Benzimidazole derivatives and pharmaceutical compositions...

Details Benzimidazole derivatives and pharmaceutical compositions... Benzimidazole derivatives and pharmaceutical compositions...

2001-12-12

2003-11-18

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S364000, C514S381000, C514S378000, C514S370000, C514S322000, C514S338000, C514S232800, C514S254060, C514S254030, C514S254040, C514S254050, C548S306100, C548S131000, C548S314400, C548S304400, C548S215000, C548S235000, C548S237000, C546S199000, C546S273400, C544S062000, C544S139000, C544S370000, C544S369000, C544S367000, C544S366000

Reexamination Certificate

active

06649609

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith.
The 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, and in particular for inducing and maintaining anaesthesia, sedation and muscle relaxation, as well as for combating febrile convulsions in children.
The compounds of the invention may also be used by veterinarians.
BACKGROUND ART
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 (antagonists or ligands without intrinsic activity).
Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce pro-convulsive, anti-inebriant or anxiogenic effects. Compounds with anxiolytic effects, but with or without reduced muscle relaxant, hypnotic and sedative effects, are characterised as partial agonists. Partial inverse agonists are considered to be useful as cognition enhancers.
Full agonists of the benzodiazepine receptor are considered useful as anaesthetics. However, many drugs presently available as anaesthetics, and especially pre-anaesthetics, give rise to hang-over effects as well as long awakening times, wherein careful monitoring of the patient is necessary. Anaesthetics with a long half-life may also impose difficulties during incidents of overdosing i.e. prolonged respiratory depression. Furthermore, some currently used drugs cannot be used for anaesthetising children as deaths have been reported in children after prolonged use of Propofol. Some anaesthetics are gasses which inherently possesses a contamination problem for the medical staff.
A well known anaesthetic, Propofol, is administered as a mixture of soybean oil, glycerol and purified egg phosphatide, which mixture nourish bacterial growth. Administration of bacterially contaminated Propofol has been reported to cause sepsis and death [Wiklund et al.;
The New England Journal of Medicine
1997 337 (16) 1132-1141]. Further, compounds with a long in vivo half-life will give problems with accumulation during and after prolonged treatment e.g. when administered to patients constrained to a respirator. Short half-lives wherein the compounds are metabolised to inactive metabolites allow for a predictable correlation of dose and duration of pharmacological effect.
Ideally the anaesthestising effect should be observed shortly after a bolus injection or infusion of the compound. A rapid onset of action minimises the period of anxiety and uneasiness experienced by patients going into surgery.
Patients suffering from severe and continuous epileptic attacks presently treated with large amounts of sedatives, e.g. benzodiazepines, will benefit from shorter acting compounds with no hang-over or long lasting sedating effect.
As the preferred route of administration is by intravenous injection or infusion, the anaesthestising compounds should preferably be water soluble.
EP 616807 describes benzimidazole compounds for use as benzodiazepine receptor ligands.
WO 96133194, WO 96133191 and WO 96/33192 describe benzimidazole compounds having affinity for the GABA receptor complex.
WO 98134923 describes phenylbenzimidazole derivatives as ligands for the GABA receptor complex.
WO 98/17651 describes benzimidazole compounds for use as e.g. anaesthetics. However, the presently disclosed compounds are superior to the compounds previously described.
SUMMARY OF THE INVENTION
It is an object of the invention to provide novel compounds useful as anaesthetics and/or pre-anaesthetics, sedatives, muscle relaxants, and for the treatment of febrile convulsions in children, status epilepticus, for use to patients constrained to a respirator as well as for veterinarian uses.
In its first aspect, the invention provides a benzimidazole derivative represented by the general Formula I,
or a pharmaceutically acceptable salt thereof,
wherein,
R′ represents a group of the formula -(alk)
q
-R′,
wherein
(alk) represents alkyl, alkenyl or alkynyl,
q is 0 or 1,
R
1
represents a group of the formula —CO
2
R
2
, wherein
R
2
represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, alkyl-“Heterocycle”, or -alkyl-NR
3
R
4
,
wherein
“Heterocycle” represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, and a group of the formula -(alkyl)
p
-CN, -(alkyl)
p
-aryl, -(alkyl)
p
-“Heterocycle”, -(alkyl)
p
-CO
2
-“Heterocycle” or -(alkyl-CO
2
)
s
-(alkyl)
t
-COR
5
,
in which formulas
p, s and t independently of each another is 0 or 1,
“Heterocycle” represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R
5
represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxy—alkoxy, thioalkoxy-alkoxy, or a group of the formula —NR
6
R
7
or —O-alkyl-NR
6
R
7
,
in which formulas
R
6
and R
7
independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R
6
and R
7
together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
R
3
and R
4
independently of each another represent hydrogen, alkyl or cycloalkyl, or
R
3
and R
4
together with the nitrogen to which they are attached form a mono- or poly-cyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyt; or
R
1
represents a group of the formula
X represents N or CH,
R
12
represents hydrogen, alkyl alkoxy or hydroxy-alkyl, and
R
13
represents hydrogen, hydroxy, alkyl, alkoxy or hydroxy-alkyl; or
R
1
represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl)
p
-aryl, -(alkyl)
p
-“Heterocycle”, -(alkyl)
p
-CN or -(alkyl-CO
2
)
s
-(alkyl)
t
-COR
5
,
in which formulas
p, s and t independently of each another is 0 or 1,
“Heterocycle” represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R
5
represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxy—alkoxy, thioalkoxy-alkoxy, or a group of the formula —NR
6
R
7
or —O-alkyl-NR
6
R
7
,
in which formulas
R
6
and R
7
independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of haloge

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