Polymer compound and use thereof

Abstract

Provided are a novel polymer compound, composition, substrate, and medical device, each exhibiting excellent antithrombotic properties. Provided is a polymer compound having a main chain containing a sequence of mutually bonded carbon atoms, wherein a group containing a structure contributing to the retention of intermediate water is bonded as a side chain to the main chain at a portion of the carbon atoms, the polymer compound being characterized in that the sequence of carbon atoms includes a portion in which two or more carbon atoms to which side chains are bonded are consecutively present.

Description

Polymer compounds and their uses

[0001] This invention relates to polymer compounds and their use. This application claims priority based on the application filed in the United States on September 10, 2024 (Application No. 63 / 692,719), the contents of which are incorporated herein by reference.

[0002] In recent years, research into medical materials utilizing various polymer materials has progressed, and their use is expected in applications such as artificial kidney membranes, plasma separation membranes, catheters, stents, artificial lung membranes, and artificial blood vessels. Since synthetic materials, which are foreign to the body, will be used in contact with biological tissues and blood, biocompatibility is required for medical materials. When medical materials are used in contact with blood, the suppression of platelet adhesion and activation is an important aspect of biocompatibility.

[0003] It has been revealed that biocompatible substances can contain water molecules in a state called "intermediate water" (see Patent Document 1). Intermediate water refers to water in which, during the heating process from -100°C, a sharp exothermic peak originating from cold crystallization (hereinafter abbreviated as "CC") based on low-temperature crystallization of water is observed in the temperature range of -60°C to less than 0°C. This low-temperature crystallization is a dislocation from amorphous ice to crystalline ice, and is thought to be water organized by specific interactions with polymer chains.

[0004] Patent No. 7586496

[0005] The present invention aims to provide novel polymer compounds, compositions, substrates, and medical devices that exhibit excellent antithrombotic properties.

[0006] The present invention includes the following aspects. [1] A polymer compound having a main chain containing a chain of mutually bonded carbon atoms, and a group containing a structure contributing to the inclusion of interstitial water is bonded as a side chain to a part of the carbon atoms to the main chain, wherein the chain of carbon atoms includes a portion where two or more carbon atoms to which side chains are bonded are continuously present. [2] The polymer compound according to [1], wherein the ratio of the carbon atoms to which side chains containing a structure contributing to the inclusion of interstitial water are bonded among the carbon atoms contained in the main chain of the polymer compound is more than 1 / 2 and 1 or less. [3] The polymer compound according to [2], wherein the ratio of the carbon atoms to which side chains containing a structure contributing to the inclusion of interstitial water are bonded among the carbon atoms contained in the main chain of the polymer compound is 1. [4] The polymer compound according to [1], characterized by containing a monomer unit represented by the following formula (1).

[0007] [In formula (1), R １ is a hydrogen atom or a monovalent hydrocarbon group which may have an ether bond, R ２ is a linker part, and is selected from unit structures having an ester bond, an ether bond, an amide bond, a disulfide bond, a silylene group, a phenylene group, an alkylene group having 1 carbon atom or a combination thereof, R ３ is a divalent hydrocarbon group which may have an ether bond, R ４ is a monovalent linear hydrocarbon group having 1 to --6 carbon atoms which may have an ether bond. ] [5] The polymer compound according to [4], wherein R ２ is an ester bond, and R ３ is --(CH ２ ). ｍ --(m is 1 or more and 5 or less). [6] The polymer compound according to [4], wherein R ４ is a methyl group. [7] The polymer compound according to [1], wherein the glass transition temperature Tg when containing water is -10°C or lower.

[0008] [8] A composition characterized by containing a polymer compound as described in any of [1] to [7]. [9] The composition according to [8], characterized by being an antithrombotic material.

[10] A substrate comprising at least one of a resin, a metal, or a ceramic, wherein at least a portion of the surface of the substrate is coated with the composition according to [8].

[11] A medical device characterized by containing the substrate according to

[10] .

[0009] According to the present invention, it is possible to provide novel polymer compounds, compositions, substrates, and medical devices that exhibit excellent antithrombotic properties.

[0010] This is a schematic diagram showing the structure of the aqueous layer formed on the surface of a hydrated compound. This diagram explains the characteristics of each layer constituting the aqueous layer formed on the surface of a hydrated compound. This figure shows the results of measuring the release of latent heat by DSC for the polymer compounds (at saturated water content) of the examples and comparative examples. This figure shows the results of measuring the absorption of latent heat by DSC for the polymer compounds (at saturated water content) of the examples and comparative examples. This figure shows the results of measuring the release of latent heat by DSC for the polymer compounds (without free water) of the examples and comparative examples. This figure shows the results of measuring the absorption of latent heat by DSC for the polymer compounds (without free water) of the examples and comparative examples. The number of moles of antifreeze water per mole of polymer compound of the examples and comparative examples was calculated. The number of moles of intermediate water per mole of polymer compound of the examples and comparative examples was calculated. These are photographs of platelets at levels 1 to 3 in the platelet adhesion test of the examples. This figure shows the results of the platelet adhesion test of the examples.

[0011] (Polymer Compound) The polymer compound according to this embodiment has a main chain comprising rows of interconnected carbon atoms. A group containing a structure that contributes to the inclusion of intermediate water is bonded to a portion of the interconnected carbon atoms as a side chain to the main chain. The rows of interconnected carbon atoms include portions where two or more carbon atoms to which the side chain is bonded exist consecutively.

[0012] <Main Chain> The main chain of the polymer compound according to this embodiment includes a row of carbon atoms bonded to each other. In the row of carbon atoms, the bonds between carbon atoms can be saturated bonds or double bonds, with saturated bonds being preferred.

[0013] The main chain of the polymer compound according to this embodiment may or may not have atoms other than carbon atoms bonded to each other. Examples of atoms other than carbon atoms bonded to each other include nitrogen atoms, oxygen atoms, sulfur atoms, silicon atoms, boron atoms, phosphorus atoms, and the like.

[0014] The polymer compound according to this embodiment may contain intermediate water by including a structure that contributes to the inclusion of intermediate water. Intermediate water will be described in detail below. Hereinafter, the polymer compound and other compositions according to this embodiment may be referred to as hydrating compounds.

[0015] <Intermediate Water> Intermediate water is thought to be a collection of water molecules contained in a hydrated compound, in which their degrees of freedom are restricted by weak interactions with the hydrated compound. It has been confirmed that surfaces where intermediate water is present exhibit blood compatibility, such as difficulty for blood components such as blood cells to adhere. The mechanism by which surfaces with intermediate water exhibit blood compatibility is thought to be as follows.

[0016] It is believed that the surface of various cells in the blood, such as hematopoietic cells, is stabilized by the formation of a hydration shell, which suppresses unwanted activation when they come into contact with biological tissues. On the other hand, it is thought that when this hydration shell comes into direct contact with a foreign surface, it is disturbed or destroyed, leading to adhesion to the foreign surface and activation. A typical example of this is the reaction in which platelets, which are stably present in blood vessels, become activated and cause blood to coagulate when they come into contact with a foreign surface due to bleeding, etc.

[0017] In contrast, on the surface of a hydrated compound containing intermediate water, the intermediate water forms a kind of hydration shell, acting as a cushion to prevent biomaterials from directly contacting the surface (Figure 1). As a result, disturbance of hydration shells of cells and proteins that come into contact with the surface is suppressed. This is thought to result in blood compatibility, such as difficulty in the adhesion of blood components. Furthermore, since intermediate water has been confirmed to be present on the surfaces of various cells and within the hydration shells formed by proteins, it is thought that the surface of a hydrated compound containing intermediate water mimics the structure of the surface of biological tissue. The polymer compound according to this embodiment is preferably an antithrombotic material.

[0018] The phenomenon of inhibiting the adhesion of various cells and other organisms on the surface of hydrated compounds containing intermediate water is particularly pronounced on the surface of hydrated compounds containing large amounts of intermediate water, and it has been confirmed that it can inhibit the adhesion of almost all cells and other organisms present in blood.

[0019] It has been revealed that when hydrated compounds are saturated with water, the state of the water molecules can be broadly classified into three types (Figure 2).

[0020] Water molecules most strongly affected by hydrating compounds are in a state that could be called "crystalline water," where they are strongly constrained by the hydrating compound and cannot move freely as water molecules. Because they cannot freeze and form solid water (ice) even when cooled to extremely low temperatures, they are classified as "nonfreezing water." Generally, in the initial stages of water absorption (when the water content is low), all of the absorbed water molecules form nonfreezing water.

[0021] On the other hand, saturated hydrated compounds contain water molecules that are hardly constrained by the composition molecules and behave similarly to water molecules in pure water; these water molecules are classified as "free water." Free water is characterized by its ability to coagulate and dissolve at around 0°C, similar to pure water. Conversely, when bio-related substances such as proteins or certain synthetic polymers are hydrated, it has been shown that there are water molecules that exhibit behavior not classified as "nonfreezing water" or "free water"; these water molecules are classified as "intermediate water."

[0022] Intermediate water is typically characterized by unique latent heat release and absorption observed during the heating process after supercooling. Specifically, in substances containing intermediate water, unique latent heat release and absorption are observed during cooling or heating in the temperature range of -100 to -20°C, such as latent heat release around -50 to -20°C or latent heat absorption in the temperature range of -15°C to 0°C. Such latent heat release and absorption can be quantitatively observed using a differential scanning calorimetry (DSC) or similar equipment.

[0023] The latent heat release in the -50 to -20°C range corresponds to the latent heat released when the intermediate water, which solidified in an irregular state during rapid cooling, undergoes a cold crystallization (CC) transformation during the subsequent gradual heating process. The latent heat absorption in the -15°C to 0°C range corresponds to the latent heat released when the ordered intermediate water undergoes a phase transformation (melting) and the melting of free water.

[0024] For hydrated compounds containing water, the glass transition temperature Tg corresponds to the baseline change that corresponds to the change in specific heat observed by methods such as DSC (Differential Scanning Calorimetry).

[0025] The amount of intermediate water contained in a hydrated compound can be calculated from the amount of latent heat transfer (enthalpy change) due to the phase transformation of the intermediate water. Specifically, by observing the amount of latent heat transfer during the cooling or heating of a hydrated compound containing water in the temperature range of -100 to -20°C using a DSC or similar device, the amount of latent heat released (ΔHcc) around -50 to -20°C can be measured, and by dividing this by the latent heat of fusion of water (Cp: 334 J / g) according to equation (1), the amount of intermediate water (Wfb) contained in the hydrated compound can be calculated. Wfb (g) = ΔHcc (J) / Cp (J / g) ...Equation (1)

[0026] Furthermore, if the amount of free water (Wf) contained in a hydrated compound can be calculated, for example, from the amount of latent heat released near 0°C during the cooling process, the amount of intermediate water contained in the hydrated compound can also be calculated by subtracting the amount of absorption expected to be due to free water from the amount of latent heat absorbed in the temperature range of -15°C to 0°C during the heating process (ΔHm) to obtain the amount of absorption due to the melting of ordered intermediate water, and then dividing this by the latent heat of fusion of water. In addition, since the antifreeze water contained in a hydrated compound does not undergo phase transformation within the range of measurement by DSC, etc., it is difficult to calculate the amount of antifreeze water (Wnf) from the amount of latent heat transfer. For this reason, the amount of antifreeze water contained in a hydrated compound is calculated by subtracting the amount corresponding to intermediate water and free water from the total water content (Wc).

[0027] The cell adhesion particles according to the present invention are used in contact with aqueous solutions such as blood. Therefore, when used, the hydration compounds on the surface of the cell adhesion particles reach saturation water content, and the intermediate water content at that time is defined as the saturated intermediate water content (SWfb). Table 1 shows an example of the results of the inventors' measurements of the saturated intermediate water content for various hydration compounds. Note that the saturated intermediate water content fluctuates depending on the molecular weight of the polymer used for measurement and does not correspond to a constant, unchanging physical property value. Therefore, when manufacturing cell adhesion particles according to the present invention, it is desirable to confirm the intermediate water content for each hydration compound used.

[0028]

[0029] As shown in Table 1, intermediate water is contained in various hydrating compounds, and it is known that the saturated intermediate water content changes depending on the molecular structure. Furthermore, intermediate water is known to be present in a large proportion of bio-derived polymers such as BSA.

[0030] <Groups containing structures that contribute to the inclusion of intermediate water> Preferred structures that contribute to the inclusion of intermediate water include ether bonds (-O-), carbon-nitrogen bonds (C-N), sulfide bonds (-S-), or betaine structures that are electrically neutral in the biological environment.

[0031] Groups containing structures that contribute to the inclusion of intermediate water may be linear, cyclic, or have both structures. Preferably, the oxygen atom constituting the ether bond, the nitrogen atom constituting the carbon-nitrogen bond, or the sulfur atom constituting the sulfide bond, and the carbon atoms adjacent to them constitute a linear hydrocarbon group.

[0032] A betaine structure refers to a structure in which the cation and anion moieties are located in separate, non-adjacent positions within the same molecule.

[0033] A cationic group is a group of atoms that carries a positive charge, and is referred to as a cationic group. Examples of cationic groups include primary amino groups, secondary amino groups (-NHR), and tertiary amino groups (-NR). ２ ), quaternary ammonium group (-NR ３ ＋ Examples include ), and imino groups. In secondary amino groups, tertiary amino groups, and quaternary ammonium groups, R is an alkyl group or an aryl group. When a single group has multiple Rs, the Rs may be different or the same. Examples of Rs include methyl groups, ethyl groups, and propyl groups. Cationic groups also include salt forms formed with anions such as fluoride ions, chloride ions, bromide ions, iodide ions, hydrochloride ions, acetate ions, sulfate ions, hydrofluoric acid ions, and carbonate ions.

[0034] An anionic moiety is a group of atoms that carries a negative charge, and is referred to as an anionic group. Examples of anionic groups include phosphate groups, phosphonic acid groups, phosphinic acid groups, sulfonic acid groups, sulfen groups, carboxyl groups, hydroxyl groups, thiol groups, and boronic acid groups. Phosphate groups are preferred. Anionic groups also include salt forms, which are formed by salts with alkali metal ions such as sodium ions and potassium ions, and alkaline earth metal ions such as calcium ions.

[0035] Preferred betaine structures that are electrically neutral in a biological environment include phosphobetaine structures, carboxybetaine structures, sulfobetaine structures, or aminooxide structures.

[0036] When a polymer compound has groups containing structures that contribute to the inclusion of two or more intermediate water molecules, these groups may be identical or different.

[0037] The ratio of the number of carbon atoms to which a side chain containing a structure that contributes to the inclusion of intermediate water is attached, relative to the total number of carbon atoms in the main chain of the polymer compound, is preferably greater than 1 / 2 and less than or equal to 1, more preferably between 3 / 5 and 1, even more preferably between 3 / 4 and 1, particularly preferably between 4 / 5 and 1, and most preferably 1.

[0038] <Monomer Unit> The polymer compound according to this embodiment preferably contains a monomer unit represented by the following formula (1).

[0039] [In equation (1), R 1 R is a monovalent hydrocarbon group which may have a hydrogen atom or an ether bond, ２ The linker portion is selected from a unit structure having an ester bond, an ether bond, an amide bond, a disulfide bond, a silylene group, a phenylene group, a one-carbon alkylene group, or a combination thereof, R ３ R is a divalent hydrocarbon group which may have an ether bond, ４ This is a monovalent, chain-like hydrocarbon group having 1 to 6 carbon atoms, which may have an ether bond.

[0040] In this specification, the hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group. The hydrocarbon group may be a linear hydrocarbon group or a cyclic hydrocarbon group. The linear hydrocarbon group may be a straight chain or a branched chain. The cyclic hydrocarbon group may be an aliphatic hydrocarbon group or an aromatic group. The cyclic hydrocarbon group may be a monocyclic group or a polycyclic group.

[0041] In this specification, an aromatic group is a group having at least one aromatic ring. The aromatic ring is not particularly limited as long as it is a cyclic conjugated system having 4n+2 π electrons, and may be monocyclic or polycyclic. The aromatic ring may have substituents that substitute for the hydrogen atoms of the aromatic ring. Examples of aromatic rings include aromatic hydrocarbon rings and aromatic heterocycles in which part of the ring skeleton is composed of heteroatoms.

[0042] In this specification, specific examples of aromatic hydrocarbon rings include benzene, naphthalene, anthracene, and phenanthrene. Examples of heteroatoms in aromatic heterocycles include oxygen atoms, sulfur atoms, and nitrogen atoms. Specific examples of aromatic heterocycles include pyridine rings and thiophene rings.

[0043] R 1 The number of carbon atoms in the hydrocarbon group is preferably 1 to 30, more preferably 1 to 20, even more preferably 1 to 10, particularly preferably 1 to 7, and most preferably 1 to 4. 1 A hydrogen atom is preferred as the element.

[0044] R ２ Preferably, one selected from the group consisting of ester bonds and ether bonds is preferred, with ester bonds being more preferred.

[0045] R ３ In this, a divalent chain hydrocarbon group is preferred. From the viewpoint of enhancing antithrombotic properties, ３ The number of carbon atoms in the hydrocarbon group is, for example, 1 to 6, preferably 1 to 5, more preferably 1 to 4, and even more preferably 1 to 3. ３ As for, - (CH ２ ) ｍ - (m is preferably 1 or more and 5 or less). m is preferably 1 to 5, more preferably 1 to 4, and even more preferably 1 to 3.

[0046] R ４ The number of carbon atoms in the chain hydrocarbon group is preferably 1 to 6, more preferably 1 to 4, even more preferably 1 to 2, and a methyl group is particularly preferred.

[0047] -R ２-R ３ -O-R ４ The groups represented by the following formulas (S-1) to (S-4) are preferred, the groups represented by the following formulas (S-1) to (S-3) are more preferred, and the groups represented by the following formulas (S-1) to (S-2) are even more preferred.

[0048] [In the formula, * represents a bond that connects to the carbon atoms of the main chain in formula (1) above.]

[0049] The monomer unit represented by formula (1) is preferably the monomer unit represented by the following formulas (1-1) to (1-4), more preferably the monomer unit represented by the following formulas (1-1) to (1-3), and even more preferably the monomer unit represented by the following formulas (1-1) to (1-2).

[0050]

[0051] The monomer unit represented by formula (1) that may be included in the polymer compound according to this embodiment may be one type or two or more types.

[0052] The polymer compound may consist of one type of monomer unit, or it may be a copolymer consisting of two or more types of monomer units. If the polymer compound contains two or more types of monomer units, it may also contain monomer units other than the monomer unit represented by formula (1).

[0053] In the polymer compound, the content of the monomer unit represented by formula (1) is preferably 20 to 100% by mass, more preferably 40 to 100% by mass, even more preferably 60 to 100% by mass, particularly preferably 80 to 100% by mass, and most preferably 100% by mass, based on the total amount of monomer units (100% by mass).

[0054] The polymer compound according to this embodiment preferably has a glass transition temperature Tg of -10°C or lower when hydrated, more preferably -20°C or lower, and even more preferably -40°C or lower. The lower limit of Tg is not particularly limited, but may be -200°C or higher, -150°C or higher, or -100°C or higher.

[0055] The number-average molecular weight of the polymer compound according to this embodiment is not particularly limited as long as the effects of the present invention are achieved, but may be 1,000 to 200,000, 3,000 to 100,000, or 5,000 to 50,000 as measured by gel permeation chromatography (in terms of polymethyl methacrylate).

[0056] The molecular weight dispersion of the polymer compound according to this embodiment is not particularly limited as long as the effects of the present invention are achieved, but may be 0.5 to 3.0 or 1.0 to 2.0 as measured by gel permeation chromatography (weight-average molecular weight / number-average molecular weight in terms of polymethyl methacrylate).

[0057] (Method for producing polymer compounds) The polymer compounds according to this embodiment can be produced by appropriately combining known methods, as shown in the synthesis method in the example.

[0058] The polymer compound according to this embodiment, as described above, has a group whose side chain contains a structure that contributes to the inclusion of intermediate water, and the main chain contains a portion in which two or more carbon atoms to which the side chain is attached are consecutively located. Because the polymer compound according to this embodiment has two or more carbon atoms to which the side chain is attached consecutively, the group containing the structure that contributes to the inclusion of intermediate water is in close proximity, making it easier to contain intermediate water. As a result, when blood comes into contact with the polymer compound, it is possible to further suppress platelet activation and exhibit excellent antithrombotic properties.

[0059] (Composition) The composition according to this embodiment contains the polymer compound according to the embodiment. The polymer compound in the composition may be one type or two or more types.

[0060] The composition according to this embodiment is preferably an antithrombotic material. The composition according to this embodiment can also be described as an antithrombotic material containing the polymer compound according to the embodiment as an active ingredient.

[0061] The composition according to this embodiment may contain other components in addition to the polymer compound according to the embodiment, as long as it achieves the effects of the present invention. Examples of other components include polymer compounds other than the polymer compound according to the embodiment, solvents, antioxidants, ultraviolet absorbers, lubricants, flow modifiers, mold release agents, antistatic agents, light diffusing agents, and other additives, as well as inorganic fillers such as glass fibers, carbon fibers, and clay compounds.

[0062] The form of the composition according to this embodiment is not particularly limited and may be in the form of a solution containing a diluent solvent, in the form of a coating film obtained by applying the solvent to the surface of a substrate or the like, or in the form of a sheet obtained by drying the coating film.

[0063] In the composition according to this embodiment, the content of the polymer compound according to the embodiment is not particularly limited as long as the effects of the present invention are achieved, but may be, for example, 0.001 to 30 wt / vol%, 0.01 to 10 wt / vol%, or 0.05 to 5 wt / vol% relative to the total volume (100 vol%) of the composition.

[0064] In the composition according to this embodiment, the content of the polymer compound according to the embodiment is not particularly limited as long as the effects of the present invention are achieved, but is preferably 20 to 100% by mass, more preferably 40 to 100% by mass, even more preferably 60 to 100% by mass, and particularly preferably 80 to 100% by mass, based on the total mass (100% by mass) of the components other than the solvent.

[0065] The composition according to this embodiment exhibits excellent antithrombotic properties due to containing the polymer compound according to the above embodiment.

[0066] (Substrate) The substrate according to this embodiment includes at least one of resin, metal, or ceramic. At least a portion of the surface of the substrate is coated with the composition according to the embodiment.

[0067] The resin, metal, and ceramic are not particularly limited as long as the effects of the present invention are achieved, and known materials can be used.

[0068] Medical devices are preferred as the base material, and medical devices having parts that can come into contact with blood are more preferred. Examples of medical devices include artificial lung devices, dialysis machines, blood storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guide wires, stents, artificial blood vessels, endoscopes, and the like.

[0069] As the base material, a base material used in areas that come into contact with biological substances such as blood is preferred. Preferably, at least the surface of the base material in areas that come into contact with biological substances such as blood is coated with the composition.

[0070] The resin, metal, and ceramic that constitute the substrate to be coated are not particularly limited as long as the effects of the present invention are achieved, and known materials can be used. Examples of resins that constitute the substrate to be coated include polyolefins, polyesters, polyamides, polystyrenes, polyurethanes, and fluoropolymers. Examples of metals that constitute the substrate to be coated include stainless steel.

[0071] The substrate according to this embodiment exhibits excellent antithrombotic properties because at least a portion of its surface is coated with the composition according to the embodiment.

[0072] (Other Embodiments) In one embodiment, the present invention provides the use of a polymer compound to impart antithrombotic properties to a composition. In one embodiment, the present invention provides the use of a polymer compound to impart antithrombotic properties to a substrate. In one embodiment, the present invention provides the use of a composition to impart antithrombotic properties to a substrate. Examples of the substrate, polymer compound, and composition are the same as those described above in the above embodiments.

[0073] In one embodiment, the present invention provides the use of a polymer compound for producing a composition. In one embodiment, the present invention provides the use of a polymer compound for producing a substrate. In one embodiment, the present invention provides the use of a composition for producing a substrate. Examples of substrates, polymer compounds, and compositions are the same as those described above in the embodiments.

[0074] The present invention will be described in detail below with reference to the following examples. However, the present invention is not limited to the following examples.

[0075] <Example 1> The polymer compound of Example 1, consisting of constituent units represented by the following formula (1-1), was synthesized. The synthesis scheme of the polymer compound of Example 1 is as follows.

[0076]

[0077] For information on monomer synthesis methods, please refer to the following literature: Shimomoto et al., Synthesis of polymers with densely-grafted oligo (ethylene glycol)s by Pd-initiated polymerization of oxyethylene-containing diazoacetates, Polym. Chem., 2015, 6, 8124-8131, DOI https: / / doi.org / 10.1039 / c5py01378j

[0078]

[0079] The specific procedure for monomer synthesis was as follows: Under a nitrogen atmosphere, bromoacetyl bromide (2.6 mL, 30 mmol) was mixed with acetonitrile (100 mL) cooled to 0°C, 2-methoxyethanol (1.6 mL, 20 mmol), and NaHCO3. ３ (5.09 g, 60.6 mmol) was added dropwise to a stirred suspension, and the mixture was stirred at this temperature for 10 minutes. After adding water to the mixture, the mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was used in the next reaction without purification. The obtained residue and N,N'-disylhydrazine (13.8 g, 40.4 mmol) were dissolved in THF (100 mL) and cooled to 0°C. DBU (15.1 mL, 101 mmol) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 10 minutes. Saturated NaHCO3 ３After stopping the reaction by adding a solution, the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over magnesium sulfate, and evaporated to obtain the crude product. This was purified using recycled GPC to obtain the monomer as a pale yellow oily substance.

[0080] Regarding the obtained monomer, １ The following signals were detected by H-NMR measurement. １ 1H NMR (CDCl ３ , 400MHz), δ (ppm): 4.82 (s, 1H, °-CHvN2), 4.32 (t, J = 4.4Hz, 2H, -CO ２ CH ２ CH ２ O-), 3.61 (t, J=4.8Hz, 2H, -CO ２ CH ２ CH ２ O-), 3.39 (s, 3H, -OCH3). １３ CNMR (CDCl ３ , 100MHz), δ (ppm): 166.8, 70.5, 63.8, 58.9, 46.3.

[0081] The polymer compound of Example 1 was obtained from the monomer obtained by the polymerization scheme shown below.

[0082]

[0083] For the polymerization scheme described above, see, for example, the following publication: Ihara E et al., (N-Heterocyclic Carbene)Pd / Borate Initiating Systems for Polymerization of Ethyl Diazoacetate, Macromolecules, 42, 8608-8610 (2009), DOI https: / / doi.org / 10.1021 / ma901857s

[0084] As the Pd complex, 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene(1,4-naphthoquinone)palladium(0) dimer (CAS No. 467220-49-1, FW1138.0) was used. NaBPh was used as a co-catalyst. ４(CAS No. 143-66-8, FW 342.22) was used.

[0085] The specific polymerization procedure was as follows: Under a nitrogen atmosphere, the Pd complex (74 mg, 6.5 × 10) was placed in a Schlenk tube. －２ A 5 mL THF solution containing mmol (a dimer, therefore [Pd] = 0.13 mmol) was added. The solution was cooled to -78°C, and NaBPh was added to it. ４ A solution of (54 mg, 0.16 mmol, 1.2 eq of [Pd]) in THF (5 mL) was slowly added dropwise, and the solution was stirred at -78°C for 15 minutes. A solution of monomer (FW = 144.13, 1.88 g, 13.0 mmol, [M] / {Pd} = 100) in THF (5 mL) was slowly added dropwise to the Schlenk tube. The reaction solution was slowly heated to 30°C and stirred at 30°C for 15 hours. After removing the solvent under reduced pressure, the organic phase was separated using a separatory funnel with chloroform and 1 N HClaq, and washed with water. The organic phase was then separated into NaSO4. ４ After drying, the solvent was removed by vacuum distillation. The target polymer was isolated from the resulting residue by recycled preparative SEC using chloroform as the eluent. The yield of the target polymer was 0.61 g, and the yield was 40%.

[0086] Regarding the polymer compound obtained in Example 1, １ The following signals were detected by H-NMR measurement. １ H-NMR (500MHz, CDCl ３ , δ): 4.0-4.4 (br, 2Hxn, -CO ２ CH ２ -), 3.4-3.8 (br, 2Hxn, -CH ２ OCH ３ ), 3.3(br, 3Hxn, -OCH ３ ), 2.9-3.5 (br-m, 1Hxn, mainchainCH).

[0087] The number-average molecular weight of the polymer compound in Example 1 was 14140. The following number-average molecular weight measurements are calculated as polymethyl methacrylate equivalents using gel permeation chromatography.

[0088] The molecular weight dispersion of the polymer compound in Example 1 was 1.708. Hereafter, the molecular weight dispersion is calculated from the polymethyl methacrylate equivalent value obtained by gel permeation chromatography, using the ratio of weight-average molecular weight to number-average molecular weight.

[0089] <Example 2> A polymer compound of Example 2, consisting of constituent units represented by the following formula (1-2), was synthesized. The synthesis scheme for the polymer compound of Example 2 is as follows.

[0090]

[0091] For information on monomer synthesis methods, please refer to the following literature: Toma et al., N,N'-Ditosylhydrazine: A Convenient Reagent for Facile Synthesis of Diazoacetates, Organic Letters. 2007, 9, 16, 3195-3197, DOI https: / / doi.org / 10.1021 / ol701432k

[0092]

[0093] The specific procedure for monomer synthesis was as follows: Under a nitrogen atmosphere, NaHCO3 was placed in a two-necked round-bottom flask fitted with a three-way stopcock. ３ (3.94 g, 46.9 mmol), 3-methoxy-1-propanol (1.5 mL, 16 mmol), and 30 mL of acetonitrile were added and cooled to 0°C. Bromoacetyl bromide (4.6 g, 23 mmol) was slowly added dropwise at 0°C and stirred for 10 min at 0°C. Liquid-liquid separation was performed using a separatory funnel with water and dichloromethane, and the organic phase was washed with saturated saline solution and dried over magnesium sulfate. Magnesium sulfate was filtered off, and volatile components were removed from the filtrate under reduced pressure. The residue was transferred to a two-necked round-bottom flask fitted with a three-way stopcock, and N,N'-distosylhydrazine (10.7 g, 31.3 mmol) and THF (90 mL) were added under a nitrogen atmosphere and cooled to 0°C. DBU (11.7 mL, 78.2 mmol) was slowly added dropwise to the solution at 0°C and stirred for 10 min at 0°C. Saturated NaHCO3 ３An aqueous solution and dichloromethane were added, and the organic phase was extracted using a separatory funnel. The organic phase was washed with water and saturated saline solution, and then dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and volatile components were removed from the filtrate under reduced pressure. The resulting residue was purified using a recycled preparative SEC with chloroform as the eluent to obtain 1.80 g of the target product (yield 73%).

[0094] Regarding the obtained monomer, １ The following signals were detected by H-NMR measurement. １ H-NMR (500MHz, CDCl ３ , δ): 4.74 (br-s, 1H, N ２ = CH-CO ２ -), 4.26 (t, J = 6.5Hz, 2H, CO ２ CH ２ -), 3.45 (t, J = 6.5Hz, 2H, -CH ２ OCH ３ ), 3.34 (s, 3H, -OCH ３ ), 1.92 (quint, J=6.5Hz, 2H, -OCH ２ CH ２ CH ２ O-).

[0095] The polymer compound of Example 2 was obtained from the monomer obtained by the polymerization scheme shown below.

[0096]

[0097] For more information on the polymerization scheme described above, please refer to the following publication: Ihara et al., π-AllylPdCl-Based Initiating Systems for Polymerization of Alkyl Diazoacetates: Initiation and Termination Mechanism Based on Analysis of Polymer Chain End Structures, Macromolecules 2012, 45, 17, 6869-6877, DOI https: / / doi.org / 10.1021 / ma3013527

[0098] Allylpalladium(II) Chloride Dimer (CAS No. 12012-95-2, FW 365.89) was used as the Pd complex. NaBPh was used as the co-catalyst. ４ (CAS No. 143-66-8, FW 342.22) was used.

[0099] The specific polymerization procedure was as follows: Under a nitrogen atmosphere, the Pd complex (24 mg, 6.5 x 10) was placed in a Schlenk tube. －２ A 5 mL solution of NaBPh (a dimer, so [Pd] = 0.13 mmol) was added to THF. The solution was cooled to -78°C, and NaBPh ４ A solution of (54 mg, 0.16 mmol, 1.2 eq of [Pd]) in THF (2.5 mL) was slowly added dropwise, and the solution was stirred at -78°C for 10 min. A solution of monomer (FW = 158.15, 2.06 g, 13.0 mmol, [M] / {Pd} = 100) in THF (6 mL) was slowly added dropwise to the Schlenk tube. The reaction solution was slowly raised to -20°C and stirred at -20°C for 15 hours. After removing the solvent under reduced pressure, the organic phase was separated using a separatory funnel with chloroform and 1 N HCl, and washed with water. The organic phase was then separated into NaSO4. ４ After drying, the solvent was removed by vacuum distillation. The target polymer was isolated from the resulting residue by recycled preparative SEC using chloroform as the eluent. Yield: 0.57 g (34% yield).

[0100] Regarding the obtained polymer compound, １ The following signals were detected by H-NMR measurement. １ H-NMR (500MHz, CDCl ３ , δ): 3.9-4.3 (br, 2Hxn, -CO ２ CH ２ -), 3.4-3.6 (br, 2Hxn, -CH ２ OCH ３ ), 3.3 (br, 3Hxn, OCH ３ ), 2.8-3.4 (br-m, 1Hxn, mainchainCH), 1.8-2.0 (br, 2Hxn, C(=O)OCH ２ CH ２ CH ２ O-).

[0101] The number average molecular weight of the obtained polymer compound in Example 2 was 9,763. The molecular weight distribution of the obtained polymer compound in Example 2 was 1.322.

[0102] <Example 3> Using the same scheme as in Example 1, a polymer compound of Example 3 composed of a structural unit represented by the following formula (1-2) was synthesized from the monomers used in Example 2. The specific procedure for the polymerization was as follows.

[0103]

[0104] Under a nitrogen atmosphere, a THF (3 mL) solution of a Pd complex (61 mg, 5.3x10 －２ mmol, since it is a dimer, [Pd] = 0.11 mmol) was placed in a Schlenk tube. The solution was cooled to -78 °C, and a THF (4 mL) solution of NaBPh ４ (44 mg, 0.13 mmol, 1.2 eq of [Pd]) was slowly added dropwise thereto, and then the solution was stirred at -78 °C for 15 min. A THF (5 mL) solution of the monomer (FW = 158.15, 1.68 g, 10.7 mmol, [M] / [Pd] = 100) was slowly added dropwise to the Schlenk tube. The reaction solution was slowly warmed to +30 °C and stirred at +30 °C for 15 hours. After distilling off the solvent under reduced pressure, liquid separation was performed using a separating funnel with chloroform and 1N HClaq, and the organic phase was washed with water. The organic phase was dried over NaSO ４ and the solvent was distilled off under reduced pressure. The target polymer was isolated from the obtained residue by recycling preparative SEC using chloroform as the eluent. Yield 0.69 g (yield 50%).

[0105] For the obtained polymer compound, １ the following signals were detected by 1H-NMR measurement. １ 1H-NMR (500 MHz, CDCl ３ [[ID=!--ERROR--]]<000009!> 3.9-4.3 (br, 2Hxn, -CO ２ CH ２ -), 3.4-3.6 (br, 2Hxn, -CH ２ OCH ３ ), 3.3 (br, 3Hxn, OCH ３), 2.8 - 3.4 (br - m, 1Hxn, main chain CH), 1.8 - 2.0 (br, 2Hxn, C(=O)OCH ２ CH ２ CH ２ O -).

[0106] The number average molecular weight of the polymer compound of Example 3 obtained was 25,574. The molecular weight distribution of the polymer compound of Example 3 obtained was 1.551.

[0107]

[0108] As Comparative Examples 1 - 3 of the polymer compounds, poly(2 - methoxyethyl acrylate) (PMEA) was used as Comparative Example 1, poly(3 - methoxypropyl acrylate)(PM3A) was used as Comparative Example 2, and poly(2 - methacryloyloxyethyl phosphorylcholine was used as Comparative Example 3.Number average molecular weights and molecular weight distributions of Comparative Examples 1 -

[0109] <000033*2>[[ID=**18]] The number average molecular weight of the polymer compound of Comparative Example 1 was 28,000. The molecular weight distribution of the polymer compound of Comparative Example 1 was 3.*16. The number average molecular weight of the polymer compound of Comparative Example 2 was 25,000. The molecular weight distribution of the polymer compound of Comparative Example 2 was 3.31. The number average molecular weight of the polymer compound of Comparative Example 3 was 500,000.<000033*4> [[ID=**22]]

[0112] <Measurement of Saturated Water Content>For the polymer compounds of Examples 1 - 3 and Comparative Examples 1 - 2, based on the measurement results by DSC, the saturated water content was calculated. The results of measuring the release of latent heat during the cooling process are shown in Figure 3A. The results of measuring the absorption of latent heat during the heating process are shown in Figure 3B. The saturated water content of each example is shown in Table 2. [[ID=**23]] [[ID=**24]]

[0113] In Example 1, the hydrophilicity was enhanced compared to Comparative Example 1. In Examples 2 - 3, the hydrophilicity was enhanced compared to Comparative Example 2. Note: There are some unclear notations in the original text (such as "br - m", "Hxn", etc. which might be specific notations in a certain field but not common chemical notations. Also, the repeated use of <000032x> and <000033x> tags without clear indication of their function makes the translation a bit challenging to ensure complete accuracy in terms of context understanding. The translation above tries to maintain the original format as much as possible while making sense of the chemical - related content.)<Measurement of Antifreeze Water and Intermediate Water Content> The water content (mass%) of the polymer compounds of Examples 1-3 and Comparative Examples 1-2 was measured at the highest water content where no free water was detected. This water content represents the total water content of antifreeze water and intermediate water. In addition, the number of moles of antifreeze water or intermediate water per mole of polymer compound in each example was calculated. The results are shown in Figures 3C, 3D, 3E, 3F, and Table 3.

[0114]

[0115] Example 1 showed higher levels of nonfreezing water (mol / mol) and intermediate water (mol / mol) compared to Comparative Example 1. Examples 2 and 3 also showed higher levels of nonfreezing water (mol / mol) and intermediate water (mol / mol) compared to Comparative Example 2.

[0116] <Preparation of coating substrate> The polymer compounds of the examples and comparative examples were applied to a polycarbonate substrate (hereinafter sometimes referred to as a PC substrate) according to the following procedure to create a film on the PC substrate and obtain a coating substrate.

[0117] The polymer compounds of Examples 1 to 3 were each dissolved in methanol. The polymer compounds of Comparative Examples 1 and 3 were each dissolved in methanol. The polymer compound of Comparative Example 2 was dissolved in methanol. The concentration of the solutions of the polymer compounds in each example was 0.2 wt% / vol. The solutions of the polymer compounds in each example were applied to the surface of a PC substrate by spin coating to prepare the coated substrates of each example.

[0118] <Platelet Adhesion Test> For each coated substrate, a platelet adhesion test was performed according to the following procedure.

[0119] Preparation of platelet suspension: Human whole blood was centrifuged at 400 rcf for 5 minutes using a tabletop centrifuge (2420, KUBOTA). Approximately 500 μL of the supernatant (pale yellow translucent liquid) was collected and designated as platelet-rich plasma (PRP). After collection, the PRP was further centrifuged at 2,500 rcf for 10 minutes, and approximately 2 mL of the supernatant (pale yellow transparent liquid) was collected and designated as platelet-poor plasma (PPP). The platelet concentration in the PRP was calculated by counting the platelets in the PRP diluted 800-fold with PBS(-) using a hemocytometer, and the dispersal concentration was 3.0 × 10⁶. ７ cells / cm ２ Platelet suspension was prepared by diluting PRP with PPP to achieve the desired result.

[0120] 150 μL (approximately 100 μL / cm²) of the prepared platelet suspension was placed on the surface of each coated substrate and incubated at 37°C for 1 hour to adhere the platelets. Afterward, the platelet suspension was removed, and the substrates were washed twice with PBS. The attached platelets were then immobilized on the substrate by immersion in a 1% glutaraldehyde solution (25% glutaraldehyde, Polyscience, Inc. 01909 diluted to 1 / 25 with PBS(-)) and incubated at 37°C for 2 hours. After immobilization, the substrates were washed once each by immersion in PBS(-) (10 minutes), PBS(-):water = 1:1 (8 minutes), and water (8 minutes, 10 minutes). After washing, the substrates were air-dried for 3 hours, and then dried in a container with silica gel for at least 1 day. After drying, the substrate surface was observed using a scanning electron microscope (SEM, KEYENCE, 3D Real Surface View Microscope VE-9800). The number of platelets corresponding to each level on the substrate surface was counted according to the following evaluation criteria.

[0121] [Platelet Adhesion Assessment] Level 1: Platelets are disc-shaped and not activated. Level 2: Platelets have one filopodia. Level 3: Platelets are activated and have multiple filopodia. Figure 4A shows photographs of platelets at each level.

[0122] The results of the platelet adhesion test are shown in Figure 4B. In Figure 4B, * means p < 0.05 and ** means p < 0.01 (t-test). It was confirmed that Example 1 could suppress platelet adhesion more effectively than Comparative Example 1. It was confirmed that Examples 2 and 3 could suppress platelet adhesion more effectively than Comparative Example 2. It was confirmed that Examples 1 to 3 could suppress platelet adhesion more effectively than Comparative Example 3.

[0123] <Measurement of Contact Angle> For the polymer compounds of the examples and comparative examples, the water droplet contact angle and the bubble contact angle were measured according to the following procedure. For the measurements, the coated substrates of each example, which were prepared in the platelet adhesion test, were used.

[0124] Water droplet contact angle: A 2 μL water droplet was placed in contact with the coated substrate of each example, and the angle was measured 30 seconds after dropping. For each coated substrate, the average of three different measurements on the same substrate was taken as the water droplet contact angle. The measurement results are shown in Table 4. A smaller water droplet contact angle indicates higher hydrophilicity of the polymer compound and its coated substrate surface.

[0125] For each example of the coated substrate, the bubble contact angle was measured after immersion in water and contact with 2 μL of bubbles at 30 seconds, 1 hour, and 24 hours. For each example of the coated substrate, the average of three different measurements on the same substrate was taken as the bubble contact angle. The measurement results are shown in Table 4. A smaller bubble contact angle indicates higher hydrophilicity of the polymer compound and its coated substrate surface.

[0126]

[0127] The polymer compounds of the present invention can be suitably used as antithrombotic materials.

Claims

1. A polymer compound having a main chain comprising a row of interconnected carbon atoms, wherein a group containing a structure that contributes to the inclusion of intermediate water is bonded to a portion of the carbon atoms as a side chain to the main chain, characterized in that the row of carbon atoms includes a portion in which two or more carbon atoms to which the side chain is bonded are present consecutively.

2. The polymer compound according to claim 1, characterized in that, among the carbon atoms in the main chain of the polymer compound, the proportion of carbon atoms to which a side chain containing a structure that contributes to the inclusion of intermediate water is bonded is greater than 1 / 2 and less than or equal to 1.

3. The polymer compound according to claim 2, characterized in that the proportion of carbon atoms in the main chain of the polymer compound to which a side chain containing a structure that contributes to the inclusion of intermediate water is bonded is 1.

4. The polymer compound according to claim 1, characterized by containing a monomer unit represented by the following formula (1). [In equation (1), R １ R is a monovalent hydrocarbon group which may have a hydrogen atom or an ether bond, ２ The linker portion is selected from a unit structure having an ester bond, an ether bond, an amide bond, a disulfide bond, a silylene group, a phenylene group, a one-carbon alkylene group, or a combination thereof, R ３ R is a divalent hydrocarbon group which may have an ether bond, ４ This is a monovalent, chain-like hydrocarbon group having 1 to 6 carbon atoms, which may have an ether bond.

5. R ２ This is an ester bond, and R ３ is, -(CH ２ ) ｍ The polymer compound according to claim 4, wherein m is 1 or more and 5 or less.

6. R ４ The polymer compound according to claim 4, wherein R is a methyl group.

7. The polymer compound according to claim 1, wherein the glass transition temperature Tg when hydrated is -10°C or lower.

8. A composition characterized by containing the polymer compound described in any one of claims 1 to 7.

9. The composition according to claim 8, characterized in that it is an antithrombotic material.

10. A substrate comprising at least one of a resin, a metal, or a ceramic, wherein at least a portion of the surface of the substrate is coated with the composition described in claim 8.

11. A medical device characterized by comprising the base material described in claim 10.

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