Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-20
2002-03-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S019000, C546S086000, C514S278000, C514S292000, C514S233200, C514S253050, C544S126000, C544S361000, C544S058600
Reexamination Certificate
active
06358946
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a series of C-6-substituted pyrido[1,2-a]benzimidazole derivatives and to pharmaceutical compositions containing them. The compounds are ligands for the BZD site on GABA-A receptors and are thus useful for the treatment of disorders of the central nervous system.
BACKGROUND OF THE INVENTION
The gamma-aminobutyric acid-A (GABA-A receptor) is the most abundant inhibitory receptor in the brain of mammals. 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 (Smith and Olsen, Trends Pharm. Sci., 1995, 16, 162; Stephenson, Biochem. J., 1995, 310, 1). The so-called benzodiazepine (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, 985, 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 thus 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 and their use. 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. In addition, related compounds are disclosed in U.S. Pat Nos. 5,817,668, 5,817,668, 5,639,760, 5,521,200 and 5,922,731. The novel compounds differ from the prior art compounds in that they contain a ring substituent in the 6-position of the A ring.
DISCLOSURE OF THE INVENTION
The present invention is directed to compounds of the following formula:
wherein R
1
, R
2
, R
3
, X and n are as defined hereinafter. The compounds of Formula 1 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, antidepressants, anticonvulsants/antiepileptics, anti-inebriants, and antidotes for drug overdose.
The present invention also comprises pharmaceutical compositions containing one or more of the compounds of formula 1 as the active ingredient and methods for the treatment of disorders to the central nervous system including convulsions such as epileptic seizures, anxiety, depression, muscular spasms, sleep disorders, attention deficit hyperactivity disorder (ADHD) and benzodiazepine overdoses.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention is directed to compounds of the general formula:
wherein:
R
1
is independently selected from the group consisting of hydrogen; C
1-8
alkyl (including C
1-8
straight chain alkyl and C
3-8
branched chain alkyl); halogen; perfluoroC
1
4
alkyl; hydroxy; C
1-4
alkoxy; amino; di(C
1-4
alkyl)amino; aminoC
1-4
alkylamino; nitro; C
1-4
alkoxycarbonyl; and C
1-4
alkylthio; There may be up to three independent R
1
substituents on the ring (n=1-3); R
1
is preferably hydrogen, C
1-8
alkyl, halogen or C
1-4
alkoxy;
R
2
is selected from the group consisting of hydrogen; C
1-6
alkyl (including C
1-6
straight chain alkyl and C
3-6
branched chain alkyl); aralkyl; heteroaryl(C
1
4)alkyl; (R
4
)
2
N(CH
2
)
p
wherein R
4
is the same or different and is independently selected from H, C
1-4
alkyl, aralkyl, aryl or substituted aryl wherein the substituents are independently selected from C
1-4
alkyl, C
1-4
alkoxy, nitro, amino or halo, and p is 1-5; or R
4
together with the nitrogen to which they are attached may form a heterocyclic group selected from piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolyl, triazolyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, pyrrolyl or indazolyl, preferably morpholinyl, piperidinyl or pyrrolidinyl; R
5
O(CH
2
)
p
wherein R
5
is selected from C
1-4
alkyl, aralkyl, aryl or substituted aryl wherein the substituents are independently selected from C
1-4
alkyl, C
1-4
alkoxy, nitro, amino or halo and p is 1-5; and R
5
S(CH
2
)
p
; wherein R
5
and p are as defined above; R
2
is preferably H or C
1-6
alkyl;
R
3
is independently selected from the group consisting of aryl; substituted aryl, wherein the substituents are selected from C
1-8
alkyl, halo, perfluoroC
1-4
alkyl, hydroxy, C
1-4
alkoxy, amino, di(C
1-4
alkyl)amino, C
1-4
alkoxycarbonyl, aminoC
2-6
alkoxy, C
1-8
alkylaminoC
2-6
alkoxy, di(C
1-8
alkyl)aminoC
2-6
alkoxy, or C
1-4
alkylthio; a heteroaryl group selected from pyridyl; thiazolyl; thiophenyl; furyl; indolyl; imidazolyl; benzothiophenyl; pyridazinyl; pyrimidinyl; indolyl; indolinyl; quinolinyl; indazolyl; benzofuryl; triazinyl; pyrazinyl; isoquinolinyl; isoxazolyl; thiadiazolyl; benzothiazolyl; triazolyl; or benzotriazolyl; a substituted heteroaryl group wherein the substituent is selected from oxo, halo, perfluoroC
1-4
alkyl, nitro, amino, C
1-4
alkylthio, C
1-4
alkoxy, C
1-4
alkylamino, di(C
1-4
)alkylamino, carboxy or C
1-4
alkoxycarbonyl; and cycloalkyl having
3-8
carbon atoms; R
3
is preferably aryl, haloaryl, C
1-4
alkoxyaryl or heteroaryl;
X is a heterocyclic or carbocyclic ring selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxazolinyl, triazolyl, tetrazolyl, oxadiazolyl, dioxaazaspirodecanyl, thiadiazolyl, purinyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, indolyl; cyclo(C
3-8
)alkyl; phenyl; and naphthyl; a substituted heterocyclic, carbocyclic, or aryl ring wherein the substituents are independently selected from C
1-8
alkyl (including C
1-8
straight chain alkyl and C
3-8
branched chain alkyl), halogen, perfluoroC
1-4
alkyl, hydroxy, amino, nitro, oxo, C
1-4
alkoxy, C
1-4
alkylamino,
Nortey Samuel O.
Reitz Allen B.
Sanfilippo Pauline
Scott Malcolm K.
Appollina Mary
Liu Hong
Ortho-McNeil Pharmaceutical , Inc.
Raymond Richard L.
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