Application of crystalline porous material in preparation of blood anticoagulant

Abstract

The invention relates to application of a crystalline porous material in preparation of a blood anticoagulant, and the crystalline porous material is a covalent organic framework material and / or a metal organic framework material. Four detection results of blood coagulation show that both the covalent organic framework material and the metal organic framework material show excellent anticoagulant activity.

Description

Technical Field

[0001] The present invention relates to the medical field, in particular to the field of blood anticoagulants. Background Art

[0002] Blood purification technology is a process in which the patient's blood is drawn out of the body, processed by specific physical or chemical methods, to remove toxins and pathogenic factors in the blood in an extracorporeal device, and then returned to the patient's body in order to quickly and effectively relieve the condition and regulate the body's internal environment. It has become a key treatment for diseases such as end-stage renal disease, liver failure, and acute poisoning.

[0003] However, during clinical blood purification, platelets and coagulation factors aggregate, which can lead to thrombosis. Therefore, it is very necessary to take adequate anticoagulation measures to maintain the patency of the extracorporeal circuit of the blood purification device and avoid excessive bleeding. Various anticoagulants, such as heparin anticoagulants and direct thrombin inhibitors (such as argatroban and hirudin) are widely used to achieve systemic anticoagulation and avoid thrombosis in the extracorporeal circuit of blood purification. However, the use of these anticoagulants can lead to the continuous inactivation of coagulation factors, resulting in delayed hemostasis recovery in patients, which may further cause complications such as bleeding and organ damage, and even threaten life. Therefore, local dilution of the blood by using materials that only contact the blood in the extracorporeal circuit may be a highly safe strategy.

[0004] Crystalline porous materials are a type of functional materials with high porosity, diverse structures, and controllable functions, among which zeolites, covalent-organic frameworks (COFs), and metal-organic frameworks (MOFs) are the most representative.

[0005] Covalent organic frameworks (COFs) are a type of crystalline porous polymers composed of organic building blocks connected by covalent bonds. The pore size of COFs is uniform, so they are also called "organic zeolites". Compared with inorganic porous materials, COFs have the following characteristics: 1) Structural diversity. By selecting building blocks with different geometric shapes or changing the connection method of building blocks, frameworks with different topological structures can be obtained; 2) Open and controllable pores. The pore size, shape and chemical environment can be regulated through structural design and functionalization; 3) The organic molecules that make up COFs are connected by strong covalent bonds (such as BO, C=N, CN, C=C, etc.), which makes COFs not easily attacked by chemical reagents or dissociated by high temperatures, and thus have higher chemical and thermal stability.

[0006] Metal organic frameworks (MOFs) are a new type of crystalline porous hybrid materials formed by self-assembly of metal ions or metal clusters and organic ligands in the form of coordination bonds. Metal organic frameworks have the advantages of both inorganic and organic porous materials, with high specific surface area, orderly and repeatable pores, rich functional groups, good stability, and diverse structures.

[0007] These two crystalline porous materials have controllable structures and pores, rich topological structures, high porosity and specific surface area, which make them show great application prospects in the fields of adsorption, separation and purification. Summary of the invention

[0008] In view of the problems in the prior art, the present invention provides a new use of crystalline porous materials for blood anticoagulation.

[0009] One aspect of the present invention provides a use of a crystalline porous material in preparing a blood anticoagulant, wherein the crystalline porous material is a covalent organic framework material and / or a metal organic framework material.

[0010] Preferably, the blood anticoagulant is used in an extracorporeal circuit of a blood purification device.

[0011] More preferably, the blood purification device is selected from the group consisting of a hemodialysis device, a hemoperfusion device, a hemofiltration device, a plasma exchange device, and an immunoadsorption device.

[0012] Preferably, the blood anticoagulant is implanted in a patient for use.

[0013] Preferably, the blood anticoagulant prolongs at least two of the activated partial thromboplastin time, the prothrombin time, and the plasma thrombin time, and reduces the fibrinogen concentration.

[0014] More preferably, the blood anticoagulant prolongs activated partial thromboplastin time, prothrombin time and plasma thrombin time, and reduces fibrinogen concentration.

[0015] Preferably, the covalent organic framework material is formed by reacting a first monomer comprising an amino group and a second monomer comprising an aldehyde group.

[0016] More preferably, the first monomer is 1,3,5-tris(4-aminophenyl)benzene, 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) or p-phenylenediamine.

[0017] More preferably, the second monomer is 2,5-dihydroxyterephthalaldehyde, 4,4′-((2,3-dimethoxy-1,4-phenylene)bis-(ethyn-2,1-diyl))benzaldehyde, 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde, 2,5-dihydroxyterephthalaldehyde, 4,4′-(1,4-phenylenebis(ethyn-2,1-diyl))benzaldehyde, 4,4′-(((2,3-dimethoxy-1,4-phenylene)bis(ethyn-2,1-diyl))bis(4,1-phenylene))bis-(ethyn-2,2-diyl))benzaldehyde or 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde.

[0018] More preferably, the covalent organic framework material is one or more of the following: The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Figure 1 As shown; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-((2,3-dimethoxy-1,4-phenylene)bis-(acetylene-2,1-diyl))dibenzaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Figure 4 As shown; The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Figure 7 As shown; The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene, 2,5-dihydroxyterephthalaldehyde and 2,5-dihydroxyterephthalyldimethoxy. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.10 As shown; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-(1,4-phenylenebis(acetylene-2,1-diyl))dibenzaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.13 As shown; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-((((2,3-dimethoxy-1,4-phenylene)bis(acetylene-2,1-diyl))bis(4,1-phenylene))bis-(acetylene-2,2-diyl))dibenzaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown in FIG. Fig.16 As shown; The covalent organic framework material is formed by the reaction of p-phenylenediamine and 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.19 shown.

[0019] Preferably, the metal organic framework material is formed by the action of a metal source and an organic ligand, the metal source is selected from at least one of copper, cadmium, zinc, zirconium and nickel, and the organic ligand is selected from at least one of trimesic acid, terephthalic acid, 2-methylimidazole, 2-aminoterephthalic acid and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid.

[0020] More preferably, the metal organic framework material is one or more of the following: The metal organic framework material is formed by the reaction of copper acetate monohydrate and trimesic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig. 22 As shown; The metal organic framework material is formed by the reaction of cadmium nitrate nonahydrate and terephthalic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows Fig.25 As shown; The metal organic framework material is formed by the reaction of zinc nitrate hexahydrate and 2-methylimidazole. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows Fig.28 As shown; The metal organic framework material is formed by the reaction of zirconium tetrachloride and 2-aminoterephthalic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.31 As shown; The metal organic framework material is formed by the reaction of nickel nitrate hexahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.34 As shown; The metal organic framework material is formed by the reaction of zinc nitrate nonahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.37 As shown; The metal organic framework material is formed by the reaction of copper nitrate trihydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid. The X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows: Fig.40 shown.

[0021] Preferably, the crystalline porous material is used in combination with a second blood anticoagulant.

[0022] In the process of studying crystalline porous materials, the inventors of the present invention found that covalent organic framework materials and metal organic framework materials have blood anticoagulant effects. After testing the four coagulation parameters of these two materials, it was found that they have excellent anticoagulant activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. Together with the following specific embodiments, they are used to explain the present invention, but do not constitute a limitation of the present invention.

[0024] Figure 1 is the X-ray powder diffraction pattern of COF-A; Figure 2 is the infrared spectrum of COF-A; Figure 3 N of COF-A 2 Adsorption-desorption curves; Figure 4 is the X-ray powder diffraction pattern of COF-B; Figure 5 is the infrared spectrum of COF-B; Figure 6 N of COF-B 2 Adsorption-desorption curves; Figure 7 is the X-ray powder diffraction pattern of COF-C; Figure 8is the infrared spectrum of COF-C; Fig. 9 N of COF-C 2 Adsorption-desorption curves; Fig.10 is the X-ray powder diffraction pattern of COF-D; Fig.11 is the infrared spectrum of COF-D; Fig.12 N of COF-D 2 Adsorption-desorption curves; Fig.13 is the X-ray powder diffraction pattern of COF-E; Fig.14 is the infrared spectrum of COF-E; Fig.15 N of COF-E 2 Adsorption-desorption curves; Fig.16 is the X-ray powder diffraction pattern of COF-F; Fig.17 is the infrared spectrum of COF-F; Fig.18 N of COF-F 2 Adsorption-desorption curves; Fig.19 is the X-ray powder diffraction pattern of COF-G; Fig. 20 is the infrared spectrum of COF-G; Fig.21 N of COF-G 2 Adsorption-desorption curves; Fig. 22 is the X-ray powder diffraction pattern of MOF-A; Fig.23 is the infrared spectrum of MOF-A; Fig.24 N of MOF-A 2 Adsorption-desorption curves; Fig.25 is the X-ray powder diffraction pattern of MOF-B; Fig.26 is the infrared spectrum of MOF-B; Fig. 27 N of MOF-B 2 Adsorption-desorption curves; Fig.28 is the X-ray powder diffraction pattern of MOF-C; Fig.29 is the infrared spectrum of MOF-C; Fig.30N of MOF-C 2 Adsorption-desorption curves; Fig.31 is the X-ray powder diffraction pattern of MOF-D; Fig.32 is the infrared spectrum of MOF-D; Fig.33 N of MOF-D 2 Adsorption-desorption curves; Fig.34 is the X-ray powder diffraction pattern of MOF-E; Fig.35 is the infrared spectrum of MOF-E; Fig.36 This is the carbon dioxide adsorption and desorption curve of MOF-E; Fig.37 is the X-ray powder diffraction pattern of MOF-F; Fig.38 is the infrared spectrum of MOF-F; Fig.39 This is the carbon dioxide adsorption-desorption curve of MOF-F; Fig.40 is the X-ray powder diffraction pattern of MOF-G; Fig.41 is the infrared spectrum of MOF-G; Fig.42 This is the carbon dioxide adsorption-desorption curve of MOF-G; Fig.43 The activated partial thromboplastin time (APTT) test results of the covalent organic framework materials of Examples 1-7; Fig.44 The activated partial thromboplastin time (APTT) test results of the metal organic framework materials of Examples 8-14; Fig.45 The plasma prothrombin time (PT) test results of the covalent organic framework materials of Examples 1-7; Fig.46 The plasma prothrombin time (PT) test results of the metal organic framework materials of Examples 8-14; Fig.47 The thrombin time (TT) test results of the covalent organic framework materials of Examples 1-7; Fig.48 The thrombin time (TT) test results of the metal organic framework materials of Examples 8-14; Fig.49 The fibrinogen concentration (FIB) test results of the covalent organic framework materials of Examples 1-7; Fig.50These are the fibrinogen concentration (FIB) test results of the metal organic framework materials of Examples 8-14. DETAILED DESCRIPTION

[0025] The specific implementation of the present invention is described in detail below in conjunction with the accompanying drawings. It should be understood that the specific implementation described here is only used to illustrate and explain the present invention, and is not used to limit the present invention.

[0026] The terms used in the present invention have the meanings generally used in the art. Some technical terms used in the present invention are explained and defined below.

[0027] Covalent organic framework materials The "covalent organic framework material" in the present invention, also known as COFs, is a type of crystalline polymer material formed by long-range orderly connection of organic monomers through covalent bonds. The pore size of the covalent organic framework material is uniform, so it is also called "organic zeolite". The covalent organic framework material has the characteristics of regular and adjustable pores, large specific surface area, high porosity, good stability, and easy functionalization. The covalent organic framework material used in the present invention can be synthesized by methods known in the art, such as Xiong Chen et al. Towards covalent organic frameworks with predesignable and aligned open docking sites. Chem. Commun., 2014, 50, 6161-6163, DOI: 10.1039 / c4cc01825g; Laura Ascherl et al. Molecular docking sites designed for the generation of highly crystalline covalent organic frameworks. Nature Chemistry, 2016, DOI: 10.1038 / NCHEM.2444. The above patents or documents are fully introduced into the present invention.

[0028] Metal-organic framework materials The "metal organic framework material" in the present invention, also known as MOFs, is a type of functional porous material, which is constructed by the coordination of metal sources (such as metal clusters, metal oxides or metal salts, etc.) and organic ligands, and has the advantages of both inorganic and organic porous materials, and has the characteristics of high specific surface area, orderly and repeatable pores, rich functional groups, good stability, and diverse structures. The metal organic framework material used in the present invention can be synthesized using methods known in the art, such as hydrothermal method, stirring static method, electrolysis method, spinning method, microwave method, hot pressing method, etc. The above-mentioned synthesis method is recorded in, for example, Katz, MJ et al. Afacile synthesis of UiO-66, UiO-67 and their derivatives. Chem. Commun. 49,9449-9451, (2013); Park, KS et al. Exceptional chemical and thermalstability of zeolitic imidazolate frameworks. P. Natl. Acad. Sci. USA.103,10186-10191, (2006); Li S. et al. Creating Lithium-Ion Electrolytes withBiomimetic Ionic Channels in Metal-Organic Frameworks. DOI: 10.1002 / adma.201707476; ZL201510630401.X and other documents, and the above-mentioned patents or documents are fully introduced into the present invention.

[0029] Hemodialysis Hemodialysis (HD) is a blood purification technology that introduces the patient's blood from the body into a dialysis device equipped with a dialysis membrane outside the body. The concentration difference on both sides of the membrane is used as the driving force. Through pore size screening, metabolic waste in the body is removed, electrolytes and acid-base balance are maintained, and excess water in the body is removed. The purified blood is then returned to the body for transfusion. Hemodialysis is generally used to remove small molecule toxins from the patient's blood, such as metabolic wastes such as creatinine, urea nitrogen, uric acid, and potassium. It is currently one of the renal replacement therapies for patients with acute and chronic renal failure. During hemodialysis, blood is easily thrombotic when it comes into contact with different materials outside the body. When it comes into contact with air in the venous pot, the inherent waterfall reaction of the coagulation process is activated, causing thrombin formation and fibrin precipitation in the extracorporeal circulation, mainly in the hollow fibers of the dialysis device, which makes coagulation more likely to occur, resulting in impaired function and blockage of the coagulation device. Severe cases may even cause dialysis to terminate. To ensure the smooth progress of dialysis, anticoagulants are required during the dialysis process. The purpose of using anticoagulants is to: 1) maintain a good extracorporeal circulation state; 2) prevent the risk of thrombotic diseases caused by coagulation activation induced by extracorporeal circulation; 3) reduce the inflammatory response induced by the contact between blood cells and dialysis membranes, thereby improving biocompatibility and ensuring the effective implementation of hemodialysis treatment. Anticoagulants can be used systemically or set in the extracorporeal circuit for local anticoagulation.

[0030] Hemoperfusion Hemoperfusion (HP) is a blood purification technology that introduces the patient's blood from the body into an external perfusion device equipped with adsorbents, and removes exogenous or endogenous toxins, drugs or metabolic wastes in the blood that cannot be removed by dialysis through adsorption. Unlike hemodialysis based on the principle of membrane separation, hemoperfusion can efficiently remove protein-bound toxins and macromolecular toxins in the blood. Among them, protein-bound toxins refer to toxins that exist mostly in a bound form in plasma and accumulate due to abnormal metabolism under pathological conditions. Since the free level of protein-bound toxins in the blood is low, protein-bound toxins cannot pass through the dialysis membrane, and therefore are difficult to remove through conventional hemodialysis technology. For example, uremic protein-bound toxins (PBUTs), bilirubin, bile acid, parathyroid hormone, etc. Similar to hemodialysis, since the blood needs to be processed in an extracorporeal hemoperfusion device, anticoagulants are also required during the hemoperfusion process.

[0031] Hemofiltration Hemofiltration (HF) is a technology that introduces the patient's blood from the body into an extracorporeal hemofiltration device, purifies the blood through the principle of convection, and then returns it to the body. Unlike hemodialysis, it does not use dialysate during the blood purification process. Instead, a certain amount of replacement fluid is continuously added to the vascular access, fully mixed with the blood, and then ultrafiltered at the same rate to achieve the purpose of removing excess water and toxins from the body. Compared with hemodialysis, hemofiltration has the advantages of less impact on hemodynamics and high clearance rate of middle-molecular substances. Hemofiltration is commonly used to treat acute kidney injury (AKI). Similar to hemodialysis, anticoagulants are also required during the hemofiltration process.

[0032] Plasma exchange Plasma exchange (PE) is the process of extracting whole blood from the body and separating it into plasma and cellular components, discarding the patient's plasma, and then returning the separated plasma to the body at the same rate with fresh plasma, albumin solution, balanced solution and other plasma substitutes, in order to reduce pathological damage and remove pathogenic substances. This blood purification technology can be used for renal damage caused by rapidly progressive glomerulonephritis, IgA nephropathy, Wegener's granulomatosis and polyarteritis, immune diseases such as myasthenia gravis crisis, Guillain-Barré syndrome, rheumatoid arthritis, systemic lupus erythematosus, acute drug poisoning and many other diseases. Anticoagulants are also required during plasma exchange.

[0033] Immunoadsorption Immunoadsorption (IA) is a blood purification technology developed in the past 15 years. It combines highly specific antigens, antibodies or substances (ligands) with specific physical and chemical affinity with adsorption materials (carriers) to form adsorbents (columns), which selectively or specifically remove pathogenic factors in the blood, thereby purifying the blood and alleviating the condition. Immunoadsorption therapy is different from general non-specific blood perfusion. Immunoadsorption therapy is a new technology developed on the basis of plasma exchange. Its advantages are higher selectivity for the removal of pathogenic factors in plasma, and the loss range and quantity of useful components in plasma are smaller, while avoiding various adverse effects caused by plasma transfusion. Immunoadsorption can be used to treat a variety of diseases such as rheumatism, kidney disease, nervous system diseases, blood diseases, cardiovascular diseases, etc. In the process of immunoadsorption, the use of anticoagulants is also required.

[0034] Blood anticoagulants The use of physical or chemical methods to remove or inhibit certain coagulation factors in the blood and prevent blood from clotting is called anticoagulation. Chemical reagents or substances that can prevent blood from clotting are called blood anticoagulants or blood anticoagulant substances. At present, blood anticoagulants mainly include ordinary heparin, low molecular weight heparin, heparinoids, citrate, oxalate, ethylenediaminetetraacetate, coumarin anticoagulants, hirudin, argatroban, prostaglandins, nafamostat, aspirin, etc.

[0035] Four coagulation tests The four coagulation tests include partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB). Regarding APTT, coagulation factor XII (FⅫ) in plasma can be activated by contacting anionic surfaces, and active FⅫ (FⅫa) then activates coagulation factor XI (FⅪ) to become active FⅪ (FⅪa), and then FⅪa activates coagulation factor IX (FⅨ), and active FⅨ (FⅨa) is activated on phospholipids (PL) and calcium ions (Ca 2+ ) and active coagulation factor VIII (FVIIIa), and the intrinsic coagulation pathway is initiated. The normal value of APTT is 31-43 seconds for blood from healthy people. Regarding PT, coagulation factor VII (FVII) in plasma combines with tissue factor (III) released into the blood after tissue damage to form a complex. 2+ The extrinsic coagulation pathway is activated by the participation of , and then directly activates coagulation factor X (FX) to make it active FX (FXa), and the extrinsic coagulation pathway is initiated. The normal value of PT for blood from healthy people is 11-13 seconds. Regarding TT, both the intrinsic and extrinsic coagulation pathways activate FX, thereby converting prothrombin (II) into thrombin (IIa). Thrombin can convert fibrinogen into soluble fibrin monomers. In the presence of active coagulation factor XIII (FXIII) and high concentrations of Ca 2+ With the participation of soluble fibrin monomers, they form firm insoluble fibrin polymers, which is the common pathway of blood coagulation. When testing blood from healthy people, the normal value of TT is 12-19 seconds. Regarding FIB, plasma fibrinogen is the precursor of fibrin. In the final stage of coagulation, soluble fibrinogen is converted into insoluble fibrin, which makes the blood coagulate. When testing blood from healthy people, the normal value of FIB is 2-4 g / L. When testing blood, if any two or more of APTT, PT, and TT are prolonged and the concentration of FIB is reduced after adding blood anticoagulants compared with those without adding blood anticoagulants, it indicates that the anticoagulant has excellent anticoagulant activity.

[0036] The present invention is described in detail below.

[0037] The present invention provides a use of a crystalline porous material in preparing a blood anticoagulant, wherein the crystalline porous material is a covalent organic framework material and / or a metal organic framework material. The covalent organic framework material and the metal organic framework material are used for the detection of four coagulation items, and the results show that the covalent organic framework material and the metal organic framework material can prolong the time of more than two of APTT, PT, and TT, and can reduce the FIB concentration, indicating that the covalent organic framework material and the metal organic framework material have excellent anticoagulant activity.

[0038] The blood anticoagulant of the present invention can be used in vitro. Preferably, the blood anticoagulant of the present invention is used in the extracorporeal circuit of a blood purification device. In this way, not only can the blood anticoagulant function be achieved, but the blood anticoagulant of the present invention does not enter the human body, and does not cause the continuous inactivation of coagulation factors after the completion of blood purification, thereby avoiding the delay in the recovery of hemostasis and the complications such as bleeding and organ damage that may be caused thereby, and the safety factor is higher. The blood purification device can be a hemodialysis device, a hemoperfusion device, a hemofiltration device, a plasma exchange device, an immunoadsorption device, and the like.

[0039] In addition, since the covalent organic framework materials and metal organic framework materials have good biocompatibility and good long-term effectiveness, the blood anticoagulant of the present invention can also be prepared into an implant and implanted into the patient's body for use in the prevention and treatment of thromboembolic diseases.

[0040] Preferably, the covalent organic framework material in the present invention is formed by reacting a first monomer containing an amino group and a second monomer containing an aldehyde group. Such a covalent organic framework material has better mechanical properties. More preferably, the first monomer is 1,3,5-tris(4-aminophenyl)benzene, 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) or p-phenylenediamine; the second monomer is 2,5-dihydroxyterephthalaldehyde, 4,4'-((2,3-dimethoxy-1,4-phenylene)bis-(acetylene-2,1-diyl))dibenzaldehyde, 2,5-bis( Prop-2-yn-1-yloxy)terephthalaldehyde, 2,5-dihydroxyterephthalaldehyde, 4,4′-(1,4-phenylenebis(ethyn-2,1-diyl))benzaldehyde, 4,4′-((((2,3-dimethoxy-1,4-phenylene)bis(ethyn-2,1-diyl))bis(4,1-phenylene))bis-(ethyn-2,2-diyl))benzaldehyde or 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde. The covalent organic framework material is one or more of the following: the covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalaldehyde, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as follows Figure 1As shown; the covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4′-((2,3-dimethoxy-1,4-phenylene)bis-(acetylene-2,1-diyl))dibenzaldehyde, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Figure 4 As shown; the covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Figure 7 As shown; the covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene, 2,5-dihydroxyterephthalaldehyde and 2,5-dihydroxyterephthalyldimethoxy, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.10 As shown; the covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-(1,4-phenylenebis(acetylene-2,1-diyl))dibenzaldehyde, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.13 As shown; the covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-((((2,3-dimethoxy-1,4-phenylene)bis(acetylene-2,1-diyl))bis(4,1-phenylene))bis-(acetylene-2,2-diyl))dibenzaldehyde, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is shown as Fig.16 As shown; the covalent organic framework material is formed by the reaction of p-phenylenediamine and 2,4,6-trihydroxybenzene-1,3,5-triformaldehyde, and the X-ray powder diffraction pattern of the formed covalent organic framework material is as shown Fig.19 shown.

[0041] Preferably, the metal organic framework material in the present invention is formed by the action of a metal source and an organic ligand, the metal source is selected from at least one of copper, cadmium, zinc, zirconium, and nickel, and the organic ligand is selected from at least one of trimesic acid, terephthalic acid, 2-methylimidazole, 2-aminoterephthalic acid, and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid. More preferably, the metal organic framework material is one or more of the following: the metal organic framework material is formed by the action of copper acetate monohydrate and trimesic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is as follows: Fig. 22As shown; the metal organic framework material is formed by the reaction of cadmium nitrate nine hydrate and terephthalic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is as shown Fig.25 As shown; the metal organic framework material is formed by the reaction of zinc nitrate hexahydrate and 2-methylimidazole, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.28 As shown; the metal organic framework material is formed by the reaction of zirconium tetrachloride and 2-aminoterephthalic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is as shown Fig.31 As shown; the metal organic framework material is formed by the reaction of nickel nitrate hexahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole]) dibenzoic acid, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.34 As shown; the metal organic framework material is formed by the reaction of zinc nitrate nonahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole]) dibenzoic acid, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.37 As shown; the metal organic framework material is formed by the reaction of copper nitrate trihydrate and 4,4'-(1H,1'H-[2-2'-biimidazole]) dibenzoic acid, and the X-ray powder diffraction spectrum of the formed covalent organic framework material is as shown Fig.40 shown.

[0042] In addition, the blood anticoagulant of the present invention can also be used in combination with a second blood anticoagulant, and the second blood anticoagulant is selected from one or more of the group consisting of heparin, low molecular weight heparin, heparinoids, citrate, oxalate, ethylenediaminetetraacetate, coumarin anticoagulants, hirudin, argatroban, prostaglandins, nafamostat, and aspirin. For example, the blood anticoagulant of the present invention and the second blood anticoagulant are used in the extracorporeal circuit of the blood purification device at the same time, and are used in vivo at the same time, or one of them is used in the extracorporeal circuit of the blood purification device and the other is used in vivo.

[0043] The covalent organic framework materials and metal organic framework materials used in the embodiments of the present invention can be synthesized using methods known in the art, and their structures and properties can be characterized using an infrared spectrometer, an X-ray powder diffractometer, a gas adsorption instrument, and a fully automatic coagulation analyzer smart4 (French Stago).

[0044] 1.1 Characterization of structure and basic performance The structures of covalent organic framework materials and metal organic framework materials were characterized using infrared spectrometer and X-ray powder diffractometer. The specific instruments and parameters are as follows: Infrared spectrometer: Bruker ALPHA, wavelength range 400 cm -1 ~ 4000 cm-1 , Bruker Company, USA. X-ray powder diffractometer: Model Bruker Foucus D8, Bruker Company, USA; wherein, the powder sample scanning temperature is 298 K, the pressure is 40 kV, the current is 50 mA, and the X-ray radiation source is Cu-Kα.

[0045] The pores of covalent organic framework materials and metal organic framework materials were characterized using a gas adsorption instrument. The instrument and parameters are as follows: Gas adsorption instrument: Model Quantachrome (ASiQMVH002-5), Quantachrome Company, USA; the adsorption amount of nitrogen or carbon dioxide by the prepared material was tested under standard atmospheric pressure (101 kPa), and the purity of the gas used in the test was 99.999%.

[0046] 2. Blood anticoagulant activity test The blood used in the blood anticoagulant activity test came from volunteers in the laboratory. The whole blood was collected into sodium citrate anticoagulant blood collection tubes, and the whole blood was centrifuged at 3000 rpm for 10 min to obtain plasma, which was then frozen and stored at -20 degrees.

[0047] Weigh 10 mg of covalent organic framework material and / or metal organic framework material and soak it in PBS overnight. After centrifugation at 4000 rpm for 2 min to remove PBS, add 1 mL of plasma for 2 h, centrifuge at 4000 rpm for 2 min to remove the material, and collect the plasma after contact with the material for four coagulation tests. The four coagulation tests are given by a fully automatic coagulation analyzer.

[0048] The following describes the implementation of the present invention through specific embodiments, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific implementations, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention. Example Example 1

[0049] 1,3,5-Tris(4-aminophenyl)benzene (Tapb) (30.2 mg, 0.08 mmol) and 2,5-dihydroxyterephthalaldehyde (Dhta) (21.6 mg, 0.12 mmol) were added to a mixed solvent of mesitylene and 1,4-dioxane (1.7 / 0.3 mL) to prepare a specific concentration and disperse by ultrasonication. Then 0.2 mL of 8 M acetic acid was added and the mixture was shaken to mix well. After three freeze-pump-thaw cycles, the tube was sealed and then reacted at 120°C for 3 days without interference. As the reaction proceeded, a precipitate gradually formed. The mother liquor was removed by centrifugation, the precipitate was collected, washed three times with tetrahydrofuran (THF), replaced three times with anhydrous ethanol, and then heated at 80 o C and dried under vacuum for 12 h to obtain COF-A.

[0050] Figure 1 is the X-ray powder diffraction pattern of COF-A, and curve 1 in the figure represents the simulation curve of COF-A. Those skilled in the art can obtain the simulation curve of X-ray powder diffraction of the covalent organic framework material involved in each embodiment of the present invention through a commonly used database, such as the database CSDS of the Cambridge Crystal Data Center CCDC. Curve 2 represents the measurement curve of the synthesized COF-A, and the characteristic peak in curve 2 coincides with curve 1, indicating that the above-mentioned covalent organic framework material has been successfully synthesized.

[0051] Figure 2 is the infrared spectrum of COF-A, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0052] Figure 3 N of COF-A 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-A has a mesoporous structure. Example 2

[0053] Add 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) (TBA-NH 2) (17 mg, 0.03 mmol), 4,4′-((2,3-dimethoxy-1,4-phenylene)bis-(ethynyl-2,1-diyl))benzaldehyde (18 mg, 0.045 mmol), then a mixed solution of o-dichlorobenzene / n-butanol (0.6 / 1.4 mL) was added, and then the ampoule was sealed with a sealing film and ultrasonicated for 5 minutes to mix evenly. Subsequently, 400 μL of acetic acid aqueous solution (6 M) was added, and the sealing film was sealed again and ultrasonicated for 10 minutes. Then it underwent three cycles of liquid nitrogen freezing-vacuuming-thawing, and then the ampoule was sealed by high-temperature melting in a vacuum state, and then placed in a 150 °C oven for reaction for 5 days. After the reaction was completed, the powder sample was collected and alternately soaked-standing-decanted in tetrahydrofuran and methanol, three times a day, until the supernatant no longer had fluorescence under 365 nm ultraviolet light. The sample fully soaked in methanol was then activated using a supercritical carbon dioxide dryer to obtain bright yellow powdered COF-B.

[0054] Figure 4 is the X-ray powder diffraction spectrum of COF-B. Curve 3 in the figure represents the simulation curve of COF-B, and curve 4 represents the measurement curve of the synthesized COF-B. The characteristic peak in curve 4 is consistent with curve 3, indicating that the above covalent organic framework material has been successfully synthesized.

[0055] Figure 5 is the infrared spectrum of COF-B, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0056] Figure 6 N of COF-B 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-B has a mesoporous structure. Example 3

[0057] 1,3,5-tris(4-aminophenyl)benzene (Tapb, 14.1 mg, 0.04 mmol) and 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde (Bpta, 14.5 mg, 0.06 mmol) were pre-added in a 20 mL glass bottle. Then 5 mL of acetonitrile was added to the glass bottle and sonicated until the organic monomer was completely dissolved. After that, 0.5 mL of acetic acid (12 M) was added as a catalyst. Subsequently, the mixture was gently shaken for 10 s and placed at room temperature (RT) for 72 h. After the reaction was completed, the yellow precipitate was collected by centrifugation and washed 5 times with tetrahydrofuran and ethanol, respectively. Finally, supercritical CO 2 The activated product was dried to obtain yellow powder COF-C.

[0058] Figure 7is the X-ray powder diffraction spectrum of COF-C. Curve 5 in the figure represents the simulation curve of COF-C, and curve 6 represents the measurement curve of the synthesized COF-C. The characteristic peak in curve 6 is consistent with curve 5, indicating that the above covalent organic framework material has been successfully synthesized.

[0059] Figure 8 is the infrared spectrum of COF-C, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0060] Fig. 9 N of COF-C 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-C has a mesoporous structure. Example 4

[0061] 1,3,5-Tris(4-aminophenyl)benzene (Tapb) (28.1 mg, 0.08 mmol), 2,5-dihydroxyterephthalaldehyde (Dhta) (10 mg, 0.06 mmol) and 2,5-dihydroxyterephthalaldehyde (DMA) (11.7 mg, 0.06 mmol) were added to a mixed solvent of o-dichlorobenzene and n-butanol (1 / 1 mL) to prepare a specific concentration and dispersed by ultrasonication. Then 0.2 mL of 6M acetic acid solution was added and shaken. After three freeze-pump-thaw cycles, the tube was sealed and then reacted at 120°C for 3 days without interference. As the reaction proceeded, a precipitate gradually formed. The mother liquor was removed by centrifugation, and the precipitate was collected, washed with tetrahydrofuran (THF) three times, replaced with acetone three times, and then dried in vacuum at 120°C for 12 h to obtain COF-D.

[0062] Fig.10 is the X-ray powder diffraction spectrum of COF-D. Curve 7 in the figure represents the simulation curve of COF-D, and curve 8 represents the measurement curve of the synthesized COF-D. The characteristic peak in curve 8 is consistent with curve 7, indicating that the above covalent organic framework material has been successfully synthesized.

[0063] Fig.11 is the infrared spectrum of COF-D, where 1642 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0064] Fig.12 N of COF-D 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-D has a mesoporous structure. Example 5

[0065] Add TBA-NH to a 10 mL ampoule.2 (17 mg, 0.03 mmol), BD-CHO (15 mg, 0.045mmol), then add a mixed solution of o-dichlorobenzene / n-butanol (0.7 / 0.3 mL), then seal the ampoule with a sealing film and sonicate for 5 minutes to mix the added building monomers evenly. Then add 200mL of acetic acid aqueous solution (6 M), seal the ampoule again and sonicate for 10 minutes. Then undergo three cycles of liquid nitrogen freezing-vacuuming-thawing, then melt the sealed ampoule at high temperature in a vacuum state, and then place it in a 150 °C oven for 5 days. After the reaction is completed, the powder sample is collected and alternately soaked-standing-decanted in tetrahydrofuran and methanol, three times a day, until the supernatant no longer has fluorescence under 365 nm wavelength ultraviolet light. Then the sample fully soaked in methanol is activated using a supercritical carbon dioxide dryer to obtain bright yellow powder COF-E.

[0066] Fig.13 is the X-ray powder diffraction spectrum of COF-E. Curve 9 in the figure represents the simulation curve of COF-E, and curve 10 represents the measurement curve of the synthesized COF-E. The characteristic peak in curve 10 is consistent with curve 9, indicating that the above covalent organic framework material has been successfully synthesized.

[0067] Fig.14 is the infrared spectrum of COF-E, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0068] Fig.15 N of COF-E 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-E has a mesoporous structure. Example 6

[0069] Add TBA-NH to a 10 mL ampoule. 2(12 mg, 0.02 mmol), BDMBD-CHO (18 mg, 0.03mmol), and then add a mixed solution of mesitylene / 1,4-dioxane (1.0 / 1.0 mL), then seal the ampoule with a sealing film and sonicate for 5 minutes to mix the added building monomers evenly. Then add 200 mL of acetic acid aqueous solution (6 M), seal the ampoule again and sonicate for 10 minutes. Then undergo three cycles of liquid nitrogen freezing-vacuuming-thawing, then melt the sealed ampoule at high temperature in a vacuum state, and then place it in a 150 °C oven for 5 days. After the reaction is completed, the powder sample is collected and alternately soaked-standing-decanted in tetrahydrofuran and methanol, three times a day, until the supernatant no longer has fluorescence under 365 nm wavelength ultraviolet light. Then the sample fully soaked in methanol is activated using a supercritical carbon dioxide dryer to obtain bright yellow powder COF-F.

[0070] Fig.16 is the X-ray powder diffraction spectrum of COF-F. Curve 11 in the figure represents the simulation curve of COF-F, and curve 12 represents the measurement curve of the synthesized COF-F. The characteristic peak in curve 12 is consistent with curve 11, indicating that the above covalent organic framework material has been successfully synthesized.

[0071] Fig.17 is the infrared spectrum of COF-F, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0072] Fig.18 N of COF-F 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that COF-F has a mesoporous structure. Example 7

[0073] 33 mg of p-phenylenediamine and 70 mg of 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde were weighed and dissolved in a mixture of 1.5 mL of 1,4-dioxane and 1.5 mL of mesitylene and sonicated in a Pyrex tube for 10 minutes to allow for uniform mixing. Then, 0.5 mL of 3 M acetic acid was added and sonicated for another 10 minutes. The tube was degassed by three freeze-pump-thaw cycles, evacuated to an internal pressure of 150 mTorr, and flame-sealed. The sealed tube was warmed to room temperature and then transferred to an oven and heated at 120 °C for 3 days. A light red powder was isolated and thoroughly washed with THF and ethanol. Finally, the wet sample was dried using a supercritical carbon dioxide dryer to obtain COF-G.

[0074] Fig.19is the X-ray powder diffraction spectrum of COF-G. Curve 13 in the figure represents the simulation curve of COF-G, and curve 14 represents the measurement curve of the synthesized COF-G. The characteristic peak in curve 14 is consistent with curve 13, indicating that the above covalent organic framework material has been successfully synthesized.

[0075] Fig. 20 is the infrared spectrum of COF-G, where 1640 cm -1 The appearance of the characteristic peak of imine bond indicated that the monomers were covalently bound.

[0076] Fig.21 N of COF-G 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type I, indicating that COF-G has a microporous structure. Example 8

[0077] Trimesic acid (BTC, 2.1 g, 10 mmol) and Cu(OAc) were added to a mixed solution of 400 mL ethanol and water (1:1). 2 ·H 2 O (3.21 g, 16 mmol) was heated at 110 °C for 4 h. The product was obtained by centrifugation, washed with ethanol 4 times, and dried in vacuum to obtain MOF-A.

[0078] Fig. 22 is the X-ray powder diffraction spectrum of MOF-A. Curve 15 in the figure represents the simulation curve of MOF-A, and curve 16 represents the measurement curve of the synthesized MOF-A. The characteristic peak in curve 16 is consistent with curve 15, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0079] Fig.23 This is the infrared spectrum of MOF-A, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0080] Fig.24 N of MOF-A 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type I, indicating that MOF-A has a microporous structure. Example 9

[0081] 2 g of chromium nitrate nonahydrate and 0.83 g of terephthalic acid were added to 20 mL of deionized water and ultrasonically treated for 30 min. The dark blue suspension was then transferred to a stainless steel reactor lined with polytetrafluoroethylene for reaction and heated at 218 °C for 18 h. After the reaction was completed, the hydrothermal reactor was taken out and cooled at room temperature. The sample was washed several times with N,N-dimethylformamide (DMF) and ethanol and dried at 65 °C overnight to obtain MOF-B.

[0082] Fig.25 is the X-ray powder diffraction spectrum of MOF-B. Curve 17 in the figure represents the simulation curve of MOF-B, and curve 18 represents the measurement curve of the synthesized MOF-B. The characteristic peak in curve 18 is consistent with curve 17, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0083] Fig.26 This is the infrared spectrum of MOF-B, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0084] Fig. 27 N of MOF-B 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type IV, indicating that MOF-B has a mesoporous structure. Example 10

[0085] Take 2.4 g of zinc nitrate hexahydrate and dissolve it in 30 mL of methanol solution. Stir it with a magnetic stirrer for 1 h at room temperature and record it as solution A. Take 5.2 g of 2-methylimidazole and dissolve it in 30 mL of methanol solution. Stir it with a magnetic stirrer for 1 h at room temperature and record it as solution B. Mix solution A and solution B and stir them at room temperature for 12 h. Centrifuge the obtained white emulsion to obtain a white solid substance, wash it three times with methanol, and dry it at 65 °C overnight to obtain MOF-C.

[0086] Fig.28 is the X-ray powder diffraction spectrum of MOF-C. Curve 19 in the figure represents the simulation curve of MOF-C, and curve 20 represents the measurement curve of the synthesized MOF-C. The characteristic peak in curve 20 is consistent with curve 19, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0087] Fig.29 This is the infrared spectrum of MOF-C, in which the characteristic peak of the NH bond in 2-methylimidazole does not appear, proving the successful synthesis of MOF-C.

[0088] Fig.30 N of MOF-C 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type I, indicating that MOF-C has a microporous structure. Embodiment 11

[0089] Take a 50 mL beaker and pipette 13.2 ml of N, N-dimethylformamide into the beaker, then pipette 2.7 mL of glacial acetic acid into the beaker, weigh 0.0093 g of zirconium tetrachloride into the beaker, and ultrasonicate until the zirconium tetrachloride is dissolved to obtain solution 1. Take another 10 mL beaker, pipette 4 mL of N, N-dimethylformamide into a 10 mL beaker, add 0.028 g of 2-aminoterephthalic acid, and stir for 5 minutes to obtain solution 2. Transfer solution 2 to the beaker of solution 1 and continue stirring for 10 minutes to obtain solution 3. Transfer all of solution 3 into a 50 ml stainless steel reactor lined with polytetrafluoroethylene, put it in an oven, heat the oven by 20 °C per hour, keep it at 120 °C for 36 hours, cool it down, filter it, wash it with ethanol stirring twice, each time for 12 hours, filter it and dry it to obtain a light yellow sample MOF-D.

[0090] Fig.31 It is the X-ray powder diffraction spectrum of MOF-D. Curve 21 in the figure represents the simulation curve of MOF-D, and curve 22 represents the measurement curve of the synthesized MOF-D. The characteristic peak in curve 22 is consistent with curve 21, indicating that the above-mentioned metal organic framework material is successfully synthesized.

[0091] Fig.32 This is the infrared spectrum of MOF-D, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0092] Fig.33 N of MOF-D 2 The adsorbent-desorption curve spectrum and the adsorption isotherm curve show type I, indicating that MOF-D has a microporous structure. Example 12

[0093] MOF-E is made of Ni(NO 3 ) 2 6H 2 O (0.0174 g, 0.06 mmol), 4,4'-(1H,1'H-[2-2'-biimidazole]) (H 2 BDA, 0.0224 g, 0.06 mmol), DMF (5.5 mL), and NH 3 ·H 2 O (0.3 mL) was sonicated in a sealed 20 mL glass bottle for 3 min until a homogeneous turbid solution was obtained and then heated to 120 °C. o The reaction mixture was heated in a Yamato oven at 400 °C for 48 h. After the oven was cooled to room temperature, the green flaky crystals obtained from the mother liquor were separated, washed several times with DMF and ethanol, and dried in vacuum at 60 °C for 8 h.

[0094] Activation conditions of MOF-E: The sample after replacement with ethanol and drying was placed in a glass tube and heated at 120 o C for 8 hours under vacuum.

[0095] Fig.34 is the X-ray powder diffraction spectrum of MOF-E. Curve 23 in the figure represents the simulation curve of MOF-E, and curve 24 represents the measurement curve of the synthesized MOF-E. The characteristic peak in curve 24 is consistent with curve 23, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0096] Fig.35 This is the infrared spectrum of MOF-E, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0097] Fig.36 This is the carbon dioxide adsorption-desorption curve of MOF-E. The adsorption isotherm curve shows type I, indicating that MOF-E has a microporous structure. Example 13

[0098] MOF-F is composed of Zn(NO 3 ) 2 9H 2 O (0.0535 g, 0.18 mmol), H 2 BDA (0.0224 g, 0.06mmol), DMF (5.6 mL) and NH 3 ·H 2 O (0.4 mL) was sonicated in a sealed 20 mL glass bottle for 3 min until a homogeneous turbid solution was obtained and then heated to 120 °C. o C in a Yamato oven for 48 hours. After the oven was cooled to room temperature, the colorless rod-shaped crystals obtained by separating the mother liquor were washed several times with DMF and ethanol and heated at 60 o C for 8 hours in vacuum.

[0099] MOF-F activation conditions: The sample was replaced with ethanol and dried in a glass tube at 120 o C for 8 hours under vacuum.

[0100] Fig.37 is the X-ray powder diffraction spectrum of MOF-F. Curve 25 in the figure represents the simulation curve of MOF-F, and curve 26 represents the measurement curve of the synthesized MOF-F. The characteristic peak in curve 26 is consistent with curve 25, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0101] Fig.38This is the infrared spectrum of MOF-F, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0102] Fig.39 This is the carbon dioxide adsorption-desorption curve of MOF-F. The adsorption isotherm curve shows type I, indicating that MOF-F has a microporous structure. Embodiment 14

[0103] MOF-G is composed of Cu(NO 3 ) 2 ·3H 2 O (0.0535 g, 0.06 mmol), H 2 BDA (0.0224 g, 0.06mmol), DMF (7 mL) and NH 3 ·H 2 O (0.3 mL) was sonicated in a sealed 20 mL glass bottle for 3 min until a homogeneous turbid solution was obtained and then heated to 120 °C. o C in a Yamato oven for 48 h. After the oven was cooled to room temperature, the blue rod-shaped crystals obtained from the mother liquor were separated, washed several times with DMF and ethanol, and heated at 60 o C for 8 hours in vacuum.

[0104] Activation conditions of MOF-G: The sample washed three times by centrifugation with ethanol was placed in a Soxhlet extractor and precipitated at 70 °C with acetone as solvent. o C for 48 hours, and then o C for 8 hours in vacuum.

[0105] Fig.40 is the X-ray powder diffraction spectrum of MOF-G. Curve 27 in the figure represents the simulation curve of MOF-G, and curve 28 represents the measurement curve of the synthesized MOF-G. The characteristic peak in curve 28 is consistent with curve 27, indicating that the above-mentioned metal organic framework material has been successfully synthesized.

[0106] Fig.41 This is the infrared spectrum of MOF-G, in which there are no characteristic peaks corresponding to free carboxylic acid groups, proving that all the carboxylic acid groups in the ligand are coordinated with the metal.

[0107] Fig.42 This is the carbon dioxide adsorption-desorption curve of MOF-G. The adsorption isotherm curve shows type I, indicating that MOF-G has a microporous structure. Embodiment 15

[0108] For the covalent organic framework materials and metal organic framework materials in Examples 1-14, four blood coagulation tests were performed according to the method described in "(II) Blood anticoagulant activity test" of this application specification. The results are as follows: Figure 43-50 shown. Fig.43 and 44 The activated partial thromboplastin time (APTT) of Examples 1-14 shows that the activated partial thromboplastin time of the experimental group added with the blood anticoagulant of the present invention is prolonged compared with the plasma control group not added with the blood anticoagulant of the present invention. Figures 45-48 It can be seen that compared with the control group, the plasma prothrombin time (PT) and thrombin time (TT) of the experimental group added with the blood anticoagulant of the present invention were prolonged to varying degrees. Figures 49-50 As described above, compared with the control group, the fibrinogen concentration (FIB) of the experimental group to which the blood anticoagulant of the present invention was added was reduced. It can be seen that the covalent organic framework material and the metal organic framework material have excellent anticoagulant activity.

Claims

1. Use of crystalline porous materials in the preparation of blood anticoagulants, It is characterized in that The crystalline porous material is a covalent organic framework material and / or a metal organic framework material.

2. The use according to claim 1, It is characterized in that The blood anticoagulant is used in the extracorporeal circuit of a blood purification device.

3. The use according to claim 2, It is characterized in that The blood purification device is selected from the group consisting of a hemodialysis device, a hemoperfusion device, a hemofiltration device, a plasma exchange device and an immunoadsorption device.

4. The use according to claim 1, It is characterized in that The blood anticoagulant is implanted in a patient for use.

5. The use according to claim 1, It is characterized in that The blood anticoagulant prolongs at least two of the activated partial thromboplastin time, the prothrombin time, and the plasma thromboplastin time, and reduces the fibrinogen concentration.

6. The use according to claim 5, It is characterized in that The blood anticoagulant prolongs the activated partial thromboplastin time, the prothrombin time and the plasma thrombin time, and reduces the fibrinogen concentration.

7. The use according to claim 1, It is characterized in that The covalent organic framework material is formed by reacting a first monomer containing an amino group and a second monomer containing an aldehyde group.

8. The use according to claim 7, It is characterized in that The first monomer is 1,3,5-tris(4-aminophenyl)benzene, 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) or p-phenylenediamine.

9. The use according to claim 7, It is characterized in that The second monomer is 2,5-dihydroxyterephthalaldehyde, 4,4′-((2,3-dimethoxy-1,4-phenylene)bis-(ethyn-2,1-diyl))benzaldehyde, 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde, 2,5-dihydroxyterephthalaldehyde, 4,4′-(1,4-phenylenebis(ethyn-2,1-diyl))benzaldehyde, 4,4′-(((2,3-dimethoxy-1,4-phenylene)bis(ethyn-2,1-diyl))bis(4,1-phenylene))bis-(ethyn-2,2-diyl))benzaldehyde or 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde.

10. The use according to claim 7, It is characterized in that The covalent organic framework material is one or more of the following: The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-dihydroxyterephthalaldehyde, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG1 ; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-((2,3-dimethoxy-1,4-phenylene)bis-(acetylene-2,1-diyl))dibenzaldehyde. The X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG4 ; The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene and 2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG7 ; The covalent organic framework material is formed by the reaction of 1,3,5-tris(4-aminophenyl)benzene, 2,5-dihydroxyterephthalaldehyde and 2,5-dihydroxyterephthalyloxy. The X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG10 ; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-(1,4-phenylenebis(acetylene-2,1-diyl))dibenzaldehyde. The X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG13 ; The covalent organic framework material is formed by the reaction of 4',4''',4'''''-(1,3,5-triazine-2,4,6-triyl)tris(([[1,1'-biphenyl]-4-amine)) and 4,4'-((((2,3-dimethoxy-1,4-phenylene)bis(acetylene-2,1-diyl))bis(4,1-phenylene))bis-(acetylene-2,2-diyl))dibenzaldehyde, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG16 ; The covalent organic framework material is formed by the reaction of p-phenylenediamine and 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde. The X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG19 .

11. The use according to claim 1, It is characterized in that The metal organic framework material is formed by the action of a metal source and an organic ligand, wherein the metal source is selected from at least one of copper, chromium, zinc, zirconium and nickel, and the organic ligand is selected from at least one of trimesic acid, terephthalic acid, 2-methylimidazole, 2-aminoterephthalic acid and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid.

12. The use according to claim 11, It is characterized in that The metal organic framework material is one or more of the following: The metal organic framework material is formed by the reaction of copper acetate monohydrate and trimesic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG22 ; The metal organic framework material is formed by the reaction of cadmium nitrate nonahydrate and terephthalic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG25 ; The metal organic framework material is formed by the reaction of zinc nitrate hexahydrate and 2-methylimidazole, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG28 ; The metal organic framework material is formed by the reaction of zirconium tetrachloride and 2-aminoterephthalic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG31 ; The metal organic framework material is formed by the reaction of nickel nitrate hexahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG34 ; The metal organic framework material is formed by the reaction of zinc nitrate nonahydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG37 ; The metal organic framework material is formed by the reaction of copper nitrate trihydrate and 4,4'-(1H,1'H-[2-2'-biimidazole])dibenzoic acid, and the X-ray powder diffraction pattern of the formed covalent organic framework material is shown in FIG40 .

13. The use according to any one of claims 1 to 12, It is characterized in that The crystalline porous material is used in combination with a second blood anticoagulant.

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