Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-06-30
2001-04-17
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S579000
Reexamination Certificate
active
06218384
ABSTRACT:
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 allosteric 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:
wherein R, R
1
, R
2
, R
3
, R
4
, A, n, X, and Y are as defined hereinafter. The compounds of formula I are useful in treating central nervous system disorders. 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 such as epileptic seizures, anxiety, muscular spasms, sleep disorders, and benzodiazepine overdoses employing a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the invention is directed to compounds of the following formula I:
wherein
R
1
is selected from any of alkyl (C
1
-C
12
), cycloalkyl (C
3
-C
10
), phenyl; substituted phenyl where there are one or more substituents which are independently selected from any of halogen, alkyl (C
1
-C
5
), perfluoro(lower)alkyl, nitro, lower alkoxy, hydroxy, amino, lower alkylamino, di(loweralkyl)amino, di(loweralkyl)aminoalkyl, carboxy, lower alkoxycarbonyl, aminocarbonyl, lower alkylthio, cyano, and aminosulfonyl; aralkyl and substituted aralkyl where the aryl substituents are as described above with respect to substituted phenyl; a heterocycle where the heterocycle is selected from any of pyridine, thiazole, thiophene, furan, indole, benzothiophene, pyridazine, pyrimidine, indole, indoline, quinoline, indazole, imidazole, benzofuran, triazine, pyrazine, isoquinoline, isoxazole, thiadiazole, benzothiazole, triazole or benzotriazole; a substituted heterocycle where there are one or more substituents which are independently selected from any of halogen, perfluoro(lower)alkyl, nitro, lower alkylthio, lower alkoxy, lower alkyl, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, piperidin-3-yl, piperidin-4-yl, morpholin-4-yl, heterocyclic -CH
2
—, heterocyclic-CH
2
CH
2
—, or substituted heterocyclic-CH
2
— and heterocyclic-CH
2
CH
2
— (where the heterocycle is as previously defined and where the substituent groups are as previously defined for the heterocycle group). More preferably, R
1
is selected from any of alkyl (C
1
-C
12
), cycloalkyl (C
3
-C
10
), phenyl, substituted phenyl (where the substituents are independently selected from the group consisting of halogen, perfluoro(lower) alkyl, nitro, lower alkoxy, lower alkyl, hydroxy, amino, di(lower alkyl) amino, lower alkoxycarbonyl, lower alkylthio, cyano and aminosulfonyl), aralkyl, a heterocycle selected from any of pyridine, pyridinylmethyl, thiazole, pyrimidine, indoline, quinoline, indazole, benzofuran, triazine, pyrazine, isoquinoline, isoxazole, thiazole, thiadiazole, benzothiazole, triazole, or benzotriazole, or a substituted heterocycle from the preferred group of heterocycles which are pyridine, isoxazole, thiadiazole, and quinoline (where there is one or more substituents which are independently selected from any of halogen, perfluoro(lower) alkyl, nitro, lower alkylthio, lower alkoxy, lower alkyl, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl).
R
2
is selected from any of hydrogen, alkyl (C
1
-C
12
), cycloalkyl (C
3
-C
10
), aralkyl and substituted aralkyl, where the aryl substituents are as previously defined in connection with the definition of R
1
. R
2
is more preferably any of H, lower alkyl or aralkyl.
R is selected from one or more of hydrogen, alkyl (C
1
-C
8
), branched alkyl (C
3
-C
8
), halogens, perfluoro(lower alkyl), hydroxy, lower alkoxy, di(lower alkyl) amino, lower alkoxycarbonyl or lower alkylthio. There may be up to 4 independent R substituents on the phenyl. More preferably, R is selected from any of lower alkoxy, H, halogen or alkyl (C
1
-C
8
). Preferably, there is only one R substituent other than H.
n is selected from zero or 1.
A is selected from methylene or substituted methine where the substituents are selected from the group consisting of alkyl (C
1
-C
2
). More preferably, A is methylene.
R
3
and R
4
are independently selected from hydrogen, alkyl (C
1
-C
3
) or may be taken together to form a double bond within the ring. R
3
and R
4
are more preferably selected from any of hydrogen or are taken together to form a double bond.
X is selected from oxygen or sulfur.
Y is selected from NH, oxygen or sulfur, provided that when R
1
is an alkyl or a heterocycle or substituted heterocycle, Y may not be sulfur or oxygen; and Y and R
1
may also be taken together to form an NH
2
group.
As used herein unl
Ho Winston
Maryanoff Bruce E.
McComsey David F.
Kifle Bruck
Ortho-McNeil Pharmaceutical , Inc.
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