Quinoxalinediones

Details Quinoxalinediones Quinoxalinediones

1998-09-04

2002-04-23

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S249000, C544S116000, C544S238000, C544S295000, C544S354000

Reexamination Certificate

active

06376490

ABSTRACT:

This invention relates to 2,3(1H,4H)-quinoxalinedione derivatives which are selective antagonists of N-methyl-D-aspartate receptors. More particularly, this invention relates to 5-heteroaryl-2,3(1H,4H)-quinoxalinedione derivatives and to the preparation of, compositions containing, the uses of and the intermediates used in the synthesis of, such derivatives.
L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg
2+
,Zn
2+
). Since the NMDA receptor has an absolute requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.
In the region of a cerebral infarct, anoxia, for example, causes abnormally high concentrations of glutamic acid to be released. This leads to an over-stimulation of NMDA receptors resulting in the degeneration and death of neurones. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo, may be useful in the treatment and/or prevention of any pathological condition in which NMDA receptor activation is thought to be important. Examples of such conditions include acute neurodegenerative disorders arising from events such as stroke, transient ischaemic attack, peri-operative ischaemia, global ischaemia (following cardiac arrest) and traumatic head injury to the brain or spinal cord. In addition, NMDA antagonists may be of use in treating certain chronic neurological disorders such as senile dementia, Parkinson's disease and Alzheimer's disease. They may also have utility in conditions in which peripheral nerve function has been impaired such as retinal and macular degeneration.
Furthermore, NMDA antagonists have been shown to possess anti-convulsant and anxiolytic activity and may therefore be used to treat epilepsy and anxiety. NMDA antagonists may also attenuate the effects of alcohol withdrawal from physically dependent animals (K.A. Grant et al., J Pharm.Exp.Ther., 260, 1017 (1992)) and thus NMDA antagonists may be of use in the treatment of alcohol addiction and pain. NMDA antagonists may also be useful in the treatment of hearing disorders (e.g. tinnitus), migraine and psychiatric disorders.
EP-A-0572852 describes pyrrol-1-yl-substituted 2,3(1H,4H)-quinoxalinedione derivatives useful for the treatment of neurodegenerative illnesses and neurotoxic disorders of the central nervous system.
EP-A-0556393 disclosed, inter alia, imidazolyl- or triazolyl-substituted 2,3(1H,4H)-quinoxalinedione derivatives with glutamate receptor antagonising activity, particularly NMDA-glycine receptor and AMPA receptor antagonising activities. However, no 5-triazolyl-substituted compounds are specifically described therein.
The present compounds are potent antagonists of the NMDA (glycine site) receptor. In addition, they are highly selective antagonists for the NMDA (glycine site) receptor in comparison to the AMPA receptor to which they have little, if any, affinity.
The present invention relates to a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon or nitrogen atom, or is a 6-membered ring heteroaryl group containing from 1 to 3 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon atom, either of said groups being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
3
-C
7
cycloalkyl, halo, hydroxy, C
1
-C
4
alkoxy, C
3
-C
7
cycloalkyloxy, —COOH, C
1
-C
4
alkoxycarbonyl, —CONR
3
R
4
, —NR
3
R
4
, —S(O)
p
(C
1
-C
4
alkyl), —SO
2
NR
3
R
4
, aryl, aryloxy, aryl(C
1
-C
4
)alkoxy and het, said C
1
-C
4
alkyl being optionally substituted by C
3
-C
7
cycloalkyl, halo, hydroxy, C
1
-C
4
alkoxy, halo(C
1
-C
4
)alkoxy, C
3
-C
7
cycloalkyloxy, C
3
-C
7
cycloalkyl(C
1
-C
4
)alkoxy, —COOH, C
1
-C
4
alkoxycarbonyl, —CONR
3
R
4
, —NR
3
R
4
, —S(O)
p
(C
1
-C
4
alkyl), —SO
2
(aryl), —SO
2
NR
3
R
4
, morpholino, aryl, aryloxy, aryl(C
1
-C
4
)alkoxy or het, and said C
2
-C
4
alkenyl being optionally substituted by aryl;
R
1
and R
2
are each independently selected from H, fluoro, chloro, bromo, C
1
-C
4
alkyl and halo(C
1
-C
4
)alkyl;
R
3
and R
4
are either each independently selected from H and C
1
-C
4
alkyl or, when taken together, are C
5
-C
7
alkylene;
p is 0, 1 or 2;
“aryl”, used in the definition of R and “het”, means phenyl or naphthyl, each optionally substituted by 1 or 2 substitutents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, hydroxy, halo, halo(C
1
-C
4
)alkyl and —NR
3
R
4
;
“het”, used in the definition of R, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
4
alkoxy, halo, hydroxy, —COOH, C
1
-C
4
alkoxycarbonyl, allyloxycarbonyl, —CONR
3
R
4
, —NR
3
R
4
, —S(O)
p
(C
1
-C
4
alkyl), —SO
2
NR
3
R
4
, halo(C
1
-C
4
)alkyl, hydroxy(C
1
-C
4
)alkyl, C
1
-C
4
alkoxy(C
1
-C
4
)alkyl, R
3
R
4
NCO(C
1
-C
4
)alkyl, aryl, arylalkyl, het
1
and het
1
(C
1
-C
4
)alkyl, and/or by an oxido substituent on a ring nitrogen heteroatom when “het” includes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group; and “het
1
”, used in the definition of “het”, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1 or 2 C
1
-C
4
alkyl substituents.
In the above definitions, “halo” means fluoro, chloro, bromo or iodo and alkyl, alkoxy and alkylene groups having three or more carbon atoms and alkenyl groups having 4 or more carbon atoms can be straight- or branched-chain.
The definition “C
1
-C
4
alkyl” covers methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups. The definition “C
1
-C
4
alkoxy” covers the corresponding alkoxy groups.
Where R is a 5-membered ring heteroaryl group, this definition covers 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl.
Where R is a 6-membered ring heteroaryl group, this definition includes, in particular, 2-, 3- and 4-pyridinyl, 3- or 4pyridazinyl, 2-, 4- or 5-pyrimidinyl and 2-pyrazinyl.
Where “het” is a benzo-fused heteroaryl group, this may be attached to the remainder of the molecule via the heteroaryl or benzo-fused portion of the “het” group.
Preferably, R is triazolyl or tetrazolyl, each substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
3
-C
7
cycloalkyl, halo, hydroxy, C
1
-C
4
alkoxycarbonyl, aryl and het, said C
1
-C
4
alkyl being optionally substituted by halo, hydroxy, C
1
-C
4
alkoxy, halo(C
1
-C
4
)alkoxy, C
3
-C
7
cycloalkyl(C
1
-C
4
)alkoxy, —COOH, C
1
-C
4
alkoxycarbonyl, —NR
3
R
4
, —SO
2
(aryl), morpholino, aryl, aryloxy, aryl(C
1
-C
4
)alkoxy or het; or is pyridinyl or pyrimidinyl.
More preferably, R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3yl, 1,2,4-triazol-4-yl or tetrazol-5yl, each substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
3
-C
7
cycloalkyl, halo, hydr

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