Aryl-substituted amide compounds, preparation method thereof, pharmaceutical composition containing same and application thereof

A compound and composition technology, which can be used in the preparation of organic compounds, drug combinations, carboxylic acid amides, etc., can solve the problems of lowering low-density lipoprotein, poor patient tolerance, and large dosage, and achieves the goal of regulating blood lipids, promoting The effect of expulsion

Active Publication Date: 2018-06-29
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 compounds, preparation method thereof, pharmaceutical composition containing same and application thereof
  • Aryl-substituted amide compounds, preparation method thereof, pharmaceutical composition containing same and application thereof
  • Aryl-substituted amide compounds, preparation method thereof, pharmaceutical composition containing 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 Company, purity>99%) (0.80g, 5mmol) was added in a 50mL round bottom flask, 25mL N, N-dimethylformamide was added, and 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 distilled off under reduced pressure, and after adding 30 mL of water, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The ethyl acetate extract was concentrated and eluted through a silica gel column with ethyl acetate:petroleum ether=1:3 to obtain 1.14g of CD1 pure product (yield 82%), white solid, mp159-160°C (literature value 156-157°C). MS(ESIm / z)280.28(M+H) + , HRMS(ESIm / z)[M+H] + Theoretical formula C 17 h 18 N...

Embodiment 2

[0172] Example 2: Activity of Compounds on ABCA1 Up-regulation Screening Model

[0173] ABCA1p-LUC HepG2 cells were obtained from the National Laboratory of New Drugs (Microbiology), Institute of Medical Biotechnology, Chinese Academy of Medical Sciences. For the treatment process of the cells, see, for example, the article Identification of Up-regulators of Human ATP-binding Cassette Transporter Al via High-throughput Screening of Synthetic and Natural Compound Library by Jie Gao et al. Discovery of human ABCA1 up-regulator). J Biomol Screen. 2008, 13(7): 648-656, and Gao Jie's doctoral thesis "Construction and application of a new anti-atherosclerosis drug screening model targeting ABCA1".

[0174] ABCA1-LUC HepG2 cells were added to 5×10 4 Each cell / well was inoculated in a 96-well cell culture plate, and after about 6 hours after the cells adhered to the wall, they were replaced with serum-free RPMI-1640 medium (Hyclone) containing a series of diluted concentrations of th...

Embodiment 3

[0179] Example 3: Activity of Compounds on SR-BI / CLA1 Up-regulator Screening Model

[0180] CLAp-LUC HepG2 was obtained from the National Laboratory of New Drugs (Microorganisms), Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences. The treatment process of this cell can be referred to for example the article Identification of Novel Human High-Density Lipoprotein Receptor Up-regulators Using a Cell-Based High-Throughput Screening Assay of Yuan Yang et al. In vivo regulator). J Biomol Screen2007, 12(2): 211-219, and Yang Yuan's doctoral thesis "Screening, discovery and related activity research of microorganism-derived high-density lipoprotein receptor upregulators".

[0181] CLAp-LUC HepG2 cells were added to 5×10 4 Each cell / well was inoculated in a 96-well cell culture plate, and after about 6 hours of cell attachment, they were replaced with serum-free MEM-EBSS medium (200 μl / well) containing a series of dilutions of the compound of the present i...

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Abstract

The present invention relates to aryl-substituted amide compounds of formula (I) and their preparation methods, pharmaceutical compositions containing them and their application in pharmacy, wherein Ar1, L1, M1, M2, L2 and Ar2 are as described herein definition. The aryl-substituted amide compound of the present invention can stimulate TRPV1, stimulate nuclear receptors (LXRs, PPARs, RXR), regulate the expression of cholesterol efflux-related protein ABCA1 / G1, SR-BI, regulate inflammation-related protein TNF-α, etc. , so as to play the role of promoting cholesterol and lipid efflux, lowering blood sugar, regulating blood lipids, anti-inflammation, lowering blood pressure, etc., and is used to treat and / or prevent and / or alleviate cardiovascular and cerebrovascular diseases, regulate blood lipids, and resist atherosclerosis Sclerosis, diabetes, anti-inflammatory, pain and anti-hypertensive diseases.

Description

technical field [0001] The present invention relates to an aryl-substituted amide compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same and an application thereof. Background technique [0002] Atherosclerosis (AS) is the common pathophysiological basis of various cardiovascular and cerebrovascular diseases such as coronary heart disease, myocardial infarction, stroke, and hypertension. The number of deaths caused by this disease accounts for 1 / 3 of the total number of deaths in the world every year. [0003] The pathogenesis of AS is relatively complex, which is closely related to lipid infiltration, vascular endothelial injury, and inflammation. Macrophages take up lipids, cholesterol and denatured low-density lipoprotein (m-LDL) indefinitely through the SR-A and CD36 receptors on their surface, forming macrophage foaming. A large amount of lipids (mainly cholesterol and cholesteryl esters) ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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