CN109627218B - Anticoagulant small molecule compound, application thereof and medicine containing anticoagulant small molecule compound - Google Patents
Anticoagulant small molecule compound, application thereof and medicine containing anticoagulant small molecule compound Download PDFInfo
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- CN109627218B CN109627218B CN201811427632.0A CN201811427632A CN109627218B CN 109627218 B CN109627218 B CN 109627218B CN 201811427632 A CN201811427632 A CN 201811427632A CN 109627218 B CN109627218 B CN 109627218B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
Abstract
The invention relates to an anticoagulant micromolecule compound, application thereof and a medicament containing the anticoagulant micromolecule compound, wherein the structural formula of the anticoagulant micromolecule compound is shown in the specification
Description
Technical Field
The invention belongs to the field of biological medicine. Specifically, the invention relates to anticoagulant polypeptide and application of the anticoagulant polypeptide in preparation of medicines for preventing and treating thrombotic diseases.
Background
At present, the most important and common complication of clinical antithrombotic drug prevention and treatment is bleeding, so that finding an effective antithrombotic drug with low bleeding risk has a very urgent clinical need. In recent years, animal experiments for knocking out FXI gene and antithrombotic experiments for FXIa inhibitors have shown, through clinical studies from hemophilia C (FXI deficiency syndrome): FXI has the characteristics of wide drug treatment window and small bleeding side effect as a new anti-thrombosis prevention and treatment target, but the research on the fXIa inhibitor as a new drug is paid attention recently, and the selectable inhibitor molecules are very limited.
The incidence of thromboembolic diseases is high, but the fatality rate and disability rate are the first causes of various diseases, and about 25 percent of the death in the world is caused by thromboembolic diseases such as myocardial infarction, cerebral infarction, pulmonary embolism and the like. At present, the medicines for preventing and treating thromboembolic diseases mainly comprise anticoagulant, thrombolytic and antiplatelet medicines. The traditional blood coagulation medicaments such as warfarin, heparin and the like or new medicaments such as FXa inhibitors (rivaroxaban, apixaban and the like) (remarks: the current hottest medicament is rivaroxaban and is on the market) and thrombin inhibitors (dabigatran etexilate, hirudin and the like) have good blood coagulation effect but have fatal defect, and the medicament treatment window is narrow, so bleeding complications are easily caused. Therefore, a new target for researching medicines with small bleeding side effect is widely concerned.
FXIa belongs to a member of the trypsin-like serine protease family, its precursor is FXI, which is not only one of the essential coagulation factors in the coagulation cascade caused by the intrinsic pathway of travel, but also in the coagulation cascade, thrombin can positively feed back and activate FXI, and activated FXIa produces more thrombin, having an amplifying effect. Human FXI deficiency (hemophilia C) which gives mild bleeding, in contrast to spontaneous bleeding, skin ecchymosis and post-operative bleeding if FVIII or FIX deficient patients are treated with the usual conditions. Epidemiological investigation shows that the incidence rate of ischemic shock nuclear venous thrombosis in patients with FXI deficiency is obviously lower than that of normal people; at present, inhibitors of FXI mainly comprise five major classes of polypeptide/protease, peptide mimetics, antisense nucleotide (ASO), monoclonal antibodies, small molecule inhibitors and the like. Navaneetham D et al found that protease linker 2(PN2) has strong activity on FXIa (Ki ═ 0.81), and animal models showed that PN2 can effectively prevent thrombosis without causing obvious reactions. AcaNAP10 isolated and modified from hookworm as a subject of professor Pengium engiengii of Guangdong medical university has strong specific nuclear inhibitory activity on FXIa, and preclinical research is currently being conducted
Disclosure of Invention
The invention aims to provide an anticoagulant small-molecule compound, application thereof and a medicament containing the anticoagulant small-molecule compound.
The technical scheme for solving the technical problems is as follows:
the invention provides an anticoagulant micromolecule compound, wherein the anticoagulant micromolecule has a structural formulaAnd derivatives thereof.
Further, the derivatives are as defined inA compound formed by substitution, deletion or addition of one or more functional groups.
Further, the functional group includes a fluorine benzene ring, phenylimidazole, and ethyl propionate.
the synthesis steps of the anticoagulant small molecule compound are as follows:
will be provided withAnd CH2(COOH)2According to the molar ratioAt a ratio of 1:1.1, reacting at 76 ℃ to obtainThen will beReacting with ethanol at a molar ratio of 1:1 at 76 deg.C to obtain
2) Will be provided withReacting with thionyl chloride according to the molar ratio of 1:22 at 79 ℃ to obtain
3) Subjecting the product obtained in step 1)With the product obtained in step 2)Reacting at 0 ℃ according to the molar ratio of 1:1 to obtain
The invention has the beneficial effects that: the anticoagulant small molecule compound provided by the invention is a selective inhibitor of the blood coagulation factor XIa (fXIa), has stronger inhibitory activity to the blood coagulation factor XIa (fXIa), and basically has no inhibitory activity to a tissue factor and blood coagulation factor Vila complex (TF/fVIIa); the anticoagulant polypeptide provided by the invention can obviously prolong the thromboplastin time (aPTT) of activated part of plasma, has little influence on prothrombin time and has no influence on thrombin time.
An application of anticoagulant micromolecule in synthesizing a medicament for preventing and treating thrombotic diseases.
An agent for the prophylaxis and treatment of a thrombotic disease, the active ingredient of which comprises at least one anticoagulation small molecule compound as described above. The polypeptide has obvious antithrombotic effect, has no obvious influence on the hemostatic function and the platelet aggregation activity, and can be used as or developed into antithrombotic medicaments with small hemorrhagic side effect.
Other aspects of the invention will be readily apparent to those skilled in the art and can be made as a result of the disclosure contained herein. For example, the anticoagulant small molecule compound can reduce side effects when being combined with other anticoagulant and antithrombotic drugs, the anticoagulant small molecule compound can be clinically applied, and the anticoagulant small molecule compound can be applied as an anticoagulant preparation.
The anticoagulant small molecular compound has the advantages that: the anticoagulant polypeptide provided by the invention can be prepared into a medicament for effectively preventing and treating thrombotic diseases, does not influence the normal hemostatic function of human bodies and animals, has small bleeding side effect, and has great significance for solving bleeding side complications in clinical anticoagulant and antithrombotic treatment at present.
Drawings
FIG. 1 is a graph of the effect of anticoagulant small molecule compounds on activated partial thromboplastin time (aPTT) in example 2 of the present invention;
FIG. 2 is a graph showing the effect of an anticoagulant small molecule compound on Prothrombin Time (PT) in example 2 of the present invention;
FIG. 3 is a graph showing the effect of the anticoagulant small molecule compound of example 2 on Thrombin Time (TT) according to the present invention.
Detailed Description
The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention.
The invention provides an anticoagulant micromolecule compound, wherein the anticoagulant micromolecule has a structural formulaAnd derivatives thereof. Wherein, the derivatives are as defined inA compound formed by substitution, deletion or addition of one or more functional groups. The functional groups include a fluorobenzene ring, phenylimidazole and ethyl propionate.
the synthesis steps of the anticoagulant small molecule compound are as follows:
will be provided withAnd CH2(COOH)2Reacting at 76 ℃ according to the molar ratio of 1:1.1 to obtainThen will beReacting with ethanol at a molar ratio of 1:1 at 76 deg.C to obtain
2) Will be provided withReacting with thionyl chloride according to the molar ratio of 1:22 at 79 ℃ to obtain
3) Subjecting the product obtained in step 1)With the product obtained in step 2)Reacting at 0 ℃ according to the molar ratio of 1:1 to obtain
The anticoagulant small molecule compound provided by the invention is a selective inhibitor of the blood coagulation factor XIa (fXIa), has stronger inhibitory activity to the blood coagulation factor XIa (fXIa), and basically has no inhibitory activity to a tissue factor and blood coagulation factor Vila complex (TF/fVIIa); the anticoagulant polypeptide provided by the invention can obviously prolong the thromboplastin time (aPTT) of activated part of plasma, has little influence on prothrombin time and has no influence on thrombin time.
The invention also provides application of the anticoagulation micromolecule in synthesizing a medicament for preventing and treating thrombotic diseases.
The invention also provides a medicament for preventing and treating thrombotic diseases, wherein the active ingredient of the medicament for preventing and treating thrombotic diseases comprises at least one anticoagulant small molecule compound. The polypeptide has obvious antithrombotic effect, has no obvious influence on the hemostatic function and the platelet aggregation activity, and can be used as or developed into antithrombotic medicaments with small hemorrhagic side effect. The anticoagulant polypeptide provided by the invention can be prepared into a medicament for effectively preventing and treating thrombotic diseases, does not influence the normal hemostatic function of human bodies and animals, has small bleeding side effect, and has great significance for solving bleeding side complications in clinical anticoagulant and antithrombotic treatment at present.
Example 1
The synthesis equation of anticoagulant small molecule compound for selectively inhibiting coagulation factor XIa is as follows:
the synthesis steps of the anticoagulant small molecules comprise:
will be provided withAnd CH2(COOH)2Reacting at 76 ℃ according to the molar ratio of 1:1.1 to obtainThen will beReacting with ethanol at a molar ratio of 1:1 at 76 deg.C to obtain
2) Will be provided withReacting with thionyl chloride according to the molar ratio of 1:22 at 79 ℃ to obtain
3) Subjecting the product obtained in step 1)With the product obtained in step 2)Reacting at 0 ℃ according to the molar ratio of 1:1 to obtain
Example 2
The anticoagulation activity of the anticoagulation small molecular compound provided by the invention
The anticoagulant activity of the anticoagulant small molecular compound provided by the invention is observed by detecting the activated partial thromboplastin time (aPTT) and the Prothrombin Time (PT).
Prothrombin Time (PT) assay: preparing 1 part of anticoagulant micromolecule compound with different concentrations and 4 parts of normal human plasma, mixing uniformly, incubating for 15min at 37 ℃, and setting the measurement parameters as follows by using a coagulometer S5100(SYSMEX, Japan): mixed plasma 50ul +50ul primary aPTT reagent +50ul primary calcium chloride reagent. The instrument reads the results. Each concentration was repeated 2 times and averaged. The results of the experiment are shown in FIG. 1.
Prothrombin Time (PT) assay: preparing 1 part of anticoagulant micromolecule compound with different concentrations and 4 parts of normal human plasma, mixing uniformly, incubating for 15min at 37 ℃, and setting the measurement parameters as follows by using a coagulometer S5100(SYSMEX, Japan): plasma was mixed at 50ul +100ul bulk PT reagent. The instrument reads the results. Each concentration was repeated 2 times and averaged. The results of the experiment are shown in FIG. 2.
Prothrombin time (TT) assay: preparing 1 part of anticoagulant micromolecule compound with different concentrations and 4 parts of normal human plasma, mixing uniformly, incubating for 15min at 37 ℃, and setting the measurement parameters as follows by using a coagulometer S5100(SYSMEX, Japan): mixed plasma 50ul +100ul of bulk TT reagent. The instrument reads the results. Each concentration was repeated 2 times and averaged. The results of the experiment are shown in FIG. 3.
The data in fig. 1-3 show that the anticoagulant small molecule compound can significantly prolong the plasma activated partial thromboplastin time (aPTT) with little effect on Prothrombin Time (PT) and no effect on thrombin time (aPTT).
Example 3
Effect of anticoagulant small molecule compound on blood coagulation time of rat
40 SPF-grade SD rats (provided by Guangdong university of medicine laboratory animals center) weighing 250 + -50 g were randomly divided into 4 groups of 10 blank control group (distilled water), anticoagulant small molecule low dose group (20mg/kg), anticoagulant small molecule medium dose group (40mg/kg) and anticoagulant small molecule high dose group (80 mg/kg). The drug is administrated by gavage, 3 hours later, blood is taken from tail vein or eyeball, and injected into plastic tube added with 3.8% sodium citrate (blood: anticoagulant: 9:1), and the mixture is shaken gently. The plasma was separated by centrifugation at 1500Xg for 10 min. aPTT and PT were determined by the method described in (2). The results are shown in Table 1
The results show that
The anticoagulant small molecular compound can obviously prolong the thromboplastin time (aPTT) of an activated part of plasma, and has little influence on the prothrombin time.
TABLE 1 Effect of anticoagulant Small molecule Compounds on clotting time in rats
VS normal saline control group in high-medium-low dose group of anti-coagulation small molecule compound with P <0.05
Example 3
Effect of anticoagulant micromolecular compound on rat inferior vena cava thrombosis
40 SPF-grade SD rats (provided by Guangdong university of medicine laboratory animals center) weighing 250 + -50 g were randomly divided into 4 groups of 10 blank control group (distilled water), anticoagulant small molecule low dose group (20mg/kg), anticoagulant small molecule medium dose group (40mg/kg) and anticoagulant small molecule high dose group (80 mg/kg). After the administration for 3 hours by gavage, the rats were weighed, and were intraperitoneally injected with a 2% sodium pentobarbital solution at a dose of 1.5 mL/kg-1, and were fixed on the operating table in a supine position after the anesthesia. The 75% medical alcohol is used for disinfecting the skin of the abdomen of a rat, the incision of the middle of the lower abdomen is 4-5 cm, the abdominal cavity is exposed, the small intestine is drawn to the right side of the visual field, and the small intestine is wrapped by gauze dipped with sterile physiological saline. The inferior vena cava is bluntly isolated between the renal vein and the iliac vein to avoid miscutting other vessels and vagus nerves that accompany it. Carefully and cleanly separating the inferior vena cava from the peritoneum, and filling a layer of black plastic film under the inferior vena cava. The inferior vena cava was encircled with filter paper (0.5 cm. times.2.5 cm) soaked with 7.5% FeCl3 for 3min, the filter paper was removed, and the vessels and local tissues were washed 3 times with 0.9% NaCl injection. After 20 minutes, the molded vessel was cut off by 1cm, washed with physiological saline, and then carefully blotted with filter paper to remove excess liquid, weighed on an analytical balance with a precision of 0.0001g, and the weight of the vessel was recorded. The ratio of thrombus formation in each group was calculated based on the normal control group. The results are shown in table 2, which shows that the anticoagulant micromolecule has obvious effect of resisting rat venous thrombosis. Table 2 shows the effect of anticoagulant small molecule compounds on rat inferior vena cava thrombosis.
Model group of P < 0.01vs
Example 4
The effect of anticoagulant small molecule compounds on rat inferior vena cava thrombosis.
40 SPF-grade BALB/c mice (provided by the Experimental animals center of Guangdong university of medicine) were randomly divided into 4 groups of 10 mice each, namely a blank control group (distilled water), an anticoagulated small molecule low dose group (20mg/kg), an anticoagulated small molecule medium dose group (40mg/kg) and an anticoagulated small molecule high dose group (80 mg/kg). After the mice are subjected to gastric lavage for 3 hours, the mice are cut at a position 1.5mm away from the tail tip, when the blood automatically overflows, the timing is started, blood drops are sucked by using filter paper for 1 time every 30 seconds until no blood is sucked by using the filter paper, and the time from the beginning of tail tip breakage to the time when no blood is sucked is recorded, namely the tail bleeding time, which is expressed by the standard deviation of mean soil. The results are shown in Table 3.
TABLE 3 Effect of anticoagulant Small molecule Compounds on bleeding time at the tail of mice
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (3)
2. Use of the anticoagulation small molecule compound according to claim 1 for the preparation of a medicament for the prophylaxis and treatment of thrombotic diseases.
3. An agent for the prophylaxis and treatment of a thrombotic disease, wherein an active ingredient of said agent for the prophylaxis and treatment of a thrombotic disease comprises at least one anticoagulation small-molecule compound according to claim 1.
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