Use of aminoacetonitrile derivatives against endoparasites

1. A method of treating a filarial endoparasitic infection in an animal in need thereof, comprising administering to said animal an effective amount of a Formula (I) compound

stereoisomer thereof, or a veterinarily acceptable salt thereof, wherein:

R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from U, halo, CN, CF 3 , methyl, methoxy, —OCF 3 , and —SCH 3 , wherein said compound is effective in treating said endoparasitic infection.

2. The method of claim 1 wherein said Formula (1) compound is selected from the group consisting of:

N-{1-cyano-2-{5-cyano-2-(trifluoromethyl)phenoxy}-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(2-chloro-4-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(2-chloro-5-cyanophenoxy)-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[3-cyano-5-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(3-chloro-4-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(2,4-dichlorophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(3-chloro-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(4-chlorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(4-chloro-2-cyanophenoxy)-1-cyano-1-methylethyl]4(pentafluorothio)-benzamide;

N-[1-cyano-2-(2-cyanophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(4-iodophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{1-cyano-1-methyl-2-[2-(trifluoromethyl)phenoxy]ethyl}-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(4-cyanophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(2-chlorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(3-chloro-2-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(2-chloro-4-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(2-cyano-4-fluorophenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(4-chloro-2-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-{2-[4-bromo-2-(trifluoromethyl)phenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-chloro-4-(trifluoromethyl)phenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(3-chloro-5-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(3-chlorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(3-cyano-5-fluorophenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-{1-cyano-2-[4-cyano-2-fluoro-6-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(2-bromo-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(3-cyanophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(2-bromo-4-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

4-(2-cyano-2-{[4-(pentafluorothio)benzoyl]amino}propoxy)-3-(trifluoromethyl)-benzamide;

N-[2-(2-bromo-4-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(4-bromo-2-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(3-bromo-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(2-chloro-3-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-{1-no-2-[3-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)-benzamide;

N-[2-(5-bromo-2-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(2-bromo-3-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(3,4-dichlorophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(2,5-dichlorophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(4-cyano-2-methylphenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(3-cyano-4-methoxyphenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-{1-cyano-2-[4-methoxy-2-trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(5-cyano-2-methylphenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[1-cyano-2-(2,6-dichlorophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-[2-(2-chloro-6-fluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

3-chloro-4-(2-cyano-2-{[4-(pentafluorothio)benzoyl]amino}propoxy)benzamide;

4-cyano-2-(2-cyano-2-{[4-(pentafluorothio)benzoyl]amino}propoxy)benzamide;

3-cyano-5-(2-cyano-2-{[4-(pentafluorothio)benzoyl]amino}propoxy)benzamide;

N-[1-cyano-2-(2,4-dicyanophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{2-[3-chloro-2-(trifluoromethyl)phenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{(1S)1-cyano-2-[4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothio)benzamide;

N-[1-cyano-2-(4-cyano-2,6-difluorophenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-(1-cyano-1-methyl-2-{[4-(methylthio)benzyl]oxy}ethyl)-4-(pentafluorothio)-benzamide;

N-[1-cyano-2-(2-cyano-4,6-difluorophenoxy)-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-{1-cyano-2-[5-cyano-2-(trifluoromethoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[4-cyano-2-(trifluoromethoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(2-chloro-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide;

N-[2-(2-bromo-4,5-difluorophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)benzamide; and

N-{1-cyano-2-[4,5-difluoro-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide, stereoisomer thereof, or a veterinarily acceptable salt of said compound or stereoisomer thereof.

3. The method of claim 2 wherein said Formula (1) compound is selected from the group consisting of:

N-{1-cyano-2-[3-cyano-5-(trifluoromethyl)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-[2-(2-bromo-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-(pentafluorothio)-benzamide; and

N-{(1S)1-cyano-2-[4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothio)benzamide, stereoisomer thereof, or a veterinarily acceptable salt of said compound or stereoisomer thereof, and wherein said animal is a companion animal.

4. A method of treating a filarial endoparasitic infection in an animal in need thereof, comprising administering to said animal an effective amount of a Formula (II) compound

stereoisomer thereof; or a veterinarily acceptable salt thereof; wherein;

wherein R 1a , R 1b , R 1d , and R 1e are each independently selected from the group consisting of hydrogen, halo, CF 3 , —OCH 3 , methyl, and hydroxyl.

5. The method of claim 4 wherein said Formula (11) compound is selected from the group consisting of:

N-[1-cyano-2-(5-cyano-2-phenoxyphenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(4-fluorophenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chloro-2-fluorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(2-chloro-4-fluorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chlorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,4-dichlorophenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-(1-cyano-2-[5-cyano-2-(4-methoxyphenoxy)phenoxy]-1-methylethyl)-4-(pentafluorothio)benzamide;

N-(1-cyano-2-{5-cyano-2-[4-(trifluoromethyl)phenoxy]phenoxy}-1-methylethyl)-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(3-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(4-fluoro-2-methylphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(2-chloro-4-methylphenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,4-dimethylphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2-fluorophenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2-fluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(2-chloro-4-methoxyphenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,3-difluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,6-difluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(3,5-difluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide; and

N-{1-cyano-2-[5-cyano-2-(4-hydroxy-2-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide, stereoisomer thereof, or a veterinarily acceptable salt thereof, wherein said compound is effective in treating said endoparasitic infection.

6. The method of claim 5 wherein said Formula (II) compound is selected from the group consisting of:

N-{1-cyano-2-[5-cyano-2-(4-fluorophenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chloro-2-fluorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chlorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-(1-cyano-2-{5-cyano-2-[4-(trifluoromethyl)phenoxy]phenoxy}-1-methylethyl)-4-(pentafluorothio)benzamide;

N-{2-[2-(2-chloro-4-methylphenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,4-dimethylphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide; and

N-{1-cyano-2-[5-cyano-2-(3,5-difluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide, stereoisomer thereof, or a veterinarily acceptable salt thereof, wherein said compound is effective in treating said endoparasitic infection and wherein said animal is a companion animal.

7. The method according to claim 1 , or 4 , wherein said filarial endoparasitic infection is caused by an endoparasite selected from Brugia malayi, Brugia pahangi, Brugia timori, Wuchereria bancrofti, Dirofilaria immitis, Dirofilaria repens, Dirofilaria ursi, Dirofilaria tenuis, Dirofilaria spectans, Dirofilaria lutrae, Dipetalonema reconditum, Dipetalonema repens, Onchocerca gibsoni, Onchocerca gutturosa , and Onchocerca volvulus , or combinations thereof.

8. The method of claim 7 wherein the filarial endoparasitic infection is caused by Dirofilarial endoparasites.

9. The method of claim 8 , wherein the Dirofilarial endoparasite is Dirofilaria immitis.

10. The method of claim 9 further comprising at least one additional veterinary agent, selected from the group consisting of ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin, milbemycin oxime, albendazole, demiditraz, amitraz, oxfendazole, levamisole, pyrantel pamoate, praziquantel, 2-desoxoparaherquamide, fipronil, spinosad, imidacloprid, indoxacarb, S-methoprene, pyriproxyfen, and an isoxazoline selected from the group consisting of 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methylsulfonyl)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfonyl)ethanone; 1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylsulfonyl)ethanone; (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(1,1-dioxidothietan-3-yl)methanone; (1,1-dioxidothietan-3-yl)(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-1-yl)methanone; (3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(1,1-dioxidothietan-3-yl)methanone; 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone; 2-(methylsulfonyl)-1-(5′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)ethanone; 1-(5′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone; 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthamide; 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide; (S)-2-((4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)sulfonyl)-N-(2,2,2-trifluoroethyl)acetamide; 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1-dioxidothietan-3-yl)-2-methylbenzamide; 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)-N-(1,1-dioxidothietan-3-yl)-2-methylbenzamide; and 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1-dioxidothietan-3-yl)-1-naphthamide; and 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone, or combinations thereof.

11. The method of claim 10 , wherein the additional veterinary agent is selected from moxidectin, milbemycin oxime, ivermectin, selamectin, 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuan]-1-yl)-2-(methylsulfonyl)ethanone; or mixture thereof.

12. A compound selected from the group consisting of

N-{1-cyano-2-[5-cyano-2-(4-fluorophenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chloro-2-fluorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{2-[2-(4-chlorophenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-(1-cyano-2-{5-cyano-2-[4-(trifluoromethyl)phenoxy]phenoxy}-1-methylethyl)-4-(pentafluorothio)benzamide;

N-{2-[2-(2-chloro-4-methylphenoxy)-5-cyanophenoxy]-1-cyano-1-methylethyl}-4-(pentafluorothio)benzamide;

N-{1-cyano-2-[5-cyano-2-(2,4-dimethylphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide; and

N-{1-cyano-2-[5-cyano-2-(3,5-difluoro-4-methoxyphenoxy)phenoxy]-1-methylethyl}-4-(pentafluorothio)benzamide, stereoisomers, and pharmaceutically or veterinarily acceptable salts thereof.

13. The method of claim 3 or 6 wherein the companion animal is a dog.