CN107488213B - warfarin-4-O-acetyl-YIGSK, its synthesis, pharmacological activity and application - Google Patents
warfarin-4-O-acetyl-YIGSK, its synthesis, pharmacological activity and application Download PDFInfo
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Abstract
The invention discloses warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys, discloses a preparation method thereof, discloses the anti-arterial thrombosis activity thereof, discloses the activity of reducing the content of vitamin K in vivo, discloses the activity of reducing the content of blood coagulation factor II in vivo, and discloses the activity of inhibiting platelet aggregation. Therefore, the invention discloses the application of the compounds in preparing anti-arterial thrombosis medicaments, the application in preparing anti-venous thrombosis medicaments, the application in preparing medicaments for inhibiting platelet aggregation, the application in preparing vitamin K antagonists and the application in preparing blood coagulation factor II antagonists.
Description
Technical Field
The invention relates to warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys, a preparation method thereof, anti-arterial thrombosis activity thereof, an effect of reducing the content of vitamin K in vivo, an effect of reducing the content of blood coagulation factor II in vivo and an effect of inhibiting platelet aggregation. Therefore, the invention relates to the application of the vitamin K antagonist in preparing the anti-arterial thrombosis medicine, the anti-venous thrombosis medicine, the platelet aggregation inhibiting medicine, the vitamin K antagonist and the blood coagulation factor II antagonist. The invention belongs to the field of biological medicine.
Background
Both arterial and venous thrombosis have become diseases with a high incidence of morbidity and mortality. Wherein the venous thrombosis mainly comprises deep vein thrombosis and pulmonary embolism. The number of patients with deep vein thrombosis and pulmonary embolism exceeds the total number of patients with myocardial infarction and apoplexy, and is higher than the total number of deaths caused by breast cancer and AIDS. Because the incidence of arterial thrombosis and venous thrombosis increases exponentially with age, the threat of the two diseases to the health of people in the aging countries in China is particularly serious. If the population cardinality is considered, the absolute negative influence on the national civilization of China is particularly serious. Therefore, prevention and treatment of arterial thrombosis and venous thrombosis have been the focus of attention in the field of medicine. Although warfarin was used in clinical practice as a representative drug in 1941, its activity is manifested by a common complex role of its pharmacokinetic profile, coagulation factor metabolism, and availability of vitamin K. The dose-response relationship of warfarin shows great variability, which indicates that there is a great dose range for the anticoagulant therapy of warfarin and that there are great individual differences. Due to the narrow window of warfarin, under-dosing may lead to pulmonary embolism, while overdosing risks fatal bleeding. A great deal of structural modification is carried out on warfarin for more than 50 years in the past, but analogs with strong anti-thrombus activity and low bleeding side effect cannot be obtained. Contrary to the conventional thinking, the aim of the inventor for modifying the structure of warfarin is to convert warfarin into an analogue with double activities of resisting arterial thrombosis and resisting arterial thrombosis. However, it has not been satisfactory. Cell adhesion is involved in the development of various diseases in human. The adhesion between cells and the extracellular matrix, mediated by cell adhesion molecules, adhesion proteins, and their association with thrombosis has received attention from a wide range of researchers. The research of the polypeptide for inhibiting the cell adhesion activity aims to convert the polypeptide Tyr-Ile-Gly-Ser-Lys with the cell adhesion inhibition activity into an analogue with double activities of resisting arterial thrombosis and resisting venous thrombosis. However, it has not been satisfactory. After 5 years of exploration, the inventor finds that 4-bit of warfarin is modified by acetyl Tyr-Ile-Gly-Ser-Lys, and the generated warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys shows excellent anti-platelet aggregation activity on an in vitro anti-platelet aggregation model. Obviously, they are not prodrugs of warfarin. The antitarthrombosis activity of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is 1670 times stronger than that of aspirin, and the antitarthrombosis activity is 487 times stronger than that of warfarin. It can be seen that the present invention has significant technical advances. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first content of the invention is to provide warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys.
The second aspect of the present invention provides a method for synthesizing warfarin derivatives, comprising:
1. synthesizing warfarin-4-O-benzyl acetate;
2. synthesizing warfarin-4-O-acetic acid;
3. synthesizing HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl by adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst;
4. adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst, condensing warfarin-4-O-acetic acid with HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl;
5. synthesizing warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys.
The third content of the present invention is to evaluate the effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys on resisting arterial thrombosis.
The fourth aspect of the present invention is to evaluate the anti-venous thrombosis effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys.
The fifth aspect of the present invention is to evaluate the effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys in inhibiting platelet aggregation induced by Platelet Activating Factor (PAF), Thrombin (TH) and Adenosine Diphosphate (ADP).
The sixth aspect of the present invention is to evaluate the effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys in reducing the vitamin K content in vivo.
The seventh aspect of the present invention is to evaluate the effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys in reducing the content of blood coagulation factor II in vivo.
Drawings
FIG. 1 synthetic route for warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys (i) bromo-2-benzyl acetate, acetone, K2CO3,45℃；(ii)CH3OH,Pd/C,H2(ii) a (iii) DCC, HOBt, NMM, THF; (iv)4N hydrogen chloride in ethyl acetate; (v)2N NaOH;
figure 2 the anti-arterial thrombotic activity of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys, n ═ 10;
figure 3 warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys anti-thrombogenic activity, n ═ 10;
FIG. 4 inhibition of platelet aggregation induced by PAF, TH and ADP by warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys, where n is 3.
Figure 5 effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys on vitamin K content in vivo, n ═ 5;
FIG. 6 the effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys on F II content in rats, n ═ 5.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of warfarin-4-O-benzyl acetate
Placing 3.31g (10.00mmol) warfarin in 100mL eggplant bottle, adding about 40mL acetone, not completely dissolving, heating in 45 deg.C oil bath and stirring until warfarin is dissolved, adding 1.73mL (11.00mmol) bromine-2-benzyl acetate, continuing to react at 45 deg.C oil bath, and after about 1h, finding white solid attached to the bottleOn the bottle wall. After 48h of reaction, the progress of the reaction was monitored by thin layer chromatography (TLC, 2:1 petroleum ether/ethyl acetate), warfarin disappeared, the colorless solid produced by the reaction was filtered off, acetone was removed under reduced pressure to give a pale yellow oil, which was purified by silica gel column chromatography (8: 1 petroleum ether/ethyl acetate) to give 3.02g (65%) of the title compound as a colorless solid. ESI-MS (M/e) 457[ M + H]+；1H-NMR(300MHz,DMSO-d6)δ/ppm＝7.89(dd,J1＝3.0Hz,J2＝9.0Hz,1H),7.63(dt,J1＝3.0Hz,J2＝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,J1＝9.0Hz,J2＝18.0Hz,2H),2.11(s,3H)。
EXAMPLE 2 preparation of warfarin-4-O-acetic acid
2.26g (4.95mmol) of warfarin-4-O-benzyl acetate was dissolved in 20mL of methanol, 220mg of palladium on carbon (Pd/C) was added, air was pumped out of a water pump with stirring, hydrogen was introduced, and the operation was repeated 3 times with stirring at room temperature with hydrogen. The reaction was monitored by TLC for completion, Pd/C was removed by filtration, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was solidified with petroleum ether and triturated with anhydrous ether to give 1.72g (93%) of the title compound as a colorless solid. ESI-MS (M/e):367[ M + H]+；1H-NMR(300MHz,DMSO-d6):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,J1＝15.0Hz,J2＝30.0Hz,2H),3.54～3.47(m,2H),2.14(s,3H)。
EXAMPLE 3 preparation of Boc-Ile-Gly-OBzl
2.00g (8.65mmol) of Boc-Ile was dissolved in a 250mL eggplant flask with 50mL of anhydrous tetrahydrofuran, and 1.17g (8.66mmol) of HOBt and 1.78g (8.69mmol) of DCC were added under ice bath (0 ℃ C.) to activate for 30 min. There was a significant amount of DCU evolved. 1.75g (8.69mmol) of HCl & Gly-OBzl was dissolved in 50mL of anhydrous tetrahydrofuran, added to the reaction mixture in an ice bath, adjusted to pH 8-9 with N-methylmorpholine (NMM), stirred at room temperature for 4 hours, and then TLC (dichloromethane/methanol ═ TLC)35:1) monitoring the progress of the reaction, disappearance of the starting material spot, filtration of DCU, removal of the solvent from the filtrate under reduced pressure, dissolution of the residue in 100mL of ethyl acetate, filtration of the insoluble DCU, and respective addition of saturated Na to the filtrate2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated KHSO4Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated Na2CO3The solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3) was washed, and the ethyl acetate phase was dried over anhydrous sodium sulfate for 2 hours. The sodium sulfate was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 3.18g (97%) of a pale yellow solid. ESI-MS (M/e):379[ M + H]+。
EXAMPLE 4 preparation of HCl. Ile-Gly-OBzl
3.01g (7.96mmol) of Boc-Ile-Gly-OBzl was weighed into a 100mL eggplant flask, 20mL of anhydrous ethyl acetate was added thereto and dissolved completely, 10mL of a 4N ethyl acetate solution of hydrogen chloride was added thereto in an ice salt bath (-10 ℃ C.), and the reaction was stirred further in the ice bath. TLC (dichloromethane/methanol ═ 35:1) monitored the progress of the reaction, the starting material disappeared, the reaction mixture was concentrated under reduced pressure using a water pump, the residue was redissolved with anhydrous ethyl acetate and concentrated under reduced pressure, and this was repeated 3 times to give a yellow oil, which was soaked with anhydrous ether and concentrated under reduced pressure, and this was repeated 3 times to give 2.40g (96%) of a pale yellow syrupy residue.
EXAMPLE 5 preparation of Boc-Tyr-Ile-Gly-OBzl
2.23g (7.93mmol) of Boc-Tyr was dissolved in a 250mL eggplant flask with 50mL of anhydrous tetrahydrofuran, and 1.07g (7.92mmol) of HOBt and 1.92g (14.17mmol) of DCC were added under ice bath (0 ℃ C.) to activate for 30 min. There was a significant amount of DCU evolved. Dissolving 2.39g (7.58mmol) of HCl & Ile-Gly-OBzl in 70mL of anhydrous dry tetrahydrofuran, adding the mixture into the reaction solution under ice bath, adjusting the pH value to 8-9 by NMM, stirring the mixture at room temperature for 6h, monitoring the reaction completion by TLC (dichloromethane/methanol 20:1), filtering DCU, removing the solvent from the filtrate under reduced pressure, dissolving the residue by 100mL of dichloromethane, filtering insoluble DCU, and respectively using saturated Na for the filtrate2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated KHSO4Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated Na2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3) wash, twoThe chloromethane phase is dried over 4h with anhydrous sodium sulfate. The sodium sulfate was filtered off, the solvent was removed from the filtrate under reduced pressure to give a pale yellow solid, which was purified by column chromatography (dichloromethane/methanol 60:1) to give 3.78g (88%) of a colorless solid. ESI-MS (M/e) 542[ M + H]+。
EXAMPLE 6 preparation of Boc-Tyr-Ile-Gly
3.40g (6.28mmol) Boc-Tyr-Ile-Gly-OBzl was weighed into a 100mL eggplant flask, dissolved in 20mL methanol in ice bath (0 ℃) and adjusted to pH 12 with 2N NaOH aqueous solution, the reaction was stirred for about 4h, TLC (dichloromethane/methanol 20:1) monitored for the progress of the reaction, the starting point disappeared and saturated KHSO was added4The solution was adjusted to pH 7, concentrated under reduced pressure to remove methanol, adjusted to pH 3, extracted with ethyl acetate (40 mL. times.3), washed with saturated NaCl (40 mL. times.3), the ethyl acetate layer was dried over anhydrous sodium sulfate for 2h or more, the solvent was removed under reduced pressure, triturated with petroleum ether, filtered, and concentrated under reduced pressure to dryness to give 2.78g (98%) of a colorless oil.
EXAMPLE 7 preparation of Boc-Ser-Lys (Z) -OBzl
5.02g (24.48mmol) of Boc-Ser was dissolved in a 250mL eggplant flask with 80mL of anhydrous tetrahydrofuran, and 3.29g (24.37mmol) of HOBt and 5.98g (29.02mmol) of DCC were added under ice bath (0 ℃ C.) to activate for 30 min. There was a significant amount of DCU evolved. Dissolving 9.91g (24.37mmol) of HCl & Lys (Z) -OBzl in 50mL of anhydrous tetrahydrofuran, adding the mixture into the reaction solution under ice bath, adjusting the pH value to 8-9 by NMM, stirring the mixture at room temperature for 4h, monitoring the reaction progress by TLC (dichloromethane/methanol ═ 20:1), filtering out DCU after the raw material point disappears, removing the solvent from the filtrate under reduced pressure, dissolving the residue by 100mL of ethyl acetate, filtering out insoluble DCU, and respectively using saturated Na for the filtrate2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated KHSO4Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated Na2CO3The solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3) was washed, and the ethyl acetate phase was dried over anhydrous sodium sulfate for 2 hours. The sodium sulfate was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 11.10g (81%) of a pale yellow solid. ESI-MS (M/e):557[ M + H ]]+。
EXAMPLE 8 preparation of HCl Ser-Lys (Z) -OBzl
6.16g (11.07mmol) of Boc-Ser-Lys (Z) -OBzl was weighed into a 100mL eggplant flask, 30mL of anhydrous ethyl acetate was added thereto and dissolved completely, and 10mL of a 4N ethyl acetate solution of hydrogen chloride was added to the flask in an ice salt bath (-10 ℃ C.), and the reaction was stirred while maintaining the ice bath. TLC (dichloromethane/methanol ═ 20:1) monitored the progress of the reaction, the starting material disappeared, the reaction mixture was concentrated under reduced pressure using a water pump, the residue was redissolved with anhydrous ethyl acetate and concentrated under reduced pressure, repeated 3 times to give a yellow oil, which was soaked with anhydrous ether and concentrated under reduced pressure, repeated 3 times to give a pale yellow syrupy residue 5.44g (98%).
EXAMPLE 9 preparation of Boc-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl
5.02g (11.13mmol) of Boc-Tyr-Ile-Gly was dissolved in 250mL eggplant flask with 50mL of anhydrous tetrahydrofuran, and 1.49g (11.04mmol) of HOBt and 2.74g (13.31mmol) of DCC were added under ice bath (0 ℃ C.) to activate for 30 min. There was a significant amount of DCU evolved. Dissolving 5.44g (11.02mmol) of HCl, Ser-Lys (Z) -OBzl in 100mL of anhydrous tetrahydrofuran, adding the mixture into the reaction solution under ice bath, adjusting the pH value to 8-9 by NMM, stirring the mixture at room temperature for 10h, monitoring the reaction progress by TLC (dichloromethane/methanol 15:1), removing a raw material point, filtering DCU, removing the solvent from the filtrate under reduced pressure, dissolving the residue by 100mL of dichloromethane, filtering insoluble DCU, and respectively using saturated Na for the filtrate2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated KHSO4Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated Na2CO3The solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3) was washed, and the methylene chloride phase was dried over anhydrous sodium sulfate for 4 hours. The sodium sulfate was filtered off, the solvent was removed from the filtrate under reduced pressure to give a pale yellow solid, which was purified by column chromatography (dichloromethane/methanol ═ 15:1) to give 5.45g (55%) of a colorless solid. ESI-MS (M/e):890[ M + H]+。
EXAMPLE 10 preparation of HCl Tyr-Ile-Gly-Ser-Lys (Z) -OBzl
1.50g (1.69mmol) of Boc-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl was weighed into a 100mL eggplant flask, 5mL of anhydrous ethyl acetate was added thereto and dissolved completely, 10mL of a 4N ethyl acetate solution of hydrogen chloride was added thereto in an ice salt bath (-10 ℃), and the reaction was stirred in the ice bath. TLC (dichloromethane/methanol 15:1) monitored the progress of the reaction, the starting material disappeared, the reaction was concentrated under reduced pressure using a water pump, the residue was redissolved with anhydrous ethyl acetate and concentrated under reduced pressure 3 times to give a yellow oil, which was soaked with anhydrous ether and concentrated under reduced pressure 3 times to give a pale yellow syrupy residue 1.30g (93%).
EXAMPLE 11 preparation of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl
0.61g (1.67mmol) of warfarin-4-O-acetic acid was dissolved in 100mL eggplant bottles with 30mL of anhydrous tetrahydrofuran, and 0.22g (1.63mmol) of HOBt and 0.42g (2.03mmol) of DCC were added under ice bath (0 ℃ C.) to activate for 30 min. There was a significant amount of DCU evolved. Dissolving 1.30g (1.57mmol) of HCl & Tyr-Ile-Gly-Ser-Lys (Z) -OBzl in 30mL of anhydrous tetrahydrofuran, adding the solution into a reaction solution under an ice bath, adjusting the pH value to 8-9 by using NMM, stirring the reaction solution at room temperature for 8 hours, monitoring the reaction progress by TLC (dichloromethane/methanol ═ 20:1), removing a raw material point, filtering out DCU, removing the solvent from the filtrate under reduced pressure, dissolving the residue in 50mL of dichloromethane, filtering out insoluble DCU, and respectively using saturated Na for the filtrate2CO3Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated KHSO4Solution (40 mL. times.3), saturated NaCl solution (40 mL. times.3), saturated Na2CO3The solution (40 mL. times.3) and a saturated NaCl solution (40 mL. times.3) were subjected to extraction washing, and the methylene chloride phase was dried over anhydrous sodium sulfate for 2 hours. The sodium sulfate was filtered off, the solvent was removed from the filtrate under reduced pressure to give a pale yellow solid, which was purified by column chromatography (dichloromethane/methanol ═ 8:1) to give 0.98g (51%) of a colorless solid. ESI-MS (M/e):1139[ M + H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.30～8.07(m,3H),7.90(d,J＝8.1Hz,1H),7.68～7.60(m,2H),7.36(m,18H),7.08(t,J＝6.6Hz,2H),6.65(d,J＝7.5Hz,2H),5.10(d,J＝3.6Hz,2H),5.00(s,2H),4.83(m,1H),4.72(m,1H),4.40～4.36(m,2H),4.28～4.23(m,2H),3.79(m,3H),3.51(m,6H),2.96～2.76(m,4H),2.12(s,3H),1.76～1.64(m,2H),1.38～1.24(m,4H),1.33(m,2H),1.13(m,2H),0.85(m,6H)。
EXAMPLE 12 preparation of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys (warfarin-4-O-acetyl-YIGSK)
0.51g (0.45mmol) of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys(Z) -OBzl was dissolved in 20mL of methanol, 50mg of Pd/C was added, air was pumped out of the solution under stirring by a water pump, hydrogen was introduced, and the operation was repeated 3 times, and the reaction was stirred for about 10 hours at room temperature with introduction of hydrogen. TLC (dichloromethane/methanol ═ 10:1) monitored the progress of the reaction, the starting material point disappeared, Pd/C was filtered off, the filtrate was freed of solvent under reduced pressure, it was solidified with petroleum ether to a colorless solid, which was purified by column chromatography to give 131mg (32%) of the product as a colorless solid. Mp:157-160 deg.C;
ESI-MS(m/e):915[M+H]+；IR(cm-1):3281,3063,2938,1650,1565,1517,1453,1397,1354,1227,1199,1164,1147,1102,1069,1019,910,893,756,699,602；1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.44(d,J＝8.1Hz,1H),8.34(t,J＝7.8Hz,1H),8.27(dd,J1＝9.0Hz,J2＝14.1Hz,1H),8.16(m,1H),8.08(m,1H),7.71～7.60(m,3H),7.43～7.14(m,8H),7.02(t,J＝8.4Hz,2H),6.64(dd,J1＝2.4Hz,J2＝8.4Hz,2H),4.84(m,1H),4.67(m,1H),4.44～4.40(m,2H),4.28～4.25(m,2H),3.87(d,J＝5.7Hz,1H),3.81(m,2H),3.60～3.34(m,6H),2.96(m,1H),2.83(m,1H),2.71(m,2H),2.12(s,3H),1.72(m,2H),1.50(m,4H),1.30(m,2H),1.12(m,2H),0.84(t,J＝6.9Hz,3H),0.81(t,J＝9.3Hz,3H).
EXAMPLE 13 evaluation of the anti-arterial thrombotic Effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys
Experimental Material
Urethane (CAS: 51-79-6, national drug group chemical Co., Ltd.), heparin sodium (CAS: 9041-08-1, Bailingwei science Co., Ltd.), and physiological saline (Shijiazhuang four drugs Co., Ltd.).
Laboratory animal
SD strain rats, male, 200 + -20 g, purchased from Experimental animals technologies, Inc. of Wei Tongli, Beijing.
Experimental method an arteriovenous bypass thrombosis model is adopted in the experiment.
Bypass cannula preparation
The bypass intubation consists of three sections, wherein a polyethylene tube with the inner diameter of 1.0mm and the outer diameter of 2.0mm is heated and drawn into a thin tube with one end being an oblique opening, the length of the thin tube is 10.0cm, the thin tube is respectively a right carotid vein intubation and a left carotid artery intubation and is positioned at two ends of the bypass intubation; the middle section is composed of a polyethylene pipe with the inner diameter of 3.5mm, and the fixed length is 8.0 cm; the length of the silk thread with rough surface is fixed to 6.0cm, and the silk thread with 4.0 plus or minus 0.1mg weight and the same rough degree is selected.
Silanization is carried out on the inner walls of the three sections of polyethylene tubes by using 1% of silicon ether solution (1% of silicon oil in ether solution), after the polyethylene tubes are completely dried, silk threads are placed in the middle section of polyethylene tubes in the carotid artery intubation direction, the three sections of polyethylene tubes are assembled and fixed by using a sealing film, and the tubes are filled with heparin before intubation.
Grouping and dosing
The dose of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys of the compound is 0.1 mu mol/kg; the positive control aspirin dose is 167 mu mol/kg and 16.7 mu mol/kg, and the negative control is physiological saline
Preparation of the used reagent
The anesthetic is 20% urethane aqueous solution prepared by normal saline, and the anticoagulant is 42mg/100mL heparin sodium aqueous solution prepared by normal saline.
Experimental procedures
Rats were each gavaged at a dose of 0.3mL/100g body weight, and anesthetized 30min later by abdominal injection of a 20% urethane solution (0.7mL/100 g). Fixing a rat on a rat fixing plate in a supine position, cutting the skin of the neck, separating a right common carotid artery and a left external jugular vein, ligating the distal ends of the right common carotid artery and the left external jugular vein respectively by using an operation line, cutting a V-shaped small opening on the exposed left external jugular vein, inserting the inclined port of the vein end of the bypass cannula manufactured on the upper side into the proximal end of the opening of the left external jugular vein, fixing a blood vessel and a polyethylene tube at the cannula position by using the operation line, accurately injecting heparin sodium water solution through the bypass cannula at the dose of 0.1mL/100g of body weight, and ensuring that an injector does not withdraw from the polyethylene tube. Clamping the proximal end of the right common carotid artery by an artery clamp, cutting a V-shaped small opening on the exposed artery, taking the tip of the polyethylene tube down from the injector, inserting the tube into the proximal end of the right common carotid artery, fixing the artery blood vessel and the polyethylene tube by an operation line, loosening the artery clamp and establishing an extracorporeal circulation bypass.
The body temperature of a rat and the blood flow in a bypass cannula are kept smooth, after the body circulation is carried out for 15min, the venous end cannula is firstly cut to observe whether the blood circulation is smooth, a thrombus thread is taken out from the arterial end of the cannula, and after floating blood on the thread is absorbed on filter paper, the wet weight of the filter paper is weighed and recorded, which represents the anti-arterial thrombosis activity. Data were counted using t-test.
Results of the experiment
The data are shown in FIG. 2. The result shows that the thrombus weight (16.57 +/-3.65 mg) of the warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rat is obviously less than that of the normal saline treated rat (30.42 +/-3.49 mg, p is less than 0.05), which indicates that the 0.1 mu mol/kg of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys shows the activity of resisting arterial thrombus. And the thrombus weight of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rats at 0.1 mu mol/kg dose is not significantly different from the thrombus weight of aspirin treated rats at 167 mu mol/kg dose (19.87 +/-3.91 mg, p >0.05), while the aspirin at 16.7 mu mol/kg dose has no anti-arterial thrombus activity, which indicates that the anti-arterial thrombus activity of the compound warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is at least 1670 times stronger than that of aspirin. This is an unexpected technical effect.
EXAMPLE 14 evaluation of the anti-venous Thrombus Effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys
Experimental Material
Uratan (ethyl carbamate, CAS: 51-79-6, national drug group chemical reagents Co., Ltd.), normal saline (Shijiazhuang four drugs Co., Ltd.) warfarin sodium (CAS: 129-06-6, Bailingwei science and technology Co., Ltd.);
laboratory animal
SD strain rats, male, 250 + -20 g, purchased from Experimental animals technologies, Inc. of Wei Tongli, Beijing.
Experimental methods the rat inferior vena cava ligation model was used for the experiments.
Grouping and dosing
The dosage of the compound warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is 0.1 mu mol/kg, the dosage of a positive control warfarin is 4.87 mu mol/kg, and a negative control is physiological saline.
Preparation of the used reagent
The anesthetic is a 20% urethane solution prepared from normal saline.
Experimental procedures
The experimental rats were acclimatized and fasted for one day before surgery, and were administered with gavage at a dose of 0.3mL/100g body weight, administered in a gavage manner, and administered 30min later with a 20% urethane solution 2min before surgery for intraperitoneal anesthesia. Rats were fixed on a rat fixing plate, and 2mL of blood was taken from the carotid artery and used for measurement of blood-related indices. Preparing skin of abdomen of rat, sterilizing, opening abdominal cavity along the leucorrhea line, descending to coagulated gland, and ascending to expose one corner of liver. The organs such as small intestine in abdominal cavity are pulled out to expose inferior vena cava, and the pulled-out organs are wrapped with gauze soaked with normal saline. Blunt-separating connective tissue around blood vessel, exposing inferior vena cava and its branch, peeling off abdominal aorta and inferior vena cava below renal vein, ligating inferior vena cava at junction of inferior vena cava and left renal vein with suture soaked with physiological saline, placing organs such as intestine back into abdominal cavity according to anatomical position, and suturing abdominal cavity layer by layer with suture.
After the operation, the rat is placed in an environment with the temperature of 25-28 ℃ for circulation for 4h, after the abdominal cavity is opened, the branches of the rat are tied one by one, the 2cm inferior vena cava is taken out from the tying position of the junction of the inferior vena cava and the left renal vein, and the thrombus is taken out from the inferior vena cava. The blood weight was calculated and the results were counted using the t-test. The operation was performed alternately with two per group. The experimental data are shown in FIG. 3.
Results of the experiment
The result shows that the thrombus weight (8.80 +/-2.26 mg) of a rat treated by the compound 0.1 mu mol/kg warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is obviously smaller than the thrombus weight (22.93 +/-5.03 mg, p is less than 0.01) of a rat treated by normal saline, which indicates that the compound warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys shows the anti-vein thrombus activity. And the anti-venous thrombosis activity of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys has a dose dependence relationship. And the plug weight of the compound warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rat at the dose of 0.1. mu. mol/kg was significantly less than the plug weight of the warfarin treated rat at the dose of 4.87. mu. mol/kg (12.12 + -3.86 mg, p <0.01), indicating that the compound warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys has an anti-arterial thrombosis activity at least 487 times stronger than that of warfarin. This is an unexpected technical effect.
EXAMPLE 15 evaluation of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys for PAF, TH and ADP induced platelet aggregation
Inhibition of
Experimental materials:
sodium citrate (CAS: 68-04-2, national drug group chemical Co., Ltd.), physiological saline (Shijiazhuang Siyao Co., Ltd.), thrombin (TH, CAS:506-32-1, SIGMA reagent Co., Ltd.), adenosine diphosphate (ADP, CAS:58-64-0, SIGMA reagent Co., Ltd.), platelet activating factor (PAF, CAS:74389-68-7, SIGMA reagent Co., Ltd.).
Laboratory apparatus
Platelet aggregation apparatus: MODEL 700, CHRONO-LOG
Blood for experiment
Fresh pig carotid blood
Experiment grouping
The negative control of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is physiological saline.
Preparation of the used reagent
The anticoagulant is 3.8% sodium citrate solution prepared from normal saline, the platelet activator is 50U/mL TH solution prepared from normal saline, 1mM ADP solution prepared from normal saline, and 5 × 10 solution prepared from normal saline-5A solution of mpaf. The final concentration of inducer was 1U/mL TH, 20. mu. ADP M, PAF 1X 10-6mM。
Experimental methods
A blood collection bottle silanized and air dried one day in advance was charged with 50mL of an aqueous solution of sodium citrate (1: 9 ratio to blood). Collecting fresh pig carotid artery blood, shaking gently, rapidly centrifuging at 1000rpm for 10min, collecting supernatant to obtain Platelet Rich Plasma (PRP), centrifuging the rest blood at 3500rpm for 10min, and collecting supernatant to obtain Platelet Poor Plasma (PPP).
Add 500. mu.L of PPP to the cuvette on the platelet aggregation apparatus, to the PPP wells, add 480. mu.L of PRP to the cuvette, and to the PRP wells. The PRP used was incubated at 37 ℃ for 10min before measurement. After the instrument started running, the rotor was added and zeroed, 10 μ L of saline or compound aqueous solution was added to the PRP, followed by 10 μ L of platelet activation inducer. The change of the light transmittance is recorded, and the inhibition rate of the compound on platelet aggregation is calculated. The results of the experiment are shown in FIG. 4.
Results of the experiment
Experimental results show that warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys can inhibit platelet aggregation induced by PAF, TH and ADP. The inhibition rate of PAF-induced platelet aggregation is 36.4%; the inhibition rate of TH-induced platelet aggregation is 31.6%; the inhibition rate of ADP-induced platelet aggregation was 24.4%. warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys is not a prodrug because it inhibits platelet aggregation in vitro. This is an unexpected technical effect.
EXAMPLE 16 evaluation of the Effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys in reducing vitamin K content in rats
Experimental Material
Sodium citrate (CAS: 68-04-2, national drug group chemical Co., Ltd.), NS (Shijiazhuang Siyao Co., Ltd.), and distilled water.
Experimental sample
Example 14 warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys followed by carotid artery blood in rats.
Experimental methods
Detection was performed using rat vitamin K1 elisa kit.
Sample collection
Taking 3.8% sodium citrate solution as anticoagulant, collecting 0.1 mu mol/kg warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rat carotid blood, centrifuging at 4 ℃ and 1000rpm within 30min for 15min, and taking supernatant as a sample for detection.
Standard preparation
And (3) taking the standard substance out of the kit, diluting 150 mu L of original-time standard substance by using 150 mu L of standard substance diluent, fully mixing to obtain a standard substance S5, arranging 4 centrifuge tubes of 1.5mL in sequence, adding 150 mu L of sample diluent respectively, sucking 150 mu L of standard substance S5 into an S4 centrifuge tube, blowing and uniformly mixing, and sequentially preparing an S5-S1 standard substance. The concentrations of the standard were S5(6ng/mL), S4(3ng/mL), S3(1.5ng/mL), S2(0.75ng/mL), S1(0.375ng/mL) and S0(0ng/mL), respectively.
A blank hole, a standard hole and a serum hole to be detected are respectively arranged. Adding 50 mu L of standard substance into the enzyme-labeled coated plate, adding 40 mu L of sample diluent into the serum hole to be detected, adding 10 mu L of serum to be detected, and slightly shaking and uniformly mixing. The plates were sealed with a sealing plate and incubated at 37 ℃ for 30 min. Carefully remove the coversheet membrane, discard the liquid, and wash the plate 5 times. Adding 50 mu L of enzyme labeling reagent into each hole except the blank hole, incubating for 30min at 37 ℃, washing, adding 50 mu L of color development agent A into each hole, adding 50 mu L of color development agent B, shaking gently, mixing uniformly, and developing for 10min at 37 ℃ in a dark place. The reaction was stopped by adding 50. mu.L of stop solution to each well, and the absorbance (OD value) of each well was measured at a wavelength of 450nm while the blank wells were zeroed within 15 min. A standard curve was drawn according to the OD value of the standard, and the concentration of the serum sample was calculated, and the data are shown in FIG. 5.
Results of the experiment
As can be seen from the data in FIG. 5, the vitamin K content of 0.1. mu. mol/kg warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rats was significantly lower than that of saline treated rats (p <0.05), i.e., warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys reduced the vitamin K content in rats at a dose of 0.1. mu. mol/kg and was comparable to that of 4.87. mu. mol/kg warfarin treated rats. As can be seen, the activity of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys for reducing the content of vitamin K in the rat body is 48.7 times stronger than that of warfarin. This is an unexpected technical effect.
EXAMPLE 17 evaluation of the Effect of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys in reducing the level of clotting factor II in rats
Experimental Material
Sodium citrate (CAS: 68-04-2, national drug group chemical reagents, Inc.), physiological saline (Shijiazhuang Siyao, Inc.), pipette (Germany Prandde), distilled water;
experimental sample
EXAMPLE 14 post-warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys rat carotid blood
Experimental methods
The experiment was performed using a rat F II ELISA kit.
Collection of samples
Collecting 0.1 mu mol/kg warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated carotid artery blood of a rat by using a 3.8% sodium citrate solution as an anticoagulant, centrifuging the carotid artery blood for 15min at 1000rpm at 4 ℃ within 30min, and taking supernatant (blood plasma) as a sample for detection.
Preparation of standard substance
And (3) taking the standard substance out of the kit, diluting 150 mu L of original-time standard substance by using 150 mu L of standard substance diluent, fully mixing to obtain a standard substance S5, arranging 4 centrifuge tubes of 1.5mL in sequence, adding 150 mu L of sample diluent respectively, sucking 150 mu L of standard substance S5 into an S4 centrifuge tube, blowing and uniformly mixing, and sequentially preparing an S5-S1 standard substance. The concentrations of the standard were S5(6ng/mL), S4(3ng/mL), S3(1.5ng/mL), S2(0.75ng/mL), S1(0.375ng/mL) and S0(0ng/mL), respectively.
A blank hole, a standard hole and a serum hole to be detected are respectively arranged. Adding 50 mu L of standard substance into the enzyme-labeled coated plate, adding 40 mu L of sample diluent into the serum hole to be detected, adding 10 mu L of serum to be detected, and slightly shaking and uniformly mixing. The plates were sealed with a sealing plate and incubated at 37 ℃ for 30 min. Carefully remove the coversheet membrane, discard the liquid, and wash the plate 5 times. Adding 50 mu L of enzyme labeling reagent into each hole except the blank hole, incubating for 30min at 37 ℃, washing, adding 50 mu L of color development agent A into each hole, adding 50 mu L of color development agent B, shaking gently, mixing uniformly, and developing for 10min at 37 ℃ in a dark place. The reaction was stopped by adding 50. mu.L of stop solution to each well, and the absorbance (OD value) of each well was measured at a wavelength of 450nm while the blank wells were zeroed within 15 min. A standard curve was drawn according to the OD value of the standard, and the concentration of the serum sample was calculated, and the data are shown in FIG. 6.
Results of the experiment
As can be seen from the data in FIG. 6, the FII content of 0.1. mu. mol/kg warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys treated rats was significantly lower than that of saline treated rats (p <0.05), i.e., warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys reduced FII content in rats at a dose of 0.1. mu. mol/kg and was comparable to that of 4.87. mu. mol/kg warfarin treated rats. As can be seen, the activity of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys for reducing the FII content in the rat body is 48.7 times stronger than that of warfarin. This is an unexpected technical effect.
Claims (5)
1. The structure is warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys,
2. a method of making warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys according to claim 1, the method comprising:
(1) synthesizing warfarin-4-O-benzyl acetate;
(2) synthesizing warfarin-4-O-acetic acid;
(3) synthesizing HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl by adopting a liquid phase condensation method with Dicyclohexylcarbodiimide (DCC) as a condensing agent and 1-hydroxybenzotriazole (HOBt) as a catalyst;
(4) adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst, condensing warfarin-4-O-acetic acid with HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl;
(5) synthesizing warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys.
3. Use of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys of claim 1 in the preparation of an anti-thrombotic agent.
4. Use of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys of claim 1 in the preparation of a medicament for inhibiting platelet aggregation.
5. Use of warfarin-4-O-acetyl-Tyr-Ile-Gly-Ser-Lys of claim 1 in the preparation of a vitamin K antagonist.
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