CN108299398B - Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof - Google Patents
Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN108299398B CN108299398B CN201810390133.2A CN201810390133A CN108299398B CN 108299398 B CN108299398 B CN 108299398B CN 201810390133 A CN201810390133 A CN 201810390133A CN 108299398 B CN108299398 B CN 108299398B
- Authority
- CN
- China
- Prior art keywords
- carbazole
- quinazoline derivative
- containing quinazoline
- pharmaceutically acceptable
- acceptable salt
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention designs and synthesizes a carbazole-containing quinazoline derivative with anti-tumor activity and researches the in-vitro anti-tumor activity of the carbazole-containing quinazoline derivative, and the results show that the carbazole-containing quinazoline derivative has better inhibiting effect on human non-small cell lung cancer cells (A-549), human ovarian cancer cells (SKOV-3), human breast cancer cells (MCF-7), human leukemia cells (HL-60) and the like; especially, the inhibition effect on human leukemia cell HL-60 is obviously better than that of other cancer cells.
Description
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to a carbazole-containing quinazoline derivative and pharmaceutical application thereof.
Background
Tumors belong to one of the important diseases which harm human health nowadays, according to statistics of international agency for research on cancer (IARC), about 1410 ten thousands of new cancer cases are added in 2012 worldwide, and the number of cancer deaths reaches 820 thousands, so that obtaining of high-efficiency, low-toxicity and specific anti-tumor drugs is still a hot spot of global research.
Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase receptor that has been extensively studied, and many EGFR signaling abnormalities, including lung, breast and uterine cancers, are found in human tumor cells. By genetic immunochemical testing, results indicate that high levels of EGFR are found on the cell membrane of many types of epithelial malignancies such as head and neck, ovarian, uterine, bladder and esophageal cancers. Therefore, EGFR is an important target for tumor drug research.
In the study of drugs targeting EGFR, small molecule inhibitors have been intensively studied and approved for the treatment of breast cancer, skin cancer, lung cancer, and the like. Such inhibitors include gefitinib, erlotinib and the like (for example, patent CN03108814.7, US5616582 and the like), and such tinib drugs basically take quinazoline as a parent nucleus.
Quinazoline is a very important nitrogen-containing heterocycle, which shows good biological activity in the aspects of pesticides, medicines and the like, and becomes one of the hot spots for the research of scholars in the chemical and biological industries. In particular to the field of antitumor drugs, gefitinib, lapatinib, erlotinib and the like are available on the market.
However, with the long-term use of the marketed drugs, the marketed drugs also show many disadvantages, such as large toxic and side effects, drug resistance, and the like, so that the field of antitumor drugs continuously requires the emergence of new antitumor drugs to replace the original drugs.
Carbazole is a very important nitrogen-containing heterocycle, wherein photoelectric materials, medicines, dyes and the like have wide potential application prospects, but at present, no report is available about the application of carbazole and quinazoline in antitumor drugs after the carbazole and quinazoline are connected.
The inventor tries to use groups/substituents which are greatly different from the existing drugs for structural modification on the basis of the common parent nucleus of the existing tinib drugs (namely quinazoline) so as to obtain a high-efficiency, low-toxicity and specific compound. In particular, carbazole and benzyloxy are introduced into the quinazoline parent nucleus in a combined design, and the in-vitro anti-tumor activity of the quinazoline parent nucleus is measured.
Disclosure of Invention
The invention aims to provide a novel carbazole-containing quinazoline derivative with high-efficiency and/or specific antitumor activity, in particular to leukemia.
The invention relates to a carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof.
In particular to a carbazole-containing quinazoline derivative or a pharmaceutically acceptable salt or a solvate thereof, wherein the carbazole-containing quinazoline derivative is a compound shown in a formula I,
the invention also provides a method for preparing the carbazole-containing quinazoline derivative shown as the formula I:
dissolving the compound 1 in an organic solvent, adding a first alkali, heating and stirring, dropwise adding chlorotoluene, heating to reflux, reacting for 3 hours, cooling to 60 ℃, adding a second alkali and carbazole, heating to 90 ℃, stirring and reacting for 3 hours, cooling to room temperature after the reaction is finished, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and carrying out silica gel column chromatography to obtain a compound I.
Wherein the organic solvent is DMF;
the first base is potassium carbonate, and the second base is potassium hydroxide;
the method is a one-pot method, wherein potassium carbonate with weak alkalinity is used in the first step, potassium hydroxide with strong alkalinity is used in the second step (carbazole needs to be activated by a substance with strong alkalinity), and an intermediate prepared after chlorotoluene is added is directly reacted without separation.
The preparation formula of the carbazole-containing quinazoline derivative shown in the formula I is as follows:
in the present invention, compound 1 is
The invention also relates to application of the carbazole-containing quinazoline derivative shown in the formula I or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention also relates to application of the carbazole-containing quinazoline derivative shown in the formula I or pharmaceutically acceptable salt thereof in preparing a medicament for treating leukemia.
The invention also relates to a pharmaceutical composition containing the carbazole-containing quinazoline derivative or a pharmaceutically acceptable salt thereof.
The in vitro MTT method experiment shows that: the quinazoline derivative containing carbazole in the formula I has better inhibiting effect on human non-small cell lung cancer cells (A-549), human ovarian cancer cells (SKOV-3), human breast cancer cells (MCF-7), human leukemia cells (HL-60) and the like; wherein the inhibitory effect of the compound I on human leukemia cell HL-60 is obviously better than that of other cancer cells and is about 1 order of magnitude higher.
The quinazoline derivative containing carbazole in the formula I can be used as a potential anti-tumor medicament, in particular to a medicament for treating leukemia.
Detailed Description
Example 1:
dissolving 2.1g of compound 1 in 14ml DMF, adding 0.7g of potassium carbonate, heating and stirring to 50 ℃, dropwise adding chlorotoluene (1.27g), heating to reflux, reacting for 3h, cooling to 60 ℃, adding 0.6g of KOH and 1.67g of carbazole, heating to 90 ℃, stirring and reacting for 3h, cooling to room temperature after the reaction is finished, filtering, evaporating the solvent from the filtrate under reduced pressure, and performing silica gel column chromatography (ethyl acetate: petroleum ether ═ 5:1) to obtain compound I (3.67g, yield 85.15%).
Mass Spectrometry (CI, m/z): 432[ M +1 ]]+；
1H-NMR spectrum (DMSO-d6) delta: 8.65(s, 1H), 7.38-7.50(m, 6H), 7.05-7.25(m, 9H), 5.4(s, 2H), 3.68(s, 3H).
Example 2:
determination of in vitro Activity by MTT method:
cell lines: human non-small cell lung cancer cell (A-549), human ovarian cancer cell (SKOV-3), human breast cancer cell (MCF-7), and human leukemia cell (HL-60).
Cell culture: inoculating the cells in DMEM or DMEM/F12 complete culture solution containing 10% calf serum, 100IU/ml penicillin G sodium salt and 100ug/ml streptomycin sulfate, standing at 37 deg.C and 100% relative humidity, and containing 5% C02The culture box of (5), passage 3 times for standby.
And (3) MTT colorimetric detection: cells in logarithmic phase are taken, digested by 0.25% trypsin (suspension cells are not required to be digested), suspended in culture solution containing 10% calf serum, slightly blown by a glass dropper to form single cell suspension, and viable cells are counted by a blood cell counting plate under a microscope. The 96-well culture plate was inoculated with 90. mu.l of cell suspension per well (cell concentration 3-6X 10)4one/mL), and after 24 hours in an incubator, 10. mu.l of the liquid medicine is added to each well. In addition, each concentration was set with a negative control (equal concentration of DMSO) and a blank background (no cells added), and each group was set with 6 replicate wells. The culture was continued for another 48 hours, then 10. mu.l of 5mg/mL MTT solution was added to each well, and after further culture for 4 hours, the supernatant was aspirated. Adding 100 μ l DMSO into each well, placing in a micro oscillator, shaking for 5min to dissolve the crystal completely, and placing in a microplate reader 530nm single-wavelength colorimetry, and the OD value is measured, and the test results are shown in Table 1.
The inhibition ratio (%) was [1- (experimental OD mean-blank OD mean)/(control OD mean-blank OD mean) ] × 100%.
Calculation of test Compound IC by Bliss method50The value is obtained.
TABLE 1 inhibitory Activity of the Compounds of the invention against four tumor cells
The results in table 1 show that: the quinazoline derivative containing carbazole in the formula I has obvious inhibition effect on human non-small cell lung cancer cells (A-549), human ovarian cancer cells (SKOV-3), human breast cancer cells (MCF-7), human leukemia cells (HL-60) and the like; wherein the inhibitory effect of the compound I on human leukemia cell HL-60 is obviously better than that of other cancer cells and is about 1 order of magnitude higher.
Therefore, the quinazoline derivative containing carbazole in the formula I can be used as a potential anti-tumor medicament, in particular to a medicament for treating leukemia.
Claims (6)
1. A carbazole-containing quinazoline derivative which is a compound of formula I, or a pharmaceutically acceptable salt thereof,
2. a method for producing the carbazole-containing quinazoline derivative as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of:
dissolving the compound 1 in an organic solvent, adding a first alkali, heating and stirring, dropwise adding chlorotoluene, heating to reflux, reacting for 3 hours, cooling to 60 ℃, adding a second alkali and carbazole, heating to 90 ℃, stirring and reacting for 3 hours, cooling to room temperature after the reaction is finished, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and carrying out silica gel column chromatography to obtain a compound I;
wherein the first base is potassium carbonate and the second base is potassium hydroxide;
wherein the preparation equation is:
3. the method of claim 2, wherein the organic solvent is DMF.
4. The use of a carbazole-containing quinazoline derivative as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of an anti-neoplastic drug.
5. Use of a carbazole-containing quinazoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of leukaemia.
6. A pharmaceutical composition containing the carbazole-containing quinazoline derivative of claim 1 or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810390133.2A CN108299398B (en) | 2018-04-27 | 2018-04-27 | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810390133.2A CN108299398B (en) | 2018-04-27 | 2018-04-27 | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108299398A CN108299398A (en) | 2018-07-20 |
| CN108299398B true CN108299398B (en) | 2021-04-02 |
Family
ID=62846647
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810390133.2A Active CN108299398B (en) | 2018-04-27 | 2018-04-27 | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108299398B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020061470A1 (en) * | 2018-09-21 | 2020-03-26 | Spectrum Pharmaceuticals, Inc. | Novel quinazoline egfr inhibitors |
| CN110256363A (en) * | 2019-07-09 | 2019-09-20 | 宿州学院 | A kind of preparation method and application of the EGFR inhibitor containing quinazoline structure |
| CN114057696B (en) * | 2021-11-04 | 2024-03-19 | 中山大学 | Carbazole-pyrimidine derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804308A (en) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof |
| WO2016151144A1 (en) * | 2015-03-25 | 2016-09-29 | Pierre Fabre Medicament | Substituted quinazoline derivatives as dna methyltransferase inhibitors |
-
2018
- 2018-04-27 CN CN201810390133.2A patent/CN108299398B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804308A (en) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof |
| WO2016151144A1 (en) * | 2015-03-25 | 2016-09-29 | Pierre Fabre Medicament | Substituted quinazoline derivatives as dna methyltransferase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents;Jaeki Min等;《J.Med.Chem.》;20151203;第59卷;559-577 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108299398A (en) | 2018-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108299398B (en) | Carbazole-containing quinazoline derivative with anti-tumor activity and pharmaceutical application thereof | |
| CN107245075A (en) | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines | |
| CN110330474A (en) | Apiolin-dithiocarbamate derivative preparation and antitumor application thereof | |
| CN108558865B (en) | Derivative taking pyrido [2,3-d ] pyrimidine structure as mother nucleus, and preparation method and application thereof | |
| CN110981882B (en) | Chelidonium nitric oxide donor derivatives, and preparation method and application thereof | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN109942499A (en) | Quinazoline derivant and its preparation method and application | |
| CN110698512B (en) | Tin complex with 2-acetylpyridine thiosemicarbazone as ligand and synthesis method thereof | |
| CN108358855B (en) | Quinazoline derivative containing benzhydrylamine and application thereof | |
| CN109265449B (en) | EGFR and HER2 double-target tyrosine kinase inhibitor and preparation method and application thereof | |
| CN107827877B (en) | Dialkylamino quinazoline compound and application thereof in preparation of antitumor drugs | |
| CN107652275B (en) | Quinazoline derivative and preparation method and application thereof | |
| CN105037265A (en) | Preparation method of quinolinone derivative containing chalcone framework, and application of the quinolinone derivative in anti-cancer medicines | |
| CN109160902B (en) | Asymmetric bisquinazoline Schiff base derivative for treating tumors and preparation and medical application thereof | |
| CN115197201B (en) | Chrysin derivative containing aminopyrimidine ring as well as preparation method and application thereof | |
| CN111875605B (en) | Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units | |
| CN115304605B (en) | Oxetane derivatives with antitumor activity, and preparation method and application thereof | |
| CN114436925B (en) | M-diphenol ether compound, preparation method and application thereof | |
| CN115073410B (en) | Cerbera Manghas essence type anti-prostatic cancer proliferation inhibitor and preparation method thereof | |
| CN111393416B (en) | Preparation method and application of pyrazole compound containing 1-methylpyridine-3- (4-chlorphenyl) pyrazole unit | |
| CN113527321B (en) | Trifluoromethyl pyrazolo heptatomic ring compound, crystal structure and preparation method | |
| CN112047940B (en) | Preparation and application of pyrazole compound containing 1- (3, 4-dimethoxyphenyl) -beta-carboline unit | |
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof | |
| CN110950896B (en) | Copper (II) complex with 9-aldehyde-10-pyrimidinehydrazone as ligand and synthetic method and application thereof | |
| CN111848580B (en) | Crystal form of quinoline compound containing 1,2, 4-triazine-3, 5-diketone as well as preparation method and application 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 | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210315 Address after: 510000 room 512, building a, No. 11, Nanyun 5th Road, Huangpu District, Guangzhou City, Guangdong Province Applicant after: Guangzhou Furui value medical and Health Industry Co.,Ltd. Address before: Room 213, building 4, Fenghui business square, 158 Shanji Road, Yuanhe street, Xiangcheng District, Suzhou City, Jiangsu Province Applicant before: SUZHOU HUAZHEN MEDICAL TECHNOLOGY Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230822 Address after: 510000 A502 room 11, Nan Yun five road, hi tech Industrial Development Zone, Guangzhou, Guangdong. Patentee after: GUANGZHOU FURUI HEALTH TECHNOLOGY Co.,Ltd. Address before: 510000 room 512, building a, No. 11, Nanyun 5th Road, Huangpu District, Guangzhou City, Guangdong Province Patentee before: Guangzhou Furui value medical and Health Industry Co.,Ltd. |
|
| TR01 | Transfer of patent right |