Oxomidazopyridine-carboxamides

Details Oxomidazopyridine-carboxamides Oxomidazopyridine-carboxamides

2001-05-24

2004-04-20

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C546S123000, C514S300000

Reexamination Certificate

active

06723332

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to oxo-imidazopyridine-carboxamides that bind with high selectively and high affinity to the benzodiazepine site of GABA
A
receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of central nervous system (CNS) diseases.
2. Description of the Related Art
The GABA
A
receptor super-family represents one of the classes of receptors through which the major inhibitory neurotransmitter, &ggr;-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA
A
receptor, which causes alteration in chloride conductance and membrane polarization. In addition to being the site of neurotransmitter action, a number of drugs including the anxiolytic and sedating benzodiazepines bind to this receptor. The GABA
A
receptor comprises a chloride channel that generally, but not invariably, opens in response to GABA, allowing chloride to enter the cell. This, in turn, effects a slowing of neuronal activity through hyper-polarization of the cell membrane potential.
GABA
A
receptors are composed of five protein subunits. A number of cDNAs for these GABA
A
receptor subunits have been cloned and their primary structures determined. While these subunits share a basic motif of 4 membrane-spanning helices, there is sufficient sequence diversity to classify them into several groups. To date at least 6&agr;, 3&bgr;, 3&ggr;, 1&egr;, 1&dgr; and 2&rgr; subunits have been identified. Native GABA
A
receptors are typically composed of 2&agr;, 2&bgr;, and 1&ggr; subunits (Pritchett & Seeburg
Science
1989; 245:1389-1392, and Knight et. al., Recept.
Channels
1998; 6:1-18). Various lines of evidence (such as message distribution, genome localization and biochemical study results) suggest that the major naturally occurring receptor combinations are &agr;
1
&bgr;
2
&ggr;
2
, &agr;
2
&bgr;
3
&ggr;
2
, &agr;
3
&bgr;
3
&ggr;
2
, and &agr;
5
&bgr;
3
&ggr;
2
(Mohler et al.
Neuroch. Res.
1995; 20(5):631-36).
The GABA
A
receptor binding sites for GABA (2 per receptor complex) are formed by amino acids from the &agr; and &bgr; subunits. Amino acids from the &agr; and &ggr; subunits together form 1 benzodiazepine site per receptor. Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA
A
receptor. In addition to the benzodiazepine site (sometimes referred to as the benzodiazepine or BDZ receptor), the GABA
A
receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and a barbiturate site. The benzodiazepine site of the GABA
A
receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for other classes of drugs that bind to the receptor or for GABA (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6
th
ed., 1991, pp. 145-148, Oxford University Press, New York).
In a classic allosteric mechanism, the binding of a drug to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzodiazepines and related drugs that enhance the ability of GABA to open GABA
A
receptor channels are known as agonists or partial agonists depending on the level of GABA enhancement. Other classes of drugs, such as &bgr;-carboline derivatives, that occupy the same site and negatively modulate the action of GABA are called inverse agonists. A third class of compounds exists. These compounds occupy the same site as both the agonists and inverse agonists and yet have little or no effect on GABA activity. These compounds will, however, block the action of agonists or inverse agonists and are thus referred to as GABA
A
receptor antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early, and the distribution of activities at different subtype receptors has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects. These include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABA
A
selective ligands also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) display greater antidepressant activity when used in combination with GABA
A
selective ligands than when used alone.
SUMMARY OF THE INVENTION
This invention provides oxo-imidazopyridine-carboxamide derivatives that bind with high affinity and high selectivity to the benzodiazepine site of GABA
A
receptors, including human GABA
A
receptors. Compounds of the invention bind, preferably with high selectivity and affinity, to GABA
A
receptors and thereby act as agonists, antagonists or inverse agonists of such receptors. As such, they are useful in the treatment of various CNS disorders.
The compounds of the invention bind with high selectivity and high affinity to the benzodiazepine site of GABA
A
receptors.
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from certain CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention in conjunction with the administration of another CNS active compound.
In another, aspect this invention relates to the use of compounds of Formula I as probes for the localization of GABA
A
receptors in tissue sections. Such probes may be used in vitro (e.g., in binding assays) or in vivo (e.g., in PET or SPECT Scans).
Accordingly, in a broad aspect, the invention is directed to compounds of Formula I
and the pharmaceutically acceptable non-toxic salts thereof wherein:
A, B and C independently represent hydrogen, halogen, C
1
-C
6
alkyl,
wherein said C
1
-C
6
alkyl is straight, branched or cyclic, contains zero, one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, mono- or di(C
1
-C
6
)alkylamino, C
1
-C
3
alkoxy, and C
3
-C
7
cycloalkyl,
C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, C
3
-C
7
cycloalkyl, mono- or di(C
1
-C
6
)alkylamino (C
1
-C
6
) alkyl, mono- or di(C
1
-C
6
)alkylamino (C
1
-C
6
)alkoxy, aryl(C
1
-C
6
)alkyl and substituted aryl(C
1
-C
6
)alkyl;
E is selected from hydrogen, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
mono- or di(C
1
-C
6
)alkyl amino(C
1
-C
6
)alkyl;
F is selected from hydrogen, halogen, hydroxy, amino, and C
1
-C
6
alkyl;
G is selected from aryl and heteroaryl, each of which is optionally substituted with up to three groups independently selected from the group consisting of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl, hydroxy, mono- or di(C
1
-C
6
)alkylamino, and C
1
-C
6
alkyl substituted with one or two groups independently selected from —OR
2
, —NR
6
R
7
, and heterocycloalkyl, where R
2
, R
6
and R
7
are the same or different and represent hydrogen, C
1

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