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Aryl-substituted amide compound, preparing method thereof, medicine composition comprising same, and application thereof

A technology for compounds and medicinal salts, applied in the preparation of organic compounds, drug combinations, preparation of carboxylic acid amides, etc., can solve the problems of lowering low-density lipoprotein, poor patient tolerance, large dosage, etc. The effect of promoting efflux

Active Publication Date: 2015-12-30
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Bile acid sequestrants have disadvantages such as large doses, obvious gastrointestinal reactions, and poor patient tolerance.
Statins are the first-line drugs for the treatment of hyperlipidemia. Their mechanism of action is to inhibit the activity of hydroxymethylglutaryl-CoA reductase in the body and reduce the level of low-density lipoprotein (LDL). However, long-term use can lead to rhabdomyolysis and gastrointestinal dysfunction. Serious adverse reactions such as syndrome, rash, and liver damage

Method used

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  • Aryl-substituted amide compound, preparing method thereof, medicine composition comprising same, and application thereof
  • Aryl-substituted amide compound, preparing method thereof, medicine composition comprising same, and application thereof
  • Aryl-substituted amide compound, preparing method thereof, medicine composition comprising same, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1: Synthesis of representative compounds

[0112] (1) N-(2-(1H-indol-3-yl)ethyl)-2-aminobenzamide (CD1)

[0113] Tryptamine (purchased from Adamas, purity>99%) (0.80g, 5mmol) was added to a 50mL round-bottomed flask, 25mL N, N-dimethylformamide was added, followed by 2-aminobenzoic acid (0.68g , 5mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDCI) hydrochloride (all purchased from Beijing Coupling Technology Co., Ltd., purity>98%) (0.96g, 5mmol), React overnight at room temperature. Most of the solvent was evaporated under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate and dried with anhydrous sodium sulfate. The ethyl acetate extract was concentrated and eluted through a silica gel column with ethyl acetate: petroleum ether = 1:3 as the eluent to obtain 1.14g of pure CD1 (yield 82%), white solid, mp159-160℃ (literature value) 156-157°C). MS(ESIm / z)280.28(M+H) + , HRMS(ESIm / z)[M+H] + Theoretical formula C 17 H ...

Embodiment 2

[0172] Example 2: The compound's activity on ABCA1 upregulator screening model

[0173] ABCA1p-LUCHepG2 cells were obtained from the National New Drug (Microbiology) Laboratory, Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences. For the processing process of the cell, please refer to the article Identification of Up-regulators of HumanATP-binding Cassette Transporter Alvia High-throughput Screening of Synthetic and Natural Compound Library by Jie Gao et al. JBiomolScreen.2008, 13(7): 648 -656, and Gao Jie's doctoral dissertation "Construction and application of a new anti-atherosclerotic drug screening model targeting ABCA1".

[0174] Transfer ABCA1-LUCHepG2 cells to 5×10 4 Cells / well were seeded in a 96-well cell culture plate. After the cells adhered to the wall for about 6 hours, they were replaced with serum-free RPMI-1640 medium (Hyclone) (200 μl / well) containing a series of diluted concentrations of the compound of the present invention. Wells wi...

Embodiment 3

[0179] Example 3: The activity of the compound on the SR-BI / CLA1 upregulator screening model

[0180] CLAp-LUCHepG2 was obtained from the National Laboratory of New Drugs (Microbiology), Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences. For the treatment process of this cell, please refer to the article IdentificationofNovelHumanHigh-DensityLipoproteinReceptorUp-regulatorsUsingaCell-BasedHigh-ThroughputScreeningAssay by Yuan Yang et al. JBiomolScreen2007, 12(2): 211-219, and Yang Yuan’s doctoral dissertation "Screening, Discovery and Related Activity Study of Microorganism-derived High Density Lipoprotein Receptor Upregulators".

[0181] Transfer CLap-LUCHepG2 cells to 5×10 4 Each cell / well was seeded in a 96-well cell culture plate, and after the cells adhered to the wall for about 6 hours, they were replaced with serum-free MEM-EBSS medium (200 μl / well) containing a series of diluted concentrations of the compound of the present invention. Keep the ...

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Abstract

The invention relates to an aryl-substituted amide compound in the formula (I), a preparing method thereof, a medicine composition comprising the same, and application of the amide compound and the medicine composition to pharmacy, wherein Arl, L1, M1, M2, L2 and Ar2 are defined as in the text. The aryl-substituted amide compound can excite TRPV1 and nuclear receptors (LXRs, PPARs and RXR), adjust expression of cholesterol excretion gap-associated protein ABCA1 / G1, SR-BI, adjust expression of inflammation gap-associated protein TNF-alpha and the like, and play roles in promoting excretion of cholesterol and lipid, reducing sugar, adjusting blood lipid, resisting inflammation and reducing blood pressure, and can be used for treating and / or preventing and / or relieving cardiovascular and cerebrovascular diseases, adjusting blood lipid, and resisting atherosclerosis, diabetes mellitus, inflammation, pain and hypertension.

Description

Technical field [0001] The invention relates to an aryl substituted amide compound or a pharmaceutical salt thereof, a preparation method thereof, a pharmaceutical composition containing the same, and application thereof. Background technique [0002] Atherosclerosis (AS) is the common pathophysiological basis of coronary heart disease, myocardial infarction, stroke, hypertension and other cardiovascular and cerebrovascular diseases. The death toll caused by this disease each year accounts for 1 / 3 of the total death toll in the world. [0003] The pathogenesis of AS is complex, which is closely related to lipid infiltration, vascular endothelial injury, inflammation and so on. Macrophages unrestricted uptake of lipids, cholesterol, and denatured low-density lipoprotein (m-LDL) through the SR-A and CD36 receptors on their surface to form the foam of macrophages. A large amount of lipids (mainly cholesterol and cholesterol esters) accumulate in the foamed cells of the vascular inti...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07D209/18C07D209/42C07D401/12C07C231/02C07C237/42C07C235/60A61K31/4045A61K31/625A61K31/404A61K31/405A61K31/4439A61K31/4709A61K31/609A61K31/167A61K31/166A61P9/10A61P9/00A61P3/06A61P3/10A61P29/00A61P9/12
Inventor 司书毅李永臻许艳妮冯婷婷刘畅王潇刘鹏巫晔翔贺晓波李东升陈明华刘伟
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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