CN105985298B - 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application - Google Patents
2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application Download PDFInfo
- Publication number
- CN105985298B CN105985298B CN201510068464.0A CN201510068464A CN105985298B CN 105985298 B CN105985298 B CN 105985298B CN 201510068464 A CN201510068464 A CN 201510068464A CN 105985298 B CN105985298 B CN 105985298B
- Authority
- CN
- China
- Prior art keywords
- imino group
- nhcor
- benzal
- alkyl
- thiazolin
- 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.)
- Expired - Fee Related
Links
- 0 CC(C1=CC2C=C(C*)C=C[C@]12)=C(*)C(*C(I)=**1=*C(C)=C(C)C23C1C2C3)=O Chemical compound CC(C1=CC2C=C(C*)C=C[C@]12)=C(*)C(*C(I)=**1=*C(C)=C(C)C23C1C2C3)=O 0.000 description 3
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to the ketone of 2 shown in chemical structural formula I, II, III or IV [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazoline 4 or its mixture：Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1~X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.The application of the ketone of 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazoline 4 or its mixture in neuraminidase inhibitor is prepared.
Description
Technical field
The present invention relates to the preparation and application of a kind of noval chemical compound, specifically 2- [(5- halogen thiazol-2-yl) imino group] -5-
Benzal thiazolin 4 one is prepared and its in the application as influenza virus neuraminidase inhibitor.
Background technology
Avian influenza virus can cause the respiratory apparatus or systemic infection of birds, and HPAIV can directly be felt
Birds are contaminated, also can directly or indirectly infect the mankind.HPAIV is one of the initiation influenza in crowd potential
Hazards, and can seriously threaten human health.20th century, 4 flu outbreaks once occurred for the mankind：1918 to 1919
" the spanish influenza " (H in year1N1Hypotype), nineteen fifty-seven to " Asia influenza " (H in 19582N2Hypotype), nineteen sixty-eight to 1969
" Mao flu " (H3N2Hypotype) and " Russian influenza " (H in 19771N1Hypotype).Avian influenza virus contains two surfaces
Albumen：Avian influenza virus, according to the difference of the two protein antigenicities, can be divided into by hemagglutinin (HA) and neuraminidase (NA)
16 HA hypotypes (H1~H16) and 9 NA hypotypes (N1~N9).So far find that the avian influenza virus subtype of energy direct infection people has：
H5N1、H7N1、H7N2、H7N3、H7N7、H9N2、H7N9And H10N8Hypotype.Wherein, highly pathogenic H5N1Hypotype is first in Hong Kong in 1997
The secondary discovery energy direct infection mankind, after in July, 2003, H5N1Bird flu epidemic situation present it is unprecedented breaks out, involve Asia,
17 North America, Europe And Africa countries and regions, hundreds of people infection and death are caused, it is beautiful that direct economic loss is up to 10,000,000,000
Member.H occurs in March, 2003, Holland7N7Type bird flu simultaneously involves whole Europe, and human infection person not only causes people up to 83
The injures and deaths of class, while inflicted heavy losses on poultry farming.In by the end of March, 2009, and Mexico breaks out people and infects H1N1Type swine flu epidemic situation simultaneously expands
It is scattered to all over the world, according to the World Health Organization in the A type H of issue on 2 26th, 20101N1The report of influenza global picture, at least
16226 patients for having 213 countries and regions die from this big influenza [Zeng Xiangxing, Li Kangsheng.Medical science and society, 2010,
11,4-6.].By gene sequencing, H1N1Type virus includes human influenza virus, North America avian influenza virus and North America, Europe, Asia
Swine influenza virus genetic fragment, it is the mixing strain of several different plant species influenza viruses, and a kind of swine flu of non-individual or fowl stream
Influenza Virus.In March, 2013, finder infects H first in China7N9Bird flu case, end on January 25th, 2015, world health group
Knit the H of announcement7N9494 people, dead 221 people are made a definite diagnosis in bird flu.Therefore the research and development to Anti-avian influenza virus drugs, it has also become the world
One of national governments and health and epidemic prevention department's growing interest and the significant problem that actively addresses.
Avian influenza virus is a kind of virus containing envelope protein, and its genome is the sub-thread minus strand for including 8 sections
RNA, a variety of virus proteins of codified：Virus surface proteins (hemagglutinin HA, neuraminidase NA), stromatin (M1, M2) core
Albumen (NP), non-structural protein (NS1, NS2), RNA polymerase P protein complexes PA, PB1, PB2) [CN101990534A].HA
It is the agglutinin that combination and viral genome of a kind of mediate retroviral to target cell enter target cell.NA can catalytic pyrolysis host it is thin
The N- acetylaminos of cellular surface glycoprotein end, discharge progeny virus from infection cell.NA can also be by changing surface glycoprotein
HA carbohydrate portions, strengthen toxicity, promote virus to be discharged from infected host cell, cause or aggravate influenza disease
Shape [CN103755697A].In addition, NA has relative conservative in the mutation process of influenza virus, become design, close
Into the extraordinary target of Tamiflu.Therefore, using NA as action target, replicated by suppressing NA activity to suppress influenza virus
NA inhibitor with toxicity is the First Line medicine of anti-avian influenza virus, represent medicine have Zanamivir, Oseltamivir and
Peramivir and its derivative, wherein Oseltamivir are widely used.But studies have found that some Strain pair
Oseltamivir generates drug resistance.
Thiazoles and thiazoline ketone compounds have anti-influenza virus activity：Chinese invention patent [ZL
200810152537.4,2010.12.22 are authorized, and ZL 201010223400.0,2012.07.25 are authorized] report series and have
The thiazole of anti-influenza virus activity and thiazole-substituted mercaptoacetamide derivative；Chinese invention patent [CN
103830233A, 2014.06.04 are disclosed, CN 103705511A, and 2014.04.09 is disclosed] describe 5- (1,2,4- triazole -1-
Base) -2- phenylacetamido-thiazoles and N- [5- (1,2,4- triazol-1-yl) thiazol-2-yl] fatty acid amide anti-influenza activity；In
State's patent of invention [CN 103755697A, 2014.04.30 are disclosed, CN 103739599A, and 2014.04.23 is disclosed] reports 3-
[[2- (2- benzyls imino group) thiazole -5- bases] methyl] (1H) -one of quinoline -2 and 3- [[2- (2- benzyls hydrazono-) thiazole -5- bases] first
Base] quinoline -2 (1H) -one preparation and anti-influenza activity；In addition, [CN 103648282A, 2014.03.19 are public for Chinese patent
Open, CN101990534A, 2008.10.3 is disclosed] it also reported thiazole compound in terms of viral infection is prevented and treated
Purposes.
The content of the invention
It is an object of the invention to provide [(the 5- halogen thiazol-2-yl) imido of the 2- shown in chemical structural formula I, II, III or IV
Base] -5- benzals thiazolin 4 one or its mixture：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2
Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1、X5It is selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight or branched alkyl, dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl, C3~C4Directly
Chain or C3~C4Branched alkyl；X2、X4It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight chain or C3~C4Branched alkyl；X3It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2
Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one shown in I formula is (2E, 5Z) -2-
[(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones；2- [(5- halogen thiazol-2-yl) imido shown in II formula
Base] -5- benzals thiazolin 4 one is (2Z, 5Z) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolines -4-
Ketone；2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one shown in III formula is (2E, 5E) -2- [(5- halogen
Thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones；2- [(5- halogen thiazol-2-yl) imino group] -5- shown in IV formula
Benzal thiazolin 4 one is (2Z, 5E) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones.
It is an object of the invention to provide 2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one choosing
From following compounds：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2
Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；N is selected from：1st, 2 or 3；(NH2)nIt is selected from：
2-NH2、3-NH2、4-NH2、2,4-(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5-(NH2)2、2,3,4-
(NH2)3Or 2,3,5- (NH2)3。
It is an object of the invention to provide 2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one choosing
From following compounds：
Wherein, R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkane
Base, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2Alkyl, bromo C1~C2Alkyl or iodo C1~C2
Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；N is selected from：1st, 2 or 3；(NHCOR)nIt is selected from：2-NHCOR、3-NHCOR、4-NHCOR、2,
4-(NHCOR)2、2,5-(NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3,5-(NHCOR)2、2,3,4-(NHCOR)3Or
2,3,5-(NHCOR)3。
It is an object of the invention to provide structural formula I shown in 2- [(5- halogen thiazol-2-yl) imino group] -5- benzals
Thiazolin 4 one is selected from：2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (3- nitrobenzals) thiazoline -4-
(3- amino is sub- by ketone, 2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (4- nitrobenzals) thiazolin 4 one, 5-
Benzyl) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one, 5- (4- amino benzal) -2- [(5-
Bromo- 4- tertiary butyl thiazoles -2- bases) imino group] thiazolin 4 one, 5- (3- acetylaminos benzal) -2- [(tertiary fourths of the bromo- 4- of 5-
Base thiazol-2-yl) imino group] thiazolin 4 one, 5- (4- acetylaminos benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- of 5-
Base) imino group] thiazolin 4 one.
It is an object of the invention to provide 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones
Preparation method, it is characterised in that its preparation reaction is as follows：
In formula, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2
Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1、X5It is selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight chained alkyl, C3~C4Branched alkyl or nitro；X2、X4It is selected from：Dimethylamino or nitro；X3It is selected from：Dimethylamino or
Nitro.
It is an object of the invention to provide 5- (amino benzal) -2- [(5- halogen thiazol-2-yl) imino group] thiazoline -4-
The preparation method of ketone and 5- (acetylamino benzal) -2- [(5- halogen thiazol-2-yl) imino group] thiazolin 4 one, its feature
It is that their preparation reaction is as follows：
In formula, R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkane
Base, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2Alkyl, bromo C1~C2Alkyl or iodo C1~C2
Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；N is selected from 1,2 or 3；(NO2)nIt is selected from：2-NO2、3-NO2、4-NO2、2,4-(NO2)2、2,
5-(NO2)2、2,6-(NO2)2、3,4-(NO2)2、3,5-(NO2)2、2,3,4-(NO2)3Or 2,3,5- (NO2)3；(NH2)nIt is selected from：2-
NH2、3-NH2、4-NH2、2,4-(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5-(NH2)2、2,3,4-
(NH2)3Or 2,3,5- (NH2)3；(NHCOR)nIt is selected from：2-NHCOR、3-NHCOR、4-NHCOR、2,4-(NHCOR)2、2,5-
(NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3,5-(NHCOR)2、2,3,4-(NHCOR)3Or 2,3,5- (NHCOR)3。
It is an object of the invention to provide 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones to have
Influenza neuraminidase inhibitory activity, the application in influenza virus neuraminidase inhibitor is prepared.
The present invention has the following advantages that compared with prior art：
2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones of the present invention have influenza virus neural
Propylhomoserin enzyme inhibition activity.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
The preparation method of (2E, 5E) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one (III) is such as
Described in embodiment 1~7.
Embodiment 1
The preparation of 2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one (2)
The bromo- 4- tertiary butyl thiazoles -2- amine of 7.05g (30mmol) 5-, 100mL dichloromethane, stirring and dissolving, add 4.14g
(30mmol) Anhydrous potassium carbonate, stirring at normal temperature 30min, 2.5ml (30mmol) chloracetyl chloride, normal-temperature reaction 2.0h is added dropwise.Reaction
Liquid pours into frozen water, dichloromethane extraction, and saturated aqueous sodium carbonate washs, merging organic phase, anhydrous sodium sulfate drying, precipitation,
Ethyl alcohol recrystallization obtains 7.55g white solids 1, yield 81%, m.p.118~120 DEG C.
4.5g (14.4mmol) compound 3,2.1g (21.7mmol) potassium rhodanide, the dissolving of 50ml ethanol, it is heated to reflux anti-
Answer 7.0h.Reaction solution precipitation, re-crystallizing in ethyl acetate obtain 4.00g red solids 2, yield 83%, m.p.202~203 DEG C.1H
NMR(CDCl3, 400MHz) and δ:1.47 (s, 9H, 3 × CH3), 3.88 (s, 2H, CH2), 11.92 (s, 1H, NH).
Embodiment 2
(2E, 5E) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (3- nitrobenzals) thiazoline -4-
The preparation of ketone
35ml acetic acid 0.65g sodium acetates prepare the cushioning liquid of pH=4~5, add the He of 2.0mmol intermediates 2
4.0mmol 3- nitrobenzaldehydes, heating reflux reaction 10h.Cooling, wash, filtering, ethyl alcohol recrystallization obtain yellow solid (2E,
5E) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (3- nitrobenzals) thiazolin 4 one, yield 85%,
M.p.244~246 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.55 (s, 9H, 3 × CH3), 7.68 (t, J=7.8Hz, 1H,
C6H4), 7.81~7.92 (m, 2H, C6H4,=CH), 8.29 (d, J=7.8Hz, 1H, C6H4), 8.41~8.51 (m, 1H, C6H4)。
Embodiment 3
(2E, 5E) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (4- nitrobenzals) thiazoline -4-
The preparation of ketone
Operating method compound 2 and 4- nitrobenzaldehydes, reacts 10h with embodiment 2, obtain yellow solid (2E, 5E)-
2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (4- nitrobenzals) thiazolin 4 one, yield 78%,
M.p.263~265 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.53 (s, 9H, 3 × CH3), 7.71 (s, 2H, C6H4), 7.86 (s,
1H ,=CH), 8.34 (d, J=8.6Hz, 2H, C6H4)。
Embodiment 4
(2E, 5E) -5- (3- amino benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazoline -4-
The preparation of ketone
1.0mmol (2E, 5E) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (3- nitrobenzals) thiophene
Oxazoline -4- ketone is dissolved in 10ml dichloromethane and 10ml acetic acid, adds appropriate iron powder and 1ml water, stirring at normal temperature reaction 5h.Filtering,
Washing, dichloromethane extraction, saturated aqueous sodium carbonate washing organic phase, anhydrous sodium sulfate drying, precipitation obtain yellow solid
(2E, 5E) -5- (3- amino benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one, yield
85%, m.p.215~216 DEG C.1H NMR (DMSO, 400MHz) δ:1.48 (s, 9H, 3 × CH3), 5.35 (s, 2H, NH2), 6.68
(d, J=7.6Hz, 1H, C6H4), 6.79 (d, J=6.8Hz, 2H, C6H4), 7.16 (t, J=7.9Hz, 1H, C6H4), 7.52 (s,
1H ,=CH), 12.60 (s, 1H, NH).
Embodiment 5
(2E, 5E) -5- (4- amino benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazoline -4-
The preparation of ketone
Operating method is the same as embodiment 4, (2E, 5E) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] -5- (4- nitre
Base benzal) thiazolin 4 one is raw material, 5h reacted, obtains yellow solid (2E, 5E) -5- (4- amino benzal) -2- [(5-
Bromo- 4- tertiary butyl thiazoles -2- bases) imino group] thiazolin 4 one, yield 89%, m.p.214~216 DEG C.1H NMR (DMSO,
400MHz)δ:1.50 (s, 9H, 3 × CH3), 6.14 (s, 2H, NH2), 6.65 (d, J=7.9Hz, 2H, C6H4), 7.37 (d, J=
7.2Hz, 2H, C6H4), 7.53 (s, 1H ,=CH), 12.46 (s, 1H, NH).
Embodiment 6
(2E, 5E) -5- (3- acetylaminos benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazole
The preparation of quinoline -4- ketone
0.5mmol (2E, 5E) -5- (3- amino benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiophene
Oxazoline -4- ketone is dissolved in 10ml acetic acid, and 0.5mmol chloroacetic chlorides, stirring at normal temperature reaction 1h is added dropwise.Washing, ethyl acetate extraction, saturation
Aqueous sodium carbonate washs organic phase, anhydrous sodium sulfate drying, and precipitation obtains yellow solid (2E, 5E) -5- (3- acetylamino benzal
Base) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one, yield 64%, m.p.241~243 DEG C.1H
NMR (DMSO, 400MHz) δ:1.47 (s, 9H, 3 × CH3), 2.06 (s, 3H, COCH3), 7.31 (d, J=7.5Hz, 1H, C6H4),
7.42~7.48 (m, 2H, C6H4), 7.65 (s, 1H ,=CH), 8.11 (s, 1H, C6H4), 10.11 (s, 1H, NHAc), 12.72
(s, 1H, NH).
Embodiment 7
(2E, 5E) -5- (4- acetylaminos benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazole
The preparation of quinoline -4- ketone
Operating method is the same as embodiment 6, (2E, 5E) -5- (4- amino benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- of 5-
Base) imino group] thiazolin 4 one is raw material, reacts 1h, obtain yellow solid (2E, 5E) -5- (4- acetylaminos benzal) -
2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one, yield 82%, m.p.243~245 DEG C.1H NMR
(DMSO, 400MHz) δ:1.50 (s, 9H, 3 × CH3), 2.08 (s, 3H, COCH3), 7.60 (d, J=8.8Hz, 2H, C6H4),
7.64 (s, 1H ,=CH), 7.73 (d, J=8.8Hz, 2H, C6H4), 10.26 (s, 1H, NHAc), 12.68 (s, 1H, NH).
(2E, 5Z) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzal is prepared according to the method described in embodiment 1~7
Base thiazolin 4 one (I), (2Z, 5Z) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 ones (II) and
(2Z, 5E) -2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one (IV).
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2
Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1、X5It is selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight or branched alkyl, dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl, C3~C4Directly
Chain or C3~C4Branched alkyl；X2、X4It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight chain or C3~C4Branched alkyl；X3It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2
Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
Embodiment 8
2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 one resisiting influenza virus neuraminidase activities
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the caused metabolite under neuraminic acid enzyme effect
In the case where 360nm irradiations excite, 450nm fluorescence can be produced, the change 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, finite concentration sample is suspended in reaction buffer with influenza neuraminidase NA
(pH6.5), add fluorogenic substrate MUNANA and start reaction system, after 37 DEG C are incubated 40 minutes, add reaction terminating liquid terminating reaction.
In the case where excitation wavelength 360nm and launch wavelength are 450nm Parameter Conditions, fluorescence intensity level is determined.According to subtracting for fluorescence intensity
Inhibiting rate of the compound to NA activity can be calculated on a small quantity.
3. detect sample：2- [(5- halogen thiazol-2-yl) imino group] -5- benzals thiazolin 4 one (I, II, III or IV)
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, fluoro C1~C2Alkyl, chloro C1~C2
Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1、X5It is selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight or branched alkyl, dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl, C3~C4Directly
Chain or C3~C4Branched alkyl；X2、X4It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl,
C3~C4Straight chain or C3~C4Branched alkyl；X3It is selected from：Dimethylamino, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2
Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
4. Activity Results
Preferred compound is in reaction system to the inhibiting rate and its IC of neuraminidase during 40.0 μ g/mL of detectable concentration50
It is worth tabulated below 1：
Suppression of table 12- [(5- halogen thiazol-2-yl) the imino group] -5- benzals thiazolin 4 one to neuraminidase is lived
Property
2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones have good resisiting influenza virus nerve
Propylhomoserin enzymatic activity, available for preparing influenza virus neuraminidase inhibitor.
Claims (5)
1. 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolines -4- shown in chemical structural formula I, II, III or IV
Ketone：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl；X is selected from：Fluorine, chlorine, bromine or iodine；X1And X5Choosing
From：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl；X2~X4It is selected from：Dimethylamino, amino or NHCOR；Wherein R is selected
From：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
2. a kind of 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones, selected from following compounds：
Wherein, R1It is as claimed in claim 1 with X；N is selected from 1,2 or 3；(NH2)nIt is selected from：2-NH2、3-NH2、4-NH2、2,4-
(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5-(NH2)2、2,3,4-(NH2)3Or 2,3,5- (NH2)3。
3. a kind of 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones, selected from following compounds：
Wherein, R, R1, X it is as claimed in claim 1；N is selected from 1,2 or 3；(NHCOR) n is selected from：2-NHCOR、3-NHCOR、4-
NHCOR、2,4-(NHCOR)2、2,5-(NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3,5-(NHCOR)2、2,3,4-
(NHCOR)3Or 2,3,5- (NHCOR)3。
4. a kind of 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones, are selected from：5- (3- amino benzal
Base) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-) imino group] thiazolin 4 one, [(5- is bromo- by -2- by 5- (4- amino benzal)
4- tertiary butyl thiazole -2- bases) imino group] thiazolin 4 one, 5- (3- acetylaminos benzal) -2- [(bromo- 4- tert-butyl groups thiophenes of 5-
Azoles -2- bases) imino group] thiazolin 4 one or 5- (4- acetylaminos benzal) -2- [(the bromo- 4- tertiary butyl thiazoles -2- bases of 5-)
Imino group] thiazolin 4 one.
5. 2- [(5- halogen thiazol-2-yl) imino group] -5- benzal thiazolin 4 ones according to any one of claims 1 to 4
Application in neuraminidase inhibitor is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510068464.0A CN105985298B (en) | 2015-02-10 | 2015-02-10 | 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510068464.0A CN105985298B (en) | 2015-02-10 | 2015-02-10 | 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105985298A CN105985298A (en) | 2016-10-05 |
| CN105985298B true CN105985298B (en) | 2018-02-23 |
Family
ID=57041715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510068464.0A Expired - Fee Related CN105985298B (en) | 2015-02-10 | 2015-02-10 | 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105985298B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102137666A (en) * | 2008-07-02 | 2011-07-27 | 阿斯利康(瑞典)有限公司 | Chemical compounds 251 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008054475A2 (en) * | 2006-03-13 | 2008-05-08 | The Trustees Of Columbia University In The City Of New York | Neuraminidase inhibitors and uses thereof |
-
2015
- 2015-02-10 CN CN201510068464.0A patent/CN105985298B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102137666A (en) * | 2008-07-02 | 2011-07-27 | 阿斯利康(瑞典)有限公司 | Chemical compounds 251 |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones;P. Vicini et al.;《Bioorg. Med. Chem.》;20061231;第14卷;第3859–3864页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105985298A (en) | 2016-10-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103705511B (en) | Medical application of N- [5- (1,2, 4-triazole-1-yl) thiazole-2-yl ] fatty amide | |
| CN106032365B (en) | Benzal thiazolinone of 2 (base of thiazole 2) imino group 5 and preparation method and application | |
| CN104774199B (en) | 2‑（2 benzyl hydrazono-s）‑5‑（1,2,4 triazole, 1 base）Thiazole and its preparation and application | |
| TW201201804A (en) | Quinoline compounds and their use for treating viral infection | |
| EP3079693B1 (en) | Small molecule inhibitors of influenza a rna-dependent rna polymerase | |
| CN105985298B (en) | 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application | |
| CN103755697B (en) | 3-[[2-(2-benzyl imino-) thiazole-5-base] methyl] quinoline-2 (1H)-one and preparation and application thereof | |
| CN1990479A (en) | 3-alkoxy substituted-2, 5, 7-tri-substituted benzopyran-4-ketones compounds, preparing method thereof and pharmaceutical compounds containing same | |
| CN1793120A (en) | Thiourea kind compund with inhibiting virus capsid protain activity and its preparation process and application thereof | |
| CN105985332B (en) | 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolinones and the preparation method and application thereof | |
| CN103830233B (en) | 5-(1,2,4-triazol-1-yls) medical usage of-2-phenylacetamido-thiazole | |
| Shi et al. | Design, synthesis and biological activity of novel chalcone derivatives as anti-influenza agents | |
| CN104817539B (en) | 2 phenoxyquinoxaline derivatives and its medical usage | |
| CN104829607B (en) | Application of N-thiazole benzoxazinone derivatives serving as neuraminidase inhibitors | |
| CN106317049B (en) | 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] application of -5- benzal -4- thiazolinones as NA inhibitor | |
| CN103739599A (en) | 3-[[2-(2-benzyl hydrazono) thiazole-5-base] methyl] quinoline-2 (1H)-ketone and preparation and applications thereof | |
| CN104817491B (en) | The phenoxy group fatty acid amide of N pyridine radicals 2 and its medical usage | |
| CN104771397B (en) | N‑（5 benzyl thiazole, 2 base）Benzamide and its medical usage | |
| CN104771399B (en) | N [5 (1,2,4 triazole 1 base) thiazole 2 base] virtue amide and medical usage thereof | |
| CN105985376B (en) | [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester and preparation method and application | |
| CN107827830B (en) | Oseltamivir derivative and preparation method and application thereof | |
| CN103705508B (en) | 2-[1-(1,2,4-triazol-1-yl) butyl-2-methylene aminooxy group] acethydrazide and medical usage thereof | |
| CN104788369B (en) | Double pyridine phenoxyl fat amide derivants and its medical usage | |
| CN104628717A (en) | 3-[5-(1,2,4-triazole-1-yl) thiazole-2-yl] benzoxazine and application thereof | |
| CN104771398B (en) | N-[5-(2-nitro ethyl)thiazole-2-yl]benzamide, and pharmaceutical applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180223 Termination date: 20220210 |