Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-02-16
1997-06-17
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 86, 546 87, A61K 3144, C07D47104
Patent
active
056397607
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The gamma-aminobutyric acid-A receptor (GABA-A receptor) is the most abundant inhibitory receptor in mammalian brain. It is comprised of a heteropolymeric structure that forms a chloride ion channel, and bears multiple recognition sites for the binding of modulatory molecules. The binding of GABA to its specific recognition site on the GABA-A receptor opens the ion channel and allows chloride ions to flow into the nerve cell. This action hyperpolarizes the cell membrane of that neuron and thereby makes the cell less reactive to excitatory stimuli. The chloride ion current may also be regulated by various drugs that serve as positive or negative modulators of the GABA-A receptor (Puia, G. et al. Molecular Pharm. 1991, 39, 691 ). The so-called benzo-diazepine (BZD) receptor is a site for such allostedc modulators on the GABA-A receptor. This site mediates two opposing effects, one that amplifies the action of GABA ("positive" efficacy) and the other that reduces the action of GABA ("negative" efficacy). Agents facilitating GABA-receptor/chloride ion-channel functions via the BZD site are referred to as agonists, while agents reducing such function are referred to as inverse agonists. Antagonists at this site block the effects of agonists or inverse agonists by competitively inhibiting their binding. It is thus possible to have a series of compounds in which members equally bind to the BZD site but have equal and opposite regulatory effects on the GABA-A receptor/chloride ion channel. Also, within the series a continuum of activity is possible (Takada, S. et al. J. Med. Chem. 1988, 31, 1738). Thus, BZD receptor ligands can induce a wide spectrum of pharmacological effects ranging from muscle relaxant, hypnotic, sedative, anxiolytic, and anticonvulsant activities, produced by full or partial agonists ("positive"), to the proconvulsant, anti-inebriant, and anxiogenic activities, produced by inverse agonists ("negative"). (A further understanding of this area can be gleaned from: Mohler, H. Arzneim.-Forsch./Drug Res. 1992, 42 (2a), 211; Haefely, W. et al., Advances in Drug Research, Academic Press, vol. 14, 1985, pp. 165-322; Skolnick, P. et al., GABA and Benzodiazepine Receptors, Squires, R., Ed., 1987, pp. 99-102 and references cited therein.)
The benzodiazepines are a class of compounds which bind to the BZD receptor with high affinity. Most of the drugs in use are agonist-type ligands for the receptor. Such compounds are generally useful for their anticonvulsant, anxiolytic, sedative, and muscle relaxant effects. Antagonists of the BZD binding site are useful for the treatment of benzodiazepine drug overdose and inverse agonists are useful in managing alcoholism.
The present invention is concerned with novel compositions of matter based on 3-oxo-pyrido(1,2-a)benzimidazole-4-carboxyl and 4-oxo-azepino(1,2-a)benzimidazole-5-carboxyl derivatives. Compounds having some structural similarity to those of the present invention are described in Rida, S. M. et al. J. Het. Chem. 1988, 25, 1087; Soliman, F.S.G. et al. Arch. Pharm. 1984, 317, 951; Volovenko, Y. M. et al. U.S.S.R. Patent SU 1027166 (Chem Abs. 99(25) 212524t); Ohta, S. et al. Heterocycles 1991, 32, 1923; Ohta, S. et al. Chem. Pharm. Bull. 1991, 39, 2787.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the following formula I: ##STR2##
wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, n, X, and Y are as defined hereinafter. The compounds of formula I are useful in treating central nervous system disorder. The compounds are ligands for the BZD binding site on GABA-A receptors, and are thus useful as muscle relaxants, hypnotics/sedatives including sleep-aids, anxiolytics, anticonvulsants/antiepileptics, anti-inebriants, and antidotes for drug overdose (particularly benzodiazepine overdose).
The present invention also comprises pharmaceutical compositions containing one or more of the compounds of formula I and methods for the treatment of disorders to the central nervous system including convulsions
REFERENCES:
Rida et al. J. Heterocyclic Chem. 25, 1087, 1988 pp. 1087-1093.
Ohta et al. Heterocycles vol. 32, No. 10, 1991 pp. 1923-1929.
Ho Winston
Maryanoff Bruce E.
McComsey David F.
Gupta Yogendra N.
Palo Ralph R.
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