CN105693665A - Aryl formyl hydrazone derivative including benzofuran ring and preparing method and medical application of aryl formyl hydrazone derivative - Google Patents

Aryl formyl hydrazone derivative including benzofuran ring and preparing method and medical application of aryl formyl hydrazone derivative Download PDF

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Publication number
CN105693665A
CN105693665A CN201610103855.6A CN201610103855A CN105693665A CN 105693665 A CN105693665 A CN 105693665A CN 201610103855 A CN201610103855 A CN 201610103855A CN 105693665 A CN105693665 A CN 105693665A
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hydroxyl
hydrazone
phenyl
acetone
base
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CN105693665B (en
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胡艾希
林定
叶姣
刘艾林
连雯雯
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Hunan University
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Hunan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Abstract

The invention discloses an aryl formyl hydrazone derivative including a benzofuran ring, medically-acceptable salt of the aryl formyl hydrazone derivative, a preparing method and a medicine composition of the aryl formyl hydrazone derivative and application of the aryl formyl hydrazone derivative in preparing an influenza virus neuraminidase inhibitor. The aryl formyl hydrazone derivative is shown in the structural formula I.

Description

Hydrazone derivant containing benzofuran ring and preparation method thereof and medical usage
Technical field
The present invention relates to class noval chemical compound and preparation method thereof and application；The specifically preparation of the hydrazone derivant containing benzofuran ring and the application as influenza virus neuraminidase inhibitor。
Background technology
The anti-influenza virus medicament listed as neuraminidase inhibitor mainly has zanamivir (Zanamivir), GS-4104 (Oseltamivir) and Peramivir (Peramivir)。
Duarte etc. [Bioorg.Med.Chem., 2007,15:2421-2433] have synthesized the acylhydrazone containing piperonyl cyclonene, it has been found that it has good anti-inflammatory activity。
Acylhydrazone structure is introduced in indole ring by Ye Ying etc. [organic chemistry, 2009,29 (6): 993-997], and antibacterial activity test shows, the indole acylhydrazone MIC to staphylococcus aureus50Value and MBC value respectively 0.612 μ g/mL and 1.10 μ g/mL, lower than the antibacterials profit azoles amine (1～8 μ g/mL) used by clinic, Linezolid (1～4 μ g/mL) and amikacin (1.56 μ g/mL)。
Basu etc. [JournalofVirology, 2009,83 (4): 1881-1891] report the anti-influenza virus activity of compound N SC125044。Duarte etc. [Bioorg.Med.Chem., 2012,20:487-497] have synthesized a series of 2-(2-hydroxybenzoyl) hydrazone compound on this basis, it has been found that they all have certain anti-influenza virus activity。
Barman etc. [Eur.J.Med.Chem., 2014,71:81-90] have synthesized a series of naphthalene-ring containing acyl hydrazone derivative, and test its inhibitory activity to influenza A virus, it has been found that when having hydroxyl to replace for 2 of naphthalene nucleus, and activity is better。Shih etc. [J.Biomed.Sci, 2010,17:13] describe the BPR1P0034 inhibitory activity for various subtype influenza virus, it has been found that suitable for its inhibitory activity of part hypotype and positive control zanamivir。
Chinese invention patent [CN103360315] has synthesized the assorted oxygen acetyl hydrazone of a series of virtue containing pyrazoles, and tests its inhibitory activity to H1N1 influenza virus, the EC of outstanding compound50Less than 10 μMs。Fedichev etc. [PLOSCurrentsInfluenza.2011] describe the inhibitory action for multiple subtype influenza virus of the acyl hydrazone derivative containing 1,2,4-triazole。
Summary of the invention
Present invention solves the technical problem that and be to provide the class hydrazone derivant containing benzofuran ring, its preparation method, pharmaceutical composition and medical usage。
For solving the technical problem of the present invention, the present invention provides following technical scheme:
The first aspect of technical solution of the present invention there is provided a class such as the hydrazone derivant containing benzofuran ring shown in chemical constitution formula I and pharmaceutically acceptable salt thereof:
Wherein R is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl；X1、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or amino；X2、X4It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl；X3It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino；The hydrazone derivatives chemical containing benzofuran ring shown in formula I is called 1-[4-hydroxyl/alkoxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone benzoyl hydrazone or 1-[4-hydroxyl/alkoxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone substituted benzoyl acylhydrazone。
Further, it is preferred that compound is selected from:
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone benzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-aminobenzoic acylhydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-aminobenzoic acylhydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-acetyl amino phenyl formyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-nitrobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-nitrobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3,5-dinitro benzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-(2-hydroxybenzoyl) hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-(2-hydroxybenzoyl) hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-(2-hydroxybenzoyl) hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4-dihydroxybenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-fluorobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-fluorobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-fluorobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4-difluorobenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-trifluoromethylbenzoyl hydrazone, 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-trifluoromethylbenzoyl hydrazone。
The preparation method that the second aspect of technical solution of the present invention there is provided the hydrazone derivant described in first aspect containing benzofuran ring, it is characterised in that its preparation reaction is as follows:
Wherein R is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl；X1、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or amino；X2、X4It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl；X3It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino。
The third aspect of technical solution of the present invention is to provide the pharmaceutical composition containing compound described in first aspect and pharmaceutically acceptable salt thereof, this pharmaceutical composition contains the hydrazone derivant containing benzofuran ring and the pharmaceutically acceptable salt thereof of the present invention of therapeutically effective amount, and optional containing pharmaceutical carrier。Wherein said pharmaceutical carrier refers to the pharmaceutical carrier that pharmaceutical field is conventional；This pharmaceutical composition can be prepared according to method well known in the art。Can pass through, by the compounds of this invention and pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant combination, to make any dosage form being suitable to human or animal's use。The compounds of this invention and pharmaceutically acceptable salt content in its pharmaceutical composition thereof are generally 0.1%～95% percentage by weight。
The compounds of this invention and pharmaceutically acceptable salt or the pharmaceutical composition containing it thereof can be administered in a unit, route of administration can be intestinal or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.。
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form。Liquid dosage form can be solution (including true solution and colloid solution), Emulsion (including o/w type, w/o type and emulsion), suspensoid, injection (including aqueous injection, injectable powder and transfusion), eye drop, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, oral cavity disintegration tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, drop pill, suppository, membrane, paster, gas (powder) mist agent, spray etc.；Semisolid dosage form can be ointment, gel, paste etc.。
The compounds of this invention and pharmaceutically acceptable salt thereof can be made ordinary preparation, also make is slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system。
In order to the compounds of this invention and pharmaceutically acceptable salt thereof are made tablet, it is possible to widely use various excipient well known in the art, including diluent, adhesive, wetting agent, disintegrating agent, lubricant, fluidizer。Diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethanol, isopropanol etc.；Binding agent can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.；Disintegrating agent can be dried starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and fluidizer can be Pulvis Talci, silicon dioxide, stearate, tartaric acid, liquid paraffin, Polyethylene Glycol etc.。
Tablet can also be made coated tablet further, for instance sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet。
In order to administration unit is made capsule, it is possible to effective ingredient the compounds of this invention and pharmaceutically acceptable salt thereof are mixed with diluent, fluidizer, mixture is placed directly within hard capsule or soft capsule。Also effective ingredient the compounds of this invention and pharmaceutically acceptable salt thereof first can be made granule or micropill with diluent, adhesive, disintegrating agent, then be placed in hard capsule or soft capsule。For preparing each diluent of the compounds of this invention and pharmaceutically acceptable salt tablet thereof, adhesive, wetting agent, disintegrating agent, fluidizer kind can also be used for preparing the capsule of the compounds of this invention and pharmaceutically acceptable salt thereof。
For the compounds of this invention and pharmaceutically acceptable salt thereof are made injection, it is possible to adjust agent, osmotic pressure regulator with water, ethanol, isopropanol, propylene glycol or their mixture as solvent addition solubilizing agent commonly used in the art in right amount, cosolvent, pH。Solubilizing agent or cosolvent can be poloxamer, lecithin, HP-β-CD etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc.。As prepared lyophilized injectable powder, mannitol, glucose etc. also can be added as proppant。
Additionally, if desired, coloring agent, preservative, spice, correctives or other additive can also be added in pharmaceutical preparation。
For reaching medication purpose, strengthening therapeutic effect, the medicine of the present invention or pharmaceutical composition can be administered by any known medication。
The fourth aspect of technical solution of the present invention is to provide described in first aspect present invention the application in preparation influenza virus inhibitor of the pharmaceutical composition described in the hydrazone derivant containing benzofuran ring and pharmaceutically acceptable salt thereof and the third aspect。
Further, fourth aspect is to provide described in first aspect present invention pharmaceutical composition application in preparing influenza virus neuraminidase inhibitor described in the hydrazone derivant containing benzofuran ring and pharmaceutically acceptable salt thereof and the third aspect。
Advantageous Effects:
The hydrazone derivant containing benzofuran ring of the present invention is the compound with influenza neuraminidase inhibitory activity of a class new construction type。
Detailed description of the invention
Following example are intended to illustrate the present invention rather than limitation of the invention further。
Embodiment 1
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone
(1) preparation of 4-pi-allyl-2-(2-methyl benzofuran-5-base) phenol
Autoclave adds 10mmol honokiol, 0.2mmolPdCl2, 2.0mmolNaOAc, 56mlDMA/H2O (6:1), logical 8atmO2, react 16h in 60 DEG C。After reaction terminates, add the dilution of 100ml water, by 3 × 30ml extraction into ethyl acetate, anhydrous Na2SO4Dry, vacuum distillation recovered solvent。Crude product purifies through column chromatography, obtains yellow oily liquid 4-pi-allyl-2-(2-methyl benzofuran-5-base) phenol, yield 86.0%。1HNMR(400MHz,CDCl3) δ: 7.53 (d, J=1.5Hz, 1H, benzofuran ring 4-H), 7.50 (d, J=8.4Hz, 1H, benzofuran ring 7-H), 7.26 (dd, J=8.4,1.5Hz, 1H, benzofuran ring 6-H), 7.10～7.07 (m, 2H, C6H33,5-H), 6.94 (d, J=8.8Hz, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.98 (ddt, J=16.9,10.0,6.7Hz, 1H ,=CH), 5.21 (s, 1H, OH), 5.13～5.03 (m, 2H ,=CH2), 3.36 (d, J=6.7Hz, 2H, CH2), 2.49 (s, 3H, CH3)。
(2) preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone
Autoclave adds 10mmol4-pi-allyl-2-(2-methyl benzofuran-5-base) phenol, 0.15mmolPdCl2, 40mlDMA/H2O (4:1), logical 8atmO2, react 10h in 60 DEG C。After reaction terminates, add the dilution of 100ml water, by 3 × 30ml extraction into ethyl acetate, anhydrous Na2SO4Dry, vacuum distillation recovered solvent。Crude product purifies through column chromatography, obtains white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, yield 63.9%；Fusing point 118～121 DEG C；1HNMR (400MHz, CDCl3) δ: 7.52 (d, J=1.6Hz, 1H, benzofuran ring 4-H), 7.49 (d, J=8.4Hz, 1H, benzofuran ring 7-H), 7.25 (dd, J=8.4,1.8Hz, 1H, benzofuran ring 6-H), 7.10～7.07 (m, 2H, C6H33,5-H), 6.97 (d, J=7.8Hz, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.35 (br, 1H, OH), 3.66 (s, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 3H, CH3)。
Embodiment 2
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone benzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol benzoyl hydrazine, add 0.2ml glacial acetic acid with 20ml ethanol after dissolving, after backflow 1h, adding 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain faint yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone benzoyl hydrazone, yield 90.0%；Fusing point 98～102 DEG C；1HNMR (400MHz, CDCl3) δ: 7.85～7.73 (m, 2H, C6H52,6-H), 7.53～7.44 (m, 5H, benzofuran rings 4,7-H+C6H53,4,5-H), 7.28～7.23 (m, 1H, benzofuran ring 6-H), 7.16～7.12 (m, 1H, C6H33-H), 7.09～7.02 (m, 1H, C6H35-H), 6.98～6.95 (m, 1H, C6H36-H), 6.40 (s, 1H, benzofuran ring 3-H), 5.56 (br, 1H, OH), 3.71～3.53 (m, 2H, CH2), 2.48 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 1H, CH3), 1.88 (s, 2H, CH3)。
Embodiment 3
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3 trifluoromethylbenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol3-trifluoromethylbenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 4h is stirred at room temperature, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry to obtain faint yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-trifluoromethylbenzoyl hydrazone, yield 85.8%；Fusing point 85～90 DEG C；1HNMR (400MHz, CDCl3) δ 8.17～7.93 (m, 2H, C6H42,6-H), 7.78～7.67 (m, 1H, C6H44-H), 7.55～7.42 (m, 3H, benzofuran rings 4,7-H+C6H45-H), 7.28～7.20 (m, 1H, benzofuran ring 6-H), 7.13～7.01 (m, 2H, C6H33,5-H), 6.96 (d, J=9.6Hz, 1H, C6H36-H), 6.36 (s, 1H, benzofuran ring 3-H), 5.84 (br, 1H, OH), 3.78～3.40 (m, 2H, CH2), 2.46 (s, 3H, benzofuran ring 2-CH3), 2.16 (s, 1H, CH3), 1.88 (s, 2H, CH3)。
Embodiment 4
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4 trifluoromethylbenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-trifluoromethylbenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 4h is stirred at room temperature, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-trifluoromethylbenzoyl hydrazone, yield 90.1%；Fusing point 95～100 DEG C；1HNMR (400MHz, CDCl3) δ 7.98～7.85 (m, 2H, C6H42,6-H), 7.72 (d, J=7.5Hz, 2H, C6H43,5-H), 7.53～7.48 (m, 2H, benzofuran rings 4,7-H), 7.27～7.23 (m, 1H, benzofuran ring 6-H), 7.18～7.13 (m, 1H, C6H33-H), 7.11～7.06 (m, 1H, C6H35-H), 6.99～6.93 (m, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.46 (br, 1H, OH), 3.78～3.64 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 1H, CH3), 1.90 (s, 2H, CH3)。
Embodiment 5
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-aminobenzoic acylhydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol2-amino benzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 4h is stirred at room temperature, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-aminobenzoic acylhydrazone, yield 53.4%；Fusing point 87～93 DEG C；1HNMR (400MHz, DMSO-d6) δ: 9.37 (s, 1H, OH), 7.70～7.62 (m, 1H, C6H46-H), 7.54～7.44 (m, 2H, benzofuran rings 4,7-H), 7.40～7.35 (m, 1H, C6H44-H), 7.30～7.26 (m, 1H, benzofuran ring 6-H), 7.15 (s, 1H, C6H33-H), 7.08～6.98 (m, 2H, C6H35,6-H), 6.92～6.84 (s, 2H, C6H43,5-H), 6.57 (s, 1H, benzofuran ring 3-H), 3.67～3.49 (m, 2H, CH2), 2.45 (s, 3H, benzofuran ring 2-CH3), 1.87～1.69 (m, 3H, CH3)。
Embodiment 6
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-aminobenzoic acylhydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-amino benzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 3h is stirred at room temperature, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain faint yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-aminobenzoic acylhydrazone, yield 71.4%；Fusing point 107～113 DEG C；1HNMR (400MHz, DMSO-d6) δ: 9.99-9.97 (m, 1H, NH), 9.39 (s, 1H, OH), 7.65～7.57 (m, 2H, C6H42,6-H), 7.53～7.45 (m, 2H, benzofuran rings 4,7-H), 7.41～7.37 (m, 1H, benzofuran ring 6-H), 7.16 (s, 1H, C6H33-H), 7.03 (d, J=7.5Hz, 1H, C6H35-H), 6.90 (d, J=7.5Hz, 1H, C6H36-H), 6.60～6.53 (m, 3H, benzofuran ring 3-H+C6H43,5-H), 5.71 (br, 2H, NH2), 3.71～3.52 (m, 2H, CH2), 2.45 (s, 3H, benzofuran ring 2-CH3), 2.11 (s, 1H, CH3), 1.86 (s, 2H, CH3)。
Embodiment 7
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-acetyl amino phenyl formyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-acetylamino benzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 5h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry to obtain faint yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-acetyl amino phenyl formyl hydrazone, yield 83.5%；Fusing point 127～131 DEG C；1HNMR (400MHz, DMSO-d6) δ: 10.33 (s, 1H, NHAc), 10.21～10.17 (m, 1H, NH), 9.39 (s, 1H, OH), 7.88～7.78 (m, 2H, C6H43,5-H), 7.69～7.65 (m, 2H, C6H42,6-H), 7.56～7.47 (m, 2H, benzofuran rings 4,7-H), 7.41～7.37 (m, 1H, benzofuran ring 6-H), 7.16 (s, 1H, C6H33-H), 7.04 (d, J=8.0Hz, 1H, C6H35-H), 6.91 (d, J=8.0Hz, 1H, C6H36-H), 6.59 (s, 1H, benzofuran ring 3-H), 3.74～3.56 (m, 2H, CH2), 2.45 (s, 3H, benzofuran ring 2-CH3), 2.08 (s, 1H, CH3), 2.07 (s, 3H, COCH3), 1.88 (s, 2H, CH3)。
Embodiment 8
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-nitrobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol2-nitrobenzoyl hydrazides, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-nitrobenzoyl hydrazone, yield 63.2%；Fusing point 109～113 DEG C；1HNMR (400MHz, CDCl3) δ: 8.12 (d, J=8.0Hz, 1H, C6H43-H), 7.75 (s, 1H, C6H33-H), 7.72 (d, J=7.4Hz, 1H, C6H46-H), 7.67～7.64 (m, 1H, C6H44-H), 7.63～7.58 (m, 1H, C6H45-H), 7.51 (s, 1H, benzofuran ring 4-H), 7.49 (d, J=6.5Hz, 1H, benzofuran ring 7-H), 7.28 (dd, J=6.5,2.0Hz, 1H, benzofuran ring 6-H), 7.21 (dd, J=8.3,1.7Hz, 1H, C6H35-H), 6.93 (d, J=8.3Hz, 1H, C6H36-H), 6.42 (s, 1H, benzofuran ring 3-H), 5.55 (br, 1H, OH), 5.30 (br, 1H, NH), 3.66～3.29 (m, 2H, CH2), 2.50 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 1H, CH3), 1.81 (s, 2H, CH3)。
Embodiment 9
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-nitrobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-nitrobenzoyl hydrazides, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-nitrobenzoyl hydrazone, yield 94.8%；Fusing point 99～105 DEG C；1HNMR (400MHz, CDCl3) δ: 8.31 (d, J=8.7Hz, 2H, C6H43,5-H), 7.99～7.92 (m, 2H, C6H42,6-H), 7.54～7.47 (m, 2H, benzofuran rings 4,7-H), 7.29～7.25 (dd, J=10.8Hz, 1.6Hz, 1H, benzofuran ring 6-H), 7.10 (s, 1H, C6H33-H), 7.06 (m, 1H, C6H35-H), 7.00～6.93 (m, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.51 (br, 1H, OH), 3.79～3.65 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 1H, CH3), 1.92 (s, 2H, CH3)。
Embodiment 10
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3,5-dinitro benzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol3,5-dinitro benzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after backflow 1h, adding 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry to obtain faint yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3,5-dinitro benzoyl hydrazone, yield 95.8%；Fusing point 105～109 DEG C；1HNMR (400MHz, CDCl3) δ: 9.10 (m, 3H, C6H32,4,6-H), 7.51～7.45 (m, 2H, benzofuran rings 4,7-H), 7.24～7.18 (m, 1H, benzofuran ring 6-H), 7.10～7.02 (m, 2H, C6H33,5-H), 6.97～6.91 (m, 1H, C6H36-H), 6.40 (s, 1H, benzofuran ring 3-H), 3.82～3.53 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.19 (s, 1H, CH3), 1.97 (s, 2H, CH3)。
Embodiment 11
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-(2-hydroxybenzoyl) hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol2-hydroxybenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after backflow 5h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-(2-hydroxybenzoyl) hydrazone, yield 82.1%；Fusing point 113～118 DEG C；1HNMR (400MHz, CDCl3) δ: 7.55～7.51 (m, 2H, C6H44,6-H), 7.50～7.42 (m, 2H, benzofuran rings 4,7-H), 7.28～7.26 (m, 1H, benzofuran ring 6-H), 7.10 (s, 1H, C6H33-H), 7.08～7.03 (m, 2H, C6H35-H+C6H45-H), 6.97 (d, J=9.1Hz, 1H, C6H43-H), 6.93～6.88 (m, 1H, C6H36-H), 6.43 (s, 1H, benzofuran ring 3-H), 5.63 (br, 1H, OH), 5.27 (br, 1H, NH), 3.76～3.63 (m, 2H, CH2), 3.51 (br, 1H, OH), 2.50 (s, 3H, benzofuran ring 2-CH3), 2.49 (s, 1H, CH3), 2.18 (s, 2H, CH3)。
Embodiment 12
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-(2-hydroxybenzoyl) hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol3-hydroxybenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after backflow 2h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-(2-hydroxybenzoyl) hydrazone, yield 67.6%；Fusing point 117～123 DEG C；1HNMR (400MHz, CDCl3) δ: 7.55～7.48 (m, 3H, benzofuran rings 4,7-H+C6H45-H), 7.40 (s, 1H, C6H42-H), 7.33 (d, J=6.6Hz, 1H, C6H46-H), 7.26 (dd, J=11.0Hz, 1.6Hz, 1H, benzofuran ring 6-H), 7.17～7.07 (m, 2H, C6H33-H+C6H44-H), 7.03 (d, J=8.5Hz, 1H, C6H35-H), 6.97 (d, J=8.5Hz, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.60 (br, 1H, OH), 5.28 (br, 1H, NH), 3.73～3.65 (m, 2H, CH2), 3.52 (br, 1H, OH), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.17 (s, 2H, CH3), 1.88 (s, 1H, CH3)。
Embodiment 13
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-(2-hydroxybenzoyl) hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-hydroxybenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after backflow 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-(2-hydroxybenzoyl) hydrazone, yield 77.3%；Fusing point 134～138 DEG C；1HNMR (400MHz, CDCl3) δ: 7.87～7.64 (m, 2H, C6H42,6-H), 7.53～7.49 (m, 3H), 7.26 (dd, J=10.2,1.4Hz, 1H, benzofuran ring 6-H), 7.15～7.06 (m, 2H), 7.00～6.96 (m, 1H, C6H35-H), 6.94～6.86 (m, 1H, C6H36-H), 6.42 (s, 1H, benzofuran ring 3-H), 5.28 (s, 1H, OH), 3.66 (s, 2H, CH2), 3.53 (br, 1H, OH), 2.50 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 3H, CH3)。
Embodiment 14
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4-dihydroxybenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-hydroxybenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after backflow 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain yellow solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4-(2-hydroxybenzoyl) hydrazone, yield 59.2%；Fusing point 116～120 DEG C；1HNMR (400MHz, CDCl3) δ: 7.78 (d, J=1.8Hz, 1H), 7.74 (dd, J=8.4,1.8Hz, 1H), 7.56 (d, J=1.4Hz, 1H), 7.54～7.47 (m, 3H), 7.29 (dd, J=8.4,1.7Hz, 1H, benzofuran ring 6-H), 7.07 (d, J=8.4Hz, 1H), 6.95～6.85 (m, 1H), 6.43 (s, 1H, benzofuran ring 3-H), 5.70 (br, 1H, OH), 5.33 (br, 1H, NH), 3.80～3.52 (m, 2H, CH2), 2.50 (s, 3H, benzofuran ring 2-CH3), 2.18～1.78 (m, 3H, CH3)。
Embodiment 15
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2 fluorobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol2-fluorobenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-fluorobenzoyl hydrazone, yield 76.9%；Fusing point 109～114 DEG C；1HNMR (400MHz, CDCl3) δ: 7.79～7.71 (m, 2H, C6H44,6-H), 7.51～7.47 (m, 2H, benzofuran rings 4,7-H), 7.28 (dd, J=8.6,1.5Hz, 1H, benzofuran ring 6-H), 7.24～7.21 (m, 2H, C6H43,5-H), 7.10～6.93 (m, 3H, C6H33,5,6-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.74 (s, 1H, OH), 5.42 (br, 1H, NH), 3.88～3.50 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 2H, CH3), 1.89 (s, 1H, CH3)。
Embodiment 16
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3 fluorobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol3-fluorobenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-fluorobenzoyl hydrazone, yield 86.5%；Fusing point 91～95 DEG C；1HNMR (400MHz, CDCl3) δ: 7.55～7.43 (m, 4H, benzofuran rings 4,7-H+C6H42,6-H), 7.26 (dd, J=9.6,1.3Hz, 1H, benzofuran ring 6-H), 7.20～7.12 (m, 2H, C6H44,5-H), 7.10 (s, 1H, C6H33-H), 7.09～7.00 (m, 1H, C6H35-H), 6.98～6.94 (m, 1H, C6H36-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.34 (br, 1H, OH), 3.77～3.61 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18 (s, 1H, CH3), 1.89 (s, 2H, CH3)。
Embodiment 17
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4 fluorobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol4-fluorobenzoyl hydrazine, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, add 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-fluorobenzoyl hydrazone, yield 67.3%；Fusing point 109～113 DEG C；1HNMR (400MHz, CDCl3) δ: 7.54～7.46 (m, 4H, benzofuran rings 4,7-H+C6H42,6-H), 7.24 (d, J=8.0Hz, 1H, benzofuran ring 6-H), 7.15～7.09 (m, 3H, C6H33-H+C6H43,5-H), 7.07～6.93 (m, 2H, C6H35,6-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.73 (br, 1H, OH), 5.40 (br, 1H, NH), 3.85～3.45 (m, 2H, CH2), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.18～1.88 (m, 3H, CH3)。
Embodiment 18
The preparation of 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4 difluorobenzoyl hydrazone
0.5mmol1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone, 0.55mmol2,4-difluorobenzohydrazide, 0.2ml glacial acetic acid is added with 20ml ethanol after dissolving, after 50 DEG C of reaction 1h, adding 50ml ethanol, decompression is distilled to residue 5ml solution, and TLC monitoring reaction is complete；Add water, fully shake, stand, precipitate out solid, filtration, filter cake water and 50% washing with alcohol, dry and to obtain white solid 1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4 difluorobenzene formyl hydrazone, yield 73.7%；Fusing point 85～90 DEG C；1HNMR (400MHz, CDCl3) δ: 8.31～8.16 (m, 1H), 7.54～7.46 (m, 2H, benzofuran rings 4,7-H), 7.25～7.19 (m, 1H, benzofuran ring 6-H), 7.16 (s, 1H), 7.10～6.94 (m, 3H), 6.93～6.84 (m, 1H), 6.40 (s, 1H, benzofuran ring 3-H), 5.97 (br, 1H, OH), 5.46 (br, 1H, NH), 3.80～3.58 (m, 2H, CH2), 2.48 (s, 3H, benzofuran ring 2-CH3), 2.17 (s, 1H, CH3), 1.88 (s, 2H, CH3)。
Embodiment 19
The resisiting influenza virus neuraminidase activity of the hydrazone derivant containing benzofuran ring
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the metabolite produced under neuraminidase effect is under 360nm irradiates and excites, it is possible to producing 450nm fluorescence, the change of fluorescence intensity can react neuraminidase activity delicately。Enzyme both is from A/PR/8/34 (H1N1) virus stain。
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza virus god NA are suspended in reaction buffer (pH6.5), add fluorogenic substrate MUNANA and start reaction system, 37 DEG C hatch 40 minutes after, add reaction terminating liquid and terminate reaction。Under the Parameter Conditions that excitation wavelength 360nm and transmitting wavelength are 450nm, measure fluorescence intensity level。The fluorescence intensity of reaction system can reflect the activity of enzyme。Minimizing amount according to fluorescence intensity can the computerized compound suppression ratio to NA activity。
3. detection sample: embodiment compound。
4. Activity Results
Preferred compound honokiol in response system during detectable concentration 40.0 μ g/mL to the suppression ratio of neuraminidase and IC50(μ g/mL) is tabulated below:
The table hydrazone derivant containing benzofuran ring is to the suppression ratio of neuraminidase and IC50
By the known hydrazone derivant containing benzofuran ring of data in table, neuraminidase had good inhibitory activity, and inhibitory activity is better than honokiol, can be applicable to prepare neuraminidase inhibitor。

Claims (6)

1. the hydrazone derivant containing benzofuran ring shown in a class chemical constitution formula I and pharmaceutically acceptable salt thereof:
Wherein R is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl；X1、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or amino；X2、X4It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl；X3It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C5Straight chained alkyl or C3～C5Branched alkyl, hydroxyl, C1～C5Unbranched alkoxy, C3～C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino。
2. the hydrazone derivant containing benzofuran ring described in claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that described compound is selected from:
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone benzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-aminobenzoic acylhydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-aminobenzoic acylhydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-acetyl amino phenyl formyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-nitrobenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-nitrobenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3,5-dinitro benzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-(2-hydroxybenzoyl) hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-(2-hydroxybenzoyl) hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-(2-hydroxybenzoyl) hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4-dihydroxybenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2-fluorobenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-fluorobenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-fluorobenzoyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-2,4 difluorobenzene formyl hydrazone,
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-3-trifluoromethylbenzoyl hydrazone or
1-[4-hydroxyl-3-(2-methyl benzofuran-5-base) phenyl]-2-acetone-4-trifluoromethylbenzoyl hydrazone。
3. the preparation method of the hydrazone derivant containing benzofuran ring described in claim 1, it is characterised in that its preparation reaction is as follows:
In formula, R, X1～X5Definition as claimed in claim 1。
4. the application in preparation influenza virus inhibitor of the hydrazone derivant containing benzofuran ring described in claim 1 or 2。
5. the application in preparing influenza virus neuraminidase inhibitor of the hydrazone derivant containing benzofuran ring described in claim 1 or 2。
6. a pharmaceutical composition, including carrier available at least one compound of claim 1～2 and pharmacopedics。
CN201610103855.6A 2016-02-25 2016-02-25 Hydrazone derivative of the ring containing benzofuran and preparation method thereof and medical usage Expired - Fee Related CN105693665B (en)

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CN109651189A (en) * 2019-01-31 2019-04-19 上海应用技术大学 A kind of benzoyl hydrazone class neuraminidase inhibitor and its preparation method and application
CN110183349A (en) * 2019-06-11 2019-08-30 湖南大学 Oxalyl hydazone derivative and the preparation method and application thereof
CN110183349B (en) * 2019-06-11 2021-04-30 湖南大学 Oxalyl hydrazone derivative and preparation method and application thereof
CN111072610A (en) * 2019-12-16 2020-04-28 杭州师范大学 Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor
CN111072610B (en) * 2019-12-16 2022-08-30 杭州师范大学 Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor

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