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Carboxylic acid derivatives and preparation method and use in medicines thereof

A compound, selected technology, applied in the field of medicine

Active Publication Date: 2018-03-06
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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  • Carboxylic acid derivatives and preparation method and use in medicines thereof
  • Carboxylic acid derivatives and preparation method and use in medicines thereof
  • Carboxylic acid derivatives and preparation method and use in medicines thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] 3-(1-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)-1H-indazole-5-carboxamido)propanoic acid 1

[0148] (R)-3-(1-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)-1H-indazole-5-formyl Amino)propionic acid 1A

[0149] (S)-3-(1-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butyl)-1H-indazole-5-formyl Amino)propionic acid 1B

[0150]

[0151]

[0152] first step

[0153] 4'-(Trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde

[0154] 4-Bromobenzaldehyde 1a (1.60g, 8.8mmol), 4-(trifluoromethyl)phenylboronic acid 1b (2.0g, 10.5mmol), tetrakistriphenylphosphopalladium (508mg, 0.44mmol) and sodium carbonate ( 2.33g, 22.0mmol) was dissolved in 34mL of a mixed solution of ethylene glycol dimethyl ether and water (V / V=15 / 2), and reacted at 90°C for 12 hours under the protection of argon. After the reaction solution was concentrated under reduced pressure, 200 mL of water was added, extracted with ethyl acetate (200 mL×3), the combined organic phases were dried o...

Embodiment 2

[0182] 3-(1-(1-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)butyl)-1H-indazole-5-carboxamido)propionic acid

[0183]

[0184]

[0185] first step

[0186] 4-(6-(Trifluoromethyl)pyridin-3-yl)benzaldehyde

[0187] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2a (2.32g, 10.0mmol), 5-bromo-2-( Trifluoromethyl)pyridine 2b (2.94 g, 13.0 mmol), tetrakistriphenylphosphopalladium (578 mg, 0.50 mmol) and sodium carbonate (3.18 g, 30.0 mmol) were dissolved in 34 mL of 1,4-dioxane and water ( In the mixed solution of V / V / V=9 / 1), react at 100° C. for 6 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde 2c (2.00 g, pale yellow solid), yield: 79.7%. MS m / z(ESI): 251.9[M+1]

[0188] second step

[0189] 1-(4-(6-(trifluoromethyl)pyridin-3-yl)...

Embodiment 3

[0210] 3-(1-(1-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)butyl)-1H-indazole-5-carboxamido)propionic acid

[0211]

[0212] first step

[0213] 4-(5-(Trifluoromethyl)pyridin-2-yl)benzaldehyde

[0214] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2a (2.32g, 10.0mmol), 2-bromo-5-( Trifluoromethyl)pyridine 3a (2.05g, 9.10mmol), tetrakistriphenylphosphopalladium (526mg, 0.445mmol) and sodium carbonate (2.40g, 22.6mmol) were dissolved in 25mL of ethylene glycol dimethyl ether and water (V / V=4 / 1) in the mixed solution, reacted at 90° C. for 5 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde 3b (1.58 g, white solid), yield: 69.3%.

[0215] MS m / z(ESI): 251.9[M+1]

[0216] second step

[0217] 1-(4-(5-(trifluoromethyl)pyridin-2-yl)...

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Abstract

The invention relates to carboxylic acid derivatives and a preparation method and use in medicines thereof. Specifically, the invention relates to carboxylic acid derivatives as shown in the general formula (I), a preparation method and pharmaceutically acceptable salts of the carboxylic acid derivatives, and use of the carboxylic acid derivatives and the pharmaceutically acceptable salts as therapeutic agents, particularly as glucagon receptor antagonists thereof, wherein the definition of each substituent in the general formula (I) is the same as in the description (The general formula (I) is shown in the description).

Description

field of invention [0001] The present invention relates to the field of medicine, and more specifically, relates to a new carboxylic acid derivative, its preparation method, 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 hor...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D401/10C07D403/06C07D401/06A61K31/416A61K31/4439A61K31/506A61P3/10A61P3/04A61P5/50A61P9/10A61P3/00
CPCC07D231/56C07D401/06C07D401/10C07D403/06
Inventor 关东亮陈磊白骅陈明孝蒙卓明
Owner ZHEJIANG HISUN PHARMA CO LTD