WO2025027117A1 - Carboxamide-4-quinoline compounds with anthelmintic activity - Google Patents

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.

Description

CARBOXAMIDE-4-QUINOLINE COMPOUNDS WITH ANTHELMINTIC ACTIVITY

Technical field

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

Background art

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

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.

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.

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.

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.

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).

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

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 10⁵ microfilariae 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.

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).

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.

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

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.

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

In a first aspect, the present invention provides a compound with Formula (I):

Formula (I) wherein each of R^A is independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents R^A 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; n is 0-5,

R^B is either H or CH3, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof.

In a second aspect, the invention provides a method of manufacture of the compound with Formula (I), comprising the step of reacting a compound of Formula (A)

Formula (A) wherein R^A and n have the meaning as defined in any of the embodiments described herein, with a compound of Formula (B) or its halide:

Formula (B) wherein R^B is either H or CH3.

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

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

The invention further provides the compound according to the invention for use in treatment or prevention of a disease caused by a parasitic nematode in animals.

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 parasitic nematode in animals.

In a further aspect, the invention provides a method of treatment or prevention of a disease caused by a 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.

Brief description of drawings

Figure 1 shows plasma profiles of compounds 1 , 3, 5 according to some embodiments of the invention and comparative compounds C151 , C243, C254 after oral administration of 10 mg/kg BW in dogs.

Figure 2 shows plasma profiles of compounds 1 , 3, 5, 6 according to some embodiments of the invention and comparative compounds C151 , C243, C254 after intravenous administration of 1 mg/kg BW in dogs.

Detailed description

The present invention relates to compounds with Formula (I):

Formula (I) wherein each of R^A is independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents R^A 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; n is 0-5,

R^B is either H or CH3.

The 5- or 6-membered ring formed by two adjacent R^A can 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 R^A can be selected from the group of naphthyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, indole, isoindole, benzimidazole, indazole; preferably naphthyl, quinoline.

In some embodiments, R^A is one or more substituents of the phenyl ring, which are independently selected from Cl, F, methyl, methoxy or trifluoromethyl, 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 R^A, while the remaining C atoms in the phenyl ring are unsubstituted. R^B is either H or CH3, preferably H.

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

In some embodiments, R^B is hydrogen.

In some of these embodiments, n can be 3 and the substituent R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl, preferably Cl or F. The phenyl ring substituted with R^A can 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.

In some of these embodiments, n can be 3 and the substituent R^A can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy, preferably Cl or F. The phenyl ring substituted with R^A can 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.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl, preferably Cl or F. The phenyl ring substituted with R^A can be selected from the group consisting of 2,3-diflurorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-5- fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, preferably 2,3-dichlorophenyl, 2-chloro-3- fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3,5-dichlorophenyl, 5-chloro-2-fluorophenyl, more preferably 3-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 2,3- dichlorophenyl.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl. The phenyl ring substituted with R^A can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro- 2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3- trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3methylphenyl, 2-chloro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3-fluoro-5- trifluoromethylphenyl, preferably 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2- methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5- chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, more preferably 2-fluoro-5-trifluoromethyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy. The phenyl ring substituted with R^A can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3- chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2- fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro- 3methylphenyl, 2-chloro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3- fluoro-5-trifluoromethylphenyl, 2-fluoro-3-trifluoromethoxy, 2-fluoro-5-trifluoromethoxy, 2-chloro-3- trifluoromethoxy, 2-chloro-5-trifluoromethoxy, preferably 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro- 5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-fluoro-5-trifluoromethoxy, 2-chloro-5-trifluoromethoxy, more preferably 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, 3-chloro- 2-methoxyphenyl, 2-chloro-5-trifluoromethoxy.

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

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

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

In some embodiments, R^B is CH3 (methyl group).

In some of these embodiments, n can be 3 and the substituent R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl, preferably Cl or F. The phenyl ring substituted with R^A can 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.

In some of these embodiments, n can be 3 and the substituent R^A can be independently selected from Cl, F, methyl, methoxy, trifluoromethoxy or trifluoromethyl, preferably Cl or F. The phenyl ring substituted with R^A can 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.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl, preferably Cl or F. The phenyl ring substituted with R^A can be selected from the group consisting of 2,3-diflurorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-5- fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, preferably 2,3-dichlorophenyl, 2-chloro-3- fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3,5-dichlorophenyl, 5-chloro-2-fluorophenyl, more preferably 3-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 2,3- dichlorophenyl.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy or trifluoromethyl. The phenyl ring substituted with R^A can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro- 2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3- trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3methylphenyl, 2-chloro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3-fluoro-5- trifluoromethylphenyl, preferably 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2- methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5- chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, more preferably 2-fluoro-5-trifluoromethyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl.

In some of these embodiments, n can be 2 and each of the substituents R^A can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl or trifluoromethoxy. The phenyl ring substituted with R^A can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3- chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2- fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro- 3methylphenyl, 2-chloro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3- fluoro-5-trifluoromethylphenyl, 2-fluoro-3-trifluoromethoxy, 2-fluoro-5-trifluoromethoxy, 2-chloro-3- trifluoromethoxy, 2-chloro-5-trifluoromethoxy, preferably 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2- methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro- 5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-fluoro-5-trifluoromethoxy, 2-chloro-5-trifluoromethoxy, more preferably 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, 3-chloro- 2-methoxyphenyl, 2-chloro-5-trifluoromethoxy.

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

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

In some embodiments, the compound has the Formula (C):

Formula (C) wherein each of R1, R2, R3 and R^c is independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or wherein each two adjacent substituents from R1, R2, R3 and R^c 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 wherein R^B is either H or CH3.

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

In some embodiments, R2 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably from H, Cl and F, more preferably it is Cl.

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. In some embodiments, R^c is 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. Table C. Prepared compounds

In some embodiments, the compound is selected from the list consisting of compounds 1 to 28.

In some embodiments, the compound is selected from compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, preferably compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9, 15,

17, 23 and 27, more preferably compounds 1 , 2, 3, 5, 6, 7, 8, 17, 23, yet more preferably compounds 1 , 3, 5, 6, 7, 8, 23 or compounds 1 , 3, 5, 7, 8 or compounds 1 , 5, 23. Most preferred, compound 1 or 5. In some embodiments, the compound is compound 1. In other embodiments, the compound is compound 5. In an embodiment, the compound has Formula (II) or is a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof:

Formula (II)

In some embodiments, each of Ri, R2 and R3 is independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or R1 and R2 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 R^B is either H or CH3.

In some embodiments, each of R1, R2 and R3 is independently selected from H, Cl, F, methyl, methoxy and trifluoromethyl. R^B is as indicated above.

In some embodiments, R1 is selected from H, Cl, F, methyl, methoxy and trifluoromethyl, preferably from Cl, F, methyl and methoxy, more preferably it is F or Cl, most preferably Cl.

In some embodiments, R2 is selected from H, Cl, F, methyl, methoxy and trifluoromethyl, preferably from H, Cl and F, more preferably it is Cl.

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

In some embodiments, R^c is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy and trifluoromethyl, preferably from H and F, more preferably H.

Exemplary compounds of Formula (II) are presented in Table A.

Table A. Exemplary compounds of Formula (II)

In some embodiments, the compound is selected from the list consisting of compounds 1 to 17.

In some embodiments, the compound is selected from compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16 and 17, preferably compounds 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 17, more preferably compounds 1 , 3, 5, 6, 7, yet more preferably compounds 1 , 3, 5, 6 or compounds 1 , 4, 5 and most preferably compound 1 .

In one embodiment, the compound is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 3).

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

In yet another embodiment, the compound is N-(8-(2-chloro-3-fluorophenyl)-7-fluoro-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 6).

In yet a further embodiment, the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 1).

In a further embodiment, the compound is N-(8-(3,5-dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 10).

In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(2,3,5-trifluorophenyl)quinolin-3- yl)quinoline-4-carboxamide (compound 2).

In a further embodiment, the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3-yl)-2- methylquinoline-4-carboxamide (compound 7). In a further embodiment, the compound is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)-2-methylquinoline-4-carboxamide (compound 17).

In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-(trifluoromethyl)phenyl)-4- morpholinoquinolin-3-yl)quinoline-4-carboxamide (compound 4).

In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-methoxyphenyl)-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 1 1).

In a further embodiment, the compound is N-(8-(2-chloro-5-methoxyphenyl)-7-fluoro-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 12).

In a further embodiment, the compound is N-(8-(2-chloro-5-fluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 13).

In a further embodiment, the compound is N-(8-(2-chloro-5-(trifluoromethyl)phenyl)-7-fluoro-4- morpholinoquinolin-3-yl)quinoline-4-carboxamide (compound 14).

In a further embodiment, the compound is N-(8-(3-chloro-2-methylphenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 8).

In a further embodiment, the compound is N-(8-(3-chloro-2-methoxyphenyl)-7-fluoro-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 9).

In a further embodiment, the compound is N-(8-(5-chloro-2-methylphenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 15).

In a further embodiment, the compound is N-(8-(5-chloro-2-methoxyphenyl)-7-fluoro-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 16).

In a further embodiment, the compound is N-(8-(2,3-difluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 18).

In a further embodiment, the compound is N-(8-(2,5-difluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 19).

In a further embodiment, the compound is N-(8-(2-chloro-5-methylphenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 20). In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-methylphenyl)-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 21).

In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(2,4,5-trifluorophenyl)quinolin-3- yl)quinoline-4-carboxamide (compound 22).

In a further embodiment, the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)-2-methylquinoline-4-carboxamide (compound 23).

In a further embodiment, the compound is N-(7-fluoro-8-(5-fluoro-2-methylphenyl)-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 24).

In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-3-methoxyphenyl)-4-morpholinoquinolin- 3-yl)quinoline-4-carboxamide (compound 25).

In a further embodiment, the compound is N-(8-(2-chloro-5-(trifluoromethoxy)phenyl)-7-fluoro-4- morpholinoquinolin-3-yl)quinoline-4-carboxamide (compound 26).

In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(naphthalen-1-yl)quinolin-3- yl)quinoline-4-carboxamide (compound 27).

In a further embodiment, the compound is N-(7'-fluoro-4'-morpholino-[5,8'-biquinolin]-3'-yl)quinoline-4- carboxamide (compound 28).

The compounds with Formula (I), (II) 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.

Particularly, the compounds of Formula (I) can be obtained by reaction comprising the step of reacting a compound of Formula (A):

Formula (A) wherein R^A and n have the meaning as defined in any of the embodiments described above, with a compound of Formula (B) or its halide:

Formula (B) wherein R^B is either H or CH3.

Particularly, each of R^A is preferably independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or each two adjacent substituents R^A can 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.

“Halide” means in this case a compound with a group -COHal, wherein Hal is selected from F, Cl, Br and I, preferably Cl.

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

In an embodiment of the invention and/or embodiments thereof, the amine of Formula (A) and the acid according to Formula (B) or its halide can be submitted to form the corresponding amide group in an organic solvent, optionally in the presence of a coupling agent or an auxiliary alkaline compound.

A coupling agent can be regarded as a substance generally facilitating the formation of an ester or an amide. The coupling agent reacts with a carboxy group by forming a reactive intermediate which is subsequently further reacted with an alcohol or an amine to form the final product, i.e. an ester or an amide. In an embodiment of the invention and/or embodiments thereof, the coupling agent is selected from N,N’- dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-etyhl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 1-etyhl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCI) and carbonyldiimidazole (CDI). More preferably the coupling agent is 1-etyhl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.

In an embodiment of the invention and/or embodiments thereof, the process can be carried out in the presence of an auxiliary alkaline compound. Suitable alkaline compounds include, but are not limited to, pyridines such as 4-(dimethylamino) pyridine (DMAP), amidines such 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines such as triethylamine and diisopropylethylamine (DIPEA), preferably triethylamine is used.

Organic solvents are known to the skilled person. A suitable organic solvent for the process according to the present invention can for example be acetonitrile, dioxane, tetra hydrofuran (THF) and dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane, preferably dichloromethane. In an embodiment of the invention and/or embodiments thereof, the process can be carried out at a temperature of 5° to 120°C, preferably at 20 to 100°C.

In an alternative embodiment of the invention and/or embodiments thereof, a halide of compound B is used. For example, the carboxylic acid according to Formula (B) can be reacted with thionyl chloride or oxalyl chloride, preferably oxalyl chloride, to form the corresponding acid chloride. Subsequently the corresponding acid chloride can be submitted to a reaction with the amine according to Formula (A) to obtain the compound of Formula (I).

In an alternative embodiment of the invention and/or embodiments thereof, the alternative process can be carried out in an organic solvent and/or in the presence of an auxiliary alkaline compound. A suitable organic solvent can for example be acetonitrile, toluene, dioxane, tetrahydrofuran, chloroform or dichloromethane. As far as the auxiliary alkaline compound is concerned, the same applies as described above, preferred are pyridine, DMAP, triethylamine and diisopropylethylamine, most preferred triethylamine.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Administration and dosage forms

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.

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.

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

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).

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

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.

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.

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.

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, tetra hydrofurfury I 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.

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, gelatin, 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.

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.

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.

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

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.

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.

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.).

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

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.

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.

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 (an hydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

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

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).

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.

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.

Pharmaceutical compositions

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

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.

Pharmaceutically acceptable excipients are known in the art. For example, they are described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20^th Edition, 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.

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.

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.

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 (T_g) 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 (T_g) and become plastically deformable without breaking. The glass transition temperature or melting point are determined via methods known by the skilled person.

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.

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 %.

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.

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 %.

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 %.

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 %.

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 %.

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 %.

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 %.

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 %.

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).

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.

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.

Methods of use

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. The invention further includes a method of treatment or prevention of a disease caused by a parasitic nematode, 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.

The phrase “control of helminth infestation” means to reduce or eradicate parasite numbers in an animal, and/or to partially or completely inhibit the development of parasite infestation 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. The compound according to the present invention acts against animal parasites, in particular 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 pests which commonly infect animals, and include the egg, larval, and adult stages thereof. Such parasites include helminths (roundworms, hookworms, tapeworms, heartworms), and are commercially important because they cause serious diseases in animals.

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. 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) burdens in the animal below that level at which economic loss occurs.

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.

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

In a preferred embodiment the compounds according to this invention are used to prevent or treat a helminth infection, 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.; Ancylostoma spp.; Toxocara spp.; especially Dirofilaria immitis. Particularly, the compound according to the invention is effective against parasitic nematodes, more particularly roundworms. More particularly, the compound according to the invention is effective against heartworm (Dirofilaria immitis), french heartworm (Angiostrongylus vasorum), against gastrointestinal nematodes such as Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Spirocerca lupi, 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 and against lungworms such as Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

In one embodiment, the compound according to the invention is effective against heartworm (Dirofilaria immitis) and french heartworm (Angiostrongylus vasorum), preferably against heartworm (Dirofilaria immitis).

In other embodiments, the compound is effective against gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, 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.

In another embodiment, the compound is effective against lungworms such as Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

It is understood that the term “treating” or “treatment” used herein includes prophylactic, metaphylactic and therapeutic treatment or curative treatment. Prophylactic or metaphylactic treatment, i.e. deworming, is commonly used to prevent helminth infection so to control parasitic infections in animals. In addition, helminths can infect humans and therefore pose a threat to human health as well. Prophylactic treatments comprise treatments which are done at regular intervals such as 1-6 times per year, or 2-4 times per year or 1-4 per month. 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.

In therapeutic or curative treatment the compounds are administered after clinical diagnosis. 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 labour input.

The present invention provides the compounds according to the invention or the veterinary composition according to the present invention for use as a medicament. In one embodiment the compounds according to the invention or the veterinary composition according to the present invention are for use as in the treatment of helminth infection of animals such as filariasis and in particular heartworm disease.

In another embodiment the compounds according to the invention or the veterinary composition according to the present invention are for use in the treatment of infection of animals caused by gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, 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.

The compounds according to the present invention or the veterinary composition according to the present invention are used to make a medicament. 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.

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 gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, 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.

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. 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 gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, 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.

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 parasites, preferably helminths, preferably 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.; Anecator spp.; Angiostrongylus 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. Necatorspp. 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.; more preferably nematodes, in particular Dirofilaria spp.; Haemonchus spp.; Strongylus spp; Cyathostomum spp.; Ostertagia spp.; Cooperia spp.; Trichostrongylus spp.; Nematodirus spp.; Teladorsagia spp.; Oesophagostomum spp.; Ancylostoma spp.; Toxocara spp.; especially Dirofilaria immitis.

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 gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Haemonchus contortus, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, or a disease caused by lungworms such as Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis. 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 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.

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 placei and 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 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.

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 Anchylostoma spp. and in particular Ancylostoma caninum.

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.

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.

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 axei and Trichostrongylus colubriformis.

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.

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.

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.

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.

It is contemplated that 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.).

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 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 compounds according to the present invention or the veterinary composition according to present invention are administered to treat or prevent disorders/diseases caused by one or more helminths selected from the group consisting of a) cestodes: e.g. Acanthocheilonema spp.; 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. Aelurostrongylus spp.; Ancylostoma spp.; Anecator spp.; Angiostrongylus 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.; more preferably nematodes, in particular Dirofilaria spp.; Haemonchus spp.; Strongylus spp; Cyathostomum spp.; Ostertagia spp.; Cooperia spp.; Trichostrongylus spp.; Nematodirus spp.; Teladorsagia spp.; Oesophagostomum spp.; Ancylostoma spp.; Toxocara spp.; especially Dirofilaria immitis.

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 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 axei, 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.

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.

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. 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 other words, 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.

The invention is also directed to a method for treating an animal with diseases caused 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 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. 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 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 placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

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.

In one embodiment the parasitic nematode is a gastrointenstinal nematode and the animal treated is selected from the group consisting of dogs, cats, ruminants, horses and poultry.

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.

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. 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.

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.

In one embodiment, the animal that is treated is a sheep and the disease that is treated is 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.

In one embodiment, the animal that is treated is cattle and the disease that is treated is helminth infection such as of 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.

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

In some embodiment, the parasitic nematode belongs to the Dirofilaria species and the animal treated is selected from cats and dogs.

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

In other embodiments, the animal that is treated is a cat and the disease that is treated is filariasis and in particular heartworm disease.

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

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

The frequency of the administration 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, bi-monthly, 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.

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.

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.

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.

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

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

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 of parasite infestations of animals and/ or for the protection of animals from infestation by parasites, 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.

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 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.

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 symptoms in the diseased animal.

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.

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%.

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.

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%. 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.

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%.

The duration of activity or efficacy (i.e., “knockdown,” onset of activity and/ or sustained effects) can be the primary concern in antiparasitic product choices. The durations over which the compounds are effective against parasites is important for the required treatment interval.

In one embodiment, the compounds of the invention provide an efficacy against the parasites of about 100% for about 1 month or longer.

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.

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 1 1 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.

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

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

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

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

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

Therefore, in another embodiment of the invention the compound is administered every 9 months.

Particularly, the compound is especially suitable for use in the prevention of heartworm disease in mammals. The heartworm disease is prevented when Dirafilaria 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.

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.

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. Examples of contemplated combination therapies

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.

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.

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.

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.

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.

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).

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.

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. 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.

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.

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.

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.

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,

WO2020/131629, W02020/131631 , W02020/083971 , WO2021/018839, W02021/204930,

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.

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).

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.

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.

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

• fluralaner, afoxolaner, sarolaner, lotilaner, tigolaner; and/or

• closantel, oxyclozanide, rafoxanide, niclosamide; and/or

• nitroxynil, nitroscanate, clorsulon; and/or

• praziquantel, epsiprantel; and/or

• emodepside, derquantel, monepantel.

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.

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 clazuri I, diclazuril and letrazuril.

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.

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.

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

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- 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-

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

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

2007/026965, WO 2007/070606, WO 2007/075459, WO 2007/079162, WO 2007/105814, WO

2007/125984, WO 2008/019760, WO 2008/122375, WO 2008/150393, WO 2009/002809, WO

2009/003075, WO 2009/022746, WO 2009/035004, WO 2009/045999, WO 2009/051956, WO

2009/035004.

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

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.

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 .

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.

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.

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.

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

Examples

Column: Xbridge BEH C18 Waters, 2.1x50 mm, 2.5p

Oven: 40 °C

Eluents: Solvent A: water I HCO2H (0.05%); Solvent B: acetonitrile I HCO2H (0.05%)

Flow: 0.8 ml / min

Gradient:

Run time: 2.2 min + 0.5 min equilibration time

Example 1 - Synthesis of N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3- yl)quinoline-4-carboxamide (compound 1)

1. Diethyl 2-(((2-bromo-3-fluorophenyl)amino)methylene)malonate

2-Bromo-3-fluoroaniline (61.7 g, 325 mmol) together with diethyl 2-(ethoxymethylene)-malonate (65.0 ml, 325 mmol) was dissolved in ethanol (310 ml) and the mixture was stirred under reflux for 5 hours. The mixture was cooled to room temperature, diluted with 150 ml ethanol and the resulting precipitate was isolated by filtration. The solid residue was washed with ethanol (3 x 100 ml) and dried to give the title compound as a solid. MS (ESI) 362.0 [M+H]⁺. 2. Ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate

Diethyl 2-(((2-bromo-3-fluorophenyl)amino)methylene)malonate (60.0 g, 167 mmol) was combined with Dowtherm® A (180 ml) and the mixture was stirred at 250°C for 3 hours. The mixture was cooled to room temperature and diluted with 1500 ml n-heptane. The resulting precipitate was isolated by filtration, washed with n-heptane (3 x 100 ml) and dried to afford the title compound as a solid. MS (ESI) 315.9 [M+H]⁺. 3. 8-Bromo-7-fluoro-4-hydroxyquinoline-3-carboxylic acid

Ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate (44.4 g, 0.12 mol) was suspended in a solution of sodium hydroxide (40.2 g, 1 mol) in water (430 ml) and the mixture was stirred under reflux for 1 hour. The mixture was cooled to room temperature and acidified with hydrochloric acid (5M, 221 ml, 1.1 mol) with stirring. The resulting precipitate was isolated by filtration, washed with water (3 x 100 ml) and dried to yield the title compound as a solid. MS (ESI) 287.9 [M+H]⁺.

4. 8-Bromo-7-fluoroquinolin-4-ol

8-Bromo-7-fluoro-4-hydroxyquinoline-3-carboxylic acid (33.0 g, 102 mmol) was suspended in Dowtherm® A (330 ml) and the mixture was stirred at 260°C. After 5 hours the mixture was cooled to 60°C and diluted with 1200 ml n-heptane. The mixture was cooled to room temperature, the resulting precipitate was isolated by filtration, washed with n-heptane (3 x 300 ml) and dried to yield the title compound as a solid. MS (ESI) 243.9 [M+H]⁺.

5. 8-Bromo-7-fluoro-3-nitroquinolin-4-ol

8-Bromo-7-fluoroquinolin-4-ol (34.6 g, 143 mmol) was combined with propionic acid (170 ml) and heated to 100°C. Nitric acid (65%, 24.6 ml, 0.357 mol) was added dropwise with stirring over 15 min. at 100°C. After completion of the addition the mixture was stirred at 125°C. After 90 min. the mixture was cooled to room temperature and ethanol (170 ml) was added followed by water (510 ml). The resulting precipitate was isolated by filtration, washed with a 3 to 1 mixture of water and ethanol (200 ml) and dried under reduced pressure at 40°C to afford the title compound as a solid. MS (ESI) 288.0 [M+H]⁺.

6. 4-(8-Bromo-7-fluoro-3-nitroquinolin-4-yl)morpholine

8-Bromo-7-fluoro-3-nitroquinolin-4-ol (6 g, 20.90 mmol) was combined with chloroform (70 ml) and dimethylformamide (1.8 ml, 23 mmol). Thionyl chloride (1.83 ml, 25 mmol) was added dropwise at room temperature. After completion of the addition the mixture was stirred under reflux for 4 hours and cooled to 0°C. Then triethylamine (5.83 ml, 41.8 mmol) followed by morpholine (2.73 ml, 31.4 mmol) were added slowly. The reaction mixture was again heated to reflux and stirred overnight at reflux. The mixture was allowed to cool to room temperature, diluted with dichloromethane and washed with water, HCI (1 M) and saturated sodium bicarbonate solution. The organic layer was dried over MgSC and concentrated under reduced pressure. The solid residue was suspended in ethyl acetate and the mixture was stirred for 45 min. at 45°C. The precipitate was isolated by filtration, washed with n-pentane and dried to afford the title compound as a solid. MS (ESI) 358.0 [M+H]⁺.

7. 4-(8-(2,3-Dichlorophenyl)-7-fluoro-3-nitroquinolin-4-yl)morpholine 4-(8-Bromo-7-fluoro-3-nitroquinolin-4-yl)morpholine (5 g, 14 mmol), tetrakis(triphenyl-phosphine)palladium (1 .62 g, 1 .4 mmol) and sodium carbonate (5.95 g, 56.2 mmol) were combined under argon with degassed 1 ,4-dioxane (160 ml) and water (40 ml). The mixture was heated to 110°C, then (2,3-dichlorophenyl)boronic acid (9.34 g, 42.1 mmol) dissolved in 1 ,4-dioxane (40 ml) was added dropwise with stirring over 2.5 hours. Stirring was continued at 110°C, then the mixture was poured into water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgSCM and concentrated under reduced pressure. The residue was treated with methyl tert-butyl ether (120 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to ca. 30 ml, the resulting precipitate was isolated by filtration and washed with methyl tert-butyl ether. The mother liquor was concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient of dichloromethane / ethyl acetate from 100:1 to 80:20). The product was combined with the isolated precipitate to afford the title compound as a solid. MS (ESI) 442.0 [M+H]⁺.

8. 8-(2,3-Dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3-amine 4-(8-(2,3-Dichlorophenyl)-7-fluoro-3-nitroquinolin-4-yl)morpholine (5.14 g, 11.8 mmol) was dissolved in a mixture of tetra hydrofuran (86 ml) and methanol (12 ml) under argon. Platinum on carbon (5%, sulfided, 0.46 g, 0.118 mmol) was added, the flask was closed with a septum and the mixture was purged with argon followed by hydrogen and stirred at ambient temperature in a hydrogen atmosphere overnight. The mixture was filtered over a cake of celite and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in DCM (10 mL) and treated with methyl tertbutyl ether (10 mL). The resulting precipitate was isolated by filtration, washed with methyl tert-butyl ether and dried to afford the title compound as a solid. MS (ESI) 392.0 [M+H]⁺.

9. Quinoline-4-carbonyl chloride

Quinoline-4-carboxylic acid (2.5 g, 14.44 mmol) was combined with dichloromethane (48 ml). Dimethylformamide (0.224 ml, 2.89 mmol) was added followed by oxalyl chloride (1.39 ml, 15.88 mmol) and the mixture was stirred at room temperature. After 90 min. the mixture was concentrated under reduced pressure to yield a solid that was used directly in the next step.

10. N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3-yl)quinoline-4-carboxamide 8-(2,3-Dichlorophenyl)-7-fluoro-4-morpholinoquinolin-3-amine (4.71 g, 12 mmol) was dissolved in dichloromethane (96 ml) and the resulting solution was cooled to 0 °C. Triethylamine (4.18 ml, 30 mmol) was added followed by quinoline-4-carbonyl chloride (HCI salt, 3.01 g, 13.2 mmol) and the mixture was stirred at ambient temperature. After 5 hours additional quinoline-4-carbonyl chloride (HCI salt, 0.547 g, 2.4 mmol) was added and stirring was continued for 2 hours. The reaction mixture was diluted with water (50mL) and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 solution (50 mL) and brine (50 ml), dried over MgSO4 and concentrated under reduced pressure to dryness. The residue was combined with methyl tert-butyl ether (50 mL) and dichloromethane (20 mL) and the resulting mixture was concentrated at 45°C with stirring. The resulting precipitate was filtered off, suspended in acetonitrile (50 mL) and heated to 80°C for 30 min, filtered off and combined with methyl tertbutyl ether (50 mL). The resulting mixture was stirred at 45°C for 3 hours, the precipitate was filtered off, dried and combined with ethanol (50 mL). The mixture was stirred at 80°C for 1 hour, cooled to 0°C and the resulting precipitate was isolated by filtration and dried under reduced pressure to afford the title compound as a solid. Similar procedures as described above were used to prepare exemplary compounds of Formula (C) listed in Table 1 .

Formula (C)

Table 1. Prepared compounds

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

Example 2 - In vitro studies

In the following examples compounds according to the invention are compared with prior art compounds C146, C151 , C243, C254, C399, which are disclosed as compounds 146, 151 , 243, 254, 399, respectively, in WO 2021/122911 A1 . These compounds were investigated in the following in vitro assays.

In vitro assay: Ascaridia galli and Oesophagostumum dentatum

Ascaridia galli (intestinal roundworm of chicken), larval stage 3 ("L3"); and Oesophagostumum 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.

In vitro assay: Haemonchus contortus

Solutions of compounds with declining concentrations in DMSO were prepared, diluted with nutrient medium and distributed to 96 well microtiterplates. 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.

In vitro assay: Dirofilaria immitis L1

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. In vitro assay: Dirofilaria immitis L4

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.

The results are presented in Table 2. Table 2. Activity in vitro against gastrointestinal nematodes and heartworm, MEC resp. EC50 [pM]

It can be seen from Table 2 that compounds 1-28 were found effective against larvae of Ascaridia, Oesophagostomum, Haemonchus and Dirofilaria.

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

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.

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 MgCL, 0.8mM NaH2PO4, 5mM Glucose, 28mM Hepes, pH 7.4, including the voltage sensitive dye). The stimulation (in %) is calculated as value 2 / 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.

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.

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

It can be seen from Table 3 that for compounds 1-28 the potential for target-related adverse reactions in the host such as mammal (e.g. a human being) is low. In vitro assay: aqueous solubility

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.

Table 4: Aqueous solubility

Compound Solubility [mg/L, pH7]

As can be seen in Table 4 the aqueous solubility at pH7 of compound 1 is at least 10-fold higher than for the comparative example C151. For compound 2 the aqueous solubility is about 100-fold higher than for the comparative example C399.

Example 3 - In vivo efficacy against A. viteae in jird

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 5.

Table 5: Efficacy against A. viteae in jird

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

In another study efficacy was evaluated in jirds according to a similar procedure as described above. The results are in Table 6.

Table 6: Efficacy against A. viteae in jird

It can be seen that compound 1 shows a higher efficacy against A. viteae than the comparative compounds C151 , C254 and C399. In the case of Dirofilaria efficacy of 100% is desired to provide effective protection of the animal. It is therefore of high importance to have in this filarial model an efficacy that is as high as possible.

Example 5 - In vivo efficacy against A. viteae in jird

Efficacy was evaluated in not 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 shown in Table 7.

Table 7: Efficacy against A. viteae in jird

As can be seen, compound 10 shows higher efficacy than comparative example C146 in Example 3; and compound 2 shows higher efficacy than comparative example C399 in Example 3 and Example 4.

Example 6 - Pharmacodynamics study in sheep

The efficacy of compound 1 and of C151 (compound 151 in WO 2021/122911 A1 , used as comparative example) was determined against gastrointestinal nematodes in sheep after subcutaneous administration. Sheep of approximately 12 to 16 weeks of age were challenged each with L3-larvae of Haemonchus contortus (approx. 4,000 larvae) and Trichostrongylus colubriformis (approx. 6,000 larvae) by oral gavage. All sheep that were included in the study were tested negative for strongyle eggs in a qualitative fecal examination prior to infestation.

The sheep were allocated to treatment groups with 3 animals per group. Sheep in treatment group 1 were not treated and served as negative control group. Sheep in the other treatment groups were treated with either compound 1 or compound C151 at a dose of 10 mg/kg bodyweight by subcutaneous injection of a solution 33 or 34 days after infestation.

Seven days after treatment all sheep underwent necropsy, their abomasum and small intestine were processed for parasite recovery. All sheep in the untreated control group harboured adequate infections of H. contortus and T. colubriformis. The efficacy of each treatment group was calculated relative to the untreated control group.

The results are presented in Table 7.

Table 8. Efficacy in sheep [% worm reduction]

As can be seen from Table 7, the efficacy of compound 1 is significantly higher than for the comparative compound C151 known from prior art.

Example 7 - Pharmacokinetics study in dogs

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

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.

Figure 1 shows the plasma profile after oral administration of 10 mg/kw BW for compounds 1 , 3, 5, C151 , C254, C243. All compounds shown in Figure 1 were administered in the identical vehicle and dose.

As can be seen from Figure 1 , compounds 1 , 3, and 5 show unexpectedly significantly higher exposure (as expressed by higher plasma concentrations) than the comparative compounds C151 and C254 after oral administration. Compound C243 also shows high exposure but has shown insufficient efficacy in vitro (Table 2).

Figure 2 shows the plasma profile after intravenous administration of 1 mg/kg BW for compounds 1 , 3, 5, 6, C151 , C243, C254. All compounds shown in Figure 1 were administered in the identical vehicle and dose. As can be seen from Figure 2, compounds 1 , 3, 5 and 6 show unexpectedly significantly higher exposure (as expressed by higher plasma concentrations) than the comparative compounds C151 and C243 after intravenous administration.

Claims

Claims

1. A compound with Formula (I):

Formula (I) wherein each of R^A is independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents R^A 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; n is 0-5,

R^B is either H or CH3, or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

2. The compound according to claim 1 , having the Formula (C):

Formula (C) wherein each of Ri, R2, R3 and R^c is independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or wherein each two adjacent substituents from R1, R2, R3 and R^c 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 wherein R^B is either H or CH3.

The compound according to claim 1 or 2, having the Formula (II):

Formula (II) wherein each of R1, R2 and R3 is independently selected from H, Cl, F, OCF3, methyl, methoxy and trifluoromethyl, or wherein R1 and R2 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 R^B is either H or CH3.

4. The compound according to claim 3, wherein each of R1, R2 and R3 is independently selected from H, Cl, F, methyl, methoxy and trifluoromethyl and R^B is either H or CH3.

5. The compound according to any one of claims 1-4, being N-(8-(3-chloro-2-fluorophenyl)-7-fluoro- 4-morpholinoquinolin-3-yl)quinoline-4-carboxamide.

6. The compound according to any one of claims 1-4, being N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-

4-morpholinoquinolin-3-yl)quinoline-4-carboxamide.

7. The compound according to any one of claims 1-4, being N-(8-(2-chloro-3-fluorophenyl)-7-fluoro- 4-morpholinoquinolin-3-yl)quinoline-4-carboxamide.

8. The compound according to any one of claims 1-4, being N-(8-(2,3-dichlorophenyl)-7-fluoro-4- morpholinoquinolin-3-yl)quinoline-4-carboxamide.

9. The compound according to any one of claims 1-4, being N-(8-(2,3-dichlorophenyl)-7-fluoro-4- morpholinoquinolin-3-yl)-2-methylquinoline-4-carboxamide.

10. The compound according to any one of claims 1-4, being N-(8-(3-chloro-2-methylphenyl)-7-fluoro- 4-morpholinoquinolin-3-yl)quinoline-4-carboxamide.

11. The compound according to any one of claims 1-4, being N-(8-(5-chloro-2-fluorophenyl)-7-fluoro- 4-morpholinoquinolin-3-yl)-2-methylquinoline-4-carboxamide.

12. The compound according to any one of claims 1-4, being N-(7-fluoro-8-(2-fluoro-5- (trifluoromethyl)phenyl)-4-morpholinoquinolin-3-yl)quinoline-4-carboxamide.

13. Method of manufacture of the compound according to any one of claims 1-12, comprising the step of reacting a compound of Formula (A)

Formula (A) wherein each of R^A is independently selected from Cl, F, OCF3, methyl, methoxy or trifluoromethyl, or wherein each two adjacent substituents R^A 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; n is 0-5, with a compound of Formula (B) or its halide:

Formula (B) wherein R^B is either H or CH3.

14. A pharmaceutical composition comprising the compound according to any one of claims 1-12 and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, further comprising one or more additional active ingredients.

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

17. The compound according to any one of claims 1 -12, for use in treatment or prevention of a disease caused by a parasitic nematode in animals.

18. The compound for use according to claim 17, wherein the parasitic nematode is a gastrointestinal nematode and the animal is selected from the group consisting of dogs, cats, ruminants, horses and poultry.

19. The compound for use according to claim 17, wherein the parasitic nematode belongs to the Dirofilaria species and the animal is selected from cats and dogs.