CN111961048B - 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 PDF

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CN111961048B
CN111961048B CN202010867601.8A CN202010867601A CN111961048B CN 111961048 B CN111961048 B CN 111961048B CN 202010867601 A CN202010867601 A CN 202010867601A CN 111961048 B CN111961048 B CN 111961048B
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carboline
substituted beta
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pyrazole amide
trifluoromethyl pyrazole
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CN111961048A (en
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戴红
钱程
黄美岭
周逸开
缪何一
张燕
施磊
张海军
王志鹏
李建华
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Nantong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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 a composition containing a substituted beta-carboline structureTrifluoromethyl pyrazole amide (I) 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

Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof
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,
Figure BDA0002650164260000011
preferably, the trifluoromethyl pyrazole amide containing a substituted beta-carboline structure has the following structure:
Figure BDA0002650164260000021
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,
Figure BDA0002650164260000031
preferably, the preparation method of the trifluoromethyl pyrazole amide containing the substituted beta-carboline structure comprises the following steps:
Figure BDA0002650164260000032
Figure BDA0002650164260000041
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:
Figure BDA0002650164260000042
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:δ11.84(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:
Figure BDA0002650164260000051
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:δ11.80(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:
Figure BDA0002650164260000052
8mmol of intermediate IIIc, 30mmol of pyridine and 30mL of tetrahydrofuran are added into a reaction flask, 9mmol of intermediate II is added dropwise under ice-bath conditions, and stirring is continued for 6 hours under ice-bath 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:δ11.80(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:
Figure BDA0002650164260000061
adding 5mmol of intermediate IIId, 2mL of triethylamine and 30mL of dichloromethane into a reaction bottle, dropwise adding 6mmol of intermediate II into the reaction bottle under the ice bath condition, and continuously stirring the mixture for 4 hours under the 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:δ11.92(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 CO2After 24 hours of incubation in an incubator, the supernatant was discarded, 10. mu.L of 5% MTT was added to each well, and the incubation was carried out for 4 hours, and then the supernatant was aspirated and discarded, 100. mu.L of DMSO was added to each well, and the mixture was shaken in a shaker for 20 minutes, and OD value was measured at a wavelength of 570nm with a microplate reader, and the cell inhibition ratio was calculated. 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, the compounds Ia and Ib have good antitumor effect on human gastric cancer cell SGC-7901, and the 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:
Figure FDA0003550971610000011
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:
Figure FDA0003550971610000021
3. the use of the trifluoromethyl pyrazole amide I containing a substituted β -carboline structure according to claim 1 for the preparation of an antitumor medicament, wherein: the tumor cell is SGC-7901 or A549.
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Citations (4)

* Cited by examiner, † Cited by third party
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
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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