EA044142B1 - ANTIPARASITIC ISOXAZOLINE COMPOUNDS, LONG-ACTING INJECTABLE COMPOSITIONS CONTAINING THEM, METHODS AND APPLICATION - Google Patents

Description

Field of technology to which the invention relates

The invention describes pesticidal and antiparasitic isoxazoline compounds and long-acting injectable compositions containing at least one isoxazoline active ingredient, liquid polyethylene glycol (PEG) and, optionally, a co-solvent. The invention also describes the use of these compounds and compositions against pests and parasites (including ectoparasites (eg, fleas or ticks) and/or endoparasites), and methods for controlling pests and preventing or treating parasitic infections and infestations in animals.

Cross reference to related applications

The invention claims the benefit of U.S. Provisional Patent Application No. 62/293,333, filed February 24, 2016, and 62/379,348, filed August 25, 2016, both of which are incorporated herein by reference.

Prior Art

Animals such as mammals and birds are often susceptible to parasitic infestations/infections. Such parasites may be ectoparasites such as fleas, ticks and parasitic flies, and endoparasites such as nematodes and other worms. Domesticated animals such as cats and dogs are often infected with one or more of the following ectoparasites:

fleas (eg Ctenocephalides spp. such as Ctenocephalides felis and the like);

parasitiform mites (for example, Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., etc.);

acariform mites (for example, Demodex spp., Sarcoptes spp., Otodectes spp., etc.);

lice (for example, Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.);

mosquitoes (Aedes spp., Culex spp., Anopheles spp., etc.); and flies (Hematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.).

Fleas are a problem because they not only negatively affect the health of an animal or person, but also cause great psychological stress. Moreover, fleas also transmit pathogenic agents such as the tapeworm (Dipylidium caninum) to animals and humans.

Likewise, parasitiform mites are also harmful to the physical and/or psychological health of an animal or human. However, the most serious problem associated with parasitiform ticks is that they transmit pathogenic agents that affect both humans and animals. Major diseases that can be transmitted by ticks include borreliosis (Lyme disease, caused by Borrelia burgdorferi), babesiosis (or piroplasmosis, caused by Babesia spp.), and rickettsial diseases (eg, Rocky Mountain spotted fever). Parasitiform mites also produce toxins that cause inflammation or paralysis in the host. Sometimes these toxins can be fatal to the host.

Likewise, farm animals are also susceptible to parasitic infestations. For example, cattle and other ruminants can be susceptible to a large number of parasites. The dominant parasite of cattle in some regions are parasitiform ticks of the genus Rhipicephalus, especially the species microplus (ringed tick), decoloratus and annulatus. Parasitiform mites such as Rhipicephalus microplus (previously designated Boophilus microplus) are difficult to control because they lay eggs in farm animal pastures. This species of parasitiform tick is considered a single-host tick, and in its immature and adult stages resides on a single animal until the female is fertilized and falls off the host to lay eggs in the environment. The life cycle of such mites is approximately three to four weeks. In addition to cattle, Rhipicephalus microplus can infect buffalo, horses, donkeys, goats, sheep, deer, pigs and dogs. This type of stress on animals can reduce productivity and harm hides, and also spreads diseases such as babesiosis (bovine piroplasmosis) and anaplasmosis.

Animals and humans also suffer from endoparasitic infections, including, for example, helminthiasis, caused by parasitic worms classified as cestodes (tapeworms), nematodes (roundworms) and trematodes (flatworms or flukes). These parasites negatively affect the animal's nutrition and cause great economic damage when raising pigs, sheep, horses and cattle, and also negatively affect domestic animals and poultry. Other parasites that are found in the gastrointestinal tract of animals and humans include members of the genus Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius, and parasites that are found in blood vessels or other tissues and organs , including filarial worms and additional intestinal stages of Strogyloides, Toxocara and Trichinella.

Isoxazole- and isoxazoline-containing compounds have recently been shown to be effective against parasites that infect animals. For example, US Pat. No. 7,964,204 (issued to DuPont, incorporated herein by reference in its entirety) discloses isoxazoline compounds having Formula (I) below, which exhibit activity against ectoparasites and/or endoparasites.

- 1 044142

In addition, published patent applications US 2010/0254960 A1, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, US7951828 and US7662972, US 2010/0137372 A1, US 2010/0 179194 A2, US 2011 /0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1 and WO 2007/075459 A2, and US Patents 7,951,828 and 7,662,972 disclose various other parasiticidal isoxazoline compounds. Other published patent applications that disclose various other parasiticidal isoxazoline compounds and preparations containing them include WO 2007/079162 A1, WO 2008/154528 A1, WO 2009/002809 A2, WO 2011/149749 A1, WO 2014/439475 A1, US 8,466,115, WO 2012/120399, WO 2014/039484, WO 2014/189837, (Zoetis) and WO 2012 120135A1 (Novartis). WO 2012/089623 describes isoxazoline compositions for external topical use containing glycofurol. WO 2013/039948 A1 describes veterinary compositions for external use containing at least one isoxazoline active ingredient, and WO 2013/119442 A1 describes oral veterinary compositions, such as soft chewable compositions, which contain at least one isoxazoline active ingredient.

In addition to dosage forms for external and oral use, it is sometimes possible to include active ingredients in long-acting formulations, depending, for example, on the physicochemical properties of the individual active ingredient; such properties include, for example, solubility, bioavailability, etc. For example, US patents 6,733,767 and 8,362,086 describe long-acting injectable compositions containing bioactive substances, such as, for example, avermectin or milbemycin, and a biologically acceptable polymer.

Despite the highly active isoxazoline active ingredients and compositions containing isoxazoline active ingredients, alone or in combination with other active ingredients, described in the above documents, there is a need for more effective isoxazoline compounds and veterinary compositions and methods with improved efficacy, bioavailability and spectrum of action to protect animals from endoparasites and/or ectoparasites. More specifically, there is a need to develop a long-acting injectable composition containing an isoxazoline compound that has good bioavailability and less irritation at the injection site while maintaining effectiveness against parasites (e.g., fleas and ticks) over a long period of time (e.g., three (3) to six (6) months).

Incorporation by reference.

Any of the foregoing applications and all documents cited therein or during the consideration thereof (documents cited in the application), and all documents or references in documents cited in the application, and all documents cited or referred to herein (documents cited in herein), and all documents cited or referred to in documents cited herein, together with all manufacturer's instructions, descriptions, product data sheets and data sheets for any products mentioned herein or in any document incorporated by reference herein are incorporated herein by reference and may be used in the practice of the invention.

Citation or reference to any document in the present invention does not constitute an admission that such document is considered prior art to the present invention.

The essence of the invention

In a first aspect, the present invention describes new and innovative long-acting injectable preparations for the treatment or prevention of parasitic infections or infestations in an animal, containing an antiparasitic effective amount of at least one isoxazoline compound, a liquid PEG and/or a pharmaceutically acceptable neutral oil, optionally a co-solvent and optionally a pharmaceutically acceptable additive or excipient.

According to a first aspect of the present invention, it has been found that the long-acting compositions of the present invention generally exhibit the desired bioavailability and duration of action while causing minimal irritation at the injection site. The described compositions also have the desired safety profile in relation to warm-blooded animals and birds. In addition, it has been found that single administration of such compositions generally provides sufficient activity against one or more parasites (eg, ectoparasites), while providing rapid onset of action, duration of action and/or the desired safety profile.

The present invention covers the use or veterinary use of those described in

- 2 044142 worth the invention of isoxazoline compounds and compositions for the treatment or prevention of parasitic infections and infestations in animals or on the integument of animals (wild or domestic), including farm and pet animals such as cats, dogs, horses, chickens, sheep, goats, pigs , turkeys and cattle, with the goal of ridding said host animals of parasites commonly found in such animals.

In addition, the compounds described in the present invention having formula (Id) can be used for protecting crops, plants, plant propagation material or material containing or derived from wood from pests.

The present invention also describes methods of treating or preventing parasitic infections and infestations in animals, comprising administering an effective amount of long-acting injectable compositions containing an antiparasitic effective amount of at least one isoxazoline compound together with at least one liquid PEG and/or a pharmaceutically acceptable neutral oil and, optionally, a cosolvent, pharmaceutically acceptable additive and/or excipient, wherein said composition does not contain a pharmaceutically acceptable biodegradable polymer as defined herein. Surprisingly, it has been discovered that the innovative isoxazoline-containing compositions described in the present invention demonstrate a broader spectrum of effectiveness against damaging parasites (e.g., ectoparasites such as fleas and ticks), acting faster and over a longer period of time compared to other injectable compositions containing isoxazoline active ingredients known in the art, while exhibiting minimal irritation at the injection site.

The present invention also describes the use of isoxazoline in the preparation of a long-acting injectable composition for the treatment or prevention of parasitic infections in animals.

In one embodiment, the present invention provides long-acting injectable compositions containing antiparasitic effective amounts of at least one isoxazoline having formula (I) below, in combination with a pharmaceutically or veterinarily acceptable liquid carrier, wherein the variables A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , B ^{1, B 2} , B ³ , R ^{1 , R 2 ,} R ⁴ , R ⁵ , W and n have the meanings specified in the present invention.

^w (I)

In another embodiment, the present invention discloses long-acting injectable compositions containing an isoxazoline compound having formula (Ic):

(1c) or a pharmaceutically acceptable salt thereof; where X ¹ , X ² and X ³ are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Long-acting compositions containing a compound having formula (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, have unexpectedly long-lasting and high effectiveness against Rhipicephalus microplus, with a rapid onset of action and very long lasting effect.

In another embodiment, the described long-acting injectable compositions and methods include 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]N-[ 2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide as active ingredient.

In other embodiments, long-acting injectable compositions may further contain one or more additional active ingredients having systemic activity. Systemic active ingredients may include, but are not limited to, isoxazoline active ingredients of various structures, neonicotinoid systemic active ingredient, 1-N-arylpyrazole systemic active ingredient, macrocyclic lactones such as avermectin and milbemycin, cyclic depsipeptide such as emodepside or PF1022A or their analogs, benzimidazoles, imidazothiazoles, tetrahydropyrimidine active ingredient, organophosphate active ingredient, levamisole, paraherquiamide and/or marcfortine, praziquantel, closantel, chlorsulon, morantel, pyrantel, spinosyn or spinosinode, aminoacetonitrile active ingredient, aryloazol- 2-yl cyanoethyl , systemic insect growth regulator. In one embodiment, the long-acting injectable compositions contain at least one macrocyclic lactone, including (but not limited to)

- 3 044142 avermectins or milbemycins. In some embodiments, the avermectins or milbemycins are eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin.

In other embodiments, the compositions and methods described include at least one of the following: thiabendazole, oxybendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, chlorsulon, aminoacetontrile active ingredient, or aryloazol-2-yl cyanoethylamine.

In a preferred embodiment, the present invention discloses a long-acting injectable composition for treating or preventing a parasitic infection or infestation in an animal, comprising:

a) an effective amount of at least one parasiticidal isoxazoline active substance, which is a compound having formula (Ic):

or a pharmaceutically acceptable salt thereof;

where X ¹ , X ² and X ³ are each independently halogen, C ₁ -C ₃ alkyl or C1 -C3 haloalkyl; And

b) neutral oil, which is selected from triglycerides of fractionated vegetable fatty acids with a chain length from C ₈ to C ₁₀ .

In a second aspect, the present invention discloses new and innovative pesticidal and parasiticidal isoxazoline compounds having the following formula (Id):

where X ¹ represents a bromine, chlorine, iodine or fluorine atom; and X ² represents a chlorine, fluorine or CF ₃ atom;

Y represents the group Y-1, Y-2, Y-3, Y-4, where Z represents N or CH, Y-5 or Y-6

and Q is OH, -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3,

-C(O)NHCH2CH2SCH3 or (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

Compounds having formula (Id) are highly active against arthropod pests and parasites, and can be used to protect animals, including farm animals and companion animals such as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys and cattle, from parasites that infect such animals. The present invention also describes pesticide compounds having formula (Id) for protecting crops, plants, plant propagation material or material containing or derived from wood from pests.

It is the object of the present invention not to include in the present invention any previously known product, method of making, or method of using a product, such that applicants retain and waive rights to any previously known product, process, or method. It should also be noted that the present invention does not include within its scope any product, method of making a product, or method of using a product that does not comply with the written description and requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (section 83 of the EPC), so that applicants retain and waive rights to any previously known product, method of making a product, or method of using a product.

These and other embodiments are described in or are apparent from the following detailed description.

Detailed Description of the Invention

Long-acting injectable compositions.

In a first aspect, the present invention describes new and innovative long-acting injectable compositions for the treatment or prevention of parasitic infections or infestations in an animal, containing an antiparasitic effective amount of at least one isox

- 4 044142 zoline compound, liquid PEG and/or pharmaceutically acceptable neutral oil and, optionally, a co-solvent, pharmaceutically acceptable additive and/or excipient, which do not contain any other pharmaceutically acceptable polymers as defined in the present invention.

The present invention also describes methods and uses for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising administering to an animal in need thereof a long-acting composition containing an antiparasitic effective amount of at least one isoxazoline compound, liquid PEG and/or a pharmaceutically acceptable neutral oil and, optionally, a cosolvent, pharmaceutically acceptable additive and/or excipient.

In another embodiment, the present invention describes long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animals, containing an antiparasitic effective amount of at least one isoxazoline compound and an effective amount of at least one additional active ingredient , PEG and/or a pharmaceutically acceptable neutral oil and, optionally, a cosolvent, pharmaceutically acceptable additive and/or excipient.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline active substance, which is:

i) an isoxazoline compound having formula (I):

W (I) where: A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ are independently selected from the group consisting of CR ³ and N, provided that a maximum of 3 of A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ represent N;

B ¹ , B ² and B ³ are independently selected from the group consisting of CR ² and N;

W represents O or S;

R ¹ is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C 7 -alkylcycloalkyl or C _{4 -C 7 -cycloalkylalkyl} , each of which is optionally substituted with one or more substituents independently selected from R ⁶ ;

each R ² independently represents H, a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C1C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, a C ₁ -C ₆ - alkylthio group, C ₁ -C ₆ -haloalkylthio group, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -haloalkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, C1-C6haloalkylsulfonyl, C ₁ -C ₆ -alkylamino group, C ₂ -C ₆ -dialkylamino group, C ₂ -C ₄ -alkoxycarbonyl, -CN or -NO ₂ ;

each R ³ independently represents H, a halogen atom, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₁ -C ₆ -alkoxy- group, C ₁ -C ₆ -haloalkoxy group, C ₁ -C ₆ -alkylthio group, C ₁ -C ₆ -haloalkylthio group, C 1 -C ₆ -alkylsulfinyl, C 1 -C ₆ -haloalkylsulfinyl, C ₁ - C ₆ -alkylsulfonyl, C ₁ -C ₆ -haloalkylsulfonyl, C ₁ -C ₆ -alkylamino group, C ₂ -C ₆ -dialkylamino group, -CN or -NO ₂ ;

R ⁴ represents H, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₇ alkylcycloalkyl, C ₄ -C ₇ -cycloalkylalkyl, C ₂ -C ₇ -alkylcarbonyl or C ₂ -C ₇ -alkoxycarbonyl;

R ⁵ represents H, OR ¹⁰ , NR11R ¹² or Q ¹ ; or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₇ -alkylcycloalkyl or C ₄ -C ₇ -cycloalkylalkyl, each of which is optionally substituted with one or more substituents independently selected from R ⁷ ; or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are combined to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, wherein said ring is optional substituted with 1-4 substituents independently selected from the group consisting of a C ₁ -C ₂ alkyl, a halogen atom, -CN, -NO ₂ and a C ₁ -C ₂ alkoxy group;

each R ⁶ independently represents a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy group, a C1C ₆ alkylthio group, a C ₁ -C ₆ alkylsulfinyl, a C ₁ -C ₆ alkylsulfonyl, -CN or -NO ₂ ;

each R ⁷ independently represents a halogen atom; C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C6 alkoxy group, C ₁ -C ₆ -alkylthio group, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, C1- C6alkylamino group, C2 _- C8-dialkylamino group, _C3 - _C6 -cycloalkylamino group, _C2 - _C7 -alkylcarbonyl, _C2 - _C7 -alkoxycarbonyl, _C2 - _C7 -alkylaminocarbonyl, _C3 - C ₉ -dialkylaminocarbonyl, C ₂ -C ₇ haloalkylaminocarbonyl, C ₂ -C ₇ -haloalkoxycarbonyl, C ₂ -C ₇ -haloalkylaminocarbonyl, C ₃ -C ₉ dihaloalkylaminocarbonyl, hydroxy group, -NH ₂ , -CN or -NO ₂ ; or Q ² ;

- 5 044142 each R ⁸ independently represents a halogen atom, a C ₁ -C6 alkoxy group, a C ₁ -C ₆ haloalkoxy group, a C 1 -C ₆ alkylthio group, a C 1 -C ₆ haloalkylthio group, C 1 -C ₆ -alkylsulfinyl, C ₁ -C ₆ -haloalkylsulfinyl, C 1 -C ₆ -alkylsulfonyl, C 1 -C ₆ -haloalkylsulfonyl, C 1 -C ₆ -alkylamino group, C ₂ -C ₆ -dialkylamino group, C ₂ -C ₄ -alkoxycarbonyl, -CN or -NO2;

each R ⁹ independently represents a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C3-C6 cycloalkyl, a C ₃ -C ₆ halocycloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ - C ₆ -haloalkoxy group, C ₁ -C ₆ alkylthio group, C 1 -C ₆ -haloalkylthio group, C 1 -C ₆ -alkylsulfinyl, C 1 -C ₆ -haloalkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -haloalkylsulfonyl, C ₁ -C ₆ -alkylamino group, C ₂ -C ₆ -dialkylamino group, -CN, -NO2, phenyl or pyridinyl;

R ¹⁰ represents H; or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₇ -alkylcycloalkyl or C ₄ -C ₇ -cycloalkylalkyl, each of which is optionally substituted with one or more halogen atoms;

R ¹¹ represents H, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₇ alkylcycloalkyl, C ₄ -C ₇ -cycloalkylalkyl, C ₂ -C ₇ -alkylcarbonyl or C ₂ -C ₇ -alkoxycarbonyl;

R ¹² represents H; Q ³ ; or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C4 -C7 -alkylcycloalkyl or C4 -C7 -cycloalkylalkyl, each of which is optionally substituted one or more substituents independently selected from R ⁷ ; or

R ¹¹ and R ¹² , together with the nitrogen atom to which they are attached, are combined to form a ring containing 2-6 carbon atoms and, optionally, one additional atom selected from the group consisting of N, S and O, wherein said ring is optional substituted with 1-4 substituents independently selected from the group consisting of C ₁ -C ₂ -alkyl, halogen atom, -CN, -NO2 and C ₁ -C ₂ -alkoxy group;

Q ¹ represents a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic system, optionally containing 1-3 heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, where each ring or cyclic system is optionally substituted with one or more substituents independently selected from R ⁸ ;

each Q ² is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, wherein each ring is optionally substituted with one or more substituents independently selected from R ⁹ ;

Q ³ represents a phenyl ring or a 5- or 6-membered heterocyclic ring, wherein each ring is optionally substituted with one or more substituents independently selected from R ⁹ ; and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or ii) an isoxazoline compound having formula (II):

Y (P) where: R ₁ represents alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or has one or more substituents selected from halogen, hydroxy, amino -groups, alkyl or di(alkyl)amino groups, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy groups, haloalkoxy groups, alkylthio groups, haloalkylthio groups, R ₇ S(O)-, R ₇ S(O) ₂ -, R ₇ C(O)-, R ₇ R ₈ NC(O)-, R ₇ OC(O)-, R ₇ C(O)O-, R7C(O)NR8- , -CN or -NO2;

X represents aryl or heteroaryl, each of which may be unsubstituted or have one or more substituents selected from halogen, hydroxy, amino, alkyl or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy group, haloalkoxy group, alkylthio group, haloalkylthio group, R7S(O)-, R7S(O)2-, R7QO)-, R7RNC(O)-, R7OC(O )-, R7C(O)O-, R7C(O)NR8-, -CN or -NO2;

A ₁ represents an oxygen atom; And

A ₂ represents an oxygen atom, NR2 or CR ₇ R ₈ ;

G is G-1 or G-2;

G-l G-2

B1, _B2 , _B3 , _B4 and _B5 are independently N or C-R9;

Y represents a hydrogen atom, a halogen atom, -CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl, each of which may be unsubstituted or

- 6 044142 have one or more substituents selected from a halogen atom, hydroxy group, amino group, alkyl or di(alkyl)amino group, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy group , haloalkoxy groups, alkylthio groups, haloalkylthio groups, R ₇ S(O)-, R ₇ S(O) ₂ -, R ₇ C(O)-, R ₇ R ₈ NC(O)-, R ₇ OC(O)-, R ₇ C(O)O-, R ₇ C(O)NR ₈ -, -CN or -NO ₂ ; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Yl 1, Y-12 or Y-13;

R ₂ , R ₃ independently represent a hydrogen atom, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, RioS(O)-, RioS(0)2-, RioC(O) -, RioC(S)-, R _w R11NC(O)-, R _w R11NC(S)-, R _w OC(O)-;

R4, R5 and R6 independently represent hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

R ₇ and R ₈ independently represent hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

R ₉ represents a hydrogen atom, a halogen atom, -CN, or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or has one or more substituents selected from a halogen atom , hydroxy groups, amino groups, alkyl or di(alkyl)amino groups, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy groups, haloalkoxy groups, alkylthio groups, haloalkylthio groups, R ₇ S(O)-, R ₇ S(O) ₂ -, R ₇ C(O)-, R7R8NC(O)-, R7OC(O)-, R7C(O)O-, R7C(O)NR8-, - CN or -NO2;

R ₁₀ , R 11 , R ₁₂ and R ₁₃ each independently represent hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or

R ₁₀ together with R11 forms =0, =S or =NR ₂ ; or

R ₁₂ together with R ₁₃ forms =0, =S or =NR ₂ ;

W represents O, S or NR ₂ ;

n is 1-4; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or iii) an isoxazoline compound having formula (III)

or a pharmaceutically acceptable salt thereof; and/or iv) an isoxazoline compound having formula (IV)

or a pharmaceutically acceptable salt thereof; and/or v) an isoxazoline compound having formula (V):

where R ¹ , R ² and R ³ independently represent H, Cl, F or CF ₃ ; Y represents a diradical group

- 7 044142

T represents a C ₁ -C ₆ alkyl group that is unsubstituted or substituted with a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group -group, C ₁ -C ₆ -alkylthio group, C ₁ -C ₆ -alkylthio group, carboxy group, carbamoyl group or C ₂ -C ₆ -alkanoyl group, which may be unsubstituted or substituted in the alkyl part by a halogen atom, or a pharmaceutically acceptable salt thereof; and/or vi) an isoxazoline compound having formula (VI):

where Y represents a hydrogen, fluorine, chlorine or bromine atom;

R ¹ represents phenyl substituted with 2-4 substituents selected from a halogen atom, methyl, difluoromethyl, trifluoromethyl, methoxy group, trifluoromethoxy group or trifluoropentoxy group;

R ² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;

R ^3a and R ^3b are independently selected from hydrogen, methyl, ethyl or fluoromethyl; or R ^3a and R ^3b are combined with the hydrogen atom to which they are attached to form a cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline active substance, which is:

i) an isoxazoline compound having the above formula (I), or a pharmaceutically acceptable salt thereof; and/or ii) an isoxazoline compound having the above formula (II), or a pharmaceutically acceptable salt thereof; and/or iii) an isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof; and/or iv) an isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof; and/or

v) an isoxazoline compound having the above formula (V), or a pharmaceutically acceptable salt thereof; and/or vi) an isoxazoline compound having the above formula (VI), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline active substance, which is:

i) an isoxazoline compound having the above formula (I), or a pharmaceutically acceptable salt thereof; and/or ii) an isoxazoline compound having the above formula (II), or a pharmaceutical form thereof

- 8 044142 ski acceptable salt; and/or iii) an isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof; and/or iv) an isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof; and/or

v) an isoxazoline compound having the above formula (V), or a pharmaceutically acceptable salt thereof; and/or vi) an isoxazoline compound having the above formula (VI), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (I), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (I), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline active substance having the above formula (I), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ia):

- 9 044142

or a pharmaceutically acceptable salt thereof

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ia) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ia) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ia) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is a C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present. In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound

- 10 044142 nenium having the above formula (Ia), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (e.g. MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (e.g. MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally, a surfactant, and optionally at least one other pharmaceutically acceptable additive, excipient, or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (1a) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is a C ₁ -C ₆ alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ia) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ia) above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (Ia), or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

- 11 044142

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ib):

(TH) or a pharmaceutically acceptable salt thereof, wherein: R ² is independently halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ⁴ represents H or C ₁ -C ₆ -alkyl;

R ⁵ is C1-C ₄ alkyl, optionally substituted with one or more R ⁷ substituents; And

R ⁷ represents C ₂ -C ₇ -alkylcarbonyl, C ₂ -C ₇ -alkoxycarbonyl, C ₂ -C ₇ -alkylaminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl, C ₂ -C ₇ -haloalkylcarbonyl, C ₂ -C ₇ - haloalkoxycarbonyl, C ₂ -C ₇ haloalkylaminocarbonyl, C ₃ -C ₉ -dihaloalkylaminocarbonyl (for example, -CH ₂ C(O)NHCH ₂ CF ₃ ); and n is 0, 1 or 2;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is

- 12 044142 liquid PEG and/or pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerin formal, or a combination of them;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ -triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, where said co-solvent is a C ₁ -C ₆ alcohol, benzyl alcohol or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, where said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is

- 13 044142 liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is a C8-Clo triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib) described above, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C8-Clo triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (II), or a pharmaceutically acceptable salt thereof,

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (II), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (II), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound

- 14 044142 neniya, having formulas 11-1.001 - II-1.025 or II-2.00 - II-2.018

Compounds II-1.001 - II-1.025

Connection No. (Z)p B ⁵ B ⁴ B ³ B ² B ¹ R ¹⁵ R ¹⁶ 1.001 3.5-Ch C-H C-H C-H C-H N H CH ₂ C(O)NHCH ₂ CF ₃ 1.002 3.5-Ch C-H C-H C-H C-H N H ch ₂ cf ₃ 1.003 3.5- (SRz) ₂ C-H C-H C-H C-H N CH ₃ CH ₂ CO ₂ CH ₃ 1.004 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H N CH ₃ CH2CO2H 1.005 3.5-(CF ₃ )2 C-H C-H C-H C-H N CH ₃ CH ₂ C(O)NHCH ₂ CF ₃ 1.006 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H N H CH ₂ C(O)NHCH ₂ CF ₃ 1.007 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H N H CH ₂ CH ₂ SCH ₃ 1.008 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH ₂ C(O)NHCH ₂ CF ₃ 1.009 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH ₂ CH ₂ SCH ₃ 1.010 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH ₂ CF ₃ 1.011 3.5-Ch C-H C-H C-H C-H C-H H CH ₂ C(O)NHCH2CF ₃ 1.012 3.5-Ch C-H C-H C-H C-H C-H H ch ₂ cf ₃ 1.013 3.5-Ch C-H C-H C-H C-H C-H H CH2CH2SCH3 1.014 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H CH ₂ C(O)NHCH ₂ CF ₃ 1.015 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H CH2CF3 1.016 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H CH2CH ₂ SCH ₃ 1.017 3.5-Ch C-H C-H C-Me C-H C-Me H CH ₂ C(O)NHCH ₂ CF ₃ 1.018 3.5-Ch C-H C-H C-Me C-H C-Me H CH2CF3 1.019 3.5-Ch C-H C-H C-Me C-H C-Me H CH2CH2SCH3 1,020 3.5-(CF ₃ ) ₂ C-H C-H C-Me C-H C-Me H CH2C(O)NHCH ₂ CF ₃ 1.021 3.5-(CF ₃ ) ₂ C-H C-H C-Me C-H C-Me H CH2CF3 1.022 3.5-(CF ₃ ) ₂ C-H C-H C-Me C-H C-Me H CH ₂ CH ₂ SCH ₃ 1.023 3-Cl,5-CF ₃ C-H C-H C-Me C-H C-Me H CH ₂ C(O)NHCH ₂ CF ₃ 1.024 3-Cl,5-CF ₃ C-H C-H C-Me C-H C-Me H CH2CF3 1.025 3-Cl,5-CF ₃ C-H C-H C-Me C-H C-Me H CH2CH2SCH3

Connections II-2.001 - II-2.018

Connection No. (Z)p B ⁵ B ⁴ B ³ B ² B ¹ R ¹⁵ R ¹⁶ 2,001 3.5-Ch C-H C-H N C-H C-H H CH ₂ C(O)NHCH ₂ CF ₃ 2,002 3.5-Ch C-H C-H N C-H C-H H ch ₂ cf ₃ 2,003 3.5-Ch C-H C-H N C-H C-H H CH ₂ CH ₂ SCH ₃ 2,004 3.5-(CF ₃ ) ₂ C-H C-H N C-H C-H H CH ₂ C(O)NHCH ₂ CF ₃ 2.005 3.5-(CF ₃ )2 C-H C-H N C-H C-H H CH2CF3 2,006 3.5-(CF ₃ ) ₂ C-H C-H N C-H C-H H CH ₂ CH ₂ SCH ₃ 2,007 3-Cl,5-CF ₃ C-H C-H N C-H C-H H CH ₂ C(O)NHCH ₂ CF ₃ 2,008 3-Cl,5-CF ₃ C-H C-H N C-H C-H H ch ₂ cf ₃ 2,009 3-Cl,5-CF ₃ C-H C-H N C-H C-H H ch ₂ ch ₂ sch ₃ 2,010 3.5-Ch C-H C-H C-H C-H C-H H CH ₂ C(O)NHCH2CF ₃ 2,011 3.5-Ch C-H C-H C-H C-H C-H H ch ₂ cf ₃ 2,012 3.5-Ch C-H C-H C-H C-H C-H H CH ₂ CH ₂ SCH ₃ 2,013 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH ₂ C(O)NHCH ₂ CF3 2,014 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH2CF3 2.015 3.5-(CF ₃ ) ₂ C-H C-H C-H C-H C-H H CH ₂ CH ₂ SCH ₃ 2,016 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H CH2C(O) _NHCH2CF3 2,017 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H ch ₂ cf ₃ 2,018 3-Cl,5-CF ₃ C-H C-H C-H C-H C-H H ch ₂ ch ₂ sch ₃

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optional, antioxidant; And

- 15 044142

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formulas II-1.001 - II-1.025 or II-2.00 - II-2.018, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optional, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formulas II-1.001 - II-1.025 or II-2.00 - II-2.018, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (III) or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

- 16 044142

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is a C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

- 17 044142

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (III), or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

- 18 044142

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerin formal, or a combination of them;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is a C1-C ₆ alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

- 19 044142

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (IV), or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (V), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (V), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

- 20 044142

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (V), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integument, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the formula (Va):

(Va)

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is

C1-C6 alcohol, glycol ether (for example, including but not limited to) monoethyl

- 21 044142 DIETITILENGICOL EIRALLICOL EURAR, Butyldlycol, the non-butyl glycol ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylers of deprophylene glycol, propylene glycol monomethyl, monoethyl ether glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is a C ₁ -C ₆ alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is

- 22 044142 is a C8-C ₁₀ triglyceride, benzyl alcohol or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the formula (Va) described above, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C8- _C10 triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integument, comprising:

a) an antiparasitic effective amount of at least one compound having formula (VI) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (VI), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having the above formula (VI), or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present. In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one compound having formula (VIa):

- 23 044142

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is a C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

- 24 044142

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, where said co-solvent is Ci-Cg alcohol, benzyl alcohol or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, where said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (VIa) described above, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, where said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol or a combination thereof;

d) optionally, antioxidant; And

- 25 044142

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of at least one isoxazoline compound having formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R ² is independently halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ⁴ represents H or C ₁ -C ₆ -alkyl;

R ⁵ is C1-C ₄ alkyl, optionally substituted with one or more R ⁷ substituents; And

R ⁷ represents C ₂ -C ₇ -alkylcarbonyl, C ₂ -C ₇ -alkoxycarbonyl, C ₂ -C ₇ -alkylaminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl, C ₂ -C ₇ -haloalkylcarbonyl, C ₂ -C ₇ - haloalkoxycarbonyl, C ₂ -C ₇ haloalkylaminocarbonyl, C ₃ -C ₉ -dihaloalkylaminocarbonyl (for example, -CH ₂ C(O)NHCH ₂ CF ₃ ); and n is 0, 1 or 2.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein

X ¹ , X ² and X ³ are each independently H, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

- 26 044142

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In one embodiment, the long-acting injectable compositions of the present invention contain a compound having formula (Ic), wherein X ¹ and X ³ independently represent a halogen, and X ² represents a hydrogen atom.

In another embodiment, the long-acting injectable compositions of the present invention contain a compound having formula (Ic) wherein X ¹ , X ² and X ³ are each independently a halogen.

In another embodiment of the present invention, long-acting injectable compositions contain a compound having formula (Ic), wherein X ¹ and X ³ are each independently halogen, and X ² is a C ₁ -C ₃ haloalkyl.

In another embodiment, the present invention describes a long-acting injectable composition containing a compound having formula (Ic), wherein X ¹ and X ² independently represent a halogen, and X ³ represents a C ₁ -C ₃ -haloalkyl.

In another embodiment, the present invention describes a long-acting injectable composition containing a compound having formula (Ic), wherein X ¹ and X ² independently represent halogen, and X ³ represents CF ₃ .

In another embodiment, the present invention describes a long-acting injectable composition containing a compound having formula (Ic), wherein X ¹ and X ³ represent a chlorine atom, and X ² represents a hydrogen atom.

In another embodiment, the present invention describes a long-acting injectable composition containing a compound having formula (Ic) wherein X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3.

In another embodiment, the present invention describes a long-acting injectable composition containing a compound having formula (Ic), wherein X ¹ and X ³ represent a chlorine atom, and X ² represents a fluorine atom.

In another embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of 4-[5-[3-chloro-5(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]- N-[2-oxo-2-[(2,2,2trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (compound having formula Ia).

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic):

(Ic) or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ are each independently halogen or C ₁ -C ₃ haloalkyl; And

X ² represents a halogen or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ are each independently halogen or C ₁ -C ₃ haloalkyl; And

X ² represents a halogen or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

- 27 044142

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ³ are each independently halogen or C ₁ -C ₃ haloalkyl; And

X ² represents a halogen or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF3;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

- 28 044142

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF3;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is a C1-C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether , dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal , or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally, at least one surfactant and/or at least one additional pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, where said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present. In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound

- 29 044142 nenium having the formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ² each independently represent a chlorine atom or a fluorine atom; And

X ³ represents a chlorine atom or CF3;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ each represent a chlorine atom; And

X ² represents a fluorine atom or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ each represent a chlorine atom; And

X ² represents a fluorine atom or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ³ each represent a chlorine atom; And

X ² represents a fluorine atom or a hydrogen atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ represents a chlorine atom;

- 30 044142

X ² represents a fluorine atom; And

X ³ represents CF3;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF3;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, where said co-solvent is

C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether etc.), glycerin, propylene glycol, cyclic carbonates (eg, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

- 31 044142 where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one surfactant and, optionally, at least one additional pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

- 32 044142

X ³ represents CF ₃ ;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally at least one co-solvent, wherein said co-solvent is a C ₈ -C ₁ o-triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of at least one isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ represents a chlorine atom;

X ² represents a fluorine atom; And

X ³ represents CF ₃ ;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer which is

- 33 044142 liquid PEG and/or pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerin formal, or a combination of them;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one surfactant, and optionally at least one additional pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, at least one co-solvent, where said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

- 34 044142 where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ and X ³ represent a chlorine atom; And

X ² represents a fluorine atom;

b) at least one neutral oil, wherein said neutral oil is a C8-C ₁ o-triglyceride;

c) optionally at least one co-solvent, where the co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) above, or a pharmaceutically acceptable salt thereof; Where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof; Where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound as described

- 35 044142 the above formula (Ic), or a pharmaceutically acceptable salt thereof; Where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide, dimethyl sulfoxide or glycerin formal, or a combination of them;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, a co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® 812), C ₈ -C ₁₀ triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one surfactant, and optionally at least one additional pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ , X ² and X ³ each represent a chlorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, a co-solvent, where said co-solvent is a C ₁ -C ₆ alcohol, benzyl alcohol, or a combination thereof;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the above formula (Ic), or a pharmaceutically acceptable salt thereof, where

X ¹ , X ² and X ³ each independently represent a chlorine atom or a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

- 36 044142

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ , X ² and X ³ each independently represent a chlorine atom or a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention describes a long-acting injectable composition for the treatment and/or prevention (prophylaxis) of parasitic infections and infestations in animals or on animal integuments, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (Ic) described above, or a pharmaceutically acceptable salt thereof, where

X ¹ , X ² and X ³ each independently represent a chlorine atom or a fluorine atom;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is immiscible with water or only partially soluble in water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof;

where no other pharmaceutically acceptable polymers are present.

The compounds having formulas (I)-(VIa) may exist as stereoisomers, and each individual stereoisomer present is covered by the structural formulas provided herein. The various stereoisomers mentioned include enantiomers, diastereomers and atropoisomers. For the avoidance of doubt, when an isoxazoline compound (e.g., any of the isoxazoline active ingredients described herein) includes two or more stereoisomers (e.g., (S)- and (R)-enantiomers), the formulas provided herein do not include explicitly stereochemical configuration include each of the possible stereoisomers. One skilled in the art will appreciate that one stereoisomer of the isoxazoline active ingredient may be more active and/or exhibit additional beneficial properties compared to the other enantiomer. In addition, one skilled in the art knows how to separate, enrich and/or selectively obtain the stereoisomer of the isoxazoline compounds described herein. The isoxazoline compounds described in the present invention contain a chiral carbon atom in the five-membered isoxazoline ring (indicated by an asterisk (*) in the structures below); therefore, these compounds contain at least two possible stereoisomers. As an example for compounds having formula (Ia), two possible stereoisomers at the quaternary carbon atom are shown as formulas (S)-Ia and (R)-Ia:

The compound having the above formula (S)-Ia has the (S) configuration at the chiral carbon atom, and the compound having the formula (R)-Ia has the (R) configuration. The representations of molecules provided in the present invention follow standard conventions for depicting stereochemistry. To indicate stereo configuration, bonds extending out of the drawing plane towards the reader are depicted as solid wedges, where the wide end of the wedge is attached to an atom extending above the drawing plane towards the reader. Connections extending out of the drawing plane in the direction away from the reader are depicted as dotted wedges, where the narrow end of the wedge is attached to

- 37 044142 to the atom located further from the reader. Lines of constant width indicate bonds that are in the opposite or neutral direction to the bonds shown by solid or dotted wedges; lines of constant width also indicate bonds in molecules or parts of molecules in which a specific stereo configuration is not intended to be indicated.

In one embodiment of the present invention, the more biologically active enantiomer is considered to be a compound having the formula (S)-Ia. Similarly, the more biologically active enantiomers of isoxazoline compounds having the formula (Ib), (Ic) and (II)-(VIa) are considered to be compounds with a ^-configuration at the chiral carbon atom in the isoxazoline ring. In some embodiments, the isoxazoline compound of the present invention or compositions containing the compound are enriched with an enantiomer that exhibits significant in vitro and in vivo activity (eutomer) and a favorable toxicological profile, compared to a compound or composition enriched with another corresponding enantiomer that exhibits significantly lower activity in vitro and in vivo (distomer).

In the case of enantiomeric enrichment, one enantiomer is present in greater quantity than the other, and the degree of enrichment can be estimated by the value of enantiomeric excess (ee), which is calculated as (2χ-1) 100%, where x is the mole fraction of the dominant enantiomer in the mixture (e.g. , its 20% corresponds to a 60:40 enantiomer ratio). In some embodiments, the compositions of the present invention contain compounds that have an enantiomeric excess of at least 50%. In other embodiments, the compositions of the present invention contain compounds that have an enantiomeric excess of the more active isomer of at least 75%, an enantiomeric excess of the more active isomer of at least 90%, or an enantiomeric excess of the more active isomer of at least 94%. Of particular note are enantiomerically pure embodiments of the more active isomer (eutomer).

The compounds of the present invention may also exist as one or more conformational isomers due to limited rotation around an amide bond attached to an aryl or heteroaryl ring (eg, the amide attached to a naphthyl group in formula (I)). The present invention includes mixtures of conformational isomers. In addition, the present invention includes compounds that are enriched in one conformer over others.

It should be understood that in addition to the compounds having formula (Ia), other isoxazoline compounds having formula (I), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II- 2.001)-(II-018), (III), (IV), (V), (Va), (VI) and (VIa), will also have at least two possible enantiomers as a result of the presence of a quaternary carbon atom in the isoxazoline ring. In addition, some compounds may contain other chiral centers on one or more substituents.

The present invention includes racemic mixtures, for example equal amounts of enantiomers having formulas (I)-(VIa). The present invention also includes compounds having formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-018 ), (III), (IV), (V), (Va), (VI) or (VIa), which are enriched in one enantiomer compared to the racemic mixture. Also included in the present invention are substantially pure enantiomers of compounds having formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001)- (II-018), (III), (IV), (V), (Va), (VI) or (VIa).

Thus, in one embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of at least one isoxazoline having the formula (I), (Ia), (Ib), (Ic), (II), (II- 1.1001)-(II-1.025), (II-2.001)-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is significantly enriched in one enantiomer , or a pharmaceutically acceptable salt thereof. The term substantially enriched means that the compound contains approximately 1.5 times or more by weight the target enantiomer. In another embodiment, the long-acting compositions of the present invention contain at least one isoxazoline compound having the formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II- 1.025), (II-2.001)-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in one enantiomer in a weight ratio of at least 2 :1, at least 5:1 or at least 10:1. In another embodiment, the compositions contain at least one compound having formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)(II-1.025), (II-2.001 )-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in one enantiomer in a weight ratio of at least 15:1 or at least 20 :1, or a pharmaceutically acceptable salt thereof. In one embodiment, isoxazoline compounds having formula (I), formula (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001)-( II-018), (III), (IV), (V), (Va), (VI) or (VIa) present in the compositions of the present invention are substantially pure enantiomers.

In another embodiment of the present invention, the compositions contain a compound having formula (I), formula (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001 )-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in the (S)-enantiomer in a weight ratio of at least about 1.5: 1 or 2:1. In another embodiment, the compositions of the present invention contain a compound having the formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001 )-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in the (S)-enantiomer in a weight ratio of at least

- 38 044142 at least approximately 5:1 or more. In another embodiment, the compositions of the present invention contain a compound having the formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II-1.025), (II-2.001 )-(II018), (III), (IV), (V), (Va), (VI) or (VIa), which is enriched in the (S)-enantiomer in a weight ratio of at least about 10:1, 20: 1 or more. In another embodiment, the compositions of the present invention contain a compound having the formula (I), (Ia), (Ib), (Ic), (II), (II-1.1001)-(II1.025), (II-2.001 )-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is an essentially pure (S)-enantiomer.

In one embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in one enantiomer. In another embodiment, the long-acting injectable compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in the (S)enantiomer. In another embodiment, the long-acting injectable compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in the (R)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer in a weight ratio of at least about 1.5:1 or 2 :1 or more. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer in a weight ratio of at least about 5:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is enriched in the (S)-enantiomer in a weight ratio of at least about 10:1, 20: 1 or more. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic), which is a substantially pure (S)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formula (I), (Ia), (Ib) or (Ic) that is enriched in the (R)-enantiomer in a weight ratio of at least about 2:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic) that is enriched in the (R)enantiomer in a weight ratio of at least about 5:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (1c), which is enriched in the (R)-enantiomer in a weight ratio of at least about 10:1, 20: 1 or more. In another embodiment, the compositions of the present invention contain a compound having formula (I), (Ia), (Ib) or (Ic), which is a substantially pure (R)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formula (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-018), (III), (IV), ( V), (Va), (VI) or (VIa) which is enriched in the (R)-enantiomer in a weight ratio of at least about 2:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-018), (III), (IV), (V), (Va), (VI) or (VIa) which is enriched in the (R)-enantiomer in a weight ratio of at least about 5:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-018), (III), (IV), (V), (Va), (VI) or (VIa) which is enriched in the (R)-enantiomer in a weight ratio of at least about 10:1, 20:1 or greater. In another embodiment, the compositions of the present invention contain a compound having formula (II), (II-1.1001)-(II-1.025), (II-2.001)-(II-018), (III), (IV), (V), (Va), (VI) or (VIa), which is the substantially pure (R)-enantiomer.

In another embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of at least one isoxazoline described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 WO 2008/122375, WO 2014/439475 A1 and WO2012 120135 A1, which are all are incorporated herein in their entirety by reference.

In another embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of at least one isoxazoline compound described in WO 2009/02451 A2 and WO 2011/075591 A1, both of which are incorporated herein by reference in their entirety.

In another embodiment, the long-acting injectable compositions of the present invention contain an antiparasitic effective amount of at least one isoxazoline, which is compound 11-1 described in WO 2009/02451 A2, which has the structure:

- 39 044142

In one embodiment, the compositions of the present invention may contain from about 0.5 to about 50% (w/v) isoxazoline active ingredient having any of formulas (I), (Ia), (Ic), (II) , (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof, either as a racemic mixture or in a single enantiomer enriched form as described above. In another embodiment, the compositions of the present invention may contain from about 1 to about 40% (w/v) isoxazoline active ingredient having any of formulas (I), (Ia), (Ib), (Ic), ( II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the present invention may contain from about 1 to about 30, from about 1 to about 20, or from about 1 to about 15% (w/v) isoxazoline active ingredient having any of formula (I) , (Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the present invention may contain from about 0.5 to about 10, or from about 0.5 to about 5% (wt./vol.) isoxazoline active ingredient having any of formulas (I), ( Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof.

In another embodiment, the compositions of the present invention may contain from about 5 to about 40, or from about 5 to about 30% (w/v) isoxazoline active ingredient, or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions described may contain from about 10 to about 40% (w/v) isoxazoline active ingredient, or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the present invention may contain from about 15 to about 40% (wt./vol.), from about 15 to about 35% (wt./vol.), or from about 15 to about 30% ( w/v) of an isoxazoline compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above) , or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) cosolvent;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In another embodiment, the present invention describes long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integument, containing:

a) from about 0.5 to 20% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above) , or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) cosolvent;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention describes injectable compounds

- 40 044142 long-acting formulations for the treatment and/or prevention of parasitic infections and infestations in animals or on the integument of animals, containing:

a) from about 5 to 30% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above), or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) cosolvent;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above) , or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In another embodiment, the present invention describes long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integument, containing:

a) from about 0.5 to 20% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above) , or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 5 to 30% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above), or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

- 41 044142

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) of an isoxazoline active substance having formula (Ia) (for example, a compound having formula I-VIa), such as a compound having the formula:

where X ¹ , X ² and X ³

independently represent a chlorine atom, a fluorine atom or CF ₃ ;

where X ¹ , X ² and X ³

independently represent a chlorine atom, a fluorine atom or CF ₃ ;

where X ¹ , X ² and X ³

independently represent a chlorine atom, a fluorine atom or CF ₃ ;

- 42 044142

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, n -dipropylene glycol butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, Nmethylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represents a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (VIa) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a C1-C6 alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol, n -dipropylene glycol butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, Nmethylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (wt./vol.) isoxazoline active substance having the formula

- 43 044142 (la), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (Va) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, glycol ether (for example, including but not limited to diethylene glycol monoethyl ether, butyl diglycol , dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, Nmethylpyrrolidone , dimethylisosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (Va) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a C ₁ -C ₆ alcohol, a glycol ether (for example, including but not limited to) diethylene glycol monoethyl ether, butyl diglycol , dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), glycerin, propylene glycol, cyclic carbonates (for example, propylene carbonate), 2-pyrrolidone, Nmethylpyrrolidone , dimethylisosorbide (DMI), dimethylacetamide, dimethyl sulfoxide or glycerol formal, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represents a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (Va) or (S)-VIa shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ triglycerides (for example, MIGLYOL® 810 and MIGLYOL® ™ 812), C ₈ -C ₁₀ -triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ -triglycerides in combination with succinic acid

- 44 044142 that (for example, MIGLYOL® 829), propylene glycol diester with C ₈ -C ₁₀ fatty acids (for example, MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represents a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (Va) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 5 to 40% (w/v) co-solvent, where the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ -triglycerides (for example, MIGLYOL® 810 and MIGLYOL ® 812), C ₈ -C ₁₀ -triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ -triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ - With ₁₀ -fatty acids (eg MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (Va) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, where the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ -triglycerides (for example, MIGLYOL® 810 and MIGLYOL ® 812), C ₈ -C ₁₀ -triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ -triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ - With ₁₀ fatty acids (eg MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (VIa) or (S)-VIa shown above;

- 45 044142 or its pharmaceutically acceptable salt,

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, where the co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, C ₈ -C ₁₀ -triglycerides (for example, MIGLYOL® 810 and MIGLYOL ® 812), C ₈ -C ₁₀ -triglycerides in combination with linoleic acid (for example, MIGLYOL® 818), C ₈ -C ₁₀ -triglycerides in combination with succinic acid (for example, MIGLYOL® 829), propylene glycol diester with C ₈ - With ₁₀ fatty acids (eg MIGLYOL® 840), castor oil, cottonseed oil, soybean oil and safflower oil, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (wt./vol.) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent an atom chlorine, fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (wt./vol.) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent an atom chlorine, fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

- 46 044142

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 1 to 40% (w/v) co-solvent, wherein said co-solvent is a C1-C6 alcohol, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF ₃ ; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, wherein X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF ₃ as shown above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is a C ₈ -C ₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in

- 47 044142 animals or on animal covers, containing:

a) from about 0.5 to 30% (wt./vol.) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally, from about 1 to 40% (w/v) of a co-solvent, wherein said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 40% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive

- 48 044142 ki, excipients or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 1 to 20% (w/v) of a co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 1 to 20% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 1 to 20% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

- 49 044142

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 1 to 20% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 1 to 20% (w/v) of a co-solvent wherein said co-solvent is a C8- _C10 triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of at least one pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C ₈ -C ₁₀ triglyceride;

c) optionally, from about 1 to 20% (w/v) of at least one co-solvent, wherein said co-solvent is ethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of at least one pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (w/v) of a co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive

- 50 044142 ki, excipients or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 20% (w/v) isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine, and X ³ represents CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (wt./vol.) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF3; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (wt./vol.) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 15% (w/v) of an isoxazoline active substance having the formula (Ia), (S)-Ia, (Ic), where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF ₃ ; or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3, as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (wt./vol.) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 15% (w/v) of an isoxazoline active substance having the formula (S)-Ia or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF3 as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (w/v) of a co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

- 51 044142

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 5 to 20% (w/v) of an isoxazoline active substance having the formula (S)-Ia or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ represents CF ₃ ; as shown above, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 15% (wt./vol.) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 5 to 15% (w/v) isoxazoline active substance having the formula (S)-Ia or (S)-Ic, where X ¹ represents a chlorine atom, X ² represents a fluorine atom, and X ³ is CF ₃ as shown above, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 2 to 10% (w/v) co-solvent, where the co-solvent is ethanol, isopropanol or benzyl alcohol or a combination thereof;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

In some embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 0.5 to 30% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above) such as a compound having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof:

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, from about 5 to 40% (w/v) of a co-solvent selected from the group consisting of ethanol and isopropanol;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the total composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 30% (w/v) isoxazoline active substance, such as, for example,

- 52 044142 any of the isoxazoline compounds described above in the embodiments (for example, a compound having any of the formulas I-VIa described above), such as a compound having formula (Ia), (S)-Ia, (R)-Ia, (Ic) where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)Va, (VIa) or (S)-VIa shown above;

or a pharmaceutically acceptable salt thereof:

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 5 to 40% (w/v) of a co-solvent selected from the group consisting of ethanol and isopropanol;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the overall composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 1 to 20% (w/v) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having formula I-VIa), such as a compound having formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa shown above; or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG and/or a neutral oil;

c) optionally, from about 5 to 40% (w/v) of a co-solvent selected from the group consisting of ethanol and isopropanol;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG and wherein liquid PEG and/or neutral oil is present in the composition in an amount that complements the overall composition of the composition to 100%.

In other embodiments, the present invention discloses long-acting injectable compositions for the treatment and/or prevention of parasitic infections and infestations in animals or on animal integuments, comprising:

a) from about 5 to about 20% (wt./vol.), or from about 5 to about 15% (wt./vol.) isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments ( for example, a compound having the formula I-VIa), such as a compound having the formula (Ia), (S)-Ia, (R)-Ia, (Ic), where X ¹ , X ² and X ³ independently represent an atom chlorine, fluorine atom or CF3; (S)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF3; (R)-Ic, where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa shown above; or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer, which is a liquid PEG;

c) optionally, from about 5 to 40% (w/v) of a co-solvent selected from the group consisting of ethanol and isopropanol;

d) optionally, from about 0.01 to about 2.0% (w/v) antioxidant; And

e) optionally, from about 0.01 to about 5.0% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof;

wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is liquid PEG, and wherein liquid PEG is present in the composition in an amount that complements the total composition of the composition to 100%.

Another embodiment of the present invention is a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on animals, consisting mainly of the following components:

- 53 044142

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having formula I-VIa), and optionally at least one additional active ingredient specified in the present invention;

b) liquid PEG and/or pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent, wherein said co-solvent is a polar solvent miscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

Another embodiment of the present invention is a long-acting injectable composition for the treatment and/or prevention of parasitic infections and infestations in animals or on the integument of animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described above in the embodiments (for example, a compound having formula I-VIa), and optionally at least one additional active ingredient specified in the present invention;

b) liquid PEG and/or pharmaceutically acceptable neutral oil;

c) at least one co-solvent, where said co-solvent is immiscible with water;

d) optionally, antioxidant; And

e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

As used herein and in the claims, terms such as contains, containing, having, and the like have the meanings assigned to them under US patent law, i.e. may mean includes including and the like; the terms consists principally of and consisting principally of also have the meaning prescribed in the patent law, and these terms are non-exclusive, allowing for the presence of more than those listed, provided that the essential or novel characteristics of that listed are not altered by the presence of more than listed, but excluding options known in the prior art. The term consisting of excludes any element, step or ingredient not specified in the statement.

Definitions.

As used herein, terms have the meaning generally accepted in the art unless otherwise noted. The organic moieties indicated in the definitions of the variables present in formula (I) are - like the term halogen - collective terms for lists of individual group members. The prefix C _n -Cm in each case indicates the possible number of carbon atoms in the group.

The term animal is used in the present invention to include all mammals, birds and fish, and also includes all vertebrates. Animals include (but are not limited to) cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. They also include the individual animal at all stages of development, including the embryonic and fetal stages. In some embodiments, animal means non-human animals.

The term substantially pure is used herein to indicate that a compound or enantiomer is at least about 90% pure, at least about 95% pure, at least about 98% pure, or greater.

The term alkyl refers to saturated linear, branched, primary, secondary or tertiary hydrocarbons, including hydrocarbons containing from 1 to 20 atoms. In some embodiments, alkyl groups include C ₁ -C ₁₂ , CrC ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ or C ₁ -C ₄ alkyl groups. Examples of C ₁ -C ₁₀ alkyls include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl , 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl -1-methylpropyl, 1-ethyl-2methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl, and their isomers. C1-C4 alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups or cycloalkyl include groups with 3-10 carbon atoms containing one or more fused rings. In some embodiments, cycloalkyl groups include C ₄ -C7 or C ₃ -C ₄ cyclic alkyl groups. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The alkyl groups described herein may be unsubstituted or substituted

- 54 044142 one or more fragments selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy group, amino group, alkyl or dialkylamino group, amido, arylamino group, alkoxy group, aryloxy -group, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thio-ester, thio-ether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoacid, phosphate, phosphonate, or any other possible functional group that does not inhibit the biological activity of the compounds of the present invention, in unprotected or optionally protected form, as known to those skilled in the art, for example, as described in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, incorporated herein by reference.

Terms including the term alkyl, such as alkylcycloalkyl, cycloalkylalkyl, alkylamino group or dialkylamino group, are to be understood as containing an alkyl group as defined above linked to another functional group, wherein said group is linked to the remainder of the compound through the last listed group , as will be appreciated by one skilled in the art.

The term alkenyl refers to straight and branched carbon chains containing at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C ₂ -C ₂₀ alkenyl groups. In other embodiments, alkenyl includes C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₄ alkenyl groups. In one variant of alkenyl, the number of double bonds is 1-3; in another variant of alkenyl, the number of double bonds is one or two.

Other numbers of carbon-carbon double bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkenyl moiety in the molecule. C ₂ -C ₁₀ alkenyl groups can contain more than one double bond in the chain. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl , 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1butenyl, 1-methyl-2-butenyl, 2-methyl-2- butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1- propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1methyl- 1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl- 4-pentenyl, 3-methyl-4-pentenyl, 4methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1, 2-dimethyl2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3butenyl, 2,2-dimethyl- 3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl- 2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

The term alkynyl refers to linear and branched carbon chains containing at least one carbon-carbon triple bond. In one alkynyl embodiment, the number of triple bonds is 1-3; in another variant of alkynyl, the number of triple bonds is one or two. In some embodiments, alkynyl groups include C2-C20 alkynyl groups. In other embodiments, alkynyl groups may include C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₄ alkynyl groups. Other numbers of carbon-carbon triple bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkynyl moiety in the molecule. C ₂ -C ₁₀ -alkynyl as used in the present invention refers to linear or branched unsaturated hydrocarbon groups containing from 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl , prop-2-in-1-yl, n-but-1in-1-yl, n-but-1-in-3-yl, n-but-1-in-4-yl, n-but-2 -in-1-yl, n-pent-1-in-1-yl, n-pent-1-in-3-yl, n-pent-1in-4-yl, n-pent-1-in-5 -yl, n-pent-2-in-1-yl, n-pent-2-in-4-yl, n-pent-2-in-5-yl, 3-methylbut-1-in-3-yl , 3-methylbut-1-in-4-yl, n-hex-1-in-1-yl, n-hex-1-in-3-yl, n-hex-1-in-4-yl, n -hex-1-in-5-yl, n-hex-1-in6-yl, n-hex-2-in-1-yl, n-hex-2-in-4-yl, n-hex-2 -in-5-yl, n-hex-2-in-6-yl, n-hex-3-in-1-yl, n-hex-3in-2-yl, 3-methylpent-1-in-1 -yl, 3-methylpent-1-in-3-yl, 3-methylpent-1-in-4-yl, 3-methylpent-1-in-5-yl, 4-methylpent-1-in-1-yl , 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl, etc.

The term haloalkyl refers to an alkyl group, as defined herein, that is substituted with one or more halogen atoms. For example, C ₁ -C ₄ -haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl , 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and so on.

- 55 044142

The term haloalkenyl refers to an alkenyl group, as defined herein, that is substituted with one or more halogen atoms.

The term haloalkynyl refers to an alkynyl group, as defined herein, which is substituted with one or more halogen atoms.

The term alkoxy refers to the group alkyl-O-, where alkyl has the meaning given above. Similarly, the terms of alkeniloxy, alkynilox, halogenicox, halogenalcenilox, halogenoxyloxy, cycloralcoxy, cycloalcenyloxy, halogencicicalcoxy and halogencicicigonexyloxy belong to the groups of alkenil-o-, alkinyl-o-, haloenalcenil-on-, halogen-oo- -, cycloalkil- O-, cycloalkenyl-O-, halocycloalkyl-O- and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl and halocycloalkenyl are as defined above. Examples of C ₁ -C ₆ -alkoxy include, but are not limited to, methoxy, ethoxy, C ₂ H ₅ -CH ₂ O-, (CH ₃ ) ₂ CHO-, n-butoxy, C ₂ H ₅ CH (CH ₃ )O-, (CH ₃ ) ₂ CH-CH ₂ O-, (CH ₃ ) ₃ CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2- dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2dimethylbutoxy, 1,3-dimethylbutoxy, 2, 2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl- 2-methylpropoxy, etc.

The term alkylthio refers to the group alkyl-S-, where alkyl has the meaning given above. Likewise, the terms haloalkylthio, cycloalkylthio and the like. refer to the groups haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl have the above meanings.

The term alkylsulfinyl refers to the group alkyl-S(O)-, where alkyl has the meaning given above. Likewise, the term haloalkylsulfinyl refers to the group haloalkyl-S(O)-, where haloalkyl has the meaning given above.

The term alkylsulfonyl refers to the group alkyl-S(O) ₂ -, where alkyl has the above meaning. Likewise, the term haloalkylsulfonyl refers to the group haloalkyl-S(O) ₂ -, where haloalkyl has the above meaning.

The terms alkylamino and dialkylamino refer to alkyl-NH- and (alkyl) _2N- groups, where alkyl has the meaning given above. Likewise, the term haloalkylamino refers to the group haloalkyl-NH-, where haloalkyl has the meaning given above.

The terms alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl refer to the groups alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino have the meanings indicated above. Similarly, the terms haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl and dihaloalkylaminocarbonyl refer to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)-, where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino have the meanings indicated above.

The term aryl refers to a monovalent carbocyclic group containing from 6 to 14 carbon atoms, having one ring or several fused rings. In some embodiments, aryl groups include C ₆ -C ₁₀ aryl groups. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl and indanyl. Aryl groups may be unsubstituted or substituted with one or more substituents selected from the following: halogen atom, cyano group, nitro group, hydroxy group, mercapto group, amino group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group, haloalkenyloxy group, haloalkynyloxy group, cycloalkoxy group, cycloalkenyloxy group, halocycloalkoxy group, halocyclo alkenyloxy group, alkylthio- group, haloalkylthio group, cycloalkylthio group, halocycloalkylthio group, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, gal ogenalkenylsulfonyl, haloalkynylsulfonyl, alkylamino group, alkenylamino group, alkynylamino group, di(alkyl)amino group, di(alkenyl)amino group, di(alkynyl)amino group or trialkylsilyl.

The terms aralkyl or arylalkyl refer to an aryl group that is linked to the remainder of the compound via a diradical alkylene bridge, (-CH ₂ -) _n , where n is 1-12 and where aryl is as defined above.

The term heteroaryl refers to a monovalent aromatic group containing 1-15 carbon atoms, preferably 1 to 10 carbon atoms, containing one or more ring heteroatoms of oxygen, nitrogen and sulfur, preferably 1-4 heteroatoms or 1-3 heteroatoms. Nitrogen and sulfur heteroatoms can optionally be oxidized. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings, provided that the point of attachment is on a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pi

- 56 044142 ridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl and benzothio phenyl Heteroaryl rings may be unsubstituted or substituted by one or more moieties as defined above for the term aryl.

The terms heterocyclyl, heterocyclic or heterocyclo refer to fully saturated or unsaturated cyclic groups, for example 3-7 membered monocyclic or 4-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic systems, which may contain at least one heteroatom in a ring containing at least one carbon atom. Each ring of the heterocyclic group containing a heteroatom may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. A heterocyclic group may be attached at any heteroatom or carbon atom in a ring or cyclic system, and may be unsubstituted or substituted with one or more substituents, as described above for aryl groups.

Examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1, 3-dioxolane and tetrahydro-1,1dioxothienyl, triazolyl, triazinyl, etc.

Examples of bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl , indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, Furo[3,2-b]pyridinyl] or Furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro- 4-oxo-quinazolinyl), tetrahydroquinolinyl, etc.

Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term halogen refers to fluorine, chlorine, bromine and iodine atoms. The designation halogen (for example, as in the term haloalkyl) refers to all degrees of substitution from single substitution to perhalogen substitution (for example, can be illustrated for methyl: chloromethyl (-CH ₂ Cl), dichloromethyl (-CHCl ₂ ), trichloromethyl (-CCl ₃ )).

By enriched is meant that the w/w ratio is at least about 1.05 or greater in favor of an enantiomer that exhibits significant activity in vitro and in vivo (eutomer).

Stereoisomers and polymorphic forms.

Those skilled in the art will appreciate that certain compounds in the compositions of the present invention may exist and be isolated as optically active and racemic forms. Compounds having one or more chiral centers, including that on a sulfur atom, may be present as single enantiomers or diastereomers or as mixtures of enantiomers and/or diastereomers. For example, it is well known that sulfoxide compounds can be optically active and can exist as individual enantiomers or racemic mixtures. In addition, the compounds in the compositions of the present invention may include one or more chiral centers that result in the existence of a theoretical number of optically active isomers. Where the compounds in the compositions of the present invention include n chiral centers, the compounds may have up to 2 ⁿ optical isomers. The present invention covers the partial enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the present invention, which have the beneficial properties described herein. In addition, the present invention covers compositions containing one or more conformational isomers (eg, rotamers), as well as mixtures of conformational isomers. Conformational isomers of isoxazoline compounds can be formed by hindering rotation around an amide bond attached to an aryl or heteroaryl ring (eg, an amide bond attached to a naphthyl group in Formula (I)). Optically active forms can be obtained, for example, by resolution of racemic forms by selective crystallization, synthesis from optically active precursors, chiral synthesis, chromatographic resolution using a chiral stationary phase, or by enzymatic resolution.

In addition, the compounds in the compositions of the present invention may exist as hydrates or solvates in which certain stoichiometric amounts of water or solvent are associated with the molecule in crystalline form. Compositions of the present invention

- 57 044142 may include hydrates and solvates of the active substances. In some embodiments, the compositions of the present invention may include up to 15, up to 20, or up to 30% (w/w) of the specified solid form.

Salt.

Also included within the scope of the present invention are salts of the compounds described herein with acids and bases, where possible.

The term salt with acid covers salts of compounds with all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment, the acids are linear or branched, saturated or unsaturated C1- _C2o aliphatic carboxylic acids, which are optionally substituted with halogens or hydroxyl groups, or _C6 - _C12 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids containing from 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butanoic acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylstearic acid. Other acids include gluconic acid, glucoheptonic acid and lactobionic acid.

The term salts with bases covers salts of compounds with all pharmaceutically acceptable inorganic or organic bases, including alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. Salts formed with such bases include, for example, alkali or alkaline earth metal salts, including, but not limited to, lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include salts with conventional hydrocarbon and heterocyclic amines, which include, for example, ammonium (NH ₄ ⁺ ) salts, alkyl and dialkylammonium salts, and cyclic amine salts such as morpholine and piperidine salts.

In another embodiment, the long-acting injectable compositions of the present invention contain an effective amount of at least one isoxazoline or a pharmaceutically acceptable salt thereof in combination with at least one other active ingredient. In one embodiment, the long-acting injectable compositions contain an effective amount of at least one isoxazoline compound having formula (I)(VI), or a pharmaceutically acceptable salt thereof, in combination with at least one other active ingredient having systemic activity.

Additional veterinary/pharmaceutically active ingredients may be used in the compositions of the present invention. In some embodiments, additional active ingredients may include, but are not limited to, acaricides, anthelmintics, antiparasitics, and insecticides. Antiparasitic agents may include ectoparasiticidal and/or endoparasiticidal agents.

Veterinary pharmaceutical agents that can be included in the compositions of the present invention are well known in the art (see, for example, Plumb' Veterinary Drug Handbook, ^5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, ^9th Edition, (January 2005)) and include (but are not limited to) acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitrecin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotrecin B deoxycholate, amphotrecin B na lipid-based, ampicillin, amprolium, antacids (oral), antivenin, apomorphion, apramycin sulfate, ascorbic acid, aspraginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen , barbiturates, benazepril, betamethasone, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carpro hair dryer, carvedilol, cefadroxil, cefazolin sodium, cefixime,

- 58 044142 clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cephapirin, activated charcoal, chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, claona zepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cycloheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferox amine mesylate , deracoxib, deslorelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dextraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol ( DES), difloxacin, digoxin, dihydrotachysterol ( DHT), diltiazem, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, calcium disodium edetate, calcium E DTA , edrophonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/sodium ethacrine, ethanol (alcohol), sodium etidronate, etodolac , etomidate , euthanasia agents with pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5 FU) , fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine/chondroitin sulfate, glutamine, glyburide, gly cerin (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (oxyglobin®), heparin, hydroxyethyl starch, sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipro pionat, impenem- cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprin, itraconazole, ivermectin, kaolin /pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, levprolide, levamisole, levitiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, fur lorethamine, meclizine , meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomin, melatonin, meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate , methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decano at, naproxen, narcotic ( opiate) agonistic analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiate antidiarrheals, orbi floxacin, oxacillin sodium, oxazepam , oxybutynin chloride, oxymorphone, oxytetracycline, oxytocin, disodium pamidronate, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, penicillamine, commonly known penicillins, penicillin G, penicillin V potassium, pentazocine, sodium pentobarbital, sodium pentosan polysulfate, pentoxifylline, pergo lida mesylate, phenobarbital , phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone/pred nizon, primidone , procainamide, procarbazine, prochlorperazine, propantheline bromide, propionic acne bacteria injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium bulk laxative, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adeno zyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin, selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine/trimetroprim, sulfadimentoxin, sulfadimentoxin/ormetroprim, sulfasalazine, taurine, tepoxaline, terbinaflin, terbutaline sulfate, testosterone he, tetracycline, thiabedazole, sodium thiacetarsamide, thiamine , thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium, ti

- 59 044142 letamine/zolazepam, tilmoxin, tiopronin, tobramycin sulfate, tocainide, tolazolone, telfenamic acid, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxine tartrate with prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the present invention, arylpyrazole compounds known in the art, such as phenylpyrazoles, can be combined with isoxazoline compounds in the long-acting injectable compositions of the present invention. Examples of such arylpyrazole compounds include, but are not limited to, those described in US Pat. No. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and 6,998,131 (all incorporated herein by reference, each issued by Merial, Ltd., Duluth, GA).

In another embodiment of the present invention, one or more macrocyclic lactones that act as an acaricide, anthelmintic, and insecticide can be added to the compositions of the present invention.

Macrocyclic lactones include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ml-1,694,554, and milbemycins such as milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of the listed avermectins and milbemycins. Examples of combinations of arylpyrazole compounds with macrocyclic lactones include, but are not limited to, those described in US Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 (all incorporated herein by reference, all issued by Merial, Ltd., Duluth, GA).

Macrocyclic lactone compounds are known in the art and can be readily prepared commercially or by synthetic techniques known in the art. Reference is made to widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference can be made, for example, to the work of Ivermectin and Abamectin, 1989, authored by M.N. Fischer and N. Mrozik, William C. Campbell, published by Springer Verlag, or Albers-Schonberg et al. (1981), Avermectins Structure Determination, J. Am. Chem. Soc., 103, 4216-4221. Regarding doramectin, you can consult Veterinary Parasitology, vol. 49, No. 1, July 1993, 5-15. Regarding milbemycins, reference may be made, among others, to Davies H.G. et al., 1986, Avermectins and Milbemycins, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis Of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US Pat. No. 4,134,973 and EP 0,677,054.

Macrocyclic lactones are natural compounds or their semisynthetic derivatives. The structures of avermectins and milbemycins are closely related, for example they share a complex 16-membered macrocyclic lactone ring. Natural avermectins are described in US Patent No. 4,310,519, and 22,23-dihydroavermectin compounds are described in US Patent No. 4,199,569 (both incorporated herein by reference). Also worthy of mention are US Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 A1, UK Patent 1 390 336, EP 0 002 916, and New Zealand Patent No. 237 086. Naturally occurring milbemycins are described in U.S. Patent No. 3,950,360 and in various references cited in The Merck Index ^12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in International Nonproprietary Names for Pharmaceutical Substances (INN), WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003). Semi-synthetic derivatives of the above classes of compounds are well known in the art and are described, for example, in US Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,19 9,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148 and EP 0,667,054.

In another embodiment, the present invention provides a long-acting injectable composition containing an isoxazoline compound in combination with systemic compounds from the class of acaricides or insecticides known as insect growth regulators (IGRs). Compounds belonging to this group are well known to those skilled in the art and represent a wide variety of different classes of chemical compounds. These compounds are active by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in US Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, European Patent 0,179,022 or UK Patent 2,140,010, as well as in US Patents 6,096,329 and 6,68 5.954 (all of which are included in this text by links).

In one embodiment, the IGR is a compound that is a juvenile hormone mimic. Examples of juvenile hormone mimics include azadirachtin, diophenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3 (2H)-on.

In one embodiment, the long-acting injectable compositions of the present invention contain an effective amount of at least one isoxazoline having formula (I)-(VIa), or a pharmaceutically acceptable salt thereof, in combination with methoprene or pyriprock

- 60 044142 siphen.

In another embodiment, the IGR compound is a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumorone, lufenuron, tebufenozide, teflubenzuron, triflumoron, nofaluron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl) phenylurea, 1-(2,6-difluorobenzoyl)3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)phenylurea and 1-(2,6-difluorobenzoyl)-3-(2- fluoro-4trifluoromethyl)phenylurea.

In another embodiment of the present invention, insecticides that kill adult insects and mites can also be added to the long-acting compositions of the present invention. These include pyrethrins (which include cynerin I, cinerin II, jasmoline I, jasmoline II, pyrethrin I, pyrethrin II, and mixtures thereof) and pyrethroids, and carbamates, including (but not limited to) benomyl, carbanolate, carbaryl, carbofuran, methiocarb , metolcarb, promacil, propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxim and thiophanox. In one embodiment, the compositions may include permethrin in combination with an isoxazoline active ingredient.

In some embodiments, the long-acting compositions of the present invention may include one or more antinematode agents, including, but not limited to, active agents from the following classes: benzimidazoles, imidazothiazoles, tetrahydropyrimidines, or organophosphates. In some embodiments, the compositions may include benzimidazoles, including but not limited to thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, and an o,o-dimethyl analogue thereof. .

In other embodiments, the long-acting compositions of the present invention may include imidazothiazole compounds, including, but not limited to, tetramizole, levamisole, and butamizole. In other embodiments, the long-acting compositions of the present invention may include tetrahydropyrimidine active ingredients, including, but not limited to, pyrantel, oxantel, and morantel. Suitable organophosphate active ingredients include, but are not limited to, coumaphos, trichlorfon, haloxon, naphthalophos and dichlorvos, heptenophos, mevinphos, monocrotophos, tetraethylpyrophosphate and tetrachlorvinphos.

In other embodiments, the long-acting compositions of the present invention may include the anti-nematode compounds phenothiazine and piperazine as neutral compounds or as various salts, diethylcarbamazine, phenols such as disophenol, arsenic compounds such as arsenamide, ethanolamines such as bephenium, tenium closylate and methyluridine; cyanine dyes, including pyrvinium chloride, pyrvinium pamoate and dithiazanine iodide; isothiocyanates, including bitoscanate, suramin sodium, phthalophine, and various natural substances including, but not limited to, hygromycin B, α-santonin and kainic acid.

In other embodiments, the long-acting compositions of the present invention may include anti-fluke agents. Suitable anti-fluke agents include, but are not limited to, miracils such as miracil D and mirasan, praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenolic compounds known in the art. the art, including hexachlorophene, bithionol, bithionol sulfoxide and menichlorofolane; various salicylanilide compounds including tribromosalan, oxyclozanide, dioxanide, rafoxanide, brotianide, bromoxanide and closantel; triclabendazole, diamphenetide, clorsulon, getolin and emetine.

Anticestodal compounds may also be advantageously used with the long-acting compositions of the present invention, including, but not limited to, arecoline in the form of various salts, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.

In other embodiments, the long-acting compositions of the present invention may include other active ingredients effective against arthropod parasites. Suitable active ingredients include (but are not limited to) bromocyclene, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothione, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthione, diemthoate, dioxathione, ethione , famfour, fenitrothion, fenthion, phosphpirate, iodofenphos, malathion, naled, phosalon, phosmet, phoxim, propetamphos, ronnel, styrophos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucitrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzylbene zoate, disulfide carbon, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, metroprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H) -dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl- 2,5pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

The antiparasitic agent that can be combined with isoxazoline compounds in the long-acting compositions of the present invention may be a biologically active peptide or protein, including but not limited to depsipeptides, which

- 61 044142 act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, which leads to paralysis and death of parasites. In one embodiment of the depsipeptide, the depsipeptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86). In another embodiment of the depsipeptide, the depsipeptide is PF1022a or a derivative thereof.

In other embodiments, the long-acting injectable compositions of the present invention may include an active ingredient from the neonicotinoid class of pesticides. Neonicotinoids bind to and inhibit specific nicotinic acetylcholine receptors in insects. In one embodiment, the neonicotinoid insecticidal agent that can be combined with an isoxazoline compound to form the long-acting injectable composition of the present invention is imidacloprid. Imidacloprid is a well-known neonicotinoid active ingredient and is the key active ingredient in the topical parasiticidal products Advantage®, Advantage® II, K9 Advantix® and K9 Advantix® II marketed by Bayer Animal Health and in Advantus™ oral soft chew formulation from Bayer Animal Health. Piedmont Animal Health. Agents from this class are described, for example, in US patent No. 4,742,060 or in EP 0 892 060.

In another embodiment, the long-acting injectable compositions of the present invention may include nitenpyram, another active ingredient in the neonicotinoid class of pesticides. Nitenpyram has the chemical structure shown below and is the active ingredient in the oral product CAPSTAR™ Tablets marketed by Novartis Animal Health.

HN _V

Nitenpyram is active against adult fleas when administered daily via an oral tablet. Nitenpyram works by disrupting normal nerve transmission and causing the death of the insect. Nitenpyram has a very rapid onset of action against fleas. For example, CAPSTAR™ Tabets begin to work against fleas within 30 minutes of administration and are intended to be used once daily. However, activity for nitenpyram is only known when administered orally as a systemic parasiticide, as is the case with CAPSTAR™ Tablets.

In another embodiment, the present invention describes long-acting compositions of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5(trifluoromethyl)-3-isoxazolyl] -N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (compound of formula Ia) in combination with nitenpyram.

In another embodiment, the present invention describes long-acting compositions of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5(trifluoromethyl)-3-isoxazolyl] -N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (compound of formula Ia) in combination with imidacloprid.

In some embodiments, the insecticidal agent that can be combined with the long-acting compositions of the present invention is a semicarbazone, such as metaflumizone.

In another embodiment, the long-acting compositions of the present invention may preferably contain a combination of isoxazoline compounds known in the art. Such active agents are described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/ 024541, WO 2005/085216 and US 2007/0066617 and WO 2008/122375, all of which are incorporated herein by reference in their entirety.

In another embodiment of the present invention, nodulisporic acid and its derivatives (a class of known acaricidal, anthelmintic, antiparasitic and insecticidal agents) can be added to the long-acting compositions of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in US Pat. Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, each of which is incorporated herein by reference in its entirety. The compositions may include one or more of the known nodulisporic acid derivatives, including all stereoisomers, such as those described in the patents cited above.

In another embodiment, anthelmintic compounds from the aminoacetonitrile (AAD) class, such as monepantel (ZOLVIX) and the like, can be combined with the long-acting compositions of the present invention. These compounds are described, for example, in WO 2004/024704 and US Patent No. 7,084,280 (incorporated by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13 March 2008, 176-181.

- 62 044142

The compositions of the present invention may also include aryloazol-2-yl cyanoethylamino compounds, such as those described in U.S. Patent No. 8,088,801 to Soll et al., the entire contents of which are incorporated by reference herein, and thioamide derivatives of these compounds, as described in U.S. Pat. No. 7,964,621, which is incorporated herein by reference.

The long-acting injectable compositions of the present invention can also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology , 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds that contain a spirodioxepinoindole core with activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492 ). In addition, the structurally related family of marcfortines, such as the marcfortines A-C, are also known and can be combined with the compositions of the present invention (see J. Chem. Soc. Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Additional information on paraherquamide derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, Wo 09/004432, US patent no. 5,703,078 and U.S. Patent No. 5,750,695, each of which is incorporated herein by reference in its entirety.

In general, the additional active ingredient is included in the long-acting compositions of the present invention in an amount of from about 0.1 μg to about 1000 mg. More commonly, the additional active ingredient may be included in an amount of from about 10 μg to about 500 mg, from about 1 mg to about 300 mg, from about 10 to about 200 mg, or from about 10 to about 100 mg.

In other embodiments of the present invention, the additional active ingredient may be included in the composition in an amount to provide a dosage of from about 5 to about 50 mg/kg of animal weight. In other embodiments, the additional active ingredient may be included in the composition in an amount sufficient to provide a dosage of from about 0.01 to about 30, from about 0.1 to about 20, or from about 0.1 to about 10 mg/kg body weight animal. In other embodiments, the additional active ingredient may be present at a dosage of from about 5 to about 200 μg/kg, or from about 0.1 to about 1 mg/kg of animal weight. In another embodiment of the present invention, the additional active ingredient is present at a dosage of from about 0.5 to about 50 mg/kg.

The long-acting compositions of the present invention, which contain at least an isoxazoline active ingredient, at least one liquid PEG and/or neutral oil and optionally a co-solvent, have surprisingly shown to be stable and effective against a wide range of ectoparasites, and possibly also endoparasites, if the composition contains another active substance, for an extended period of time; for example, a period of three (3) to six (6) months, while demonstrating excellent injection site properties.

Liquid PEGs for the purposes of the present invention are those polyethylene glycols that are liquid at room temperature (20-30°C). Polyethylene glycols have the following structural formula:

H-(O-CH ₂ -CH ₂ ) _p -OH.

Non-limiting examples of n in the above formula include compounds where n is from 1 to about 10,000 (eg, from about 4 to about 25). Liquid PEGs include combinations of different polyethylene glycols. Non-limiting examples of liquid PEGs include PEG 200, PEG 300, PEG 400, PEG 600 and PEG 1000, or combinations thereof.

Pharmaceutically acceptable polymers other than PEG are specifically excluded from the innovative long-acting compositions described herein. Examples of pharmaceutically acceptable polymers that are specifically excluded from the innovative long-acting compositions described herein include polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyetheramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates , polyalkylene oxides, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan and copolymers, terpolymers or combinations or mixtures thereof, including copolymers of polylactides, polycaprolactones, polyglycolides (for example , poly(lactide-co-glycolide).

In some embodiments, poloxamers may be included in the composition. In the context of the compositions described in the present invention, poloxamers are not considered as pharmaceutically acceptable polymers, but as solvents or surfactants. Poloxamers are a family of synthetic block copolymers of ethylene oxide and propylene oxide. Poloxamers can be liquid, milky white pastes or powders, and are represented by the following structure:

- 63 044142

The viscosity of long-acting injectable compositions is an important parameter in terms of the composition's ability to be easily administered to animals. Typically, a viscosity below about 150 centipoise (cP) is acceptable. Thus, in one embodiment, the viscosity of the composition of the present invention at 25°C is less than about 150 cP. In other embodiments, the viscosity of the composition of the present invention at 25°C is less than about 140, less than about 130, or less than about 120 cP. In other embodiments, the viscosity of the composition of the present invention at 25°C is less than about 110 or less than about 100 cP.

Cosolvents used in long-acting injectable compositions may be an individual cosolvent or a mixture of cosolvents. Co-solvents can be used in the compositions of the present invention to improve the solubility of the isoxazoline active ingredient and/or to reduce the viscosity of the compositions. Non-limiting examples of these co-solvents include ethanol, isopropanol, benzyl alcohol, glycol ethers (e.g. including, but not limited to, diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), propylene glycol, glycerin, carbonates (for example, propylene carbonate or ethylene carbonate), 2-pyrrolidone, substituted 2-pyrrolidones, including Nmethylpyrrolidone, 1-ethylpyrrolidone, 1 -octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone, 1-(sec- or tert- or n-butyl)pyrrolidone, 1-hexylpyrrolidone, 1-vinyl-2pyrrolidone, 1-cyclohexylpyrrolidone, 1-(2-hydroxyethyl)pyrrolidone, 1-( 3-hydroxypropyl)pyrrolidone, 1-(2-methoxyethyl)-pyrrolidone, 1-(3-methoxypropyl)pyrrolidone and 1-benzylpyrrolidone; dimethyl isosorbide (DMI), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), glycerol formal, or a mixture of at least two of these solvents.

In one embodiment, the long-acting compositions of the present invention contain a polar protic solvent, including but not limited to an alcohol such as a C1-C6 alcohol, including but not limited to ethanol, isopropanol. In another embodiment, the polar protic solvent is a glycol, such as glycerol or propylene glycol, or a glycol ether, such as diethylene glycol monoethyl ether (Transcutol) or other commonly used glycol ethers such as those described above.

In another embodiment, the long-acting injectable compositions of the present invention contain a polar aprotic solvent, including, but not limited to, N-methylpyrrolidone, dimethyl isosorbide, dimethyl acetamide, dimethyl sulfoxide, or propylene carbonate.

In another embodiment of the present invention, the compositions of the present invention include water-immiscible cosolvents or solvents that are only partially soluble in water. Water-immiscible solvents include esters of aliphatic carboxylic acids (including fatty acids) and glycerol (glycerides), or esters of aliphatic carboxylic acids (including fatty acids) and propylene glycol. Water-immiscible solvents also include oils suitable for injectable compositions. Non-limiting examples of such cosolvents include benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipids, triglycerides, including medium chain triglycerides such as C ₈ -C ₁₀ triglycerides, such as capric/caprylic triglycerides, propylene glycol derivatives (eg, propylene glycol monolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (a nonionic water-dispersible surfactant), isopropyl myristate, or a mixture of at least two of these cosolvents.

In one embodiment, the composition of the present invention may include pharmaceutically acceptable neutral oils as the main component of the composition or co-solvent with liquid PEG. When neutral oil is used in combination with liquid PEG, it may be necessary to use an additional solvent or surfactant to ensure miscibility. Some neutral oils are triglycerides of fractionated plant fatty acids with chain lengths ranging from _C8 to _C10 , including caprylic/capric acid triglycerides. Two commercially available products are known under the brand names MIGLYOL® 810 and MIGLYOL® 812. In another embodiment, the neutral oil is a triglyceride of fractionated plant fatty acids of chain length C ₈ and C ₁₀ , in combination with linoleic acid (approximately 4-5%) . The commercially available product is known as MIGLYOL® 818. In another embodiment, the neutral oil is an ester of glycerol and fractionated vegetable fatty acids of chain length C ₈ and C ₁₀ , in combination with succinic acid. The commercially available product is known as MIGLYOL® 829. In another embodiment, the neutral oil may be a propylene glycol diester and is saturated

- 64 044142 vegetable fatty acids with chain length C ₈ and Cu. The commercially available product is known as MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In another embodiment, the cosolvent may be a mixture of two or more neutral oils. Other suitable oils for inclusion in the long-acting injectable compositions of the present invention include, but are not limited to, castor oil, cottonseed oil, sesame oil, soybean oil and safflower oil.

In one embodiment, the compositions of the present invention may contain from about 0.5 to about 70% (w/v) cosolvent. In another embodiment, the compositions of the present invention may contain from about 0.5 to about 60, or from about 1 to about 50% (w/v) cosolvent. In another embodiment, the compositions may contain from about 1 to about 40, from about 5 to about 50, from about 5 to about 40, or from about 5 to about 35% (w/v) cosolvent. In other embodiments, the compositions of the present invention may contain from about 1 to about 20, from about 2 to about 15, or from about 2 to about 10% (w/v) cosolvent.

The long-acting injectable compositions of the present invention may include pharmaceutically acceptable additives or excipients. Pharmaceutically acceptable additives and excipients include, but are not limited to, surfactants, antioxidants, preservatives, pH stabilizers (eg, buffer additives), and other inactive excipients. In another embodiment, the compositions of the present invention may contain from about 0.01 to about 20% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof. In other embodiments, the compositions may contain from about 0.01 to about 5, from about 0.1 to about 10, or from about 0.1 to about 5% (wt/vol) of a pharmaceutically acceptable additive, excipient, or the same. mixtures. In other embodiments, the compositions may contain from about 5 to about 15 or from about 5 to about 10% (w/v) of a pharmaceutically acceptable additive, excipient, or mixture thereof. In another embodiment, the compositions may contain from about 7 to about 10% pharmaceutically acceptable additive, excipient, or mixture thereof.

Surfactants may be present in the compositions of the present invention in concentrations of from about 0.1 to about 10, from about 1 to about 10, or from about 5 to about 10% (wt./wt.). More typically, surfactants may be present in concentrations of from about 0.1 to about 5, or from about 1 to about 5% (w/w). Examples of surfactants that can be used in the compositions of the present invention include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, ethylene oxide-propylene oxide copolymers (e.g. poloxamers such as LUTROL® F87, etc.), polyethylene glycol derivatives of castor oil, including polyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride esters including glycerol caprylate/caprate (CAPMUL® MSM), polyglycolysed glycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen® 767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleic glycerides ( Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate, etc.). Polyethylene glycol stearates (synonyms include macrogol stearates, polyoxystearates, polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers. Polyethylene glycol hydroxystearate is a mixture of mono- and diesters of hydroxystearic acid with polyethylene glycols. One polyethylene glycol hydroxystearate that can be used in the compositions of the present invention is polyethylene glycol 12-hydroxystearate. In another embodiment, the compositions of the present invention may contain the surfactant polyethylene glycol 15 12-hydroxystearate (Kolliphor® HS 15 from BASF), a mixture of mono- and diesters of 12-hydroxystearic acid with 15 moles of ethylene oxide. Again, these compounds, as well as their amounts, are well known in the art. In another embodiment of the present invention, the compositions of the present invention may contain polyoxyl 35 castor oil (Kolliphor® EL) as a surfactant. In other embodiments, the compositions of the present invention may contain polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) or polyoxyl 60 hydrogenated castor oil as surfactants. The compositions of the present invention may also include a combination

- 65 044142 surfactants.

The compositions described in the present invention may contain other inert ingredients, such as antioxidants, preservatives or pH stabilizers. Such compounds are well known in the art. Antioxidants such as vitamin E, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated) can be added to the composition of the present invention. hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, tert-butylhydroquinone (TBHQ), etc. Antioxidants are typically added to the compositions of the present invention in amounts of from about 0.01 to about 3%, or from about 0.01 to about 2% (w/v), based on the total weight of the composition (w/w). ). In another embodiment, the compositions of the present invention contain from about 0.05 to about 1.0% (wt/wt) of a single antioxidant or mixture of antioxidants.

Preservatives such as parabens (methylparaben and/or propylparaben) are suitably used in the composition in amounts of from about 0.01 to about 2%, especially preferably from about 0.05 to about 1.0%. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imideurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercury nitrate , potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, etc. Preferred inputs of these compounds include a range from about 0.01 to about 5%.

The present invention also includes compounds that stabilize the pH value of the composition. Such compounds are also well known to those skilled in the art, as is the manner in which they are used. Buffer systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartaric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycinate, tris , glutamic acid/glutamates and sodium carbonate.

Dosage forms may contain from about 0.5 mg to about 5 g of active ingredient or combination of active ingredients. More commonly, the amount of active ingredient(s) in the compositions of the present invention is from about 1 mg to about 3 g. In another embodiment, the amount of active ingredient(s) in the compositions is from about 20 mg to about 3 g. In another embodiment In one embodiment, the amount of active ingredient(s) in the compositions is from about 20 mg to about 2 g, from about 20 mg to about 1.5 g, or from about 20 mg to about 1 g. In other embodiments, the amount of active ingredient(s) is ( substances) in the compositions is from about 20 to about 500, from about 30 to about 200, or from about 50 to about 200 mg. In another embodiment, the amount of active ingredient(s) in the compositions is from about 50 mg to about 2 g, from about 50 mg to about 1 g, or from about 50 mg to about 500 mg. In another embodiment of the present invention, the amount of active ingredient(s) in the compositions is from about 100 mg to about 2 g, from about 100 mg to about 1 g, or from about 100 mg to about 500 mg.

In another embodiment, the amount of active ingredient(s) in the composition of the present invention is from about 1 to about 500, from about 1 to about 100, or from about 1 to about 25 mg. In other embodiments, the amount of active ingredient in the compositions is from about 10 to about 50, or from about 10 to about 100 mg. In other embodiments, the amount of active ingredient in the compositions is from about 50 to about 200, from about 100 to about 300, from about 100 to about 400, from about 200 to about 500, from about 300 to about 600, from about 400 to about 800, or about 500 to about 1000 mg.

The compositions of the present invention are prepared by mixing an appropriate amount of active ingredients, liquid PEG and/or neutral oil, a cosolvent (if present) and, optionally, an antioxidant, pharmaceutically acceptable additive and/or excipient, to obtain a composition of the present invention. In some embodiments, the compositions of the present invention can be prepared according to methods of preparation of such forms described in well-known sources in the art, for example, Remington - The Science and Practice of Pharmacy ( ^21st Edition) (2005), Goodman &Gilman's The Pharmacological Basis of Therapeutics ( ^11th Edition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems ( ^8th Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005).

Methods of treatment.

In another aspect of the present invention, a method of preventing or treating a parasitic infection/infestation in an animal is described, comprising administering to the animal a long-acting injectable composition containing an effective amount of at least one isoxazoline compound, a liquid PEG and/or neutral oil, optionally a co-solvent and optionally an anti-oxidant.

- 66 044142 sidant, pharmaceutically acceptable additive and/or excipient. The compositions of the present invention have long-term effectiveness against ectoparasites (eg, fleas and ticks), and in some embodiments may also have activity against endoparasites affecting animals.

In one embodiment of the present invention, methods are described for treating or preventing a parasitic infection or infestation in livestock, comprising administering to the animal a long-acting injectable composition containing an effective amount of at least one isoxazoline active ingredient. Ectoparasites against which the methods and compositions of the present invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice. In some embodiments, when the compositions of the present invention include one or more additional active ingredients that are active against internal parasites, the described compositions and methods of the present invention may also have activity against endoparasites, including but not limited to cestodes, nematodes, hookworms and roundworms from the digestive tract of animals and humans.

In an alternative embodiment of the present invention, methods are described for treating or preventing a parasitic infection or infestation in a domestic animal, comprising administering to the animal a long-acting injectable composition containing an effective amount of at least one isoxazoline active ingredient. Ectoparasites against which the methods and compositions of the present invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice. In some embodiments, when the compositions of the present invention include one or more additional active ingredients that are active against internal parasites, the described compositions and methods of the present invention may also have activity against endoparasites, including but not limited to cestodes, nematodes, hookworms and roundworms from the digestive tract of animals and humans.

In one embodiment of treatment for ectoparasites, the ectoparasites are one or more insects or arachnids, including members of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus , Haematopinus, Solenoptes, Trichodecte and Felicola.

In another embodiment of treatment for ectoparasites, the ectoparasites belong to the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. Ectoparasites treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include (but are not limited to) dog and cat fleas (Ctenocephalides felis, Ctenocephalides sp., etc.), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., etc.). ) and itch (Demodex sp., Sarcoptes sp., Otodectes sp., etc.), lice (Trichodectes sp., Cheyletiella sp., Linognathus sp., etc.), mosquitoes (Aedes sp., Culex sp., Anopheles sp., etc.) and flies (Haematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys calcitrans, Dermatobia sp., Cochliomyia sp., etc.).

Additional examples of ectoparasites include, but are not limited to, mites of the genus Boophilus, especially microplus species, decoloratus and annulatus; myiases such as Dermatobia hominis (known in Brazil as Berne) and Cochliomyia hominivorax (green carrion); sheep myiases, such as Lucilia sericata, Lucilia cuprina (known in Australia, New Zealand and South Africa as blowfly strike), true flies, namely those in which the adults are parasites, such as Haematobia irritans (lesser cow fly) and Stomoxys calcitrans (common burner); lice such as Linognathus vituli, etc.; and pruritus such as Sarcoptes scabiei and Psoroptes ovis. The above list is not complete, and other ectoparasites are well known in the art to be harmful and dangerous to animals and humans. These include, for example, the larvae of migratory dipterans.

In some embodiments of the present invention, the composition can also be used for treatment of endoparasites, such as helminths selected from the group consisting of Anaplocephala, Ancylostoma, Necator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostomum, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris and Trichostrongylus, among others.

In one embodiment, the present invention describes methods for treating and preventing parasitic infections and infestations in or on animals (wild or domestic), including farm and pet animals such as cats, dogs, horses, birds (including chickens), sheep , goats, pigs, deer, turkeys and cattle, with the goal of ridding said host animals of parasites commonly found in such animals.

In one embodiment, the present invention describes methods and compositions for treating or preventing parasitic infections and infestations in livestock (eg, sheep and cattle) or pets, including, but not limited to, cats and

- 67 044142 dogs. The described methods and compositions are particularly effective for preventing or treating parasitic infections in sheep and cattle in the form of fleas and ticks.

In another embodiment, the methods and compositions of the present invention are used to treat or prevent parasitic infections and infestations in cattle or sheep. When treating farm animals such as cattle or sheep, the methods and compositions described are particularly effective against Rhipicephalus (Boophilus) microplus, Haematobia irritans, Stomoxys calcitrans, and ovine myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa).

The terms treat or treat are intended to mean administering a long-acting composition of the present invention to an animal that is suffering from a parasitic infection to kill the parasites or reduce the number of parasites affecting the animal being treated. It should be noted that the compositions of the present invention can be used to prevent such parasitic infestations.

The terms prevent, prevent, or prophylaxis are intended to mean administering the long-acting composition of the present invention to an animal before a parasitic infestation or infection occurs, so that said infestation or infection does not occur. Administration of the long-acting composition at recommended regular intervals is effective in preventing new parasitic infestations or infections in animals by killing new parasites attacking the animal before they can multiply to the extent that they can cause infestation or infection.

The compositions of the present invention are administered in parasiticidal effective amounts suitable for reducing the number of specific parasites to the desired extent, as described below. In each aspect of the invention, the compounds and compositions of the present invention can be used against a single species of parasite or against combinations thereof.

By the term antiparasitic effective amount is meant an amount of the composition of the present invention sufficient to kill or reduce the number of parasites infecting an animal. In some embodiments, the effective amount of the active ingredient achieves at least 70% effectiveness against a given parasite. In other embodiments, the effective amount of the active ingredient achieves at least 80%, or at least 90% effectiveness against a given parasite. Preferably, the effective amount of the active substance achieves at least 95%, at least 98% or 100% effectiveness against the given parasites.

In general, a dosage of about 0.001 to about 100 mg per kg of body weight, either as a single dose or as several divided doses, over a period of 1 to 5 days will be sufficient, but of course there may be cases where more is indicated. high or low dosages, and such cases are also included in the scope of the present invention. A person skilled in the art will have the skill to determine the specific dosage regimen for each host and parasite.

In some pet embodiments, the dosage of the isoxazoline active ingredient administered from the topical composition of the present invention is from about 0.1 to about 50 mg per kg of body weight. More typically, the dosage of isoxazoline active ingredient administered is from about 0.5 to about 30, or from about 0.5 to about 30 mg/kg body weight. In another embodiment, the dosage of the isoxazoline active ingredient is from about 0.5 to about 20, from about 0.5 to about 10, or from about 0.5 to about 5 mg/kg body weight. In another embodiment, the dosage is from about 0.5 to about 2.5 mg/kg body weight. In another embodiment, the dosage of isoxazoline active ingredient administered is from about 10 to about 30, from about 15 to about 30, or from about 20 to about 30 mg/kg body weight.

In other embodiments, the dosage administered may be lower, depending on the animal and the isoxazoline administered. For example, if the composition contains a more active enantiomer of isoxazoline compounds, a lower dosage may be administered. In some embodiments, the dosage is from about 0.1 to about 30 mg/kg body weight. In another embodiment, the dosage may be from about 0.1 to about 20, or from about 0.1 to about 10 mg/kg body weight. In another embodiment, a dosage of from about 0.1 to about 5, from about 0.1 to about 2.5 mg/kg body weight is used. In other embodiments, the dosage may be from about 1 to about 20 mg/kg body weight, or from about 1 to about 10 mg/kg. In another embodiment, the dosage may be from about 5 to about 20, or from about 10 to about 20 mg/kg body weight.

The dose volume of long-acting injectable compositions is typically less than about 10 ml/50 kg body weight of the animal being treated. In other embodiments, the injected volume is less than about 7 ml/50 kg body weight. In other embodiments, the injected volume is less than about 5 ml/50 kg, the injected volume is example

- 68 044142 but 3 ml/50 kg body weight or the injected volume is approximately 2 ml/50 kg body weight. In other embodiments, the injected volume is from about 0.1 to about 2 ml/50 kg of animal body weight. In other embodiments, the injected volume is from about 0.05 to about 1 ml/50 kg of animal body weight.

In other embodiments, for treating farm animals such as cattle or sheep, the dosage of isoxazoline active ingredient administered may be from about 0.1 to about 40 mg/kg body weight. More typically, the dosage administered is from about 1 to about 30, from about 1 to about 20, or from about 1 to about 10 mg/kg body weight. In another embodiment, the dosage may be from about 10 to about 25, from about 15 to about 30, or from about 20-30 mg/kg body weight.

In one embodiment of the method of application to farm animals (for example, sheep or cattle), the long-acting compositions of the present invention containing an isoxazoline compound are effective against ectoparasites, including, but not limited to, fleas, ticks, ticks and parasitic flies of at least about 90.0% or higher, for about 3 months or more. In another embodiment, the long-acting compositions of the present invention provide an efficacy against ectoparasites of at least 95.0% or greater for about 3 months or more.

In another embodiment, the long-acting compositions of the present invention provide an effectiveness against ectoparasites in farm animals (eg, sheep or cattle) of at least about 80% or greater for 2 months or more. In another embodiment, in another embodiment, the long-acting compositions of the present invention provide at least about 90% effectiveness against ectoparasites in farm animals (eg, sheep or cattle) for at least about 2 months. In another embodiment, the compositions provide about 90% effectiveness for about 2 months or more. In another embodiment, the long-acting compositions of the present invention provide about 90% effectiveness against ectoparasites in farm animals (eg, sheep or cattle) for about 3 months or more. In another embodiment, the compositions provide about 95% effectiveness for about 3 months or more.

In another embodiment, the long-acting compositions of the present invention provide at least about 80% effectiveness against ectoparasites for about 3 months or more. In another embodiment, the long-acting compositions of the present invention provide at least about 90% effectiveness against ectoparasites for 3 months or more. In another embodiment, the long-acting compositions of the present invention provide at least about 95% effectiveness against ectoparasites for 3 months or more. In another embodiment, the long-acting compositions of the present invention provide at least 80% or at least 90% effectiveness against ectoparasites in farm animals (eg, sheep or cattle) for about 3-6 months or more.

In other embodiments, the long-acting compositions of the present invention provide at least about 90% effectiveness against ectoparasites, including, but not limited to, fleas, ticks, mites, and parasitic flies, for about 7 months or greater, about 8 months or more or approximately 9 months or more. In other embodiments, the long-acting compositions of the present invention provide at least about 90% effectiveness against ectoparasites, including, but not limited to, fleas, ticks, mites, and parasitic flies, for about 10 months or more, about 11 months or more, or even approximately 12 months or more.

In another aspect of the present invention, a kit is described for treating or preventing a parasitic infection in an animal, which includes a long-acting composition of the present invention and a syringe.

Antiparasitic compounds.

The second aspect of the present invention describes new and innovative pesticide and parasiticidal isoxazoline compounds having formula (Id):

(Id) where X ¹ represents a bromine, chlorine, iodine or fluorine atom; and X ² represents a chlorine, fluorine or CF ₃ atom;

Y represents the group Y-1, Y-2, Y-3, Y-4, where Z represents N or CH, Y-5 or Y-6

- 69 044142

Q represents OH, -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O)CH ₂ S(O) ₂ CH ₃ , -C(O)NHCH ₂ CH ₂ SCH ₃ or (- CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

The second aspect of the present invention includes at least the following features:

(a) in one embodiment, the present invention describes novel compounds having formula (Id), or pharmaceutically or agriculturally acceptable salts thereof, that are active against arthropod pests and parasites that cause harm to animals and plants;

(b) veterinary and pesticide compositions for the extermination and control of pests and parasites, containing a pesticidal or parasiticidal effective amount of compounds having formula (Id), or pharmaceutically or agriculturally acceptable salts thereof, in combination with a pharmaceutically or agriculturally acceptable carrier or diluent;

(c) plant propagation material (eg seeds) containing at least one compound having formula (Id) or agriculturally acceptable salts thereof.

(d) veterinary and pesticide compositions for the control of arthropod pests and parasites, containing a pesticidal or parasiticidal effective amount of the compounds of the present invention, or pharmaceutically or agriculturally acceptable salts thereof, in combination with at least one additional active ingredient, and a pharmaceutically or agriculturally acceptable carrier or diluent;

(e) methods of treating a parasitic infestation/infection in an animal or on the integument of an animal are described, which include administering a parasiticidal effective amount of a compound having formula (Id), or pharmaceutically acceptable salts thereof, to an animal in need thereof;

(f) methods of preventing parasitic infestation/infection in an animal, which comprises administering a parasiticidal effective amount of a compound having formula (Id), or pharmaceutically acceptable salts thereof, to an animal in need thereof;

(g) methods of exterminating or controlling pests causing damage to crops, plants, plant propagation material, or material containing or derived from wood, involving contact of crops, plants, plant propagation material, or material containing or derived from wood tree, with a pesticidal effective amount of a compound having formula (Id), or an agriculturally acceptable salt thereof, or a composition containing such compounds;

(h) methods for exterminating or controlling pests at a locus, comprising administering a pesticidal or parasiticidal effective amount of a compound of formula (Id), or pharmaceutically or agriculturally acceptable salts thereof, to the locus;

(i) the use of compounds of formula (Id), or pharmaceutically or agriculturally acceptable salts thereof, for the control of pests, including parasites, in or on an animal or on a crop, plant, plant propagation material, or wood-containing material or obtained from wood; and (j) the use of compounds having formula (Id), their pharmaceutically acceptable salts, in the manufacture of a veterinary medicinal product for the control of pests, including parasites.

An important aspect of the present invention is the development of isoxazoline active ingredients that have unexpected fast-acting and long-lasting effectiveness against parasites, in particular ticks, than isoxazoline active ingredients having different substitution patterns on the phenyl ring bonded to the quaternary carbon atom of the isoxazoline ring. Thus, it has been found that a compound having formula (Id) wherein Y is Y-2, Q is C(O)NHCH2C(O)NHCH2CF ₃ , X ¹ is a fluorine atom, and X ² is a chlorine atom , which is not specifically described in WO 2007/079162 A1 or WO 2009/002890 A2, has an unexpectedly improved duration of activity against the tick Rhipicephalus microplus (formerly known as Boophilus microplus) in cattle, compared to known isoxazoline compounds in which Y is is Y-2, and Q is -C(O)NHCH2C(O)NHCH2CF3, but the phenyl ring has a different substitution pattern.

In addition, it was also found that a compound having the formula (Id), wherein Y represents Y-2, Q represents -C(O)NHCH2C(O)NHCH2CF3, X ¹ represents a fluorine atom, and X ² represents chlorine atom, has unexpectedly improved rapid efficacy against the Rhipicephalus microplus tick on cattle, compared to the known isoxazoline compounds in which Y is Y-2 and Q is -C(O)NHCH ₂ C( O)NHCH ₂ CF ₃ , but the phenyl ring has a different substitution pattern.

In one embodiment, the present invention describes a compound having formula (Id), wherein the group Y is Y-1. In another embodiment, Y is Y-2. In another embodiment, Y is Y-3. In another embodiment, Y is Y-4. In another embodiment, Y is Y-5. In another embodiment, Y is Y-6.

In one embodiment, the present invention describes a compound having formula (Id) wherein Y is Y-1, X ¹ is a fluorine atom, and Q is C(O)NHCH2C(O)NHCH2CF3, -C(O )CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a fluorine atom, and Q is C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, or -C(O)NHCH2CH2SCH3 . In another embodiment, Y is Y-3, X ¹ is a fluorine atom, and Q is (-CH2-)(CH ₂ -)N(CO)CH ₂ S(O) ₂ CH ₃ where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-4, X ¹ is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, or -C(O) NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, or -C(O) NHCH2CH2SCH3. In another embodiment, Y is Y-6, X ¹ is a fluorine atom, and Q is OH.

In another embodiment, the present invention describes a compound having formula (Id) wherein Y is Y-1, X ¹ is a chlorine atom, and Q is C(O)NHCH2C(O)NHCH2CF3, -C(O )CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a chlorine atom, and Q is C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, or -C(O)NHCH2CH2SCH3 . In another embodiment, Y is Y-3, X ¹ is a chlorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, wherein each terminal CH2 is bonded to a benzyl carbon group Y-3. In another embodiment, Y is Y-4, X ¹ is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH ₂ CF ₃ , -C(O)CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Y is Y-5, X ¹ is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, or -C(O) NHCH2CH2SCH3. In another embodiment, Y is Y-6, X ¹ is a chlorine atom, and Q is OH.

In one embodiment, Y is Y-1, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is a fluorine atom, X ² is CF ₃ , and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In another embodiment, Y is Y-1, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is a chlorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In one embodiment, Y is Y-1, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is bromine, X ² is fluorine, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is bromine, X ² is CF3, and Q is X(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O)CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-1, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-1, X ¹ is an iodine atom, X ² is CF3, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O) CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-2, X ¹ is a fluorine atom, X ²

- 71 044142 represents a chlorine atom, and Q represents -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O)CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH2CH2SCH ₃ . In another embodiment, Y is Y-2, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a fluorine atom, X ² is CF ₃ , and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In another embodiment, Y is Y-2, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a chlorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In one embodiment, Y is Y-2, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is a bromine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is bromine, X ² is CF3, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O) CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-2, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-2, X ¹ is an iodine atom, X ² is CF ₃ , and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-3, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3; where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is (-CH2-)(-CH ₂ -)N(CO)CH ₂ S(O ) ₂ CH _3; where each terminal CH ₂ is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a fluorine atom, X ² is CF3, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group.

In another embodiment, Y is Y-3, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3; where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is (-CH2-)(-CH ₂ -)N(CO)CH ₂ S(O ) ₂ CH ₃ , where each terminal CH ₂ is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a chlorine atom, X ² is CF ₃ , and Q is (-CH ₂ -)(-CH ₂ -)N(CO)CH ₂ S( O) ₂ CH ₃ , where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group.

In one embodiment, Y is Y-3, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a bromine atom, X ² is a fluorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is bromine, X ² is CF ₃ , and Q is (-CH ₂ -)(-CH ₂ -)N(CO)CH ₂ S( O) ₂ CH ₃ , where each terminal CH ₂ is bonded to the benzyl carbon of the Y-3 group.

In one embodiment, Y is Y-3, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is (-CH2-)(-CH ₂ -)N(CO)CH ₂ S(O ) ₂ CH ₃ , where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is an iodine atom, X ² is CF ₃ , and Q is (-CH ₂ -)(-CH ₂ -)N(CO)CH ₂ S( O) ₂ CH ₃ , where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group.

In one embodiment, Y is Y-4, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Y represents Y-4, X ¹ represents

- 72 044142 Et represents a fluorine atom, X ² represents a fluorine atom, and Q represents -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is a fluorine atom, X ² is CF3, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O) CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In one embodiment, Y is Y-4, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is a bromine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is bromine, X ² is CF ₃ , and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-4, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-4, X ¹ is an iodine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In one embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is CF ₃ , and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-5, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O )CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Y is Y-5, X ¹ is a bromine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is bromine, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3.

In one embodiment, Y is Y-5, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O) 2CH3 or -C(O)NHCH2CH2SCH3. In another embodiment, Y is Y-5, X ¹ is an iodine atom, X ² is CF3, and Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ , -C(O) CH ₂ S(O) ₂ CH ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ .

In one embodiment, Y is Y-6, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is a fluorine atom, X ² is CF3, and Q is OH.

In another embodiment, Y is Y-6, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is

- 73 044142 chlorine atom, X ² represents CF3, and Q represents OH.

In one embodiment, Y is Y-6, X ¹ is a bromine atom, X ² is a chlorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is a bromine atom, X ² is a fluorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is bromine, X ² is CF ₃ , and Q is OH.

In one embodiment, Y is Y-6, X ¹ is an iodine atom, X ² is a chlorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is an iodine atom, X ² is a fluorine atom, and Q is OH. In another embodiment, Y is Y-6, X ¹ is an iodine atom, X ² is CF3, and Q is OH.

In another embodiment, Y is Y-1, X ¹ is a fluorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-1, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH ₂ CF ₃ .

In one embodiment, Y is Y-2, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-1, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH ₂ CF ₃ .

In one embodiment, Y is Y-3, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is (-CH ₂ -)(-CH ₂ -)N(CO)CH ₂ S( O) ₂ CH ₃ , where each terminal CH ₂ is bonded to the benzyl carbon of the Y-3 group. In another embodiment, Y is Y-3, X ¹ is a fluorine atom, X ² is CF3, and Q is (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3, where each terminal CH2 is bonded to the benzyl carbon of the Y-3 group.

In one embodiment, Y is Y-4, where Z is CH, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-4 where Z is CH, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH ₂ CF ₃ . In another embodiment, Y is Y-4, X ¹ is a fluorine atom, X ² is CF ₃ , and Q is -C(O)NHCH2C(O)NHCH2CF3.

In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-4, X ¹ is a chlorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3.

In one embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH ₂ CF ₃ . In another embodiment, Y is Y-5, X ¹ is a fluorine atom, X ² is CF3, and Q is -C(O)NHCH2C(O)NHCH2CF3.

In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is a chlorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is a fluorine atom, and Q is -C(O)NHCH2C(O)NHCH2CF3. In another embodiment, Y is Y-5, X ¹ is a chlorine atom, X ² is CF ₃ , and Q is -C(O)NHCH2C(O)NHCH2CF3.

In a preferred embodiment, the present invention describes a compound having formula (Ie) below, or a pharmaceutically acceptable salt thereof:

As noted above, isoxazoline compounds having formula (Id) can exist as stereoisomers because they contain a chiral center in the molecule. Individual stereoisomers are covered by the structural formulas depicted in the present invention. The various stereoisomers include enantiomers, diastereomers and atropoisomers.

Thus, in another embodiment, the present invention discloses isoxazoles

- 74 044142 new compounds having formula (Id), and compositions containing these compounds, enriched with one enantimer, or a pharmaceutically or agriculturally acceptable salt thereof.

In another embodiment, the present invention discloses isoxazoline compounds having formula (Id), and compositions containing said compounds enriched in an enantiomer exhibiting significant in vitro and in vivo activity and a favorable toxicity profile (eutomer), or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the more biologically active enantiomer of a compound having formula (Id) is considered to be a compound having formula (S)-Id shown below. Accordingly, the more biologically active enantiomers of isoxazoline compounds having the formula (Id), where Y is Y-1, Y-2, Y-3, Y-4, Y-5 and Y-6, have an (S) chiral configuration carbon atom in the isoxazoline ring.

In one embodiment, compounds having formula (Id), (including (Ie)), or compositions containing these compounds, are enriched in one enantiomer relative to the other enantiomer in a weight ratio of at least 1.5:1. In another embodiment, compounds having formula (Id) and compositions containing these compounds are enriched in one enantiomer in a weight ratio of at least 2:1, at least 5:1, at least 10:1, or at least 20:1.

In another embodiment, the compounds having formula (Id), or compositions containing these compounds, are substantially pure enantiomers. In one embodiment, the compound and composition of the present invention is a compound having formula (Id) that is substantially enriched in one enantiomer. The term substantially enriched means that w/w. the ratio is at least about 1.5:1 or greater, favoring the target enantiomer. In another embodiment, the compounds and compositions of the present invention are substantially enriched in the (S)-enantiomer. In another embodiment, the compounds and compositions of the present invention are substantially enriched in the (R)-enantiomer.

In another embodiment of the present invention, compounds having formula (Id), or compositions containing the compounds, are enriched in the (S)-enantiomer in a weight ratio of at least about 2:1, (S):(R), or greater. In another embodiment, the compounds or compositions of the present invention contain a compound having formula (Id) that is enriched in the (S)-enantiomer in a weight ratio of at least about 5:1, (S):(R), or greater. In another embodiment, the compounds and compositions of the present invention contain a compound having formula (Id) that is enriched in the (S)-enantiomer in a weight ratio of at least about 10:1, (S):(R), or greater. In another embodiment, the compounds and compositions of the present invention contain a compound having formula (Id) that is enriched in the (S)-enantiomer in a weight ratio of at least about 20:1, (S):(R), or greater. In another embodiment, the compounds and compositions of the present invention contain a compound having formula (Id), which is a substantially pure (S)-enantiomer.

In one embodiment, the present invention describes a compound having the formula (S)-Ie shown below, or a pharmaceutically acceptable salt thereof:

(S)-Ie.

In another embodiment, the present invention describes a compound having the formula (R)-Ie shown below, or a pharmaceutically acceptable salt thereof:

GL

In another embodiment, the present invention describes pesticide and parasiticidal compositions containing a compound having the formula (S)-Ie. In another embodiment, the present invention discloses pesticide and parasiticidal compositions containing a compound having the formula (R)-Ie. For the sake of clarity, compositions of the present invention containing a compound having formula (S)-Ie or (R)-Ie may be enriched with the desired enantiomer to the extent discussed above for the compound having formula (Id).

Methods for preparing compounds having formula (Id).

Compounds having formula (Id) and intermediates used in the methods for preparing these compounds can be prepared by methods that are adaptations of the methods described in US 7964204, US 8410153, US 8546 618, US 8217180, US 8 546613, US 7662972, US 8466115 , US 8383659, US

- 75 044142

8853186, US 8618126, US 2014/0371464, US 2015/0291612 and WO 2014/090918, all of which are incorporated herein by reference in their entirety.

In one embodiment, the compounds of the present invention can be prepared according to the general method shown in Scheme 1 below, wherein Y, Q, X ¹ and X ² are as defined above for formula (Id), W is Cl, Br or I , and R represents alkyl.

Scheme 1

This general method is described, for example, in US 8,546,618 for the preparation of compounds in which Y is Y-2. By using suitably substituted compounds having the formula Id-1 and Id-4, a variety of compounds having the formula (Id) can be prepared. Methods for preparing intermediates having the formula Id-1, Id-3, Id-4 and Id-5 are described in US 8,546,618 and US 8,217,180, both of which are incorporated herein by reference. The formation of isoxazoline compounds having formula (Id) from Id-5 is also described in US 8,546,618 and US 8,217,180. Additional information on methods for preparing intermediates Id-1, Id-3, Id-4 and Id-5, which can be used to prepare compounds having formula (Id), can be found in US 7,662,972, US 8,466,115, US 8,383,659, US 8,853,186, US 2014/0371464, US 2015/0291612 and WO 2014/090918, all of which are incorporated herein by reference in their entirety.

Application in the field of veterinary medicine.

I. Veterinary compositions.

Compounds having formula (Id) and compositions containing these compounds can be used to prevent and treat parasitic infestations/infections in animals. The compositions of the present invention contain an effective amount of at least one isoxazoline compound having formula (Id), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent and, optionally, other inactive auxiliary compounds. In a preferred embodiment, the compositions of the present invention contain an effective amount of an isoxazoline having formula (Ie) or (S)-Ie, or a pharmaceutically acceptable salt thereof. The compositions may take the form of various solid or liquid formulations that are suitable for various methods of application or administration to animals. For example, veterinary compositions containing the innovative compounds may be in the form of compositions suitable for oral administration, injection, including subcutaneous and parenteral administration, and topical application (eg, spot application or infusion). The compositions are intended for administration to an animal, including (but not limited to) mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other farm or domestic mammals. Examples of birds include turkeys, chickens, ostriches, and other farm or poultry birds. Particularly useful are the compounds having formula (Id) for protecting companion animals such as dogs and cats, and farm animals such as sheep and cattle, from ectoparasites.

As described above, the compositions of the present invention may be in a suitable oral form (see, for example, U.S. Patent No. 4,564,631, incorporated herein by reference), dietary supplements, lozenges, lozenges, chewable tablets, tablets, hard or soft capsules, boluses, emulsions, aqueous or oily suspensions, aqueous or oily solutions, compositions for infusion into the oral cavity, dispersible powders or granules, ready-made mixtures, syrups or elixirs, enteric compositions or pastes. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and these compositions can contain one or more sweeteners, bitters, flavorings, colors and preservatives to obtain pharmaceutically superior and visually attractive preparations.

Tablets may contain the active ingredient mixed with a non-toxic pharmaceutical supplement

- 76 044142 filler suitable for the production of tablets. Such excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders, for example starch, gelatin or acacia gum, and lubricants, for example magnesium stearate, stearic acid or talc, tablets may be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract, which ensures prolonged action over a longer period of time. For example, long-lasting materials such as glyceryl monostearate or glyceryl distearate may be used. Tablets can also be coated using the method described in US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 (incorporated herein by reference), for the preparation of controlled release osmotic therapeutic tablets.

Compositions for oral administration include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules in which the active ingredient is mixed with water or a water-miscible solvent such as propylene glycol, polyethylene glycols (PEG) and ethanol, or an oily medium such as peanut oil, liquid paraffin or olive oil. .

In one embodiment, compounds having formula (Id) can be administered in the form of soft tablet compositions or soft chewable compositions, such as those described in US 9,233,100 B2, US 9,259,417, US 2010/0087492, US 2006/0222684, US 2004/0151759 , US 7955632, US 2015/0057321, US 2015/0057239 and WO 2016/073347, all of which are incorporated herein by reference in their entirety.

Veterinary compositions may be in the form of soft chewable compositions (soft chews) that are attractive and acceptable to mammals. In addition to the active ingredient(s), the soft chews of the present invention may include one or more of the following components: a solvent or mixture of solvents, one or more excipients, one or more binders, one or more surfactants, one or more humectants, one or more lubricants, one or more disintegrants, one or more colorants, one or more antimicrobial agents, one or more antioxidants, one or more pH modifiers, and one or more flavoring agents.

Solvents that can be used in the compositions of the present invention include, but are not limited to, various grades of liquid polyethylene glycol (PEG), including PEG 200, PEG 300, PEG 400 and PEG 540; propylene carbonate; propylene glycol; triglycerides including, but not limited to, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride (e.g., MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride, propylene glycol dicaprylate/dicaprate, etc.; water, sorbitol solution , glycerol caprylate/caprate and polyglycosylated glycerides (GELUCIRE®) or combinations thereof.

Various excipients known in the art can be used in the soft chewable compositions of the invention. Fillers include, but are not limited to, corn starch, pre-gelatinized corn starch, micronized soy protein, corn cob meal, corn gluten meal, and the like. In some embodiments, a combination of two or more excipients may be used in the compositions.

Binders that can be used in the compositions of the invention include, but are not limited to, polyvinylpyrrolidone (eg, povidone), cross-linked polyvinylpyrrolidone (crospovidone), polyethylene glycols of various categories, including PEG 3350, PEG 4000, PEG 6000, PEG 8000 and even PEG 20,000, copolymers of vinylpyrrolidone and vinyl acetate (eg, copovidone), such as those sold by BASF under the trade name Kollidon® VA 64 and the like, starch, such as potato starch, tapioca starch, and corn starch; molasses, corn syrup, honey, maple syrup and various types of sugars; or a combination of two or more binders.

Humectants that can be used in the compositions include, but are not limited to, glycerol (also referred to herein as glycerol), propylene glycol, cetyl alcohol or glycerol monostearate, and the like. Polyethylene glycols of various categories can also be used as humectants.

Surfactants may be present in the chewable composition at a concentration of from about 0.1 to about 10, from about 1 to about 10, or from about 5 to about 10% (w/w). More typically, surfactants may be present at a concentration of from about 0.1 to about 5, or from about 1 to about 5% (w/w). Examples of surfactants that may be used in the compositions include, but are not limited to

- 77 044142 containing them, glyceryl monooleate, polyoxyethylene esters of sorbitol and fatty acids, sorbitol esters, including sorbitol monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide (e.g. poloxomers such as LUTROL® F87, etc.), polyethylene glycol derivatives of castor oil, including polyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 castor oil (Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL®); glycerol esters including glycerol caprylate/caprate (CAPMUL® MSM), polyglycolysed glycerides (GELUCIRE®), PEG 300 caprylic/capric triglycerides (Softigen® 767), PEG 400 caprylic/capric triglycerides (Labrasol®), PEG 300 oleic glycerides (Labrafil ® M-1944CS), PEG 300 linoleic glycerides (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl stearate 40 (PEG 1750 monostearate), etc. Polyethylene glycol stearates (their synonyms include macrogol stearates, polyoxystearates, polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers. Polyethylene glycol hydroxystearate is a mixture of mono- and diesters of hydroxystearic acid with polyethylene glycols. One polyethylene glycol hydroxystearate that can be used in the compositions of the present invention is polyethylene glycol 12hydroxystearate. In another embodiment, the compositions may include the surfactant polyethylene glycol 15 12-hydroxystearate (Solutol® HS 15 from BASF), a mixture of mono- and diesters of 12-hydroxystearic acid with 15 moles of ethylene oxide. Again, these compounds, as well as the amounts used, are well known in the art. In another embodiment of the present invention, the compositions may include polyoxyl 35 castor oil (Cremophor® EL) as a surfactant. In other embodiments, chewable compositions may include polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) or polyoxyl 60 hydrogenated castor oil (Cremophor® RH60) as surfactants. The compositions of the present invention may also include a combination of surfactants.

Chewable compositions may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are also well known in the art of formulation. Antioxidants can be added to the compositions of the invention to inhibit the degradation of the active agents. Suitable antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol, etc. P.

The chewable compositions of the present invention may also include one or more lubricants/excipients. In some cases, the lubricant can also act as a solvent, and, accordingly, some components of the original compositions can perform dual functions. Lubricants/auxiliaries include, but are not limited to, polyethylene glycols of various molecular weight ranges, including PEG 3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenated vegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil .

Many flavoring agents can be used in the compositions of the present invention to improve the palatability of oral veterinary compositions. Preferred flavoring agents are those that are not derived from animal sources. In various embodiments, flavor components may be used derived from fruits, meats (including, but not limited to, pork, beef, chicken, fish, poultry, etc.), vegetables, cheese, bacon, bacon cheese and/or artificial flavorings. The flavoring aromatic component is usually selected according to the type of animal for which the soft chewing gum is intended. For example, a horse may prefer an apple flavoring component, while a dog may prefer a meat flavoring component. Although flavoring agents derived from non-animal sources are preferred, in some embodiments natural flavoring agents containing extracts of beef or liver and the like may be used, such as stew flavor additive, artificial powdered beef flavor additive, flavor additive roasted beef, and corned beef flavor additive, among others.

In another embodiment of the present invention, the active composition can be administered by oral infusion. Oral infusion compositions are liquid compositions of the present invention that are administered to the mouth or throat of an animal.

The compositions of the present invention may also take the form of oil-in-water or water-in-oil emulsions. The oil phase may be a vegetable oil, such as olive oil

- 78 044142 or peanut oil, or mineral oil, for example liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural phosphatides, eg soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, eg sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, eg polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners, bitters, flavors and/or preservatives.

In one embodiment, the composition of the present invention may be in the form of a microemulsion. Microemulsions are well suited as liquid carriers. Microemulsions are four-component systems containing an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are transparent and isotropic liquids.

Microemulsions consist of stable dispersions of microdroplets of the aqueous phase in the oil phase, or vice versa - microdroplets of the oil phase in the aqueous phase. The size of such microdroplets can be less than 200 nm (from 1000 to 100,000 nm for emulsions). The film at the interface may consist of alternating surfactant and co-surfactant molecules, which, by reducing the surface tension coefficient, make possible the spontaneous formation of a microemulsion.

In one embodiment of the oil phase, the oil phase may be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or, alternatively, from mixtures of the foregoing. In one embodiment of the oil phase, the oil phase is formed by triglycerides; in another embodiment of the oil phase, the triglycerides are medium chain triglycerides, for example, C ₈ -C ₁₀ caprylic/capric triglyceride. In another embodiment, the percentage (v/v) of the oil phase is selected from the group consisting of the following ranges: about 2 to about 15; from about 7 to about 10; and about 8 to about 9% (v/v) microemulsion.

The aqueous phase includes, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol or glycerol. In one embodiment of the glycol derivative, the glycol may be propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. In general, the aqueous phase constitutes from about 1 to about 4% (v/v) of the microemulsion.

Microemulsion surfactants may include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C ₈ -C ₁₀ glycerides or polyglyceryl 6-dioleate. In addition to the surfactants listed, co-surfactants may include short-chain alcohols such as ethanol and propanol.

Some substances are common to the three components discussed above, i.e. an aqueous phase, a surfactant and a co-surfactant. However, one skilled in the art may use different substances for each component in a single composition. In one embodiment of the surfactant/co-surfactant ratio, the ratio of co-surfactant to surfactant is from about 1/7 to about 1/2. In another embodiment of the amount of co-surfactant, the ratio is from about 25 to about 75% (v/v) surfactant and from about 10 to about 55% (v/v) co-surfactant in the microemulsion.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol. Sweeteners such as sucrose, saccharin or aspartame, bitters and flavorings may be added to formulate a palatable oral preparation. The described compositions can be preserved by the addition of an antioxidant such as ascorbic acid or other known preservatives.

Aqueous suspensions may contain the active substance in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersants or wetting agents may be natural phosphatides, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids. acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may contain one or more preservatives, for example, ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners and/or bittering agents, such as those described above.

Dispersible powders and granules, suitable for preparing an aqueous suspension by adding water, contain the active ingredient mixed with a dispersant or wetting agent.

- 79 044142 vom, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents as well as suspending agents are those already listed above. Additional excipients such as sweeteners, bitters, flavors and colors may also be present.

Syrups and elixirs may contain sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such compositions may also contain a demulcent, preservative, sweetener(s) and/or colorant(s).

In another embodiment of the present invention, the composition may be in the form of a paste. Examples of paste formulations include, but are not limited to, those described in US Patent Nos. 6,787,342 and 7,001,889, both of which are incorporated herein by reference. In addition to the compounds of the present invention, the paste may also contain highly dispersed silicon dioxide; viscosity modifier; carrier; optionally, adsorbent; and, optionally, a colorant, stabilizing agent, surfactant or preservative.

In one embodiment of the composition, the composition may be a paste containing the compounds of the present invention, highly dispersed silicon dioxide, a viscosity modifier, an adsorbent, a dye; and a hydrophilic carrier which is a triacetin, monoglyceride, diglyceride or triglyceride.

The paste may also include a viscosity modifier. Suitable viscosity modifiers include, but are not limited to, polyethylene glycols (PEG), including but not limited to PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerin, propylene glycol, polyoxyethylene (20) sorbitan mono -oleate (polysorbate 80 or Tween 80), and polyoxamers (for example, Plutonic L 81); an adsorbent such as magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives; and a colorant including, but not limited to, titanium dioxide, iron oxide, FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of a sterile injectable composition. The injectable composition may be a solution in organic solvents or an aqueous or oily suspension. Such a suspension can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Acceptable carriers and solvents suitable for use include water, Ringer's solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol, glycerol formal or polyethylene glycols can also be used. Preservatives such as phenol or benzyl alcohol can be used.

In addition, sterile fatty oils can be used as a solvent or suspending medium. Any brand of fatty oil can be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable compositions.

In another embodiment, the present invention provides long-acting injectable compositions containing an isoxazoline compound having formula (Id), a poloxamer, and optionally a cosolvent. It has been surprisingly found that long-acting compositions containing an isoxazoline compound of formula (Id), a poloxamer and a co-solvent are stable and effective against a wide range of ectoparasites and possibly also endoparasites if another active ingredient is included, over an extended period of time. ; for example, over a period of three (3) to six (6) months or more, while having beneficial properties at the injection site.

Poloxamers are a family of synthetic block copolymers of ethylene oxide and propylene oxide. Poloxamers can be liquid, milky white paste or powder and have the following structure:

where a is an integer from 2 to 130, and b is an integer from 15 to 67 (see US 3,740,421). Poloxamers are available from commercial sources such as BASF and Croda. An example of a poloxamer is P124, which is solid at room temperature. In one embodiment, the P-124 poloxamer has values of a = 12 and b = 20. Other poloxamers include P-128 (a = 38 and b = 29), P-181 (a = 3 and b = 30), P188 (a = 80 and b = 27), P-237 (a = 64 and b = 37), P338 (a = 141 and b = 44) and P407 (a = 101 and b = 56).

The cosolvents used in long-acting injectable compositions containing a compound having formula (Id) and a poloxamer may be a single cosolvent or a mixture of cosolvents. In one embodiment, co-solvents used in the injectable compositions of the present invention include polar solvents, mixtures

- 80 044142 bathed in water. Non-limiting examples of such cosolvents include ethanol, isopropanol, benzyl alcohol, glycol ethers (for example, including but not limited to diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, monomethyl ether ethylene glycol, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), liquid polyethylene glycols (PEG) (e.g. PEG 400), propylene glycol, carbonates (e.g. propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide, glycerol formal, or a mixture of at least two of these solvents.

In one embodiment, the long-acting compositions of the present invention contain a polar protic solvent, including but not limited to an alcohol such as ethanol, isopropanol or glycol or glycol ether. In another embodiment, the long-acting injectable compositions of the present invention contain a polar aprotic solvent such as N-methylpyrrolidone, dimethyl isosorbide, dimethyl acetamide, dimethyl sulfoxide or propylene carbonate.

In another embodiment of the present invention, the long-acting injectable compositions of the present invention include water-immiscible cosolvents. Non-limiting examples of such cosolvents include benzyl benzoate, ethyl acetate, triacetin, lipids, triglycerides, including medium chain triglycerides such as C ₈ -C ₁₀ triglycerides, such as caprylic/capric triglycerides, propylene glycol derivatives (eg, propylene glycol monolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (nonionic water-dispersible surfactants), isopropyl myristate, or a mixture of at least two of these co-solvents. In one embodiment, the compositions include a protic solvent that is not fully miscible with water, including but not limited to benzyl alcohol.

In another embodiment, the long-acting injectable composition of the present invention may include neutral oils as a co-solvent. Neutral oils are triglycerides of fractionated plant fatty acids with a chain length from C ₈ to C ₁₀ . Two commercially available products are known under the brand names MIGLYOL® 810 and MIGLYOL® 812. In another embodiment, the neutral oil is a triglyceride of fractionated plant fatty acids of chain length C ₈ and C ₁₀ , in combination with linoleic acid (approximately 4-5%) . The commercially available product is known as MIGLYOL® 818. In another embodiment, the neutral oil is an ester of glycerol and fractionated vegetable fatty acids of C ₈ and C ₁₀ chain length, in combination with succinic acid. The commercially available product is known as MIGLYOL® 829. In another embodiment, the neutral oil may be a diester of propylene glycol and saturated vegetable fatty acids of _C8 and _C10 chain length. The commercially available product is known as MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In another embodiment, the cosolvent may be a mixture of two or more neutral oils.

In another embodiment, the present invention provides sustained release injectable compositions for the treatment or prevention of parasitic infestations or infections in animals, comprising an antiparasitic effective amount of at least one isoxazoline compound having formula (Id), a pharmaceutically acceptable polymer, and, optionally, a solvent or mixture of solvents. Pharmaceutically acceptable polymers in injectable sustained release compositions include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyether amides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, pseudo poly(amides) ), polyhydroxyalkanoates, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic ether), chitin, chitosan, and copolymers, terpolymers or combinations or mixtures thereof including copolymers of polylactides, polycaprolactones, polyglycolides (for example, poly(lactide-co-glycolide), and copolymers of polyethylene glycol or methoxy polyethylene glycol with one or more of polycaprolactone, polylactide, or any other representative of the polymers and groups of polymers listed above. Also included are pharmaceutical derivatives suitable polymers such as hydroxylated derivatives including polycaprolactone diols and the like.

The solvents used in the injectable sustained release compositions of the present invention may be individual solvents or mixtures of solvents. Non-limiting examples of these solvents include alcohols such as ethanol, 1-propanol, isopropanol, glycol ethers (for example, including but not limited to diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, monoethyl glycol ethylene glycol ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.),

- 81 044142 liquid polyethylene glycols (PEG), including (but not limited to) PEG 200, PEG 300 and PEG 400; propylene glycol, glycerin, glycerol esters including glycerol triacetate (triacetin), benzyl benzoate, ethyl acetate, cyclic carbonates (e.g. ethylene carbonate and propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethyl acetamide (DMA), dimethylformamide (DMF) ), caprolactam, glycerol formal, acetone, dimethyl sulfoxide (DMSO), ethyl acetate, ethyl lactate, benzyl benzoate, or a mixture of at least two of these solvents.

Compositions for topical, dermal and subcutaneous use may include, but are not limited to, emulsions, creams, ointments, gels, pastes, powders, shampoos, douches, ready-to-use compositions, spot-on solutions and suspensions, dipping solutions and sprays. External application of an innovative compound or a composition containing at least one innovative compound among other active ingredients, in the form of a composition for spot application, spraying or dousing, allows for absorption of the innovative compositions through the skin and achievement of systemic concentration, distribution through the sebaceous glands or over the surface of the skin , ensuring the achievement of the desired concentration over the entire area of cover. When the compound is distributed through the sebaceous glands, they can act as a reservoir, thanks to which a long-lasting (up to several months) effect can be achieved. Spot-on compositions are typically applied to a localized area, constituting an area distinct from the entire animal. In one embodiment, the localized area may be an area between the shoulder blades. In another embodiment, it may be a stripe, such as a stripe from the head to the tail of the animal.

Pouring compositions are described in US Patents 6,010,710 and 9,180,121, both of which are incorporated herein by reference. Pouring compositions may advantageously be oily and typically contain a diluent or carrier, as well as a solvent (eg an organic solvent) for the active substance if it is insoluble in the diluent.

Organic solvents that can be used in the present invention include, but are not limited to, acetyl butyl citrate, fatty acid esters such as dimethyl ether, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, ethyl alcohol, butyl diglycol, dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, dimethyl isosorbide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, benzyl benzoate, ethyl acetate, triacetin, C1-C10 esters of carboxylic acids such as butyl or octyl acetate, glycerol formal, dialkyl esters of dicarboxylic acids including diethyl sebacate, diisopropyl sebacate, diisopropyl adipate and the like, and diethyl phthalate, or a mixture of at least at least two of the solvents listed.

The solvent is used in proportion to the concentration of the active substance and its solubility in this solvent. The smallest volume possible should be used. The carrier makes up the remaining amount to 100%.

Carriers or diluents for these compositions may include dimethyl sulfoxide (DMSO), glycol derivatives such as, for example, propylene glycol, glycol ethers, polyethylene glycols or glycerin. Vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, mineral oils such as (but not limited to) petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or, alternatively, for example medium chain (such as C ₈ -C ₁₂ ) triglycerides.

In another embodiment of the present invention, a softener and/or spreader and/or film-forming agent can be added. In one embodiment, the softener and/or spreader and/or film-forming agent may be:

(a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate-vinylpyrrolidone copolymers, polyethylene glycols, benzyl alcohol, mannitol, glycerin, sorbitol, polyoxyethylene sorbitan esters, lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), e.g. containing silanol functional groups, or 45V2 oil, (b) anionic surfactants such as alkali metal stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (eg sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (for example, coconut oil derivatives), (c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N ⁺ R'RR'R'Y', in which the radicals R are optionally hydroxylated hydrocarbon radicals, and Y ^- represents is an anion of a strong acid such as halide, sulfate and sulfonate anions; Among the suitable cationic surfactants is also cetyltrimethylammo

- 82 044142 nia bromide, (d) amine salts of the formula N ⁺ R'RR', in which the radicals R are optionally hydroxylated hydrocarbon radicals; Suitable cationic surfactants also include octadecylamine hydrochloride, (e) nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (eg polysorbate 80), polyoxyethylenated alkyl ethers; polyoxypropylene fatty alcohols such as polyoxypropylene styrene ether; polyethylene glycol stearate, polyoxyethylenated castor oil derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, ethylene oxide-propylene oxide copolymers, (f) amphoteric surfactants such as substituted betaine lauryl compounds, and (g) a mixture of at least two of the above. .

In one embodiment, the amount of softener is from about 0.1 to 50%, or from 0.25 to 5%, by volume. In another embodiment, the amount of softener is from about 0.1 to about 30, from about 1 to about 30, from about 1 to about 20, or from about 5 to about 20%, by volume.

In another embodiment of the present invention, the compositions may be a ready-to-use spot-on solution, as described, for example, in US Pat. Nos. 6,395,765 and 9,180,121, both of which are incorporated herein by reference. In addition to the compounds of the present invention, the ready-to-use solution may contain a crystallization inhibitor, an organic solvent or an organic co-solvent. In some embodiments, water may be included in the composition along with the organic solvent.

In various embodiments of the present invention, the compositions may include a crystallization inhibitor in an amount of from about 1 to about 50, or from about 5 to about 40% (w/v) based on the total weight of the composition. In other embodiments, the amount of crystallization inhibitor in the innovative compositions may be from about 1 to about 30, from about 5 to about 20, from about 1 to about 15, or from about 1 to about 10% (w/w). The type of crystallization inhibitor used in innovative compositions is not limited, provided that it inhibits the crystallization of active or inert substances from the composition. For example, in some embodiments of the present invention, a solvent or co-solvent in the composition may also serve as a crystallization inhibitor if it sufficiently inhibits the formation of crystals after administration of the composition.

Crystallization inhibitors that can be used in the present invention include (but are not limited to):

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerin, sorbitol or polyoxyethylenated sorbitan esters; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as acrylates or methacrylates or polymers or copolymers thereof, polyethylene glycols (PEG) or polymers containing polyethylene glycols such as glycofurols and the like, and others;

(b) anionic surfactants such as alkali metal stearates (eg sodium, potassium or ammonium stearates); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include (but are not limited to) sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids (for example, coconut oil), (c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N ⁺ R'RR'R'Y', in which the radicals R are the same or optionally different hydroxylated hydrocarbon radicals, a Y ^- represents a strong acid anion, such as the halide sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the suitable cationic surfactants, (d) amine salts of the formula N ⁺ R'RR', in which the radicals R are the same or optionally different hydroxylated hydrocarbon radicals; Octadecylamine hydrochloride is one of the cationic surfactants suitable for use;

(e) nonionic surfactants, such as, if desired, polyoxyethylenated sorbitan esters, for example polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated castor oil derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and propylene oxide;

(f) amphoteric surfactants, such as substituted betaine lauryl compounds, or (g) a mixture of at least two of the compounds listed in (a) to (f) above, or (h) an organic solvent or mixture of solvents that inhibit crystal formation or an amorphous solid after administration of the composition.

- 83 044142

In one embodiment of the crystallization inhibitor, a pair of inhibitors may be used. Such pairs include, for example, a combination of a polymer-type film-forming agent and a surfactant. These agents may be selected from the compounds listed above as crystallization inhibitors.

In some embodiments, the organic solvent(s) may have a dielectric constant from about 10 to about 35 or from about 20 to about 30. In other embodiments, the organic solvent may have a dielectric constant from about 10 to about 40 or from about 20 to about 30. The content of the organic solvent or mixture of solvents in the composition is not limited, and it is present in an amount sufficient to dissolve the target components at the desired concentration. As discussed above, the organic solvent may also act as a crystallization inhibitor in the composition.

In some embodiments, the one or more organic solvents may have a boiling point below about 100, or below about 80°C. In other embodiments, the organic solvent(s) may have a boiling point below about 300, below about 250, below about 230, below about 210, or below about 200°C.

In some embodiments, when a mixture of solvents is present, e.g. solvent and co-solvent, solvents may be present in the composition in a weight/weight ratio of from about 1/50 to about 1/1. Typically, solvents are present in a ratio of from about 1/30 to about 1/1, from about 1/20 to about 1/1, or from about 1/15 to about 1/1 by weight. Preferably, the two solvents are present in a w/w ratio of about 1/15 to about 1/2. In some embodiments, at least one of the solvents present may improve the solubility of the active ingredient or act as a drying accelerator. In particular embodiments, at least one of the solvents is miscible with water.

The composition may also contain an antioxidant designed to inhibit air oxidation, and the antioxidant may be present in an amount of from about 0.005 to about 1% (w/v), from about 0.01 to about 0.1%, or from about 0.01 to about 0.05%.

In one embodiment of the film-forming agent, the agents are polymer-type agents, which include, but are not limited to, various grades of polyvinylpyrrolidone, polyvinyl alcohols, and vinyl acetate-vinylpyrrolidone copolymers.

In one embodiment of surfactants, these substances include, but are not limited to: substances made from non-ionic surfactants; in another surfactant embodiment, the surfactants are polyoxyethylenated sorbitan ester. In another embodiment of surfactants, these substances include various grades of polysorbate, for example Polysorbate 80.

In another embodiment of the present invention, the film-forming agent and surfactant may be present in similar or equal amounts, within the above limits of the total amount of crystallization inhibitor.

In another embodiment, topical compositions include the compound crotamiton, which can inhibit the crystallization of active substances from solution.

A crystallization inhibitor suppresses the formation of crystals on the integument and improves the preservation of the cosmetic appearance of the skin or fur; without creating a feeling of stickiness or a sticky appearance, despite the high concentration of the active substance. In the present invention, substances other than those specified in the present invention can also be used as crystallization inhibitors. In one embodiment, the effectiveness of the crystallization inhibitor can be demonstrated by a test in which 0.3 ml of a solution containing 10% (w/v) of the active substance in the above suitable solvent and 10% (w/v) a compound acting as a crystallization inhibitor is placed on a glass plate at 20°C for 24 hours, after which less than 10 crystals, preferably 0 crystals, are visible to the naked eye on the glass surface.

In one embodiment of antioxidants, these agents are known in the art and include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or a mixture of at least two compounds having antioxidant properties.

Formulation excipients are well known to those skilled in the art and can be purchased from commercial suppliers or prepared by known methods. The concentrated compositions described are generally prepared by simply mixing the components described above; Preferably, the starting point is mixing the active substance with the main solvent, followed by the addition of other ingredients or excipients.

The volume of the composition used depends on the type of animal, the size of the animal, as well as the strength of the composition and the activity of the active ingredients. In one embodiment, an amount of from about 0.3 to about 20 ml of the composition can be used for a mammal. In another embodiment, the volume may be from about 0.1 to about 10, from about 0.3 to about

- 84 044142

5, from about 0.5 to about 10, or from about 0.3 to about 3 ml.

In another embodiment of the present invention, spot application of the composition of the present invention may also provide a long-lasting, broad-spectrum effect when the solution is applied to an animal or bird. Spot-on compositions provide topical application of a concentrated solution, suspension, microemulsion or emulsion for periodic application to a specific area of the animal, typically between two shoulders (spot-on solution).

In the case of compositions for spot application, the carrier may be a liquid carrier, as described in US patents 6,426,333; 6,395,765 (incorporated herein by reference), which may contain a solvent or mixture of solvents including, but not limited to, acetone, an aliphatic alcohol such as methanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol, heptanol, octanol , nonanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, etc.; an aromatic alcohol such as phenol, cresol, naphthol, benzyl alcohol and the like; acetonitrile, butyl diglycol, organic amide such as dimethylacetamide, dimethylformamide, monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone and the like; propylene or ethylene carbonate, dimethyl sulfoxide (DMSO), glycol polymer or its ether, such as polyethylene glycol (PEG) of various grades, polypropylene glycols of various grades, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, fatty acid esters such as diethyl or diisobutyl adipate, or a mixture of at least two of these solvents.

In another embodiment, the solvents used in the spot-on or pour-on compositions of the present invention are those described in US Pat. No. 9,180,121 (incorporated herein by reference). Solvents used in spot-on or pour-on compositions may include, but are not limited to, carboxylic acid esters, dicarboxylic acid diesters, carboxylic acid esters, or dicarboxylic acid diesters, or a combination thereof, including but not limited to isopropyl palmitate , isostearyl lactate, diisopropyl adipate, dibutyl adipate, diethyl sebacate, dibutyl sebacate, octyl palmitate, polyethylene glycol (PEG) stearate and cetearyl octanoate; oils, including (but not limited to) mineral oil, diglycerides, triglycerides, jojoba oil, lecithin and castor oil, or a combination thereof; long chain aliphatic alcohols such as isostearyl alcohol and the like; fatty alcohols and their esters, including, for example, cetyl alcohol, cetearyl alcohol and the like, or a combination thereof; polyethylene glycols with various molecular weight ranges, including (but not limited to) PEG 300, PEG 400, PEG 600 and PEG 1000, or a combination thereof; and glycol ethers, including (but not limited to) diethylene glycol monoethyl ether (Transcutol®), butyl diglycol, propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether and dipropylene glycol monomethyl ether, or their combination; or a combination of two or more of the above solvents.

Excipients that may help the active substance remain in the skin for a longer period of time and may be contained in the compositions of the present invention include, but are not limited to, mixed esters of sucrose and carboxylic acids, including sucrose acetate isobutyrate (SAIB), and the like. .; low melting waxes, hydrogenated vegetable oils, caprylic/capric acid glycerides; glycerol esters including, for example, triacetin, glycerol monooleate, glycerol monolinoleate, glycerol stearate, glycerol distearate and the like; triglycerides including, for example, caprylic, capric/myristic/stearic acid triglyceride; thermoreversible polymers such as Pluronic and poloxamers, including, for example, Lutrol F127 alone or in mixtures with other poloxamers; or a combination thereof.

In another embodiment of the present invention, a pharmaceutically acceptable carrier for a topical composition comprises a mixture of dicarboxylic acid diesters, alone or in combination with one or more of the additional solvents listed above, and/or an oleaginous lipophilic agent, including a liquid or low melting point lipophilic active ingredient such as (S)-methoprene, pyriproxyfen and/or permethrin; and/or sucrose carboxylic acid esters, including sucrose acetic and isobutyric acid esters such as sucrose acetate isobutyrate (SAIB), and/or low melting waxes and/or solid fats.

In one embodiment, the dicarboxylic acid diester in the topical composition is diethyl sebacate or diisopropyl adipate. In another embodiment, the dicarboxylic acid ester solvent mixture comprises a glycol or polyglycol, or a glycol or polyglycol ester or ester, including but not limited to ethylene glycol (EG), propylene glycol (PG), liquid polyoxyethylene glycols (PEG) various grades, including PEG 400, EG or PG monocaprylate, EG or PG caprylate, EG or PG monolaurate, EG or

- 85 044142

PG dicaprylate/dicaprate, diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc., or their combination; ether, including (but not limited to) dimethyl isosorbide; ester or diester, including (but not limited to) triacetin, lauryl lactate; and other solvents, including glycerol formal, or mixtures thereof.

In preferred embodiments, the carrier for the topical composition is a dialkyl ester of a dicarboxylic acid, such as diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate, or a combination thereof, alone or in combination with solvents selected from the following:

propylene glycol ester (PG), including PG monocaprylate, PG caprylate, PG monolaurate, PG dicaprylate/dicaprate, or a combination thereof;

an ether solvent including dimethyl isosorbide, diethylene glycol monoethyl ether (also known as DGME or Transcutol®), or a combination thereof;

a carboxylic acid ester, including (but not limited to) triacetin, lauryl lactate, isopropyl palmitate, diisopropyl sebacate, or a combination thereof; and other oily or lipophilic organic solvents including glycerin formal and the like.

In some embodiments, the amount of additional solvent combined with the carboxylic acid ester or dicarboxylic acid diester is at least about 1, at least about 5, at least about 9.0, at least about 13, at least about 17 or at least about 20% (v/v). Preferably, additional solvents are present in an amount of at least about 9% (v/v).

In other embodiments, additional solvents are present in an amount of about 5-70, about 10-60, about 10-50, about 15-60, or about 15-50% (v/v). In preferred embodiments, additional solvents are present in an amount of about 20-70, about 20-60, about 20-50, or about 25-50% (v/v).

In some embodiments, the liquid carrier may optionally contain a crystallization inhibitor, including (but not limited to) those described above in paragraphs (a)-(h), or a compound that can simultaneously act as a solvent and a crystallization inhibitor (as described above) , or a mixture of these crystallization inhibitors.

Compositions for spot application can be prepared by dissolving the active ingredients in a pharmaceutically or veterinarily acceptable carrier. Alternatively, a spot-on composition can be prepared by encapsulating the active ingredient so that the remainder of the therapeutic agent remains on the animal's integument. The composition of such compositions may vary in terms of the content of the therapeutic agent in the combination, depending on the species of animal being treated, the extent and type of infection, and the weight of the animal.

Dosage forms typically contain from about 0.1 mg to about 5 g of active ingredient. In other embodiments, the dosage form may contain from about 0.5 mg to about 5 g of active ingredient. In one dosage form embodiment, the dosage may range from about 1 to about 500 mg of active ingredient, typically about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 800, or about 1000 mg.

In one embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.05 to about 10% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.1 to about 2% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.25 to about 1.5% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of about 1% w/v.

II. Methods of treatment.

As described above, the compounds having formula (Id) are effective against ectoparasites and can be used for the treatment and prevention of parasite infestation in animals or on animal integuments. In one embodiment, the present invention describes a method of treating or preventing ectoparasite infestation in animals or on the integument of animals (e.g., mammals or birds), comprising administering to the animal an ectoparasiticidal effective amount of a compound having formula (Id), pharmaceutically acceptable salts thereof, or a composition containing the specified compound. In another embodiment, the methods of the present invention comprise administering to an animal an effective amount of a compound having formula (Ie) or (S)-Ie, or a pharmaceutically acceptable salt thereof.

In another embodiment, when compounds having formula (Id) are administered in combination

- 86 044142 with compounds active against endoparasites, the present invention describes a method of treating or preventing endoparasitic infection and infection by ectoparasites in an animal or on the integument of an animal, comprising administering to the animal a composition containing an effective amount of a compound having formula (Id), in combination with an effective an amount of at least one second active ingredient, or pharmaceutically acceptable salts thereof.

Mammals that may be treated include, but are not limited to, humans, cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep and yaks. In one embodiment of the present invention, the animals being treated are humans, cats or dogs.

In one embodiment of the present invention, compositions of the present invention containing a compound having formula (Id), in combination with an additional compound active against endoparasites, are effective against endoparasites resistant to active substances from the class of macrocyclic lactones. In one embodiment, the compounds and compositions of the present invention are effective for controlling Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds.

In another embodiment, the present invention describes a method of treating a parasitic infection and/or parasite infestation in an animal, comprising administering an effective amount of a compound having formula (Id), in combination with an effective amount of invertebrate GABA receptor activators, including avermectin or milbemycin, to a mammal in need in that. Avermectins that can be used in combination with the compounds of the present invention include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin and selamectin. Milbemycins that can be used in combination with the compounds of the present invention include, but are not limited to, milbemictin, milbemycin D, milbemycin oxime, moxidectin and nemadectin. Also included are 5-oxo and 5-oxime derivatives of these avermectins and milbemycins.

In one treatment option against ectoparasites, the ectoparasites belong to the genus Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola. Ectoparasites to be treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Particular examples include (but are not limited to) cat and dog fleas (Ctenocephalides felis, genus Ctenocephalides, etc.), parasitic mites (genus Rhipicephalus, Ixodes, Dermacentor, Amblyomma, etc.), and acariform mites (genus Demodex, Sarcoptes, Otodectes, etc.), lice (genus Trichodectes, Cheyletiella, Linognathus, etc.), mosquitoes (genus Aedes, Culex, Anopheles, etc.) and flies (genus Haematobia, Musca, Stomoxys , Dermatobia, Cochliomyia, etc.). In another embodiment for treating ectoparasites, the ectoparasite is a flea and/or tick.

Additional examples of ectoparasites that can be controlled with compounds of formula (Id) include, but are not limited to, Rhipicephalus microplus mite, Rhipicephalus decoloratus and Rhipicephalus annulatus; myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (green carrion); sheep myiases, such as Lucilia sericata, Lucilia cuprina (known as the carrion fly in Australia, New Zealand and South Africa), flies themselves, namely those whose adult forms are parasites, such as Haematobia irritans (small cow fly); lice such as Linognathus vituli and the like; and acariform mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive, and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example, migrating dipteran larvae.

In one embodiment, when administered with another compound active against endoparasites, the compounds and compositions of the present invention can be used to treat or prevent endoparasitic infection of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia , Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrong ylus, Oesophagostomum, Onchocerca, Ostertagia , Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus, Uncinaria, Wuchereria, and combinations thereof.

In another embodiment of the present invention, the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, Dirofilaria immitis, and combinations thereof.

In another embodiment of the present invention, the compounds and compositions of the present invention are suitable for controlling pests such as insects selected from the group consisting of Blatella germanica, Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitum and combinations thereof.

- 87 044142

Phytoparasitic nematodes include, for example, species of the genera Anguina, Aphelenchoides, Belonolaimus, Bursaphelenchus, Ditylenchus dipsaci, Globodera, Helicotylenchus, Heterodera, Longidorus, Meloidogyne, Pratylenchus, Radopholus similis, Rotylenchus, Trichodorus, Tylenchorhynchus, Tylenchulus, Tylenchulus semipenetrans, Xiphinema.

In addition, with or without the addition of other pesticidal agents to the composition, the present invention can also be used to control other pests, which include, but are not limited to, the following pests:

(1) from the order Isopoda, for example Oniscus asellus, Armadillidium vulgare and Porcellio scaber;

(2) from the order Diplopoda, for example Blaniulus guttulatus;

(3) from the order Chilopoda, for example Geophilus carpophagus and species of the genera Scutigera;

(4) from the order Symphyla, for example Scutigerella immaculata;

(5) from the order Thysanura, for example Lepisma saccharina;

(6) from the order Collembola, for example Onychiurus armatus;

(7) from the order Blattaria, for example Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica;

(8) from the order Hymenoptera, for example species of the genera Diprion, Hoplocampa, Lasius, Monomorium pharaonis and Vespa;

(9) from the order Siphonaptera, for example Xenopsylla cheopis and species of the genera Ceratophyllus;

(10) from the order Anoplura (Phthiraptera), for example species of the genera Damalinia, Haematopinus, Linognathus, Pediculus, Trichodectes;

(11) from the Araachnida class, such as Acarus Siro, Aceria Sheldoni, Types of Giving Aculops, Aculus, AmblyMma, Argas, BOOPHILUS, BREVIPALPUS, Bryobia Praetiosa, Chorioptes, Dermanyssus Gallinae, Eot Etranychus, Epitrimerus Pyri, Eutetranychus, Eriophyes, Hemitarsonemus, Hyalommma, Ixodes , Latrodectus mactans, Metatetranychus, Oligonychus, Ornithodoros, Panonychus, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes, Rhipicephalus, Rhizoglyphus, Sarcoptes, Scorpio maurus, Steneotarsonemus, Tarsonemus, Tetranychus, Vasates lycopersici;

(12) from the class Bivalva, for example species of the genus Dreissena;

(13) from the order Coleoptera, for example Acanthoscelides obtectus, species of the genera Adoretus, Agelastica alni, Agriotes, Amphimallon solstitialis, Anobium punctatum, Anoplophora, Anthonomus, Anthrenus, Apogonia, Atomaria, Attagenus, Bruchidius obtectus, Bruchus, Ceuthorhynchus, Cleonus mendicus, Conoderus, Cosmopolites, Costelytra zealandica, Curculio, Cryptorhynchus lapathi, Dermestes, Diabrotica, Epilachna, Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus, Lachnostema consanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus, Lixus, Lyctus, Meligethes aeneus, Melolontha melolontha, Migdolus, Monochamus, Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Popillia japonica, Premnotrypes, Psyl liodes chrysocephala, Ptinus, Rhizobius ventralis, Rhizopertha dominica, Sitophilus, Sphenophorus, Sternechus, Symphyletes, Tenebrio molitor, Tribolium, Trogoderma, Tychius, Xylotrechus, Zabrus;

(14) from the order Diptera, for example species of the genera Aedes, Anopheles, Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia, Cochliomyia, Cordylobia anthropophaga, Culex, Cuterebra, Dacus oleae, Dermatobia hominis, Drosophila, Fannia, Gastrophilus, Hylemyia, Hyppobosca, Hypoderma, Liriomyza, Lucilia, Musca, Nezara, Oestrus, Oscinella frit, Pegomyia hyoscyami, Phorbia, Stomoxys, Tabanus, Tannia, Tipula paludosa, Wohlfahrtia;

(15) from the class Gastropoda, for example species of the genera Arion, Biomphalaria, Bulinus, Deroceras, Galba, Lymnaea, Oncomelania, Succinea;

(16) from the class of helminths, for example Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, species of the genera Ancylostoma, Ascaris lubricoides, Ascaris, Brugia malayi, Brugia timori, Bunostomum, Chabertia, Clonorchis, Cooperia, Dicrocoelium

Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola, Haemonchus, Heterakis, Hymenolepis nana, Hyostrongulus, Loa Loa, Nematodirus, Oesophagostomum, Opisthorchis, Onchocerca volvulus, Ostertag ia, Paragonimus, Schistosomen, Strongyloides fuelleborni, Strongyloides stercoralis, Stronyloides, Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus, Trichuris trichuria, Wuchereria bancrofti;

(17) from the order Heteroptera, for example Anasa tristis, species of the genera Antestiopsis, Blissus, Calocoris, Campylomma livida, Cavelerius, Cimex, Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus, Euschistus, Eurygaster, Heliopeltis, Horcias nobilellus, Leptocori sa , Leptoglossus phyllopus, Lygus, Macropes excavatus, Miridae, Nezara, Oebalus, Pentomidae, Piesma quadrata, Piezodorus, Psallus seriatus, Pseudacysta persea, Rhodnius, Sahlbergella singularis, Scotinophora, Stephanitis nashi, Tibraca, Triatoma;

(18) From the Homoptera detachment, for example, the types of birth Acyrthosipon, Aenelamia, Agonoscena, Aleurodes, Aleurolobus Barodensis, Aleurothrixus, Amrasca, Anuranis Cardhii, Aonidiella, Aphanostigma Piri , Aphis, Arboridia Apicalis, Aspidiella, Aspidiotus, Atanus, Aulacorthum Solani, Bemisia, Brachycaudus helichrysii

- 88 044142

Brachycolus, Brevicoryne brassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes, Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus , Cryptomyzus ribis, Dalbulus, Dialeurodes, Diaphorina, Diaspis, Doralis, Drosicha, Dysaphis, Dysmicoccus, Empoasca, Eriosoma, Erythroneura, Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis, Icerya, Idiocerus, Idioscopus, Laodelphax striatellus, Lecanium, Lepidosaphes, Lipaphis erys imi, Macrosiphum, Mahanarva fimbriolata, Melanaphis sacchari, Metcalfiella, Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzus, Nasonovia ribisnigri, Nephotettix, Nilaparvata lugens, Oncometopia, Orthezia praelonga, Parabemisia myricae, Paratrioza, Parlatoria, Pemphigus, Peregrinus maidis, Phenacoccus, Phloeomyzu s passerinii, Phorodon humuli, Phylloxera, Pinnaspis aspidistrae, Planococcus, Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus, Psylla, Pteromalus, Pyrilla, Quadraspidiotus, Quesada gigas, Rastrococcus, Rhopalosiphum, Saissetia, Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata, So Gatella furcifera, Sogatodes, Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis, Toxoptera, Trialeurodes vaporariorum, Trioza, Typhlocyba, Unaspis, Viteus vitifolii;

(19) from the order Isoptera, for example species of the genera Reticulitermes, Odontotermes;

(20) from the order Lepidoptera, for example Acronicta major, Aedia leucomelas, species of the genera Agrotis, Alabama argillacea, Anticarsia, Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo, Choristoneura fumiferana, Clysia ambiguella, Cnaphalocems, Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa, Feltia, Galleria mellonella, Helicoverpa, Heliothis, Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella, Laphygma, Lithocolletis blancardella, Lithophane antennata, Loxagrotis albi costa, Lymantria, Malacosoma neustria, Mamestra brassicae, Mocis repanda, Mythimna separata, Oria, Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris, Plutella xylostella, Prodenia spp., Pseudaletia, Pseudoplusia includens, Pyrausta nubilalis, Spodoptera, Thermesia gemmatalis, Tinea pell ionella, Tineola bisselliella, Tortrix viridana, Trichoplusia;

(21) from the order Orthoptera, for example Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, species of the genera Locusta, Melanoplus, Periplaneta americana, Schistocerca gregaria;

(22) from the order Thysanoptera, for example Baliothrips biformis, Enneothrips flavens, species of the genera Frankliniella, Heliothrips, Hercinothrips femoralis, Kakothrips, Rhipiphorothrips cruentatus, Scirtothrips, Taeniothrips cardamoni, Thrips;

(23) from the class Protozoa, for example species of the genus Eimeria.

In each aspect of the present invention, the compounds and compositions of the present invention can be used against a single pest or a combination thereof.

Non-veterinary use.

For use in the method of exterminating pests that damage plants, plant propagation material and crops, or material obtained from wood, according to the present invention, compounds having formula (Id) can be included in ready-made compositions, for example, solutions, emulsions, suspensions , dusts, powders, pastes, granules and spray solutions. The form of application depends on the specific purpose and method of application. The preparations and methods of application are selected to ensure in each case an accurate and uniform distribution of the compound having formula (Id) of the present invention.

I. Agricultural compositions.

These compositions are prepared in a known manner (see, for example, for review: US 3,060,084, EP-A 707 445 (for liquid concentrates), Browning, Agglomeration, Chemical Engineering, Dec. 4, 1967, 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pp. 8-57, WO 91/13546, US 4,172,714, US 4,144,050, US 3,920,442, US 5,180,587, US 5,232,701, US 5,208,030, GB 2,095, 558, US 3,299,566, Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989, and Mollet, H., Grubemann, A. , Formulation technology, Wiley VCH Verlag GmbH, Weinheim (Germany), 2001, 2. D. A. Knowles, Chemistry and Technology of Agrochemical Formulations, Kluwer Academic Publishers, Dordrecht, 1998 (ISBN 07514-0443-8, all of which are included herein in by reference in its entirety), for example by mixing the active substance with auxiliary compounds suitable for agrochemical compositions, such as solvents and/or carriers, if necessary with emulsifiers, surfactants and dispersants, preservatives, defoamers, additives for lowering the freezing point and, for seed treatment compositions, optionally, dyes and/or binders and/or gelling agents.

The following solvents/carriers may be used in the compositions of the present invention:

solvents such as water, aromatic solvents (e.g. Solvesso brand products, xylene, etc.), paraffins (e.g. petroleum fractions), alcohols (e.g. methanol, butanol, pentanol, benzyl alcohol), ketones (e.g. cyclohexanone, gamma-butyrolactone), pyrrolidones (N

- 89 044142 methylpyrrolidone (NMP), N-octylpyrrolidone (NOP)), acetates (glycol diacetate), alkyl lactates, lactones such as gamma-butyrolactone, glycols, fatty acid dimethylamides, fatty acids and fatty acid esters, triglycerides, oils vegetable or animal origin, and modified oils such as alkylated vegetable oils. In principle, it is also possible to use solvent mixtures;

carriers such as ground natural minerals and ground synthetic materials such as silica gel, fine silicic acid, silicates, talc, kaolin, attaglin, limestone, chalk, calcareous clay, loess, clay, dolomite, diatomaceous earth, calcium sulfate and magnesium sulfate, magnesium oxide, ground synthetic materials, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, and plant products such as ground grains, branches and trunks, wood and nut shells, powdered cellulose and other solid carriers .

Suitable emulsifiers include nonionic and anionic emulsifiers (eg, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates).

Examples of suitable dispersants include lignin sulfite waste liquor and methylcellulose.

Suitable surface-active substances include salts of alkaline, alkaline-earth metals and ammonium with lignosephoronic acid, naphthalain sulfate, phenol sulfate, dibylnaphthalin sulfate, alkylaryl sulfates, alkyl sulfates, alkyl sulfates, sulfates of fatty alcohols, fatty acids and esters of sulfuric fats. alcohols with glycols, as well as condensates of sulfed naphthalene and naphthalene derivatives with formaldehyde, condensates of naphthalene or naphthalene sulfonic acid with phenol and formaldehyde, polyoxyethylene octylphenyl ether, ethoxylated isooctylphenol, octylphenol, nonylphenol, alkylphenyl polyglycol ethers, tributylphenyl polyglycol ether, tristearylphenyl polyglycol ether, alkylaryl polyether alcohols, alcohol and fatty alcohol/ethylene oxide condensates , ethoxylated castor oil, polyoxyethylene alkyl ethers, ethoxylated polyoxypropylene, lauryl alcohol polyglycol ester acetal, sorbitol esters.

In some embodiments, an antifreeze such as glycerin, ethylene glycol, propylene glycol, and bactericides can be added to the composition.

In other embodiments, antifoam agents may be included in the compositions. Suitable defoamers include silicone or magnesium stearate based defoamers.

The compositions of the present invention may contain preservatives. Suitable preservatives include, for example, dichlorophenyl and benzyl alcohol hemiformal.

In other embodiments, the compositions of the present invention may include thickeners known in the art. Suitable thickeners include compounds that provide pseudoplastic behavior of the composition, i.e. high viscosity at rest and low viscosity when stirred. Such thickeners include, for example, commercially available polysaccharide thickeners such as xanthan gum (Kelzan® from Kelco), Rhodopol® 23 (Rhone Poulenc) or Veegum® (from R.T. Vanderbilt), or organic phyllosilicates such as Attaclay® (from Engelhardt). Defoamers suitable for use in the dispersions of the present invention are, for example, silicone emulsions (such as, for example, Silikon® SRE, Wacker or Rhodorsil® from Rhodia), long chain alcohols, fatty acids, organofluorine compounds and mixtures thereof. Biocides can be added to stabilize the compositions of the present invention against microbial attack. Suitable biocides are based, for example, on isothiazolones, such as the compounds sold under the trade names Proxel® from Avecia (or Arch) or Acticide® RS from Thor Chemie and Kathon® MK from Rohm & Haas. Suitable antifreezes are organic polyols such as ethylene glycol, propylene glycol or glycerin. They are usually used in quantities of no more than 10 wt.%, based on the total weight of the composition with the active substance. If necessary, the active ingredient composition of the present invention may contain from 1 to 5% by weight of a buffer additive, based on the total amount of the finished composition, to adjust the pH, the amount and type of buffer additive used depending on the chemical properties of the active ingredient or active ingredients. substances. Examples of buffer additives are alkali metal salts with weak inorganic or organic acids, such as, for example, phosphoric acid, boric acid, acetic acid, propionic acid, citric acid, fumaric acid, tartaric acid, oxalic acid and succinic acid.

Substances suitable for the preparation of spray solutions, emulsions, pastes or oil dispersions are petroleum fractions with a medium to high boiling point, such as kerosene or diesel fuel, as well as coal oil and oils of vegetable or animal origin, aliphatic, cyclic and aromatic hydrocarbons, e.g. toluene, xylene, paraffin, tetrahydronaphthalene, alkylated naphthalenes or their derivatives, methanol, ethanol, propanol, butanol, cyclohexanol, cyclohexanone, isophorone, highly polar solvents,

- 90 044142 example dimethyl sulfoxide, N-methylpyrrolidone and water.

Powders, spraying and dusting compositions can be prepared by mixing or parallel grinding of the active substances with a solid carrier.

Granules, for example coated granules, impregnated granules and homogeneous granules, can be prepared by mixing the active ingredients with solid carriers. Examples of solid carriers are natural minerals such as silica gels, silicates, talc, kaolin, attaglina, sandstone, limestone, chalk, bol, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic substances, fertilizers , such as, for example, ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, and plant products such as ground grains, shredded twigs and wood, as well as ground nut shells, powdered cellulose and other solid carriers.

In general, the compositions typically contain from about 0.01 to about 95, preferably from about 0.1 to about 90, weight percent of active ingredient.

The active substances used typically have a purity of from about 90 to about 100, preferably from about 95 to about 100% (by NMR spectrum).

For seed treatments, the compositions can be diluted 2-10 times, resulting in concentrations in ready-to-use preparations of from about 0.01 to about 60 wt.% active ingredient, preferably from about 0.1 to about 40 wt.%.

The compound having formula (Id) can be used in pure form, in the form of a composition or in the form of preparations, for example in the form of spray solutions, powders, suspensions or dispersions, emulsions, oil dispersions, pastes, dusting powders, surface spreading compositions , or granules, which can be applied by spraying, atomizing, dusting, smearing or pouring. The forms of application depend entirely on the intended use; in each case they should ensure that the active compounds of the present invention are distributed as uniformly as possible.

The following are examples of compositions.

1. Products for dilution with water. For seed treatment purposes, such products can be applied to the seeds diluted or undiluted.

A. Water-soluble concentrates (SL, LS).

wt.h. the active substance is dissolved in 90 parts by weight. water or water-soluble solvent. Alternatively, humectants or other excipients are added. When diluted with water, the active compound dissolves, thus forming a preparation with a 10% concentration (w/w) of the active substance.

B. Dispersible concentrates (DC).

wt.h. the active substance is dissolved in 70 parts by weight. cyclohexanone with the addition of 10 parts by weight. dispersant, for example polyvinylpyrrolidone. Dilution with water gives a dispersion, thus obtaining a drug with a 20% (w/w) concentration of the active substance.

C. Emulsifiable concentrates (EC).

wt.h. the active substance is dissolved in 7 parts by weight. xylene with the addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). Dilution with water gives an emulsion, thus obtaining a drug with a 15% (w/w) concentration of the active substance.

D. Emulsions (EW, EO, ES).

wt.h. the active substance is dissolved in 35 parts by weight. xylene with the addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). This mixture is added to 30 parts by weight. water using an emulsifier (for example, Ultraturrax) and turn into a homogeneous emulsion. Dilution with water gives an emulsion, and thus a preparation with a 25% (w/w) concentration of the active substance is obtained.

E. Suspensions.

In a shaken ball mill 20 parts by weight. the active substance is ground into powder with the addition of 10 parts by weight. dispersants, humectants and 70 parts by weight. water or an organic solvent, obtaining a thin suspension of the active substance. Dilution with water allows to obtain a stable suspension of the active substance, thereby obtaining a drug with a 20% (w/w) concentration of the active substance.

F. Water-dispersible granules and water-soluble granules (WG, SG).

wt.h. the active substance is finely ground with the addition of 50 parts by weight. dispersants and humectants and formed into water-dispersible or water-soluble granules using technical equipment (eg extrusion equipment, spray column, fluidized bed apparatus). Dilution with water gives a stable dispersion or solution of the active substance, and thus a preparation with a 50% (w/w) concentration of the active substance is obtained.

G. Water-dispersible powders and water-soluble powders (WP, SP, SS, WS).

wt.h. the active substance is ground in a rotor-stator mill with the addition of 25

- 91 044142 wt.h. dispersants, humectants and silica gel. Dilution with water gives a stable dispersion or solution of the active substance, and thus a preparation with a 75% (w/w) concentration of the active substance is obtained.

N. Gel preparation (GF).

In a shaken ball mill 20 parts by weight. the active substance is ground into powder with the addition of 10 parts by weight. dispersants, 1 part by weight gelling agent and 70 parts by weight. water or an organic solvent, obtaining a thin suspension of the active substance. Dilution with water gives a stable suspension of the active substance, and thus a preparation with a 20% (w/w) concentration of the active substance is obtained.

2. Products to be applied undiluted for foliar application. For seed treatment purposes, these products can be applied to the seeds diluted or undiluted.

I. Dust-like powders (DP, DS).

wt.h. the active substance is finely ground and thoroughly mixed with 95 parts by weight. fine kaolin. The result is a dust-like product with a 5% (w/w) concentration of active substance.

J. Granulates (GR, FG, GG, MG).

0.5 wt.h. the active substance is finely ground and combined with 95.5 parts by weight. carriers, thereby obtaining a drug with a 0.5% (w/w) concentration of the active substance. Currently used methods are extrusion, spray drying or fluidized bed granulation. As a result, granulates are formed for foliar application in undiluted form.

K. ULV ultra-low volume (UL) solutions.

wt.h. the active substance is dissolved in 90 parts by weight. organic solvent, such as xylene. The result is a product with a 10% (w/w) concentration of active ingredient, which is used undiluted for foliar application.

Aqueous formulations can be prepared from emulsion concentrates, pastes or wettable powders (sprayable powders, oil dispersions) by adding water. To prepare emulsions, pastes or oil dispersions, the substances, pure or dissolved in an oil or solvent, can be homogenized in water using a wetting agent, tackifier, dispersant or emulsifier. Alternatively, concentrates can be prepared consisting of the active ingredient, wetting agent, tackifier, dispersant or emulsifier and, if necessary, solvent or oil, and such concentrates are suitable for dilution with water.

Concentrations of the active substance in ready-to-use products can vary within relatively wide limits. In general, they range from about 0.0001 to about 10, preferably from about 0.01 to about 1%.

Active ingredients can also be successfully applied using the ultra-low volume (ULV) method, where compositions containing more than 95 wt.% active ingredient can be used, or even the active ingredient can be used without any additives.

II. Mixtures with other active ingredients.

In the method of the present invention, compounds having formula (Id), including in particular (Ie) and (S)-Ie, can be used together with other active ingredients, for example other pesticides, insecticides, herbicides, fertilizers such as nitrate ammonium, urea, potash and superphosphate, phytotoxins and plant growth regulators, preservatives and nematicides. The listed additional ingredients can be used sequentially or in combination with the compositions described above, and if necessary, added immediately before use (tank mix). For example, the plant (or plants) can be sprayed with the composition of the present invention before or after treatment with other active substances.

The following list of M pesticides with which the compounds of the present invention can be used and with which a synergistic effect may potentially occur is illustrative of possible combinations, but is not limiting:

M.1) organic (thio)phosphate compounds: acephate, azametifos, azinophos-ethyl, azinophosmethyl, chlorethoxyphos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos , dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprofos, famfour, fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate, heptenophos, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, parathion , parathion-methyl, phentoate, phorate, phosalon, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiophos, pyraclofos, pyridafention, quinalphos, sulfotep, tebupirimphos, temefos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon , vamidotion ;

M.2) carbamate compounds: aldicarb, alanicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, etiophencarb, fenobucarb, formatenate, furatiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propox ur, thiodicarb, thiopha

- 92 044142 nox, trimetacarb, CMS, xylylcarb, triazamate;

M.3) pyrethroid compounds: acrinathrin, allethrin, d-cis-trans-allethrin, d-trans-allethrin, bifenthrin, bioallethrin, bioallethrin S-cyclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin, betacifluthrin, cyhalothrin, lambda-cyhalothrin, gamma cyhalothrin, cypermethrin, alpha-cypermethrin, betacypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, empentrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucitrinate, flumethrin, tau-fluvalinate, halfenprox, imiprotrin, metofluthrin, permethrin in, phenothrin, prallethrin, pofluthrin, pyrethrin (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin, transfluthrin;

M.4) juvenile hormone mimetics: hydroprene, kinoprene, methoprene, fenoxycarb, pyriproxyfen;

M.5) Agonists/Antagonists of the nicotine receptor: acetamypid, Benesultap, cartap hydrochloride, clotianidine, dinothefuran, imidaclopride, triametoxam, nytenpira, nicotine, spinosades (allosteric agonist), spinators (allosteric agonist), thiacloprides, thycycles, thyudo-nuclear tanks, thiosultapa-nuclear power plants and AKD1022 ;

M.6) antagonists of chlorine ion channels of GABA receptors: chlordane, endosulfan, gamma-NSN (lindane); ethiprole, fipronil, pirafluprole, pyriprole;

M.7) activators of chlorine ion channels: abamectin, emamectin benzoate, milbemectin, lepimectin;

M.8) METI I compounds: phenazachine, fenpiroximate, pyrimidifene, pyridaben, tebufenpyrad, tolfenpyrad, flufenerim, rotenone;

M.9) METI II and III compounds: acequinocyl, fluacyprim, hydramethylnon;

M.10) uncouplers of oxidative phosphorylation: chlorfenapyr, dinitro-ortho-cresol;

M.11) inhibitors of oxidative phosphorylation: azocyclotine, cyhexatin, diafenthiuron, fenbutatin oxide, propargite, tetradiphon;

M.12) compounds that disrupt the molting process: cyromazine, chromafenozide, halofenozide, methoxyfenozide, tebufenozide;

M.13) synergists: piperonyl butoxide, tribufos;

M.14) sodium channel blockers: indoxacarb, metaflumizone;

M.15) fumigants: methyl bromide, chloropicrin sulfuryl fluoride;

M.16) selective nutrition blockers: krylotay, pymetrozine, flonicamid;

M.17) mite growth inhibitors: clofentezine, hexythiazox, etoxazole;

M.18) chitin synthesis inhibitors: buprofezin, bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenuxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron, triflumuron;

M.19) lipid biosynthesis inhibitors: spirodiclofen, spiromesifen, spirotetramat;

M.20) ocatapaminergic agonists: amitraz;

M.21) ryanodine receptor modulators: flubendiamide and phthalamide compound (R)-, (S)-3chloro-N 1 - {2-methyl-4-[ 1,2,2,2-tetrafluoro-1 -(trifluoromethyl)ethyl ]phenyl} -N2-(1 -methyl-2methylsulfonylethyl)phthalamide (M21.1);

M.22) isoxazoline compounds: 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethylbenzamide (M22.1),

4-[5-(3,5-dichlorophenyl)-5trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoroethyl)benzamide (M22 .2), 4-[5-(3,5dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro- ethylcarbamoyl)methyl]benzamide (M22.3), 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]naphthalene-1-carboxylic acid [( 2,2,2-trifluoroethylcarbamoyl)methyl]amide (M22.4)4-[5-(3,5dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[( methoxyimino)methyl]-2-methylbenzamide (M22.5), 4-[5-(3-chloro-5-trifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydro-uzoxazol-3-yl]-2- methyl-N[(2,2,2-trifluoroethylcarbamoyl)methyl]benzamide (M22.6), 4-[5-(3

-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]naphthalene-1-carboxylic

-chloro-5-trifluoromethyl-phenyl)-5

[(2,2,2-trifluoroacids ethylcarbamoyl)methyl]amide (M22.7) and 5-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3 -yl]-2-[1,2,4]triazol-1 -yl-benzonitrile (M22.8);

M.23) anthranilamide compounds: chlorantraniliprole, cyantraniliprole,

5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic ethylcarbamoyl)-6-methyl-phenyl]amide (M23.1),

5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic cyclopropyl-ethylcarbamoyl)phenyl]amide (M23.2),

5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic cyclopropyl-ethylcarbamoyl)phenyl]amide (M23.3)

5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic cyclopropyl-ethylcarbamoyl)phenyl]amide (M23.4), acids [4-cyano-2-(1-cyclopropyl acids

[2-chloro-4-cyano-6-(1 acid

[2-bromo-4-cyano-6-(1 acid

[2-bromo-4-chloro-6-(15-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [2,4-dichloro-6-(1- cyclopropylethylcarbamoyl)phenyl]amide (M23.5),

5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-carboxylic acid [4-chloro-2-(1-cyclopropyl

- 93 044142 ethylcarbamoyl)-6-methyl-phenyl]amide (M23.6), ^-(2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3- carbonyl]amino}-5-chloro-3-methylbenzoyl)hydrazinecarboxylic acid methyl ester (M23.7), ^-(2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H- pyrazole-3-carbonyl]amino}-5-chloro-3-methyl-benzoyl)N'-methyl-hydrazinecarboxylic acid methyl ester (M23.8), ^-(2-{[5-bromo-2-(3- chloro-pyridin-2-yl)-2H-pyrazol-3-carbonyl]amino}-5-chloro-3-methyl-benzoyl)N,N'-dimethylhydrazinecarboxylic acid methyl ester (M23.9),

N'-(3,5-dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3carbonyl]amino}benzoyl)hydrazinecarboxylic acid methyl ester (M23.10 ),

N'-(3,5-dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-carbonyl]amino}benzoyl)-N'methyl-hydrazinecarboxylic acid methyl ester (M23.11) and N'-(3,5-dibromo-2-{[5-bromo-2-(3-chloropyridin-2-yl)-2H-pyrazol-3-carbonyl]amino}benzoyl )-N,N'-dimethylhydrazinecarboxylic acid methyl ester (M23.12);

M.24) malononitrile compounds: 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (CF ₂ H-CF ₂ -CF ₂ -CF ₂ -CH ₂ -C(CN) ₂ -CH ₂ -CH ₂ -CF ₃ ) (M24.1) and 2-(2,2,3,3,4,4,5,5octafluoropentyl)-2 -(3,3,4,4,4-pentafluorobutyl)malonodinitrile (CF ₂ H-CF ₂ -CF ₂ -CF ₂ -CH ₂ -C(CN) ₂ -CH ₂ CH ₂ -CF ₂ -CF3) (M24 .2);

M.25) microbiological preparations: Bacillus thuringiensis subsp. Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp. Aizawai, Bacillus thuringiensis subsp. Kurstaki, Bacillus thuringiensis subsp. Tenebrionis;

M.26) aminofuranone compounds:

4-{[(6-bromopyrid-3-yl)methyl] (2-fluoroethyl)amino} furan-2(5H)-one (M26.1), 4-{[(6-fluoropyrid-3 yl)methyl] (2,2-difluoroethyl)amino}furan-2(5H)-one (M26.2), 4-{[(2-chloro-1,3-thiazol-5-yl)methyl](2-fluoroethyl)amino }furan-2(5H)-one (M26.3), 4-{[(6-chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)one (M26.4), 4-{[(6-chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-one (M26.5), 4-{[(6-chloro-5fluoropyrid-3 -yl)methyl](methyl)amino}furan-2(5H)-one (M26.6), 4-{[(5,6-Dichloropyrid-3-yl)methyl](2fluoroethyl)amino}furan-2( 5H)-one (M26.7), 4-{[(6-chloro-5-fluoropyrid-3yl)methyl](cyclopropyl)amino}furan-2(5H)-one (M26.8), 4-{[ (6-chloropyrid-3yl)methyl](cyclopropyl)amino}furan-2(5H)-one (M26.9) and 4-{[(6-chloropyrid-3yl)methyl](methyl)amino}furan-2( 5H)-on (M26.10);

M.27) various compounds: aluminum phosphide, amidoflumet, benclothiaz, benzoximate, biphenazate, borax, bromopropylate, cyanide, cyanopyrafen, cyflumetofen, quinomethionate, dicofol, fluoroacetate, phosphine, pyridalyl, pyrifluquinazone, sulfur, organosulfur compounds, potassium antimonyl tartrate, sulfoxaflor, N-R'-2,2-dihalo-1-Rcyclopropanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoroptolyl)hydrazone or N-R'-2,2-di(R ')propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone, where R' represents methyl or ethyl, halogen represents a chlorine or bromine atom, R'' represents a hydrogen or methyl, and R''' represents methyl or ethyl, 4-but-2-ynyloxy-6-(3,5dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine (M27.1), cyclopropaneacetic acid 1,1'[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[[(2-cyclopronylacetyl)oxu]methyl]-1,3,4,4a,5,6,6a ,12,12a,12bdecahydro-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4e]pyran -3,6-diyl]ether (M27.2) and 8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1] octane (M27.3).

Commercially available group M compounds can be found in The Pesticide Manual, 13th Edition, British Crop Protection Council (2003), among other publications.

Paraoxon and its preparation were described in Farm Chemicals Handbook, Volume 88, Meister Publishing Company, 2001. Flupyrazophos was described in Pesticide Science 54, 1988, p. 237-243 and in US 4822779. AKD 1022 and its preparation were described in US 6300348 Anthranilamides M23.1-M23.6 were described in WO 2008/72743 and WO 200872783, and M23.7-M23.12 in WO 2007/043677. Phthalamide M 21.1 is known from WO 2007/101540. The alkynyl ether compound M27.1 is described, for example, in JP 2006131529. Organosulfur compounds are described in WO 2007060839. The isoxazoline compounds M 22.1-M 22.8 are described, for example, in WO2005/085216, WO 2007/079162, WO 2007/026 965, WO 2009 /126668 and WO2009/051956. The aminofuranone compounds M 26.1 to M 26.10 have been described, for example, in WO 2007/115644. The pyripyropene derivative M 27.2 was described in WO 2008/66153 and WO 2008/108491. The pyridazine compound M 27.3 was described in JP 2008/115155. Malononitrile compounds such as (M24.1) and (M24.2) have been described in WO 02/089579, WO 02/090320, WO 02/090321, WO 04/006677, WO 05/068423, WO 05/068432 and WO 05/063694. All documents listed above are incorporated into this text by reference in their entirety.

Fungicides that can be mixed with the compounds of the present invention include, but are not limited to, acylalanines such as benalaxyl, metalaxyl, ofuras, oxadixyl; amine derivatives such as aldimorph, dodine, dodemorph, fenpropimorph, fenpropidine, guazatin, iminoctadine, spiroxamine, tridemorph; anilinopyrimidines such as pyrimethanil, mepanipyrim or

- 94 044142 cyrodinil; antibiotics such as cycloheximide, griseofulvin, kasugamycin, natamycin, polyoxin or streptomycin; azoles such as bitertanol, bromoconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquiconazole, flusilazole, hexaconazole, imazalil, metconazole, myclobutanil, penconazole, propiconazole, prochloraz, prothioconazole, tebuconazole, triadimefon, triadimenol, triflumizole, triticonazole, flutriafol; dicarboximides such as iprodione, myclozolin, procymidone, vinclozolin; dithiocarbamates such as ferbam, nabam, maneb, mancozeb, metam, metiram, propineb, polycarbamate, thiram, ziram, zineb; heterocyclic compounds such as anilazine, benomyl, boscalid, carbendazim, carboxin, hydroxycarboxin, cyazofamide, dazomet, dithianone, famoxadone, fenamidone, fenarimol, fuberidazole, flutolanil, furamethpyr, isoprothiolane, mepronil, naurimol, probenazole, proquinazide, pyrifenox, quinoxifen , silthiopham , thiabendazole, tifluzamide, thiophanate methyl, tiadinil, tricyclazole, triforin; copper-containing fungicides such as Bordeaux mixture, copper acetate, copper oxychloride, basic copper sulfate; nitrophenyl derivatives such as binapacryl, dinocap, dinobuton, nitrophthalisopropyl; phenylpyrroles such as fenpiclonil or fludioxanil,

Sulfur, other fungicides such as acibenzolar-S-methyl, benthiavalicarb, carpropamide, chlorothalonil, cyflufenamide, cymoxanil, diclomesin, diclocymet, diethofencarb, edifen-phos, ethaboxam, fenhexamide, fentin acetate, fenoxanil, ferimzone, fluazinam, fosetil, fos ethyl -aluminum, iprovalicarb, hexachlorobenzene, metrafenone, pencicuron, propamocarb, phthalide, toloclofos-methyl, quintozene, zoxamide; strobilurins such as azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin or trifloxystrobin; sulfenic acid derivatives such as captafol, captan, dichlofluanid, folpet, tolylfluanid; cinnamic acid amides and analogues such as dimethomorph, flumetover or flumorph.

III. Application and methods.

Due to their excellent activity, the compounds having the formula (Id), and in particular the compounds having the formula (Ie) and (S)-Ie, can be used for pest control. Accordingly, the present invention also describes a method for controlling animal pests, including treating the pests, their food, their habitat or breeding sites, or crops, plant propagation material (such as seeds), soil, area, material or environment, in which pests grow or are likely to grow, or materials, crops, plant propagation material (such as seeds), soil, surfaces or spaces that need to be protected from attack by pests or infestation by pests, a pesticidal effective amount of a compound having formula (Id) , or a salt thereof, or the composition described above.

In one embodiment, the method of the present invention serves to protect plant propagation material (such as seeds) and the plant that grows from it from attack or infestation by animal pests and includes treating the plant propagation material (such as seeds) with a pesticide effective an amount of a compound having formula (Id) or an agriculturally acceptable salt thereof described above, or a pesticidal effective amount of an agricultural composition described above and below. The method of the present invention is not limited to protecting the substrate (plant, plant propagation material, soil, etc.) that is subjected to the treatment of the present invention, but also has a preventive effect, such as protecting a plant that grows from the treated material for propagation of plants (such as seeds), without the plant itself being processed.

In one embodiment of the present invention for agricultural use, the animal pests are preferably selected from arthropods and nematodes, more preferably from pests, arachnids and nematodes, and even more preferably from pests, mites and nematodes.

The present invention also describes an agricultural composition for the control of such animal pests, which contains an amount of at least one compound having formula (Id), or at least one agriculturally acceptable salt thereof, and at least one inert liquid and/or a solid agriculturally acceptable carrier having a pesticidal effect, and, if necessary, at least one surfactant. Such a composition may contain one active substance having formula (Id), or a salt thereof, or a mixture of several active substances having formula (Id), or salts thereof, according to the present invention. The composition of the present invention may contain an individual isomer or mixtures of isomers, as well as individual tautomers or mixtures of tautomers.

Pest animals, i.e. insects, mites and nematodes, the plant, the soil or water in which the plant grows, can be brought into contact with the compounds of the present invention having formula (Id), or with the composition(s) containing them, by any methods known in the art. areas. The term contact itself includes both direct contact (application of the compound/composition directly to the pest animal or plant - typically the foliage, stem or roots of the plant) and indirect contact (application of the compound/composition to the locus of the pest animal or plants).

- 95 044142

The compounds having formula (Id), or pesticide compositions containing them, can be used to protect growing plants and crops from attack or infestation by animal pests, especially insects, mites or arachnids, by contacting the plant/crop with a pesticidal effective amount of the compounds, having formula I. The term harvest refers to the crop that has not yet been harvested (growing) and that has already been harvested.

The compounds of the present invention and compositions containing them are particularly useful for the control of several insects on various crop plants, such as cereals, roots, oilseeds, vegetables, spices, ornamental plants, for example, durum and other wheat seeds, barley, oats , rye, corn (fodder corn and sweet corn/sweet and field corn), soybeans, oilseeds, cruciferous crops, cotton, sunflowers, bananas, rice, oilseed rape, oilseed turnips, sugar beets, fodder beets, eggplants, potatoes, grass, lawn, peat, forage grasses, tomatoes, leeks, pumpkins and giant squash, cabbage, iceberg lettuce, peppers, cucumbers, melons, Brassica plants, watermelons, peas, garlic, onions, carrots, grapes, tubers such as potatoes , sugarcane, tobacco, grapes, petunias, geraniums/pelargoniums, pansies and impatiens.

The compounds of the present invention are used in pure form or in the form of compositions for the treatment of insects or plants, plant propagation materials such as seeds, soils, surfaces or spaces that need to be protected from insect attack by an insecticidal effective amount of active substances. Application can be made both before and after insect infestation of plants, plant propagation materials such as seeds, soil, surfaces, materials or spaces.

The present invention also includes a method of controlling animal pests, which involves contacting the animal pests, their habitat, breeding site, their food, crops, seeds, soil, area, material or environment in which the animal pests grow or may grow , or materials, plants, seeds, soil, surfaces or spaces that need to be protected from attack or infestation by animals, with a pesticidal effective amount of a mixture of at least one active ingredient having formula (Id). In addition, animal pests can be controlled by contacting the target pest, its food, habitat, breeding site or its locus with a pesticidal effective amount of compounds having Formula I. Treatment can be carried out before or after pest infestation of the locus, growing plants or harvested crop.

In one embodiment, the compounds of the present invention can also be used preventively in areas where pests are expected to occur.

The compounds having formula (Id) can also be used to protect growing plants from attack or infestation by pests by contacting the plant with a pesticidal effective amount of the compounds having formula (Id). The term contact includes both direct contact (application of compounds/compositions directly to the pest and/or plant - typically the foliage, stem or roots of the plant) and indirect contact (application of compounds/compositions to the locus of the pest and/or plant).

The term locus means the habitat, breeding site, plant, seed, soil, area, material or environment in which a pest or parasite grows or can grow, excluding the body of the animal itself.

The term plant propagation material means any part of a plant that is capable of propagation. In general, plant propagation material includes the product of the mature ovule of gymnosperms and angiosperms, which is formed after fertilization and some growth in the mother plant and includes seeds, fruits, false fruits, infructescences, as well as rhizosomes (rhizosomes), bulbs, roots, tubers and cuttings.

The term plant propagation material means all generative parts of plants, such as seeds, and vegetative plant material, such as cuttings and tubers (eg potatoes), that can be used to propagate the plant. It includes seeds, roots, fruits, roots, tubers, rhizosomes, seedlings, shoots and other parts of plants. This term also includes seedlings and young plants that are transferred after germination or after emerging from the soil. These plant propagation materials may be treated prophylactically with a plant protection compound during or after planting or transplanting.

The term crop plants should be understood to include plants that have been modified through crossing, mutagenesis or genetic engineering. Genetically modified plants are plants whose genetic material has been modified using recombinant DNA technology in a way that cannot be achieved naturally through crossing, mutation or natural recombination. Typically, one or more genes are integrated into the genetic material of a genetically modified plant to improve certain properties of the plant. Such genetic modifications also include, but are not limited to, targeted post-translational modifications of the protein(s) (oligo- or polypeptides), for example by glycosylation or the addition of polymers such as prenylated, acetylated or farnesylated moieties or PEG moieties (eg

- 96 044142 measures as described in Biotechnol Prog. 2001 Jul-Aug;17(4):720-8, Protein Eng Des Sel. 2004 Jan;17(1):57-66, Nat Protoc. 2007;2(5):1225-35, Curr Opin Chem Biol. 2006 Oct;10(5):487-91. Epub 2006 Aug 28, Biomaterials. Mar 2001; 22(5):405-17, Bioconjug Chem. 2005 Jan-Feb;16(1):113-21).

The term crop plants should also be understood to include plants that have been rendered resistant to specific classes of herbicides, such as hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors; acetolactate synthase (ALS) inhibitors such as sulfonylureas (see, for example, US 6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO 98/02526, WO 98/02527, WO 04/106529, WO 05 /20673, WO 03/14357, WO 03/13225, WO 03/14356, WO 04/16073) or imidazolinones (see, for example, US 6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO 98/02526, WO 98/02527, WO 04/106529, WO 05/20673, WO 03/14357, WO 03/13225, WO 03/14356, WO 04/16073); enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors such as glyphosate (see, for example, WO 92/00377); glutamine synthetase (GS) inhibitors such as glufosinate (see, for example, EP-A-0242236, EP-A-242246) or oxynyl herbicides (see, for example, US 5,559,024), as a result of well-known breeding methods or genetic engineering. Several crop plants have been rendered resistant to herbicides by common breeding methods (mutagenesis), for example Clearfield® rapeseed (canola) is resistant to imidazolinones such as imazamox. Genetic engineering techniques have been used to make crops such as soybeans, cotton, corn, beets and canola resistant to herbicides such as glyphosate and glufosinate, some of which are commercially available under the trade names RoundupReady® (glyphosate) and LibertyLink® (glufosinate). .

The term crop plants should also be understood to include plants which, thanks to recombinant DNA technologies, are capable of synthesizing one or more insecticidal proteins, especially those known from the genus Bacillus bacteria, in particular Bacillus thuringiensis, such as endotoxins, for example CryIA(b), CryIA(c) , CrylF, CryIF(a2), CryIIA(b), CryIIIA, CryIIIB(b1) or Cry9с; plant insecticidal proteins (VIPs), for example VIP1, VIP2, VIP3 or VIP3A; insecticidal proteins of bacteria that colonize nematodes, for example species of the genus Photorhabdus or species of the genus Xenorhabdus; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins, or other insect-specific neurotoxins; toxins produced by fungi, such as streptomycete toxins, plant lectins, such as pea or barley lectins; agglutinins; proteinase inhibitors such as trypsin inhibitors, serine protease inhibitors, palatin, cystatin or papain inhibitors; ribosome inactivating proteins (RIPs), such as ricin, corn RIP, abrin, luffin, saporin or bryodin; steroid metabolic enzymes such as 3-hydroxysteroid oxidase, ecdysteroid IDP glycosyl transferase, cholesterol oxidase, ecdysone inhibitors or HMGCoA reductase; ion channel blockers such as sodium or calcium channel blockers; juvenile hormone esterase; diuretic hormone receptors (heliokinin receptors); stilbene synthase, bibenzyl synthase, chitinases or glucanases. In the context of the present invention, these insecticidal proteins or toxins are also understood as pretoxins, fusion proteins, processed or otherwise modified proteins. Fusion proteins are characterized by a new combination of protein domains (see, for example, WO 02/015701). Other examples of such toxins or genetically modified plants capable of synthesizing such toxins are described, for example, in EP-A 374 753, WO 93/007278, WO 95/34656, EP-A 427 529, EP-A 451 878, WO 03/ 018810 and WO 03/052073. Methods for producing such genetically modified plants are generally known to those skilled in the art and are described, for example, in the publications listed above. Such insecticidal proteins contained in genetically modified plants provide plants that produce such proteins with protection from dangerous pests from certain taxa of arthropods, in particular from beetles (Coleoptera), flies (Diptera) and butterflies and moths (Lepidoptera), as well as from parasitic on plants nematodes (Nematoda).

The term crop plants should also be understood to include plants that, through recombinant DNA techniques, are capable of synthesizing one or more proteins to enhance the resistance or resistance of such plants to bacterial, viral or fungal pathogens. Examples of such proteins are the so-called pathogenesis-related proteins (PR proteins, see, for example, EP-A 0 392 225), plant disease resistance genes (for example, potato cultivars that express resistance genes to the oomycete species Phytophthora infestans, isolated from the wild Mexican potato Solanum bulbocastanum), or T4-lysozyme (for example, potato cultivars capable of synthesizing these proteins, with increased resistance against bacteria such as Erwinia amylvora). Methods for producing such genetically modified plants are generally known to those skilled in the art and are described, for example, in the publications listed above.

The term crop plants should also be understood to include plants that, through recombinant DNA techniques, are capable of synthesizing one or more proteins to improve productivity (e.g. biomass yield, grain yield, starch content, oil content or protein content), drought tolerance, salinity or other environmental factors limiting growth, or resistance to pests and fungal, bacterial or virus

- 97 044142 pathogens for such plants.

The term crop plants should also be understood to include plants which, thanks to recombinant DNA techniques, contain modified amounts of substances or new substances, in particular improving human or animal nutrition, for example oilseeds that produce health-promoting long-chain omega-3 fatty acids or unsaturated omega-9 fatty acids (such as Nexera® canola).

The term cultivated plants should also be understood to include plants that, thanks to recombinant DNA techniques, contain modified amounts of substances or new substances, in particular increasing the production of a certain type of raw material, for example potatoes, which produce increased amounts of amylopectin (for example, Amflora® potatoes) .

In general, a pesticidal effective amount means the amount of active ingredient necessary to achieve a noticeable effect on growth, including the effects of necrosis, killing, retardation, prevention and removal, destruction or otherwise reducing the appearance and activity of the target organism. The pesticide effective amount may vary for different compounds/compositions of the present invention. The pesticidally effective amount of the compositions also varies depending on prevailing conditions, such as the target pesticide effect and its duration, weather conditions, target organism, locus, route of application, and the like.

In the case of soil treatment or application to a pest habitat or nest, the amount of active ingredient is in the range of from about 0.0001 to about 500 g per 100 m ² , preferably from about 0.001 to about 20 g per 100 m ² .

Typical application rates for protecting materials are, for example, from about 0.01 to about 1000 g of active ingredient per m ² of material treated, preferably from about 0.1 g to about 50 g per m ² .

Insecticidal compositions for use in impregnating materials typically contain from about 0.001 to about 95, preferably from about 0.1 to about 45, and more preferably from about 1 to about 25 weight percent of at least one repellent and/or insecticide.

For the treatment of growing plants, the application rate of the active ingredients of the present invention may range from about 0.1 g to about 4000 g per hectare, preferably from about 25 g to about 600 g per hectare, more preferably from about 50 g to about 500 g per hectare. g per hectare.

Compounds having formula (Id) are effective both by contact (when applied to soil, glass, wall, bed net, carpet, plant parts or animal parts) and by ingestion (baits or plant parts).

The compounds of the present invention can also be used against non-agricultural pests such as ants, termites, wasps, flies, mosquitoes, crickets or cockroaches. When used against these non-agricultural pests, compounds having formula (Id) are preferably used in the form of bait compositions. The bait may be a liquid, solid or semi-solid composition (eg, gel). Solid baits can be shaped into different shapes to suit the respective application, such as granules, blocks, sticks, disks. Liquid baits can be placed in a variety of devices for proper application, such as open containers, spray devices, drip devices, or evaporation devices. Gels can be water-based or oil-based, and their properties can be adjusted in terms of tack, moisture resistance, or stability over time.

The bait used in the composition is a product attractive enough to be eaten by insects such as ants, termites, wasps, flies, mosquitoes, crickets, etc., or cockroaches. Attraction can be controlled using food attractants or sex pheromones. Food attractants are selected from (but not limited to) animal or vegetable proteins (meat, fish or blood, insect parts, egg yolk), fats and oils of animal and/or vegetable origin, or mono-, oligo- or polysaccharides, in particular from sucrose, lactose, fructose, dextrose, glucose, starch, pectin or even molasses or honey. Fresh or rotten parts of fruits, grains, plants, animals, insects or their individual parts can also serve as a food attractant. Sex pheromones are more specific to insects. Particular variants of pheromones are described in the literature and are known to specialists in this field.

When used in bait compositions, typical active ingredient levels range from about 0.001 to about 15, preferably from about 0.001 to about 5 weight percent active ingredient.

Formulated formulations of compounds of Formula (Id) as aerosols (e.g., spray bottles), oil sprays, or atomizer formulations are well suited to the lay user for controlling pests such as flies, fleas, ticks, mosquitoes, or cockroaches. . Aerosol formulations preferably consist of an active ingredient,

- 98 044142 solvents such as lower alcohols (for example methanol, ethanol, propanol, butanol), ketones (for example acetone, methyl ethyl ketone), paraffinic hydrocarbons (for example kerosene) having a boiling point range from about 50 to 250 ° C, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, aromatic hydrocarbons such as toluene, xylene, water, as well as auxiliary compounds such as emulsifiers such as sorbitol monooleate, oleyl ethoxylate containing 3-7 mol ethylene oxide (e.g. Labrafil® M 1944 CS ), fatty alcohol ethoxylate, perfume oils such as essential oils, esters of medium chain fatty acids with lower alcohols, aromatic carbonyl compounds, if necessary stabilizers such as sodium benzoate, amphoteric surfactants, lower epoxides, triethyl orthoformate, and, if necessary, propellants such as propane, butane, nitrogen, compressed air, dimethyl ether, carbon dioxide, nitric oxide or mixtures of these gases.

Oil spray formulations differ from aerosol formulations in that they do not use propellants. When used in spray compositions, the active ingredient content is from about 0.001 to about 80, preferably from about 0.01 to about 50, and most preferably from about 0.01 to about 15 weight percent.

The compounds having formula (Id), or salts thereof, and their corresponding compositions can also be used in mosquito fumigating coils, smoke cartridges, evaporation plates or long-lasting evaporators, as well as in anti-moth papers, moth pads or other evaporative systems without heater.

Methods of controlling infectious diseases carried by insects (for example, malaria, dengue and yellow fever, lymphatic filariasis and leishmaniasis), using compounds having formula (Id), or salts thereof and their corresponding compositions, also include surface treatments in homes, airborne spraying and impregnation of curtains, tents, clothing, bed nets, tsetse fly traps, etc. Insecticidal compositions for application to fabrics, fibers, woven fabrics, nonwovens, mesh materials, film or canvas preferably contain a mixture comprising an insecticide, optionally a repellent and at least one binder. Suitable repellents are, for example, N,N-diethyl-meta-toluamide (DEET), N,N-diethylphenylacetamide (DEPA), 1-(3-cyclohexan-1-yl-carbonyl)-2-methylpiperidine, lactone (2hydroxymethylcyclohexyl )acetic acid, 2-ethyl-1,3-hexanediol, indalone, methylneodecanamide (MNDA), non-insect control pyrethroid such as {(+/-)-3-allyl-2-methyl-4oxocyclopent-2 -(+)-enyl-(+)-trans-chrysanthemum (esbiotrin), repellent derived from or identical to plant extracts, such as limonene, eugenol, (+)-eucamalol (1), (-)-1-epi -eucamalol, or crude plant extracts such as plant extracts of Eucalyptus maculata, Vitex rotundifolia, Cymbopogan martinii, Cymbopogan citratus (lemongrass), Cymopogan nartdus (citronella). Suitable binders are selected, for example, from polymers and copolymers of vinyl esters of aliphatic acids (such as vinyl acetate and vinyl versatate), acrylic and methacrylic esters of alcohols such as butyl acrylate, 2-ethylhexyl acrylate and methyl acrylate, mono- and di-unsaturated hydrocarbons such as styrene , and aliphatic dienes such as butadiene. Impregnation of curtains and bed nets is usually carried out by immersing the textile material in insecticide emulsions or dispersions or by spraying the nets.

Compounds having formula (Id) and their compositions can also be used to protect wooden materials, such as trees, fences, wooden supports, etc., and buildings, such as houses, cottages, factories, as well as building materials, furniture , leather goods, fibers, vinyl goods, electrical wires and cables, etc., from ants and/or termites, and to prevent ant and termite damage to crops or people (for example, where pests invade houses and public buildings). Compounds having formula (Id) are not only applied to the surface of the surrounding soil or to the soil under floors to protect wooden materials, but they can also be applied to structural materials, such as concrete surfaces in crawl spaces, pergola supports, beams and logs, plywood, furniture, etc., to wood products such as chipboards and planks, etc., and vinyl products such as electrical wire insulation, vinyl sheets, thermal insulation materials such as polystyrene foam, etc. In the case of application against ants causing damage to crops or people, the ant control agent of the present invention is applied to the crop or surrounding soil, or directly applied to an ant nest or the like.

IV. Seed treatment.

In some embodiments of the present invention, compounds having formula (Id) can also be used to treat seeds to protect them from insect pests, in particular from soil-dwelling insect pests, as well as to protect developing roots and shoots of plants from living in the soil of insect pests and insects that damage foliage.

The compounds having formula (Id) are particularly suitable for protecting seeds from soil-dwelling insect pests and for protecting developing roots and shoots of plants from soil-dwelling and foliar pests. It is preferable to protect the roots and shoots of plants. It is more preferable to protect plant shoots from sucking insects

- 99 044142 clods and hole-making insects, with the most preferred protection against plant aphids.

Thus, the present invention includes a method of protecting seeds from insects, in particular from soil-dwelling insects, and shoots and roots of seedlings from insects, in particular from soil-dwelling insects and from insects damaging foliage, wherein the method includes contacting the seeds before sowing and/or after germination with a compound having the general formula (Id) or a salt thereof. Particularly preferred is a method in which the roots and shoots of a plant are protected, more preferably a method in which the shoots of a plant are protected from sucking insects and bore-boring insects, and most preferred is a method in which the shoots of a plant are protected from plant aphids.

The term seeds covers seeds and seedlings of plants of all types, including (but not limited to) true seeds, seed parts, shoots, corms, tubers, fruits, roots, grains, cuttings, shoots and the like, and in a preferred embodiment means true seeds.

True seed treatment includes all suitable seed treatment technologies known in the art, such as seed spraying, seed coating, seed dusting, seed dipping, and seed pelletizing.

The present invention also covers seeds to which the active substance of the present invention is applied and/or which contain the active substance of the present invention.

The term seeds to which the active ingredient of the present invention is applied and/or which contain the active ingredient of the present invention generally means that the active ingredient is present substantially on the surface of the plant propagation material at the time of application, although a greater or lesser portion of the active ingredient may penetrate into plant propagation material, depending on the treatment method. When said propagation material is planted in the soil, it can adsorb the active substance.

Suitable seeds include, but are not limited to, cereal seeds, root crops, oilseeds, vegetable seeds, herbs, ornamental plants, e.g. durum and other wheat seeds, barley, oats, rye, corn (fodder and sweet corn) /sweet and field corn), soybeans, oilseeds, cruciferous plants, cotton, sunflowers, bananas, rice, oilseed rape, oilseed turnips, sugar beets, fodder beets, eggplants, potatoes, lawn grass, forage grasses, tomatoes, leeks , pumpkins, cabbage, iceberg lettuce, peppers, cucumbers, melons, different types of cabbage, beans, peas, garlic, onions, carrots, tubers such as potatoes, sugar cane, tobacco, grapes, petunias, geraniums/pelargoniums, pansies and balsam.

In addition, the active substances of the present invention can also be used to treat the seeds of plants that are resistant to herbicides or fungicides due to selection, including genetic engineering methods. For example, the active ingredients of the present invention can be used to treat the seeds of plants that are resistant to herbicides from the group consisting of sulfonylureas, imidazolinones, glufosinate ammonium or glyphosatisopropylammonium, and similar active ingredients (see, for example, EP-A-0242236, EP-A-242246) (WO 92/00377) (EP-A-0257993, US Patent No. 5,013,659), or for the treatment of transgenic plants, such as cotton, capable of producing Bacillus thuringiensis toxins (Bt toxins), which make the plant resistant to certain types of pests (EP-A-0142924, EP-A-0193259).

In addition, the active substances of the present invention can also be used to treat the seeds of plants that have modified characteristics compared to existing plants, which can be obtained, for example, by traditional breeding methods and/or by generating mutations or recombinant methods. For example, a number of cases have been described of recombinant modifications in crop plants generated for the purpose of modifying starch synthesized in plants (for example, WO 92/11376, WO 92/14827, WO 91/19806), or transgenic crop plants having a modified fatty acid composition (WO 91/13972).

Treatment of seeds with the active compound of the present invention is usually carried out by spraying or dusting the seeds before sowing the plants and before germination of the plants.

Compositions which may be particularly useful for treating seeds include:

A) soluble concentrates (SL, LS);

D) emulsions (EW, EO, ES);

E) suspensions (SC, OD, FS);

F) water-dispersible granules and water-soluble granules (WG, SG);

G) water-dispersible powders and water-soluble powders (WP, SP, WS);

H) gel preparations (GF);

I) fine powders (DP, DS).

Commonly used seed treatment compositions include, for example, FS flowable concentrates, LS solutions, DS dry treatment powders, water-dispersible water treatment powders.

- 100 044142 suspension form WS, water-soluble powders SS, emulsions ES and EC, and gel compositions GF. The listed compositions can be applied to seeds in diluted or undiluted form. Application to seeds is carried out before sowing, directly on seeds or after germination of seeds.

In a preferred embodiment, the FS composition is used to treat the seeds. Typically, the FS composition may contain about 1-800 g/L active ingredient, about 1-200 g/L surfactant, about 0-200 g/L antifreeze, about 0-400 g/L binder , from about 0 to 200 g/l of pigment and up to about 1 liter of solvent, preferably water.

Particularly preferred FS compositions of compounds having formula I for seed treatment typically contain from about 0.1 to about 80 wt.% (1-800 g/l) of active ingredient, from about 0.1 to about 20 wt.% (1 -200 g/l) of at least one surfactant, for example, from about 0.05 to about 5 wt.% water, and from about 0.5 to about 15 wt.% dispersant, to about 20 wt.% %, for example, from about 5 to about 20% antifreeze, from about 0 to about 15 wt.%, for example, from about 1 to about 15 wt.%, pigment and/or dye, from about 0 to about 40 wt.% , for example, from about 1 to about 40 wt.% binder (adhesive agent), optionally up to about 5 wt.%, for example, from about 0.1 to about 5 wt.% thickener, optionally from about 0.1 to about 2% antifoam, and optionally a preservative such as a biocide, antioxidant, or the like, for example, in an amount of from about 0.01 to about 1 wt.%, and a filler/carrier in an amount up to 100 wt.%.

Seed treatment compositions may also further contain binders and optionally colorants. Binders can be added to improve the adhesion of the active ingredients to the seeds after treatment. Suitable binders include, but are not limited to, homo- and copolymers of alkylene oxides such as ethylene oxide or propylene oxide, polyvinyl acetate, polyvinyl alcohols, polyvinylpyrrolidones, and copolymers thereof, ethylene/vinyl acetate copolymers, acrylic homo- and copolymers, polyethylene amines, polyethylene amides and polyethylenimines, polysaccharides such as cellulose, tylose and starch, polyolefin homo- and copolymers such as olefin/maleic anhydride copolymers, polyurethanes, polystyrene homo- and copolymers.

Optionally, dyes can also be included in the composition. Suitable colorants for seed treatment compositions include, but are not limited to, rhodamine B, C.I. pigments. Pigment Red 112, C.I. Solvent Red 1, pigment blue 15:4, pigment blue 15:3, pigment blue 15:2, pigment blue 15:1, pigment blue 80, pigment yellow 1, pigment yellow 13, pigment red 112, pigment red 48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigment orange 43, pigment orange 34, pigment orange 5, pigment green 36, pigment green 7, pigment white 6, pigment brown 25, basic violet 10, basic violet 49, acid red 51, acid red 52, acid red 14, acid blue 9, acid yellow 23, basic red 10, basic red 108.

A gelling agent may also be added to some compositions of the present invention. One non-limiting example of a gelling agent is carrageenan (Satiagel®).

When treating seeds, the application rate of compounds having formula (Id) is generally from about 0.1 g to about 10 kg per 100 kg of seed, preferably from about 1 g to about 5 kg per 100 kg of seed, more preferably from about 1 g to about 1000 g per 100 kg of seeds, and in particular from about 1 g to about 200 g per 100 kg of seeds.

Thus, the present invention also relates to seeds containing the compound of the present invention having formula (Id) or an agriculturally acceptable salt thereof. The amount of the compound having formula (Id) or an agriculturally acceptable salt thereof generally ranges from about 0.1 g to about 10 kg per 100 kg of seeds, preferably from about 1 g to about 5 kg per 100 kg of seeds, and in particular from approximately 1 g to approximately 1000 g per 100 kg of seeds. Application rates vary depending on the individual plant, as is known to those skilled in the art. For certain crops, such as lettuce, application rates may be higher than indicated above.

The present invention is described in more detail below by way of non-limiting examples.

Examples

The present invention is described in more detail by means of non-limiting examples, which further illustrate the present invention, but are not and should not be interpreted as limiting the scope of the present invention.

Examples of synthesis.

Synthesis example 1. Synthesis of (S)-Ie.

The compound having formula (S)-Ie of the present invention was prepared according to Scheme 2 below. Compound 2-1 is described in US 7,951,828 B1, incorporated herein by reference. The preparation of compound 2-4 is described in US 8,217,180 B2 and US 8,546,618 B2, both of which are incorporated herein by reference in their entirety. A chiral phase transfer catalyst based on cinchone alkaloids, similar to 2-6, was prepared according to methods described, for example, in US 9,126,995 B2, WO 2011/104089 and US 2014/0206633, all incorporated herein by reference. In addition, Matoba et al., Angew. Chem. 2010, 122, 5898-5902 describes the use of these catalysts for the preparation of enantiomerically pure isoxazoline compounds.

Scheme 2

P ' , ί I THF 1 1 EKE l-PrMgCI

F from -20 to -10“С

2-1 and o a Ν 1'

T [V CFj

_ _ „-h G

2-Me-T F, mol.sieve. 0 2% w/w ^G ~ 'g' Ί g 'g

2 3(8 K;CO 80-85 C A _Y A o p .·,

2-5

LW, 30 rev., from -15 to -10“ C ' 1|

5.0 eq. NH OH. 6.0 equiv NaOH [, j _T1 y |S)-le

-V _r 1' J G ' F C1

Stage 1.

1-Chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene (2-1, 100 g, 0.31 mol) and tetrahydrofuran (THF, 200 ml, 2 volumes) were charged into a 500 ml reactor under atmosphere nitrogen. The mixture was cooled to -15 to -20°C and a solution of i-PrMgCl in THF (2 M, 170 mL, 0.34 mol, 1.1 eq.) was slowly added to the reactor (over 30 min) at from -20 to -5°C. The resulting mixture was stirred for another 0.5-1 hour and the progress of the reaction was checked by GC-MS, which showed that the starting compound had reacted completely. Methyl 2,2,2-trifluoroacetate was added to the reaction mixture over 0.5-1 hour at a temperature of -20 to -5°C. The resulting mixture was stirred overnight at a temperature of -20 to 10°C and the degree of conversion in the reaction was checked. When the reaction was complete, an aqueous solution of HCl (1M, 500 ml) was added and the mixture was stirred for 1-2 hours at -5 to 5°C. The reaction mixture was quenched and extracted with cyclohexane twice (500 mL, 200 mL) and the combined organic layers were evaporated in vacuo to give intermediate 2-3 as crude product (62.0 g, 98.4% purity, 77.7%) .

Stage 2.

2-Methyltetrahydrofuran (2-Me-THF, 25 ml, 5 vol.), intermediate 2-4 (5.0 g, 17 mmol, 1 eq.), molecular sieves (1.0 g, 20% w/w .) and potassium carbonate (0.7 g, 5.1 mmol, 0.3 eq.) were charged into a 100 mL 3-neck flask. The resulting mixture was heated to 75-85°C and compound 2-3 was added dropwise to the mixture at 75-85°C for 0.5-1 hour. The mixture was then stirred for another 4 hours at the same temperature and the progress of the reaction was monitored by the method HPLC. Additional K ₂ CO ₃ (0.2 g, 1.7 mmol) and 2-3 (0.1 g, 0.34 mmol, 0.2 eq.) were added and the mixture was stirred for an additional 16 hours. The mixture was cooled to 30-40°C and filtered. The filtrate was evaporated to give a brown solid. The product was purified by chromatography (silica gel, petroleum ether/ethyl acetate) to give the product as a yellow solid (6.6 g, 79.7% purity). The resulting product was then recrystallized from acetonitrile to give compound 2-5 in 44.9% yield (4.0 g) and 91.6% purity.

Stage 3.

Dichloromethane (DCM, 150 mL, 30 vol) and 2-5 (5.0 g, 7.95 mmol, 1.0 eq.) were charged into a 500 mL 3-neck flask. The mixture was stirred for 10-30 minutes until the compound was completely dissolved and then cooled to a temperature of -10 to 15°C. Chiral phase transfer catalyst 2-6 (0.18 g, 0.024 mmol, 0.03 eq) was added to the solution, and then a solution of NH ₂ OH (50% w/w)/NaOH/H ₂ O ( 20 ml, 5 vol.) at a temperature from -10 to 15°C for 0.5-1 hour. The resulting mixture was stirred for 16 hours at a temperature from -10 to 15°C and samples were taken for HPLC analysis to check the completion of the reaction , while the analysis showed less than 3% of the original compound. The organic layer was separated and washed with saturated KH2PO4 solution (20 ml, 4 vol.) twice. The resulting organic layer was washed two more times with saturated aqueous sodium chloride (20 ml) and then evaporated in vacuo at 3040°C, then toluene (20 ml, 4 vol.) was added and evaporated to dryness.

To 4.9 g of isolated crude product, 15 ml of toluene was added in a 3-neck flask and the mixture was heated to 60-70°C to dissolve the precipitate. The resulting solution was slowly cooled to 45-50° over 1 hour and seeds (0.025 g, 0.05% w/w) were added. The mixture with seeds was stirred for 1 hour at 45-50°C and then cooled to 37-42°C for 1 hour and stirred for another 6 hours. At this time, crystallization of the product from solution was observed. The mixture was cooled to 30-35°C for 1 hour and stirred for another 3 hours. The precipitate was filtered off and washed on the filter with toluene (10 ml, 2 vol.). The filter cake was then dried in a oven at 40-45° in vacuum for 6 hours, obtaining 2.3 g (45.1% yield) of (S)-Ie with a purity of 99.4% and chiral

- 102 044142 purity 99.3%.

Using the same approach, but a different chiral phase transfer catalyst (eg, isomer 2-6), compound (R)-Ie can be prepared. Alternatively, the racemic compound having formula (Ie) can be prepared without the use of a chiral phase transfer catalyst. The last stage in these processes is described in the examples below.

Synthesis example 2. Racemic compound (Ie).

Stage 3.

A 5 L reactor was charged with 2 L (10 volumes) of DCM and 200.0 g (0.32 mol, 1.0 eq.), and the mixture was stirred for 10-30 minutes to dissolve the solid precipitate. The solution was cooled to 0-5°C and NH2OH (50% w/w)/NaOH/H ₂ O (104.9 g/76.3 g/1.0 L) was added dropwise at 0-25°C for 30-60 min. The resulting mixture was stirred at 10-25°C for 3 hours and then a sample was taken to monitor the conversion by HPLC, which showed that the parent compound was present in an amount of less than 3.5%. The mixture was allowed to settle and the dichloromethane layer was washed with saturated KH ₂ PO ₄ solution (0.8 L, 4 vol.) twice. The resulting organic layer was then washed twice with saturated sodium chloride solution (0.8 L, 4 vol). The combined organic layers were evaporated in vacuo at 30-40°C to dryness, yielding the crude product as a yellow solid (196.0 g, purity: 94%, chiral purity: 49.7%). The crude product was purified by silica gel chromatography using DCM:ethanol (100:1 to 20:1) to obtain 138.0 g of pure product (purity: 99.5%, chiral purity: 49.7%). The resulting product was then dried to remove the toluene, yielding 125.0 g of a light yellow solid (yield 61.2%, purity: 99.5%, chiral purity: 49.7%).

Synthesis Example 3. Preparation of compound (S)-If.

The compound having the formula (S)-If was prepared in a manner similar to that described above for (S)Ie, where the key difference was the use of 1-iodo-3,5-dichlorobenzene as the starting compound instead of 1-chloro-2-fluoro-5 -iodo-3-(trifluoromethyl)benzene. The method for preparing (S)-If is shown in Scheme 3 below and the detailed procedure for step 3 is given.

ΰ ' F ₃ * 1ι 1 :.ι ci

3-3 cf,

ΝΗ

€)-J

Scheme 3 ft -__ ^sg a THF, i-PrMgCI no o N 1)

[ oh oh ! 1 ' g ¹ 2-4 % ¹ g

3-5

2-Me-THF. mop screen

NHjQH, NaOH I | ^f -J- _F

THF, from Odo 5° C I _r . _τ _.'| (S)-lf ci

Stage 3.

Dichloromethane (150 ml, 30 vol.) and intermediate 3-5 (5.0 g, 8.66 mmol, 1.0 eq.) were charged into a 500 ml 3-neck flask and stirred for 10-30 min to dissolve the solid precipitate . The solution was then cooled to 0-5°C and chiral phase transfer catalyst 2-6 (0.20 g, 0.026 mmol, 0.03 eq) was added. A solution of NH2OH (50% w/w)/NaOH/H ₂ O (20 ml, 5 vol.) was added dropwise to the resulting solution at 0-5°C for 0.5-1 hour. The reaction mixture was stirred for 2 h at 0-5°C and then a sample was taken to monitor the conversion of the reaction by HPLC, which showed the presence of less than 1% of the starting material. The mixture was allowed to separate and the dichloromethane layer was washed with saturated KH ₂ PO ₄ solution (20 mL, 4 vol.) twice. The organic layer was then washed with saturated sodium chloride solution (20 ml, 4 vol.) twice. The combined organic layers were evaporated in vacuo at 30-40°C, followed by the addition of toluene (20 ml, 4 vol, twice) and evaporation to dryness. Toluene (15 ml, 3 vol.) and the resulting crude product (5.0 g) were charged into a 50 ml 3-neck flask, and the mixture was heated to 6070°C to dissolve the solid precipitate. The resulting mixture was slowly cooled to 45-50°C over 2 hours and filtered. The filter cake was washed with toluene (10 ml, 2 vol.) and the filtrate was dried in a vacuum oven at 40-50°C for 6 hours to obtain the product (2.5 g, yield: 49.0%, purity 99, 4%, chiral purity: 99.3%).

Synthesis example 4. Preparation of compound (Ic), where X ¹ and X ² = Cl, and X ³ = F.

The compound having formula (Ic), where X ¹ and X ² = Cl, and X ³ = F, was prepared using a procedure similar to

- 103 044142 described above in Schemes 2 and 3, where the key difference was the use of 1,3-dichloro-2-fluoro-5iodobenzene as the starting compound instead of 1-chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene . Stage 3 of this process is described in detail below.

Compound 4-5 (5 g, 8.4 mmol, 1.0 eq) and THF (30 mL, 6 vol) were charged into a 100 mL 3-neck flask. The solid was dissolved and added to a mixture of NaOH (1.5 g, 50%, 18.5 mmol, 2.2 eq) and hydroxylamine sulfate (0.6 g, 4.62 mmol, 0.55 eq) at 0 -5°C. The reaction mixture was stirred for 90 minutes and a sample was taken for analysis by HPLC, which showed the presence of less than 1.0% of the original compound. KH2PO4 (1.3 g, 10.9 mmol, 1.3 eq.) was added to the resulting mixture and the mixture was heated to 20-25°C. The mixture was left to separate and the organic layer was separated. THF was removed by distillation, followed by the addition of acetonitrile (20 ml, 4 vol) twice, and then evaporated to dryness. Acetonitrile (20 ml, 4 vol) was added to dissolve the precipitate, and the solution was slowly cooled to 25-30°C and stirred at this temperature for 180 minutes. The precipitate was filtered off and washed on the filter with acetonitrile (10 ml, 2 vol.). The solid residue was dried under vacuum at 30-35°C for 6 hours to give the product (2.1 g, 98.9% purity, 41.2% yield).

Examples of long-acting veterinary injectables.

The long-acting injectable compositions described below were prepared by mixing the following ingredients.

Example of drug 5.

The compound having formula (Ia), 30% (w/v).

Ethanol 9% (w/v).

PEG 400 remaining quantity.

Example of drug 6.

The compound having formula (Ia), 15% (w/w).

PEG 400 85% (w/w).

Example of drug 7.

The compound having formula (Ia), 26% (w/w).

PEG 400 74% (w/w).

Example of drug 8.

The compound having formula (Ia), 26% (w/w).

PEG 400 66% (w/w).

Ethanol 8% (w/w).

Example of drug 9.

The compound having formula (Ia), 26% (w/w).

PEG 400 66% (w/w).

Isopropanol 8% (w/w).

Example of drug 10.

The compound having formula (Ia), 26% (w/w).

PEG 400 64% (w/w).

Capryol 90 10% (w/w).

Example of drug 11.

The compound having formula (Ia), 26% (w/w).

PEG 66% (w/w).

Benzyl alcohol 8% (w/w).

Example of drug 12.

The compound having the formula (S)-Ia, 13% (w/w).

PEG 400 79% (w/w).

Ethanol 8% (w/w).

Example of drug 13:

A compound having the formula Ic, where X ¹ , X ³ = Cl, X ² = F 30% (w/v).

Ethanol 9% (w/v).

PEG 400 remaining quantity.

Example of drug 14.

A compound having formula (Ic), where X ¹ = Cl, X ² = F, X ³ = CF ₃ 30% (w/v).

Ethanol 9% (w/v).

PEG 400 remaining quantity.

Example of drug 15.

- 104 044142

A compound having the formula (S)-Ic, where X ¹ , X ³ = Cl, X ² = F 13% (w/w).

PEG 400 79% (w/w).

Ethanol 8% (w/w).

Example of drug 16.

A compound having the formula (S)-Ic where X ¹ = Cl, X ² = F, X ³ = CF ₃ 13% (w/w).

PEG 400 79% (w/w).

Ethanol 8% (w/w).

Example of drug 17.

A compound having the formula (S)-Ic, where X ¹ , X ³ = Cl, X ² - H 13% (w/w).

PEG 400 79% (w/w).

Ethanol 8% (w/w).

Example of drug 18.

A compound having the formula (S)-Ic, where X ¹ , X ² , X ³ = Cl 13% (w/w).

PEG 400 79% (w/w).

Ethanol 8% (w/w).

Example of drug 19.

A compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 10% (w/v).

Ethanol 8% (w/w).

PEG 400 remaining quantity.

Example of drug 20.

A compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 10% (w/v).

PEG 400 remaining quantity.

Example of drug 21.

A compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 5% (w/v).

PEG 400 remaining quantity.

Example of drug 22.

A compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 10% (w/v).

Ethanol 3% (w/v).

PEG 400 remaining quantity.

Preparation example 23

Compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 5% (w/v)

Ethanol 8% (w/v).

PEG 400 remaining quantity.

Example of drug 24.

A compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 2.5% (w/v).

PEG 400 remaining quantity.

Preparation example 25

Compound having the formula (S)-Ic, X ¹ = Cl, X ² = F, X ³ = CF ₃ 2.5% (w/v)

Ethanol 8% (w/v).

PEG 400 remaining quantity.

Example of drug 26.

A compound having the formula (S)-Ie, 20% (w/v).

Medium chain triglycerides (for example, Miglyol® 812) the rest.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 27.

A compound having the formula (S)-Ie, 10% (w/v).

Medium chain triglycerides (for example, Miglyol® 812) the rest.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 28.

A compound having the formula (S)-Ie, 5% (w/v).

Medium chain triglycerides (for example, Miglyol® 812) the rest.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 29.

The compound having the formula (S)-Ie, 2.5% (w/v).

Medium chain triglycerides (for example, Miglyol® 812) the rest.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 30.

- 105 044142

A compound having the formula (S)-Ie, 20% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 31.

A compound having the formula (S)-Ie 10% (w/v).

PEG 400 remaining quantity.

Medium Chain Triglycerides (e.g. Miglyol® 812) 30% (w/v)

Sorbitan monooleate 0.5% (w/v)

Benzyl alcohol 8% (w/v).

Example of drug 32.

A compound having the formula (S)-Ie, 5% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 33.

The compound having the formula (S)-Ie, 2.5% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 34.

A compound having the formula (S)-Ie, 20% (w/v).

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) remaining quantity.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 35.

A compound having the formula (S)-Ie 10% (w/v).

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) remaining quantity.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 36.

A compound having the formula (S)-Ie, 5% (w/v).

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) remaining quantity.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 37.

The compound having the formula (S)-Ie, 2.5% (w/v).

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) remaining quantity.

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 38.

A compound having the formula (S)-Ie, 20% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 39.

A compound having the formula (S)-Ie, 10% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 40.

A compound having the formula (S)-Ie, 5% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

- 106 044142

Example of drug 41.

The compound having the formula (S)-Ie, 2.5% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Benzyl alcohol 8% (w/v).

Example of drug 42.

A compound having the formula (S)-Ie, 20% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 43.

A compound having the formula (S)-Ie, 10% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 44.

A compound having the formula (S)-Ie, 5% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 45.

The compound having the formula (S)-Ie, 2.5% (w/v).

PEG 400 remaining quantity.

Propylene glycol dicaprylate/dicaprate (e.g. Miglyol® 840) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 46.

A compound having the formula (S)-Ie, 20% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 47.

A compound having the formula (S)-Ie, 10% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 48.

A compound having the formula (S)-Ie, 5% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example of drug 49.

The compound having the formula (S)-Ie, 2.5% (w/v).

PEG 400 remaining quantity.

Medium chain triglycerides (e.g. Miglyol® 812) 30% (w/v).

Sorbitan monooleate 0.5% (w/v).

Example 50. Viscosity of long-acting preparations.

The viscosity of the formulations of Examples 19-25 was measured to determine their suitability for injection. Polyethylene glycol 400 (PEG 400) was used as a reference sample. The following conditions were used for measurements:

device: LVDV-E Brookfield viscometer;

spindle: S31;

speed: 60 revolutions per minute (rpm);

temperature: 25°C;

sample volume: 9.0 ml;

measurement time: 2-3 min.

- 107 044142

The viscosity of each of the compositions from examples 18-24 allows these compositions to be used for injection.

Examples of performance evaluation.

Example 51. Efficacy of an injectable drug against Rhipicephalus (Boophilus) microplus ticks.

The effectiveness of long-acting injectable compositions of the present invention containing compounds of formula (Ie) and (S)-Ie against Rhipicephalus microplus ticks on cattle was determined in comparison with a control group that was not administered any drugs. The effectiveness of compositions containing compounds (Ie) and (S)-e was also compared with injectable compositions containing afoxolaner (formula Ia, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5dihydro-5 -(trifluoromethyl)-3-isoxazolyl]-K-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1naphthalenecarboxamide) and comparative compounds having the following formulas (If) and (S )-If.

Each compound was formulated into an injectable formulation at a concentration of 10% (w/v) in a vehicle containing 8% (w/v) ethanol and polyethylene glycol 400 (the remainder). The racemic compounds afoxolaner and (If) were administered at a dosage of 1.0 mg/kg body weight, and the (S)-enantiomers ((S)-Ie and (S)-If) were administered at a dosage of 0.5 mg/kg body weight. There were six healthy cattle in each group. Cows in group 1 were not administered any treatment (untreated control). Cows in groups 2, 3, 4, 5 and 6 were administered subcutaneously on day 0 with injectable compositions containing compounds having the formula Ie, (S)-If, (S)-Ie, afoxolaner (Ia) and (If), respectively. Several weeks before treatment, cows were infested three times a week with approximately 2500 Rhipicephalus microplus larvae to establish a stable infestation. Each animal was infected with approximately 5000 R. microplus larvae on days 7 and 21 and every 14 days thereafter. Ticks that fell off each animal in the previous 24 h were collected daily and counted from day 1 until the end of the study. When the effect of treatment in groups 3, 5 and 6 was significantly reduced, cows from these groups were not further infected.

In table 1A, 1B and 1C below show, expressed in total mite numbers, the percentage of effectiveness of injectable compositions containing compounds ((Ie) and (S)-Ie) of the present invention against R. microplus for some days up to day 110 after treatment , compared to an untreated control group and isoxazoline comparators. As follows from the data given in table below. 1A, 1B and 1C, compositions containing compounds (Ie) and (S)-Ie of the present invention, at a dosage of 1.0 and 0.5 mg/kg, respectively, provide unexpected effectiveness against Rhipicephalus microplus ticks over an extended period of time, compared with

- 108 044142 compositions containing afoxolaner, (If) or (S)-If. In addition, the effect of compounds (1e) and (S)-Ie occurs faster than from compositions containing other isoxazoline compounds. The higher efficacy of compounds (1e) (racemate) and (S)-Ie against R. microplus mites is unexpected and unpredictable.

Table 1A

Efficacy against Rhipicephalus microplus expressed in mite numbers

Group Average % efficiency (by number of mites) Day Day Day 5 10 20 Day 30 Day Day 40 49 Day 55 Group 2 (1e) 69 100 100 100 100 100 100 Group 3 ((S)-If) 39 27 33 86 100 36 0 Group 4 ((S)-Ie) 66 93 100 100 100 100 100 Group 5 afoxolaner 38 48 77 99 100 94 73 Group 6 (If) 70 62 57 84 100 70 14 Table 1B Efficacy against Rhipicephalus microplus, expressed in the number of ticks Group Average % efficiency (by number of mites) Day Day Day Day Day Day 60 65 70 75 80 85 Day 88 Group 2 (1e) 100 100 100 100 100 100 100 Group 3 ((S)-If) - - - Group 4 ((S)-Ie) 100 100 100 100 100 90 88 Group 5 afoxolaner 71 48 3 0 - - Group 6 (If) - - - Table 1C Efficacy against Rhipicephalus microplus, expressed in the number of ticks Group Average % efficiency (by number of mites) Day 95 Day 100 Day 105 Day 110 Group 2 (1e) 100 100 93 82 Group 3 ((S)-If) - - - Group 4 ((S)-Ie) 92 88 76 65 Group 5 afoxolaner - - Group 6 (If) - - -

Example 52. Efficacy of long-acting injectable compositions against Haematobia irritans (small cow fly) in cattle.

The effectiveness of a long-acting injectable composition containing a compound having the formula (S)-Ie against cow's fly in cattle was evaluated. Two groups of 15 cows each were selected for the study and randomly assigned to one of two groups. Cows in Group 1 were not subjected to any treatment, and cows in Group 2 were administered a long-acting composition of the present invention containing 10% (w/v) of a compound having the formula (S)-Ie in a vehicle containing 8% (w/v). ./vol.) ethanol in PEG 400 (the remaining amount). The composition was administered to cows in group 2 at a dosage of 0.25 ml/50 kg body weight. Each animal was naturally infected with a small cow fly and the number of flies was counted on days -2, 3, 7, 10, 13, 16, 20, 23, 27, 30, 34, 37, 43, 45 and 48. Table. 2A and 2B below show the number of small cowbirds and the % reduction in their number in the treatment group compared to the control group.

Table 2A

Arithmetic mean of small numbers cow burners Group and % reduction Day Day Day Day Day Day Day Day 3 7 10 13 16 20 23 27 Group 1 (control) 254.3 136.0 78.3 60.0 104.7 83.0 53.3 59.3 Group 2 ((S)-Ie) 26.7 35.0 16.0 22.0 44.7 36.0 3.7 22.7 % reduction 89.5 74.3 79.6 63.3 57.3 56.6 42.5 61.8 Table 2B Arithmetic mean of small numbers cow Group zhigalok and % decrease Day Day Day Day . Day Day 48 thirty 34 37 43 45 Group 1 (control) 71.0 47.7 73.3 43.0 66.7 44.0 Group 2 ((S)-Ie) 23.0 26.3 28.0 26.0 43.0 30.3 % reduction 67.6 44.8 61.8 39.5 35.5 31D

Although various embodiments of the present invention have been described in detail, it should be understood that the present invention as described above is not limited to the particular details set forth in the description, as many obvious variations are possible without departing from the spirit and scope of the present invention.

- 109-

Claims (25)

CLAIM 1. A long-acting injectable composition for the treatment or prevention of parasitic infection or parasite infestation in an animal, containing: a) an effective amount of at least one parasiticidal isoxazoline active substance, which is a compound having formula (Ic): or a pharmaceutically acceptable salt thereof; where X ¹ , X ² and X ³ are each independently halogen, C1- _C3 alkyl or C1-C3haloalkyl; And b) neutral oil, which is selected from triglycerides of fractionated vegetable fatty acids with a chain length from C ₈ to C ₁₀ . 2. The long-acting injectable composition according to claim 1, further containing at least one co-solvent. 3. Long-acting injectable composition according to any one of claims 1 or 2, additionally containing an antioxidant. 4. Long-acting injectable composition according to any one of claims 1 to 3, where the isoxazoline active substance is enriched with one enantiomer. 5. Long-acting injectable composition according to claim 4, where the isoxazoline active substance is a compound having the formula (S)-Ic: where X ¹ , X ² and X ³ independently represent a chlorine atom, a fluorine atom or CF ₃ ; or a pharmaceutically acceptable salt thereof. 6. Long-acting injectable composition according to any one of claims 2-5, containing a co-solvent consisting of a C1-C6 alcohol, glycol ether, glycerin, propylene glycol, cyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide, dimethyl acetamide, dimethyl sulfoxide or glycerol formal or a combination thereof. 7. A long-acting injectable composition according to any one of claims 2-5, containing a co-solvent consisting of benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, lipid, C ₈ -C ₁₀ triglyceride, C ₈ -C ₁₀ triglyceride in combination with linoleic acid, C ₈ -C ₁₀ triglyceride in combination with succinic acid, propylene glycol diester with C ₈ -C ₁₀ fatty acids, castor oil, cottonseed oil, sesame oil, soybean oil or safflower oil, or a combination thereof. 8. Long-acting injectable composition according to any one of claims 2-5, containing a co-solvent consisting of ethanol, isopropanol or benzyl alcohol or a mixture thereof. 9. Long-acting injectable composition according to any one of claims 1 to 8, further containing a pharmaceutically acceptable excipient, which is a surfactant. 10. The long-acting injectable composition according to claim 9, where the surfactant is selected from the group consisting of glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan monooleate, polyvinyl alcohol, polysorbate 20, polysorbate 80, d-αtocopherol polyethylene glycol 1000 succinate, sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide, polyethylene glycol derivatives of castor oil, propylene glycol monolaurate, glycerin caprylate/caprate, polyglycosylated glycerides, PEG 300 caprylic/capric glycerides, PEG 400 caprylic/capric glycerides, PEG 3 00 oleic glycerides, PEG 300 linoleic glycerides, polyethylene glycol stearates and polyethylene glycol hydroxystearates or combinations thereof. 11. Long-acting injectable composition according to claim 1, containing: a) from 0.5 to 30% (w/v) isoxazoline compounds having formula (Ic): - 110 044142 or a pharmaceutically acceptable salt thereof; wherein X ¹ , X ² and X ³ are each independently halogen, C ₁ -C ₃ alkyl or C 1 -C 3 haloalkyl; And b) neutral oil, which is selected from triglycerides of fractionated vegetable fatty acids with a chain length from C ₈ to C ₁₀ ; where the neutral oil is present in the composition in an amount that complements the composition of the composition to 100%. 12. Long-acting injectable composition according to claim 11, where: X ¹ represents Cl; X ² represents F; and X ³ is -CF ₃ . 13. Long-acting injectable composition according to any one of claims 1 to 12, further containing an effective amount of at least one additional active substance. 14. The long-acting injectable composition according to claim 13, wherein the additional pharmaceutically active substance is a macrocyclic lactone, a neonicotinoid active substance, a 1-X-arylpyrazole active substance, a cyclic depsipeptide, a benzimidazole, an imidazothiazole, a tetrahydropyrimidine active substance, an organophosphate active substance, levamisole, paraherquiamide, marcfortine, praziquantel, closantel, pyrantel, morantel, clorsulon, spinosyn, spinozoid active substance, aminoacetonitrile active substance, aryloazol-2-yl cyanoethyl active substance or insect growth regulator. 15. The long-acting injectable composition according to claim 14, wherein the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, moxidectin or nemadectin. 16. A long-acting injectable composition according to claim 1 for the treatment or prevention of parasite infestation in an animal in need thereof, providing treatment or prevention of parasite infestation for a period of 3 to 6 months. 17. The long-acting injectable composition according to claim 16, wherein the animal is a dog, cat, small ruminant or cattle. 18. A long-acting injectable composition according to claim 16, wherein treatment of an animal against parasites or prevention of parasite infection in an animal is provided for a period of 5 to 6 months. 19. Long-acting injectable composition according to claim 16, wherein the parasites are fleas and/or ticks. 20. Pesticidal and parasiticidal isoxazoline compound having formula (Ie): or a pharmaceutically or agriculturally acceptable salt thereof. 21. Pesticidal and parasiticidal isoxazoline compound having the formula (S)-Ie: or a pharmaceutically or agriculturally acceptable salt thereof. 22. A veterinary parasiticidal composition comprising an effective amount of a compound having formula (Ie) as defined in claim 20, or a compound having formula (S)-Ie as defined in claim 21, in combination with a pharmaceutically acceptable carrier. 23. A pesticide composition for controlling pests damaging plants, plant propagation material, crops or materials derived from wood, containing an effective amount of a compound having formula (Ie) as defined in claim 20, or a compound having formula (S )-Ie, as defined in claim 21, in combination with an agriculturally acceptable carrier. 24. Use of a compound of formula (Ie) as defined in claim 20, or a compound of formula (S)-Ie as defined in claim 21, for the treatment or prevention of parasite infestation in an animal. - 111 044142 25. A method for controlling pests damaging plants, plant propagation material, crops or materials derived from wood, comprising applying an effective amount of a compound having formula (1e) as defined in claim 20, or a compound having formula (S) -Ie, as defined in paragraph 21, to plants, soil in which plants grow, plant propagation material, crops or material derived from wood. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 112 -