CN109232570B - Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof - Google Patents

Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof Download PDF

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CN109232570B
CN109232570B CN201811172908.5A CN201811172908A CN109232570B CN 109232570 B CN109232570 B CN 109232570B CN 201811172908 A CN201811172908 A CN 201811172908A CN 109232570 B CN109232570 B CN 109232570B
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indolizine
pyridazinone
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pyrazoline
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王玮
邓莉平
胡春霞
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Changsha Yaoxiang Biotechnology Co.,Ltd.
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Shaoxing University Yuanpei College
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Abstract

The invention discloses a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof, wherein a1, 3-dipole cycloaddition method is used for introducing a pyrazole ring into a (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone structure, so that the pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative is synthesized. The pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a basis for further application in the medical field.

Description

Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof.
Background
(E) -7-benzylidene-6, 7-indolizin-8 (5H) -one having the following chemical formula:
Figure GDA0002262638550000011
wherein Ar is ═ C6H5。
The 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research. In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. The indolizine skeleton is a common structural unit in bioactive alkaloids, and has remarkable anti-mitotic property or the effect of treating cardiovascular diseases and hypertension. Therefore, it is of great significance to research the influence of different heterocycles on pharmacological activity caused by aggregation in the same molecule.
Disclosure of Invention
The invention aims to provide a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof, and the pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative has a chemical structural formula as follows:
Figure GDA0002262638550000021
wherein Ar is ═ C6H5。
The invention also provides a preparation method of the pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, which comprises the following steps:
step 1, synthesizing a chromone aldehyde hydrazone derivative containing a pyridazinone structure;
step 2, synthesizing α -chloropyridazinone structure chromone aldehyde hydrazone derivatives;
and 3, adding (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone and the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after the dropwise adding is finished, tracking by TLC (thin layer chromatography), removing the solvent by rotary evaporation after the reaction is completed, dissolving the residue left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain the spiro [ indolizine-pyrazoline ] derivative with the pyridazinone structure.
Further, the mass ratio of the α -chloropyridazinone structure chromone aldehyde hydrazone derivative to the (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone is 1.6: 1-2: 1.
Further, the volume ratio of triethylamine to dichloromethane is: 1: 10-1: 20.
further, the spreading agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)＝1:5。
The invention also provides application of the pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative in antitumor drugs.
The invention provides a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and a preparation method and application thereof, wherein a1, 3-dipole cycloaddition method is used for introducing a pyrazole ring into a (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone structure, so that the pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative is synthesized. The pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a basis for further application in the medical field.
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FIG. 1 is a flow chart of a preparation method of compound 1 and compound 2 containing a pyridazinone structure according to the present invention;
FIG. 2 is a schematic diagram of the chemical structure of the compound 4 of the present invention.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to the drawings and examples, which should not be construed as limiting the present invention.
In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. The indolizine skeleton is a common structural unit in bioactive alkaloids, and has remarkable anti-mitotic property or the effect of treating cardiovascular diseases and hypertension.
In order to better research the influence of different heterocycles on pharmacological activity caused by aggregation in the same molecule, the technical scheme synthesizes the spiro [ indolizine-pyrazoline ] derivative containing a pyridazinone structure through 1, 3-dipolar cycloaddition reaction.
One embodiment of the present invention provides a pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, which has a chemical structural formula as follows:
Figure GDA0002262638550000031
wherein: ar ═ C6H5And Br is bromine.
The invention provides a preparation method of a pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, which comprises the following steps:
step 1, synthesizing a chromone aldehyde hydrazone derivative containing a pyridazinone structure.
The invention synthesizes the chromone aldehyde hydrazone derivative containing a pyridazinone structure by a method of generating Schiff base by dehydration reaction of 6-bromo chromone with a formaldehyde group substituted at the 3-position and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate. The chromone aldehyde hydrazone derivative having a pyridazinone structure is also referred to as compound 1 hereinafter.
Example 1: adding 2mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 15mL of ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding 20mL of anhydrous ethanol solution in which 2mmol of 6-bromochromone substituted by 3-formaldehyde groups is dissolved, continuing refluxing and stirring in the boiling water bath for 1 hour, dropwise adding 10 drops of hydrochloric acid, and allowing a light yellow precipitate to appear. And (3) refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of the light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product. Washing with anhydrous ether for multiple times, recrystallizing with ethanol, and vacuum drying to obtain compound 1: chromone aldehyde hydrazone derivatives containing a pyridazinone structure.
And 2, synthesizing α -chloropyridazinone structure chromone aldehyde hydrazone derivatives.
Example 2 Compound 1(10.0mmol) was added to 12.5mL of DMF, and the mixture was completely dissolved under stirring at room temperature, the reaction was controlled to 35 ℃ or lower, 15.0mmol NCS was added in 5 to 10 portions, followed by TLC, and after completion of the reaction, the mixture was poured into water, extracted with diethyl ether for 3 times, the extracted solution was dried over anhydrous magnesium sulfate, and after removing the diethyl ether by rotary evaporation, the mixture was recrystallized from chloroform/petroleum ether to obtain a chromone aldehyde hydrazone derivative having a structure of α -chloropyridazinone, and a chromone aldehyde hydrazone derivative having a structure of α -chloropyridazinone was hereinafter also referred to as Compound 2.
It should be noted that many methods have been studied in the art for synthesizing compounds 1 and 2, and this example only exemplifies specific examples used in a laboratory, and those skilled in the art can also prepare compounds 1 and 2 by other methods.
And 3, adding (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone and the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after the dropwise adding is finished, tracking by TLC (thin layer chromatography), removing the solvent by rotary evaporation after the reaction is completed, dissolving the residue left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain the spiro [ indolizine-pyrazoline ] derivative with the pyridazinone structure.
Example 3 adding 1mmol of Compound 3((E) -7-benzylidene-6, 7-indolizin-8 (5H) -one) and 1.6mmol of Compound 2 (chromone aldehyde hydrazone derivative of α -chloropyridazinone structure) to 20mL of dichloromethane, dropping a mixture of 0.5mL of triethylamine and 5mL of dichloromethane to the solution using a constant pressure dropping funnel, stirring at room temperature for 24 hours after dropping, tracking by TLC, removing the solvent by rotary evaporation after the reaction is completed, dissolving 3mL of ethyl acetate for standby, and finally dissolving with V(Ethyl acetate):V(Petroleum ether)Silica gel column chromatography 1:5 gave compound 4.
It should be noted that the above dichloromethane is a reaction solvent for dissolving the compounds 2 and 3, and the present invention is not limited to a specific amount of dichloromethane.
In the step, the mass ratio of the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure to the (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone is 1.6: 1-2: 1, and the volume ratio of triethylamine to dichloromethane in the mixed solution of triethylamine and dichloromethane is 1: 10-1: 20.
Example 4 adding 1mmol of the Compound 3((E) -7-benzylidene-6, 7-indolizin-8 (5H) -one) and 2mmol of the Compound 2 (the chromone aldehyde hydrazone derivative of the α -chloropyridazinone structure) to 20mL of dichloromethane, dropping a mixture of 0.5mL of triethylamine and 10mL of dichloromethane to the solution using a constant pressure dropping funnel, continuing stirring at room temperature for 24 hours after the dropping is completed, and tracking by TLCAfter the reaction is completed, the solvent is removed by rotary evaporation, 3mL ethyl acetate is taken for dissolving for standby, and finally V is used(Ethyl acetate):V(Petroleum ether)Silica gel column chromatography 1:5 gave compound 4.
In examples 3, 4, ethyl acetate was used to dissolve the residue remaining from the rotary evaporation, to facilitate removal, and to facilitate addition to the top of the column. It will be readily understood that the residue may be dissolved with a solvent other than ethyl acetate, for example, ethanol, acetone may also be used.
Preferably, the expanding agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)1: 5. Of course, other proportions of extender may be used, e.g. V(Ethyl acetate):V(Petroleum ether)＝1:6。
The experimental data are as follows: a pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative (compound 4) is a pale yellow powder, yield 57.3%, melting point: 193-:
1H NMR(DMSO-d6)δ:10.15(s,1H,NHN),7.34-7.18(m,10H,Ar-H),6.87(t,J＝8.0,1H),6.58(s,1H),6.49(s,1H,C＝C-H),6.31(d,J＝4.0,1H),4.51(t,J＝12.5,1H),4.45(s,1H,C＝C-H),4.02(d,J＝12.5,1H),2.44(t,J＝14.0,1H),1.68(d,J＝14.5,1H),
IR(KBr)v/cm-13427(N-C＝O),3105(ArH),1774(C＝O,pyridazinone),1663(C＝O),1633,1580,1465(C＝N,C＝C),1258(C-O-C),1608(chromone-ring)
m/e:609(100.0％)
Anal.calcd.for C30H20BrN5O5：C,59.01；H,3.34；N,11.45。
wherein pyridazinone is pyridazinone and chromone-ring is chromone mother ring.
In this example, MTT method is used to determine the in vitro inhibitory effect of compound 4 on different tumor strains, and the results of the determination of the anti-tumor activity of pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivatives are as follows:
dissolving compound 4 in DMSO, diluting, and culturing tumor cells KB: (Oral cancer cells), SGC7901 (gastric cancer cells), HL-60 (leukemia cells), Bel-7402 (human liver cancer cells), HO8901 (ovarian cancer cells), ECA109 (intestinal cancer cells) were seeded in 4000/200. mu.L/well in 96-well plates, 2. mu.L of compound was added to each well to a final concentration of 12.0. mu.M, 6.0. mu.M, 3.0. mu.M, 1.5. mu.M, together at 37 ℃ with 5% CO2The cells were incubated in an incubator for 72 hours, with DMSO (1%) as a blank control. After 72 hours, MTT was added to a final concentration of 0.25mg/mL and the mixture was left at 37 ℃ with 5% CO2After 4 hours in the cell incubator, the solvent was blotted, 100. mu.l DMSO was added to each well, absorbance (OD value) was measured at 570nm with an enzyme-linked immunosorbent assay, and the data obtained was used to calculate IC50The value is obtained. Selecting compounds with high inhibitory activity, and determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
Figure GDA0002262638550000061
TABLE 1
In Table 1, spiro [ indolizine-pyrazoline ] containing pyridazinone structure is shown]IC of derivative (Compound 4) against six tumor cell lines50The values show that the compound has stronger tumor cell inhibiting effect on KB (oral cancer cells), SGC7901 (gastric cancer cells), HL-60 (leukemia cells) and Bel-7402 (human liver cancer cells), and provide a foundation for further application in the medical field.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.

Claims (6)

1. The pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative is characterized in that the pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative has the following chemical structural formula:
Figure FDA0002279225180000011
wherein Ar is ═ C6H5。
2. A preparation method of pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivatives is characterized in that the preparation method of pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivatives comprises the following steps:
step 1, synthesizing a chromone aldehyde hydrazone derivative containing a pyridazinone structure by adopting 6-bromochromone with a formaldehyde group substitution at the 3-position and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate, wherein the chromone aldehyde hydrazone derivative containing the pyridazinone structure has the following chemical structural formula:
Figure FDA0002279225180000012
step 2, synthesizing α -chloropyridazinone structure chromone aldehyde hydrazone derivative, wherein the α -chloropyridazinone structure chromone aldehyde hydrazone derivative has the following chemical structural formula:
Figure FDA0002279225180000013
step 3, adding (E) -7-benzylidene-6, 7-indolizine-8 (5H) -ketone and a chromone aldehyde hydrazone derivative with a α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after the dropwise adding is finished, tracking by TLC, performing rotary evaporation to remove a solvent after the reaction is completed, dissolving residues left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain a spiro [ indolizine-pyrazoline ] derivative with a pyridazinone structure, wherein the spiro [ indolizine-pyrazoline ] derivative with the pyridazinone structure has the following chemical structural formula:
Figure FDA0002279225180000021
wherein Ar is ═ C6H5。
3. The method for preparing a pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative according to claim 2, wherein the ratio of the amounts of the α -chloropyridazinone-structure chromone aldehyde hydrazone derivative to the (E) -7-benzylidene-6, 7-indolizine-8 (5H) -one is 1.6: 1 to 2: 1.
4. The method for preparing a pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative according to claim 2, wherein the mixed solution of triethylamine and dichloromethane has a volume ratio of triethylamine to dichloromethane of: 1: 10-1: 20.
5. pyridazinone-structure-containing spiro [ indolizine-pyrazoline according to claim 2]The preparation method of the derivative is characterized in that the expanding agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)＝1:5。
6. Use of the pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative according to claim 1 for the preparation of an antitumor agent.
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