CN100357264C - Charles ketone oxime and its composition , preparation method and uses - Google Patents
Charles ketone oxime and its composition , preparation method and uses Download PDFInfo
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Abstract
本发明涉及下述式(1)表示的查尔酮肟，还涉及该化合物的组合物、制备方法和在治疗肿瘤的应用。本发明式(1)化合物通过2′，4′-二羟基-6′-甲氧基-3′，5′-二甲基查尔酮与盐酸羟胺在吡啶中经加热回流反应得到。该化合物溶解性好，可以直接注射给药，并且经试验表明，能显著抑制血管内皮生长因子受体、HER2受体、PDGFR受体酪氨酸激酶的活性，抑制乳腺癌、肝癌等细胞的体外生长，对ECV304细胞中KDR磷酸化、MDA-MB-453细胞中HER2磷酸化、C6细胞中PDGFR受体磷酸化均有明显的抑制作用，呈现浓度效应关系，而KDR受体、HER2受体、PDGFR受体蛋白表达水平不受其影响，因而显示了良好的抗肿瘤活性，可用于治疗肿瘤。
The present invention relates to chalcone oxime represented by the following formula (1), and also relates to the composition, preparation method and application of the compound in treating tumors. The compound of formula (1) of the present invention is obtained by reacting 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone and hydroxylamine hydrochloride in pyridine by heating and refluxing. The compound has good solubility and can be administered directly by injection. Tests have shown that it can significantly inhibit the activity of vascular endothelial growth factor receptors, HER2 receptors, and PDGFR receptor tyrosine kinases, and inhibit the in vitro viability of breast cancer, liver cancer and other cells. Growth, it has obvious inhibitory effect on KDR phosphorylation in ECV304 cells, HER2 phosphorylation in MDA-MB-453 cells, and PDGFR receptor phosphorylation in C6 cells, showing a concentration-effect relationship, while KDR receptors, HER2 receptors, The expression level of PDGFR receptor protein is not affected by it, so it shows good anti-tumor activity and can be used for treating tumors.
Description
Technical field
The present invention relates to a kind of Charles ketone oxime, relate to 2 specifically ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-the dimethyl Charles ketone oxime, and relate to its preparation method, be composition of active components and the application in the medicine for treating tumor thing with it.
Background technology
Malignant tumour is a kind of common disease of serious harm human health, has become second cause of the death that the mankind are only second to cerebro-vascular diseases.The tumor chemotherapeutic drug of cell toxicant class develops decades, and the treatment tumour is approaching or reach plateau, presses for new medicine or method.
There is the unusual of signal transduction pathway in many tumours, in the generation of kinds of tumors, development, play an important role at vasculogenesis as vascular endothelial growth factor receptor (VEGFR), the overexpression of common EGFR family receptors in the epithelial cell tumour, the amplification and the overexpression of common epithelial growth factor receptors 2 (HER2 acceptor) such as mammary cancer, ovarian cancer, prostate cancer, lung cancer, overexpression of common platelet-derived property growth factor receptors (PDGFR) family etc. in the glioma.The overexpression of these acceptors or the overexpression of somatomedin cause that the excessive activation of acceptor and intracellular kinase sudden change activate etc., cause the enhancing of its downstream signal approach, activate signal pathways such as Ras/MAPK, PI3K/AKT, finally cause transformation, propagation and opposing apoptosis, promote cell survival.Therefore, many scholars are devoted to study new antitumor drug from disabling signal transduction pathway angle, and have obtained huge breakthrough, as the humanized antibody Herceptin at the HER2 acceptor
TMBy drugs approved by FDA be used for treatment that HER2 crosses the mammary cancer of expression, at the Iressa treatment nonsmall-cell lung cancer of EGFR Tyrosylprotein kinase etc., at the antibody Avastin treatment transitivity colorectal carcinoma in late period of VEGF.Vasculogenesis is meant the process that produces neovascularity from already present vescular bed, numerous disease such as tumour, vasculogenesis that can occur continuing, uncontrollable.It is necessary that vasculogenesis is not only tumor growth, and be to cause the reason of tumour to distant metastasis.Tumor-blood-vessel growth is a frontier in the treatment and prevention of tumour research.VEGF is the intense stimulus factor of vasculogenesis, and the activation of its acceptor is a step important in the vasculogenesis step, disturbs vascular endothelial growth factor receptor (VEGFR) signal transduction pathway to become the New Policy of oncotherapy.The angiogenesis inhibitor inhibitor at vascular endothelial growth factor and acceptor thereof that enters clinical trial at present has SU5416, SU6668, ZK222584 etc., and wherein SU5416 is terminated owing to unsatisfactory curative effect after entering clinical trial.SU11248 has obvious effects at multiple receptor tyrosine kinase inhibitors such as PDGFR, VEGFR, FLT3, KIT to leukemia, solid tumor performance, and approval is new antitumor drug in the near future probably.Vasculogenesis is the process of a complexity, except the VEGF/VEGFR signal pathway, many receptor tyrosine kinases participate in vasculogenesis, EGFR, HER2, PDGFR, FGFR etc. all can promote vasculogenesis, therefore many target drugs of the inhibitor of the multiple receptor tyrosine kinase of target show better therapeutic clinically, having better prospect, is the main direction of the contemporary research of antineoplastic new target drug in the world.Suppressing multiple receptor tyrosine kinase can not only suppress and the closely-related vasculogenesis of tumor development better, tumour cell to the high expression level tyrosine kinase receptor has good growth-inhibiting effect simultaneously, promptly suppress the growth that vasculogenesis can suppress tumour cell itself again, therefore have significant advantage as antitumor drug.
Found that in the world chalcone derivative has blood vessel formation against function (reference: WO 01/46110).Domestic, we from plant, found a natural chalcone derivative of angiogenesis inhibitor (2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-the dimethyl cinnamophenone, DMD) and prove that it has anti-knurl effect (reference: Mol Pharmacol in the significant body, 2005,67:1444-1450).But the general solvability of natural cinnamophenone is relatively poor, is difficult to by drug administration by injection, and oral bioavailability is lower.
Summary of the invention
The objective of the invention is to develop a kind of have antitumous effect and the good chalcone derivative of solvability, another purpose provides the preparation method of this compound, it is composition of active components that further purpose provides with this compound, and another purpose provides this compound and the application of composition in prevention and treatment tumour thereof.
The present invention by 2 ', 4 '-dihydroxy-6 '--methoxyl group-3 ', 5 '-dimethyl cinnamophenone and oxammonium hydrochloride in pyridine through heating reflux reaction obtain 2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-the dimethyl Charles ketone oxime, this compound dissolution is good, and is the composition that activeconstituents has been made antitumor action with this compound, thereby has realized purpose of the present invention.
A kind of Charles ketone oxime of the present invention is characterized in that structure represented by formula (1):
Formula (1)
The preparation method of a kind of Charles ketone oxime of the present invention, it is characterized in that 2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-dimethyl cinnamophenone and oxammonium hydrochloride dissolve in pyridine, and reflux is separated, and purifying obtains product.
Described 2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-the dimethyl cinnamophenone can be with conventional method preparation, reference: Zhang Fengxian etc. for example, Botany Gazette, 1990,32 (6): 469-472, described return time can be 2 hours, and described separation can be adopted usual method, for example phegma is precipitated in water or in the sour water, filter collecting precipitation then, described purifying is with above-mentioned precipitation acetic acid ethyl dissolution, is evaporated to dried after solution with water is washed, last silicagel column separates with 6: 1 sherwood oil-acetone wash-outs of volume ratio.
The compound that composition of the present invention contains the above-mentioned formula (1) for the treatment of significant quantity is an activeconstituents, and contains one or more pharmaceutically acceptable carriers.
Pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine, composition of the present invention can use common pharmaceutical dosage form, the form of injection, tablet, pill, capsule, solution, suspension agent or emulsion for example, be used for prevention and treatment malignant tumour by oral, vein, muscle, percutaneous drug delivery, various formulations can be according to the ordinary method preparation of pharmaceutical field.
The compound and the composition thereof of the above-mentioned formula of the present invention (1) can be used for treating tumour.
Charles ketone oxime solvability of the present invention is good, can direct injection, and the results showed, the activity that can significantly suppress vascular endothelial growth factor receptor, HER2 acceptor, PDGFR receptor tyrosine kinase, suppress mammary cancer, the isocellular growth in vitro of liver cancer, PDGFR receptor phosphorylation in HER2 phosphorylation, the C6 cell in KDR phosphorylation, the MDA-MB-453 cell in the ECV304 cell all there is the obvious suppression effect, present concentration effect relation, and KDR acceptor, HER2 acceptor, PDGFR receptor protein expression level are not influenced by it.
Description of drawings
Fig. 1: DMDO is to the restraining effect of vascular endothelial growth factor receptor Tyrosylprotein kinase phosphorylation (phospho-KDR)
Fig. 2: DMDO is to the restraining effect of epithelial growth factor receptor 2 Tyrosylprotein kinase phosphorylations (phospho-HER2)
Fig. 3: DMDO is to the restraining effect of platelet-derived property growth factor receptor tyrosine kinase phosphorylation (phospho-PDGFR)
Embodiment:
Following examples are to further specify of the present invention, are not limitations of the present invention.
Embodiment 1: the preparation of the compound of formula (1)
Get 2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-dimethyl cinnamophenone 100mg, oxammonium hydrochloride 100mg, add the dissolving of 7mL pyridine, reflux 2 hours, reaction solution is poured in the aqueous hydrochloric acid of 50mL 1mol/L, filtered collecting precipitation, use acetic acid ethyl dissolution, changing in the separating funnel ethyl acetate solution over to water gives a baby a bath on the third day after its birth time, be evaporated to driedly, last silicagel column separate to obtain product with sherwood oil-acetone (volume ratio 6: 1) wash-out.
Embodiment 2: the evaluation of embodiment 1 product
Yellow powder shape solid.Positive ion HRTOFMS (m/z): 314.1398[C
18H
19NO
1+ H]
+(calculated value: 314.1392).Positive ion ESIMS:352[M+K]
+, 336[M+Na]
+, 314[M+H]
+, 296[M-H
2O+H]
+, 280,220,208,193,103.
1H NMR (400 MHz, acetone-d
6): 7.42 (2H, d, J=8.0Hz, H-2 and H-6), 7.30 (2H, t, J=8.0Hz, H-3 and H-5), 7.22 (1H, t, J=8.0Hz, H-4), 7.05 (1H, d, J=16Hz, H-β), 6.41 (1H, d, J=16Hz, H-α), 3.53 (3H, s, OCH3), 2.11 (3H, s, CH
3), 2.09 (3H, s, CH
3);
13C NMR (100MHz, acetone-d
6): 155.8 (C * 2), 155.1 (C), 151.2 (C), 137.6 (C), 134.6 (CH), 129.4 (CH * 2), 128.8 (CH), 127.5 (CH * 2), 127.0 (CH), 110.0 (C), 108.4 (C), 107.0 (C), 61.0 (OCH
3), 9.3 (CH
3), 9.2 (CH
3).By analyzing, confirm that the product that embodiment 1 obtains is the compound of formula (1), promptly 2 ', 4 '-dihydroxyl-6 '-methoxyl group-3 ', 5 '-dimethyl Charles ketone oxime (DMDO).
Embodiment 3:DMDO is to the restraining effect of receptor tyrosine kinase phosphorylation
The ECV304 that takes the logarithm vegetative period (VEGFR2 or KDR), MDA-MB-453 (HER2), C6 (PDGFR) cell are made into 5 * 10 with nutrient solution
5/ mL adds it in 12 orifice plates again, and every hole adds 1mL.The 2nd day, with the nutrient solution sucking-off, and adding serum-free medium, add again and tried different concns DMDO processing 30 minutes, the antibody of using anti-KDR, anti-HER2, anti-PDGFR respectively carries out immunoprecipitation, detects KDR, HER2, PDGFR phosphorylation level with anti-phosphotyrosine antibody Western blot again.The results are shown in accompanying drawing 1～3.
Embodiment 4:DMDO is to the restraining effect of growth in vitro such as breast cancer cell MDA-MB-453, liver cancer cell Hep3B
Breast cancer cell MDA-MB-453, the liver cancer cell Hep3B that grows that take the logarithm adds in 96 orifice plates, and every hole 100 μ L contain 2000～4000 cells.Add medicine again, establish 3 parallel holes for every group, put 37 ℃ and cultivated 72 hours, 4h added 10 μ L 5mg/mL MTT liquid before experiment stopped, cultivate 4h again, discard nutrient solution and add 0.2mL DMSO, on enzyme connection detector, detect the OD value in every hole of 570nm wavelength after the dissolving to be crystallized.Obtain growth inhibition ratio by following formula, obtain half inhibiting rate (IC50 value) by BLISS method computer program again.The results are shown in Table 1.
Table 1 DMDO is to the growth in vitro restraining effect of human breast cancer cell MDA-MB-453, liver cancer cell Hep3B
| Drug level (μ g/mL) | Cell strain and inhibiting rate (%) | |
| MDA-MB-453 | Hep3B | |
| 0 0.78 1.56 3.125 6.25 12.5 25.0 | - 27.8 48.8 66.1 74.9 79.6 83.4 | - - 4.2 10.7 16.3 30.9 84.0 |
Claims (5)
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101941919B (en) * | 2009-07-07 | 2014-07-02 | 天津药物研究院 | Method for preparing derivatives of cis-oximes and oxime ethers |
| CN103102283B (en) * | 2011-11-09 | 2014-05-28 | 南京大学 | Preparation method of chalcone oxime compound and application of the same as novel immunosuppressant |
| CN104055755A (en) * | 2013-03-19 | 2014-09-24 | 浙江科技学院 | Application of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl chalcone in preparation of antitumor drugs |
| CN103664689A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Chalcone oxime derivatives having inhibiting effect on cancer cell tubulin polymerization, and preparation method thereof |
| WO2020158840A1 (en) * | 2019-01-30 | 2020-08-06 | 日産化学株式会社 | Anti-cancer agent |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6462075B1 (en) * | 1999-12-23 | 2002-10-08 | The University Of Georgia Research Foundation, Inc. | Chalcone and its analogs as agents for the inhibition of angiogensis and related disease states |
| CN1454895A (en) * | 2002-11-12 | 2003-11-12 | 中山大学肿瘤防治中心 | Use of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl chalcone for preparing anticancer medicine |
-
2005
- 2005-11-25 CN CNB2005101017176A patent/CN100357264C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6462075B1 (en) * | 1999-12-23 | 2002-10-08 | The University Of Georgia Research Foundation, Inc. | Chalcone and its analogs as agents for the inhibition of angiogensis and related disease states |
| CN1454895A (en) * | 2002-11-12 | 2003-11-12 | 中山大学肿瘤防治中心 | Use of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethyl chalcone for preparing anticancer medicine |
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