CN105017174B - N‑（4 alkyl, 5 benzyl thiazole, 2 base）Acrylamide and preparation method and application - Google Patents

N‑（4 alkyl, 5 benzyl thiazole, 2 base）Acrylamide and preparation method and application Download PDF

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CN105017174B
CN105017174B CN201510406074.XA CN201510406074A CN105017174B CN 105017174 B CN105017174 B CN 105017174B CN 201510406074 A CN201510406074 A CN 201510406074A CN 105017174 B CN105017174 B CN 105017174B
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preparation
alkyl
acrylamide
thiazol
tert
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CN105017174A (en
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彭俊梅
申坤
丁娜
胡艾希
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University of South China
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

Abstract

The present invention relates to shown in chemical constitution formula IN‑（4 alkyl, 5 benzyl thiazole, 2 base）Acrylamide or its salt：In I formulas, R is selected from：C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, methyl, ethyl；N is selected from：1st, 2,3,4,5,6 or 7；Z is selected from：Hydrogen, methyl or phenyl；Salt is selected from：Hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, tosilate.N‑（4 alkyl, 5 benzyl thiazole, 2 base）The application of acrylamide or its salt in cancer therapy drug is prepared.

Description

N-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide and preparation method and application
Technical field
The present invention relates to the preparation method of noval chemical compound and application, specificallyN-（4- alkyl -5- benzyl thiazol-2-yls） The preparation of acrylamide with as the application for preparing anticarcinogen.
Background technology
Dasatinib（Dasatinib）It is a kind of oral Mutiple Targets tyrosine kinase of Bristol-Myers Squibb Co.'s research and development Inhibitor, trade name SPRYCEL（Sprycel）.In June, 2006, U.S. FDA approval Dasatinib are used for losing the past treatment The Adult chronic's granulocyte leukemia for losing or not tolerating（CML）All stadium（Chronic phase, accelerator, the lymphoid lineage cell sudden turn of events Phase and myelocyte acute transformation phase）Patient, while be additionally operable to treat to other therapy drug resistances or the Philadelphia Chromosome Positive not tolerated Acute lymphatic leukemia adult patient（Ph+All）.It is representative in the market in molecular targeted therapy.2012 In on May 5, in, Dasatinib goes through in Discussion on Chinese Listed.Dasatinib by oral administration after can be rapidly absorbed, in 0.5-3 hours Reach peak concentration.In patient, the population mean t1/2 of Dasatinib is about 5-6 hour.Dasatinib main Untoward reaction includes：Bone marrow depression（Thrombocytopenia, Neutrophilic granulocytopenia and anemia）, the phase between bleeding, fluid retention and QT Extend etc..
Holla etc. [European Medical Chemistry, 2003,38：313-318] describe 2- fragrant amino -4- （2,4- bis- chloro- 5- fluorophenyls）The preparation of thiazole and biological activity；Chinese invention patent（CN1018445026, CN101781269）Describe 5-（4- chlorophenylmethyls）- 4- tertiary butyl thiazole derivatives and the 4- tert-butyl group -2-（Nitrobenzyl imido Base）The preparation of thiazole and its as the application for preparing antitumor drug.Chinese invention patent（CN101277692A, 2008.10.01 it is open）Describe the preparation of 5- benzyls -4- methyl/trifluoromethyl -2- fragrant amino thiazoles.Chinese invention patent （CN102070556A, 2011.5.25 are disclosed；CN102067845A, 2011.5.25 are disclosed）Describe 5- benzyl -4- alkyl -2- The preparation of fragrant amino thiazole hydrobromide salt.Chinese invention patent（CN102964312A, 2013.3.13 are disclosed； CN102924400A, 2013.2.13 are disclosed；CN102936229A；2013.2.20 it is open）DescribeN-（The 4- tert-butyl group -5- benzyls Base thiazol-2-yl）The preparation of amide and its biological activity.
Content of the invention
It is an object of the invention to provideN-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide（I）Or its salt；
I
In formula, R is selected from：C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, methyl, ethyl, hydroxyl Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, methyl, ethyl；N is selected from：1st, 2,3,4,5,6 or 7；Z is selected From：Hydrogen, methyl or phenyl；Salt is selected from：Hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, to first Benzene sulfonate.
It is an object of the invention to provideN-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide is selected from following compounds：
.
It is an object of the invention to provideN-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide and its salt prepare anti-human Lung adenocarcinoma cell（A549 cells）Or human breast cancer cell（MCF-7 cells）Application in medicine.
The present invention is had the advantage that compared with prior art：
The present invention is prepared firstN-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide and its salt, and findN-（4- alkane Base -5- benzyl thiazol-2-yls）Acrylamide or its salt have anti-human lung adenocarcinoma cell（A549 cells）Or human breast cancer cell （MCF-7 cells）Activity.
Specific embodiment
Following examples are intended to illustrate rather than limitation of the invention further.
Embodiment 1
NThe preparation of-(the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) acrylamide
The 1 mmol 4- tert-butyl group -5- (4- chlorobenzyls) thiazole -2- amine and 20 mL dichloromethane, ice bath are stirred, and are added 0.5 mL triethylamines, Deca are dissolved in 1.2 mmol acryloyl chlorides in 2 mL dichloromethane, TLC monitoring reactions, reaction 1.0 h.Revolving solvent, dry method loading, column chromatography for separation obtain yellow solidN- (the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) third Acrylamide, yield 83.2%, 128 ~ 130 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：8.93（S, 1H, CONH）, 7.26 （D,J =8.4 Hz, 2H, C6H4）, 7.12（D,J =8.4 Hz, 2H, C6H4）, 6.50（D,J =16.8 Hz, 1H, COCH）, 6.19（Dd,J =16.8 Hz,J =10.4 Hz, 1H ,=CH2）, 5.87（D,J =10.4 Hz, 1H ,=CH2）, 4.21（S, 2H, CH2）, 1.35（S, 9H, 3 × CH3）.
Embodiment 2
NThe preparation of-(the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) crotonamide
（1）The preparation of crotonyl chloride
19.9 mmol .beta.-methylacrylic acids and 15 mL thionyl chlorides, stirring, 60 DEG C of 5.0 h of reaction rotate excessive dichloro sub- Sulfone, obtains orange-yellow liquid crotonyl chloride, is put into Refrigerator store standby.
（2）NThe preparation of-(the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) crotonamide
According to the preparation method of embodiment 1,1.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (4- chlorobenzyls) Thiazol-2-yl) crotonamide, yield 67.4%, 135 ~ 136 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：8.91（S, 1H, CONH）, 7.25（D,J =8.4 Hz, 2H, C6H4）, 7.12（D,J =8.4 Hz, 2H, C6H4）, 5.92（Dd,J = 12.0 Hz, 1H, COCH）, 4.20（S, 2H, CH2）, 2.79（Dd,J =12.0 Hz, 1H, C=CH）, 1.93（Dd,J =6.8 Hz, 2H, CH3）, 1.61（D,J =6.8 Hz, 1H, CH3）, 1.35（S, 9H, 3 × CH3）.
Embodiment 3
NThe preparation of-(the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) Pyrusussuriensiss amide
The 1 mmol 4- tert-butyl group -5- (4- chlorobenzyls) thiazole -2- amine and 20 mL dichloromethane, stirring add 0.16 Mmol DMAP and 1.2 mmol sorbic acid, stir 0.5 h, add 1.2 mmol DCC, TLC monitoring reactions to react 3.0 h； Revolving solvent, dry method loading, column chromatography for separation obtain yellow solidN- (the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) Pyrusussuriensiss Amide, yield 91.1%, 185 ~ 186 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：7.38~7.32（M, 1H, COCH= CH）, 7.25（D, 2H,J =8.4 Hz, C6H4）, 7.09（D, 2H,J =8.4 Hz, C6H4）, 6.21 ~ 6.19（M, 2H,J = 4.4 Hz, CH=CH）, 5.82（D, 1H, COCH）, 4.20（S, 2H, CH2）, 1.87（D, 1H,J =4.4 Hz, CH3）, 1.34（S, 9H, 3 × CH3）.
Embodiment 4
NThe preparation of-(the 4- tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl) cinnamamide
According to the preparation method of embodiment 1,1.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (4- chlorobenzyls) Thiazol-2-yl) cinnamamide, yield 67.1%, 163 ~ 165 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：7.80（D, 1H,J =15.6 Hz, C6H5CH）, 7.53（Dd, 2H,J =5.6 Hz,J =2.0 Hz, C6H52-H, 6-H）, 7.40（T, 3H,J =5.6 Hz,J =2.0 Hz, C6H53-H, 4-H, 5-H）, 7.27（D, 2H,J =8.4 Hz, C6H4）, 7.14（D, 2H,J =8.4 Hz, C6H4）, 6.50（D, 1H,J =15.6 Hz, COCH）, 4.25（S, 2H, CH2）, 1.37（S, 9H, 3 × CH3）.
Embodiment 5
N -The preparation of (the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) acrylamide
The 1 mmol 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazole -2- amine and 20 mL dichloromethane, ice bath are stirred, plus Enter 0.5 mL triethylamines, Deca is dissolved in 1.2 mmol acyl chlorides in 2 mL dichloromethane, and 1.0 h are reacted in TLC monitoring reactions. Revolving solvent, dry method loading, column chromatography for separation obtain yellow solidN -(the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) Acrylamide, yield 78.2%, 144 ~ 145 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：8.96（S, 1H, CONH）, 7.39（D,J =2.0 Hz, 1H, C6H33-H）, 7.16（Dd,J =8.4 Hz,J =2.0 Hz, 1H, C6H35-H）, 7.04 （D,J =8.4 Hz, 1H, C6H36-H）, 6.50（D,J =16.8 Hz, 1H, COCH）, 6.22（Dd,J =16.8 Hz,J = 10.4 Hz, 1H ,=CH2）, 5.87（D,J =10.4 Hz, 1H ,=CH2）, 4.27（S, 2H, CH2）, 1.34（S, 9H, 3 × CH3）.
Embodiment 6
NThe preparation of-(the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) crotonamide
According to the preparation method of embodiment 1,2.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (2,4- benzyl dichlorides Base) thiazol-2-yl) crotonamide, yield 58.1%, 172 ~ 173 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：8.85 （S, 1H, CONH）, 7.39（D, 1H,J =2.0 Hz, C6H33-H）, 7.16（Dd, 1H,J =8.4 Hz,J =2.0 Hz, C6H35-H）, 7.10（Dd, 1H,J =15.2 Hz, CH3 CHCH）, 7.04（D, 1H,J =8.4 Hz, C6H36-H）, 5.92 （Dd, 1H,J =15.2 Hz,J =1.6 Hz, COCHCH）, 4.26（S, 2H, CH2）, 1.93（Dd, 3H,J =1.6 Hz, CH3）, 1.34（S, 9H, 3 × CH3）.
Embodiment 7
NThe preparation of-(the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) Pyrusussuriensiss amide
According to the preparation method of embodiment 3,3.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (2,4- benzyl dichlorides Base) thiazol-2-yl) Pyrusussuriensiss amide, yield 85.7%, 165 ~ 166 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：7.39 （D, 1H,J =2.0 Hz, C6H33-H）, 7.38 ~ 7.33（M, 1H, COCH=CH）, 7.16（Dd, 1H,J =8.4 Hz,J = 2.0 Hz, C6H35-H）, 7.04（D, 1H,J =8.4 Hz, C6H36-H）, 6.22 ~ 6.20（M, 2H,J =4.4 Hz, CH= CH）, 5.84（D, 1H, COCH）, 4.26（S, 2H, CH2）, 1.87（D, 1H,J =4.4 Hz, CH3）, 1.34（S, 9H, 3 × CH3）.
Embodiment 8
NThe preparation of-(the 4- tert-butyl group-5- (2,4-dichloro benzyl) thiazol-2-yls) cinnamamide
According to the preparation method of embodiment 1,1.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group-5- (2,4-dichloros Benzyl) thiazol-2-yl) cinnamamide, yield 54.5%, 173 ~ 174 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：9.20 （S, 1H, CONH）, 7.82 ~ 7.05（M, 9H, C6H3, C6H5, C6H5CH）, 6.51（D, 1H, COCH）, 4.28（S, 2H, CH2）, 1.35（S, 9H, 3 × CH3）.
Embodiment 9
NThe preparation of-(the 4- tert-butyl group -5- (4- methoxy-benzyls) thiazol-2-yl) acrylamide
According to the preparation method of embodiment 1,2.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (4- methoxybenzyls Base) thiazol-2-yl) acrylamide, yield 86.6%, 147 ~ 148 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：7.11 （D, 2H,J =8.4 Hz, C6H4）, 6.81（D, 2H,J =8.4 Hz, C6H4）, 6.48（D, 1H,J =15.8 Hz, CH=）, 6.21（Dd, 1H,J =15.8 Hz,J =10.4 Hz ,=CH2）, 5.82（Dd, 1H,J =10.4 Hz,J =4.4 Hz ,= CH2）, 4.18（S, 2H, CH2）, 3.79（S, 1H, OCH3）, 1.36（S, 9H, 3 × CH3）.
Embodiment 10
NThe preparation of-(the 4- tert-butyl group -5- (4- methoxy-benzyls) thiazol-2-yl) crotonamide
According to the preparation method of embodiment 1,2.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (4- methoxybenzyls Base) thiazol-2-yl) crotonamide, yield 77.1%, 180 ~ 182 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：8.95 （S, 1H, CONH）, 7.11（D, 2H,J =8.4 Hz, C6H4）, 7.05（Dd, 1H,J =15.2 Hz,J =6.8 Hz, COCH）, 6.82（D, 2H,J =8.4 Hz, C6H4）, 5.91（Dd, 1H,J =15.2 Hz,J =2.0 Hz, CH）, 4.17（S, 2H, CH2）, 3.77（S, 3H, OCH3）, 1.92（Dd, 3H,J =6.8 Hz,J =2.0 Hz, CH3）, 1.37（S, 9H, 3 × CH3）.
Embodiment 11
NThe preparation of-(the 4- tert-butyl group -5- (4- methoxy-benzyls) thiazol-2-yl) cinnamamide
According to the preparation method of embodiment 1,2.0 h are reacted, yellow solid is obtainedN- (the 4- tert-butyl group -5- (4- methoxybenzyls Base) thiazol-2-yl) cinnamamide, yield 75.6%, 152 ~ 153 DEG C of m.p..1H NMR（400 MHz, CDCl3）δ：7.70 （D, 1H,J =15.6 Hz, CH）, 7.45（Dd, 2H, C6H52-H, 6-H）, 7.32（T, 3H, C6H53-H, 4-H, 5-H）, 7.06 （D, 2H,J =8.4 Hz, C6H4）, 6.77（D, 2H,J =8.4 Hz, C6H4）, 6.41（D, 1H,J =15.6 Hz, COCH）, 4.12（S, 2H, CH2）, 3.72（S, 3H, OCH3）, 1.31（S, 9H, 3 × CH3）.
Embodiment 12
N-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide and its anti-tumor activity of salt
1. anti-tumor activity principle
Mtt assay biological activity test, also known as MTT colorimetrys, is a kind of method of detection cell survival and growth.MTT is analyzed Method is with living cells metabolite reducing agent tetrazolium bromide [3-（4,5- dimethyl -2- thiazoles）- 2,5- diphenyl bromination tetrazole；3-（4, 5-dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide, MTT] based on.MTT is a kind of The dyestuff of hydrogen atom can be received.In living cells mitochondria, the MTT of yellow can be converted by the dehydrogenase in the cell related to NADP Into insoluble hepatic first a ceremonial jade-ladle, used in libation（formazon）, and dead cell is then without this function.After with DMSO dissolving formazon, one Optical density value is determined with microplate reader under standing wave length, both Crestor measured the survival rate of cell.Observed according to the change of optical density value Inhibitory action of the sample to tumor cell.
2. anti-tumor activity experiment
Sample：N-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide（I）And its salt：
I
In formula, R is selected from：C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, methyl, ethyl, hydroxyl Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, methyl, ethyl；N is selected from：1st, 2,3,4,5,6 or 7；Z is selected From：Hydrogen, methyl or phenyl.
Cell line：Lung adenocarcinoma cell line A549 and breast cancer cell line MCF-7（Xiangya Medical College, Zhongnan Univ cell bank is carried For）.
Reagent：Tetrazolium bromide（MTT）, RPMI RPMI-1640s, new-born calf serum, antibiotic（U.S.'s hero's life technology Company）；Pancreatin（AMRESCO companies of the U.S.）；96 well culture plates（Hero Life Technologies, Inc. of the U.S.）；Dimethyl sulfoxide（The U.S. Sigma companies）.
Instrument：HFsafe-1500 type superclean benches, HF151UV types CO2Incubator（Shanghai power Shen scientific instrument are limited Company）；XSP-15C type inverted microscopes（The rectangular optical instrument company limited in Shanghai）；Multiskan MK3 type microplate reader（Beautiful Thermo companies of state）；Ultra-pure water preparing instrument（Milli-Q companies of the U.S.）.
Experimental implementation：Test of the sample to A549 cells and MCF-7 cells.The experimental implementation process of every kind of cell is identical, In experimentation, per sample (p.s.) arranges 5 Concentraton gradient（0.010 μmol/mL、0.030 μmol/mL、0.100 μ Mol/mL, 0.300 μm of ol/mL and 1.000 μm of ol/mL）, four parallel samples of each concentration, per group of experiment are parallel 3 times, and Reached a conclusion by blank group control.Microplate reader detects each hole OD values, 570 nm of Detection wavelength.
3. antitumor activity evaluation
1）Cell inhibitory rate is calculated：
2）IC50Value is calculated
Sample solution concentration logarithm value and cell inhibitory rate linear regression, suppress dense using computed in software sample to the half of cell Degree IC50Value.N- (the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) acrylamide is to human lung adenocarcinoma cell（A549Carefully Born of the same parents）And human breast cancer cell（MCF-7 cells）IC50Respectively 64.0 μm ol/L and 52.0 μm of ol/L.
Active testing result shows,N-（4- alkyl -5- benzyl thiazol-2-yls）Acrylamide or its salt are thin to human lung adenocarcinoma Born of the same parents（A549 cells）And human breast cancer cell（MCF-7 cells）There is good inhibitory activity, can be used to prepare antitumor drug.

Claims (1)

1.N- (the 4- tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl) acrylamide or its salt are preparing human breast cancer cell Application in medicine；Salt is selected from：Hydrochlorate, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, to toluene sulphur Hydrochlorate.
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