CN105622558B - Acyl hydrazone derivative of the ring containing benzofuran and preparation method and application - Google Patents
Acyl hydrazone derivative of the ring containing benzofuran and preparation method and application Download PDFInfo
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- CN105622558B CN105622558B CN201610100379.2A CN201610100379A CN105622558B CN 105622558 B CN105622558 B CN 105622558B CN 201610100379 A CN201610100379 A CN 201610100379A CN 105622558 B CN105622558 B CN 105622558B
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- benzofuran
- alkyl
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- hydrazone derivative
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- 0 CCCC(C)C([C@](C1C(CC)C=C)*1*1(C)**(CC)C(C)C1)=CC1*(C)C1 Chemical compound CCCC(C)C([C@](C1C(CC)C=C)*1*1(C)**(CC)C(C)C1)=CC1*(C)C1 0.000 description 2
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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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the acyl hydrazone derivative and its pharmaceutically acceptable salt of the ring containing benzofuran shown in a kind of structural formula I, its preparation method and pharmaceutical composition and its application in influenza virus neuraminidase inhibitor is prepared.Wherein R is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branched alkyl；R1It is selected from：C1~C2Alkyl, C3~C17Straight chained alkyl or C3~C17Branched alkyl.
Description
Technical field
The present invention relates to a kind of noval chemical compound and preparation method and application；Specifically the acylhydrazone of the ring containing benzofuran derives
The preparation of thing 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 acyl hydrazone derivative, its preparation method, the medicine of a kind of ring containing benzofuran
Compositions and purposes.
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
Acyl hydrazone derivative and its pharmaceutically acceptable salt：
Wherein R is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branched alkyl；R1It is selected from：C1~C2
Alkyl, C3~C17Straight chained alkyl or C3~C17Branched alkyl；The acyl hydrazone derivative chemistry of the ring containing benzofuran shown in formula I is entitled
1- [4- hydroxyls/alkoxy -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone fat acylhydrazones.
The second aspect of technical solution of the present invention there is provided the acyl hydrazone derivative of the ring containing benzofuran described in first aspect
Preparation method, it is characterised in that it preparation reaction it is as follows：
Wherein R is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C5Straight chained alkyl or C3~C5Branched alkyl；R1It is selected from：C1~C2
Alkyl, C3~C17Straight chained alkyl or C3~C17Branched alkyl.
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 pharmaceutical composition contains the acyl hydrazone derivative of the ring of the invention containing benzofuran of therapeutically effective amount
And its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to pharmaceutical field and commonly used
Pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.Can be by by the compounds of this invention and its medicine
Acceptable salt combines with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent on, is made suitable
In any formulation that human or animal uses.The compounds of this invention and its pharmaceutically acceptable salt containing in its pharmaceutical composition
Amount is 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 acylhydrazone that the fourth aspect of technical solution of the present invention is to provide the ring containing benzofuran described in first aspect present invention spreads out
Biology and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza neuraminidase suppression
Application in terms of preparation.
Advantageous effects：
The acyl hydrazone derivative of the ring containing benzofuran of the present invention is that a kind of new construction type has influenza virus nerve ammonia
The compound of sour 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 acetyl hydrazones
0.5mmol 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone, 1.0mmol acethydrazides,
0.2ml glacial acetic acid is added after being dissolved with 20ml ethanol, after 50 DEG C are reacted 5h, 50ml ethanol is added, is evaporated under reduced pressure to remaining 5ml
Solution, TLC monitoring reactions finish.A large amount of water are added, fully shaking, are stood, separate out solid, filtering, filter cake is washed with water, and dries
Obtain faint yellow solid 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone acetyl hydrazones, yield 58.9%；It is molten
92~95 DEG C of point.1H NMR(400MHz,CDCl3)δ：7.57-7.53 (m, 2H, benzofuran ring 4,7-H), 7.28~7.24 (m,
1H, benzofuran ring 6-H), 7.10~7.08 (m, 1H, C6H33-H), 7.06~7.02 (m, 1H, C6H35-H), 6.98~6.94
(m, 1H, C6H36-H), 6.43 (s, 1H, benzofuran ring 3-H), 5.70 (br, 1H, OH), 5.38 (br, 1H, NH), 3.66 (s,
1H, CH2), 3.52 (s, 2H, CH2), 2.50 (s, 3H, COCH3), 2.49 (s, 3H, benzofuran ring 2-CH3), 2.35 (s, 3H,
CH3)。
Embodiment 3
The resisiting influenza virus neuraminidase activity of the acyl 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
Preferable 1- [4- hydroxyls -3- (2- methyl benzofuran -5- bases) phenyl] -2- acetone acetyl hydrazone honokiols are anti-
It is respectively 40.87% and 4.37% to the inhibiting rate of neuraminidase when answering 40.0 μ g/mL of detectable concentration in system.
The acyl hydrazone derivative of the ring containing benzofuran has preferable inhibitory activity to neuraminidase, and inhibitory activity is better than
Honokiol, it can be applied to prepare neuraminidase inhibitor.
Claims (4)
1. the acyl 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；R1It is selected from：C1~C2Alkyl, C3Straight chained alkyl or C3Branched alkyl.
2. the preparation method of the acyl hydrazone derivative of the ring containing benzofuran described in claim 1, it is characterised in that preparing for it is anti-
Should be as follows：
In formula, R, R1Definition it is as claimed in claim 1.
3. the acyl hydrazone derivative of the ring containing benzofuran described in claim 1 is in influenza virus neuraminidase inhibitor is prepared
Application.
A kind of 4. available carrier in pharmaceutical composition, including at least one compound of claim 1 and pharmaceutics.
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| CN108272786B (en) * | 2018-04-17 | 2022-05-27 | 南华大学 | Medical application of 1- [3- (benzofuran-5-yl) phenyl ] -2-acetone benzoyl hydrazone |
| CN109096231A (en) * | 2018-09-12 | 2018-12-28 | 长沙理工大学 | 4- allyl -2- (benzofuran -5- base) phenol and its application |
| CN110950825B (en) * | 2018-09-27 | 2023-01-03 | 湖南大学 | 6- (piperazinemethyl) -2- (benzofuran-5-yl) phenol and application thereof as anti-cancer drug |
| CN110183349B (en) * | 2019-06-11 | 2021-04-30 | 湖南大学 | Oxalyl hydrazone derivative and preparation method and application thereof |
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| US9487476B2 (en) * | 2011-10-12 | 2016-11-08 | Yale University | Catechol diethers as potent anti-HIV agents |
| CN103127040B (en) * | 2011-11-29 | 2016-05-25 | 天津市国际生物医药联合研究院 | Magnolia cortex P.E is applied in the medicine of preparing treatment and prevent AIDS |
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