CN108047160A - 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its medical usage - Google Patents
2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its medical usage Download PDFInfo
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- CN108047160A CN108047160A CN201810010630.5A CN201810010630A CN108047160A CN 108047160 A CN108047160 A CN 108047160A CN 201810010630 A CN201810010630 A CN 201810010630A CN 108047160 A CN108047160 A CN 108047160A
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- 0 Cc1c(**)[s]c(N)n1 Chemical compound Cc1c(**)[s]c(N)n1 0.000 description 3
- ZBEAYGJLAJKGGT-FESCUDFNSA-O C/C(/O)=C\C(\O)=C(/C=C)\C=[NH2+] Chemical compound C/C(/O)=C\C(\O)=C(/C=C)\C=[NH2+] ZBEAYGJLAJKGGT-FESCUDFNSA-O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
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- Thiazole And Isothizaole Compounds (AREA)
Abstract
The present invention relates to (2 benzyl hydrazono-) 5 acyl group thiazoles and its pharmaceutically acceptable salt 2 shown in formula I, pharmaceutical composition and its application in influenza virus neuraminidase inhibitor is prepared.Wherein, R is selected from：Methyl, ethyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
Description
Technical field
The present invention relates to a kind of noval chemical compound, its preparation method and applications, are specifically 2- (2- benzyls hydrazono-) -5- acyl group thiophenes
Azoles, its preparation method and its preparing the application of influenza virus neuraminidase inhibitor.
Background technology
Chinese invention patent [ZL201610061123.5,2017.12.29 are authorized] discloses 2- (2- benzyls hydrazono-) thiophene
Azoles -5- carboxylates and its as the application prepared in terms of influenza virus neuraminidase inhibitor：
P.Makam etc. [Eur.J.Med.Chem., 2013.69:564-576, Eur.J.Pharm.Sci., 2014.52:
138-145] report 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ethyl ester (A) with good Killing Mycobacterium Tuberculosis effect with
Anti-malarial acts on；[Int.J.Mol.Sci., 2014.15 (12) such as A.Grozav:22059-22072] synthesize benzyl hydrazono- thiophene
Azoles -5- carboxylic acid, ethyl esters (B) find that part of compounds lives to two kinds of cancer cells (MDA-MB231 and HeLa) with apparent antiproliferative
Property；[Chem.Pharm.Bull., 2007.55 (8) such as M.H.Shin:1126-1135] find benzyl hydrazono- thiazole-5-carboxylic acid second
Ester (C) has certain inoxidizability.
B：Y=2,4-Cl2, 4-CH3O, 3-Cl；
C:Y=H, 4-CH3, 4-CH3O, 4-Cl, 4-CN.
[the The Synthesis and Antiproliferative Activities of New such as A.Grozav
Arylidene-Hydrazinyl-Thiazole Derivatives Int.J.Mol.Sci.2014,15,22059-22072]
Also disclose that 2- (2- benzyls hydrazono-) -5- acyl group thiazoles and preparation method thereof.
The content of the invention
The technical problem to be solved by the present invention is to provide a kind of 2- (2- benzyls hydrazono-) -5- acyl groups thiazole, its preparation method, medicines
Compositions and purposes.
The technical issues of to solve the present invention, the present invention provide following technical solution：
The first aspect of technical solution of the present invention 2- (2- benzyls hydrazono-) -5- acyls as shown in structural formula I there is provided one kind
Base thiazole and its pharmaceutically acceptable salt：
Wherein, R is selected from：Ethyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Directly
Chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, two
Chloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitre
Base, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~
C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, two
Methylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, second
Oxygroup, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, ethyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl,
Trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1
~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxylic
Base, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxy
Base, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or ethoxy
Carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino,
Dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino,
Carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, first
Oxygroup, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or second
Oxygen carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, first ammonia
Base, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetyl
Amino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl,
Methoxyl group, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or ethoxy
Carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino,
Dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetyl
Amino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl
Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group
Or carbethoxyl group；X3It is selected from：Deuterium, C1~C2Alkyl, hydroxyl, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
A kind of 2- (2- benzyls hydrazono-) -5- acyl groups thiazole that the first aspect of technical solution of the present invention also provides is selected from following
Compound：
The second aspect of technical solution of the present invention there is provided 2- (2- benzyls hydrazono-) -5- acyl group thiazoles preparation method,
It is characterized in that its preparation reaction is as follows：
Wherein, R is selected from：Ethyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Directly
Chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, two
Chloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitre
Base, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~
C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, two
Methylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, second
Oxygroup, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, ethyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl,
Trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1
~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxylic
Base, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxy
Base, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or ethoxy
Carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino,
Dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino,
Carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, first
Oxygroup, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or second
Oxygen carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, first ammonia
Base, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetyl
Amino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl,
Methoxyl group, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or ethoxy
Carbonyl；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino,
Dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
Or R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, two
Methyl fluoride, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：
Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetyl
Amino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl
Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group
Or carbethoxyl group；X3It is selected from：Deuterium, C1~C2Alkyl, hydroxyl, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
X is selected from：Cl or Br；HX is selected from：Hydrochloric acid, hydrobromic acid.
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 contain therapeutically effective amount the present invention 2- (2- benzyls hydrazono-) -5- acyl group thiophenes
Azoles and its pharmaceutically acceptable salt and optional contain pharmaceutical carrier.It is normal that the wherein described pharmaceutical carrier refers to pharmaceutical field
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 is combined with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, is made
Any dosage form used suitable for human or animal.The compounds of this invention and its pharmaceutically acceptable salt are in its pharmaceutical composition
Content is usually 0.1%~95% weight percent.
The compounds of this invention and its pharmaceutically acceptable salt can be in a unit containing its pharmaceutical composition
Administration, administration route 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), suspension, injection is (including liquid drugs injection, powder-injection
And infusion), 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, pellet, dripping pill, suppository, film, patch, 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 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, ethyl alcohol, 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, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, carbon
Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol aliphatic 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 double
Synusia and multilayer tablet.
It, can be by active ingredient the compounds of this invention and its pharmaceutically acceptable in order to which administration unit is made capsule
Salt is mixed with diluent, glidant, and mixture is placed directly in hard shell capsules or soft capsule.It also can be by the active ingredient present inventionization
Close object and its pharmaceutically acceptable salt and particle or pellet first be made with diluent, binder, disintegrant, then be placed in hard shell capsules or
In soft capsule.It is used to prepare 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 injection, can use water, ethyl alcohol, isopropanol,
Propylene glycol or their mixture as solvent simultaneously add in 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, can also add in mannitol, glucose etc. as proppant.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
Prescription method is administered.
The fourth aspect of technical solution of the present invention be to provide 2- of the present invention (2- benzyls hydrazono-) -5- acyl groups thiazoles and its
Pharmaceutically acceptable salt and third aspect described pharmaceutical composition are in terms of influenza virus neuraminidase inhibitor is prepared
Application.
The fourth aspect of technical solution of the present invention also provides following four kinds of 2- (2- benzyls the hydrazono-) -5- acyl groups of the present invention
Application of the thiazole in terms of influenza virus neuraminidase inhibitor is prepared.
Advantageous effects：
2- (2- benzyls hydrazono-) -5- acyl group thiazoles of the present invention are a kind of new construction types with influenza virus nerve ammonia
The compound of sour enzyme inhibition activity.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of 2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 3- acetyl bromides acetone：
20.00g acetylacetone,2,4-pentanediones, 35.60g NBS, 30mL acetone, ice bath reaction 2h are filtered, and filtrate revolving adds in
50mLCH2Cl2, washing 3 times, anhydrous Na2SO4It is dry, red liquid is rotated to obtain, it is spare.
(2) preparation of 2- (2- hydroxyl benzyls hydrazono-) thioformamide
0.61g (5.0mmol) Benzaldehyde,2-hydroxy, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；
It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (2- hydroxyl benzyls hydrazono-) thioformamide, spare.
(3) preparation of 2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (2- hydroxyl benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethyl alcohol, adds in 1.07g
In the 12mL ethanol solutions of (2.0mmol) 3- acetyl bromide acetone, flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry black 2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.245~246 DEG C, yield 73.3%；1H NMR (400MHz, DMSO-d6) δ：12.32 (s, 1H, NH), 10.38 (s, 1H,
OH), 8.43 (s, 1H ,=CH), 7.63~6.90 (m, 4H, C6H4), 2.50 (s, 3H, thiazole ring-CH3), 2.41 (s, 3H,
COCH3)。
Embodiment 2
The preparation of 2- (2- (3- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (3- hydroxyl benzyls hydrazono-) thioformamide
0.61g (5.0mmol) 3- hydroxy benzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；
It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (3- hydroxyl benzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (3- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (3- hydroxyl benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (3- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.256~258 DEG C, yield 62.2%；1H NMR (400MHz, DMSO-d6) δ：8.03 (s, 1H ,=CH), 7.24~6.82
(m, 4H, C6H4), 2.51 (s, 3H, thiazole ring-CH3), 2.41 (s, 3H, COCH3)。
Embodiment 3
The preparation of 2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- hydroxyl benzyls hydrazono-) thioformamide
0.61g (5.0mmol) 4- hydroxy benzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；
It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (4- hydroxyl benzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- hydroxyl benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry green 2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.270~272 DEG C, yield 77.8%；1H NMR (400MHz, DMSO-d6) δ：12.28 (s, 1H, NH), 9.92 (s, 1H,
OH), 8.01 (s, 1H ,=CH), 7.52 (d, J=7.8Hz, 2H, C6H4), 6.83 (d, J=7.7Hz, 2H, C6H4), 2.49 (s,
3H, thiazole ring-CH3), 2.40 (s, 3H, COCH3)。
Embodiment 4
The preparation of 2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (2,4- hydroxyl benzyls hydrazono-) thioformamide
0.69g (5.0mmol) 2,4- 4-dihydroxy benzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol return
Flow 6h；It filtering, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (2,4- hydroxyl benzyl hydrazono-) thioformamide,
It is spare.
(2) preparation of 2- (2- (2,4- hydroxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (2,4- hydroxyl benzyl hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (2,4- dihydroxy benzyl hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.283~285 DEG C, yield 52.4%；1H NMR (400MHz, DMSO-d6) δ：12.22 (s, 1H, NH), 10.48 (s, 1H,
OH), 9.92 (s, 1H, OH), 8.32 (s, 1H ,=CH), 7.41 (d, J=8.2Hz, 1H, C6H3), 6.36 (d, J=9.0Hz, 2H,
C6H3), 2.48 (s, 3H, thiazole ring-CH3), 2.39 (s, 3H, COCH3)。
Embodiment 5
The preparation of 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (3- fluorine benzyls hydrazono-) thioformamide
0.62g (5.0mmol) 3- fluorobenzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；It takes out
Filter, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (3- fluorine benzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (3- fluorine benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.219~220 DEG C, yield 72.7%；1H NMR (400MHz, DMSO-d6) δ：8.08 (s, 1H ,=CH), 7.52~7.19
(m, 4H, C6H4), 2.47 (s, 3H, thiazole ring-CH3), 2.36 (s, 3H, COCH3)。
Embodiment 6
The preparation of 2- (2- (4- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- fluorine benzyls hydrazono-) thioformamide
0.62g (5.0mmol) 4- fluorobenzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；It takes out
Filter, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (4- fluorine benzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (4- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
Product 2- (4- fluorine benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry green 2- (2- (4- fluorine benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.286~288 DEG C, yield 71.9%；1H NMR (400MHz, CDCl3)δ：7.88 (s, 1H ,=CH), 7.70~7.62 (m,
2H, C6H4), 7.11 (d, J=8.0Hz, 2H, C6H4), 2.61 (s, 3H, thiazole ring-CH3), 2.43 (s, 3H, COCH3)。
Embodiment 7
The preparation of 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- methoxycarbonyl group benzyls hydrazono-) thioformamide
0.82g (5.0mmol) 4- methoxycarbonyl group benzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol return
Flow 6h；It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry yellow 2- (4- methoxycarbonyl group benzyls hydrazono-) thio formyl
Amine, it is spare.
(2) preparation of 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- methoxycarbonyl group benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, is added in
1.07g (2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3PH=7~8 are adjusted, are filtered,
Filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl -5- acetyl
Base thiazole；M.p.254~255 DEG C, yield 65.9%；1H NMR (400MHz, CDCl3)δ：8.07 (d, J=7.5Hz, 2H,
C6H4), 7.92 (s, 1H ,=CH), 7.74 (d, J=7.4Hz, 2H, C6H4), 3.94 (s, 3H, OCH3), 2.62 (s, 3H, thiazoles
Ring-CH3), 2.49 (s, 3H, COCH3)。
Embodiment 8
The preparation of 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- carboxyl benzyls hydrazono-) thioformamide
0.75g (5.0mmol) 4- carboxyl benzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；
It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (4- carboxyl benzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- carboxyl benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.315~317 DEG C, yield 75.2%；1H NMR (400MHz, DMSO-d6) δ：12.79 (s, 1H, NH), 8.16 (s, 1H ,=
CH), 7.99 (d, J=7.6Hz, 2H, C6H4), 7.80 (d, J=7.7Hz, 2H, C6H4), 2.50 (s, 3H, thiazole ring-CH3),
2.43 (s, 3H, COCH3)。
Embodiment 9
The preparation of 2- (2- (4- nitrobenzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- nitrobenzyls hydrazono-) thioformamide
5.0mmol 4- nitrobenzaldehydes, 5.0mmol thiosemicarbazides are in 12mL ethanol solutions, and flow back 6h, filters, filter
Cake is washed successively with ice water, ice ethyl alcohol is washed, dry faint yellow 2- (4- nitrobenzyls hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (4- nitrobenzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- nitrobenzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (4- nitrobenzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.279~281 DEG C, yield 92.1%.1H NMR (400MHz, DMSO-d6) δ：12.71 (s, 1H, NH), 8.24 (d, J=
8.1Hz, 2H, C6H4), 8.15 (s, 1H ,=CH), 7.89 (d, J=8.1Hz, 2H, C6H4), 2.50 (s, 3H, thiazole ring-CH3),
2.42 (s, 3H, COCH3)。
Embodiment 10
The preparation of 2- (2- (4- amino benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
0.15g (0.5mmol) 2- (2- (4- nitrobenzyls hydrazono-)) -4- methyl -5- acetylthiazoles, 5mL CH2Cl2,
Then 5mL water, 5mL acetic acid add in appropriate iron powder, react at room temperature 15h, filter, a large amount of CH2Cl2Filter cake is washed, filtrate is with 10%
NaHCO3PH=7~8 are adjusted, are washed 3 times, anhydrous Na2SO4Dry, revolving obtains yellow green 2- (2- (4- amino benzyls hydrazono-)) -4-
Methyl -5- acetylthiazoles；M.p.223~225 DEG C, yield 85.4%；1H NMR (400MHz, DMSO-d6) δ：7.92 (s,
1H ,=CH), 7.35 (d, J=7.8Hz, 2H, C6H4), 6.58 (d, J=7.8Hz, 2H, C6H4), 5.59 (s, 2H, NH2), 2.45
(s, 3H, thiazole ring-CH3), 2.34 (s, 3H, COCH3)。
Embodiment 11
The preparation of 2- (2- (4- dimethylamino benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- dimethylamino benzyls hydrazono-) thioformamide
0.75g (5.0mmol) 4- dimethylaminobenzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol return
Flow 6h；It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (4- dimethylamino benzyls hydrazono-) thio formyl
Amine, it is spare.
(2) preparation of 2- (2- (4- dimethylamino benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- dimethylamino benzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, is added in
1.07g (2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3PH=7~8 are adjusted, are filtered,
Filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry green 2- (2- (4- dimethylamino benzyls hydrazono-)) -4- methyl -5- acetyl
Base thiazole；M.p.235~237 DEG C, yield 90.1%；1H NMR (400MHz, DMSO-d6) δ：8.00 (s, 1H ,=CH), 7.48
(d, J=8.0Hz, 2H, C6H4), 6.73 (d, J=8.1Hz, 2H, C6H4), 2.95 (s, 6H, 2 × CH3), 2.45 (s, 3H, thiazoles
Ring-CH3), 2.32 (s, 3H, COCH3)。
Embodiment 12
The preparation of 2- (2- (4- acetylamino benzyls hydrazono-)) -4- methyl -5- acetylthiazoles
0.10g (0.6mmol) CDI, stirring at normal temperature 0.5h is added portionwise in 0.10g (0.6mmol) acetic acid, 6mLDMF, adds in
0.14g (0.5mmol) 2- (2- (4- amino benzyls hydrazono-)) -4- methyl -5- acetylthiazoles, flow back 5h, and reaction solution is poured into
In 10mL water, there are a large amount of solids to be precipitated, filter, washing, ice ethyl alcohol is washed, dry yellow 2- (2- (4- acetylamino benzyls Asia hydrazines
Base)) -4- methyl -5- acetylthiazoles；M.p.290~291 DEG C, yield 78.5%；1H NMR (400MHz, DMSO-d6) δ：
12.32 (s, 1H, NH), 10.14 (s, 1H, CONH), 8.04 (s, 1H ,=CH), 7.64 (q, J=7.9Hz, 4H, C6H4), 2.49
(s, 3H, thiazole ring-CH3), 2.41 (s, 3H, COCH3), 2.06 (s, 3H, NCH3)。
Embodiment 13
The preparation of 2- (2- benzyls hydrazono-) -4- methyl -5- acetylthiazoles
(1) preparation of 2- benzyls hydrazono- thioformamide
0.53g (5.0mmol) benzaldehyde, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；It filters,
Filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- benzyls hydrazono- thioformamide, spare.
(2) preparation of 2- (2- benzyls hydrazono-) -4- methyl -5- acetylthiazoles
The 2- benzyl hydrazono- thioformamides that upper step obtains are dissolved in 12mL ethanol solutions, add in 1.07g (2.0mmol) 3-
Acetyl bromide acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3PH=7~8 are adjusted, are filtered, filter cake washed successively with ice water,
Ice ethyl alcohol is washed, dry yellow 2- (2- benzyls hydrazono-) -4- methyl -5- acetylthiazoles；M.p.223~225 DEG C, yield
69.9%.
Embodiment 14
The preparation of 2- (2- (4- methoxybenzyls hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (4- methoxybenzyls hydrazono-) thioformamide
0.68g (5.0mmol) 4-methoxybenzaldehyde, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, reflux
6h；It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (4- methoxybenzyls hydrazono-) thioformamide, standby
With.
(2) preparation of 2- (2- (4- methoxybenzyls hydrazono-)) -4- methyl -5- acetylthiazoles
2- (4- methoxybenzyls hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (4- methoxybenzyls hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.213~215 DEG C, yield 76.0%；1H NMR (400MHz, DMSO-d6) δ：8.06 (s, 1H ,=CH), 7.64 (d, J=
8.1Hz, 2H, C6H4), 7.01 (d, J=8.0Hz, 2H, C6H4), 3.80 (s, 3H, OCH3), 2.50 (s, 3H, thiazole ring-CH3),
2.41 (s, 3H, COCH3)。
Embodiment 15
The preparation of 2- (2- (3- benzyl chlorides hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (3- benzyl chlorides hydrazono-) thioformamide
0.71g (5.0mmol) 3- chlorobenzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, flow back 6h；It takes out
Filter, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (3- benzyl chlorides hydrazono-) thioformamide, spare.
(2) preparation of 2- (2- (3- benzyl chlorides hydrazono-)) -4- methyl -5- acetylthiazoles
2- (3- benzyl chlorides hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow 2- (2- (3- benzyl chlorides hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.226~228 DEG C, yield 91.0%；1H NMR (400MHz, DMSO-d6) δ：8.09 (s, 1H ,=CH), 7.72~7.46
(m, 4H, C6H4), 2.50 (s, 3H, thiazole ring-CH3), 2.42 (s, 3H, COCH3)。
Embodiment 16
The preparation of 2- (2- (2,4- benzyl dichlorides hydrazono-)) -4- methyl -5- acetylthiazoles
(1) preparation of 2- (2,4- benzyl dichlorides hydrazono-) thioformamide
0.86g (5.0mmol) 2,4- dichlorobenzaldehydes, 0.46g (5.0mmol) thiosemicarbazides and 12mL ethyl alcohol, reflux
6h；It filters, filter cake is washed successively with ice water, ice ethyl alcohol is washed, dry white 2- (2,4- benzyl dichloride hydrazono-) thioformamide, standby
With.
(2) preparation of 2- (2- (2,4- benzyl dichlorides hydrazono-)) -4- methyl -5- acetylthiazoles
2- (2,4- benzyl dichloride hydrazono-) thioformamide that upper step obtains is dissolved in 12mL ethanol solutions, adds in 1.07g
(2.0mmol) 3- acetyl bromides acetone is in 12mL ethanol solutions, and flow back 6h, 10%NaHCO3Adjust pH=7~8, filter, filter cake according to
It is secondary washed with ice water, ice ethyl alcohol is washed, dry yellow green 2- (2- (2,4- benzyl dichloride hydrazono-)) -4- methyl -5- acetylthiazoles；
M.p.265~267 DEG C, yield 85.6%；1H NMR (400MHz, DMSO-d6) δ：12.59 (s, 1H, NH), 8.35 (s, 1H ,=
CH), 7.91 (d, J=8.5Hz, 1H, C6H3) 7.64 (s, 1H, C6H3), 7.47 (d, J=8.5Hz, 1H, C6H3) 2.49 (s, 3H,
Thiazole ring-CH3), 2.41 (s, 3H, COCH3)。
Embodiment 17
The resisiting influenza virus neuraminidase activity of 2- (2- benzyls hydrazono-) -5- acyl group thiazoles
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effect
Under 360nm irradiation excitations, 450nm fluorescence can be generated, the variation of fluorescence intensity can delicately react neuraminic acid enzyme activity
Property.Enzyme both is from A/PR/8/34 (H1N1) virus stain and A/ Fujian prevents/15/90 (H3N2) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample is suspended in reaction buffer (pH 6.5) with influenza virus god NA,
It adds in fluorogenic substrate MUNANA and starts reaction system, 37 DEG C are incubated after forty minutes, and reaction terminating liquid is added to terminate reaction.In excitation wave
Under long 360nm and the Parameter Conditions that launch wavelength is 450nm, fluorescence intensity level is measured.The fluorescence intensity of reaction system can be anti-
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 is in reaction system to the inhibiting rate and IC of neuraminidase during 40.0 μ g/mL of detectable concentration50(μ
G/ml) value is included in table 1 and 2；3 are shown in Table with the activity comparison of 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester.
1 2- of table (2- benzyls hydrazono-) -5- acetyl thiazoles (40.0 μ g/mL) to the inhibitory activity of neuraminidase H1N1 and
IC50(μg/ml)
| X | Inhibiting rate/% | IC50μg/ml |
| H | 78.74±1.12 | 13.68±1.37 |
| 3-F | 73.19±6.86 | 17.09±3.41 |
| 4-F | 85.29±3.37 | 13.4±1.28 |
| 3-Cl | 86.38±0.55 | 12.47±1.06 |
| 2,4-Cl2 | 64.52±6.03 | 22.22±3.82 |
| 2-OH | 77.62±4.48 | 16.2±2.75 |
| 3-OH | 87.93±0.07 | 11.84±1.23 |
| 4-OH | 85.77±5.42 | 11.26±0.23 |
| 2,4-(OH)2 | 88.57±1.62 | 12.92±1.73 |
| 4-OCH3 | 63.99±9.48 | 27.61±6.58 |
| 4-NO2 | 86.79±1.81 | 15.09±0.19 |
| 4-NH2 | 84.94±2.17 | 14.91±1.31 |
| 4-N(CH3)2 | 54.51±2.78 | 34.34±3.24 |
| 4-NHCOCH3 | 80.99±2.2 | 13.15±1.18 |
| 4-CO2CH3 | 89.93±0.43 | 8.62±0.12 |
| 4-COOH | 91.16±1.62 | 9.35±0.46 |
2 2- of table (2- benzyls hydrazono-) -5- acetyl thiazoles (40 μ g/ml) are to the inhibitory activity and IC of neuraminidase H3N250
(μg/ml)
| X | Inhibiting rate/% | IC50μg/ml |
| 3-Cl | 83.28±2.06 | 17.39±0.71 |
| 2,4-Cl2 | 70.61±1.87 | 21.88±0.88 |
| 4-OCH3 | 70.72±3.58 | 22.06±2.74 |
| 4-NO2 | 75.64±3.73 | 21.06±0.86 |
| 4-NH2 | 80.17±2.25 | 16.38±0.36 |
| 4-N(CH3)2 | 74.12±2.35 | 20.07±1.48 |
| 4-NHCOCH3 | 82.84±1.66 | 15.69±0.76 |
Suppression of 3 2- of table (2- benzyls hydrazono-) -5- acetyl (carboxylate) thiazole (40 μ g/mL) to neuraminidase (H1N1)
Expression activitiy processed
"-" does not carry out H1N1 active testings for inhibiting rate less than 50% in table
2- (2- benzyls hydrazono-) -5- acyl groups thiazole has resisiting influenza virus neuraminidase activity, available for preparing influenza
Neuraminidase inhibitor.
Claims (10)
1. 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I：
Wherein, R is selected from：Ethyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or
C3~C4Branched alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethane
Base or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, ammonia
Base, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkane
Base, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethoxy
Base, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
2. 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I：
R is selected from：Methyl；R1It is selected from：Hydrogen, ethyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl, fluoroform
Base, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkane
Base, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, first
Oxygen carbonyl or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, second
Oxygroup, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
3. 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I：
R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl,
Trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Deuterium, C1~
C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, first
Oxygen carbonyl or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, second
Oxygroup, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；
X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
4. 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I：
R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl,
Trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1
~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxylic
Base, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group,
Ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group；X3
It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, diformazan ammonia
Base, acetylamino, carboxyl, methoxycarbonyl group or carbethoxyl group.
5. 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I：
R is selected from：Methyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl, methyl fluoride, difluoromethyl,
Trifluoromethyl, bromomethyl, two bromomethyls, trisbromomethyl, chloromethyl, dichloromethyl or trichloromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1
~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxylic
Base, methoxycarbonyl group or carbethoxyl group；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxy
Base, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl group or ethoxy
Carbonyl；X3It is selected from：Deuterium, C1~C2Alkyl, hydroxyl, ethyoxyl, fluorine, bromine, iodine, nitro, amino, methylamino, dimethylamino, acetyl
Amino, carboxyl, methoxycarbonyl group or carbethoxyl group.
6. one kind 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt, selected from following compounds：
The preparation method of claim 1~6 any one of them 2- 7. (2- benzyls hydrazono-) -5- acyl group thiazoles, which is characterized in that
Its preparation reaction is as follows：
In formula, R, R1And X1~X5As described in claim 1~6；X is selected from：Cl or Br.
8. claim 1~6 any one of them 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its pharmaceutically acceptable salt
Application in influenza virus neuraminidase inhibitor is prepared.
9. a kind of pharmaceutical composition, including available load at least one of any one of claim 1~6 compound and pharmaceutics
Body.
10. application of one kind 2- (2- benzyls hydrazono-) -5- acyl group thiazoles in influenza virus neuraminidase inhibitor is prepared；Institute
2- (2- benzyls the hydrazono-) -5- acyl group thiazoles stated are selected from：
X=H, 2,4-Cl2, 4-CH3O, 3-Cl.
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| CN111153898A (en) * | 2019-07-02 | 2020-05-15 | 南华大学 | Thiourea derivative and preparation method and application thereof |
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| CN111153898A (en) * | 2019-07-02 | 2020-05-15 | 南华大学 | Thiourea derivative and preparation method and application thereof |
| CN111100074B (en) * | 2019-07-02 | 2022-10-28 | 南华大学 | Pyridazine hydrazone derivative and preparation method and application thereof |
| CN111153898B (en) * | 2019-07-02 | 2022-11-11 | 南华大学 | Thiourea derivative and preparation method and application thereof |
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