A blood coagulation factor Xa inhibitor containing bicyclic amide structure and its application

Abstract

The invention relates to the field of medicines related to venous thromboembolic diseases, and particularly relates to an FXa inhibitor containing a bicycle-amide structure, a preparation method of the FXa inhibitor and application of the FXa inhibitor in preparation of medicines for treating venous thromboembolic diseases. The inhibitor structure is as shown in the specification.

Description

technical field

[0001] The invention relates to the field of drugs for the treatment of venous thrombosis diseases. More specifically, the present invention relates to a FXa inhibitor containing a bicyclic amide structure that has a therapeutic effect on venous thrombosis, its preparation method, and its use in pharmacy. Background technique

[0002] Deterioration of coagulation ability is unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis, disseminated intravascular coagulation syndrome, after valve replacement An important factor in thrombosis during revascularization, reocclusion after revascularization, or thrombosis during cardiopulmonary bypass. In the arterial system, abnormal thrombosis is mainly related to coronary arteries, cerebrovascular and peripheral blood vessels, and diseases related to thrombotic closure of these vessels mainly include acu...

Examples

Embodiment 1

[0017] The synthesis of embodiment 1 compound I

[0018]

[0019] A. Synthesis of Compound III

[0020] Compound II (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) were dissolved in 10mL of dry DMF, stirred under cooling in an ice-water bath, slowly added dropwise from triphenylchloromethane (TrCl; 3.07g, 11mmol) and 10 mL of dry DMF solution. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction mixture was poured into 120 mL of ice water, CH 2 Cl 2 (50mL×3) was extracted, and the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound III, a white solid, ESI-MS, m / z=369 ([M+H] + ).

[0021] B. Synthesis of Compound V-1

[002...

Embodiment 2

[0027] The synthesis of embodiment 2 reference compound D-1

[0028] Compound D-1 is also a compound designed by the present inventors in the course of research (not yet disclosed).

[0029]

[0030] A. Synthesis of Compound III

[0031] Compound II (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) were dissolved in 10mL of dry DMF, stirred in an ice-water bath, slowly added dropwise from triphenylchloromethane (TrCl; 3.07g, 11mmol) and 10 mL of dry DMF solution. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction mixture was poured into 120 mL of ice water, CH 2 Cl 2 (50mL×3) was extracted, and the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromat...

Embodiment 3

[0038] Inhibitory test of embodiment 3 compound to FXa in vitro

[0039] 5% DMSO solution (10 μ L) of the embodiment compound to be tested and positive drug EDOXABAN (its concentration is set appropriately step by step), Tris buffer solution (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH7.4) (40 μ l) and 0.0625U / mL human FXa (EnzymeResearchLabolatories, Inc., dissolved and diluted (10 μl) with Tris buffer solution were put into the wells of a 96-well microplate, and a 750 μM aqueous solution (40 μl) of S2222 (Chromogenix Co.) was added to measure 10 Absorbance at 405 nm at room temperature for 1 minute, thereby measuring absorbance increase (ΔOD / min).As a negative control, Tris buffer was used instead of test compound.

[0040] According to the following formula, the percent inhibitory rate (%) at the initial concentration of the test compound and the final concentration of the test compound are respectively plotted on the ordinate and abscissa of the logarithmic orth...

technical field

[0001] The invention relates to the field of drugs for the treatment of venous thrombosis diseases. More specifically, the present invention relates to a FXa inhibitor containing a bicyclic amide structure that has a therapeutic effect on venous thrombosis, its preparation method, and its use in pharmacy. Background technique

[0002] Deterioration of coagulation ability is unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis, disseminated intravascular coagulation syndrome, after valve replacement An important factor in thrombosis during revascularization, reocclusion after revascularization, or thrombosis during cardiopulmonary bypass. In the arterial system, abnormal thrombosis is mainly related to coronary arteries, cerebrovascular and peripheral blood vessels, and diseases related to thrombotic closure of these vessels mainly include acu...

Examples

Embodiment 1

[0017] The synthesis of embodiment 1 compound I

[0018]

[0019] A. Synthesis of Compound III

[0020] Compound II (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) were dissolved in 10mL of dry DMF, stirred under cooling in an ice-water bath, slowly added dropwise from triphenylchloromethane (TrCl; 3.07g, 11mmol) and 10 mL of dry DMF solution. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction mixture was poured into 120 mL of ice water, CH 2 Cl 2 (50mL×3) was extracted, and the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound III, a white solid, ESI-MS, m / z=369 ([M+H] + ).

[0021] B. Synthesis of Compound V-1

[002...

Embodiment 2

[0027] The synthesis of embodiment 2 reference compound D-1

[0028] Compound D-1 is also a compound designed by the present inventors in the course of research (not yet disclosed).

[0029]

[0030] A. Synthesis of Compound III

[0031] Compound II (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) were dissolved in 10mL of dry DMF, stirred in an ice-water bath, slowly added dropwise from triphenylchloromethane (TrCl; 3.07g, 11mmol) and 10 mL of dry DMF solution. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction mixture was poured into 120 mL of ice water, CH 2 Cl 2 (50mL×3) was extracted, and the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromat...

Embodiment 3

[0038] Inhibitory test of embodiment 3 compound to FXa in vitro

[0039] 5% DMSO solution (10 μ L) of the embodiment compound to be tested and positive drug EDOXABAN (its concentration is set appropriately step by step), Tris buffer solution (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH7.4) (40 μ l) and 0.0625U / mL human FXa (EnzymeResearchLabolatories, Inc., dissolved and diluted (10 μl) with Tris buffer solution were put into the wells of a 96-well microplate, and a 750 μM aqueous solution (40 μl) of S2222 (Chromogenix Co.) was added to measure 10 Absorbance at 405 nm at room temperature for 1 minute, thereby measuring absorbance increase (ΔOD / min).As a negative control, Tris buffer was used instead of test compound.

[0040] According to the following formula, the percent inhibitory rate (%) at the initial concentration of the test compound and the final concentration of the test compound are respectively plotted on the ordinate and abscissa of the logarithmic orth...

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