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Amide derivatives, their preparation method and their use in medicine

A technology of use and medicine, applied in the field of amide derivatives, their preparation and their use in medicine

Active Publication Date: 2021-01-29
ZHEJIANG HISUN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such properties can lead to improved safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, ease of preparation, etc.

Method used

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  • Amide derivatives, their preparation method and their use in medicine
  • Amide derivatives, their preparation method and their use in medicine
  • Amide derivatives, their preparation method and their use in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] (R)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) Butyl)benzoyl)piperidine-3-carboxylic acid

[0139]

[0140] first step

[0141] Methyl 4-(1-hydroxybutyl)benzoate

[0142] Methyl p-formylbenzoate 1a (10.0 g, 60.92 mmol) was dissolved in 100 mL of tetrahydrofuran, and propylmagnesium bromide (33.5 mL, 67.0 mmol) was added at -78°C, and reacted at room temperature for 3 hours. Add 300mL of ethyl acetate, wash with saturated ammonium chloride solution (200mL) and saturated sodium chloride solution (200mL), the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography ( Eluent: petroleum ether: ethyl acetate system) purification to obtain 4-(1-hydroxybutyl)methyl benzoate 1b (8.66g, colorless liquid), yield: 68.0%

[0143] MS m / z(ESI): 209.0[M+1]

[0144] second step

[0145] Methyl 4-butyrylbenzoate

[0146] Dissolve methyl 4-(1-...

Embodiment 2

[0170] (R)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) Butyl)-2-fluorobenzoyl)piperidine-3-carboxylic acid

[0171]

[0172] first step

[0173] Methyl 2-fluoro-4-(1-hydroxybutyl)benzoate

[0174] Methyl 2-fluoro-4-formylbenzoate 2a (3.0g, 16.5mmol) was dissolved in 60mL of tetrahydrofuran, under nitrogen protection, under stirring at -78°C, slowly added propylmagnesium bromide (8.6mL, 17.3mmol) , react at room temperature for 2 hours. The reaction solution was cooled to 0°C, and saturated ammonium chloride solution (30 mL) was slowly added, extracted with ethyl acetate (20 mL x3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography method (eluent: petroleum ether: ethyl acetate system) to obtain 2-fluoro-4-(1-hydroxybutyl)methyl benzoate 2b (850mg, colorless liquid), yield: 23.0%

[0175] 1 H NMR (400MHz, CDCl 3):δ7.86(d...

Embodiment 3

[0202] (S)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) Butyl)-2-fluorobenzoyl)piperidine-3-carboxylic acid

[0203]

[0204] first step

[0205] (S)-1-(2-fluoro-4-(R)-1-hydroxybutyl)benzoylpiperidinyl)-3-carboxylic acid ethyl ester

[0206] (R)-2-fluoro-4-(1-hydroxybutyl)benzoic acid 2e (150mg, 0.71mmol), (S)-piperidine-3-carboxylic acid ethyl ester 3a (142uL, 0.92mmol), bis( 2-oxo-3-oxazolidinyl)phosphoryl chloride (270mg, 1.06mmol) and N,N-diisopropylethylamine (0.50mL, 2.82mmol) were dissolved in 5mL tetrahydrofuran, and the reaction solution was heated at room temperature React for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: petroleum ether: ethyl acetate system) to obtain (S)-1-(2-fluoro-4-(R)-1 -Hydroxybutyl)benzoylpiperidinyl)-3-carboxylic acid ethyl ester 3b (250 mg, colorless liquid), yield: 99.0%.

[0207] MS...

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PUM

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Abstract

The invention relates to an amide derivative, its preparation method and its application in medicine. Specifically, the present invention relates to an amide derivative represented by general formula (I), a preparation method thereof and a pharmaceutically acceptable salt thereof, and their use as a therapeutic agent, especially as a glucagon receptor antagonist purposes, wherein the definition of each substituent in the general formula (I) is the same as the definition in the description.

Description

[0001] field of invention [0002] The present invention relates to a novel amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a GCGR antagonist. [0003] Background of the invention [0004] Glucagon is a linear polypeptide composed of 29 amino acids secreted by pancreatic α cells, with a molecular weight of 3485; its concentration in serum is 50-100 ng / L, and its half-life in plasma is 5-10 minutes. Glucagon specifically binds to B-type G protein-coupled receptors (glucagon receptors, GCGR) on the surface of target cells such as liver and kidney, activates downstream signal transduction pathways, and exerts physiological effects. Contrary to the effect of insulin, it is a hormone that promotes catabolism. It has a strong effect of promoting glycogenolysis and gluconeogenesis, which can significantly increase blood sugar. 1mol / L hormone can make 3×10 6 mol / L of glucose is ra...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/454A61P3/10A61P3/04A61P5/50A61P9/10A61P3/00
CPCC07D401/12
Inventor 关东亮白骅盛首一陈明孝王中利赵伟峰
Owner ZHEJIANG HISUN PHARMA CO LTD