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WO2025225513A1 - Composé d'acide boronique ayant un site chromogène et un site polymérisable, et son utilisation - Google Patents

Composé d'acide boronique ayant un site chromogène et un site polymérisable, et son utilisation

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Publication number
WO2025225513A1
WO2025225513A1 PCT/JP2025/015167 JP2025015167W WO2025225513A1 WO 2025225513 A1 WO2025225513 A1 WO 2025225513A1 JP 2025015167 W JP2025015167 W JP 2025015167W WO 2025225513 A1 WO2025225513 A1 WO 2025225513A1
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Prior art keywords
polymerizable
boronic acid
compound
group
acid compound
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English (en)
Japanese (ja)
Inventor
仁美 中山
優貴 伊東
佳子 山崎
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Seed Co Ltd
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Seed Co Ltd
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Publication of WO2025225513A1 publication Critical patent/WO2025225513A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof

Definitions

  • Glucose is the energy source for almost all cells and is an important compound for maintaining biological activity. However, if there is an abnormality in the body, the glucose concentration will increase, so the health of the body can be monitored by using the glucose concentration in the blood (blood glucose level) as an indicator.
  • tears contain various biochemical components that reflect the physiological state of the body, and it has been reported that changes in their concentration correlate with the state of the blood. For example, it is known that the glucose concentration in tears is about one-tenth of the blood sugar level, and that changes in glucose concentration in tears follow blood sugar levels with a delay of about five minutes.
  • 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.
  • One possible method for detecting changes in glucose concentration in the eye is to use a glucose sensor that utilizes changes in optical properties resulting from a chemical reaction between glucose and the components of the contact lens substrate.
  • boronic acids which can reversibly form ester bonds with cis-diols such as glucose in aqueous solution to form cyclic boronate esters
  • cis-diols such as glucose in aqueous solution to form cyclic boronate esters
  • an azo compound having a boronic acid at its end dissolved in aqueous solution undergoes an ester bond with glucose to form a cyclic boronate ester, causing a change in the absorption wavelength of the molecule, and it is known that changes in glucose concentration can be detected based on this change in absorption wavelength (see, for example, Non-Patent Document 1).
  • polymerizable boronic acid compounds have a polymerizable moiety and can be copolymerized with other monomers.
  • contact lenses can be formed to detect changes in glucose concentration in tears.
  • Patent Document 1 the polymerizable boronic acid compound described in Patent Document 1 is prone to change shape when irradiated with ultraviolet light, depending on the photoisomerization properties of the azobenzene in its structure.
  • the problem that the present invention aims to solve 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.
  • the inventors conducted extensive research into the structural changes that occur in boronic acids when they are bonded to cis-diol compounds such as glucose.
  • boronic acid in an aqueous medium, is in an acid dissociation equilibrium state between an electrically neutral triangular planar structure, -B(OH) 2 , and an anionic tetrahedral structure, -B(OH) 3 (top panel of Figure 1).
  • the acid dissociation constant of boronic acid is approximately 9. Therefore, at physiological conditions, such as pH 7.4, trigonal planar boronic acid (-B(OH) 2 ) predominates (upper left panel of Figure 1), and upon contact with a cis-diol moiety, it forms a trigonal planar boronic acid ester (lower left panel of Figure 1). Furthermore, the acid dissociation constant of cyclic boronic acid esters is approximately 7. As a result, tetrahedral cyclic boronic acid esters predominate (lower right panel of Figure 1).
  • the inventors therefore focused on a structure in which the polymerizable moiety and boronic acid are bonded via the azo group, which is a chromophore.
  • 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 structural changes in the boronic acid.
  • They then hypothesized that by introducing a bulky structure to one of the azo groups, rotational movement around the azo group would be inhibited, making it possible to suppress photoisomerization.
  • the inventors furthered their research and development through repeated trial and error, and finally discovered that in polymerizable boronic acid compounds in which a naphthalene ring has been introduced to one of the azo groups, the electronic state of the azo group changes based on structural changes in the boronic acid, further reducing rotational movement around the azo group, and also exhibiting excellent copolymerizability with other polymerizable compounds (monomers).
  • R 1 to 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.
  • the substituent having a polymerizable group is General formula (2) (In the formula, R8 represents a hydrogen atom or a methyl group; R9 represents an oxygen atom or an amino group, and the wavy line represents the bonding site to the compound of general formula (1).
  • 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 from 1 to 3
  • n is an integer of 1 to 3
  • the wavy line is the bonding site to the compound of general formula (1).
  • a method for detecting a compound having a cis-diol structure in the molecule comprising: The method according to item [3], further comprising a step of detecting a compound having a cis-diol structure in the molecule in the solution based on a change in absorbance of the polymer compound before and after contacting the polymer compound with the solution.
  • 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) that contains boronic acid as a constituent unit.
  • the polymerizable boronic acid compound of one embodiment of the present invention can be copolymerized with a hydrophilic monomer to form a hydrogel.
  • a hydrogel can be used to detect changes in the concentration of cis-diol compounds such as glucose.
  • the polymerizable boronic acid compound of one embodiment of the present invention has reduced photoisomerization properties due to physical disturbances and further has a color-forming moiety. Therefore, 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 its structure and optical properties before and after detecting changes in the concentration of cis-diol compounds such as glucose, making it suitable for use as an ophthalmic lens.
  • FIG. 1 is a diagram schematically illustrating the reaction mechanism between boronic acid and cis -diol.
  • 2 shows 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 to peak absorbance.
  • Constant is synonymous with concentration and amount used (amount added), and refers to the ratio of the amount of a component to the total amount of the final product. However, the total amount of the component content does not exceed 100%.
  • 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.
  • the use of "to” in a numerical range includes both the preceding and following numerical values, and also includes ranges excluding either of the included 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.
  • "about 100” means 100 ⁇ 10%, i.e., 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. Also, the number of digits after the decimal point in a decimal value matches the number of significant digits. For example, 0.1 has one significant digit, and 0.10 has two significant digits.
  • 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):
  • At least one of R 1 to R 7 represents a substituent having a polymerizable group.
  • a polymerizable group is a group that can participate in a polymerization reaction; specifically, a group that can participate in a polymerization reaction by active radicals generated from a polymerization initiator, an acid, or the like.
  • Any polymerizable group having a double bond between two carbon atoms can be used, and examples include vinyl groups, isopropenyl groups, and (meth)acryloyl groups. Note that (meth)acryloyl groups are a general term for acryloyl groups and methacryloyl groups.
  • the substituent having a polymerizable group may be any substituent having a polymerizable group.
  • the substituent having a polymerizable group may contain one or more polymerizable groups; the type of polymerizable group may be one or more; and the position of the polymerizable group may be at the terminal end of the functional group or inside the functional group.
  • substituents having a polymerizable group are substituents represented by general formula (2) and general formula (3).
  • R8 represents a hydrogen atom or a methyl group
  • R9 represents an oxygen atom or an amino group
  • R10 represents a hydrogen atom or a methyl group
  • R11 and R12 each independently represent an oxygen atom or an amino group.
  • m is an integer of 1, 2, or 3
  • n is an integer of 1, 2, or 3.
  • One embodiment of the polymerizable boronic acid compound of the present invention has a phenylboronic acid group at one end of the azo group, which is the chromophore, and a naphthalene ring at the other end. Because of the bulky structure of the naphthalene ring, rotational movement around the azo group is suppressed, reducing the occurrence of photoisomerization due to the effects of ultraviolet light.
  • the number of substituents having a polymerizable group may be one or two or more, but in order to prevent polymerization of the polymerizable groups in the polymerizable boronic acid compound with each other, it is preferable that there is one substituent having a polymerizable group.
  • R 1 to R 7 other than the substituent having a polymerizable group are each independently a hydrogen atom, a hydroxy group, a carboxyl group, an amino group, or an alkyl group, but it is preferable that at least one of R 1 to R 7 is a hydroxy group, for example, in consideration of compatibility with hydrophilic monomers.
  • 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.
  • Examples of embodiments of the polymerizable boronic acid compound represented by general formula (1) include, for example, polymerizable boronic acid compounds in which, in general formula (1), one of R 1 to 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, but are not limited to, polymerizable boronic acid compounds [I] to [V] represented by the following formulas:
  • 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.
  • 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 resulting intermediate is then reacted with a dioxaborolane aniline compound to obtain a polymerizable boronic acid compound.
  • polymer compound Another aspect of the present invention is a polymer compound.
  • the polymer compound of one aspect of the present invention contains the polymerizable boronic acid compound of one aspect of the present invention as a constituent unit.
  • a polymeric compound is also called a polymer or a polymerized polymer.
  • a polymer is formed by polymerizing monomeric compounds (monomers).
  • the structural units derived from each monomer in a polymer are also called moieties.
  • the polymeric compound (polymer) of one embodiment of the present invention has a structural unit (polymerizable boronic acid compound moiety) derived from a polymerizable boronic acid compound (monomer).
  • 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 compounds to a copolymerization reaction.
  • polymerization reaction and copolymerization reaction are used interchangeably to refer to a chain reaction of compounds (monomers) having polymerizable groups.
  • a polymer compound according to one embodiment of the present invention can detect cis-diol compounds having a cis-diol structure within the molecule due to the polymerizable boronic acid compound moiety, which is a structural unit.
  • 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 within the polymerizable boronic acid compound moiety.
  • the color-developing state of the polymer compound according to one embodiment of the present invention changes. Therefore, the presence of cis-diol compounds in the environment can be detected by detecting changes in the absorption spectrum of a polymer compound according to one embodiment of the present invention before and after placement in the environment.
  • the cis-diol compound is not particularly limited as long as it has a cis-diol structure in its molecule, but examples include glucose, fructose, lactose, and dopamine. Below, the present invention will be described assuming that the cis-diol compound is glucose.
  • the polymer compound of one embodiment of the present invention preferably further comprises, as a structural 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 obtained in this manner has, as structural units, a polymerizable boronic acid compound moiety of one embodiment of the present invention and a copolymerizable monomer moiety.
  • 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 possesses. Therefore, the copolymerizable monomer has a polymerizable group.
  • 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.
  • a 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 the absorption spectrum upon contact with glucose.
  • 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 content of the polymerizable boronic acid compound of one embodiment of the present invention 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.
  • the polymer compound of one embodiment of the present invention When the polymer compound of one embodiment of the present invention is used as an ophthalmic lens such as a contact lens, it is preferable that the polymer compound have good luminous transmittance.
  • 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, in this case, the content of the polymerizable boronic acid compound is preferably, for example, 0.001 mol% to 1 mol%, and more preferably 0.01 mol% to 0.1 mol% or 0.02 mol% to 0.05 mol%.
  • the polymer compound of one embodiment of the present invention is preferably a hydrogel in a hydrated state.
  • Hydrogels are polymer matrices that swell with and retain aqueous liquids, such as water or water-containing solutions.
  • aqueous liquids such as water or water-containing solutions.
  • the polymer itself, excluding the aqueous liquid is also referred to as the hydrogel matrix.
  • Hydrogels are based on polymers that contain hydrophilic monomers as structural units. Specific examples of hydrogels include hydrogels made using hydrophilic monomers, hydrophilic and hydrophobic monomers, and hydrophilic monomers such as crosslinkable monomers and copolymerizable monomers.
  • 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 at a level that allows responsiveness to glucose to be 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.
  • the polymer compound of one embodiment of the present invention contains a hydrophilic monomer as one of the copolymerizable monomers.
  • 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, but 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-ethylform
  • 2-hydroxyethyl (meth)acrylate 2-hydroxypropyl (meth)acrylate, and (meth)acrylic acid are preferred.
  • hydrophilic monomer one of these can be used alone, or two or more can be used in combination.
  • 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 through the hydrophilic monomer moiety. For example, it is preferably 15 mol% or more relative to the total amount of copolymerizable monomer components.
  • the water content of the resulting hydrogel is at a level that is responsive to glucose, it 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%.
  • 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.
  • the polymer compound of one embodiment of the present invention may contain a crosslinking monomer as one type of copolymerizable monomer in order to form a network structure within the molecule and to impart heat resistance and mechanical strength.
  • the crosslinking monomer is not particularly limited as long as it is a polymerizable compound having two or more polymerizable groups in the molecule, and examples include (meth)acrylate-based crosslinking 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; and vinyl-based crosslinking monomers such as 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
  • the content of the crosslinking monomer may be set appropriately depending on the desired network structure formability, heat resistance, and mechanical strength. For example, it is 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 amount of crosslinking monomer exceeds 5 mol%, the flexibility of the resulting hydrogel may decrease.
  • the polymer compound of one embodiment of the present invention can contain hydrophobic monomers, silicon-containing monomers, and other copolymerizable monomers as constituent components in order to provide the desired physical properties, such as oxygen permeability, mechanical strength, shape stability, flexibility, and optical properties.
  • 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, but examples 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.
  • one hydrophobic monomer may be used alone, or two or more may be used in combination.
  • 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, but examples include ⁇ -mono(methacryloyloxymethyl)polydimethylsiloxane, ⁇ , ⁇ -di(methacryloyloxymethyl)polydimethylsiloxane, ⁇ -mono(3-methacryloyloxypropyl)polydimethylsiloxane, ⁇ , ⁇ -di(3-methacryloyloxypropyl)polydimethylsiloxane, ⁇ -mono(3-methacryloyloxybutyl)polydimethylsiloxane, ⁇ , ⁇ -di(3-methacryloyloxybutyl)polydimethylsiloxane, ⁇ -monovinyl
  • suitable silicon-containing monomers include polydimethylsiloxane, ⁇
  • the content of the hydrophobic monomer and silicon-containing monomer is not particularly limited as long as it does not interfere with the solution of the problems of the present invention, and can be set appropriately so that the resulting polymer compound has the desired physicochemical properties, such as oxygen permeability and water content.
  • the polymer compound of one embodiment of the present invention may contain, in addition to monomer components such as polymerizable boronic acid compounds and copolymerizable monomers, additives or components such as diluents, stabilizers, dyes, pigments, antibacterial compounds, and mold release agents.
  • monomer components such as polymerizable boronic acid compounds and copolymerizable monomers
  • additives or components such as diluents, stabilizers, dyes, pigments, antibacterial compounds, and mold release agents.
  • the polymer compound of one embodiment of the present invention can be produced by combining steps known to those skilled in the art.
  • 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.
  • the method for producing the polymer compound of one embodiment of the present invention is not particularly limited, but examples thereof include a method for obtaining a hydrogel, the method including the following steps (1) to (3): (1) a step of stirring and dissolving a mixture of a monomer component including the polymerizable boronic acid compound according to 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 it as necessary, and then hydrating and swelling it to obtain a hydrogel.
  • the mixture of the monomer components and the polymerization initiator may be stirred and dissolved according to conventional methods.
  • the monomer mixture may be prepared by stirring and mixing the monomer components and the polymerization initiator using a stirring device, a mixer, 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 section above (Polymer Compounds).
  • the polymerization initiator may be selected appropriately 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). One of these polymerization initiators 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 the copolymerization reaction of the monomers.
  • peroxide-based polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are common radical polymerization initiators
  • azo-based polymerization initiators such as azobisdimethylvaleronitrile and azobisisobutyronit
  • 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 sealed.
  • the mold containing the monomer mixture is then heated stepwise or continuously to a temperature between 25°C and 120°C in a thermostatic bath or the like, 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 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.
  • step (3) of obtaining the hydrogel the mold used in the copolymerization reaction is cooled to room temperature, the polymer is then peeled off from the mold, and the resulting polymer is cut and/or polished as necessary before being hydrated and swollen to form the hydrogel.
  • liquids used for hydration and swelling include water, saline, isotonic buffer solutions, alcohol, and combinations of these.
  • 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, it is preferable to remove unpolymerized monomers contained in the polymer during the hydration and swelling treatment.
  • the polymer compound of one embodiment of the present invention when in the form of a hydrogel, 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 embodiment of the present invention is small, for example, 1 mol % or less relative to the total amount of the monomer components.
  • the polymer compound of one embodiment of the present invention can be composed mostly of monomer components for use in a specific application.
  • the polymer compound of one embodiment of the present invention can be, for example, hydrophilic, flexible, transparent, and oxygen permeable. Due to 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)).
  • the thickness be 50 ⁇ m to 150 ⁇ m.
  • the polymer compound of one embodiment of the present invention is used as an ophthalmic lens, it is preferable that it be highly transparent.
  • 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 even more preferably 80% or more.
  • 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.
  • 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].
  • 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].
  • 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].
  • 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].
  • the NMR spectrum of the obtained polymerizable boronic acid compound [V] was as follows. 1 H-NMR (500MHz, DMSO-d6) ⁇ 9.56 (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)
  • the resulting monomer mixture was placed into a disk-shaped resin mold and heated over a period of approximately 10 hours at a temperature ranging from 30°C to 105°C, yielding 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, allowing it to hydrate and swell, yielding a hydrogel.
  • PBS ethanol-containing phosphate-buffered saline
  • the resulting hydrogel was subjected to autoclaving while immersed in PBS, yielding Hydrogel 1 as a standard device.
  • Example 7 Formation of Hydrogel 2 According to Table 1, 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 0.05 mol %.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • V-750 ultraviolet-visible spectrophotometer
  • 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).
  • PBS phosphate-buffered saline
  • Glc glucose-containing phosphate-buffered saline
  • hydrogels 1 to 8 in Examples 6 to 13 contained polymerizable boronic acid compounds as structural units that contained polymerizable groups within the molecules, so they did not detach from the hydrogel and the immersion liquid did not become colored. Therefore, these hydrogels had good copolymerization properties.
  • hydrogels 1 to 8 in Examples 6 to 13 all had a visual transmittance of 70%, and hydrogels 1 to 7 in Examples 6 to 12 in particular had excellent visual transmittances of over 80%.
  • hydrogels 1 to 8 in Examples 6 to 13 exhibited changes in absorption spectra depending on the presence or absence of glucose, demonstrating glucose responsiveness.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Polymers & Plastics (AREA)
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Abstract

Le but de la présente invention est de fournir un composé d'acide boronique polymérisable qui présente une structure différente à la fois d'une fraction azobenzène et d'une structure d'acide phénylboronique d'acrylamide et permet de détecter un changement de concentration de glucose par formation de glucose et d'un ester d'acide boronique cyclique. La solution selon l'invention porte sur un composé d'acide boronique polymérisable ou similaire représenté par la formule générale (1) (dans la formule, au moins l'un de R1 à R7 représente un substituant ayant un groupe polymérisable, et les fractions restantes représentent indépendamment un substituant choisi dans le groupe constitué par un atome d'hydrogène, un groupe hydroxy, un groupe carboxyle, un groupe amino et un groupe alkyle).
PCT/JP2025/015167 2024-04-22 2025-04-18 Composé d'acide boronique ayant un site chromogène et un site polymérisable, et son utilisation Pending WO2025225513A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5918711A (ja) * 1982-07-21 1984-01-31 Konishiroku Photo Ind Co Ltd 有色ポリマ−ラテツクス
JP2015110623A (ja) * 2010-05-26 2015-06-18 国立研究開発法人物質・材料研究機構 糖応答性ゲル及び薬剤投与デバイス
JP2022168103A (ja) * 2018-01-30 2022-11-04 アルコン インク． その上に潤滑性コーティングを有するコンタクトレンズ
JP2024016459A (ja) * 2022-07-26 2024-02-07 富士フイルム株式会社 高分子化合物、組成物、光学フィルムおよび光学積層体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5918711A (ja) * 1982-07-21 1984-01-31 Konishiroku Photo Ind Co Ltd 有色ポリマ−ラテツクス
JP2015110623A (ja) * 2010-05-26 2015-06-18 国立研究開発法人物質・材料研究機構 糖応答性ゲル及び薬剤投与デバイス
JP2022168103A (ja) * 2018-01-30 2022-11-04 アルコン インク． その上に潤滑性コーティングを有するコンタクトレンズ
JP2024016459A (ja) * 2022-07-26 2024-02-07 富士フイルム株式会社 高分子化合物、組成物、光学フィルムおよび光学積層体

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