CN109305979A - 4- dimethylaminobenzaldehyde is preparing the application in NA inhibitor - Google Patents

4- dimethylaminobenzaldehyde is preparing the application in NA inhibitor Download PDF

Info

Publication number
CN109305979A
CN109305979A CN201710615507.1A CN201710615507A CN109305979A CN 109305979 A CN109305979 A CN 109305979A CN 201710615507 A CN201710615507 A CN 201710615507A CN 109305979 A CN109305979 A CN 109305979A
Authority
CN
China
Prior art keywords
base
picoline
dimethylaminophenyl
thiadiazine
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710615507.1A
Other languages
Chinese (zh)
Other versions
CN109305979B (en
Inventor
胡艾希
陶全洋
元科阳
叶姣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hunan Xianshi Pharmaceutical Co ltd
Original Assignee
Hunan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hunan University filed Critical Hunan University
Priority to CN201710615507.1A priority Critical patent/CN109305979B/en
Publication of CN109305979A publication Critical patent/CN109305979A/en
Application granted granted Critical
Publication of CN109305979B publication Critical patent/CN109305979B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The present invention relates to 6- shown in formula I (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyls -6; 7- dihydro -5H- [1; 2; 4] triazol [3; 4-b] [1; 3,4] thiadiazine and its pharmaceutically acceptable salt, pharmaceutical composition and its preparing the application in influenza virus neuraminidase inhibitor.Using 4- dimethylaminobenzaldehyde as raw material; through with 4- amino -3- (6- picoline -3- base) -1H-1; 2; 4- triazole -5 (4H)-thioketones, which reacts, is made 4- [(4- dimethylaminophenyl) methene amido] -3- (6- picoline -3- base) -1H-1; 2; 4- triazole -5 (4H)-thioketones; 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6 is made in cyclization again; 7- dihydro -5H- [1; 2,4] triazol [3,4-b] [1; 3,4] thiadiazine.

Description

4- dimethylaminobenzaldehyde is preparing the application in NA inhibitor
Technical field
The present invention relates to a kind of noval chemical compound, preparation method and application, specifically 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine, its Preparation method and its preparing the application in resisiting influenza virus neuraminidase inhibitor.
Background technique
4- dimethylaminobenzaldehyde is fine chemistry industry and pharmaceutical-chemical intermediate, is had been widely used in field of medicaments. 4- dimethylaminobenzaldehyde is reacted with -5 (4H)-thioketones of 4- amino -3- phenyl -1H-1,2,4- triazole can prepare 4- [(4- bis- Methylamino phenyl) methene amido] -5 (4H)-thioketones (A) of -3- phenyl -1H-1,2,4- triazole；Compound A has treatment molten Organize entamoeba effect, IC50Respectively less than 0.5 μM [Bioorganic&Medicinal Chemistry Letters, 2012,22(8):2768-2771]。
4- dimethylaminobenzaldehyde is reacted with -5 (4H)-thioketones of 4- amino -3- (pyridin-3-yl) -1H-1,2,4- triazole Prepare -5 (4H)-thioketones of 4- [(4- dimethylaminophenyl) methene amido] -3- (pyridin-3-yl) -1H-1,2,4- triazole (B)[Journal of Pharma Research,2014,3(3):20-22]；Compound B has preferable antibacterium and fungi Activity；Also have preferable anticonvulsant action [Indian Journal of Heterocyclic Chemistry, 2005,15 (1):15-18]；
4- dimethylaminobenzaldehyde is reacted with -5 (4H)-thioketones of 4- amino -3- (pyridin-4-yl) -1H-1,2,4- triazole Prepare -5 (4H)-thioketones of 4- [(4- dimethylaminophenyl) methene amido] -3- (pyridin-4-yl) -1H-1,2,4- triazole (C)；Compound C has preferable antibacterium and antifungal activity [International Journal of Pharma&Bio Sciences,2010,1(1):1-17；Indian Journal of Pharmaceutical Sciences,2004,66(6): 818-821；Journal of the Chilean Chemical Society,2010,55(3):359-362]；Compound C With antiinflammation [Archives of Pharmacal Research, 2011,34 (8): 1239-1250].
Zheng Yuguo etc. [organic chemistry, 2011,31 (6), 912-916] describes 4- dimethylaminobenzaldehyde in preparation 6,7- Application in dihydro -5H- [1,2,4] triazole [3,4-b] [1,3,4] diazthines compound；Wherein, 6- (4- dimethylamino Phenyl) -3- (3,4,5- trimethoxyphenyl) -7- benzoyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3, 4] for thiadiazine (D) in 10 μm of ol/L, the inhibiting rate to PC3 cancer cell is 75.9%.
Summary of the invention
The technical problem to be solved by the present invention is to provide 4- dimethylaminobenzaldehydes to have resisiting influenza virus nerve in preparation Application in propylhomoserin enzymatic activity compound.
To solve technical problem of the invention, the invention provides the following technical scheme:
There is provided 6- shown in structural formula I (4- dimethylaminophenyl) -3- for the first aspect of technical solution of the present invention (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine and Its pharmaceutically acceptable salt:
In formula；R is selected from: hydrogen, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine.
Further, preferred compound is selected from:
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- benzoyl -6,7- dihydro -5H- [1,2, 4] triazol [3,4-b] [1,3,4] thiadiazine, 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- chlorine Benzoyl) -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine or 6- (4- dimethylamino benzene Base) -3- (6- picoline -3- base) -7- (4- methoxybenzoyl base) -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine.
There is provided 6- (4- dimethylaminophenyl) -3- described in first aspect for the second aspect of technical solution of the present invention (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine Preparation method, it is characterised in that 4- dimethylaminobenzaldehyde be raw material, through with 4- amino -3- (6- picoline -3- base) - 1H-1,2,4- triazole -5 (4H)-thioketones, which reacts, is made 4- [(4- dimethylaminophenyl) methene amido] -3- (6- methyl pyrrole Pyridine -3- base) -1H-1, -5 (4H)-thioketones of 2,4- triazole, then obtained 6- (4- dimethylaminophenyl) -3- (the 6- methyl pyrrole of cyclization Pyridine -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine (I)；Preparation reaction It is as follows:
In formula；R is selected from: hydrogen, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine.
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, which contains 6- (4- dimethylaminophenyl) -3- of the invention of therapeutically effective amount (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine and Its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein the pharmaceutical carrier refers to that pharmaceutical field is common Pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.It can be by by the compounds of this invention and its pharmacy Upper acceptable salt is combined with one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant, is made and is suitable for Any dosage form that human or animal uses.The content of the compounds of this invention and its pharmaceutically acceptable salt in its pharmaceutical composition 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, subcutaneous injection, nasal cavity, oral cavity are viscous 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 type, w/o type and emulsion), suspension, injection (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 capsule, 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 tablet is made in the compounds of this invention and its pharmaceutically acceptable salt, can be widely used known in this field Various 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 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.；It is fine that disintegrating agent can be dried starch, crystallite 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 effective component the compounds of this invention and its pharmaceutically acceptable in order to which capsule is made in administration unit Salt 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 inventionization Close object and its pharmaceutically acceptable salt and particle or pellet first be made with diluent, binder, disintegrating agent, then be placed in hard capsule or In soft capsule.It is used to prepare the compounds of this invention and its each diluent of pharmaceutically acceptable salt tablet, binder, wetting Agent, 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 solvent Regulator.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 also be added 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 The administration of prescription method.
The fourth aspect of technical solution of the present invention is to provide 6- described in first aspect present invention (4- dimethylaminophenyl)- 3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine And its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza virus neuraminidase inhibitor The application of aspect.
Advantageous effects:
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro-of the invention 5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine is a kind of change with influenza neuraminidase inhibitory activity Close object.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
4- [(4- dimethylaminophenyl) methene amido] -3- (6- picoline -3- base) -1H-1,2,4- triazole -5 The preparation of (4H)-thioketones
5.0mmol 4- amino -3- (6- picoline -3- base) -1H-1,2,4- triazole -5 (4H)-thioketones, 5.1mmol4- (dimethylamino) benzaldehyde and 10mL acetic acid, flow back 5.0h, cooling, and solid is precipitated, and filters, dry yellow solid 4- [(4- Dimethylaminophenyl) methene amido] -3- (6- picoline -3- base) -1H-1, -5 (4H)-thioketones of 2,4- triazole, yield 89%, m.p.233~235 DEG C.1H NMR (400MHz, CDCl3+D2O) δ: 9.63 (s, 1H, N=CH), 9.18 (d, J= 2.0Hz, 1H, pyridine ring 2-H), 8.23 (dd, J=8.0Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.75 (d, J=8.4Hz, 2H, C6H43,5-H), 7.29 (s, 1H), 6.72 (d, J=8.4Hz, 2H, C6H4, 2,6-H), 3.08 (s, 6H, CH3NCH3), 2.65 (s, 3H, CH3)。
Embodiment 2
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- benzoyl -6,7- dihydro -5H- [1,2, 4] triazol [3,4-b] [1,3,4] thiadiazine
1.0mmol 4- [(4- is added in 1.1mmol 2- bromoacetophenone, 2.0mmol triethylamine and 5ml ethyl alcohol, stirring and dissolving Dimethylaminophenyl) methene amido] -3- (6- picoline -3- base) -1H-1, -5 (4H)-thioketones of 2,4- triazole, reflux It is cooling that solid is precipitated to fully reacting, it filters, solid is immersed in 4ml saturated sodium bicarbonate solution, stirring 30min removes three Ethylamine hydrobromide filters, dry, obtains white solid 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- Benzoyl -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine, yield 66%, m.p.197~199 ℃。1H NMR (400MHz, CDCl3+D2O) δ: 9.20 (d, J=2.0Hz, 1H, pyridine ring 2-H), 8.24 (dd, J=8.4Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.95 (d, J=7.6Hz, 2H, C6H52,6-H), 7.67 (t, J=7.6Hz, 1H, C6H5 4- H), 7.54 (t, J=7.6Hz, 2H, C6H53,5-H), 7.27~7.23 (m, 2H, C6H4), 7.22 (d, J=8.4Hz, 1H, pyrroles Phenazine ring 4-H), 6.60 (d, J=8.4Hz, 2H, C6H4), 5.24 (d, J=3.2Hz, 1H, CH), 5.12 (d, J=3.2Hz, 1H, CH), 2.90 (s, 6H, CH3NCH3), 2.61 (s, 3H, CH3)。
Embodiment 3
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- chlorobenzene formacyl) -6,7- dihydro - 5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine
It is prepared by 2 method of embodiment: 4- [(4- dimethylaminophenyl) methene amido] -3- (6- picoline -3- Base) -1H-1, -5 (4H)-thioketones of 2,4- triazole reacts 1.0h with the bromo- 1- of 2- (4- chlorphenyl) ethyl ketone, obtains white solid 6- (4- bis- Methylamino phenyl) -3- (6- picoline -3- base) -7- (4- chlorobenzene formacyl) -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine, yield 74%, m.p.182~184 DEG C.1H NMR (400MHz, CDCl3+D2O) δ: 9.13 (d, J=1.6Hz, 1H, pyridine ring 2-H), 8.14 (dd, J=8.4Hz, 1.6Hz, 1H, pyridine ring 4-H), 7.86 (d, J=8.8Hz, 2H, C6H4), 7.37~7.30 (m, 4H, C6H4), 7.08 (d, J=8.4Hz, 1H, pyridine ring 5-H), 6.58 (d, J=8.8Hz, 2H, C6H4), 5.67 (d, J=6.4Hz, 1H, CH), 4.83 (d, J=6.4Hz, 1H, CH), 2.87 (s, 6H, CH3NCH3), 2.54 (s, 3H, CH3)。
Embodiment 4
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- methoxybenzoyl base) -6,7- two Hydrogen -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine
It is prepared by 2 method of embodiment: 4- [(4- dimethylaminophenyl) methene amido] -3- (6- picoline -3- Base) -1H-1, -5 (4H)-thioketones of 2,4- triazole reacts 1.5h with the bromo- 1- of 2- (4- methoxyphenyl) ethyl ketone, obtains white solid 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- methoxybenzoyl base) -6,7- dihydro -5H- [1,2, 4] triazol [3,4-b] [1,3,4] thiadiazine, yield 59%, m.p.199~201 DEG C.1H NMR (400MHz, CDCl3+D2O) δ: 9.16 (d, J=1.6Hz, 1H, pyridine ring 2-H), 8.19 (dd, J=8.0Hz, 1.6Hz, 1H, pyridine ring 4-H), 7.92 (d, J =8.6Hz, 2H, C6H4), 7.36 (d, J=8.4Hz, 2H, C6H4), 7.12 (d, J=8.0Hz, 1H, pyridine ring 5-H), 6.91 (d, J=8.6Hz, 2H, C6H4), 6.59 (t, J=8.4Hz, 2H, C6H4), 5.46 (d, J=4.8Hz, 1H, CH), 4.94 (d, J =4.8Hz, 1H, CH), 3.86 (s, 3H, OCH3), 2.88 (s, 6H, CH3NCH3), 2.58 (s, 3H, CH3)。13C NMR (100MHz, CDCl3) δ: 193.87,164.67,159.67,150.77,150.46,147.84,143.69,135.32, 131.28,128.19,127.33,122.89,122.68,119.92,114.39,112.47,58.71,55.64,41.33, 40.25 24.44.
Embodiment 5
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2, 4] the resisiting influenza virus neuraminidase activity of triazol [3,4-b] [1,3,4] thiadiazine and its salt
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effect Under 360nm irradiation excitation, 450nm fluorescence can produce, the variation of fluorescence intensity can delicately reflect neuraminidase activity. Enzyme is all from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample and influenza neuraminidase NA are suspended in reaction buffer (pH6.5), fluorogenic substrate MUNANA is added and starts reaction system, 37 DEG C are incubated for after forty minutes, and reaction terminating liquid is added to terminate reaction. Under the Parameter Conditions that excitation wavelength 360nm and launch wavelength are 450nm, fluorescence intensity level is measured.According to subtracting for fluorescence intensity Compound can be calculated on a small quantity to the active inhibiting rate of NA.
3. test sample: embodiment compound
4. Activity Results
In reaction system when 40.0 μ g/mL of detectable concentration, the inhibiting rate of embodiment compounds on nerve propylhomoserin enzyme is included in Table 1:
1 6- of table (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2,4] inhibitory activity of triazol [3,4-b] [1,3,4] thiadiazine to neuraminidase
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- dihydro -5H- [1,2, 4] triazol [3,4-b] [1,3,4] thiadiazine has good resisiting influenza virus neuraminidase activity, can be used for preparing influenza Neuraminidase inhibitor.

Claims (5)

1. 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- virtue formyl shown in a kind of chemical structural formula I Base -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine and its pharmaceutically acceptable salt:
In formula；R is selected from: hydrogen, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine.
2. 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- described in claim 1 Dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine is selected from:
6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- benzoyl -6,7- dihydro -5H- [1,2,4] three Azoles simultaneously [3,4-b] [1,3,4] thiadiazine, 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- chlorobenzene first Acyl group) -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine or 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- (4- methoxybenzoyl base) -6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3, 4] thiadiazine.
3. 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- described in claim 1 The preparation method of dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine, it is characterised in that select 4- dimethyl Aminobenzaldehyde as raw material, through with 4- amino -3- (6- picoline -3- base) -1H-1, -5 (4H)-thioketones of 2,4- triazole is anti- 4- [(4- dimethylaminophenyl) methene amido] -3- (6- picoline -3- base) -1H-1,2,4- triazole -5 should be made 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl -6,7- is made in (4H)-thioketones, then cyclization Dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine (I)；Preparation reaction is as follows:
In formula；The definition of R is as described in claim 1.
4. 6- (4- dimethylaminophenyl) -3- (6- picoline -3- base) -7- sweet-smelling formacyl-of any of claims 1 or 2 6,7- dihydro -5H- [1,2,4] triazol [3,4-b] [1,3,4] thiadiazine and its pharmaceutically acceptable salt are in preparation influenza Application in neuraminidase inhibitor.
5. available carrier in one of a kind of pharmaceutical composition, including claims 1 or 2 compound and pharmaceutics.
CN201710615507.1A 2017-07-26 2017-07-26 Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor Active CN109305979B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710615507.1A CN109305979B (en) 2017-07-26 2017-07-26 Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710615507.1A CN109305979B (en) 2017-07-26 2017-07-26 Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor

Publications (2)

Publication Number Publication Date
CN109305979A true CN109305979A (en) 2019-02-05
CN109305979B CN109305979B (en) 2021-03-16

Family

ID=65201955

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710615507.1A Active CN109305979B (en) 2017-07-26 2017-07-26 Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor

Country Status (1)

Country Link
CN (1) CN109305979B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110183453A (en) * 2019-05-24 2019-08-30 浙江农林大学暨阳学院 A method of no metal catalytic prepares 3- phenyl-[1,2,4] triazole [4,3-a] pyridine compounds and their

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725368A (en) * 2015-03-16 2015-06-24 湖南大学 3-[5-(1,2,4-triazolyl-1-yl)thiazolyl-2-yl]benzoxazine, and preparation method and application thereof
CN106032365A (en) * 2015-03-11 2016-10-19 湖南大学 2-(thiazol-2-yl)imino-5-(benzylidene)thiazolidin-4-one, and preparing method and applications thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032365A (en) * 2015-03-11 2016-10-19 湖南大学 2-(thiazol-2-yl)imino-5-(benzylidene)thiazolidin-4-one, and preparing method and applications thereof
CN104725368A (en) * 2015-03-16 2015-06-24 湖南大学 3-[5-(1,2,4-triazolyl-1-yl)thiazolyl-2-yl]benzoxazine, and preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BEI ZHANG，等: "Design, synthesis and biological evaluation of novel 1,2,4-triazolo [3,4-b][1,3,4] thiadiazines bearing furan and thiophene nucleus", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
KEYANG YUAN，等: "Design and one-pot synthesis of 2-thiazolylhydrazone derivatives as influenza neuraminidase inhibitors", 《MOLECULAR DIVERSITY》 *
贺丽敏，等: "4-乙酰氨基-3-(3-戊氧基)苯甲酸的合成", 《广东药学学报》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110183453A (en) * 2019-05-24 2019-08-30 浙江农林大学暨阳学院 A method of no metal catalytic prepares 3- phenyl-[1,2,4] triazole [4,3-a] pyridine compounds and their
CN110183453B (en) * 2019-05-24 2021-08-24 浙江农林大学暨阳学院 Method for preparing 3-phenyl- [1,2,4] triazolo [4,3-a ] pyridine compound under catalysis of no metal

Also Published As

Publication number Publication date
CN109305979B (en) 2021-03-16

Similar Documents

Publication Publication Date Title
CN106536506A (en) Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer
CN110437205A (en) Pyridine alkenyl piperidine derivative and application thereof
CN101674823A (en) Method for the treatment of conditions associated with increased 5-lipoxygenase and/or leukotriene activity
CN105777664B (en) Carboxylate of 2 (2 benzyl hydrazono-) thiazole 5 and preparation method thereof and medical usage
CN104870431B (en) Salt form and crystal form
CN103298786B (en) Arylsulfonyl amine salt CCR3 antagonist
CN105693665B (en) Hydrazone derivative of the ring containing benzofuran and preparation method thereof and medical usage
CN102892754A (en) Arylsulfonamide ccr3 antagonists
CN105622558B (en) Acyl hydrazone derivative of the ring containing benzofuran and preparation method and application
CN107098886A (en) Quinazolinones PARP-1/2 inhibitor containing piperazinones and preparation method thereof, pharmaceutical composition and purposes
CN110272425A (en) Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives and application thereof
CN107987033A (en) The application of vanillic aldehyde and its isomers in NA inhibitor is prepared
CN108503604A (en) (4- alkyl -5- acyl group -2- thiazoles) hydazone derivative and its medical usage
TW201929846A (en) Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications
CN109305979A (en) 4- dimethylaminobenzaldehyde is preparing the application in NA inhibitor
CN104211661A (en) Chalcone compound, preparation method and medicinal application thereof
CN105531270B (en) (+) -5- (3,4- difluorophenyl) -5- [((the 2H)-yl of 3- methyl -2- oxy picolinates -1) methyl] imidazolidine-2,4-diones and the medicine containing the compound
CN108047160A (en) 2- (2- benzyls hydrazono-) -5- acyl groups thiazoles and its medical usage
CN105541591B (en) 1‑（The aryl phenyl of 4 hydroxyl 3）2 acetone and preparation method and application
CN107286133A (en) (4H) the thioketones imines of 3 aryl, 1,2,4 triazole 5 as NA inhibitor application
CN108530439A (en) Furoyl amine derivative and the preparation method and application thereof
CN107011337B (en) N- [5- (1,2,4- triazol-1-yl) thiazol-2-yl] piperidyl amide and its medical usage
CN109293644A (en) 6- methyinicotinate is preparing the application in NA inhibitor
CN107118176B (en) N-(5- benzyl thiazol-2-yl) morpholinyl amide and its medical usage
CN107141267B (en) N- (5- acyl group thiazol-2-yl) amide and the preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20230626

Address after: No. 424, Phase I Complex Building, Changsha E Center, No. 18, Xiangtai Road, Liuyang Economic and Technological Development Zone, Changsha, Hunan 410000

Patentee after: Hunan Xianshi Pharmaceutical Co.,Ltd.

Address before: H Hunan University, No.1 Lushan South Road, Changsha City, Hunan Province

Patentee before: HUNAN University