Substituted quinazolines and analogs and the use thereof

Details Substituted quinazolines and analogs and the use thereof Substituted quinazolines and analogs and the use thereof

2002-08-16

2004-07-20

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S250000, C544S115000, C514S267000

Reexamination Certificate

active

06765006

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the field of medicinal chemistry. In particular, the invention is related to novel substituted quinazolines and analogs thereof. These compounds are antagonists of x-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) ionotropic receptors. Certain of these compounds are positive modulators of AMPA receptors. The invention also is directed to the use of novel substituted quinazolines and analogs thereof for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions, as anticonvulsants, as cognitive enhancers, and for the treatment of schizophrenia, Parkinson's disease and myoclonus. The compounds of the invention are also useful for treatment or prevention of pain, including acute and chronic pain. The invention also is directed to a process for the preparation of the substituted quinazolines and analogs thereof.
RELATED ART
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 agonist 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 phosphoinositide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic connections during development, but also change in the efficiency of synaptic transmission throughout life. (Schoepp, Bockaert, and Sladeczek,
Trends Pharm. Sci.
11:508 (1990); McDonald and Johnson,
Brain Res. Rev.
15:41 (1990)). The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by a mechanism known as excitotoxicity. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. (See U.S. Pat. No. 5,284,957).
Antagonists of the AMPA receptor are considered useful in treating, preventing and ameliorating a number of neurologic disorders which are due to overstimulation by the excitatory amino acids. These include acute neurologic disorders such as domoic acid poisoning; cerebral ischemia, global ischemia associated with cardiac arrest; stroke; spinal cord trauma; hypoxia; anoxia; poisoning by carbon monoxide, manganese or cyanide; hypoglycemia; mechanical trauma to the nervous system; epileptic seizures; and chronic neurologic disorders such as Huntington's disease, neuronal injury associated with HIV and AIDS, AIDS dementia, neuropathic pain syndrome, olivopontocerebral atrophy, Parkinson's disease, amyotrophic lateral sclerosis, mitochondrial abnormalities, Alzheimer's disease, hepatic encephalopathy, Tourette's syndrome, drug addiction and urinary incontinence (see Lipton and Rosenberg,
N. Engl. J. Med.
330: 613-622 (1994)) and treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia. AMPA receptor antagonists are also useful in treating, preventing and ameliorating acute and chronic pain, pain associated with post-therapeutic neurolgia, interstitial cystitis, osteoarthritis, spinal cord injury, cancer and diabetic neuropathy.
There is much evidence suggesting that the interaction of glutamate with membrane receptors plays a key role on many critical neurological functions such as cognition, learning and memory. Cognitive deficits likely arising from hypoactivity of glutamate receptors are known to be associated with neurodegenerative disorders such as Alzheimer's disease. Hypoactivity of glutamate receptors also might be associated with schizophrenia. One therapeutic approach is the direct stimulation of glutamate receptors with agonists. However, this approach increases the risk of excitotoxicity and may lead to further neurodegeneration. Selective positive modulation of certain glutamate receptor subtypes would be a better approach. Therefore positive modulators of AMPA receptors are expected to be useful for the treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia, Alzheimer's disease and malnutrition and neural maldevelopment (Thomas, R. J.,
J. Am. Geriatr. Soc.
43. 1279-1289 (1995)). It has been shown that the AMPA receptor positive modulator BDP 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine and its derivatives enhance memory in rat (Staubli et al.,
Proc. Natl. Acad. Sci.
91: 777-778 (1994)). The AMPA positive modulator BDP-29 also has been shown to attenuate the amount of stereotypic rearings seen in rats after methamphetamine injection, suggesting that AMPA receptor modulators might be useful for the treatment of schizophrenia (Larson et al.
Brain Res.
738, 353-356 (1996)). Furthermore, piracetam, a well known nootropic agent which is used to treat cognitive impairment in the elderly, was found to be a positive modulator of AMPA receptors (Copani et al.
J. Neurochem.
58: 1199-1204 (1992)). A recent clinical study showed that piracetam was effective in treating patients with myoclonus, especially that of cortical origin (Ikeda et al.
Movement Disorders
11: 691-700 (1996)). Thus, AMPA receptor positive modulators are useful in treating myoclonus.
Recent 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 to be effective in preventing global and focal ischemic damage. (Sheardown et al.,
Science
247:571 (1990); Buchan et al.,
Neuroreport.
2:473 (1991); Lepeillet et al.,
Brain Res.
571:115 (1992)). The noncompetitive AMPA receptor antagonist GKYI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine-hydrochloride) has been shown to be an effective neuroprotective agent in rat global ischemia models. (Lapeillet et al.,
Brain Res.
571:115 (1992)). GYKI 52466 has also been shown to be an effective anticonvulsant (DeSarro et al.,
Eur. J. Pharmacol.
294:411 (1995)).
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 are useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in animals. (See U.S. Pat. No. 5,284,957).
Hunter and Singh reported that 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX), a prototypical AMPA receptor antagonist, is active in blocking animal model of acute pain (
Neurosci. Lett.
174(2): 217-221 (1994)).
Sang et al., reported recently that (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY2935586) was effective in blocking the sensitization in the spinal neuron that mediates capsaicin-evoked allodymia and hyperalgesia in human, (
Soc. Neurosci
. Abstract #401.14, 1997) a human model of chronic pain.
Anderson et. al., (
J. Am. Chem. Soc.
117.12358-12359 (1995)) reported the synthesis of 5-H-2,3-benzodiazepine (LY3300164) shown below. The compound is said to be a noncompetitive antagonist of AMPA receptors with anticonvulsant activity.
Pelletier el. al. (
J. Med. Chem.
39: 343-346 (1996)) reported recently substituted 1,2-dihydrophthalazines as noncompetitive inhibitors of the AMPA receptor. For example, the compound shown below is said to be active as an anticonvulsant in the maximal electroshock model.
A group of 1-alkyl-4-aryl-2(1H)-quinazolinones and quinazolinethiones were reported to have antiinflammatory activity (
J. Med. Che

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