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Warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA1 as well as synthesis, activity and application thereof

A -gly-pro, warfarin technology, applied in the directions of active ingredients of heterocyclic compounds, medical preparations of non-active ingredients, drug combinations, etc., can solve problems such as large bleeding side effects due to dose differences

Pending Publication Date: 2022-01-14
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, warfarin has the disadvantages of large differences in individual dosage and serious bleeding side effects.

Method used

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  • Warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA1 as well as synthesis, activity and application thereof
  • Warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA1 as well as synthesis, activity and application thereof
  • Warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA1 as well as synthesis, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1 prepares warfarin-4-O-benzyl acetate (1)

[0023] Disperse 26.48g (80.00mmol) warfarin in 400mL acetone, stir at 45°C until the warfarin dissolves, add 12.1g (88.0mmol) K 2 CO 3 , then add 14mL (88mmol) benzyl bromoacetate, continue to stir at 45°C for 96 hours, TLC (petroleum ether / ethyl acetate, 2 / 1) shows that the raw material point disappears, filter, and concentrate the filtrate under reduced pressure to obtain a light yellow oil The compound was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 8 / 1) to obtain 19.77 g (54%) 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 =9.0Hz,1H),7.63(dt,J 1 =3.0Hz,J 2 =9.0Hz, 1H), 7.43~7.31(m, 9H), 7.24(t, J=9.0Hz, 2H), 7.15(tt, J=9.0Hz, 1H), 5.26(s, 2H), 5.61(s ,1H),5.02(d,J=15.0Hz,1H),4.85(d,J=15.0Hz,1H),4.97(t,J=9.0Hz,1H),3.45(dq,J 1 =9.0Hz,J 2 =18.0Hz, 2H), 2.11(s, 3H).

Embodiment 2

[0024] Embodiment 2 prepares warfarin-4-O-acetic acid (2)

[0025] Dissolve 19.77g (43.36mmol) of warfarin-4-O-benzyl acetate (1) in 150mL of tetrahydrofuran, add 4.94g of Pd / C and stir, remove the air, introduce hydrogen, and stir at room temperature for 72 hours. TLC (petroleum ether / ethyl acetate, 2 / 1) showed that the raw material point disappeared. After filtration, the filtrate was concentrated under reduced pressure to obtain 15.58 g (98.%) 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(dd, J 1 =15.0Hz,J 2 =30.0Hz, 2H), 3.54~3.47(m, 2H), 2.14(s, 3H).

Embodiment 3

[0026] Embodiment 3 prepares Boc-Gly-Pro-OBzl

[0027] Dissolve 7.730g (44.15mmol) Boc-Gly in 100mL dry tetrahydrofuran, add 5.940g (44.00mmol) 1-hydroxybenzotriazole and 9.888g (48.00mmol) dicyclohexylcarbodiimide at 0°C, stir 30 minutes. Add 9.665g (40.00mmol) HCl Pro-OBzl to the reaction solution at 0°C, adjust the pH value of the reaction solution to 9 with N-methylmorpholine, stir at room temperature for 17 hours, TLC (dichloromethane / methanol, 20 / 1) It shows that the raw material point disappears, filter, concentrate the filtrate under reduced pressure, dissolve the residue with 150mL ethyl acetate, filter, and use saturated NaHCO 3 Wash with aqueous solution (50mL×3), wash with saturated NaCl aqueous solution (50mL×3), 5% KHSO 4 Wash with aqueous solution (50mL×3), wash with saturated NaCl aqueous solution (50mL×3), and wash with saturated NaHCO 3 Wash with aqueous solution (50mL×3), wash with saturated NaCl aqueous solution (50mL×3), dry the ethyl acetate phase wit...

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Abstract

The invention discloses four kinds of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA compounds, a preparation method of the compounds, an advantage of the compounds without bleeding side effects, an antagonistic effect of the compounds on a blood coagulation factor II, and an antagonistic effect of the compounds on a tissue factor / blood coagulation factor VII, and discloses the venous thrombosis resisting effect of the compounds.

Description

technical field [0001] The present invention relates to four kinds of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA compounds, to their preparation methods, to their advantages of no bleeding side effects, to their activities and in the preparation of medicines Applications. The invention belongs to the field of biomedicine. Background technique [0002] Thrombotic disease is a disease that seriously threatens human life and health, and has the characteristics of high morbidity and mortality. Thromboembolic diseases can be divided into arterial thromboembolic diseases and venous thromboembolic diseases according to the location of thrombus formation, among which venous thromboembolic diseases (VTE) are the most common thrombotic diseases, and its main symptoms include deep vein thrombosis Thrombosis (DVT) and pulmonary embolism (PE), the mortality rate caused by PE is very high, and if DVT is neglected, it can also bring serious complications. The main clinical treatment of VTE ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06A61K31/37A61K47/64A61P7/02
CPCC07K7/06A61K31/37A61K47/64A61P7/02
Inventor 赵明彭师奇张筱宜侯梦雨
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES