Boronic acid compound having chromogenic site and polymerizable site, and use therefor

Abstract

[Problem] The purpose of the present invention is to provide a polymerizable boronic acid compound that has a structure different from both an azobenzene moiety and an acrylamide phenylboronic acid structure and makes it possible to detect a change in glucose concentration by forming glucose and a cyclic boronic acid ester. [Solution] The problem is solved by a polymerizable boronic acid compound or the like represented by general formula (1) (in the formula, at least one of R1 to R7 denotes a substituent having a polymerizable group, and the remaining moieties independently denote a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group).

Description

Boronic acid compound having a color-forming moiety and a polymerizable moiety and use thereof

[0001] The present invention relates to a polymerizable boronic acid compound having a color-forming moiety and a polymerizable moiety.

[0002] Glucose is the energy source for almost all cells and is an important compound for maintaining biological activity. However, since glucose levels increase when there is an abnormality in the body, the health of the body can be monitored by using blood glucose levels (blood glucose levels) as an indicator.

[0003] The most common method for measuring blood glucose levels involves pricking the fingertip with a special lancing device to collect blood, and then measuring the glucose concentration in the blood directly with a simple blood glucose meter. However, this method is invasive and places a heavy burden on the user.

[0004] Therefore, instead of directly measuring the glucose concentration in blood, there is a method to measure blood glucose levels indirectly and non-invasively by detecting changes in glucose concentration in bodily fluids that are different from blood and have a correlation with blood glucose levels, such as sweat, saliva, and tears.

[0005] Among these, tears contain various biochemical components that reflect the physiological state of the living body, and it has been reported that changes in their concentrations correlate with the state of blood. For example, it is known that the glucose concentration in tears is about one-tenth of the blood glucose level, and that changes in the glucose concentration in tears follow the blood glucose level with a delay of about five minutes.

[0006] By using a glucose sensor applicable to the eye that can detect changes in glucose concentration in tears, it becomes possible to measure blood glucose levels non-invasively without invasively sampling blood. For example, a glucose sensor applicable to the eye can detect changes in glucose concentration by utilizing changes in optical properties caused by a chemical reaction between glucose and components of a contact lens substrate.

[0007] As an example of a material applicable to such a method, boronic acids that can form cyclic boronate esters by reversible ester bonds with cis-diols such as glucose in aqueous solution have attracted attention as new glucose probes (see Figure 1). For example, it is known that an azo compound having a boronic acid at its terminal dissolved in aqueous solution undergoes an ester bond with glucose to form a cyclic boronate ester, resulting in a change in the absorption wavelength of the molecule, and that this change in absorption wavelength can be used to detect changes in glucose concentration (see, for example, Non-Patent Document 1).

[0008] Also, several monomers are known that have a boronic acid in the molecule and can form a polymer by polymerization reaction. Examples of such monomers include a polymerizable boronic acid compound having an azobenzene moiety and a boronic acid moiety that can form a cyclic boronic acid ester with 4-nitrophenyl-α-mannopyrazide (see, for example, Patent Document 1), and 3-acrylamidophenylboronic acid, 4-acrylamidophenylboronic acid, and 5-fluoro-2-methylacrylamidophenylboronic acid, each of which has an acrylamidephenylboronic acid structure (see, for example, Patent Documents 2 and 3).

[0009] JP 2004-224828 A International Publication No. 2017 / 026044 Pamphlet JP 2007-506999 A

[0010] Nicolas DiCesare et al., Organic Letters, 3(24):3891-3 (2001)

[0011] Unlike the boronic acid compounds described in Non-Patent Document 1, polymerizable boronic acid compounds have a polymerizable moiety and are therefore copolymerizable with other monomers. For example, contact lenses can be formed using these compounds to detect changes in glucose concentration in tears.

[0012] However, the polymerizable boronic acid compound described in Patent Document 1 is prone to change form when irradiated with ultraviolet light, depending on the photoisomerization properties of the azobenzene in the structure.

[0013] By using a polymer synthesized using the polymerizable boronic acid compound described in Patent Documents 2 and 3, the amount of glucose can be measured based on changes in the turbidity and optical properties of the polymer caused by binding of glucose to the boronic acid group in the polymer. However, because the polymerizable boronic acid compounds described in Patent Documents 2 and 3 do not have a chromophore in their structure, the responsiveness of the resulting polymer to changes in turbidity and optical properties is poor, and the content of the polymerizable boronic acid compound in the polymer must be increased. As a result, the content of other monomer components becomes small, which creates problems such as limitations on polymer design, such as making it impossible to obtain a polymer with the desired water content.

[0014] Furthermore, few polymerizable boronic acid compounds have been known to date that can detect changes in glucose concentration by having a structure that forms a cyclic boronic acid ester with glucose, rather than an azobenzene moiety like the polymerizable boronic acid compounds described in Patent Document 1 or an acrylamide phenylboronic acid structure like the polymerizable boronic acid compounds described in Patent Documents 2 and 3.

[0015] Therefore, an object of the present invention is to provide a polymerizable boronic acid compound that has an azobenzene moiety and a structure different from an acrylamide phenylboronic acid structure, and that can detect changes in glucose concentration by forming a cyclic boronic acid ester with glucose.

[0016] In order to solve the above problems, the present inventors have extensively investigated the structural changes of boronic acids caused by binding to cis-diol compounds such as glucose.

[0017] As shown in Figure 1, boronic acid has an electrically neutral trigonal planar structure, -B(OH), in aqueous media. ２ and anionic tetrahedral structure -B(OH) ３ When boronic acid in this state comes into contact with a compound having a cis-diol moiety, -B(OH) ２ and a cis-diol moiety form a cyclic ester, and a trigonal planar cyclic boronic acid ester, -B(OH)３ The state changes to an acid dissociation equilibrium with a tetrahedral cyclic boronic acid ester in which the cis-diol moiety forms a cyclic ester (Figure 1, bottom panel).

[0018] The acid dissociation constant of boronic acid is approximately 9. Therefore, at physiological conditions, pH 7.4, the trigonal planar structure of boronic acid (-B(OH) ２ ) are predominantly present (upper left panel of Figure 1), and when they come into contact with the cis-diol moiety, they form a triangular planar boronic acid ester (lower left panel of Figure 1). Furthermore, the acid dissociation constant of cyclic boronic acid esters is approximately 7. Therefore, tetrahedral cyclic boronic acid esters are predominantly present (lower right panel of Figure 1).

[0019] According to the above, when glucose, which has a cis-diol structure within its molecule, comes into contact with a boronic acid under physiological conditions in the presence of body fluids such as tears, the triangular planar boronic acid structure changes to a tetrahedral cyclic boronate ester structure. The inventors therefore hypothesized that this structural change might also affect other structures within the molecule, such as the electronic state of the azo group, which serves as a chromophore, thereby changing the absorption wavelength in the visible light region. They then conducted extensive research into polymerizable boronic acid compounds with structures that can significantly change the absorption wavelength of the molecule by changing the structure from the triangular planar boronic acid to a tetrahedral cyclic boronate ester structure. Using such polymerizable boronic acid compounds, it becomes possible to detect contacted glucose by measuring the change in absorption wavelength in the visible light region.

[0020] Therefore, the present inventors focused on a structure in which the polymerizable moiety and the boronic acid are bonded via an azo group, which is a chromophore. In particular, they attempted to reduce the occurrence of photoisomerization of the azo group due to UV irradiation by changing the electronic state of the azo group based on the structural change of the boronic acid. They then hypothesized that introducing a bulky structure to one side of the azo group would inhibit rotational movement around the azo group, thereby suppressing photoisomerization.

[0021] Based on the above-mentioned concept, the present inventors further pursued research and development through repeated trial and error, and finally discovered that in a polymerizable boronic acid compound in which a naphthalene ring has been introduced to one of the azo groups, the electronic state of the azo group changes based on a structural change in the boronic acid, thereby reducing rotational motion around the azo group as an axis, and the compound has excellent copolymerizability with other polymerizable compounds (monomers).

[0022] Based on the above findings, the present inventors have finally succeeded in creating a polymerizable boronic acid compound that can solve the problems of the present invention. The present invention was completed based on the findings and successful examples first obtained by the present inventors.

[0023] That is, according to the present invention, the following aspects are provided: [1] General formula (1) (In the formula, R １ ~R ７ [2] A polymerizable boronic acid compound represented by the general formula (2): wherein at least one of the groups represents a substituent having a polymerizable group, and the remaining groups each independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group. (In the formula, R ８ represents a hydrogen atom or a methyl group, R ９ represents an oxygen atom or an amino group, and the wavy line represents a bonding site with the compound of general formula (1). (In the formula, R １０ represents a hydrogen atom or a methyl group, R １１ and R １２each independently represent an oxygen atom or an amino group, m is an integer of 1 to 3, n is an integer of 1 to 3, and the wavy line represents a bonding site with the compound of general formula (1). The polymerizable boronic acid compound according to item [1], wherein the substituent having a polymerizable group is represented by the formula: [3]. A polymeric compound comprising the polymerizable boronic acid compound according to item [1] or [2] as a structural unit. [4]. The polymeric compound according to item [3], wherein the polymeric compound is used for detecting a compound having a cis-diol structure in the molecule. [5]. The polymeric compound according to item [4], wherein the compound having a cis-diol structure in the molecule is a compound selected from the group consisting of glucose, fructose, lactose, and dopamine. [6]. The polymeric compound according to item [3], further comprising a compound copolymerizable with the polymerizable boronic acid compound as a structural unit. [7]. The polymeric compound according to item [6], wherein the compound copolymerizable with the polymerizable boronic acid compound is at least one hydrophilic monomer. [8] The polymer compound according to item [3], wherein the polymer compound is a hydrogel. [9] The polymer compound according to item [8], wherein the hydrogel has a water content of 25% or more.

[10] A method for detecting a compound having a cis-diol structure in its molecule, comprising the step of detecting a compound having a cis-diol structure in its molecule in a solution based on a change in absorbance of the polymer compound according to item [3] before and after contacting the polymer compound with the solution.

[0024] According to the present invention, it is possible to detect changes in glucose concentration in body fluids such as tears. The polymerizable boronic acid compound of one embodiment of the present invention has a color-forming moiety and a polymerizable moiety, and therefore functions as a monomer that can be copolymerized with other monomers, including hydrophilic monomers, to provide a polymer compound (polymer) containing boronic acid as a constituent unit.

[0025] The polymerizable boronic acid compound according to one embodiment of the present invention can be copolymerized with a hydrophilic monomer to form a hydrogel, which can be used to detect changes in the concentration of cis-diol compounds such as glucose.

[0026] The polymerizable boronic acid compound of one embodiment of the present invention has suppressed photoisomerization properties due to physical disturbances and further has a color-forming moiety, so that by using the resulting hydrogel as an ophthalmic lens such as a contact lens, it is expected that changes in the concentration of cis-diol compounds such as glucose in tears within the eye can be detected with high sensitivity. Furthermore, the hydrogel obtained from the polymerizable boronic acid compound of one embodiment of the present invention has reduced changes in structure and optical properties before and after detection of changes in the concentration of cis-diol compounds such as glucose, and therefore can be suitably used as an ophthalmic lens.

[0027] Figure 1 is a schematic diagram showing the reaction mechanism between boronic acid and cis-diol. Figure 2 shows the UV-visible absorption spectra of hydrogels 1, 2, 4, and 5 of Examples 6, 7, 9, and 10 immersed in PBS or Glc, as described in the Examples below. The spectra were normalized by peak absorbance.

[0028] Each aspect of the present invention will be described in detail below, but the technical scope of the present invention is not limited to the details of these items, and the present invention can take various forms as long as it achieves its object.

[0029] Unless otherwise specified, each term in this specification is used in the meaning commonly used by a person skilled in the chemical industry and should not be construed as having an unduly limiting meaning. Furthermore, the speculations and theories made in this specification are based on the inventors' knowledge and experience to date, and therefore the present invention is not limited solely to such speculations and theories.

[0030] "Independent" substituents may all be the same or some or all may be different. "And / or" refers to any one of the listed related items, or any or all combinations of two or more. "Comprise" means that elements other than those explicitly stated as included can be added (synonymous with "comprise at least"), but also encompasses "consist" and "essentially consist." That is, "comprise" can mean including the explicitly stated elements and any one or more elements, consisting of the explicitly stated elements, or essentially consisting of the explicitly stated elements. Elements include limitations such as components, steps, conditions, and parameters. "Content" is synonymous with concentration and usage amount (addition amount) and refers to the ratio of the amount of a component to the total amount of the final product. However, the total content of a component does not exceed 100%. When a commercially available product is used, the content of the component is preferably the amount of the component contained in the commercially available product, but may also be the amount of the commercially available product itself. A numerical range "to" includes the numerical values ​​before and after it, and also includes a range excluding one of the inclusive limits. For example, "0% to 100%" means 0% or more, 100% or less, or 0% or more and 100% or less. "About" means an amount within ±10% of the quantity following the term. For example, "about 100" means 100 ±10%, that is, 90 to 110. The number of digits in an integer value matches the number of significant digits. For example, 1 has one significant digit, and 10 has two significant digits. Furthermore, for decimal values, the number of digits after the decimal point matches the number of significant digits. For example, 0.1 has one significant digit, and 0.10 has two significant digits.

[0031] (Polymerizable Boronic Acid Compound) One aspect of the present invention is a polymerizable boronic acid compound. The polymerizable boronic acid compound of one aspect of the present invention is represented by the following general formula (1).

[0032]

[0033] In general formula (1), R １ ~R ７ represents a substituent having at least one polymerizable group.

[0034] The polymerizable group is a group that can participate in a polymerization reaction, specifically, a group that can participate in a polymerization reaction by an active radical generated from a polymerization initiator, an acid, or the like. The polymerizable group may be any group having a double bond between two carbon atoms, and examples thereof include a vinyl group, an isopropenyl group, and a (meth)acryloyl group. Note that a (meth)acryloyl group is a general term for an acryloyl group and a methacryloyl group.

[0035] The substituent having a polymerizable group may be any as long as it has a polymerizable group. For example, in the substituent having a polymerizable group, the number of polymerizable groups contained therein may be one or two or more; the type of polymerizable group may be one or two or more; and the position of the polymerizable group may be the terminal end of the functional group or may be inside the functional group.

[0036] Preferred specific examples of the substituent having a polymerizable group are the substituents represented by general formula (2) and general formula (3).

[0037]

[0038]

[0039] In general formula (2), R ８ represents a hydrogen atom or a methyl group, and R ９ represents an oxygen atom or an amino group.

[0040] In general formula (3), R １０ represents a hydrogen atom or a methyl group, and R １１ and R １２ each independently represents an oxygen atom or an amino group. In general formula (3), m is an integer of 1, 2 or 3, and n is an integer of 1, 2 or 3.

[0041] In general formula (2) and general formula (3), the wavy line indicates the bonding site with the compound of general formula (1). Therefore, the substituents shown in general formula (2) and general formula (3) are bonded to R of the compound of general formula (1) at the wavy line portion. １ ~R ７ Concatenate with either

[0042] The polymerizable boronic acid compound of one embodiment of the present invention has a phenylboronic acid group at one end of a chromophore azo group and a naphthalene ring at the other end. The bulky naphthalene ring structure suppresses rotation around the azo group, thereby reducing photoisomerization caused by ultraviolet light.

[0043] R in general formula (1) １ ~R ７ In the above, the number of substituents having a polymerizable group may be one or two or more, but it is preferable that the number of substituents having a polymerizable group is one so that the polymerizable groups in the polymerizable boronic acid compound do not polymerize with each other. １ ~R ７ are each independently a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, or an alkyl group. For example, in consideration of compatibility with hydrophilic monomers, R １ ~R ７ Preferably, at least one of the alkyl groups is a hydroxy group. The alkyl group is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, and more preferably a linear alkyl group having 1 to 3 carbon atoms.

[0044] As an embodiment of the polymerizable boronic acid compound represented by the general formula (1), for example, in the general formula (1), R １ ~R ７ is a substituent having a polymerizable group, another is a hydroxy group, and the remaining all are hydrogen atoms, and further examples include polymerizable boronic acid compounds [I] to [V] represented by the following formulae, but are not limited to these.

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] (Method for Producing Polymerizable Boronic Acid Compound) The polymerizable boronic acid compound can be produced, for example, by the method described in the Examples below, or by a method in which the method is appropriately modified to obtain the desired polymerizable boronic acid compound.

[0051] Specific examples of methods for producing polymerizable boronic acid compounds include, but are not limited to, a method in which a naphthalene compound is reacted with a compound having a polymerizable group to obtain an intermediate that is a naphthalene compound having a substituent with a polymerizable group, and the obtained intermediate is then reacted with a dioxaborolane aniline compound to obtain a polymerizable boronic acid compound.

[0052] (Polymer Compound) Another aspect of the present invention is a polymer compound. The polymer compound of one embodiment of the present invention contains the polymerizable boronic acid compound of one embodiment of the present invention as a constituent unit.

[0053] A polymeric compound is also called a polymer or a polymer. A polymer is formed by polymerizing monomeric compounds (monomers). The structural units derived from each monomer in a polymer are also called moieties. A polymeric compound (polymer) according to one embodiment of the present invention has a structural unit (polymerizable boronic acid compound moiety) derived from a polymerizable boronic acid compound (monomer).

[0054] The polymer compound of one embodiment of the present invention can be produced by subjecting any one of the polymerizable boronic acid compounds of one embodiment of the present invention to a polymerization reaction alone, or by subjecting a combination of two or more of the polymerizable boronic acid compounds to a copolymerization reaction. Note that, in this specification, the terms polymerization reaction and copolymerization reaction are used interchangeably and refer to a chain reaction of compounds (monomers) having polymerizable groups.

[0055] The polymer compound of one embodiment of the present invention can detect cis-diol compounds having a cis-diol structure in the molecule due to the polymerizable boronic acid compound moiety, which is a structural unit. When the polymer compound of one embodiment of the present invention comes into contact with a cis-diol compound, the boronic acid in the polymerizable boronic acid compound moiety forms a cyclic boronic acid ester, changing the electronic state within the polymerizable boronic acid compound moiety and changing the color-developing state of the azo group, which is the chromophore in the polymerizable boronic acid compound moiety. As a result, the color-developing state of the polymer compound of one embodiment of the present invention, specifically, its absorption spectrum, changes. Therefore, the presence of cis-diol compounds in an environment can be detected by detecting changes in the absorption spectrum of the polymer compound of one embodiment of the present invention before and after placement in the environment.

[0056] The cis-diol compound is not particularly limited as long as it has a cis-diol structure in the molecule, and examples thereof include glucose, fructose, lactose, dopamine, etc. Hereinafter, the present invention will be described assuming that the cis-diol compound is glucose.

[0057] The polymer compound of one embodiment of the present invention preferably further comprises, as a constituent unit, a compound copolymerizable with the polymerizable boronic acid compound of one embodiment of the present invention. The polymer compound of one embodiment of the present invention can be produced by subjecting the polymerizable boronic acid compound of one embodiment of the present invention and a compound copolymerizable with the polymerizable boronic acid compound (hereinafter also referred to as a copolymerizable monomer) to a copolymerization reaction. The polymer compound thus obtained has, as constituent units, a polymerizable boronic acid compound moiety of one embodiment of the present invention and a copolymerizable monomer moiety.

[0058] The polymerizable boronic acid compound of one embodiment of the present invention and the copolymerizable monomer are bonded to each other via the polymerizable group that each of them possesses. Therefore, the copolymerizable monomer has a polymerizable group. As long as the polymerizable boronic acid compound of one embodiment of the present invention and the copolymerizable monomer can be bonded to each other through a copolymerization reaction, the polymerizable group possessed by the polymerizable boronic acid compound of one embodiment of the present invention and the polymerizable group possessed by the copolymerizable monomer may be the same polymerizable group or different polymerizable groups.

[0059] The polymer compound of one embodiment of the present invention has a polymerizable boronic acid compound moiety of one embodiment of the present invention in an amount that is responsive to glucose, i.e., an amount that causes a change in absorption spectrum upon contact with glucose. From this viewpoint, the content of the polymerizable boronic acid compound of one embodiment of the present invention in the polymer compound of one embodiment of the present invention is, for example, preferably 0.001 mol% or more, more preferably 0.005 mol% or more, relative to 100 mol% of the total amount of copolymerizable monomers. From the viewpoint of good absorbance intensity of the polymer compound, it is even more preferably 0.01 mol% or more. The upper limit of the content of the polymerizable boronic acid compound of one embodiment of the present invention is not particularly limited, but is, for example, preferably 20 mol% or less, more preferably 10 mol% or less, and even more preferably 5 mol% or less, or 1 mol% or less.

[0060] When the polymer compound according to one embodiment of the present invention is used as an ophthalmic lens such as a contact lens, the polymer compound preferably has good luminous transmittance. In this case, the content of the polymerizable boronic acid compound may prevent light transmission through the polymer compound by absorbing visible light as a dye compound. Therefore, the content of the polymerizable boronic acid compound in this case is preferably 0.001 mol% to 1 mol%, more preferably 0.01 mol% to 0.1 mol% or 0.02 mol% to 0.05 mol%, for example.

[0061] The polymer compound of one embodiment of the present invention is preferably a hydrogel in a water-containing state from the viewpoint of responsiveness to glucose.

[0062] A hydrogel is a polymer matrix that swells with and retains an aqueous liquid, such as water or a water-containing solution. In this specification, the polymer itself, excluding the aqueous liquid, is also referred to as the hydrogel matrix.

[0063] Hydrogels are based on polymers containing hydrophilic monomers as structural units. Specific examples of hydrogels include hydrogels produced using hydrophilic monomers, hydrophilic and hydrophobic monomers, and hydrogels produced using hydrophilic monomers and copolymerizable monomers such as crosslinkable monomers.

[0064] When the polymer compound of one embodiment of the present invention is a hydrogel with a low water content, the amount of glucose that comes into contact with the polymer compound is reduced, which may result in poor responsiveness to glucose. Therefore, the water content of the polymer compound of one embodiment of the present invention is preferably such that responsiveness to glucose is observed, more preferably 10% or more, even more preferably 20% or more, and even more preferably 25% or more. The water content of the hydrogel is measured by the method described in the Examples below.

[0065] In order for the polymer compound of one embodiment of the present invention to be a hydrogel, it preferably contains a hydrophilic monomer as one of the copolymerizable monomers.

[0066] The hydrophilic monomer is not particularly limited as long as it is a polymerizable compound having at least one hydrophilic group and a polymerizable group in the molecule. Examples include (meth)acrylic monomers such as N,N-dimethylacrylamide, hydroxymethyl(meth)acrylate, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, (meth)acrylic acid, 2,3-dihydroxypropyl(meth)acrylate, 2-polyethylene glycol mono(meth)acrylate, 2-polypropylene glycol (meth)acrylate, glycerol (meth)acrylate, N,N-dimethyl(meth)acrylamide, and N,N-diethyl(meth)acrylamide; and vinyl monomers such as N-vinylpyrrolidone, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, and N-vinylformamide. Among these, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, and (meth)acrylic acid are preferred. As the hydrophilic monomer, one of these may be used alone, or two or more of them may be used in combination.

[0067] The content of the hydrophilic monomer may be any amount that allows the polymer compound of one embodiment of the present invention to form a hydrogel via the hydrophilic monomer moiety, and is, for example, preferably 15 mol% or more relative to the total amount of copolymerizable monomer components. In order to ensure that the water content of the resulting hydrogel is at a level that is responsive to glucose, the content is more preferably 15 mol% to 99.9 mol%, even more preferably 20 mol% to 99.9 mol%, and even more preferably 50 mol% to 99.9 mol%, 70 mol% to 99.9 mol%, 80 mol% to 99.9 mol%, 90 mol% to 99.9 mol%, or 95 mol% to 99.9 mol%. If the content of the hydrophilic monomer is less than 15 mol% relative to the total amount of monomer components, the water content of the resulting hydrogel may be at a level that is not responsive to glucose, and further, the softness may be reduced, which may result in a reduced wearing comfort.

[0068] The polymer compound of one embodiment of the present invention may contain a crosslinkable monomer as one type of copolymerizable monomer in order to form a network structure in the molecule and to impart heat resistance and mechanical strength.

[0069] The crosslinkable monomer is not particularly limited as long as it is a polymerizable compound having two or more polymerizable groups in the molecule, and examples thereof include (meth)acrylate crosslinkable monomers such as ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, and pentaerythritol tri(meth)acrylate; allyl methacrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl phthalate, triallyl cyanurate, triallyl isocyanurate, diethylene glycol bisallyl carbonate, triallyl phosphate, triallyl trimellitate, diallyl ether, N,N-diallyl melamine, and divinylbenzene; and vinyl crosslinkable monomers such as divinylbenzene; and among these, ethylene glycol di(meth)acrylate is preferred. The crosslinkable monomer may be used alone or in combination of two or more types depending on the desired physical properties.

[0070] The content of the crosslinking monomer may be appropriately set depending on the desired network structure formability, heat resistance, and mechanical strength, and is, for example, preferably 0.01 mol % to 5 mol %, more preferably 0.1 mol % to 5 mol %, and even more preferably 0.2 mol % to 1 mol %, relative to the total amount of copolymerizable monomer components. If the content of the crosslinking monomer exceeds 5 mol %, the flexibility of the resulting hydrogel may decrease.

[0071] The polymer compound of one embodiment of the present invention can contain, as a constituent component, a hydrophobic monomer, a silicon-containing monomer, or the like as a copolymerizable monomer in order to provide the polymer compound with desired physical properties such as oxygen permeability, mechanical strength, shape stability, flexibility, and optical properties.

[0072] The hydrophobic monomer is not particularly limited as long as it is a polymerizable compound that does not have a hydrophilic group in the molecule and has a polymerizable group, and examples thereof include (meth)acrylic monomers such as trifluoroethyl (meth)acrylate, siloxanyl (meth)acrylate, methyl (meth)acrylate, n-butyl (meth)acrylate, tert-butyl (meth)acrylate, benzyl (meth)acrylate, ethylhexyl (meth)acrylate, and lauryl (meth)acrylate. The hydrophobic monomer may be used alone or in combination of two or more types depending on the desired physical properties.

[0073] The silicon-containing monomer is not particularly limited as long as it is a polymerizable compound having a siloxane bond structure in the molecule and a polymerizable group, and examples thereof include α-mono(methacryloyloxymethyl)polydimethylsiloxane, α,ω-di(methacryloyloxymethyl)polydimethylsiloxane, α-mono(3-methacryloyloxypropyl)polydimethylsiloxane, α,ω-di(3-methacryloyloxypropyl)polydimethylsiloxane, α-mono(3-methacryloyloxybutyl)polydimethylsiloxane, α,ω-di(3-methacryloyloxybutyl)polydimethylsiloxane, α-monovinyl Examples of the silicon-containing monomer include polydimethylsiloxane, α,ω-divinylpolydimethylsiloxane, 3-tris(trimethylsiloxy)silylmethyl(meth)acrylate, 3-tris(trimethylsiloxy)silylpropyl(meth)acrylate, 3-methylbis(trimethylsiloxy)silylmethyl(meth)acrylate, 3-methylbis(trimethylsiloxy)silylpropyl(meth)acrylate, 3-trimethylsiloxydimethylsilylmethyl(meth)acrylate, 3-trimethylsiloxydimethylsilylpropyl(meth)acrylate, and 3-methyldimethoxysilylpropyl(meth)acrylate. The silicon-containing monomer may be used alone or in combination of two or more, depending on the desired physical properties.

[0074] The contents of the hydrophobic monomer and the silicon-containing monomer are not particularly limited as long as they do not interfere with the solution of the problems of the present invention, and can be appropriately set, for example, so that the resulting polymer compound has desired physicochemical properties such as oxygen permeability and water content.

[0075] The polymer compound according to one embodiment of the present invention may contain, in addition to monomer components such as a polymerizable boronic acid compound and a copolymerizable monomer, additives or components such as a diluent, a stabilizer, a dye, a pigment, an antibacterial compound, and a release agent.

[0076] (Method for Producing Polymer Compound) The polymer compound of one embodiment of the present invention can be produced by combining steps known to those skilled in the art. For example, the polymer compound of one embodiment of the present invention can be produced by a method for obtaining a polymer from a monomer that has been known so far, or a method for obtaining a hydrogel from the obtained polymer.

[0077] The method for producing the polymer compound of one embodiment of the present invention is not particularly limited, and examples thereof include a method comprising the following steps (1) to (3) for obtaining a hydrogel: (1) a step of stirring and dissolving a mixture of monomer components consisting of the polymerizable boronic acid compound of one embodiment of the present invention and a copolymerizable monomer, and a polymerization initiator, to obtain a monomer mixture; (2) a step of pouring the obtained monomer mixture into a desired mold and subjecting it to a copolymerization reaction to obtain a copolymer; and (3) a step of peeling the obtained copolymer from the mold that has been cooled after the copolymerization reaction, cutting and / or polishing as necessary, and then hydrating and swelling it to obtain a hydrogel.

[0078] In step (1) of obtaining the monomer mixture, a mixture of the monomer components and the polymerization initiator may be stirred and dissolved according to a conventional method. For example, the monomer mixture may be prepared by stirring and mixing the monomer components and the polymerization initiator using a stirring device, a stirrer, or the like. The monomer mixture may also contain other additives or components known in the art, as needed. Such additives or other components are, for example, as described in the above section (Polymer Compound).

[0079] The polymerization initiator may be appropriately selected depending on the properties of the monomers used, and is not particularly limited. Examples include peroxide-based polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are common radical polymerization initiators; and azo-based polymerization initiators such as azobisdimethylvaleronitrile and azobisisobutyronitrile (AIBN). As the polymerization initiator, one of these may be used alone, or two or more may be used in combination. The amount of polymerization initiator added is not particularly limited as long as it is an amount that can achieve a copolymerization reaction of the monomers.

[0080] In step (2) of obtaining the copolymer, the monomer mixture is placed in a mold consisting of a male and female mold made of metal, glass, plastic, or the like, and the mold is then sealed, and the mold containing the monomer mixture is then heated stepwise or continuously in a thermostatic bath or the like to a temperature in the range of 25°C to 120°C, and subjected to a copolymerization reaction for 5 to 120 hours. The copolymerization reaction may be carried out so as to induce radical polymerization, and may be a copolymerization reaction by heating, a copolymerization reaction using light such as ultraviolet light, electron beams, or gamma rays, or a copolymerization reaction in which a solvent such as water or an organic solvent is added to the monomer mixture and solution polymerization is carried out.

[0081] In step (3) of obtaining the hydrogel, the mold used in the copolymerization reaction is cooled to room temperature, the polymer is then peeled from the mold, and the resulting polymer is cut and / or polished as necessary, followed by hydration and swelling to form the hydrogel. Examples of the liquid (swelling liquid) used for hydration and swelling include water, physiological saline, isotonic buffer solution, alcohol, and combinations thereof. The hydration and swelling treatment is preferably carried out by immersing the copolymer in a swelling liquid heated to 60°C to 100°C for a certain period of time to bring the copolymer into a swollen state. Furthermore, in the hydration and swelling treatment, it is preferable to remove unpolymerized monomers contained in the polymer.

[0082] After hydration and swelling, the hydrogel may contain about 30 wt % to about 80 wt % copolymer (polymer). That is, the hydrogel matrix comprises about 40 wt % to about 80 wt % of the hydrogel. The remainder of the hydrogel is typically formed from the liquid component (e.g., water) that hydrates the hydrogel matrix.

[0083] (Embodiments of Polymer Compounds) The polymer compound of one aspect of the present invention is in the form of a hydrogel, and therefore is responsive to glucose and can be used as a hydrogel for glucose detection even when the content of the polymerizable boronic acid compound of one aspect of the present invention is small, for example, 1 mol % or less relative to the total amount of the monomer components. As a result, the polymer compound of one aspect of the present invention can be composed mostly of monomer components for use in a specific application.

[0084] The polymer compound of one embodiment of the present invention can be, for example, hydrophilic, flexible, transparent, and oxygen permeable. Because of these properties, the polymer compound of one embodiment of the present invention can be applied to, for example, ophthalmic lenses used on or inside the eye, and can be preferably used as contact lenses, intraocular lenses, etc. The contact lenses are hydrophilic lenses, and can be soft contact lenses or hard contact lenses (i.e., rigid gas permeable (RGP)).

[0085] When the polymer compound of one embodiment of the present invention is used as an ophthalmic lens, it preferably has a thickness of 50 μm to 150 μm.

[0086] When the polymer compound of one embodiment of the present invention is used as an ophthalmic lens, it is preferable that the polymer compound has high transparency. For example, the luminous transmittance measured by the method described in the Examples below is more preferably 60% or more, even more preferably 70% or more, and still more preferably 80% or more.

[0087] (Method of Using Polymer Compound) Another aspect of the present invention is a method for detecting a cis-diol compound such as glucose, fructose, lactose, or dopamine using a polymer compound according to an embodiment of the present invention. The method according to an embodiment of the present invention includes a step of detecting the cis-diol compound in a solution based on a change in absorbance of the polymer compound before and after contacting the polymer compound with the solution.

[0088] The change in absorbance is determined by the wavelength (λ ｍｉｎ ) after contact with the solution (A ｍｉｎ ) 、 and the wavelength at which the change in absorbance is greatest (λ ｍａｘ ) after contact with the solution (A ｍａｘ ) and the absorbance ratio (R = A ｍａｘ / A ｍｉｎ ) is compared with the absorbance ratio measured and calculated using a control solution containing no cis-diol compound instead of the solution, and based on the presence of a difference between the two, it can be determined that the cis-diol compound has been detected in the solution.

[0089] The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples, and the present invention can take various forms as long as the problems of the present invention can be solved.

[0090] [1. Synthesis of Polymerizable Boronic Acid Compound] (Example 1) Synthesis of Polymerizable Boronic Acid Compound [I] 1-1. Overview According to the following scheme (I), polymerizable boronic acid compound [I] was synthesized from 2,6-dihydroxynaphthalene via intermediate [I].

[0091]

[0092] 1-2. Synthesis of Intermediate [I] A mixture of 2,6-dihydroxynaphthalene (3.34 g, 20.85 mmol), triethylamine (1.06 g, 10.43 mmol), and dehydrated dichloromethane (23 mL) was cooled to 0°C with stirring. To the cooled mixture, methacrylic acid chloride (0.73 g, 6.95 mmol) was added dropwise over 30 minutes, and the resulting mixture was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with pure water and saturated brine, in that order, and then dried over anhydrous magnesium sulfate. Solids were removed from the dried solution by filtration, and the resulting filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 0.66 g of Intermediate [I].

[0093] The NMR spectrum of the obtained intermediate [I] was as follows: １ H-NMR (500MHz, CD ３ OD) δ7.54 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H), 7.15 (d, 1H), 6.98 (d, 1H), 6.91 (s, 1H), 6.42 (s, 1H), 5.81 (s, 1H), 2.10 (s, 3H)

[0094] 1-3. Synthesis of Polymerizable Boronic Acid Compound [I] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g, 2.28 mmol), concentrated hydrochloric acid (0.75 mL), and tetrahydrofuran (5 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.17 g, 2.39 mmol) dissolved in 7.5 mL of pure water was added dropwise in small portions, and the resulting mixture was stirred for 15 minutes. To the stirred mixture, intermediate [I] dissolved in 7.5 mL of tetrahydrofuran was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution (1 mL). Ethyl acetate was added to the neutralized reaction solution, and the solution was washed with pure water and saturated brine, followed by drying over anhydrous magnesium sulfate. The solid content was removed by filtration from the dried solution, and the resulting filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 0.20 g of polymerizable boronic acid compound [I].

[0095] The NMR spectrum of the resulting polymerizable boronic acid compound [I] was as follows: １ H-NMR (500MHz, DMSO-d6) δppm: 8.52 (d, 1H), 7.96 (d, 2H), 7.89 (d, 1H), 7.78 (d, 2H), 7.58 (d, 1H), 7.39 (d, 1H), 6.90 (d, 1H), 6.33 (s, 1H), 5.93 (s, 1H), 2.03 (s, 3H)

[0096] Example 2 Synthesis of Polymerizable Boronic Acid Compound [II] 2-1. Overview According to the following scheme (II), polymerizable boronic acid compound [II] was synthesized from 5-amino-2-naphthol via intermediate [II].

[0097]

[0098] 2-2. Synthesis of Intermediate [II] 5-amino-2-naphthol (1.00 g, 6.28 mmol), methacrylic acid (0.59 g, 6.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.54 mmol), and 4-dimethylaminopyridine (0.92 g, 7.54 mmol) were dissolved in dehydrated dichloromethane (25 mL), and the resulting solution was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain Intermediate [II] (0.61 g, 2.68 mmol).

[0099] The NMR spectrum of the obtained intermediate [II] was as follows: １ H-NMR (500MHz, CD ３ OD) 8.02 (d, 1H), 7.47 (d, 1H), 7.25 (t, 1H), 7.17 (t, 2H), 6.79 (d, 1H), 6.37 (s, 1H), 5.83 (s, 1H), 2.07 (s, 3H)

[0100] 2-3. Synthesis of Polymerizable Boronic Acid Compound [II] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.55 g, 2.50 mmol), concentrated hydrochloric acid (0.8 mL), and tetrahydrofuran (5.5 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.18 g, 2.63 mmol) dissolved in 0.8 mL of purified water was added dropwise in small amounts, and the resulting mixture was stirred for 15 minutes. To the stirred mixture, intermediate [II] (0.61 g, 2.68 mmol) dissolved in 8.2 mL of tetrahydrofuran was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in this order, and then purified by column chromatography to obtain 0.30 g of polymerizable boronic acid compound [II].

[0101] The NMR spectrum of the resulting polymerizable boronic acid compound [II] was as follows:１ H-NMR (500MHz, DMSO-d6) δ8.57 (s, 1H), 8.29 (d, 1H), 8.15 (s, 2H), 7.93 (m, 3H), 7.82 ( d, 2H), 7.33 (d, 1H), 7.07 (s, 1H), 6.79 (d, 1H), 6.37 (s, 1H), 5.95 (s, 1H), 2.06 (s, 3H)

[0102] Example 3 Synthesis of Polymerizable Boronic Acid Compound [III] 3-1. Overview According to the following scheme (III), a polymerizable boronic acid compound [III] was synthesized from 3-amino-2-naphthol via an intermediate [III].

[0103]

[0104] 3-2. Synthesis of Intermediate [III] 3-amino-2-naphthol (1.00 g, 6.28 mmol), methacrylic acid (0.59 g, 6.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.54 mmol), and 4-dimethylaminopyridine (0.92 g, 7.54 mmol) were dissolved in dehydrated dichloromethane (25 mL), and the resulting solution was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain Intermediate [III] (0.42 g, 1.84 mmol).

[0105] The NMR spectrum of the obtained intermediate [III] was as follows: １ H-NMR (500MHz, CD ３ OD) δ8.58 (s, 1H), 7.69 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.26 (t, 1H), 7.18 (s, 1H), 5.92 (s, 1H), 5.56 (s, 1H), 2.10 (s, 3H)

[0106] 3-3. Synthesis of Polymerizable Boronic Acid Compound [III] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.36 g, 1.64 mmol), concentrated hydrochloric acid (0.5 mL), and tetrahydrofuran (3.6 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.12 g, 1.72 mmol) dissolved in 0.5 mL of purified water was added dropwise in small portions, and the resulting mixture was stirred for 15 minutes. To the resulting solution, intermediate [III] (0.40 g, 1.76 mmol) dissolved in 5.4 mL of tetrahydrofuran was added dropwise, and the resulting solution was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in this order, and then purified by column chromatography to obtain 0.03 g of polymerizable boronic acid compound [III].

[0107] The NMR spectrum of the resulting polymerizable boronic acid compound [III] was as follows: １ H-NMR (500MHz, DMSO-d6) δ8.97 (s, 1H), 8.55 (s, 1H), 8.28 (d, 1H), 8.14 (s, 2H), 7.92 (d, 2H) , 7.72 (d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.36 (t, 1H), 5.93 (s, 1H), 5.59 (s, 1H), 2.03 (s, 3H)

[0108] Example 4 Synthesis of Polymerizable Boronic Acid Compound [IV] 4-1. Overview According to the following scheme (IV), a polymerizable boronic acid compound [IV] was synthesized from 5-amino-2-naphthol via an intermediate [IV].

[0109]

[0110] 4-2. Synthesis of Intermediate [IV] 5-amino-2-naphthol (1.00 g, 6.28 mmol), methacryloyloxyethyl succinic acid (1.59 g, 6.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.54 mmol), and 4-dimethylaminopyridine (0.92 g, 7.54 mmol) were dissolved in dehydrated dichloromethane (25 mL), and the resulting solution was stirred at room temperature for 18 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain Intermediate [IV] (1.50 g, 4.04 mmol).

[0111] The NMR spectrum of the obtained intermediate [IV] was as follows: １ H-NMR (500MHz, CDCl ３ ) δ7.80 (d, 1H), 7.49 (d, 1H), 7.27 (m, 2H), 7.18 (dd, 1H), 6.73 (dd, 1H), 6.1 2 (s, 1H), 5.56 (s, 1H), 4.38 (q, 4H), 2.94 (t, 2H), 2.80 (t, 2H), 1.93 (s, 3H)

[0112] 4-3. Synthesis of polymerizable boronic acid compound [IV] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g, 2.26 mmol), concentrated hydrochloric acid (0.6 mL), and tetrahydrofuran (3.8 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.16 g, 2.36 mmol) dissolved in 0.6 mL of purified water was added dropwise in small amounts, and the resulting mixture was stirred for 15 minutes. The mixture was stirred. To the stirred mixture, intermediate [IV] (0.70 g, 1.88 mmol) dissolved in 5.7 mL of tetrahydrofuran was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with a 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in that order, and then purified by column chromatography to obtain 0.05 g of polymerizable boronic acid compound [IV].

[0113] The NMR spectrum of the resulting polymerizable boronic acid compound [IV] was as follows: １ H-NMR (500MHz, DMSO-d6) δ8.53 (s, 1H), 8.27 (d, 1H), 8.16 (s, 2H), 7.95 (d, 2H), 7.81 (d, 2H), 7.24 (d, 2H) , 7.07 (s, 1H), 6.78 (d, 1H), 6.01 (s, 1H), 5.61 (s, 1H), 4.33 (d, 4H), 2.94 (t, 2H), 2.76 (t, 1H), 1.82 (s, 3H)

[0114] Example 5 Synthesis of Polymerizable Boronic Acid Compound [V] 5-1. Overview According to the following scheme (V), a polymerizable boronic acid compound [V] was synthesized from 3-amino-2-naphthol via an intermediate [V].

[0115]

[0116] 5-2. Synthesis of Intermediate [V] 3-Amino-2-naphthol (1.00 g, 6.28 mmol), methacryloyloxyethyl succinic acid (1.45 g, 6.28 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (2.69 g, 6.28 mmol) were dissolved in anhydrous N,N-dimethylformamide (25 mL), and the resulting solution was stirred at room temperature for 45 minutes. Next, N,N-diisopropylethylamine (0.81 g, 6.28 mmol) was added to the stirred solution, and the mixture was stirred at room temperature for 2 hours to obtain a reaction solution. After stirring, the reaction solution was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, in that order, and then subjected to purification by column chromatography to obtain Intermediate [V] (1.60 g, 4.31 mmol).

[0117] The NMR spectrum of the obtained intermediate [V] was as follows: １ H-NMR (500MHz, CD ３ OD) δ8.30 (s, 1H), 8.10 (s, 1H), 7.66 (d, 2H), 7.59 (d, 1H), 7.33 (t, 1H), 7.28 (t, 1H), 7.2 6 (s, 2H), 6.12 (s, 1H), 5.55 (s, 1H), 4.37 (s, 4H), 2.82 (t, 2H), 2.76 (t, 2H), 1.92 (s, 3H)

[0118] 5-3. Synthesis of Polymerizable Boronic Acid Compound [V] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.94 g, 4.31 mmol), concentrated hydrochloric acid (1.3 mL), and tetrahydrofuran (8.6 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (0.31 g, 4.52 mmol) dissolved in 12 mL of purified water was added dropwise in small amounts, and the resulting mixture was stirred for 15 minutes. To the stirred mixture, intermediate [V] (1.59 g, 4.31 mmol) dissolved in 12 mL of tetrahydrofuran was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide solution. Ethyl acetate was added to the neutralized reaction solution, and the resulting solution was washed with pure water and saturated brine in this order, and then purified by column chromatography to obtain 0.70 g of polymerizable boronic acid compound [V].

[0119] The NMR spectrum of the obtained polymerizable boronic acid compound [V] was as follows. １ H-NMR (500MHz, DMSO-d6) δ9.56 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H), 8.16 (s, 2H), 7.95 (d, 2H), 7.71 (d, 2H), 7.58 ( d, 1H), 7.47 (t, 1H), 7.40 (t, 1H), 6.02 (s, 1H), 5.63 (s, 1H), 4.04 (s, 4H), 2.82 (t, 2H), 2.64 (t, 2H), 1.84 (s, 3H)

[0120] [2. Synthesis of Color-Developing Non-Polymerizable Boronic Acid Compound] (Comparative Example 1) Synthesis of Non-Polymerizable Boronic Acid Compound [VI] 1-1. Overview Non-polymerizable boronic acid compound [VI] was synthesized from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline according to the following scheme (VI).

[0121]

[0122] 1-2. Synthesis of Non-Polymerizable Boronic Acid Compound [VI] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.00 g, 4.56 mmol), concentrated hydrochloric acid (1.5 mL), and purified water (10 mL) was cooled to 0°C with stirring. To the cooled mixture, sodium nitrite (1.00 g, 4.78 mmol) dissolved in 15 mL of purified water was added dropwise in small amounts, and the resulting mixture was stirred for 15 minutes. To the stirred mixture, disodium 3-hydroxy-2,7-naphthalenedisulfonate dissolved in 10 mL of purified water was added dropwise, and the resulting mixture was stirred for 15 minutes to obtain a reaction solution. After stirring, the reaction solution was neutralized with 20% aqueous sodium hydroxide. The precipitate was filtered from the neutralized reaction solution, and the resulting solid was dissolved in a small amount of purified water and reprecipitated in acetone for purification. This gave 0.75 g of non-polymerizable boronic acid compound [VI].

[0123] The NMR spectrum of the obtained non-polymerizable boronic acid compound [VI] was as follows: １ H-NMR (500MHz, D ２ O) δppm: 7.91 (d, 1H), 7.79 (m, 2H), 7.50 (s, 1H), 7.23 (d, 2H), 6.96 (2H)

[0124] 3. Formation of Hydrogels Containing Polymerizable Boronic Acid Compounds Example 6 Formation of Hydrogel 1 According to Table 1, 0.02 mol % of the polymerizable boronic acid compound [I], 99.55 mol % of hydroxyethyl methacrylate, 0.45 mol % of ethylene glycol dimethacrylate, and 0.25 mol % of AIBN were mixed with stirring at room temperature to prepare a monomer mixture.

[0125] The resulting monomer mixture was placed in a disk-shaped resin mold and subjected to a heating treatment in the range of 30°C to 105°C over approximately 10 hours to obtain a polymer. The resulting polymer was removed from the resin mold, which had been returned to room temperature, and then immersed in 70°C ethanol-containing phosphate-buffered saline (PBS) and then in PBS for 30 minutes, successively, to hydrate and swell, yielding a hydrogel. The resulting hydrogel, while immersed in PBS, was subjected to autoclaving to obtain Hydrogel 1 as a fixed-form device.

[0126] Example 7 Formation of Hydrogel 2 Hydrogel 2 was obtained in the same manner as in Example 6, except that the blending amount of the polymerizable boronic acid compound [I] was set to 0.05 mol % in accordance with Table 1.

[0127] (Example 8) Formation of Hydrogel 3 Hydrogel 3 was obtained in the same manner as in Example 6, except that a monomer mixture solution was prepared by stirring and mixing 0.05 mol % of the polymerizable boronic acid compound [I], 49.55 mol % of hydroxyethyl methacrylate, 50 mol % of hydroxypropyl methacrylate, 0.45 mol % of ethylene glycol dimethacrylate, and 0.25 mol % of AIBN according to Table 1 at room temperature.

[0128] (Example 9) Formation of Hydrogel 4 Hydrogel 4 was obtained in the same manner as in Example 6, except that a monomer mixture solution was prepared by stirring and mixing 0.05 mol % of the polymerizable boronic acid compound [I], 97.55 mol % of hydroxyethyl methacrylate, 2.0 mol % of methacrylic acid, 0.45 mol % of ethylene glycol dimethacrylate, and 0.25 mol % of AIBN at room temperature according to Table 1.

[0129] (Example 10) Formation of Hydrogel 5 Hydrogel 5 was obtained in the same manner as in Example 6, except that a monomer mixture solution was prepared by stirring and mixing 0.05 mol % of the polymerizable boronic acid compound [I], 94.55 mol % of hydroxyethyl methacrylate, 5.0 mol % of methacrylic acid, 0.45 mol % of ethylene glycol dimethacrylate, and 0.25 mol % of AIBN at room temperature according to Table 1.

[0130] Example 11 Formation of Hydrogel 6 Hydrogel 6 was obtained in the same manner as in Example 6, except that 0.05 mol % of the polymerizable boronic acid compound [II] was used in accordance with Table 1.

[0131] Example 12 Formation of Hydrogel 7 Hydrogel 7 was obtained in the same manner as in Example 6, except that 0.05 mol % of the polymerizable boronic acid compound [III] was used in accordance with Table 1.

[0132] Example 13 Formation of Hydrogel 8 Hydrogel 8 was obtained in the same manner as in Example 6, except that the polymerizable boronic acid compound [I] was used at 0.08 mol % in accordance with Table 1.

[0133] [4. Formation of Hydrogel Containing Non-Polymerizable Boronic Acid Compound] (Comparative Example 2) Formation of Hydrogel 9 According to Table 1, Hydrogel 9 was obtained in the same manner as in Example 6, except that 0.05 mol % of the non-polymerizable boronic acid compound [VI] was used.

[0134] [5. Evaluation Method] (1) Copolymerizability One sheet of polymer before hydration swelling was immersed in 5 mL of water or a water / ethanol mixed solvent (v / v = 1 / 1) for 24 hours, and the presence or absence of coloration of the immersion liquid was visually confirmed, and the copolymerizability of the polymerizable boronic acid compound and the non-polymerizable boronic acid compound was evaluated according to the following criteria: ○: No coloration (copolymerizable) ×: Coloration (no copolymerizability)

[0135] (2) Luminous transmittance The light transmittance of the hydrogel (wavelength range: 380 nm-780 nm; interval: 5 nm) was measured using an ultraviolet-visible spectrophotometer ("V-750"; manufactured by JASCO Corporation). The obtained measurement data was normalized to a center thickness equivalent to 0.08 mm based on the Lambert-Beer law, and the luminous transmittance (%) was calculated based on the test method of ISO 18369-3. Three hydrogels were used, and the average of the calculated values ​​was used as the measured value.

[0136] (3) Water content After wiping off excess water from the hydrogel, the mass of the hydrated hydrogel (W １After that, the hydrogel was dried in a dryer at 90°C for 16 hours, and the weight of the dried hydrogel (W ２ ) was measured. From the obtained measurements, the water content was calculated according to the following formula. Three hydrogels were used, and the average of the calculated values ​​was taken as the water content of the hydrogel. Water content (wt%) = [(W １ -W ２ ) / W １ ]×100

[0137] (4) Glucose Responsiveness: The hydrogel was immersed in phosphate-buffered saline (PBS) or glucose-containing phosphate-buffered saline (Glc) containing 1 mol / L of glucose for 3 hours. After immersion, excess water was wiped off from the hydrogel, and the absorption spectrum (wavelength range: 380 nm to 780 nm; interval: 1 nm) was measured using an ultraviolet-visible spectrophotometer ("V-750" manufactured by JASCO Corporation).

[0138] The measurement data after immersion in each saline solution was compared to determine the wavelength (λ) at which the change in absorbance due to the presence or absence of glucose was smallest. ｍｉｎ ) and the wavelength at which the change in absorbance is greatest (λ ｍａｘ ) and two points were detected. ｍｉｎ and λ ｍａｘ The absorbance (A ｍｉｎ , A ｍａｘ ) to calculate the absorbance ratio R in phosphate buffered saline according to the following formula: ＰＢＳ , and the absorbance ratio R in glucose-containing phosphate buffered saline Ｇｌｃ The absorbance ratio R = A ｍａｘ / A ｍｉｎ

[0139] The obtained R ＰＢＳ and R Ｇｌｃ The significance of the difference was determined using a t-test (significance level 5%) and evaluated according to the following criteria: ○: significant difference ×: no significant difference

[0140] [6. Evaluation Results] The copolymerizability, luminous transmittance, water content, and λ for the hydrogels 1 to 9 of Examples 6 to 13 and Comparative Example 2 were evaluated. ｍｉｎ and λ ｍａｘThe results of evaluating the glucose responsiveness containing the hydrogels are shown in Table 1. The absorption spectra of the hydrogels 1, 2, 4 and 5 of Examples 6, 7, 9 and 10 when immersed in PBS and Glc are shown in Figure 2.

[0141] As a result of the evaluation of copolymerizability, the polymerizable boronic acid compounds contained as structural units in the hydrogels 1 to 8 of Examples 6 to 13 had polymerizable groups in the molecules, and therefore did not detach from the hydrogels and did not color the immersion liquid. Therefore, these hydrogels had good copolymerizability.

[0142] On the other hand, in the case of Hydrogel 9 of Comparative Example 2, the non-polymerizable boronic acid compound used did not have a polymerizable group in the molecule, and therefore it was detached from the hydrogel, causing the immersion liquid to become colored. This indicates that the boronic acid compound contained as a constituent unit in Hydrogel 9 of Comparative Example 2 does not have copolymerizability. Furthermore, since no dye remained in the hydrogel, evaluation of glucose responsiveness was not possible for Hydrogel 9 of Comparative Example 2.

[0143] As a result of the evaluation of visual transmittance, all of the hydrogels 1 to 8 in Examples 6 to 13 had a visual transmittance of 70%, and in particular, the hydrogels 1 to 7 in Examples 6 to 12 had an excellent visual transmittance of 80% or more.

[0144] The evaluation results of water content showed that hydrogels 1 to 8 in Examples 6 to 13 had water contents of 30% to 62%, indicating that the desired water content can be adjusted even when a polymerizable boronic acid compound is contained as a constituent unit. Furthermore, production examples of other hydrogels have shown that a low content of polymerizable boronic acid compound and a low water content can result in poor glucose responsiveness.

[0145] As a result of evaluating glucose responsiveness, hydrogels 1 to 8 of Examples 6 to 13 exhibited changes in absorption spectrum depending on the presence or absence of glucose, and were therefore glucose responsive.

[0146]

[0147] The polymerizable boronic acid compound of one embodiment of the present invention can be used as a monomer capable of detecting changes in glucose concentration by forming a cyclic boronic acid ester with glucose, and can be used, for example, as an ophthalmic hydrogel such as a contact lens. Furthermore, since the polymer compound of one embodiment of the present invention can detect changes in glucose concentration in tears, it can also be used as a medical device for managing blood glucose levels, thereby contributing to the health and welfare of individual organisms. CROSS-REFERENCE TO RELATED APPLICATIONS

[0148] This application claims priority from Japanese Patent Application No. 2024-069077, filed April 22, 2024, the entire disclosure of which is incorporated herein by reference. In addition, the entire disclosures of all documents referenced in the detailed description of the invention of this application, including Patent Documents 1 to 3 and Non-Patent Document 1, are incorporated herein by reference.

Claims

1. General formula (1) (In the formula, R １ ~R ７ represents a substituent having a polymerizable group, and the rest each independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, and an alkyl group.

2. The substituent having a polymerizable group is represented by general formula (2): (In the formula, R ８ represents a hydrogen atom or a methyl group, R ９ represents an oxygen atom or an amino group, and the wavy line represents a bonding site with the compound of general formula (1). (In the formula, R １０ represents a hydrogen atom or a methyl group, R １１ and R １２ each independently represent an oxygen atom or an amino group, m is an integer of 1 to 3, n is an integer of 1 to 3, and the wavy line is a bonding site to the compound of general formula (1).

3. A polymeric compound comprising the polymerizable boronic acid compound according to claim 1 or 2 as a constituent unit.

4. The polymer compound according to claim 3, which is used to detect a compound having a cis-diol structure in the molecule.

5. The polymer compound according to claim 4, wherein the compound having a cis-diol structure in the molecule is a compound selected from the group consisting of glucose, fructose, lactose, and dopamine.

6. The polymer compound according to claim 3, further comprising a compound copolymerizable with said polymerizable boronic acid compound as a constituent unit.

7. The polymer compound according to claim 6, wherein the compound copolymerizable with the polymerizable boronic acid compound is at least one hydrophilic monomer.

8. The polymer compound according to claim 3, wherein the polymer compound is a hydrogel.

9. The polymer compound according to claim 8, wherein the hydrogel has a water content of 25% or more.

10. A method for detecting a compound having a cis-diol structure in its molecule, comprising the step of detecting a compound having a cis-diol structure in its molecule in a solution based on a change in absorbance of the polymer compound described in claim 3 before and after contacting the polymer compound with the solution.

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