Method for preventing and treating animal ectoparasites

Abstract

The present invention relates to a method for controlling ectoparasites in animals, in particular mammalian and poultry, livestock animals, comprising contacting the animal, parts thereof, propagation material thereof, pests, food supply, habitat or breeding site thereof with one or more compounds of formula I. The invention also relates to a method for controlling ectoparasites in animals, in particular mammalian and poultry, livestock animals.

Description

Technical Field

[0001] The present invention relates to the technical field of parasite control, and in particular to a method for controlling animal ectoparasites using pyrazole derivatives. Background Art

[0002] 1-Arylpyrazoles are a class of chemicals well known in the art, and certain compounds in this class have been found to have potent activity against a wide range of pests and parasites that harm animals and plants. For example, 1-arylpyrazole derivatives are known in the art to prevent, treat, or control ectoparasite infestations in mammals such as cats, dogs, and cattle.

[0003] With the development of animal husbandry and public health security, traditional drugs for treating external parasitic diseases, such as trichlorfon, which are highly toxic, are gradually being eliminated. In contrast, ideal antiparasitic drugs with safe, broad-spectrum, high efficiency, no or low residue, physical and chemical properties suitable for mass administration, and low price are coming to the stage.

[0004] Therefore, the present application provides a phenylpyrazole derivative with a novel structure for use in a method for preventing and treating animal ectoparasites. Summary of the Invention

[0005] The present invention also provides a method for treating, controlling, preventing and protecting animals from parasitic infestation and infection, which comprises orally, topically or parenterally administering or applying to the animal a parasiticidally effective amount of a compound of formula I or its enantiomer or veterinary acceptable salt or a composition comprising the same.

[0006] The present invention also provides a process for preparing a composition for treating, controlling, preventing or protecting animals from parasitic infestation or infection, the composition comprising a parasiticidally effective amount of a compound of formula I or an enantiomer or veterinarily acceptable salt thereof or a composition comprising the same.

[0007] Activity of compounds against agricultural pests does not imply their suitability for controlling endo- and ectoparasites in and on animals, the latter requiring, for example, low non-emetic doses in the case of oral administration, metabolic compatibility with animals, low toxicity and safe handling.

[0008] The present inventors have surprisingly and unexpectedly found that compounds of formula I have now been found to be useful for reducing infestation or infection by endo- and ectoparasites in and on animals.

[0009] The present invention provides a phenylpyrazole derivative with a novel structure.

[0010]

[0011] in,

[0012] X1, X2, X3, X4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0013] R1 is selected from hydrogen, C 1-6 Alkyl, halogen;

[0014] R2 is selected from C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl may be monosubstituted or polysubstituted by one or more identical or different substituents selected from the group consisting of: halogen, cyano, C 1-3 alkyl;

[0015] R3 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-6 Heterocyclic group, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 3-6 Heterocyclyl C 1-6 alkyl,

[0016] or R3 is selected from -C(=O)-R4, wherein R4 is selected from C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, C 3-8 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 3-12 Cycloalkyl C 1-6 alkyl;

[0017] R3 and R4 may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C6-12 aryl;

[0018] W is selected from nitrogen or carbon.

[0019] In a preferred embodiment, in the compound of formula I,

[0020] X1, X2, X3, X4 are each independently selected from hydrogen, halogen, C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy;

[0021] R1 is selected from hydrogen, C 1-3 Alkyl, halogen;

[0022] R2 is selected from C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkyl may be monosubstituted or polysubstituted by one or more identical or different substituents selected from the group consisting of: halogen, cyano, C 1-3 alkyl;

[0023] R3 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-6 Heterocyclic group, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 3-6 Heterocyclyl C 1-3 alkyl,

[0024] or R3 is selected from -C(=O)-R4, wherein R4 is selected from C 1-3 Alkyl, C 1-4 Alkenyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Alkylthio C 1-3 Alkyl, C 1-3 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 alkyl;

[0025] R3 and R4 may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 6-12 aryl;

[0026] W is selected from nitrogen or carbon.

[0027] In a preferred embodiment, the compound of formula I is selected from compounds II to 1-23, which are:

[0028] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(oxacyclopropyl-2-ylmethyl)nicotinamide (I-1);

[0029] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-(oxeran-2-yl)ethyl)nicotinamide (I-2);

[0030] 2-chloro-N-cyclopropyl-N-(cyclopropylmethyl)-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-3);

[0031] 2-chloro-N-cyclopropyl-N-(2-cyclopropylethyl)-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-4);

[0032] Methyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-5);

[0033] 2-Chloroethyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-6);

[0034] 2-Methoxyethyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-7);

[0035] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(dimethylcarbamoyl)nicotinamide (I-8);

[0036] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(diisopropylcarbamoyl)nicotinamide (I-9);

[0037] 2-chloro-N-(cyclopropanecarbonyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-10);

[0038] N-Acetyl-2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-11);

[0039] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-propionylnicotinamide (I-12);

[0040] 2-chloro-N-(2-chloropropionyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-13);

[0041] (E)-N-(But-2-enyl)-2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-14);

[0042] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(3-methylbut-2-enyl)nicotinamide (I-15);

[0043] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-methoxyacetyl)nicotinamide (I-16);

[0044] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(3-(methylthio)propionyl)nicotinamide (I-17);

[0045] 2-Chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-phenoxypropanoyl)nicotinamide (I-18);

[0046] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(furan-2-carbonyl)nicotinamide (I-19);

[0047] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-methylbenzoyl)nicotinamide (I-20);

[0048] 2-chloro-N-(4-cyanobenzoyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-21);

[0049] 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(4-(dimethylamino)benzoyl)nicotinamide (I-22);

[0050] 2-Chloro-N-(6-chloronicotinoyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-23).

[0051] The compounds of the invention or their enantiomers or veterinarily acceptable salts and compositions comprising them are preferably used for controlling and preventing infestations and infections in mammals, livestock and poultry. They are suitable, for example, for controlling and preventing infestations and infections in mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, cattle, sheep, pigs, camels, deer, horses, piglets, poultry, rabbits, goats, dogs, cats, buffaloes, donkeys, fallow deer and reindeer, as well as in fur-bearing animals such as mink, chinchillas and raccoons, livestock such as hens, geese, turkeys and ducks, and fish such as freshwater fish and saltwater fish such as salmon, carp and eels.

[0052] In a preferred embodiment, the compounds of the invention or their enantiomers or veterinarily acceptable salts and compositions comprising them are used for controlling and preventing infestations and infections in mammals such as cats, dogs, cattle, sheep, horses, pigs, donkeys, camels, mules, deer.

[0053] In a preferred embodiment, the compounds of the invention or their enantiomers or veterinarily acceptable salts and compositions comprising them are used for controlling and preventing infestations and infections in livestock and poultry animals such as chickens, ducks, geese and rabbits.

[0054] The compounds of the invention or their enantiomers or veterinarily acceptable salts and compositions comprising them are suitable for the systemic and / or non-systemic control of ecto- and / or endoparasites in animals.

[0055] The compounds of the present invention are useful in the treatment and control of various life cycle stages of parasites, including eggs, nymphs and larvae, juveniles and adults.

[0056] The compounds of the present invention are particularly useful for preventing and / or treating ectoparasites in animals.

[0057] In a preferred embodiment, the prevention and / or treatment of animal ectoparasites is selected from the class Nematoda, Insecta or Arachnida.

[0058] In a preferred embodiment, the parasite is selected from the order Strongylida, Rhabditis, Ascaris, Acroura, Spirulina, Filariales, Flagylaria, Stomatidae, Acarina, Acarina, Blattodea, Pseudacrida, Thysanoptera, Homoptera, Hemiptera, Hymenoptera, Isoptera, Diptera or Siphonaptera.

[0059] In a preferred embodiment, the parasite is selected from the family Trichomydae, Uncinata, Nodaceae, Dictyomydae, Cynomydae, Ascaridae, Toxoceratinidae, Aviascaridae, Oxyuracidae, Tubulidae, Spirulina, Capillariidae, Trichomydae, Trichuridae, Culicidae, Muscidae, Formicidae, Puccinidae, Fleabidae, Gamascaridae, Ixodidae or Sarcoptes.

[0060] In a particularly preferred embodiment, the parasite is selected from:

[0061] Fleas (e.g. Pulex spp., Ctenocephalides spp., such as Ctenocephalides felis, etc.),

[0062] Ticks (e.g., Rhipicephalus spp., Ixodes spp., Haemaphysalis spp., Dermacentor spp., Amblyoma spp., Boophilus spp., etc.),

[0063] Mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., etc.),

[0064] Lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.),

[0065] Mosquitoes (Aedes spp., Culux spp., Anopheles spp., Bradysia spp., etc.),

[0066] flies (Hematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Coclyomia spp., etc.), and / or

[0067] Termites, fire ants, and cockroaches.

[0068] In a particularly preferred embodiment, the parasite is selected from the group consisting of Ctenocephalides felis, Rhipicephalus sanguineus, Boophilus microplus, Bradygia leekis, Aedes albopictus, housefly, termite, fire ant, and American cockroach.

[0069] The compounds of the present invention can be administered in a prophylactic or therapeutic manner.

[0070] The active compounds of the present invention are administered directly or in the form of suitable preparations orally, topically / transdermally or parenterally.

[0071] For oral administration to animals, the compounds of this invention can be formulated into animal feed, animal feed premix, animal feed concentrate, pill, solution, paste, suspension, immersion, gel, tablet, bolus and capsule. In addition, the compounds of this invention can be administered to animals in their drinking water. For oral administration, selected dosage form should provide 0.01-100mg / kg animal body weight / day, preferably 0.1-100mg / kg animal body weight / day of formula I compound for animals.

[0072] Alternatively, the compounds of this invention can be administered to animals parenterally, for example, by intracavitary, intramuscular, intravenous or subcutaneous injection. The compounds of this invention can be dispersed or dissolved in a physiologically acceptable carrier for subcutaneous injection. Alternatively, the compounds of this invention can be formulated into an implant for subcutaneous administration. In addition, the compounds of this invention can be administered to animals transdermally. For parenteral administration, the selected dosage form should provide the animal with 0.01-100 mg / kg animal body weight / day of the compound of this invention.

[0073] Compositions useful in the present invention may generally contain from about 0.001% to 95% of a compound of formula I.

[0074] It is generally advantageous to administer the compounds of the invention in a total amount of 0.5 to 100 mg / kg / day, preferably 1 to 50 mg / kg / day.

[0075] The ready-to-use preparations contain the compounds acting against parasites, preferably ectoparasites, in a concentration of 10 ppm to 80% by weight, preferably 0.1-65% by weight, more preferably 1-50% by weight, most preferably 5-40% by weight.

[0076] The preparations to be diluted before use contain the compounds active against ectoparasites in a concentration of 0.5 to 90% by weight, preferably 1 to 50% by weight.

[0077] Furthermore, the preparations comprise the compounds of the formula I acting against endoparasites in a concentration of 10 ppm to 2% by weight, preferably 0.05-0.9% by weight, very particularly preferably 0.005-0.25% by weight.

[0078] The compounds of the present invention can also be administered topically to animals in the form of immersions, dusts, powders, rings, medallions, sprays, shampoos, spot-on and pour-on formulations, as well as in ointments or oil-in-water or water-in-oil emulsions. For topical administration, immersions and sprays typically contain 0.5-5,000 ppm, preferably 1-3,000 ppm, of the compounds of the present invention. In addition, the compounds of the present invention can be formulated as ear patches for animals, particularly quadrupeds such as cattle and sheep.

[0079] In another preferred embodiment, topical application is carried out in the form of shaped articles containing the compound, such as rings, tags, ear patches, bandages for fastening to body parts, as well as adhesive strips and foils.

[0080] Suitable formulations are:

[0081] - solutions, such as oral solutions, concentrates for oral administration after dilution, solutions for application on the skin or in body cavities, spray formulations, gels;

[0082] - Emulsions and suspensions for oral or dermal administration; semisolid preparations;

[0083] - formulations in which the active compound is processed in an ointment base or in an oil-in-water or water-in-oil emulsion base;

[0084] - solid preparations such as powders, premixes or concentrates, granules, pills, tablets, boluses, capsules; aerosols and inhalants, and shaped articles containing the active compound.

[0085] Compositions suitable for injection are prepared by dissolving the active ingredient in a suitable solvent and optionally adding other ingredients such as acids, bases, buffer salts, preservatives and solubilizers. These solutions are filtered and filled aseptically.

[0086] Suitable solvents are physiologically tolerated solvents such as water, alkanols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, N-methylpyrrolidone, 2-pyrrolidone and mixtures thereof.

[0087] The active compounds can optionally be dissolved in physiologically tolerable vegetable or synthetic oils suitable for injection.

[0088] Suitable solubilizers are solvents which promote the dissolution of the active compound in the main solvent or prevent its precipitation. Examples are polyvinyl pyrrolidone, polyvinyl alcohol, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.

[0089] Suitable preservatives are benzyl alcohol, chlorobutanol, parabens and n-butanol.

[0090] Oral solutions are administered directly. Concentrates are administered orally after being diluted to the intended use concentration. Oral solutions and concentrates are prepared according to the prior art described above for injections, and sterile procedures are not required.

[0091] Solutions for use on the skin are dripped, spread, rubbed, sprinkled or sprayed.

[0092] Solutions for application to the skin are prepared according to the prior art and as described above for injections, sterile procedures not being necessary.

[0093] It is generally advantageous to administer a solid formulation which releases the compound of the invention in a total amount of 1-300 mg / kg, preferably 10-200 mg / kg, most preferably 10-160 mg / kg body weight of the treated animal over three weeks.

[0094] Generally speaking, a "parasiticidally effective amount" refers to the amount of active ingredient required to achieve an observable effect on growth, including necrosis, mortality, retardation, prevention, and removal, destruction, or reduction of the presence and activity of the target organism. The parasiticidally effective amount may vary for the various compounds / compositions used in the present invention. The parasiticidally effective amount of a composition will also vary depending on prevailing conditions such as the desired parasiticidal effect and duration, the target species, the mode of administration, and the like.

[0095] The compounds of the present invention can be administered alone or in the form of compositions, and can be administered internally or externally in unmodified form or preferably together with adjuvants conventionally used in the pharmaceutical formulation art.

[0096] The present invention also relates to a composition for controlling parasites in and on animals comprising a parasiticidally effective amount of a pyrazole derivative of formula I, its stereoisomers, salts, tautomers or N-oxides and an acceptable carrier.

[0097] In a preferred embodiment, the compounds of the present invention can be combined with an acceptable carrier, such as a C1-C 10 Alcohol or ester, C 10 -C 18 Saturated fatty acids or esters, C 10 -C 18 Monounsaturated fatty acids or esters, monoesters or diesters of aliphatic diacids, monoglycerides, diglycerides, triglycerides, glycols, glycol ethers, glycol esters, glycol carbonates, polyethylene glycol, polyethylene glycol monoethers, polyethylene glycol diethers, polyethylene glycol monoesters, polyethylene glycol diesters, or mixtures thereof, as a component in a pharmaceutically or veterinarily acceptable carrier or diluent. In other embodiments, the composition can include acetone, acetonitrile, benzyl alcohol, ethanol, isopropyl alcohol, diisobutyl adipate, diisopropyl adipate, glycerol ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol monomethyl ether, propylene glycol monoethyl ether, isosorbide dimethyl ether, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, glyceryl triacetate, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, or any combination thereof in a pharmaceutically or veterinarily acceptable carrier or diluent.

[0098] In a preferred embodiment, the compounds of the present invention can be processed by known methods to obtain, for example, liquid preparations (e.g., spot-on, pour-on, spray-on, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semi-solid preparations (e.g., creams, ointments, pastes, gels, liposomal preparations) and solid preparations (e.g., food additive tablets, including, for example, capsules, powders, including soluble powders, granules or embeddings of the active ingredient in a polymeric substance, such as implants and microparticles).

[0099] These preparations can be prepared by means known per se. Usually, the compound according to the present invention or composition are mixed with a developer (such as a liquid diluent or carrier, a liquid gas diluent or carrier, a solid diluent or carrier), and optionally mixed with a surfactant (such as an anionic surfactant, a cationic surfactant and a nonionic surfactant, such as dioctyl sodium sulfosuccinate) and / or a dispersant. In addition, except for the developer and the optional surfactant and / or dispersant, other adjuvant ingredients may be present in the preparation, such as emulsifier, foam-forming agent or defoamer (such as dimethicone), preservative, adhesive and / or colorant. The preparation of active compound or composition preferably comprises a developer, an emulsifier and / or dispersant and / or a foam-forming agent.

[0100] Ectoparasites in the present invention are understood to encompass organisms that reside on the skin or outer coverings of another organism (host organism) for varying periods of time, such as the scales, feathers, hair, and in particular those that are dependent on the other organism for maintenance, such as a blood meal. That is, the term ectoparasite includes those organisms that remain on the skin or outer coverings of a host organism for relatively long periods of time, such as ticks and fleas, as well as organisms that remain on the host for relatively short periods of time, such as mosquitoes and tsetse flies, which may be referred to as transient ectoparasites.

[0101] In a preferred embodiment, the present invention reduces the infestation of ectoparasites by the expelling activity of the preparations or compounds of the present invention and / or the killing activity of the preparations or compounds of the present invention. Therefore, the preparations or compounds of the present invention can have both expelling activity and killing activity against ectoparasites such as insects and / or ticks or expelling activity or killing activity. Expelling and / or killing activity can be determined using the methods provided herein, specifically the methods employed in the Examples section below.

[0102] The compounds of the present invention can be used in particular for controlling the following parasites respectively:

[0103] From the order of the Acarina, for example, Rhipicephalus spp., Boophilus spp., Olygonychus spp., Panonychus spp., Eotetranychus spp., Rhizoglyphus spp., Bryobia spp., Sarcoptes spp., Ixodes spp., Tetranychus spp.;

[0104] From the order Blattaria, for example, Blatta orientalis, Periplaneta americana, Blattella germanica, Suppella longipalpa, and Supella spp.;

[0105] From the order of the Anoplurida, for example, Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp., Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asini macrocephalus, Haematopinus usurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloera vastatrix, pubic lice (Phthiruspubis), and hairy tube lice (Solenopotes capillatus);

[0106] From the order of the Hymenoptera, for example, Acromyrmex, Arge spp., Atta spp., Cephus spp., Diprion spp., Diprionidae, Gilpinia polytoma, Hoplocampa spp., Lasius spp., Monomorium pharaonis, Neodiprions spp., Pogonomyrmex spp., Imported Fire Ant, Solenopsis spp. and Vespa spp.;

[0107] From the order Isoptera, for example, Coptotermes spp., Corniternes cumulans, Incisitermes spp., Macrotermes spp., Mastotermes spp., Microtermes spp., Reticulitermes spp.; Tropical fire ant (Solenopsis geminate);

[0108] From the order Diptera and the suborder Nematocerina and Brachycerina, for example, Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmia spp., Hybomitras spp., Atylotus spp. spp.), Tabanus spp., Haematopotas spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp.), Hippobosca spp., Lipoptena spp., Melophagus spp., Rhinoestrus spp., Tipula spp., Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora erythrocephala, Chrysozonapluvialis, Culex quinquefasciatus, Culexpipiens), Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxyscalcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Phlebotomus papatasi, Phlebotomus longipalpis, Odagmia ornata, Wilhelmia equina, Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea, Chrysopscaecutiens, Chrysopsrelictus, Haematopota pluvialis, Haematopota italica, Musca autumnalis, Musca domestica, Haematobia irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea albipuncta, Chrysomya chloropyga, Chrysomya bezziana, Oestrusovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus), Lipoptena capreoli, Lipoptena cervi, Hippoboscavariegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilushaemorroidalis), Gasterophilusinermis, Gasterophilus nasalis, Gasterophilusnigricornis, Gasterophilus peeorum, and Braula coeca;

[0109] From the order of the Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp., Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsyllacheopis;

[0110] The compounds of the present invention are particularly useful for controlling pests of the orders Acarina, Blattaria, Pediculus, Hymenoptera, Isoptera, Diptera and Siphonaptera.

[0111] Compared with the prior art, the advantages of the present invention are:

[0112] The pyrazole derivatives involved in the present invention are all of medium to low toxicity to animals. Compared with similar products, such as highly toxic avermectin and fipronil, the toxicity of the compounds of the present invention is significantly reduced. Therefore, the product is more environmentally friendly and has better market application prospects. DETAILED DESCRIPTION

[0113] The present invention is further described below by way of examples. It must be pointed out that these examples are intended to illustrate the present invention and should not be construed as limiting the present invention.

[0114] The pyrazole derivatives of formula I of the present invention can be prepared by the methods disclosed in a series of patent applications previously filed by the applicant.

[0115] The biological activities of the pyrazole derivatives of formula I of the present invention can be confirmed and evaluated in the biological tests described below.

[0116] Example A: In vitro evaluation of ingestion activity against adult cat fleas

[0117] To prepare the test blood mixture for feeding fleas, the test substance is dissolved in dimethyl sulfoxide and diluted to the desired concentration with citrated bovine blood. To assemble the test apparatus, approximately 20 unfed adult male and female cat fleas (Ctenocephalides felis) are placed in a chamber sealed at the top and bottom with gauze. A metal cylinder is sealed at one end with parafilm, placed on the chamber together with a sealed base, and filled with the test blood mixture, which the fleas can absorb through the parafilm. The blood cylinder portion of the assembled test apparatus is housed in an insulated air-heated container at approximately 37°C, located above an insulated carrier plate containing the flea chamber. The flea chamber portion is maintained at room temperature. After 48 hours, the insecticidal activity against fleas is determined.

[0118] In this test, at a dose of 10 mg / L, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12. I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, and I-23 showed more than 80% insecticidal activity;

[0119] In this test, at a dose of 1 mg / L, compounds of formula I, including I-3, I-5, I-6, I-8, I-10, I-11, I-12, I-13, I-16, I-19, I-20, I-22, and I-23, exhibited a killing activity of more than 70%.

[0120] Example B: In vitro evaluation of contact activity against adult brown dog ticks

[0121] In vitro contact tests with ticks were performed using adult male and female Rhipicephalus sanguineus. For coating the test vials, the test substance was dissolved and diluted with acetone to the desired concentration. The solution was then applied evenly to the inner wall and bottom of the glass vial by rotating and shaking on an orbital shaker until the solvent had completely evaporated. For example, a 900 ppm solution of the test substance was used to obtain a concentration of 5 μg / cm 2 After complete evaporation of the solvent, 5-10 adult ticks were applied to each coated test vial, which was then sealed with a perforated plastic cap and incubated in a horizontal position in the dark at room temperature and ambient humidity. Acaricidal activity was determined after 48 hours. To do this, ticks were gently tapped to dislodge them from the bottom of the test vial, which was then incubated on a hot plate at 45-50°C for no more than 5 minutes. Ticks that remained stationary at the bottom of the test vial or moved uncoordinatedly without intentionally climbing up to escape the heat were considered dead or moribund.

[0122] In this test, 5 μg / cm 2 At the dosage, I-3, I-4, I-5, I-6, I-7, I-8, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-22, and I-23 among the compounds of formula I exhibit more than 90% insecticidal activity.

[0123] Example C: In vitro evaluation of systemic activity against Boophilus microplus

[0124] An in vitro drug immersion test on the microscopic boophilus tick (B. microplus) was conducted. The collected microscopic boophilus ticks were divided into groups, with 10 in each group and 3 replicates in each group. Two control groups were also set up. The ticks in each group were immersed in different drugs for 5 minutes using an in vitro immersion method. The drug solution on the surface of the ticks was then blotted dry with filter paper, placed in a test tube, sealed with a cloth, and incubated in a 25-28°C incubator. The two control groups were treated with solvents and untreated microscopic boophilus ticks as controls, and the other processes were the same as the experimental groups. Statistics on the tick-killing effect: The number of molting ticks in each group was mainly recorded. Ticks that were able to molt and develop into adult ticks were considered to have molted successfully (the fewer the number of molting ticks, the better the effect of the drug on tick-killing). Data were sorted using EXCEL software to obtain the average molting rate of the microscopic boophilus ticks. The standard deviation of the molting rate was obtained using the standard deviation (STDEVPA) function of the sample population in EXCEL. SPPS19.0 statistical analysis software was used to compare the molting rates of Boophilus microplus at the same concentration of the same drug by Duncan's significant difference analysis.

[0125] In this test, at a dose of 10 mg / L, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I among the compounds of formula I -12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23 show 100% tick killing effect;

[0126] In this test, at a dose of 1 mg / L, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12. I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, and I-23 show more than 85% tick killing effect.

[0127] Example D: Activity test on Bradysia chinensis

[0128] Lay clean filter paper flat on an 8cm diameter Petri dish with agar underneath. Add 1mL of the prepared solution to the filter paper. Cut the pseudostem of leek into approximately 2cm segments and soak them in 50mg / L and 5mg / L solutions for 30s, respectively. Remove the segments and remove them with absorbent paper to remove excess solution. Place the segments on filter paper dripping with the same concentration of solution, 5 segments per Petri dish. Then, use a brush to select uniformly sized third-instar Bradysoma leek fungus gnat larvae and place them in the Petri dishes, 30 per dish, repeat three times, and set up a blank control. After 48 hours, observe the results. Gently touch the insect body with a brush; no reaction is considered dead.

[0129] In this test, at a dose of 50 mg / L, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I among the compounds of formula I -12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23 showed 100% insecticidal activity;

[0130] In this test, at a dose of 5 mg / L, I-3, I-5, I-6, I-8, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-19, I-20, I-21, I-22, and I-23 of the compounds of formula I showed more than 90% insecticidal activity.

[0131] Example E: Activity test against Aedes albopictus

[0132] Aedes albopictus mosquitoes were a susceptible strain imported from the Centers for Disease Control and Prevention and naive to any insecticide exposure. They were reared in a sanitary pest control room. Rearing conditions included a temperature of 26±1°C, a relative humidity of 65%±10%, and a photoperiod of 12h / 12h. For the larval toxicity test, healthy, uniformly sized fourth-instar larvae were selected. The toxicity of the test samples against Aedes albopictus larvae was determined using the standard immersion method according to the WHO (1981).

[0133] In this test, at a dose of 20 mg / L, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12. I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, and I-23 showed more than 70% insecticidal activity.

[0134] Example F: Determination of activity against termites

[0135] Dilute the test agent into a series of gradients. Place a 7 cm diameter qualitative filter paper in a 9 cm disposable Petri dish. Use a pipette to evenly dispense 1 ml of the solution from the outer edge to the center of the dish. Place on a laboratory bench to dry in the shade until ready to use. Inoculate 30 Reticulitermes flavipes workers in each dish and seal the dish to prevent termites from escaping. A control treatment uses a solvent without the agent. Repeat each treatment three times. Count live and dead insects 48 hours after application. The test concentration is 20 mg / L.

[0136] In this test, at a dose of 20 mg / L, I-3, I-5, I-6, I-8, I-9, I-10, I-11, I-12, I-13, I-15, I-16, I-18, I-19, I-20, I-22, and I-23 of the compounds of formula I showed an insecticidal activity of more than 70%.

[0137] Example G: Determination of activity against cockroaches

[0138] For the test, uniformly healthy, fourth-instar male nymphs of the American cockroach (Periplaneta americana) were selected. After being anesthetized with carbon dioxide, the test insects were arranged in a supine position on a plate. Ten insects were treated with each concentration of each agent, with 1 μl of the agent solution dripped onto the ventral plate between the second and third pairs of leg bases, starting from low to high concentrations, using a micropipette. A control treatment was performed with a solvent containing no agent. Each treatment was repeated three times. After the drips, the insects were fed normally, and the number of live and dead insects was examined 48 hours later. The test concentration was 200 mg / L.

[0139] In this test, at a dose of 200 mg / L, I-1, I-2, I-3, I-5, I-6, I-8, I-10, I-11, I-12, I-13, I-16, I-17, I-18, I-19, I-20, I-22, and I-23 of the compounds of formula I exhibited insecticidal activity of more than 70%.

[0140] From the above effects, it can be seen that the compounds of general formula I of the present invention can be used for the prevention and / or treatment of animal ectoparasites, and have unexpected control effects. It can be foreseen that even if the dosage of the compound is further reduced, the compounds of the present invention still have outstanding control effects and have good development prospects.

[0141] In addition to pest control properties, the compounds according to the present invention surprisingly show improved degradation properties compared to the compounds of the prior art. In addition, the compounds according to the present invention surprisingly show lower toxicity to bees (or aquatic animals) compared to the compounds of the prior art.

[0142] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

Claims

1. A method for controlling ectoparasites in animals, comprising contacting the animals, parts thereof, their propagation material, pests, their food supply, habitat or breeding grounds with a pyrazole derivative of the general formula I, or a stereoisomer, salt, tautomer or N-oxide thereof, or a composition comprising at least one compound of the formula (I): in, X1, X2, X3, X4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-12 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R1 is selected from hydrogen, C 1-6 Alkyl, halogen; R2 is selected from C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl may be monosubstituted or polysubstituted by one or more identical or different substituents selected from the group consisting of: halogen, cyano, C 1-3 alkyl; R3 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-6 Heterocyclic group, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 3-6 Heterocyclyl C 1-6 alkyl, or R3 is selected from -C(=O)-R4, wherein R4 is selected from C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, C 3-8 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkylthio C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 3-12 Cycloalkyl C 1-6 alkyl; R3 and R4 may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-12 aryl; W is selected from nitrogen or carbon.

2. The method according to claim 1, characterized in that In the pyrazole derivatives of general formula I, X1, X2, X3, X4 are each independently selected from hydrogen, halogen, C 1-3 Alkyl, C 3-12 Cycloalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy; R1 is selected from hydrogen, C 1-3 Alkyl, halogen; R2 is selected from C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkyl may be monosubstituted or polysubstituted by one or more identical or different substituents selected from the group consisting of: halogen, cyano, C 1-3 alkyl; R3 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-6 Heterocyclic group, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 3-6 Heterocyclyl C 1-3 alkyl, or R3 is selected from -C(=O)-R4, wherein R4 is selected from C 1-3 Alkyl, C 1-4 Alkenyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Alkylthio C 1-3 Alkyl, C 1-3 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 alkyl; R3 and R4 may be substituted or polysubstituted by one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 6-12 aryl; W is selected from nitrogen or carbon.

3. The method according to claim 1, characterized in that The compound of formula I is selected from compound II to 1-23, which is: 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(oxacyclopropyl-2-ylmethyl)nicotinamide (I-1); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-(oxeran-2-yl)ethyl)nicotinamide (I-2); 2-chloro-N-cyclopropyl-N-(cyclopropylmethyl)-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-3); 2-chloro-N-cyclopropyl-N-(2-cyclopropylethyl)-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-4); Methyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-5); 2-Chloroethyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-6); 2-Methoxyethyl (2-chloro-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinoyl)(cyclopropyl)carbamate (I-7); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(dimethylcarbamoyl)nicotinamide (I-8); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(diisopropylcarbamoyl)nicotinamide (I-9); 2-chloro-N-(cyclopropanecarbonyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-10); N-Acetyl-2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-11); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-propionylnicotinamide (I-12); 2-chloro-N-(2-chloropropionyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-13); (E)-N-(But-2-enyl)-2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-14); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(3-methylbut-2-enyl)nicotinamide (I-15); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-methoxyacetyl)nicotinamide (I-16); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(3-(methylthio)propionyl)nicotinamide (I-17); 2-Chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-phenoxypropanoyl)nicotinamide (I-18); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(furan-2-carbonyl)nicotinamide (I-19); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(2-methylbenzoyl)nicotinamide (I-20); 2-chloro-N-(4-cyanobenzoyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-21); 2-chloro-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(4-(dimethylamino)benzoyl)nicotinamide (I-22); 2-Chloro-N-(6-chloronicotinoyl)-N-cyclopropyl-5-(1-(2,6-dichloro-4-(perfluoropropan-2-yl)phenyl)-1H-pyrazol-4-yl)nicotinamide (I-23).

4. The method according to any one of claims 1 to 3, characterized in that The animal is selected from mammals, livestock, and poultry.

5. The method according to any one of claims 1 to 3, characterized in that The parasite is selected from the class Nematoda, Insecta or Arachnida.

6. The method according to claim 4, characterized in that The animals are selected from cats, dogs, cows, sheep, horses, pigs, camels, donkeys, mules, deer, chickens, ducks, geese, rabbits, and pigeons.

7. The method according to claim 5, characterized in that The parasite is selected from the order Strongylida, Rhabditis, Ascaris, Acroura, Spirulina, Filariales, Flagylaria, Stomatidae, Acarina, Acarina, Blattodea, Pseudoptera, Thysanoptera, Homoptera, Hemiptera, Hymenoptera, Isoptera, Diptera or Siphonaptera.

8. A method for treating, controlling, preventing or protecting an animal from parasitic infestation or infection, characterized in that: The method is carried out by orally, topically or parenterally administering or applying the pyrazole derivative of the general formula (I) according to claim 1 or a composition comprising at least one compound of the formula (I) to an animal.

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