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1-benzyl-2-pyrroline ketone-4-amide compounds and preparing method and application thereof

A technology of amide compounds and pyrrolidone, which is applied in the direction of drug combination, organic chemistry, and pharmaceutical formulations, to achieve the effect of inhibiting cell proliferation and angiogenesis and significant curative effect

Inactive Publication Date: 2015-03-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the development of small-molecule protein kinase inhibitors is still in its infancy, and people are eager to obtain new drugs with high affinity for target kinases and good therapeutic effects on diseases related to abnormal cell proliferation and angiogenesis

Method used

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  • 1-benzyl-2-pyrroline ketone-4-amide compounds and preparing method and application thereof
  • 1-benzyl-2-pyrroline ketone-4-amide compounds and preparing method and application thereof
  • 1-benzyl-2-pyrroline ketone-4-amide compounds and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] A1-Benzyl-2-pyrrolidinone-4-carboxylic acid

[0056]

[0057] With itaconic acid (18g, 0.138mol) and benzylamine (14.8g, 0.138mol) in reaction bottle, N 2 Under protection, heat up to 130°C, slowly melt and stir, react for 2.5h, stop heating, when cooled to 100°C, add 200ml of 10% NaOH solution under stirring, cool to room temperature, wash the aqueous layer with ethyl acetate, wash with 10 % hydrochloric acid solution was added dropwise to the water layer, a large amount of white solids were formed until pH = 1-2, filtered and washed with water until the pH was about 6 to obtain 25.1 g of white granular solids, yield 82.9%, mp143-145 ° C, HRMS =220.0886[M+H] + .

[0058] B1-Benzyl-2-pyrrolidinone-4-formyl chloride

[0059]

[0060] Add 30ml of dichloromethane to the above compound 1A (6g, 27.4mmol), heat to boiling, gradually dissolve, slowly add 3.2ml (44.0mmol) of thionyl chloride dropwise under stirring, continue to react for 24h, cool naturally...

Embodiment 2

[0065] Example 2: In vitro VEGFR2 inhibitory activity test.

[0066] VEGFR2 enzyme system test solution: 50mM Tris-HCl pH 7.5 buffer, 5mM MnCl 2 , 5 mM MgCl 2 , 0.01% Tween-20, and 2 mM DTT, containing 10 μM ATP, 0.1 μg / mL biocylated polyglutamic acid / tyrosine (4:1), and 0.1 nM VEGFR2 (Millipore, UK).

[0067] ATP catalytic inhibition: Compounds and enzymes were incubated at room temperature for 5min, then added 25μL 100mM EDTA solution, 10μg / mL AlphaScreen streptavidin protein donor and 10μg / mL acceptor 62.5mM HEPES pH7.4 solution and 250mM A solution of NaCl and 0.1% BSA. Detection was carried out by a microplate reader, and the concentration of the test substance when the inhibition rate was 50% was calculated.

[0068] Among them, 15 showed strong enzyme inhibitory activity, as shown in Table 2.

[0069] Table 2

[0070]

[0071] IC of the remaining 84 compounds 50 Value >100nM.

Embodiment 3

[0072] Example 3: Determination of anti-cancer activity in vitro.

[0073] The above-mentioned 15 compounds with strong enzyme inhibitory activity were tested for their inhibitory activity on tumor cell lines by MTT method, and Dasatinib was used as a positive control drug. For specific experimental steps, refer to the literature Modern Experimental Methods in Pharmacology [M]. Beijing: Peking Union Medical College and Beijing Medical University Press, 1998: 818. The tumor cells used are: Hun78T lymphocytic leukemia cells, A549 human lung cancer cells, PC3 human prostate cells, MDA-MB-435 human breast cancer cells, HT-29 human colon cancer cells and BGC-823 human gastric cancer cells. According to the BLLIS method, the concentration IC of the drug required for the half inhibition rate of cell proliferation was calculated. 50 . See Table 3 for specific data.

[0074] table 3

[0075]

[0076] "-" means IC 50 Out of measurement range, no corresponding data obtained.

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Abstract

The invention discloses 1-benzyl-2-pyrroline ketone-4-amide compounds represented by the general formula. According to independent R1, R2, R3, R4, R5, R6, R7, R8, R9 or R10, 1-3 C1-4 alkyl groups substituted by substituent groups are selected from a non-substituent C1-4 alkyl group, a non-substituent C1-3 alkoxy group, halogen, an amine sulfonyl group, a nitryl group and hydrogen or from halogen, a nitryl group, a C1-3 alkyl group and a C1-2 alkoxy group, or 1-3 C1-3 alkoxy groups substituted by substituent groups are selected from halogen, a nitryl group, a C1-3 alkyl group and a C1-2 alkyl group. The halogen is fluorine, chlorine or bromine. The invention further discloses a preparing method and application of the compounds. The compounds can restrain tyrosine kinase signal transduction and unhealthy cell hyperplasia and angiogenesis, and obvious curative effect is achieved on diseases such as tumors especially.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to 1-benzyl-2-pyrrolidinone-4-amide compounds capable of inhibiting the activity of certain protein kinases, their preparation method and application. Background technique [0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of hydroxyl groups on specific tyrosine, valine, or threonine residues in proteins. This phosphorylation interferes with protein function and, as a result, protein kinases play key roles in the regulation of various cellular processes including metabolism, cell proliferation, cell differentiation, and cell survival, as well as blood vessel growth. These processes are associated with the occurrence of diseases such as tumors, and are especially necessary for the growth of solid tumors. [0003] Since the 21st century, scientists have successively discovered many small molecular structures that can inhibit the a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61K31/427A61P35/00A61P9/00
CPCC07D417/12
Inventor 杨照王志祥方正郭凯
Owner CHINA PHARM UNIV
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