Title:
6,7-ASYMMETRICALLY DISUBSTITUTED QUINOXALINECARBOXYLIC ACID DERI VATIVES, ADDITION SALTS THEREOF, AND PROCESSES FOR THE PREPARATION OF BOTH
Document Type and Number:
WIPO Patent Application WO/1999/011632
Kind Code:
A1
Abstract:
Excitatory amino acid receptors comprising as the active ingredient 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives or addition salts thereof, particularly compounds exhibiting antagonism against AMPA receptors; and processes for the preparation of both. The disubstituted quinoxalinecarboxylic acid derivatives are represented by formula (1), wherein Q is halogeno, optionally halogenated lower alkyl, Ar-P- (wherein Ar is phenyl optionally substituted with one or more substituting groups, or naphthyl; and P is lower alkylene, lower alkenylene, lower alkynylene, oxygen or sulfur) or L-A-; R is nitro, trifluoromethyl, optionally substituted amino or a group of general formula (7), R?1¿ is aralkyl, phenyl, naphthyl, a 5- or 6-membered heterocycle or a fused ring thereof (which may have one or more substituting groups on the aromatic ring or the heterocycle), hydrogen, optionally halogenated lower alkyl or cycloalkyl; and R?2¿ is hydroxyl, lower alkoxy or a group of general formula (6).
Inventors:
TAKANO YASUO (JP)
SHIGA FUTOSHI (JP)
TAKADOI MASANORI (JP)
UCHIKI HIDEHARU (JP)
ASANO JUN (JP)
ANRAKU TSUYOSHI (JP)
FUKUCHI KAZUNORI (JP)
UDA JUNICHIRO (JP)
ANDO NAOKI (JP)
SHIGA FUTOSHI (JP)
TAKADOI MASANORI (JP)
UCHIKI HIDEHARU (JP)
ASANO JUN (JP)
ANRAKU TSUYOSHI (JP)
FUKUCHI KAZUNORI (JP)
UDA JUNICHIRO (JP)
ANDO NAOKI (JP)
Application Number:
PCT/JP1998/003832
Publication Date:
March 11, 1999
Filing Date:
August 28, 1998
Export Citation:
Assignee:
KYORIN SEIYAKU KK (JP)
TAKANO YASUO (JP)
SHIGA FUTOSHI (JP)
TAKADOI MASANORI (JP)
UCHIKI HIDEHARU (JP)
ASANO JUN (JP)
ANRAKU TSUYOSHI (JP)
FUKUCHI KAZUNORI (JP)
UDA JUNICHIRO (JP)
ANDO NAOKI (JP)
TAKANO YASUO (JP)
SHIGA FUTOSHI (JP)
TAKADOI MASANORI (JP)
UCHIKI HIDEHARU (JP)
ASANO JUN (JP)
ANRAKU TSUYOSHI (JP)
FUKUCHI KAZUNORI (JP)
UDA JUNICHIRO (JP)
ANDO NAOKI (JP)
International Classes:
C07D241/44; C07D401/04; C07D401/14; C07D403/04; C07D403/12; C07D403/14; C07D405/14; C07D409/14; C07D521/00; (IPC1-7): C07D241/44; C07D401/04; C07D401/14; C07D403/04; C07D403/06; C07D403/12; C07D403/14; C07D405/14; C07D409/14; A61K31/495; A61K31/505; A61K31/535
Domestic Patent References:
| WO1992011245A1 | 1992-07-09 |
Foreign References:
| JPS565416A | 1981-01-20 | |||
| JPS5681569A | 1981-07-03 | |||
| JPS5569514A | 1980-05-26 |
Other References:
MATSUI KUNIO et al., "Formation of Roseoflavin from Guanine Through Riboflavin", J. BIOCHEM., 1979, Vol. 86, No. 1, pp. 167-175.
WILDING TIMOTHY J. et al., "Antagonist Pharmacology of Kainate- and alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolep ropionic Acid-Preferring Receptors", MOLECULAR PHARMACOLOGY, 1996, Vol. 49, No. 3, pp. 540-6.
HAYS SHERYL J. et al., "N-Sulfonyl Derivatives of 6,7-Dichloro-3,4-Dihydro-3-Oxo-Quinoxalinec arboxylate as Glycine-Site NMDA and AMPA Antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1993, Vol. 3, No. 1, pp. 77-80.
YONEDA Y. et al., "Support for Radiolabeling of a Glycine Recognition Domain on the N-Methyl-D-Aspartate Receptor Ionophore Complex by 5,7-(3H)Dichlorokynurenate in Rat Brain", JOURNAL OF NEUROCHEMISTRY, 1993, Vol. 60, No. 2, pp. 634-645.
POLLAN LINDA M. et al., "Comparison of Binding at Strychnine-Insensitive(N-Methyl-D-Aspartate Receptor)Glycine Binding", NEUROSCIENCE LETTERS, 1992, Vol. 148, No. 1-2, pp. 199-201.
RANDLE JOHN R.C. et al., "Quinoxaline Derivatives: Structure-Relationships and Physiological Implications of Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Synaptic Potentials", MOLECULAR PHARMACOLOGY, 1992, Vol. 41, No. 2, pp. 337-45.
KESSLER MARKUS et al., "Quinoxaline Derivatives are High-Affinity Antagonists of the NMDA Receptor-Associated Glycine Sites", BRAIN RESEARCH, 1989, Vol. 489, No. 2, pp. 377-82.
BIRCH PHILLIP J. et al., "Antagonist Profile of 6,7-Dichloro-3-Hydroxy-2-Quinoxalinecarboxy late at Excitatory Amino Acid Receptors in the Neonatal Rat Spinal Cord", EUROPEAN JOURNAL OF PHARMACOLOGY, 1989, Vol. 163, No. 1, pp. 127-31.
See also references of EP 1020453A4
WILDING TIMOTHY J. et al., "Antagonist Pharmacology of Kainate- and alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolep ropionic Acid-Preferring Receptors", MOLECULAR PHARMACOLOGY, 1996, Vol. 49, No. 3, pp. 540-6.
HAYS SHERYL J. et al., "N-Sulfonyl Derivatives of 6,7-Dichloro-3,4-Dihydro-3-Oxo-Quinoxalinec arboxylate as Glycine-Site NMDA and AMPA Antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1993, Vol. 3, No. 1, pp. 77-80.
YONEDA Y. et al., "Support for Radiolabeling of a Glycine Recognition Domain on the N-Methyl-D-Aspartate Receptor Ionophore Complex by 5,7-(3H)Dichlorokynurenate in Rat Brain", JOURNAL OF NEUROCHEMISTRY, 1993, Vol. 60, No. 2, pp. 634-645.
POLLAN LINDA M. et al., "Comparison of Binding at Strychnine-Insensitive(N-Methyl-D-Aspartate Receptor)Glycine Binding", NEUROSCIENCE LETTERS, 1992, Vol. 148, No. 1-2, pp. 199-201.
RANDLE JOHN R.C. et al., "Quinoxaline Derivatives: Structure-Relationships and Physiological Implications of Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Synaptic Potentials", MOLECULAR PHARMACOLOGY, 1992, Vol. 41, No. 2, pp. 337-45.
KESSLER MARKUS et al., "Quinoxaline Derivatives are High-Affinity Antagonists of the NMDA Receptor-Associated Glycine Sites", BRAIN RESEARCH, 1989, Vol. 489, No. 2, pp. 377-82.
BIRCH PHILLIP J. et al., "Antagonist Profile of 6,7-Dichloro-3-Hydroxy-2-Quinoxalinecarboxy late at Excitatory Amino Acid Receptors in the Neonatal Rat Spinal Cord", EUROPEAN JOURNAL OF PHARMACOLOGY, 1989, Vol. 163, No. 1, pp. 127-31.
See also references of EP 1020453A4
Attorney, Agent or Firm:
Minoura, Kiyoshi (7F 2-2, Kudankita 3-chome Chiyoda-ku Tokyo, JP)
Download PDF: