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Epoxy-substituted oxopyridine derivatives and their preparation method and application in medicine

A technology of heterocyclic group and cycloalkyl group, which is applied in the field of epoxy-substituted oxopyridine derivatives, its preparation and its application in medicine, and can solve the problems of negligible effect

Active Publication Date: 2018-03-13
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that in the thrombus model, inhibiting FXIa factor can effectively inhibit the formation of thrombus, but in the case of more severe thrombus, the effect of FXIa is negligible (Blood.2010; 116(19):3981-3989)

Method used

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  • Epoxy-substituted oxopyridine derivatives and their preparation method and application in medicine
  • Epoxy-substituted oxopyridine derivatives and their preparation method and application in medicine
  • Epoxy-substituted oxopyridine derivatives and their preparation method and application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] 5-(2-(4-(5-chloro-2-benzonitrile)-5-(cyclopentyloxy)-2-oxopyridin-1(2H)-yl)-4-methoxybutyrylamino )-1H-indole-2-carboxylic acid

[0160]

[0161] first step

[0162] Methyl 2-bromo-4-methoxybutyrate 1b

[0163] Add methyl 4-methoxybutyrate 1a (1.6g, 12.1mmol) into 50mL of tetrahydrofuran, cool down to -78°C with a dry ice-acetone bath, and slowly add lithium bistrimethylsilylamide (12.7mL, 12.7mmol), added, stirred and reacted for 1 hour, added trimethylchlorosilane (1.31g, 12.1mmol), continued to stir and reacted for 20 minutes, then added N-bromosuccinimide (2.15g, 12.1mmol) , and stirred for 2 hours. The dry ice-acetone bath was removed, the temperature of the reaction solution was naturally raised to room temperature, the reaction was quenched with saturated ammonium chloride solution, the reaction solution was extracted with ethyl acetate (50mL×3), the organic phases were combined, and the organic phases were respectively saturated with water (50mL). Washed ...

Embodiment 2

[0196] 5-(2-(4-(5-chloro-2-benzonitrile)-5-cyclobutyloxy-2-oxopyridin-1(2H)-yl)-4-methoxybutyramide

[0197] base)-1H-indole-2-carboxylic acid

[0198]

[0199] first step

[0200] 5-cyclobutoxy-2-methoxypyridine 2b

[0201] Dissolve 1c (5.0g, 39.96mmol) in 50mL of N,N-dimethylformamide, add potassium carbonate (11.05g, 79.92mmol), heat to 95°C, add cyclobutyl bromide 2a (6.20g , 45.95mmol), the addition was completed, and the reaction solution was stirred at 90°C for 16 hours. Heating was stopped, the temperature of the reaction solution was naturally cooled to room temperature, 15 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, and the organic phase was washed with a saturated sodium chloride solution (50 mL × 3). Dry over sodium sulfate, remove the desiccant by filtration, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with...

Embodiment 3

[0229]5-((S)-2-(4-(5-Chloro-2-benzonitrile)-2-oxo-5-((R)-tetrahydrofuran-3-oxo)pyridin-1(2H)-yl) -3-phenylpropanamide)-1H-indole-2-carboxylic acid 3

[0230]

[0231] first step

[0232] (R)-2-methoxy-5-(tetrahydrofuran-3-oxo)pyridine 3b

[0233] 1c (1.78g, 14.24mmol) and (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonyl ester 3a (3.45g, 14.24mmol) were sequentially prepared using a known method "Guangzhou Chemical Industry, 2012, 40 (16 ), 62-63” prepared), dissolved in 20mL of N,N-dimethylformamide, added potassium carbonate (4.92g, 35.60mmol), heated to 95°C, and the reaction solution was stirred at 90°C for 16 Hour. Heating was stopped, the temperature of the reaction solution was naturally cooled to room temperature, 50 mL of water was added to the reaction solution, extracted with ethyl acetate (40 mL × 3), the organic phases were combined, and the organic phase was washed with a saturated sodium chloride solution (25 mL × 3). Dry over sodium sulfate, remove the de...

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PUM

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Abstract

The invention relates to epoxy-substituted oxopyridine derivatives and their preparation method and application in medicine and concretely, relates to epoxy-substituted oxopyridine derivatives shown in the general formula (I), their preparation method, a pharmaceutical composition containing the derivatives and a use of the derivatives as therapeutic agents and especially as blood coagulation factor XIa (called as FXIa for short) inhibitors and in preparation of drugs for treating diseases such as thromboembolism. The definition of each substituent in the general formula (I) is the same as thedefinition in the specification.

Description

technical field [0001] The present invention relates to a new class of epoxy-substituted oxopyridine derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an inhibitor of factor XIa (Faxtor XIa, FXIa for short). Inhibitor and its use in the preparation of medicines for treating and preventing diseases such as thromboembolism. Background technique [0002] Cardiovascular and cerebrovascular diseases such as cerebrovascular disease, cerebral infarction, myocardial infarction, coronary heart disease and arteriosclerosis claim the lives of nearly 12 million people every year in the world, accounting for nearly 1 / 4 of the total death toll in the world, becoming the number one enemy of human health. In China, more than 2.6 million people die from cardiovascular diseases every year, and 75% of the surviving patients are disabled, and more than 40% of them are seriously disabled. The throm...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D405/14A61K31/4439A61K31/4433A61P7/02A61P9/10A61P9/00
CPCC07D401/12C07D405/14
Inventor 杨方龙池江涛贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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