Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-11-26
2004-10-26
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S602000, C514S603000, C564S081000, C564S430000
Reexamination Certificate
active
06809119
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:
R
3
is H, halogen, alkyl, carboxy, alkoxy, substituted alkoxy; R
1
, R
2
, R
4
and R
5
are independently, H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, NO
2
, halogen, or CF
3
;
R
6
or R
7
are independently, H, halogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, C(CH
2
)
n
—NHSO
2
-aryl, C(CH
2
)
n
—NHSO
2
-substituted aryl, (CH
2
)
n
—NHSO
2
-alkyl, (CH
2
)
n
—NHSO
2
-substituted alkyl, (CH
2
)
n
—NHSO
2
-arylalkyl, (CH
2
)
n
—NHSO
2
-substituted arylalkyl, NHSO
2
-aryl, NHSO
2
-substituted aryl, NHSO
2
-alkyl, NHSO
2
-substituted alkyl, NHSO
2
-arylalkyl, NHSO
2
-substituted arylalkyl, (CH
2
)
n
-aryl, (CH
2
)
n
-substituted aryl, (CH
2
)
n
-alkyl, (CH
2
)
n
-substituted alkyl, O-aryl, O-substituted aryl, O-alkyl, O-substituted alkyl, O-arylalkyl, O-substituted arylalkyl, (CH
2
)
n
—SO
2
NH-aryl, (CH
2
)
n
—SO
2
NH-substituted aryl, (CH
2
)
n
—SO
2
NH-alkyl, (CH
2
)
n
—SO
2
NH-substituted alkyl, (CH
2
)
n
—C(O)NH-arylalkyl, (CH
2
)
n
—C(O)NH-substituted arylalkyl, (CH
2
)
n
—C(O)NH-aryl, (CH
2
)
n
—C(O)NH-substituted aryl, (CH
2
)
n
—C(O)NH-alkyl, (CH
2
)
n
—C(O)NH-substituted alkyl, (CH
2
)
n
—SO
2
NH-arylalkyl, (CH
2
)
n
—SO
2
NH-substituted arylalkyl, (CH
2
)
n
—NH
2
, (CH
2
)
n
—NH-aryl, (CH
2
)
n
—NH-substituted aryl, (CH
2
)
n
—NH-alkyl, (CH
2
)
n
—NH-substituted alkyl, (CH
2
)
n
—NH-arylalkyl, (CH
2
)
n
—NH-substituted arylalkyl, (CH
2
)
n
—NHSO
2
-aryl, (CH
2
)
n
—NHSO
2
-substituted aryl, (CH
2
)
n
—NHSO
2
-alkyl, (CH
2
)
n
—NHSO
2
-substituted alkyl, (CH
2
)
n
—NHC(O)-arylalkyl, (CH
2
)
n
—NHC(O)-substituted arylalkyl, (CH
2
)
n
—NO
2
, (C≡C)-alkyl. (C≡C)-substituted alkyl, (C≡C)-arylalkyl, (C≡C)-substituted arylalkyl, (C≡C)-aryl, or (C≡C)-substituted aryl; and
n is 0, 1, 2, or 3.
or a pharmaceutically acceptable salt, ester, prodrug, or amide thereof;
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
1
, R
2
, R
3
, R
4
, and R
5
are hydrogen; and R
6
or R
7
is —NHSO
2
-aryl, —NHSO
2
-substituted aryl, —NHSO
2
-alkyl, or —NHSO
2
-substituted alkyl.
The invention also relates to compounds selected from:
Benzoic acid, 4-nitro-2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-amino-2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(2,4,6-trichlorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(3,4-dimethoxyphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[[(4-phenoxy)benzene]sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(2-chloro-6methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[(methylsulfonyl)amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-ethylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-propylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-butylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-n-pentylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(4-fluorophenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[phenylsulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
4-Benzylamino-benzoic acid 2-(phenylsulfonyl)hydrazide;
Benzoic acid, 4-[[(3-methylphenyl)sulfonyl]amino]-, 2-(phenylsulfonyl)hydrazide;
4-Phenoxybenzoic acid, 2-[(3-methyl)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[3-bromophenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-chlorophenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-(trifluoromethoxy)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[(4-methyl-3-nitro)phenylsulfonyl]hydrazide;
4-Phenoxybenzoic acid, 2-[2-trifluorophenylsulfonyl]hydrazide;
4-(1,1-Dimethylethyl)-benzoic acid 2-(phenylsulfonyl)hydrazide;
[1,1′-Biphenyl]-4-carboxylic acid 2-(phenylsulfonyl)hydrazide;
3-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
2-Phenoxybenzoic acid, 2-(phenylsulfonyl)hydrazide;
4-Phenoxybenzoic acid, 2-(phenylsulfonyl
Hu Lain-Yen
Kesten Suzanne Ross
Lei Huangshu
Ryder Todd Robert
Wustrow David Juergen
O'Sullivan Peter
Scully Scott Murphy & Presser
Warner-Lambert Company LLC
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