CN113929742A - warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA 2 and synthesis, activity and application thereof - Google Patents
warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA 2 and synthesis, activity and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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Abstract
The invention discloses 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA in the formula)2Met residue, Ser residue, Thr residue and Trp residue), their preparation, their advantages without bleeding side effects, their antagonism against coagulation factor II, their antagonism against soluble fibrin monomer complex, and their anti-thrombogenic effects.
Description
Technical Field
The invention relates to 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA compounds, a preparation method thereof, the advantage of no bleeding side effect thereof, the antagonism of coagulation factor II, the antagonism of soluble fibrin monomer compound and the anti-vein thrombosis effect thereof. The invention thus relates to their use for preparing antagonists of coagulation factor II, to their use for preparing antagonists of soluble fibrin monomer complex, and to their use for preparing anti-thrombotic drugs without bleeding side effects. The invention belongs to the field of biological medicine.
Background
Thrombotic diseases are diseases seriously threatening the life and health of human beings, and have the characteristics of high morbidity and high mortality. According to the location of the formation of thrombus mass, the thrombotic diseases can be divided into arterial thromboembolic diseases and venous thromboembolic diseases, wherein the venous thromboembolic diseases (VTE) are the most common thrombotic diseases, the main symptoms of the venous thromboembolic diseases comprise Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE), the death rate caused by PE is high, and the DVT can bring serious complications if the DVT is kept away. The main clinical treatment regimen for VTE is anticoagulation therapy using anticoagulation drugs, and vitamin K1 antagonists, typified by warfarin, are among the most commonly used anticoagulation drugs. However, warfarin has the disadvantages of large individual dosage difference, serious bleeding side effect and the like. Defect to warfarin the inventors have disclosed warfarin-4-oxoacetyl-Gly-Pro-Arg-Pro (CN 107686506A) and warfarin-4-oxoacetyl-Gly-Pro-Arg-Pro-AA (AA is Ala, Glu, Gly, and Pro residues, CN 108976285A; and AA is Asp, Ile, Leu, Phe, Tyr, and Val residues, CN 108976284A). However, they do not antagonize tissue factor/factor VII in the sense of venous thrombosis. In further research and study efforts, the inventors found that warfarin-4-oxoacetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue) not only antagonizes coagulation factor II, but also antagonizes soluble fibrin monomer complex. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue) of the following formula.
The second aspect of the present invention provides a process for producing 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue or Trp residue), which comprises:
1) synthesizing warfarin-4-O-benzyl acetate;
2) synthesizing warfarin-4-O-acetic acid;
3) synthesizing Boc-Gly-Pro-OBzl;
4) converting Boc-Gly-Pro-OBzl into Gly-Pro-OBzl;
5) warfarin-4-O-acetic acid reacts with Gly-Pro-OBzl to synthesize warfarin-4-O-acetyl-Gly-Pro-OBzl;
6) converting warfarin-4-O-acetyl-Gly-Pro-OBzl into warfarin-4-O-acetyl-Gly-Pro;
7) synthesis of Boc-Arg (NO)2)-Pro-Met-OBzl,Boc-Arg(NO2)-Pro-Ser-OBzl,Boc-Arg(NO2) -Pro-Thr-OBzl and Boc-Arg (NO)2)-Pro-Trp-OBzl；
8) Boc-Arg (NO)2)-Pro-Met-OBzl,Boc-Arg(NO2)-Pro-Ser-OBzl,Boc-Arg(NO2) -Pro-Thr-OBzl and Boc-Arg (NO)2) Conversion of-Pro-Trp-OBzl to Arg (NO), respectively2)-Pro-Met-OBzl,Arg(NO2)-Pro-Ser-OBzl,Arg(NO2) -Pro-Thr-OBzl and Arg (NO)2)-Pro-Trp-OBzl；
9) warfarin-4-O-acetyl-Gly-Pro and Arg (NO)2)-Pro-Met-OBzl,Arg(NO2)-Pro-Ser-OBzl,Arg(NO2) -Pro-Thr-OBzl and Arg (NO)2) Synthesis of warfarin-4-O-acetyl-Gly-Pro-Arg (NO) by-Pro-Trp-OBzl reaction2) -Pro-Met-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Ser-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Thr-OBzl and warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Trp-OBzl；
10) warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Met-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Ser-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Thr-OBzl and warfarin-4-O-acetyl-Gly-Pro-Arg(NO2) -Pro-Trp-OBzl to 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue) of claim 1.
The third aspect of the present invention is to evaluate the antithrombotic activity of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue).
The fourth aspect of the present invention was to evaluate the bleeding side effects of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue).
The fifth aspect of the present invention was to evaluate the antagonistic action of 4 species of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue) on blood coagulation factor II.
The sixth aspect of the present invention was to evaluate the antagonistic action of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue) on the soluble fibrin monomer complex.
Drawings
FIG. 1. synthetic route for warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (AA is Met residue, Ser residue, Thr residue and Trp residue.) bromine-2-benzyl acetate, acetone, K2CO3,45℃；(ii)CH3OH,Pd/C,H2(ii) a (iii) Dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine, tetrahydrofuran; (iv) hydrogen chloride in ethyl acetate (4N); (v) trifluoroacetic acid, trifluoromethanesulfonic acid.
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 (1)
Dispersing 26.48g (80.00mmol) of warfarin in 400mL of acetone, stirring at 45 ℃ until warfarin is dissolved, adding 12.1g (88.0mmol) of K into the reaction solution2CO3Then 14mL (88mmol) of benzyl bromoacetate was added and stirring continued at 45 ℃ for 96 hours, TLC (petroleum ether/ethyl acetate, 2/1) showed spot quenching of the starting materialThe residue was filtered, the filtrate was concentrated under reduced pressure, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 8/1) to give 19.77g (54%) 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)
19.77g (43.36mmol) of warfarin-4-O-benzyl acetate (1) were dissolved in 150mL of tetrahydrofuran, 4.94g of Pd/C was added thereto and the mixture was stirred, and then air was purged and purged with hydrogen and stirred at room temperature for 72 hours. TLC (petroleum ether/ethyl acetate, 2/1) showed the starting material spot to disappear, filtered and the filtrate was concentrated under reduced pressure to give 15.58g (98%) 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(dd,J1＝15.0Hz,J2＝30.0Hz,2H),3.54～3.47(m,2H),2.14(s,3H)。
EXAMPLE 3 preparation of Boc-Gly-Pro-OBzl
7.730g (44.15mmol) of Boc-Gly were dissolved in 100mL of dried tetrahydrofuran, and 5.940g (44.00mmol) of 1-hydroxybenzotriazole and 9.888g (48.00mmol) of dicyclohexylcarbodiimide were added at 0 ℃ and stirred for 30 minutes. 9.665g (40.00mmol) HCl Pro OBzl is added to the reaction solution at 0 ℃, the pH value of the reaction solution is adjusted to 9 by N-methylmorpholine, the reaction solution is stirred for 17 hours at room temperature, TLC (dichloromethane/methanol, 20/1) shows that the raw material point disappears, the filtrate is filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in 150mL ethyl acetate and filtered, the filtrate is saturated NaHCO3Aqueous solution (50 mL. times.3), saturated aqueous NaCl solution (50 mL. times.3), 5% KHSO4Aqueous solution (50 mL. times.3), saturated aqueous NaCl solution (50 mL. times.3), saturated aqueous NaHCO solution3Aqueous wash (50 mL. times.3), saturated aqueous NaCl wash (50 mL)3), the ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated by evaporation under reduced pressure, and the resulting pale yellow solid was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1) to give 13.42g (92.7%) of the title compound as a colorless solid. ESI-MS (M/e) 363[ M + H]+。
EXAMPLE 4 preparation of HCl.Gly-Pro-OBzl
13.42g (37.05mmol) Boc-Gly-Pro-OBzl was dissolved in 50mL dry ethyl acetate, 100mL of 4N hydrogen chloride in ethyl acetate was added at 0 deg.C, the reaction was stirred at room temperature until TLC (dichloromethane/methanol, 10/1) showed completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in dry ethyl acetate and then concentrated under reduced pressure, and the resulting colorless oil was triturated with dry ether. Diethyl ether was decanted to give 10.85g (98.0%) of the title compound as a colorless, sticky solid. ESI-MS (M/e):263[ M + H]+。
EXAMPLE 5 preparation of warfarin-4-O-acetyl-Gly-Pro-OBzl (3)
The procedure of example 3 was used to obtain 21.07g (89%) of the title compound as a colorless solid from 15.58g (42.57mmol) of warfarin-4-O-acetic acid and 11.56g (38.70mmol) of HCl Pro-OBzl. ESI-MS (M/e):611[ M + H]+；1H NMR(300MHz,DMSO-d6)δ/ppm＝8.50(dd,J1＝5.7Hz,J2＝11.4Hz,1H),7.91(dt,J1＝1.5Hz,J2＝8.7Hz,1H),7.64(td,J1＝1.5Hz,J2＝6.0Hz,1H),7.43(d,J＝7.5Hz,4H),7.34(m,6H),7.29(t,J＝3.3Hz,2H),7.19(m,1H),5.15(m,2H),4.92(t,J＝7.5Hz,1H),4.58(t,J＝3.9Hz,2H),4.44(dd,J1＝3.9Hz,J2＝9.0Hz,1H),4.10(m,2H),3.61(m,2H),3.47(d,J＝7.2Hz,2H),2.22(m,1H),2.14(s,3H),1.99～1.76(m,3H)。
EXAMPLE 6 preparation of warfarin-4-O-acetyl-Gly-Pro (4)
21.07g (34.53mmol) of warfarin-4-O-acetyl-Gly-Pro-OBzl was dissolved in 100mL of tetrahydrofuran, 4.214g of Pd/C was added thereto, and the mixture was stirred, purged of air, charged with hydrogen, and stirred at room temperature for 3 days. TLC (dichloromethane/methanol, 15/1 with 2 drops of glacial acetic acid) showed the disappearance of the starting material spot, filtered and the filtrate was concentrated under reduced pressure to give 14.68g (82%) of the title compound as a colourless solid. ESI-MS (M/e):521[ M + H]+。
EXAMPLE 7 preparation of Boc-Pro-Arg-OBzl
Using the method of example 3 from 2.365g (11.00mmol) Boc-Pro and 4.357g (9.989mmol) tos.Arg (NO)2) OBzl gave 4.69g (84%) of the title compound as a pale yellow solid. ESI-MS (M/e):507[ M + H]+。
EXAMPLE 8 preparation of HCl Pro-Arg (NO)2)-OBzl
From 3.800g (7.510mmol) Boc-Pro-Arg-OBzl, 3.05g (100%) of the title compound was obtained as a light yellow powder by the method of example 4. ESI-MS (M/e):407[ M + H]+。
EXAMPLE 9 preparation of Boc-Pro-Met-OBzl
Using the method of example 3, from 2.372g (11.03mmol) Boc-Pro and 4.112g (10.00mmol) Tos. Met-OBzl was obtained 4.21g (96%) of the title compound as a light yellow oil. ESI-MS (M/e):437[ M + H]+。
EXAMPLE 10 preparation of HCl Pro-Met-OBzl
The procedure of example 4 was used to obtain 3.42g (100%) of the title compound as a colorless solid from 4.00g (9.17mmol) of Boc-Pro-Met-OBzl. ESI-MS (M/e):337[ M + H]+。
EXAMPLE 11 preparation of Boc-Arg (NO)2)-Pro-Met-OBzl
Using the method of example 3 from 3.153g (9.884mmol) Boc-Arg (NO)2) And 3.42g (9.18mmol) HCl Pro-Met-OBzl gave 3.88g (66%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6)δ/ppm＝8.47(m,1H),8.33(d,J＝7.5Hz,1H),7.36(m,5H),6.94(d,J＝7.5Hz,1H),5.11(m,2H),4.38(m,2H),4.14(m,1H),3.59(m,2H),3.11(m,2H),2.46(m,1H),2.01(s,3H),2.00～1.41(m,11H),1.37(s,9H)。
EXAMPLE 12 preparation of HCl.Arg (NO)2)-Pro-Met-OBzl
From 0.527g (0.83mmol) of Boc-Arg (NO) by the method of example 42) -Pro-Met-OBzl gave 0.475g (100%) of the title compound as a colorless solid. ESI-MS (M/e):538[ M + H]+。
EXAMPLE 13 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Met-OBzl(5a)
Starting from 0.475g (0.91mmol) of warfarin-4-O-acetyl-Gly-Pro (4) and 0.475g (0.83mmol) of HCl. Arg (NO) using the method of example 32) -Pro-Met-OBzl yielded 0.44g (51%) of the title compound as a colorless solid.1H NMR(500MHz,DMSO-d6)δ/ppm＝8.41(m,2H),8.31(m,1H),8.14(d,J＝7.7Hz,1H),7.88(m,1H),7.61(t,J＝8.0Hz,1H),7.39(m,1H),7.37～7.29(m,8H),7.23(t,J＝7.6Hz,2H),7.14(m,1H),5.09(m,2H),4.88(m,1H),4.55(m,2H),4.49(m,1H),4.39(m,2H),4.29(m,1H),4.03(m,2H),3.66～3.37(m,4H),3.43(d,J＝7.3Hz,2H),3.10(m,2H),2.44(m,2H),2.11(s,3H),1.98(s,3H),1.97～1.55(m,14H)。
EXAMPLE 14 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-Met (6a)
110mg (0.11mmol) of warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Met-OBzl (5a) was dissolved in 4mL of trifluoroacetic acid, followed by dropwise addition of 1.5mL of trifluoromethanesulfonic acid, reaction at 0 ℃ for 1 hour, and TLC (ethyl acetate/glacial acetic acid/water, 3/1/1) showed disappearance of starting material spot. The reaction mixture was concentrated at 0 ℃ under reduced pressure, the residue was triturated with 30mL of ice-cold diethyl ether, left to stand for 10 minutes and the supernatant solution was decanted again. Finally, the residue was dissolved in 2mL of water, the pH of the solution was adjusted to 7 with 10% aqueous ammonia at 0 ℃, filtered to give 3mL of a light yellow solution, which was initially purified by Sephadex-G10 gel filtration chromatography, the eluate monitored for UV coloration by TLC was collected and lyophilized to give 40mg (40%) of the title compound as a colorless solid. ESI-MS (M/e):903[ M-H]-；1H NMR(500MHz,DMSO-d6):δ/ppm＝9.63(m,1H),8.39(m,1H),8.22(d,J＝7.3Hz,1H),7.88(m,1H),7.62(m,1H),7.41(d,J＝8.4Hz,1H),7.39～7.33(m,3H),7.24(d,J＝7.5Hz,2H),7.15(t,J＝7.4Hz,2H),7.10(m,2H),4.88(m,1H),4.55(d,J＝5.5Hz,2H),4.49(m,1H),4.37(dd,J1＝8.4Hz,J2＝3.3Hz,1H),4.19(m,1H),4.03(m,2H),3.70(m,3H),3.56～3.41(m,2H),3.44(d,J＝7.4Hz,2H),3.07(m,2H),2.33(m,2H),2.12(s,3H),2.04(m,2H),1.97(m,3H),1.91～1.75(m,10H),1.59～1.47(m,2H)。
EXAMPLE 15 preparation of Boc-Pro-Ser-OBzl
Using the procedure of example 3 from 2839g (13.20mmol) Boc-Pro and 2.775g (11.98mmol) HCl Ser-OBzl gave 4.70g (100%) of the title compound as yellow oil. ESI-MS (M/e) 393[ M + H ]]+。
EXAMPLE 16 preparation of HCl Pro-Ser-OBzl
From 4.70g (11.98mmol) Boc-Pro-Ser-OBzl, 3.77g (96%) of the title compound was obtained as a pale yellow solid powder using the method of example 4. ESI-MS (M/e):293[ M + H]+。
EXAMPLE 17 preparation of Boc-Arg (NO)2)-Pro-Ser-OBzl
Starting from 4.204g (13.18mmol) of Boc-Arg (NO) using the method of example 32) And 3.77g (11.5mmol) HCl Pro-Ser-OBzl to give 5.91g (87%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6):δ/ppm＝8.47(s,1H),8.25(d,J＝7.5Hz,1H),7.36(s,5H),6.93(d,J＝7.6Hz,1H),5.10(m,2H),4.43(m,1H),4.36(m,1H),4.14(m,1H),3.77(m,1H),3.62(m,2H),3.52(m,1H),3.11(m,2H),1.98～1.47(m,8H),1.36(s,9H)。
EXAMPLE 18 preparation of HCl Arg (NO)2)-Pro-Ser-OBzl
From 1.483g (2.500mmol) of Boc-Arg (NO) by the method of example 42) -Pro-Ser-OBzl gave 1.32g (100%) of the title compound as a colorless solid. ESI-MS (M/e):494[ M + H)]+。
EXAMPLE 19 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Ser-OBzl(5b)
From 1.426g (2.741mmol) of warfarin-4-O-acetyl-Gly-Pro (4) and 1.32g (2.50mmol) of HCl.Arg (NO) using the method of example 32) -Pro-Ser-OBzl gave 1.22g (49%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6)δ/ppm＝8.44(m,2H),8.26(m,1H),8.15(m,1H),7.90(d,J＝7.8Hz,1H),7.63(m,1H),7.38(m,2H),7.35(m,7H),7.26(t,J＝7.2Hz,2H),7.18(m,1H),5.11(m,3H),4.90(t,J＝7.2Hz,1H),4.58(m,2H),4.40(m,4H),4.05(m,2H),3.78(m,2H),3.56(m,2H),3.46(d,J＝7.2Hz,2H),3.12(s,2H),2.14(s,3H),2.10～1.40(m,12H)。
EXAMPLE 20 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-Ser (6b)
From 320mg using the method of example 14(0.32mmol) warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Ser-OBzl (5b) gave 130mg (47%) of the title compound as a colorless solid. ESI-MS (M/e):859[ M-H]-；1H NMR(300MHz,DMSO-d6):δ/ppm＝9.43(m,1H),8.41(m,1H),8.25(d,J＝7.2Hz,1H),7.90(m,1H),7.64(m,1H),7.45～7.35(m,5H),7.29～7.15(m,6H),4.91(m,1H),4.58(d,J＝2.7Hz,2H),4.51(m,2H),4.41(dd,J1＝8.1Hz,J2＝3.0Hz,1H),4.24(m,1H),4.05(m,2H),3.71(m,2H),3.63(m,4H),3.47(d,J＝7.2Hz,2H),3.10(m,2H),2.14(s,3H),2.08～1.53(m,12H)。
EXAMPLE 21 preparation of Boc-Pro-Thr-OBzl
From 0.591g (2.75mmol) Boc-Pro and 0.953g (2.50mmol) tos.Thr-OBzl, 1.00g (99%) of the title compound was obtained as a light yellow oil using the method of example 3. ESI-MS (M/e):407[ M + H]+。
EXAMPLE 22 preparation of HCl Pro-Thr-OBzl
From 1.00g (2.46mmol) Boc-Pro-Thr-OBzl, 0.842g (100%) of the title compound was obtained as a colorless solid by the method of example 4. ESI-MS (M/e):307[ M + H]+。
EXAMPLE 23 preparation of Boc-Arg (NO)2)-Pro-Thr-OBzl
Using the method of example 3, from 0.702g (2.20mmol) of Boc-Arg (NO)2) And 0.685g (2.00mmol) HCl Pro-Thr-OBzl gave 0.852g (70%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6)δ/ppm＝8.46(s,1H),8.00(d,J＝8.4Hz,1H),7.35(m,5H),6.93(d,J＝7.8Hz,1H),5.12(m,2H),5.00(d,J＝5.1Hz,1H),4.51(m,1H),4.30(dd,J1＝8.4Hz,J2＝3.0Hz,1H),4.17(m,1H),3.57(m,2H),3.12(s,2H),2.01～1.45(m,8H),1.37(s,9H),1.08(d,J＝6.3Hz,3H)。
EXAMPLE 24 preparation of HCl.Arg (NO)2)-Pro-Thr-OBzl
Using the method of example 4, from 0.759g (1.25mmol) of Boc-Arg (NO)2) Pro-Thr-OBzl gave 0.679g (100%) of the title compound as a pale yellow solid. ESI-MS (M/e):508[ M + H]+。
EXAMPLE 25 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Thr-OBzl(5c)
The procedure of example 3 was used to separate the reaction mixture from 0.715g (1.37mmol) of warfarin-4-O-acetyl-Gly-Pro (4) and 0.679g (1.25mmol) of HCl. Arg (NO)2) Pro-Thr-OBzl gave 0.724g (57%) of the title compound as a colorless solid. ESI-MS (M/e):1008[ M-H [)]-
EXAMPLE 26 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-Thr (6c)
From 123mg (0.12mmol) of warfarin-4-O-acetyl-Gly-Pro-Arg (NO) using the method of example 142) -Pro-Thr-OBzl (5c) gave 57mg (54%) of the title compound as a colorless solid. ESI-MS (M/e):873[ M-H]-；1H NMR(500MHz,DMSO-d6):δ/ppm＝9.34(s,1H),8.40(m,1H),8.22(d,J＝7.4Hz,1H),7.88(m,1H),7.62(m,1H),7.42～7.33(m,5H),7.24(t,J＝7.5Hz,3H),7.15(m,2H),7.04(m,1H),4.88(m,1H),4.56(d,J＝5.8Hz,2H),4.51(m,1H),4.38(dd,J1＝8.4Hz,J2＝3.2Hz,1H),4.22(m,1H),4.03(m,2H),3.90(m,1H),3.68～3.63(m,3H),3.60～3.47(m,2H),3.44(d,J＝7.4Hz,2H),3.08(m,2H),2.12(s,3H),2.05～1.50(m,12H),0.89(m,3H)。
EXAMPLE 27 preparation of Boc-Pro-Trp-OBzl
From 2.364g (11.00mmol) Boc-Pro and 3.306g (9.996mmol) HCl. Trp-OBzl, 4.83g (98%) of the title compound were obtained as a yellow solid by the method of example 3. ESI-MS (M/e):492[ M + H]+。
EXAMPLE 28 preparation of HCl Pro-Trp-OBzl
From 4.83g (9.84mmol) Boc-Pro-Trp-OBzl, 4.20g (100%) of the title compound were obtained as a brown solid using the method of example 4. ESI-MS (M/e):392[ M + H]+。
EXAMPLE 29 preparation of Boc-Arg (NO)2)-Pro-Trp-OBzl
Using the method of example 3 from 3.478g (10.90mmol) of Boc-Arg (NO)2) And 4.20g (9.82mmol) HCl Pro-Trp-OBzl gave 2.42g (36%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6)δ/ppm＝10.90(s,1H),8.35(d,J＝7.2Hz,1H),7.48(d,J＝7.8Hz,1H),7.36(d,J＝8.1Hz,1H),7.30(m,3H),7.16(s,1H),7.14(m,2H),7.10(m,1H),6.96(m,2H),5.03(m,2H),4.51(m,1H),4.41(m,1H),4.12(m,1H),3.52(m,2H),3.12(m,4H),2.09～1.40(m,8H),1.37(s,9H)。
EXAMPLE 30 preparation of HCl.Arg (NO)2)-Pro-Trp-OBzl
From 1.501g (2.168mmol) Boc-Arg (NO) by the method of example 42) -Pro-Trp-OBzl gave 1.37g (100%) of the title compound as a dark green solid. ESI-MS (M/e):593[ M + H]+。
EXAMPLE 31 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Trp-OBzl(5d)
From 1.236g (2.376mmol) of warfarin-4-O-acetyl-Gly-Pro (4) and 1.358g (2.161mmol) of HCl. Arg (NO) by the method of example 32) -Pro-Trp-OBzl gave 1.17g (49%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6)δ/ppm＝8.42(m,2H),8.33(m,1H),8.15(d,J＝7.8Hz,1H),7.89(m,1H),7.63(m,1H),7.48(d,J＝7.8Hz,1H),7.42(m,2H),7.36(m,3H),7.27(m,5H),7.16(m,4H),7.08(m,1H),6.95(m,1H),4.98(m,2H),4.90(m,1H),4.57(m,2H),4.52(m,2H),4.41(m,2H),4.06(m,2H),3.55(m,4H),3.46(d,J＝7.2Hz,2H),3.15(m,4H),2.13(s,3H),2.10～1.40(m,12H)。
EXAMPLE 32 preparation of warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-Trp (6d)
From 386mg (0.35mmol) of warfarin-4-O-acetyl-Gly-Pro-Arg (NO) using the method of example 142) Pro-Trp-OBzl (5d) gives 128mg (38%) of the title compound as a colorless solid. ESI-MS (M/e):961[ M + H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝8.43(m,1H),8.20(d,J＝7.2Hz,1H),7.89(m,1H),7.64(m,1H),7.46(m,2H),7.38(m,3H),7.26(m,3H),7.19～7.06(m,4H),7.00(m,1H),6.94～6.87(m,2H),4.90(t,J＝7.5Hz,1H),4.57(d,J＝3.0Hz,2H),4.49(m,1H),4.37(m,1H),4.19(m,1H),4.03(m,2H),3.91(m,1H),3.52(m,4H),3.46(d,J＝7.5Hz,2H),3.12(m,2H),3.02(m,2H),2.14(s,3H),2.10～1.24(m,12H)。
EXAMPLE 33 evaluation of the antithrombotic Effect of 6a-d
Experimental Material
Uratan (Ethyl carbamate, CAS:51-79-6, national pharmaceutical group chemical Co., Ltd.), warfarin sodium (CAS:129-06-6, Bailingwei science and technology Co., Ltd.).
Laboratory animal
Male SD rats (250. + -.20 g) purchased from Experimental animals technology, Inc. of Weitongli, Beijing. For evaluation, the rat inferior vena cava ligation model was prepared.
Dosage to be administered
4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA (wherein AA is Arg residue, Asn residue, Gln residue and Lys residue) of the invention is dissolved in normal saline, and the dosage is 0.82 mu mol/kg; dissolving the positive control warfarin in normal saline, wherein the dosage is 0.82 mu mol/kg; the negative control was physiological saline.
Experimental procedures
Rats were acclimatized and fasted for one day prior to surgery, and were gavaged with a saline solution of compounds 6a-d at a dose of 0.1 μmol/kg; or a normal saline solution of warfarin, the dosage is 4.87 mu mol/kg; or physiological saline. Rats were anesthetized with a 20% urethane solution by intraperitoneal administration 30 minutes after administration and 2 minutes before surgery. Then fixing on a rat fixing plate, preparing skin at the abdomen, sterilizing, opening the abdominal cavity along the leucorrhea line, and getting up to expose one corner of the liver, wherein the opening is about 4cm long. The organs such as small intestine in the abdominal cavity were removed and wrapped with gauze soaked with normal saline. Blunt separating connective tissues around blood vessels, exposing inferior vena cava and branches thereof, peeling off the abdominal aorta and the inferior vena cava below the left renal vein, ligating the inferior vena cava at the junction of the inferior vena cava and the left renal vein by using a suture soaked by normal saline, moving organs such as intestines back to the abdominal cavity according to anatomical positions, suturing the abdominal cavity layer by using the suture, and then placing the rat in an environment at 25-28 ℃ for circulation for 4 hours. Then, the patient is subjected to ether anesthesia, the abdominal cavity is opened, the branch vessels of the inferior vena cava are ligated one by one, the inferior vena cava with the length of 2cm is extracted from the ligation site at the junction of the inferior vena cava and the left renal vein, and the thrombus is extracted from the inferior vena cava. Blood was reserved as samples for the determination of factor II and tissue factor/factor VII. The thrombus was weighed and the results were counted using the T-test. The operation was performed alternately with four of each group. The thrombus weights are shown in Table 1.
TABLE 1 treatment of venous thrombosis in rats
a) The ratio of P to normal saline is less than 0.01; b) p < 0.01 to normal saline, P >0.05 to Warfarin, n-8
The data in Table 1 show that compound 6a-d effectively inhibits venous thrombosis in rats at an oral dose of 0.1 μmol/kg for 4 hours of treatment. Therefore, the invention has obvious technical effect. Furthermore, compounds 6a-d of the present invention were at least 48.7 times more active than warfarin in against venous thrombosis.
EXAMPLE 34 evaluation of the Effect of 6a-d on bleeding time
The rats of example 33 were anesthetized before embolectomy, and then a 2mm deep wound was opened with a scalpel at 8cm from the rat tail, while timing was started, blood was wiped off with filter paper every 5 seconds, and timing was stopped when no blood stain was visible on the filter paper, and the time was recorded as the tail bleeding time of the rats. The bleeding time was counted by means of the T test. The operation was performed alternately with four of each group. The bleeding time is shown in table 2.
TABLE 2 treatment of rat tail bleeding time
a) The ratio of P to the normal saline and 6a-d is less than 0.01; n is 11
The data in Table 2 show that the compounds 6a-d treated at an oral dose of 0.1. mu. mol/kg for 4 hours showed no difference in the tail bleeding time of the rats from saline treated rats, whereas warfarin treated at an oral dose of 4.87. mu. mol/kg for 4 hours showed a significantly longer tail bleeding time than saline treated rats, indicating significant bleeding side effects. Compounds 6a-d did not cause a bleeding event similar to warfarin and were safer than warfarin. It can be seen that the present invention has an unexpected technical effect.
Example 35 evaluation of the Effect of 6a-d on clotting time
The rats of example 33 were anesthetized before they had their abdomen laid down on a rat plate, their rat tails were wiped with absorbent cotton balls dipped with medical alcohol to sterilize them, 8cm was measured from the rat tail tip with a ruler and marked, a blood vessel located at the center of the rat tail was found at a position about in the middle of the rat tail, a wound about 5mm long and about 2mm deep was cut with a surgical blade, and a drop of blood was immediately taken with a glass plate and a timer was started when blood flowed out. And repeatedly picking up a blood drop by using the needle tip of the syringe, wherein the frequency is about 2 times/second, and the timing is stopped until the needle tip can pick up the filamentous thrombus, so that the obtained time is the blood coagulation time of the rat. The obtained clotting times were counted using the t-test. The operation was performed alternately with four of each group. The clotting times are shown in Table 3.
TABLE 3 clotting time in treated rats
a) The ratio of P to normal saline and 6a-d is less than 0.01; n-10
The data in Table 3 show that the rat tail clotting time of rats treated with compounds 6a-d at an oral dose of 0.1 μmol/kg was not different from that of saline treated rats for 4 hours, whereas the tail clotting time of warfarin treated with warfarin at an oral dose of 4.87 μmol/kg was significantly longer than that of saline treated rats for 4 hours, showing significant bleeding side effects. Compounds 6a-d did not cause a bleeding event similar to warfarin and were safer than warfarin. It can be seen that the present invention has an unexpected technical effect.
Example 36 evaluation of the Effect of 6a-d on the International normalized ratio in rats
The international normalized ratio reflects prothrombin time and can be automatically calculated by a semi-automatic hemagglutination instrument (model TS6000, MD Pacific). The specific test method is that 3.6 mL/rat whole blood collected in example 33 is placed in a centrifuge tube containing 0.4mL sodium citrate solution (3.8%), centrifuged at 2500g for 15 minutes, then platelet plasma (PPP) for upper layer anemia is sucked, 100. mu.L PPP is added into a test cup, a test magnetic bead is added, a sample to be tested is pre-warmed in a pre-warm area of the instrument for 180 seconds, then 200. mu.L prothrombin time test solution (kit cat # 20-7011, MD Pacific) is added, the instrument starts to automatically detect to obtain prothrombin time, and automatically calculates the international standardized ratio, and the statistical result by means of T test shows that the international standardized ratio is shown in Table 4.
TABLE 4 International normalized ratio of treated rats
a) The ratio of P to normal saline and 6a-d is less than 0.01; n-10
The data in Table 4 show that the international normalized ratio of the rats treated with compounds 6a-d at an oral dose of 0.1 μmol/kg for 4 hours is not different from that of the saline-treated rats, whereas the international normalized ratio of warfarin at an oral dose of 4.87 μmol/kg for 4 hours is significantly greater than that of the saline-treated rats, indicating significant bleeding side effects. Compounds 6a-d did not cause a similar bleeding event to warfarin for 4 hours and were safer than warfarin. It can be seen that the present invention has an unexpected technical effect.
Example 37 evaluation of the Effect of 6a-d on rat plasma coagulation factor II (FIIa) levels
Example 33 Whole blood of rats collected 4.0 mL/mouse was placed in a centrifuge tube containing 0.4mL of sodium citrate solution (3.8%), centrifuged at 1000g for 15 minutes, and then Platelet Poor Plasma (PPP) was aspirated. PPP samples of 6 rats after administration were taken from each experimental group, diluted 1:1 with the specimen diluent in the kit, and 50ul of the diluted sample was added to the reaction well. At the same time, 50. mu.L of the diluted standard was added to the reaction well. Immediately 50 μ L of biotin-labeled antibody was added. Cover the membrane plate, mix by gentle shaking, incubate for 1 hour at 37 ℃. And then throwing off liquid in the holes, filling the holes with the cleaning solution, oscillating for 30 seconds, throwing off the cleaning solution, and patting dry by using absorbent paper. This operation was repeated 3 times. Then 80. mu.L of streptavidin-HRP was added to each well, mixed by gentle shaking, and incubated at 37 ℃ for 30 minutes. And (3) throwing off liquid in the holes after the incubation is finished, filling washing liquid in each hole, oscillating for 30 seconds, throwing off the washing liquid, patting the holes dry by using absorbent paper, and repeating the operation for 3 times. 50 μ L of substrate A, B was added to each well, mixed by gentle shaking, and incubated at 37 ℃ for 10 minutes. Avoiding illumination, taking out the ELISA plate, quickly adding 50 mu L of stop solution, immediately measuring the result after adding the stop solution, and measuring the OD value of each hole at the wavelength of 450nm by using an ELISA reader. And subtracting the OD value read at 540nm from the OD value read at 450nm, taking the OD value as an ordinate, taking the concentration of the blood coagulation factor II (FIIa) standard product as an abscissa, and drawing a standard curve, wherein the FIIa content of the sample can be converted into the corresponding concentration according to the OD value of the sample from the standard curve. Differences in FIIa content among groups were analyzed using the one-way analysis of variance (ANOVA one-way, LSD) method in SPSS 22.0, and FIIa content in rat plasma is shown in Table 5.
TABLE 5 FIIa content in plasma of treated rats
a) The ratio of P to normal saline is less than 0.01; n is 5
The data in Table 5 show that treatment with compounds 6a-d at an oral dose of 0.1. mu. mol/kg for 4 hours is effective in reducing plasma FIIa levels in rats. Therefore, the invention has obvious technical effect.
EXAMPLE 38 evaluation of the Effect of 6a-d on rat plasma Soluble Fibrin Monomer Complex (SFMC) content
Example 33 Whole blood of rats collected 4.0 mL/mouse was placed in a centrifuge tube containing 0.4mL of sodium citrate solution (3.8%), centrifuged at 1000g for 15 minutes, and then Platelet Poor Plasma (PPP) was aspirated. Each experimental group was prepared by taking PPP samples from 6 rats after administration, diluting the PPP samples 200-fold with the sample diluent in the kit, adding 100 μ L of each sample and standard substance to each well, incubating at 37 ℃ for 2 hours after coating the cover plate membrane, then pouring all the liquid in the plate, not washing the plate, directly adding 100 μ L of Biotin solution to each well, incubating at 37 ℃ for 1 hour after coating the new cover plate membrane. Then, the plate liquid was discarded, 200. mu.L of the washing solution was added to each well, and the washing solution was discarded after standing for 2min and the 96-well plate was patted dry, and this was repeated 3 times. Then 100. mu.L of HRP-avidin per well was added and incubated at 37 ℃ for another 1 hour after coating with a new coversheet membrane. After incubation, the plate washing operation was repeated 5 times to remove the liquid from each well. Adding 90 mu L of 3,3',5,5' -tetramethyl benzidine into each well, covering a new cover plate membrane, incubating for 20 minutes at 37 ℃ in the dark, adding 50 mu L of stop solution into each well, and rapidly reading the OD value of each well by using an enzyme-linked immunosorbent assay at the dual wavelengths of 450nm and 540 nm. And subtracting the OD value read at 540nm from the OD value read at 450nm, drawing a standard curve by taking the OD value as a vertical coordinate and the SFMC standard concentration as a horizontal coordinate, and converting the SFMC content of the sample into the corresponding concentration from the standard curve according to the OD value. The difference in SFMC content of each group was analyzed by one-way analysis of variance (ANOVA one-way, LSD) method in SPSS 22.0, and the SFMC content in rat plasma is shown in table 6.
TABLE 6 SFMC content in plasma of treated rats
a) The ratio of P to normal saline is less than 0.05; n is 5
The data in Table 6 show that treatment with compounds 6a-d at an oral dose of 0.1. mu. mol/kg for 4 hours is effective in reducing the SFMC levels in rat plasma. Therefore, the invention has obvious technical effect.
It should be noted that the above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention.
Claims (5)
1. The structural formula is 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA,
wherein AA is Met residue, Ser residue, Thr residue or Trp residue.
2. The process of claim 1 for the preparation of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA, the process comprising:
1) synthesizing warfarin-4-O-benzyl acetate;
2) synthesizing warfarin-4-O-acetic acid;
3) synthesizing Boc-Gly-Pro-OBzl;
4) converting Boc-Gly-Pro-OBzl into Gly-Pro-OBzl;
5) warfarin-4-O-acetic acid reacts with Gly-Pro-OBzl to synthesize warfarin-4-O-acetyl-Gly-Pro-OBzl;
6) converting warfarin-4-O-acetyl-Gly-Pro-OBzl into warfarin-4-O-acetyl-Gly-Pro;
7) synthesis of Boc-Arg (NO)2)-Pro-Met-OBzl,Boc-Arg(NO2)-Pro-Ser-OBzl,Boc-Arg(NO2) -Pro-Thr-OBzl and Boc-Arg (NO)2)-Pro-Trp-OBzl；
8) Boc-Arg (NO)2)-Pro-Met-OBzl,Boc-Arg(NO2)-Pro-Ser-OBzl,Boc-Arg(NO2) -Pro-Thr-OBzl and Boc-Arg (NO)2) Conversion of-Pro-Trp-OBzl to Arg (NO), respectively2)-Pro-Met-OBzl,Arg(NO2)-Pro-Ser-OBzl,Arg(NO2) -Pro-Thr-OBzl and Arg (NO)2)-Pro-Trp-OBzl；
9) warfarin-4-O-acetyl-Gly-Pro and Arg (NO)2)-Pro-Met-OBzl,Arg(NO2)-Pro-Ser-OBzl,Arg(NO2) -Pro-Thr-OBzl and Arg (NO)2) Synthesis of warfarin-4-O-acetyl-Gly-Pro-Arg (NO) by-Pro-Trp-OBzl reaction2) -Pro-Met-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Ser-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Thr-OBzl and warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2)-Pro-Trp-OBzl；
10) warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Met-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Ser-OBzl, warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Thr-OBzl and warfarin-4-O-acetyl-Gly-Pro-Arg (NO)2) -Pro-Trp-OBzl to 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA according to claim 1.
3. Use of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA according to claim 1 for the preparation of a coagulation factor II antagonist.
4. The use of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA in the preparation of soluble fibrin monomer complex antagonists according to claim 1.
5. The use of 4 warfarin-4-O-acetyl-Gly-Pro-Arg-Pro-AA in the preparation of an anti-thrombotic medicament without bleeding side effects.
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