Carboxamide-4-quinoline compounds with anthelmintic activity

Abstract

The present invention provides novel carboxamide-4-quinoline compounds that can be used as medicaments, particularly in the treatment and prevention of diseases in animals caused by helminths. The disclosed compounds are particularly found active against helminths from the species Ascaridia, Oesophagostomum, Haemonchus and Dirofilaria.

Description

[0001] Carboxamide-4-quinoline compounds with anthelmintic activity

[0002] Technical field

[0003] The present invention relates to the field of veterinary sciences, particularly to compounds with anthelmintic activity. In particular, the invention relates to compounds useful in prevention and treatment of diseases caused by helminths.

[0004] Background art

[0005] Parasitic diseases in animals cause substantial suffering and economic losses throughout the world. Thus, treatment of parasitic infections remains an important global endeavor.

[0006] Parasitic worms (helminths) are known to cause worm infection (helminthiasis) in humans and animals. There are numerous species of these parasites, which can be broadly classified into the following groups: flatworms, thorny-headed worms, tapeworms, flukes, and roundworms. Helminths live mainly in the gastrointestinal tract, but they can also be found in the cardiovascular system, or other organs of their hosts, where they induce physiological damage.

[0007] Helminths, particularly gastrointestinal (Gl) nematodes, are important in livestock production, especially in ruminants such as cattle and sheep. The largest impact is the decrease in voluntary feed intake, followed by decreased absorption and digestion of critical nutrients. This has negative impact on livestock production leading to large economic losses in the agriculture and livestock industry worldwide.

[0008] With the growing use of anthelmintics, resistance of various helminths, especially gastrointestinal parasites, is also growing and is now widespread. It is a major threat to the sustainability of modern ruminant livestock production, resulting in reduced productivity, compromised animal health and welfare, and increased greenhouse gas emissions through increased parasitism and farm inputs.

[0009] The ability of parasites to survive treatments that are generally effective at the recommended doses is a major threat to the future control of worm parasites in animal, such as ruminants, horses, poultry and pets. This is especially true for nematodes (roundworms). Treatment with an anthelmintic drug kills worms whose phenotype renders them susceptible to the drug, but resistant parasites survive and pass on their "resistance" genes. Resistant varieties accumulate, and treatment failure finally occurs.

[0010] Another example of an important disease caused by helminths is heartworm disease, also known as cardiovascular dirofilariasis, a serious and mostly fatal disease that is endemic in some parts of North and South America, Europe, Asia, and Australia. The disease is caused by parasitic nematodes, Dirofilaria immitis, which in the adult stage live in the heart, lungs and associated blood vessels of a host animal causing severe lung disease, heart failure and damage to other inner organs such as the liver and kidneys. The heartworm disease is known to affect pets, in particular dogs, which are considered as the definitive host. Dirofilaria immitis is often referred to as the canine heartworm but can also infect cats and ferrets, wolves, coyotes, jackals, foxes, bears, sea lions and in very rare cases even humans (zoonosis).

[0011] At least 70 species of mosquitoes can serve as intermediate hosts; Aedes, Anopheles, and Culex are the most common genera acting as vectors.

[0012] As for most parasites, the life cycle of Dirofilaria immitis, includes a variety of life forms. Adult forms of the parasite are quite large and inhabit the heart and pulmonary arteries of an animal. Male worms are typically about 12 cm (centimeters) to about 20 cm long and about 0.7 mm to about 0.9 mm wide; female worms are about 25 cm to about 31 cm long and about 1 .0 to about 1 .3 mm wide. Sexually mature female worms, after mating with male worms, produce microfilariae which are only about 300 pm (micrometers) long and about 7 pm wide. The microfilariae traverse capillary beds and circulate in the vascular system of the dog in concentrations of about 103to about 105microfilariae per ml of blood. If the dog is maintained in an insect- free environment, the life cycle of the parasite cannot progress. However, when microfilariae are ingested by the female mosquito during blood feeding on an infected dog, subsequent development of the microfilariae into larvae occurs in the mosquito. The microfilariae go through two larval stages (L1 and L2) and finally become mature third stage larvae (L3), the infective larval stage, of about 1.1 mm length, which can then be transmitted back to the dog through the bite of the mosquito. It is this L3 stage, therefore, that accounts for the initial infection. As early as three days after infection, the L3 molt to the fourth larval (L4) stage, and subsequently to the fifth stage, or immature adults. The immature adults migrate via the circulatory system to the heart and pulmonary arteries, where they mature and reproduce, with the female worms thus producing the microfilariae in the blood.

[0013] Presently, macrocyclic lactones are used for the prevention of heartworm disease in dogs, e.g. ivermectin (sold under the brand names Heartgard, Iverhart, etc.), milbemycin oxime (Interceptor Flavor Tabs and Sentinel Flavor Tabs) and moxidectin (Proheart 6 and 12).

[0014] Therefore, there is a need for new anthelmintic compounds. Further challenges that are desirable to overcome include toxicity and safety of existing compounds both for the animal and the user, their efficacy (potency and duration), bioavailability, pharmacokinetics and pharmacodynamics.

[0015] WO 2021 / 122911 A1 describes compounds comprising a quinoline structure with anthelmintic activity.

[0016] Hence, it is an object of the present invention to provide new compounds that can effectively be used against parasitic nematodes, particularly against parasitic nematodes in animals.

[0017] It is desired that the new compounds are compatible with standard antiparasitic treatments in animals. It is further desired to provide pharmaceutical compositions comprising the new compound, which can be conveniently administered to animals. Summary of invention

[0018] In a first aspect, the present invention provides a compound with Formula (I): Formula (I) wherein each of RAis independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents RAform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; n is 0-5,

[0019] RBis either H or CH3, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof.

[0020] In a second aspect, the invention provides a method of manufacture of the compound with Formula (I), comprising the step of r Formula (A) wherein RBis either H or CH3 and wherein X is a halogen with a compound of Formula (B): Formula (B) wherein RAand n have the meaning as defined in any of the embodiments described herein, and wherein Y is B(OH)2 or B(ORD)2 with RDbeing alkyl.

[0021] In a further aspect, the invention provides a pharmaceutical composition comprising the compound with Formula (I) and at least one pharmaceutically acceptable excipient.

[0022] In another aspect, the invention provides the compound according to the invention for use as a medicament.

[0023] The invention further provides the compound according to the invention for use in treatment or prevention of a disease caused by a helminth, e.g. parasitic nematode, in animals.

[0024] The invention also provides the use of the compound according to the invention for the manufacture of a medicament for the treatment or prevention of a disease caused by a helminth, e.g. parasitic nematode, in animals.

[0025] In a further aspect, the invention provides a method of treatment or prevention of a disease caused by a helminth, e.g. parasitic nematode, comprising administering to a warm-blooded animal an effective amount of the compound according to the invention or the composition according to the invention and optionally an effective amount of one or more additional active ingredients.

[0026] Detailed description

[0027] The present invention relates to compounds with Formula (I): Formula (I) wherein each of RAis independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents RAform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; n is 0-5,

[0028] RBis either H or CH3.

[0029] The 5- or 6-membered ring formed by two adjacent RAcan be an aryl, heteroaryl or a cycloalkyl, preferably aryl or heteroaryl. Examples include a phenyl ring or pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, preferably phenyl or pyridine. The ring system that is formed by the phenyl ring together with two adjacent RAcan be selected from the group of naphthyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, indole, isoindole, benzimidazole, indazole; preferably naphthyl, quinoline.

[0030] In some embodiments, RAis one or more substituents of the phenyl ring, which are independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably from Cl, F, methyl or methoxy, more preferably from Cl or F. Integer n is selected from the range 0-5, preferably 1-3, more preferably 1 or 2, most preferably 2. If n is 0, the phenyl ring is unsubstituted. If n is 1-5, the phenyl ring is substituted with 1-5 RA, while the remaining C atoms in the phenyl ring are unsubstituted. RBis either H or CH3, preferably H.

[0031] The invention further relates to a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug of the compound with Formula (I).

[0032] In some embodiments, RBis hydrogen.

[0033] In some of these embodiments, n can be 3 and the substituent RAcan be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably Cl or F, more preferably F. The phenyl ring substituted with RAcan be selected from the group consisting of 2,3,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2-fluoro-3,5-dichlorophenyl, 2,3-difluoro-5-chlorophenyl, 3,5-dichloro-4-fluorophenyl, 2- chloro-3,5-difluorophenyl, 3,4,5-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3-dichloro-5-flurophenyl, preferably 2,3,5-trifluorophenyl, 2,3,5-trichlorophenyl, 2,3-dichloro-5-fluorophenyl, more preferably 2,3,5- trifluorophenyl.

[0034] In some of these embodiments, n can be 2 and each of the substituents RAcan be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably Cl, F, methyl or methoxy, more preferably Cl, F or methyl. The phenyl ring substituted with RAcan be selected from the group consisting of 2,3-dichlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-5-cholorophenyl, 2-fluoro-3-chlorophenyl, 2- chloro-3-fluorophenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-methyl-5-fluorophenyl, 2- methyl-5-chlorophenyl, 2-chloro-5-fluorophenyl, 2,3-diflurorophenyl, 2-chloro-5-methoxyphenyl, 2-fluoro-5- methoxyphenyl, preferably 2,3-dichlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-5-cholorophenyl, 2- fluoro-3-chlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2- methyl-5-fluorophenyl, 2-methyl-5-chlorophenyl, 2-chloro-5-fluorophenyl, more preferably 2,3- dichlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-5-cholorophenyl, 2-fluoro-3-chlorophenyl, 2-chloro-3- fluorophenyl, yet more preferably 2,3-dichlorophenyl, 2-methyl-3-chlorophenyl, 2-fluoro-5-cholorophenyl. In some embodiments, the phenyl ring substituted with RAcan be 2,3-dichlorophenyl. In some embodiments, the phenyl ring substituted with RAcan be 2-methyl-3-chlorophenyl. In some embodiments, the phenyl ring substituted with RAcan be 2-fluoro-5-cholorophenyl.

[0035] In some of these embodiments, n can be 1 and the substituent RAcan be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably Cl, F or methoxy, more preferably Cl or F. The phenyl ring substituted with RAcan be selected from the group consisting of 3-fluorophenyl, 3- chlorophenyl, preferably 3-chlorophenyl.

[0036] In some of these embodiments, n can be 1 and the substituent RAcan be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably Cl or F. The phenyl ring substituted with RAcan be selected from the group consisting of 3-fluorophenyl, 3-chlorophenyl, preferably 3-chlorophenyl.

[0037] In some of these embodiments, the phenyl ring is substituted with two adjacent RAwhich form a 5 or 6- membered aromatic or heteroaromatic ring. The ring system that is formed by the phenyl ring together with two adjacent RAis selected from the group of naphthyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, indole, isoindole, benzimidazole, indazole; preferably naphthyl, quinoline.

[0038] In some embodiments, RBis CH3 (methyl group). In these embodiments, n can be 1 , 2 or 3 and the substituent RAcan be selected as described in the above embodiments for RBbeing hydrogen.

[0039] In some embodiments, the compound has the Formula (C): Formula (C) wherein each of R1, R2, R3 and Rcis independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or wherein each two adjacent substituents from R1, R2, R3 and Rcform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; and wherein RBis either H or CH3.

[0040] In some embodiments, R1 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably from Cl, F and methyl. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is methyl. In some embodiments, R2 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably from H, Cl, F and methyl. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is methyl.

[0041] In some embodiments, R3 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably from H, Cl and trifluoromethyl, more preferably H or Cl, most preferably it is H.

[0042] In some embodiments, Rcis selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably H or F, more preferably H. Exemplary compounds of Formula (C) are presented in Table C.

[0043] Table C. Prepared compounds In some embodiments, the compound is selected from the list consisting of compounds 1 to 14.

[0044] In some embodiments, the compound is selected from compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, preferably from compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, more preferably from compounds 2, 3, 4, 5 and 8, yet more preferably from compounds 2, 3, 5, and 8, most preferably compound 2. In other embodiments, the compound is compound 5. In yet other embodiments, the compound is compound 3. In yet other embodiments, the compound is compound 8.

[0045] In one embodiment, the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-isopropylquinolin-3-yl)quinoline- 4-carboxamide (compound 2).

[0046] In another embodiment, the compound is N-(8-(3-chloro-2-methylphenyl)-7-fluoro-4-isopropylquinolin-3- yl)quinoline-4-carboxamide (compound 5).

[0047] In yet another embodiment, the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-isopropylquinolin-3- yl)quinoline-4-carboxamide (compound 8).

[0048] In a further embodiment, the compounds is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-isopropylquinolin-3- yl)quinoline-4-carboxamide (compound 3).

[0049] The compounds with Formula (I) or (C) can be prepared by general synthetic routes known to the skilled person, specific examples of which are described in more details in the Examples.

[0050] Particularly, the compounds of Formula (I) can be obtained by reaction comprising the step of reacting a compound of Formula Formula (A) wherein RBis either H or CH3. and wherein X is halogen, preferably Cl, Br or I, with a compound of Formula (B), which is a boronic acid or a boronic ester: Formula (B) wherein RAand n have the meaning as defined in any of the embodiments described herein, and wherein Y is B(OH)2 or B(OR°)2 with RDbeing alkyl.

[0051] Particularly, each of RAis preferably independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or each two adjacent substituents RAcan form a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; and n is 0-5.

[0052] Each of RDis an alkyl, e.g. C1-6 alkyl, or preferably two RDtogether with the O and B atoms form a 5- or 6-membered heterocycle ring.

[0053] In some embodiments, Y is B(OH)2 and the compound of Formula (B) is a boronic acid:

[0054] In some embodiments, Y is B(ORD)2 with RDbeing alkyl and the compound of Formula (B) is a boronic ester. A preferred example of such an ester is as follows:

[0055] The compounds of Formula (A) and Formula (B) are either commercially or synthetically available.

[0056] In an embodiment of the invention the compound of formula (A) reacts with a compound of formula (B) with the latter being a boronic acid (Y = B(OH)2) or a boronic ester (Y=B(O-alkyl)2). This reaction is known in the art as a Suzuki cross coupling reaction.

[0057] In an embodiment of the invention the compound of formula (A) reacts with a compound of formula (B) in the presence of a catalytic system. This catalytic system can be composed of a transition metal such as palladium and a ligand like an alkyl- or aryl phosphine. In an embodiment the catalytic system is composed of tetrakis(triphenylphosphin)palladium(0).

[0058] In an embodiment of the invention the process is carried out in the presence of a base, which can be a nitrogen base like a trialkylamine such as triethylamine or a phosphate salt such as potassium phosphate or a carbonate salt such as potassium carbonate.

[0059] In an embodiment of the invention the process is carried out in the presence of potassium phosphate.

[0060] In an embodiment of the invention the process is carried out in a solvent or a mixture of solvents. Suitable solvents include water, toluene, tetrahydrofurane, 1 ,4-dioxane or dimethylformamide.

[0061] In an embodiment of the invention the process is carried out in a mixture of 1 ,4-dioxane and water.

[0062] In an embodiment of the invention the process is carried out at temperature of 60 °C to 120°C, preferably at 80°C to 100°C.

[0063] The invention also provides a pharmaceutically acceptable salt, solvate, polymorph or prodrug of the compounds of Formula (I).

[0064] The terms “salt” or “salts” refer to an acid addition or base addition salt of the compound of the present invention. “Salts” include in particular “pharmaceutically acceptable salts”, which refers to salts that retain the biological effectiveness and properties of the compounds of this invention and which typically are not biologically or otherwise undesirable. Particularly, the compound of the present invention is capable of forming acid salts by virtue of the presence of amino groups.

[0065] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

[0066] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from a basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting a free base form of a compound of Formula (I) with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.

[0067] A solvate of a compound can be regarded as a compound in which an organic solvent or water adheres to said compound. Organic solvents refer to the ones which are known by the skilled person. In case that water is adhered to the compound the corresponding compound is known as a hydrate.

[0068] The term “polymorph” as used herein and as generally understood by the skilled person refers to different crystalline forms of the same molecular entity. Therefore, due to their different chemical compositions, solvates and hydrates as discussed above are not included in the definition of polymorphism but are rather designated “pseudopolymorphs” instead.

[0069] The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above Formula (I), for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

[0070] The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit / risk ratio and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

[0071] The compounds of the invention have been found to be active against various species of helminths including gastrointestinal nematodes and heartworm. Therefore, the compounds of the invention are particularly suitable as active ingredients of anthelmintic compositions. The compounds have been found selectively active against at least larvae of Ascaridia, Oesophagostomum, Haemonchus and Dirofilaria, while the potential for target-related adverse reactions in the host such as mammal (e.g. humans) is low.

[0072] The compounds further have beneficial physicochemical properties such as aqueous solubility. Improved aqueous solubility is a desired property in the design of pharmaceutically active compounds.

[0073] Administration and dosage forms

[0074] The compounds according to this invention may be administered in various dosage forms. The term “dosage form” means that the compounds according to this invention are formulated into a product suitable for administering to the animal via the envisaged administration route. Such dosage forms are sometimes referred to herein as formulations or pharmaceutical compositions.

[0075] The formulation type chosen for a dosage form in any instance will depend upon the animal to which it will be administered and the particular purpose, envisaged and the physical, chemical, and biological properties of the compound according to this invention.

[0076] The pharmaceutical compositions of this invention and / or embodiments thereof can be administered to animals via various administration routes.

[0077] One possible administration route is the oral route, wherein the compound according to this invention is administered via the mouth. Oral dosage forms suitable for oral administration comprise liquids (e.g., drench, feed or drinking water formulations), semi-solids (e.g., pastes, gels), and solids (e.g., tablets, capsules, powders, granules, chewable treats, premixes, and medicated blocks).

[0078] In an embodiment of the invention and / or embodiments thereof, the veterinary composition is an oral composition.

[0079] Liquid dosage forms of the compounds are generally solutions, suspensions or emulsions. A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. A suspension consists of insoluble solid particles dispersed in a liquid medium, with the solid particles accounting for about 0.5% to about 30% of the suspension. The liquid may be aqueous, oily or both. An emulsion is a heterogeneous dispersion of one immiscible liquid in another; it relies on an emulsifying agent for stability.

[0080] A number of veterinary compositions are known to be suitable for oral administration to animals, but they vary for the different animal species. For small ruminants such as sheep conventionally pharmaceutically active ingredients are administered orally as solids (e.g., tablets or boluses) or liquids, or via their feed or drinking water. In large sheep and cattle flocks the use of oral drenches is the most common oral dosage form, especially when administering anthelmintic compounds.

[0081] Drenching means that a liquid, potentially slightly viscous composition comprising the compound and pharmaceutically acceptable excipients is applied via the mouth with a specific drenching gun that dispenses the composition into the animal’s (sheep's) throat. When the composition is administered in the animal recipient's drinking water or as a drench, it may be convenient to use a solution or suspension formulation. This formulation can be, for example, a concentrated suspension that is mixed with water or a dry preparation that is mixed and suspended in the water.

[0082] A dry powder (or granule) for reconstitution is mixed and reconstituted with a diluent (e.g. water) as a solution, or as a suspension immediately prior to administration. The principal advantage of this dosage form is that it overcomes the problem of instability in solution or suspension. In addition to the active compounds, the liquid dosage forms may contain pharmaceutically acceptable excipients commonly used in the art such as, for example, inert diluents such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitane and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring agents.

[0083] Solid dosage forms for oral administration include e.g. capsules, tablets, pills, powders and granules, chewable treats, premixes and medicated blocks. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatine, polyvinyl pyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0084] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art such as enteric coatings, release-controlling coatings and other coatings. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g. tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes.

[0085] Several modified-release delivery systems have been developed, that take advantage of the unique anatomy of the ruminant forestomach, i.e., for intra-ruminal administration. An intraruminal bolus is a specific formulation for ruminants (cattle, sheep, goats, buffalos, camelids, deer etc.). It is a veterinary delayed release delivery system which remains in the rumeno-reticular sac of a ruminant animal over an extended period of time and in which the therapeutically active substance has a predictable and delayed release pattern. Such intraruminal boluses are usually administered using a balling gun or another suitable device. Semi-solid oral formulations (pastes or gels) are generally administered via an applicator directly into the mouth of an animal or mixed with the feed.

[0086] Solid oral formulations are either administered directly to an animal (tablet, capsule, bolus) or mixed with the feed or via medicated feed blocks.

[0087] When the oral formulation is administered via a non-human animal's feed, it may, for example, be fed as a discrete feed or as a chewable treat or soft chew. Alternatively (or additionally), it may for example be intimately dispersed in the animal recipient's regular feed, used as a top dressing or in the form of solid pellets, paste or liquid that is added to the finished feed. When the oral Formulation is administered as a feed additive, it may be convenient to prepare a "premix" in which the oral Formulation is dispersed in a small amount of a liquid or solid carrier. This "premix" is, in turn, dispersed in the animal's regular feed using for example a conventional mixer.

[0088] Soft chews for dogs are a chewable dosage form increases acceptance of the medication and even make the animals take up the dosage form free choice. A “Soft chew” or “Soft chewable pharmaceutical product” is intended to mean a veterinary pharmaceutical unit dose that is solid at room temperature and that is after oral administration soft to chew by the dog and which is functionally chewy because the product has some plastic rheological behaviour and texture during the process of mastication in the mouth.

[0089] Compounds according to this invention may alternatively be administered via non-oral dosage routes, such as topically (e.g., via a spot-on, pour-on, spray), or parenterally (e.g., subcutaneous injection, intravenous injection, intramuscular injection, etc.).

[0090] In an embodiment of the invention and / or embodiments thereof, the veterinary composition is an injectable composition.

[0091] Injectable compositions, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Preferred is subcutaneous administration of injectable formulations.

[0092] The injectable formulations can be sterilized, for example by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. Preferred is subcutaneous administration.

[0093] This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution that, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulation matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0094] Alternatively, a solid implant can be administered by injection (e.g., subcutaneous implant).

[0095] In an embodiment of the invention and / or embodiments thereof, the veterinary composition is a topical composition. For instance, the compounds according to this invention may be administered topically using a transdermal formulation (i.e., a formulation that passes through the skin of the animal).

[0096] The pour-on or spot-on methods, for example, comprise applying the formulation to a specific location of the skin or coat, such as on the neck or backbone of the animal. This may be achieved by, for example, applying a swab or drop of the pour-on or spot-on formulation to a relatively small area of the recipient animal's skin or coat.

[0097] The concentration of the compounds according to this invention in the applied dosage form may vary widely depending on the dosage route. In general, the concentration of the present compound or embodiments thereof in the composition according to the present invention or embodiments thereof is from 1 to 70% by weight, based on the total weight of the composition. In some embodiments the concentration is from 1 to 50% by weight, or from 10 to 50% by weight. In other embodiments, the concentration is from 35 to 65% by weight, from 40 to 60% by weight, from 45 to 55% by weight, or about 50% by weight.

[0098] Pharmaceutical compositions

[0099] In another aspect the present invention thus provides a pharmaceutical composition.

[0100] Pharmaceutical compositions of the present invention and / or embodiments thereof comprise an effective amount of one or more, preferably one compound according to the invention and at least one pharmaceutically acceptable excipient. The composition can comprise one or more of the compounds according to the invention. The pharmaceutical composition is particularly a veterinary composition, sometimes called (veterinary) dosage form. In the veterinary compositions of the present invention and / or embodiments thereof a compound of the present invention and / or embodiments thereof is formulated together with one or more pharmaceutically acceptable excipient(s). The pharmaceutically acceptable excipient(s) need to be suitable for the (veterinary) dosage form and administration route.

[0101] Pharmaceutically acceptable excipients are known in the art. For example, they are described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20thEdition, 2000). All such pharmaceutically acceptable excipients must be substantially pharmaceutically or veterinary pure and non-toxic in the amounts employed and must be compatible with the active ingredients.

[0102] In one preferred embodiment of the invention and / or embodiments thereof the one or more pharmaceutically acceptable excipient(s) is selected from carriers, binders, antioxidants, buffers, sugar components, surfactants, lubricants, stabilizers, flow agents, disintegration agents and preservatives and mixtures thereof.

[0103] As used herein, the term "carrier" means a non-toxic, inert, solid, semi-solid or liquid filler or diluent carrying / encapsulating material of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; esters such as ethyl oleate and ethyl laurate; agar.

[0104] A binder is a substance which is capable of making other substances stick together. The binder is a component that, in case binder is a polymer, preferably has a melting temperature or a glass transition temperature (Tg) in the range of 25 to 100°C, preferably 35 to 85°C, in particular 40 to 70°C. The glass transition temperature is the temperature at which a polymer becomes brittle as it cools down and soft as it heats up. This means that hydrophilic polymers become soft at temperatures above the glass transition temperature (Tg) and become plastically deformable without breaking. The glass transition temperature or melting point are determined via methods known by the skilled person.

[0105] In one preferred embodiment of the invention and / or embodiments thereof the binder is selected from polyethylene glycol, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymer, microcrystalline wax, glycerol monostearate, hydrogenated castor oil, polyethylene glycol glycerol hydroxystearate, polysaccharides, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylates, polyvinylpyrrolidone-polyacetate copolymer and mixtures thereof.

[0106] Antioxidants are substances that are used to inhibit oxidation. Antioxidants suitable to be comprised in the veterinary dosage form include, but are not limited to, ascorbic acid, glutathione, tocopherol and its esters, tert-butylhydroquinone (TBHQ), butyl hydroxy anisole (BHA also referred to as 2-tert-butyl-4-hydroxy anisole, 3-tert-butyl-4-hydroxy anisole or a mixture thereof) and butyl hydroxy toluene (BHT also referred as 2,6-di tert-butyl 4-methyl phenol. In one preferred embodiment of the invention and / or embodiments thereof antioxidants comprised in the veterinary dosage form may be in the range of 0.001 to 1 .00 weight %.

[0107] Buffers are substances to maintain / adjust the pH value of a product. Non-limiting examples of buffers are hydrogen carbonate salts, dihydrogen phosphate salts, hydrogen phosphate salts.

[0108] Sugar components are used in oral dosage forms to sweeten the taste of a product. They comprise natural sugars (carbohydrates) as well as sugar substitutes. In one preferred embodiment of the invention and / or embodiments thereof sugar components comprised in the veterinary dosage form may be in the range of 1 to 10 weight %.

[0109] Especially in oral dosage forms, surfactants can be regarded as substances lowering the interfacial tension between two phases. Common surfactants are alkylsulfates (for example sodium lauryl sulfate), alkyl trimethyl ammonium salts, alcohol ethoxylates and the like. In one preferred embodiment of the invention and / or embodiments thereof surfactants comprised in the veterinary dosage form may be in the range of 0.1 to 10.0 weight %.

[0110] Lubricants generally can be regarded as substances which are suitable to reduce friction, such as static friction, sliding friction and rolling friction. The lubricant is preferably a stearate or fatty acid, more preferably an earth alkali metal stearate, such as magnesium stearate. In one preferred embodiment of the invention and / or embodiments thereof lubricants comprised in the veterinary dosage form may be in the range of 0.1 to 10.0 weight %.

[0111] A stabiliser is a pharmaceutically acceptable excipient which helps to preserve the product. Examples include, but are not limited to, alginates, carrageen, gelatine, pectin and natural gums. In one preferred embodiment of the invention and / or embodiments thereof stabilizers comprised in the veterinary dosage form may be in the range of 0.01 to 3.0 weight %.

[0112] Flow agents, also referred to as glidants, can be used to improve the flowability. Traditionally, talc was used as glidant but is nowadays nearly fully replaced by colloidal silica. In one preferred embodiment of the invention and / or embodiments thereof flow agents comprised in the veterinary dosage form may be in the range of 1 to 3 weight %.

[0113] Disintegration agents, also referred to as disintegrants, are compounds (generally in solid dosage forms) which enhance the ability of the dosage form, preferably the ability of the tablet, when in contact with a liquid, preferably water, to break into smaller fragments. Non-limiting examples of disintegration agents include sodium carboxymethyl starch, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl glycolate, preferably sodium starch glycolate. In one preferred embodiment of the invention and / or embodiments thereof surfactants comprised in the veterinary dosage form may be in the range of 1 .0 to 7.0 weight %.

[0114] Preservatives are substances that can be added to prevent decomposition by microbial growth or by undesirable chemical changes. Non-limiting examples include lactic acid, benzoic acid benzoates and hydroxybenzoates. In one preferred embodiment of the invention and / or embodiments thereof preservatives comprised in the veterinary dosage form may be in the range of 0.01 to 1 .0 weight %.

[0115] Pharmaceutical compositions of the present invention may be manufactured by processes known in the art. These processes include, for example, a variety of known mixing, dissolving, granulating, emulsifying, encapsulating, entrapping, and lyophilizing processes. Optimal formulation depends on, for example, the dosage form and administration route (e.g., oral, parenteral by injection, topical).

[0116] Solid dosage forms, for example, may be prepared by, for example, intimately and uniformly mixing the compounds with fillers, binders, lubricants, glidants, disintegrants, flavoring agents (e.g., sweeteners), buffers, preservatives, pharmaceutical-grade dyes or pigments, and controlled release agents.

[0117] Oral dosage forms other than solids may be prepared by mixing the compounds with, for example, one or more solvents, viscosity-enhancing agents, surfactants, preservatives, stabilizers, resins, fillers, binders, lubricants, glidants, disintegrants, co-solvents, sweeteners, flavorings, buffers, suspending agents, and pharmaceutical-grade dyes or pigments.

[0118] Methods of use

[0119] The compound according to the invention can be used as a medicament, especially as veterinary antiparasitic medicament to control parasite infestations of animals. The invention is also understood to include the use of compound of the invention and / or embodiments thereof as described in this application in the manufacture of a medicament for the control of parasite infestations of animals, or for the treatment or prevention of a disease caused by a parasitic nematode in animals.

[0120] The compounds according to this invention and compounds corresponding to the use according to the invention may be used to treat animals, including humans and non-human animals, especially non-human mammals. Such non-human mammals include, for example, livestock mammals (e.g., swine, livestock ruminants like bovines, sheep, goats, etc.), laboratory mammals (e.g., mice, rats, jirds, etc.), companion mammals (e.g., dogs, cats, equines, etc.), and wild and zoo mammals (e.g., buffalo, deer, etc.). It is contemplated that the compounds also are suitable to treat non-mammals, such as poultry (e.g., turkeys, chickens, ducks, etc.) and fish (e.g., salmon, trout, koi, etc.).

[0121] Suitably the subject is a warm-blooded animal, particularly a mammal, more in particular a sheep, a bovine, an equine, a dog or a cat, especially a dog or a cat. The compound according to the invention are for use for the treatment and / or control of parasites of animals.

[0122] In one embodiment the compound according to the invention has persistent activity and is used to control the reinfestation of the treated animal with parasites.

[0123] In one embodiment the compound according to the invention is for the treatment of mixed infections of animals with different species of nematode parasites, such as e.g., roundworms, hookworms, or whipworms.

[0124] In one embodiment the compound according to the invention is used to reduce of the level of infection of the animal by immature adult and adult parasite stages of parasites.

[0125] In one embodiment the compound according to the invention is used to control in an animal inhibited, immature, and adult stages of gastro-intestinal nematodes and respiratory nematodes.

[0126] In another embodiment the compound according to the invention is for use in the treatment and control of adult and immature round worms of the gastrointestinal tract.

[0127] In another embodiment the compound according to the invention is for use in treatment and prevention of mixed infections of gastro-intestinal nematodes and respiratory nematodes.

[0128] The compound according to the present invention acts against animal parasites, particularly endoparasites. Endoparasites are parasites that live in the internal organs or tissues of its host. The term "endoparasites" includes especially helminths such as cestodes, nematodes or trematodes, and protozoa such as coccidia. Endoparasites include nematode parasites which commonly infect animals, and include the egg, larval, and adult stages thereof. Such endoparasites include helminths (roundworms, hookworms, tapeworms, heartworms, lungworms), and are commercially important because they cause serious diseases in animals. The phrase “control of parasite or parasite infestation” means to reduce or eradicate parasite numbers in an animal, and / or to inhibit the development of parasite infestation partially or completely in an animal. This may be achieved by, for example, killing, repelling, expelling, incapacitating, deterring, eliminating, alleviating, or minimizing the parasite. The effect of the compounds can be, for example, ovicidal, larvicidal, adulticidal, or a combination thereof. In addition, the effect can manifest itself directly by killing the parasites either immediately or after some time has elapsed (e.g., when molting occurs or by destroying eggs). The effect alternatively (or additionally) can manifest itself indirectly by, for example, reducing the number of eggs laid and / or the hatch rate.

[0129] The compounds according to the invention can be used to control parasites by killing the adults or immature larvae stages, that are identified by numbers depending on the lifecycle of the parasite. L1 means first larval stage, L2 second stage etc. Depending on the target parasite the immature stages are sometimes referred to as inhibited larvae stages. The skilled person is aware of the lifecycle of the parasite and able to identify the desired targeted parasite stage.

[0130] The invention further includes a method of treatment or prevention of a disease caused by a parasitic nematode infestation, comprising administering to an animal an effective amount of the compound according to the invention or the composition according to the invention and optionally an effective amount of at least one other active ingredient.

[0131] It is understood that the term “treating” or “treatment” used herein includes prophylactic, metaphylactic and therapeutic treatment or curative treatment. Prophylactic or metaphylactic treatment of endoparasite infestations , also called “ deworming”, is commonly used to control helminth infestation so to control parasitic infections in animals so that they do not lead to subclinical or clinical conditions in the treated animals. In addition, helminths can infect humans and therefore pose a threat to human health as well.

[0132] Prophylactic treatments comprise treatments of animals that are in general at risk to acquire a parasite infestation, which are in general done at regular intervals such as 1-6 times per year, or 2-4 times per year or 1-4 per month.

[0133] Metaphylactic treatment comprise treatment of all animals of a group that are in contact with each other e.g. in the same area, when a number of animals is diagnosed with a helminth infection to prevent the spread of the parasite to the other animals.

[0134] In therapeutic or curative treatment, the compounds are administered individually to animals after diagnosis of a clinical or subclinical parasite infestation in such animal. In this method, there is reduced expenses for anthelmintics, possibility of selection for resistance is significantly reduced if only some animals are treated and this will ensure the presence of a susceptible parasite population within the herd or flock, but its disadvantage is that it requires regular monitoring which increases labor input.

[0135] The term “(parasitic) infection” includes conditions associated with or caused by one or more (parasitic) pathogens; said conditions include clinical conditions (parasitoses) and sub-clinical conditions.

[0136] The term “treatment of parasitic infection” thus includes both the treatment of parasitoses and the treatment of sub-clinical conditions. The treatment of a parasite infection generally implies the suppression of parasite (e.g., helminth) burden in the animal below that level at which economic loss occurs.

[0137] The term "parasitoses" relates to clinically manifest pathologic conditions and diseases associated with or caused by an infection by one or more parasites, such as, for example parasitic gastroenteritis or anemia in ruminants e.g., sheep and goats or colic in horses.

[0138] Sub-clinical conditions are typically conditions not directly leading to clinical symptoms in the parasite infected animal but leading to economic losses. Such economic losses can be e.g., by depression of growth in young animals, lower feed efficiency, lower weight gain in meat producing animals, lower milk production in ruminants, lower egg production in laying hens, or lower wool-production in sheep.

[0139] The phrase “prevention of parasitoses” means to inhibit the development of parasitoses of an animal.

[0140] In general, the control of parasitic infestation including parasitoses is achieved by administering an effective amount of a compound according to this invention.

[0141] In one embodiment an existing parasite infestation of the animal is treated or controlled. In another embodiment an existing parasite infestation of the animal is treated or controlled, and the animal is protected from a parasite infestation.

[0142] Another embodiment is a method of protecting animals that are at risk to be infested by parasites or developing a parasitosis comprising administering an effective amount of at least one compound of the invention and / or embodiments thereof to the animal using a single administration.

[0143] The term "parasitoses" relates to clinically manifest pathologic conditions and diseases associated with or caused by an infestation by one or more parasites directly, such as, for example, haemonchosis, ascaridiasis, oesophagostomiasis or dirofilariosis. It also includes pathologic conditions or diseases associated with caused by one or more vector-transmitted pathogens, such as heartworm disease from vector mosquitos. Another example is parasitic gastroenteritis or anemia in ruminants e.g., sheep and goats or colic in horses.

[0144] In one embodiment the invention provides a composition comprising an effective amount of a compound of the invention and / or embodiments thereof when used for the treatment and / or control of parasite infestations of animals wherein the composition is administered to an animal that has been diagnosed or is suspected to be infested by parasites. In one embodiment, the composition is administered to an animal that is at risk to be infested by parasites to protect it from such infestation.

[0145] The compounds according to this invention are useful in a medicament, especially a medicament for treating and controlling such parasitic infestations of animals. In such medicament or pharmaceutical composition or dosage form a concentration of a compound of the invention and / or embodiments thereof is present that is administered as an effective amount to an animal in need thereof.

[0146] An "effective amount," is the amount or quantity of a compound that is required to cause a measurable reduction in the parasite population infesting an animal, and / or to inhibit the development of parasite infestations of an animal, in whole or in part or at least to diminish the clinical or symptoms or the subclinical effects in the diseased animal.

[0147] This amount is readily determined by observation or detection of the parasite numbers both before and after contacting the animals with the compound. When the compound shows an effect via feeding / ingestion by the parasite, an effective amount generally constitutes an amount that results in blood concentrations generally toxic to the target parasite.

[0148] Alternatively, the Fecal egg count reduction tests (FECRTs) can be used to determine the parasite load of the animal, especially with gastrointestinal parasites. It can be further used to investigate effectiveness of the treatment using the compounds according to the invention. After deworming, a reduction in fecal egg count should be seen, at least by 10%, by 50% and preferably a 90%+ reduction.

[0149] The difference in numbers from such counts made before and after treatment indicates the efficacy of the dose applied e.g., the parasite count is reduced, after a first administration, by an amount ranging from 5% to about 100%.

[0150] So, although reductions at or close to 100 % are aimed for, however a reduction in parasite numbers of about 50 % may already constitute a significant reduction. This because even such a modest reduction already alleviates certain symptoms for affected animals, and / or may restore the animals to an improved economic production level.

[0151] In one embodiment, an effective amount of the active agent achieves at least about 80%, or at least about 90% efficacy against the target parasites. In a specific preferred embodiment, the efficacy is at least about 95%.

[0152] In a preferred embodiment, the reduction of infestation on an animal, or the control and / or reduction achieved, regards a reduction in the number of a particular type of parasite by at least 50, 60, 70, 75, 80, 85, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or even 100 %, in that order of preference.

[0153] In certain instances, including the prevention of Dirofilaria immitis, the term "effective amount" may provide efficacy as high as 100%. In one embodiment the efficacy against Dirofilaria immitis is 100%.

[0154] The present invention provides the compounds according to the invention or the veterinary composition according to the present invention for use as a medicament.

[0155] In a preferred embodiment the compounds according to the present invention or the veterinary composition according to the present invention are used to make a medicament for the treatment of helminth infection such as filariasis and in particular heartworm disease.

[0156] It has been shown by the inventors that the compounds of the current invention as disclosed and defined earlier are especially suitable for the treatment of parasitosis by helminth infection such as of haemonchosis, trichostrongylosis or oesophagostomiasis, particular in sheep or cattle, or ostertagiosis or cooperiosis, particular in cattle, or anchylostomiasis, particular on dogs, or toxocariasis, particular in dogs, and of filariasis, particular in dogs or cats and in particular heartworm disease, especially in dogs. The term “treatment” as used herein refers to reversing, alleviating, inhibiting the progress of a disease, disorder or condition. In case of the helminth infection such as filariasis and in particular heartworm disease, this means that the clinical symptoms (reduced function of lung, heart, liver and / or kidney) are alleviated.

[0157] Thus, the invention provides a method of treating a disease caused by helminths such as nematodes which comprises administering to an animal, in particular a sheep or a dog, a therapeutically effective amount of a compound according to the present invention or the composition according to the present invention. In otherwords, the invention provides a method of treating helminth infection such as filariasis and in particular heartworm disease comprising administering a therapeutically effective amount of a compound according to the invention or the composition according to the present invention to a mammal in need thereof.

[0158] In one embodiment, the animal that is treated is a sheep and the disease that is treated is caused helminth infection such as of haemonchosis, trichostrongylosis or oesophagostomiasis and in particular haemonchosis. In another embodiment, the animal is a sheep and the disease that is treated is trichostrongylosis. In another embodiment, the animal is a sheep and the disease that is treated is oesophagostomiasis.

[0159] In one embodiment, the animal that is treated is cattle and the disease that is treated is haemonchosis, trichostrongylosis, ostertagiosis, or cooperiosis and in particular ostertagiosis. In another embodiment, the animal is and the disease that is treated is trichostrongylosis. In another embodiment, the animal is cattle and the disease that is treated is haemonchosis. In another embodiment, the animal is cattle and the disease that is treated is cooperiosis.

[0160] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of haemonchosis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Haemonchus spp. and in particular Haemonchus place! and Haemonchus contortus.

[0161] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of toxocariasis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Toxocara spp. and in particular Toxocara canis.

[0162] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of anchylostomiasis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Ancylostoma spp. and in particular Ancylostoma caninum.

[0163] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of ascaridiasis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Ascaridia galli.

[0164] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of oesophagostomiasis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Oesophagostomum spp. and in particular Oesophagostomum venulosum, Oesophagostomum radiatum and Oesophagostomum dentatum.

[0165] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of trichostrongylosis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Trichostrongylus spp. and in particular Trichostrongylus axel and Trichostrongylus colubriformis.

[0166] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of ostertagiosis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Ostertagia spp. and in particular Ostertagia ostertagi.

[0167] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of cooperiosis. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Cooperia spp. and in particular Cooperia oncophora and Cooperia punctata.

[0168] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of helminthiasis caused by Nematodirus infection. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Nematodirus spp. and in particular Nematodirus helvetianus, Nematodirus spathiger.

[0169] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of helminthiasis caused by Teladorsagia infection. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases caused by helminths, wherein the helminths are Teladorsagia spp. and in particular Teladorsagia circumcincta and Teladorsagia trifurcata.

[0170] In other embodiments, the animal that is treated is a dog and the disease that is treated is filariasis and in particular heartworm disease.

[0171] In other embodiments, the animal that is treated is a dog and the disease that is treated is anchylostomiasis.

[0172] In other embodiments, the animal that is treated is a dog and the disease that is treated is toxocariasis.

[0173] More preferably, compounds according to the present invention or the veterinary composition according to present invention are administered to treat or prevent infection with helminths such as of haemonchosis, oesophagostomiasis, trichostrongylosis, particular in sheep or cattle, or ostertagiosis or cooperiosis, particular in cattle, or anchylostomiasis, particular on dogs, or toxocariasis, particular in dogs, or filariasis, particular in dogs or cats, in particular heartworm disease in dogs.

[0174] In a preferred embodiment the compounds according to this invention are used to control ortreat a helminth infection of an animal, such as an infection caused by one or more helminths selected from the group consisting of a) cestodes: e.g. Anaplocephala spp.; Dipylidium spp.; Diphyllobothrium spp.; Echinococcus spp.; Moniezia spp.; Taenia spp.; b) trematodes e.g. Dicrocoelium spp.; Fasciola spp.; Paramphistomum spp.; Schistosoma spp.; or c) nematodes, e.g. Acanthocheilonema spp.; Aelurostrongylus spp.; Ancylostoma spp.; Angiostrongylus spp.; Anecator spp.; Ascaridia spp.; Ascaris spp.; Brugia spp.; Bunostomum spp.; Capillaria spp.; Chabertia spp.; Cooperia spp.; Crenosoma spp.; Cyathostomum spp.; Cylicocyclus spp.; Cylicodontophorus spp.; Cylicostephanus spp.; Craterostomum spp.; Dictyocaulus spp.; Dipetalonema spp; Dirofilaria spp.; Dracunculus spp.; Enterobius spp.; Filaroides spp.; Habronema spp.; Haemonchus spp.; Heterakis spp.; Hyostrongylus spp.; Metastrongylus spp.; Meullerius spp. Necator spp.; Nematodirus spp.; Nippostrongylus spp.; Oesophagostomum spp.; Onchocerca spp.; Oncocercidae spp; Ostertagia spp.; Oxyuris spp.; Parascaris spp.; Spirocerca spp.; Stephanurus spp.; Strongylus spp.; Syngamus spp.; Toxocara spp.; Strongyloides spp.; Teladorsagia spp.; Toxascaris spp.; Trichinella spp.; Trichuris spp.; Trichostrongylus spp.; Triodontophorous spp.; Uncinaria spp., and / or Wuchereria spp.; preferably nematodes; in particular Dirofilaria spp.; Haemonchus spp.; Ascaridia spp; Strongylus spp; Cyathostomum spp.; Ostertagia spp.; Cooperia spp.; Trichostrongylus spp.; Nematodirus spp.; Teladorsagia spp.; Oesophagostomum spp.;

[0175] Ancylostoma spp.; Toxocara spp.; especially Dirofilaria sp. , especially Dirofilaria immitis.

[0176] Moreover, the present invention provides the compounds according to the present invention or the composition of the present invention for use in the treatment of disorders / diseases caused by the such parasites.

[0177] In another embodiment the compounds according to the invention or the veterinary composition according to the present invention are for use in the control or treatment of infection of animals caused by gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Uncinaria stenopcephala, Toxocara canis, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axel, Trichostrongylus colubriformis, Haemonchus place!, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi. Preferably, the compounds of the present invention or the veterinary composition according to the present invention are used for the manufacture of a medicament for the treatment of helminth infection such as filariasis and in particular heartworm disease, or infection caused by such gastrointestinal nematodes.

[0178] In another embodiment, embodiment the compounds according to the present invention or the veterinary composition according to the present invention are used to make a medicament for the treatment of infection caused by such gastrointestinal nematodes.

[0179] In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of helminth infection such as filariasis and in particular heartworm disease or a disease caused by such gastrointestinal nematodes.

[0180] Further, the invention provides the use of the compounds of the present invention or the veterinary composition according to the present invention for the manufacture of a medicament for the treatment of helminth infection such as filariasis and in particular heartworm disease, or infection caused by gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum dentatum, Haemonchus contortus. In a preferred embodiment of the invention or embodiments thereof, the compounds according to the present invention or the composition of the present invention are for use in the treatment of disorders / diseases of animals caused by helminths, wherein the helminths are Dirofilaria spp., Ascaridia spp., Oesophagostomum spp., Haemonchus spp., Ancylostoma spp., Toxocara spp., Angiostrongylus spp., Crenosoma spp., Spirocerca spp., Aelurostrongylus spp., Ostertagia spp., Cooperia spp., Trichostrongylus spp., Nematodirus spp., Teladorsagia spp., Chabertia spp., Parascaris spp., Oxyuris spp., Dictyocaulus spp., Aelurostrongylus spp., Crenosoma spp., Cyathostomum spp., more in particular Dirofilaria repens, Dirofilaria immitis, Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

[0181] In particular, the compounds according to the present invention or the veterinary composition according to present invention are administered to treat or prevent disorders / diseases of animals caused by one or more helminths selected from the group consisting of a) Cestodes such as Monezia expansa; b) Trematodes such as Fasciola hepatica, Fascioloides magna, Dicrocoelium dentriticum, Paramphistomum cervi; and c) nematodes: Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axel, Haemonchus placei, Haemonchus contortus, Nematodirus helvetianus, Nematodirus spathiger, Trichostrongylus colubriformis, Trichostrongylus circumcincta, Oesophagostomum venulosum, Chabertia ovina, Teladorsagia circumcincta, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Dictyocaulus viviparus, Dictyocaulus filaria, Dirofilaria immitis, Dirofilaria repens.

[0182] The invention is also directed to a method for treating an animal with infection by a nematode comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of Ascaridia spp., Oesophagostomum spp., Haemonchus spp., Dirofilaria spp., Ancylostoma spp., Toxocara spp., Angiostrongylus spp., Crenosoma spp., Spirocerca spp., Aelurostrongylus spp., Ostertagia spp., Cooperia spp., Trichostrongylus spp., Nematodirus spp., Teladorsagia spp., Chabertia spp., Parascaris spp., Oxyuris spp., Dictyocaulus spp., Aelurostrongylus spp., Crenosoma spp., Cyathostomum spp., in particular Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Dirofilaria repens, Dirofilaria immitis, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axel, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

[0183] The invention is also directed to a method for treating a mammal, preferably a bovine, a sheep, an equine, a cat or a dog, suffering from a disease caused by a helminth, in particular a nematode, comprising administering to the subject in need thereof an effective amount of a compound according the present invention or the composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group Ascaridia spp., Oesophagostomum spp., Haemonchus spp., Dirofilaria spp., Ancylostoma spp., Toxocara spp., Angiostrongylus spp., Crenosoma spp., Spirocerca spp., Aelurostrongylus spp., Ostertagia spp., Cooperia spp., Trichostrongylus spp., Nematodirus spp., Teladorsagia spp., Chabertia spp., Parascaris spp., Oxyuris spp., Dictyocaulus spp., Aelurostrongylus spp., Crenosoma spp., Cyathostomum spp., in particular Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Dirofilaria repens, Dirofilaria immitis, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placet, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

[0184] According to the method of treatment by the compounds of the present invention and / or embodiments thereof, diseases caused by helminths, in particular nematodes, especially wherein the nematode is at least one selected from the group Ascaridia, Oesophagostomum, Haemonchus, Dirofilaria, Ancylostoma, Toxocara, Angiostrongylus, Crenosoma, Spirocerca, Aelurostrongylus, Ostertagia, Cooperia, Trichostrongylus, Nematodirus, Teladorsagia, Chabertia, Parascaris, Oxyuris, Dictyocaulus, Aelurostrongylus, Crenosoma, Cyathostomum, are treated or prevented in a mammal, in particular a dog, by administering to the animal an effective amount of a compound of the invention in such amounts and for such time as is necessary to achieve the desired result.

[0185] In one embodiment the parasitic nematode is a gastrointestinal nematode and the animal treated is selected from the group consisting of dogs, cats, ruminants such as cattle and small ruminants (sheep and goat), horses, pigs, and poultry.

[0186] A preferred use of the compounds according to the present invention or the composition according to the present invention is in cattle. The compounds according to the present invention or the composition according to the present invention can be used in animals of different weight, including animals of a weight higher than 50 kg, such as 50-1200 kg. In one embodiment the cattle animal is beef cattle. In an alternative embodiment the animal is dairy cattle. The dairy cattle animal preferably is in lactation.

[0187] The invention is also directed to a method to control a nematode infestation of cattle comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of:

[0188] Lungworms, such as adult Dictyocaulus viviparus; Stomach worms, (4th stage inhibited larvae): such as adult +L4 (Ostertagia ostertagi) (Type II Ostertagiasis), Adult and fourth stage larvae (Haemonchus contortus & H. placet), Adult and fourth stage larvae (Trichostrongylus axei); Intestinal worms (Adult and fourth stage larvae), such as Bunostomum phlebotomum, (Nematodirus helvetianus, (Cooperia punctata & C. oncophora, Trichostrongylus colubriformis and Oesophagostomum radiatum).

[0189] In one embodiment in such method the nematodes are selected from: Gastrointestinal Roundworms (Adult, L4 and Inhibited L4): Ostertagia ostertagi; Gastrointestinal Roundworms (Adult and L4) Ostertagia lyrate, Cooperia oncophora, C. pectinate, C. punctata, Haemonchus placei, Trichostrongylus axei, T. colubriformis, Bunostomum phlebotomum, Oesophagostomum radiatum; Gastrointestinal Roundworms (Adult) Strongyloides papillosus, Nematodirus helvetianus, Nematodirus spathige, Trichuris spp.; Lungworms (Adult and L4) Dictyocaulus viviparus; Eye Worms (Adult) Thelazia spp. A preferred use of the compounds according to the present invention or the composition according to the present invention is in small ruminants, such as sheep or goats. The compounds according to the present invention or the composition according to the present invention can be used in animals of different weight, including animals of a weight higher than 45 kg, such as 50-100 kg.

[0190] The invention is also directed to a method to control a nematode infestation of small ruminants comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of:

[0191] Gastro-intestinal nematodes: Haemonchus contortus (adults L4 and L3), Ostertagia (Teladorsagia) circumcincta (adults L4 and L3, including inhibited larvae), Trichostrongylus axei (adults), Trichostrongylus colubriformis (adults and L3), Nematodirus spathiger (adults), Cooperia curticei (macmasteri) (adults), Cooperia punctata (adults), Oesophagostomum columbianum (L3) Chabertia ovina (adults); Respiratory tract nematodes: Dictyocaulus filaria, Dictyocaulus viviparus and Protostrongylus rufescens (adults).

[0192] Sheep: For the treatment of sheep infected with one or more of Ostertagia spp., Haemonchus spp., Trichostrongylus spp., Nematodirus spp., Cooperia spp., Oesophagostomum spp., Chabertia spp., Bunostomum spp., Strongyloides spp., Dictyocaulus filaria parasites.

[0193] A preferred use of the compounds according to the present invention or the composition according to the present invention is in horses. The compounds according to the present invention or the composition according to the present invention can be used in animals of different weight, including animals of a weight higher than 100 kg, such as 100-1000 kg.

[0194] The invention is also directed to a method to control a nematode infestation of horses comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of:

[0195] Large strongyles: Strongylus vulgaris (adults and arterial larval stages), Strongylus edentatus (adults and tissue larval stages), Strongylus equinus (adults), Triodontophorus spp. (adults), Triodontophorus brevicauda, Triodontophorus serratus, Craterostomum acuticaudatum (adults); Adult and immature (intraluminal fourth-stage larvae) of small strongyles or cyathostomes: Coronocyclus spp., Coronocyclus coronatus, Coronocyclus labiatus, Coronocyclus labratus, Cyathostomum spp., Cyathostomum catinatum, Cyathostomum pateratum, Cylicocyclus spp., Cylicocyclus ashworthi, Cylicocyclus elongatus, Cylicocyclus insigne, Cylicocyclus leptostomum, Cylicocyclus nassatus, Cylicodontophorus spp., Cylicodontophorus bicornatus, Cylicostephanus spp., Cylicostephanus calicatus, Cylicostephanus gold!, Cylicostephanus longibursatus, Cylicostephanus minutus, Parapoteriostomum spp., Parapoteriostomum mettami, Petrovinema spp., Petrovinema poculatum, Poteriostomum spp.; Adult hairworms: Trichostrongylus axei; Adult and immature (fourth stage larvae) pinworms: Oxyuris equi; Adult, third- and fourth-stage larvae of roundworms (ascarids): Parascaris equorum; Microfilariae of neck threadworms: Onchocerca spp.; Adult intestinal threadworms: Strongyloides wester!; Adult large-mouth stomach worms: Habronema muscae; Oral and gastric stages of bots: Gasterophilus spp.; Adult and immature (inhibited fourth stage larvae) lungworms: Dictyocaulus arnfieldi.

[0196] The invention is also directed to a method to control a nematode infestation of poultry comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of: Heterakis gallinarum (adult stages), Ascaridia gall! (adult stages) or Capillaria spp. C. obsignata (adult stages).

[0197] The invention is also directed to a method to control a nematode infestation of pigs comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of: Gastrointestinal Roundworms (Adult and L4) Ascaris suum, Hyostrongylus rubidus, Oesophagostomum spp. Trichuris suis : Gastrointestinal Roundworms (Adult and somatic larval stages) Strongyloides ransom! Lungworms (Adult) Metastrongylus spp.

[0198] Another preferred use of the compounds according to the present invention or the composition according to the present invention is in pets such as cats and dogs, particularly in dogs. The compounds according to the present invention or the composition according to the present invention can be used in animals of different weight.

[0199] The invention is also directed to a method to control a nematode infestation of dogs comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of: Ascarids: Toxocara canis, Toxascaris leonina (adult and late immature forms); Hookworms: Uncinaria stenocephala, Ancylostoma caninum, Angiostrongylus vasorum (adults);Whipworms: Trichuris vulpis (adults) Crenosoma vulpis, Thelazia callipaeda.

[0200] Puppies and kittens: For the treatment of weaned puppies and kittens infected with gastro-intestinal nematodes and puppies infected with protozoa (Giardia spp). Pregnant dogs: For the treatment of pregnant dogs to reduce prenatal infections with Toxocara canis and the transfer of T. canis and Ancylostoma caninum to their pups via the milk.

[0201] Also for the treatment of dogs infected with lungworm Oslerus (Filaroides) osleri or protozoa Giardia spp. and cats infected with lungworm Aelurostrongylus abstrusus.

[0202] Other exemplary animals that can be treated with the compounds according to the present invention or the composition according to the present invention are smaller pets such as cats.

[0203] The invention is also directed to a method to control a nematode infestation of cats comprising administering to the subject in need thereof an effective amount of a compound according to the present invention or a composition according to the present invention and / or embodiments thereof, wherein the nematode is at least one selected from the group of: gastrointestinal nematodes (L3, L4 larvae and adults of Toxocara cati, L4 larvae and adults of Ancylostoma tubaeforme and Ancylostoma ceylanicum, and adult forms of Toxascaris leonina and Ancylostoma braziliense); pulmonary nematodes feline lungworms (L4 larvae and adults of Troglostongylus brevior, L3, L4 larvae and adults of Aelurostrongylus abstrusus) Prevention of aelurostrongylosis (by reduction of the level of infection with L3, L4 larvae of Aelurostrongylus abstrusus); vesical worms (Capillaria plica).

[0204] Puppies and kittens: For the treatment of weaned puppies and kittens infected with gastro-intestinal nematodes and puppies infected with protozoa (Giardia spp). Pregnant dogs: For the treatment of pregnant dogs to reduce prenatal infections with Toxocara canis and the transfer of T.canis and Ancylostoma caninum to their pups via the milk.

[0205] In one embodiment the compounds according to the present invention or the composition according to the present invention are used to prevent diseases of dogs or cats such as severe lung disease, heart failure and damage to other inner organs caused by Dirofilaria spp., more especially Dirofilaria immitis.

[0206] In some embodiment, the parasitic nematode belongs to Dirofilaria spp. and the animal treated is selected from cats and dogs.

[0207] Particularly, the compound is especially suitable for use in the prevention of heartworm disease in mammals. The heartworm disease is prevented when Dirofilaria larvae present in a host mammal are not allowed to develop into adult worms. Mammals include dog, cats, wolves, coyotes, jackals, foxes, ferrets, bears, seals, sea lions, particularly, dogs and cats, more particularly in dogs.

[0208] The frequency of the administration for the prevention of dirofilariasis in dogs or cats will be dependent upon several factors and can be a single dose administered, or depending on the protection period once a week, once a month, once every two, three, four, or six months, or nine months, or once every year. In some embodiments, the frequency of administration may be, for example, weekly, bi-weekly, monthly, bimonthly, every 3 month, every 4 month, every 5 month, every 6 month, every 9 months or every 12 month or the equivalent administration frequency expressed in days or weeks that approximate such frequency. Administration of the compound of the current invention is contemplated to be once a month. However, an extended duration formulation may allow for dosing once every 2, 3, 4, 5, or 6 months.

[0209] In one embodiment, the compounds of the invention provide an efficacy against the parasites, especially Dirofilaria spp. of about 100% for about 1 month or longer.

[0210] In other embodiments, the compounds of the invention have an efficacy of about 100% against the parasites, of about 3 months or longer, about 8 months or longer or about 9 months or longer.

[0211] In other embodiments, the compounds of the invention have an efficacy of at least about 90% against the parasites of about 10 months or longer, about 11 months or longer or even about 12 months or longer. Therefore, one embodiment of the invention is a method wherein the compound is administered every month.

[0212] Therefore, in another embodiment of the invention the compound is administered every 6 weeks.

[0213] Therefore, in another embodiment of the invention the compound is administered every 2 months.

[0214] Therefore, in another embodiment of the invention the compound is administered every 10 weeks.

[0215] Therefore, in another embodiment of the invention the compound is administered every 3 months.

[0216] Therefore, in another embodiment of the invention the compound is administered every 6 months.

[0217] Therefore, in another embodiment of the invention the compound is administered at least every 9 months.

[0218] Particularly, the compound is especially suitable for use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection.

[0219] In one embodiment the compound is for prevention of heartworm disease of dogs or cats caused by Dirofilaria immitis. The compound according to the invention t may be safely administered to animals infected with adult heartworms, however, it is recommended, in accordance with good veterinary practice, that all animals 6 months of age or more living in countries where a vector exists should be tested for existing adult heartworm infections before beginning medication with the compound .

[0220] The present invention further provides the use of the compound according to the invention for the manufacture of a medicament for the prevention of heartworm disease in animals.

[0221] Examples of contemplated combination therapies

[0222] In one embodiment of the invention or embodiments thereof the veterinary compositions of the present invention and / or embodiments thereof comprise an effective amount of a compound of the present invention and / or embodiments thereof as the single active ingredients.

[0223] In another embodiment of the invention or embodiments thereof the veterinary compositions of the present invention and / or embodiments thereof comprise an effective amount of a compound of the present invention and / or embodiments thereof in combination with one or more other (known) active ingredients.

[0224] The compound of the present invention may be administered in a pharmaceutical composition as sole active ingredient, or in combination with at least one other additional antiparasitic agent to form a parasiticide giving an even broader spectrum of veterinary utility. Thus, the present invention also envisions a combination veterinary pharmaceutical composition comprising an effective amount of the compound of the present invention in combination with at least one other additional antiparasitic agent and can further comprise at least one veterinary acceptable excipient.

[0225] These one or more other active ingredient(s) may be of a similar anthelmintic or antiparasitic spectrum as the compounds of the present invention to synergistically enhance treatment of the infections covered by the spectrum of the present compound.

[0226] Alternatively, these one or more other known active ingredient(s) are of a different antiparasitic spectrum as the compounds of the present invention, when infestation with multiple parasitic species are suspected in which another active ingredient of a different spectrum may be required in addition to a compound of the present invention.

[0227] The treatment can involve administering a composition having a compound of the present invention and one or more further known active ingredient(s) or administration of the inventive compounds followed by or preceded by administration of one or more additional active ingredient(s).

[0228] Consequently, the methods and pharmaceutical compositions of this invention encompass methods wherein a compound according to this invention is the sole active ingredient administered to the recipient animal. However, that the methods and compositions also encompass wherein a compound is administered in combination with one or more other pharmaceutically acceptable active ingredients. The other active ingredient(s) may target the same and / or different parasites and conditions.

[0229] Contemplated active ingredient(s) that may be administered in combination with the compounds of the invention include, for example, pharmaceutically acceptable anthelmintics, insecticides and acaricides, insect growth regulators, anti-protozoals.

[0230] In one embodiment of the description, arylpyrazole compounds such as phenylpyrazoles may be included in the veterinary compositions of the description. Arylpyrazoles are known in the art and may be suitable for combination with the compound of Formula (I) in the compositions of the description. Examples of such arylpyrazole compounds include but are not limited to those described in U.S. Pat. Nos. 6,001 ,384; 6,010,710; 6,083,519; 6,096,329; 6,174, 540; 6,685,954, 6,998,131 and 7,759,381 (all of which are incorporated herein by reference). A particularly preferred arylpyrazole active agent is fipronil.

[0231] In another embodiment, the compositions of the description may advantageously include one or more isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against a variety of ectoparasites and combination with the compound of Formula (I) would expand the scope of efficacy against these parasites.

[0232] Particularly useful isoxazoline active agents that can be combined with the compound include afoxolaner (including substantially pure active enantiomer), sarolaner, fluralaner (including substantially pure active enantiomer) and lotilaner. Preferably, with fluralaner. Another combination partner is 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1 ,1 ,2,2,2- pentafluoroethyl)-4-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436). This compound is known as tigolaner.

[0233] In another embodiment, the compositions of the description may advantageously include one or more SLO- 1 modulator compounds known in the art. SLO-1 modulator active agents are highly effective against a variety of parasites and combination with the compound of Formula (I) would expand the scope of efficacy against these parasites. Particularly useful SLO-1 modulator active agents that can be combined with the compound include compounds disclosed in WO2017 / 178416, WO2018 / 087036, WO2018 / 197401 , WO2019 / 002132, WO2019 / 025341 , WO2019 / 115768, WO2019 / 215182, W02020 / 14068,

[0234] WO2020 / 131629, W02020 / 131631 , W02020 / 083971 , WO2021 / 018839, WO2021 / 204930,

[0235] WO2023 / 036821 , WO2023 / 036821 , W02020 / 191091 , WO2021 / 242581 , WO2023 / 073641 , WO2020 / 247747, WO2022 / 106469 and WO 2022 / 117783 all of which are incorporated herein by reference in their entirety.

[0236] The additional active compounds are preferably pharmaceutically acceptable insecticides or acaricides. Such pharmaceutically acceptable insecticides and acaricides include, for example, acetamiprid, acetoprole, amitraz, amidoflumet, avermectin, azadirachtin, bifenthrin, bifenazate, buprofezin, bistrifluron, chlorfenapyr, chlorfluazuron, chlorantraniliprole, chlorpyrifos, chromafenozide, clothianidin, cyantraniliprole, cyflumetofen, p-cyfluthrin, cyhalothrin, A-cyhalothrin, cymiazole cypermethrin, cyromazine, deltamethrin, demiditraz, diafenthiuron, diazinon, diflubenzuron, dimefluthrin, dinotefuran, emamectin, esfenvalerate, ethiprole, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, tau-fluvalinate, flufenoxuron, halofenozide, hexaflumuron, imidacloprid, indoxacarb, lufenuron, metaflumizone, methoprene, metofluthrin, methoxyfenozide, nitenpyram, novaluron, noviflumuron, permethrin, phosmet, profluthrin, protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, tolfenpyrad, tralomethrin, isoxazolines as described above and triflumuron. General references discussing antiparasitic agents, such as insecticides and acaricides, include, for example, The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K. (2003).

[0237] The compounds as described herein can be combined with anthelmintic compounds, more preferably selected from the group consisting of SLO- 1 modulating depsipeptide compounds such as emodepside and SLO-1 modulators as described above, avermectins (e.g., ivermectin, selamectin, doramectin, abamectin, and eprinomectin); milbemycins (moxidectin and milbemycin oxime); pro-benzimidazoles (e.g., febantel, netobimin, and thiophanate); benzimidazole derivatives, such as triclabendazole or a thiazole benzimidazole derivative (e.g., thiabendazole and cambendazole) or a carbamate benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide), mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole); an imidazothiazoles (e.g., levamisole and tetramisole); a tetrahydropyrimidine (morantel and pyrantel), organophosphates (e.g., trichlorphon, haloxon, dichlorvos, and naphthalophos); salicylanilides (e.g., closantel, oxyclozanide, rafoxanide, and niclosamide); nitrophenolic compounds (e.g., nitroxynil and nitroscanate); benzenedisulphonamides (e.g., clorsulon); pyrazineisoquinolines (e.g., praziquantel and epsiprantel); heterocyclic compounds (e.g., piperazine, diethylcarbamazine, dichlorophen, and phenothiazine); arsenicals (e.g., thiacetarsamide, melorsamine, and arsenamide); cyclooctadepsipeptides (e.g., emodepside); paraherquamides ( e.g. derquantel); and amino-acetonitrile compounds (e.g. monepantel, AAD 1566); tribendimidine (amidine compound); amidine compounds (e.g., amidantel and tribendimidin), including all pharmaceutically acceptable forms, such as salts, solvates or N- oxides.

[0238] Preferred combinations are comprising a) one compound selected from the group of compounds according to Formula (I) as defined elsewhere in the description, (or enantiomers, salts, solvates, N-oxides or prodrugs thereof) and b) one compound selected from the group consisting of anthelmintic avermectins (e.g., ivermectin, selamectin, doramectin, abamectin, emamectin and eprinomectin); milbemycins (moxidectin and milbemycin oxime); pro-benzimidazoles (e.g., febantel, netobimin, and thiophanate); benzimidazole derivatives, such as thiazole benzimidazole derivatives (e.g., thiabendazole and cambendazole), carbamate benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide), mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole, and triclabendazole); imidazothiazoles (e.g., levamisole and tetramisole); tetrahydropyrimidines (morantel and pyrantel), organophosphates (e.g., trichlorphon, haloxon, dichlorvos, and naphthalophos); salicylanilides (e.g., closantel, oxyclozanide, rafoxanide, and niclosamide); nitrophenolic compounds (e.g., nitroxynil and nitroscanate); benzenedisulphonamides (e.g., clorsulon); pyrazineisoquinolines (e.g., praziquantel and epsiprantel); heterocyclic compounds (e.g., piperazine, diethylcarbamazine, dichlorophen, and phenothiazine); arsenicals (e.g., thiacetarsamide, melorsamine, and arsenamide); cyclooctadepsipeptides (e.g., emodepside); paraherquamides (e.g. derquantel); amino-acetonitrile compounds (e.g. monepantel, AAD 1566); tribendimidine (amidine compound); and amidantel (amidine compound); including all pharmaceutically acceptable forms, such as salts.

[0239] Preferred combinations comprise at least one compound selected from the group of compounds according to Formula (I) as defined elsewhere in the description, and

[0240] • fluralaner, afoxolaner, sarolaner, lotilaner, tigolaner; and / or

[0241] • closantel, oxyclozanide, rafoxanide, niclosamide; and / or

[0242] • nitroxynil, nitroscanate, clorsulon; and / or

[0243] • praziquantel, epsiprantel; and / or

[0244] • emodepside, derquantel, monepantel.

[0245] In an embodiment, the compounds as described herein can be combined with anti-parasitic cyclopropyl amide compounds disclosed in WO2022 / 161972, WO2022 / 162001 , WO2022 / 162016, all of which are incorporated herein by reference in their entirety. The compounds as described herein can be combined with pharmaceutically acceptable insect growth regulators. Such pharmaceutically acceptable insect growth regulators include, for example, methoprene, pyriproxyfen, tetrahydroazadirachtin, chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, ifenuron, tebufenozide, and triflumuron. These compounds tend to provide both initial and sustained treatment of parasite infestations at all stages of insect development, including eggs, on the animal subject, as well as within the environment of the animal subject.

[0246] The compounds as described herein can be combined with pharmaceutically acceptable anti-protozoals. Such pharmaceutically acceptable anti-protozoals include, for example, triazintriones like toltrazuril and ponazuril and triazindiones such as clazuril, diclazuril and letrazuril.

[0247] In some contemplated embodiments, the compounds are administered with pyridylmethylamine derivatives, such as, for example, pyridylmethylamine derivatives discussed in European Patent Appl. EP0539588 or Int'l Patent Appl. Publ. W02007 / 115643.

[0248] In some contemplated embodiments, the compounds are administered with nodulisporic acids and derivatives thereof, such as, for example, compounds discussed in US Patent 5,399,582; 5,945,317; 5,962,499; 5,834,260; 6,221 ,894; or 5,595,991 ; or WO 1996 / 29073.

[0249] In some contemplated embodiments, the compounds are administered with dihydroazole compounds, such as, for example, compounds discussed in WO 2010 / 75591.

[0250] Other antiparasitic compounds contemplated to be useful in combination therapies with the compounds include, for example, imidazo[1 ,2-b] pyridazine compounds discussed in US Patent Appl. Publ. No. 2005-

[0251] 0182059; 1-(4-Mono and di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compounds discussed US Patent 7,361 ,689; trifluoromethanesulfonanilide oxime ether compounds discussed in US Patent 7,312,248; n-[(phenyloxy)phenyl]-1 ,1 ,1 -trifluoromethanesulfonamide and n-

[0252] [(phenylsulfanyl)phenyl]-1 ,1 ,1 -trifluoromethanesulfonamide compounds discussed in US Patent Appl. Publ.

[0253] 2006-0281695; and 2-phenyl-3-(1 H-pyrrol-2-yl)acrylonitrile compounds discussed in US Appl. Publ. 2006 / 0128779; isoxazoline compounds discussed in WO Patent Appl, Publ. 2005-085216, WO

[0254] 2007 / 026965, WO 2007 / 070606, WO 2007 / 075459, WO 2007 / 079162, WO 2007 / 105814, WO

[0255] 2007 / 125984, WO 2008 / 019760, WO 2008 / 122375, WO 2008 / 150393, WO 2009 / 002809, WO

[0256] 2009 / 003075, WO 2009 / 022746, WO 2009 / 035004, WO 2009 / 045999, WO 2009 / 051956, WO

[0257] 2009 / 035004.

[0258] Alternatively, the other additional active ingredient is not an antiparasitic agent.

[0259] Contemplated non antiparasitic active ingredient(s) that may be administered in combination with the compounds of the invention include, for example, anti-inflammatories, anti-infectives, hormones, and immunobiologicals (e.g., vaccines and antisera) for disease prevention. In the contemplated combination therapies, the compounds according to this invention may be administered before, simultaneously, and / or after the other active ingredient(s). In addition, the compounds according to this invention may be administered in the same composition as the other active ingredient(s) and / or in separate compositions from the other active ingredient(s). Further, the compounds according to this invention and other active ingredient(s) may be administered via the same and / or different dosage route.

[0260] When the compounds according to this invention are administered in a combination therapy, the weight ratio of the active ingredients may vary widely. Factors influencing this ratio include, for example, the particular compounds; the identity of the other active ingredient(s) be administered in the combination therapy; the dosage route of the compounds and other active ingredient(s); the target condition and pathogen; the type (e.g., species and breed), age, size, sex, diet, activity, and condition of the animal; and pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the compounds and other active ingredient(s). In some contemplated embodiments, for example, the weight ratio of the compounds to the other active ingredient(s) is, for example, is from about 1 :3000 to about 3000:1. In some such instances, the weight ratio is from about 1 :300 to about 300:1. In other such instances, the weight ratio is from about 1 :30 and about 30:1 .

[0261] This invention also is directed to kits that are, for example, suitable for use in performing the methods of treatment described above. The kit comprises an effective amount of one or more compounds of this invention, and an additional component. The additional component(s) may be, for example, one or more of the following: another ingredient (e.g., an excipient or active ingredient), an apparatus for combining the compound of this invention with another ingredient and / or for administering the compound of this invention, or a diagnostic tool.

[0262] This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants’ invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only.

[0263] This invention, therefore, is not limited to the preferred embodiments described in this specification and may be variously modified. In addition, for conciseness purposes and readability only some combinations of embodiments are explicitly described, however it should be understood that other combinations of embodiments are also contemplated.

[0264] The invention will now be further described by the following, non-limiting examples.

[0265] Examples

[0266] Chromatographic system: Column: Xbridge BEH C18 Waters, 2.1x50 mm, 2.5p

[0267] Oven: 40 °C

[0268] Eluents: Solvent A: water / HCO2H (0.05%); Solvent B: acetonitrile I HCO2H (0.05%)

[0269] Flow: 0.8 ml I min Gradient:

[0270] Run time: 2.2 min + 0.5 min equilibration time

[0271] Example 1 - N-(8-(2,3-dichlorophenyl)-7-fluoro-4-isopropylquinolin-3-yl)quinoline-4- carboxamide (compound 2)

[0272] 1 . 8- Ethyl 8-bromo-7-fluoro-4-isopropylquinoline-3-carboxylate To a solution of ethyl 4,8-dibromo-7-fluoroquinoline-3-carboxylate (described in WO2019 / 215182; 23.7 g,

[0273] 62.9 mmol) in THF (700 mL) at -70°C lithium bromide (16.4 g, 5.4 mL, 189 mmol) was added in one portion under argon and the mixture was stirred for 5 min. at -70°C. The mixture was allowed to reach 16°C over 60 min. and cooled to -65°C. Copper(l) iodide (35.92 g, 189 mmol) was added in several portions over 10 min. and the mixture was stirred for additional 5 min. at -60°C and then allowed to reach 15°C over 30 min. The mixture was cooled again to -70°C, isopropyl magnesium chloride (16 g, 80 mL, 2.0 M, 0.16 mol) was added dropwise over 15 min. at -70°C. The mixture was allowed to reach 0°C, quenched with 850 ml water and stirred for 15 min. The mixture was concentrated (500 ml THF were removed) under reduced pressure. The resulting slurry was filtered over a plug of celite and the filtrate was extracted with 500ml ethyl acetate. The aqueous phase was extracted with 100ml ethyl acetate, the organic phases were combined, dried over Na2SO4, filtered and evaporated under reduced pressure to yield the title compound as a solid. MS (ESI) 342.0 [M+H]+.

[0274] 2. 8-Bromo-7-fluoro-4-isopropylquinoline-3-carboxylic acid

[0275] To ethyl 8-bromo-7-fluoro-4-isopropylquinoline-3-carboxylate (20.9 g, 61.4 mmol) in 1 ,4-dioxane (120 mL) was added lithium hydroxide (2.94 g, 123 mmol) and water (60 mL), the mixture was heated to 95°C (bath temperature), and stirred for 20 min. The mixture was cooled to 14-16°C, hydrochloric acid (4M, 5.38 g,

[0276] 36.9 mL, 147 mmol) was added and the mixture stirred for another 15 min at ambient temperature. Then 100ml ethyl acetate was added, stirring was continued for 15 min and then the phases were separated, the aqueous phase was extracted with 50 ml ethyl acetate, the combined org. phases were dried with Na2SC>4, filtered and concentrated under reduced pressure to yield the title compound as a solid. MS (ESI) 313.9 [M+H]+.

[0277] 3. 8-Bromo-7-fluoro-4-isopropylquinoline-3-carboxamide

[0278] To a mixture of 8-bromo-7-fluoro-4-isopropylquinoline-3-carboxylic acid (16.94 g, 54.26 mmol) in DCM (100 mL) was added a drop of DMF and then carefully dropwise oxalyl chloride (7.57 g, 5.2 mL, 59.7 mmol). The mixture was stirred at ambient temperature and concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), triethylamine (10.98 g, 15.1 mL, 108 mmol) was added under stirring and then at 14-16°C a solution of ammonia in 1 ,4-dioxane (0.5M, 325.5 mL, 162.8 mmol) was added over 15 min and the mixture stirred at ambient temperature for 1 h. The mixture was quenched with 100 ml water, 150 ml ethyl acetate was added, the mixture was filtered and the phases separated. The aqueous phase was acidified with 1 N HCI, extracted again with 100 ml ethyl acetate, the combined organic phases were dried with Na2SO4, filtered and evaporated under reduced pressure to yield the title compound as a solid. MS (ESI) 310.9 [M+H]+.

[0279] 4. 8-Bromo-7-fluoro-4-isopropylquinolin-3-amine 8-Bromo-7-fluoro-4-isopropylquinoline-3-carboxamide (15.32 g, 49.24 mmol) was combined with water (150 mL) and acetonitrile (75 mL). NaOH (3.94 g, 98.5 mmol) was added followed after 5 min by sodium hypochlorite (11 % aq. solution, 33.32 g, 27.63 mL, 49.24 mmol). After stirring at ambient temperature for 20 min, additional sodium hypochlorite (4.8 g, 4.0 mL, 7.1 mmol) was added. After stirring for 5 minutes the temperature was raised to 66°C (internal), and stirring was continued for 45 min. Heating was stopped and stirring continued overnight at ambient temperature. The mixture was diluted with 100 ml ethyl acetate, neutralized with 1 N HCI, the phases were separated, the aqueous phase was extracted with 100ml ethyl acetate, the combined organic phases dried with Na2SC>4, filtered and evaporated under reduced pressure to yield the title compound as a solid. MS (ESI) 282.9 [M+H]+.

[0280] 5. N-(8-Bromo-7-fluoro-4-isopropylquinolin-3-yl)quinoline-4-carboxamide 8-Bromo-7-fluoro-4-isopropylquinolin-3-amine (570 mg, 2.01 mmol) was combined with DCM (50 mL) and pyridine (637 mg, 651 pL, 8.05 mmol) was added. At 0°C quinoline-4-carbonyl chloride (771 mg, 4.03 mmol) was added portionwise and the mixture was stirred at ambient temperature. After 4.5 hrs additional pyridine (159 mg, 163 pL, 2.01 mmol) and quinoline-4-carbonyl chloride (193 mg, 1.01 mmol) were added and stirring was continued for 2 hrs. Water (10 ml) was added and the mixture was extracted with DCM (2x10 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography (silica, elution with a gradient of dichloromethane and ethyl acetate / acetonitrile 1 :1 , followed by isocratic elution with ethyl acetate I methanol 1 :1 basified with ammonia) to yield the title compound as a solid. MS (ESI) 437.9 [M+H]+.

[0281] 6. N-(8-(2,3-Dichlorophenyl)-7-fluoro-4-isopropylquinolin-3-yl)quinoline-4-carboxamide

[0282] A 25 mL flask was charged with N-(8-bromo-7-fluoro-4-isopropylquinolin-3-yl)quinoline-4-carboxamide (120 mg, 0.27 mmol), (2,3-dichlorophenyl)boronic acid (73 mg, 0.38 mmol) and potassium carbonate (114 mg, 0.82 mmol). The flask was purged with argon, tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 13.7 pmol) was added under argon. A mixture of 1 ,4-dioxane (3.2 mL) and water (0.8 mL) was added and the reaction mixture was stirred at 100 °C. After 105 min additional (2,3-dichlorophenyl)boronic acid (36.6 mg, 0.19 mmol), potassium carbonate (57 mg, 0.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.5 mg, 8.2 pmol) were added and stirring was continued at 100°C for 90 min. The mixture was cooled to ambient temperature, diluted with water (15 ml) and extracted with dichloromethane (2x20 ml). The combined organic extracts were dried (Mg2SC>4), filtered and the solvent was evaporated under reduced pressure.

[0283] The residue was purified by column chromatography (silica, gradient of dichloromethane I ethyl acetate from 100:1 to 80:20) to yield the title compound as a solid. MS (ESI) 503.9 [M+H]+.

[0284] Similar procedures as described above were used to prepare exemplary compounds of Formula (C) listed in Table 1 .

[0285] Formula (C)

[0286] Table 1. Prepared compounds

[0287] Rt: retention time on chromatographic system (HPLC-MS); mass signal: m / z on HPLC-MS; MW: molecular weight

[0288] Example 2 - In vitro studies

[0289] In vitro assay: Ascaridia galli and Oesophagostomum dentatum

[0290] Ascaridia galli (intestinal roundworm of chicken), larval stage 3 ("L3"); and Oesophagostomum dentatum (nodular worm of swine), larval stages 3 and 4 (respectively "L3" and "L4") were suspended in a nutrient medium and distributed to 96 well plates with 20 larvae per well. The wells were spiked with DMSO solutions of the compounds with declining concentration. The anthelmintic effects were determined by microscopic examination and defined by the minimum effective concentration ("MEC"), which is the concentration by which at least one of the larvae shows mortality, a change in motility or a change in progression of development.

[0291] The following compounds showed an MEC of 10 pM or less against Ascaridia galli L3: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an MEC of 1 pM or less against Ascaridia galli L3: 1 , 2, 3, 4, 5, 10.

[0292] The following compounds showed an MEC of 10 pM or less against Oesophagostomum dentatum L3: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an MEC of 1 pM or less against Oesophagostomum dentatum L3: 1 , 2, 3, 4, 5, 8, 9, 11 , 12, 13. The following compounds showed an MEC of 0.1 pM or less against Oesophagostomum dentatum L3: 2, 4, 5.

[0293] The following compounds showed an MEC of 10 pM or less against Oesophagostomum dentatum L4: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an MEC of 1 pM or less against Oesophagostomum dentatum L4: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an MEC of 0.1 pM or less against Oesophagostomum dentatum L4: 1 , 2, 3, 4, 5, 6, 7, 8, 10, 11 , 12.

[0294] In vitro assay: Haemonchus contortus

[0295] Solutions of compounds with declining concentrations in DMSO were prepared, diluted with nutrient medium and distributed to 96 well microtiter plates. Exsheathed L3 larvae of Haemonchus contortus were incubated for 20 min at 37°C in a water bath, separated by centrifugation and added to the wells with 300 to 350 larvae / well. After incubation for 7 days motility was assessed by automated microscopy. Ivermectin was used as positive control, DMSO as negative control and EC50 values were calculated which represent the concentration for an individual compound that reduces motility by 50% with respect to the positive control.

[0296] The following compounds showed an EC50 of 1 pM or less against Haemonchus contortus L3: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an EC50 of 0.1 pM or less against Haemonchus contortus L3: 1 , 2, 3, 4, 5, 8, 12.

[0297] In vitro assay: Dirofilaria immitis microfilaria

[0298] Approximately 100 to 300 D. immitis microfilaria were added to wells of a microtiter plate containing a nutrient medium and the test compound in DMSO at varying concentrations. After incubation for 3 days, activity was evaluated as reduction in motility as compared to DMSO as negative control. Compounds were tested in duplicates. Based on the concentration response curves EC50 values were calculated. The following compounds showed an EC50 of 0.1 pM or less against Dirofilaria immitis microfilaria: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an EC50 of 0.01 pM or less against Dirofilaria immitis microfilaria: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14.

[0299] In vitro assay: Dirofilaria immitis L4

[0300] 10 Larvae L4 of D. immitis were added to wells of a microtiter plate containing a nutrient medium and the test compound in DMSO at varying concentrations. After incubation for 3 days, activity was evaluated as reduction in motility as compared to DMSO as negative control. Compounds were tested in duplicates. Based on the concentration response curves EC50 values were calculated.

[0301] It can be seen from the examples above that compounds 1-14 were found effective against larvae of Ascaridia, Oesophagostomum, Haemonchus and Dirofilaria. In this and other examples compounds according to the invention are compared with prior art compounds C146, C150, C187, C249, C260, C261 which are disclosed as compounds 146, 150, 187, 249, 260, 261 , respectively, in WO 2021 / 122911 A1 . The chemical formulas of the comparative compounds are presented below.

[0302]

[0303] 5

[0304] Table 2. Activity in vitro against gastrointestinal nematodes and heartworm, MEC resp. EC50 [pM]

[0305] It can be seen from Table 2 that the compounds 1 and 2 from the invention have higher activity than closely related compounds from the prior art WO2022 / 122911 . Comparative compound C146 also showed high activity in vitro, but later showed reduced in vivo efficacy as shown in Table 6.

[0306] In vitro assay: agonistic activity at D. immitis slo-1 channel and human Maxi K channel (BK channel)

[0307] For determination of the agonistic potential of the compounds stably transfected CHO KI cell lines expressing Dirofilaria immitis slo-1 (Accession No JQ730003; pcDNA::Dimslo1) or the Homo sapiens Maxi K channel (subunits KCNMA1 / KCNMB1 ; Ponte et al, Molecular Pharmacology 2012, 81 (4), 567-577) were used. Activity on the Maxi K channel is measured for the purposes of selectivity on the slo-1 channel and also to assess potential for target-related adverse reactions in animals.

[0308] For fluorescent membrane potential dye assays, the cells were seeded in black 384-well plates (clear bottom) in a concentration of 10,000 cells / well (except the human cells: 20,000 cells / well) in 25pl medium and cultured for 20 to 24 hours (37°C; 5% CO2). 25pl of FMP-dye Blue-Tyrode’s was added to each well and incubated at room temperature for 30min. Thereafter, the cells were incubated for further 10min with 12.5pl of the diluted test compounds. For the membrane potential measurements, the prepared cell plate and KCI solution plate were placed in the FLIPR Tetra (Molecular Devices). The baseline fluorescence was recorded for 20sec (Exc. 510-545 nm, Emm. 565-625 nm). 12.5pl KCI solution was added to start the ion influx in the cells (final assay concentration of the KCI-Tyrode: 70mM KCI, 2mM CaCh, 1 mM MgCh, 0.8mM NabhPC , 5mM Glucose, 28mM Hepes, pH 7.4, including the voltage sensitive dye). The stimulation (in %) is calculated as value 2 1 value 1 * 100 (Value 1 : FLIPR signal before stimulation (average recording 5 to 10s), Value 2: FLIPR signal after stimulation (average recording 120 to 140s)). Measurement in total: 150s.

[0309] EC50 values were determined in triplicate utilizing compound dilution series. The data were determined at least in two independent tests. The data were proceeded by using the ActivityBase XE Runner software (IDBS) for curve fitting and calculation of the half-maximal effective concentration. The results are presented in Table 3.

[0310] The following compounds showed an EC50 value below 10 pM on Dirofilaria immitis-. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14. The following compounds showed an EC50 value below 1 pM on Dirofilaria immitis-. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12.

[0311] The following compounds showed an EC50 value greater than 30 pM on human Maxi K channel: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14.

[0312] These results show that for compounds 1-14 the potential for target-related adverse reactions is low.

[0313] In Table 3 compounds according to the invention are compared with prior art compounds C146, C150, C187, C249, C260, C261 , which are disclosed as compounds 146, 150, 187, 249, 260, 261 , respectively, in WO 2021 / 122911 A1.

[0314] Table 3. Agonistic activity on the slo-1 channel EC50 [pM]

[0315]

[0316] It can be seen from Table 3 that compounds 1 and 2 of the invention have higher on target activity than closely related compounds of the prior art WO2021 / 122911 A1 and a lower potential for target-related adverse reactions. Comparative compound C146 also showed high activity in vitro but showed higher potential for target-related adverse reactions and reduced in vivo efficacy as shown in Table 6.

[0317] Aqueous solubility

[0318] For the compounds a stock solution in DMSO was prepared (1% by weight). An aliquot (5 pl) of the stock solution was added to 10 ml of a 10mM aqueous phosphate buffer solution (pH7). The resulting suspension was shaken by gentle inversion for 72 hours at room temperature. For removal of non-dissolved particles the suspension was allowed to settle for 24 hours followed by centrifugation (4000 rpm, 5 min). The supernatant was separated and analyzed by HPLC-UV / MS. The concentration of compounds was determined by comparison of the UV-signal with calibration curves of the identical respective test compound.

[0319] Table 4: Aqueous solubility

[0320] As can be seen in Table 4 the aqueous solubility at pH7 of compound 1 and 2 is at least 10-fold higher than for the comparative examples C249 and C150.

[0321] Example 3 - In vivo efficacy against H. contortus in jird

[0322] Jirds (Meriones unguiculatus, immunosuppressed) were orally infected with approximately 1500 third-stage larvae of Haemonchus contortus. Ten days after infection, the jirds in the treatment groups were treated once either orally or subcutaneously with compounds at a dose of 10 mg bodyweight. For treatment, compounds were dissolved in a mixture of 10% Transcutol, 10% Cremophor EL and 80% physiological sodium chloride solution. Three days after treatment, the jirds were necropsied, and the larvae burden in the stomach was determined. The efficacy was defined as the reduction of the mean larvae count in the infected jirds of the treatment group in comparison to the infected jirds in an untreated control group (negative control).

[0323] Table 5: Efficacy against H. contortus in jird

[0324] It can be seen from Table 5 that compounds 2, 3, 5, 8 show higher efficacy against the gastrointestinal nematode H. contortus than the prior art compound C150.

[0325] Example 4 - In vivo efficacy against A. viteae in jird

[0326] Efficacy was evaluated in immunosuppressed jirds (Meriones unguiculatus) that were experimentally infected with 80 L3-larvae of the filarial nematode Acanthocheilonema viteae. On days 5, 6, and 7 after infection animals were treated once daily with 10 mg / kg bodyweight of the test compound by oral gavage. 10 weeks after infection the jirds were euthanized and the larvae burden was determined. The efficacy was calculated as the reduction of the mean larvae count in the infected jirds of the treatment group in comparison to the infected jirds in an untreated control group (negative control) using Abbott’s formula. In this study also compounds of invention are tested. The results are presented in Table 6. Table 6: Efficacy against A. viteae in jird

[0327] It can be seen from Table 6 that compound 2, 3, 5, 8 show higher efficacy against the filarial nematode A. viteae than the prior art compound C146.

[0328] Example 5 - Pharmacokinetics study in dogs

[0329] The pharmacokinetic behavior of the test compounds was evaluated by dosing to beagle dogs.

[0330] Test compounds were dissolved in appropriate vehicles (pharmaceutically acceptable excipients) or mixtures thereof. Dogs were divided into treatment groups (n = 4 for intravenous administration, n = 5 for oral administration) and received the compounds by oral gavage (dose = 10 mg / kg) or intravenous bolus administration (dose = 1 mg / kg). Blood samples were collected at predetermined time points (0, 0.5, 1 , 2, 4, 6, 8, 12, 24, 32, 48, 72, 120, 168 hours for oral administration) after treatment. Samples were processed to plasma, deep-frozen and stored at -75°C until analysis. For quantitative determination of test compounds, the samples were thawed, deproteinized and analyzed by HPLC-MS / MS using calibration curves.

[0331] Figure 1 shows the plasma profile after oral administration of 10 mg / kw BW for compounds 2 and C151. Both compounds shown in Figure 1 were administered in the identical vehicle and dose.

[0332] As can be seen from Figure 1 , compound 2 shows unexpectedly significantly higher exposure (as expressed by higher plasma concentrations) than the comparative compound C151 after oral administration.

[0333] Figure 2 shows the plasma profile after intravenous administration of 1 mg / kg BW for compounds 2 and C151. Both compounds shown in Figure 1 were administered in the identical vehicle and dose. As can be seen from Figure 2, compound 2 shows unexpectedly significantly higher exposure (as expressed by higher plasma concentrations) than the comparative compound C151 after intravenous administration.

Claims

1. Claims1. A compound with Formula (I):Formula (I) wherein each of RAis independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents RAform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; n is 0-5,RBis either H or CH3, or a pharmaceutically acceptable salt, solvate or a polymorph thereof.

2. The compound according to claim 1 , having the Formula (C):Formula (C) wherein each of R1, R2, R3 and Rcis independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or wherein each two adjacent substituents from R1, R2, R3 and Rcform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl;and wherein RBis either H or CH3.

3. The compound according to claim 2, wherein each of R-i, R2, R3 and Rcis independently selected from H, Cl, F, methyl, methoxy, trifluoromethyl and trifluoromethoxy and RBis H.

4. The compound according to any one of claims 1-3, as defined in the following Table:

5. The compound according to claim 4, being N-(8-(2,3-dichlorophenyl)-7-fluoro-4-isopropylquinolin- 3-yl)quinoline-4-carboxamide (compound 2).

6. The compound according to claim 4, being N-(8-(3-chloro-2-methylphenyl)-7-fluoro-4- isopropylquinolin-3-yl)quinoline-4-carboxamide (compound 5).

7. The compound according to claim 4, being N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4- isopropylquinolin-3-yl)quinoline-4-carboxamide (compound 8).

8. Method of manufacture of the compound according to any one of claims 1-7, comprising the step of reacting a compound of Formula (A)Formula (A) wherein RBis either H or CH3 and wherein X is a halogen with a compound of FormulaFormula (B) wherein each of RAis independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents RAform a 5- or 6-membered ring, containing 0, 1 or 2 N atoms, which is optionally substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy and trifluoromethyl; n is 0-5, and wherein Y is B(OH)2 or B(OR°)2 with RDbeing alkyl.

9. A pharmaceutical composition comprising the compound according to any one of claims 1-7 and at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, further comprising one or more additional active ingredients.11 . The pharmaceutical composition according to claim 10, wherein the one or more additional active ingredient is selected from the list consisting of fluralaner, afoxolaner, sarolaner, lotilaner, tigolaner, preferably fluralaner.

12. The compound according to any one of claims 1-7 for use as a medicament.

13. The compound according to any one of claims 1 -7, for use in treatment or prevention of a disease caused by a helminth in animals.

14. The compound for use according to claim 13, wherein the helminth is a gastrointestinal nematode and the animal is selected from the group consisting of dogs, cats, ruminants, horses and poultry.

15. The compound for use according to claim 13, wherein the helminth belongs to the Dirofilaria species and the animal is selected from cats and dogs.

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