BR122020024991B1 - USE OF ISOXAZOLINE - Google Patents

Abstract

This invention relates to methods for controlling parasitic infestations of animals and their environments, and, more particularly, to methods using isoxazolines to control parasites in animals or their environments, as well as treating animal parasites. Isoxazolines include substituted 4-(isoxazolinyl)-benzamides (specifically, 4-(5-(halomethyl)-5-phenylisoxazolin-3-yl)-benzamides) and 4-(isoxazolinyl)-benzothioamides (specifically, 4-(5- (halomethyl)-5-phenyl-isoxazolin-3-yl)-substituted benzothio-amides). This invention also relates to compositions comprising isoxazolines for use in such methods, to the use of isoxazolines to manufacture medicaments for use in such methods, and to kits comprising isoxazolines for carrying out such methods. This invention also relates to the use of isoxazolines as medicines, particularly medicines that can be used in the above-mentioned method.

Description

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

[001] This patent claims priority to US Provisional Patent Application No. 61/080,444 (filed July 14, 2008); US Provisional Patent Application No. 60/956,448 (filed August 17, 2007); European Patent Application No 07016152.6 (filed August 17, 2007); and European Patent Application No 07150309.8 (filed December 21, 2007). The full texts of each of these patent applications are incorporated by reference in this patent.

FIELD OF INVENTION

[002] This invention relates to methods for controlling parasitic infestations of animals and their environments, and, more particularly, to methods using isoxazolines to control parasites in or on animals or their environments, as well as treating animal parasites. Isoxazolines include substituted 4-(isoxazoline)-benzamides (specifically, 4-(5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzamides) and 4-(isoxazolinyl)-benzothioamides (specifically, 4-( substituted 5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzothio-amides). This invention also relates to compositions comprising isoxazolines for use in such methods, the use of isoxazolines to manufacture medicaments for use in such methods and to kits comprising isoxazolines for carrying out such methods. This invention also relates to the use of isoxazolines as medicines, particularly medicines that can be used in the methods mentioned above.

BASICS OF THE INVENTION

[003] Various pests and parasites are known to infest warm-blooded animals. These pests and parasites can be a huge nuisance for both animals and their owners. For example, virtually all pets and livestock can be affected by ectoparasites such as ticks, mites, lice and fleas. Ectoparasites tend to irritate animals and can also cause clinical disease and adverse subclinical conditions, either by themselves or by carrying vector-borne pathogens. To date, several treatments have been developed to control ectoparasites in warm-blooded animals. Nevertheless, a need continues to exist for compositions (and methods for their use) which are bioavailable, can provide contact or systemic activity, are potently effective, have a rapid onset of activity, have a long duration of activity, and/or or are safe for animal recipients and/or their human owners. This invention addresses this need.

SUMMARY OF THE INVENTION

[004] Briefly, this invention is generally directed to isoxazoline compositions (particularly 4-(isoxazolinyl)-benzamide compositions (also known as, for example, “amide acid 4-(4,5-dihydroisoxazole)” compositions). 3-yl)-benzoic acid”) and 4-(isoxazolinyl)-benzothioamide compositions (also known as, for example, “4-(4,5-dihydroisoxazol-3-yl)-benzothioamide compositions”)) and for use to control ectoparasites in or on warm-blooded animals. In accordance with this invention, it has been discovered that these compositions generally exhibit desirable bioavailability and can provide contact and/or systemic activity. Many of the compositions also provide desirable safety profiles for warm-blooded animal recipients and/or their owners. Furthermore, it has been found that a single administration of such compositions generally provides potent activity against one or more ectoparasites, while also tending to provide desirable rapid onset of activity, long duration of activity, and/or safety profiles.

[005] This invention, therefore, is directed, in part, to a method for controlling ectoparasitic infestation of an animal. The method comprises administering the isoxazolines, an isoxazoline salt, or an isoxazoline solvate or salt to the animal. Isoxazoline corresponds in structure to Formula (I): Here: One of A1 and A2 is selected from the group consisting of halogen and halomethyl. One of A1 and A2 is selected from the group consisting of hydrogen, halogen and halomethyl. A3 is selected from the group consisting of hydrogen, halogen and halomethyl. R is halomethyl. X is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, ethyl and haloethyl.

[006] In some embodiments, Z1 and Z2 are independent substituents. In these embodiments: Z1 is independently selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethyl-aminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynyl-aminocarbonylmethyl, N- phenyl-N-methyl-amino, haloethylaminocarbonyl-methyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonyl-methyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethyl-aminocarbonylcyclopropyl,

[007] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl , ethylaminocarbonylmethyl, ethyl-aminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethyl-aminocarbonylmethyl and haloethylaminocarbonylethyl.

[008] When Z1 is hydrogen, Z2 is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropyl-carbonyl, methoxycarbonyl, methoxymethylcarbonyl and aminocarbonyl.

[009] In other embodiments, Z1 and Z2 together form a substituent selected from the group consisting of: Z3 is selected from the group consisting of O and S. ZA is selected from the group consisting of hydrogen, halogen and cyano.

[0010] This invention is also directed, in part, to a method for treating parasites in an animal. This method comprises administering the above-described isoxazoline, salt, or solvate to the animal.

[0011] This invention is also directed, in part, to a method for controlling an ectoparasitic infestation in an environment that is occupied (periodically or continuously) by an animal (e.g., a pet, such as a cat or puppy). This method comprises administering an above-described isoxazoline, salt, or solvate to the animal.

[0012] This invention is also directed, in part, to the use of an above-described isoxazoline, salt, or solvate as a medicament.

[0013] This invention is also directed, in part, to the use of an above-described isoxazoline, salt, or solvate to manufacture a medicament for treating parasitic diseases in an animal.

[0014] This invention is also directed, in part, to an above-described isoxazoline, salt, or solvate for treating parasites in an animal.

[0015] This invention is also directed, in part, to a parasiticidal composition for use in an animal. The composition comprises an above-described isoxazoline, salt, or solvate in an amount that is effective to control an ectoparasitic infestation when the composition is administered to the animal. The composition also comprises an excipient (i.e., it comprises at least one excipient).

[0016] This invention is also directed, in part, to a therapeutic kit. The kit comprises an above-described isoxazoline, salt, or solvate and an additional component. The additional component may be, for example, a diagnostic tool, instructions for administration, a device for administration, an excipient or other active ingredient, or a memory aid.

[0017] Other benefits of the applicant's invention will be evident to those skilled in the art from reading this specification.

BRIEF DESCRIPTION OF FIGURES

[0018] Figure 1 presents the mean plasma concentration of Compound 11-1 during the study in Example 6, which evaluates the effectiveness of Compound 11-1 against cat fleas (Ctenocephalides felis) and brown dog ticks (Rhipicephalus sanguineus) in dogs. In Figure 1, “PO” data refers to Group A (1 mg/kg body weight of Compound 11-1 in the form of a tablet for oral administration); “SC” data refers to Group B (1 mg/kg body weight of Compound 11-1 in the form of an injectable solution for subcutaneous administration); “TOP WITH ENH” data refers to Group C (1 mg/kg body weight of Compound 11-1 in the form of a topical solution on the site containing an absorption enhancer); “TOP WITH ENH and DIFFUSION” data refer to Group D (1 mg/kg body weight of Compound 11-1 in the form of a topical solution on the site containing an absorption enhancer and diffusion agent); and “TOP WITH ETHYL LACTATE” data refers to Group E (1 mg/kg body weight of Compound 11-1 in the form of a topical solution on the site containing ethyl lactate as a solvent).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] This detailed description of the preferred embodiments is intended solely to instruct other persons skilled in the art with the applicant's invention, its principles and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms , whereas these may be better suited to the requirements of a particular use. This detailed description and specific examples thereof, while indicating preferred embodiments of this invention, are intended for illustration purposes only. This invention, therefore, is not limited to the preferred embodiments described in this specification and may be modified in various ways.

1. Isoxazolines

[0020] The isoxazolines used according to this invention generally include the compounds of formula (I):

[0021] Preferred substituents in formula (I) include the following:

A. Preferred embodiments of A1 and A2

[0022] One of A1 and A2 is selected from the group consisting of halogen and halomethyl. The other of A1 and A2 is selected from the group consisting of hydrogen, halogen and halomethyl.

[0023] In some embodiments, A1 is halogen. In some such embodiments, A1 is bromine. In other embodiments, A1 is chlorine.

[0024] In some embodiments, A1 is halomethyl. In some such embodiments, A1 is trifluoromethyl.

[0025] In some embodiments, A2 is hydrogen;

[0026] In some embodiments, A2 is halogen.

[0027] In some such embodiments, A2 is fluorine. In other embodiments, A2 is chlorine.

B. Preferred Embodiments of A3

[0028] A3 is selected from the group consisting of hydrogen, halogen and halomethyl.

[0029] In some embodiments, A3 is hydrogen.

[0030] In some embodiments, A3 is halogen. In some such embodiments, A3 is chlorine. In other embodiments, A3 is bromine.

[0031] In some embodiments, A3 is halomethyl. In some such embodiments, A3 is trifluoromethyl.

C. Preferred Embodiments of R

[0032] R is halomethyl. In some embodiments, R is monochloromethyl. In other embodiments, R is trifluoromethyl. In still other embodiments, R is monochloro-difluoromethyl.

D. Preferred Embodiments of X

[0033] X is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, ethyl and haloethyl. In some embodiments, X is hydrogen. In other embodiments, X is bromine. In other embodiments, X is iodine. In other embodiments, X is chlorine. In other embodiments, X is methyl. In other embodiments, X is ethyl. In other embodiments, X is trifluoromethyl.

E. Preferred Embodiments of Z1 and Z2

[0034] In some embodiments, Z1 and Z2 are independent substituents. In these embodiments, Z1 is selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxy-methyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N -methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonyl-methyl, haloethylaminocarbonylcyclopropyl,

[0035] In some such embodiments, Z1 is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxy-methyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2-propynylaminocarbonyl-methyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl) -aminocarbonyl]ethyl, tetrahydrofuryl, methylamino-carbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, isopropylamino-carbonylmethyl, cyclopropylaminocarbonylmethyl, (2-propenyl)-amino-carbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylcyclopropyl, (2-fluoroethyl)-aminocarbonylmethyl, (2-chloroethyl)-aminocarbonylmethyl, 1-(ethylaminocarbonyl)-ethyl,

[0036] In other embodiments, Z1 is selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N -phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonyl-methyl, haloethylaminocarbonylcyclopropyl,

[0037] In other embodiments, Z1 is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylamino - carbonylmethyl, 2,2-dimethoxyethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-aminocarbonyl] ethyl, tetrahydrofuryl, methylaminocarbonyl-methyl, (N,N-dimethylamino)-carbonylmethyl, isopropylaminocarbonyl-methyl, cyclopropylaminocarbonylmethyl, (2-propenyl)-aminocarbonyl-methyl, (2,2,2-trifluoroethyl)-aminocarbonylcyclopropyl, (2-fluoroethyl )-aminocarbonylmethyl, (2-chloroethyl)-aminocarbonylmethyl, 1-(ethylamino-carbonyl)-ethyl,

[0038] In other embodiments, Z' is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-aminocarbonyl ]ethyl, tetrahydrofuryl,

[0039] In other embodiments, Z1 is selected from the group consisting of hydrogen, methyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2 -propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-amino-carbonyl]ethyl, tetrahydrofuryl,

[0040] In other embodiments, Z1 is selected from the group consisting of hydrogen, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2, 2-trifluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[0041] In other embodiments, Z1 is selected from the group consisting of hydrogen, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2-propynyl - aminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-aminocarbonyl] ethyl, tetrahydro-furyl,

[0042] In other embodiments, Z1 is selected from the group consisting of N-phenyl-N-methyl-amino,

[0043] In other embodiments, Z1 is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)-methyl,

[0044] In other embodiments, Z1 is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)-methyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methylamino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-tri-fluoroethyl)-amino-carbonyl]ethyl, tetrahydrofuryl,

[0045] In other embodiments, Z1 is selected from the group consisting of 1-[(2,2,2-trifluoroethyl)-aminocarbonyl]-ethyl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl , isopropylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, (2-propenyl)-aminocarbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylcyclopropyl, (2-fluoro-ethyl)-aminocarbonylmethyl, (2-chloroethyl)-aminocarbonylmethyl, 1-( ethyl-aminocarbonyl)- ethyl,

[0046] In other embodiments, Z1 is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[0047] In other embodiments, Z1 is selected from the group consisting of methoxymethyl, ethoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[0048] In other embodiments, Z1 is selected from the group consisting of methoxymethyl, ethoxymethyl and tetrahydrofuryl.

[0049] In other such embodiments, Z1 is:

[0050] In other embodiments, Z1 is haloethylaminocarbonylmethyl. In some such embodiments, Z1 is (2,2,2-trifluoroethyl)-aminocarbonylmethyl.

[0051] When Z1 is hydrogen, Z2 is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl and aminocarbonyl. In some such embodiments, Z2 is methoxycarbonyl. In other embodiments, Z2 is aminocarbonyl.

[0052] When Z1 is an independent substituent other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, ethylaminocarbonylethyl, dimethoxyethyl, propynyl-aminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylamino-carbonylethyl.

[0053] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl , cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethyl-aminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethyl-aminocarbonylmethyl and haloethylaminocarbonylethyl.

[0054] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is hydrogen.

[0055] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is ethyl.

[0056] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is methoxymethyl.

[0057] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is methylcarbonyl.

[0058] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is ethylcarbonyl.

[0059] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is isopropylcarbonyl.

[0060] In some embodiments when Z1 is an independent other than hydrogen, Z2 is cyclopropylcarbonyl.

[0061] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is methoxycarbonyl.

[0062] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is methoxymethylcarbonyl.

[0063] In some embodiments when Z1 is an independent substituent other than hydrogen, Z2 is selected from the group consisting of hydrogen, methylcarbonyl and ethylcarbonyl.

[0064] In some embodiments, Z1 and Z2 together form a single substituent rather than being independent substituents. In these embodiments, Z1 and Z2 together form the following structure:

[0065] In these embodiments, isoxazoline corresponds in structure to:

[0066] In some embodiments, Z1 and Z2 together form a single substituent rather than being independent substituents. In these embodiments, Z1 and Z2 together form the following structure:

[0067] In these embodiments, isoxazoline corresponds in structure to:

F. Preferred Embodiments of Z3

[0068] In some embodiments, Z3 is O (i.e., oxygen). In other embodiments, Z3 is S (i.e., sulfur).

G. Preferred Embodiments of ZA

[0069] ZA is selected from the group consisting of hydrogen, halogen and cyano. In some such embodiments, ZA is hydrogen. In other embodiments, ZA is bromine. In other embodiments, ZA is chlorine. In other embodiments, ZA is cyan.

H. Illustrative Combinations of Substituents

[0070] The following substituent combinations are simply illustrative and not listed in any particular order of preference.

H1. Illustrative Combination of Substituents 1

[0071] In some embodiments, A1 and A3 are independently selected from the group consisting of halogen and halomethyl and A2 is hydrogen. In some such embodiments, for example, each of A1 and A3 is chlorine such that the isoxazoline corresponds in structure to the following formula:

H2. Illustrative Combination of Substituents 2

[0072] In some embodiments, Z1 and Z2 are independent substituents or together form a single substituent as follows:

[0073] When Z1 and Z2 are independent substituents: Z1 is independently selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethyl-aminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynyl-aminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonyl-methyl, haloethylaminocarbonylethyl, tetrahydrofuryl,

[0074] When Z1 is hydrogen and Z2 is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl and amino carbonyl.

[0075] When Z1 is other than hydrogen and Z2 is independently selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethyl-aminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynyl-aminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylamino-carbonylethyl.

[0076] When Z1 and Z2 together form a single substituent, they form:

H3. Illustrative Combination of Substituents #3

[0077] In some embodiments, the substituents of formula (I) are defined as follows: A1 is selected from the group consisting of chlorine, bromine and trifluoromethyl. A2 is selected from the group consisting of hydrogen, chlorine and fluorine. A3 is selected from the group consisting of chlorine, bromine and trifluoromethyl. R is selected from the group consisting of monochloromethyl, trifluoromethyl and monochloro-difluoro-methyl. X is selected from the group consisting of hydrogen, bromine, iodine, chlorine, methyl, ethyl and trifluoromethyl. Z3 is O. Z1 is selected from the group consisting of hydrogen, bromine, chlorine and cyano.

[0078] In some such embodiments, Z1 and Z2 are independent substituents such that: Z1 is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, (2,2,2 -trifluoro-ethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxy-ethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methylamino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2, 2,2-trifluoroethyl)-aminocarbonyl] ethyl, tetrahydrofuryl,

[0079] When Z1 is hydrogen, Z2 is selected from the group consisting of methoxycarbonyl and aminocarbonyl.

[0080] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

[0081] In other such embodiments, Z1 and Z2 together form:

H4. Illustrative Combination of Substituents 4

[0082] In some embodiments, Z1 and Z2 are independent substituents or together form a single substituent as follows:

[0083] When Z1 and Z2 are independent substituents: Z1 is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoro-ethoxy)-methyl, isopropoxymethyl , ethylaminocarbonylmethyl, 2,2-dimethoxy-ethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl) -aminocarbonyl] ethyl, tetrahydrofuryl,

[0084] When Z1 is hydrogen, Z2 is selected from the group consisting of methoxycarbonyl and amino carbonyl.

[0085] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

[0086] When Z1 and Z2 together form a single substituent, they form:

[0087] Examples of isoxazolines covered by such embodiments include the following:

H5. Illustrative Combination of Substituents 5

[0088] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[0089] Isoxazoline corresponds in structure to:

[0090] A1 is selected from the group consisting of chlorine and bromine.

[0091] A3 is selected from the group consisting of chlorine and bromine.

[0092] X is selected from the group consisting of hydrogen, bromine, iodine, chlorine, methyl, ethyl and trifluoromethyl.

[0093] In some such embodiments, Z1 and Z2 are independent substituents such that: Z1 is selected from the group consisting of hydrogen, methyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, (2,2, 2-trifluoroethoxy)-methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxy-ethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methylamino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2 ,2,2-trifluoroethyl)-aminocarbonyl] ethyl, tetrahydrofuryl,

[0094] When Z1 is hydrogen, Z2 is selected from the group consisting of methoxycarbonyl and aminocarbonyl.

[0095] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

[0096] In other such embodiments, Z1 and Z2 together form:

[0097] Examples of isoxazolines covered by the embodiments include the following:

[0098] Still other examples covered by these embodiments include the following:

H6. Illustrative Combination of Substituents 6

[0099] In some embodiments, the substituents of formula (I) are defined as follows: A1 and A3 are independently selected from the group consisting of chlorine, bromine and trifluoromethyl. A2 is selected from the group consisting of hydrogen, chlorine and fluorine. R is selected from the group consisting of trifluoromethyl and monochloro-difluoro-methyl. X is selected from the group consisting of hydrogen, bromine, iodine, chlorine, methyl and trifluoromethyl. Z3 is O. ZA is selected from the group consisting of bromine, chlorine and cyano.

[00100] In some such embodiments, Z1 and Z2 are independent substituents such that: Z1 is selected from the group consisting of hydrogen, methyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, iso -propoxymethyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2-propynyl-amino carbonylmethyl, N-phenyl-N-methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2- trifluoroethyl)-aminocarbonyl] ethyl, tetrahydrofuryl,

[00101] When Z1 is hydrogen, Z2 is aminocarbonyl.

[00102] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl. When Z1 is hydrogen, Z2 is aminocarbonyl.

[00103] In other such embodiments, Z1 and Z2 together form:

[00104] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to exhibit particularly beneficial in vivo flea inhibition within 24 and 48 hours after infestation. See, for example, Example 3 below.

[00105] Examples of isoxazolines covered by these embodiments include the following:

[00106] Still other examples covered by these embodiments include the following:

H7. Illustrative Combination of Substituents 7

[00107] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00108] Isoxazoline corresponds in structure to:

[00109] X is selected from the group consisting of chlorine and methyl.

[00110] Z1 is selected from the group consisting of N-phenyl-N-methyl- It is

[00111] Z2 is selected from the group consisting of hydrogen, ethylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

[00112] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to exhibit particularly beneficial in vivo flea inhibition within 24 and 48 hours after infestation. See, for example, Example 3 below.

[00113] Examples of isoxazolines covered by these embodiments include the following:

H8. Illustrative Combination of Substituents 8

[00114] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00115] Isoxazoline corresponds in structure to:

[00116] R is selected from the group consisting of trifluoromethyl and monochlorodifluoro-methyl.

[00117] X is selected from the group consisting of iodine and methyl.

[00118] Z1 is selected from the group consisting of hydrogen, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, ethylaminocarbonylmethyl, 2,2-dimethoxyethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N - methyl-amino, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-aminocarbonyl]ethyl, tetrahydrofuryl,

[00119] When Z1 is hydrogen, Z2 is aminocarbonyl.

[00120] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, methylcarbonyl, ethylcarbonyl and methoxycarbonyl.

[00121] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to show particularly beneficial results in vivo with respect to inhibiting fleas within 24 and 48 hours after infestation, and ticks for at least 8 days. See, for example, Examples 3 and 4 below.

[00122] Examples of isoxazolines covered by these embodiments include the following:

H9. Illustrative Combination of Substituents 9

[00123] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00124] Isoxazoline corresponds in structure to:

[00125] X is selected from the group consisting of iodine and methyl.

[00126] Z1 is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)-methyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, (2,2, 2-trifluoroethyl)-aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)-aminocarbonyl]ethyl, tetrahydro-furyl,

[00127] When Z1 is hydrogen, Z2 is aminocarbonyl.

[00128] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen and ethylcarbonyl.

[00129] In accordance with this invention, it has been discovered that isoxazolines of these embodiments also tend to show particularly beneficial results in vivo with respect to both the inhibition of fleas within 24 and 48 hours and ticks for at least 8 days. See, for example, Examples 3 and 4 below.

H10. Illustrative Combination of Substituents 10

[00130] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00131] Isoxazoline corresponds in structure to:

[00132] X is selected from the group consisting of iodine and methyl.

[00133] Z1 is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)-methyl,

[00134] When Z1 is hydrogen, Z2 is aminocarbonyl.

[00135] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, methylcarbonyl and ethylcarbonyl.

[00136] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to show particularly beneficial results in vivo with respect to inhibiting fleas within 24 and 48 hours after infestation and ticks for at least 8 days. See, for example, Examples 3 and 4 below.

[00137] Examples of isoxazolines covered by these embodiments include the following:

H11. Illustrative Combination of Substituents 11

[00138] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00139] Isoxazoline corresponds in structure to:

[00140] Z1 is selected from the group consisting of methoxymethyl, ethoxymethyl and tetrahydro furyl.

[00141] Z2 is selected from the group consisting of hydrogen and methoxycarbonyl.

[00142] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to show particularly beneficial results in vivo with respect to inhibiting fleas within 24 and 48 hours after infestation and ticks for at least 8 days. See, for example, Examples 3 and 4 below.

[00143] Examples of isoxazolines covered by these embodiments include the following:

H12. Illustrative Combination of Substituents 12

[00144] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00145] Isoxazoline corresponds in structure to:

[00146] Zl is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-tri-fluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[00147] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to show particularly beneficial results in vivo with respect to the inhibition of fleas within 1, 24 and 48 hours after infestation and of ticks for at least 8 days . See, for example, Examples 3 and 4 below.

[00148] Examples of isoxazolines covered by these embodiments include the following:

[00149] Other isoxazolines encompassed by these embodiments include the following:

[00150] The chemical name for this isoxazoline is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxy- imino)-methyl]-2-methylbenzamide. This can be found in, for example, CAS RN [92878976-8].

[00151] Still other isoxazolines encompassed by these embodiments include the following:

[00152] The chemical name for this isoxazoline is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2, 2,2-trifluoroethylcarbamoyl)-methyl]-benzamide.

[00153] This can be found, for example, in CAS RN [864731-61-3]. In accordance with this invention, Compound 11-1 has been found to exhibit particularly beneficial results in vivo with respect to the duration of flea inhibition using one of several routes of administration, including topical, oral or subcutaneous. See, for example, Example 5 below.

H13. Illustrative Combination of Substituents 13

[00154] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00155] Isoxazoline corresponds in structure to Formula (I):

[00156] R is selected from the group consisting of monochloromethyl and trifluoromethyl.

[00157] X is selected from the group consisting of iodine and methyl.

[00158] Z1 is selected from the group consisting of hydrogen, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)-methyl, isopropoxy-methyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl) - amino carbonylmethyl, tetrahydrofuryl,

[00159] When Z1 is hydrogen, Z2 is aminocarbonyl.

[00160] When Z1 is other than hydrogen, Z2 is selected from the group consisting of hydrogen, methylcarbonyl, ethylcarbonyl and methoxycarbonyl, except that:

H14. Illustrative Combination of Substituents 14

[00161] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00162] Isoxazoline corresponds in structure to:

[00163] Z1 is selected from the group consisting of methoxymethyl, ethoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[00164] Z2 is selected from the group consisting of hydrogen and methoxycarbonyl.

H15. Illustrative Combination of Substituents 15

[00165] In some embodiments, the isoxazoline of formula (I) is defined as follows:

[00166] Isoxazoline corresponds in structure to:

[00167] Z1 is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)-aminocarbonylmethyl, tetrahydrofuryl,

[00168] In accordance with this invention, it has been discovered that the isoxazolines of these embodiments tend to show particularly beneficial results in vivo with regard to flea inhibition within 1, 24 and 48 hours after infestation. See, for example, Example 3.

[00169] An example of an isoxazoline encompassed by these embodiments include the following:

H16. Illustrative Combination of Substituents 16

[00170] In some embodiments, isoxazoline corresponds in structure to:

[00171] In these embodiments, Z1 and Z2 are independent substituents or together form a single substituent.

[00172] When Z1 and Z2 are independent substituents: Z1 is selected from the group consisting of 1-[(2,2,2-trifluoroethyl)-aminocarbonyl]-ethyl, methylaminocarbonylmethyl, (N,N-di-methylamino) - carbonylmethyl, isopropylaminocarbonylmethyl, cyclopropyl-aminocarbonylmethyl, (2-propenyl)-aminocarbonylmethyl, aminocarbonylcyclopropyl, (2-fluoroethyl)-aminocarbonylmethyl, (2-chloroethyl)-aminocarbonylmethyl, 1-(ethylaminocarbonyl)-ethyl, Z2 is selected from the group consisting of hydrogen, methylcarbonyl and ethylcarbonyl. When Z1 and Z2 together form a single substituent, they form:

[00173] Examples of isoxazolines covered by these embodiments include the following:

H17. Illustrative Combination of Substituents 17

[00174] In some embodiments, isoxazoline corresponds in structure to:

H18. Illustrative Combination of Substituents 18

[00175] In some embodiments, isoxazoline corresponds in structure to:

[00176] Examples of isoxazolines covered by these embodiments include the following compound:

I. Isomers

[00177] The isoxazolines used in this invention generally can have two or more conformational structures. At a minimum, for example, all isoxazolines 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 “left-handed”) configuration. Such isoxazolines include those having the following structure:

[00178] In some such embodiments, for example, isoxazolines correspond in structure to:

[00179] An example of such a compound is:

[00180] In other embodiments, the chiral carbon has a left-handed (or “R” or “straight”) configuration. Such isoxazolines include those that correspond to the following structure:

[00181] An example of such a compound is:

[00182] Isoxazolines may additionally have other conformational isomers, such as, for example, substituents with a cis or trans double bond.

[00183] A specific isomer can often be isolated from the corresponding racemic mixture (or a salt thereof) using, for example, chiral high-performance liquid chromatography (HPLC) techniques. One such technique is illustrated in Example 7 below for isolating the R and S enantiomers of racemic Compound 11-1. In some examples, when an isomer is difficult to separate, a more easily isolatable derivative of the isomer is isolated from the mixture of the corresponding racemic derivative (or a salt thereof) and then converted to the isomer. Alternatively, a specific isomer can often be synthesized directly from, for example, an optically pure starting material.

[00184] In some embodiments, the ratio of one enantiomer (e.g., Compound 17-1) to another enantiomer (e.g., Compound 11-1R) in the pharmaceutical composition used with this invention is greater than 1:1 . In some examples, for example, the ratio is greater than about 70:30, greater than about 85:15, greater than about 90:10, greater than about 95:5, greater than about of 98:2, or greater than about 99:1.

[00185] In some embodiments, the concentration of an enantiomer (e.g., Compound 17-1) in the composition (or, more typically, a precursor composition) is greater than about 50% (by weight). In some such embodiments, for example, the concentration is greater than about 70% (by weight), greater than about 85% (by weight), greater than about 90% (by weight), greater than about 95% (by weight), greater than about 98% (by weight), greater than about 99% (by weight), or greater than about 99.5% (by weight).

[00186] Unless otherwise stated, an isoxazoline structure that does not indicate a particular configuration is intended to encompass compositions all possible conformational isomers of the isoxazoline, as well as compositions comprising fewer than all (e.g., only one of the ) possible conformational isomers.

J. Salts of isoxazolines

[00187] As indicated above, many isoxazolines used with this invention can be in the form of a salt. A salt may be advantageous due to one or more of the physical properties, such as pharmaceutical stability at different temperature and humidity and; crystalline properties; and/or a desirable solubility in water, oil, or other solvents. Acid and base salts can typically be formed, for example, by mixing a compound with an acid or base, respectively, using various methods known in the art. In general, when the salt is intended to be administered in vivo (i.e., to an animal) for a therapeutic benefit, the salt is preferably pharmaceutically acceptable.

[00188] In some examples, a base addition salt of an isoxazoline of formula (I) can be prepared by reacting the isoxazoline with an approximately stoichiometric amount of an inorganic or organic base, typically a strong inorganic or organic base. Examples of base addition salts may include, for example, metallic salts and organic salts. Metal salts, in particular, include alkali metal salts (group Ia, e.g., lithium, sodium, or potassium), alkaline earth metal salts (group IIa, e.g., barium, calcium, and magnesium), heavy metal salts (for example, zinc and iron) and other metallic salts acceptable from a physiological point of view. Such salts can be made from calcium, lithium, magnesium, potassium, sodium and zinc. For example, a free acid isoxazoline can be mixed with sodium hydroxide to form such a base addition salt.

[00189] In some examples, an acid addition salt of an isoxazoline of formula (I) can be prepared by reacting the isoxazoline with an approximately stoichiometric amount of an inorganic or organic acid. Examples of inorganic acids considered to make pharmaceutically acceptable salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Examples of organic acids frequently suitable for making pharmaceutically acceptable salts in general include, for example, the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids. Specific examples of organic acids include cholic, sorbic, lauric, acetic, trifluoroacetic, formic, propionic, succinic, glycolic, gluconic, digluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic acid, glutamic, aryl carboxylic acid (e.g., benzoic), anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) acids, alkylsulfonic (e.g., ethanesulfonic), arylsulfonic (e.g., benzenesulfonic ), pantothenic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, (3-hydroxybutyric, galacturonic, galacturonic, adipic, alginic, butyric, camphoric, camphorsulfonic, cyclopentane-propionic, dodecylsulfic, glycoheptanoic, glycerophosphoric, heptanoic, hexanoic, nicotinic, 2 -naphthalosulfonic, oxalic, palmoic, pectinic, 3-phenylpropionic, picric, pivalic, thiocyanic, tosylic and undecanoic.

[00190] In some examples, an organic salt of an isoxazoline of formula (I) can be made, for example, by quaternizing a basic nitrogen-containing group on the isoxazoline with an agent such as a C1C6 alkyl halide (e.g., chlorides, bromides, or methyl, ethyl, propyl, and butyl iodide), dialkyl sulfate (e.g., dimethyl, diethyl, dibutyl, or diamyl sulfate), long-chain halide (e.g., chlorides, bromides, and decyl, lauryl, myristyl iodide and stearyl), arylalkyl halide (e.g. benzyl and phenethyl bromide) and others.

[00191] It should be understood that the counterion of an acidic or basic salt may, in some examples, be optically active (e.g., D-lactate and L-lysine salts) or racemic (e.g., DL- tartrate and DL-arginine).

K. Isoxazoline solvates

[00192] In some examples, the isoxazolines of formula (I) are in the form of stable complexes with solvent molecules that remain intact after the uncomplexed solvent molecules are removed from the compounds. These complexes are generally referred to as “solvates.” In some examples, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. A “solvate” encompasses both solution-phase and isolatable solvates. Examples of suitable solvates include ethanolates, methanolates and the like. A “hydrate” is a solvate in which the solvent molecule is water. A solvate intended for use in vivo is preferably pharmaceutically acceptable.

L. Isoxazoline prodrugs

[00193] It is considered that the isoxazoline prodrugs of formula (I) can be used with the methods of this invention. As used in this patent, the term “prodrug” is a compound that can undergo conversion in use (e.g., in vivo) through metabolic means or other processes (e.g., hydrolysis) to an isoxazoline of the formula ( I). In some embodiments, releasing the isoxazoline in a prodrug form achieves enhanced release of the isoxazoline by improving its physicochemical or pharmacokinetic properties, for example, by enhancing systemic absorption, delaying release, or delaying the derangement in vivo.

II. Preparation of the isoxazolines of formula (I)

[00194] Methods for preparing isoxazolines are known in the art. Methods for preparing the various isoxazolines of formula (I), for example, have been disclosed in U.S. Patent Published No. US2007/0066617 (incorporated herein by reference in its patent). International Patent Publication No. WO2007/026965 (incorporated by reference in this patent) and Japanese Patent Application Published No. JP2007/308471 (incorporated by reference in this patent). For example, U.S. Patent Published No. US2007/0066617 discloses the preparation of Compound 11-1 in Example 21 on page 72, the preparation of Compound 5-19 in Example 28 on pages 74 and 75, the preparation of Compound 5-61 in Example 30 on pages 76 and 77 and the preparation of Compound 5-64 in Example 34 on pages 77 and 78; International Patent Publication No. WO2007/026965 discloses the preparation of Compound 5-16 in Example 21 on page 317, the preparation of Compound 5-25 in Example 22 on page 317 and 318, the preparation of Compound 5-49 in Example 12 on page 312, the preparation of Compound 5-60 in Example 11 on page 311-312 and the preparation of Compound 10-1 in Example 32 on page 321-322; and Japanese Patent Application Published No JP2007/308471 discloses the preparation of Compound 5-45 in Example 38 on page 381. Furthermore, methods for preparing the various isoxazolines are also disclosed, for example, in International Patent Publication No WO 2005 /085216 (incorporated by reference in this patent), International Patent Application No PCT/JP/2008/054096 (incorporated by reference in this patent), Published European Patent Application No EP1932836 (incorporated by reference in this patent) and Published Japanese Patent Application . In JP2008/133242 (incorporated by reference in this patent). Other isoxazolines of formula (I) can be prepared using, for example, the methods illustrated in these references, alone or in combination with other practices known in the art.

III. Treatment methods using a composition of this invention

[00195] The isoxazolines of formula (I) in general can be used to control ectoparasites in animals, and, instead, diseases directly caused by such ectoparasites and/or diseases caused by pathogens carried by such ectoparasites. It is considered that the composition can be used to treat a range of animals, especially warm-blooded animals. Such warm-blooded animals include, for example, mammals. Mammals include, for example, humans. Other mammals include, for example, farm or farmed mammals (e.g. pigs, cattle, sheep, goats, etc.), laboratory mammals (e.g. mice, rats, gerbils, etc.), pet mammals (e.g. e.g., dogs, cats, equines, etc.), fur-bearing animals (e.g., mink, foxes, chinchillas, rabbits, etc.), and wild and zoo mammals (e.g., buffalo, deer, etc.). In some embodiments, the compositions are used to treat canines (e.g., dogs, such as, e.g., purebred and/or mixed-blood pet dogs, show dogs, working dogs, herd dogs, hunting dogs , guard dogs, police dogs, racing dogs, and/or laboratory dogs). In other embodiments, the compositions are used to treat felines (e.g., domestic cats). It is considered that the compositions are also suitable for treating non-mammals, such as birds (e.g., turkeys, chickens, geese, ducks, parrots, etc.). It is also considered that such compositions may be useful for treating cold-blooded animals as well, such as, for example, fish (e.g., salmon, trout, carp, etc.).

[00196] In accordance with this invention, it has been discovered that the isoxazolines of formula (I) are in general of particular value for controlling ectoparasites, that is, anthropoids that are harmful, or disseminate or act as vectors of diseases in warm-blooded animals. . Isoxazolines are generally beneficial for controlling various stages of the parasite life cycle, including egg, nymph, larval, juvenile, and adult stages. Ectoparasites (generally insects and mite pests) include the following.

[00197] A. Stinging insects. These include, for example, migratory dry larvae, such as, for example, Hypoderma sp. in cattle, Gastrophilus in horses and Cuterebra sp. In rodents; biting flies, such as, for example, adult blood-sucking flies (e.g. horn flies (Haematobia irritans), horseflies (Tabanus spp.), stable flies (Stomoxis calcitrans), black flies (Simulium spp.), deer flies (Chrysops spp.), louse flies (Melophagus ovinus), tse-tse flies (Glossina spp.)); parasitic fly larvae, such as, for example, botflies (Oestrus ovis and Cuterebra spp.), house flies (Phaenicia spp.), blowfly larvae (Cochliomyia hominivorax), cattle larvae (Hypoderma spp.) and blowflies; and mosquitoes, such as, for example, Culex spp., Anopheles spp. and Aedes spp.

B. Mites. These include:

[00198] i. Mesostigmata spp., such as mites, which include chicken mites (Dermanyssus gallinae).

[00199] ii. Astigmata spp., such as itch or scabies mites, which include Sarcoptidae spp. (e.g. Sarcoptes scabiei); and scabies mites, which include Psoroptidae spp. (e.g. Chorioptes bovis and Psoroptes ovis).

[00200] iii. Prostigmata spp, such as mites, which include Trombiculidae spp. (e.g. North American mites, Trombicula alfreddugesi).

iv. Demodex.

[00201] C. Ticks. These include, for example, soft-bodied ticks such as Argasidae spp. (e.g. Argas spp. and Ornithodoros spp.); and hard-bodied ticks, such as Ixodidae spp. (e.g. Ixodes ricinus, Rhipicephalus sanguineus, Haemaphysalis spp, Dermacentor reticulates, Dermacentor variabilis, Amblyomma americanum and Boophilus spp.).

[00202] D. Lice. These include, for example, chewing lice such as Menopon spp. and Bovicola spp.; and sucking lice, such as Haematopinus spp., Linognathus spp. and Solenopotes spp.

[00203] E. Fleas. These include, for example, Ctenocephalides spp., such as dog fleas (Ctenocephalides canis) and cat fleas (Ctenocephalides felis); Xenopsilla spp., such as eastern rat fleas (Xenopsilla cheopis); Pulex spp., such as human fleas (Pulex irritans); porcupine fleas (Archaeopsilla erinacei); and bird fleas (Ceratophillus gallinae).

[00204] F. True Bugs. These include, for example, Cimicidae or the common mattress bugs (Cimex lectularius); and Triatominae spp., such as triatomid bugs (also known as kissing bugs) (e.g., Rhodnius prolixus and Triatoma spp.).

[00205] An “infestation” refers to the presence of parasites in numbers that present a risk of nuisance or harm to humans or animals. The presence can be in the environment (for example, in the forage that the animal sleeps on), in the hide or skin of an animal, etc. Unless otherwise stated, when the infestation is within an animal (e.g., in the blood or other internal tissue), the term infestation is intended to be synonymous with the term, “infection,” whereas this term is generally understood in technique.

[00206] The term “ectoparasite infestation control” means to reduce or eradicate the numbers of parasites in and/or the animal, and/or to partially or completely inhibit the development of parasite infestation in and/or the animal. This can be achieved, for example, by killing, repelling, expelling, incapacitating, preventing, eliminating, relieving, or minimizing the parasite. Ectoparasite control can be insecticide and/or acaricide. The effect of isoxazoline may be, for example, ovicide, larvicide, nymphicide, adulticide, or a combination of these. Furthermore, the effect can manifest itself directly by killing the parasites immediately or after some time has passed (for example, when fusion occurs by destroying the eggs). The effect may alternatively (or additionally) manifest itself indirectly, for example, by reducing the number of eggs laid and/or the hatching rate.

[00207] In general, an amount of an isoxazoline that is sufficient to “control” or be “effective” against a target parasite is an amount that is sufficient to reduce or eradicate multiple parasites in and/or the animal, and/or inhibit partially or completely the development of parasite infestation in and/or in the animal. When isoxazoline is administered systemically, an effective amount generally constitutes an amount that results in tissue and/or blood concentrations that are generally toxic when ingested by a target parasite.

[00208] One of ordinary skill in the art can typically determine an "effective" dose, for example, by observing or detecting changes in a host animal's clinical condition or behavior, as well as by observing or detecting the relative changes in parasite numbers after such treatment. In general, a dose is considered effective for controlling a target parasite when the dose is sufficient to cause an existing or potential target parasite to be counted as reduced by at least about 5%. In some such examples, for example, the dose is considered effective when the dose is sufficient to cause an existing or potential parasite to be counted as reduced by at least about 10% (or at least about 30%, at least about 50%). , at least about 60%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%).

[00209] The optimal dosage in general depends on multiple factors, including, for example, the particular isoxazoline; the identity of any other active ingredient being administered to the recipient animal; the route of administration; the type and severity of the target condition and pathogen; o (e.g. species and gender), age, size, sex, diet, activity and condition of the intended recipient animal; and pharmacological considerations, such as the activity, efficacy, pharmacokinetic and toxicological profiles of the isoxazoline and other active ingredient(s) being administered to the recipient animal. To the extent that multiple active ingredients are administered for a combined effect on a target parasite or condition, the amount of each ingredient that constitutes an “effective amount” is an amount that, when combined with the other active ingredients, causes the effect wanted.

[00210] The isoxazolines of formula (I) can be administered multiple times for a single treatment. Such multiple dosage treatments are considered to include multiple doses per day for one or more days, daily doses for multiple days, and/or doses administered two or more days alone. In some embodiments of this invention, however, a single dose is administered to effectively control a target parasite for a longer duration, such as, for example, at least about a week. In some such embodiments, for example, the single dose is effective to control a target parasite for at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about at least about 3 months, at least about 4 months, or at least about 6 months. Therefore, in some embodiments, the frequency of treatments may be, for example, weekly, bi-weekly, monthly, bi-monthly, quarterly, semi-annual, or even longer (e.g., annually). The durations over which the isoxazolines of formula (I) tend to be effective against various ectoparasites through systemic administration are surprising. This is particularly true given that such long activities, in many instances, can be obtained using low doses that are non-toxic to animal receptors without requiring the use of a controlled release medium. Without being limited to any particular theory, it is hypothesized that this long-lasting activity supports isoxazolines having particularly high toxicity when ingested by the target parasite.

[00211] For many animal recipients, the dose and formulation of isoxazoline are chosen to maintain a serum level of isoxazoline of at least about 1 ng/ml (e.g., 1 to 50 ng/ml). In general, the amount of isoxazoline administered to the recipient animal is from about 0.001 to about 200 mg/kg of body weight. In some embodiments, for example, from about 0.01 to about 200 mg/kg of body weight is administered. In other embodiments, for example, from about 0.001 to about 100 mg/kg body weight is administered. In some such embodiments, for example, from about 0.01 to about 100 mg/kg of body weight is administered. In other such embodiments, from about 1 to about 30 mg/kg of body weight is administered. Larger doses tend to provide a longer duration of activity.

[00212] It is considered that the duration of activity of an isoxazoline can be extended even (or made more consistent) using a controlled-release formulation or dosage form. For example, isoxazoline can be administered in microspheres, granules or implants (e.g., a subcutaneous implant) that release the isoxazoline, for example, through diffusion and/or erosion. The use of such a dosage form containing from about 1 to about 50 mg/kg body weight (or from about 10 to about 30 mg/kg body weight, such as about 20 mg/kg body weight body) of isoxazoline may allow consistent activity lasting for several months or more (e.g., a year).

[00213] In some embodiments of this invention, an isoxazoline of formula (I) is administered to treat parasites of an animal (or manufacture a medicament for treating parasites of an animal). The term “parasitic diseases” includes pathological conditions and diseases associated with or caused by one or more ectoparasites directly, such as, for example, anemia and flea allergy dermatitis. It also includes pathological conditions or diseases associated with or caused by one or more vector-borne pathogens, such as, for example, Lyme disease, ehrlichiosis (particularly canine ehrlichiosis), and Rocky Mountain spotted fever from tick vectors. The term “parasite treatment” means to partially or completely inhibit the development of parasites in an animal susceptible to parasites, to reduce or completely eliminate the symptoms of parasites in an animal having parasites, and/or to partially or completely cure the parasites. parasites of an animal having the parasites. In general, the treatment of parasites is obtained by administering an isoxazoline of formula (I) to control an ectoinfestation of parasites.

[00214] This invention also relates to treatment methods in which at least one ancillary goal of controlling in and/or the animal is to control an ectoparasitic infestation in an environment that is occupied (periodically or continuously) by the animal. In some such embodiments, for example, the animal is a pet (e.g., a cat or dog). The environment can be, for example, a house or other shelter; a bedroom; a chicken coop, stable, or other means of confinement; resting place; etc.

[00215] The terms “administer” and “administration” refer to the release of an isoxazoline of formula (I), isoxazoline salt, isoxazoline solvate or salt, or isoxazoline prodrug. In some embodiments of this invention, systemic administration is desirable. “Systemic administration” is administration at a location remote from a location in which at least a portion of the parasitic targets reside. With systemic administration, at least a portion of the isoxazoline reaches the target parasite through the recipient animal's bloodstream, other body fluids (lymph fluids), and/or tissues (e.g., skin or adipose tissue). Typically, the parasite ingests the isoxazoline along with the recipient animal's blood, other body fluids, and/or tissues. Systemic administration can be achieved in several ways.

[00216] In some embodiments, the isoxazoline composition is systemically administered via an oral route in a single dosage form, such as, for example, a hard or soft capsule, a pill, a powder, granules, a tablet (e.g., a chewable tablet), a paste, a solution, a suspension (aqueous or non-aqueous), an emulsion (oil-in-water or water-in-oil), an elixir, a syrup, a bolus , a dose, or through the food or drinking water of the recipient animal. When the composition is administered through the animal's diet, the animal may, for example, be fed as a discrete feed or as a chewable treat. Alternatively (or additionally), this may, for example, be intimately dispersed into the recipient animal's regular feed, used as a topping, or in the form of pellets or liquid which is added to the finished feed. When the composition is administered as a food additive, it may be convenient to prepare a “premix” in which the composition is dispersed in a liquid or solid carrier. This “premix” is, in turn, dispersed into the animal's feed using, for example, a conventional mixer. When the composition is administered in the recipient animal's drinking water or as a liquid medicine, it may be convenient to use a solution or suspension formulation. This formulation may be, for example, a concentrated suspension that is mixed with water or a dry preparation that is mixed and suspended in water. In both examples, it is preferable to have the isoxazoline in a finely powdered form.

[00217] The isoxazoline composition alternatively (or additionally) can be systemically administered topically using a transdermal formulation (i.e., a formulation that passes through the skin). Alternatively (or additionally), the composition can be systemically administered topically through the mucosa. Typical formulations for transdermal and mucosal administration include, for example, pour-ons, spot-ons, dips, aerosols, mousses, shampoos, powders, gels, hydrogels, lotions, solutions, creams, ointments, sprays, plasters, foams, films, skin patches, limb bandages, necklaces, ear tags, dumplings, sponges, fibers, bandages and microemulsions. The “pour-on” or “spot-on” methods, for example, comprise applying the isoxazoline composition to a specific location on the hide or skin, such as the animal's neck or nape. This can be achieved, for example, by applying a cotton swab or drop of pour-on or spot-on formulation to a relatively small area of the recipient animal's hide or skin (i.e., generally no more than about 10% of the recipient animal's hide or skin). In some embodiments, the isoxazoline is dispersed from the site of application to broad areas of the skin due to the diffusive nature of the components in the formulation and the movements of the animal while, in parallel, being absorbed through the skin and distributed through fluids. and/or tissues of the recipient animal.

[00218] The isoxazoline composition alternatively (or additionally) can be systemically administered parenterally, such as via intramuscular injection, intravenous injection, subcutaneous injection, implant (e.g., subcutaneous implant), infusion, bolus, etc. In some such embodiments, the dosage form provides the recipient animal with about 0.01 to about 200 mg/kg body weight of the isoxazoline.

[00219] Other considered forms of administration include, for example, rectally, vaginally and through inhalation (for example, through a mist or aerosol).

IV. Pharmaceutical compositions

[00220] This invention is also directed to pharmaceutical compositions (or medicines) comprising an isoxazoline of formula (I), isoxazoline salt, isoxazoline solvate or salt, or isoxazoline prodrug. The compositions may also comprise (and generally will comprise) one or more pharmaceutically acceptable excipients.

[00221] The pharmaceutical compositions of the present invention can be manufactured, for example, through processes known in the art. These processes include, for example, a variety of known mixing, dissolving, granulating, emulsifying, encapsulating, entrapping and freeze-drying processes. The optimal formulation depends, for example, on the route of administration.

[00222] Solid dosage forms, for example, can be prepared, for example, by intimately and uniformly mixing isoxazoline with fillers, binders, lubricants, glidants, disintegrants, flavoring agents (e.g., sweeteners) , buffers, preservatives, pharmaceutical grade dyes or pigments, and controlled release agents.

[00223] Oral dosage forms other than solids can be prepared by mixing isoxazoline with, for example, one or more solvents, viscosity enhancing agents, surfactants, preservatives, stabilizers, resins, fillers, binders, lubricants, glidants , disintegrants, co-solvents, sweeteners, flavors, perfume agents, buffers, suspending agents and pharmaceutical grade dyes or pigments.

[00224] The binders considered include, for example, gelatin, acacia and carboxymethylcellulose.

[00225] Lubricants considered include, for example, magnesium stearate, stearic acid and talc.

[00226] Disintegrants considered include, for example, corn starch, alginic acid, sodium carboxymethyl cellulose and croscarmellose sodium.

[00227] Buffers considered include, for example, sodium citrate and magnesium and calcium carbonate and bicarbonate.

[00228] Solvents considered include, for example, water, petroleum, animal oils, vegetable oils, mineral oils and synthetic oil. Physiological saline solutions or glycols (e.g., ethylene glycol, propylene glycol, or polyethylene glycol) may also be included. The solvent preferably has chemical properties and amounts sufficient to keep the isoxazoline solubilized at temperatures at which the composition is stored and used.

[00229] Viscosity enhancing agents considered include, for example, polyethylene, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, tragacanth, methylcellulose, carbomer, xanthan gum , guar gum, povidone, sodium carboxymethyl cellulose, magnesium aluminum silicate, carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, laponite, water-soluble salts, cellulose ethers, natural gums, colloidal magnesium, aluminum silicate or finely divided silica, homopolymers of acrylic acid crosslinked with an alkyl ether of pentaerythritol or an alkyl ether of sucrose and carbomers.

[00230] The surfactants considered include, for example, fatty acid polyoxyethiene sorbitan esters; monoalkyl polyoxyethylene ether; sucrose monoesters; lanolin esters and ethers; alkyl sulfate salts; and sodium, potassium and ammonium salts of fatty acids.

[00231] Preservatives considered include, for example, phenol, alkyl esters of parahydroxybenzoic acid (e.g., methyl p-hydroxybenzoate (or “methylparaben”) and propyl p-hydroxybenzoate (or “propylparaben”)), sorbic acid, o-phenylenol benzoic acid and its salts, chlorobutanol, benzyl alcohol, thimerosal, phenylmercury acetate and nitrate, nitromersol, benzalkonium chloride and cetylpyridinium chloride.

[00232] The stabilizers considered include, for example, chelating agents and antioxidants.

[00233] Solid dosage forms may also comprise, for example, one or more excipients to control the release of isoxazoline. For example, it is considered that isoxazoline can be dispersed, for example, in hydroxypropylmethylcellulose. Some oral dosage forms (e.g., tablets and pills) can also be prepared with enteric coatings.

[00234] Topical administration can be achieved using, for example, a solution, suspension (aqueous or non-aqueous), emulsion (water-in-oil or oil-in-water), or concentrated microemulsion comprising a dissolved isoxazoline, placed in suspension, or equalized in a pharmaceutically acceptable liquid vehicle. In such embodiments, a crystallization inhibitor may generally be optionally present.

[00235] When a liquid formulation is used topically on the skin, it can be administered, for example, by pouring, diffusing, rubbing, atomizing, spraying, dipping, bathing or washing yourself. A “pour-on” or “spot-on” type formulation, for example, can be poured or atomized onto a limited location on the skin (typically no more than about 10% of the skin). In some such embodiments, the formulation allows or facilitates the isoxazoline to penetrate the skin and act on other parts of the body (e.g., the entire body). Such a “pour-on” or “spot-on” formulation can be prepared by dissolving, suspending, or emulsifying isoxazoline in a skin-friendly solvent or solvent mixture. Other excipients may be included, as well as, for example, a surfactant, dye, antioxidant, stabilizer, adhesive, etc. Solvents considered include, for example, water, alkanol, glycol, polyethylene glycol, polypropylene glycol, glycerin, benzyl alcohol, phenylethanol, phenoxyethanol, ethyl acetate, butyl acetate, benzyl benzoate, dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oil, DMF, liquid paraffin, silicone, dimethylacetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.

[00236] In some embodiments, a topical formulation (particularly a “pour-on” or “spot-on” type formulation) comprises a carrier that promotes the absorption or penetration of isoxazoline through the bloodstream, other bodily fluids. (lymph), and/or body tissue (adipose tissue). Considered examples of dermal penetration enhancers include, for example, dimethyl sulfoxide, isopropyl myristate, dipropylene glycol pelargonate, silicone oil, aliphatic esters, triglyceride and fatty alcohols.

[00237] Topical formulations may also (or alternatively) comprise, for example, one or more dispersing agents. These substances act as carriers that help distribute an active ingredient over the skin or leather of the recipient animal. These may include, for example, isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, and/or fatty alcohols. Various dispersion oil/solvent combinations may also be suitable, such as, for example, oily solutions, alcoholic and isopropanolic solutions (e.g. 2-octyl dodecanol or oleyl alcohol solutions), monocarboxylic acid ester solutions (e.g. , isopropyl myristate, isopropyl palmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate and caproic acid esters of saturated fatty alcohols having a chain of 12 to 18 carbons), solutions of esters of dicarboxylic acids (e.g., dibutyl phthalate, diisopropyl isophthalate, diisopropyl ester of adipic acid and di-n-butyl adipate), or solutions of esters of aliphatic acids (e.g. glycols). When the formulation comprises a diffusing agent, it may also be advantageous to include a dispersant, such as, for example, pyrrolidin-2-one, N-alkylpyrrolidin-2-one, acetone, polyethylene glycol or an ether or ester thereof, propylene glycol, or synthetic triglycerides.

[00238] When formulated in, for example, an ointment, it is considered that isoxazoline can be mixed with, for example, a paraffinic or water-miscible ointment base. When formulated into a cream, it is considered that isoxazoline can be formulated with, for example, a creamy oil-in-water base. In some examples, the aqueous phase of the cream base includes, for example, at least about 30% (w/w) of a polyhydric alcohol, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, or a mixture of these.

[00239] Injectable preparations can be formulated according to, for example, the known technique using suitable solvents, solubilizing agents, protecting agents, dispersing agents, wetting agents, and/or suspending agents. Carrier materials considered include, for example, water, ethanol, butanol, benzyl alcohol, glycerin, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides). , vegetable oil (e.g., corn oil), dextrose, mannitol, fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and nonionic detergents), N-methylpyrrolidone, propylene glycol, and/or or polyethylene glycols (e.g. PEG 400). The solubilizing agents considered include, for example, polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan ester and others. Protective agents considered include, for example, benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol and others.

[00240] In some embodiments, a parenteral formulation is, for example, prepared from sterile powders or granules having one or more of the carrier materials disclosed above for other formulations. Isoxazoline is, for example, dissolved or suspended in a liquid comprising water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or multiple tampons. The pH can generally be adjusted if necessary with a suitable acid base or buffer.

[00241] For rectal administration, a suppository can be used. Suppositories can be prepared, for example, by mixing an isoxazoline with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperatures and will therefore melt in the rectum to release the medicine. Excipients considered include, for example, cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols.

[00242] Other inert ingredients can generally be added to the composition as desired. To illustrate, it is considered that these may include, for example, lactose, mannitol, sorbitol, calcium carbonate, sodium carbonate, tribasic calcium phosphate, dibasic calcium phosphate, sodium phosphate, kaolin, compressible sugar, starch, sodium sulfate. calcium, dextro or microcrystalline cellulose, colloidal silicon dioxide, starch, sodium starch glycolate, crospovidone, microcrystalline cellulose, tragacanth, hydroxypropylcellulose, pregelatinized starch, povidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose.

[00243] A general argument regarding the formulation of medications and various excipients can be found, for example, in Gennaro, A.R., et al., eds., Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins, 20th Ed ., 2000). Another argument regarding the formulation of drugs and various excipients can be found, for example, in Liberman, H. a., et al., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.I., 1980).

[00244] The concentration of the isoxazoline of formula (I) (or any isoxazoline salt, isoxazoline solvate or salt, or isoxazoline prodrug) in the composition can vary widely depending, for example, on the mode of administration. In general, the concentration is from about 1 to about 70% (by weight). In some such embodiments, for example, the concentration is from about 1 to about 50% (by weight), or from about 10 to about 50% (by weight). In other embodiments, the concentration is from about 35 to about 65% (by weight), from about 40 to about 60% (by weight), from about 45 to about 55% (by weight) , or about 50% (by weight).

V. Examples of the combination therapies considered

[00245] The methods of this invention encompass methods in which an isoxazoline is the sole active ingredient administered to the recipient animal. Nevertheless, it is considered that the methods also cover combination therapies in which an isoxazoline is administered in combination with one or more other active ingredients. The other active ingredients may be, for example, one or more other isoxazolines. Alternatively (or additionally), the other active ingredients may be one or more compounds that are not isoxazolines. The other active ingredients may target the same and/or different pathogens and conditions.

[00246] Active ingredients considered that can be administered in combination with isoxazoline include, for example, anthelmintics, insecticides and acaricides, insect growth regulators and juvenile hormone analogues, anti-inflammatories, anti-infection agents, hormones, preparations dermatological (e.g., antiseptics and disinfectants) and immunobiological (e.g., vaccines and antisera) for disease prevention.

[00247] Anthelmintics include, for example, avermectins (e.g. ivermectin, moxidectin and milbemycin), benzimidazoles (e.g. fenbendazole, albendazole and triclabendazole), salicylanilides (e.g. closantel and oxyclozanide), substituted phenols (e.g. nitroxynyl), pyrimidines (e.g. pyrantel), imidazothiazoles (e.g. Levamisole), cyclooctadepsipeptide (e.g. Emodepside) and tetrahydropyrimidines (e.g. praziquantel). Anthelmintics also include, for example, amino acetonitrile derivatives, such as, for example, those disclosed in Kaminsky, R., et al., “A new class of anthelmintics effective against drug-resistant nematodes,” Nature, vol. 452, pp. 176-180 (March 13, 2008); and International Patent Publication Nos. WO2006/050887 and WO2005/044784.

[00248] In some embodiments, isoxazoline is administered in combination with (and, in some examples, in the same composition with) one or more endectocidal lactone macrocyclic parasiticides. These parasiticides tend to be useful against, for example, a broad spectrum of endoparasites and ectoparasites in mammals.

[00249] A particularly considered macrocyclic endectocidal lactone parasiticide is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B1a and less than 20% 22,23-dihydroavermectin B1b. Ivermectin is disclosed in US Patent 4,199,569. Ivermectin has been used as an antiparasitic agent to treat several parasitic diseases since the mid-1980s.

[00250] Other macrocyclic lactone parasiticides include, for example:

[00251] A. Abamectin. This compound is, for example, identified as avermectin B1a/B1b in U.S. Patent 4,310,519. Abamectin contains at least 80% avermectin B1a and no more than 20% avermectin B1b.

[00252] B. Doramectin. This compound is known as 25-cyclohexyl-avermectin B1. Its structure and preparation are disclosed, for example, in US Patent 5,089,480.

[00253] C. Moxidectin. This compound is disclosed, for example, in US Patent. 4,916,154.

[00254] D. Selamectin. This compound is also known as 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22, 23-dihydro-5-(hydroxyimino)-avermectin B1 monosaccharide.

[00255] E. Milbemycin. This compound is also known as B41. This is isolated from the fermentation broth of a strain of Streptomyces that produces Milbemycin. The microorganism, fermentation conditions and isolation procedures are disclosed, for example, in US Patents 3,950,360 and 3,984,564.

[00256] F. Emamectin. This compound is also known as 4”-deoxy-4”-epi-methylaminoavermectin B1. Its preparation is disclosed, for example, in US Patents Nos. 5,288,710 and 5,399,717. This is a mixture of two homologues, 4”-deoxy-4”-epi-methylaminoavermectin B1a and 4”-deoxy-4”-epi-methylaminoavermectin B1b. Emamectin salt is commonly used. Non-limiting examples of such salts are those disclosed in US Patent 5,288,710, which includes salts derived from benzoic acid, substituted benzoic acid, benzenesulfonic acid, citric acid, phosphoric acid, tartaric acid and maleic acid. A particularly considered salt is emamectin benzoate.

[00257] G. Eprinomectin. This compound is known as 4”-epia-acetylamino-4”-deoxyavermectin B1. This has been developed for use across all livestock classes and age groups. It was the first avermectin overall to exhibit a broad spectrum of activity against both endo- and ecto-parasites, whilst also leaving minimal residues in meat and milk. In general, this has the added advantage of being highly potent when released topically.

[00258] Insecticides and acaricides include, for example, acephate, acetamiprid, acetoprol, amitraz, amidoflumet, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, bistrifluron, buprofezin, carbofuran, cartap, chlorfenapyr, chlorfluazuron, chlorantraniliprol) , chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyflumetofen, cyfluthiin, 13- cyfluthrin, cyhalothrin, y-cyhalothrin emamectin, endosulfan, esfenvalerate, etiprol, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucitrinate, tau-fluvalinate, flufenerim, flufenoxuron, fonofos, halo fenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenfos, lufenuron , malathion , meta-flumizone, metaldehyde, methamidophos, metidathion, methomyl, methoprene, methoxychlor, metofluthrin, monocrotophos, methoxyfenozide, monocrotophos, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosfamidori , pirimicarb, profenofos, profluthrin, protrifenbut, pymetrozine, pyrafluprol, pyrethrin, pyridalyl, pyrifluquinazon, piriprol, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbu fos, tetrachlorvinphos, thiacloprid , thiamethoxam, tiodicarb, tiosultap-sodium, tolfenpyrad, tralometrin, triazamate, trichlorphone and triflumuron. General references examining antiparasitic agents such as insecticides and acaricides include, for example, The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, UK (2003).

[00259] In some considered embodiments, isoxazoline is administered with pyridylmethylamine derivatives, such as, for example, pyridylmethylamine derivatives disclosed in European Patent Application EP0539588 or International Patent Application Publication WO2007/115643.

[00260] In some considered embodiments, isoxazoline is administered with noduliesporic acids and derivatives thereof, such as, for example, compounds disclosed in US Patent 5,399,582; 5,945,317; 5,962,499; 5,834,260; 6,221,894; or 5,595,991; or Publication of International Patent Application 1996/29073.

[00261] Insect growth regulators include, for example, agridino, diofenolan, fenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, chlorfluazuron, cyro-mazine, diflubenzuron, fluazuron, flucicloxuron, flufenoxuron, hexaflumuron, ifenuron, tebufenozide and triflumuron. These compounds tend to provide both initial and sustained control of parasites at all stages of insect development, including eggs, in the animal patient, as well as within the animal patient's environment.

[00262] Other antiparasitic compounds considered to be useful in combination therapies with isoxazoline include, for example, the imidazo[1,2-b]pyridazine compounds disclosed in U.S. Patent Application Publication No. 2005-0182059; 1-(4-mono and dihalomethylsulfonylphenyl)-2-acylamino-3-fluoropropanol compounds disclosed in US Patent 7,361,689; oxime trifluoromethanesulfonanilide ether compounds in US Patent 7,312,248; n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and n-[(phenylsulfanyl)-phenyl]-1,1,1-trifluoromethanesulfonamide compounds disclosed in U.S. Patent Application Publication 2006-0281695; and 2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile compounds disclosed in US Application Publication 2006/0128779.

[00263] Anti-inflammatory agents include, for example, corticosteroids, which in turn include, for example, beclomethasone dipropionate, betamethasone dipropionate, betamethasone valerate, budesonide, ciclesonide, deflazacort, dexamethasone, fluocinolone acetonide, fluticasone , propionate, fluticasone furoate, loteprednol, etabonate, mometasone and mometasone furoate, methylprednisolone, prednisolone, prednisone, rofleponide and triamcinolone acetonide. Anti-inflammatory agents also include, for example, one or more non-steroidal anti-inflammatory drugs (“NSAIDs”). NSAIDs include, for example, salicylates, arylalkanoic acids, 2-arylpropionic acids (or “profens”), N-aryl anthranilic acids, pyrazolidine derivatives, oxicans, COX-2 inhibitors, sulfonanilides and licofelone. Anti-inflammatory ingredients may also include, for example, antihistamines. Antihistamines include, for example, H1 receptor agonists, H2 receptor agonists, H3 receptor agonists, H4 receptor agonists, mast cell stabilizers and vitamin C.

[00264] In the combination therapies considered, isoxazoline of formula (I) can be administered before, simultaneously, and/or after the other active ingredients. Furthermore, isoxazoline can be administered in the same composition as the other active ingredients and/or in a separate composition from the other active ingredient. Furthermore, isoxazoline and the other active ingredients can be administered via the same and/or different routes of administration.

[00265] When isoxazoline is administered in a combination therapy, the weight ratio of the active ingredients can vary widely. Factors influencing this ratio include, for example, the particular isoxazoline; the identity of the other active ingredients to be administered in the combination therapy; the method of administration of isoxazoline and other active ingredients; the target condition and pathogen; the type (e.g., species and gender), age, size, sex, diet, activity, and condition of the intended recipient; and pharmacological considerations, such as the activity, efficacy, pharmacokinetic and toxicological profiles of isoxazoline and other active ingredients. In some considered embodiments, for example, the weight ratio of isoxazoline to the other active ingredients, for example, is from about 1:3000 to about 3000:1. In some such examples, the weight ratio is from about 1:300 to about 300:1. In other such examples, the weight ratio is from about 1:30 to about 30:1.

[00266] In addition to the other active ingredients, it is considered that isoxazoline can be administered with one or more other compounds that beneficially affect (e.g., enhance or prolong) the activity (or other characteristic, such as safety) of isoxazoline. For example, it is considered that isoxazoline can be administered with one or more synergists, such as, for example, piperonyl butoxide (PBO) and triphenyl phosphate (TPP). Other synergists include, for example: N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboxamide (also known as “ENT 8184” or “MGK 264”) and Verbutin (also known as “MB-599”). A discussion related to insecticide synergists can be found, for example, in The Pesticide Manual, 13th Edition, cited above.

SAW. Therapeutic kits

[00267] This invention is also directed to kits that are, for example, suitable for use in carrying out treatment methods described above. In general, such a kit will comprise a therapeutically effective amount of an isoxazoline of formula (I) and an additional component. Additional components may be, for example, one or more of the following: a diagnostic tool, instructions for administering the composition, a device for administering the composition, a container comprising an excipient or other active ingredient to be mixed or administered in combination. with the composition, or a memory aid (e.g., a print to adhere to a calendar to remind an animal owner of the dates of administration of a subsequent dose of the composition).

EXAMPLES

[00268] The following examples are merely illustrative and not limiting the remainder of this disclosure in any way. The compound numbers indicated in these examples refer to the compound numbers for the structures in the above detailed description and claims below.

Example 1. Efficacy of compounds 10-1 and 11-1 against cat fleas (Ctenocephalides felis).

[00269] Adult fleas (20-30) were fed on artificial membranes with blood reinforced with Compound 10-1, Compound 11-1, or a positive control (fipronil) at a concentration of 100, 10, or 1 ppm. Flea efficacy was assessed after 48 hours of continuous feeding by comparing the number of dead and damaged fleas with the number of fed fleas. Flea efficacy was 100% for Compound 10-1, Compound 11-1 and fipronil at 100, 10 and 1 ppm.

Example 2. Model animal studies for Compound 11-1.

[00270] The objective of these studies was to evaluate the effectiveness of Compound 11-1 against various parasites. The parasites were:

X. Effectiveness against fleas on mice

[00271] Mice were divided into groups of three and treated topically with 100 ppm body weight, orally with 10 mg/kg body weight, or subcutaneously with 10 mg/kg body weight of Compound 11-1, fipronil (control positive), or nothing (negative control). These mice were sedated and infested with adult fleas (C. felis) 1, 3, 6 and 24 hours after treatment. Fleas were recovered from the mice after approximately 30 minutes of feeding. Flea inhibition assessment (% of dead and injured fleas) was conducted 1 and 24 hours after each infestation. The results are shown in Table 1. Table 1 Results of the Experiment Evaluation In vivo Efficacy of Compound 11-1 Against Fleas in Mice

[00272] In general, with Compound 11-1, only a few damaged fleas were found relative to dead fleas. With fipronil, however, dead and damaged fleas were generally found in equal quantities. No side effects were observed with Compound 11-1 or fipronil during this experiment.

B. Efficacy against mites in mice

[00273] All mice used in the study have a present mite infestation with M. musculinus consisting of all stages of the parasite with at least a medium infestation rate (“++”). Mice were divided into groups of three and treated topically with 100 ppm body weight, orally with 10 mg/kg body weight, or subcutaneously with 10 mg/kg body weight of Compound 11-1, fipronil (positive control), or nothing (negative control). This treatment was then repeated 7 days later. The mouse infestation rate (“+” = low infestation rate, “++” = medium infestation rate, “+++” = high infestation rate) was assessed repeatedly on days 1, 6, 9, 13 and 23. Efficacy was defined as the inhibition of the rate of mite infestation in the treated mice relative to the negative control group. The results are shown in Table 2. Table 2 Results of the Experiment Evaluation In vivo Efficacy of Compound 11-1 Against Mites in Mice

[00274] No side effects were observed with Compound 11-1 or fipronil during the efficacy study on mites.

C. Effectiveness against soft ticks (argaside) and mattress bugs in guinea pigs

[00275] Six guinea pigs were treated orally, subcutaneously, or intraperitoneally with 10 mg/kg body weight of Compound 11-1 or fipronil (positive control). Guinea pigs were locally co-infested with young soft ticks (O. moubata) and mattress bugs (C. lectularius) once before treatment and at different time points after treatment between days 2 and 50. Then fed ticks/insects were collected to assess the percentage of dead individuals per species 24 hours after each infestation.

[00276] For guinea pigs treated with Compound 11-1, ticks and mattress bugs died within 1 to 5 hours after infestation by day 29 and within 8 to 24 hours after day 29. For fipronil-treated guinea pigs, ticks and mattress bugs died within 1 to 7 hours after infestation by Day 29 and within 8 to 24 hours after Day 29. Tick-free efficacy results are shown in Table 3. Table 3 Results for Assessing the In Vivo Efficacy of the Compound 11-1 Experiment Against Soft Ticks (O. moubata) in Guinea Pigs

[00277] The results of the efficacy against mattress insects are shown in Table 4 Table 4 Results for Evaluating the Efficacy of the In vivo Experiment of Compound 11-1 Against Mattress Bugs (C. lectularius) in Guinea Pigs Efficacy of 70 to 100% was observed by Day 31. and No efficacy was detected by Day 48.

[00278] No side effects were observed with Compound 11-1 or fipronil during this study. Although guinea pigs orally treated with Compound 11-1 (i.e., Animal No. 1) died after Day 31, their deaths had no clinical symptoms and were not considered treatment-related, as this occurred long after the treatment.

D. Effectiveness against hard ticks (ixodida) in Guinea Pigs

[00279] Guinea pigs were divided into groups of three. Each group was subjected to one of the following treatments with Compound 11-1, fipronil (positive control), or none (negative control):

Study 1:

[00280] 100 ppm in body weight of topical administration by immersion of the animal

[00281] 10 mg/kg in body weight for oral administration

[00282] 10 mg/kg in body weight for subcutaneous administration

[00283] No treatment (negative control)

Study 2:

[00284] 25 ppm in body weight of topical administration by immersing the animal

[00285] 2.5 mg/kg in body weight for oral administration

[00286] 2.5 mg/kg in body weight for subcutaneous administration

[00287] No treatment (negative control)

[00288] One day before treatment, all Guinea Pigs were infested with 100 live young hard ticks (brown dog ticks, R. sanguineus). Separated blood-clogged nymphs were counted (eN) from Day 4 to Day 8 to calculate the effectiveness of treatments according to the following formula:

[00289] Furthermore, the collected ticks were evaluated for ecdysis in the next step.

[00290] In the first study, 32 clogged R. sanguineus nymphs were collected from animals in the untreated negative control group. And in the second study, 75 clogged R. sanguineus nymphs were collected from the animals in the untreated negative control group. Ecdysis in the next stage was observed in the negative control groups of both studies. In contrast, no nymphs were collected from any of the Compound 11-1 or fipronil-treated groups in the study. Thus, the inhibition of clogged nymphs for both Compound 11-1 and fipronil was 100%. No side effects were observed with Compound 11-1 or fipronil during the study.

Example 3. Efficacy of various isoxazolines against cat fleas (Ctenocephalides felis) on mice.

[00291] In this experiment, mice were randomly assigned to a treatment group or a negative control (untreated) group. Each group consisted of three mice. Mice in the treatment group were orally administered with 20 mg/kg body weight of various isoxazolines dissolved in 7% DMF premix and 93% purified water (aqua ad injectabilia). The application volume of these treatments was 0.01 ml/g in body weight. One hour after treatment, each mouse was sedated and generally infested (whole body) with 30 live adult fleas (C. felis). To achieve this, sedated mice were placed in an infestation jar and fleas were placed directly on the skin. After approximately 30 minutes of feeding, fleas were recovered from the mice. Assessments regarding inhibition and mortality were carried out 1 hour, 24 hours and 48 hours after each infestation. Efficacy was calculated as the percentage of fleas inhibited in the treatment groups relative to the negative control group.

[00292] Efficacy results are shown in Table 5. All treatments shown in Table 5 were well tolerated by the mice. Table 5 Results for the experimental evaluation of the In vivo Efficacy of various isoxazolines against fleas in Mice Example 4. Efficacy of various isoxazolines against brown dog ticks (Rhipicephalus sanguineus) in Guinea Pigs.

[00293] In this experiment, guinea pigs were randomly assigned to a treatment group or a negative control (untreated) group. Each group consisted of three Guinea Pigs. On day Zero, each guinea pig was infested with 100 live R. sanguineus nymphs. On Day 1, Guinea Pigs in the treatment groups were orally administered with 10 mg/kg body weight of various isoxazolines dissolved in 7% DMF premix and 93% purified water (aqua ad injectabilia). Separated clogged nymphs were counted (eN) from Day 4 to Day 8 to calculate the effectiveness of isoxazolines according to the following formula:

[00294] Furthermore, the collected ticks were evaluated for ecdysis in the next step. Efficacy results are shown in Table 6. No side effects were observed with any of the compounds in Table 6 during the study. Table 6 Results for the Experimental Evaluation of the In vivo Efficacy of Various Isoxazolines against Brown Dog Ticks in Guinea Pigs

Example 5. Efficacy of Compound 11-1 against cat fleas (C. felis) and brown dog ticks (R. sanguineus) in dogs.

[00295] On Day Zero, a group of 4 beagles were treated orally with gelatin capsules containing 20 mg/kg body weight of Compound 11-1. Another group of 4 beagles were treated topically by washing with 2 L of solution containing 200 ppm body weight of Compound 11-1 dissolved in a DMF/tap water premix (1:100, based on volume). . Finally, a group of 3 remaining untreated beagles as the negative control. Two days before treatment on Day Zero, all beagles were each infested with approximately 80 unfed adult fleas (C. felis) and approximately 60 unfed adult ticks (R. sanguineus). Each beagle's parasite load was assessed on Day 2 (approximately 48 hours after treatment) by removing and counting fleas and ticks. Fleas and ticks were classified according to vitality (fleas: dead or alive; ticks: dead or alive and clogged or not clogged). Efficacy was calculated from the average number of live fleas and ticks in the treated groups (Mt) relative to the average number of live fleas and ticks in the untreated control groups (Mc) using the following formula:

[00296] Compound 11-1 showed 100% efficacy against fleas and ticks after oral and topical treatment. No side effects were observed during this study.

Example 6. Another efficacy study of Compound 11-1 against cat fleas (C. felis) and brown dog ticks (R. sanguineus) in dogs.

[00297] The beagles were randomly assigned to 5 treatment groups of 4 animals each and an untreated control group of 3 animals. Dogs in the treatment groups were treated on day zero as shown in Table 7: Table 7 Treatment Groups for Studying the Efficacy of Compound 11-1 Against Cat Fleas (C. felis) and Brown Dog Ticks (R. sanguineus ) in Beagles

[00298] The dogs were infested with approximately 80 fleas (C. felis) and 60 ticks (R. sanguineus) on days 2, 7, 14, 21, 28, 35, 42 and 49. Fleas and ticks were counted on the Day 2 (approximately 48 hours after treatment), as well as Days 9, 16, 23, 30, 37, 44 and 51 (approximately 48 hours after each post-treatment and re-infestation) to assess insecticidal and acaricidal activity in the treated groups. In Group B, an additional flea and tick infestation was conducted on Day 56, with a respective flea and tick count on Day 58. Additionally, for flea and tick counts, blood samples were collected before treatments, as well as approximately 2 hours, 4 hours, 8 hours, 24 hours and 72 hours after treatment on Day Zero and then once on each of Days 7, 14, 21, 28, 35, 42, 49 and 56. The concentration of Compound 11-1 in blood plasma was analyzed by HPLC/MS/MS. The LOQ of this method was 5 ng/ml. Table 8 shows the observed tick efficacies: Table 8 Efficacies of Various Treatments with Compound 11-1 Against Brown Dog Ticks (R. sanguineus) in Beagles

[00299] Table 9 shows the efficacies on fleas observed: Table 9 Efficacies of Various Treatments with Compound 11-1 Against Cat Fleas (C. felis) on Beagles

[00300] The observed mean plasma concentration of Compound 11-1 over the duration of the study is shown in Figure 1. In Figure 1, “PO” data refers to Group A, “SC” data refers to Group B, the data “TOPO WITH ENH” refers to Group C, the data “TOPO WITH ENH and DIFFUSION” refers to Group D and the data “TOPO WITH ETHYL LACTATE” refers to Group E. The data for Group F ( control) were not included in Figure 1, as Compound 11-1 was not administered to this group.

Example 7. Isolation of the R and S enantiomers of Compound 11-1.

[00301] Compound 11-1 (260 mg) was dissolved in a 1:1 mixture of n-hexane/ethanol (13 ml) at 40° C. 80% of this solution was separated into 400 μl aliquots in a system semi-preparative liquid chromatography equipped with a Diacel Quiralpak® AD-H column with 250 mm column length, 10 mm diameter and 5 μm particle size. The mobile phase consisted of an 8:2 mixture of n-hexane/ethanol. A flow rate of 4 ml/min was used. The chiral fractions of both enantiomers were collected and evaporated in vacuum. The purity of the pooled fractions was controlled through analytical chiral chromatography using a Diacel Quiralpak® AD-H column (250 x 4.6 mm, 5 μm) and UV detection at 254 nm. For both enantiomers, a purity of more than 99% was determined. This technique produced 88 mg of Compound 17-1 (the S enantiomer), which had an optical rotation of [a]D23 +63.97° (ethanol, c = 2.97 mg/ml); and 80 mg of Compound 11-1R (the R enantiomer), which had an optical rotation of [a]D23 -61.07° (ethanol, c = 3.93 mg/ml).

[00302] The words “understand”, “comprises” and “which understands” should be interpreted inclusively rather than exclusively. This interpretation is intended to be the same as the interpretation which these words are given under the United States Patent Law.

[00303] The term “pharmaceutically acceptable” is used in an adjectival manner to mean that the modified noun is appropriate for use in a pharmaceutical product. When used, for example, to describe a salt, excipient, or solvate, it characterizes the salt, excipients, or solvates as being compatible with the other ingredients of the composition and not deleterious to the intended recipient animal to the degree that the deleterious effects exceed in value the benefits of the salt, excipient, or solvate.

[00304] All references cited here are incorporated by reference in this patent.

[00305] The above detailed description of the preferred embodiments is only intended to inform other persons skilled in the art with the invention, its principles and its practical application so that other persons skilled in the art can adapt and apply the invention in its numerous forms, whereas they may be better suited to the needs of a particular use. This invention, therefore, is not limited to the above embodiments and can be modified in various ways.

Claims (7)

1. Use of an isoxazoline of Formula (11-1): or a salt thereof, characterized in that it is for the production of a medicine to control an infestation of brown dog tick (Rhipicephalus sanguineus) in a dog and/or cat. 2. Use according to claim 1, characterized by the fact that the isoxazoline is in the form of a racemic mixture. 3. Use according to claim 1, characterized by the fact that isoxazoline is in the form of an enantiomer of Formula (17-1): 4. Use according to any one of claims 1 to 3, characterized in that the medicament comprises from 10 to 50%, by weight, of isoxazoline. 5. Use according to any one of claims 1 to 4, characterized by the fact that the medicine is in the form of a chewable tablet. 6. Use according to any one of claims 1 to 4, characterized by the fact that the medicine is in the form of a “spot-on” type formulation. 7. Use according to any one of claims 1 to 4, characterized by the fact that the medicine is in the form of an injectable formulation.