HK1140641A - Combination product for controlling parasites on animals - Google Patents

Description

Combination for controlling parasites on animals

The invention relates to novel agents (Mittel) for controlling parasites on animals, comprising N-arylpyrazoles and pyrethroids (Pyrethroids) in a formulation comprising aliphatic cyclic carbonates and aliphatic cyclic or acyclic polyethers.

N-arylpyrazoles and their good insecticidal and acaricidal activity are known from US2006014802A1, WO2005090313A1, FR2834288A1, WO09828277, US06069157, WO200031043, DE19824487, WO09804530, WO09962903, EP00933363, EP00911329, WO09856767, US05814652, WO09845274, WO9840359, WO09828279, WO09828278, DE19650197, WO 824767, EP 0084096686, EP00839809, WO09728126, EP 80378 007007378, GB02308365, US05629335, WO09639389, US 055873, EP 0559006745, US 05118040, EP-A-321 234119, EP-A-295117 and WO 98/24769. Although this application is achieved with a number of N-arylpyrazole structures, in most indications, one outstanding structure type shows the best activity by comparison. 1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -3-cyano-4- [ (trifluoromethyl) sulfinyl ] -5-aminopyrazole (INN: fipronil) is generally considered to be the most effective compound in this class of compounds for controlling most parasites.

N-arylpyrazoles have been marketed as ectoparasiticides for more than 10 years (Hunter, J.S., III, D.M. Keister and P.Jeannin.1994. Fipronil: A new compound for animal health. Proc. Amer. Assoc. vet. Parasitol.39th Ann. Mtg. san Francisco, page 48 of CA.). They are known for good and broad spectrum activity and acceptable compatibility. It is well known that the existing ones have high contentFormulations of amounts of DEE (Transcutol (ethylene glycol monoethyl ether)) comprise a strong skin penetration (FR 1996-11446A; Sicherheitsdatenblatt [ safety data sheet ]]：ISO/DIS 11014/29CFR 1910.1200/ANSI Z400.1 Printing date 10/23/2001：TOP SPOT^TM: fipronil 9.7% w/w) fraction. This facilitates penetration into the sebaceous and epithelial lining by the formulation (Skin distribution of the lipid by microultrasound administration to the leather dog. Cochet; Birckel, P.; Bromet-Petit, M.: Bromet, N.: Weil, A.; European Journal of drug metabolism and pharmaceuticals (1997), 22(3), 211-. If carrying the active substance, high concentrations of sebaceous glands may contribute to the long-lasting effectiveness of the active substance by sebum secretion from the sebaceous glands. However, with conventional preparations, penetration of the N-arylpyrazoles into the blood circulation Is also likely, since the individual hair follicles are fed through blood vessels and the hair follicles are therefore only separated from the blood circulation by a very thin barrier (Transfollicullar drug-Is a realityMeidan, Victor M.; Bonner, Michael C.; Michniak, Bozena B.; International Journal of pharmaceuticals (2005), 306(1-2), 1-14). Thus, the effectiveness of an active substance on an animal is limited by both duration and concentration, as the active substance enters the blood circulation and its effective concentration in sebum is thereby reduced.

Further, it is well known that N-arylpyrazoles are less potent against the genus hard tick (Ixod) than against the genus other ticks (Zeckengattung) (Endris RG, Matthewson, Cooke D & Amo die D (2000). Relency and efficacy of 65% permethrin and 9.7% engineering againt Ixodes ricinus. vet Therapeutics, Vol.1 (No. 3): 159-) -168); endris RG, Cooke D, Amdie D, SweenwyDL & Katz TL (2002), replication and efficiency of 65% permethrin and fluorescence activity spot-on relationships, intake Ixodes and velocities on volumes, VetThepeatics, Vol.3 (phase 1): 64-71).

Pyrethroids (pyrethioids) do also have a relatively broad spectrum of insecticidal action, and some representative compounds also show good acaricidal effects; however, the use of these compounds is often incompatible, and only specific non-toxic representative compounds with limited effectiveness can be used in cats. Recently, WO 04/098290 describes a solution to this problem, in which doses tolerated by cats can be obtained with the aid of synergists, acaricidal pyrethroids and neonicotinoids. The different physicochemical properties of the materials used require special formulations.

Furthermore, pyrethroid compounds are generally known to be less active against ticks of the genus Dermacentella than N-arylpyrazoles. Recently, it has additionally been found that in pyrethroid-resistant insects there is no cross-resistance between pyrethroids and N-arylpyrazoles. In turn, the selection of said mosquito strains using N-arylpyrazoles leads to even a partial withdrawal of pyrethroid resistance (reveertierung). [ laboratory evaluation of fisonil, a phenyl pyrazole reflecting, against adult phenols (Diptera: Curicidae) and innovation of its point of distribution-resistance with dieldrin in Anopheles stephensi.Kolaczinski, Jan; curtis, Chris. London School of Aquene and clinical Medicine, London, UK. Pest Management Science (2001), 57(1), 41-45 ].

WO 2001/065941 a1 and EP 1013170 a1 propose to combine N-arylpyrazoles and pyrethroids in applications against plant pests. JP 11049618A 2 uses similar mixtures to prevent bite damage on wooden constructions (). WO 95/22902 a1 uses the above mixture for direct control of termites. FR 2713891 a1 and WO 95/22902 a1 even claim a synergistic effect of such mixtures, but do not clearly demonstrate this effect.

However, [ Antagonism of dental specificity by piperonyl butoxide and S, S, S-tributyl phosphotriethioate in the German cockroach (Dictyopttera: Blattellidae.) Valles, Steven M.; koehler, Philip g.; brenner, Richard J.center for Medical, Agricultural and Veterinary Entomogy, USDA-ARS, Gainesville, FL, USA. journal of Economic Entomogy (1997), 90(5), 1254-1258] states that inhibitors of oxidative metabolism (P450 oxidase inhibitors) have antagonistic effects on N-arylpyrazoles in cockroaches. Since most pyrethroids are detoxified by the p450 oxidase pathway, they, like MGK264 or piperonyl butoxide, are rather considered antagonists rather than potentiators of N-arylpyrazoles.

GB2396557 a1 teaches that when concentrated powder formulations are used, it is possible to treat ectoparasites with mixtures of N-arylpyrazoles and pyrethroids, if appropriate with the addition of synergists, for example MGK264 or piperonyl butoxide. WO 95/22902 a1 describes soil treatments with improved efficacy against termites by the combined use of phenylpyrazole and a pyrethroid. The mixtures used here are also not suitable for use on warm-blooded animals.

The abovementioned formulations can therefore only be used with difficulty in practice and, owing to the additional toxicological risks found with the granulate (GB2396557), the object must be to prepare self-spreading liquid formulations with high user safety which combine pyrethroids with the positive activity properties of N-arylpyrazoles and which, even in the presence of further synergists from the p450 oxidase inhibitor series, do not lead to a reduction in the efficacy of the N-arylpyrazoles.

To this end, we have now identified, by means of a detailed analysis and series of tests, from a number of additives, solvents and spreading agents (spreitmitel), formulations having properties capable of generally increasing the good arthropodicidal efficacy of N-arylpyrazoles in combination with pyrethroids. Surprisingly, the expected antagonistic effect was not observed here.

The invention relates to novel agents for controlling parasites on animals, comprising N-arylpyrazoles and pyrethroids in a formulation comprising:

aliphatic cyclic carbonates

Aliphatic cyclic or acyclic polyethers.

The arthropodicidal agents of the present invention are novel and have significantly better and longer lasting effects than the formulations described so far, while improving safety for the user and the target animal.

For this agent, the combination partner as an N-arylpyrazole compound is preferably an arthropodicidal pyrethroid, in particular a Cyanopyrethroid (Cyanopyrethroid) type (e.g. flumethrin), a type-1 pyrethroid (e.g. permethrin) or a non-ester pyrethroid (ethofenprox) type.

Here, alpha-cyano pyrethroids (e.g. alpha-cypermethrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate) are preferably used in a concentration range of 0.01 to 5% by weight and, if appropriate, synergists are added (e.g. as described in WO 04/098290). The use of cypermethrin, cyfluthrin, deltamethrin and flumethrin in a concentration range of 0.025 to 0.25% by weight is particularly preferred. Very particular preference is given to using flumethrin in a concentration range of 0.05 to 1.25% by weight.

Type-1 pyrethroids (e.g. allethrin, bioallethrin, permethrin, phenothrin, resmethrin, tetramethrin, transfluthrin) are preferably used in a concentration range of 20 to 70% by weight. It is particularly preferred to use permethrin, cyphenothrin in a concentration range of 30 to 60% by weight. Very particular preference is given to using permethrin in a concentration range of 40 to 50% by weight.

Non-ester pyrethroids (e.g. ethofenprox, benzoxafen, silafluofen) are typically used in a concentration range of 10 to 60% by weight. Preferred are ethofenprox, benzoxyfen; the use of ethofenprox in a concentration range of 25 to 55% is particularly preferred.

N-arylpyrazoles are known per se as arthropodicidal active substances, for example from the abovementioned documents, which are incorporated herein by reference, to the person skilled in the art.

Preferred phenylpyrazoles are those of formula (I):

wherein

X represents ═ N-or C-R¹，

R¹And R³Each independently of the other represents a halogen atom,

R²represents halogen, C_1-3Haloalkyl, S (O)_nCF₃Or SF₅，

n represents a number of 0, 1 or 2,

R⁴represents hydrogen, cyano or a group of formula

Or one of the following cyclic substituents:

R⁵represents hydrogen, C_2-4-alkynyl, C_2-4-alkenyl, which may optionally be substituted by halogen or C_1-3Alkyl mono-or polysubstituted, or R⁵Represents C_1-4-alkyl- (C ═ O) -, C_1-4alkyl-S-, C_1-4-haloalkyl-S-, -S (═ O) -C_1-4-alkyl or-S (═ NH) -C_1-4-alkyl, phenyl optionally substituted by halogen, -furyl optionally substituted by halogen, -NR¹⁴R¹⁵Group, optionally substituted by C_1-4-alkyl or C_1-4-an ethylene oxide group mono-or polysubstituted with a haloalkyl group, or optionally substituted with halogen, C_1-4-alkyl or C_1-4-a haloalkyl mono-or polysubstituted cyclopropyl,

R⁶represents hydrogen, C_1-4-alkylcarbonyl or-NR¹⁶R¹⁷The radical(s) is (are),

R⁷represents hydrogen, C_1-4Alkyl radical, C_1-4-alkyl-S-or-NR⁹R¹⁰，

Y represents ═ S, ═ O, ═ NH, ═ N-C_1-4-alkyl, ═ N-OH or

R⁸Represents C_1-4-an alkyl group,

R⁹and R¹⁰Independently of one another, represents hydrogen, hydroxy or C_1-4-an alkyl group,

R¹¹represents hydrogen, C_1-4-alkyl, -COO-C_1-4-alkyl or-CONR¹²R¹³，

R¹²And R¹³Independently of one another, represents hydrogen or C_1-4-an alkyl group,

R¹⁴and R¹⁵Independently of one another, represents hydrogen, C_1-4Alkyl radical, C_1-4-haloalkyl or C_1-4-alkyl-SO₂-，

R¹⁶And R¹⁷Independently of one another, represents hydrogen, C_1-4-alkoxy or C_1-4-alkyl, wherein C_1-4-alkyl may optionally be substituted by phenyl, pyrazinyl (pyranzyl) or pyridyl, wherein phenyl, pyrazinyl (pyranzyl) or pyridyl may be substituted by hydroxy, C_1-4-alkyl radical, C_1-4-haloalkyl and/or C_1-4Alkoxy is mono-or polysubstituted, or

R¹⁶And R¹⁷Represents C_1-4-alkylcarbonyl group, C_1-4Alkoxycarbonyl radical, C_1-4-alkoxy-C_1-4-alkylcarbonyl or- (C ═ O) NR²⁰R²¹A group, or

R¹⁶And R¹⁷Together represent ═ CR bound to the nitrogen via a double bond¹⁸R¹⁹The radical(s) is (are),

R¹⁸and R¹⁹Independently of one another represent optionally substituted hydroxy, C_1-4Alkyl radical, C_1-4-haloalkyl and/or C_1-4Phenyl mono-or polysubstituted with alkoxy, and/or R¹⁸And R¹⁹Represents hydrogen, C_1-4Alkyl radical, C_1-4-alkenyl or C_1-4-alkoxy, wherein C_1-4Alkyl radical, C_1-4-alkenyl or C_1-4-alkoxy may be optionally substituted by phenyl, said phenyl being optionally substituted by hydroxy, C_1-4Alkyl radical, C_1-4-haloalkyl and/or C_1-4-alkoxy is mono-or polysubstituted,

R²⁰and R²¹Independently of one another, represents hydrogen, C_1-4-alkyl or phenyl, optionally substituted by hydroxy, C_1-4Alkyl radical, C_1-4-haloalkyl and/or C_1-4-alkoxy is mono-or polysubstituted,

R²²represents C_1-4-an alkyl group.

Halogen preferably represents fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

C_1-4Alkyl represents a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl.

C_1-4Haloalkyl represents a linear or branched alkyl radical having 1 to 4 carbon atoms, substituted by one or more identical or different halogen atoms; also included are perhaloalkyl compounds. Preferred are fluoroalkyl groups. Example is-CF₂H、-CF₃、-CH₂CF₃、-CF₂CF₃。

Preferably, the substituents have the following meanings:

x preferably represents C-R¹。

R¹And R³Preferably each independently represents chlorine or bromine.

R²Preferably represents C_1-3Haloalkyl or SF₅。

R⁴Preferably represents hydrogen, cyano or a group of formula

Or one of the following cyclic substituents:

R⁵preferably represents hydrogen, C_2-3-alkynyl, C_2-3-alkenyl, which may optionally be substituted by halogenOr C_1-3-alkyl monosubstitution; or R⁵Preferably represents C_1-3-alkyl- (C ═ O) -, C_1-3alkyl-S-, C_1-3-haloalkyl-S-, -S (═ O) -C_1-3-alkyl or-S (═ NH) -C_1-3-alkyl, phenyl optionally substituted by halogen, furyl optionally substituted by halogen, the group-NR¹⁴R¹⁵Optionally with C_1-3-an ethylene oxide group substituted by a haloalkyl group or optionally by halogen, C_1-4-alkyl or C_1-4-a haloalkyl mono-or polysubstituted cyclopropyl,

R⁶preferably represents hydrogen, C_1-3-alkylcarbonyl or-NR¹⁶R¹⁷A group.

R⁷Preferably represents hydrogen, C_1-4Alkyl radical, C_1-4-alkyl-S-or-NR⁹R¹⁰。

Y preferably represents ═ S, ═ O, ═ NH, ═ N-OH or

R⁸Preferably represents C_1-3-an alkyl group.

R⁹And R¹⁰Preferably independently of one another, represents hydrogen, hydroxy or C_1-3-an alkyl group.

R¹¹Preferably represents hydrogen, C_1-4-alkyl or-CONR¹²R¹³。

R¹²And R¹³Preferably independently of one another, represents hydrogen or C_1-3-an alkyl group.

R¹⁴And R¹⁵Preferably represents hydrogen, C independently of one another_1-3-alkyl radical, C_1-3-haloalkyl or C_1-3-alkyl-SO₂-。

R¹⁶And R¹⁷Preferably represents hydrogen, C independently of one another_1-3-alkoxy or C_1-3-alkyl, wherein C_1-3-alkyl is optionally substituted by phenyl, pyrazinyl or pyridyl, wherein phenyl, pyrazinyl or pyridyl may be substituted by hydroxy, C_1-3-alkyl radical, C_1-3-haloalkyl and/or C_1-3Alkoxy is mono-or disubstituted, or

R¹⁶And R¹⁷Represents C_1-4-alkylcarbonyl group, C_1-4Alkoxycarbonyl, C_1-4-alkoxy-C_1-4-alkylcarbonyl or- (C ═ O) NR²⁰R²¹A group, or

R¹⁶And R¹⁷Together represent ═ CR bound to the nitrogen via a double bond¹⁸R¹⁹A group.

R¹⁸And R¹⁹Preferably independently of one another, represents optionally substituted hydroxy, C_1-3Alkyl radical, C_1-3-haloalkyl and/or C_1-3-alkoxy mono-or disubstituted phenyl, and/or R¹⁸And R¹⁹Represents hydrogen, C_1-3Alkyl radical, C_1-3-alkenyl or C_1-3-alkoxy, wherein C_1-3Alkyl radical, C_1-3-alkenyl or C_1-3-alkoxy may be optionally substituted by phenyl, said phenyl being optionally substituted by hydroxy, C_1-4Alkyl radical, C_1-4-haloalkyl and/or C_1-4-alkoxy mono-or disubstituted.

R²⁰And R²¹Preferably represents C independently of one another_1-3-alkyl or optionally substituted by hydroxy, C_1-3Alkyl radical, C_1-3-haloalkyl and/or C_1-3-alkoxy mono-or disubstituted phenyl.

R²²Represents C_1-3-an alkyl group.

Particularly preferably, the substituents of the formula (I) have the following meanings:

x represents C-R¹。

R¹And R³Each of which isRepresents Cl.

R²Represents CF₃。

R⁴Represents CN, -C (═ S) NH₂or-C (═ O) CH₃。

R⁵represents-SCHF₂、-S(＝O)CF₃、-S(＝O)CH₃、-S(＝O)CH₂CH₃Or represents a 1-trifluoromethyloxirane group.

R⁶Represents amino or one of the following groups

Preferred examples of compounds which can be used according to the invention are listed below:

particularly preferred examples of compounds which can be used according to the invention are:

an example of a particularly preferred N-arylpyrazole is fipronil.

Another example of a very particularly preferred N-arylpyrazole is 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole.

Depending on the nature and arrangement of the substituents, the active substances may, if appropriate, be present in various stereoisomeric forms, in particular as enantiomers and racemates. According to the invention, both pure stereoisomers and mixtures thereof can be used.

The active substances can, if appropriate, also be used in the form of their salts, where appropriate pharmaceutically usable acid addition salts and base salts are suitable.

Suitable pharmaceutically acceptable salts are salts of inorganic or organic acids, for example carboxylic acids or sulphonic acids. Examples which may be mentioned are salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, methylenepamoic acid, glutamic acid or aspartic acid. Suitable pharmaceutically usable basic salts are, for example, alkali metal salts, such as sodium or potassium salts, and alkaline earth metal salts, such as magnesium or calcium salts.

They can furthermore be used in the form of solvates of the active substances, in particular hydrates. Solvates are understood to mean both solvates of the active substance itself (in particular hydrates) and solvates of the salts of the active substance (in particular hydrates).

As a solid, the active substance may in some cases form a plurality of crystalline modifications. Stable variants with suitable dissolution characteristics are advantageously used in the medicament.

Unless otherwise indicated, percentage data is understood to be weight percentages based on the weight of the finished formulation.

Typically, the agent comprises from 1 to 27.5% by weight of arylpyrazole, preferably from 5 to 20% by weight, particularly preferably from 7.5 to 15% by weight.

The aliphatic cyclic carbonates are preferably ethylene carbonate or propylene carbonate, it being possible for mixtures to be used.

The content of aliphatic cyclic carbonates in the formulation can vary widely from 10% by weight to 70% by weight, preferably from 12.5 to 50% by weight, particularly preferably from 15 to 40% by weight.

Aliphatic cyclic and/or acyclic ethers are compounds known per se. Preferably, they are ethers from glycols having up to 8 carbon atoms, such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol. In acyclic ethers, one or two OH groups carry C_1-4-alkyl, preferably only one OH group is etherified; particularly preferred examples are: diethylene glycol monoethyl ether, diethylene glycol monopropyl ether and dipropylene glycol monopropyl ether. Preferred 5-or 6-membered cyclic ethers have an epoxy atom and 4 or 5 ring carbon atoms and are optionally loaded with C_1-4-an alkyl substituent; preferably, they are directly on the ring or at C_1-4The alkyl substituents carry free OH groups. A particularly preferred example is tetrahydrofurfuryl alcohol. The content of aliphatic cyclic and/or acyclic ethers in the agent according to the invention can vary within a wide range from 20 to 77.5% by weight, and a content in the range from 25 to 65% by weight is particularly preferred, and a content in the range from 25 to 50% by weight is very particularly preferred.

According to a preferred embodiment, the agent according to the invention may additionally comprise one or more esters of dihydric or trihydric alcohols having up to three carbon atoms and of organic fatty acids having from 6 to 18 carbon atoms. As alcohol component, the esters used according to the invention comprise diols or triols having up to three carbon atoms, for example ethylene glycol, propylene glycol or glycerol. Typically, at least two, preferably all, of the hydroxyl groups of the alcohol are esterified. The acid component of the ester is a fatty acid having 6 to 18 carbon atoms, which may be straight or branched chain and mono or polyunsaturated. Mixed esters or mixtures of various types of esters may be used. The preferred triglyceride is caprylic-capric acid (C:)) Triglycerides and caprylic/capric/linoleic triglycerides. Likewise, preferred are the esters of propylene glycol with caprylic and/or capric acid (propylene glycol caprylate caprate). Particularly preferably, these caprylic-capric acids are glycerolThe oil or propylene glycol ester has a viscosity in the range of 0.08 to 1.3Pa.s (20 deg.C), and preferably 0.08 to 0.40 Pa.s. Polyethylene oxide-, polypropylene oxide-and/or propylene carbonate-modified derivatives thereof having the above-mentioned viscosity ranges may also be used. Mention may be made, as examples, of propylene glycol dicaprylate, propylene glycol caprylate caprate, caprylic-capric diglycidyl succinate (Capryl-capric-diglycidyl-succinate) having an average viscosity of 0.23pa.s, medium-chain caprylic-capric triglyceride having a viscosity of 0.27-0.30pa.s, with a viscosity ranging from 0.09 to 0.12 pa.s.

The liquid formulation according to the invention may comprise one or more of the above-mentioned esters. In general, the agents according to the invention comprise esters or ester mixtures in a proportion of from 0 to 40% by weight, preferably from 1 to 35% by weight, particularly preferably from 1 to 12.5% by weight and very particularly preferably from 2.5 to 7.5% by weight.

If appropriate, conventional organic or inorganic antioxidants can be used to stabilize the formulations. As the inorganic antioxidant, for example, sulfite and bisulfite, especially sodium bisulfite are mentioned. Preference is given to phenolic antioxidants, such as anisole, butylhydroxytoluene and hydroxyanisole, and also mixtures thereof with one another. Usually, 0.01 to 1% by weight, preferably 0.05 to 0.5% by weight, particularly preferably 0.075 to 0.2% by weight, is used.

The formulation components mentioned, in particular the organic esters, may be stabilized against possible hydrolytic degradation by means of acidifying agents. Suitable acidifying agents are pharmaceutically acceptable acids, especially carboxylic acids, for example succinic acid, tartaric acid, lactic acid or citric acid. They are preferably present in a range of 0 to 0.5% by weight, but preferably 0 to 0.2% by weight.

Polymethoxysiloxane-based polymeric surfactants having a low surface tension of < 30mN/m, preferably < 22mN/m, can be used as further formulation auxiliaries for improving spreadability. The surfactants mentioned are known ethoxylated and/or propoxylated, preferably neutral or particularly preferably cationic, formulation auxiliaries. Mention may be made, as an example of preferred polymer auxiliaries, of the methoxysilane/ethylene oxide copolymer Belisil Silvet L77 from Bayer GE Siliconics GmbH. The content of these formulation auxiliaries may be appropriately varied within a wide range of 0.01 to 1.0% by weight. A preferred range is 0.2 to 0.4% by weight.

The formulations may, if appropriate, further comprise pharmaceutically acceptable auxiliaries and additives.

In addition to the arylpyridines and pyrethroids, the reagent according to the invention may also comprise one or more further active substances. Mention may be made, as preferred examples of the above-mentioned co-active substances: growth inhibitors, for example, chitin biosynthesis inhibitors, such as benzoylphenylureas (e.g., Triflumuron, Lufenuron (Lufenuron)); phenyl oxazolines (e.g., etoxazole (Etoxazol)); juvenile hormone analogues (e.g. methoprene (Methopren), hydroprene (Hydropren), pyriproxyfen (Pyriproxifen)) and mixtures of these active substances with one another. Their content may vary within a wide range from 0.1 to 7.5% by weight, but is preferably from 0.25 to 5.0% by weight, particularly preferably from 0.25 to 2.5% by weight.

The formulation according to the invention may further comprise a synergist. Synergists in the sense of the present application are understood as meaning compounds which do not have the desired activity themselves, but which are capable of increasing the activity of the active substance as mixed participants. Mention may be made here, by way of example, of piperonyl butoxide, MGK264, synergistic alkynes (Verbutin), defoliant (S, S, S-tributylphosphotrithioate). In the formulations according to the invention, the synergist is preferably used in the case of α -cyano pyrethroids, in particular as a synergist: pyrethroids are used in a ratio of 20-50: 1 (see also WO 04/098290). A preferred synergist is MGK 264.

The agent according to the invention is environmentally friendly and has reduced toxicity compared to known agents. They are therefore user-friendly and are furthermore distinguished by easy handling. The reagent has a flash point advantageously > 70 ℃ and can therefore be produced in simple apparatus without further explosion-proof measures.

Because of the favourable warm-blooded animal toxicity, the agents according to the invention are suitable for controlling parasitic arthropods, in particular insects and arachnids, in particular fleas and ticks, on animals, in particular warm-blooded animals, particularly preferably mammals. These animals may be domestic and beneficial animals as well as zoo, laboratory and laboratory animals and pets.

The agents described herein are particularly useful against ectoparasites on pets, particularly dogs and cats, and beneficial animals.

The agents of the invention are active against all or individual developmental stages of the pest and against resistant or normally sensitive pest species.

The pests include:

from the order of the louse (Anoplura), for example, the species diaphorina (haemantoponus spp.), the species diaphorina (lingnathus spp.), the species tubostis (solenoptes spp.), the species louse (Pediculus spp.), the species diaphorina (ptherus spp.);

mallophaga (Mallophaga), e.g., Trimenopon spp, coleus sp (Menopon spp), Eomenacanthus spp, pediculus sp (menacanthus spp), rodent sp (trichodictyotes spp), pediculus felis sp (Felicola spp), damalina spp, pediculus bovis (Bovicola spp);

diptera (Diptera), brachycota (Brachycera), for example, ptecticus species (chrysospp), Tabanus species (Tabanus spp.), muscus species (Musca spp.), hydroxytape spp., pythium species (muscadin spp.), Hydrotaea spp., pythium species (Muscina spp.), haematobos spp., hematomyiasis species (Haematobia spp.), staphylus species (Stomoxys spp.), latticidae spp.), gracilia species (fantia p.), glossomyzidae species (Glossiana spp.), lucilia species (lucilia spp.), calliphoria species (calliphoria spp.), eustia species (scleroderma spp.), eustis species (sclerostipa), pyrus species (sclerostipa spp.), eustis species (sclerostigmas spp.), eustis species (coriaria spp.), eustigmas spp.), eustigmatis spp.), eustis species (sclerostipa spp.), eustipa spp.), eustis species (sclerostigma spp.), eustis species (sclerostia spp.), eustia spp.), eustis species (sclerostis, eustia species (coriaria spp.), eustis species (eustis spp.), eustia species (eustis, eustigmas spp.), eustis species (eustis spp.), eustis species (eustis) and eustis, eustis species (eustis) of eustis, eustis species (eustis, eustis species (eustis), eustis species (eustis) of eustis, Nasal lyssodes species (Rhinoestrus spp.), tick flies species (Melophagus spp.), pediculus spp.

From the order of the Diptera (Diptera), from the sub-order of the Angioptera (Nematocera), for example, Culex species (Culex spp.), Aedes species (Aedes spp.), Anopheles species (anophesepp.), Culicoides species (Culicoides spp.), Chrysophytum species (Phlebotomus spp.), Arachis species (Simulium spp.).

Siphonaptera (Siphonaptera), for example, species of the genus ctenophora (Ctenocephalides spp.), species of the genus coronaria (Echidnophaga spp.), species of the genus ceratophyllum (Ceratophyllus spp.), species of the genus siphonopsis (Pulex spp.).

Posterior stomata (Metastigmata), for example, species of the genus vitreophthyrium (hyalmaspp.), species of the genus Rhipicephalus (Rhipicephalus spp.), species of the genus bopagus (boophilus spp.), species of the genus Amblyomma (ambyomma spp.), species of the genus haemaphysalis (haemaphysisssp.), species of the genus dermaphyllus (haemaphysalis spp.), species of the genus dermaphyllus (Dermacentor spp.), species of the genus ixodex (ixodex spp.), species of the genus hard ticks (ixodex spp.), species of the genus Argas (Argas spp.), species of the genus amblyoplasma (ornithorus spp.), species of the genus rhyomma spp.;

from the order of the Mesotorgata, for example, the species Dermanyssusp, Dermanyssus sp, Ornithonysus sp, Postirus sp.

From the phylogenales Prostigmata (Prostigmata), for example, the genus Acacia species (Cheyletiella spp.), Psorergates spp., the genus Hypoderma species (Myobia spp.), the genus Demodexspecuroides species (Demodexspp.), the genus Neotsutsugami species (Neotrambicula spp.);

phylogenetic sub-orders (astomata), for example, acarina species (Acarus spp.), dermatophagoides species (mycopes spp.), Psoroptes species (Psoroptes spp.), dermatophagoides species (chlamydoptes spp.), collectins species (trichoderma spp.), pelycosis species (scabies spp.), goniothyrium species (knediophores spp.), neonomycosis spp., cytodimoides spp., and Laminositides spp.;

particular emphasis is given to the action against: fleas (Siphonaptera), for example, species of the genus Ctenocephalides (Ctenocephalides spp.), species of the genus Geotrichum (Echidnophagaspp.), species of the genus Ceratophyllum (Ceratophyllus spp.), species of the genus Philippinensis (Pulex spp.), species of the genus Peropis (Hyalomys spp.), species of the genus Rhipicephalus (Rhipicephalus spp.), species of the genus Bolus (Boophilus spp.), species of the genus Blatomys (Amblyomma spp.), species of the genus Haemophilus (Haemaphysalis spp.), species of the genus Dermacentor spp., species of the genus Iressus (Ixospos spp.), species of the genus Ardisia spp., species of the genus Ardisia spp, species of the genus Blatomys spp (Haemophilus spp.), species of the genus Blastomycophagus spp.), species of the genus Haemophilus spp Stable species (Stomoxys spp.), latrine species (Fannia spp.), glossomyzis species (Glossina spp.), viridid species (Lucilia spp.), callyphora species (Calliphora spp.), Pyromystis species (Automeria spp.), Marasmus species (Cordylobia spp.), Convolvulus species (Cochliomysia spp.), Chrysomyzidae species (Chrysomyia spp.), Marasmius species (Sarcophaga spp.), Musca species (Wohlfartia spp.), Gastropharia species (Gasterophila spp.), Oeromysp.

Beneficial animals and farm animals include mammals, e.g., cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, e.g., mink, chinchilla, racoon, birds, e.g., hens, geese, turkeys, ducks.

Laboratory and test animals include mice, rats, guinea pigs, rabbits, hamsters, dogs, and cats.

Pets include dogs and cats.

Particular emphasis is given to the use in cats and dogs.

The use may be either prophylactic or therapeutic.

Preferably, the liquid formulation according to the invention is used for spot-on, pour-on or spray application, wherein the spray application may be by e.g. using a pumped spray or an aerosol spray (pressurized spray). For special indications, the formulation may also be used as a soaking bath (Tauchbad) after dilution with water; in this case, the formulation should contain an emulsifying additive.

Preferred forms of application are pump sprays, pour-ons and spot-ons. Spot-on applications are particularly preferred.

The formulations according to the invention are characterized by their excellent compatibility with conventional "Single-Dose" plastic tubes, and by their storage stability in various climatic regions. They have a low viscosity and can be applied without any problems.

The liquid formulation according to the present invention may be prepared by mixing the respective amounts of the components with each other using, for example, a conventional stirring vessel or other suitable apparatus. If the composition is desired, it can also be carried out in a protective atmosphere or by other methods for excluding oxygen.

Examples

Example 1

100ml of a liquid formulation consisting of:

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

57.30g of diethylene glycol monoethyl ether

0.10g of BHT

BHA of 0.20g

30.02g of propylene carbonate

5.00g of propylene glycol caprylate caprate (propylglykoloctanoatatdecanoat)

0.24g of flumethrin

10.36g of MGK264

0.02g of citric acid

Example 2

100ml of a liquid formulation consisting of:

10.00g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

0.24g of flumethrin

0.02g of citric acid

0.20g of BHT

68.00g of dipropylene glycol monomethyl ether

13.40g of propylene carbonate

5.00g of demineralized water

5.00g propylene glycol caprylate caprate

5.00g of MGK264

Example 3

100ml of a liquid formulation consisting of:

10.00g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

0.50g of PPF (pyriproxyfen)

0.24g of flumethrin

0.02g of citric acid

0.20g of BHT

67.50g of dipropylene glycol monomethyl ether

13.40g of propylene carbonate

5.00g of demineralized water

5.00g propylene glycol caprylate caprate

5.00g of MGK264

Example 4

100ml of a liquid formulation consisting of:

10.00g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

0.50g of PPF (pyriproxyfen)

0.24g of flumethrin

0.02g of citric acid

0.20g of BHT

60.90g of diethylene glycol monoethyl ether

20.00g of propylene carbonate

5.00g of demineralized water

5.00g propylene glycol caprylate caprate

5.00g of MGK264

Example 5

100ml of a liquid formulation consisting of:

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

45.00g permethrin

37.90g of diethylene glycol monoethyl ether

0.10g of BHT

BHA of 0.20g

25.00g of propylene carbonate

5.00g propylene glycol caprylate caprate

0.02g of citric acid

Example 6

100ml of a liquid formulation consisting of:

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

45.00g permethrin

1.00g of PPF

36.90g of diethylene glycol monoethyl ether

0.10g of BHT

BHA of 0.20g

25.00g of propylene carbonate

5.00g propylene glycol caprylate caprate

0.02g of citric acid

Example 7

100ml of a liquid formulation consisting of:

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

45.00g permethrin

1.00g of PPF

0.25g of Silvet L77 from GE Siliconcs GmbH D-51368Leverkusen

36.65g of diethylene glycol monoethyl ether

0.10g of BHT

BHA of 0.20g

25.00g of propylene carbonate

5.00g propylene glycol caprylate caprate

0.02g of citric acid

Example 8

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

45.00g permethrin

1.00g of PPF

0.25g of Silvet L77 (from Bayer-GE Silicones GmbH, D-51368Leverkusen)

36.65g of diethylene glycol monoethyl ether

0.10g of BHT

BHA of 0.20g

25.00g of Carboxylic ester ethylene ester

5.00g propylene glycol caprylate caprate

0.02g of citric acid

Comparative example 1

A commercially available 10% spot-on formulation of fipronil from Merial Ltd., 3239 Satellite Blvd., Duluth, GA 30096-.

Comparative example 2

Formulation comprising 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole, but without the addition of flumethrin or MGK 264:

100ml of a liquid formulation consisting of:

10.0g of 5-amino-4-trifluoromethylsulfinyl-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole

57.7g of diethylene glycol monoethyl ether

40.0g of propylene carbonate

5.0g of propylene glycol caprylate caprate

0.1g of butylhydroxytoluene

0.2g of butylhydroxyanisole

Comparative example 3

Formulations containing flumethrin and MGK264 and PPF, but replacing the 3-thiocarbamoylpyrazole mentioned in the application with the known insecticide imidacloprid.

100ml of a liquid formulation consisting of:

10.0g imidacloprid

0.50g of PPF

56.80g of benzyl alcohol

0.10g of BHT

BHA of 0.20g

30.02g of propylene carbonate

5.00g propylene glycol caprylate caprate

0.24g of flumethrin

10.36g of MGK264

0.02g of citric acid

Biological examples

All compounds were dosed precisely by weight to ensure better comparability. For this purpose, 20 pipettes of a commercial preparation containing fipronil were injected into glass bottles and likewise blinded via the code.

All samples were applied as separate spots to the neck (cats and smaller dogs) using an Eppendorf pipette (to a volume of 0.95 ml). For application volumes in excess of 1ml, the volume was bisected and applied to the neck as two points approximately 10cm apart.

Further laboratory tests on the activity against fleas and ticks, according to example 2, show that the preparation of the above-mentioned formulation according to the invention has a very good and long-lasting effect against ticks and fleas, which in this test is also consistently superior to the prior art (comparative example 1 to comparative example 3). Furthermore, the formulations of the above-mentioned formulations according to the invention are superior in their tolerance by the target animals and users, and they are therefore very suitable for controlling fleas and ticks on small animals.

A. Activity against fleas (Ctenocephalides felis) on dogs

Dogs were infested 1-2 times during days-4 and-1 with an amount of approximately 100 mature uneaten Ctenocephalides felis per dog. Fleas are placed on the neck of the animal.

On day 0, the results of the infestation on the dog were investigated by examining fleas on the awakened animals. The number of live fleas was recorded.

After flea counting, the animals were treated. The dogs in the control group were not treated. The agent to be tested is administered to the skin of the animal as a spot injection at an administration rate of 0.1-0.15ml/kg body weight, or as a spray at an administration rate of 1-1.5ml/kg body weight. One administration was performed on day 0. Only clinically healthy animals were used.

On days 1 and 2, all dogs were examined for live fleas. The results are recorded together with the initial data.

All dogs were again infested on days 7, 14, 21, 28 and 35 and, if necessary, also on days 42 and 49 with an amount of about 100 mature uneaten Ctenocephalides felis (Ctenocephara sfelis) per dog. In all cases after one additional day of infestation, all dogs were examined for live fleas. The results are recorded together with the initial data.

Formulations are considered to be very effective if > 95% efficacy is found between 24 and 48 hours after re-infestation, and the effect lasts at least 3-4 weeks.

Efficacy was calculated using the correction formula according to Abbott:

KG: a control group; BG: treatment group

It was found that the agent of formulation example 2, administered by spot injection at a dose of 0.15ml/kg, was very effective against Ctenocephalides felis.

B. Against ticks (Rhipicephalus sanguineus) on dogs, Activity of Dermacentor variabilis)

During the-4 th and-1 st day, 2% was used(Bayer AG, active substance: xylazine hydrochloride) (0.1ml/kg body weight) the dogs were sedated. Once all dogs have been enrolledQuietly (after about 10-15 minutes), they are transferred to a shipping box and 50 red Rhipicephalus sanguineus (Rhipicephalus sanguineus) or dermatan variabilis (dermatacor variabilis) (25 |,) Applied to the neck of an animal. After about 11/2 hours, the animals were re-transferred from the transport box to the cages.

On day 0, the results of the infestation on dogs were investigated by examining ticks which awakened the animals. The search was conducted thoroughly in the head and ear region (including the folds of the ears), in the neck region, on the lower abdomen, on the lower chest, on the flanks and in the middle of the toes and on the extremities. The number of ticks that were sucking was recorded. Dead ticks were removed.

After tick counting, animals were treated. The dogs in the control group were not treated. The agent to be tested is administered to the skin of the animal as a spot injection at an administration rate of 0.1-0.15ml/kg body weight, or as a spray at an administration rate of 1-1.5ml/kg body weight. One administration was performed on day 0. Only clinically healthy animals were used.

On days 1 and 2, all dogs were examined for live and dead ticks. The results are recorded together with the initial data. On day 2, all live and dead ticks were removed from the dogs.

On days 7, 14, 21, 28 and 35 and, if desired, also on days 42 and 49, 50 red rhipicephalus (Rhipicephalussanguineus) or dermanylus variabilis (Dermacentor variabilis) (25 |,) The amount of (c) again infests all dogs. After two days of reinfection in each case, all dogs were examined for live and dead ticks. The results are recorded together with the initial data. The next day after re-infestation, all live and dead ticks were removed from the dogs.

The formulations are considered to be very effective if > 90% efficacy is found on day 2 and in each case the day after re-infestation, and the effect lasts at least 3 weeks.

To calculate the efficacy, a correction formula according to Abbott was used:

KG: a control group; BG: treatment group

The agent of formulation example 2, administered by spot injection at a dose of 0.15ml/kg, was found to be very effective against Rhipicephalus sanguineus.

C. Activity against fleas (Ctenocephalides felis) on cats

On day-1, cats are infested with an amount of about 100 mature uneaten Ctenocephalides felis per cat. Fleas are placed on the neck of the animal.

On day 0, the results of the infestation on the cat were investigated by examining fleas on the awakened animals. The number of live fleas was recorded.

After flea counting, the animals were treated. Cats in the control group were not treated. The agent to be tested is administered to the skin of the animal as a spot-on at an administration rate of 0.1-0.15ml/kg body weight. One application was performed on day 0. Only clinically healthy animals were used.

On day 2, all cats were examined for live fleas. The results are recorded together with the initial data.

All cats were again infested with an amount of about 100 mature uneaten ctenopharopeides felis (ctenocephales) per cat on days 7, 14, 21, 28 and 35 and, if desired, also on days 42 and 49. In all cases after two days of re-infestation, all cats were examined for live fleas. The results are recorded together with the initial data.

Formulations were considered to be very effective if > 95% efficacy was found on day 2 and the day after re-infestation in all cases, and the effect lasted at least 3-4 weeks.

Efficacy was calculated using the correction formula according to Abbott:

KG: a control group; BG: treatment group

It was found that the agent of formulation example 2, administered by spot injection at a dose of 0.15ml/kg, was very effective against Ctenocephalides felis.

D. Activity against ticks (Ixodes ricinus) on cats

In all cases, cats were sedated with mild sedative (acepromazine maleate) on day-2. Once all cats have been sedated (after about 10-15 minutes), 30-50 ticks (Ixodes ricinus) per cat (15-25,) Applied to the neck of an animal.

On day-1, the results of the infestation on cats were investigated by examining ticks which wake up the animals. The search was conducted thoroughly in the head and ear area, in the neck area, on the lower abdomen, on the lower chest, on the flank and on the extremities. The number of ticks ingested was recorded. Dead ticks were removed.

After tick counting, animals were grouped. Treatment was performed on day 0. Cats in the control group were not treated. The agent to be tested is administered to the skin of the animal as a spot-on at an administration rate of 0.1-0.15ml/kg body weight. One administration was performed on day 0. Only clinically healthy animals were used.

All cats were examined for live and dead ticks on day 2. The results are recorded together with the initial data. All live and dead ticks were removed from the cats.

On days 7, 14, 21, 28 and 35 and, if desired, also on days 42 and 49, in each case 30-50 hard ticks (Ixodes ricinus) (15-25,) The amount of (c) again infests all cats. After two days of re-infestation in each case, all cats were examined for live and dead ticks. The results are recorded together with the initial data. The next day after re-infestation, all live and dead ticks were removed from the cats.

The formulation is considered to be very effective if > 90% efficacy is found on day 2 and in all cases the next day after re-infestation, and the effect lasts at least 3 weeks.

To calculate the efficacy, a correction formula according to Abbott was used:

KG: a control group; BG: treatment group

It was found that the agent according to formulation example 2 was very effective against hard ticks (Ixodes ricinus) by spot-injection at a dose of 0.15 ml/kg.

E. Efficacy against fleas and ticks for 4 to 7 weeks

The agents according to the invention were tested for efficacy against fleas and ticks over a period of four to seven weeks. The test was performed as described in items A to D.

Claims (12)

1. An agent for controlling parasites on animals comprising an N-arylpyrazole and a pyrethroid in a formulation comprising:

aliphatic cyclic carbonates

Aliphatic cyclic or acyclic polyethers.

2. The reagent according to claim 1, additionally comprising esters of one or more diols or triols having up to three carbon atoms and organic fatty acids having from 6 to 18 carbon atoms.

3. The agent according to any one of the preceding claims, comprising from 1 to 27.5% by weight of arylpyrazole.

4. The agent according to any one of the preceding claims, comprising 10 to 70% by weight of aliphatic cyclic carbonate.

5. The agent according to any one of the preceding claims, comprising from 20 to 77.5% by weight of an aliphatic cyclic or acyclic polyether.

6. An agent according to any preceding claim comprising an alpha-cyano pyrethroid.

7. An agent according to claim 6 comprising alpha-cypermethrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, flumethrin or tau-fluvalinate.

8. An agent according to any one of claims 1 to 5, comprising a pyrethroid of type 1.

9. The reagent according to claim 8, comprising allethrin, bioallethrin, permethrin, phenothrin, resmethrin, tetramethrin, or transfluthrin.

10. An agent according to any one of claims 1 to 5 comprising a non-ester pyrethroid.

11. An agent according to claim 10 comprising ethofenprox, benzoxim, silafluofen.

12. Use of an agent according to any one of the preceding claims for the preparation of a medicament for controlling parasites on animals.