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Aromatic polycyclic carboxylic acid derivatives

A technology of compounds and substituents, applied in the field of aromatic polycyclic carboxylic acid derivatives

Active Publication Date: 2015-07-22
吉林升通化工有限公司 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Diabetes with the same pathogenesis can be effectively treated by using GPR40 receptor agonists. So far, there is no officially marketed new drug targeting GPR40

Method used

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  • Aromatic polycyclic carboxylic acid derivatives
  • Aromatic polycyclic carboxylic acid derivatives
  • Aromatic polycyclic carboxylic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0255] Example 12-(6-((2'-cyclopropyl-4'-((tetrahydrofuran-3-yl)oxy)-[1,1'-biphenyl]-3-yl)methoxy)- Preparation of 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 1)

[0256]

[0257] (1) Preparation of methyl 2-(6-((3-bromobenzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate

[0258]

[0259] 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)methyl acetate (1.04g, 5.0mmol) and 3-bromobenzyl alcohol (935mg, 5.0mmol) and azodicarbonyl Dipiperidine (1.89 g, 7.5 mmol) was dissolved in anhydrous THF (30 mL), and stirred thoroughly for 30 minutes. Dissolve n-butylphosphine (1.51g, 7.5mmol) in anhydrous tetrahydrofuran (30mL), add it dropwise to the reaction system with a dropping funnel, stir fully for 2 hours, and the reaction solution is directly concentrated under reduced pressure and then chromatographed on a silica gel column ( The eluent petroleum ether / ethyl acetate=15:1) isolated the product 1.1g, and the yield was 58%.

[0260] (2) 2-(6-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborola...

Embodiment 2

[0283] Example 22-(6-((2'-cyclopropyl-4'-(2-(methylsulfonylamino)ethoxy)-[1,1'-biphenyl]-3-yl)methoxy base)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 3)

[0284]

[0285] (1) Preparation of 2-(tert-butoxycarbonylamino) ethyl methanesulfonate

[0286]

[0287] Dissolve N-tert-butoxycarbonylethanolamine (6.2g, 38.5mmol) in anhydrous tetrahydrofuran (150mL), add triethylamine (9.7g, 96mmol), add methanesulfonyl chloride (5.3g, 46mmol) dropwise under ice-cooling, The dropwise addition was completed within 20 minutes, and the reaction was continued for 12 hours at room temperature. The system was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure, then extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7.7 g of the title compound as a brown oil, with a yield of 83.7%.

[0288] (2) Preparation of tert-butyl 2-(4-bromo-3-formylphenoxy...

Embodiment 3

[0314] Example 3 (S)-2-(6-((2'-cyclopropyl-4'-(2-(1,1-dioxoisothiazolidin-2-yl)ethoxy)-[1 ,1'-biphenyl]-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 6)

[0315]

[0316] (1) Preparation of 2-(tert-butoxycarbonylamino) ethyl methanesulfonate

[0317]

[0318] Dissolve N-tert-butoxycarbonylethanolamine (15g, 93mmol) in anhydrous tetrahydrofuran (400mL) under ice-cooling, add triethylamine (23.5g, 233mmol), add dropwise methanesulfonyl chloride (12.8g, 111.6mmol), drop After the addition was complete, it was raised to room temperature and reacted for 12 hours. Filtrate with suction, concentrate the filtrate under reduced pressure, add ethyl acetate (300mL) and water (300mL), extract with ethyl acetate (300mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to give the title compound as a brown oil 18.9 g, 85% yield.

[0319](2) Preparation of tert-butyl 2-(4-bromo-3-formylphenoxy)ethylcarbamate

[0320] ...

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Abstract

The invention specifically relates to aromatic polycyclic carboxylic acid derivative GPR40 receptor agonists as shown in a general formula (I) which is described in the specification, and pharmaceutically acceptable salts, esters or stereoisomers thereof, belonging to the technical field of medicine. R1, R2, R3, R4 and R5 in the general formula (I) are as defined in the specification. The invention also relates to a preparation method, a medicinal preparation and a pharmaceutical composition of the compounds, and application of the compounds and the pharmaceutical composition in preparation of drugs used as GPR40 receptor agonists for prevention and / or treatment of diabetes.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to aromatic polycyclic carboxylic acid derivatives GPR40 receptor agonists, their pharmaceutically acceptable salts, their esters and their stereoisomers, their preparation methods, pharmaceutical preparations and The pharmaceutical composition, and the application of these compounds as GPR40 receptor agonists in the preparation of medicines for preventing and / or treating diabetes. 2. Background technology [0002] The latest research shows that the GPR40 receptor agonist compound is a new drug for the treatment of type II diabetes. Its effect of improving blood sugar control is similar to that of glimepiride, but the risk of causing hypoglycemia is significantly lower than the latter. [0003] Type II diabetes is the most common type of diabetes. About 150 million people in the United States currently suffer from diabetes, 90% of whom have type 2 diabetes. The deg...

Claims

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Application Information

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IPC IPC(8): C07D307/79C07D417/12A61K31/343A61K31/427A61K31/433A61K31/541A61K31/549A61P3/10A61P3/06A61P9/12A61P3/04A61P7/10A61P37/02A61P29/00A61P7/02A61P19/10A61P25/28A61P13/00A61P35/00A61P3/00A61P25/00A61P13/12A61P27/02A61P5/50
CPCC07D307/79C07D417/12
Inventor 吴永谦
Owner 吉林升通化工有限公司
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