WO2018087160A1

WO2018087160A1 - Substituted heterocyclic compounds for use in controlling parasitic crustaceans on fish

Info

Publication number: WO2018087160A1
Application number: PCT/EP2017/078634
Authority: WO
Inventors: Dan Isaksson; Lena MÅRTENSSON LINDBLAD
Original assignee: iTech AB
Current assignee: iTech AB
Priority date: 2016-11-09
Filing date: 2017-11-08
Publication date: 2018-05-17
Anticipated expiration: 2019-05-09

Abstract

A compound of formula (I) or a salt thereof for use in controlling parasitic crustaceans, such as sea lice, on fish, e.g. salmon. A method of improving water flow into and out of a cage or net for fish farming, by providing said cage or net with a surface coating containing a compound of formula (I) or a salt thereof in an amount effective to reduce biofouling of said cage or net. The coating is capable of releasing the compound or a salt thereof into the water in the cage or net in an amount effective to reduce or prevent parasitic infestation of the fish in the cage or net.

Description

SUBSTITUTED HETEROCYCLIC COMPOUNDS FOR USE IN CONTROLLING PARASITIC

CRUSTACEANS ON FISH

FIELD OF THE INVENTION

The present invention relates to compounds for reducing and preventing parasitic crustaceans in marine environments.

BACKGROUND OF THE INVENTION

Fish farming is a form of aquaculture, also called pisciculture, which utilizes enclosures such as ponds, cages or nets of various formats both in fresh-water, sea-water or brackish water, usually for food-fish production. The most common food-fish are carp, salmon and catfish.

Driven by a continuously higher demand for fish and fish protein, aquaculture nowadays represents a large part of seafood production (estimated approx. 40% in 2005) also mirrored by high economic impacts. Two types of fish aquaculture exist, extensive aquaculture (depends on local photosynthetic production) and intensive aquaculture (depends on external food supply). Off-shore cultivation involves submerged cages or nets that are placed at sea, with different geometries, consisting of a metal or plastic frame with mesh or net to contain the fish. It is highly important for the fish welfare to keep these nets clean so that they are not subjected to for example bio fouling, in order to sustain the flow of water and water circulation through the nets to provide fresh, clean, oxygenated water to the caged fish. Recent advances in cage construction have also involved the use of copper alloys in the nets to prevent biofouling, due to coppers antimicrobial/algaecidal and antifouling properties, and the copper alloy nets are also corrosion resistant. Copper alloys such as copper-zinc brass, copper nickel and copper-silicon are for example used.

Fish densities are kept high inside the cages, and such high densities make the fish prone to various types of disease, parasites and related stress factors compared to outside the nets. The fish therefore need monitoring and various types of treatments to keep healthy, through e.g. vaccinations and use of bactericides. Sea lice or parasitic crustaceans present one of the major threats besides infections of various types for fish farms with salmon for example, represented by mainly two Copepodae species, Lepeophtheirus (L. salmonis) and Caligus. Damage to the fish by these types of sea lice or parasites are found mainly on the scales, epithelium, mucose and in worse cases the dermis, which may also lead to secondary infections and ultimately death if the wounds are severe, thus leading to financial losses of the fish farm. L. salmonis exist in different larval stages, including the copepodid stage, which attach to the fish and then develop to adults through different stages.

Various ways have been developed to handle the parasites in fish farms, including the use of various pest control substances. However, some of these cause problems to the marine environment since they have to be used in high concentrations to be effective. Substances with low toxicity, higher degradability and no injury to marine life except sea lice are described in WO2011157733. Compositions of these types of substances may be added to the cages in the form of solutions, emulsions, suspensions, powders or tablets and the like. The fish may also be transferred and handled by various types of bath treatments, in order to treat, prevent and minimize the infestations of the parasites. Also, the treatment may involve the use of injectable formulations, and in may such cases with the purpose to vaccinate the fish against the parasites. This type of handling of fish can however be stressful and damaging to the fish as well, and in some cases also contributing to a loss in yield in the fish farms. The substances may also be given to the fish through their food (pellets etc.). There has also been some initial trial to utilize certain species of wrasses, to reduce the parasitic infestations of food-fish populations, mimicking and taking advantage of natural behavior of the wrasses to feed on the parasites of the host-fish. SUMMARY OF THE INVENTION

One aspect of the present invention is to use the compounds of the invention as agents for antifouling in marine environments, more specifically to reduce and prevent marine bio fouling on the cages submersed in water utilized for fish farming, and thus subsequently improve the flow of water through the cages.

A related aspect of the invention is to reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages.

Another aspect of the invention relates to a coating or a paint comprising the compounds of the invention, applied to cages for fish farming, whereby the compounds of the invention slowly leaks from the coating or paint of the cage immersed in water, to reduce and prevent bio fouling on the cages and also to reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages. Another aspect of the invention is to provide an effective amount of the compounds of the invention to the cages via delivery systems, exemplified but not limited to solutions, emulsions, suspensions, powders, tablets and the like, or formulated and encapsulated in beads, capsules, gels and the like, to reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages.

Thus, the compounds of the invention may be formulated and encapsulated in beads, capsules, gels and the then added to the cages or nets via water-permeable containers or bags and the like that are attached to lines that span the height of the cage or net and are distributed evenly over the volume of the cage or net. The compounds of the invention slowly leak into the surrounding water. The lines are connected to a floating part, above the water, and a sinker or weight below the water. Such water-permeable containers or bags and the like that are attached to lines, containing the compounds of the invention formulated and encapsulated in beads, capsules, gels and the like, are easily exchanged or replaced when the concentration of the compounds of the invention is close to a minimum concentration, or e.g. at predetermined intervals.

In one as ect a compound of formula (I)

or a salt thereof, is provided, for use in controlling parasitic crustaceans on fish, said parasitic crustaceans belonging to the Copepodae subclass, wherein

A₂ is N or CR₇; and

(i) Ri, R₂, R₃, Re and R₇ are independently selected from H, OH, NH₂, R_aC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II)

at least one and at most three of Ri, R₂, R₃, R6 and R₇ being a moiety of formula (II); R4 and R₅ are independently selected from H and C1-C3 alkyl; or when R₂ is a moiety of formula (II), then R4 and R_g together may form a methylene or ethylene bond; and when R3 is a moiety of formula (II), then R5 and R_g together may form a methylene or ethylene bond; or R4 and R₅ together form a covalent bond;

Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

Rc, Rd, Re, Rf, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and Rc and Rd, or Rj and R_e, or Re and Rf, or Rf and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring;

n is O or l;

when n is 1, one of Z and W is selected from CRhRi, O, and NRj; and the other one is selected from CRhRi, and C=X; or one of Z and W is CRhRi; and the other one is selected from CRhRi, O, NRj and C=X;

when n is 0, W is selected from CRhRi, O, NRj and C=X;

Rh and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by

OH;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂;

provided that the compound is not 4-(l-(2,3-dimethylphenyl)ethyl)-lH-imidazole or a tautomer thereof.

Another aspect is a method of improving water quality in an enclosure for fish, by providing said enclosure with a surface coating containing a compound of formula (I)

a salt thereof, wherein

A₂ is N or CR₇; Ri, R₂, R₃, Re and R₇ are independently selected from H, OH, NH₂, R_aC(O)-, C1-C4 alkyl optionally substituted by R_b, and a moiety of formula (II)

at least one and at most three of Ri, R₂, R₃, R6 and R₇ being a moiety of formula (II);

R4 and R₅ are independently selected from H and C1-C3 alkyl; or when R₂ is a moiety of formula (II), then R4 and R_g together may form a methylene or ethylene bond; and when R₃ is a moiety of formula (II), then R5 and R_g together may form a methylene or ethylene bond; or R4 and R₅ form together a covalent bond;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-; R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and R_c and R_d, or Rj and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring; n is 0 or 1 ; when n is 1 , one of Z and W is selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X; when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by

OH; R_j is selected from H and C1-C4 alkyl; and X is selected from O and CH₂;

The coating preferably contains the compound of formula (I) in an amount effective to reduce biofouling of said enclosure. In some embodiments the coating contains the compound of formula (I) in an amount effective to essentially prevent biofouling of said enclosure. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic representation of a delivery system of the compounds of the invention.

Figure 2 A-G Results from the settlement assay showing the effects of the compounds, classifying the barnacle cyprid larvae as swimming/living, dead and settled. Each experiment was made in five replicates and maintained up to 7 days. The inhibition of settling was thereafter examined by using a stereomicroscope and checked for settled or non-settled larvae.

Fig 2 A. Settlement assay for Detomidine.

Fig 2 B. Settlement assay for Clonidine. CL 0 is the control.

Fig 2 C. Settlement assay for Naphazoline. NP 0 is the control.

Fig 2 D. Settlement assay for Med3.

Fig 2 E. Settlement assay for Med6.

Fig 2 F. Settlement assay for Lofexidine. Lofexidine 0 is the control.

Fig 2 G. Settlement assay for 1-Benzylimidazole. Figure 3

Results from the kicking assay. The investigated compounds (Detomidine (DT), Clonidine (CL), Naphazoline (NP), Med3 (M3), Med6 (M6), Lofexidine (LO), 1-Benzylimidazole (BI), SI 8616 (SP)) were added at 100 nM concentration and individual cyprid movements were counted as kicks per minute under a stereo microscope. The numbers of kicks were counted before and after three hours incubation with the investigated compounds

DETAILED DESCRIPTION OF THE INVENTION

The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention may be embodied in different 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 skilled person will understand that 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. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in the description of the embodiments of the invention, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Thus, such references may be replaced with a reference 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 will be understood to refer to from one to a plurality (e.g. two, three or four) of such components or integers. It will be understood that references to "one or more" of a particular component or integer will include a particular reference to one such integer. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%>, 5%, 1%, 0.5%>, or even 0.1%> of the specified amount. When a range is employed (e.g., a range from x to y) it is it meant that the measurable value is a range from about x to about y, or any range or value therein including x and y, such as about xi to about y_{l s} etc. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, components and/or groups, but do not preclude 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 in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

"Effective amount" as used herein refers to an amount of a compound, composition and/or formulation of the invention that is sufficient to produce a desired effect or parts thereof. For example, attenuates, ameliorates, or eliminates one or more symptoms of the particular parasitic infection, infestation, or biofouling and/or prevents or delays the onset of one or more symptoms of the particular parasitic infection or infestation, or biofouling, as described herein.

By the term "treat," "treating," or "treatment of (and grammatical variations thereof) it is meant that the severity of the subject's condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in symptom is achieved and/or there is a delay in the progression of the disease or disorder.

A "therapeutically effective" amount as used herein is an amount that is sufficient to treat (as defined herein) the subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. The term "therapeutically effective" as used herein in reference to an amount or dose refers to an amount of a compound, composition and/or formulation of the invention that is sufficient to produce a desired effect, which can be a therapeutic and/or beneficial effect. As used herein the term "concomitant administration" or "combination administration" of a compound, chemical agent, therapeutic agent or known drug, including pesticides, with a compound of the present invention means administration of a known medication or drug and, in addition, the one or more compounds of the invention at such time that both the known drug and the compound will have a therapeutic effect. In some cases this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the known drug with respect to the

administration of a compound of the present invention. A person skilled in the art will have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds of the present invention.

In addition, in some embodiments, the compounds of this invention will be used, either alone or in combination with one or more other active ingredients as described herein.

Pharmaceutically acceptable salts include, but are not limited to, acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques

(e.g. in vacuo or by freeze-drying). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example, using a suitable ion exchange resin. For the avoidance of doubt, other pharmaceutically acceptable derivatives of compounds of the invention are included within the scope of the invention (e.g. solvates).

For the purpose of the present invention, "pharmaceutically acceptable" refers to acceptability for veterinary use, more particularly for use in the treatment of aquatic animals, preferably vertebrate aquatic animals and more preferably fish.

The term "bio fouling" as used herein generally refers to the undesirable accumulation, adhesion, and growth of microorganisms, plants, algae, tubeworms, barnacles, mollusks, epibiontic organismsand other organisms, in particular barnacles, on a solid surface. The former term also includes other external, aquatic pests and diseases, such as sea lice which directly or indirectly affects aquatic animals such as fish.

The term anti- fouling refers to prevention and reduction of fouling organisms on marine surfaces. The term marine surfaces includes any surface that may present, or be at risk of, biofouling. Such surfaces are submerged under water, and may also be partly or intermittently submerged under water, and thus be exposed to biofouling organisms. Such surfaces may include any type of surface, e.g. organic, inorganic, metallic or the surfaces of living marine organisms. Hence, the former term also means to combat aquatic pests, including

ectoparasites which reside on vertebrate aquatic animal, which is topically exposed in treatment methods of this invention. The compounds of the invention have anti- fouling effects by reducing and preventing bio fouling on marine surfaces.

Compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallization or HPLC, techniques. Alternatively, the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemization or epimerization, or by derivatization, for example with a homochiral acid followed by separation of the

diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In the event of conflicting terminology, the present specification is controlling. Further, the embodiments described in one aspect of the present invention are not limited to the aspect described. The embodiments may also be applied to a different aspect of the invention as long as the embodiments do not prevent these aspects of the invention from operating for their intended purpose. Accordin to one aspect, a compound of formula (I)

or a salt thereof, is provided, for use in controlling parasitic crustaceans on fish, said parasitic crustaceans belonging to the Copepodae subclass, as described herein.

The compound of formula (I) or salt thereof is also useful in a method of improving water quality in an enclosure for fish by providing said enclosure with a surface coating containing the compound or a salt thereof. The compound preferably is present in the coating in an amount effective to reduce biofouling of said enclosure. In some embodiments, the compound is present in the coating in an amount effective essentially to prevent biofouling of said enclosure. In some embodiments, the compound is present in the coating in an amount effective at least to inhibit biofouling of said enclosure, i.e. biofouling is reduced compared to biofouling in an enclosure which does not have a coating containing the compound of formula

(I)-

In some embodiments, the coating is capable of releasing the compound of formula (I) or the salt thereof into the water in the enclosure whereby infestation of the fish in the enclosure is inhibited compared to infestation in an enclosure which does not have a coating containing the compound of formula (I).

Preferably, the coating is capable of releasing the compound of formula (I) or the salt thereof into the water in the enclosure, e.g. in an amount effective to reduce or prevent parasitic infestation of the fish in the enclosure. The enclosure for example may be a net or a cage for fish farming.

In formula (I), Ai is O, S, CReH or NRe; and A₂ is N or CR₇.

In some embodiments, Ai is C ^tl or N ^; and A₂ is N or CR₇, e.g. Ai is C ^tl or N ^; and A₂ is N or CH, in particular A₂ is N.

In some other embodiments, Ai is O, S, C ^tl or N ^; and A₂ is N; e.g. Ai is O, S or N ^; and A₂ is N, or Ai is O or N ^; and A₂ is N. In still other embodiments, Ai is C ^tl or N ^; and A₂ is CR₇.

In some particular embodiments, Ai is NR6 and A₂ is N, and the compound of formula (I) may be represented by formula (la)

wherein R_{l s} R₂, R₃, R4, R₅ and 5 are as defined herein. In some other particular embodiments, Ai is O and A₂ is N, and the compound of formula (I) may be represented by formula (lb)

wherein R_{l s} R₂, R3, R4, and R₅ are as defined herein. In some embodiments of a compound of formula (I),

Ri, R₂, R₃, Re and R₇ are independently selected from H, OH, NH₂, R_aC(O)-, C1-C4 alkyl optionally substituted by R_b, and a moiety of formula (II)

at least one and at most three of Ri, R₂, R3, R₀ and R₇ being a moiety of formula (II);

R4 and R₅ are independently selected from H and C1-C3 alkyl; or R4 and R₅ together form a covalent bond;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and R_c and R_d, or R_d and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring; n is 0 or 1 ; when n is 1 , one of Z and W is selected from CR_hRi, O, and NR¾; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X; when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH; R_j is selected from H and C1-C4 alkyl; and X is selected from O and CH₂.

It should be realized that when more than one of Ri, R₂, R₃, Re and R₇ is a moiety of formula (II), then each such moiety is independently selected. In some embodiments, one or two of Ri, R₂, R₃, Re and R₇ is a moiety of formula (II). In some embodiments, only one of Ri, R₂, R₃, Re and R₇ is a moiety of formula (II).

In some embodiments, R6 is a moiety of formula (II). In some of these embodiments, any one or two, preferably one, of Ri, R₂, R₃ and R₇, e.g. one of Ri, R₂, and R₃, e.g. R₂, is also a moiety of formula (II). In some other embodiments, only R^ is a moiety of formula (II).

In some embodiments, Ri is a moiety of formula (II). In some of these embodiments, any one or two, preferably one, of R₂, R₃, Re and R₇, e.g. one of R₂ and R₃, is also a moiety of formula (II). In some other embodiments, only Ri is a moiety of formula (II).

In some embodiments, R₂ is a moiety of formula (II). In some of these embodiments, any one or two, preferably one, of Ri, R₃, Re and R₇, e.g. one of Ri and Re, is also a moiety of formula (II). In some other embodiments, only R₂ is a moiety of formula (II).

In some embodiments, R₃ is a moiety of formula (II). In some of these embodiments, any one or two, preferably one, of Ri, R₂, Re and R₇, e.g. one of Ri and R₇, is also a moiety of formula (II). In some other embodiments, only R₃ is a moiety of formula (II). In some embodiments, Ri, R₂, R₃, 5 (if present), and R₇ (if present) are independently selected from H, C1-C4 alkyl, and a moiety of formula (II) as defined herein above, e.g. from H, C1-C3 alkyl and a moiety of formula (II) as defined herein above, or from H, and a moiety of formula (II) as defined herein above.

In some embodiments, Ai is N ₅ or CHR₅, preferably NR₅, and A₂ is N, and Ri, R₂, R₃, and Re are independently selected from H, C1-C4 alkyl, and a moiety of formula (II) as defined herein above, e.g. from H, C1-C3 alkyl and a moiety of formula (II) as defined herein above, e.g. from H, methyl and a moiety of formula (II) as defined herein above, or from H and a moiety of formula (II) as defined herein above.

In some embodiments, Ai is CHR6 or NR₅, in particular Ai is NR¾; A₂ is N, Ri is selected from H, OH, and NH₂; R₂ is selected from H and a moiety of formula (II); R₃ is H or C1-C4 alkyl, e.g. H; and 5 is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.

In some embodiments, Ai is CHR6 or NR₅, in particular Ai is NR¾; A₂ is N, Ri is selected from H, OH, and NH₂; R₂ is a moiety of formula (II); R₃ is selected from H and C1-C4 alkyl,

In some further embodiments, Ai is CHR6 or NR₅, in particular Ai is NR¾; A₂ is N, Ri is H; R₂ is selected from H and a moiety of formula (II); R₃ is H; and R6 is selected from H and benzyl.

In some embodiments, Ai is CHR6 or NR₅, in particular Ai is NR₅, A₂ is N, R₂ is a moiety of formula (II), and Ri, R₃ and R₆ are H.

In some embodiments, Ai is CHR6 or NR₅, in particular Ai is NR¾; A₂ is N, Ri is selected from H, OH, and NH₂; one of R₂ and R₃ is selected from H and a moiety of formula (II); and the other one is selected from H and C1-C4 alkyl, e.g. H; and R6 is H. In some embodiments, Ai is CHR₆ or NR₆, in particular Ai is NR¾; A₂ is N, one of R₂ and R₃ is a moiety of formula (II); and the other one is H; and Ri and R6 are H.

In a compound of formula (I), R4 and R₅ are independently selected from H and C1-C3 alkyl; or when R₂ is a moiety of formula (II), then R4 and R_g together may form a methylene or ethylene bond; and when R₃ is a moiety of formula (II), then R5 and R_g together may form a methylene or ethylene bond; or R4 and R₅ together form a covalent bond.

In some embodiments, R4 and R₅ are independently selected from H and C1-C3 alkyl; or R4 and R₅ together form a covalent bond. In some embodiments, R4 and R₅ are independently selected from H and C1-C3 alkyl, e.g. from H and methyl. In some embodiments, both R4 and R₅ are H. In some other embodiments, R4 and R₅ are independently selected from H and methyl; or R4 and R₅ together form a covalent bond. In some other embodiments, both R4 and R5 are H; or R4 and R₅ together form a covalent bond. In some embodiments, R4 and R₅ form a covalent bond.

In some embodiments, when R₂ is a moiety of formula (II), then R4 and R_g together form a methylene or ethylene bond, i.e. the compound of formula (I) may be represented by formula

wherein R_{l s} R₃, R₅, R_c, Rj, R_e, R_f, A_{l s} A₂, W, Z, and n, are as defined herein, and r is 1 or 2, e.g. r is 1.

In some embodiments of a compound of formula (Ic), A₂ is N; e.g. A₂ is N and AI is NR₅, O or S; e.g. A₂ is N and Ai is O or S; or A₂ is N and Ai is O or NR6; in particular; A₂ is N and

In some other embodiments, when R₃ is a moiety of formula (II), then R5 and R_g together form a methylene or ethylene bond, e.g. R₅ and R_g together form a methylene bond. In some embodiments, Ai is CHR^ or NR₆, in particular Ai is NR^; A₂ is N, Ri is selected from H, OH, and NH₂; R₂ is selected from H and a moiety of formula (II); R₃ is H or C1-C4 alkyl, e.g. H; R₄ and R₅ together form a covalent bond, and R^ is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.

For example, in some embodiments, Ai is CHR^ or NR₆, in particular Ai is NR^; A₂ is N, Ri is H; R₂ is selected from H and a moiety of formula (II); R₃ is H or C1-C4 alkyl, e.g. H; R₄ and R₅ together form a bond, and R^ is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.

In some other embodiments, Ai is CHR^ or NR₆, in particular Ai is NR^; A₂ is N, R₂ is a moiety of formula (II); R₄ and R₅ together form a bond, and Ri, R₃ and R^ are H.

In the moiety RaC(O)-, Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH, e.g. from C2-C3 alkenyl and C2-C3 alkenyl substituted by COOH. In some embodiments, Ra is selected from:

The moiety R_b is selected from OH, and C1-C4 alkyl-C(0)0-, e.g. from OH and C1-C3 alkyl- C(0)0-. In some embodiments, Rb is selected from OH and C₂H₅C(0)0-. In still other embodiments, Rb is OH.

In the moiety of formula (II)

Rc, Rd, Re, R_f, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and Rc and Rd, or Rd and R_e, or Re and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring. In some embodiments, R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and C1-C4 alkyl substituted by OH.

In some embodiments, any R_c, R_d, R^, R_f, and R_g, selected from H, halogen, OH, C1-C4 alkyl, and C1-C4 alkyl substituted by OH, more particularly is selected from H, halogen, OH, Cl- C3 alkyl and C1-C3 alkyl substituted by OH, e.g. from H, halogen, OH, CH₃ and CH₂OH, or from H,

In some embodiments, R_c, R_d, R_e, R_f, and R_g are selected from H, halogen, and C1-C4 alkyl, more particularly from H, halogen, and C1-C3 alkyl, or from H, halogen and CH₃.

In some embodiments, R_c, R_d, R_e, R_f, and R_g are selected from H, halogen, and C1-C4 alkyl, more particularly from H, halogen, and C1-C3 alkyl, or from H, halogen and CH₃. In some embodiments, R_c, R_d, R_e, R_f, and R_g are selected from H, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH, more particularly from H, OH, C1-C3 alkyl and C1-C3 alkyl substituted by OH, e.g. from H, OH, CH₃ and CH₂OH.

In some embodiments, R_c, R_d, R_e, R_f, and R_g are selected from H and C1-C4 alkyl more particularly from H, and C1-C3 alkyl, e.g. from H and CH₃.

When any one of R_c, R_d, R_e, R_f, and R_g, is halogen, it e.g. may be F, CI and Br, in particular CI. When any one of R_c, R_d, R_e, R_f, and R_g is selected from C1-C4 alkyl, such alkyl more particularly may be selected from C1-C3 alkyl, or from C1-C2 alkyl, e.g. CH₃.

In some particular embodiments, R_c, R_d, R_e, R_f, and R_g are all H. In some other particular embodiments, R_e and R_f are both H, and R_c, R_d, and R_g are as defined herein above. In some embodiments, at least one of R_c, R_d, R_e, R_f, and R_g is different from H; e.g. R_c is as defined herein above, but is not H.

In some embodiments, at least two of R_c, R_d, R_e, R_f, and R_g are different from H; e.g. R_c and R_d are as defined herein above, but are not H; or R_c and R_g are as defined herein above, but are not H.

In some embodiments, R_c and R_d are as defined herein above, but are not H, and R_e, R_f, and R_g are H.

In some other embodiments, R_c and R_g are as defined herein above, but are not H, and R_d, R_e, and R_f are H.

In some embodiments, R_c and R_d, or R_d and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring.

In some embodiments, when R_c and R_d, or R_d and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, such ring is a benzene ring or a 5- or 6-membered heteroaromatic ring. In some embodiments, the ring is a 6-membered ring, e.g. a benzene ring. In some embodiments, when any pair of adjacent two moieties selected from Rc, Rd, Re, Rf, and R_g form a ring, the others of R_c, Rd, Re, Rf, and R_g are independently selected from H, halogen, OH, C1-C4 alkyl, and C1-C4 alkyl substituted by OH, e.g. from H, halogen, and C1-C4 alkyl; or from H, halogen and C1-C3 alkyl, or from H, halogen and CH3, e.g. all are H.

In some embodiments, R_c and R_d, together with the carbon atoms to which they are attached, form a ring as defined herein above. In some particular embodiments, R_c and R_d form a ring as defined herein above, and R_e, R_f, and R_g are H. In some embodiments, R_c and R_d are independently selected from halogen, OH, C1-C4 alkyl, and C1-C4 alkyl substituted by OH, or, together with the carbon atoms to which they are attached, form a ring as defined herein above; and R_e, R_f and R_g are H; or R_c and R_g are independently selected from halogen, OH, C1-C4 alkyl, and C1-C4 alkyl substituted by OH,

In some embodiments, R_c and Ra are independently selected from halogen, and C1-C4 alkyl, or, together with the carbon atoms to which they are attached, form a ring as defined herein above; and R_e, R_f and R_g are H; or R_c and R_g are independently selected from halogen, and C1-C4 alkyl, and R_d, R_e and R_f are H.

In some embodiments, the phenyl ring carrying the moieties R_c-R_g is selected from 2,3- dimethylphenyl, 2,3-dichlorophenyl, 2,5-dimethylphenyl, and 2,5-dichlorophenyl, e.g. from 2,3-dimethylphenyl and 2,3-dichlorophenyl; or from 2,3-dimethylphenyl and 2,5- dimethylphenyl, or from 2,3-dimethylphenyl and 2,5-dichlorophenyl. In some embodiments, the phenyl ring carrying the moieties R_c-R_g is 2,3-dimethylphenyl. In the moiety of formula (II), n is 1 or 0. When n is 1 , the moiety of formula (II) may be represented by formula (Ila)

wherein one of Z and W selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NRj and C=X.

In some embodiments of a moiety of formula (Ila), one of Z and W is selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; e.g. one of Z and W is O or NR_j, and the other one is selected from CR_hRi, and C=X.

In some other embodiments of a moiety of formula (Ila), one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X, e.g. from CR_hRi, O, and C=X; or from CRhRi and O; or from CR_hRi and C=X.

In some embodiments of a moiety of formula (Ila), one of Z and W is O; and the other one is selected from CR_hRi and C=X, e.g. one of Z and W is O; and the other one is CR_hRi. In some embodiments of a moiety of formula (Ila), Z is selected from CR_hRi, O, and NR_j; and W is selected from CR_hRi, and C=X; e.g. Z is CR_hRi, and W is selected from CR_hRi, O, NR_j and C=X.

In some other embodiments of a moiety of formula (Ila), Z is selected from CR_hRi, O, and NR_j, and W is selected from CR_hRi, and C=X; e.g. Z is O or NR_j, and W is selected from CRhRi, and C=X. In some other embodiments of a moiety of formula (Ila), Z is CR_hRi; and W is CR_hRi, O, NR_j or C=X, e.g. W is CR_hRi, O, or C=X; or W is CR_hRi or O; or W is CR_hRi or C=X.

In some embodiments of a moiety of formula (Ila), Z is O; and W is selected from CR_hRi and C=X, e.g. Z is O; and W is CR_hRi.

In some other embodiments of a moiety of formula (Ila), W is CR_hRi, O, or NR_j; and Z is CRhRi, or C=X; e.g. W is CR_hRi, and Z is selected from CR_hRi, O, NRj and C=X.

In some other embodiments of a moiety of formula (Ila), W is selected from CR_hRi, O, and NR_j, and Z is selected from CR_hRi, and C=X; e.g. W is O or NR_j, and Z is selected from CRhRi, and C=X.

In some other embodiments of a moiety of formula (Ila), W is CR_hRi; and Z is selected from CR_hRi, O, NR_j and C=X, e.g. from CR_hRi, O, and C=X; or from CR_hRi and O; or from CR_hRi and C=X.

In some embodiments of a moiety of formula (Ila), W is O; and Z is selected from CR_hRi and C=X, e.g. W is O; and Z is CR_hRi.

In some other embodiments of the moiety of formula (II), n is 0, i.e. said moiety may be represented by formula (lib)

wherein W is selected from CR_hRi, O, NR_j and C=X.

In some embodiments of a moiety of formula (lib), W is selected from CR_hRi, O, and NR_j, e.g. from CR_hRi and O; or from CR_hRi and NR_j. In some other embodiments of a moiety of formula (lib), W is selected from CR_hRi, O, and C=X, e.g. from CR_hRi and C=X; e.g. W is CRhRi.

In some other embodiments of a moiety of formula (lib), W is CR_hRi, NR_j, or C=X.

In some embodiments of a moiety of formula (lib), W is selected from O, NR_j and C=X, e.g. from O and NR_j; or from O and C=X. In some other embodiments of a moiety of formula (lib), W is selected from NR_j and C=X, e.g. W is C=X. In some embodiments of a moiety of formula (lib), W is O. In some other embodiments of a moiety of formula (lib), W is NR_j.

The moieties R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH, e.g. R_h and Ri are independently selected from H, OH, and C1-C3 alkyl optionally substituted by OH, or from H, OH, CH₃ and CH₂OH. In some embodiments, R_h and Ri are independently selected from H and C1-C4 alkyl, e.g. from H and C1-C3 alkyl, such as from H and C¾. In some embodiments, R_h and Ri are both H. In still other embodiments, R_h is selected from H and C1-C4 alkyl, and Ri is selected from H, OH, and C1-C4 alkyl optionally substituted by OH, e.g. from H, OH, and C1-C3 alkyl optionally substituted by OH, or from H, OH, CH₃ and CH₂OH, or from OH and CH₂OH.

In other embodiments, R_h is selected from OH, and C1-C4 alkyl optionally substituted by OH, e.g. from OH and C1-C4 alkyl substituted by OH, e.g. from OH and C1-C3 alkyl substituted by OH such as from OH and CH₂OH; e.g. R_h is OH; and Ri is selected from H and C1-C4 alkyl. In still other embodiments, R_h is as defined herein above, and Ri is H; e.g. R_h is C1-C4 alkyl, or R is C1-C3 alkyl; or R is CH₃; and Ri is H.

The moiety R_j is selected from H and C1-C4 alkyl. In some embodiments, R_j is selected from H and C1-C3 alkyl, e.g. R_j is selected from H and CH₃.

In some embodiments, R_j is H. In still other embodiments, R_j is C1-C4 alkyl, e.g. R_j is C1-C3 alkyl; or R_j is CH₃. The moiety X is selected from O and CH₂. In some embodiments, X is O. In other embodiments, X is CH₂.

In some particular embodiments, when either R₂ is a moiety of formula (II) and R4 and R_g together form a methylene or ethylene bond; or R₃ is a moiety of formula (II) and R₅ and R_g together form a methylene or ethylene bond; n is 1 and W and Z are both CR_hRi; or n is 0 and W is CR_hRi. In some other particular embodiments, when either R₂ is a moiety of formula (II) and R4 and R_g together form a methylene or ethylene bond; or R₃ is a moiety of formula (II) and R₅ and R_g together form a methylene or ethylene bond, then n is 1 and both W and Z are CH₂; or n is 0 and W is CH₂.

In some embodiments, the ring formed by W, Z, R_g and either R4 or R5 is a 6-membered ring, e.g. a 6-membered carbocyclic ring. In some other embodiments, the ring formed by W, Z, R_g and either R4 or R5 is a 5-membered ring, e.g. a 5-membered carbocyclic ring.

In some further embodiment, the moiety formed by (Z)_n and W is selected from:

For example, the moiety formed by (Z)_n and W may be selected from:

or from

In some particular embodiments of the compound of formula (I), Ai is NR¾; and A₂ is N; i.e. the compound is a compound of formula (la) as defined herein above.

In some particular embodiments of the compound of formula (la),

Ri , R₂, and ¾ are independently selected from H, OH, NH₂, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II) as defined herein;

at least one and at most three of Ri , R₂, and R6 being a moiety of formula (II);

R₃ is H;

R₄ and R₅ are independently selected from H and C1-C3 alkyl; or when R₂ is a moiety of formula (II), then R₄ and R_g together may form a methylene or ethylene bond; or R₄ and R₅ together form a covalent bond;

Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

Rc, Rd, Re, Rf, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and Rc and Rd, or Rj and R_e, or Re and Rf, or Rf and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring; n is 1 or 0;

when n is 1, one of Z and W is selected from CRhRi, O, and NR¾; and the other one is selected from CRhRi, and C=X; or one of Z and W is CRhRi; and the other one is selected from CRhRi, O, NR_j and C=X;

when n is 0, W is selected from CRhRi, O, NR_j and C=X;

Rh and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some of the above embodiments, at most two or R_{l s} R₂, and R6 are a moiety of formula (II). In some other of the above embodiments, one of Ri , R₂, and R6 is a moiety of formula (II).

In some further particular embodiments of the compound of formula (la),

Ri is selected from H, OH, and NH₂;

R₂ is selected from H and a moiety of formula (II);

R₃ is H;

R4 and R₅ are independently selected from H and C1-C3 alkyl; or when R₂ is a moiety of formula (II), then R4 and R_g together may form a methylene or ethylene bond; or R4 and R₅ together form a covalent bond;

5 is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl;

Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

n is 1 or 0;

when n is 1, one of Z and W is selected from CRhRi, O, and NR_j; and the other one is selected from CRhRi, and C=X; or one of Z and W is CRhRi; and the other one is selected from CRhRi, O, NR_j and C=X;

when n is 0, W is selected from CRhRi, O, NR_j and C=X;

Rh and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH; R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la),

Ri is selected from H, OH, and NH₂;

R₂ is a moiety of formula (II);

R₃ is H;

5 is selected from H, R_aC(O)-, C1-C4 alkyl optionally substituted by R_b, and benzyl;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and R_c and R_d, or Rj and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring;

when n is 1, one of Z and W is selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X;

when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂. In some further particular embodiments of the compound of formula (la),

Ri is selected from H, OH, and NH₂;

R₂ is a moiety of formula (II);

R₃ is H;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH; R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

n is 1 or 0;

when n is 1, one of Z and W is selected from CR_hRi, O, and NR¾; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X;

when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

R_j is selected from H and C1-C4 alkyl; and

Ri is H;

R₂ is a moiety of formula (II);

R₃ is H;

R4 and R₅ together form a covalent bond;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

R_c, R_d, R_e, R_f, and R_g, are independently selected from H, OH, C1-C4 alkyl and optionally substituted by OH;

n is 0;

W is selected from CR_hRi and C=X;

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la),

Ri is H;

R₂ is a moiety of formula (II); R₃ is H;

R₄ and R₅ together form a covalent bond;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C 1 -C4 alkyl-C(0)0-;

Rc and Rj are independently selected from H, C1-C4 alkyl, and C1-C4 alkyl substituted by OH; and

Re, R_f, and R_g, are independently selected from H and OH;

n is 0;

W is selected from CR_hRi and C=X;

Ri is H;

R₂ is a moiety of formula (II);

R₃ is H;

R₄ and R₅ together form a covalent bond;

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

R_c and Rj are independently selected from C1-C4 alkyl;

n is 0;

W is selected from CR_hRi and C=X;

R_h and Ri are independently selected from H and C1-C4 alkyl; and

X is CH₂. In some further particular embodiments of the compound of formula (la),

Ri is selected from H, OH, and NH₂;

R₂ is a moiety of formula (II);

R₃ is H; R4 and R₅ are independently selected from H and C1-C3 alkyl; or R4 and R₅ together form a covalent bond;

Re is H;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

Rc, Rd, Re, Rf, and R_g, are independently selected from H, halogen, and C1-C4 alkyl;

n is 0;

W is selected from CR_hRi, NR_j, and C=X;

Rh and Ri are independently selected from H, and C1-C4 alkyl;

R_j is selected from H, and C1-C4 alkyl; and

X is CH₂.

In some further particular embodiments of the compound of formula (la),

Ri is selected from H, OH, and NH₂;

R₂ is a moiety of formula (II);

R4 and R₅ are both H;

Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

n is 1 or 0;

when n is 0, W is selected from CRhRi, O, NR_j and C=X;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la), Ri is selected from H, OH, and NH₂;

R₂ is H;

R₃ is H;

5 is moiety of formula (II);

n is 1 or 0;

when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

R_j is selected from H and C1-C4 alkyl; and

Ri is selected from H, OH, and NH₂;

R₂ is H;

R₃ is H;

R4 and R₅ together form a covalent bond;

5 is moiety of formula (II);

n is 1 or 0;

when n is 1 , one of Z and W is selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X;

when n is 0, W is selected from CR_hRi, O, NR_j and C=X; R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la),

Ri, R₂, R₃ are H;

R₄ and R₅ form together a covalent bond;

5 is moiety of formula (II);

R_c, R_d, R_e, R_f, and R_g, are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

n is 0;

W is selected from CR_hRi, and C=X;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la),

Ri, R₂, R₃ are H;

R₄ and R₅ form together a covalent bond;

5 is moiety of formula (II);

R_c and Rj are independently selected from H, C1-C4 alkyl, and C1-C4 alkyl optionally substituted by OH;

R_e, R_f, and R_g are independently selected from H and OH;

n is 0;

W is selected from CR_hRi, and C=X;

R_j is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂.

In some further particular embodiments of the compound of formula (la), Ri , R₂, and ¾ are independently selected from H, OH, NH₂, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II) as defined herein;

R₃ is H;

R4 and R₅ are both H;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

n is 1 or 0;

when n is 0, W is selected from CRhRi, O, NRj and C=X;

Rj is selected from H and C1-C4 alkyl; and

X is selected from O and CH₂. In some of the above particular embodiments, Rh and Ri are independently selected from H, and C1-C4 alkyl, e.g. Rh and Ri are both H or CH₃; or both Rh and Ri are H.

Some examples of compounds for use according to the invention are shown in Table 1. Table 1

For controlled release purposes, a combination of the compounds of the invention and a polymer complex may be utilized, as additives to self-polishing paints (e.g. US2006223906 Method and use of acidified modified polymers to bind biocides in paints).

Controlled release may also involve nanoparticles of various types, including

copper(II)- and zinc(II)oxide formulated into nanoparticle sizes (US 20060201379). Due to the large specific surface area (ratio between surface area and particle volume), the nanoparticles contribute to adsorb the antifouling agent, e.g. the compounds of the invention. The antifouling agent, e.g. the compounds of the invention, bound to nanosized metal oxide is a compound that leaks out of the paint into water in a controlled fashion. The antifouling agent bound to nanosized metal oxide thus has excellent dispersion stability because of its large size, compared to the antifouling agent particle alone. In some embodiments, the compounds of the invention is used together with one or more other active ingredients, e.g. one or more anti-bio fouling agents, such as algicides, herbicides, fungicides and/or one or more therapeutically active agents for veterinary use, e.g. for use in the treatment of fish, such as vaccines, antibiotics, anti-viral agents, anti-parasitic agents, e.g. one or more further compounds active against parasitic crustaceans, etc.

Referring to biofouling and anti-fouling effects, the compounds of the invention demonstrate effects of anti-fouling on barnacle cyprids but no effect on algal growth. There are several methods to prevent algal growth, among them the use of copper and other metals in fairly high concentrations or the use of certain algicides. The compounds of the invention may therefore be utilized in combination with algicides such as zinc- and copper pyrithion, fungicides like tolyfluanid and dichlofluanid, herbicides such as DIURON™ and

IRGAROL™, or more general biocides such as SEANINE™ or ECONEA™ (2-(p- chlorophenyl)-3-cyano-4-bromo-5-trifluoromethyl) pyrrole by Janssen Pharmaceutical, Titusville, NJ, USA. Specific preferred algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051™ (2-methylthio- 4-tert- butylamino-6-cyclopropylamino-s-triazine), zinc pyrithione (Zinc, bis(l- hydroxy-2(lH)- pyridinethionato-0,S)-, (T-4)-), copper pyrithione (Copper, bis(l- hydroxy-2(lH)- pyridinethionato-0,S)-, (T-4)-), diclofiuanid (NT -dimethyl-N- phenylsulphamide), ZINEB™ (zinc ethylene bisdithiocarbamate), ZINRAM™ (Zinc bis(dimethylthiocarbamates)), maneb (manganese ethylene bisdithiocarbamate), quaternary ammonium compounds, SEANINE™ (4,5-dichloro-2-n-octyl-3(2H)-isothiazolone), and ECONEA™ (2-(p-chlorophenyl)- 3-cyano- 4-bromo-5-trifluoromethyl).

In some embodiments, the compounds of the invention is used in combination with one or more other compound(s) known to be active against parasitic crustaceans (e.g. sea lice), e.g. one or more compounds selected from hydrogen peroxide, formaldehyde, trichlorfon, malathion dichlorvos, azamethiphos, ivermectin, emamectin benzoate, moxidectin, teflubenzuron diflubenzuron, hexaflumuron, lufenuron, fluazuron, cypermethrin c/s-40 : trans-60, deltamethrin, high c/ s cypermethrin c/s-80: trans- 20, imidacloprid, nitenpyram, thiamethoxam, thiacloprid, clothianidin, acetamiprid spinosad, epofenonane, triprene, methoprene, hydroprene, kinoprene, phenoxycarb. In some embodiments, the compound of the invention is combined with a compound selected from an organophosphate, a pyrethroid such as cypermethrin or deltamethrin, a macrocyclic lactone such as emamectin benzoate, hydrogen peroxide or a benzoylurea, such as diflubenzuron, lufenuron or hexaflumuron. In one aspect, the present invention generally relates to the inhibition of marine bio fouling of surfaces in marine environments, specifically to the use of the compounds of the invention as an agent for prevention of marine bio fouling of solid surfaces, more specifically cages submersed in water utilized for fish farming. More specifically, the invention concerns the use of the compounds of the invention as an antifouling component of coatings or paints for cages submersed in water utilized for fish farming, for the dual and/or combined purpose of reducing and preventing bio fouling of the cages submersed in water utilized for fish farming in order 1) to improve the flow of water through the nets of the cages and also 2) to prevent and reduce the fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages.

In a related aspect of the invention, the compounds of the invention is added to a marine paint for application to the nets or cages containing the food-fish in fish farms, specifically to reduce the settlement of barnacles to the cages or nest, thus reducing the bio fouling of these cages or nets and improving the flow of water and water circulation through the nets or cages. In such a marine paint, the compounds of the invention will be present at 0.01-2%, preferably 0.1-0.3%. In another related aspect of the invention, for improving the flow of water and water circulation through the nets or cages, such a marine paint may comprise the use of nanoparticles, including copper(II)- and zinc(II)oxide formulated into nanoparticle sizes, for controlled release purposes. Also, in a related aspect of the invention, for improving the flow of water and water circulation through the nets or cages, a combination of the compounds of the invention and a polymer complex may be utilized, as additives to self-polishing paints. In another aspect of the invention, for improving the flow of water and water circulation through the nets or cages, the compounds of the invention will be used in combination with algicides such as zinc- and copper pyrithion, fungicides like tolyfluanid and diclofluanid, herbicides such as DIURON™ and IRGAROL™, or more general biocides such as SEANINE™ or ECONEA™ (2-(p- chlorophenyl)-3-cyano-4-bromo-5-trifluoromethyl) by Janssen

Pharmaceutical, Titusville, NJ, USA. Specific preferred algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051™ (2- methylthio- 4-tert-butylamino-6-cyclopropylamino-s-triazine), zinc pyrithione (Zinc, bis(l- hydroxy-2(lH)-pyridinethionato-0,S)-, (T-4)-), copper pyrithione (Copper, bis(l- hydroxy- 2(lH)-pyridinethionato-0,S)-, (T-4)-), diclofluanid (N' -dimethyl-N- phenylsulphamide), ZINEB™ (zinc ethylene bisdithiocarbamate), ZINRAM™ (Zinc bis(dimethylthiocarbamates)), maneb (manganese ethylene bisdithiocarbamate), quaternary ammonium compounds, SEANINE™ (4,5-dichloro-2-n-octyl-3(2H)-isothiazolone), and ECONEA™ (2-(p-chlorophenyl)- 3-cyano-4-bromo-5-trifluoromethyl). Fish densities inside the cages or nets for fish farming are kept high, and the fish are therefore more prone to various types of parasites, infections and disease. In one aspect of the invention the compounds of the invention is specifically used to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to

Lepeophtheirus (L. salmonis) inside the cages or nets of fish farms.

In a related aspect of the invention, the compounds of the invention is added to a marine paint for application to the nets or cages containing the food-fish in fish farms, where the compounds of the invention leaks out into the water to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to

Lepeophtheirus (L. salmonis), inside the cages or nets of fish farms. In another related aspect of the invention, where the compounds of the invention leaks out into the water to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to Lepeophtheirus (L. salmonis), such a marine paint may comprise the use of nanoparticles, including copper(II)- and zinc(II)oxide formulated into nanoparticle sizes, for controlled release purposes. Also, in a related aspect of the invention, where the compounds of the invention leaks out into the water to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to Lepeophtheirus (L.

salmonis), a combination of the compounds of the invention and a polymer complex may be utilized, as additives to self-polishing paints. In another aspect of the invention, where the compounds of the invention leaks out into the water to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to

Lepeophtheirus (L. salmonis), the compounds of the invention will be used in combination with algicides such as zinc- and copper pyrithion, fungicides like tolyfiuanid and diclofiuanid, herbicides such as DIURON™ and IRGAROL™, or more general biocides such as

SEANINE™ or ECONEA™ (2-(p- chlorophenyl)-3-cyano-4-bromo-5-trifluoromethyl) by

Janssen Pharmaceutical, Titusville, NJ, USA. Specific preferred algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051™ (2- methylthio- 4-tert-butylamino-6-cyclopropylamino-s-triazine), zinc pyrithione (Zinc, bis(l- hydroxy-2(lH)-pyridinethionato-0,S)-, (T-4)-), copper pyrithione (Copper, bis(l- hydroxy- 2(lH)-pyridinethionato-0,S)-, (T-4)-), diclofluanid (N' -dimethyl-N- phenylsulphamide), ZINEB™ (zinc ethylene bisdithiocarbamate), ZINRAM™ (Zinc

bis(dimethylthiocarbamates)), maneb (manganese ethylene bisdithiocarbamate), quaternary ammonium compounds, SEANINE™ (4,5-dichloro-2-n-octyl-3(2H)-isothiazolone), and ECONEA™ (2-(p-chlorophenyl)- 3-cyano-4-bromo-5-trifluoromethyl).

In such a marine paint, the compounds of the invention will be present at 0.01-2%, preferably 0.1-0.3%, thus creating an effective concentration in the water inside the cages or nets containing the food- fish to reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to Lepeophtheirus (L. salmonis).

In another aspect of the invention, the compounds of the invention is added to a marine paint for application to the nets or cages containing the food-fish in fish farms, specifically with the dual and/or combined purposes to :

1) reduce the settlement of barnacles to the cages or nest, thus reducing the bio fouling of these cages or nets and improving the flow of water and water circulation through the nets or cages and/or

2) reduce, prevent and treat parasitic infestations of parasitic crustaceans, such as sea lice, exemplified but not limited to Lepeophtheirus (L. salmonis) inside the cages or nets of fish farms.

In some embodiments, the fish are present in a container, such as a cage or net, said container having openings allowing water to enter and exit the container and the compounds of the invention is brought into contact with the surface of the container so as to allow for a reduction of bio fouling of the container surface at least in the vicinity of the openings. For example, the compounds of the invention may be present in the water inside the container or in a coating applied to the container at least in the vicinity of the openings. In some embodiments, a method is provided for improving or maintaining a flow of water through openings of a container for fish, such as a cage, net or similar confinement, or an aquarium, or tank, by bringing at least part of the surface (e.g. the inside walls) of the container into contact with the compounds of the invention, e.g. dissolved in the water inside the container or applied in a coating on at least part of the surface of the container, preferably close to the openings for water flowing into and out of the container.

In a related aspect of the invention, an effective amount of the compounds of the invention is delivered to the cages via delivery systems, exemplified but not limited to solutions, emulsions, suspensions, powders, tablets and the like, or formulated and encapsulated in beads, capsules, gels and the like, to reduce and prevent fish parasitic crustaceans, such as sea lice, on the fish that are farmed inside the cages. Such delivery system will be able to continuously distribute an effective amount of the compounds of the invention at a controlled rate inside the cages or nets. In a related aspect of the invention such solutions, emulsions, suspensions, powders, tablets of the compounds of the invention and the like, or the compounds of the invention formulated and encapsulated in beads, capsules, gels and the like are added to the cages or nets via the inlet or tube or similar that is used for providing the food supply to the fish kept in the cages or nets. In another aspect of the invention, the compounds of the invention formulated and encapsulated in beads, capsules, gels and the like are added to the cages or nets via water-permeable containers or bags and the like that are attached to lines that span the height of the cage or net and are distributed evenly over the volume of the cage or net. Such water-permeable containers or bags and the like that are attached to lines, containing the compounds of the invention formulated and encapsulated in beads, capsules, gels and the like, which are easily exchanged or replaced when the concentration of the compounds of the invention is close to a minimum concentration or at timed intervals. Figure 1 provides a schematic illustration of one embodiment of a delivery system according to the invention. The concentration of the compounds of the invention inside an enclosure for fish, e.g. a cage or net, should preferably be between 1 nanogram/liter (0.005 nM) to 100 micro gram liter (500 nM), e.g. from 20 nanogram/liter (0.1 nM) to 80 microgram/liter (400 nM), or from 100 nanogram/liter (0.5 nM) to 40 microgram/liter (200 nM), and more preferably between 200 nanogram/liter (1 nM) to 20 microgram/liter (100 nM).

In some embodiments, the compounds of the invention or a salt thereof is released into water, e.g. from a prolonged release formulation in a container or bag, in vicinity to a source of light, e.g. an underwater solar lamp or an underwater LED lamp. For example, in some embodiments any parts of the lines connecting to the floating part or the floating part itself connected to the sinker or weight below the surface water, can be associated with a light source in order to attract parasitic crustaceans that are photo tactic, e.g. salmon lice. By locating the compounds of the invention dosing apparatus in vicinity to the light source, the photo tactic parasite, attracted by and striving towards the light source, will come into vicinity of the dosing apparatus, where the concentration of the compounds of the invention in the water may be expected to be the highest, which will increase the anti-parasitic efficacy.

The compounds of the invention or a salt thereof are suitably used in the control of various fish-parasitic crustaceans. Using generally accepted taxonomic classification, the parasitic organisms more particularly belong to the subphylum "Crustacea", the class "Maxillopoda", the subclass "Copepoda" and the order "Siphonostomatoida", and to various families within this order, e.g. to the following families: Caligidae, Cecropidae, Dichelesthiidae,

Lernaeopodidae, Pandaridae, Pennellidae, Sphyriidae, Lernaeidae, Bomolochidae,

Chondracanthidae, Philichthyidae, and Ergasilidae. Thus, the fish-parasitic crustaceans may be selected from the family Caligidae with representative genus Dissonus, Caligus (i.e. C. curtus, C. elongatus, C. clemensi, C. rogercresseyii), and Lepeophtheirus (i.e. L. salmonis);

Families Cecropidae, Dichelesthiidae, Lernaeopodidae with representative genus Salmincola;

Families Pandaridae, Pennellidae with representative genus Lernaeocera and Pennella; and Family Sphyriidae; Family Lernaeidae with representative genus Lernaea; Families

Bomolochidae, Chondracanthidae, Ergasilidae and Philichthyidae.

In some embodiments, the fish-parasitic crustaceans are selected from the family Caligidae. In some embodiments, the fish-parasitic crustaceans are selected from the family Caligidae and from the genuses Caligus and Lepeophtheirus. In some embodiments, the fish-parasitic crustaceans are selected from the family Caligidae and from the genus Caligus. In some other embodiments the fish-parasitic crustaceans are selected from the family Caligidae and from the genus Lepeophtheirus. For example, the fish-parasitic crustaceans may be selected from C. curtus, C. elongatus, C. clemensi, C. rogercresseyii, and L. salmonis.

It should be realized that any fish susceptible to infestation by a fish-parasitic crustacean as mentioned herein above may be treated according to the invention. Such fish include food fish, breeding fish, and aquarium, pond, river, and reservoir fish of all ages occurring in freshwater, sea water and brackish water. Examples of fish that may be treated according to the invention include, but are not limited to, bass, bream, carp, catfish, char, chub, cichlid, cod, eel, flounder, gourami, grayling, grouper, halibut, mullet, plaice, pompano, roach, rudd, salmon, sole, tilapia, trout, whitefish, and yellowtail.

In some embodiments, the fish are food fish or breeding fish, in particular food fish. In some embodiments, the fish are aquarium fish. In some embodiments, the fish are fish in a container, such as a net or cage, e.g. in a fish farm. In some embodiments, the fish belong to the family Salmonidae, especially of the subfamily salmoninae, and preferably, the Atlantic salmon (Salmon salar), rainbow trout (Oncorhynchus mykiss), brown or sea trout (S. trutta), the Pacific salmon: Cherry salmon or seema (O.

masou), Taiwanese salmon (O. masou formosanum), chinook salmon or King salmon (O. tshawytscha), chum salmon or Calico salmon (O. keta), coho salmon or silver salmon (O. kisutch), pink salmon (O. gorbuscha), Sockeye salmon or Red salmon (O. nerka), artifically propagated species, such as Salmo clarkii, and Salvelinus species such as Brook trout (S. fontinalis). In some particular embodiments, the fish are selected from Atlantic and Pacific salmon and the sea trout. The antiparasitic compositions of this invention normally comprise 0.1 to 100%, preferably 0.1 to 95%, of the compounds of the invention and 1 to 99.9%, preferably 5 to 99.9%, - at least - of a solid or liquid adjuvant, 0 to 25%, preferably 0.1 to 20%, of the composition preferably being surfactants (% = percent by weight). While concentrated compositions are sometimes preferred as commercial goods, the end user, e.g. for bath application, normally uses compositions which are diluted with water and which have a substantially lower active substance content.

For example, in case of a bath treatment a concentration of from 0.001 to 50 ppm (by weight), preferably 0.005 to 20 ppm and in particular 0.005 to 10 ppm, based on the entire bath, of the compounds of the invention may be used. In addition, the concentration of the compounds of the invention during application depends on the manner and duration of treatment and also on the age and condition of the fish so treated. A typical bath treatment time is from 15 minutes to 4 hours, in particular from 30 minutes to 1 hour. The bath can contain further adjuvants, such as stabilizers, antifoams, viscosity regulators, binders, tackifiers as well as other active substances for achieving special effects.

EXAMPLES

EXAMPLE 1

Inhibiton of settlement of the barnacle cyprid larvae.

The settlement assay was performed using Petri dishes containing 5 ml filtered sea water with a salinity of 25 ±l%o. Approximately 20 barnacle cyprid larvae were added to each Petri dish. The tested substances were thereafter added and given the final concentration. The control consisted of filtered sea water only. Each experiment was made in five replicates and maintained up to 7 days. The inhibition of settling was thereafter examined by using a stereomicroscope and checked for settled or non settled larvae. The tested substances were:

Detomidine

Detomidine is an imidazole derivative and a2-adrenergic agonist, used as a large animal sedative, primarily used in horses.

Detomidine is a slightly less potent analogue of medetomidine. On the other hand, all of the material is active since detomidine only comes in one isomer and expresses no stereo chemistry.

Clonidine

Clonidine is as a centrally acting o2 adrenergic partial agonist and an imidazoline receptor agonist that has been in clinical use for over 40 years.

Naphazoline

Naphazoline is a direct acting sympathomimetic unspecific adrenoceptor agonist used to induce systemic vasoconstriction. - 4-(l-(2,3-dimethylphenyl)ethyl)-l-benzylimidazole

A synthesized analog of medetomidine where the nitrogen in 1-postion of the imidazole ring is protected with a benzyl group. - 4-(2-(3,4-dimethyl-l-hydroxyphenyl)ethyl)-lH-imidazole

A hydroxyl functionalized analog of medetomidine.

Lofexidine

Lofexidine is structurally analogous to clonidine. Lofexidine is an a2A adrenergic receptor agonist, historically used as an antihypertensive, but more commonly used to alleviate the physical symptoms of heroin and other types of opioid withdrawal. -Benzylimidazo le

In contrast to all other substances described being receptor agonists, 1 -Benzylimidazo to have multiple biological effects and is mainly used as a CYP inhibitor.

SI 8616, (5)-spiro[(l-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro- ,2',3',4'- tetrahydronaphthalene)]

S18616 is an a2-adrenergic agonist with similar potency as dexmedetomidine and to be used as an analgesic substance but has not been developed to a pharmaceutical product.

RESULTS

Results from the settlement assay are shown in Figure 2 A-G. As demonstrated, the compounds show effects and inhibit settlement of the barnacle larvae.

EXAMPLE 2

KICKING ASSAY

Cyprids, as described in example 1, were made immobile by using agarose (A-2576 from Sigma- Aldrich, St. Louis, MO, USA). Agarose was dissolved in filtered seawater (FSW) to a final concentration of 2 %, heated and melted and thereafter allowed to cool to just above the gelling temperature. The cyprid larvae were then incorporated and distributed randomly into the agarose by shaking the dish gently. When the agarose was no longer fluid, 5 ml of filtered seawater (FSW) was added atop of the agarose layer and thereafter the dishes were left for one hour to allow a steady state to form between cyprid, agarose and FSW. The investigated compounds (Detomidine (DT), Clonidine (CL), Naphazoline (NP), Med3 (M3), Med6 (M6), Lofexidine (LO), 1-Benzylimidazole (BI), SI 8616 (SP)) were then added and individual cyprid movements were counted as kicks per minute under a stereo microscope. The numbers of kicks were counted before and after three hours incubation with the investigated compounds. EXAMPLE 3

SALMON LICE MOTILITY

Salmon lice test protocol

Test subjects

To determine the effects of the compounds of the invention on sea lice, in particular salmon lice, fresh animals are picked, newly every day from infected salmons. The lice can further be stored in a cooler until they are going to be used. The lice can be of any developmental stage and they can be categorised according to the development stage, and preferably the lice are of one stage and even more preferably, the lice are categorised as pre-adults stage II for the assay.

The experiments are in Petri dishes filled with 20 ml of sea water. In experiments, 10-15 lice per dish are used. The experiments are performed with a paired study design, however other options are available and are well known to those skilled in the art. Each Petri dish is its own control resulting in two observations, before and after treatment, for every individual experiment and for the compounds being investigated (Detomidine, Clonidine, Naphazoline, Med3, Med6, Lofexidine, 1-Benzylimidazole, S18616). Next, the before and after values are compared and the before value are detracted from the after values and the new value is denoted as the number of delta event.

Before the start of the treatment, both Petri dishes are filmed with a camera for one or more minutes, preferably 1 minute. After the film capture, 200 of compound solution are added to the test dish and thereafter the dish is incubated in the cooler for one or more hours, preferably for two hours.

After the incubation step, the lice are returned to the lab bench and once more, the activity of the lice is captured over one or more minutes, preferably 1 minute. Thereafter, the motility of the lice is registered. As the lice prefer to be attached to the surface of the dish, the number of times when the individual louse de-attach from the surface is determined. De-attachments are noted and reflect the motility of the lice as an effect of the compounds of the invention. EXAMPLE 4

METHODS OF TREATMENT

In a method of treatment of farmed fish, including but not limited to salmon, for aquatic pests, including but not limited to sea lice, i the fish are introduced into an aqueous environment containing the treatment agent or caused to transit such an environment, or have the treatment agent introduced into the aqueous environment containing the fish, i.e. compound of the invention is topically administered.

Fish are transferred into a tank for treatment or caused to pass from one holding zone, e.g. a tank or cage, into another through a conduit, e.g. a pipe or channel, containing the treatment agent. In the former method, the treatment agents are released into the cage, tank or pond containing the fish, optionally after surrounding the cage with an impervious barrier, to cause at least temporary retention of the treatment agent within the water in the cage. Where the agents are to be released into a sea cage, the sea-cage net can (typically) be raised to a depth of 5-15 (e.g. 10) meters and then surrounded by impervious barrier to isolate the cage to be treated. Typically, the depth of enclosed water is often such that there will be some space (e.g. about 0.5- 1 m) between the net bottom and the impervious barrier.

Alternative methods can comprise that the treatment agents are released into the water within a cage, e.g. a sea cage, over an extended period so as to ensure exposure of the fish to the treatment agent before the agent is flushed out of the cage by the flow of surrounding water. An example of this type of exposure is through a coating or a paint that comprise the compounds of the invention, which are applied to the cages or nets for fish farming, whereby the compounds of the invention slowly leaks from the coating or paint of the cage immersed in water, to reduce and prevent bio fouling on the cages and also to reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages. The reduction and prevention of bio fouling will improve the water quality inside the cages and thus reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages. Another example to deliver the compounds of the invention to the cages are via delivery systems, exemplified but not limited to solutions, emulsions, suspensions, powders, tablets and the like, or formulated and encapsulated in beads, capsules, gels and the like, to reduce and prevent fish parasitic crustaceans including sea lice on the fish that is farmed inside the cages. The compounds of the invention slowly leak into the surrounding water. The lines are connected to a floating part, above the water, and a sinker or weight below the water. Such water-permeable containers or bags and the like that are attached to lines, containing the compounds of the invention formulated and encapsulated in beads, capsules, gels and the like, are easily exchanged or replaced when the concentration of the compounds of the invention is close to a minimum concentration, or e.g. at predetermined intervals.

Optionally, the first treatment may be combined with a second treatment and/or followed by a second treatment. The delay between the first and the second treatment can range between nil time and 5, 10, 20, 30, 45, 60 or 90 minutes, 6, 7 and 8 hours.

The concentration of the compounds of the invention inside an enclosure for fish, e.g. a cage or net, should preferably be between 1 nanogram/liter (0.005 nM) to 100 microgram/liter (500 nM), e.g. from 20 nanogram/liter (0.1 nM) to 80 microgram/liter (400 nM), or from 100 nanogram/liter (0.5 nM) to 40 microgram/liter (200 nM), and more preferably between 200 nanogram/liter (1 nM) to 20 microgram/liter (100 nM). For example, in case of a bath treatment a concentration of from 0.001 to 50 ppm (by weight), preferably 0.005 to 20 ppm and in particular 0.005 to 10 ppm, based on the entire bath, of the compounds of the invention may be used. In addition, the concentration of the compounds of the invention during application depends on the manner and duration of treatment and also on the age and condition of the fish so treated. The duration of treatment can also depend on the temperature of the water. A typical bath treatment time is from 15 minutes to 4 hours, in particular from 30 minutes to 1 hour. The bath can contain further adjuvants, such as stabilizers, antifoams, viscosity regulators, binders, tackifiers as well as other active substances for achieving special effects.

The results of the former methods of treatment can include a 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% reduction in the number of sea lice adversely affecting farmed fish.

Claims

1. A com ound of formula (I)

or a salt thereof, for use in controlling parasitic crustaceans on fish, said parasitic crustaceans belonging to the Copepodae subclass, wherein

A₂ is N or CR₇;

Ri, R₂, R₃, Re and R₇ are independently selected from H, OH, NH₂, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II)

Ra is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-;

Rc, Rd, Re, Rf, and R_g, are independently selected from H, halogen, OH, C1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and Rc and Rd, or Rj and R_e, or Re and Rf, or Rf and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring; n is 0 or 1 ; when n is 1, one of Z and W is selected from CR_hRi, O, and NR¾; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X; when n is 0, W is selected from CR_hRi, O, NR_j and C=X; R_h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

R_j is selected from H and C1-C4 alkyl; and X is selected from O and CH₂; provided that the compound is not 4-(l-(2,3-dimethylphenyl)ethyl)-lH-imidazole or a tautomer thereof.

2. The compound or salt for use according to claim 1, wherein Ai is NR¾; and A₂ is N.

3. The compound or salt for use according to claim 2, wherein

Ri is selected from H, OH, and NH₂;

R₂ is selected from H and a moiety of formula (II); and

Re is selected from H, R_aC(O)-, C1-C4 alkyl optionally substituted by R_b, and benzyl.

4. The compound or salt for use according to claim 3, wherein R₂ is a moiety of formula (II).

5. The compound or salt for use according to claim 4, wherein

Ri is H;

n is 0; and W is selected from CR_hRi and C=X.

6. The compound or salt for use according to claim 5, wherein

R_c and R_d are independently selected from H, C1-C4 alkyl, and C1-C4 alkyl substituted by OH; and

R_e, R_f, and R_g, are independently selected from H and OH.

7. The compound or salt for use according to claim 6, wherein

R_c and R_d are independently selected from C1-C4 alkyl;

R_e and R_f, are both H;

R_h and Ri are independently selected from H and C1-C4 alkyl; and

X is CH₂.

8. The compound or salt for use according to claim 4, wherein

Rs is H;

R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, and C1-C4 alkyl; n is 0;

W is selected from CR_hRi, NR_j, and C=X;

R_h and Ri are independently selected from H, and C1-C4 alkyl;

R_j is selected from H, and C1-C4 alkyl; and

X is CH₂.

9. The compound or salt for use according to claim 2, wherein

Ri is selected from H, OH, and NH₂;

R₂ is H, and

Rs is moiety of formula (II).

10. The compound or salt for use according to claim 9, wherein

Ri is H;

n is 0; and

W is selected from CR_hRi, and C=X.

11. The compound or salt for use according to claim 10, wherein

R_c and R_<j are independently selected from H, C1-C4 alkyl, and C1-C4 alkyl optionally substituted by OH; and

R_e, R_f, and R_g, are independently selected from H and OH.

12. The compound or salt for use according to any one of the claims 1 to 11, wherein R₄ and R5 form covalent bond.

13. The compound or salt for use according to any one of the claims 1 to 11, wherein R₄ and R₅ are both H.

14. The compound or a salt thereof for use according to any one of the claims 1 to 13, claim wherein the compound is administered to the fish by introducing the compound into water surrounding the fish.

15. A composition containing a compound according to any one of claims 1 to 14, wherein said composition is capable of releasing the compound when the composition is brought into contact with water, for use in controlling parasitic crustaceans on fish, said parasitic crustaceans belonging to the Copepodae subclass.

16. A method of improving water quality in an enclosure for fish, by providing said enclosure with a surface coating containing a compound of formula (I)

a salt thereof, wherein

R_a is selected from C2-C4 alkenyl and C2-C4 alkenyl substituted by COOH;

R_b is selected from OH, and C1-C4 alkyl-C(0)0-; R_c, R_d, R_e, R_f, and R_g, are independently selected from H, halogen, OH, C 1-C4 alkyl, and Cl- C4 alkyl substituted by OH; and R_c and R_d, or Rj and R_e, or R_e and R_f, or R_f and R_g, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring; n is 0 or 1 ; when n is 1 , one of Z and W is selected from CR_hRi, O, and NR_j; and the other one is selected from CR_hRi, and C=X; or one of Z and W is CR_hRi; and the other one is selected from CR_hRi, O, NR_j and C=X; when n is 0, W is selected from CR_hRi, O, NR_j and C=X;

OH; R_j is selected from H and C1-C4 alkyl; and X is selected from O and CH₂; provided that the compound is not 4-(l-(2,3-dimethylphenyl)ethyl)-lH-imidazole or a tautomer thereof.

17. The method according to claim 16, wherein Ai is NR^; and A₂ is N.

18. The method according to claim 17, wherein

Ri is selected from H, OH, and NH₂;

R₂ is selected from H and a moiety of formula (II); and

Re is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.

19. The method according to claim 18, wherein R₂ is a moiety of formula (II).

20. The method according to claim 19, wherein

Ri is H;

Rc, Rd, Re, R_f, and R_g, are independently selected from H, OH, C1-C4 alkyl and optionally substituted by OH;

n is 0; and

W is selected from CR_hRi and C=X.

21. The method according to claim 20, wherein

Re, R_f, and R_g, are independently selected from H and OH.

22. The method according to claim 21, wherein

Rc and Rd are independently selected from C1-C4 alkyl;

R_h and Ri are independently selected from H and C1-C4 alkyl; and

X is CH₂.

23. The method according to claim 19, wherein

Re is H;

Rc, Rd, Re, R_f, and R_g, are independently selected from H, halogen, and C1-C4 alkyl;

n is 0;

W is selected from CR_hRi, NR_j, and C=X;

R_h and Ri are independently selected from H, and C1-C4 alkyl;

R_j is selected from H, and C1-C4 alkyl; and

X is CH₂.

24. The method according to claim 17, wherein

Ri is selected from H, OH, and NH₂;

R₂ is H, and

Re is moiety of formula (II).

25. The method according to claim 24, wherein

Ri is H;

Rc, Rd, Re, R_f, and R_g, are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;

n is 0; and

W is selected from CR_hRi, and C=X.

26. The method according to claim 25, wherein

R_c and Rj are independently selected from H, C1-C4 alkyl, and C1-C4 alkyl optionally substituted by OH; and

Re, R_f, and R_g, are independently selected from H and OH.

27. The method according to any one of the claims 16 to 26, wherein R₄ and R₅ form covalent bond.

28. The method according to any one of the claims 16 to 26, wherein R₄ and R₅ are both H.

29. The method according to any one of the claims 16 to 28, wherein the coating is capable of releasing the compound of formula (I) or the salt thereof into the water in the enclosure in an amount effective to reduce or prevent parasitic infestation of the fish in the enclosure.

30. The method according to any one of the claims 16 to 29, wherein the enclosure is a net or a cage for fish farming.