Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-07
2001-02-13
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S590000, C544S242000, C544S319000, C544S333000, C544S334000
Reexamination Certificate
active
06187769
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel benzoxazepine derivatives and their salts. More particularly, it relates to novel benzoxazepine derivatives and their salts useful as medicaments for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders, and also emesis or disorders involving the cerebral circulatory system accompanying cerebral infarction and cerebral hemorrhage and also medicaments containing these as effective ingredients and also novel synthetic intermediates of the same.
BACKGROUND ART
In the past, anxiety disorders, phobias, obsessive-compulsive disorders, etc. have been treated using diazepam, oxazepam, and other benzodiazepine-based medicaments. However, these benzodiazepine-based medicaments have side effects such as drowsiness, muscle relaxation, and dependency. To lighten these side effects, buspirone, tandospirone, and other serotonergic agents have been developed as anxiolytics. However, these compounds, while partially alleviating the various side effects compared with the conventional benzodiazepine-based medicaments, still cannot be said to be sufficient. Development of anxiolytics with even less side effects is desired.
Further, for cerebral infarction and other cerebrovascular diseases, the thromboxane A
2
synthesizing enzyme inhibitor ozagrel has been confirmed to be effective for cerebral vasospasms and cerebral ischemic disorders, but it increases the tendency for hemorrhaging, and therefore, is suited for only limited diseases.
SUMMARY OF THE INVENTION
In consideration of this situation, the problem to be solved by the present invention is to provide a medicament which can be used for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders, and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders and also emesis, or disorders involving the cerebral circulatory system accompanying cerebral infarction and cerebral hemorrhage more effectively and with fewer side effects.
The present inventors engaged in repeated intensive studies to develop a superior medicament free from the above problems and, as a result, found that the compounds of the present invention, that is, the novel benzoxazepine derivatives and their salts, have beneficial pharmacological effects, that is, the compounds of the present invention have an anxiolytic activity, an activity suppressing cerebral infarction, and other protective effects-on the brain in ischemic brain diseases.
It is known that when there is nonselective affinity with serotonin receptors and affinity with dopamine D
2
receptors in the central nervous system, there is a possibility of extrapyramidal syndromes and other side effects occurring, which is not desirable. The present inventors previously found that certain types of benzoxazepine derivatives exhibited an anticonflict activity (see Japanese Unexamined Patent Publication (Kokai) No. 2-256671). Further, recently, the involvement of cerebral serotonergic neuron in cerebral ischemic conditions has been suggested. Among the types of serotonin receptor related activities, there have been reports that a serotonin
1A
type receptor agonist has a protective effect on the brain in cerebral ischemic conditions (G. W. Bielenberg et al., Stroke Supplement IV, vol. 21, p. 161, 1990, etc.) and that a serotonin
2
type receptor antagonist exhibits a protective effect in ischemic neuronal damage (Brain Res., vol. 494, no. 2, p. 387-390, 1989, etc.)
The present inventors, based on the above findings, synthesized compounds using as key indicators the affinity with a serotonergic receptor and the affinity with a dopamine D
2
receptor and discovered that the specific benzoxazepine derivatives and their salts of the following general formulas (I), (II), and (III) exhibit an anxiolytic activity confirmed by the anticonflict activity as an indicator and that they have suppressive activity in cerebral infarction and other protective effects of the brain in ischemic brain diseases in a transient right middle cerebral artery occlusion (MCAO) model and accordingly found that these compounds were useful as medicaments for use for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders, and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders, and also emesis, or disorders involving the cerebral circulatory system accompanying cerebral infarction and cerebral hemorrhage more effectively and with fewer side effects, whereby the present invention was completed.
Accordingly, the object of the present invention is to provide the novel benzoxazepine derivatives.
Another object of the present invention is to provide medicaments containing these benzoxazepine derivatives or their pharmaceutically acceptable salts as essential ingredients and usable for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, schizophrenia, post-cardiac trauma stress disorders, depression disorders, psychosomatic disorders, and other psychoneurotic disorders, eating disorders, menopausal disorders, infantile autism and other disorders, and also emesis, or disorders involving the cerebral circulatory system accompanying cerebral infarction and cerebral hemorrhage.
In accordance with the present invention, there is provided a novel benzoxazepine derivative having the general formula (I) and its salts:
wherein, n is an integer of 2 to 5, R
1
indicates a hydrogen atom, halogen atom, C
1
to C
4
lower alkyl group, C
1
to C
4
lower alkoxyalkyl group, C
1
to C
4
halogenoalkyl group, cyano group, or ester group, R
2
indicates a hydrogen atom, halogen atom, C
1
to C
4
lower alkyl group, C
1
to C
4
lower alkoxy group, or hydroxy group, a dotted line indicates the presence or absence of a binding bond, W indicates C, CH, or CH
2
or a nitrogen atom, provided that, when W is a nitrogen atom, Z is bonded to W and the dotted line indicates the absence of a bond, and Z indicates an unsubstituted or substituted aromatic hydrocarbon ring group or an unsubstituted or substituted heterocyclic group selected from phenyl group, naphthyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, 2-thiazolyl group, 2-oxazolyl group, 2-benzathiazolyl group, 2-thienyl group, and 3-thienyl group, which may be substituted with a C
1
to C
4
lower alkyl group, C
1
to C
4
lower alkoxy group, hydroxy group, amino group, and/or halogen atom.
In accordance with the present invention, there is also provided a novel benzoxazepine derivative having the general formula (II) and its salts:
wherein, n, R
1
, R
2
, and Z are the same as defined above.
In accordance with the present invention, there is further provided a novel benzoxazepine derivative having the general formula (III) and its salts:
wherein, n, R
1
, and R
2
are the same as defined above, a dotted line indicates the presence or absence of a combining bond, and Z′ indicates an unsubstituted or substituted heteroaromatic group.
In accordance with the present invention, there is still further provided a novel benzoxazepine derivative and its salts wherein, in the general formula (III), the group Z′ indicates the following general formula (IV):
wherein, Y indicates CH, or a nitrogen atom, R
3
and R
4
respectively indicate a hydrogen atom, halogen atom, C
1
to C
4
lower alkyl group, or hydroxy group).
In accordance with the present invention, there is still further provided a benzoxazepine derivative having the general formula (V) and its salts:
wherein
Hirotsu Ichiro
Inoue Teruyoshi
Kamei Katsuhide
Maeda Noriko
Nakajima Mika
Berch Mark L.
Burns Doane Swecker & Mathis L.L.P.
Suntory Limited
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