Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-08
2001-08-28
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S370000
Reexamination Certificate
active
06281218
ABSTRACT:
The present invention relates to novel pharmacologically active benzimidazolone derivatives and their addition salts which bind the serotonin and dopamine receptors, to their preparation and their use for therapeutic purposes. These compounds, owing to their pharmacological activity, are useful in the treatment of CNS disorders.
BACKGROUND OF THE INVENTION
Serotonin (5-HT) and Dopamine recognize several well-defined cell surface receptors. Among these, 5-HT
1A
, 5-HT
2A
, and D
4
at which serotonin and dopamine, respectively, have high affinity, are known to be implicated in many Central Nervous System (CNS) disorders such as depression, anxiety, schizophrenia, Parkinson's disease, and neurodegenerative diseases.
In the previous art, several classes of compounds able to interfere with the neurotransmission at serotonin or dopamine receptor subtypes are known. Particularly, derivatives based on the core structure of the arylpiperazine and benzimidazolone have been described (e.g., GB 2,023,594; U.S. Pat. No. 3,472,854; U.S. Pat. No. 4,954,503; and WO 98/33784), and targeted both to generic serotonin or dopamine receptors and to a specific receptor subtype. In another patent (U.S. Pat. No. 5,576,318), compounds based both on the benzimidazolone and phenyl piperazine structures are described: in this latter case the described affinities are limited to 5-HT
1A
and 5-HT
2A
receptor subtypes.
DETAILED DESCRIPTION OF THE INVENTION
Here we describe, and this is the object of the present invention, new hydroxylated derivatives based on the benzimidazolone phenyl piperazine structure. Surprisingly it was discovered that the compounds according to this invention possess an interesting affinity profile at the said 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 other have a mixed affinity at all the said receptors.
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 an:d thus may be of value in the treatment of those diseases where an altered functioning of neurosignal transmission is present. Examples of these CNS disorders include depression, schizophrenia, Parkinson's disease, anxiety, sleep disturbances, sexual and mental disorders, and age-associated memory impairment.
According to the present invention, we provide compounds of general formula (I)
wherein:
R
1
, R
2
, R
3
, and R
4
denote hydrogen or hydroxy with the proviso that R
1
, R
2
, R
3
, and R
4
cannot simultaneously represent hydrogen.
Preferred compounds according to the invention are those of general formula (I) wherein two or three of the four radicals R
1
, R
2
, R
3
, and R
4
denote hydrogen.
Also preferred are compounds of general formula (I) wherein one of the radicals R
1
, R
2
, R
3
, and R
4
denotes hydroxy, while the other radicals represent hydrogen.
Of particular interest are compounds selected from the group consisting of:
(a) 5-hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one;
(b) 6-hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3 -dihydrobenzimidazol-2-one;
(c) 4-hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one;
(d) 7-hydroxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one;
(e) 1-{2-[4-(4-hydroxy-3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one;
(f) 1-{2-[4-(3-hydroxy-5-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one;
(g) 1-{2-[4-(2-hydroxy-5-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one; and
(h) 1-{2-[4-(2-hydroxy-3-trifluoromethylphenyl)piperazin-1-yl]-ethyl}-1,3-dihydrobenzimidazol-2-one.
For pharmaceutical use, the compounds of general formula (I) may be used either as free base or in the form of physiologically acceptable acid addition salts. The term “acceptable acid addition salts” includes both organic and inorganic acids such as maleic, citric, tartaric, methanesulphonic, acetic, benzoic, succinic, gluconic, isethionic, glycinic, lactic, malic, mucoic, glutamic, sulfamic, and ascorbic acid; inorganic acids include hydrochloric, hydrobromic, nitric, sulfuric, or phosphoric acid.
The compounds of general formula (I) may be conveniently prepared by a variety of synthetic processes analogous to those known in the art using conventional methods and starting from suitable intermediates in which the hydroxy function (generally in the form of a methoxy precursor group) is inserted in a well defined position, and suitable for originating the final target compound. When a masked (i.e., protected) hydroxy function is used throughout all the synthetic process, the hydroxy function is generated in the last step as exemplarily outlined in Scheme 1.
As protective groups conventional ether protective groups are applicable (e.g., methyl, methoxymethyl, benzyl). The preferred protecting group according to the invention is the methyl ether. The deprotection of the hydroxy group can be easily carried out by conventional known procedures. In case of the preferred protecting group (methoxy), the deprotection is achieved by treatment with strong aqueous acids such as 48% hydrobromic acid at high temperatures or alternatively by treatment with boron derivatives, such as BBr
3
, at low temperatures in chlorinated solvents such as methylene dichloride.
As mentioned before, the compounds of formula (I) according to the present invention, surprisingly show interesting pharmacological properties owing to their different profile at the serotonin or dopamine receptor subtypes, such as 5-HT
1A
, 5-HT
2A
and D
4
. The biochemical profile of the compounds was assessed by evaluating their affinity for the 5-HT
1A
, 5-HT
2A
and D
4
receptors, according to the methods described below.
Receptor Binding Studies
Binding studies were carried out to determine the affinity of the compounds for 5-HT
1A
, 5-HT
2A
, and D
4
receptors
5-HT
1A
Receptor
Tissue preparation:
Male Sprague-Dawley rats (200-250 g) were used. The hippocampus taken from these animals was homogenized in 10 volumes of ice cold 50 mM TIUS buffer (pH 7.4). The homogenate was diluted 1:400 (w:v) in the same buffer to have a final protein concentration of about 200 &mgr;g/ml, filtered and incubated at 37° C. for 10 minutes before use.
Binding Assay:
Displacement experiments were performed by incubating the homogenate (980 &mgr;l) in the presence of [
3
H]-8-OH-DPAT (10 &mgr;l; 1.0-1.2 nM) and different concentrations of the test compounds dissolved in DMSO (10 &mgr;l), at 30° C. for 15 minutes (final volume: 1 ml). Nonspecific binding was determined in the presence of 10 &mgr;M 5-HT (10 &mgr;l). The reaction was stopped by rapid filtration through Inotech IH 201 filters using an Inotech Cell Harvester. The radioactivity was counted by liquid scintillation spectrometry.
5 HT
2A
Receptor
Tissue preparation:
Male Sprague-Dawley rats (200-250 g) were used. Cerebral cortex was homogenized in 10 volumes of ice cold 0.32 M sucrose. After the centrifugation of the homogenate (1,000×g for 10 minutes) the supernatant was then recentrifuged at 48,000×g for 15 minutes. The resulting pellet was suspended in 10 volumes of 50 mM TRIS buffer (pH 7.4), incubated at 37° C. for 10 minutes and recentrifuged at 48,000 × g for 15 minutes. The residue was then resuspended in 10 volumes of 50 mM TRIS buffer (pH 7.4).
Binding Assay:
The tissue was diluted 1:100 (w:v) in 50 mM TRIS buffer (pH 7.4) to have a final concentration of about 200 &mgr;g/ml. Displacement experiments were performed by incubating the homogenate (980 &mgr;l) in the presence of [
3
H]-Ketanserine (10 &mgr;l; 0.5-0.6 nM) and different concentrations of the test compound
Bignotti Maura
Cereda Enzo
Schiavi Giovanni Battista
Bernhardt Emily
Ingelheim Italia S.p.A.
Raymond R. P.
Witkowski T. X.
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