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HDM2 and HDMX dual inhibitor 3-nitrile quinoline derivative and preparation method and application thereof

A technology of nitrile quinoline and derivatives, which is used in drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc. Cancer effects, etc.

Inactive Publication Date: 2014-05-21
JIANGSU TANGGUO MEDICINE SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] As a structurally similar protein to HDM2, HDMX was discovered several years later than HDM2, but the function of this protein has not been fully appreciated until the latest research published by Cancer Cell in 2010 pointed out that HDMX can also bind to p53 protein so that it cannot exert its tumor suppressor effect. Therefore, it can be used as a target for tumor drug development. In 2012, Nature Medicine also published a research paper from an independent laboratory pointing out that HDMX is a very potential target for tumor drug development. The study also pointed out that specific HDM2-p53 inhibitors are likely to bring To solve the problem of drug resistance, that is, if only the HDM2-p53 interaction is inhibited, tumor cells can easily "compensate" the effect of HDM2 inhibitors by up-regulating the expression of HDMX and increasing the ability of GDMX to bind p53 to inactivate it, and develop HDM2 / HDMX dual inhibitors are the most promising research direction

Method used

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  • HDM2 and HDMX dual inhibitor 3-nitrile quinoline derivative and preparation method and application thereof
  • HDM2 and HDMX dual inhibitor 3-nitrile quinoline derivative and preparation method and application thereof
  • HDM2 and HDMX dual inhibitor 3-nitrile quinoline derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: 3-isopropoxy-4-methylnitrobenzene (1)

[0068] Add 60g (0.39mol) of 3-hydroxy-4-methylnitrobenzene and 100g (0.72mol) of potassium carbonate into a 500ml three-necked flask, dissolve in 300ml of acetone, stir mechanically, and slowly add 50ml of 2-bromopropane ( 0.50mol), react at 40°C for 6 hours. Then the reaction liquid was poured into 1000 ml of water, extracted three times with chloroform, the extract was concentrated, and vacuum-dried to obtain 72.2 g of a brownish-yellow liquid product with a yield of 95%. Molecular formula: C10H13NO3, molecular weight: 195.22

[0069] MS (EI) m / z 195.

Embodiment 2

[0070] Example 2: 3-isopropoxy-4-methylaniline (2)

[0071] Add 41g (0.73mol) of iron powder, 200ml of water, 50ml of acetic acid and 50ml of ethanol into a 500ml three-necked bottle, stir and heat to 30°C for 20min, then slowly drop 3-isopropoxy-4-methyl Nitrobenzene 60g (0.31mol), reacted at 50°C for 2 hours, suction filtered, combined filtrates, extracted 3 times with chloroform, concentrated the extract, and dried in vacuo to obtain 45g of brown oily liquid. Yield 89%. Molecular formula: C10H15NO, molecular weight: 165.24.

[0072] MS (EI) m / z 165.

Embodiment 3

[0073] Example 3: (Z)-2-cyano-3-(3-isopropoxy-4-methylphenyl-amino)-acrylic acid ethyl ester (3)

[0074] Add 45g (0.27mol) of 3-isopropoxy-4-methylaniline, 51g (0.30mol) of (Z)-3-ethoxy-2-nitrile-ethyl acrylate and 160ml of toluene into a 250ml three-necked flask , heated and stirred, refluxed for 4 hours, cooled to room temperature, a large amount of white solid was precipitated, filtered with suction, recovered toluene in the filtrate, and the filter cake was recrystallized with ethanol to obtain 72 g of the product, with a yield of 93%. Molecular formula: C16H20N2O3, molecular weight: 288.35. Mp: 138°C.

[0075] MS (EI) m / z 288.

[0076] 1 H-NMR (AV-500, δ, DMSO-d 6 ):1.21-1.28(m,9H);2.08(s,3H);4.14-4.26(t,2H);4.55-4.57(m,1H);6.81-6.89(m,2H);7.01-7.02(d ,1H);8.26-8.39(t,1H);10.58-10.68(d,1H)

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a HDM2 and HDMX dual inhibitor 3-nitrile quinoline derivative and a preparation method and application thereof. The invention provides the quinoline derivative whose structure is shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound provided by the invention can inhibit the respective ability of combining with p53 specificity of HDM2 and HDMX, can be used as an anti-tumor drug, and has a wide clinical application prospect.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a 3-cyanoquinoline derivative of HDM2 and HDMX dual inhibitor and its preparation method and application. Background technique [0002] The p53 gene is a powerful tumor suppressor gene, located on human chromosome 17p13.1, encoding a 53kD nuclear phosphorylated protein composed of 393 amino acids, called p53 protein. The p53 gene is a negative regulator in the cell growth cycle, which is related to important biological functions such as cell cycle regulation, DNA repair, cell differentiation, and cell apoptosis. Why does the human body still have cancer when there are powerful tumor suppressor genes such as the p53 gene in the human body? This is because there are two ways that the p53 tumor suppressor gene cannot effectively exert its tumor suppressor effect. One is that p53 mutation (deletion) leads to p53 structure abnormality and thus loses its normal function. ...

Claims

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Application Information

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IPC IPC(8): C07D215/54C07D401/12C07D417/12C07D417/14A61K31/496A61K31/5377A61K31/4709A61P35/00
CPCC07D401/12C07D215/54C07D417/12C07D417/14
Inventor 王森曹鑫曹聪戴振亚陆爱军
Owner JIANGSU TANGGUO MEDICINE SCI & TECH
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