Fused indole and quinoxaline derivatives, their preparation and

Details Fused indole and quinoxaline derivatives, their preparation and Fused indole and quinoxaline derivatives, their preparation and

1997-05-20

1998-09-01

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540557, 544345, 546 84, 548433, 514217, 514292, 514411, C07D48704, C07D47104, A61K 31435, A61K 31495

Patent

active

058011749

DESCRIPTION:

BRIEF SUMMARY
The present application is a U.S. national stage application filed under 35 U.S.C. .sctn.371 of International Application PCT/EP95/03594, filed on Sept. 12, 1995.
The present invention relates to novel ring fused compounds capable of antagonising the biological effects 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.
Another object of the present invention is to provide a method of treating disorders or diseases of mammals, including a human, responsive to glutamic and/or aspartic acid 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 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)- 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.


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 SO.sub.2 NR'R", CONR'R", and COR'" --(CH.sub.2).sub.p --W, wherein p is 0, 1, 2, 3, 4, 5, or 6, and W is hydroxy, amino, alkoxycarbonyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF.sub.3, NO.sub.2, amino, alkyl, alkoxy or methylenedioxy; or wherein R' and R" together is (CH.sub.2).sub.r Z(CH.sub.2).sub.s wherein r and s each independently are 0, 1, 2, 3, 4, 5, or 6 and Z is O, S, CH.sub.2 or NR"" wherein R"" is hydrogen, alkyl, or --(CH.sub.2).sub.p --W, wherein p is 0, 1, 2, 3, 4, 5, or 6, and W is hydroxy, amino, alkoxycarbonyl, or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF.sub.3, NO.sub.2, amino, alkyl, alkoxy or methylenedioxy; and wherein R"" is hydrogen, alkyl, alkoxy or phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF.sub.3, NO.sub.2, amino, alkyl, alkoxy or methylenedioxy;
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, Y, n, R.sup.1, R.sup.6, and R.sup.12 have the meanings set forth above; ##STR4## or a pharmaceutically acceptable salt thereof; wherein X, Y, n, R.sup.1, R.sup.6, and R.

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