CN109276563A - Application of pharmaceutical composition in preparing medicine for treating or preventing individual infection virus - Google Patents

Application of pharmaceutical composition in preparing medicine for treating or preventing individual infection virus Download PDF

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Publication number
CN109276563A
CN109276563A CN201710994334.9A CN201710994334A CN109276563A CN 109276563 A CN109276563 A CN 109276563A CN 201710994334 A CN201710994334 A CN 201710994334A CN 109276563 A CN109276563 A CN 109276563A
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dimethoxy
virus
toluene
compound
drug
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CN201710994334.9A
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CN109276563B (en
Inventor
李书豪
吴彰哲
李庆国
杨舒涵
郑育淞
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Zhuhai Xinyaolong Investment Development Co ltd
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Zhuhai Xinzhan Biotechnology Co ltd
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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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a use of a pharmaceutical composition for preparing a medicament for treating or preventing an infection of a subject with a virus, wherein the pharmaceutical composition comprises an effective component selected from the group consisting of a compound of formula (I) and a compound of formula (II). Specifically, the pharmaceutical composition prepared by the embodiment of the present invention can prevent viral infection and reduce the amount of virus infection and lung injury caused by the virus infection.

Description

A kind of medical composition is used to prepare the drug for treating or preventing individual virus infection Purposes
Technical field
Embodiments of the present invention are that the individual virus infection for the treatment of or prevention is used to prepare about a kind of medical composition The purposes of drug.
Background technique
Influenza virus (Influenza virus) is easily by droplet infection and contagion in person to person, people It scatters between vertebrate, because its antigen changes fast characteristic, so prevalence often either large or small in scale all over the world.Sense The malicious patient that catches an illness can often cause many concurrent severes, and these concurrent severes are usually the main cause of the death of flu victims, wherein Most common is injury of lungs caused by acute lung inflammation caused by influenza.It, will when virus debates knowledge by the receptor of cell Deactivate macrophage, and macrophage can go to discharge some cytohormones or albumen for inspiring inflammation by the path of NF- κ B Matter, including iNOS, COX-2, IL-6 etc., and cytohormone can activate and start congenital immunity reaction entered with resisting virus Invade, if but immune response excessively will cause serious inflammation phenomenon and occur.Accordingly, development has the therapeutic scheme of good efficacy, For current urgent demand.
Summary of the invention
One aspect of the present invention is to provide a kind of medical composition and is used to prepare the individual virus infection for the treatment of or prevention Drug purposes, wherein the medical composition includes an effective component, described effectively at being selected from by 1,2,3,4- tetra- methoxy Base -5- toluene, 1,2- dimethoxy benzene, 1,2,3- trimethoxy-benzene, 2,3,4- trimethoxy -6- sylvan, 3,4- dimethoxy Base -6- toluene -1,2- glycol, 3,4- dimethoxy -5- toluene -1,2- glycol, 2,4- dimethoxy -6- toluene -1,3- two Alcohol, 3,6- dimethoxy-4 '-toluene -1,2- glycol, 4,5- dimethoxy -7- toluene simultaneously [d] [1,3] dioxane, 4,5- bis- Simultaneously simultaneously [d] [1,3] dioxane, 5- are iodo- for [d] [1,3] dioxane, 4,7- dimethoxy -5- toluene for methoxyl group -6- toluene 4,7- dimethoxy -6- toluene simultaneously [d] [1,3] dioxane, the iodo- 2,3,4,5- tetramethoxy -6- toluene of 1-, 1,2,3,4- Tetramethoxy -5- methyl -6- (3- methyl fourth 3- alkene -1- alkynes -1- base) benzene, 4,7- dimethoxy -5- methyl -6- (3- methyl Butyl- 3- alkene -1- alkynes -1- base) benzo [d] [1,3] dioxane, 1,2,4- trimethoxy-benzene, the iodo- 2,4,5- trimethoxy of 1- Benzene, 3,4- dimethoxy phenol, 4,5- dimethoxy -2- sylvan, 2,5- dimethoxy phenol, 2,4- dimethoxy phenol and combinations thereof Composed group.
According to certain embodiments of the present invention, which is that can reduce cell by the infection of virus.
According to certain embodiments of the present invention, which is the quantity that can reduce the individual pulmonary infection virus.
According to certain embodiments of the present invention, which is lung caused by capable of reducing the individual pulmonary infection virus Damage.
According to certain embodiments of the present invention, which is that can reduce inflammation cells reaction.
According to certain embodiments of the present invention, the dosage of the drug is that the individual per kilogram of body weight bestows 12.5- 37.5 milligrams.
According to certain embodiments of the present invention, the virus be H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, It is H7N2, H7N3, H10N7, H5N2, H5N3, H5N6, H5N8, H6N1, H7N9, H10N8, Chicken Infectious Anemia Virus (CAV), new City virus (NDV), avian infectious bursal disease malicious (IBDV), pig reproduction and breathing syndrome virus (PRRSV), second type pig Orbivirus (PCV2), swine fever virus (CSFV), porcine respiratory coronavirus (PRCV), pig parvoviral (PPV) or pig are infected Property gastroenteritis virus (TGEV).
According to certain embodiments of the present invention, which is that can reduce be situated between white element (IL-6), tumor necrosis factor (TNF) and be situated between -1 β of white element (IL-1 β) performance amount.
Another aspect of the present invention is to provide a kind of manufacturing method of compound, includes: in the presence of aluminium chloride, inciting somebody to action The compound of structure with chemical formula (III) reacts in the environment that argon gas is protected with methylene chloride, has chemistry to be formed The compound of the structure of formula (I),
The wherein structure of the chemistry formula (III) are as follows:
In the chemistry formula (III), R7With R8It is to be independently selected from the group as composed by hydrogen, methoxyl group, hydroxy and methyl Group；
The chemistry formula (I) are as follows:
In the chemistry formula (I), R1、R2、R3With R4It is to be independently selected from by hydrogen, methyl, methoxyl group and hydroxy institute group At group.
According to certain embodiments of the present invention, the chemicals of the above-mentioned structure with chemical formula (I), wherein R1For hydrogen Oxygroup, R2For hydroxy, R3For methoxyl group and R4For hydrogen or methyl.
Detailed description of the invention
The embodiment of the present invention is read according to narration collocation attached drawing in greater detail below.
Fig. 1 is drawn according to a variety of different embodiments, the flow chart of compound 1-22 synthesis；
Fig. 2 to Fig. 5 is painted according to various different embodiments, the result figure of cell survival rate in prophylactic tria；
Fig. 6 to Fig. 9 is painted according to various different embodiments, the result figure of cell survival rate in therapeutic test；
Figure 10 is painted according to various different embodiments, various immunocyte quantity contained in mouse blood；
Figure 11 is painted according to various different embodiments, the result of mouse lung tissue H1N1 nucleoprotein gene performance amount Figure；
Figure 12 is painted according to various different embodiments, after mouse lung tissue is sliced, with hematoxylin eosin staining Coloration result figure afterwards；
Figure 13 is painted according to various different embodiments, after mouse lung tissue is sliced, after immunofluorescence dyeing Coloration result figure；
Figure 14 to Figure 15 is painted according to various different embodiments, its survival rate and changes of weight after mouse infection is viral Result figure；
Wherein, symbol description:
100 step 200 steps
300 step 400 steps.
Specific embodiment
For keep the narration of this disclosure more detailed with it is complete, below for state sample implementation of the invention and specific real It applies example and proposes illustrative description；But this not implements or uses the unique forms of the specific embodiment of the invention.It is disclosed below Each embodiment, beneficial in the case of can be combined with each other or replace, can also add others embodiments in one embodiment, And without further record or explanation.In the following description, many specific details be will be described in detail so that reader can be abundant Understand embodiment below.However, the embodiment of the present invention can be practiced without these specific details.
The use for treating or preventing the drug of individual virus infection is used to prepare the present invention relates to a kind of medical composition On the way, wherein this medical composition includes an effective component, and the effective component is selected from the compound by having chemical formula (I) And group composed by the compound of chemical formula (II), wherein the chemistry formula (I) has following chemical structure:
Wherein R1、R2、R3With R4It is to be independently selected from hydrogen, methyl, iodine, methoxyl group, hydrogen-oxygen Base andComposed group；Wherein, which has following chemical structure:Wherein R5With R6Be be independently selected from hydrogen, methyl, iodine, methoxyl group, hydroxy andComposed group.
In one embodiment, the effective component that above-mentioned medical composition includes is selected from by 1,2,3,4- tetramethoxy -5- Toluene (1,2,3,4-tetramethoxy-5-methylbenzene), 1,2- dimethoxy benzene (1,2- Dimethoxybenzene), 1,2,3- trimethoxy-benzene (1,2,3-trimethoxybenzene), 2,3,4- trimethoxy- 6- sylvan (2,3,4-trimethoxy-6-methylphenol), 3,4- dimethoxy -6- toluene -1,2- glycol (3,4- Dimethoxy-6-methylbenzene-1,2-diol), 3,4- dimethoxy -5- toluene -1,2- glycol (3,4- Dimethoxy-5-methylbenzene-1,2-diol), 2,4- dimethoxy -6- toluene -1,3- glycol (2,4- Dimethoxy-6-methylbenzene-1,3-diol), 3,6- dimethoxy-4 '-toluene -1,2- glycol (3,6- Dimethoxy-4-methylbenzene-1,2-diol), 4,5- dimethoxy -7- toluene simultaneously [d] [1,3] dioxane (4, 5-dimethoxy-7-methylbenzo [d] [1,3] dioxole), 4,5- dimethoxy -6- toluene simultaneously [d] [1,3] dioxy Heterocycle (4,5-dimethoxy-6-methylbenzo [d] [1,3] dioxole), 4,7- dimethoxy -5- toluene simultaneously [d] [1, 3] dioxane (4,7-dimethoxy-5-methylbenzo [d] [1,3] dioxole), the iodo- 4,7- dimethoxy -6- of 5- Toluene simultaneously [d] [1,3] dioxane (5-iodo-4,7-dimethoxy-6-methylbenzo [d] [1,3] dioxole), 1- Iodo- 2,3,4,5- tetramethoxy -6- toluene (1-iodo-2,3,4,5-tetramethoxy -6-methylbenzene), 1,2, 3,4- tetramethoxy -5- methyl -6- (3- methyl fourth 3- alkene -1- alkynes -1- base) benzene (1,2,3,4-tetramethoxy-5- Methyl-6- (3-methylbut-3-en-1-yn-1-yl) benzene), 4,7- dimethoxy -5- methyl -6- (3- methyl Butyl- 3- alkene -1- alkynes -1- base) benzo [d] [1,3] dioxane (4,7-dimethoxy-5-methyl-6- (3- Methylbut-3-en-1-yn-1-yl) benzo [d] [1,3] dioxole), 1,2,4- trimethoxy-benzene (1,2,4- Trimethoxybenzene), the iodo- 2,4,5- trimethoxy-benzene (1-iodo-2,4,5-trimethoxybenzene) of 1-, 1, 2,4- trimethoxy -5- (3- methyl butyl- 3- alkene -1- alkynes -1- base) benzene (1,2,4-trimethoxy-5- (3-methylbut- 3-en-1-yn-1-yl) benzene), 3,4- dimethoxy phenol (3,4-dimethoxyphenol), 4,5- dimethoxy -2- Sylvan (4,5-dimethoxy-2-methylphenol), 2,5- dimethoxy phenol (2,5-dimethoxyphenol), 2, 4- dimethoxy phenol (2,4-dimethoxyphenol) with and combinations thereof composed by group.
In one embodiment, embodiments of the present invention provide a kind of manufacture of compound with chemical formula (I) structure Method includes: in the presence of a catalyst, by the compound and a methine halide chemical combination of the structure with chemical formula (III) Object reaction has the compound of the structure of chemical formula (I) with formation, wherein the structure of the chemistry formula (III) are as follows:In the chemistry formula (III), R7With R8It is to be independently selected from by hydrogen, methoxyl group, hydroxy and first Group composed by base, the chemistry formula (I) are as follows:In the chemistry formula (I), R1、R2、R3With R4 It is to be independently selected from the group as composed by hydrogen, methyl, methoxyl group and hydroxy.By preceding method, it is only necessary to a reaction step It can be prepared by the compound of the structure with chemical formula (I).In one embodiment, having can be obtained by above-mentioned manufacturing method The compound of formula (I), wherein R1For hydroxy, R2For hydroxy, R3For methoxyl group and R4For hydrogen or methyl.Implement one In example, which may include, but are not limited to aluminium chloride, iron oxide, zinc chloride, stannic chloride or aluminium bromide.
According to some embodiments, which may include, but are not limited to methylene chloride, methylene bromide, three Chloromethanes or bromoform.In addition, in some embodiments, above-mentioned halogen alkyl compound in addition to methine halide compound it Outside, still including but not limited to level-one halogen alkyl compound, second level halogen alkyl compound, three-level halogen alkyl compound.
Term " halogen ", it is intended that fluorine, chlorine, bromine or iodine.
In one embodiment, the aforementioned compound with chemical formula (III) structure is with reacting for methine halide compound It is carried out in the environment containing inert gas to provide protective effect (such as preventing unnecessary oxidation reaction from generating), and this Inert gas may include, but are not limited to nitrogen, argon gas or helium.
In one embodiment, the virus is influenza virus, Chicken Infectious Anemia Virus (chicken infectious Anemia virus, CAV), Newcastle virus (newcastle disease virus, NDV), avian infectious bursal disease poison (infectious bursa disease virus, IBDV), pig reproduction and breathing syndrome virus (porcine Reproductive and respiratory syndrome virus, PRRSV), second type porcine circovirus (porcine Circovirus type 2, PCV2), swine fever virus (classical swine fever virus, CSFV), porcine respiratory Coronavirus (porcine respiratory coronavirus, PRCV), pig parvoviral (porcine Parvovirus, PPV) or transmissible gastroenteritis of swine virus (transmissible gastroenteritis virus, TGEV).In another embodiment, the virus is influenza virus, and this influenza virus is A type influenza virus.Influenza virus It can be according to antigenicity caused by virus nucleoprotein (nucleoprotein, NP) and stromatin (matrix protein, MP) Albumen distinguishes tri- type of A, B, C.
In one embodiment, said medicine is for preventing or treating individual infected with influenza A virus." sense referred to herein Dye influenza A " refers to the infection as caused by influenza A.In addition, according to viral big envelope glycoprotein hemagglutination Plain (HA) and the various combination of neural amino acid zymoprotein (NA), influenza A can further discriminate between into different hypotypes.? In one embodiment, the influenza A for test may include, but are not limited to H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H5N2, H5N3, H5N6, H5N8, H6N1, H7N9 and H10N8.In a preferred embodiment In, the influenza A for test is H1N1.
" individual " referred to herein (subject) refers to the animal comprising the mankind, is subject to various embodiment party of the invention Formula.
" prevention " referred to herein refers to the preventive measure for protecting or preventing the individual of not yet virus infection from being done. " treatment " referred to herein refers to after individual virus infection, various embodiments through the invention can cure, improve, mitigating, Mitigate, influence or change the infection situation of this virus.In a preferred embodiment, the individual for receiving prevention or treatment is lactation Class or birds.Aforementioned mentioned mammality, may include, but are not limited to the mankind, mouse, pig, sheep, ox, horse, cat, rabbit, deer, monkey and Dog.Aforementioned mentioned birds, may include, but are not limited to pigeon, chicken, duck and goose.In one embodiment, when receiving prevention or treatment Individual be the mankind when, this individual can be newborn, teenager or adult.Above-mentioned newborn refers to (packet in birth 28 days Containing 28 days) baby.
When cell stage test, in one embodiment, unpredictably discovery is made using aforementioned various different compounds Standby medical composition can be used for reducing cell by the infection of influenza A.In some embodiments, above-mentioned cell is Derived from cell strain including but not limited to BHK-21 cell, chicken embryo fetus cells, CHO cell, CHO-K1 cell, CHO-K1 cell, NS-1 cell, MRC-5 cell, WI -38 cell, 3T3 cell, 293 cells, Per.C6 cell, BSC cell, HeLa cell, HepG2 cell, LLC-MK cell, CV-1 cell, RAF cell or LLCPK cell.For example, in certain embodiments, use In test cell be BHK-21 cell.BHK-21 cell by before H1N1 virus infection above-mentioned or infection after, if through benzene 2, The processing of 4- dimethoxy -6- toluene -1,3- glycol, can effectively promote the survival rate of BHK-21 cell.Above-mentioned benzene 2,4- dimethoxy The concentration of base-6- toluene-1,3- glycol is about 3.125-100 μ g/ml.In some embodiments, benzene 2,4- dimethoxy -6- Dosage used in toluene -1,3- glycol may be, for example, 3.125 μ g/ml, 6.25 μ g/ml, 12.5 μ g/ml, 25 μ g/ml, 50 μ G/ml or 100 μ g/ml.
In addition, injury of lungs caused by lung inflammation (lung injury) is because of stream after individual is because of influenza infection Feel dead key factor.In one embodiment, the individual that the drug is bestowed via foregoing pharmaceutical treatment or prevention property, can have Effect reduces the individual lung by the infective dose of influenza A.In one embodiment, this drug can reduce the individual lung because Injury of lungs caused by infected with influenza A virus, such as the situation that immunocyte ball infiltrates in alveolar, or because inflammation is made At bronchus swelling.In another embodiment, this drug can also reduce the situation of inflammation cells reaction.
Rise in addition, inflammatory response caused after virus infection also results in the relevant cytohormone of inflammation in individual. These cytohormones are immune-related cytohormone, and inflammation can be then caused when immune response degree is excessively high.In an embodiment In, drug of the invention, which can reduce, to be situated between white plain (IL-6), tumor necrosis factor (TNF) and is situated between -1 β of white element (IL-1 β) in being felt Performance amount in dye individual.
According to certain embodiments of the present invention, unpredictably find that the drug is needed for capable of being promoted in animal experiment The survival rate of individual infected with influenza A virus.In one embodiment, the dosage that said medicine is bestowed is the individual per kilogram Weight bestows 12.5-37.5 milligrams.In one embodiment, the dosage that said medicine is bestowed is that the individual per kilogram of body weight is applied Give 15 milligrams, 17.5 milligrams, 20 milligrams, 22.5 milligrams, 25 milligrams, 27.5 milligrams, 30 milligrams, 32.5 milligrams or 35 milligrams.It lifts For example, in certain embodiments, the individual for receiving prevention or treatment is mammality or birds.Aforementioned mammality or birds sense After contaminating the viral preceding or virus of H1N1, if bestowing 25 milligrams of drug per kilogram of body weight of the invention, its survival can be effectively improved Rate.In a preferred embodiment, the drug bestowed include benzene 2,4- dimethoxy -6- toluene -1,3- glycol, receive prevention or The individual for the treatment of is mammality or birds, and preferably administration dosage is that the individual per kilogram of body weight bestows 25 milligrams.This hair Bestowing for bright drug is harmless for the individual, implies that the generation for not having side effect.In addition, in some embodiments, this The drug of invention is to bestow the individual immediately after bestowing the individual or virus infection immediately before virus infection.In an embodiment In, said medicine is to be used to prepare the drug for treating or preventing individual infected with influenza A virus, can be deployed according to dosing mode At various dosage forms, such as pastille, liquor, particle, capsule, pulvis or combinations thereof.
Embodiments of the present invention still include pharmaceutically acceptable diluent, excipient or carrier.It should be understood that It is that above-mentioned pharmaceutically acceptable diluent, excipient or carrier can be compatible with effective component, and to the individual nothing bestowed Evil.In one embodiment, diluent may include, but are not limited to buffered saline, potassium chloride, potassium hydrogen phosphate, biphosphate Potassium, sodium sulphate, sodium chloride, potassium hydroxide or combinations thereof.Above-mentioned diluent can be used for adjusting drug of the invention osmotic pressure, PH-value, reduction/increase density or solubility.
In one embodiment, excipient can be antioxidant, sweetener, flavoring agent, colorant, preservative or combinations thereof.
In one embodiment, carrier may include, but are not limited to various emulsifiers, alcohol-based liquid, polysorbate, glycerol or A combination thereof.Above-mentioned alcohol-based liquid can be but be not limited to monohydric alcohol or polyalcohol, for example, monohydric alcohol includes methanol, ethyl alcohol, positive third Alcohol, isopropanol, n-butanol, the second butanol, third butanol, isobutanol, n-hexyl alcohol, n-heptanol, n-octyl alcohol or Decanol.And In one embodiment, polysorbate may be, for example, polysorbate20 (Tween 20), polysorbate40 (Tween 40), gather Sorbitol ester 60 (Tween 60), polysorbate80 (Tween 80) or combinations thereof.
According to some embodiments, drug of the invention still cooperates with other supplements to be used together or be prepared into other Composition.Above-mentioned supplement including but not limited to polysaccharide body (polysaccharides), adenosine (adenosine), vitamin, Three note class compounds (triterpenoids), steroid, lignin or combinations thereof.
In a state sample implementation, drug of the invention still include antibody, immunoglobulin or it is other known it is immune because Sub- therapeutic agent reinforces the effect of drug of the invention using immunotherapy for the specificity of object (such as virus).
To confirm that embodiments of the present invention can prepare the drug with treatment or prevention influenza virus then by following examination It tests and is illustrated, it is noted that following embodiments are provided merely as an demonstration purpose, are not intended to limit the present invention.
The preparation of compound
Compound 1 used in embodiment 1, embodiment 2, embodiment 3 and embodiment 16, compound 2, compound 3 and chemical combination Object 16 is purchased from Sigma Co., USA, respectively 1,2,3,4- tetramethoxy -5- toluene, 1,2- dimethoxy benzene, 1,2,3- Trimethoxy-benzene and 1,2,4- trimethoxy-benzene.Wherein compound 1 and compound 16 are for closing as compound in embodiment At starting material.
Then Fig. 1 is please referred to, is the flow chart of the preparation method of compound in embodiment, utilizes following step 100-400 The compound of synthetic example.
Step 100: at room temperature, 1,2,3, the 4- tetramethyls of 4.43 mMs (mmol) are added in 25 milliliters of round-bottomed bottles Oxygroup -5- toluene (compound 1) is then added in the methylene chloride (dichloromethane, DCM) of 6 milliliters (mL), then plus Enter 0.65 gram of aluminium chloride (AlCl3) then fill argon gas.40 DEG C of sustained responses are heated to after 16 hours with thin layer chromatography (thin layer chromatorgraphy, TLC) is tracked.Above-mentioned reactant is then moved into room temperature cooling, 30 millis are added It rises ice water and methylene chloride extracts.Finally utilize column chromatography, n-hexane (hexane) and acetic acid in varing proportions Ethyl ester (ethyl acetate, EA) can obtain 2,3,4- trimethoxy -6- sylvans, 2,4- dimethoxy as agent purifying is purged with Base -6- toluene -1,3- glycol, 3,4- dimethoxy -6- toluene -1,2- glycol, 3,4- dimethoxy -5- toluene -1,2- glycol And 3,6- dimethoxy-4 '-toluene -1,2- glycol, respectively the compound 4-8 of embodiment 4-8.
The starting material (compound 1) of abovementioned steps 100 is if change compound 16 into, i.e., by 1,2,3,4- tetramethoxy -5- first Benzene changes 1,2,4- trimethoxy-benzenes into, can be made with same steps 3,4- dimethoxy phenol, 4,5- dimethoxy -2- sylvan, 2,5- dimethoxy phenol and 2,4- dimethoxy phenol, respectively the compound 19-22 of embodiment 19-22.
Step 200: at room temperature, 1.49 mMs of 3,4- dimethoxy -6- first is added in 25 milliliters of round-bottomed bottles Benzene -1,2- glycol (compound 6) is then added 250 milligrams of lithium hydroxides (LiOH) and fills argon gas afterwards, adds 3 milliliters of dimethyl Formamide (dimethylformamide, DMF).Then it is slowly added to 0.42 milliliter of methylene bromide (dibromomethane), it is heated to tracking after 80 DEG C of sustained responses stay overnight (overnight) with thin layer chromatography. After above-mentioned reactant moves to room temperature cooling, 15 milliliters of ice water and 15 milliliters of ethyl acetate extractions are added, add isometric Saturated salt solution.Column chromatography is finally utilized, n-hexane and ethyl acetate in varing proportions, can as agent purifying is purged with 4,5- dimethoxy -7- toluene simultaneously [d] [1,3] dioxane is obtained, is the compound 9 of embodiment 9.
4,5- dimethoxy can be made if changing compound 7 into the starting material (compound 6) of abovementioned steps 200 with same steps Base -6- toluene simultaneously [d] [1,3] dioxane is the compound 10 of embodiment 10.
4,7- dimethoxy can be made if changing compound 8 into the starting material (compound 6) of abovementioned steps 200 with same steps Base -5- toluene simultaneously [d] [1,3] dioxane is the compound 11 of embodiment 11.
Step 300: at room temperature, 4.43 mMs of 4,7- dimethoxy -5- toluene is added in 25 milliliters of round-bottomed bottles And [d] [1,3] dioxane (compound 11), 2 milligrams of acetonitriles (acetonitrile), 1.1 mMs of N- iodos are then added Succimide (N-iodosuccinimide, NIS) adds 0.3 milliliter of trifluoroacetic acid (CF3COOH), and with masking foil It encases.50 DEG C of sustained responses are heated to track after 5 hours with thin layer chromatography.It is cold that room temperature is moved to above-mentioned reactant But after, 5 milliliters of sodium dithionites (sodium dithionite) is added.Then it is extracted, is added with 6 milliliters of methylene chloride 10 milliliters can obtain iodo- 4, the 7- dimethoxy -6- toluene of 5- simultaneously [d] [1,3] dioxane with water extraction, be the change of embodiment 12 Close object 12.
1- iodo- 2,3 can be made if changing compound 1 into the starting material (compound 11) of abovementioned steps 300 with same steps, 4,5- tetramethoxy -6- toluene are the compound 13 of embodiment 13.
1- iodo- 2 can be made if changing compound 16 into the starting material (compound 11) of abovementioned steps 300 with same steps, 4,5- trimethoxy-benzenes are the compound 17 of embodiment 17.
Step 400: at room temperature, 10 mMs of iodo- 4, the 7- dimethoxy -6- of 5- is added in 25 milliliters of round-bottomed bottles Toluene simultaneously [d] [1,3] dioxane (compound 12), 130 milligrams of cuprous iodides (CuI), 130 milligrams, acid chloride (Pd (OAc)2), 1.0 milliliters of triethylamines (trimethylamine, Et are then added3N), it is heated to 60 DEG C to be reacted, and in anti- It should be slowly added to 192 milligrams of 2- methyl but-1-ene -3- alkynes (2-methylbut-1-en-3-yne) on the way and react 36 hours, Then it is tracked with thin layer chromatography.After above-mentioned reactant moves to room temperature cooling, 15 milliliters of ethyl acetate extractions are added It takes, then filters, wash away impurity, concentration and vacuum drying with 6 milliliters of water, finally utilize column chromatography, in varing proportions N-hexane and ethyl acetate as purge with agent purifying can obtain 4,7- dimethoxy -5- methyl -6- (3- methyl butyl- 3- alkene -1- Alkynes -1- base) benzo [d] [1,3] dioxane is the compound 15 of embodiment 15.
The starting material (compound 12) of abovementioned steps 400 can be made 1,2,3,4- if changing compound 13 into same steps Tetramethoxy -5- methyl -6- (3- methyl fourth 3- alkene -1- alkynes -1- base) benzene is the compound 14 of embodiment 14.
The starting material (compound 12) of abovementioned steps 400 can be made 1,2,4- tri- if changing compound 17 into same steps Methoxyl group -5- (3- methyl butyl- 3- alkene -1- alkynes -1- base) benzene is the compound 18 of embodiment 18.
As described in following table one, it is modulated into the solution of various concentration then using compound 1-22 to carry out subsequent various tests.
Table one
Cell culture
Present embodiment is baby hamster kidney cell BHK-21 (ATCC CCL-10, baby hamster for the cell of test kidney cells).When cell carries out squamous subculture when growing full to eight points on culture medium.Firstly, cell culture fluid is absorbed, Residual serum and cell metabolite are washed away with phosphate buffer (phosphate buffered saline, PBS), is added 1 After milliliter trypsase-EDTA (typsin-EDTA), it is placed at 37 DEG C and acts on 3-5 minutes.Then with 0.5 milliliter of fetal calf serum (fetal bovine serum, FBS) stops the effect of trypsase-EDTA, is cleaned and is collected with RPMI-1640 culture solution Cell.It is sub-packed in 50 milliliters of centrifuge tubes, with 500G centrifugation 5 minutes at a temperature of 4 DEG C, removes supernatant, then with RPMI- 1640 culture medium suspension cell after carrying out cell count, is finally further cultured in the cell culture fluid containing 10% fetal calf serum.
Virus culture
It is numerous with hole progress of sealing with wax after injection influenza A 100 microlitres of (H1N1) (μ l) to the chorioallantoic membrane of egg embryo It grows, places and cultivated 1 to 2 day in incubator, then be placed in 4 DEG C of waiting condensations.Finally liquid in chorioallantoic membrane is extracted out, is placed in -80 DEG C It saves.
Virus titer measurement
BHK-21 cell inoculation is placed in 6 hole culture plates containing 5%CO when squamous subculture2Incubator.It is thin to it Born of the same parents cultivate to 6 to 7 points it is full when, draw cell culture fluid, residual cell liquid cleaned with PBS, and the disease of different extension rates is added Malicious suspension.After being placed in incubator infection 1 hour, viral suspension is absorbed, is added and contains 2%FBS and 2% Ago-Gel The RPMI-1640 culture solution of (agarose gel) stands and cultivates 2 to 3 days in incubator after its solidification.It is subsequently added into 2 10% Formalin of milliliter (formalin) removes gel after standing 1 hour at room temperature, with 1% crystal violet (crystal Violet it) dyes 1 hour.Remaining crystal violet is finally washed away with clear water, viral class quantity is calculated, makes virus titer.Unit is PFU/ml(plaque forming unit)。
Statistical analysis
The data of test result indicate it with average value (means) ± standard error (SEM), and with Student ' s t- Test respectively handles the otherness between group.It is indicated with asterisk " * " with significant difference, * expression p < 0.05；* expression p < 0.01；* * indicates p < 0.001.
Cytotoxicity test
Cytotoxicity test is detected using MTS test (MTS assay).With 1 × 104The BHK-21 of cells/well is thin Born of the same parents' amount is inoculated in 96 hole culture plates, is placed at 37 DEG C and is contained 5%CO2Incubator in cultivate 24 hours after, so that it is waited for cell It pastes, culture acts on 48 hours the sample to be tested and cell for being separately added into various concentration in the incubator.Finally, MTS examination is added Agent surveys it in the light absorption value of wavelength 490nm, to detect cell survival rate after being protected from light in culture solution 1 hour.
The various compounds (compound 1-22) of measurement present embodiment are able to for influenza virus using MTS test Prevention or therapeutic effect.In embodiment 1-22, it is 3.125 μ g/ that each compound, which is all modulated into 6 kinds of different concentration for test, Ml, 6.25 μ g/ml, 12.5 μ g/ml, 25 μ g/ml, 50 μ g/ml and 100 μ g/ml.The cell for not doing any processing is control group (control), other other relative survival rates of processing group can and with the survival rate of control group be calculated for 100%.Only infection disease Group that is malicious but not doing any prevention and treatment processing is virus group.Further, since compound 1-22 is all using DMSO as molten Agent, therefore DMSO group refers to the control group only handled after virus infection with DMSO.Tamiflu is commercially available anti-virus formulation, as just Control group experimental concentration is respectively 25 μ g/ml, 50 μ g/ml, 100 μ g/ml, 200 μ g/ml, 400 μ g/ml and 800 μ g/ml.Root According to above-mentioned, this test is divided into two big groups according to untested compound 1-22 addition time point then:
(1) prevent (prophylaxis) test group: by BHK-21 cell culture in 96 hole culture plates, being first added different The compound 1-22 of concentration is acted on 1 hour in incubator.Then add virus infection dosage (multiplicities of Infection, MOI) it is acted on 1 hour for 0.1 H1N1 influenza virus.Then culture solution is removed, is added containing 2%FBS's PRMI-1640 culture solution is placed in 37 DEG C and contains 5%CO2Incubator in cultivate 48 hours, with MTS test survey its cell survival Rate.
(2) treat (treatment) test group: by BHK-21 cell culture in 96 hole culture plates, MOI, which is first added, is 0.1 H1N1 influenza virus acts on 1 hour.Then virus is removed again, adds the compound 1-22 of various concentration in incubator Effect 1 hour.Culture solution is finally removed, the PRMI-1640 culture solution containing 2%FBS is added, is placed in 37 DEG C and contains 5%CO2's It is cultivated 48 hours in incubator, is tested with MTS and survey its cell survival rate.
Referring to Fig. 2 to Fig. 5, the cell survival rate of prophylactic tria group is shown.Any place is not done after virus infection as the result is shown The virus group survival rate of reason is only 35.27%.Compared with viral group, after the compound 1-22 of embodiment 1-22 is processed, all Can effectively pre- preventing virus infection, and have significant difference.Embodiment 20 when 12.5 μ g/ml of dosage survival rate up to 80% More than.And embodiment 4, embodiment 5 and 9 effect of embodiment are best, all close to 80% and dosage correlation is presented in survival rate (dose-dependent)。
With continued reference to Fig. 6 to Fig. 9, the cell survival rate of therapeutic test group is shown.Do not appoint after virus infection as the result is shown The virus group survival rate of where reason is only 36.52%.Compared with viral group, the compound 1-22 through embodiment 1-22 is processed Afterwards, virus infection all can be effectively treated, and there is significant difference.In addition, Tamiflu group is shown in 25 μ g/ml of concentration, 50 μ When g/ml, 100 μ g/ml, 200 μ g/ml, 400 μ g/ml and 800 μ g/ml, survival rate is respectively 57.60 ± 4.73%, 55.51 ± 4.07%, 66.39 ± 4.68%, 61.39 ± 3.72%, 55.57 ± 2.76%, 54.18 ± 4.79%.Embodiment 5 in addition to It is presented except dosage correlation in treatment stage, in experimental concentration 50 μ g/ml and 100 μ g/ml all close to 80%, effect is also higher than The Tamiflu of positive control group.According to above-mentioned, the 5 further progress animal experiment of compound of selection example 5 then.
Zootype is established
This test is mouse using the BALB/c product purchased from National Laboratory Animal center, and all mouse are all raised in Taiwan Ocean university life academy of sciences animal house.
Animal experiment mode is divided into four groups by this test:
(1) control group: mouse sucks PBS when attacking poison in attacking malicious front tube hello PBS with nasal cavity.
(2) viral group: mouse is in attacking malicious front tube hello PBS, with the H1N1 virus of nasal cavity sucking 500PFU/ mouse when attacking poison.
(3) Tamiflu group: mouse is in attacking malicious front tube hello PBS, with the H1N1 disease of nasal cavity sucking 500PFU/ mouse when attacking poison Poison carries out pipe with about 20 milligrams of daily per kilogram of body weight of Tamiflu (20mg/kg/day) and feeds after one hour.
(4) embodiment 5: mouse is in attacking malicious front tube hello PBS, with the H1N1 virus of nasal cavity sucking 500PFU/ mouse when attacking poison After one hour, pipe is carried out with about 25 milligrams of daily per kilogram of body weight of compound 5 (25mg/kg/day) and is fed.
Blood analysis is immune
Mouse is in the 9th day with CO2After sacrifice, Mouse whole blood is collected in a manner of Culling heart blood.Utilize blood cell analysis machine (Exigo Veterinary Hematology analyzer, Medonic, Stockholm, Sweden) carries out blood analysis.
As shown in Figure 10, display is after above-mentioned four kinds different groups are processed, white blood cell (leukocyte), lymph corpuscle (lymphocyte), intermediate cell (intermediate cell) and neutrophil cell (neutrophile Granulocyte cell quantity).Compared to control group, in the mouse blood after embodiment 5 is processed white blood cell, Lymph corpuscle, intermediate cell and neutrophil cell do not have significant difference.It follows that embodiment 5 will not influence exempting from for mouse Epidemic disease cell quantity.
Real-time and quantification polymerase chain reaction (Real-time PCR) detects viral performance amount
Since H1N1 virus is RNA virus, therefore reverse transcription is that the side cDNA can carry out determining immediately again after need to first extracting its RNA Measure polymerase chain reaction.
External member RNeasy is extracted using commercially available RNA after lung tissue's block grinds it with grinding rod firstly, weighing (QIAGEN, Germantown, USA) carries out total serum IgE extraction, takes 2 μ l RNA and DEPC (diethylpyrocarbonate) water 10 times of dilution surveys it and is converted into RNA concentration and purity after the light absorption value under wave 260nm and 280nm wavelength.It then takes and has determined The RNA of amount is added DEPC water and mends to 12.5 μ l, add 1 μ l Oligo (dT) introduction in PCR pipe, reacts 2 points in 72 DEG C It is put immediately into ice bath after clock, 4 μ l, 5 times of buffers, 1 μ l 10mM dNTP mixture, 1 μ l M-MLV reverse transcriptase are sequentially added And 0.5 μ l RNase inhibitor, it is reacted 1 hour in 42 DEG C after evenly mixing, then in 95 DEG C of reactions removal reverse transcription in 5 minutes The activity of enzyme can obtain the cDNA of aforementioned RNA.
Then, it takes 5 μ l through 100 times of diluted cDNA, is subsequently added into 12.5 μ l iQTM SYBR Supermix 10 μM of two-way introductions of (Bio-Rad, Hercules, USA) and each 0.5 μ l, being eventually adding sterile water makes to react total volume 25 μl.With PCR reactor (iCyclerMulticolor Real-Time PCR Detection System,BIO-RAD) Polymerase chain reaction is carried out using the most suitable tack temperature of each introduction, the performance of H1N1 nucleoprotein gene can be obtained to the end of its reaction Amount.
Referring to Fig.1 1, display is after aforementioned four kinds different groups are processed, H1N1 nucleoprotein gene performance amount.Compared to Viral group not processed attacked after poison, and the group of Tamiflu and embodiment 5 all declines about 5 times or more and there were significant differences.This Outside, embodiment 5 declines degree approximation Tamiflu group, it follows that embodiment 5 can be such that virus infectivity declines.
Mouse lung pathological tissue specimens paraffin embedding slices
Mouse lung tissue is immersed in 10% Formalin solution, in 4 DEG C stand one day after, sequentially with 70%, 90% with And 100% alcohol and dimethylbenzene be dehydrated.Histotomy is carried out after paraffin embedding.Slide is placed in 50 DEG C of baking ovens and is dried Piece then can save or carry out tissue staining in 4 DEG C.
Hematoxylin eosin staining (Hematoxylin and eosin stain, H&E stain)
Before dyeing, the paraffin of aforementioned surrounding structure is covered into water with dimethylbenzene dewaxing, slide is impregnated into hematoxylin dyeing later With flowing water flushing 15 minutes after 10 seconds.Then it to be rinsed with flowing water after eosin stains 1 minute, after slide is dry, sequentially impregnates 70%, 90% and 100% alcohol and be dehydrated for dimethylbenzene 5 minutes, after slide is dry can mounting save.
As shown in figure 12, it attacks after poison and does not do viral group for the treatment of processing, the range that surrounding alveolar has immunocyte ball to infiltrate Intensive compared with control group, injury of lungs caused by showing it is more serious.Compared to viral group, treated through Tamiflu and embodiment 5 Mouse its Infiltrating extrent it is more slight.It can thus be appreciated that embodiment 5 can reduce injury of lungs caused by influenza virus.
Immunofluorescence dyeing (Immunofluorescence stain)
Slide is made using aforementioned specimens paraffin embedding slices, after five minutes in the effect of 65 DEG C of baking ovens, by slide with dimethylbenzene into After then cleaning three times with PBST (PBS-Tween 20), 5% bovine serum albumin (bovine serum is added in row dewaxing Albumin, BSA) filled up (blocking) effect 1 hour.It is cleaned three times, is added small with PBST after filling up effect Mouse anti influenza A/WSN/33M protein antibodies (Mouse anti-influenza A/WSN/33M-protein), are placed in 4 DEG C of reactions (overnight) overnight.Next day is cleaned three times with PBST, and fluorescein isothiocyanate-goat anti-mouse antibody (FITC- is added Goat anti mouse IgG) effect 1 hour, then three times with PBST cleaning, with the 4' of 1 μ g/ml, 6- diamidino -2- phenyl Indoles (4', 6-Diamidino-2-phenylindole dihydrochloride, DAPI) contaminates core, aobvious followed by fluorescence The performance of micro mirror observation tissue fluorescence signal.
Referring to Fig.1 3, attacking viral group for not doing treatment processing after poison as the result is shown according to fluorescent staining has a large amount of viruses to deposit ?.Conversely, 5 fluorescence signal of embodiment reduces many, and similar with Tamiflu result.Demonstrate again that embodiment 5 can effectively drop The virus infection amount of low lung tissue.
Mouse survival rate and changes of weight
Zootype as the aforementioned is established, and test group is control group, viral group, Tamiflu group and embodiment 5.But it is small Mouse observes the survival rate after its virus infection and records its changes of weight without sacrificing.
4 and Figure 15 referring to Fig.1, display mouse is after four kinds of groups are processed, and 19 days survival rates and weight become by a definite date Change.The control group mouse survival rate that is not infected by the virus until 19 days is 100%；Only independent virus infection is not for virus group Any treatment is done, therefore started to occur at the 9th day dead, mouse survival rate only remains 25% when by the 19th day；Tamiflu group is Start within 14 days to occur dead, mouse survival rate is 40% when by the 19th day；The group that compound 5 through embodiment 5 is handled, Start within 14th day to occur dead, mouse survival rate is up to 80%, and compared to other groups when by the 19th day, and weight is gradually Go up to original weight.
In conclusion embodiments of the present invention are using aforementioned 22 kinds of compounds, the drug being prepared into can be used for controlling Treat or prevent influenza A.Specifically, A type stream can be not only reduced using drug prepared by embodiments of the present invention Influenza Virus infective dose and injury of lungs caused by it is reduced, and mouse survival rate can be promoted in animal experiment and reduce body The percentage declined again.
The feature of the several embodiments of foregoing general description is so that persons skilled in the art is better understood this disclosure Aspect.Persons skilled in the art designs or modifies it will be appreciated that can easily be used as this disclosure for realizing identical purpose And/or reach the other methods of the same advantage of the embodiment introduced herein or the basis of processing procedure.Persons skilled in the art also answers Recognize, such equivalent without prejudice to this disclosure spirit and scope, and can without prejudice to this disclosure spirit and Various changes can be made in this in the case where scope, substitution and change.

Claims (10)

1. a kind of medical composition is used to prepare the purposes for treating or preventing the drug of individual virus infection, which is characterized in that its In the medical composition include an effective component, the effective component is selected from by 1,2,3,4- tetramethoxy -5- toluene, 1,2- Dimethoxy benzene, 1,2,3- trimethoxy-benzene, 2,3,4- trimethoxy -6- sylvan, 3,4- dimethoxy -6- toluene -1,2- Glycol, 3,4- dimethoxy -5- toluene -1,2- glycol, 2,4- dimethoxy -6- toluene -1,3- glycol, 3,6- dimethoxy - Simultaneously [d] [1,3] dioxane, 4,5- dimethoxy -6- toluene is simultaneously for 4- toluene -1,2- glycol, 4,5- dimethoxy -7- toluene [d] [1,3] dioxane, 4,7- dimethoxy -5- the toluene simultaneously iodo- 4,7- dimethoxy -6- first of [d] [1,3] dioxane, 5- Benzo [d] [1,3] dioxane, the iodo- 2,3,4,5- tetramethoxy -6- toluene of 1-, 1,2,3,4- tetramethoxy -5- methyl -6- (3- methyl fourth 3- alkene -1- alkynes -1- base) benzene, 4,7- dimethoxy -5- methyl -6- (3- methyl butyl- 3- alkene -1- alkynes -1- base) benzene And [d] [1,3] dioxane, 1,2,4- trimethoxy-benzene, the iodo- 2,4,5- trimethoxy-benzene of 1-, 3,4- dimethoxy phenol, 4,5- Group composed by dimethoxy -2- sylvan, 2,5- dimethoxy phenol, 2,4- dimethoxy phenol and combinations thereof.
2. purposes as described in claim 1, which is characterized in that wherein the drug is to reduce cell by the infection of virus.
3. purposes as described in claim 1, which is characterized in that wherein the drug can reduce the individual pulmonary infection virus Quantity.
4. purposes as described in claim 1, which is characterized in that wherein the drug is to reduce the individual pulmonary infection virus institute Caused by injury of lungs.
5. purposes as described in claim 1, which is characterized in that wherein the drug is to reduce inflammation cells reaction.
6. purposes as described in claim 1, which is characterized in that wherein the dosage of the drug is the individual per kilogram of body weight Bestow 12.5-37.5 milligrams.
7. purposes as described in claim 1, which is characterized in that wherein the virus be H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H5N2, H5N3, H5N6, H5N8, H6N1, H7N9, H10N8, chicken infectious anemia Malicious (CAV), Newcastle virus (NDV), avian infectious bursal disease malicious (IBDV), pig reproduction and breathing syndrome virus (PRRSV), Second type porcine circovirus (PCV2), swine fever virus (CSFV), porcine respiratory coronavirus (PRCV), pig parvoviral (PPV) Or transmissible gastroenteritis of swine is viral (TGEV).
8. purposes as described in claim 1, which is characterized in that wherein the drug be can reduce be situated between white plain (IL-6), tumour it is bad The performance amount of necrosis factor (TNF) and Jie -1 β of white element (IL-1 β).
9. a kind of manufacturing method of compound, characterized by comprising:
In the presence of aluminium chloride, ring that the compound of the structure with chemical formula (III) and methylene chloride are protected in argon gas It is reacted in border, to form the compound of the structure with chemical formula (I),
The wherein structure of chemical formula (III) are as follows:
In chemical formula (III), R7With R8It is to be independently selected from the group as composed by hydrogen, methoxyl group, hydroxy and methyl；
Chemical formula (I) are as follows:
In chemical formula (I), R1、R2、R3With R4It is to be independently selected from the group as composed by hydrogen, methyl, methoxyl group and hydroxy.
10. method as claimed in claim 9, which is characterized in that wherein R1For hydroxy, R2For hydroxy, R3For methoxyl group, And R4For hydrogen or methyl.
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