WO2015132592A1

WO2015132592A1 - Novel isoxazolines and their use in controlling pests

Info

Publication number: WO2015132592A1
Application number: PCT/GB2015/050635
Authority: WO
Inventors: Seamus MCCOOEY; Andrzej Manikowski
Original assignee: Norbrook Laboratories Limited
Priority date: 2014-03-06
Filing date: 2015-03-05
Publication date: 2015-09-11
Also published as: GB201403980D0; GB2523811A

Abstract

Disclosed herein are novel isoxazoline compounds of the general formula (I), compositions comprising these novel compounds, and uses of these compounds in the control of pests in both animal health and plant protection contexts. The compounds can be combined with other biologically active materials such as organophosphate pesticides, carbamate -type pesticides, organochlorine type pesticides, pyrethrins/pyrethroids, neonicotinoids, avermectins, milbemycins, benzimidazoles, salicylanilides, substituted phenols, pyrimidines, tetrahydropyrimidines, imidazothiazoles, amino/amido acetonitrile derivatives, febantel, clorsulon, levamisole, morantel, and praziquantel, juvenile hormone mimics and chitin synthesis inhibitors. (I)

Description

NOVEL ISOXAZOLINES AND THEIR USE IN CONTROLLING PESTS

Field of the Invention

[0001] Disclosed herein are novel isoxazoline compounds, compositions comprising these novel compounds, and uses of these compounds in the control of pests in both animal health and plant protection contexts.

Background to the Invention

[0002] Effective management of plant and animal pest populations is of critical importance in inter alia forestry, agriculture, and animal health. Invertebrate pests can cause massive losses in crop production/yield, and can deleteriously affect the health of both livestock and companion animals.

[0003] Many different classes of chemical compounds are utilised in the treatment of plant and animal invertebrate pests. One such class of compounds are the isoxazolines. Examples of suitable isoxazoline compounds are disclosed in European Patent Application No. EP1731512 to Nissan Chemical Industries Limited and International Patent Application Publication Nos. WO2007079162 and WO2009002809 to DuPont.

[0004] Notwithstanding the state or the art there remains a need for new pesticidal compounds to which resistance has yet to evolve, and that are, for example, more effective, less costly, less toxic, environmentally safer, etc. than existing compounds.

Summary of the Invention

[0005] In a first aspect the present invention provides for a compound of the general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an N- oxide thereof, or a solvate thereof,

wherein:

A is a tricyclic fused aryl or heteroaryl ring system;

p is 0-6;

each R¹ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyl, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆ b/^'sfalkyOsulfonamido, C C₆ bis(haloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(Ci-C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, and nitro; or

where two R¹ substituents are on adjacent atoms, each R¹ and the atom to which they are attached may form a 5-6 membered ring selected from the group consisting of an aliphatic ring, an aryl ring, a heteroaliphatic ring, and a heteroaryl ring wherein each is optionally substituted with one or more R⁸;

R² is selected from the group consisting of SF₅, S(C C₆ alkyl), S(C₂-C₆ alkenyl), S(C₂-C₆ alkynyl), C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyi, C₄-C₇ alkylcycloalkyi, and C₄-C₇ cycloalkylalkyl, wherein each is optionally substituted with one or more substituents independently selected from R⁴;

q is 0-5;

B is selected from the group consisting of a phenyl ring, a 6 membered heteroaryl ring, thiophene, and furan;

each R³ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyi, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆

b/^'salkylsulfonamido, C C₆ £>/s(haloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(Ci-C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, and nitro; or

where two R³ substituents are on adjacent carbons, each R³ and the carbon to which they are attached may form a 5-6 membered ring selected from the group consisting of an aliphatic ring, an aryl ring, a heteroaliphatic ring, and a heteroaryl ring wherein each is optionally substituted with one or more R⁸;

R⁴ is selected from the group consisting of halogen, OH, SH, NH₂, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, NH(C C₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), SF₅, SCN, cyano, and nitro;

Q is selected from the group consisting of C(W)NR⁵R⁶, a 3-6 membered heterocyclic ring optionally substituted with one or more R⁷, a C₃-Ci₂ fused or unfused carbocyclic ring system optionally substituted with one or more R⁷, and an 8-12 membered fused heterocyclic ring system optionally substituted with one or more R⁷;

Wis O orS;

R⁵ is selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyi, C₄-C₇ alkylcycloalkyi, C₄-C₇ cycloalkylalkyi, C₂-C₇ alkylcarbonyl and C₂-C₇ alkoxycarbonyl;

R⁶ is selected from the group consisting of H, 0(d-C₆ alkyl), NH(C C₆ alkyl), N(C C₆ alkyl)(C C₆ alkyl), C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyi, C₄-C₇ cycloalkylalkyi, CH=NO(CrC₆ alkyl),

alkynyl), CH=NO(C₅-C₁₂ aryl), and CH=NO(C₃-Cn heteroaryl), C₅-C₁₂ aryl, C₃-Cn heteroaryl, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇

haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl;

each R⁷ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyi, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆

b/^'sfalkyOsulfonamido, C C₆ £>/s(haloalkyl)sulfonamido, NH(Ci-C₆ alkyl), N(C C₆ alkyl)₂, NH(Ci-C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, or nitro; or

where two R⁷ substituents are on adjacent atoms, each R⁷ and the atom to which they are attached may form a 5-6 membered ring selected from the group consisting of an aliphatic ring, an aryl ring, a heteroaliphatic ring, and a heteroaryl ring wherein each is optionally substituted with one or more R⁸; and

each R⁸ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyi, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆

b/^'sfalkyOsulfonamido, C C₆ £>/s(haloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, or nitro. [0006] With reference to the compound of the present invention, the variable R² may be selected from the group consisting of C C₆ alkyi, S(C C₆ alkyi), and SF₅ wherein each is optionally substituted with one or more substituents independently selected from R⁴.

[0007] R⁴ may be selected from the group consisting of halogen, OH, SH, NH₂, SF₅, SCN, cyano, and nitro. Suitably, R⁴ may be selected from the group consisting of halogen and SF₅.

[0008] For example, R² may be C C₆ alkyi optionally substituted with a halogen, or SF₅. In one embodiment, R² is CF₃.

[0009] The ring B may be a phenyl ring, or a 6 membered heteroaryl ring. For example, the compound of the present invention la (II):

wherein

A, p, R¹ , R², R³, R⁴, Q, W, R⁵, R⁶, and R⁷ are as defined above;

B¹ , B² and B³ are the same or different and are independently selected from the group consisting of CR³ and N; and

each R^3' is independently of the other H or R³.

[0010] The tricyclic fused ring system A may be a carbocyclic, tricyclic fused aromatic ring system. For example, the ring A may be selected from the group consisting of:

wherein R¹ and p are as defined above.

[0011] The ring A may be:

[0012] With reference to the compound of the present invention, in a preferred embodiment, Q is C(W)NR⁵R⁶.

[0013] With reference to the compound of the present invention, R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl. For example, R⁵ may be selected from the group consisting of H, and C C₆ alkyl. In one embodiment, R₅ is H.

[0014] R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyi, wherein each is optionally substituted with at least one of a halogen, hydroxy, Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C3-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl. For example, R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl.

Suitably, R⁶ may be selected is C C₆ alkyl optionally substituted with at least one of a halogen, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl.

[0015] R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, and R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyi, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl.

[0016] R⁵ may H, and R⁶ may be selected from the group consisting of C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄- C₇ cycloalkylalkyi, wherein each is optionally substituted with at least one of a halogen, hydroxy, Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl.

[0017] R⁵ may H, and R⁶ may be C C₆ alkyl optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl. [0018] R⁵ may H, and R⁶ may be C C₆ alkyl optionally substituted with at least one of a halogen, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl.

[0019] R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, and R² may be selected from the group consisting of C C₆ alkyl, S(C C₆ alkyl), and SF₅, wherein each is optionally substituted with one or more substituents independently selected from R⁴.

[0020] R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-Cg dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be selected from the group consisting of C C₆ alkyl, S(C C₆ alkyl), and SF₅, wherein each is optionally substituted with one or more substituents independently selected from R⁴.

[0021] R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,

R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be selected from the group consisting of C C₆ alkyl, S(C C₆ alkyl), and SF₅, wherein each is optionally substituted with one or more substituents independently selected from R⁴.

[0022] R⁵ may H,

R⁶ may be selected from the group consisting of C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be selected from the group consisting of C C₆ alkyl, S(C C₆ alkyl), and SF₅, wherein each is optionally substituted with one or more substituents independently selected from R⁴.

[0023] R⁵ may H,

R⁶ may be C C₆ alkyl optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃- C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be selected from the group consisting of C C₆ alkyl, S(C C₆ alkyl), and SF₅, wherein each is optionally substituted with one or more substituents independently selected from R⁴

[0024] R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, and R² may be C C₆ alkyl optionally substituted with a halogen, or SF₅.

[0025] R⁶ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyl, C₄-C₇

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy,

Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl,

C3-C9 dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C3-C9 halodialkylaminocarbonyl, and R² may be C C₆ alkyl optionally substituted with a halogen, or SF₅.

[0026] R⁵ may be selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be C C₆ alkyl optionally substituted with a halogen, or SF₅.

[0027] R⁵ may H,

cycloalkylalkyl, wherein each is optionally substituted with at least one of a halogen, hydroxy, Ci-C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be C C₆ alkyl optionally substituted with a halogen, or SF₅.

[0028] R⁵ may H,

R⁶ may be C C₆ alkyl optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, Cs- Cg dialkylaminocarbonyl, C₂-C₇ haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl, and R² may be C C₆ alkyl optionally substituted with a halogen, or SF₅.

[0029] With reference to the compound of the present invention, the integer p may be 0. For example, the compound of the present invention may be of the general formula (III):

wherein R², R³, R⁴, R⁵, and R⁶ are as defined above. [0030] In one embodiment, the compound of the invention is of the general formula (IV)

wherein R², each R³ , and R⁴ are as defined above.

[0031] In a further embodiment, R³ may be selected from the group consisting of a halogen and CF₃.

[0032] For example, the compound of the invention may be selected from the group consisting

[0033] It will be appreciated by those of skill in the art that certain compounds of the invention may exist and be isolated in optically active and racemic forms. Compounds having one or more chiral centers, including at a sulfur atom, may be present as single enantiomers or

diastereomers or as mixtures of enantiomers and/or diastereomers. The present invention encompasses the specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and/or diastereomers of the compounds of the invention that possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution.

[0034] The compounds within the compositions of present invention may also be present in different solid forms such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms as well as amorphous forms of the inventive compounds.

[0035] In addition, the compounds within the compositions of the invention may exist as hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in the crystalline form. The compositions of the invention may include hydrates and solvates of the active agents.

[0036] In a further aspect, the present invention provides for a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient. The formulations according to the invention are effective for long durations of time in the treatment of parasites of mammals and, in particular, of fleas and ticks in small mammals such as dogs and cats.

[0037] The compounds of the present invention may be present in the compositions at a concentration of about 0.1 to about 40% (w/w). In another embodiment, the concentration of the isoxazoline compound(s) is about 0.1 to about 30% (w/w). In some embodiments of the invention, the isoxazoline agents are present in the composition at a concentration from about 1 to about 25% (w/w), about 1 to about 20% (w/w), about 1 to about 10% (w/w), about 1 to about 5% (w/w), or about 1 to about 3% (w/w). In still other embodiments, the compounds of the present invention are present in a concentration of about 0.1 to about 5% (w/w), about 0.5 to about 5% (w/w), about 0.5 to about 3% (w/w) or about 1 to about 3% (w/w) in the composition. In further embodiments, the compounds of the present invention are in a relatively higher concentration in the formulations, including about 5% (w/w) to about 15% (w/w), about 10% (w/w) to about 20% (w/w), about 10% (w/w) to about 15% (w/w) or about 15% (w/w) to about 20% (w/w) in the composition.

[0038] In addition to the compound of the present invention, the pharmaceutical compositions of the present invention may comprise a second biologically active compound selected from the group consisting of:

Pesticides/insecticides, such as organophosphate pesticides, carbamate -type pesticides, organochlorine type pesticides, pyrethrins/pyrethroids, and neonicotinoids;

Anthelminthics, such as avermectins, milbemycins, benzimidazoles, salicylanilides, substituted phenols, pyrimidines, tetrahydropyrimidines, imidazothiazoles, amino/amido acetonitrile derivatives, febantel, clorsulon, levamisole, morantel, and praziquantel; and Insect Growth Regulators such as Juvenile Hormone Mimics and Chitin synthesis Inhibitors.

[0039] In some embodiments, the combination of certain active agents with a compound of the present invention will expand the therapeutic scope of the compositions of the invention depending on the biological activity of the additional active agent. For example, it is

contemplated that combination of the isoxazoline compounds of the invention with one or more additional active agents that are active against internal parasites such as parasitic nematodes, (including roundworm, hookworm, whipworm and others), and/or Dirofilaria immitis (Heartworm) will provide treatment and/or protection against internal parasites as well as external parasites (e.g. fleas and ticks, etc.).

[0040] Thus, the invention provides a method for the (simultaneous) treatment and/or prevention of an ectoparasitic infestation and an endoparasitic infection, comprising

administering to the animal in need a compound according to the present invention in combination with at least one compound that is active against endoparasites.

[0041] For example, the invention provides a method for treating and/or preventing an endoparasitic infestation and ectoparasitic infection in an animal comprising administering a compound according to the present invention together with an effective amount of at least one of an avermectin or milbemycin.

[0042] Of particular note are combinations of the compounds of the present invention with Anthelminthics, and/or Insect Growth Regulators. In particular, combinations of the compounds of the present invention with an avermectin or a milbemycin are desirable. For example, the compounds of the present invention may be combined with at least one of an avermectin or a milbemycin, and praziquantel.

[0043] The avermectins and milbemycins are potent macrocyclic lactone endectocides.

Examples include abamectin, doramectin, moxidectin, selamectin, ivermectin, milbemycin, milbemycin oxime, emamectin, and eprinomectin.

[0044] Suitable combinations include a compound of the present invention, and:

Eprinomectin, and praziquantel;

Selamectin, and praziquantel;

Ivermectin, and praziquantel;

Milbemycin Oxime, and praziquantel; and

Moxidectin, and praziquantel.

[0045] Benzimidazoles include thiabendazole, oxfendazole, oxibendazole, mebendazole, fenbendazole, albendazole, and triclabendazole.

[0046] Salicylanilides include closantel and oxyclozanide.

[0047] Tetrahydropyrimidines include praziquantel.

[0048] Substituted phenols include nitroxynil. [0049] Pyrimidines include pyrantel.

[0050] Imidazothiazoles include levamisole.

[0051] Cyclooctadepsipeptides include emodepside.

[0052] Amino acetonitrile derivatives include monepantel.

[0053] Insect growth regulators compatible with the compositions of the present invention include agridyne, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, chlorfluazuron, cyromazine, diflubenzuron, fluazuron, fluey cloxuron, flufenoxuron, hexaflumuron, ifenuron, novaluron, tebufenozide, and triflumuron.

[0054] The compounds of the present invention may also be formulated with other biologically active compounds selected from the group consisting of acephate, acetamiprid, acetoprole, amitraz, amidoflumet, avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, bistrifluron, buprofezin, carbofuran, cartap, chlorfenapyr, chlorfluazuron,

chlorantraniliprole, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyflumetofen, cyfluthiin, β-cyfluthrin, cyhalothrin, γ-cyhalothrin, λ-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, tau- fluvalinate, flufenerim, flufenoxuron, fonophos, halofenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, metofluthrin,

monocrotophos, methoxyfenozide, monocrotophos, nitenpyram, nithiazine, novaluron, noviflumuron, oxamyl, parathion, parathionmethyl, permethrin, phorate, phosalone, phosmet, phosphamidori, pirimicarb, profenofos, profluthrin, protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon, and triflumuron

[0055] The compounds of the present invention may also be formulated with corticosteroid antiinflammatory agents such as beclomethasone dipropionate, betamethasone diproprionate, betamethasone valerate, budesonide, ciclesonide, deflazacort, dexamethasone, fluocinolone acetonide, fluticasone propionate, fluticasone furoate, loteprednol, etabonate, mometasone, and mometasone furoate, methylprednisolone, prednisolone, prednisone, rofleponide, and triamcinolone acetonide.

[0056] The compounds of the present invention may also be formulated with non-steroidal antiinflammatory drugs ("NSAIDs") such as salicylates, arylalkanoic acids, 2-arylpropionic acids, N- arylanthranilic acids, pyrazolidine derivatives, oxicams, COX-2 inhibitors, sulphonanilides, and licofelone. [0057] The pharmaceutical compositions of the present invention may be administered by conventional means, such as by:

enteral administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories;

parenteral administration, such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal), or implants;

shaped articles such as collars and ear tags;

nasal administration; or by

transdermal or topical administration.

[0058] The compounds of the present invention may be formulated for administration by instant release or sustained release.

[0059] Pharmaceutical compositions for injection may include aqueous solutions of water- soluble forms of active ingredients (e.g., a salt of an active compound), preferably in

physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation.

[0060] Suspensions of the compounds of the present invention may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle.

[0061] When administered by inhalation, the compounds of the invention can be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant. The delivered dosage may be controlled by providing a valve to deliver a metered amount.

[0062] The compounds of the present invention may be delivered orally in the form of solutions, emulsions, suspensions, pastes, gels, capsules, tablets, boluses, powders, granules, and feed/water/lick blocks.

[0063] The compounds of the present invention can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g. , magnesium stearate), disintegrating agents (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid) and dyes or pigments can be added. Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.

[0064] The compositions of the present invention may also be delivered topically in the form of a liquid solution or suspension that comprises a pharmaceutically acceptable carrier or diluent that is suitable for application to the skin of an animal. Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, ready-to-use formulations, spot-on solutions and suspensions. In one

embodiment, the topical compositions will be in the form of a spray formulation, an aerosol or a foam formulation suitable for administration to an animal.

[0065] Particularly preferred topical or dermal formulations are spot-on or pour-on compositions. Topical spot-on and pour-on formulations of the present invention may take the form of solutions, emulsions or suspensions, and are prepared by known techniques in the art.

[0066] Such spot-on and pour-on compositions may contain penetration enhancers to increase the amount of the active that is delivered into the systemic circulation. Suitable penetration enhancers may be selected from the group consisting of dimethylsulfoxide (DMSO),

pyrrolidones, ethanol, propylene glycol, ethyl acetate, dimethylacetamide, laurocapram, fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid and the like; certain fatty acid esters such as isopropyl myristate, methyl noanoate, methyl caprate and others.

[0067] Spreading agents may also be used in the topical compositions of the present invention, and may include isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated C12-C18 fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils, dipropylene glycol methyl ether, and combinations thereof.

[0068] The topical compositions of the present invention may comprise a carrier selected from at least one of carboxylic acid esters, diesters of dicarboxylic acids, fatty acid esters or diesters of fatty diacids, or a combination thereof, including, but not limited to, isopropyl palmitate, isostearyl lactate, diisopropyl adipate, dibutyl adipate, diethyl sebacate, dibutyl sebacate, octyl palmitate, polyethyleneglycol (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 of different 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, diethyleneglycol monoethyl ether, 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 a combination thereof. [0069] In a preferred embodiment, the topical compositions of the invention are dissolved in a pharmaceutically acceptable carrier comprising one or more solvents. In some embodiments of the invention solvents include, but are not limited to, dimethyl isosorbide, glycerol formal, triacetin, liquid polyethyleneglycols including PEG 400, diisopropyl adipate, isopropyl palmitate, silicone fluids including SILICONE FLUID 200, propylene glycol (or other aliphatic dihydric alcohols), benzyl alcohol, propylene glycol esters including propylene glycol

dicaprylate/dicaprate, propylene carbonate, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate and propylene glycol dilaurate, alkyl esters of dicarboxylic acids including diethyl sebacate, diisopropyl sebacate, and esters or diesters of fatty acid, or combinations thereof.

[0070] The compositions of the present invention may also contain excipients that promote the retention of the active agent in the skin of the animal and include mixed esters of sucrose and carboxylic acids including sucrose acetate isobutyrate, low temperature melting waxes, hydrogenated vegetable oils, caprylic/capric glycerides, glycerol esters, including for example, triacetin, glycerol monooleate, glycerol monolinoleate, glycerol stearate, glyceryl distearate and the like, triglycerides, including for example, caprylic, capric/ myristic/ stearic triglyceride, thermoreversible polymers, such as Pluronic and poloxamers, or combination thereofs.

[0071] The topical compositions of the invention may include at least one surfactant. The surfactants may be anionic, cationic, non-ionic or amphoteric surfactants.

[0072] Anionic surfactants include, but are not limited to, alkaline stearates; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulfates; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, and the like.

[0073] Examples of cationic surfactant include, but are not limited to, water-soluble quaternary ammonium salts, e.g. cetyltrimethylammonium bromide and octadecylamine hydrochloride.

[0074] Non-ionic surfactants that may be used in the compositions include, but are not limited to, polyoxyethylenated (PEGylated) esters including, but not limited to, sorbitan esters and fatty acid esters; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, and copolymers of ethylene oxide and propylene oxide including, but not limited to, block copolymers of ethylene oxide and propylene oxide such as poloxamers available under the trade name LUTROL from BASF.

[0075] It will be apparent to those of skill in the art that where the topical compositions of the present invention are in solution form the carrier or diluent of the topical compositions must be able to deliver the active agents to the targeted location without the active agents precipitating from solution or forming crystals. Accordingly, the topical compositions of the invention may include a crystallization inhibitor component in addition to the carrier or diluent. [0076] Crystallization inhibitors which are useful for the invention include but are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, 2-pyrrolidone including N-methylpyrrolidone, dimethylsulfoxide, polyethylene glycols, copolymers of polyoxyethylene and polyoxypropylene, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as polymers derived from acrylic monomers including polyacrylates or polymethacrylates; and, a solvent as described herein that inhibits the crystallization of the active agent, and similar compounds;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium, potassium or ammonium stearate); 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 dioctyl sulphosuccinate; or fatty acids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammonium salts;

(d) non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, e.g.

Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate,

polyoxyethylenated derivatives of castor oil including hydrogenated castor oil and its derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide;

(e) amphoteric surfactants, or

(f) combinations thereof.

[0077] In another aspect of the invention, the pharmaceutical composition of the present invention may be formulated into a chewable product, e.g. a chewable treat/tablet.

[0078] In addition to the compounds of the present invention, the chewable products of the invention may include one or more of the following components: a solvent or mixture of solvents, one or more fillers, 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.

[0079] The chewable product may comprise a forming agent or binder to provide texture to the chew product, like for example polyethylene glycol (PEG), microcrystalline wax, cetyl alcohol or polyvinylpyrrolidone (PVP). For example, the forming agent may be polyethylene glycol (PEG). Moreover, depending upon the desired consistency of the soft chew, different molecular weight PEG may be utilized, e.g. PEG600, PEG3500, PEG8000.

[0080] Other suitable binders that may be used in the chewable compositions of the invention include, but are not limited to, polyvinylpyrrolidone (e.g. Povidone), cross-linked

polyvinylpyrrolidone (Crospovidone), polyethylene glycols of various grades including PEG 3350, PEG 4000, PEG 6000, and PEG 8000; co-polymers of vinylpyrrolidone and vinyl acetate (e.g. Copovidone); starch such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and sugars of various types; or a combination of two or more binders.

[0081] The chewable product may comprise a solvent. Examples of solvents are pyrrolidone solvents, such as 2-pyrrolidone, and /V-methylpyrrolidone, dimethyl acetamide (DM AC), dimethyl sulfoxide, dimethylformamide, diethylene glycol monoethyl ether, ethyl lactate, ethylene monomethyl ether, glycofurol, and combinations thereof.

[0082] Other solvents that may be employed in the compositions of the present invention include liquid polyethylene glycols (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, caprylic/capric/succinic triglyceride, propylene glycol dicaprylate/dicaprate, and the like; water, sorbitol solution, glycerol caprylate/caprate and polyglycolized glycerides, and combinations thereof.

[0083] In a further aspect, the present invention provides for a method of treating and/or preventing parasitoses of an animal comprising administering an effective amount of a compound according to the present invention to the animal.

[0084] The compounds of the invention may be administered continuously in multiple small doses or in a single large dose for treatment or prevention of parasitic infections or infestations. In this manner, the compounds of the invention deliver an effective amount of the active compounds to the animal in need thereof to control the target parasites.

[0085] In yet a further aspect, the present invention relates to a method of treating a parasitic infection in an environment or area that is occupied (periodically or continuously) by an animal comprising treating the environment or area occupied by the animal with effective amount of a compound of the present invention. In some such embodiments, for example, the animal is a companion animal (e.g., a cat or dog). The environment may be, for example, a house or other shelter, a room, a pen, a stall, or other confinement means, bedding, etc.

[0086] Where suitable, it will be appreciated that all optional and/or preferred features of one embodiment of the invention may be combined with optional and/or preferred features of another/other embodiment(s) of the invention.

Definitions

[0087] The words "comprises/comprising" and the words "having/including" when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. [0088] The term "parasitic insect- and acarid" refers to ectoparasites that commonly infest or infect animals. Examples of such ectoparasites include the egg, larval, pupal, nymphal and adult stages of lice, fleas, mosquitoes, mites, ticks, and biting or nuisance fly species.

[0089] The formulations of the present invention are especially suitable for combating parasites that infest animals (including humans). Animal subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Of particular note to the present invention are domesticated dogs and cats.

[0090] As used herein, the term "pharmaceutical" includes veterinary and animal health applications.

[0091] As used herein, the term "w/w" designates weight/weight, the term "w/v" designates weight/volume, % w/w and % w/v represent the percentage by weight or volume respectively of an ingredient in the product.

[0092] As used herein, the term C_x-C_y aliphatic refers to linear, branched, saturated and unsaturated hydrocarbon chains comprising C_x-C_y carbon atoms (and includes C_x-C_y alkyl, C_x-C_y alkenyl and C_x-C_y alkynyl). Similarly, references to C_x-C_y alkyl, C_x-C_y alkenyl and C_x-C_y alkynyl include linear and branched C_x-C_y alkyl, C_x-C_y alkenyl and C_x-C_y alkynyl

[0093] As used herein, the term "C_x-C_y cycloaliphatic" refers to unfused, fused, spirocyclic, polycyclic, saturated and unsaturated hydrocarbon rings comprising C_x-C_y carbon atoms (and includes C_x-C_y cycloalkyl, C_x-C_y cycloalkenyl and C_x-C_y cycloalkynyl).

[0094] The terms heteroaliphatic and heterocycloaliphatic embrace compounds of the above definitions, but where the carbon atoms of the hydrocarbon chains and hydrocarbon rings, respectively, are interspaced one or more times with at least one O, N or S.

[0095] As used herein, the term aryl/aromatic refers to an aromatic carbocyclic structure which, when stated to be, is monocyclic or polycyclic, and unfused or fused.

[0096] As used herein, the term heterocycle refers to cyclic compounds having as ring members atoms of at least two different elements. Where stated, the heterocyclic compounds may be monocyclic or polycyclic, and unfused or fused.

[0097] As used herein, the term heteroaromatic/heteroaryl refers to an aromatic heterocyclic structure having as ring members atoms of at least two different elements. Where stated, the heterocycle may be monocyclic or polycyclic, and unfused or fused.

[0098] The term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted by one or more halogen atoms. The term "haloalkenyl" refers to an alkenyl group, as defined herein, which is substituted by one or more halogen atoms. The term "haloalkynyl" refers to an alkynyl group, as defined herein, which is substituted by one or more halogen atoms. [0099] The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above. Similarly, the terms "haloalkylthio," "cycloalkylthio," and the like, refer to haloalkyl-S- and cycloalkyl-S- where haloalkyl and cycloalkyl are as defined above.

[00100] The term "alkylsulfinyl" refers to alkyl-S(O)-, wherein alkyl is as defined above.

Similarly, the term "haloalkylsulfinyl" refers to haloalkyl-S(O)- where haloalkyl is as defined above.

[00101] The term "alkylsulfonyl" refers to alkyl -S(0)2-, wherein alkyl is as defined above.

Similarly, the term "haloalkylsulfonyl" refers to haloalkyl -S(0)2- where haloalkyl is as defined above.

[00102] The term alkylamino and dialkylamino refer to alkyl-NH- and (alkyl)₂N- where alkyl is as defined above. Similarly, the terms "haloalkylamino" refers to haloalkyl-NH- where haloalkyl is as defined above.

[00103] The terms "alkylcarbonyl," "alkoxy carbonyl," "alkylaminocarbonyl," and

"dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino- C(O)- where alkyl, alkoxy, alkylamino and dialkylamino are as defined 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 are as defined above.

[00104] As used herein the term "chewable product" is intended to mean a product which is solid at room temperature and that is soft to chew and which is functionally chewy because the product has some plastic texture during the process of mastication in the mouth.

[00105] The term "parasitoses" includes infestations and pathologic conditions and diseases associated with or caused by one or more ectoparasites directly, for example, anemia and flea allergy dermatitis. It also includes pathologic conditions or diseases associated with caused by one or more vector-transmitted pathogens.

[00106] The expression "effective amount" as used herein means a concentration of the active agent sufficient to elicit the desired biological response to the target parasite(s) after

administration to the animal, as measured by methods known in the art. In some embodiments, an "effective amount" of the active agent in the composition will provide an efficacy of at least 70% against the target parasite compared to an untreated control. In other embodiments, "an effective amount" of the active agent will provide an efficacy of at least 80%, or at least 85% compared to untreated controls. More typically, "an effective amount" of the active agent will provide an efficacy of at least 90%, at least 93%, at least 95% or at least 97% against the target parasite.

[00107] By "treating" or "treat" or "treatment" is intended the application or administration of a compound of the invention to an animal that has a parasitic infestation for the eradication of the parasite or the reduction of the number of the parasites infesting the animal undergoing treatment.

Detailed Description of the Invention

[00108] It should be readily apparent to one of ordinary skill in the art that the examples disclosed herein below represent generalised examples only, and that other arrangements and methods capable of reproducing the invention are possible and are embraced by the present invention.

[00109] Two exemplar molecules within the scope of the present invention are illustrated as A1 and A2 below.

[00110] The molecules of the present invention are active against ectoparasites of the following genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Ambylomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Gasterophilus, Lucilia, Dermatobia, Cochliomyia, Chrysomyia, Damalinia, Linognathus, Haematopinus, Solenopotes, Trichodectes, and Felicola.

[00111] For example, the molecules of the present invention may, in particular, be useful in the treatment ectoparasites from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. The ectoparasites treated include but are not limited to fleas, ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof. Specific examples include, but are not limited to:

cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp.); ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., Haemaphysalis sp.);

mites (Demodex sp., Sarcoptes sp., Otodectes sp., Cheyletiella sp.);

lice (Trichodectes sp., Felicola sp., Linognathus sp.);

mosquitoes (Aedes sp., Culex sp., Anopheles sp.); and

flies (Hematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys calcitrans, Dermatobia sp., Cochliomyia sp.).

[00112] Further examples of parasitic pests controlled by the molecules of the present invention include ectoparasites (arthropods, acarines, etc.) including: flies such as Haematobia

(Lyperosia) irritans (horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis,

Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine, Gastrophilus instestinalis, Gastrophilus haemorrhoidalis and Gastrophilus naslis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus,

Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; keds such as Melophagus ovinus; mites such as Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites); ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyomma spp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).

[00113] It is envisaged that the molecules of the present invention will be synthesised according to the following synthetic protocol.

Synthesis of Building Block 1

Preparation of 1 ,3-dichloro-5-(1 -trifluoromethyl-vinyl)-benzene (R=CI)

[00114] 3,5-Dichlorophenylboronic acid (1 eq), potassium carbonate (2 eq) and dichlorobis- (triphenylphosphine)palladium(ll) (0.015 eq) were placed in a pressure tube. A mixture of THF/H₂0 (2: 1) was added and the tube was sealed with septum. After being degassed for 10min with nitrogen the reaction mixture was cooled down to 0 °C and 2-Bromo-3,3,3- trifluoroprop-1-ene (1.2 eq) was added via syringe. Next the solution was heated to 90 °C for 6 h, cooled down to room temperature and diluted with ethyl acetate. After separation, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure till dryness. BB1 (R=CI) was purified by means of silica-gel column chromatography using 100% cyclohexane as mobile phase to deliver the title product in 80% yield as a white gel-like substance. LCMS gave no ionization.

Preparation of 1-chloro-3-trifluoromethyl-5-(1 -trifluoromethyl-vinyl)-benzene (R=CH₃)

[00115] In the synthesis applied the same procedure as for 1 ,3-dichloro BB1 delivered title compound after purification on silica gel column in 80% yield as colourless oil. LCMS gave no ionization.

Synthesis of Building Block 2

Step 1. 2- V-(iert-Butoxycarbonyl)-1 -oxo-1 -N-(2,2,2-trifluoroethyl)-1,2-diaminoethane

[00116] Boc-Gly-OH (1 eq) was dissolved in dry DCM and a solution was cooled down to 5°C. DMAP (0.2 eq) and A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride (EDCI) were added and the whole was stirred for 15 min. 2,2,2-Trifluoroethylamine (1.4 eq) was added and the reaction mixture was left overnight at room temperature. After quenching with water, the organic layer was separated and dried over anhydrous sodium sulfate. Product was purified on silica gel column chromatography using cyclohexane/EtOAc gradient (80%->20%) to afford off white solid in 65% yield. MS confirmed.

Step 2. 1 -oxo-1-N-(2,2,2-trifluoroethyl)-1 ,2-diaminoethane hydrochloride

[00117] 2-/V-(te/f-Butoxycarbonyl)-1 -oxo-1-N-(2,2,2-trifluoroethyl)-1 ,2-diaminoethane (1 eq) was dissolved in 2M HCI/MeOH and stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure till dryness to afford the title compound in quantitative yield.

Synthesis of Building Block 3

Route A

Step 1. 9-Chloro-10-anthracenecarboxaldehyde oxime

[00118] To a suspension of 9-chloro-10-anthracenecarboxaldehyde (1 eq) and hydroxylamine hydrochloride (4 eq) in anhydrous MeCN was added freshly distilled Et3N (4 eq). The reaction mixture was heated under reflux for 3 h to afford yellow suspension. After cooling down to room temperature, the precipitate was filtered off and purified by means of silica gel column chromatography using EtOAc as an eluent. The title product was obtained as a yellow solid in 78% yield.

Step 2. 10-carboxaldehyde oxime-9-anthracenecarboxylic acid

[00119] To a suspension of 9-Chloro-10-anthracenecarboxaldehyde oxime (1 eq) in THF was dropwise added a n-hexane solution of nBuLi (2.1eq) at -78°C. After stirring for 1 h, some pellets of dry ice were added under a stream of nitrogen. The yellow solution was kept at the same temperature for additional 30 min and then was allowed to warm to room temperature. The reaction was quenched with small amount of 1 % HCI and the whole was concentrated under reduced pressure to obtain yellowish solid. Purification by means of silica gel column using EtOAc/EtOH gradient (100%->60%) as an eluent delivered product in 64% yield as an orange powder.

Route B

BB3

Step 1. 9-Bromo-10-anthracenecarboxaldehyde

[00120] 9,10-Dibromoanthracene (1 eq) in THF was cooled to -78°C, producing a yellow suspension. Dropwise addition of n-BuLi (1.2 eq, 2.7 M in heptane) gave an orange solution. The solution was stirred for 30min and treated with anhydrous DMF (2 eq). The reaction mixture was slowly warmed up to room temperature, stirred for 12 h and quenched with water. Product was extracted several times with DCM. The combined organic phases were washed with aq NH₄CI solution and water, and dried over MgS0₄. After filtration and evaporation to dryness, product was purified by column chromatography using silica gel and hexane-DCM gradient (100%->50%). The targeted compound was obtained in 35% yield as an orange powder. LCMS gave no ionization.

Step 2. 9-bromo-10-anthracenecarboxaldehyde oxime

[00121] To a suspension of 9-bromo-10-anthracenecarboxaldehyde (1 eq) and hydroxylamine hydrochloride (4 eq) in anhydrous MeCN was added freshly distilled Et3N (4 eq). The reaction mixture was heated under reflux for 3 h to afford yellow suspension. After cooling down to room temperature, the precipitate was filtered off and purified by means of silica gel column chromatography using EtOAc as an eluent. The title product was obtained as a yellow solid in 86% yield. LCMS gave no ionization.

Step 3. 10-carboxaldehyde oxime-9-anthracenecarboxylic acid

[00122] The synthesis was performed similar to Route A, step 2 (nBuLi 1.1 eq) afforded the title product in 76% yield as orange powder.

Route C

Step 1. 10-bromo-9-anthracenecarboxylic acid

[00123] To a suspension of 9, 10-dibromoanthracene (1 eq) in THF was dropwise added a n- hexane solution of nBuLi (1.1 eq) at -78°C. After stirring for 1 h, some pellets of dry ice were added under a stream of nitrogen. The yellow solution was kept at the same temperature for additional 30 min and then was allowed to warm to room temperature. A small amount of distilled water was added and solvents were concentrated under reduced pressure to obtain yellow solid. Purification by means of silica gel column using EtOAc/EtOH gradient (100%- >60%) as an eluent delivered product in 84% yield as an orange powder. Step 2. isoPropyl 10-bromo-9-anthracenecarboxylate

[00124] isoPropyl 10-bromo-9-anthracenecarboxylate (1 eq) was treated at room temperature with dry iPrOH and catalytical amount of acetyl chloride. The reaction mixture was stirred over night and evaporated to dryness. Product was purified by silica gel column chromatography using hexane-DCM gradient (100%->50%). The title compound was obtained in 55% yield as a yellow powder. LCMS gave no ionization.

Step 3. isoPropyl 10-carboxaldehyde-9-anthracenecarboxylate

[00125] A yellow suspension of isopropyl 10-bromo-9-anthracenecarboxylate (1 eq) in THF was cooled to -78 °C. Dropwise addition of n-BuLi (1.2 eq, 2.7 M in heptane) gave an orange solution that was stirred for 30 min and next treated with anhydrous DMF (2 eq). The reaction mixture was slowly warmed up to room temperature, stirred for 12 h and quenched with water. Product was extracted several times with DCM. The combined organic phases were washed with aq NH₄CI solution and water, and dried over MgS0₄. After filtration and evaporation to dryness, product was purified by column chromatography using silica gel and hexane-DCM gradient (100%->50%). The targeted compound was obtained in 62% yield as slightly orange powder. LCMS gave no ionization.

Step 4. 10-carboxaldehyde-9-anthracenecarboxylic acid

[00126] isoPropyl 10-carboxaldehyde- 9-anthracenecarboxylate (1 eq) was dissolved in THF at room temperature, treated with 5% LiOH solution and stirred for 24 h. The reaction mixture was next acidified with 2% HCI solution to get pH=5 and whole mass was concentrated under reduced pressure till dryness. Purification by means of silica gel column chromatography using EtOAc as an eluent afforded the title compound in 81 % yield.

Step 5. 10-carboxaldehyde oxime-9-anthracenecarboxylic acid

[00127] To a suspension of 10-carboxaldehyde-9-anthracenecarboxylic acid (1 eq) and hydroxylamine hydrochloride (4 eq) in anhydrous MeCN was added freshly distilled Et₃N (4 eq). The reaction mixture was heated under reflux for 3 h to afford yellow suspension. After cooling down to room temperature the reaction mixture was evaporated under reduced pressure till dryness and product was purified by means of silica gel column chromatography using

EtOAc/EtOH gradient (100%->60%) as an eluent. The title product was obtained as a yellow solid in 69% yield. Route D

Step 1. 9-anthracenecarboxylic acid

[00128] The synthesis was performed similar to Route C, step 1 afforded product in 86% yield as orange powder.

Step 2. 10-carboxaldehyde-9-anthracenecarboxylic acid

[00129] 9-Anthracenecarboxylic acid (1 eq) was dissolved in DMF and cooled down to 10°C. POCI₃ (1 eq) was added dropwise and orange suspension was stirred for 10 min. The reaction mixture was next heated up to 50 °C and stirred for additional 12 h. Evaporation to dryness and purification by silica gel column chromatography using EtOAc as an eluent afforded the title compound in 41 % yield.

Step 3. 10-carboxaldehyde oxime-9-anthracenecarboxylic acid

[00130] This step was performed according to Route C, step 5.

1.oxime halogenation

Step 1. 10-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-9- anthracenecarboxylic acid (R=CI)

[00131] To a solution of 10-carboxaldehyde oxime-9-anthracenecarboxylic acid (1 eq) and 1 ,3- dichloro-5-(1-trifluoromethyl-vinyl)-benzene (1 eq) in THF at 5 °C was added an aqueous solution of sodium hypochlorite (5% Clorox brand) and a few drops of triethylamine. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. After addition of water product was extracted with DCM. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a solid residue. Product was purified by silica gel column chromatography to deliver the title compound in 39% yield.

Step 2. 10-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-9-(2- oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)anthraceamide (R=CI)

[00132] A/,A/-Diisopropylethylamine (1 eq) was added dropwise to a 0 °C stirring solution of 10- (4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1 ,2-oxazol-3-yl)-9- anthracenecarboxylic acid (1 eq), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDCI, 1 eq) and A/,A/-dimethylaminopyridine (0.1 eq) in dry DCM. The reaction mixture was then stirred at room temperature for 8 h and was quenched with 1 % HCI. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography using Hex/EtOAc gradient (90%->50%) afforded the title compound in 71 %. MS confirmed.

Step 1. 10-(4-(5-(3-Chloro-5-trif luoromethylphenylphenyl)-5-(trifluoromethyl)-4,5-dihydro- 1,2-oxazol-3-yl)-9-anthracenecarboxylic acid (R=CF₃)

[00133] In the synthesis applied the same procedure as for 1 ,3-dichloro analogue (R=CI). The title compound was obtained after purification on silica gel column in 57% yield. MS confirmed.

Step 2. 4-(5-(3-chloro-5-trifluoromethylphenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol- 3-yl)-2-methyl-n-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)anthracemide (R=CF₃)

[00134] In the synthesis applied the same procedure as for 1 ,3-dichloro analogue (R=CI). The title compound was obtained after purification on silica gel column in 69% yield. MS confirmed.

[00135] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Claims

1. A compound of the general formula (I), a pharmaceutically acceptable salt thereof, a

stereoisomer thereof, a tautomer f, or a solvate thereof,

) wherein:

A is a tricyclic fused aryl or heteroaryl ring system;

p is 0-6;

each R¹ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyi, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆

b/^'sfalky sulfonamido, C C₆ bis(haloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, and nitro; or

R² is selected from the group consisting of SF₅, S(C C₆ alkyl), S(C₂-C₆ alkenyl), S(C₂-C₆ alkynyl), C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyi, C₄-C₇ alkylcycloalkyi and C₄-C₇ cycloalkylalkyi, wherein each is optionally substituted with one or more substituents independently selected from R⁴;

q is 0-5;

each R³ is the same or different and is independently selected from the group consisting of halogen, C C₆ alkyl, C C₆ haloalkyi, C C₆ alkoxy, C C₆ haloalkoxy, C C₆ alkylthio, C C₆ haloalkylthio, C C₆ alkylsulfinyl, C C₆ haloalkylsulfinyl, C C₆ alkylsulfonyl, C C₆ haloalkylsulfonyl, C C₆ alkylsulfonamido, C C₆ haloalkylsulfonamido, C C₆ 6/salkylsulfonamido, C C₆ £>/shaloalkylsulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, and nitro; or

Q is selected from the group consisting of C(W)NR⁵R⁶, a 3-6 membered heterocyclic ring optionally substituted with one or more R⁷, a C₃-C₁₂ fused or unfused carbocyclic ring system optionally substituted with one or more R⁷, and an 8-12 membered fused heterocyclic ring system optionally substituted with one or more R⁷;

Wis O orS;

R⁶ is selected from the group consisting of H, 0(C C₆ alkyl), NH(C C₆ alkyl), N(C C₆ alkyl)(C C₆ alkyl), C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloaliphatic, C₃-C₆ heterocycloaliphatic, C₄-C₇ alkylcycloalkyi, C₄-C₇ cycloalkylalkyi, CH=NO(CrC₆ alkyl), CH=NO(C C₆ alkenyl), CH=NO(C C₆ alkynyl), CH=NO(C₅-C₁₂ aryl), and CH=NO(C₃-Cn heteroaryl), C₅-Ci₂ aryl, C₃-Cn heteroaryl, wherein each is optionally substituted with at least one of a halogen, hydroxy, C C₆ alkoxy, C C₆ alkylthio, C C₆ alkylsulfinyl, C C₆ alkylsulfonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl, C₂-C₇

haloalkylaminocarbonyl and C₃-C₉ halodialkylaminocarbonyl;

b/^'sfalky sulfonamido, C C₆ £>/s(haloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, or nitro; or

5/^'s(alkyl)sulfonamido, C C₆ £>/shaloalkyl)sulfonamido, NH(CrC₆ alkyl), N(C C₆ alkyl)₂, NH(C C₆ haloalkyi), N(C C₆ haloalkyl)₂, N(C C₆ alkyl)(C C₆ haloalkyi), C(0)NH(C C₆ alkyl), C(0)N(C C₆ alkyl)₂, C(0)NH(C C₆ haloalkyi), C(0)N(C C₆ haloalkyl)₂, C(0)N(C C₆ alkyl)(C C₆ haloalkyi), C(0)H, C(0)C C₆ alkyl, C(0)C C₆ haloalkyi, C(0)0(C C₆ alkyl), C(0)0(C C₆ haloalkyi), OC(0)C C₆ haloalkyi, OC(0)C C₆ alkyl, SF₅, SCN, cyano, or nitro.

2. A compound according to Claim of the general formula (II)

wherein

A, p, R¹, R², R³, R⁴, Q, W, R⁵, R⁶, and R⁷ are as defined above;

B¹, B² and B³ are the same or different and are independently selected from the group consisting of CR³ and N; and

each R^3' is independently of the other H or R³.

3. A compound according to any preceding Claim, wherein the ring A is selected from the group consisting of

wherein R¹ and p are as defined above.

4. A compound according to any preceding Claim, wherein Q is C(W)NR⁵R⁶ and R⁵ and R⁶ are as defined above.

5. A compound according to any one of Claims 2 to 4, wherein B¹ , B² and B³ are CR³ and R^3' is as defined above.

6. A compound according to any preceding Claim, wherein p is 0.

7. A compound according to any preceding Claim, wherein the compound is of the general formula (III):

wherein R², R³, R⁴, R⁵ and R⁶ are as defined above.

8. A compound according to any preceding Claim, wherein R² is CF₃.

9. A compound according to any proceeding Claim, wherein R⁵ is H.

10. A compound according to any preceding Claim, wherein the compound is of the general formula (IV)

wherein R², each R³, and R⁴ are as defined above.

11. A compound according to any preceding Claim, wherein R³ is selected from the group consisting of a halogen and CF₃.

12. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 11 and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition according to Claim 12 further comprising a second

biologically active compound selected from the group consisting organophosphate pesticides, carbamate -type pesticides, organochlorine type pesticides,

pyrethrins/pyrethroids, neonicotinoids, avermectins, milbemycins, benzimidazoles, salicylanilides, substituted phenols, pyrimidines, tetrahydropyrimidines, imidazothiazoles, amino/amido acetonitrile derivatives, febantel, clorsulon, levamisole, morantel, and praziquantel, juvenile hormone mimics and chitin synthesis inhibitors.

14. A pharmaceutical composition according to any one of Claims 12 to 13, wherein the composition is for dermal or oral administration.

15. A pharmaceutical composition according to Claim 14, wherein the composition is a pour-on or spot-on composition.

16. A pharmaceutical composition according to Claim 14, wherein the composition is a chewable product for oral administration.

17. A method of treating and/or preventing parasitoses of an animal comprising administering an effective amount of a compound according to any one of Claims 1 to 11 to the animal.

18. A method of treating a parasitic infection in an environment or area that is occupied by an animal comprising treating the environment or area occupied by the animal with effective amount of a compound according to any one of Claims 1 to 11.

19. A method for treating and/or preventing an endoparasitic infestation and ectoparasitic infection in an animal in need thereof comprising administering an effective amount of a compound according to any one of Claims 1 to 11 together with an effective amount of at least one of an avermectin or milbemycin to the animal.

20. A method according to Claim 19 further comprising administering praziquantel to the animal.