WO2022258797A1

WO2022258797A1 - Tick control methods

Info

Publication number: WO2022258797A1
Application number: PCT/EP2022/065798
Authority: WO
Inventors: Heike Williams; Hartmut Zoller
Original assignee: Intervet International B.V.; Intervet Inc.
Priority date: 2021-06-11
Filing date: 2022-06-10
Publication date: 2022-12-15
Also published as: EP4351341A1; IL309139A

Abstract

The present invention relates to the treatment of parasitic arthropods, especially Hyalomma spp. tick infestations of animals, by using isoxazoline compounds of Formula (I).

Description

TICK CONTROL METHODS

FIELD OF THE INVENTION

The present invention relates to the treatment of parasitic arthropod infestations of animals.

BACKGROUND OF THE INVENTION

A number of parasites are known to infest animals. These parasites can be great nuisances to both the animals and their owners. Treatment of animals to prevent infestation by parasites, or to reduce or control the proliferation of these parasites, especially ectoparasites of animals such as ticks in animals is thus important.

The compounds currently available for tick control do not always demonstrate good efficacy for relevant tick species .

Several studies report Hyalomma spp. having a similar or slightly lower sensitivity to tested acaricides compared to other ticks (e.g. Haemaphysalis spp., Rhipicephalus spp.). Ticks of the genus Hyalomma (Acari: Ixodidae) are endemic in semi-arid regions across Asia, Africa and Europe. They affect livestock such as cattle, sheep, goats, horses, camels, dromedaries, but also pets such as dogs or cats, and humans. There are about 30 Hyalomma species worldwide, with species-specific distribution and prevalence.

The most relevant Hyalomma species for livestock and pets are the following: Hyalomma anatolicum, Hyalomma dromedarii, Hyalomma lusitanicum, Hyalomma marginatum, and Hyalomma truncatum.

Several pyrethroides, organophosphates and amitraz have been used to control Hyalomma spp. Ticks. There are reports of acaricide resistance of Hyalomma spp. ticks to such acaricidal compounds. Reports about the efficacy of macrocyclic lactone compounds with systemic activity such as ivermectin against Hyalomma- spp. show variable efficacy..

Therefore neither macrocyclic lactones (e.g. doramectin, eprinomectin, ivermectin, moxidectin), nor other acaricides seem to ensure adequate control of Hyalomma spp. ticks on animals.

Consequently, there is a need for new options to control this tick species of high economic importance and especially effective compounds for the treatment of Hyalomma spp. infestations of animals.

Surprisingly, it has been found that isoxazoline compounds of Formula (I) as described below, especially fluralaner exhibit very high efficacy against Hyalomma spp. ticks and address the shortcomings of the prior art. SUMMARY OF THE INVENTION

The current invention is directed to an isoxazoline compound of Formula (I)

wherein R¹ is halogen, CF₃, OCF₃, CN, n is an integer from 0 up to and including 3, preferably 1, 2 or 3,

R² is CrC₃-haloalkyl, preferably CF₃ or CF2CI,

T is a 5 to 12 membered mono or bicyclic ring system, which is optionally substituted by one or more radicals Y, Y is methyl, halomethyl, halogen, CN, N0₂, NH₂-C=S, or two adjacent radicals Y form together a chain, especially a three or four-membered chain;

Q is X-NR³R⁴, NR⁵-NR⁶-X-R³, X-R₃ ora 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;

X is CH₂, CH(CH₃), CH(CN), CO, CS, R³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonyl- methyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N- dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halo- ethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsufinalkyl, alkylsulfonalkyl, cycloalkyl,

wherein Z^A is hydrogen, halogen, cyano, halomethyl, preferably CF₃;

R⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxy methyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethyl- aminocarbonylethyl;

R⁵ is hydrogen, alkyl or haloalkyl;

R⁶ is hydrogen, alkyl or haloalkyl; or R³ and R⁴ together form a substituent selected from the group consisting of:

or a salt or solvate thereof for use in the treatment of a parasitic tick infestation of an animal characterized in that the parasite tick infestation is an infestation with a tick of Hyalomma spp. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the tick inhibition in % of in vitro contact activity of various concentrations of fluralaner against Hyalomma marginatum, Rhipicephalus sanguineus and Amblyomma amehcanum

Figure 2 shows the tick mortality in % of in vitro contact activity of various concentrations of fluralaner against Hyalomma marginatum, Rhipicephalus sanguineus and Amblyomma americanum

DETAILED DESCRIPTION OF THE INVENTION

This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants’ invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only.

This invention, therefore, is not limited to the preferred embodiments described in this specification and may be variously modified. In addition, for conciseness purposes and readability only some combinations of embodiments are explicitly described, however it should be understood that other combinations of embodiments are also contemplated.

The term “(parasitic) infestation” means the presence of at last one tick on the animal’s coat. Generally tick infestation causes harm or risk to the infested host animal and conditions associated with or caused by one or more (parasitic) pathogens; said conditions include clinical conditions (parasitoses) and sub-clinical conditions.

The term “treatment of parasitic infestation” thus includes both the treatment of parasitoses and the treatment of sub-clinical conditions. The treatment of a parasite infestation generally implies the suppression of parasite burden of the animal below that level at which economic loss occurs. Treating (parasitic) infestations” means to partially or completely inhibit the development of (parasitic) infestations of an animal susceptible to (parasitic) infestation, reduce or completely eliminate the symptoms of infestations of an animal having infestations, and/or partially or completely cure infestations of an animal having infestations. This can be achieved by alleviating or reducing pathogen numbers such as parasite numbers in or on an animal.

The term ‘treatment,’ and similar terms such as ‘treating’ or ‘treat’ as used herein, refer to the administration of an effective amount of at least one compound as described for use in the invention to an animal which has an infestation -of more or less severity- with at least one Hyalomma spp. tick. The animal might or might not be co-infested with other one or more species of other parasites and includes preventive treatment . “Preventive treatment” of an animal against a parasite infestation with Hyalomma spp. designates a treatment made before the animal has been exposed to or in contact with the parasite, especially infectious stages of Hyalomma spp. ticks. , or after said exposure/contact but before development of the detrimental conditions (e.g. before sub-clinical conditions, such as production losses in livestock appear, before appearance of clinical symptoms or at an early stage of development of the disease. Also, the term “preventive treatment”, in relation to a population of animals, designates the treatment of all members of the population even after the disease or condition (e.g., parasite infestation) has been detected in only one or certain animals, to limit or avoid spreading of and contamination to the other members of the animal population.

A” sub-clinical condition” is typically a condition that is not directly leading to clinical symptoms in the parasite-infested animal but leading to economic losses. Such economic losses can be e.g. by depression of growth in young animals, lower feed efficiency, lower weight gain in meat producing animals, lower milk production in ruminants, or lower wool-production in sheep.

The term "parasitoses" relates to clinically manifest pathologic conditions and disease of an animal that is associated with or caused by an infestation of the animal by the parasite directly, such as, for example, anemia and dermatitis. It also includes pathologic conditions or diseases associated with one or more vector- transmitted pathogens that is transmitted by the parasite. The phrase “treatment of parasitoses” means to partially or completely inhibit the development of parasitoses of an animal, reduce or completely eliminate the symptoms of parasitoses of an animal, and/or partially or completely cure existing parasitoses of an animal.

Hyalomma spp. ticks transmit a number of viral, bacterial and parasitic diseases making these ticks economically important. The Hyalomma spp. ticks may also act as reservoir of many viral pathogens. Besides disease transmission, certain species of Hyalomma, e.g,. H. truncatum, contain toxin in their saliva that causes sweating sickness, an acute dermatitis, in cattle, particularly calves that are infested with H. truncatum.

Among the diseases transmitted by Hyalomma spp., theileriosis and babesiosis caused by members of the apicomplexan parasite genera Theileria and Babesia, respectively, are probably the most economically important.

Tropical theileriosis, also known as tropical piroplasmosis and Mediterranean fever, is a disease of cattle caused by T. annulata and transmitted by several Hyalomma species. T ropical theileriosis is of high economic importance and an overall number of 250 million cattle are estimated to be at risk.

Hyalomma spp. ticks can transmit tick-borne pathogens such as Crimean-Congo hemorrhagic fever virus and spotted fever Rickettsioses,

In one embodiment therefore the parasitosis is Babesiosis, Anaplasmosis, Theileriosis, Rickettsioses or Crimean-Congo haemorrhagic fever. In one embodiment the compound for use according to the invention is an isoxazoline compound of the Formula (I)

Formula (I), wherein

R¹ is halogen, CF₃, OCF₃, CN, n is an integer from 0 up to and including 3, preferably 1, 2 or 3,

R² is CrC₃-haloalkyl, preferably CF₃ or CF2CI,

T is a 5 to 12 membered mono or bicyclic ring system, which is optionally substituted by one or more radicals Y,

Y is methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent radicals Y form together a chain, especially a three or four-membered chain;

Q is X-NR³R⁴, NR⁵-NR⁶-X-R³, X-R3 ora 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;

X is CH₂, CH(CH₃), CH(CN), CO, CS,

R³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylamino- carbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N- dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halo- ethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsufinalkyl, alkylsulfonalkyl, cycloalkyl

wherein Z^A is hydrogen, halogen, cyano, halomethyl, preferably CF₃;

R⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxy- methyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethyl- aminocarbonylethyl;

R⁵ is hydrogen, alkyl or haloalkyl;

or a salt or solvate thereof.

In a preferred embodiment of the invention and/or embodiments thereof T is selected from

T24 T25 wherein in T-1, T-3 and T-4, the radical Y is preferably hydrogen, halogen, methyl, halomethyl, ethyl or haloethyl.

In a preferred embodiment of the invention and/or embodiments thereof Q in Formula (I) is selected from

Q 9 wherein R³, R⁴, X and Z^A are as defined above and Z^B is

Z^D-1 Z^D-2 Z^D-3 Z^D-4 Z^D-5 or

Preferred compounds of Formula (I) are listed in Table 1: Table 1:

In a particularly preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is represented by Formula (II)

Formula (II) wherein

R^1a, R^1b, R^1c are independently from each other hydrogen, Cl or CF₃. Preferably R^1a and R^1c are Cl or CF₃and R^1b is hydrogen,

T is

wherein Y is methyl, bromine, Cl, F, CN or C(S)NH2 and Q is as described above.

In another preferred embodiment of the invention and/or embodiments thereof in the isoxazoline compound of Formula (I) , R³ is H and R⁴ is -CH₂-C(O)-NH-CH₂-CF₃, -CH₂-C(O)- NH-CH₂-CH3, -CH₂-CH₂-CF₃ or -CH₂-CF₃.

In another preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is selected from fluralaner, afoxolaner, sarolaner, and lotilaner.

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-/\/- [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3). This compound is also known as fluralaner and is especially preferred. In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4, 5-dihydro- 5-(trifluoromethyl)-3- isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalene-carboxamide (CAS RN 1093861 -60-9). This compound is also known as a 4-[5-(5-chloro-a,a,a-trifluoro-m-tolyl)- 4,5-dihydro-5-(trifluoromethyl)-1,2-oxazol-3yl]-/\/-[2-oxo-2-[(2,2,2- trifluoroethylamino]ethyl]naphthalene-1-or as INN afoxolaner. Afoxolaner is for example disclosed in WO 2007/079162.

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3- yl)-3'H-spiro[azetidine-3,T-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one, preferably 1- (5'-((5S)-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H- spiro[azetidine-3,T-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one (CAS RN: 1398609- 39-6). This compound is known as sarolaner.

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[5-(3,4,5- trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide, preferably methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[(5S)-5(3,4,5-trichloro- phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is known as lotilaner.

In an alternative embodiment of the invention and/or embodiments thereof an alternative compound 2-chloro-/\/-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1, 1,2,2, 2-pentafluoroethyl)-4- (trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436) is used. This compound is known as tigolaner.

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N- [(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N- (thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO 2009/0080250.

In one preferred embodiment of the invention and/or embodiments thereof the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl- N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]- 2-thiophenecarboxamide (CAS RN 1231754- 09-8) that was disclosed in WO 2010/070068.

Especially preferred is fluralaner (corresponding to 4-[5-(3,5-dichlorophenyl)-5- trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-/\/-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]- benzamide). An isoxazoline compound for use in the current invention may exist in various isomeric forms. A reference to an isoxazoline compound for use in the current invention always includes all possible isomeric forms of such a compound. Unless otherwise stated, a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers. In some embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.

Compounds for use in this invention comprises racemic mixtures, for example, equal amounts of the enantiomers of such isoxazoline compounds as described above. In addition, the compounds can be isoxazoline compounds that are enriched compared to the racemic mixture in an enantiomer of Formula (I). Also included are the essentially pure enantiomers of such isoxazoline compounds.

When enantiomerically enriched, one enantiomer is present in greater amounts than another(s), and the extent of enrichment can be defined by an expression of enantiomeric excess ("ee"), which is defined as (2x-l)-100 %, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20 % corresponds to a 60:40 ratio of enantiomers). Preferably the compositions for use in the current invention have at least a 50 % enantiomeric excess; more preferably at least a 75 % enantiomeric excess; still more preferably at least a 90 % enantiomeric excess; and the most preferably: at least a 94 % enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.

Isoxazoline compounds as described above can comprise additional chiral centers. The compounds for use in this invention comprises racemic mixtures as well as enriched and essentially pure stereo configurations at these additional chiral centers.

For example, the isoxazolines of Formula (I) can comprise a chiral (or asymmetric) carbon at the 5-position of the isoxazoline ring. In some embodiments, for example, the chiral carbon has a left-handed (or "S" or "sinister") configuration. An example of such a compound is:

Such compound is especially preferred. In other embodiments, the chiral carbon has a right- handed (or "R" or "rectus") configuration. An example of such a compound is:

In one preferred embodiment the active enantiomer (s)-fluralaner is used.

In another preferred embodiment the active enantiomer (s)-afoxolaner is used.

Unless otherwise stated, an isoxazoline structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the isoxazoline, as well as compositions comprising fewer than all (e.g., just one of) the possible conformational isomers.

The reference to isoxazoline compound in this specification includes enantiomers, salts and solvates thereof that can be produced by conventional methods.

The term “salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

The term “solvate” is used herein to describe a molecular association comprising one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term “hydrate” is used when said solvent is water.

Isoxazoline compounds of Formula (I) can be prepared according to one or other of the processes described e.g. in patent applications US 2007/0066617, WO 2007/079162,

WO 2009/002809, WO 2009/080250, WO 2010/070068, WO 2010/079077,

WO 2011/075591 and WO 2011/124998 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is regarded as having at her/his disposal, inter alia, the entire contents of "Chemical Abstracts" and of the documents cited therein.

The compound for use according to the present invention is particularly useful for treating parasite infestation of a ruminant animal such as cattle, sheep, goat, deer, camels, llama, especially when the animal is a livestock animal, kept for meat and milk or wool or alternatively as working animal. In one embodiment the animal is selected from the group consisting of cattle, sheep, goat, and camel.

In one embodiment the animal is a bovine animal such as cattle. Bovine animals are ruminant mammals of the genus Bos and include, but are not limited to cattle, steers, heifers, cows (lactating and non-lactating), calves, bulls, and also buffalo. Especially preferred are beef cattle, i.e. cattle animals kept for meat or alternatively dairy cows. In another embodiment the animals are sheep. In another embodiment the animal is a goat.

In another embodiment the animal is a camel.

In some embodiments, the compound is used to treat a Hyalomma spp. tick infestation of a companion animal, especially a horse, a dog or a cat. Preferred is a horse. In one embodiment the compound is used in a dog. In other embodiments, the compound is used in a cat.

The compound for use in the current invention is able to treat an infestation of an animal with Hyalomma spp. that show resistance against existing acaricide compounds. This means such parasites are no longer susceptible to certain parasiticides. The susceptibility can be determined in in vitro experiments when exposing such parasites to varying concentrations of the parasiticides to determine their resistance level. In case no inhibition or killing effect was found when applying higher concentration the parasites are considered resistant to such parasiticide. Resistance can appear after parasites have been exposed to a low dose of parasiticides that enables some parasites to survive, and these have genes that may allow them to survive higher doses that would normally kill all parasites.

Continued use of the same chemical or chemical group allows the resistant parasites to survive, breed and increase in numbers until they make up the majority of the population. Sometimes, when resistance is present, treatment suppresses parasites, but does not completely eradicate them. These suppressed infestations are difficult to detect and increase the chance of parasites spreading between flocks.

The current invention can be used on an animal that is infested with a Hyalomma spp. tick that is resistant to any one of organophosphates, synthetic pyrethroids, the amidine compound Amitraz or any one of macrocyclic lactone compounds and will still provide effective treatment of Hyalomma spp infestations. Macrocyclic lactones are e.g. ivermectin, moxidectin, abamectin, doramectin or eprinomectin. Synthetic pyrethroids are e.g. permethrin, cypermethrin or deltamethrin.

In one embodiment a single dose of an effective amount of an isoxazoline compound as described above is administered to an animal, or a flock of animals, especially livestock animal such as cattle, sheep, camels or goats, that have been diagnosed to be infested with Hyalomma ticks.

In one embodiment a single dose of an effective amount of the isoxazoline compound is administered to a sheep, cattle animal, camel, goat, or a flock of sheep, cattle animal, camel or goat that has been in contact with an animal that has been diagnosed with Hyalomma spp. tick infestation and is therefore at risk to be infested.

The isoxazoline compounds for use in the invention can be made available during a treatment period to a single animal. More advantageous is the treatment at the same time of a group of animals, or to all animals in a single stable, pen, net, group, house, or farm. A single administration of a compound is typically sufficient to treat a parasitic infestation with a Hyalomma spp. tick.

Although such a single dose is typically preferred, it is contemplated that multiple doses can be used.

The frequency of the administration will be dependent upon several factors and can be a single dose administered once a day, once a week, once a month, once every two, three, four, or six months, or one every year.

In some embodiments, the frequency of administration may be, for example, weekly, biweekly, monthly, bi-monthly, every 3 months, every 4 months, every 5 months, every 6 months or every 12 months or the equivalent administration frequency expressed in days or weeks that approximate such frequency.

The duration of activity or efficacy (i.e. , “knockdown,” onset of activity and/or sustained effect) can be the primary concern in antiparasitic product choices. Products are evaluated based on both their immediate and residual speed of kill and duration of efficacy.

A rapid residual speed of kill, sometimes called: onset of activity/efficacy is critically important when attempting to reduce the chances of a tick parasite transmitting a pathogen and to avoid acting as a vector for such pathogens that might cause parasitosis.

The duration over which the compounds for use in the invention are effective against the Hyalomma spp. ticks is important for the required treatment interval.

In one embodiment, the compound exhibits long lasting efficacy and controls Hyalomma spp. tick infestation in a livestock animal or companion animal for at least one month.

In another embodiment, the compound exhibits very long-lasting efficacy of at least 50% against Hyalomma spp. tick for a period of at least 1 month, at least 2 months, at least 3 months, or at least 4 months.

In another embodiment, the compound for use according to the invention exhibits very long- lasting efficacy of at least 70% against Hyalomma spp. tick for a period of at least 1 month, at least 2 months, at least 3 months, or at least 4 months.

In another embodiment, the compound for use according to the invention exhibits very long- lasting efficacy of at least 90% against Hyalomma spp. tick for a period of at least 1 month, at least 2 months, at least 3 months, or at least 4 months.

Therefore, one embodiment of the invention is a compound for use according to the invention wherein the compound is administered every month. In another embodiment of the invention the compound is administered every 6 weeks. In another embodiment of the invention the compound is administered every 2 months. In another embodiment of the invention the compound is administered every 3 months.

The compound for use according to this invention may be administered in various dosage forms to animals to treat Hyalomma spp infestations. The term “dosage form” means that the compound is formulated into a product suitable for administering to the animal via the envisaged administration route, such dosage form or product further includes physiologically acceptable formulation excipients. Such dosage forms are sometimes referred to herein as formulations or pharmaceutical compositions. Dosage forms useful in the current invention can be liquid, semi-solid or solid dosage forms. Liquid dosage forms are generally solutions, suspensions, or emulsions. A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level.

A suspension has insoluble solid particles dispersed in a liquid medium, with the solid particles accounting for about 0.5% to about 30% of the suspension. The liquid may be aqueous, oily, or both. An emulsion is a heterogeneous dispersion of one immiscible liquid in another; it relies on an emulsifying agent for stability.

A dry powder (or granule) for reconstitution is reconstituted as a solution or as a suspension immediately prior to injection. The principal advantage of this dosage form is that it overcomes the problem of instability in a solution or suspension.

One possible administration route is the oral route, wherein the compound for use according to this invention is administered via the mouth. Oral dosage forms suitable for oral administration comprise liquids (e.g., drench or drinking water formulations), semi-solids (e.g., pastes, gels), and solids (e.g., tablets, capsules, powders, granules, chewable treats, premixes.

In one embodiment the isoxazoline compound of Formula (I) is administered orally to the animal. A number of veterinary compositions are known to be suitable for oral administration to animals, but they vary for the different animal species.

Conventional pharmaceutically active ingredients are administered orally as solids (e.g., tablets or boluses) or liquids, and via their feed or drinking water. In large sheep, goat, camel and cattle flocks the use of oral drenches is the most common oral dosage form, especially when administering anthelmintic compounds.

Drenching means that a liquid, potentially slightly viscous, composition comprising the compound and excipients is applied via the mouth with a specific drenching gun that dispenses a compound into the sheep or cattle, goat or camel’s throat.

Semi-solid oral formulations (pastes or gels) are generally administered via an applicator directly into the mouth of an animal or mixed with the feed. They are especially suitable for horses.

Solid oral formulations are either administered directly to an animal (tablet, capsule, bolus) or mixed with the feed or via medicated feed blocks.

When the oral formulation is administered via an animal's feed, it may be fed as a discrete feed or as a chewable treat. An especially preferred oral dosage form for dogs is a soft chewable composition that is generally of a pliable texture and very palatable and can be offered as a treat that is voluntarily ingested. Such compositions have been used to administer the compounds for use of the current invention. Alternatively, the compound for use in the invention may, for example, be intimately dispersed in the animal recipient's regular feed, used as a top dressing, or in the form of solid pellets, paste or liquid that is added to the finished feed. When the oral formulation is administered as a feed additive, it may be convenient to prepare a "premix" in which the oral formulation is dispersed in a liquid or solid carrier. This "premix" is, in turn, dispersed in the animal's feed.

Several modified-release delivery systems have been developed, that take advantage of the unique anatomy of the ruminant forestomach, i.e. , for intra-ruminal administration. An intraruminal bolus is a specific formulation for ruminants (cattle, sheep, goats, buffalos, camelids, deer etc.). It is a veterinary delayed release delivery system which remains in the rumeno-reticular sac of a ruminant animal over an extended period of time and in which the therapeutically active substance has a predictable and delayed release pattern. Such intraruminal boluses are usually administered using a balling gun or another suitable device. Compounds for use according to this invention may alternatively be administered via nonoral dosage routes, such as topically (e.g., via a spot-on, pour-on, spray), or parenterally (e.g., subcutaneous injection, intravenous injection, intramuscular injection, etc.).

Therefore, in another embodiment the isoxazoline compound of Formula (I) for use in the current invention is administered parenterally to the animal. Preferably the isoxazoline compound of Formula (I) is administered by subcutaneous administration.

Alternatively, the isoxazoline compound of Formula (I) for use in the current invention is administered topically to the animal. Preferably, the isoxazoline compound is administered by pour-on administration.

For instance, the compounds for use according to this invention may be administered topically using a transdermal formulation (i.e., a formulation that passes through the skin). Topical dosage forms suitable for topical administration comprise liquids (e.g. bath, spray, spot-on), semi-solids (e.g. creams, gels), and solids (e.g. patches, powders, collars). Typical topical formulations for animals are liquid or semi-liquid dosage forms.

Typical formulations for topical and transdermal administration include, for example pour-on, spot-on, dips, sprays, mousses, shampoos, powders, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, limb bands, collars, ear tags, wafers, sponges, fibers, bandages, and microemulsions. When a liquid formulation is used topically on skin, it can be administered by, for example pouring on (pour- on or spot-on), spreading, rubbing, atomizing, spraying, dipping, bathing, or washing.

The pour-on or spot-on methods, for example, comprise applying the formulation to a specific location of the skin or coat, such as on the neck or backbone of the animal. This may be achieved by, for example, applying a swab or drop of the pour-on or spot-on formulation to a relatively small area of the recipient animal's skin or coat (i.e. generally no greater than about 10% of the animal recipient's skin or coat).

Parenteral formulations and delivery systems for non-oral routes comprise liquids (e.g. solutions, suspensions, emulsions, and dry powders for reconstitution), semi-solids and solids (e.g. implants). The majority of implants that are used in veterinary medicine are compressed tablets or dispersed matrix systems in which the drug is uniformly dispersed within a biodegradable or nondegradable polymer or are extrusion products.

This invention is also directed to compounds for use in the current invention when such compound is administered by way of a veterinary composition comprising more than one pharmaceutically active ingredient, i.e. wherein the composition e.g. for subcutaneous , oral or topical administration comprises additionally another active pharmaceutical ingredient. Those of ordinary skill in the veterinary pharmaceutical arts will be entirely familiar with the identity of such active ingredients which may include, without limitation antiparasitics such as endoparasiticides (including anthelmintics) and endecto-parasticides, hormones and/or derivatives thereof, and minerals and vitamins.

Especially preferred is a combination with minerals or vitamins, especially with copper or selenium, especially as sodium selenate.

Especially preferred are combinations with macrocyclic lactones such as ivermectin, moxidectin, abamectin, doramectin or eprinomectin.

In one embodiment a (fixed) combination of an effective amount of an isoxazoline compound of Formula (I) and another active ingredient that controls a different parasite infestation, e.g. against parasitic helminths or other ectoparasites is used.

A composition conventionally further comprises physiologically acceptable formulation excipients known in the art e.g. as described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20th Edition, 2000) incorporated by reference herein.

All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinarily pure and non-toxic in the amounts employed and must be compatible with the pharmaceutically active ingredients. EXAMPLES

Investigation of the acaricidal in vitro contact activity of fluralaner against Hyalomma marginatum, Rhipicephalus sanguineus and Amblyomma Americanum

H. marginatum (IS Insect Services GmbH, Berlin), R. sanguineus and A. americanum (both MSD Animal Health) ticks were examined simultaneously by exposure to fluralaner in an immersion test (Adult Immersion Test, AIT).

Thirty unfed adult ticks of each species were immersed in fluralaner test solution (fluralaner dissolved in a DMSO-emulsifier-deionized water mixture) for about five minutes (test concentrations between 1000 - 0.5 ppm, dilution factor 1:2). One untreated group and one solvent-treated group per tick species served as negative controls. To facilitate the later evaluation ticks were separated according to species into three Petri dishes of ten ticks each (three replicates per species) and kept for 48 hours at 26 °C (± 1 °C) and 85 % relative humidity (RH; ± 2 % RH) incubated until evaluation.

The calculated test parameter in comparison to the negative control was the tick inhibition (%; based on the number of dead and damaged ticks) and the tick mortality (%; based on the number of dead ticks) per fluralaner test concentration.

The effective concentration values (EC50 and EC90) and lethal concentration values (LC50 and LC90) were determined for each tick species by means of regression analysis.

LC50 and LC90 values (based on number of dead ticks) at which 50% or 90% of the test organisms had an effect are presented in Table 1.

Table 1: Lethal concentration

EC₅₀ and EC₉₀ values (based on number of dead and damaged ticks) at which 50% or 90% of the test organisms had an effect are presented in Table 2:

Table 2: Effective concentration

Conclusions

The isoxazoline fluralaner showed acaricidal in vitro contact activity against all three tested tick species ( H . marginatum, R. sanguineus and A. americanum).

Fluralaner displayed very high acaricidal activity against H. marginatum (EC50: 1.5 ppm) compared to the other tested tick species.

Claims

1. An isoxazoline compound of Formula (I)

Formula (I), wherein

R¹ is halogen, CF₃, OCF₃, CN, n is an integer from 0 up to and including 3, preferably 1 , 2 or 3,

R² is Ci-C₃-haloalkyl, preferably CF₃ or CF2CI,

Y is methyl, halomethyl, halogen, CN, N0₂, NH₂-C=S, or two adjacent radicals Y form together a chain, especially a three or four-membered chain;

X is CH₂, CH(CH₃), CH(CN), CO, CS,

R³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxy- ethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylamino- carbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N- dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halo- ethylaminocarbonylcyclopropyl, alkylsulfanyl, alkylsufinalkyl, alkylsulfonalkyl, cycloalkyl

R³-15 R³-16 R³-17 R³-18 wherein Z^A is hydrogen, halogen, cyano, halomethyl, preferably CF₃;

R⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, halo- ethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropyl- carbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylamino- carbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethyl- aminocarbonylethyl;

R⁵ is hydrogen, alkyl or haloalkyl;

or a salt or solvate thereof for use in the treatment of a parasitic tick infestation of an animal, characterized in that the parasite tick infestation is an infestation with a tick of Hyalomma spp.

2. The isoxazoline compound for use according to claim 1 , characterized in that the animal is selected from the group consisting of cattle, sheep, goat, and camel.

3. The isoxazoline compound for use according to claim 1 , characterized in that the animal is selected from the group consisting of a horse, dog and cat.

4. The isoxazoline compound for use according to any one of claims 1 to 3, characterized in that parasite tick infestation is an infestation with a tick of Hyalomma marginatum.

5. The isoxazoline compound for use according to any one of claims 1 to 3, characterized in that the animal is infested with a Hyalomma spp. tick that is resistant to an acaricide, preferably any one of organophosphates, synthetic pyrethroids, the amitraz or macrocyclic lactone compounds.

6. The isoxazoline compound for use according to any one of claims 1 to 5, characterized in that the isoxazoline compound of Formula (I) is selected from the group consisting of fluralaner, afoxolaner, sarolaner and lotilaner.

7. The isoxazoline compound for use according to claim 6, characterized in that the isoxazoline compound of Formula (I) is fluralaner.

8. The isoxazoline compound for use according to any one of claims 1 to 7, characterized in that the isoxazoline compound of Formula (I) is administered orally to the animal.

9. The isoxazoline compound for use according to any one of claims 1 to 7, characterized in that the isoxazoline compound of Formula (I) is administered parenterally to the animal.

10. The isoxazoline compound for use according to claim 9, characterized in that the isoxazoline compound is administered by subcutaneous administration.

11. The isoxazoline compound for use according to any one of claims 1 to 7, characterized in that the isoxazoline compound of Formula (I) is administered topically to the animal.

12. The isoxazoline compound for use according to claim 11, characterized in that the isoxazoline compound is administered by pour-on administration.

13. The isoxazoline compound for use according to any one of claims 1 to 12 characterized in that the compound is used in a method to treat a parasitosis of an animal that is caused by a parasite tick infestation with a tick of Hyalomma spp.

14. The isoxazoline compound for use according to claim 13, characterized in that the parasitosis is one or more selected from Babesiosis, Anaplasmosis, Theileriosis, Rickettsioses and Crimean-Congo haemorrhagic fever.

15. The isoxazoline compound for use according to any one of claims 1 to 12 characterized in that it is used as preventive treatment of a parasitic tick infestation of an animal with a tick of Hyalomma spp.