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WO 2014/041424 Al 20 March 2014 (20.03.2014) P O P C T

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WO 2014/041424 Al 20 March 2014 (20.03.2014) P O P C T (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 WO 2014/041424 Al 20 March 2014 (20.03.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every Λ 61Κ 31/16 (2006.01) C07C 259/06 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/381 (2006.01) C07D 209/08 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/404 (2006.01) C07D 295/088 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/495 (2006.01) C07D 295/192 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/5375 (2006.01) C07D 333/24 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, A61P 31/10 (2006.01) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/IB20 13/002 183 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 13 September 2013 (13.09.201 3) ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/701,337 14 September 2012 (14.09.2012) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: METHYLGENE INC. [CA/CA]; 7150 Fred MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, erick-banting, Suite 200, Montreal, QC H4S 2A1 (CA). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: RAEPPEL, Franck; 3194 Claude Jodoin, Montreal, QC H1Y 3M2 (CA). RAEPPEL, Stephane; Published: 2620 De L'etrier, St-Lazare, QC J7T 3L8 (CA). VAIS- — with international search report (Art. 21(3)) BURG, Arkadii; 10 Riverwood Grove, Kirklan, QC H9J 2X2 (CA). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agent: MBM INTELLECTUAL PROPERTY LAW amendments (Rule 48.2(h)) LLP; 270 Albert Street, 14th Floor, Ottawa, Ontario KIP 5GB (CA). (54) Title: HISTONE DEACETYLASE INHIBITORS FOR ENHANCING ACTIVITY OF ANTIFUNGAL AGENTS o (57) Abstract: The present invention relates to compositions and methods to selectively treat fungal infection. More particularly, the o invention relates to compounds, compositions thereof, and methods for selectively enhancing fungal sensitivity to antifungal com - pounds. The compositions of the invention are comprised of a combination of a histone deacetylase inhibitor, or an N-oxide, hy drate, solvate, pharmaceutically acceptable salt, agricultural formulation, prodrug or complex thereof, and an antifungal agent, the histone deacetylase inhibitor being a compound of Formula (I). HISTONE DEACETYLASE INHIBITORS FOR ENHANCING ACTIVITY OF ANTIFUNGAL AGENTS BACKGROUND OF THE INVENTION [0001] This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 61/701,337 filed September 14, 20 2, which is hereby incorporated by reference in its entirety. Field of the invention [8002] The invention relates to compounds, compositions thereof, and methods to treat fungal infection. More particularly, the invention relates to compounds, compositions thereof, and methods for enhancing fungal sensitivity to antifungal compounds. Summary of the Related Art [8003] In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, w h the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA Approximately 46 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin. [8004] Csordas, (1990, Biochem. J., 286: 23-38) teaches that histones are subject to post- translationa] acetylation of amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (ΗΑΤΊ ). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton ei al. (1996, Science, 272: 408-41 1), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton ei al. (supra) further teaches that an enrichment in under-acetylated histone H4 has been found in transcriptionally silent regions of the genome. [8005] Histone acetylation is a reversible modification, with deaeetylatton being catalyzed by a family of enzymes termed histone deacetyfases (HDACs). The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Based on phylogeneiic analyses and sequence homology to yeast pd3 (reduced potassium dependency 3), Hdal and Sir2 (silent information regulator 2), HDACs are grouped into different classes (Jang and Gregoire, 2005, Molecular a d Cellular Biology, 25(8):2873-2884). In humans there are 18 known HDACs, which are divided into four classes: class I (HDAC1, -2, -3 and -8; homologous to Rpd3), class II (HDAC4, -5, -6, -7, -9 and - 10; related to Hdal), class III (Sirtl, -2, -3, -4, -5, -6 and - 7; similar to Sir2) and class IV (HDAC 11). Class I, II and IV HDACs are zinc-dependent enzymes. Class III HDACs are NAD + dependent deacetylases. In Saccharomyces cerevisiae there are known HDACs, which are divided into three classes: class I (Rpd3, Hos and Hos2), class II (Hda l and Hos3), and class II (Sir2 and four Hst proteins, homologs of Sir2). [8(506] It has been unclear what roles these individual HDAC enzymes play. Trojer et al. (2003, Nucleic Acids Research, 3 1(14):397 1-398 ) indicate that HdaA and RpdA are major contributors to total HDA C activity of the filamentous fungus Aspergillusnidulans, with HdaA accounting for the main part of the HDAC activity [8007] Studies utilizing known HDAC inhibitors have established a link between acefylation and gene expression. Numerous studies have examined the relationship between HDAC a d gene expression. Taunton et al., Science 272:408-4 (1996), discloses a human HDAC that is related to a yeast transcriptional regulator. Cress et al , J. Cell. Phys. 84: 1-16 (2000), discloses thai, in the context of human cancer, the role of HDAC is as a corepressor of transcription. Ng et al., TIBS 25: March (2000), discloses HDAC as a pervasive feature of transcriptional repressor systems. Magnaghi-Jaulin et al. Prog. Cell Cycle Res. 4:4 1-47 (2000), discloses HDAC as a transcriptional co-regulator important for cell cycle progression. [8008] Numerous reports have been made describing inhibitors of HDAC activity . For example, Richon et al. , Proc. Natl. Acad. Sci. USA, 95: 3003-3007 ( 998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyceshygroscopicus, which has been shown to inhibit histone deacetylase activity and arrest cell cycle progression in cells in the G and G2 phases (Yoshida et al., 990, J. Biol. Chem. 265: 17 74- 17179; Yoshida e t al., 1988, Exp. Cell Res. 177: 22-13 1), and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu ( 988, Exper. Cell Res., 77: 122- 13 1) teach that TSA causes arrest of rat fibroblasts at the Gj and G2 phases of the cell cycle, implicating HDAC in ceil cycle regulation. Indeed, Finnin et al. ( 1999, Nature, 40 :188- 93), teach that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice. Other non-limiting examples of compounds that serve as HDAC inhibitors include those of WO 0 1/38322 and WO 01/70675. The A. nidulans Hdal enzyme is highly sensitive to the HDAC inhibitor TSA, while HosB has been shown to be highly resistant to both TSA and another HDAC inhibitor, HC toxin (Trojer et al., supra). [8( 09 Smith and Edlind (2002, Antimicrobial Agents and Chemotherapy, 46(1 i):3532- 3539) tested the ability of known HDAC pan- inhibitors TSA, apicidin, sodium bu yra e and trapoxisi to enhance the sensitivity of selected fungal species to azole antifungal agents. They found that only TSA was able to enhance the sensitivity of Candida albicans. However, the concentrations of TSA required were higher than those toxic to mammalian cells. TSA was not found to enhance the sensitivity Candida glabrata. [00 ] The use of, and need for, antifungal agents is widespread and ranges from the treatment of mycotic infections in animals; to disinfectant formulations; to pharmaceuticals for human use. A major problem with current antifungal formulations is their toxicity to the infected host. This is particularly important in cases where many fungal infestations are opportunistic infections secondary to debilitating diseases, such as AIDS or from cancer chemotherapy or organ transplants. Correspondingly, at least for antifungal agents that are to be administered to humans and other animals, the therapeutic index is preferably such that toxicity is selective to the targeted fungus without being toxic to the host [001 ] Serious fungal infections, caused mostly by opportunistic species such as Candida spp.
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