Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-21
2003-07-01
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S333000, C544S295000, C544S370000, C546S016000, C546S087000, C546S199000, C514S278000, C514S292000, C514S254060, C514S326000
Reexamination Certificate
active
06586435
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel pharmacologically active N,N′-disubstituted benzimidazolone derivatives and their addition salts which bind the serotonin or dopamine receptors, to their preparation and their use for therapeutic purposes. These compounds are able to discriminate the different serotonin and dopamine receptor subtypes like 5-HT
1A
, 5-HT
2A
, and D
4
at which they can act as agonists or antagonists. Owing to this pharmacological activity, the present compounds are useful in the treatment of anxiety disorders, affective disorders such as depression, psychosis and schizophrenia, eating disorders, sexual disorders, Parkinson, stroke and traumatic brain injury.
BACKGROUND OF THE INVENTION
Serotonin (5-HT) and dopamine (DA) recognize several well defined cell surface receptor subtypes. Among these, 5-HT
1A
and 5-HT
2A
having a high and a low affinity for 5-HT, respectively, and D
4
at which DA has high affinity, have been implicated in many Central Nervous System (CNS) disorders.
In the previous art, several classes of compounds able to interfere with the neurotransmission at 5-HT or DA receptor subtypes are known. Particularly, derivatives based on the core structure of the aryl piperazine and benzimidazolone have been described (e.g., GB 2023594; U.S. Pat. No. 3,472,854; U.S. Pat. No. 4,954,503; WO-9616949; WO-9501965; and WO-9833784), and targeted both to generic 5-HT or DA receptors and to a specific receptor subtype. In another patent (U.S. Pat. No. 5,576,318) are described compounds based both on the benzimidazolone and phenylpiperazine structures: in this latter case the described affinities are limited to 5-HT
1A
and 5-HT
2A
receptor subtypes.
DETAILED DESCRIPTION OF THE INVENTION
Now we describe, and this is the object of the present invention, new derivatives of a benzimidazolone core structure. The N-substituents are simple alkyl chains whereas the N′-substituents are alkenyl spacers connecting the benzimidazolone scaffold to a large set of secondary amines bearing other diversity points. The compounds included in this invention possess an interesting affinity profile at the serotonin and dopamine receptor subtypes: indeed some of them have a high and preferential affinity at a given site (e.g., 5-HT
1A
, 5-HT
2A
, or D
4
) whereas some others have a mixed affinity at the said receptors. Moreover a selected pool of compounds possesses an agonistic activity at the 5-HT
1A
receptor coupled with an antagonistic activity at the 5-HT
2A
receptor. Owing to their peculiar profile, the present compounds may play a role in the regulation of neurotransmission at the serotonin and/or the dopamine sites and thus may be of value in the treatment of those diseases where an altered functioning of neurosignal transmission is present. Examples of these disorders include anxiety, depression, schizophrenia, Parkinson, sleep, sexual and eating disorders, stroke and brain injury. Particularly the compounds included in the present invention can be of value in the treatment of depression according to the mounting evidence that 5-HT
1A
full agonists or high efficiency partial agonists are required for a robust antidepressant effect. In fact, electrophysiology studies suggest that repeated administration of a variety of antidepressant treatments facilitate 5-HT
1A
neurotransmission in the hippocampus, possibly through either an increased sensitivity of post-synaptic 5-HT
1A
receptors or a decreased sensitivity of 5-HT
1A
autoreceptors. Furthermore, there is some evidence from controlled clinical trials to support this suggestion. In addition to the compound's ability to block the 5-HT
2A
receptor is also of value: indeed, the stimulation of 5-HT
1A
and 5-HT
2A
receptors lead to opposite electrical events, inhibitory and excitatory, respectively. Thus only a concurrent activation of 5-HT
1A
coupled with antagonism at 5-HT
2A
receptors may completely and rapidly inhibit 5-HT post-synaptic cells, an important physiological event for antidepressant effect.
The present invention pertains to compounds of general formula (I)
wherein
R
1
denotes hydrogen or C
1
-C
6
-alkyl, being optionally substituted by C
3
-C
6
-cycloylalkyl;
R
2
and R
3
together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain nitrogen or oxygen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from phenyl, benzyl, and diphenylmethyl, said group being optionally mono- or di-substituted by one or two groups selected from CF
3
, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyl, benzyl, halogen, and OH, or
R
2
and R
3
together with the nitrogen form a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain nitrogen or oxygen as an additional heteroatom, said heterocyclic ring being linked via a single bond, a methylene-bridge, or spiro-connected to another saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, said heterocyclic group being optionally mono- or di-substituted by a group selected from CF
3
, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyl, benzyl, halogen, ═O, and OH, or
R
2
and R
3
together with the nitrogen form a saturated or unsaturated bi- or tricyclic heterocyclic ring system which may contain nitrogen or oxygen as an additional heteroatom, said heterocyclic ring system being optionally substituted by a group selected from CF
3
, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyl, benzyl, halogen, ═O, and OH;
A C
2
-C
6
-alkenylene, preferably C
2
-C
4
-alkenylene,
or a pharmaceutically acceptable salt thereof.
Preferred compounds are those of formula (I), wherein
R
1
denotes hydrogen or C
1
-C
6
-alkyl, being optionally substituted by C
3
-C
6
-cycloylalkyl;
R
2
and R
3
together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring which may contain nitrogen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from phenyl, pyridinyl, pyrimidinyl, benzimidizalonyl, and substituted phenyl being mono- or di-substituted by a group selected from CF
3
, CH
3
, OCH
3
, F, and Cl;
A C
2
-C
4
-alkenylene,
or a pharmaceutically acceptable salt thereof.
Also of interest are compounds of formula (I), wherein
R
1
denotes hydrogen or C
1
-C
4
-alkyl, being optionally substituted by cyclohexyl;
R
2
and R
3
together with the nitrogen form a 6-membered saturated or unsaturated heterocyclic ring which may contain nitrogen as an additional heteroatom, whilst the heterocyclic ring is substituted by a group selected from pyridyl, pyrimidinyl, phenyl, and substituted phenyl being mono- or di-substituted by a group selected from CF
3
, CH
3
, OCH
3
, F, and Cl;
A butenylene,
or a pharmaceutically acceptable salt thereof.
Of particular interest are compounds of formula (I), wherein
R
1
denotes hydrogen, methyl, ethyl, n-propyl, or cyclohexylmethyl;
R
2
and R
3
together with the nitrogen form a ring selected from the group consisting of piperazine, piperidine, and tetrahydropyridine, which is substituted by a group selected from pyridyl, pyrimidinyl, phenyl, and substituted phenyl being mono- or di-substituted by a group selected from CF
3
, CH
3
, and Cl;
A butenylene,
or a pharmaceutically acceptable salt thereof.
Furthermore preferred are compounds of formula (I), wherein
R
1
denotes hydrogen, methyl, n-propyl, or cyclohexylmethyl;
R
2
and R
3
together with the nitrogen form a piperazine ring, being substituted by a group selected from trifluoromethylphenyl, chlorophenyl, pyridyl, and pyrimidinyl;
A butenylene,
or a pharmaceutically acceptable salt thereof.
The most preferred compounds according to the invention are:
(a) 1-Methyl-3-(4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-(2Z)-butenyl)-1,3-dihydro-2H-benzimidazol-2-one;
(b) 1-n-Propyl-3-(4-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-(2Z)-butenyl)-1,3-dihydro-2H-benzimidazol-2-one;
(c) 1-Methyl-3-(4-{4-[3-
Brambilla Alessandro
Cereda Enzo
Giraldo Ettore
Maiocchi Luciano
Schiavi Giovanni Battista
Berch Mark L.
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen
Habte Kahsay
Raymond Robert P.
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