CN103830233A - Medical application of 5-(1, 2, 4-triazole-1-yl)-2-phenylacetyl aminothiazole - Google Patents

Abstract

The invention relates to an application of 5-(1, 2, 4-triazole-1-yl)-2-phenylacetyl aminothiazole shown as a chemical structural formula I (img file='597988dest_path_image001. TIF' wi='279' he='152'/) in preparing an influenza virus neuraminidase inhibitor, wherein R is selected from C1-C2 alkyl, C3-C4 straight chain or branch chain alkyl, and X1-X5 are selected from hydrogen, deuterium, C1-C2 alkyl and C3-C4 straight chain or branch chain alkyl.

Description

The medical usage of 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole

Technical field

The present invention relates to the preparation method of compound, specifically 5-(1,2,4-triazol-1-yl) preparation method of-2-phenylacetamido-thiazole and in the application of preparing in influenza virus neuraminidase inhibitor.

Background technology

There are two kinds of glycoproteins on influenza virus surface: hemagglutinin (HA) and neuraminidase (NA).Because NA has relative conservative in the mutation process of influenza virus, become design, the synthetic extraordinary target of Tamiflu.NA can catalytic pyrolysis host cell surface glycoprotein end N-acetylamino neuraminidase, discharge ripe influenza virus body, and stop the gathering of new virus body.In addition, NA, by changing the carbohydrate part of surface glycoprotein HA, strengthens toxicity, promotes virus to discharge from infected host cell, causes or increase the weight of flu-like symptom.Therefore, NA inhibitor can suppress that influenza virus is copied and toxicity by suppressing NA activity.

People infects bird flu, is the human diseases being caused by bird flu virus.Influenza virus generally can be divided into A type, Type B and C type, and wherein A type is usually said bird flu, and people and many animals are had to pathogenicity.The antigenic variability of A type influenza virus is the strongest, is often divided into 16 HA hypotype (H according to HA and the antigenic difference of NA ₁~ H ₁₆) and 9 NA hypotype (N ₁~ N ₉).So far the avian influenza virus subtype of finding energy direct infection people has: H ₅n ₁, H ₇n ₁, H ₇n ₂, H ₇n ₃, H ₇n ₇, H ₉n ₂, H ₇n ₉and H ₁₀n ₈hypotype.Wherein, highly pathogenic H ₅n ₁hypotype was found the energy direct infection mankind first in Hong Kong in 1997, after in July, 2003, and H ₅n ₁bird flu epidemic situation presents unprecedented breaking out, and involves Asia, North America, 17 countries and regions of Europe And Africa, causes hundreds of people to infect and death, and direct economic loss is up to 10,000,000,000 dollars.In March, 2003, there is H in Holland ₇n ₇type bird flu also involves whole Europe, and human infection person reaches 83 examples, has not only caused the mankind's injures and deaths, has inflicted heavy losses on poultry farming simultaneously.Mexico breaks out people and infects H in by the end of March, 2009 ₁n ₁type swine flue epidemic situation is also diffused into all over the world, the A type H issuing on February 26th, 2010 according to World Health Organization (WHO) ₁n ₁influenza whole world situation report, has at least 16226 routine patients of 213 countries and regions to die from this large influenza.Through gene sequencing, H ₁n ₁type virus comprises human influenza virus, North America bird flu virus and North America, Europe, sub-swine influenza virus genetic fragment, is the mixing strain of several different plant species influenza virus, but not independent a kind of swine flue or bird flu virus.In March, 2013, China first finder infects H ₇n ₉bird flu case, ends December in 2013 26, the H that World Health Organization (WHO) announces ₇n ₉bird flu is made a definite diagnosis 148 people, dead 43 people, and this epidemic situation causes economic loss to reach 6,500,000,000 dollars of left and right.In by the end of March, 2013 to 2,014 12 o'clock evenings of 19, on January, whole nation accumulative total reporter infects H ₇n ₉confirmed cases have exceeded 200 examples.In December, 2013 so far, H ₇n ₉in more active state, " onset peak occurs again again.”。H at present ₇n ₉epidemic situation still in distributed state, but is mainly distributed in China region of Southeast in the human world, as provinces such as Zhejiang, Shanghai, Guangdong.According to Xinhua News Agency's statistics, 1 to 26 January in 2014, the whole nation has been made a definite diagnosis people and has been infected H ₇n ₉bird flu case 96 examples, 83 examples are made a definite diagnosis in three provinces, Shanghai, Zhejiang and Guangdong, dead 20 examples, wherein dead 12 examples in Zhejiang, Guangdong 4-case death, Shanghai 4-case death, comprises 1 medical worker.

" people infects H to new edition ₇n ₉bird flu diagnosis and treatment scheme " (be called for short " scheme ") point out, people infects H ₇n ₉bird flu is by H ₇n ₉the acute infections of respiratory tract disease that bird flu virus causes, wherein severe pneumonia case often can merge adult respiratory distress syndrome, septic shock, even multiple organ dysfunction syndrome.Diagnosis and treatment scheme is to H ₇n ₉one of bird flu new " identity identification ".The clearer and more definite H of scheme ₇n ₉gene source, the avian influenza virus subtype that can infect people is H ₅n ₁, H ₉n ₂, H ₇n ₇, H ₇n ₂, H ₇n ₃deng, be this time H ₇n ₉bird flu virus.This virus is novel reprovision virus, and the gene source of coding HA is in H ₇n ₃, the gene source of coding NA is in H ₇n ₉, its 6 internal gene come from H ₉n ₂bird flu virus [is defended planning commission: H ₇n ₉do not get rid of limited non-lasting human-to-human transmission, Beijing Times. on January 27th, 2014].

Along with the acceleration variation of influenza virus and the increase of different subtype virus recombination probability between species, influenza, as the popular sexually transmitted disease of worldwide seasonality, increases and sternness just day by day to the threat of human health.Neuraminidase (NA) inhibitor is the First Line medicine of anti-influenza type A virus.Neuraminidase (NA) inhibitor has the type compounds such as Zanamivir, Oseltamivir and Peramivir, and wherein Oseltamivir is widely used.But research has found that some Strain have produced drug resistance to Oseltamivir, therefore in the urgent need to studying novel anti-influenza type A virus medicine.

Summary of the invention

The object of the present invention is to provide 5-(1 shown in chemical constitution formula I, 2,4-triazol-1-yl)-2-phenylacetamido-thiazole is in the application of preparing in influenza virus neuraminidase inhibitor:

In formula, R is selected from: C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl; X ¹, X ², X ³, X ⁴, X ⁵be selected from respectively: hydrogen, deuterium, C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl.

The object of the present invention is to provide 5-(1,2,4-triazol-1-yl) preparation method of-2-phenylacetamido-thiazole: the preparation manipulation that it is characterized in that it is: 4-alkyl-5-(1,2,4-triazol-1-yl) thiazole-2-amine and phenylacetic acid be in dichloromethane, taking DMAP as catalyst, N, N '-dicyclohexylcarbodiimide is dehydrant, room temperature reaction 6.0 h, make 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole; Preparation feedback is as follows:

In formula, R is selected from: C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl; X ¹, X ², X ³, X ⁴, X ⁵be selected from respectively: hydrogen, deuterium, C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl.

The present invention compared with prior art tool has the following advantages:

Find first 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole has resisiting influenza virus neuraminic acid enzymatic activity

Detailed description of the invention

Embodiment 1

The 4-tert-butyl group-5-(1,2,4-triazol-1-yl) preparation of-2-phenylacetamido-thiazole:

The 2.0 mmol 4-tert-butyl group-5-(1, 2, 4-triazol-1-yl) 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'-dicyclohexylcarbodiimide (DCC), stirring at room temperature, react 6.0 h, reactant liquor neutralizes with sodium bicarbonate aqueous solution, leave standstill, layering, organic layer anhydrous sodium sulfate drying, filter, revolve steaming, column chromatography obtains the 4-tert-butyl group-5-(1, 2, 4-triazol-1-yl)-2-phenylacetamido-thiazole, yield 58.1%, m.p. 177 ~ 180 DEG C. ¹H?NMR（400?MHz，CDCl ₃）δ：1.09（s，9H，3×CH ₃），3.85（s，2H，CH ₂），7.33（d，J?=?7.2?Hz，2H，C ₆H ₅?2,6-H），7.38-7.45（m，3H，C ₆H ₅?3,4,5-H），8.11（s，1H，C ₂N ₃H ₂?3-H），8.25（s，1H，C ₂N ₃H ₂?5-H），9.03（s，1H，NH）。

Embodiment 2

5-(1,2,4-triazol-1-yl) preparation of-2-phenylacetamido-thiazole (I):

In formula, R is selected from: C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl; X ¹, X ², X ³, X ⁴, X ⁵be selected from respectively: hydrogen, deuterium, C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl

Prepare the 5-(1 shown in chemical constitution formula I by the method for embodiment 1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole.

Embodiment 3

5-(1,2,4-triazol-1-yl) the resisiting influenza virus neuraminic acid enzymatic activity of-2-phenylacetamido-thiazole

1. experimental principle

Compound MUNANA is the specific substrate of neuraminidase, and the metabolite producing under neuraminidase effect, under 360 nm irradiations excite, can produce 450 nm fluorescence, and the variation of fluorescence intensity can be reacted neuraminic acid enzymatic activity delicately.Enzyme is all 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 (pH 6.5) in reaction buffer, add fluorogenic substrate MUNANA to start reaction system, and 37 C were hatched after 40 minutes, added reaction terminating liquid cessation reaction.Be under the Parameter Conditions of 450 nm at excitation wavelength 360 nm and emission wavelength, measure fluorescence intensity level.The fluorescence intensity of reaction system can reflect the activity of enzyme.Can the suppression ratio of computerized compound to NA activity according to the reduction of fluorescence intensity

3. detect sample: 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole (I):

In formula, R is selected from: C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl; X ¹~ X ⁵be selected from: hydrogen, deuterium, C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl

4. active result

The preferred compound 4-tert-butyl group-5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole is 41.17% to the suppression ratio of neuraminidase when detectable concentration 40.0 μ g/mL in response system.

Claims (2)

1. chemical structural formula ishown 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole is in the application of preparing in influenza virus neuraminidase inhibitor:

In formula, R is selected from: C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl; X ¹, X ², X ³, X ⁴, X ⁵be selected from respectively: hydrogen, deuterium, C ₁~ C ₂alkyl, C ₃~ C ₄straight or branched alkyl.

2. application as claimed in claim 1, its Chinese style ishown 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole is selected from the 4-tert-butyl group-5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole.