KR20160034311A - Use of the enantiomer levomedetomidine as inhibitor for marine biofouling of surfaces - Google Patents

Abstract

The present invention relates to a marine anti-fouling agent, the use of a relatively high amount of levomedetomidine, or a salt or solvate thereof, as compared to dexmedetomidine. The present invention also relates to a surface coating composition comprising the medetomidine, a surface coated with the medetomidine, and a method for preventing marine biofouling using the medetomidine.

Description

Use of the enantiomer levomethotomidine as an inhibitor of marine biofouling on a surface United States Patent Application 20060162992 Kind Code:

The present invention relates generally to the use of materials as agents for inhibiting marine biofouling of surfaces in marine environments, in particular for preventing marine biofouling of solid surfaces. More specifically, the present invention relates to the use of certain forms of medetomidine that serve as such agonists.

The economic advantages of reducing biofouling in marine and desalination plants are, for example, only a few, for example, reduced fuel efficiency in ships with the presence of fouling organisms in the hull of a ship, A loss of time during the cleaning procedure to reduce biofouling on the hull, and also a reduced cooling capacity of the cooling water system. In addition to vessels, other underwater facilities such as aquaculture and oil / gas offshore installations also suffer from serious problems of biofouling.

Currently, a number of different approaches for preventing and reducing biofouling have been devised and are commonly used. Several chemical compounds having anti-fouling activity, including toxicides or biocides, are used as additives in coatings or paints for surfaces exposed to underwater installations. As an alternative to toxicides and biocides, mechanical washing of the oceanic surface has been introduced. Particularly, water jet cleaning and mechanical cleaning using a brush are used. However, most of these methods are labor-intensive and therefore expensive. It has also been reported that the selection of pharmacological compounds that act on serotonin and dopaminergic neurotransmitters has the ability to inhibit or promote the attachment of scabies. Serotonin antagonists such as cyproheptadine and ketanserine, and dopamine agonists such as R (-) - NPA and (+) - bromocriptine have shown inhibitory properties. Another pharmacological agent that has been found to be an effective inhibitor in the context of scavenging is the highly selective alpha 2-adrenergic receptor agonist medetomidine or (±) -4 (5) - [1- (2, Dimethylphenyl) ethyl] -1H-imidazole. Fixation of larvae is already inhibited at low concentrations, 1 nM to 10 nM. Medetomidine is a new class of alpha 2 -receptor agonists that have a high selectivity for 2-adrenergic receptors and include 4-substituted imidazole rings. Receptors that are affected by catecholamine neurotransmitters such as norepinephrine and epinephrine are referred to as adrenergic receptors (or adrenoceptors) and can be divided into alpha-and beta-subclasses. The alpha 2-adrenergic receptor belongs to an automatic inhibition mechanism of the release of neurotransmitters and regulates hypertension (high blood pressure), control of bradycardia (reduced heart rate) and even arousal and painlessness (reduced sensitivity to pain) It plays an important role in.

WO00 / 42851 discloses the use of medetomidine as an agonist for the inhibition of marine biofouling on surfaces.

WO2006 / 096129 discloses the use of a sulfonated, acid sulphate ester, phosphonic acid, carboxylic acid or acid phosphate ester modified polymer backbone, such as, for example, mesotomidine bound to polystyrene or acrylate polymers, A method and use of a fouling preventive paint for preventing settlement are disclosed.

The present invention solves the problem of reducing the human effect of medetomidine present in various products used for prevention of marine biofouling.

The main object of the present invention is to provide a medicament which acts as an agent for antifouling in the marine environment and which is a specific enantiomeric form of medetomidine which has less effect on humans, medetomidine) are used separately and separately. Another object of the present invention is to use a composition in the form of an enantiomeric form of medetomidine which has less effect on humans as a substance acting as an agent for preventing fouling in marine environments, Which is different from the racemic mixture (1: 1) in the enantiomeric form. A further object of the present invention is to use a composition of a mixture of two enantiomeric forms wherein levomethomidine is used to prevent fouling in marine environments that have less impact on humans than racemic mixtures of medetomidine , Which constitutes at least 90, 80, 70, 60, 50% of the mixture. Other objects and advantages will become more apparent from the following disclosure and appended claims

Fig.
The structure of levomethotomidine (an example represents HCl salt).
2a.
Experiments on the Fixation Experiment of Medicinal Herbs Using Racemic Medtomidine.
2b.
Experiments on the confluence of enantiomers using the enantiomer levomethotomidine.

These and other aspects of the present invention will now be described in detail with reference to the description and methodology provided herein. It is to be understood that the invention may be embodied in other 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 terms used in the description of the invention herein are merely for the purpose of describing particular embodiments and are not intended to limit the invention. As used in describing embodiments of the present invention, the singular forms "a,""an," and "the" . Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more associated enumerated items. In addition, as used herein, the term "about" refers to a quantity that is 20%, 10%, 5% , 1%, 0.5%, or even 0.1%. When a range is used ( e.g. , in the range of x to y), the measurable value means a range from about x to about y, or any range therein, such as from about x ₁ to about y ₁ . The terms "comprises" and / or "comprising " when used herein specify the presence of stated features, integers, steps, operations, elements, and / It will be further understood, however, that it does not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / Unless otherwise defined, all terms used in the description, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

All patents, patent applications, and publications referred to in this specification are incorporated by reference in their entirety. Where the terms conflict, the present specification prevails. In addition, the embodiments described in one aspect of the present invention are not limited to the embodiments described. Embodiments may also be applied to other aspects of the invention, as long as the embodiments do not preclude that these aspects of the invention act for its intended purpose.

The present invention relates generally to the use of compositions for the coating of surfaces exposed to substances and marine environments as agents for the inhibition of marine biofouling of surfaces in a marine environment, in particular for the prevention of marine biofouling of solid surfaces . More specifically, the present invention relates to the use of a particular enantiomeric form of the medetomidine, i.e., levomethotomidine (Figure 1), which acts as such an agonist.

In one embodiment, the present invention thus relates to a surface coating composition comprising medetomidine, wherein said composition comprises a relatively higher amount of levomethotomidine as compared to dexmedetomidine. The surface coating composition may further comprise a binding phase known in the art of surface coating compositions, a pigment, and a suitable solvent. The surface coating composition may be a coating for marine use, such as a self-polishing paint composition for marine use.

The a2-adrenocceptor agonist medetomidine is known to cause sedation and locomotor inhibition when given to mammals and fish (Sinclair, 2003; Ruuskanen et al., 2005). Medtomidine (10 nM) has been found to be opposite in the cyprid larvae, as it strongly enhanced kicking of the nymphs with a kick of over 100 times per minute (Mol Pharmacol 78: 237 -248, 2010). Thus, medetomidine has different physiological effects in vertebrates and invertebrates and demonstrates hyperactivity rather than sedation / and motility inhibition as in vertebrates. Medtomidine induces motility-activating responses in the hatching rhizosphere, which is the major cause of inhibition. More specifically, an increase in the kinking of anterior projections (legs) is proposed as a fixation-preventing manner of medetomidine.

(±) 4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole, which was originally described in EP 72615, has two optical enantiomers, levo- (MacDonald et al., 1991; Savola and Virtanen, 1991) with the generic names levomethotomidine 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 prior syntheses use expensive 4-substituted imidazole derivatives as starting materials, but in WO 2011/070069 synthesis is carried out from inexpensive starting materials commercially available, where imidazole rings are formed instead during synthesis .

Medtomidine has been studied in human clinical trials and has also been used as an animal anesthetic for the active ingredient, the (S) -enantiomer, dexmedetomidine. On the other hand, although levomedetomidine has no apparent sedation or analgesic effect (Kuusela et al. J Vet Pharmacol Ther 23 (1), 15-20, 2000), higher doses of levomedetomidine are dexmedetomidine (Kuusela et al. Am J Vet Res 62 (4), 616-621, 2001). This suggests that the sole administration of dexmedetomidine for sedation or analgesic effect may be advantageous over administration of a racemic mixture of medetomidine comprising the same amount of dexmedetomidine and levomedetomidine. Based on this type of study, the pure preparation of dexmedetomidine has been justified and traded under a variety of names, such as Dexdor (Orion Pharma AB). Dexdor is directed against mild to moderate sedation in adult ICU patients and EMA / 789509/2011 Drug Use Advisory Committee (CHMP), Dexdomitor beta (Orion Pharma AB) is indicated for veterinary applications. Such pure preparation is carried out by separation and purification of dexmedetomidine from a racemic mixture, wherein levomedetomidine is considered to be a major impurity of pure dexmedetomidine.

As mentioned above, racemic mixtures of medetomidine or (±) -4 (5) - [1- (2,3-dimethylphenyl) ethyl] -1H- imidazole are effective inhibitors . Surprisingly, as disclosed in the present invention, both the racemic mixture and the enantiomeric forms of the medetomidine (dexmedetomidine and levomethotomidine) have similar inhibitory effects. This is in contrast to other well-documented uses of only one particular enantiomeric form of the molecule, in which, for example, drugs in the pharmaceutical industry, including medetomidine, have only one enantiomeric form active and the other enantiomeric form inert . It is an unexpected and surprising effect that levomethotomidine has a similar inhibitory effect.

The inhibition of the fixation of the nematocidal cyfrid larvae is described in Example 1 below and in Figures 2a and 2b.

A preferred embodiment of the present invention is therefore the use of levomethotomidine as the active ingredient / component in the application of marine coatings to prevent biofouling on various surfaces submerged in marine environments.

Since levomedetomidine has been documented to have a very limited effect on humans and animals compared to the racemic mixture of medtomidine and the other enantiomer dexmedetomidine, the use of enantiomeric forms of levomethotomidine has been reported to humans Will provide a solution for the end-product with less effect. The risk of handling any product (s), including medtomidine or dexmedetomidine during manufacture, transportation, storage and application, for example, for the person engaged in the application of the end-user, It is reduced by the use of medetomidine. In addition, the metabolism of levomethotomidine has been found to be more rapid in mammals, which is more advantageous compared to the use of the racemic mixture of medetomidine or the enantiomer dexmedetomidine. In addition, levomedetomidine can be considered to be an impurity and thus has an advantageous price level because it is discarded during dexmedetomidine processing and purification, the enantiomer for clinical applications. This also means that the invention herein also helps to solve the problem of treating waste from the production of dexmedetomidine. The purification of dexmedetomidine is disclosed in the preparation process of WO2013069025, dexmedetomidine, wherein dexmedetomidine is prepared in high yield with enantiomeric purity greater than 99%. A similar approach using the same methodology could also be applied for the preparation of levomethotomidine instead. Methods for resolving levo and dexero enantiomers are also disclosed in CN200910093379. The use of levomethotrimine as a drug for use in the prophylaxis or treatment of conditions associated with overexpression or hypersenzitation of adrenergic a-2 receptors is disclosed in EP0858338.

A preferred embodiment of the present invention is therefore a use of levomethotomidine, which is a specific enantiomeric form of medetomidine which has less effect on humans, acting as an agent for preventing fouling in marine environments, separately and separately .

Another preferred embodiment of the present invention is to use a composition in the form of an enantiomeric form of medetomidine which has less effect on humans as a substance acting as an agent for preventing fouling in marine environments, It differs from the racemic mixture (1: 1) in that it is the dominant enantiomeric form. Another preferred embodiment of the present invention is the use of a composition of a mixture of two enantiomeric forms wherein levomethomidine is used in a marine environment with less effect on humans than the racemic mixture of medetomidine It constitutes at least 90, 80, 70, 60, 50% of the mixture.

A related preferred embodiment of the present invention is the use of a combination of biocide-polymer complexes as an additive in a self-polishing paint for controlled release purposes as disclosed in WO2006 / 096129. Specifically, such preferred embodiments utilize levomedetomidine coupled to a sulfonated, acid sulphate ester, phosphonic acid, carboxylic acid, or acid phosphate ester modified polymer backbone, such as a polystyrene or acrylate polymer, for example, The present invention relates to a method and a use of a fouling preventive paint which specifically and effectively inhibits the fixing of a brittle flow on a surface of a substrate. Another desirable object of the present invention is to create a fouling prevention method that requires reduced biocidal capacity through appropriate control of the release of anti-fouling material from the paint film. For example, levomethotomidine molecules bound to polystyrene-block-poly (ethylene-lan-butylene) -block-polystyrene will produce a slow release of active-compound from water to paint in a controlled manner. The levomedetomidine-polymer ion pair will only dissolve on the actual film surface when in contact with water, resulting in the release of levomethotomidine. Surface-active-compounds in anti-fouling coatings are likely to have a greater impact on the settlement of the larval larvae than compounds that leach from paint into the water, since surface activity will increase near-surface concentrations.

In related preferred embodiments, the controlled release of the fouling agent is also CuO, ZnO, TiO _2, Al ₂ O _3, SiO _2, MgO, and preferably a copper (II) oxide blended with nano particle size - and zinc (II ) Can be utilized. Due to the large specific surface area (the ratio between the surface area and the volume of the particles), the nanoparticles may contain anti-fouling agents such as levomethotomidine, or other anti-fouling agents such as Chlorothalonil, Dichlofluanide ), SeaNine, Irgarol, Diuron, and Tolylfluanid. CuO and ZnO particles generate a specific surface area of 29 and 21 m ² .g -1, respectively. This allows the possibility of designing a paint system containing a small amount of both levomethotomine and nanoparticles to limit the diffusion movement of the anti-fouling agent through the paint film. When replacing nanoparticles with micrometer-sized particles, the adsorption appears to be negligible. These results show the importance of large surface area in relation to the adsorption of anti-fouling agent on the particle surface. Anti-fouling agents, such as levomedetomidine bound to nano-sized metal oxides, are compounds that leach out of the paint in a controlled manner. The anti-fouling agent bonded to the nano-sized metal oxide has excellent dispersion stability due to its large size as compared with anti-fouling agent particles alone. Due to the size characteristics, the anti-fouling agent-metal oxide particles are fixed in the paint film and do not leak into water. As a result, the concentration of the anti-fouling particles in the paint film remains uniform during the "lifetime ". As a result, the concentration of the anti-fouling agent will be the same in the entire paint film. Another important point is that the overall surface area of the nanoparticles is sufficient to adsorb the anti-fouling agent and there is no waste of biocides.

Compounds that interfere with neural signal transduction or other specific actions on animal fauna of marine bio-fouling organisms, such as the mangrove currents, have been previously described, for example, US 6,762,227 describes the use of medetomidine, Swedish Patent Application No. 0300863-8 also describes the use of spiroimidazoline for the same purpose. However, the use of such products has little or no effect on the algae. For example, medetomidine has a specific action on the asthmatic rhizosphes, but does not affect algal growth due to deficient target proteins in the algae. There are several ways to prevent bird growth, including the use of very high concentrations of copper and other metals. Algicides are often invented as herbicides and include photosynthetic inhibitors such as DIURON (TM) (3- (3,4-dichlorophenyl) -1,1-dimethylurea) by DuPont Agricultural Products, Wilmington, IRGAROL ™ 1051 (2-methylthio-4-tert-butylamino-6-cyclopropylamino-s-triazine) by Ciba Inc. A more general strategy is to use fungicides such as zinc pyrithione (zinc, bis (1-hydroxy-2 (1H) -pyridine thioneate-O, S) -, (T- Copper pyrithione (copper, bis (1-hydroxy-2 (1H) -pyridine thionate-O, S) -, (T-4) -) by Arc Chemicals Inc, USA, Pa., Pittsburgh N (dichlorofluoromethylthio) -N ', N'-dimethyl-Np-tolylsulfamide by Bayer Chemicals, diclofluanide (N'-dimethyl- Zinc (ethylene bisdithiocarbamate) by FMC corp., ZINRAM ™ (zinc bis (dimethylthiocarbamate) by Taminco), MANEB (manganese ethylene bisdithiocarbamate) Ammonium compounds are used. A third strategy is to use compounds that are toxic but have a short half-life, such as SEANINE ™ (4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone ) And related compounds. The principles of the method of the present invention thus include the use of a substance or agent, in this case levomethotomidine, which interferes with or blocks neuronal signaling to the target cells in the Saifrid larvae, with anti-aldic compounds such as zinc- and copper pyrophthion zinc- and copper pyrothion), tolyl dE No flu and flu dichloride and not de fungicides, diuron (TM) and Irgarol ^TM and the like herbicides, or more general biocides such as SeaNine ^TM or the United States, NJ, Titusville materials such In combination with EcoNea ^TM (2- (p-chlorophenyl) -3-cyano-4-bromo-5-trifluoromethyl) by Janssen Pharmaceutical. A preferred embodiment of the invention is, for example, the addition of such a material to a base polymer coating to be applied to the ship hull. Thus, in a related preferred embodiment, the invention comprises applying a protective coating to a material, said coating comprising: a) a material comprising levomedetomidine and preventing shoddy biofouling, and b) . Certain preferred algicides are copper, zinc, and other metals, Diuron (3- (3,4- dichlorophenyl) -l, l- dimethyl-urea), Irgarol 1051 ^TM (2- methylthio - 4-tert- butylamino -6 (1-hydroxy-2 (1H) -pyridine thionate-O, S) -, (T-4) -), copper pyrophosphate Thion (copper, bis (l-hydroxy-2 (lH) -pyridine thionate-O, S) -, (T- Zineb ^TM (zinc ethylenebisdithiocarbamate), Zinram ^TM (zinc bis (dimethylthiocarbamate)), maneb (manganese ethylene bisdithiocarbamate), quaternary ammonium compounds, SeaNine ^TM (4,5 3-cyano-4-bromomethyl-5-trifluoromethyl) - dichloro -2-n- octyl -3 (2H) - isothiazolone), and EcoNea ^TM (2- (p- chlorophenyl) .

As used herein, the terms "medetomidine "," dexmedetomidine ", and "levomethotomidine" include salts and solvates thereof unless specifically stated otherwise. Acceptable salts of levomethotomidine include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction with free acids or free base forms of the compounds of the invention and at least one equivalent of an appropriate acid or base in a solvent or medium which is optionally insoluble in the salt , Followed by removal of the solvent, or the medium, using standard techniques (e.g., by vacuum or lyophilization). Salts may also be prepared by the exchange of counter-ions and other counter-ions of the compounds of the present invention in the form of their salts, for example using suitable ion exchange resins. To avoid ambiguity, other acceptable derivatives of levomethotomidine are included within the scope of the present invention (e.g., solvates, prodrugs, etc.). Preferred solvents are: n-butanol, iso-butanol, methanol, benzyl alcohol and 1-methoxy-2-propanol.

The enantiomers of the medtomidine can be isolated and separated from one another by separation of racemic or other mixtures of enantiomers using chiral resolution or chiral column chromatography as known in the art. Instead, the desired enantiomer may be prepared by optical selective synthesis, also referred to as chiral synthesis or asymmetric synthesis, in which one or more new elements of chirality are formed in the substrate molecule, which is an unequal amount of stereoisomer (enantiomer or Diastereomer) product (or reaction procedure) that produces the product (IUPAC).

Preferably, the barrier coating may further comprise a marine paint.

Example  One

Materials and methods

Inhibition of the settlement of the larval fly larvae.

Fixation assays were performed using a Petri dish containing 5 ml of filtered seawater with a salinity of 32 ± 1 ‰. Approximately 200,000 angular hyphae were added to each petri dish. Medetomidine / levomedetomidine was then added and given final concentrations (10 ^-9 and 10 ^-10 M, respectively). Controls consist solely of filtered seawater. Each experiment was repeated 5 times and kept for a maximum of 3 days. Inhibition of fixation was then examined using a stereoscopic microscope to identify fixed or unfixed larvae. The results are shown in Fig.

references

Sinclair 2003: Sinclair, MD, Can Vet J 44, 885-897 (2003)

Ruuskanen 2005: Ruuskanen, JO 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, JM, Virtanen, R., Eur J Pharmacol, 195, 193-199 (1991)

Claims (27)

Characterized in that it comprises a relatively greater amount of levomedetomidine, or a salt or solvate thereof, as compared to dexmedetomidine. The method of claim 1, wherein the amount of levomethotomidine is at least 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 100% of the total amount of medtomidine Surface coating composition. The surface coating composition according to claim 1 or 2, wherein the surface coating composition is a coating for marine use. 4. The surface coating composition according to any one of claims 1 to 3, wherein the levomedetomidine is bonded to the sulfonated, acid sulphate ester, phosphonic acid, carboxylic acid or acid phosphate ester modified polymer backbone. 5. The composition of claim 4 wherein the polymer backbone is a surface coating composition selected from the group consisting of polystyrene and acrylate polymers 6. The composition of any one of claims 1 to 5, wherein said composition is a surface coating composition that provides controlled release of said levomedetomidine 7. The surface coating composition of claim 6, wherein the levomedetomidine is adsorbed to the nanoparticles. The surface coating composition of claim 7, wherein the nanoparticles are selected from the group consisting of oxides of copper, zinc, titanium, aluminum, silicon, and magnesium, preferably copper (II) oxide and zinc (II) oxide. The surface coating composition according to claim 7 or 8, wherein the nanoparticles have a specific surface area of 10-50 m ² / g, preferably 20-30 m ² / g. 10. The surface coating composition according to any one of claims 1 to 9, further comprising at least one additional anti-fouling agent. 11. The surface coating composition of claim 10, wherein the additional anti-fouling agent is selected from the group consisting of fungicides, fungicides, herbicides and common biocides. 12. The composition of claim 10 or 11, wherein the additional anti-fouling agent is selected from the group consisting of chlorotaronyl, diclofenid, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone , 2-methylthio-4-tert-butylamino-6-cyclopropylamino-s-triazine (Irgarol), 3- (3,4-dichlorophenyl) -1,1-dimethylurea Zirconium ethylenebisdithiocarbamate (Zineb), zinc bis (dimethylthiocarbamate) (Zinram (R)), manganese ethylene bisdithiocarbamate A surface coating composition is selected from the group consisting of Maneb®, quaternary ammonium compounds, 2- (p-chlorophenyl) -3-cyano-4-bromo-5-trifluoromethyl (EcoNea®). 13. A surface coated with a composition according to any one of claims 1 to 12. 14. The surface of claim 13 wherein said surface is intended for flooding in a marine environment. 15. The method of claim 14, wherein the surface is a marine hull, As anti-marine anti-fouling agents, the use of a relatively higher amount of levomedetomidine, or a salt or solvate thereof, as compared to dexmedetomidine. 18. Use according to claim 16, wherein the medtomidine is comprised of at least 60%, 70%, 80%, 90%, 99% or 100% levomedetomidine, consisting of more than 50% of levomethotomidine . 18. The use according to any one of claims 16 to 17, for inhibiting the settlement of the cyfrid larva on the surface. 19. Use according to any one of claims 16 to 18, in combination with at least one additional marine anti-fouling agent. 20. Use according to claim 19, wherein the further anti-fouling agent is selected from the group consisting of fungicides, fungicides, herbicides and common biocides. 21. The method of claim 19 or 20, wherein the additional anti-fouling agent is selected from the group consisting of chlorotaronyl, diclofenid, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone , 2-methylthio-4-tert-butylamino-6-cyclopropylamino-s-triazine (Irgarol), 3- (3,4-dichlorophenyl) -1,1-dimethylurea Zirconium ethylenebisdithiocarbamate (Zineb), zinc bis (dimethylthiocarbamate) (Zinram (R)), manganese ethylene bisdithiocarbamate (Maneb®), quaternary ammonium compounds, 2- (p-chlorophenyl) -3-cyano-4-bromo-5-trifluoromethyl (EcoNea®). Comprising applying to the surface a relatively higher amount of levomedetomidine, or a salt or solvate thereof, as compared to dexmedetomidine, to the surface, thereby preventing marine biofouling of the surface. 23. The method according to claim 22, wherein the medtomidine is comprised of at least 60%, 70%, 80%, 90%, 99% or 100% levomedetomidine, consisting of more than 50% of levomethotomidine . 24. A method according to any one of claims 22 to 23, for inhibiting the settlement of the nasal prick larvae on said surface. 25. A method according to any one of claims 22 to 24, further comprising applying at least one additional marine anti-fouling agent to the surface. 26. The method of claim 25, wherein the additional anti-fouling agent is selected from the group consisting of fungicides, fungicides, herbicides, and common biocides. 26. The composition of claim 25, wherein the additional anti-fouling agent is selected from the group consisting of chlorotaronyl, diclofenid, 4,5-dichloro-2-n-octyl-3 (2H) -isothiazolone , 2-methylthio-4-tert-butylamino-6-cyclopropylamino-s-triazine (Irgarol), 3- (3,4-dichlorophenyl) -1,1-dimethylurea Zirconium ethylenebisdithiocarbamate (Zineb), zinc bis (dimethylthiocarbamate) (Zinram (R)), manganese ethylene bisdithiocarbamate (Maneb®), quaternary ammonium compounds, 2- (p-chlorophenyl) -3-cyano-4-bromo-5-trifluoromethyl (EcoNea®).

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