CN108299398A - It is a kind of that there is quinazoline derivant and its pharmaceutical applications of the antitumor activity containing carbazole - Google Patents
It is a kind of that there is quinazoline derivant and its pharmaceutical applications of the antitumor activity containing carbazole Download PDFInfo
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- CN108299398A CN108299398A CN201810390133.2A CN201810390133A CN108299398A CN 108299398 A CN108299398 A CN 108299398A CN 201810390133 A CN201810390133 A CN 201810390133A CN 108299398 A CN108299398 A CN 108299398A
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- Prior art keywords
- carbazole
- quinazoline derivant
- cell
- alkali
- pharmaceutically acceptable
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- 0 C*c1cc2ncnc(-[n]3c(cccc4)c4c4c3cccc4)c2cc1OCc1ccccc1 Chemical compound C*c1cc2ncnc(-[n]3c(cccc4)c4c4c3cccc4)c2cc1OCc1ccccc1 0.000 description 2
- ZBOFUZBKDHGCAF-UHFFFAOYSA-N COc(c(O)c1)cc2c1c(Cl)nc[n]2 Chemical compound COc(c(O)c1)cc2c1c(Cl)nc[n]2 ZBOFUZBKDHGCAF-UHFFFAOYSA-N 0.000 description 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N c(cc1)cc2c1[nH]c1c2cccc1 Chemical compound c(cc1)cc2c1[nH]c1c2cccc1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 1
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
Present invention design has synthesized a kind of quinazoline derivant with anti-tumor activity containing carbazole and has studied its anti tumor activity in vitro, as a result show that the quinazoline derivant containing carbazole of the invention all has good inhibiting effect to Non-small cell lung carcinoma cell (A 549), Proliferation of Human Ovarian Cell (SKOV 3), human breast cancer cell (MCF 7), human leukemia cell (HL 60) etc.；It is substantially better than other cancer cells especially for the inhibition of human leukemia cell HL 60.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of quinazoline derivant and its pharmaceutical applications containing carbazole,
The quinazoline derivant containing carbazole can be used for preparing antitumor drug, especially treat the drug of leukaemia.
Background technology
Tumour belongs to one of the important diseases for nowadays endangering human health, is counted according to international cancer research institution (IARC),
The newly-increased cases of cancer about 14,100,000 in the whole world in 2012, number of cancer deaths is up to 8,200,000, therefore, obtains efficient, low toxicity, special
Property antitumor drug still be the whole world research hot spot.
EGF-R ELISA (EGFR) is a kind of tyrosine kinase receptor extensively and profoundly studied, in human tumor
Find that many EGFR signal transductions are abnormal in cell, including lung cancer, breast cancer and uterine cancer etc..It is surveyed by inherent immunity chemistry
Examination, the results showed that in the epithelial cell malignant tumour such as head and neck cancer of many types, oophoroma, uterine cancer, carcinoma of urinary bladder and the cancer of the esophagus
It was found that expressing high-caliber EGFR on the cell membrane of these cancer cells.Therefore, EGFR becomes the important target of tumour medicine research.
Using EGFR as in the drug research of target, micromolecular inhibitor is furtherd investigate, and is approved for mammary gland
The treatment of cancer, cutaneum carcinoma and lung cancer etc..This kind of inhibitor includes Gefitinib, Tarceva etc. (such as patent
CN03108814.7, US5616582 etc.), and it is this kind of for Buddhist nun's class drug be using quinazoline as parent nucleus substantially.
Quinazoline is a kind of very important nitrogen heterocyclic ring, and it is living to show good biology in pesticide and medicine etc.
Property, become one of the hot spot that region of chemistry is studied with biological educational circles scholars.Field of antineoplastic medicaments specifically is wanted, the drug listed
Have Gefitinib, Lapatinib, Tarceva etc..
But with the long-time service of marketed drug, also show many disadvantages, for example, toxic side effect it is big, generate
Drug resistance etc., thus field of antineoplastic medicaments constantly requires have new antitumor drug to occur, to substitute original drug.
Carbazole is a kind of highly important nitrogen heterocyclic ring, and wherein photoelectric material, medicine, dyestuff etc. has widely
Potential application foreground, but at present do not have yet carbazole is connect with quinazoline after for antitumor drug relevant report.
Inventor attempts use and existing drug on the basis of existing shared parent nucleus for Buddhist nun's class drug (i.e. quinazoline)
The larger group of difference/substituent group carries out structural modification, to obtain compound efficiently, less toxic, specific.Specific to this hair
The bright Combination Design on quinazoline parent nucleus introduces carbazole and benzyloxy, and determines its anti tumor activity in vitro.
Invention content
New have efficiently and/or the active quinoline containing carbazole of specificity antineoplastic the purpose of the present invention is to provide a kind of
Oxazoline derivative, in particular for leukaemia.
The present invention relates to a kind of with quinazoline derivant and pharmacy application of the antitumor activity containing carbazole.
Specifically, be related to it is a kind of containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt or its solvate,
The quinazoline derivant containing carbazole is the compound of Formulas I,
The present invention also provides a kind of methods of the quinazoline derivant containing carbazole shown in formula I：
Compound 1 is dissolved in organic solvent, the first alkali is added, heating stirring is added dropwise chlorotoluene, is heated to flowing back, instead
After answering 3h, 60 DEG C are cooled to, the second alkali, carbazole is added, is heated to 90 DEG C, is stirred to react 3h, after reaction, be cooled to room
Solvent is evaporated off in temperature, filtering, filtrate decompression, and silicagel column column chromatography obtains compound I.
The wherein described organic solvent is DMF；
First alkali is potassium carbonate, and second alkali is potassium hydroxide；
The method is one kettle way, and the first step uses the strong hydroxide of alkalinity using the weaker potassium carbonate of alkalinity, second step
Potassium (carbazole needs the stronger substance activation of alkalinity), but the intermediate being prepared after chlorotoluene is added is not necessarily to separation, directly
It is reacted.
Quinazoline derivant containing carbazole shown in Formulas I to prepare equation as follows：
Compound 1 is in the present invention
The invention further relates to Formulas I containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt prepare it is antitumor
Application in drug.
The invention further relates to Formulas I to prepare treatment in vain containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt
Application in blood medicine.
The invention further relates to a kind of pharmaceutical composition, contains containing the quinazoline derivant of carbazole or its is pharmaceutically acceptable
Salt.
The present invention is shown by the experiment of external mtt assay：Formulas I contains the quinazoline derivant containing carbazole to people's non-small cell lung
Cancer cell (A-549), Proliferation of Human Ovarian Cell (SKOV-3), human breast cancer cell (MCF-7), human leukemia cell (HL-60) etc.
All have better inhibition effect；It is thin that wherein compound I is substantially better than other cancers to the inhibition of human leukemia cell line HL-60
Born of the same parents are higher by 1 number magnitude.
The quinazoline derivant containing carbazole of Formulas I can become potential antitumor drug, especially treat the medicine of leukaemia
Object.
Specific implementation mode
Embodiment 1：
2.1g compounds 1 are dissolved in 14mLDMF, 0.7g potassium carbonate is added, chlorotoluene is added dropwise to 50 DEG C in heating stirring
(1.27g) is heated to flowing back, and after reacting 3h, is cooled to 60 DEG C, 0.6gKOH, 1.67g carbazole is added, and is heated to 90 DEG C, stirring
Reaction 3h is cooled to room temperature after reaction, is filtered, and solvent, silicagel column column chromatography (ethyl acetate is evaporated off in filtrate decompression：Oil
Ether=5:1) compound I (3.67g, yield 85.15%), is obtained.
Mass spectrum (CI, m/z)：432[M+1]+；
1H-NMR composes (DMSO-d6) δ：8.65 (s, 1H), 7.38-7.50 (m, 6H) 7.05-7.25 (m, 9H), 5.4 (s,
2H), 3.68 (s, 3H)
Embodiment 2：
Mtt assay measures external activity：
Cell strain：Non-small cell lung carcinoma cell (A-549), Proliferation of Human Ovarian Cell (SKOV-3), human breast cancer cell
(MCF-7), human leukemia cell (HL-60).
Cell culture：Cell inoculation is containing 10% calf serum, 100IU/ml penicillin G sodium salts and 100ug/ml sulfate chains
In DMEM the or DMEM/F12 complete culture solutions of mycin, sets 37 DEG C, 100% relative humidity, contains 5%C02Incubator in, passage
It is spare after 3 times.
MTT colorimetric determinations：The cell of logarithmic growth phase, (suspension cell need not after 0.25% trypsin digestion
Digestion), it is suspended in the culture solution containing 10% calf serum, single cell suspension is gently blown and beaten into glass dropper, under microscope
With blood cell counts plate numeration living cells.Per 90 μ l of hole inoculating cell suspension, (cell concentration is 3-6 × 10 to 96 well culture plates4A/
ML), after setting incubator for 24 hours, add 10 μ l liquids per hole.In addition, each concentration sets negative control (isoconcentration DMSO) and blank sheet
Bottom (is not added with cell), and each group is all provided with 6 multiple holes.48h is continuously cultivated again, and the MTT solution of 10 μ l 5mg/mL is then added per hole,
Continue after cultivating 4h, sucks supernatant.100 μ l DMSO are added per hole, set micro oscillator concussion 5min so that crystallization is completely molten
Solution measures OD values in microplate reader 530nm Single wavelength colorimetrics, and test result is shown in Table 1.
Inhibiting rate (%)=[1- (experimental group OD mean values-blank group OD mean values)/(control group OD mean values-blank group OD is equal
Value)] × 100%.
Bliss methods calculate test-compound IC50Value.
Table 1. the compounds of this invention pair, four kinds of inhibiting tumour cells activity
Table 1 the result shows that：The quinazoline derivant containing carbazole of Formulas I is to Non-small cell lung carcinoma cell (A-549), people
Ovarian cancer cell (SKOV-3), human breast cancer cell (MCF-7), human leukemia cell (HL-60) etc. all have apparent inhibition
Effect；Wherein compound I is substantially better than other cancer cells to the inhibition of human leukemia cell line HL-60, is higher by 1 order of magnitude
Left and right.
Therefore, the quinazoline derivant containing carbazole of Formulas I can become potential antitumor drug, especially treat leukaemia
Drug.
Claims (6)
1. a kind of containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt or its solvate, the quinoline containing carbazole
Oxazoline derivative is the compound of Formulas I,
2. a kind of preparation method described in claim 1 containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt,
Include the following steps：
Compound 1 is dissolved in organic solvent, the first alkali is added, heating stirring is added dropwise chlorotoluene, is heated to flowing back, and reacts 3h
Afterwards, 60 DEG C are cooled to, the second alkali, carbazole is added, is heated to 90 DEG C, is stirred to react 3h, after reaction, be cooled to room temperature, mistake
Solvent is evaporated off in filter, filtrate decompression, and silicagel column column chromatography obtains compound I；
Wherein described first alkali is potassium carbonate, and second alkali is potassium hydroxide；
Wherein preparing equation is：
3. preparation method according to claim 2, wherein the organic solvent is DMF.
4. described in claim 1 in the preparation of antitumor drugs containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt
Application.
5. preparing treatment leukaemia medicine containing the quinazoline derivant of carbazole or its pharmaceutically acceptable salt described in claim 1
Application in object.
6. a kind of pharmaceutical composition, it is described in claim 1 containing containing the quinazoline derivant of carbazole or its can pharmaceutically connect
The salt received.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113056272A (en) * | 2018-09-21 | 2021-06-29 | 光谱医药公司 | Novel quinazoline EGFR inhibitors |
| CN114057696A (en) * | 2021-11-04 | 2022-02-18 | 中山大学 | Carbazole-pyrimidine derivative and preparation method and application thereof |
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| 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 |
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2018
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| 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 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113056272A (en) * | 2018-09-21 | 2021-06-29 | 光谱医药公司 | 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 |
| CN114057696A (en) * | 2021-11-04 | 2022-02-18 | 中山大学 | Carbazole-pyrimidine derivative and preparation method and application thereof |
| CN114057696B (en) * | 2021-11-04 | 2024-03-19 | 中山大学 | Carbazole-pyrimidine derivative and preparation method and application thereof |
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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. |
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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. |