Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-23
2001-10-16
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S284000, C544S287000, C544S290000
Reexamination Certificate
active
06303615
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel compounds of the formula I, described below, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.
The compounds of the invention are potent AMPA receptor antagonists. AMPA receptors are a subspecies of glutamate receptors, identified by their ability to bind &agr;-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA), that are implicated as post-synaptic neurotransmitter receptors for excitatory amino acids.
The role of excitatory amino acids, such as glutamic acid and aspartic acid, as the predominant mediators of excitatory synaptic transmission in the central nervous system has been well established. Watkins & Evans,
Ann. Rev. Pharmacol. Toxicol
., 21, 165 (1981); Monaghan, Bridges, and Cotman,
Ann. Rev. Pharmacol. Toxicol
., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore,
Trans. Pharm. Sci
., 11, 25 (1990). These amino acids function in synaptic transmission primarily through excitatory amino acid receptors. These amino acids and their receptors also participate in a variety of other physiological processes such as motor control, respiration, cardiovascular regulation, sensory perception, and cognition.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed “ionotropic.” This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), &agr;-amino-3-hydroxy-5methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type is the G-protein or second messenger-linked “metabotropic” excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinosoitide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connection during development and changes in the efficiency of synaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek.
Trends in Pharmacol. Sci
., 11, 508 (1990); McDonald and Johnson,
Brain Research Reviews
, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions including cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, ocular damage and retinopathy, and idiopathic and drug-induced Parkinson's Disease. Other neurological conditions, that are caused by glutamate dysfunction, require neuromodulation. These other neurological conditions include muscular spasms, migraine headaches, urinary incontinence, psychosis, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), opiate tolerance, anxiety, emesis, brain edema, chronic pain, convulsions, retinal neuropathy, tinnitus and tardive dyskinesia. The use of a neuro-protective agent, such as an AMPA receptor antagonist, is believed to be useful in treating these disorders and/or reducing the amount of neurological damage associated with these disorders. The EAA antagonists are also useful as analgesic agents.
Several studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f-]quinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al.,
Science
, 247, 571 (1900); Buchan et al.,
Neuroreport
, 2, 473 (1991); LePeillet et al.,
Brain Research
, 571, 115 (1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al.,
Brain Research
, 671, 115 (1992). These studies strongly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in part by AMPA receptor activation. Thus, AMPA receptor antagonists may prove useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in humans.
SUMMARY OF THE INVENTION
The present invention relates to a bicyclic compound of the formula
wherein R
1
is optionally substituted phenyl of the formula Ph
1
or heteroaryl wherein said heteroaryl is selected from the group consisting of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein said heteroaryl may optionally be substituted on any of the ring carbon atoms capable ot forming an additional bond, up to a maximum of three substituents per ring, with a substituent selected from hydrogen, (C
1
-C
6
)alkyl, halogen, trifluoromethyl, amino-(CH
2
)
n
—, (C
1
-C
6
)alkylamino-(CH
2
)
n
—, di(C
1
-C
6
)alkyl-amino-(CH
2
)
n
—, (C
1
-C
6
)alkoxy, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-O—(C
1
-C
6
)alkyl-, —CN,
hydroxy, H—C(═O)—, (C
1
-C
6
)alkyl-C(═O)—(CH
2
)
n
—, HO—C(═O)—(CH
2
)
n
—, (C
1
-C
6
)alkyl-O—C(═O)—(CH
2
)
n
—, NH
2
—C(═O)—(CH
2
)
n
—, (C
1
-C
6
)alkyl-NH—C(═O)—(CH
2
)
n
—, and di(C
1
-C
6
)alkyl-NH—C(═O)—(CH
2
)
n
—;
wherein said Ph
1
is a group of the formula
R
2
is phenyl of the formula Ph
2
or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula
wherein “N” is nitrogen; wherein said ring positions “K”, “L” and “M” may be independently selected from carbon or nitrogen, with the proviso that i) only one of “K”, “L” or “M” can be nitrogen and ii) when “K”, “L” or “M” is nitrogen then its respective R
15
, R
16
or R
17
is absent;
wherein said five membered heterocycle has the formula
wherein said “T” is —CH—, N, NH, O or S; wherein said ring positions “P” and “Q” may be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that only one of “P,” “Q” or “T” can be oxygen or sulfur and at least one of “P,” “Q” or “T” must be a heteroatom;
wherein said Ph
2
is a group of the formula
R
3
is hydrogen, halo, —CN, —NO
2
, CF
3
, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy;
R
5
is hydrogen, (C
1
-C
6
)alkyl, halo, CF
3
, (C
1
-C
6
)alkoxy or (C
1
-C
6
)alkylthiol;
R
6
is hydrogen or halo;
R
7
is hydrogen or halo;
R
8
is hydrogen or halo;
R
9
is hydrogen, halo, CF
3
, (C
1
-C
6
)alkyl optionally substituted with one to three halogen atoms, (C
1
-C
6
)alkoxy optionally substituted with one to three halogen atoms, (C
1
-C
6
)alkylthiol, amino-(CH
2
)
s
—, (C
1
-C
6
)alkyl-NH—(CH
2
)
s
—, di(C
1
-C
6
)alkyl-N—(CH
2
)
s
—, (C
3
-C
7
)cycloalkyl-NH—(CH
2
)
s
—, H
2
N—(C═O)—(CH
2
)
s
—, (C
1
-C
6
)alkyl-HN—(C═O)—(CH
2
)
s
—, di(C
1
-C
6
)alkyl-N—(C═O)—(CH
2
)
s
—, (C
3
-C
7
)cycloalkyl-NH—(C═O)—(CH
2
)
s
—, R
13
O—(CH
2
)
s
—, R
13
O—(C═O)—(CH
2
)
s
—, H(O═C)—NH—(CH
2
)
s
—, (C
1
-C
6
)alkyl-(O═C)—NH—(CH
2
)
s
—, (C
1
-C
6
)alkyl-(O═C)—
H—(C═O)—(CH
2
)
s
—,
Chenard Bertrand L.
Elliott Mark L.
Welch Willard M.
Balasubramanian Venkataraman
Ginsburg Paul
Konstas Kristina L.
Pfizer Inc
Richardson Peter C.
LandOfFree
2,3 disubstituded-4(3H)-quinazolinones does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2,3 disubstituded-4(3H)-quinazolinones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2,3 disubstituded-4(3H)-quinazolinones will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2554849