CN106397445B - Pyrazoles N- p-bromophenyl maleimide derivatives containing chromone structure and preparation method and application - Google Patents
Pyrazoles N- p-bromophenyl maleimide derivatives containing chromone structure and preparation method and application Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses one kind 3（6 bromine, 4 oxygen 4H chromones）1 phenyl 5 p-bromophenyl 1,6a pyrrolin quinoline [3,4 c] pyrazoles 4,6（3aH,5H）Diketone and preparation method and application, which introduces in N p-bromophenyls maleimide on the basis of five yuan of pyrazole rings the structure for having imported chromone with 1,3 dipole-diople interaction method, so as to synthesize one new 3（6 bromine, 4 oxygen 4H chromones）1 phenyl 5 p-bromophenyl 1,6a pyrrolin quinoline [3,4 c] pyrazoles 4,6（3aH,5H）Diketone, above-claimed cpd have good inhibitory action for tumor cell line, wherein having better inhibiting rate and selectivity for leukaemia, are preparing antitumor drug etc., have extraordinary prospects for commercial application.
Description
Technical field：
The present invention relates to a kind of new pyrazoles N- p-bromophenyl maleimide derivatives containing chromone structure, specifically
Refer to 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6
(3aH, 5H)-diketone and preparation method and application.
Background technology：
N- p-bromophenyl maleimides, chemical name：1- p-bromophenyl pyrrolidines -2,5- diketone, chemical structural formula are as follows：
1- p-bromophenyl pyrrolidine-2,5-diones
1,3- Dipolar Cycloadditions are with its good region and main selectivity and as synthesis five member ring heterocyclic compound
More active a kind of reaction in most important method, and heterocyclic drug chemical research.In recent years, since chromone is extensive
Bioactivity, anticancer, antibacterial inhibit platelet aggregation etc. and receive much attention.So either from pharmacology still from conjunction
Angled to consider, this heterocyclic compounds has very high synthesis value.
Pyrazole derivatives as a kind of useful intermediate and themselves shown multi-medicament activity out and
It gets more and more people's extensive concerning.The present invention is assembled in same molecule and to caused by pharmacological activity by studying different heterocycles
It influences, so as to provide a kind of brand-new pyrazoles N- p-bromophenyl maleimide derivatives containing chromone structure.
The content of the invention：
The first aspect of the present invention purpose is to provide a kind of new pyrazoles N- p-bromophenyls Malaysia containing chromone structure
Imide derivative.
The technical solution that the present invention takes is as follows：
A kind of pyrazoles N- p-bromophenyl maleimide derivatives containing chromone structure, chemical name are：3-(6-
Bromo- 4- oxygen -4H- chromones) -1- phenyl -5- p-bromophenyl -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6 (3aH, 5H)-two
Ketone, structural formula are as follows：
The compound relevant experimental data is as follows：
Applicant is had found by studying：Substituted using chromone derivative in the structure of pyrazoles, to N- p-bromophenyls
Maleimide carries out structure of modification, obtains a kind of brand-new pyrazoles N- p-bromophenyl maleimides containing chromone structure
Amine derivative, the compound can change pharmacological activity.
The second aspect of the present invention purpose is to provide a kind of above-mentioned pyrazoles N- p-bromophenyls Malaysia containing chromone structure
The preparation method of imide derivative, which is characterized in that comprise the following steps：Maleic anhydride and para-bromoaniline reaction are closed
Into N- p-bromophenyls maleimide (3), then there is the 6- bromos chromone that carboxaldehyde radicals substitutes to be closed with phenylhydrazine dehydration using 3
Into 6- bromo chromone phenylhydrazones (4), N- p-bromophenyls maleimide (3) and 6- bromo chromone phenylhydrazones (4) are finally subjected to dipole
Cycloaddition reaction synthesizes 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyl -1,6a- pyrrolin quinolines [3,4-c]
Pyrazoles -4,6 (3aH, 5H)-diketone (5).
Reaction equation of the present invention is as follows：
Further, a kind of 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyl -1,6a- dihydros
The preparation method of pyrrolin [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone, which is characterized in that comprise the following steps：
(1), the synthesis of N- p-bromophenyls maleimide：
Maleic anhydride and para-bromoaniline are dissolved in acetone solvent, react under stiring and progressively generated faint yellow
Precipitation, when room temperature reaction 1 is small after, take a small amount of precipitation, through washing, dry, sequentially add manganese acetate, triethylamine and aceticanhydride, heat up
Afterwards, precipitation progressively dissolves, and when reaction 2 is small at 50~60 DEG C, solution becomes red-black by orange, gradually appears new precipitation, cold
But to room temperature, precipitation obtains product N- p-bromophenyls maleimide (3) through washing, drying with acetone recrystallization in water；
(2), the synthesis of 6- bromos chromone phenylhydrazone:
The 6- bromo chromone phenylhydrazones (4) are known compound, and No. CAS is 68287-82-1, and the present invention is had using 3
The 6- bromos chromone of carboxaldehyde radicals substitution and the method for phenylhydrazine dehydration generation schiff bases are synthesized：The phenylhydrazine of 2mmol is taken to add
In the flask for entering to fill 10mL tetrahydrofurans, then boiling water bath return stirring is slowly added dropwise into 20mL to dissolving dissolved with 2mmol 3
There is the ethanol solution of the 6- bromo chromones of carboxaldehyde radicals substitution in position, continues boiling water bath return stirring 1h, and 10 drop hydrochloric acid are added dropwise, have
Pale yellow precipitate occurs；Continuous boiling water bath return stirring 5h, stops water-bath, people 20mL distilled water is added to stir, pale yellow precipitate face
Discoloration is deep, filters to obtain 6- bromo chromone phenylhydrazones, is the needle-shaped product of yellowish red color, is rinsed repeatedly with anhydrous ether, being dried in vacuo must produce
Object 6- bromo chromone phenylhydrazones (4)；
(3), 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrrole
The synthesis of azoles -4,6 (3aH, 5H)-diketone：
By 1mmol N- p-bromophenyls maleimides (3) and 1.1mmol 6- bromo chromone phenylhydrazones (4) in 20mL ethyl alcohol
In, 1.2mL toluene-sodium-sulfonchloramides are added, when reflux 12 is small, precipitation is filtered, cleaning is recrystallized with methanol, produced after vacuum drying
Object 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6 (3aH,
5H)-diketone (5).
Further it is provided in：
In the step (1), pale yellow precipitate obtained by the reaction need to be filtered under diminished pressure.
The third aspect of the present invention purpose is to provide a kind of 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- to bromobenzene
Base -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6 (3aH, the 5H)-application of diketone in terms of antitumor drug is prepared.Pass through
Experimental verification：Above-claimed cpd, for different knurl strains for example human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell,
Leukaemia, colon-cancer cell etc., are respectively provided with inhibitory action, wherein having more preferably inhibiting rate and selection for leukaemia
Property, antitumor drug can be prepared separately, can also be used as active ingredient and other antitumor drugs prepare anti-tumor compositions, tool
There is extraordinary prospects for commercial application.
Beneficial effects of the present invention are as follows：
The applicant it has been investigated that, substituted using chromone derivative in the structure of pyrazoles, to N- p-bromophenyls
Maleimide carries out structure of modification, obtains a kind of brand-new pyrazoles N- p-bromophenyl maleimides containing chromone structure
Amine derivative, the compound can change pharmacological activity, through further experiment and analysis, study different heterocycles in same molecule
Assemble on influence caused by pharmacological activity, applicant has synthesized the pyrazoles containing chromone structure by Dipolar Cycloaddition
Class N- p-bromophenyl maleimide derivatives, the new pyrazoles N- p-bromophenyl horses containing chromone structure prepared by this method
Carry out imide derivative, in terms of antitumor drug is prepared, there is extraordinary prospects for commercial application.
Specific embodiment：
Toluene-sodium-sulfonchloramide：English name Chloramine-T, chemical constitution are
The present invention is described further with reference to embodiments, but embodiment should not be construed as limiting the model of the present invention
It encloses.
The synthesis of embodiment 1, N- p-bromophenyl maleimides：
Maleic anhydride and para-bromoaniline are dissolved in a certain amount of acetone solvent, it is under stiring that para-bromoaniline is molten
Drop adds to the reaction bulb containing maleic acid anhydride solution, and exothermic heat of reaction simultaneously progressively generates pale yellow precipitate, and room temperature reaction 1 is small
Shi Hou takes a small amount of precipitation, through washing, dry, sequentially adds manganese acetate, triethylamine and aceticanhydride, and after heating, precipitation progressively dissolves,
When reaction 2 is small at 50~60 DEG C, solution becomes red-black by orange, gradually appears new precipitation, is cooled to room temperature, is precipitated in water
Through massive laundering, drying, product N- p-bromophenyls maleimide (3) is obtained with acetone recrystallization.
The synthesis of embodiment 2,6- bromo chromone phenylhydrazones：
The phenylhydrazine of 2mmol is taken to add in the flask for filling 10mL tetrahydrofurans, boiling water bath return stirring to dissolving, Ran Houhuan
It is slow to be added dropwise to ethanol solutions of the 20mL dissolved with 3 6- bromo chromones for thering is carboxaldehyde radicals to substitute of 2mmol, continue boiling water bath and return
Stream stirring 1h is added dropwise 10 drop hydrochloric acid, there is pale yellow precipitate appearance.Continuous boiling water bath return stirring 5h, stops water-bath, adds people 20mL
Distilled water stirs, and pale yellow precipitate darkens, and filters to obtain phenylhydrazone, the needle-shaped product of yellowish red color.It is rinsed repeatedly, very with anhydrous ether
Empty dry product 6- bromo chromone phenylhydrazones (4).
Embodiment 3,3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyl -1,6a- pyrrolin quinolines [3,4-
C] pyrazoles -4,6 (3aH, 5H)-diketone synthesis：
By 1mmol N- p-bromophenyls maleimides and 1.1mmol 6- bromo chromone phenylhydrazones (4) in 20mL ethyl alcohol,
1.2mL toluene-sodium-sulfonchloramides are added, when reflux 12 is small.Precipitation is filtered, cleaning is recrystallized with methanol, product 3- is obtained after vacuum drying
(the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6 (3aH, 5H) -
Diketone (5).Product is yellow crystal, yield 74.6%, m.p.187.5-189 DEG C.
Compound (5) structural confirmation：C26H15Br2N3O4
1H NMR(DMSO)δ:7.234-7.493 (m, 12H, Ar-H), 6.47 (s, 1H, C=C-H), 5.82 (d, J=
1010Hz, 1H), 5.34 (d, J=1014Hz, 1H),
IR 3457 (N-C=O), 3085 (ArH), 1720 (C=O), 1577 (C=N), 1296 (C-O-C) cm-1
m/e:592.94 (100.0%), 590.94 (51.3%), 594.94 (48.9%).
Anal.calcd.for C26H15Br2N3O4：C,52.66；H,2.58；N,7.08.
Application Example 4：Using mtt assay detection test-compound (5) to the antitumor activity of different knurl strains.
Compound (5) prepared by above-described embodiment, with different knurl strains, [(human liver cancer is thin by tumour cell Bel-7402 respectively
Born of the same parents), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia),
ECA109 (colon-cancer cell)] it is experimental subjects, test compound (5) is for the In-vitro Inhibitory Effect of different knurl strains：Experiment uses
The micro enzyme reaction colorimetric method (mtt assay) of tetramethyl azo azoles salt, activity represent (IC with half-inhibition concentration50)。
Specific experiment step is as follows：
Compound 5 is dissolved with DMSO, dilute, tumour cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity),
SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia), ECA109 (colon-cancer cell) are in 96 holes
It is planted on plate into 4000/200 μ L/ holes, 2 μ L of often hole addition compound, 6.0 μM, 3.0 μM, 1.5 μM, are total to by final concentration of 12.0 μM
It is same as 37 DEG C, 5%CO2When incubation 72 is small in cell incubator, with DMSO (1%) for blank control.72 it is small when after, add in eventually it is dense
The MTT for 0.25mg/mL is spent, is placed in 37 DEG C, 5%CO2In cell incubator 4 it is small when, blot solvent afterwards, per hole add in 100 μ
L DMSO, absorbance (OD values) is measured with enzyme linked immunological instrument at 570nm, and the data obtained is used to calculate IC50Value.Inhibition is selected to live
Property high compound, measure influence of the compound effects time difference under various concentration to human tumor cells cycle and apoptosis.
The test-compound of various concentration carries out scalping with 96 orifice plates, according to the inhibiting rate of gained, calculates IC50Value, as a result
It see the table below.
Table 1, pyrazoles N- p-bromophenyls maleimide derivatives are to the IC of six kinds of tumor cell lines50Value
It can be seen that by upper table data：Compound prepared by the present invention is respectively provided with inhibition for six kinds of tumor cell lines
Wherein having better inhibiting rate and selectivity for HL-60 (leukaemia), antineoplastic can be prepared separately in effect
Object can also be used as active ingredient and other antitumor drugs prepare anti-tumor compositions, before having extraordinary commercial Application
Scape.
Claims (5)
1.3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6
(3aH, 5H)-diketone, structural formula are as follows：。
2. a kind of 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -
The preparation method of 4,6 (3aH, 5H)-diketone, which is characterized in that comprise the following steps：Maleic anhydride and para-bromoaniline is anti-
N- p-bromophenyl maleimides should be synthesized, then have the 6- bromos chromone that carboxaldehyde radicals substitutes and phenylhydrazine dehydration using 3
6- bromo chromone phenylhydrazones are synthesized, it is anti-that N- p-bromophenyls maleimide and 6- bromo chromones phenylhydrazone finally are carried out dipole-diople interaction
Should, synthesize 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyl -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6
(3aH, 5H)-diketone.
3. a kind of 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- two according to claim 2
The preparation method of hydrogen pyrrolin [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone, which is characterized in that comprise the following steps：
(1), the synthesis of N- p-bromophenyls maleimide：
It is faint yellow heavy that maleic anhydride and para-bromoaniline are dissolved in acetone solvent, react under stiring and progressively generated
Form sediment, when room temperature reaction 1 is small after, take a small amount of precipitation, through washing, dry, sequentially add manganese acetate, triethylamine and aceticanhydride, after heating,
Precipitation progressively dissolves, and when reaction 2 is small at 50~60 DEG C, solution becomes red-black by orange, gradually appears new precipitation, is cooled to
Room temperature, precipitation obtains product N- p-bromophenyl maleimides through washing, drying with acetone recrystallization in water；
(2), the synthesis of 6- bromos chromone phenylhydrazone:
The phenylhydrazine of 2mmol is taken to add in the flask for filling 10mL tetrahydrofurans, then boiling water bath return stirring is slowly dripped to dissolving
Ethanol solutions of the 20mL dissolved with 3 6- bromo chromones for having carboxaldehyde radicals to substitute of 2mmol is added in, continues boiling water bath reflux and stirs
1h is mixed, 10 drop hydrochloric acid are added dropwise, there is pale yellow precipitate appearance；Continuous boiling water bath return stirring 5h, stops water-bath, adds in 20mL and steams
Distilled water stirs, and pale yellow precipitate darkens, and filters to obtain 6- bromo chromone phenylhydrazones, is the needle-shaped product of yellowish red color, uses anhydrous ether
It rinses repeatedly, is dried in vacuo to obtain product；
(3), 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,
The synthesis of 6 (3aH, 5H)-diketone:
By 1mmol N- p-bromophenyls maleimides and 1.1mmol 6- bromo chromone phenylhydrazones in 20mL ethyl alcohol, add
1.2mL toluene-sodium-sulfonchloramides, when reflux 12 is small, precipitation is filtered, and cleaning is recrystallized, product 3- is obtained after vacuum drying, and (6- is bromo- with methanol
4- oxygen -4H- chromones) -1- phenyl -5- p-bromophenyls -1,6a- pyrrolin quinoline [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone.
4. a kind of 3- (the bromo- 4- oxygen -4H- chromones of 6-) -1- phenyl -5- p-bromophenyls -1,6a- two according to claim 3
The preparation method of hydrogen pyrrolin [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone, it is characterised in that：In the step (1), instead
The pale yellow precipitate that should be obtained need to be filtered under diminished pressure.
5. a kind of application of the compound in terms of antitumor drug is prepared described in claim 1.
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| CN109988179B (en) * | 2019-04-30 | 2021-08-24 | 绍兴文理学院元培学院 | Pyrazole structure-containing N-phenyl substituted maleimide alpha-terpinene cycloaddition derivative and preparation method and application thereof |
| CN110105364B (en) * | 2019-04-30 | 2021-08-24 | 绍兴文理学院元培学院 | Pyrazole structure-containing N-p-chlorophenyl substituted maleimide alpha-terpinene cycloaddition derivative, and preparation method and application thereof |
| CN109988177B (en) * | 2019-04-30 | 2021-08-24 | 绍兴文理学院元培学院 | Pyrazole structure-containing N-p-methoxyphenyl substituted maleimide alpha-terpinene cycloaddition derivative and preparation method and application thereof |
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