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Ep 2459565 B (19) TZZ _T (11) EP 2 459 565 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 487/14 (2006.01) A61P 29/00 (2006.01) 02.05.2018 Bulletin 2018/18 (86) International application number: (21) Application number: 10772881.8 PCT/US2010/034035 (22) Date of filing: 07.05.2010 (87) International publication number: WO 2010/129864 (11.11.2010 Gazette 2010/45) (54) SAXITOXIN DERIVATIVES, METHODS AND COMPOSITIONS FOR STUDYING, IMAGING, AND TREATING PAIN SAXITOXIN DERIVATE, VERFAHREN UND ZUSAMMENSETZUNGEN ZUM STUDIEREN, DARSTELLEN UND BEHANDELN VON SCHMERZ DÉRIVÉS DE SAXITOXIN, PROCÉDÉS ET COMPOSITIONS POUR ÉTUDIER, VISUALISER PAR IMAGERIE ET TRAITER LA DOULEUR (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB EP-A1- 0 857 972 WO-A1-03/006507 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A1- 2006 057 647 PL PT RO SE SI SK SM TR • SATO S ET AL: "Identification of thioether (30) Priority: 07.05.2010 US 800053 intermediates in the reductive transformation of 07.05.2009 US 176172 P gonyautoxins into saxitoxins by thiols", BIOORGANIC & MEDICINAL CHEMISTRY (43) Date of publication of application: LETTERS, PERGAMON, ELSEVIER SCIENCE, 06.06.2012 Bulletin 2012/23 GB, vol. 10, no. 16, 21 August 2000 (2000-08-21), pages 1787-1789, XP004215999, ISSN: (73) Proprietor: The Board of Trustees of The Leland 0960-894X, DOI: 10.1016/S0960-894X(00)00332-2 Stanford • NEGRI, A. ET AL.: ’Three Novel Hydroxybenzoate Junior University Saxitoxin Analogues Isolated from the Palo Alto, CA 94306-1160 (US) Dinoflagellate Gymnodinium catenatum’ CHEMICAL RESEARCH IN TOXICOLOGY vol. 16, (72) Inventors: 2003, pages 1029 - 1033, XP008156009 • DU BOIS, Justin • ONODERA, H. ET AL.: ’New Saxitoxin Analogues Palo Alto, CA 94304 (US) From the Freshwater Filamentous • MULCAHY, John Cyanobacterium Lyngbya wollei’ NATURAL Stanford, CA 94305 (US) TOXINS vol. 5, 1997, pages 146 - 151, • ANDRESEN, Brian XP008156014 Menlo Park, CA 94025 (US) • DELL’AVERSANO, C. ET AL.: ’Isolation and • YEOMANS, David C. Structure Elucidation of New and Unusual Sunnyvale, CA 94305 (US) Saxitoxin Analogues from Mussels’ JOURNAL • BISWAL, Sandip OF NATURAL PRODUCTS vol. 71, 2008, pages Sanford, CA 94305 (US) 1518 - 1523, XP008156016 • SHIMIZU, Y.: ’Toxigenesis and biosynthesis of (74) Representative: Vossius & Partner saxitoxin analogues’ PURE AND APPLIED Patentanwälte Rechtsanwälte mbB CHEMISTRY vol. 58, no. 2, 1986, pages 257 - 262, Siebertstrasse 3 XP002690593 81675 München (DE) 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 2 459 565 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 459 565 B1 • Brian M. Andresen ET AL: "De Novo Synthesis of Remarks: Modified Saxitoxins for Sodium Ion Channel Thefile contains technical information submitted after Study", Journal of the American Chemical the application was filed and not included in this Society, vol. 131, no. 35, 9 September 2009 specification (2009-09-09), pages 12524-12525, XP055341715, US ISSN: 0002-7863, DOI: 10.1021/ja904179f • Lubna Zaman ET AL: "Occurrence of a methyl derivative of saxitoxin in Bangladeshi freshwater puffers", TOXICON, vol. 36, no. 4, 1 May 1998 (1998-05-01), pages 627-630, XP055341716, US ISSN: 0041-0101, DOI: 10.1016/S0041-0101(97)00086-X 2 EP 2 459 565 B1 Description BACKGROUND 5 [0001] The waters of the "red tide" are awash with noxious agents, the most infamous of which are the paralytic shellfish poisons (PSP) (Seafood and Freshwater Toxins: Pharmacology, Physiology, and Detection; Botana, L. M., Ed.; Marcel Dekker: New York, 2000.) Small molecule, bis-guanidinium structures - saxitoxin, neosaxitoxin, and the gonyautoxins - unique in both their form and function, represent the principle constituents of PSP’s. (For leading reviews, see: (a) Llewellyn, L. E. Nat. Prod. Rep. 2006, 23, 200-222. (b) Hall, S.; Strichartz, G.; Moczydlowski, E.; Ravindran, A.; Reichardt, 10 P. B. ACS Symp. Series 1990, 418, 29-65.) These highly polar, heteroatom-rich compounds are exquisitely designed + corks that act to stopper ion flux through voltage-gated Na channels (NaV), thus inhibiting electrical conduction in cells. (see, e.g., Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium Channel; Eds. C. Y. Kao; S. R. Levinson; Ann. New York Acad. Sci.: New York, Vol 479, 1986; Tikhonov, D. B.; Zhorov, B. S. Biophys. J. 2005, 88, 184-197, and references therein.) 15 [0002] The intricate molecular shape common to these toxins coupled with their importance as pharmacological tools forion channelstudy have inspired effortsaimed attheir de novoassembly. Three priorworks have described preparations of saxitoxin (STX) and one a decarbamoyloxy form. ((See, e.g., (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 2818-2819. (b) Kishi, Y. Heterocycles 1980, 14, 1477-1495. (c) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594-5598. (d) Martinelli, M. J.; Brownstein, A. D.; Jacobi, P. A.; Polanc, S. 20 Croat. Chem. Acta 1986, 59, 267-295. (e) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926-3927. (f) Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975. Following their earlier report, Kishi et al have described an asymmetric synthesis of (-)-decarbamoylsaxitoxin, see: Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114, 7001-7006. See also, e.g., Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K. Angew. Chem. Int. Ed. 2007, 46, 8625-8628.) 25 [0003] Pain sensations include sharp pain, dull pain, ache, and other forms of pain sensations. Pain is a sensation that may be of varying intensity and duration, and may result from a variety of causes. For example, pain may be acute, e.g., as a result of injury, illness or trauma; may be chronic, e.g., as a result of a chronic disease or condition, inflammation, cancer, or other cause; may be localized or diffuse; may be of low intensity, or of moderate intensity, or of high intensity. Thus, pain is a varied sensation, which includes, for example, acute pain, chronic pain, visceral pain, surgical pain, joint 30 pain, bone pain, back pain, headache pain, neurogenic pain, phantom-limb pain, and other forms and experiences of pain. However, in general, whatever the intensity or duration, and whatever the cause, people prefer to lessen or eliminate the pain sensation, wherever possible. [0004] Pain can often be alleviated by the administration of pharmaceuticals to a subject. One mechanism of alleviating pain sensation is to block the transmission of nerve signals, as, for example, by blocking conduction of nerve impulses 35 along nerve fibers. For example, such impulses can be blocked by reducing, blocking, or altering the action of sodium channels. Sodium channels can be affected by compounds such as saxitoxin, gonyautoxin, zetekitoxin, and other mol- ecules known as "site one sodium channel blockers" (see, e.g,. Llewellyn, Nat. Prod. Rep. 23: 200-222 (2006)). However, as suggested by the term "toxin" in their names, such molecules may also have effects in addition to blocking pain sensation. Thus, identification of molecules which are effective to alleviate the sensation of pain, without dangerous side 40 effects, is desired. [0005] US 2006/057647 A1 is directed to a method for capturing a saxiphilin to allow for detection, characterisation, isolation and/or purification. [0006] Chronic pain is a major, universal health problem and one of the most common reasons that people seek medical care. "Why am I in (chronic) pain?" "What’s causing my pain?" or "Where is the pain coming from?" are some 45 of the tough questions that individuals suffering from chronic pain often struggle with to get answers. The paucity of objective, diagnostic tests and a limited armamentarium of effective and safe medicines no doubt fuel the aggravation shared by chronic pain sufferers and their caregivers. Current methods used to diagnose a patient’s pain are highly subjective and rely on patient self-reporting. Individuals suffering from chronic pain endure a number of tests and are often relegated to empiric analgesic testing and surgical procedures with limited objective basis for such treatments. 50 Additionally, currently used state-of-the-art medical imaging technologies such as x-rays, computed tomography (CT), ultrasound, and conventional magnetic resonance imaging (MRI), have been inadequate in the assessment of chronic pain syndromes because they rely heavily upon anatomic abnormalities. Significant intervertebral disc abnormalities using conventional MRI, for example, can be found in 27-31% asymptomatic subjects. Additionally, the natural progres- sion of degenerative disc disease in individuals does not correlate with development of pain symptomology, and pro- 55 vocative discography and MR-based morphometric measurements have only weak association with back pain episodes. More recently, meniscal tears as detected on MRI have been found to be nearly equally prevalent ( ∼60%) in symptomatic and asymptomatic knees of middle aged and elderly persons, again, underscoring the poor relationship between MR findings and pain causation. Yet, despite such evidence to the contrary, the use of such anatomy-based imaging findings 3 EP 2 459 565 B1 unfortunately remains an important part of the treatment algorithm for a wide range of diseases! As a result, a large number of patients are subject to unnecessary surgeries and inadequate treatments. SUMMARY 5 [0007] Briefly described, embodiments of this disclosure include compounds, compositions, pharmaceutical compo- sitions for use in treating pain, methods of studying pain, methods of imaging pain, and the like.
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