Topical Localized Isoxazoline Formulation

Abstract

This invention provides topical localized formulations comprising an isoxazoline compound and a pharmaceutically or veterinary acceptable liquid carrier vehicle comprising N,N-diethyl-3-methylbenzamide as a solvent and an improved method for controlling, and preventing parasite infestation in animals.

1 . A topical localized formulation for the treatment or prophylaxis of parasite infestation in animals which comprises an effective amount of at least one isoxazoline compound of the Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 =halogen, CF 3 , OCF 3 , CN, 
 n=integer from 0 to 3, preferably 1, 2 or 3, 
 R 2 =C 1 -C 3 -haloalkyl, 
 T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y, 
 Y=methyl, halomethyl, halogen, CN, NO 2 , NH 2 —C═S, or two adjacent radicals Y form together a chain CH—CH═CH—CH, N—CH═CH—CH, CH—N═CH—CH, CH—CH═N—CH, or CH—CH═CH—N, HC═HC—CH, CH—CH═CH, CH═CH—N, N—CH═CH 
 Q=X—NR 3 R 4  or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals; 
 X=CH 2 , CH(CH 3 ), CH(CN), CO, CS, 
 R 3 =hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, 
 
       
         
           
           
               
               
           
         
         wherein Z A =hydrogen, halogen, cyano, halomethyl (CF 3 ); 
         R 4 =hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, am inocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 
         Or R 3  and R 4  together form a substituent selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and a veterinary acceptable liquid carrier vehicle wherein the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as a solvent. 
       
     
     
         2 . The topical localized formulation according to  claim 1 , wherein the isoxazoline compound is a compound of formula II 
       
         
           
           
               
               
           
         
       
       wherein
 R 1a , R 1b , R 1c  are independently from each other hydrogen, Cl or CF 3 , 
 T= 
 
       
         
           
           
               
               
           
         
       
       wherein Y is methyl, bromine, Cl, F, CN or C(S)NH 2 . 
     
     
         3 . The topical localized formulation according to  claim 1 , wherein R 3  is H and R 4  is —CH 2 —C(O)—NH—CH 2 —CF 3 , —CH 2 —C(O)—NH—CH 2 —CH 3 , —CH 2 —CH 2 —CF 3  or —CH 2 —CF 3 . 
     
     
         4 . (canceled) 
     
     
         5 . The topical localized formulation according to  claim 1 , wherein the formulation comprises 1 to 50% N,N-diethyl-3-methylbenzamide. 
     
     
         6 . The topical localized formulation according to  claim 1 , wherein the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as solvent and a co-solvent selected from the group consisting of dimethyl sulfoxide, acetone, dimethylacetamide, ethyl alcohol, eucalyptol, dipropylene glycol monomethyl ether, methylethyl ketone, glycofurol, ethyl-L-lactate, and a mixture of at least two of these co-solvents. 
     
     
         7 . The topical localized formulation according to  claim 6  wherein the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as solvent and a mixture of at least two of acetone, ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide and glycofurol. 
     
     
         8 . The topical localized formulation according to  claim 6  wherein there is a weight/weight ratio of the cosolvent/solvent in the spot-on composition and the weight/weight ratio of the cosolvent/solvent is between 4/1 and 1/5. 
     
     
         9 . The topical localized formulation according to  claim 1 , wherein the formulation further comprises an effective amount of one or more compounds selected from a macrocyclic lactone compound or an insect growth regulator compound. 
     
     
         10 . (canceled) 
     
     
         11 . A method for treatment or prophylaxis of parasite infestation of an animal comprising spot-on or pour-on administration of a localized topical formulation of  claim 1 . 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11  wherein the veterinary acceptable liquid carrier comprises a co-solvent of at least two of acetone, ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide and glycofurol. 
     
     
         14 . The method of  claim 11  wherein the topical localized formulation comprises additionally an effective amount of a macrocyclic lactone compound and/or an insect growth regulator compound. 
     
     
         15 . The method of  claim 14  wherein the macrocyclic lactone compound is selected from ivermectin, moxidectin, milbemycin, selamectin, emamectin, latidectin and lepimectin or a salt thereof and the insect growth regulator compound is selected from fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen. 
     
     
         16 . The topical localized formulation of  claim 1 , wherein the liquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide as solvent and a co-solvent selected from the group consisting of dimethyl sulfoxide, dimethylacetamide, ethyl alcohol, eucalyptol, dipropylene glycol monomethyl ether, methylethyl ketone, glycofurol, ethyl-L-lactate, and a mixture of at least two of these co-solvents. 
     
     
         17 . The topical localized formulation of  claim 16 , wherein the formulation further comprises an effective amount of one of more compounds selected from a macrocyclic lactone compound or an insect growth regulator compound. 
     
     
         18 . The topical localized formulation of  claim 17 , wherein the macrocyclic lactone compound is selected from ivermectin, moxidectin, milbemycin, selamectin, emamectin, latidectin and lepimectin or a salt thereof and the insect growth regulator compound is selected from fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen. 
     
     
         19 . The method of  claim 13 , wherein the veterinary acceptable liquid carrier comprises a co-solvent of at least two of ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide and glycofurol. 
     
     
         20 . The topical localized formulation of  claim 1 , wherein R 2  is CF 3  or CF 2 Cl. 
     
     
         21 . The topical localized formulation of  claim 2 , wherein R 1a  and R 1c  are Cl and R 1b  is hydrogen,