ACYL UREA COMPOUNDS FOR THE TREATMENT OF COCCIDIODOMYCOSIS IN WARM-BLOODED ANIMALS

摘要

1. A method for the treatment or prophylaxis of C.immitis infections in warm-blooded animals which comprises administering to an animal in need of such treatment a therapeutic effective amount of an acyl urea represented by the following formula: wherein R1 is unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, R2 is hydrogen or C1-C6alkyl, R3 is R4 to R8 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or C1-C6alkylthio, R9 is hydrogen or C1-C6alkyl, and X<+> is a pharmaceutically or agronomically acceptable inorganic or organic cation; and pharmaceutically or agronomically acceptable salts thereof. 2. The method according to Claim 1 in which in said acyl urea is a benzoylurea compound represented by the formula: wherein: Hal is independently chloro; bromo; or fluoro. R is hydrogen; chloro; bromo; fluoro; methyl; trifluoromethyl; trifluoromethoxy; 2-chloro-1,1,2-trifluoroethoxy; 2-bromo-1,1,2-triflouroethoxy; 1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy; R is hydrogen or chloro; and R is hydrogen; chloro; 5-trifluoromethylpyrid-2-yloxy; or 3-chloro-5-trifluoromethylpyrid-2-yloxy; and at least one of R and R being other than hydrogen; and pharmaceutically or agronomically acceptable salts thereof. 3. The method according to Claim 2 wherein said benzoylurea is N-(2,6-difluorobenzoyl)-N'-(3,6-dichloro-4-R-phenyl)urea in which R is 2-chloro-1,1,2-trifluoroethoxy; 2-bromo-1,1,2-trifluoroethoxy; 1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy. 4. The method according to Claim 3 wherein said benzoylurea is N-(2,6-difluorobenzoyl)-N'-(3,5-dichloro-4-R-phenyl)urea in which R is 2-chloro-1,1,2-trifluoroethoxy; 2-bromo-1,1,2-trifluoroethoxy; 1,1,2,2-tetrafluoroethoxy; or 1,1,2,3,3,3-hexafluoroprop-1-oxy. 5. The method according to Claim 1 wherein said acyl urea is administered orally, parenterally or through implantation. 6. The method according to Claim 5 wherein the amount of said acyl urea administered is from 0.01 to about 1000 mg per kg of body weight. 7. The method according to Claim 6 wherein the amount of said acyl urea administered is from 1 to about 30 mg per kg of body weight. 8. The method according to Claim 6 wherein the amount of said acyl urea administered is from 0.5 to about 200 mg per kg of body weight. 9. The method according to Claim 5 in which said benzoylurea is selected from the group: N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-chloro-1,1,2-trifluoro-1-ethoxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-chloro-1,1,2-trifluoro-1-ethoxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(2-bromo-1,1,2-trifluoro-1-ethoxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]urea. N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea and N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea. 10. The method according to Claim 5 in which said benzoylurea is selected from the group: N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-chlorophenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(3-chloro-5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-bromophenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-methylphenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3,5-difluoro-4-(1,1,2,3,3,3-hexafluoroprop-2-oxy)phenyl]urea, N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-chlorophenyl]urea, and N-(2,6-difluorobenzoyl)-N'-[3-(5-trifluoromethylpyrid-2-yloxy)-4-fluorophenyl]urea, 11. A method for the treatment or prophylaxis of coccidioidomycosis in a host dog or cat comprises administering to a dog or cat in need of such treatment a therapeutic effective amount of an acyl urea according Claim 1 or a pharmaceutically or agronomically acceptable salt thereof. 12. A method according Claim 11 wherein an acyl urea is an acyl urea according any of Claim 2-4. 13. The method according to Claim 11 wherein said acyl urea is administered orally, parenterally or through implantation. 14. The method according to Claim 13 wherein the amount of said acyl urea administered is from 0.01 to about 1000 mg per kg of body weight. 15. The method according to Claim 13 in which said acyl urea is N-(2,6-difluorobenzoyl)-N'-[3,6-dichloro-4-(1,1,2,3,3,3-hexafluoroprop-1-oxy)phenyl]urea. 16. The use of acyl urea according any of Claim 1-4 or 9-10 or a pharmaceutically or agronomically acceptable salt thereof for treatment or prophylaxis of C.immitis infections in warm-blooded animals. 17. The use of acyl urea according any of Claim 1-4 or 9-10 or a pharmaceutically or agronomically acceptable salt for preparation of pharmaceutical composition for treatment or prophylaxis of C.immitis infections in warm-blooded animals. 18. The use of acyl urea according any of Claim 1-4 or 9-10 or a pharmaceutically or agronomically acceptable salt thereof for treatment or prophylaxis of coccidioidomycosis in a host dog or cat. 19. The use of acyl urea according any of Claim 1-4 or 9-10 or a pharmaceutically or agronomically acceptable salt for preparation of pharmaceutical composition for treatment or prophylaxis of coccidioidomycosis in a host dog or cat.