RU2847564C1 - Pharmaceutical composition for controlling parasites in non-human organisms - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics, specifically to a pharmaceutical composition for the treatment or prevention of parasitic infestation and the use of said composition as an agent for the treatment or prevention of parasitic infestation, including in non-human organisms. Disclosed is a pharmaceutical composition for the treatment or prevention of parasitic infestation, comprising at least one pharmaceutically active ingredient that is soluble in the solvent phase, where the pharmaceutically active ingredient is a fluorinated heteroarylamide and is selected from a compound of defined structure and its salts, N-oxides and tautomeric forms, wherein the pharmaceutically active ingredient is present in an amount from more than or equal to 0.1 wt. % to less than or equal to 5 wt. %, the solvent phase is a mixture of solvents containing at least a first solvent and a second solvent, different from the first solvent, wherein the first solvent is selected from C₁-C₄ alkanols, optionally substituted with at least one C₁-C₄ alkoxy group or phenyl group, where the second solvent is selected from aliphatic C₁-C₄ carbonates, optionally substituted with a hydroxy group, where the first solvent is present in proportion of 50 wt. % to 95 wt. % and where the second solvent is present in proportion of 5 wt. % to 50 wt. %, based on the total amount of solvents in the solvent phase. Using said composition as an agent for treating or preventing parasitic infestation. Use of said composition as an agent for treating or preventing parasitic infestation in non-human organisms.

EFFECT: said group of inventions provides a pharmaceutical composition for use in non-human organisms, using a solvent in which antiparasitic agents from the group of heteroarylamides have high solubility and good applicability in animals.

12 cl, 13 tbl, 5 ex

Description

The present invention relates to a pharmaceutical composition for combating parasites in non-human organisms. The present invention relates, in particular, to dermal formulations with improved applicability to the body for combating ectoparasites in mammals and livestock.

Modern fluorinated antiparasitic active compounds, also known as fluorinated antiparasitics, such as fluralaner, afoxolaner, sarolaner, lotilaner, and fipronil, which have been known for a relatively long time, and the active ingredients described in WO 2015/067646 and WO 2015/067647, exhibit good insecticidal and acaricidal efficacy. However, many of these active compounds have very low solubility in solvents suitable for topical administration to animals. To prevent the drug from dripping off the fur after administration or incomplete distribution on the animal's skin, the active compound should be dissolved in a small volume of solvent. In addition, the solvent must be toxicologically safe and have high skin compatibility.

WO 96/17520 relates to preparations applied to the skin of animals for the control of parasitic insects, having the following composition: agonists or antagonists of nicotinic acetylcholine receptors of insects in a concentration of from 1 to 20% by weight based on the total weight of the composition; solvents of the benzyl alcohol group or optionally pyrrolidones in a concentration of at least 20% by weight based on the total weight of the composition; optionally other solvents from the group of cyclic carbonates or lactones in a concentration of from 5.0 to 80% by weight based on the total weight of the composition; additionally other auxiliary substances from the group of thickeners, spreaders, dyes, antioxidants, foaming agents, preservatives, adhesives, emulsifiers in a concentration of from 0.025 to 10% by weight based on the total weight of the composition.

There are known topical antiparasitic products for animals that contain isopropanol as a solvent. These include products containing the active ingredient ivermectin, such as Baymec® Pour-on (Bayer®), Ivomec® Pour-on (Merial®), and others. Examples of pour-on products containing isopropanol with other active ingredients include Sebacil® Pour-on (Bayer®, active ingredient Phoxim), and Dectomax® (Elanco, active ingredient Doramectin).

The objective of the present invention is to create a pharmaceutical composition for topical use in non-human organisms using a solvent in which modern, for example, fluorinated antiparasitic agents, especially from the heteroarylamide group, have a sufficiently high solubility and at the same time good applicability in animals, especially in the form of pour-on formulations.

The present invention relates to a pharmaceutical composition comprising at least one parasiticidal pharmaceutically active ingredient and particularly easy to apply to animals, wherein the active ingredient is completely soluble in a solvent phase, wherein the pharmaceutically active ingredient, in particular, belongs to the group of fluorinated heteroarylamides, preferably pyridylamides, and wherein the solvent phase is in the form of a mixture of solvents and contains a first solvent and a second solvent different from the first solvent, wherein the first solvent includes a C1-C15 alcohol, wherein the second solvent contains an organic carbonate, and wherein the first solvent is present in a proportion of from 50 wt. % to 95 wt. % and wherein the second solvent is present in a proportion of from 5 wt. % to 50 wt. % in each case, based on the total amount of solvents in the solvent phase.

For example, the first solvent and the second solvent may be in a quantitative ratio to each other from 50 wt. %:50 wt. % to 95 wt. %:5 wt. %, in this case based on the total amount of solvents in the solvent phase.

According to a further embodiment, the first solvent may comprise only one solvent or a combination of two or more, preferably two, C1-C15 alcohols, wherein in this configuration, the majority of the C1-C15 alcohols are present together in the aforementioned amount and are collectively referred to as the first solvent. Therefore, in the context of the present invention, the term "solvent" does not necessarily refer to only one substance, but may also refer to a mixture of different substances. However, it is assumed that all substances forming the first solvent are C1-C15 alcohols.

Alternatively or additionally, it may be envisaged that the second solvent consists of a single substance or may be a combination of two or more substances, preferably two substances, wherein all substances forming the second solvent are organic carbonates. In this configuration, two or more organic carbonates are present together in the aforementioned amount.

A solvent phase consisting only of a first solvent and a second solvent is also called a binary solvent phase.

The composition according to the present invention, in particular, makes it possible to obtain new liquid medicinal products for topical or cutaneous application to non-human organisms using a solvent in which, in particular, fluorinated antiparasitic agents from the heteroarylamide group have a sufficiently high solubility and at the same time good applicability in animals, especially in the form of pour-on compositions.

The pharmaceutical composition described herein also contains at least one pharmaceutically active ingredient, also referred to herein as an active ingredient, which may also be referred to as an API (active pharmaceutical ingredient). In particular, the active ingredient may be the actual active substance in the composition and therefore primarily or entirely responsible for the antiparasitic effect, as described in detail below. Accordingly, the active ingredient should be effective, in particular, against non-human organisms.

In principle, the pharmaceutically active ingredient is not limited. However, it is envisaged that the pharmaceutically active ingredient consists of a group, in particular, of fluorinated heteroarylamides, which are described in more detail below. In principle, a heteroarylamide could be, for example, a pyridylamide, which is a pyridine group linked to an amide via an aryl group. For example, a heteroarylamide could be fluorinated.

Regarding the pharmaceutically active ingredient, it is further stipulated that it is completely soluble in the solvent phase. This ensures, in particular, preferable skin applicability, making it possible to apply it as a pour-on or pour-on solution, among other things.

Pouring-on application, where one embodiment may be a spot-on formulation, is understood in particular as an application of a type in which relatively small amounts of the formulation are applied, for example, up to 100 ml/100 kg, approximately in the range of 1 ml/100 kg to 100 ml/100 kg, for example in the range of 1 ml/100 kg to 20 ml/100 kg, approximately in the range of 5 ml/100 kg to 10 ml/100 kg, based on the amount of formulation applied to the body weight, to limited areas of the skin, typically the neck or back of a non-human organism. Accordingly, a pour-on formulation is understood to be a formulation of a type that is suitable and intended for use as a pour-on agent.

Particularly important for such applications, i.e., in so-called pour-on solutions, is achieving a high level of solubility of the active ingredient, which ensures the desired concentration of the active ingredient in the solution. Furthermore, good distribution characteristics on the skin must be achieved. Distribution characteristics can be understood, in particular, as the distribution of the composition on the skin. Distribution characteristics can therefore be used to determine whether the composition, when presented as a solution, achieves the desired distribution throughout the body and, in particular, whether it does not drip or run excessively from the application site, so that localized application is possible, and no active ingredient is lost due to runoff after application.

In order to provide the above-mentioned advantageous properties, especially for pour-on compositions, the composition described herein contemplates that the solvent phase is in the form of a solvent mixture and comprises a first solvent and a second solvent different from the first solvent, wherein the first solvent comprises a C1 - C15 alcohol, wherein the second solvent is an organic carbonate, and wherein the first solvent is present in a proportion of from 50 wt. % to 95 wt. % and wherein the second solvent is present in a proportion of from 5 wt. % to 50 wt. %, in each case based on the total amount of solvents in the solvent phase, wherein in the binary solvent phase the first solvent and the second solvent are present in a quantitative ratio to each other of from 50 wt. %: 50 wt. % to 95 wt. %: 5 wt. %, based on the total amount of solvents in the solvent phase. However, it should be noted that the sum of the proportions of the first and second solvents does not necessarily have to be up to 100 wt. %, since, for example, ternary systems with additional solvents are possible and may be preferable.

According to one embodiment, such a configuration can advantageously ensure a sufficient concentration of the fully dissolved active ingredient heteroarylamide in the solvent phase and thus is possible in the formulation, and advantageous distribution characteristics are achievable during pour-on application. According to one embodiment, the active heteroarylamide is dissolved at least 95% by weight (of the active substance). According to another embodiment, the active substance is dissolved at least 97% by weight (of the active substance). According to a preferred embodiment, the active substance is dissolved at 99% by weight (of the active substance). According to a preferred embodiment, the active substance is dissolved at 100% by weight (of the active substance).

Thus, contrary to prior art assumptions, it has been demonstrated that using a solvent mixture comprising a C1-C15 alcohol, particularly a C1-C10 alcohol, such as a C1-C7 alcohol, and an organic carbonate can yield beneficial properties. For example, the solvent mixture may consist of one or more C1-C15 alcohols and one or more organic carbonates. When combined, they exhibit, for example, good solubility of the active ingredient, particularly one formed from a group of fluorinated heteroarylamides, and good distribution properties.

In principle, C1 - C15 alcohols are understood to be aliphatic or aromatic alcohols containing from 1 to 15 carbon atoms.

Organic carbonates also include acyclic or cyclic carbonate esters, which are themselves polar solvents with low volatility and low toxicity. By carefully selecting the alcohols used to synthesize the esters, the physical properties of the resulting carbonates can be tailored to the desired application.

Thus, the present invention provides a very suitable pour-on composition, both in terms of distribution characteristics, ease of administration, and in terms of the concentration of the active ingredient, i.e., effectiveness.

Other advantages of the formulation described herein include good compatibility and safety for the treated organism, such as reduced adverse effects on the animal, such as skin and/or fur, irritation, or residual effects in the animal's body, including in animals entering the food chain. The formulations and ease of administration (good applicability due to viscosity and spreadability) ensure excellent environmental stability, resulting in high consumer acceptance and reduced adverse side effects. This is even applicable for use in animal husbandry and food production. Furthermore, the formulation allows the active ingredient, through increased dissolved concentrations, to achieve high efficacy in a shorter time to be effective, thus ensuring a prolonged active period, eliminating the need for frequent application. Finally, good manageability and user convenience are achieved with concomitant low production costs. Good bioavailability and a wide range of applications are also advantageous.

Furthermore, the composition according to the present invention can be easily applied to an animal, for example, with respect to viscosity and spreading properties. The composition, particularly the active ingredient, also has a low tendency to be washed off, for example, by rain. In fact, the effectiveness can be maintained even if the animal is wet or exposed to sunlight. The compositions are generally highly stable and exhibit reduced degradation and reduced secondary reactions of the composition components, for example, with each other. The preferred stability achieved by the composition described herein includes a shelf life of at least 12 months, approximately 24 months, at 30°C. After application, the composition dries easily, especially when a readily evaporating solvent is added, without significantly deteriorating the animal's appearance.

With regard to the solvent present in the solvent phase or solvent mixture, the following solvents are particularly preferred. The first solvent is different from the second solvent. According to one embodiment, the first solvent, unlike the second solvent, is not a carbonate.

According to one embodiment, the first solvent preferably comprises C1-C4 alkanols, which are optionally substituted with at least one C1-C4 alkoxy group or phenyl group, wherein the hydroxyl group can, in principle, be in any selected position. According to a particular embodiment, the first solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, butanol, for example isobutanol or n-butanol, especially ethanol and/or isopropanol. In addition to good dissolution properties, especially in connection with the described organic carbonates, such solvents have the additional advantage of suitable toxicity for use on non-human organisms, so that their use is possible without adverse effects on animals.

The second solvent is an organic aliphatic C1-C4 carbonate, optionally substituted with a hydroxyl group. According to a specific embodiment, the second solvent is selected from the group consisting of ethylene carbonate, propylene carbonate, and glycerol carbonate. In addition to good dissolution properties, particularly with respect to the alcohols described, such solvents have the additional advantage of suitable toxicity for use on non-human organisms, allowing their use without adverse effects on animals.

According to a particularly preferred embodiment, the first solvent is isopropanol and the second solvent is propylene carbonate. It has been found that a solvent phase containing, for example, isopropanol and propylene carbonate as a solvent provides the above-mentioned advantages in terms of good solubility of the active ingredient, advantageous distribution characteristics, and at the same time has lower toxicity.

According to another embodiment, the solvent mixture comprises 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 may be sufficient solely as a solvent, wherein, understandably, one of the first solvents described and one of the second solvents described may be sufficient to form the solvent mixture.

According to another embodiment, with regard to the relative ratio of the first solvent to the second solvent, it is preferable that the second solvent, i.e. the organic carbonate, is present in an amount of ≥ 20% by weight to ≤ 45% by weight, preferably at a content of ≥ 30% by weight to ≤ 40% by weight, based on the total amount of solvents in the solvent mixture. According to this embodiment, the first solvent is present in a content of ≥ 55% by weight to ≤ 80% by weight, preferably at a content of ≥ 60% by weight to ≤ 70% by weight, based on the total amount of solvents in the solvent mixture. In this configuration, the above-mentioned advantages with respect to the solubility of the active ingredient with the accompanying good distribution properties can be particularly effectively ensured. In other words, exceptional solubility of the active ingredient can be ensured with stable results. Thus, advantageous applicability is ensured together with stable storage properties. Due to the high solubility of the active ingredient, relatively small quantities of the solvent mixture are required. This allows the formulation to be stored.

Furthermore, according to another embodiment, the solvent mixture, in addition to the first solvent and the second solvent, contains a third solvent different from the first solvent and the second solvent. Therefore, the third solvent is not intended to be the first solvent and the second solvent, as described above.

By using an additional solvent, the solubility and/or distribution characteristics can be further improved or at least adjusted to suit the desired application.

According to a specific embodiment, the solvent phase is configured as a mixture of at least three solvents, wherein the third solvent is neither a C1-C15 alcohol nor an organic carbonate, but rather has a different definition. However, this does not exclude the possibility that the first solvent and/or the second solvent and/or the third solvent are present in each case, for example, as a binary solvent mixture.

In principle, when providing a ternary solvent phase, the first solvent and the second solvent may be present in the range described above, in which the proportion of the first solvent and the second solvent may consist of the proportion of the third solvent. In particular, according to an embodiment, the third solvent replaces a portion of the first solvent, in which the first solvent is still present in the described range from 50% to 95% by weight, based on the sum of solvents in the solvent phase, and in which the second solvent is also present in the quantitative range described above, namely in a proportion from 5% to 50% by weight, in each case based on the total amount of solvent in the solvent phase. The third solvent, as well as the first solvent and the second solvent, must be pharmaceutically compatible and also must not adversely affect the solubility of the active ingredients. It may be useful to use penetration-enhancing solvents.

Preferred examples of the third solvent, which is different from the first solvent and the second solvent, are selected from the group consisting of water, butylhydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, benzyl benzoate, octyldodecanol, paraffin, triglycerides such as caprylic/capric acid triglycerides (e.g. Miglyol 812), propylene glycol octanoate decanoate (e.g. Miglyol 840), glycol ethers such as diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether.

According to one embodiment, the solvent phase may be a ternary system and, therefore, consist of a first solvent or solvents, a second solvent or solvents, and a third solvent or solvents. According to this embodiment, the first solvent(s), second solvent(s), and third solvent(s) are selected as defined above.

In particular, according to an embodiment of the ternary system, one non-limiting example is that the sum of the first and third solvents and the second solvent is present in a quantitative ratio to each other of from 50 wt. %:50 wt. % to 95 wt. %:5 wt. %, based on the total amount of solvents in the solvent phase. With regard to the relative ratio of the first solvent and the second solvent, preferably the second solvent is present in an amount of ≥ 20 wt. % to ≤ 45 wt. %, preferably at a content of ≥ 30 wt. % to ≤ 40 wt. %, based on the total amount of solvents in the solvent mixture. Accordingly, the first solvent and optionally the third solvent can be present together at a content of ≥ 55 wt. % to ≤ 80 wt. %, preferably at a content of ≥ 60 wt. % to ≤ 70 wt. %, based on the total amount of solvents in the solvent mixture.

Non-limiting examples of solvent mixtures can be composed, for example, as follows: a mixture of isopropanol (32.5), ethanol (32.5) and propylene carbonate (35) can be used, where the numbers in parentheses indicate the content in wt. % based on the solvent mixture. Additional examples include 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 also a mixture of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), where the numbers in parentheses, in turn, indicate the content in wt. % based on the solvent mixture.

According to one embodiment, one first solvent and one solvent mixture are present, consisting, for example, of two second solvents and, optionally, one or more third solvents. According to another embodiment, one second solvent and a solvent mixture are present, consisting, for example, of two first solvents and, optionally, one or more third solvents.

Furthermore, the composition's components may be limited to the solvent and active ingredient, such that the composition may consist of a first solvent, a second solvent, optionally a third solvent, and an active ingredient. However, other components are not excluded and are defined elsewhere.

Preferably, the fluorinated heteroarylamide is designed as described in WO 2015067646 A1 or WO 2015067647 A1. The active ingredients thereof are preferably configured as follows and include compounds of general formula (I):

Where

R ¹ is H, in each case optionally substituted C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aryl-(C ₁ -C ₃ )-alkyl, heteroaryl-(C ₁ -C ₃ )-alkyl, or is optionally substituted C ₁ -C ₆ -alkyl, preferably H or preferably C ₁ -C ₂ -alkyl, particularly preferably H or methyl, in particular H,

the fragments are as follows:

A ₁ is CR ² or N,

A ₂ is CR ³ or N,

A ₃ is CR ⁴ or N,

A ₄ is CR ⁵ or N,

B ₁ is CR ⁶ or N,

B ₂ is CR ⁷ or N,

B ₃ is CR ⁸ or N,

B ₄ is CR ⁹ or N, and

B ₅ is CR ¹⁰ or N,

but no more than three of the fragments A ₁ - A ₄ are N and no more than three of the fragments B ₁ - B ₅ are N;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ each independently of one another are H, halogen, cyano, nitro, in each case optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, NC ₁ -C ₆ alkoxyimino-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, NC ₁ -C ₆ alkylamino, N,N-di-C ₁ -C ₆ alkylamino or NC ₁ -C ₃ alkoxy-C ₁ -C ₄ alkylamino or 1-pyrrolidinyl;

if neither of the moieties A ₂ and A ₃ is N, R ³ and R ⁴ together with the carbon atom to which they are bound may form a 5- or 6-membered ring containing 0, 1 or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom; or

if neither of the fragments A ₁ and A ₂ is N, R ² and R ³ together with the carbon atom to which they are attached may form a 6-membered ring containing 0, 1, or 2 nitrogen atoms;

R ⁸ is halogen, cyano, nitro, in each case optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, NC ₁ -C ₆ alkoxyimino-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, NC ₁ -C ₆ alkylamino or N,N-di-C ₁ -C ₆ alkylamino;

W represents O or S,

Q is H, formyl, hydroxyl, amino, or in each occurrence optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₅ heterocycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl, C ₆ -, C ₁₀ -C ₁₄ aryl, C ₁ -C ₅ heteroaryl, C ₆ -, C ₁₀ -, C ₁₄ aryl-(C ₁ -C ₃ )-alkyl, C ₁ -C ₅ heteroaryl-(C ₁ -C ₃ )-alkyl, NC ₁ -C ₄ -alkylamino, NC ₁ -C ₄ -alkylcarbonylamino, or N,N-di-C ₁ -C ₄ -alkylamino; or

is an optionally poly-V-substituted unsaturated 6-membered carbocycle; or

is an optionally poly-V-substituted unsaturated 4-, 5-, or 6-membered heterocyclic ring, where

V independently of one another are halogen, cyano, nitro, in each case optionally substituted _C1 - _C6 alkyl, _C1 - _C4 alkenyl, _C1 - _C4 alkynyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, NC1- _C6 alkoxyimino- _{C1 - C3} alkyl, _C1 - _C6 alkylsulfanyl, _C1 - _C6 alkylsulfinyl, _C1 - _C6 alkylsulfonyl or N,N-di-( _C1 - _C6 alkyl)amino;

T is an optionally substituted 5-membered heteroaromatic system containing no more than 2 heteroatoms (1 or 2 heteroatoms), such as 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,

and salts, N-oxides and tautomeric forms of the compounds of formula (I).

The present document describes, for example, compounds of formula (Ia)

Where

fragments D ₁ , D ₂ each independently of one another represents CR ¹¹ or a heteroatom selected from N and O;

the fragments D ₃ and D ₄ independently of one another represent C or represent a heteroatom selected from N (in other words: the fragments D ₃ and D ₄ independently of one another represent C or N);

wherein no more than one (1) or two moieties selected from D ₁ , D ₂ , D ₃ and D ₄ represent a heteroatom, wherein one (1) or two moieties selected from D ₁ , D ₂ , D ₃ and D ₄ represent a heteroatom selected from N or O in the case of D ₁ and D ₂ , or N in the case of D ₃ and D ₄ ;

is an aromatic system; and

R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , B ₁ , B 2 , B ₃ , B ₄ , B ₅ , 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 each have the meaning as described above herein, wherein no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two fragments selected from A ₁ , A ₂ , A ₃ , A ₄ may represent N and no more than one fragment selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ represents N,

and salts, N-oxides and tautomeric forms of the compounds of formula (I).

According to one embodiment, the present invention relates to compounds of formula (Ia‘)

in which

R ¹ , R ¹¹ , Q, W, A ₁ , A ₂ , A ₃ , A ₄ , B ₁ , B ₂ , B ₄ and B ₅ each have the meaning as described above herein, wherein no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or wherein one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N;

D ₁ and D ₂ independently of one another represent CR ¹¹ or a heteroatom, preferably CR ¹¹ or a heteroatom selected from N, O or S, more preferably CR ¹¹ or a heteroatom selected from N or O;

the fragments D ₃ and D ₄ independently of each other represent C or a heteroatom selected from N;

wherein no more than one (1) or two moieties selected from D ₁ , D ₂ , D ₃ and D ₄ is/are a heteroatom, wherein one (1) or two moieties selected from D ₁ , D ₂ , D ₃ and D ₄ are a heteroatom selected from N or O in the case of D ₁ and D ₂ , or N in the case of D ₃ and D ₄ ;

is an aromatic system,

and R ⁸ has the meaning as defined herein, preferably is perfluorinated C ₁ -C ₄ alkyl.

According to another embodiment, the present invention relates to compounds of formula (Ia‘‘)

in which

D ₁ is CR ¹¹ or a heteroatom selected from N or O;

D ₂ is CR ¹¹ or a heteroatom selected from N or O;

D ₃ represents C or N;

D ₄ represents C or N;

D ₅ is CR ¹¹ or N;

wherein no more than one (1) or two moieties selected from D ₁ , D ₂ , D ₃ , D ₄ and D ₅ represent a heteroatom;

is an aromatic system; and

R ¹ is H, in each case optionally substituted C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aryl-(C ₁ -C ₃ )-alkyl or heteroaryl-(C ₁ -C ₃ )-alkyl, or is optionally substituted C ₁ -C ₆ -alkyl, particularly preferably H;

the fragments are as follows:

A ₁ is CR ² or N,

A ₂ is CR ³ or N,

A ₃ is CR ⁴ or N,

A ₄ is CR ⁵ or N,

B ₁ is CR ⁶ or N,

B ₂ is CR ⁷ or N,

B ₃ is CR ⁸ or N,

B ₄ is CR ⁹ or N, and

B ₅ is CR ¹⁰ or N,

but no more than three of the fragments A ₁ to A ₄ represent N and no more than three of the fragments B ₁ to B ₅ simultaneously represent N;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ each independently of one another are H, halogen, cyano, nitro, in each case optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, NC ₁ -C ₆ alkoxyimino-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, NC ₁ -C ₆ alkylamino or N,N-di-C ₁ -C ₆ alkylamino;

if neither of the fragments A ₂ and A ₃ is N, R ³ and R ⁴ together with the carbon atom to which they are bonded may form a 5- or 6-membered ring containing 0, 1, or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom, or

if neither of the fragments A ₁ and A ₂ is N, R ² and R ³ together with the carbon atom to which they are bound may form a 6-membered ring containing 0, 1, or 2 nitrogen atoms;

R ⁸ is halogen, cyano, nitro, in each case optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, NC ₁ -C ₆ alkoxyimino-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, NC ₁ -C ₆ alkylamino or N,N-di-C ₁ -C ₆ alkylamino;

R ¹¹ independently of one another are H, halogen, cyano, nitro, amino or optionally substituted C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkylsulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, preferably H;

W represents O or S,

Q is H, formyl, hydroxyl, amino, or in each occurrence optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₅ heterocycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl, C ₆ -, C ₁₀ -C ₁₄ aryl, C ₁ -C ₅ heteroaryl, C ₆ -, C ₁₀ -, C ₁₄ aryl-(C ₁ -C ₃ )-alkyl, C ₁ -C ₅ heteroaryl-(C ₁ -C ₃ )-alkyl, NC ₁ -C ₄ -alkylamino, NC ₁ -C ₄ -alkylcarbonylamino, or N,N-di-C ₁ -C ₄ -alkylamino; or

is an optionally poly-V-substituted unsaturated 6-membered carbocycle; or

is an optionally poly-V-substituted unsaturated 4-, 5-, or 6-membered heterocyclic ring, where

V independently of one another are halogen, cyano, nitro, in each case optionally substituted _C1 - _C6 alkyl, _C1 - _C4 alkenyl, _C1 - _C4 alkynyl, _C3 - _C6 cycloalkyl, _C1 - _C6 alkoxy, NC1- _C6 alkoxyimino- _{C1 - C3} alkyl, _C1 - _C6 alkylsulfanyl, _C1 - _C6 alkylsulfinyl, _C1 - _C6 alkylsulfonyl, or N,N-di-( _C1 - _C6 alkyl)amino;

and salts, N-oxides and tautomeric forms of compounds of formula (Ia‘‘).

Also suitable are compounds of formula (Ia‘‘), wherein the compounds of formula (Ia‘‘ are compounds of formula (I-T3)

in which R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , R ¹¹ , B ₁ , B ₂ , B ₄ , B ₅ , R ⁸ , Q and W each have the meaning as described above herein, where no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

According to another embodiment, the present invention relates to compounds of formula (Ia‘‘) which are compounds of formula (I-T2)

in which R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , R ¹¹ , B ₁ , B ₂ , B ₄ , B ₅ , R ⁸ , Q and W each have the meaning as described above herein, where no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

According to another embodiment, the present invention relates to compounds of formula (Ia‘‘), wherein the compounds of formula (Ia‘‘) are compounds of formula (I-T4)

in which R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , R ¹¹ , B ₁ , B ₂ , B ₄ , B ₅ , R ⁸ , Q and W each have the meaning as described above herein, where no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

Also suitable are compounds of formula (Ia‘‘), wherein the compounds of formula (Ia‘‘ are compounds of formula (I-T22)

in which R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , R ¹¹ , B ₁ , B ₂ , B ₄ , B ₅ , R ⁸ , Q and W each have the meaning as described above herein, where no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

Also suitable are compounds of formula (Ia‘‘), wherein the compounds of formula (Ia‘‘ are compounds of formula (I-T23)

in which R ¹ , A ₁ , A ₂ , A ₃ , A ₄ , R ¹¹ , B ₁ , B ₂ , B ₄ , B ₅ , R ⁸ , Q and W each have the meaning as described above herein, where no more than one moiety selected from A ₁ , A ₂ , A ₃ , A ₄ is N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N; or where one or two moieties selected from A ₁ , A ₂ , A ₃ , A ₄ may be N and no more than one moiety selected from B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

Also suitable are compounds according to the formulas and embodiments described herein wherein R ¹¹ is H and W is O.

Also suitable are compounds according to the formulas and embodiments described herein, wherein R ¹¹ is H, and W is O, and B ₃ is CR ⁸ , R ⁸ is halogen-substituted C ₁ -C ₃ -alkyl (preferably perhalogenated C ₁ -C ₃ -alkyl, more preferably perfluorinated C ₁ -C ₃ -alkyl) or halogen-substituted C ₁ -C ₃ -alkoxy (preferably perhalogenated C ₁ -C ₃ -alkoxy, more preferably perfluorinated C ₁ -C ₃ -alkoxy).

Also suitable are compounds according to the formulas and embodiments described herein, wherein the moieties A ₁ - A ₄ and B ₁ - B ₅ are as follows:

A ₁ is CH,

A ₂ is CR ³ or N,

A ₃ is CR ⁴ ,

A ₄ is CH,

B ₁ is CR ⁶ or N,

B ₂ is CH,

B ₃ is CR ⁸ ,

B ₄ is CH and

B ₅ is CR ¹⁰ or N.

Also suitable are compounds according to the formulas and embodiments described herein wherein R ¹ is H.

Also suitable are compounds according to the formulas 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 -oxidothiethan-3-yl, 1,1-dioxidothiethan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

Also suitable are compounds according to the formulas and embodiments described herein wherein R ⁸ is halogen or halogen-substituted C ₁ -C ₄ alkyl.

Also suitable are compounds according to the formulas described herein wherein R ¹¹ is H.

Also suitable are compounds according to the formulas described herein, wherein R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are independently of one another H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, N-alkoxyiminoalkyl, C ₁ -C ₄ alkylsulfanyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, NC ₁ -C ₄ alkylamino, N,N-di-C ₁ -C ₄ alkylamino.

Also suitable are compounds according to the formulas described herein, wherein R ² , R ³ , R ⁴ and R ⁵ are independently of one another H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, NC ₁ -C ₄ alkoxyimino-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylsulfanyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, NC ₁ -C ₄ alkylamino or N,N-di-C ₁ -C ₄ alkylamino.

Also suitable are compounds according to the formulas described herein, wherein the fragments A ₁ - A ₄ and B ₁ - B ₅ are as follows:

A ₁ is CH,

A ₂ is CR ³ or N,

A ₃ is CR ⁴ ,

A ₄ is CH,

B ₁ is CR ⁶ or N,

B ₂ is CH,

B ₃ is CR ⁸ ,

B ₄ is CH and

B ₅ is CR ¹⁰ or N.

Also suitable are compounds according to the formulas described herein, wherein R ¹ is H.

Also suitable are compounds according to the formulas described herein wherein R ¹ is methyl.

Also suitable are compounds according to the formulas described herein, wherein Q is fluoro-substituted or carbonamide(-C(=O)N(R) ₂ , wherein R are independently of one another 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-oxidothiethan-3-yl, 1,1-dioxidothiethan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

Also suitable are compounds according to the formulas 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-oxidothiethan-3-yl, 1,1-dioxidothiethan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

Also suitable are compounds according to the formulas described herein wherein R ⁸ is halogen or halogen-substituted C ₁ -C ₄ alkyl.

The following examples can be given which are preferred as active ingredients with parasiticidal effect for non-human organisms:

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-pyrazol-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-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide:

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

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

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

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

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

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

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

The active ingredients described above may in this case be part of the composition described herein and thus provide antiparasitic efficacy as detailed below.

In the context of the present invention, preference may be given to the active ingredients of formulas I-1 to I-5 and the active ingredients of formulas II-1 to II-6 described above, where in particular preference may be given to the active ingredients according to formulas I-1 to I-5.

According to preferred embodiments, a compound of formula I-1 may be present as the active ingredient, wherein the solvent mixture may be a mixture of isopropanol (32.5), ethanol (32.5) and propylene carbonate (35), or a mixture of isopropanol (32.5), ethanol (32.5) and glycerol carbonate (35), or a mixture of isopropanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), or also a mixture of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), wherein the numbers in brackets indicate the content in wt. % based on the solvent mixture.

According to another preferred embodiment, solvent mixtures can be used for the active ingredient according to formula I-2, or formula I-3, or formula I-4, or formula I-5.

However, in particular, preference is given to active ingredients according to formulas I-1, I-2, I-3, I-4 and I-5 using only the first and second solvents.

In addition to the components listed above, the composition according to the present invention may also contain conventional pharmaceutically acceptable excipients. Examples include: dispersants, antioxidants, pH regulators, crystallization inhibitors, surfactants, dyes, pigments, penetration enhancers, and preservatives.

Distributors are, for example, distributors such as di-2-ethylhexyl adipate, isopropyl myristate, dipropylene glycol pelargonate, cyclic and acyclic silicone oils such as dimethicones, as well as their copolymers and terpolymers with ethylene oxide, propylene oxide and formalin, fatty acid esters, triglycerides, fatty alcohols. They can be additionally added in a proportion of ≥ 1 - ≤ 40% w/v. According to further embodiments, distributors can be present in proportions of ≥ 0.01 - ≤ 1% w/v, ≥ 0.1 - ≤ 10% w/v, ≥ 1 - ≤ 20% w/v, ≥ 20 - ≤ 50% w/v. or ≥ 10 - ≤ 30% w/v.

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 - ≤ 2% w/v. According to additional embodiments, antioxidants can be present in proportions of ≥ 0.01 to ≤ 1% w/v, ≥ 0.05 to ≤ 0.5% w/v, or ≥ 1 to ≤ 2% w/v.

The pH regulators are preferably organic acids or bases, such as citric acid or triethanolamine. They can be additionally added in a proportion of ≥ 0.001 to ≤ 5% w/v. According to further embodiments, the pH regulators can be present in proportions of ≥ 0.01 to ≤ 1% w/v, ≥ 0.05 to ≤ 0.5% w/v, or ≥ 0.1 to ≤ 3% w/v.

Crystallization inhibitors are, for example, cellulose ethers such as hydroxypropyl methylcellulose (HPMC); polyvinylpyrrolidone (PVP). They can be additionally added in a proportion of ≥ 0.1 to ≤ 50% w/v. According to further embodiments, the crystallization inhibitors can be present in proportions 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.

The surfactants that may be mentioned are: nonionic surfactants, such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether; ampholytic surfactants, such as di-Na-N-lauryl-β-iminodipropionate or lecithin; anionic surfactants, such as Na-lauryl sulfate, fatty alcohol ether sulfates, monoethanolamine salt of orthophosphoric acid ether of mono/dialkyl polyglycol; cationic surfactants, such as cetyltrimethylammonium chloride. These may be additionally added in a proportion of ≥ 0.1 - ≤ 20% w/v. According to further embodiments, they may be present in proportions of ≥ 0.1 - ≤ 10% w/v, ≥ 0.1 - ≤ 1% w/v, ≥ 1 - ≤ 10% w/v, or ≥ 0.2 - ≤ 5% w/v.

Dyes may also be added to the pharmaceutical composition. They may be dissolved or suspended in the composition. Examples that may be mentioned are Brilliant Blue, D&C Violet No. 2, FD&C Yellow, Sunset Yellow FCF, or natural food colors such as chlorophyllin. They may be additionally added in a proportion of ≥ 0.01 to ≤ 2% w/v. According to additional embodiments, they may be present in an amount of ≥ 0.01 to ≤ 1% w/v or ≥ 0.1 to ≤ 2% w/v.

The pharmaceutical compositions may contain penetration enhancers such as: menthol, 1,8-cineole, glycol ethers (e.g. diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether). These may be present in amounts of ≥ 2 to ≤ 50% w/v. According to further embodiments, the penetration enhancers may be present in proportions of ≥ 1 to ≤ 20% w/v, ≥ 0.5 to ≤ 20% w/v, ≥ 0.1 to ≤ 10% w/v, ≥ 10 to ≤ 50% w/v, or ≥ 10 to ≤ 40% w/v.

In principle, the concentration of the active ingredient is not limited, but it should also be taken into account that all active ingredients must be in solution. With regard to the preferred pour-on application, for high efficacy it may also be preferable for the pharmaceutically 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 may 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 easily achieved due to the solvent mixture configuration described above and are particularly advantageous for topical application. In principle, however, active ingredient concentrations of up to 30% by weight or higher are also possible without departing from the scope of the present invention.

Thus, the compositions according to the present invention are typically liquid and suitable for topical or dermal application, especially in the form of so-called pour-on compositions.

The ectoparasiticidal efficacy of the compositions according to the present invention, containing active ingredients from the aforementioned group, particularly fluorinated benzamides, is highly effective, particularly when applied by pour-on application as described above. Thus, when using this composition, the amount of active ingredient required can be reduced, and the long-term effect can be enhanced. Accordingly, its use offers economic and environmental benefits.

The compositions of the present invention are particularly suitable for use in the control or prophylaxis of parasites. Thus, the pharmaceutical compositions described herein are used for the treatment or prevention of parasitic infestations, particularly for the treatment or prophylaxis of ectoparasites.

The compositions according to the present invention are particularly suitable for the control or prevention of ectoparasites, preferably mites and/or ticks and/or flies or fly larvae and/or lice, in non-human organisms, especially in animals, especially in warm-blooded animals, preferably mammals.

According to one embodiment, the animals may be pets, such as caged birds, or mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, or in particular dogs, cats.

According to another more preferred embodiment, the animals may be livestock, which includes, for example, poultry such as turkeys, ducks, geese and, in particular, chickens; or preferably mammals such as sheep, goats, horses, donkeys, camels, buffalo, rabbits, reindeer, fallow deer and, in particular, cattle and pigs.

According to a particularly preferred embodiment, the compositions of the present invention are used for the control and/or prevention of ectoparasites in cattle.

Since treated animals also typically distribute a certain amount of the composition used into the environment, for example by rubbing or with residues, the effect of the composition according to the present invention may be exerted not only directly on the animal, but also to a corresponding extent on their environment.

As described above, the composition described herein is suitable for treating or preventing parasitic infestations of non-human organisms by dripping or pouring the composition onto the non-human organism and thus for pour-on application.

Parasites against which the compositions of the present invention may be effective include:

from the order Anoplura, for example, Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;

from the order Mallophaga, for example, Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovicola spp;

from the order Diptera z.B. Aedes spp., Anopheles spp., Culex spp., Simulium spp., Phlebotomus spp., Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.

from the order Siphonaptera, for example, Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp.

from the order Metastigmata, e.g. Hyalomma spp., Rhipicephalus spp. (including the genus formerly called Boophilus), Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.;

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

from the order Prostigmata, for example, Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.;

from the order Astigmata, for example, Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidocoptes spp. Cytodites spp., Laminosioptes spp.

from the order Diptera, where especially preferred are 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 order Metastigmata Hyalomma spp., Rhipicephalus spp. (including the genus formerly called Boophilus), Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.; from the order Anoplura Haematopinus spp., Linognathus spp., Solenopotes spp.;

from the order Mallophaga Damalinea spp., Bovicola spp., Trichodectes spp.; from the order Mesostigmata Dermanyssus spp., Ornithonyssus spp.; from the order Astigmata Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp.

Particularly preferred arthropod species or genera include Haematobia irritans irritans, Haematobia irritans exigua, Hydrotea irritans, Musca autumnalis, Culicoides spp., Stomoxys calcitrans, Glossina spp., Aedes spp., Anopheles spp., Culex spp., Damalinia (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 scapularis, Ixodes holocyclus, Haemaphysalis longicornis, Otobius megnini.

The compositions according to the present invention can be prepared by conventional methods, for example, by mixing the active ingredients with additional components under stirring to form a solution. This solution can be further filtered. Plastic tubes, for example, are suitable for filling.

The liquid formulations according to the present invention are characterized by excellent storage stability for at least one year, preferably at least two years, more preferably at least three years in all climatic zones. Due to the very high efficiency, the application volumes can be low. Preferred application volumes are 0.01 - 1 ml/kg [body weight of the animal being treated], preferably 0.05 - 0.1 ml/kg [body weight of the animal being treated].

The compositions according to the present invention also exhibit excellent skin compatibility and low toxicity. Finally, they are environmentally friendly due to their biodegradability.

Solubility experiments

Experiments on dissolving active ingredients I-1, I-2, I-3, and I-4 in solvents for the pharmaceutical composition according to the present invention are presented below. To achieve a biological effect, the active ingredient must be included in the formulation at a specific dose or amount; ideally, this should be a solution within the formulation, so that the active ingredient is dissolved in the solvent. The solvent requires a certain minimum solubility because the application volume is limited.

Table 1 shows the results of active ingredient I-1 dissolution experiments. In this case, 10 g of the appropriate solvent or solvent mixture was first added, and the active ingredient was added until the solution was saturated. Isopropanol (IPA) and propylene carbonate (PPC) were used as solvents. The samples were stirred for 3 days. If the active ingredient was completely dissolved, it was added again. The samples were then stored for an additional 4 days at the appropriate temperature and centrifuged to remove undissolved particles. The supernatants were analyzed for active ingredient content in each case using HPLC-UV.

Table 1 Solvent (mixture) and dissolution temperature Saturation concentration % [w/w] Isopropanol 5°C 0.98 Isopropanol 23°C 1.56 Propylene carbonate 5°C 1.80 Propylene carbonate 23°C 2.43 IPA/PPC 25/75 23°C 7.58 IPA/PPC 35/65 23°C 8.79 IPA/PPC 50/50 23°C 9.26 IPA/PPC 60/40 23°C 8.60 IPA/PPC 65/35 5°C 6.32 IPA/PPC 65/35 23°C 8.31 IPA/PPC 70/30 23°C 7.49 IPA/PPC 75/25 23°C 6.70 IPA/PPC 80/20 23°C 5.90 IPA/PPC 90/10 23°C 3.74

Table 1 shows that the desired criteria were not met in the individual solvents isopropanol and propylene carbonate, particularly with regard to sufficient solubility. Particularly preferred desired active ingredient solubilities, which are advantageous and consistent with the invention, are in the range of at least 5% w/v, where a sufficient gap from saturation solubility must be present. Surprisingly, a significant increase in solubility was demonstrated in a mixture of isopropanol and propylene carbonate compared to the pure solvents, as detailed in Table 1.

In addition, solubility experiments were conducted for three more active ingredients from the fluorinated heteroarylamides class in various solvents. The solubility experiments were conducted similarly to those described above, but only at room temperature, and a 65:35% [m/m] isopropanol/propylene carbonate solvent mixture was selected. The results are presented in Table 2.

Table 2 Active connection Solvent Saturation solubility % [w/w] I-2 Isopropanol 6.99 I-2 Propylene carbonate 5.34 I-2 Isopropanol/propylene carbonate 65/35 24.20 I-3 Isopropanol 4.18 I-3 Propylene carbonate 4.89 I-3 Isopropanol/propylene carbonate 65/35 17.57 I-4 Isopropanol 13.42 I-4 Propylene carbonate 11.76 I-4 Isopropanol/propylene carbonate 65/35 29.38

It was also found that for the active ingredients I-2, I-3 and I-4, very good solubility of the active ingredient of the heteroarylamide family, especially for certain structures, can be achieved using the solvent mixture or solvent phase of the composition according to the present invention.

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

Table 3 Active connection Solvent Saturation solubility % [w/w] I-1 Isopropanol 1.56 I-1 Propylene carbonate 2.43 I-1 Ethanol 2.76 I-1 glycerol carbonate 0.15 I-1 Isopropanol/ glycerol carbonate 65:35 5.98 I-1 Ethanol/glycerol carbonate 65:35 6.48 I-1 Ethanol/propylene carbonate 65:35 9.45

Table 3 clearly shows that increased solubility can be achieved with other solvents. Thus, the invention can be extended to other solvents within the described range. As examples, this document provides experiments with ethanol and glycerol carbonate, their mixtures, and combinations with the solvents already described, isopropanol, and propylene carbonate.

Experiments were also conducted with solvent systems in which the primary solvent consisted of two alcohols. The results are presented in Table 4.

Table 4 Active connection Solvent Solubility % [w/w] I-1 Isopropanol/ethanol/propylene carbonate 32.5:32.5:35 >5 I-1 Isopropanol/ethanol/glycerol carbonate 32.5:32.5:35 >5 I-1 Isopropanol/propylene carbonate/glycerol carbonate 65: 17.5: 17.5 >5 I-1 Ethanol/propylene carbonate/glycerol carbonate 65:17.5:17.5 >5

It can also be shown that such binary systems provide good solubility of the active ingredient according to formula I-1.

Examples of compositions

Below are examples of the preparation of formulations containing active ingredients I-1, I-2, I-3, and I-4, as defined above, with additives. In all examples, the respective active ingredient was completely dissolved, and stability was achieved.

Here in Table 5 the corresponding formulation examples are shown with data on the solvent mixture, the active ingredient and optionally further additives.

Table 5 No. Components Quantity 1 I-1 1.5 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 2 I-1 2 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 3 I-1 4.5 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 4 I-1 4.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 5 I-1 0.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 6 I-4 4.5 g water 1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 7 I-1 1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 8 I-1 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 9 I-1 4 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 10 I-1 0.25 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 11 I-4 3 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 12 I-4 2 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 13 I-2 3 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 14 I-2 3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 15 I-3 1.5 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 16 I-3 4.5 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 17 I-4 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 18 I-1 1.9 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 19 I-1 2 g Ascorbic acid 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 20 I-4 4.5 g Water 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 21 I-1 2 g Ascorbic acid 0.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 22 I-1 2 g Disodium EDTA 0.09 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 23 I-1 2 g Brilliant Blue 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 24 I-1 2 g Brilliant Blue 0.0225 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 25 I-1 2 g Delta tocopherol 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 26 I-1 2 g Thioglycerol 0.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 27 I-1 2 g Butylated hydroxytoluene 0.1 g Butylated hydroxyanisole 0.1 g Citric acid 0.3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 28 I-1 2 g Citric acid 0.3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 29 I-1 2 g Butylated hydroxyanisole 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 30 I-1 2 g D&C Violet No. 2 0.0225 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 31 I-1 2 g Water 0.2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 32 I-1 2 g Water 0.4 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 33 I-1 2 g Water 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 34 I-1 2 g Water 3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 35 I-1 2 g Water 5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 36 I-1 2 g Water 5 g Triethanolamine 0.06 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 37 I-1 2 g Water 5 g Citric acid 0.00006 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 38 I-1 1.99 g Water 10 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 39 I-1 1.99 g Water 5 g Isopropanol/propylene carbonate 61.3:31.5% w/w up to 100 ml 40 I-1 1.99 g Water 0.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 41 I-1 1.99 g Water 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 42 I-1 1.99 g Water 1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 43 I-1 2.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 44 I-1 2 g Isopropanol/propylene carbonate 68:32% w/w up to 100 ml 45 I-1 1.99 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 46 I-4 4.5 g Water 5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 47 I-1 4.5 g Water 1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 48 I-1 4.5 g Water 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 49 I-1 4.5 g Water 5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 50 I-2 2 g Butylated hydroxytoluene 0.1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 51 I-1 2 g Ethanol/propylene carbonate 65:35% w/w up to 100 ml 52 I-4 4.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 53 I-1 2 g Isopropanol/propylene carbonate 62:38% w/w up to 100 ml 54 I-1 35 g N-methylpyrrolidone up to 100 ml 55 I-1 2 g Propylene carbonate up to 100 ml 56 I-1 1 g Isopropanol up to 100 ml 57 I-2 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 58 I-2 4.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 59 I-1 4.5 g Isopropanol/ethanol/propylene carbonate 32.5:32.5:35% w/w up to 100 ml 60 I-1 4.5 g Isopropanol/ethanol/glycerol carbonate 32.5:32.5:35% w/w up to 100 ml 61 I-1 4.5 g Isopropanol/propylene carbonate/glycerol carbonate 65:17.5:17.5% w/w up to 100 ml 62 I-1 4.5 g Ethanol/propylene carbonate/glycerol carbonate 65:17.5:17.5% w/w up to 100 ml 63 I-2 4.5 g Water 1 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 64 I-2 4.5 g Water 2 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 65 I-2 4.5 g Water 5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml

Table 6 shows the formulations that can be prepared according to the solubility experiments.

Table 6 No. Components Quantity 66 I-1 1.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 67 I-1 3 g Ethanol/propylene carbonate 65:35% w/w up to 100 ml 68 I-1 1.99 g Ethanol/propylene carbonate 65:35% w/w up to 100 ml 69 I-1 3 g Ethanol/glycerol carbonate 65:35% w/w up to 100 ml 70 I-1 1.99 g Ethanol/glycerol carbonate 65:35% w/w up to 100 ml 71 I-1 3 g Isopropanol/glycerol carbonate 65:35% w/w up to 100 ml 72 I-1 1.99 g Isopropanol/glycerol carbonate 65:35% w/w up to 100 ml 73 I-1 3 g Benzyl alcohol/glycerol carbonate 65:35% w/w up to 100 ml 74 I-1 1.99 g Benzyl alcohol/glycerol carbonate 65:35% w/w up to 100 ml 75 I-1 3 g Benzyl alcohol/propylene carbonate 65:35% w/w up to 100 ml 76 I-1 1.99 g Benzyl alcohol/propylene carbonate 65:35% w/w up to 100 ml 77 I-1 1.5 g 1-Methoxy-2-propanol/glycerol carbonate 65:35% w/w up to 100 ml 78 I-1 4.5 g 1-Methoxy-2-propanol/propylene carbonate 65:35% w/w up to 100 ml 79 I-1 1.5 g 1-Methoxy-2-propanol/propylene carbonate 65:35% w/w up to 100 ml 80 I-2 1.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 81 I-3 4.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 82 I-3 1.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 83 I-4 4.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 84 I-4 1.5 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 85 I-1 3 g Isopropanol/propylene carbonate 25:75% w/w up to 100 ml 86 I-1 3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 87 I-1 4.5 g Ethanol/propylene carbonate 65:35% w/w up to 100 ml 88 I-1 1.5 g Ethanol/propylene carbonate 65:35% w/w up to 100 ml 89 I-1 4.5 g Ethanol/glycerol carbonate 65:35% w/w up to 100 ml 90 I-1 1.5 g Ethanol/glycerol carbonate 65:35% w/w up to 100 ml 91 I-1 4.5 g Isopropanol/glycerol carbonate 65:35% w/w up to 100 ml 92 I-1 1.5 g Isopropanol/glycerol carbonate 65:35% w/w up to 100 ml 93 I-1 4.5 g Benzyl alcohol/glycerol carbonate 65:35% w/w up to 100 ml 94 I-1 1.5 g Benzyl alcohol/glycerol carbonate 65:35% w/w up to 100 ml 95 I-1 4.5 g Benzyl alcohol/propylene carbonate 65:35% w/w up to 100 ml 96 I-1 1.5 g Benzyl alcohol/propylene carbonate 65:35% w/w up to 100 ml 97 I-1 3 g 1-Methoxy-2-propanol/glycerol carbonate 65:35% w/w up to 100 ml 98 I-1 1.99 g 1-Methoxy-2-propanol/glycerol carbonate 65:35% w/w up to 100 ml 99 I-1 3 g 1-Methoxy-2-propanol/propylene carbonate 65:35% w/w up to 100 ml 100 I-1 1.99 g 1-Methoxy-2-propanol/propylene carbonate 65:35% w/w up to 100 ml 101 I-2 1.99 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 102 I-3 3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 103 I-3 1.99 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 104 I-4 3 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 105 I-4 1.99 g Isopropanol/propylene carbonate 65:35% w/w up to 100 ml 106 I-1 4.5 g Isopropanol/propylene carbonate 25:75% w/w up to 100 ml 107 I-1 1.5 g Isopropanol/propylene carbonate 25:75% w/w up to 100 ml

Compositions with numbers 1-65 were obtained and good solubility and complete dissolution of the active ingredient were observed.

Experiments 66 - 107 are additional hypothetical examples for which the desired solubility can be predicted based on the solubility experiments performed, the actual examples obtained, and the chemical structure of the active ingredients and the solvent chosen.

Examples of in vitro and in vivo testing

Additional properties and effectiveness of the compositions of the present invention are described below.

Example 1

Determination of the distribution properties of colored placebo formulations on the skin of cattle

The purpose of this in vitro study was to determine the distribution properties of colored placebo formulations (i.e., those without the active ingredient) on bovine skin. The results obtained in these tests can be applied to the distribution effects of formulations containing the active ingredient. The tests were conducted with a dual solvent phase consisting of isopropanol (IPA) and propylene carbonate (PPC).

For this purpose, lightly colored epidermal pieces measuring approximately 10 x 10 cm were obtained from cattle after slaughter and placed on a hot plate covered with aluminum. The plate was heated to 34°C +/- 0.5°C. Pieces of clipped skin and natural-length hair were analyzed. 0.025% Brilliant Blue FCF was added as a dye. The behavior of the formulations on the skin surface and the application area were measured for 60 minutes. Distribution was additionally assessed using a rating system. In this case, such formulations were particularly preferred and suitable for subsequent application to the animal, as their distribution properties ensured sufficient distribution on the skin piece during the observation period.

The results are presented in Table 7, which shows the distribution characteristics of the placebo colored formulations on the skin pieces.

Table 7 shows the area that the composition occupies on the skin sample immediately after application and after one hour, and also shows the volumes of the composition applied, the length of hair on the skin and the skin temperature.

Table 7 Composition (see Table 8) IPA:PPC Volumes [µl] Hair length Surface temperature [°C] Area [cm²] (0 min after application) Area [cm²] (1 hour after application) i 1:0:100 250 shaved off 34 1.445 1.963 ii 2; 25:75 250 shaved off 34 6.872 7.846 iii 3; 50:50 250 shaved off 34 12.566 12.566 IV 4; 65:35 250 shaved off 34 14.184 15.904 v 5; 75:25 250 shaved off 34 14.137 15.708 vi 6; 90:10 250 shaved off 34 12.566 19,635 vii 7; 100: 0 250 shaved off 34 7.069 15.504 i. 1:0:100 250 not shaved 34 1.319 1.374 ii. 2; 25:75 250 not shaved 34 3.534 3.789 iii. 3; 50:50 250 not shaved 34 2.827 3.471 iv. 4; 65:35 250 not shaved 34 6,480 7.265 v. 5; 75:25 250 not shaved 34 2.356 2.937 vi 6; 90:10 250 not shaved 34 10.603 19.439 vii 7; 100: 0 250 not shaved 34 3.927 4.909

The table clearly demonstrates particularly favorable distribution characteristics. The best results were achieved with a 65:35 isopropanol (IPA) to propylene carbonate (PPC) ratio.

Although the test also shows good results with a 90:10 isopropanol (IPA) to propylene carbonate (PPC) ratio, this solvent phase has poorer solubility compared to the composition according to the present invention.

Table 8 Composition number Brilliant Blue FCF dye Isopropanol (IPA):propylene carbonate (PPC) ratio I 0.025% w/w 0:100 II 0.025% w/w 25:75 III 0.025% w/w 50:50 IV 0.025% w/w 65:35 V 0.025% w/w 75:25 Vi 0.025% w/w 90:10 VII 0.025% w/w 100:0

Example 2

In Example 2, the spreading and flow properties of colored placebo formulations on cattle skin were determined. The aim of this in vitro study was to determine the spreading and flow properties of colored placebo formulations on cattle skin. 0.025% Brilliant Blue FCF was added as a dye.

The compositions used correspond to the compositions indicated in Table 8.

For this purpose, pieces of the lightest possible colored hide, approximately 10 x 10 cm in size, were obtained from slaughtered cattle and placed on an aluminum-coated plate. The plate was heated to 34±0.5°C. For the spreading test, the heating plates were set at an angle of 45°±2°. A piece of filter paper was secured under the hide piece.

The behavior of the formulations on the skin surface and the flow rate were recorded on video for one minute, and the flow rate was then calculated using a ruler. Distribution was assessed using a rating system.

In this case, the formulations were particularly suitable for subsequent application to animals, as their runoff properties during the observation period resulted in minimal or no staining of the filter paper. The formulations also achieved sufficient distribution on the skin sample.

The results are shown in Table 9, where the flow rate of the longest cycle curve was measured for 1 minute after application of 750 µl of the colored placebo composition.

Table 9 IPA: PPC Composition No. Natural hair length variations Behavior Speed of the longest trace [mm/s] Passing through the filter Surface distribution 0:100 I Average length Remains on the surface of the hair and flows down from the surface in 3 narrow paths 85.0 It starts in 2 seconds and then drips intensively. The application strip remains narrow (<1 cm), but slightly sinks into the wool from the surface 25:75 ii Average length It sinks into the wool, forming two narrow paths that run down and join at the bottom. 10.0 It starts after 40 seconds and then drips, drops less than 0:100 The application strip remains narrow (<2 cm) and flows from the skin, not from the coat. 50:50 iii long It quickly sinks into the wool and a blue sheen is visible under the wool - there are no sharp traces of flow, rather a superficial spreading 0.8 The filter after 9 minutes has blue drops, but their quantity is less than 25:72 The application strip remains narrow (<2 cm) and flows from the skin, not from the coat. 65:35 IV Average length It quickly sinks into the wool and a blue sheen is visible under the wool - no narrow flow paths - wide spreading 1.3
square Filter at 7.22 seconds with a small blue dot n The application strip expands (2-4 cm) and flows down the skin surface 75:25 v long The line is not wide - relatively wide thin tracks going down 3.3
[square] Doesn't pass through the filter/ drips The application strip remains narrow (<1 cm), the drip paths first pass and then narrow 90:10 vi Average length fast, very flat with runoff tracks 1.7
square Doesn't pass through the filter/ drips The application strip expands up and down (4 cm) and short lines run down the skin surface. 100:0 vii long Spreads quickly over a large area with wide paths 2.7
square Doesn't pass through the filter/ drips The application strip appears narrow on the surface - quick distribution on the skin in an area with 3 visible short lines

In turn, it can be seen from these tests that the test with the stated proportions of isopropanol (IPA) and propylene carbonate (PPC) gave very good results, since the flow properties here during the observation period resulted in no or minimal staining of the filter paper and in this case sufficient distribution on the piece of leather was achieved.

Example 3

In Example 3, the efficacy of dousing formulations against horn flies (Haematobia irritans irritans) on cattle was determined. The aim of the study was to determine the prophylactic efficacy of insecticidal formulations against experimentally induced Haematobia irritans infestations in cattle.

The study was conducted as a single-blind, negative-controlled, randomized, parallel-group efficacy trial. Each group consisted of five animals. All animals were sorted in descending order by fly counting before treatment and then grouped into 4 (x) blocks of five animals. Cattle were randomly assigned to blocks and sorted in ascending order. Cattle were individually tethered in gauze enclosures. Each animal was infested with approximately 200 unfed flies on days -5, 1, 7, 14, 21, 28, and in some cases also on days 35 and 42. Fly counts on cattle were determined on day 1, 4 hours after infestation, 24 hours after infestation on day 2, and on days 8, 15, 22, and 29, and, if necessary, on days 36, 43, 50, and 57. Efficacy against fly infestations was determined by comparing the fly counts on treated cattle with those on untreated cattle. Treatment was considered successful if the treatment group achieved at least a 90% response rate compared to the control group.

The results are presented in Table 10, which illustrates the effect of the compositions according to the present invention on small horn flies (Haematobia irritans irritans) in cattle.

Table 10 Test block Example of composition Dose mg/kg dpt 2 dpt 8 dpt 15 dpt 22 dpt 29 dpt 36 dpt 43 dpt 50 dpt 57 C 5 0.5 >90 >90 >90 >90 >90 >90 <90 <90 <90 C 7 1 >90 >90 >90 >90 >90 >90 >90 <90 <90 B 1 1.5 >90 >90 >90 >90 >90 >90 >90 na na C 8 2 >90 >90 >90 >90 >90 >90 >90 >90 >90 C 9 4 >90 >90 >90 >90 >90 >90 >90 >90 >90 B 3 4.5 >90 >90 >90 >90 >90 >90 >90 na na A 15 1.5 >90 >90 >90 >90 <90 <90 na na na A 16 4.5 >90 >90 >90 >90 <90 <90 na na na A 13 3 >90 >90 >90 >90 >90 <90 na na na B 11 3 >90 >90 >90 >90 >90 >90 >90 na na

Dpt = days after treatment

na=no data

Table 10 shows that examples 5 and 7 have a long-lasting and effective effect even in small doses. Furthermore, examples 8, 9, 1, 3, and 11 are also effective over a long period of time.

Example 4

In Example 4, the effectiveness of pour-on compositions against ticks (Rhipicephalus (Boophilus) microplus) on cattle was determined.

The aim of the study was to determine the therapeutic and prophylactic efficacy of acaricidal formulations in experimentally created Rhipicephalus (Boophilus) microplus infestations of cattle.

The study was conducted as a parallel, non-blind, negative-controlled, randomized efficacy trial. Each group consisted of five animals. Prior to treatment, all animals were sorted in descending order by sex and individual tick infestation count (days -14 to -2) and then grouped into two (x) blocks of five animals. Cattle were randomly assigned to blocks and sorted in ascending order of numbers. Each animal was infested with 3,000 larvae on days -35, -33, and -29. -27, -22, -20, -15, -13, -8, -6, -1, 5, 7, 12, 14, 19, 21, 26, and 28. Engorged females were collected daily on days -14 through -2 and 0 through 56. Ticks from -14 through -2 were used for grouping, ticks from days 1 through 28 were used to determine the therapeutic effect, and ticks from day 29 until the end of the tick drop phase were used to determine the prophylactic effect. Tick fecundity was also determined. This was achieved by assessing oviposition and larval hatching of laid eggs from mixed samples of engorged female ticks. In this case, >60% larval hatching signifies a normal hatching rate. The tested compounds did not achieve a significant additional effect here.

Regarding therapeutic efficacy against existing tick infestations, treatment was considered successful when a 90% response rate (based on the number of engorged female ticks that fell off within 1-28 days after treatment) was measured for the treatment group compared to the control group. Accordingly, efficacy was considered absent if the response rate was less than 90%.

Regarding prophylactic efficacy against recurring tick infestations, treatment was considered successful when a 90% response rate (based on the number of engorged female ticks falling off 29-56 days after treatment) was measured for the treatment group compared to the control group. Accordingly, efficacy was not demonstrated if the response rate was less than 90%.

The results are presented in Tables 11 and 12. Table 11 shows the therapeutic effect of the compositions according to the present invention on cattle at all stages of cattle tick (Rhipicephalus (Boophilus) microplus) infestation, and Table 12 shows the prophylactic effect of the compositions according to the present invention on cattle with new cattle tick (Rhipicephalus (Boophilus) microplus) infestations.

From Tables 11 and 12 it can be seen that all the active ingredients in the compositions according to the present invention have high efficacy even at low doses in terms of both prophylactic and therapeutic efficacy against tick infestation.

Example 5

In accordance with Example 5, the efficacy of douche formulations against head lice (Bovicola bovis) on cattle was determined. The aim of the study was to determine the therapeutic and prophylactic efficacy of insecticidal formulations against cattle infestations with naturally occurring Bovicola bovis.

The study was conducted as a parallel, non-blinded efficacy study with a negative control. Each group consisted of 5 animals. Lice were counted on day -2 before treatment and on days 2, 14, 28, and 42. In this case, the hair coat of each animal was examined on 10 sections, and all nymphal and adult stages of head lice were counted. Results were summarized for each animal, averaged between animals in the same group, and compared with the number of head lice in the untreated control. Acute efficacy against existing head lice infestations was determined on day 2. In this case, treatment was considered successful if the treatment group achieved an effect of at least 90% compared to the control group. Continued efficacy against existing head lice infestations was measured in counts on days 14, 21, and 42.

In this case, treatment was considered successful if the treatment group achieved a 100% effect compared to the control group. Accordingly, if the effect was less than 100%, treatment was considered unsuccessful.

Table 13 Test block Example of composition Dose 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

Dpt = days after treatment

Table 13 shows the effect of the compositions according to the present invention on head lice (Bovicola bovis) in cattle.

From Table 13 it can be seen that Examples 2 and 16 in particular exhibited relatively rapid high efficiency when used in the composition according to the present invention with a certain solvent mixture.

Thus, it is evident from the above that the pharmaceutically active compositions according to the present invention exhibit good solubility for active ingredients of the benzamide class, allowing for the production of an effective active composition, particularly for use in the treatment or prevention of parasitic infestations, particularly in non-human organisms. In this case, application by pouring is particularly preferred.

Claims (84)

1. A pharmaceutical composition for the treatment or prevention of parasitic infestation, comprising at least one pharmaceutically active ingredient that is soluble in a solvent phase, wherein the pharmaceutically active ingredient is a fluorinated heteroarylamide, and is selected from a compound of general formula (Ia'') in which D ₁ is CR ¹¹ or a heteroatom selected from N or O; D ₂ is CR ¹¹ or a heteroatom selected from N or O; D ₃ represents C or N; D ₄ represents C or N; D ₅ is CR ¹¹ or N; wherein no more than one (1) or two moieties selected from D ₁ , D ₂ , D ₃ , D ₄ and D ₅ are a heteroatom; is an aromatic system; and R ¹ is H, in each case optionally substituted C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, aryl-(C ₁ -C ₃ )-alkyl or heteroaryl-(C ₁ -C ₃ )-alkyl, or is optionally substituted C ₁ -C ₆ -alkyl; the fragments are as follows: A ₁ is CR ² or N, A ₂ is CR ³ or N, A ₃ is CR ⁴ or N, A ₄ is CR ⁵ or N, B ₁ is CR ⁶ or N, B ₂ represents CR ⁷ or N, B ₄ is CR ⁹ or N and B ₅ is CR ¹⁰ or N, but no more than three of the fragments A ₁ -A ₄ represent N and no more than three of the fragments B ₁ -B ₅ simultaneously represent N; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ each independently of one another are H, halogen, cyano, nitro, in each case optionally substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, N-C ₁ -C ₆ alkoxyimino-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkylsulfanyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, N-C ₁ -C ₆ alkylamino or N,N-di-C ₁ -C ₆ alkylamino; if neither of the fragments A ₂ and A ₃ is N, R ³ and R ⁴ together with the carbon atom to which they are bonded may form a 5- or 6-membered ring containing 0, 1 or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom, or, if neither of the A ₁ or A ₂ moieties is N, R ² and R ³ together with the carbon atom to which they are attached may form a 6-membered ring containing 0, 1, or 2 nitrogen atoms; R ⁸ is perhalogenated C ₁ -C ₃ -alkyl or perhalogenated C ₁ -C ₃ -alkoxy; R ¹¹ is H; W represents O; Q is H, formyl, hydroxyl, amino, or in each case optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₅ heterocycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkyl-C 3 -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl-C ₁ -C ₆ alkyl, C ₆ -,C ₁₀ -C ₁₄ aryl, C ₁ -C ₅ heteroaryl, C ₆ -,C ₁₀ -,C ₁₄ aryl-(C ₁ -C ₃ )-alkyl, C ₁ -C ₅ heteroaryl-(C ₁ -C ₃ )-alkyl, N-C ₁ -C ₄ -alkylamino, N-C ₁ -C ₄ -alkylcarbonylamino or N,N-di-C ₁ -C ₄ -alkylamino; or is an optionally poly-V-substituted unsaturated 6-membered carbocycle; or is an optionally poly-V-substituted unsaturated 4-, 5-, or 6-membered heterocyclic ring, wherein V independently of one another are 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; and salts, N-oxides and tautomeric forms of compounds of formula (Ia''), wherein the pharmaceutically active ingredient is present in an amount of greater than or equal to 0.1 wt.% to less than or equal to 5 wt.%, and wherein the solvent phase is a mixture of solvents 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 optionally substituted with at least one _C1 - _C4 alkoxy group or phenyl group, wherein the second solvent is selected from aliphatic _C1 - _C4 carbonates optionally substituted with a hydroxy group, wherein the first solvent is present in a proportion of 50 to 95 wt.% and wherein the second solvent is present in a proportion of 5 to 50 wt.% based on the total amount of solvents in the solvent phase. 2. The pharmaceutical composition according to claim 1, wherein the first solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, butanol. 3. The pharmaceutical composition according to claim 1, wherein the first solvent is isopropanol and the second solvent is propylene carbonate. 4. The pharmaceutical composition according to claim 1, wherein the solvent mixture consists of a first solvent and a second solvent. 5. The pharmaceutical composition of claim 1, wherein the solvent mixture further comprises a third solvent, different from the first solvent and the second solvent, in addition to the first solvent and the second solvent. 6. The pharmaceutical composition according to claim 5, wherein the third solvent is selected from the group consisting of water, butylhydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, benzyl benzoate, octyldodecanol, paraffin, triglycerides, propylene glycol octanoate decanoate, glycol ether. 7. The pharmaceutical composition of claim 1, wherein the second solvent is present at a content of ≥20 wt.% to ≤45 wt.% based on the total amount of solvents in the solvent mixture. 8. The pharmaceutical composition according to claim 1, wherein the active ingredient is selected from the group consisting of 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-pyrazol-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-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]benzamide 2-chloro-N-cyclopropyl-5-[4-[2,6-dimethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide 2-chloro-N-(1-cyanocyclopropyl)-5-[4-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazol-1-yl]benzamide 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazol-5-yl]-N-cyclopropylbenzamide 2-chloro-N-(1-cyanocyclopropyl)-5-[3-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazol-5-yl]benzamide 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrrol-3-yl]benzamide 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrrol-1-yl]-N-cyclopropylbenzamide 9. Use of a pharmaceutical composition according to any one of paragraphs 1-8 as a means for the treatment or prevention of parasitic infestation. 10. The use according to claim 9, wherein the parasitic infestation is an ectoparasite infestation. 11. Use of a pharmaceutical composition according to any one of claims 1-8 as a means for the treatment or prevention of parasitic infection in non-human organisms. 12. The use according to claim 11, wherein the treatment or prevention of parasitic infestation in non-human organisms is carried out by dripping or pouring the composition onto the non-human organism.