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Novel targeting antineoplastic drug and manufacture method thereof and application thereof

An anti-tumor drug and targeting technology, applied in the field of new targeted anti-tumor drugs and their preparation, can solve the problem of high price, achieve clear metabolite process, low probability of occurrence, and relieve physiological symptoms

Active Publication Date: 2013-06-05
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, these protein tyrosine kinase inhibitors are all developed by foreign pharmaceutical companies, and the price is very high. For example, Tekaro and Gleevec are priced at ￥18,800-23,000 per box (150mg×30 tablets). It is very difficult to afford, and it is very necessary to develop tyrosine kinase inhibitor anti-tumor drugs with our own intellectual property rights

Method used

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  • Novel targeting antineoplastic drug and manufacture method thereof and application thereof
  • Novel targeting antineoplastic drug and manufacture method thereof and application thereof
  • Novel targeting antineoplastic drug and manufacture method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of Epidermal Growth Factor Receptor Inhibitor (ERI-09)

[0024] Add 1.68 g of raw material A 2,4,5-trihydroxyacetophenone (10 mmol) into a 25 ml single-necked round bottom flask, dissolve the raw material with 10 ml of acetonitrile and add 6.9 g of potassium carbonate (50 mmol) while stirring, Methyl chloroformate-acetonitrile solution (32 mmol) was slowly added dropwise at -20°C. After reacting for 1 hour, TLC detected whether the conversion of the raw material was complete. After the conversion of the raw material A was complete, the mixture was stirred for 0.5 hours, then filtered, and acetonitrile was removed by rotary evaporation to obtain 3.2 g of product B. Redissolve B in anhydrous toluene, add metal sodium after heating to reflux, and B undergoes a condensation reaction under the catalysis of metal sodium to obtain 3.3 g of a crude product containing product C. After separation by chromatographic column, 1.65 g of pure product C was obtain...

Embodiment 2

[0026] Example 2: Synthesis of Epidermal Growth Factor Receptor Inhibitor (ERI-13)

[0027] After 1.5 g of product D was dissolved in acetonitrile, 3.5 g of potassium carbonate (25 mmol) was added under stirring, and methyl bromide-acetonitrile solution (20 mmol) was slowly added dropwise at 20°C. After reacting for 1 hour, TLC detected whether the conversion of compound D was complete. After the conversion of D was complete, the reaction was terminated with 25% formic acid. The product was extracted with ethyl acetate, dried, and 1.1 g of the final product F was obtained after rotary evaporation. The synthetic route is as follows:

[0028]

Embodiment 3

[0029] Example 3 Detection of the level of EGFR inhibitor (ERI-09) in non-small cell lung cancer A549 cells

[0030] Human non-small cell lung cancer cell line A549 was cultured in HAM'S / F-12 medium (HyClone, USA) containing 10% fetal bovine serum (FBS, Hyclone, USA), and 100ng / ml epidermal growth factor was added to this medium (EGF, Sigma, USA), the above cells were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and placed in CO 2Constant temperature incubator, used for experiments after 3-5 days of cultivation.

[0031] Cells in the logarithmic growth phase were collected and seeded in 96-well plates (6500 cells / well / 100 ul, RPMI1640 containing 100 ng / ml EGF). 100, 50, 25, 12.5, 6.25, 1 μM / L); RPMI1640 with the same volume of 100ng / ml EGF added with 1% dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) was set as the experimental control group; only culture medium but no Cells are the blank group. Three paral...

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Abstract

The invention provides a novel targeting antineoplastic drug and a manufacture method thereof and application thereof. The antineoplastic drug is a tyrosine kinase inhibitor, a novel core section of the drug is a catechol part and the left side is a hydroxide radical etherification part. The manufacture method of the drug is that 2, 4, 5-trihydroxy acetophenone reacts with methylclhlorofonmate; through an aldol reaction, a benzo dihydropyran structure is generated in a mode of cyclization through the aldol reaction; then the benzo dihydropyran structure reacts with interhalogen aniline or acetylene aniline to generate 4-interhalogen aniline-6, 7-dyhydroxy coumarin or 4-acetylene aniline-6, 7-dyhydroxy coumarin; methyl formate of benzene dihydroxy is removed; etherification is performed; and purification and crystallization are performed through flash chromatography to obtain the target product. The drug is used for treating people with locally advanced or metastatic non-small cell lung cancer and receiving chemical treatment before.

Description

technical field [0001] The invention belongs to the field of new drug design and medicinal chemistry, and specifically relates to a novel targeting antitumor drug and its preparation method and application. Background technique [0002] Protein tyrosine kinase (PTK) is a group of key enzymes in the most active and rapidly progressing cell signal transduction process in the process of tumorigenesis. It catalyzes the transfer of the phosphate group on ATP to the tyrosine of many important proteins. Phosphorylate the residues, thereby activating various substrate enzymes, and affecting cell growth, proliferation and differentiation through a series of reactions. PTK activity is abnormally elevated in most tumor cells, and nearly 80% of oncogenes contain tyrosine kinase coding. Therefore PTK is a very important and valuable anti-tumor target. Inhibition of tyrosine kinase receptors can effectively control the phosphorylation of downstream signals, thereby inhibiting the growth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/18A61K31/352A61P35/00
Inventor 杨凌艾纯芝葛广波于洋夏杨柳刘兆明
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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