CN110734442B - 3,4,5-Trimethoxyphenyl substituted spiro[indazole-pyrazoline] derivatives containing pyrazole structure and preparation method and application - Google Patents
3,4,5-Trimethoxyphenyl substituted spiro[indazole-pyrazoline] derivatives containing pyrazole structure and preparation method and application Download PDFInfo
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- 125000003003 spiro group Chemical group 0.000 title claims abstract description 32
- 125000003226 pyrazolyl group Chemical group 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 title claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
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- 239000003480 eluent Substances 0.000 claims description 4
- PSXCLWPFIRHOJO-UHFFFAOYSA-N 1-phenyl-6,7-dihydro-5h-indazol-4-one Chemical compound O=C1CCCC2=C1C=NN2C1=CC=CC=C1 PSXCLWPFIRHOJO-UHFFFAOYSA-N 0.000 claims description 3
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- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
本发明属于医药技术领域，尤其涉及一种3,4,5‑三甲氧基苯基取代含吡唑结构的螺[吲唑‑吡唑啉]衍生物及制备方法与应用。本发明一种如权利要求1所述的3,4,5‑三甲氧基苯基取代含吡唑结构的螺[吲唑‑吡唑啉]衍生物的制备方法，其特征在于，包括如下步骤：（1）1‑苯基‑3‑甲基‑5‑(1,2,4‑三唑基)‑4‑吡唑甲醛的合成；（2）1‑苯基‑3‑甲基‑5‑（1,2,4‑三氮唑‑1‑基）‑4‑吡唑甲醛腙的合成；（3）1‑苯基‑3‑甲基‑5‑（1,2,4‑三氮唑‑1‑基）‑α‑氯‑4‑吡唑甲醛腙的合成；（4）5‑(3,4,5‑三甲氧基苄基)‑1‑苯基‑6,7‑二氢‑1H‑吲唑‑4（5H）‑酮的合成；（5）3,4,5‑三甲氧基苯基取代含吡唑结构的螺[吲唑‑吡唑啉]衍生物的合成。
The invention belongs to the technical field of medicine, and in particular relates to a 3,4,5-trimethoxyphenyl-substituted spiro[indazole-pyrazoline] derivative containing a pyrazole structure, a preparation method and application thereof. A method for preparing a 3,4,5-trimethoxyphenyl-substituted spiro[indazole-pyrazoline] derivative containing a pyrazole structure as claimed in claim 1, wherein the method comprises the following steps : (1) synthesis of 1-phenyl-3-methyl-5-(1,2,4-triazolyl)-4-pyrazolecarboxaldehyde; (2) 1-phenyl-3-methyl-5 Synthesis of -(1,2,4-triazole-1-yl)-4-pyrazolecarboxaldehyde hydrazone; (3) 1-phenyl-3-methyl-5-(1,2,4-triazol azole-1-yl)-α-chloro-4-pyrazolecarboxaldehyde hydrazone; (4) 5-(3,4,5-trimethoxybenzyl)-1-phenyl-6,7-dihydro Synthesis of -1H-indazole-4( 5H ) -ketone ; (5) Synthesis of 3,4,5-trimethoxyphenyl-substituted spiro[indazole-pyrazoline] derivatives containing pyrazole structure .
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure, and a preparation method and application thereof.
Background
5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one, of the following chemical formula:
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. The triazole has aromaticity and abundant electrons in a molecular structure, can interact with enzymes and receptors in organisms by forming hydrogen bonds, and has various biological activities. The isoxazole skeleton is an important pharmacophore in the application of medicaments, and has remarkable physiological and pharmacological activities. In addition, spiroisoxazoles synthesized by 1, 3-dipolar cycloaddition of nitrile oxides to exocyclic double bonds have attracted attention by pharmacologists because they exhibit some important physiological properties. 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. In order to better study the influence of different heterocycles on the pharmacological activity caused by the aggregation in the same molecule, a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is synthesized through a 1, 3-dipolar cycloaddition reaction.
Disclosure of Invention
The invention aims to provide a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure and a preparation method thereof, and the 3,4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing the pyrazole structure is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure has the following chemical structural formula:
wherein: ar is 3,4,5- (CH)3O)3C6H2-。
A method for preparing 3,4, 5-trimethoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivatives containing pyrazole structure according to claim 1, comprising the steps of:
(1) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde (compound 1): dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasound at normal temperature of 25 ℃ for half an hour, performing rotary evaporation on ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 5-chloro-1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, pouring the mixture into 200mL of ice water after TLC detection is finished, precipitating light yellow solid, and performing suction filtration; drying the solid matter, and recrystallizing with ethanol-water to obtain a compound 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (compound 1);
(2) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2): adding 22mmol of phenylhydrazine into a flask containing 10mL of tetrahydrofuran, refluxing and stirring in a boiling water bath until the phenylhydrazine is dissolved, slowly dropwise adding 20mL of anhydrous ethanol solution in which 20mmol of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (compound 1) is dissolved, continuing refluxing and stirring in the boiling water bath for 1h, and dropwise adding 10 drops of concentrated hydrochloric acid until a light yellow precipitate appears; 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 a light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product; washing with anhydrous ether for several times, and vacuum drying to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2);
(3) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde hydrazone (compound 3): adding 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2) into 50ml of 1, 2-dichloroethane and 30ml of isopropanol, completely dissolving the mixture by magnetic stirring, then adding tert-butyl hypochlorite into a cold salt bath at the temperature of-12 ℃ in three times, and vigorously stirring for 2 hours, wherein the temperature is controlled below-5 ℃ during the period to obtain a light blue transparent liquid; transferring the product into a round-bottom flask, and evaporating the solvent at 50 ℃ under reduced pressure to obtain a light yellow oily substance; adding a small amount of petroleum ether, heating for mixing, dissolving, separating out a large amount of yellow solid, and performing vacuum filtration to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -alpha-chloro-4-pyrazole formaldehyde hydrazone (compound 3);
(4) synthesis of 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4): dissolving 10mmol of 1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one and 10mmol of 3,4, 5-trimethoxybenzaldehyde in 10mL of ethanol, adding 2mL of 40% aqueous NaOH solution, stirring at 80 ℃ for 3 hours, filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product, namely 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (a compound 4);
(5) adding 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one (compound 4) and 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -alpha-chloro-4-pyrazole formaldehyde hydrazone (compound 3) into 20mL of ethanol, dropwise adding a mixed solution of 0.5mL of pyridine and 10mL of ethanol into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 2 hours after the dropwise adding, tracking the reaction by TLC, filtering after the reaction is completed, concentrating the filtrate under reduced pressure, performing silica gel column chromatography, and using ethyl acetate and petroleum ether as eluents to obtain a final product.
The mass ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2) to the tert-butyl hypochlorite substance is 5: 8.
The ratio of the amount of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -alpha-chloro-4-pyrazole formaldehyde oxime (compound 3) to the amount of the 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4) is 3: 2.
V in the eluent(Ethyl acetate):V(Petroleum ether)＝1:8。
The 3,4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is applied to antitumor drugs.
The invention provides a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure and a preparation method thereof, wherein the preparation method is characterized in that an isoxazole ring is introduced into a 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one structure by using a 1, 3-dipolar cycloaddition method, so that a pyrazole substituted spiro [ indazole-pyrazoline ] derivative containing a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure is synthesized. The pyrazole-substituted spiro [ indazole-pyrazoline ] derivative containing a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure, which is prepared by the invention, has a strong tumor cell inhibition effect, and provides a foundation for further application in the field of medicines.
Drawings
FIG. 1 is a flow chart of the preparation method of steps (1) to (3) in the preparation method of a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to the present invention;
FIG. 2 is a flow chart of a preparation method of step (4) in the preparation method of a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to the present invention;
FIG. 3 is a flow chart of a preparation method of step (5) in the preparation method of a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to 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.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. In order to better study the influence of different heterocycles on the pharmacological activity caused by the aggregation in the same molecule, a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is synthesized through a 1, 3-dipolar cycloaddition reaction.
The invention provides a3, 4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure, which has the following chemical structural formula:
wherein: ar is 3,4,5- (CH)3O)3C6H2-。
Example 1
(1) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde (compound 1): dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasound at normal temperature of 25 ℃ for half an hour, performing rotary evaporation on ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 5-chloro-1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, pouring the mixture into 200mL of ice water after TLC detection is finished, precipitating light yellow solid, and performing suction filtration. Drying the solid matter, and recrystallizing with ethanol-water to obtain the compound 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde.
(2) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2): 22mmol of phenylhydrazine is added into a flask containing 10mL of tetrahydrofuran, reflux and stirring are carried out in a boiling water bath until the phenylhydrazine is dissolved, then 20mL of absolute ethanol solution dissolved with 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (20mmol) is slowly dripped, reflux and stirring are carried out in the boiling water bath for 1h, 10 drops of concentrated hydrochloric acid are dripped, and light yellow precipitate appears. And (4) 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 several times, and vacuum drying to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2).
(3) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde hydrazone (compound 3): compound 2(10.0mmol) was added to 50ml of 1, 2-dichloroethane and 30ml of isopropanol and dissolved completely by magnetic stirring, then 18ml (16g, 16mmol) of tert-butyl hypochlorite was added in three portions in a cold salt bath to-12 ℃ and stirred vigorously for 2h, during which time the temperature was carefully controlled below-5 ℃ to give a pale blue transparent liquid. The product was transferred to a round bottom flask and the solvent was evaporated under reduced pressure (50 ℃ C.) to give a light yellow oil. Then, a small amount (m.p. ═ 60-90 ℃) of petroleum ether was added, and the mixture was mixed by heating, and a large amount of yellow solid was precipitated, followed by suction filtration under reduced pressure to obtain compound 3.
(4) Synthesis of 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4): dissolving 10mmol of 1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one and 10mmol of 3,4, 5-trimethoxybenzaldehyde in 10mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing by using ethanol for purification, filtering and drying to obtain the product ketone.
(5) Adding 1mmol of compound 4(5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one) and 1.5mmol of compound 3 (1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -alpha-chloro-4-pyrazolecarboxaldehyde hydrazone) into 20mL of ethanol, dropwise adding a mixed solution of 0.5mL of pyridine and 10mL of ethanol into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 2 hours after the dropwise adding is finished, tracking the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate under reduced pressure, carrying out silica gel column chromatography, and eluting with ethyl acetate/petroleum ether (60-90 ℃) 1/8(V/V), compound 5 is obtained.
The experimental data are as follows: a3, 4, 5-trimethoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure (compound 5) as a pale yellow powder, with a yield of 76.2%, a melting point: 164-165 ℃, the nuclear magnetic hydrogen spectrum data and the element analysis data are as follows:
1H NMR(CDCl3)δ:8.18(s,1H,N＝C-H),8.06(s,1H,triazole-H),7.98(s,1H,triazole-H),7.51-7.41(m,17H,Ar-H),6.47(s,1H),3.76(s,9H,-OCH3),3.13(t,J＝6.5Hz,2H),3.02(t,J＝6.5Hz,2H),2.55(s,3H,CH3).
IR(KBr)v/cm-1 3439(N-C＝O),3136(ArH),2983(CH3),1781(C＝O),1615,1597,1465(C＝N,C＝C),
m/e:731(100.0％)
Anal.calcd.for C42H37N9O4：C,68.93；H,5.10；N,17.23found C,68.90；H,5.14；N,17.19。
in this example, MTT method is used to determine the in vitro inhibitory effect of compound 5 on different tumor strains, and the results of the determination of the antitumor activity of spiro [ indazole-pyrazoline ] derivatives containing 3,4, 5-trimethoxyphenyl substituted pyrazole structure are as follows:
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.
TABLE 1 Compound 53,4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] containing pyrazole structure]IC of derivatives on six tumor cell lines50Value of
In Table 1,3, 4, 5-trimethoxyphenyl-substituted spiro [ indazole-pyrazoline having pyrazole structure]IC of derivative (Compound 5) against six tumor cell lines50The values show that the compound has stronger tumor cell inhibition effect on A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), NCL-H460 (non-small cell lung cancer) and provide a foundation for further application in the medical field.
Examples 2 to 5
Examples 2-5 the same as example 1 except that the amount ratio of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) -4-pyrazolecarboxaldehyde hydrazone (compound 2) to the tert-butyl ester of hypochloride material in step (3) was varied, for comparison, table 2 was prepared:
TABLE 2
Examples 6 to 9
Examples 6-9 were otherwise the same as in example 1 except that the ratio of the amounts of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde oxime (compound 3) to 5- (3,4, 5-trimethoxybenzyl) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4) material in step (5) was varied to prepare tables 3 for ease of comparison:
TABLE 3
Examples 10 to 13
Examples 10-13 were otherwise identical to example 1 except that the addition of tert-butyl hypochlorite in step (3) was different (total amount added, and average addition), for comparison purposes, as shown in Table 4:
TABLE 4
| Number of additions | Yield of | |
| Example 1 | 3 | 92％ |
| Example 10 | 1 | 57％ |
| Example 11 | 2 | 85％ |
| Example 12 | 4 | 87％ |
| Example 13 | 5 | 84％ |
Examples 14 to 16
Examples 14-16 were otherwise identical to example 1 except that the temperature of the ice salt bath in step (3) was different and for ease of comparison, Table 5 was prepared:
TABLE 5
| Temperature of the Ice salt bath | Yield of | |
| Example 1 | -12 | 92％ |
| Example 14 | 0 | 0％ |
| Example 15 | -5 | 37％ |
| Example 16 | -8 | 66％ |
Comparative example 1
3,4, 5-trimethoxy substituted spiro [ indolizine-isoxazoline containing pyrazole structure prepared in example 1 of patent publication No. CN 108640929A]Derivatives, which were diluted in DMSO, tumor cells HepG2 (hepatoma cells), A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), NCL-H460 (non-small cell lung carcinoma), SKOV3 (ovarian 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 inhibition50The values, results are given in table 6 below.
TABLE 63, 4, 5-trimethoxy substituted spiro [ indolizine-isoxazolines with pyrazole structure]IC of derivatives on six tumor cell lines50Value of
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 (5)
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