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(12) STANDARD PATENT (11) Application No. AU 2015276941 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2015276941 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2015276941 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Parasiticidal compositions comprising indole derivatives, methods and uses thereof (51) International Patent Classification(s) C07D 401/04 (2006.01) C07D 209/10 (2006.01) A01N 43/38 (2006.01) C07D 401/12 (2006.01) A01N 43/40 (2006.01) HO3K 5/04 (2006.01) A01P 15/00 (2006.01) HO3K 7/00 (2006.01) C07D 209/08 (2006.01) (21) Application No: 2015276941 (22) Date of Filing: 2015.06.19 (87) WIPO No: W015/196014 (30) Priority Data (31) Number (32) Date (33) Country 62/014,245 2014.06.19 US (43) Publication Date: 2015.12.23 (44) Accepted Journal Date: 2018.07.19 (71) Applicant(s) Merial, Inc. (72) Inventor(s) Meng, Charles;Le Hir De Fallois, Loic (74) Agent / Attorney FB Rice Pty Ltd, L 23 44 Market St, Sydney, NSW, 2000, AU (56) Related Art Spycher, S., et al. "Mode of action-based classification and prediction of activity of uncouplers for the screening of chemical inventories."(2008) SAR and QSAR in Environmental Research vol 19(5-6) page 433-463. JOHN F. POLETTO ET AL, "Synthesis and antiinflammatory evaluation of certain 5-alkoxy-2,7-dialkyltryptamines", JOURNAL OF MEDICINAL CHEMISTRY, (1973), vol. 16, no. 7, pages 757 - 765 CONDE J J ET AL, "Towards the synthesis of osteoclast inhibitor SB-242784", TETRAHEDRON LETTERS, (2003), vol. 44, no. 15, pages 3081 - 3084 WANG ET AL, JOURNAL OF FLUORINE CHEMISTRY, (2007), vol. 128, no. 10, pages 1143 - 1152 WO 2012088431 Al WO 2011060746 Al HONG X ET AL, "Photodesulfonylation of indoles initiated by electron transfer from triethylamine", TETRAHEDRON LETTERS, (2006) vol. 47, no. 14, pages 2409 - 2412 CAN ZHU ET AL, "Coupling and Cyclization of o -lodoanilines and Propargylic Bromides via Allenes: An Efficient Entry to Indomethacin", ORGANIC LETTERS, (2013), vol. 15, no. 11, pages 2782 - 2785 LARISA V. POLITANSKAYA ET AL, "Synthesis of indoles with a polyfluorinated benzene ring", TETRAHEDRON, (2013), vol. 69, no. 39, pages 8477 - 8486 JP 2008179621 A CAS Registry Number: 1557409-29-6, STN entry Date: 28 Feb 2014; Chemical name: 1H-indole-5-propanamine, 2-methyl CAS Registry Number: 1525574-68-8, STN entry Date: 21 Jan 2014; Chemical name: 1H-indole-5-propanamine, 4-chloro-2-methyl CAS Registry Number: 1535977-75-3, STN entry Date: 04 Feb 2014; Chemical name: IH-Indole, 4-chloro-2-methv-5-(3-Dvrrolidinvl- 1 H-indole-5-ethanamine, 2-(trifluoromethyl) CAS Registry Number: 1427419-53-1, STN entry Date: 08 Apr 2013; Chemical name: 1H-indole, 6-chloro-2-ethyl-5-methyl WO 2012/088431 Al JP 2008/037760 A DE 19515371 Al Lim, Y.-K. and Cho, C.-G., Expedient synthesis of indoles from N-Boc aryihydrazines, Tetrahedron Letters, (2004), vol 45, pages 1857-1859 CAS Registry Number: 906780-86-7; STN entry date: 15 Sep 2006; Chemical name: 1H-indole, 2-(1,1-dimethylethyl)-5-phenyl CAS Registry Number: 1368588-05-9; STN entry date: 15 Apr 2012; Chemical name: 1H-indole, 2-methyl-5-phenoxy Mattsson, C. et al. "Structure5E"activity relationship of 5-chloro-2-methyl-3-(1, 2, 3, 6-tetrahydropyridin-4-y)-1 H-indole analogues as 5-HT 6 receptor agonists." European Journal of Medicinal Chemistry, (2013), vol 63, pages 578-588. (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2015/196014 A1 23 December 2015 (23.12.2015) W I P 0 I P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated,for every C07D 401/04 (2006.01) A01N43/38 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 401/12 (2006.01) A01N 43/40 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 209/08 (2006.01) A01P 15/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 209/10 (2006.01) DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2015/036580 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 19 June 2015 (19.06.2015) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated,for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/014,245 19 June 2014 (19.06.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: MERIAL, INC. [US/US]; 3239 Satellite DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Blvd., Duluth, GA 30096 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: MENG, Charles; 2291 Chance Lane, Grayson, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GA 30017 (US). LE HIR DE FALLOIS, Loic; 2259 GW, KM, ML, MR, NE, SN, TD, TG). Fairhaven Circle NE, Atlanta, GA 30305 (US). Published: (74) Agent: JARECKI-BLACK, Judy; 3239 Satellite Blvd., - with internationalsearch report (Art. 21(3)) Duluth, GA 30096 (US). (54) Title: PARASITICIDAL COMPOSITIONS COMPRISING INDOLE DERIVATIVES, METHODS AND USES THEREOF f (57) Abstract: The invention relates to oral, topical or injectable compositions for combating liver fluke parasites in mammals, com prising at least one indole derivative active agent. The invention also provides for an improved method for eradicating and con trolling liver fluke parasite infections and infestations in a mammal comprising administering the compositions of the invention to the mammal in need thereof. WO 2015/196014 PCT/US2015/036580 PARASITICIDAL COMPOSITIONS COMPRISING INDOLE DERIVATIVES, METHODS AND USES THEREOF INCORPORATION BY REFERENCE This application claims priority to provisional application USSN 62/014,245, filed on 19 June, 2014, and incorporated by reference herein in its entirety. FIELD OF THE INVENTION The present invention provides parasiticidal indole derivatives and oral, topical or injectable veterinary compositions comprising an indole 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. BACKGROUND OF THE INVENTION 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 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). 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 as intermediate hosts. Liver flukes can cause liver condemnation, secondary infections, reduced milk and meat production, abortion and fertility problems. Several types of control measures for liver flukes have been introduced over the past century. First, halogenated hydrocarbons (e.g., CCl 4 ; 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, halogenated phenols were administered in the late 1950s (e.g., hexachlorophene and bithionol sulfoxide) followed by 1 WO 2015/196014 PCT/US2015/036580 the similar halogenated salicylanilides (e.g., oxyclozanide, bromoxanide). Fourth, benzimidazole carbamates (e.g., albendazole, 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, benzene sulfonamides (e.g., clorsulon) were studied in the 1970s. Extensively modified examples of this class demonstrate 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. 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 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. Further, Keiser et al., report the testing of artemether and OZ78 in triclabendazole-resistant F. hepatica, although at high concentrations. For a short review of triclabendazole resistance see Brennan et al., Experimental and Molecular Pathology, 82, (2007) pp. 104-109. There is, however, little in the literature disclosing indoles as a treatment for trematodes.
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