CN104771399B - N [5 (1,2,4 triazole 1 base) thiazole 2 base] virtue amide and medical usage thereof - Google Patents

N [5 (1,2,4 triazole 1 base) thiazole 2 base] virtue amide and medical usage thereof Download PDF

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CN104771399B
CN104771399B CN201410009358.0A CN201410009358A CN104771399B CN 104771399 B CN104771399 B CN 104771399B CN 201410009358 A CN201410009358 A CN 201410009358A CN 104771399 B CN104771399 B CN 104771399B
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triazol
thiazol
tert
butyl group
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CN104771399A (en
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胡艾希
戴明崇
孙晓潇
叶姣
刘艾琳
连雯雯
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Hunan University
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Abstract

The present invention relates to N [5 (1,2,4 triazole 1 base) the thiazole 2 base] Benzoylamide 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；R1、R5It is selected from: hydrogen, deuterium, methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro or trifluoromethyl；R2、R4It is selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino or acetylamino；R3It is selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, cyano group, amino or acetylamino.

Description

N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide and medical usage thereof
Technical field
The present invention relates to the new opplication of compound, and specifically N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide Application in preparing influenza virus neuraminidase inhibitor.
Background technology
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).Extremely The modern avian influenza virus subtype finding energy direct infection people has: H5N1、H7N1、H7N2、H7N3、H7N7、H9N2And H7N9Hypotype.Wherein, Highly pathogenic H5N1Hypotype found first in Hong Kong in 1997 can the direct infection mankind, since in July, 2003, this state of an illness in Show the most unprecedented breaking out, involve Asia, North America, 17 countries and regions of Europe And Africa, cause hundreds of people to infect and dead Dying, 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, the mankind The infected reaches 83 examples, not only causes the injures and deaths of the mankind, has inflicted heavy losses on poultry farming simultaneously.Mexico breaks out in by the end of March, 2009 People infects H1N1Type swine flue epidemic situation is also diffused into all over the world, the A type issued on February 26th, 2010 according to World Health Organization (WHO) H1N1Influenza global picture is reported, at least 16226 example patients of 213 countries and regions die from this big influenza.Through gene Sequence analysis, H1N1Type virus comprises human influenza virus, North America bird flu virus and North America, Europe, sub-swine influenza virus gene sheet Section, 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, the H that World Health Organization (WHO) announces7N9Fowl is flowed 148 people, dead 43 people are made a definite diagnosis in sense.
Along with acceleration variation and different subtype virus increase of recombination probability between species of influenza virus, influenza is as generation The seasonal epidemic infectious 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 have Zanamivir, The type compounds such as Oseltamivir and Peramivir, wherein Oseltamivir is widely used.But research has been found that some are sick Strain creates drug resistance to Oseltamivir, therefore in the urgent need to studying novel anti-influenza type A virus medicine.Chinese patent is retouched State the application as resisiting influenza virus neuraminidase inhibitor of thiazide and Radix seu Caulis Derridis Trifoliatae ring propionic acid amide.: (1) 4-tert-butyl group-6-benzene Base-2-amino-6H-1, the preparation method of 3-thiazine salt and medical usage, Chinese invention patent, ZL200910043678.7, 2010.8.18 authorize；(2) 4-alkyl-6-aryl-2-acylamino--1,3-thiazine-5-formic acid esters and preparation method and application, Chinese invention patent, ZL201010225483.7,2012.3.14 authorize；(3) 4-alkyl-6-aryl-5-acetyl group-1,3-thiophene Piperazine is as preparing the application of neuraminidase inhibitor, and 2011.3.30 applies for, ZL201110077574.5,2013.2.27 award Power；(4) Radix seu Caulis Derridis Trifoliatae ring propionic acid amide. and preparation method and application, 2011.8.9 applies for, ZL201110226848.2,2013.3.20 Authorize.
Summary of the invention
It is an object of the invention to provide N-shown in chemical constitution formula I [5-(1,2,4-triazol-1-yls) thiazol-2-yl] benzene Methanamide application in preparing influenza virus neuraminidase inhibitor:
In formula, R is selected from: C1～C2Alkyl, C3～C4Straight or branched alkyl；R1、R5It is selected from: hydrogen, deuterium, methyl, ethyl, first Epoxide, ethyoxyl, fluorine, chlorine, bromine, nitro or trifluoromethyl；R2、R4It is selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethoxy Base, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino or acetylamino；R3Be selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, Ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, cyano group, amino or acetylamino.
Object of the present invention is to provide N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] Benzoylamide to be selected from down Row compound:
Object of the present invention is to provide N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-furoylamide to exist Prepare the application in influenza virus neuraminidase inhibitor:
The present invention compared with prior art has the advantage that
N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide is preparing influenza virus neuraminidase inhibitor In application.
Detailed description of the invention
Following example are intended to illustrate rather than limitation of the invention further.
Embodiment 1
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl] Benzoylamide
The 2mmol4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is dissolved in 20.0mL oxolane, adds 8mmol Anhydrous potassium carbonate, the lower dropping 3mmol Benzenecarbonyl chloride. of ice bath stirring, it is stirred at room temperature, reacts 2.0h, filter, filtrate rotation is steamed, Column chromatography obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl] Benzoylamide, yield 70.2%, m.p.257 ～260 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.55(t, J=7.6Hz, 2H, C6H53,5-H), 7.65 (t, J=7.6Hz, 1H, C6H54-H), 7.97 (d, J=7.6Hz, 2H, C6H52,6-H), 8.13(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.51(s, 1H, NH).
Embodiment 2
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methoxy benzamide
The 2mmol4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is dissolved in 20.0mL dichloromethane, adds 2.2mmol2-methoxybenzoic acid, 0.03g4-dimethylamino naphthyridine (DMAP), add 2.2mmol N, N'-bis-hexamethylene after 0.5h Base carbodiimide (DCC), is stirred at room temperature, and reacts 8.0h, and reactant liquor sodium bicarbonate aqueous solution neutralizes, and stands, layering, organic layer Be dried with anhydrous sodium sulfate, filter, rotation steam, column chromatography obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2- Base]-2-methoxy benzamide, yield 46.7%, m.p.178～180 DEG C.1H NMR(400MHz, CDCl3) δ: 1.20(s, 9H, 3×CH3), 4.17(s, 3H, OCH3), 7.09(d, J=8.0Hz, 1H, C6H43-H), 7.16(t, J=8.0Hz, 1H, C6H45-H), 7.59(td, J=8.0Hz, J=2.2Hz, 1H, C6H44-H), 8.12(s, 1H, C2N3H23-H), 8.27(s, 1H, C2N3H25-H), 8.27(dd, J=8.0Hz, J=2.2Hz, 1H, C6H46-H), 11.22(s, 1H, NH).
Embodiment 3
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-nitrobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is anti-with 3-nitrobenzoic acid Answer 5.0h, obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-nitrobenzamide, yield 84.4%, m.p.207～211 DEG C.1H NMR(400MHz, CDCl3) δ: 1.20(s, 9H, 3 × CH3), 7.79(t, J=8.0Hz, 1H, C6H45-H), 8.15(s, 1H, C2N3H23-H), 8.31(s, 1H, C2N3H25-H), 8.41(d, J=8.0Hz, 1H, C6H46- H), 8.50(d, J=9.6Hz, 1H, C6H44-H), 8.89(s, 1H, C6H42-H).
Embodiment 4
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-nitrobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is anti-with 4-nitrobenzoic acid Answer 5.0h, obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-nitrobenzamide, yield 89.6%, m.p.236～239 DEG C.1H NMR(400MHz, CDCl3) δ: 1.20(s, 9H, 3 × CH3), 8.15(s, 1H, C2N3H23- H), 8.21(d, J=8.8Hz, 2H, C6H43,5-H), 8.30(s, 1H, C2N3H25-H), 8.41(d, J=8.8Hz, 2H, C6H42,6- H).
Embodiment 5
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2-methyl-3-nitro Benzoic acid 6.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methyl-3-nitro benzene Methanamide, yield 58.9%, m.p.235～239 DEG C.1H NMR(400MHz, CDCl3) δ: 1.16(s, 9H, 3 × CH3), 2.62 (s, 3H, CH3), 7.50(t, J=8.0Hz, 1H, C6H35-H), 7.78(d, J=8.0Hz, 1H, C6H36-H), 7.98(d, J= 8.0Hz, 1H, C6H34-H), 8.12(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.68(s, 1H, NH).
Embodiment 6
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3, the preparation of 5-dinitrobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 3,5-dinitro benzene first Acid reaction 6.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-dinitrobenzamide, Yield 55.2%, m.p.213～216 DEG C.1H NMR(400MHz, CDCl3) δ: 1.22(s, 9H, 3 × CH3), 8.18(s, 1H, C2N3H23-H), 8.36(s, 1H, C2N3H25-H), 9.27(s, 3H, C6H32,4,6-H).
Embodiment 7
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-trifluoromethyl benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2-trifluoromethylbenzene first Acid reaction 4.5h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-trifluoromethyl benzamide, Yield 60.8%, m.p.246～248 DEG C.1H NMR(400MHz, CDCl3) δ: 1.15(s, 9H, 3 × CH3), 7.68-7.71(m, 3H, C6H43,4,5-H), 7.81(m, 1H, C6H46-H), 8.10(s, 1H, C2N3H23-H), 8.27(s, 1H, C2N3H25-H), 9.44(s, 1H, NH).
Embodiment 8
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-trifluoromethyl benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 3-trifluoromethylbenzene first Acid reaction 8.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-trifluoromethyl benzamide, Yield 36.5%, m.p.180～182 DEG C.1H NMR(400MHz, CDCl3) δ: 1.19(s, 9H, 3 × CH3), 7.72(t, J= 7.6Hz, 1H, C6H45-H), 7.81(d, J=7.6Hz, 1H, C6H44-H), 8.15(s, 1H, C2N3H23-H), 8.20(d, J= 7.6Hz, 1H, C6H46-H), 8.27(s, 1H, C6H42-H), 8.31(s, 1H, C2N3H25-H), 9.91(s, 1H, NH).
Embodiment 9
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-trifluoromethyl benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 4-trifluoromethylbenzene first Acid reaction 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-trifluoromethyl benzamide, Yield 41.5%, m.p.148～152 DEG C.1H NMR(400MHz, CDCl3) δ: 1.19(s, 9H, 3 × CH3), 7.84(t, J= 8.0Hz, 2H, C6H43,5-H), 8.15(s, 1H, C2N3H23-H), 8.20(d, J=8.0Hz, 2H, C6H42,6-H), 8.32(s, 1H, C2N3H25-H), 11.53(s, 1H, NH).
Embodiment 10
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide Preparation
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 3,5-bis-(fluoroform Base) benzoic acid 5.0h, obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-bis-(fluoroform Base) Benzoylamide, yield 56.2%, m.p.224～226 DEG C.1H NMR(400MHz, CDCl3) δ: 1.19(s, 9H, 3 × CH3), 8.14(s, 1H, C6H34-H), 8.16(s, 1H, C2N3H23-H), 8.34(s, 1H, C2N3H25-H), 8.50(s, 2H, C6H32,6- H).
Embodiment 11
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chlorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine reacts with 2-chlorobenzoic acid 6.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chlorobenzamide, yield 63.0%, M.p.241～244 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.42-7.46(m, 1H, C6H46-H), 7.46-7.52(m, 2H, C6H44,5-H), 7.90(d, J=8.0Hz, 1H, C6H43-H), 8.12(s, 1H, C2N3H23-H), 8.27 (s, 1H, C2N3H25-H), 9.82(s, 1H, NH).
Embodiment 12
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-chlorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine reacts with 4-chlorobenzoic acid 6.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-chlorobenzamide, yield 47.0%, M.p.220～222 DEG C.1H NMR(400MHz, CDCl3) δ: 1.18(s, 9H, 3 × CH3), 7.54(d, J=8.4Hz, 2H, C6H43, 5-H), 7.95(d, J=8.4Hz, 2H, C6H42,6-H), 8.13(s, 1H, C2N3H23-H), 8.29(s, 1H, C2N3H25-H), 9.80 (s, 1H, NH).
Embodiment 13
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2, the preparation of 4-dichloro-benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2,4-dichlorobenzoic acid Reaction 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,4-dichloro-benzamide, yield 63.1%, m.p.202～205 DEG C.1H NMR(400MHz, CDCl3) δ: 1.16(s, 9H, 3 × CH3), 7.43(dd, J=8.0Hz, J =2.0Hz, 1H, C6H36-H), 7.54(d, J=2.0Hz, 1H, C6H35-H), 7.87(d, J=8.0Hz, 1H, C6H33-H), 8.12 (s, 1H, C2N3H23-H), 8.27(s, 1H, C2N3H25-H), 9.80(s, 1H, NH).
Embodiment 14
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3, the preparation of 4-dichloro-benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 3,4-dichlorobenzoic acid Reaction 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,4-dichloro-benzamide, yield 48.8%, m.p.201～204 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.64(d, J=8.8Hz, 1H, C6H35-H), 7.82(dd, J=8.8Hz, J=2.0Hz, 1H, C6H36-H), 8.11(d, J=2.0Hz, 1H, C6H32-H), 8.14 (s, 1H, C2N3H23-H), 8.30(s, 1H, C2N3H25-H), 9.83(s, 1H, NH).
Embodiment 15
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2, the preparation of 6-dichloro-benzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2,6-dichlorobenzoic acid Reaction 8.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,6-dichloro-benzamide, yield 30.4%, m.p.249～254 DEG C.1H NMR(400MHz, CDCl3) δ: 1.16(s, 9H, 3 × CH3), 7.40-7.42(m, 3H, C6H33,4,5-H), 8.12(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H).
Embodiment 16
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-fluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine reacts with 2-fluobenzoic acid 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-fluorobenzamide, yield 56.0%, M.p.159～163 DEG C.1H NMR(400MHz, CDCl3) δ: 1.18(s, 9H, 3 × CH3), 7.17-7.21(m, 1H, C6H45-H), 7.82(t, J=7.6Hz, 1H, C6H43-H), 7.60-7.65(m, 1H, C6H44-H), 8.13(s, 1H, C2N3H23-H), 8.20(t, J=7.6Hz, 1H, C6H46-H), 8.30(s, 1H, C2N3H25-H), 9.96(s, 1H, NH).
Embodiment 17
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-fluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine reacts with 3-fluobenzoic acid 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-fluorobenzamide, yield 77.3%, M.p.239～242 DEG C.1H NMR(400MHz, CDCl3) δ: 1.19(s, 9H, 3 × CH3), 7.36(t, J=8.0Hz, 1H, C6H45- H), 7.54-7.58(m, 1H, C6H44-H), 7.75(d, J=8.8Hz, 1H, C6H42-H), 7.80(d, J=7.2Hz, 1H, C6H46- H), 8.14(s, 1H, C2N3H23-H), 8.30(s, 1H, C2N3H25-H), 10.31(s, 1H, NH).
Embodiment 18
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-fluorobenzamide
As described in Example 1, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is anti-with 4-fluorobenzoyl chloride Answer 5.0h, obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-fluorobenzamide, yield 69.6%, M.p.220～222 DEG C.1H NMR(400MHz, CDCl3) δ: 1.18(s, 9H, 3 × CH3), 7.24(t, J=8.4Hz, 2H, C6H43, 5-H), 8.02(t, J=6.8Hz, 2H, C6H42,6-H), 8.13(s, 1H, C2N3H23-H), 8.29(s, 1H, C2N3H25-H), 9.57 (s, 1H, NH).
Embodiment 19
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,4 difluorobenzene Methanamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2,4 difluorobenzene formic acid Reaction 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,4 difluorobenzene Methanamide, yield 74.4%, m.p.164～166 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.02(td, J=8.4Hz, J =2.4Hz, 1H, C6H33-H), 7.09-7.13(m, 1H, C6H35-H), 8.13(s, 1H, C2N3H23-H), 8.23(td, J= 8.4Hz, J=2.4Hz, 1H, C6H36-H), 8.28(s, 1H, C2N3H25-H), 9.84(s, 1H, NH).
Embodiment 20
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3, the preparation of 4-difluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 3,4-difluoro-benzoic acid Reaction 5.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,4-difluorobenzamide, yield 89.8%, m.p.208～211 DEG C.1H NMR(400MHz, CDCl3) δ: 1.18(s, 9H, 3 × CH3), 7.35(q, J=8.4Hz, 1H, C6H35-H), 7.79-7.81(m, 1H, C6H32-H), 7.88-7.93(m, 1H, C6H36-H), 8.14(s, 1H, C2N3H23- H), 8.30(s, 1H, C2N3H25-H), 10.32(s, 1H, NH).
Embodiment 21
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2, the preparation of 6-difluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2,6-difluoro-benzoic acid Reaction 4.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,6-difluorobenzamide, yield 68.9%, m.p.190～193 DEG C.1H NMR(400MHz, CDCl3) δ: 1.16(s, 9H, 3 × CH3), 7.07(t, J=8.4Hz, 2H, C6H33,5-H), 7.51-7.55(m, 1H, C6H34-H), 8.12(s, 1H, C2N3H23-H), 8.29(s, 1H, C2N3H25-H), 9.94(s, 1H, NH).
Embodiment 22
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2, the preparation of 4,5-benzamide trifluoroacetates
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2,4,5-trifluoromethyl benzonitriles Acid reaction 4.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2,4,5-benzamide trifluoroacetates, Yield 54.4%, m.p.174～176 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.13-7.19(m, 1H, C6H23-H), 8.03-8.09(m, 1H, C6H26-H), 8.12(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.78(s, 1H, NH).
Embodiment 23
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chloro-4-fluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2-chloro-4-fluorobenzene first Acid reaction 4.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chloro-4-fluorobenzamide, receives Rate 84.2%, m.p.204～208 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.32(td, J= 7.6Hz, J=2.4Hz, 1H, C6H35-H), 7.26-7.28(m, 1H, C6H36-H), 7.97(dd, J=8.8Hz, J=2.0Hz, 1H, C6H33-H), 8.12(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.93(s, 1H, NH).
Embodiment 24
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chloro-6-fluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 2-chloro-6-fluorobenzene first Acid reaction 4.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-chloro-6-fluorobenzamide, receives Rate 80.7%, m.p.234～238 DEG C.1H NMR(400MHz, CDCl3) δ: 1.15(s, 9H, 3 × CH3), 7.14(t, J=8.0Hz, 1H, C6H35-H), 7.32(d, J=8.0Hz, 1H, C6H33-H), 7.43-7.45(m, 1H, C6H34-H), 8.12(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.51(s, 1H, NH).
Embodiment 25
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-chloro-2-fluorobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine and 4-chloro-2-fluorobenzene first Acid reaction 4.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-chloro-2-fluorobenzamide, receives Rate 74.6%, m.p.163～167 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 7.32(dd, J= 12.0Hz, J=1.6Hz, 1H, C6H35-H), 7.37(dd, J=8.4Hz, J=2.0Hz, 1H, C6H36-H), 8.12-8.16(m, 1H, C6H33-H), 8.18(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.80(s, 1H, NH).
Embodiment 26
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-cyanobenzamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine is anti-with 4-cyanobenzoic acid Answer 5.0h, obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-cyanobenzamide, yield 69.4%, m.p.238～240 DEG C.1H NMR(400MHz, CDCl3) δ: 1.15(s, 9H, 3 × CH3), 7.86(d, J=8.0Hz, 2H, C6H43,5-H), 8.15(d, J=8.0Hz, 2H, C6H42,6-H), 8.16(s, 1H, C2N3H23-H), 8.32(s, 1H, C2N3H25-H).
Embodiment 27
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-AB
1mmol N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-nitrobenzamide is dissolved in In 10.0mL dichloromethane, add 10.0mL10%CH3COOH, is stirred at room temperature, and is slowly added to 5mmol Fe powder, reacts 1.5h, mistake Filtering Fe powder, filtrate stratification, organic facies is washed, aqueous phase CH2Cl2Back extraction, merges organic facies, and partial solvent is steamed in rotation, quiet Put, separate out solid, filter, be dried to obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3-aminobenzoic Amide, yield 54.8%, m.p.195～197 DEG C.1H NMR(400MHz, CDCl3) δ: 1.18(s, 9H, 3 × CH3), 6.73(d, J =8.4Hz, 1H, C6H44-H), 6.91-6.93(m, 1H, C6H42-H), 7.29-7.31(m, 2H, C6H45,6-H), 8.13(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H).
Embodiment 28
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-aminobenzamide
By the method for embodiment 27, and N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-nitrobenzoyl Amide reaction 1.5h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-aminobenzamide, receives Rate 50.3%, m.p.206～209 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 6.72(d, J=8.0Hz, 2H, C6H43,5-H), 7.82(d, J=8.0Hz, 2H, C6H42,6-H), 8.15(s, 1H, C2N3H23-H), 8.32(s, 1H, C2N3H25-H), 9.74(s, 1H, NH).
Embodiment 29
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methyl-3-AB
1mmol N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide It is dissolved in 10.0mL methanol, adds Raney Ni, be stirred at room temperature, be slowly added dropwise 0.5g80% hydrazine hydrate, react 1.0h, cross and filter Removing Raney Ni, filtrate is spin-dried for, and adds dichloromethane and dissolves, and organic facies is washed, aqueous phase CH2Cl2Back extraction, merges organic facies, nothing Aqueous sodium persulfate is dried, and filters, is spin-dried for, and is dried to obtain N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-first Base-3-AB, yield 92.1%, m.p.218～222 DEG C.1H NMR(400MHz, CDCl3) δ: 1.19(s, 9H, 3 × CH3), 2.30(s, 3H, CH3), 6.88(d, J=7.6Hz, 1H, C6H34-H), 7.07(m, 1H, C6H35-H), 7.16(t, J= 7.6Hz, 1H, C6H36-H), 8.13(s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.74(s, 1H, NH).
Embodiment 30
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3, the preparation of 5-diaminobenzene Methanamide
By the method for embodiment 29, and N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-dinitro Benzoylamide reaction 1.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-diaminobenzene first Amide, yield 74.6%, m.p.204～208 DEG C.1H NMR(400MHz, CDCl3) δ: 1.16(s, 9H, 3 × CH3), 6.22(s, 1H, C6H34-H), 6.62(s, 2H, C6H32,6-H), 8.12(s, 1H, C2N3H23-H), 8.27(s, 1H, C2N3H25-H), 9.37 (s, 1H, NH).
Embodiment 31
The preparation of N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-furoylamide
As described in Example 2, the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazole-2-amine reacts with furancarboxylic acid 10.0h, obtains N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-furoylamide, yield 37.6%, M.p.205～207 DEG C.1H NMR(400MHz, CDCl3) δ: 1.17(s, 9H, 3 × CH3), 6.64(dd, J=3.6Hz, J= 1.6Hz, 1H, C4H3O4-H), 7.38(d, J=3.6Hz, 1H, C4H3O3-H), 7.61(d, J=0.8Hz, 1H, C4H3O5-H), 8.12 (s, 1H, C2N3H23-H), 8.28(s, 1H, C2N3H25-H), 9.49(s, 1H, NH).
Embodiment 32
N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide resisiting influenza virus neuraminidase activity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase NA, and the metabolism produced under neuraminidase effect is produced Thing, under 360nm irradiates and excites, can produce 450nm fluorescence, and 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 virus NA float on (pH6.5) in reaction buffer, add glimmering Light substrate MUNANA starts reaction system, after 37 DEG C hatch 40 minutes, adds reaction terminating liquid and terminates reaction.In excitation wavelength Under the Parameter Conditions of 360nm and a length of 450nm of transmitted wave, measure fluorescence intensity level.The fluorescence intensity of reaction system 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: N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide:
4. Activity Results
Preferred compound is under in response system, during detectable concentration 40.0 μ g/mL, suppression ratio to neuraminidase is listed in Table:
Table 1 N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide is to neuraminic acid enzyme inhibition activity
N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide Suppression ratio/%
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl] Benzoylamide 32.74
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-methoxy benzamide 30.72
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-chlorobenzamide 44.24
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-trifluoromethyl benzamide 30.69
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide 48.35
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-4-nitrobenzamide 55.72
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-3,5-dinitrobenzamide 54.96
N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yls) thiazol-2-yl]-2-furoylamide 41.65
Active testing result shows, N-[5-(1,2,4-triazol-1-yls) thiazol-2-yl] virtue amide has good anti-current Influenza Virus neuraminidase activity, can be used for preparing influenza virus neuraminidase inhibitor.

Claims (3)

1. N-[5-(1,2, the 4-triazol-1-yl) thiazol-2-yl] Benzoylamide shown in chemical constitution Formulas I is preparation influenza virus Application in neuraminidase inhibitor:
In formula, R is selected from: C1～C2Alkyl, C3～C4Straight or branched alkyl；R1、R5It is selected from: hydrogen, deuterium, methyl, ethyl, methoxyl group Or ethyoxyl；R2、R4It is selected from: hydrogen, deuterium, methyl, ethyl, nitro or trifluoromethyl；R3Be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, Chlorine, bromine or nitro.
2. the application described in claim 1, wherein N-[5-(1,2, the 4-triazol-1-yl) thiazol-2-yl] benzoyl shown in Formulas I Amine is selected from following compounds: N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yl) thiazol-2-yl] Benzoylamide, N-[the tertiary fourth of 4- Base-5-(1,2,4-triazol-1-yl) thiazol-2-yl]-2-methoxy benzamide, N-[the 4-tert-butyl group-5-(1,2,4-triazole- 1-yl) thiazol-2-yl]-4-chlorobenzamide, N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yl) thiazol-2-yl]-2-trifluoro Methyl benzamide, N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yl) thiazol-2-yl]-3,5-bis-(trifluoromethyl) benzoyl Amine, N-[the 4-tert-butyl group-5-(1,2,4-triazol-1-yl) thiazol-2-yl]-4-nitrobenzamide or N-[the 4-tert-butyl group-5- (1,2,4-triazol-1-yl) thiazol-2-yl]-3,5-dinitrobenzamide.
3.N-[5-(1,2,4-triazol-1-yl) thiazol-2-yl]-2-furoylamide presses down preparing influenza neuraminidase Application in preparation:
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