CN111423413B - Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit - Google Patents
Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit Download PDFInfo
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- CN111423413B CN111423413B CN202010397356.9A CN202010397356A CN111423413B CN 111423413 B CN111423413 B CN 111423413B CN 202010397356 A CN202010397356 A CN 202010397356A CN 111423413 B CN111423413 B CN 111423413B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to preparation and application of pyrazole derivatives (I) containing (3-methoxy-4-substituted pyridylmethoxy) phenyl units. Obtained by reacting 1, 3-dimethyl-5-aryloxy pyrazol-4-formaldehyde oxime with (3-methoxy-4-substituted pyridylmethoxy) phenyl methyl chloride. The pyrazole derivative containing the (3-methoxy-4-substituted pyridylmethoxy) phenyl unit shows a good inhibition effect on tumor cells HepG2 and SMMC-7721, and the compound can be used for preparing anti-tumor cell medicines.
Description
Technical Field
The invention relates to the field of medicines, in particular to preparation and application of a pyrazole derivative containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit.
Background
Malignant tumors have serious threats to human health in recent years, and the incidence rate of cancer is on the rise. Therefore, the search and discovery of new antitumor drugs is one of the hot topics of general attention in the medical field.
Substituted pyridyl is an important nitrogen-containing unit, and the substituted pyridyl derivative plays an important role in the field of medicine.
Pyrazole group is also an important nitrogen-containing heterocyclic fragment, and a plurality of pyrazole derivatives have wide application in the field of medicine, such as antipyrine which has good analgesic treatment effect.
Therefore, a novel antitumor drug is hopeful to be obtained by organically linking the substituted pyridyl and the pyrazole active fragment.
Disclosure of Invention
The invention aims to provide pyrazole derivatives containing (3-methoxy-4-substituted pyridylmethoxy) phenyl units, which have excellent inhibitory effects on human hepatoma cells HepG2 and human hepatoma cells SMMC-7721.
Another object of the present invention is to provide a process for the preparation of the above compounds.
The invention also aims to provide the application of the compound in preparing anti-tumor cell medicines.
In order to solve the above technical problems, the present invention provides a pyrazole derivative (I) containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit, having the following structure:
the invention provides the pyrazole derivative (I) containing the (3-methoxy-4-substituted pyridylmethoxy) phenyl unit, which is characterized by comprising the following reaction steps:
the pyrazole derivative (I) containing the (3-methoxy-4-substituted pyridylmethoxy) phenyl unit disclosed by the invention has an excellent inhibitory effect on human liver cancer cells HepG2 and human liver cancer cells SMMC-7721, and therefore, can be used for preparing anti-tumor cell medicines.
Detailed Description
To facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. These examples are provided for illustrative purposes only and are not intended to limit the scope or the principles of the invention.
Example 1:
a reaction flask was charged with 15mmol of compound IIa, 12mmol of compound III and 35mL of acetonitrile, 50mmol of pyridine was added thereto with stirring at room temperature, and then the reaction solution was further stirred at room temperature for 20 hours. Stopping the reaction, concentrating the reaction solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ia;1H NMR(500MHz,CDCl3):δ8.44(d,J=2.0Hz,1H,Py-H),7.75~7.77(m,1H,Py-H),7.72(s,1H,CH=N),7.32(d,J=8.0Hz,1H,Py-H),7.07~7.10(m,1H,Ar-H),6.96~6.98(m,1H,Ar-H),6.90(s,1H,Ar-H),6.82~6.85(m,3H,Ar-H),6.71~6.72(m,1H,Ar-H),5.10(s,2H,CH2),4.92(s,2H,CH2),3.88(s,3H,OCH3),3.85(s,3H,OCH3),3.66(s,3H,CH3),2.38(s,3H,CH3).
example 2:
10mmol of intermediate IIb, 13mmol of intermediate III and 30mL of 2-butanone are added into a reaction flask, 30mmol of triethylamine is added into the reaction flask under stirring at room temperature, and after the addition, the reaction solution is heated and refluxed for 10 hours. Stopping reaction, filtering, concentrating the mother liquor to dryness, and purifying the obtained crude product by silica gel column chromatographyObtaining a compound Ib;1H NMR(500MHz,CDCl3):δ8.44(d,J=2.0Hz,1H,Py-H),7.75~7.77(m,2H,Py-H and CH=N),7.33(d,J=8.5Hz,1H,Py-H),7.16~7.19(m,1H,Ar-H),6.92(d,J=7.5Hz,2H,Ar-H),6.82(s,2H,Ar-H),6.66~6.68(m,2H,Ar-H),5.10(s,2H,CH2),4.94(s,2H,CH2),3.85(s,3H,OCH3),3.64(s,3H,CH3),2.42(s,3H,CH3),2.31(s,3H,CH3).
example 3:
a reaction flask was charged with 8mmol of intermediate IIc, 15mmol of intermediate III and 35mL of DMF, followed by addition of 20mmol of potassium carbonate thereto under stirring at room temperature, and after completion of the addition, the reaction mixture was heated to 60 ℃ for reaction for 15 hours. Stopping reaction, performing suction filtration, concentrating the mother liquor to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ic;1H NMR(500MHz,CDCl3):δ8.43(d,J=2.5Hz,1H,Py-H),7.74~7.76(m,1H,Py-H),7.73(s,1H,CH=N),7.32(d,J=8.0Hz,1H,Py-H),7.07(d,J=7.5Hz,1H,Ar-H),6.91(s,1H,Ar-H),6.79~6.82(m,3H,Ar-H),6.29(s,1H,Ar-H),5.09(s,2H,CH2),4.94(s,2H,CH2),3.85(s,3H,OCH3),3.59(s,3H,CH3),2.40(s,3H,CH3),2.30(s,3H,CH3),2.20(s,3H,CH3).
example 4:
screening of samples for Activity against tumor cells
The in vitro anti-tumor activity of the compound on human liver cancer cells HepG2 and SMMC-7721 is tested by adopting a tetramethyl azole blue colorimetric Method (MTT). In addition, 5-fluorouracil (5-FU) was selected as a positive control. Taking a bottle of cells in exponential growth phase, adding 0.25% trypsin for digestion to make adherent cells fall off, and preparing the solution containing 2 × 10 cells per ml4~4×104A suspension of individual cells. Inoculating the cell suspension to a 96-well plate at a volume of 180. mu.L/well, and placing in a constant temperature CO2The culture was carried out in an incubator for 24 hours. Changing the solution, adding the compound (the compound is dissolved in DMSO)Diluted with PBS after lysis), 20 μ L per well, and cultured for 48 hours. MTT was added to a 96-well plate at 20. mu.L per well and reacted in an incubator for 4 hours, then the supernatant was aspirated and DMSO was added at 150. mu.L per well and shaken on a plate shaker for 5 minutes. The absorbance of each well was measured at a wavelength of 570nm using an enzyme linked immunosorbent assay to calculate the cell inhibition rate. The cell inhibition rate (negative control OD value-test substance OD value)/negative control OD value × 100%. Calculation of IC of Compounds by simplified probability Unit50The value is obtained.
TABLE 1 antitumor Activity data (IC) of Ia-Ic50,μmol/L)
Compound (I) | HepG2 | SMMC-7721 |
Ia | 3.20 | 2.21 |
Ib | 1.50 | 1.17 |
Ic | 4.20 | 3.27 |
5-FU | 37.8 | 35.7 |
Related antitumorThe activity data are listed in table 1. As can be seen from Table 1, the compounds Ia-Ic showed excellent inhibitory activity on human hepatoma cell HepG2 and human hepatoma cell SMMC-7721, and the IC of the compounds Ia-Ic on human hepatoma cell HepG250The values are respectively 3.20, 1.50 and 4.20 mu mol/L, which are superior to the control effect of the positive control drug 5-FU; IC of compounds Ia-Ic on human hepatoma cell SMMC-772150The values are respectively 2.21, 1.17 and 3.27 mu mol/L, which are obviously superior to the inhibitory activity of a positive control drug 5-FU and have the value of deep research. Meanwhile, valuable experimental data are provided for the research of the pyrazole derivatives with the antitumor activity in the future.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited by the foregoing examples, which are provided to illustrate the principles of the invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention, which is also intended to be covered by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
3. the use of a pyrazole derivative I containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit according to claim 1 in the preparation of a medicament for treating human hepatoma cells HepG2 and human hepatoma cells SMMC-7721.
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Citations (5)
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CN86108691A (en) * | 1985-12-27 | 1988-01-20 | 日本农药株式会社 | Pyrazole oxime derivatives, process for their preparation and their use |
JPH01197471A (en) * | 1988-02-02 | 1989-08-09 | Nissan Chem Ind Ltd | Pyrazole oxime derivative and insecticide, acaricide and germicide |
CN104193727A (en) * | 2014-08-04 | 2014-12-10 | 南通大学 | Preparation and application of pyrazole oxime ether compound containing trifluoro methyl pyridine |
CN104725366A (en) * | 2015-02-28 | 2015-06-24 | 南通大学 | Preparation method and application of trifluoromethyl pyrazole oxime derivative containing 5-alkoxy thiadiazole structure |
CN104961728A (en) * | 2015-05-22 | 2015-10-07 | 南通大学 | Preparation method and application of pyridinyl methoxybiphenyl structure-containing pyrazole oxime ester compound |
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Patent Citations (5)
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CN86108691A (en) * | 1985-12-27 | 1988-01-20 | 日本农药株式会社 | Pyrazole oxime derivatives, process for their preparation and their use |
JPH01197471A (en) * | 1988-02-02 | 1989-08-09 | Nissan Chem Ind Ltd | Pyrazole oxime derivative and insecticide, acaricide and germicide |
CN104193727A (en) * | 2014-08-04 | 2014-12-10 | 南通大学 | Preparation and application of pyrazole oxime ether compound containing trifluoro methyl pyridine |
CN104725366A (en) * | 2015-02-28 | 2015-06-24 | 南通大学 | Preparation method and application of trifluoromethyl pyrazole oxime derivative containing 5-alkoxy thiadiazole structure |
CN104961728A (en) * | 2015-05-22 | 2015-10-07 | 南通大学 | Preparation method and application of pyridinyl methoxybiphenyl structure-containing pyrazole oxime ester compound |
Non-Patent Citations (3)
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王誉蓉等.新型含1,2,4-***环结构的吡唑肟醚化合物的合成及其生物活性.《有机化学》.2019,第39卷 * |
石玉军等.新型含氟甲基吡唑结构的氰基丙烯酸酯类化合物的合成及其生物活性.《有机化学》.2016,第36卷 * |
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