Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-05
2001-08-28
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S253130, C514S254100, C514S254010, C514S255030, C544S360000, C544S365000, C544S372000, C544S374000, C544S379000, C544S392000
Reexamination Certificate
active
06281214
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biphenyl derivatives. More particularly, it relates to biphenyl derivatives which exhibit dopamine 2 receptor antagonism and/or serotonin 2 receptor antagonism and which are clinically useful as therapeutic and ameliorative agents for mental disorders such as cerebrovascular disorder, aggressive behavior due to senile dementia, mental excitation, poriomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disturbance, depression, neurosis, psychophysiologic disorder and anxiety neurosis.
2. Description of the Related Art
Mental disorders such as cerebrovascular disorder and dementia are frequently found in the aged, which becomes a significant problem with the approach of an aging society. In many cases, these diseases are accompanied with mental and/or behavior disorders which specifically appear as delirium, hallucination, hyperkinesia, poriomania, mental excitation or other sign or symptom. These signs and symptoms not only have an adverse effect on a patient himself, but also necessitate everyday care, imposing a heavy burden on the people around the patient. Under these circumstances, the development of a highly clinically useful medicine which can treat the above mental disorders medically has been expected not only by patients and their families, but also socially.
Only Tiapride is now authorized as a therapeutic and ameliorative agent for the above diseases, and Haloperidol which is an antischizophrenic drug is also used, though the diseases are not included in the indications for which the drug is efficacious.
As novel compounds having an antipsychotic activity, benzisothiazole derivatives and benzisoxazole derivatives are disclosed in European Patent Publication-A No. 196132, and pyridine derivatives are disclosed in U.S. Pat. No. 5,021,421.
Tiapride and haloperidol are medicines exhibiting dopamine 2 (D
2
) receptor antagonism. A medicine of this type has a problem of causing extrapyramidal syndrome including dystonia (hypermyotonia or muscle hypotonia), hypokinesis (akinesis), hyperkinesia (abnormal movement) and so forth as an adverse reaction, though the medicine is clinically efficacious.
Risperidone which is a representative example of the benzisoxazole derivative disclosed in the above European Patent Publication-A No. 196132 is authorized as an antischizophrenic drug in the United States, the United Kingdom and Canada. However, this drug is problematic in that blood-pressure drop occurs as an adverse reaction owing to the high &agr;
1
blocking activity of the drug and that the QT
C
interval in electro-cardiogram is lengthened to induce arrhythmia, being undesirable particularly when administered to a patient of advanced age.
The pyridine derivative disclosed in the above U.S. Pat. No. 5,021,421 also exhibits potent dopamine 2 receptor antagonism and is therefore feared to cause extrapyramidal syndrome like Tiapride or Haloperidol. Further, the pyridine derivative has not been used clinically as yet, so that its safeness in prolonged application is not apparent.
As described above, there has not been found any therapeutic and ameliorative agent for mental disorders such as cerebrovascular disorder, aggressive behavior due to senile dementia, mental excitation, poriomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disturbance, depression, neurosis, psychophysiologic disorder and anxiety neurosis, which has high clinical usefulness and is excellent in safeness.
DISCLOSURE OF THE INVENTION
3. Summary of the Invention
An object of the present invention is to provide novel biphenyl derivatives and pharmacologically acceptable salts thereof which exhibit dopamine 2 receptor antagonism and/or serotonin 2 receptor antagonism, are clinically useful as therapeutic and ameliorative agents for mental diseases, is improved in the disadvantageous extrapyramidal syndrome as compared with dopamine 2 receptor antagonists of the prior art such as Tiapride and Haloperidol, and is freed from the adverse reactions caused by the above benzisoxazole derivative (such as Risperidone), for example, blood-pressure drop and induction of arrhythmia.
Another object of the present invention is to provide processes for the preparation of the biphenyl derivatives described above.
Another object of the present invention is to provide phenylpiperazine derivatives and salts thereof which are useful as intermediates in the production of the biphenyl derivatives and pharmacologically acceptable salts thereof described above.
The present inventors have extensively studied to find an extremely safe and useful therapeutic and ameliorative agent for mental disorders which exhibits dopamine 2 receptor antagonism and does not cause extrapyramidal syndrome, blood-pressure drop, induction of arrhythmia or other adverse reaction, with their attention being paid to compounds exhibiting both dopamine 2 receptor antagonism and serotonin 2 receptor antagonism. As a result, they have found that specific biphenyl derivatives and pharmacologically acceptable salts thereof which are novel compounds have an excellent therapeutic and ameliorative effect on mental disorders and are excellent in safeness, solving the above problems. The present invention has been accomplished on the basis of this finding.
Thus, the present invention provides a biphenyl derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof:
wherein R
1
represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a pyrrolidyl group, a lower alkyl group, a halogenated lower alkyl group, a cyano lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a lower alkoxyalkyl group, a heteroarylalkyl group, a halogenated heteroarylalkyl group, a lower acylalkyl group, a heteroarylalkoxyalkyl group, a cycloalkyloxyalkyl group, an aralkyloxyalkyl group, an alkenyloxyalkly group, a lower alkoxycarbonylalkyl group, a lower alkoxyalkoxyalkyl group, an arylhydroxyalkyl group, a hydroxyheteroarylalkyl group, a cycloalkylalkoxyalkyl group, an alkonyl group, a halogenated alkenyl group, an alkynyl group, an aralkyl group, a halogenated aralkyl group, a hydroxyaralkyl group, a halogenated hydroxylminoaralkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a lower alkoxyalkoxy group, an aryl group, a hydroxyaryl group, a halogenated aryl group, a lower alkoxyaryl group, a heteroaryl group, a hydroxyheteroaryl group, a halogenated heteroaryl group, a lower alkoxyheteroaryl group, a formyl group, a lower acyl group, an aromatic acyl group, a heteroaromatic acyl group, an aralkylcarbonyl group, a cycloalkylalkylcarbonyl group, a heteroarylalkylcarbonyl group, a halogenated aralkylcarbonyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, a lower alkylamino group, a lower alkylsulfonylamino group, a halogenated lower alkylsulfonylamino group, an arylsulfonylamino group, a halogenated arylsulfonylamino group, an aralkylsulfonyl amino group, a cycloether group, a lower cyclic acetal group, a lower cyclic thioacetal group, a lower alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, a heteroarylsulfonyl group, a cycloalkylsulfonyl group, an aminosulfonyl group, a lower alkylaminosulfonyl group, an arylaminosulfonyl group, a pyrrolidylsulfonyl group, a cycloalkylaminosulfonyl group, a halogenated lower alkylsulfonyl group, a halogenated aryloxy lower alkylsulfonyl group or a cyano lower alkylsulfonyl group;
R
2
and R
3
may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxyalkyl group, a lower alkoxy group or a halogenated lower alkoxy group;
R
4
represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy
Akasaka Kozo
Higurashi Kunizo
Kajiwara Akiharu
Kitazawa Noritaka
Komatsu Makoto
Bernhardt Emily
Birch & Stewart Kolasch & Birch, LLP
Eisai Co., Ltd
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