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Warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, synthesis, activities and applications thereof

A technology of warfarin and acetyl, applied in warfarin-4-O-acetyl-Arg/Asp, its synthesis, activity and application fields

Inactive Publication Date: 2017-12-19
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, synthesis, activities and applications thereof
  • Warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, synthesis, activities and applications thereof
  • Warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, synthesis, activities and applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Embodiment 1 prepares warfarin-4-O-acetic acid benzyl ester

[0022] Put 3.31g (10.00mmol) of warfarin in a 100mL eggplant bottle, add about 40mL of acetone, but it cannot be completely dissolved, heat and stir in an oil bath at 45°C until the warfarin dissolves, add 1.73mL (11.00mmol) of bromine- 2-Benzyl acetate, continue to react in an oil bath at 45°C, and after about 1 hour, a white solid is found attached to the bottle wall. After 48 hours of reaction, the reaction progress was monitored by thin layer chromatography (TLC, petroleum ether / ethyl acetate=2:1), warfarin disappeared, and the colorless solid produced in the reaction was filtered off, and acetone was removed under reduced pressure to obtain a light yellow oil The product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 3.02 g (65%) of the title compound as a colorless solid. ESI-MS(m / e):457[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 )δ / ppm=7.89(dd,J 1 =3.0Hz,J ...

Embodiment 2

[0023] Embodiment 2 prepares warfarin-4-O-acetic acid

[0024] Dissolve 2.26g (4.95mmol) of warfarin-4-O-benzyl acetate in 20mL of methanol, add 220mg of palladium carbon (Pd / C), under stirring, pump out the air in the water pump, and pass in hydrogen, and repeat the operation Carry out 3 times, and stir at room temperature for 10 h by introducing hydrogen gas. The completion of the reaction was monitored by TLC, Pd / C was removed by filtration, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was solidified with petroleum ether, and washed with anhydrous ether to obtain 1.72 g (93%) of the title compound as a colorless solid. ESI-MS(m / e):367[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ):δ / ppm=12.86(s,1H),7.90(d,J=6.0Hz,1H),7.63(t,J=6.0Hz,1H),7.43~7.34(m,4H),7.27(t, J=9.0Hz, 2H), 7.17(t, J=9.0Hz, 1H), 4.99(t, J=9.0Hz, 1H), 4.75(q, J 1 =15.0Hz,J 2 =30.0Hz, 2H), 3.54~3.47(m, 2H), 2.14(s, 3H).

Embodiment 3

[0025] Embodiment 3 prepares warfarin-4-O-acetyl-Arg (NO 2 )-OBzl

[0026] Add 2.03g (5.55mmol) warfarin-4-O-acetic acid into a 100mL eggplant bottle and dissolve it with 30mL dry tetrahydrofuran, add 0.74g (5.48mmol) HOBt and 1.36g ( 6.60mmol) DCC, activated for 45min. A large amount of dicyclohexyl urea (DCU) was precipitated. 2.38g (5.48mmol) Tos Arg (NO 2 )-OBzl was dissolved in 30mL tetrahydrofuran, added to the reaction solution under ice bath, adjusted to pH 8-9 with N-methylmorpholine (NMM), stirred at room temperature for 8 hours, then TLC (dichloromethane / methanol=20:1) monitor the reaction process, the raw material point disappears, filter out DCU, remove the solvent from the filtrate under reduced pressure, dissolve the residue with 50mL ethyl acetate, filter out the insoluble DCU, and use saturated Na 2 CO 3 solution (40mL×3), saturated NaCl solution (40mL×3), saturated KHSO 4 solution (40mL×3), saturated NaCl solution (40mL×3), saturated NaCl 2 CO 3 solu...

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Abstract

The present invention discloses warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, preparation methods, anti-arterial thrombus activities, anti-venous thrombosis activities, in vivo vitamin K content lowering activities, in vivo blood coagulation factor II content lowering activities, and platelet aggregation inhibition activities thereof, such that the invention discloses applications of warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp in preparation of anti-arterial thrombus drugs, anti-venous thrombosis drugs, platelet aggregation inhibition drugs, vitamin K antagonists, and blood coagulation factor II antagonists.

Description

technical field [0001] The present invention relates to warfarin-4-O-acetyl-Arg and warfarin-4-O-acetyl-Asp, to their preparation methods, to their anti-arterial thrombosis activity, to their anti-venous thrombosis activity, to their Their function of reducing the content of vitamin K in the body involves their function of reducing the content of coagulation factor II in the body and their function of inhibiting platelet aggregation. Thus the present invention relates to their application in the preparation of anti-arterial thrombosis drugs, their application in the preparation of anti-venous thrombosis drugs, their application in the preparation of platelet aggregation inhibiting drugs, their use in the preparation of vitamin K antagonists and their use in the preparation of coagulation factor II Antagonist applications. The invention belongs to the field of biomedicine. Background technique [0002] Both arterial thrombosis and venous thrombosis have become diseases with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/56A61P7/02A61P9/10A61P3/00A61P3/02
CPCC07D311/56
Inventor 彭师奇赵明吴建辉王玉记张薪
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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