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Pentapeptide-modified warfarin containing gly-pro-arg-pro, its synthesis, activity and application

A technology of warfarin and liquid phase method, applied in the field of biomedicine, which can solve the problems of narrow warfarin safety window, fatal bleeding, and failure to obtain anti-venous thrombosis activity

Inactive Publication Date: 2021-11-30
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although warfarin was used in clinical practice as a representative drug in 1941, the safety window of warfarin is narrow
Underdose can cause pulmonary embolism, overdose risks fatal bleeding
Over the past 50 years, a large number of structural modifications have been made to warfarin, but there is no analogue that can obtain satisfactory anti-venous thrombosis activity

Method used

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  • Pentapeptide-modified warfarin containing gly-pro-arg-pro, its synthesis, activity and application
  • Pentapeptide-modified warfarin containing gly-pro-arg-pro, its synthesis, activity and application
  • Pentapeptide-modified warfarin containing gly-pro-arg-pro, its synthesis, activity and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1 prepares warfarin-4-O-acetic acid benzyl ester

[0017] 26.48g (80.00mmol) of warfarin and 400mL of acetone were stirred at 45°C until the warfarin was dissolved. 14 mL (88 mmol) benzyl bromoacetate was added to the obtained solution, and stirring was continued at 45° C. for 96 h. Thin layer chromatography (TLC, petroleum ether / ethyl acetate=2 / 1) showed that the reaction was complete. The reaction solution was filtered off, and the filtrate was concentrated under reduced pressure. The obtained pale yellow oil 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,...

Embodiment 2

[0018] Embodiment 2 prepares warfarin-4-O-acetic acid

[0019] 19.77 g (43.36 mmol) of benzyl warfarin-4-O-acetate was dissolved in 150 mL of tetrahydrofuran, and then suspended with 4.94 g of palladium on carbon (Pd / C). Pass hydrogen gas inside for 72h. TLC (petroleum ether / ethyl acetate=2 / 1) showed that the reaction was complete. The Pd / C was filtered off and the filtrate was concentrated under reduced pressure to afford 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

[0020] Embodiment 3 prepares Boc-Gly-Pro-OBzl

[0021] Dissolve 7.730g (44.15mmol) Boc-Gly in 100mL of anhydrous tetrahydrofuran, add 5.940g (44.00mmol) 1-hydroxybenzotriazole (HOBt) and 9.888g (48.00mmol) dicyclohexyl to the solution at 0°C Carbodiimide (DCC), stirred at 0°C for 30min and added 9.665g (40.00mmol) HCl·Pro-OBzl to it. The pH of the reaction solution was adjusted to 9 with N-methylmorpholine, stirred at room temperature for 17 h, and TLC (dichloromethane / methanol=20 / 1) showed that the reaction was complete. The insoluble matter in the reaction solution was filtered off, the filtrate was concentrated under reduced pressure, the residue was dissolved in 150 mL ethyl acetate, the colorless solid was filtered off, and the filtrate was washed with saturated NaHCO 3 Solution washing (50mL×3), saturated NaCl solution washing (50mL×3), 5% KHSO 4 Solution washing (50mL×3), saturated NaCl solution washing (50mL×3), saturated NaHCO 3 Solution washing (50mL × 3), saturat...

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Abstract

Pentapeptide-modified warfarin containing Gly-Pro-Arg-Pro, its synthesis, activity and application, the present invention discloses warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA of the following formula (wherein AA is Asp residue, Ile residue, Leu residue, Phe residue, Tyr residue and Val residue), discloses their preparation method, discloses their antivenous thrombosis activity, thus the present invention discloses Their application in the preparation of anti-venous thrombosis drugs has been discussed.

Description

technical field [0001] The present invention relates to warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA, to their preparation methods, to their anti-venous thrombosis activity, and thus the present invention relates to their use in the preparation of anti-venous thrombosis drugs application. The invention belongs to the field of biomedicine. Background technique [0002] Venous thrombosis has become a disease with high morbidity and mortality. Venous thrombosis mainly includes deep vein thrombosis and pulmonary embolism. The number of patients with deep vein thrombosis and pulmonary embolism not only exceeds the total number of myocardial infarction and stroke, but also exceeds the total number of deaths caused by breast cancer and AIDS. Since the incidence of venous thrombosis increases exponentially with age, it poses a particularly serious threat to the health of people in an aging country like my country. If the population base is taken into consideration, the absolute negati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/02A61K38/08A61P7/02
CPCA61K38/00C07K7/06
Inventor 赵明彭师奇王玉记吴建辉侯梦雨
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES