CN105693665B - Hydrazone derivative of the ring containing benzofuran and preparation method thereof and medical usage - Google Patents

Hydrazone derivative of the ring containing benzofuran and preparation method thereof and medical usage Download PDF

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Publication number
CN105693665B
CN105693665B CN201610103855.6A CN201610103855A CN105693665B CN 105693665 B CN105693665 B CN 105693665B CN 201610103855 A CN201610103855 A CN 201610103855A CN 105693665 B CN105693665 B CN 105693665B
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bases
hydroxyls
phenyl
acetone
benzofuran
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CN105693665A (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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention discloses the hydrazone derivative and its pharmaceutically acceptable salt, its preparation method and pharmaceutical composition of the ring containing benzofuran shown in structural formula I and its application in influenza virus neuraminidase inhibitor is prepared.

Description

Hydrazone derivative of the ring containing benzofuran and preparation method thereof and medical usage
Technical field
The present invention relates to a kind of noval chemical compound and preparation method and application；The specifically hydrazone of the ring containing benzofuran The preparation of derivative and the application as influenza virus neuraminidase inhibitor.
Background technology
Mainly there is zanamivir (Zanamivir) as the anti-influenza virus medicament that neuraminidase inhibitor has listed, GS-4104 (Oseltamivir) and Peramivir (Peramivir).
Duarte etc. [Bioorg.Med.Chem., 2007,15：2421-2433] synthesize the acylhydrazone class containing piperonyl cyclonene Compound, it is found that it has preferable anti-inflammatory activity.
[organic chemistry, 2009,29 (6) such as Ye Ying：993-997] acylhydrazone structure is introduced into indole ring, antibacterial activity is surveyed Take temperature bright, MIC of the indoles acylhydrazone to staphylococcus aureus50Value and MBC values are respectively 0.612 μ g/mL and 1.10 μ G/mL, less than the antibacterials profit azoles amine (1~8 μ g/mL) used in clinic, Ma Lin azolactones (1~4 μ g/mL) and amikacin (1.56μg/mL)。
[Journal of Virology, 2009,83 (4) such as Basu：1881-1891] report compound N SC125044 Anti-influenza virus activity.Duarte etc. [Bioorg.Med.Chem., 2012,20：487-497] one has been synthesized on this basis Serial 2- (2-hydroxybenzoyl)s hydrazone compound, it is found that they all have certain anti-influenza virus activity.
Barman etc. [Eur.J.Med.Chem., 2014,71：81-90] synthesize a series of naphthalene-ring containing acylhydrazones derivatives Thing, and its inhibitory activity to influenza A virus is tested, find when having hydroxyl substitution for 2 of naphthalene nucleus, activity is preferably.Shih Deng [J.Biomed.Sci, 2010,17：13] inhibitory activity of the BPR1P0034 for various subtype influenza virus is described, is found For part hypotype, its inhibitory activity is suitable with positive control zanamivir.
Chinese invention patent [CN103360315] has synthesized a series of fragrant miscellaneous oxygen acetyl hydrazones containing pyrazoles, and it is right to test its The inhibitory activity of H1N1 influenza viruses, the EC of outstanding compound50Less than 10 μM.[the PLOS Currents such as Fedichev Influenza.2011] describe inhibitory action of the acyl hydrazone derivative for a variety of subtype influenza virus of the triazole containing 1,2,4-.
The content of the invention
Present invention solves the technical problem that it is to provide the hydrazone derivative of a kind of ring containing benzofuran, its preparation side Method, pharmaceutical composition and medical usage.
To solve 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 it is a kind of as shown in chemical structural formula I containing benzofuran ring Hydrazone derivative and its pharmaceutically acceptable salt：
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 alkane Epoxide, fluorine, chlorine, bromine, iodine, nitro or amino；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branch Alkyl group, hydroxyl, C1~C5Unbranched alkoxy, C3~C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl；X3Choosing From：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branched alkyl, hydroxyl, C1~C5Unbranched alkoxy, C3~C5 Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino；The virtue of the ring containing benzofuran shown in formula I The entitled 1- of formyl hydrazone derivatives chemical [4- hydroxyls/alkoxy -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone benzene first Acylhydrazone or 1- [4- hydroxyls/alkoxy -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone substituted benzoyl acylhydrazones.
Further, preferable compound is selected from：
1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone benzoyls hydrazone, 1- [4- hydroxyl -3- (2- Methyl benzofuran -5- bases) phenyl] -2- acetone -2- aminobenzoics acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofurans -5- Base) phenyl] -2- acetone -4- aminobenzoics acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone - 4- acetyl amino phenyls formyl hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- nitrobenzene formyls Hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- nitrobenzoyl hydrazones, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3,5- dinitro benzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzos Furans -5- bases) phenyl] -2- acetone -2- (2-hydroxybenzoyl)s hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] - 2- acetone -3- (2-hydroxybenzoyl)s hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- hydroxy benzenes Formyl hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4- dihydroxybenzoyls hydrazone, 1- [4- Hydroxyl -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzos Furans -5- bases) phenyl] -2- acetone -3- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- Acetone -4- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4 difluorobenzene first Acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- trifluoromethylbenzoyls hydrazone, 1- [4- hydroxyls Base -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- trifluoromethylbenzoyl hydrazones.
The hydrazone that the second aspect of technical solution of the present invention there is provided the ring containing benzofuran described in first aspect spreads out The preparation method of biology, 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 alkane Epoxide, fluorine, chlorine, bromine, iodine, nitro or amino；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branch Alkyl group, hydroxyl, C1~C5Unbranched alkoxy, C3~C5Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl；X3Choosing From：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branched alkyl, hydroxyl, C1~C5Unbranched alkoxy, C3~C5 Branched alkoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino.
The third aspect of technical solution of the present invention, which is to provide, contains compound described in first aspect and its pharmaceutically acceptable Salt pharmaceutical composition, the hydrazone for the ring of the invention containing benzofuran that the pharmaceutical composition contains therapeutically effective amount spreads out Biology and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to pharmaceutical field Conventional pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.Can by by the compounds of this invention and Its pharmaceutically acceptable salt combines with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, makes Into any formulation used suitable for human or animal.The compounds of this invention and its pharmaceutically acceptable salt are in its pharmaceutical composition Content be usually 0.1%~95% percentage by weight.
The compounds of this invention and its pharmaceutically acceptable salt can be in a unit containing its pharmaceutical composition Administration, method of administration can be enteron aisle or non-bowel, and such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral cavity are glued Film, 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 colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
It is sustained release preparation, control that the compounds of this invention and its pharmaceutically acceptable salt, which can be made ordinary preparation, also be made, Release formulation, targeting preparation and various particulate delivery systems.
In order to which the compounds of this invention and its pharmaceutically acceptable salt are made into tablet, can widely use known in this field Various excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate Deng；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl Cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, crystallite fibre Tie up element, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, carbon Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be Talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double Synusia and multilayer tablet.
, can be by active ingredient the compounds of this invention and its pharmaceutically acceptable in order to which administration unit is made into capsule Salt is mixed with diluent, glidant, and mixture is placed directly within hard shell capsules or soft capsule.Also can be by the active ingredient present inventionization First particle or micropill is made with diluent, binder, disintegrant in compound and its pharmaceutically acceptable salt, then be placed in hard shell capsules or In soft capsule.For preparing each diluent, binder, wetting of the compounds of this invention and its pharmaceutically acceptable salt tablet Agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For the compounds of this invention and its pharmaceutically acceptable salt are made into injection, can use water, ethanol, isopropanol, Propane diols or their mixture as solvent simultaneously add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure Conditioning agent.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphorus Hydrochlorate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, vinegar Hydrochlorate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can be also added and be used as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any Prescription method is administered.
The fourth aspect of technical solution of the present invention is to provide the fragrant formyl of the ring containing benzofuran described in first aspect present invention Hydazone derivative and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza virus inhibitor side The application in face.
Further, fourth aspect is to provide the hydrazone derivative of the ring containing benzofuran described in first aspect present invention And its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza virus neuraminidase inhibitor The application of aspect.
Advantageous effects：
The hydrazone derivative of the ring containing benzofuran of the present invention is a kind of new construction type with influenza virus god Compound through propylhomoserin enzyme inhibition activity.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone
(1) preparation of 4- pi-allyls -2- (2- methyl benzofuran -5- bases) phenol
10mmol honokiols, 0.2mmol PdCl are added in autoclave2, 2.0mmol NaOAc, 56ml DMA/H2O(6:1) 8atm O, are led to2, react 16h in 60 DEG C.After reaction terminates, the dilution of 100ml water is added, with 3 × 30ml acetic acid Ethyl ester extracts, anhydrous Na2SO4Dry, vacuum distillation recovered solvent.Crude product purifies through column chromatography, obtains yellow oily liquid 4- allyls Base -2- (2- methyl benzofuran -5- bases) phenol, yield 86.0%.1H NMR(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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone
10mmol 4- pi-allyls -2- (2- methyl benzofuran -5- bases) phenol is added in autoclave, 0.15mmol PdCl2, 40ml DMA/H2O(4:1) 8atm O, are led to2, react 10h in 60 DEG C.After reaction terminates, 100ml is added Water dilutes, and is extracted with 3 × 30ml ethyl acetate, anhydrous Na2SO4Dry, vacuum distillation recovered solvent.Crude product purifies through column chromatography, Obtain white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, yield 63.9%；Fusing point 118~ 121℃；1H NMR (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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone benzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol benzoyls Hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 1h that flows back, add 50ml ethanol, be evaporated under reduced pressure molten to remaining 5ml Liquid, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake is washed with water and 50% ethanol, Dry faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone benzoyl hydrazones, yield 90.0%；98~102 DEG C of fusing point；1H NMR (400MHz, CDCl3)δ：7.85~7.73 (m, 2H, C6H5, 7.53 2,6-H)~ 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 system of 1- [4- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-3-trifluoromethylbenzoyl hydrazones It is standby
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 3- trifluoros Toluyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 4h is stirred at room temperature, add 50ml ethanol, decompression is steamed Evaporate to remaining 5ml solution, TLC monitoring reactions and finish；Add water, fully shaking, stand, separate out solid, filtering, filter cake water and 50% ethanol washs, dry faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- Trifluoromethylbenzoyl hydrazone, yield 85.8%；85~90 DEG C of fusing point；1H NMR (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 ring 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 system of 1- [4- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-4-trifluoromethylbenzoyl hydrazones It is standby
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- trifluoros Toluyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 4h is stirred at room temperature, add 50ml ethanol, decompression is steamed Evaporate to remaining 5ml solution, TLC monitoring reactions and finish；Add water, fully shaking, stand, separate out solid, filtering, filter cake water and 50% ethanol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- three Methyl fluoride benzoyl hydrazone, yield 90.1%；95~100 DEG C of fusing point；1H NMR (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 ring 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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- aminobenzoic acylhydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 2- amino Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 4h is stirred at room temperature, add 50ml ethanol, be evaporated under reduced pressure extremely Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% Ethanol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- aminobenzenes Formyl hydrazone, yield 53.4%；87~93 DEG C of fusing point；1H NMR (400MHz, DMSO-d6)δ：9.37 (s, 1H, OH), 7.70~ 7.62 (m, 1H, C6H46-H), 7.54~7.44 (m, 2H, benzofuran ring 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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- aminobenzoic acylhydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- amino Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 3h is stirred at room temperature, add 50ml ethanol, be evaporated under reduced pressure extremely Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% Ethanol washs, dry faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- amino Benzoyl hydrazone, yield 71.4%；107~113 DEG C of fusing point；1H NMR (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 ring 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 system of 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- acetyl amino phenyl formyl hydrazones It is standby
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- acetyl Amino benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 5h, add 50ml ethanol, decompression is steamed Evaporate to remaining 5ml solution, TLC monitoring reactions and finish；Add water, fully shaking, stand, separate out solid, filtering, filter cake water and 50% ethanol washs, dry faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- Acetyl amino phenyl formyl hydrazone, yield 83.5%；127~131 DEG C of fusing point；1H NMR (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, C6H4, 7.69 3,5-H)~ 7.65 (m, 2H, C6H42,6-H), 7.56~7.47 (m, 2H, benzofuran ring 4,7-H), 7.41~7.37 (m, 1H, benzofurans 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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- nitrobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 2- nitros Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure extremely Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% Ethanol washs, dry yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- nitrobenzene Formyl hydrazone, yield 63.2%；109~113 DEG C of fusing point；1H NMR (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, benzo furans Mutter 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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- nitrobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- nitros Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure extremely Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% Ethanol washs, dry yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- nitrobenzene Formyl hydrazone, yield 94.8%；99~105 DEG C of fusing point；1H NMR (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 ring 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 system of 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3,5- dinitro benzoyl hydrazones It is standby
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 3,5- bis- Nitrobenzoyl hydrazides, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 1h that flows back, add 50ml ethanol, be evaporated under reduced pressure extremely Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% Ethanol washs, dry faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3,5- bis- Nitrobenzoyl hydrazone, yield 95.8%；105~109 DEG C of fusing point；1H NMR (400MHz, CDCl3)δ：9.10 (m, 3H, C6H32, 4,6-H), 7.51~7.45 (m, 2H, benzofuran ring 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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- (2-hydroxybenzoyl) hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 2- hydroxyls Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 5h that flows back, add 50ml ethanol, be evaporated under reduced pressure to residue 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% ethanol Washing, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- (2-hydroxybenzoyl)s Hydrazone, yield 82.1%；113~118 DEG C of fusing point；1H NMR (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- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- (2-hydroxybenzoyl) hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 3- hydroxyls Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 2h that flows back, add 50ml ethanol, be evaporated under reduced pressure to residue 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% ethanol Washing, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- (2-hydroxybenzoyl)s Hydrazone, yield 67.6%；117~123 DEG C of fusing point；1H NMR (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, benzos Furan nucleus 2-CH3), 2.17 (s, 2H, CH3), 1.88 (s, 1H, CH3)。
Embodiment 13
The preparation of 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- (2-hydroxybenzoyl) hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- hydroxyls Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 1h that flows back, add 50ml ethanol, be evaporated under reduced pressure to residue 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% ethanol Washing, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- (2-hydroxybenzoyl)s Hydrazone, yield 77.3%；134~138 DEG C of fusing point；1H NMR (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 system of 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4- dihydroxybenzoyl hydrazones It is standby
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- hydroxyls Benzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after the 1h that flows back, add 50ml ethanol, be evaporated under reduced pressure to residue 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% ethanol Washing, dry yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4- hydroxy benzenes first Acylhydrazone, yield 59.2%；116~120 DEG C of fusing point；1H NMR (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, benzo furans Mutter ring 3-H), 5.70 (br, 1H, OH), 5.33 (br, 1H, NH), 3.80~3.52 (m, 2H, CH2), 2.50 (s, 3H, benzo furans Mutter ring 2-CH3), 2.18~1.78 (m, 3H, CH3)。
Embodiment 15
The preparation of 1- [4- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-2-fluorobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 2- fluorobenzene Formylhydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure to surplus Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% second Alcohol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- fluorobenzoyls Hydrazone, yield 76.9%；109~114 DEG C of fusing point；1H NMR (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- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-3-fluorobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 3- fluorobenzene Formylhydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure to surplus Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% second Alcohol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- fluorobenzoyls Hydrazone, yield 86.5%；91~95 DEG C of fusing point；1H NMR (400MHz, CDCl3)δ：7.55~7.43 (m, 4H, benzofuran ring 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- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-4-fluorobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 4- fluorobenzene Formylhydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure to surplus Remaining 5ml solution, TLC monitoring reactions finish；Water is added, fully shaking, is stood, separates out solid, filtering, filter cake water and 50% second Alcohol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- fluorobenzoyls Hydrazone, yield 67.3%；109~113 DEG C of fusing point；1H NMR (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- hydroxyls-3- (2- methyl benzofuran-5- bases) phenyl]-2- acetone-2,4-difluorobenzoyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 0.55mmol 2,4- bis- Fluorobenzoyl hydrazine, 0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 1h, add 50ml ethanol, be evaporated under reduced pressure To remaining 5ml solution, TLC monitoring reactions finish；Add water, fully shaking, stand, separate out solid, filtering, filter cake water and 50% ethanol washs, dry white solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4- Difluorobenzoyl hydrazone, yield 73.7%；85~90 DEG C of fusing point；1H NMR (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 derivative of the ring containing benzofuran
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the caused metabolite under neuraminic acid enzyme effect In the case where 360nm irradiations excite, 450nm fluorescence can be produced, the change of fluorescence intensity can delicately react neuraminic acid enzyme activity Property.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, finite concentration sample is suspended in reaction buffer (pH6.5) with influenza virus god NA, adds Enter fluorogenic substrate MUNANA and start reaction system, after 37 DEG C are incubated 40 minutes, add reaction terminating liquid terminating reaction.In excitation wavelength Under 360nm and the Parameter Conditions that launch wavelength is 450nm, fluorescence intensity level is determined.The fluorescence intensity of reaction system can reflect The activity of enzyme.Inhibiting rate of the compound to NA activity can be calculated according to the decrement of fluorescence intensity.
3. detect sample：Embodiment compound.
4. Activity Results
Preferred compound honokiol is in reaction system to the inhibiting rate of neuraminidase during 40.0 μ g/mL of detectable concentration And IC50(μ g/mL) is tabulated below：
Inhibiting rate and IC of the hydrazone derivative of table ring containing benzofuran to neuraminidase50
Understand that the hydrazone derivative of the ring containing benzofuran has neuraminidase by data in table preferably to suppress Activity, and inhibitory activity is better than honokiol, can be applied to prepare neuraminidase inhibitor.

Claims (5)

1. the hydrazone derivative and its pharmaceutically acceptable salt of the ring containing benzofuran shown in a kind of chemical structural formula I：
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 alkane Base, 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 alkane Epoxide, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, amino or acetylamino.
2. the hydrazone derivative of the ring containing benzofuran described in claim 1, it is characterised in that described derivative choosing From：
1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone benzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl Benzofuran -5- bases) phenyl] -2- acetone -2- aminobenzoics acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) benzene Base] -2- acetone -4- aminobenzoics acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- second Acylamino- benzoyl hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- nitrobenzoyl hydrazones, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- nitrobenzoyl hydrazones, 1- [4- hydroxyl -3- (2- Methyl benzofuran -5- bases) phenyl] -2- acetone -3,5- dinitro benzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzo furans Mutter -5- bases) phenyl] -2- acetone -2- (2-hydroxybenzoyl)s hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- Acetone -3- (2-hydroxybenzoyl)s hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- hydroxy benzenes first Acylhydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4- dihydroxybenzoyls hydrazone, 1- [4- hydroxyls Base -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzo furans Mutter -5- bases) phenyl] -2- acetone -3- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- third Ketone -4- fluorobenzoyls hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -2,4 difluorobenzene formyl Hydrazone, 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -3- trifluoromethylbenzoyls hydrazones or 1- [4- hydroxyls Base -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone -4- trifluoromethylbenzoyl hydrazones.
3. the preparation method of the hydrazone derivative of the ring containing benzofuran described in claim 1, it is characterised in that its system It is standby to react as follows：
In formula, R, X1~X5Definition it is as claimed in claim 1.
4. the hydrazone derivative of the ring containing benzofuran described in claim 1 or 2 is preparing influenza neuraminidase Application in inhibitor.
A kind of 5. available carrier in pharmaceutical composition, including at least one compound of claim 1~2 and pharmaceutics.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Influenza virus neuraminidase inhibitors;Larisa V Gubareva，et al;《THE LANCET》;20000304;第355卷;第827-835页 *
毛秔子梢中天然高活性的神经氨酸酶抑制成分的研究;杜昕等;《化学学报》;20151231;第73卷;第741-748页 *

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