Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1998-11-25
2002-01-22
Ford, John M. (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S354000, C540S599000
Reexamination Certificate
active
06340758
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns conformationally semi-constrained analogs of substituted quinoxaline 2,3-diones having utility as glutamate receptor antagonists. The quinoxaline 2,3-dione system is substituted by an amino acid derivative or nitrogen heterocyclic ring which includes bioisosteres of carboxylic acid derivatives via a carbon atom linkage. The compounds are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as the I-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor. The invention also relates, therefore, to the use of those quinoxaline-2,3-diones as neuroprotective agents for treating conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as to treat chronic neurodegenerative disorders such as Alzheimer's Disease, Parkinsonism, and Huntington's Disease, and seizure disorders and pain. The compounds of the present invention may also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain, and drug addiction.
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) receptor, the I-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. AMPA/kainate receptors may be referred to jointly as non-NMDA receptors. This excitotoxic action is considered 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 hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.
Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (Bigge C. F. and Malone T. C.,
Curr. Opin. Ther. Pat
., 1993:951; Rogawski M. A.,
TiPS
, 1993;14:325). AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (Li H. and Buchan A. M.,
J. Cerebr. Blood Flow Metab
., 1993;13:933; Nellg{dot over (a)}rd B. and Wieloch T.,
J. Cerebr. Blood Flow Metab
., 1992;12:2) and focal cerebral ischemia (Bullock R., Graham D. I., Swanson S., and McCulloch J.,
J. Cerebr. Blood Flow Metab
., 1994;14:466; Xue D., Huang Z.-G., Barnes K., Lesiuk H. J., Smith K. E., and Buchan A. M.,
J. Cerebr. Blood Flow Metab
.,1994;14:251). AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-J., Hao J.-X, Seiger A., and Wiesenfeld-Hallin Z.,
J. Pharmacol. Exp. Ther
., 1993;267:140), and epilepsy (Namba T., Morimoto K., Sato K., Yamada N., and Kuroda S.,
Brain Res
., 1994;638:36; Brown S. E. and McCulloch J.,
Brain Res
., 1994;641:10; Yamaguchi S. I., Donevan S. D., and Rogawski M. A.,
Epilepsy Res
., 1993;15:179; Smith S. E., Durmuller N., and Meldrum B. S.,
Eur. J. Pharmacol
., 1991;201:179). AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism (Klockgether T., Turski L., Honoré T., Zhang Z., Gash D. M., Kurlan R., and Greenamyre J. T.,
Ann. Neurol
., 1993;34(4):585-593).
Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain, and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's Disease (Klockgether T. and Turski L.,
Ann. Neurol
., 1993;34:585-593), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's Disease (Francis P. T., Sims N. R., Procter A. W., and Bowen D. M.,
J. Neurochem
., 1993;60(5):1589-1604), and Huntington's Disease. (See Lipton S.,
TINS
, 1993;16(12):527-532; Lipton S. A. and Rosenberg P. A.,
New Eng. J. Med
., 1994;330(9):613-622; and Bigge C. F.,
Biochem. Pharmacol
., 1993;45:1547-1561 and references cited therein.) NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (European Patent Application 488,959A).
The compounds of the instant invention differ from the art in that they provide non-coplanar compounds with greater solubility and, therefore, better ability to penetrate the blood-brain barrier. These are important attributes in pharmaceuticals. It is a further object to cover conformationally semi-constrained quinoxaline-2,3-dione derivatives.
SUMMARY OF THE INVENTION
Described are quinoxaline-dione compounds of Formula I
wherein
R is an amino acid, a derivative thereof, or nitrogen heterocyclic ring which is saturated or unsaturated of from 5 to 8 members which may have additional oxygen or sulfur atoms therein and which may be substituted by one or more substituents selected from:
alkyl of from 1 to 4 carbon atoms,
hydroxyl,
alkoxy of from 1 to 4 carbon atoms,
—CF
3
,
—CN,
-amino,
—C(O)R
11
, or
—(CH
2
)
n
-aryl of from 6 to 12 carbon atoms;
R must be attached through a carbon to the quinoxalinyl ring;
R
1
is H, alkyl of from 1 to 4 carbon atoms, phosphonoalkyl of from 1 to 4 carbon atoms, phosphoroalkyl of from 1 to 4 carbon atoms, carboxyalkyl of from 1 to 4 carbon atoms, —(CH
2
)
m
C(O)R
11
, or hydroxy;
R
2
is hydrogen, hydroxy, or amine;
R
3
and R
4
are each independently H, alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 5 to 7 carbon atoms, alkenyl of from 2 to 6 carbon atoms, halogen, haloalkyl of from 1-6 carbon atoms, nitro, cyano, SO
2
CF
3
, CH
2
SO
2
R
7
, (CH
2
)
m
CO
2
R
7
, (CH
2
)
m
CONR
7
R
8
, (CH
2
)
m
SO
2
NR
8
R
9
, or NHCOR
7
;
R
5
is H, alkyl of from 1 to 4 carbon atoms, alkenyl of from 2 to 6 carbon atoms, cycloalkyl of from 5 to 7 carbon atoms, halogen, haloalkyl of from 1 to 4 carbon atoms, —(CH
2
)
m
aryl of from 6 to 10 carbon atoms, nitro, cyano, SO
2
CF
3
, (CH
2
)
m
CO
2
R
9
, (CH
2
)
m
CONR
9
R
10
, SO
2
NR
9
R
10
, SO
2
R
7
, (CH
2
)
m
SO
2
R
7
, NHCOR
9
, —(CH
2
)
m
heterocyclic of from 6 to 10 atoms which may contain nitrogen, oxygen, sulfur, and/or —(CH
2
)
n
R;
R
5
may be joined at R
4
to form a cyclic aromatic or a heterocyclic ring of from 5 to 7 members which may contain nitrogen, oxygen, or sulfur;
R
7
, R
8
, R
9
, and R
10
are each independently selected from hydrogen, alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 5 to 7 carbon atoms, haloalkyl of from 1 to 4 carbon atoms, or —(CH
2
)
m
R
11
;
R
11
is alkyl or alkoxy of from 1 to 4 carbon atoms, hydroxy, or amino;
m is an integer of from 0 to 4;
n is an integer of from 0 to 4;
or a pharmaceutically acceptable salt thereof.
Preferred compounds are those of Formula I wherein
R is an amino acid attached via an alkyl side-chain to the quinoxaline-2,3-dione ring at C-5 or C-6. The amino acid is R or S or RS(±). The point of attachment is I- to the carboxylic acid moiety, e.g.,
wherein
p is an integer of from 0 to 4;
R
12
is —OH, alkoxy, or —NR
7
R
8
;
R
1
Kornberg Brian Edward
Nikam Sham Shridhar
Rafferty Michael Francis
Anderson Elizabeth M.
Ashbrook Charles W.
Balasubramanian Venkataraman
Berven Heidi M.
Ford John M.
LandOfFree
Conformationally semi-constrained quinoxaline 2,3-diones as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Conformationally semi-constrained quinoxaline 2,3-diones as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Conformationally semi-constrained quinoxaline 2,3-diones as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2874298