Antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof

Abstract

This invention relates to long-acting injectable compositions for combating parasites in animals, comprising at least one isoxazoline active agent, a liquid PEG and/or a neutral oil, optionally a co-solvent, and optionally a pharmaceutically acceptable additive or excipient. This invention also provides new isoxazoline active agents with long-lasting efficacy against ectoparasites. The invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the novel isoxazoline compounds and long-acting injectable compositions of the invention to the animal in need thereof.

What is claimed is: 
     
         1 . A pesticidal and parasiticidal isoxazoline compound of formula (Ie): 
       
         
           
           
               
               
           
         
         or a pharmaceutically or agriculturally acceptable salt thereof. 
       
     
     
         2 . A pesticidal and parasiticidal isoxazoline compound of formula (S)-Ie: 
       
         
           
           
               
               
           
         
         or a pharmaceutically or agriculturally acceptable salt thereof. 
       
     
     
         3 . A veterinary parasiticidal composition comprising an effective amount of the compound of formula (Ie) in  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
         4 . A pesticidal composition for controlling pests that harm plants, plant propagation material, crops or material derived from wood, comprising an effective amount of the compound of formula (Ie) in  claim 1  in combination with an agriculturally acceptable carrier. 
     
     
         5 . A veterinary parasiticidal composition comprising an effective amount of the compound of formula (S)-Ie in  claim 2  in combination with a pharmaceutically acceptable carrier. 
     
     
         6 . A pesticidal composition for controlling pests that harm plants, plant propagation material, crops or material derived from wood, comprising an effective amount of the compound of formula (S)-Ie in  claim 2  in combination with an agriculturally acceptable carrier. 
     
     
         7 . A method for the treatment or prevention of a parasitic infestation in an animal comprising administering to the animal an effective amount of the compound of formula (Ie) in  claim 1 . 
     
     
         8 . A method for the treatment or prevention of a parasitic infestation in an animal comprising administering to the animal an effective amount of the compound of formula (S)-Ie in  claim 2 . 
     
     
         9 . method for controlling pests that harm plants, plant propagation material, crops or material derived from wood, comprising administering an effective amount of the compound of formula (Ie) in  claim 1  to the plants, the soil in which the plants grow, plant propagation material, crops or material derived from wood. 
     
     
         10 . method for controlling pests that harm plants, plant propagation material, crops or material derived from wood, comprising administering an effective amount of the compound of formula (S)-Ie in  claim 2  to the plants, the soil in which the plants grow, plant propagation material, crops or material derived from wood. 
     
     
         11 . A long-acting injectable composition for the treatment or prevention of a parasitic infection or infestation in an animal comprising an effective amount of at least one parasiticidal isoxazoline active agent, a liquid PEG and/or a neutral oil and, optionally, a co-solvent, wherein no other pharmaceutically acceptable polymers are present. 
     
     
         12 . The long-acting injectable composition according to  claim 11  comprising:
 a) an effective amount of at least one parasiticidal isoxazoline active agent, which is:
 i) an isoxazoline compound of formula (I): 
 
 
       
         
           
           
               
               
           
         
       
       wherein:
 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 at most 3 of A 1 , A 2 , A 3 , A 4 , A 5  and A 6  are N; 
 B 1 , B 2  and B 3  are independently selected from the group consisting of CR 2  and N; 
 W is 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 optionally substituted with one or more substituents independently selected from R 6 ; 
 each R 2  is independently H, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylthio, C 1 -C 6  haloalkylthio, 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, C 2 -C 6  dialkylamino, C 2 -C 4  alkoxycarbonyl, —CN or —NO 2 ; 
 each R 3  is independently H, halogen, 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, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylthio, C 1 -C 6  haloalkylthio, 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, C 2 -C 6  dialkylamino, —CN or —NO 2 ; 
 R 4  is 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  is H, OR 10 , NR 11 R 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 optionally substituted with one or more substituents independently selected from R 7 ; or 
 R 4  and R 5  are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2  alkyl, halogen, —CN, —NO 2  and C 1 -C 2  alkoxy; 
 each R 6  is independently halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfinyl, C 1 -C 6  alkylsulfonyl, —CN or —NO 2 ; 
 each R 7  is independently halogen; C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfinyl, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylamino, C 2 -C 8  dialkylamino, C 3 -C 6  cycloalkylamino, 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, hydroxy, —NH 2 , —CN or —NO 2 ; or Q 2 ; 
 each R 8  is independently halogen, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylthio, C 1 -C 6  haloalkylthio, 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, C 2 -C 6  dialkylamino, C 2 -C 4  alkoxycarbonyl, —CN or NO 2 ; 
 each R 9  is independently halogen, 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, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylthio, C 1 -C 6  haloalkylthio, 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, C 2 -C 6  dialkylamino, —CN, —NO 2 , phenyl or pyridinyl; 
 R 10  is 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 optionally substituted with one of more halogen; 
 R 11  is 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  is H; Q 3 ; 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 optionally substituted with one or more substituents independently selected from R 7 ; or 
 R 11  and R 12  are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1 -C 2  alkyl, halogen, —CN, —NO 2  and C 1 -C 2  alkoxy; 
 Q 1  is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10-membered fused bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system 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, each ring optionally substituted with one or more substituents independently selected from R 9 ; 
 Q 3  is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring 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 of formula (II): 
 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, 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 ; 
         X is aryl or heteroaryl, which may be unsubstituted or substituted by one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, 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 ; 
         A 1  is oxygen; and 
         A 2  is oxygen, NR 2  or CR 7 R 8 ; 
         G is G-1 or G-2; 
       
       
         
           
           
               
               
           
         
         B 1 , B 2 , B 3 , B 4  and B 5  are independently N or C—R 9 ; 
         Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, 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, Y-11, Y-12 or Y-13; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3  are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, R 10 S(O)—, R 10 S(O) 2 —, R 10 C(O)—, R 10 C(S)—, R 10 R 11 NC(O)—, R 10 R 11 NC(S)— R 10 OC(O)—; 
         R 4 , R 5  and R 6  are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl; 
         R 7  and R 8  are independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; 
         R 9  is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, 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 ; 
         R 10 , R 11 , R 12  and R 13  are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or 
         R 10  together with R 11  form ═O, ═S or ═NR 2 ; or 
         R 12  together with R 13  form ═O, ═S or ═NR 2 ; 
         W is O, S or NR 2 ; 
         n is 1-4; and 
         m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or
 iv) an isoxazoline compound of formula (III) 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and/or
 iv) an isoxazoline compound of formula (IV) 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and/or
 v) an isoxazoline compound of formula (V): 
 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are independently H, Cl, F or CF 3 ; 
         Y is the diradical group 
       
       
         
           
           
               
               
           
         
       
       and
 T is a C 1 -C 6 -alkyl group which is unsubstituted or substituted by halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylthio, carboxy, carbamoyl or C 2 -C 6 -alkanoyl group which may be unsubstituted or substituted in the alkyl portion by halogen or a pharmaceutical acceptable salt thereof; and/or
 vi) an isoxazoline compound of formula (VI): 
 
 
       
         
           
           
               
               
           
         
         wherein Y is hydrogen, fluoro, chloro or bromo;
 R 1  is phenyl substituted with 2-4 substituents selected from halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy; 
 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  together combine with the carbon 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 neutral oil; 
         c) optionally, at least one co-solvent; 
         d) optionally, an antioxidant; and 
         e) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof 
         wherein no other pharmaceutically acceptable polymers are present. 
       
     
     
         13 . The long-acting injectable composition according to  claim 12 , wherein the at least one isoxazoline compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The long-acting injectable composition according to  claim 13 , wherein in the isoxazoline active agent is a compound of the formula (Ib): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         R 2  independently is halogen, C 1 -C 6  alkyl or C 1 -C 6  haloalkyl 
         R 4  is H or C 1 -C 6  alkyl; 
         R 5  is C 1 -C 4  alkyl optionally substituted with one or more R 7 ; and R 7  is 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; and 
         n is 0, 1 or 2. 
       
     
     
         15 . The long-acting injectable composition according to  claim 14 , wherein the isoxazoline active agent is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The long-acting injectable composition according to  claim 13 , wherein the isoxazoline active agent is a compound of 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. 
       
     
     
         17 . The long-acting injectable composition according to  claim 11  or  12 , wherein the isoxazoline active agent is enriched in an enantiomer. 
     
     
         18 . The long-acting injectable composition according to  claim 17 , wherein the isoxazoline active agent is a compound of formula (S)-Ia or (S)-Ic: 
       
         
           
           
               
               
           
         
         wherein X 1 , X 2  and X 3  are independently chloro, fluoro or CF 3 ; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The long-acting injectable composition according to any one of  claims 11  to  18 , wherein the liquid PEG is PEG 200, PEG 300 or PEG 400, or a mixture thereof. 
     
     
         20 . The long-acting injectable composition according to any one of  claims 11  to  19 , wherein the composition comprises a co-solvent, and wherein said co-solvent is a C 1 -C 6 alcohol, a glycol ether, glycerol, propylene glycol, a cyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethylsulfoxide or glycerol formal, or a combination thereof. 
     
     
         21 . The long-acting injectable composition according to any one of  claims 11  to  19 , wherein the composition comprises a co-solvent, and wherein said co-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin, a lipid, a C 8 -C 10  triglyceride, a C 8 -C 10  triglyceride combined with linoleic acid, a C 8 -C 10  triglyceride combined with succinic acid, a propylene glycol diester of C 8 -C 10  fatty acids, castor oil, cottonseed oil, sesame oil, soybean oil or safflower oil, or a combination thereof. 
     
     
         22 . The long-acting injectable composition according to any one of  claims 11  to  19 , wherein the composition comprises a co-solvent, and wherein the co-solvent is ethanol, isopropanol or benzyl alcohol, or a mixture thereof. 
     
     
         23 . The long-acting injectable composition according to any one of  claims 11  to  22 , wherein the composition comprises a pharmaceutically acceptable excipient, and wherein the excipient is a surfactant. 
     
     
         24 . The long-acting injectable composition according to  claim 23 , wherein the surfactant is selected from the group consisting of glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan monooleate, polyvinyl alcohol, polysorbate 20, polysorbate 80, d-a-tocopherol polyethylene glycol 1000 succinate, sodium lauryl sulfate, co-polymers of ethylene oxide and propylene oxide, polyethylene glycol castor oil derivatives, propylene glycol monolaurate, glycerol caprylate/caprate, polyglycolized glycerides, PEG 300 caprylic/capric glycerides, PEG 400 caprylic/capric glycerides, PEG 300 oleic glycerides, PEG 300 linoleic glycerides, polyethylene glycol stearates and polyethylene glycol hydroxy stearates, or a combination thereof. 
     
     
         25 . The long-acting injectable composition according to  claim 13  comprising:
 a) about 0.5 to about 30% (w/v) of the isoxazoline compounds of formula (I); 
 b) pharmaceutically acceptable polymer which is a liquid PEG, and/or a neutral oil; 
 c) optionally, about 1% to 15% (w/v) of co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol, or a combination thereof; 
 d) optionally, about 0.01% to about 2% (w/v) of an antioxidant; and 
 e) optionally about 0.01% to about 10% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof 
 wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is a liquid PEG and wherein the liquid PEG and/or the neutral oil are present in the overall composition in a proportion representing the complement to 100% of the composition. 
 
     
     
         26 . The long-acting injectable composition according to  claim 25 , wherein the composition comprises:
 a) about 5 to 15% (w/v) of an isoxazoline compound of formula (Ia):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         b) pharmaceutically acceptable polymer which is a liquid PEG; 
         c) optionally, about 2% to 10% (w/v) of co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol, or a combination thereof; 
         d) optionally, about 0.01% to about 2% (w/v) of an antioxidant; and 
         e) optionally, about 0.5% to about 10% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof 
         wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is a liquid PEG and wherein the liquid PEG is present in the overall composition in a proportion representing the complement to 100% of the composition. 
       
     
     
         27 . The long-acting injectable composition according to  claim 26 , wherein the isoxazoline compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The long-acting injectable composition according to  claim 25 , wherein the composition comprises:
 a) about 5 to 15% (w/v) of an isoxazoline compound of 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) pharmaceutically acceptable polymer which is a liquid PEG; 
         c) optionally, about 2% to 10% (w/v) of co-solvent, wherein said co-solvent is ethanol, isopropanol or benzyl alcohol, or a combination thereof; 
         d) optionally, about 0.01% to about 2% (w/v) of an antioxidant; and 
         e) optionally, about 0.5% to about 10% (w/v) of a pharmaceutically acceptable additive, excipient or mixtures thereof 
         wherein the only pharmaceutically acceptable polymer present in said long-acting injectable composition is a liquid PEG and wherein the liquid PEG is present in the overall composition in a proportion representing the complement to 100% of the composition. 
       
     
     
         29 . The long-acting injectable composition according to  claim 28 , wherein;
 X 1  is Cl; X 2  is F; and X 3  is —CF 3 .   
     
     
         30 . The long-acting injectable composition according to any one of  claims 11  to  29 , wherein the parasites are treated or prevented for about 3 to 6 months. 
     
     
         31 . The long-acting injectable composition according to any one of  claims 11  to  29  wherein the parasites are treated or prevented for about 5 to 6 months. 
     
     
         32 . The long-acting injectable composition according to any one of  claims 11  to  29 , wherein the parasites are treated or prevented for about 6 months. 
     
     
         33 . The long-acting injectable composition according to any one of  claim 30 ,  31  or  33  wherein the parasites are fleas or ticks 
     
     
         34 . The long-acting composition according to any one of  claims 11  to  33 , which further comprises an effective amount at least one additional active agent. 
     
     
         35 . The long-acting composition according to  claim 34 , wherein the additional pharmaceutically active agent is a macrocyclic lactone, a neonicotinoid active agent, a 1-N-arylpyrazole active agent, a cyclic depsipeptide, a benzimidazole, an imidazothiazole, a tetrahydropyrimidine active agent, an organophosphate active agent, levamisole, a paraherquamide active agent, a marcfortine active agent, praziquantel, closantel, pyrantel, morantel, clorsulon, a spinosyn active agent, a spinosoid active agent, an amino acetonitrile active agent, an aryloazol-2-yl cyanoethyl active agent or an insect growth regulator. 
     
     
         36 . The long-acting composition according to  claim 35 , wherein the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, milbemectin, milbemycin D, moxidectin or nemadectin. 
     
     
         37 . A method for treating or preventing parasites in an animal in need thereof for a period of 3 to 6 months which comprises administering the long acting injectable composition according to  claim 1  to said animal. 
     
     
         38 . The method according to  claim 37  wherein the animal is a dog, a cat, an ovine or a bovine. 
     
     
         39 . The method according to  claim 37  wherein the parasites are treated or prevented for about 5 to 6 months 
     
     
         40 . The method according to  claim 37  wherein the parasites are fleas and/or ticks. 
     
     
         41 . The use of an isoxazoline in the preparation of a long-acting injectable composition for the treatment or prevention of a parasite infestation or infection on or in an animal.