CN102964312A - 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole as well as preparation method and application thereof - Google Patents

4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole as well as preparation method and application thereof Download PDF

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CN102964312A
CN102964312A CN 201210508742 CN201210508742A CN102964312A CN 102964312 A CN102964312 A CN 102964312A CN 201210508742 CN201210508742 CN 201210508742 CN 201210508742 A CN201210508742 A CN 201210508742A CN 102964312 A CN102964312 A CN 102964312A
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tertiary butyl
ethyl
aryl
nitre
nitre ethyl
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胡艾希
彭俊梅
申坤
李婉
颜晓维
方毅林
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Hunan University
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Hunan University
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Abstract

The invention relates to 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole and salts thereof shown in a chemical structure formula I disclosed in the specification, wherein Y1, Y2, Y3 and Y4 in the formula are selected from H, methyl, ethyl, hydroxyl, methoxyl, ethyoxyl, fluorine, chlorine, bromine, nitryl, trifluoromethyl or trifluoromethoxy; Z is selected from C1-C2 alkyl, C3-C4 linear or branched alkyl, alkyl containing chlorine C1-C2, linear or branched alkyl containing chlorine C3-C4 or aryl. 4,4-dimethyl-1-aryl-1-alkenyl-3-pentanone is added, halogenated and cyclized for preparing 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-amino thiazole; and the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole is acylated to obtain 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole. The invention also relates to an application of the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole and salts in preparation of anti-cancer drugs.

Description

The 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole and preparation method thereof and application
Technical field
The present invention relates to preparation method and the application of new compound, specifically the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-the synthetic application with as the preparation anticarcinogen of 2-acylaminothiazole.
Background technology
5-(4-the chlorophenylmethyl)-4-tertiary butyl-thiazolamine hydrobromate is that the compound that important medicine intermediate: 5-(4-the chlorophenylmethyl)-4-tertiary butyl-thiazolamine and aromatic aldehyde reaction obtain has biological activity, in pharmacy, use [Hunan University's journal natural science edition as cox 2 inhibitor, 2009,36(2), 70-74; Chinese invention patent, CN 101492426].Chinese invention patent (CN1018445026, CN101781269) has been described the 5-(4-chlorophenylmethyl)-4-tertiary butyl thiazole derivatives and the 4-tertiary butyl-2-(nitrobenzyl imino-) preparation of thiazole and the application of conduct preparation antitumor drug thereof.
Summary of the invention
The object of the present invention is to provide the 4-tertiary butyl shown in the chemical structural formula I-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole and salt thereof:
Figure BDA0000251622331
Y in the formula 1Be selected from: H, methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Y 2, Y 4Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Y 3Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Z is selected from: C 1~ C 2Alkyl, C 3~ C 4Straight or branched alkyl, chloride C 1~ C 2Alkyl, chloride C 3~ C 4The straight or branched alkyl or the aryl shown in the formula II:
Figure BDA0000251622332
R in the formula II 1, R 5Be selected from: H, methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R 2, R 4Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R 3Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Salt is selected from: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, mesylate, benzene sulfonate, tosilate.
The object of the present invention is to provide the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-kharophen thiazole hydrobromide salt or the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-propionamido thiazole hydrobromide salt.
Figure BDA0000251622333
The object of the present invention is to provide the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(the 4-chlorobenzoyl is amino) thiazole hydrobromide salt or the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] thiazole hydrobromide salt.
The object of the present invention is to provide the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt or the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt.
The object of the present invention is to provide the 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt or the 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt.
The object of the present invention is to provide the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-preparation method of 2-acylaminothiazole and salt thereof, it is characterized in that the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-thiazolamine and salt thereof makes the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl through acidylate)-2-acylaminothiazole and salt thereof; Preparation feedback is as follows:
Figure BDA0000251622337
Or
Figure BDA0000251622338
Or
Figure BDA0000251622339
The object of the present invention is to provide the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole or the application of its salt in the preparation anticarcinogen.
The present invention compared with prior art has following advantage:
The present invention has prepared the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl first)-2-acylaminothiazole and salt thereof.And find that it has antitumour activity.
Figure BDA00002516223310
Embodiment
Following examples are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of thiazolamine and hydrobromate thereof
Figure BDA00002516223311
(1) 5-(4-chloro-phenyl-)-2, the preparation of 2-dimethyl-6-nitro-3-hexanone
0.12 mol 4,4-dimethyl-1-(4-chloro-phenyl-)-1-thiazolinyl-propione, 150 mL methyl alcohol, 0.60 mol Nitromethane 99Min. and 0.30 mol diethylamine, reflux 19.5 h.Revolve the steaming solvent, rare HCl transfers pH to neutral, the dilution of 300 mL methylene dichloride, washing, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, leave standstill, filter, revolve the steaming methylene dichloride, get crude product, a small amount of sherwood oil/alcohol mixed solvent washing, drying, get the 5-(4-chloro-phenyl-)-2,2-dimethyl-6-nitro-3-hexanone, yield 54.9 %, m.p.68～70 ℃. 1H NMR(CDCl 3，400MHz) δ：1.08(s，9H，3×CH 3)，2.89(dd，J=17.6 Hz，J=7.2 Hz，1H，CH 2)，2.98(dd，J=17.6 Hz， J=7.2 Hz，1H，CH 2)，4.02～4.05 (m， H，CH)，4.60(dd，J=12.0 Hz，J=7.2 Hz，1H，O 2NCH 2)，4.68(dd，J=12.0 Hz，J=7.2 Hz，1H，O 2NCH 2)，7.17(d，J=8.0 Hz，2H，C 6H 4 2，6-H)，7.30(d，J=8.0 Hz，2H，C 6H 4 3，5-H)。
(2) 4-bromo-5-(4-chloro-phenyl-)-2, the preparation of 2-dimethyl-6-nitro-3-hexanone
0.01 mol 5-(4-chloro-phenyl-)-2,2-dimethyl-6-nitro-3-hexanone, 15 mL trichloromethanes and 3 acetone, stopped heating after the reflux drips the bromine that 0.012mol is dissolved in 5 mL trichloromethanes, keeps reaction solution to be blush, reacts 1.0 h.Cooling, revolve the steaming solvent, ethyl alcohol recrystallization gets 4-bromo-5-(4-chloro-phenyl-)-2,2-dimethyl-6-nitro-3-hexanone, yield 86.3%, m.p.117～119 ℃. 1H NMR(CDCl 3，400MHz)，δ：0.94(s，9H，3×CH 3)，4.22～4.29(m，1H，CH)， 4.76～4.89(m，2H，CH 2NO 2)，5.22(dd，J=13.6 Hz，J=4.8 Hz，1H，CHBr)，7.15(d，J=8.4 Hz，2H，C 6H 4 2，6-H)，7.29(d，J=8.4 Hz，2H，C 6H 4 3，5-H)。
(3) the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of thiazolamine hydrobromate
5.0 mmol 4-bromo-5-(4-chloro-phenyl-)-2,2-dimethyl-6-nitro-3-hexanone, 5.0 mmol thiocarbamides and 50 mL ethanol, stirring and refluxing 19.5 h are cooled to room temperature, revolve the steaming solvent, white solid is separated out in cooling, filters a small amount of washing with alcohol of filter cake, dry, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-the thiazolamine hydrobromate, yield 82.3 %, 179 ~ 182 ℃ of m.p.. 1H NMR(DMSO-d 6，400MHz)，δ：1.37(s，9H，3×CH 3)，5.21~5.24(m，1H，CH)，5.40~5.48 (m，2H，CH 2)，7.49(s，4H，C 6H 4)，8.64(br，2H，NH 2）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-the thiazolamine hydrobromate processes through sodium hydroxide solution and obtains the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine.
Embodiment 2
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-kharophen thiazole and hydrobromate thereof
Figure BDA00002516223312
0.8 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 3 mL diacetyl oxides, stirring and dissolving, 60 ℃ of reactions, TLC monitoring reaction.After reaction is finished, under stirring, reaction solution is poured in the frozen water, separated out white solid, filter, drying gets the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-kharophen thiazole hydrobromide salt, yield 53.5 %, 192 ~ 194 ℃ of m.p.. 1H NMR(DMSO-d 6，400MHz)，δ：1.35(s，9H，3×CH 3)，2.09(s，3H，COCH 3)，5.09(dd，J = 14.0 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.36(dd，J = 14.0 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.53(t，J = 8.0 Hz，1H，CH)，7.43(s，4H， C 6H 4Cl)，11.96(br，1H，NHCO）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-kharophen thiazole hydrobromide salt processes through pyridine and obtains the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-kharophen thiazole.
Embodiment 3
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-propionamido thiazole and hydrobromate thereof
0.8 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 3 mL propionic anhydrides, stirring and dissolving, 60 ℃ of reactions, TLC monitoring reaction.After reaction is finished, add 30 mL water, 2 * 30 mL dichloromethane extractions merge organic phase, anhydrous sodium sulfate drying, leave standstill, filter, revolve the steaming solvent, cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-propionamido thiazole hydrobromide salt, yield 35.5 %, 146 ~ 148 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.25(t，J = 7.2 Hz，3H，CH 3)，1.38(s，9H，3×CH 3)，2.46(q，J = 7.2 Hz，2H，CH 2)，4.80(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.93(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.61(t，J = 8.0 Hz，1H，CH)，7.27(d，J = 8.8 Hz，2H，C 6H 4Cl 2,6-H)，7.32(d，J = 8.8 Hz，2H，C 6H 4Cl 3,5-H)，8.78(br，1H，NHCO）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-propionamido thiazole hydrobromide salt processes through sodium hydrogen carbonate solution and obtains the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-propionamido thiazole.
Embodiment 4
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-chloro acetylamino thiazole
Figure BDA00002516223314
1.2 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 20 mL tetrahydrofuran (THF)s, stirring and dissolving, add 0.4 mL pyridine, drip the chloroacetyl chloride that 0.4 mL is dissolved in 10 mL tetrahydrofuran (THF)s under the ice bath, about 30 min drip off, transfer room temperature reaction to, the TLC monitoring reaction.After reaction is finished, separate out white solid, filter, washing, drying gets the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-chloro acetylamino thiazole, yield 19.8 %, 145 ~ 147 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.40(s，9H，3×CH 3)，4.25(s，2H，CH 2)，4.81(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.94(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.63(t，J = 8.0 Hz，1H，CH)，7.27(d，J = 8.8 Hz，2H，C 6H 4Cl 2,6-H)，7.32(d，J = 8.8 Hz，2H，C 6H 4Cl 3,5-H)，9.45(br，1H，NHCO）。
Embodiment 5
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(3,5-dinitrobenzene formamido group) thiazole and hydrobromate thereof
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 3,5-dinitrobenzoic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt, yield 30.2 %, 160 ~ 163 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.50(s，9H，3×CH 3)，4.88(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.98(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.60(t，J = 8.0 Hz，1H，CH)，7.30(d，J = 8.4 Hz，2H，C 6H 4 2,6-H)，7.38(d，J = 8.4 Hz，2H，C 6H 4 3,5-H)，9.22(s，1H，C 6H 3 4-H)，9.29(s，2H，C 6H 3 2,6-H）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt is processed through sodium carbonate solution and is obtained the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole.
Embodiment 6
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] preparation of thiazole and hydrobromate thereof
Figure BDA00002516223316
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 3,5-two trifluoromethylbenzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] thiazole hydrobromide salt, yield 18.7 %, 94 ~ 97 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.45(s，9H，3×CH 3)，4.86(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.98(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.64(t，J = 8.0 Hz，1H，CH)，7.30(d，J = 8.8 Hz，2H，C 6H 4 2,6-H)，7.36(d，J = 8.8 Hz，2H，C 6H 4 3,5-H)，8.10(s，1H，C 6H 3 4-H)，8.46(s，2H，C 6H 3 2,6-H）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] thiazole hydrobromide salt processes through sodium carbonate solution and makes the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] thiazole.
Embodiment 7
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] preparation of thiazole and hydrobromate thereof
Figure BDA00002516223317
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol o-trifluoromethyl phenylformic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] thiazole hydrobromide salt, yield 20.1 %, 105 ~ 108 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.32(s，9H，3×CH 3)，4.97(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.22(dd，J = 13.6 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.64(t，J = 8.0 Hz，1H，CH)，7.40~7.45(m，5H，C 6H 4Cl，C 6H 4CF 3 5-H)，7.55~7.62(m，3H，C 6H 4CF 3 3,4,6-H）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] the treated ammoniacal liquor of thiazole hydrobromide salt obtains the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] thiazole.
Embodiment 8
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 2,6-difluoro-benzoic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt, yield 39.7 %, 185 ~ 188 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.40(s，9H，3×CH 3)，4.83(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.97(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.64(t，J = 8.0 Hz，1H，CH)，7.04(t，J = 8.4 Hz，2H，C 6H 3 3,5-H)，7.30(d，J = 8.8 Hz，2H，C 6H 4 2,6-H)，7.34(d，J = 8.8 Hz，2H，C 6H 4 3,5-H)，7.48~7.54(m，1H，C 6H 3 4-H）。
Embodiment 9
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(4-dinitrobenzene formamido group) thiazole hydrobromide salt
Figure BDA00002516223319
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol p-nitrobenzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(4-dinitrobenzene formamido group) thiazole hydrobromide salt, yield 37.0 %, 131 ~ 133 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.44(s，9H，3×CH 3)，4.86(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.98(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.65(t，J = 8.0 Hz，1H，CH)，7.30(d，J = 8.8 Hz，2H，C 6H 4Cl 2,6-H)，7.35(d，J = 8.8 Hz，2H，C 6H 4Cl 3,5-H)，8.16(d，J = 8.8 Hz，2H，C 6H 4NO 2 2,6-H)，8.39(d，J = 8.8 Hz，2H，C 6H 4NO 2 3,5-H）。
Embodiment 10
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(2-methyl-3-nitro benzamido) thiazole hydrobromide salt
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 2-methyl 3-nitrobenzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(2-methyl-3-nitro benzamido) thiazole hydrobromide salt, yield 25.4 %, 84 ~ 87 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.42(s，9H，3×CH 3)，2.61(s，3H，CH 3)，4.85(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.98(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.66(t，J = 8.0 Hz，1H，CH)，7.31(d，J = 8.8 Hz，2H，C 6H 4 2,6-H)，7.36(d，J = 8.8 Hz，2H，C 6H 4 3,5-H)，7.47(t，J = 8.0 Hz，1H，C 6H 3 5-H)，7.74(d，J = 8.0 Hz，1H，C 6H 3 6-H)，7.95(d，J = 8.0 Hz，1H，C 6H 3 4-H)，9.11(br，1H，NHCO）。
Embodiment 11
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(2-methoxybenzoyl amino) thiazole hydrobromide salt
Figure BDA00002516223321
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol o-methoxybenzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(the 2-methoxybenzoyl is amino) thiazole hydrobromide salt, yield 17.3 %, 73 ~ 76 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.43(s，9H，3×CH 3)，4.11(s，3H，OCH 3)，4.84(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.97(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.63(t，J = 8.0 Hz，1H，CH)，7.06(d，J = 8.0 Hz，1H，C 6H 4OCH 3 3-H)，7.13(t，J = 8.0 Hz，1H，C 6H 4OCH 3 5-H)，7.32(s，4H，C 6H 4Cl)，7.56(t，J = 8.0 Hz，1H，C 6H 4OCH 3 4-H)，8.26(d，J = 8.0 Hz，1H，C 6H 4OCH 3 6-H)，10.91(br，1H，NHCO）。
Embodiment 12
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(4-chlorobenzoyl amino) thiazole hydrobromide salt
Figure BDA00002516223322
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol Chlorodracylic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(the 4-chlorobenzoyl is amino) thiazole hydrobromide salt, yield 15.2 %, 115 ~ 119 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.44(s，9H，3×CH 3)，4.85(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.97(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.65(t，J = 8.0 Hz，1H，CH)，7.29 (d，J = 8.4 Hz，2H，C 6H 4Cl 2,6-H)，7.34(d，J = 8.4 Hz，2H，C 6H 4Cl 3,5-H)，7.50(d，J = 8.0 Hz，2H，NHCOC 6H 4Cl 3,5-H)，7.94(d，J = 8.0 Hz，2H，NHCOC 6H 4Cl 2,6-H）。
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(4-chlorobenzoyl amino) thiazole hydrobromide salt makes the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl through ammonia treatment]-2-(the 4-chlorobenzoyl is amino) thiazole.
Embodiment 13
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(2,6-dichloro-benzoyl amino) thiazole hydrobromide salt
Figure BDA00002516223323
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 2,6-dichlorobenzoic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(2,6-dichloro-benzoyl is amino) thiazole hydrobromide salt, yield 41.5 %, 101 ~ 104 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.41(s，9H，3×CH 3)，4.84(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.99(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.64(t，J = 8.0 Hz，1H，CH)，7.26~7.38 (m，7H，C 6H 4，C 6H 3)，9.06(br，1H，NHCO）。
Embodiment 14
The 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-preparation of 2-(2-chlorobenzoyl amino) thiazole hydrobromide salt
Figure BDA00002516223324
0.75 the mmol 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 0-chloro-benzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(the 2-chlorobenzoyl is amino) thiazole hydrobromide salt, yield 22.1 %, 95 ~ 98 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.40(s，9H，3×CH 3)，4.84(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，4.97(dd，J = 13.2 Hz，J = 8.0 Hz，1H，CH 2NO 2)，5.64(t，J = 8.0 Hz，1H，CH)，7.30~7.35(m，4H，C 6H 4Cl)，7.40~7.42(m，1H，NHCOC 6H 4Cl 6-H)，7.47~7.49(m，2H，NHCOC 6H 4Cl 4,5-H)，7.82(d，J = 7.6 Hz，1H，NHCOC 6H 4Cl 3-H)，9.51(br，1H，NHCO）。
Embodiment 15
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-preparation of thiazolamine and hydrobromate thereof
Figure BDA00002516223325
(1) 5-(2, the 4-dichlorophenyl)-2, the preparation of 2-dimethyl-6-nitro-3-hexanone
0.01 mol 4,4-dimethyl-1-(2,4-dichlorophenyl)-1-thiazolinyl-propione and 20 mL ethanol, stir lower add 0.05 mol Nitromethane 99Min. and 0.001 mol salt of wormwood, reflux 4.5 h.Cooling, 20 mL water place refrigerator to place and spend the night, and separate out white solid, filter, drying gets 5-(2, the 4-dichlorophenyl)-2,2-dimethyl-6-nitro-3-hexanone, yield 88.1%, 84 ~ 86 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.12(s，9H，3×CH 3)，3.03～3.06(m，2H，CH 2)，4.42～4.43(m，1H，CH)，4.75(d，J=6.0 Hz，2H，CH 2NO 2)，7.15(d，J=8.4 Hz，1H，C 6H 3 6-H)，7.22 (dd，J=8.4 Hz，J=2.0 Hz，1H，C 6H 3 5-H)，7.42(d，J=2.0 Hz，1H，C 6H 3 3-H)。
(2) 4-bromo-5-(2, the 4-dichlorophenyl)-2, the preparation of 2-dimethyl-6-nitro-3-hexanone
0.01 mol 5-(2, the 4-dichlorophenyl)-2,2-dimethyl-6-nitro-3-hexanone, 15 mL trichloromethanes and 3 acetone, stopped heating after the reflux, drip the bromine that 0.012mol is dissolved in 5 mL trichloromethanes, keep reaction solution to be blush, stopped reaction behind 1.0 h.The steaming solvent is revolved in cooling, crosses post, gets 4-bromo-5-(2, the 4-dichlorophenyl)-2,2-dimethyl-6-nitro-3-hexanone. 1H NMR(CDCl 3，400MHz)，δ：1.11(s，9H，3×CH 3)，4.53～4.58(m，1H，CH)，5.11～5.16(m，2H，CH 2)，5.30(dd，J=13.6 Hz，J=4.4 Hz，1H，CHBr)，7.23～7.26(m，2H，C 6H 3 5，6-H)，7.41(s，1H，C 6H 3 3-H)。
(3) the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-preparation of thiazolamine hydrobromate
10.0 mmol 4-bromo-5-(2, the 4-dichlorophenyl)-2,2-dimethyl-6-nitro-3-hexanone, 11.0 mmol thiocarbamides and 50 mL ethanol stir reflux, react 19 h, be cooled to room temperature, revolve the steaming solvent, cross post and get the 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-the thiazolamine hydrobromate, yield 25.1 %. 1H NMR(CDCl 3，400MHz)，δ：1.29(s，9H，3×CH 3)，4.55(dd，J = 13.6 Hz，J = 9.6 Hz，1H，CH 2NO 2)，4.86(dd，J = 13.6 Hz，J = 9.6 Hz，1H，CH 2NO 2)，5.13(br，2H，NH 2)，5.88(t，J = 9.6 Hz，1H，CH)，7.25 (dd，J = 8.4 Hz，J = 2.0 Hz，1H，C 6H 3 5-H)，7.34(d，J = 8.4 Hz，1H，C 6H 3 6-H)，7.45(d，J = 2.0 Hz，1H，C 6H 3 3-H）。
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-the thiazolamine hydrobromate processes through pyridine and obtains the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-thiazolamine.
Embodiment 16
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-preparation of 2-(3,5-dinitrobenzene formamido group) thiazole hydrogen and bromate thereof
Figure BDA00002516223326
0.75 the mmol 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 3,5-dinitrobenzoic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h adds 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt, yield 14.2 %, 138 ~ 140 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.42(s，9H，3×CH 3)，4.78(dd，J = 14.0 Hz，J = 10.0 Hz，1H，CH 2NO 2)，4.93(dd，J = 14.0 Hz，J = 6.0 Hz，1H，CH 2NO 2)，5.60(q，J = 10.0 Hz，J = 6.0 Hz，1H，CH)，7.29(dd，J = 8.4 Hz，J = 2.4 Hz，1H，C 6H 3 5-H)，7.38(d，J = 8.4 Hz，1H，C 6H 3 6-H)，7.50(d，J = 2.4 Hz，1H，C 6H 3 3-H)，9.21(t，J = 2.4 Hz，1H， NHCOC 6H 3 4-H)，9.27(d，J = 2.4 Hz，2H，NHCOC 6H 3 2，6-H）。
The 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt makes the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl through ammonia treatment]-2-(3,5-dinitrobenzene formamido group) thiazole.
Embodiment 17
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] preparation of thiazole hydrobromide salt
0.75 the mmol 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol o-trifluoromethyl phenylformic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-[2-(trifluoromethyl) benzamido] thiazole hydrobromide salt, yield 8.9 %, 91 ~ 93 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.36(s，9H，3×CH 3)，4.75(dd，J = 14.0 Hz，J = 9.2 Hz，1H，CH 2NO 2)，4.94(dd，J = 14.0 Hz，J = 6.4 Hz，1H，CH 2NO 2)，5.60(q，J = 9.2 Hz，J = 6.4 Hz，1H，CH)，7.29(dd，J = 8.4 Hz，J = 2.0 Hz，1H，C 6H 3 5-H)，7.39(d，J = 8.4 Hz，1H，C 6H 3 6-H)，7.48(d，J = 2.0 Hz，1H，C 6H 3 3-H)，7.65～7.70(m，4H，C 6H 4）。
Embodiment 18
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-preparation of 2-(2,6-difluorobenzene formamido group) thiazole and hydrobromate thereof
Figure BDA00002516223328
0.75 the mmol 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol 2,6-difluoro-benzoic acid and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h adds 1.0 mmol N, N '-dicyclohexylcarbodiimide, the TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt, yield 10.1 %, 92 ~ 94 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.34(s，9H，3×CH3)，4.74(dd，J = 14.0 Hz，J = 9.2 Hz，1H，CH 2NO 2)，4.93(dd，J = 14.0 Hz，J = 6.4 Hz， 1H，CH 2NO 2)，5.64(q，J = 9.2 Hz，J = 6.4 Hz， 1H，CH)，7.25～7.28(m，1H，C 6H 3 5-H)，7.38(d，J = 8.8 Hz，1H，C 6H 3 6-H)，7.46(d，J = 2.0 Hz，1H，C 6H 3 3-H)，7.03～7.07 (m，2H，NHCOC 6H 3 3，5-H)，7.49～7.53 (m，1H，NHCOC 6H 3 4-H)，9.33(br，1H，NHCO）。
The 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt is processed through pyridine and is made the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole.
Embodiment 19
The 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-preparation of 2-(4-nitrobenzoyl amido) thiazole hydrobromide salt
Figure BDA00002516223329
0.75 the mmol 4-tertiary butyl-5-[1-(2, the 4-dichlorophenyl)-2-nitre ethyl]-thiazolamine hydrobromate, 1.0 mmol p-nitrobenzoic acids and 40 mL methylene dichloride, stirring at room, add 0.125 mmol DMAP, stirring reaction 0.5 h, add 1.0 mmol N, N '-dicyclohexylcarbodiimide, TLC monitoring reaction.After reaction is finished, remove by filter the part dicyclohexylurea (DCU), cross post, get the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(4-nitrobenzoyl amido) thiazole hydrobromide salt, yield 5.9 %, 141 ~ 143 ℃ of m.p.. 1H NMR(CDCl 3，400MHz)，δ：1.35(s，9H，3×CH 3)，4.75(dd，J = 13.6 Hz，J = 9.6 Hz，1H，CH 2NO 2)，4.94(dd，J = 13.6 Hz，J = 6.0 Hz，1H，CH 2NO 2)，6.02(q，J = 9.6 Hz，J = 6.0 Hz，1H，CH)，7.26(dd，J = 8.8 Hz，J = 2.0 Hz，1H，C 6H 3 5-H)，7.36(d，J = 8.8 Hz，1H，C 6H 3 6-H)，7.48(d，J = 2.0 Hz，1H，C 6H 3 3-H)，8.15(d，J = 8.4 Hz，2H，C 6H 4 2,6-H)，8.38(d，J = 8.4 Hz，2H，C 6H 4 3,5-H)，9.84(br，1H，NHCO）。
Embodiment 20
The 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-anti-tumor activity of acylaminothiazole and salt thereof
1. anti-tumor activity principle
The mtt assay biological activity test claims again the MTT colorimetry, is a kind of method that detects cell survival and growth.The MTT analytical method is with viable cell metabolite reductive agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-phenylbenzene bromination tetrazole; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] be the basis.MTT is a kind of dyestuff that can accept hydrogen atom.Desaturase relevant with NADP in the viable cell plastosome can change into the MTT of yellow insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) in cell, dead cell is then without this function.Behind DMSO dissolving formazon, under certain wavelength, measure optical density value with microplate reader, both can quantitatively measure the survival rate of cell.Observe sample to the restraining effect of tumour cell according to the variation of optical density value.
2. anti-tumor activity experiment
Sample: the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole and salt thereof.
Clone: cervical cancer tumer line Hela; Lung adenocarcinoma cell line A549 and hepatoma cell line Bel7402(Xiangya Medical College, Zhongnan Univ cell bank provide).
Reagent: tetrazolium bromide (MTT), RPMI RPMI-1640, new-born calf serum, microbiotic (U.S. hero Life Technologies, Inc.); Pancreatin (U.S. AMRESCO company); 96 well culture plates (U.S. hero Life Technologies, Inc.); Dimethyl sulfoxide (DMSO) (U.S. Sigma company).
Instrument: HFsafe-1500 type Bechtop, HF151UV type CO 2Incubator (Shanghai Lishen Scientific Equipment Co., Ltd.); XSP-15C type inverted microscope (the rectangular opticinstrument in Shanghai company limited); Multiskan MK3 type microplate reader (U.S. Thermo company); Ultrapure water preparing instrument (U.S. Milli-Q company).
Experimental implementation: sample is for the test of Hela cell, A549 cell and Bel7402 cell.The experimental implementation process of every kind of cell is identical, in the experimentation, per sample (p.s.) arranges 5 concentration gradients (0.010 μ mol/mL, 0.030 μ mol/mL, 0.100 μ mol/mL, 0.300 μ mol/mL and 1.000 μ mol/mL), four parallel samples of each concentration, test parallel 3 times for every group, and reach a conclusion by the contrast of blank group.Microplate reader detects each hole OD value, detects wavelength 570 nm.
3. anti-tumor activity evaluation
1) cell inhibitory rate calculates:
Figure BDA00002516223330
2) IC 50Value is calculated
Sample solution concentration logarithmic value and cell inhibitory rate linear regression utilize the computed in software sample to the half-inhibition concentration IC of cell 50Value.Preferred compound is for the IC of Hela cell, A549 cell and Bel7402 cell 50See Table 1 ~ 3.
The table 1 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-inhibition of 2-acylaminothiazole or its salt pair Hela cell is active
Figure BDA00002516223331
The table 2 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-inhibition of 2-acylaminothiazole salt pair A549 cell is active
Figure BDA00002516223332
The table 3 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-inhibition of 2-acylaminothiazole or its salt pair Bel7402 cell is active
Figure BDA00002516223333
The active testing result shows, the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-that 2-acylaminothiazole or its salt have a good inhibition for cervical cancer cell (Hela cell), human lung adenocarcinoma cell (A549 cell) and human liver cancer cell (Bel7402 cell) is active, can be used for exploitation preparation antitumor drug.

Claims (10)

1. the tertiary butyl of the 4-shown in the chemical structural formula I-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole or its salt:
Figure FDA0000251622321
Y in the formula 1Be selected from: H, methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Y 2, Y 4Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Y 3Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Z is selected from: C 1~ C 2Alkyl, C 3~ C 4Straight or branched alkyl, chloride C 1~ C 2Alkyl, chloride C 3~ C 4The straight or branched alkyl or the aryl shown in the formula II:
Figure FDA0000251622322
R in the formula II 1, R 5Be selected from: H, methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R 2, R 4Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; R 3Be selected from: H, methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl or trifluoromethoxy; Salt is selected from: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, mesylate, benzene sulfonate, tosilate.
2. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-kharophen thiazole hydrobromide salt or the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-propionamido thiazole hydrobromide salt.
Figure FDA0000251622323
3. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(the 4-chlorobenzoyl is amino) thiazole hydrobromide salt.
4. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-[3,5-two (trifluoromethyl) benzamido] thiazole hydrobromide salt.
Figure FDA0000251622325
5. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt.
Figure FDA0000251622326
6. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(4-chloro-phenyl-)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt.
Figure FDA0000251622327
7. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(3,5-dinitrobenzene formamido group) thiazole hydrobromide salt.
Figure FDA0000251622328
8. the described 4-tertiary butyl of claim 1-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole salt is the 4-tertiary butyl-5-[1-(2,4 dichloro benzene base)-2-nitre ethyl]-2-(2,6-difluorobenzene formamido group) thiazole hydrobromide salt.
Figure FDA0000251622329
9. each described 4-tertiary butyl-5-(1-aryl-2-nitre ethyl in the claim 1 ~ 8)-preparation method of 2-acylaminothiazole or its salt, it is characterized in that the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-preparation method of 2-acylaminothiazole is the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole and hydrobromate thereof make the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl through acidylate)-2-acylaminothiazole and hydrobromate thereof; The 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylaminothiazole hydrobromate makes the 4-tertiary butyl-5-(1-aryl-2-nitre ethyl through neutralization)-the 2-acylaminothiazole; Preparation feedback is as follows:
Figure FDA00002516223210
Or
Figure FDA00002516223211
Or
Figure FDA00002516223212
Y in the formula 1, Y 2, Y 3, Y 4, Z definition as claimed in claim 1.
10. each described 4-tertiary butyl-5-(1-aryl-2-nitre ethyl in the claim 1 ~ 8)-2-acylaminothiazole or the application of its salt in the preparation cancer therapy drug.
CN 201210508742 2012-12-03 2012-12-03 4-tertiary butyl-5-(1-aryl-2-nitre ethyl)-2-acylamino thiazole as well as preparation method and application thereof Pending CN102964312A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601697A (en) * 2012-12-03 2014-02-26 湖南大学 4-tertiary butyl-5-(2-nitroethyl)-2-acylamino thiazole and preparation method and application thereof
CN104771398A (en) * 2014-01-09 2015-07-15 湖南大学 N-[5-(2-nitro ethyl)thiazole-2-yl]benzamide, and pharmaceutical applications thereof
CN105017174A (en) * 2015-07-13 2015-11-04 南华大学 N- (4-alkyl-5-benzyl thiazole-2-base) enoyl-amine and preparation method and application thereof
CN105078977A (en) * 2015-08-31 2015-11-25 南华大学 Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601697A (en) * 2012-12-03 2014-02-26 湖南大学 4-tertiary butyl-5-(2-nitroethyl)-2-acylamino thiazole and preparation method and application thereof
CN104771398A (en) * 2014-01-09 2015-07-15 湖南大学 N-[5-(2-nitro ethyl)thiazole-2-yl]benzamide, and pharmaceutical applications thereof
CN104771398B (en) * 2014-01-09 2017-01-18 湖南大学 N-[5-(2-nitro ethyl)thiazole-2-yl]benzamide, and pharmaceutical applications thereof
CN105017174A (en) * 2015-07-13 2015-11-04 南华大学 N- (4-alkyl-5-benzyl thiazole-2-base) enoyl-amine and preparation method and application thereof
CN105017174B (en) * 2015-07-13 2017-03-15 南华大学 N‑（4 alkyl, 5 benzyl thiazole, 2 base）Acrylamide and preparation method and application
CN105078977A (en) * 2015-08-31 2015-11-25 南华大学 Application of 5-(2-nitro ethyl) thiazole derivatives as anticancer drug

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