Parasiticidal compositions comprising an isoxazoline active agent, methods and uses thereof

Abstract

This invention relates to topical compositions for combating ectoparasites and endoparasites in animals, comprising at least one isoxazoline active agent and a pharmaceutically acceptable carrier, optionally in combination with one or more additional active agents. This invention also provides for an 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.

1 . A topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal comprising:
 a) 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, Ci-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; and     b) a pharmaceutically acceptable carrier that is suitable for the application to the skin of an animal; and wherein the carrier does not comprise glycofurol and is not a binary mixture of propylene glycol and glycerol formal.   
     
     
         2 . The topical veterinary composition of  claim 1 , wherein:
 WisO;   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 topical veterinary composition of  claim 1 , wherein:
 WisO;   R 1  is CF 3 ;   B 2  is CH;   B 1  is chloro;   B 3  is 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 topical veterinary composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises a diester of a dicarboxylic acid, a glycol ester, a glycol ether, a fatty acid ester, a polyethylene glycol, or polyethylene glycol ester, an oil, an alcohol, a glycerol ester, a glycerol ether, propylene glycol, ethylene glycol, a glycol carbonate, dimethyl isosorbide, N-methylpyrrolidone, or a mixture thereof. 
     
     
         5 . The topical veterinary composition of  claim 4 , wherein the diester of a dicarboxylic acid is a diester of a C 6 -C 16  dicarboxylic acid. 
     
     
         6 . The topical veterinary composition of  claim 5 , wherein the diester of a C 6 -C 16  dicarboxylic acid is diethyl sebacate or diisopropyl adipate. 
     
     
         7 . The topical veterinary composition of  claim 4 , wherein the pharmaceutically acceptable carrier comprises mixture of a diester of a dicarboxylic acid and a propylene glycol ester, a fatty acid ester, a polyethylene glycol ester, a polyethylene glycol, an oil, a C 6 -C 20  long-chain aliphatic alcohol, a C 1 -C 8  alcohol, glycol ether, or a combination thereof. 
     
     
         8 . The topical veterinary composition of  claim 4 , wherein the pharmaceutically acceptable carrier comprises a mixture of a diester of a dicarboxylic acid and further comprises a mixed ester of sucrose and acetic and isobutyric acid, a low melting wax, a hard fat or a block copolymer of ethylene oxide and propylene oxide, or a combination thereof. 
     
     
         9 . The topical veterinary composition of  claim 4 , wherein the pharmaceutically acceptable carrier comprises dimethyl isosorbide, glycerol formal, propylene carbonate, triacetin, diethyleneglycol monoethyl ether, polyethylene glycol 400 or benzyl alcohol, or a mixture thereof. 
     
     
         10 . The topical veterinary composition of  claim 1 , further comprising at least a second active agent. 
     
     
         11 . The topical veterinary composition of  claim 10 , wherein the at least second active agent is an insect growth regulator, a neonicotinoid or an avermectin or milbemycin. 
     
     
         12 . The topical veterinary composition of  claim 11 , 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-naphthalanecarboxamide and the neonicotinoid is nitenpyram. 
     
     
         13 . The topical veterinary composition of  claim 11 , wherein the at least second active agent is an insect growth regulator. 
     
     
         14 . The topical veterinary composition of  claim 13 , wherein the insect growth regulator is (S)-methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron, or novaluron. 
     
     
         15 . The topical veterinary composition of  claim 11 , wherein the avermectin or milbemycin is eprinomectin, ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin. 
     
     
         16 . The topical veterinary composition of  claim 10 , wherein the at least second active agent is an anthelmintic active agent selected from thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, an amino acetonitrile active agent, or an aryloazol-2-yl cyanoethylamino active agent. 
     
     
         17 . The topical veterinary composition of  claim 1 , wherein the composition is a spot-on composition. 
     
     
         18 . The topical veterinary composition of  claim 1 , wherein the composition is a pour-on composition. 
     
     
         19 . A method for the treatment or prevention of a parasitic infestation or infection in an animal comprising administering to the animal an effective amount of the topical veterinary composition of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the isoxazoline 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. 
     
     
         21 . (canceled)