Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-04-02
2003-11-11
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S123000, C514S235200, C514S300000
Reexamination Certificate
active
06646124
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to substituted 4-oxo-napthyridine-3-carboxamides and, in particular, such compounds which selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, and sleep, seizure and cognitive disorders.
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 electro-physiological 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 (Pritchet 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).
Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylic acids and esters have been disclosed. See, for example, Eur. J. Med. Chem.-Chim. Ther. (1977), 12 (6), 549-55.
Polish Patent No. 125299 discloses compounds of the formula:
wherein N denotes a ring nitrogen in the 5- or 6-position, and R is CO
2
H or CO
2
Et.
Several 1,4-dihydro-4-oxo-1,5-napthyridine-3-carboxamide derivatives of penicillin said to possess antibacterial activity have been disclosed. For example, German Patent No. DD 279887 discloses a compound of the formula
Japanese Patent No. 72-45118 discloses ampicillin derivatives of 1,4-dihydro-4-oxo-3-naphthyridines.
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, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
wherein:
X is hydrogen, halogen, —OR
1
, C
1
-C
6
alkyl optionally substituted with up to three groups selected independently from halogen and hydroxy, or —NR
2
R
3
;
X is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with up to three groups selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono or di(C
1
-C
6
)alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; or
X represents a carbocyclic group (“the X carbocyclic group”) containing from 3-7 members, up to two of which members are optionally hetero atoms selected from oxygen and nitrogen, where the X carbocyclic group is optionally substituted with one or more groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, or a heterocyclic group;
Y is lower alkyl having 1-8 carbon atoms optionally substituted with up to two groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, a heterocyclic group, —OR
4
, —NR
5
R
6
, SR
7
, or aryl; or
Y is a carbocyclic group (“the Y carbocyclic group”) having from 3-7 members atoms, where up to three of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the Y carbocyclic group is optionally substituted with halogen, —OR
4
, —NR
5
R
6
, SR
7
, aryl or a heterocyclic group;
R
1
is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where each alkyl may be optionally substituted with —OR
4
, or —NR
5
R
6
;
R
2
and R
3
are the same or different and represent
hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy, aryl, halogen, or mono- or di-lower alkyl;
aryl or aryl(C
1
-C
6
)alkyl where each aryl is optionally substituted with up to three groups selected from halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or mono- or di(C
1
-C
6
)alkylamino;
cycloalkyl having 3-7 carbon atoms optionally mono or disubstituted with halogen, alkoxy, or mono- or di-lower alkyl; or
—SO
2
R
8
;
R
4
is as defined for R
1
;
R
5
and R
6
carry the same definitions as R
2
and R
3
, respectively;
R
7
is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; and
R
8
is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or optionally substituted phenyl.
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. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed big the invention can be described by the general Formula I set forth above.
In Formula I above, —NR
2
R
3
can also represent a heterocyclic group such as, for example, piperidine i
Albaugh Pamela A.
DeSimone Robert W.
Liu Gang
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Seaman D. Margaret
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