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Receptor signal transduction positive modulator, preparation method and purpose thereof

A technology of solvates and compounds, which can be used in medical preparations containing active ingredients, pharmaceutical formulations, metabolic diseases, etc., and can solve the problem of inconvenient oral administration of polypeptide drugs

Inactive Publication Date: 2009-10-28
THE NAT CENT FOR DRUG SCREENING +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the inconvenient oral administration of peptide drugs, efforts to find non-peptide GLP-1R agonists have continued
At present, there are no reports about the successful use of non-peptide small molecule GLP-1R agonists in clinical treatment

Method used

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  • Receptor signal transduction positive modulator, preparation method and purpose thereof
  • Receptor signal transduction positive modulator, preparation method and purpose thereof
  • Receptor signal transduction positive modulator, preparation method and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Embodiment 1. Preparation of compound 6Aa

[0140] [Chemical Reaction Formula 5]

[0141]

[0142] According to the chemical reaction above:

[0143] Step 1: Add 1.46g (0.01mol) CH to a 100mL three-necked bottle 3 NCS, 2.5g (0.0098mol) of p-chloroaniline and 20mL of absolute ethanol were stirred until the solid was dissolved, heated to reflux, and followed by TLC to monitor the reaction. After the reaction was completed, the reaction solution was placed in a refrigerator at 4° C. for cooling and crystallization, filtered with suction, and dried to obtain 3.4 g of white solid 3a (yield 87%).

[0144] Step 2: Add 3.4g (0.0169mol) of compound 3a, 4.8g (0.0508mol) of chloroacetic acid, 4.17g (0.0508mol) of sodium acetate, a small amount of TEBA and 20mL of absolute ethanol into a 100mL three-necked flask. Heated to reflux, followed by TLC to monitor the reaction. After the reaction was completed, it was filtered while it was hot, and the filtrate was concentrated und...

Embodiment 2

[0147] The preparation of embodiment 2. compound 6Ba

[0148] [Chemical Reaction Formula 6]

[0149]

[0150] According to the chemical reaction above:

[0151] Step 1: Compound 3b was prepared in the same manner as the first step in Example 1, except that raw materials 1b and 2b were used instead of 1a and 2a in the first step in Example 1, respectively.

[0152] The second step: Compound 4b was prepared in the same manner as the second step in Example 1, except that 3a in the second step in Example 1 was replaced by starting material 3b.

[0153] The third step: Compound 6Ba was prepared by the same method as the third step in Example 1, except that raw materials 4b and 5b were used instead of 4a and 5a in the third step in Example 1, respectively.

[0154] Compound 6Ba: 1 H NMR (300MHz, DMSO-d 6 )δ0.930(t, 3H, J=7.35Hz), 1.358(sex, 2H, J=7.5Hz), 1.691(qu, 2H, J=7.35Hz), 2.283(s, 6H), 3.892(t, 2H, J=6.9Hz), 7.055(d, 2H, J=8.4Hz), 7.393(d, 1H, J=8.4Hz), 7.457(m, 4H), ...

Embodiment 3

[0155] Embodiment 3. Preparation of compound 6Ca

[0156] [Chemical Reaction Formula 7]

[0157]

[0158] According to the chemical reaction above:

[0159] Step 1: Add 1.7g (22mmol) NH to a 50mL three-necked bottle 4 SCN and 10mL of acetone were stirred at room temperature until the solid was dissolved, and 2.82g (20mmol) of benzoyl chloride was slowly added dropwise, a white solid appeared, and the solution gradually turned yellow and thickened. After the dropwise addition, reflux for half an hour, and slowly add 2.551 g (20 mmol) of p-chloroaniline 2a in acetone (10 mL) dropwise to the reaction system. After the dropwise addition, the reflux was continued, and the reaction was tracked and monitored by TLC. After the reaction was completed, it was cooled, and the reaction solution was poured into 150 mL of water, stirred, and a yellow solid was precipitated. After suction filtration, the solid was dissolved in 3 g NaOH aqueous solution (27 mL), boiled for 5 minutes, c...

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PUM

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Abstract

The invention provides a substitute five membered heterocyclic compound represented by the following formula, and salt, ester, solvate and metal composition which are all accepted by pharmacy or a prodrug having the same biological activity. The invention also provides a purpose of the compound as a glucagon-like peptide-1 receptor (GLP-1R) signal transduction positive modulator and an application for preventing and / or curing metabolic diseases (including but not being limited to type-2 diabetes, insulin resistance and adiposity, and the like), angiocardiopathy and neurodegenerative diseases (such as Alzheimer's disease, AD) also called presenile dementia, and the like.

Description

technical field [0001] The present invention relates to a class of substituted five-membered heterocyclic compounds and their properties as a signal transduction potentiator (Positive modulator) for glucagon-like peptide-1 receptor (GLP-1R). Able to enhance the biological activity and / or response potency of the GLP-1R agonist. The present invention relates to the use of such compounds in the prevention and / or treatment of metabolic diseases (including but not limited to type 2 diabetes, insulin resistance and obesity, etc.), cardiovascular diseases and neurodegenerative diseases [such as "Alzheimer's disease" (Alzheimer's Disease, AD), also known as Alzheimer's dementia (Alzheimer's dementia)] and other medical purposes. Background technique [0002] Glucose metabolism disorder, especially diabetes, has become a major disease that seriously threatens human health and life in modern society. It is predicted that diabetes patients in the world are increasing at an annual rat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/54A61K31/426A61P25/28A61P9/00A61P3/10
CPCC07D417/06C07D277/54A61P3/04A61P3/10A61P5/48A61P9/00A61P25/00A61P25/28
Inventor 王明伟苑芸芸周玲安德鲁·A·杨张翱高林东苏昊然吴茜茜汪佳王菊
Owner THE NAT CENT FOR DRUG SCREENING
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