CN101502523B - Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament - Google Patents
Application of benzoyl fluorobenzene salicylamide compound in preparing anti-tumor medicament Download PDFInfo
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Abstract
本发明公开了如式(I-1)～式(I-12)所示之一的苯甲酰氟苯水杨酰胺类化合物在制备抗肿瘤药物中的应用。本发明提供了一种新的有显著抗肿瘤活性的抗肿瘤药物，为新药筛选提供了研究基础；其中，式(I-10)或式(I-11)所示的化合物具有非常显著的抗肿瘤作用，式(I-2)、式(I-3)、式(I-4)、式(I-5)或式(I-9)所示的化合物具有显著的抗肿瘤作用，式(I-1)、(I-6)、(I-7)或(I-8)具有较好的抗肿瘤作用，式(I-12)所示的化合物具有一定的抗肿瘤作用。The invention discloses the application of benzoyl fluorophenyl salicylic amide compound as one of the formulas (I-1) to (I-12) in the preparation of antitumor drugs. The present invention provides a new anti-tumor drug with significant anti-tumor activity, which provides a research basis for new drug screening; wherein, the compound shown in formula (I-10) or formula (I-11) has very significant anti-tumor activity Tumor effect, the compound shown in formula (I-2), formula (I-3), formula (I-4), formula (I-5) or formula (I-9) has significant antitumor effect, formula ( I-1), (I-6), (I-7) or (I-8) have better anti-tumor effect, and the compound represented by formula (I-12) has certain anti-tumor effect.
Description
(1) technical field
The present invention relates to a kind of antineoplastic reactive compound---benzoyl fluoride benzene salicylamide compounds that has, and the application in the preparation antitumor drug.
(2) background technology
Malignant tumor is one of commonly encountered diseases of serious harm human health.According to the latest news, the whole world has more than 4,000 ten thousand people to suffer from malignant tumor, wherein annual newly-increased patient more than 900 ten thousand, dead more than 700 ten thousand, the annual malignant tumor number of the infected of China about 1,600,000, dead about 1,300,000.Malignant tumor takes place and the dead trend that is on the rise in addition at present, and some area has become human mortality's first cause.Therefore, the novel antitumor drug of exploitation has great importance.
Benzoyl fluoride benzene salicylamide compounds is a kind of chemical compound of contain fluorine atoms.Because the fluorine atom radius is little, have maximum electronegativity again, formed C-F bond energy can be much bigger than c h bond, increased the stability of organic fluorocompound; And because the volume of fluorine atom is little, thereby often think the non-classical isostere of H atom, easily produce antagonism, that is: do not disturb interaction between fluorine-containing medicine and corresponding cell receptor, can replace the homergy medicine at molecular level, mix biomacromolecule to fraudulence, it is synthetic to cause causing death.When introducing fluorine atom in the drug molecule, its electrical effect and mimic effect have not only changed the distribution of intramolecule electron density, and can also improve the fat-soluble and permeability of chemical compound, dissolubility on biomembrane is enhanced, promote it to absorb in vivo and transmission speed, physiological action is changed.So fluorine-containing medicine has characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong.
The research and development of fluorine-containing medicine mainly concentrate in the research and development of fluorine-containing fragrance, heterocyclic compound, have good anti-inflammatory activity as diflunisal (difunisal).Though diflunisal as NSAID (non-steroidal anti-inflammatory drug) be applied to clinical in, but by diflunisal is carried out structural modification, preparation has the fluorine-containing new drug of anti-tumor activity, has very significant meaning, also will cause increasing scientist's concern.
In inventor's early-stage Study, prepared structure suc as formula the benzoyl fluoride benzene salicylamide compounds shown in (I).
In the formula (I):
R
1, R
2Independent separately is the alkyl of H, C1～C6 or substituted alkyl, the cycloalkyl of C3～C6, aryl or the substituted aryl of C6～C10, the substituent group of described substituted alkyl is: phenyl, halogen, nitro or C1～C3 alkoxyl, and the substituent group of described substituted aryl is: the alkyl of halogen, nitro, C1～C3 alkoxyl, C1～C3; Perhaps R
1, R
2Connect ring formation, with same R
1, R
2The N that links to each other constitutes the heterocyclic radical of C4～C10.
Chemical compound shown in the formula (I) is open in Chinese patent publication number CN101318909A, and discloses the application in preparation anti-inflammatory drug and analgesic.
(3) summary of the invention
The invention discloses the new medical use of chemical compound shown in the formula (I), suc as formula the application of the benzoyl fluoride benzene salicylamide compounds one of shown in (I-1)～formula (I-12) in the preparation antitumor drug;
(I-12)。
The application of benzoyl fluoride benzene salicylamide compounds of the present invention in the preparation antitumor drug, the chemical compound that described benzoyl fluoride benzene salicylamide compounds one of is preferably shown in formula (I-1)～formula (I-11), more preferably the chemical compound shown in formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-9), formula (I-10) or the formula (I-11) most preferably is the chemical compound shown in formula (I-10) or the formula (I-11).
Comparatively concrete, through inventor's experiment confirm, during pulmonary carcinoma that described tumor causes for the A549 cell strain, chemical compound shown in the formula (I-10) has notable antitumor activity, chemical compound shown in the formula (I-2) has better antitumor activity, and the chemical compound shown in formula (I-3) or the formula (I-12) has certain anti-tumor activity.
During carcinoma of endometrium that described tumor causes for the Ishikawa cell, chemical compound shown in formula (I-10) or the formula (I-11) has the anti-tumor activity of highly significant, formula (I-3), (I-4), (I-5) or (I-9) shown in chemical compound have notable antitumor activity, formula (I-1), (I-6), (I-7) or (I-8) have better antitumor activity, the chemical compound shown in the formula (I-2) has certain anti-tumor activity.
The preparation method of benzoyl fluoride benzene salicylamide compounds involved in the present invention and character and characterisitic parameter, at Chinese patent publication number CN101318909A and Chin Chem Lett, 2008,19, described in the 1419-1422.
The beneficial effect that benzoyl fluoride benzene salicylamide compounds of the present invention is used is mainly reflected in: (1), provide a kind of new antitumor drug that remarkable anti-tumor activity is arranged, for new medicament screen provides the research basis; (2), the chemical compound shown in formula (I-10) or the formula (I-11) has the antitumor action of highly significant, chemical compound shown in formula (I-2), formula (I-3), formula (I-4), formula (I-5) or the formula (I-9) has remarkable antitumor effect, formula (I-1), (I-6), (I-7) or (I-8) have the good antitumor effect, the chemical compound shown in the formula (I-12) has certain antitumor action.(3) described tumor cause for the A549 cell strain pulmonary carcinoma the time, the chemical compound shown in the formula (I-10) has notable antitumor activity, the chemical compound shown in the formula (I-2) has better antitumor activity.(4) described tumor cause for the Ishikawa cell carcinoma of endometrium the time, chemical compound shown in formula (I-10) or the formula (I-11) has the anti-tumor activity of highly significant, chemical compound shown in formula (I-3), (I-4), (I-5), (I-9) has notable antitumor activity, (I-1), (I-6), (I-7) or (I-8) shown in chemical compound have better antitumor activity.
(4) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
The preparation benzoyl fluoride benzene salicylamide compounds
According to the Compound I-1～I-12 shown in the described preparation method preparation formula of Chinese patent publication number CN101318909A (I-1)～formula (I-12).
Embodiment 1～12: the anti-lung cancer activity test
Method of testing: anti tumor activity in vitro method of testing
A. principle: cell is decomposed into water-fast blue purple crystal by the mitochondrion hydrolytic enzyme with Thiazolyl blue (MTT) and is deposited in the cell, crystal can be by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, reflect the propagation situation and the number change of cell indirectly.
B. cell: A549, lung cancer cell line.
C. experimental procedure
(1) preparation of sample: get Compound I-1～I-12, for solvable sample, every 1mg dissolves with 20 μ L DMSO, gets 2 μ L and dilutes with 1000 μ L culture fluid, and making concentration is 100 μ g/mL, and the serial dilution of reuse culture fluid is to working concentration.
(2) cultivation of cell
Culture medium preparation: contain 800,000 unit penicillins, 1.0g streptomycin, 10% deactivation calf serum in every 1000mL culture medium.
The cultivation of cell: tumor cell inoculation in culture medium, is put 37 ℃, 5%CO
2Cultivate in the incubator, 3～5d goes down to posterity.
(3) working sample is to the inhibitory action of growth of tumour cell
Cell is digested with EDTA-trypsinization liquid, and be diluted to 1 * 10 with culture medium
6/ mL is added in the 96 porocyte culture plates, and every hole 100 μ L put 37 ℃, 5%CO
2Cultivate in the incubator.Behind the inoculation 24h, the culture medium of inclining adds the sample with the culture medium dilution, every hole 200 μ L, and each concentration adds 3 holes, puts 37 ℃, 5%CO
2Cultivate in the incubator, add the MTT of 5mg/mL behind the 72h in the cell culture hole, every hole 10 μ L put 37 ℃ and hatch 3h, add DMSO, every hole 150 μ L, and with the agitator vibration, Shi Jia Za dissolves fully, with microplate reader colorimetric under the 490nm wavelength.With similarity condition with do not contain sample, contain same concentration DMSO culture medium culturing cell in contrast, calculation sample is to the half-inhibition concentration (IC of growth of tumour cell
50).
Comparative Examples 1
Anti tumor activity in vitro method of testing according to embodiment 1～12 is tested, and different is that the sample of use is the cisplatin medicine.
Benzoyl fluoride benzene salicylamide compounds I-1～the I-12 of preparation has been carried out anti-A549 active testing, and result of the test is as follows:
Table 1: each chemical compound is to the IC of A549
50(μ mol/L)
| Embodiment | Chemical compound | IC 50μmol/L | Estimate |
| 1 | I-1 | 103.01 | Invalid |
| 2 | I-2 | 11.85 | Effectively |
| 3 | I-3 | 22.41 | The weak effect |
| 4 | I-4 | 57.08 | Invalid |
| 5 | I-5 | 58.72 | Invalid |
| 6 | I-6 | 86.57 | Invalid |
| 7 | I-7 | 94.01 | Invalid |
| 8 | I-8 | 53.21 | Invalid |
| 9 | I-9 | 56.14 | Invalid |
| 10 | I-10 | 8.36 | Significantly |
| 11 | I-11 | 171.06 | Invalid |
| 12 | I-12 | 29.67 | The weak effect |
| Comparative Examples 1 | Cisplatin | 8.73 | Significantly |
According to the evaluation criterion of anti-tumor activity, Compound I-10 has significant anti-A549 lung carcinoma cell activity, and Compound I-2 has anti-preferably A549 lung carcinoma cell activity, and Compound I-3 and I-12 have certain anti-A549 lung carcinoma cell activity.
Embodiment 13～24: anti-carcinoma of endometrium active testing
Method of testing: anti tumor activity in vitro method of testing:
A. principle: cell is decomposed into water-fast blue purple crystal by the mitochondrion hydrolytic enzyme with Thiazolyl blue (MTT) and is deposited in the cell, crystal can be by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, reflect the propagation situation and the number change of cell indirectly.
B. cell: Ishikawa, the endometrial carcinoma cell strain.
C. experimental procedure
(1) preparation of sample: get Compound I-1～I-12, for solvable sample, every 1mg dissolves with 20 μ L DMSO, gets 2 μ L and dilutes with 1000 μ L culture fluid, and making concentration is 100 μ g/mL, and the serial dilution of reuse culture fluid is to working concentration.
(2) cultivation of cell
Culture medium preparation: contain 800,000 unit penicillins, 1.0g streptomycin, 10% deactivation calf serum in every 1000mL culture medium.
The cultivation of cell: tumor cell inoculation in culture medium, is put 37 ℃, 5%CO
2Cultivate in the incubator, 3～5d goes down to posterity.
(3) working sample is to the inhibitory action of growth of tumour cell
Cell is digested with EDTA-trypsinization liquid, and be diluted to 1 * 10 with culture medium
6/ mL is added in the 96 porocyte culture plates, and every hole 100 μ L put 37 ℃, 5%CO
2Cultivate in the incubator.Behind the inoculation 24h, the culture medium of inclining adds the sample with the culture medium dilution, every hole 200 μ L, and each concentration adds 3 holes, puts 37 ℃, 5%CO
2Cultivate in the incubator, add the MTT of 5mg/mL behind the 72h in the cell culture hole, every hole 10 μ L put 37 ℃ and hatch 3h, add DMSO, every hole 150 μ L, and with the agitator vibration, Shi Jia Za dissolves fully, with microplate reader colorimetric under the 490nm wavelength.With similarity condition with do not contain sample, contain same concentration DMSO culture medium culturing cell in contrast, calculation sample is to the half-inhibition concentration (IC of growth of tumour cell
50).
Comparative Examples 2
Anti tumor activity in vitro method of testing according to embodiment 13～24 is tested, and different is that the sample of use is the cisplatin medicine.
The anti-tumor activity test result
Benzoyl fluoride benzene salicylamide compounds I-1～the I-12 of preparation has been carried out anti-Ishikawa active testing, and result of the test is as follows:
Table 2: chemical compound is to the IC of Ishikawa
50(μ mol/L)
| Embodiment | Chemical compound | IC 50μmol/L | Estimate |
| 13 | I-1 | 14.72 | Effectively |
| 14 | I-2 | 37.46 | The weak effect |
| 15 | I-3 | 2.00 | Significantly |
| 16 | I-4 | 7.50 | Significantly |
| 17 | I-5 | 1.87 | Significantly |
| 18 | I-6 | 17.39 | Effectively |
| 19 | I-7 | 11.88 | Effectively |
| 20 | I-8 | 18.32 | Effectively |
| 21 | I-9 | 4.05 | Significantly |
| 22 | I-10 | 0.13 | Highly significant |
| 23 | I-11 | 0.69 | Highly significant |
| 24 | I-12 | 63.03 | Invalid |
| Comparative Examples 2 | Cisplatin | 12.20 | Effectively |
Evaluation criterion according to anti-tumor activity, Compound I-10 and I-11 have the anti-Ishikawa endometrial carcinoma cell activity of highly significant, Compound I-3, I-4, I-5 and I-9 have significant anti-Ishikawa endometrial carcinoma cell activity, Compound I-1, I-6, I-7 and I-8 have anti-preferably Ishikawa endometrial carcinoma cell activity, and Compound I-2 has certain anti-Ishikawa endometrial carcinoma cell activity.
Claims (4)
1. suc as formula the application of the benzoyl fluoride benzene salicylamide compounds one of shown in (I-1)～formula (I-11) in the preparation antitumor drug, the carcinoma of endometrium that described tumor causes for the Ishikawa cell;
2. the application of benzoyl fluoride benzene salicylamide compounds as claimed in claim 1 in the preparation antitumor drug is characterized in that the application of chemical compound in the endometrium cancer drug that anti-Ishikawa cell causes shown in formula (I-10) or the formula (I-11).
3. the application of the benzoyl fluoride benzene salicylamide compounds shown in (I-2), formula (I-3), formula (I-10) or formula (I-12) in the preparation antitumor drug, the pulmonary carcinoma that described tumor causes for the A549 cell strain,
4. the application of benzoyl fluoride benzene salicylamide compounds as claimed in claim 3 in the preparation antitumor drug is characterized in that the application of the chemical compound shown in the formula (I-10) in the lung-cancer medicament that anti-A549 cell strain causes.
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| CN101502523B true CN101502523B (en) | 2011-01-05 |
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600182B (en) * | 2012-03-05 | 2013-09-11 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound in preparation of lung-cancer-resisting medicament |
| CN102603559B (en) * | 2012-03-05 | 2014-01-29 | 浙江工业大学 | A kind of phenylacetyl fluorophenyl salicylamide compound and its application |
| CN102614200B (en) * | 2012-03-05 | 2013-09-11 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorobenzene salicylamide compound in preparation of medicine for resisting breast cancer |
| CN102614196B (en) * | 2012-03-05 | 2013-07-24 | 浙江工业大学 | Application of phenylacetyl fluorobenzene salicylamide compound in preparation of anti-breast-cancer medicines |
| CN102614198B (en) * | 2012-03-05 | 2014-05-14 | 浙江工业大学 | Application of (4-substituted benzene formyl) fluorobenzene salicylamide compound in preparation of anti-lung-cancer medicines |
| CN102614199B (en) * | 2012-03-05 | 2013-06-19 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorophenyl salicylamide compounds in the preparation of anti-cervical cancer drugs |
| CN102600181B (en) * | 2012-03-05 | 2013-07-31 | 浙江工业大学 | Application of (4-substituted benzoyl) fluorobenzene salicylamide compound in preparing anti-leukemie medicament |
| CN104800227B (en) * | 2014-01-28 | 2019-04-12 | 杭州民生药物研究院有限公司 | A kind of application of O- benzoyl-(4- trifluoromethyl) salicylamide compound in preparation treatment lung-cancer medicament |
| CN104800225B (en) * | 2014-01-28 | 2018-12-18 | 杭州民生药物研究院有限公司 | A kind of application of O- phenylacetyl-(4- trifluoromethyl) salicylamide compound in preparation treatment lung-cancer medicament |
| CN106748914B (en) * | 2016-11-18 | 2019-04-09 | 浙江工业大学 | O-benzenesulfonyl-4-trifluoromethylsalicylamide compounds and their application in the preparation of anti-gastric cancer drugs |
| CN106588716B (en) * | 2016-11-18 | 2019-04-09 | 浙江工业大学 | O-benzenesulfonyl-4-trifluoromethylsalicylamide compounds and their application in the preparation of anti-lung cancer drugs |
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|---|---|---|---|---|
| US3714226A (en) * | 1970-06-09 | 1973-01-30 | Merck & Co Inc | Phenyl benzoic acid compounds |
| CN101318909A (en) * | 2008-07-16 | 2008-12-10 | 浙江工业大学 | A kind of benzoyl fluorophenyl salicylamide compound and its preparation and application |
-
2009
- 2009-03-06 CN CN2009100965564A patent/CN101502523B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3714226A (en) * | 1970-06-09 | 1973-01-30 | Merck & Co Inc | Phenyl benzoic acid compounds |
| CN101318909A (en) * | 2008-07-16 | 2008-12-10 | 浙江工业大学 | A kind of benzoyl fluorophenyl salicylamide compound and its preparation and application |
Non-Patent Citations (2)
| Title |
|---|
| Guang Xiang zhong,et al.Synthesis and anti-inflammatory-analgesic activity of 2",4"-difluoro-3-(carbamoyl)biphenyl-4-yl benzoates..Chinese Chemical Letters.2008,19(12),1419-1422. * |
| Guang-Xiang Zhong,et al.Synthesis and biological evaluation of amide derivatives of diflunisal as potential anti-inflammatory agents..Bioorganic & Medicinal Chemistry Letters.2008,19(2),516-519. * |
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