Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-13
2002-07-23
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S301000, C544S127000, C544S362000, C546S114000
Reexamination Certificate
active
06423711
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to heterocyclic amino substituted heteroaryl fused pyridines, and more specifically to such compounds that selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness. The interaction of heterocyclic amino substituted heteroaryl fused pyridines of the invention with a GABA binding site, the benzodiazepines (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.
2. Description of the Related Art
&ggr;-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 40 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA.
The 1,4-Benzodiazepines, such as diazepam, continue to be among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists.
The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into &agr;, &bgr;, &ggr;, &dgr;, &egr;, and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The &ggr; subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
With the discovery of the “receptor” for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I:
wherein:
the C ring represents a thiophene, pyridine, pyrazine, pyridazine, or pyrimidine ring, each of which is optionally mono- or disubstituted with lower alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, amino, mono- or di(C
1
-C
6
) alkylamino, or trifluoromethyl;
n is 0 or an integer of from 1-3;
X is CH, nitrogen, or oxygen;
Z is an electron pair when X is oxygen;
Z is hydrogen;
Z is aryl or heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, lower alkoxy, amino, mono- or di(C
1
-C
6
)alkylamlno, or halogen; or
where
Z is
Y is oxygen or sulfur;
R is lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, or aminoalkyl, or mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl;
R is aryl or heteroaryl each of which is mono or disubstituted independently with halogen, thio, hydroxyl, lower alkyl, lower alkoxy, amino or mono- or di(C
1
-C
6
)alkylamino;
R is amino, optionally substituted with one or two groups independently selected from
lower alkyl, hydroxyalkyl, C
3
-C
7
cycloalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;
heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted with one or two groups independently selected from halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or
a C
3
-C
7
carbocyclic group having, where up to two of which atoms of the carbocyclic group are optionally hetero atoms selected from oxygen and nitrogen and where any atom of the carbocyclic group is optionally substituted with halogen, lower alkyl or lower alkoxy; or
R is a carbocyclic group having from 3-7 members, where up to three of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the carbocyclic group is optionally substituted with halogen, lower alkyl, or lower alkoxy;
A and B are the same or different and represent hydrogen or lower alkyl; and
W is aryl or heteroaryl, each of which may be mono-, or di-, or trisubstituted independently with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or di(C
1
-C
6
)alkylamino, trifluoromethyl or nitro.
These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. In other words, while the compounds of the invention all interact with GABAa brain receptors, they do not display identical physiological activity. Thus, these compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. For example, these compounds can be used to treat overdoses of benzodiazepine-type drugs as they would competitively bind to the benzodiazepine receptor.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
In addition, the present invention also encompasses compounds of Formula IIa and IIb
wherein A, B, W, X, Z, and n are as defined above for Formula I; and
R
a
and R
b
independently represent hydrogen, lower alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, amino, mono- or di(C
1
-C
6
)alkylamino, or trifluoromethyl.
Preferred compounds of Formula IIa and IIb are R
a
and R
b
are hydrogen, and a where W is phenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy. Other preferred compounds of Formula IIa and IIb are t
Albaugh Pamela A.
Cai Guolin
Chen Guoquing
Liu Gang
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Stockton Laura L.
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