Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-04-29
2001-01-09
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S354000
Reexamination Certificate
active
06172065
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns novel urea and thiourea derivatives of substituted quinoxaline 2,3-diones having utility as glutamate receptor antagonists. The fused ring quinoxaline 2,3-dione system is substituted at the a- or b-position by urea or thiourea derivatives. 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 &agr;-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 &agr;-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., Honor{acute over (e)} 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 (Eur. Pat. Appl. 488,959A).
Copending U.S. Ser. No. 08/443,507 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula:
wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl, or CH
2
CH
2
OH. This application does not disclose or suggest compounds having the instant ureas or thioureas as substituents, or the requisite methodology to prepare the same.
Copending application U.S. Ser. No. 08/404,400 teaches glutamate receptor antagonists which are quinoxalinediones of formula
or a pharmaceutically acceptable salt thereof wherein
R
1
is hydrogen, an alkyl, or an alkylaryl;
X and Y are independently hydrogen, halogen, nitro, cyano, trifluoromethyl, COOH, CONR
4
R
5
SO
2
CF
3
, SO
2
R
4
, SONR
4
R
5
, alkyl, alkenyl, (CH
2
)
z
CONR
4
R
5
, (CH
2
)
z
COOR
4
, or NHCOR
4
, wherein R
4
and R
5
are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, or alkylaryl, and z is an integer from 0 to 4,
R
2
is alkylCOOR
3
, alkylamine, alkylguanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR
3
alkyl, CONR
3
aryl, CONR
3
alkylaryl, CSNR
3
alkyl, CSNR
3
alkylaryl or a common amino acid moiety joined by an amide bond, wherein R
3
is hydrogen, alkyl, or alkylalyl; and
m and n are independently 0, 1, or 2 provided that m+n is >1.
This application does not disclose or suggest the compounds of the instant invention having ureas or thoureas as substituents at the a- or b-positions nor the methodology to prepare them.
JP62281 12-A discloses glutamate receptor antagonists which are quinoxaline-2,3(1H,4H)-dione derivatives of formula
wherein R
1
is H, NO
2
, or CF
3
;
Ring A is a nitrogen-containing saturated heterocyclic group which may contain sulfur or oxygen;
R
2
is H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH
2
, or lower alkoxy carbonyl-amino.
This reference does not teach or suggest the instant compounds which must be attached to the quinoxaline dione fused ring system by an alkylene.
WO 93/08188 covers a tricyclic quinoxalinedione of formula
as useful or selective antagonists of glutamate receptors.
European Patent Application 0627434 covers tricyclic quinoxalinedione of Formula I below which are selective antagonists of glycine binding site of the NMDA receptor
wherein X represents hydrogen, alkyl, halogen, cyano, trifluoromethyl, or nitro;
R
1
represents hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl;
G represents —CONR
2
— or —NR
2
CO—, wherein R
2
represents hydrogen or alkyl;
J represents an acidic group or a group which is convertible thereto in vivo;
E represents a basic group or a group which is convertible thereto in vivo;
Y represents a single bond, alkylene, alkenylene, substituted alkylene, or Y
1
—Q—Y
2
, wherein Y
1
represents a single bond or alkylene, Y
2
represents alkylene, and Q represents a heteroatom selected from oxygen or sulfur; and
Z r
Anderson Elizabeth M.
Bernhardt Emily
Vag Linda A.
Warner-Lambert & Company
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