CN111961048A - Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof - Google Patents
Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof Download PDFInfo
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- CN111961048A CN111961048A CN202010867601.8A CN202010867601A CN111961048A CN 111961048 A CN111961048 A CN 111961048A CN 202010867601 A CN202010867601 A CN 202010867601A CN 111961048 A CN111961048 A CN 111961048A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to trifluoromethyl pyrazole amide (I) containing a substituted beta-carboline structure, and a preparation method and application thereof. Obtained by the reaction of trifluoromethyl pyrazole formyl chloride and substituted beta-carboline. The trifluoromethyl pyrazole amide containing the substituted beta-carboline structure shows good inhibition effect on tumor cells, 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 trifluoromethyl pyrazole amide containing a substituted beta-carboline structure, and a preparation method and application thereof.
Background
Malignant tumors are always threatening the life and health of human beings. Therefore, the search for effective anticancer drugs is a task of current pharmaceutical chemists.
Beta-carboline is an important nitrogen-containing heterocycle, and the beta-carboline derivative plays an important role in medical care.
Trifluoromethyl pyrazole is also an important nitrogen-containing heterocyclic group, and trifluoromethyl pyrazole compounds have wide application in the field of pharmaceutical industry, and in recent years, some trifluoromethyl pyrazole compounds have been reported to have good inhibitory activity on tumor cells.
Therefore, in order to continuously find out a drug with excellent antitumor activity from the trifluoromethylpyrazole compound, the substituted β -carboline unit is rationally linked with the trifluoromethylpyrazole active fragment. The invention discloses a trifluoromethyl pyrazole amide containing a substituted beta-carboline structure with medicinal value.
Disclosure of Invention
The invention aims to provide trifluoromethyl pyrazole amide containing a substituted beta-carboline structure, which has good prevention and treatment effects on tumor cells.
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 technical problems, the invention provides trifluoromethyl pyrazole amide containing a substituted beta-carboline structure, which has a structure shown in a general formula I,
preferably, the trifluoromethyl pyrazole amide containing a substituted beta-carboline structure has the following structure:
the invention provides a preparation method of the trifluoromethyl pyrazole amide containing the substituted beta-carboline structure, which is characterized by comprising the following steps:
dissolving the intermediate III and an acid-binding agent in a certain amount of organic solvent, adding the intermediate II, reacting for a period of time, evaporating the solvent, separating the obtained crude product by silica gel column chromatography to obtain a target compound I,
preferably, the preparation method of the trifluoromethyl pyrazole amide containing the substituted beta-carboline structure comprises the following steps:
intermediate II was synthesized according to the reference (j.agric.food chem.2013,61,8730) and intermediate III was synthesized according to the reference (chi.j.org.chem.2016, 36,1431).
The compound of the general formula I shows good antitumor activity on tumor cells.
The trifluoromethyl pyrazole amide containing the substituted beta-carboline structure disclosed by the invention has a good inhibition effect on tumor cells SGC-7901 or A549, so that the trifluoromethyl pyrazole amide 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:
10mmol of intermediate IIIa, 50mmol of pyridine and 50mL of chloroform were added to a reaction flask, 11mmol of intermediate II was added dropwise thereto under ice-bath conditions, followed by stirring at room temperature for 10 hours. Purifying a crude product formed by evaporating the solvent by silica gel column chromatography to obtain a target compound Ia;1H NMR:11.84(s,1H,NH),8.88(t,1H,J＝6.0Hz,CONH),8.82(s,1H,Ar-H),8.49(t,1H,J＝5.6Hz,CONH),8.41(d,1H,J＝7.6Hz,Ar-H),8.35(s,1H,Pyrazole-H),8.09(d,2H,J＝8.0Hz,Ar-H),7.70(d,1H,J＝8.4Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.42(d,2H,J＝8.0Hz,Ar-H),7.31(t,1H,J＝7.6Hz,Ar-H),3.92(s,3H,CH3),3.54-3.58(m,2H,CH2),3.43-3.47(m,2H,CH2),2.46(s,3H,CH3).
example 2:
10mmol of intermediate IIIb, 3mL of triethylamine and 35mL of chloroform were added to a reaction flask, 9mmol of intermediate II was added dropwise thereto under ice-bath conditions, and then stirred at room temperature for 8 hours. Concentrating the reaction solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ib;1H NMR:11.80(s,1H,NH),8.87(t,1H,J＝6.0Hz,CONH),8.79(s,1H,Ar-H),8.42(t,2H,J＝8.0Hz,CONH and Ar-H),8.30(s,1H,Pyrazole-H),8.15(d,2H,J＝8.8Hz,Ar-H),7.69(d,1H,J＝8.4Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.31(t,1H,J＝8.0Hz,Ar-H),7.15(d,2H,J＝8.8Hz,Ar-H),3.92(s,3H,CH3),3.89(s,3H,CH3),3.52-3.57(m,2H,CH2),3.43-3.47(m,2H,CH2).
example 3:
adding 8mmol of intermediate IIIc, 30mmol of pyridine and 30mL of tetrahydrofuran into a reaction bottle, dropwise adding 9mmol of intermediate II under the ice bath condition, and carrying out ice bathStirring was continued for 6 hours under the conditions. Concentrating the reaction solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Ic;1H NMR:11.80(s,1H,NH),8.85(t,1H,J＝6.4Hz,CONH),8.78(s,1H,Ar-H),8.39(d,1H,J＝7.6Hz,Ar-H),8.29-8.31(m,2H,CONH and Pyrazole-H),8.17(d,2H,J＝8.8Hz,Ar-H),7.69(d,1H,J＝8.0Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.31(t,1H,J＝7.2Hz,Ar-H),7.18(d,2H,J＝8.8Hz,Ar-H),3.92(s,3H,CH3),3.89(s,3H,CH3),3.42-3.46(m,2H,CH2),3.24-3.32(m,2H,CH2),1.75-1.82(m,2H,CH2).
example 4:
5mmol of intermediate IIId, 2mL of triethylamine and 30mL of dichloromethane are added into a reaction flask, 6mmol of intermediate II is added dropwise under ice bath condition, and then stirring is continued for 4 hours under ice bath condition. Concentrating the reaction solution to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain a compound Id;1H NMR:11.92(s,1H,NH),8.72(t,1H,J＝6.0Hz,CONH),8.68(s,1H,Ar-H),8.34(d,1H,J＝7.6Hz,Ar-H),8.27-8.29(m,2H,Pyrazole-H and CONH),7.64(d,1H,J＝8.4Hz,Ar-H),7.58(t,1H,J＝8.0Hz,Ar-H),7.28(t,1H,J＝7.6Hz,Ar-H),3.93(s,3H,CH3),3.40-3.45(m,2H,CH2),3.24-3.29(m,2H,CH2),1.74-1.81(m,2H,CH3),2.84(s,3H,CH3).
example 5:
determination of the Activity of Compounds on tumor cells
The in vitro anti-tumor activity of the compound is determined by using a tetramethylazole blue colorimetric Method (MTT). The test subjects were human gastric cancer cell SGC-7901 and human lung cancer cell A549. Preparing 4 × 10 cancer cells in exponential growth phase3Cell suspension of individual cells/mL, seeded in 96-well plates in CO2The culture was carried out in an incubator for 36 hours. Test solutions (10. mu.L) of the test compounds were then added to the test wells at each concentration in parallel wells and an equal amount of DMSO was used as a blank in CO2Cultured in an incubatorAfter 24 hours, the supernatant was discarded, 10. mu.L of 5% MTT was added to each well, and the cells were cultured for 4 hours, and then the supernatant was aspirated and discarded, 100. mu.L of DMSO was added to each well, and the cells were shaken in a shaker for 20 minutes, and the OD value was measured at a wavelength of 570nm with a microplate reader to calculate the cell inhibition ratio. The cell inhibition rate (negative control group OD value-test substance group OD value)/negative control group OD value is multiplied by 100%, and the IC of the compound is calculated by a probability unit weighted regression method50The value is obtained.
TABLE 1 antitumor Activity data (IC) of Ia-Id50,μM)
| Compound (I) | SGC-7901 | A549 |
| Ia | 5.81 | - |
| Ib | 15.84 | - |
| Ic | - | 7.76 |
| Id | - | 0.03 |
"-" means not determined
As can be seen from the data in Table 1, compounds Ia and Ib are pairedHuman gastric cancer cell SGC-7901 shows better anti-tumor effect and IC thereof50Values of 5.81 and 15.84. mu.M, respectively; compounds Ic and Id show good inhibitory activity on human lung cancer cell A549, and IC thereof50The values were 7.76 and 0.03. mu.M, respectively.
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 trifluoromethyl pyrazole amide I containing a substituted beta-carboline structure is characterized by having a structure as follows:
2. the process for preparing trifluoromethylpyrazole amides I containing a substituted β -carboline structure according to claim 1, wherein the process comprises the following steps:
3. the use of the trifluoromethyl pyrazole amide I containing a substituted β -carboline structure according to claim 1 for combating tumour cells, wherein: the bisamide-based compound I containing trifluoromethylpyrazole and carboline structure according to claim 1, wherein said bisamide-based compound I has a good inhibitory effect on SGC-7901 or A549 tumor cells.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114957243A (en) * | 2021-02-25 | 2022-08-30 | 沈阳药科大学 | Beta-carbopol NO donor derivatives and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6191147B1 (en) * | 1998-12-24 | 2001-02-20 | Ppd Discovery, Inc. | Pyrazole compounds and uses thereof |
| CN102584679A (en) * | 2011-01-13 | 2012-07-18 | 中国科学院上海药物研究所 | Benzocarbazole acylamide compound and preparation method and application thereof |
| CN103396400A (en) * | 2013-07-16 | 2013-11-20 | 浙江医药高等专科学校 | Pyrazole amide compounds, and preparation method and application thereof |
| CN106432183A (en) * | 2016-07-28 | 2017-02-22 | 浙江工业大学 | Trifluoromethyl group-containing pyridylpyrazole carboxamide derivative, and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6191147B1 (en) * | 1998-12-24 | 2001-02-20 | Ppd Discovery, Inc. | Pyrazole compounds and uses thereof |
| CN102584679A (en) * | 2011-01-13 | 2012-07-18 | 中国科学院上海药物研究所 | Benzocarbazole acylamide compound and preparation method and application thereof |
| CN103396400A (en) * | 2013-07-16 | 2013-11-20 | 浙江医药高等专科学校 | Pyrazole amide compounds, and preparation method and application thereof |
| CN106432183A (en) * | 2016-07-28 | 2017-02-22 | 浙江工业大学 | Trifluoromethyl group-containing pyridylpyrazole carboxamide derivative, and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957243A (en) * | 2021-02-25 | 2022-08-30 | 沈阳药科大学 | Beta-carbopol NO donor derivatives and application thereof |
| CN114957243B (en) * | 2021-02-25 | 2024-02-02 | 沈阳药科大学 | Beta-carbolin NO donor derivative and application thereof |
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