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4 (1H)-pyridone compound as well as pharmaceutical composition and application thereof

A technique for pyridone and compounds, applied in the field of 4-pyridone compounds, capable of solving problems such as single structure

Active Publication Date: 2021-11-26
SHANGHAI MEIYUE BIOTECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the defect of single structure of the existing FXIa inhibitors, and provide a 4(1H)-pyridone compound, Its pharmaceutical composition and use

Method used

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  • 4 (1H)-pyridone compound as well as pharmaceutical composition and application thereof
  • 4 (1H)-pyridone compound as well as pharmaceutical composition and application thereof
  • 4 (1H)-pyridone compound as well as pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0257] The synthesis of embodiment 1 compound 26, 26-P1, 26-P2

[0258]

[0259] Reaction formula:

[0260]

[0261] The first step: the synthesis of compound 26-2

[0262] DAST (17.5g) was added to a solution of compound 26-1 (16g) in DCM (200mL) at 0°C, stirred at 25°C for 16 hours, washed with saturated sodium bicarbonate (100mL), extracted with DCM (100*3mL), It was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether) to obtain compound 26-2 (17.1 g, yield 97%).

[0263] The second step: the synthesis of compound 26-4

[0264] Compound 26-2 (2.4g), compound 26-3 (3.04g), potassium acetate (2.44g), Pd(dppf)Cl 2 (0.22g) was added to dioxane (50mL) solution, reacted at 85 degrees Celsius under the protection of reaction liquid nitrogen for 16 hours, added water (20mL) and extracted with ethyl acetate (20mL*3), the organic phase was concentrated under reduced pressure, and the residue Purification with silica gel co...

Embodiment 2

[0281] The synthesis of embodiment 2 compound 296, 296-P1, 296-P2

[0282]

[0283] Reaction formula:

[0284]

[0285] The first step: the synthesis of compound 296-6

[0286] Compound 296-4 (316mg), compound 296-5 (0.73g), sodium carbonate (0.42g), Pd(dppf)Cl 2 (0.29g) was added to a mixed solution of DME (50mL), ethanol (6mL) and water (6mL), reacted at 95 degrees Celsius for 16 hours under the protection of reaction liquid nitrogen, added water (20mL), extracted with ethyl acetate (20mL*3) , the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / petroleum ether=1 / 5) to obtain compound 296-6 (920 mg, yield 75%).

[0287] The second step: the synthesis of compound 296-7

[0288] Compound 296-6 (2.2 g) was added to THF (40 mL) solution at 25 degrees Celsius, NaBH 4 (1.02g), methanol (20mL), the reaction solution was stirred at 40°C for 16 hours, quenched by adding 5mL of ammonium chloride to the re...

Embodiment 3

[0309] The synthesis of embodiment 3 compound 28, 28-P1, 28-P2

[0310]

[0311] Reaction formula:

[0312]

[0313] The first step: the synthesis of compound 28-2

[0314] Compound 28-1 (12g), cesium carbonate (37.8g), and sodium difluorochloroacetate (22g) were successively dissolved in a mixed solution of DMF (450mL) and water (50mL), stirred at 100°C for 16 hours, then added with water (2000mL) Extracted with ethyl acetate (200 mL*3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether / ethyl acetate=20 / 1) to obtain compound 28-2 (11 g, yield 69%).

[0315] The second step: the synthesis of compound 28-3

[0316] Compound 28-2 (2g), bis-boron (2.4g), potassium acetate (1.9g), Pd(dppf)Cl 2 (170mg) was added to dioxane (80mL) solution, reacted at 100 degrees Celsius under the protection of reaction liquid nitrogen for 16 hours, added water (20mL) and extracted with ethyl acetate (20mL*3), the org...

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PUM

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Abstract

The invention discloses a 4 (1H)-pyridone compound as well as a pharmaceutical composition and application thereof. The invention provides a 4 (1H)-pyridone compound as shown in a formula I or a pharmaceutically acceptable salt of the 4 (1H)-pyridone compound. The compound can be used as an FXIa inhibitor; the compound can be used for preparing anticoagulant drugs and preventing and / or treating thrombus, such as human thrombotic diseases, including cerebral arterial thrombosis, deep vein thrombosis and the like.

Description

technical field [0001] The invention relates to a 4(1H)-pyridone compound, its pharmaceutical composition and application. Background technique [0002] Blood coagulation is the result of the coordinated activation of various plasma proteins, cofactors, and platelets. This cascade of reactions is divided into an intrinsic (contact activation) pathway, an extrinsic (tissue factor activation) pathway, and a common (prothrombin and thrombin generation) pathway. The most important physiological process during blood coagulation is the activation of tissue factor. Tissue factor forms a complex with factor VIIa, catalyzes the activation of factor ten (FX), and the activated FXa then cleaves prothrombin to generate activated thrombin (FIIa). Activated thrombin (FIIa), as the central catalytic enzyme of the blood coagulation process, catalyzes the cracking of fibrinogen into fibrin and plays a role in blood coagulation. The number of enzymes involved in the exogenous pathway is sm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10C07D213/68C07D401/14C07D213/81A61P9/10A61P9/00A61K31/4412A61K31/444A61K31/4439
CPCC07D401/10C07D213/68C07D401/14C07D213/81A61P9/10A61P9/00A61K31/4439A61K31/444A61K31/4412
Inventor 野国中栾林波唐春兰程一帆陈永凯王朝东
Owner SHANGHAI MEIYUE BIOTECH DEV
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