CN111423413A - 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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- CN111423413A CN111423413A CN202010397356.9A CN202010397356A CN111423413A CN 111423413 A CN111423413 A CN 111423413A CN 202010397356 A CN202010397356 A CN 202010397356A CN 111423413 A CN111423413 A CN 111423413A
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- methoxy
- substituted pyridylmethoxy
- pyrazole derivative
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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 cancers 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 group 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:
adding 15mmol of compound IIa, 12mmol of compound III and 35m of L acetonitrile into a reaction bottle, adding 50mmol of pyridine into the reaction bottle while stirring at room temperature, continuing stirring the reaction solution 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):8.44(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:
adding 10mmol of intermediate IIb, 13mmol of intermediate III and 30m of L2-butanone into a reaction bottle, then adding 30mmol of triethylamine into the reaction bottle under stirring at room temperature, heating and refluxing the reaction solution for 10 hours after the addition, stopping the reaction, performing suction filtration, concentrating the mother solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ib;1H NMR(500MHz,CDCl3):8.44(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:
adding 8mmol of intermediate IIc, 15mmol of intermediate III and 35m L DMF into a reaction bottle, then adding 20mmol of potassium carbonate into the reaction bottle under stirring at room temperature, heating the reaction solution to 60 ℃ after the addition, reacting for 15 hours, stopping the reaction, performing suction filtration, concentrating the mother solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ic;1H NMR(500MHz,CDCl3):8.43(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 compound is tested to human liver cancer cell HepG2 and human by adopting a tetramethyl azole blue colorimetric Method (MTT)In vitro antitumor activity of hepatocarcinoma cell SMMC-7721, 5-fluorouracil (5-FU) is selected as positive control drug, one bottle of cells in exponential growth phase is taken, 0.25% trypsin is added for digestion to make adherent cells fall off, and the solution is prepared to contain 2 × 10 per ml4～4×104Inoculating the cell suspension onto a 96-well plate at 180. mu. L per well, and placing in a constant temperature CO2After 24 hours of incubation in an incubator, the solution was changed, the compound (the compound was dissolved in DMSO and diluted with PBS) was added to 20 μ L per well, and the incubation was performed for 48 hours, MTT was added to a 96-well plate at 20 μ L per well, the reaction was performed in the incubator for 4 hours, then the supernatant was aspirated, DMSO was added to 150 μ L per well, and the plate was shaken on a shaker for 5 minutes, the absorbance of each well was measured at a wavelength of 570nm using an enzyme linked immunosorbent assay, and the cell inhibition rate was calculated (negative control OD value-test object OD value)/negative control OD value × 100%. the IC value of the compound was calculated by a simplified probability unit method50The 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 |
The relevant antitumor 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 prevention and treatment effect of positive control drug 5-FU, and the IC of the compound Ia-Ic to 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 in-depth research.
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)
1. A pyrazole derivative (I) containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit is characterized by having the structure:
2. a process for the preparation of pyrazole derivatives (I) containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit according to claim 1, characterized in that the process comprises:
3. use of a pyrazole derivative (I) containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit according to claim 1 for inhibiting tumor cells or the like, wherein: the pyrazole derivative (I) containing a (3-methoxy-4-substituted pyridylmethoxy) phenyl unit according to claim 1 shows good inhibitory activity against human hepatoma cells HepG2 and human hepatoma cells SMMC-7721.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2020
- 2020-05-12 CN CN202010397356.9A patent/CN111423413B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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)
| Title |
|---|
| 戴红等: "新型含取代吡啶环的取代吡唑甲醛肟的合成及生物活性测定", 《有机化学》, vol. 35, 31 December 2015 (2015-12-31), pages 2399 - 2404 * |
| 王誉蓉等: "新型含1,2,4-三唑环结构的吡唑肟醚化合物的合成及其生物活性", 《有机化学》, vol. 39, 31 December 2019 (2019-12-31), pages 2053 - 2061 * |
| 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》, vol. 36, 31 December 2016 (2016-12-31), pages 1431 - 1437 * |
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