4- (4- hydroxy phenyl methylene amino) -1,2,4- triazole -5- thioketones and its applicationTechnical field
The present invention relates to a kind of noval chemical compound, preparation method and application, specifically 4- (4- hydroxy phenyl methylene amino)-1H-1,2,4- triazole -5 (4H)-thioketones and its in the application for preparing influenza virus neuraminidase inhibitor.
Background technique
- 5 (4H)-thioketones (1) of 4- (aryl methylene amino) -3- alkyl -1H-1,2,4- triazole and its bioactivity are summarized such asUnder:
Summary of the invention
The technical problem to be solved by the present invention is to provide 4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazoles -5 (4H) -Thioketones, preparation method, pharmaceutical composition and purposes.
To solve technical problem of the invention, the invention provides the following technical scheme:
The first aspect of technical solution of the present invention provides one kind (4- hydroxy phenyl methylene ammonia of the 4- as shown in structural formula IBase) -1H-1,2,4- triazole -5 (4H)-thioketones and its pharmaceutically acceptable salt:
Wherein, R1It is selected from: C2Alkyl, C3~C7Straight chain or C3~C7Branched alkyl, fluorine, chlorine, bromine, iodine；Phenyl, 4- fluorobenzeneBase；X is selected from: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl；R is selected from: hydrogen, methoxyl group, ethyoxyl, C3~C4Straight chainAlkoxy or C3~C4Branched alkoxy；
Or, R1It is selected from: C1~C2Alkyl, C3~C7Straight chain or C3~C7Branched alkyl, fluorine, chlorine, bromine, iodine；Phenyl, 4- fluorobenzeneBase；X is selected from: fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl；R is selected from: hydrogen, methoxyl group, ethyoxyl, C3~C4Straight chain alkaneOxygroup or C3~C4Branched alkoxy.
A kind of 4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- that the first aspect of technical solution of the present invention also providesTriazole -5 (4H)-thioketones is selected from following compounds:
The second aspect of technical solution of the present invention provides 4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazole -5The preparation method of (4H)-thioketones, it is characterised in that its preparation reaction is as follows:
Wherein, R1It is selected from: C2Alkyl, C3~C7Straight chain or C3~C7Branched alkyl, fluorine, chlorine, bromine, iodine；Phenyl, 4- fluorobenzeneBase；X is selected from: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl；R is selected from: hydrogen, methoxyl group, ethyoxyl, C3~C4Straight chainAlkoxy or C3~C4Branched alkoxy；
Or, R1It is selected from: C1~C2Alkyl, C3~C7Straight chain or C3~C7Branched alkyl, fluorine, chlorine, bromine, iodine；Phenyl, 4- fluorobenzeneBase；X is selected from: fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl；R is selected from: hydrogen, methoxyl group, ethyoxyl, C3~C4Straight chain alkaneOxygroup or C3~C4Branched alkoxy.
The third aspect of technical solution of the present invention, which is to provide, contains compound described in first aspect and its pharmaceutically acceptableSalt pharmaceutical composition, which contains the 4- (4- hydroxy phenyl methylene amino)-of the invention of therapeutically effective amount1H-1, -5 (4H)-thioketones of 2,4- triazole and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.It is wherein describedPharmaceutical carrier refer to the common pharmaceutical carrier of pharmaceutical field；The pharmaceutical composition can be prepared according to method well known in the art.It canBy the way that the compounds of this invention and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solids or liquid are assignedShape agent and/or adjuvant combination, are made any dosage form used suitable for human or animal.The compounds of this invention and its pharmaceutically acceptableContent of the salt in its pharmaceutical composition be usually 0.1%~95% weight percent.
The compounds of this invention and its pharmaceutically acceptable salt can be in a unit containing its pharmaceutical compositionAdministration, administration route can be enteron aisle or non-bowel, and such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral cavity are viscousFilm, 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 (includingTrue solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injectionAnd 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 capsule, soft capsule, capsulae enterosolubilis), granule, dissipateAgent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gelAgent, 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 tablet is made in the compounds of this invention and its pharmaceutically acceptable salt, can be widely used known in this fieldVarious excipient, including diluent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch,Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonateDeng；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, ethylCellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；It is fine that disintegrating agent can be dried starch, crystalliteTie up element, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, carbonSour hydrogen sodium and citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.；Lubricant and glidant can beTalcum 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 doubleSynusia and multilayer tablet.
It, can be by effective component the compounds of this invention and its pharmaceutically acceptable in order to which capsule is made in administration unitSalt is mixed with diluent, glidant, and mixture is placed directly in hard capsule or soft capsule.It can also be by the effective component present inventionizationClose object and its pharmaceutically acceptable salt and particle or pellet first be made with diluent, binder, disintegrating agent, then be placed in hard capsule orIn soft capsule.It is used to prepare the compounds of this invention and its each diluent of pharmaceutically acceptable salt tablet, binder, wettingAgent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For injection is made in the compounds of this invention and its pharmaceutically acceptable salt, can with water, ethyl alcohol, isopropanol,Simultaneously appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure is added in propylene glycol or their mixture as solventRegulator.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphorusHydrochlorate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, vinegarHydrochlorate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can also be added as proppant.In addition, if desired, can also be withColorant, preservative, fragrance, corrigent or other additives are added into pharmaceutical preparation.To reach medication purpose, enhancing treatmentEffect, drug of the invention or pharmaceutical composition can be administered with any well known medication.
The fourth aspect of technical solution of the present invention is to provide 4- of the present invention (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazole -5 (4H)-thioketones and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are in preparation influenza diseaseApplication in terms of malicious neuraminidase inhibitor:
Wherein, R1It is selected from: hydrogen, C1~C2Alkyl, C3~C7Straight chain or C3~C7Branched alkyl, fluorine, chlorine, bromine, iodine；Phenyl,4- fluorophenyl；X is selected from: H, fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl；R is selected from: hydrogen, methoxyl group, ethyoxyl, C3~C4Unbranched alkoxy or C3~C4Branched alkoxy.
Advantageous effects:
4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazole -5 (4H)-thioketones of the invention is a kind of with influenzaThe noval chemical compound of neuraminidase inhibitory activity.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- methyl-1 H-1,2,4- triazole
- 5 (4H)-thioketones of 0.26g (2.0mmol) 4- amino -3- methyl-1 H-1,2,4- triazole, 0.33g (2.2mmol) are fragrantOxalaldehyde, 3mL acetic acid, back flow reaction 4h is cooling, filters, methylene chloride or ethanol washing, and ethyl alcohol recrystallization is dry, obtains white solidBody 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- methyl-1 H-1, -5 (4H)-thioketones of 2,4- triazole, yield 81.4%,M.p.229~231 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.64(s,1H,NH),9.98(s,1H,OH),9.60(s,1H,), NCH 7.50 (d, J=1.8Hz, 1H, C6H32-H), 7.35 (dd, J=8.0,1.8Hz, 1H, C6H3), 6.96 (d, J=8.0Hz,1H,C6H3),3.88(s,3H,OCH3),2.36(s,3H,CH3).13C NMR(100MHz,DMSO-d6)δ:165.24,161.71,151.85,148.61,148.55,124.78,123.77,116.11,110.96,56.14,11.23。
Embodiment 2
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy phenyl methylene amino) -3- ethyl -1H-1,2,4- triazole
It is prepared by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- ethyl -1H-1,2,4- triazole and 4- hydroxy benzenes firstAldehyde flows back 2.5h, obtains white solid 4- (4- hydroxy phenyl methylene amino) -3- ethyl -1H-1, -5 (4H)-thioketones of 2,4- triazole,Yield 56.5%, m.p.247~250 DEG C.1H NMR(400MHz,DMSO)δ:13.68(s,1H,NH),10.37(s,1H,OH),9.59 (s, 1H, NCH), 7.75 (d, J=8.4Hz, 2H, C6H42,6-H), 6.92 (d, J=8.4Hz, 2H, C6H4 3,5-H),2.70 (q, J=7.4Hz, 2H, CH2), 1.21 (t, J=7.4Hz, 3H, CH3)。
Embodiment 3
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- ethyl -1H-1,2,4- triazole
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- ethyl -1H-1,2,4- triazole and vanillic aldehyde flow back2.5h obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- ethyl -1H-1, -5 (4H)-sulphur of 2,4- triazoleKetone, yield 80.1%, m.p.193~195 DEG C.1H NMR(400MHz,DMSO)δ:13.69(s,1H,NH),10.03(s,1H,OH),9.55(s,1H,NCH),7.47(s,1H,C6H32-H), 7.33 (d, J=8.0Hz, 1H, C6H3), 6.93 (d, J=8.0Hz,1H,C6H3),3.85(s,3H,OCH3), 2.72 (q, J=7.4Hz, 2H, CH2), 1.22 (t, J=7.4Hz, 3H, CH3)。
Embodiment 4
The preparation of -5 (4H)-thioketones of 4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- ethyl -1H-1,2,4- triazole
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- ethyl -1H-1,2,4- triazole and vanillic aldehyde flow back5.5h obtains white solid 4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- ethyl -1H-1, -5 (4H)-sulphur of 2,4- triazoleKetone, yield 62.1%, m.p.183~185 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.70(s,1H,NH),9.97(s,1H,), OH 9.56 (s, 1H, NCH), 7.47 (d, J=1.9Hz, 1H, C6H32-H), 7.34 (dd, J=8.0,1.9Hz, 1H, C6H3),6.96 (d, J=8.0Hz, 1H, C6H3), 4.11 (q, J=7.0Hz, 2H, OCH2), 2.73 (q, J=7.5Hz, 2H, CH2),1.38(t, J=7.0Hz, 3H, OCH2CH3), 1.23 (t, J=7.5Hz, 3H, CH3)。
Embodiment 5
The preparation of 4- (4- hydroxy phenyl methylene amino) -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketones
By 1 method of embodiment prepare: (S) -4- amino -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketones with4- hydroxy benzaldehyde flows back 2.5h, obtains white solid 4- (4- hydroxy phenyl methylene amino) -3- (1- ethoxy) -1H-1, and 2,4-Triazole -5 (4H)-thioketones, yield 83.3%, m.p.206~208 DEG C.1H NMR(400MHz,DMSO)δ:13.81(s,1H,NH),10.38(s,1H,C6H44-OH), 9.44 (s, 1H, NCH), 7.78 (d, J=8.0Hz, 2H, C6H4 2,6-H),6.93(d,J=8.0Hz, 2H, C6H43,5-H), 5.60 (s, 1H, OH), 4.86 (q, J=6.4Hz, 1H, CH), 1.45 (d, J=6.4Hz,3H,CH3)。
Embodiment 6
4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketonesPreparation
By 1 method of embodiment prepare: (S) -4- amino -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketones withVanillic aldehyde flows back 2.5h, obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- (1- ethoxy) -1H-1, and 2,4- triazole -5 (4H)-thioketones, yield 55.2%, m.p.170~172 DEG C.1H NMR(400MHz,DMSO)δ:13.80(s,1H,NH),10.03(s,1H,C6H34-OH),9.39(s,1H,NCH),7.50(s,1H,C6H32-H), 7.35 (d, J=8.0Hz,1H,C6H3), 6.93 (d, J=8.0Hz, 1H, C6H3), 5.60 (s, 1H, OH), 4.86 (q, J=6.4Hz, 1H, CH), 3.85 (s,3H,OCH3), 1.45 (d, J=6.4Hz, 3H, CH3)。
Embodiment 7
4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketonesPreparation
By 1 method of embodiment prepare: (S) -4- amino -3- (1- ethoxy) -1H-1,2,4- triazole -5 (4H)-thioketones withVanillic aldehyde flows back 4h, obtains faint yellow solid 4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- (1- ethoxy) -1H-1, and 2,4- triazole -5 (4H)-thioketones, yield 81.2%, m.p.154~156 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.78(s,1H,NH),9.91(s,1H,C6H34-OH), 9.44 (s, 1H, NCH), 7.51 (d, J=1.9Hz, 1H, C6H3 2-H),7.36(dd, J=8.0,1.9Hz, 1H, C6H3), 6.97 (d, J=8.0Hz, 1H, C6H3), 5.58 (d, J=5.8Hz, 1H, OH), 4.90(q, J=6.7Hz, 1H, CH), 4.13 (q, J=6.9Hz, 2H, OCH2), 1.49 (d, J=6.7Hz, 3H, CH3), 1.40 (t, J=6.9Hz,3H,CH3)。
Embodiment 8
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- propyl -1H-1,2,4- triazole
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- propyl -1H-1,2,4- triazole and vanillic aldehyde flow back4h, obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- propyl -1H-1, -5 (4H)-thioketones of 2,4- triazole,Yield 76.0%, m.p.183~185 DEG C.1H NMR(400MHz,DMSO)δ:13.70(s,1H,NH),10.03(s,1H,OH),9.55(s,1H,NCH),7.47(s,1H,C6H32-H), 7.33 (d, J=8.0Hz, 1H, C6H3), 6.93 (d, J=8.0Hz,1H,C6H3),3.85(s,3H,OCH3), 2.68 (t, J=7.3Hz, 2H, C3H7 1-H),1.73-1.64(m,2H,C3H7 2-H),0.94 (t, J=7.3Hz, 3H, C3H7 3-H)。
Embodiment 9
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- amyl -1H-1,2,4- triazole
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- amyl -1H-1,2,4- triazole and vanillic aldehyde flow back5h, obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- amyl -1H-1, -5 (4H)-thioketones of 2,4- triazole,Yield 62.5%, m.p.162~164 DEG C.1H NMR(400MHz,CDCl3)δ:10.67(s,1H,NH),10.02(s,1H,NCH),7.45(s,1H,C6H32-H), 7.36 (d, J=8.0Hz, 1H, C6H3), 7.01 (d, J=8.0Hz, 1H, C6H3),6.06(s,1H,OH),3.98(s,3H,OCH3), 2.80 (t, J=7.3Hz, 2H, C5H11 1-H),1.80-1.72(m,2H,C5H11 2-H),1.42-1.34(m,4H,C5H113,4-H), 0.91 (d, J=5.9Hz, 3H, CH3)。
Embodiment 10
The system of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- isopropyl -1H-1,2,4- triazoleIt is standby
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- isopropyl -1H-1,2,4- triazole and vanillic aldehyde return5h is flowed, white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- isopropyl -1H-1,2,4- triazoles -5 (4H)-are obtainedThioketones, yield 60.0%, m.p.155~157 DEG C.1H NMR(400MHz,DMSO)δ:13.70(s,1H,NH),10.02(s,1H,OH),9.53(s,1H,NCH),7.47(s,1H,C6H32-H), 7.34 (d, J=8.0Hz, 1H, C6H3), 6.93 (d, J=8.0Hz,1H,C6H3),3.84(s,3H,OCH3), 3.15-3.09 (m, 1H, CH), 1.25 (d, J=6.8Hz, 6H, 2CH3)。
Embodiment 11
The system of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- sec-butyl -1H-1,2,4- triazoleIt is standby
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- sec-butyl -1H-1,2,4- triazole and vanillic aldehyde return5h is flowed, white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- sec-butyl -1H-1,2,4- triazoles -5 (4H)-are obtainedThioketones, yield 73.9%, m.p.157~159 DEG C.1H NMR(400MHz,DMSO)δ:13.74(s,1H,NH),10.05(s,1H, OH), 9.56 (s, 1H, NCH), 7.49 (d, J=1.6Hz, 1H, C6H32-H), 7.36 (dd, J=8.4,1.6Hz, 1H,C6H3), 6.96 (d, J=8.4Hz, 1H, C6H3),3.87(s,3H,OCH3),3.03-2.97(m,1H,CH),1.81-1.74(m,1H,CH2),1.63-1.56(m,1H,CH2), 1.26 (d, J=7.2Hz, 3H, CH3), 0.88 (t, J=7.4Hz, 3H, CH3)。
Embodiment 12
The preparation of -5 (4H)-thioketones of 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- benzyl -1H-1,2,4- triazole
Prepare by 1 method of embodiment: -5 (4H)-thioketones of 4- amino -3- benzyl -1H-1,2,4- triazole and vanillic aldehyde flow back5h, obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- benzyl -1H-1, -5 (4H)-thioketones of 2,4- triazole,Yield 71.8%, m.p.189~191 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.84(s,1H,NH),10.05(s,1H,OH),9.66(s,1H,NCH),7.44(s,1H,C6H3 2-H),7.34-7.26(m,6H,C6H3,C6H5), 6.94 (d, J=8.0Hz,1H,C6H3),4.15(s,2H,CH2),3.87(s,3H,OCH3)；13CNMR(100MHz,DMSO-d6)δ:164.03,161.86,151.82,150.67,148.61,135.69,129.37,128.95,127.32,124.95,123.81,116.03,110.48 56.06,31.21.
Embodiment 13
4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- is to -5 (4H)-thioketones of luorobenzyl -1H-1,2,4- triazolePreparation
Prepare by 1 method of embodiment: 4- amino -3- is to -5 (4H)-thioketones of luorobenzyl -1H-1,2,4- triazole and vanillic aldehydeFlow back 6h, obtains white solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- to luorobenzyl -1H-1,2,4- triazoles -5(4H)-thioketones, yield 83.7%, m.p.210~212 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.80(s,1H,NH),10.01(s,1H,OH),9.62(s,1H,NCH),7.40(s,1H,C6H3 2-H),7.35-7.31(m,2H,C6H4),7.27(d,J=8.0Hz, 1H, C6H3), 7.13 (t, J=8.4Hz, 2H, C6H4), 6.91 (d, J=8.0Hz, 1H, C6H3),4.12(s,2H,CH2),3.85(s,3H,OCH3)。
Embodiment 14
4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- is to -5 (4H)-thioketones of hydroxybenzyl -1H-1,2,4- triazolePreparation
Prepare by 1 method of embodiment: 4- amino -3- is to -5 (4H)-thioketones of hydroxybenzyl -1H-1,2,4- triazole and vanillaAldehyde flows back 6h, obtains faint yellow solid 4- (4- hydroxy 3-methoxybenzene base methylene amino) -3- to hydroxybenzyl -1H-1, and 2,4- tri-Azoles -5 (4H)-thioketones, yield 84.3%, m.p.213~215 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.75(s,1H,NH),10.01(s,1H,OH),9.59(s,1H,OH),9.30(s,1H,NCH)7.42(s,1H,C6H32-H), 7.27 (d, J=8.0Hz,1H,C6H3), 7.06 (d, J=8.0Hz, 2H, C6H4), 6.91 (d, J=8.0Hz, 1H, C6H32-H), 6.66 (d, J=8.0Hz,2H,C6H4),3.97(s,2H,CH2),3.85(s,3H,OCH3)。
Embodiment 15
4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- is to -5 (4H)-thioketones of hydroxybenzyl -1H-1,2,4- triazolePreparation
Prepare by 1 method of embodiment: 4- amino -3- is to -5 (4H)-thioketones of hydroxybenzyl -1H-1,2,4- triazole and chinese cymbidiumElement reflux 6h, obtains white solid 4- (4- hydroxyl -3- ethoxyl phenenyl methylene amino) -3- to hydroxybenzyl -1H-1, and 2,4- tri-Azoles -5 (4H)-thioketones, yield 70.3%, m.p.222~224 DEG C.1H NMR(400MHz,DMSO-d6)δ:13.75(s,1H,NH),9.93(s,1H,OH),9.58(s,1H,OH),9.31(s,1H,NCH),7.40(s,1H,C6H32-H), 7.25 (d, J=8.0Hz,1H,C6H3), 7.06 (d, J=8.0Hz, 2H, C6H4), 6.92 (d, J=8.0Hz, 1H, C6H3), 6.66 (d, J=8.0Hz,2H,C6H4),4.09(q,2H,OCH2),3.97(s,2H,CH2),1.39(t,3H,CH3)。
Embodiment 16
4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazole -5 (4H)-thioketones resisiting influenza virus neuraminidaseActivity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effectUnder 360nm irradiation excitation, 450nm fluorescence can produce, the variation of fluorescence intensity can delicately react neuraminic acid enzyme activityProperty.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample and influenza virus NA are suspended in reaction buffer (pH 6.5), addEnter fluorogenic substrate MUNANA starting reaction system, 37 DEG C are incubated for after forty minutes, and reaction terminating liquid is added to terminate reaction.In excitation wavelengthUnder the Parameter Conditions that 360nm and launch wavelength are 450nm, fluorescence intensity level is measured.The fluorescence intensity of reaction system can reflectThe activity of enzyme.Compound can be calculated to the active inhibiting rate of NA according to the reduction amount of fluorescence intensity.
3. test sample: embodiment compound
4. Activity Results
Preferred compound is in reaction system to the inhibiting rate and IC of neuraminidase when 40.0 μ g/mL of detectable concentration50(μG/mL) value is included in table 1；
1 compound of table (40.0 μ g/mL) is to the inhibitory activity and IC of neuraminidase H1N150(μg/mL)
| X | R1 | R | 40 μ g/mL, inhibiting rate/% | IC50, μ g/mL |
| H | H | OCH3 | 74.6±1.04 | 17.61±0.21 |
| H | CH3 | H | 58.58±0.48 | 30.04±0.55 |
| H | CH3 | OCH3 | 75.81±2.24 | 14.68±0.49 |
| H | CH3 | OC2H5 | 59.63±4.89 | 26.26±3.43 |
| H | C2H5 | OCH3 | 62.6±2.83 | 22.19±3.02 |
| H | n-C4H9 | OCH3 | 58.47±6.16 | 31.05±5.74 |
| H | C6H5 | OCH3 | 50.37±2.42 | 39.85±4.23 |
| H | 4-FC6H4 | OCH3 | 65.44±1.72 | 25.81±0.75 |
| H | 4-OHC6H4 | OCH3 | 74.59±4.15 | 18.11±1.34 |
| CH3 | CH3 | OCH3 | 64.77±2.25 | 19.47±2.26 |
| CH3 | CH3CH2 | OCH3 | 77.23±0.93 | 15.24±1.01 |
| OH | CH3 | H | 68.21±1.18 | 22.08±0.27 |
| OH | CH3 | OCH3 | 79.79±0.71 | 14.97±0.7 |
| OH | CH3 | OC2H5 | 75.67±0.47 | 15.58±0.84 |
4- (4- hydroxy phenyl methylene amino) -1H-1,2,4- triazole -5 (4H)-thioketones has resisiting influenza virus neuraminic acidEnzymatic activity can be used for preparing influenza virus neuraminidase inhibitor.