Treatment of Fascioliasis

Abstract

The present invention relates to compounds of formula (I) and compositions for treating fascioliasis in mammals. [Formula 1] TIFF2025527799000025.tif43158

Description

[Technical Field]

[0001] The present invention relates to compounds and compositions for treating fascioliasis in mammals. [Background technology]

[0002] Fascioliasis is an important zoonotic disease that causes significant losses in food resources and animal productivity. Fascioliasis is a disease of both veterinary and public health importance, affecting over 600 million animals. The infection causes significant losses through liver failure, reduced milk, meat, and wool production, increased veterinary care, metabolic disorders, and increased mortality.

[0003] Fascioliasis is caused by the trematode parasite Fasciola spp. Fasciola hepatica and Fasciola gigantica are the two main species responsible for most cases of fascioliasis in mammals. Fasciola hepatica is present virtually worldwide due to its ability to infect a wide variety of species, while Fasciola gigantica is more common in the tropics, although both species are found in Africa and Asia.

[0004] Fascioliasis can be caused by the migration of many immature fluke larvae through the liver, by the presence of adult flukes in the bile duct, or both. Fascioliasis occurs in three main clinical forms: acute, subacute, and chronic. The form that develops depends on the number of infective metacercariae ingested and the duration over which they are ingested.

[0005] The primary impact of fascioliasis is on domestic ruminants. However, they are not selective regarding their final host and can infect a wide range of mammals, including humans. Among domestic ruminants, fascioliasis can result in economic losses of billions of dollars annually worldwide.

[0006] Adult liver flukes (F. hepatica) are large lobular flukes, approximately 3-5 cm long and 1 cm wide. Both immature and mature stages of the parasite feed by secreting enzymes (specifically, cysteine ​​proteases) that destroy blood and liver tissue. The parasite irritates the bile duct wall, causing hyperplasia of the biliary epithelium.

[0007] There are many products available for treating mammals (particularly ruminants, such as sheep and cattle) against fascioliasis. When recommending a treatment plan, it is important to use agents that target the adult stages of Fasciola spp. that are most likely to be present in the diseased animal at the time, in order to reduce selective pressure.

[0008] Of the available flukecidal compounds, only one compound, triclabendazole (TCBZ), is effective against the adult stage of liver fluke (Fasciola hepatica) and all immature stages, i.e., early immature larvae (1-6 weeks old) and immature larvae (6-9 weeks old). In fact, it is the only flukicide effective against all early immature liver fluke larvae.

[0009] However, repeated and frequent use can lead to resistance to flukeicides. To reduce the likelihood of TCBZ-resistance developing, alternative drugs should be used whenever possible, especially in late winter and spring.

[0010] Other drugs for treating livestock infected with Fasciola include albendazole, closantel, nitroxynil, and oxyclozanide. However, all of these drugs are effective only against mature flukes and not against immature stages, such as early immature larvae (1-6 weeks old) and immature larvae (6-9 weeks old). Closantel is partially effective against flukes 3-8 weeks old and fully effective against mature flukes; nitroxynil is effective against flukes from 8 weeks after infection, and clorsulon, oxyclozanide, and albendazole are only effective against mature flukes.

[0011] Therefore, current treatment options have the drawback that most compounds are ineffective against immature flukes in the migratory stage, where the most severe damage to liver tissue occurs as they migrate toward the bile duct.

[0012] Due to the impending resistance to triclabendazole and other flukecidal compounds and the lack of effective alternative drugs, there is an urgent need in the art for alternative treatment options.

[0013] SUMMARY OF THE INVENTION It is an object of the present invention to overcome at least one of the above problems.

[0014] Isoxazoline compounds are known in the art and are described, for example, in U.S. Patent Application US2007 / 0066617 and International Patent Applications WO2005 / 085216, WO2007 / 079162, WO2009 / 002809, WO2009 / 024541, WO2009 / 003075, WO2009 / 080250, WO2010 / 070068 and WO2010 / 079077. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] US2007 / 0066617 [Patent Document 2] WO2005 / 085216 [Patent Document 3] WO2007 / 079162 [Patent Document 4] WO2009 / 002809 [Patent Document 5] WO2009 / 024541 [Patent Document 6] WO2009 / 003075 [Patent Document 7] WO2009 / 080250 [Patent Document 8] WO2010 / 070068 [Patent Document 9] WO2010 / 079077 Summary of the Invention [Problem to be solved by the invention]

[0016] This class of compounds is known to have excellent activity against ectoparasites, i.e., parasites that live permanently or temporarily on the external surface of animals (e.g., parasitic insects and mites such as ticks, fleas, and mites).

[0017] However, the efficacy of isoxazoline compounds for treating fascioliasis has not been reported in the prior art. [Means for solving the problem]

[0018] Summary of the Invention The present applicant has addressed the problems of the prior art by identifying compounds that are effective in treating fascioliasis.

[0019] The present invention provides a compound of formula (I) for use in the treatment of fascioliasis in mammals [ka] [During the ceremony, R 1 ~R 5is H, F, Cl or CF3; X is O or S, preferably O; Y is [ka] is selected from where: [ka] indicates a bond to an isoxazoline or isothiazolinone; [ka] indicates the bond to the carbonyl group; Z is [ka] is selected from where [ka] indicates a bond to a carbonyl group. The present invention provides a compound represented by the formula:

[0020] Another aspect of the invention is a composition comprising the compound described above and a pharmaceutically acceptable carrier for use in the treatment of fascioliasis in a mammal.

[0021] In an alternative embodiment, the compound for use according to the present invention is tigolaner.

[0022] Detailed Description of the Invention The present inventors have discovered that compounds of formula (I) address this problem by providing a new option for the treatment of fascioliasis.

[0023] These compounds have been found to be particularly effective against immature liver flukes in mammals (i.e., liver flukes less than 9 weeks old), whereas most commercially available fasciolicides are more effective against mature liver flukes (i.e., liver flukes greater than 9 weeks old), and indeed many such commercially available compounds are not very effective against immature liver flukes.

[0024] Thus, the use of compounds of formula (I) provides a valuable complementary treatment for fascioliasis when used alone or in combination with existing therapies. DETAILED DESCRIPTION OF THE INVENTION

[0025] Definitions and General Preferred Embodiments As used herein, unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meaning that such terms may enjoy in the art.

[0026] Unless the context requires otherwise, the use of the singular herein should be construed to include the plural and vice versa. The word "a" or "an" when used in reference to an entity should be construed to refer to any one or more of that entity. As such, the terms "a" (or "an"), "any or more," and "at least one" are used interchangeably herein.

[0027] The term "fascioliasis" refers to clinical or asymptomatic disease in mammals associated with infection with the mammalian liver fluke Fasciola hepatica or Fasciola gigantica.

[0028] In one embodiment, fascioliasis results from infestation with immature or early immature liver flukes and the symptoms associated with such infestation.

[0029] The severity of fascioliasis ranges from devastating disease in sheep, pseudoruminants such as alpacas, and llamas to asymptomatic infections that are more common in cattle.

[0030] Acute disease develops 2-6 weeks after ingestion of a large number of metacercariae in a short period of time. In sheep, acute fascioliosis occurs seasonally and is manifested by abdominal distension and pain, anemia, and sudden death. The acute syndrome can be exacerbated by co-infection with Clostridium novyi, resulting in black disease (clostridial necrotic hepatitis).

[0031] In subacute disease, large numbers of metacercariae are ingested over a prolonged period; even in cases of extensive liver damage, survival is relatively long (7-10 weeks), but death occurs due to hemorrhage and anemia. Subacute fascioliasis is characterized by jaundice, poor growth, and anemia. The perforating stage causes extensive tissue damage, leading to hemorrhage and liver damage, resulting in severe anemia, liver failure, and death.

[0032] Chronic fascioliosis can occur in any season but occurs primarily in late autumn and winter and results from the ingestion of moderate numbers of metacercariae over a long period of time.

[0033] Chronic fascioliasis is the most common form of liver fluke infection in sheep, goats, and cattle, and especially in more resistant hosts such as horses and pigs. It develops when the parasite reaches the bile ducts of the liver. The flukes feed on blood, causing severe anemia and chronic inflammation and enlargement of the bile ducts. Clinical signs appear slowly. The animal becomes increasingly anemic, loses appetite, develops pale mucous membranes of the mouth and eyes, and some animals develop swelling under the jaw ("bottle jaw"). Infected animals become reluctant to move.

[0034] Significant productivity losses due to (especially subclinical) fascioliasis in livestock include: in sheep, reduced wool production and quality, reduced birth rate, reduced lamb growth rate, and / or increased replacement livestock costs; in cattle, reduced birth rate, reduced calf growth rate, and / or increased replacement livestock costs; in dairy cows, reduced milk production and quality, and in feedlot cattle, reduced growth rate and feed conversion.

[0035] The term "liver fluke infection" refers to the infestation of a mammal with the parasite Fasciola hepatica or Fasciola gigantica. Unless otherwise indicated, the term includes infestation or infection with any and all adult stages of flukes and mixed adult stages.

[0036] Liver flukes have a complex life cycle: in the definitive host, Fasciola spp. are divided into three stages: early immature, immature and mature (commonly referred to as adult).

[0037] In one embodiment, fascioliasis is caused by infection with early immature stages of liver flukes, ie, early immature larvae (1-6 weeks old).

[0038] In another embodiment, fascioliasis is caused by infection with immature liver flukes, ie, immature larvae (6-9 weeks old).

[0039] In another embodiment, fascioliasis is caused by liver fluke infection with adult liver flukes, ie, mature flukes (>9 weeks old).

[0040] In a preferred embodiment, the compounds for use according to the invention are effective against all immature liver fluke larvae.

[0041] In a further preferred embodiment, the compounds for use according to the invention are effective against all stages of liver fluke.

[0042] The term "mammal" refers to a warm-blooded vertebrate animal having hair or fur and whose females produce milk for the nourishment of their young, including humans. Particular mammals are ruminants, such as cattle, sheep, goats, bison, cape buffalo, water buffalo, antelope, deer, moose, elk, and giraffes.

[0043] Furthermore, the term "mammals" also includes so-called pseudoruminants, such as llamas and alpacas.

[0044] Additionally, the term "mammal" includes other susceptible animals such as horses, pigs, and donkeys.

[0045] More particularly, mammals are understood to be sheep, goats, bison, cape buffalo, water buffalo and cattle. Even more particularly, mammals are sheep and cattle.

[0046] In one embodiment, the mammal is a ruminant. In a preferred embodiment, the mammal is selected from the group consisting of sheep and cattle. In one embodiment, the ruminant is a sheep. In another embodiment, the ruminant is a cattle.

[0047] According to the present invention, the term "veterinary" has the same definition as "pharmaceutical", but applied to mammalian animals (meaning non-human).

[0048] More precisely, "veterinary drug" (or pharmaceutical product or composition) means a compound or mixture of compounds (customarily together with inactive formulation ingredients) that is used, or manufactured, sold, or represented as suitable for use, in the diagnosis, treatment, control, eradication, mitigation, or prevention of disease or abnormal physical or mental condition, or symptoms thereof, in animals; or in the restoration, correction, control, or alteration of physical, mental, or organic function in animals.

[0049] As used herein, "treatment" and similar terms, such as "treating" or "treat," refer to the administration of an effective amount of a compound described for use herein to a mammal diagnosed with and / or exhibiting symptoms of more or less severe fascioliasis.

[0050] A skilled clinician can readily determine which mammals require the treatment of the present invention. Typical symptoms of acute, subacute, and chronic fasciolosis have been described above. Symptomatic fasciolosis can be detected by antibody tests, particularly ELISA tests, of blood and milk, among others.

[0051] Fascioliasis, a symptomatic cause of Fasciola spp. infection, can also be diagnosed by testing stool specimens, including ELISA tests. Furthermore, modeling based on season, rainfall, temperature, and other local conditions can be used to predict when fascioliasis is likely to occur.

[0052] Preferably, fascioliasis is treated during the fall, winter or early spring seasons.

[0053] Autumn is the time when grazing mammals are most likely to ingest large numbers of liver fluke metacercariae in pastures. In Australia, this is April / May. Once ingested, liver fluke larvae migrate through the liver, damaging liver tissue and causing blood loss.

[0054] This high-risk situation often continues into the winter and early spring seasons (e.g., depending on weather conditions), so another treatment can be administered during the late winter / early spring, which in Australia is August / September.

[0055] It is therefore important that certain compounds provide effective treatment of the developmental stages of liver flukes present during this high-risk period. These include all developmental stages of liver flukes, but of particular importance is activity against the immature larval stages, and in particular the early immature larvae present during this period.

[0056] In one embodiment, the compounds for use according to the invention are particularly useful in situations where fascioliasis in mammals (especially cattle or sheep) is due to infection with immature liver fluke stages and such infections are treated in the autumn, winter or early spring seasons. This provides a highly useful treatment option for treating fascioliasis and the symptoms of such diseases during seasons when the risk of injury to infected animals is particularly high, when immature liver fluke stages predominate.

[0057] In another embodiment, the compounds for use according to the present invention are used for summer treatment (sometimes referred to as "mid-season treatment"), when the mammal being treated has primarily adult stages of liver flukes and symptoms of this infection present. In Australia, this occurs in January / February.

[0058] An "effective amount" for use in the present invention is the amount, therapeutic dose or quantity of a compound described herein that is necessary to significantly reduce the parasite infestation in the animal and that, when administered to a mammal for treating a disease, is sufficient to alleviate or prevent the symptoms of acute, subacute or chronic fascioliasis and effect such treatment of the disease.

[0059] The "therapeutically effective amount" for the treatment of various forms of fascioliasis will vary depending on the particular compound, the form of veterinary medicine, the age, weight, etc. of the mammal being treated.

[0060] Compounds of formula (I) for use in the present invention are as follows: [ka] R 1 ~R 5 is H, F, Cl or CF3; X is O or S, preferably O; Y is [ka] is selected from where: [ka] indicates a bond to an isoxazoline or isothiazolinone; [ka] indicates the bond to the carbonyl group; Z is [ka] is selected from where [ka] indicates a bond to a carbonyl group.

[0061] In a preferred embodiment of the present invention and / or its embodiments, the compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3), also known as fluralaner.

[0062] In one preferred embodiment of the invention and / or its embodiments, the compound is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalene-carboxamide (CAS RN 1093861-60-9). This compound is also known as 4-[5-(5-chloro-α,α,α-trifluoro-m-tolyl)-4,5-dihydro-5-(trifluoromethyl)-1,2-oxazol-3-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethylamino]ethyl]naphthalene-1-, or afoxolaner. Afoxolaner is disclosed, for example, in WO 2007 / 079162. In one embodiment, the isoxazoline compound is esafoxolaner.

[0063] In one particularly preferred embodiment of the present invention and / or its embodiments, the compound is 1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidin-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one, preferably 1-(5'-((5S)-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidin-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one (CAS RN: 1398609-39-6). This compound is known as sarolaner.

[0064] In one preferred form of the invention and / or its embodiments, the compound is 3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide, preferably methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[(5S)-5(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is known as lotilaner.

[0065] In one preferred form of the invention and / or its embodiment, the compound used instead 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), also known as tigolaner.

[0066] In one preferred form of the invention and / or its embodiments, the compound is 4H-cyclopenta[c]thiophene-1-carboxamide, 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-(CAS 1414642-93-5), also known as mivorilaner.

[0067] In one preferred form of the invention and / or its embodiments, the compound of formula (I) is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).

[0068] In one preferred form of the invention and / or its embodiments, the compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0), which is disclosed in WO2009 / 0080250.

[0069] In one preferred form of the invention and / or its embodiments, the compound is 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN 1231754-09-8), which is disclosed in WO2010 / 070068.

[0070] In one preferred form of the invention and / or embodiment thereof, the compound of formula (I) is selected from fluralaner (which includes (S)-fluralaner), afoxolaner (which includes esafoxolaner), sarolaner or lotilaner.

[0071] Particularly preferred as systemic insecticide and / or acaricide (a) is fluralaner (which corresponds to "4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide"), which has the formula (II): [ka] It is expressed as:

[0072] Compounds for use according to the present invention can exist in various isomeric forms. Reference to a compound always encompasses all possible isomeric forms of such a compound. Unless otherwise indicated, a compound structure that does not depict a particular conformation is intended to encompass all possible conformational isomeric compositions of that compound, and compositions of fewer than all possible conformations.

[0073] The compounds of formula (I) can be prepared, for example, according to any of the processes described in patent applications US2007 / 0066617, WO2007 / 079162, WO2009 / 002809, WO2009 / 080250, WO2010 / 070068, WO2010 / 079077, WO2011 / 075591 and WO2011 / 124998, or according to any other process within the capabilities of a person skilled in chemical synthesis.

[0074] With regard to chemical preparations, the skilled artisan is deemed to have at his disposal, inter alia, the entire contents of Chemical Abstracts and the references cited therein.

[0075] The present invention also covers compositions for use according to the invention that comprise two or more pharmaceutically active ingredients (ie, the composition for oral administration comprises another pharmaceutically active ingredient).

[0076] As used herein, the term "comprise" or variations thereof, such as "comprises" or "comprising," is to be interpreted as indicating the inclusion of any stated integer (e.g., feature, element, characteristic, property, method / process step or limitation) or group of integers (e.g., feature, element, characteristic, property, method / process step or limitation) and not the exclusion of any other integer or group of integers.

[0077] Thus, as used herein, the term "comprising" is inclusive or open-ended and does not exclude additional, unrecited components or method / process steps.

[0078] As used herein, the terms "in combination with," "combination," and "synergistic combination" are understood to mean that a compound other than the compound of formula (I) or another compound of formula (I) is administered before, during, or after the administration of a compound of formula (I), i.e., sequentially or simultaneously to a mammal. In a preferred embodiment, the combination is with a compound other than the compound of formula (I).

[0079] Typically, sequential administration means administration within three days of the other.

[0080] More typically, the compounds used in the present invention, along with the combination compounds, will be administered within one day of each other, and even more typically, on the same day.

[0081] Sequential administration also means administration of such compounds within an hour, or even within minutes, of the administration of the other compound.

[0082] Co-administration preferably includes the presence of such compounds in the same veterinary drug.

[0083] Those skilled in the art of veterinary pharmacy are fully familiar with the identity of such active ingredients, which include, but are not limited to, antiparasitic agents, such as endoparasiticides (including anthelmintics) and ectoparasiticides, hormones and / or their derivatives, anti-inflammatory compounds, and minerals and vitamins.

[0084] Particularly preferred is a combination with selenium, especially sodium selenate.

[0085] The active ingredient is preferably an antiparasitic agent, more preferably an endoparasiticide, preferably an anthelmintic agent, and is preferably selected from the group consisting of: avermectins (e.g., ivermectin, doramectin, abamectin, eprinomectin); milbemycins (moxidectin and milbemycin oxime); probenzimidazoles (e.g., febantel, netobimin and thiophanate); benzimidazole derivatives, for example, thiazole benzimidazole derivatives (e.g., thiabendazole and cambindazole), carbamate benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide), mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole and triclabendazole); imidazothiazoles (e.g., levamisole and tetramisole); tetrahydropyrifos amides (morantel and pyrantel); salicylanilides (e.g., closantel, oxyclozanide, rafoxanide, and niclosamide); nitrophenols (e.g., nitroxynil and nitroscanate); benzenedisulfonamides (e.g., clorsulon); pyrazoinoisoquinolines (e.g., praziquantel and epsiprantel); heterocyclic compounds (e.g., piperazine, diethylcarbamazine, and phenazine); Thiazines); dichlorophen; arsenic compounds (e.g., thiacetarsamide, melorusamine, and arsenamide); cyclooctadepsipeptides (e.g., emodepside); paraherquamides (e.g., dequantel); and aminoacetonitrile compounds (e.g., monempantotel); amidine compounds (e.g., amidantel and tribendimidine); these include all pharmaceutically acceptable forms (e.g., salts, solvates, or N-oxides).

[0086] Particularly preferred are combinations with ivermectin, eprinomectin, moxidectin, levamisole, fenbendazole, abamectin, monepantel, derquantel, oxfendazole, albendazole, closantel and combinations thereof.

[0087] An effective amount of a compound for use according to the present invention may be administered orally or parenterally to a mammal.

[0088] In one embodiment, the effective amount is administered orally to the mammal.

[0089] In one embodiment, the effective amount is administered parenterally to the mammal.

[0090] Generally, the compounds will be administered to an animal in need thereof in the form of a pharmaceutical or veterinary composition.

[0091] Such compositions for oral administration contain ingredients conventionally used in the art of formulation and can therefore be processed in known manner to give, for example, solutions, emulsions, soluble powders, powder mixtures, granules or microcapsules in polymeric materials.

[0092] Such formulations, preparations or compositions optionally include a solid or liquid adjuvant and are prepared in a manner well known in the art, for example by intimately mixing and / or comminuting the active ingredient with the adjuvant (e.g., solvent, solid carrier, etc.).

[0093] Oral administration can be by drench, gavage, tablet, capsule or in the feed.

[0094] Many veterinary compositions are known to be suitable for oral administration to animals, although these vary for different animal species. Oral administration can be carried out in conventional dosage forms, such as by drench, gavage, tablet, capsule or included in the feed.

[0095] In sheep, pharmaceutically active ingredients are traditionally administered orally as a solid (e.g., tablet or bolus) or liquid and via the sheep's feed or drinking water. In large sheep flocks, oral drenches are the most common form of oral administration.

[0096] Drenching refers to the oral administration of a liquid pharmaceutical composition containing a pharmaceutical active ingredient and excipients, which may be slightly viscous, using a special drenching gun that delivers the composition down the sheep's throat.

[0097] Oral drench compositions are generally solutions or suspensions, and typically no more than 20 mL (preferably no more than 15 mL) of drench is administered per sheep.

[0098] In one embodiment, the compound for use according to the invention is administered to sheep by drench application using a concentrated solution.

[0099] In another embodiment, a suspension formulation is used for drench application.

[0100] Excipients may include conventional inactive ingredients or excipients that are pharmaceutically and veterinarily acceptable, such as fillers, binders, flavoring agents, solvents, coloring agents, glidants, preservatives, viscosity enhancers, surfactants, stabilizers (e.g., antioxidants), and the like.

[0101] Pharmaceutical excipients are excipients well known to those skilled in the art, for example those described in the European Pharmacopoeia.

[0102] Parenteral administration includes injectable administration, particularly subcutaneous administration, which is the preferred route of administration for large ruminants such as cattle.

[0103] Many veterinary compositions (generally liquid compositions, e.g., solutions or suspensions of a compound of formula (I) in pharmaceutically acceptable solvents and / or suspending agents) are known to be suitable for subcutaneous administration to animals.

[0104] Compositions for subcutaneous administration can be either liquid solutions or suspensions, or semi-solid or solid compositions (eg, implants).

[0105] A solution is a mixture of two or more components that forms a single, molecularly uniform phase. A suspension consists of insoluble solid particles dispersed in a liquid medium, where the solid particles comprise from about 0.5% to about 30% of the suspension. The liquid can be aqueous, oil-based, or both.

[0106] An example of a suitable injectable solution of the compound (particularly fluralaner) is a pharmaceutical composition comprising an isoxazoline compound and a pharmaceutically acceptable carrier, which includes 2-pyrrolidone, PEG, and propylene glycol. An alternative is an aqueous suspension.

[0107] The amount of each component in the final product may vary widely depending on the nature of the pharmaceutical active ingredient, the weight and condition of the subject to be treated and the desired unit dosage.

[0108] Generally, an effective dose of a compound of formula (I) is 0.5 mg / kg body weight to 50 mg / kg body weight. One skilled in the art would be able to adjust the dosage of a particular compound in the composition in light of the teachings of the present disclosure and available information regarding such compounds.

[0109] Products according to the present invention will conventionally further comprise physiologically acceptable pharmaceutical excipients known in the art, for example, as described in Gennaro, Remington: The Science and Practice of Pharmacy (20th Edition, 2000), which is incorporated herein by reference.

[0110] All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinarily pure and non-toxic in the amounts used, and must be compatible with the pharmaceutical active ingredient.

[0111] Veterinary compositions for use according to the present invention may, in one embodiment, be mixed with existing commercial products prior to administration to the animal.

[0112] In one embodiment, the composition comprises an effective amount of a compound for use according to the invention in combination with another compound (or a commercial product comprising such a compound) that controls another parasitic infection (e.g. a parasitic helminth, or alternatively an ectoparasite, in particular myiasis). In a particular embodiment, two compounds of formula (I) as described above are included in a composition that controls different parasites.

[0113] Example The present invention will now be described with reference to specific examples, which are merely exemplary and for illustrative purposes only; they are not intended in any way to limit the scope of the claimed exclusive rights or the invention described. [Example]

[0114] Example Materials and Methods: The effects of test compounds in a whole organism screen of newly excysted juvenile (NEJ) stages of Fasciola hepatica were investigated along with DMSO (-control), triclabendazole (10 μM, +control) and medium, and their anti-trematocidal activity was assessed at both 24 and 72 h time points.

[0115] Compounds were tested at 10 μM and / or at decreasing concentrations of test compound: 25 μM, 12.5 μM, 6.25 μM, 3.125 μM and 1.562 μM.

[0116] [Table 1]

[0117] TIFF2025527799000016.tif55162

[0118] Detection of viability in Fasciola hepatica NEJ is based on qualitative microscopic assessment of motility and phenotype, as well as on measurement of propidium iodide to exploit differential uptake of fluorescent substances (e.g., propidium iodide) by the organism.

[0119] NEJs were prepared according to Edwards et al. [1]. Approximately 12 NEJ / compound cocultures were cultured. NEJ / compound cocultures were placed at 37°C in a humidified atmosphere containing 5% CO2. NEJ / compound cocultures were cultured for a total of 72 hours. At 24 hours, all NEJ / compound cocultures were evaluated for gross phenotype and brightfield images were taken. At 72 hours, both phenotype and motility were quantified compared to live DMSO controls using the microscopic scoring method detailed in [1] and summarized in Table 1 below.

[0120] Propidium iodide (PI) was then added to the NEJ / compound co-cultures (final concentration 2 μg / mL), and these co-cultures were imaged in both bright field and Texas Red settings.

[0121] result: The following compounds were found to be active against Fasciola hepatica NEJ upon viability assessment after 24 hours: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0122] The following compounds caused significant changes in both phenotype and reduced motility after 72 hours that were significantly different from DMSO: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0123] The following compounds were found to induce propidium iodide positivity rates of greater than 90%: 2, 3, 4, 5, 6, 7, and 9.

[0124] Thus, the following compounds showed significant activity against the juvenile stages of Fasciola hepatica: 1, 2, 3, 4, 5, 6, 7, 8 and 9.

[0125] [Table 2]

[0126] Comparative GABA antagonist compounds that did not exhibit antiflukicidal effects against Fasciola hepatica NEJ (phenotypic score less than 3) are shown in Table 2 below. [Table 3]

[0127] References [1] Edwards J, Brown M, Peak E, Bartholomew B, Nash RJ, Hoffmann KF. The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica. PLoS neglected tropical diseases. 2015;9(3):e0003604. Epub 2015 / 03 / 15. doi: 10.1371 / journal.pntd.0003604. PubMed PMID: 25768432。

Claims

1. Formula (I) for use in the treatment of fasciosis in mammals 【Chemistry 1】 [During the ceremony, R １ ~R ５ is H, F, Cl or CF ３ And; X is either O or S, preferably O; Y is, 【Chemistry 2】 Selected from, Here, 【Transformation 3】 This indicates binding to isoxazoline or isothiazolin. 【Chemistry 4】 This indicates bonding to a carbonyl group; Z is, 【Transformation 5】 Selected from, Here 【Transformation 6】 This indicates bonding to a carbonyl group. A pharmaceutical composition containing a compound represented by [the specified formula].

2. The pharmaceutical composition according to claim 1, wherein the compound is selected from fluralaner, (S)-fluralaner, afoxolaner, salolaner, or lotilaner.

3. A pharmaceutical composition comprising a compound for use in the treatment of fasciosis in mammals, wherein the compound is tigolaner.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the mammal is selected from the group consisting of sheep and cattle.

5. A pharmaceutical composition according to any one of claims 1 to 3, wherein fasciosis of the liver is treated in the autumn, winter, or early spring season.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the fasciosis is caused by infection with early immature liver flukes in mammals by early immature larvae aged 1 to 6 weeks.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the fasciosis is caused by infection of a mammal with immature liver flukes by immature larvae aged 6 to 9 weeks.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the fasciosis is caused by mature liver fluke infection in mammals by mature flukes exceeding 9 weeks of age.

9. A pharmaceutical composition for use in the treatment of mammalian fasciitis, comprising a compound referred to in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, comprising an additional active ingredient.

11. The pharmaceutical composition according to claim 9, wherein the composition is administered orally to a mammal.

12. The pharmaceutical composition according to claim 10, wherein the composition is administered orally to a mammal.

13. The pharmaceutical composition according to claim 9, wherein the composition is administered subcutaneously to a mammal.

14. The pharmaceutical composition according to claim 10, wherein the composition is administered subcutaneously to a mammal.

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