CN102603728A - 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof - Google Patents
4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof Download PDFInfo
- Publication number
- CN102603728A CN102603728A CN2012100525462A CN201210052546A CN102603728A CN 102603728 A CN102603728 A CN 102603728A CN 2012100525462 A CN2012100525462 A CN 2012100525462A CN 201210052546 A CN201210052546 A CN 201210052546A CN 102603728 A CN102603728 A CN 102603728A
- Authority
- CN
- China
- Prior art keywords
- triazol
- thiazole
- alkyl
- amino
- tertiary butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 Cc1c(*)c(*)c(*)c(*)c1Nc1nc(*)c(-[n]2ncnc2)[s]1 Chemical compound Cc1c(*)c(*)c(*)c(*)c1Nc1nc(*)c(-[n]2ncnc2)[s]1 0.000 description 2
- FORBXFFOHUJHJN-UHFFFAOYSA-N CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc(cc2)ccc2OC)n1 Chemical compound CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc(cc2)ccc2OC)n1 FORBXFFOHUJHJN-UHFFFAOYSA-N 0.000 description 1
- SPKQEDWBWLZEEN-UHFFFAOYSA-N CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc2ccc(C)cc2)n1 Chemical compound CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc2ccc(C)cc2)n1 SPKQEDWBWLZEEN-UHFFFAOYSA-N 0.000 description 1
- VCFVPBLKZHOWPP-UHFFFAOYSA-N CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc2cccc(C)c2)n1 Chemical compound CC(C)(C)c1c(-[n]2ncnc2)[s]c(Nc2cccc(C)c2)n1 VCFVPBLKZHOWPP-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole shown as a chemical structural formula I and a salt thereof. The chemical structural formula I is shown in the specifications, wherein R is selected from H, alkyl with 1-2 carbon atoms, or straight chain alkyl or branch chain alkyl with 3-4 carbon atoms; and X1, X2, X3, X4 and X5 is selected from hydrogen, alkyl with 1-2 carbon atoms, hydroxyl, methoxyl, oxethyl, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino. A preparation method of the 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole comprises the following steps of: feeding 2-(1,2,4-triazol-1-yl)-2-bromoalkylketone and aryl thiourea in the molar ratio of 1:1, and carrying out a reflux reaction in ethanol; and after reacting, distilling under reduced pressure to remove a solvent, adding ethyl acetate for washing, filtering, drying to obtain 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole hydrobromide, neutralizing the hydrobromide with ammonia water, extracting with ethyl acetate, drying, and distilling under reduced pressure to obtain 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole. The 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole has high antitumor activity, and can be applied to preparation of an anticancer medicament.
Description
Technical field
The present invention relates to one type of new compound, specifically is 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and preparation method thereof and as the application of cancer therapy drug.
Background technology
The azole Hete rocyclic derivatives is high with its good biological activity and drug effect; Fungicidal spectrum is wide; Characteristics such as interior absorption is good receive medicine and agricultural chemicals worker's attention [Comperhensive Heterocylic Chemistry.Pergamon Oxford, 1983 always very much; 5:733-735], and triazole class is wherein comparatively influential one type.The bactericidal mechanism of triazole class sterilant is the formation that influences fungal cell wall through the biosynthesizing that hinders the fungi ergosterol, and most fungal diseases that damage to crops is grown all have good control effect.The triazole class sterilant has certain plant growth regulating activity [agricultural chemicals, 1994,33 (4): 19-20 simultaneously; J Med Chem, 1996,39 (12): 842-849],, eliminate the plant apical dominance, multiple functions such as having raising the output, precocity, resist, be degeneration-resistant through suppressing the synthetic of plant materials inner gibberellin.The triazole class sterilant is compared with other sterilant, has characteristics such as efficient, wide spectrum, low toxicity, low resistance, economic benefits and social benefits property (sterilization, control long), becomes the most promising sterilant type [agricultural chemicals, 1989,28 (1): 48-52].Shao Ling etc. have described 4-aryl-5-triazolyl thiazole-2-imine compound, and the biological activity determination result shows that part of compounds has fungicidal activity (SCI, 2007,28,270) to apple wheel line bacterium.The 4-tertiary butyl-5-(1,2, the 4-triazol-1-yl)-2-benzyl imino-thiazole preparation and fungicidal activity, insecticidal activity and anti-tumor activity are described [organic chemistry, 2010,30 (6): 923-927; CN101602761; CN201010290133.9; CN101836979].4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and preparation method and and do not research and develop report as the application of cancer therapy drug.
Designing and preparing of the present invention 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole novel cpd.
Summary of the invention
The object of the present invention is to provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and salt thereof.
Wherein, R is selected from: H, C
1~C
2Alkyl, C
3~C
4Straight chained alkyl or branched-chain alkyl; X
1Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
2Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
3Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
4Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
5Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; Its salt is selected from hydrochloride, hydrobromate, nitrate salt, vitriol, phosphoric acid salt, mesylate, tosilate, tartrate, lactic acid salt or malate.
The objective of the invention is to also provide the preparation method of 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole, its preparation comprises the steps:
2-(1,2, the 4-triazol-1-yl)-2-bromine alkyl ketone and aryl thiourea feed intake by 1: 1 mol ratio, react in reflux in ethanol.Reaction is complete, and underpressure distillation removes and desolvates, and adds the ETHYLE ACETATE washing, filters, and drying gets 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and drying, underpressure distillation gets 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole; Preparation is undertaken by following reaction formula:
In the reaction formula, R is selected from: H, C
1~C
2Alkyl, C
3~C
4Straight chained alkyl or branched-chain alkyl; X
1Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
2Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
3Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
4Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
5Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; Its salt is selected from hydrochloride, hydrobromate, nitrate salt, vitriol, phosphoric acid salt, mesylate, tosilate, tartrate, lactic acid salt or malate.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-phenylamino-5-(1,2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 4-anisole is amino)-5-(1,2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 2-chlorobenzene is amino)-5-(1; 2,4-triazol-1-yl) thiazole, the 4-tertiary butyl-2-(the 4-chlorobenzene is amino)-5-(1,2; The 4-triazol-1-yl) thiazole or the 4-tertiary butyl-2-(2; The 3-dichlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 2-bromobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1; 2; The 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 3-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole or the 4-tertiary butyl-2-(the 4-methylbenzene is amino)-5-(1; 2, the 4-triazol-1-yl) thiazole.
The objective of the invention is to also provide the 4-alkyl shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(2; The 4-xylidino)-5-(1; 2, the 4-triazol-1-yl) thiazole or the 4-tertiary butyl-2-(2, the 6-xylidino)-5-(1; 2, the 4-triazol-1-yl) thiazole.
The 4-alkyl that the object of the present invention is to provide-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole or its salt have good antineoplastic activity, can in the preparation cancer therapy drug, use.
The object of the present invention is to provide the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole crystalline structure.Its crystal belongs to rhombic system, and spacer is Pbca.Unit cell parameters is:
Z=8,
D
c=1.359g/cm
3, F (000)=1328, μ=0.223mm
-1, 2590 considerable measuring points [I>2 σ (I)], the final discrepancy factor R=0.034 of considerable measuring point refine, wR=0.097, (Δ/σ)
Max=0.001, S=1.05,
4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is that the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole crystalline structure atom is numbered as follows:
Description of drawings
Fig. 1 is the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole crystalline molecular structure.
Fig. 2 is the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole crystalline crystal accumulation figure.
The present invention compared with prior art has following advantage:
1. the present invention designs first and has prepared one type of 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole.
2. find first that 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and salt thereof have anti-tumor activity, can be used for preparing cancer therapy drug.
Embodiment
Following examples are intended to explain the present invention rather than to further qualification of the present invention.
The preparation of the 4-tertiary butyl-2-phenylamino-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
3,3-dimethyl--1-(1,2, the 4-triazol-1-yl)-1-bromo-2-butanone and phenylthiourea compounds feed intake by 1: 1 mol ratio, react in reflux in ethanol.Reaction is complete, and underpressure distillation removes and desolvates, and adds the ETHYLE ACETATE washing, filters, the dry 4-tertiary butyl-2-phenylamino-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt that gets; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation gets the 4-tertiary butyl-2-phenylamino-5-(1,2, the 4-triazol-1-yl) thiazole, 186~188 ℃ of fusing points.
1HNMR(CDCl
3,400MHz),δ:1.17(s,9H,3×CH
3),1.83(brs,1H,NH),7.10~7.40(m,5H,C
6H
5),8.10(s,1H,C
2H
2N
33-H),8.26(s,1H,C
2H
2N
35-H)。
Embodiment 2
The preparation of the 4-tertiary butyl-2-(the 3-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
Press the method for embodiment 1, reaction 9.0h; Get the 4-tertiary butyl-2-(the 3-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation gets the 4-tertiary butyl-2-(the 3-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 98~100 ℃ of fusing points;
1H NMR (CDCl
3, 400MHz), δ: 1.16 (s, 9H, 3 * CH
3), 2.36 (s, 3H, CH
3), 6.94 (d, J=8.0Hz, 1H, C
6H
44-H), 7.12 (d, J=6.4Hz, 1H, C
6H
46-H), 7.13 (s, 1H, C
6H
42-H), 7.25 (t, 1H, J=7.2Hz, 1H, C
6H
45-H), 8.08 (s, 1H, C
2H
2N
33-H), 8.24 (s, 1H, C
2H
2N
35-H).
Embodiment 3
The preparation of the 4-tertiary butyl-2-(the 4-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole
Press the method for embodiment 1, reaction 4.0h; Obtain the 4-tertiary butyl-2-(the 4-methylbenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 147~150 ℃ of fusing points;
1HNMR (CDCl
3, 400MHz), δ: 1.17 (s, 9H, 3 * CH
3), 2.34 (s, 3H, CH
3), 7.18 (d, J=8.8Hz, 2H, C
6H
53,5-H), 7.22 (d, J=8.8Hz, 2H, C
6H
52,6-H), 8.08 (s, 1H, C
2H
2N
33-H), 8.24 (s, 1H, C
2H
2N
35-H).
Embodiment 4
The preparation of the 4-tertiary butyl-2-(2, the 4-xylidino)-5-(1,2, the 4-triazol-1-yl) thiazole
Press the method for embodiment 1, reaction 1.5h; Obtain the 4-tertiary butyl-2-(2, the 4-xylidino)-5-(1,2, the 4-triazol-1-yl) thiazole; 169~172 ℃ of fusing points;
1HNMR (CDCl
3, 400MHz), δ: 1.15 (s, 9H, 3 * CH
3), 1.85 (brs, 1H, NH), 2.23 (s, 3H, CH
3), 2.25 (s, 3H, CH
3), 7.06~7.12 (m, 3H, C
6H
3), 8.07 (s, 1H, C
2H
2N
33-H), 8.23 (s, 1H, C
2H
2N
35-H).
Embodiment 5
The preparation of the 4-tertiary butyl-2-(2,6-YLENE is amino)-5-(1,2, the 4-triazol-1-yl) thiazole
Press the method for embodiment 1, reaction 1.5h; Obtain the 4-tertiary butyl-2-(2,6-YLENE is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 187~189 ℃ of fusing points;
1HNMR (CDCl
3, 400MHz), δ: 1.13 (s, 9H, 3 * CH
3), 2.35 (s, 6H, 2 * CH
3), 6.75 (brs, 1H, NH), 7.12~7.19 (m, 3H, C
6H
3), 8.02 (s, 1H, C
2H
2N
33-H), 8.20 (s, 1H, C
2H
2N
35-H).
Embodiment 6
The preparation of the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
Press the method for embodiment 1, reaction 5.0h; Get the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation obtains the 4-tertiary butyl-2-(2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole; 193~195 ℃ of fusing points;
1H NMR (DMSO, 400MHz), δ: 1.10 (s, 9H, 3 * CH
3), 7.03~7.30 (m, 3H, C
6H
4), 8.42 (t, J=8.0Hz, 1H, C
6H
43-H), 8.22 (s, 1H, C
2H
2N
33-H), 8.93 (s, 1H, C
2H
2N
35-H), 10.17 (brs, 1H, NH).
Embodiment 7
The preparation of the 4-tertiary butyl-2-(the 2-bromobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
Press the method for embodiment 1, reaction 7.0h; Get the 4-tertiary butyl-2-(the 2-bromobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation obtains the 4-tertiary butyl-2-(the 2-bromobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 139~141 ℃ of fusing points;
1H NMR (CDCl
3, 400MHz), δ: 1.18 (s, 9H, 3 * CH
3), 6.96 (t, J=7.6Hz, 1H, C
6H
45-H), 7.34 (t, J=7.6Hz, 1H, C
6H
44-H), 7.49 (brs, 1H, NH), 7.59 (d, J=7.6Hz, 1H, C
6H
46-H), 8.06 (d, J=7.6Hz, 1H, C
6H
43-H), 8.10 (s, 1H, C
2H
2N
33-H), 8.27 (s, 1H, C
2H
2N
35-H).
Embodiment 8
The preparation of the 4-tertiary butyl-2-(the 2-chlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
Press the method for embodiment 1, reaction 5.0h; Get the 4-tertiary butyl-2-(the 2-chlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation obtains the 4-tertiary butyl-2-(the 2-chlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 120~122 ℃ of fusing points;
1H NMR (CDCl
3, 400MHz), δ: 1.18 (s, 9H, 3 * CH
3), 7.02 (t, J=8.0Hz, 1H, C
6H
45-H), 7.30 (t, J=8.0Hz, 1H, C
6H
44-H), 7.42 (d, J=8.0Hz, 1H, C
6H
46-H), 7.52 (brs, 1H, NH), 8.07~8.27 (m, 3H, C
2H
2N
33,5-H, C
6H
43-H).
Embodiment 9
The preparation of the 4-tertiary butyl-2-(the 4-chlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole
Press the method for embodiment 1, reaction 7.0h; Obtain the 4-tertiary butyl-2-(the 4-chlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 198~200 ℃ of fusing points;
1HNMR (CDCl
3, 400MHz), δ: 116 (s, 9H, 3 * CH
3), 7.33 (m, 4H, C
6H
4), 8.09 (s, 1H, C
2H
2N
33-H), 8.26 (s, 1H, C
2H
2N
35-H).
Embodiment 10
The preparation of the 4-tertiary butyl-2-(2, the 3-dichlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole
Press the method for embodiment 1, reaction 1.5h; Obtain the 4-tertiary butyl-2-(2, the 3-dichlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 167~169 ℃ of fusing points;
1H NMR (CDCl
3, 400MHz), δ: 1.18 (s, 9H, 3 * CH
3), 7.18 (dd, J
1=8.0Hz, J
2=1.6Hz, 1H, C
6H
34-H), 7.23 (d, J=8.4Hz, 1H, C
6H
36-H), 7.63 (brs, 1H, NH), 8.08 (s, 1H, C
6H
35-H), 8.11 (s, 1H, C
2H
2N
33-H), 8.27 (s, 1H, C
2H
2N
35-H).
Embodiment 11
The preparation of the 4-tertiary butyl-2-(the 4-anisole is amino)-5-(1,2, the 4-triazol-1-yl) thiazole and hydrobromate thereof
Press the method for embodiment 1, reaction 8.0h; Get the 4-tertiary butyl-2-(the 4-anisole is amino)-5-(1,2, the 4-triazol-1-yl) thiazole hydrobromide salt; Hydrobromate neutralizes with ammoniacal liquor, ethyl acetate extraction, and underpressure distillation obtains the 4-tertiary butyl-2-(the 4-anisole is amino)-5-(1,2, the 4-triazol-1-yl) thiazole; 112~114 ℃ of fusing points;
1H NMR (CDCl
3, 400MHz), δ: 1.15 (s, 9H, 3 * CH
3), 3.81 (s, 3H, OCH
3), 6.90 (d, J=9.2Hz, 2H, C
6H
43,5-H), 7.04 (brs, 1H, NH), 7.27 (d, J=9.2Hz, 2H, C
6H
42,6-H), 8.06 (s, 1H, C
2H
2N
33-H), 8.22 (s, 1H, C
2H
2N
35-H).
Embodiment 12
The anti-tumor activity of 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole
1. anti-tumor activity principle
The mtt assay biological activity test is claimed the MTT colourimetry again, 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 Wasserstoffatoms.Desaturase relevant with NADP in the viable cell plastosome can change into insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) with xanchromatic MTT in cell, dead cell does not then have this function.Behind DMSO dissolving formazon, under certain wavelength, measure OD value with ELIASA, both can quantitatively measure the survival rate of cell.According to the variation observation sample of OD value restraining effect to tumour cell.
2. anti-tumor activity experiment
Sample: 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole.
Clone: cervical cancer tumer line Hela; Lung adenocarcinoma cell is A549 (the Xiangya Medical College, Zhongnan Univ cell bank provides).
Reagent: tetrazolium bromide (MTT), RPMI RPMI-1640, NBCS, microbiotic (U.S. hero Life Technologies, Inc.); Pancreatin (U.S. AMRESCO company); 96 well culture plates (U.S. hero Life Technologies, Inc.); DMSO 99.8MIN. (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 ltd); Multiskan MK3 type ELIASA (U.S. Thermo company); Ultrapure water preparing instrument (U.S. Milli-Q company).
Experimental implementation: sample is for the test of Hela cell and A549 cell.The experimental implementation process of every kind of cell is identical; In the experimentation; Per sample (p.s.) is provided with 5 concentration gradients (0.025 μ mol/mL, 0.05 μ mol/mL, 0.1 μ mol/mL, 0.25 μ mol/mL and 0.5 μ mol/mL); Four parallel samples of each concentration are tested parallel 3 times for every group, and reach a conclusion through the blank control group contrast.ELIASA detects each hole OD value, detects wavelength 570nm.
3. anti-tumor activity evaluation
1) cell inhibitory rate calculates:
2) IC
50Value is calculated
Sample solution concentration logarithmic value and cell inhibitory rate linear regression utilize the half-inhibition concentration IC of computed in software sample pair cell
50Value.Preferred compound is for the IC of Hela cell and A549 cell
50See table 1.
Table 1 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is for Hela cell and A549 cell inhibiting activity
The active testing result shows that 4-alkyl-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and salt thereof have good inhibition activity for human cervical carcinoma cell (Hela cell) and human lung adenocarcinoma cell (A549 cell) etc., can be used for preparing antitumor drug.
Claims (10)
1. the alkyl of the 4-shown in the chemical structural formula I-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole and salt thereof:
Wherein, R is selected from: H, C
1~C
2Alkyl, C
3~C
4Straight chained alkyl or branched-chain alkyl; X
1Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
2Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
3Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
4Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; X
5Be selected from: hydrogen, C
1~C
2Alkyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, fluorine, chlorine, bromine, nitro or amino; Its salt is selected from hydrochloride, hydrobromate, nitrate salt, vitriol, phosphoric acid salt, mesylate, tosilate, tartrate, lactic acid salt or malate.
4. the said 4-alkyl of claim 1-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 2-chlorobenzene is amino)-5-(1; 2,4-triazol-1-yl) thiazole, the 4-tertiary butyl-2-(the 4-chlorobenzene is amino)-5-(1,2; The 4-triazol-1-yl) thiazole or the 4-tertiary butyl-2-(2; The 3-dichlorobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole:
5. the said 4-alkyl of claim 1-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(the 2-bromobenzene is amino)-5-(1,2, the 4-triazol-1-yl) thiazole:
8. the said 4-alkyl of claim 1-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole is the 4-tertiary butyl-2-(2; The 4-xylidino)-5-(1,2, the 4-triazol-1-yl) thiazole or the 4-tertiary butyl-2-(2; The 6-xylidino)-5-(1,2, the 4-triazol-1-yl) thiazole:
9. the crystalline structure of the said 4-tertiary butyl-2-of claim 6 (2-fluoroanilino)-5-(1,2, the 4-triazol-1-yl) thiazole; The crystal that it is characterized in that it belongs to rhombic system, and spacer is Pbca, and unit cell parameters is:
Z=8,
D
c=1.359g/cm
3, F (000)=1328, μ=0.223mm
-1, 2590 considerable measuring points [I>2 σ (I)], the final discrepancy factor R=0.034 of considerable measuring point refine, wR=0.097, (Δ/σ)
Max=0.001, S=1.05,
10. the described 4-alkyl of claim 1-2-virtue amino-5-(1,2, the 4-triazol-1-yl) thiazole or the application of its salt in anti-human cervical carcinoma of preparation or human lung adenocarcinoma medicine.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100525462A CN102603728A (en) | 2012-03-02 | 2012-03-02 | 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof |
CN201210351893.5A CN102887892B (en) | 2012-03-02 | 2012-09-20 | 4-tertiary butyl-2-(2-fluorophenylamino)-5-(1,2,4-triazole-1-yl) thiazole crystals |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100525462A CN102603728A (en) | 2012-03-02 | 2012-03-02 | 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102603728A true CN102603728A (en) | 2012-07-25 |
Family
ID=46521558
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2012100525462A Pending CN102603728A (en) | 2012-03-02 | 2012-03-02 | 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof |
CN201210351893.5A Expired - Fee Related CN102887892B (en) | 2012-03-02 | 2012-09-20 | 4-tertiary butyl-2-(2-fluorophenylamino)-5-(1,2,4-triazole-1-yl) thiazole crystals |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210351893.5A Expired - Fee Related CN102887892B (en) | 2012-03-02 | 2012-09-20 | 4-tertiary butyl-2-(2-fluorophenylamino)-5-(1,2,4-triazole-1-yl) thiazole crystals |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN102603728A (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102942535A (en) * | 2012-12-03 | 2013-02-27 | 湖南大学 | 4-tertiary butyl-5-(2-nitroxyethyl)-2-aminothiazole, as well as preparation method and application thereof |
CN103664927A (en) * | 2012-12-10 | 2014-03-26 | 湖南大学 | N-[5-(1,2,4-triazole-1-yl)thiazole-2-yl]aryl amide, preparation method, and applications thereof |
CN105367564A (en) * | 2014-09-01 | 2016-03-02 | 湖南大学 | N-[4-phenyl-5-(1,2,4-triazole-1-yl)thiazole-2-yl]amide and preparation and application thereof |
CN105440029A (en) * | 2014-09-02 | 2016-03-30 | 湖南大学 | 5-(1,2,4-Triazol-1-yl)-2-benzylaminothiazole derivatives and application thereof as antitumor drug |
CN107459513A (en) * | 2017-09-14 | 2017-12-12 | 南华大学 | N, the thiazole amine derivative of 4 diphenyl 5 (1,2,4 triazolyl) 2 and its medical usage |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10175975A (en) * | 1996-12-17 | 1998-06-30 | Sagami Chem Res Center | Thiazole derivative and agrochemical containing the same |
CN101602761B (en) * | 2009-07-17 | 2011-03-16 | 湖南大学 | 4-tert-butyl-5-(1,2,4-triazol-1-yl)-2-benzylimino thiazole and preparation method and application thereof |
CN102675303B (en) * | 2011-10-19 | 2014-04-09 | 湖南大学 | 4-alkyl-2-arylamino-5-(1,2,4-triazole-1-group) thiazole and application thereof to preparation of medicaments for resisting cancer |
-
2012
- 2012-03-02 CN CN2012100525462A patent/CN102603728A/en active Pending
- 2012-09-20 CN CN201210351893.5A patent/CN102887892B/en not_active Expired - Fee Related
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102942535A (en) * | 2012-12-03 | 2013-02-27 | 湖南大学 | 4-tertiary butyl-5-(2-nitroxyethyl)-2-aminothiazole, as well as preparation method and application thereof |
CN102942535B (en) * | 2012-12-03 | 2014-04-30 | 湖南大学 | 4-tertiary butyl-5-(2-nitroxyethyl)-2-aminothiazole, as well as preparation method and application thereof |
CN103664927A (en) * | 2012-12-10 | 2014-03-26 | 湖南大学 | N-[5-(1,2,4-triazole-1-yl)thiazole-2-yl]aryl amide, preparation method, and applications thereof |
CN103664927B (en) * | 2012-12-10 | 2015-06-24 | 湖南大学 | N-[5-(1,2,4-triazole-1-yl)thiazole-2-yl]aryl amide, preparation method, and applications thereof |
CN105367564A (en) * | 2014-09-01 | 2016-03-02 | 湖南大学 | N-[4-phenyl-5-(1,2,4-triazole-1-yl)thiazole-2-yl]amide and preparation and application thereof |
CN105367564B (en) * | 2014-09-01 | 2018-03-23 | 湖南大学 | N [base of 4 phenyl 5 (base of 1,2,4 triazole 1) thiazole 2] acid amides and its preparation and application |
CN105440029A (en) * | 2014-09-02 | 2016-03-30 | 湖南大学 | 5-(1,2,4-Triazol-1-yl)-2-benzylaminothiazole derivatives and application thereof as antitumor drug |
CN107459513A (en) * | 2017-09-14 | 2017-12-12 | 南华大学 | N, the thiazole amine derivative of 4 diphenyl 5 (1,2,4 triazolyl) 2 and its medical usage |
CN107459513B (en) * | 2017-09-14 | 2020-08-07 | 南华大学 | N, 4-diphenyl-5- (1,2, 4-triazolyl) -2-thiazolamine derivatives and medical application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN102887892A (en) | 2013-01-23 |
CN102887892B (en) | 2014-07-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102675303B (en) | 4-alkyl-2-arylamino-5-(1,2,4-triazole-1-group) thiazole and application thereof to preparation of medicaments for resisting cancer | |
CN101781269B (en) | 4-tertiary butyl-2-(nitrobenzyl imino) thiazole derivative as well as preparation method and application thereof | |
CN101580477B (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
CN102070556B (en) | 5-benzyl-4-alkyl-2-aminothiazole as well as preparation and application of 5-benzyl-4-alkyl-2-aminothiazole | |
CN105175410B (en) | Compound in triazine class and preparation method thereof and antitumor application thereof | |
CN102603728A (en) | 4-alkyl-2-aryl amino-5-(1,2,4-triazol-1-yl)thiazole and preparation method and application thereof | |
CN102010405B (en) | 4-(benzofuran-5-yl)-2-benzal aminothiazole and application of 4-(benzofuran-5-base)-2-benzal aminothiazole as antineoplastic agent | |
CN101845026B (en) | 5-(4-chlorophenylmethyl)-4-tertiary butyl thiazole derivatives and preparation method and application thereof | |
CN103145700A (en) | 2-(2-benzyl hydrazono)-4-(benzofuran-5-yl) thiazole and preparation method and application thereof | |
CN105130927B (en) | One class benzene connection azacyclo- chalcone derivative and its preparation method and application | |
CN104592252A (en) | Oxazinoquinolinone C-3 sym-triazole sulfide ketone thiosemicarbazone derivative as well as preparation method and application thereof | |
CN105585562B (en) | 1- (benzofuran -5- bases) -3- aryl -2- (triazol-1-yl) propenone and its application as anticarcinogen | |
CN102070628B (en) | 4-alkyl-6-aryl-5-(1, 2, 4-triazole-1-yl)-2-amino-1, 3-thiazine and application thereof | |
CN103524417B (en) | One group of 3-methyl-4-formyl pyrazole compound | |
CN102603726B (en) | 5-(2-aminothiazole-4-yl) benzofuranol etheric compound with herbicidal activity and preparation method | |
CN105585563A (en) | 1-(benzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)propenol and application thereof | |
CN102070565B (en) | 4-alkyl-6-aryl-5-acetyl-1, 3-thiazine, and preparation method and application thereof | |
CN103319463B (en) | N1 substituted 3, 4-dihydropyrimidine-2-one-C60compounds and their prepn | |
CN104292219B (en) | 1-(cumarone-5-base)-2-(1,2,4-triazol-1-yl) ketoxime heterocycle methyl ether and the application as anticarcinogen thereof | |
CN104327055A (en) | 1-(benzofuran-5-yl)-2-(1, 2, 4-triazole-1-yl)ketoxime ether amide, preparation method and application thereof | |
CN102942535B (en) | 4-tertiary butyl-5-(2-nitroxyethyl)-2-aminothiazole, as well as preparation method and application thereof | |
CN103450181B (en) | Medical application of 2-[4-(quinoxaline-2-oxy)phenoxy]amide | |
CN104327064B (en) | Acridine-1,3,4-oxadiazole compound having anti-tumor activity, preparation method and uses thereof | |
CN104387373A (en) | 1-(7-propoxy benzofuran-5-group)-3-(2-methoxyl phenyl)-2-(1,2,4-triazole-1- group)acrylketone | |
Wilson et al. | Oxidative reactivity and cytotoxic properties of a platinum (II) complex prepared by outer-sphere amide bond coupling |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120725 |