Topically administrable formulation for the control and prevention of animal parasites

Abstract

The invention relates to novel liquid formulations suitable for topical administration to animals, which formulations comprise a fluorine-containing antiparasitic active compound and also triethyl phosphate, and to their use for the control and prevention of animal parasites.

Claims

1. A liquid formulation, comprising a fluorine-containing antiparasitic active compound and triethyl phosphate, wherein the liquid composition is a homogenous solution.

2. The liquid formulation according to claim 1, wherein the fluorine-containing active compound comprises at least one fluorine atom per 200 u of the molecular weight.

3. The liquid formulation according to claim 1, wherein the fluorine-containing active compound comprises at least one trifluoromethyl group per 500 u of the molecular weight.

4. The liquid formulation according to claim 1, wherein the fluorine-containing active compound is a compound of formula (I): ##STR00024## in which R.sup.1 represents H, optionally substituted C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-alkoxycarbonyl, aryl-(C.sub.1-C.sub.3)-alkyl, or heteroaryl-(C.sub.1-C.sub.3)-alkyl, A.sub.1 represents CR.sup.2 or N, A.sub.2 represents CR.sup.3 or N, A.sub.3 represents CR.sup.4 or N, A.sub.4 represents CR.sup.5 or N, B.sub.1 represents CR.sup.6 or N, B.sub.2 represents CR.sup.7 or N, B.sub.3 represents CR.sup.8 or N, B.sub.4 represents CR.sup.9 or N, and B.sub.5 represents CR.sup.10 or N, wherein not more than three of the A.sub.1 to A.sub.4 moieties represent N and not more than three of the B.sub.1 to B.sub.5 moieties represent N; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9 and R.sup.10 each independently of one another represent H, halogen, cyano, nitro, in each case optionally substituted C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, N—C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, N—C.sub.1-C.sub.6-alkylamino, N,N-di-C.sub.1-C.sub.6-alkylamino or N—C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.4-alkylamino or 1-pyrrolidinyl; wherein if neither of the A.sub.2 and A.sub.3 moieties represents N, R.sup.3 and R.sup.4 together with the carbon atom to which they are bonded may form a 5- or 6-membered ring containing 0, 1 or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom; or wherein if neither of the A.sub.1 and A.sub.2 moieties is N, R.sup.2 and R.sup.3 together with the carbon atom to which they are attached may form a 6-membered ring containing 0, 1 or 2 nitrogen atoms; R.sup.8 represents halogen, cyano, nitro, each optionally substituted with C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, N—C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, N—C.sub.1-C.sub.6-alkylamino or N,N-di-C.sub.1-C.sub.6-alkylamino; W represents O or S, Q represents H, formyl, hydroxyl, amino, each optionally substituted with C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.5-heterocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.6-,C.sub.10-C.sub.14-aryl, C.sub.1-C.sub.5-heteroaryl, C.sub.6-,C.sub.10-,C.sub.14-aryl-(C.sub.1-C.sub.3)-alkyl, C.sub.1-C.sub.5-heteroaryl-(C.sub.1-C.sub.3)-alkyl, N—C.sub.1-C.sub.4-alkylamino, N—C.sub.1-C.sub.4-alkylcarbonylamino, or N,N-di-C.sub.1-C.sub.4-alkylamino; or represents an optionally poly-V-substituted unsaturated 6-membered carbocycle; or represents an optionally poly-V-substituted unsaturated 4-, 5- or 6-membered heterocyclic ring, where V independently of one another represents halogen, cyano, nitro, each optionally substituted with C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.4-alkenyl, C.sub.1-C.sub.4-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, N—C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, or N,N-di-(C.sub.1-C.sub.6-alkyl)amino; T represents an optionally substituted 5-membered heteroaromatic system containing not more than 2 heteroatoms (1 or 2 heteroatoms), optionally four carbon atoms and one (1) heteroatom, optionally one (1) nitrogen, one (1) oxygen or one (1) sulfur atom or three carbon atoms and two heteroatoms, optionally two nitrogen atoms, one (1) nitrogen and one (1) oxygen atom, or one (1) nitrogen and one (1) sulfur atom, provided that the compound of formula (I) comprises at least one fluorine atom per 200 u of the molecular weight; or a salt, N-oxide or tautomeric form of a compound of formula (I).

5. The liquid formulation according to claim 1, where the fluorine-containing active compound is selected from the group consisting of: 2-chloro-N-cyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide, 2-chloro-N-(1-cyanocyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide, 2-chloro-N-cyclopropyl-5-[4-[2,6-dimethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide, 2-chloro-N-(1-cyanocyclopropyl)-5-[4-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide, 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazol-5-yl]-N-cyclopropylbenzamide, 2-chloro-N-(1-cyanocyclopropyl)-5-[3-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazol-5-yl]benzamide, 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrrol-3-yl]benzamide, 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrrol-1-yl]-N-cyclopropylbenzamide, 2-chloro-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl]-N-cyclopropyl-3-pyridinecarboxamide (Compound 1), 2-chloro-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]-N-cyclopropyl-3-pyridinecarboxamide (Compound 2), tigolaner, fluralaner, afoxolaner (WO2009126668), sarolaner, lotilaner, fluxametamide, pyriprole, and fipronil.

6. The liquid formulation according to claim 1, having an active compound content of 1-60% (w/w).

7. The liquid formulation according to claim 1, comprising at least 10% (w/w) triethyl phosphate.

8. The liquid formulation according to claim 7, comprising 10 to 95% (w/w) triethyl phosphate.

9. The liquid formulation according to claim 1, comprising a cosolvent.

10. The liquid formulation according to claim 9, comprising a cosolvent selected from the group consisting of 1-methoxy-2-propyl acetate, 2-methoxy-1,3-dioxolane, 1-methoxy-2-butanol, 3,4-hexanedione, 2-heptanone, 2,3-pentadione, 3-hexanone, acetone, laurocapram, ethyl acetate, 1-dodecyl-2-pyrrolidinone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, cyclohexanone, propylene glycol, polyethylene glycol, triacetine, limonene, medium-chain triglycerides, ethyl oleate, triethyl citrate, ethylene glycol, 6-methyl-2,4-heptanedione, 2-methoxy-1-propanol, tert-butanol, 1-butanol, tetraglycol, isopropanol, 2-amino-6-methylheptane, isosorbide dimethyl ether, diethylene glycol monoethyl ether, solketal, diethyl carbonate, 3,5-heptanedione, 2,3-heptanedione, ethanol, 2-phenoxyethanol, diethyl phthalate, tributyl 2-acetylcitrate, 2,6-dimethylpyridine, tris-(2-ethylhexyl) phosphate, 4-methyl-2-pentanone, propylene glycol monoethyl ether acetate, octyldodecanol, and 6-methyl-3,5-heptanedien-2-one.

11. The liquid formulation according to claim 9, comprising 1 to 85% (w/w) cosolvent.

12. The liquid formulation according to claim 1 for use for controlling parasites in/on animals.

13. The liquid formulation according to claim 2, wherein the fluorine-containing active compound comprises at least one fluorine atom per 160 u of the molecular weight.

14. The liquid formulation according to claim 2, wherein the fluorine-containing active compound comprises at least one fluorine atom per 100 u of the molecular weight.

15. The liquid formulation according to claim 4, wherein R.sup.1 represents C.sub.1-C.sub.6-alkyl, substituted C.sub.1-C.sub.2-alkyl, methyl, or H.

16. The liquid formulation according to claim 15, wherein R.sup.1 represents H.

Description

EXAMPLES

Example 1

(1) TABLE-US-00002 2-chloro-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1- 30.0 g (trifluoromethyl)ethyl]-6-(methoxy) phenyl]-1H- pyrazol-4-yl]-N-cyclopropyl-3-pyridinecarboxamide (Compound 1) triethyl phosphate 87.1 g 117.1 g = 100 ml

Example 2

(2) TABLE-US-00003 Compound 1 30.0 g 1-methoxy-2-propanol 47.4 g DMSO 15.8 g triethyl phosphate 15.8 g 109.0 g = 100 ml

Example 3

(3) TABLE-US-00004 2-chloro-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1- 30.0 g (trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-1H- pyrazol-4-yl]-N-cyclopropyl-3-pyridinecarboxamide (Compound 2) triethyl phosphate 85.6 g 115.6 g = 100 ml

Example 4

(4) TABLE-US-00005 fipronil 30.0 g triethyl phosphate 70.0 g 100.0 g 

Example 5

(5) TABLE-US-00006 fluralaner 30.0 g triethyl phosphate 70.0 g 100.0 g
Biological Example In-Vivo Efficacy Data (Cats, Dogs)

(6) To test the efficacy of substances acting on ectoparasites, cats and dogs are experimentally populated (infested) with fleas and ticks. In the efficacy evaluation, the data of the treated animals are compared to the data of untreated control animals.

(7) Per infestation, 40-50 ticks and about 100 fleas are applied to each individual animal.

(8) The treatment day is counted as Day 0; correspondingly, the first week is counted as Week 0 (Days 0-6). Accordingly, Week 1 corresponds to Days 7-13 and Week 8 to Days 56-62 after treatment.

(9) Fleas are left on the dog or cat for 24 or 48 (±4 h) hours. After this time, the fleas are removed from the animal using a flea comb. The fleas removed by combing are collected and counted. When counting the fleas, the fleas are categorized into live and dead fleas. For the parasite count, only the live fleas are taken into consideration.

(10) Ticks are left on the dog or cat for 48 (±4 h) hours. After this time, the ticks are manually removed from the animal, optionally using a pair of tweezers. The removed ticks are collected and counted. When counting the ticks, the ticks are categorized into free live ticks, attached live ticks, free dead ticks and attached dead ticks. For the parasite count, only the attached live ticks are taken into consideration.

(11) The efficacy against the parasite in question is calculated using the formula below:
% efficacy=(N2−N1)/N2×100.
N1=geometric mean of the parasite count in the treated group (parasite count: live fleas or live attached ticks)
N2=geometric mean of the parasite count in the untreated group. (parasite count: live fleas or live attached ticks)

(12) In animal experiments with dogs and cats at a dosage of 0.1 ml per kg of body weight (30% w/v solution, corresponds to 30 mg per kg), the examples in the table below showed an efficacy of at least 8 weeks against fleas (Ctenocephalides) and ticks (Dermacentor, Rhipicephalus and Ixodes). For details, see Table 2 below:

(13) TABLE-US-00007 TABLE 2 Data for efficacy against ectoparasites Animal Formu- Ixodes Rhipicephalus Dermacentor species lation fleas ricinus saguineus variabilis dog Exam- 9 weeks  9 weeks  9 weeks 8 weeks ple 3 (100%) (100%) (100%) (92%) count 24 count 48 h count 48 h count 48 h (±4) h (±4) h (±4) h (±4) h dog Exam- 8 weeks 10 weeks 10 weeks 8 weeks ple 1 (100%) (100%) (99%) (100%) count 24 count 48 h count 48 h count 48 h (±4) h (±4) h (±4) h (±4 )h dog Exam- 8 weeks 10 weeks 10 weeks 8 weeks ple 2 (100%) (100%) (100%) (100%) count 24 count 48 h count 48 h count 48 h (±4) h (±4) h (±4) h (±4) h cat Exam- 8 weeks  8 weeks not not ple 1 (100%) (100%) examined examined count 24 count 48 h (±4) h (±4) h