Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-20
2004-03-23
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S139000
Reexamination Certificate
active
06710044
ABSTRACT:
TECHNICAL FIELD
The present 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 of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA
A
receptor complex, such as for example anxiety, sleep disorders, anaestesia, memory disorders, and epilepsia or other convulsive disorders.
BACKGROUND ART
GABA
A
receptors for &ggr;-aminobutyric acid (GABA) are the most abundant inhibitory receptors in the mammalian brain. The GABA
A
receptors are structurally constituted as macromolecular heteropentameric assemblies (combinations of &agr;, &bgr;, and &ggr;/&dgr; protein subunits). Several subtypes of such GABA
A
receptors have been described by techniques of modern molecular biology.
Each GABA
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
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. Compounds with anxiolytic effects but without or with reduced muscle relaxant, hypnotic and sedative effects are characterised as partial agonists. Partial inverse agonists are considered to be useful as cognition enhancers.
Numerous compounds belonging to different chemical 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.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel benzimidazole derivatives 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
A
receptor complex, and in particular the positive modulation of the GABA
A
receptor complex, and having a favorable pharmacodynamic and pharmacokinetic behavior.
Accordingly, the invention provides a chemical compound represented by the general formula (I):
in which formula (I),
o is 0, 1, 2 or 3;
R
1
represents an alkyl group, a phenyl group, or a monocyclic heterocyclic group, which groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogen, trifluoromethyl, cyano, amino, and nitro;
or R
1
represents a cyano group, or a group of the formula -alkyl-CO
2
R
2
, alkenyl-CO
2
R
2
, —CO—R
2
, —CO
2
(CH
2
)
m
R
2
, or —C(R
3
)═N—OR
2
, in which formulas
m is 0, 1, 2 or 3;
R
2
and R
3
independently represents hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R
2
and R
3
may independently represent a group of the formula —(CH
2
)
q
—NR
4
R
5
, —(CH
2
)
q
—CON(R
4
R
5
), —(CH
2
)
q
—CO
2
R
4
, or -alkyl-CO
2
R
4
, in which formulas
R
4
and R
5
independently represent hydrogen or alkyl; and
q is 0, 1, 2 or 3;
R
11
represents a group of the general formula —CO
2
—R
9
, wherein
R
9
represents hydrogen or alkyl, which alkyl may optionally be substituted with a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro;
or R
9
may be a 5- or 6-membered heterocyclic group, which 5- or 6-membered heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, amino, or nitro; or R
9
represent a group of the general formula -alkyl-N(R
10
R
12
), in which formula
R
10
and R
12
independently represent hydrogen or alkyl;
or R
11
represents a group of general formula (II):
in which formula (II),
n is 0, 1, 2, or 3;
R′ and R″ each independently represents hydrogen or alkyl;
or R′ and R″ together with the N atom to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a —CH═CH— chain;
and in which formula the 5- to 7-membered heterocyclic ring formed by R′ and R″ may optionally be substituted one ore more times with a group of the formula —(CH
2
)
p
X, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula —CO
2
R
6
;
or X represents a group of the formula —CO—R
6
, —CO
2
—R
6
, —CON—R
6
R
7
, or —COO—R
6
—NR
7
R
8
, in which formulas
R
6
, R
7
and R
8
independently represents hydrogen or alkyl;
or R
11
may represent a group of the general formula (III):
in which formula (III),
n is 0, 1, 2 or 3;
R′ is hydrogen or alkyl;
R′″ and R″″ together with the atoms to which they are attached form a 5- to 7-membered heterocyclic ring, which heterocyclic ring may optionally comprise as a ring member, one oxygen atom, and/or one additional nitrogen atom, and/or a —CH═CH— chain;
and in which formula the 5- to 7-membered heterocyclic ring formed by R′″ and R″″ may optionally be substituted one ore more times with a group of the formula —(CH
2
)
p
X, wherein
p is 0, 1, 2 or 3;
X represents hydrogen, hydroxy, alkyl or alkenyl, which alkyl and alkenyl may optionally be substituted one or more times with a group of the formula —CO
2
R
6
;
or X represents a group of the formula —CO—R
6
, —CO
2
—R
6
, —CON—R
6
R
7
, or —COO—R
6
—NR
7
R
8
, in which formulas
R
6
, R
7
and R
8
independently represents hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof or an oxide thereof.
In another aspect, the invention provides pharmaceutical compositions comprising the novel benzimidazole compounds of the invention.
Still another object of the present invention is to provide novel methods of treatment using the novel benzimidazole compounds of the invention.
A further object of the present invention is to provide a method of preparing the novel pharmaceutical compositions of the invention.
Additional objects will be obvious from the following description, and others will be obvious to a person skilled in the art.
DETAILED DISCLOSURE OF THE INVENTION
Benzimidazole Derivatives
In its first aspect the invention provides novel
Teuber Lene
Wätjen Frank
Birch & Stewart Kolasch & Birch, LLP
McKane Joseph K.
NeuroSearch A/S
Saeed Kamal
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