Antifouling compounds

Abstract

The present embodiments relate to antifouling polymers comprising a plurality of repeat units, at least a portion of which comprise medetomidine, or an enantiomer, base, or salt thereof, covalently attached to the repeat unit via a hydrolyzable bond. The antifouling polymer can be included in an antifouling composition applied as a surface coating to an underwater or submerged structure to prevent or at least inhibit marine biofouling on the surface of the structure.

Description

[Technical Field]

[0001] This embodiment generally relates to antifouling compounds, methods for producing such antifouling compounds, and their use in surface coatings. [Background technology]

[0002] Biofouling presents various problems for underwater structures, and therefore, preventing and reducing biofouling on such structures is generally required. Numerous antifouling approaches are currently in use, including the use of specific coatings that inhibit biofouling, the use of toxins or biocides with antifouling activity as additives in coatings or paints for surfaces, and the use of mechanical cleaning of surfaces. Toxins or biocides can cause physiological damage or disturbance to organisms, or result in their death. Toxicity or biocidal effects can occur before, during, or after organism attachment, ultimately leading to the detachment of organisms from the painted surface. For this purpose, a wide variety of substances are used depending on the organism to prevent surface contamination. Certain coatings provide surfaces that physically deter organisms, resulting in organisms being unable to easily adhere to the surface. These types of coatings, such as elastomers like silicone rubber, are generally hydrophobic, smooth, slippery, and have low friction. Self-polishing coatings (SPCs) gradually degrade over time, resulting in the scraping or detachment of attached organisms from the painted surface. This degradation is often brought about by the slow, controlled hydrolysis of components in the coating (usually binder components) and the dissolution of water-soluble pigments.

[0003] Reducing biofouling on marine and freshwater facilities has both economic and environmental benefits. For example, to name a few, biofouling reduces the fuel efficiency of ships, shortens the ship's useful sailing time during biofouling cleanup procedures, and reduces the cooling capacity of cooling water systems.

[0004] U.S. Patent No. 7,531,581 discloses a method and use for an antifouling paint that specifically and efficiently prevents the attachment of, for example, barnacles to floating structures by forming ion pairs between an imidazole-containing compound such as medetomidine and a polymer backbone (such as polystyrene or acrylate polymer) modified with a sulfonated acid sulfate ester, phosphonic acid, carboxylic acid, or acid phosphate ester.

[0005] U.S. Patent No. 10,239,898 discloses compounds based on adducts with isocyanates, methods for preparing them including reacting 3-isocyanatopropyltrimethoxysilane with medetomidine, compositions containing these compounds, and their use as or for manufacturing paints.

[0006] Czech Patent No. 30799 discloses a hydrophobic antimicrobial polymer system comprising a reactive polymer or a reactive polymerizable monomer having at least one covalently bonded antimicrobial substance having an acidic hydrogen atom in its structure, and at least one major hydrophobic component. The major hydrophobic component is 2,2,3,3-tetrafluoro-1-propanol or 2,2,3,3,4,4,5,5-octafluoro-1-pentanol, or a combination thereof. The hydrophobic antimicrobial polymer system includes at least one excipient, which is a catalyst or a pH stabilizer.

[0007] However, there is still a need for antifouling compounds that, in addition to antifouling capabilities, possess the desired and improved properties for use in paints and materials used in underwater or submersible equipment and machinery. [Overview of the project]

[0008] The general objective is to provide antifouling polymers that act as polymer carriers for antifouling agents, and monomers that can be polymerized into such antifouling polymers.

[0009] A specific objective is to provide antifouling polymers and monomers that can be used for surface coatings on underwater or submerged equipment and machinery.

[0010] These and other objectives are achieved by the embodiments disclosed herein.

[0011] The present invention is defined by the independent claims. Further embodiments of the present invention are defined by the dependent claims.

[0012] One aspect of the present invention relates to an antifouling polymer comprising a plurality of repeating units. At least a portion of the plurality of repeating units comprises medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds.

[0013] Another aspect of the present invention relates to a polymerizable monomer comprising a medetomidine or its enantioma, base, or salt covalently bonded to a polymerizable monomer via a hydrolyzable bond.

[0014] A further aspect of the present invention relates to a method for producing a medetomidine monomer. This method involves reacting a polymerizable monomer containing an electrophilic moiety with medetomidine or its enantioma, base, or salt to covalently bond the medetomidine or its enantioma, base, or salt to the monomer via a hydrolyzable bond formed between the electrophilic moiety and the nitrogen on the imidazole ring of the medetomidine or its enantioma, base, or salt.

[0015] Another aspect of the present invention relates to a method for producing an antifouling polymer. The method includes polymerizing a monomer having medetomidine or its enantiomer, base or salt covalently bonded to the monomer via a hydrolyzable bond, and optionally polymerizing a monomer not containing medetomidine or its enantiomer, base or salt, to form an antifouling polymer containing a plurality of repeating units derived from the monomers. At least a part of the plurality of repeating units contains medetomidine or its enantiomer, base or salt covalently bonded to the repeating unit via a hydrolyzable bond.

[0016] A further aspect of the present invention relates to a method for producing an antifouling polymer. The method includes covalently bonding medetomidine or its enantiomer, base or salt to a polymer containing a plurality of repeating units, such that at least a part of the plurality of repeating units contains medetomidine or its enantiomer, base or salt covalently bonded to the repeating unit via a hydrolyzable bond.

[0017] The antifouling compounds of the present invention, namely antifouling polymers and polymerizable monomers, have several advantages compared to using free medetomidine in antifouling paints. In this antifouling compound, the antifouling agent (i.e., medetomidine) is uniformly distributed throughout the antifouling paint, and the release rate of medetomidine from the antifouling compound in the antifouling paint is controlled to extend the lifespan of the antifouling paint. As a result, the amount of medetomidine used in the antifouling paint can be reduced compared to an antifouling paint containing free medetomidine, and the corresponding antifouling effect can still be achieved. In addition, this antifouling compound enables the formulation of an antifouling paint without the need for an inorganic carrier such as metal oxide particles, thereby enabling the formulation of a paint that does not contain metal. The following describes various aspects of the present invention, although some of these may overlap with other descriptions. However, the present invention is not limited to the following. [1] An antifouling polymer comprising a plurality of repeating units, wherein at least a portion of the plurality of repeats comprises units of medetomidine or its enantioma, base, or salt covalently bonded to the repeats via hydrolyzable bonds. [2] The aforementioned polymer A copolymer comprising a first type of repeat containing medetomidine or its enantiomer, base, or salt as units, and the first type of repeat not containing medetomidine or its enantiomer, base, or salt as units, A copolymer comprising a first type of repeat comprising medetomidine or its enantiomer, base or salt as units, a second different type of repeat comprising medetomidine or its enantiomer, base or salt as units, and optionally the first type of repeat not comprising medetomidine or its enantiomer, base or salt as units, and / or optionally the second different type of repeat not comprising medetomidine or its enantiomer, base or salt as units, or A copolymer comprising a first type of repeating unit containing medetomidine or its enantiomer, base, or salt as a unit, a second different type of repeating unit not containing medetomidine or its enantiomer, base, or salt, and optionally the first type of repeating unit not containing medetomidine or its enantiomer, base, or salt as a unit, The polymer described in [1], which is one of the following. [3] The polymer according to [2], wherein the polymer is a copolymer comprising repeats of the first type containing medetomidine or its enantioma, base, or salt as units, and repeats of the first type not containing medetomidine or its enantioma, base, or salt as units. [4] The polymer according to [1], wherein the polymer is a repeating homopolymer containing medetomidine or its enantioma, base, or salt as a unit. [5] The polymer according to [4], wherein the homopolymer is selected from the group consisting of poly(medetomidine methacrylate), poly(allylsulfonylmedetomidone), poly(allylmedetomidine), poly(medetomidine acrylate), and poly(silylmedetomidine). [6] The polymer according to any one of [1] to [5], wherein a medetomidine or its enantioma, base, or salt is covalently bonded to the repeating unit via the hydrolyzable bond between the nitrogen on the imidazole ring of the medetomidine or its enantioma, base, or salt and the monomer. [7] The repeating unit comprising medetomidine or its enantioma, base, or salt is of general formula II or III: [C1] JPEG0007860101000001.jpg8281 It has, R 1 It is selected from the group consisting of equations IV to VI, [C2] JPEG0007860101000002.jpg30129 R 2 It is selected from the group consisting of equations VII and VIII, [C3] JPEG0007860101000003.jpg2599 n is either 0 or 1. R 3 It is selected from the group consisting of equations IX to XIV, [C4] JPEG0007860101000004.jpg31145 m is 0, 1, 2, or 3. [5] JPEG0007860101000005.jpg47145 R is independently H or alkyl, and the alkyl is preferably C1-C6 alkyl, more preferably C1-C4 alkyl, for example methyl or ethyl, preferably methyl and as R 4 、R 5 and R6 The polymer according to any one of [1] to [6], wherein is independently an alkoxy, preferably a C1-C6 alkoxy, more preferably a C1-C4 alkoxy, such as methoxy, ethoxy, or propoxy. [8] The repeating unit comprising medetomidine or its enantioma, base, or salt is 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 1-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, 5-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, propa-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, propa-2-en-1-yl 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 5-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 3-(4-[1-(2,A polymer selected from the group consisting of 3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate and 3-(5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate, as described in any of [1] to [7]. [9] A polymerizable monomer comprising a medetomidine or its enantioma, base, or salt covalently bonded to the polymerizable monomer via a hydrolyzable bond.

[10] The monomer according to [9], wherein a medetomidine or its enantioma, base, or salt is covalently bonded to the monomer via the hydrolyzable bond between the nitrogen on the imidazole ring of the medetomidine or its enantioma, base, or salt and the monomer.

[11] The monomer comprising medetomidine or its enantioma, base, or salt is of general formula II or III: [6] JPEG0007860101000006.jpg7882 It has, In the formula, R 1 It is selected from the group consisting of equations IV to VI, [7] JPEG0007860101000007.jpg29128 R 2 It is selected from the group consisting of equations VII and VIII, [8] JPEG0007860101000008.jpg2699 n is either 0 or 1. R 3 It is selected from the group consisting of equations IX to XIV, [9] JPEG0007860101000009.jpg33144 m is 0, 1, 2, or 3. [C10] JPEG0007860101000010.jpg48147 R is independently H or alkyl, and the alkyl is preferably C1-C6 alkyl, more preferably C1-C4 alkyl, for example methyl or ethyl, preferably methyl, and R 4 、R 5 and R 6 The monomers described in [9] or

[10] are independently alkoxy, preferably C1-C6 alkoxy, more preferably C1-C4 alkoxy, such as methoxy, ethoxy, or propoxy.

[12] The monomer comprising medetomidine or its enantioma, base, or salt is 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 1-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, 5-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, propa-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, propa-2-en-1-yl 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 5-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate, 2-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate, 3-(4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate and 3-(5-[1-(2,A monomer selected from the group consisting of 3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate, as described in any of [9] to

[11] .

[13] An antifouling composition comprising a polymer and / or a monomer according to any one of [1] to [8] and a solvent.

[14] The composition according to

[13] further comprises a free medetomidine or its enantioma, base, or salt that is not covalently bonded to any repeating unit or monomer.

[15] An article, wherein at least a portion of the surface of the article, designed to be immersed in water, is coated with a surface coating comprising a polymer according to any one of [1] to [8], a monomer according to any one of [9] to

[12] , and / or an antifouling composition according to

[13] or

[14] , for the purpose of inhibiting the attachment of marine organisms to the surface.

[16] A method for producing a medetomidine monomer, comprising reacting a polymerizable monomer containing an electrophilic moiety with medetomidine or its enantioma, base, or salt, thereby covalently bonding medetomidine or its enantioma, base, or salt to the monomer via a hydrolyzable bond formed between the electrophilic moiety and the nitrogen on the imidazole ring of medetomidine or its enantioma, base, or salt.

[17] Dissolving medetomidine or its enantioma, base, or salt in a solvent to form a medetomidine solution, Adding the polymerizable monomer to the medetomidine solution, The method described in

[16] , further including the method described in

[16] .

[18] Dissolving medetomidine or its enantiomer, base, or salt includes dissolving medetomidine or its enantiomer, base, or salt, and diisopropylethylamine in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of allyl chloroformate to the medetomidine solution.

[19] Dissolving medetomidine or its enantiomer, base, or salt includes dissolving medetomidine or its enantiomer, base, or salt, and optionally pyridine, in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of allyl isocyanate to the medetomidine solution.

[20] Dissolving medetomidine or its enantiomer, base, or salt includes dissolving medetomidine or its enantiomer, base, or salt, and trimethylamine in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of 2-propenylsulfonyl chloride to the medetomidine solution.

[21] Dissolving medetomidine or its enantiomer, base, or salt includes dissolving medetomidine or its enantiomer, base, or salt, and N,N-dimethyl-4-aminopyridine in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of methacrylic anhydride or methacryloyl chloride to the medetomidine solution.

[22] Dissolving medetomidine or its enantioma, base, or salt includes dissolving medetomidine or its enantioma, base, or salt in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of isocyanatoethyl methacrylate to the medetomidine solution.

[23] Dissolving medetomidine or its enantioma, base, or salt includes dissolving medetomidine or its enantioma, base, or salt in dichloromethane to form the medetomidine solution. The method according to

[17] , wherein the addition of the polymerizable monomer is the addition of isocyanatoethyl acrylate to the medetomidine solution.

[24] A method for producing an antifouling polymer, the method comprising polymerizing a monomer, which is a monomer and contains medetomidine or an enantiomer, base, or salt covalently bonded to the monomer via a hydrolyzable bond, and optionally a monomer that does not contain medetomidine or an enantiomer, base, or salt, to form an antifouling polymer comprising a plurality of repeating units derived from the monomer, wherein at least a portion of the plurality of repeating units contains medetomidine or an enantiomer, base, or salt covalently bonded to the repeating unit via a hydrolyzable bond.

[25] A method for producing an antifouling polymer, the method comprising covalently bonding medetomidine or its enantioma, base, or salt to a polymer containing a plurality of repeating units, wherein at least a portion of the plurality of repeating units contains medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds.

[0018] Embodiments, along with their further objectives and advantages, can best be understood by referring to the following description in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0019] [Figure 1] This figure shows a reaction scheme for producing 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one (M1), 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole (M2), and 4-[1-(2,3-dimethylphenyl)ethyl]-1-(methanesulfonyl)-1H-imidazole (M0) according to one embodiment. [Figure 2] This figure shows a reaction scheme for producing propa-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate (M3), 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide (M4), and 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate (M5) according to one embodiment. [Figure 3] This figure shows a reaction scheme for producing 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate (M6) and polystyrenemedetomidine (PSB) according to one embodiment. [Figure 4] Figure 4 shows the structures of methyl methacrylate (MMA), ethylene glycol dimethacrylate (EGDMA), and azobisisobutyronitrile (AIBN) used to produce copolymers according to various embodiments. [Figure 5] This figure shows the time-dependent release of medetomidine from polystyrene medetomidine (PSB). [Figure 6]This figure plots the concentration (nM) of medetomidine in incubation medium (0.05M phosphate buffer at pH 8.0 containing 3% NaCl) against incubation time for three evaluation incubation temperatures: (Figure 6A): +5°C, (Figure 6B): room temperature (RT), and (Figure 6C): +50°C. [Figure 7] This figure plots the amount of medetomidine released (pmol) against the incubation period from day 1 (24 hours) to day 21 (504 hours), which is considered a specific period for compound release. The slope represents the amount of medetomidine released per hour, calculated in pmol units. (Figure 7A): +5°C, (Figure 7B): Room temperature (RT), (Figure 7C): +50°C. [Figure 8] This diagram schematically illustrates a medetomidine-containing polymer and the release of free medetomidine through its hydrolysis. A: Polymer, copolymer (binder or polymer particles) having medetomidine covalently bonded to the polymer; B: Water-soluble polymer; C: Free medetomidine ready to act as an antifouling agent; D: Hydrolysis occurs upon contact with water, releasing free medetomidine. Through the same process, the polymer residues become more water-soluble, which then helps in polishing and renewing surfaces. [Figure 9] This figure shows an epoxy control PMMA test plate after 13 weeks of immersion. [Figure 10] This figure shows a PMMA test plate with a free medetomidine preparation after 13 weeks of immersion. [Figure 11] This figure shows a PMMA test plate of formulation number #2 after 13 weeks of immersion. [Figure 12] This figure shows a PMMA test plate of formulation number #3 after 13 weeks of immersion. [Figure 13] This figure shows a PMMA test plate of formulation number #4 after 13 weeks of immersion. [Figure 14] This figure shows a PMMA test plate of formulation number #5 after 13 weeks of immersion. [Figure 15] This figure shows a PMMA test plate of formulation number #6 after 13 weeks of immersion. [Modes for carrying out the invention]

[0020] The embodiments described above and other aspects will be described in more detail below with respect to the descriptions and methodologies provided herein. It should be understood that the present invention is implementable in various forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments make this disclosure thorough and complete and present the scope of the invention to those skilled in the art.

[0021] Those skilled in the art will understand that the scientific terms used in this description are for the sole purpose of describing specific embodiments and are not intended to limit the invention. Unless otherwise defined, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by those skilled in the art to which the invention pertains.

[0022] When used in the description of embodiments, the singular forms “a,” “an,” and “the” are intended to include the plural form unless otherwise specified in the context. Thus, such references may be replaced by references to “one or more” (e.g., “one”) of the relevant component or integer. As used herein, all references to “one or more” of a particular component or integer are understood to refer to one to multiple (e.g., two, three, or four) of such components or integers. References to “one or more” of a particular component or integer are understood to include a specific reference to one such integer. Furthermore, as used herein, “and / or” refers to and encompasses one or any possible combination of the relevant enumerated items. Additionally, as used herein when referring to measurable values ​​such as the amount, dose, time, or temperature of a compound, the term “about” refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. Where a range is used, for example, the range x~y means that the measurable values ​​are within the range of approximately x~approximately y, or any range or value within that range, including both x and y. It should be further understood that the terms “comprises” and / or “comprising,” as used herein, identify the presence of at least one of the described features, integers, processes, operations, elements, components, or groups, but do not exclude the presence or addition of one or more other features, integers, processes, operations, elements, components, and / or groups thereof.

[0023] As used herein, "effective amount" refers to the amount of compound, composition, and / or preparation sufficient to produce the desired effect.

[0024] All patents, patent applications, and publications referenced herein are incorporated in their entirety by reference. In the event of any inconsistency in academic terminology, this specification shall prevail.

[0025] This embodiment generally relates to antifouling compounds, methods for producing such antifouling compounds, and their use in surface coatings.

[0026] Medetomidine, also known as (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (see formula I), is a highly selective α2-adrenergic receptor agonist. The imidazole group of medetomidine has two tautomers, resulting in 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole as shown in formula I, or its tautomer, 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. [ka]

[0027] Medetomidine is a highly efficient inhibitor of barnacles, already preventing larval attachment at low concentrations of 1-10 nM. Medetomidine interacts with octopamine receptors in barnacle cyprid larvae, causing the larvae to kick their legs, thereby preventing the larvae from attaching to medetomidine-containing or medetomidine-releasing surfaces. Medetomidine also exhibits effects against other hard-to-attach organisms, such as tube worms.

[0028] Medetomidine is a racemic mixture of two optical enantiomers, levomedetomidine and dexmedetomidine, which have the common names levomedetomidine and dexmedetomidine, respectively (Journal of Pharmacology and Experimental Therapeutics, Vol. 259, pp. 848-854 (1991); European Journal of Pharmacology, Vol. 195, pp. 193-199 (1991)). The method for preparing a racemic mixture of medetomidine and related intermediates is disclosed in International Publication No. 2011 / 070069. Many conventional medetomidine syntheses have used expensive 4-substituted imidazole derivatives as starting materials. However, the synthesis presented in International Publication No. 2011 / 070069 is produced from affordable, commercially available starting materials, and in this method, the imidazole ring is formed rather during synthesis. International Publication No. 2013 / 014428 describes a novel method for preparing medetomidine, including a novel intermediate for medetomidine, which avoids the potentially unfavorable use of imidazole derivatives as starting materials. International Publication No. 2016 / 120635 concerns a novel method for preparing intermediates useful for the synthesis of medetomidine (e.g., 3-arylbutanal).

[0029] As used herein, the terms medetomidine, dexmedetomidine, and levomedetomidine include salts, bases, and solvates of medetomidine, dexmedetomidine, and levomedetomidine unless otherwise specified. Acceptable salts of medetomidine, dexmedetomidine, and levomedetomidine include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of medetomidine, dexmedetomidine, and levomedetomidine with one equivalent or more equivalents of a suitable acid or base, optionally in a solvent or a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques, for example, by vacuum or freeze-drying. Salts may also be prepared by exchanging the counterions of medetomidine, dexmedetomidine, and levomedetomidine in salt form with other counterions, for example, using a suitable ion exchange resin. An exemplary but non-limiting example of a salt of medetomidine is medetomidine hydrochloride. To avoid misunderstanding, it should be added that other acceptable derivatives of medetomidine, dexmedetomidine, and levomedetomidine, such as solvates, are also within the scope of the present invention.

[0030] Enantiomas of medetomidines can be isolated and separated from each other by separating racemic or other mixtures of enantiomas using chiral resolution or chiral column chromatography known in the art. Alternatively, the desired enantiomas may be prepared by enantioselective synthesis, also called chiral synthesis or asymmetric synthesis. Enantioselective synthesis is defined as a chemical reaction or reaction sequence in which one or more new elements of chirality are formed in a substrate molecule, producing unequal amounts of stereoisomer products.

[0031] The base form of medetomidine is sold by I-Tech AB under the product name SELEKTOPE®.

[0032] Regarding medetomidine, it has been suggested that using it in a free form, i.e., as free medetomidine molecules, in an antifouling composition allows for diffusion of medetomidine molecules throughout the antifouling coating when a surface is painted with the antifouling composition. This can lead to accelerated depletion of medetomidine in the antifouling coating and a shortened lifespan of the coating. Therefore, it has been suggested that medetomidine bound to a support can reduce this risk and help control the elution rate. Conventionally, support materials in the form of metal oxide particles, particularly zinc oxide (ZnO) or copper(I) oxide (Cu2O) or copper(II) oxide (CuO) particles, have been used in antifouling compositions (U.S. Patent Application Publication No. 2006 / 0201379). However, since it may be desirable to have antifouling compositions that do not contain zinc or copper, such metal oxide particles limit the applications of antifouling compositions.

[0033] The present invention is based on the use of polymerizable monomers as a carrier for medetomidine, which can be further polymerized into polymers that act as polymer carriers for the antifouling agent medetomidine. Such medetomidine monomers and polymers solve the problem of accelerated leaching of free medetomidine from antifouling coatings, thereby extending the lifespan of the antifouling coatings. Furthermore, this improved control of the leaching rate of medetomidine is achieved without the need to use metal oxide particles.

[0034] In some antifouling compositions, medetomidine cannot be added directly due to incompatibility issues. For example, the solvent for medetomidine may be incompatible with other components of the antifouling composition, and / or, the use of additional components may be limited due to incompatibility issues caused by some metal oxide particles used as a medetomidine support. A related problem is that some binder systems used in antifouling compositions are susceptible to the addition of additives containing organic biocides such as free medetomidine, which can cause gelation of the antifouling composition. This problem can be eliminated or at least reduced by binding medetomidine to a monomer or polymer support according to the present invention.

[0035] Hereinafter, various aspects and embodiments of the present invention will be described in further detail with reference to medetomidine. These aspects and embodiments also include enantiomers of medetomidine, such as dexmedetomidine or levomedetomidine, salts of medetomidine, salts of dexmedetomidine, or salts of levomedetomidine, or bases of medetomidine, bases of levomedetomidine, or bases of dexmedetomidine, which are collectively referred to herein as medetomidine or its enantiomers, bases, or salts. Accordingly, unless otherwise indicated, references to medetomidine herein should be considered to relate to at least one of medetomidine, salts of medetomidine, bases of medetomidine, dexmedetomidine, salts of dexmedetomidine, bases of dexmedetomidine, levomedetomidine, salts of levomedetomidine, or bases of levomedetomidine.

[0036] One aspect of the present invention relates to an antifouling polymer comprising a plurality of repeating units. According to the present invention, at least a portion of the plurality of repeating units comprises medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds.

[0037] The antifouling polymer of the present invention comprises a plurality of monomers, also called repeating units or repetitive units in the art, at least a portion of which are carriers for medetomidine, that is, they contain medetomidine bonded to the repeating units via hydrolyzable covalent bonds. Therefore, the antifouling polymer comprises a plurality of repeating units derived from monomers. The covalent bonds between at least a portion of the repeating units in the antifouling polymer and the medetomidine mean that these repeating units, and by extension the antifouling polymer, act as carriers for the medetomidine. However, the covalent bonds are hydrolyzable. This means that when in contact with water, medetomidine can be released from the repeating units in the antifouling polymer by hydrolysis (see Figure 8). Such hydrolysis of covalent bonds makes it possible to control the release and elution of free medetomidine produced from the antifouling polymer of the present invention and from antifouling paints containing the antifouling polymer of the present invention.

[0038] A further advantage of covalently bonding medetomidine to a monomer or repeating units derived from such monomers via hydrolyzable bonds is that as the medetomidine is hydrolyzed from its repeating units, the antifouling polymer becomes more hydrophilic and more water-soluble. As a result, the surface of the antifouling coating containing the antifouling polymer is polished and renewed by hydrolysis. Therefore, such polishing and renewal effects caused by the hydrolysis of the covalent bonds between the repeating units in the antifouling polymer and medetomidine contribute even more to the antifouling performance of the antifouling coating containing the antifouling polymer of the present invention.

[0039] The antifouling polymer of the present invention may be a homopolymer, that is, a polymer containing only a single type of repeating unit (i.e., monomer) comprising medetomidine. Therefore, in such embodiments, the antifouling polymer is a homopolymer of repeating units comprising medetomidine or its enantioma, base, or salt.

[0040] Exemplary but non-limiting examples of such homopolymers include medetomidine methacrylates, e.g., 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one (M1) or 1-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate (M6) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-Methylpropaneate; allylsulfonylmedetomidine, e.g., 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propane-2-en-1-sulfonyl)-1H-imidazole (M2) or 5-[1-(2,3-dimethylphenyl)ethyl]-1-(propane-2-en-1-sulfonyl)-1H-imidazole; allylmedetomidine, e.g., propane-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate (M3) or propane-2-en-1-yl 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide (M4) or 5-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide; medetomidine acrylate, e.g., 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate (M5) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate;and silylmedetomidine, for example, homopolymers produced from repeating units or monomers selected from the group consisting of 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethylpropane-2-enoate (M10) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethylpropane-2-enoate, 3-(4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropane-2-enoate (M11) or 3-(5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropane-2-enoate).

[0041] In one embodiment, the homopolymer is selected from the group consisting of poly(medetomidine methacrylate), poly(allylsulfonylmedetomidine), poly(allylmedetomidine), poly(medetomidine acrylate), and poly(silylmedetomidine).

[0042] However, the present invention is not limited to antifouling polymers in the form of homopolymers. Therefore, the antifouling polymer may alternatively be in the form of a copolymer, i.e., a polymer containing two or more types of repeating units (i.e., monomers). Thus, in one embodiment, the antifouling polymer is a copolymer comprising a first type of repeating unit containing medetomidine or its enantioma, base, or salt, and a first type of repeating unit not containing medetomidine or its enantioma, base, or salt. Thus, in this copolymer, the same type of repeating unit is used in polymerization to form an antifouling polymer. However, some of these repeating units contain medetomidine or its enantioma, base, or salt covalently bonded to the repeating unit via hydrolyzable bonds, while the remaining repeating units in the copolymer do not contain medetomidine.

[0043] Alternatively, the antifouling polymer may be a copolymer of different types of repeating units. In one embodiment, the antifouling polymer is a copolymer comprising: a first type of repeating unit comprising medetomidine or its enantioma, base, or salt; a second different type of repeating unit comprising medetomidine or its enantioma, base, or salt; and optionally, a first type of repeating unit not comprising medetomidine or its enantioma, base, or salt; and / or optionally, a second different type of repeating unit not comprising medetomidine or its enantioma, base, or salt. In this embodiment, both the first and second repeating units contain medetomidine covalently bonded using hydrolyzable bonds. In another embodiment, the antifouling polymer is a copolymer comprising: a first type of repeating unit comprising medetomidine or its enantioma, base, or salt; a second different type of repeating unit not comprising medetomidine or its enantioma, base, or salt; and optionally, the first type of repeating unit not comprising medetomidine or its enantioma, base, or salt. In this embodiment, medetomidine is covalently bonded only to the first type of repeating unit, while the second type of repeating unit does not contain covalently bonded medetomidine.

[0044] The present invention also encompasses copolymers comprising three or more types of repeating units. In such embodiments, all of the different types of repeating units may contain medetomidines covalently bonded via hydrolyzable bonds, or only one or a portion of the different types of repeating units may be used as the medetomidine carrier.

[0045] Exemplary but non-limiting examples of monomers or repeating units that do not contain covalently bonded medetomidines can be selected from the monomers or repeating units described above and include methyl methacrylate (MMA), methyl acrylate, butyl methacrylate (BMA), butyl acrylate, 2-methoxyethyl acrylate (MEA), tri-isopropylsilyl methacrylate, and / or tri-isopropylsilyl acrylate (TIPSA).

[0046] Exemplary but non-limiting examples of copolymers include copolymers between any monomer M0 to M11 and at least one other monomer that does not contain the medetomidines described above (i.e., at least one of MMA, BMA, butyl acrylate, MEA, tri-isopropylsilyl methacrylate, or TIPSA). Exemplary examples of copolymers include copolymers of M6 and MMA, e.g., copolymers CP6R1 or CP6R2 disclosed herein; copolymers of M5 and MMA, e.g., copolymer CP5R1 disclosed herein; copolymers of M6, MMA, and TIPS; copolymers of M5, MMA, TIPSA, and MEA; copolymers of M6, MMA, TIPSA, and BMA; copolymers of M5, MMA, TIPSA, and MEA; or copolymers of M5, MMA, TIPSA, and BMA.

[0047] Another aspect of the present invention relates to a polymerizable monomer comprising a medetomidine or its enantioma, base, or salt covalently bonded to a polymerizable monomer via a hydrolyzable bond.

[0048] In one embodiment, medetomidine or its enantioma, base, or salt is covalently bonded to the monomer via a hydrolyzable bond between the nitrogen on the imidazole ring of medetomidine or its enantioma, base, or salt and the monomer.

[0049] The imidazole ring of medetomidine contains two nitrogen atoms at positions 1 and 3, of which the hydrogen-bonded nitrogen is at position 1. In one embodiment, medetomidine or its enantioma, base, or salt is covalently bonded to the monomer via a hydrolyzable bond between the nitrogen at position 1 on the imidazole ring of medetomidine or its enantioma, base, or salt and the monomer.

[0050] In certain embodiments, medetomidine or its enantioma, base, or salt is covalently bonded to the monomer via a hydrolyzable bond between the nitrogen on the imidazole ring of medetomidine or its enantioma, base, or salt and the carbon, silicon, or sulfur on the monomer. Therefore, in this particular embodiment, the hydrolyzable bond is an NC bond, an N-Si bond, or an NS bond.

[0051] In one embodiment, a monomer comprising medetomidine or its enantioma, base, or salt has general formula II or III. [ka]

[0052] In one embodiment, R 1 R is selected from the group consisting of carbonyl, sulfonyl, and dimethylsilyl. Therefore, in a particular embodiment, R 1 This is selected from the group consisting of equations IV to VI. [ka]

[0053] In one embodiment, R 2 R is selected from the group consisting of oxygen and amines. Therefore, in a particular embodiment, R 2 This is selected from the group consisting of equations VII and VIII. [ka]

[0054] In one embodiment, n is 0 or 1.

[0055] In one embodiment, R 3 This is selected from the group consisting of equations IX to XIV. [ka]

[0056] In one embodiment, R is independently H or alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl. In a specific embodiment, R is independently H, methyl or ethyl, preferably H or methyl. In one embodiment, R 4 , R 5 and R 6 Independently, R is an alkoxy, preferably a C1-C6 alkoxy, more preferably a C1-C4 alkoxy. In certain embodiments, R 4 , R 5 and R 6 m is independently methoxy, ethoxy, or propoxy. In one embodiment, m is 0, 1, 2, or 3.

[0057] In one embodiment, the monomer comprising medetomidine or its enantioma, base, or salt is medetomidine methacrylate, for example, 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one (M1) or 1-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate (M6) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-Methylpropaneate; allylsulfonylmedetomidine, e.g., 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propane-2-en-1-sulfonyl)-1H-imidazole (M2) or 5-[1-(2,3-dimethylphenyl)ethyl]-1-(propane-2-en-1-sulfonyl)-1H-imidazole; allylmedetomidine, e.g., propane-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate (M3) or propane-2-en-1-yl 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide (M4) or 5-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide; medetomidine acrylate, e.g., 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate (M5) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate;and silylmedetomidines, selected from the group consisting of, for example, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethylpropane-2-enoate (M10) or 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethylpropane-2-enoate, 3-(4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropane-2-enoate (M11) or 3-(5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropane-2-enoate).

[0058] The present invention also relates to an antifouling composition comprising a polymer and / or monomer and a solvent according to an embodiment.

[0059] In one embodiment, the antifouling composition comprises an antifouling polymer containing a plurality of repeating units, and at least a portion of the antifouling composition comprises medetomidine or its enantioma, a base, or salt covalently bonded to the repeating units via hydrolyzable bonds, and a solvent.

[0060] In another embodiment, the antifouling composition may also include, in addition to the antifouling polymer and solvent, a monomer comprising a medetomidine or its enantioma, base, or salt, in which at least a portion is covalently bonded to the monomer via a hydrolyzable bond. Thus, in this embodiment, the antifouling composition also includes a non-polymerized monomer that can support medetomidine.

[0061] In one embodiment, the antifouling composition may also include free medetomidine or its enantioma, base, or salt that is not covalently bonded to any monomer or repeating unit.

[0062] In one embodiment, the solvent is selected from the group consisting of xylene, toluene, 1-methoxy-2-propanol, 1-methoxy-2-propanoyl acetate, methyl isobutyl ketone, solvent naphtha, and mixtures thereof.

[0063] The antifouling composition may optionally contain one or more pigments, such as Cu2O, ZnO, TiO2, or iron oxide (Fe x O y The mixture may contain, but is not limited to, at least one of the following: one or more fillers or extender pigments, e.g., at least one of talc, CaCO3, BaSO4, or mica (phyllosilicate); one or more rheological modifiers, e.g., at least one of fumed silica, silica, or clay; and / or one or more biocides.

[0064] In one embodiment, the antifouling composition includes at least one other biocide in addition to medetomidine. This at least one other biocide may be an antifouling agent, an algaecide, a fungicide, a herbicide, or a combination thereof.

[0065] Non-limiting and illustrative examples of biocides other than medetomidine that can be used according to embodiments are listed on pages 11, line 16 to page 12, line 10 of International Publication No. 2012 / 175469 and on pages 10, line 22 to page 13, line 2 of International Publication No. 2013 / 182641, the teachings of which are incorporated herein by reference with respect to biocides that can be used according to embodiments.

[0066] Other non-limiting biocides that can be used according to the embodiments include chlorothalonil (2,4,5,6-tetrachlorobenzene-1,3-dicarbonitride), diclofluanide (N-{[dichloro(fluoro)methyl]sulfanil}-N',N'-dimethyl-N-phenyl sulfate diamide), DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one), sibutrin (2-N-tert-butyl-4-N-cyclopropyl-6-methylsulfanil-1,3,5-triazine-2,4-diamine), DCMU (3-(3,4-dichlorophenyl)-1,1-dimethylurea), and tolfluanide (N-[dichloro(fluoro)methyl]sulfanil-N-(dimethyl Examples include, but are not limited to, sulfamoyl)-4-methylaniline), (bis(2-pyridylthio)zinc-1,1'-dioxide)pyrithione zinc, (bis(2-pyridylthio)copper-1,1'-dioxide)pyrithione copper, sibutrin (2-N-tert-butyl-4-N-cyclopropyl-6-methylsulfanyl-1,3,5-triazine-2,4-diamine), ethane-1,2-diylbis(dithiocarbamato)zinc, bis(dimethylthiocarbamato)zinc, ethylene-1,2-bisdithiocarbamatomanganese polymer, 4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (tralopyril) and mixtures thereof.

[0067] Medetomidine has a specific effect on hard fouling, particularly against barnacle cyprids, but is usually ineffective against algae growth. Therefore, the use of at least one other biocide, such as an algicide, can also prevent algae growth.

[0068] The antifouling compositions, polymers, and monomers according to the present invention can be incorporated into surface coatings (e.g., antifouling paints, antifouling coatings, or antifouling coatings) of articles such as devices or structures submerged or underwater. In this case, the antifouling composition may be considered to be an antifouling paint composition or formulation, an antifouling coating composition or formulation, or an antifouling paint composition or formulation. Therefore, the article includes a surface coating using at least one of the polymers, monomers, or antifouling compositions according to the present invention on at least a portion of the surface of the article, which is designed or configured to be immersed in water, in order to suppress the fouling of marine organisms on the surface.

[0069] For example, antifouling compositions or polymers can be applied as paints, coatings, or coatings to underwater or submerged devices or structures in the form of spray coatings, coatings, or paints.

[0070] The items may include, but are not limited to, propeller tunnels, guide vanes, fenders, mooring equipment, underwater ropes, underwater wires, underwater nets, ships or hulls, etc.

[0071] When the surface coating of an article is submerged in water and comes into contact with water, the covalent bonds between the repeating units in the polymer of the surface coating and medetomidine, and / or the covalent bonds between the free monomer units in the surface coating and medetomidine, are hydrolyzed, thereby releasing medetomidine from the surface coating (see Figure 8). At this time, the free medetomidine can act as an antifouling agent, inhibiting the attachment of marine organisms to the surface of the article submerged in water.

[0072] The release rate of medetomidine can be controlled by various methods, such as the concentration of the antifouling polymer in the surface coating. Generally, a higher concentration of the antifouling polymer results in a faster release rate of medetomidine and a longer release period. Furthermore, the proportion of medetomidine-supported repeating units in the antifouling polymer affects the release rate of medetomidine from the surface coating. Therefore, generally, a higher proportion of medetomidine-supported repeating units in the antifouling polymer results in a faster release rate of medetomidine and a longer release period. Moreover, by using different types of medetomidine-supported repeating units in the antifouling polymer, the release rate of medetomidine from the surface coating can be controlled and adjusted to achieve a target release rate. In addition, the release of medetomidine from the antifouling polymer depends on the hydrophilicity or hydrophobicity of the antifouling polymer and the coating film containing the antifouling polymer.

[0073] Free medetomidine molecules diffuse freely through surface coatings, interacting with other coating components depending on their chemical formula. This can accelerate the depletion of medetomidine in surface coatings and shorten the antifouling lifespan of the coating. By binding medetomidine to a polymer or monomer support, this risk is reduced, and the release or elution rate can be controlled. Furthermore, by covalently bonding medetomidine to repeating units in antifouling polymers, the medetomidine is more uniformly dispersed within the antifouling composition during the formulation stage.

[0074] In certain antifouling compositions, medetomidine may not be directly added due to incompatibility. For example, the solvent for medetomidine may be incompatible with at least some other components in the antifouling composition.

[0075] Furthermore, by binding medetomidine to repeating units within the polymer, the polymer can function as a carrier for an antifouling agent. In this case, the polymer can be used as a binder in the antifouling composition, either alone or in combination with other polymers, or as carrier particles to immobilize medetomidine in the surface coating until needed. Moreover, when the surface coating comes into contact with water, the water penetrates into the surface coating and induces hydrolysis, releasing medetomidine. At the same time, the polymer becomes more water-soluble, which polishes and renews the surface coating.

[0076] The antifouling polymer of the present invention can act as a metal-free carrier for medetomidine, thereby preventing the release of zinc and copper into water compared to conventionally used metal oxide carriers. Therefore, the antifouling composition of the present invention may be in the form of a composition that does not contain zinc and copper.

[0077] Furthermore, by binding medetomidine to the repeating units of the antifouling polymer, problems associated with certain binder systems (such as silyl acrylates, which are sensitive to free medetomidine molecules and cause undesirable gelation) are suppressed.

[0078] A further aspect of the present invention relates to a method for producing a medetomidine monomer. This method involves reacting a polymerizable monomer containing an electrophilic moiety with medetomidine or its enantioma, base, or salt to covalently bond the medetomidine or its enantioma, base, or salt to the monomer via a hydrolyzable bond formed between the electrophilic moiety and the nitrogen on the imidazole ring of the medetomidine or its enantioma, base, or salt.

[0079] In one embodiment, the method further comprises dissolving medetomidine or its enantioma, base, or salt in a solvent to form a medetomidine solution, and adding a polymerizable monomer to the medetomidine solution.

[0080] In certain embodiments, a medetomidine solution is formed by dissolving medetomidine or its enantioma, base, or salt, and diisopropylethylamine in dichloromethane. In these specific embodiments, allyl chloroformate is added to the medetomidine solution as a polymerizable monomer.

[0081] In another specific embodiment, medetomidine or its enantioma, base or salt, and optionally pyridine, are dissolved in dichloromethane to form a medetomidine solution. In this specific embodiment, allyl isocyanate is added to the medetomidine solution as a polymerizable monomer.

[0082] In a further specific embodiment, medetomidine or its enantioma, base or salt, and trimethylamine are dissolved in dichloromethane to form a medetomidine solution. In this particular embodiment, 2-propenylsulfonyl chloride is added to the medetomidine solution as a polymerizable monomer.

[0083] In another specific embodiment, a medetomidine solution is formed by dissolving medetomidine or its enantioma, base, or salt, and N,N-dimethyl-4-aminopyridine in dichloromethane. In this specific embodiment, methacrylic anhydride or methacryloyl chloride is added to the medetomidine solution as a polymerizable monomer.

[0084] In further specific embodiments, medetomidine or its enantioma, base, or salt is dissolved in dichloromethane to form a medetomidine solution. In optional embodiments, pyridine may be added to the medetomidine solution as a catalyst. In this particular embodiment, isocyantoethyl methacrylate is added to the medetomidine solution as a polymerizable monomer.

[0085] In yet another specific embodiment, medetomidine or its enantioma, base, or salt is dissolved in dichloromethane to form a medetomidine solution. In an optional embodiment, pyridine may be added to the medetomidine solution as a catalyst. In this particular embodiment, isocyantoethyl acrylate is added to the medetomidine solution as a polymerizable monomer.

[0086] In the above specification, dichloromethane, pyridine, and xylene may be used as solvents, if available.

[0087] A further aspect of the present invention relates to a method for producing an antifouling polymer. This method comprises polymerizing a monomer containing medetomidine or its enantiomer, base, or salt covalently bonded to the monomer via hydrolyzable bonds, and optionally polymerizing a monomer that does not contain medetomidine or its enantiomer, base, or salt, to form an antifouling polymer comprising a plurality of repeating units derived from the monomer, wherein at least a portion of the plurality of repeating units contains medetomidine or its enantiomer, base, or salt covalently bonded to the repeating unit via hydrolyzable bonds.

[0088] A further aspect of the present invention relates to a method for producing an antifouling polymer. This method comprises covalently bonding medetomidine or its enantioma, base, or salt to a polymer comprising a plurality of repeating units, wherein at least a portion of the plurality of repeating units comprises medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds. [Examples]

[0089] Example 1 A set of monomers was designed based on the coupling of the polymerizable moiety of medetomidine to an imidazole. The hydrolyzable bond between medetomidine and the polymerizable moiety of the molecule consists of one of the following bond / functional groups: an amide bond, a sulfonamide, urea, or a carbamate. Initially, at least one of pyridine, DMAP, or Et3N was used as a catalyst for the reaction, but it was found that a catalyst was often unnecessary.

[0090] Preparation of 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one (M1) Compound M1 was prepared from the acylation of imidazole, and a series of acylating agents and reactions were investigated. M1 was obtained from both methacrylic anhydride and methacryloyl chloride, as shown in Figure 1.

[0091] Methacrylic anhydride or methacryloyl chloride (1.12 mL, 7.5 mmol, 1.5 equivalents) was added dropwise to a solution of medetomidine (I) (1 g, 5.0 mmol, 1.0 equivalent) and N,N-dimethyl-4-aminopyridine (DMAP; 0.061 g, 0.5 mmol, 10 mol%) in anhydrous dichloromethane (DCM; 10 mL), and the reaction mixture was stirred at room temperature for 24 hours. The resulting mixture was washed twice with saturated sodium bicarbonate, and then subjected to flash column chromatography on silica gel using petroleum ether:acetone (8:2) as the eluent to obtain acylated medetomidine M1 as a colorless liquid. 1 ¹H NMR (500MHz, chloroform-d):δ 8.00 (d, J=1.4Hz, 1H), 7.27 (s, 1H), 7.13-7.10 (m, 1H), 7.10-7.02 (m, 3H), 5.83 (d, J=1.6Hz, 1H), 5.64 (d, J=1.4Hz, 1H), 4.39 (q, J=8.1, 7.2Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H), 1.60 (d, J=7.1Hz, 3H). 13¹³C NMR (126 MHz, chloroform-d): δ 166.75, 149.61, 142.24, 138.37, 137.49, 136.90, 134.20, 128.15, 125.58, 125.38, 124.37, 113.07, 35.12, 21.06, 20.42, 19.47, 14.96. The yield was 69% when using methacryloyl chloride, but even lower when using methacrylic anhydride.

[0092] We also repeated the synthesis as shown in Figure 1, using N,N'-dicyclohexylcarbodiimide (DCC) instead of DMAP as the coupling reagent, and obtained M1 in substantially the same yield.

[0093] Preparation of 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-ene-1-sulfonyl)-1H-imidazole (M2) Medetomidine (200 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) were dissolved in dichloromethane (10 ml) at -78°C. After 30 minutes at -78°C, 2-propenylsulfonyl chloride was added, and the reaction mixture was stirred at -78°C for 4 hours. Hydrogen chloride (1 M) and diethyl ether were added. The organic layer was dried over (Na2SO4), filtered through Celite, and the solvent was evaporated. The gross yield was 259 mg. NMR showed the presence of two positional isomers and other impurities. This indicates the formation of two polymerizable monomers, including medetomidine bonded to propenylsulfonyl via one of the two imidazole nitrogen atoms. Figure 1 shows the reaction scheme for producing one of these polymerizable monomers containing medetomidine.

[0094] Preparation of propa-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate (M3) Medetomidine (200 mg, 1 mmol) and diisopropylethylamine (194 mg, 1.5 mmol) were dissolved in dichloromethane (10 ml) at -78°C. Allyl chloroformate was added, and the solution was stirred at -78°C for 3 hours. Water and diethyl ether were added. The organic layer was dried over (Na2SO4), filtered through Celite, and the solvent was evaporated. The gross yield was 240 mg, and the yield was 85%. 1 ¹H-NMR (CDCl3): 1.59 (d, 3H), 2.25 (s, 3H), 2.30 (s, 3H), 4.37 (q, 1H), 4.84 (d, 2H), 5.36 (dd, 1H), 5.43 (dd, 1H), 5.99 (m, 1H), 6.99 (d, 1H), 7.02-7.09 (b, 3H), 8.08 (d, 1H). Figure 2 shows the reaction scheme for producing this polymerizable monomer containing medetomidine.

[0095] Preparation and Synthesis of 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboamide (M4) I Medetomidine (200 mg, 1 mmol) and allyl isocyanate (88 ml, 1 mmol) were added to dichloromethane at room temperature (20-25°C). The reaction mixture was stirred for 3 hours. Water and diethyl ether were added. The organic layer was dried over (Na2SO4), filtered through Celite, and the solvent was evaporated. The gross yield was 280 mg, and the yield was 99%. 1 ¹H-NMR (CDCl3): 1.50 (d, 3H), 2.14 (s, 3H), 2.25 (s, 3H), 3.75 (m, 2H), 4.26 (q, 1H), 5.08 (d, 1H), 5.14 (d, 1H), 5.75 (m, 1H), 6.89-7.01 (m, 3H), 7.14 (b, 1H), 8.05 (b, 1H). Figure 2 shows the reaction scheme for producing this polymerizable monomer containing medetomidine.

[0096] Preparation and Synthesis of 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboamide (M4) II Allylmedetomidine M4 was prepared from I and allyl isocyanate according to the reaction scheme shown in Figure 2.

[0097] Allyl isocyanate (1.91 mL, 21.6 mmol, 2.94 equivalents) was added in three portions to a solution of anhydrous dichloromethane (7.5 mL) containing I (1.47 g, 7.36 mmol, 1.0 equivalent) and pyridine (1.8 mL, 22.3 mmol, 3.04 equivalents). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation under reduced pressure. The crude product was redissolved in toluene, and the solvent was removed again under reduced pressure. The crude product was dissolved in ethyl acetate, and subjected to flash column chromatography on silica gel using ethyl acetate / heptane (1:1) to ethyl acetate as the eluent to obtain pure allylmedetomidine M4 (determined by LC-MS and TLC analysis). After removing the solvent, the purified M4 was dissolved in acetonitrile / H2O (1:1) and lyophilized to obtain 1.96 g (94%) of pure crystalline M4.

[0098] Preparation of 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethylpropa-2-enoate (M5) and 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate (M6) Multiple reactions / preparations were performed and indicated using R following the corresponding monomer M5 or M6, with an index number following R. In the initial synthesis, pyridine was used as a catalyst to assist the conjugation reaction between isocyanate and medetomidine. Isocyanatoethyl methacrylate (IEM) or isocyanatoethyl acrylate (IEA) was combined with medetomidine in a 5% molar excess (see Figures 2 and 3). In the initial synthesis, pyridine was added in an amount three times the molar amount of medetomidine. In subsequent synthesis, pyridine was reduced to an equimolar ratio with medetomidine or eliminated. Reducing or eliminating pyridine in this way facilitates subsequent purification.

[0099] Table 1 summarizes the molar ratios and reaction times for various synthesis methods. [Table 1] *IEM was used as the isocyanate in M6R1~M6R6, and IEA was used as the isocyanate in M5R1.

[0100] Synthesis protocols for M6R1, M6R2, and M6R4 A 100 mL three-necked round-bottom flask was immersed in a temperature-controlled oil bath. Nitrogen gas was introduced into the left neck of the three-necked round-bottom flask. A removable and replaceable glass stopper was attached to the middle neck of the three-necked round-bottom flask to allow for sampling of reaction samples at different times. A condenser was placed at the right neck of the three-necked round-bottom flask to prevent the leakage of dichloromethane (DCM) solvent, and cold water was circulated as a coolant.

[0101] First, medetomidine (M6R1: 5.0781 g; M6R2: 5.3057 g; M6R4: 5.03225 g) was dissolved in 25 mL of DCM. Next, 6.03 mL of pyridine, which acts as a catalyst, was introduced into the medetomidine solution. Then, 3.71 mL of IEM was added dropwise, and the thermocouple sensor rose above the set temperature, indicating a significant exothermic reaction. Fourier transform infrared spectroscopy (FTIR) readings at 4 hours showed a significant decrease in the isocyanate peak, so the reaction was continued for 4.5 hours.

[0102] purification In the second preparation of M4 described above, the crude mixture was dissolved in toluene, and the pyridine was simultaneously evaporated from the mixture in a rotary evaporator at room temperature to purify the allyl isocyanate conjugated to medetomidine. This procedure was followed for M6R1, M6R2, and M6R4.

[0103] In the next step, unreacted medetomidine and isocyanate were separated from the adduct using a flash chromatography column. The original protocol used an ethyl acetate and heptane gradient, first dissolving the product in a 50:50 mixture. M6R1 immediately precipitated, forming a solid mass, which was previously a viscous liquid mixture containing a small amount of toluene. M6R2 and M6R4 were stored without flash chromatography purification.

[0104] Without further purification to prevent undesirable precipitation / crosslinking of unreacted isocyanate chains, M6R2 and M6R4 were stored and used for chemical characterization and release testing.

[0105] Synthesis of M6R5 Medetomidine (5.03830 g) was added to 25 mL of DCM to dissolve in a 100 mL three-necked round-bottom flask. Pyridine (2.01 mL) was then added. The starting temperature of the oil bath was 31.7 °C. IEM (3.71 mL) was added using a 200 μL stage. Synthesis was carried out for 24 hours. The following day, the reaction mixture was used directly for CP6R1 polymerization.

[0106] Synthesis of M6R3 and M6R6 HPLC analysis of M6R4 determined that the reaction had an efficiency of 90±2%. To reduce the time spent on pyridine removal, the synthesis of M6R3, M6R6, and M10R1 was attempted without pyridine.

[0107] Medetomidine (M6R3: 1.0013 g; M6R6: 4.02450 g) was first dissolved in DCM solvent (M6R3: 5 mL; M6R6: 20.53 mL) in the reaction flask. Then, IEM was added dropwise, and the flask was sealed. Samples were taken at different time intervals to monitor the progress of the reaction. The synthesis was carried out over a longer period to allow sufficient time for the addition reaction to occur (see Table 6).

[0108] Synthesis of M5R1 To dissolve the substance in a 100 mL three-necked round-bottom flask, 30 mL of DCM was used to add medetomidine (5.03104 g). The starting temperature of the oil bath was 31.7 °C. IEA (3.36 mL) was added using a 200 μL stage.

[0109] M5R1 precipitated in heptane. The previous observation with M6 showed that when the monomer was kept at room temperature for use and then thawed, it became insoluble in acetone and the solvent, even though it was previously soluble. However, this was not the case with M5R1. The monomer / heptane slurry was placed in a fume hood, and the remaining organic solvent was evaporated over two days. When acetone was added to resolubilize it, the M5R1 monomer redissolved without any problems.

[0110] Preparation of 4-[1-(2,3-dimethylphenyl)ethyl]-1-(methanesulfonyl)-1H-imidazole (M0) Medetomidine (200 mg, 1 mmol) and triethylamine (152 mg, 1.5 mmol) were added to dichloromethane (10 ml) at -78°C. After 30 minutes, methanesulfonyl chloride was added at -78°C. The reaction mixture was stirred at -78°C for 3 hours. Diethyl ether and water were added. The organic layer was dried over (Na2SO4), filtered through Celite, and the solvent was evaporated. The yield was 270 mg, with a yield of 97%. NMR showed two positional isomers in a 1:1 ratio. This indicates the formation of two polymerizable monomers containing medetomidine bonded to propenylsulfonyl via one of the two imidazole nitrogen atoms. The reaction scheme for producing this medetomidine-containing sulfonamide compound M0 is shown in Figure 1.

[0111] Example 2 The monomer stability / hydrolysis rate was tested under the two settings described below.

[0112] Setting 1 The stability of medetomidine carbamate derivatives (M3), urea derivatives (M4), and sulfonyl derivatives (M2 and M0) was tested in ethanol and phosphate-buffered saline (PBS) buffers. Thin-layer chromatography (TLC) was used to track the degradation of the derivatives to free medetomidine. It took approximately two weeks for most of the derivatives stored at room temperature to degrade. No degradation was observed at a storage temperature of +6°C.

[0113] material and method Nine vials were prepared. Vial 1 contained the reference compound medetomidine dissolved in ethanol (1 ml). Substance M2 (25 mg) was added to vials 2 and 3. Substance M3 (25 mg) was added to vials 4 and 5. Substance M4 (25 mg) was added to vials 6 and 7, and substance M0 was added to vials 8 and 9. The solid substances in vials 2-9 were dissolved in ethanol (1 ml) and PBS buffer (1 ml) at pH 7.4 to simulate seawater containing different salts and having a slightly basic pH. Ethanol was chosen as the solvent to increase the solubility of the substances. During the test period, vials 1, 3, 5, 7, and 9 were stored at room temperature, while vials 2, 4, 6, and 8 were stored in a refrigerator at +6°C. The stability of the compound was tested at 0, 1, 2, 5, 6, 9, 13, and 15 days after the start of TLC and using dichloromethane-methanol (95-5) as the eluent.

[0114] result The Rf value of sample M2 was approximately 0.6, the Rf value of sample M3 was approximately 0.8, the Rf value of sample M4 was 0.55-0.60, and the Rf value of sample M0 was 0.7. The Rf value of medetomidine was 0.1. After 2 days, only the starting material (monomers containing medetomidine) was visible in all vials, indicating that no degradation had occurred. After 1 week, the degradation of the derivative was more evident, mainly in vials stored at room temperature. After 2 weeks, for sample M2, the vial stored at room temperature showed only medetomidine, while the vial stored in the refrigerator showed a mixture of medetomidine and the starting material. For sample M3, the vial stored at room temperature showed only medetomidine, while the other vials stored in the refrigerator showed a mixture of medetomidine and the starting material. Samples M2 and M3 appeared to have very similar stabilities. Sample M4 remained stable after two weeks when stored in a refrigerator, but vials stored at room temperature showed degradation to both M4 (which did not undergo hydrolysis) and medetomidine. Sample M0 was stable after two weeks at both room temperature and in a refrigerator. The stability experiments showed that the urea derivative was the most stable, and the carbamate derivative was the least stable. The stability of the sulfonamide derivative was highly dependent on the size of the alkyl group.

[0115] Setting 2 material and method The stability of M1 and M4 was evaluated by quantifying the release of I into artificial seawater (3% NaCl, pH 8.0). For the experiment, compound M1 (0.023 g) was suspended in 5 mL of artificial seawater, while M4 (0.044 g) was suspended in 10 mL of artificial seawater. The solutions were stirred at ambient temperature (300 rpm), and samples were collected on days 10, 15, 20, and 25. The samples were stored in a freezer for 2 to 2.5 months and then analyzed by LC-MS.

[0116] LC-MS analysis The release test samples were analyzed using LC-MS. The LC-MS system consisted of an Acquity I-class UPLC equipped with a Waters Xevo G2-S Qtof. Chromatographic separation was performed on a C18 column using gradient elution (eluent A: 0.1% NH4 in MQ water, and eluent B: 100% acetonitrile). The samples (removed from the freezer) were extracted with hexane, and the organic extracts were analyzed by LC-MS. Three external calibration curves for I, M1, and M4 were prepared using the same method as the samples and used for quantification.

[0117] As summarized in Table 2, LC-MS was used to investigate and quantify both the stability of monomers in artificial seawater and the potential release of I. [Table 2] *Results could not be obtained due to technical problems during the analysis.

[0118] Stability tests of compounds M1 and M4 showed that all samples produced a nearly constant amount of I. This suggests either rapid hydrolysis occurred before the first data point on day 10, or contamination with I occurred during monomer preparation. The concentration in M1 was approximately 9 μg / mL, and in M4, approximately 5 μg / mL. Since complete hydrolysis of both monomers would yield a concentration of 3.3 mg / mL relative to I, this may indicate contamination by low concentrations of unreacted I residues from the synthesis of M1 and M4. Because I is present in monomer samples at concentrations of 0.16–0.27%, such low concentrations of contamination are not easily detected by either NMR or LC-MS, and the I detected in the monomer stability tests may actually be contamination. The possibility of low-level hydrolysis during sample storage (freezer) cannot be ruled out.

[0119] Example 3 After polymerizing the monomers into both homopolymers and copolymers, the properties were evaluated as described below.

[0120] Polymers from M1 and M4 were prepared using radical polymerization initiated by UV irradiation, according to Analytica Chimica Acta, Vol. 435, pp. 19-24 (2001). The general polymerization method is as follows:

[0121] Homopolymerization of M1 and M4 Homopolymers of M1 and M4 were further prepared to evaluate the reactivity of individual monomers. For homopolymer preparation, 0.26 g each of M1 and M4 was dissolved in 2 mL of CHCl3, and azobisisobutyronitrile (AIBN) (0.026 g) was added. The solution was purged with N2 (g) for 5 minutes and placed in a UV cabinet to cure for 24 hours initially. After 24 hours, the degree of polymerization was low (clear, non-viscous solution), and therefore polymerization was continued for another 24 hours. The experiment was terminated after 48 hours, and the resulting viscous solution was dried at ambient temperature to remove the solvent.

[0122] Copolymerization of M1 and M4 using MMA and EGDMA As shown in Figure 4, copolymers M1 and M4 were prepared using AIBN as a free radical polymerization initiator, methyl methacrylate (MMA), and ethylene glycol dimethacrylate (EGDMA) as a crosslinking agent.

[0123] 1.32 mL (7 mmol) and 745 μL (7 mmol) of MMA were dissolved in 5 mL of CHCl3 in a 20 mL glass scintillation vial. 89 mg of M4 and AIBN (24 mg, 0.15 mmol) were added to the solution, and oxygen was removed from the reaction vessel by purging with N2 (g) for 5 minutes. The vessel was sealed and cured in a UV cabinet at room temperature for 24 hours at 365 nm. This resulted in the formation of a solid white polymer monolith inside the vial.

[0124] After polymerization, the solid polymer monoliths were washed with acetone (10 mL, discarded), ground using a mortar and pestle (in acetone slurry), and passed through a sieve (60 μm) to produce a uniform polymer particle distribution for release testing. The polymer particles were allowed to settle from the (discarded) acetone and dried at room temperature before further testing.

[0125] Polymers prepared using only MMA as the copolymer did not form solid polymers because they did not contain crosslinking monomers; instead, they formed transparent gels. These polymers were also washed with acetone before analysis.

[0126] Various polymers with different compositions of EGDMA and MMA, incorporating compounds I, M1, and M4 (only one compound at a time, not combined), were prepared according to Table 3. [Table 3]

[0127] Polymers incorporating approximately 0.3% monomer M1 and approximately 0.3% monomer M4 were also prepared according to the ratios summarized in Table 1. Furthermore, polymers incorporating 10% M4 were also prepared using a solvent-free (neat) EGDMA polymer composition.

[0128] Polymer characterization We attempted to quantify M1 and M4 covalently incorporated into copolymers, and the prepared polymers were characterized using FTIR. The reference spectra of monomers and I were compared with the IR spectra of pulverized and washed polymers. Polymers prepared with 10% M4 were also analyzed using FTIR.

[0129] Monomers M1 and M4 were incorporated into various copolymer systems with EGDMA and MMA in molar ratios ranging from 0.3 to 10%. The polymerization reaction appeared to be successful visually, and this material was used for release testing. Simultaneously, the polymers were evaluated using FTIR. Both M1 and M4 released approximately 1750 cm³. -1 A strong carbonyl signal was observed, but unfortunately, this signal overlapped with the carbonyl signals of both EGDMA and MMA, making it difficult to clearly evaluate monomer incorporation using this signal.

[0130] We attempted to increase the ratio of M4 by incorporating it at a higher molar ratio. However, this result suggests that the polymer integration is the same for both the "3%" and "10%" polymers.

[0131] Ninhydrin test Furthermore, we attempted to evaluate the presence of covalently incorporated medetomidine monomers by using ninhydrin to stain primary and secondary amines on prepared polymers. A ninhydrin solution was prepared by dissolving 100 mg of ninhydrin in 5 mL of acetone (2 w / v%). A polymer sample (5-10 mg) suspended in 0.5 mL of acetone was mixed with 0.5 mL of the ninhydrin solution in a 1 mL clear high-performance liquid chromatography (HPLC) vial. After heating this sample at 90°C for 5 minutes, the sample was evaluated for changes in colorimetric quantification indicating the presence of amines in the polymer. In addition, seawater from "day 30" of the polymer stability test (Example 4) was also analyzed for the presence of released ion I by latent detection of amines in the seawater.

[0132] Some polymer samples showed a weak positive reaction compared to positive controls I and M4, suggesting the presence of amines in the polymer matrix. None of the water samples examined in the polymer release test suggested the presence of I in water.

[0133] Gel permeation chromatography (GPC) To investigate the ability of monomers (M1 and M4) to form linear homopolymers, gel permeation chromatography (refractive index detection) was performed on polymer samples dissolved in tetrahydrofuran (THF) using a Styragel HR (Waters) column and constant composition elution with THF at 1 mL / min. w The approximate molecular weights of the prepared polymers were determined using 480, 1050, and 2200 g / mol.

[0134] The results showed that the prepared material eluted with a retention time close to that of the 500 g / mol standard, indicating that the polymer yield could be increased by further optimizing the polymerization conditions.

[0135] Copolymerization of M5 or M6 with MMA CP6R1 copolymer synthesis (M6 and MMA) CP6R1 was synthesized from M6R5 without purifying the M6R5 monomer. Azobisisobutyronitrile (AIBN) (0.82118 g), methyl methacrylate (MMA) (26.6 mL), and an additional 35 mL of DMF were added to the M6R5 reaction product in 5 mL of dimethylformamide (DMF). The mixture was purged with argon gas and then sealed. The reaction was carried out for 5 hours.

[0136] The crude mixture was precipitated in 400 mL of Tris buffer, then washed with pure water, and finally washed with acetonitrile. The acetonitrile / polymer slurry was dried to obtain a hard white polymer as the final product.

[0137] CP6R2 copolymer synthesis (M6 and MMA) CP6R2 was synthesized from M6R6 without purifying the M6R6 monomer. AIBN (1.65376 g), MMA (8.54 mL), and an additional 78 mL of DMF were added to the M6R6 reaction product in 5 mL of DMF. The mixture was purged with argon gas and then sealed. The reaction was carried out for 4 hours.

[0138] CP6R1 had an AIBN:MMA:M6 ratio of 0.5:10:1, while CP6R2 had an AIBN:MMA:M6 ratio of 1:8:2. The resulting copolymer CP6R2 was soluble in acetone and could be precipitated in water.

[0139] CP5R1 copolymer synthesis (M5 and MMA) CP5R1 was synthesized from M5R1 after purification of the M5R1 monomer. Viscous M5R1 (4.0090 g) was dissolved in 45 mL of DMF. Then, AIBN (0.96481 g) and MMA (5.010 mL) were added, and the mixture was purged with argon gas. The reaction was carried out for 4.5 hours.

[0140] Copolymerization of M5 or M6 with multiple other monomers Copolymerization of M5 with other monomers and M6 with other monomers was found to be best carried out using newly prepared monomers, and polymerization could be continued in the same pot. Therefore, both monomer synthesis and polymer synthesis are described in the following examples.

[0141] Table 4 shows all the synthetic polymers, divided into groups (PoC, CP5, CP6, and MS), using the same method within each group. The only difference between the syntheses within each group was the ratio of reagents to monomers used. Therefore, only one detailed example from each group is shown below. The reaction temperature for PoC_R2 and PoC_R3 was 70°C, while the reaction temperature for all other polymers was 65°C.

[0142] The PoC- group included M5 or M6, triisopropylsilyl acrylate (TIPSA), and MMA.

[0143] The CP5- and CP6- groups have M5 or M6, TIPSA and MMA, and may contain either 2-methoxyethyl acrylate (MEA) or butyl methacrylate (BMA) to improve hydrophilicity or hydrophobicity.

[0144] The MS-group consists of non-RAFT synthesis based on the corresponding polymers produced with similar CP6 monomer ratios. Exceptions to this are MS_R13a, MS_R13b, and MS_R13c. MS synthesis was performed on a smaller scale using scintillation vials. Four monomers were used: M6, TIPSA, MMA, and either MEA or BMA. [Table 4] AIBIN: Azobisisobutyronitrile, DSDA: Tetraethylthiuram disulfide, I: Medetomidine, IEA: Isocyanatoethyl acrylate, IEM: Isocyanatoethyl methacrylate, MMA: Methyl methacrylate, BMA: Butyl methacrylate, TIPSA: Triisopropylsilyl acrylate, 2-MEA: 2-Methoxyethyl acrylate, V: Solvent volume, t: Reaction time

[0145] PoC_R2 (M6 10 mol%, TIPSA 45 mol%, and MMA 45 mol%) In a 100 mL three-necked round-bottom flask, medetomidine I (1.07068 g) was dissolved in 10 mL of DCM using a magnetic stirrer set to room temperature. IEM (750 μl) was added dropwise. After 3 hours, MMA (2.81 mL) and TIPSA (6.08 mL) were added. AIBN (0.14472 g) and butanone (40 mL) were added, the mixture was homogenized, and the flask was sealed with a rubber stopper and Parafilm under an argon atmosphere. The reaction was left at 70°C for 5.5 hours with stirring. The flask was removed from the oil bath, the flask was opened, and the reaction was terminated by introducing oxygen to stop radicals.

[0146] CP6_R4 (M6 6 mol%, TIPSA 21.15 mol%, MMA 63.45 mol%, and MEA 9.4 mol%) In a three-necked round-bottom flask, medetomidine I (0.6808 g) was dissolved in 10 ml of DCM by stirring with a magnet. Then, without sealing the flask, IEM (480 μl) was added dropwise, and finally the DCM was evaporated overnight. MMA (2.81 mL), TIPSA (6.11 mL), and MEA (0.68 mL) were added. Xylene (20 mL) was added to the flask and mixed to homogenize.

[0147] AIBN (0.15206 g) and DSDA (0.19585 g) were added to separate scintillation vials. Butanone (1 ml) was added to the scintillation vial containing AIBN to dissolve it. After dissolution, xylene (9 ml) was added. This AIBN solution was then added to the reaction flask. Xylene (10 mL) was added to the scintillation vial containing DSDA to dissolve it. This DSDA solution was then added to the reaction flask. The reaction flask was purged with argon and sealed with a rubber stopper and Parafilm. The reaction was started by submerging the reaction flask in an oil bath at 65°C. After reacting in the bath for 6.5 hours, the flask was removed from the bath, the flask was opened, and the reaction was terminated by stopping radicals with oxygen.

[0148] MS_R12 (M6 6 mol%, TIPSA 21.15 mol%, MMA 63.45 mol%, and MEA 9.4 mol%) In a scintillation vial, medetomidine I (0.31741 g) was dissolved in 4 ml of DCM by agitation with a magnet. Next, IEM (220 μL) was added dropwise to an unsealed vial, and finally the DCM was evaporated overnight.

[0149] AIBN (0.06865 g), MMA (1.96 mL), TIPSA (1.42 mL), and MEA (0.32 mL) were added to a vial. The vial was sealed with a rubber stopper and wrapped in Parafilm. 6 mL of butanone was introduced using a glass syringe. The contents of the vial were mixed at room temperature. The vial was purged with argon for 20 minutes, then submerged in an oil bath to initiate the polymerization reaction, and left at 65°C for 5 hours. The vial was removed from the bath, the container was opened, and the reaction was terminated by terminating the radicals with oxygen.

[0150] Example 4 Release of medetomidine from M4 copolymer in artificial seawater The release of 1 from the selected polymers was also established in artificial seawater according to monomer release tests. For the tests, 0.5 g of polymer (three polymer systems from Table 3 incorporating M4 as medetomidine monomer) was added to 20 mL of artificial seawater and stirred at ambient temperature (300 rpm). 1 mL samples were taken after 2 days, 10 days, and 15 days. These samples were filtered through a 0.22 μm syringe-driven filter to remove solid residues and then analyzed using LC-MS. The samples were stored in a freezer (for approximately 2 months) before analysis.

[0151] As shown in the graph in Figure 5, polymer PSBs showed a time-dependent linear release of low 1.

[0152] Selected polymers (Table 3) were also incubated in seawater, and the release of 1(I) from the materials was analyzed. LC-MS analysis did not detect any release of 1(I) from any of the polymer samples. The absence of release indicates that there was little or no incorporation of monomers into the polymer, or that there was no hydrolysis of the incorporated monomers under the experimental conditions used. The previous results (monomer release tests and FT-IR investigations) suggest that both events are possible and that it is impossible to distinguish the potential individual contributions of both events to the results here. Potential residual free 1(I) from polymer synthesis is washed away during workup and does not result in the "constant" release observed in the monomer release tests.

[0153] Example 5 Furthermore, medetomidine was bonded to isocyanate-functionalized polystyrene beads (manufactured by Biotage) and used as a model polymer system (shown in Figure 3) to investigate the release of medetomidine from the polymer.

[0154] Preparation of medetomidine-supported polystyrene beads (PSBs) Using the same coupling conditions used to produce M4, I was reacted with polystyrene methyl isocyanate to produce polystyrene-immobilized medetomidine (PSB) (see Figure 3).

[0155] PSB synthesis was performed in a syringe (20 mL) fitted with a filter to hold the polystyrene beads. 1 g of polystyrene methyl isocyanate beads (Biotage, product number: 800261, batch number: 04446, volume: 1.48 mmol / g) was added to the syringe, followed by the addition of 10 mL of anhydrous dichloromethane (10 mL) dissolved in 14I (446 mg, 2.23 mmol, 1.5 equivalents) and pyridine (0.36 mL, 4.46 mmol, 3 equivalents). The syringe was stirred overnight at room temperature. After 24 hours, the liquid was drained from the syringe, the beads were washed three times with dichloromethane, and the material was freeze-dried. 5 mg of PSB was extracted and exposed to 1 mL of TFA / dichloromethane (1:1) under sonication. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed the release of 14I, indicating cleavage of the urea bond with the polystyrene beads. Two batches of PSB totaling 2g were prepared.

[0156] The washed and dried beads were investigated using Fourier transform infrared spectroscopy (FTIR), and a comparison of PSB with unreacted polystyrene methyl isocyanate revealed a concentration of 2259 cm⁻¹. -1 Complete loss of isocyanate peak and 1720cm -1 The emergence of a weak carbonyl signal was revealed, which could be linked to the urea-binding carbonyl within the PSB.

[0157] Example 6 Incubation of medetomidine-supported polymers in seawater-simulating buffer solution Three weighed samples (5 mg each) of medetomidine-supported polystyrene beads (PSBs) from Example 5 were added to three 50 mL glass vials with screw caps. 20 mL of seawater simulation buffer and 0.05 M phosphate buffer at pH 8 containing 3% NaCl were added, and the polymer was placed on the surface of the solution. The three vials were incubated in the dark at +5°C (refrigerated room), room temperature (RT), and +50°C (water bath) with slow stirring, while the polymer remained on the surface. The solutions at +5°C and RT were slowly stirred with a magnetic stirrer, and the vials in the +50°C water bath were gently shaken.

[0158] Aliquots were removed from the incubation at 1 hour, 4 hours, and 1 day, 4 days, 7 days, 11 days, 14 days, 18 days, and 21 days. The concentration of medetomidine in the samples was quantified using a calibration curve. More specifically, the sampling volume (100 μL) was added directly to an LC vial with an insert, and the solution was injected as is. At subsequent time points, samples from the incubation at +50°C were diluted to 1:10 (10 μL + 90 μL buffer) and 1:20 (10 μL + 190 μL buffer), respectively, before injection.

[0159] Six working standard solutions containing medetomidine, diluted with water / ethanol (volume 75 / 25), were prepared at 100-fold dilutions of the final concentration in seawater simulation buffer (see Table 5). First, 10 mM storage solutions containing medetomidine in EtOH were diluted 1:100 to a concentration of 100 μM by adding 5 μL to 495 μL of water / ethanol (volume 75 / 25). S1 was prepared by adding 60 μL of a 100 μM solution to 540 μL of water / ethanol (volume percentage 75 / 25). S2 was prepared by adding 300 μL of S1 to 700 μL of water / ethanol (volume percentage 75 / 25). S3 is prepared by adding 300 μL of S2 to 600 μL of water / ethanol (volume percentage 75 / 25). S4 is prepared by adding 300 μL of S3 to 700 μL of water / ethanol (volume percentage 75 / 25). S5 is prepared by adding 300 μL of S4 to 600 μL of water / ethanol (volume percentage 75 / 25). S6 is prepared by adding 300 μL of S5 to 700 μL of water / ethanol (volume percentage 75 / 25).

[0160] A 10 μL working standard solution was individually added to 990 μL of pH 8 seawater simulation buffer containing 3% NaCl. Dilutions were prepared directly in glass LC vials. Blank samples were prepared by adding 10 μL of water / ethanol (volume percentage 75 / 25) to 990 μL of seawater simulation buffer. [Table 5]

[0161] Several injections were performed beforehand to ensure that the measuring device was equilibrated. Calibration curves were inserted at the beginning and end of the analysis sequence, and unknown samples were identified using the bracketing method.

[0162] To track changes in concentration, all samples were analyzed within 24 hours of sampling, along with a three-point calibration curve. Subsequently, until the final sampling, samples were stored in LC vials in the dark at RT, and all samples were analyzed / re-analyzed and quantified against a newly prepared calibration curve. Re-analyzed samples showed good agreement with the initial analysis, with differences of less than 10% for most samples, and only 2 out of 27 samples showed differences exceeding 20%. All calculations are based on data from the final analysis.

[0163] The sample injection sequence in the final analysis sequence was as follows: Blank, Calibration samples S1-S6, Blank, 1 hour (+5°C, room temperature, +50°C), 4 hours (+5°C, room temperature, +50°C), 24 hours (+5°C, room temperature, +50°C), 96 hours (+5°C, room temperature, +50°C 1:10), 168 hours (+5°C, room temperature, +50°C 1:10), 264 hours (+5°C, room temperature, +50°C 1:20), 336 hours (+5°C, room temperature, +50°C 1:20), 432 hours (+5°C, room temperature, +50°C 1:20), 504 hours (+5°C, room temperature, +50°C 1:20), Blank, Calibration samples S1-S6, Blank.

[0164] The data showed that medetomidine release was faster in the initial phase up to approximately 24 hours, potentially corresponding to a washout phase of unbound medetomidine from the polymer. Subsequently, another release phase followed during the last 20 days of the 3-week incubation, characterized by a consistently slower rate. This was demonstrated at all three evaluation temperatures (+5°C, RT, and +50°C) (see Figures 6A–6C). However, the medetomidine release rate differed among the three evaluation temperatures. The total amount of released medetomidine was calculated in picomoles (pmol) and plotted against time over a period of constant compound release (days 1–21) (see Figures 7A–7C). The release rate was calculated in units of pmol / h / mg polymer. Assuming a linear relationship, the release rate of medetomidine was approximately 0.007 pmol / h / mg polymer under incubation at +5°C, approximately 0.18 pmol / h / mg polymer under incubation at RT, and approximately 4.6 pmol / h / mg polymer under incubation at +50°C.

[0165] Table 6 summarizes the results plotted in Figures 6 and 7. [Table 6]

[0166] Example 7 Elution rate of medetomidine(I) from copolymer Crude polymer products from MS_R7 and MS_R13a were precipitated in methanol, and the methanol / monomer / reaction residue mixture was separated by decantation. The "wet polymer" contained small amounts of butanone and methanol. The wet polymer was redissolved in butanone and returned to the body immediately before use in the elution rate test.

[0167] In weighed scintillation vials, 200–500 μl of polymer solution was poured into the bottom of the vials (the inner diameter of these vials was 25 mm), and the vials were dried for two days. The vials were weighed again to determine the mass of the polymer.

[0168] Artificial seawater (1.5 ml) was added to a vial and sealed with a cap. After one month, all the seawater in the vial was removed and fresh artificial seawater was added. This was repeated for three months. The concentration of medetomidine in the artificial seawater was determined each time using HPLC after one month. [Table 7]

[0169] Following an initial burst of release, medetomidine was gradually released over time. The results indicate that the polymer hydrolyzed, releasing medetomidine over time.

[0170] Example 8 Paint formulation and performance of medetomidine-containing copolymers in marine paint formulations on underwater test plates Application to paint mixtures and test panels Table 8 shows the contents of medetomidine, Cu-Pt, and Cu2O in Formulations 1 to 6. A general description of the preparation of the control formulation is as follows. 8 g of hydrogenated rosin ((2E)-3-phenylprop-2-en-1-yl β-D-glucopyranoside) was dissolved in 28 ml of xylene using a speed mixer (Synergy Devices Ltd, UK) at 3000 rpm for 2 minutes. Subsequently, 0.5 g of soybean lecithin, 9 g of acrylic resin were added in 5 + 4 g aliquots, 2 g of plasticizer, 8 g of iron oxide, 2 g of galamite (registered trademark) clay, 0.5 g of mica, 10 g of barium sulfate were added in 5 + 5 g aliquots, 9 g of talc was added in 5 + 4 g aliquots, and then 10 g of Cu2O was added. After each addition step, a mixing step was performed at 3000 rpm for 2 - 5 minutes depending on the dispersion of the components (visual inspection). After these steps, the viscosity was adjusted by adding 3 - 16 ml of xylene and mixing was continued until the temperature reached 40°C, and the paint components showed good dispersion. During the preparation of Formulation No. #2, Cu-Pt (1 g) and medetomidine (0.1 g) were added before the talc addition step. In Formulation Nos. #3 - 6, a polymer conjugated with medetomidine was added first and then the rosin was dissolved. Approximately 1.5 g of this polymer was added either as a crude product (dissolved in butanone) or as a precipitate (after washing with MeOH) to obtain a final concentration of bound medetomidine within the range of 0.10 - 0.18 wt% (Table 8). To compensate for the addition of the medetomidine-containing binder, the acrylic resin was reduced to 8 g.

Table 8

[0171] Three PMMA test plates (25 × 15 cm) were first painted with an epoxy primer. Then, two layers of Formulation Nos. #1 - 6 were applied using a roller to obtain a dry weight of approximately 5 g per painted / test plate. Drying or application was carried out at ambient humidity and temperature.

[0172] Field test Field tests were conducted at the Kristineberg Centre on the west coast of Sweden (58°25′01.0″N 11°44′45.3″E, Baltic Transition Zone). Painted PMMA test plates (25 × 15 cm) were positioned by suspending them on an aluminum frame (190 × 91 cm) using tie straps through pre-drilled holes in the corners of the test plates. The test plates were randomly distributed on the frame to achieve both longitudinal and transverse random distribution. Unpainted test plates (epoxy primer) and a control coating without medetomidine (composition number #1) were used as negative controls. A coating with free medetomidine (composition number #2) was used as a positive control. The water depth ranged from 25 cm to 205 cm. Field testing began in June (June 23, 2021), when adhesion pressure is known to be highest. Visual inspections and photographs were conducted monthly throughout the summer, with the final inspection on September 9, 2021. The degree and type of adhesion were evaluated based on visual inspections and photographs.

[0173] result Both the epoxy control and the control formulation (formulation #1) exhibited high levels of fouling and accumulation after 13 weeks of immersion (Figures 9 and 10). Fouling species on the expoxy control included, for example, barnacles, mussels, bryozoans, tunicates, green algae, filamentous algae, and tubeworms (Figure 9). On the control formulation (formulation #1), biofouling was primarily barnacles (Figure 10). Although a small number of tunicates were visible, the control formulation was thus chosen for barnacle accumulation for use in investigating the effects of both the addition of free medetomidine and polymer-bound medetomidine. By adding (free) medetomidine dispersed at 0.1% in the coated material (formulation number #2), no barnacle accumulation was observed, demonstrating the potential of medetomidine in preventing barnacle adhesion (Figure 11). Similar results were observed when examining barnacle adhesion on formulations containing medetomidine bound to an erosive polymer binder (formulation numbers #3-6). Although formulation number #3 showed some barnacle adhesion along the periphery of the test plate, the function of the formulation was generally satisfactory. Formulation number #3 contained 0.1% unrefined polymer (crude product from synthesis was used directly in the formulation) (Figure 12). Interestingly, adding this polymer at a slightly higher concentration (0.18%), as in formulation #4, improved performance (Figure 13), and no barnacle adhesion was observed on this formulation. In formulations #5 (Figure 14) and #6 (Figure 15), the molar composition of the polymer was altered by decreasing the MMA in the feedstock during polymerization and increasing the molar concentration of TIPSA. Formulation #5 used a polymer synthesized by radical polymerization, while formulation #6 used a polymer synthesized by RAFT polymerization. As can be seen from Figures 14 and 15, all of these formulations exhibited performance comparable to formulation #2 (free medetomidine), which did not show barnacle adhesion.However, some tunicates and filamentous algae were observed on formulation #6 (Figure 15). In conclusion, formulations containing medetomidine bound to polymers can exhibit performance comparable to formulations in which medetomidine is dispersed (released) upon hydrolysis for release. [Table 9] *1 individual **A small number of individuals**

[0174] The embodiments described above should be understood as a few exemplary examples of the present invention. Those skilled in the art will understand that various modifications, combinations, and changes can be made to the embodiments without departing from the scope of the invention. In particular, solutions of various parts in various embodiments can be combined in other configurations where technically possible. However, the scope of the invention is defined by the appended claims.

Claims

1. An antifouling polymer comprising a plurality of repeating units, wherein at least a portion of the plurality of repeating units comprises medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds.

2. The aforementioned polymer A copolymer comprising a first type of repeating unit containing medetomidine or its enantiomer, base, or salt, and the first type of repeating unit not containing medetomidine or its enantiomer, base, or salt, A copolymer comprising a first type of repeating unit comprising medetomidine or its enantiomer, base or salt, a second different type of repeating unit comprising medetomidine or its enantiomer, base or salt, and optionally the first type of repeating unit without medetomidine or its enantiomer, base or salt, and / or optionally the second different type of repeating unit without medetomidine or its enantiomer, base or salt, or A copolymer comprising a first type of repeating unit containing medetomidine or its enantiomer, base, or salt; a second different type of repeating unit not containing medetomidine or its enantiomer, base, or salt; and optionally the first type of repeating unit not containing medetomidine or its enantiomer, base, or salt. The polymer according to claim 1, which is any of the following.

3. The polymer according to claim 2, wherein the polymer is a copolymer comprising a repeating unit of the first type containing medetomidine or its enantioma, base, or salt, and a repeating unit of the first type not containing medetomidine or its enantioma, base, or salt.

4. The polymer according to claim 1, wherein the polymer is a homopolymer of repeating units containing medetomidine or its enantioma, a base, or a salt.

5. The polymer according to claim 4, wherein the homopolymer is selected from the group consisting of poly(medetomidine methacrylate), poly(allylsulfonylmedetomidone), poly(allylmedetomidine), poly(medetomidine acrylate), and poly(silylmedetomidine).

6. The polymer according to any one of claims 1 to 5, wherein medetomidine or its enantioma, base, or salt is covalently bonded to the repeating unit via the hydrolyzable bond between the nitrogen on the imidazole ring of medetomidine or its enantioma, base, or salt and the monomer.

7. The repeating unit comprising medetomidine or its enantioma, base, or salt is of general formula II or III: 【Chemistry 1】 It has, R １ It is selected from the group consisting of formulas IV to VI, 【Chemistry 2】 R ２ It is selected from the group consisting of formulas VII and VIII, 【Transformation 3】 n is either 0 or 1, R ３ It is selected from the group consisting of formulas IX to XIV, 【Chemistry 4】 m is 0, 1, 2, or 3. 【Transformation 5】 R is independently H or alkyl, and R ４ , R ５ and R ６ The polymer according to any one of claims 1 to 6, wherein is independently an alkoxy.

8. The repeating unit comprising medetomidine or its enantioma, base, or salt is 1-{4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 1-{5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-yl}-2-methylpropa-2-en-1-one, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl 2-methylpropa-2-enoate, 4-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, 5-[1-(2,3-dimethylphenyl)ethyl]-1-(propa-2-en-1-sulfonyl)-1H-imidazole, propa-2-en-1-yl 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, propa-2-en-1-yl 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate, 4-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 5-[1-(2,3-dimethylphenyl)ethyl]-N-(propa-2-en-1-yl)-1H-imidazole-1-carboxamide, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl propa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 2-({4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 2-({5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carbonyl}amino)ethyl Propa-2-enoate, 3-(4-[1-(2,A polymer according to any one of claims 1 to 7, selected from the group consisting of 3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate and 3-(5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-dimethylsilyl)propyl 2-methylpropa-2-enoate.

9. An antifouling composition comprising a polymer according to any one of claims 1 to 8 and a solvent.

10. The composition according to claim 9, further comprising a free medetomidine or its enantioma, base, or salt that is not covalently bonded to any repeating unit or monomer.

11. An article, wherein at least a portion of the surface of the article, designed to be immersed in water, is coated with a surface coating comprising a polymer according to any one of claims 1 to 8 and / or an antifouling composition according to claim 9 or 10, for the purpose of inhibiting the adhesion of marine organisms to the surface.

12. A method for producing an antifouling polymer, the method comprising polymerizing a monomer, which is a monomer and contains medetomidine or an enantiomer, base, or salt covalently bonded to the monomer via a hydrolyzable bond, and optionally a monomer that does not contain medetomidine or an enantiomer, base, or salt, to form an antifouling polymer comprising a plurality of repeating units derived from the monomer, wherein at least a portion of the plurality of repeating units contains medetomidine or an enantiomer, base, or salt covalently bonded to the repeating unit via a hydrolyzable bond.

13. A method for producing an antifouling polymer, the method comprising covalently bonding medetomidine or its enantioma, base, or salt to a polymer containing a plurality of repeating units, wherein at least a portion of the plurality of repeating units contains medetomidine or its enantioma, base, or salt covalently bonded to the repeating units via hydrolyzable bonds.

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