Mite infestation treatment

Abstract

Providing mite infestation treatment. [Solution] The present invention relates to a compound of formula (I), its salt or a composition containing the same as an acaricide, a method for reducing or preventing infestation of animals by mites which comprises exposing mites to a compound of formula (I), a composition containing the compound of formula (I), one or more attractants and polymers for honeybees, a strap suitable for use in beekeeping which contains the compound of formula (I), and a honeybee hive which contains the compound of formula (I).

Description

[Technical field]

[0001] The present invention relates to the use of alpha-2-adrenergic agonist compounds as acaricides, and to a method of reducing or preventing varroa mite infestations in honey bee hives which consists in exposing the mites to alpha-2-adrenergic agonist compounds. [Background technology]

[0002] Most animals can be infested with mites. This applies to domestic animals such as, for example, dogs, cats, horses, but also livestock such as bees, cattle, sheep, poultry, etc. Beyond the inconvenience caused to the animals, mites can debilitate the animals, transmit disease, or even cause the death of the animals.

[0003] Colony Collapse Disorder (CCD) is the name given to the phenomenon of abnormal and recurrent mass mortality observed since the 1990s in honeybee colonies worldwide. Several explanations for this phenomenon have already been proposed, in particular the increase in parasitic diseases, more specifically caused by Varroa and Varroasis mites. This mite parasitizes honeybees and weakens the colony by reducing its immune defense and its physiological state, and can be a vector for viruses. The treatment of this parasite is a major problem for the survival of the colony and therefore for the maintenance of pollination as well as its productivity.

[0004] Nowadays, everyone is aware of the impact of Varroa mites on bee colonies. Many techniques are used to determine colony infestation. These include, among others, the use of cleaning agents, liquids containing alcohol, CO 2It is based on the calculation of the percentage of honeybee infestation by removing Varroa mites attached to honeybees (percentage of pheasant Varroa mites per 100 honeybees) using a sieve or powdered sugar and then counting the detached Varroa mites [1]. Several more or less complex devices for removing Varroa mites from honeybees are described in the literature, in particular the device described in Canadian Patent Application No. 2943917 or the device described in Community Model No. 003419415-0001. The percentage of infestation corresponds to the number of Varroa mites found in 100 adult honeybees. Depending on the time of year, it is possible to generate indicators: At infestations between 0-2% colonies are functioning well. At around 5% infestation, population dynamics and honey production are affected (approximately 25% lower yields during honey flow, [2]). At infestations of around 10% or more, colonies die more or less rapidly and do not survive winter.

[0005] It is very important that the infestation in the spring is less than 1% in order for the colony to have a maximum infestation of 5% at the end of the season.

[0006] Despite more than 30 years of research and experimental efforts, the therapeutic arsenal available to combat this mite has been reduced to a small number of products, leaving beekeepers feeling helpless in the face of this scourge. However, although the latter have several treatments that intervene to protect the colony, very few compounds are actually approved to treat varroasis.

[0007] In France, there are currently six active compounds for use against varroasis with variable efficiency.

[0008] Treatments are currently divided into two categories: chemical and biological compounds, but are also differentiated by the duration of treatment (long-term or short-term). Long-term treatments are generally carried out at the end of the beekeeping season (mid-August) before the peak of the deadly Varroa mite in August / September, and can also be applied in the spring, in addition to limiting summer infestations as much as possible. Short-term treatments must be carried out in the absence of brood (outside of the summer) and are used in addition to long-term treatments to increase their efficiency.

[0009] There are three chemical compounds derived from synthetic molecules: amitraz, tau-fluvalinate and flumethrin. Amitraz has the following formula: [ka] It is a compound of the formula:

[0010] There are three natural compounds used in organic beekeeping: thymol, oxalic acid and formic acid.

[0011] Some of them unfortunately become less effective due to the increasing resistance of Varroa mites to certain compounds used. This is especially true for the compounds tau-fluvalinate and flumethrin. Furthermore, the reduced number of available treatments does not allow for sufficient changes in the context of effective health care.

[0012] These compounds have also shown efficacy in treating mite infestations in animals other than honeybees.

[0013] Therefore, research is still needed to identify new molecules that are effective against mites and do not involve risks to treated animals and humans, especially those aimed at combating Varroa mites, without compromising the quality of honey for human consumption, and without risks to both the colony and the environment and to the beekeeper. Summary of the Invention [Means for solving the problem]

[0014] According to a first aspect, the present invention relates to the use of a compound of formula (I), a salt thereof or a composition containing it, as an acaricide, wherein said compound of formula (I) is [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) , regarding use.

[0015] According to a second aspect, the present invention relates to a method for reducing or preventing infestation by mites, comprising exposing mites to a compound of formula (I), a salt thereof or a composition containing same, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) This relates to a method.

[0016] According to a third aspect, the present invention relates to a composition suitable for use as a varroacide in honeybees, comprising a compound of formula (I) or a salt thereof, one or more honeybee attractants, and one or more polymers selected from plastic materials, rubbers, adhesives, resins and polyholoside fibres, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) The present invention relates to a composition,

[0017] According to a fourth aspect, the present invention relates to a strap, preferably suitable for use in beekeeping, comprising (i) a compound of formula (I), a salt thereof, a composition containing it, or (ii) a composition according to the invention, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) That is, regarding the strap.

[0018] According to a fifth aspect, the present invention relates to (i) a compound of formula (I), a salt thereof, or a composition containing same, (ii) a composition according to the invention, or (iii) a beehive comprising a strap according to the invention, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) This is about beehives. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Definition of the compounds of formula (I)

[0020] The compounds of formula (I) are alpha-2-adrenergic agonists. [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) It is.

[0021] Advantageously, Y is the following group (IV) or (V): [ka] [ka] It is.

[0022] Advantageously, the compound of formula (I) [ka] (In the formula, A is a group (II), X is NH, Y is a group (IV), and Z 1 is a halogen, Z 2 is H and Z 3 is a halogen, A is group (II) and X is CH 2 or CH-CH 3 Y is a group (V) and Z 1 CH 3and Z 2 CH 3 and Z 3 is H, or A is a group (III), X is NH, Y is a group (IV), and Z 4 is a halogen) It is.

[0023] Advantageously, the allogen is selected from F, Cl or Br.

[0024] In certain embodiments, the compound of formula (I) is selected from detomidine (CAS number: 76631-46-4), medetomidine (D) (i.e. dexmedetomidine - CAS number: 113775-47-6), medetomidine (L) (i.e. levomedetomidine - CAS number: 119717-21-4), romifidine (CAS number: 65896-16-4), clonidine (CAS number: 4205-90-7), tizanidine (CAS number: 51322-75-9) or a mixture of two or more of these compounds. It may be, for example, a racemic mixture, for example the racemate of medetomidine (CAS number: 86347-14-0).

[0025] Detomidine is also known by the chemical name 4-[(2,3-dimethylphenyl)-methyl]-3H-imidazole, which has the following formula: [ka] has.

[0026] Dexmedetomidine corresponds to the dextrorotatory enantiomer of medetomidine. Dexmedetomidine is also known by the chemical name (S)-4-[1-(2,3-dimethylphenyl)-ethyl]-1H-imidazole. It has the following formula: [ka] has.

[0027] Clonidine is also known by the chemical name N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine. It has the following formula: [ka] has.

[0028] Romifidine is also known by the chemical name N-(2-bromo-6-fluorophenyl)-4,5-dihydro-1H-imidazol-2-amine, which has the following formula: [ka] has.

[0029] Tizanidine is also known by the chemical name 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-8-thia-7,9-diazabicyclo,nona-2,4,6,9-tetraen-5-amine. It has the following formula: [ka] has.

[0030] In a particularly preferred embodiment, the compound of formula (I) is dexmedetomidine, which is a particularly interesting compound for use in beekeeping, as the applicant has shown that this compound has Varroa acaricidal properties without toxicity to honeybees.

[0031] The compounds of formula (I) according to the invention may be in the form of salts. The term "salt" refers to ionic compounds composed of cations and anions forming a neutral product with no net charge. The skilled artisan will know how to select suitable salts for carrying out the invention, i.e. salts that are non-toxic for the handler and / or for the consumption of bees and / or honey. The salts may be selected from the following salts: hydrochloride, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthalene ... Phthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, xinofoates, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. For example, salts known to be pharma- ceutically acceptable are suitable for the implementation of the present invention, and are in particular mentioned in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0032] Particularly suitable salts for carrying out the invention are salts of a compound chosen from detomidine, medetomidine (D) (i.e. dexmedetomidine), medetomidine (L) (i.e. levomedetomidine), romifidine, clonidine, tizanidine or a mixture of two or more of these compounds. Advantageously, the salt is the hydrochloride salt. The salt may be, for example, medetomidine (L) hydrochloride (i.e., levomedetomidine hydrochloride - CAS number: 190000-46-5) and / or medetomidine (D) hydrochloride (e.g., dexmedetomidine hydrochloride - CAS number: 145108-58-3 or medetomidine hydrochloride - CAS number: 86347-15-1), clonidine hydrochloride (CAS number: 4205-91-8), tizanidine hydrochloride (CAS number: 64461-82-1), or detomidine hydrochloride (CAS number: 90038-00-9).

[0033] In the context of the present invention, some compounds of formula (I) may be associated with each other.

[0034] A particularly suitable salt for implementing the invention in the field of beekeeping is dexmedetomidine hydrochloride, since the applicant has shown that this compound has Varroa acaricidal properties without being toxic to honeybees.

[0035] definition

[0036] The term "acaricide" refers to a compound that has the property of killing mites. For example, the compound may have the property of killing mites by paralysis. In certain embodiments of the invention, the acaricide may be a "varroa acaricide", i.e., a compound that has the property of killing Varroa mites.

[0037] In the context of the present invention, mites are · The suborder metastigmata (ticks), in particular ticks of the family Ixodidae, such as Ixodes ricinus, Ixodes scapularis, Rhipicephalus sanguineus and Boophilus microplus (cattle ticks), Dermacentor variabilis, Amblyomma americanum; · Mites of the suborder Mesostigmata, in particular of the family Dermanyssidae, e.g. Dermanyssus gallinae (poultry lice) or of the family Varroidae, e.g. Varroa; the suborder Astigmata ("gall mites"), in particular mites of the family Sarcoptidae, such as Sarcoptes scabiei and Notoedres cati, or mites of the family Psoroptidae, such as Psoroptes ovis, Chorioptes bovis and Otodectes cynotis; or Mites from the suborder Prostigmata, in particular the family Demodicidae, such as Demodex bovis and Demodex canis, or from the family Cheyletiellidae, such as Cheyletiella yasguri It could be.

[0038] In this particular embodiment of the invention, the mite is a Varroa mite. The term "Varroa" refers to a parasitic honeybee mite, which is parasitic in all stages of its development and affects the health of honeybees, especially the health of the colony in the honeybee hive. In the context of the present invention, the Varroa is preferably the Varroa destructor mite.

[0039] The term "animals" in the context of the present invention denotes, for example, dogs, cats, horses, poultry, cows, sheep, bees.

[0040] The term "honeybee" refers to an insect of the order Hymenoptera and the genus Apis. There are four species of honeybee: Apis dorsata, Apis florea, Apis cerana and Apis mellifera. In a particular embodiment of the present invention, the honeybee is Apis mellifera.

[0041] The term "beehive" refers to a structure that houses a colony of bees. The interior of a beehive consists of a comb formed by hexagonal holes in beeswax. Bees use these holes for food storage (honey and pollen) and for colony reproduction (eggs, larvae and pupae). In beekeeping, a beehive is a living unit constructed by a beekeeper to house a colony of bees. It is usually a wooden or plastic box.

[0042] The term "strap" denotes a strip made by cutting or weaving a flexible material. The flexible material may be, for example, a plastic material, rubber, a fabric, a resin or a polyholoside fiber. The strap may have various shapes. It may be, for example, a cat collar, a dog collar or a strap used in beekeeping. Preferably, the strap is a strap suitable for use in beekeeping, i.e. a non-circular strap, preferably a flat strap, with a size, stiffness and shape adapted so that the strap can be slid between the frames of a beehive.

[0043] The present invention stems from the advantages demonstrated by the inventors of the acaricidal effect of compounds of formula (I).

[0044] Uses and Methods

[0045] According to a first aspect, the present invention relates to the use of a compound of formula (I), a salt thereof or a composition containing it, as an acaricide, wherein said compound of formula (I) is [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) , regarding use.

[0046] Advantageously, the compound of formula (I) To reduce or prevent tick infestations, To reduce or prevent infestation by mites in animals (e.g. the animals are cats, dogs, horses, poultry, cattle, sheep or bees), To reduce or prevent infestation by mites in honey bee hives, preferably the mites being Varroa mites. Used for.

[0047] According to a second aspect, the present invention relates to a method for reducing or preventing mite infestation, comprising the step of exposing Varroa mites to a compound of formula (I), a salt thereof or a composition containing same, said compound of formula (I) being [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3is) This relates to a method.

[0048] According to a second aspect of the invention, the infestation by mites is mite infestations in animals (for example, the animals are cats, dogs, horses, poultry, cattle, sheep or bees), Infestation by mites in honey bee hives (preferably the mites are Varroa mites) It could be.

[0049] In the context of the present invention, a composition of a compound of formula (I) or a composition of a salt of a compound of formula (I) contains 0.001 to 200 μg / μL, preferably 0.01 to 100 μg / μL, 0.1 to 100 μg / μL, for example about 0.1 μg / μL, about 1 μg / μL, about 10 μg / μL, about 25 μg / μL, about 50 μg / μL, about 75 μg / μL, or even about 100 μg / μL of a compound of formula (I) or a salt thereof.

[0050] The compound of formula (I) or a salt thereof may be dissolved in a solvent, which may be, for example, acetonitrile, acetone, ethanol or methanol.

[0051] The compound of formula (I) or a salt thereof may be in the form of a composition, which may be a composition according to the invention as defined below.

[0052] The compound of formula (I), its salt or a composition containing it may be contained in and / or on a strap, which may be a strap according to the invention as defined below.

[0053] In a particular embodiment of the present invention, the reduction of mite infestation is at least 25%, preferably at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or even 100% reduction in the number of live mites attached to animals.Such reduction is advantageously obtained less than 24 hours (h) after treatment, for example less than 12 hours, less than 6 hours or even less than 3 hours after treatment, for example by carrying out the test described in the example section.In practical conditions, the reduction can be obtained after several days or even weeks.The reduction of infestation can be easily measured, for example, in the case of honeybee infestation by Varroa mites, by removing 100 honeybees from a beehive and counting the number of Varroa mites attached to them. It is therefore easy to compare the number of Varroa mites on bees between treated and untreated hives, or between a hive before treatment and the same hive after treatment. A 50% reduction means that the treated animals have half the number of mites as the untreated animals. A 100% reduction means that the animals are no longer carrying mites.

[0054] Advantageously, the use according to the invention and the implementation of the method according to the invention do not affect the survival of the animals. If the animals are honeybees, preferably less than 20%, preferably less than 15%, less than 10%, less than 5% of the bees are killed by treating the beehives with a compound of formula (I), ideally no bees are killed at all.

[0055] Exposure to the compound can be achieved by contacting the mites with the compound of formula (I), for example by evaporation, sublimation, smoking, spraying or vaporizing the compound of formula (I) or a salt thereof. Exposure of the mites can also be achieved after the animal has ingested the compound of formula (I) or a salt thereof.

[0056] The exposure can be carried out to prevent infestation or to treat infestation by mites. If the animal is a honey bee and the mite is a Varroa mite, the exposure to the compound of formula (I), its salt or a composition containing it can be carried out in the spring when the Varroa population in the apiary is too high, at the beginning of summer for beekeepers who want to leave their supervision to obtain buckwheat or calluna honey, or at the end of summer (end of July / mid-August) just after the last honey flow. The exposure can also be carried out in the winter.

[0057] The compound of formula (I), a salt thereof or a composition containing same may be applied to at least a part of the animal.

[0058] When the animal is a honeybee and the mite is a Varroa mite, the compound of formula (I), its salt or a composition containing it can be applied to at least a part of the beehive, for example, at the entrance of the beehive on a device placed in the beehive, for example, a strap, directly to the bees or directly to the Varroa mite. The form in which the compound is applied can be varied, for example, in the form of a powder, in the form of a gel, in the form of a polymer, in the form of a smoke, in the form of a solution, etc., as long as it allows it to have the desired Varroa mite-killing effect.

[0059] In certain embodiments, the compound of formula (I) is combined in a composition with one or more bee attractants.Bee attractants are widely described in the literature, for example in EP 0499510.Among the bee attractants, mention may be made, for example, of geraniol, citral, nerolic acid, lemongrass, farnesol and / or royal jelly components, for example adipic acid, pinelic acid, suberic acid and / or 4-hydroxybenzoic acid. (See the paper "Compounds which affect the behavior of the honeybee Apis mellifera - Bee world 69-1988-104-123). The addition of one or more bee attractants to the compound of formula (I) makes it possible to attract the honeybees. The honeybees will then naturally move towards the compound of formula (I) and thus find themselves in contact with said compound of formula (I). As a result, the honeybees self-apply the compound of formula (I) to at least a part of their body.

[0060] composition

[0061] The present disclosure relates to a composition comprising a compound of formula (I) or a salt thereof and one or more polymers selected from plastic materials, rubbers, adhesives, resins and polysaccharide fibers, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) The present invention relates to a composition,

[0062] According to a third aspect, the present invention relates to a composition suitable for use as a Varroa mite killer in honeybees, comprising a compound of formula (I) or a salt thereof, one or more honeybee attractants and one or more polymers selected from plastic materials, rubbers, adhesives, resins and polyholoside fibres, The formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) The present invention relates to a composition,

[0063] The plastic material may be a copolymer of ethylene and vinyl acetate (EVA copolymer).

[0064] The resin may be a natural or synthetic resin.

[0065] The polysaccharide fibre is cellulose, starch or inulin.

[0066] The composition is advantageously suitable for use as an acaricide, for example as an acaricide in animals. In the context of the present invention, the composition is suitable for use as a Varroa acaricide in honeybees, said composition further comprising one or more honeybee attractants. Honeybee attractants are widely described in the literature, for example in EP 0 499 510. Among the honeybee attractants, mention may be made, for example, of geraniol, citral, nerolic acid, lemongrass, farnesol and / or components of royal jelly, such as adipic acid, pinelic acid, suberic acid and / or 4-hydroxybenzoic acid. (See the article "Compounds which affect the behavior of the honeybee Apis mellifera-Bee world 69-1988-104-123").

[0067] The composition must contain enough of the compound of formula (I) or one of its salts to allow a reduction in mite infestation, preferably at least 25%, preferably at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or even 100% reduction in the number of live mites attached to the animal. Such reduction is advantageously obtained less than 24 hours (h) after treatment, for example less than 12 hours, less than 6 hours or even less than 3 hours after treatment. In certain embodiments, such reduction can be obtained in beehives several days after application of the treatment, for example at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, for example up to 12 weeks after application of the treatment.

[0068] The compositions of the present invention should not be toxic to honeybees: preferably, less than 20%, preferably less than 15%, less than 10%, less than 5% of the honeybees are killed when in contact with the compositions of the present invention, and ideally, no honeybees are killed.

[0069] Therefore, the concentration of the compound of formula (I) or its salt is suitable for killing mites without being toxic to animals. Those skilled in the art can easily adapt the concentration as needed. For example, the composition of the compound of formula (I) or the composition of the salt of the compound of formula (I) contains 0.001-200 μg / μL, preferably 0.01-100 μg / μL, 0.1-100 μg / μL, such as about 0.1 μg / μL, about 1 μg / μL, about 10 μg / μL, about 25 μg / μL, about 50 μg / μL, about 75 μg / μL, or even about 100 μg / μL of the compound of formula (I) or its salt.

[0070] strap

[0071] According to a fourth aspect, the present invention relates to a strap, preferably suitable for use in beekeeping, comprising (i) a compound of formula (I), a salt thereof, a composition containing it, or (ii) a composition according to the invention, wherein said formula (I) is [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH 2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) That is, regarding the strap.

[0072] Straps are commonly used in the veterinary field in acaricide treatments, for example in the form of collars for dogs or cats. Straps are also commonly used in beekeeping in Varroa acaricide treatments. Several straps suitable for beekeeping are commercially available (e.g. APIVAR® devices).

[0073] Generally, the acaricidal compound migrates from inside the strap to its surface and comes into contact with the animals and / or mites. This is the case with APIVAR® products. The bees rub against the strap and take up the compound. The compound is then distributed among the bees by contact. Thus, the Varroa mites attached to the bees are exposed to the compound which causes their death. The Varroa mites then detach from the bees. In the beehive, the Varroa mites thus detached fall to the bottom of the beehive.

[0074] The strap of the invention may therefore be suitable for use in beekeeping. In particular, it has a size, rigidity and shape adapted to be able to slide into a beehive, i.e. adapted so that the strap can slide between the frames of a beehive. The adapted shape corresponds to a non-circular or non-curved strap, preferably a flat strap. The adapted size corresponds to a strap with a width comprised between 1 cm and 20 cm, preferably between 4 cm and 20 cm, and a length comprised between 5 cm and 50 cm, preferably between 15 cm and 25 cm. The thickness of the strap is ideally comprised between 0.5 mm and 5 mm, preferably with a thickness of 1 mm to 2 mm. The adapted rigidity corresponds to a rigidity sufficient to break the beeswax bridges that may be formed between the frames of the beehive. The straps can be impregnated or coated with the acaricidal compound, for example by spraying the straps with the compound. The straps can also be made from a mixture already containing the acaricidal compound, for example by extruding the mixture into the desired shape, or by molding.

[0075] Beehive

[0076] According to a fifth aspect, the present invention relates to (i) a compound of formula (I), a salt thereof, or a composition containing same, (ii) a composition according to the invention, or (iii) a beehive comprising a strap according to the invention, Formula (I) [ka] (In the formula, A is group (II) or (III): [ka] [ka] Selected from; X is NH, CH2 or CH-CH 3 and; Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z 1 is halogen, H or CH 3 and; Z 2 is halogen, H or CH 3 and; Z 3 is halogen, H or CH 3 and; Z 4 is halogen, H or CH 3 is) This is about beehives.

[0077] The beehive comprises a sufficient amount of (i) a compound of formula (I), a salt thereof or a composition containing same, (ii) a composition according to the present invention, or (iii) a strap according to the present invention.

[0078] In certain embodiments, all or a portion of a bee hive is covered with the acaricidal compound, for example, by spraying the bee hive with the acaricidal compound.

[0079] In another particular embodiment, a bee hive contains a colony and the colony is coated with the miticidal compound, for example by spraying the colony with the miticidal compound.

[0080] In another particular embodiment, a bee hive comprises one or more straps according to the present invention.

[0081] Other purposes

[0082] Another object relates to a nutritional composition for honeybees comprising a compound of formula (I) as defined in "Definition of the compound of formula (I)". The nutritional composition for honeybees can be in various forms, for example in the form of a bee syrup, a sweet paste or a bee protein paste.

[0083] Another object relates to a device for veterinary use, for example in beekeeping, comprising a compound of formula (I) as defined in "Definition of the compound of formula (I)". The device can be a strap or a beehive. The device can be impregnated or coated with the acaricidal compound, for example by spraying the device with the compound. The device can also be manufactured from a mixture already containing the acaricidal compound, for example by extruding the mixture into the desired shape or by molding.

[0084] Another object relates to the compounds of formula (I) as defined in "Definition of the compounds of formula (I)" for use in treating or preventing an infestation by mites as defined above in an animal. [Brief description of the drawings]

[0085] [Figure 1A] Figure 1A depicts the toxicity of certain solvents to Varroa mites. The negative control corresponds to untreated honeybees, i.e., bees that have not received thorax deposition. [Figure 1B] Figure 1B illustrates the toxicity of certain solvents to honeybees. The negative control corresponds to untreated honeybees, i.e., bees that have not received thorax deposition. [Figure 2A] Figure 2A is a diagram measuring the Varroa acaricidal effect of amitraz. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent made it possible to solubilize the molecules and / or to carry out dilution or concentration. [Figure 2B] FIG. 2B is a diagram measuring the effect of amitraz on honeybees. The negative control corresponds to untreated honeybees, i.e. bees that have not undergone thoracic deposition. The solvent made it possible to solubilize the molecules and / or to carry out dilution or concentration. [Figure 3A]Figure 3A is a diagram measuring the Varroa acaricidal effect of clonidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to carry out dilution or concentration. [Figure 3B] Figure 3B is a diagram of measuring the effect of clonidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e., honeybees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 4A] Figure 4A is a diagram measuring the Varroa acaricidal effect of detomidine hydrochloride monohydrate. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to carry out dilution or concentration. [Figure 4B] Figure 4B is a diagram measuring the effect of detomidine hydrochloride monohydrate on honeybees. The negative control corresponds to untreated honeybees, i.e. bees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 5A] Figure 5A is a diagram measuring the Varroa acaricidal effect of dexmedetomidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 5B] Figure 5B is a diagram measuring the effect of dexmedetomidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e. bees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 6A] Figure 6A is a diagram measuring the Varroa acaricidal effect of romifidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 6B]Figure 6B is a diagram of measuring the effect of romifidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 7A] Figure 7A is a diagram measuring the Varroa acaricidal effect of tizanidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 7B] Figure 7B is a diagram measuring the effect of tizanidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e., bees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 8A] Figure 8A is a diagram measuring the Varroa acaricidal effect of medetomidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 8B] FIG. 1 measures the effect of medetomidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e. bees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 9] Figure 9 shows the Varroa acaricidal effect of dexmedetomidine hydrochloride by feeding on honeybees. The negative control corresponds to honeybees receiving only pure syrup. [Figure 10A] Figure 10A is a diagram measuring the Varroa acaricidal effect of levmedetomidine hydrochloride. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 10B]Figure 10B is a diagram measuring the effect of levomedetomidine hydrochloride on honeybees. The negative control corresponds to untreated honeybees, i.e., bees that have not undergone thoracic deposition. The solvent makes it possible to solubilize the molecules and / or to dilute or concentrate them. [Figure 11A] Figure 11A is a diagram measuring the Varroa acaricidal effect of octopamine. The negative control corresponds to untreated honeybees, i.e. honeybees that have not undergone thorax deposition. The solvent made it possible to solubilize the molecule. [Figure 11B] Figure 11B is a diagram measuring the effect of octopamine on honeybees. The negative control corresponds to untreated honeybees, i.e. bees that have not undergone thoracic deposition. The solvent made it possible to solubilize the molecule. [Figure 12] FIG. 12 is a photograph showing a feeding unit for rearing ticks. [Figure 13] FIG. 13 depicts the percentage of dead ticks from various treatments over a seven day period. [Figure 14] FIG. 14 measures the cumulative efficacy of test compounds as a function of treatment time against Varroa mites in honey bee hives. [Figure 15] FIG. 15 is a diagram measuring adult honeybee mortality following application of test compounds in honeybee hives. EXAMPLES

[0086] Example 1: Demonstration of the acaricidal effect of compounds of formula (I) against Varroa destructor

[0087] material and method

[0088] Preparation of Varroa mites

[0089] Approximately 300 honeybees (Apis mellifera) infected with Varroa mites were taken from a hive of bees superinfected with Varroa mites. The bees were then placed in a device (apparatus described in Community Model No. 003419415-0001) that allows the detachment of Varroa mites attached to the bees filled with powdered sugar. The device was agitated for 2 minutes to sample the Varroa mites attached to the bees. The powdered sugar allows interference between the bees and the Varroa mites attached to the bees. The Varroa mites were harvested with the powdered sugar because, unlike the honeybees, they pass through the holes in the device. The Varroa mites were then separated from the powdered sugar.

[0090] The Varroa mites thus collected were sent into boxes (10 Varroa mites per box). Two boxes were used to test each compound at the same dose in order to obtain data on 20 Varroa mites.

[0091] 1. Preparation of Honeybees

[0092] To ensure that the experimental effects were not due to previous treatments, bees were harvested from hives that had not received any treatment during the last 6 months.

[0093] The bees were then sent into the boxes (10 / box). Two boxes were used to test the same compound at the same dose in order to obtain data for 20 bees.

[0094] Then, CO was administered to deposit 1 μL of the compound to be tested on the thorax using a pipette. 2 The bees were put to sleep for a few minutes using a 20-second flow rate of 3 liters. It should be noted that the bees that received romifidine hydrochloride at a concentration of 10 μg / μL received 2 μL of the product. The bees were unconscious for the time that the compounds to be tested were deposited, i.e., about 3 minutes, and then woke up.

[0095] After the test compound was deposited on the thorax, 10 bees from the same box were transferred to a box containing 10 Varroa mites (see "Preparation of Varroa Mites" above). Liquid sugar was left in each box to feed the bees during observation. The series of boxes was then placed in an oven at 25°C with 50% humidity to approximate as closely as possible the conditions in a honeybee hive. After 5 minutes, it was confirmed that all Varroa mites had attached to the bees.

[0096] Effect of compounds on Varroa mites and honeybees

[0097] Varroa mites and bee mortality were then monitored 5 minutes, 2 hours, 4 hours and 24 hours after application of the test compound to the bees. Dead Varroa mites correspond to Varroa mites that have detached from the bees. Dead bees correspond to bees that are no longer moving and are often placed in the thorax.

[0098] Examination of the solvents used

[0099] Solvents were tested to ensure there was no effect (positive or negative) on the results. Four solvents were tested: ethanol, methanol, acetone and acetonitrile.

[0100] result

[0101] The results are shown in Figure 1. The solvents tested did not prove to be significantly toxic to either Varroa mites or honey bees.

[0102] conclusion

[0103] The solvents tested did not affect the viability of honeybees and Varroa mites and therefore can be used to dilute test compounds.

[0104] Compound testing

[0105] Test Compounds

[0106] The following compositions were applied to the thorax of the honeybees: Solvents, 1 μg / μL amitraz in acetone, Clonidine hydrochloride in methanol at 100 μg / μL, 10 μg / μL, 1 μg / μL and 0.1 μg / μL; Detomidine hydrochloride monohydrate at 1 μg / μL in methanol, Dexmedetomidine hydrochloride at 100 μg / μL, 10 μg / μL, 1 μg / μL and 0.1 μg / μL in methanol; Romifidine hydrochloride at 10 μg / μL and 5 μg / μL in methanol; 1 μg / μL tizanidine hydrochloride in methanol, Medetomidine hydrochloride at 0.1 μg / μL in ethanol, Levomedetomidine hydrochloride at 100 μg / μL, 10 μg / μL, 1 μg / μL and 0.1 μg / μL in methanol; Octopamine at 1 μg / μL in ethanol.

[0107] result

[0108] Amitraz: 100% of the Varroa mites were killed, and 0% of the bees were killed (Figure 2). As expected, amitraz is very effective in fighting Varroa mites. Amitraz is the positive control.

[0109] Clonidine hydrochloride: The results are presented in Figure 3. At concentrations of 100 μg / μL and 10 μg / μL, the mortality of the Varroa mites reached 85%, while only 10% of the honeybees were killed. Surprisingly, the efficiency of the compound against the Varroa mites was particularly remarkable at a concentration of 1 μg / μL, with zero mortality of the honeybees and 95% mortality of the Varroa mites. The kinetics of this molecule appeared rather slow compared to the positive control, since it showed its complete efficiency after 24 hours.

[0110] Detomidine hydrochloride monohydrate: Results are presented in Figure 4. Detomidine hydrochloride monohydrate proved to be particularly effective as after 2 hours 40% of the Varroa mites were killed without any bee mortality. After 24 hours 100% of the Varroa mites were killed without any bee mortality.

[0111] Dexmedetomidine hydrochloride: Results are presented in Figure 5. The results revealed that only the concentration of 100 μg / μL was toxic to honeybees. At other concentrations (10 μg / μl; 1 μg / μl; 0.1 μg / μl), after 24 hours, less than 5% mortality was observed for honeybees and systematically 100% mortality for Varroa mites. Thus, Varroa was sensitive to this compound.

[0112] Romifidine hydrochloride: the results are presented in Figure 6. This molecule proved to be very effective. Two hours after depositing 2 μl of the 10 μg / μL product, the mortality of the Varroa mites was 75%, then 95% after 4 hours. At a concentration of 5 μg / μL, it took 24 hours to obtain the same level of Varroa mite mortality. At all doses and even after 24 hours, the mortality of the honeybees remained zero (figure not shown).

[0113] Tizanidine hydrochloride: Results are shown in Figure 7. This product was found to be highly effective at 1 μg / μL after 24 hours (80% Varroa mite mortality) with no toxicity to honeybees.

[0114] Medetomidine hydrochloride: The results are shown in Figure 8. This product proved to be highly effective.

[0115] Levomedetomidine hydrochloride: The results are shown in Figure 10. The results are similar to those obtained with dexmedetomidine. Thus, the Varroa mites were sensitive to this compound.

[0116] Octopamine: Results are shown in Figure 11. No Varroa acaricidal effect was observed. Honeybee mortality also remained zero.

[0117] Example 2: Exposure to compounds of formula (I) by feeding

[0118] Honeybees and Varroa mites were obtained and contacted as detailed in Example 1 (without the treatment step).

[0119] Honeybees infested with Varroa mites (10 honeybees in contact with 10 Varroa mites) Pure syrup (negative control), or Syrup containing dexmedetomidine hydrochloride at 100 μg / mL syrup was given.

[0120] The syrup was offered to the bees ad libitum in 1.5 mL Eppendorf tubes.

[0121] result

[0122] The results are presented in FIG. 9 for Varroa acaricidal efficacy and in Table 1 for toxicity to honeybees.

[0123] [Table 1]

[0124] Example 3: Demonstration of the acaricidal effect of the compounds according to the invention against Ixodes ricinus

[0125] Compounds tested according to the present invention

[0126] SN0305: Dexmedetomidine hydrochloride

[0127] SN0306: Medetomidine hydrochloride

[0128] SN0307: Detomidine hydrochloride

[0129] overview

[0130] Laboratory tests were carried out to determine the oral acaricidal properties of three compounds according to the invention (SN0305, SN0306 and SN0307) against Ixodes ricinus. Each compound was tested at 1, 10 and 100 ppm and compared to a negative control corresponding to the solvent only (0.1% DMSO). Amitraz at 100 ppm was used as a positive control.

[0131] Ixodes ricinus ticks (nymphs and adults) were placed on the membrane in feeding wells containing blood mixed with test compounds for 24 h. Tick mortality (number of dead, moribund, or uninfected ticks in each well), attachment to the membrane (number of attached / detached ticks in each well), and behavior (presence or absence of twitching) were examined 1, 3, 6, 12, 24, 48, 72, and 96 h after the start of tick exposure to compounds.

[0132] method

[0133] Test system - Arthropods

[0134] Ticks (Ixodes ricinus) were collected. Collected adult females were kept separate from the nymphs and both were placed in a sterile tube in a humidified chamber at approximately 80% humidity and 17°C. Only healthy ticks (females / nymphs) were selected for the experiment.

[0135] Batches of 12 adults or nymphs were inserted into the feeding wells. After about 24 hours, they were checked for attachment with a brush. Dead or moribund ticks and unattached ticks were removed.

[0136] Test item - compound

[0137] The efficiency of three compounds (SN0305, SN0306 and SN0307), each tested at three concentrations (1, 10, 100 ppm), was compared to a solvent control (0.1% DMSO, Sigma-Aldrich D-5879; Lot 101K0028) and a positive control (100 ppm Amitraze).

[0138] film

[0139] Silicone-coated membranes with thicknesses comprised between 110 and 140 μm were used to construct the feeding units.

[0140] Feeding Unit

[0141] Feeding units (sterile acrylic glass tubes) were placed into feeding wells made in sterile 6-well plates.

[0142] 3.1 ml sterile 10 -3 M ATP-enriched blood was applied to each feeding well, which was then inserted into a heated water bath (FIG. 12) and maintained at 37° C.±2° C.

[0143] Test Compounds and Applications

[0144] A stock solution of 100000 ppm was prepared and 10-fold dilutions were made in 0.1% DMSO to reach the desired concentration. After tick attachment (24 hours after ticks were placed in the feeding well), 3.1 μl of solution was added to each feeding well containing 3.1 ml of blood. After 12 hours, blood was replaced with a fresh replenishment of the compound to be tested. Ticks were exposed to the products for a total of 24 hours, after which the blood was replaced again with fresh untreated blood.

[0145] evaluation

[0146] Tick ​​mortality (number of dead, moribund, or uninfected ticks in each well), attachment (number of attached / detached ticks in each well), and behavior (presence and intensity of twitches) were examined 1, 3, 6, 12, 24, 48, 72, and 96 hours after the start of tick exposure to the compounds.

[0147] result

[0148] Tick ​​contractions, morbidity or mortality

[0149] The three test compounds (SN0305, SN0306 and SN0307) showed strong effects on ticks (tick twitching, morbidity or mortality) from 1 hour exposure, regardless of the concentration tested. 100% of the ticks were morbid. The amitraz positive control gave comparable results on nymphs, but a much weaker effect was observed on adult ticks (Table 2). No effect was observed for the vehicle (negative control) over the 96 hour experiment.

[0150] [Table 2]

[0151] Table 2: Mean percentage of diseased adult ticks (tick twitching, diseased or dead) after the start of oral exposure to 100 ppm amitraz.

[0152] Tick ​​detachment

[0153] The three products tested (SN0305, SN0306 and SN0307) showed very limited effectiveness in terms of tick detachment. Only very isolated cases were observed: 1 detached nymph in the 1 ppm SN0305 replica, 1 detached adult tick in the 100 ppm SN0305 replica, and 2 detached adults in the 1 ppm SN0307 replica. 55% of fully fed nymphs were released naturally between 72 and 96 hours in the solvent control. No adult ticks detached in the solvent control.

[0154] Amitraz induced strong detachment of adult ticks (Table 3).

[0155] [Table 3]

[0156] Table 3: Mean percentage of attached adult ticks after the start of exposure to 100 ppm amitraz.

[0157] Tick ​​mortality

[0158] The three products tested (SN0305, SN0306 and SN0307) caused 100% mortality (moribund or dead ticks) in nymphs and adult ticks after 96 hours. Amitraz caused 100% mortality in nymphs and 97.5% mortality in adults. No mortality was observed with the solvent (Tables 4 and 5).

[0159] [Table 4]

[0160] Table 4: Mean percentage mortality (moribund or dead nymphs) of tick nymphs exposed to 1, 10 and 100 ppm of SN0305, SN0306 and SN0307, ​​solvent control (0.1% DMSO) or 100 ppm of amitraz.

[0161] [Table 5]

[0162] Table 5: Mean percentage of adult tick mortality (moribund or dead adult ticks) exposed to 1, 10 and 100 ppm SN0305, SN0306 and SN0307, ​​vehicle (0.1% DMSO) or 100 ppm AMITRAZE. Survival of adult ticks in the amitraz treatments may be caused by premature detachment of the ticks.

[0163] conclusion

[0164] All the tested compounds showed acaricidal activity against Ixodes ricinus.

[0165] Example 4: Demonstration of the acaricidal effect of the compounds according to the invention against Rhipicephalus sanguineus

[0166] overview

[0167] Laboratory tests were carried out to determine the acaricidal properties of three compounds according to the invention (SN0305, SN0306 and SN0307) against Rhipicephalus sanguineus. Each compound was tested at 1, 10 and 100 ppm and compared to a negative control corresponding to the solvent only (0.1% DMSO). Amitraz at 100 ppm was used as a positive control.

[0168] method

[0169] Test system

[0170] Second-stage brown dog ticks, Rhipicephalus sanguineus, from a single cohort were used.

[0171] Test Compounds and Applications

[0172] Three compounds were tested, as well as a reference compound (Amitraze). For each test compound and amitraz, four doses (1000, 100, 10 and 1 ppm) were applied topically to the ticks. A negative control (acetone) and an untreated group were included for comparison. Experiments were performed in triplicate.

[0173] Experimental protocol

[0174] Ten ticks were placed in a clear plastic container with a diameter of approximately 120 mm and a height of 45 mm. The ticks were then anesthetized by direct exposure to carbon dioxide (10 seconds). Treatments were then applied to the back (dorsal) of each tick using a Hamilton syringe with a maximum of 0.5 μl of treatment per tick (single application).

[0175] Water-soaked cotton was placed in each container to provide humidity throughout the experiment. The containers were also aerated throughout the experiment using tubes to introduce air into each container. The containers were maintained at a temperature of 23±3°C. Survival, shock and dead tick counts were collected daily after treatment for 7 days.

[0176] statistical analysis

[0177] The mean percentages for each assessment category (healthy, knockdown, and death) and standard errors were calculated. Analysis of variance (ANOVA) was performed using Minitab software, version 16.

[0178] Results and Conclusions

[0179] The results are shown in Figure 14.

[0180] 1000ppm treatment

[0181] Treatment at 1000 ppm resulted in 100% mortality for compounds SN0305, SN0306, SN0307 and amitraz 7 days after treatment, with no statistically significant differences between the compounds.

[0182] 100ppm treatment

[0183] The 100 ppm treatment resulted in 100%, 93.3%, 50% and 96.7% mortality for compounds SN0305, SN0306, SN0307 and amitraz, respectively, 7 days after treatment. Mortality levels at 7 days were significantly higher for compounds SN0305, SN0306 and amitraz compared to compound SN0307.

[0184] 10ppm treatment

[0185] Treatment at 10 ppm resulted in 93.3%, 66.7%, 23.3% and 46.7% mortality for compounds SN0305, SN0306, SN0307 and amitraz, respectively, 7 days after treatment. Compound SN0305 caused significantly higher mortality compared to all other treatments. Compound SN0306 caused significantly higher mortality compared to SN0307, ​​but not compared to amitraz.

[0186] Treatment at 1 ppm

[0187] Treatment at 1 ppm resulted in much lower mortality of 20%, 26.7%, 26.7% and 30% for compounds SN0305, SN0306, SN0307 and amitraz, respectively, 7 days after treatment.

[0188] Negative control

[0189] Mortality observed in the controls remained low, with 3.3% mortality reported with acetone and 6.7% mortality observed in the untreated controls after 7 days.

[0190] Example 5: Demonstration of the acaricidal effect of compounds of formula (I) against Varroa destructor mites in outside beehive and brood conditions

[0191] material and method

[0192] 1. Preparation of Beehives

[0193] Eighteen honeybee hives were divided into six groups of three homogenous honeybee hives with regard to colony strength (number of bees) and Varroa infestation.

[0194] The queen of each hive was caged three weeks prior to application of the test compound, thus allowing for the forced passage of Varroa mites from the reproductive stage to the piscine stage (so they are all present on the bees).

[0195] The test compounds were applied in the form of a gel 3 weeks after the queens were caged. The activity of the compounds was tested for 9 days.

[0196] After these 9 days of treatment, a control treatment with oxalic acid was performed (treatment period equal to 1 week).

[0197] The number of Varroa mites that had fallen to the floor was counted at regular intervals, and the number of dead Varroa mites was quantified.

[0198] Treatment efficiency was calculated by taking the sum of all Varroa mites dead from DO to D9 (test compound) and dividing this by the sum of all Varroa mites dead from DO to D16 (test compound + control treatment).

[0199] To demonstrate the potential toxicity of the tested compounds, bee mortality was also quantified. For this purpose, dead bee traps placed in front of the bee hives were used.

[0200] Compound testing

[0201] Test Compounds

[0202] The following compounds were tested: Dexmedetomidine in hydrochloride form, 55 mg / hive Dexmedetomidine in hydrochloride form, 110mg / hive Dexmedetomidine in hydrochloride form, 220mg / hive Detomidine in hydrochloride form, 38.4 mg / hive Detomidine in hydrochloride form, 110mg / hive Detomidine in hydrochloride form, 220mg / hive

[0203] result

[0204] The results for the calculation of the efficacy of the test compounds are presented in Figure 14. The dose effect of dexmedetomidine on efficacy against Varroa mites appears clearly. The most effective dose was 220 mg / hive (overall efficacy 94.5%).

[0205] Regarding detomidine, the results showed that a dose of 220 mg / bee hive was able to have a Varroa acaricidal effect.

[0206] Therefore, dexmedetomidine was the most effective compound against Varroa mites.

[0207] The results regarding bee mortality are presented in Figure 15. The results showed an increase in bee mortality at 220 mg / hive of detomidine, whereas no increase in bee mortality was observed with dexmedetomidine.

[0208] These results support the interest of detomidine and dexmedetomidine as Varroa acaricides, especially dexmedetomidine, which requires low doses and is not toxic to honeybees.

[0209] References [1] Macedo,PA,WU,J.,and ELLIS,Marion D.Using inert dusts to detect and assess varroa infestations in honey bee colonies.Journal of Apicultural Research,2002,vol.41,n°1-2,p.3-7

[0210] [2] Kretzschmar A.(2016).APIMODEL,functional modeling of bee colony activity to characterize dysfunction thresholds at the apiary scale.Generalization from lavender honey flow.INRA-BioSP,Avignon.http: / / w3.avignon.inra.fr / lavandes / biosp / rapportfinal2016.pdf

Claims

1. Use of a compound of formula (I), a salt thereof or a composition containing same as an acaricide for reducing or preventing Varroa mite infestation in honeybee hives, comprising: The formula (I) 【Chemistry 1】 (In the formula, A is group (II) or (III): 【Chemistry 2】 【Chemistry 3】 Selected from: X is NH, CH ２ or CH-CH ３ and Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z １ is halogen, H or CH ３ and Z ２ is halogen, H or CH ３ and Z ３ is halogen, H or CH ３ and Z ４ is halogen, H or CH ３ (It is) and said compound of formula (I) is selected from the group consisting of detomidine, dexmedetomidine, medetomidine, romifidine, clonidine, tizanidine, and a salt of one of these compounds.

2. A method for reducing or preventing Varroa mite infestation in honeybee hives, comprising the step of exposing the mites to a compound of formula (I), a salt thereof or a composition containing same, The formula (I) 【Chemistry 4】 (In the formula, A is group (II) or (III): 【Chemistry 5】 【Chemistry 6】 Selected from: X is NH, CH ２ or CH-CH ３ and Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z １ is halogen, H or CH ３ and Z ２ is halogen, H or CH ３ and Z ３ is halogen, H or CH ３ and Z ４ is halogen, H or CH ３ (It is) and said compound of formula (I) is selected from the group consisting of detomidine, dexmedetomidine, medetomidine, romifidine, clonidine, tizanidine, and a salt of one of these compounds.

3. 3. The method or use according to claim 1 or 2, wherein the composition of the compound of formula (I) or the composition of the salt of the compound of formula (I) contains 0.001 to 200 μg / μL of the compound of formula (I) or salt thereof.

4. The method or use according to any one of claims 1 to 3, wherein the beehive is a hive of bees of the genus Apis mellifera, Apis cerana, Apis dorsata or Apis florea.

5. A method or use according to any one of claims 1 to 4, wherein the reduction in Varroa mite infestation is a reduction of at least 25% in the number of live Varroa mites attached to the honeybees.

6. 6. The method or use according to any one of claims 1 to 5, wherein the compound of formula (I), the salt thereof or the composition containing same is comprised in and / or on a strap.

7. A composition for use as a Varroa mite killer in honeybees, comprising a compound of formula (I) or a salt thereof, one or more honeybee attractants, and one or more polymers selected from plastic materials, rubbers, adhesives, resins and polyholoside fibers, wherein said compound of formula (I) 【Chemistry 7】 (In the formula, A is group (II) or (III): 【Chemistry 8】 【Chemistry 9】 Selected from: X is NH, CH ２ or CH-CH ３ and Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z １ is halogen, H or CH ３ and Z ２ is halogen, H or CH ３ and Z ３ is halogen, H or CH ３ and Z ４ is halogen, H or CH ３ (It is) and said compound of formula (I) is selected from the group consisting of detomidine, dexmedetomidine, medetomidine, romifidine, clonidine, tizanidine, and a salt of one of these compounds.

8. A strap for use in beekeeping comprising (i) a compound of formula (I), a salt thereof, a composition containing same, or (ii) a composition according to claim 7, The formula (I) 【Chemistry 10】 (In the formula, A is group (II) or (III): 【Chemistry 11】 【Chemistry 12】 Selected from: X is NH, CH ２ or CH-CH ３ and Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z １ is halogen, H or CH ３ and Z ２ is halogen, H or CH ３ and Z ３ is halogen, H or CH ３ and Z ４ is halogen, H or CH ３ (It is) and the compound of formula (I) is selected from the group consisting of detomidine, dexmedetomidine, medetomidine, romifidine, clonidine, tizanidine, and a salt of one of these compounds.

9. (i) a compound of formula (I), a salt thereof, or a composition containing the same; (ii) a composition according to claim 7; or (iii) 9. A honeybee hive including a strap according to claim 8, The formula (I) 【Chemistry 13】 (In the formula, A is group (II) or (III): 【Chemistry 14】 【Chemistry 15】 Selected from: X is NH, CH ２ or CH-CH ３ and Y is a 5-bonded heterocycle containing at least one nitrogen atom; Z １ is halogen, H or CH ３ and Z ２ is halogen, H or CH ３ and Z ３ is halogen, H or CH ３ and Z ４ is halogen, H or CH ３ (It is) and said compound of formula (I) is selected from the group consisting of detomidine, dexmedetomidine, medetomidine, romifidine, clonidine, tizanidine, and a salt of one of these compounds.

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