CN103830233B - 5-(1,2,4-triazol-1-yls) medical usage of-2-phenylacetamido-thiazole - Google Patents
5-(1,2,4-triazol-1-yls) medical usage of-2-phenylacetamido-thiazole Download PDFInfo
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- CN103830233B CN103830233B CN201410065694.7A CN201410065694A CN103830233B CN 103830233 B CN103830233 B CN 103830233B CN 201410065694 A CN201410065694 A CN 201410065694A CN 103830233 B CN103830233 B CN 103830233B
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Abstract
The present invention relates to 5 (1,2,4 triazole 1 base) the 2 phenylacetamido-thiazoles application in preparing influenza virus neuraminidase inhibitor shown in chemical constitution Formulas I:In formula, R is selected from: C1~C2Alkyl, C3~C4Straight or branched alkyl；X1~X5It is selected from: hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl.
Description
Technical field
The present invention relates to the preparation method of compound, specifically 5-(1,2,4-triazol-1-yls)-2-phenylacetamido-thiazole
Preparation method and application in preparing influenza virus neuraminidase inhibitor.
Background technology
Influenza surface has two kinds of glycoproteins: hemagglutinin (HA) and neuraminidase (NA).Owing to NA is influenza virus
Mutation process in there is relative conservative so that it is become design, synthesis the extraordinary target of Tamiflu.NA can be catalyzed and split
Solve the N-acetylamino neuraminidase of host cell surface glycoprotein end, discharge the Influenza Virosomes of maturation, and stop
The gathering of new virus body.Additionally, NA is by changing the carbohydrate portions of surface glycoprotein HA, strengthen toxicity, promote virus
Discharge from infected host cell, cause or increase the weight of flu-like symptom.Therefore, NA inhibitor can be pressed down by suppression NA activity
Influenza virus processed is replicated and toxicity.
People infects bird flu, is the human diseases caused by bird flu virus.Influenza virus generally can be divided into A type, Type B and
C-type, the bird flu that wherein A type is the most usually said, people and many animals there are is pathogenicity.The antigenic variability of influenza A
The strongest, often it is classified as 16 HA hypotype (H according to the antigenic difference of HA and NA1~H16) and 9 NA hypotype (N1~N9).So far
Find that the avian influenza virus subtype of energy direct infection people has: H5N1、H7N1、H7N2、H7N3、H7N7、H9N2、H7N9And H10N8Hypotype.Its
In, highly pathogenic H5N1Hypotype found first in Hong Kong in 1997 can the direct infection mankind, after in July, 2003, H5N1Fowl is flowed
Sense epidemic situation presents unprecedented breaking out, and involves Asia, North America, 17 countries and regions of Europe And Africa, causes hundreds of people
Infecting and dead, direct economic loss is up to 10,000,000,000 dollars.In March, 2003, there is H in Holland7N7Type bird flu also involves whole
Europe, human infection person reaches 83 examples, not only causes the injures and deaths of the mankind, has inflicted heavy losses on poultry farming simultaneously.In by the end of March, 2009,
Mexico breaks out people and infects H1N1Type swine flue epidemic situation is also diffused into all over the world, according to World Health Organization (WHO) on February 26th, 2010
A type H issued1N1Influenza global picture is reported, at least 16226 example patients of 213 countries and regions die from this big stream
Sense.Through gene sequencing, H1N1Type virus comprises human influenza virus, North America bird flu virus and North America, Europe, sub-swine flue
Viral gene fragment, for the mixing strain of several different plant species influenza virus, and non-individual one swine flue or bird flu virus.
In March, 2013, China finder first infects H7N9Bird flu case, ends December in 2013 26, and World Health Organization (WHO) announces
H7N9Bird flu makes a definite diagnosis 148 people, dead 43 people, and this epidemic situation causes economic loss to reach about 6,500,000,000 dollars.2013 the most extremely
During the January in 2014 of evening 12 on the 19th, the accumulative reporter in the whole nation infects H7N9Confirmed cases are more than 200 examples.In December, 2013 so far,
H7N9Being in again the state that comparison is active, " onset peak occurs again.”.H at present7N9Epidemic situation in the human world still in distributed state,
But it is mainly distributed on China region of Southeast, such as provinces such as Zhejiang, Shanghai, Guangdong.Adding up according to Xinhua News Agency, on January 1st, 2014 is extremely
26, the whole nation was made a definite diagnosis people and has been infected H7N9Bird flu case 96 example, 83 examples, dead 20 examples, wherein Zhejiang are made a definite diagnosis in province, Shanghai, Zhejiang and Guangdong three
Dead 12 examples, Guangdong 4-case death, Shanghai 4-case death, including 1 medical worker.
" people infects H to new edition7N9Bird flu diagnosis and treatment scheme " (be called for short " scheme ") point out, people infects H7N9Bird flu is by H7N9
The acute infections of respiratory tract disease that bird flu virus causes, wherein often can to merge acute respiratory distress comprehensive for severe pneumonia case
Levy, septic shock, even multiple organ dysfunction syndrome.Diagnosis and treatment scheme is to H7N9Bird flu one is new " identity identification ".Scheme is brighter
Really H7N9Gene source, the avian influenza virus subtype that can infect people is H5N1、H9N2、H7N7、H7N2、H7N3Deng, it is this time H7N9Fowl
Influenza virus.This virus is novel reassortant virus, and the gene source of coding HA is in H7N3, the gene source of coding NA is in H7N9, its
6 internal gene come from H9N2Bird flu virus [defends planning commission: H7N9It is not excluded for limited non-continuous human-to-human transmission, Beijing Times.
On January 27th, 2014].
Along with acceleration variation and different subtype virus increase of recombination probability between species of influenza virus, influenza is as generation
The seasonal epidemic sexually transmitted disease of boundary's scope, the threat to human health is increasingly being and severe.Neuraminidase (NA)
Inhibitor is the First Line medicine of anti-influenza type A virus.Neuraminidase (NA) inhibitor has Zanamivir, Oseltamivir
With type compounds such as Peramivir, wherein Oseltamivir is widely used.But research has been found that some Strain pair
Oseltamivir creates drug resistance, therefore in the urgent need to studying novel anti-influenza type A virus medicine.
Summary of the invention
It is an object of the invention to provide 5-(1 shown in chemical constitution formula I, 2,4-triazol-1-yls)-2-phenylacetylamino thiophene
Azoles application in preparing influenza virus neuraminidase inhibitor:
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X3、X4、X5It is respectively selected from: hydrogen, deuterium, C1~
C2Alkyl, C3~C4Straight or branched alkyl.
It is an object of the invention to provide 5-(1,2,4-triazol-1-yls) preparation method of-2-phenylacetamido-thiazole: its
The preparation manipulation being characterised by it is: 4-alkyl-5-(1,2,4-triazol-1-yls) thiazole-2-amine with phenylacetic acid at dichloromethane
In, with DMAP as catalyst, N, N '-dicyclohexylcarbodiimide is dehydrant, room temperature reaction 6.0 h, prepares
5-(1,2,4-triazol-1-yls)-2-phenylacetamido-thiazole；Preparation reaction is as follows:
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X3、X4、X5It is respectively selected from: hydrogen, deuterium, C1~
C2Alkyl, C3~C4Straight or branched alkyl.
The present invention compared with prior art has the advantage that
Finding 5-(1,2,4-triazol-1-yls first)-2-phenylacetamido-thiazole has resisiting influenza virus neuraminidase
Activity
Detailed description of the invention
Embodiment 1
The 4-tert-butyl group-5-(1,2,4-triazol-1-yls) preparation of-2-phenylacetamido-thiazole:
The 2.0 mmol 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is dissolved in 20.0 mL dichloromethane,
Add 2.2 mmol phenylacetic acids, 0.03 g DMAP (DMAP), after 0.5 h, add 2.2 mmol N, N'-bicyclo-
Hexyl carbodiimide (DCC), is stirred at room temperature, and reacts 6.0 h, and reactant liquor sodium bicarbonate aqueous solution neutralizes, and stands, and layering has
Machine layer anhydrous sodium sulfate is dried, and filters, and rotation is steamed, and column chromatography obtains the 4-tert-butyl group-5-(1,2,4-triazol-1-yls)-2-benzene second
Acylaminothiazole, yield 58.1%, m.p. 177 ~ 180 DEG C.1H NMR(400 MHz, CDCl3) δ: 1.09(s, 9H, 3 × CH3),
3.85(s, 2H, CH2), 7.33(d, J=7.2 Hz, 2H, C6H52,6-H), 7.38-7.45(m, 3H, C6H53,4,5-H),
8.11(s, 1H, C2N3H23-H), 8.25(s, 1H, C2N3H25-H), 9.03(s, 1H, NH).
Embodiment 2
5-(1,2,4-triazol-1-yls) preparation of-2-phenylacetamido-thiazole (I):
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X3、X4、X5It is respectively selected from: hydrogen, deuterium, C1~
C2Alkyl, C3~C4Straight or branched alkyl
Prepare the 5-(1 shown in chemical constitution formula I, 2,4-triazol-1-yls as described in Example 1)-2-phenylacetylamino
Thiazole.
Embodiment 3
5-(1,2,4-triazol-1-yls) the resisiting influenza virus neuraminidase activity of-2-phenylacetamido-thiazole
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite produced under neuraminidase effect
Under 360 nm irradiate and excite, can produce 450 nm fluorescence, the change of fluorescence intensity can react neuraminidase delicately
Activity.Enzyme both is from A/PR/8/34 (H1N1) virus stain
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza neuraminidase NA are suspended in reaction buffer
(pH 6.5), adds fluorogenic substrate MUNANA and starts reaction system, after 37 C hatch 40 minutes, adds reaction terminating liquid and terminates anti-
Should.Under the Parameter Conditions of a length of 450 nm of excitation wavelength 360 nm and transmitted wave, measure fluorescence intensity level.Reaction system
Fluorescence intensity can reflect the activity of enzyme.Decrement according to fluorescence intensity can be with the computerized compound suppression ratio to NA activity
3. detection sample: 5-(1,2,4-triazol-1-yls)-2-phenylacetamido-thiazole (I):
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight or branched alkyl；X1~X5It is selected from: hydrogen, deuterium, C1~C2Alkyl, C3~C4
Straight or branched alkyl
4. Activity Results
The preferred compound 4-tert-butyl group-5-(1,2,4-triazol-1-yls)-2-phenylacetamido-thiazole examines in response system
During survey concentration 40.0 μ g/mL, the suppression ratio to neuraminidase is 41.17%.
Claims (1)
- The 1.4-tert-butyl group-5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole is neural at preparation influenza H1N1 virus strain Application in propylhomoserin enzyme inhibitor.
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| CN109293644B (en) * | 2017-07-24 | 2021-07-27 | 湖南大学 | Application of 6-methyl nicotinate in preparation of NA inhibitor |
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