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European Patent Office of Opposition to That Patent, in Accordance with the Implementing Regulations (19) TZZ _T (11) EP 2 895 465 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 235/10 (2006.01) C07D 235/18 (2006.01) 03.10.2018 Bulletin 2018/40 C07D 235/28 (2006.01) A01N 43/52 (2006.01) A61K 31/4184 (2006.01) (21) Application number: 13719345.4 (86) International application number: (22) Date of filing: 18.04.2013 PCT/US2013/037193 (87) International publication number: WO 2013/158894 (24.10.2013 Gazette 2013/43) (54) PARASITICIDAL COMPOSITIONS COMPRISING BENZIMIDAZOLE DERIVATIVES, METHODS AND USES THEREOF PARASITIZIDE ZUSAMMENSETZUNGEN MIT BENZIMIDAZOLDERIVATEN, VERFAHREN UND VERWENDUNGEN DAVON COMPOSITIONS PARASITICIDES COMPRENANT DES DÉRIVÉS DE BENZIMIDAZOLE, LEURS PROCÉDÉS ET LEURS UTILISATIONS (84) Designated Contracting States: • CHOMICZ, LIDIA ET AL: "Anti-Pentatrichomonas AL AT BE BG CH CY CZ DE DK EE ES FI FR GB hominis activity of newly synthesized GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO benzimidazole derivatives - in vitro studies", PL PT RO RS SE SI SK SM TR ACTA PARASITOLOGICA , 54(2), 165-171 Designated Extension States: CODEN: ACTPEO; ISSN: 1230-2821, 2009, BA ME XP009170028, • DIAZ-CHIGUER, DYLAN L. ET AL: "In vitro and in (30) Priority: 20.04.2012 US 201261635961 P vivo trypanocidal activity of some benzimidazole derivatives against two strains of Trypanosoma (43) Date of publication of application: cruzi", ACTA TROPICA , 122(1), 108-112 CODEN: 22.07.2015 Bulletin 2015/30 ACTRAQ; ISSN: 0001-706X, 2012, XP009170026, • PEREZ-VILLANUEVA, JAIME ET AL: (60) Divisional application: "Structure-activity relationships of 18186136.0 benzimidazole derivatives as antiparasitic agents: Dual activity-difference (DAD) maps", (73) Proprietor: Merial, Inc. MEDCHEMCOMM , 2(1), 44-49 CODEN: MCCEAY; Georgia 30096 (US) ISSN: 2040-2503, 2011, XP009170027, • PEREZ-VILLANUEVA, JAIME ET AL: "Towards a (72) Inventor: MENG, Charles, Q. systematic characterization of the antiprotozoal Johns Creek, GA 30097 (US) activitylandscape of benzimidazolederivatives", BIOORGANIC & MEDICINAL CHEMISTRY , (74) Representative: D Young & Co LLP 18(21), 7380-7391 CODEN: BMECEP; ISSN: 120 Holborn 0968-0896, 2010, XP027415393, London EC1N 2DY (GB) • KAZIMIERCZUK, Z. ET AL: "Synthesis and antimycobacterial activity of 2-substituted (56) References cited: halogenobenzimidazoles", EUROPEAN DE-A1- 2 016 622 DE-A1- 2 502 116 JOURNAL OF MEDICINAL CHEMISTRY , 40(2), DE-A1- 2 815 621 JP-A- 1 135 773 203-208 CODEN: EJMCA5; ISSN: 0223-5234, US-A- 3 749 789 2005, XP027857753, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 895 465 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 895 465 B1 • HERNANDEZ-LUIS, FRANCISCO ET AL: • ROJAS-AGUIRRE, YARELI ET AL: "Studies on "Synthesis and biological activity of 6-chloro-5-(1-naphthyloxy)-2-(trifluoromet 2-(trifluoromethyl)-1H-benzimidazolederivatives hyl)-1H- against some protozoa and Trichinella spiralis", benzimidazole/2-hydroxypropyl-.beta.-cyclo EUROPEAN JOURNAL OF MEDICINAL dextrin association: Characterization, molecular CHEMISTRY ,45(7), 3135-3141 CODEN: EJMCA5; modeling studies, and in vivo", BIOORGANIC & ISSN: 0223-5234, 2010, XP027050440, MEDICINALCHEMISTRY ,19(2), 789-797 CODEN: • NAVARRETE-VAZQUEZ, G. ET AL: "Synthesis BMECEP; ISSN: 0968-0896, 2011, XP009170199, and antiparasitic activity of 2-(trifluoromethyl)benzimidazole derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS , 11(2), 187-190 CODEN: BMCLE8; ISSN: 0960-894X, 2001, XP004314844, • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HERNANDEZ-LUIS, FRANCISCO ET AL: "Synthesis and biological activity of 2-(trifluoromethyl)-1H-benzimidazolederivatives against some protozoa and Trichinella spiralis", XP027050440, retrieved from STN Database accession no. 2010:619036 2 EP 2 895 465 B1 Description [0001] This application claims priority to U.S. Provisional Patent Application number 61/635,961, filed April 20, 2012. 5 FIELD OF THE INVENTION [0002] The present invention provides oral, topical or injectable veterinary compositions comprising a benzimidazole derivative active agent for controlling liver flukes in mammals. The use of these compounds and compositions against liver flukes and methods for treating parasitic infections and infestations in mammals is presented herein. 10 BACKGROUND OF THE INVENTION [0003] Animals such as mammals (including humans) are often susceptible to parasite infections and infestations. These parasites may be ectoparasites, such as insects, and endoparasites such as filariae and other worms. Production 15 animals, such as cows, pigs, sheep and goats, can be infected with one or more trematodes. Of particular concern here is Fasciola hepatica (i.e., liver fluke or F. hepatica). [0004] Liver flukes are a particular problem because they adversely affect the health of the animal or human and can inflict significant economic loss in a domestic livestock population. It is estimated that F. hepatica poses a risk to at least 250 million sheep and 350 million cattle worldwide. Moreover, domestic animals other than sheep and cows may serve 20 as intermediate hosts. Liver flukes can cause liver condemnation, secondary infections, reduced milk and meat produc- tion, abortion and fertility problems. [0005] Several types of control measures for liver flukes have been introduced over the past century. First, halogenated hydrocarbons (e.g., CCl4; carbon tetrachloride) were introduced for ruminants in the 1920s. Halogenated hydrocarbons had limited success and are no longer used primarily because of their adverse effects and variable efficacy. Second, 25 halogenated phenols were administered in the late 1950s (e.g., hexachlorophene and bithionol sulfoxide) followed by the similar halogenated salicylanilides (e.g., oxyclozanide, bromoxanide). Fourth, benzimidazole carbamates (e.g., al- bendazole, luxabendazole) were found to have a broad anthelmintic spectrum against nematodes and mature F. hepatica. Another benzimidazole - the chlorinated methylthiobenzimidazole derivative triclabendazole - has a high success rate against F. hepatica. Fifth, bisanilino compounds introduced in the 1960s were intolerable due to toxic side effects. Finally, 30 benzene sulfonamides (e.g., clorsulon) were studied in the 1970s. Extensively modified examples of this class demon- strate high efficacy on both mature and immature F. hepatica. Of these six classes of anthelmintics the benzimidazole class is perhaps the most widely used for its high efficacy. [0006] The benzimidazole anthelmintics are widely used to treat internal worm parasites. U.S. Patent No. 4,197,307 discloses 6-phenyl substituted benzimidazoles useful for treating trematodes. The ’307 patent discloses a substitution 35 from the sulfur atom at the 2-position of the imidazole ring as well as a substituted aryloxy or thioaryl group from the 6- position of the benzene ring. [0007] U.S. Patent No. 4,205,077 discloses benzimidazole sulfides as anthelmintic agents. While claiming the same basic 6-phenyl substituted structure of the ’307 patent, the ’077 patent differs in that the sulfur at the 2-position of the imidazole ring is not substituted, leaving it available to form a dimer linked by a disulfide bond. 40 [0008] U.S. Patent No. 4,336,262 discloses a pour-on anthelmintic that is heavily substituted at the 7-position of the benzimidazole ring. In particular, the substitution is a sulfamoyl moiety while the 5- and 6-positions are minimally sub- stituted. [0009] U.S. Patent No. 4,468,390 discloses an anthelmintic composition that is a mixture of a macrolide antibiotic and one of a benzimidazole, a salicylamide or an isoquinoline compound. The benzimidazole compounds disclosed as 45 suitable for use in the ’390 patent are 2-(methoxycarbonylamino)benzimidazole, 5-butyl-2-(methoxycarbonylamino)ben- zimidazole, 5 -propoxy-2-(methoxycarbonylamino)benzimidazole, 5 -ethoxy-2-ethoxycarbonylaminobenzimidazole, 5- propylthio-2-(methoxycarbonylamino)benzimidazole, 5-phenylthio-2-(methoxycarbonylamino)benzimidazole, 5-phenyl- sulphinyl-2-(methoxycarbonylamino)benzimidazole, 5-(2,4-dichlorophenoxy)-6-chloro-2-methylthiobenzimidazole, 6- chloro-5-(2,3-dichlorophenoxy)-2-methylthiobenzimidazole, 2-(4-thiazolyl)benzimidazole, and 5-isopropoxycarbo- 50 nylamino-2-(4-thiazolyl)benzimidazole, however, data is provided only for albendazole ( i.e., 5-propylthio-2-methoxycar- bonylaminobenzimidazole). [0010] Indeed, triclabendazole is the current drug of choice against mature and immature liver flukes. Not surprisingly, however, reports of parasite resistance are increasing. For example, Mottier et al., report that a population of resistant F. hepatica (Sligo) may use an altered influx/efflux mechanism to selectively decrease the amount of triclabendazole 55 and triclabendazole sulfoxide but not albendazole. See Mottier et al., J. Parasitol., 92(6), 2006, pp. 1355-1360. McConville et al., report that juvenile triclabendazole-resistant F. hepatica are somewhat susceptible to compound alpha i.e.,( 5- chloro-2-methylthio-6-(1-naphthyloxy)-1H-benzimidazole) via a tubulin-independent mechanism. See McConville et al., Parasitol. Res., (2007) 100:365-377.
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