CN103664932A - Indole grafted thiazole hydrazone derivatives, preparation method thereof and inhibiting effect of indole grafted thiazole hydrazone derivatives for polymerization of cancer cell microtubulin - Google Patents
Indole grafted thiazole hydrazone derivatives, preparation method thereof and inhibiting effect of indole grafted thiazole hydrazone derivatives for polymerization of cancer cell microtubulin Download PDFInfo
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- thiazole
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- -1 thiazole hydrazone derivatives Chemical class 0.000 title claims abstract description 31
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000006116 polymerization reaction Methods 0.000 title claims abstract description 6
- 201000011510 cancer Diseases 0.000 title claims abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 59
- 230000002401 inhibitory effect Effects 0.000 title abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical group 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000000843 powder Substances 0.000 claims description 35
- 150000002475 indoles Chemical class 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 6
- 230000000630 rising effect Effects 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 210000004688 microtubule Anatomy 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000000452 restraining effect Effects 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 238000002474 experimental method Methods 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 27
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical class CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 18
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 235000015097 nutrients Nutrition 0.000 description 8
- 239000012530 fluid Substances 0.000 description 7
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 238000013016 damping Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012737 fresh medium Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 0 *c1ccc2[n](*)cc(C=NNc3nc(-c4c(*)c(*)c(*)cc4)c[s]3)c2c1 Chemical compound *c1ccc2[n](*)cc(C=NNc3nc(-c4c(*)c(*)c(*)cc4)c[s]3)c2c1 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical class C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 description 1
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 1
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 1
- NZQOPDASYJNMLV-SRZZPIQSSA-N C[n]1c2ccccc2c(/C=N/Nc2nc(-c(cc3)ccc3OC)c[s]2)c1 Chemical compound C[n]1c2ccccc2c(/C=N/Nc2nc(-c(cc3)ccc3OC)c[s]2)c1 NZQOPDASYJNMLV-SRZZPIQSSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000025090 microtubule depolymerization Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940074386 skatole Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses indole grafted thiazole hydrazone derivatives with the general formula as shown in the specification. Experiments prove that the novel indole grafted thiazole hydrazone derivatives disclosed by the invention have a remarkable inhibiting effect for polymerization of cancer cell microtubulin. Therefore, the indole grafted thiazole hydrazone derivatives can be applied to the preparation of anticancer drugs. The invention discloses a preparation method of the indole grafted thiazole hydrazone derivatives, in the formula, R1 and R2 are selected from hydrogen, C1-10 alkyl groups, naphthenic bases, C1-5 alkoxy groups, halogens, halogen substituted C1-5 alkyl groups, nitryl and amino groups, and R3, R4 and R5 are selected from hydrogen, C1-5 alkyl groups, C1-5 alkoxy groups, halogens, halogen substituted C1-5 alkyl groups, nitryl and amino groups.
Description
Technical field
The present invention relates to the function of class indoles grafting thiazole hydrazone analog derivative and preparation method thereof and inhibition tumor cell tubulin polymerization.
Background technology
Depolymerization and the polymerization of indoles medicine energy inhibition tumor cell tubulin, carry out the activity of anticancer in vivo by destroying microtubule with external morphology and function, thus performance antitumous effect.Some indoles medicine can promote and the polymerized form of stable tubulin (nearest research shows, medicine is due to they interference to microtubule dynamics to the restraining effect of microtubule depolymerization, rather than the change of tubulin polymerization thing amount.); And some indoles medicine is by suppressing the polymerization of microtubule with the strong combination of colchicine binding site.
In recent years, containing thiazole ring compound, at aspects such as drug research and biology, demonstrate more and more important effect, wherein aminothiazole compounds has stronger physiologically active, is especially subject to investigator's attention.Thereby thiazole compound can show multiple biological activity with targeted integration such as plurality of enzymes in organism and acceptors.The inhibition of the generation of tumour and the apoptotic signal of tumour cell own is closely bound up, so apoptosis plays an important role in the chemotherapy of tumour, and a lot of medicines is all by reconstituted cell apoptosis, to reach the object for the treatment of tumour.Excessive ROS (intracellular reactive oxygen species) can induce mitochondrial membrane potential (MMP) collapse, the dead factor in plastosome is discharged, inducing cell death; The accumulation of ROS simultaneously can cause lipid peroxidation, the oxidation inactivation of protein, enzyme and the oxidative damage of DNA.Research shows, tumour cell has the ROS level higher than normal cell, more responsive to the attack of ROS, so the relevant drug development of ROS becomes a focus of antitumor drug research and development.Develop it and there is certain theory significance and actual value, therefore, we design and have synthesized a series of indoles grafting thiazole hydrazone analog derivatives that (E)-4-(4-methoxyl group)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole is female ring of take.
Summary of the invention
The object of the present invention is to provide class indoles grafting thiazole hydrazone analog derivative and preparation method thereof.
Technical scheme of the present invention is as follows:
1. a class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have following general formula:
In formula, R
1, R
2be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-10 alkyl, cycloalkyl, C1-5 alkoxyl group, halogen, halogen replacement;
R
3, R
4, R
5be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-5 alkyl, C1-5 alkoxyl group, halogen, halogen replacement.
2. prepare a class indoles grafting thiazole hydrazone analog derivative method for making claimed in claim 1, they are synthesized by the following step:
Step 1., in stink cupboard, under cold condition, adds in flask after organic solvent DMF certain volume, slowly drips the POCl of same volume
3again the compound 1 that is dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, stirring reaction is after for some time, rising temperature, to room temperature, is followed the tracks of reaction through TLC, after question response is complete, reaction solution is poured in the frozen water of certain volume, with alkali, regulate pH value to slight alkalinity, then use organic solvent extraction, be spin-dried for and obtain yellow powder 2.
Step 2. is mixed compound 2 obtained above and thiosemicarbazide, adds a certain amount of organic solvent dissolution, stirring reaction at room temperature, TLC follows the tracks of reaction, after reacting completely, filtration, purified must yellow powder 3.
Step 3. is compound 3 obtained above, containing various substituent alpha-brominated methyl phenyl ketones, is dissolved in appropriate organic solvent, through TLC, follows the tracks of reaction, after reacting completely, filters, and purifiedly obtains target compound indole derivatives of the present invention.
3. experimental result shows, new indole grafting thiazole hydrazone analog derivative of the present invention has obvious restraining effect to the polymerization of cancer cells microtubule.Therefore indoles grafting thiazole hydrazone analog derivative of the present invention can be applied to prepare cancer therapy drug.
Embodiment:
Embodiment mono-: the preparation of (E)-4-(4-p-methoxy-phenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl
3slowly drop in flask, then the 1-skatole (1.32g, 10.0mmoL) that is dissolved in 10mL DMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na
2cO
3or K
2cO
3regulate pH value to 9, be extracted with ethyl acetate, be spin-dried for and obtain yellow powder.Get solid obtained above (0.61g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.43mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 77.9mg such as add again, 0.43mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 82.3%.m.p.205~207 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
20h
18n
4oS: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 bis-: the preparation of (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4-phenyl thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with α bromoacetophenone, obtains yellow powder shape target compound.Productive rate 69.5%.m.p.207~208 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
19h
16n
4s:C, 68.65; H, 4.85; N, 16.85%; Found:C, 68.63; H, 4.86; N, 16.86%.
Embodiment tri-: the preparation of (E)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4-(4-(trifluoromethyl) phenyl) thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-bromoacetophenone, obtains yellow powder shape target compound.Productive rate 86.3%.m.p.230~235 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
20h
15f
3n
4s:C, 59.99; H, 3.78; N, 13.99%; Found:C, 59.98; H, 3.77; N, 13.97%.
Embodiment tetra-: the preparation of (E)-4-(4-bromophenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine) thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 87.3%.m.p.237~241 ℃.
1h NMR (DMSO-d
6, 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 C
19h
15brN
4s: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 radical) hydrazine) phenyl) preparation of thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 84.5%.m.p.195~198 ℃.
1h NMR (DMSO-d
6, 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 C
19h
15brN
4s:C, 55.48; H, 3.68; N, 13.62%; Found:C, 55.46; H, 3.69; N, 13.64%.
Embodiment six: (E)-4-(o-methoxyphenyl)-2-(2-((1-methyl isophthalic acid-H-indol-3-yl) methylene radical) hydrazine)-4 phenyl) preparation of thiazole
Preparation method, with embodiment mono-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with O-methoxy-alpha-brominated methyl phenyl ketone.Productive rate 81.3%.m.p.218~219 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
20h
18n
4oS: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: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl
3slowly drop in flask, then the 1-H indoles (1.17g, 10.0mmoL) that is dissolved in 10mL DMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na
2cO
3or K
2cO
3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.55g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.46mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 11mg such as add again, 0.46mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205~207 ℃ .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 C
19h
16n
4oS: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 radical) hydrazine)-4-phenyl thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 84.2%.m.p.245~246 ℃.
1h NMR (DMSO-d
6, 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 C
18h
14n
4s:C, 67.90; H, 4.43; N, 17.60%; Found:C, 67.89; H, 4.42; N, 17.58%.
Embodiment nine: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with O-methoxy-α-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.4%.m.p.245~246 ℃.
1h NMR (DMSO-d
6, 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 C
19h
16n
4oS: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 radical) hydrazine)-4-(3-bromophenyl) thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-α of 3--methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 88.4%.m.p.237~238 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
18h
13brN
4s:C, 54.42; H, 3.30; N, 14.10%; Found:C, 54.43; H, 3.33; N, 14.12%.
Embodiment 11: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 90.4%.m.p.201~202 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
19h
13f
3n
4s:C, 59.06; H, 3.39; N, 14.50%; Found:C, 59.04; H, 3.38; N, 14.52%.
Embodiment 12: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-bromophenyl) thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-α of 4--methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 87.2%.m.p.209~210 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
18h
13brN
4s:C, 54.42; H, 3.30; N, 14.10%; Found:C, 54.44; H, 3.29; N, 14.11%.
Embodiment 13: the preparation of (E)-2-(2-((1-H-indol-3-yl) methylene radical) hydrazine)-4-((1,1 '-biphenyl)-4-yl) thiazole
Preparation method, with embodiment tetra-, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with O-methoxy-α-methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.4%.m.p.245~246 ℃.
1h NMR (DMSO-d
6, 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 C
24h
18n
48:C, 73.07; H, 4.60; N, 14.20%; Found:C, 73.06; H, 4.61; N, 14.22%.
Embodiment 14: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mL POCl
3slowly drop in flask, 5-methoxy-Indole (the 1.47g of 10mL DMF will be dissolved in again, 10.0mmoL) be slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na
2cO
3or K
2cO
3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.67g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.41mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 9.39mg such as add again, 0.41mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205~207 ℃.
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 C
20h
18n
4o
2s: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: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-phenyl thiazole
Preparation method, with embodiment seven, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 85.5%.m.p.209~210 ℃.
1h NMR (DMSO-d
6, 400MHz) δ: 3.88 (s, 3H), 6.87 (dd, J
1=9Hz, J
2=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 C
19h
10n
4oS: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: the preparation of (E)-4-(4-bromophenyl)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine) thiazole
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 79.8%.m.p.175~176 ℃.
1h NMR (DMSO-d
6, 400MHz) δ: 3.87 (s, 3H), 6.87 (dd, J
1=9Hz, J
2=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 C
19h
15brN
4oS: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: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with 4-trifluoromethyl-alpha-bromoacetophenone, obtains yellow powder shape target compound.Productive rate 88.8%.m.p.165~166 ℃.
1h NMR (DMSO-d
6, 400MHz) δ: 3.87 (s, 3H), 6.86 (dd, J
1=8.72Hz, J
2=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 C
20h
15f
3n
4oS: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: the preparation of (E)-4-(3-bromophenyl)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine) thiazole
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 86.2%.m.p.229~230 ℃.
1h NMR (DMSO-d
6, 400MHz) δ: 3.88 (s, 3H), 6.86 (dd, J
1=6.57Hz, J
2=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 C
19h
15brN
4oS: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: the preparation of (E)-2-(2-((5-methoxyl group-1-H-indol-3-yl) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Preparation method, with embodiment seven, replaces alpha-brominated methyl phenyl ketone with O-methoxy-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 89.8%.m.p.175~176 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
20h
18n
4o
2s: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: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-p-methoxy-phenyl) thiazole
In stink cupboard, under cold condition, in 100mL single necked round bottom flask, add the DMF of 10mL, by 5mLPOCl
3slowly drop in flask, then the 5-bromo indole (1.96g, 10.0mmoL) that is dissolved in 10mLDMF is slowly added drop-wise in flask, after the about 2h of stirring reaction, rising temperature, to room temperature, is reacted about 2-3h, after reaction finishes, standing after it is cooling, reactant is joined in 20mL frozen water, use Na
2cO
3or K
2cO
3regulate pH value to 9, the solid filtering post-drying of separating out, obtains yellow powder.Get solid obtained above (0.85g, 3.8mmoL) and join in 50mL single necked round bottom flask, add 25mL Virahol and dissolve, the thiosemicarbazide that adds again 0.35g, stirring reaction under room temperature, TLC follows the tracks of reaction, after about 24h, finish reaction, filter, obtain yellow solid.Get above-mentioned yellow solid (0.1g, 0.34mmoL) be placed in the single necked round bottom flask of 50mL, adding 25mL Virahol dissolves, amount (the 7.79mg such as add again, 0.34mmoL) to methoxyl group-alpha-brominated methyl phenyl ketone, stirring reaction under room temperature, TLC follows the tracks of, after about 24h, react completely, filter and obtain yellow powder shape target compound.Productive rate 81%.m.p.205~207 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
19h
15brN
4oS: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 preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4 phenyl thiazoles
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound.Productive rate 82.9%.m.p.92~93 ℃.
1h NMR (DMSO-d
6, 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 C
18h
13brN
4s:C, 53.42; H, 3.30; N, 14.10%; Found:C, 53.41; H, 3.33; N, 14.11%.
Embodiment 22: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(3-bromophenyl) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 3-, obtains yellow powder shape target compound.Productive rate 86.1%.m.p.94~95 ℃.
1h NMR (DMSO-d
6, 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 C
18h
12br
2n
4s:C, 45.40; H, 2.54; N, 11.77%; Found:C, 45.41; H, 2.53; N, 11.76%.
Embodiment 23: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(o-methoxyphenyl) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with O-methoxy-alpha-brominated methyl phenyl ketone.Productive rate 82.9%.m.p.92~93 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
19h
15brN
4oS: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: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-trifluoromethyl) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 79.4%.m.p.175~176 ℃.
1h NMR (DMSO-d
6, 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 C
19h
12brF
3n
4oS:C, 49.05; H, 2.60; N, 12.04%; Found:C, 49.04; H, 2.62; N, 12.03%.
Embodiment 25: the preparation of (E)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine)-4-(4-bromophenyl) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone with the bromo-alpha-brominated methyl phenyl ketone of 4-, obtains yellow powder shape target compound.Productive rate 83.4%.m.p.186~187 ℃.
1h NMR (DMSO-d
6, 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 C
18h
12br
2n
4s:C, 45.40; H, 2.54; N, 11.77%; Found:C, 45.42; H, 2.53; N, 11.76%.
Embodiment 26: the preparation of (E)-4 ((1,1 '-biphenyl)-4-yl)-2-(2-((the bromo-1-H-indol-3-yl of 5-) methylene radical) hydrazine) thiazole
Preparation method, with embodiment ten, replaces 4-methoxyl group-alpha-brominated methyl phenyl ketone, obtains yellow powder shape target compound with 4-phenyl-alpha-brominated methyl phenyl ketone.Productive rate 85.5%.m.p.228~229 ℃.
1h NMR (DMSO-d
6, 400MHz) 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 C
24h
17brN
4s:C, 60.89; H, 3.62; N, 11.84%; Found:C, 60.88; H, 3.64; N, 11.84%.
Embodiment 27: the research of indoles grafting thiazole hydrazone analog derivative anti tumor activity in vitro
Adopt MTT[3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazoles are blue] method measures the half-inhibition concentration (IC of indoles grafting thiazole hydrazone analog derivative to human breast cancer cell strain (MCF-7) and Human Lung Cancer cell strain (A549)
so).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, add after tri-distilled water dissolving the NaHCO with 5.6%
3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl8.00g, KCl0.40g, Na
2hPO
412H
2o0.06g, KH
2pO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: test sample is dissolved and is made into storing solution with a small amount of tri-distilled water, general by 10 times of preparation storing solutions of experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then add tri-distilled water dissolving.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cultivation of human breast cancer cell MCF-7: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO
2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) human lung cancer cell A549's cultivation: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO
2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: the tumour cell in the vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 * 10
5individual ml
-1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 ℃, 5%CO
2in incubator, cultivate 24h.Cultivate after 24h, by design, add liquid respectively.
(8) dosing: test liquid is joined respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in to 37 ℃, 5%CO
2in incubator, cultivate 48h.The activity of positive control medicine is measured according to the method for test sample.
(9) mensuration of survivaling cell: in having cultivated 96 orifice plates after 48h, every hole adds MTT40 μ l (being made into 4mg/ml with D-Hanks damping fluid).At 37 ℃, place after 4h, remove supernatant liquor.Every hole adds 150 μ l DMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, utilize automatic microplate reader at 570nm wavelength place, to detect the optical density(OD) (OD value) in each hole.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
experiment-OD
blank)/(OD
contrast-OD
blank)] * 100% (OD
experimentthe average optical that represents testing drug group, OD
contrastthe average optical that represents control group, OD
blankthe average optical that represents control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC recording
50be shown in Table 1.
The inhibition IC of the listed indoles grafting of form 1 the present invention thiazole hydrazone analog derivative to tumour cell
50value
Claims (3)
1. a class indoles grafting thiazole hydrazone analog derivative, is characterized in that they have following general formula:
In formula, R
1, R
2be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-10 alkyl, cycloalkyl, C1-5 alkoxyl group, halogen, halogen replacement;
R
3, R
4, R
5be selected from C1-5 alkyl, nitro, the amino of hydrogen, C1-5 alkyl, C1-5 alkoxyl group, halogen, halogen replacement.
2. prepare a class indoles grafting thiazole hydrazone analog derivative method for making claimed in claim 1, they are become by the following step:
Step 1., in stink cupboard, under cold condition, adds in flask after organic solvent DMF certain volume, slowly drips the POCl of same volume
3again the compound 1 that is dissolved in same volume organic solvent is added drop-wise in above-mentioned flask, stirring reaction is after for some time, rising temperature, to room temperature, is followed the tracks of reaction through TLC, after question response is complete, reaction solution is poured in the frozen water of certain volume, with alkali, regulate pH value to slight alkalinity, then use organic solvent extraction, be spin-dried for and obtain yellow powder 2.
Step 2. is mixed compound 2 obtained above and thiosemicarbazide, adds a certain amount of organic solvent dissolution, stirring reaction at room temperature, TLC follows the tracks of reaction, after reacting completely, filtration, purified must yellow powder 3.
Step 3. is compound 3 obtained above, containing various substituent alpha-brominated methyl phenyl ketones, is dissolved in appropriate organic solvent, through TLC, follows the tracks of reaction, after reacting completely, filters, and purifiedly obtains target compound indole derivatives of the present invention.
3. experimental result shows, new indole grafting thiazole hydrazone analog derivative of the present invention has obvious restraining effect to the polymerization of cancer cells microtubule.Therefore indoles grafting thiazole hydrazone analog derivative of the present invention can be applied to prepare cancer therapy drug.
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