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WO 2017/053776 Al 30 March 2017 (30.03.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2017/053776 Al 30 March 2017 (30.03.2017) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07D 223/14 (2006.01) C07C 281/16 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 16/053407 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 23 September 2016 (23.09.201 6) 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, 62/232,626 25 September 2015 (25.09.2015) 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: YALE UNIVERSITY [US/US]; Two Whitney DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Avenue, New Haven, CT 065 11 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: SPIEGEL, David; 94 Morris Cove Road, New GW, KM, ML, MR, NE, SN, TD, TG). Haven, CT 065 12 (US). Published: (74) Agent: COLEMAN, Henry, D.; Cosud Intellecutal Prop erty Solutions, P.C., 714 Colorado Avenue, Bridgeport, CT — with international search report (Art. 21(3)) 06605-1601 (US). — before the expiration of the time limit for amending the (81) Designated States (unless otherwise indicated, for every claims and to be republished in the event of receipt of kind of national protection available): AE, AG, AL, AM, amendments (Rule 48.2(h)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (54) Title: THE TOTAL SYNTHESIS OF GLUCOSEPANE AND COMPOUNDS OBTAINED THEREFROM (57) Abstract: Glucosepane is a structurally complex protein post-translational modification (PTM) believed to exist in all living or - ganisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging; yet comprehensive biological investigations of this 'metabolite have been 'greatly hindered by a scarcity of chemically homo - geneous material available for study. Glucosepane possesses a unique chemical structure that incorporates a surprising, never-before- o prepared non-aromatic tautomer of imidazole (hereafter termed an "iso-imidazole"), rendering it a challenging target for chemical synthesis. In this application, the inventors report the first total synthesis of glucosepane, enabled by the development of a novel o one-pot method for preparation of the iso-imidazole core. The synthesis of the present invention is concise (8-steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. These results should prove useful to the art and practice of heterocyclic chemistry, and critical for the study of glucosepane and its role in human health and disease, especially o the treatment of diabetic disorders or its impact on aging processes. Methods of synthesis, compounds obtained therefrom, pharma ceutical compositions and methods of treatment provide embodiments of the present invention. THE TOTAL SYNTHESIS OF GLUCOSEPANE AND COMPOUNDS OBTAINED THEREFROM Field of the Invention The present invention is directed to a novel, highly efficient total synthesis of glucosepane and related derivatives and chemical reactions which make this synthesis possible. In particular, methods of introducing an iso-imidazole moiety onto a substituted oxo-azepine precursor to provide glucosepane and derivatives thereof are disclosed. Additional embodiments of the present invention include compounds (for t e r biological activity and/or t eir use as synthetic intermediates, pharmaceutical compositions and methods of treatment a otherwise described herein. Related Applications This application claims the benefit of support of United States provisional application no. US62/232,626, entitled "The Total Synthesis of Glucosepane and Related Chemical Reactions", filed September 25, 2 5, the entire contents of which application is incorporated by reference herein. Background of the Invention Post-translation modifications (PTMs) of proteins are responsible fo a host of critical functions, ranging from accelerating protein folding to mediating protein-protein interactions.'' ' Protein "glycation" is a non-enzymatic process for PTM formation wherein protein side-chains react spontaneously with open chain tauiomers of carbohydrates. Mounting evidence suggests that protein glycation adducts, also called "advanced glycation end-products" o "AGEs", are critically involved in both healthy and disease processes, including inflammation, diabetes, cancer, and normal human aging. ' Notably, AGEs often possess highly complex chemical structures, impeding their detailed chemical and biological characterization. Glucosepane (1) is an important member of the AGE family that is both biologically and chemically significant (See Figure 1). The molecule is formed as a "crosslink" from reaction sequences between arginine and lysine side-chains and one equivalent of hexose carbohydrate (most commonly glucose Glucosepane s present on long-lived plasma proteins in the human body, such as collagen and lens crystalling and is also found in high levels in various dietary sources, especially alkali-treated baked goods.1* ' Researchers have speculated that glucosepane is directly involved in the pathophysiology of various conditions (e.g., diabetes, diabetes-related complications, and aging) due to patterns of glucosepane formation on disease-associated proteins. For example analysis of skin biopsies obtained through the Diabetes Control and Complications Trial (DCCT) has determined that increases in skin glucosepane levels represent a significant, independent risk factor for the onset of diabetic nephropathy, retinopathy, and neuropathy/ ' ' Additional studies have demonstrated that non-enzymatic glucosepane crosslinks outnumber enzyme-catalyzed crosslinks in human ' collagen in people over 65 years of age. -' By age 0, glucosepane levels reach 2 nmol'mg collagen, which is almost ten times normal levels, whereas levels in diabetic patients can achieve up to twenty times those in healthy controls/ > Several mechanisms have been proposed for glucosepane 1s involvement in disease complications. For example, researchers have hypothesized that glucosepane modification can decrease protein turnover rate and impair the renewal of damaged proteins. Glucosepane crosslinks may also be responsible for reported age- and diabetes-related decreases i collagen digestibility.^'" " ' '' ' > Others have speculated that glucosepane-induced Arg modification can decrease the number of integrin binding sites in collagen, causing endothelial ceil apoptosis, extracellular matrix deposition, and basement membrane thickening .{ ) Glucosepane may also serve as ligand for pattern recognition receptors such as RAGE/ '1leading to chronic inflammation, or as a neoepitope that drives the breaking of self-tolerance against modified extracellular matrix proteins, serving as a trigger for the induction of autoimmune processes. Finally, due to high levels of glucosepane and other AGEs in the human diet, it has been suggested that these materials may function as uremic toxins, leading to complications in the setting of renal failure. ) Despite glucosepaue s health implications, biological investigations have been hampered by scarcity of chemically homogeneous material available for study. Its complex non-enzymatic biosynthesis involves serial tautomerizations of Amadori adduct 4 to provide glucosone 3 (a process termed "carbonyl mobility", Figure B). During this process, each stereocenter undergoes epimerization, and therefore the glucosepane core exists in nature as a mixture of all eight possible diastereomers/ i, These stereoisomers can only be ehromatograpliieally resolved int lour binar mixtures each containing two spectroscopically indistinguishable diastereomers with the same relative configuration at the 6, 7 and Sa positions, but opposite absolute configurations with respect to the enantioraerically pure backbone ami o acids.*7 Despite significant effort, purification of stereochemical y homogeneous giucosepane from biological samples has proven impossible. It is therefore unknown which of the eight stereoisomers is the most prevalent in vivo. Furthermore, these binary diastereomeric mixtures can only be isolated in low yields (0.2- .4%) following model reactions between lysine, arginine and glucose, and extensive chromatographic ' Importantly, because of these difficulties in purification, antibody reagents to enable biological detection of giucosepane in unprocessed tissue preparations are unavailable. To our knowledge, therefore, a l published investigations into giucosepane biology have relied upon time-consuming extraction protocols, involving exhaustive enzymatic hydrolysis followed by HPLC purification. The development of synthetic routes toward chemically-defined giucosepane constructs represents
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