CN104370799B - A kind of 3 oxo diazanyl substituted indole ketones derivants and preparation method and application - Google Patents
A kind of 3 oxo diazanyl substituted indole ketones derivants and preparation method and application Download PDFInfo
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- CN104370799B CN104370799B CN201410705355.0A CN201410705355A CN104370799B CN 104370799 B CN104370799 B CN 104370799B CN 201410705355 A CN201410705355 A CN 201410705355A CN 104370799 B CN104370799 B CN 104370799B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention relates to a kind of 3 oxo diazanyl substituted indole ketones derivant and preparation method and application, the general structure of the derivative is that (I) is shown,Wherein, R2 is hydrogen, halogen or alkyl；Using meta aniline as raw material, by into oxime, cyclization, Heck Coupl ing, alkylation, synthesize 3 oxo diazanyl substituted indole ketones derivants into hydrazine series reaction, there is application value in terms of antineoplastic is prepared.
Description
Technical field
The present invention relates to production of chemicals field, especially a kind of 3- oxos diazanyl substituted indole ketones derivant and its system
Preparation Method and application.
Background technology
Isatin is the indoles quinones being widely present in natural products, is also to be present in mammalian tissues and body
Endogeneous activity composition in liquid, its N- alkyl-substituted derivative is in addition to having anti-leukocythemia liveness, in antiviral and antimicrobial
Thing research field also has application.
The indolone derivatives of document report, majority is the derivatization on indolone aromatic ring, the thio oxo diazanyl substitutions of 3-
The synthesis of indolone and the research of bioactivity and its structure-activity relationship report are less.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of 3- oxos diazanyl substituted indole ketones derivant.
Another technical problem to be solved by this invention is to provide above-mentioned 3- oxos diazanyl substituted indole ketones derivant
Preparation method.
Another technical problem to be solved by this invention is to provide above-mentioned 3- oxos diazanyl substituted indole ketones derivant
Application.
In order to solve the above technical problems, the technical scheme is that：
A kind of 3- oxos diazanyl substituted indole ketones derivant, its general structure is that (I) is shown,
Wherein, R2 is hydrogen, halogen or alkyl.
It is preferred that, above-mentioned 3- oxos diazanyl substituted indole ketones derivant works as R2During for hydrogen, as 1- methyl -3- benzene first
Hydrazides -4- methyl acrylate indole diones, its hydrogen nuclear magnetic resonance modal data is1H NMR(CDCl3400MHz):δ/ppm 3.27
(s,3H),3.83(s,3H),6.53-6.57(d,1H),6.82-6.84(d,1H),7.01-7.21(m,2H),7.27-7.35
(m,5H),8.62-8.66(d,1H),12.92(s,1H)。
It is preferred that, above-mentioned 3- oxos diazanyl substituted indole ketones derivant works as R2During for 4- methyl, as 1- methyl -3-
(4- toluyls hydrazine) -4- methyl acrylate indole diones.
It is preferred that, above-mentioned 3- oxos diazanyl substituted indole ketones derivant works as R2During for 4- methoxyl groups, as 1- methyl-
3- (4- methoxybenzoyls hydrazine) -4- methyl acrylate indole diones.
It is preferred that, above-mentioned 3- oxos diazanyl substituted indole ketones derivant works as R2During for 4- chlorine, as 1- methyl -3- (4-
Chlorobenzoyl hydrazine) -4- methyl acrylate indole diones.
The preparation method of above-mentioned 3- oxos diazanyl substituted indole ketones derivant, using meta aniline as raw material, by into oxime,
Cyclization, Heck-Coupl ing, alkylation, synthesize 3- oxo diazanyl substituted indole ketones derivants into hydrazine series reaction,
Its specific synthetic route is as follows：
Wherein, R2 is hydrogen, halogen or alkyl.
Application of the above-mentioned 3- oxos diazanyl substituted indole ketones derivant in antineoplastic is prepared.
It is preferred that, the application of above-mentioned 3- oxos diazanyl substituted indole ketones derivant, the tumour is human leukemia, people's knot
Intestinal cancer and human liver cancer.
The beneficial effects of the invention are as follows：
Above-mentioned 3- oxos diazanyl substituted indole ketones derivant, be using meta aniline as raw material, by into oxime, cyclization,
Heck-Coupl ing, alkylation, synthesize the 3- oxo diazanyl substituted indoles with antitumor activity into hydrazine series reaction
Ketones derivant, the measure through cell in vitro antitumor activity is inhibited to activity of tumor cells, particularly with following
Three kinds of tumour cells：Human leukemia cell (K562), human colon cancer cell (HT-29) and human liver cancer cell (HepG2) suppress to make
With obvious, this kind of derivative I C is as a result shown50<100 μM, with preferable anti-tumor biological, have very well to tumour cell
Lethal effect, can be applied to prepare antineoplastic, opened up a class new type antineoplastic medicine；And the system of the analog derivative
Preparation Method has gentle simple to operate, reaction condition, synthesis technique and purification process are simple, high income, assay method are simple etc.
Advantage, the need for being adapted to scale industrial production.
Brief description of the drawings
Fig. 1 is 1- methyl -3- benzoyl hydrazine -4- methyl acrylate indole dione proton nmr spectras.
Embodiment
In order that those skilled in the art is better understood from technical scheme, with reference to embodiment
Technical scheme of the present invention is described in further detail.
Embodiment 1
1- methyl -3- benzoyl hydrazine -4- methyl acrylates indole diones (compound 1)
(1) synthesis of synthetic intermediate 4- bromo indoles diketone
Take 3- bromanilines 10.00g (58.13mmol) to be put into 1000mL round-bottomed flasks, add 500mL water, in stirring feelings
Anhydrous sodium sulfate 64.41g (453.43mmol) and hydroxylamine hydrochloride 13.33g (191.84mmol) is added under condition, is then added
2mol/L hydrochloric acid solution 10mL, stir 5min at room temperature, are eventually adding chloraldurate 10.58g (63.95mmol).Reaction is mixed
15min is stirred at room temperature in compound, and then 90 DEG C are heated to reflux lower reaction 2h.TLC detection raw materials disappear, and are subsequently cooled to room temperature, take out
Filter, vacuum drying, obtains light yellow solid 12.90g.
The 40mL concentrated sulfuric acids are taken to be added in 100mL round-bottomed flasks, in being slowly added to 12.90g yellow solid at 50 DEG C
Into the concentrated sulfuric acid, 30min is reacted at 65 DEG C after being added completely into.Reaction is cooled to room temperature after terminating, and then falls reactant mixture
Enter into mixture of ice and water, stir 30min, suction filtration is obtained and dried under red solid, vacuum drying chamber, petroleum ether：Ethyl acetate=
5:1,200 mesh silica gel column chromatography is purified, and obtains 4- bromo indole diketone 7.42g, yield 51%.
(2) synthetic intermediate 4- methyl acrylates indole dione
Take 4- bromo indole diketone 1.0g (4.4mmol), methyl acrylate 0.46g (5.3mmol), PdCl2(PPh3)20.15g
(0.22mmol), K3PO41.6g (6.2mmol), is put into microwave reaction bottle, adds 5mL DMF, argon filling gas shielded is anti-in microwave
Answer 145 DEG C of reaction 30min in device.After TLC detection reactions completely, reaction solution is washed 3 times with 100mL saturated common salts, with two
Chloromethanes is extracted, and merges organic phase, and anhydrous sodium sulfate drying uses solvent petroleum ether：Ethyl acetate=5:1-1:1,200-300
Mesh silica gel column chromatography is purified, and obtains 4- methyl acrylate indole dione 0.65g, yield 64%.
(3) synthetic intermediate 1- methyl -4- methyl acrylate indole diones
Take 4- methyl acrylate indole dione 0.5g (2.16mmol) to be put into 25mL round-bottomed flasks, add 2mL N, N-
Dimethylformamide, stirring makes it fully dissolve, and then adds Anhydrous potassium carbonate 0.9g (6.49mmol), adds iodomethane
0.64g(4.32mmol).6h is reacted at room temperature, and TLC detection raw materials disappear, and add 30mL water, then ethyl acetate is extracted
(100mL × 3), merge organic phase, and solvent, petroleum ether are removed in anhydrous sodium sulfate drying, decompression rotation：Ethyl acetate=10:1-5:
1200-300 mesh silicagel column is purified.Obtain 1- methyl -4- methyl acrylate indole dione 0.47g, yield 88%.
(4) 1- methyl -3- benzoyl hydrazine -4- methyl acrylate indole diones are synthesized
Take 1- methyl -4- methyl acrylate indole dione 0.20g (0.8mmol) to be put into 25mL round-bottomed flasks, add
The drop of acetic anhydride two and benzoyl hydrazine 0.12g (0.97mmol) are added under 15mL absolute ethyl alcohols, stirring state, is flowed back after being added completely into
React 2h.TLC detection reactions are cooled to room temperature after terminating, and then reactant mixture are poured into mixture of ice and water, Ran Houyong
Ethyl acetate is extracted three times, merges organic phase, and solvent, petroleum ether are removed in anhydrous sodium sulfate drying, decompression rotation：Ethyl acetate=3:1,
200 mesh silica gel column chromatographies are purified, and obtain 1- methyl -3- benzoyl hydrazine -4- methyl acrylate indole dione 0.19g, yield 65%.
After measured, as shown in figure 1,1H NMR(CDCl3400MHz):δ/ppm 3.27(s,3H),3.83(s,3H),6.53-
6.57(d,1H),6.82-6.84(d,1H),7.01-7.21(m,2H),7.27-7.35(m,5H),8.62-8.66(d,1H),
12.92(s,1H).
In addition, the preparation method of other derivatives (compound 2-4), be the same as Example 1, wherein, in step (4)By R24- methyl, 4- first are replaced with for hydrogen
Epoxide or 4- chlorine, respectively obtain compound 2-4, are specially：
Work as R2During for 4- methyl, as 1- methyl -3- (4- toluyls hydrazine) -4- methyl acrylates indole dione (is changed
Compound 2)；
Work as R2During for 4- methoxyl groups, as 1- methyl -3- (4- methoxybenzoyls hydrazine) -4- methyl acrylate indole diones
(compound 3)；
Work as R2During for 4- chlorine, as 1- methyl -3- (4- chlorobenzoyls hydrazine) -4- methyl acrylate indole dione (compounds
4)。
Embodiment 2
The preparation of solution：
The preparation of DMEM low sugar nutrient solutions：Buy HyClone MEM low sugar culture mediums, every bottle of 500mL, the tire of addition 10%
Cow's serum and 1% mycillin solution, i.e., every bottle culture medium add 50mL hyclone and 5mL mycillin, culture
The configuration of base is carried out in superclean bench, rear to place 4 DEG C of preservations of refrigerator.
The preparation of DMEM/F-12 nutrient solutions：HyClone MEM/F-12 culture mediums are bought, every bottle of 500mL adds 10%
Hyclone and 1% mycillin solution, i.e., every bottle culture medium add 50mL hyclone and 5mL mycillin, training
The configuration for supporting base is carried out in superclean bench, rear to place 4 DEG C of preservations of refrigerator.
The preparation of PBS：In 1000mL conical flasks, sodium chloride 8g, potassium chloride 0.2g, 12 hypophosphite monohydrates are weighed
Disodium hydrogen 2.9g, potassium dihydrogen phosphate 0.2g, add after 800mL pure water is sufficiently stirred for dissolving and are settled to 1000mL, autoclaving
4 DEG C of preservations of refrigerator are placed afterwards.
The preparation of MTT solution：MTT dry powder 0.5g are weighed, are dissolved in 100mL PBSs, with 0.22 μM of membrane filtration
After degerming, -12 DEG C of preservations of refrigerator are placed.
The specific steps of antitumor cytolytic activity：
3 tumour cells used in antitumor cytolytic activity of the present invention：Human liver cancer cell (HepG2), leukaemia (K562)
With human colon cancer cell (HT-29).
I utilizes human liver cancer cell HepG2 active testings
The nutrient solution that HepG2 cells are used is containing 1% Pen .- Strep solution, the DMEM of 10% hyclone
Cell culture fluid, condition of culture is 37 DEG C, containing 5%CO2Constant incubator.Specific steps：
(1) after being counted with blood counting chamber to cell, it is diluted to with DMEM low glucose nutrient solutions
5x104Individual/mL；
(2) the piping and druming mixing of 100 μ L cell suspensions, 37 DEG C of incubation 24h of incubator are added in each hole of 96 orifice plates；
(3) wanted test compound is diluted to 5 kinds of concentration：2mM, 0.2mM, 20 μM, 2 μM, 0.2 μM, according to concentration according to
The secondary μ L/ holes of dosing 0.5,37 DEG C of incubation 48h of incubator；
(4) MTT that concentration is 5mg/mL, 37 DEG C of incubation 4h of incubator are added；
(5) DMSO is added to dissolve cell, the OD values that ELIASA is surveyed under 490nm and 630nm；
(6) processing data, IC is calculated according to OD values50Value, the results are shown in Table 1.
II utilizes Leukemia K562 cell active testing
The nutrient solution that K562 cells are used be containing 1% Pen .- Strep solution, 10% hyclone
PRMI1640 cell culture fluids, condition of culture is 37 DEG C, containing 5%CO2Constant incubator.Specific steps：
(1) after being counted with blood counting chamber to cell, 5x10 is diluted to RPMI nutrient solutions4Individual/mL；
(2) 100 μ L cell suspensions, 37 DEG C of incubation 2h of incubator are added in each hole of 96 orifice plates；
(3) wanted test compound is diluted to 5 kinds of concentration：2mM, 0.2mM, 20 μM, 2 μM, 0.2 μM, according to concentration according to
The secondary μ L/ holes of dosing 0.5,37 DEG C of incubation 48h of incubator；
(4) MTT that concentration is 5mg/mL is added, 37 DEG C of incubator is incubated 4 hours；
(5) isopropanol and hydrochloric acid lysate, the OD values that ELIASA is surveyed under 570nm and 630nm are added；
(6) processing data, IC is calculated according to OD values50Value, the results are shown in Table 1.
III utilizes human leukemia cell's HT-29 active testings
The nutrient solution that HT-29 cells are used is containing 1% Pen .- Strep solution, the DMEM/ of 10% hyclone
F-12 cell culture fluids, condition of culture is 37 DEG C, containing 5%CO2Constant incubator.Specific steps：
(1) after being counted with blood counting chamber to cell, 5x10 is diluted to with DMEM/F-12 nutrient solutions4Individual/
mL；
(2) the piping and druming mixing of 100 μ L cell suspensions, 37 DEG C of incubation 24h of incubator are added in each hole of 96 orifice plates；
(3) wanted test compound is diluted to 5 kinds of concentration：2mM, 0.2mM, 20 μM, 2 μM, 0.2 μM, according to concentration according to
The secondary μ L/ holes of dosing 0.5,37 DEG C of incubation 48h of incubator；
(4) MTT that concentration is 5mg/mL, 37 DEG C of incubation 4h of incubator are added；
(5) DMSO is added to dissolve cell, the OD values that ELIASA is surveyed under 490nm and 630nm；
(6) processing data, IC is calculated according to OD values50Value, the results are shown in Table 1.
Table 13- oxo diazanyl substituted indole ketones derivant antitumor activity results
As a result show, compound 1-4 IC50<100 μM, with preferable anti-tumor biological.
Above-mentioned reference embodiment is to a kind of 3- oxos diazanyl substituted indole ketones derivant and preparation method thereof
The detailed description carried out with application, is illustrative rather than limited, can include several realities according to limited scope
Example, therefore changing and modifications in the case where not departing from present general inventive concept are applied, should be belonged within protection scope of the present invention.
Claims (1)
1. a kind of preparation method of 3- oxos diazanyl substituted indole ketones derivant, it is characterised in that：Using meta aniline as raw material,
By into oxime, cyclization, Heck-Coupling, alkylation, synthesize 3- oxo diazanyl substituted indole ketones into hydrazine series reaction
Derivative, specific synthetic route is as follows：
Wherein, R2 is hydrogen.
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