Oxo-pyridoimidazole-carboxamides: GABA brain receptor ligands

Details Oxo-pyridoimidazole-carboxamides: GABA brain receptor ligands Oxo-pyridoimidazole-carboxamides: GABA brain receptor ligands

2001-01-16

2002-09-17

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S253030, C514S233200, C544S126000, C544S361000, C546S086000, C546S064000, C546S194000

Reexamination Certificate

active

06451809

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel oxo-pyridoimidazole-carboxamides 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, depression and sleep, seizure and cognitive disorders. The interaction of certain substituted oxo-pyridoimidazole-carboxamides of the invention with a GABA binding site, the benzodiazepine (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 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 action 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. Recently, 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., 1988). 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).
U.S. Pat. No. 5,639,760, PCT publication WO 94/04532,
Bioorg. Med. Chem. Lett.
1996, 6 (3), 333-338, and J. Med. Chem. 1995, 38 (1), 16-20 disclose 3-oxo-pyrido[1,2-a]-benzimidazole-4-carboxyl and 4-oxo-azepino[1,2-a]-benzimidazole-5-carboxyl derivatives, useful as muscle relaxants, hypnotics/sedatives, anxiolytics, anticonvulsants/antiepileptics, anti-inebriants, and antidotes for benzodiazepine overdose.
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, depression, sleep, cognitive and seizure disorders, overdose with benzodiazepine drugs and for enhancement of alertness. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
wherein:
represents a carbocyclic-containing ring system which is optionally substituted with up to two groups R
1
and R
2
;
R
1
and R
2
are the same or different and represent halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
3
-C
7
cycloalkyl, C
3
-C
7
cycloalkoxy, each of which may be optionally substituted with NR
5
R
6
;
R
5
and R
6
are the same or different and represent hydrogen, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl; or
R
5
and R
6
may be taken together to form a nitrogen containing ring having from 5-7 members;
R
3
represents hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy(C
1
-C
6
)alkyl, C
3
-C
7
cycloalkyl, or C
3
-C
7
cycloalkoxy C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, where any R
3
with the exception of hydrogen may be substituted with NR
5
R
6
; and
R
4
is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, where each aryl group is optionally substituted with up to three groups independently selected from halogen, hydroxy, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, mono- or di(C
1
-C
6
)alkylamino, or C
1
-C
6
alkoxy or C
3
-C
7
cycloalkoxy, either of which may be substituted with NR
5
R
6
;
provided that
(i) if R
3
is not substituted with NR
5
R
6
, then either R
1
or R
4
is substituted with NR
5
R
6
;
(ii) if R
4
is not substituted with NR
5
R
6
, then either R
1
or R
3
is substituted with NR
5
R
6
;
(iii) if R
1
is not substituted with NR
5
R
6
, then either R
2
or R
4
is substituted with NR
5
R
6
; and
(iv) if R
3
is substituted with NR
5
R
6
, R
4
is arylalkyl or heteroarylalkyl, where each aryl group is optionally substituted with up to three groups independently selected from halogen, hydroxy, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, mono- or di(C
1
-C
6
)alkylamino, or
C
1
-C
6
alkoxy or C
3
-C
7
cycloalkoxy, either of which may be substituted with NR
5
R
6
.
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, depression, sleep, cognitive and seizure disorders, overdose with benzodiazepine drugs and for enhancement of alertness.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts
The invention provides compounds with Formula II that are within the scope of Formula I:
wherein:
R
1
, R
2
, R
3
, and R
4
are as defined above.
In addition, the invention provides compounds of Formula III:
where R
1
, R
2
, R
3
, and R
4
are as defined above and n is 1, 2, or 3.
The present invention also encompasses compounds of Formula IV:
wherein R
2
, R
3
, R
4
, R
5
, and R
6
are as defined above, and
Y is C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
3
-C
7
cycloalkyl, or C
3
-C
7
cycloalkoxy.
In addition, the invention provides compounds of Formula V:
wherein R
1
, R
2
, R
5
, and R
6
are as defined above and
R
4
is arylalkyl or heteroarylalkyl, where each aryl group is optionally substituted with up to three groups independently selected from halogen, hydroxy, C
1
-C

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