CN103664932B - One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the inhibitory action to cancer cell tubulin polymerization - Google Patents

One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and the inhibitory action to cancer cell tubulin polymerization Download PDF

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CN103664932B
CN103664932B CN201310541158.5A CN201310541158A CN103664932B CN 103664932 B CN103664932 B CN 103664932B CN 201310541158 A CN201310541158 A CN 201310541158A CN 103664932 B CN103664932 B CN 103664932B
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grafting
preparation
indoles
thiazole
reaction
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CN103664932A (en
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朱海亮
王彦婷
秦亚娟
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Nanjing University
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

One class indoles grafting thiazole hydrazone analog derivative, it has below formula.It is demonstrated experimentally that the new indole grafting thiazole hydrazone analog derivative of the present invention has obvious inhibitory action to the polymerization of cancer cell tubulin.Therefore the indoles grafting thiazole hydrazone analog derivative of the present invention can apply to prepare cancer therapy drug.The invention discloses the preparation method of indoles grafting thiazole hydrazone analog derivative.In formula, R1、R2Selected from C1 10 alkyl, C1 5 alkoxyl, halogen, C1 5 alkyl of halogen substiuted, nitro, amino；R3、R4、R5Selected from hydrogen, C1 5 alkyl, C1 5 alkoxyl, halogen, C1 5 alkyl of halogen substiuted, nitro, amino；The most do not include following compound: R1=CH3, R2=R3=R4=R5=H；R1=CH2CH3, R2=R3=R4=R5=H；R1=CH3, R2=NO2, R3=R4=R5=H.

Description

One class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and pipe micro-to cancer cell The inhibitory action of albumen polymerization
Technical field
The present invention relates to class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and suppression tumour cell micro-pipe egg The function of white polymerization.
Background technology
Indoles medicine can suppress depolymerization and the polymerization of tumour cell tubulin, i.e. by destroying micro-pipe in vivo and body Outer form and function carry out the activity of inhibition cancer cell, thus play antitumaous effect.Some indoles medicine can promote and surely Determine the polymerized form of tubulin (it has recently been demonstrated that medicine is owing to they are to micro-pipe to the inhibitory action of microtubule depolymerization Dynamic (dynamical) interference rather than the change of tubulin polymerization thing amount.)；And some indoles medicine is by tying with colchicin Close the strong combination in site and suppress the polymerization of micro-pipe.
In recent years, demonstrate the most important effect containing thiazole ring compound at the aspect such as drug research and biology, Wherein aminothiazole compounds has stronger physiologically active, is particularly subject to the attention of researcher.Thiazole compound can be with life The targeted integration such as multiple enzyme and acceptor in object thus show multiple biologically active.The generation of tumour and tumour cell itself are withered The suppression of signal of dying is closely bound up, and therefore Apoptosis plays an important role in the chemotherapy of tumour, and a lot of medicines is all Reach to treat the purpose of tumour by reconstituted cell apoptosis.ROS (the intracellular reactive oxygen of excess Species) can collapse with inducing mitochondrial film potential (MMP), make the death factors in mitochondria discharge, inducing cell death； The accumulation of ROS simultaneously can cause lipid peroxidation, protein, the Oxidative inactivation of enzyme and the oxidative damage of DNA.Research shows, swollen Oncocyte has ROS level more higher than normal cell, and the attack to ROS is more sensitive, and therefore relevant for ROS drug development becomes One focus of antineoplastic research and development.Develop it and there is certain theory significance and actual value, therefore, Wo Menshe Meter has synthesized The indoles grafting thiazole hydrazone analog derivative of female ring.
Summary of the invention
It is an object of the invention to provide class indoles grafting thiazole hydrazone analog derivative and preparation method thereof.
Technical scheme is as follows:
One class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have a below formula:
In formula, R1、R2Selected from C1-10 alkyl, C1-5 alkoxyl, halogen, the C1-5 alkyl of halogen substiuted, nitro, amino；
R3、R4、R5Selected from hydrogen, C1-5 alkyl, C1-5 alkoxyl, halogen, the C1-5 alkyl of halogen substiuted, nitro, amino；
The most do not include following compound: R1=CH3, R2=R3=R4=R5=H；R1=CH2CH3, R2=R3=R4 =R5=H；R1=CH3, R2=NO2, R3=R4=R5=H.
The preparation method of indoles grafting thiazole hydrazone analog derivative described in a kind of claim 1, step is as follows:
Step 1. is in fume hood, under cryogenic conditions, after adding organic solvent DMF certain volume, is slowly added dropwise in flask The POCl of same volume3, then the compound 1 being dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, stir reaction one After the section time, liter high-temperature to room temperature, follow the tracks of reaction through TLC, after question response is complete, reactant liquor pours the frozen water of certain volume into In, by alkali regulation pH value to alkalescence, then extract with organic solvent, be spin-dried for obtaining the compound 2 of yellow powder；
Compound 2 and thiosemicarbazides that step 1 is obtained by step 2. mix, and add a certain amount of organic solvent and dissolve, Stirring reaction under room temperature, TLC follows the tracks of reaction, after reaction completely, filtration, purified obtain yellow powder compound 3；
The compound 3 that step 2 is obtained by step 3., the alpha-brominated acetophenone containing various substituents is dissolved in appropriate organic molten In agent, follow the tracks of reaction through TLC, after reaction completely, filter, purified obtain indoles grafting thiazole hydrazone class described in claim 1 and spread out Biological.
Detailed description of the invention:
Further describe the present invention by following example, but the scope of the present invention is not appointed by these embodiments What limits.
Embodiment one: (E)-4-(4-methoxyl group)-2-(2-((1-methyl isophthalic acid H indol-3-yl) methylene) hydrazine) thiazole Preparation
In fume hood, under cryogenic conditions, 100mL single necked round bottom flask adds the DMF of 10mL, by 5mL POCl3Slow Slowly drop in flask, then the 1-methyl indol (1.32g, 10.0mmoL) being dissolved in 10mL DMF be slowly dropped in flask, After about 2h is reacted in stirring, liter high-temperature, to room temperature, reacts about 2-3h, after reaction terminates, stands after it cools down, is added by reactant Enter in 20mL frozen water, use Na2CO3Or K2CO3Regulation pH value, to 9, is extracted with ethyl acetate, is spin-dried for obtaining yellow powder.Take State the solid (0.61g, 3.8mmoL) obtained to join in 50mL single necked round bottom flask, add 25mL isopropanol and dissolve, add The thiosemicarbazides of 0.35g, stirring reaction under room temperature, TLC terminates reaction after following the tracks of reaction, about 24h, filters, obtain yellow solid. Take above-mentioned yellow solid (0.1g, 0.43mmoL) to be placed in the single necked round bottom flask of 50mL, add 25mL isopropanol and dissolve, add Deng material amount (77.9mg, 0.43mmoL) to methoxyl group-alpha-brominated acetophenone, under room temperature stirring reaction, TLC follow the tracks of, about 24h Rear reaction is complete, is filtrated to get yellow powder target compound.Productivity 82.3%.m.p.205～207 DEG C.1H NMR (DMSO-d6, 400MHz) and δ: 3.84 (s, 3H), 3.74 (s, 3H), 6.92～7.07 (m, 2H), 7.16～7.35 (m, 2H), 7.50～7.56 (m, 2H), 7.64～7.76 (m, 2H), 7.92 (s, 1H), 8.21 (d, J=5.76Hz, 1H), 8.55 (s, 1H) .MS (ESI): 363.12 ([M+H]+).Anal.calc.for C20H18N4OS:C, 66.28；H, 5.01；O, 4.41%；N, 15.46%；Found:C, 66.26；H, 5.02；O, 4.42%；N, 15.46%.
Embodiment two: the system of (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene) hydrazine)-4-phenyl thiazole Standby
Preparation method, with embodiment one, replaces 4-methoxyl group-alpha-brominated acetophenone with α bromoacetophenone, obtains yellow powder Powder target compound.Productivity 69.5%.m.p.207～208 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.83 (s, 3H), 7.21～7.33 (m, 4H), 7.42 (t, J=7.58Hz, 2H), 7.52 (d, J=8.08Hz, 1H), 7.77 (s, 1H), 7.87 (d, J=7.28Hz, 2H), 8.23～8.27 (m, 2H), 11.84 (s, 1H) .MS (ESI): 333.11 ([M+H]+) .Anal.calc.for C19H16N4S:C, 68.65；H, 4.85；N, 16.85%；Found:C, 68.63；H, 4.86；N, 16.86%.
Embodiment three: (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene) hydrazine)-4-(4-(trifluoromethyl Phenyl) phenyl) preparation of thiazole
Preparation method, with embodiment one, replaces 4-methoxyl group-alpha-brominated benzene second with 4-trifluoromethyl-alpha-bromoacetophenone Ketone, obtains yellow powder target compound.Productivity 86.3%.m.p.230～235 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.83 (s, 3H), 7.21～7.29 (m, 2H), 7.36 (s, 1H), 7.52 (d, J=8.08Hz, 1H), 7.61 (d, J= 8.56Hz, 2H), 7.80 (t, J=10.26Hz, 3H), 8.18～8.20 (m, 2H), 11.82 (s, 1H) .MS (ESI): 401.1 ([M+H]+).Anal.calc.for C20H15F3N4S:C, 59.99；H, 3.78；N, 13.99%；Found:C, 59.98；H, 3.77；N, 13.97%.
Embodiment four: (E)-4-(4-bromophenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene) hydrazine) thiophene The preparation of azoles
Preparation method, with embodiment one, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 4-, obtains Yellow powder target compound.Productivity 87.3%.m.p.237～241 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 3.83 (s, 3H), 7.21～7.31 (m, 2H), 7.37 (s, 1H), 7.52 (d, J=8.08Hz, 1H), 7.61 (d, J=8.56Hz, 2H), 7.80 (t, J=10.26Hz, 3H), 8.22～8.26 (m, 2H), 11.9 (s, 1H) .MS (ESI): 411.02 ([M+H]+) .Anal.calc.for C19H15BrN4S:C, 55.48；H, 3.68；N, 13.62%；Found:C, 55.47；H, 3.66；N, 13.64%.
Embodiment five: (E)-4-(3-bromophenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene) hydrazine) benzene Base) preparation of thiazole
Preparation method, with embodiment one, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 3-, obtains Yellow powder target compound.Productivity 84.5%.m.p.195～198 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 3.83 (s, 3H), 7.22～7.31 (m, 2H), 7.38 (t, J=7.86Hz, 1H), 7.45 (s, 1H), 7.51 (t, J=7.06Hz, 2H), 7.78 (s, 1H), 7.87 (d, J=7.88Hz, 1H), 8.06 (s, 1H), 8.24 (t, J=8.10Hz, 2H), 11.92 (s, 1H) .MS (ESI): 411.02 ([M+H]+).Anal.calc.for C19H15BrN4S:C, 55.48；H, 3.68；N, 13.62%； Found:C, 55.46；H, 3.69；N, 13.64%.
Embodiment six: (2-((1-methyl isophthalic acid-H-indol-3-yl) methylene) joins (E)-4-(o-methoxyphenyl)-2- Ammonia)-4 phenyl) preparation of thiazole
Preparation method, with embodiment one, replaces 4-methoxyl group-alpha-brominated acetophenone with O-methoxy-alpha-brominated acetophenone, Obtain yellow powder target compound.Productivity 81.3%.m.p.218～219 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.84 (s, 3H), 3.92 (s, 3H), 7.05 (t, J=5.6Hz, 1H), 7.15 (d, J=8.20Hz, 1H), 7.23～7.38 (m, 4H), 7.53 (d, J=8.08Hz, 1H), 7.83 (s, 1H), 7.92 (s, 1H), 8.22～8.27 (m, 1H), 8.34 (s, 1H), 12.1 (s, 1H) .MS (ESI): 363.12 ([M+H]+).Anal.calc.for C20H18N4OS:C, 66.28；H, 5.01；O, 4.41；N, 15.46%；Found:C, 66.29；H, 5.03；O, 4.43；N, 15.45%.
Embodiment seven: (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-(4-methoxyphenyl) thiazole Preparation
In fume hood, under cryogenic conditions, 100mL single necked round bottom flask adds the DMF of 10mL, by 5mL POCl3Slow Slowly drop in flask, then the 1-H indoles (1.17g, 10.0mmoL) being dissolved in 10mL DMF is slowly dropped in flask, stirring After reacting about 2h, liter high-temperature, to room temperature, reacts about 2-3h, after reaction terminates, stands after it cools down, is added by reactant In 20mL frozen water, use Na2CO3Or K2CO3Regulation pH value is to 9, and the solid of precipitation filters post-drying, obtains yellow powder.Take State the solid (0.55g, 3.8mmoL) obtained to join in 50mL single necked round bottom flask, add 25mL isopropanol and dissolve, add The thiosemicarbazides of 0.35g, stirring reaction under room temperature, TLC terminates reaction after following the tracks of reaction, about 24h, filters, obtain yellow solid. Take above-mentioned yellow solid (0.1g, 0.46mmoL) to be placed in the single necked round bottom flask of 50mL, add 25mL isopropanol and dissolve, add Deng material amount (11mg, 0.46mmoL) to methoxyl group-alpha-brominated acetophenone, under room temperature stirring reaction, TLC follow the tracks of, after about 24h Reaction completely, is filtrated to get yellow powder target compound.Productivity 81%.m.p.205～207 DEG C of .1H NMR (DMSO-d6, 400MHz) δ: 6.92～7.09 (m, 2H), 7.09～7.29 (m, 3H), 7.44～7.76 (m, 3H), 7.79 (d, J=8.80Hz, 1H), 7.85～7.92 (m, 1H), 8.07～8.24 (m, 1H), 8.37～8.57 (m, 1H), 11.66 (s, 1H) .MS (ESI): 349.10([M+H]+).Anal.calc.for C19H16N4OS:C, 65.50；H, 4.63；O, 4.59；N, 16.08%；Found: C, 65.47；H, 4.64；O, 4.58；N, 16.06%.
Embodiment eight: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-phenyl thiazole
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with alpha-brominated acetophenone, obtains yellow powder Powder target compound.Productivity 84.2%.m.p.245～246 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.18～7.25 (m, 2H), 7.32～7.37 (m, 2H), 7.43～7.48 (m, 2H), 7.7～7.86 (m, 3H), 8.23 (d, J=6Hz, 1H), 8.37 (s, 1H), 11.6 (s, 1H) .MS (ESI): 319.09 ([M+H]+).Anal.calc.for C18H14N4S:C, 67.90；H, 4.43；N, 17.60%；Found:C, 67.89；H, 4.42；N, 17.58%.
Embodiment nine: (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-(o-methoxyphenyl) thiazole Preparation
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with O-methoxy-α-acetophenone, obtains Yellow powder target compound.Productivity 85.4%.m.p.245～246 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 3.92 (s, 3H), 7.07 (t, J=5.6,1H), 7.17～7.29 (m, 3H), 7.34 (s, 1H), 7.40 (t, J=5.31Hz, 1H), 7.49 (d, J=5.40Hz, 1H), 7.84～7.91 (m, 2H), 8.21 (d, J=5.49Hz, 1H), 8.45 (s, 1H), 11.71 (s, 1H) .MS (ESI): 349.10 ([M+H]+).Anal.calc.for C19H16N4OS:C, 65.50；H, 4.63；O, 4.59；N, 16.08%；Found:C, 65.48；H, 4.64；O, 4.60；N, 16.07%.
Embodiment ten: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-(3-bromophenyl) thiazole
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-α of 3--acetophenone, obtains yellow Powder target compound.Productivity 88.4%.m.p.237～238 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 7.18～7.23 (m, 2H), 7.38 (s, 1H), 7.45 (d, J=7.40Hz, 2H), 7.61 (d, J=8.52Hz, 2H), 7.76～7.82 (m, 3H), 8.27 (d, J=7.68Hz, 1H), 8.30 (s, 1H), 11.56 (s, 1H) .MS (ESI): 397.00 ([M+H]+) .Anal.calc.for C18H13BrN4S:C, 54.42；H, 3.30；N, 14.10%；Found:C, 54.43；H, 3.33；N, 14.12%.
Embodiment 11: (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-(4-trifluoromethyl) thiophene The preparation of azoles
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with 4-trifluoromethyl-alpha-acetophenone, To yellow powder target compound.Productivity 90.4%.m.p.201～202 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 7.11 ～7.37 (m, 3H), 7.44～7.62 (m, 2H), 7.62～7.81 (m, 3H), 7.85 (s, 1H), 7.94～8.02 (m, 1H), 8.01～8.25 (m, 1H), 8.34～8.47 (m, 1H), 11.6 (s, 1H) .MS (ESI): 387.08 ([M+H]+) .Anal.calc.for C19H13F3N4S:C, 59.06；H, 3.39；N, 14.50%；Found:C, 59.04；H, 3.38；N, 14.52%.
Embodiment 12: the system of (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-(4-bromophenyl) thiazole Standby
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-α of 4--acetophenone, obtains yellow Powder target compound.Productivity 87.2%.m.p.209～210 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 7.17～7.24 (m, 2H), 7.37 (s, 1H), 7.45 (d, J=7.40Hz, 2H), 7.61 (d, J=8.52Hz, 2H), 7.79～7.83 (m, 3H), 8.22 (d, J=7.68Hz, 1H), 8.30 (s, 1H), 11.60 (s, 1H) .MS (ESI): 397.00 ([M+H]+) .Anal.calc.for C18H13BrN4S:C, 54.42；H, 3.30；N, 14.10%；Found:C, 54.44；H, 3.29；N, 14.11%.
Embodiment 13: (E)-2-(2-((1-H-indol-3-yl) methylene) hydrazine)-4-((1,1 '-biphenyl)-4-base) The preparation of thiazole
Preparation method, with embodiment four, replaces 4-methoxyl group-alpha-brominated acetophenone with O-methoxy-α-acetophenone, obtains Yellow powder target compound.Productivity 85.4%.m.p.245～246 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.15～ 7.23 (m, 2H), 7.38 (s, 1H), 7.42 (d, J=7.40Hz, 2H), 7.59 (d, J=8.50Hz, 2H), 7.79～7.83 (m, 3H), 7.80～7.92 (m, 4H), 7.93～7.95 (m, 1H), 8.35 (d, J=7.68Hz, 1H), 8.38 (s, 1H), 11.68 (s, 1H) .MS (ESI): 395.13 ([M+H]+).Anal.calc.for C24H18N48:C, 73.07；H, 4.60；N, 14.20%； Found:C, 73.06；H, 4.61；N, 14.22%.
Embodiment 14: (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene) hydrazine)-4-(4-methoxyl group Phenyl) preparation of thiazole
In fume hood, under cryogenic conditions, 100mL single necked round bottom flask adds the DMF of 10mL, by 5mL POCl3Slow Slowly drop in flask, then the 5-methoxy-Indole (1.47g, 10.0mmoL) being dissolved in 10mL DMF is slowly dropped to flask In, after about 2h is reacted in stirring, liter high-temperature, to room temperature, reacts about 2-3h, after reaction terminates, stands after it cools down, will react Thing joins in 20mL frozen water, uses Na2CO3Or K2CO3Regulation pH value is to 9, and the solid of precipitation filters post-drying, obtains yellow powder End.Take solid obtained above (0.67g, 3.8mmoL) to join in 50mL single necked round bottom flask, add 25mL isopropanol and dissolve, Adding the thiosemicarbazides of 0.35g, stirring reaction under room temperature, TLC terminates reaction after following the tracks of reaction, about 24h, filters, obtain Huang Look solid.Take above-mentioned yellow solid (0.1g, 0.41mmoL) to be placed in the single necked round bottom flask of 50mL, add 25mL isopropanol molten Solve, add wait material amount (9.39mg, 0.41mmoL) to methoxyl group-alpha-brominated acetophenone, under room temperature stirring react, TLC Following the tracks of, after about 24h, reaction completely, is filtrated to get yellow powder target compound.Productivity 81%.m.p.205～207 DEG C.1H NMR (DMSO-d6,400MHz) δ: 3.80 (s, 3H), 3.87 (s, 3H), 6.88～6.85 (m, 1H), 7.02～6.96 (m, 2H), 7.15 (s, 1H), 7.36 (d, J=6.57Hz, 1H), 7.90～7.66 (m, 4H), 8.34 (s, 1H), 11.47 (s, 1H) .MS (ESI): 379.12 ([M+H]+).Anal.calc.for C20H18N4O2S:C, 63.47；H, 4.79；O, 8.46；N, 14.80%； Found:C, 63.48；H, 4.78；O, 8.45；N, 14.79%.
Embodiment 15: (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene) hydrazine)-4-phenyl thiazole Preparation
Preparation method, with embodiment seven, replaces 4-methoxyl group-alpha-brominated acetophenone with alpha-brominated acetophenone, obtains yellow powder Powder target compound.Productivity 85.5%.m.p.209～210 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.88 (s, 3H), 6.87 (dd, J1=9Hz, J2=9Hz, 1H), 7.33～7.38 (m, 4H), 7.44～7.48 (m, 2H), 7.77 (s, 1H), 7.81 ～7.84 (m, 3H), 8.40 (s, 1H), 11.50 (s, 1H) .MS (ESI): 349.10 ([M+H]+).Anal.calc.for C19H10N4OS:C, 65.50；H, 4.63；O, 4.59；N, 16.08%；Found:C, 65.48；H, 4.63；O, 4.58；N, 16.09%.
Embodiment 16: (2-((5-methoxyl group-1-H-indol-3-yl) methylene) joins (E)-4-(4-bromophenyl)-2- Ammonia) preparation of thiazole
Preparation method, with embodiment seven, replaces alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 4-, obtains yellow powder Target compound.Productivity 79.8%.m.p.175～176 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.87 (s, 3H), 6.87 (dd, J1=9Hz, J2=9Hz, 1H), 7.34～7.37 (m, 2H), 7.61 (d, J=6,3H), 7.73 (s, 1H), 7.78～ 7.82 (m, 3H), 8.27 (s, 1H), 11.40 (s, 1H) .MS (ESI): 427.01 ([M+H]+).Anal.calc.for C19H15BrN4OS:C, 53.40；H, 3.54；O, 3.74；N, 13.11%；Found:C, 53.41；H, 3.53；O, 3.74；N, 13.12%.
Embodiment 17: (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene) hydrazine)-4-(4-fluoroform Base phenyl) preparation of thiazole
Preparation method, with embodiment seven, replaces alpha-brominated acetophenone with 4-trifluoromethyl-alpha-bromoacetophenone, obtains yellow Powder target compound.Productivity 88.8%.m.p.165～166 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.87 (s, 3H), 6.86 (dd, J1=8.72Hz, J2=8.76Hz, 1H), 7.35 (d, J=8.76Hz, 1H), 7.53 (s, 1H), 7.74～7.79 (m, 5H), 8.07 (d, J=8.12Hz, 2H), 8.29 (s, 1H), 11.43 (s, 1H) .MS (ESI): 417.09 ([M+H]+) .Anal.calc.for C20H15F3N4OS:C, 57.69；H, 3.63；O, 3.84；N, 13.45%；Found:C, 57.68；H, 3.64；O, 3.84；N, 13.43%.
Embodiment 18: (2-((5-methoxyl group-1-H-indol-3-yl) methylene) joins (E)-4-(3-bromophenyl)-2- Ammonia) preparation of thiazole
Preparation method, with embodiment seven, replaces alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 3-, obtains yellow powder Target compound.Productivity 86.2%.m.p.229～230 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.88 (s, 3H), 6.86 (dd, J1=6.57Hz, J2=6.60Hz, 1H), 7.35～7.41 (m, 3H), 7.45 (s, 1H), 7.51 (d, J=7.88Hz, 1H), 7.76 (s, 1H), 7.79 (s, 1H), 7.87 (d, J=7.84Hz, 1H), 8.06 (s, 1H), 8.29 (s, 1H), 11.4 (s, 1H) .MS (ESI): 427.01 ([M+H]+).Anal.calc.for C19H15BrN4OS:C, 53.40；H, 3.54；O, 3.74；N, 13.11%；Found:C, 53.41；H, 3.53；O, 3.74；N, 13.12%.
Embodiment 19: (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene) hydrazine)-4-(O-methoxy Phenyl) preparation of thiazole
Preparation method, with embodiment seven, replaces alpha-brominated acetophenone with O-methoxy-alpha-brominated acetophenone, obtains yellow powder Powder target compound.Productivity 89.8%.m.p.175～176 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.77 (s, 3H), 3.91 (s, 3H), 6.86～6.94 (m, 2H), 7.02～7.22 (m, 2H), 7.33～7.56 (m, 4H), 7.75 (s, 1H), 7.93 (s, 1H), 8.47～8.61 (s, 1H), 11.70 (s, 1H) .MS (ESI): 479.12 ([M+H]+).Anal.calc.for C20H18N4O2S:C, 63.47；H, 4.79；O, 8.46；N, 14.80%；Found:C, 63.46；H, 4.78；O, 8.47；N, 14.80%.
Embodiment 20: (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4-(4-methoxybenzene Base) preparation of thiazole
In fume hood, under cryogenic conditions, 100mL single necked round bottom flask adds the DMF of 10mL, by 5mLPOCl3Slowly Dropping in flask, then be slowly dropped in flask by the 5-bromo indole (1.96g, 10.0mmoL) being dissolved in 10mLDMF, stirring is anti- High-temperature should be risen to room temperature, reacts about 2-3h, after reaction terminates, stand after it cools down, reactant is joined after about 2h In 20mL frozen water, use Na2CO3Or K2CO3Regulation pH value is to 9, and the solid of precipitation filters post-drying, obtains yellow powder.Take above-mentioned The solid (0.85g, 3.8mmoL) obtained joins in 50mL single necked round bottom flask, adds 25mL isopropanol and dissolves, adds The thiosemicarbazides of 0.35g, stirring reaction under room temperature, TLC terminates reaction after following the tracks of reaction, about 24h, filters, obtain yellow solid. Take above-mentioned yellow solid (0.1g, 0.34mmoL) to be placed in the single necked round bottom flask of 50mL, add 25mL isopropanol and dissolve, add Deng material amount (7.79mg, 0.34mmoL) to methoxyl group-alpha-brominated acetophenone, under room temperature stirring reaction, TLC follow the tracks of, about 24h Rear reaction is complete, is filtrated to get yellow powder target compound.Productivity 81%.m.p.205～207 DEG C.1H NMR(DMSO- d6, 400MHz) and δ: 3.80 (s, 3H), 7.00 (d, J=8.76Hz, 2H), 7.19 (s, 1H), 7.34～7.37 (m, 1H), 7.44 ～7.46 (m, 2H), 7.79 (d, J=8.84Hz, 2H), 7.88 (s, 1H), 8.30 (s, 1H), 8.40 (s, 1H), 11.77 (s, 1H) .MS (ESI): 427.01 ([M+H]+).Anal.calc.for C19H15BrN4OS:C, 53.40；H, 3.54；O, 3.74；N, 13.11%；Found:C, 53.42；H, 3.54；O, 3.74；N, 13.12%.
Embodiment 21: the system of (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4 phenyl thiazoles Standby
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with alpha-brominated acetophenone, obtains yellow powder Powder target compound.Productivity 82.9%.m.p.92～93 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.33～7.36 (m, 3H), 7.41～7.47 (m, 4H), 7.78～7.90 (m, 3H), 8.30～8.41 (m, 2H), 11.80 (s, 1H) .MS (ESI): 397.00([M+H]+).Anal.calc.for C18H13BrN4S:C, 53.42；H, 3.30；N, 14.10%；Found:C, 53.41；H, 3.33；N, 14.11%.
Embodiment 22: (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4-(3-bromophenyl) The preparation of thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 3-, obtains Yellow powder target compound.Productivity 86.1%.m.p.94～95 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.33～ 7.45 (m, 4H), 7.49 (s, 2H), 7.86 (s, 2H), 8.06 (s, 1H), 8.25 (s, 1H), 8.40 (s, 1H), 11.73 (s, 1H) .MS (ESI): 474.91 ([M+H]+).Anal.calc.for C18H12Br2N4S:C, 45.40；H, 2.54；N, 11.77%； Found:C, 45.41；H, 2.53；N, 11.76%.
Embodiment 23: (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4-(O-methoxy benzene Base) preparation of thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with O-methoxy-alpha-brominated acetophenone, Obtain yellow powder target compound.Productivity 82.9%.m.p.92～93 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 3.91 (s, 3H), 7.06～7.19 (m, 1H), 7.35～7.52 (m, 5H), 7.74～7.87 (m, 2H), 7.96～8.10 (m, 1H), 8.30～8.50 (m, 2H), 11.6 (s, 1H) .MS (ESI): 427.01 ([M+H]+).Anal.calc.for C19H15BrN4OS: C, 53.40；H, 3.54；O, 3.74；N, 13.11%；Found:C, 53.41；H, 3.53；O, 3.74；N, 13.12%.
Embodiment 24: (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4-(4-trifluoromethyl Phenyl) preparation of thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 4-, obtains Yellow powder target compound.Productivity 79.4%.m.p.175～176 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.17～ 7.32 (m, 1H), 7.32～7.60 (m, 3H), 7.70～7.80 (m, 2H), 7.85～8.18 (m, 3H), 8.21～8.38 (m, 1H), 8.46～8.67 (m, 1H), 11.83 (s, 1H) .MS (ESI): 464.99 ([M+H]+).Anal.calc.for C19H12BrF3N4OS:C, 49.05；H, 2.60；N, 12.04%；Found:C, 49.04；H, 2.62；N, 12.03%.
Embodiment 25: (E)-2-(2-((5-bromo-1-H-indol-3-yl) methylene) hydrazine)-4-(4-bromophenyl) The preparation of thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with the bromo-alpha-brominated acetophenone of 4-, obtains Yellow powder target compound.Productivity 83.4%.m.p.186～187 DEG C.1H NMR(DMSO-d6, 400MHz) δ: 7.33～ 7.45 (m, 3H), 7.54～7.73 (m, 3H), 7.75～7.86 (m, 3H), 8.25 (s, 1H), 8.41 (s, 1H), 11.7 (s, 1H) .MS (ESI): 474.91 ([M+H]+).Anal.calc.for C18H12Br2N4S:C, 45.40；H, 2.54；N, 11.77%； Found:C, 45.42；H, 2.53；N, 11.76%.
Embodiment 26: (E)-4 ((1,1 '-biphenyl)-4-base)-2-(2-((5-bromo-1-H-indol-3-yl) methylene Base) hydrazine) preparation of thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated acetophenone with 4-phenyl-alpha-brominated acetophenone, To yellow powder target compound.Productivity 85.5%.m.p.228～229 DEG C.1H NMR(DMSO-d6, 400MHz) and δ: 7.43 ～7.36 (m, 3H), 7.73～7.57 (m, 3H), 7.86～7.75 (m, 3H), 8.17 (s, 1H), 8.25 (s, 1H), 8.28～ 8.38 (m, 4H), 8.41 (s, 1H), 11.70 (s, 1H) .MS (ESI): 473.04 ([M+H]+).Anal.calc.for C24H17BrN4S:C, 60.89；H, 3.62；N, 11.84%；Found:C, 60.88；H, 3.64；N, 11.84%.
Embodiment 27: indoles grafting thiazole hydrazone analog derivative anti tumor activity in vitro research
MTT [3-(4,5)-bis-methyl-2-thiazoles-(2,5)-phenyl bromination tetrazole is blue] method is used to measure indoles grafting Thiazole hydrazone analog derivative is to Breast cancer lines (MCF-7) and the half-inhibition concentration of Human Lung Cancer cell line (A549) (ICso)。
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag of powder (10.4g), newborn ox blood Clear 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin Solution (200,000 U/ml) 0.5ml, after adding tri-distilled water dissolving, use The NaHCO of 5.6%3Solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: ibid, then Add NaHCO32.00g, HEPES2.38g.
(2) preparation of D-Hanks buffer solution (every liter): NaCl8.00g, KCl0.40g, Na2HPO4·12H2O0.06g, KH2PO40.06g, NaHCO30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks buffer solution to be made into concentration is 0.5% trypsin solution.Cross and filter Bacterium.
(4) preparation of liquid is tested: test sample dissolved with a small amount of tri-distilled water and be made into storing solution, 10 times of preparation storing solutions of high concentration.Different according to compound dissolubility, available tri-distilled water directly dissolves, or helps with a small amount of DMSO Molten, then add tri-distilled water dissolving.DMSO concentration in nutrient solution is unsuitable excessive, the end of DMSO in the every porocyte suspension after dosing Concentration is usually no more than 0.05%-0.1%.Storing solution is stored in-20 DEG C of refrigerators standby.
(5) cultivation of human breast cancer cell line Bcap-37: for adherent growth cell, cellar culture is in RPMI-1640 nutrient solution (containing 10% calf serum, 100U/ml streptomysin), puts 37 DEG C, 5%CO2Incubator is cultivated, passed on once every 3-4 days.Pass Dai Shixian discards original fluid, then uses D-Hanks buffer solution；Then with 0.5% Trypsin Induced about 30 seconds, add A small amount of fresh medium terminates digestion；Piping and druming, makes attached cell split away off from blake bottle wall；Pipette appropriate to fresh cultured In Ping, it is supplemented with fresh medium to original volume (nutrient solution volume is about the 1/10 of blake bottle capacity).
(6) cultivation of human lung cancer cell A549: for adherent growth cell, cellar culture (contains in RPMI-1640 nutrient solution 10% calf serum, 100U/ml streptomysin), put 37 DEG C, 5%CO2Incubator is cultivated, passed on once every 3-4 days.Pass on Time first discard original fluid, then use D-Hanks buffer solution；Then with 0.5% Trypsin Induced about 30 seconds, add few Amount fresh medium terminates digestion；Piping and druming, makes attached cell split away off from blake bottle wall；Pipette appropriate to fresh cultured bottle In, it is supplemented with fresh medium to original volume (nutrient solution volume is about the 1/10 of blake bottle capacity).
(7) cell incubation: the tumour cell in growth period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 105Individual ml-1.? In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 DEG C, 5%CO2Incubator is cultivated 24h.After cultivating 24h, press respectively Design adds liquid.
(8) dosing: being added separately in each hole according to the concentration gradient of ultimate density by test liquid, each concentration sets 6 parallel holes.Experiment is divided into drug test group (being separately added into the test medicine of variable concentrations), control group (only to add nutrient solution with thin Born of the same parents, are not added with testing medicine) and blank group (only adding nutrient solution, be not added with cell and test medicine).96 orifice plates after dosing are placed in 37 DEG C, 5%CO2Incubator is cultivated 48h.The activity of positive control medicine measures according to the method for test sample.
(9) mensuration of survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT40 μ l and (buffers with D-Hanks Liquid is made into 4mg/ml).After placing 4h at 37 DEG C, remove supernatant.Every hole adds 150 μ l DMSO, and vibrate 5min, makes formazan Crystallization is dissolved.Finally, automatic ELIASA is utilized to detect the optical density (OD value) in each hole at 570nm wavelength.
The calculating of inhibiting rate: the inhibiting rate of cell growth calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(ODExperiment-ODBlank)/(ODComparison-ODBlank)] × 100% (ODExperimentRepresent the AO of testing drug group, ODComparisonRepresent the AO of control group, ODBlankRepresent the flat of control group All optical density).
Half-inhibition concentration (IC50) it is defined as the drug concentration when the tumor cell survival of 50%.According to the light measured Density (OD value), makes the calibration curve of inhibitory rate of cell growth, tries to achieve the drug concentration of its correspondence on calibration curve.
The IC recorded50It is shown in Table 1.
The indoles grafting thiazole hydrazone analog derivative suppression IC to tumour cell listed by form 1 present invention50Value

Claims (3)

1. a class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have a below formula:
In formula, R1、R2Selected from C1-10 alkyl, C1-5 alkoxyl, halogen, the C1-5 alkyl of halogen substiuted, nitro, amino；
R3、R4、R5Selected from hydrogen, C1-5 alkyl, C1-5 alkoxyl, halogen, the C1-5 alkyl of halogen substiuted, nitro, amino；
The most do not include following compound: R1=CH3, R2=R3=R4=R5=H；R1=CH2CH3, R2=R3=R4=R5= H；R1=CH3, R2=NO2, R3=R4=R5=H.
2. a preparation method for indoles grafting thiazole hydrazone analog derivative described in claim 1, step is as follows:
Step 1. is in fume hood, under cryogenic conditions, after adding organic solvent DMF certain volume, is slowly added dropwise identical in flask The POCl of volume3, then the compound 1 being dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, during stirring reaction one section After between, liter high-temperature to room temperature, follow the tracks of reaction through TLC, after question response is complete, reactant liquor is poured in the frozen water of certain volume, uses Alkali regulation pH value is to alkalescence, then extracts with organic solvent, is spin-dried for obtaining the compound 2 of yellow powder；
Compound 2 and thiosemicarbazides that step 1 is obtained by step 2. mix, and add a certain amount of organic solvent and dissolve, in room temperature Lower stirring reaction, TLC follows the tracks of reaction, after reaction completely, filtration, purified obtain yellow powder compound 3；
The compound 3 that step 2 is obtained by step 3., the alpha-brominated acetophenone containing various substituents is dissolved in appropriate organic solvent In, follow the tracks of reaction through TLC, after reaction completely, filter, purified obtain indoles grafting thiazole hydrazone class described in claim 1 and derive Thing.
3. indoles grafting thiazole hydrazone analog derivative application in preparing cancer therapy drug described in claim 1.
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