Pharmaceutical composition for controlling parasites on non-human organisms

Abstract

The invention relates to a pharmaceutical composition comprising at least one pharmaceutically active ingredient which is completely dissolved in a solvent phase, characterized in that the pharmaceutically active ingredient is in particular selected from the group of fluorinated heteroaryl amides and the solvent phase is formulated as a solvent mixture and comprises at least one first solvent and a second solvent which is different from the first solvent, wherein the first solvent comprises a C1 to C15-alcohol, wherein the second solvent comprises an organic carbonate, and wherein the first solvent is present in a proportion of 50 to 95 % by weight and wherein the second solvent is present in a proportion of 5 to 50 % by weight, in each case based on the sum of the solvents in the solvent phase.

Description

[0001] The present invention relates to pharmaceutical compositions for the control of parasites on non-human organisms. The invention particularly relates to skin suitable formulations with improved suitability for organisms for the control of ectoparasites of mammals and domestic animals.

[0002] Modern fluoro-containing antiparasitic active compounds, also called fluorinated antiparasitics, such as fluralaner, afoxolaner, sarolaner, lotilaner, fipronil, which have been known for quite some time, as well as the active ingredients described in WO 2015 / 067646 and WO 2015 / 067647, have good insecticidal and acaricidal efficacy. However, many of these active compounds, which are suitable for topical application to animals, have very low solubility in solvents. In order to avoid dripping of the formulation from the coat after application, or incomplete distribution on the skin of the animal, the active compounds should preferably be dissolved in a small amount of solvent. Furthermore, the solvent must be toxicologically safe and have high skin compatibility.

[0003] WO 96 / 17520 relates to a formulation for transdermal application to animals for the control of parasitic insects, having the following components: an agonist or antagonist of the insect nicotinic acetylcholine receptor in a concentration of 1 to 20% by weight, based on the total weight of the formulation; a benzyl alcohol group or optionally a pyrrolidone solvent in a concentration of at least 20% by weight, based on the total weight of the formulation; optionally, a further solvent selected from cyclic carbonates or lactones in a concentration of 5.0 to 80% by weight, based on the total weight of the formulation; optionally, further auxiliaries selected from thickeners, spreading agents, dyes, antioxidants, foaming agents, preservatives, adhesives, emulsifiers in a concentration of 0.025 to 10% by weight, based on the total weight of the formulation.

[0004] Topical pour-on products against animal parasites are known, the formulation of which comprises isopropyl alcohol as solvent. These include inter alia products containing the active ingredient ivermectin, such as Pour-on Pour-on and the like. Examples of pour-on products comprising isopropyl alcohol and other active ingredients are: Pour-on the active ingredient Phoxim, (Elanco, active ingredient: Doramectin).

[0005] It is an object of the present invention to provide a pharmaceutical composition for topical application to non-human organisms using a solvent in which modern, e.g. fluorinated, antiparasitic agents, in particular from the group of heteroaryl amides, have a sufficiently high solubility while at the same time having a good suitability for animals, in particular as pour-on formulations.

[0006] A pharmaceutical composition is provided, comprising at least one parasiticidal, pharmaceutically active ingredient and being particularly easy to apply to animals, which is completely dissolved in a solvent phase, wherein the pharmaceutically active ingredient is in particular selected from the group of fluorinated heteroaryl amides, preferably pyridyl amides and wherein the solvent phase is configured as a solvent mixture and comprises a first solvent and a second solvent different from the first solvent, wherein the first solvent comprises a Ci to Ci5-alcohol, wherein the second solvent comprises an organic carbonate and wherein the first solvent is present in a proportion of 50 to 95 % by weight and wherein the second solvent is present in a proportion of 5 to 50 % by weight, in each case based on the sum of the solvents in the solvent phase.

[0007] For example, the quantitative ratio of the first solvent and the second solvent to each other can be 50:50 to 95:5 % by weight, based on the sum of the solvents in the solvent phase.

[0008] According to a further embodiment, the first solvent can comprise only one solvent or a combination of two or more, preferably a combination of two Ci to Ci5-alcohols, wherein in this configuration the majority of the Ci to Ci5-alcohols are present together in the above-mentioned amounts and are collectively referred to as the first solvent. Thus, in the context of the present invention, a solvent is not necessarily understood as only one substance, but a solvent can also be understood as a mixture of different substances. It is noted, however, that the substances forming the first solvent are all Ci to Ci5-alcohols.

[0009] Alternatively or additionally, the condition is that the second solvent consists of one substance or can be a combination of two or more, preferably two substances, wherein the substances forming the second solvent are all organic carbonates. In this configuration, the two or more organic carbonates are present together in the above-mentioned amounts.

[0010] The solvent phase consisting only of the first solvent and the second solvent is also referred to as a binary solvent phase.

[0011] The composition of the present invention is in particular capable of providing a novel liquid medicament for topical or dermal application to non-human organisms using a solvent in which fluorinated antiparasitic agents, in particular selected from the group of heteroaryl amides, have a sufficiently high solubility and at the same time have a good suitability for animals, in particular as pour-on formulations.

[0012] The pharmaceutical compositions described herein also comprise at least one pharmaceutically active ingredient, hereinafter also referred to as active ingredient, which can also be referred to as API (active pharmaceutical ingredient). In particular, the active ingredient can be the actual active substance in the composition and thus primarily or exclusively responsible for the anti-parasitic effect, which will be described in detail hereinafter. Accordingly, the active ingredient should be particularly effective against non-human organisms.

[0013] In principle, the pharmaceutically active ingredient is not limited. However, it is provided that the pharmaceutically active ingredient consists in particular of a fluorinated heteroaryl amide, which is described in more detail hereinafter. In principle, the heteroaryl amide can be, for example, a pyridyl amide, which is a pyridine group bonded via an aryl group to an amide. For example, the heteroaryl amide can be fluorinated.

[0014] With regard to the pharmaceutically active ingredient, it is also provided that it is completely soluble in the solvent phase. This in particular enables advantageous skin applicability, wherein in particular a pour-on application or a solution for a pour-on is possible.

[0015] A pour-on application, wherein a spot-on formulation can be one embodiment, is understood to mean in particular a type of application to a limited skin area, typically on the neck or back of a non-human organism, wherein a relatively small amount of the formulation is applied, for example up to 100 mL per 100 kg, about 1 mL per 100 kg to 100 mL per 100 kg, for example 1 mL per 100 kg to 20 mL per 100 kg, about 5 mL per 100 kg to 10 mL per 100 kg, based on the amount of formulation applied per weight of the organism. Accordingly, a pour-on formulation is understood to mean a formulation of the kind which is suitable for and intended for application as a pour-on.

[0016] For this type of application, i.e. in a so-called pour-on solution, it is particularly important that a high solubility of the active ingredient is achieved, which enables the active ingredient in the solution to be brought to the desired concentration. In addition, good spreading properties should be achieved on the skin. The spreading properties can be understood to mean in particular the distribution of the formulation on the skin. Thus, by means of the spreading properties, it can be determined whether the formulation present in the form of a solution achieves the desired distribution on the organism, in particular without excessive dripping or running off from the application site, so that a locally limited application is possible and the active ingredient is not lost due to running off after the application.

[0017] To achieve the above-mentioned advantageous properties, in particular for pour-on formulations, it is intended in the compositions described herein to configure the solvent phase as a solvent mixture and to comprise a first solvent and a second solvent different from the first solvent, wherein the first solvent comprises a Ci to Ci5-alcohol, wherein the second solvent is an organic carbonate, and wherein the first solvent is present in a proportion of 50 to 95 % by weight, and wherein the second solvent is present in a proportion of 5 to 50 % by weight, in each case based on the sum of the solvents in the solvent phase, wherein in the binary solvent phase the first solvent and the second solvent are present in a quantitative ratio of 50:50 to 95:5 % by weight to each other, based on the sum of the solvents in the solvent phase. It should be noted, however, that the sum of the proportions of the first and second solvents does not necessarily have to amount to 100 % by weight, since for example ternary systems with further solvents can also be considered and can be preferred.

[0018] In one embodiment, such a configuration can advantageously provide a sufficient concentration of completely dissolved heteroaryl amide active ingredient in the solvent phase, thus being possible in the formulation, and also advantageous spreading properties can be obtained for pour-on application. In one embodiment, the active heteroaryl amide is at least 95 % by weight (of active ingredient) dissolved. In another embodiment, the active is at least 97 % by weight (of active ingredient) dissolved. In yet another embodiment, the active is 99 % by weight (of active ingredient) dissolved. In a preferred embodiment, the active is 100 % by weight (of active ingredient) dissolved.

[0019] Thus, contrary to the assumptions made in the prior art, it has been shown that using a solvent mixture comprising a Ci to Ci5-alcohol, in particular a Ci to Cio-alcohol, for example a Ci to C7-alcohol, and an organic carbonate can achieve positive properties. For example, the solvent mixture can consist of one or more Ci to Ci5-alcohols and one or more organic carbonates. These combinations show, for example, good solubility of the active ingredient, in particular of active ingredients formed from fluorinated heteroaryl amides, and good spreading properties.

[0020] Ci to Ci5-alcohols are understood in principle to mean aliphatic or aromatic alcohols having 1 to 15 carbon atoms.

[0021] Organic carbonates are also understood to mean acyclic or cyclic carbonates, which are themselves low-volatile polar solvents, which are characterized by their low toxicity. By skillfully selecting the alcohol used for ester synthesis, the physical properties of the resulting carbonates can be adjusted to the desired field of application.

[0022] Thus, the present application provides a composition which is very well suited for pour-on application, both in terms of spreading properties, ease of administration, but also in terms of active ingredient concentration, i.e. efficacy.

[0023] Further advantages of the formulations described herein are good compatibility and safety with respect to the organisms treated, for example reduced adverse effects on animals, for example adverse effects on the skin and / or the coat, for example irritation or residues in the animal, including in animals that enter the food chain. The formulations and ease of administration, with good applicability due to viscosity and spreading properties, provide excellent environmental sustainability, resulting in high acceptance by the consumer and reduced adverse side effects. This applies even in the case of use in food production for livestock. Furthermore, the formulations allow the active ingredients present to provide high efficiency in a shorter period of time by increased solubility concentration, thus being effective and thus providing a sustained period of activity without the need for frequent application. Ultimately, good handling and user friendliness are achieved, while reducing the costs of formulation manufacture. Also advantageous are good bioavailability and the range of use.

[0024] Furthermore, the compositions of the present application can be easily applied to animals, for example taking into account the viscosity and spreading properties. The compositions, in particular the active ingredients, also have a low tendency to be washed off, for example by rain. In fact, the efficacy can be maintained even in the case of wet animals or sunlight. The compositions generally have high stability and exhibit reduced degradation and reduced secondary reactions of the components of the composition with each other. Preferred stability achieved by the compositions described herein includes a shelf life of at least 12 months, preferably 24 months, at 30°C. After application, the compositions dry very easily, in particular by the addition of a good evaporating solvent, without significantly impairing the appearance of the animals.

[0025] The following solvents are particularly advantageous for the solvent present in the solvent phase or solvent mixture. The first solvent is different from the second solvent. In one embodiment, the first solvent is not a carbonic acid ester, different from the second solvent.

[0026] In one embodiment, the first solvent preferably comprises a C1-C4-alkanol, optionally substituted by at least one C1-C4-alkoxy group or a phenyl group, wherein the hydroxyl group can in principle be in any alternative position. In a particular embodiment, the first solvent is selected from ethanol, n-propanol, isopropanol, butanol, for example isobutanol or n-butanol, in particular ethanol and / or isopropanol. In addition to good solubility properties, in particular in combination with the organic carbonic acid ester described, such solvents also provide the further advantage of suitable toxicity for non-human organisms, so that they can be applied in animals without adverse effects.

[0027] The second solvent is preferably an organic aliphatic Ci-C4-carbonate, which is optionally substituted by a hydroxyl group. In a particular embodiment, the second solvent is selected from the group consisting of ethylene carbonate, propylene carbonate, glycerol carbonate. In addition to good solubility properties, especially in combination with the alcohol, such solvents also provide the additional advantage of suitable toxicity for non-human organisms, so that they can be administered in animals without adverse effects.

[0028] In a particularly preferred embodiment, the first solvent is isopropanol and the second solvent is propylene carbonate. It has been found that a solvent phase comprising isopropanol and propylene carbonate as solvents, for example, offers the advantages described above with regard to good solubility of the active ingredient, advantageous spreading properties and at the same time a lower toxicity.

[0029] In another embodiment, the solvent mixture consists of a first solvent (i.e. one or more first solvents as described above) and a second solvent (i.e. one or more second solvents as described above). In other words, the aforementioned first solvent and second solvent can be sufficient as solvents alone, wherein in an understandable manner, one of the first solvents and one of the second solvents can be sufficient to form a solvent mixture.

[0030] In an embodiment, with regard to the relative proportion of the first solvent to the second solvent, the second solvent (i.e. the organic carbonate) is preferably present in a content of > 20 wt.-% to < 45 wt.-%, preferably in a content of > 30 wt.-% to < 40 wt.-%, based on the sum of the solvents in the solvent mixture. In this embodiment, the first solvent is present in a content of > 55 wt.-% to < 80 wt.-%, preferably in a content of > 60 wt.-% to < 70 wt.-%, based on the total amount of solvents in the solvent mixture. In this configuration, the aforementioned advantages with regard to the solubility of the active ingredient can be particularly effectively provided, while at the same time good spreading properties are achieved. In other words, by virtue of consistent results, excellent solubility of the active ingredient can be promoted. Thus, at the same time, advantageous applicability as well as stable storage properties are provided. Due to the high solubility of the active ingredient, a relatively small amount of solvent mixture is required. As a result, the composition can be stored.

[0031] Furthermore, in another embodiment, the solvent mixture comprises, in addition to the first solvent and the second solvent, a third solvent which is different from the first solvent and the second solvent. Thus, the third solvent is not designed as described above for the first solvent and the second solvent.

[0032] By using further solvents, the solubility and / or the spreading properties can potentially be further improved or at least adjusted to the desired use.

[0033] In one specific embodiment, the solvent phase is configured as a mixture of at least three solvents, wherein the third solvent is neither a Ci to Ci5-alcohol nor an organic carbonic acid ester, but has a hitherto different definition. This, however, does not exclude that the first solvent and / or the second solvent and / or the third solvent is / are present in each case, for example, as a binary solvent mixture.

[0034] In principle, by providing a ternary solvent phase, the first solvent and the second solvent can be present in the ranges mentioned above, wherein the proportion of the first solvent and the second solvent can include the proportion of the third solvent. In particular, in one embodiment, the third solvent replaces a portion of the first solvent, wherein the first solvent is still present in the range mentioned of 50 to 95 % by weight, based on the sum of the solvents in the solvent phase, and wherein the second solvent is likewise present in the range of amounts mentioned, i.e. in a proportion of 5 to 50 % by weight, in each case based on the sum of the solvents in the solvent phase. The third solvent, as well as the first solvent and the second solvent, should be pharmaceutically compatible and also not adversely affect the solubility of the active ingredient. It can be advantageous to use a penetration-enhancing solvent.

[0035] Advantageous examples of the third solvent, which is different from the first solvent and the second solvent, are selected from the group consisting of water, butylated hydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, benzoic acid benzyl ester, octyldodecanol, paraffin, triglycerides, such as caprylic / capric triglyceride (e.g. Miglyol 812), propylene glycol caprylate caprate (e.g. Miglyol 840), glycol ethers such as diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether.

[0036] In one embodiment, the solvent phase can be a ternary system and thus consists of a first solvent or a plurality of first solvents, a second solvent or a plurality of second solvents and a third solvent or a plurality of third solvents. In this embodiment, the first solvent (a plurality of first solvents), the second solvent (a plurality of second solvents) and the third solvent (a plurality of third solvents) can be selected as defined above.

[0037] In particular, in the embodiment of the ternary system, one non-limiting example is that the sum of the first and the third solvent and the second solvent is in a quantitative ratio of 50:50 to 95:5 % by weight to each other, based on the sum of the solvents in the solvent phase. With regard to the relative proportion of the first solvent to the second solvent, it is preferred that the second solvent is present in a content of > 20 to < 45 % by weight, preferably in a content of > 30 to < 40 % by weight, based on the sum of the solvents in the solvent mixture. Thus, the first solvent and optionally the third solvent can together be present in a content of > 55 to < 80 % by weight, preferably in a content of > 60 to < 70 % by weight, based on the sum of the solvents in the solvent mixture.

[0038] Non-limiting examples of solvent mixtures can be configured, for example, as follows: a mixture of isopropanol (32.5), ethanol (32.5) and propylene carbonate (35), wherein the numbers in brackets mean the content in % by weight, based on the solvent mixture. As further examples, a mixture of isopropanol (32.5), ethanol (32.5) and glycerol carbonate (35), isopropanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), or a mixture of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5) can be used, wherein the numbers in brackets again mean the content in % by weight, based on the solvent mixture.

[0039] In one embodiment, there is a first solvent and a solvent mixture consisting of, for example, two second solvents and optionally one or more third solvents. In another embodiment, there is a second solvent and a solvent mixture consisting of, for example, two first solvents and optionally one or more third solvents.

[0040] Furthermore, the ingredients of the composition can be limited to the solvent and the active ingredient, so that the composition can consist of the first solvent, the second solvent, the optional third solvent and the active ingredient. However, other ingredients are not intended to be excluded and are defined elsewhere.

[0041] Preferably, the fluorinated heteroaryl amide is designed as described in WO 2015067646 A1 or WO 2015067647 A1. Such active ingredient is preferably configured as follows and comprises a compound of the general formula (I), as well as salts, N-oxides and tautomeric forms of the compounds of the formula (I):

[0042]

[0043] wherein

[0044] R 1 is H; C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6- alkylcarbonyloxy, aryl-(C1-C3)-alkyl, heteroaryl-(C1-C3)-alkyl, each of which is optionally substituted; or optionally substituted C1-C6-alkyl, preferably H or preferably C1-C2-alkyl, very particularly preferably H or methyl, in particular H,

[0045] These moieties are as follows:

[0046] A1is CR 2 or N,

[0047] A2is CR 3 or N,

[0048] A3 is CR 4 or N,

[0049] A4 is CR 5 or N,

[0050] B1 is CR 6 or N,

[0051] B2 is CR 7 or N,

[0052] B3 is CR 8 or N,

[0053] B4 is CR 9 or N, and

[0054] B5 is CR 10 or N,

[0055] but not more than three of the moieties A1 to A4 are N and not more than three of the moieties B1 to B5 are N;

[0056] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 are each, independently of one another, H, halogen, cyano, nitro, in each case optionally substituted C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, N-C1-C6-alkoxyimino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N-C1-C6-alkylamino, N,N-di-C1-C6-alkylamino or N-C1-C3-alkoxy-C1-C4-alkylamino or 1-pyrrolidinyl; if neither the moieties A2 and A3 are N, then R 3 and R 4 may form, together with the carbon atom to which they are bonded, a 5- or 6-membered ring which contains 0, 1 or 2 nitrogen atoms and / or 0 or 1 oxygen atoms and / or 0 or 1 sulfur atoms; or if neither the moieties A1 and A2 are N, then R 2 and R 3 may form, together with the carbon atom to which they are bonded, a 6-membered ring which contains 0, 1 or 2 nitrogen atoms;

[0057] R 8halogen, cyano, nitro; in each case optionally substituted Ci-C6-alkyl, C3-C6-cycloalkyl, Ci-C6-alkoxy, N-Ci-C6-alkoxyimino-Ci-C3-alkyl, Ci-C6-alkylsulfanyl, Ci-C6-alkylsulfinyl, Ci-C6-alkylsulfonyl, N-Ci-C6-alkylamino or N,N-di-Ci-C6-alkylamino;

[0058] W is O or S,

[0059] Q is H, formyl, hydroxy, amino or in each case optionally substituted Ci-C6-alkyl; C2-C6-alkenyl; C2-C6-alkynyl; C3-C6-cycloalkyl; Ci-C5-heterocycloalkyl; Ci-C4-alkoxy; Ci-C6-alkyl-C3-C6-cycloalkyl; C3-C6-cycloalkyl-Ci-C6-alkyl; C6, C 10 -aryl; Ci-C5-heteroaryl; C6, C 14 -aryl; Ci-C5-heteroaryl; C6, C 10 -aryl; Ci-C5-heteroaryl; C6, C 14 -aryl; Ci-C5-heteroaryl; C6, C

[0060] V is independently of one another halogen, cyano, nitro; in each case optionally substituted Ci-C6-alkyl, Ci-C4-alkenyl, Ci-C4-alkynyl, C3-C6-cycloalkyl, Ci-C6-alkoxy, N-Ci-C6-alkoxyimino-Ci-C3-alkyl, Ci-C6-alkylsulfanyl, Ci-C6-alkylsulfinyl, Ci-C6-alkylsulfonyl or N,N-di-(Ci-C6-alkyl)amino;

[0061] T is an optionally substituted 5-membered heteroaromatic system, which contains not more than 2 heteroatoms (1 or 2 heteroatoms), for example four carbon atoms and one (1) heteroatom, preferably one (1) nitrogen atom, one (1) oxygen atom or one (1) sulfur atom; or three carbon atoms and two heteroatoms, preferably two nitrogen atoms, one (1) nitrogen atom and one (1) oxygen atom, or one (1) nitrogen atom and one (1) sulfur atom.

[0062] The compounds of the formula (Ia), for example, as well as the salts, N-oxides and tautomeric forms of the compounds of the formula (I) are described below:

[0063]

[0064] wherein

[0065] each of the D1, D2moieties independently of each other is C-R 11 or a heteroatom selected from N and O;

[0066] each of the D3and D4moieties independently of each other is C or represents a heteroatom selected from N (in other words:

[0067] each of the D3and D4moieties independently of each other represents C or N);

[0068] wherein not more than one (1) or two of the D1, D2, D3and D4moieties are a heteroatom, wherein one (1) or two of the D1, D2, D3and D4moieties are a heteroatom, said heteroatom in the case of D1 and D2being selected from N or O, or in the case of D3and D4being selected from N;

[0069] is an aromatic system; and

[0070] R 1 , A1, A2, A3, A4, B1, B2, B3, B4, B5, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , W, Q, V and T are each as defined herein, wherein not more than one of the A l , A2, A3, A4moieties is N and not more than one of the B1, B2, B3, B4and B5moieties is N; or wherein one or two of the A1, A2, A3, A4moieties can be N and not more than one of the B1, B2, B3, B4and B5moieties is N

[0071] One embodiment of the present application relates to compounds of formula (Ia')

[0072]

[0073] wherein

[0074] R 1 , R 11each of Q, W, A1, A2, A3, A4, B1, B2, B4 and B5 is defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two of the moieties selected from A1, A2, A3, A4 can be N and no more than one of the moieties selected from B1, B2, B3, B4 and B5 is N;

[0075] D1and D2are each independently of the other C-R 11 or a heteroatom, preferably C-R 11 or a heteroatom selected from N, O or S, more preferably C-R 11 or a heteroatom selected from N or O;

[0076] D3and D4moieties are each independently of the other C or a heteroatom selected from N;

[0077] wherein no more than one (1) or two of the moieties selected from D1, D2, D3and D4is a heteroatom, wherein one (1) or two of the moieties selected from D1, D2, D3and D4is a heteroatom, in the case of D1and D2selected from N or O, or in the case of D3and D4selected from N;

[0078] is an aromatic system,

[0079] R 8 is preferably perfluorinated C1-C4-alkyl as defined herein.

[0080] Another embodiment of the present application relates to compounds of formula (Ia") and salts, N-oxides, and tautomeric forms of compounds of formula (Ia")

[0081]

[0082] wherein

[0083] D1is C-R 11 or a heteroatom selected from N or O;

[0084] D2is C-R 11 or a heteroatom selected from N or O;

[0085] D3is C or N;

[0086] D4is C or N;

[0087] D5is C-R 11 or N;

[0088] wherein no more than one (1) or two of the moieties selected from D1, D2, D3, D4and D5is a heteroatom;

[0089] is an aromatic system; and

[0090] R 1 is H, in each case optionally substituted C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, aryl-(C1-C3)-alkyl or heteroaryl-(C1-C3)-alkyl or optionally substituted C1-C6-alkyl, particularly preferably H;

[0091] These moieties are as follows:

[0092] A1is CR 2 or N,

[0093] A2is CR 3 or N,

[0094] A3is CR 4 or N,

[0095] A4is CR 5 or N,

[0096] B1is CR 6 or N,

[0097] B2is CR 7 or N,

[0098] B3is CR 8 or N,

[0099] B4is CR 9 or N, and

[0100] B5is CR 10 or N,

[0101] but not more than three of the moieties A1to A4are N and not more than three of the moieties B1to B5are simultaneously N; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 are each, independently of one another, H, halogen, cyano

[0102] halogen, cyano, nitro, in each case optionally substituted C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, N-C1-C6-alkoxyimino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N-C1-C6-alkylamino or N,N-di-C1-C6-alkylamino; if A2and A3moieties are not both N, then R 3 and R 4 may form, together with the carbon atom to which they are bonded, a 5- or 6-membered ring containing 0, 1 or 2 nitrogen atoms and / or 0 or 1 oxygen atoms and / or 0 or 1 sulfur atoms; or if A1and A2moieties are not both N, then R 2 and R 3 may form, together with the carbon atom to which they are bonded, a 6-membered ring containing 0, 1 or 2 nitrogen atoms;

[0103] R 8 halogen, cyano, nitro; in each case optionally substituted C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, N-C1-C6-alkoxyimino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, N-C1-C6-alkylamino or N,N-di-C1-C6-alkylamino;

[0104] R 11 independently of one another H, halogen, cyano, nitro, amino or optionally substituted C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, preferably H;

[0105] W is O or S,

[0106] Q is H, formyl, hydroxy, amino or in each case optionally substituted C1-C6-alkyl; C2-C6-alkenyl; C2-C6-alkynyl; C3-C6-cycloalkyl; C1-C5-heterocycloalkyl; C1-C4-alkoxy; C1-C6-alkyl-C3-C6-cycloalkyl; C3-C6-cycloalkyl-C1-C6-alkyl; C6, C 10 -C 14 -aryl; C1-C5-heteroaryl; C6, C 10 -, C 14C1-C5-heteroaryl-(C1-C3)-alkyl; N-C1-C4-alkylamino; N-C1-C4-alkylcarbonylamino or N,N-di-C1-C4-alkylamino; or is an optionally multi-V-substituted unsaturated 6-membered carbocyclic ring; or is an optionally multi-V-substituted unsaturated 4-, 5- or 6-membered heterocyclic ring, wherein

[0107] V is independently of each other halogen, cyano, nitro; in each case optionally substituted C1-C6-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, C3-C6-cycloalkyl, C1-C6-alkoxy, N-C1-C6-alkoxyimino-C1-C3-alkyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl or N,N-di-(C1-C6-alkyl)amino.

[0108] Also suitable are compounds of formula (Ia") wherein the compound of formula (Ia") is a compound of formula (I-T3)

[0109]

[0110] wherein R 1 , A1, A2, A3, A4, R 11 , B1, B2, B4, B5, R 8 , Q and W are each defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two moieties selected from A1, A2, A3, A4 can be N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N.

[0111] Another embodiment of the present application relates to compounds of formula (Ia") wherein the compound of formula (Ia") is a compound of formula (I-T2)

[0112]

[0113] wherein R 1 , A1, A2, A3, A4, R 11 , B1, B2, B4, B5, R 8 , Q and W are each defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two moieties selected from A1, A2, A3, A4 can be N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N.

[0114] Another embodiment of the present application relates to compounds of formula (Ia") wherein the compound of formula (Ia") is a compound of formula (I-T4)

[0115]

[0116] wherein R 1 , A1, A2, A3, A4, R 11 , B1, B2, B4, B5, R8, Q and W are each defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two moieties selected from A1, A2, A3, A4 can be N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N.

[0117] Also suitable are compounds of formula (Ia") wherein the compound of formula (Ia") is a compound of formula (I-T22)

[0118]

[0119] wherein R 1 , A1, A2, A3, A4, R 11 , B1, B2, B4, B5, R 8 , Q and W are each defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two moieties selected from A1, A2, A3, A4 can be N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N.

[0120] Also suitable are compounds of formula (Ia") wherein the compound of formula (Ia") is a compound of formula (I-T23)

[0121]

[0122] wherein R 1 , A1, A2, A3, A4, R 11 , B1, B2, B4, B5, R 8 , Q and W are each defined as described herein, wherein no more than one moiety selected from A1, A2, A3, A4 is N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N; or wherein one or two moieties selected from A1, A2, A3, A4 can be N and no more than one moiety selected from B1, B2, B3, B4 and B5 is N.

[0123] Also suitable are compounds of the formulae and embodiments described herein, wherein R 11 is H and W is O.

[0124] Also suitable are compounds of the formulae and embodiments described herein, wherein R 11 is H and W is O and B3 is C-R 8 , R 8 is halogen-substituted C1-C3-alkyl (preferably perhalo C1-C3-alkyl, more preferably perfluorinated C1-C3-alkyl) or halogen-substituted C1-C3-alkoxy (preferably perhalo C1-C3-alkoxy, more preferably perfluorinated C1-C3-alkoxy).

[0125] Also suitable are compounds of the formulae and embodiments described herein, wherein the moieties A1to A4and B1to B5are as follows:

[0126] A1is C-H,

[0127] A2is CR 3 or N,

[0128] A3is CR 4 ,

[0129] A4is C-H,

[0130] B1is CR 6 or N,

[0131] B2is C-H,

[0132] B3is CR 8 ,

[0133] B4is C-H and

[0134] B5is CR 10 or N.

[0135] Also suitable are compounds of the formulae and embodiments described herein, wherein R 1 is H.

[0136] Also suitable are compounds of the formulae and embodiments described herein, wherein Q is fluoro-substituted C1-C4-alkyl, C3-C4-cycloalkyl, optionally cyano or fluoro-substituted C3-C4-cycloalkyl, C4-C6-heterocycloalkyl, 1-oxidothietan-3-yl, 1,1-dioxidothietan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

[0137] More suitable are compounds of the formulae and embodiments described herein, wherein R 8represents halogen or halogen-substituted C1-C4-alkyl.

[0138] Also suitable are compounds of the formulae described herein, wherein R 11 is H.

[0139] Also suitable are compounds of the formulae described herein, wherein R 6 , R 7 , R 9 and R 10 are independently of each other H, halogen, cyano, nitro, in each case optionally substituted C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, N- alkoxyiminoalkyl, C1-C4-alkylsulfanyl, C1-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, N-C1-C4- alkylamino, N,N-di-C1-C4-alkylamino.

[0140] Also suitable are compounds of the formulae described herein, wherein R 2 , R 3 , R 4 and R 5 are independently of each other H, halogen, cyano, nitro, in each case optionally substituted C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, N- alkoxyiminoalkyl, C1-C4-alkylsulfanyl, C1-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, N-C1-C4- alkylamino, N,N-di-C1-C4-alkylamino.

[0141] Also suitable are compounds of the formulae described herein, wherein the moieties A1 to A4 and B1 to B5 are as follows:

[0142] A1 is C-H,

[0143] A2 is CR 3 or N,

[0144] A3 is CR 4 ,

[0145] A4 is C-H,

[0146] B1 is CR 6 or N,

[0147] B2 is C-H,

[0148] B3 is CR 8 ,

[0149] B4 is C-H and

[0150] B5 is CR 10 or N.

[0151] Also suitable are compounds of the formulae described herein, wherein R 1 is H.

[0152] Also suitable are compounds of the formulae described herein, wherein R 1 is methyl.

[0153] Also suitable are compounds of the formulae described herein, wherein Q is fluoro- substituted or carbamoyl (-C(=0)N(R)2, wherein R independently of one another is H, C1-C3- alkyl or halogen-substituted C1-C3-alkyl)-substituted C1-C4-alkyl, optionally cyano- or fluoro-substituted C3-C4-cycloalkyl, C4-C6-heterocycloalkyl, 1-oxothietan-3-yl, 1,1- dioxothietan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2- trifluoroethylamino)ethyl.

[0154] Also suitable are compounds of the formulae described herein, wherein Q is 2,2,2- trifluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, cyclobutyl, 1- cyanocyclopropyl, trans-2-fluorocyclopropyl, or cis-2-fluorocyclopropyl, oxetan-3-yl, thietan-3-yl, 1-oxothietan-3-yl, 1,1-dioxothietan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

[0155] Also suitable are compounds of the formulae described herein, wherein R 8 is halogen or halogen-substituted C1-C4-alkyl.

[0156] The following examples can be mentioned, which are preferably active ingredients having a parasiticidal action on non-human organisms:

[0157] 2-chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)-ethyl]phenyl]-1H-pyrazol-4-yl]-N-methylpyridine-3-carboxamide

[0158]

[0159] 2-chloro-N-cyclopropyl-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl]-3-pyridinecarboxamide:

[0160]

[0161] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0162]

[0163] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0164]

[0165] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0166]

[0167] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0168]

[0169] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0170]

[0171] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0172]

[0173] 2-chloro-5-[l-[2-chloro-4-[l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethyl]-6- (trifluoromethoxy)phenyl]-lH-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide

[0174]

[0175] 2-chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]phenyl]pyrazol-4-yl]benzamide

[0176]

[0177] 2-chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]phenyl]pyrazol-4-yl]-N-methylbenzamide

[0178]

[0179] 2-chloro-N-cyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-2- methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide:

[0180]

[0181] 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)- 2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide:

[0182]

[0183] 2-chloro-N-cyclopropyl-5-[4-[2,6-dimethyl-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide:

[0184]

[0185] 2-chloro-N-(1-cyanocyclopropyl)-5-[4-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide:

[0186]

[0187] 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6- (trifluoromethyl)phenyl]isoxazol-5-yl]-N-cyclopropylbenzamide:

[0188]

[0189] 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:

[0190]

[0191] 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1- (trifluoromethyl)ethyl]phenyl]pyrrol-3-yl]benzamide:

[0192]

[0193] 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6- (trifluoromethyl)phenyl]pyrrol-1-yl]-N-cyclopropylbenzamide:

[0194]

[0195] In this case, the active ingredients mentioned above are part of the formulations described herein and thus enable the efficacy against parasites as described in detail below.

[0196] In the context of the present application, the active ingredients of the above-mentioned formulae I-1 to I-5 and of formulae II-1 to II-6 can be preferred, wherein the active ingredients of formulae I-1 to I-5 can be particularly preferred.

[0197] According to one preferred embodiment, the compound of formula I-1 can be present as active ingredient, wherein the following mixtures can be used as solvent mixture: a mixture of isopropyl alcohol (32.5), ethanol (32.5) and propylene carbonate (35); or a mixture of isopropyl alcohol (32.5), ethanol (32.5) and glycerol carbonate (35); or a mixture of isopropyl alcohol (65), propylene carbonate (17.5) and glycerol carbonate (17.5); and a mixture of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), wherein the numbers in brackets are intended to indicate the content in percent by weight, based on the solvent mixture.

[0198] According to another embodiment, the above-mentioned solvent mixtures can be used for the active ingredients of formula I-2 or of formula I-3 or of formula I-4 or of formula I-5.

[0199] However, the use of the active ingredients of formulae I-1, I-2, I-3, I-4 and I-5 using only the first and the second solvent is particularly preferred.

[0200] In addition to the ingredients listed above, the compositions of the present application can also contain conventional pharmaceutically acceptable auxiliary agents. Examples of these that can be mentioned are dispersing agents, antioxidants, pH regulators, crystallization inhibitors, surfactants, dyes, pigments, penetration enhancers and preservatives.

[0201] Dispersing agents are, for example, dispersible oils, such as di-2-ethylhexyl adipate, isopropyl myristate, dipropylene glycol nonanate; cyclic and acyclic silicone oils, such as polydimethylsiloxanes and their copolymers and terpolymers with ethylene oxide, propylene oxide and formaldehyde; fatty acid esters, triglycerides, fatty alcohols. They can be additionally added in a proportion of > 1 to < 40% w / v. According to other embodiments, the dispersing agents can be present in a proportion of > 0.01 to < 1% w / v, > 0.1 to < 10% w / v, > 1 to < 20% w / v, > 20 to < 50% w / v or > 10 to < 30% w / v.

[0202] Antioxidants are, for example, ascorbic acid, di-Na-EDTA, BHT, BHA, delta-tocopherol, thioglycerol. They can be additionally added in a proportion of > 0.01 to < 2% w / v. According to other embodiments, the antioxidants can be present in a proportion of > 0.01 to < 1% w / v, > 0.05 to < 0.5% w / v or > 1 to < 2% w / v.

[0203] pH regulators are preferably organic acids or bases, such as citric acid, triethanolamine. They can be additionally added in a proportion of > 0.001 to < 5% w / v. According to other embodiments, the pH regulators can be present in a proportion of > 0.01 to < 1% w / v, > 0.05 to < 0.5% w / v or > 0.1 to < 3% w / v.

[0204] Crystallization inhibitors are, for example, cellulose ethers, such as hydroxypropylmethylcellulose (HPMC); polyvinylpyrrolidone (PVP). They can be additionally added in a proportion of > 0.1 to < 50% w / v. According to other embodiments, the crystallization inhibitors can be present in a proportion of > 1 to < 30% w / v, > 1 to < 20% w / v, > 5 to < 15% w / v, > 1 to < 20% w / v or > 0.1 to < 10% w / v.

[0205] Surfactants that can be mentioned are: non-ionic surfactants, such as polyoxyethylene castor oil, polyoxyethylene sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers; amphoteric surfactants, such as di-Na-N-lauryl beta-iminodipropionate or lecithin; anionic active surfactants such as sodium dodecyl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphates monoethanolamine salts and the like; cationic active surfactants such as hexadecyltrimethylammonium chloride. They can be additionally added in a proportion of > 0.1 - < 20% w / v. According to other embodiments, they can be present in a proportion of > 0.1 - < 10% w / v, > 0.1 - < 1% w / v, > 1 - < 10% w / v or > 0.2 - < 5% w / v.

[0206] Dyes can also be added to the pharmaceutical composition. They can be dissolved or suspended in the composition. Examples that can be mentioned are brilliant blue, D&C violet 2, FD&C yellow, sunset yellow FCF or natural food colorings such as chlorophyll. They can be additionally added in a proportion of > 0.01 - < 2% w / v. According to other embodiments, they can be present in a proportion of > 0.01 - < 1% w / v or > 0.1 - < 2% w / v.

[0207] The pharmaceutical composition can contain a penetration enhancer, such as, for example: menthol, 1,8-cineole, glycol ethers (such as diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether). They can be present in a proportion of > 2 - < 50% w / v. According to other embodiments, the penetration enhancer can be present in a proportion of > 1 - < 20% w / v, > 0.5 - < 20% w / v, > 0.1 - < 10% w / v, > 10 - < 50% w / v or > 10 - < 40% w / v.

[0208] In principle, the concentration of the active ingredient is not limited, but account should also be taken of the fact that all active ingredients should be in solution. With regard to advantageous pour-on application, for high efficiency, it can also be preferred for the pharmaceutical active ingredient to be present in an amount of greater than or equal to 0.1% by weight to less than or equal to 8% by weight, for example greater than or equal to 0.1% by weight to less than or equal to 5% by weight. This can correspond, for example, to a proportion of 0.2-4 g / 100 ml, for example 1-3 g / 100 ml, based on the pharmaceutical composition. Such concentrations can be achieved without difficulty by configuration of the solvent mixture described above and are particularly advantageous for topical pour-on application. However, in principle, concentrations of up to 30% by weight or more of the active ingredient are also possible without leaving the scope of the application.

[0209] The formulations according to the application are therefore generally liquid and suitable for topical or dermal application, in particular as so-called pour-on formulations.

[0210] The compositions according to the present application comprising the active ingredients from the above group, in particular fluorinated benzamides, are very effective in providing ectoparasiticidal efficacy, especially in the case of the above-mentioned pour-on application. Thus, by using the compositions, the amount of active ingredient required can be reduced and the long-term effect can be increased. Their use thus achieves economic and ecological advantages.

[0211] The compositions of the present application are very suitable for use in the control or prevention of parasites. Thus, the pharmaceutical compositions described herein are used for the treatment or prevention of a parasitic infestation, in particular for the treatment or prevention of ectoparasites.

[0212] The compositions of the present application are particularly suitable for use in the control or prevention of ectoparasites, preferably ticks and / or mites, and / or flies or fly larvae, and / or lice, on non-human organisms, in particular animals, in particular warm-blooded animals, preferably mammals.

[0213] According to one embodiment, the animal can be a domestic animal, for example a cage bird; or a mammal, for example a hamster, a guinea pig, a rat, a mouse, a chinchilla, a ferret or, in particular, a dog, a cat.

[0214] According to another, more preferred embodiment, the animal can be an agricultural domestic animal, including, for example, poultry, such as turkeys, ducks, geese, in particular chickens; or preferably a mammal, for example a sheep, a goat, a horse, a donkey, a camel, a water buffalo, a rabbit, a reindeer, a roe deer, in particular a cow and a pig.

[0215] According to one particularly preferred embodiment, the compositions of the present application are used for the control and / or prevention of ectoparasites on cattle.

[0216] Since, as a rule, also an amount of the composition is spread into the environment of the animals treated, for example, by abrasion or with debris, the action of the compositions of the present application can not only act directly on the animals, but also, to a corresponding extent, in their environment.

[0217] As mentioned above, the compositions described herein are preferably suitable for the treatment or prevention of a parasitic infestation in a non-human organism by instilling or pouring the composition onto the non-human organism, and are thus suitable for pour-on application.

[0218] Parasites against which the formulations of the present application can be effective are possibly mentioned:

[0219] Genera from the order Anoplura, such as Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., and Phtirus spp.

[0220] Genera from the order Mallophaga, such as *Trimenopon* spp., *Menopon* spp., *Eomenacanthus*, *Trichodectes* spp., *Felicola* spp., *Damalina* spp., and *Bovicola* spp.

[0221] Genera from the order Diptera, such as *Aedes* spp., *Anopheless* spp., *Culex* spp., *Simulium* spp., *Phlebotomus* spp., *Chrysops* spp., *Tabanus* spp., *Musca* spp., *Hydrotaea* spp., *Haematobosca* spp., *Haematobia* spp., *Stomoxys* spp., *Fannia* spp., *Glossina* spp., *Lucilia* spp., and *Calliphora*. The genera *Auchmeromyia*, *Cordylobia*, *Cochliomyia*, *Chrysomyia*, *Sarcophaga*, *Wohlfahrtia*, *Gasterophilus*, *Oesteromyia*, *Oedemagena*, *Hypoderma*, *Oestrus*, *Rhinoestrus*, *Melophagus*, and *Hippobosca* are all genera of flies.

[0222] from the order Siphonapterida, for example Ctenocephalides spp., Echidnophaga, Ceratophyllus spp., Pulex spp.

[0223] from the order Metastigmata, for example Hyalomma spp., Rhipicephalus spp. (including the genera formerly known as Boophilus), Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.

[0224] from the order Mesostigmata, for example Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp.

[0225] from the suborder Prostigmata, for example Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.

[0226] from the suborder Astigmata, for example Acarus spp., Myocoptes, Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidocoptes, Cytodites spp., Laminosioptes spp.

[0227] Herein, from the family Diptera, in particular from the genera Tabanus spp., Musca spp., Hydrotaea spp., Haematobia spp., Stomoxys spp., Glossina spp., Lucilia spp., Calliphora spp., Aedes spp., Anopheles spp., Culex spp., Simulium spp., Phlebotomus spp.; from the family Metastigmata, in particular from the genera Hyalomma, Rhipicephalus spp. (including the genera formerly known as Boophilus), Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.; from the order Anoplura, in particular from the genera Haematopinus spp., Linognathus spp., Solenopotes spp.; from the order Mallophaga, in particular from the genera Damalina spp., Bovicola spp., Trimenopon spp.; from the order Mesostigmata, in particular from the genera Dermanyssus spp., Ornithonyssus spp.; from the suborder Astigmata, in particular from the genera Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp.

[0228] from the order Mallophaga, in particular from the genera Damalina spp., Bovicola spp., Trimenopon spp.; from the order Mesostigmata, in particular from the genera Dermanyssus spp., Ornithonyssus spp.; from the suborder Astigmata, in particular from the genera Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp.

[0229] Mentioned as particularly preferred are species or genera of arthropods: Haematobia irritans irritans, Haematobia irritans exigua, Hydrotea irritans, Musca autumnalis, Culicoides spp., Stomoxys spp., Glossina spp., Aedes spp., Anopheles spp., Culex spp., Damalinia bovis (Bovicola bovis), Linognathus vituli, Haematopinus eurystemus, Solenopotes capillatus, Psoroptes bovis, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) decoloratus, Ixodes ricinus, Amblyomma maculatum, Amblyomma variegatum, Ixodes cyclxcapular, Haemaphysalis longicornis, Otobius megnini.

[0230] The compositions according to the application can be prepared by customary methods, for example by mixing the active ingredient with the other ingredients under stirring to form a solution. This can optionally be filtered. For example, plastic tubes are suitable for filling.

[0231] The liquid formulations according to the application are characterized by their excellent storage stability in all climatic zones for at least one year, preferably at least two years, more preferably at least three years. Due to the very high efficacy, the application rate can be kept low. The preferred application volume is 0.01 to 1 ml / kg [body weight of the animal to be treated], preferably 0.05 to 0.1 ml / kg [body weight of the animal to be treated].

[0232] The compositions according to the application also have excellent skin compatibility and have low toxicity. Finally, they are environmentally friendly due to their biodegradability.

[0233] Solubility Experiment

[0234] The solubility experiments of the active ingredients I-1, I-2, I-3 and I-4 in the solvents of the pharmaceutical compositions of the present application are shown below. For a biological effect, the active ingredient should be incorporated into a formulation in a certain dose or amount, which, ideally, should be in solution form in the formulation, so that the active ingredient is thus dissolved in the solvent. Due to the limited application volume, a certain minimum solubility is required for the solvent.

[0235] Table 1 shows the results of the solubility experiments of the active ingredient I-1. In this case, 10 g of the appropriate solvent or solvent mixture were initially added and as much active ingredient as possible was added until the solution was saturated. Isopropyl alcohol (IPA) and propylene carbonate (PPC) were used as solvents. The samples were stirred for 3 days. If the active ingredient was completely dissolved, the active ingredient was added again. Subsequently, the samples were stored for a further 4 days at the relevant temperature and centrifuged to remove the undissolved particles. The active ingredient content of the supernatant was analysed by HPLC-UV in each case.

[0236] Table 1:

[0237]

[0238]

[0239] As can be seen from Table 1, in the single solvents isopropyl alcohol and propylene carbonate, the required criteria were not met, in particular in terms of sufficient solubility. A particularly preferred desired solubility of the active ingredients which are advantageous and according to the present application is in the range of at least 5% m / V, wherein a sufficient gap to the saturation solubility should be present. Surprisingly, the isopropyl alcohol and propylene carbonate mixture shows a significant increase in solubility compared to the pure solvents, which is listed in detail in Table 1.

[0240] In addition, solubility experiments of three other active ingredients selected from the class of fluorinated heteroaryl amides in different solvents were also carried out. The solubility experiments were carried out analogously to the experiments described above, however, only at room temperature and the solvent mixture isopropyl alcohol / propylene carbonate 65:35% [m / m] was chosen. The results are listed in Table 2.

[0241] Table 2:

[0242]

[0243]

[0244] It was also found that for the active ingredients I-2, I-3 and I-4, very good solubility of the active ingredients of the class of heteroaryl amides, in particular for the defined structures, can be achieved by the solvent mixture or the solvent phase of the compositions of the present application.

[0245] It was also shown that the significant increase in solubility is not limited to mixtures of isopropyl alcohol and propylene carbonate, but also shows for other solvents of the alcohol and carbonate series, as defined above for the first and second solvent.

[0246] Table 3:

[0247]

[0248] It is clear from Table 3 that an increase in solubility can be achieved using other solvents. The application can therefore be extended to other solvents within the range described. Shown here as an example is an embodiment of ethanol and glycerol carbonate, mixtures thereof and combinations thereof with the already shown solvents, isopropyl alcohol and propylene carbonate.

[0249] Experiments were also carried out with solvent systems in which the first solvent comprised two alcohols. The results are shown in Table 4.

[0250] Table 4:

[0251]

[0252] It can also be shown that this binary system enables good solubility of the active ingredient of the formula I-1.

[0253] Formulation Examples

[0254] Described below are preparation examples of formulations comprising the active ingredients I-1, I-2, I-3 and I-4 as defined above and additives. In all the examples of the specific implementation, the respective active ingredient is completely dissolved and the stability is as desired.

[0255] Here, Table 5 shows suitable formulation examples with data for the solvent mixture, active ingredient and optionally further additives.

[0256] Table 5:

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] Table 6 shows formulations which can be prepared according to the solubility tests

[0264]

[0265]

[0266]

[0267] Formulations numbered 1 to 65 were prepared, and good solubility and complete dissolution of the active ingredients were observed.

[0268] Experiments numbered 66 to 107 are further speculative examples in which the desired solubility can be predicted based on the solubility experiments performed, the actual examples prepared, and the chemical structure of the active ingredient and the selected solvent.

[0269] In vitro and in vivo test examples

[0270] Other properties and effects of the formulations of the present invention are described below.

[0271] Example 1

[0272] Determining the spreading properties of a colored placebo formulation on bovine skin

[0273] The aim of this in vitro study was to determine the diffusion characteristics of a colored placebo formulation (i.e., one without the active ingredient) on bovine skin. The results of these tests will be applicable to the spreading effect of formulations containing the active ingredient. The tests were conducted using a two-solvent phase consisting of isopropanol (IPA) and propylene carbonate (PPC).

[0274] For this purpose, approximately 10 x 10 cm skin flakes with the lightest possible hair color were obtained from cattle post-slaughter and placed on a hot plate covered with aluminum. The plate was heated to 34°C + / - 0.5°C. Skin flakes of trimmed skin and natural hair length were examined. 0.025% Brilliant Blue FCF was added as a coloring agent. The behavior of the formulation on the skin surface and spreading area was measured over 60 minutes. Spreading was also evaluated using a grading system. In this case, the formulation was particularly advantageous and suitable for subsequent use on animals because its spreading properties achieved adequate distribution on the skin flakes during the observation period.

[0275] The results are shown in Table 7, which illustrates the spreading characteristics of the colored placebo formulation on skin patches.

[0276] Table 7 shows the area of ​​the formulation directly on the skin sample after application and one hour later, and also shows the volume of the applied formulation, the hair length of the hair on the skin, and the skin temperature.

[0277] Table 7:

[0278]

[0279] From this table it is clear that the spreading properties are particularly advantageous. The best results are achieved when the ratio of isopropyl alcohol (IPA) to propylene carbonate (PPC) is 65:35.

[0280] Although this test also shows good results for a ratio of isopropyl alcohol (IPA) to propylene carbonate (PPC) of 90:10, the solvent phase has a poorer solubility compared to the formulation according to the application.

[0281] Table 8:

[0282]

[0283] Example 2

[0284] In Example 2, the spreading and run-off properties of a coloured placebo formulation on bovine skin were determined. The aim of this in-vitro study was to determine the spreading and run-off properties of a coloured placebo formulation on bovine skin. 0.025% Brilliant Blue FCF was added as colouring agent.

[0285] The formulations used correspond to those in Table 8.

[0286] For this purpose, as soon as possible after slaughter, a piece of hide of approximately 10 x 10 cm was obtained from a cow which was as light in colour as possible and placed on a hot plate covered with aluminium. The plate was heated to 34 + / - 0.5°C. For the run-off test, the hot plate was set at an angle of 45° + / - 2°. A piece of filter paper was fixed under the piece of skin.

[0287] The behaviour of the formulation on the surface of the skin and the run-off rate were recorded on video for more than one minute, after which the run-off rate was calculated by means of a ruler. The spreading was assessed by means of a rating system.

[0288] In this case, these formulations are particularly suitable for later use on animals, since the run-off properties during the observation period result in no or only minimal colouring of the filter paper. The formulations also achieve sufficient distribution on the piece of skin.

[0289] The results are shown in Table 9, which measures the run-off rate of the longest flow track within 1 minute after application of 750 μl of the coloured placebo formulation.

[0290] Table 9:

[0291]

[0292] From these tests it is clear that the tests using the claimed ratio of isopropyl alcohol (IPA) and propylene carbonate (PPC) have provided very good results, since the run-off properties during the observation period result in no or only minimal colouring of the filter paper, in this case achieving sufficient distribution on the piece of skin.

[0293] Example 3

[0294] In Example 3, the efficacy of the pour-on formulation against horn flies (Haematobia irritans irritans) on cattle was determined. The objective of the study was to determine the preventive efficacy of the insecticide formulation against experimentally induced horn fly infestations on cattle.

[0295] The study was conducted as a blind, negative control, randomized parallel group efficacy study. Each group included 5 animals. Prior to treatment, all animals were ranked in descending order by fly count and then the 5 animals were grouped into 4 (x) zones. Cattle were randomly assigned to zones and ranked in ascending order. Cattle were individually tethered in a screen enclosed space. Each animal was infested with approximately 200 unfed flies on days -5, 1, 7, 14, 21, 28 and in some cases on days 35 and 42. Fly counts on cattle were determined 4 hours after the first infestation, 24 hours after the second infestation, on days 8, 15, 22, 29, and if appropriate, on days 36, 43, 50 and 57. Efficacy against fly infestations was determined by comparing the number of flies on treated cattle to the number of flies on untreated cattle. In this case, treatment was judged successful if the treatment group measured at least 90% efficacy compared to the control group.

[0296] The results are shown in Table 10, which illustrates the effect of the formulation of the present application on the horn flies on cattle.

[0297] Table 10:

[0298]

[0299] Dpt = days post treatment

[0300] na = no data

[0301] As is evident from Table 10, Examples 5 and 7 had a long lasting and effective effect even at low doses. In addition, Examples 8, 9, 1, 3 and 11 were also long lasting and effective.

[0302] Example 4

[0303] In Example 4, the efficacy of the pour-on formulation against ticks (Rhipicephalus (Boophilus) microplus) on cattle was determined.

[0304] The objective of the study was to determine the treatment and preventive efficacy of the acaricide formulation against experimentally induced Rhipicephalus (Boophilus) microplus infestations on cattle.

[0305] The study was conducted as a parallel group, open-label, negative control, randomized efficacy study. Each group included 5 animals. All animals were pre-classified by sex and number of individual ticks infested in descending order before treatment (Day -14 to -2), and then 5 animals were divided into 2 (x) zones. Cattle were randomly assigned to zones and classified in ascending order. Each animal was infested with 3000 larvae on Day -35, -33, -29, -27, -22, -20, -15, -13, -8, -6, -1, 5, 7, 12, 14, 19, 21, 26, and 28. Engorged females were collected daily from Day -14 to -2 and Day 0 to 56. Ticks from Day -14 to -2 were used for grouping, ticks from Day 1 to 28 were used to determine the efficacy of treatment, and ticks from Day 29 to the end of the tick drop phase were used to determine the efficacy of prevention. The fecundity of ticks was also determined. This was done by assessing the egg laying and larval hatching from pooled samples of engorged female ticks. In this case, > 60% of larvae hatching indicated normal hatching rate. The compounds tested here did not achieve a significant additional effect.

[0306] For the treatment effect against existing tick infestation, treatment was judged to be successful when 90% effect was measured in the treatment group compared to the control group (based on the number of engorged female ticks dropped from Day 1 to 28 after treatment). Therefore, if the effect was less than 90%, there was no effect.

[0307] For the prevention effect against emerging tick infestation, treatment was judged to be successful when 90% effect was measured in the treatment group compared to the control group (based on the number of engorged female ticks dropped from Day 29-56 after treatment). Therefore, if the effect was less than 90%, there was no sufficient effect shown.

[0308] The results are shown in Tables 11 and 12. Table 11 shows the treatment effect of the formulation of the present invention on cattle against all stages of cattle ticks (Boophilus microplus) on cattle, and Table 12 shows the prevention effect of the formulation of the present invention on emerging tick infestation by cattle ticks (Boophilus microplus) on cattle.

[0309] Table 11:

[0310]

[0311]

[0312] na = no data

[0313] Table 12:

[0314]

[0315] na = no data

[0316] In Tables 11 and 12, it can be seen that all active ingredients in the compositions according to the application have a high efficacy for the prevention and treatment of infestation by ticks, even at low doses.

[0317] Example 5

[0318] According to Example 5, the efficacy of pour-on formulations against Bovicola bovis on cattle was determined. The aim of the study was to determine the curative and preventive efficacy of the insecticidal formulations against naturally occurring infestation by Bovicola bovis on cattle.

[0319] The study was carried out as a parallel-group, non-blind, negative control efficacy study. Each group comprised 5 animals. The lice were counted on Day -2 before treatment and on Days 2, 14, 28 and 42. In this case, the hair of each animal was screened at 10 sites and all larval and adult stages of Bovicola bovis were counted. The results for each animal were pooled, averaged between the animals in a group and compared with the number of lice in the untreated control. The acute effect on existing infestation by Bovicola bovis was determined on Day 2. In this case, the treatment was judged to be successful if at least 90% efficacy was measured in the treatment group compared with the control group. The sustained effectiveness on existing infestation by Bovicola bovis was measured in the counts on Days 14, 21 and 42.

[0320] In this case, the treatment was judged to be successful if 100% efficacy was measured in the treatment group compared with the control group. In the case of less than 100% efficacy, the treatment was therefore judged to be unsuccessful.

[0321] Table 13:

[0322] Test area Formulation Examples Dosage mg / kg dpt 2 dpt 14 dpt 28 dpt 42 B 2 2 >90 100 100 100 B 12 2 >90 100 100 100 A 16 3 <90 <100 <100 100 A 13 3 <90 <100 100 100 A 15 3 <90 <100 100 100

[0323] Dpt = days after treatment

[0324] Table 13 shows the effect of the formulations according to the application on Bovicola bovis on cattle.

[0325] It is evident from Table 13 that Examples 2 and 16, in particular, have a relatively rapid high efficacy when they are used in the form of the compositions according to the application in combination with the solvent mixture described.

[0326] It is therefore evident from the foregoing that the pharmaceutical active compositions according to the application exhibit good solubility for the active ingredients of the benzamides and that using these it is possible to produce effective active compositions, in particular for the treatment or prevention of infestation by parasites, in particular in the case of non-human organisms. In this case, use as a pour-on application is particularly advantageous.

Claims

1. A pharmaceutical composition comprising at least one pharmaceutically active ingredient soluble in a solvent phase, wherein the pharmaceutically active ingredient is a fluorinated heteroaryl amide selected from compounds of formula (Ia”) and salts of compounds of formula (Ia”). in D1 is CR 11 Or heteroatoms selected from N or O; D2 is CR 11 Or heteroatoms selected from N or O; D3 is either C or N; D4 is either C or N; D5 is CR 11 Or N; Of which no more than one (1) or two of the components selected from D1, D2, D3, D4 and D5 are heteroatoms; For the Aromaticae system; and R 1 It is H or C1-C6-alkyl; These parts are as follows: A1 is CR 2 Or N, A2 is CR 3 Or N, A3 is CR 4 Or N, A4 is CR 5 Or N, B1 is CR 6 , B2 is CR 7 , B4 is CR 9 ,and B5 is CR 10 , However, no more than three of the parts A1 to A4 are N; R 2 R 3 R 4 R 5 R 6 R 7 R 9 and R 10 Each is independently H, halogen, and optionally substituted C1-C6-alkyl or C1-C6-alkoxy in each case; R 8 It is a fully halo-C1-C3-alkyl or a fully halo-C1-C3-alkoxy group; R 11 For H; W is O, Q is H or, in each case, a C3-C6-cycloalkyl group that is optionally substituted; or It may be fluralaner, afoxolaner, or lotileraner. And the solvent phase is a solvent mixture comprising at least a first solvent and a second solvent different from the first solvent, wherein the first solvent is selected from C1-C4-alkanols, wherein the second solvent is selected from aliphatic C1-C4-carbonates, which are optionally substituted with hydroxyl groups, wherein the first solvent is present in a proportion of 50% to 95% by weight and wherein the second solvent is present in a proportion of 5% to 50% by weight, based on the total amount of solvents in the solvent phase.

2. The pharmaceutical composition according to claim 1, wherein R 1 For H and / or R 8 It is a perfluorinated C1-C3-alkyl or a perfluorinated C1-C3-alkoxy group.

3. The pharmaceutical composition according to claim 1, wherein the first solvent is selected from ethanol, n-propanol, isopropanol, and butanol.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The first solvent is isopropanol, and the second solvent is propylene carbonate.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the solvent mixture comprises the first solvent and the second solvent.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the solvent mixture contains, in addition to the first solvent and the second solvent, a third solvent different from the first solvent and the second solvent.

7. The pharmaceutical composition according to claim 6, wherein the third solvent is selected from water, butylated hydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, methyl benzoate, octyl dodecyl alcohol, paraffin, triglycerides, propylene glycol octanoate, and glycol ethers.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the second solvent is present in an amount of ≥20% by weight to ≤45% by weight, based on the total amount of solvents in the solvent mixture.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the second solvent is present in an amount of ≥30% by weight to ≤40% by weight, based on the total amount of solvents in the solvent mixture.

10. The pharmaceutical composition according to claim 1, wherein the active ingredient is selected from: 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)-ethyl]phenyl]pyrazol-4-yl]-N-methylpyridine-3-carboxamide 2-Chloro-N-cyclopropyl-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl]-3-pyridinecarboxamide: 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: 2-Chloro-5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl]-N-cyclopropylpyridine-3-carboxamide 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-4-yl]pyridine-3-carboxamide 2-Chloro-N-cyanocyclopropyl-5-[1-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazole-4-yl]benzamide: 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazol-4-yl]-N-cyclopropylbenzamide 5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazol-4-yl]-2-chloro-N-cyclopropylbenzamide 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrazol-4-yl]-N-cyclopropylbenzamide 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-4-yl]benzamide 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-4-yl]-N-methylbenzamide 2-Chloro-N-cyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]benzamide: 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[4-(1,1,1,2,3,3,3-heptafluoroprop-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]isoxazo-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]isoxazo-5-yl]benzamide: 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrrole-3-yl]benzamide: 2-Chloro-5-[3-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrrolo-1-yl]-N-cyclopropylbenzamide:

11. The pharmaceutical composition according to any one of claims 1 to 3, wherein the active pharmaceutical ingredient is present in an amount greater than or equal to 0.1% by weight and less than or equal to 5% by weight.

12. The pharmaceutical composition according to any one of claims 1 to 3, for treating or preventing parasitic infection.

13. The pharmaceutical composition according to claim 12, for treating or preventing ectoparasitic infection.

14. The pharmaceutical composition according to any one of claims 1 to 3, for treating or preventing parasitic infection in non-human organisms.

15. The pharmaceutical composition of claim 14, for treating or preventing parasitic infection in a non-human organism by dripping or pouring the composition onto the non-human organism.

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