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(12) United States Patent (10) Patent No.: US 8,822,539 B2 Jensen (45) Date of Patent: Sep USOO8822.539B2 (12) United States Patent (10) Patent No.: US 8,822,539 B2 Jensen (45) Date of Patent: Sep. 2, 2014 (54) COMBINATION THERAPIES: INHIBITORS Bialer et al., “Progress report on new antiepileptic drugs: a Summary OF GABA TRANSAMINASE AND NKCC1 of the Seventh Eilat Conference (EILATVII).” Epilepsy Res., 61:1- 48, 2004 (Abstract only). (75) Inventor: Frances E. Jensen, Boston, MA (US) Clift and Silverman, “Synthesis and Evaluation of Novel Aromatic Substrates and Competitive Inhibitors of GABA Aminotransferase.” (73) Assignee: Children's Medical Center Bioorg. Med. Chem. Left., 18:3122-3125, 2008. Crewther et al., “Potassium Channel and NKCC Cotransporter Corporation, Boston, MA (US) Involvement in Ocular Refractive Control Mechanisms. PlosOne, 3:e2839, 2008. (*) Notice: Subject to any disclaimer, the term of this Cubells et al., “In vivo action of enzyme-activated irreversible inhibi patent is extended or adjusted under 35 tors of glutamic acid decarboxylase and gamma-aminobutyric acid U.S.C. 154(b) by 149 days. transaminase in retina vs. brain.” J. Pharmacol. Exp. Ther. 238:508 514, 1986 (Abstract only). (21) Appl. No.: 13/069,311 Duboc et al., “Vigabatrin, the GABA-transaminase inhibitor, dam ages cone photoreceptors in rats.” Ann. Neurol. 55:695-705, 2004 (22) Filed: Mar 22, 2011 (Abstract only). Dzhala et al., “Bumetanide enhances phenobarbital efficacy in a (65) Prior Publication Data neonatal seizure model.” Ann. Neurol. 63:222-235, 2008 (Abstract US 2011/0237554 A1 Sep. 29, 2011 only). Dzhala et al., “NKCC1 transporter facilitates seizures in the devel oping brain.” Nature Med., 11:1205-1213, 2005 (Abstract only). Follett et al., “Glutamate Receptor-Mediated Oligodendrocyte Tox Related U.S. Application Data icity in Periventricular Leukomalacia: A Protective Role for Topiramate.” J. Neurosci., 24:4412-4420, 2004. (60) Provisional application No. 61/318,352, filed on Mar. Follett et al., “NBQX Attenuates Excitotoxic Injury in Developing 28, 2010. White Matter, J. Neurosci., 20:9235-9241, 2000. International Preliminary Report on Patentability for PCT/US2011/ (51) Int. Cl. 029467, issued Oct. 2, 2012. AOIN 4I/06 (2006.01) Jammoul et al., “Taurine deficiency is a cause of vigabatrin-induced A6 IK3I/08 (2006.01) retinal Phototoxicity.” Ann. Neurol. 65:98-107, 2009. AOIN37/00 (2006.01) John et al., “Micro-vacuolation in rat brains after long term admin istration of GABAtransaminase inhibitors. Comparison of effects of A6 IK3I/9 (2006.01) ethanolamine-Osulphate and vigabatrin.” Biochem. Pharmacol., C07C303/00 (2006.01) 36:1467-1473, 1987 (Abstract only). C07C307/00 (2006.01) Kahle et al., “The bumetanide-sensitive Na-K-2C1 cotransporter C07C 309/00 (2006.01) NKCC1 as a potential target of a novel mechanism-based treatment C07C3II/00 (2006.01) strategy for neonatal seizures.” Neurosurg. Focus, 25:E22, 2008 CD7C 6L/00 (2006.01) (Abstract only). CD7C 6L/08 (2006.01) Li et al., “Spatial and temporal distribution patterns of Na-K-2C1 cotransporter in adult and developing mouse retinas. Vis. Neurosci. (52) U.S. Cl. 25:109-123, 2008 (Abstract only). USPC .......................................................... S14f603 Lopez-Samblas et al., “The pharmacokinetics of bumetanide in the (58) Field of Classification Search newborn infant.” Biol. Neonate, 72:265-272, 1997 (Abstract only). USPC ...................... 514/603, 557:564/86; 562/400 Manning et al., “NMDA Receptor Blockade with Memantine Attenu See application file for complete search history. ates White Matter Injury in a Rat Model of Periventricular Leukomalacia, J. Neurosci., 28:6670-6678, 2008. (56) References Cited Neal et al., “Immunocytochemical evidence that vigabatrin in rats causes GABA accumulation in glial cells of the retina, Neurosci. U.S. PATENT DOCUMENTS Left., 98:29-32, 1989 (Abstract only). Pan et al., “Conformationally-restricted vigabatrin analogs as irre 6,495,601 B1 12/2002 Hochman versible and reversible inhibitors of gamma-aminobutyric acid 7,214,711 B2 5, 2007 Hochman aminotransferase.” Bioorg. Med. Chem., 12:5719-5725, 2004 2005/O1872O5 A1 8/2005 Lamberty et al. (Abstract only). 2006.0025387 A1 2/2006 Hochman 2008/0206324 A1 8/2008 Gryczke et al. Prescribing information for BUMEX (NDA 18225/S-024) dated Sep. 2009,0258844 A1 10, 2009 Hochman 9, 2009. OTHER PUBLICATIONS (Continued) International Search Report and Written Opinion of PCT/US2011/ Primary Examiner — Kendra D Carter 029467, Dec. 22, 2011. (74) Attorney, Agent, or Firm — Fish & Richardson P.C. Aicardi et al., “Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer (57) ABSTRACT Review Groups.” Epilepsia, 37:638-642, 1996 (Abstract only). Andre et al., “Vigabatrin protects against hippocampal damage but is Inhibitors of NKCC1, such as bumetanide, when coadminis not antiepileptogenic in the lithium-pilocarpine model of temporal tered with inhibitors of GABA transaminase, such as lobe epilepsy.” Epilepsy Res., 47:99-117, 2001 (Abstract only). vigabatrin, attenuate both the retinal toxicity and the intramy Bauer, “Photic release of radioactivity from rabbit retina preloaded elinic edema. with 3H GABA.” Acta Ophthalmol., 56:270-281, 1978 (Abstract only). 11 Claims, No Drawings US 8,822.539 B2 Page 2 (56) References Cited Talos et al., “Developmental regulation of alpha-amino-3-hydroxy 5-methyl-4-isoxazole-propionic acid receptor Subunit expression in OTHER PUBLICATIONS forebrain and relationship to regional Susceptibility to hypoxic? ischemic injury. I. Rodent cerebral white matter and cortex.” J. Comp. Project No. 1 RC1NS068938-01 from NIH Research Portfolio Online Neurol. 497:42-60, 2006 (Abstract only). Reporting Tools website (http://projectreporter.nih.gov/project Talos et al., “Developmental regulation of AMPA receptor subunit info details.cfm?aid=7829070&icde=0), award notice date Sep. 25. expression in forebrain and relationship to regional Susceptibility to 2009, project start date Sep. 30, 2009. hypoxic/ischemic injury: Part II. Human cerebral white matter and Putney et al., “Na-K-C1 Cotransport in Normal and Glaucomatous cortex.” J. Comp. Neurol. 497:61-77, 2006. Human Trabecular Meshwork Cells.” Invest. Ophthalmol. Vis. Sci., Thoreson et al., “Reciprocal Interactions Between Calcium and 40:425-434, 1999. Chloride in Rod Photoreceptors.” J. Neurophysiol. 90:1747-1753, SABRIL (vigabatrin) prescribing information, revised Apr. 2010. 2003. Sills, “Pre-clinical studies with the GABAergic compounds Wang et al., “Treatment of epilepsy: the GABA-transaminase inhibi vigabatrin and tiagabine.” Epileptic Disord., 5:51-56, 2003 (Abstract tor, vigabatrin, induces neuronal plasticity in the mouse retina, Eur. only). J. Neurosci., 27:2177-2187. 2008. US 8,822,539 B2 1. 2 COMBINATION THERAPES: INHIBITORS the GABA transaminase inhibitor is an optionally confor OF GABA TRANSAMNASE AND NKCC1 mationally-constrained vigabatrin analog: the GABA transaminase inhibitor is gamma-vinyl-GABA This application claims priority to U.S. 61/318,352 filed (vigabatrin); Mar. 28, 2010. 5 the GABA transaminase inhibitor is 4-hydroxybenzalde This work was supported by NIH Grant RC1 NS068938 hyde or a 4-hydroxybenzaldehyde analogue; 01. The U.S. government has rights in any patent issuing on the GABA transaminase inhibitor is a 4-hydroxybenzalde this application. hyde analogue selected from 3-chloro-1-(4-hydroxyphenyl) propan-1-one, and 4-acryloylphenol; BACKGROUND OF THE INVENTION 10 the NKCC1 inhibitor is selected from: Bumetanide, Furo semide, Ethacrynic acid and Torsemide; The field of the invention is combination therapies of the GABA transaminase inhibitor is vigabatrin, and the inhibitors of Y-aminobutyric acid (GABA) transaminase and NKCC1 inhibitor is selected from: Bumetanide, Furosemide, Na—K C1 cotransporter (NKCC1). 15 Ethacrynic acid and Torsemide; and/or Na-K Clcotransporter antagonists have been proposed the GABA transaminase inhibitor is vigabatrin, and the to treat seizures (e.g. Hochman: US2009/0258844; U.S. Pat. NKCC1 inhibitor is Bumetanide. Nos. 7,214,711; and 6,495,601), and in particular, Bumet In another aspect the invention provides an effective unit anide has been proposed to be useful to treat neonatal seizures dosage of a Subject composition further comprising a phar (Dzhala et al. Nat. Med. 2005 November, 11(11): 1205-13), maceutically-acceptable excipient. and has been reported to enhance Phenobarbital efficacy in In another aspect the invention provides a Subject compo neonatal seizure model (Dzhala et al. Ann Neurol 2008, 632: sition wherein the transaminase inhibitor and the NKCC1 222-235) inhibitor are contained in a unit dosage form. Vigabatrin (VGB) is a known anticonvulsant that acts as an In another aspect the invention provides a Subject compo irreversible inhibitor of gamma-aminobutyric acid (GABA) 25 sition wherein the transaminase inhibitor and the NKCC1 transaminase, the enzyme responsible for the catabolism of inhibitor are copackaged. the inhibitory neurotransmitter GABA. The resultant increase In another aspect the invention provides a Subject compo in brain GABA levels is thought to be the mechanism of its sition wherein the transaminase inhibitor and the NKCC1 anticonvulsant actions in infantile spasms and for refractory inhibitor are coformulated. seizures. 30 In another aspect the invention provides a Subject compo Vigabatrin is associated with well documented retinal tox sition wherein the transaminase inhibitor and the NKCC1 icity resulting in peripheral visual field deficits and also ani inhibitor
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