CN103705508B - 2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and medical usage thereof - Google Patents
2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and medical usage thereof Download PDFInfo
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Abstract
The present invention relates to 2-[1-(1,2, the 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide shown in chemical structural formula I or the application in influenza virus neuraminidase inhibitor is being prepared in its isomer:
wherein, R, R
1be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; X in formula
1, X
5be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
2, X
4be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
3be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, dimethylamino, trifluoromethyl or trifluoromethoxy.
Description
Technical field
The present invention relates to the application of a compounds, specifically 2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide is preparing the application in influenza virus neuraminidase inhibitor.
Background technology
Influenza surface has two kinds of glycoproteins: hemagglutinin (HA) and neuraminidase (NA).Because NA has relative conservative in the mutation process of influenza virus, become design, the extraordinary target of synthesis Tamiflu.NA can the N-acetylamino neuraminidase of catalytic pyrolysis host cell surface glycoprotein end, discharges ripe Influenza Virosomes, and stops the gathering of new virus body.In addition, NA, by changing the carbohydrate portions of surface glycoprotein HA, strengthens toxicity, promotes that virus discharges from infected host cell, causes or increase the weight of flu-like symptom.Therefore, NA inhibitor suppresses influenza virus to be copied and toxicity by suppressing NA activity.
People infects bird flu, is the human diseases caused by bird flu virus.Influenza virus generally can be divided into A type, Type B and C type, and wherein A type and usually said bird flu, have pathogenicity to people and many animals.The antigenic variability of influenza A is the strongest, is often divided into 16 HA hypotype (H according to the antigenic difference of HA and NA
1~ H
16) and 9 NA hypotype (N
1~ N
9).So far find that the avian influenza virus subtype of energy direct infection people has: H
5n
1, H
7n
1, H
7n
2, H
7n
3, H
7n
7, H
9n
2, H
7n
9and H
10n
8hypotype.Wherein, highly pathogenic H
5n
1hypotype in 1997 Hong Kong Late Cambrian energy direct infection mankind, after in July, 2003, H
5n
1bird flu epidemic situation presents unprecedented breaking out, and involves Asia, North America, Europe And Africa 17 countries and regions, and cause hundreds of people to infect and death, direct economic loss is up to 10,000,000,000 dollars.In March, 2003, there is H in Holland
7n
7type bird flu also involves whole Europe, and human infection person reaches 83 examples, not only causes the injures and deaths of the mankind, has inflicted heavy losses on poultry farming simultaneously.Mexico breaks out people and infects H in by the end of March, 2009
1n
1type swine flue epidemic situation is also diffused into all over the world, according to the A type H that World Health Organization (WHO) issued on February 26th, 2010
1n
1influenza global picture is reported, has at least 16226 of 213 countries and regions routine patients to die from this large influenza.Through gene sequencing, H
1n
1type virus comprises human influenza virus, North America bird flu virus and North America, Europe, sub-swine influenza virus genetic fragment, is the mixing strain of several different plant species influenza virus, and a kind of swine flue of non-individual or bird flu virus.In March, 2013, China Late Cambrian people infects H
7n
9bird flu case, ends December in 2013 26, the H that World Health Organization (WHO) announces
7n
9bird flu makes a definite diagnosis 148 people, dead 43 people, and this epidemic situation causes economic loss to reach about 6,500,000,000 dollars.
Along with the acceleration variation of influenza virus and the increase of different subtype virus recombination probability between species, influenza, as worldwide seasonal epidemic sexually transmitted disease, increases the threat of human health and sternness just day by day.Neuraminidase (NA) inhibitor is the First Line medicine of anti-influenza type A virus.Neuraminidase (NA) inhibitor has the type compounds such as Zanamivir, Oseltamivir and Peramivir, and wherein Oseltamivir is widely used.But research has found that some Strain create drug resistance to Oseltamivir, therefore in the urgent need to studying novel anti-influenza type A virus medicine.Chinese patent describes the application as influenza virus neuraminidase inhibitor of thiazide and Radix seu Caulis Derridis Trifoliatae ring propionic acid amide.: (1) 4-tert-butyl group-6-phenyl-2-amino-6H-1, the preparation method of 3-thiazine salt and medical usage, Chinese invention patent, ZL200910043678.7,2010.8.18 authorize; (2) 4-alkyl-6-aryl-2-acylamino--1,3-thiazine-5-formic acid esters and preparation method thereof and application, Chinese invention patent, ZL201010225483.7,2012.3.14 authorize; (3) 4-alkyl-6-aryl-5-acetyl-1,3-thiazine is as the application preparing neuraminidase inhibitor, and 2011.3.30 applies for, ZL201110077574.5,2013.2.27 authorize; (4) Radix seu Caulis Derridis Trifoliatae ring propionic acid amide. and preparation method thereof and application, 2011.8.9 applies for, ZL201110226848.2,2013.3.20 authorize.
Chinese invention patent [CN103113316A, 2013.5.22 are open] describes 2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and has good bactericidal activity.
Summary of the invention
[1-(1,2, the 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide of the 2-shown in chemical constitution formula I or its isomer is the object of the present invention is to provide to prepare the application in influenza virus neuraminidase inhibitor:
Wherein, R, R
1be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; X in formula
1, X
5be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
2, X
4be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
3be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, dimethylamino, trifluoromethyl or trifluoromethoxy.
2-[1-(1 shown in the structural formula I that the object of the present invention is to provide, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide is selected from: N '-(benzylidene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-fluorobenzylidene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-chlorobenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-bromobenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-methyl benzylidene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-Nitrobenzol methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-phenol methylene)-2-[3, 3-dimethyl-1-(1H-1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-dimethylamino benzylidene)-2-[3, 3-dimethyl-1-(1H-1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2-phenol methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2-methoxybenzylidene)-2-[3, 3-dimethyl-1-(1H-1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2-Nitrobenzol methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3-chlorobenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3-Nitrobenzol methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2, 4-dichloro-benzenes methylene)-2-[3, 3-dimethyl-1-(1H-1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2, 4-dihydroxy benzenes methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3, 4-dihydroxy benzenes methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3, 5-di-t-butyl benzylidene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-hydroxy 3-methoxybenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(5-nitro-2-chlorobenzene methylene)-2-[3, 3-dimethyl-1-(1H-1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2-hydroxyl-3, 5-dichloro-benzenes methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(2-hydroxyl-3, 5-dibromobenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide or N '-(2-hydroxyl-3, 5-diiodo-benzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide.Its structural formula is as follows:
The object of the present invention is to provide N '-(2-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide or N '-(4-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide preparing the application in influenza virus neuraminidase inhibitor:
The present invention compared with prior art tool has the following advantages:
Invent 2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide first and there is influenza neuraminidase inhibit activities.
Detailed description of the invention
Following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
The preparation of 2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2)
9.1g(50mmol) 3,3-dimethyl-1-(1,2,4-triazol-1-yl) diacetylmonoxime, 6.1g (50mmol) ethyl chloroacetate, 80mL acetone, stirring and dissolving, adds 14g (100mmol) Anhydrous potassium carbonate and 0.8gKI, 60 DEG C of reaction 4h.Reactant liquor pours frozen water into, extraction into ethyl acetate, anhydrous sodium sulfate drying, precipitation, obtains pale yellow oil 1.
Crude product 1 is dissolved in 20mL ethanol, 12.0g80% hydrazine hydrate and 10ml alcoholic solution is added under stirring, normal-temperature reaction 2h, precipitation, re-crystallizing in ethyl acetate, obtain 7.98g white solid 2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2), two step total recoverys 59.6%, m.p.146-148 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.13(s，9H，3×CH
3)，2.84(bs，2H，NH
2)，4.71(s，2H，CH
2)，5.03(s，2H，NOCH
2)，8.05(s，1H，C
2H
2N
33-H)，8.17(s，1H，C
2H
2N
35-H)，9.09(s，1H，CONH)。
Embodiment 2
The preparation of N '-(4-fluorobenzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
0.51g(2.0mmol) 2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2), 0.26g(2.1mmol) 4-Fluorobenzaldehyde, ethanol 10mL, acetic acid 2-3 drips, 80 DEG C of reaction 1h(TLC follow the tracks of), cold filtration, filter cake brine ice and petroleum ether 2-3 time, dry, ethyl alcohol recrystallization obtains 0.55g white solid N '-(4-fluorobenzylidene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 76.4%, m.p.184 ~ 185.5 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.15(s，9H，3×CH
3)，4.80、5.11(s，2H，CH
2)，5.10、5.26(s，2H，NOCH
2)，7.08～7.10(m，2H，C
6H
43，5-H)，7.75～7.80(m，2H，C
6H
42，6-H)，7.91、8.25(s，1H，C
2H
2N
33-H)，8.02、8.36(s，1H，C
2H
2N
35-H)，7.97、9.06(s，1H，N=CH)，10.59、10.66(s，1H，CONH)。
Embodiment 3
The preparation of N '-(4-chlorobenzene methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
0.51g(2.0mmol) 2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2), 0.30g(2.1mmol) 4-chloro-benzaldehyde, ethanol 10mL, acetic acid 2-3 drips, microwave 600W, 80 DEG C, reaction 5min, cold filtration, filter cake brine ice and petroleum ether 2-3 time, dry, ethyl alcohol recrystallization obtains white solid N '-(4-chlorobenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 80.0%, m.p.207 ~ 209 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.15(s，9H，3×CH
3)，4.80、5.10(s，2H，CH
2)，5.10、5.25(s，2H，NOCH
2)，7.37～7.39(m，2H，C
6H
43，5-H)，7.68～7.72(m，2H，C
6H
42，6-H)，7.92、8.26(s，1H，C
2H
2N
33-H)，8.02、8.37(s，1H，C
2H
2N
35-H)，7.93、9.05(s，1H，N=CH)，10.42、10.64(s，1H，CONH)。
Embodiment 4
The preparation of N '-(4-bromobenzene methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and p-bromobenzaldehyde react 5min, obtain white solid, yield 70.2%, m.p.215.5 ~ 217.5 DEG C.
1H NMR(DMSO，400Hz)δ:1.09(s，9H，3×CH
3)，4.65、5.09(s，2H，CH
2)，5.12、5.16(s，2H，NOCH
2)，7.63～7.68(m，4H，C
6H
42，3，5，6-H)，7.94、8.02(s，1H，C
2H
2N
33-H)，7.97、8.25(s，1H，C
2H
2N
35-H)，8.73、8.86(s，1H，N=CH)，11.42、11.60(s，1H，CONH)。
Embodiment 5
The preparation of N '-(4-methyl benzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and p-tolyl aldehyde react 5min, obtain white solid, yield 70.4%, m.p.194 ~ 196 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.14、1.15(s，9H，3×CH
3)，2.38(s，3H，CH
3)，4.80、5.10(s，2H，CH
2)，5.11、5.25(s，2H，NOCH
2)，7.19～7.22(m，2H，C
6H
43，5-H)，7.67、7.61(d，J=8.0Hz，2H，C
6H
42，6-H)，7.91、8.27(s，1H，C
2H
2N
33-H)，8.02、8.30(s，1H，C
2H
2N
35-H)，7.89、8.99(s，1H，N=CH)，10.28、10.54(s，1H，CONH)。
Embodiment 6
The preparation of N '-(4-Nitrobenzol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 2,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2) and paranitrobenzaldehyde react 1h, faint yellow solid N '-(4-Nitrobenzol methylene)-2-[3 is obtained after DMF+ ethanol (1 ﹕ 2) recrystallization, 3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 90.9%, m.p.227 ~ 229 DEG C.
1H NMR(DMSO，400Hz)δ:1.10(s，9H，3×CH
3)，4.68、5.10(s，2H，CH
2)，5.16(s，2H，NOCH
2)，7.94～8.02(m，3H，C
6H
42，6-H，C
2H
2N
33-H)，8.10、8.38(s，1H，C
2H
2N
35-H)，8.26～8.31(m，2H，C
6H
43，5-H)，8.72、8.83(s，1H，N=CH)，11.65、11.82(s，1H，CONH)。
Embodiment 7
The preparation of N '-(4-phenol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (2) and hydroxy benzaldehyde react 5min, obtain white solid N '-(4-phenol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 51.6%, m.p.181 ~ 183 DEG C.
1H NMR(DMSO，400Hz)δ:1.09(s，9H，3×CH
3)，4.61、5.08(s，2H，CH
2)，5.08、5.16(s，2H，NOCH
2)，6.81、6.83(d，J=8.8Hz，2H，C
6H
43，5-H)，7.50、7.55(d，J=8.8Hz，2H，C
6H
42，6-H)，7.89、8.00(s，1H，C
2H
2N
33-H)，7.94、8.16(s，1H，C
2H
2N
35-H)，8.73、8.89(s，1H，N=CH)，9.89、9.94(s，1H，OH)，11.10、11.32(s，1H，CONH)。
Embodiment 8
The preparation of N '-(4-dimethylamino benzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 4-dimethylaminobenzaldehyde react 10min, obtain white solid, yield 67.5%, m.p.204 ~ 205.5 DEG C.
1HNMR(CDCl
3，400Hz)δ:1.14、1.15(s，9H，3×CH
3)，3.03(s，6H，N(CH
3)
2)，4.78、5.11(s，2H，CH
2)，5.10、5.22(s，2H，NOCH
2)，6.71（d，J=8.8Hz，2H，C
6H
43，5-H)，7.55、7.66(d，J=8.8Hz，2H，C
6H
42，6-H)，7.70、8.01(s，1H，C
2H
2N
33-H)，7.90、8.17(s，1H，C
2H
2N
35-H)，8.23、8.88(s，1H，N=CH)，9.22、10.32(bs，1H，CONH)。
Embodiment 9
The preparation of N '-(benzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and benzaldehyde react 5min, obtain white solid, yield 60.1%, m.
p.158 ~ 160 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.15(s，9H，3×CH
3)，4.80、5.10(s，2H，CH
2)，5.10、5.26(s，2H，NOCH
2)，7.40～7.41(m，3H，C
6H
43，4，5-H)，7.71～7.80(m，2H，C
6H
42，6-H)，7.91、8.02(s，1H，C
2H
2N
33-H)，8.26、8.35(s，1H，C
2H
2N
35-H)，8.00、9.02(s，1H，N=CH)，9.81、10.60(s，1H，CONH)。
Embodiment 10
The preparation of N '-(2-phenol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and Benzaldehyde,2-hydroxy react 5min, obtain white solid, yield 81.7%, m.p.149 ~ 151 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.13、1.15(s，9H，3×CH
3)，4.81(s，2H，CH
2)，5.11(s，2H，NOCH
2)，6.92(t，J=8.0Hz，1H，C
6H
45-H)，7.02(d，J=8.4Hz，1H，C
6H
43-H)，7.232(dd，J=8.0，1.6Hz，1H，C
6H
46-H)，7.32(td，J=8.0，1.6Hz，1H，C
6H
44-H)，7.96、8.05(s，1H，C
2H
2N
33-H)，8.11、8.27(s，1H，C
2H
2N
35-H)，8.66、9.15(s，1H，N=CH)，10.93、10.21(s，1H，CONH)，11.20(bs，1H，OH)。
Embodiment 11
The preparation of N '-(2-methoxybenzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and Benzaldehyde,2-methoxy react 5min, obtain white solid, yield 57.7%, m.p.175 ~ 177 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.11、1.16(s，9H，3×CH
3)，3.86、3.92(s，3H，OCH
3)，4.84、5.11(s，2H，CH
2)，5.11、5.21(s，2H，NOCH
2)，6.92(d，J=8.0Hz，1H，C
6H
43-H)，7.00(t，J=7.6Hz，1H，C
6H
45-H)，7.38(t，J=8.0Hz，1H，C
6H
44-H)，7.85、8.16(d，J=8.0Hz，1H，C
6H
46-H)，8.21(s，1H，C
2H
2N
33-H)，8.24(s，1H，C
2H
2N
35-H)，8.79、8.89(s，1H，N=CH)，10.84(s，1H，CONH)。
Embodiment 12
The preparation of N '-(2-Nitrobenzol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 1-Formyl-2-nitrobenzene react 5min, obtain light green solid, yield 72.4%, m.p.160 ~ 163.5 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.15、1.16(s，9H，3×CH
3)，4.82、5.12(s，2H，CH
2)，5.10and5.23(s，2H，NOCH
2)，7.54～7.58(m，1H，C
6H
44-H)，7.66～7.70(m，1H，C
6H
45-H)，8.02～8.09(m，1H，C
6H
43-H)，8.19、7.92(s，1H，C
2H
2N
33-H)，8.25、8.48(s，1H，C
2H
2N
35-H)，8.335(dd，J=8.0，1.6Hz，1H，C
6H
46-H)，8.94、8.97(s，1H，N=CH)，10.40、11.02(s，1H，CONH)。
Embodiment 13
The preparation of N '-(3-chlorobenzene methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and m chlorobenzaldehyde react 5min, obtain white solid, yield 70.7%, m.p.192 ~ 194 DEG C.
1H NMR(DMSO，400Hz)δ:1.09(s，9H，3×CH
3)，4.65、5.10(s，2H，CH
2)，5.14、5.15(s，2H，NOCH
2)，7.43～7.50(m，2H，C
6H
44，5-H)，7.64、7.70(d，J=6.4Hz，1H，C
6H
46-H)，7.76、7.78(s，1H，C
6H
42-H)，7.94、8.02(s，1H，C
2H
2N
33-H)，7.97、8.25(s，1H，C
2H
2N
35-H)，8.73、8.85(s，1H，N=CH)，11.49、11.64(s，1H，CONH)。
Embodiment 14
The preparation of N '-(3-Nitrobenzol methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and m-nitrobenzaldehyde react 8min, obtain white solid, yield 78.8%, m.p.188 ~ 190 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.15、1.16(s，9H，3×CH
3)，4.81、5.15(s，2H，CH
2)，5.13、5.33(s，2H，NOCH
2)，7.60(t，J=8.0Hz，1H，C
6H
45-H)，8.06(d，J=8.8Hz，1H，C
6H
44-H)，8.17～8.21(m，1H，C
6H
46-H)，8.24(s，1H，C
6H
42-H)，8.26、8.38(s，1H，C
2H
2N
33-H)，8.52、8.65(s，1H，C
2H
2N
35-H)，8.88、9.38(s，1H，N=CH)，10.97、11.39(s，1H，CONH)。
Embodiment 15
The preparation of N '-(2,4-dichloro-benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 2,4-dichlorobenzaldehyde react 10min, obtain white solid, yield 47.6%, m.p.179 ~ 181 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.13、1.16(s，9H，3×CH
3)，4.82、5.11(s，2H，CH
2)，5.11、5.20(s，2H，NOCH
2)，7.30(d，J=8.4Hz，1H，C
6H
35-H)，7.42(d，J=2.0Hz，1H，C
6H
33-H)，8.16(s，1H，C
2H
2N
33-H)，8.19(d，J=8.4Hz，1H，C
6H
36-H)，8.26(s，1H，C
2H
2N
35-H)，8.69、8.90(s，1H，N=CH)，10.24、11.16(s，1H，CONH)。
Embodiment 16
The preparation of N '-(2,4-dihydroxy benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 2,4-4-dihydroxy benzaldehyde react 15min, obtain white flaky solid, yield 41.4%, m.p.166 ~ 169 DEG C.
1H NMR(DMSO，400Hz)δ:1.08、1.09(s，9H，3×CH
3)，4.63、5.10(s，2H，CH
2)，5.04、5.16(s，2H，NOCH
2)，6.29～6.36(m，2H，C
6H
33-H，5-H)，7.35、7.45(d，J=8.0Hz，1H，C
6H
36-H)，7.93、8.02(s，1H，C
2H
2N
33-H)，8.16、8.36(s，1H，C
2H
2N
35-H)，8.72、8.88(s，1H，N=CH)，9.96(s，1H，4-OH)，9.80、11.12(s，H，2-OH)，11.27、11.32(s，H，CONH)。
Embodiment 17
The preparation of N '-(3,4-dihydroxy benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3,4-4-dihydroxy benzaldehyde react 10min, obtains white solid N '-(3,4-dihydroxy benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 55.1%, m.p.177 ~ 179 DEG C.
1HNMR(DMSO，400Hz)δ:1.09(s，9H，3×CH
3)，4.60、5.07(s，2H，CH
2)，5.09、5.16(s，2H，NOCH
2)，6.77(t，J=7.4Hz，1H，C
6H
35-H)，6.89、6.93(d，J=8.0Hz，1H，C
6H
36-H)，7.12、7.20(s，1H，C
6H
32-H)，7.81、8.00(s，1H，C
2H
2N
33-H)，7.94、8.07(s，1H，C
2H
2N
35-H)，8.74、8.90(s，1H，N=CH)，9.21，9.29、9.43(s，2H，C
6H
33，4-OH)，11.10、11.30(s，1H，CONH)。
Embodiment 18
The preparation of N '-(3,5-di-t-butyl benzylidene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3,5-di-tert-butyl formaldehyde reaction 5min, obtain white solid, yield 61.7%, m.p.208 ~ 210 DEG C.
1HNMR(CDCl
3，400Hz)δ:1.15(s，9H，3×CH
3)，1.35(s，18H，6×CH
3)，4.80、5.11(s，2H，CH
2)，5.11、5.28(s，2H，NOCH
2)，7.47～7.58(m，3H，C
6H
42，4，6-H)，7.92、8.03(s，1H，C
2H
2N
33-H)，8.28、8.40(s，1H，C
2H
2N
35-H)，7.95、9.10(s，1H，N=CH)，10.57(s，1H，CONH)。
Embodiment 19
The preparation of N '-(4-hydroxy 3-methoxybenzene methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3-methoxy-4-hydroxybenzaldehyde react 5min, obtain white solid, yield 90.1%, m.p.188 ~ 190 DEG C.
1H NMR(DMSO，400Hz)δ:1.09(s，9H，3×CH
3)，3.82(s，3H，OCH
3)，4.62、5.09(s，2H，CH
2)，5.11、5.15(s，2H，NOCH
2)，6.82(t，J=8.8Hz，1H，C
6H
35-H)，7.05～7.10(m，1H，C
6H
36-H)，7.25、7.30(s，1H，C
6H
32-H)，7.88、8.00(s，1H，C
2H
2N
33-H)，7.94、8.14(s，1H，C
2H
2N
35-H)，8.75、8.89(s，1H，N=CH)，9.50、9.56(s，1H，OH)，11.13、11.34(s，1H，CONH)。
Embodiment 20
The preparation of N '-(5-nitro-2-chlorobenzene methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 5-nitro-2 chlorobenzaldehyde react 5min, obtain white solid, yield 60.7%, m.p.212 ~ 215 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.14、1.16(s，9H，3×CH
3)，4.85、5.12(s，2H，CH
2)，5.12、5.28(s，2H，NOCH
2)，7.58(d，J=8.8Hz，1H，C
6H
33-H)，8.16-8.19(m，1H，C
6H
34-H)，7.94、8.15(s，1H，C
2H
2N
33-H)，8.26、8.30(s，1H，C
2H
2N
35-H)，8.76、8.90(s，1H，N=CH)，9.02(d，J=2.8Hz，1H，C
6H
36-H)，10.24、11.16(s，1H，CONH)。
Embodiment 21
The preparation of N '-(2-hydroxyl-3,5-dichloro-benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3,5-dichloro-salicylaldehyde react 10min, obtains white solid N '-(2-hydroxyl-3,5-dichloro-benzenes methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 77.5%, m.p.195-197 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.14(s，9H，3×CH
3)，4.81(s，2H，CH
2)，5.12(s，2H，NOCH
2)，7.16(d，J=2.4Hz，1H，C
6H
46-H)，7.40(d，J=2.4Hz，1H，C
6H
44-H)，8.06(s，1H，C
2H
2N
33-H)，8.29(s，1H，C
2H
2N
35-H)，8.78(s，1H，N=CH)，11.21(s，1H，CONH)，11.90(bs，1H，OH)。
Embodiment 22
The preparation of N '-(2-hydroxyl-3,5-dibromobenzene methylene)-2-[3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3,5-Dibromosalicylaldehyde react 10min, obtains faint yellow solid N '-(2-hydroxyl-3,5-dibromobenzene methylene)-2-[3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 75.9%, m.p.215 ~ 216 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.14(s，9H，3×CH
3)，4.81(s，2H，CH
2)，5.12(s，2H，NOCH
2)，7.33(d，J=2.0Hz，1H，C
6H
46-H)，7.69(d，J=2.0Hz，1H，C
6H
44-H)，8.07(s，1H，C
2H
2N
33-H)，8.34(s，1H，C
2H
2N
35-H)，8.76(s，1H，N=CH)，11.24(s，1H，CONH)，11.96(bs，1H，OH)。
Embodiment 23
The preparation of N '-(2-hydroxyl-3,5-diiodo-benzene methylene)-2-[3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 3,5-diiodo-salicylide react 10min, obtains yellow solid N '-(2-hydroxyl-3,5-diiodo-benzene methylene)-2-[3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 91.9%, m.p.219.5 ~ 220.5 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.09(s，9H，3×CH
3)，4.70(s，2H，CH
2)，5.16(s，2H，NOCH
2)，7.92(s，1H，C
6H
46-H)，8.03(s，1H，C
6H
44-H)，8.05(s，1H，C
2H
2N
33-H)，8.30(s，1H，C
2H
2N
35-H)，8.70(s，1H，N=CH)，12.03(s，1H，CONH)，12.64(bs，1H，OH)。
Embodiment 24
The preparation of N '-(4-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide
Prepare by the method for embodiment 3,2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and 4-pyridine carboxaldehyde react 10min, obtain white solid N '-(4-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, yield 52.5%, m.p.170 ~ 172 DEG C.
1H NMR(CDCl
3，400Hz)δ:1.14、1.15(s，9H，3×CH
3)，4.82、5.10(s，2H，CH
2)，5.11、5.28(s，2H，NOCH
2)，7.68(t，J=4.8Hz，2H，C
6H
4N2，6-H)，8.69(d，J=5.6Hz，2H，C
6H
4N3，5-H)，7.92、8.04(s，1H，C
2H
2N
33-H)，7.98、8.00、8.24(s，1H，C
2H
2N
35-H)，8.51、8.52、9.01、9.04(s，1H，N=CH)，10.62、10.81、10.96(s，1H，CONH)。
Embodiment 25
2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide resisiting influenza virus neuraminidase activity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the metabolite produced under neuraminidase effect is under 360nm irradiation excites, and can produce 450nm fluorescence, the change of fluorescence intensity can react neuraminidase activity delicately.Enzyme is all from A/PR/8/34(H1N1) virus stain.
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza neuraminidase NA are suspended in (pH6.5) in reaction buffer, add fluorogenic substrate MUNANA start reaction system, 37 DEG C hatch 40 minutes after, add reaction terminating liquid cessation reaction.Under excitation wavelength 360nm and emission wavelength are the Parameter Conditions of 450nm, measure fluorescence intensity level.The fluorescence intensity of reaction system can reflect the activity of enzyme.According to the reduction of fluorescence intensity can computerized compound to the suppression ratio of NA activity.
3. detect sample: 2-[1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide (I), N '-(2-pyridine methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3-pyridine methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide or N '-(4-pyridine methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide.
Wherein, R, R
1be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; X in formula
1, X
5be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
2, X
4be selected from: hydrogen, C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine or nitro; X
3be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, dimethylamino, trifluoromethyl or trifluoromethoxy.
4. Activity Results
Preferred compound lists following table 1 in the suppression ratio of neuraminidase during detectable concentration 40.0 μ g/mL in response system:
Table 12-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide is to the inhibit activities of neuraminidase
2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide has good resisiting influenza virus neuraminidase activity, can be used for preparing influenza virus neuraminidase inhibitor.
Claims (3)
1. 2-[1-(1,2, the 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide shown in chemical structural formula I is preparing the application in influenza virus neuraminidase inhibitor:
Wherein, R is selected from: C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; R
1be selected from: hydrogen; X
1, X
5be selected from: hydrogen or hydroxyl; X
2, X
4be selected from: hydrogen, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine; X
3be selected from: hydrogen or hydroxyl.
2. apply as claimed in claim 1, 2-[1-(1 wherein shown in formula I, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide is selected from: N '-(2, 4-dihydroxy benzenes methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(4-hydroxy 3-methoxybenzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide or N '-(2-hydroxyl-3, 5-diiodo-benzene methylene)-2-[3, 3-dimethyl-1-(1, 2, 4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide.
3.N '-(2-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide, N '-(3-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide or N '-(4-pyridine methylene)-2-[3,3-dimethyl-1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide preparing the application in influenza virus neuraminidase inhibitor.
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