JP6621407B2 - Use of enantiomeric levomedetomidine as an inhibitor against surface marine organism adhesion - Google Patents

Description

  The present invention relates generally to the inhibition of surface marine biofouling in marine environments, and in particular to the use of substances as agents to prevent solid surface marine biofouling. More specifically, the present invention relates to the use of specific forms of medetomidine that act as such agents.

  The economic benefits of reducing biofouling in marine and freshwater installations include, for example, reduced fuel economy for ships with organisms attached to the hull, loss of valuable time during cleaning procedures to reduce hull biofouling. Furthermore, it comes from several causes, including a reduction in the cooling power of the water cooling device. In addition to those derived from ships, other underwater facilities such as aquaculture equipment and oil / gas offshore facilities also have significant biofouling problems.

  Currently, many different approaches have been devised and commonly used to prevent and reduce biofouling. Several chemical compounds, including toxides or biocides with antifouling activity, are used as coating or paint additives for surfaces exposed to underwater equipment. Mechanical cleaning of ship surfaces has been introduced as an alternative to toxides and biocides. In particular, water jet cleaning and mechanical cleaning using a brush are used. However, most of these methods are work intensive and therefore expensive. Furthermore, it has been reported that selection of pharmacological compounds that act on serotonin and dopamine neurotransmitters has the potential to either interfere with or promote barnacle attachment. Serotonin antagonists such as cyproheptadine and ketanserin and dopamine agonists such as R (−)-NPA and (+)-bromocriptine showed inhibitory properties. Another agent that has proven to be an effective inhibitor of barnacle colonization is the highly selective alpha 2-adrenergic receptor agonist medetomidine, ie, (±) -4 (5)-[1- (2,3-Dimethylphenyl) ethyl] -1H-imidazole. The establishment of the larvae is already hampered at low concentrations of 1 nM to 10 nM. Medetomidine belongs to a new class of alpha 2-receptor agonists containing 4-substituted imidazole rings with high selectivity for 2-adrenergic receptors. Receptors affected by catecholamine neurotransmitters such as norepinephrine and epinephrine are called adrenergic receptors (or adrenoceptors) and can be divided into alpha- and β-subclasses. Alpha2-adrenergic receptors are involved in the mechanism of self-inhibition of neurotransmitter release, regulating hypertension (high blood pressure), bradycardia (low heart rate), and even arousal and analgesia (low sensitivity to pain). It plays an important role in regulation.

WO 00/42851 discloses the use of medetomidine as an inhibitor of marine organism adhesion at the surface.
WO2006 / 096129 is sulfonate, acid sulphate ester, phosphonic acid, carboxylic acid, or modified with an acidic phosphoric acid ester and using medetomidine attached to the polymer backbone, such as polystyrene or acrylate les Toporima barnacles in underwater structures Disclosed are methods and uses for antifouling paints that hinder the settling of materials.

The present invention solves the problem of reducing the human impact of medetomidine contained in various products used to prevent marine organism adhesion.
The primary objective of the present invention is to use levomedetomidine, a specific enantiomeric form of medetomidine, individually and separately as a substance that acts as an antifouling agent in marine environments with less impact on humans. Another object of the present invention is to use a composition in the enantiomeric form of medetomidine that has less impact on humans as a substance that acts as an antifouling agent in the marine environment, which is a racemic mixture (1: 1). Unlike levomedetomidine is the major enantiomeric form. Another object of the invention is to use a composition of a mixture of two enantiomeric forms, in which case levomedetomidine is at least 90% of the mixture as a substance that acts as an antifouling agent in the marine environment. It accounts for 80, 70, 60, 50% and has less human impact than a racemic mixture of medetomidine. Other objects and advantages will become more fully apparent from the ensuing disclosure and appended claims.

(Including figures and graphs.)
FIG. 1 shows the structure of levomedetomidine (showing its HCl salt as an example). FIG. 2a relates to a barnacle fixation experiment using a racemate of medetomidine. FIG. 2b relates to a barnacle fixation experiment using the enantiomer Levomedetomidine.

  These and other aspects of the present invention will now be described in more detail with respect to the description and methods provided herein. It should be understood that the present invention can be implemented in a variety of forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular forms “a”, “an” and “the” as used in describing embodiments of the invention are intended to include the plural forms as well, unless expressly stated otherwise. Further, “and / or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, when referring to measurable values such as amount, dose, time, temperature, etc. of a compound, the term “about” as used herein refers to 20%, 10%, 5%, 1% of a specified amount. %, 0.5%, or even 0.1% variation. Where a range (eg, a range from X to Y) is used, the measurable value is in the range from about X to about Y, or any of them, eg, from about X ₁ to about Y ₁ It means that it is in the range. Further, the terms “comprising” and / or “including”, as used herein, specify the presence of the described feature, integer, process, operation, element, and / or component. It should be understood that this does not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used herein, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Have

All patents, patent applications and publications mentioned herein are incorporated by reference in their entirety. In case of conflicting terms, the present specification will prevail. Furthermore, the embodiments described in one aspect of the invention are not limited to the described aspects. Furthermore, embodiments may be applied to other aspects of the invention as long as the embodiments do not interfere with the operation of these aspects of the invention for its intended purpose.
The present invention relates generally to the inhibition of surface marine biofouling in the marine environment, specifically the use of substances as agents to prevent marine biofouling of solid surfaces and surfaces exposed to the marine environment. The present invention relates to a composition for coating. More specifically, the present invention relates to the use of a specific enantiomeric form of medetomidine that acts as such a drug, namely levomedetomidine (FIG. 1).

  Accordingly, in one aspect, the present invention relates to a surface coating composition comprising medetomidine, the composition comprising a relatively higher amount of levomedetomidine compared to dexmedetomidine. Furthermore, the surface coating composition may further comprise a binder phase, a pigment, and a suitable solvent as is known in the surface coating composition art. The surface coating composition may be a paint for use on a ship, such as a ship self-polishing paint composition.

  The α2-adrenergic receptor agonist medetomidine is known to provide sedation and motor suppression when given to mammals and fish (Sinclair, 2003; Ruuskanen et al., 2005). Medetomidine (10 nM) strongly increased the kick of cyprid larvae, exceeding 100 kicks per minute, and the opposite was found in Cypris larvae (Mol Pharmacol 78: 237-248). Page, 2010). Thus, medetomidine has different physiological effects in vertebrates and invertebrates and is more hyperactive than sedation / motor inhibition as in vertebrates. This is the most likely basis for inhibition of colonization since medetomidine causes a barley cyprus to cause a motor activation response. More specifically, an increase in the movement (kick) of the front protrusion (leg) is suggested to be an effect of the anti-fixation mode of medetomidine.

  The medetomidine first described in EP72615, ie (±) 4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole, has two optical enantiomers, namely levorotatory and dextrorotatory optics. It is a racemic mixture of equal proportions of isomers (MacDonald et al., 1991; Savola and Virtanen, 1991) and the common names are levomedetomidine and dexmedetomidine, respectively. WO 2011/070069 discloses a process for the preparation of racemic mixtures of medetomidine ((±) 4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole) and related intermediates. Many of the previous syntheses use expensive 4-substituted imidazole derivatives as starting materials, but in WO 2011/070069, they are synthesized from affordable commercial starting materials, and the imidazole ring, rather than during synthesis, Made.

  Medetomidine has been studied in human clinical trials and is also used as an anesthetic for animals with the active ingredient (S) -enantiomer dexmedetomidine. Levomedetomidine, on the other hand, has no apparent sedative or analgesic effect (Kuesela et al., J Vet Pharmacol Ther 23 (1), 15-20, 2000), but higher doses of levomedetomidine are not dexmedetomidine. It showed a low sedation and analgesic effect associated with administration (Kusela et al., Am J Vet Res 62 (4), 616-621, 2001). This suggests that administering dexmedetomidine alone for sedation and analgesic effects is more beneficial than administering a racemic mixture of medetomidine containing equal amounts of dexmedetomidine and levomedetomidine. Based on these types of studies, it is justified to prepare dexmedetomidine purely and is marketed under various names such as Dexdor® (Orion Pharma AB). Dexdor is indicated for mild sedation in adult ICU patients (EMA / 789509/2011 Human Medicine Committee (CHMP)), and Dexdomitor® (Orion Pharma AB) is indicated for veterinary use . Such pure preparation is done by separation and purification of dexmedetomidine from the racemic mixture, in which case levomedetomidine is considered to be the main impurity of pure dexmedetomidine.

  As noted above, the racemic mixture of medetomidine, (±) -4 (5)-[1- (2,3-dimethylphenyl) ethyl] -1H-imidazole, is an efficient inhibitor for barnacle colonization. It has been shown previously. Surprisingly, as demonstrated in the present invention, both the racemic mixture and the enantiomeric form of medetomidine (dexmedetomidine and levomedetomidine) have similar inhibitory effects. This means that if only one enantiomeric form is active and the other enantiomeric form is inactive, the use of only one of the specific enantiomeric forms of the molecule in the pharmaceutical industry, for example in the pharmaceutical industry, including medetomidine, This is the opposite of what is often posted in That levomedetomidine has a similar inhibitory effect is particularly unexpected and significant. Inhibiting colonization of Barnacle Cyprus larvae is described in Example 1 below and FIGS. 2a and 2b.

Accordingly, a preferred embodiment of the present invention is to use levomedetomidine as an active ingredient / component in marine paint applications to prevent biofouling on various surfaces immersed in the marine environment. .
Because levomedetomidine has been reported to have a very limited effect on humans and animals compared to the racemic mixture of medetomidine and the other enantiomer, dexmedetomidine, the enantiomer form of levomedetomidine is used. This provides a solution for the final product with less impact on humans. This ensures that any risk of handling of any product (s) containing medetomidine or dexmedetomidine, such as during manufacture, transportation, storage and application, to end users such as individuals involved in the application of paint, Reduced by use of medetomidine. Furthermore, metabolism of levomedetomidine has been shown to be more rapid in mammals, which is beneficial compared to the use of dexmedetomidine, a racemic mixture or enantiomer of medetomidine. In addition, levomedetomidine is considered an impurity when processing and purifying dexmedetomidine, which is an enantiomer for clinical use, and is therefore discarded, thus providing an advantageous price level. Furthermore, this means that the invention herein is also useful in solving the problem of handling waste from the manufacture of dexmedetomidine. The purification of dexmedetomidine is disclosed in WO2013069025 "Preparation of dexmedetomidine", where dexmedetomidine is prepared in high yield and the enantiomer purity is higher than 99%. Of course, a similar approach using the same method would rather be applicable to the preparation of levomedetomidine. A method for separating levorotatory and dextrorotatory enantiomers is also described in CN200910093379. The use of levomedetomidine as a medicament for use in the prevention or treatment of symptoms is associated with overexpression or hypersensitivity of the adrenergic α-2 receptor as described in EP 0858338.

Accordingly, a preferred embodiment of the present invention is the use of levomedetomidine, a specific enantiomer of medetomidine, which has less human impact, as a substance that acts as an antifouling agent in the marine environment, individually and separately. is there.
Another preferred embodiment of the present invention is the use of a composition in the enantiomeric form of medetomidine with less human impact as a substance acting as an antifouling agent in the marine environment, which is a racemic mixture (1 Unlike 1), levomedetomidine is the main enantiomeric form. Another preferred embodiment of the present invention is to use a composition of a mixture of two enantiomeric forms, in which case levomedetomidine is at least 90% of the mixture as a substance that acts as an antifouling agent in the marine environment. 80, 70, 60, 50%, and has less human impact than the racemic mixture of medetomidine.

A related preferred embodiment of the present invention is to use the biocide-polymer complex combination as an additive in self-polishing paints for controlled release as disclosed in WO 2006/096129. . Specifically, such a preferred embodiment, the use of sulfonate, acid sulphate ester, phosphonic acid, polymer backbone modified with a carboxylic acid or acid phosphate ester, a Rebomedetomijin bound to such as polystyrene or acrylate les Toporima etc. The present invention relates to a method and use relating to antifouling paints that specifically and efficiently prevent, for example, the fixing of barnacles on underwater structures. Another preferred object of the present invention is to create an antifouling method that requires less biocide dosage by appropriately inhibiting the release of antifouling substances from the coating. For example, levomedetomidine molecules attached to polystyrene-block-poly (ethylene-ran-butylene) -block-polystyrene will allow the active compound from the paint to slowly escape in a controlled manner in water. The levomedetomidine-polymer ion pair dissolves only at the actual membrane surface when contacted with water, resulting in the release of levomedetomidine. Thus, surface active compounds in antifouling paints appear to have a greater impact on barnacle larval colonization than compounds that leak from paint into water because surface activity increases the concentration near the surface.
In a related preferred embodiment, suppression of release from the antifouling agent includes nano-sized CuO, ZnO, TiO ₂ , AlO ₃ , SiO ₂ , MgO, preferably copper (II) oxide, and zinc (II) Nanoparticles made of oxides can also be used. Due to the large specific surface area (ratio between surface area and particle volume), the nanoparticles are antifouling agents such as levomedetomidine, or other antifouling agents such as chlorothalonil, diclofluraneide, SeaNine, irgarol, Contributes to the adsorption of diuron and tolyl fluoride. CuO and ZnO particles are 29 and 21 m ² . It is a specific surface area of g-1. This makes it possible to design a coating system containing a small amount of both levomedetomidine and nanoparticles in order to limit the diffusion movement of the antifouling agent through the coating film. When the nanoparticles were replaced with micrometer sized particles, the adsorption appeared to be negligible. From these results, it is understood that a large surface area is important for the adsorption of the antifouling agent on the particle surface. Antifouling agents, such as levomedetomidine bound to nano-sized metal oxides, are compounds that leak into the water in a controlled manner. Therefore, the antifouling agent bonded to the nano-sized metal oxide has an excellent dispersion stability because its size is larger than that of the antifouling agent particles alone. Due to the size characteristics, the antifouling agent-metal oxide particles remain in the coating film and do not leak into the water. As a result, the concentration of antifouling particles in the coating remains the same for the “lifetime”. As a result, the concentration of antifouling agent will be equal throughout the coating. Another result is that the total surface area of the nanoparticles is sufficient to adsorb all of the antifouling agent and there will be no waste of biocides.

  Compounds have previously been described that interfere with neural signals or other specific effects on marine-adherent organisms such as barnacles, eg US Pat. No. 6,762,227 describes the use of medetomidine. , And further Swedish patent application No. 0300863-8 describes the use of spiromidazoline for the same purpose. However, the use of such products has little or no effect on algae. For example, medetomidine has a specific action on barnacle cyprus, but has no effect on the growth of algae because algae has no target protein. There are several ways to prevent the growth of algae, some of which use fairly high concentrations of copper and other metals. Algaegic agents are often invented as herbicides and are photosynthesis inhibitors such as DIURON (trade name) (3- (3,4-dichlorophenyl) -1, by DuPont Agricultural Products, Wilmington, Delaware, USA. 1-dimethylurea) and IRGAROL (trade name) 1051 (2-methylthio-4-tert-butylamino-6-cyclopropylamino-s-triziane) by Ciba, Tarrytown, NY, USA . As a more general strategy, bactericides such as zinc pyrithione (Zinc, Bis (1-hydroxy-2 (1H) -pyridinethionate-O, S)-, (T-4)-) and Arc by Arc Chemicals) and Arc Copper pyrithione (Copper, bis (1-hydroxy-2 (1H) -pyridinethionate-O, S)-, (T-4)-) by Chemicals, Tolylfluoride by Bayer Chemicals, Pittsburgh, USA (N- (dichlorofluoromethylthio) -N ′, N′-dimethyl-Np-tolylsulfamide), dichlorofluanide (N′-dimethyl-N-phenylsulfamide) by Bayer Chemicals, by FMC ZINEB (trade name) (zinc ethylene bisdithiocarbamate), Ta ZINRAM by inco (trade name) (Zinc bis (dimethyl thiocarbamate)), are sometimes used MANEB (manganese ethylenebis dithiocarbamate) or a quaternary ammonium compound. The third strategy is a toxic but short half-life compound such as SEANINE (trade name) (4,5-dichloro-2-n-octyl-3 by Rohm and Haas, Philadelphia, Pennsylvania, USA). (2H) -isothiazolone), and related compounds. Therefore, the principle of the method of the present invention includes, in the presence of levomedetomidine, an antialgal compound such as zinc- and copper-pyrothion, fungicides such as tolylfluoride and diclofluanide, Diuron (trade name) and Irgarol. Herbicides such as (trade name), or more common biocides such as SeaNine (trade name) or EcoNea (trade name) (2- (p-chlorophenyl)-by Janssen Pharmaceutical, Titusville, NJ, USA In combination with 3-cyano-4-bromo-5-trifluoromethyl) to use substances or agents that block or block neural signals to target cells of Cypris larvae. A preferred embodiment of the present invention is to add the material to the base polymer paint, which is applied to the hull, for example. Accordingly, in a related preferred embodiment, the present invention includes applying a protective coating to a substrate, the coating comprising: a) a substance that inhibits barnacle biofouling, including levomedetomidine, and b) algae An agent is contained. Certain preferred algaecides include copper, zinc and other metals, Diuron (3- (3,4-dichlorophenyl) -1,1-dimethylurea), Irgarol 1051 (trade name) (2-methylthio-4- tert-butylamino-6-cyclopropylamino-s-triazine), zinc pyrothion (zinc, bis (1-hydroxy-2 (1H) -pyridinethionate-O, S)-, (T-4)-), Copper pyrothion (copper, bis (1-hydroxy-2 (1H) -pyridinethionate-O, S)-, (T-4)-), dichlorofluanide (N'-dimethyl-N-phenylsulfamide) , Zineb (trade name) (zinc ethylene bisdithiocarbamate), Zinram (trade name) (zinc bis (dimethylthiocarbamate)), maneb (manganese ethylene bis Thiocarbamate), quaternary ammonium compounds, SeaNine (trade name) (4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone), and EcoNea (trade name) (2- (p-chlorophenyl) ) -3-cyano-4-bromo-5-trifluoromethyl).

The terms “medetomidine”, “dexmedetomidine” and “levomedetomidine” as used herein include salts and solvates thereof, unless otherwise specified. Acceptable salts of levomedetomidine include acid addition salts . Such salts may be formed by conventional means, for example, optionally in a solvent, or salt in insoluble medium, the compound of the present invention of Yu away base form one or more equivalents of the appropriate It can be formed by reacting with an acid or base and then removing the solvent, or the medium, using standard techniques (eg, in vacuo or by lyophilization). Furthermore, the salts can also be prepared by exchanging the counter ion of a compound according to the invention in salt form with another counter ion, for example using a suitable ion exchange resin. For the avoidance of doubt, other acceptable derivatives of levomedetomidine are included within the scope of the present invention (eg, solvates, prodrugs, etc.). Preferred solvents are, but not limited to, n-butanol, iso-butanol, methanol, benzyl alcohol and 1-methoxy-2-propanol. The enantiomers of medetomidine can be isolated and separated from each other by separating the racemate or other mixture of enantiomers using chiral resolution or chiral column chromatography known in the art. Alternatively, the desired enantiomer can be prepared by enantioselective synthesis, also referred to as chiral synthesis or asymmetric synthesis, in which one or more novel chiral elements are formed in the substrate molecule and the stereoisomer (Enantiomers or diastereomers) are defined as chemical reactions (or reaction sequences) that produce products in unequal amounts (IUPAC). Preferably, the protective coating further includes marine paint.

Example 1
Materials and Methods Inhibition of Barnacle Cyprus Larva Settlement The settling assay was performed using a Petri dish containing 5 ml of filtered seawater with a salinity of 32 ± 1%. About 20 Barnacle Cyprus larvae were added to each Petri dish. Thereafter, medetomidine / levomedetomidine was added and brought to final concentrations (10 ⁻⁹ and 10 ⁻¹⁰ M, respectively). The control consisted only of filtered seawater. Each experiment was performed in replicate and maintained for up to 3 days. Subsequently, inhibition of colonization was examined using a stereomicroscope and confirmed for colonized or non-colonized larvae. The result is shown in FIG.

Reference Sinclair 2003: Sinclair, M .; D. , Can Vet J 44, 885-897 (2003)
Ruuskanen 2005: Ruuskanen, J. et al. O. Et al. Journal of Neurochemistry, 94, 1559-1569 (2005)
MacDonald 1991: MacDonald, E .; Et al. J Pharmacol Exp Ther. 259, 848-854, (1991)
Savola and Virtanen 1991: Savola, J. et al. M.M. Virtanen, R .; , Eur J Pharmacol, 195, 193-199 (1991).

Claims (28)

A surface coating composition comprising medetomidine in which the amount of levomedetomidine is 100% of the total amount of medetomidine as a compound for preventing marine organism adhesion on the surface, which is a paint for use in ships. Medetomidine, a salt thereof or a salt thereof, wherein the amount of levomedetomidine as a compound for preventing marine organism adhesion on the surface, which is a paint for use on ships, is greater than 50% of the total amount of medetomidine consisting of levomedetomidine and dexmedetomidine. A surface coating composition comprising a solvate .   A polymer skeleton modified with sulfonate, a polymer skeleton modified with acidic sulfate, a polymer skeleton modified with phosphonic acid, a polymer skeleton modified with carboxylic acid or a polymer modified with acidic phosphate The surface coating composition of claim 1, wherein the surface coating composition binds to a scaffold.   The levomedetomidine and dexmedetomidine are modified with a polymer skeleton modified with sulfonate, a polymer skeleton modified with acidic sulfate, a polymer skeleton modified with phosphonic acid, a polymer skeleton modified with carboxylic acid, or an acidic phosphate. The surface coating composition of claim 2, wherein the surface coating composition is bonded to the polymer backbone. The polymer backbone is selected from the group consisting of polystyrene and acrylate les Toporima, surface coating composition according to claim 3 or 4.   The surface coating composition of claim 1, 3, or 5, wherein the composition provides a controlled release of the levomedetomidine.   The surface coating composition according to claim 1, 3, 5, or 6, wherein the levomedetomidine is adsorbed to nanoparticles. 6. A surface coating composition according to claim 2, 4 or 5, wherein the levomedetomidine and dexmedetomidine are adsorbed to nanoparticles. The surface coating composition according to claim 7 or 8 , wherein the nanoparticles are selected from the group consisting of oxides of copper, zinc, titanium, aluminum, silicon, and magnesium. The surface coating composition according to claim 7, wherein the nanoparticles have a specific surface area of 10 to 50 m ² / g. 11. A surface coating composition according to any one of claims 1 to 10 , further comprising at least one further antifouling agent. 12. A surface coating composition according to claim 11 , wherein the further antifouling agent is selected from the group consisting of algae, fungicides, herbicides and general biocides. Said further antifouling agents are chlorothalonil, dichlorofluanide, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone (SeaNine®), 2-methylthio-4-tert-butylamino -6-cyclopropylamino-s-tridian (Irgarol®), 3- (3,4-dichlorophenyl) -1,1-dimethylurea (Diuron®), tolylfuranide, zinc pyrithione, copper Pirichio emissions, zinc ethylenebis dithiocarbamate (Zineb (registered trademark)), zinc bis (dimethyl thiocarbamate) (Zinram (registered trademark)), manganese ethylenebis dithiocarbamate (Maneb (registered trademark)), a fourth Secondary ammonium compound, 2- (p-chlorophenyl) -3-cyano-4-bromo 5-trifluoromethyl pyrrole is selected from the group consisting of (EcoNea (TM)), according to claim 11 or surface coating composition according to 12. Coated surface with a composition as claimed in any one of claims 1 13. 15. A surface according to claim 14 , wherein the surface is a surface intended for immersion in a marine environment. The surface according to claim 15 , wherein the surface is a hull or a seawater pipe. Use of medetomidine in which the amount of levomedetomidine is 100% of the total amount of medetomidine , or a salt thereof or a solvate thereof as a marine antifouling agent . The amount of Rebomedetomijin is Rebomedetomijin and dexfenfluramine Medellin preparative greater than 50% of the total amount of medetomidine consisting thymidine medetomidine, or use as sea Yobo fouling agent of a salt or solvate thereof. 19. Use according to claim 17 or 18 , for inhibiting the establishment of Cypris larvae on the surface. 20. Use according to any one of claims 17 to 19 in combination with at least one further marine antifouling agent. 21. Use according to claim 20 , wherein the further antifouling agent is selected from the group consisting of algae, fungicides, herbicides and general biocides. Said further antifouling agents are chlorothalonil, dichlorofluanide, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone (SeaNine®), 2-methylthio-4-tert-butylamino -6-cyclopropylamino-s-triziane (Irgarol®), 3- (3,4-dichlorophenyl) -1,1-dimethylurea (Diuron®), tolylfluanide, zinc pyrithione, copper Pirichio emissions, zinc ethylenebis dithiocarbamate (Zineb (registered trademark)), zinc bis (dimethyl thiocarbamate) (Zinram (registered trademark)), manganese ethylenebis dithiocarbamate (Maneb (TM)) , Quaternary ammonium compound, 2- (p-chlorophenyl) -3 It is selected from the group consisting of cyano-4-bromo-5-trifluoromethyl pyrrole (EcoNea (registered trademark)), use of claim 20 or 21. Applying to the surface a composition comprising medetomidine in which the amount of levomedetomidine is 100% of the total amount of medetomidine , or a salt or solvate thereof, as a compound for preventing marine organism adhesion How to prevent marine organisms from sticking. Applied as a compound for preventing marine biofouling, the amount of Rebomedetomijin is Rebomedetomijin and dexfenfluramine Medellin preparative greater than 50% of the total amount of medetomidine consisting thymidine medetomidine, or a salt thereof or composition comprising a solvate thereof to a surface how to prevent including, of the surface marine biofouling to. 25. A method according to claim 23 or 24 for inhibiting the establishment of Cypris larvae on the surface. 26. A method according to any one of claims 23 to 25 , wherein the composition comprises at least one further marine antifouling agent. 27. The method of claim 26 , wherein the additional antifouling agent is selected from the group consisting of algae, fungicides, herbicides and general biocides. Said further antifouling agents are chlorothalonil, dichlorofluanide, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone (SeaNine®), 2-methylthio-4-tert-butylamino -6-cyclopropylamino-s-tridian (Irgarol®), 3- (3,4-dichlorophenyl) -1,1-dimethylurea (Diuron®), tolylfuranide, zinc pyrithione, copper Pirichio emissions, zinc ethylenebis dithiocarbamate (Zineb (registered trademark)), zinc bis (dimethyl thiocarbamate) (Zinram (registered trademark)), manganese ethylenebis dithiocarbamate (Maneb (registered trademark)), a fourth Quaternary ammonium compounds and 2- (p-chlorophenyl) -3-cyano-4-but It is selected from the group consisting of Mo-5-trifluoromethyl pyrrole (EcoNea (registered trademark)), use of Rebomedetomijin in a method of preventing biofouling of a surface according to claim 26 or 27.