CYCLOPROPYLAMIDE COMPOUNDS AGAINST PARASITES IN FISH

Abstract

The present invention relates to cyclopropylamide compounds that are useful in the treatment of parasitic infestations of fish. The compounds have the formula (I).

##STR00001##

Claims

1. A method to control parasite infestations in fish comprising administering to a fish a compound of the following formula ##STR00087## and N-oxides, veterinary acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, stereoisomers, and tautomers, R.sup.1 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, and (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2; R.sup.2 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2, and S-(Halo).sub.5; R.sup.3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2, and S-(Halo).sub.5; R.sup.4 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2, and S-(Halo).sub.5; R.sup.5 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, and (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2; R.sup.6 is selected from the group consisting of H and (C.sub.1-C.sub.6)alkyl; R.sup.7 is selected from the group consisting of H, F, Cl, Br, and I; R.sup.8 is selected from the group consisting of F, Cl, Br, and I; R.sup.9 is selected from the group consisting of H and (C.sub.1-C.sub.6)alkyl; R.sup.10 is selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.6)alkoxy, C(?O)(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxyC(?O)(C.sub.1-C.sub.6)alkyl; R.sup.11 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, and (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2; R.sup.12 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, and (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2; R.sup.13 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, CHO, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2, and triazolyl; R.sup.14 is selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)halocycloalkyl, (C.sub.2-C.sub.6)haloalkenyl, (C.sub.3-C.sub.6)halocycloalkenyl, (C.sub.1-C.sub.6)haloalkoxy, S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, S(C.sub.1-C.sub.6)haloalkyl, S(O)(C.sub.1-C.sub.6)haloalkyl, S(O).sub.2(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl-S(O).sub.2NH.sub.2, and (C.sub.1-C.sub.6)haloalkyl-S(O).sub.2NH.sub.2; R.sup.15 is selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.6)alkoxy, C(?O)(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxyC(?O)(C.sub.1-C.sub.6)alkyl; R.sup.16 is selected from the group consisting of (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkylphenyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O)(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2(C.sub.1-C.sub.8)alkyl, O-phenyl, O(C.sub.2-C.sub.8)alkenyl, O(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl, O(C.sub.1-C.sub.8)alkylphenyl, (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-C(?O)NH(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-NHC(O)(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O)(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2NH.sub.2, and a heterocycle, wherein each alkyl, alkenyl, alkynyl, alkyl-cycloalkyl, haloalkyl, and phenyl, may be optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, CN, OH, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl, N((C.sub.1-C.sub.8)alkyl).sub.2, C(O)O(C.sub.1-C.sub.8)alkyl, benzothioenyl, oxoimidazolidinyl, furanyl, pyrazolyl, pyridinyl, thiazolyl, and triazolyl, and wherein the heterocycle is selected from the group consisting of, azetidinyl, 2,5-dioxoimidazolidinyl, 2,4-dioxo-1,3-diazaspiro[4.4]nonanylisoxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, morpholinyl, oxazolidinonyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-oxide, tetrahydrothiophenyl-dioxide, thietanyl, thietanyl-oxide, thietanyl-dioxide, and thioxothiazolidinonyl, and wherein each (C.sub.3-C.sub.8)cycloalkyl and heterocycle may be optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, oxo, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)haloalkyl, C(?O)O(C.sub.1-C.sub.4)alkyl, (C?O)NH(C.sub.1-C.sub.4)alkyl, (C?O)NH(C.sub.1-C.sub.4)haloalkyl, C(?O)(C.sub.3-C.sub.6)cyclopropyl, C(?O)(C.sub.1-C.sub.4)haloalkyl, C(?O)(C.sub.1-C.sub.4)alkyl(C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)alkyl-morpholinyl R.sup.15 and R.sup.16 together can optionally form a 2- to 5-membered saturated or unsaturated, hydrocarbyl link, which may contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein said hydrocarbyl link may be optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, CN, NH.sub.2, and NO.sub.2; Q.sup.1 and Q.sup.2 are each independently selected from the group consisting of O and S.

2. A method to control parasite infestations in fish according to claim 1, wherein R.sup.16 is selected from the group consisting of (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O)(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O)(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2(C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2NH.sub.2, and heterocycle, wherein each alkyl, alkenyl, alkynyl, alkyl-cycloalkyl, and haloalkyl in R.sup.16, may be optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, CN, OH, NH.sub.2, NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl, C(O)O(C.sub.1-C.sub.8)alkyl, oxoimidazolidinyl, furanyl, and pyrazolyl, wherein each (C.sub.3-C.sub.8)cycloalkyl, may be optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, oxo, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)haloalkyl, C(?O)O(C.sub.1-C.sub.4)alkyl, (C?O)NH(C.sub.1-C.sub.4)alkyl, (C?O)NH(C.sub.1-C.sub.4)haloalkyl, C(?O)(C.sub.3-C.sub.6)cyclopropyl, C(?O)(C.sub.1-C.sub.4)haloalkyl, C(?O)(C.sub.1-C.sub.4)alkyl(C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)alkyl-morpholinyl, wherein the heterocycle is selected from the group consisting of azetidinyl, imidazolidinonyl, isoxazolidinonyl, oxetanyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiophenyl-oxide, wherein, each heterocycle in R.sup.16 may be optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, I, CN, oxo, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C?O)NH(C.sub.1-C.sub.4)alkyl, (C?O)NH(C.sub.1-C.sub.4)haloalkyl, and C(?O)(C.sub.1-C.sub.4)alkyl(C.sub.1-C.sub.4)alkoxy.

3. A method to control parasite infestations in fish claim 1, wherein R.sup.16 is selected from the group consisting of (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.1-C.sub.8)alkyl-S(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O)(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkyl-S(O).sub.2(C.sub.1-C.sub.8)alkyl, and (C.sub.1-C.sub.8)alkyl-O(C.sub.1-C.sub.8)haloalkyl, wherein each alkyl, cycloalkyl, alkenyl, alkynyl, and haloalkyl, may be optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, C(O)O(C.sub.1-C.sub.8)alkyl, and oxoimidazolidinyl, wherein in the (C.sub.3-C.sub.8)cycloalkyl, may be optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, oxo, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C?O)NH(C.sub.1-C.sub.4)alkyl, and (C?O)NH(C.sub.1-C.sub.4)haloalkyl.

4. A method to control parasite infestations in fish according to claim 1, wherein Q.sup.1 and Q.sup.2 are O.

5. A method to control parasite infestations in fish according to claim 1, wherein: R.sup.5 is H; R.sup.6 is H; R.sup.7 is selected from the group consisting of Cl and Br; R.sup.8 is selected from the group consisting of Cl and Br; R.sup.9, R.sup.10, and R.sup.11 is H;

6. A method to control parasite infestations in fish according to claim 1, wherein R.sup.13 is selected from the group consisting of H, F, Cl, CH.sub.3 and CF.sub.3.

7. A method to control parasite infestations in fish according to claim 1, wherein R.sup.12 is selected from the group consisting H, F, Cl, Br, CH.sub.3.

8. A method to control parasite infestations in fish according to claim 1, wherein R.sup.14 is H or F.

9. A method to control parasite infestations in fish according to claim 1, wherein R.sup.15 is selected from the group consisting of H and CH.sub.3.

10. A method to control parasite infestations in fish according to claim 1, wherein the parasite infestation is a sea lice infestation.

11. A method to control parasite infestations in fish according to claim 1, wherein the parasite is at least one of Lepeophtheirus salmonis, Caligus celmensi, Caligus curtus, Caligus dussumieri, Caligus elongates, Caligus longicaudatus, Caligus rogercresseyi or Caligus stromii.

12. A method to control parasite infestations in fish according to claim 1, wherein the parasite infestation is with copepodites, pre-adult, or adult sea lice or a mixed infestation with various stages.

13. A method to control parasite infestations in fish according to claim 1, wherein the rate of infestation of the fish is between 0.5 and 3 parasites on average per fish in a fish facility.

14. A method to control parasite infestations in fish according to claim 1, wherein the method comprises administering to fish the compound of Formula (I) as defined in claim 1 by oral administration, or by topical administration such as by bath treatment or by intraperitoneal or intramuscular injection.

15. A method to control parasite infestations in fish, wherein the method comprises administering to fish the compound of Formula (I) as defined in claim 1 by oral administration, wherein the oral administration comprises administering a medicated fish feed comprising a therapeutically effective amount the compound and fish feed.

16. A method to control parasite infestations in fish according to claims, wherein the method comprises administering the compound of Formula (I) as defined in claim 1, by bath treatment, wherein the bath treatment comprises immersion of fish in water with a therapeutically effective amount of a compound.

17. A method to control parasite infestations in fish according to claim 1, wherein the fish is a salmonide.

18. A method to control parasite infestations in fish according to claim 1, wherein the compound is a compound of the following formula ##STR00088## and N-oxides, veterinary acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, stereoisomers, and tautomers, wherein the compound is selected from the group consisting of TABLE-US-00006 # R2 R3 R4 R12 R13 R14 R15 R.sup.16 1585 Cl Br H H Cl H H 1-cyanocyclopropyl 1586 Cl Br H H Cl H H 1-cyanocyclopropyl 1587 F CHF.sub.2 H H Cl H H 1-cyanocyclopropyl 1588 Cl CHF.sub.2 H H Cl H H (1-cyanocyclopropyl) 1589 Cl F H F F H H 1-cyanocyclopropyl 1592 Cl H Cl H Cl H H 2,2,2-trifluoroethyl 1593 F F F H Cl H H 2,2,2-trifluoroethyl 1594 Cl H Cl F F H H 1-cyanocyclopropyl 1600 H Cl F H Cl H H 1-cyanocyclopropyl 1601 H H CF.sub.3 H Cl H H 3,3-difluorocyclobutyl 1602 F F F H Cl H H 2,2,2-trifluoro-1-methyl-ethyl 1603 F F F H Cl H H 2,2,2-trifluoro-1,1-dimethyl-ethyl 1604 F F F H Cl H H 1-(trifluoromethyl)cyclopropyl 1605 Cl H Cl H F H H 1-cyanocyclopropyl 1607 Cl F Cl H Cl H H 1-cyanocyclopropyl 1608 H F Cl H Cl H H 1-cyanocyclopropyl 1609 Cl F Cl H Cl H H 1-cyanocyclopropyl 1610 Cl H Cl H CN H H 1-cyanocyclopropyl 1611 CF.sub.3 H H H Cl H H 3,3-difluorocyclobutyl 1612 CF.sub.3 H CF.sub.3 H Cl H H 1-cyanocyclopropyl 1613 CF.sub.3 H CF.sub.3 H Cl H H 2,2,2-trifluoroethyl 1614 CF.sub.3 H CF.sub.3 H Cl H H prop-2-ynyl 1615 CF.sub.3 H CF.sub.3 F F H H 1-cyanocyclopropyl 1616 Cl H Cl F F H H 1-methylcyclopropyl 1617 Cl H Cl F F H H 1-ethynylcyclopropyl 1618 Cl H Cl F F H H cyclopropyl 1619 Cl H Cl H Cl H H 1-methylcyclopropyl 1620 Cl H Cl H Cl H H 1-ethynylcyclopropyl 1621 Cl H Cl H Cl H H cyclopropyl 1622 Cl H Cl H Cl H H prop-2-ynyl 1623 F F F H F H H 1-cyanocyclopropyl 1624 F F F H Cl H H 1-cyanocyclopropyl 1626 Cl H Cl H F H H 1-methylcyclopropyl 1627 Cl H Cl H F H H 1-(trifluoromethyl)cyclopropyl 1628 Cl H Cl F F H H 3,3-difluorocyclobutyl 1629 Cl H Cl F F H H prop-2-ynyl 1630 Cl H Cl H F H H 3,3-difluorocyclobutyl 1631 Cl H Cl H F H H prop-2-ynyl 1632 Cl H Cl H F H H cyclopropyl 1633 Cl H Cl H F H H 1-ethynylcyclopropyl

19. A premix comprising a compound of Formula (I) as defined in claim 1, wherein the premix further comprises nutrients.

20. The premix according to claim 19, wherein the premix comprises nutrients in the form of pellets wherein the pellets are coated with a composition comprising a compound of Formula (I).

21. A medicated fish feed comprising the premix as defined in claim 19 and fish feed.

22. A compound of the following formula ##STR00089## and N-oxides, veterinary acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, stereoisomers, and tautomers, wherein the compound is selected from the group consisting of TABLE-US-00007 # R2 R3 R4 R12 R13 R14 R15 R.sup.16 1585 Cl Br H H Cl H H 1-cyanocyclopropyl 1586 Cl Br H H Cl H H 1-cyanocyclopropyl 1587 F CHF.sub.2 H H Cl H H 1-cyanocyclopropyl 1588 Cl CHF.sub.2 H H Cl H H (1-cyanocyclopropyl) 1589 Cl F H F F H H 1-cyanocyclopropyl 1592 Cl H Cl H Cl H H 2,2,2-trifluoroethyl 1593 F F F H Cl H H 2,2,2-trifluoroethyl 1594 Cl H Cl F F H H 1-cyanocyclopropyl 1600 H Cl F H Cl H H 1-cyanocyclopropyl 1601 H H CF.sub.3 H Cl H H 3,3-difluorocyclobutyl 1602 F F F H Cl H H 2,2,2-trifluoro-1-methyl-ethyl 1603 F F F H Cl H H 2,2,2-trifluoro-1,1-dimethyl-ethyl 1604 F F F H Cl H H 1-(trifluoromethyl)cyclopropyl 1605 Cl H Cl H F H H 1-cyanocyclopropyl 1607 Cl F Cl H Cl H H 1-cyanocyclopropyl 1608 H F Cl H Cl H H 1-cyanocyclopropyl 1609 Cl F Cl H Cl H H 1-cyanocyclopropyl 1610 Cl H Cl H CN H H 1-cyanocyclopropyl 1611 CF.sub.3 H H H Cl H H 3,3-difluorocyclobutyl 1612 CF.sub.3 H CF.sub.3 H Cl H H 1-cyanocyclopropyl 1613 CF.sub.3 H CF.sub.3 H Cl H H 2,2,2-trifluoroethyl 1614 CF.sub.3 H CF.sub.3 H Cl H H prop-2-ynyl 1615 CF.sub.3 H CF.sub.3 F F H H 1-cyanocyclopropyl 1616 Cl H Cl F F H H 1-methylcyclopropyl 1617 Cl H Cl F F H H 1-ethynylcyclopropyl 1618 Cl H Cl F F H H cyclopropyl 1619 Cl H Cl H Cl H H 1-methylcyclopropyl 1620 Cl H Cl H Cl H H 1-ethynylcyclopropyl 1621 Cl H Cl H Cl H H cyclopropyl 1622 Cl H Cl H Cl H H prop-2-ynyl 1623 F F F H F H H 1-cyanocyclopropyl 1624 F F F H Cl H H 1-cyanocyclopropyl 1626 Cl H Cl H F H H 1-methylcyclopropyl 1627 Cl H Cl H F H H 1-(trifluoromethyl)cyclopropyl 1628 Cl H Cl F F H H 3,3-difluorocyclobutyl 1629 Cl H Cl F F H H prop-2-ynyl 1630 Cl H Cl H F H H 3,3-difluorocyclobutyl 1631 Cl H Cl H F H H prop-2-ynyl 1632 Cl H Cl H F H H cyclopropyl 1633 Cl H Cl H F H H 1-ethynylcyclopropyl

Description

[1012] FIG. 1 shows the structures of the compounds

EXAMPLES

[1013] The compounds are synthesized according to WO2018071327, WO2016168058, WO2016168056 and the following compounds were made according to the following synthesis scheme:

Synthetic Scheme of 1633

[1014] ##STR00073##

Step-1

Synthesis of 2-fluoro-5-nitrobenzoyl chloride (1)

[1015] ##STR00074##

Experimental Procedure:

[1016] To a stirred solution of 2-fluoro-5-nitrobenzoic acid (SM-1) (4 g, 21.62 mmol) in DCM (60 ml) was added oxalyl chloride (2.5 ml, 32.43 mmol) at 0? C. and stirred for 5 min. To this catalytic amount of DMF (0.1 ml) was added and the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC (50% Ethyl acetate in pet ether). After completion of reaction the reaction mixture was completely distilled off under vacuum to afford 2,fluoro-5-nitrobenzoyl chloride (1) (4.1 g, Crude) as light brown semi solid.

Step-2

Synthesis of N-(1-ethynylcyclopropyl)-2-fluoro-5-nitrobenzamide (2)

[1017] ##STR00075##

Experimental Procedure:

[1018] The stirred solution of 1-ethynylcyclopropan-1-amine (SM-2) (1.4 g, 12.35 mmol) in THF (21 ml) was cooled to 0? C. and added DIPEA (5.3 ml, 30.88 mmol), stirred for 10 minutes. To this 2-fluoro-5-nitrobenzoyl chloride (1) (2.1 g, 10.29 mmol) in THF (20 ml) was added and reaction mixture stirred at RT for 6 h. The progress of the reaction was monitored by TLC (50% Ethyl acetate in pet ether (Rf=0.7). After completion of reaction H2O (20 ml) added to the reaction mixture and extracted in EtOAC (2?30 ml), dried over Na2SO4 and concentrated under reduced pressure to afford N-(1-ethynylcyclopropyl)-2-fluoro-5-nitrobenzamide (2) (2.8 g, crude) as brown solid. ESIMS m/z 249.19 ([M+H].sup.+).

Step-3

Synthesis of 5-amino-N-(1-ethynylcyclopropyl)-2-fluorobenzamide (3)

[1019] ##STR00076##

Experimental Procedure:

[1020] The stirred solution of N-(1-ethynylcyclopropyl)-2-fluoro-5-nitrobenzamide (2) (6.0 g, 22.53 mmol) in MeOH/H.sub.2O (85 ml, 1:1 ratio), Fe (3.1 g, 56.45 mmol) and NH.sub.4Cl (6.0 g, 112.90 mmol) were added and RM stirred at 80? C. for 3 hours. The progress of the reaction was monitored by TLC (50% Ethyl acetate in pet ether (0.3 Rf). After completion of reaction, RM filtered through celite bed, washed with MeOH (50 ml) concentrated. H2O (40 ml) added and extracted in EtOAc (3?80 ml), dried over Na2SO4 and concentrated. Crude compound was purified through column chromatography (silica gel 100-200), Eluent gradient 30% Ethyl acetate in pet ether. Combined column fractions were concentrated and dried under reduced pressure to afford 5-amino-N-(1-ethynylcyclopropyl)-2-fluorobenzamide (3) (400 mg, 16%) as brown solid. ESIMS m/z 219.2 ([M+H].sup.+).

Step-4

Synthesis of 5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)-2-fluorobenzamide (1633)

[1021] ##STR00077##

Experimental Procedure:

[1022] The stirred solution of (R,R)-11 (0.4 g, 1.33 mmol) in DCM (20 ml) was cooled to 0? C. and EDC.Math.HCl (0.38 g, 1.99 mmol), DMAP (0.24 g, 1.99 mmol) were added and stirred for 10 min. To this mixture, 5-amino-2,3-difluoro-N-(prop-2-yn-1-yl)benzamide (3) (0.28 g, 1.33 mmol) was added and stirred at RT for 16 h. The progress of the reaction was monitored by TLC (50% Ethyl acetate in pet ether). After completion of reaction H.sub.2O (40 ml) added to the reaction mixture and extracted in DCM (2?50 ml), and the combined organic phases dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was purified through column chromatography (silica gel 100-200). Eluent gradient 10% Ethyl acetate in pet ether to give -5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)-2-fluorobenzamide (1633) (0.38 g, 40%) as pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? ppm 1.075 (s, 2H), 1.235-1.123 (m, 2H), 3.014 (s, 1H), 3.492-3.471 (d, J=8.4 Hz, 1H), 3.620-3.599 (d, J=8.4 Hz 1H), 7.300-7.254 (t, 1H), 7.547 (s, 2H), 7.622 (s, 1H), 7.749-7.731 (m, 1H), 7.862-7.848 (m, 1H) 8.954 (s, 1H), 10.770 (s, 1H): ESIMS m/z 499.02 ([M+H].sup.+).

Synthetic Scheme of 1620

[1023] ##STR00078##

Step-1

Synthesis of 2-chloro-N-(1-ethynylcyclopropyl)-5-nitrobenzamide (2)

[1024] ##STR00079##

Experimental Procedure:

[1025] The stirred solution of 1-ethynylcyclopropan-1-amine hydrochloride SM-2 (1.06 g, 9.09 mmol 0.82(d) in DCM (40 mL) was cooled to 0? C. and added TEA (3.83 ml, 27.27 mmol), stirred for 10 minutes. To this 2-chloro-5-nitrobenzoyl chloride (1) (2.0 g, 9.09 mmol) in DCM (10 mL) was added and the mixture was stirred at RT for 6 h. The progress of the reaction was monitored by TLC (50% Ethyl acetate in pet ether (0.7 Rf). After completion of reaction H.sub.2O (20 ml) added to the reaction mixture and extracted in DCM (2?30 ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 2-chloro-N-(1-ethynylcyclopropyl)-5-nitrobenzamide (2) (2.1 g, crude) as brown solid.

Step-2

Synthesis of 5-amino-2-chloro-N-(1-ethynylcyclopropyl)benzamide (3)

[1026] ##STR00080##

Experimental Procedure:

[1027] The stirred solution of 2-chloro-N-(1-ethynylcyclopropyl)-5-nitrobenzamide (2) (2.1 g, 7.94 mmol) in EtOH/H.sub.2O (63 mL, 4:1 ratio), Fe (2.21 g, 39.71 mmol) and NH.sub.4Cl (2.12 g, 39.71 mmol) were added and RM stirred at 80? C. for 3 hours. The progress of the reaction was monitored by TLC (Ethyl acetate (0.4 Rf). After completion of reaction, RM filtered through celite bed, washed with 10% MeOH/DCM (50 mL). H.sub.2O (40 mL) added and extracted in 10% MeOH/DCM (3?80 mL), dried over Na.sub.2SO.sub.4 concentrated. Crude compound was purified through column chromatography (silica gel 100-200). Eluent gradient 15% Ethyl acetate in pet ether. Combined column fractions were concentrated and dried under reduced pressure to afford 5-amino-2-chloro-N-(1-ethynylcyclopropyl)benzamide (3) (0.8 g, 43%) as light brown solid.

Step-3

Synthesis of 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)benzamide (1620)

[1028] ##STR00081##

Experimental Procedure:

[1029] The stirred solution of (R,R)-11 (0.3 g, 1.00 mmol) in DCM (20 mL) was cooled to 0? C. and EDC.Math.HCl (0.28 g, 1.5 mmol), DMAP (0.18 g, 1.5 mmol) were added and stirred for 10 min. To this 5-amino-2-chloro-N-(1-ethynylcyclopropyl)benzamide (3) (0.23 g, 1.00 mmol) was added and Rm stirred at RT for 6 h. The progress of the reaction was monitored by TLC (30% Ethyl acetate in pet ether (0.6 Rf). After completion of reaction H.sub.2O (40 mL) added to the reaction mixture and extracted in DCM (2?50 mL), dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was purified through column chromatography (silica gel 100-200). Eluent gradient 27% Ethyl acetate in pet ether. Combined column fractions were concentrated and dried under reduced pressure to afford 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)benzamide (1620) (0.23 g, 45%) as off white solid. 1H NMR (400 MHz, DMSO-d6) ? ppm 1.06-1.03 (m, 2H), 1.23-1.15 (m, 2H), 3.031 (s, 1H), 3.50 (d, J=8.4 Hz, 1H), 3.621 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.54 (s, 2H), 7.62 (s, 1H), 7.71-7.66 (m, 2H), 9.07 (s, 1H), 10.84 (s, 1H): ESIMS m/z 515.10 ([M+H].sup.+).

Synthetic Scheme of 1617

[1030] ##STR00082##

Step-1

Synthesis of 2,3-difluoro-5-nitrobenzoyl chloride (1)

[1031] ##STR00083##

[1032] To a stirred solution of 2,3-difluoro-5-nitrobenzoic acid (SM-1) (5 g, 24.63 mmol) in DCM (50 mL) was added oxalyl chloride (2.67 ml, 29.55 mmol) at 0? C. and stirred for 5 min. To this, a catalytic amount of DMF (0.1 mL) was added and the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC (30% Ethyl acetate in petrolether). After completion of reaction the volatiles were completely distilled off under vacuum to afford 2,3-difluoro-5-nitrobenzoyl chloride (1) (5.2 g, Crude) as light brown semi solid.

Step-2

Synthesis of N-(1-ethynylcyclopropyl)-2,3-difluoro-5-nitrobenzamide (2)

[1033] ##STR00084##

Experimental Procedure:

[1034] A stirred solution of 1-ethynylcyclopropan-1-amine SM-2 (1.32 g, 11.28 mmol) in DCM (25 mL) was cooled to 0? C. Triethylamine (TEA) (4.7 mL, 33.85 mmol) was added, and the mixture was stirred for additional 10 minutes. A solution of 2,3-difluoro-5-nitrobenzoyl chloride (1) (2.5 g, 11.28 mmol) in DCM (10 mL) was added and the mixture was stirred for another 6 h at room temperature (RT). The progress of the reaction was monitored by TLC (50% ethyl acetate in petrolether; Rf=0.7). After completion of reaction, H.sub.2O (20 mL) was added to the reaction and the mixture was extracted with DCM (2?30 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford N-(1-ethynylcyclopropyl)-2,3-difluoro-5-nitrobenzamide (2) (2.87 g, crude) as a brown solid. ESIMS m/z 267.2 ([M+H]+).

Step-3

Synthesis of 5-amino-N-(1-ethynylcyclopropyl)-2,3-difluorobenzamide (3)

[1035] ##STR00085##

Experimental Procedure:

[1036] A stirred solution of N-(1-ethynylcyclopropyl)-2,3-difluoro-5-nitrobenzamide (2) (2.87 g, 10.78 mmol) in EtOH/H.sub.2O (57 mL, 4:1 ratio) was brought to reaction with Fe (3.01 g, 53.94 mmol) and NH.sub.4Cl (2.88 g, 53.94 mmol) at 80? C. for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate in petrolether; Rf=0.2). After completion of the reaction, the mixture was filtered through a bed of celite, and washed with 10% MeOH/DCM (50 mL). The organic phase was diluted with H.sub.2O (40 mL), extracted with 10% MeOH/DCM (3?80 mL) and dried over Na.sub.2SO.sub.4. The crude compound was purified by column chromatography (silica gel 100-200; eluent gradient 18% ethyl acetate in petrolether) to afford 5-amino-N-(1-ethynylcyclopropyl)-2,3-difluorobenzamide (3) (1.7 g, 67%) as an off white solid. ESIMS m/z 237.2 ([M+H]+).

Step-4

Synthesis of 5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)-2,3-difluorobenzamide (1617)

[1037] ##STR00086##

Experimental Procedure:

[1038] A stirred solution of (R,R)-11 (0.350 g, 1.16 mmol) in DCM (20 mL) was cooled to 0? C. EDC.Math.HCl (0.33 g, 1.74 mmol) and DMAP (0.21 g, 1.74 mmol) were added and stirred for 10 min. To this mixture 5-amino-N-(1-ethynylcyclopropyl)-2,3-difluorobenzamide (3) (0.27 g, 1.16 mmol) was added and stirred at RT for 16 h. The progress of the reaction was monitored by TLC (30% ethyl acetate in petrolether; Rf=0.5). After completion, the reaction was diluted with H.sub.2O (40 mL). The organic phase was extracted with DCM (2?50 mL) and dried over Na.sub.2SO.sub.4. The crude compound was purified through column chromatography (silica gel 100-200; eluent gradient 15% ethyl acetate in petrolether) to afford 5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(1-ethynylcyclopropyl)-2,3-difluorobenzamide (18D) (0.24 g, 40%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) ? ppm 1.08 (br s, 2H), 1.18 (br s, 2H), 3.04 (s, 1H), 3.50 (d, J=8.4, 1H), 3.63 (d, J=8.4 Hz, 1H), 7.62-755 (m, 4H), 7.89-7.85 (m, 1H), 9.13 (s, 1H), 10.95 (s, 1H): ESIMS m/z 517.12 ([M+H].sup.+).

Chromatographic System:

[1039] Column: Xbridge BEH C18 Waters, 2.1?50 mm, 2.5?

[1040] Oven: 40? C.

[1041] Eluents: Solvent A: water/HCO.sub.2H (0.05%); Solvent B: acetonitrile/HCO.sub.2H (0.05%)

[1042] Flow: 0.8 ml/min

[1043] Gradient:

TABLE-US-00004 Time [min] Solvent A [%] Solvent B [%] 0.0 98 2 1.2 0 100 1.7 0 100 2.2 98 2

[1044] Run time: 2.2 min+0.5 min equilibration time

TABLE-US-00005 HPLC mass Rt signal MW # 1.219 561.8 562.1 1585 1.212 540.9 541.7 1601 1.228 535.8 535.6 1609

EXAMPLES

Example 1: Juvenile Sea Lice Contact Assay

[1045] Copepodids (juvenile sea lice stage of Lepeophtheirus salmonis) were exposed to seawater spiked with declining concentrations of a test compound (dissolved in a DMSO sea-water mixture). Sea lice inhibition (% of dead+damaged copepodids) was assessed after approximately 24 hours of continuous exposure. The vitality of used parasites was confirmed in a negative (solvent) control group.

[1046] Results: The following compounds showed ?80% inhibition at a test concentration of 100 nM:

[1047] (* denotes 100% inhibition)

[1048] 1514*, 1532*, 1544*, 1545*, 1546*, 1547*, 1549*, 1585*, 1587*, 1591*, 1606*, 1611*, 1616*, 1617*, 1625*, 1627, 1629*, 1631*.

[1049] The following compounds showed ?80% inhibition at a test concentration of 10 nM:

[1050] (* denotes 100% inhibition)

[1051] 1500, 1501, 1502*, 1508*, 1509*, 1510*, 1513*, 1515*, 1526*, 1531*, 1537*, 1539*, 1541*, 1552, 1553*, 1554, 1557*, 1561*, 1566*, 1570, 1573*, 1602*, 1603, 1604*, 1609*, 1612*, 1613*, 1615*, 1618*, 1619*, 1620*, 1621*, 1622, 1626, 1628*, 1630*.

[1052] The following compounds showed 80% inhibition at a test concentration of 1 nM:

[1053] (* denotes 100% inhibition)

[1054] 1523, 1567*, 1574, 1589, 1590, 1601*, 1614, 1633.

[1055] The following compounds showed 80% inhibition at a test concentration of 0.1 nM:

[1056] (* denotes 100% inhibition)

[1057] 1584*, 1592, 1594, 1623*, 1624*.

[1058] The following compounds showed 80% inhibition at a test concentration of 0.01 nM:

[1059] (* denotes 100% inhibition)

[1060] 1536*, 1538*, 1551*, 1558*, 1559*, 1563*, 1565*, 1593*, 1605*, 1608*, 1632.

Example 2: Adult Sea Lice Contact Assay

[1061] Mobile stages of sea lice (i.e., pre-adults, adults of Lepeophtheirus salmonis) were exposed to seawater spiked with declining concentrations of a test compound (dissolved in a PEG sea-water mixture). Sea lice inhibition (% of dead+damaged sea lice) was assessed after approximately 1 and 24 hours of continuous exposure in comparison to a negative (solvent) control group.

[1062] Results: The following compounds had an EC.sub.50?25 nM and >10 nM:

[1063] 1514, 1532, 1545, 1546, 1548, 1602, 1603, 1604, 1606, 1612.

[1064] The following compound had an EC.sub.50?10 nM and >1 nM:

[1065] 1508, 1541, 1547, 1585, 1601, 1609, 1615, 1623, 1624, 1626, 1628.

[1066] The following compounds had an EC.sub.50?1 nM:

[1067] 1584, 1587, 1589, 1590, 1592, 1593, 1594, 1605, 1608, 1613, 1614, 1617, 1618, 1619, 1620, 1621, 1622, 1625, 1630, 1632, 1633.

Example 3: Sea Lice Resistance Assay

[1068] A sea lice resistance assay was carried out using mobile sea lice stages (i.e., pre-adults, adults) of several Lepeophtheirus salmonis-isolates with known resistance profiles (i.e., fully susceptible or multiresistant (resistant to azametiphos (OP), emamectin benzoate (ML), deltamethrin (SP)). Sea lice were exposed to seawater spiked with declining concentrations of a test compound (dissolved in a PEG300/sea-water mixture). Sea lice inhibition (% of dead+damaged sea lice) was assessed after approximately 24 and 48 hours of continuous exposure in comparison to a negative (solvent) control group.

[1069] Results: Compound 1590 was equally effective against the sensitive isolate (EC.sub.50 4.12 ppb after 24 hours and 0.40 ppb after 48 hours) and the multi-resistant isolate (EC.sub.50 3.75 ppb after 24 hours and 0.58 ppb after 48 hours).

SalmonIn Vivo Efficacy Against Sea Lice

Example 4: Efficacy Trials Using Gavage Administration

[1070] Salmon (Salmo salar) were treated once orally by gavage at a dose of 5 mg/kg bodyweight per fish (Day 0). As formulation DMSO 5%/fish oil 95% was used. Salmon of the negative control group received only the excipients of the formulation.

[1071] The fish were infested with Lepeophtheirus salmonis copepodids twice before treatment (i.e., around day ?28 and day ?3) and once after treatment (i.e., day 17).

[1072] At day 7, fish were examined under sedation and (pre-)adult sea lice on each fish were counted and removed (assessment of therapeutic efficacy against (pre-)adult sea lice from day ?28 infestation).

[1073] Around day 28 (end of animal phase), fish were euthanized, and lice on each fish were classified ((pre-)adult or juvenile stage) and counted. The number of (pre-) adult and juvenile parasite stages corresponding to the respective infestation time point were used for efficacy calculation, i.e., assessment of therapeutic efficacy against juvenile sea lice from day ?3 infestation and assessment of prophylactic efficacy from day 17 re-infestation. Efficacy is expressed as a % reduction of sea lice in treated groups versus a control group, using the Abbott's formula.

[1074] Results: The following compounds had a therapeutic efficacy of 80% against (pre-)adult sea lice:

[1075] (* denotes 100% efficacy)

[1076] 1541, 1584*, 1585*, 1587, 1590*, 1592*, 1593*, 1594*, 1601*, 1605*, 1606*, 1608*, 1609*, 1617*, 1618*, 1619*, 1620*, 1621*, 1622*, 1623*, 1624*, 1625*, 1626*, 1628*, 1630*, 1632*, 1633*.

[1077] The following compounds had a therapeutic efficacy of 80% against juvenile sea lice:

[1078] (* denotes 100% efficacy)

[1079] 1541*, 1585*, 1590, 1592*, 1593, 1594*, 1601*, 1605*, 1606*, 1608*, 1609*, 1617*, 1618*, 1619, 1620, 1621, 1623, 1624, 1625*, 1626, 1628*, 1630*, 1632, 1633*.

[1080] The following compounds had a prophylactic efficacy of 80% at re-infestation on Day 17

[1081] (* denotes 100% efficacy):

[1082] 1541*, 1590, 1594*, 1609*, 1617*, 1618*, 1624, 1625*, 1628*, 1630*, 1633.

Example 5: Efficacy Trials Using In-Feed Administration

[1083] Four study groups of fish (one group for assessment of therapeutic efficacy, one for assessment of prophylactic efficacy and their respective controls) were used. Commercial fish feed pellets were coated with formulated test compound. As formulation DMSO 5%/fish oil 95% was used. Salmon (Salmo salar) were treated orally with 1 mg/kg fish biomass via coated feed for 7 consecutive days. Salmon of the negative control groups received only feed coated with the excipients of the formulation.

[1084] Fish of the therapeutic groups were infested with Lepeophtheirus salmonis copepodids twice before treatment (around day ?28 and day ?3).

[1085] Around day 8, fish were examined under sedation and (pre) adult sea lice on each fish were counted and removed (assessment of therapeutic efficacy against (pre-)adult sea lice from around day ?28 infestation).

[1086] Around day 25, fish were euthanized and (pre-) adult sea lice on each fish were counted (assessment of therapeutic efficacy against juvenile sea lice from around day ?3 infestation.

[1087] Fish of the prophylactic groups were infested at several time points after treatment in 2-week intervals. The fish were assessed for (pre-)adult sea lice approximately 3 weeks after each re-infestation. At each assessment, all (pre-)adult sea lice were removed from the fish. The number of sea lice on fish corresponding to the respective re-infestation time point were used for prophylactic efficacy calculation. Efficacy is expressed as a % reduction of sea lice in treated groups versus a control group using the Abbott's formula.

[1088] Results: For compounds 1541, 1590, and 1594 100% therapeutic efficacy against (pre-)adult and juvenile sea lice was achieved.

[1089] Against re-infestation after treatment, prophylactic efficacies were 100% (D14) and 100% (D28) for compounds 1541 and 1594.

[1090] Against re-infestation after treatment, prophylactic efficacies were 100% (D14) and 79.2% (D28) for compound 1590.