RU2796536C9 - Use of isoxazoline compounds in poultry - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: invention relates to the use of an isoxazoline compound selected from 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 — USAN fluralaner), or a salt or solvate thereof, for the prevention or treatment of chicken lice infestation in poultry, wherein the effective amount of isoxazoline compound is administered with drinking water as two separate doses with the interval of 7 days.

EFFECT: invention provides for the treatment or prevention of parasitic arthropod infestation of poultry, especially laying hens, by administering an effective amount of the isoxazoline compound with the drinking water.

4 cl, 2 tbl, 1 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the prevention or treatment of parasitic arthropod infestations in poultry and their environment.

BACKGROUND OF THE INVENTION

Many parasitic arthropods infect domestic birds and cause damage and annoyance to animals and therefore represent significant problems in terms of economic loss, animal welfare and epidemiological problems of disease transmission.

Bird mites such as Dermanyssus gallinae (red bird mite), Ornithonyssus sylviarum (northern chicken mite) and Ornithonyssus bursa (tropical bird mite) are important parasitic problems, especially in laying hen production facilities.

Conventional methods for controlling parasitic arthropods, and especially bird mite control, include chemicals that are applied as sprays, coarse or solid stream, mist, aerosol, dust, and/or as a wash solution for uninhabited or inhabited areas for animals and their environment. Other control measures include pollinating or spraying infested poultry with powdered or liquid synthetic organic chemicals, or adding powdered synthetic organic chemicals to the manure or dust bath. Examples of synthetic organic chemical groups that have been used in such chemical processing include pyrethroids, organic phosphates, carbamates, spinosad, and the like.

Recently, chemical treatment has been increasingly scrutinized due to the widespread development of immunity, as well as environmental and occupational safety concerns.

Alternatively, amorphous silica is used as an inert dust that kills parasitic arthropods through dehydration. Silica powder treatment can be done in the presence of poultry, but requires a very strong dosage and obliges to fill the entire area with silica powder. In addition, silica powder is known to cause a number of lung diseases in both birds and humans.

An additional problem is that some parasitic arthropods, such as poultry mites, are known to inhabit the crevices and crevices of poultry houses and are therefore difficult to kill using known indoor chemical and silica powder treatments.

Alternative methods, including insect attractants/repellents, predatory mites and vaccines, have been described, but so far do not provide any uniform or practical solutions for widespread use in poultry production.

Mite problems often reoccur in affected poultry houses after treatment. Thus, due to limited efficacy, frequent re-treatment is required. Repeated treatments can be stressful for birds, and can in particular lead to loss of egg production in laying hens and breeding birds.

Thus, none of these methods satisfies the needs of the poultry producer.

Thus, there is a need in the art to find a better solution to the problem of controlling parasitic arthropods, and especially bird mites, in the poultry industry without harming animals or humans.

SUMMARY OF THE INVENTION

The present invention relates to the use of an isoxazoline compound of formula (I)

wherein

R ¹ = halogen, CF ₃ , OCF ₃ , CN,

n=an integer from 0 to 3, preferably 1, 2 or 3,

R ² =C ₁ -C ₃ haloalkyl, preferably CF ₃ or CF ₂ Cl,

T=5- or 6-membered ring which is optionally substituted with one or more Y radicals,

Y=methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S, or two adjacent Y radicals together form a chain, generally a three- or four-membered chain;

Q=X-NR ³ R ⁴ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals;

X \u003d CH ₂ , CH (CH ₃ ), CH (CN), CO, CS,

R ³ =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

where Z ^A =hydrogen, halogen, cyano, halomethyl (CF ₃ );

R ⁴ = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanogen omethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

or R ³ and R ⁴ together form a substituent selected from the group consisting of:

or a salt thereof or a solvate thereof in the prevention or treatment of parasitic arthropod infestations of poultry, wherein an effective amount of the isoxazoline compound is administered via the drinking water.

The present invention also relates to a pharmaceutical composition for use in the prevention or treatment of parasitic arthropod infestations in poultry, especially chickens, especially laying hens, through the administration of drinking water containing an effective amount of an isoxazoline compound as described herein and a pharmaceutically acceptable carrier.

The present invention also provides a method for controlling arthropods in a poultry environment, characterized in that the isoxazoline compound as described herein is administered via drinking water administration to poultry occupying the environment.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that parasitic arthropod infestations of poultry, especially laying hens, can be treated or prevented by administering an effective amount of an isoxazoline compound of formula (I) via the drinking water.

The advantages of this method are as follows:

a) such a method is effective in both treating existing parasitic arthropod infestations and preventing the emergence of new parasitic arthropod infestations and controlling the population of parasitic arthropods in the environment, and therefore prevents re-infestation of animals with parasites;

b) the buckling properties of such isoxazoline compounds are very favorable, ie. parasitic arthropods are highly susceptible to the overwhelming or damaging effects of such isoxazolines;

c) such a method is more convenient than the use of other prior art compounds indoors because such a method can be used at a time when poultry occupy the premises, for example in the case of laying hens during the laying period, and such a method does not require special equipment for administration (such as required for application to the premises of synthetic organic chemicals in poultry houses);

d) such a method is more convenient than prior art animal applications (e.g. application as a spray or dust) because it avoids the labour-intensive production methods and avoids the stress of poultry as with such prior art methods. In addition, the use of spray or dust acaricides raises animal safety and user safety concerns at the time of administration;

e) such a method is easy to implement, using available equipment for the introduction of drugs into the water in poultry farms and, therefore, requires no or only minimal investment in new equipment; and

f) In this way it is possible to simultaneously introduce a large number of animals over a certain period of time and therefore effectively control the population of parasitic arthropods throughout the production unit.

Another advantage of administering the isoxazoline compound through the drinking water to laying hens is that it allows dosage and schedule to be adjusted so that efficacy is maintained, no egg culling is required due to the very low concentration of the isoxazoline compound, mainly fluralaner, in eggs. This non-critical low concentration of fluralaner in eggs allows the use of eggs for human consumption from laying hens that have been treated with isoxazoline compounds (mainly fluralaner).

Therefore, the ability to administer isoxazoline compounds offers a number of advantages over existing methods for controlling parasitic arthropods in the poultry and aviary industry.

Administration of an effective amount of the isoxazoline compound via drinking water increases egg production and also improves egg size and egg quality compared to infected but not treated animals. It can further improve reproductive efficiency in breeding birds.

As shown in the examples, administration of the isoxazoline compounds of formula (I) as described below, mainly fluralaner, via drinking water to poultry such as laying hens, can effectively control parasitic arthropod infestations of such animals, especially red bird mite and northern chicken mite infestations.

An isoxazoline compound for use in the present invention may be represented by formula (I):

Where

R ¹ = halogen, CF ₃ , OCF ₃ , CN,

n=an integer from 0 to 3, preferably 1, 2 or 3,

R ² =C ₁ -C ₃ haloalkyl, preferably CF ₃ or CF ₂ Cl,

T=5- or 6-membered ring which is optionally substituted with one or more Y radicals,

Y=methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S, two adjacent Y radicals together form the chain CH-CH=CH-CH, N-CH=CH-CH, CH-N=CH-CH, CH-CH=N-CH or CH-CH=CH-N, HC=HC-CH, CH-CH=CH, CH=CH-N, N-CH=CH;

Q=X-NR ³ R ⁴ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals Z ^A , Z ^B Z ^D ;

X \u003d CH ₂ , CH (CH ₃ ), CH (CN), CO, CS,

R ³ =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

R ⁴ = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanogen omethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

or

R ³ and R ⁴ together form a substituent selected from the group consisting of:

where Z ^A =hydrogen, halogen, cyano, halomethyl (CF ³ ).

In one preferred embodiment, in formula (I), T is selected from

where in T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl, halomethyl, ethyl, haloethyl.

In a preferred embodiment, in formula (I), Q is selected from

where R ³ , R ⁴ , X and Z ^A have the above meanings.

Preferred isoxazoline compounds of formula (I) for use in the present invention are:

( ^R1 ) _n ^{R2 R3 R4} T Y Q Z X 3-Cl, 5Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - C(O) 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 - T-2 - Q-6 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-7 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-5 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-2 ^ZD -1 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ CH ₃ T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - C(O) 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-1 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - C(O)

Particularly preferred isoxazoline compounds for use in the present invention are

( ^R1 ) _n ^{R2 R3 R4} T Y Q Z X 3-Cl, 5Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - C(O) 3-Cl, 5Cl _CF3 - T-2 - Q-6 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-7 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-5 ^ZB -7 3-Cl, 5Cl _CF3 - - T-2 - Q-2 ^ZD -1 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - C(O) 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - C(O) 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - C(O) 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - C(O) 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - C(O)

A more preferred isoxazoline compound for use in the present invention has the formula (II),

wherein

R ^1a , R ^1b , R ^1c are independently hydrogen, Cl or CF ₃ , preferably R ^1a and R ^1c are Cl or CF ₃ and R ^1b is hydrogen,

T represents

Where

Y is methyl, bromine, Cl, F, CN or C(S)NH ₂ , and

Q is as described above.

In another preferred embodiment, in formula (II), R ³ is H and R ⁴ is -CH ₂ -C(O)-NH-CH ₂ -CF ₃ , -CH ₂ -C(O)-NH-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CF ₃ or -CH ₂ -CF ₃ .

In a preferred embodiment, the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 - USAN fluralaner).

In another embodiment, 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 another embodiment, 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), which was disclosed in WO 2009/0080250.

In another embodiment, the isoxazoline compound is 1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidine-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)ethanone-(Sarolaner) (CAS RN 139860 9-39-6).

In another embodiment, the isoxazoline compound is 5-((5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-thiophenecarboxamide-(Lotilaner INN) (CAS RN 1369852- 71-0).

In another preferred embodiment, 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-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN - afox olaner) which was disclosed in WO 2007/079162.

In another embodiment, 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), which was disclosed in WO 2 010/070068.

Isoxazoline compounds and their use as antiparasitic agents are described, for example, in US patent application US 2007/0066617, and international patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003 075, WO 2010/070068 and WO 2010/079077.

The method (or use) of the present invention involves the use of racemic mixtures, for example, equal amounts of enantiomers of such isoxazoline compounds as described above. In addition, the method of the present invention includes isoxazoline compounds that are enriched relative to the racemic mixture in an enantiomer of formula 1. Also included are substantially pure enantiomers of such isoxazoline compounds.

In enantiomeric enrichment, one enantiomer is present in greater amounts than the other, and the degree of enrichment can be determined by the 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 (for example, ee 20% corresponds to an enantiomeric ratio of 60:40). Preferably the compositions for use according to the present invention have at least 50% enantiomeric excess; more preferably at least 75% enantiomeric excess; even more preferably at least 90% enantiomeric excess; and most preferably at least 94% enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer.

The isoxazoline compounds described above may contain additional chiral centers. The method of this invention includes racemic mixtures as well as enriched and substantially pure stereoconfigurations at these additional chiral centers.

Reference to an isoxazoline compound in this specification includes enantiomers, salts and solvates, as well as N-oxides, which can be prepared by conventional methods.

A number of different parasitic arthropods can infect poultry, especially laying hens. In the event that at least one parasitic arthropod member (adult parasite or one developmental/larval stage member) is continuously or temporarily present on the animal, then parasitic arthropod invasion occurs.

Parasitic arthropods are usually ectoparasites that live on or in the skin and feathers of such animals. According to their biological life cycle, they can be divided into permanent or temporary parasitic arthropods.

Persistent parasitic arthropods are those that spend their entire (adult) life on their host, the poultry. Examples of important resident parasitic arthropods in poultry, especially chickens, are the northern chicken mite ( Ornithonyssus sylviarum ), the sucking flea ( Echidnophaga gallinacean ), the chicken flea ( Ceratophyllus gallinae ), the mutant mite ( Knemidokoptes Mutans ) and chicken lice, e.g. pale chicken ( Menopon gallinae ).

Transient parasitic arthropods feed on, but do not permanently live on, their host, poultry, but spend most of their (adult) life surrounded by such a host, poultry. Examples of transient parasitic arthropods in poultry are Persian ticks ( Argas persicus ), red bird ticks ( Dermanyssus gallinae ), tropical bird ticks ( Ornithonyssus Bursa ), and bed bugs ( Cimex lectularius ).

The control of transient parasites is notoriously difficult because they can be present both on poultry and in the environment.

The present inventors have found that by administering one or more of the isoxazoline compounds as defined above through drinking water to poultry, both permanent parasitic arthropods and transient parasitic arthropods of poultry can be effectively controlled, and both existing infestations of poultry can be treated and re-invasion of animals from the environment can be prevented.

In addition, administration through drinking water of the isoxazoline compounds as defined above, especially fluralaner, is effective in reducing the number of parasitic arthropods in poultry environments.

In addition, drinking-water administration of isoxazoline compounds as defined above, especially fluralaner, at a dose that is effective in treating or preventing arthropod infestation, can be used in laying hens during egg production, as no withdrawal of eggs from animals from human consumption is required.

Some important parasitic arthropods that can be controlled by the method and application of the present invention are described in more detail below:

Ticks: Ticks are arachnid parasites that infect mammals and poultry. Examples of commercially important poultry mites are described below.

Common free-living ectoparasitic mites of poultry belong to the family Dermanyssidae and include, for example, chicken tick, northern chicken tick and tropical bird tick. They are bloodsuckers and can run fast on skin and feathers.

The red bird mite (chicken mite), also called the chicken mite, red mite, or roost mite, is found throughout the world and is of particular concern in the warmer parts of the temperate zone. The mites stay on the host only to feed and then move to nearby cracks and crevices to lay their eggs. Under favorable conditions, the life cycle of the parasite can be completed within 1 week and large populations can be established quickly. Not only can these mites cause anemia, thereby seriously reducing production and increasing feed conversion rates, but they actually kill birds, especially chicks and hens or laying hens. Layers in production may refuse to lay eggs in infested nests. The red bird mite is a temporary parasitic arthropod.

Ticks are found in both cage batteries and floor systems. However, this problem is the most common and widespread in the "enriched" cage system that was created in Europe due to animal welfare concerns; due to the presence of a large number of suitable shelters for ticks.

The northern chicken mite ( Omithonyssus sylviarum ) is the most common and most important persistent pest of poultry in all major poultry production areas in the United States. It is also recognized as a serious pest throughout the temperate zone of other countries. These mites suck blood, and the resulting scabs can be detrimental to the appearance of a butchered bird. Of even greater concern is the economic importance of this mite for the production of caged eggs from infected laying hens. The northern chicken mite is a persistent parasitic arthropod.

The tropical bird mite ( Ornithonyssus bursa ) is spreading throughout the warmer regions of the world and possibly displacing the northern chicken mite in these regions. The tropical bird mite is a temporary parasitic arthropod.

Lice: Lice are common external parasites of birds. They belong to the order Mallophaga , the lice. Over 40 species have been recorded in domesticated birds. There are many types of bird lice, but only a few are commonly seen. Chicken lice are, for example, the two-bristle chicken lice ( Menacanthus stramineus ) and the pale chicken lice ( Menopon gallinae ). Lice will move from one bird species to another if these hosts are in close contact. Lice are not highly pathogenic to mature birds, but lice-infected chickens may die. Clinical evidence suggests that lice can irritate nerve endings, thereby interfering with rest and sleep. Lice often accompanies manifestations of ill health such as internal parasitism, infectious diseases and malnutrition, as well as poor sanitation. They are permanent parasitic arthropods.

Bed bugs: Bed bugs are another family of parasitic arthropods. The family Cimicidae of the order Hemiptera includes several blood-sucking parasites of birds. The most common of these bugs is the bed bug ( Cimex lectularius ), which attacks humans, most other mammals, and birds. It is most common in temperate and subtropical regions. Birdhouses and dovecotes can become densely populated. The most basic bird bug is the chicken bug ( Haematosiphon inodora ). They are temporary parasitic arthropods.

Fleas: Fleas are another family of parasitic arthropods. Fleas (order Siphonaptera ) are parasites in the adult stage, but free-living as larvae. The sucking flea ( Echidnophaga gallinacea ) is more common in the southern United States. Another type of flea in chickens is the chicken flea ( Ceratophyllus gallinae ). Irritation and blood loss can cause serious damage to the bird, especially young birds, which can die. In older birds, production is reduced. They are permanent parasitic arthropods.

One skilled in the art will appreciate that a parasitic arthropod population may consist of one or more (parasitic) arthropod species. These parasitic arthropods may be temporary or permanent parasite species, or it may be a mixed infestation of temporary and permanent parasites (such as Dermanyssus gallinae and Ornithonyssus sylviarum , for example).

Infestation of poultry, especially chickens, especially laying hens, by such parasitic arthropods (parasites) can be treated or prevented by administering an effective amount of an isoxazoline compound, as described in this application, via administration through drinking water.

"Poultry" means birds kept for oviposition or meat production, such as chickens, ducks, geese, turkeys, pheasants, etc. "Chickens" are chickens ( Gallus gallus domesticus ).

The term "laying hen" or "laying hen" is a general term for adult female hens ( Gallus domesticus ) that are primarily kept for oviposition. Such eggs are commonly used for consumption as human food. The term "laying hen" in this application includes breeding birds that are kept for the production of eggs from which laying hens are subsequently hatched.

"Repair chicks", also known as post-brooding chicks or hens, are female chicks aged 12-17 weeks. The term "replacements" means that they will replace old layers destined for removal at the end of their laying cycle.

Broilers are domesticated, chicken-like wild birds that are bred and bred specifically for meat production.

By "treatment" or "treat" or "treatment" is meant the use or administration of a compound or composition to an animal that has a parasitic infestation to eliminate the parasite or reduce the number of parasites infecting the animal.

The effect may be, for example, ovicidal, larvicidal and/or an effect on adults only, or a combination thereof. The effect can manifest itself directly, i.e. by killing parasites either immediately or after some time has elapsed, such as when molting occurs, or by destroying their eggs, or indirectly, such as by reducing the number of eggs laid and/or the rate of hatching.

"Prophylaxis" or "prevention" means that a new infestation of animals with parasites is prevented by killing the adult parasites and any developmental/larval stages that are capable of infecting the host, before infecting the host, or by killing or inhibiting parasites when they infect an animal that has been treated with an isoxazoline compound as described above, or by preventing the emergence of offspring of parasites, for example, by reducing the number of eggs laid and/or the rate of hatching from eggs.

The term "effective amount" means a dosage or amount of an isoxazoline compound, as described above, which is required to treat or prevent infestations by parasitic arthropods of animals, that is, to partially reduce or reduce the number of parasites on the animal, and/or to inhibit the development of a parasitic infection on the animal in whole or in part.

This value is easily determined by observing or detecting the number of parasites on the animal before and after administration of the isoxazoline compound as described above through the drinking water of such animals, for example, the number of parasites is reduced after the first administration by 5% to about 100%, preferably by more than 50%, by more than 70%, by more than 90%, by more than 95%, by more than 99%.

Factors affecting the effective amount may include, for example, the types of parasites to be treated and the developmental stages of the parasites, the type (eg, species and breed), age, size, sex, diet, activity, and condition of the infected animals; environmental conditions (temperature, humidity), pharmacological aspects such as potency, efficacy, pharmacokinetic and toxicological profiles of the particular isoxazoline compound administered; and whether an isoxazoline compound is administered as part of an active ingredient combination. Thus, the preferred amount of the compound according to the present invention may vary.

It has been found that an effective amount of the isoxazoline compound as described above can be administered to laying hens that is effective in controlling parasitic arthropods while no egg culling is required due to the residual amount.

Such an effective amount of an isoxazoline compound, especially fluralaner, is in one embodiment divided into two dosages administered 7 or 14 days apart. Preferably, divided doses (each containing, for example, 50% of the normal dose) are administered at 7-day intervals, for example, 2 times a 0.5 mg/kg body weight dose of an isoxazoline compound (eg, fluralaner).

In one embodiment, an isoxazoline compound as described above is administered via drinking water administration for the treatment or prevention of tick infestations in chickens using a dosage regimen as described herein. Commercially important tick infestations are Dermanyssus sp. (e.g. D. gallinae ) and/or Ornithonyssus sp . Treatment or prevention of Dermanyssus gallinae infestation is preferred. Another preferred option is the treatment or prevention of Ornithonyssus sylviarum infestation.

An effective amount of an isoxazoline compound, as described above, for treating or preventing parasitic arthropod infestation is typically greater than about 0.01 mg/kg (i.e., milligram of a compound of the present invention per kilogram of body weight of treated animals).

In some embodiments of the present invention, an effective amount is from about 0.01 to about 50 mg/kg, from about 0.05 to about 20 mg/kg, from about 0.1 to 10 mg/kg, or from about 0.15 to 5 mg/kg of body weight, especially from 0.2 to 2 mg/kg of body weight.

In some embodiments, the effective amount is from about 0.5 to about 1.5 mg/kg, from about 0.75 to about 1 m/kg.

In the method according to the present invention, the isoxazoline compound is administered via drinking water. For "drinking water administration", an effective amount of the isoxazoline compound as described above is formulated in drinking water that is offered to animals that are either infested with parasitic arthropods (which require treatment) or animals that are not infected but are at risk of infestation with parasitic arthropods (prophylaxis of parasitic arthropods). Preferably, the isoxazoline compound as defined above is administered to a population that includes poultry that are infested with parasitic arthropods.

By incorporating an effective amount of an isoxazoline compound, as described above, into the composition of drinking water that is offered to an animal, "medicated drinking water" is formed. This therapeutic drinking water is administered using the normal drinking water supply system in the poultry house.

Medicated drinking water is formed by adding (or mixing with) drinking water to a (concentrated) pharmaceutical composition, as described below, which is either dissolved in drinking water, mixed with drinking water, or resulting in a suspension of the isoxazoline compound in drinking water.

The isoxazoline compound in the treatment water should be evenly distributed over the treatment period (as defined below) and allow an effective and accurate amount of the compound to be administered to all animals that have access to such treatment water. Preferably, all animals in a room, such as a poultry house, are treated at the same time, i.e. access to medicinal water is provided for all poultry in a certain production area.

Therefore, this invention also relates to a pharmaceutical composition for use in the prevention or treatment of parasitic arthropod infestations in laying hens that produce eggs for human consumption, comprising an effective amount of an isoxazoline compound as described above and a pharmaceutically acceptable carrier. Such a pharmaceutical composition is also referred to as a "concentrated pharmaceutical composition" or either a "concentrated solution" or a "concentrated suspension".

The isoxazoline compound as disclosed above is typically present in such concentrated pharmaceutical compositions in an amount of from about 0.1 mg/mL to about 500 mg/mL. The preferred pharmaceutical composition of the present invention is a concentrated solution. This concentrated solution contains between 1.5 mg/ml and 100 mg/ml of an isoxazoline compound, mainly fluralaner.

An example of a suitable concentrated solution of an isoxazoline compound, especially fluralaner, is a pharmaceutical composition that contains an isoxazoline compound and a pharmaceutically acceptable carrier containing diethylene glycol monoethyl ether and a polysorbate surfactant.

An alternative concentrated pharmaceutical composition for use in the present invention contains the isoxazoline compound described above in the form of a concentrated suspension, especially a concentrated aqueous suspension. Such a concentrated suspension contains from 100 mg/ml to 500 mg/ml of an isoxazoline compound, mainly fluralaner.

In one embodiment, such a concentrated suspension is an aqueous suspension of a wet-milled isoxazoline compound, primarily fluralaner, particles in a composition containing a polysorbate surfactant. In addition, such an aqueous suspension composition may contain a preservative such as benzyl alcohol and defoamers such as simethicone.

Such pharmaceutical compositions can be obtained by methods known in the art. These methods include, for example, a variety of known mixing, dissolving and emulsifying methods.

For the preparation of medicinal drinking water in the first stage, a concentrated pharmaceutical composition is obtained containing an isoxazoline compound, as described above, and a pharmaceutically acceptable carrier, either in the form of a solution (micellar) or in the form of a suspension. This concentrated pharmaceutical composition is then diluted (in one or more steps) with water to form medicinal drinking water.

Medicinal water is prepared by diluting an amount (volume) of a (concentrated) pharmaceutical composition that contains the isoxazoline compound described above at a dose that provides (after dilution) an effective amount for all animals treated with a volume of drinking water that substantially corresponds to the volume that will be consumed by such animals during the period of treatment.

This therapeutic drinking water is then offered to the animals for consumption through the drinking water supply system. Such drinking water supply systems on commercial farms can be complex systems of tanks, pipes, coils, machine drinkers and cups and/or nipples. An average room may contain hundreds of meters of pipes with many turns and hundreds of individual cups and/or nipples.

It is common practice to ensure that only therapeutic drinking water is provided to animals for a limited period of time (treatment period), typically less than 24 hours, e.g. 4-5 hours to 8 hours, as the sole source of drinking water to ensure that an effective amount of the isoxazoline compound as described above is consumed by each animal during that time.

Medicinal drinking water may be available during the entire treatment period to one animal; or at the same time a group of animals or all animals in the same room (house) or farm.

The isoxazoline compound as described above can be delivered through the selected drinking water supply by mixing and diluting the concentrated pharmaceutical composition as described above with drinking water in a central water tank or in a separate drug and storage tank to form therapeutic drinking water that is offered to animals for consumption.

Alternatively, the concentrated pharmaceutical composition as described above is injected continuously into a high or low pressure drinking water distribution ring system using a metering dispenser or a metering pump system or a drug dispenser system.

Dosing pump systems employ a pump that delivers metered amounts of the concentrated composition to the water pipes at a typical dilution of 1-5%. Within dosing pump systems, it is possible to use electronic dosing pump systems such as Buerkert's KONTI-DOS or mechanical dosing pumps such as dosing pumps with DOSATRON® hydraulic motor, DOSMATIC® hydraulic drive, proportional medicators.

The variety of field installations also concerns the water supply systems themselves: dead-end or closed loop systems of various lengths with different pipe materials (e.g. PVC, galvanized iron) and drinkers that are adapted to the target animals, such as bell drinkers, nipples.

The concentration of the isoxazoline compound in therapeutic drinking water depends on the effective amount, the total body weight of the treated animals, the water intake of the animals and the period of treatment.

The medicator uses, for example, 10 ml of the concentrated composition and is further diluted with water at a ratio of about 1:200 to provide medicinal drinking water having a concentration of an isoxazoline compound, e.g., fluralaner, from 0.001 to about 1 mg/ml, most preferably from about 0.05 to about 0.2 mg/ml. In one embodiment, the medicinal water has a concentration of the isoxazoline compound from 0.002 to 0.02 mg/mL.

In one particular embodiment, for a particular fluralaner isoxazoline compound, the concentration is calculated to provide an effective amount of fluralaner per body weight (BW) of the treated poultry in the range of about 0.5 mg to about 2 mg of fluralaner per kilogram of body weight per day in the volume of drinking water typically consumed by the treated poultry during a treatment period of 2 to 24 hours, preferably 4 to 5 to 8 hours.

A single administration of an effective amount of an isoxazoline compound, as described above, may be sufficient to treat a parasitic infestation. However, multiple doses of the isoxazoline compound may be used. One period of making medicinal water as described above available to poultry (duration typically up to one day) is a single administration through drinking water.

The therapeutic frequency of drinking water administration depends on the parasite being treated or prevented (and its biological life cycle, which may depend on environmental conditions in the poultry house, such as temperature) and the production cycle of the poultry host being treated.

Therefore, the isoxazoline compound as described above, mainly fluralaner, is administered via drinking water administration at least once or more than once, ie 2 times or 3 times in one poultry production run. In the case of laying hens, this is the laying period. In the case of other poultry, the production cycle is the period during which a group of poultry remains in the house (for example, the fattening period in the case of broilers). The preferred frequency of administration is two times during the laying period. The length of the laying period varies, but is usually between one and two years.

Particularly preferred are two administrations via drinking water to laying hens between 16 and 72 weeks of age.

It is preferred to administer two doses of the isoxazoline compound, as described above, approximately 7 days or 14 days apart (depending on the life cycle of the parasite and the production cycle of the host animal). Particularly preferred is the administration of an effective amount of the isoxazoline compound at intervals of 7 days. In a preferred embodiment, 1 mg of fluralaner per kg of body weight is divided into two doses of 0.5 mg/kg, which are administered through drinking water with an interval of 7 days.

With this regimen of administration at approximately 7 or 14 days intervals, longer lasting efficacy against parasitic arthropods can be achieved due to the different life cycle stages of parasites that can be affected by such administration.

The specific time interval may vary between different parasitic arthropods and may depend on environmental conditions that affect the life cycle of the parasite.

With a second dose, parasites that have developed (after the parasite life cycle) from non-susceptible or difficult to influence stages, such as those that have matured from juvenile parasite stages (such as eggs, nymphs or pupae) during this period, can be affected.

With this mode of administration, the parasite population can be significantly reduced to a level that can cause only minimal harm to the animal and minimal loss of production during that production run, or even more than one production run. One particular advantage of such a regimen is that a low dose of the isoxazoline compound can be administered such that residues in eggs can be minimized by such a regimen while maintaining effective control of parasitic arthropods.

Another aspect of the present invention is a method for controlling harmful arthropods in a poultry environment, especially chickens, in which an isoxazoline compound as described above is administered through drinking water to poultry(s), especially chickens, especially laying hens, occupying this environment.

Poultry "occupying this environment" means an animal that is permanently or temporarily housed in such an environment, has access to such an environment, either for a limited time (temporary, such as free-roaming laying hens) or permanently (for example, broiler houses).

An effective amount in the context of this (non-medical) method of controlling (parasitic) arthropods in a poultry environment is an amount of an isoxazoline compound, as described above, that is capable of reducing the number of arthropods in the animal's environment, e.g. a poultry house or house, and/or suppressing the development of arthropods to a significant reduction in population size. Such declines in arthropod numbers can be tracked using special traps in open areas in the poultry environment.

This value is easily determined by observing or detecting the abundance of parasites in the environment of the animal (for example, using a trap), both before and after the introduction of an isoxazoline compound through drinking water to one or more animals occupying such an environment, for example, the number of arthropods is reduced by 5% to 100%, in particular by more than 50%, more than 75%, more than 90%. Preferably, the number of arthropods in the environment is reduced to a level that does not allow population growth during the production cycle, which leads to production losses in the poultry population occupying such environment (egg production or meat production or animal death, etc.).

The parasitic arthropods that can be controlled by such a method can be both permanent parasitic arthropod stages and transient parasitic arthropod stages, as described above, that are present in the environment of the animal.

The stages of parasitic arthropods can be all stages of the life cycle that are known to those skilled in the art, ie both juvenile/larval stages and adult insect stages.

In one embodiment, the stages of parasitic arthropods, as described above, that are present in the environment of poultry, especially chickens, preferably laying hens, are controlled.

In one embodiment, such arthropods are chicken parasitic arthropods.

Administration of an effective amount of the isoxazoline compound by administration via drinking water is useful for controlling arthropods in the breeding environment and oviposition of poultry and other bird species kept for a production cycle that exceeds a period of approximately 8 weeks. Especially if such animals are kept on an industrial scale, for example, laying hens, rearing of hens or replacement chickens, breeding layers, and rearing of broiler hens and breeding birds.

In general, such a method can also be applied to other types of poultry, such as, for example, turkeys, geese, ducks, pigeons, quails or pheasants.

Preferably, such parasitic arthropods are mites of the species Dermanyssus and/or mites of the species Ornithonyssus , preferably Dermanyssus gallinae .

This method also aims to control arthropods in poultry environment, especially chickens, chickens, and especially laying hens and broiler chickens, which, as a rule, do not infect animals directly, but do harm to animals.

In one embodiment, a method for controlling darklings is provided by administering an isoxazoline compound, as described above, to poultry occupying an environment in which darklings are present. The darkling beetle ( Alphitobius diaperinus ) is the most common beetle in poultry litter. It is also called the dusk or night beetle due to its high activity at dusk.

Darkling beetles affect birds and poultry producers by reducing production and productivity, increasing disease potential and transmission, and increasing building and energy costs due to facility destruction. Darkling beetles are a worldwide common insect in poultry houses.

The beetles live in litter, where they feed on spilled poultry feed, manure, and dead or dying birds. Beetles can be found throughout the poultry house; eggs, larvae, pupae and adults are found in manure and soil. Fighting is difficult with any single approach, as the beetles use many niches.

In one embodiment, arthropods, especially darklings, are controlled in a broiler or laying hen environment. For such control, isoxazoline spray application as described above can be used instead of drinking water administration or in addition to drinking water administration.

In such a method of controlling (parasitic) arthropods in a poultry environment, in general, the same isoxazoline compounds, administration regimens, therapeutic drinking water, and pharmaceutical compositions as described herein above for the prevention and treatment of parasitic arthropods can be used.

Another aspect of the present invention is a method for controlling transient parasitic arthropods or arthropods in a poultry environment as defined above, comprising the steps of:

1. Assessing the population of transient parasitic arthropods (such as, for example, Dermanyssus gallinae ) in the poultry house by placing traps in locations in the poultry environment that are preferred by such transient parasites and estimating the number of parasites caught in such traps.

2. Determining, based on the length of the production run and the number of temporary parasites from the traps and environmental conditions (eg temperature), the "expected pest exposure" to the poultry that occupy the house during the entire production run.

3. Determine the amount of drug applied per production cycle needed to control the parasitic arthropod population to achieve a level that does not cause production losses in poultry. Treatment consists of two administrations of isoxazoline compounds via drinking water as described above, mainly fluralaner, 7 days apart.

4. Measure treatment success by assessing the arthropod population as described in step 1).

5. If the arthropod population exceeds a certain threshold, adjust the treatment schedule.

EXAMPLES

Example 1

The efficacy of fluralaner, administered orally via medicated drinking water, against artificially induced red bird mite ( Dermanyssus gallinae ) infestation in laying hens was investigated. Groups A - D (n=6) were treated with doses of 2, 1 and 0.5 mg fluralaner/kg body weight at a time or 1 mg fluralaner/kg body weight in divided doses (0.5 mg/kg body weight 2 times).

Materials and methods:

The consumption of drinking water in each of the groups was measured three days before administration to calculate the average daily water intake. Medicated water was prepared by diluting a solution of fluralaner (10 mg/ml) as shown in the table below to the calculated concentration of fluralaner.

Components Compound Compound Function (%v/v) (mg/ml) Fluralaner 0.95% 10 Active Ingredient Transcutol V 24.76% Up to 1ml* Solvent (diethylene glycol monoethyl ether) Twin 80 74.29% Surface-active substance

On D0 (group D additional on D7), hens in groups A-D received fluralaner via medicinal drinking water. Group E received unlimited drug-free water.

The dose for administration was calculated based on the average body weight of each treatment group obtained one day before treatment (D-1, D 6). A concentrated solution of fluralaner was diluted in drinking water to obtain medicinal water ready for consumption.

The therapeutic drinking water was prepared in such a way that fluralaner was administered according to the following dosing regimen:

The amount of medicinal water offered per group at D0 (group D also at D7) was approximately 50% of the estimated average daily water intake measured previously in the respective group, in order to ensure that the entire dose was consumed.

After all the medicinal water was consumed, the other 50% of the volume of the average daily water intake was supplied as tap water to the same drinker.

On Day 1, Day 5, Day 8, Day 12, D15, D19 and D22, four of the six hens in each group were infested with about 200 viable D. gallinae mites (naked nymphs and adults that had been starved to infection for 7 days).

From each infected chicken, approximately 25 bloodshot mites were collected and incubated for approximately 24 hours. Dead, injured and/or live ticks were counted visually using a binocular.

Ticks were classified as dead if no movement was detected or the ticks were in a dorsal position. Ticks were classified as damaged if their movement was uncoordinated.

The percentage of tick mortality and tick suppression was calculated for each treated group compared to the untreated negative control group.

Results:

Fluralaner was well tolerated by chickens.

The % mortality and % suppression of red mites ( Dermanyssus gallinae ) estimated at approximately 24 hours post-challenge in laying hens treated with fluralaner orally via drinking water are shown in Tables 1 and 2. Rapid onset of action was demonstrated by all doses administered.

Table 1
% Mortality of D. gallinae was assessed 24 hours after the invasion Group fluralaner (mg/kg BW) % Tick mortality after 24 hours infestation on D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 77 1 0 B 1 100 100 100 94 77 2 0 C 0.5 100 100 97 55 15 0 0 D 1 (2×0.5) 100 100 100 100 98 59 14

table 2
% D. gallinae suppression was assessed 24 hours after invasion Group fluralaner (mg/kg BW) % suppression of mites after 24 hours infestation on D1 D5 D8 D12 D15 D19 D22 A 2 100 100 100 100 81 14 0 B 1 100 100 100 95 81 3 0 C 0.5 100 100 100 75 19 0 0 D 1 (2×0.5) 100 100 100 100 99 66 27

At each time point assessed, ticks observed in the untreated control group were viable and showed their normal behavior.

Claims (5)

1. Use of an isoxazoline compound selected from 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 - Fluralaner USAN), or a salt or solvate thereof, for the prevention or treatment of infestation chicken lice in poultry, wherein an effective amount of the isoxazoline compound is administered via drinking water in two separate doses 7 days apart. 2. Use according to claim 1, wherein the isoxazoline compound is fluralaner. 3. Use according to claim 1 or 2, wherein the poultry is a laying hen. 4. Use according to claim 1 or 2, wherein the chicken lice infestation is Menacanthus cornutus . 5. Use according to any one of claims 1 to 4, wherein the effective amount is from 0.01 to 50 mg/kg body weight of the animals to be treated.