HK1149695A - Ectoparasite control method - Google Patents

Description

Ectoparasite control method

Technical Field

The present invention relates to certain methods of controlling ectoparasitic insects on a warm-blooded animal.

Background

In animals, including humans, ectoparasitic insects are particularly troublesome. They are annoying and can be harmful due to the underlying spread of the disease. Although there is a great need in the industry for products to control or eradicate such ectoparasites, prior art efforts have failed to provide effective formulations capable of completely eradicating or controlling them while also being non-toxic to humans and animals.

To meet consumer demand for products with this characteristic, a variety of pesticide, insecticide and repellent formulations have been developed. These products are generally limited by drawbacks related to their toxicity or lack of efficacy due to the evolution of resistance by the parasites. Thus, there is an urgent need for novel compounds that are effective against such pests, which are relatively non-toxic to the animal species for which they are used to protect.

Summary of The Invention

The present invention relates to a method of controlling or preventing infestation of animals by ectoparasitic insects, preferably hematophagous ectoparasitic insects, by applying to the animals a composition comprising a parasiticidally effective amount of a compound of formula 1, or an N-oxide or salt thereof,

wherein

R¹Me, Cl, Br or F;

R²is F, Cl, Br, C₁-C₄Haloalkyl or C₁-C₄A haloalkoxy group;

R³f, Cl or Br;

R⁴is H; c₁-C₄Alkyl radical, C₃-C₄Alkenyl radical, C₃-C₄Alkynyl, C₃-C₅Cycloalkyl, or C₄-C₆Cycloalkylalkyl, each of which is optionally substituted with one substituent selected from halogen, CN, SMe, S (O) Me, S (O)₂Me and OMe;

R⁵is H or Me;

R⁶h, F or Cl; and

R⁷h, F or Cl.

The invention also includes compounds of formula 1 for use as medicaments.

The invention also relates to the use of a compound of formula 1 for the manufacture of a medicament for treating animal infestations by ectoparasitic insects.

Detailed Description

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not to an exclusive "or". For example, the condition a or B is satisfied in any of the following cases: a is true (or present) and B is spurious (or absent), a is spurious (or absent) and B is true (or present), and both a and B are true (or present).

Also, the indefinite articles "a" or "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be understood to include one or at least one and the singular forms of an element or component also include the plural unless the number clearly indicates the singular.

In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl", includes straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, i-propyl, or the different butyl isomers. The term "halogen", alone or in compound words such as "haloalkoxy", includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words such as "haloalkyl" or "haloalkoxy", said alkyl or alkoxy groups may be partially or fully substituted by the same or different halogen atoms. Examples of "haloalkyl" include F₃C、ClCH₂、CF₃CH₂And CF₃CCl₂. Examples of "haloalkoxy" include CF₃O、HCF₂O、CCl₃CH₂O、HCF₂CH₂CH₂O and CF₃CH₂O。

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires an available lone pair to oxidize to an oxide. Those skilled in the art will be aware of those nitrogen-containing heterocycles which can form N-oxides. Those skilled in the art will also appreciate that tertiary amines can form N-oxides. Synthetic methods for preparing heterocyclic and tertiary amine N-oxides are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the following documents, see for example: comprehensive Organic Synthesis by T.L.Gilchrist, Vol.7, pp.748-; comprehensive Heterocyclic Chemistry by m.tisler and b.stanovnik, volume 3, pages 18-20 (compiled by a.j.boulton and a.mckillop, Pergamon Press); advances in Heterocyclic Chemistry, Vol.43, pp.149-161, by M.R.Grimett and B.R.T.Keene (eds. A.R.Katritzky, Academic Press); advances in Heterocyclic Chemistry, Vol.9, pp.285-291, by M.Tisler and B.Stanovnik (A.R.Katritzky and A.J.Boulton eds., Academic Press); and Advances in heterocyclic chemistry, Vol.22, p.390-.

The compounds of the present invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). In addition, one skilled in the art knows how to isolate, enrich, and/or selectively prepare the stereoisomers. Accordingly, the present invention includes compounds selected from formula 1, N-oxides and salts thereof. Pharmaceutically or veterinarily acceptable salts suitable for the mode of administration are envisaged. The compounds of the present invention may exist as mixtures of stereoisomers, individual stereoisomers, or as optically active forms.

Salts of the compounds of the present invention include acid-addition salts formed with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric. In the compositions and methods of the invention, the compound salts of the invention are preferably suitable for veterinary/medical use as described herein.

Of note are compounds of formula I wherein

R⁴Is H or C optionally substituted by one substituent selected from CN, SMe and OMe₁-C₄An alkyl group;

R⁵is H or Me;

R⁶is H; and

R⁷is H.

It is also noteworthy that:

a) a compound of formula 1, wherein

R¹Me or Cl;

R²is Cl, Br, CF₃、OCF₂H、OCF₃Or OCH₂CF₃(ii) a And

R⁴is H, Me, Et, i-Pr, t-Bu, CH₂CN、CH(Me)CH₂SMe or C (Me)₂CH₂SMe。

b) The above compound a), wherein

R²Is Cl, Br, CF₃Or OCH₂CF₃；

R⁴Is H, Me, Et or i-Pr; and

R⁵is H.

c) Compound b), wherein:

R¹is Me; r²Is Br; r³Is Cl; r⁴Is Me.

Also of note are compounds a, b, c above, wherein R is⁶Is H; and R is⁷Is H.

Compounds of particular interest are:

or 3-bromo-1- (3-chloro-2-pyridinyl) -N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl ] phenyl ] -1H-pyrazole-5-carboxamide.

Preferred compositions of the invention are those comprising the preferred compounds described above. Preferred methods of use are those involving the preferred compounds described above.

By "ectoparasitic insect" is meant an insect ectoparasite of a warm-blooded animal.

Hematophagous insect ectoparasites are ectoparasitic insects that attack their host by ingesting blood. By "ingest" is meant not only piercing the animal's coat and sucking blood from the circulatory system, but also absorbing host tissue or tissue fluids, thereby necessarily absorbing blood or blood components. Fleas, ticks, biting flies, mites, lice and stink bugs are included in the definition of hematophagous ectoparasitic insects.

"warm blooded animal" refers to a warm blooded animal. The term is intended to include all such animals, including humans and especially important agricultural or companion animals, such as cattle, sheep, horses, goats, pigs, llamas, camels, buffalo, donkeys, rabbits, elk, reindeer, mink, chinchilla, ferret, raccoon, chicken, goose, turkey, duck, dog, cat, mouse and the like.

For the purposes of the present invention, the term flea is understood to mean all the usual and incidental species of parasitic fleas of the order siphonaptera. One family of siphonaptera families known to infest companion animals is the siphonaptera family, such as arcaeopssyllinae (cat and dog fleas), Spilopsyllinae (rabbit fleas), and the like.

Of particular interest are species of the genus Ctenocephalides, in particular, Ctenocephalides felis and Ctenocephalides felis, Ctenocephalides cinerea (Xenopsylla) and Ctenocephalides (Pryptes).

For the purposes of the present invention, the terms ticks and mites are intended to relate to haematophagous arthropod parasites belonging to the order acarid. Some ticks and mites of the order acarina which infest productive and companion animals are known to be species of the genus Irelaria, Dermatophagoides gallinae, species of the genus Ornitus, species of the genus Rhipicephalus, species of the genus Irelaphus, species of the genus Hyalomma, species of the genus Iris, species of the genus Pruritus, species of the genus Dermanychus, species of the genus Sarcophagoides, species of the genus Hypocrea and the like.

Two families of ticks that have been identified are the hard tick family (hard tick) and the cryptorhynchophthirinae family (soft tick). Ticks, after infesting an animal, often cause injury in three ways: direct damage caused by parasitism, such as local injury and blood loss; damage through parasitically injected toxins and damage through disease transmission. Ticks can be a source of zoonotic disease, particularly for companion animals.

For the purposes of the present invention, a "lice" (singular: lice) is an ectoparasite of the order of the phthira. Among the pediculopathies known as animal parasites are: the family of psophilidae, such as the boetomorpha (important lice biting cattle), the sheep lice (lice biting sheep) or the horse lice (lice biting horses); the family of the animal lice, such as the pig blood louse (pig lice) or donkey blood louse (horse lice); pediculosis family, such as Tilaparvata lugens (goat lice) or Tilaparvata lugens (Pediculus longus); and so on.

"flies" are dipteran insects, meaning "dipteran". The real fly has a pair of wings for flying. Behind the wings are a pair of handled spherical structures (called balance bars) that are smooth organs. Flies undergo complete metamorphosis, i.e. the life cycle consists of the following stages: eggs, larvae (called maggots), pupae, and adults. Each phase of the lifecycle can be the subject of control and intervention.

Flies can be divided into two functional categories, "biting" and "non-biting," with biting flies being of primary interest herein.

"biting flies" have a particularly suitable mouthpiece well suited to piercing the coat of a host animal. Stable flies (stable flies) are a suitable example of biting flies. Stable flies have beaks that can be used to pierce the skin and draw blood. Both males and females are hematophagous. Stable flies are typically the only biting blood-sucking flies that multiply in any suitable number in and around the stable-breeding site. Another example of a biting fly is a horn fly (blood-disturbing fly), which, like a stable fly, is also a blood-sucking animal and has a major impact on economy. Like stable flies, horn flies have mouthpieces for piercing/sucking.

A "parasiticidally effective amount" is the amount of active ingredient required to achieve a visual effect that reduces the appearance or activity of a target parasitic pest. One skilled in the art will appreciate that the parasiticidally effective dose can vary with the different compounds and compositions of the present invention, the parasiticidal effect and duration desired, the target invertebrate pest species, the animal to be protected, the mode of administration, and the like, and the amount required to achieve a particular effect can be determined by simple experimentation.

When applied to an infestation, "treatment" or "treating" refers to preventing and controlling the infestation.

As a mode of administration, "parenteral administration" means ingestion into the body or administration in a manner other than through the digestive tract, such as by injection.

As a mode of administration, "enteral administration" refers to ingestion into the body or administration through the digestive tract, such as by oral administration.

Embodiments of the invention include:

embodiment 1: the method or use described in the summary of the invention, wherein the ectoparasitic insect is a hematophagous ectoparasitic insect.

Embodiment 2: the method or use described in the summary of the invention, wherein

R¹Me or Cl;

R²is Cl, Br, CF₃、OCF₂H、OCF₃Or OCH₂CF₃(ii) a And

R⁴is H, Me, Et、i-Pr、t-Bu、CH₂CN、CH(Me)CH₂SMe or C (Me)₂CH₂SMe。

Embodiment 3: the method or use described in the summary of the invention, wherein

R²Is Cl, Br, CF₃Or OCH₂CF₃；

R⁴Is H, Me, Et or i-Pr; and is

R⁵Is H.

Embodiment 4: the method or use described in the summary of the invention, wherein the compound is 3-bromo-1- (3-chloro-2-pyridinyl) -N- [ 4-cyano-2-methyl-6 [ (methylamino) carbonyl ] phenyl ] -1H-pyrazole-5-carboxamide.

Embodiment 5: the method or use as described in the summary of the invention or in any of the embodiments above, wherein the ectoparasite is a blood-feeding ectoparasite.

Embodiment 6: the method or use of embodiment 5, wherein the hematophagous ectoparasite is selected from the group consisting of fleas, ticks, lice, mites, and biting flies.

Embodiment 7: the method or use of any of the embodiments above, wherein said administering is oral.

Embodiment 8: the method or use of any of the embodiments above, wherein said administering is parenteral administration.

Embodiment 9: the method or use of any of the embodiments above, wherein said administering is topical administration.

Embodiment 10: the method or use of any of the embodiments above, wherein the animal is a warm-blooded animal.

Embodiment 10 a: the method or use of embodiment 10 wherein the animal is a cat or dog.

Embodiment 11: the method or use of embodiment 10, wherein the animal is a social animal.

Embodiment 12: the method or use of any of the embodiments above, wherein the composition comprises at least one additional component selected from the group consisting of solvents and/or carriers, emulsifiers and/or dispersants.

Embodiment 13: the method or use of embodiment 12, wherein said composition comprises at least one additional biologically active compound or agent.

Embodiment 14: a method or use according to embodiment 13 wherein the additional biologically active compound or agent is selected from the group consisting of macrocyclic lactones, acetyl cholinesterase inhibitors, arthropodgrowth regulators, GABA-gated chloride channel antagonists, mitochondrial electron transport inhibitors, nicotinic acetylcholine agonists/antagonists/activators, oxidative phosphorylation inhibitors, anthelminthics, sodium channel modulators or other antiparasitic compounds.

Embodiment 15: a method or use according to embodiment 14 wherein the biologically active compound is a macrolide.

Embodiment 16: a method or use according to embodiment 14 wherein the biologically active compound is an acetylcholinesterase inhibitor selected from the group consisting of organophosphates and carbamates.

Embodiment 17: a method or use according to embodiment 14 wherein the biologically active compound is an arthropod growth regulator selected from chitin synthesis inhibitors, ecdysone agonists/interferons, lipid biosynthesis inhibitors and juvenile hormone mimics.

Embodiment 18: the method or use of embodiment 14 wherein said biologically active compound is a GABA-gated chloride channel antagonist.

Embodiment 19: the method or use of embodiment 14, wherein said biologically active compound is a mitochondrial electron transport inhibitor.

Embodiment 20: the method or use of embodiment 14 wherein said biologically active compound is a nicotinic acetylcholine agonist/antagonist/activator.

Embodiment 21: the method or use of embodiment 14, wherein said biologically active compound is an oxidative phosphorylation inhibitor.

Embodiment 22: the method or use of embodiment 14, wherein said biologically active compound is an anthelmintic.

Embodiment 23: the method or use of embodiment 14 wherein said biologically active compound is a sodium channel modulator.

The present invention relates to a method of controlling or preventing infestation of an animal by ectoparasites, preferably hematophagous ectoparasites, by administering to the animal a composition comprising a parasiticidally effective amount of a compound of formula 1, or an N-oxide, or a pharmaceutically or veterinarily acceptable salt thereof.

The compounds of formula 1 are administered orally, topically or parenterally and are useful for protecting animals against infestation by ectoparasitic insects.

It is therefore to be understood that the present invention includes compounds of formula 1 (and compositions containing them) for use as animal medicaments, or more specifically as ectoparasiticidal agents. The animals to be protected include those described in any of embodiments 10, 10a or 11. Ectoparasitic pests include those described in embodiment 5 or 6. The medicament may be in an oral, topical or parenteral dosage form.

It is also to be understood that the invention includes the use of a compound of formula 1 or a compound of any of embodiments 2, 3 or 4 in the manufacture of a medicament for protecting an animal from an invertebrate parasitic pest. The animals to be protected include those described in any of embodiments 10, 10a or 11. Ectoparasitic pests include those described in embodiment 5 or 6. The medicament may be in an oral, topical or parenteral dosage form.

It is also to be understood that the present invention includes the compounds of formula 1 or the compounds of any of embodiments 2, 3 or 4 for use in the manufacture of a medicament for protecting an animal from an invertebrate parasitic pest. The animals to be protected include those described in any of embodiments 10, 10a or 11. Ectoparasitic pests include those described in embodiment 5 or 6. The medicament may be in an oral, topical or parenteral dosage form.

It is also to be understood that the present invention includes compounds of formula 1 or compounds of any of embodiments 2, 3 or 4 packaged and presented to protect an animal from an invertebrate parasitic pest. The animals to be protected include those described in any of embodiments 10, 10a or 11. Ectoparasitic pests include those described in embodiment 5 or 6. The compounds of the invention may be packaged and presented for oral, topical or parenteral administration.

It is also to be understood that the present invention includes a method for producing a composition for protecting an animal from an invertebrate parasitic pest, the method characterized by admixing a compound of formula 1 with at least one pharmaceutically or veterinarily acceptable carrier. The animals to be protected include those described in any of embodiments 10, 10a or 11. Ectoparasitic pests include those described in embodiment 5 or 6. The compositions of the present invention may be packaged and presented for oral, topical or parenteral administration.

According to the present invention, the compound of formula 1 which can be used has excellent efficacy against ectoparasitic insects, particularly hematophagous ectoparasitic insects. The compounds are uniquely suited for entry and diffusion through the host blood circulation while being well tolerated by animals. The present invention therefore represents a real complement to the prior art.

The compounds according to the invention have good ectoparasiticidal activity and at the same time low toxicity to animals. The compounds of formula 1 can be prepared by methods as described in U.S. patent publication 2006/0111403a1, which is incorporated herein by reference, and variations that will be apparent to the skilled artisan without violating the disclosure herein.

Synthetic methods for preparing heterocyclic and tertiary amine N-oxides are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the following documents, see for example: comprehensive Organic Synthesis by T.L.Gilchrist, Vol.7, pp.748-750, eds S.V.Ley, Pergamon Press); comprehensive heterocyclic Chemistry by m.tisler and b.stanovnik, volume 3, pages 18-20, compiled by a.j.boulton and a.mckillop, Pergamon Press); advances in Heterocyclic Chemistry, Vol.43, p.149-161, ed. A.R.Katritzky, Academic Press, M.R.Grimett and B.R.T.Keene); advances in Heterocyclic Chemistry, Vol.9, pp.285-291, ed. A.R.Katritzky and A.J.Boulton, Academic Press, of M.Tisler and B.Stanovnik); and Advances in heterocyclic chemistry, Vol.22, p.390-.

It is expected that the following compounds, shown by way of example and not by way of limitation, may be advantageous in the practice of the present invention.

TABLE 1

TABLE 2

TABLE 3

The invention described herein relates to a method of controlling or preventing infestation of animals by flies by applying to the animals an insecticidally effective amount of a compound of formula 1.

Administration of the Compounds of the invention

The compounds of formula 1 according to the invention can be administered to warm-blooded animals in need of treatment or prevention of ectoparasite infestations. Especially conceivable are important agricultural or companion animals, such as cattle, sheep, horses, goats, pigs, llamas, camels, buffalo, donkey, rabbits, elk, reindeer, mink, chinchilla, ferret, raccoon, chicken, goose, turkey, duck, dog, cat, rat, etc. Can be used for treating animals of social group, such as cattle, sheep, goat, horse, donkey, camel, pig, reindeer and bison. Can also be used for treating human diseases.

Any one of the compounds of the invention or a suitable combination of such compounds can be administered directly to an animal recipient and/or indirectly by administering it to the local environment in which the animal resides, such as bedding, pens and the like. Direct administration includes contacting the skin, fur or feathers of the animal recipient with the compound, or feeding the compound to the animal or injecting the compound into the animal.

Topical administration of drugs

When topical administration is desired, it may be administered to the animal or environment in the following manner, including, by way of non-limiting example, formula 1. Sprays, powders, pour-on treatments, and controlled release devices of compounds and compositions including compounds such as ear tags and strips, neck straps, ear tags, tail straps, limb straps, or halters. In addition to sprays and pour-on treatments, application can also be via other forms of topical administration, such as immersion or immersion forms, washing forms, forms coated with powder, or forms applied to small areas of the animal's body.

The compositions according to the invention can be administered to the animals to be treated generally via solutions, emulsions, suspensions, (drenches), powders and drench treatments.

The pour-on or spot-on method comprises applying the compound of formula 1 to a designated area of the skin or coat of the animal, preferably to the neck and back. This can be done, for example, by swabbing or spraying a pour-on or spot-on formulation onto a small area of the fur, from where the active substance is almost automatically dispersed onto a large area of the fur due to the diffusivity of the components within the formulation and with the aid of animal activity.

Importantly, the compound of formula 1 can be indirectly administered to an animal by administering it to the animal's inhabited local environment (such as litter, pens, and the like). The effective amount will be about 1.0 to 50mg/m²In the range, but as low as 0.1mg/m²May also be sufficient, or up to 150mg/m²The amount of (c) may also be desired. One skilled in the art can readily determine the biologically effective amount needed to achieve the desired degree of pest control.

The invention provides, inter alia, methods for controlling hematophagous ectoparasites in small mammals, especially cats and dogs, by local deposition on the skin, preferably on a small area (spot application). Preferably, the treatment according to the invention is performed on cats and dogs every month, every two months or every three months.

The compounds of the invention may be administered in a controlled release form, for example as a subcutaneous slow release formulation, or in the form of a controlled release device such as a flea-killing collar, which is immobilised on an animal. Controlled release insecticide collars for the long-term prevention of infestation of companion animals by fleas are known in the art and are described, for example, in U.S.3,852,416, U.S.4,224,901, U.S.5,555,848, and U.S.5,184,573.

Large animals (particularly social animals) can be effectively treated by a variety of methods well known in the art.

The animal whole body spray can quickly reduce the influence of flies. Animal sprays are typically applied at high pressure as a dilute coarse spray to penetrate the skin, or as a more concentrated fine small volume mist.

The self-application device comprises a backing rubber coated with an absorbent material treated with an insecticide oil solution, or a dusting bag filled with an insecticide powder. The back rubber and breading bags should be placed close to the water and feed sources access and other areas where animals will frequently touch them.

Controlled release ear tags and tapes are generally very effective in controlling flies in certain areas of the agricultural field.

Drench treatments involve the application of insecticides at the prescribed dosage of the topical product along the back line of the animal. In cases where it is difficult or time consuming to treat all animals with a more labor intensive administration method, the pour-on or spot-on method may be particularly advantageous for herding animals such as cattle, horses, sheep or pigs.

Oral administration

The compounds of the invention can be delivered to the animal to be protected by ingestion. After ingestion by an animal to be protected, parasiticidally effective concentrations of the compounds of the present invention in the bloodstream protect the treated animal from infestation by blood-sucking pests such as fleas, ticks and lice.

Parenteral administration

The compounds of formula 1 may be administered by parenteral administration (including injection). The injection may be intravenous, intramuscular or subcutaneous.

Compositions of the invention

The compounds of the invention may be administered or dosed separately, but are generally formulated into veterinary or pharmaceutical compositions. The compounds can be formulated or compounded into the compositions in a known manner, for example by extrusion of the active compounds with solvents and/or carriers, if appropriate with the use of emulsifiers and/or dispersants; if, for example, water is used as diluent, organic solvents can be used as cosolvents, if appropriate.

The parasiticidal compositions according to the invention generally comprise a compound of formula 1 in admixture with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries, which are selected according to the desired route of administration (e.g. buccal, topical or parenteral such as injection) and according to standard procedures. In addition, suitable carriers are selected based on compatibility with one or more active ingredients in the composition, including considerations such as relative stability with respect to pH and water content. Thus, of note are compositions for protecting animals against infestation by ectoparasitic pests, which compositions comprise a parasiticidally effective amount of a compound of the invention and at least one carrier.

Formulations for topical administration are typically in the form of powders, creams, suspensions, sprays, emulsions, foams, pastes, aerosols, salves, ointments or gels. Topical formulations may be aqueous solutions, which may be in the form of concentrates that are diluted prior to use. Parasiticidal compositions suitable for topical administration generally comprise a compound of the invention and one or more topically suitable carriers.

When the parasiticidal composition is topically applied to the outside of the animal body in the form of lines or dots (i.e. precision therapy), the active ingredient migrates on the surface of the animal body to cover most or all of its external surface area. Thus, the treated animals may be immunized particularly against invertebrate pests such as ticks, fleas and lice that feed from the animal's epidermis. Thus, formulations for topical, site-specific administration typically comprise at least one organic solvent to facilitate delivery of the active ingredient on the skin of the animal and/or penetration into the epidermis of the animal. The pour-on or spot-on formulation suitably comprises a carrier which promotes rapid partitioning on the skin surface or in the coat of the host animalLoose, and generally considered as a diffusion oil. Suitable carriers are, for example, oily solutions; alcohol and isopropanol solutions, such as 2-octyldodecanol or oleyl alcohol; solutions of monocarboxylic acid esters, such as isopropyl myristate, isopropyl palmitate, oxalate laurate, oleyl oleate, decyl oleate, hexyl laurate, oleyl oleate, decyl oleate, chain length C₁₂-C₁₈Saturated fatty alcohol decanoate of (1); solutions of dicarboxylic acid esters such as dibutyl phthalate, diisopropyl isophthalate, diisopropyl adipate, di-n-butyl adipate, and ester solutions of aliphatic acids (e.g., ethylene glycol). It may be advantageous to additionally present dispersants, such as dispersants known from the pharmaceutical or cosmetic industry. Examples are 2-pyrrolidone, 2- (N-alkyl) pyrrolidone, acetone, polyethylene glycol and their ethers and esters, propylene glycol or synthetic triglycerides.

The oily solution includes, for example, a vegetable oil such as olive oil, peanut oil, sesame oil, pine oil, linseed oil or castor oil. The vegetable oil may also be present in epoxidized form. Paraffin and silicone oils may also be used.

It may also be advantageous to have crystallization inhibitors or dispersants known to the pharmaceutical or cosmetic industry.

Pour-on or spot-on formulations typically comprise from 1% to 20% by weight of a compound of formula 1, from 0.1% to 50% by weight of a dispersant and from 45% to 98.9% by weight of a solvent.

Compositions for spot application may advantageously comprise:

(a) crystallization inhibitors, in particular in a proportion of 1% to 20% (w/v), preferably 5% to 15%, which satisfy the following tests: 0.3mL of a 10% (w/v) solution of the compound of formula 1 in the solvent indicated below (c) and 10% of this inhibitor are deposited on a glass slide at 20 ℃ for 24 hours, after which little or no crystals, in particular less than 10 crystals, preferably 0 crystals, are observed on the slide with the naked eye,

(b) an organic solvent having a dielectric constant of between 10 and 35, preferably between 20 and 30, the content of this solvent (b) in the overall composition preferably constituting a difference of 100%,

(c) an organic co-solvent having a boiling point below 100 ℃, preferably below 80 ℃ and a dielectric constant between 10 and 40, preferably between 20 and 30; this co-solvent may advantageously be present in the composition in a (c)/(b) weight/weight (w/w) ratio comprised between 1/15 and 1/2. The solvent is volatile, in order to be particularly useful as a drier, and is miscible with water and/or with solvent (b).

Drench formulations may also be formulated to control parasites on animals of agricultural value. The pour-on formulation of the invention may be in the form of a liquid, powder, emulsion, foam, paste, aerosol, salve, ointment or gel. Pour-on formulations are typically liquid. These pour-on formulations can be effectively administered to sheep, cattle, goats, other ruminants, camelids, pigs and horses. The pour-on formulation is typically applied by pouring it in the form of one or more thin lines, or exactly over the midline (back) or shoulders of the back of the animal. More typically, the formulation is administered by pouring the formulation along the spine along the back of the animal. The formulation may also be applied via other conventional methods, including wiping at least a small area of the animal with the impregnated material, or using a commercially available applicator, by syringe, by spray or by using a spray bar passageway. The pour-on formulation includes a carrier and may also include one or more additional ingredients. Examples of suitable additional ingredients are stabilizers such as antioxidants, spreading agents, preservatives, adhesion promoters, active solubilizers such as oleic acid, viscosity regulators, UV blockers or absorbers, and colorants. Surfactants may also be included in these formulations, including anionic, cationic, nonionic, and amphoteric surfactants.

The pour-on formulation includes a carrier and may also include one or more additional ingredients. Examples of suitable additional ingredients are stabilizers such as antioxidants, spreading agents, preservatives, adhesion promoters, active solubilizers such as oleic acid, viscosity regulators, UV blockers or absorbers, and colorants. Surfactants may also be included in these formulations, including anionic, cationic, nonionic, and amphoteric surfactants.

The formulations of the present invention typically comprise an antioxidant, such as BHT (butylated hydroxytoluene). The antioxidant is generally contained in an amount of 0.005% to 5% (w/v), and a proportion of 0.005% to 1% (w/v) is generally used, and usually 0.01% to 0.05% is preferred.

The compositions of the invention intended for pets, in particular cats and dogs, can generally be applied by deposition on the skin ("spot" or "pour-on" application); this is generally applied topically to less than 10cm²In particular between 5 and 10cm²In between, in particular at two points, and preferably locally between the shoulders of the animal. After deposition, the composition is spread, in particular over the whole body of the animal, and then dried without crystallizing or altering the appearance (in particular the appearance without any white precipitate or dust) or feel of the pelt.

Compositions for spot application according to the present invention are particularly advantageous due to their efficacy, their speed of action and a pleasing appearance of animal skins after application and drying.

As the organic solvent (b) usable in the present invention, specifically mentioned are: acetone, acetonitrile, benzyl alcohol, butyl diethylene glycol, dimethylacetamide, dimethylformamide, dipropylene glycol N-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyethylene glycols, propylene glycol, 2-pyrrolidone (in particular N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or mixtures of at least two of these solvents.

As the crystallization inhibitor (a) usable in the present invention, specifically mentioned are: polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylene sorbitan esters; lecithin, sodium carboxymethylcellulose, acrylic acid derivatives (such as methacrylates and the like), anionic surfactants (such as alkali metal salts of stearic acid, in particular sodium stearate, potassium stearate or ammonium stearate); calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzene sulfonate, dioctyl sodium sulfosuccinate; fatty acids (in particular those derived from coconut oil), cationic surfactants (such as water-soluble quaternary ammonium salts having the structure N + R 'R "R'", Y-wherein the group R is optionally a hydroxyalkylated hydrocarbon group and Y-is a strong acid anion, such as halide, sulfate and sulfonate anions; cetyl trimethyl ammonium bromide is one of the cationic surfactants that can be used, amine salts having the structure N + R 'R "R'", wherein the group R is optionally a hydroxyalkylated hydrocarbon group; octadecyl amine hydrochloride is one of the cationic surfactants that can be used, nonionic surfactants such as optionally polyoxyethylated sorbitan esters, in particular polysorbate 80, polyoxyethylene alkyl ethers; polyethylene glycol stearates, polyoxyethylene derivatives of castor oil, polyglycerol esters, glycerol esters, Polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as lauryl-substituted betaine compounds, or preferably mixtures of at least two of these crystallization inhibitors.

The crystallization inhibitor pair, i.e., a polymeric film former in combination with a surfactant, may be used in a particularly preferred form. In particular, these agents may be selected from the compounds mentioned as crystallization inhibitors (b).

Among the polymeric film formers which are particularly advantageous, mention may be made of: various grades of polyvinylpyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinylpyrrolidone.

As surfactants, mention may be made most particularly of nonionic surfactants, preferably polyoxyethylene sorbitan esters, in particular polysorbates of various grades, such as polysorbate 80.

In particular, the film former and surfactant may be incorporated in similar or equal amounts within the limits of the total amount of crystallization inhibitor mentioned elsewhere.

The pair of combinations thus obtained ensures in a remarkable way that the target is free from crystallization on the hair and that the coat maintains an aesthetic appearance, that is to say, despite a high concentration of active substance, without any tendency to be sticky or tacky in appearance.

As co-solvents (c) are specifically mentioned: absolute ethyl alcohol, isopropanol and methanol.

As antioxidants, standard agents can be used, such as in particular: butyl hydroxyanisole, butyl hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate and sodium thiosulfate, or a mixture of no more than two of these agents.

Compositions for spot application according to the present invention can generally be prepared by simply mixing the components as specified previously; advantageously, the active substance is initially mixed in the main solvent, and the other ingredients or adjuvants are then added.

The volume administered is about 0.3 to 5mL, preferably about 0.5mL for cats and about 0.3 to 3mL for dogs, depending on the weight of the animal.

The compositions according to the invention may be in the form of concentrated emulsions, suspensions or solutions, applied as drops to the skin of small-area animals, generally between the shoulders (drop-type solutions). In another aspect of the invention, the solution or suspension to be sprayed, the solution, suspension or emulsion to be poured or spread onto the animal body (pour-on solution), an oil, cream or ointment or any other fluid formulation for topical administration may be provided.

Other delivery systems for relatively hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are examples of well-known delivery vehicles or carriers for hydrophobic drugs. In addition, an organic solvent such as dimethyl sulfoxide may be used.

The concentration of the compound of formula 1 in the composition is generally from 0.1% to 95% by weight, preferably from 0.5% to 90% by weight. Preparations intended for direct application comprise the active compounds according to the invention in a concentration of between 0.001% and 5% by weight, preferably 0.005% to 3% by weight.

The dose can range from 0.0001mg of the compound of formula 1 per kg of animal body weight to about 1000mg of the compound of formula 1 per kg of animal body weight. In some cases the dosage may be from 0.1mg/kg to about 200mg/kg of animal body weight. An amount of from about 0.01 to about 100mg or from 0.02 to about 50mg/kg is often advantageous, and in many cases from 0.1 to 75 mg/kg. The treatment is preferably carried out to administer a dose of 0.1 to 40mg/kg, in particular 1 to 30mg/kg, to the animal. Administration can be carried out in a single dose or in a timed intermittent manner, and can be carried out once daily, once weekly, once monthly, once every two months or once a season to obtain an effective effect.

However, it is sometimes necessary to deviate from the above-mentioned amounts and in particular, according to the test animal body weight and/or the method of administration, and according to the animal species and its unique behaviour towards the drug, or the characteristics of the latter formulation and its time or interval of administration. In some cases it is therefore sufficient to carry out the treatment below the minimum mentioned, while in other cases the upper limit must be exceeded. When administered in large amounts, it is advisable to divide these into several separate administrations during the day. The general meanings of the other statements made above are also applicable.

For parenteral administration (including intravenous, intramuscular, and subcutaneous injection), the compounds of the invention may be formulated as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain adjuvants, such as suspending, stabilizing, and/or dispersing agents. The compounds of the invention may also be formulated for bolus injection or continuous instillation. Pharmaceutical compositions for injection include aqueous solutions preferably in pharmaceutically compatible buffers containing other excipients or adjuvants known in the art of pharmaceutical formulation. Furthermore, suspensions of the active compounds can be prepared in lipophilic vehicles. Suitable lipophilic carriers include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Formulations for injection may be presented in unit dosage form in, for example, ampule containers or multidose containers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In addition to the above formulations, the compounds of the present invention may also be formulated as long acting formulations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular or subcutaneous injection. For this route of administration, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (e.g., in an emulsion containing a pharmaceutically acceptable oil), with ion exchange resins, or as sparingly soluble derivatives, such as, but not limited to, a sparingly soluble salt.

For administration by inhalation, the compounds of the present invention may be delivered in the form of an aerosol spray using pressurized packs or a nebulizer and a suitable propellant, such as, without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount. Gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds of the invention can be delivered to the animal to be protected via ingestion. After ingestion by an animal to be protected, the parasiticidally effective concentration of the compounds of the present invention in the blood protects the treated animal from blood-sucking pests such as fleas, ticks and lice. Of note, therefore, are compositions in oral form (i.e., comprising, in addition to a parasiticidally effective amount of a compound of the present invention, one or more carriers selected from the group consisting of binders and fillers suitable for oral administration and concentrated feed carriers) for protecting animals from invertebrate parasitic pests.

For oral administration in the form of solutions (the most readily available forms for absorption), emulsions, suspensions, pastes, gels, capsules, tablets, boluses, powders, granules, rumen retentate and foodstuffs/water/licks, the compounds of the invention can be formulated with binders/fillers known in the art to be suitable for oral compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starches (e.g., corn starch, wheat starch, rice starch, potato starch), celluloses and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gels), and synthetic polymers (e.g., polyvinyl alcohol, polyvinyl pyrrolidone). If desired, lubricating agents (e.g., magnesium stearate), disintegrating agents (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid), and dyes or pigments may be added. Pastes and gels typically also contain binders (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to help keep the composition in contact with the oral cavity and not easily expelled.

If the parasiticidal composition is in the form of a concentrated feed, the carrier is generally selected from high performance feeds, cereals for feeds or concentrated proteins. Such compositions comprising concentrated feed comprise, in addition to the parasiticidal active ingredient, additives which promote the health or growth of the animals, improve the meat quality from the slaughtered animals or are useful in animal husbandry. Such additives include, for example, vitamins, antibiotics, chemotherapeutic agents, bacteriostatic agents, fungistatic agents, anticoccidial agents, and hormones.

The concentration of the compound of formula 1 in the composition is generally from 0.1% to 95% by weight, preferably from 0.5% to 90% by weight. Formulations intended for direct administration comprise the active compounds according to the invention in a concentration of between 0.001% and 5% by weight, preferably 0.005% to 3% by weight.

The dose can range from 0.0001mg of the compound of formula 1 per kg of animal body weight to about 1000mg of the compound of formula 1 per kg of animal body weight. In some cases the dosage may be from 0.1mg/kg to about 200mg/kg of animal body weight. An amount of from about 0.01 to about 100mg or from 0.02 to about 50mg/kg is often advantageous, and in many cases from 0.1 to 75 mg/kg. The treatment is preferably carried out to administer a dose of 0.1 to 40mg/kg, in particular 1 to 30mg/kg, to the animal. Administration can be carried out in a single dose or in a timed intermittent manner, and can be carried out once daily, once weekly, once monthly, once every two months or once a season to obtain an effective effect.

However, it is sometimes necessary to deviate from the above-mentioned amounts and in particular, according to the test animal body weight and/or the method of administration, and according to the animal species and its unique behaviour towards the drug, or the characteristics of the latter formulation and its time or interval of administration. In some cases it is therefore sufficient to carry out the treatment below the minimum mentioned, while in other cases the upper limit must be exceeded. When administered in large amounts, it is advisable to divide these into several separate administrations during the day. The general meanings of the other statements made above are also applicable.

The compositions of the invention may contain additional active compounds：

It is contemplated that additional biologically active compounds may be administered, either simultaneously or non-simultaneously, to achieve a broader spectrum of parasite control effects. Such additional biologically active compounds may be packaged with the compound of formula 1 as a kit. For convenience, such additional biologically active compounds may be formulated into the same composition containing the compound of formula 1 and selected according to the parasite to be controlled and the suitability of the compound for the mode of administration (oral, parenteral, topical, etc.). The present invention therefore envisages the use of compositions which are characterized in that, in addition to the compounds of formula 1, they may comprise further adjuvants and/or active compounds such as additional biologically active compounds, it being possible for disinfectants (in the case of topical application) or antibiotics to be incorporated into the formulation, or into the ready-to-use solution, in addition to the customary solid or liquid supplements, diluents and/or surfactants.

Of note are additional biologically active compounds or agents selected from anthelmintics known in the art, such as avermectins (e.g., ivermectin, moxidectin, milbemycin), benzimidazoles (e.g., albendazole, trichlorobenzimidazole), salicylanilides (e.g., closantel, hydroxychlorozamide), substituted phenols (e.g., nitrolofenapyr), pyrimidines (e.g., pyrantel), imidazolethizoles (e.g., levamisole), and praziquantel.

Other biologically active compounds or agents useful in the compositions of the present invention may be selected from Insect Growth Regulators (IGR) and Juvenile Hormone Analogs (JHA), such as diflubenzuron, chlorbenzuron, fluazuron, thifluzam, methoprene, and the like, to provide initial and sustained control of parasites (at all stages of insect growth, including eggs) to animal subjects, as well as to the environment of the animal subjects.

The compounds of formula 1 according to the present invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same activity range, for example to increase the activity, or with substances having another activity range, for example to extend the activity range. It is also suitable to add so-called repellents. If it is desired to extend the range of activity to endoparasites, such as anthelmintics, the compounds of formula 1 may suitably be combined with substances having endoparasiticidal properties. Of course, they may also be used in combination with antimicrobial compositions.

Preferred groups of combination partners, in particular preferred groups of combination partners, are described below, wherein a combination may comprise one or more of these partners in addition to a compound of formula 1.

Suitable pairs in the mixture may be biocides, such as insecticides and acaricides having different mechanisms of action, which are described below and which are known to the person skilled in the art at all times, for example chitin synthesis inhibitors, growth regulators; as an active ingredient of juvenile hormone; as active ingredients for adulticides; broad-spectrum insecticides, broad-spectrum acaricides and nematicides; as well as the well-known anthelmintic and insect and/or mite-inhibiting substances, and repellent or dissociating agents.

Examples of such biologically active compounds include, but are not limited to, the following: organophosphates, which are a class of substances generally known as acetylcholinesterase inhibitors: acephate, pirimiphos-methyl, glutethion-ethyl, glutethion-methyl, bromophos-ethyl, cadusafos, tetrachlorethophos, chlorfenphos, chlorfenvinphos, chlormephos, demeton-S-methyl sulfone, chlorphosphorous, diphos, dichlorvos, chlormephos, dimethoate, ethoprophos, etrimfos, disulfoton, fenamiphos, phos, fenphos, difenofos, fosthiazate, aphifos, clofenphos, isoprophos, isoxazolfos, malathion, chlorfenvinphos, methamidophos, methidathion, methyl-parathion, monocrotophos, naled-methyl, oxydisup-methyl, paraoxon, parathion-methyl, phenthofos-methyl, phenthoate-methyl, fenpropamocarb-methyl, fenphos-methyl, fenpropamocarb-methyl, The pesticide composition comprises fluvophos, cotton phosphorus, phocarbocarb, phosmet, phosphamidon, phorate, phoxim, pyrimidylphos-methyl, profenofos, propaphos, amicarbazone, profenofos, pyrazofos, pyridaphenthion, quinalphos, thiofenamiphos, disulfoton, terbufos, butylpyrimidinophos, chlorfenapyr, fosetyl methyl, triazophos, trichlorfon and pirimiphos.

Carbamates, which are a class of substances generally known as acetylcholinesterase inhibitors: the composition comprises the components of synthetic boll, aldicarb, 2-sec-butylphenyl carbamate, benfuracarb, carbaryl, carbofuran, ethiofencarb, fenoxycarb, furacarb, HCN-801, isoprocarb, indoxacarb, methomyl, oxamyl, 5-methyl-isopropyl butyrylcarbamate methyl ester, oxamyl, pirimicarb, propoxur, thiodicarb, tetramethocarb, triazamate and UC-51717. Pyrethroids, which are a class of substances generally known as sodium channel modulators: fluthrin, allethrin, alpha-cypermethrin, (E) - (1R) -cis-2, 2-dimethyl-3- (2-oxathiolan-3-ylidenemethyl) cyclopropanecarboxylic acid 5-benzyl-3-furyl methyl ester, bifenthrin, 8-cyfluthrin, oc-cypermethrin, 8-cypermethrin, bioallethrin ((S) -I cyclopentyl isomer), tetramethrin, bifenthrin, NCI-85193, cycloprothrin, cyfluthrin, cythrin, deltamethrin, prallethrin, esfenvalerate, etofenprox, fenfluthrin, fenpropathrin, flucythrinate, flumethrin, cyfluthrin (D isomer), Prallethrin, cyhalothrin, \/-cyhalothrin, permethrin, phenothrin, esfenthrin, prallethrin, pyrethrin (natural product), pyrethrin, pyrethrum, tefluthrin, transfluthrin, theta-cypermethrin, silafluofen, T-tau-fluvalinate, tefluthrin, tetrabromthrin, zeta-cypermethrin.

Arthropod growth regulators include: a) chitin synthesis inhibitors: benzoyl urea: chlorfluazuron, diflubenzuron, floxuron, epoxiconazole, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, chlorfluazuron, chlorpheniramine, thifenpropine, etoxazole and chlorfendazine; b) ecdysone agonist/interferon: chlorfenozide, methoxyfenozide, tebufenozide; c) juvenile hormone mimics: pyriproxyfen, methoprene, fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen. Other antiparasitic agents: fenaminoquinone, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, chlorfenapyr, bifenazate, binapacryl, bromopropylate, BTG-504, I BTG-505, toxaphene, cartap, chlorfenapyr, chlorfenamidine, chlorfenapyr, dinol, clonidine, cyromazine, diacloden, diafenthiuron, DBI-3204, diethofectin, dihydroxymethyl dihydroxypyrrolidine, dinocap, propargyl, endosulfan, ethiprole, ethofenprox, fenazaquin, flufenzine, MTI-800, fenpyroximate, flufenamidothion, flufenpropathrin, flufenzine, trifloxystrobin, fenpropathrin, fentexon, hydrazone, IKII-220, kanemite, trinecorter-196, neguard, nidene furan, nitenpyram, WL-35651, SD-477, pyridalyl, pyrazone, pyrazofenozide, pyrazone, pyrazofos, pyrazofenoxate, pyrazoxy, NC-1111, R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, S1-8601, silafluofen, silomadine, spinosad, tebufenpyrad, tetraclocidal sulfone, tetramycin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, spinosad, trimotoxin, propargyl ether, veralec, Y1-5301 fungicide: benzothiadiazole, cartap, 1-aminopropyl phosphoric acid, metoclopramide, penconazole, azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, boldo, bromuconazole, bupirimate, cyclopropanoamide, captafol, captan, carbazolyl, 2- (2-chlorophenyl) -1H-benzimidazole, dicyclopentadine, trichloronitromethane, chlorothalonil, ethiprole, cupric, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, esteram, RH-7281, dicloryanamide, chlorotriazole, diclofenamate, niclosamide, difenoconazole, RP-407213, dimethomorph, dimoxystrobin, diniconazole, difenoconazole, fenamidone, fenbuconazole, valcarb, valicarb, Fenpiclonil, fenpropidin, fenpropimorph, fentin, fluazinam, fludioxonil, flufenamido, flumorph/flumorph, fentin, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, phycophytate, furalaxyl, furametpyr, hexaconazole, ipconazole, iprobenfos, prochloraz, isoprothiolane, kasugamycin, strobilurin, mancozeb, maneb, mefenoxam, propamocarb, basidinium, metalaxyl, metconazole, metominostrobin/metominostrobin, metrafenone, myclobutanil, mechloraz, boscalid, dimoxystrobin, oxadixyl, penconazole, pyrifenoxuron, prochloraz, propamocarb, prozoxyquinoline, prothioconazole, fenpyroximate, pyraclostrobin, dimetachlor, fluquinconazole, fenchlorambucil, fluazid, thiflufenazamide, thiflutriafol, thifluzamide, flufenazamide, flufenclofencloxacarb, flufenapyr, Thiophanate-methyl, thiuram disulfide, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozolin biologics: bacillus thuringiensis subsp.yasha subsp.sp.kurstaki, bacillus thuringiensis delta-endotoxins, baculovirus, entomopathogenic bacteria, viral and fungal fungicides: chlortetracycline, oxytetracycline, streptomycin.

Other more specific examples of paired insecticides and acaricides are listed below:

classes of compounds

Abamectin	Macrolides
		AC 303 630	Energy production regulators
Acephate	Acetyl cholinesterase inhibitors
		Fluthrin	Sodium channel modulators
Cotton boll	Acetyl cholinesterase inhibitors
		Aldicarb	Acetyl groupCholinesterase inhibitors
Alpha-cypermethrin	Sodium channel modulators
		Cis-cypermethrin	Sodium channel modulators
Amitraz (amitraz)	Octopamine receptor ligands
		Abamectin and its preparation method	Macrolides
Guthion A	Acetyl cholinesterase inhibitors
		Guthion M	Acetyl cholinesterase inhibitors
Guthion	Acetyl cholinesterase inhibitors
		Tin triazoles	Oxidative phosphorylation inhibitors
Bacillus subtilis toxins
		Bendiocarb	Acetyl cholinesterase inhibitors
Benfuracarb	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		Insecticidal composition	Nicotinic acetylcholine agonists/antagonists
Beta-cyfluthrin	Sodium channel modulators
		Biphenthrin	Sodium channel modulators
Benzyl mite ether	Sodium channel modulators
		Bromoethion A	Acetyl cholinesterase inhibitors
Butylbenzene urethane	Acetyl cholinesterase inhibitors
		Pediculicide	Chitin synthesis inhibitor
Butanone methyl ethyl ketone	Acetyl cholinesterase inhibitors
		Cadusafos	Acetyl cholinesterase inhibitors
Xiweiyin medicine	Acetyl cholinesterase inhibitors
		Carbofuran	Acetyl cholinesterase inhibitors
Tri-sulfur phosphorus	Acetyl cholinesterase inhibitors
		Badan pill	Nicotinic acetylcholine agonists/antagonists
Dichongwei-medicine for killing pests	Acetyl cholinesterase inhibitors
		Tetrachloro ethylene phosphorus	Acetyl cholinesterase inhibitors
Chlorfenapyr	Oxidative phosphorylation inhibitors
		Dingchonglong (Chinese insect and drug for curing insect disease)	Chitin synthesis inhibitor
Phosphorus oxychloride	Acetyl cholinesterase inhibitors
		Chlorfenapyr	Acetyl cholinesterase inhibitors
Cis-resmethrin	Sodium channel modulators

Abamectin	Macrolides
		Mite killing medicine
Cyanophos	Acetyl cholinesterase inhibitors
		Beta-cypermethrin	Sodium channel modulators
Cyhalothrin	Sodium channel modulators
		Tricyclic tin	Oxidative phosphorylation inhibitors
D2341 (Bifenazate)
		Bromophrin	Sodium channel modulators
Systemic phosphorus M	Acetyl cholinesterase inhibitors
		Systemic phosphorus S	Acetyl cholinesterase inhibitors
Systemic phosphorus-S-methyl	Acetyl cholinesterase inhibitors
		Phosphorus wire	Acetyl cholinesterase inhibitors
Dicliphos	Acetyl cholinesterase inhibitors
		Ethos	Acetyl cholinesterase inhibitors
Diflubenzuron	Chitin synthesis inhibitor
		Leguo (fruit of musical instruments)	Acetyl cholinesterase inhibitors
Calcium diphacinone	Acetyl cholinesterase inhibitors
		Difenafos	Acetyl cholinesterase inhibitors
Doramectin	Macrolides
		DPX-MP062 (indoxacarb)	Sodium channel modulators
Dipheny phosphorus	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		Methylamino avermectin	Macrolides
Endosulfan	gaba-gated chloride channel antagonists
		Yilinoking	Macrolides
Cis-fenvalerate	Sodium channel modulators
		Insecticidal pill	Acetyl cholinesterase inhibitors
Ethos	Acetyl cholinesterase inhibitors
		Ether chrysanthester	Sodium channel modulators
Miao ethephon	Acetyl cholinesterase inhibitors
		Etrimfos	Acetyl cholinesterase inhibitors
Phenyllin phosphorus	Acetyl cholinesterase inhibitors
		Fenazaquin	Mitochondrial electron transport inhibitors
Fenbutatin oxide	Oxidative phosphorylation inhibitors
		Fenitrothion	Acetyl cholinesterase inhibitors
Fenobucarb (BPMC)	Acetylcholinesterase inhibitionPreparation
		Thiophenecar	Acetyl cholinesterase inhibitors
Fenoxycarb	Juvenile hormone mimics
		Fenpropathrin	Sodium channel modulators
Tebufenpyrad	Mitochondrial electron transport inhibitors
		Fenpyroximate	Mitochondrial electron transport inhibitors
Fenthion	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		Cyanophenyl ether pyrethrin	Sodium channel modulators
Fipronil	gaba-gated chloride channel antagonists
		Fluazinam	Oxidative phosphorylation uncoupling agents
Fluorosulfuron	Chitin synthesis inhibitor
		Epoxicarburils	Chitin synthesis inhibitor
Fluorofenvalerate	Sodium channel modulators
		Flubenuron	Chitin synthesis inhibitor
Trifluoretherpyrethrin	Sodium channel modulators
		Dafu pine	Acetyl cholinesterase inhibitors
All-grass of Anguo	Acetyl cholinesterase inhibitors
		Fosthiazate	Acetyl cholinesterase inhibitors
HCH	gaba-gated chloride channel antagonists
		Aphidrophos	Acetyl cholinesterase inhibitors
Hexaflumuron	Chitin synthesis inhibitor
		Hexythiazox
Hydroprene	Juvenile hormone mimics
		Imidacloprid	Nicotinic acetylcholine agonists/antagonists
Active fungus of insect
		Active nematode of insect
Insect active virus

Abamectin	Inside the great ringEsters as pesticides
		Iprobenfos	Acetyl cholinesterase inhibitors
Isosaliphos	Acetyl cholinesterase inhibitors
		Isoprocarb	Acetyl cholinesterase inhibitors
Isoxazolyl phosphorus	Acetyl cholinesterase inhibitors
		Ivermectin	Chloride channel activators
High cyhalothrin	Sodium channel modulators
		Lufenuron	Chitin synthesis inhibitor
Malathion	Acetyl cholinesterase inhibitors
		Myzus phosphate	Acetyl cholinesterase inhibitors
Mesulfenphos	Acetyl cholinesterase inhibitors
		Snail enemy
Methamidophos	Acetyl cholinesterase inhibitors
		Insect killing medicine	Acetyl cholinesterase inhibitors
Ethoxycarb	Acetyl cholinesterase inhibitors
		Methoprene	Juvenile hormone mimics
Sumeiwei-medicine	Acetyl cholinesterase inhibitors
		Fast extinguishing phosphorus	Acetyl cholinesterase inhibitors
Mimie heater	Macrolides
		Moxidectin	Macrolides
Phosphorus dibromide	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		NI-25, acetamiprid	Nicotinic acetylcholine agonists/antagonists
Nitenpyram	Nicotinic acetylcholine agonists/antagonists
		Nodulisporic acids/derivatives	Macrolides
Omethoate	Acetyl cholinesterase inhibitors
		Grass acyl	Acetyl cholinesterase inhibitors
Sulfone phosphorus absorption M	Acetyl cholinesterase inhibitors
		Phosphorous sulfooxide	Acetyl cholinesterase inhibitors
Parathion	Acetyl cholinesterase inhibitors
		Parathion-methyl	Acetyl cholinesterase inhibitors
Permethoprim	Sodium channel modulators
		Rice Fengshu san	Acetyl cholinesterase inhibitors
Phorate	Acetyl cholinesterase inhibitors
		Futhion	Acetyl cholinesterase inhibitors
Imidothion	Acetyl cholinesterase inhibitors
		Oxime phosphorus nitrile	Acetyl cholinesterase inhibitors
Pirimicarb	Acetyl cholinesterase inhibitors
		Pyrimidine phosphorus A	Acetyl cholinesterase inhibitors
Pyrimidine phosphorus M	Acetyl cholinesterase inhibitors
		Chongwei	Acetyl cholinesterase inhibitors
P. propyl insect phosphorus	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		Killing drug	Acetyl cholinesterase inhibitors
Phoxim	Acetyl cholinesterase inhibitors
		Hair growth	Acetyl cholinesterase inhibitors
Pyrachlophos	Acetyl cholinesterase inhibitors
		Pyridazethion	Acetyl cholinesterase inhibitors
Pyresmethrin	Sodium channel modulators
		Pyrethrum Cinerifolium (L.) Roxb	Sodium channel modulators
Pyridaben	Mitochondrial electron transport inhibitors
		Pyriminostrobin	Mitochondrial electron transport inhibitors
Mosquito and fly ether	Juvenile hormone mimics
		RH 5992	Ecdysone agonists
RH-2485	Ecdysone agonists
		Phosphorus for vegetables and fruits	Acetyl cholinesterase inhibitors
Selamectin	Macrolides
		Fluorosilate	Sodium channel modulators
Spinosad	Nicotinic acetylcholine activators
		Thiotepu	Acetyl cholinesterase inhibitors
Thioprophos	Acetyl cholinesterase inhibitors
		Tebufenozide	Ecdysone agonists
Tebufenpyrad	Mitochondrial electron transport inhibitors

Abamectin	Macrolides
		Pyriproxyfen	Acetyl cholinesterase inhibitors
Vorticulate urea	Chitin synthesis inhibitor
		Tefluthrin	Sodium channel modulators
Phosphothion	Acetyl cholinesterase inhibitors
		Terbufos	Acetyl cholinesterase inhibitors
Pesticide	Acetyl cholinesterase inhibitors
		Thiafenox
Thiodimethomyl	Acetyl cholinesterase inhibitors
		Special ammonia furacarb	Acetyl cholinesterase inhibitors
Sulfophosphazine	Acetyl cholinesterase inhibitors
		Thuringiensis extract
Tetrabromopyrethrin	Sodium channel modulators
		Triarathen
Triazamate	Acetyl cholinesterase inhibitors
		Triazophos	Acetyl cholinesterase inhibitors
Trichlorfon	Acetyl cholinesterase inhibitors
		Insecticidal ureas	Chitin synthesis inhibitor
Mixed weedicide	Acetyl cholinesterase inhibitors
		Mieduo aphid	Acetyl cholinesterase inhibitors

Abamectin	Macrolides
		XMC (3, 5-xylylcarbamate)	Acetyl cholinesterase inhibitors
Micicide	Acetyl cholinesterase inhibitors
		YI 5301/5302
Zeta-cypermethrin	Sodium channel modulators
		Beta-cypermethrin	Sodium channel modulators

Non-limiting examples of suitable anthelmintics are set out below, some representative materials having insecticidal and acaricidal activity in addition to anthelmintic activity and are set out in part in the table above.

(A1) Praziquantel ═ 2-cyclohexylcarbonyl-4-oxo-1, 2, 3, 6, 7, 11 b-hexahydro-4H-pyrazino [2, 1-. alpha. ] isoquinoline

(A2) Chloro-3, 5-diiodo-N- [ 5-chloro-2-methyl-4- (a-cyano-4-chlorobenzyl) phenyl ] -salicylamide

(A 3) Trichlorophenylimidazole ═ 5-chloro-6- (2, 3-dichlorophenoxy) -2-methylsulfanyl-1H-benzimidazole

(A4) Levamisole ═ L- (-) -2, 3, 5, 6-tetrahydro-6-phenylimidazo [2, 1b ] thiazole

(A5) Mebendazole (5-benzoyl-1H-benzimidazol-2-yl) carbamic acid methyl ester

(A6) Macrocyclic fermentation products of the fungal light-emitting umbilicus mushrooms described in WO97/20857

(A7) Abamectin B1

(A8) Ivermectin 22, 23-dihydroavermectin B1

(A9) moxidectin-5-O-demethyl-28-deoxy-25- (1, 3-dimethyl-1-butenyl) -6-, 28-epoxy-23- (methoxyimino) -milbemycin B

(A10) doramectin-25-cyclohexyl-5-O-demethyl-25-de (1-methylpropyl) -avermectin A1a

(A11) Mixture of milbemycin A3 and milbemycin A4

(A12) 5-oximes of milbemycin

Non-limiting examples of suitable repellents and debonders are

(R1) DEET (N, N-diethyl-m-toluamide)

(R2) KBR 3023N-butyl-2-oxycarbonyl- (2-hydroxy) -piperidine

(R3) symiprazole ═ N, -2, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-2, 4-dimethylaniline

Such pairs in mixtures are well known to those skilled in the art. Most are described in various versions of The "Pesticide Manual" (The British Crop Protection Council, London), others are described in various versions of The "Merck Index" (Merck & co., inc., Rahway, n.j., USA) or patent literature. The following list is therefore limited in that it is possible to find their several origins by way of example.

(I) 2-methyl-2- (methylthio) propanal-O-methylcarbamoyloxime (aldicarb), ex "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p.26);

(II) S- (3, 4-dihydro-4-oxobenzo [ d ] - [1, 2, 3] -triazin-3-ylmethyl) O, O-dimethyldithiophosphate (glutathion) from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 67);

(III) N- [2, 3-dihydro-2, 2-dimethylbenzofuran-7-yloxycarbonyl- (-methyl) aminothio ] -N-isopropyl-. beta. -alanine ethyl ester (propylthiocarb), from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.96);

(IV) 2-Methylbiphenyl-3-ylmethyl- (Z) - (1RS) -cis-3- (2-chloro-3, 3, 3-trifluoroprop-1-enyl) -2, 2-dimethylcyclopropanecarboxylate (bifenthrin), from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.118);

(V) 2-tert-butylimino-3-isopropyl-5-phenyl-1, 3, 5-thiadiazin-4-one (chlorpheniramine) from "The Pesticide Manual" 11 th edition (1997, The british crop Protection Council, London, page 157);

(VI) methyl 2, 3-dihydro-2, 2-dimethylbenzofuran-7-yl-carbamate (carbofuran), from "The Pesticide Manual" 11 th edition (1997, The British crop Protection Council, London, p.186);

(VII) methyl 2, 3-dihydro-2, 2-dimethylbenzofuran-7-yl- (dibutylaminosulfanyl) carbamate (furacarb), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 188);

(VIII) S, S' - (2-dimethylamino-1, 3-propanediyl) -bis (thiocarbamate) (cartap), ex "The Pesticide Manual" 11 th edition (1997, The british crop Protection Council, London, p.193);

(IX)1- [3, 5-dichloro-4- (3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl ] -3- (2, 6-difluorobenzoyl) urea (chlorfluazuron), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 213);

(X) O, O-diethyl-O-3, 5, 6-trichloro-2-pyridylthio-phosphate (chlorpyrifos) from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p 235);

(XI) (RS) -. alpha. -cyano-4-fluoro-3-phenoxybenzyl- (1RS, 3 RS; 1RS, 3RS) -3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate (cyfluthrin), ex "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.293);

(XII) (S) -. alpha. -a mixture of cyano-3-phenoxybenzyl- (Z) - (1R, 3R) -3- (2-chloro-3, 3, 3-trifluoropropenyl) -2, 2-dimethylcyclopropanecarboxylate and (R) -. alpha. -cyano-3-phenoxybenzyl- (Z) - (1R, 3) -3- (2-chloro-3, 3, 3-trifluoropropenyl) -2, 2-dimethylcyclopropanecarboxylate (cyfluthrin-per), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 300);

(XIII) racemate consisting of (S) -. alpha. -, cyano-3-phenoxybenzyl- (2) - (1R, 3R) -3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate and (R) -. alpha. -, cyano-3-phenoxybenzyl- (1S, 3S) -3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate (alpha-cypermethrin), from "The Pesticide Manual" 11 th edition (1997, The british crop Protection Council, London, p.308);

(XIV) (S) -ccc-cyano-3-phenoxybenzyl (1RS, 3RS, 1RS, 3RS) -3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate, a mixture of stereoisomers (zeta-cypermethrin) from "The Pesticide Manual" 11 th edition (1997, The british crop Protection Council, London, p.314);

(XV) (S) -. alpha. -cyano-3-phenoxybenzyl- (1R, 3R) -3- (2, 2-dibromovinyl) -2, 2-dimethylcyclopropanecarboxylate (deltamethrin), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 344);

(XVI) (4-chlorophenyl) -3- (2, 6-difluorobenzoyl) urea (diflubenzuron), ex "The pesticide Manual" 11 th edition (1997, The British Crop protection council, London, p 395);

(XVII) (1, 4,5, 6, 7, 7-hexachloro-8, 9, 10-trinorbornen-5-en-2, 3-ylidenebismethylene) -sulphite (endosulfan) from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 459);

α -ethylthio-o-tolyl-carbamic acid methyl ester (chlordane) from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p.479);

(XIX) O, O-dimethyl-O-4-nitro-m-tolyl-thiophosphoric acid (fenitrothion), from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, page 514);

(XX) methyl 2-sec-butylbenzylcarbamate (fenobucarb), from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.516);

(XXI) (RS) - α -cyano-3-phenoxybenzyl- (RS) -2- (4-chlorophenyl) -3-methylbutyrate (fenpropathrin), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.539);

(XXII) S- [ formyl (methyl) carbamoylmethyl ] -O, O-dimethyldithiophosphate (Dimethoate) from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.625);

(XXIII) methyl 4-methylthio-3, 5-xylylcarbamate (Imidacloprid), ex "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p. 813);

(XXIV) 7-chlorobicyclo [3.2.0] hepta-2, 6-dien-6-yl-dimethylphosphate (Aphis pirifolius), ex "The Pesticide Manual" 11 th edition (1997, The British crop Protection Council, London, page 670);

(XXV)1- (6-chloro-3-pyridylmethyl) -N-nitroimidazolin-2-ylimine (imidacloprid), from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p.706);

(XXVI) methyl 2-isopropylphenyl carbamate (isoprocarb) from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.729);

(XXVII) O, S-Dimethylthiophosphoramide (methamidophos), from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 808);

(XXVIII) S-methyl-N- (methylcarbamoyloxy) thioacetamide (acetoximoyl), from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p. 815);

(XXIX) methyl 3- (dimethoxyphosphinyloxy) but-2-enoate (Ciphorate) from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.844);

(XXX) O, O-diethyl-O-4-nitrophenyl thiophosphoric acid (parathion) from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.926);

(XXXI) O, O-dimethyl-O-4-nitrophenyl thiophosphoric acid (parathion-methyl), from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, page 928);

(XXXII) S-6-chloro-2, 3-dihydro-2-oxo-1, 3-benzoxazol-3-ylmethyl-O, O-diethyldithiophosphate (Vothion), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.963);

(XXXIII) 2-dimethylamino-5, 6-dimethylpyrimidin-4-yl-dimethylcarbamate (pirimicarb), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.985);

(XXXIV) methyl 2-isopropoxyphenyl carbamate (propoxur), from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.1036);

(XXXV)1- (3, 5-dichloro-2, 4-difluorophenyl) -3- (2, 6-difluorobenzoyl) urea (teflubenzuron), from "The Pesticide Manual" 11 th edition (1997, The British crop Protection Council, London, p. 1158);

(XXXVI) S-tert-butylthiomethyl-O, O-dimethyldithiophosphate (terbufos) from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p 1165);

(XXXVII) (3-tert-butyl-1-dimethylcarbamoyl-1H-1, 2, 4-triazol-5-ylthio) -acetic acid ethyl ester (triazamate), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 1224);

(XXXVIII) Abamectin, from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 3);

(XXXIX) methyl 2-sec-butylphenyl carbamate (fenobucarb), from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.516);

(XL) N-tert-butyl-N' - (4-ethylbenzoyl) -3, 5-dimethylbenzoyl hydrazine (tebufenozide), ex "The Pesticide Manual" 11 th edition (1997, The British crop Protection Council, London, p. 1147);

(XLI) (+ -) -5-amino-1- (2, 6-dichloro-. alpha.,. alpha. -trifluoro-p-tolyl) -4-trifluoromethylsulfinylpyrazole-3-carbonitrile (fipronil) from "The pesticide manual" 11 th edition (1997, The British Crop Protection Council, London, p.545);

(XLII) (RS) -. alpha. -cyano-4-fluoro-3-phenoxybenzyl (1RS, 3 RS; 1RS, 3RS) -3- (2, 2-dichlorovinyl) -2, 2-dimethylcyclopropanecarboxylate (. beta. -cyfluthrin), ex "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p. 295);

(XLIII) (4-ethoxyphenyl) - [3- (4-fluoro-3-phenoxyphenyl) propyl ] (dimethyl) silane (silafluofen) from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.1105);

(XLIV) (E) - α - (1, 3-dimethyl-5-phenoxypyrazol-4-ylmethylenenitroxy) p-toluic acid tert-butyl ester (fenpyroximate), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 530);

(XLV) 2-tert-butyl-5- (4-tert-butylbenzylthio) -4-chloropyridazin-3- (2H) -one (pyridaben) from "The Pesticide Manual" 11 th edition (1997, The british crop Protection Council, London, p 1161);

(XLVI)4- [ [4- (1, 1-dimethylphenyl) phenyl ] ethoxy ] quinazoline (fenazaquin), ex "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p 507);

(XLVII) 4-phenoxyphenyl- (RS) -2- (pyridyloxy) propyl ether (pyriproxyfen), ex "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p.1073);

(XLVIII) 5-chloro-N- {2- [4- (2-ethoxyethyl) -2, 3-dimethylphenoxy ] ethyl- } -6-ethylpyrimidin-4-amine (pyriminostrobin), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p.1070);

(XLIX) (E) -N- (6-chloro-3-pyridylmethyl) -N-ethyl-N' -methyl-2-nitroethenediamine (nitenpyram), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 880);

(L) (E) -N.sup.1- [ (6-chloro-3-pyridyl) methyl ] -N.sup.2-cyano-N.sup.1-methylethylamidine (NI-25, acetamiprid) ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 9);

(LI) Avermectin B.sub.1, from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 3);

(LII) insect-active extracts from plants, in particular (2R, 6aS, 12aS) -1, 2, 6, 6a, 12, 12 a-hexahydro-2-isopropenyl-8, 9-dimethoxybenzopyran [3, 4-b ] furoyl [2, 3-h ] chromen-6-one (rotenone), from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 1097); and extracts from neem, especially azadirachtin, from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 59); and

(LII) preparations comprising insect-active nematodes, preferably Bacteroides heterodera and heterodera, from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p. 671); steiner, from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.1115); and Steinemama scaptedsci from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.1116);

(LIV) preparation from Bacillus subtilis, from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 72); or a preparation derived from a bacillus thuringiensis strain other than the compound isolated from GC91 or NCTC 11821; from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 73);

(LV) preparations containing an insect-active fungus, preferably verticillium dahliae, from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p. 1266); beauveria bassiana, from "The pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 85); and Beauveria bassiana, from "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, page 83);

(LVI) a preparation comprising an insect-active virus, preferably Neodipridon Sertifer NPV, from "The Pesticide Manual" 11 th edition (1997, The British crop protection Council, London, p.1342); cabbage looper NPV from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p. 759); and codling moth granulosis virus, from "The pesticide Manual" 11 th edition (1997, The British Crop protection Council, London, p.291);

(CLXXXI) 7-chloro-2, 3, 4a, 5-tetrahydro-2- [ methoxycarbonyl (4-trifluoromethoxyphenyl) -carbamoyl ] indole [1, 2e ] oxazoline-4 a-carboxylate (DPX-MP062, york), ex "The Pesticide Manual" 11 th edition (1997, The British patent protection Council, London, p 453);

(CLXXXII) N '-tert-butyl-N' - (3, 5-dimethylbenzoyl) -3-methoxy-2-methylbenzoyl hydrazine (RH-2485, methoxyfenozide), ex "The Pesticide Manual" 11 th edition (1997, The British Crop Protection Council, London, p. 1094); and

(CLXXXIII) (N' - [ 4-methoxybiphenyl-3-yl ] -hydrazinecarboxylic acid isopropyl ester (D2341) from Brighton Crop Protection Conference (pages 487 to 493, 1996);

(R2) "Book of extracts" (212th ACS National meeting Orlando, Fla., 1996, 8 months, pages 25 to 29, AGRO-020, Publisher: American Chemical Society (Washington, D.C.), CONEN: 63 BFAF).

Generally, anthelmintic compositions according to the invention comprise from 0.1% to 99%, especially from 0.1% to 95% by weight of an active ingredient of formula 1 and mixtures thereof, from 99.9% to 1%, especially from 99.8% to 5% by weight of a solid or liquid mixture comprising from 0% to 25%, especially from 0.1% to 25% by weight of a surfactant.

As noted above, in another embodiment of the method according to the present invention, the compound of formula 1 and the additional compound described above may be administered in different and independent manners over time.

The following tests demonstrate the control efficacy of the compounds of the present invention against specific pests. However, the pest control protection provided by the compounds is not limited to these species.

Biological examples of the present invention

Test A

Feed assay for adult horn fly

Determination of test Compound (3-bromo-1- (3-chloro-2-pyridyl) -N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl) by the blood powder assay]Phenyl radical]-1H-pyrazole-5-carboxamide) LC against adult horn flies₅₀. Six (6) serial dilutions of the test compound were prepared in cryopreserved bovine blood with coagulation factors removed. Ivermectin was included as a positive control compound, and a negative control was included in each assay. Flies were collected from commercial beef cattle housed in pens with a net just prior to each assay. About 100 adults were introduced into a cylinder mould (30X 30cm), and the insects were collectedThe net cage contained a piece of gauze (4X 1cm) soaked with a portion of blood/insecticide concentrate. There were 3 replicate cages each with blood/insecticide concentrate. The gauze with blood was replaced every 12 hours. The untreated control mesh cage contained untreated blood with the coagulation factor removed. All the netpens were labeled and stored in the dark for 72 hours at 25 ℃ to 27 ℃ and ambient relative humidity (70% to 85%). Every 12 hours, the number of dead flies in each cage was counted. At 72 to 96 hours, all flies were counted and the percent mortality was calculated. If dose-effect relationships exist in the assay, the data are subjected to log-probability analysis to determine LC₅₀。

Feed assay for adult horn fly

Test B

Aedes adult contact assay

Adult aedes were exposed to six concentrations of the positive control compound, permethrin, and the test compound diluted with acetone. The test compound (3-bromo-1- (3-chloro-2-pyridyl) -N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl ] phenyl ] -1H-pyrazole-5-carboxamide) was used at 0ppm (acetone only), 0.1ppm, 1ppm, 10ppm, 20ppm, 50ppm, 100ppm, 500ppm and 1000ppm in diluted form. Each concentration was assayed in 5 replicates.

The test was performed in a 100mL Erlenmeyer flask. The day before the treatment was applied, the entire inner wall of the flask was coated with Coatasil. 0.5mL aliquots of each concentration were applied to the bottom of the flask only. After 24 hours of surface treatment, food grade carbon dioxide was used to anesthetize the aedes, and 10 aedes were introduced into each erlenmeyer flask and the flask mouth was covered with a paraffin cap film. Several small holes were made in the paraffin sealing film to allow air gas exchange. The bioassay was carried out at 25. + -. 2 ℃ and about 70% relative humidity for 8 hours.

Aedes adult contact assay

Compound (I)	LC50 (ug/flask)	LC90 (ug/flask)
			Test compounds	0.025	0.033

Compound (I)	LC50 (ug/flask)	LC90 (ug/flask)
			Permethoprim	0.025	0.046

Mortality of untreated control-6%

Test C

In vivo evaluation of Artificial infestation of dogs with Cat fleas (Cat fleas) and Brown dog tick (Rhipicephalus sanguineus) Stator

Twenty-five dogs were used in this study to study the efficacy of the test compound (3-bromo-1- (3-chloro-2-pyridinyl) -N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl ] phenyl ] -1H-pyrazole-5-carboxamide) against fleas and ticks. Two groups (one treated and one untreated) each containing five dogs were used to assess anti-flea efficacy, while two groups (one treated and one untreated) each containing five dogs were used to study anti-ticks efficacy. Dogs in each group were infested weekly with 40 adult ticks that had not been fed and 100 cat fleas. One group was treated with adavantix and used as a positive control. The dogs in this group were infested with fleas and ticks simultaneously. Test compounds were formulated in NMP. The treatment was administered via syringe topically in a back-line pour-down form on the animal's dorsal midline at a dose rate of 60 mg/kg. The efficacy of the compounds was assessed by counting ticks and fleas per week. The weekly numbers of treated groups were compared to the number of positive and negative untreated control (UTC) groups to assess the efficacy of the test compounds.

In vivo assessment of dog infestation with Cat fleas and Rhipicephalus sanguineus

Flea removal efficacy (%)

	Treating agent	Day 2	Day 9	Day 16	Day 23	Day 29
							4	Test compounds	99.6	99.7	99.7	98.7	97.3
5	ADVANTIX	100	100	89.0	76.7	69.1
							UTC (average flea count)	Carrier (NMP)	57.0	73.8	78.2	76.4	73.2

Tick-removing efficacy (%)

	Treating agent	Day 2	Day 9	Day 16	Day 23	Day 29
							3	Test compounds	74.0	94.9	95.0	90.6	86.2
5	ADVANTIX	44.0	99.3	89.7	84.2	79.7
							UTC (average tick count)	Carrier (NMP)	10.0	27.6	25.2	27.8	24.6

A small number of hyperphagic ticks were found on dogs in both the experimental and positive control treated groups for all assay times. During the 30 day period, the test compound provided similar levels of control ticks as the positive control product, ADVANTIX, in all but one assessment, with a slightly lower number of live ticks collected from the dogs. At 48 hours post-treatment, the test compound achieved 74% efficacy compared to the negative control. This result is 30% higher than the advanix that achieved 44% efficacy. The test compounds provided greater than 94.9%, 90.5% and 90.6% efficacy at 9, 16 and 23 days post-treatment, respectively, with this control level being similar to advataix at 99.3%, 89.7% and 84.2% efficacy, respectively. The test compound provided high protection continuously within 30 days after treatment, with 86.2% efficacy being comparable to 79.7% efficacy provided by advatax.

Overall, the test compound treatment was more effective against fleas than the positive control product. Efficacy exceeded 99.5% during the first three assessments at 2, 9 and 16 days post-treatment; and 30 days after treatment, the efficacy was 97.3%. While advataix achieved 100% efficacy on the first 9 days post-administration, this fell below 90% on day 16 and below 70% on day 30.

Test D

In vivo assessment of human infestation of mice with Cat fleas (Cat fleas)

To evaluate the control effect on Ctenocephalides felis (Ctenocephalides felis), the control of Ctenocephalides felisMice (approximately 30g, male, available from Charles River Laboratories, Wilmington, Mass.) were orally administered test compounds dissolved in propylene glycol/glycerol formal (60: 40) in an amount of 10 mg/kg. Approximately 8 to 16 adult fleas were applied to each mouse two hours after oral administration of the test compound. Fleas mortality was then assessed 48 hours after application to the mice.

3-bromo-1- (3-chloro-2-pyridinyl) -N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl ] phenyl ] -1H-pyrazole-5-carboxamide causes 45% mortality.

Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (19)

1. A method of controlling or preventing infestation of a warm-blooded animal by haematophagous ectoparasitic insects by administering to said animal a composition comprising a parasiticidally effective amount of 3-bromo-N- [ 4-cyano-2-methyl-6- [ (methylamino) carbonyl ] phenyl ] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxamide, or an N-oxide or a pharmaceutically or veterinarily acceptable salt thereof.

2. The method of claim 1, wherein said hematophagous ectoparasitic insect is selected from the group consisting of fleas, ticks, lice, mites, and biting flies.

3. The method of claim 1, wherein the administration is oral.

4. The method of claim 1, wherein the administration is parenteral.

5. The method of claim 1, wherein said administering is topical.

6. The method of claim 1 wherein the animal is a cat or dog.

7. The method of claim 1 wherein the animal is a social animal.

8. The method of any one of claims 1 to 7, wherein the composition comprises at least one additional component selected from solvents and/or carriers, emulsifiers and/or dispersants.

9. The method of claim 8, wherein the composition comprises at least one additional biologically active compound or agent.

10. The method of claim 9, wherein the additional biologically active compound or agent is selected from the group consisting of macrocyclic lactones, acetyl cholinesterase inhibitors, arthropodgrowth regulators, GABA-gated chloride channel antagonists, mitochondrial electron transport inhibitors, nicotinic acetylcholine agonists/antagonists/activators, oxidative phosphorylation inhibitors, anthelminthics, sodium channel modulators, or other antiparasitic compounds.

11. The method of claim 10, wherein the biologically active compound is a macrolide.

12. The method of claim 10, wherein the biologically active compound is an acetyl cholinesterase inhibitor selected from the group consisting of organophosphates and carbamates.

13. The method of claim 10 wherein said biologically active compound is an arthropod growth regulator selected from the group consisting of chitin synthesis inhibitors, ecdysone agonists/interferons, lipid biosynthesis inhibitors and juvenile hormone mimics.

14. The method of claim 10 wherein said biologically active compound is a GABA-gated chloride channel antagonist.

15. The method of claim 10, wherein the biologically active compound is a mitochondrial electron transport inhibitor.

16. The method of claim 10 wherein the biologically active compound is a nicotinic acetylcholine agonist/antagonist/activator.

17. The method of claim 10, wherein the biologically active compound is an oxidative phosphorylation inhibitor.

18. The method of claim 10 wherein the biologically active compound is an anthelmintic.

19. The method of claim 10, wherein the biologically active compound is a sodium channel modulator.