CN110128444A - Spiral shell [indazole-isoxazole] derivative and preparation method of p-nitrophenyl substitution structure containing chromone and application - Google Patents
Spiral shell [indazole-isoxazole] derivative and preparation method of p-nitrophenyl substitution structure containing chromone and application Download PDFInfo
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- CN110128444A CN110128444A CN201910530325.3A CN201910530325A CN110128444A CN 110128444 A CN110128444 A CN 110128444A CN 201910530325 A CN201910530325 A CN 201910530325A CN 110128444 A CN110128444 A CN 110128444A
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Abstract
Spiral shell [indazole-isoxazole] derivative of the structure containing chromone and preparation method and application the invention belongs to pharmaceutical technology field more particularly to p-nitrophenyl substitution.P-nitrophenyl of the present invention replaces the preparation method of spiral shell [indazole-isoxazole] derivative of the structure containing chromone, includes the following steps: the synthesis of the bromo- 4- oxygen -4H- chromene -3- formaldoxime of (1) 6-；(2) 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1HThe synthesis of indazole -4 (5H) -one；(3) 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H(5H) -one of indazole -4 and the bromo- 4- oxygen -4H- chromene -3- formaldoxime of compound 6- occur 1,3- Dipolar Cycloaddition under toluene-sodium-sulfonchloramide effect and obtain spiral shell [indazole-isoxazole] derivative that p-nitrophenyl replaces the structure containing chromone.
Description
Technical field
The invention belongs to spiral shell [the different evils of indazole-that pharmaceutical technology field more particularly to p-nitrophenyl replace the structure containing chromone
Azoles] derivative and preparation method and application.
Background technique
- 4 (5H) -one of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole, chemical structural formula are as follows:
1,3- Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity
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.Isoxazole skeleton drug application in be
One important pharmacophoric group, there is significant physiology and pharmacological activity.In addition, 1, the 3- dipole of itrile oxides and exocyclic double bond
The spiral shell isoxazole class compound of cycloaddition reaction synthesis causes drug scholars because showing some important physiological properties
Pay attention to.So either still from a synthetic point of view from pharmacology, this heterocyclic compounds has very high synthesis to be worth.
Assemble in same molecule and in order to preferably study different heterocycles on influence caused by pharmacological activity, Wo Mentong
Cross spiral shell [indazole-isoxazole] derivative that 1,3- Dipolar Cycloaddition has synthesized a kind of p-nitrophenyl substitution structure containing chromone
Object.
Summary of the invention
The object of the present invention is to provide spiral shell [indazole-isoxazole] derivatives that a kind of p-nitrophenyl replaces the structure containing chromone
And preparation method and application.
To achieve the goals above, technical solution of the present invention is as follows:
A kind of chemical structural formula of spiral shell [indazole-isoxazole] derivative of p-nitrophenyl substitution structure containing chromone is as follows:
Wherein: Ar=4-NO2C6H4-。
A kind of preparation method of spiral shell [indazole-isoxazole] derivative of p-nitrophenyl substitution structure containing chromone, including such as
Lower step:
(1) the bromo- 4- oxygen-of 50.0mL6- the synthesis of the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-: is added in ethanol
4H- chromene -3- formaldehyde, takes distilled water to be completely dissolved 316.0mg hydroxylamine hydrochloride and 464.0mg sodium acetate, is dripped with constant pressure
Liquid funnel is added dropwise in the solution of front, is heated to reflux, and TLC tracking is filtered to after reaction, be cooled to room temperature, and is washed, and is produced
95% ethyl alcohol recrystallization of object obtains the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-；
(2) synthesis of -4 (5H) -one of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole: by 10mmol1-
- 4 (5H) -one of phenyl -6,7- dihydro -1H- indazole and 10mmol paranitrobenzaldehyde are dissolved in 10mL ethyl alcohol, and 2mL mass is added
The NaOH aqueous solution that score is 40%, 80 DEG C are stirred 3 hours, are then separated with filtered on buchner funnel, use ethyl alcohol after filter cake washing
Recrystallization purifying, filtering drying obtain -4 (5H) -one of product 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole；
(3) in 30mL dehydrated alcohol, 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole -4 is added
(5H) -one and the bromo- 4- oxygen -4H- chromene -3- formaldoxime dissolution of 6-, add toluene-sodium-sulfonchloramide inorganic salts, flow back 12 hours, carry out
1,3- dipole-diople interaction addition reaction, TLC tracking depressurize rotary distillation after complete reaction and remove solvent, take 3mL ethyl acetate
Dissolution is stand-by, and spiral shell [the different evil of indazole-of the structure containing chromone is finally replaced with the isolated p-nitrophenyl of solvent silica gel column chromatography
Azoles] derivative.
(4- nitro is sub- for toluene-sodium-sulfonchloramide inorganic salts and the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6- and 5- in the step (3)
Benzyl) -1- phenyl -6,7- dihydro -1H- indazole -4 the ratio between the amount of (5H) -one substance be 7:6:5.
Solvent in the step (3) is ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate and petroleum ether is
V(ethyl acetate):V(petroleum ether)=1:5.
A kind of p-nitrophenyl replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone in terms of anti-tumor drug
Using.
A kind of p-nitrophenyl proposed by the present invention replaces spiral shell [indazole-isoxazole] derivative and its system of the structure containing chromone
Preparation Method, the preparation method is with 1,3- dipole-diople interaction method in 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- Yin
Isozole ring and chromone structure are introduced in azoles -4 (5H) -one structure, thus spiral shell [the different evil of indazole-of one structure containing chromone of synthesis
Azoles] derivative.Spiral shell [indazole-isoxazole] derivative of the structure prepared by the present invention containing chromone has the suppression of stronger tumour cell
System and antiphlogistic effects provide the foundation for its further field of medicaments application.
Detailed description of the invention
Fig. 1 is the preparation flow figure of the bromo- 4- oxygen -4H- chromene -3- formaldoxime (compound 2) of 6- in the present invention；
Fig. 2 is -4 (5H) -one (compound of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole in the present invention
3) preparation flow figure；
Fig. 3 is spiral shell [indazole-isoxazole] derivative (compound 4) that p-nitrophenyl replaces the structure containing chromone in the present invention
Preparation flow figure.
Specific embodiment
Technical solution of the present invention is described in further details with reference to the accompanying drawings and examples, following embodiment is not constituted
Limitation of the invention.
Due to the extensive bioactivity of chromone, anticancer, antibacterial inhibit platelet aggregation etc. and receive much attention.In order to
It preferably studies different heterocycles to assemble in same molecule on influence caused by pharmacological activity, we pass through 1,3- dipole-ring
Addition reaction has synthesized a kind of spiral shell [indazole-isoxazole] derivative of p-nitrophenyl substitution structure containing chromone.
The present invention provides spiral shell [indazole-isoxazole] derivatives that a kind of p-nitrophenyl replaces the structure containing chromone, change
It is as follows to learn structural formula:
Wherein: Ar=4-NO2C6H4-。
The present embodiment is a kind of preparation side of spiral shell [indazole-isoxazole] derivative that p-nitrophenyl replaces the structure containing chromone
Method, the preparation method include:
(1) the bromo- 4- oxygen-of 50.0mL6- the synthesis of the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-: is added in ethanol
4H- chromene -3- formaldehyde, takes distilled water to be completely dissolved 316.0mg hydroxylamine hydrochloride and 464.0mg sodium acetate, is dripped with constant pressure
Liquid funnel is added dropwise in the solution of front, is heated to reflux, and TLC tracking is filtered to after reaction, be cooled to room temperature, and is washed, and is produced
95% ethyl alcohol recrystallization of object obtains the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-；
(2) synthesis of -4 (5H) -one of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole: by 10mmol1-
- 4 (5H) -one of phenyl -6,7- dihydro -1H- indazole and 10mmol paranitrobenzaldehyde are dissolved in 10mL ethyl alcohol, and 2mL mass is added
The NaOH aqueous solution that score is 40%, 80 DEG C are stirred 3 hours, are then separated with filtered on buchner funnel, use ethyl alcohol after filter cake washing
Recrystallization purifying, filtering drying obtain -4 (5H) -one of product 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole；
(3) in 30mL dehydrated alcohol, 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole -4 is added
The bromo- 4- oxygen -4H- chromene -3- formaldoxime 1.2mmol dissolution of (5H) -one 1mmol and 6-, adds toluene-sodium-sulfonchloramide inorganic salts
1.4mmol flows back 12 hours, carries out the addition reaction of 1,3- dipole-diople interaction, TLC tracking, and decompression rotation after complete reaction is steamed
It evaporates except solvent, takes the dissolution of 3mL ethyl acetate stand-by, finally use V(ethyl acetate):V(petroleum ether)=1:5 silica gel column chromatography is isolated right
Spiral shell [indazole-isoxazole] derivative of nitrobenzophenone substitution structure containing chromone.
Experimental data is as follows: a kind of p-nitrophenyl replaces spiral shell [indazole-isoxazole] derivative (chemical combination of the structure containing chromone
Object 4), pale yellow powder, yield 34.5%, fusing point: 166-167 DEG C, nucleus magnetic hydrogen spectrum data and Elemental analysis data are as follows:
1H NMR(CDCl3) δ: 8.22 (s, 1H, N=C-H), 7.51-7.23 (m, 12H, Ar-H), 6.55 (s, 1H), 6.47
(s, 1H, C=C-H), 3.15-3.13 (m, 2H), 3.05 (t, J=6.5Hz, 2H)
IR(KBr)v/cm-13109 (ArH), 1674 (C=O), 1631,1582,1463 (C=N, C=C),
M/e:610 (100.0%)
Anal.calcd.For C30H19BrN4O6: C, 58.93；H,3.13；N,9.16；found C,58.96；H,3.14；
N,9.13。
The present embodiment replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone using mtt assay measurement p-nitrophenyl
To the In-vitro Inhibitory Effect of different tumor strains, replace the spiral shell [indazole-isoxazole] of the chromone of bromine containing 6- structure derivative containing p-nitrophenyl
The antitumor cytolytic activity result of object is as follows:
Replace spiral shell [indazole-isoxazole] derivative of the structure containing chromone to be dissolved with DMSO p-nitrophenyl, dilutes, tumour
Cell KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HCT116 (colon cancer cell), Bel-7402 (human liver cancer cell),
HO8901 (ovarian cancer cell), K562 (leukaemia cell) are planted on 96 orifice plates into 4000/200 holes μ L/, and chemical combination is added in every hole
Object 2 μ L, final concentration of 12.0 μM, 6.0 μM, 3.0 μM, 1.5 μM, jointly in 37 DEG C, 5%CO2It is small that 72 are incubated in cell incubator
When, with DMSO (1%) for blank control.After 72 hours, the MTT of final concentration of 0.25mg/mL is added, is placed in 37 DEG C, 5%CO2
4 hours in cell incubator, solvent is blotted later, and every hole is added 100 μ l DMSO, measures suction at 570nm with enzyme linked immunological instrument
Luminosity (OD value), the data obtained is for calculating IC50Value.The high compound of inhibitory activity is selected, the chemical combination under various concentration is measured
Influence of the object action time difference to human tumor cells period and apoptosis.
The test-compound of various concentration carries out scalping with 96 orifice plates, according to resulting inhibiting rate, calculates IC50Value, as a result
See the table below 1, (p-nitrophenyl replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone to the IC of six kinds of tumor cell lines50
Value).
Table 1
In table 1, there is shown spiral shell [indazole-isoxazole] derivative (chemical combination of p-nitrophenyl substitution structure containing chromone
Object 4) to the IC of six kinds of tumor cell lines50Value, illustrate compound to SGC7901 (stomach cancer cell), HCT116 (colon cancer cell),
Bel-7402 (human liver cancer cell), K562 (leukaemia cell) have stronger inhibiting tumour cells effect, are its further doctor
The application of medicine field provides the foundation.
Extracorporeal anti-inflammatory active testing
Cell Proliferation is a complicated process, regulation of the whole process by signal path internetworking, including is extracellularly believed
Number and intracellular cascade amplified signal.The transmitting for blocking cell proliferation signals, can suppress the proliferation of RAW264.7 cell, mitigate
Inflammation occurs, to have the function of anti-inflammatory.
Experimental implementation, test sample: compound 4.RAW264.7 cell is divided into 6 experimental groups, respectively Control
Group, LPS group, LPS+ various concentration (5,10,20,40ug/mL) sample sets.The culture of RAW264.7 cell: RAW264.7 is thin
Born of the same parents cultivate in DMEM culture medium to logarithmic growth phase, with containing volume fraction 0.25% pancreatin and 0.01%EGTA-Na disappear
Change liquid digestion, the washing centrifugation of DMEM culture medium adjusts cell density appropriate, is inoculated in 96 orifice plates, 200 holes μ L/ are placed in 37
DEG C, saturated humidity, 5%CO2Incubator culture is for 24 hours.Every hole adds the samples of 10 μ L various concentrations, and (concentration is respectively 5,10,20,40
μ g/mL, each concentration set 3 multiple holes, and 37 DEG C, 5%CO2Incubator is incubated for 24 hours.
The present embodiment uses influence of the mtt assay test sample to the LPS RAW264.7 cell Proliferation stimulated: LPS (10 is added
μ g/mL) for 24 hours after, 20 μ L MTT working solutions are added in every hole, be placed in 37 DEG C, saturated humidity, 5%CO2Incubator culture is for 24 hours.From
The heart, after absorbing supernatant, every hole adds 100 μ L dimethyl alums (DMSO), after being completely dissolved, is examined at 492nm using microplate reader
It surveys absorbance (A value), calculates group of cells inhibiting rate.
Cell inhibitory rate=(1- experimental group A mean value/control group A mean value) × 100%, obtaining compound 4 stimulates LPS
RAW264.7 cell Proliferation influence result.
Table 2
Illustrate that compound 4 is able to suppress the cell Proliferation of LPS induction, there is preferable extracorporeal anti-inflammatory activity, and be in dosage
Dependence provides the foundation for its further field of medicaments application.
The above embodiments are merely illustrative of the technical solutions of the present invention rather than is limited, without departing substantially from essence of the invention
In the case where mind and its essence, those skilled in the art make various corresponding changes and change in accordance with the present invention
Shape, but these corresponding changes and modifications all should fall within the scope of protection of the appended claims of the present invention.
Claims (5)
1. spiral shell [indazole-isoxazole] derivative of p-nitrophenyl substitution structure containing chromone, which is characterized in that the p-nitrophenyl
Base replaces the chemical structural formula of spiral shell [indazole-isoxazole] derivative of the structure containing chromone as follows:
Wherein: Ar=4-NO2C6H4-。
2. a kind of p-nitrophenyl as described in claim 1 replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone
Preparation method, which comprises the steps of:
(1) the bromo- 4- oxygen -4H- benzene of 50.0mL6- the synthesis of the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-: is added in ethanol
And pyrans -3- formaldehyde, it takes distilled water to be completely dissolved 316.0mg hydroxylamine hydrochloride and 464.0mg sodium acetate, uses constant pressure funnel
It is added dropwise in the solution of front, is heated to reflux, TLC tracking is filtered to after reaction, be cooled to room temperature, and washing, product is used
95% ethyl alcohol recrystallization obtains the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6-；
(2) synthesis of -4 (5H) -one of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole: by 10mmol1- benzene
- 4 (5H) -one of base -6,7- dihydro -1H- indazole and 10mmol paranitrobenzaldehyde are dissolved in 10mL ethyl alcohol, and 2mL mass point is added
The NaOH aqueous solution that number is 40%, 80 DEG C are stirred 3 hours, are then separated with filtered on buchner funnel, with ethyl alcohol weight after filter cake washing
Crystallization purifying, filtering drying obtain -4 (5H) -one of product 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole；
(3) in 30mL dehydrated alcohol, -4 (5H) -one of 5- (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole is added
With the bromo- 4- oxygen -4H- chromene -3- formaldoxime dissolution of 6-, toluene-sodium-sulfonchloramide inorganic salts are added, are flowed back 12 hours, it is even to carry out 1,3-
Polar ring addition addition reaction, TLC tracking, after complete reaction depressurize rotary distillation remove solvent, take 3mL ethyl acetate dissolution to
With finally replacing the spiral shell [indazole-isoxazole] of the structure containing chromone to spread out with the isolated p-nitrophenyl of solvent silica gel column chromatography
Biology.
3. the preparation that p-nitrophenyl as claimed in claim 2 replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone
Method, it is characterised in that: toluene-sodium-sulfonchloramide inorganic salts and the bromo- 4- oxygen -4H- chromene -3- formaldoxime of 6- and 5- in the step (3)
The ratio between amount of -4 (5H) -one substance of (4- nitrobenzal) -1- phenyl -6,7- dihydro -1H- indazole is 7:6:5.
4. the preparation that p-nitrophenyl as claimed in claim 2 replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone
Method, it is characterised in that: solvent in the step (3) is ethyl acetate and petroleum ether, and ethyl acetate and petroleum ether
Volume ratio is V(ethyl acetate):V(petroleum ether)=1:5.
5. a kind of p-nitrophenyl as described in claim 1 replaces spiral shell [indazole-isoxazole] derivative of the structure containing chromone to exist
Application in terms of antitumor and anti-inflammatory drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253331A (en) * | 2020-03-17 | 2020-06-09 | 南京林业大学 | Novel method for synthesizing spiroisoxazoline by using dihydrochalcone as raw material |
| CN114790213A (en) * | 2022-04-29 | 2022-07-26 | 徐诺药业(南京)有限公司 | Synthetic method of spiro [ indazole-isoxazole ] derivative applied to methoxyphenyl substituted chromone-containing structure |
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| CN103554135A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure containing isoxazole norcantharidin derivatives as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103554135A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure containing isoxazole norcantharidin derivatives as well as preparation method and application thereof |
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| NAIR, VIJAY，等: "1,3-Dipolar cycloaddition reactions of nitrile-N-oxides with o-benzoquinones", 《TETRAHEDRON》 * |
| REN, DEMIN，等: "1,3-Dipolar cycloaddition of diphenylnitrilimine and 5-arylmethylidene-1-phenyl-1,5,6,7-tetrahydro-4H-indazol-4-ones to afford novel spiro[indazole-5,3"-pyrazole] derivatives", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253331A (en) * | 2020-03-17 | 2020-06-09 | 南京林业大学 | Novel method for synthesizing spiroisoxazoline by using dihydrochalcone as raw material |
| CN114790213A (en) * | 2022-04-29 | 2022-07-26 | 徐诺药业(南京)有限公司 | Synthetic method of spiro [ indazole-isoxazole ] derivative applied to methoxyphenyl substituted chromone-containing structure |
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