|||||||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. 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