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 PDFInfo
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- 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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- 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
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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
- A61K31/33—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
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- 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
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- 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
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- 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
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- 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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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
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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| TW106124631 | 2017-07-21 |
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| CN109276563B (en) | 2021-04-09 |
| TWI650120B (en) | 2019-02-11 |
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