Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof

Abstract

This invention relates to oral veterinary compositions for combating ectoparasites and endoparasites in animals, comprising at least one systemically-acting active agent in combination with a pharmaceutically acceptable carrier. This invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the compositions of the invention to the animal in need thereof.

What is claimed is: 
     
         1 . A soft chewable veterinary composition for treating and/or preventing a parasitic infection or infestation in an animal comprising:
 a)
 (i) at least one isoxazoline active agent 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
 (ii) at least one systemically-acting active agent that is active against internal parasites, wherein the systemically-acting active agent that is active against internal parasites is one or more macrocyclic lactones, one or more benzimidazoles, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more amino acetonitrile active agents or one or more aryloazol-2-yl cyanoethylamino active agents, or a combination of thereof; or 
 (iii) a combination of at least one isoxazoline active agent of formula (I) and at least one systemically-acting active agent, wherein the systemically active agent is one or more macrocyclic lactones, one or more spinosyn compounds, one or more spinosoid compounds, one or more benzimidazoles, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more amino acetonitrile active agents, one or more insect growth regulators, one or more neonicotinoids or one or more aryloazol-2-yl cyanoethylamino active agents, or a combination of thereof; and 
 
 b) a pharmaceutically acceptable carrier. 
 
     
     
         2 . The soft chewable veterinary composition of  claim 1 , wherein:
 W is O;   R 4  is H or C 1 -C 6  alkyl;   R 5  is —CH 2 C(O)NHCH 2 CF 3 ;   each of A 1 , A 2 , A 3 , A 4 , A 5  and A 6  is CH;   R 1  is C 1 -C 6  alkyl each optionally substituted with one or more substituents independently selected from R 6 ;   R 6  is halogen or C 1 -C 6  alkyl; and   B 1 , B 2 , and B 3  are independently CH, C-halogen, C—C 1 -C 6  alkyl, C—C 1 -C 6  haloalkyl, or C—C 1 -C 6  alkoxy.   
     
     
         3 . The soft chewable veterinary composition of  claim 1 , wherein:
 W is O;   R 1  is CF 3 ;   B 2  is CH;   B 1  is C—Cl;   B 3  is C—CF 3 ;   each of A 1 , A 2 , A 3 , A 4 , A 5  and A 6  is CH;   R 4  is H; and   R 5  is —CH 2 C(O)NHCH 2 CF 3 .   
     
     
         4 . The soft chewable veterinary composition of  claim 1 , wherein the carrier comprises one or more fillers, at least one flavoring agent, at least one binder, one or more solvents, one or more surfactants, at least one humectant, optionally an antioxidant, and optionally a preservative. 
     
     
         5 . The soft chewable veterinary composition of  claim 4 , wherein the one or more fillers is soy protein fines, corn starch, or a mixture thereof. 
     
     
         6 . The soft chewable veterinary composition of  claim 4 , wherein the binder is polyvinylpyrrolidone or a polyethylene glycol, or a combination thereof. 
     
     
         7 . The soft chewable veterinary composition of  claim 4 , wherein the solvent is a liquid polyethylene glycol or a caprylic/capric triglyceride, or a combination thereof. 
     
     
         8 . The soft chewable veterinary composition of  claim 4 , wherein the surfactant is polyethylene glycol hydroxystearate. 
     
     
         9 . The soft chewable veterinary composition of  claim 4 , wherein the humectant is glycerin. 
     
     
         10 . The soft chewable veterinary composition of  claim 4 , wherein the flavoring agent is an artificial meat or beef flavor. 
     
     
         11 . The soft chewable veterinary composition of  claim 4 , wherein the composition comprises:
 a) a filler selected from corn starch, pre-gelatinized corn starch, corn gluten meal and soy protein fines, or a combination thereof;   b) a solvent selected from liquid polyethylene glycols, propylene glycol, propylene carbonate, caprylic/capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, glycerol caprylate/caprate and polyglycolized glycerides, or a combination thereof,   c) a binder selected from polyvinylpyrrolidone, polyethylene glycols, co-polymers of vinyl acetate and vinylpyrrolidone, potato starch and corn starch, or a combination thereof;   d) a humectant selected from glycerol, propylene glycol, cetyl alcohol, glycerin monostearate and polyethylene glycols, or a combination thereof;   e) a surfactant selected from glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyvinyl alcohol, polysorbates, sodium lauryl sulfate, co-polymers of ethylene oxide and propylene oxide, propylene glycol monolaurate, glycerol caprylate/caprate, polyglycolized glycerides and polyethylene glycol hydroxystearate, or a combination thereof; and   f) a natural or artificial beef or meat flavor.   
     
     
         12 . The soft chewable veterinary composition of  claim 11 , wherein the composition comprises a compound of formula (I) at a concentration of about 1% to about 20% by weight. 
     
     
         13 . The soft chewable veterinary composition of  claim 12 , wherein:
 a) the filler is a combination of corn starch and soy protein fines and is present at a concentration of about 30% to about 50% (w/w);   b) the solvent is a mixture of liquid polyethylene glycol and caprylic/capric triglycerides and is present at a concentration of about 5% to about 20% (w/w);   c) the binder is polyethylene glycol or polyvinylpyrrolidone, or a combination thereof, and is present at a concentration of about 5% to about 15% (w/w);   d) the humectant is glycerin and is present at a concentration of about 5% to about 20%;   e) the surfactant is polyethylene glycol 12-hydroxystearate or polyoxyl hydrogenated castor oil and is present at a concentration of about 1% to about 5% (w/w).   
     
     
         14 . The soft chewable veterinary composition of  claim 12 , wherein the compound of Formula (I) is present at a concentration of about 1% to about 5% by weight. 
     
     
         15 . The soft chewable veterinary composition of  claim 12 , wherein the compound of Formula (I) is present at a concentration of about 10% to about 20% by weight. 
     
     
         16 . The soft chewable veterinary composition of  claim 1 , wherein the composition comprises a systemically-acting active agent that is active against selected from the group consisting of one or more macrocyclic lactones, one or more spinosyn compounds, one or more spinosoid compounds, one or more benzimidazoles, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more amino acetonitrile active agents, one or more insect growth regulators, one or more neonicotinoids and one or more aryloazol-2-yl cyanoethylamino active agents, or a combination of thereof. 
     
     
         17 . The soft chewable veterinary composition of  claim 1 , wherein the composition comprises a combination of at least one isoxazoline active agent of formula (I) and at least one systemically-acting active agent selected from the group consisting of one or more macrocyclic lactones, one or more spinosyn compounds, one or more spinosoid compounds, one or more benzimidazoles, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more amino acetonitrile active agents, one or more insect growth regulators, one or more neonicotinoids and one or more aryloazol-2-yl cyanoethylamino active agents, or a combination of thereof. 
     
     
         18 . The soft chewable veterinary composition of  claim 17 , wherein the macrocyclic lactone is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin, or a combination thereof. 
     
     
         19 . The soft chewable veterinary composition of  claim 17 , wherein the isoxazoline active agent is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide and the systemically-acting active agent is an avermectin, milbemycin oxime or moxidectin, or a combination thereof. 
     
     
         20 . A method for the treatment and/or prevention of a parasitic infestation and/or infection in an animal comprising administering to the animal an effective amount of the soft chewable veterinary composition of  claim 1  to the animal. 
     
     
         21 . The method of  claim 20 , wherein the composition comprises an isoxazoline active agent, and wherein the isoxazoline active agent is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide. 
     
     
         22 . The method of  claim 20 , wherein the soft chewable composition comprises a systemically-acting active agent selected from the group consisting of one or more avermectin or milbemycin compounds, one or more benzimidazole active agents, one or more a spinosyn compounds, one or more a spinosoid compounds, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, one or more amino acetonitrile active agents, one or more insect growth regulators, one or more neonicotinoids and one or more aryloazol-2-yl cyanoethylamino active agents, or a combination thereof. 
     
     
         23 . The method of  claim 20 , wherein the parasite are fleas or ticks. 
     
     
         24 . The method of  claim 21 , wherein the parasite is a nematode, a cestode, a trematode or a filarial parasite. 
     
     
         25 . Use of a compound of Formula (I) in  claim 1  in the manufacture of a soft chewable veterinary composition for the treatment and/or prevention of a parasitic infestation and/or infection in an animal.