Pharmaceutical composition for controlling parasites of non-human organisms

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions for controlling parasites in non-human organisms. In particular, the present invention relates to skin-applicable formulations with improved biological applicability for controlling ectoparasites in mammals and livestock. [Background technology]

[0002] Modern fluorine-containing antiparasitic compounds, also known as fluorinated antiparasitic drugs, such as fluralaner, afoxolaner, sarolaner, lotilaner, fipronil, and the active ingredients described in WO2015 / 067646 and WO2015 / 067647, have good insecticidal and acaricidal effects.

[0003] However, many of these active compounds have very low solubility in solvents suitable for topical administration to animals. To avoid the formulation dripping from the coat after administration or incomplete distribution onto the animal's skin, 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.

[0004] WO96 / 17520 refers to a formulation having the following composition, applied to the skin of an animal for the control of parasitic insects: an insect nicotinic acetylcholine receptor agonist or antagonist in a concentration of 1 to 20% by weight, based on the total weight of the formulation; a solvent of the benzyl alcohol group or optionally pyrrolidone in a concentration of at least 20% by weight, based on the total weight of the formulation; optionally another solvent from the cyclic carbonate or lactone group in a concentration of 5.0 to 80% by weight, based on the total weight of the formulation; optionally other auxiliary agents from the group of thickeners, spreading agents, dyes, antioxidants, foaming agents, preservatives, adhesives, and emulsifiers in a concentration of 0.025 to 10% by weight, based on the total weight of the formulation.

[0005] Externally applicable pour-on products for parasitic infections in animals are known, and these formulations contain isopropanol as a solvent. These include products containing the active ingredient ivermectin, such as Baymec® Pour-on (Bayer®) and Ivomec® Pour-on (Merial®). Examples of other pour-on products containing active ingredients and isopropanol include Sebacil® Pour-on (Bayer®, active ingredient foxim) and Dectomax® (Elanco, active ingredient: doramectin). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] WO2015 / 067646 [Patent Document 2] WO2015 / 067647 [Patent Document 3] WO96 / 17520 [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide pharmaceutical compositions for topical application to non-human organisms using modern solvents that have sufficiently high solubility for fluorinated antiparasitic drugs (particularly from the group of heteroarylamides) and that are also well applicable to animals (particularly as po-on formulations). [Means for solving the problem]

[0008] A pharmaceutical composition is provided which is completely soluble in a solvent phase, contains at least one pharmaceutically active ingredient that is antiparasitic, and is particularly easy to apply to animals, wherein the pharmaceutically active ingredient is particularly from the group of fluorinated heteroarylamides, preferably pyridylamides, and the solvent phase is configured as a solvent mixture comprising 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 comprises an organic carbonate, wherein in either case, 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.

[0009] For example, the first solvent and the second solvent may be in a quantitative ratio of 50%:50% to 95%:5% based on the total amount of solvent in the solvent phase.

[0010] In further embodiments, the first solvent may consist of only one solvent or a combination of two or more, preferably two C1-C15 alcohols, in which the majority of the C1-C15 alcohols are present together in the aforementioned amounts and collectively referred to as the first solvent. Thus, in the context of the present invention, the solvent may be understood not only to mean a single substance, but also to mean a mixture of different substances. However, it is intended that all substances forming the first solvent are C1-C15 alcohols.

[0011] Alternatively, the second solvent may consist of one substance or 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 amounts described above.

[0012] A solvent phase consisting only of a first solvent and a second solvent is also called a two-component solvent phase.

[0013] The compositions according to the present invention enable the provision of novel liquid agents for topical or cutaneous application to non-human organisms, particularly by using a solvent in which fluorinated antiparasitic agents from the group of heteroarylamides have sufficiently high solubility, and at the same time have good applicability to animals, especially as a poa-on formulation.

[0014] The pharmaceutical compositions described herein also comprise at least one pharmaceutically active ingredient, also referred to hereafter as the active ingredient, which may also be called an API (active pharmaceutical ingredient). In particular, the active ingredient may be the actual active substance in the composition and thus produce, primarily or entirely, the antiparasitic effect described in detail below. Therefore, the active ingredient should be effective in particular in non-human organisms.

[0015] In principle, the pharmaceutically active components are not limited. However, it is provided that the pharmaceutically active components consist particularly of a group of fluorinated heteroarylamides, which are described in more detail below. In principle, heteroarylamides may be pyridylamides, for example, pyridine groups bonded to an amide via an aryl group. For example, heteroarylamides may be fluorinated.

[0016] With respect to the pharmaceutically active ingredient, it is further provided that it is completely soluble in the solvent phase. This allows for particularly advantageous skin applicability, and especially enables pour-on application or solutions for pour-on application.

[0017] Pore-on application is understood to mean a type of application in which a relatively small amount of the formulation is applied, based on the amount of the formulation applied relative to the weight of the organism, for example, up to 100 mL / 100 kg, for example, in the range of approximately 1 mL / 100 kg to 100 mL / 100 kg, for example, in the range of 1 mL / 100 kg to 20 mL / 100 kg, or for approximately 5 mL / 100 kg to 10 mL / 100 kg, and is typically applied to a skin area limited to the neck or back of a non-human organism. Therefore, pore-on formulation is understood to mean a type of formulation that is preferred and intended to be applied as a pore-on application.

[0018] In such applications, i.e., so-called pore-on solutions, it is particularly important that a high level of solubility of the active ingredient is achieved, enabling the desired concentration of the active ingredient in the solution. Furthermore, good spreadability on the skin should be achieved. Spreadability can be understood as specifically referring to the distribution of the formulation on the skin. Thus, through spreadability, locally confined application is possible, and it is possible to determine whether the formulation, existing as a solution, achieves the desired distribution to the organism, in particular, whether it does not drip or run off excessively from the application site, so that the active ingredient is not lost due to runoff after application.

[0019] To enable the aforementioned advantageous properties, particularly for pore-on formulations, the solvent phase is configured as a solvent mixture comprising a first solvent and a second solvent distinct from the first solvent, wherein the first solvent comprises a C1-C15 alcohol, the second solvent is an organic carbonate, and in each case, based on the total amount of solvents in the solvent phase, the first solvent is present in a proportion of 50% to 95% by weight, and the second solvent is present in a proportion of 5% to 50% by weight, and in the two-component solvent phase, the first and second solvents are intended to be present in a quantitative ratio of 50%:50% to 95%:5% by weight, based on the total amount of solvents in the solvent phase, in the compositions described herein. However, it should be noted that the sum of the proportions of the first and second solvents does not necessarily need to be added up to 100% by weight, as a three-component system including further solvents is also conceivable and may be preferable. [Modes for carrying out the invention]

[0020] In one embodiment, such a configuration can advantageously provide a sufficient concentration of the fully dissolved active component of the heteroarylamide in the solvent phase, and thus, spreadability advantageous for pore-on application can also be achieved in formulations. In one embodiment, at least 95% by weight of the active heteroarylamide is dissolved. In another embodiment, at least 97% by weight of the active heteroarylamide is dissolved. In a further embodiment, 99% by weight of the active heteroarylamide is dissolved. In a preferred embodiment, 100% by weight of the active heteroarylamide is dissolved.

[0021] Therefore, in contrast to the assumptions made in the prior art, it has been shown that positive properties can be obtained using solvent mixtures containing C1-C15 alcohols, particularly C1-C10 alcohols, such as C1-C7 alcohols, and organic carbonates. For example, the solvent mixture may consist of one or more C1-C15 alcohols and one or more organic carbonates. These, in combination, exhibit good solubility and good spreadability of active ingredients, for example, those formed from the group of fluorinated heteroarylamides.

[0022] C1-C15 alcohols are generally understood to mean aliphatic or aromatic alcohols having 1 to 15 carbon atoms.

[0023] Organic carbonates are also understood to mean acyclic or cyclic carbonate esters, which are themselves low-toxicity polar solvents. By skillfully selecting the alcohol for ester synthesis, the physical properties of the resulting carbonates can be tailored to the desired application field.

[0024] Therefore, the present invention provides a composition that is highly suitable for pore-on application in terms of both spreadability, ease of administration, and concentration of the active ingredient, i.e., efficacy.

[0025] Further advantages of the formulations described herein include good compatibility and safety for the treated organism, and reduced adverse effects such as irritation or residue on animals, e.g., on the skin and / or coat, including animals in the food chain, and within the animal's body. The ease of formulation and administration (good applicability due to viscosity and spreadability) provides excellent environmental sustainability, achieving high consumer acceptance and reducing adverse side effects. This is even true in the case of use in livestock in food production. Furthermore, the formulations are effective due to increased solubility, allowing the active ingredients present to deliver high potency in a shorter time, thus providing a sustained period of activity that eliminates the need for frequent application. Finally, good handling and ease of use are achieved with the low cost associated with the manufacture of the formulations. Good bioavailability and use spectrum are also advantageous.

[0026] Furthermore, the compositions of the present invention may be readily applicable to animals, for example, in terms of viscosity and spreadability. The compositions, particularly the active ingredients, also have a low tendency to be washed away, for example, by rain. In fact, the efficacy can be maintained even in the case of wet animals or exposure to sunlight. The compositions generally have high stability and exhibit reduced decomposition and, for example, reduced secondary reactions of the components of the composition. The 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 readily without significantly impairing the appearance of the animals, especially with the addition of a good evaporative solvent.

[0027] With regard to the solvent present in the solvent phase or solvent mixture, the following solvents are particularly advantageous. The first solvent is different from the second solvent. In one embodiment, the first solvent is not a carbonate, unlike the second solvent.

[0028] In one embodiment, the first solvent preferably comprises a C1-C4 alkanol which may be substituted with at least one C1-C4 alkoxy group or phenyl group, where the hydroxyl group can be in any selectable position in principle. In a particular embodiment, the first solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, butanol, e.g., isobutanol or n-butanol, and especially ethanol and / or isopropanol. In addition to the good solubility associated with the organic carbonates described in particular, such solvents offer the further advantage of toxicity suitable for use in non-human organisms, so that they can be applied without adverse effects on animals.

[0029] The second solvent is preferably an organoaliphatic C1-C4 carbonate, which may be substituted with a hydroxyl group. In certain embodiments, the second solvent is selected from the group consisting of ethylene carbonate, propylene carbonate, and glycerol carbonate. In particular with respect to the alcohols described, in addition to good solubility, such solvents offer the further advantage of toxicity suitable for use in non-human organisms, so that they can be applied without adverse effects on animals.

[0030] In a particularly preferred embodiment, the first solvent is isopropanol and the second solvent is propylene carbonate. Solvent phases containing isopropanol and propylene carbonate as solvents have been found to offer the aforementioned advantages, for example, good solubility and favorable spreadability of the active ingredient, while simultaneously having lower toxicity.

[0031] In another embodiment, the solvent mixture comprises a first solvent, i.e., one or more of the first solvents described above, and a second solvent, i.e., one or more of the second solvents described above. In other words, the aforementioned first and second solvents may be sufficient as solvents alone, where, in an understandable manner, one of the described first solvents and one of the described second solvents may be sufficient to form a solvent mixture.

[0032] In one embodiment, with respect to the relative ratio of the first solvent to the second solvent, the second solvent, i.e., the organic carbonate, is preferably present in a content of ≥20% to ≤45% by weight, and more preferably ≥30% to ≤40% by weight, based on the total amount of solvents in the solvent mixture. In this embodiment, the first solvent is present in a content of ≥55% to ≤80% by weight, and more preferably ≥60% to ≤70% by weight, based on the total amount of solvents in the solvent mixture. This configuration can particularly effectively provide the aforementioned advantages regarding the solubility of the active ingredient and the accompanying good spreadability. In other words, it can promote the exceptional solubility of the active ingredient with consistent results. Thus, advantageous applicability is provided together with stable storage properties. 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.

[0033] Furthermore, in another embodiment, the solvent mixture includes a third solvent different from the first and second solvents, in addition to the first and second solvents. Therefore, the third solvent is not designed in the same way as the first and second solvents described above.

[0034] By using additional solvents, solubility and / or spreadability can potentially be further improved, or at least adjusted to the desired use.

[0035] In certain embodiments, the solvent phase is composed of a mixture of at least three solvents, where the third solvent is neither a C1-C15 alcohol nor an organic carbonate, but rather has a different definition than that herein. However, this does not preclude the first and / or second and / or third solvents from existing in each case, for example, as a two-component solvent mixture.

[0036] In principle, by providing a three-component solvent phase, the first and second solvents can be present within the ranges described above, where the proportions of the first and second solvents may be determined by the proportion of the third solvent. In particular, in one embodiment, the third solvent replaces a portion of the first solvent, where the first solvent still exists in the described range of 50% to 95% by weight based on the total amount of solvents in the solvent phase, and the second solvent also exists in the above quantitative range, i.e., 5% to 50% by weight, based on the total amount of solvents in the solvent phase. The third solvent, as well as the first and second solvents, should be pharmaceutically compatible and should not have an undesirable effect on the solubility of the active ingredient. It may be useful to use a penetration-enhancing solvent.

[0037] Favorable examples of a third solvent, different from the first and second solvents, 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 triglyceride (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, and diethylene glycol monobutyl ether.

[0038] In one embodiment, the solvent phase may be a three-component system, and thus consist of a first solvent or a first solvent(s), a second solvent or a second solvent(s), and a third solvent or a third solvent(s). In this embodiment, the first solvent(s), the second solvent(s), and the third solvent(s) are selectable as defined above.

[0039] In particular, in the three-component system embodiment, one non-limiting example is that, based on the total amount of solvents in the solvent phase, the total amounts of the first and third solvents and the second solvent are present in a quantitative ratio of 50% by weight:50% by weight to 95% by weight:5% by weight. With respect to the relative ratio of the first solvent to the second solvent, it is preferable that the second solvent is present in a content of ≥20% by weight to ≤45% by weight, preferably ≥30% by weight to ≤40% by weight, based on the total amount of solvents in the solvent mixture. Thus, the first solvent and optionally the third solvent can be present together in a content of ≥55% by weight to ≤80% by weight, preferably ≥60% by weight to ≤70% by weight, based on the total amount of solvents in the solvent mixture.

[0040] Non-limiting examples of solvent mixtures can be, 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 are intended to be the weight % content based on the solvent mixture. Further 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 a mixture of ethanol (65), propylene carbonate (17.5), and glycerol carbonate (17.5), where the numbers in parentheses are intended to be the weight % content based on the solvent mixture.

[0041] In one embodiment, for example, there is a solvent mixture comprising one first solvent, for example, two second solvents, and optionally one or more third solvents. In another embodiment, there is a solvent mixture comprising one second solvent, for example, two first solvents, and optionally one or more third solvents.

[0042] Furthermore, the components of the composition can be limited to solvents and active ingredients such that the composition can consist of a first solvent, a second solvent, optionally a third solvent and an active ingredient. However, additional components are not intended to be excluded and are defined elsewhere.

[0043] Preferably, the fluorinated heteroaryl amide is designed as described in WO2015067646A1 or WO2015067647A1. This type of active ingredient is preferably configured as follows, general formula (I):

Chemical formula

[0044] For example, formula (Ia) will be listed. [ka] [During the ceremony, The D1 and D2 sections are independent of each other, CR 11 It is either a heteroatom selected from N and O; The D3 and D4 portions independently represent either C or a heteroatom selected from N (in other words, the D3 and D4 portions independently represent C or N); Here, one or two portions selected from D1, D2, D3, and D4 are heteroatoms, where one or two portions selected from D1, D2, D3, and D4 are heteroatoms selected from N or O in the case of D1 and D2, and N in the case of D3 and D4; [ka] It is an aromatic system; and 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 defined as described herein, respectively, where one or fewer parts selected from A1, A2, A3, and A4 are N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N; or one or two parts selected from A1, A2, A3, and A4 may be N, and one or fewer parts selected from B1, B2, B3, B4, and B5 may be N. The compounds are as well as salts, N-oxides, and tautomers of the compound of formula (I).

[0045] One embodiment of the present invention is given by equation (Ia'): [ka] [During the ceremony, R 1 , R 11 Q, W, A1, A2, A3, A4, B1, B2, B4, and B5 are defined as described herein, respectively, where one or fewer parts selected from A1, A2, A3, and A4 are N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N; or one or two parts selected from A1, A2, A3, and A4 are N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N; D1 and D2 are independent of each other, CR 11 or heteroatoms, 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 D3 and D4 portions are heteroatoms independently selected from C or N; Here, one or two portions selected from D1, D2, D3, and D4 are heteroatoms, where one or two portions selected from D1, D2, D3, and D4 are heteroatoms selected from N or O in the case of D1 and D2, and N in the case of D3 and D4; [ka] It is an aromatic compound, and, R 8 [This is as defined herein, and is preferably a perfluorinated C1-C4 alkyl group.] Regarding the compounds.

[0046] Further embodiments of the present invention are given by formula (Ia'') [ka]

[0047] [During the ceremony, D1 is CR 11 or a heteroatom selected from N or O; D2 is CR 11 or a heteroatom selected from N or O; D3 is either C or N; D4 is either C or N; D5 is CR 11 or N; Here, one or two or fewer parts selected from D1, D2, D3, D4, and D5 are heteroatoms; [ka] It is an aromatic system; and R 1 H is, in each case, a 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 a C1-C6-alkyl which may be substituted, particularly preferably H; The relevant section is 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 or N, B2 is CR 7 or N, B3 is CR 8 or N, B4 is CR 9 or N, and B5 is CR 10 or N, However, if there are three or fewer cells in the A1 to A4 section, that is N, and simultaneously if there are three or fewer cells in the B1 to B5 section, that is N; R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 Each of these is independently of the others a 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, which may be substituted with H, halogen, cyano, or nitro, respectively; If neither A2 nor A3 is N, then R 3 and R 4 They may form a five-membered or six-membered ring containing 0, 1 or 2 nitrogen atoms and / or 0 or 1 oxygen atom and / or 0 or 1 sulfur atom, together with the carbon atoms to which they are bonded, or If neither A1 nor A2 is N, then R 2 and R 3 These may form a six-membered ring containing 0, 1, or 2 nitrogen atoms together with the carbon atoms to which they are bonded; R 8 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 may be substituted with halogen, cyano, or nitro in each case; R 11 These are independently H, halogen, cyano, nitro, amino, or optionally substituted C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkylcarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, preferably H; W is either O or S, Q may be H, formyl, hydroxyl, amino, or substituted in each case: 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 14 -aryl-(C1-C3)-alkyl, C1-C5-heteroaryl-(C1-C3)-alkyl, N-C1-C4-alkylamino, N-C1-C4-alkylcarbonylamino, or N,N-di-C1-C4-alkylamino; or A poly-V-substituted or otherwise unsaturated 6-membered carbon ring; or A poly-V-substituted, unsaturated 4-membered, 5-membered, or 6-membered heterocyclic ring, where V is independently a 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, which may be substituted with halogen, cyano, or nitro in each case. The present invention relates to compounds of formula (Ia''), as well as salts, N-oxides, and tautomers of the compound of formula (Ia'').

[0048] Compounds of formula (Ia'') are even more preferred, where compound (Ia'') is of formula (I-T3) [ka] [In the formula, where R 1 A1, A2, A3, A4, R 11 B1, B2, B4, B5, R8 Q and W are defined as described herein, respectively, where one or fewer parts selected from A1, A2, A3, and A4 are N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N; or one or two parts selected from A1, A2, A3, and A4 may be N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N. It is a compound of [the compound].

[0049] Further embodiments of the present invention relate to compounds of formula (Ia''), where the compound of formula (Ia'') is formula (I-T2): [ka] [In the formula, where R 1 A1, A2, A3, A4, R 11 B1, B2, B4, B5, R 8 Q and W are defined as described herein, respectively, where one or fewer parts selected from A1, A2, A3, and A4 are N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N; or one or two parts selected from A1, A2, A3, and A4 may be N, and one or fewer parts selected from B1, B2, B3, B4, and B5 are N. It is a compound of [the compound].

[0050] Further embodiments of the present invention relate to compounds of formula (Ia''), where the compound of formula (Ia'') is formula (I-T4): [ka] [In the formula, where R 1 A1, A2, A3, A4, R 11 B1, B2, B4, B5, R 8, Q, and W are each defined as described herein, where at most one moiety selected from A1, A2, A3, A4 is N, and at most one moiety selected from B1, B2, B3, B4, and B5 is N; or, one or two moieties selected from A1, A2, A3, A4 may be N, and at most one moiety selected from B1, B2, B3, B4, and B5 is N〕 is a compound of.

[0051] Compounds of formula (Ia'') are even more preferred, where the compounds of formula (Ia'') are of formula (I-T22)

Chemical formula

[0052] Compounds of formula (Ia'') are even more preferred, where the compounds of formula (Ia'') are of formula (I-T23)

Chemical formula

[0053] More preferred is R 11 is H and W is O, a compound according to the formulas and embodiments described herein.

[0054] More preferred is R 11 is H, W is O, B3 is C-R 8 and R 8 is halogen-substituted C1-C3-alkyl (preferably perhalogenated C1-C3-alkyl, more preferably perfluorinated C1-C3-alkyl) or halogen-substituted C1-C3-alkoxy (preferably perhalogenated C1-C3-alkoxy, more preferably perfluorinated C1-C3-alkoxy), a compound according to the formulas and embodiments described herein.

[0055] More preferred is that the moieties of A1 to A4 and B1 to B5 are as follows: A1 is C-H, [[ID=2​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0056] A more preferable option is R 1 The compound according to the formula and embodiments described herein is H.

[0057] More preferably are compounds according to the formulas and embodiments described herein, in which Q is a fluorine-substituted C1-C4-alkyl, C3-C4-cycloalkyl, optionally cyano- or fluorine-substituted C3-C4-cycloalkyl, C4-C6-heterocycloalkyl, 1-oxidethiethane-3-yl, 1,1-dioxidethiethane-3-yl, benzyl, pyridine-2-ylmethyl, methylsulfonyl, or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

[0058] A more preferable option is R 8 However, these are compounds according to the formulas and embodiments described herein, which represent a halogen or halogen-substituted C1-C4 alkyl group.

[0059] A more preferable option is R 11 It is a compound according to the formula described herein, wherein H is present.

[0060] A more preferable option is R 6 , R 7 , R 9 and R 10 However, each compound is a C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, N-alkoxyiminoalkyl, C1-C4-alkylsulfanyl, C1-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, N-C1-C4-alkylamino, or N,N-di-C1-C4-alkylamino compound according to the formula described herein, which may be independently substituted with H, halogen, cyano, or nitro, respectively.

[0061] A more preferable option is R 2 , R 3 , R 4 and R 5The compounds are those of the formulas described herein, which are C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, N-C1-C4-alkoxyimino-C1-C4-alkyl, C1-C4-alkylsulfanyl, C1-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, N-C1-C4-alkylamino, or N,N-di-C1-C4-alkylamino, which may be independently substituted with H, halogen, cyano, or nitro, respectively.

[0062] Even better, here, portions A1-A4 and B1-B5 are as follows: A1 is CH, A2 is CR 3 or N, A3 is CR 4 And, A4 is CH, B1 is CR 6 or N, B2 is CH, B3 is CR 8 And, B4 is CH, and B5 is CR 10 or N This is a compound according to the formula described herein.

[0063] A more preferable option is R 1 It is a compound according to the formula described herein, wherein H is present.

[0064] A more preferable option is R 1 The compound is a compound according to the formula described herein, wherein the compound is methyl.

[0065] More preferably are compounds according to the formulas described herein, in which Q is a C1-C4 alkyl group substituted with fluorine or a carbonamide (-C(=O)N(R)2, where R is independently H, C1-C3-alkyl or halogen-substituted C1-C3-alkyl group), a C3-C4 cycloalkyl group substituted with cyano or fluorine, a C4-C6 heterocycloalkyl group, a 1-oxidethioethane-3-yl group, a 1,1-dioxidethioethane-3-yl group, a benzyl group, a pyridine-2-ylmethyl group, a methylsulfonyl group, or a 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl group.

[0066] More preferably 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-oxidethioethane-3-yl, 1,1-dioxidethioethane-3-yl, benzyl, pyridine-2-ylmethyl, methylsulfonyl, or 2-oxo-2-(2,2,2-trifluoroethylamino)ethyl.

[0067] A more preferable option is R 8 However, the compound is a C1-C4 alkyl group that is halogenated or halogenated, according to the formula described herein.

[0068] The following are preferred examples of active ingredients that have parasitic effects on non-human organisms: 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)-ethyl]phenyl]pyrazole-4-yl]-N-methylpyridine-3-carboxamide [ka] 2-Chloro-N-cyclopropyl-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazole-4-yl]-3-pyridinecarboxamide: [ka] 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]-N-cyclopropyl-3-pyridinecarboxamide: [ka] 2-Chloro-5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazole-4-yl]-N-cyclopropylpyridine-3-carboxamide [ka] 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]pyridine-3-carboxamide [ka] 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: [ka] 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazole-4-yl]-N-cyclopropylbenzamide [ka] 5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazole-4-yl]-2-chloro-N-cyclopropylbenzamide [ka] 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrazole-4-yl]-N-cyclopropylbenzamide [ka] 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]benzamide [ka] 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]-N-methylbenzamide [ka] 2-Chloro-N-cyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]benzamide: [ka] 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]benzamide: [ka] 2-Chloro-N-cyclopropyl-5-[4-[2,6-dimethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-1-yl]benzamide: [ka] 2-Chloro-N-(1-cyanocyclopropyl)-5-[4-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-1-yl]benzamide: [ka] 2-Chloro-5-[3-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazole-5-yl]-N-cyclopropylbenzamide: [ka] 2-Chloro-N-(1-cyanocyclopropyl)-5-[3-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazole-5-yl]benzamide: [ka] 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrrole-3-yl]benzamide: [ka] 2-Chloro-5-[3-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrrole-1-yl]-N-cyclopropylbenzamide: [ka]

[0069] The above-mentioned active ingredients may, in this case, be part of the formulation described herein, and thus enable the efficacy against the parasites described in detail below.

[0070] In the context of the present invention, the active components of formulas I-1 to I-5 and the active components of formulas II-1 to II-6 are preferred, and the active components of formulas I-1 to I-5 are particularly preferred.

[0071] According to a preferred embodiment, the compound of formula I-1 can be present as an active ingredient, where a mixture of isopropanol (32.5), ethanol (32.5), and propylene carbonate (35) can be used as the solvent mixture, 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 a mixture of ethanol (65), propylene carbonate (17.5), and glycerol carbonate (17.5), where the numbers in parentheses are intended to indicate the content in weight percent based on the solvent mixture.

[0072] According to further embodiments, the solvent mixtures identified above can be used for the active ingredient according to formula I-2, or formula I-3, or formula I-4, or formula I-5.

[0073] However, active ingredients according to formulas I-1, I-2, I-3, I-4, and I-5, using only the first and second solvents, are particularly preferred.

[0074] In addition to the components listed above, the compositions according to the present invention may also contain conventionally pharmaceutically acceptable adjuvants. Examples of these include spreaders, antioxidants, pH adjusters, crystallization inhibitors, surfactants, dyes, pigments, penetration enhancers, and preservatives.

[0075] The diffusing agents are, for example, di-2-ethylhexyl adipate, isopropyl myristate, dipropylene glycol pelargonic acid, cyclic and acyclic silicone oils, such as dimethicone, as well as their copolymers and terpolymers with ethylene oxide, propylene oxide and formalin, fatty acid esters, triglycerides, and fatty alcohols. These can be added in proportions of ≥1 to ≤40% w / v. According to further embodiments, the diffusing agents may be present in proportions 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.

[0076] Antioxidants include, for example, ascorbic acid, di-Na-EDTA, BHT, BHA, delta-tocopherol, and thioglycerol. These can be added in proportions of ≥0.01 to ≤2% w / v. According to further embodiments, antioxidants may be present in proportions of ≥0.01 to ≤1% w / v, ≥0.05 to ≤0.5% w / v, or ≥1 to ≤2% w / v.

[0077] The pH adjuster is preferably an organic acid or base, such as citric acid or triethanolamine. These can be added in amounts of ≥0.001 to ≤5% w / v. According to further embodiments, the pH adjuster may be present in amounts of ≥0.01 to ≤1% w / v, ≥0.05 to ≤0.5% w / v, or ≥0.1 to ≤3% w / v.

[0078] Crystallization inhibitors include, for example, cellulose ethers, such as hydroxypropyl methylcellulose (HPMC); and polyvinylpyrrolidone (PVP). These can be added in proportions of ≥0.1 to ≤50% w / v. According to further embodiments, the crystallization inhibitor may 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.

[0079] The surfactants that can be listed are nonionic surfactants, e.g., polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers; amphoteric surfactants, e.g., di-Na-N-lauryl β-iminodipropionate or lecithin; anionic surfactants, e.g., Na-lauryl sulfate, fatty alcohol ether sulfate, mono / dialkyl polyglycol ether orthophosphate monoethanolamine salts; cationic surfactants, e.g., cetyltrimethylammonium chloride. These can be added in proportions of ≥0.1 to ≤20% w / v. According to further embodiments, they may be present in proportions of ≥0.1 to ≤10% w / v, ≥0.1 to ≤1% w / v, ≥1 to ≤10% w / v, or ≥0.2 to ≤5% w / v.

[0080] Dyes can also be added to pharmaceutical compositions. They may be dissolved in the composition or suspended. Examples include natural food colorants such as Brilliant Blue, D&C Violet No. 2, FD&C Yellow, Sunset Yellow FCF, or chlorophyllin. These can be added in amounts of ≥0.01 to ≤2% w / v. According to further embodiments, they may be present in amounts of ≥0.01 to ≤1% w / v or ≥0.1 to ≤2% w / v.

[0081] The pharmaceutical composition may contain penetration enhancers such as menthol, 1,8-cineole, and 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 proportions 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.

[0082] In principle, the concentration of the active ingredient is not limited, but the fact that all active ingredients should be present in the solution should also be considered. For advantageous pore-on application, for high efficacy, it may be preferable for the pharmaceutically active ingredient to be present in an amount of 0.1% to 8% by weight, for example, 0.1% to 5% by weight. This can correspond to a ratio of 0.2 to 4 g / 100 ml, for example, 1 to 3 g / 100 ml, depending on the pharmaceutical composition. Such concentrations can be easily achieved by the composition of the solvent mixture described above and are particularly advantageous for topical pore-on application. However, in principle, concentrations of 30% by weight or less or more of the active ingredient are also possible without exceeding the scope of the present invention.

[0083] Therefore, the formulations according to the present invention are typically liquids and are suitable for topical or skin application, particularly so-called pore-on formulations.

[0084] In particular, the extrinsic effect of compositions according to the present invention, which contain active ingredients from the aforementioned group of fluorinated benzamides, is provided very effectively, especially in the case of the aforementioned po-on application. Therefore, by using this composition, the amount of active ingredient required can be reduced and the long-term effect can be increased. Thus, their use achieves economic and ecological advantages.

[0085] The compositions according to the present invention are particularly suitable for use in the control or prevention of parasitic infections. Therefore, the pharmaceutical compositions described herein are useful for use in the treatment or prevention of parasite infestations, especially in the treatment or prevention of ectoparasites.

[0086] The compositions according to the present invention are particularly suitable for controlling or preventing external parasites in non-human organisms, especially animals, especially warm-blooded animals, preferably mammals, preferably ticks and / or mites, and / or flies or fly larvae, and / or lice.

[0087] According to one embodiment, the animal may be livestock, such as caged birds; or mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, or especially dogs and cats.

[0088] In a further more preferred embodiment, the animal may be poultry such as turkeys, ducks, geese, and especially chickens; or preferably agricultural livestock such as mammals such as sheep, goats, horses, donkeys, camels, buffaloes, rabbits, reindeer, fallow deer, and especially cattle and pigs.

[0089] In a particularly preferred embodiment, the composition is used for the control and / or prevention of external parasites in cattle.

[0090] Since treated animals also generally distribute a certain amount of the composition used into the environment, for example, by abrasion or fragmentation, the effects of the composition according to the present invention may occur not only directly on the animals but also to a corresponding degree in their environment.

[0091] As described above, the compositions described herein are preferably suitable for pore-on application in the treatment or prevention of parasitic infections in non-human organisms, by dropping or pouring the compositions onto the non-human organisms.

[0092] The following are parasites that may be effectively treated by the formulation of the present invention: From the order Anoplura, for example, genera such as Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., and Pthirus spp.; From the order Mallophaga, for example, the genera Trimenopon, Menopon, Eomenacanthus, Menacanthus, Trichodectes, Felicola, Damalinea, and Bobicola; From the order Diptera, for example, there are genera such as Aedes, Anopheles, Culex, Simulium, Phlebotomus, Chrysops, Tabanus, Musca, Hydrotaea, Muscina, Haematobosca, Haematobia, Stomoxys, Fannia, Glossina, and 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 genus, From the order Siphonaptera, for example, genera such as Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., and Pulex spp. From the suborder Metastigmata, for example, the genera Hyalomma, Rhipicephalus (including the genus formerly called Boophilus), Amblyomma, Haemaphysalis, Dermacentor, Ixodes, Argas, Ornithodorus, and Otobius; From the suborder Mesostigmata, for example, the genera Dermanyssus, Ornithonyssus, and Pneumonyssus, From the suborder Prostigmata, for example, the genera Cheyletiella, Psorergates, Myobia, Demodex, and Neotrombi-cula; The suborder Astigmata includes genera such as Acarus, Myocoptes, Psoroptes, Chorioptes, Otodectes, Sarcoptes, Notoedles, Knemidocoptes, Neoknemidocoptes, Cytodites, and Laminosioptes.

[0093] From the order Diptera, the genera Tabanus, Musca, Hydrotaea, Haematobia, Stomoxys, Glossina, Lucilia, Calliphora, Aedes, Anopheles, Culex, Simulium, and Phlebotomus are particularly preferred; from the suborder Metastigmata, the genus Hyalomma The genera Rhipicephalus (spp.), Rhipicephalus (spp.) (including the genus formerly known as Boophilus), Amblyomma (spp.), Haemaphysalis (spp.), Dermacentor (spp.), Ixodes (spp.), Argas (spp.), Ornithodorus (spp.), and Otobius (spp.) are particularly preferred; From the order Mallophaga, the genera Damalinea spp., Bobicola spp., and Trichodectes spp. are particularly preferred; from the suborder Mesostigmata, the genera Dermanyssus spp. and Ornithonyssus spp. are particularly preferred; and from the suborder Astigmata, the genera Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., and Notoedres spp. are particularly preferred.

[0094] Among those particularly favored are 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, and Linognathus bituli. vituli), Haematopinus eurystemus, Solenopotes capillatus, Psoroptes bovis, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) decoloratus, Ixodes ricinus, Amblyomma maculatum, Amblyomma variegatum, Ixodes scapularis These are arthropods belonging to the species or genus Ixodes holocyclus, Haemaphysalis longicornis, and Otobius megnini.

[0095] The composition according to the present invention can be prepared by conventional methods, for example, by mixing the active ingredient with further ingredients while stirring to produce a solution. This can optionally be filtered. Plastic tubes are suitable for filling.

[0096] The liquid formulation according to the present invention features excellent storage stability of at least one year, preferably at least two years, and more preferably at least three years, in all climate zones. Due to its very high potency, the application volume can be kept low. The preferred application volume is 0.01 to 1 ml / kg [body weight of the treated animal], preferably 0.05 to 0.1 ml / kg [body weight of the treated animal].

[0097] The compositions according to the present invention also have excellent skin compatibility and low toxicity. Finally, they are environmentally friendly due to their biodegradability. [Examples]

[0098] Solubility experiment The following describes dissolution experiments of active ingredients I-1, I-2, I-3, and I-4 in solvents for pharmaceutical compositions according to the present invention. For biological effects, the active ingredients should be incorporated into the formulation in a certain dose or volume, and ideally, they should be in solution in the formulation so that they dissolve in the solvent. Since the volume of application is limited, the solvent requires a specific minimum solubility.

[0099] Table 1 shows the results of the dissolution experiment for active ingredient I-1. In this case, 10 g of a suitable solvent or solvent mixture was initially added, and the active ingredient was gradually added until the solution was saturated. Isopropanol (IPA) and propylene carbonate (PPC) were used as solvents. The sample was stirred for 3 days. Once the active ingredient was completely dissolved, the active ingredient was added again. Subsequently, the sample was stored at the relevant temperature for a further 4 days and then centrifuged to remove undissolved particles. The supernatant was analyzed by HPLC-UV for the active ingredient content in each case.

[0100] Table 1: [Table 1]

[0101] Table 1 shows that, in single solvents, the desired criteria are not met, particularly with respect to sufficient solubility, for isopropanol and propylene carbonate. The advantageous and particularly preferred desired solubility for the active ingredients according to the present invention should be in the range of at least 5% m / V, with a sufficient gap from the saturated solubility. Unexpectedly, a significant increase in solubility has been shown in the mixture of isopropanol and propylene carbonate compared to the pure solvent, which is detailed in Table 1.

[0102] Furthermore, solubility experiments were conducted using three additional active ingredients from a class of fluorinated heteroarylamides in different solvents. The solubility experiments were carried out in the same manner as above, but only at room temperature, using a solvent mixture of isopropanol / propylene carbonate 65:35% [m / m]. The results are shown in Table 2.

[0103] Table 2: [Table 2]

[0104] It was also found that very good solubility for active components I-2, I-3, and I-4 of the heteroarylamide family, particularly for the defined structures, can be achieved by the solvent phase or solvent mixture of the composition according to the present invention.

[0105] Significant increases in solubility were also shown to be limited to mixtures of isopropanol and propylene carbonate, and were demonstrated for other solvents of the series of alcohols and carbonates defined above for the first and second solvents.

[0106] Table 3: [Table 3]

[0107] Table 3 clearly shows that increased solubility can be achieved using other solvents. Therefore, the present invention can extend to other solvents within the scope described. Herein, experiments using ethanol and glycerol carbonate, mixtures thereof, and combinations of these with the previously mentioned solvents, isopropanol and propylene carbonate are shown as examples.

[0108] Experiments were also conducted using a solvent system in which the first solvent contained two alcohols. The results are shown in Table 4.

[0109] Table 4: [Table 4]

[0110] Furthermore, such a two-component system may be shown to enable good solubility of the active ingredient according to formula I-1.

[0111] Formulation Examples The following describes examples of preparations of formulations containing the active ingredients I-1, I-2, I-3, and I-4 defined above, together with additives. In all the examples identified as performed, each active ingredient was completely dissolved and its stability was as desired.

[0112] Here, Table 5 shows a suitable formulation example with data for the solvent mixture, active ingredient, and any further additives.

[0113] Table 5: [Table 5] TIFF0007850666000037.tif254152TIFF0007850666000038.tif254149TIFF0007850666000039.tif254153TIFF0007850666000040.tif249153

[0114] Table 6 shows the formulations that can be prepared according to the solubility experiment.

[0115] Table 6: [Table 6] TIFF0007850666000042.tif254157TIFF0007850666000043.tif48160

[0116] Formulations numbered 1 through 65 were manufactured, and good solubility and complete dissolution of the active ingredient were observed.

[0117] Experiments numbered 66-107 are further hypothetical examples prepared based on the solubility experiments performed, and in which the desired solubility can be predicted based on the chemical structure of the selected solvent and active ingredient.

[0118] Examples of in vitro and in vivo studies Further characteristics and efficacy of the formulation according to the present invention are described below.

[0119] Example 1 Determination of the spreadability of a colored placebo formulation on bovine skin. The purpose of this in vitro study was to determine the spreadability of a colored placebo formulation, i.e., one without the active ingredient, on bovine skin. The results shown in these studies can be applied to the diffusion effect of formulations containing the active ingredient. The studies were conducted using a double solvent phase consisting of isopropanol (IPA) and propylene carbonate (PPC).

[0120] For this purpose, epidermal strips with the lightest colored outer skin, approximately 10 × 10 cm in size, were obtained from slaughtered cattle and placed on an aluminum-covered hot plate. The plate was heated to 34°C + / - 0.5°C. Skin strips with shaved skin and natural hair length were examined. 0.025% Brilliant Blue FCF was added as a coloring agent. The behavior and spread area of ​​the formulation on the skin surface were measured over 60 minutes. Spread was further evaluated by an evaluation system. In this case, such formulations were particularly advantageous and suitable for subsequent use on animals due to their spreadability, which achieved sufficient distribution on the skin strips within the observation period.

[0121] The results are listed in Table 7, which shows the spreadability of the colored placebo formulation on skin samples.

[0122] Table 7 shows the area occupied by the formulation on skin samples immediately after application and one hour later, as well as the volume of the applied formulation, the length of hair on the skin, and the skin temperature.

[0123] Table 7: [Table 7]

[0124] This table clearly shows that spreadability is particularly advantageous. The best results were achieved with an isopropanol (IPA) to propylene carbonate (PPC) ratio of 65:35.

[0125] The tests also showed good results with a 90:10 isopropanol (IPA) to propylene carbonate (PPC) ratio, but this solvent phase had insufficient solubility compared to the formulation according to the present invention.

[0126] Table 8: [Table 8]

[0127] Example 2 In Example 2, the spreadability and efflux characteristics of a colored placebo formulation on bovine skin were determined. The purpose of this in vitro study was to determine the diffusion and efflux characteristics of a colored placebo formulation on bovine skin. 0.025% Brilliant Blue FCF was added as a coloring agent.

[0128] The formulations used correspond to those listed in Table 8.

[0129] For this purpose, skin fragments with the lightest colored outer skin, approximately 10 x 10 cm in size, were taken from slaughtered cattle and placed on an aluminum-covered hot plate. The plate was heated to 34 ± 0.5°C. In the runoff test, the hot plate was set to an angle of 45° ± 2°. A piece of filter paper was secured beneath the skin fragment.

[0130] The behavior and outflow rate of the formulation on the skin surface were recorded on video for one minute, and the outflow rate was then calculated using a straight ruler. The spread was evaluated using an evaluation system.

[0131] In this case, the formulation was particularly suitable for subsequent use on animals because the efflux characteristics during the observation period resulted in little to no discoloration of the filter paper. The formulation also achieved sufficient distribution on skin samples.

[0132] The results are shown in Table 9, which measures the runoff rate of the longest run trace over one minute after application of 750 μl of colored placebo.

[0133] Table 9: [Table 9]

[0134] These tests clearly demonstrate that the tests using the claimed proportions of isopropanol (IPA) and propylene carbonate (PPC) yielded very favorable results, as the elution characteristics during the observation period resulted in little to no discoloration of the filter paper, and in this case, sufficient distribution was achieved on the skin sample.

[0135] Example 3 In Example 3, the effectiveness of a pore-on formulation against flies (Haematobia irritans irritans) in cattle was determined. The purpose of this study was to determine the preventive effect of the insecticide against experimentally induced Haematobia irritans infestation in cattle.

[0136] This study was conducted as a blinded, negative-controlled, randomized, parallel-group efficacy trial. Each group consisted of 5 animals. All animals were sorted in descending order before treatment by fly counting, and then grouped into 4(x) blocks of 5 animals each. The cattle were randomly assigned to the blocks and then sorted in ascending order. The cattle were individually tethered in gauze-lined spaces. Each animal was infested with approximately 200 unfeeded flies on days 5, 1, 7, 14, 21, and 28, and optionally on days 35 and 42. The number of flies in the cattle was determined 4 hours after infestation on day 1, 24 hours after infestation on day 2, and on days 8, 15, 22, 29, and, if necessary, on days 36, 43, 50, and 57. Efficacy against fly infestation was determined by comparing the number of flies in treated cattle with that in untreated cattle. In this case, the treatment was considered successful if at least 90% effectiveness was measured in the treatment group compared to the control group.

[0137] The results are shown in Table 10, which demonstrate the effect of the formulation according to the present invention on small stable flies (Haematobia irritans irritans) on cattle.

[0138] Table 10: [Table 10]

[0139] Table 10 clearly shows that Examples 5 and 7 have long-lasting and effective effects even at low doses. Furthermore, Examples 8, 9, 1, 3, and 11 are also effective in the long term.

[0140] Example 4 In Example 4, the efficacy of a pore-on formulation against cattle ticks (Rhipicephalus (Boophilus) microplus) was determined.

[0141] The purpose of this study was to determine the therapeutic and prophylactic effects of acaricidal agents against experimentally induced Rhipicephalus (Boophilus) microplus parasitism in cattle.

[0142] This study was conducted as a parallel-group, open-label, negative-controlled, randomized efficacy trial. Each group consisted of 5 animals. All animals were pre-sorted in descending order based on the sex and individual tick count of the parasites present before treatment (days -14 to -2), and then divided into 2(x) blocks of 5 animals each. The cattle were randomly assigned to the blocks and sorted in ascending order. Each animal was infested with 3000 larvae on days -35, -33, -29, -27, -22, -20, -15, -13, -8, -6, -1, 5, 7, 12, 14, 19, 21, 26, and 28. Decaying congested females were collected daily from day -14 to -2 and from day 0 to 56. For grouping, mites between -14 and -2 days old were used; for determining therapeutic effect, mites between 1 and 28 days old were used; and for determining preventive effect, mites from day 29 until the end of the mite shedding period were used. Mite reproductive capacity was also determined. This was achieved by evaluating oviposition from mixed samples of congested female mites and the hatching of larvae from the laid eggs. In this case, >60% larval hatching represents a normal hatching rate. The compounds tested did not achieve any significant additional effect here.

[0143] For the therapeutic effect on existing tick infestations, treatment was considered successful if a 90% effect (based on the number of congested female ticks shed between 1 and 28 days post-treatment) was measured compared to the control group. Therefore, if the effect was less than 90%, no efficacy was observed.

[0144] Regarding the preventive effect against newly emerging mite parasitism, if the effect of 90% in the treatment group (based on the number of engorged female mites that dropped off on the 29th to 56th days after treatment) was measured compared to the control group, the treatment was determined to be successful. Therefore, if the effect is less than 90%, sufficient effectiveness is not shown.

[0145] The results are shown in Tables 11 and 12. Table 11 shows the treatment effect of the formulation according to the present invention on cattle at all stages of the cattle tick (Rhipicephalus (Boophilus) microplus), and Table 12 shows the preventive effect of the formulation according to the present invention on cattle against the parasitism of the emerging cattle tick (Rhipicephalus (Boophilus) microplus).

[0146] Table 11:

Table 11

[0147] Table 12:

Table 12

[0148] In Tables 11 and 12, it can be seen that all the active ingredients in the composition according to the present invention have high effectiveness even at low doses for both preventive and therapeutic effectiveness against mite parasitism.

[0149] Example 5 According to Example 5, the effectiveness of the Paoon formulation against the cattle louse (Bovicola bovis) was determined. The purpose of this study was to determine the therapeutic and preventive effects of the insecticidal formulation against the parasitism of naturally occurring Bovicola bovis on cattle.

[0150] This study was conducted as a parallel-group, open-label, negative-controlled efficacy study. Each group consisted of five animals. Lice were counted on day 2 before treatment, and on days 2, 14, 28, and 42. In this case, the fur of each animal was screened 10 times, and head lice at all stages, nymph and adult, were counted. The results were totaled for each animal, averaged among the animals in each group, and compared to the number of head lice in the untreated control. The acute effect on existing head louse infestations was measured on day 2. In this case, treatment was considered successful if at least 90% of the effect was measured in the treatment group compared to the control group. The sustained effectiveness on existing head louse infestations was counted on days 14, 21, and 42.

[0151] In this case, if a 100% effect was measured in the treatment group compared to the control group, the treatment was judged to be successful. Therefore, if the effect was less than 100%, the treatment was judged to be unsuccessful.

[0152] Table 13: [Table 13]

[0153] Table 13 shows the effect of the formulation of the present invention on cattle head lice (Bovicola bovis).

[0154] Table 13 clearly shows that Examples 2 and 16 exhibit relatively rapid and high efficacy when used in compositions according to the present invention with a particularly defined solvent mixture.

[0155] Therefore, from the above, it is clear that the pharmaceutically active compositions according to the present invention exhibit good solubility with active ingredients of the benzamide class, thereby enabling effective active compositions for use, particularly in the treatment or prevention of parasitic infections, especially in non-human organisms. In this case, use as a poa-on application is particularly advantageous.

Claims

1. A pharmaceutical composition comprising a solvent phase and at least one pharmaceutically active component soluble in the solvent phase, Here, the pharmaceutically active component is: Compounds of general formula (Ia''); 【Chemistry 1】 [During the ceremony, D1 is a heteroatom selected from C-R11 or N or O; D2 is a heteroatom selected from C-R11 or N or O; D3 is either C or N; D4 is either C or N; D 5 is C-R 11 or N; Here, one or fewer portions selected from D1, D2, D3, D4, and D5 are heteroatoms; 【Chemistry 2】 It is an aromatic compound; and R1 is H, which may be substituted in each case, a 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 a substituted C1-C6-alkyl; A1 is CR2 or N, A2 is CR3 or N, A3 is CR4 or N, A4 is CR5 or N, B1 is CR6 or N, B2 is CR7 or N, B4 is CR9 or N, and B5 is CR10 or N, However, there are no more than three instances of parts A1 to A4, and at the same time, there are no more than three instances of parts B1 to B5; R2, R3, R4, R5, R6, R7, R9, and R10 are each independently of each other, and may be substituted with H, halogen, cyano, nitro, in each case, 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 neither portion A2 nor A3 is N, R3 and R4 may, together with the carbon atoms to which they are bonded, form a five-membered or six-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 A1 nor A2 is nitrogen, R2 and R3, together with the carbon atoms to which they are bonded, may form a six-membered ring containing 0, 1, or 2 nitrogen atoms; R8 is a perhalide C1-C3-alkyl or perhalide C1-C3-alkoxy; R 11 is H; W is O, Q is H, formyl, hydroxyl, amino, or may be substituted in each case: 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-, C10-C14-aryl, C1-C5-heteroaryl, C6-, C10-, C14-aryl-(C1-C3)-alkyl, C1-C5-heteroaryl-(C1-C3) )-alkyl, N-C1-C4-alkylamino, N-C1-C4-alkylcarbonylamino, or N,N-di-C1-C4-alkylamino; or A poly-V-substituted, possibly unsaturated, six-membered carbon ring; or A poly-V-substituted, unsaturated four-membered, five-membered, or six-membered heterocyclic ring, where V is independently a halogen, cyano, or nitro, which may be substituted in each case 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, or a fluorinated heteroarylamide which is a salt, N-oxide or tautomer of a compound of general formula (Ia''); or, These are fluralaner, afoxolaner, sarolaner, lotilaner, or fipronil; And here, the solvent phase is a solvent mixture comprising at least a first solvent and a second solvent different from the first solvent, Here, the first solvent is selected from C1-C4 alkanols which may be substituted with at least one C1-C4 alkoxy group or phenyl group. Here, the second solvent is selected from aliphatic C1-C4 carbonates which may be substituted with hydroxyl groups. The pharmaceutical composition wherein, based on the total amount of the solvent in the solvent phase, the first solvent is present in a proportion of 50% to 95% by weight, and the second solvent is present in a proportion of 5% to 50% by weight.

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

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the first solvent is isopropanol and the second solvent is propylene carbonate.

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

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the solvent mixture further comprises, in addition to the first solvent and the second solvent, a third solvent different from 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, and glycol ethers.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the second solvent is present in a content of ≥20% to ≤45% by weight, based on the total amount of solvents in the solvent mixture.

8. The pharmaceutical composition according to claim 1, wherein the active component is selected from the group consisting of the following: 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)-ethyl]phenyl]pyrazole-4-yl]-N-methylpyridine-3-carboxamide 【Transformation 3】 2-Chloro-N-cyclopropyl-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazole-4-yl]-3-pyridinecarboxamide: 【Chemistry 4】 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]-N-cyclopropyl-3-pyridinecarboxamide: 【Transformation 5】 2-Chloro-5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]-1H-pyrazole-4-yl]-N-cyclopropylpyridine-3-carboxamide 【Transformation 6】 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]pyridine-3-carboxamide 【Transformation 7】 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: 【Transformation 8】 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazole-4-yl]-N-cyclopropylbenzamide 【Chemistry 9】 5-[1-[2-bromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)phenyl]pyrazole-4-yl]-2-chloro-N-cyclopropylbenzamide 【Chemistry 10】 2-Chloro-5-[1-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrazole-4-yl]-N-cyclopropylbenzamide 【Chemistry 11】 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]benzamide 【Chemistry 12】 2-Chloro-N-cyclopropyl-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-4-yl]-N-methylbenzamide 【Chemistry 13】 2-Chloro-N-cyclopropyl-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]benzamide: 【Chemistry 14】 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methyl-6-(trifluoromethyl)phenyl]-1H-pyrazole-4-yl]benzamide: 【Chemistry 15】 2-Chloro-N-cyclopropyl-5-[4-[2,6-dimethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-1-yl]benzamide: 【Chemistry 16】 2-Chloro-N-(1-cyanocyclopropyl)-5-[4-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole-1-yl]benzamide: 【Chemistry 17】 2-chloro-5-[3-[2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazole-5-yl]-N-cyclopropylbenzamide: [Chemistry 18] 2-Chloro-N-(1-cyanocyclopropyl)-5-[3-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]isoxazole-5-yl]benzamide: 【Chemistry 19】 2-Chloro-N-(1-cyanocyclopropyl)-5-[1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrrole-3-yl]benzamide: 【Chemistry 20】 2-Chloro-5-[3-[2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]pyrrole-1-yl]-N-cyclopropylbenzamide: 【Chemistry 21】

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutically active component is present in an amount of 0.1% by weight or more and 5% by weight or less.

10. A pharmaceutical composition according to any one of claims 1 to 9, for use in the treatment or prevention of parasitic infections.

11. The pharmaceutical composition according to claim 10, for use in the treatment or prevention of external parasitic infections.

12. A pharmaceutical composition according to any one of claims 1 to 11, for use in the treatment or prevention of parasitic infections in non-human organisms.

13. The pharmaceutical composition according to claim 12, for use in the treatment or prevention of parasitic infections in non-human organisms by dropping or pouring the composition onto a non-human organism.

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