in the case of food, beverages such as tea, jelly, candy, chocolate, chewing gum, etc. can be mentioned. As with the above preparation, tablet form, pill form, capsule form, liquid form, syrup form, powder form, granule It may be a form or the like. Examples of feed include forms such as mash, pellets, and flakes, and can be used for livestock, poultry, small animals, and the like. In addition, cosmetics can be used as external preparations for skin, cleaning agents, etc., and can be provided in various dosage forms such as lotions, emulsions, gels, creams, solids, powders, granules, etc., depending on the method of use. .
　インフルエンザ予防・治療用組成物における式（１）の化合物、あるいは前記抽出物の含有量は、形態、用途等によっても異なるが、一般に０．００１～５質量％、特に０．００１～１質量％が好ましい。 The content of the compound of formula (1) or the extract in the composition for preventing or treating influenza varies depending on the form, use, etc., but is generally 0.001 to 5% by mass, particularly 0.001 to 1% by mass. Is preferred.
　次に実施例を挙げて、本発明をさらに詳細に説明するが、本発明はこれら実施例に何ら限定されるものではない。 Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
実施例１
　以下、リョウキョウから各種のジフェニルヘプタノイド類化合物を分離精製する方法の一例を、図１を用いて説明する。 Example 1
Hereinafter, an example of a method for separating and purifying various diphenylheptanoid compounds from Ryoko will be described with reference to FIG.
　リョウキョウのメタノール抽出エキスは、先ず酢酸エチル－水（１：１）で溶媒分画を行い、酢酸エチル画分（回収量：２５．７ｇ）と水層を得た。 The methanol extract of Ryokyo was first subjected to solvent fractionation with ethyl acetate-water (1: 1) to obtain an ethyl acetate fraction (collected amount: 25.7 g) and an aqueous layer.
　次に酢酸エチル画分について、Ｓｅｐｈａｄｅｘ　ＬＨ－２０－カラムクロマトグラフィー（以下、カラムクロマトグラフィーを「ＣＣ」と略す。）［Ｓｅｐｈａｄｅｘ　ＬＨ－２０使用量：１２０ｇ、溶出液：クロロホルム－メタノール（１：１）］により７の画分（フラクション１～７）に分画した。 Next, for the ethyl acetate fraction, Sephadex LH-20-column chromatography (hereinafter, column chromatography is abbreviated as “CC”) [Sephadex LH-20 usage: 120 g, eluent: chloroform-methanol (1: 1 )] Was fractionated into 7 fractions (fractions 1 to 7).
　上記画分のうちフラクション（以下、「Ｆｒ．」と略す。）４（回収量：１．５ｇ）はシリカゲル－ＣＣ（シリカゲル使用量：３００ｇ、溶出溶媒：クロロホルム－メタノール）により、１０の画分（フラクション４－１～４－１０）に分画した。 Among the above fractions, the fraction (hereinafter abbreviated as “Fr.”) 4 (recovered amount: 1.5 g) was separated into 10 fractions by silica gel-CC (silica gel use amount: 300 g, elution solvent: chloroform-methanol). Fractions were fractionated (fractions 4-1 to 4-10).
　Ｆｒ．４－３（回収量：５２．３ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：１００ｇ、溶出溶媒：ｎ－ヘキサン―酢酸エチル（４：１）］により、５の画分（フラクション４－３－１～４－３－５）に分画した。Ｆｒ．４－３－４（回収量：４４．３ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（５Ｓ）－１，７－ジフェニル－５－メトキシ－３－ヘプタノン（化合物１ｉ；回収量：４２ｍｇ）を得た。 Fr. 4-3 (recovery amount: 52.3 mg) was obtained by fractionating 5 into fractions (fraction 4-3-1) using silica gel-CC [silica gel use amount: 100 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. Fractionated to 4-3-5). Fr. 4-3-4 (recovered amount: 44.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5S) -1,7-diphenyl-5-methoxy-3-heptanone (compound 1i; recovered amount: 42 mg). )
　Ｆｒ．４－５（回収量：６２ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：１００ｇ、溶出溶媒：ｎ－ヘキサン－酢酸エチル（４：１）］により、５の画分（フラクション４－５－１～４－５－５）に分画した。一方、Ｆｒ．４－５－４（回収量：４１ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、７－（４”－ヒドロキシ－３”－メトキシフェニル）－１－フェニル－４Ｅ－ヘプテン－３－オン（化合物１ｂ；回収量：３６ｍｇ）を得た。 Fr. 4-5 (recovered amount: 62 mg) was obtained by fractionating 5 (fractions 4-5-1 to 4-4) with silica gel-CC [silica gel use amount: 100 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. -5-5). On the other hand, Fr. 4-5-4 (Recovery amount: 41 mg) was obtained by repeating preparative ODS-HPLC to give 7- (4 ″ -hydroxy-3 ″ -methoxyphenyl) -1-phenyl-4E-hepten-3-one ( Compound 1b; recovery amount: 36 mg) was obtained.
　Ｆｒ．４－７（回収量：３１３ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：２００ｇ、溶出溶媒：ｎ－ヘキサン－酢酸エチル（４：１）］により、３の画分（フラクション４－７－１～４－７－３）に分画した。Ｆｒ．４－７－２（回収量：２７５ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（５Ｒ）－７－（４”－ヒドロキシ－３”－メトキシフェニル）－５－メトキシ－１－フェニル－３－ヘプタノン（化合物１ｃ；回収量：２７０ｍｇ）を得た。 Fr. 4-7 (recovered amount: 313 mg) was obtained by adding 3 fractions (fractions 4-7-1 to 4) to silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. It was fractionated into -7-3). Fr. 4-7-2 (recovery amount: 275 mg) was obtained by repeating preparative ODS-HPLC to obtain (5R) -7- (4 ″ -hydroxy-3 ″ -methoxyphenyl) -5-methoxy-1-phenyl- 3-Heptanone (Compound 1c; recovery amount: 270 mg) was obtained.
　Ｆｒ．４－８（回収量：１１２ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：２００ｇ、溶出溶媒：ｎ－ヘキサン－酢酸エチル（４：１）］により、５の画分（フラクション４－８－１～４－８－５）に分画した。Ｆｒ．４－８－２（回収量：１００．８ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、５－ヒドロキシ－７－（４”－ヒドロキシ－３”－メトキシフェニル）－１－フェニル－３－ヘプタノン（化合物１ａ；回収量：９７ｍｇ）を得た。 Fr. 4-8 (recovered amount: 112 mg) was obtained by fractionating 5 into fractions (fractions 4-8-1 to 4-4) using silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (4: 1)]. It was fractionated into -8-5). Fr. 4-8-2 (recovery amount: 100.8 mg) was obtained by repeating preparative ODS-HPLC to give 5-hydroxy-7- (4 ″ -hydroxy-3 ″ -methoxyphenyl) -1-phenyl-3- Heptanone (Compound 1a; recovery amount: 97 mg) was obtained.
　Ｆｒ．４－９（回収量：３３１ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：２００ｇ、溶出溶媒：ｎ－ヘキサン－酢酸エチル（３：１）］により、６の画分（フラクション４－９－１～４－９－６）に分画した。Ｆｒ．４－９－２（回収量：１７０．３ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（５Ｒ）－１，７－ジフェニル－５－ヒドロキシ－３－ヘプタノン（化合物１ｆ；回収量：１５５．６ｍｇ）を得た。次に、Ｆｒ．４－９－３（回収量：３１ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、７－（４”－ヒドロキシフェニル）－１－フェニル－４Ｅ－ヘプテン－３－オン（化合物１ｄ；回収量：２４ｍｇ）を得た。更に、Ｆｒ．４－９－５（回収量：５６．８ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、１，７－ジフェニル－４Ｅ－ヘプテン－３－オン（化合物１ｅ；回収量：４０ｍｇ）を得た。 Fr. 4-9 (recovered amount: 331 mg) was obtained by adding 6 fractions (fractions 4-9-1 to 4) to silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (3: 1)]. -9-6). Fr. 4-9-2 (recovered amount: 170.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5R) -1,7-diphenyl-5-hydroxy-3-heptanone (compound 1f; recovered amount: 155 0.6 mg) was obtained. Next, Fr. 4-9-3 (recovered amount: 31 mg) was obtained by repeating preparative ODS-HPLC to give 7- (4 ″ -hydroxyphenyl) -1-phenyl-4E-hepten-3-one (compound 1d; recovered amount). In addition, Fr.4-9-5 (recovered amount: 56.8 mg) was obtained by repeating preparative ODS-HPLC to obtain 1,7-diphenyl-4E-hepten-3-one ( Compound 1e; recovery amount: 40 mg) was obtained.
　Ｆｒ．４－１０（回収量：３９８ｍｇ）はシリカゲル－ＣＣ［シリカゲル使用量：２００ｇ、溶出溶媒：ｎ－ヘキサン－酢酸エチル（３：１）］により、８の画分（フラクション４－１０－１～４－１０－８）に分画した。Ｆｒ．４－１０－２（回収量：１７．３ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（５Ｓ）－７－（４”－ヒドロキシフェニル）－５－メトキシ－１－フェニル－３－ヘプタノン（化合物１ｇ；回収量：１２ｍｇ）を得た。Ｆｒ．４－１０－３（回収量：７．３ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（３Ｒ，５Ｒ）－１，７－ジフェニル－３，５－ヘプタンジオール（化合物１ｊ；回収量：３．６ｍｇ）を得た。次に、Ｆｒ．４－１０－４（回収量：２２ｍｇ）は、分取ＯＤＳ－ＨＰＬＣを繰返すことにより、（５Ｓ）－５－ヒドロキシ－７－（４”－ヒドロキシフェニル）－１－フェニル－３－ヘプタノン（化合物１ｈ；回収量：１３．２ｍｇ）を得た。 Fr. 4-10 (recovered amount: 398 mg) was obtained from 8 fractions (fractions 4-10-1 to 4) by silica gel-CC [silica gel use amount: 200 g, elution solvent: n-hexane-ethyl acetate (3: 1)]. Fractionated to -10-8). Fr. 4-10-2 (recovery amount: 17.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (5S) -7- (4 ″ -hydroxyphenyl) -5-methoxy-1-phenyl-3-heptanone. (1 g of compound; recovered amount: 12 mg) Fr.4-10-3 (recovered amount: 7.3 mg) was obtained by repeating preparative ODS-HPLC to obtain (3R, 5R) -1,7- Diphenyl-3,5-heptanediol (compound 1j; recovery amount: 3.6 mg) was obtained, and then Fr.4-10-4 (recovery amount: 22 mg) was obtained by repeating preparative ODS-HPLC. , (5S) -5-hydroxy-7- (4 ″ -hydroxyphenyl) -1-phenyl-3-heptanone (Compound 1h; recovery: 13.2 mg) was obtained.
実施例２（抗インフルエンザウイルス活性）
（方法）
（１）インフルエンザウイルス増殖抑制
　ＭＴＴ（３－［４，５－ｄｉｍｅｔｈｙｌｔｈｉａｚｏｌ－２－ｙｌ］－２，５－ｄｉｐｈｅｎｙｌｔｅｔｒａｚｏｌｉｕｍ　ｂｒｏｍｉｄｅ）法を用いて評価した。以下、詳細を記述する。
　ジアリルへプタノイド類はジメチルスルホキシド（ＤＭＳＯ）に溶解後、維持培地（０．１％ウシアルブミン血清含有ＭＥＭ培地）を加えて希釈し、最終濃度を０．１、０．３、１．３、１０、３０、５０μｇ／ｍＬとした。なお、ＤＭＳＯの最終濃度は０．５％以下とし、細胞への毒性が出ない濃度とした。
　インフルエンザウイルス（Ａ／Ｈ１Ｎ１／ＰＲ８／３４株）は、１％ウシアルブミン血清含有リン酸緩衝溶液にて希釈しウイルス液として用いた。細胞はＭＤＣＫ（イヌ腎臓細胞由来）細胞を用いた。 Example 2 (anti-influenza virus activity)
(Method)
(1) Inhibition of influenza virus growth The MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) method was used for evaluation. Details are described below.
Diallyl heptanoids are dissolved in dimethyl sulfoxide (DMSO), diluted by adding a maintenance medium (MEM medium containing 0.1% bovine albumin serum), and final concentrations of 0.1, 0.3, 1.3, 10 30 and 50 μg / mL. The final concentration of DMSO was 0.5% or less, and was a concentration that did not cause toxicity to cells.
Influenza virus (A / H1N1 / PR8 / 34 strain) was diluted with a phosphate buffer solution containing 1% bovine albumin serum and used as a virus solution. MDCK (canine kidney cell-derived) cells were used as the cells.
　まず、９６ｗｅｌｌプレートに２×１０４個／ｗｅｌｌのＭＤＣＫ細胞を増殖培地（１０％ウシ胎児血清含有ＭＥＭ培地）にて培養した。培養４日後、増殖培地を除去した後に、リン酸緩衝溶液を用いて細胞を洗浄し、ウイルス液５０μｌ（ＭＯＩ＝０．００３／ｗｅｌｌに相当）を各ｗｅｌｌに加えて３７℃でインキュベートした。なお、非感染コントロールとして、ウイルス非存在下のｗｅｌｌを１列（計６ｗｅｌｌ）作製した。１時間インキュベート後、各濃度にて希釈したジアリルへプタノイド類の存在あるいは、非存在下（ウイルス感染コントロール）にて維持培地を各々５０μｌ／ｗｅｌｌ加え、３７℃で培養した。４日後、ＭＴＴ－リン酸緩衝溶液（７．５ｍｇ／ｍＬ）１０μｌ／ｗｅｌｌを加え、３７℃にてインキュベートした。４時間後、２０％含有ドデシル硫酸ナトリウム／５０％含有Ｎ，Ｎ－ジメチルホルムアミド混液を各々１００μｌ／ｗｅｌｌ加え、５４０ｎｍにおける吸光度を測定した。
　なお、非感染コントロールの吸光度：（ＯＤｃ）ｍ、ウイルス感染コントロールの吸光度：（ＯＤｃ）ｖ、及びウイルス感染後ジアリルへプタノド類添加群の吸光度：（ＯＤｔ）ｖをそれぞれ測定後、以下の数式（ｉ）を用いて各ジアリルへプタノイド類のＥＣ５０を算出し、それぞれの抗ウイルス活性とした。 First, 2 × 10 4 cells / well of MDCK cells were cultured on a 96-well plate in a growth medium (MEM medium containing 10% fetal bovine serum). After 4 days of culture, the growth medium was removed, the cells were washed with a phosphate buffer solution, and 50 μl of virus solution (corresponding to MOI = 0.003 / well) was added to each well and incubated at 37 ° C. In addition, as a non-infectious control, one well (total 6 wells) was prepared in the absence of virus. After incubation for 1 hour, each of the maintenance media was added at 50 μl / well in the presence or absence of diallyl heptanoids diluted at each concentration (virus infection control) and cultured at 37 ° C. After 4 days, 10 μl / well of MTT-phosphate buffer solution (7.5 mg / mL) was added and incubated at 37 ° C. After 4 hours, 100 μl / well of a 20% sodium dodecyl sulfate / 50% N, N-dimethylformamide mixture was added, and the absorbance at 540 nm was measured.
After measuring the absorbance of the non-infected control: (ODc) m, the absorbance of the virus infection control: (ODc) v, and the absorbance of the diallyl heptanodo addition group after virus infection: (ODt) v, respectively, The EC 50 of each diallyl heptanoid was calculated using i) and defined as the respective antiviral activity.
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000001
（２）細胞毒性
　上記（１）の方法に従い、ＭＤＣＫ細胞を培養後、維持培地にて各濃度に希釈したジアリルヘプタノイド類の存在、あるいは非存在下における細胞への毒性について検討を行った。
（結果） (2) Cytotoxicity According to the method of (1) above, after culturing MDCK cells, the presence or absence of diallyl heptanoids diluted to various concentrations in a maintenance medium was examined for toxicity to cells.
(result)
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１から明らかなように、式（１）の化合物は優れたインフルエンザウイルス増殖抑制作用を有し、細胞毒性は低い。 As is clear from Table 1, the compound of the formula (1) has an excellent influenza virus growth inhibitory action and has low cytotoxicity.
実施例３
　化合物（１ｂ）及び（１ｈ）について、抗ヘルペスウイルス活性を検討した。
（方法）
（１）ヘルペスウイルス増殖抑制
　プラーク減少法を用いて評価した。以下、詳細を記述する。
　ジアリルへプタノイド類はＤＭＳＯに溶解後、メチルセルロース含有維持培地（２％ウシ血清含有ＭＥＭ培地）に加えて、最終濃度を（１ｂ）は０．１、１、３、１０、３０μｇ／ｍＬ、（１ｈ）は０．１、１、３、１０、５０、８０μｇ／ｍＬとした。なお、ＤＭＳＯの最終濃度は０．１％以下とし、細胞への毒性が出ない濃度とした。
　ヘルペスウイルスには、単純ヘルペスウイルス１型（７４０１Ｈ株）を用い、維持培地にて希釈しウイルス液として用いた。細胞はＶｅｒｏ（アフリカミドリザル腎臓由来）細胞を用いた。
　まず、６０ｍｍディッシュに５×１０５個／ディッシュのＶｅｒｏ細胞を増殖培地（８％ウシ血清含有ＭＥＭ培地）にて培養した。培養４日後、増殖培地を除去した後に、リン酸緩衝溶液を用いて細胞を洗浄し、ウイルス液２００μｌ（１００ｐｆｕ／ディッシュに相当）を各ディッシュに加えて３７℃でインキュベートした。１時間インキュベート後、リン酸緩衝溶液を用いて細胞を洗浄し、各濃度にて希釈したジアリルへプタノイド類の存在あるいは、非存在下（ウイルス感染コントロール）にてメチルセルロース含有維持培地を各々５ｍＬ／ディッシュ加え、３７℃で培養した。４日後、５％ホルマリン液５ｍＬを加え、細胞を固定した。一晩放置後、ホルマリン液を洗い流し、０．０３％メチレンブルー染色液を各々５ｍＬ／ディッシュ加え染色した。染色液を洗い流し、風乾後、プラークを計数した。
（２）細胞毒性
　可視的に細胞毒性を評価した。以下、詳細を記述する。
　上記（１）と同時に、ディッシュからの染色細胞の脱落を肉眼的に観察した。非感染細胞と比較して、細胞脱落の程度により細胞毒性が強い（５０％以上脱落）、中程度（５０‐１０％脱落）、弱い（１０％以下脱落）として評価した。
　結果、化合物（１ｂ）及び（１ｈ）はいずれも１０μｇ／ｍＬにおいて弱い細胞毒性を示した。 Example 3
Compounds (1b) and (1h) were examined for anti-herpesvirus activity.
(Method)
(1) Inhibition of herpesvirus growth Evaluation was made using the plaque reduction method. Details are described below.
After diallyl heptanoids are dissolved in DMSO, they are added to a methylcellulose-containing maintenance medium (2% bovine serum-containing MEM medium), and the final concentration (1b) is 0.1, 1, 3, 10, 30 μg / mL, (1 h ) Was 0.1, 1, 3, 10, 50, 80 μg / mL. The final concentration of DMSO was set to 0.1% or less so as not to cause toxicity to cells.
As herpesvirus, herpes simplex virus type 1 (7401H strain) was used, diluted with a maintenance medium and used as a virus solution. Vero (African green monkey kidney-derived) cells were used as cells.
First, 5 × 10 5 Vero cells / dish were cultured in a growth medium (MEM medium containing 8% bovine serum) in a 60 mm dish. After 4 days of culture, the growth medium was removed, the cells were washed with a phosphate buffer solution, and 200 μl of virus solution (corresponding to 100 pfu / dish) was added to each dish and incubated at 37 ° C. After incubating for 1 hour, the cells were washed with a phosphate buffer solution, each containing 5 mL / dish of methylcellulose-containing maintenance medium in the presence or absence of diallyl heptanoids diluted at each concentration (virus infection control). In addition, the cells were cultured at 37 ° C. After 4 days, 5 mL of 5% formalin solution was added to fix the cells. After standing overnight, the formalin solution was washed off, and 0.03% methylene blue staining solution was added to each 5 mL / dish for staining. The staining solution was washed away, air-dried, and plaques were counted.
(2) Cytotoxicity Cytotoxicity was evaluated visually. Details are described below.
Simultaneously with the above (1), dropping of the stained cells from the dish was visually observed. The cytotoxicity was evaluated as strong (over 50% loss), moderate (50-10% loss), and weak (less than 10% loss) depending on the degree of cell loss compared to uninfected cells.
As a result, both compounds (1b) and (1h) showed weak cytotoxicity at 10 μg / mL.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２の結果より、化合物（１ｂ）及び（１ｈ）は、抗ヘルペスウイルス活性を示さなかった。従って、一般式（１）の化合物はインフルエンザウイルスの増殖を特異的に抑制する。 From the results of Table 2, compounds (1b) and (1h) did not show anti-herpesvirus activity. Therefore, the compound of general formula (1) specifically inhibits the growth of influenza virus.
実施例４
　化合物（１ｂ)について、インフルエンザウイルス感染マウスに対する抗インフルエンザウイルス活性を検討した。
（方法）
（１）インフルエンザウイルス感染マウスの体重変化と生存日数
　化合物（１ｂ）をジメチルスルホキシド（ＤＭＳＯ）に溶解後、注射用精製水を加えて希釈し、最終濃度３０ｍｇ／０．２ｍＬ、１００ｍｇ／０．２ｍＬとした。なお、ＤＭＳＯの最終濃度は１％以下とし、マウスへの毒性が出ない濃度とした。
　インフルエンザウイルス（Ａ／Ｈ１Ｎ１／ＰＲ８／３４株）は、リン酸緩衝溶液にて希釈しウイルス液（５００ＰＦＵ）として用いた。マウスは雌のＢＡＬＢ／ｃＮマウス（６週齢、２０～２２ｇ）を用いた。 Example 4
Compound (1b) was examined for anti-influenza virus activity against influenza virus-infected mice.
(Method)
(1) Body weight change and survival days of influenza virus infected mice Compound (1b) was dissolved in dimethyl sulfoxide (DMSO) and then diluted by adding purified water for injection, final concentrations of 30 mg / 0.2 mL, 100 mg / 0.2 mL It was. The final concentration of DMSO was set to 1% or less so as not to cause toxicity to mice.
Influenza virus (A / H1N1 / PR8 / 34 strain) was diluted with a phosphate buffer solution and used as a virus solution (500 PFU). As the mice, female BALB / cN mice (6 weeks old, 20-22 g) were used.
　マウスへのインフルエンザウイルス感染は、麻酔下マウスに対して経鼻にてウイルス液を注入して行った。各濃度に希釈した化合物（１ｂ)を経口投与にて、感染日（Ｄａｙ０）の感染４時間前に１回、感染後２時間以内に１回、さらに４時間後に１回投与を行った。また、感染５日後迄１日３回投与を行った。非投与群は、注射用精製水を用いて、投与群と同様にマウスへ投与を行った。
　感染８日後迄、毎朝投与前に体重を測定した。また、感染５，６，７，９，１１日後におけるウイルス感染マウスの生存数を計測した。 Influenza virus infection in mice was performed by injecting the virus solution nasally into mice under anesthesia. The compound (1b) diluted to each concentration was orally administered once every 4 hours before the infection day (Day 0), once within 2 hours after the infection, and once after another 4 hours. In addition, administration was performed 3 times a day until 5 days after infection. The non-administration group was administered to mice using purified water for injection in the same manner as the administration group.
Body weight was measured every morning before administration until 8 days after infection. In addition, the number of surviving virus-infected mice was counted after 5, 6, 7, 9, and 11 days after infection.
（２）ウイルス感染３，６日後（Ｄａｙ３，６）に、リン酸緩衝溶液にてマウスの肺を洗浄し、その肺洗浄液中に含まれるインフルエンザウイルスのウイルス価を評価した。
　ウイルス価の評価は、プラーク減少法を用いて行った。以下、詳細を記述する。
　６０ｍｍディッシュで２×１０５個／ディッシュのＭＤＣＫ細胞を増殖培地（１０％ウシ胎児血清含有ＭＥＭ培地）にて培養した。培養４日後、増殖培地を除去した後に、リン酸緩衝溶液を用いて細胞を洗浄し、１％ウシアルブミン血清含有リン酸緩衝溶液にて希釈し１０７倍まで段階希釈した肺洗浄液２００μｌを各ディッシュに加えて３７℃でインキュベートした。１時間インキュベート後、リン酸緩衝溶液を用いて細胞を洗浄し、アガロース含有維持培地をそれぞれ５ｍＬ／ディッシュを加え、３７℃で培養した。３日後、５％ホルマリン液５ｍＬを加え、細胞を固定した。一晩放置後、ホルマリン液を洗い流し、０．０３％メチレンブルー染色液をそれぞれ５ｍＬ／ディッシュ加え染色した。染色液を洗い流し、風乾後、プラークを計数した。ウイルス価は以下の数式（ｉｉ）にて表す。 (2) Three to six days after virus infection (Days 3 and 6), the lungs of the mice were washed with a phosphate buffer solution, and the virus titer of influenza virus contained in the lung washings was evaluated.
The virus titer was evaluated using the plaque reduction method. Details are described below.
MDCK cells of 2 × 10 5 cells / dish in a 60 mm dish were cultured in a growth medium (MEM medium containing 10% fetal bovine serum). After 4 days of culture, the growth medium was removed, the cells were washed with a phosphate buffer solution, diluted with a phosphate buffer solution containing 1% bovine albumin serum, and 200 μl of a lung wash solution serially diluted to 10 7 times in each dish. And incubated at 37 ° C. After incubating for 1 hour, the cells were washed with a phosphate buffer solution, 5 mL / dish of agarose-containing maintenance medium was added, and the mixture was cultured at 37 ° C. Three days later, 5 mL of 5% formalin solution was added to fix the cells. After standing overnight, the formalin solution was washed away, and 0.03% methylene blue staining solution was added to each 5 mL / dish for staining. The staining solution was washed away, air-dried, and plaques were counted. The virus titer is expressed by the following formula (ii).
Figure JPOXMLDOC01-appb-M000002
Figure JPOXMLDOC01-appb-M000002
（結果）
（１）図２に示すように、インフルエンザウイルス感染マウスの体重減少は、式（１）化合物の１００ｍｇ／０．２ｍＬ投与群で有意に抑制された（＊：ｐ＜０．０５）。また、図３に示すように、インフルエンザウイルス感染マウスの生存日数は、式（１）化合物の１００ｍｇ／０．２ｍＬ投与群で有意に延長した（＊：ｐ＜０．０５）。 (result)
(1) As shown in FIG. 2, weight loss of influenza virus-infected mice was significantly suppressed in the 100 mg / 0.2 mL administration group of the compound of formula (1) (*: p <0.05). Moreover, as shown in FIG. 3, the survival days of influenza virus infected mice were significantly prolonged in the 100 mg / 0.2 mL administration group of the compound of formula (1) (*: p <0.05).
（２）表３から明らかなように、感染３日後のインフルエンザウイルス感染マウス肺洗浄液中のウイルス価は、式（１）化合物の１００ｍｇ／０．２ｍＬ投与群で有意に減少した（＊：ｐ＜０．０５）。また、感染６日後のインフルエンザウイルス感染マウス肺洗浄液中のウイルス価は、式（１）化合物の３０ｍｇ、１００ｍｇ／０．２ｍＬ投与群でそれぞれ有意に減少した（＊：ｐ＜０．０５）。
　なお、各ポイントは平均±標準誤差で示し、統計処理は、ｔｗｏ－ｗａｙ　ＡＮＯＶＡで検定しコントロールとの比較を行った。 (2) As is clear from Table 3, the virus titer in the lung lavage fluid of influenza virus-infected mice 3 days after infection was significantly reduced in the 100 mg / 0.2 mL administration group of the compound of formula (1) (*: p < 0.05). Moreover, the virus titer in the lung lavage fluid of influenza virus-infected mice 6 days after infection was significantly decreased in the 30 mg and 100 mg / 0.2 mL groups of the compound of formula (1) (*: p <0.05).
Each point is shown as mean ± standard error, and statistical processing was tested with two-way ANOVA and compared with the control.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003

Claims (12)

  1. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000003
     （式中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示し；Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ｒ２～Ｒ４は同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示し；破線部は、当該結合が二重結合であってもよいことを示す）
    で表されるジフェニルヘプタノイドを有効成分とする抗インフルエンザウイルス剤。     General formula (1)
    Figure JPOXMLDOC01-appb-C000003
     Wherein X represents C═O or CH—OH; R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group; R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group. A broken line indicates that the bond may be a double bond)
    The anti-influenza virus agent which uses the diphenyl heptanoid represented by this as an active ingredient.
  2. 　Ｒ１が水素原子、ヒドロキシ基又はメトキシ基であり、Ｒ２～Ｒ４が同一又は異なって、水素原子、ヒドロキシ基又はメトキシ基である請求項１記載の抗インフルエンザウイルス剤。 The anti-influenza virus agent according to claim 1 , wherein R 1 is a hydrogen atom, a hydroxy group or a methoxy group, and R 2 to R 4 are the same or different and are a hydrogen atom, a hydroxy group or a methoxy group.
  3. 　Ｒ２が水素原子であり、Ｒ３が水素原子又はヒドロキシ基であり、Ｒ４が水素原子又はメトキシ基である請求項１又は２記載の抗インフルエンザウイルス剤。 The anti-influenza virus agent according to claim 1 or 2, wherein R 2 is a hydrogen atom, R 3 is a hydrogen atom or a hydroxy group, and R 4 is a hydrogen atom or a methoxy group.
  4. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000004
     （式中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示し；Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ｒ２～Ｒ４は同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示し；破線部は、当該結合が二重結合であってもよいことを示す）
    で表されるジフェニルヘプタノイド、並びに薬学的に許容される担体を含有してなるインフルエンザの予防及び／又は治療用組成物。     General formula (1)
    Figure JPOXMLDOC01-appb-C000004
     Wherein X represents C═O or CH—OH; R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group; R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group. A broken line indicates that the bond may be a double bond)
    A composition for preventing and / or treating influenza comprising a diphenylheptanoid represented by formula (1) and a pharmaceutically acceptable carrier.
  5. 　Ｒ１が水素原子、ヒドロキシ基又はメトキシ基であり、Ｒ２～Ｒ４が同一又は異なって、水素原子、ヒドロキシ基又はメトキシ基である請求項４記載のインフルエンザの予防及び／又は治療用組成物。 The composition for preventing and / or treating influenza according to claim 4, wherein R 1 is a hydrogen atom, a hydroxy group or a methoxy group, and R 2 to R 4 are the same or different and are a hydrogen atom, a hydroxy group or a methoxy group. .
  6. 　Ｒ２が水素原子であり、Ｒ３が水素原子又はヒドロキシ基であり、Ｒ４が水素原子又はメトキシ基である請求項４又は５記載のインフルエンザの予防及び／又は治療用組成物。 The composition for preventing and / or treating influenza according to claim 4 or 5, wherein R 2 is a hydrogen atom, R 3 is a hydrogen atom or a hydroxy group, and R 4 is a hydrogen atom or a methoxy group.
  7. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000005
     （式中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示し；Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ｒ２～Ｒ４は同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示し；破線部は、当該結合が二重結合であってもよいことを示す）
    で表されるジフェニルヘプタノイドの抗インフルエンザウイルス剤製造のための使用。     General formula (1)
    Figure JPOXMLDOC01-appb-C000005
     Wherein X represents C═O or CH—OH; R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group; R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group. A broken line indicates that the bond may be a double bond)
    Use of diphenylheptanoid represented by the formula for production of an anti-influenza virus agent.
  8. 　Ｒ１が水素原子、ヒドロキシ基又はメトキシ基であり、Ｒ２～Ｒ４が同一又は異なって、水素原子、ヒドロキシ基又はメトキシ基である請求項７記載の使用。 The use according to claim 7, wherein R 1 is a hydrogen atom, a hydroxy group or a methoxy group, and R 2 to R 4 are the same or different and are a hydrogen atom, a hydroxy group or a methoxy group.
  9. 　Ｒ２が水素原子であり、Ｒ３が水素原子又はヒドロキシ基であり、Ｒ４が水素原子又はメトキシ基である請求項７又は８記載の使用。 The use according to claim 7 or 8, wherein R 2 is a hydrogen atom, R 3 is a hydrogen atom or a hydroxy group, and R 4 is a hydrogen atom or a methoxy group.
  10. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000006
     （式中、ＸはＣ＝Ｏ又はＣＨ－ＯＨを示し；Ｒ１は水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ｒ２～Ｒ４は同一又は異なって、水素原子、ヒドロキシ基又は低級アルコキシ基を示し；破線部は、当該結合が二重結合であってもよいことを示す）
    で表されるジフェニルヘプタノイドの有効量を投与するインフルエンザの予防及び／又は治療方法。     General formula (1)
    Figure JPOXMLDOC01-appb-C000006
     Wherein X represents C═O or CH—OH; R 1 represents a hydrogen atom, a hydroxy group or a lower alkoxy group; R 2 to R 4 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group. A broken line indicates that the bond may be a double bond)
    A method for preventing and / or treating influenza, which comprises administering an effective amount of diphenylheptanoid represented by:
  11. 　Ｒ１が水素原子、ヒドロキシ基又はメトキシ基であり、Ｒ２～Ｒ４が同一又は異なって、水素原子、ヒドロキシ基又はメトキシ基である請求項１０記載のインフルエンザの予防及び／又は治療方法。 The method for preventing and / or treating influenza according to claim 10, wherein R 1 is a hydrogen atom, a hydroxy group or a methoxy group, and R 2 to R 4 are the same or different and are a hydrogen atom, a hydroxy group or a methoxy group.
  12. 　Ｒ２が水素原子であり、Ｒ３が水素原子又はヒドロキシ基であり、Ｒ４が水素原子又はメトキシ基である請求項１０又は１１記載のインフルエンザの予防及び／又は治療方法。 The method for preventing and / or treating influenza according to claim 10 or 11, wherein R 2 is a hydrogen atom, R 3 is a hydrogen atom or a hydroxy group, and R 4 is a hydrogen atom or a methoxy group.
PCT/JP2009/003937 2008-11-27 2009-08-19 Anti-influenza virus agent WO2010061497A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2010540295A JPWO2010061497A1 (en) 2008-11-27 2009-08-19 Anti-influenza virus agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-302042 2008-11-27
JP2008302042 2008-11-27

Publications (1)

Publication Number Publication Date
WO2010061497A1 true WO2010061497A1 (en) 2010-06-03

Family

ID=42225389

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/003937 WO2010061497A1 (en) 2008-11-27 2009-08-19 Anti-influenza virus agent

Country Status (2)

Country Link
JP (1) JPWO2010061497A1 (en)
WO (1) WO2010061497A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101811848B1 (en) 2011-06-13 2017-12-22 한국생명공학연구원 Composite comprising curcuminoid/stevioside for prevention or treatment of influenza virus
KR20200129288A (en) * 2019-05-08 2020-11-18 연세대학교 산학협력단 Compositions for inhibiting the activity of neuraminidase comprising diarylheptanoids from Alpinia officinarum

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0625003A (en) * 1992-04-27 1994-02-01 Showa Shell Sekiyu Kk Galenical drug-containing antiviral agent
JP2002121145A (en) * 2000-10-16 2002-04-23 Fancl Corp Xanthine oxidase inhibitor
US20050215635A1 (en) * 2004-03-08 2005-09-29 Rafi M Mohamed Diarylheptanoid compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0625003A (en) * 1992-04-27 1994-02-01 Showa Shell Sekiyu Kk Galenical drug-containing antiviral agent
JP2002121145A (en) * 2000-10-16 2002-04-23 Fancl Corp Xanthine oxidase inhibitor
US20050215635A1 (en) * 2004-03-08 2005-09-29 Rafi M Mohamed Diarylheptanoid compounds and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
P. M. JACOBS ET AL., THE JOURNAL OF ORGANIC CHEMISTRY, vol. 39, no. 23, 1974, pages 3427 - 3429 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101811848B1 (en) 2011-06-13 2017-12-22 한국생명공학연구원 Composite comprising curcuminoid/stevioside for prevention or treatment of influenza virus
KR20200129288A (en) * 2019-05-08 2020-11-18 연세대학교 산학협력단 Compositions for inhibiting the activity of neuraminidase comprising diarylheptanoids from Alpinia officinarum
KR102226992B1 (en) 2019-05-08 2021-03-11 연세대학교 산학협력단 Compositions for inhibiting the activity of neuraminidase comprising diarylheptanoids from Alpinia officinarum

Also Published As

Publication number Publication date
JPWO2010061497A1 (en) 2012-04-19

Similar Documents

Publication Publication Date Title
KR101566441B1 (en) Composition for prevention and treatment of influenza virus and composition for inhibiting the activity of neuraminidase comprising extracts of Turmeric
Wu et al. Antiviral flavonoids from Mosla scabra
KR101317318B1 (en) A composition comprising the extract of Galla Rhois or the compounds isolated therefrom showing inhibiting activity of novel influenza, avian influenza, or SARS syndrome
CN108473493B (en) Functionalized valeric acids for influenza virus infection
KR101782532B1 (en) A composition comprising extract of Angelica dahurica or furanocoumarins isolated therefrom for preventing or treating Avian influenza, Swine influenza or Corona virus
JPH0543469A (en) Beta-glucuronidase inhibitor
WO2011049348A2 (en) Antiviral agents obtained from curcuma longa, having inhibitory activities against avian influenza, swine influenza, and novel influenza
WO2012104845A1 (en) Compositions comprising beta-caryophyllene and methods of utilizing the same
TW200826954A (en) Herbal extract with anti-influenza virus activity and preparation of same
RU2684100C1 (en) Fillygenin and glucuronic acid derivative, method for production thereof and use thereof
WO2010061497A1 (en) Anti-influenza virus agent
Yu et al. Secondary metabolites of petri-dish cultured Antrodia camphorata and their hepatoprotective activities against alcohol-induced liver injury in mice
KR20150055683A (en) Composition comprising ginsenosides for treating or preventing Cold, Avian influenza, or Swine influenza
KR101966124B1 (en) Composition comprising extract of Ecklonia cava or phlorotannin compounds isolated from thereof for preventing or treating influenza
US10136663B2 (en) Curcuminoid-based compound/stevioside-containing complex for the prevention and treatment of an influenza virus infection
KR102456749B1 (en) Composition for preventing or treating swine influenza virus disease comprising Curcuma longa extract or sesquiterpenoids isolated therefrom as active ingredients
WO2021256547A1 (en) Composition for treating, preventing, or alleviating sars-cov-2 infectious disease
JPH0418019A (en) Sialidase inhibitor
KR101989349B1 (en) Composition for treating and preventing viral infection comprising extracts from Camellia japonica
US8414938B2 (en) Schisandrae fructus extracts for inhibition or prevention of H1N1 influenza virus infection and its application thereof
KR20150095605A (en) Composition comprising ginsenosides for treating or preventing Cold, Avian influenza, or Swine influenza
EP3884938A1 (en) 1,2,4-trioxane compounds and compositions comprising the same for use in the treatment of covid-19
JP2014136693A (en) Amyloid formation inhibitor and amyloid formation inhibition method
KR101704111B1 (en) Composition containing polyphenols isolated from the fruiting bodies of Inonotus obliquus for preventing or treating of influenza virus infection
EP4151226A1 (en) Coronavirus therapeutic agent comprising zanthoxylum piperitum leaf extract as active ingredient

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09828747

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2010540295

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09828747

Country of ref document: EP

Kind code of ref document: A1