CN111892595B - Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit - Google Patents
Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit Download PDFInfo
- Publication number
- CN111892595B CN111892595B CN202010868016.XA CN202010868016A CN111892595B CN 111892595 B CN111892595 B CN 111892595B CN 202010868016 A CN202010868016 A CN 202010868016A CN 111892595 B CN111892595 B CN 111892595B
- Authority
- CN
- China
- Prior art keywords
- methyl
- carboline
- preparation
- difluoromethyl pyrazole
- carboline derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method and application of carboline derivatives containing 1-methyl-3-difluoromethyl pyrazole units. Obtained by condensing 1-methyl-3-difluoromethyl pyrazole-4-formyl chloride and substituted beta-carboline amide. The carboline derivative containing the 1-methyl-3-difluoromethyl pyrazole unit has good inhibitory activity on tumor cells SGC-7901, 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 a preparation method and application of carboline derivatives containing 1-methyl-3-difluoromethylpyrazole units.
Background
Malignant tumors have in recent years seriously threatened human health. Therefore, there is a need for pharmaceutical chemists to explore and discover highly effective antitumor drugs.
Pyrazole derivatives play an important role in the field of medical care as important nitrogen-containing heterocycles, and for example, celecoxib which is a medicament containing a pyrazole ring is used for treating a plurality of diseases.
The beta-carboline compound is also an important heterocyclic unit and also shows excellent inhibition effect on some tumor cells.
Therefore, in order to further search for a drug having a good antitumor effect from β -carboline compounds, a substituted pyrazole ring and a β -carboline structure are combined together. The invention discloses carboline derivatives containing 1-methyl-3-difluoromethyl pyrazole units and having medicinal values.
Disclosure of Invention
The invention aims to provide carboline derivatives containing 1-methyl-3-difluoromethyl pyrazole units, which have good inhibition effect on human gastric cancer cells SGC-7901.
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 a carboline derivative containing a 1-methyl-3-difluoromethyl pyrazole unit, which has the following structure:
the invention provides a preparation method of the carboline derivative containing the 1-methyl-3-difluoromethyl pyrazole unit, which is characterized by comprising the following reaction steps:
the intermediate is prepared by a method of a substitute beta-carboline amide reference document (Chin.J.org.chem.2016,36,1431), and the intermediate is prepared by a method of a 1-methyl-3-difluoromethylpyrazole-4-formyl chloride reference document (J.Agric.food chem.2013,61,8730).
The compound of the general formula I has a good inhibition effect on tumor cells, wherein the tumor cells comprise SGC-7901 and the like.
The carboline derivative containing the 1-methyl-3-difluoromethyl pyrazole unit disclosed by the invention has good inhibitory activity on human gastric cancer cells SGC-7901, 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:
dissolving 7mmol of intermediate IIa and 30mmol of pyridine in 30mL of acetonitrile, adding 8mmol of intermediate III under the ice bath condition, and heating and refluxing for reaction for 9 hours after the addition. Removing the solvent to obtain a crude product, and purifying the crude product through silica gel column chromatography to obtain a target compound Ia;1H NMR:δ11.84(s,1H,NH),8.90(t,1H,J＝5.6Hz,CONH),8.81(s,1H,Ar-H),8.52(t,1H,J＝5.6Hz,CONH),8.40(d,1H,J＝8.0Hz,Ar-H),8.30(s,1H,Pyrazole-H),8.09(d,2H,J＝8.0Hz,Ar-H),7.70(d,1H,J＝8.0Hz,Ar-H),7.59(t,1H,J＝7.2Hz,Ar-H),7.43(d,2H,J＝8.0Hz,Ar-H),7.34(s,1H,CHF2),7.29(t,1H,J＝7.2Hz,Ar-H),3.91(s,3H,CH3),3.54-3.58(m,2H,CH2),3.45-3.49(m,2H,CH2),2.46(s,3H,CH3).
example 2:
5mmol of the intermediate IIb and 2mL of triethylamine are dissolved in 35mL of dichloromethane, 6mmol of the intermediate III is added under ice bath conditions, and after the addition, the stirring in ice bath is continued for 4 hours. Removing the solvent to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a target compound Ib;1H NMR:δ11.69(s,1H,NH),8.80(s,1H,Ar-H),8.71(t,1H,J＝6.4Hz,CONH),8.40(d,1H,J＝8.0Hz,Ar-H),8.21-8.24(m,2H,Pyrazole-H and CONH),8.06(d,2H,J＝8.4Hz,Ar-H),7.69(d,1H,J＝8.0Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.45(d,2H,J＝8.0Hz,Ar-H),7.20-7.34(m,2H,CHF2 and Ar-H),3.90(s,3H,CH3),3.40-3.45(m,2H,CH2),3.22-3.27(m,2H,CH2),2.46(s,3H,CH3),1.54-1.66(m,4H,CH2).
example 3:
6mmol of intermediate IIc was dissolved in 35mL of DMF, and then 12mmol of sodium bicarbonate was added thereto, and 6mmol of intermediate III was added thereto under stirring in ice bath, and after addition, the mixture was stirred at room temperature for 13 hours. Removing the solvent to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a target compound Ic;1H NMR:δ11.81(s,1H,NH),8.89(t,1H,J＝6.0Hz,CONH),8.78(s,1H,Ar-H),8.39(d,1H,J＝8.0Hz,Ar-H),8.32(t,1H,J＝5.6Hz,CONH),8.24(s,1H,Pyrazole-H),8.18(dd,2H,J1＝2.0Hz,J2＝6.8Hz,Ar-H),7.69(d,1H,J＝8.4Hz,Ar-H),7.59(t,1H,J＝8.0Hz,Ar-H),7.38(t,J＝54.0Hz,1H,CHF2),7.31(t,1H,J＝7.2Hz,Ar-H),7.19(d,2H,J＝8.8Hz,Ar-H),3.90(d,6H,J＝5.6Hz,CH3),3.41-3.46(m,2H,CH2),3.29-3.32(m,2H,CH2),1.75-1.82(m,2H,CH2).
example 4:
activity testing of samples on tumor cells
The in vitro antitumor activity of the sample is tested by a tetramethylazole blue colorimetric Method (MTT). The test object is human gastric cancer cell SGC-7901. FTS served as a positive control. Preparing cancer cells in exponential growth phase into 4 × 103Cell 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 test compounds were added to the test wells at each concentration in parallel wells and an equal amount of DMSO was used as a blank in CO2Culturing in an incubator for 24 hours, discarding the supernatant, adding 10. mu.L of 5% MTT to each well, culturing for 4 hours, removing the supernatant, adding 100. mu.L of DMSO to each well, shaking in a vibrator for 20 minutes, measuring the OD value at a wavelength of 570nm by using a microplate reader, and calculating the cell inhibition rate. The cell inhibition rate (negative control group OD value-test substance group OD value)/negative control group OD value x 100%, and the IC of the sample was calculated by probability unit weighted regression50The value is obtained.
TABLE 1 antitumor Activity data (IC) of Ia-Ic50,μM)
| Compound (I) | SGC-7901 |
| Ia | 2.26 |
| Ib | 9.27 |
| Ic | 7.62 |
| FTS | 41.30 |
As can be seen from the experimental data in Table 1, the prepared compounds Ia-Ic all show better anti-tumor effects on human gastric cancer cells SGC-7901, and the drug effects are better than those of the positive control drug FTS. The result also shows that the novel compound obtained by combining the substituted pyrazole ring and the beta-carboline structure has better inhibition effect on human gastric cancer cells SGC-7901.
The foregoing shows and describes the general principles, principal 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 carboline derivative I containing 1-methyl-3-difluoromethyl pyrazole unit is characterized by having the following structure:
2. the process for producing the carboline derivative I containing 1-methyl-3-difluoromethylpyrazole unit according to claim 1, characterized by comprising:
3. the use of the carboline derivative I containing 1-methyl-3-difluoromethylpyrazole unit according to claim 1 for the preparation of a medicament for treating tumor cells, wherein: the carboline derivative I containing the 1-methyl-3-difluoromethyl pyrazole unit shows an inhibiting effect on the tumor cells SGC-7901.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010868016.XA CN111892595B (en) | 2020-08-26 | 2020-08-26 | Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010868016.XA CN111892595B (en) | 2020-08-26 | 2020-08-26 | Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111892595A CN111892595A (en) | 2020-11-06 |
| CN111892595B true CN111892595B (en) | 2022-07-12 |
Family
ID=73225547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010868016.XA Active CN111892595B (en) | 2020-08-26 | 2020-08-26 | Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111892595B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106589056A (en) * | 2015-10-16 | 2017-04-26 | 首都医科大学 | beta-carboline-3-formyl-Trp-Lys-Lys-OBzl, synthesis and applications thereof |
-
2020
- 2020-08-26 CN CN202010868016.XA patent/CN111892595B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| β-咔啉-3-甲酰胺类衍生物的合成及与DNA的作用;林伟 等;《北京大学学报（医学版）》;20010618;第33卷(第3期);第277-279页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111892595A (en) | 2020-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111892595B (en) | Preparation method and application of carboline derivative containing 1-methyl-3-difluoromethyl pyrazole unit | |
| CN112047880A (en) | Azaflavone derivatives and application thereof as antitumor drugs | |
| CN110511214B (en) | Diamine substituted aromatic heterocyclic compound and preparation method and application thereof | |
| CN111961048B (en) | Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof | |
| CN114605407B (en) | Indoloquinolinone compound and synthetic method and application thereof | |
| CN111875605B (en) | Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units | |
| CN110511226B (en) | Compound or salt or solvate thereof, application thereof and pharmaceutical composition | |
| CN111961049B (en) | Beta-carboline derivative containing 1, 3-dimethyl-5-aryloxy pyrazole and preparation method and application thereof | |
| CN111892596B (en) | Preparation and application of beta-carboline compound containing polyfluoropyrazole structure | |
| CN111393416B (en) | Preparation method and application of pyrazole compound containing 1-methylpyridine-3- (4-chlorphenyl) pyrazole unit | |
| CN111440153B (en) | Preparation and application of pyrazole compound containing (3-methoxy-4-pyrimidinyloxy) phenyl unit | |
| CN112047940B (en) | Preparation and application of pyrazole compound containing 1- (3, 4-dimethoxyphenyl) -beta-carboline unit | |
| CN111499568B (en) | Preparation and application of cyanoacrylate derivative containing pyridine bi-4-mercaptoaryl unit | |
| CN116199687B (en) | Beta-carboline-3-position connected 1,2, 3-triazole compound as well as preparation method and application thereof | |
| CN111423413B (en) | Preparation and application of pyrazole derivative containing (3-methoxy-4-substituted pyridylmethoxy) phenyl unit | |
| CN111393413B (en) | Pyrazole compound containing chloropyridine biphenyl unit, and preparation method and application thereof | |
| CN112920242B (en) | Benzimidazole derivative BI292 and preparation method and application thereof | |
| CN112358517B (en) | Benzimidazole derivative BI305 and preparation method and application thereof | |
| CN115057850B (en) | Aloe-emodin derivative and preparation method and application thereof | |
| CN111333578B (en) | Preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit | |
| CN111423415A (en) | Pyrazole oxime derivative containing chloropyridine ring dipyrazole unit, and preparation method and application thereof | |
| CN112250725B (en) | Benzimidazole derivative BI345 and preparation method and application thereof | |
| CN111518084B (en) | Pyrazole derivative containing pyrimidine heterocyclic unit and preparation method and application thereof | |
| JP7278649B2 (en) | JAK inhibitor and method for producing the same | |
| CN110818706B (en) | Four-condensed ring quinoxaline derivative and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |