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Heterocyclic compound and application thereof

A technology of heterocyclic compounds, applied in the field of heterocyclic compounds, can solve the problems of lethality, inability to protect patients from acute myocardial ischemia, low incidence of deep vein thrombosis, etc.

Pending Publication Date: 2021-02-09
SHANGHAI MEIYUE BIOTECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a limited sample size (115 patients) study showed that FXIa factor deficiency did not protect patients from acute myocardial ischemia, such patients were found to have a lower incidence of ischemic stroke and deep vein thrombosis
[0005] Selective knockout of common pathway factors (factors X, V, and II) and exogenous factors (tissue factor and factor VII) in mice results in prenatal or perinatal lethality in knockout mice
Factor VIII and factor IX knockout mice survived but often suffered from severe bleeding, similar to hemophilia A and B in humans where the lack of factors VIII and IX poses a risk of severe bleeding

Method used

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  • Heterocyclic compound and application thereof
  • Heterocyclic compound and application thereof
  • Heterocyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0225] Synthesis of target compounds 001, 001-P1, 001-P2

[0226]

[0227] Step 1: Preparation of Compound 2

[0228] Magnesium turnings (0.8 g) and a small particle of iodine were added to 20 mL of THF, benzyl bromide (2.7 g) was added dropwise at 25 degrees Celsius, and the mixture was stirred at room temperature for 2 hours. The prepared Grignard reagent was slowly added dropwise to a solution of compound 1 (3 g) in THF (20 mL) and stirred at 25 degrees Celsius for 1 hour. The reaction was quenched by adding 100 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL×3), the mixed organic phase was washed with concentrated brine (50 mL×2), dried and concentrated through the column, ethyl acetate: petroleum ether=1:5 A white solid product (ie compound 2, 2.5 g, 78% yield) was obtained. MS m / z (ESI): 404 [M+1].

[0229] Step 2: Preparation of Compound 3

[0230] Compound 2 (2.5 g) and p-toluenesulfonylmethylisonitrile (2.4 g) were dissol...

Embodiment 2

[0245]Synthesis of target compounds 002-P1 and 002-P2

[0246]

[0247] Step 1: Preparation of Compound 3

[0248] Compound 1 (41.5 g) was added to a 1000 mL single-neck flask, and the solvent DMF (400 mL) and water (40 mL) were added. Sodium 2-chloro-2,2-difluoroacetate (39.6 g) and potassium carbonate (41.5 g) were added to the reaction system, and the reaction was heated to 100 degrees Celsius for 16 hours. After the reaction, add water (300 mL) to dilute, extract twice with ethyl acetate (500 mL), wash once with brine (200 mL), and evaporate the organic phase to dryness at 45°C. Silica gel was added and the sample was mixed, and purified by column (PE) to obtain a yellow oily liquid (ie, compound 3, 46 g, yield 80%). MS m / z (GCMS): 256.

[0249] Step 2: Preparation of Compound 4

[0250] Compound 3 (46g) was added to a 1000mL single-necked bottle, a solvent dioxane (500mL) was added, pinacol biboronate (49.9g), potassium acetate (35g), Pd(dppf)Cl were added. 2 DCM...

Embodiment 3

[0278] Synthesis of target compounds 003-P1 and 003-P2

[0279]

[0280] Step 1: Preparation of Compound 2

[0281] Compound 1 (3.72g) was added to a 250mL single-neck bottle, solvent THF (50mL) was added, liquid nitrogen was cooled to -78 degrees Celsius under nitrogen protection, 2-methylpropylmagnesium bromide (2M in THF, 15mL) was slowly added Into the reaction system, the reaction mixture was naturally warmed to room temperature, and the reaction was carried out for a total of 4 hours. After the reaction, add water (50mL) to dilute, extract twice with ethyl acetate (100mL), wash once with brine (50mL), evaporate the organic phase to dryness at 45 degrees Celsius to obtain a yellow oily product (i.e. compound 2, 3.5g, yield: 90% ). MS m / z (ESI): 370 [M+1].

[0282] Step 2: Preparation of Compound 3

[0283]Compound 2 (3.7 g) was added to a 100 mL single-neck flask, solvent THF (50 mL), compound 9 (3.9 g) and t-BuOK (3.36 g) were added, and the reaction was carried o...

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PUM

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Abstract

The invention discloses a heterocyclic compound and application thereof. The invention provides a heterocyclic compound shown as a formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 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 thrombotic diseases of a human body, including cerebral arterial thrombosis and deep venous thrombosis diseases.

Description

technical field [0001] The present invention relates to a heterocyclic compound and its application. Background technique [0002] Blood coagulation is the result of coordinated activation of various plasma proteins, cofactors and platelets. This cascade is divided into an intrinsic (contact activation) pathway, an extrinsic (tissue factor activation) pathway, and a common (prothrombin and thrombin production) pathway. The most important physiological process in blood coagulation is the activation of tissue factor. Tissue factor forms a complex with factor VIIa, which catalyzes the activation of factor ten (FX), which in turn cleaves prothrombin to generate activated thrombin (FIIa). Activated thrombin (FIIa), as the central catalytic enzyme in the coagulation process, catalyzes the cleavage of fibrinogen into fibrin, and plays a role in coagulation. The number of enzymes involved in this exogenous pathway is small and the effect is quick. The endogenous pathway is the b...

Claims

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Application Information

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IPC IPC(8): C07D213/68C07D401/10C07D309/38C07D405/04A61K31/4412A61K31/4439A61K31/351A61K31/4427A61P9/10A61P7/02
CPCC07D213/68C07D401/10C07D309/38C07D405/04A61P9/10A61P7/02Y02P20/54
Inventor 刘世岚野国中李宁王朝东
Owner SHANGHAI MEIYUE BIOTECH DEV
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