1-aryl-5-alkyl pyrazole derivative compounds, processes of making and methods of using thereof
Provided are 1-aryl-5-alkyl pyrazole compounds, of formula (I): wherein: R 1 is hydrogen, cyano, halogen, R 8 , formyl, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , or —C(S)NH 2 ; R 2 is R 8 or —S(O) m R 11 ; R 3 is methyl, ethyl or C 1 -C 4 haloalkyl; R 4 , R 5 and R 7 are independently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; R 6 is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R 12 , —S(O) n R 12 or SF 5 ; Z is a nitrogen atom or C—R 13 ; R 8 is alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R 9 is hydrogen, alkyl, haloalkyl or alkoxy; R 10 is hydrogen, alkyl, haloalkyl or alkoxy; R 11 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl or cycloalkyl; R 12 is alkyl or haloalkyl; R 13 is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy; m is 0, 1 or 2; and n is 0, 1 or 2; or a salt thereof, the method of making compounds of formula (I) and the use of these compounds against ectoparasites, endoparasites and pests.
1. A topical veterinary formulation for treating or preventing a parasitic infestation or infection in an animal comprising:
(a) a 1-aryl-5-alkyl or 5-haloalkylpyrazole of formula (I):
wherein:
R 1 is hydrogen, cyano, halogen, R 8 , formyl, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , or —C(S)NH 2 ;
R 2 is R 8 or —S(O) m R 11 ;
R 3 is methyl, ethyl or C 1 -C 4 haloalkyl;
R 4 , R 5 and R 7 are independently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 6 is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R 12 , —S(O) n R 12 or SF 5 ;
Z is a nitrogen atom or C—R 13 ;
R 8 is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;
R 9 is hydrogen, alkyl, haloalkyl or alkoxy;
R 10 is hydrogen, alkyl, haloalkyl or alkoxy;
R 11 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl or cycloalkyl;
R 12 is alkyl or haloalkyl;
R 13 is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy;
m is 0, 1 or 2; and
n is 0, 1 or 2; or
a salt thereof;
(b) a veterinarily acceptable carrier; and
(c) optionally a crystallization inhibitor.
2. The topical veterinary formulation of claim 1 , wherein:
R 2 is —S(O) m R 11 ;
Z is C—R 13 ; and
R 4 , R 5 , R 7 and R 13 are each independently hydrogen or halogen.
3. The topical veterinary formulation of claim 1 , wherein:
R 2 is —S(O) m R 11 ;
Z is a nitrogen atom; and
R 4 , R 5 , and R 7 are each independently hydrogen or halogen.
4. The topical veterinary formulation of claim 1 , wherein:
R 1 is cyano, halogen or —C(S)NH 2 ; and
R 2 is —S(O) m R 11 .
5. The topical veterinary formulation of claim 1 , wherein:
R 2 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or —S(O) m R 11
R 3 is methyl, ethyl or C 1 -C 4 haloalkyl,
R 4 , R 5 and R 7 are independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyano or nitro;
R 6 is halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyloxy, cyano, nitro, —C(O)R 12 , —S(O) n R 12 or SF 5 ;
R 8 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or cycloalkyl optionally substituted with one or more halogens;
R 9 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy;
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy;
R 11 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 2 -C 4 haloalkynyl or cycloalkyl;
R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and
R 13 is hydrogen, halogen, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy.
6. The topical veterinary formulation of claim 5 , wherein:
R 2 is —S(O) m R 11 ;
R 3 is methyl or ethyl optionally substituted with one to three halogens;
R 4 , R 5 and R 7 are independently hydrogen, fluoro or chloro;
R 6 is fluoro, chloro, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy or SF 5 ;
R 8 is C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl or C 1 -C 2 chloroalkyl;
R 9 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 chloroalkyl or C 1 -C 2 alkoxy;
R 10 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 chloroalkyl or C 1 -C 2 alkoxy;
R 11 is C 1 -C 2 alkyl or C 1 -C 2 haloalkyl;
R 12 is C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl or C 1 -C 2 chloroalkyl; and
R 13 is hydrogen, C 1 -C 2 alkyl, chloro or fluoro.
7. The topical veterinary formulation of claim 5 , wherein:
R 1 is cyano;
R 2 is —S(O) m R 11 ;
R 3 is methyl or ethyl optionally substituted with one to three halogens;
R 4 , R 5 , R 7 are independently hydrogen or halogen;
R 6 is C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or SF 5 ;
R 11 is C 1 -C 4 haloalkyl; and
R 13 is C 1 -C 4 alkyl optionally substituted with one or more halogen atoms, or halogen.
8. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is methyl, ethyl, —CH 2 F or —CHF 2 ;
R 6 is —CF 3 , —OCF 3 or —SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F;
R 13 is methyl, chloro or fluoro.
9. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is methyl, ethyl, —CH 2 F or —CHF 2 ;
R 4 is hydrogen, Cl or F;
R 5 and R 7 are both hydrogen;
R 6 is —CF 3 , —OCF 3 or —SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is methyl, chloro or fluoro.
10. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is methyl or ethyl;
R 6 is —CF 3 , —OCF 3 or —SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is methyl, chloro or fluoro.
11. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is methyl or ethyl;
R 4 is hydrogen, Cl or F;
R 5 and R 7 are both hydrogen;
R 6 is —CF 3 , —OCF 3 or —SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is methyl, chloro or fluoro.
12. The topical veterinary formulation of claim 5 , wherein:
R 1 is cyano;
R 3 is methyl or ethyl substituted with one to three halogens;
R 4 , R 5 , and R 7 are independently hydrogen or halogen;
R 6 is C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or —SF 5 ;
R 11 is C 1 -C 4 haloalkyl; and
R 13 is C 1 -C 4 alkyl or halogen.
13. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is —CH 2 F, or —CHF 2 ;
R 4 is hydrogen, fluoro or chloro;
R 5 and R 7 are both hydrogen;
R 6 is —CF 3 , —OCF 3 or SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is methyl, fluoro or chloro.
14. The topical veterinary formulation of claim 6 , wherein:
R 1 is cyano;
R 3 is —CH 2 F, or —CHF 2 ;
R 4 is Cl;
R 5 and R 7 are both hydrogen;
R 6 is —CF 3 , —OCF 3 or —SF 5 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F;
R 13 is chloro or fluoro.
15. The topical veterinary formulation of claim 1 , wherein the formulation is a pour-on formulation.
16. The topical veterinary formulation of claim 1 , wherein the formulation is a spot-on formulation.
17. The topical veterinary formulation of claim 1 , wherein the veterinarily acceptable carrier comprises an organic solvent.
18. The topical veterinary formulation of claim 17 , wherein the organic solvent is acetyltributyl citrate, a fatty acid ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture thereof.
19. The topical veterinary formulation of claim 1 , wherein the formulation comprises a crystallization inhibitor which satisfies the test in which 0.3 ml of a solution comprising 10% (w/v) of the compound of formula (I) in the veterinarily acceptable liquid carrier and 10% of the crystallization inhibitor are deposited on a glass slide at 20° C. and allowed to stand for 24 hour hours, after which less than ten crystals are observable on the slide by the naked eye.
20. The topical veterinary formulation of claim 1 , wherein the formulation further comprises an antioxidant.
21. The topical veterinary formulation of claim 1 , wherein the formulation comprises a crystallization inhibitor, and wherein the crystallization inhibitor is polyvinylpyrrolidone, polyvinyl alcohol, a copolymer of vinyl acetate and vinylpyrrolidone, a polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, a polyoxyethylenated ester of sorbitan, lecithin, carboxymethylcellulose, or an acrylic derivative, an anionic surfactant, a cationic surfactant, a non-ionic surfactant, an amine salt of an amine of the formula NR′R″R′″ wherein each R′, R″ and R′″ in the amine are the same or different hydroxylated hydrocarbons, an amphoteric surfactant, or a combination thereof.
22. The topical veterinary formulation of claim 6 , wherein:
Z is C—R 13 ;
R 1 is cyano;
R 3 is methyl;
R 4 is chloro;
R 5 and R 7 are hydrogen;
R 6 is —CF 3 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is chloro.
23. The topical veterinary formulation of claim 6 , wherein:
Z is C—R 13 ;
R 1 is cyano;
R 3 is methyl;
R 4 is chloro;
R 5 and R 7 are hydrogen;
R 6 is —CF 3 ;
R 11 is —CF 3 , —CClF 2 or —CCl 2 F; and
R 13 is fluoro.
24. The topical veterinary formulation of claim 22 , wherein R 11 is CF 3 and m is 1.
25. The topical veterinary formulation of claim 23 , wherein R 11 is CF 3 and m is 1.