Bicycloloactam compounds, use thereof and intermediates for...

Details Bicycloloactam compounds, use thereof and intermediates for... Bicycloloactam compounds, use thereof and intermediates for...

2000-08-28

2002-03-12

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S512000

Reexamination Certificate

active

06355668

ABSTRACT:

TECHNICAL FIELD
The present invention relates to anxiolytic agents comprising a bicyclolactam derivative as their effective component and to the treatment of anxiety.
BACKGROUND ART
With rapid diversification of the social environment in recent years, an increasing number of people are suffering form anxiety, and it has been expected to develop psychosomatic therapies and excellent therapeutic agents.
Benzodiazepine compounds such as diazepam have found wide use as anxiolytics. This group of agents, however, generally have side effects such as hypnotic effect, muscle relaxant effect and sedative effect. Serotonin anxiolytic agents such as buspirone are also recently developed as anxiolytics which are different from the benzodiazepine compounds in activity mechanism. Reportedly these serotonin agents are generally lesser than the benzodiazepines in side effects such as hypnotic, muscle relaxant and sedative effects, but they are lower in anxiolytic effect and have the problems of diminishing voluntary movements presumably owing to their activity as a dopamine antagonist, and causing serotonin syndrome which appears attributable to their properties as a full agonist for serotonin 1A receptor.
On the other hand, the bicyclolactam derivatives of the present invention are known compounds disclosed in International Public Disclosure No. WO 91/11434, and are known to have a cerebral function improving effect, cerebral metabolism activating or anoxic brain damage protecting effect and effect against senile dementia. Nevertheless, nothing whatsoever is known about the anxiolytic effect of these compounds.
Anxiety is an essential symptom of neuroses and is a neurotic disorder involving no organic disorder of the brain.
In contrast, the term dementia refers to an organic mental disorder which is the sustained deterioration of acquired intelligence due to an organic disorder of the brain. Many of dementias are caused by a wide variety of organic disorders of the brain and involve general deterioration of mental functions such as memory, calculation, orientation and discretion, leading to failure of correct recognition, judgement or behavior as to one's own situation. “Diagnostic and Statistical Manual of Mental Disorders,” Revised 3rd Ed. (DSM-III-R), widely used as a diagnostic manual and published by American Psychiatric Association in 1987, clearly classifies these disease in the chapters “Anxiety Disorders (or Anxiety and Phobic Neuroses)” and “Organic Mental Syndromes and Organic Mental Disorders” (see “DSM-III-R Classification of Mental Disorders and Diagnostic Manual,” (2nd Ed.), translated by Saburo Takahasi et al., published by Igaku Shoin (1988), pp. 71~94 and 121~129).
An object of the present invention is to provide a novel anxiolytic agent comprising a bicyclolactum derivative as its effective component, and a therapy of anxiety.
DISCLOSURE OF THE INVENTION
We have investigated the pharmacological activities of bicyclolactam derivatives from various viewpoints, consequently found that these compounds have a very high anxiolytic effect and are yet greatly diminished in side effects such as hypnotic, muscle relaxant and sedative effects and accomplished the present invention. More specifically, the invention provides an anxiolytic agent comprising as its effective component a bicyclolactam derivative represented by the following formula
wherein R
1
is a hydrogen atom or hydroxyl group, R
2
is benzoyl group which may optionally have at least one substituent, 1 is 1 or 2, m is 0 or 1 and n is 0, 1 or 2, provided the case where both of m an n represent 0 simultaneously is excluded.
The present invention further includes a method of treating anxiety comprising administering an effective amount of the compound (1) to mammals including man, and also use of the compound (1) for the preparation of medicinals for treating anxiety.
Existing as bicyclolactam derivatives of the formula (1) are stereoisomers due to the presence of the bicyclo ring, and also geometric isomers and optical isomers due to the presence of the carbon atom at the bridgehead position of the bicyclo ring and the carbon atom having R
1
attached thereto. The present invention includes all of these isomers.
In view of the numbers l, m and n, the following ten kinds of bicyclo ring skeletons can be present in the compounds of the formula (1). The invention includes all of these cases.
Preferable among these is the case wherein the skeleton is (a), (b), (f), (g) or (h). More preferable is the case wherein m is 0, i.e., (a), (b), (f) or (g). The most preferable is (b), (f) or (g).
According to the invention, examples of substituents which may be present in the benzoyl group represented by R
2
are halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group, hydroxyl group or amino group. Examples of halogen atom are fluorine, chlorine, bromine and iodine atom, among which chlorine atom is preferable. Examples of useful lower alkyl groups are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl group. Preferable among these are methyl and ethyl groups. Methyl group is more preferable. Examples of useful lower alkoxyl groups are straight-chain or branched alkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy group, among which methoxy and ethoxy groups are preferable. Methoxy group is more preferable.
Preferable as R
2
of the compound represented by the formula (1) is a benzoyl group having as a substituent a halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group or amino group, more preferably a benzoyl group having lower alkoxyl group. Especially preferable is a benzoyl group having methoxy group. The number of substituents is preferably 1 to 3. The substituent may be present at any of the ortho-, meta- and para-positions on the phenyl ring of the benzoyl group.
Among the compounds of the formula (1), preferable are those wherein m is 0, and more preferable are those wherein R
2
is a benzoyl having lower alkoxyl group and wherein l is 1, m is 0 and n is 2, or l is 2, m is 0 and n is 1, or l is 2, m is 0 and n is 2. More preferable are those wherein R
2
is a benzoyl group having methoxy group and wherein l is 1, m is 0 and n is 2, or l is 2, m is 0 and n is 1, or l is 2, m is 0 and n is 2. In the case where R
1
is hydroxyl group, especially preferred compounds are those wherein l is 1, m is 0 and n is 2.
Examples of the compound of the above formula (1) are
2-(4-methoxybenzoyl)-2-azabicyclo[3.3.0]octane-3-one,
2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(p-toluyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(3,4-dichlorobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-cyanobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-nitrobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-aminobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-chlorobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
8-(4-methoxybenzoyl)-8-azabicyclo[4.3.0]nonane-7-one,
2-(4-hydroxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
3-(4-methoxybenzoyl)-3-azabicyclo[3.3.0]octane-4-one,
3-(4-methoxybenzoyl)-3-azabicyclo[4.3.0]nonane-4-one,
3-(4-methoxybenzoyl)-3-azabicyclo[5.3.0]decane-4-one,
3-(4-methoxybenzoyl)-3-azabicyclo[4.4.0]decane-4-one,
3-(4-methoxybenzoyl)-3-azabicyclo[5.5.0]undecane-4-one,
7-(4-methoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(p-toluyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(3,4-dichlorobenzoyl)-7-azabicyclo[4.3.0]-nonane-8-one,
7-(3,5-dimethoxybenzoyl)-7-azabicyclo[4.3.0]-nonane-8-one,
7-(4-cyanobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-nitrobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(

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