CN105985332A - 2-[5-(triazolyl-1-yl)thiazolyl-2-imino]-5-benzalthiazolinone and its preparation method and use - Google Patents
2-[5-(triazolyl-1-yl)thiazolyl-2-imino]-5-benzalthiazolinone and its preparation method and use Download PDFInfo
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- 0 Cc1c(-[n]2ncnc2)[s]c([N+]C(NC2=O)S/C2=C/c2cccc(*)c2)n1 Chemical compound Cc1c(-[n]2ncnc2)[s]c([N+]C(NC2=O)S/C2=C/c2cccc(*)c2)n1 0.000 description 4
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Abstract
The invention relates to a 2-[5-(triazolyl-1-yl)thiazolyl-2-imino]-5-benzalthiazoline-4-one shown in the chemical structural formula I, II, III or IV or its mixture. R1 is selected from hydrogen, C1-C2 alkyl, C3-C4 straight chain or branch chain alkyl and halogeneated C1-C2 alkyl, X, Y or Z represents CH or N, X1 to X5 are selected to from hydrogen, C1-C2 alkyl, C3-C4 straight chain or branch chain alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamine, methoxyl, ethoxyl, a nitro group, an amino group and NHCOR and R is selected from hydrogen, C1-C2 alkyl and C3-C4 straight chain or branch chain alkyl. The invention discloses a use of the 2-[5-(triazolyl-1-yl)thiazolyl-2-imino]-5-benzalthiazoline-4-one in preparation of an influenza virus neuraminidase inhibitor.
Description
Technical field
The present invention relates to the preparation and application of a class noval chemical compound, specifically 2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal
Preparing and in the application as influenza virus neuraminidase inhibitor of base thiazolin 4 one.
Background technology
Bird flu virus can cause respiratory apparatus or the systemic infection of birds, high pathogenic avian influenza virus can direct infection birds,
Also the mankind can directly or indirectly be infected.High pathogenic avian influenza virus is the latent dangerous factor causing influenza in crowd,
And can seriously threaten human health.20th century once there is 4 flu outbreaks in the mankind: " the western class of 1918 to 1919 years
Tooth influenza " (H1N1Hypotype), " Asia influenza " (H of nineteen fifty-seven to 1958 year2N2Hypotype), nineteen sixty-eight to 1969 year
" Mao flu " (H3N2Hypotype) and " Russia's influenza " (H in 19771N1Hypotype).Bird flu virus contains two tables
Face albumen: hemagglutinin (HA) and neuraminidase (NA), according to the difference of the two protein antigenicity, can be by bird flu
Virus is divided into 16 HA hypotype (H1～H16) and 9 NA hypotype (N1～N9).So far the fowl of energy direct infection people is found
Influenza virus sub-strain has: H5N1、H7N1、H7N2、H7N3、H7N7、H9N2、H7N9And H10N8Hypotype.Wherein, high cause
Characteristic of disease H5N1Hypotype found first in Hong Kong in 1997 can the direct infection mankind, after in July, 2003, H5N1Bird flu epidemic disease
Feelings present unprecedented breaking out, and involve Asia, North America, 17 countries and regions of Europe And Africa, cause hundreds of people to infect
And dead, direct economic loss is up to 10,000,000,000 dollars.In March, 2003, there is H in Holland7N7Type bird flu also involves whole
Europe, human infection person reaches 83 examples, not only causes the injures and deaths of the mankind, has inflicted heavy losses on poultry farming simultaneously.In March, 2009
The end, Mexico breaks out people and infects H1N1Type swine flue epidemic situation is also diffused into all over the world, according to World Health Organization (WHO) in 2010 2
A type H that the moon 26 was issued1N1Influenza global picture is reported, at least 16226 example patients of 213 countries and regions die from
This big influenza [Zeng Xiangxing, Li Kangsheng.Medical science and society, 2010,11,4-6.].Through gene sequencing, H1N1Type
Virus comprises human influenza virus, North America bird flu virus and North America, Europe, sub-swine influenza virus genetic fragment, for several not jljls
The mixing strain of kind influenza virus, and non-individual one swine flue or bird flu virus.In March, 2013, China finder first
Infect H7N9Bird flu case, ends on January 25th, 2015, the H that World Health Organization (WHO) announces7N9Bird flu makes a definite diagnosis 494
People, dead 221 people.Therefore the research and development to Anti-avian influenza virus drugs, it has also become countries in the world government and health and epidemic prevention department's day
One of significant problem that benefit is paid close attention to and actively addressed.
Bird flu virus is a kind of virus containing envelope protein, and its genome is the sub-thread strand RNA including 8 sections, can
Encode multiple virus protein: virus surface proteins (hemagglutinin HA, neuraminidase NA), stromatin (M1, M2)
Nucleoprotein (NP), non-structural protein (NS1, NS2), RNA polymerase P protein complexes PA, PB1, PB2)
[CN101990534A].HA is a kind of mediate retroviral to the combination of target cell and viral genome enters the agglutinin of target cell.
NA can the N-acetylamino of catalytic pyrolysis host cell surface glycoprotein end, discharge progeny virus from infection cell.NA is also
Toxicity can be strengthened by changing the carbohydrate portions of surface glycoprotein HA, promote that virus is from infected host cell
Release, causes or increases the weight of flu-like symptom [CN103755697A].Additionally, NA has in the mutation process of influenza virus relatively
Conservative so that it is become design, the synthesis extraordinary target of Tamiflu.Therefore, with NA as action target, by pressing down
NA activity processed suppresses influenza virus to replicate and the NA inhibitor of toxicity is the First Line medicine of anti-avian influenza virus, represents medicine
Thing has Zanamivir, Oseltamivir and Peramivir and derivant thereof, and wherein Oseltamivir is widely used.But grind
Study carefully some Strain of discovery and Oseltamivir is created drug resistance.
2010, Mohan etc. designed and synthesized the Oseltamivir analog that a class contains triazole structure, and vitro enzyme suppresses
Agent active testing filter out one NAs (Nl) is had greater activity and selective inhibitor A [Mohan S.et al,
J.Med.Chem.2010,53 (20), 7377-7391].Xie Yuanchao is basic parent nucleus with the pyrrolidine of L-hydroxyproline, and design is closed
The compound B becoming out a class to contain triazole shows preferable NA inhibitory activity [Xie Yuanchao.Shandong University, 2014.].
Thiazoles and thiazolinone compounds have an anti-influenza virus activity: Chinese invention patent [ZL 200810152537.4,
2010.12.22 authorizing, ZL 201010223400.0,2012.07.25 authorize] report series there is the thiophene of anti-influenza virus activity
Zole derivatives and thiazole-substituted mercaptoacetamide derivative；Chinese invention patent [CN 103830233 A, 2014.06.04 are open,
CN 103705511 A, 2014.04.09 are open] describe 5-(1,2,4-triazol-1-yl)-2-phenylacetamido-thiazole and N-[5-
(1,2,4-triazol-1-yl) thiazol-2-yl] anti-influenza activity of fatty acid amide；Chinese invention patent [CN 103755697 A,
2014.04.30 disclosing, CN 103739599 A, 2014.04.23 are open] report 3-[[2-(2-benzyl imino group) thiazole-5-base] methyl]
Quinoline-2 (1H)-one and the preparation of 3-[[2-(2-benzyl hydrazono-) thiazole-5-base] methyl] quinoline-2 (1H)-one and anti-influenza activity；Additionally,
Chinese patent [CN 103648282 A, 2014.03.19 are open, and CN101990534 A, 2008.10.3 are open] there was reported thiazole
Compounds purposes in terms of prevention and treatment virus infection.
Summary of the invention
It is an object of the invention to provide chemical constitution formula I, 2-[5-(nitrogen azoles-1-base) thiazole-2-imido shown in II, III or IV
Base]-5-benzal 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, Y or Z are selected from: CH or N；X1、X5It is selected from: hydrogen,
C1～C2Alkyl, C3～C4Straight or branched alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X2、X4Be selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X3It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitre
Base, amino or NHCOR；Wherein R is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one shown in I formula is (2E, 5Z)-2-[5-(nitrogen azoles-1-
Base) thiazole-2-imino group]-5-benzal thiazolin 4 one；2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal shown in II formula
Base thiazolin 4 one is (2Z, 5Z)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one；Shown in III formula
2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one is (2E, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imido
Base]-5-benzal thiazolin 4 one；2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one shown in IV formula is
(2Z, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one.
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that the present invention provides is selected from following compound:
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；X1、X5It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight or branched
Alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、
X4It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3
It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R
It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that the present invention provides is selected from following compound:
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；X1、X5It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight or branched
Alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、
X4It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3
It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R
It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that the present invention provides is selected from following compound:
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；X1、X5It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight or branched
Alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、
X4It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3
It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R
It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that the present invention provides is selected from following compound:
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；X1、X5It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight or branched
Alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、
X4It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3
It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R
It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that it is an object of the invention to provide is selected from following
Compound:
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, Y or Z are selected from: CH or N；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。
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that it is an object of the invention to provide is selected from following
Compound:
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, Y or Z are selected from: CH or N；N is selected from: 1,2 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。
2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazole shown in the structural formula I that it is an object of the invention to provide
Quinoline-4-ketone is selected from: 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-fluorine benzal) thiazoline
-4-ketone, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-fluorine benzal) thiazolin 4 one,
2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-chlorine benzal) thiazolin 4 one, 2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(3-chlorine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(4-chlorine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(2-bromine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(3-bromine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(4-bromine benzal) thiazolin 4 one, 5-benzal-2-{ [uncle 4-
Butyl-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-
Triazol-1-yl) thiazol-2-yl] imino group-5-(2-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazoles
-1-base) thiazol-2-yl] imino group-5-(3-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazole-1-
Base) thiazol-2-yl] imino group-5-(4-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls)
Thiazol-2-yl] imino group-5-(2-benzylidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls)
Thiazol-2-yl] imino group-5-(3-benzylidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls)
Thiazol-2-yl] imino group-5-(3-nitrobenzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazole
-2-base] imino group-5-(4-nitrobenzal) thiazolin 4 one, 5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-
Triazol-1-yl) thiazol-2-yl] imino group thiazolin 4 one, 5-(4-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazoles
-1-base) thiazol-2-yl] imino group thiazolin 4 one, 5-(3-acetylamino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazoles
-1-base) thiazol-2-yl] imino group } thiazolin 4 one or 5-(4-acetylamino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-tri-
Azoles-1-base) thiazol-2-yl] imino group } thiazolin 4 one.
The preparation side of 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that it is an object of the invention to provide
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, Y or Z are selected from: CH or N；X1、X5It is selected from: hydrogen,
C1～C2Alkyl, C3～C4Straight or branched alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl or
Nitro；X2、X4It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl or nitro；X3It is selected from:
Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl or nitro.
It is an object of the invention to provide 5-(amino benzal)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group] thiazolin 4 one and
The preparation method of 5-(acetylamino benzal)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group] thiazolin 4 one, it is characterised in that they
Preparation reaction 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, Y or Z are selected from: CH or N；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)n
It 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。
2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one that it is an object of the invention to provide has influenza
Neuraminidase inhibitory activity, the application in preparing influenza virus neuraminidase inhibitor.
The present invention compared with prior art has the advantage that
Invent 2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one to there is influenza neuraminidase and press down
System activity.
Detailed description of the invention
Following example are intended to illustrate rather than limitation of the invention further.
The preparation method such as embodiment of (2E, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one (III)
Described in 1～24.
Embodiment 1
2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } preparation of thiazolin 4 one (2)
11.25g (50mmol) the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazole-2-amine, 100mL dichloromethane, stirring
Dissolve, add 6.90g (50mmol) Anhydrous potassium carbonate, stirring at normal temperature 30min, drip 4.0ml (50mmol) chloracetyl chloride,
Normal-temperature reaction 2.5h.Reactant liquor pours frozen water into, and dichloromethane extracts, and saturated aqueous sodium carbonate washs, and merges organic facies, nothing
Aqueous sodium persulfate is dried, precipitation, and ethyl alcohol recrystallization obtains 13.50g white solid 1, yield 93%, m.p.130～133 DEG C.
10.25g (34mmol) compound Isosorbide-5-Nitrae .95g (34mmol) potassium thiocyanate, 100ml ethanol dissolves, and is heated to reflux anti-
Answer 5.0h.Cooling, separates out solid, sucking filtration, is dried to obtain 9.50g faint yellow solid 2, yield 86%, m.p.182～185 DEG C.
1H NMR(CDCl3, 400MHz) and δ: 1.19 (s, 9H, 3 × CH3), 3.90 (s, 2H, CH2), 8.11 (s, 1H, C2H2N3
3-H), 8.28 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 2
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-nitrobenzal) thiazole
The preparation of quinoline-4-ketone
The buffer solution of 35ml acetic acid 0.65g sodium acetate preparation pH=4～5, adds 2.0mmol intermediate 2 and 4.0
Mmol 3-nitrobenzaldehyde, heating reflux reaction 10h.Cooling, washing, filter, ethyl alcohol recrystallization obtains yellow solid
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-nitrobenzal) thiazoline-4-
Ketone, yield 80%, m.p.258～260 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.29 (s, 9H, 3 × CH3),
7.67～7.74 (m, 1H, C6H4), 7.85～7.92 (m, 2H, C6H4,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30～8.32
(m, 2H, C6H4), 8.42,8.55 (s, 1H, C2H2N35-H), 12.07 (s, 1H, NH).
Embodiment 3
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-nitrobenzal) thiazole
The preparation of quinoline-4-ketone
Operational approach, with embodiment 2, compound 2 and 4-nitrobenzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-nitrobenzal) thiazolin 4 one, yield 82%,
M.p.272～273 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.26 (s, 9H, 3 × CH3), 7.70～7.76 (m,
2H, C6H4), 7.83,7.91 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H),
8.34～8.38 (m, 2H, C6H4), 12.09 (s, 1H, NH).
Embodiment 4
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-fluorine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and the fluorine-based benzaldehyde of 2-, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-fluorine benzal) thiazolin 4 one, yield 70%,
M.p.254～256 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.19,1.24 (s, 9H, 3 × CH3), 7.17～7.22 (m,
1H, C6H4), 7.29 (d, J=7.9Hz, 1H, C6H4), 7.43～7.47 (m, 1H, C6H4), 7.59～7.65 (m, 1H,
C6H4), 8.08 (s, 1H ,=CH), 8.14 (s, 1H, C2H2N33-H), 8.33 (s, 1H, C2H2N35-H), 12.01 (s,
1H, NH).
Embodiment 5
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-fluorine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and the fluorine-based benzaldehyde of 3-, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-fluorine benzal) thiazolin 4 one, yield 81%,
M.p.203～205 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.27 (s, 9H, 3 × CH3), 7.16 (t, J=8.1
Hz, 1H, C6H4), 7.30～7.39 (m, 2H, C6H4), 7.45～7.50 (m, 1H, C6H4), 7.78,7.85 (s, 1H,
=CH), 8.13 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 6
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-chlorine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 2-chloro benzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-chlorine benzal) thiazolin 4 one, yield 67%,
M.p.286～288 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22 (s, 9H, 3 × CH3), 7.38～7.40 (m, 2H,
C6H4), 7.51～7.53 (m, 1H, C6H4), 7.64 (s, 1H, C6H4), 8.14 (s, 1H, C2H2N33-H), 8.21 (s,
1H ,=CH), 8.32 (s, 1H, C2H2N35-H)。
Embodiment 7
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-chlorine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 3-chloro benzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-chlorine benzal) thiazolin 4 one, yield 73%,
M.p.240～242 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.27 (s, 9H, 3 × CH3), 7.42～7.46 (m,
3H, C6H4), 7.53,7.64 (s, 1H, C6H4), 7.75,7.82 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H),
8.30 (s, 1H, C2H2N35-H), 12.03 (s, 1H, NH).
Embodiment 8
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-chlorine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 4-chloro benzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-chlorine benzal) thiazolin 4 one, yield 73%,
M.p.260～262 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.25 (s, 9H, 3 × CH3), 7.47～7.52 (m, 4H,
C6H4), 7.78,7.84 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H),
12.01 (s, 1H, NH).
Embodiment 9
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-bromine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 2-bromobenzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-bromine benzal) thiazolin 4 one, yield 81%,
M.p.285～287 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.19,1.21 (s, 9H, 3 × CH3), 7.28～7.32 (m,
1H, C6H4), 7.42～7.47 (m, 1H, C6H4), 7.65～7.67 (m, 1H, C6H4), 7.72 (dd, J=8.0,1.0Hz,
1H, C6H4), 8.12 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 10
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-bromine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 3-bromobenzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-bromine benzal) thiazolin 4 one, yield 82%,
M.p.251～253 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.27 (s, 9H, 3 × CH3), 7.37 (t, J=7.7
Hz, 1H, C6H4), 7.50 (d, J=7.7Hz, 1H, C6H4), 7.58 (d, J=7.9Hz, 1H, C6H4), 7.69～7.74
(s, 1H, C6H4), 7.81 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H),
12.03 (s, 1H, NH).
Embodiment 11
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-bromine benzal) thiazoline
The preparation of-4-ketone
Operational approach, with embodiment 2, compound 2 and 4-bromobenzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-bromine benzal) thiazolin 4 one, yield 81%,
M.p.268～270 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22,1.25 (s, 9H, 3 × CH3), 7.44 (dd, J=17.8,
8.0Hz, 2H, C6H4), 7.67 (dd, J=21.4,8.4Hz, 2H, C6H4), 7.75,7.82 (m, 1H ,=CH), 8.13
(s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 12.05 (s, 1H, NH).
Embodiment 12
(2E, 5E)-5-benzal-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one
Preparation
Operational approach, with embodiment 2, compound 2 and benzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-5-benzal-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, yield 75%, m.p.225～227 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.24 (s, 9H, 3 × CH3), 7.44～7.53 (m, 3H, C6H4), 7.59 (d, J=
7.2Hz, 2H, C6H4), 7.87 (s, 1H ,=CH), 8.14 (s, 1H, C2H2N33-H), 8.32 (s, 1H, C2H2N35-H)。
Embodiment 13
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-methylbenzilidene) thiazole
The preparation of quinoline-4-ketone
Operational approach, with embodiment 2, compound 2 and 2-tolyl aldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-methylbenzilidene) thiazolin 4 one, yield 60%,
M.p.260～262 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.22 (s, 9H, 3 × CH3), 2.48 (s, 3H, CH3),
7.29～7.37 (m, 3H, C6H4), 7.52～7.60 (m, 1H, C6H4), 8.07 (s, 1H ,=CH), 8.12 (s, 1H, C2H2N3
3-H), 8.30 (s, 1H, C2H2N35-H)。
Embodiment 14
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-methylbenzilidene) thiazole
The preparation of quinoline-4-ketone
Operational approach, with embodiment 2, compound 2 and 3-tolyl aldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-methylbenzilidene) thiazolin 4 one, yield 66%,
M.p.241～243 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.26 (s, 9H, 3 × CH3), 2.42 (s, 3H, CH3),
7.28～7.39 (m, 3H, C6H4), 7.44～7.70 (m, 1H, C6H4), 7.82 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N3
3-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 15
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-methylbenzilidene) thiazole
The preparation of quinoline-4-ketone
Operational approach, with embodiment 2, compound 2 and 4-tolyl aldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(4-methylbenzilidene) thiazolin 4 one, yield 62%,
M.p.245～247 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.25 (s, 9H, 3 × CH3), 2.43 (s, 3H, CH3),
7.31 (d, J=7.9Hz, 2H, C6H4), 7.49 (d, J=7.9Hz, 2H, C6H4), 7.84 (s, 1H ,=CH), 8.14
(s, 1H, C2H2N33-H), 8.32 (s, 1H, C2H2N35-H)。
Embodiment 16
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-benzylidene) thiophene
The preparation of oxazoline-4-ketone
Operational approach, with embodiment 2, compound 2 and Benzaldehyde,2-methoxy, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-benzylidene) thiazolin 4 one, yield 77
%, m.p.251～253 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.23 (s, 9H, 3 × CH3), 3.93 (s, 3H, OCH3),
6.97 (d, J=8.3Hz, 1H, C6H4), 7.07 (t, J=7.5Hz, 1H, C6H4), 7.42～7.46 (m, 1H, C6H4),
7.55 (s, 1H, C6H4), 8.13 (s, 1H ,=CH), 8.24 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 17
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-benzylidene) thiophene
The preparation of oxazoline-4-ketone
Operational approach, with embodiment 2, compound 2 and m-methoxybenzaldehyde, is reacted 10h, is obtained yellow solid (2E, 5E)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-benzylidene) thiazolin 4 one, yield 74
%, m.p.220～222 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.24 (s, 9H, 3 × CH3), 3.87 (s, 3H, OCH3),
7.01 (dd, J=8.2,2.1Hz, 1H, C6H4), 7.07～7.20 (m, 2H, C6H4), 7.41 (t, J=7.8Hz, 1H,
C6H4), 7.83 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 11.99 (s,
1H, NH).
Embodiment 18
(2E, 5E)-5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazole
The preparation of quinoline-4-ketone
10ml dichloromethane and 10ml acetic acid 1.0mmol raw material (2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-tri-
Azoles-1-base) thiazol-2-yl] imino group }-5-(3-nitrobenzal) thiazolin 4 one, add appropriate iron powder and 1ml water, room temperature stirs
Mix reaction 5h.Filtering, washing, dichloromethane extracts, saturated aqueous sodium carbonate washing organic facies, and anhydrous sodium sulfate is dried,
Precipitation obtains yellow solid (2E, 5E)-5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl]
Imino group } thiazolin 4 one, yield 81%, m.p.224～226 DEG C.1H NMR (DMSO, 400MHz) δ: 1.18 (s,
9H, 3 × CH3), 5.49 (s, 2H, NH2), 6.69 (d, J=7.7Hz, 1H, C6H4), 6.81 (d, J=6.4Hz, 2H,
C6H4), 7.18 (t, J=8.0Hz, 1H, C6H4), 7.57 (s, 1H ,=CH), 8.29 (s, 1H, C2H2N33-H), 9.03
(s, 1H, C2H2N35-H), 12.66 (s, 1H, NH).
Embodiment 19
(2E, 5E)-5-(4-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazole
The preparation of quinoline-4-ketone
Operational approach with embodiment 18, (2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imido
Base }-5-(4-nitrobenzal) thiazolin 4 one is raw material, reacts 5h, obtains yellow solid (2E, 5E)-5-(4-amino benzal
Base)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, yield 85%, m.p.
210～212 DEG C.1H NMR (DMSO, 400MHz) δ: 1.20 (s, 9H, 3 × CH3), 6.16 (s, 2H, NH2), 6.67
(d, J=7.9Hz, 2H, C6H4), 7.39 (d, J=7.6Hz, 2H, C6H4), 7.58 (s, 1H ,=CH), 8.29 (s,
1H, C2H2N33-H), 9.03 (s, 1H, C2H2N35-H), 12.59 (s, 1H, NH).
Embodiment 20
(2E, 5E)-5-(3-acetylamino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }
The preparation of thiazolin 4 one
10ml acetic acid 0.5mmol raw material (2E, 5E)-5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-tri-
Azoles-1-base) thiazol-2-yl] imino group } thiazolin 4 one, drip 0.5mmol chloroacetic chloride, stirring at normal temperature reaction 1h.Washing,
Ethyl acetate extracts, and saturated aqueous sodium carbonate washing organic facies, anhydrous sodium sulfate is dried, and precipitation obtains yellow solid (2E, 5E)-5-(3-
Acetylamino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, yield
64%, m.p.302～304 DEG C.1H NMR (DMSO, 400MHz) δ: 1.16 (s, 9H, 3 × CH3), 2.05 (s, 3H,
COCH3), 7.33 (d, J=6.1Hz, 1H, C6H4), 7.44 (d, J=6.5Hz, 2H, C6H4), 7.70 (s, 1H ,=CH),
8.20 (s, 1H, C6H4), 8.28 (s, 1H, C2H2N33-H), 9.02 (s, 1H, C2H2N35-H), 10.12 (s, 1H,
NHAc), 12.82 (s, 1H, NH).
Embodiment 21
(2E, 5E)-5-(4-acetylamino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }
The preparation of thiazolin 4 one
Operational approach with embodiment 20, (2E, 5E)-5-(4-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls)
Thiazol-2-yl] imino group } thiazolin 4 one is raw material, reacts 1h, obtains yellow solid (2E, 5E)-5-(4-acetylamino benzal
Base)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, yield 68%, m.p.
245～247 DEG C.1H NMR (DMSO, 400MHz) δ: 1.19 (s, 9H, 3 × CH3), 2.08 (s, 3H, COCH3),
7.62 (d, J=8.4Hz, 2H, C6H4), 7.69 (s, 1H ,=CH), 7.75 (d, J=7.7Hz, 2H, C6H4), 8.29
(s, 1H, C2H2N33-H), 9.02 (s, 1H, C2H2N35-H), 10.28 (s, 1H, NHAc), 12.79 (s, 1H, NH).
Embodiment 22
2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazol-2-yl] amino } preparation of thiazolin 4 one
4.4g (20mmol) the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazole-2-amine, 50mL dichloromethane, stirring and dissolving, add
2.75g (50mmol) Anhydrous potassium carbonate, stirring at normal temperature 30min, drip 1.60ml (50mmol) chloracetyl chloride, normal-temperature reaction
2.5h.Reactant liquor pours frozen water into, and dichloromethane extracts, and saturated aqueous sodium carbonate washs, and merges organic facies, anhydrous sodium sulfate
Being dried, precipitation, ethyl alcohol recrystallization obtains 4.4g white solid 3, yield 82%, m.p.175～177 DEG C.
0.9g (3mmol) compound 7,0.29g (3mmol) potassium thiocyanate, 20ml ethanol dissolves, heating reflux reaction 5.0h.
Cooling, separates out solid, sucking filtration, is dried to obtain 0.8g pink solid 4, yield 83%, m.p.241～243 DEG C.1H NMR(CDCl3,
400MHz) δ: 1.20 (s, 9H, 3 × CH3), 3.90 (s, 2H, CH2), 7.09 (s, 1H, C2H3N22-H), 7.19 (s,
1H, C2H3N24-H), 7.70 (s, 1H, C2H3N25-H), 12.08 (s, 1H, NH).
Embodiment 23
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazol-2-yl] amino }-5-(3-nitrobenzal) thiazolin 4 one
Preparation
The buffer solution of 35ml acetic acid 0.65g sodium acetate preparation pH=4～5, adds 2.0mmol intermediate 4 and 4.0
Mmol 3-nitrobenzaldehyde, heating reflux reaction 10h.Cooling, washing, filter, ethyl alcohol recrystallization obtains yellow solid
(2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazol-2-yl] amino }-5-(3-nitrobenzal) thiazolin 4 one, yield 75
%, m.p.273～275 DEG C.1H NMR(CDCl3, 400MHz) and δ: 1.23,1.30 (s, 9H, 3 × CH3), 7.11 (s, 1H,
C2H3N22-H), 7.19 (s, 1H, C2H3N24-H), 7.68～7.72 (m, 2H ,=CH, C2H3N25-H), 7.88 (m,
2H, C6H4), 8.31 (d, J=8.5Hz, 1H, C6H4), 8.56 (s, 1H, C6H4), 12.13 (s, 1H, NH).
Embodiment 24
(2E, 5E)-5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazol-2-yl] amino } thiazolin 4 one
Preparation
10ml dichloromethane and 10ml acetic acid 1.0mmol raw material (2E, 5E)-2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base)
Thiazol-2-yl] amino }-5-(3-nitrobenzal) thiazolin 4 one, add appropriate iron powder and 1ml water, stirring at normal temperature reaction 5h.
Filtering, washing, dichloromethane extracts, and saturated aqueous sodium carbonate washing organic facies, anhydrous sodium sulfate is dried, and precipitation must reduce
Product: yellow solid yellow solid (2E, 5E)-5-(3-amino benzal)-2-{ [the 4-tert-butyl group-5-(1H-imidazoles-1-base) thiazol-2-yl]
Amino } thiazolin 4 one, yield 82%, m.p.223～225 DEG C.1H NMR (DMSO, 400MHz) δ: 1.21 (s, 9H,
3×CH3), 5.43 (s, 2H, NH2), 6.68 (d, J=7.7Hz, 1H, C6H4), 6.81 (s, 2H, C2H3N22-H,
C6H4), 7.15～7.19 (m, 2H, C2H3N24-H, C6H4), 7.44～7.56 (m, 2H, C2H3N25-H, C6H4), 8.00
(s, 1H ,=CH), 11.98 (s, 1H, NH).
(2E, 5Z)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazole is prepared according to the method described in embodiment 1～24
Quinoline-4-ketone (I), (2Z, 5Z)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one (II) and
(2Z, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal 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, Y or Z are selected from: CH or N；X1、X5It is selected from: hydrogen,
C1～C2Alkyl, C3～C4Straight or branched alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X2、X4Be selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X3It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitre
Base, amino or NHCOR；Wherein R is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
Embodiment 25
2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one resisiting influenza virus neuraminidase activity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the metabolite produced under neuraminidase effect exists
360nm irradiates and excites down, can produce 450nm fluorescence, and the change of fluorescence intensity can reflect 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 (pH in reaction buffer
6.5), add fluorogenic substrate MUNANA and start reaction system, after 37 DEG C hatch 40 minutes, add reaction terminating liquid and terminate anti-
Should.Under the Parameter Conditions of a length of 450nm of excitation wavelength 360nm and transmitted wave, measure fluorescence intensity level.Strong according to fluorescence
The decrement of degree can be with the computerized compound suppression ratio to NA activity.
3. detection sample: 2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal 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, Y or Z are selected from: CH or N；X1、X5It is selected from: hydrogen,
C1～C2Alkyl, C3～C4Straight or branched alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X2、X4Be selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl,
Nitro, amino or NHCOR；X3It is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitre
Base, amino or NHCOR；Wherein R is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or C3～C4Branched alkyl.
4. Activity Results
Preferred compound suppression ratio and IC thereof to neuraminidase during detectable concentration 40.0 μ g/mL in response system50Value is listed in
Table 1 below:
Table 12-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one inhibitory activity to neuraminidase
2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one has good resisiting influenza virus neuraminidase
Activity, can be used for preparing influenza virus neuraminidase inhibitor.
Claims (11)
1. chemical constitution formula I, 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazole shown in II, III or IV
Quinoline-4-ketone or its mixture:
Wherein, R1It is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight or branched alkyl, fluoro C1～C2Alkyl, chloro
C1～C2Alkyl, bromo C1～C2Alkyl or iodo C1～C2Alkyl；X, Y or Z are selected from: CH or N；X1、X5Choosing
From: hydrogen, C1～C2Alkyl, C3～C4Straight or branched alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxy
Base, ethyoxyl, nitro, amino or NHCOR；X2、X4Be selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino,
Methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3Be selected from: fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino,
Methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from: hydrogen, C1～C2Alkyl, C3～C4Straight chain or
C3～C4Branched alkyl；2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one shown in I formula is
(2E, 5Z)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one；2-[5-(nitrogen azoles-1-base) shown in II formula
Thiazole-2-imino group]-5-benzal thiazolin 4 one is (2Z, 5Z)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiophene
Oxazoline-4-ketone；2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one shown in III formula is
(2E, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one；2-[5-(nitrogen azoles-1-shown in IV formula
Base) thiazole-2-imino group]-5-benzal thiazolin 4 one is (2Z, 5E)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal
Base thiazolin 4 one.
2. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1 is selected from following
Compound:
Wherein, R1And X1～X5As claimed in claim 1.
3. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1 is selected from following
Compound:
Wherein, R1And X1～X5As claimed in claim 1.
4. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1 is selected from following
Compound:
Wherein, R1And X1～X5As claimed in claim 1.
5. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1 is selected from following
Compound:
Wherein, R1And X1～X5As claimed in claim 1.
6. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1 is selected from following
Compound:
Wherein, R1, X, Y or Z as claimed in claim 1；(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。
7. 2-described in claim 1 [5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazolin 4 one is selected from followingization
Compound:
Wherein, R1, X, Y or Z as claimed in claim 1；N is selected from: 1,2 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。
8. 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one of structural formula I shown in claim 1
Be selected from: 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(2-fluorine benzal) thiazoline-4-
Ketone, 2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(3-fluorine benzal) thiazolin 4 one,
2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group }-5-(2-chlorine benzal) thiazolin 4 one, 2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(3-chlorine benzal) thiazolin 4 one, 2-{ [uncle 4-
Butyl-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(4-chlorine benzal) thiazolin 4 one, 2-{ [the tertiary fourth of 4-
Base-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(2-bromine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(3-bromine benzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group
-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group-5-(4-bromine benzal) thiazolin 4 one, 5-benzal-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(2-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(3-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(4-methylbenzilidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(2-benzylidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(3-benzylidene) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(3-nitrobenzal) thiazolin 4 one, 2-{ [the 4-tert-butyl group-5-(1H-1,2,
4-triazol-1-yl) thiazol-2-yl] imino group-5-(4-nitrobenzal) thiazolin 4 one, 5-(3-amino benzal)-2-{ [uncle 4-
Butyl-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 5-(4-amino benzal)-2-{ [uncle 4-
Butyl-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 5-(3-acetylamino benzal)-2-{ [4-
The tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one or 5-(4-acetylamino benzal
Base)-2-{ [the 4-tert-butyl group-5-(1H-1,2,4-triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one.
9. the preparation side of 2-[5-(nitrogen azoles-1-base) thiazole-2-the imino group]-5-benzal thiazolin 4 one described in claim 1
Method, it is characterised in that its preparation reaction is as follows:
In formula, R1、X、Y、Z、X1～X5As claimed in claim 1.
10.5-(amino benzal)-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group] thiazolin 4 one and 5-(acetylamino benzal
Base) preparation method of-2-[5-(nitrogen azoles-1-base) thiazole-2-imino group] thiazolin 4 one, it is characterised in that their preparation is reacted such as
Under:
In formula, R1、X、Y、Z、X1～X5As claimed in claim 1；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)3
Or 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)nBe 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。
2-according to any one of 11. claim 1～8 [5-(nitrogen azoles-1-base) thiazole-2-imino group]-5-benzal thiazoline-4-
Ketone application in preparing influenza virus neuraminidase inhibitor.
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| CN102250078A (en) * | 2011-04-25 | 2011-11-23 | 湖南大学 | Use of 4-(benzofuran-5-yl)-2-benzyliminothiazole in preparation of herbicide |
| CN102964267A (en) * | 2011-09-01 | 2013-03-13 | 中山大学 | Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application |
| CN103145700A (en) * | 2013-04-01 | 2013-06-12 | 湖南大学 | 2-(2-benzyl hydrazono)-4-(benzofuran-5-yl) thiazole and preparation method and application thereof |
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| CN102250078A (en) * | 2011-04-25 | 2011-11-23 | 湖南大学 | Use of 4-(benzofuran-5-yl)-2-benzyliminothiazole in preparation of herbicide |
| CN102964267A (en) * | 2011-09-01 | 2013-03-13 | 中山大学 | Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application |
| CN103145700A (en) * | 2013-04-01 | 2013-06-12 | 湖南大学 | 2-(2-benzyl hydrazono)-4-(benzofuran-5-yl) thiazole and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ÖZNUR ATES，ET AL: "Synthesis and Antimicrobial Activity of 4-Carbethoxymethyl-2-[(α-haloacyl)amino] thiazoles and 5-Nonsubstituted/substituted 2-[(4-Carbethoxymethylthiazol-2-yl)imino]-4-thiazolidinones", 《ARZNEIM.-FORSCH./DRUG RES.》 * |
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