WO2018087160A1 - Composés hétérocycliques substitués destinés à être utilisés dans la lutte contre des crustacés parasites sur des poissons - Google Patents

Composés hétérocycliques substitués destinés à être utilisés dans la lutte contre des crustacés parasites sur des poissons Download PDF

Info

Publication number
WO2018087160A1
WO2018087160A1 PCT/EP2017/078634 EP2017078634W WO2018087160A1 WO 2018087160 A1 WO2018087160 A1 WO 2018087160A1 EP 2017078634 W EP2017078634 W EP 2017078634W WO 2018087160 A1 WO2018087160 A1 WO 2018087160A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
independently selected
compound
moiety
Prior art date
Application number
PCT/EP2017/078634
Other languages
English (en)
Inventor
Dan Isaksson
Lena MÅRTENSSON LINDBLAD
Original Assignee
I-Tech Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by I-Tech Ab filed Critical I-Tech Ab
Publication of WO2018087160A1 publication Critical patent/WO2018087160A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2

Definitions

  • the present invention relates to compounds for reducing and preventing parasitic crustaceans in marine environments.
  • 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.
  • 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.
  • L. salmonis exist in different larval stages, including the copepodid stage, which attach to the fish and then develop to adults through different stages.
  • 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.
  • the treatment may involve the use of injectable formulations, and in may such cases with the purpose to vaccinate the fish against the parasites.
  • 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.
  • 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.
  • a 2 is N or CR 7 ;
  • Ri, R 2 , R 3 , Re and R 7 are independently selected from H, OH, NH 2 , R a C(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II)
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 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 R 5 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 O or l
  • Rh and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by
  • R j is selected from H and C1-C4 alkyl
  • X is selected from O and CH 2 ;
  • 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 2 is N or CR 7 ;
  • Ri, R 2 , R 3 , Re and R 7 are independently selected from H, OH, NH 2 , R a C(O)-, C1-C4 alkyl optionally substituted by R b , and a moiety of formula (II)
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 is a moiety of formula (II), then R4 and R g together may form a methylene or ethylene bond; and when R 3 is a moiety of formula (II), then R5 and R g together may form a methylene or ethylene bond; or R4 and R 5 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 h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by
  • R j is selected from H and C1-C4 alkyl; and X is selected from O and CH 2 ;
  • the compound is not 4-(l-(2,3-dimethylphenyl)ethyl)-lH-imidazole or a tautomer thereof.
  • 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.
  • 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 B Settlement assay for Clonidine.
  • CL 0 is the control.
  • Fig 2 C Settlement assay for Naphazoline.
  • NP 0 is the control.
  • 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.
  • a range e.g., a range from x to y
  • 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.
  • Effective amount 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.
  • treat 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.
  • 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.
  • concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the known drug with respect to the
  • the compounds of this invention will be used, either alone or in combination with one or more other active ingredients as described herein.
  • 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
  • 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.
  • a suitable ion exchange resin for example, but not limited to a suitable ion exchange resin.
  • other pharmaceutically acceptable derivatives of compounds of the invention are included within the scope of the invention (e.g. solvates).
  • “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.
  • bio fouling 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.
  • anti- fouling refers to prevention and reduction of fouling organisms on marine surfaces.
  • 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
  • the compounds of the invention have anti- fouling effects by reducing and preventing bio fouling on marine surfaces.
  • 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.
  • 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
  • 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.
  • the compound is present in the coating in an amount effective essentially to prevent biofouling of said enclosure.
  • 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
  • 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).
  • 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.
  • Ai is O, S, CReH or NRe; and A 2 is N or CR 7 .
  • Ai is C ⁇ tl or N ⁇ ; and A 2 is N or CR 7 , e.g. Ai is C ⁇ tl or N ⁇ ; and A 2 is N or CH, in particular A 2 is N.
  • Ai is O, S, C ⁇ tl or N ⁇ ; and A 2 is N; e.g. Ai is O, S or N ⁇ ; and A 2 is N, or Ai is O or N ⁇ ; and A 2 is N. In still other embodiments, Ai is C ⁇ tl or N ⁇ ; and A 2 is CR 7 .
  • Ai is NR6 and A 2 is N, and the compound of formula (I) may be represented by formula (la)
  • R l s R 2 , R 3 , R4, R 5 and 5 are as defined herein.
  • Ai is O and A 2 is N, and the compound of formula (I) may be represented by formula (lb)
  • R l s R 2 , R3, R4, and R 5 are as defined herein.
  • Ri, R 2 , R 3 , Re and R 7 are independently selected from H, OH, NH 2 , R a C(O)-, C1-C4 alkyl optionally substituted by R b , and a moiety of formula (II)
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or R4 and R 5 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 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 CH 2 .
  • Ri, R 2 , R 3 , Re and R 7 are a moiety of formula (II), then each such moiety is independently selected.
  • one or two of Ri, R 2 , R 3 , Re and R 7 is a moiety of formula (II).
  • only one of Ri, R 2 , R 3 , Re and R 7 is a moiety of formula (II).
  • R6 is a moiety of formula (II).
  • any one or two, preferably one, of Ri, R 2 , R 3 and R 7 , e.g. one of Ri, R 2 , and R 3 , e.g. R 2 is also a moiety of formula (II).
  • only R ⁇ is a moiety of formula (II).
  • Ri is a moiety of formula (II). In some of these embodiments, any one or two, preferably one, of R 2 , R 3 , Re and R 7 , e.g. one of R 2 and R 3 , is also a moiety of formula (II). In some other embodiments, only Ri is a moiety of formula (II).
  • R 2 is a moiety of formula (II).
  • any one or two, preferably one, of Ri, R 3 , Re and R 7 , e.g. one of Ri and Re, is also a moiety of formula (II).
  • only R 2 is a moiety of formula (II).
  • R 3 is a moiety of formula (II).
  • any one or two, preferably one, of Ri, R 2 , Re and R 7 e.g. one of Ri and R 7 , is also a moiety of formula (II).
  • only R 3 is a moiety of formula (II).
  • Ri, R 2 , R 3 , 5 (if present), and R 7 (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.
  • Ai is N 5 or CHR 5 , preferably NR 5
  • a 2 is N
  • Ri, R 2 , R 3 , 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.
  • Ai is CHR6 or NR 5 , in particular Ai is NR3 ⁇ 4;
  • a 2 is N, Ri is selected from H, OH, and NH 2 ;
  • R 2 is selected from H and a moiety of formula (II);
  • R 3 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.
  • Ai is CHR6 or NR 5 , in particular Ai is NR3 ⁇ 4;
  • a 2 is N, Ri is selected from H, OH, and NH 2 ;
  • R 2 is a moiety of formula (II);
  • R 3 is selected from H and C1-C4 alkyl,
  • Ai is CHR6 or NR 5 , in particular Ai is NR3 ⁇ 4; A 2 is N, Ri is H; R 2 is selected from H and a moiety of formula (II); R 3 is H; and R6 is selected from H and benzyl.
  • Ai is CHR6 or NR 5 , in particular Ai is NR 5 , A 2 is N, R 2 is a moiety of formula (II), and Ri, R 3 and R 6 are H.
  • Ai is CHR6 or NR 5 , in particular Ai is NR3 ⁇ 4; A 2 is N, Ri is selected from H, OH, and NH 2 ; one of R 2 and R 3 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.
  • Ai is CHR 6 or NR 6 , in particular Ai is NR3 ⁇ 4; A 2 is N, one of R 2 and R 3 is a moiety of formula (II); and the other one is H; and Ri and R6 are H.
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 is a moiety of formula (II), then R4 and R g together may form a methylene or ethylene bond; and when R 3 is a moiety of formula (II), then R5 and R g together may form a methylene or ethylene bond; or R4 and R 5 together form a covalent bond.
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or R4 and R 5 together form a covalent bond.
  • R4 and R 5 are independently selected from H and C1-C3 alkyl, e.g. from H and methyl.
  • both R4 and R 5 are H.
  • R4 and R 5 are independently selected from H and methyl; or R4 and R 5 together form a covalent bond.
  • both R4 and R5 are H; or R4 and R 5 together form a covalent bond.
  • R4 and R 5 form a covalent bond.
  • R 4 and R g together form a methylene or ethylene bond, i.e. the compound of formula (I) may be represented by formula
  • R l s R 3 , R 5 , R c , Rj, R e , R f , A l s A 2 , W, Z, and n are as defined herein, and r is 1 or 2, e.g. r is 1.
  • a 2 is N; e.g. A 2 is N and AI is NR 5 , O or S; e.g. A 2 is N and Ai is O or S; or A 2 is N and Ai is O or NR6; in particular; A 2 is N and
  • R 5 and R g together form a methylene or ethylene bond, e.g. R 5 and R g together form a methylene bond.
  • Ai is CHR ⁇ or NR 6 , in particular Ai is NR ⁇ ;
  • a 2 is N, Ri is selected from H, OH, and NH 2 ;
  • R 2 is selected from H and a moiety of formula (II);
  • R 3 is H or C1-C4 alkyl, e.g. H; R 4 and R 5 together form a covalent bond, and R ⁇ is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.
  • Ai is CHR ⁇ or NR 6 , in particular Ai is NR ⁇ ;
  • a 2 is N, Ri is H;
  • R 2 is selected from H and a moiety of formula (II);
  • R 3 is H or C1-C4 alkyl, e.g. H;
  • R 4 and R 5 together form a bond, and
  • R ⁇ is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl.
  • Ai is CHR ⁇ or NR 6 , in particular Ai is NR ⁇ ; A 2 is N, R 2 is a moiety of formula (II); R 4 and R 5 together form a bond, and Ri, R 3 and R ⁇ are H.
  • 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:
  • 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 C 2 H 5 C(0)0-. In still other embodiments, Rb is OH.
  • 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.
  • 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.
  • 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, CH 3 and CH 2 OH, or from H,
  • 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 CH 3 .
  • 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 CH 3 .
  • 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, CH 3 and CH 2 OH.
  • 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 CH 3 .
  • 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.
  • 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. CH 3 .
  • 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.
  • 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.
  • R c and R d are as defined herein above, but are not H, and R e , R f , and R g are H.
  • R c and R g are as defined herein above, but are not H, and R d , R e , and R f are H.
  • 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.
  • 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.
  • the ring is a 6-membered ring, e.g. a benzene ring.
  • R c , Rd, Re, Rf, and R g 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • the phenyl ring carrying the moieties R c -R g is 2,3-dimethylphenyl.
  • n is 1 or 0.
  • the moiety of formula (II) may be represented by formula (Ila)
  • n is 0, i.e. said moiety may be represented by formula (lib)
  • W is selected from CR h Ri, O, and NR j , e.g. from CR h Ri and O; or from CR h Ri and NR j .
  • 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, CH 3 and CH 2 OH. 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 C3 ⁇ 4. In some embodiments, R h and Ri are both H.
  • R h is selected from H and C1-C4 alkyl
  • 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, CH 3 and CH 2 OH, or from OH and CH 2 OH.
  • 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 CH 2 OH; e.g. R h is OH; and Ri is selected from H and C1-C4 alkyl.
  • 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 CH 3 ; and Ri is H.
  • 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 CH 3 .
  • 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 CH 3 .
  • the moiety X is selected from O and CH 2 . In some embodiments, X is O. In other embodiments, X is CH 2 .
  • R 2 is a moiety of formula (II) and R4 and R g together form a methylene or ethylene bond
  • R 3 is a moiety of formula (II) and R 5 and R g together form a methylene or ethylene bond
  • n is 1 and W and Z are both CR h Ri; or n is 0 and W is CR h Ri.
  • R 2 is a moiety of formula (II) and R4 and R g together form a methylene or ethylene bond
  • R 3 is a moiety of formula (II) and R 5 and R g together form a methylene or ethylene bond
  • n is 1 and both W and Z are CH 2 ; or n is 0 and W is CH 2 .
  • 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.
  • the moiety formed by (Z) n and W is selected from:
  • the moiety formed by (Z) n and W may be selected from:
  • Ai is NR3 ⁇ 4; and A 2 is N; i.e. the compound is a compound of formula (la) as defined herein above.
  • Ri , R 2 , and 3 ⁇ 4 are independently selected from H, OH, NH 2 , RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II) as defined herein;
  • R 3 is H
  • R 4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 is a moiety of formula (II), then R 4 and R g together may form a methylene or ethylene bond; or R 4 and R 5 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;
  • 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
  • X is selected from O and CH 2 .
  • R l s R 2 , and R6 are a moiety of formula (II). In some other of the above embodiments, one of Ri , R 2 , and R6 is a moiety of formula (II).
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is selected from H and a moiety of formula (II);
  • R 3 is H
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 is a moiety of formula (II), then R4 and R g together may form a methylene or ethylene bond; or R4 and R 5 together form a covalent bond;
  • R 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-;
  • 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 1 or 0;
  • 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 CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is a moiety of formula (II);
  • R 3 is H
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or R4 and R 5 together form a covalent bond;
  • R 5 is selected from H, R a C(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;
  • 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
  • X is selected from O and CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is a moiety of formula (II);
  • R 3 is H
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or when R 2 is a moiety of formula (II), then R4 and R g together may form a methylene or ethylene bond; or R4 and R 5 together form a covalent bond;
  • R 5 is selected from H, R a C(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;
  • n 1 or 0;
  • 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
  • X is selected from O and CH 2 .
  • R 2 is a moiety of formula (II);
  • R 3 is H
  • R4 and R 5 together form a covalent bond
  • R 5 is selected from H, R a C(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, OH, C1-C4 alkyl and optionally substituted by OH;
  • n 0;
  • R h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;
  • X is selected from O and CH 2 .
  • R 2 is a moiety of formula (II); R 3 is H;
  • R 4 and R 5 together form a covalent bond
  • R 5 is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and benzyl;
  • 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;
  • R f , and R g are independently selected from H and OH;
  • n 0;
  • R h and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;
  • X is selected from O and CH 2 .
  • R 2 is a moiety of formula (II);
  • R 3 is H
  • R 4 and R 5 together form a covalent bond
  • R 5 is selected from H, RaC(O)-, C1-C4 alkyl optionally substituted by Rb, 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 and Rj are independently selected from C1-C4 alkyl
  • n 0;
  • R h and Ri are independently selected from H and C1-C4 alkyl
  • X is CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is a moiety of formula (II);
  • R 3 is H;
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or R4 and R 5 together form a covalent bond;
  • 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 0;
  • Rh and Ri are independently selected from H, and C1-C4 alkyl
  • R j is selected from H, and C1-C4 alkyl
  • X is CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is a moiety of formula (II);
  • R4 and R 5 are both H
  • R 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-;
  • 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 1 or 0;
  • 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
  • X is selected from O and CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is H
  • R 3 is H
  • R4 and R 5 are independently selected from H and C1-C3 alkyl; or R4 and R 5 together form a covalent bond;
  • 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 1 or 0;
  • 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
  • X is selected from O and CH 2 .
  • Ri is selected from H, OH, and NH 2 ;
  • R 2 is H
  • R 3 is H
  • R4 and R 5 together form a covalent bond
  • 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 1 or 0;
  • n 1
  • 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
  • X is selected from O and CH 2 .
  • R 4 and R 5 form together a covalent bond
  • 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 0;
  • 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
  • X is selected from O and CH 2 .
  • R 4 and R 5 form together a covalent bond
  • 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 0;
  • 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
  • X is selected from O and CH 2 .
  • Ri , R 2 , and 3 ⁇ 4 are independently selected from H, OH, NH 2 , RaC(O)-, C1-C4 alkyl optionally substituted by Rb, and a moiety of formula (II) as defined herein;
  • R 3 is H
  • R4 and R 5 are both 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, 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 1 or 0;
  • Rh and Ri are independently selected from H, OH, and C1-C4 alkyl optionally substituted by OH;
  • Rj is selected from H and C1-C4 alkyl
  • X is selected from O and CH 2 .
  • Rh and Ri are independently selected from H, and C1-C4 alkyl, e.g. Rh and Ri are both H or CH 3 ; or both Rh and Ri are H.
  • 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
  • the nanoparticles 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.
  • the compounds of the invention is used together with one or more other active ingredients, e.g.
  • 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.
  • 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 DIURONTM and
  • IRGAROLTM or more general biocides such as SEANINETM or ECONEATM (2-(p- chlorophenyl)-3-cyano-4-bromo-5-trifluoromethyl) pyrrole by Janssen Pharmaceutical, Titusville, NJ, USA.
  • algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051TM (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), ZINEBTM (zinc ethylene bisdithiocarbamate), ZINRAMTM (Zinc bis(dimethylthiocarbamates)), maneb (manganese ethylene bisdithiocarbamate), quaternary ammonium
  • 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,
  • 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.
  • 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
  • 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.
  • 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.
  • the compounds of the invention will be present at 0.01-2%, preferably 0.1-0.3%.
  • 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.
  • a combination of the compounds of the invention and a polymer complex may be utilized, as additives to self-polishing paints.
  • 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 DIURONTM and IRGAROLTM, or more general biocides such as SEANINETM or ECONEATM (2-(p- chlorophenyl)-3-cyano-4-bromo-5-trifluoromethyl) by Janssen
  • algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051TM (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), ZINEBTM (zinc ethylene bisdithiocarbamate), ZINRAMTM (Zinc bis(dimethylthiocarbamates)), maneb (manganese ethylene bisdithioc
  • 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.
  • 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 inside the cages or nets of fish farms.
  • 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.
  • 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.
  • 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.
  • a combination of the compounds of the invention and a polymer complex may be utilized, as additives to self-polishing paints.
  • 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 DIURONTM and IRGAROLTM, or more general biocides such as
  • algicides include copper, zinc and other metals, DIURON (3-(3,4-dichlorophenyl)-l,l-dimethylurea), IRGAROL 1051TM (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), ZINEBTM (zinc ethylene bisdithiocarbamate), ZINRAMTM (Zinc
  • 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).
  • 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 :
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • 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.
  • a source of light e.g. an underwater solar lamp or an underwater LED lamp.
  • 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.
  • the photo tactic parasite 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.
  • 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,
  • 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);
  • Caligus i.e. C. curtus, C. elongatus, C. clemensi, C. rogercresseyii
  • Lepeophtheirus i.e. L. salmonis
  • 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.
  • 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.
  • the fish are food fish or breeding fish, in particular food fish.
  • the fish are aquarium fish.
  • the fish are fish in a container, such as a net or cage, e.g. in a fish farm.
  • 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.
  • the fish are selected from Atlantic and Pacific salmon and the sea trout.
  • 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.
  • 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.
  • 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 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 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 is a direct acting sympathomimetic unspecific adrenoceptor agonist used to induce systemic vasoconstriction. - 4-(l-(2,3-dimethylphenyl)ethyl)-l-benzylimidazole
  • 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
  • 1 -Benzylimidazo 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.
  • 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 from the settlement assay are shown in Figure 2 A-G. As demonstrated, the compounds show effects and inhibit settlement of the barnacle larvae.
  • 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.
  • agarose A-2576 from Sigma- Aldrich, St. Louis, MO, USA.
  • FSW filtered seawater
  • 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.
  • 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.
  • 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.
  • 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.
  • a method of treatment of farmed fish including but not limited to salmon
  • aquatic pests including but not limited to sea lice
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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).
  • 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.
  • 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.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I) ou un sel de celui-ci, destiné à être utilisé dans la lutte contre des crustacés parasites, tels que les poux de mer, sur les poissons, par exemple, du saumon. L'invention concerne également un procédé d'amélioration de l'écoulement de l'eau dans et hors d'une cage ou d'un filet pour l'élevage de poissons, en utilisant ladite cage ou ledit filet avec un revêtement de surface contenant un composé de formule (I) ou un sel de celui-ci, en une proportion efficace pour réduire le bio-encrassement de ladite cage ou dudit filet. Le revêtement est apte à libérer le composé ou un sel de celui-ci dans l'eau dans la cage ou le filet en une proportion efficace pour réduire ou empêcher l'infestation des poissons par des parasites dans la cage ou le filet.
PCT/EP2017/078634 2016-11-09 2017-11-08 Composés hétérocycliques substitués destinés à être utilisés dans la lutte contre des crustacés parasites sur des poissons WO2018087160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16198045.3 2016-11-09
EP16198045 2016-11-09

Publications (1)

Publication Number Publication Date
WO2018087160A1 true WO2018087160A1 (fr) 2018-05-17

Family

ID=57256229

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/078634 WO2018087160A1 (fr) 2016-11-09 2017-11-08 Composés hétérocycliques substitués destinés à être utilisés dans la lutte contre des crustacés parasites sur des poissons

Country Status (1)

Country Link
WO (1) WO2018087160A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042851A1 (fr) * 1999-01-25 2000-07-27 Hans Elwing Lutte contre l'encrassement biologique marin de surfaces
WO2006096129A1 (fr) * 2005-03-11 2006-09-14 I-Tech Procede et utilisation de polymeres acidifies modifies pour fixer des biocides dans des peintures
US20060201379A1 (en) 2005-03-11 2006-09-14 Magnus Nyden Method and use of nanoparticles to bind biocides in paints
WO2011157733A2 (fr) 2010-06-18 2011-12-22 Novartis Ag Nouvelle utilisation
WO2013110612A1 (fr) * 2012-01-26 2013-08-01 Bayer Intellectual Property Gmbh Cétoénols à substitution phénylique destinés à lutter contre des parasites de poisson
WO2016177884A1 (fr) * 2015-05-06 2016-11-10 I-Tech Ab Médétomidine destinée à être utilisée dans la lutte contre les crustacés parasites sur les poissons
WO2017196607A1 (fr) * 2016-05-10 2017-11-16 Elanco Tiergesundheit Ag Composé de dihydroisoxazole à utiliser pour lutter contre les poux de mer

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042851A1 (fr) * 1999-01-25 2000-07-27 Hans Elwing Lutte contre l'encrassement biologique marin de surfaces
WO2006096129A1 (fr) * 2005-03-11 2006-09-14 I-Tech Procede et utilisation de polymeres acidifies modifies pour fixer des biocides dans des peintures
US20060201379A1 (en) 2005-03-11 2006-09-14 Magnus Nyden Method and use of nanoparticles to bind biocides in paints
US20060223906A1 (en) 2005-03-11 2006-10-05 Magnus Nyden Method and use of acidified modified polymers to bind biocides in paints
WO2011157733A2 (fr) 2010-06-18 2011-12-22 Novartis Ag Nouvelle utilisation
WO2013110612A1 (fr) * 2012-01-26 2013-08-01 Bayer Intellectual Property Gmbh Cétoénols à substitution phénylique destinés à lutter contre des parasites de poisson
WO2016177884A1 (fr) * 2015-05-06 2016-11-10 I-Tech Ab Médétomidine destinée à être utilisée dans la lutte contre les crustacés parasites sur les poissons
WO2017196607A1 (fr) * 2016-05-10 2017-11-16 Elanco Tiergesundheit Ag Composé de dihydroisoxazole à utiliser pour lutter contre les poux de mer

Similar Documents

Publication Publication Date Title
DK179655B1 (en) MEDETOMIDINE FOR USE IN CONTROLLING PARASITIC CRUSTACEANS ON FISH
JP6749966B2 (ja) 海産魚類に寄生する微胞子虫及び粘液胞子虫による疾患の治療剤
US20190380981A1 (en) Treatment of fish populations with lufenuron
JP2020096599A (ja) 低濃度過酸化水素水による魚類外部寄生虫駆除方法
EP1083907B1 (fr) Lutte contre les infections parasitaires des poissons d'elevage ou sauvages
US20030158260A1 (en) Novel usage
US20150272931A1 (en) New Treatment
WO2018087160A1 (fr) Composés hétérocycliques substitués destinés à être utilisés dans la lutte contre des crustacés parasites sur des poissons
JP2022097756A (ja) スズキ目魚類の寄生虫駆除剤及び駆除方法
EP3179997B1 (fr) Compositions destinées au traitement des caligidae chez le poisson
CN112243346A (zh) 用于从鱼除去外寄生虫的处理
Liao et al. The use of chemicals in aquaculture in Taiwan, Province of China
JP4695766B2 (ja) 魚類寄生虫の駆除剤及び駆除方法
EP3331365B1 (fr) Agent pour le lutte contre les parasites de poissons
JP2023078111A (ja) グルタルアルデヒドを含む魚類寄生虫駆除剤
CN117355217A (zh) 对抗鱼类中寄生虫的环丙基酰胺化合物
JPS6160041B2 (fr)
GB2500381A (en) The combination of pyrethroid and hydrogen peroxide for control of ectoparasite infestation in fish

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17793679

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17793679

Country of ref document: EP

Kind code of ref document: A1