Heterocyclic compounds as ligands of the GABAA receptor

Details Heterocyclic compounds as ligands of the GABAA receptor Heterocyclic compounds as ligands of the GABAA receptor

2001-08-06

2003-11-25

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06653471

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to heterocyclic compounds, and more specifically to such compounds that bind with high selectivity 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 certain central nervous system (CNS) diseases.
DESCRIPTION OF THE RELATED ART
The GABA
A
receptor superfamily 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.
A number of cDNAs for GABA
A
receptor subunits have been characterized. To date at least 6&agr;, 3&bgr;, 3&ggr;, 1&egr;, 1&dgr; and 2&rgr; subunits have been identified. It is generally accepted that 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). 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): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA
A
receptor. In addition to the benzodiazepine site, the GABA
A
receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the 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 GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6
th
ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines is enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABA
A
receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABA
A
receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes 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 a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABA
A
selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABA
A
selective ligands than when used alone.
SUMMARY OF THE INVENTION
This invention provides heterocyclic compounds, such as 5,6-Dihydro-4H-1,3a,6-triaza-as-indacenes and related compounds, that bind with high affinity and high selectivity to the benzodiazepine site of the GABA
A
receptor, including human GABA
A
receptors.
Thus, the invention provides novel compounds of Formula A (shown below), and pharmaceutical compositions comprising compounds of Formula A.
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 with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABA
A
receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula A:
or a pharmaceutically acceptable salt thereof, wherein:
the b-ring is a 5-9 membered ring;
E represents (CR
1
R
2
)
k
, —CR
1
═CR
2
—, —O—(CR
1
R
2
)
k
—, —(CR
1
R
2
)
k
—O—, —N═CR
1
—, —CR
1
═N—, —NR′—(CR
1
R
2
)
k
—, or —(CR
1
R
2
)
k
—NR′—, wherein
R
1
and R
2
independently represent
hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C
1
-C
6
)alkylamino, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
6
haloalkyl, C
1
-C
6
haloalkoxy, amino(C
1
-C
6
)alkyl, or mono- or di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, or
phenyl, pyridyl, phenyl(C
1
-C
6
)alkyl, or pyridyl(C
1
-C
6
)alkyl, where each phenyl or pyridyl is optionally substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C
1
-C
6
)alkylamino;
k is 0, 1, 2, or 3;
R′ represents
hydrogen, C
1
-C
6
alkyl, C
2
-C
7
alkanoyl, C
1
-C
6
alkoxy(C
1
-C
6
)alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
6
haloalkyl, amino(C
1
-C
6
)alkyl, or mono- or di(C
1
-C
6
)alkylamino(C
3
-C
6
)alkyl, or
aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C
1
-C
6
)alkylamino;
G is oxygen or NH;
J represents (CR
5
R
6
)
d
where
d is 0 or 1; and
R
5
and R
6
together form a carbonyl group; or
R
5
and R
6
are independently hydrogen or R
100
,
where each R
100
is independently selected from halogen, hydroxy, nitro, cyano, R
10
, amino, —NH(R
10
), —N(R
10
)(R
10
), —COOH, —O(R
10
), —SO
2
NH
2
, —SO
2
NH(R
10
), —SO
2
N(R
10
)(R
10
) —NHCO(R
10
), —N(R
10
)CO(R
10
), —NHCO
2
(R
10
), —N(R
10
)CO
2
(R
10
), —NHSO
2
(R
10
), —N(R
10
)SO
2
(R
10
), —SO
2
NHCO(R
10
), —SO
2
N(R
10
)CO(R
10
) —CONHSO
2
(R
10
), —CON(R
10
)SO
2
(R
10
), —CONH
2
, —CONH(R
10
), —CON(R
10
)(R
10
), —CO
2
(R
10
), —CO(R
10
), —SR
10
, SO(R
10
), —SO2 (R
10
), aryl having from 1 to 3 rings, and heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring, and in at least one of said rings from 1 to about 3 heteroatoms selected from nitrogen, oxygen and sulfur, and where each aryl and heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C
1
-C
6
)alkylamino;
each R
10
is independently a straight, branched, or cyclic alkyl group having up to 8 carbon atoms, contains zero or one or more double or triple bonds, and is optionally substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, mono- or di-(C
1
-C
6
)alkylamino, cyano, nitro, C
1
-C
6
alkoxy, —COO

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