Phenylpropiolic acid small molecular organic compounds and synthetic method and application thereof

An organic compound, phenylpropiolic acid technology, applied in organic chemistry, organic active ingredients, medical preparations containing active ingredients, etc., can solve problems such as drug listing

Inactive Publication Date: 2019-03-26
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, TAK-875 has a remarkable therapeutic effect, but its development was terminated due to liver

Method used

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  • Phenylpropiolic acid small molecular organic compounds and synthetic method and application thereof
  • Phenylpropiolic acid small molecular organic compounds and synthetic method and application thereof
  • Phenylpropiolic acid small molecular organic compounds and synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0070] Embodiment 1-1, the preparation of compound 3-(4-(3-phenoxybenzyloxy)phenyl)propiolic acid (HL-001)

[0071]

[0072] Add 3-phenoxybenzaldehyde (1.20 g, 6.1 mmol) into a 50 mL round bottom flask, add 6 mL THF and 6 mL DME to dissolve it, and add NaBH in batches under ice-bath conditions 4 (464mg, 12.2mmol), continue to stir the reaction under ice bath for 3 hours. TLC detects and tracks the reaction. After the reaction is completed, slowly add an appropriate amount of deionized water to the reaction solution to quench, extract with ethyl acetate and water, take the organic phase and evaporate it to dryness, and purify it by column chromatography to obtain a colorless oil, namely 3-Phenoxybenzyl alcohol (1.20 g, 99.2% yield). Take the obtained 3-phenoxybenzyl alcohol (450mg, 2.3mmol) into a 50mL round-bottomed flask, dissolve it with 10mL of DCM, and add PBr dropwise under ice-bath conditions 3 liquid (0.3 mL, 2.5 mmol) and kept on ice for 3 hours. After the reaction...

Embodiment 2

[0078] Example 2, the compound of the present invention has agonism to GPR40, resulting in intracellular Ca 2+ Concentration rises.

[0079] GPR40 coupled with Gαq can stimulate the release of endoplasmic reticulum calcium flow after being activated. It is a widely used GPR40 ligand screening method to reflect the activation state of GPR40 by detecting intracellular calcium flow. The principle of the calcium flow experiment is to introduce a fluorescent dye sensitive to calcium ions into the cells to detect the changes of calcium ions in the cells. Calcium flux assays are based on the detection of second messengers. When screening agonists, the test compound is added to the system. If the compound has an agonistic effect on the receptor, it will cause intracellular Ca 2+ When the concentration increases and the fluorescence intensity increases, the agonistic activity of the test compound on GPR40 can be calculated by calculating the increase of the fluorescence intensity.

...

Embodiment 3

[0091] Example 3. Target verification and in vitro functional experiments of phenylpropiolic acid small molecule organic compounds of the present invention

[0092] After obtaining the activity screening results of the phenylpropiolic acid small molecule organic compound of the present invention, the present invention continues to confirm the target. The loss of GPCR function after agonist stimulation is a common mechanism for receptor desensitization and internalization. Since a series of compounds prepared by the present invention have similar structures and belong to one type of compound, the inventors selected one of them with relatively high activity. The good three compounds HL-009, HL-011, HL-023 verified whether they can induce GPR40 receptor desensitization and internalization.

[0093] In the present invention, TAK-875 (1 μM), HL-009 (10 μM), HL-011 (10 μM) and HL-023 (10 μM) are used for the first stimulation respectively. Such as image 3 As shown, it can be foun...

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PUM

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Abstract

The invention relate to a category of novel phenylpropiolic acid small molecular organic compounds as shown in a structural formula (I) or stereisomers, crystals, hydrates or pharmaceutically acceptable salt and an application of the phenylpropiolic acid small molecular organic compounds or stereisomers, crystals, hydrates or pharmaceutically acceptable salt and pharmaceutical compositions comprising the compounds in preparing a GPR40 agonist and drugs for promoting insulin release, treating and/or preventing diabetes or complications, treating diabetes inducing poor therapeutic effect inducedby acquired drug-resistance and complications and the like. The invention also provides a preparation method of the phenylpropiolic acid small molecular organic compounds as shown in the structural formula (I). The phenylpropiolic acid small molecular organic compounds have good anti-diabetes effect and the risk of inducing hypoglycemia is lower than that of conventional drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a class of phenylpropylic acid small-molecule organic compounds and a synthesis method and application thereof. Background technique [0002] Diabetes is one of the diseases with the highest incidence in the world. It is mainly caused by defects in insulin secretion or insensitivity of cells to insulin. It is mainly divided into type I diabetes, type II diabetes, gestational diabetes and other types of diabetes. Among them, type II diabetes patients are the most, accounting for about 90% of the total number of patients (Prentki, M.; Nolan, C.J. The Journal of Clinical Investigation 116(7), 1802-1812.). [0003] Most of the existing drugs for treating diabetes currently on the market mainly regulate blood sugar balance through three ways. One is to enhance the body’s sensitivity to insulin (such as metformin, thiazolidinediones), the other is to reduce renal glucose reab...

Claims

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Application Information

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IPC IPC(8): C07C59/68C07C59/66C07C317/22A61K31/192A61P3/10
CPCC07C59/66C07C59/68C07C317/22
Inventor 章涵堃卢伟强刘明耀胡龙龙姜兴武邱子粱
Owner EAST CHINA NORMAL UNIV
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