Benzimidazole compounds and their use as modulators of the GABA.

Details Benzimidazole compounds and their use as modulators of the GABA. Benzimidazole compounds and their use as modulators of the GABA.

1997-12-23

1999-07-13

Higel, Floyd D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514307, 514314, 514333, 514338, 514394, 544331, 544333, 5462734, 5462694, 546304, 546144, 548126, 5483051, 5483054, 5483061, C07D40110, C07D40310, C07D40510, C07D40910, C07D41710, A61K 31415

Patent

active

059227257

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel benzimidazole compounds, pharmaceutical compositions containing these compounds, methods of treating therewith, and to method of preparing such benzimidazole compounds. The novel compounds are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA.sub.A receptor complex, such as for example anxiety, sleep disorders, memory disorders, and epilepsia or other convulsive disorders,


BACKGROUND OF THE INVENTION

Receptors for .gamma.-aminobutyric acid (GABA), GABA.sub.A receptors are the most abundant inhibitory receptors in mammalian brain. The GABA.sub.A receptor are structurally constituted as macromolecular heteropentameric assemblies (combinations of a, and .gamma./.delta. protein subunits). Several subtypes of such GABA.sub.A receptors have been described by techniques of modern molecular biology. Each GABA.sub.A receptor complex comprises a chloride ion channel that controls chloride flux across the neuronal membrane, and multiple recognition sites for small modulatory molecules such as benzodiazepines, barbiturates, picrotoxin, and certain steroids. When GABA interacts with its receptor, the ion channel is opened, chloride influx is enhanced, the membrane is hyperpolarized and the cell becomes less responsive to excitatory stimuli. This GABA induced ion current can be regulated by diverse agents, including agents that interact with the benzodiazepine receptor or recognition site.
Agents that bind or interact with the modulatory sites on the GABA.sub.A receptor complex, such as for example the benzodiazepine receptor, can have either enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists by competitive block (antagonists or ligands without intrinsic activity).
Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce proconvulsant, anti-inebriant, and anxiogenic effects. Partial agonists are characterized as compounds with anxiolytic effects but without or with reduced muscle relaxant, hypnotic and sedative effects, whereas partial inverse agonists are considered to be useful as cognition enhancers.
Numerous compounds belonging to different series of compounds having affinity for the benzodiazepine receptors have been synthesized during the last three decades. However, although the benzodiazepine receptor sites are still considered as very attractive biological sites for interfering with the CNS to treat various disorders and diseases, then nearly all previously synthesized compounds acting at these receptor sites have failed during clinical development because of unacceptable side effects.
The present invention provides novel benzimidazole compounds that interact with the benzodiazepine receptor of the GABA.sub.A receptor complex. The compounds of the present invention are valuable modulators of the GABA.sub.A receptor complex.


OBJECT OF THE INVENTION

It is an object of the present invention to provide novel benzimidazole compounds and pharmaceutically-acceptable acid addition salts thereof, which are useful in the treatment of central nervous system disorders, diseases or ailments, which are responsive to the modulation of the GABA.sub.A receptor complex, and especially the positive modulation of the GABA.sub.A receptor complex.
Another object of the present invention is to provide pharmaceutical compositions comprising the novel benzimidazole compounds being useful for the above purposes. Still another object of the present invention is to provide a novel method of treating with the novel benzimidazole compounds.
A further object of the present invention is to provide a method of preparing the novel pharmaceutical compositions.
Additional objects will be obvious f

REFERENCES:
patent: 5158969 (1992-10-01), Olesen et al.
patent: 5360809 (1994-11-01), Axelsson et al.
patent: 5554632 (1996-09-01), Teuber et al.

Affiliated with

Also associated with

Rating

Benzimidazole compounds and their use as modulators of the GABA. does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzimidazole compounds and their use as modulators of the GABA., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole compounds and their use as modulators of the GABA. will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2275955