RU2816320C2 - Isoxazoline compositions and use thereof as antiparasitic agents - Google Patents

Abstract

FIELD: veterinary pharmaceutics.

SUBSTANCE: invention relates to the use of isoxazoline of structural formula (11‒1) or a salt thereof for the manufacture of a medicinal agent, formulated in the form of a single dose to be administered once a quarter for controlling infestation with fleas and brown dog ixodic tick (Rhipicephalus sanguineus) of dogs and/or cats.

EFFECT: invention provides effective control of infestation of dogs or cats with fleas or ticks.

4 cl, 1 dwg, 9 tbl, 7 ex

Description

Cross-reference to related patent applications

This application claims priority to US Provisional Patent Application 61/080444 (filed July 14, 2008); US Provisional Patent Application 60/956448 (filed August 17, 2007); European Patent Application 07016152.6 (filed August 17, 2007) and European Patent Application 07150309.8 (filed December 21, 2007). All patent applications cited are incorporated herein by reference.

Field of technology to which the invention relates

The present invention relates to methods for controlling parasite infestations in animals and their environment and, in particular, to methods of using isoxazolines to control parasites in animals or in their environment, as well as for the treatment of parasitic diseases in animals. Isoxazolines include 4-(isoxazolinyl)benzamides (specifically, substituted 4-(5-(halomethyl)-5-phenylisoxazolin-3-yl)benzamides) and 4-(isoxazolinyl)benzothioamides (specifically, substituted 4-(5-(halomethyl) -5-phenylisoxazolin-3-yl)benzothioamides). The present invention also relates to compositions containing isoxazolines for use in such methods, to the use of isoxazolines for carrying out such methods, and kits containing isoxazolines for carrying out such methods. The present invention also relates to the use of isoxazolines as drugs, in particular drugs that can be used in the above methods.

Prerequisites for creating the invention

There are a number of known pests and parasites that infect warm-blooded animals. Such pests and parasites can cause great trouble for both animals and their owners. For example, virtually all domestic and farm animals can be affected by ectoparasites such as ticks, ticks, lice and fleas. Ectoparasites tend to be irritating to animals and can also cause clinical disease and harmful subclinical conditions, either by themselves or through the introduction of vector-borne pathogens. To date, various treatment methods have been developed to combat ectoparasites in warm-blooded animals. However, there remains a need for compositions (and methods of using them) that are bioavailable, can provide contact or systemic activity, are potentially effective, have a rapid onset of action, have a long period of action and/or are safe for recipient animals and/or their owners of people. The present invention is aimed at meeting such a need.

The essence of the invention

In general, the present invention relates to isoxazoline compositions (in particular, compositions with 4-(isoxazolinyl)benzamides (also known as, for example, compositions with “4-(4,5-dihydroisoxazol-3-yl)benzoic acid amide”) and compositions with 4-(isoxazolinyl)benzothioamides (also known as, for example, compositions with “4-(4,5-dihydroisoxazol-3-yl)benzothioamide”) and their use for the control of ectoparasites in warm-blooded animals. In accordance with the present invention, it has been found that such compositions generally exhibit the desired bioavailability and can provide contact and/or systemic activity. Many compositions also provide safety profiles desired by warm-blooded recipient animals and/or their owners. In addition, it has been found that a single administration of such compositions typically provides possible activity against one or more ectoparasites while tending to provide rapid onset of action, long-lasting activity and/or desirable safety profiles.

Therefore, the present invention relates, in particular, to a method for combating infection of an animal with ectoparasites. The method involves administering to an animal isoxazoline, isoxazoline salt or isoxazoline solvate or its salt. Isoxazoline has the structural formula (I)

Where

one of A ¹ and A ² is selected from the group consisting of halogen and halogenmethyl;

one of A ¹ and A ² is selected from the group consisting of hydrogen, halogen and methyl halo;

And ³ is selected from the group consisting of hydrogen, halogen and methyl halo;

R represents halomethyl;

X is selected from the group consisting of hydrogen, halogen, methyl, halomethyl, ethyl and haloethyl.

In some embodiments, Z ¹ and Z ² are independent substituents. In such embodiments

Z ¹ is selected independently from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, haloethyls nocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl , methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

When Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonyl ethyl, dimethoxyethyl , propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylaminocarbonylethyl.

When Z ¹ represents hydrogen, Z ² is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl and aminocarbonyl.

In other embodiments, Z ¹ and Z ² together form a substituent selected from the group consisting of

And

Z ³ is selected from the group consisting of O and S.

Z ^A is selected from the group consisting of hydrogen, halogen and cyano.

The present invention also relates, in particular, to a method for treating parasitic diseases in an animal. This method involves administering to the animal the above-described isoxazoline, its salt or solvate.

The present invention also relates, in particular, to a method for controlling ectoparasite infestation in an environment occupied (occasionally or permanently) by an animal (eg, a pet such as a cat or dog). This method involves administering to the animal the above-described isoxazoline, its salt or solvate.

The present invention also relates in particular to the use of the above-described isoxazoline, a salt or solvate thereof, as a drug.

The present invention also relates in particular to the use of the above-described isoxazoline, a salt or solvate thereof, for the preparation of a medicament for the treatment of parasitic diseases in an animal.

The present invention also relates, in particular, to the above-described isoxazoline, a salt or solvate thereof, for the treatment of parasitic diseases in an animal.

The present invention also relates in particular to a parasiticidal composition for use in an animal. The composition contains the above-described isoxazoline, a salt or solvate thereof, in an amount that is effective to combat ectoparasite infestation when the composition is administered to an animal. The composition also contains an excipient (ie it contains at least one excipient).

The present invention also relates in particular to a therapeutic kit. The kit contains the above-described isoxazoline, its salt or solvate and an additional component. The additional component may be, for example, a diagnostic tool, instructions for administration, an administration device, an excipient or other active ingredient, or a reminder.

Other advantages of the invention will be apparent to those skilled in the art upon reading this specification.

Brief description of the drawing

Figure 1 shows the average plasma concentration of compound 11-1 in the study of 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, the “PO” data refers to group A (1 mg/kg body weight of compound 11-1 in oral tablet form); "SC" data refers to group B (1 mg/kg body weight of compound 11-1 in the form of an injection solution for subcutaneous administration); "TOP W/ENHANCER" data refers to group C (1 mg/kg body weight of compound 11-1 in the form of a spot application solution containing an absorption enhancer); data "TOP W/ENHANCER AND HEATER" refers to group D (1 mg/kg body weight of compound 11-1 in the form of a topical solution containing an absorption enhancer and wetting agent); and the data "TOP W/ETHYLLACTATE" refers to group E (1 mg/kg body weight of compound 11-1 in the form of a spot solution containing ethyl lactate as a solvent).

Detailed Description of Preferred Embodiments

The detailed description of the preferred embodiments is intended only to familiarize those skilled in the art with the invention, its principles and its practical application, so that others skilled in the art can adapt and apply the invention in its many forms as may best suit the requirements of practical application. This detailed description and specific examples therein showing preferred embodiments of the present invention are for purposes of illustration only. Therefore, the present invention is not limited to the preferred embodiments described herein and can be modified in various ways.

I. Isoxazolines

In general, isoxazolines useful in the present invention include compounds of formula (I)

Preferred compounds of formula (I) include the embodiments set forth below.

A. Preferred Embodiments A ¹ and A ²

One of A ¹ and A ² is selected from the group consisting of halogen and methyl halo. The other of A ¹ and A ² is selected from the group consisting of hydrogen, halogen and methyl halo.

In some embodiments, A ¹ is a halogen. In some such embodiments, A ¹ is bromine. In other embodiments, A ¹ is chlorine.

In some embodiments, A ¹ is halomethyl. In some such embodiments, A ¹ is trifluoromethyl.

In some embodiments, A ² is hydrogen.

In some embodiments, A ² is a halogen. In some such embodiments, A ² is fluorine. In other embodiments, A ² is chlorine.

B. Preferred Embodiments A ³

And ³ is selected from the group consisting of hydrogen, halogen and methyl halo.

In some embodiments, A ³ is hydrogen.

In some embodiments, A ³ is a halogen. In some such embodiments, A ³ is chlorine. In other embodiments, A ³ is bromine.

In some embodiments, A ³ is halomethyl. In some such embodiments, A ³ is trifluoromethyl.

C. Preferred Embodiments R

R represents halomethyl. In some embodiments, R is monochloromethyl. In other embodiments, R is trifluoromethyl. In yet other embodiments, R is monochlorodifluoromethyl.

D. Preferred Embodiments X

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 Z ¹ and Z ²

In some embodiments, Z ¹ and Z ² are independent substituents. In such embodiments, Z ¹ is selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, gal ogenethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

And

In some such embodiments, Z ¹ 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-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino) carbonylmethyl, isopropylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, (2-propenyl)aminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylcyclopropyl, (2-fluoroethyl)aminocarbonylmethyl, (2-chloroethyl)aminocarbonylmethyl, 1-(ethylaminocarbonyl)ethyl,

And

In other embodiments, Z ¹ is selected from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, gal ogenethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

And

In other embodiments, Z ¹ 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 -propylaminocarbonylmethyl, N-phenyl-N-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)carbonylmethyl , isopropylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, (2-propenyl)aminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylcyclopropyl, (2-fluoroethyl)aminocarbonylmethyl, (2-chloroethyl)aminocarbonylmethyl, 1-(ethylaminocarbonyl)ethyl,

And

In other embodiments, Z ¹ 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 -propylaminocarbonylmethyl, N-phenyl-N-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

And

In other embodiments, Z ¹ 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 -methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

And

In other embodiments, Z ¹ is selected from the group consisting of hydrogen, methyl, methoxymethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)methyl, isopropoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

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

And

In other embodiments, Z ¹ is selected from the group consisting of N-phenyl-N-methylamino,

And

In other embodiments, Z ¹ is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)methyl,

And

In other embodiments, Z ¹ 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-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

And

In other embodiments, Z ¹ 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-fluoroethyl)aminocarbonylmethyl, (2-chloroethyl)aminocarbonylmethyl, 1-(ethylaminocarbonyl)ethyl,

In other embodiments, Z ¹ is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

In other embodiments, Z ¹ is selected from the group consisting of methoxymethyl, ethoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

In other embodiments, Z ¹ is selected from the group consisting of methoxymethyl, ethoxymethyl, and tetrahydrofuryl.

In other such embodiments, Z ¹ is

In other embodiments, Z ¹ is haloethylaminocarbonylmethyl. In some such embodiments, Z ¹ is (2,2,2-trifluoroethyl)aminocarbonylmethyl.

When Z ¹ represents hydrogen, Z ² is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl and aminocarbonyl. In some such embodiments, Z ² is methoxycarbonyl. In other embodiments, Z ² is aminocarbonyl.

When Z ¹ is an independent substituent other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylaminocarbonylethyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl , aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylaminocarbonylethyl.

In some embodiments, when Z ¹ represents an independent substituent other than hydrogen, Z ² represents hydrogen.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is ethyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is methoxymethyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is methylcarbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is ethyl carbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is isopropylcarbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is cyclopropylcarbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is methoxycarbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is methoxymethylcarbonyl.

In some embodiments, when Z ¹ is an independent substituent other than hydrogen, Z ² is selected from the group consisting of hydrogen, methylcarbonyl, and ethylcarbonyl.

In some embodiments, Z ¹ and Z ² together form a single substituent, distinct from independent substituents. In such embodiments, Z ¹ and Z ² together form a structure

In such embodiments, the isoxazoline corresponds to the structure

In some embodiments, Z ¹ and Z ² together form a single substituent, distinct from independent substituents. In such embodiments, Z ¹ and Z ² together form a structure

In such embodiments, the isoxazoline corresponds to the structure

F. Preferred Embodiments Z ³

In some embodiments, Z ³ represents O (ie, an oxygen atom). In other embodiments, Z ³ represents S (ie, a sulfur atom).

G. Preferred Embodiments Z ^A

Z ^A is selected from the group consisting of hydrogen, halogen and cyano. In some such embodiments, Z ^A is hydrogen. In other embodiments, Z ^A is bromine. In other embodiments, Z ^A is chlorine. In other embodiments, Z ^A is cyano.

H. Illustrative Combinations of Substituents

The following combinations of substituents are merely illustrative and are not given any particular preference.

H1. Illustrative Substituent Combination No. 1

In some embodiments, A ¹ and A ³ are independently selected from the group consisting of halogen and methyl halo, and A ² is hydrogen. In some such embodiments, for example, A ¹ and A ³ are each chlorine, such that isoxazoline has the structural formula

H2. Illustrative Substituent Combination No. 2

In some embodiments, Z ¹ and Z ² are either independent substituents or together form a single substituent as follows:

when Z ¹ and Z ² are independent substituents,

Z ¹ is selected independently from the group consisting of hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, haloethyls nocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl ,

when Z ¹ represents hydrogen and Z ² is selected from the group consisting of methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl and aminocarbonyl;

when Z ¹ is other than hydrogen and Z ² is independently selected from the group consisting of hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylamino carbonylethyl , dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl and haloethylaminocarbonylethyl;

when Z ¹ and Z ² together form one substituent, they form

H3. Illustrative Substituent Combination No. 3

In some embodiments, substituents in formula (I) have the meanings set forth below.

And ¹ is selected from the group consisting of chlorine, bromine and trifluoromethyl.

And ² is selected from the group consisting of hydrogen, chlorine and fluorine.

And ³ is selected from the group consisting of chlorine, bromine and trifluoromethyl.

R is selected from the group consisting of monochloromethyl, trifluoromethyl and monochlorodifluoromethyl.

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

Z ³ represents O.

Z ^A is selected from the group consisting of hydrogen, bromine, chlorine and cyano.

In some such embodiments, Z ¹ and Z ² are independent substituents such that

Z ¹ 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-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

And ;

when Z ¹ represents hydrogen, Z ² is selected from the group consisting of methoxycarbonyl and aminocarbonyl;

when Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

In other such embodiments, Z ¹ and Z ² together form

H4. Illustrative Substituent Combination No. 4

In some embodiments, Z ¹ and Z ² are either independent substituents or together form a single substituent as follows:

when Z ¹ and Z ² are independent substituents,

Z ¹ 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-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

when Z ¹ represents hydrogen, Z ² is selected from the group consisting of methoxycarbonyl and aminocarbonyl;

when Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl;

when Z ¹ and Z ² together form one substituent, they form

Examples of isoxazolines covered by such embodiments include the following structures:

H5. Illustrative Substituent Combination No. 5

In some embodiments, isoxazolines of formula (I) have the meanings set forth below.

Isoxazoline matches the structure

And ¹ is selected from the group consisting of chlorine and bromine.

And ³ is selected from the group consisting of chlorine and bromine.

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

In some such embodiments, Z ¹ and Z ² are independent substituents such that

Z ¹ 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-methylamino, (2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

when Z ¹ represents hydrogen, Z ² is selected from the group consisting of methoxycarbonyl and aminocarbonyl;

when Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

In other such embodiments, Z ¹ and Z ² together form

Examples of isoxazolines covered by such embodiments include the following structures:

And

Still other examples covered by such embodiments include the following structures:

H6. Illustrative Substituent Combination No. 6

In some embodiments, substituents in formula (I) have the meanings set forth below.

A ¹ and A ³ are selected independently from the group consisting of chlorine, bromine and trifluoromethyl.

And ² is selected from the group consisting of hydrogen, chlorine and fluorine.

R is selected from the group consisting of trifluoromethyl and monochlorodifluoromethyl.

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

Z ³ represents O.

Z ^A is selected from the group consisting of bromine, chlorine and cyano.

In some such embodiments, Z ¹ and Z ² are independent substituents such that

Z ¹ 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-methylamino, ( 2,2,2-trifluoroethyl)aminocarbonylmethyl, 1-[(2,2,2-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

when Z ¹ represents hydrogen, Z ² represents aminocarbonyl;

when Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, ethyl, methoxymethyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl;

when Z ¹ represents hydrogen, Z ² represents aminocarbonyl.

In other such embodiments, Z ¹ and Z ² together form

According to the present invention, it is found that isoxazolines of such embodiments tend to exhibit particularly beneficial flea control in vivo within 24 and 48 hours post-infestation. See example 3 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

And

Still other examples covered by such embodiments include the following structures:

And

H7. Illustrative Substituent Combination No. 7

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

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

Z ¹ is selected from the group consisting of N-phenyl-N-methylamino,

And

Z ² is selected from the group consisting of hydrogen, ethylcarbonyl, methoxycarbonyl and methoxymethylcarbonyl.

According to the present invention, it is found that isoxazolines of such embodiments tend to exhibit particularly beneficial flea control in vivo within 24 and 48 hours post-infestation. See example 3 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

And

H8. Illustrative Substituent Combination No. 8

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

R is selected from the group consisting of trifluoromethyl and monochlorodifluoromethyl.

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

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

And

When Z ¹ represents hydrogen, Z ² represents aminocarbonyl.

When Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, methylcarbonyl, ethylcarbonyl and methoxycarbonyl.

According to the present invention, it has been found that isoxazolines of such embodiments tend to exhibit particularly favorable in vivo results in controlling fleas within 24 and 48 hours of infection and ticks for at least 8 days. See examples 3 and 4 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

H9. Illustrative Substituent Combination No. 9

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

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

Z ¹ 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-trifluoroethyl)aminocarbonyl]ethyl, tetrahydrofuryl,

And

When Z ¹ represents hydrogen, Z ² represents aminocarbonyl.

When Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen and ethyl carbonyl.

According to the present invention, it has been found that isoxazolines of such embodiments also tend to exhibit particularly favorable in vivo results in inhibiting both fleas within 24 and 48 hours and ticks for at least 8 days. See examples 3 and 4 below for example.

H10. Illustrative Substituent Combination No. 10

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

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

Z ¹ is selected from the group consisting of hydrogen, (2,2,2-trifluoroethoxy)methyl,

And

When Z ¹ represents hydrogen, Z ² represents aminocarbonyl.

When Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, methyl carbonyl and ethyl carbonyl.

According to the present invention, it has been found that isoxazolines of such embodiments tend to exhibit particularly favorable in vivo results in controlling fleas within 24 and 48 hours of infection and ticks for at least 8 days. See examples 3 and 4 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

And

H11. Illustrative Substituent Combination No. 11

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

Z ¹ is selected from the group consisting of methoxymethyl, ethoxymethyl and tetrahydrofuryl.

Z ² is selected from the group consisting of hydrogen and methoxycarbonyl.

According to the present invention, it has been found that isoxazolines of such embodiments tend to exhibit particularly favorable in vivo results in controlling fleas within 24 and 48 hours of infection and ticks for at least 8 days. See examples 3 and 4 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

And

H12. Illustrative Substituent Combination No. 12

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

Z ¹ is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

According to the present invention, it has been found that isoxazolines of such embodiments tend to exhibit particularly favorable results in vivo in controlling fleas within 1, 24 and 48 hours after infection and ticks for at least 8 days. See examples 3 and 4 below for example.

Examples of isoxazolines covered by such embodiments include the following structures:

Other isoxazolines covered by such embodiments include the structure

The chemical name of this isoxazoline is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide. It can be found, for example, in CAS RN [928789-76-8].

Still other isoxazolines covered by such embodiments include the structure

The chemical name of this isoxazoline is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoroethylcarbamoyl)methyl] benzamide. It can be found, for example, in CAS RN [864731-61-3]. According to the present invention, compound 11-1 has been found to exhibit particularly favorable results in vivo in terms of duration of flea inhibition using various routes of administration, including topical, oral or subcutaneous. See example 5 below for example.

H13. Illustrative Substituent Combination No. 13

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline has the structural formula (I)

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

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

Z ¹ 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,

And

When Z ¹ represents hydrogen, Z ² represents aminocarbonyl.

When Z ¹ is other than hydrogen, Z ² is selected from the group consisting of hydrogen, methyl carbonyl, ethyl carbonyl and methoxycarbonyl, except that

H14. Illustrative Substituent Combination No. 14

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

Z ¹ is selected from the group consisting of methoxymethyl, ethoxymethyl, ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

Z ² is selected from the group consisting of hydrogen and methoxycarbonyl.

H15. Illustrative Substituent Combination No. 15

In some embodiments, the isoxazoline of formula (I) is defined as follows.

Isoxazoline matches the structure

Z ¹ is selected from the group consisting of ethylaminocarbonylmethyl, 2-propynylaminocarbonylmethyl, (2,2,2-trifluoroethyl)aminocarbonylmethyl, tetrahydrofuryl,

And

According to the present invention, it has been found that isoxazolines of such embodiments tend to exhibit particularly favorable in vivo flea control results within 1, 24 and 48 hours post-infestation. See example 3 below for example.

An example of isoxazolines covered by such embodiments includes the following structure:

H16. Illustrative Substituent Combination No. 16

In some embodiments, the isoxazoline corresponds to the structure

In such embodiments, Z ¹ and Z ² are either independent substituents or together form a single substituent.

When Z ¹ and Z ² are independent substituents,

Z ¹ 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-fluoroethyl)aminocarbonylmethyl, (2-chloroethyl)aminocarbonylmethyl, 1-(ethylaminocarbonyl)ethyl,

And ; And

Z ² is selected from the group consisting of hydrogen, methylcarbonyl and ethylcarbonyl.

When Z ¹ and Z ² together form one substituent, they form

Examples of isoxazolines covered by such embodiments include the following structures:

And

H17. Illustrative Substituent Combination No. 17

In some embodiments, the isoxazoline corresponds to the structure

H18. Illustrative Substituent Combination No. 18

In some embodiments, the isoxazoline corresponds to the structure

Examples of isoxazolines covered by such embodiments include the following compound:

I. Isomers

The isoxazolines used in the present invention generally may have two or more conformational structures. At a minimum, for example, all isoxazolines include a chiral (or asymmetric) carbon atom at position 5 of the isoxazoline ring. In some embodiments, for example, the chiral carbon atom has a left-handed (or "S" or "left-handed") configuration. Such isoxazolines include isoxazolines having the following structure:

In some such embodiments, for example, isoxazolines correspond to the structure

An example of such a connection is

In other embodiments, the chiral carbon atom has a right-handed (or "R" or "right-handed") configuration. Such isoxazolines include isoxazolines corresponding to the following structure:

An example of such a connection is

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

A particular isomer can often be isolated from the corresponding racemic mixture (or salt thereof) using, for example, chiral high performance liquid chromatography (HPLC) techniques. This method is explained below in Example 7 for isolating the R and S isomers of the racemic compound 11-1. In some cases, when the isomer is difficult to isolate, a more soluble derivative of the isomer is isolated from a racemic mixture of the corresponding derivatives (or salts thereof) and then converted to the isomer. Alternatively, a particular isomer can often be synthesized directly from, for example, an optically pure starting material.

In some embodiments, the pharmaceutical composition of the present invention uses a ratio of one enantiomer (eg, compound 17-1) to another enantiomer (eg, compound 11-1R) greater than 1:1. In some cases, 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 98:2, or greater than approximately 99:1.

In some embodiments, the concentration of one enantiomer (eg, compound 17-1) in the composition (or more specifically the pre-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 by weight), greater than about 98% (by weight), greater than about 99% (by weight), or greater than about 99.5% (by weight).

Unless otherwise stated, the structure of an isoxazoline that does not exhibit a specific conformation is intended to encompass compositions of all possible conformational isomers of the isoxazoline, as well as compositions containing not all (eg, only one) possible conformational isomers.

J. Isoxazoline salts

As noted above, many isoxazolines useful in the present invention may be in salt form. The salt may be advantageous for one or more of its physical properties, such as pharmaceutical stability at various temperatures and humidity; crystalline properties and/or desired solubility in water, oil or other solvents. Acid and base addition salts can generally be prepared, for example, by mixing the compound with an acid or base, respectively, using various methods known in the art. In general, when the salt is to be administered in vivo (ie to an animal) primarily for therapeutic purposes, the salt is preferably pharmaceutically acceptable.

In some cases, an isoxazoline base addition salt 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, metal salts and organic salts. Metal salts particularly 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 (e.g. zinc and iron) and other physiologically acceptable metal salts. Such salts can be prepared with calcium, lithium, magnesium, potassium, sodium and zinc. For example, isoxazoline in its free acid form can be mixed with sodium hydroxide to form such a base addition salt.

In some cases, the isoxazoline acid addition salt of formula (I) can be prepared by reacting the isoxazoline with an approximately stoichiometric amount of an inorganic or organic acid. Examples of contemplated inorganic acids for preparing pharmaceutically acceptable salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Examples of generally suitable organic acids for the preparation of pharmaceutically acceptable salts generally include, for example, organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes. 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, glutamic acid , arylcarboxylic acid (for example, benzoic acid), anthranilic acid, methanesulfonic acid, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamic) acid, alkylsulfonic (for example, ethanesulfonic) acid, arylsulfonic (for example, benzenesulfonic) acid, pantothenic , 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, β-hydroxybutyric, galactaric, galacturonic, adipic, alginic, butyric, camphoric, camphorsulfonic, cyclopentanepropionic acid, dodecelsulfonic acid, glycoheptanoic, glycerophosphoric, heptanoic, hexanoic, nicotinic, 2-naphthalene sulfonic, oxalic, palmic , pectic, 3-phenylpropionic, picric, pivalic, thiocyanic, p-toluenesulfonic and undecanoic acid.

In some cases, the organic isoxazoline salt of formula (I) can be prepared, for example, by quaternization of the nitrogen-containing main group of the isoxazoline with an agent such as a (C ₁ -C ₆ )halide (for example, methyl, ethyl, propyl and butyl chloride, bromide or iodide ), dialkyl sulfate (for example, dimethyl, diethyl, dibutyl or diamyl sulfate), long chain halides (for example, decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), arylalkyl halide (for example, benzyl and phenethyl bromide) and the like agents.

It should be appreciated that the acid or base counterion may, in some cases, be optically active (eg, D-lactate and L-lysine salts) or racemic (eg, DL-tartrate and DL-arginine salts).

K. Isoxazoline solvates

In some cases, isoxazolines of formula (I) are in the form of stable complexes with solvent molecules, which remain unchanged after the uncomplexed solvent molecules are removed from the compounds. Such complexes are usually referred to as “solvates”. In some cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" covers both solution phase solvates and solvates that can be isolated. Examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate in which the solvent molecule is a water molecule. It is assumed that the solvate used in vivo is preferably pharmaceutically acceptable.

L. Isoxazoline prodrugs

It is contemplated that isoxazoline prodrugs of formula (I) may be used with the methods of the present invention. As used herein, the term “prodrug” refers to a compound that, when used (eg, in vivo), can be converted by metabolism or other processes (eg, hydrolysis) to the isoxazoline of formula (I) . In some embodiments, delivery of isoxazoline in prodrug form is an improved delivery of isoxazoline by improving physicochemical or pharmacokinetic properties, such as by enhancing systemic absorption, delaying clearance, or delaying in vivo degradation.

II. Preparation of isoxazolines of formula (I)

Methods for preparing isoxazolines are known in the art. Methods for preparing various isoxazolines of formula (I) , for example, are discussed in US Patent Publication US2007/0066617 (incorporated herein by reference), International Patent Application Publication No. WO2007/026965 (incorporated herein by reference) and Patent Application Publication Japan No. JP2007/308471 (incorporated herein by reference). For example, US Patent Publication US2007/0066617 discusses the preparation of compound 11-1 in Example 21 on page 72, the preparation of compound 5-19 in Example 28 on pages 74-75, the preparation of compound 5-61 in Example 30 on pages 76-77, and obtaining connection 5-64 in Example 34 on pages 77-78; International Application Publication No. WO2007/026965 discusses the preparation of compound 5-16 in Example 21 on page 317, the preparation of compound 5-25 in Example 22 on pages 317-318, the preparation of compound 5-49 in Example 12 on page 312, the preparation of compound 5 -60 in example 11 on pages 311-312 and obtaining connection 10-1 in example 32 on pages 321-322; and Japanese Patent Application Publication No. JP2007/308471 discusses the preparation of Compound 5-45 in Example 38 on page 381. In addition, methods for preparing various isoxazolines are also discussed, for example, in International Patent Application Publication No. WO2005/085216 (incorporated herein by reference), International Application No. PCT/JP/2008/054096 (incorporated herein by reference), European Patent Application Publication No. EP1932836 (incorporated herein by reference), and Japanese Patent Application Publication No. JP2008/133242 (incorporated herein by reference). this description by reference). Other isoxazolines of formula (I) can be prepared using, for example, the methods illustrated in these references, either alone or in combination with other methods known in the art.

III. Methods of treatment using the composition of the present invention

Isoxazolines of formula (I) can generally be used to control ectoparasites in animals and, in turn, diseases directly caused by such ectoparasites and/or diseases caused by pathogens carried by such ectoparasites. It is believed that the composition can be used to treat a number of animals, particularly warm-blooded animals. Such warm-blooded animals include, for example, mammals. Mammals include, for example, humans. Other mammals include, for example, farm animals or livestock (eg, pigs, cows, sheep, goats, etc.), laboratory animals (eg, mice, rats, gerbils, etc.), domestic animals (eg, dogs, cats, horses), fur-bearing animals (eg mink, foxes, chinchillas, rabbits, etc.) and wild and zoo animals (eg buffalo, deer, etc.). In some embodiments, the compositions are used to treat dogs (such as, for example, purebred domestic dogs and/or mongrels, show dogs, sled dogs, herding dogs, hunting dogs, guard dogs, police dogs, racing dogs, and/or laboratory dogs). In other embodiments, the compositions are used to treat cats (eg, domestic cats). The compositions are also believed to be suitable for treating non-mammalian animals such as birds (eg, turkeys, chickens, geese, ducks, parrots, etc.). It is also contemplated that such compositions may be suitable for the treatment of cold-blooded animals such as, for example, fish (eg salmon, rainbow trout, koi, etc.).

According to the present invention, it has been found that isoxazolines of formula (I) are of particular importance for the control of ectoparasites, i.e. arthropods that are harmful or spread disease, or act as disease vectors in warm-blooded animals. Isoxazolines are generally beneficial for controlling parasites at various life stages, including egg, nymphal, larval, juvenile and adult stages. Ectoparasites (usually insects and mites) include those listed below.

A. Stinging insects . These include, for example, migratory larvae of Diptera, such as Hypoderma spp. in cattle, Gastrophilus spp. in horses and Cuterbra spp. in rodents; stinging flies, such as, for example, blood-sucking adult flies (e.g., cow flies (Haematobia irritans), horse flies (Tabanus spp.), botflies (Stomoxys calcitrans), midges (Simulium spp.), horseflies (Chrysops spp.), bloodsuckers (Melophagus ovinus), tsetse flies (Clossina spp.); parasitic larvae of flies such as, for example, nasopharyngeal botflies (Oestrus ovis and Cuterebra spp.), blue blowflies (Phaencicia spp.), blowfly larvae (Cochiliomyia hominivorax), cattle larvae ( Hypoderma spp.) and hairy worms; and mosquitoes such as, for example, Culex spp., Anopheles spp. and Aedes spp.

B. Ticks . These include

i) Mesostigmata species, such as mesostigmatids, which include chicken mites (Dermanyssus gallinae);

ii) Astigmata species such as scabies or horse mites, which include Sarcoptidae species (eg Sarcoptes scabiei); and scabies, which include species of Psoroptidae (eg Chorioptes bovis and Psoroptes ovis);

iii) Prostigmata species such as mites, which include species of Trombiculidae (eg the North American trombiculid Trombicula alfreddugesi);

iv) demodexes.

C. Ixodid ticks . These include, for example, soft-shelled mites such as Argasidae species (eg Argas spp. and Orniyhodoros spp.); and hard-shelled ticks such as Ixodidae species (eg, Ixodes ricinus Rhipicephalus sanguineus, Haemaphysalis spp., Dermacentor reticulates, Dermacentor variabilis, Amblyomma americanum and Boophilus spp.).

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

E. Fleas . These include, for example, Ctenocephalides species such as dog fleas (Ctenocephalides canis) and cat fleas (Ctenocephalides felis); Xenopsylla species such as southern rat fleas (Xenopsylla cheopis); Pulex species such as flea beetles (Pulex irritans); hedgehog fleas (Archaeopsylla erinacei) and bird fleas (Ceratophyllus gallinae).

F. True hemipteran bugs . These include, for example, Cimcidae or the common bedbug (Cimex lectularius) and Triatominae species such as triatomid bugs (also known as triatomids) (for example, Rhodnius prolixus and Triatoma spp.).

The term "infestation" refers to the presence of parasites in quantities that create a risk of impairment or harm to the health of humans or animals. They may be present in the environment (eg in the animal's bedding) or on the animal's skin or fur, etc. Unless otherwise noted, when contamination is present in the animal's body (for example, in the blood or other internal tissues), is the term "contamination" assumed to be synonymous with the term "infection"? as it is commonly understood in the field.

The expression “control of ectoparasite infestation” means reducing the number or eliminating parasites in the body and/or on the animal. This can be achieved, for example, by killing, driving away, removing, inactivating, slowing down, eliminating, weakening or minimizing the activity of the parasite. Control of ectoparasites may involve the use of insecticides or acaricides. The action of isoxazolines may be on eggs, larvae, nymphs, adult insects, or a combination thereof. In addition, the effect itself may manifest itself directly in the destruction of parasites, either immediately or after some time (for example, when molting occurs or by destroying eggs). Alternatively (or additionally), the effect may itself manifest itself directly, for example, in a decrease in the number of eggs laid and/or in the rate of hatching.

Generally, the amount of isoxazoline that is sufficient to “control” or is “effective” against a target parasite is an amount sufficient to reduce the number or kill parasites in the body and/or animal and/or to partially or completely inhibit the development of parasitic infection in the body and/or on the animal. When isoxazoline is administered systemically, the effective amount is generally that which produces tissue and/or blood concentrations typically toxic when ingested by the target parasite.

One skilled in the art will usually be able to determine an "effective" dose, for example, by observing or detecting changes in the clinical condition or behavior of the host animal, and by observing or detecting corresponding changes in the number of parasites after such treatment. Generally, a dose is considered effective for control of a target parasite when it is sufficient to cause a reduction in the present or potential amount of the target parasite by at least about 5%. In some such cases, for example, a dose is considered effective when it is sufficient to cause a reduction in the available or potential amount of the target parasite 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 95%, or at least about 99%).

The optimal dosage will generally depend on a variety of factors including, for example, the specific isoxazoline, the identity of any other active ingredient(s) administered to the recipient animal, the route of administration, and the type and severity of the condition. and target pathogen, type (e.g., species and breed), age, size, sex, nutrition, activity and condition of the intended recipient animal, and pharmacological considerations such as activity, efficacy, pharmacokinetic and toxicological profiles of isoxazoline and other active(s). the ingredient(s) that are administered to the recipient animal. To a certain extent, many active ingredients are administered for a combined effect on a target parasite or condition, the amount of each ingredient constituting an "effective amount" being the amount that, when combined with other active ingredients, produces the desired effect.

The isoxazolines of formula (I) can be administered multiple times for separate treatments. Such multi-dose treatments are contemplated to include multiple doses per day over one or more days, daily doses over several days, and/or doses administered over two or more days. However, in some embodiments of the present invention, a single dose is administered to effectively control the target parasite over an extended period, such as, for example, at least about one week. In some such embodiments, for example, a single dose is effective in controlling the 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 at least about 3 months, at least about 4 months, or at least about 6 months. Accordingly, in some embodiments, the frequency of treatments may be, for example, weekly, biweekly, monthly, bimonthly, quarterly, semiannually, or even less frequent (eg, once a year). The length of periods over which isoxazolines of formula (I) tend to be effective against various ectoparasites when administered systemically is surprising. This is particularly true since it has been found that such long-lasting activity can be obtained in many cases using low doses that are non-toxic to recipient animals, without the need for release control agents. Without being bound by any theory, it is believed that such a long period of activity produces isoxazolines with particularly high toxicity when absorbed by the target parasite.

For many animal recipients, the dose of isoxazoline and composition is selected to maintain a serum isoxazoline level of at least about 1 ng/ml (eg, 1-50 ng/ml). Typically, the amount of isoxazoline administered to a recipient animal is from about 0.001 to about 200 mg/kg body weight. In some embodiments, for example, from about 0.01 to about 200 mg/kg 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 body weight is administered. In other such embodiments, for example, from about 1 to about 30 mg/kg body weight is administered. Larger dosages tend to provide longer duration of activity.

It is believed that the duration of activity of isoxazoline can be increased as well as (or more appropriately) by the use of a controlled release composition or dosage form. For example, isoxazoline can be administered in microspheres, granules or implants (eg, subdermal implants) that release isoxazoline, for example, by 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 20 mg/kg body weight) isoxazoline may allow for appropriate activity lasting for several months or longer (for example, a year).

In some embodiments of the present invention, the isoxazoline of formula (I) is administered to treat a parasitosis in an animal (or is used to prepare a medicament for the treatment of a parasitosis in an animal). The term "parasitosis" includes pathological conditions and diseases associated with or caused by one or more ectoparasites directly, such as, for example, anemia and flea allergic 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 tick-borne fever. The expression “treatment of parasitosis” means partial or complete suppression of the development of parasitosis in an animal susceptible to parasitosis, weakening or complete elimination of the symptoms of parasitosis in an animal with parasitosis and/or partial or complete cure of parasitosis in an animal with parasitosis. Typically, treatment of parasitosis is achieved by administering isoxazoline of formula (I) to combat ectoparasite infestation.

The present invention also relates to methods of treatment in which at least an auxiliary objective of combating ectoparasites in the body and/or animal is to combat ectoparasite infestation in the environment in which the animal is (periodically or permanently) exposed. In some such embodiments, for example, the animal is a pet (eg, a cat or a dog). The environment may be, for example, a house or other housing, a room, a pen, a stall or other housing area, bedding, etc.

The terms "administer" and "administration" refer to the delivery of an isoxazoline of formula (I) , an isoxazoline salt, an isoxazoline solvate or a salt thereof or an isoxazoline prodrug. In some embodiments of the present invention, systemic delivery is desirable. "System delivery" is delivery to a location remote from the location in which at least some of the parasites live. When delivered systemically, at least a portion of the isoxazoline reaches the target parasite through the recipient animal's bloodstream, other body fluids (lymphatic fluid) and/or tissue (eg, skin or adipose tissue). Typically, the parasite absorbs isoxazoline along with the recipient animal's blood, other body fluids and/or tissue. Systemic administration can be achieved in several forms.

In some embodiments, the isoxazoline composition is administered systemically by the oral route in a unit dosage form, such as, for example, a soft or hard capsule, pill, powder, granules, tablet (e.g., chewable tablet), paste, solution, suspension (aqueous or non-aqueous), emulsion (oil in water or water in oil), elixir, syrup, bolus, large dose or in food or drinking water for the recipient animal. When the composition is administered to an animal's food, it may be fed, for example, as normal food or as a chewable treatment. Alternatively (or additionally), it may, for example, be carefully distributed into the recipient animal's standing food, sprinkled on top of it, or used in the form of granules or liquid, which is added to the finished food. When the composition is administered in the form of a feed additive, it may be convenient to prepare a "premix" in which the composition is distributed in a liquid or solid carrier. This “premix,” in turn, is dispersed in the animal’s feed using, for example, a conventional mixer. When the composition is administered in the drinking water of the recipient animal or as a drench, it may be convenient to use the composition in the form of a solution or suspension. Such a composition may be, for example, a concentrated suspension which is mixed with water, or a dry preparation which is mixed and suspended in water. In both cases, it is preferable to have the isoxazoline in finely divided form.

Alternatively (or additionally), the isoxazoline composition can be administered topically using a transdermal composition (ie, a composition that penetrates the skin). Alternatively (or additionally), the composition can be administered systemically locally through the mucous membrane. Specific compositions for topical and transmucosal administration include, for example, lotions, drops, solutions, sprays, mousses, shampoos, powders, gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressings, foams, films, patches , limb bandages, collars, ear tags, wafers, sponges, fibers, bandages and microemulsions. Methods with lotions and drops include, for example, applying the isoxazoline composition to a specific area of the skin or coat, such as the neck or side of the animal. This can be achieved, for example, by using a swab or a drop of the solution as a soak or spot application to a relatively small area of the recipient animal's skin or coat (i.e., typically no more than 10% of the recipient animal's skin or coat). . In some embodiments, the isoxazoline is distributed from the site of application over large areas of the coat due to the wetting properties of the components in the composition and the movement of the animal, while at the same time it is simultaneously absorbed through the skin and distributed through the body fluids and/or tissues of the recipient animal.

Alternatively (or additionally), the isoxazoline composition can be administered systemically parenterally, for example, by intramuscular injection, intravenous injection, dermal injection, through an implant (eg, subcutaneous implant), infusion, bolus injection, etc. In some such embodiments, the parenteral dosage form provides the recipient animal with from about 0.01 to about 200 mg/kg body weight of isoxazoline.

Other contemplated routes of administration include, for example, rectal and vaginal routes and inhalation (eg, fine spray or aerosol).

IV. Pharmaceutical compositions

The present invention also relates to pharmaceutical compositions (or drugs) containing an isoxazoline of formula (I) , an isoxazoline salt, an isoxazoline solvate or a salt thereof or an isoxazoline prodrug. The compositions may also (and typically will) contain one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention can be prepared, for example, by methods known in the art. Such methods include, for example, various known methods of mixing, dissolving, granulating, emulsifying, encapsulating, entrapping and lyophilizing. The optimal composition depends, for example, on the route of administration.

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

Oral dosage forms other than solids can be prepared by mixing isoxazoline with, for example, one or more solvents, thickeners, surfactants, preservatives, stabilizers, resins, fillers, binders, lubricants, glidants, disintegrants, cosolvents, sweeteners substances, flavoring agents, fragrances, buffers, suspending agents and dyes or pigments of pharmaceutical grade.

Suspected binders include, for example, gelatin, gum acacia and carboxymethylcellulose.

Suitable lubricants include, for example, magnesium stearate, stearic acid and talc.

Suspected disintegrants include, for example, corn starch, alginic acid, sodium carboxymethylcellulose and croscarmellose sodium.

Suspected buffers include, for example, sodium citrate and magnesium calcium carbonate and bicarbonate.

Suitable solvents include, for example, water, petrolatum, animal fats, vegetable oils, mineral oil and synthetic oil. Saline or glycols (eg, ethylene glycol, propylene glycol, or polyethylene glycol) may also be included. The solvent preferably has reasonable chemical properties and quantity so that the isoxazoline remains in solution at the temperatures at which the composition is stored and used.

Suitable thickeners include, for example, polyethylene, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia gum, guar gum, xanthan gum, tragacanth, methylcellulose, magnesium aluminosilicate, polymers of vinylcarboxylic acids, carrageenan, hydroxyethylcellulose, laponite, water-soluble cellulose ester salts, natural gums, colloidal magnesium aluminosilicate or finely divided silica, acrylic acid homopolymers cross-linked with pentaerythritol ether or sucrose ether, and carbomers.

Suspected surfactants include, for example, ethoxylated sorbitan fatty acid esters, polyoxyethylene monoalkyl esters, sucrose monoesters, lanolin esters and ethers, alkyl sulfate salts and sodium, potassium and ammonium salts of fatty acids.

Suspected preservatives include, for example, phenol, alkyl esters of p-hydroxybenzoic acid (for example, methyl p-hydroxybenzoate (or "methylparaben") and propyl p-hydroxybenzoate (or "propylparaben")), sorbic acid, o-phenylphenolbenzoic acid and its salts, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and -nitrate, nitromersol, benzalkonium chloride and cetylpyridinium chloride.

Suspected stabilizers include, for example, chelating agents and antioxidants.

Solid dosage forms may also include, for example, one or more excipients that control the release of isoxazoline. For example, it is contemplated that isoxazoline may be dispersed in, for example, hydroxypropyl methylcellulose. Some oral dosage forms (eg, tablets and pills) can also be formulated with enteric coatings.

Local administration can be achieved using, for example, a concentrated solution, suspension (aqueous or non-aqueous), emulsion (water in oil or oil in water) or microemulsion containing isoxazoline dissolved, suspended or emulsified in a pharmaceutically acceptable liquid medium. In such embodiments, a crystallization inhibitor may typically, but not necessarily, be present.

When the liquid composition is used topically on the skin, it can be administered, for example, by pouring, spreading, rubbing, spraying, spraying, dipping, washing and washing. A pour-on or spot-on composition, for example, can be poured or sprayed onto a limited area of the skin (usually no more than about 10% of the skin). In some such embodiments, the composition allows or facilitates the isoxazoline to penetrate the skin and act in other parts of the body (eg, throughout the body). Such a pourable or dripping composition can be prepared by dissolving, suspending or emulsifying the isoxazoline in a suitable skin-appropriate solvent or solvent mixture. Other excipients may also be included, such as, for example, a surfactant, colorant, antioxidant, stabilizer, adhesive, etc. Suitable solvents include, for example, water, alcohol, glycol, polyethylene glycol, polypropylene glycol, glycerin, benzyl alcohol, phenylethyl alcohol, phenoxyethyl alcohol, 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-oxymethylene-1,3-dioxolane.

In some embodiments, the topical (topical) composition (particularly, a pour-on or drop-in composition) includes a carrier that promotes absorption or penetration of isoxazoline through the skin into the bloodstream, other body fluids (lymph), and/or body tissue (adipose tissue) . Examples of dermal penetration enhancers include, for example, dimethyl sulfoxide, isopropyl myristate, dipropylene glycol pelargonate, silicone oil, aliphatic esters, triglycerides and fatty alcohols.

Topical compositions may also (or alternatively) include, for example, one or more wetting agents. Such substances act as carriers that promote the distribution of the active ingredient throughout the fur or skin of the recipient animal. These may include, for example, isopropyl meristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and/or fatty alcohols. Various combinations of wetting agents with oil/solvent may also be suitable, such as, for example, oil solutions, alcohol solutions and isopropanol solutions (for example, 2-octyldodecanol or oleyl alcohol solutions), solutions of monocarboxylic acid esters (such as for example, isopropyl myristate, isopropyl palmitate, oxalic acid lauryl ester, oleic acid oleic ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate and esters of saturated fatty alcohols with a carbon chain of 12-18 carbon atoms of caproic acid), solutions of dicarboxylic acid esters (for example , dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester and di-n-butyl adipate) or solutions of aliphatic acid esters (for example, glycolic). When the composition contains a wetting agent, it may also be advantageous to include a dispersant such as, for example, pyrrolidin-1-one, N-alkylpyrrolidon-2-one, acetone, polyethylene glycol or an ester or ester thereof, propylene glycol or synthetic triglycerides.

When the composition is in the form of an ointment, for example, it is contemplated that the isoxazoline may be mixed, for example, with either a paraffin or water-miscible ointment base. When the composition is in the form of a cream, it is contemplated that the isoxazoline may be formulated with an oil-in-water cream base. In some cases, 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, glycerin, polyethylene glycol, or a mixture thereof.

Injectable preparations can be prepared, for example, according to methods known in the art, using suitable solvents, solubilizers, stabilizers, dispersants, wetting agents and/or suspending agents. Suitable carrier materials include, for example, water, ethanol, butanol, benzyl alcohol, glycerin, 1,3-butanol, Ringer's solution, isotonic sodium chloride solution, mixture of fixed oils (eg, synthetic mono- or diglycerides), vegetable oil (eg , corn oil), dextrose, mannitol, fatty acids (e.g., oleic acid), dimethylacetamide, surfactants (e.g., ionic and nonionic surfactants), N-methylpyrrolidone, propylene glycol and/or polyethylene glycols (e.g., PEG 400 ). Suspected solubilizers include, for example, polyvinylpyrrolidone, ethoxylated castor oil, ethoxylated sorbitan ester, and the like. Suspected stabilizers include, for example, benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol and the like.

In some embodiments, the parenteral composition is prepared, for example, from sterile powders or granules with one or more of the carrier materials listed above for other compositions. Isoxazoline, for example, is dissolved or suspended in a liquid such as water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution and/or various buffer solutions. If necessary, the pH can be adjusted with a suitable acid or base or buffer.

For rectal administration, a suppository can be used. A suppository can be prepared, for example, by mixing isoxazoline with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and will therefore melt in the rectum, releasing the drug. Suspected excipients include, for example, cocoa butter, synthetic mono-, di- and triglycerides, fatty acids and/or polyethylene glycols.

If desired, other inert ingredients may generally be added to the composition. By way of illustration, it is contemplated that they may include, for example, lactose, mannitol, sorbitol, calcium carbonate, sodium carbonate, tricalcium phosphate, disubstituted calcium phosphate, sodium phosphate, kaolin, compressible sugar, starch, calcium sulfate, dextro or microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, crospovidone, tragacanth, hydroxypropyl cellulose, cold water swelling starch, povidone, ethyl cellulose, hydroxypropyl methyl cellulose and methyl cellulose.

A general discussion regarding the preparation of drugs and various excipients can be found, for example, in Gennaro AR et al., eds., in Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins, ^20th Ed., 2000). Another discussion regarding the preparation of drugs and various excipients can be found, for example, in Liberman HA et al., eds., Pharmaceutical Dosage Forms (Marcel Deeker, New York, NY, 1980).

The concentration of isoxazoline of formula (I) (or any isoxazoline salt, isoxazoline solvate or salt thereof or isoxazoline prodrug) in the composition can vary widely depending, for example, on the route of administration. Typically, 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 proposed combination therapy

The methods of the present invention include methods in which isoxazoline is the only active ingredient administered to the recipient animal. However, the methods are also contemplated to include combination therapy in which isoxazoline is administered in combination with one or more other active ingredients. The other active ingredient(s) may be one or more other isoxazolines. Alternatively (or additionally), the other active ingredient(s) may be one or more compounds that are not isoxazolines. Other active ingredient(s) may be targeted for the same and/or other pathogens and conditions.

Suspected active ingredient(s) that may be administered in combination with isoxazoline include, for example, anthelmintics, insecticides and acaricides, insect growth regulators and juvenile hormone analogues, anti-inflammatory agents, antibacterial agents, hormones, dermatological preparations (for example, antiseptics and disinfectants) and immunobiological agents (for example, vaccines and antisera) to prevent disease.

Anthelmintics include, for example, avermectins (eg, ivermectin, moxidectin and milbemycin), benzimidazoles (eg, fenbendazole, albendazole and triclabendazole), salicylanilides (eg, closantel and oxyclozanide), substituted phenols (eg, nitroxynil), pyrimidines (eg, pyrantel ), imidazothiazoles (eg levamisole), cyclooctadepsipeptides (eg emodepside) and tetrahydropyrimidines (eg praziquantel). Anthelmintics also include, for example, aminoacetonitrile derivatives, such as, for example, those described by Kaminsky R. et al., in “A new class of anthelmintics effective against drug-resistant nematodes,” Nature, vol. 452, pp. 176-180 (March 13, 2008); and in the publication of international patent applications Nos. WO2006/050887 and WO2005/044784.

In some embodiments, isoxazolines are administered in combination (and in some cases in the same composition) with one or more macrocyclic lactone endectocidal parasiticides. There is a trend to use such parasiticides against, for example, a wide range of endoparasites and ectoparasites in mammals.

One particularly considered macrocyclic lactone parasitocide is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin, which is typically prepared as a mixture of at least 80% 22,23-dihydroavermectin B1 _a and less than 20% 22,23-dihydroavermectin B1 _b . Ivermectin is disclosed in US Pat. No. 4,199,569. Ivermectin has been used as an antiparasitic agent for the treatment of various parasitic diseases since the mid-1980s.

Other macrocyclic lactone parasitocides include, for example:

A. Abamecti n. This compound is, for example, identified in US Pat. No. 4,310,519 as avermectin _B1a / _B1b . Abamectin contains at least 80% avermectin B1 _a and no more than 20% avermectin B1 _b .

B. Doramectin . This compound is known as 25-cyclohexylavermectin B ₁ . Its structure and preparation are discussed, for example, in US patent 5,089,480.

C. Moxidectin . This compound is discussed, for example, in US Pat. No. 4,916,154.

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

E. Milbemitsin . This compound is also known as B41. It is isolated from the culture fluid of a milbemycin-producing Streptomyces strain. The microorganism, fermentation conditions and isolation methods are discussed, for example, in US patents 3950360 and 3984564.

F. Emamectin . This compound is also known as 4"-deoxy-4"-epimethylaminoavermectin B ₁ . Its preparation is discussed, for example, in US patents 5288710 and 5399717. It is a mixture of two homologs of 4"-deoxy-4"-epimethylaminoavermectin B1 _a and 4"-deoxy-4"-epimethylaminoavermectin B1 _b . As a rule, emamectin salt is used. Non-limiting examples of such salts are discussed in US Pat. No. 5,288,710, which describes salts prepared with benzoic acid, substituted benzoic acid, benzenesulfonic acid, citric acid, phosphoric acid, tartaric acid and maleic acid. A particularly debated salt is emamectin benzoate.

G. Eprinomectin . This compound is also known as 4"-epiacetylamino-4"-deoxyavermectin B ₁ . It is designed for use on cattle of all classes and age groups. It was the first avermectin to show a broad spectrum of activity against both endo- and exoparasites, while remaining in minimal quantities in meat and milk. It typically has the added benefit of high strength when delivered locally.

Insecticides and acaricides include, for example, acephate, acetampiride, acetoprole, amitraz, amidoflumet, avermectin, azadirachtin, azinphosmethyl, bifenthrin, bifenazate, biprofezin, bistrifluron, carbofuran, cartap, chlorfenapyr, chlorfluazuron, chlorantranilprole, chlorpyrifos, chlorpyrifosmethyl, chlormafenose id, clothianidin, cyflutiin , β-cyfluthrin, cyhalothrin, γ-cyhalothrin, λ-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diophenolan, emamectin, endosulfan, esfenvalerate, ethiprole, phenothiocar b, fenoxycarb, fenpropathrin , fenvalerate, fipronil, flonicamid, flubendiamide, flucitrinate, tau-fluvalinate, flufenerim, flufenoxuron, fonofos, halofenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaflumizone, metaldehyde, methamidophos, methidate ion, methoprene, methoxychlor, metofluthrin , monocrotophos, methoxyfenozide, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathiorimethyl, permethrin, phorate, fosalone, phosmet, phosphamidori, pirimicarb, profenofos, profluthrin, protrifenbut, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazone, pyr iprol, pyriproxyfen , rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbofos, tetrachlorvinfos, thiacloprid, thiamethoxam, thiodicarb, thiosultapsodium, tolfenpyrad, tralomethrine, triazamate, trichlor background and triflumuron. Common references that discuss antiparasitic agents such as insecticides and acaricides include, for example, The Pesticide Manual. ^13th Edition, CDS Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, UK (2003).

In some contemplated embodiments, the isoxazoline is administered with pyridylmethylamine derivatives, such as, for example, the pyridylmethylamine derivatives discussed in European Patent Application EP0539588 or International Patent Application Publication WO2007/115643.

In some contemplated embodiments, isoxazoline is administered with nodulisporic acids and derivatives thereof, such as, for example, the compounds discussed in US Pat. Nos. 5,399,582, 5,945,317, 5,962,499, 5,834,260, 6,221,894, or 5,595,991 or International Application Publication No. 1996/29073.

Insect growth regulators include, for example, agridine, diophenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, ifenuron, tebufenozide and triflumuron. These compounds tend to provide both initial and long-term control of parasites at all stages of insect development, including eggs, on the animal, as well as in the environment surrounding the animal.

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

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 nonsteroidal anti-inflammatory drugs (“NSAIDs”). NSAIDs include, for example, salicylates, arylalkanoic acids, 2-arylpropionic acids (or "prophens"), N-arylanthranilic acids, pyrazolidine derivatives, oxicams, 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.

In the intended combination therapy, the isoxazoline of formula (I) can be administered before, simultaneously and/or after the other active ingredient(s). In addition, isoxazoline can be administered in the same composition as the other active ingredient(s) and/or in separate compositions of the other active ingredient(s). In addition, the isoxazoline and the other active ingredient(s) can be administered by the same and/or different routes of administration.

When isoxazoline is administered in combination therapy, the weight ratio of the active ingredients can vary widely. Factors influencing this relationship include, for example, the specific isoxazoline, the identity of the other active ingredient(s) administered in the combination therapy, the route(s) of administration of the isoxazoline and the other active(s). ) ingredient(s), target and pathogen status, type (e.g., species and breed), age, size, sex, nutrition, activity, and condition of the intended recipient, and pharmacological considerations such as potency, efficacy, pharmacokinetic and toxicological profiles of isoxazoline and other active ingredient(s). In some contemplated embodiments, for example, the weight ratio of isoxazoline to other active ingredient(s) is, for example, from about 1:3000 to about 3000:1. In some such cases, the weight ratio is from about 1:300 to about 300:1. In other such cases, the weight ratio is from about 1:30 to about 30:1.

It is contemplated that, in addition to other active ingredients, isoxazoline may be administered with one or more other compounds that beneficially affect the activity (eg, enhance or prolong) (or other properties, such as safety) of isoxazoline. For example, it is contemplated that isoxazoline can be administered with one or more synergistically acting drugs, such as, for example, piperonyl butoxide (PBO) and triphenyl phosphate (TPP). Other synergistically active drugs include, for example, N-(2-ethylhexyl)-8,9,10-trinorborne-5-ene-2,3-dicarboxamide (also known as "ENT 8184" or "MGK 264") and verbutin (also known as "MV-599"). Discussion related to insecticidal synergistic drugs can be found, for example, in The Pesticide Manual, ^13th Edition, cited above.

VI. Therapy kits

The present invention also relates to kits which are suitable, for example, for use in carrying out the treatment methods described above. Typically, such a kit will include a therapeutically effective amount of an isoxazoline of formula (I) and other component(s). The other component(s) may be, for example, one or more of the following: a diagnostic instrument, instructions for administering the composition, an apparatus for administering the composition, a container including an excipient or other active ingredient mixed or administered into combination with the composition, or a reminder (eg, a label placed on a calendar to remind the pet owner when the next dose of the composition should be administered).

Examples

The following examples are illustrative only and do not limit the present invention in any way. The compound numbers shown in the examples refer to the compound structure numbers in the above detailed description and in the claims below.

Example 1: Efficacy of Compounds 10-1 and 11-1 against Cat Fleas (Ctenocephalides felis)

Adult fleas (2-30) are fed blood on artificial membranes supplemented with Compound 10-1, Compound 11-1, or a positive control (fipronil) at a concentration of 100, 10, or 1 ppm. Efficacy against fleas is assessed after 48 hours of continuous feeding, comparing the number of dead and damaged fleas with the number of fleas fed. Efficacy against fleas was 100% for compound 10-1, compound 11-1 and fipronil at concentrations of 100, 10 and 1 ppm.

Example 2 Animal Model Studies for Compound 11-1

The purpose of such studies is to evaluate the effectiveness of compound 11-1 against various parasites. Parasites are listed in the table below.

Arthropods View Family Common name Insects Ctenocephalides felis Common fleas Cat fleas Insects Cimex lectularius Bed bugs Bedbug Ticks Ornithodoros moubata Argasid mites Chicken mite Ticks Rhicephalus sanguineus Ixodid ticks Brown dog tick Ticks Mycoptes musculinus Mycoptidae Rodent fur mite

A. Effectiveness against fleas in mice

Mice are 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 not treated (negative control). These mice are sedated and infected with adult fleas (C. felis) 1, 3, 6, and 24 hours after treatment. Fleas are removed from mice after approximately 30 minutes of feeding. Flea suppression (% of dead and damaged fleas) is assessed 1 and 24 hours after each infestation. The results are shown in Table 1.

Table 1
Results of experimental evaluation of the in vivo effectiveness of compound 11-1 against fleas in mice Time of infection after treatment 1 hour 3 hours 6 o'clock 24 hours Flea suppression using oral administration of compound 11-1 1 hour after infestation 43.3% 44.3% 17.7% 37.7% Flea suppression using subcutaneous injection of compound 11-1 1 hour after infestation 7.7% 31.0% 21.0% 100% Flea suppression using topical administration of compound 11-1 1 hour after infestation 0% 0% 0% 2% Flea suppression using oral administration of compound 11-1 24 hours after infestation 67.7% 48.7% 26.7% 82.0% Flea control using subcutaneous injection of compound 11-1 24 hours after infestation 40.0% 42.3% 36.7% 100% Flea control using topical administration of compound 11-1 24 hours after infestation 97.7% 99.0% 81.0% 93.3% Flea control using oral fipronil 1 hour after infestation 0-2% 0-2% 0-2% 0-2% Flea control using subcutaneous fipronil 1 hour after infestation 0-2% 0-2% 0-2% 0-2% Flea control using topical fipronil 1 hour after infestation 0-2% 0-2% 0-2% 0-2% Flea control using oral fipronil 24 hours after infestation 3.3% 12.3% 6.7% 7.7% Flea control using subcutaneous fipronil 24 hours after infestation 1.0% 15.7% 97.7% 94.3% Flea control using topical fipronil 24 hours after infestation 100% 94.3% 100% 76.7% Suppression from negative control 1 hour postinfection Not detected Not detected Not detected Not detected Suppression from negative control 24 hours postinfection Not detected Not detected Not detected Not detected

Typically, with compound 11-1, only a few damaged fleas relative to dead fleas are found. However, with fipronil, dead and damaged fleas are usually found in equal numbers. No side effects were observed with compound 11-1 or fipronil during this experiment.

B. Efficacy against ticks in mice

All mice used in the study were infected with M. musculinus at all stages of parasite development with at least a moderate degree of infection (“++”). Mice are 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 not treated (negative control). This treatment is then repeated after 7 days. The degree of infection per mouse (“+” = low degree of infection, “++” = medium degree of infection, “+++” = high degree of infection) is assessed again on days 1, 6, 9, 13 and 23. Efficacy is defined as the reduction degree of infection in treated mice relative to the negative control group. The results are shown in Table 2.

table 2
Results of experimental evaluation of the in vivo effectiveness of compound 11-1 against ticks in mice Day 0 Day 1 Day 6 Day 9 Day 13 Day 23 Infection following oral administration of compound 11-1 ++ to +++ + to ++ (remaining pliers are slightly damaged) ++ 2 mice: not detected Not detected Not detected 1 mouse: + (the remaining ticks are damaged) Infection after subcutaneous administration of compound 11-1 ++ to +++ + to ++ (remaining pliers are slightly damaged) ++ Not detected Not detected Not detected Infection after topical administration of compound 11-1 ++ to +++ + (remaining pliers are seriously damaged) 2 mice: not detected Not detected Not detected Not detected 1 mouse: + (the remaining ticks are damaged) Infection after oral administration of fipronil ++ to +++ +++ ++ to +++ ++ to +++ + + Infection after subcutaneous injection of fipronil ++ to +++ +++ 2 mice: + to ++ 2 mice: + to ++ + + to ++ 1 mouse: +++ 1 mouse: +++ Infection after local administration of fipronil ++ to +++ 2 mice: + to ++ + to ++ 2 mice: not detected Not detected Not detected 1 mouse: +++ (all ticks are damaged) 1 mouse: + (the remaining ticks are damaged) Infection with negative control ++ to +++ ++ to +++ ++ to +++ ++ to +++ ++ to +++ ++ to +++

No side effects were observed with compound 11-1 or fipronil during the anti-mite efficacy study.

C. Effective against soft-shelled mites (argasids) and bedbugs on guinea pigs

Six guinea pigs are treated orally, subcutaneously or intraperitoneally with 10 mg/kg body weight of compound 11-1 or fipronil (positive control). Guinea pigs are locally co-infested with juvenile soft-shell mites (O. moubata) and bed bugs (C. lectularius) immediately before treatment and at various time points after treatment between days 2 and 50. Ten engorged mites/bugs are collected and the percentage killed is assessed. individuals by sight 24 hours after each infection.

For guinea pigs treated with Compound 11-1, mites and bed bugs die within 1-5 hours of infection until day 29 and within 8-24 hours after day 29. For guinea pigs treated with fipronil, mites and bed bugs die die within 1-7 hours after infection until day 29 and within 8-24 hours after day 29. Results for effectiveness against ticks are shown in Table 3.

Table 3
Results of an experimental evaluation of the in vivo effectiveness of compound 11-1 against soft-shelled mites (O. moubata) in guinea pigs Animal Treatment Observation 1 Oral administration of compound 11-1 Observe 100% effectiveness until day 31 2 Subcutaneous administration of compound 11-1 100% effectiveness observed until day 31. 70% effectiveness observed until day 33. No effectiveness observed after day 33 3 Intraperitoneal administration of compound 11-1 100% effectiveness observed until day 31. No effectiveness observed after day 31 4 Oral administration of fipronil Observe 100% effectiveness up to day 50 5 Subcutaneous injection of fipronil Observe 100% effectiveness up to day 50 6 Intraperitoneal administration of fipronil Observe 100% effectiveness up to day 50

Results for effectiveness against bed bugs are shown in Table 4.

Table 4
Results of an experimental evaluation of the in vivo effectiveness of compound 11-1 against bedbugs (C. lectularius) in guinea pigs Animal Treatment Observation 1 Oral administration of compound 11-1 Observe 100% effectiveness until day 31 2 Subcutaneous administration of compound 11-1 Observe 100% effectiveness until day 35. Observe 90% effectiveness until day 40. And observe 20% effectiveness until day 42. After day 42, no effectiveness is observed. 3 Intraperitoneal administration of compound 11-1 100% effectiveness is observed until day 33. And 90% effectiveness is observed until day 35. No effectiveness is observed after day 35. 4 Oral administration of fipronil 100% effectiveness observed until day 18, 80-100% effectiveness observed until day 33, and no effectiveness observed on day 46 5 Subcutaneous injection of fipronil 90-100% effectiveness is observed until day 16, 80-100% effectiveness is observed until day 35, 50% effectiveness is observed until day 37, and 0-20% effectiveness is observed after day 37. 6 Intraperitoneal administration of fipronil 100% effectiveness observed until day 18, 70-100% effectiveness observed until day 31, and no effectiveness observed on day 48

No adverse effects were observed with compound 11-1 or fipronil during this study. Although the guinea pig treated orally with Compound 11-1 (i.e. animal #1) died after day 31, the death occurred without clinical symptoms and is not considered treatment related as it occurred sufficiently long after treatment.

D. Effectiveness against hard coated ticks (ixodide) on guinea pigs

Guinea pigs are divided into groups of three. Each group was subjected to one of the following treatments with either Compound 11-1 or fipronil (positive control) or no treatment (negative control).

Study 1

1. Local administration of 100 ppm body weight by immersion of the animal.

2. Oral administration of 10 mg/kg body weight.

3. Subcutaneous administration of 10 mg/kg body weight.

4. Without treatment (negative control).

Study 2

1. Local administration of 100 ppm body weight by immersion of the animal.

2. Oral administration of 2.5 mg/kg body weight.

3. Subcutaneous administration of 2.5 mg/kg body weight.

4. Without treatment (negative control).

On the eve of treatment, all guinea pigs are infested with 100 viable young (“nymph”) hard-shelled ticks (brown dog ticks, R. sanguineus). Satiated fallen off nymphs are counted (eN) from day 4 to day 8 to calculate the effectiveness of treatments using the following formula:

In addition, collected mites are assessed for moulting at the next stage.

In the first stage, 32 saturated R. sanguineus nymphs were collected from animals in the untreated negative control group. And at the second stage, 75 saturated R. sanguineus nymphs are collected from animals in the untreated negative control group. At the next stage, molting is observed for the negative control groups of both stages. In contrast, nymphs of either group treated with compound 11-1 or fipronil were not collected in any study. Thus, the suppression of satiated nymphs in the case of both compound 11-1 and fipronil is 100%. No adverse effects were observed with compound 11-1 or fipronil during any study.

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

In this experiment, mice are randomly assigned to a treatment group or a negative control (no treatment) group. Each group consists of three mice. Mice in the treatment groups were administered orally 20 mg/kg body weight of various isoxazolines dissolved in 7% DMF premix and 93% distilled water (water for injection). The applied volume for such treatments is 0.1 ml/g body weight. One hour after treatment, each mouse is sedated and typically infested (whole body) with 30 viable adult fleas (C. felis). To achieve this, sedated mice are placed directly into a parasite inoculation jar and fleas are placed directly on the fur. After approximately 30 minutes of saturation, fleas are collected from the mice. Suppression and lethality assessments were made at 1 hour, 24 hours, and 48 hours after each challenge. Efficacy is calculated as the percentage of fleas suppressed in the treated groups relative to the negative control group.

The efficacy results are shown in Table 5. All treatments shown in Table 5 were well tolerated in mice.

Table 5
Results of experimental evaluation of the in vivo effectiveness of various isoxazolines against fleas in mice Time after infection Compounds showing <10% inhibition Compounds showing 10%≤<30% suppression Compounds showing 30%≤<60% suppression Compounds showing 60%≤<90% suppression Compounds showing ≥90% inhibition 1 hour 5-15 (0%), 5-19 (0%), 5-52 (0%), 5-53 (0%), 5-47 (0%), 5-54 (0%), 5- 16 (0%), 5-48 (0%), 5-21 (0%), 5-22 (0%), 5-23 (0%), 5-49 (0%), 5-24 ( 0%), 5-25 (0%), 5-55 (0%), 5-29 (0%), 5-26 (0%), 5-43 (0%), 5-44 (0% ), 5-51 (0%), 5-56 (0%), 5-45 (0%), 5-17 (0%), 5-46 (0%), 5-31 (0%), 5-18 (0%), 5-32 (0%), 5-57 (0%), 5-33 (0%), 5-35 (0%), 5-40 (0%), 5- 41 (0%), 5-28 (1.1%), 5-30 (2.2%), 5-34 (2.3%), 5-38 (2.3%), X-l (4, 3%), 5-20 (4.4%), 5-14 (4.4%), 5-42 (5.5%), 5-37 (7.7%) and 11-1R (0% ) 5-62 (10%), 5-58 (11.1%), 5-27 (12.2%), 5-39 (13.3%), 5-13 (16.7%), 5- 59 (18.8%), 5-61 (21.1%), 5-60 (26.6%) and 5-50 (27.7%) 5-63 (30%), 5-36 (45.7%), 5-64 (50%) and 5-65 (58.8%) 10-1 (63.3%), 5-68 (75.5%), 5-66 (77.8%), 11-1 (78.9%) and 5-67 (80%) 14-1 (97.8%) and 17-1 (100%)

Time after infection Compounds showing <10% inhibition Compounds showing 10%≤<30% suppression Compounds showing 30%≤<60% suppression Compounds showing 60%≤<90% suppression Compounds showing ≥90% inhibition 24 hours 11-1R (0%) 5-14 (13.3%) and 5-13 (18.9%) 5-15 (31.1%), 5-17 (36.7%), 5-16 (46.7%) and 5-18 (54.4%) 5-31 (65.6%), 5-29 (68.8%), 5-30 (67.8%), 5-32 (70%), 5-28 (70%), 5-27 ( 72.2%), 5-21 (75.6%), 5-25 (75.6%), 5-44 (75.6%), 5-26 (77.8%), 5-62( 81.1%), 5-53(82.2%), 5-22 (82.2%), 5-24 (84.4%), 5-46 (85.6%), 5-40 ( 85.6%), 5-57 (86.7%), 5-23 (87.8%) and 5-56 (87.8%) 5-19 (90%), 5-48 (91.1%), 5-68 (91.1%), 5-55 (92.2%), 5-43 (92.2%), 5- 45 (92.2%), 5-65 (92.2%), 5-41 (94.3%), 5-59 (94.4%), 5-47 (95.6%), 5- 61 (95.6%), 5-50 (95.6%), 5.63 (95.6%), 10-1 (95.65), 5-34 (96.6%), 5-52 (96.7%), 5-49 (96.7%), 5-38 (96.7%), 5-20 (96.7%), 5-60 (96.7%), 11-1 (96.7%), 5-51 (97.8%), 5-64 (97.8%), 5-54 (98.9%), 5-37 (99%), 5-39 (99 %), 5-36 (99%), 5-33 (100%), 5-35 (100%), 5-42 (100%), 5-58 (100%), 5-66 (100%) , 5-67 (100%), 17-1 (100%), 14-1 (100%) and X-1 (100%)

Time after infection Compounds showing <10% inhibition Compounds showing 10%≤<30% suppression Compounds showing 30%≤<60% suppression Compounds showing 60%≤<90% suppression Compounds showing ≥90% inhibition 48 hours 11-1R (0%) 5-13 (18.9%) and 5-14 (22.2%) 5-15 (36.7%), 5-17 (41.1%), 5-16 (54.4%) and 5-18 (54.4%) 5-31 (65.6%), 5-29 (68.9%), 5-30 (68.9%), 5-32 (71.1%), 5-28 (71.1%), 5-21 (77.8%), 5-26 (77.8%), 5-44 (78.9%), 5-62 (81.1%), 5-22 (83.3%), 5-25 (84.4%), 5-27 (84.4%), 5-40 (85.6%), 5-24 (86.7%), 5-46 (86.7%), 5-57 (87.7%) and 5-56 (88.9%) 5-53 (91.1%), 5-48 (91.1%), 5-43 (92.2%), 5-55 (93.3%), 5-45 (93.3%), 5-65 (93.3%), 5-19 (94.4%), 5-23 (94.4%), 5-41 (95.6%), 5-59 (95.6%), 5-68 (95.6%), 5-34 (96.6%), 5-52 (96.7%), 5-47 (96.7%), 5-60 (96.7%), 5-38 (97.7%), 5-49 (97.8%), 5-51 (97.8%), 5-20 (97.8%), 5-61 (97.8%), 5-64 (97.8%), 10-1 (97.8%), 11-1 (97.8%), 5-63 (98.9%), 5-39 (99%), 5- 36 (99%), 5-54 (100%), 5-33 (100%), 5-35 (100%), 5-42 (100%), 5-37 (100%), 5-58 ( 100%), 5-50 (100%), 5-66 (100%), 5-67 (100%), 17-1 (100%), 14-1 (100%) and X-1(100% )

Example 4: Efficacy of various isoxazolines against brown dog ticks (Rhipicephalus sanguineus) on guinea pigs

In this experiment, guinea pigs are randomly assigned to a treatment group or a negative control (no treatment) group. Each group consists of three guinea pigs. On day zero, each guinea pig is infected with 100 viable R. sanguineus nymphs. On day 1, guinea pigs in the treatment groups were orally administered 10 mg/kg body weight of various isoxazolines dissolved in 7% DMF premix and 93% distilled water (water for injection). Satiated fallen off nymphs are counted (eN) from day 4 to day 8 to calculate the effectiveness of isoxazolines using the following formula:

In addition, collected mites are assessed for moulting at the next stage. The efficacy results are shown in Table 6. No side effects were observed with any of the test compounds presented in Table 6 during the study.

Table 6
Results of an experimental evaluation of the in vivo effectiveness of various isoxazolines against brown dog ticks in guinea pigs Compounds showing <10% inhibition 5-43 (0%) and 5-45 (0%) Compounds showing 10%≤suppression<30% 5-44 (15.6%), 5-42 (16.5%), 5-14 (22.4%) and 5-46 (26.4%) Compounds showing 30%≤suppression<60% 5-50 (32.3%), 5-48 (36.5%), 5-51 (52.1%), 5-49 (54.2%) and 5-47 (58.5%) Compounds showing 60%≤suppression<90% 5-57 (71.9%), 5-56 (76.0%), 5-53 (76.4%), 5-60 (78.9%), 5-65 (79.2%), 5-63 (85.3%) and 5-62 (88.5%) Compounds showing ≥90% inhibition 5-52 (93.4%), 5-55 (94.8%), 5-59 (96.3%), 5-54 (100%), 5-58 (100%), 5-61 ( 100%), 5-64 (100%), 5-68 (100%), 5-66 (100%), 5-67 (100%), 10-1 (100%), 11-1 (100% ) and 14-1 (100%)

Example 5: Efficacy of Compound 11-1 against Cat Fleas (C. felis) and Brown Dog Ticks (R. sanguineus) on Dogs

On day zero, one group of 4 beagles are treated orally with gelatin capsules containing 20 mg/kg body weight of compound 11-1. Another group of 4 beagles are treated topically by washing 2 L of a solution containing 200 ppm body weight of compound 11-1 dissolved in DMF premix/tap water (1:100, v/v). Finally, a group of 3 beagles was left untreated as a negative control. Two days prior to treatment on day zero, all beagles are infested with approximately 80 hungry adult fleas (C. felis) and approximately 60 hungry brown dog ticks (R. sanguineus). The parasite load of each beagle is assessed on Day 2 (approximately 48 hours after treatment) by removing and counting fleas and ticks. Fleas and ticks are classified by viability (fleas: dead or alive; ticks: dead or alive and saturated or not saturated). Efficacy is calculated from the average number of live fleas and ticks in the treated group (Mt) relative to the average number of live fleas and ticks in the untreated control group (Mc) using the following formula:

Compound 11-1 shows 100% effectiveness against fleas and ticks after oral and topical treatment. No side effects were observed during this study.

Example 6 Additional study of the effectiveness of compound 11-1 against cat fleas (C. felis) and brown dog ticks (R. sanguineus) on dogs

Beagles were randomly assigned to 5 treatment groups of 4 animals each and one untreated control group of 3 animals. Dogs in treatment groups are treated on day zero as shown in Table 7.

Table 7
Treatment groups to study the effectiveness of compound 11-1 against cat fleas (C. felis) and brown dog ticks (R. sanguineus) on beagles Group Treatment A 1 mg/kg body weight of compound 11-1 in tablet form for oral administration. The composition contains 13.33% of compound 11-1; 3.29% lactose monohydrate (Granulac 200); 0.01% sodium lauryl sulfate; 0.90% povidone 25; 0.15% water; 40.98% lactose monohydrate (Flowlac 100); 33.33% corn starch; 3.00% silica, colloidal anhydrous; 4.00% sodium starch glycolate and 1.00% magnesium stearate. IN 1 mg/kg body weight of compound 11-1 in the form of an injection solution for subcutaneous administration. One ml of the composition contains 20 mg of compound 11-1; 0.4 ml dimethyl sulfoxide; 0.24 ml propylene glycol and enough ethyl lactate to bring the total volume to 1 ml. WITH 1 mg/kg body weight of compound 11-1 in the form of a solution for local administration by drops (solution includes an absorption enhancer). One ml of the composition contains 20 mg of compound 11-1; 0.35 ml of dimethyl sulfoxide and enough dipropylene glycol monomethyl ether to bring the total volume to 1 ml. D 1 mg/kg body weight of compound 11-1 in the form of a solution for local administration by drops (the solution includes an absorption enhancer and a wetting agent). One ml of the composition contains 20 mg of compound 11-1; 0.35 ml dimethyl sulfoxide; 0.1 ml isopropyl myristate and enough dipropylene glycol monomethyl ether to bring the total volume to 1 ml. E 1 mg/kg body weight of compound 11-1 in the form of a solution for topical administration by drops. One ml of the composition contains 20 mg of compound 11-1 and enough ethyl lactate to bring the total volume to 1 ml. F No treatment (negative control)

Dogs are infested with approximately 80 fleas (C. felis) and 60 brown dog ticks (R. sanguineus) on days -2, 7, 14, 21, 28, 35, 42 and 49. Fleas and ticks are counted on day 2 (approximately 48 hours after treatment), and on days 9, 16, 23, 30, 37, 44 and 51 (approximately 48 hours after each treatment after re-infestation) to evaluate insecticidal and acaricidal activity in the treated groups. In group B, an additional flea and tick infestation is carried out on day 56 with a corresponding flea and tick count on day 58. In addition to the flea and tick count, blood samples are taken before treatments, as well as after 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 is 5 ng/ml. Table 8 shows the observed effectiveness against ticks.

Table 8
Efficacy of various Compound 11-1 treatments against brown dog ticks (R. sanguineus) on beagles Group Day 2 Day 9 Day 16 Day 23 Day 30 Day 37 Day 44 Day 51 Day 58 A 99.4 99.3 98.3 98.2 98.9 94.6 82.0 82.0 IN 100 99.3 100 98.8 99.5 98.8 95.1 88.8 74.0 WITH 81.9 98.7 94.8 98.2 96.2 87.0 76.5 55.3 D 83.1 96.1 98.3 98.2 96.2 94.1 73.8 63.4 E 70.6 90.2 95.9 91.5 97.8 89.2 79.8 59.6 F 0 0 0 0 0 0 0 0

Table 9 shows the observed effectiveness against fleas.

Table 9
Efficacy of various treatments with compound 11-1 against cat fleas (C. felis) on beagles Group Day 2 Day 9 Day 16 Day 23 Day 30 Day 37 Day 44 Day 51 Day 58 A 100 100 100 100 100 100 100 100 IN 100 100 100 100 100 100 100 100 99.7 WITH 100 100 100 100 100 100 100 100 D 100 100 100 100 100 100 100 100 E 100 100 100 100 100 100 100 100 F 0 0 0 0 0 0 0 0

The observed mean plasma concentration of compound 11-1 over the course of the study is shown in Figure 1. In Fig. 1, the data "PO" refers to group A, the data "SC" refers to group B, the data "TOP W/AMP" refers to group C, the data "TOP W/AMP AND WETTER" refers to group D, and the data " TOP W/ETHYLLACTATE" refers to group E. The results for group F are not shown in Fig. 1, since it is specified that compound 11-1 is not administered to this group.

Example 7. Isolation of R- and S-isomers of compound 11-1

Compound 11-1 (260 mg) was dissolved in n-hexane/ethanol 1:1 (13 ml) at 40°C. Divide 80% of the resulting solution into 400 μl aliquots on a semipreparative liquid chromatography system equipped with a Diacel Chiralpack® AD-H column 250 mm long, 10 mm in diameter, with 5 μm particles. The mobile phase consists of a mixture of n-hexane/ethanol 8:2. Use a flow rate of 4 ml/min. The chiral fractions of both enantiomers are collected and evaporated in vacuo. The purity of the collected fractions was monitored by analytical chiral chromatography using a Diacel Chiralpack® AD-H column (250 mm × 4.6 mm, 5 μm) and UV detection at 254 nm. For both enantiomers, the purity was determined to be greater than 99%. This method gives 88 mg of compound 17-1 (S-enantiomer), which has an optical rotation [α] _D ²³ +63.97° (ethanol, c = 2.97 mg/ml); and 80 mg of compound 11-1R (R-enantiomer), which has an optical rotation [α] _D ²³ -61.07° (ethanol, c = 3.93 mg/ml).

The words “include,” “includes,” and “inclusion” should be interpreted inclusively and not exclusively. It is intended that such interpretation be similar to the interpretation of the said words as set forth in the United States Patent Act.

The term "pharmaceutically acceptable" is used as an adjective to denote the suitability of a qualified noun for use in a pharmaceutical product. When used, for example, to describe a salt, excipient or solvate, it characterizes the salt, excipient or solvate as being compatible with the other ingredients of the composition and not harmful to the intended animal recipient to the extent that the harmful effect(s) exceeds( ut) beneficial effect(s) of the salt, excipient or solvate.

All references cited herein are incorporated herein by reference.

The foregoing detailed description of the preferred embodiments is intended only to familiarize those skilled in the art with the invention, its principles, and its practical application so that those skilled in the art can adapt and practice the invention in its many forms as may best suit a particular application. Therefore, the present invention is not limited to the embodiments described above and may vary widely.

Claims (6)

1. Application of isoxazoline structural formula (11-1) or a salt thereof for the manufacture of a medicament formulated as a single dose for quarterly administration to control flea and brown dog tick (Rhipicephalus sanguineus) infestations in dogs and/or cats. 2. Use according to claim 1, where the drug contains from 10 to 50 wt.% isoxazoline. 3. Use according to claim 1 or 2, where the medicinal product is in the form of a chewable tablet. 4. Application according to any one of paragraphs. 1-3, where the drug is in the form of a composition for spot application.