Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-20
1999-06-29
Cintins, Marianne M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514110, 514322, C07D48702
Patent
active
059170530
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel ring fused compounds capable of antagonizing the effect of excitatory amino acids, such as glutamate, a method of treatment therewith, pharmaceutical compositions comprising the compounds and to a method of preparing the novel compounds of the invention.
OBJECT OF THE INVENTION
It is an object of the present invention to provide novel glutamate antagonists which are useful in the treatment of disorders or diseases in mammals, including a human, and especially in the treatment of disorders or diseases which are responsive to glutamate and/or aspartate receptor antagonists of such mammals.
Another object of the present invention is to provide a method of treating disorders or diseases of mammals, including a human, responsive to glutamate and/or aspartate receptor antagonists which comprises administering to a mammal in need thereof a compound of the invention.
A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of disorders or diseases of mammals, including a human, responsive to glutamic and/or aspartic acid receptor antagonists.
Other objectives of the present invention will be apparent to the skilled person hereinafter.
BACKGROUND OF THE INVENTION
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA), glutamate and aspartate, at the N-methyl-D-aspartate (NMDA), the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer's, and Huntington's diseases.
The compounds of the present invention may also be useful in the treatment of Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain and drug addiction.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows the 2-vessel occlusion in gerbils.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula ##STR2## or a pharmaceutically acceptable salt thereof wherein selected from the group consisting of halogen, CF.sub.3, NO.sub.2, amino, alkyl, alkoxy, phenyl and SO.sub.2 NR'R" wherein R' and R" each independently are hydrogen or alkyl or wherein R' and R" together is (CH.sub.2).sub.m wherein m is 2, 3, 4, 5 or 6;
A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals: ##STR3## or a pharmaceutically acceptable salt thereof; wherein X, R.sup.1, R.sup.5, and R.sup.12 have the meanings set forth above; ##STR4## or a pharmaceutically acceptable salt thereof; wherein X, R.sup.1, R.sup.5, and R.sup.12 have the meanings set forth above; ##STR5## or a pharmaceutically acceptable salt thereof; wherein X, R.sup.1, R.sup.5, and R.sup.12 have the meanings set forth above; ##STR6## or a pharmaceutically acceptable salt thereof; wherein X, R.sup.1, R.sup.5, and R.sup.12 have the meanings set forth above; e-3-O-acetyloxime, e-3-O-(N-ethylcarbamoyl)oxime, e-3-O-pivaloyloxime, O-acetyloxime, 3,2-h!isoquinoline-2,3-dione-3-O-(N-t-butylcarbamoyl)oxime, of a compound as any above together with at least one pharmaceutically-acceptable carrier or diluent; which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists, which comprises administering to a patient in need thereof an effective amount of a compound as any above; diseases, ALS, schizophrenia, Parkinsonism, epilepsy, anxiety, pain, drug addiction, or cerebrovascular disorders are treated; the t
REFERENCES:
Abstract to Mazilis et al., "Synthesis and antiviral activity of benzisatin-.beta.-oxime derivatives", Khim.-Farm. Zh. 23(110, pp. 1349-1352, 1989.
Moldt Peter
Watjen Frank
Cintins Marianne M.
Jones Dwayne C.
NeuroSearch A/S
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