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Antifungal Agents and Uses Thereof Antifungale Mittel Und Anwendungen Davon Agents Antifongiques Et Leurs Utilisations

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Antifungal Agents and Uses Thereof Antifungale Mittel Und Anwendungen Davon Agents Antifongiques Et Leurs Utilisations (19) TZZ Z¥_T (11) EP 2 680 873 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 7/56 (2006.01) A61K 38/12 (2006.01) 09.08.2017 Bulletin 2017/32 A61P 31/10 (2006.01) (21) Application number: 12751994.0 (86) International application number: PCT/US2012/027451 (22) Date of filing: 02.03.2012 (87) International publication number: WO 2012/119065 (07.09.2012 Gazette 2012/36) (54) ANTIFUNGAL AGENTS AND USES THEREOF ANTIFUNGALE MITTEL UND ANWENDUNGEN DAVON AGENTS ANTIFONGIQUES ET LEURS UTILISATIONS (84) Designated Contracting States: • LAUDEMAN, Christopher, Patrick AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Durham, NC 27712 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • MALKAR, Navdeep, Balkrishna PL PT RO RS SE SI SK SM TR Cary, NC 27513 (US) • RADHAKRISHNAN, Balasingham (30) Priority: 03.03.2011 US 201161448807 P Chapel Hill, NC 27517 (US) (43) Date of publication of application: (74) Representative: Carpmaels & Ransford LLP 08.01.2014 Bulletin 2014/02 One Southampton Row London WC1B 5HA (GB) (60) Divisional application: 17158336.2 / 3 192 803 (56) References cited: WO-A1-96/08507 WO-A1-2010/128096 (73) Proprietor: CIDARA THERAPEUTICS, INC. US-A1- 2005 026 819 US-A1- 2007 231 258 San Diego CA 92121 (US) US-B1- 6 506 726 (72) Inventors: • JAMES, Kenneth, Duke, Jr. Mebane, NC 27302 (US) 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 2 680 873 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 680 873 B1 Description Background of the Invention 5 [0001] This invention relates to the field of treatment of fungal infections. [0002] The need for novel antifungal treatments is significant, and is especially critical in the medical field. Immuno- compromised patients provide perhaps the greatest challenge to modern health care delivery. During the last three decades there has been a dramatic increase in the frequency of fungal infections in these patients (Herbrecht, Eur. J. Haematol., 56:12,1996; Cox et al., Curr. Opin. Infect. Dis., 6:422, 1993; Fox, ASM News, 59:515, 1993). Deep-seated 10 mycoses are increasingly observed in patients undergoing organ transplants and in patients receiving aggressive cancer chemotherapy (Alexander et al., Drugs, 54:657, 1997). The most common pathogens associated with invasive fungal infections are the opportunistic yeast, Candida albicans, and the filamentous fungus, Aspergillus fumigatus (Bow, Br. J. Haematol., 101:1,1998; Wamock, J. Antimicrob. Chemother., 41:95, 1998). There are an estimated 200,000 patients per year who acquire nosocomial fungal infections (Beck-Sague et al., J. Infect. Dis., 167:1247, 1993). Also adding to 15 the increase in the numbers of fungal infections is the emergence of Acquired Immunodeficiency Syndrome (AIDS) where virtually all patients become affected with some form of mycoses during the course of the disease (Alexander et al., Drugs, 54:657, 1997; Hood et al., J. Antimicrob. Chemother., 37:71, 1996). The most common organisms encountered in these patients are Cryptococcus neoformans, Pneumocystis carinii, and C. albicans (HIV/AIDS Surveillance Report, 1996, 7(2), Year-End Edition; Polis, M. A. et al., AIDS: Biology, Diagnosis, Treatment and Prevention, fourth edition, 20 1997). Newopportunistic fungalpathogens such as Penicilliummarneffei , C.krusei, C.glabrata, Histoplasmacapsulatum, and Coccidioides immitis are being reported with regularity in immunocompromised patients throughout the world. [0003] The development of antifungal treatment regimens has been a continuing challenge. Currently available drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols, flucytosine, a fluoropyrimidine that interferes with fungal protein and DNA biosynthesis, and a variety of azoles 25 (e.g., ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997). Even though amphotericin B has a broad range of activity and is viewed as the "gold standard" of antifungal therapy, its use is limited due to infusion-related reactions and nephrotoxicity (Wamock, J. Antimicrob. Chemother., 41:95, 1998). Also WO9608507 discloses aza cyclohexapeptide compounds having related chemical struc- tures. Said compounds have antifungal activity. Flucytosine usage is also limited due to the development of resistant 30 microbes and its narrow spectrum of activity. The widespread use of azoles is causing the emergence of clinically- resistant strains of Candida spp. Due to the problems associated with the current treatments, there is an ongoing search for new treatments. [0004] Whenthe echinocandin caspofungin wasapproved for sale in 2001, it represented the firstnew class of antifungal agents to be approved in over a decade. Since that time, two other echinocandin antifungals, anidulafungin and mi- 35 cafungin, have been approved in various markets. Each agent in this class of compound acts by inhibition ofβ-1, 3- glucan synthase, which is a key enzyme in the synthesis of glucan in the cell wall of many fungi. All three of these drugs are made semisynthetically, starting with natural products obtained through fermentation. [0005] The echinocandins are a broad group of antifungal agents that typically are comprised of a cyclic hexapeptide and lipophilic tail, the latter of which is attached to the hexapeptide core through an amide linkage. Although many 40 echinocandins are natural products, the clinically relevant members of this class have all been semisynthetic derivatives. Although the naturally occurring echinocandins possess some degree of anti-fungal activity, they have not been suitable as therapeutics, primarily because of poor aqueous solubility, insufficient potency, and/or hemolytic action. The approved echinocandins are the products of intense efforts to generate derivatives that maintain or improve upon the glucan synthase inhibition, but do not cause the hemolytic effects. As therapeutic agents, they are attractive compounds in 45 terms of their systemic half-lives, large therapeutic windows, safety profiles, and relative lack of interactions with other drugs. Unfortunately, the poor aqueous solubility and poor intestinal absorption of these compounds have relegated them to delivery by intravenous infusion. Although patients receiving these drugs are often hospitalized with serious infections, the ability to transition patients from intravenous delivery in a hospital setting to oral delivery in a home setti ng would be very desirable, especially considering the course of the regimen commonly exceeds 14 days. In addition, an 50 oral echinocandin may expand the use of this drug class to include patients that present with mild fungal infections. Summary of the Invention [0006] The present invention features derivatives of echinocandin antifungals that can have increased aqueous sol- 55 ubility. More specifically, the invention features echinocandin class compounds that have been modified such that they can exhibit (i) activity against one or more fungal species or genera; (ii) increased aqueous solubility and/or amphiphilicity; (iii) have an increased therapeutic index; (iv) suitability for topical administration; (v) suitability for intravenous adminis- tration; (vi) have an increased volume of distribution; and/or (vii) have an increased elimination half-life. 2 EP 2 680 873 B1 [0007] The invention features compounds of formula : 5 10 15 20 or a pharmaceutically acceptable salt thereof. [0008] The present disclosure also features compounds of formula (I): 25 30 35 40 1 [0009] In formula (I), Ris O(CH2CH2O)nCH2CH2X1, O(CH2CH2CH2O)nCH2CH2X1, NHCH2CH2X2, NH(CH2CH2O)mCH2CH2X2, NH(CH2CH2CH2O)mCH2CH2X2, NH(CH2CH2O)pCH2CH2X3, NH(CH2CH2CH2O)pCH2CH2X3, NHCH2CH2X4, NH[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, T O[CH2(CH2)aO]bCH{CH2[OCH2(CH2)c]dX5}2, NH(CH2CH2NH)rCH2CH2X5, NHCH2(CH2)qX6, or OCH 2(CH2)qX6; R is n- 45 A1 A1 A2 A1 A2 A3 B1 pentyl, sec-pentyl, or iso-pentyl; X1 is NH2, NHR , NR R , NR R R , or NHCH2(CH2)vZ1; X2 is OH, OR , or C1 C1 C2 C1 2 C3 D1 D2 D3 OCH2(CH2)vZ1; X3 is NH2, NHR , NR R , or NR RC R , or NHCH2(CH2)vZ1; X4 is NR R R or E1 E1 E1 E2 E1 E2 E3 NHCH2(CH2)vZ1; each X5 is, independently, selected from OH, OR, NH2, NHR , NR R , NR R R , F1 F2 F3 OCH2(CH2)vZ1, and NHCH2(CH2)vZ1; X6 is selected from NR R R or Z1; a is an integer from 1 to 2; b is an integer from 0 to 3 (e.g., 0, 1, 2, or 3); c is an integer from 1 to 2; d is an integer from 0 to 3 (e.g., 0, 1,2, or 3); n is an integer 50 from 1 to 5 (e.g., 1, 2, 3, 4, or 5); m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); p is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); r is an integer from 1 to 5 (e.g., 1, 2, 3, 4, or 5); q is an integer from 1 to 3 (e.g., 1, 2, or 3); v is an integer from 1 to 3 (e.g., 1, 2, or 3); each of RA1, RA2, RA3, RB1, RC1, RC2, RC3, RD1, RD2, RD3, RE1, RE2, RE3, RF1, RF2, and F3 R is, independently, selected from CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2; Z1 is selected from: 55 3 EP 2 680 873 B1 5 10 15 20 25 and each of R1A, R2A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, R10A, R11A, R12A, R13A, R14A, R15A, R16A, R17A, R18A, R19A, 20A 21A 22A R , R , and R is, independently, selected from H, CH 3, CH2CH3, CH2CH2CH3, and CH(CH3)2, or a pharmaceu- 30 tically acceptable salt thereof.
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