Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-26
2003-10-14
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S184000, C548S187000
Reexamination Certificate
active
06632831
ABSTRACT:
FIELD OF THE INVENTION
This invention is related to branched chain amino acid-dependent amino transferase (BCAT) inhibitors. The invention is also directed to the use of BCAT inhibitors as neuro-protective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, neuropathic pain, glaucoma, CMV retinitis, diabetic retinopathy, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's disease, Parkinsonism, amyotrophic lateral sclerosis (ALS), and Huntington's Disease.
RELATED BACKGROUND ART
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. 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 vasospasms, 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.
Excitatory amino acid receptor antagonists that block NMDA receptors are 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., 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., 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., Rosenberg P. A.,
New Eng. J. Med
., 1994;330(9):613-622; and Bigge C. F.,
Biochem. Pharmacol
., 1993;45:1547-1561, and referenced 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).
U.S. Pat. No. 5,352,683 discloses the treatment of chronic pain with a compound which is an antagonist of the NMDA receptor.
U.S. Pat. No. 4,902,695 discloses certain competitive NMDA antagonists that are useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.
U.S. Pat. No. 5,192,751 discloses a method of treating urinary incontinence in a mammal which comprises administering an effective amount of a competitive NMDA antagonist.
SUMMARY OF THE INVENTION
The invention relates BCAT inhibitor compounds of Formula I
wherein:
X is N or O;
Y is NH or CH
2
;
R
1
and R
2
are independently hydrogen, halogen or C
1
-C
3
alkyl, with the proviso that both R
1
and R
2
cannot be hydrogen at the same time;
when X is N then R
3
and R
4
are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, alkoxy, substituted alkoxy, arylalkoxy, or substituted arylalkoxy; or R
3
and R
4
together with X constitute a substituted or unsubstituted heterocyclyl group;
when X is O then R
3
is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, alkoxy, substituted alkoxy, arylalkoxy, or substituted arylalkoxy and R
4
is absent; and
R
5
is hydrogen or halogen;
where there is more than one stereoisomer, each chiral center may be independently R or S; or a pharmaceutically acceptable salt, ester, prodrug, or amide thereof.
The invention also relates to compounds of Formula I, wherein R
5
is hydrogen.
The invention also relates to compounds of Formula I, wherein R
1
is Cl.
The invention also relates to compounds of Formula I, wherein R
1
and R
2
are Cl.
The invention also relates to compounds of Formula I, wherein R
1
and R
2
are Cl and R
5
is hydrogen.
The invention also relates to compounds of Formula I, wherein R
1
is Cl, and X is O.
The invention also relates to compounds of Formula I, wherein R
1
and R
2
are Cl, X is 0 and R
3
is alkyl.
The invention also relates to compounds of Formula I, wherein R
1
and R
2
are Cl, X is N, R
3
is alkyl or cycloalkyl, and R
4
is hydrogen or alkyl, or R
3
and R
4
together with X constitute a pyrrolidine, piperidine, morpholine or N-alkylpiperazine ring.
The invention also relates to compounds of Formula I, wherein R
1
and R
2
are Cl, X is N, R
3
is alkyl, and R
4
is hydrogen.
The invention also relates to compounds selected from:
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid ethyl ester;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid tert-butyl ester;
[2-(2-Methyl-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-methyl-acetamide;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-ethyl-acetamide;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-propyl-acetamide;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-benzyl-acetamide;
[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-methoxy-acetamide;
[2-(2,4-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2,5-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2,3-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2,4,6-Trichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
[2-(2-Chloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-(2-methoxy-ethyl)-acetamide;
2-(2,6-Dichloro-phenylamino)-5-(2-oxo-2-piperidine-1-yl-ethylidene)-thiazol-4-one;
2-(2,6-Dichloro-phenylamino)-5-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethylidene)-thiazol-4-one;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-(3-pyrrolidin-1-yl-propyl)-acetamide;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-isopropyl-acetamide;
2-(2,6-Dichloro-phenylamino)-5-(2-oxo-2-pyrrolidin-1-yl-ethylidene)-thiazol-4-one;
N-Cyclohexyl-2-[2-(2,6-dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetamide;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-(2,2-dimethoxy-ethyl)-acetamide;
2-(2,6-Dichloro-phenylamino)-5-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethylidene)-thiazol-4-one;
2-(2,6-Dichloro-phenylamino)-5-[2-(3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethylidene)-thiazol-4-one;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide;
2-[2-(2,6-Dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-N-(3-methylsulfanyl-propyl)-acetamide;
2-[2-(2,6-Dichloro
Hays Sheryl Jeanne
Hu Lain-Yen
Lei Huangshu
Scholten Jeffrey David
Wustrow David Juergen
Catania R. L.
Gerstl Robert
Ginsburg P. H.
Pfizer Inc.
Richardson P. C.
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