JP2865341B2 - Benzoxazepine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound represented by the general formula (I): (Wherein A and B are both carbonyl groups or one is a methylene group and the other is a carbonyl group, R is an optionally substituted aromatic or heterocyclic group, and X is a hydrogen atom a halogen atom (preferably chlorine, bromine, fluorine), C ₁ -C ₅ lower alkyl group (preferably C ₁ -C ₃ lower alkyl group), C ₁ -C ₅ lower alkoxy group (preferably C ₁ ~
A C ₃ -C ₉ lower alkoxy group), a C ₇ -C ₉ arylalkoxy group (preferably a phenylalkoxy group), a hydroxyl group, a nitro group or an ester group (preferably a C ₁ -C ₃ lower alkyl ester group); Benzoxazepine derivatives represented by the formula (10, preferably 2 to 8, more preferably an integer of 2 to 5) and salts thereof, and a psychotropic agent containing the same as an active ingredient.

The present invention further provides a compound of the general formula (II) (Where A and B are both a carbonyl group or one is a methylene group and the other is a carbonyl group, X is a hydrogen atom, a halogen atom (preferably chlorine, bromine, fluorine),
C ₁ -C ₅ lower alkyl group (preferably C ₁ -C ₃ lower alkyl group), C ₁ ~C ₅ lower alkoxy group (preferably a C ₁ -C ₃ lower alkoxy groups), C ₇ ~C ₉ arylalkoxy group (preferably phenylalkoxy group), a hydroxyl group, a nitro group or an ester group (preferably a C ₁ -C ₃ lower alkyl ester group)
Wherein Y is a halogen atom, and n is an integer of 2 to 10, preferably 2 to 8, and more preferably 2 to 5) and salts thereof. This compound is useful as a synthetic intermediate for the compound of the general formula (I).

INDUSTRIAL APPLICABILITY The novel benzoxazepine derivative represented by the general formula (I) of the present invention and salts thereof have a strong affinity for serotonin receptors and an anti-conflict effect, and have anxiety, phobia, It is useful as a therapeutic drug for neuropsychiatric disorders such as obsessive-compulsive disorder, post-traumatic stress disorder, depressive neuropathy, and psychosomatic disorders, as well as disorders involving the serotonin nervous system such as eating disorders, climacteric disorders, and pediatric autism. .

[Conventional technology]

Conventionally, benzodiazepines, antipsychotics, antidepressants, etc. have been used as remedies for anxiety, phobia, obsessive-compulsive disorder, etc. Has become.

In particular, benzodiazepines have been used mainly for anxiety, but they have a hypnotic effect, a muscle relaxant effect, and even addictive effects. Is eagerly awaited.

In recent years, various attempts have been made to solve these problems, and among them, drugs with selective affinity for the 5HT _1A subtype of serotonin receptors may be an anxiolytic with few side effects. It is believed that there is. In fact, buspron, gepirone, ipsapirone, etc. are being developed or are being developed.

[Problems to be Solved by the Invention] The above buspirone, gepirone, ipsapirone, etc.
Compared with the conventional benzodiazepine-based drugs, various side effects are partially reduced, but it is still not enough, and there is a strong demand for the development of anxiolytics with fewer side effects and high specificity.

The present inventors have developed a more selective and more potent 5HT _1A in order to develop a superior anxiolytic without the above disadvantages.
As a result of intensive studies considering that it is essential to create a drug having an affinity for the receptor, the novel benzoxazepine derivative, which is a compound of the present invention, has an extremely potent 5HT _1A receptor affinity and an anti-conflict effect The present invention was found to have an anxiolytic effect using as an index, thereby completing the present invention.

[Means for solving the problem]

The present invention provides a benzoxazepine derivative represented by the general formula (I), a pharmacologically acceptable acid addition salt thereof, and a psychotropic agent containing these compounds as an active ingredient.

The present invention provides a benzoxazepine derivative represented by the general formula (II).

[Specific explanation]

The compound of the general formula (I) according to the present invention can be produced, for example, as follows.

Synthesis of intermediate compound (II) Synthesis of final compound (I) from intermediate compound (II) More specifically, in the compound represented by the general formula (I), the compound represented by the following general formula (Ia) wherein A is a carbonyl group and B is a methylene group is J. Chem. So of GSSidhu, G. Thyagarajan and UTBhalerao
c. reacting compound (III) of the following structure obtained according to the method described in (C), 969 (1966) and analogous methods thereto with, for example, dibromoalkane After obtaining compound (IV) having the following structure, The compound can be synthesized by condensing the compound with an amino acid derivative in a conventional manner.

In the compound represented by the general formula (I), the compound (Ib) represented by the following formula (Ib) wherein A is a methylene group and B is a carbonyl group is Kost.AN, Stankevicius, A.; Khim.Geterotsiki.Soedi
n., 7 ( 9), 1288 (1971) and a compound (V) having the following structure obtained according to a method analogous thereto and dibromoalkane are reacted to give a compound (VI) having the following structure. After getting the piperazine It can be synthesized by condensation with a derivative.

Further, among the compounds represented by the general formula (I), the compound represented by the general formula (Ic) wherein A and B are both carbonyl groups is described in A. Cattaneo, P. Galimberti, M. Mela
ndri; Boll.Chim.Farm., 102 Compound (VII) obtained according to the method described in 541 (1963) and analogous methods is reacted with dibromoalkane, After obtaining compound (VIII) having the following structure, It can be synthesized by condensation with a piperazine derivative.

In the benzoxazepine derivative of the general formula (I) according to the present invention, R represents an optionally substituted aromatic group and a heterocyclic group as described above. Examples of such an aromatic group include a C _{6 to} C ₁₀ aromatic group, specifically, a phenyl group, a naphthyl group, and the like.
For example, a halogen atom (chlorine, bromine, fluorine, etc.), a hydroxyl group, C ₁ -C ₆ lower alkyl group, C ₁ -C ₅ lower alkoxy group,
Arylalkoxy group, a nitro group, an amino group, an amido group, a cyano group, may be substituted with an ester group (e.g., COO · C ₁ ~C ₅ lower alkyl group).

On the other hand, the heterocyclic group is preferably 1 to 5 in a 5- to 7-membered ring.
A ring containing three nitrogen atoms, specifically, a pyridine group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, and the like can be mentioned, and these heterocyclic groups may be substituted with the above substituents.

The novel benzoxazepine derivative represented by the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof (eg, hydrochloride, nitrate, sulfate, hydrobromide, phosphate, methanesulfone) Acid, acetate, oxalate, succinate, malonate, tartrate, maleate, fumarate, lactate, citrate, etc.) may themselves be administered alone, If necessary or desired, it may be mixed with other usual pharmacologically acceptable carriers, excipients, diluents, etc. to obtain a desired dosage form (eg, tablet, capsule, powder, liquid, injection, suppository). It can be administered orally or parenterally. Examples of such diluents or carriers include, for example, polyvinyl pyrrolidone, gum arabic, gelatin,
Sorbitol, cyclodextrin, tragacanth, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethyl cellulose calcium, lauryl sulfate, sodium, water, ethanol, glycerin, mannitol ,
Syrup and the like can be exemplified. The concentration of the compound of formula (I) in such a pharmaceutical preparation is not particularly limited, but is generally about 1 to 100% by weight, preferably about 10 to 100% by weight in the preparation. The dose is not particularly limited, but is suitably 0.1 to 1000 mg / day / person, preferably 1 to 500 mg / day / person, and the administration frequency is usually 1 to 4 times per day.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but it goes without saying that the scope of the present invention is not limited to these Examples.

First, methods for synthesizing the intermediate compound (II) are described in Examples 1 to 18, and methods for synthesizing the final compound (I) are described in Examples 19 to 95.

Example 1 Synthesis of 4- (3-chloropropyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 2,3,4,5-tetrahydro-1,4-benzoxazepine-
1 g of 5-one is mixed with 50 ml of dioxane and 5 m of dimethyl sulfoxide.
Then, 368 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was heated and stirred at 110 ° C. for 1 hour.

After cooling the obtained reaction solution with ice, 1.82 ml (3 equivalents) of 1-bromo-3-chloropropane was added, and the mixture was stirred at room temperature for 17 hours. Dioxane was distilled off from the obtained reaction solution, ice water was added, and the mixture was extracted with ether. This ether extract was washed with brine three times and dried over anhydrous magnesium sulfate. Next, this ether solution was concentrated, and the residue was developed with hexane-ethyl acetate (6: 4) using column chromatography on silica gel to obtain 1.21 g (yield: 83%) of the title compound.

Example 2 Synthesis of 4- (3-bromopropyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,
Dissolve 100 mg of 5-dione in 10 ml of dimethylformamide,
After cooling on ice, 0.172 ml (3 equivalents) of 1,3-dibromopropane,
27.1 mg (1.2 equivalents) of 60% sodium hydride was added, and the mixture was stirred under ice water for 1 hour.

The obtained reaction solution is poured into an aqueous citric acid solution under ice cooling,
Extracted with ether. After washing with brine, the extract was dried over anhydrous magnesium sulfate. The ether solution was concentrated, and the residue was subjected to hexane-column chromatography using silica gel.
The mixture was developed with ethyl acetate (8: 2) to obtain 79.8 mg (yield 47%) of the title compound.

Example 3 4- (3-bromopropyl) -7-methoxy-2,3,4,
Synthesis of 5-tetrahydro-1,4-benzoxazepine-3.5-dione 828 mg of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 20 ml of dimethylformamide, and 1.62 g (2 equivalents) of 1,3-dibromo was dissolved. After adding propane and cooling with ice, 240 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was stirred under ice cooling for 1 hour.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (280 mg).
(21.3% yield).

Example 4 4- (3-bromopropyl) -8-methyl-2,3,4,5
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 764 mg of 8-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione in dimethylformamide
After dissolving in 20 ml, 1.62 g (2 equivalents) of 1,3-dibromopropane was added, and after cooling with ice, 240 mg (1.5 equivalents) of 60% sodium hydride was added, followed by stirring at room temperature for 30 minutes.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (417 mg).
(33.4% yield).

Example 5 Synthesis of 4- (4-bromobutyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 2,3,4,5-tetrahydro-1,4-benzoxazepine-
5-one (2 g) in dioxane (100 ml) and dimethyl sulfoxide (1)
The mixture was dissolved in 0 ml, 736 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was heated and stirred at 110 ° C. for 30 minutes. After cooling on ice, 4.49 ml (3 equivalents) of 1,4-dibromobutane was added to the reaction solution, followed by stirring at room temperature for 2 hours.

Reaction and purification were conducted in the same manner as in Example 1 to give 2.56 g of the title compound.
(70% yield).

Example 6 Synthesis of 4- (4-bromobutyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one 2,3,4,5-tetrahydro-1,4-benzoxazepine-
500 mg of 3-one was added to 50 ml of dioxane and 5 ml of dimethyl sulfoxide.
Then, 184 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was stirred with heating at room temperature for 30 minutes. 1.12 ml to this reaction solution
(3 equivalents) of 1,4-dibromobutane and 5 ml of dimethylformamide were added, and the mixture was stirred at room temperature for 3 hours.

Ice water was added to the obtained reaction solution, and the mixture was extracted with ether. The extract was washed with brine and dried over anhydrous magnesium sulfate. After concentrating the ether solution, the residue was purified by column chromatography on silica gel using hexane-ethyl acetate (7: 7).
Developed in 3) to give 504 mg (55% yield) of the title compound.

Example 7 Synthesis of 4- (4-bromobutyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 2,3,4,5-tetrahydro-1,4-benzoxazepine-
10 g of 3,5-dione was dissolved in 100 ml of dimethylformamide, and after cooling with ice, 20.7 ml (3 equivalents) of 1,4-dibromobutane and 2.71 g (1.2 equivalents) of 60% sodium hydride were added.
The mixture was stirred under ice cooling for 1.5 hours.

The reaction was worked up and purified as in Example 2 to give the title compound 10.3.
g (58% yield).

Example 8 4- (4-bromobutyl) -7-methoxy-2,3,4,5
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 414 mg of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 10 ml of dimethylformamide, and after cooling with ice, 120 mg (1.5 equivalents) of 60% hydrogen After adding sodium chloride and stirring for 10 minutes, 860 mg (2 equivalents)
Of 1,4-dibromobutane was added, and the mixture was stirred at room temperature for 1 hour.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (345 mg).
(50.4% yield).

Example 9 Synthesis of 4- (4-bromobutyl) -8-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 1.5 g of 8-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was added to dimethylformamide 4
After dissolving in 0 ml and cooling with ice, 1.30 ml (1.5 equivalents) of 1,4-dibromobutane and 340 mg (1.2 equivalents) of 60% sodium hydride were added, and the mixture was stirred under ice cooling for 30 minutes.

The reaction was treated and purified in the same manner as in Example 2 to give the title compound (920 mg).
(37% yield).

Example 10 4- (4-bromobutyl) -8-methyl-2,3,4,5-
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 764 g of 8-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was added to dimethylformamide 2
The mixture was dissolved in 0 ml, 1.72 g (2 equivalents) of 1,4-dibromobutane was added, and after cooling with ice, 240 mg (1.5 equivalents) of 60% sodium hydride was added, followed by stirring at room temperature for 1.5 hours.

The reaction was treated and purified in the same manner as in Example 2 to yield 880 mg of the title compound.
(67.5% yield).

Example 11 4- (4-bromobutyl) -8-methoxy-2,3,4,5
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 1 g of 8-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was added to dimethylformamide 3
After dissolving in 0 ml and cooling with ice, 1.77 ml (3 equivalents) of 1,4-dibromobutane and 232 mg (1.2 equivalents) of 60% sodium hydride were added, and the mixture was stirred under ice cooling for 1.5 hours.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (1.25 g).
(76% yield).

Example 12 4- (4-bromobutyl) -6-methoxy-2,3,4,5
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 204 mg of 6-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 20 ml of dimethylformamide and, after cooling with ice, 0.361 ml (3 equivalents) of 1,61 ml 4-Dibromobutane, 47.4 mg (1.2 equivalents) of 60% sodium hydride were added, and the mixture was stirred under ice cooling for 1.5 hours.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (117 mg)
(35% yield).

Example 13 6-benzyloxy-4- (4-bromobutyl) 2,3,
4,5-tetrahydro-1,4-benzoxazepine-3,5-
Synthesis of dione 6-benzyloxy-2,3,4,5-tetrahydro-1,4-
Benzoxazepine-3,5-dione (410 mg) was dissolved in dimethylformamide (40 ml), and cooled with ice.
1,4-Dibromobutane, 69.5 mg (1.2 equivalents) of 60% sodium hydride were added, and the mixture was stirred for 1 hour under ice cooling.

Reaction treatment and purification in the same manner as in Example 2 to give 450 mg of the title compound
(74% yield).

Example 14 4- (4-bromobutyl) -7-nitro-2,3,4,5-
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione 56.3 mg of 7-nitro-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 10 ml of dimethylformamide, and after cooling with ice, 0.0927 ml (3 equivalents) of 1 , 4-
Dibromobutane and 12.2 mg (1.2 equivalents) of 60% sodium hydride were added, and the mixture was stirred under ice cooling for 2 hours.

Reaction and purification were conducted in the same manner as in Example 2 to give the title compound (16.4 mg).
(18% yield).

Example 15 4- (4-bromobutyl) -7-methoxycarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-
Synthesis of 3,5-dione 7-methoxycarbonyl-2,3,4,5-tetrahydro-
125 mg of 1,4-benzoxazepine-3,5-dione was dissolved in 10 ml of dimethylformamide, and after cooling with ice, 0.193 ml (3 equivalents) of 1,4-dibromobutane, 60% of 25.3 mg (1.2 equivalents) of 25.3 mg (1.2 equivalents)
Sodium hydride was added, and the mixture was stirred under ice cooling for 1 hour.

Reaction and purification were conducted in the same manner as in Example 2 to give 124 mg of the title compound.
(63% yield).

Example 16 Synthesis of 4- (5-bromopentyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 2,3,4,5-tetrahydro-1,4-benzoxazepine-
After dissolving 300 mg of 3,5-dione in 30 ml of dimethylformamide and cooling with ice, add 0.693 ml (3 equivalents) of 1,5-dibromopentane and 81.4 mg (1.2 equivalents) of 60% sodium hydride, and cool on ice. Stirred for 30 minutes below.

The reaction was treated and purified in the same manner as in Example 2 to give 238 mg of the title compound.
(43% yield).

Example 17 4- (5-bromopentyl) -7-methoxy-2,3,4,
Synthesis of 5-tetrahydro-1,4-benzoxazepine-3,5-dione 621 mg of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione are dissolved in 10 ml of dimethylformamide, and 1.38 g (2 equivalents) of 1,5-diene are dissolved. After adding bromopentane and cooling with ice, 180 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 4 hours.

Reaction treatment and purification were carried out in the same manner as in Example 2 to give the title compound 396m
g (37.1% yield).

Example 18 4- (5-bromopentyl) -8-methyl-2,3,4,5
Synthesis of tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 764 mg of 8-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione in 20 ml of dimethylformamide and add 2.07 g (2 equivalents) of 1,5-dione. After adding bromopentane and cooling with ice, 240 mg (1.5 equivalents) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes.

Reaction treatment and purification were conducted in the same manner as in Example 2 to give the title compound (680 mg).
(50.0% yield).

Table 1 shows the physical data of the compounds obtained in Examples 1 to 18 described above.

Example 19 Synthesis of 4- (3- (4- (2-pyridyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 289 mg of the compound of Example 1 was dissolved in 30 ml of dioxane to give 0.937
ml (5 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was refluxed for 17 hours. Next, dioxane was distilled off, sodium bicarbonate water was added, and the mixture was extracted with methylene chloride.

The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. Next, the methylene chloride solution is concentrated,
The residue was developed with methylene chloride-methanol (97: 3) using silica gel column chromatography to obtain 320 mg (yield 73%) of the title compound. The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 20 Synthesis of 4- (3- (4- (3-chlorophenyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 300 mg of the compound of Example 1 was dissolved in 30 ml of dioxane, and 1.23 g
(5 equivalents) of 1- (3-chlorophenyl) piperazine was added and the mixture was refluxed for 17 hours.

Reaction treatment and purification were conducted in the same manner as in Example 19 to give the title compound (380 mg).
(76% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 21 Synthesis of 4- (3- (4- (2-pyridyl) piperazinyl) propyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 50 mg of the compound of Example 2 was dissolved in 10 ml of dioxane,
l (5 equivalents) of 1- (2-pyridyl) piperazine was added and stirred at 100 ° C. for 17 hours.

The reaction was treated in the same manner as in Example 19, and developed with ethyl acetate-hexane (3: 1) using column chromatography on silica gel to give the title compound (48.0 mg, yield 75%). still,
The hydrochloride was obtained by converting the hydrochloride by a usual method and then recrystallizing from methylene chloride-ether.

Example 22 Synthesis of 4- (3- (4- (2-pyrimidinyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 60 mg of the compound of Example 2 was dissolved in 10 ml of dioxane, and 168 mg
(5 equivalents) of 1- (2-pyrimidinyl) piperazine was added and stirred at 100 ° C. for 17 hours.

Post-treatment was carried out in the same manner as in Example 19, and purification was carried out in the same manner as in Example 21 to obtain 61.6 mg (yield: 80%) of the title compound. Incidentally, the hydrochloride was obtained by recrystallization from methylene chloride-ether after converting into a hydrochloride by a usual method.

Example 23 Synthesis of 7-methoxy-4- (3- (2-pyridyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 98 mg of the compound of Example 3 was dissolved in 10 ml of dioxane, and 147 mg
(3 equivalents) of 1- (2-pyridyl) piperazine
Stirred at 100 ° C. for 20 hours.

The reaction solution was poured into ice water and extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was developed with ethyl acetate using silica gel column chromatography to give the title compound (88 mg, yield).
71.5%). Incidentally, the hydrochloride was obtained by recrystallization from methylene chloride-ether after converting into a hydrochloride by a usual method.

Example 24 7-Methoxy-4- (3- (2-pyrimidinyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-
Synthesis of benzoxazepine-3,5-dione 98 mg of the compound of Example 3 was dissolved in 10 ml of dioxane, and 147 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added and stirred at 100 ° C. for 20 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound 107 mg.
(86.8% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 25 Synthesis of 8-methyl-4- (3- (2-pyridyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 125 mg of the compound of Example 4 was dissolved in 10 ml of dioxane, and 196 mg
(3 equivalents) of 1- (2-pyridyl) piperazine,
Refluxed for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (113 mg).
(71.7% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 26 Synthesis of 8-methyl-4- (3- (2-pyrimidinyl) piperazinyl) propyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 125 mg of the compound of Example 4 was dissolved in 10 ml of dioxane, and 196 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was stirred at 90 to 100 ° C. for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23, and 133 mg of the title compound was obtained.
(84.1% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 27 Synthesis of 4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 300 mg of the compound of Example 5 was dissolved in 30 ml of dioxane, and 0.782
ml (5 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated under reflux for 2 hours.

Post-treatment and purification were conducted in the same manner as in Example 19 to obtain the title compound (342 mg, yield 89.4%).

Example 28 Synthesis of 4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one Dissolve 300 mg of the compound of Example 5 in 30 ml of dioxane and add 825
mg (5 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was heated under reflux for 17 hours.

The reaction treatment and purification were conducted in the same manner as in Example 19 to give the title compound (275 mg).
(72% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 29 Synthesis of 4- (4- (4- (3-chlorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 300 mg of the compound of Example 5 was dissolved in 30 ml of dioxane, and 986 mg
(5 equivalents) of 1- (3-chlorophenyl) piperazine was added, and the mixture was refluxed for 4 hours.

Reaction treatment and purification were conducted in the same manner as in Example 19, and 399 mg of the title compound was obtained.
(96% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 30 Synthesis of 4- (4- (4- (2-methoxyphenyl) piperazinyl) butyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one 300 mg of the compound of Example 5 was dissolved in 30 ml of dioxane to give 0.902
ml (5 equivalents) of 98% 1- (2-methoxyphenyl) piperazine was added, and the mixture was heated under reflux for 2 hours.

The reaction treatment and purification were conducted in the same manner as in Example 19, and the title compound (387 mg) was obtained.
(94% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 31 Synthesis of 4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one 100 mg of the compound of Example 6 was dissolved in 10 ml of dioxane,
6 ml (5 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was refluxed for 11 hours.

Reaction treatment and purification were conducted in the same manner as in Example 19 to give the title compound (125 mg).
(98% yield). The hydrochloride was obtained by converting it into a hydrochloride by an ordinary method and then recrystallizing it from methylene chloride-ether.

Example 32 Synthesis of 4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one 100 mg of the compound of Example 6 was dissolved in 10 ml of dioxane and 275
mg (5 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was heated under reflux for 17 hours.

The reaction treatment and purification were conducted in the same manner as in Example 19 to give the title compound (118 mg).
(92% yield). The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 33 Synthesis of 4- (4- (4- (3-chlorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepin-3,5-one 100 mg of the compound of Example 6 was dissolved in 10 ml of dioxane, and 330 mg
(5 equivalents) of 1- (3-chlorophenyl) piperazine was added, and the mixture was heated under reflux for 11 hours.

Reaction treatment and purification were conducted in the same manner as in Example 19, to give 137 mg of the title compound.
(99% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 34 4- (4- (4-phenylpiperazinyl) butyl)-
2,3,4,5-tetrahydro-1,4-benzoxazepine-3,
Synthesis of 5-dione 156 mg of the compound of Example 7 was dissolved in 10 ml of dioxane,
(3 equivalents) of phenylpiperazine, add 1 at 90-100 ° C.
Stir for 2 hours.

Reaction treatment and purification were performed in the same manner as in Example 23 to give the title compound (180 mg).
(91.5% yield). The hydrochloride was recrystallized from methylene chloride-ethyl acetate after being converted into a hydrochloride by an ordinary method.

Example 35 Synthesis of 4- (4- (4- (2-fluorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 173 mg
(3 equivalents) of 1- (2-fluorophenyl) piperazine was added and the mixture was refluxed for 5 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 126 mg (yield: 96%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 36 Synthesis of 4- (4- (4- (2-chlorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 315 mg
(5 equivalents) of 1- (2-chlorophenyl) piperazine was added, and the mixture was refluxed for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 114 mg of the title compound (83% yield). The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 37 Synthesis of 4- (4- (4- (2-methoxyphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-1,3-dione Dissolve 174 mg of the compound of Example 7 in 20 ml of dioxane and add 0.5 ml
Of 1- (2-methoxyphenyl) piperazine, and 6
Heated to reflux for an hour.

Post-treatment was carried out in the same manner as in Example 19, and purification was carried out in the same manner as in Example 21 to obtain 198 mg (yield: 84%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 38 Synthesis of 4- (4- (4- (2-hydroxyphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 20 ml of dioxane, and 171 mg
(3 equivalents) of 1- (2-hydroxyphenyl) piperazine was added, and the mixture was stirred with heating at 100 ° C. for 17 hours.

The reaction was treated in the same manner as in Example 19, and purified in the same manner as in Example 21 to obtain 128 mg (yield 98%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 39 Synthesis of 4- (4- (4- (3-chlorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 200 mg of the compound of Example 7 in 20 ml of dioxane and 631 mg
(5 equivalents) of 1- (3-chlorophenyl) piperazine was added and the mixture was refluxed for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 266 mg (yield 97%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 40 Synthesis of 4- (4- (4- (3-methoxyphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 68.4 mg of the compound of Example 7 was dissolved in 10 ml of dioxane to give 131 m
g (3 equivalents) of 1- (3-methoxyphenyl) piperazine was added, and the mixture was heated and stirred at 100 ° C. for 12 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 82.1 mg (yield: 88%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 41 Synthesis of 4- (4- (4- (3-methylphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 20 ml of dioxane, and 169 mg
(3 equivalents) of 1- (3-methylphenyl) piperazine was added, and the mixture was heated with stirring at 100 ° C. for 10 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 127 mg (yield 97%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 42 Synthesis of 4- (4- (4- (3-trifluoromethylphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 228 mg
(3 equivalents) of 1- (3-trifluoromethylphenyl)
Piperazine was added, and the mixture was heated and stirred at 100 ° C. for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 136 mg (yield: 91%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 43 Synthesis of 4- (4- (4- (4-fluorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 151 mg
(3 equivalents) of 1- (4-fluorophenyl) piperazine was added, and the mixture was heated and stirred at 100 ° C. for 17 hours.

The reaction was conducted in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 122 mg (yield: 99%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 44 Synthesis of 4- (4- (4- (4-chlorophenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 189 mg
(3 equivalents) of 1- (4-chlorophenyl) piperazine was added, and the mixture was refluxed for 15 hours.

The reaction was conducted in the same manner as in Example 19, and purified in the same manner as in Example 21 to obtain 113 mg (yield: 83%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 45 Synthesis of 4- (4- (4- (4-methoxyphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 94.1 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 299 m
g (5 equivalents) of 1- (4-methoxyphenyl) piperazine was added, and the mixture was heated under reflux for 6 hours.

The reaction was treated in the same manner as in Example 19, and purified in the same manner as in Example 21 to obtain 104 mg (yield 81%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 46 Synthesis of 4- (4- (4- (4-acetylphenyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 100 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 216 mg
(3 equivalents) of 94% 4-piperazinoacetophenone was added, and the mixture was heated and stirred at 100 ° C for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 101 mg (yield: 72%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 47 4- (4- (4- (2-Pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 200 mg of the compound of Example 7 in 20 ml of dioxane and add 0.4
98 ml (5 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was refluxed for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 196 mg (yield 78%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 48 Synthesis of 4- (4- (4- (3-chloro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 156 mg of the compound of Example 7 was dissolved in 10 ml of dioxane,
(3 equivalents) of 1- (3-chloro-2-pyridyl) piperazine was added, and the mixture was stirred at 100 ° C. for 24 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (225 mg).
(Yield 98.0%). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 49 Synthesis of 4- (4- (4- (3-nitro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 156 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 312 mg
(3 equivalents) of 1- (3-nitro-2-pyridyl) piperazine was added and refluxed for 23 hours.

Reaction treatment and purification in the same manner as in Example 23 to give the title compound 210 mg
(95.5% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 50 Synthesis of 4- (4- (4- (3-cyano-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 156 mg of the compound of Example 7 was dissolved in 10 ml of dioxane.
(3 equivalents) of 1- (3-cyano-2-pyridyl) piperazine was added and refluxed for 20 hours.

Reaction treatment and purification in the same manner as in Example 23 to give the title compound 190 mg
(90.6% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 51 Synthesis of 4- (4- (4- (3-amino-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 94 mg of the compound of Example 7 was dissolved in 6 ml of dioxane, and 160 mg
(3 equivalents) of 1- (3-amino-2-pyridyl) piperazine was added and refluxed for 48 hours.

The reaction treatment and purification were conducted in the same manner as in Example 23 to obtain 94 mg of the title compound (yield: 76.5%). The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 52 Synthesis of 4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 500 mg of the compound of Example 7 were dissolved in 50 ml of dioxane and
1 g (5 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was refluxed for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 602 mg (yield: 95%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 53 7-Methoxy-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-
Synthesis of benzoxazepine-3,5-dione 100 mg of the compound of Example 8 was dissolved in 10 ml of dioxane, and 147 mg
(3 equivalents) of 1- (2-pyridyl) piperazine
Stirred at 90 ° C. for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (108 mg).
(84.8% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 54 7-methoxy-4- (4- (4- (3-chloro-2-
Synthesis of pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 137 mg of the compound of Example 8 was dissolved in 10 ml of dioxane, and 236 mg
(3 equivalents) of 1- (3-chloro-2-pyridyl) piperazine was added and refluxed for 40 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (209 mg).
(99.1% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 55 7-methoxy-4- (4- (4- (3-nitro-2-
Synthesis of pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 137 mg of the compound of Example 8 was dissolved in 10 ml of dioxane, and 249 mg
(3 equivalents) of 1- (3-nitro-2-pyridyl) piperazine was added and refluxed for 40 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (182 mg).
(96.9% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 56 7-methoxy-4- (4- (4- (3-cyano-2-
Synthesis of pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 138 mg of the compound of Example 8 was dissolved in 10 ml of dioxane,
(3 equivalents) of 1- (3-cyano-2-pyridyl) piperazine was added and refluxed for 40 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (182 mg).
(98.5% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 57 7-methoxy-4- (4- (4- (3-amino-2-
Synthesis of pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 244 mg of the compound of Example 55 was dissolved in 10 ml of ethanol, and 50 mg
Was added and hydrogenated for 0.5 hour.

The reaction solution was filtered, the filtrate was evaporated under reduced pressure, and the residue was eluted with ethyl acetate using silica gel column chromatography to obtain 179 mg (yield: 83.4%) of the title compound. The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 58 Synthesis of 7-methoxy-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 10 mg of the compound of Example 8 was dissolved in 10 ml of dioxane, and 147 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was stirred at 90 ° C. for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (116 mg).
(90.9% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 59 Synthesis of 8-chloro-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 98.0 mg of the compound of Example 9 was dissolved in 10 ml of dioxane to give 0.13
2 ml (3 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated and stirred at 100 ° C. for 10 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 86.8 mg (yield: 72%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 60 8-Chloro-4- (4- (4- (3-chloro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione 102 mg of the compound of Example 9 was dissolved in 10 ml of dioxane, and 58.1 g
(1 equivalent) of 1- (3-chloro-2-pyridyl) piperazine and 122 mg (3 equivalents) of potassium carbonate were added, and the mixture was heated under reflux for 2 days.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 86.3 mg (yield 63%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 61 8-Chloro-4- (4- (4- (3-nitro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione Dissolve 121 mg of the compound of Example 9 in 15 ml of dioxane, 218 mg
(3 equivalents) of 1- (3-nitro-2-pyridyl) piperazine was added and the mixture was refluxed for 5 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 133 mg (yield: 80%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 62 8-Chloro-4- (4- (4- (3-cyano-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Dione synthesis 102 mg of the compound of Example 9 was dissolved in 10 ml of dioxane, and 55.3 g
(1 equivalent) of 1- (3-cyano-2-pyridyl) piperazine and 122 mg (3 equivalents) of potassium carbonate were added, and the mixture was heated under reflux for 2 days.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 88.2 mg (yield 66%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 63 8-Chloro-4- (4- (4- (3-amino-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione 104 mg of the compound of Example 9 dissolved in 10 ml of dioxane
(3 equivalents) of 1- (3-amino-2-pyridyl) piperazine was added, and the mixture was heated under reflux for 17 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 116 mg of the title compound (87% yield). The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 64 8-Chloro-4- (4- (4- (2-pyrimidinyl)
Piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione 98.0 mg of the compound of Example 9 was dissolved in 10 ml of dioxane, and 139 m
g (3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was refluxed for 4 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 88.9 mg (yield 73%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 65 Synthesis of 8-methyl-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 130 mg of the compound of Example 10 in 10 ml of dioxane, 196 mg
(3 equivalents) of 1- (2-pyridyl) piperazine
Stirred at 90-100 ° C for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (149 mg).
(91.2% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 66 8-Methyl-4- (4- (4- (3-chloro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione Dissolve 130 mg of the compound of Example 10 in 10 ml of dioxane, 236 mg
(3 equivalents) of 1- (3-chloro-2-pyridyl) piperazine was added and refluxed for 20 hours.

Reaction treatment and purification were carried out in the same manner as in Example 23 to give the title compound (172 mg).
(97.1% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 67 8-Methyl-4- (4- (4- (3-nitro-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione Dissolve 130 mg of the compound of Example 10 in 10 ml of dioxane, 249 mg
(3 equivalents) of 1- (3-nitro-2-pyridyl) piperazine was added and refluxed for 20 hours.

Reaction treatment and purification in the same manner as in Example 23 to give the title compound (197 mg)
(97.5% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 68 8-Methyl-4- (4- (4- (3-cyano-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione Dissolve 130 mg of the compound of Example 10 in 10 ml of dioxane, 225 mg
(3 equivalents) of 1- (3-cyano-2-pyridyl) piperazine was added and refluxed for 20 hours.

Reaction treatment and purification were carried out in the same manner as in Example 23 to give the title compound (207 mg)
(Yield 96.2%). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 69 8-Methyl-4- (4- (4- (3-amino-2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione Using 249 mg of the compound of Example 67, the reaction treatment and purification were conducted in the same manner as in Example 57 to obtain 101 mg of the title compound (yield: 48.9%).
The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 70 8-Methyl-4- (4- (4- (2-pyrimidinyl)
Piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione Dissolve 130 mg of the compound of Example 10 in 10 ml of dioxane, 196 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was stirred at 90 to 100 ° C. for 48 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (155 mg).
(94.7% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 71 8-Methoxy-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione Dissolve 106 mg of the compound of Example 11 in 10 ml of dioxane, 0.144
mg (3 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was refluxed for 5 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 81.8 mg (yield 62%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 72 Synthesis of 8-methoxy-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 200 mg of the compound of Example 11 in 20 ml of dioxane, 288 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was heated under reflux for 5 hours.

The reaction was treated in the same manner as in Example 19, and purified in the same manner as in Example 21 to obtain 141 mg (57% yield) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 73 6-Methoxy-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-
Synthesis of benzoxazepine-3,5-dione 55 mg of the compound of Example 12 was dissolved in 10 ml of dioxane to give 0.0749.
ml (3 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated under reflux for 7 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 64.8 mg (yield 95%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 74 Synthesis of 6-methoxy-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 60.8 mg of the compound of Example 12 in 10 ml of dioxane, 87.4
mg (3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was refluxed for 7 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 61.0 mg (yield 81%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 75 6-Benzyloxy-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Synthesis 229 mg of the compound of Example 13 was dissolved in 20 ml of dioxane and 0.255
ml (3 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated under reflux for 7 hours. Next, dioxane was distilled off, sodium bicarbonate water was added, and the mixture was extracted with methylene chloride.

The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. Next, the methylene chloride solution is concentrated,
The residue was developed with ethyl acetate using column chromatography on silica gel to obtain 210 mg (yield 77%) of the title compound. The maleate was used as a maleate in a usual manner.

Example 76 of 6-benzyloxy-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Synthesis 206 mg of the compound of Example 13 was dissolved in 20 ml of dioxane, and 242 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added and the mixture was refluxed for 7 hours. The reaction was treated and purified in the same manner as in Example 75 to give 195 mg (yield 79%) of the title compound. In addition, the maleate was used as a maleate by a usual method.

Example 77 6-Hydroxy-4- (4- (4- (2-pyridyl)
Piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione 5 ml of ethyl acetate was added to 20.5 mg of 10% palladium-carbon, and the reaction vessel was replaced with hydrogen and stirred at room temperature for 30 minutes.
Compound (205 mg) was dissolved in ethyl acetate (5 ml) and added at room temperature.
Stir for 11 hours.

The reaction solution was filtered, the solvent was removed by filtration, and the residue was subjected to silica gel column chromatography to give hexane-ethyl acetate (1: 1).
Developed in 2) to give 140 mg (83% yield) of the title compound.
The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 78 Synthesis of 6-hydroxy-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 5 ml of ethyl acetate was added to 23.6 mg of 10% palladium-carbon, and the reaction vessel was replaced with hydrogen and stirred at room temperature for 30 minutes.
236 mg of the compound was dissolved in 5 ml of ethyl acetate and added at room temperature.
Stir for 17 hours.

Reaction treatment and purification were conducted in the same manner as in Example 77.
(83% yield). The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 79 Synthesis of 7-nitro-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 7.2 mg of the compound of Example 14 was dissolved in 3 ml of dioxane, and 0.0093
7 ml (3 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated under reflux for 2 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 2.7 mg (yield 30%) of the title compound. The maleate could be obtained by converting it into a maleate by a usual method and then recrystallizing it from methylene chloride-ether.

Example 80 7-Nitro-4- (4- (4- (2-pyrimidinyl)
Piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione 8.2 mg of the compound of Example 14 was dissolved in 3 ml of dioxane, and 11.3 ml
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added and the mixture was heated under reflux for 4 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 5.5 mg (yield: 54%) of the title compound. The maleate could be obtained by converting it into a maleate by a usual method and then recrystallizing it from methylene chloride-ether.

Example 81 of 7-methoxycarbonyl-4- (4- (4- (2-pyridyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Synthesis 60 mg of the compound of Example 15 was dissolved in 10 ml of dioxane to give 0.0751
mg (3 equivalents) of 1- (2-pyridyl) piperazine was added and the mixture was heated under reflux for 8 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 63.4 mg (yield 87%) of the title compound. The citrate is
After the citrate was converted into a citrate by an ordinary method, it could be obtained by recrystallization from methylene chloride-ether.

Example 82 of 7-methoxycarbonyl-4- (4- (4- (2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Synthesis Dissolve 60 mg of the compound of Example 15 in 10 ml of dioxane, 79.3 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added and the mixture was refluxed for 6 hours.

The reaction was conducted in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 53.1 mg (yield: 72%) of the title compound. The maleate could be obtained by converting it into a maleate by a usual method and then recrystallizing it from methylene chloride-ether.

Example 83 Synthesis of 4- (4- (4- (4-methoxy-2-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 326 mg of the compound of Example 7 was dissolved in 20 ml of dioxane, and 580 mg
(3 equivalents) of 1- (4-methoxy-2-pyrimidinyl)
Piperazine and 1- (2-methoxy-4-pyrimidinyl)
A mixture of piperazine (4: 1) was added and refluxed for 15 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (271 mg).
(70.4% yield). The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 84 Synthesis of 4- (4- (4- (2-methoxy-4-pyrimidinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 36 mg (yield 8.4%) of the title compound from the reaction and purification of Example 83
I got Incidentally, the hydrochloride, after the hydrochloride in the usual way,
Recrystallized from ethanol-ether.

Example 85 4- (4- (4- (2-pyrazinyl) piperazinyl)
Synthesis of (butyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 326 mg of the compound of Example 7 was dissolved in 20 ml of dioxane, and 492 mg
(3 equivalents) of 1-pyrazinylpiperazine was added and refluxed for 20 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (270 mg).
(68.3% yield). The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 86 4- (4- (4- (6-Chloro-2-pyrazinyl) piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4-
Synthesis of benzoxazepine-3,5-dione 163 mg of the compound of Example 7 was dissolved in 10 ml of dioxane,
(3 equivalents) of 1- (6-chloro-2-pyrazinyl) piperazine was added and refluxed for 18 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (194 mg).
(92.8% yield). The hydrochloride was converted into a hydrochloride by a usual method, and then recrystallized from ethanol-ether.

Example 87 4- (4- (4- (6-methoxy-2-pyrazinyl))
Piperazinyl) butyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione 130 mg of the compound of Example 7 was dissolved in 10 ml of dioxane, and 232 mg
(3 equivalents) of 1- (6-methoxy-2-pyrazinyl) piperazine was added and stirred at 100 ° C. for 20 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (158 mg).
(92.8% yield). The hydrochloride could be obtained by converting the hydrochloride by an ordinary method and then recrystallizing from ethanol-ether.

Example 88 Synthesis of 4- (5- (4- (2-pyridyl) piperazinyl) pentyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione 70 mg of the compound of Example 16 was dissolved in 10 ml of dioxane to obtain 0.167 m
g (5 equivalents) of 1- (2-pyridyl) piperazine was added, and the mixture was heated and stirred at 100 ° C. for 6 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 79.4 mg (yield: 91%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 89 Synthesis of 4- (5- (4- (2-pyrimidinyl) piperazinyl) pentyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 70 mg of the compound of Example 16 in 10 ml of dioxane, 176 mg
(5 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was heated and stirred at 100 ° C. for 6 hours.

The reaction was treated in the same manner as in Example 19 and purified in the same manner as in Example 21 to obtain 69.2 mg (yield 79%) of the title compound. The hydrochloride was obtained by recrystallizing from methylene chloride-ether after converting into a hydrochloride by an ordinary method.

Example 90 7-Methoxy-4- (5- (4- (2-pyridyl) piperazinyl) pentyl) -2,3,4,5-tetrahydro-1,4
-Synthesis of benzoxazepine-3,5-dione Dissolve 106 mg of the compound of Example 17 in 10 ml of dioxane, 147 mg
(3 equivalents) of 1- (2-pyridyl) piperazine,
Stirred at 90-100 ° C for 24 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound 106 mg.
(80.7% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 91 Synthesis of 7-methoxy-4- (5- (4- (2-pyrimidinyl) piperazinyl) pentyl) -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione Dissolve 106 mg of the compound of Example 17 in 10 ml of dioxane, 147 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was stirred at 90 to 100 ° C. for 24 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound 106 mg.
(80.5% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 92 8-Methyl-4- (5- (4- (2-pyridyl) piperazinyl) pentyl) -2,3,4,5-tetrahydro-1,4-
Synthesis of benzoxazepine-3,5-dione 136 mg of the compound of Example 18 was dissolved in 10 ml of dioxane, and 200 mg
(3 equivalents) of 1- (2-pyridyl) piperazine,
Stirred at 90-100 ° C for 24 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (154 mg).
(91.7% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 93 8-Methyl-4- (5- (4- (2-pyrimidinyl)
Piperazinyl) pentyl) -2,3,4,5-tetrahydro-
Synthesis of 1,4-benzoxazepine-3,5-dione 136 mg of the compound of Example 18 was dissolved in 10 ml of dioxane, and 200 mg
(3 equivalents) of 1- (2-pyrimidinyl) piperazine was added, and the mixture was stirred at 90 to 100 ° C. for 24 hours.

Reaction treatment and purification were conducted in the same manner as in Example 23 to give the title compound (140 mg).
(83.1% yield). The hydrochloride was converted into a hydrochloride by an ordinary method, and then recrystallized from methylene chloride-ether.

Example 94 4- {4- [4-3-Acetylamino-2-pyridyl) piperazin-1-yl] butyl} -2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5 -Synthesis of dione 340 mg (0.8 mM) of the compound of Example 69 was dissolved in 10 ml of methylene chloride, and 252 mg (3.3 mM, 4 equivalents) of pyridine and 163 mM of acetic anhydride were dissolved.
g (1.6 mM, 2 equivalents) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water. The organic layer was dried over magnesium sulfate (anhydrous), filtered, and the solvent was distilled off.
The residue was subjected to silica gel column chromatography,
Elution with ethyl acetate gave 102 mg (yield 28%) of the title compound.

The physical data of the compounds obtained in Examples 19 to 94 are shown in Table 2.

Example 95 Synthesis of 4- (4- (4- (6-methoxy-2-pyridyl) piperazinyl) butyl-2,3,4,5-tetrahydrobenzoxazepine-3,5-dione 163 mg of the compound of Example 2 are dissolved in 10 ml of dioxane,
mg (1.4 equivalents) of 1- (6-methoxy-2-pyridyl)
Add piperazine, 207 mg (3 equivalents) of potassium carbonate, add 1
Refluxed for 6 hours. The same treatment and purification was carried out as in Example 23 to give 1.72 mg (8
1.0%) of the title compound. The hydrochloride was converted into a hydrochloride by an ordinary method and recrystallized from ethanol-ether. ¹ H-NMR (TMS / CDCl ₃ ) δ: 1.53 to 1.76 (m, 4H), 2.43 (t, 2H,
J = 7.3Hz), 2.54 (t, 4H, j = 4.6Hz), 3.52 (t, 4H, J = 4.6
Hz), 3.86 (s, 3H), 4.02 (t, 2H, J = 7.3Hz), 4.75 (s, 2
H), 6.06 (d, 1H, J = 7.9 Hz), 6.14 (d, 1H, J = 7.9 Hz), 7.
09 (d, 1H, J = 8.2 Hz), 7.24 (m, 1H), 7.39 (t, 1H, J = 7.9
Hz), 7.51 (m, 1H), 8.16 (dd, 1H, J = 2.0 Hz, 7.9 Hz) IR (cm ^-1 ): 2940, 2820, 1710, 1650, 1590, 1460, 1300, 123
0, 1150, 1120, 1040, 990, 910, 790, 730 mp: 171 to 174 ° C [Action / Effect] The compound of the present invention shows strong affinity for the serotonin receptor and also has an anti-conflict effect, and anxiety and phobia It is useful as a therapeutic agent for neuropsychiatric disorders such as obsessive-compulsive disorder, post-traumatic stress disorder, and depressive neurosis, as well as disorders involving the serotonin nervous system, such as eating disorders, climacteric disorders, and adolescent autism. The pharmacological test results are described below.

(1) Affinity to serotonin receptor (Experimental method) STPerouka (J. Neurochem., 47 , 529-540 (1986))
Was carried out according to the method described above.

 50 mM Tri in the cerebral cortex isolated from male Wistar rats
s-HCl (pH 7.7) buffer was added, and Polytron (Polytron) was added.
) Was used for homogenization. Add this homogenate to 4
Centrifuge at 0,000G for 10 minutes and add the same buffer to the resulting precipitate
Add the solution, homogenize, and incubate at 37 ° C for 30 minutes.
I did it. Centrifuge this suspension again at 40,000G for 10 minutes
Add the same buffer to the resulting precipitate and homogenize.
And further centrifuged at 40,000 G for 10 minutes. Final obtained
50 mM Tris-HCl (10 μM pargyline, 4 mM CaCl_Two, 0.
Add 1% ascorbic acid (pH 7.4) buffer
And used for binding experiments. Used for binding experiments [^ThreeH] 8
-OHDPAT is 0.4 nM, protein amount is 0.4-0.6 mg / ml, total amount is 1 ml
Performed in After incubation at 25 ° C for 30 minutes,
Filtration using Whatman GF / B filters
Filter the mixture by the same method and filter three times with 5 ml of the same buffer.
Was washed. Scintillation filter
And then measure with a liquid scintillation counter.
Was.

(Test results) All the compounds of the present invention have a strong affinity on the order of μM or less. Among the different types of compounds, such as substituents on the benzene ring, substituents on the heterocyclic ring, the number of carbon atoms in the side chain, and the like, the receptor binding ability of the representative compounds is as shown in Table 3, and all of them are nM. It had a strong affinity on the order.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 413/12 241 C07D 413/12 241 (72) Inventor Makoto Shibata 1-1-1 Wakayamadai, Shimamotocho, Mishima-gun, Osaka Suntory (56) References JP-A-61-227565 (JP, A) Chem. abstr. , Vol. 72 (1970), p. 419, abstract. 111530d Chem. abstr. , Vol. 72 (1970), p. 392, abstract. 100779r (58) Field surveyed (Int. Cl. ⁶ , DB name) REGISTRY (STN) CA (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (I): (Wherein A and B are both carbonyl groups or one is a methylene group and the other is a carbonyl group, R is an optionally substituted aromatic or heterocyclic group, and X is a hydrogen atom , a halogen atom, C ₁ -C ₅ lower alkyl group, C ₁ -C ₅ lower alkoxy groups, C ₇ -C ₉ arylalkoxy group, a hydroxyl group, a nitro group or an ester radical, n is an integer from 2 to 10 And a salt thereof. 2. The general formula (II): (Where A and B are both carbonyl groups or one is a methylene group and the other is a carbonyl group, X is a hydrogen atom, a halogen atom, a C ₁ -C ₅ lower alkyl group, a C ₁ -C ₅ lower Alkoxy group, C ₇ -C ₉ arylalkoxy group, hydroxyl group,
A nitro group or an ester group, Y represents a halogen atom, and n is an integer of 2 to 10), and salts thereof. 3. A psychotropic agent containing the compound according to claim 1 as an active ingredient. 4. A therapeutic agent for a disease involving the serotonergic nervous system, comprising the compound according to claim 1 as an active ingredient.