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(12) STANDARD PATENT (11) Application No. AU 2015280108 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2015280108 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2015280108 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Methods of treating or ameliorating migraine (51) International Patent Classification(s) C07K 5/103 (2006.01) A61P 25/06 (2006.01) A61K 38/07 (2006.01) (21) Application No: 2015280108 (22) Date of Filing: 2015.06.23 (87) WIPO No: WO15/200322 (30) Priority Data (31) Number (32) Date (33) Country 62/015,727 2014.06.23 US 62/109,386 2015.01.29 US (43) Publication Date: 2015.12.30 (44) Accepted Journal Date: 2019.11.28 (71) Applicant(s) Northwestern University;Naurex, Inc. (72) Inventor(s) Moskal, Joseph R.;Stanton, Patrie (74) Agent / Attorney Davies Collison Cave Pty Ltd, Level 14 255 Elizabeth Street, Sydney, NSW, 2000, AU (56) Related Art WO 2014059326 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization lllllllllllllllllllllllllllllllllllllllllll^ International Bureau (10) International Publication Number (43) International Publication Date WO 2015/200322 Al 30 December 2015 (30.12.2015) WIPO I PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 5/103 (2006.01) A61P 25/06 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 38/07 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/037177 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 23 June 2015 (23.06.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/015,727 23 June 2014 (23.06.2014) US kind of regional protection available): ARIPO (BW, GH, 62/109,386 29 January 2015 (29.01.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicants: NORTHWESTERN UNIVERSITY TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [US/US]; 633 Clark Street, Evanston, IL 60208 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, NAUREX, INC. [US/US]; 1801 Maple Avenue, Suite LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 4300, Evanston, IL 60201 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: MOSKAU, Joseph, R.; 2775 Sheridan Road, ΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΙΝ Evanston, IL 60201 (US). STANTON, Patrie; 207 West Published: Lake Boulevard, Mahopac, NY 10541-3179 (US). — with international search report (Art. 21(3)) (74) Agents: KAVANAUGH, Theresa, C. et al.; Goodwin Procter LLP, Exchange Place, Boston, MA 02109 (US). ιν ζζεοοζ (54) Title: METHODS OF TREATING OR AMELIORATING MIGRAINE (57) Abstract: In certain embodiments, the invention relates to methods for treating migraine (e.g. episodic migraine, chronic mi - /sioz graine, retinal migraine, ophthalmoplegic migraine, acephalgic migraine, migrainous disorder, menstrual migraine, abdominal mi­ graine, childhood periodic syndromes, or cluster headache) by administering a peptide NMDAR partial agonist. In certain embodi - ments, the invention also relates to methods for treating or ameliorating long-term post migraine sequelae in a patient by administer­ ing a peptide NMDAR partial agonist. In certain other embodiments, the invention relates to methods for treating, suppressing, or OM preventing cortical spreading depression or a disease or condition caused by cortical spreading depression in a patient in need there­ of, comprising administering a peptide NMDAR partial agonist. For example, provided herein are methods of treating epilepsy, trau - matic brain injury, and/or stroke. WO 2015/200322 PCT/US2015/037177 1 METHODS OF TREATING OR AMELIORATING MIGRAINE CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit and priority to United States Provisional Application No. 62/015,727, filed June 23, 2014, and United States Provisional Application No. 62/109,386, filed January 29, 2015, each of which are hereby incorporated by reference in fheir entirety. BACKGROUND 5 [0002] Migraine is a primary, episodic headache pain disorder associated with debilitating attacks that are recurring, and often poorly controlled by existing pharmacotherapies that focus on vascular triggers. The onset of migraine attacks is often presaged by a scintillating scotoma, or migraine aura, caused by the phenomenon of cortical spreading depression (SD; see Ayata, Headache, 50:725-30, 2010; Eikerman-Haerter et al., Curr. Neurol. Neurosci. Rep., 10:167-73, 10 2010: and Sanchez-del-Rio et al., Curr. Opin. Neurol., 17(3):289-93, 2004). SD is a slowly propagating suppression of electrocorticographic activity triggered by a local increase in extracellular potassium and release of glutamate that produces a self-propagating wave of slow depolarization across large regions of cortex. Migraine with aura is experienced by approximately 15-30% of migraine sufferers. 15 [0003] The central nervous system (CNS) of mammals employs many neuroactive peptides to effect specialized signaling within the brain and spinal cord including the neuroactive peptides somatostatin, cholecystokinin, VIP, Substance P, enkephalin, Neuropeptide Y (NPY), Neurotensin, TRH, CCK, and dynorphin. (see generally The Biochemical Basis of Neuropharmacology, Cooper, Bloom and Roth, 5th ed., Oxford University Press, New York, 20 1986). The careful elucidation of the complex signaling pathways, which operate in the CNS, has led to identification of specific receptors modulated by these neuroactive peptides presenting important therapeutic targets for various disorders associated with the CNS. [0004] The N-methyl-D-aspartate (NMDA) receptor (NMDAR), is one such receptor that has been implicated in neurodegenerative disorders including stroke-related brain cell death, C:\Interwoven\NRPortbl\DCC\MDT\ 19509762_ 1 .docx-12/11 /2019 2 convulsive disorders, and learning and memory. NMDAR also plays a central role in 2019 modulating normal synaptic transmission, synaptic plasticity, and excitotoxicity in the central nervous system. The NMDAR is further involved in long-term potentiation (LTP). Nov LTP is the persistent strengthening of neuronal connections that underlie learning and 12 memory (See Bliss and Collingridge, 1993, Nature 361:31-39). [0005] Two general classes of glutamate receptors have been characterized in the central nervous system (CNS). They are the metabotropic glutamate receptors, which belong to the G-protein coupled receptor family of signaling proteins, and the ionotropic glutamate receptors (Muir and Lees, Stroke, 1995, 26, 503-513). The ionotropic class is further subdivided into the AMP A, kainate, and NMDA receptor subtypes by the selective 2015280108 ligands that activate them. [0006] NMDA-modulating small molecule agonist and antagonist compounds have been developed for potential therapeutic use. However, many of these are associated with very narrow therapeutic indices and undesirable side effects including hallucinations, ataxia, irrational behavior, and significant toxicity, all of which limit their effectiveness and/or safety. [0007] Thus, there remains a need for improved treatments of migraine and other related diseases with compounds that provide increased efficacy and reduced undesirable side effects. SUMMARY [0008] In certain embodiments, the disclosure relates to a method of treating migraine, comprising administering to a patient in need thereof a pharmaceutically effective amount of a GLYX peptide. In certain embodiments, the migraine may be episodic migraine, chronic migraine, retinal migraine, ophthalmoplegic migraine, acephalgic migraine, migrainous disorder, menstrual migraine, abdominal migraine, childhood periodic syndromes, and/or cluster headache. In certain embodiments, the migraine is migraine without aura (common migraine). In certain embodiments, the migraine is migraine with aura (classical migraine). In certain embodiments, the migraine is accompanied by allodynia. [0008a] In a first aspect, the present invention provides a method for treating migraine with aura in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound represented by: 2A 2019 Nov 12 or a pharmaceutically acceptable salt thereof. [0008b] In a second aspect, the present invention provides a method of treating, suppressing, and/or preventing cortical spreading depression in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound represented by: 2015280108 OH or a pharmaceutically acceptable salt thereof. [0008c] In a third aspect, the present invention provides use of a compound represented by ΐ)Η or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating migraine with aura. [0008d] In a fourth aspect, the present invention provides use of a compound represented by ''oh or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, suppressing, and/or preventing cortical spreading depression. 2B [0009] For example, the disclosed compounds
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