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|||||||III US005514680A United States Patent (19) 11 Patent Number: 5,514,680 Weber Et Al |||||||III US005514680A United States Patent (19) 11 Patent Number: 5,514,680 Weber et al. (45) Date of Patent: May 7, 1996 54 GLYCINE RECEPTOR ANTAGONISTS AND 0377112 7/1990 European Pat. Off.. THE USE THEREOF 0511152 10/1992 European Pat. Off.. 572852 12/1993 European Pat. Off.. 2451049 4/1976 Germany. (75) Inventors: Eckard Weber, Laguna Beach, Calif.; 2446543 4/1976 Germany. John F. W. Keana, Eugene, Oreg. 2847285 5/1980 Germany. 72674 11/1974 Poland. 73) Assignees: State of Oregon, acting by and WO91/13878 9/1991 WIPO. through The Oregon State Board of WO92/07847 11/1991 WIPO. Higher Education, acting for and on WO92/O2487 2/1992 WIPO. behalf of The Oregon Health Sciences WO92/11012 7/1992 WIPO. University and The University of WO92/11245 7/1992 WIPO. Oregon, Eugene, Oreg.; The Regents WO92/14740 9/1992 WIPO : of the University of California, WO92/15565 9/1992 WIPO. Oakland, Calif. 94.07500 4/1994 WIPO. OTHER PUBLICATIONS (21) Appl. No.: 148,259. Allison et al., Polyfluoroheterocyclic Compounds, Part XX. 22 Filed: Nov. 5, 1993 Preparation and Nucleophilic Substitution of Hexafluoro quinoxaline, J. Fluorine Chem. 1:59-667 (1971). Related U.S. Application Data Burton et al., Halogeno-o-phenylenediamines and Derived Heterocycles. Part I. Reductive Fission of Benzotriazoles to 63 Continuation-in-part of PCT/US93/05859, Jun. 17, 1993, o-Phenylenediamines, J. Chem. Soc. (C) 10:1268-1273 which is a continuation-in-part of Ser. No. 69,274, May 28, (1968). 1993, abandoned, which is a continuation-in-part of Ser. No. Lutfy et al., Blockade of Morphine Tolerance by 995,167, Dec. 22, 1992, abandoned, which is a continuation ACEA-1328, a novel NMDA receptor/glycine site antago in-part of Ser. No. 903,080, Jun. 22, 1992, abandoned. nist, Eur: J. Pharmacol. 273:187-189 (Jan. 1995). (51) Int. Cl. ....................... A61K 3/495 Warner et al., In Vivo Models of Cerebral Ischemia: Effects 52 U.S. C. ..................................................... 514/249 of Parenterally Administered NMDA Receptor Glycine Site (58) Field of Search ............................................... 514/249 Antagonists, J. Cereb. Blood Flow Metab. 15:188-196 (Mar. 1995). (56) References Cited Copy of the Supplementary Partial European Search Report, mailed by the European Patent Office on Aug. 10, 1995. U.S. PATENT DOCUMENTS Derwent Abstract 93-387595 (Abstract of EP572 852). 3,962,440 6/1976 St. Clair et al. ........................ 424/250 Adreasen et al., “Effects of Non-N-Methyl-D-Aspartate 3,992,378 11/1976 St. Clair et al. 260/250 Q Antagonists on Synaptic Transmission in the In Vitro Rat 4,312,807 1/1982 Fuchs .............. ... 260/154 Hippocampus', J. Physiol. 414:317-336 (1989). 4,659,713 4/1987 Hass ..... 514/249 Bigge, C., "Structural Requirements for the Development of 4,803,270 2/1989 Takemoto.... ... 544/105 Potent N-Methyl-D-Aspartic Acid (NMDA) Receptor 4,812,458 3/1989 Honoré et al. .. ... 514/249 Antagonists', Biochem. Pharm. 45:1547-1561 (1993). 4,889,855 12/1989 Jacobsen et al. ... ... 54/250 4,912,108 3/1990 Jacobsen et al. ... ... 514/250 (List continued on next page.) 4,948,794 8/1990 Honore et al. .......................... 514/249 4,975,430 12/1990 Jahr et al. ............................... 54/255 Primary Examiner-Glennon H. Hollrah 4,977,155 12/1990 Jacobsen et al. ... ... 514/250 Assistant Examiner-Mary C. Cebulak 4,994,460 2/1991 Dextraze et al. ... ..., 514/252 Attorney, Agent, or Firm-Sterne, Kessler, Goldstein & Fox 5,026,704 6/1991 Honore et al. ...... ... 514/250 5,055,465 10/1991 Davey ............. ... 54/228.2 57 ABSTRACT 5,055,470 10/1991 Boissard et al. ... 514/252 Methods of treating or preventing neuronal loss associated 5,057,516 10/1991 Jacobsen et al. ... ... 514/250 5,061,706 10/1991 Honoreé et al. ... ... 514/249 with stroke, ischemia, CNS trauma, hypoglycemia and sur 5,075,306 12/1991 Jacobsen et al. ... ... 514/250 gery, as well as treating neurodegenerative diseases includ 5,079,250 1/1992 Jacobsen et al. ... ... 514/250 ing Alzheimer's disease, amyotrophic lateral sclerosis, Hun 5,081,123 1/1992 Honoré et al. ...... ... 514/250 tington's disease and Down's syndrome, treating or 5,109,001 4/1992 Jacobsen et al. ... ... 514/250 preventing the adverse consequences of the hyperactivity of 5,166,155 11/1992 Jorgensen et al. .. ... 514/249 the excitatory amino acids, as well as treating anxiety, 5,187,171 2/1993 Cordi ...................................... 514/359 chronic pain, convulsions, inducing anesthesia and treating 5,190,941 3/1993 Nozulak et al. ... 514/229.8 psychosis are disclosed by administering to an animal in 5,196.421 3/1993 McQuaid et al. ... 514/250 need of such treatment a compound having high affinity for 5,198,461 3/1993 Watjen et al. ...... 514/411 the glycine binding site, lacking PCP side effects and which 5,268,378 12/1993 Baker et al. ............ 514/312 crosses the blood brain barrier of the animal. 5,283,244 2/1994 Sakamoto et al... 514/249 5,308,845 5/1994 Honoré et al. ...... 514/250 5,352,683 10/1994 Mayer et al. ........................... 514/289 Also disclosed are novel 1,4-dihydroquinoxaline-2,3-di ones, and pharmaceutical compositions thereof. Also dis FOREIGN PATENT DOCUMENTS closed are highly soluble ammonium salts of 1,4-dihydro 01.0722 5/1980 European Pat. Off.. quinoxaline-2,3-diones. 348872 1/1990 European Pat. Off.. 0374534 6/1990 European Pat. Off.. 26 Claims, 45 Drawing Sheets 5,514,680 Page 2 OTHER PUBLICATIONS Leeson et al., "Kynurenic Acid Derivatives. Structure-Ac tivity Relationships for Excitatory Amino Acid Antagonism Birch et al., “FG-9065 and FG-9041 antagonise responses and Identification of Potent and Selective Antagonists at the to NMDA via an action at the strychnine-insensitive glycine Glycine Site on the N-Methyl-D-aspartate Receptor”, J. receptor', Meeting of the British Pharmacological Society, Med. Chem, 34:1243-1252 (1991). Nottingham, England, Sep. 7-9, 1988, Br. J. Pharmacol. Leeson et al., “Amino Acid Bioisosteres: Design of 2-Qui 95:758P (1988). nolone Derivatives as Glycine-Site N-Methyl-D-aspartate Carling et al., "Anticonvulsant Activity of Glycine-site Receptor Antagonists', Bioorg. & Med. Chem. Lett. NMDA Antagonists", Bioorganic & Medicinal Chem. Lett. 3:299-304 (1993). 3:65-70 (1993). Leeson, P., "Glycine-Site N-Methyl-D-Aspartate Receptor Carling et al., "3-Nitro-3,4-dihydro-2(1H)-quinolones. Antagonists", pp. 339-381, in: Drug Design for Neurosci, Excitatory Amino Acid Antagonists Acting at Glycine-Site Kozikowski (ed.), Raven Press Ltd., New York (1993). NMDA and Lester et al., "Interaction of (RS)-O-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic 6-Cyano-7-nitroquinoxaline-2,3-dione with the N-Meth Acid Receptors', J. Med. Chem. 36:3397-3408 (1993). yl-D-aspartate Receptor-Associated Glycine Binding Site', Mol. Pharmacol. 35:565-570 (1989). Cheeseman, G. W. H., "Quinoxalines and Related Com Littman et al., "The quinoxalinediones DNQX, CNQX and pounds, Part VI. Substitution of 2,3-Dihydroxyquinoxaline two related congeners suppress hair cell-to-auditory nerve and its 1,4-Dimethyl Derivative', J. Chem. Soc. transmission', Hearing Res. 40:45-53 (1989). 223:1170-1176 (1962). Lodge & Jones, "Evidence for Glutamate Receptor Subtypes Davies & Collingridge, "Quinoxalinediones as Excitatory From In Vivo Electrophysiology: Studies with HA-966, Amino Acid Antigonists in the Vertebrate Central Nervous Quinoxalinediones and Philanthotoxin'", pp. 101-108 in: System”, Int. Rev. Neurobiol. 32:281-303 (1990). Excitatory Amino Acids and Neuronal Plasticity, Ben-Ari, Drejer & Honoré, "New quinoxalinediones show potent Y. (ed.), Plenum Press, New York (1990). antagonism of quisqualate responses in cultured mouse Lodge et al., "Excitatory amino acids:new tools for old cortical neurons', Neur: Lett. 87:104-108 (1988). stories or Pharmacological subtypes of glutamate recep Fletcher et al., "Quinoxalinediones selectively block tors:electrophysiological studies', Can. J. Physiol. Pharma quisqualate and kainate receptors and synaptic events in rat col. 69:1123-1128 (1991). Louvet et al., "Novel benzimidazoles as ligands for the neocortex and hippocampus and frog spinal cord in vitro', strychnine-insensitive N-methyl-D-aspartate-linked gly Br. J. Pharmacol. 95:585-597 (1988). cine receptor', Eur: J. Med. Chem, 28:71-75 (1993). Frenket al., “Absence of Side-Effects in the Anticonvulsant McFarlane & Smith, "A New Route to N-Hydroxyquinoxa Action of Cortically Applied Antagonists of N-Methyl line-2,3-diones and some AZA-Analogues', Tetrahedron -D-Aspartate', Brain Res. 373:222-226 (1986). Lett. 28:6363-6366 (1987). Hays et al., "N-Sulfonyl Derivatives of 6,7-Dichloro McQuaid et al., “Synthesis and Excitatory Amino Acid 3,4-Dihydro-3-Oxo-quinoxalinecarboxylate as Glycine-s- Pharmacology of a Series of Heterocyclic-Fused Quinox ite NMDA and AMPA Antagonists”, Bioorg. & Med. Chem. alinones and Quinazolinones', J. Med. Chem. Lett. 3:77-80 (1993). 35:3319-3324 (1992). Honoré et al., "Quinoxalinediones: Potent Competitive Non Moore et al., “Anticonvulsant Activity of Glycine-Site -NMDA Glutamate Receptor Antagonists', Science NMDA Antagonists', Bioorg. & Med. Chem. Lett. 3:61-64 241:701-703 (Aug. 5, 1988). (1993). Honoré et al., "Quinoxalinediones Non-N-Methyl-D-as Näsström et al., "Antinociceptive actions of different classes partate Receptor Antagonists as Potential Drug Candidates', of excitatory amino acid receptor antagonists in mice', Eur: J. Pharmacol. 212:21-29 (1992). pp. 451-460, in: Excitatory Amino Acids, Meldrum et al. Ogita & Yoneda, “6,7-Dichloroquinoxaline-2,3-Dione is a (eds.), Raven Press Ltd., New York (1991). Competitive Antagonist Specific to Strychnine-Insensitive Horner et al., “Derivatives of quinoxaline as isosteres of the HGlycine Binding Sites on the N-Methyl-D-Aspartate pteridines', Chem. Abst. 48:2692 (1953). Receptor Complex”, J.
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