Patent EA-002278-B1 (EA)
Title: Parasiticidal pyrazoles
Inventor: BANKS BERNARD JOSEPH
IPC: C07D231/14
Filed: 1997-11-25
Abstract: 1. A compound of formula (I):   or a pharmaceutically, veterinarily or agriculturally acceptable salt thereof, or a pharmaceutically, veterinarily or agriculturally acceptable solvate of either entity, wherein R<1> is 2,4,6-trisubstituted phenyl wherein the 2- and 6-substituents are each independently selected from halo- and the 4-substituent is selected from C1-C4alkyl optionally substituted with one or more halo-, C1-C4alkoxy optionally substituted with one or more halo-, S(O)nC1-C4alkyl optionally substituted with one or more halo-, halo- and pentafluorothio; or 3,5-disubstituted pyridin-2-yl wherein the 3-substituent is halo- and the 5-substituent is selected from C1-C4alkyl optionally substituted with one or more halo-, C1-C4alkoxy optionally substituted with one or more halo-, S(O)nC1-C4alkyl optionally substituted with one or more halo-, halo- and pentafluorothio; R<3> is C1-C4alkyl optionally substituted with hydroxy or with one or more halo-; cyano, C1-C5alkanoyl or phenyl; R<5> is hydrogen, C1-C4alkyl, amino or halo-; R<2> and R<4> each independently selected from hydrogen, C1-C4alkyl, fluoro-, chloro- and bromo- or, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl group; R<6> and R<8> are each independently selected from hydrogen, C1-C4alkyl, fluoro-, chloro- and bromo-; or, when R<2> and R<4> do not form part of a cycloalkyl group, R<2> and R<6>, together with the carbon atoms to which they are attached, may form a C5-C7cycloalkyl group; R<7> is hydrogen, C1-C4alkyl optionally substituted with one or more halo-, or C1-C4alkoxy; and n is 0,1 or 2. 2. A compound according to Claim 1, wherein R<1> is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl, 2,4,6-trichlorophenyl or 3-chloro-5-trifluoromethylpyridin-2-yl; R<3> is methyl, ethyl, prop-2-yl, 1-hydroxyethyl, 2-hydroxyprop-2-yl, difluoromethyl, dichloromethyl, trifluoromethyl, cyano, formyl, acetyl or phenyl; R<5> hydrogen, methyl, amino or chloro-; R<2> and R<4> are each independently selected from hydrogen, methyl, fluoro-, chloro- and bromo- or, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl or cyclopentyl group; R<6> and R<8> are each independently selected from hydrogen, methyl, chloro- and bromo-; or, when R<2> and R<4> do not form part of a cycloalkyl group, R<2> and R<6>, together with the carbon atoms to which they are attached, may form a cyclopentane or cyclohexane group; and R<7> is hydrogen, methyl, ethyl, trifluoromethyl, chlorodifluoromethyl, pentafluoroethyl, heptafluoropropyl or methoxy. 3. A compound according to Claim 2, wherein R<1> is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl or 3-chloro-5-trifluoromethylpyridin-2-yl; R<3> is cyano; R<5> is hydrogen or amino; R<2> and R<4> are the same and are hydrogen, chloro- or bromo-; R<6> and R<8> are hydrogen; and R<7> is hydrogen, trifluoromethyl or chlorodifluoromethyl. 4. A compound according to Claim 3, wherein the compound of formula (I) is selected from 3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; (-)-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1-trifluoromethylcyclopropyl)pyrazole; 3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; 3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 4-(1-chlorodifluoromethylcyclopropyl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 1-[(3-chloro-5-trifluoromethyl)pyridin-2-yl]-3-cyano-4-(2,2-dibromocyclopropyl)pyrazole; 5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; 5-amino-3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1-trifluoromethylcyclopropyl)pyrazole. 5. A pharmaceutical composition comprising a compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent or carrier. 6. A pharmaceutical formulation according to Claim 5, which is adapted for topical administration. 7. A veterinary or agricultural formulation comprising a compound of formula (I), or a veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, of any one of Claims 1 to 4, together with a veterinarily or agriculturally acceptable diluent or carrier. 8. A veterinary or agricultural formulation according to Claim 7, which is adapted for topical administration. 9. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, of any one of Claims 1 to 4 as a medicine. 10. The use of a compound of formula (I), or veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity, of any one of Claims 1 to 4 as a parasiticide. 11. The use of a pharmaceutical compound of any one of Claims 5 or 6 as a medicine. 12. The use of veterinary or agricultural compound of any one of Claims 7 or 8 as a parasiticide. 13. The use of a compound of formula (I), or pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, of any one of Claims 1 to 4 for producing of parasiticide medicine for human or animal. 14. The use of a pharmaceutical compound of any one of Claims 5 or 6 for producing of parasiticide medicine for human. 15. The use of a veterinary compound of any one of Claims 7 or 8 for producing of parasiticide medicine for animal. 16. A compound of formula (VII):   wherein Ar is phenyl or naphthyl either of which is optionally substituted with C1-C4alkyl, C1-C4alkoxy or halo-; R<5> is hydrogen, C1-C4alkyl or halo-; R<7> is hydrogen or C1-C4alkyl optionally substituted with one or more halo-; and R<1> and R<3> are as previously defined in Claim 1. 17. A compound of Claim 16 wherein Ar is 4-methylphenyl. 18. A method for the treatment of parasitic invasion in an animal (including a human being), which method includes processing said animal with an effective amount of a compound of formula (I), or pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, of any one of Claims 1 to 4 or a pharmaceutical compound of any one of Claims 5 or 6 or a veterinary compound of any one of Claims 7 or 8, comprising any of the above-mentioned. 19. A method of treating a parasitic invasion at a locus which comprises treating said locus with an effective amount of a compound of formula (I) or veterinarily or agriculturally acceptable salt thereof, or a veterinarily or agriculturally acceptable solvate of either entity of any one of Claims 1 to 4, or a veterinary or agricultural compound of any one of Claims 7 or 8, comprising any of the above-mentioned. 20. A method as defined in Claim 19, wherein the locus is the skin or fur of an animal, or a plant surface, or the soil around the plant to be treated. 21. A method for producing a compound of Claim 1, wherein R<2> and R<4> are either both chloro- or both bromo-, wherein a compound of formula (II)   wherein R<1>, R<3>, R<5>, R<6>, R<7> and R<8> are as previously defined in Claim, 1 are treated with chloroform or bromoform in the presence of a base, optionally followed by formation of a pharmaceutically, veterinarily or agriculturally acceptable salt of the required product or a pharmaceutically, veterinarily or agriculturally acceptable solvate of either entity. 22. A method as defined in Claim 21, wherein the base is a concentrated aqueous solution of an alkali metal hydroxide and the reaction is conducted under phase transfer catalysis conditions using a quaternary ammonium salt as catalyst in a suitable solvent at from about room temperature to about the reflux temperature of the reaction medium. 23. A method as defined in Claim 22, wherein the base is a concentrated aqueous solution of sodium hydroxide, the catalyst is benzyltriethylammoniumchloride and the solvent is dichloromethane optionally in the presence of a small amount of ethanol. 24. A method as defined in any of Claims 21-23, wherein R<1> is 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-pentafluorothiophenyl, or 2,4,6-trichlorophenyl; R<3> is methyl, ethyl, prop-2-yl, 1-hydroxyethyl, 2-hydroxyprop-2-yl, difluoromethyl, dichloromethyl, trifluoromethyl, cyano, formyl, acetyl or phenyl; R<5> is hydrogen, methyl, amino or chloro; R<2> and R<4> are each independently selected from chloro- and bromo-; R<6> and R<8> are each independently selected from hydrogen; and R<7> is hydrogen. 25. A method as defined in Claim 24, wherein R<1> is 2,6-dichloro-4-trifluoromethylphenyl, or 2,6-dichloro-4-pentafluorothiophenyl, R<3> is cyano; R<5> is hydrogen or amino; R<2> and R<4> are identical chloro- or bromo-; R<6> and R<8> are each hydrogen; and R<7> is hydrogen. 26. A method as defined in Claim 25, wherein the compound produced in accordance with Claim 1 is selected from 3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; (-)-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; 3-cyano-4-(2,2-dichlorocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 5-amino-3-cyano-4-(2,2-dibromocyclopropyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole; 5-amino-3-cyano-4-(2,2-dlbromocyclopropyl)-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole; and 5-amino-3-cyano-4-(2,2-dichlorocyclopropyl)-1-