CN104771397A - N-(5-benzyl thiazole-2-yl)benzamide, and pharmaceutical applications thereof - Google Patents
N-(5-benzyl thiazole-2-yl)benzamide, and pharmaceutical applications thereof Download PDFInfo
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Abstract
The invention relates to applications of N-(5-benzyl thiazole-2-yl)benzamide represented by chemical structural formula I in preparing neuraminidase inhibitors. According to the chemical structural formula I, R is selected from C1-C2 alkyl, C3-C4 linear alkyl or branched alkyl; Y1 is selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, and bromine; Y2 and Y4 are selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, and bromine; Y3 is selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, and bromine; R1 and R5 are selected from hydrogen, deuterium, methyl, ethyl, methoxyl, ethyoxyl, fluorine, chlorine, bromine, nitryl, trifluoromethyl, or trifluoromethoxy; R2 and R4 are selected from hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl, ethyoxyl, fluorine, chlorine, bromine, nitryl, trifluoromethyl, or trifluoromethoxy; R3 is selected from hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl, ethyoxyl, fluorine, chlorine, bromine, nitryl, trifluoromethyl, or trifluoromethoxy.
Description
Technical field
The present invention relates to the new opplication of compound, specifically N-(5-benzyl thiazol-2-yl) Benzoylamide preparing the application in 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 is a kind of envelope glycoprotein of mushroom cloud-like, and be made up of 453 ~ 466 aminoacid, its structure divides head and cervical region, and head is containing enzyme, and tool antigenicity, cervical region has hydrophobic region, makes it to be easy to insert in bilayer lipid membrane.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
2and H
7n
9hypotype.Wherein, highly pathogenic H
5n
1hypotype in 1997 Hong Kong Late Cambrian energy direct infection mankind, since in July, 2003, this state of an illness presents unprecedented breaking out, and involves Asia, North America, Europe And Africa 17 countries and regions, 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.
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 resisiting 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, 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, ZL201010225483.7,2012.3.14 authorize; (3) 4-alkyl-6-aryl-5-acetyl-1,3-thiazine is as the application preparing neuraminidase inhibitor, and ZL201110077574.5,2013.2.27 authorize; (4) Radix seu Caulis Derridis Trifoliatae ring propionic acid amide. and preparation method thereof and application, ZL201110226848.2,2013.3.20 authorize.
Summary of the invention
The object of the present invention is to provide the N-(5-benzyl thiazol-2-yl shown in chemical structural formula I) Benzoylamide or its salt preparing the application in neuraminidase inhibitor:
Wherein R is selected from: C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; Y
1be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; Y
2, Y
4be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; Y
3be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; R
1, R
5be selected from: hydrogen, deuterium, methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R
2, R
4be selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R
3be selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Salt is selected from: hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, tosilate.
The N-(5-benzyl thiazol-2-yl that the object of the present invention is to provide) Benzoylamide is selected from: N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3, 5-dinitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-nitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3, 5-bis-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methyl-3 nitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2, 6-difluorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methoxy benzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-chlorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2, 6-dichloro-benzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl] acetamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl] propionic acid amide., N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorine propionic acid amide., N-[the 4-tert-butyl group-5-[1-(4-chlorphenyl)-2-nitro-ethyl] thiazol-2-yl]-2-chloroacetamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-4-chlorobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-chlorobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-4-nitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-3, 5-dinitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-methyl-3 nitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2, 6-difluorobenzamide or N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-3, 5-bis-(trifluoromethyl) Benzoylamide.
The present invention compared with prior art tool has the following advantages:
N-(5-benzyl thiazol-2-yl of the present invention) Benzoylamide and salt thereof preparing the application in neuraminidase inhibitor.
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 N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2,6-difluorobenzamides
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol2,6-difluoro-benzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stirs 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2,6-difluorobenzamides, yield 78.1%, m.p.133 ~ 135 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.32（s，9H，3×CH
3），4.29（s，2H，CH
2），7.00～7.51（m，6H，2×C
6H
3），9.40（br，1H，NHCO）。
Embodiment 2
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-chlorobenzamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol2-chlorobenzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-chlorobenzamide, yield 78.3%, m.p.148 ~ 150 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.34（s，9H，3×CH
3），4.30（s，2H，CH
2），7.08（d，J=8.4Hz，1H，C
6H
36-H），7.18（dd，J=8.4Hz，J=2.0Hz，1H，C
6H
35-H），7.39～7.81（m，5H，ClC
6H
33-H，C
6H
4），9.50（br，1H，NHCO）。
Embodiment 3
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-4-chlorobenzamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol4-chlorobenzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-4-chlorobenzamide, yield 74.5%, m.p.137 ~ 140 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.36（s，9H，3×CH
3），4.29（s，2H，CH
2），7.06（d，J=8.4Hz，1H，C
6H
36-H），7.18（dd，J=8.4Hz，J=2.4Hz，1H，C
6H
35-H），7.41（d，J=2.4Hz，1H，C
6H
33-H），7.49（d，J=8.8Hz，2H，C
6H
43,5-H），7.89（d，，J=8.8Hz，2H，C
6H
42,6-H），9.57（br，1H，NHCO）。
Embodiment 4
The preparation of N-[the 4-tert-butyl group-5-(2-chlorobenzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide
The 1.5mmol4-tert-butyl group-5-(2-chlorobenzyl) thiazole-2-amine, 1.6mmol2-methyl-3-nitro benzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2-dichloro benzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide, yield 26.7%, m.p.176 ~ 178 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.38（s，9H，3×CH
3），2.59（s，3H，CH
3），4.36（s，2H，CH
2），7.16～7.94（m,7H，C
6H
3，C
6H
4）。
Embodiment 5
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3,5-dinitrobenzamides
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol3,5-dinitrobenzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3,5-dinitrobenzamides, yield 61.5%, m.p.93 ~ 95 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.47（s，9H，3×CH
3），4.20（s，2H，CH
2），7.16（d，J=8.4Hz，2H，C
6H
42,6-H），7.31（d，J=8.4Hz，2H，C
6H
43,5-H），9.15（d，J=2.0Hz，1H，C
6H
34-H），9.31（d，J=2.0Hz，2H，C
6H
32,6-H）。
Embodiment 6
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-nitrobenzamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol4-nitrobenzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-nitrobenzamide, yield 58.6%, m.p.184 ~ 185 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.37（s，9H，3×CH
3），4.24（s，2H，CH
2），7.15（d，J=8.4Hz，2H，C
6H
4Cl2,6-H），7.28（d，J=8.4Hz，2H，C
6H
4Cl3,5-H），8.13（d，J=8.8Hz，2H，C
6H
4NO
22,6-H），8.34（d，J=8.8Hz，2H，C
6H
4NO
23,5-H），9.75（br，1H，NHCO）。
Embodiment 7
N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-(trifluoromethyl) preparation of Benzoylamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2-(trifluoromethyl) benzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, yield 66.2%, m.p.125 ~ 127 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.34（s，9H，3×CH
3），4.23（s，2H，CH
2），7.16（d，J=8.4Hz，2H，C
6H
4Cl2,6-H），7.28（d，J=8.4Hz，2H，C
6H
4Cl3,5-H），7.63～7.64（m，3H，C
6H
4CF
33,4,5-H），7.77～7.79（m，1H，C
6H
4CF
36-H），8.91（br，1H，NHCO）。
Embodiment 8
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol3,5-bis-(trifluoromethyl) benzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmolN, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide, yield 72.6%, m.p.58 ~ 61 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.39（s，9H，3×CH
3），4.22（s，2H，CH
2），7.15（d，J=8.0Hz，2H，C
6H
42,6-H），7.29（d，J=8.0Hz，2H，C
6H
43,5-H），8.05（s，1H，C
6H
34-H），8.47（s，2H，C
6H
32,6-H），9.76（br，1H，NHCO）。
Embodiment 9
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2-nitro-3-ar-Toluic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide, yield 60.0%, m.p.157 ~ 158 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.37（s，9H，3×CH
3），2.59（s，3H，CH
3），4.25（s，2H，CH
2），7.16（d，J=8.4Hz，2H，C
6H
42,6-H），7.29（d，J=8.4Hz，2H，C
6H
43,5-H），7.45（t，J=8.0Hz，1H，C
6H
35-H），7.72（d，J=8.0Hz，1H，C
6H
36-H），7.93（d，J=8.0Hz，1H，C
6H
34-H），9.06（br，1H，NHCO）。
Embodiment 10
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2,6-difluorobenzamides
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2,6-difluoro-benzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2,6-difluorobenzamides, yield 84.1%, m.p.130 ~ 132 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.35（s，9H，3×CH
3），4.24（s，2H，CH
2），7.02～7.03（m，2H，C
6H
33,5-H），7.15（d，J=8.4Hz，2H，C
6H
42,6-H），7.28（d，J=8.4Hz，2H，C
6H
43,5-H），7.43～7.51（m，1H，C
6H
34-H），9.22（br，1H，NHCO）。
Embodiment 11
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methoxy benzamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2-methoxybenzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methoxy benzamide, yield 51.1%, m.p.142 ~ 143 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.38（s，9H，3×CH
3），4.10（s，3H，OCH
3），4.23（s，2H，CH
2），7.05（d，J=8.0Hz，1H，CH
3OC
6H
43-H），7.10～7.14（m，3H，C
6H
4Cl2,6-H，CH
3OC
6H
45-H），7.26（d，J=8.4Hz，2H，C
6H
4Cl3,5-H），7.10～7.56（m，1H，CH
3OC
6H
44-H），8.25（dd，J=8.0Hz，J=2.0Hz，1H，CH
3OC
6H
46-H），10.82（br，1H，NHCO）。
Embodiment 12
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorobenzamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2-chlorobenzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorobenzamide, yield 55.3%, m.p.105 ~ 107 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.34（s，9H，3×CH
3），4.24（s，2H，CH
2），7.15（d，J=8.4Hz，2H，C
6H
42,6-H），7.27（d，J=8.4Hz，2H，C
6H
43,5-H），7.35～7.48（m，3H，C
6H
44,5,6-H），7.79（d，J=8.8Hz，1H，C
6H
43-H），9.47（br，1H，NHCO）。
Embodiment 13
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-chlorobenzamide
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol4-chlorobenzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-chlorobenzamide, yield 79.7%, m.p.115 ~ 117 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.36（s，9H，3×CH
3），4.24（s，2H，CH
2），7.14（d，J=8.0Hz，2H，C
6H
42,6-H），7.27（d，J=8.0Hz，2H，C
6H
43,5-H），7.48（d，J=8.8Hz，2H，COC
6H
43,5-H），7.88（d，J=8.8Hz，2H，COC
6H
42,6-H），9.49（br，1H，NHCO）。
Embodiment 14
The preparation of N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2,6-dichloro-benzamides
The 1.5mmol4-tert-butyl group-5-(4-chlorobenzyl) thiazole-2-amine, 1.6mmol2,6-dichlorobenzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2,6-dichloro-benzamides, yield 64.1%, m.p.173 ~ 176 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.33（s，9H，3×CH
3），4.23（s，2H，CH
2），7.16（d，J=8.4Hz，2H，C
6H
42,6-H），7.29（d，J=8.4Hz，2H，C
6H
43,5-H），7.32～7.37（m，3H，C
6H
3），9.13（br，1H，NHCO）。
Embodiment 15
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-3,5-dinitrobenzamides
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol3,5-dinitrobenzoic acid and 40mL dichloromethane, stirring at room temperature, adds 0.15mmol4-dimethylamino naphthyridine, stirs 0.5h, add 1.6mmolN, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-3,5-dinitrobenzamides, yield 63.1%, m.p.165 ~ 167 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.46（s，9H，3×CH
3），4.26（s，2H，CH
2），7.12（d，J=8.4Hz，1H，2,4-diClC
6H
36-H），7.24（dd，J=8.4Hz，J=2.0Hz，1H，2,4-diClC
6H
35-H），7.44（d，J=2.0Hz，1H，2,4-diClC
6H
33-H），9.16（t，J=2.4Hz，1H，C
6H
34-H），9.30（d，J=2.4Hz，2H，C
6H
32,6-H）。
Embodiment 16
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-4-nitrobenzamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol4-nitrobenzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-4-nitrobenzamide, yield 73.1%, m.p.100 ~ 101 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.38（s，9H，3×CH
3），4.30（s，2H，CH
2），7.07（d，J=8.0Hz，1H，C
6H
36-H），7.20（dd，J=8.0Hz，J=2.0Hz，1H，C
6H
35-H），7.42（d，J=2.0Hz，1H，C
6H
33-H），8.15（d，J=8.8Hz，2H，C
6H
42,6-H），8.37（d，J=8.8Hz，2H，C
6H
43,5-H），9.86（br，1H，NHCO）。
Embodiment 17
N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-(trifluoromethyl) preparation of Benzoylamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol2-(trifluoromethyl) benzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmolN, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, yield 73.1%, m.p.130 ~ 133 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.32（s，9H，3×CH
3），4.29（s，2H，CH
2），7.09（d，J=8.4Hz，1H，C
6H
36-H），7.21（dd，J=8.4Hz，J=2.0Hz，1H，C
6H
35-H），7.42（d，J=2.0Hz，1H，C
6H
33-H），7.61～7.80（m，4H，C
6H
4），9.24（br，1H，NHCO）。
Embodiment 18
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol3,5-bis-(trifluoromethyl) benzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmol N, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-3,5-bis-(trifluoromethyl) Benzoylamide, yield 78.4%, m.p.110 ~ 111 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.42（s，9H，3×CH
3），4.29（s，2H，CH
2），7.08（d，J=8.4Hz，1H，2,4-diClC
6H
36-H），7.21（dd，J=8.4Hz，J=2.4Hz，1H，2,4-diClC
6H
35-H），7.43（d，J=2.4Hz，1H，2,4-diClC
6H
33-H），8.07（s，1H，C
6H
34-H），8.48（s，2H，C
6H
32,6-H），9.85（br，1H，NHCO）。
Embodiment 19
The preparation of N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide
The 1.5mmol4-tert-butyl group-5-(2,4-dichloro benzyl) thiazole-2-amine, 1.6mmol2-methyl-3-nitro benzoic acid and 40mL dichloromethane, stirring at room temperature, add 0.15mmol4-dimethylamino naphthyridine, stir 0.5h, add 1.6mmolN, N '-dicyclohexylcarbodiimide, TLC monitors reaction.Reaction is finished, and crosses post, obtains N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-2-methyl-3-nitro Benzoylamide, yield 73.7%, m.p.181 ~ 182 DEG C.
1H NMR（CDCl
3，400MHz），δ：1.34（s，9H，3×CH
3），2.60（s，3H，CH
3），4.31（s，2H，CH
2），7.08（d，J=8.0Hz，1H，2,4-diClC
6H
36-H），7.21（dd，J=8.0Hz，J=2.0Hz，1H，2,4-diClC
6H
35-H），7.43～7.94（m，4H，2,4-diClC
6H
33-H，C
6H
3），9.13（br，1H，NHCO）。
Embodiment 20
N-(5-benzyl thiazol-2-yl) the anti-neuraminidase activity of Benzoylamide and salt thereof
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase NA, 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(H
1n
1) virus stain.
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza virus NA float on (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: N-(5-benzyl thiazol-2-yl) Benzoylamide
4. Activity Results
Preferred compound lists table 1 in the suppression ratio of neuraminidase during detectable concentration 40.0 μ g/mL in response system:
Table 1N-(5-benzyl thiazol-2-yl) Benzoylamide is to neuraminic acid enzyme inhibition activity
| N-(5-benzyl thiazol-2-yl) Benzoylamide | Suppression ratio/% |
| N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3,5-dinitrobenzamides | 33.54 |
| N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-nitrobenzamide | 45.56 |
| N-[the 4-tert-butyl group-5-(2,4-dichloro benzyl) thiazol-2-yl]-4-nitrobenzamide | 36.94 |
Active testing result shows, N-(5-benzyl thiazol-2-yl) Benzoylamide has good anti-neuraminidase activity, can be used for preparing neuraminidase inhibitor.
Claims (2)
1. the N-(5-benzyl thiazol-2-yl shown in chemical structural formula I) Benzoylamide or its salt preparing the application in neuraminidase inhibitor:
Wherein R is selected from: C
1~ C
2alkyl, C
3~ C
4straight or branched alkyl; Y
1be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; Y
2, Y
4be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; Y
3be selected from: hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine; R
1, R
5be selected from: hydrogen, deuterium, methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R
2, R
4be selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R
3be selected from: hydrogen, deuterium, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Salt is selected from: hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, tosilate.
2. application according to claim 1, N-(5-benzyl thiazol-2-yl shown in its Chinese style I) Benzoylamide is selected from: N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3, 5-dinitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-nitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-3, 5-bis-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methyl-3 nitrobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2, 6-difluorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-methoxy benzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-4-chlorobenzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2, 6-dichloro-benzamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl] acetamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl] propionic acid amide., N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide, N-[the 4-tert-butyl group-5-(4-chlorobenzyl) thiazol-2-yl]-2-chlorine propionic acid amide., N-[the 4-tert-butyl group-5-[1-(4-chlorphenyl)-2-nitro-ethyl] thiazol-2-yl]-2-chloroacetamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-4-chlorobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-chlorobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-(trifluoromethyl) Benzoylamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-4-nitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-3, 5-dinitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2-methyl-3 nitrobenzamide, N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-2, 6-difluorobenzamide or N-[the 4-tert-butyl group-5-(2, 4-dichloro benzyl) thiazol-2-yl]-3, 5-bis-(trifluoromethyl) Benzoylamide.
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| CN107011337B (en) * | 2017-05-09 | 2019-07-16 | 长沙理工大学 | N- [5- (1,2,4- triazol-1-yl) thiazol-2-yl] piperidyl amide and its medical usage |
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