Quinazolin-4-one AMPA antagonists

Details Quinazolin-4-one AMPA antagonists Quinazolin-4-one AMPA antagonists

1998-05-14

2003-09-30

Rao, Deepak (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S290000, C514S266200, C514S266210, C514S266300

Reexamination Certificate

active

06627755

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to quinazolin-4-ones of the formula I, as described below, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and their use in treating neurodegenerative, psychotropic, and drug and alcohol induced central and peripheral nervous system disorders.
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 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-5-methylisoxazole-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 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, idiopathic and drug-induced Parkinson's Disease and cerebral deficits subsequent to cardiac bypass surgery and grafting. 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 and acute 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 excitatory amino acid receptor (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 antagonist GKYI 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al.,
Brain Research
, 571, 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 compounds of the formula
wherein A is a benzo or thieno fused aromatic ring;
B is phenyl, pyridyl or pyrimidyl;
X is N or CH;
Y and Z, taken together, i.e., Y-Z, are either —CH
2
NH— or —NHCH
2
—;
R
1
is selected from hydrogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, cyano, halo, amino, nitro and (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
R
2
is halo, cyano, (C
1
-C
6
) alkyl optionally substituted with from one to three fluorine atoms, nitro, amino, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms, hydroxy, H—C(═O)—, (C
1
-C
6
)alkyl-O—C(═O)— or NH
2
-C(═O)—;
R
3
and R
4
are selected, independently, from hydrogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, halo, cyano, hydroxy (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms, —C(═O)H, —CH
2
OR
5
and —CH
2
NR
6
R
7
;
R
5
is hydrogen, (C
1
-C
6
)alkyl or —C(═O)(C
1
-C
6
)alkyl; and
R
6
and R
7
are selected, independently, from hydrogen, (C
1
-C
6
)alkyl, —C(═O)H and —C(═O)(C
1
-C
6
)alkyl;
or R
6
and R
7
, taken together with the nitrogen to which they are attached, form a four to seven membered saturated or unsaturated ring wherein one of the carbon atoms of such ring may optionally be replaced by oxygen or nitrogen (for example, a morpholine, piperidine, pyrrolidine, piperizine, azetidine, pyrrole, pyridine or oxazoline ring);
and the pharmaceutically acceptable salts of such compounds.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
Examples of preferred compounds of the formula I are those wherein R
1
is fluoro.
Other Examples of preferred compounds of the formula I are those wherein Y-Z is —CH
2
NH—, ring A is a benzo ring and R
1
is fluoro.
Other examples of preferred compounds of the formula I are wherein R
2
is halo, methyl or trifluoromethyl.
Other examples of preferred compounds of the formula I are those wherein Y-Z is —CH
2
NH—, ring A is a benzo ring, R
1
is fluoro, ring B is 2-pyridyl or phenyl and R
3
is cyano, fluoro, methyl or —CH
2
NR
6
R
7
.
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