Warfarin-4-O-acetyl-RGD tetrapeptides, synthesis, activities and applications thereof

A kind of technology of warfarin and acetyl, applied in Arg-Gly-Asp-Phe, relates to the field

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-RGD tetrapeptides, synthesis, activities and applications thereof
  • Warfarin-4-O-acetyl-RGD tetrapeptides, synthesis, activities and applications thereof
  • Warfarin-4-O-acetyl-RGD tetrapeptides, synthesis, activities and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Preparation of warfarin-4-O-benzyl acetate

[0030] 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 2 =9.0H...

Embodiment 2

[0031] Example 2 Preparation of warfarin-4-O-acetic acid

[0032] 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

[0033] Example 3 Preparation of Boc-Asp(OBzl)-Val-OBzl

[0034] Add 10.21g (31.61mmol) Boc-Asp (OBzl) to a 500mL eggplant bottle, dissolve it with 250mL anhydrous tetrahydrofuran, add 4.18g (30.97mmol) HOBt and 7.65g (37.16 mmol) DCC, activated for 30 min. A large amount of dicyclohexyl urea (DCU) was precipitated. Dissolve 11.73g (30.94mmol) Tos·Val-OBzl in 150mL of anhydrous tetrahydrofuran, add it to the reaction solution under ice-cooling, adjust the pH value to 8-9 with N-methylmorpholine (NMM), and After stirring the reaction at room temperature for 6 h, TLC (dichloromethane / methanol=30:1) monitored the reaction process, the raw material point disappeared, filtered off DCU, and the filtrate was decompressed to remove the solvent, the residue was dissolved in 100 mL of ethyl acetate, and the insoluble DCU, the filtrate was saturated Na 2 CO 3 solution (40mL×3), saturated NaCl solution (40mL×3), saturated KHSO 4 solution (40mL×3), saturated NaCl solution (40mL×3), sat...

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Abstract

The present invention discloses three materials such as warfarin-4-O-acetyl-Arg-Gly-Asp-Val, warfarin-4-O-acetyl-Arg-Gly-Asp-Ser and warfarin-4-O-acetyl-Arg-Gly-Asp-Phe, 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, platelet aggregation inhibition activities thereof, and in vivo platelet membrane glycoprotein IIb / IIIa (GPIIb / IIIa) content lowering activities thereof, and discloses the advantages of no warfarin-like bleeding risk in warfarin-4-O-acetyl-Arg-Gly-Asp-Val, warfarin-4-O-acetyl-Arg-Gly-Asp-Ser and warfarin-4-O-acetyl-Arg-Gly-Asp-Phe, such that the invention discloses applications of warfarin-4-O-acetyl-Arg-Gly-Asp-Val, warfarin-4-O-acetyl-Arg-Gly-Asp-Ser and warfarin-4-O-acetyl-Arg-Gly-Asp-Phe in preparation of anti-arterial thrombus drugs, anti-venous thrombosis drugs, platelet aggregation inhibition drugs, GPIIb / IIIa antagonists, vitamin K antagonists, and blood coagulation factor II antagonists.

Description

technical field [0001] The present invention relates to warfarin-4-O-acetyl-Arg-Gly-Asp-Val, warfarin-4-O-acetyl-Arg-Gly-Asp-Ser, warfarin-4-O-acetyl-Arg -Gly-Asp-Phe, related to their preparation method, related to their anti-arterial thrombosis activity, related to their anti-venous thrombosis activity, related to their effect of reducing the content of platelet membrane glycoprotein Ⅱb / Ⅲa (GPⅡb / Ⅲa) in vivo, It involves their function of reducing the content of coagulation factor II (FII) in the body, and their function of inhibiting platelet aggregation. Therefore the present invention relates to their application in the preparation of anti-arterial thrombosis drugs, the application in the preparation of anti-venous thrombosis drugs, the application in the preparation of platelet aggregation inhibiting drugs, the application in the preparation of GPⅡb / Ⅲa antagonists and the preparation of blood coagulation factors II Antagonist Applications. The invention belongs to the f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/11C07K1/02A61K38/07A61P7/02
CPCA61K38/00C07K5/1021
Inventor 彭师奇赵明吴建辉王玉记张薪
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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