Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-04-17
1998-04-28
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544234, 546114, 546116, 546123, 546156, A61K 3150, C07D47104, C07D47114, C07D49114
Patent
active
057444714
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pyridazinedione compounds useful in the treatment of neurological disorders generally in mammals such as man. More specifically, the compounds are useful in the treatment of strokes and/or other neurodegenerative disorders such as hypoglycemia, cerebral palsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Olivo-pontocerebellar atrophy, viral-induced neurodegeneration such as in acquired immunodeficiency syndrome and its associated dementia, anoxia such as from drowning, spinal cord and brain trauma, and chronic pain, for the prevention of drug and alcohol withdrawal symptoms, and for the inhibition of tolerance and dependence to opiate analgesics. The invention particularly relates to novel pyridazinedione compounds useful in reducing neurological degeneration such as can be induced by a stroke and the associated functional impairment which can result. Treatment using a compound of the invention can be remedial or therapeutic as by administering a compound following an ischemic event to mitigate the effects of that event. Treatment can also be prophylactic or prospective by administering a compound in anticipation that an ischemic event may occur, for example in a patient who is prone to stroke.
It is known that ischemic events can trigger a dramatic increase in extracellular concentrations of the excitatory amino acids glutamate and aspartate which can, in turn, cause prolonged neuronal excitation leading to a massive influx of calcium from extracellular to intracellular sites in brain neural cells. A calcium overload can thereby be created which leads to a cascade of events leading to cell catabolism and eventually resulting in cell death. The N-methyl-D-aspartate (NHDA) receptor complex is believed to play a significant role in the cascade of events leading to cell necrosis following an ischemic event.
The compounds provided by this invention may be useful in a variety of neurodegenerative disorders because they function as excitatory amino acid antagonists. They may do so indirectly, via allosteric modulation of the glutamate binding site, specifically by acting as antagonists of the strychnine-insensitive glycine receptor on the NMDA receptor complex. They may also do so directly, by binding to the glutamate site itself on the NMDA receptor complex.
According to the invention there is provided a compound and pharmaceutical compositions thereof suitable for the treatment of neurological disorders, comprising a compound of formula I or a pharmaceutically acceptable salt thereof (formula set out, together with other formulae referred to by Roman Numerals, on pages following the Examples). and tautomers thereof wherein B-ring is reduced, the Z group may be selected from H, OH, SH or NH.sub.2 to form a compound of I'). six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R.sup.4 wherein R.sup.4 is independently selected from the group consisting of halo, (1-4C)alkyl, NO.sub.2, CN, (C1-3)perfluoroalkyl, OH, OCF.sub.3, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", SO.sub.2 NR'R", or SO.sub.m R'; a heterocyclic group, NR'COR", COR", NR'CO.sub.2 R", CO.sub.2 R', CONR'R"; substituted with 1, 2, 3 or 4 groups chosen from --O--(1-4C)alkyl, --O--(2-4C)alkenyl, --O--(2-4C)alkynyl, --O(CO-C6alkyl)phenyl, --OH, -halo, --NO.sub.2, --CN, --CF.sub.3, -(1-4C)alkylCF.sub.3, --NH(CO)R', -(1-4C)alkyl, --NR'R", --CO.sub.2 R', --CONR'R", --SO.sub.m R', --SO.sub.2 NR'R", (C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, --O(C1-C6alkyl)NR'R", --NR'(C1-C6alkyl)NR'R", -(C1-C6alkyl)NR'R", --O--(1-4C)perfluroalkyl, -1-4Cperfluroalkyl, --NR'(C1-C6alkyloxy), --NR'(C1-C6
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Bare Thomas Michael
Davenport Timothy Wayne
Empfield James Roy
McKinney Jeffrey Alan
Sparks Richard Bruce
Alexander Michael D.
Bernhardt Emily
Darkes Paul R.
Zeneca Limited
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