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Amide derivatives, and preparation method and application thereof to medicines

A compound, selected technology, applied in the direction of pharmaceutical formulations, drug combinations, medical preparations containing active ingredients, etc.

Active Publication Date: 2017-10-10
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, therape

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  • Amide derivatives, and preparation method and application thereof to medicines
  • Amide derivatives, and preparation method and application thereof to medicines
  • Amide derivatives, and preparation method and application thereof to medicines

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0135] Example 1

[0136] (R)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) (Butyl)benzoyl)piperidine-3-carboxylic acid

[0137]

[0138] first step

[0139] Methyl 4-(1-hydroxybutyl)benzoate

[0140] Methyl p-formylbenzoate 1a (10.0 g, 60.92 mmol) was dissolved in 100 mL of tetrahydrofuran, and propyl magnesium bromide (33.5 mL, 67.0 mmol) was added at -78°C, and reacted at room temperature for 3 hours. 300mL ethyl acetate was added, washed with saturated ammonium chloride solution (200mL) and saturated sodium chloride solution (200mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography ( Eluent: petroleum ether: ethyl acetate system) to obtain methyl 4-(1-hydroxybutyl)benzoate 1b (8.66g, colorless liquid), yield: 68.0%

[0141] MS m / z(ESI): 209.0[M+1]

[0142] Second step

[0143] Methyl 4-butyryl benzoate

[0144] Dissolve methyl 4-(1-hyd...

Example Embodiment

[0167] Example 2

[0168] (R)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) (Butyl)-2-fluorobenzoyl)piperidine-3-carboxylic acid

[0169]

[0170] first step

[0171] Methyl 2-fluoro-4-(1-hydroxybutyl)benzoate

[0172] Methyl 2-fluoro-4-formylbenzoate 2a (3.0g, 16.5mmol) was dissolved in 60mL of tetrahydrofuran, and under nitrogen protection, while stirring at -78°C, propylmagnesium bromide (8.6mL, 17.3mmol) was slowly added , React at room temperature for 2 hours. The reaction solution was cooled to 0°C, saturated ammonium chloride solution (30 mL) was slowly added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography Purification method (eluent: petroleum ether: ethyl acetate system) to obtain methyl 2-fluoro-4-(1-hydroxybutyl)benzoate 2b (850mg, colorless liquid), yield: 23.0...

Example Embodiment

[0199] Example 3

[0200] (S)-1-(4-((S)-1-(3,5-Dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy) (Butyl)-2-fluorobenzoyl)piperidine-3-carboxylic acid

[0201]

[0202] first step

[0203] (S)-1-(2-Fluoro-4-(R)-1-hydroxybutyl)benzoylpiperidinyl)-3-carboxylic acid ethyl ester

[0204] The (R)-2-fluoro-4-(1-hydroxybutyl)benzoic acid 2e (150mg, 0.71mmol), (S)-piperidine-3-carboxylic acid ethyl ester 3a (142uL, 0.92mmol), double ( 2-oxo-3-oxazolidinyl) hypophosphorous oxychloride (270mg, 1.06mmol) and N,N-diisopropylethylamine (0.50mL, 2.82mmol) were dissolved in 5mL tetrahydrofuran, and the reaction solution was 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: ...

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Abstract

The invention relates to amide derivatives, and a preparation method and application thereof to medicines. Specifically, the invention relates to amide derivatives shown as a general formula (I), a preparation method thereof, pharmaceutical salts thereof and application of the amide derivatives and pharmaceutical salts thereof as therapeutic agents, especially as pancreatic hyperglycemia receptor antagonists. The substituted groups in the general formula (I) are defined as in the description.

Description

field of invention [0001] 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. Background of the invention [0002] 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 rapidly decompose...

Claims

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Application Information

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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