JPH09151186A - Condensed triazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new condensed triazole compound useful as an antipsychotic agent, etc., having reduced adverse effects such as extrapyramidal symptom and endocrinosis and selectively strong blocking effect on a dopamine D4 receptor. SOLUTION: This compound is shown by formula I [R<1> and R<2> are each H, a halogen, cyano, nitro, amino, acylamino, carbamoyl, an alkylamino, etc.; W is methylene, S, SO, O, etc.; X is methylene, ethylene or vinylene; Y does not exist or is a 1-8C alkylene; Z is NH2 , NHR<4> (R<4> is an alkyl, a cycloalkyl, etc.), etc.] such as 3-(1-(2-(4-chlorophenyl)ethyl)piperidin-4-yl)-6,7-dihydro-5H-1,2,4- triazolo[3,4-a] [2] benzoazepine. The compound of formula I is obtained by reacting a compound of formula II with a chlorinating agent to give a compound of formula III and reacting the product in the presence of a compound of formula IV in a solvent such as ethanol at room temperature to 200 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel condensed triazole compound having an affinity for dopamine D ₄ (hereinafter referred to as D ₄ ; the dopamine receptor subtype described below also follows this abbreviation). This D ₄ receptor blocker is used in the medical field as a central agent, especially as an antipsychotic drug.

[0002]

The following patent applications have been published for central agents having an affinity for the D ₄ receptor. International Patent Application Publications WO94 / 10162, WO9
No. 4/21630, WO94 / 21626, D ₄
Tricyclic heteroaromatic compounds having affinity for receptors are disclosed, and International Patent Application Publication No. WO94 / 21627,
WO94 / 21628 and WO94 / 24105 disclose indole derivatives and the like having affinity for the D ₄ receptor, and International Patent Application Publication WO94 / 20459.
No. WO94 / 20497 discloses pyropyridine derivatives having an affinity for the D ₄ receptor, and International Patent Application Publication Nos. WO94 / 21615 and WO94 / 2283.
No. 9 discloses a benzimidazole derivative having an affinity for the D ₄ receptor. Further, International Patent Application Publication Nos. WO94 / 10145 and WO94 / 20471 disclose pyrazole derivatives, quinolone derivatives, etc., each having an affinity for the D ₄ receptor.

[0003]

[Problems to be solved by the invention] schizophrenia
Most of the antipsychotics are neurotransmitters in the brain
, A common pharmacological action of dopamine receptor blockade
Especially powerful D _TwoShowing a receptor blocking effect
You. These drugs (typical antipsychotics)
Positive symptoms centered on hallucinations and delusions characteristic of the acute phase
Is effective against, but is apathetic, apathetic, autistic, etc.
It was pointed out that it has almost no effect on the negative symptoms of
ing. In addition, when acute administration and long-term continuous use
Extrapyramidal manifestations (delayed dyskinesia, acute dyskinesia)
Tonia, Akathisia, etc.) and endocrine abnormalities (high prolacti)
Side effects such as blood sugar have become serious problems.

It has been recognized that the dopamine receptors are classified into two receptor subtypes by a conventional pharmacological method according to the nature of ligand binding and the form associated with adenylate cyclase [Nature 227].
Vol. 93 (1979)]. That is, the D ₁ receptor type to produce cyclic AMP by via a stimulatory G protein activated adenylate cyclase, inhibiting adenylate cyclase via inhibitory G-protein, inhibiting production of cyclic AMP D ₂ is a receptor type. However, with the recent revolutionary development of molecular biology, five different genes have been cloned in the dopamine receptor.
It has been clarified that it is classified into D ₁ and D ₅ receptors belonging to the ₁ family and D ₂ , D ₃ and D ₄ receptors belonging to the D ₂ family [Trends in Pharmacological Sciences (Trendsin Pharmac
ol Sci. ) Vol. 15, p. 264 (1994)].

Haloperidol, a typical antipsychotic, is D
Clozapine, which has a higher affinity for the D ₂ receptor than the ₄ receptor, but has less extrapyramidal side effects and is effective for negative symptoms, is D
It has been reported to show a 10-fold higher affinity for the D ₄ receptor than the ₂ receptor [Nature No. 35].
Volume 0, page 610 (1991), Trends in P (Trends in P)
harmol Sci. ) Volume 15, p. 264 (1
994)]. Moreover, it has been reported that the effective therapeutic plasma concentration of clozapine correlates with the affinity constant for the D ₄ receptor [Trends in Pharmacole S (Trends in Pharmacol S
ci. ) Vol. 15, p. 264 (1994)]. In addition, as a result of a binding test using a post-mortem brain of a schizophrenic patient, it was also reported that the D ₄ receptor was increased by 6 times as compared with a normal person [Nature, 365, 441 (1993). )]. Therefore, it is highly likely that the D ₄ receptor is involved in the etiology of schizophrenia or the site of action of therapeutic agents. Furthermore, there were differences among subtypes in the distribution of dopamine receptors in the brain, with D ₂ receptors being most abundant in the striatum, whereas D ₄ receptors being most abundant in the cortex frontal lobe, which controls emotional function. It is known that there are many.

From these things, selective D_FourReceptor a
Negagonists have less extrapyramidal side effects and are positive and negative.
It can be expected as an antipsychotic drug effective for sexual symptoms. The present invention
Is D _FourIt has a strong and selective blocking effect on receptors,
For negative and positive symptoms compared to conventional compounds
We aim to provide compounds that are effective and have few side effects.
Target.

[0007]

Means for Solving the Problems As a result of intensive investigations by the present inventors, a novel fused triazole compound represented by the following general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof was identified as D It has been found that it has a selective and stronger blocking effect on the D ₄ receptor over the ₂ receptor. Therefore, the compound of the present invention exerts an effect not only on positive symptoms such as hallucinations and delusions, which are characteristic of the acute phase, but also on negative symptoms such as apathy, apathy and autism, while D ₂ receptor The present invention has been completed by finding that it can be a useful antipsychotic drug with reduced side effects such as extrapyramidal symptoms and endocrine abnormalities that are observed when a conventional antipsychotic drug having a body antagonistic action is administered.

That is, the present invention is based on the general formula (1)

[0009]

Embedded image

[Wherein R ¹ and R ² are the same or different and are hydrogen, halogen, cyano, nitro, amino, acylamino, carbamoyl, alkylcarbamoyl, alkoxycarbonyl, acyl, alkylamino, aminoalkyl, alkylaminoalkyl, hydroxy. , Acyloxy, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, alkyl, alkenyl, alkynyl,
It represents alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl.

W is methylene, sulfur atom, SO, SO_Two,
Oxygen atom or N-R^Three(Where R ^ThreeIs hydrogen, alk
Ru, phenacyl, or optionally substituted aryl
Indicates alkyl or heteroarylalkyl. )
Show. X represents methylene, ethylene or vinylene.
Y is absent or has 1 to 8 carbons
Indicates a chain or branched alkylene chain.

Z is —NH ₂ , —NHR ⁴ (wherein R ⁴ is alkyl, cycloalkyl, optionally substituted arylalkyl, heteroarylalkyl or fused heteroarylalkyl, or substituted. Optionally represents aryl, heteroaryl or fused heteroaryl), —N (R ⁴ ) (R ⁵ ) (In the formula, R ⁴ has the same meaning as above. R ⁵ represents alkyl, cycloalkyl or a substituent. An optionally substituted arylalkyl, a heteroarylalkyl or a fused heteroarylalkyl, or an optionally substituted aryl, heteroaryl or fused heteroaryl), or a cyclic amine of the formula (a), a formula (a) cyclic amine of b) or cyclic amine of formula (c)

[0013]

Embedded image

(In the formula, the cyclic amine in the formula (a) may further have an oxygen atom in the ring, and represents pyrrolidine, piperidine or morpholine. The cyclic amine in the formula (b) is piperazine or homo. Shows piperazine, Formula (c)
The cyclic amine therein may further have an oxygen atom in the ring, and is pyrrolidine, piperidine, 3,6-dihydro-2.
Indicates H-pyridine or morpholine. The bond represented by the solid line and the dotted line represents a single bond or a double bond. A is absent or represents a straight chain or branched alkylene chain having 1 to 8 carbon atoms. B is absent or represents a sulfur atom, an oxygen atom, carbonyl or hydroxymethyl. R ⁶ represents hydrogen, hydroxy, alkyl or alkoxy. R ⁷ represents hydrogen, optionally substituted aryl, heteroaryl or fused heteroaryl, cycloalkyl, or optionally substituted arylalkyl, heteroarylalkyl or fused heteroarylalkyl. ) Is shown. ] The condensed triazole compound represented by these, its optical isomer, or its pharmaceutically acceptable salt.

The present invention also provides a pharmaceutical composition comprising a fused triazole compound of the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a compound of the general formula (1) Also provided is a medicament comprising a fused triazole compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In addition, the general formula (1) includes compounds of the following three embodiments according to the definition of X. In the formula, each symbol has the same meaning as described above.

[0016]

Embedded image

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Regarding the general formula (1), R ¹ ,
The halogen in R ² means chlorine, bromine, fluorine and the like. Acylamino means acetylamino, benzoylamino, cyclohexylcarbonylamino, cyclopropylcarbonylamino and the like. The alkylcarbamoyl refers to carbamoyl in which 1 to 2 alkyl having 1 to 4 carbon atoms is substituted on the nitrogen atom, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl. Alkoxycarbonyl refers to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like. Acyl represents alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and octanoyl, aroyl such as benzoyl and naphthoyl and heteroarylcarbonyl such as nicotinoyl, tenoyl and furoyl. Alkylamino is methylamino,
Dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino and the like are shown. Aminoalkyl refers to aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and the like. Alkylaminoalkyl means methylaminomethyl, dimethylaminomethyl, 2- (methylamino) ethyl, 2- (dimethylamino) ethyl and the like. Acyloxy means acetyloxy, propionyloxy, butyryloxy, benzoyloxy and the like. Hydroxyalkyl is hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2
-Or 3-hydroxypropyl and the like. Acyloxyalkyl means acetoxymethyl, 2-acetoxyethyl, 3-acetoxypropyl, propionyloxymethyl and the like. Alkoxyalkyl is methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxyethyl, 2-
Examples include ethoxyethyl and 3-methoxypropyl. Alkyl is methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like are shown, and alkyl having 1 to 4 carbon atoms is preferable. Alkenyl means vinyl, 1-propenyl, isopropenyl and the like. Alkynyl means ethynyl and the like. Alkoxy is methoxy, ethoxy, propoxy,
It shows isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like, and alkoxy having 1 to 4 carbon atoms is preferable. Alkylthio means methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. The alkylsulfinyl includes methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like. Alkylsulfonyl means methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like.

Alkyl for R ³ includes R ¹ and R ²
The same as the alkyl in the above can be mentioned.
Arylalkyl is benzyl, 1-phenylethyl,
2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylmethyl, 3
-Naphthylpropyl, 4-naphthylbutyl, diphenylmethyl and the like are shown. Heteroarylalkyl means pyridylmethyl, pyridylethyl, furylmethyl, furylethyl, thienylmethyl, thienylethyl and the like. These substituents include halogen such as fluorine, chlorine, bromine and iodine, haloalkyl such as trifluoromethyl, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl, methoxy, ethoxy and propoxy. , Alkoxy groups such as isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy.

The linear or branched alkylene chain having 1 to 8 carbon atoms in Y is methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
Hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene,
2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene,
1-methyltrimethylene, 2-methyltrimethylene, 3
-Methyltrimethylene and the like, with methylene or ethylene being preferred.

Alkyl in R ⁴ and R ⁵ is methyl,
It represents ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like. Cycloalkyl means cyclopropyl, cyclopentyl, cyclohexyl and the like. Arylalkyl is benzyl, 1-phenylethyl, 2-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-naphthylpropyl, 4-naphthylbutyl, diphenylmethyl and the like are shown. Heteroarylalkyl means pyridylmethyl, 2-
Pyridylethyl, furylmethyl, 2-furylethyl, thienylmethyl, 2-thienylethyl and the like are shown. Aryl represents phenyl, naphthyl, 2-indanyl and the like. Heteroaryl is pyridyl, furyl, thienyl,
Pyrimidyl etc. are shown. Fused heteroaryl means 1,
4-benzodioxan-2-yl, 6-acetyl-3-
Ethyl-4,5,6,7-tetrahydrothieno [2,3
-C] Pyridin-2-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-
Ile, indol-3-yl, benzo [b] furan-3
-Yl, benzo [b] thiophen-3-yl and the like are shown. Fused heteroarylalkyl means indole-3
-Ylmethyl, 2- (indol-3-yl) ethyl,
3- (indol-3-yl) propyl, benzo [b]
Furan-3-ylmethyl, 2- (benzo [b] furan-
3-yl) ethyl, benzo [b] thiophen-3-ylmethyl, 2- (benzo [b] thiophen-3-yl) ethyl and the like are shown. With these substituents, fluorine, chlorine,
Bromine, halogen of iodine, haloalkyl such as trifluoromethyl, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy. , Alkoxy such as pentyloxy, hexyloxy, heptyloxy, octyloxy, hydroxy, nitro, amino, methylamino, dimethylamino and the like.

Examples of the cyclic amine of the formula (a) in Z include the following.

[0022]

Embedded image

Examples of the cyclic amine of the formula (b) include the following.

[0024]

Embedded image

Examples of the cyclic amine of the formula (c) include the following.

[0026]

Embedded image

The linear or branched alkylene chain having 1 to 8 carbon atoms in A means methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
Hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene,
2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene,
1-methyltrimethylene, 2-methyltrimethylene, 3
-Methyltrimethylene and the like, with methylene or ethylene being preferred. The alkyl in R ⁶ is alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl. Alkoxy is methoxy, ethoxy, propoxy,
The alkoxy having 1 to 4 carbon atoms such as isopropoxy, butoxy, isobutoxy and tertiary butoxy is shown. Which may have a substituent in R ⁷ aryl, heteroaryl or fused heteroaryl, cycloalkyl, an optionally substituted arylalkyl, and heteroarylalkyl or fused heteroarylalkyl R ^4, R ⁵
The same thing as the case of can be mentioned. These may have a substituent, and examples of the substituent include fluorine, chlorine, bromine, halogen such as iodine, haloalkyl such as trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. And alkyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and other alkoxy, nitro, amino, methylamino and the like.

In the general formula (1), R ¹ is hydrogen,
Halogen, nitro, amino, acyl (acetyl, propionyl, etc.), alkylamino (methylamino, ethylamino, etc.), alkyl (methyl, ethyl, propyl, etc.)
Isopropyl, butyl etc.) or alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.), R ² is hydrogen, halogen or alkoxy (methoxy, ethoxy, propoxy, isopropoxy,
Butoxy) is preferred. R ¹ and R ² are particularly preferably both hydrogen. W is preferably methylene, a sulfur atom or an oxygen atom, and particularly preferably an oxygen atom. −
As YZ, Y is absent or represents a linear alkylene chain having 1 to 4 carbons, and Z is represented by the formula (a),
The cyclic amine represented by (b) or (c) is preferable, and the cyclic amine of the formula (a) is represented by the formula (2) or the cyclic amine of the formula (b) is represented by the formula (8) or the formula (c). Of the cyclic amines of formula (10)

[0029]

Embedded image

(In the formula, the bonds represented by the solid line and the dotted line represent a single bond or a double bond. A does not exist or a linear alkylene chain having 1 to 4 carbon chains. B exists. Or a carbonyl group, R ⁶ represents hydrogen, and R ⁷ represents an aryl, heteroaryl, or fused heteroaryl which may have a substituent. Here, the aryl in R ⁷ is phenyl, naphthyl, halogen, methyl, trifluoromethyl, methoxy, nitro,
It represents phenyl having 1 to 2 substituents such as amino and methylamino, and heteroaryl represents thienyl and the like. Fused heteroaryl includes halogen, methyl,
1,2-benzisoxazol-3-yl, benzo [b] furan-3-yl, 1,4-benzodioxan-2-yl having 1 to 3 substituents such as trifluoromethyl and methoxy, 6 -Acetyl-2-ethyl-4,5,6
7-Tetrahydrothieno [2,3-c] pyridine-3-
Indicates a file etc.

Preferred compounds of the general formula (1) are:
3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -6,7-dihydro-5H-1,
2,4-triazolo [3,4-a] [2] benzazepine, 3- (1- (2- (4-chlorophenyl) ethyl)
Piperidin-4-yl) -5,6-dihydro-1,2,
4-triazolo [4,3-d] [1,4] benzoxazepine, 3- (2- (4- (4-chlorophenyl) piperazin-1-yl) ethyl) -5,6-dihydro-1,
2,4-triazolo [4,3-d] [1,4] benzoxazepine, 3- (2- (4- (3-chlorophenyl))
Piperazin-1-yl) ethyl) -5,6-dihydro-
1,2,4-triazolo [4,3-d] [1,4] benzoxazepine, 3- (3- (4- (4-chlorophenyl) piperazin-1-yl) propyl) -5,6- Dihydro-1,2,4-triazolo [4,3-d] [1,
4] benzoxazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -1,
2,4-triazolo [4,3-d] [1,4] benzoxazepine, 3- (1- (2- (4-chlorophenyl))
Ethyl) piperidin-4-yl) -5,6-dihydro-
1,2,4-triazolo [4,3-d] [1,4] benzothiazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro -1,2,4-triazolo [4,3-a] isoquinoline, 3- (1- (2- (4-chlorophenyl) ethyl)
Piperidin-4-yl) -5,6-dihydro-1,2,
4-triazolo [4,3-d] [1,4] benzothiazepine 7,7-dioxide, and 5,6-dihydro-
3- (2- (4-phenylpiperidin-1-yl) ethyl) -1,2,4-triazolo [4,3-d] [1,
4] A compound selected from benzoxazepine or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of the compound of the general formula (1) includes inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Nitric acid) or organic acid (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphor sulfone) Acid, ascorbic acid, etc.).

Since the compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of hydrate or solvate, these hydrate and solvate are also included in the present invention. Included. When the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.

Compounds of general formula (1) and general formula (1)
The compound of the present invention contained in can be synthesized by the following methods (1) to (9). Method (1) General formula (13)

[0035]

Embedded image

(Wherein each symbol has the same meaning as defined above) in a suitable solvent (benzene, toluene, xylene, or any mixed solvent thereof),
By reacting with a chlorinating agent (phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, etc.) at room temperature or the reflux temperature of the solvent for 1 to 24 hours, the general formula (14)

[0037]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. This compound in a suitable solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or a mixed solvent of any of these, etc.), the compound of the general formula (15 _{) H 2 NHNOC-Y-Z} (15) ( wherein, the presence of each symbol is as defined above.) the compound represented by reacting 1 to 24 hours at 200 ° C. from room temperature, the general formula The compound of (1) is obtained. Method (2) A compound of the general formula (13) is prepared in a suitable solvent (benzene, toluene, xylene, or any mixed solvent thereof).
Medium, thionizing agents such as phosphorus pentasulfide, Lawesso
n reagent [2,4-bis (4-methoxyphenyl) -1,
3-dithia-2,4-diphosphetane-2,4-disulfide] and the like at room temperature or the reflux temperature of the solvent for 1 to 24
General reaction (16)

[0039]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. This compound in a suitable solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or a mixed solvent of any of these, etc.), the compound of the general formula (15 By reacting at room temperature to 200 ° C. for 1 to 24 hours in the presence of the compound represented by the formula (1), the compound of the general formula (1) is obtained. Method (3) benzyl chloride, p-nitrobenzyl chloride, methyl iodide, etc. in a suitable solvent (tetrahydrofuran, diethyl ether, dioxane, water or a mixed solvent thereof) which does not inhibit the reaction of the compound of general formula (16) By reacting with a base such as potassium hydroxide or potassium tertiary butoxide at room temperature or the reflux temperature of the solvent for 1 to 24 hours to give a compound of the general formula (17)

[0041]

Embedded image

(Wherein R ⁸ represents methyl, benzyl, p-nitrobenzyl, etc., and other symbols have the same meanings as described above). This compound is mixed with a suitable solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone, 1,
3-dimethyl-2-imidazolidinone or an arbitrary mixed solvent thereof and the like), the compound represented by the general formula (15) is reacted with the compound represented by the general formula (15) at room temperature or the reflux temperature of the solvent for 1 to 24 hours. The compound of 1) is obtained. Method (4) General formula (18)

[0043]

Embedded image

(Wherein each symbol has the same meaning as defined above) or an acid addition salt thereof, for example, hydrochloride, hydrobromide, sulfate, oxalate or the like, which inhibits the reaction. Do not use a suitable solvent (methylene chloride, chloroform,
In dichloroethane, tetrahydrofuran, diethyl ether, N, N-dimethylformamide, or any mixed solvent thereof, etc., general formula (19) G ¹ -R ⁴ (19) (in the formula, G ¹ is chlorine, bromine, iodine, Methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like, and R ⁴ has the same meaning as above.), And ice in the presence of a base such as triethylamine, pyridine or dimethylaminopyridine. By reacting under cold or room temperature for 1 to 24 hours, the compound of the general formula (20)

[0045]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Method (5) A compound of the general formula (20) or an acid addition salt thereof, for example, hydrochloride, hydrobromide, sulfate, oxalate, etc., can be used in a suitable solvent (methylene chloride, chloroform, dichloroethane) which does not inhibit the reaction. , Diethyl ether or any mixed solvent thereof, and the like, in the general formula (21) G ² —R ⁵ (21) (in the formula, G ² is chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoro). Rmethanesulfonyloxy and the like, and R ⁵ has the same meaning as described above.) Is reacted with a compound such as triethylamine, pyridine or dimethylaminopyridine in the presence of a base under ice cooling or at room temperature for 1 to 24 hours. By the general formula (22)

[0047]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Method 6 General formula (23)

[0049]

Embedded image

(Wherein each symbol has the same meaning as defined above) or a compound represented by the general formula (24)

[0051]

Embedded image

(Wherein each symbol has the same meaning as defined above) or an acid addition salt thereof, such as hydrochloride, hydrobromide, sulfate, oxalate, etc., inhibits the reaction. Do not use a suitable solvent (methylene chloride, chloroform,
Dichloroethane, tetrahydrofuran, diethyl ether, N, N-dimethylformamide or any mixed solvent thereof, etc.) in the general formula (25) G ³ -A-B-R ⁷ (25) (wherein G ³ is chlorine, Bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and other symbols are as defined above.), Potassium carbonate, sodium hydroxide, triethylamine, By reacting in the presence of a base such as pyridine or dimethylaminopyridine under ice cooling or at room temperature for 1 to 24 hours,
General formula (26)

[0053]

Embedded image

(Wherein each symbol has the same meaning as defined above), or a compound represented by the general formula (27)

[0055]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Method (7) A compound of the general formula (23) or a general formula (24) or an acid addition salt thereof, for example, hydrochloride, hydrobromide, sulfate,
In a suitable solvent that does not inhibit the reaction of oxalate (such as tetrahydrofuran, dichloromethane, dimethylformamide, or any mixed solvent thereof), a compound represented by the general formula (28) HOOC (CH ₂ ) m R ¹¹ (28) (wherein R is ¹¹ represents aryl or heteroaryl which may have a substituent, m represents a number of 1 to 7, and 1,3-dicyclohexyl in the presence of a compound represented by 3) and a tertiary amine such as triethylamine. Carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)
The compound of the general formula (29)

[0057]

Embedded image

(Wherein each symbol has the same meaning as defined above), or the general formula (30).

[0059]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The general formula (28)
When a reactive derivative of the compound (eg, acid chloride, acylimidazole, etc.) is used, the reaction is carried out in a suitable solvent (tetrahydrofuran, dichloromethane, chloroform, benzene or any mixed solvent thereof) which does not inhibit the reaction.
The reaction proceeds by reacting in the presence of a tertiary amine such as triethylamine or pyridine under ice cooling or at room temperature for 1 to 24 hours.

The compound of the general formula (29) or the general formula (30) thus obtained is hydrogenated in a suitable solvent (such as tetrahydrofuran, diethyl ether, toluene or any mixed solvent thereof) which does not inhibit the reaction. -78 using a reducing agent such as lithium aluminum bromide or borane
By carrying out the reduction reaction from ℃ to room temperature for 1 to 24 hours,
General formula (31)

[0062]

Embedded image

(Wherein each symbol has the same meaning as defined above), or a compound represented by the general formula (32)

[0064]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Method 8 General formula (33)

[0066]

Embedded image

(Wherein each symbol has the same meaning as defined above), the compound represented by the formula:
Deprotection by acting with hydrogen bromide, trifluoroacetic acid, etc. gives the general formula (34)

[0068]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. P-
After introducing a leaving group by acting with toluenesulfonyl chloride or methanesulfonyl chloride, etc., potassium carbonate, In the presence of a suitable dehydrogenating agent such as pyridine or triethylamine, the compound represented by the general formula (35), (36) or (37)

[0070]

Embedded image

(Wherein each symbol has the same meaning as defined above) or an acid addition salt thereof, such as hydrochloride, hydrobromide, sulfate, oxalate, etc. The compound of the general formula (22) or (27) or the general formula (38) is reacted by refluxing for 1 to 24 hours.

[0072]

Embedded image

(Wherein each symbol has the same meaning as defined above), a compound represented by the formula is obtained. Method (9) A general formula (39) in which W produced by any of the above methods is a sulfur atom.

[0074]

Embedded image

(Wherein each symbol has the same meaning as defined above) or an acid adduct thereof, such as hydrochloride, hydrobromide, sulfate, oxalate, etc., in methylene chloride, The compound of the general formula (40-a) or the general formula (40-b) can be prepared by reacting m-chloroperbenzoic acid under ice cooling or by reacting with formic acid or acetic acid in a hydrogen peroxide solution.

[0076]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The starting compound used in the above method can be synthesized by the following method. Method (10) The compound of the general formula (14), (16) or (17)
Suitable solvent that does not inhibit the reaction (methanol, ethanol, butanol, ethylene glycol, N-methyl-2
-Pyrrolidone, 1,3-dimethyl-2-imidazolidinone or any mixed solvent thereof, etc.)
1) H ₂ NHNOC-Y-NHR ⁹ (41) (In the formula, R ⁹ represents a protecting group such as a tertiary butoxycarbonyl group or a benzyloxycarbonyl group, which is not affected by the reaction. Other symbols have the same meanings as described above. By reacting at room temperature to 200 ° C. for 1 to 24 hours in the presence of the compound represented by the general formula (42).

[0078]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. Method (11) The compound of the general formula (14), (16) or (17)
Suitable solvent that does not inhibit the reaction (methanol, ethanol, butanol, ethylene glycol, N-methyl-2
-Pyrrolidone, 1,3-dimethyl-2-imidazolidinone or any mixed solvent thereof, etc.)
3) or (44)

[0080]

Embedded image

(In the formula, R ⁹ represents a protecting group such as a tertiary butoxycarbonyl group or a benzyloxycarbonyl group, which does not influence the reaction. Other respective symbols have the same meanings as described above). From room temperature to 200
By reacting at 1 ° C for 1 to 24 hours, the compound of the general formula (4
5)

[0082]

Embedded image

(Wherein each symbol has the same meaning as defined above), or a compound represented by the general formula (46):

[0084]

Embedded image

A compound represented by the formula (wherein each symbol has the same meaning as defined above) is obtained. The compound of the general formula (23) or the general formula (24) is prepared by converting the compound of the general formula (45) or the general formula (46) into a suitable acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid according to a conventional method. It is obtained by acting and deprotecting. Method (12) An appropriate solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-) which does not inhibit the reaction is prepared from the compound of the general formula (14), (16) or (17).
2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, or any mixed solvent thereof, etc.) in the general formula (47) H ₂ NHNOC-Y-OR ¹⁰ (47) (wherein R ¹⁰ is methoxy). 1 to 24 at room temperature to 200 ° C. in the presence of a compound represented by a protective group which does not influence the reaction, such as a methyl group, a tetrahydropyranyl group, a triethylsilyl group, etc. Other symbols have the same meanings as above. By reacting for a time, the compound of the general formula (33) is obtained.

The pharmaceutically acceptable salt of the compound of the general formula (1) may be an acid addition salt with an inorganic acid or an organic acid.
Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfone) Acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, etc.) to form a salt.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method or a column chromatography method. When the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid,
Alternatively, it can be divided into a desired optically active substance by passing through a column filled with an optically active carrier. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using an optically active raw material compound or the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

The compounds of the present invention, acceptable salts optical isomers or its pharmaceutically are the D ₄ receptor antagonist having a selective and strong blocking action on D ₄ receptor, negative not positive symptoms only It is a useful antipsychotic drug that is effective against symptoms. Further, it is expected to be an antipsychotic drug in which side effects such as extrapyramidal symptoms and endocrine abnormalities observed when a conventional antipsychotic drug having a D ₂ receptor antagonistic effect is administered are reduced.

When the fused triazole compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is used as a pharmaceutical, the compound of the present invention is a pharmaceutically acceptable carrier (excipient, binder, disintegrating agent, taste masking agent). Pharmaceutical compositions or preparations (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspending agents, suspending agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc.) It can be administered orally or parenterally in the form of a suspension, solution, injection, drip or suppository.

The pharmaceutical composition can be formulated according to conventional methods. As used herein, parenteral refers to
It includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or infusion. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. Furthermore, aseptic non-volatile oil can also be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration are solid at room temperature, such as the drug and a suitable nonirritating excipient, for example, cocoa butter or polyethylene glycols, but liquid at intestinal temperatures and melt in the rectum, It can be manufactured by mixing with a substance that releases a drug.
Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans,
It can be mixed with pectins, gum tragacanth, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also, as usual, contain further additives, for example inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbines, ascorbic acid. , Α
-Antioxidants such as tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweetening agents, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs,
Suspensions, solutions and the like can be mentioned, which may contain an inert diluent commonly used in the art, for example, water.

[0091] Dosage may be adjusted based on age, body weight, general health condition,
Gender, diet, time of administration, method of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated at that time may be determined in consideration of these or other factors. The compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof has low toxicity and can be used safely.
The daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, and the like.
-50 mg / person / day, preferably 0.01-20 mg /
Administered human / day and orally about 0.01-150m
g / person / day, preferably 0.1-100 mg / person / day.

[0092]

The present invention will be described in more detail with reference to the following Synthesis Examples, Examples, Formulation Examples and Experimental Examples, but the invention is not limited thereto. Raw Material Synthesis Example 1 Method of W. L. Bencze et al. [Journal of Medicinal Chemistry (J. Med. C
hem. ) Vol. 14, p. 40 (1971)].

A 300 ml acetic acid solution containing 20 g of α-tetralone and 10 g of sodium azide was added at 50 ° C. to 55 ° C.
30 ml of concentrated sulfuric acid was added dropwise at 0 ° C over 2 to 3 hours. After completion of the reaction, the mixture was treated with aqueous sodium carbonate solution, the reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate only) to give 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 1 .12 g was obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 2.12 (2H, dt, J = 6.6, 7.3H
z), 2.78 (2H, dd, J = 6.6, 7.3H)
z), 3.18-3.28 (2H, m), 7.13 (1
H, dd, J = 1.3, 7.3 Hz), 7.27-7.
40 (2H, m), 7.89-7.93 (1H, m)
9.36 (1H, m) This compound can also be obtained by reacting α-tetralone with hydroxylamine and subjecting the resulting oxime compound to a Beckmann rearrangement reaction. Raw Material Synthesis Example 2 220 ml of concentrated sulfuric acid was added dropwise at 50 ° C. to 55 ° C. over 2 to 3 hours to a 1000 ml acetic acid solution to which 135 g of chromanone and 77 g of sodium azide were added. After completion of the reaction, the mixture was treated with an aqueous sodium carbonate solution, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from toluene to obtain 123 g of 2,3-dihydro-4H-1,4-benzoxazepin-5-one.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 3.49 (2H, dd, J = 5.3, 9.5)
Hz), 4.39 (2H, dd, J = 5.6, 9.5H)
z), 7.00 (1H, dd, J = 1.3, 7.9H
z), 7, 13 (1H, ddd, J = 1.3, 7.9,
8.6 Hz), 7.42 (1H, ddd, J = 2.0,
7.9, 8.6 Hz), 7.95 (1H, dd, J =
2.0, 7.9 Hz), 8.09 (1H, br) Raw Material Synthesis Example 3 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 2
After adding 4.5 g of N-chlorosuccinimide to 50 ml of an N, N-dimethylformamide solution containing 5 g of 4-benzoxazepin-5-one, heating and stirring were performed at 80 ° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was washed with water, the organic layer was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to give 7-
5.0 g of chloro-2,3-dihydro-4H-1,4-benzoxazepin-5-one was obtained. Melting point 105-10
6 ° C. Raw Material Synthesis Example 4 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 2,
To 50 ml of a solution of 5 g of 4-benzoxazepin-5-one in N, N-dimethylformamide, 6.0 g of N-bromosuccinimide was added, and the mixture was heated with stirring at 80 ° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was washed with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to give 8-bromo-2,3.
-Dihydro-4H-1,4-benzoxazepine-5-
Ong 5.2 g was obtained. Melting point 101-103 ° C. Raw material synthesis example 5 2,3-dihydro-4H-1,4-obtained in raw material synthesis example 2 in a mixed solution of 10 ml of acetic acid and 10 ml of sulfuric acid under ice cooling.
After adding 3 g of benzoxazepin-5-one, 0.83 ml of fuming nitric acid was added dropwise, and after stirring for 30 minutes, the mixture was further stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to obtain 4.8 g of 2,3-dihydro-7-nitro-4H-1,4-benzoxazepin-5-one. Obtained. Melting point 210-212 [deg.] C. Raw material synthesis example 6 Method by H. Hofmann et al. [Liebigs. An.
n. Chem. ) Page 916 (1990)].

3.0 g of 2- (2,2-diethoxyethoxy) benzamide and 0.2 of p-toluenesulfonic acid
100 ml of a toluene solution containing 100 g of toluene at a solvent reflux temperature of 1
The mixture was heated and stirred for 2 hours. After completion of the reaction, the reaction solution was treated with saturated sodium hydrogen carbonate, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform only) to obtain 1.2 g of 1,4-benzoxazepin-5 (4H) -one. . Melting point 124-12
6 ° C. Raw material synthesis example 7 Thiochromanone 20 g and sodium azide 8.6 g
35 ml of concentrated sulfuric acid was added dropwise at 60 ° C. to 55 ° C. over a period of 2 to 3 hours to a 160 ml acetic acid solution containing After completion of the reaction, the mixture was treated with an aqueous sodium carbonate solution, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 2,3-dihydro-4H-1,4.
5.4 g of benzothiazepin-5-one were obtained. Melting point 1
87-188 ° C. Raw Material Synthesis Example 8 Method of B. Iddon et al. [Journal of Chemical Society Perkin Transactions I (JCS Perkin I) p. 180 (197)
8)] was synthesized.

To a 150 ml chloroform solution containing 24 g of (2-phenylethyl) amine and 20 g of triethylamine, 100 ml of a chloroform solution of ethyl chloroformate was added dropwise while stirring under ice cooling. After completion of dropping, the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, insoluble matter was filtered off, and the filtrate was distilled to obtain ethyl N- (2
27.5 g of -phenylethyl) carbamate was obtained. Boiling point 114 ° C. (0.6 mmHg) Next, 27.5 g of ethyl N- (2-phenylethyl) carbamate was added to polyphosphoric acid at 120 ° C., and the reaction solution was treated with water after heating and stirring for 1 hour. The organic layer was extracted with chloroform, washed with saturated sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was distilled to give 3,4-
11.2 g of dihydroisoquinolin-1-one was obtained. Boiling point 150 ° C. (0.4 mmHg) Raw Material Synthesis Example 9 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 2,
Under ice-cooling, 17.3 g of acetic anhydride and 133 g of aluminum chloride were added to 100 ml of a solution of 10 g of 4-benzoxazepin-5-one in dichloroethane, and the mixture was heated and stirred at room temperature for 1 hour and further at a solvent reflux temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice-cooled water, acidified with concentrated hydrochloric acid, the organic layer was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from isopropyl alcohol to give 1-acetyl-2,3-dihydro-4H-.
9.8 g of 1,4-benzoxazepin-5-one were obtained.

5.5 g of the above compound trifluoroacetic acid 1
21.3 ml of triethylsilane was added to the 00 ml solution,
Stir at room temperature for 1 hour. After the reaction was completed, the reaction solution was treated with an aqueous potassium carbonate solution, the organic layer was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate.
Next, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 2,3-dihydro-7-ethyl-4H. 4.5 g of -1,4-benzoxazepin-5-one was obtained.

¹ H-NMR; δ = 1.22 (t, 3
H), 2.65 (q, 2H), 3.41-3.50.
(M, 2H), 4.33 (s, 2H), 6.93 (d,
1H), 7.25 (dd, 1H), 7.76 (d, 1
H), 7.98-8.13 (br, 1H) Raw Material Synthesis Example 10 Chloropropionic acid 190 g, sodium hydrogencarbonate 14
Aqueous solution 60 of hydroquinone monomethyl ether 210 g and potassium hydroxide 120 g in 5 g of aqueous solution 600 ml.
0 ml was added, and the mixture was stirred at 85 to 95 ° C for 3 days. After completion of the reaction, the pH was adjusted to 5 with 10% hydrochloric acid, the organic layer was extracted with ethyl ether, and the aqueous layer was extracted with ethyl ether. Next, the ether layer was washed with 10% aqueous sodium hydrogen carbonate. When the washing solution was returned to pH 5 with 10% hydrochloric acid again, white crystals were obtained. This was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from benzene to give 3- (4-methoxyphenyl) propionic acid 5
6.7 g was obtained. Melting point 106-107 ° C. Next, with respect to 200 ml of acetic anhydride, 56.7 g of the above 3- (4-methoxyphenyl) propionic acid and 1 m of phosphoric acid
1 was added and the mixture was heated to reflux at 138 to 140 ° C. for 7 hours. After completion of the reaction, the reaction solution was treated with an aqueous potassium carbonate solution, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain 41 g of 6-methoxychromanone. Boiling point 65-75 / 0.14 mmHg The above 6-methoxychromanone 30 g and sodium azide 14.2 g are dissolved in glacial acetic acid 200 ml to 50-55.
While maintaining the temperature at 40 ° C., 40 ml of concentrated sulfuric acid was added dropwise over 1 to 2 hours. After the reaction was completed, the reaction solution was treated with an aqueous potassium carbonate solution, the organic layer was extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure and recrystallizing the obtained solid by toluene, 2,
19 g of 3-dihydro-7-methoxy-4H-1,4-benzoxazepin-5-one were obtained. Melting point 85 to 86 ° C. Raw material synthesis example 11 6,7-Dimethoxychromanone, sodium azide and concentrated sulfuric acid were used to carry out the same reaction and treatment as in raw material synthesis example 2 to give 2,3-dihydro-7,8. -Dimethoxy-4H-1,4-benzoxazepin-5-one is obtained. Raw Material Synthesis Example 12 2,3-Dihydro-7-methyl-4H-1, by performing the same reaction and treatment as in Raw Material Synthesis Example 2 using 7-methylchromanone, sodium azide and concentrated sulfuric acid.
4-Benzoxazepin-5-one is obtained. Starting Material Synthesis Example 13 2,3-Dihydro-7-methoxy-4 was obtained by performing the same reaction and treatment as in Starting Material Synthesis Example 2 using 7-methoxythiochromanone, sodium azide and concentrated sulfuric acid.
H-1,4-benzothiazepin-5-one is obtained. Raw Material Synthesis Example 14 Using 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one obtained in Raw Material Synthesis Example 1 and N-chlorosuccinimide, the same reaction as in Raw Material Synthesis Example 3 and By performing the treatment, 7-chloro-2,3,4,5-
Tetrahydro-1H-2-benzazepin-1-one is obtained. Raw Material Synthesis Example 15 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 7,
7-chloro-2,3-dihydro-4H was obtained by using 4-benzothiazepin-5-one and N-chlorosuccinimide to carry out the same reaction and treatment as in Raw Material Synthesis Example 3.
-1,4-Benzothiazepin-5-one is obtained. Starting Material Synthesis Example 16 By using 3,4-dihydroisoquinolin-1-one obtained in Starting Material Synthesis Example 8 and N-chlorosuccinimide to carry out the same reaction and treatment as in Starting Material Synthesis Example 3, 7-
Chloro-3,4-dihydroisoquinolin-1-one is obtained. Raw Material Synthesis Example 17 Using 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one obtained in Raw Material Synthesis Example 1 and N-bromosuccinimide, the same reaction and treatment as in Raw Material Synthesis Example 4 were performed. 8-bromo-2,3,4,5-
Tetrahydro-1H-2-benzazepin-1-one is obtained. Raw Material Synthesis Example 18 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 7,
7-Bromo-2,3-dihydro-4H was obtained by using 4-benzothiazepin-5-one and N-bromosuccinimide to carry out the same reaction and treatment as in Raw Material Synthesis Example 4.
-1,4-Benzothiazepin-5-one is obtained. Starting Material Synthesis Example 19 1,4-benzothiazepine-5 (4) was prepared by using 2- (2,2-diethoxyethylsulfanyl) benzamide and performing the same reaction and treatment as in Starting Material Synthesis Example 6.
H) -one is obtained. Raw Material Synthesis Example 20 Method of C. Corral et al. [J. Hete
rocyclic. Chem. ) Volume 99, page 99 (1
977)], 1-benzyl-2,3-dihydro-4H-1,4-benzodiazepin-5-one is obtained.

To 0.075 molar amount of aluminum chloride in 10 ml of benzene, 0.1 molar amount of methyl N-benzylanthranilate and 0.075 molar amount of aziridine were added, and the mixture was heated with stirring at 90 ° C. for 45 minutes, and then stirred. By adding the reaction solution to ice-cold water, 1-benzyl-2,3-
Crystals of dihydro-4H-1,4-benzodiazepin-5-one are obtained. Raw Material Synthesis Example 21 2,3-Dihydro-1-methyl-4H-1,4-benzodiazepine was obtained by performing the same reaction and treatment as in Raw Material Synthesis Example 20 using aluminum chloride, methyl N-methylanthranilate and aziridine. -5-one is obtained. Raw Material Synthesis Example 22 A 3 ml solution of 30 ml of toluene containing 0.97 g of 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one obtained in Raw Material Synthesis Example 1 and 1.33 g of Lawesson's reagent was added. The mixture was heated under reflux for 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to give 2,
1.1 g of 3,4,5-tetrahydro-1H-2-benzazepine-1-thione was obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 3.16 (2H, t, J = 5.9Hz), 3.
38 (2H, dd, J = 5.9, 6.6Hz), 7.3
9 (2H, m), 7.51 to 7.54 (1H, m),
7.67-7.71 (1H, m) 8.14 (1H, b
r) Raw Material Synthesis Example 23 2,3-dihydro-4H-1, obtained in Raw Material Synthesis Example 2,
4-benzoxazepin-5-one 44 g and Law
A 300 ml toluene solution containing 55 g of Esson reagent was heated under reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to give 2,3-dihydro-4H-1,4-benzoxazepine-5-thione 4
8 g were obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 3.50 (2H, dd, J = 5.9, 11.2)
Hz), 4.42 (2H, dd, J = 5.9, 11.2)
Hz), 7.04 (1H, dd, J = 1.3, 7.9H
z), 7.19 (1H, ddd, J = 1.3, 7.2,
8.4 Hz), 7.42 (1H, ddd, J = 2.0,
7.9, 8.4 Hz), 8.01 (1H, dd, J =
2.0, 7.2 Hz), 9.83 (1H, br) Raw material synthesis example 24 7-chloro-2,3-dihydro-4H-1,4-benzoxazepine-obtained in raw material synthesis example 3 A 50 ml toluene solution containing 5 g of 5-one and 5.3 g of Lawesson's reagent was heated under reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was recrystallized from toluene to obtain 7-chloro-2,3-dihydro-4H-1,4-benzoxazepine-5-thione (4.2 g). . Melting point 127-12
8 ° C. Raw Material Synthesis Example 25 7-Bromo-2,3-dihydro-4H-1,4-benzoxazepin-5-one 5.2 obtained in Raw Material Synthesis Example 4
g and Lawesson's reagent 4.5 g 50 m
The toluene solution was heated to reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous solution of sodium hydrogen carbonate, the organic layer was extracted with ethyl acetate, washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was recrystallized from toluene to give 7
There was obtained 4.8 g of -bromo-2,3-dihydro-4H-1,4-benzoxazepine-5-thione. Melting point 139-
141 ° C. Raw Material Synthesis Example 26 2,3-dihydro-7-nitro-4H-1,4-benzoxazepin-5-one 2.0 obtained in Raw Material Synthesis Example 5
30m with addition of 1.0 g and 1.0 g of Lawesson's reagent
The toluene solution was heated to reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous solution of sodium hydrogen carbonate, the organic layer was extracted with ethyl acetate, washed with saturated saline,
It was dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure and recrystallizing the obtained solid from toluene,
1.8 g of 2,3-dihydro-7-nitro-4H-1,4-benzoxazepine-5-thione was obtained. Melting point 231
Raw material synthesis example 27 1,4-benzoxazepine obtained in raw material synthesis example 6
5 (4H) -one 5 g and Lawesson's reagent 6.
A 60 ml toluene solution containing 5 g was heated to reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was recrystallized from toluene to give 1,4-benzoxazepine-5 (4
H) -Thion 3.4 g was obtained. Melting point 110-112 ° C. Raw material synthesis example 28 2,3-dihydro-4H-1, obtained in raw material synthesis example 7,
4-benzothiazepin-5-one 5.4 g and Law
A 120 ml toluene solution containing 6.7 g of Esson reagent was heated under reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was recrystallized from toluene to give 2,3-dihydro-4H-1,4-benzothiazepine-5-thione 3.8.
g was obtained. Melting point 142-145 ° C. Raw material synthesis example 29: 11.4-g of 3,4-dihydroisoquinolin-1-one obtained in raw material synthesis example 8 and Lawesson's reagent 17
A 200 ml toluene solution containing g was heated under reflux for 3 to 4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogen carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to obtain 10.4 g of 3,4-dihydroisoquinoline-1-thione. Melting point 95-98 ° C. Raw material synthesis example 30 2,3-dihydro-7-ethyl-4H-1,4-benzothiazepin-5-one 4.5 obtained in raw material synthesis example 9
g, Lawesson's reagent 4.8 g in toluene solution 50
The ml was heated and stirred at the solvent reflux temperature for 6 hours. After completion of the reaction, the reaction solution was treated with an aqueous potassium carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 2,3-dihydro-7-ethyl-4H-.
4.5 g of 1,4-benzothiazepine-5-thione was obtained. Melting point 81 to 82 ° C. Raw material synthesis example 31 2,3-dihydro-7-methoxy-4H-1,4-benzothiazepin-5-one obtained in raw material synthesis example 10.
9 g, 4.1 g of Lawesson's reagent in toluene 5
0 ml was heated with stirring at the solvent reflux temperature for 6 hours. After completion of the reaction, the reaction solution was treated with an aqueous potassium carbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and toluene was added to the resulting residue for crystallization, followed by recrystallization from toluene to give 2,3-dihydro-7-.
4.5 g of methoxy-4H-1,4-benzothiazepine-5-thione was obtained. Melting point 111-112 ° C Raw material synthesis example 32 2,3-dihydro-7,8-obtained in raw material synthesis example 11
Dimethoxy-4H-1,4-benzothiazepin-5-one and Lawesson's reagent were used to carry out the same reaction procedure as in Raw Material Synthesis Example 22, whereby 2,3-dihydro-7,
8-dimethoxy-4H-1,4-benzothiazepine-5
-Thion is obtained. Starting Material Synthesis Example 33 Using 2,3-dihydro-7-methyl-4H-1,4-benzoxazepin-5-one obtained in Starting Material Synthesis Example 12 and Lawesson's reagent, a reaction similar to Starting Material Synthesis Example 22 And by treating, 2,3-dihydro-7-methyl-4H-1,4-benzoxazepine-5
-Thion is obtained. Starting Material Synthesis Example 34 Using 2,3-dihydro-7-methoxy-4H-1,4-benzothiazepin-5-one obtained in Starting Material Synthesis Example 13 and Lawesson's reagent, the same reaction and treatment as in Starting Material Synthesis Example 22. By carrying out 2,3-dihydro-7-methoxy-4H-1,4-benzothiazepine-5
-Thion is obtained. Raw Material Synthesis Example 35 7-Chloro-2,3,4,5 obtained in Raw Material Synthesis Example 14
-Tetrahydro-1H-2-benzazepin-1-one and Lawesson's reagent were used to carry out the same reaction and treatment as in Raw Material Synthesis Example 22 to give 7-chloro-
2,3,4,5-Tetrahydro-1H-2-benzazepine-1-thione is obtained. Starting Material Synthesis Example 36 Using 7-chloro-2,3-dihydro-4H-1,4-benzothiazepin-5-one obtained in Starting Material Synthesis Example 15 and Lawesson's reagent, the same reaction and treatment as in Starting Material Synthesis Example 22. By carrying out 7-chloro-2,3
-Dihydro-4H-1,4-benzothiazepine-5-thione is obtained. Raw Material Synthesis Example 37 The 7-chloro-3,4-dihydroisoquinolin-1-one obtained in Raw Material Synthesis Example 16 and Lawesson's reagent were used to carry out the same reaction and treatment as in Raw Material Synthesis Example 22 to give 7-chloro. -3,4-Dihydroisoquinoline-1-thione is obtained. Raw Material Synthesis Example 38 7-Bromo-2,3,4,5 obtained in Raw Material Synthesis Example 17
-Tetrahydro-1H-2-benzazepin-1-one and Lawesson's reagent were used to carry out the same reaction and treatment as in Raw Material Synthesis Example 22 to give 7-bromo-
2,3,4,5-Tetrahydro-1H-2-benzazepine-1-thione is obtained. Starting Material Synthesis Example 39 Using 7-bromo-2,3-dihydro-4H-1,4-benzothiazepin-5-one obtained in Starting Material Synthesis Example 18 and Lawesson's reagent, the same reaction and treatment as in Starting Material Synthesis Example 22 were performed. By carrying out 7-bromo-2,3
-Dihydro-4H-1,4-benzothiazepine-5-thione is obtained. Raw Material Synthesis Example 40 1,4-benzothiazepine obtained in Raw Material Synthesis Example 19
By carrying out the same reaction and treatment as in Raw Material Synthesis Example 22 using 5-one and Lawesson's reagent, 1,
4-Benzothiazepine-5-thione is obtained. Raw Material Synthesis Example 41 1-Benzyl-2,3-dihydro-4H-1,4-benzodiazepin-5-one obtained in Raw Material Synthesis Example 20 and Lawesson reagent are used to carry out the same reaction and treatment as in Raw Material Synthesis Example 28. By this, 1-benzyl-
2,3-Dihydro-4H-1,4-benzodiazepine-
5-Thion is obtained. Raw Material Synthesis Example 42 The same reaction and treatment as in Raw Material Synthesis Example 22 are performed using 2,3-dihydro-1-methyl-4H-1,4-benzodiazepin-5-one obtained in Raw Material Synthesis Example 21 and Lawesson's reagent. Therefore, 2,3-dihydro-
1-Methyl-4H-1,4-benzodiazepine-5-thione is obtained. Starting Material Synthesis Example 43 After dissolving 1.1 g of 2,3,4,5-tetrahydro-1H-2-benzazepine-1-thione obtained in Starting Material Synthesis Example 22 in a mixed solvent consisting of 20 ml of water and 20 ml of tetrahydrofuran, , 0.7 g of potassium hydroxide and 1 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was added to the residue to give 4,5-dihydro-1 as crystals.
0.6 g of -methylthio-3H-2-benzazepine was obtained. Melting point 64 ° C. to 65 ° C. Raw material synthesis example 44 2,3-dihydro-4H- obtained in raw material synthesis example 23
After dissolving 48.0 g of 1,4-benzoxazepine-5-thione in a mixed solvent of 200 ml of water and 200 ml of tetrahydrofuran, 30 g of potassium hydroxide and 162 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform only) to give 2,3-dihydro-
5-methylthio-1,4-benzoxazepine 41.0
g was obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 2.58 (3H, s), 3.74 (2H, t,
J = 5.3 Hz), 4.54 (2H, t, J = 5.3H)
z), 7.03 (1H, dd, J = 1.3, 7.9H
z), 7.11 (1H, ddd, J = 2.0, 7.3
7.9 Hz), 7.37 (1H, ddd, J = 1.3,
7.3, 7.9 Hz), 7.57 (1H, dd, 2.
Raw Material Synthesis Example 45 4.0 g of 7-chloro-2,3-dihydro-4H-1,4-benzoxazepine-5-thione obtained in Raw Material Synthesis Example 24 was added to 40 ml of water and tetrahydrofuran. After dissolving in a mixed solvent consisting of 40 ml, potassium hydroxide 2.1
g and 2.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform only) to give 7-chloro-
44.2 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine was obtained. Starting Material Synthesis Example 46 4.8 g of 7-bromo-2,3-dihydro-4H-1,4-benzoxazepine-5-thione obtained in Starting Material Synthesis Example 25 was mixed with 50 ml of water and 50 ml of tetrahydrofuran. After dissolution, potassium hydroxide 2.1
g and 3 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform only) to give 7-bromo-2,
5.2 g of 3-dihydro-5-methylthio-1,4-benzoxazepine were obtained. Raw Material Synthesis Example 47 1.8 g of 2,3-dihydro-7-nitro-4H-1,4-benzoxazepine-5-thione obtained in Raw Material Synthesis Example 26 was mixed with 20 ml of water and 20 ml of tetrahydrofuran. After dissolution, potassium hydroxide 0.9
g and 0.55 ml of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform only) to give 2,3-
1.3 g of dihydro-7-nitro-5-methylthio-1,4-benzoxazepine was obtained. Starting Material Synthesis Example 48 After dissolving 3.2 g of 1,4-benzoxazepine-5 (4H) -thione obtained in Starting Material Synthesis Example 27 in a mixed solvent of 30 ml of water and 30 ml of tetrahydrofuran,
2.0 g of potassium hydroxide and 1.26 m of methyl iodide
1 was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform only) to obtain 2.8 g of 5-methylthio-1,4-benzoxazepine. Starting Material Synthesis Example 49 2,3-dihydro-4H-obtained in Starting Material Synthesis Example 28
3.8 g of 1,4-benzothiazepine-5-thione was added to 3 parts of water.
After dissolving in a mixed solvent of 0 ml and 30 ml of tetrahydrofuran, 2.1 g of potassium hydroxide and 3.4 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform only) to give 2.1 g of 2,3-dihydro-5-methylthio-1,4-benzothiazepine. Obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 2.49 (3H, s), 3.54 (2H, d
d, J = 5.3, 6.9 Hz), 3.69 (2H, d
d, J = 4.0, 6.9 Hz), 7.33-7.39
(3H, m), 7.52 (1H, dd, 7.3, 9.2
Hz) Raw material synthesis example 50 After dissolving 10.2 g of 3,4-dihydroisoquinoline-1-thione obtained in raw material synthesis example 29 in a mixed solvent consisting of 30 ml of water and 30 ml of tetrahydrofuran, 7 g of potassium hydroxide and iodide were dissolved. 14 g of methyl was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, the reaction solution is treated with water,
The organic layer was extracted with ethyl acetate, washed with saturated brine,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform only),
3,4-dihydro-1-methylthio-isoquinoline 9.
0 g was obtained.

¹ H-NMR (270 MHz, CDCl
₃ ) δ = 2.44 (3H, s), 2.73 (2H, t,
J = 7.3 Hz), 3.75 (2H, t, J = 7.3H)
z), 7.17 (1H, d, J = 7.3 Hz), 7.2
7-7.35 (2H, m), 7.64 (1H, dd,
1.3, 8.4 Hz) Raw material synthesis example 51 2,3-dihydro-7-ethyl-4H-1,4-benzothiazepine-5-thione obtained in raw material synthesis example 30.
5 g was dissolved in a mixed solvent consisting of 30 ml of water and 30 ml of tetrahydrofuran, 1.9 g of potassium hydroxide and 2.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform only) to give 2,3-dihydro-5-methylthio-1,4-benzoxazepine 3.5.
g was obtained. Starting Material Synthesis Example 52 3.7 g of 2,3-dihydro-7-methoxy-4H-1,4-benzoxazepine-5-thione obtained in Starting Material Synthesis Example 31 was added to a mixed solvent consisting of 30 ml of water and 30 ml of tetrahydrofuran. After dissolution, potassium hydroxide 1.9
g and 2.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform only) to give 2,3-dihydro-7-methoxy-5-methylthio-1,4-benzoxase. 1.72 g of pins were obtained. Melting point 46-48 [deg.] C. Raw material synthesis example 53 2,3-Dihydro-7,8- obtained in raw material synthesis example 32
Dimethoxy-4H-1,4-benzoxazepine-5-
2,3-dihydro-7,8-dimethoxy-5-methylthio-1,4-benzoxase was obtained by performing the same reaction and treatment as in Raw Material Synthesis Example 22 using thione, methyl iodide and potassium hydroxide. You get a pin. Starting Material Synthesis Example 54 Using 2,3-dihydro-7-methyl-4H-1,4-benzoxazepine-5-thione obtained in Starting Material Synthesis Example 33, methyl iodide, and potassium hydroxide, Starting Material Synthesis Example 22 By performing the same reaction and treatment as
-Dihydro-7-methyl-5-methylthio-1,4-benzoxazepine is obtained. Starting Material Synthesis Example 55 Using 2,3-dihydro-7-methoxy-4H-1,4-benzothiazepine-5-thione obtained in Starting Material Synthesis Example 34, methyl iodide, and potassium hydroxide, Starting Material Synthesis Example 22 and By performing the same reaction and treatment,
-Dihydro-7-methoxy-5-methylthio-1,4-
Benzothiazepine is obtained. Starting Material Synthesis Example 56 7-Chloro-2,3,4,5 obtained in Starting Material Synthesis Example 35
-By carrying out the same reaction and treatment as in Raw Material Synthesis Example 22 using tetrahydro-1H-2-benzazepine-1-thione, and methyl iodide and potassium hydroxide,
8-chloro-4,5-dihydro-1-methylthio-3H
-2-Benzazepine is obtained. Starting Material Synthesis Example 57 Using 7-chloro-2,3-dihydro-4H-1,4-benzothiazepine-5-thione obtained in Starting Material Synthesis Example 36, methyl iodide and potassium hydroxide, Starting Material Synthesis Example 2
By performing the same reaction and treatment as in 2, 7-chloro-2,3-dihydro-5-methylthio-1,4-benzothiazepine is obtained. Starting Material Synthesis Example 58 By performing the same reaction and treatment as in Starting Material Synthesis Example 22 using 7-chloro-3,4-dihydroisoquinoline-1-thione obtained in Starting Material Synthesis Example 37, methyl iodide and potassium hydroxide. , 7-Chloro-3,4-dihydro-1-methylthioisoquinoline is obtained. Starting Material Synthesis Example 59 8-Bromo-2,3,4,5 obtained in Starting Material Synthesis Example 38
-Tetrahydro-1H-2-benzazepine-1-thione, methyl iodide and potassium hydroxide were used to carry out the same reaction and treatment as in Raw Material Synthesis Example 22 to give 8
-Bromo-3,4-dihydro-1-methylthio-3H-
2-Benzazepine is obtained. Starting Material Synthesis Example 60 Using 7-bromo-2,3-dihydro-4H-1,4-benzothiazepine-5-thione obtained in Starting Material Synthesis Example 39, methyl iodide, and potassium hydroxide, Starting Material Synthesis Example 2
By performing the same reaction and treatment as in 2, 7-bromo-2,3-dihydro-5-methylthio-1,4-benzothiazepine is obtained. Starting Material Synthesis Example 61 4H-1,4-benzothiazepine-5-thione obtained in Starting Material Synthesis Example 40, methyl iodide, and potassium hydroxide were used to carry out the same reaction and treatment as in Starting Material Synthesis Example 22, 5-Methylthio-1,4-benzothiazepine is obtained. Starting Material Synthesis Example 62 1-Benzyl-2,3-dihydro-4H-1,4-benzodiazepine-5-thione obtained in Starting Material Synthesis Example 41, methyl iodide, and potassium hydroxide were used, and similar to Starting Material Synthesis Example 43. By carrying out the reaction and treatment, 1-benzyl-2,3-dihydro-5-methylthio-1,4-
Benzodiazepines are obtained. Starting Material Synthesis Example 63 Using 2,3-dihydro-1-methyl-4H-1,4-benzodiazepine-5-thione obtained in Starting Material Synthesis Example 42, methyl iodide, and potassium hydroxide, Starting Material Synthesis Example 4
By performing the same reaction and treatment as in 3,
Dihydro-1-methyl-5-methylthio-1,4-benzodiazepine is obtained.

The structural formulas of the compounds mentioned in the above-mentioned raw material synthesis examples are shown in the following [Chemical formula 39] to [Chemical formula 43].

[0107]

Embedded image

[0108]

Embedded image

[0109]

Embedded image

[0110]

Embedded image

[0111]

Embedded image

Example 1 10 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide 16 200 ml of butanol solution to which 0.4 g was added was heated and stirred at a reflux temperature for 3 to 4 hours. After the reaction,
The solvent was evaporated under reduced pressure, water and ethyl acetate were added to this, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The obtained residue is separated and purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give 3- (1- (tertiary butoxycarbonyl) piperidin-4-yl) -5,6-. Dihydro-
8.1 g of 1,2,4-triazolo [4,3-d] [1,4] benzoxazepine were obtained. Melting point 181-18
3 ° C.

8.1 g of the above compound was added to 80 ml of trifluoroacetic acid under ice cooling. After the reaction was completed, the reaction solution was treated with an aqueous potassium carbonate solution, and the organic layer was extracted with ethyl acetate,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and 10 ml of saturated hydrogen chloride-isopropyl alcohol was added to the obtained residue to give a solid. By recrystallizing this from methanol, 5,6-dihydro-3- (piperidin-4-yl) -1,2,4-
5.2 g of triazolo [4,3-d] [1,4] benzoxazepine dihydrochloride monohydrate was obtained. Melting point 293-2
95 ° C. Example 2 2,3-Dihydro-7-methoxy-5-methylthio-1,4-benzoxazepine and 1- (tertiary butoxycarbonyl) piperidine-4 obtained in Starting Material Synthesis Example 31
By performing the same reaction and treatment as in Example 1 using -carbohydrazide, 5,6-dihydro-10-methoxy-3- (piperidin-4-yl) -1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepine is obtained. Example 3 Reaction and treatment similar to Example 1 using 5-methylthio-1,4-benzoxazepine and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 48 By performing 3- (piperidin-4-yl) -triazolo [4,3-d]
[1,4] benzoxazepine is obtained. Example 4 Using 2,3-dihydro-5-methylthio-1,4-benzothiazepine and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 49, By performing the same reaction and treatment, 3- (piperidin-4-yl) -1,2,4-
Triazolo [4,3-d] [1,4] benzothiazepine is obtained. Example 5 2,3-Dihydro-10-methoxy-5-methylthio-1,4-benzothiazepine and 1- (tertiary butoxycarbonyl) piperidine-4 obtained in Starting Material Synthesis Example 55
By performing the same reaction and treatment as in Example 1 using -carbohydrazide, 5,6-dihydro-10-methoxy-3- (piperidin-4-yl) -1,2,4-
Triazolo [4,3-d] [1,4] benzothiazepine is obtained. Example 6 Using 5-methylthio-1,4-benzothiazepine and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 61, the same reaction and treatment as in Example 1 were carried out. By carrying out, 3- (piperidin-4-yl) -1,2,4-triazolo [4,
3-d] [1,4] benzothiazepine is obtained. Example 7 Using 1-methylthio-3,4-dihydroisoquinoline and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 50, the same reaction and treatment as in Example 1 are performed. By this, 5,6
-Dihydro-3- (piperidin-4-yl) -1,2,
4-Triazolo [4,3-a] isoquinoline is obtained. Example 8 1-Benzyl-2,3-dihydro-5-methylthio-1,4-benzodiazepine and 1- (tertiary butoxycarbonyl) piperidine-4-obtained in Starting Material Synthesis Example 62
By performing the same reaction and treatment as Example 1 using carbohydrazide, 7-benzyl-3- (piperidin-4-yl) -1,2,4-triazolo [4,3-
This gives d] [1,4] benzodiazepine. Example 9 Similar to Example 1 using 4,5-dihydro-1-methylthio-3H-2-benzazepine and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 43. By performing various reactions and treatments, 3- (piperidin-4-yl) -6,7-dihydro-5H-1,2,4-triazolo [3,4-a] is obtained.
[2] Benzazepine is obtained. Example 10 Using 7-chloro-2,3-dihydro-5-methylthio-1,4-benzothiazepine and 1- (tertiary butoxycarbonyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 57 By performing the same reaction and treatment as in Example 1, 10-chloro-5,6-dihydro-3- (piperidin-4-yl) -1,2,4-triazolo [4,3-d] [1 , 4] Benzothiazepine is obtained. Example 11 0.6 g of 4,5-dihydro-1-methylthio-3H-2-benzazepine obtained in Starting Material Synthesis Example 43 and 1-
(2- (4-chlorophenyl) ethyl) piperidine-4
-1.0 g of carbohydrazide in 1,3-dimethyl-2-
Add 100 ml of imidazolidinone to 3-4 at 280 ° C
Stirred for hours. The reaction mixture was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (chloroform:
By separating and purifying with methanol = 30: 1),
3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -6,7-dihydro-5H-1,
0.32 g of 2,4-triazolo [3,4-a] [2] benzazepine hemihydrate was obtained. Decomposition at 204 ° C. Example 12 2.4 g and 1 of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44
-(2- (4-chlorophenyl) ethyl) piperidine-
3.8 g of 4-carbohydrazide was added to 1,3-dimethyl-2.
-Add 100 ml of imidazolidinone to 2 at 280 ° C.
Stir for 3 hours. The reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (chloroform:
By separating and purifying with methanol = 30: 1),
3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4-
1.8 g of triazolo [4,3-d] [1,4] benzoxazepine were obtained. Melting point 198 [deg.] C. Example 13 2,3-Dihydro-5-methylthio-7-nitro-1,4-benzoxazepine 1.
3 g and 1- (2- (4-chlorophenyl) ethyl)
31.6 g of piperidine-4-carbohydrazide was added to 60 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C for 2 days. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 30: 1) to give 3- (1- (2- (4-chlorophenyl) ethyl) piperidine-. 4-yl) -5,6-dihydro-10-nitro-1,2,4-triazolo [4
1.1 g of 3-d] [1,4] benzoxazepine was obtained. Melting point 169 to 170 ° C. Example 14 1.2 g and 1 of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44
-(2- (4-trifluoromethylphenyl) ethyl)
2.5 g of piperidine-4-carbohydrazide was added to 1,3-
Add to 150 ml of dimethyl-2-imidazolidinone, 2
Stir at 80 ° C. for 2-3 hours. The reaction solution is treated with water,
The organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 30: 1) to give 5,6-dihydro-3- (1- (2-
(4-Trifluoromethylphenyl) ethyl) piperidin-4-yl) -1,2,4-triazolo [4,3-
1.0 g of d] [1,4] benzoxazepine was obtained. Melting point 215 to 217 ° C. Example 15 7-Chloro-2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 45
0 g and 1- (2- (4-chlorophenyl) ethyl)
2.4 g of piperidine-4-carbohydrazide was added to 50 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C for 2 days. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 20: 1) to give 10-chloro-3- (1- (2-
0.7 g of (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4-triazolo [4,3-d] [1,4] benzoxazepine
I got Melting point 182-184 [deg.] C. Example 16 7-Bromo-2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 2.
0 g and 1- (2- (4-chlorophenyl) ethyl)
2.0 g of piperidine-4-carbohydrazide was added to 50 ml of n-butanol, and the mixture was refluxed at reflux temperature for 2 days. The solvent was evaporated under reduced pressure, water and ethyl acetate were added, the organic layer was separated and extracted, washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 10
-Bromo-3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-
0.8 g of 1,2,4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 190-192 ° C. Example 17 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44 and 2- (N-benzyl-N-methylamino) 0.62 g of ethyl carbohydrazide was added to 10 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C for 24 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the obtained residue,
The organic layer was separated and extracted, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 20: 1), and an isopropyl alcohol solution containing 73 mg of oxalic acid was added to the eluent to obtain a solid. . By recrystallizing this from methanol, 3- (2- (N-benzyl-N-methylamino) ethyl) -5,6-dihydro-1,2,4-
0.17 g of triazolo [4,3-d] [1,4] benzoxazepine-3 / 2 oxalate was obtained. Melting point 183 ° C. Example 18 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44 and 2- (4- (4-chlorophenyl) piperazine-1- 0.85 g of (yl) ethyl carbohydrazide was added to 10 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C. for 24 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a solid, which was recrystallized from isopropyl alcohol to give 3- (2- (4- (4-
Chlorophenyl) piperazin-1-yl) ethyl)-
5,6-Dihydro-1,2,4-triazolo [4,3-
0.38 g of d] [1,4] benzoxazepine was obtained.
Melting point 230 ° C. Example 19 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 2- (N- (2-phenylethyl) -N- 0.67 g of methylamino) ethyl carbohydrazide was added to 10 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C for 24 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was separated and purified by silica gel chromatography (chloroform only), and an isopropyl alcohol solution containing 0.10 g of oxalic acid was added to the eluent to obtain a solid. By recrystallizing this from ethanol, 5,6-dihydro-3- (2- (N- (2
-Phenylethyl) -N-methylamino) ethyl)-
0.13 g of 1,2,4-triazolo [4,3-d] [1,4] benzoxazepine monooxalate was obtained. Melting point 183 ° C. Example 20 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44 and 3- (N-benzyl-N-methylamino) propylcarbo 0.67 g of hydrazide was added to n-ethylene glycol 10
It was added to the mixture and stirred at 180 ° C. for 24 hours. The reaction solution was treated with water, the organic layer was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was separated and purified by silica gel chromatography (chloroform only), and an isopropyl alcohol solution containing 0.21 g of oxalic acid was added to the eluent to obtain a solid. By recrystallizing this from ethanol, 3- (3- (N-benzyl-N
-Methylamino) propyl) -5,6-dihydro-1,
0.10 g of 2,4-triazolo [4,3-d] [1,4] benzoxazepine dioxalate was obtained. Melting point 19
4 ° C. Example 21 2.3 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 2
4.4 g of-(4- (3-chlorophenyl) piperazin-1-yl) ethylcarbohydrazide was added to 60 ml of 1,3-dimethyl-2-imidazolidinone and stirred at 280 ° C for 2-3 hours. The reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 20: 1) to give 3- (2- (4- (3-chlorophenyl) piperazine-1-. Yl) ethyl) -5,6-dihydro-1,2,
0.13 g of 4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 167-168 ° C. Example 22 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 3- (4- (4-chlorophenyl) piperazine- 0.89 g of 1-yl) propyl carbohydrazide was added to 10 ml of n-butanol, and the mixture was stirred at 120 to 130 ° C for 24 hours. The reaction solution was treated with water, the organic layer was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gives a solid,
By recrystallizing this from isopropyl alcohol, 3- (3- (4- (4-chlorophenyl) piperazin-1-yl) propyl) -5,6-dihydro-1,
0.35 g of 2,4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 183 ° C. Example 23 0.58 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 4- (4-chlorophenyl) piperazin-1-ylmethylcarbo Hydrazide 0.81g was added to n-butanol 15m.
In addition to 1, the mixture was stirred at 120 to 130 ° C for 24 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 3- (4- (4-chlorophenyl) piperazin-1-yl) methyl. -5,6-dihydro-1,2,
0.24 g of 4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 200 ° C. Example 24 2.8 g of 5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 48 and 1- (2- (4-chlorophenyl) ethyl) piperidine-4-carbohydrazide 0 g was added to 50 ml of n-butanol, and the mixture was stirred at reflux temperature for 2 days. The solvent was evaporated under reduced pressure, water and ethyl acetate were added, and the organic layer was separated and extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was chromatographed on silica gel (chloroform: methanol = 3).
By separating and purifying at 0: 1, 3- (1- (2
-(4-chlorophenyl) ethyl) piperidin-4-yl) -1,2,4-triazolo [4,3-d] [1,
4] 0.42 g of benzoxazepine was obtained. Melting point 207
˜209 ° C. Example 25 1.9 g of 2,3-dihydro-5-methylthio-1,4-benzothiazepine obtained in Raw Material Synthesis Example 49 and 1-
(2- (4-chlorophenyl) ethyl) piperidine-4
-3.0 g of carbohydrazide in 1,3-dimethyl-2-
It was added to 80 ml of imidazolidinone and stirred at 280 ° C. for 2 to 3 hours. The reaction solution was treated with water, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform: methanol = 20: 1) to give 3-
(1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4-triazolo [4,3-d] [1,4] benzothiazepine 0.
36 g were obtained. Melting point 204-206 [deg.] C. Example 26 7-Chloro-2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 45
0 g and 1- (2- (4-trifluoromethylphenyl) ethyl) piperidine-4-carbohydrazide 2.4
g to 50 ml of n-butanol, 120-130 ° C
And stirred for 2 days. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated and extracted, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (chloroform: methanol = 20:
By separating and purifying in 1), 10-chloro-5,
6-dihydro-3- (1- (2- (4-trifluoromethylphenyl) ethyl) piperidin-4-yl) -1,
0.54 g of 2,4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 215-217 [deg.] C. Example 27 1.3 g of 3,4-dihydro-1-methylthioisoquinoline and 2.2 g of 1- (2- (4-chlorophenyl) ethyl) piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 50 were added to 1,3 -Add to 80 ml of dimethyl-2-imidazolidinone and stir at 280 ° C for 2-3 hours. The reaction solution is treated with water, the organic layer is extracted with ethyl acetate,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained solid was recrystallized from toluene to give 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-.
0.6 g of dihydro-1,2,4-triazolo [4,3-a] isoquinoline.3 / 2 hydrate was obtained. Melting point 194-
195 ° C. Example 28 0.64 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 1- (2- (4-bromophenyl) ethyl) piperidine-4- Carbohydrazide 0.98 g was added to n-butanol 2
0 ml was added, and the mixture was heated with stirring at reflux temperature for 2 days. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (chloroform: methanol = 20: 1) to give 3- (1- (2- (4-bromophenyl) ethyl) piperidine-4-. Yl) -5,6-dihydro-
0.45 g of 1,2,4-triazolo [4,3-d] [1,4] benzoxazepine was obtained. Melting point 194-196
C. Example 29 30 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Raw Material Synthesis Example 44 and 22.7 g of ethoxycarbonylmethylcarbohydrazide were added to 300 ml of a toluene solution, and the mixture was refluxed at the reflux temperature. The mixture was heated and stirred for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 10: 1) (5,6-dihydro-1,2,4-triazolo). [4
18 g of ethyl ester of 3-d] [1,4] benzoxazepin-3-yl) acetic acid was obtained.

[0114] ¹ H-NMR: 1.25-1.72 (m,
2H), 1.88-2.00 (m, 2H), 2.64-
2.81 (m, 2H), 3.28 (dt, 1H), 4.
05 (s, 2H), 4.38-5.54 (m, 5H),
4.66-4.73 (m, 1H), 7.03-7.37
(M, 8H), 8.66 (dd, 1H) 10 g of the above compound was added with 1.5N sodium hydroxide aqueous solution.
50 ml was added, and the mixture was heated with stirring at 85 ° C. for 1 to 2 hours. Anti
After completion of the reaction, hydrochloric acid was added to the reaction solution to adjust the pH to 2, and the aqueous layer was
By filtering (5,6-dihydro-1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepi
7.3 g of N-3-yl) acetic acid was obtained. Melting point 215-21
7 ° C. Then, the obtained (5,6-dihydro-1,2,4-tri
Azolo [4,3-d] [1,4] benzoxazepine-
3-yl) acetic acid 1.0 g, 4-phenylpiperidine 0.
59 g and 1.15 ml triethylamine are added to dimethyl
Add 10 ml of formamide and add cyanophosphonic acid under ice cooling.
Add 0.15 ml of diethyl and stir at room temperature for 1 hour.
did. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a solid.
By recrystallizing from acetonitrile,
Doro-3- (2-oxo-2- (4-phenylpiperidi
N-1-yl) ethyl) -1,2,4-triazolo
0.5 g of [4,3-d] [1,4] benzoxazepine
I got Melting point 215-216 [deg.] C. Example 30 5,6-dihydro-3- (piperidi obtained in Example 1
N-4-yl) -1,2,4-triazolo [4,3-
d] [1,4] benzoxazepine and 2- (3-cu
Lolopropyl) -2- (4-fluorophenyl)-
[1,3] Dioxolane 0.71 g and potassium carbonate
Add 2.0 g to 30 ml of dimethylformamide and add 70
The mixture was heated and stirred at ℃ for 2-3 hours. After the reaction is completed, the reaction solution is
The organic layer was extracted with ethyl acetate and dissolved under reduced pressure.
The medium was distilled off, and the resulting residue was diluted with 2N hydrogen chloride-ethanol.
Solution (20 ml) was added and the mixture was heated with stirring for 3 hours. End of reaction
After that, the reaction solution is treated with an aqueous potassium carbonate solution to separate the organic layer.
Extract with chloroform, wash with saturated saline, then dry.
It was dried over magnesium sulfate. Next, the solvent is distilled off under reduced pressure.
The residue obtained was removed and the resulting residue was subjected to silica gel column chromatography.
Separation (chloroform: methanol = 10: 1)
By purifying, 3- (1- (4- (4-fluorophenyl)
Phenyl) -4-oxobutyl) piperidin-4-yl)
-5,6-Dihydro-1,2,4-triazolo [4,3
0.35 g of -d] [1,4] benzoxazepine
Was. Mp 161-162 [deg.] C Example 31 5,6-dihydro-3- (piperidyi obtained in Example 1
N-4-yl) -1,2,4-triazolo [4,3-
d] [1,4] benzoxazepine 0.75 g, Trier
0.92 g of tylamine and (naphthalen-1-yl)
30 ml of dimethylformamide solution containing 0.41 acetic acid
In contrast, 0.4 ml of diethyl cyanophosphonate under ice cooling
In addition, the mixture was further stirred at room temperature for 1 hour. End of reaction
After that, the solvent was distilled off under reduced pressure, and the resulting residue was treated with tetrahydro
In addition to 30 ml of furan, lithium aluminum hydride under ice cooling
After adding 0.25g of Um, stir for 30 minutes at 50 ° C
Was. After the reaction is complete, the reaction solution is saturated with aqueous sodium sulfate solution.
The solid that precipitates is filtered and filtered with hot isopropyl alcohol.
After washing with coal, the filtrate and washing solution are combined and concentrated under reduced pressure.
Was. The obtained residue is subjected to silica gel column chromatography.
-(Chloroform: methanol = 10: 1)
5,6-dihydro-3- (1- (2-
(1-Naphthyl) ethyl) piperidin-4-yl)-
1,2,4-triazolo [4,3-d] [1,4] ben
0.26 g of zoxazepine was obtained. Melting point 159-161
C. Example 32 The 5,6-dihydro-3- (piperidi obtained in Example 1
N-4-yl) -1,2,4-triazolo [4,3-
d] [1,4] benzoxazepine 0.75 g, Trier
0.92 g of tylamine and (naphthalen-2-yl)
Acetic acid 0.41 was added to 30 ml of dimethylformamide.
0.4 ml of diethyl cyanophosphonate under ice cooling
In addition, the mixture was further stirred at room temperature for 1 hour. End of reaction
After that, the solvent was distilled off under reduced pressure, and the resulting residue was treated with tetrahydro
Add 30 ml of furan and add lithium aluminum hydride under ice cooling.
After adding 0.25 g of sodium, the mixture was stirred at 50 ° C. for 30 minutes.
After the reaction is completed, the reaction solution is treated with saturated aqueous sodium sulfate solution.
The precipitated solid is filtered off and filtered with hot isopropyl alcohol.
After washing with water, the filtrate and washing solution are combined and concentrated under reduced pressure.
Was. The obtained residue is subjected to silica gel column chromatography.
-(Chloroform: methanol = 10: 1)
5,6-dihydro-3- (1- (2-
(2-Naphthyl) ethyl) piperidin-4-yl)-
1,2,4-triazolo [4,3-d] [1,4] ben
0.05 g of oxoxazepine was obtained. Melting point 226-228
C. Example 33 2,3-dihydro-7-ethyi obtained in Raw Material Synthesis Example 51
Lu-5-methylthio-1,2,4-triazolo [4,3
-D] [1,4] benzoxazepine 0.8 g and 2-
(4- (4-chlorophenyl) piperazin-1-yl)
1.1 g of ethyl carbohydrazide was added to n-butanol 30.
The mixture was added to the reaction mixture in ml and heated and stirred at reflux temperature for 2 days. End of reaction
After that, 1N hydrogen chloride-isopropyl alcohol was added to the obtained residue.
Cole solution was added to crystallize, and isopropyl alcohol was added.
-3 by recrystallizing with a toluene (5: 1) solution
-(2- (4- (4-chlorophenyl) piperazine-1
-Yl) ethyl) -5,6-dihydro-10-ethyl-
1,2,4-triazolo [4,3-d] [1,4] ben
0.73 g of zoxazepine dihydrochloride monohydrate was obtained.
Melting point 189-190 [deg.] C. Example 34 2,3-dihydro-7-ethyl obtained in Raw Material Synthesis Example 51
Lu-5-methylthio-1,2,4-triazolo [4,3
-D] [1,4] benzoxazepine 0.8 g and 1
-(2- (4-bromophenyl) ethyl) piperidine-
1.1 g of 4-carbohydrazide was added to 30 m of n-butanol.
1 and the mixture was heated and stirred at reflux temperature for 2 days. End of reaction
After that, the solvent was distilled off under reduced pressure and the obtained solid was washed with ethanol.
3-by recrystallizing with a ruene (3: 1) solution
(1- (4-Bromophenyl) ethyl) piperidine-4
-Yl) -5,6-dihydro-10-ethyl-1,2,
4-triazolo [4,3-d] [1,4] benzoxa
0.51 g of zepine 1/5 hydrate was obtained. Melting point 170-
171 ° C. Example 35 2,3-Dihydro-7-ethyl obtained in Raw Material Synthesis Example 51
Lu-5-methylthio-1,2,4-triazolo [4,3
-D] [1,4] benzoxazepine 0.8 g and 3
-(4- (4-chlorophenyl) piperazine-1-i
) Propylcarbohydrazide 1.1. g for n-butano
The mixture was heated and stirred at reflux temperature for 2 days. End of reaction
After that, the solvent was distilled off under reduced pressure and the resulting residue was washed with silica gel.
Separation and purification by column chromatography, and 1N salt
Add acid-ethanol solution and crystallize, then add to ethanol.
By recrystallization from 3- (3- (4- (4-chloro)
Phenyl) piperazin-1-yl) propyl) -5,6
-Dihydro-10-ethyl-1,2,4-triazolo
[4,3-d] [1,4] benzoxazepine dihydrochloride
0.73 g of salt monohydrate was obtained. Melting point 263-265 ° C. Example 36 20 g of β-propiolactone, hydrazine monohydrate 1
Add 00 ml to 200 ml of ethanol and heat and stir for 6 hours.
Stirred. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained residue
By adding toluene to the residue and crystallizing it, 2-hydro
27 g of xyethyl carbohydrazide was obtained. The above compound
10.4 g and 2,3-dihydride obtained in Raw Material Synthesis Example 44
Ro-5-methylthio-1,4-benzoxazepine 1
Add 9.3 g to 300 ml of isopropyl alcohol,
The mixture was heated and stirred at reflux temperature for 24 hours. After reaction, under reduced pressure
The solvent was distilled off and the resulting residue was subjected to silica gel column chromatography.
For graphography (chloroform: methanol = 15: 1)
2- (5,6-dihydro-1,
2,4-triazolo [4,3-d] [1,4] benzoo
11.3 g of xazepin-3-yl) ethanol was obtained.
Mp 137-138 [deg.] C. Further, 7.8 g of the above compound and 9.4 m of triethylamine.
l was added to 200 ml of dichloromethane and cooled with ice.
5.2 ml of lower mesyl chloride was added. After dropping,
Furthermore, it stirred at room temperature for 4 hours. After completion of the reaction
The solution is treated with aqueous sodium hydrogen carbonate solution and the organic layer is washed.
Extract with loroform, wash with saturated saline, and dry with anhydrous sulfur.
It was dried with magnesium acid. Next, the solvent is distilled off under reduced pressure.
Silica gel column chromatography.
-(Chloroform: methanol = 30: 1)
Methanesulfonic acid 2- (5,6-dihydride)
B-1,2,4-triazolo [4,3-d] [1,4]
Benzoxazepin-3-yl) ethyl ester 6.5
g was obtained. Melting point 141-142 ° C The above methanesulfonic acid 2- (5,6-dihydro-
1,2,4-triazolo [4,3-d] [1,4] ben
0.7 g of oxoxazepin-3-yl) ethyl ester,
2- (piperazin-1-yl) pyrimidine dihydrochloride
1.0 g, potassium carbonate 2 g and potassium iodide 1 g
Was added to 20 ml of dimethylformamide, and the mixture was heated at 70 ° C for 2 to
The mixture was heated and stirred for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure.
Aqueous potassium carbonate solution was added to the obtained residue, and chloroform was added.
Extract the organic layer with water, wash with water, and then dry magnesium sulfate.
And dried. Next, the solvent was distilled off under reduced pressure, and the obtained residue
The residue is purified by silica gel column chromatography (chloroform).
(Methanol: methanol = 20: 1)
5,6-dihydro-3- (2- (4- (2-pyrimidi
Nyl) piperazin-1-yl) ethyl) -1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepi
0.14 g was obtained. Melting point 238-239 [deg.] C. Example 37 Methanesulfonic acid.2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 4- (3-trifluoromethylpheny
Le) Piperazine ・ 1 oxalate 1.0 g, carbonate
2 g of lithium and 1 g of potassium iodide were added to dimethylform
Add to 20 ml of amide and heat with stirring at 70 ° C for 2-3 hours.
Was. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was charcoalized.
Aqueous potassium acid solution was added, and the organic layer was extracted with chloroform.
The product was taken out, washed with water and dried over anhydrous magnesium sulfate. Next
The solvent was distilled off under reduced pressure, and the resulting residue was washed with silica gel.
Rum chromagraphy (chloroform: methanol =
By separating and purifying at 20: 1) 5,6-dihydride
Ro-3- (2- (4- (3-trifluoromethylphenyl)
Ru) piperazin-1-yl) ethyl) -1,2,4-to
Liazolo [4,3-d] [1,4] benzoxazepine
0.14 g was obtained. Melting point 167-168 [deg.] C. Example 38 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 4-benzhydrylpiperazine 0.5
g, potassium carbonate 1 g, dimethylformamide 20 ml
In addition, the mixture was heated and stirred at 70 ° C. for 2 to 3 hours. End of reaction
After that, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with aqueous potassium carbonate.
Add the solution, extract the organic layer with chloroform, and wash with water.
After that, it was dried over anhydrous magnesium sulfate. Next, under reduced pressure
The solvent was distilled off, and isopropyl ether was added for crystallization.
And then recrystallized with isopropyl alcohol.
3- (2- (4-benzhydrylpiperazine-1-i
Ru) ethyl) -5,6-dihydro-1,2,4-tria
Zolo [4,3-d] [1,4] benzoxazepine 0.
13 g were obtained. Melting point 188-189 [deg.] C. Example 39 Methanesulfonic acid.2- (5,6) obtained in Example 36.
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Ter 0.7 g, 6-fluoro-3- (piperidine-4-
Ile) benzo [d] isoxazole monohydrochloride 0.5 g
And 1 g of potassium carbonate to 20 m of dimethylformamide
In addition to 1, the mixture was heated and stirred at 70 ° C. for 2 to 3 hours. End of reaction
After that, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with aqueous potassium carbonate.
Add the solution, extract the organic layer with chloroform, and wash with water.
After that, it was dried over anhydrous magnesium sulfate. Solvent under reduced pressure
Distill off and add isopropyl ether to the residue.
After crystallizing, recrystallize with isopropyl alcohol
Thereby 3- (2- (4- (6-fluoro-benzo
[D] Isoxazol-3-yl) piperidin-1-y
Ru) ethyl) -5,6-dihydro-1,2,4-tria
Zolo [4,3-d] [1,4] benzoxazepine 0.
12 g were obtained. Melting point 212-214 ° C. Example 40 Methanesulfonic acid.2- (5,6-
Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 4- (4-methoxyphenyl) piperazi
Dimethyl succinate 0.6g and potassium carbonate 1g
Add to 20 ml of chillformamide, at 70 ° C for 2-3 hours
The mixture was heated and stirred. After the reaction was completed, the solvent was distilled off under reduced pressure.
Aqueous potassium carbonate solution was added to the residue, and chloroform was added.
Extract the organic layer, wash with water, and dry over anhydrous magnesium sulfate.
Dried. The solvent was distilled off under reduced pressure, and the resulting residue
After adding pill ether and crystallizing, isopropyl alcohol was added.
5, by recrystallizing with Cole-methanol solution
6-dihydro-3- (2- (4- (4-methoxyphenyl)
Ru) piperazin-1-yl) ethyl) -1,2,4-to
Liazolo [4,3-d] [1,4] benzoxazepine
0.3 g was obtained. Melting point 218 to 219 [deg.] C. Example 41 Methanesulfonic acid.2- (5,6) obtained in Example 36.
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tellurium 0.7g, 4-phenylpiperazine 0.3g, carbonic acid
Add 1 g of potassium to 20 ml of dimethylformamide,
The mixture was heated and stirred at 70 ° C for 2 to 3 hours. After completion of the reaction,
An aqueous solution of potassium carbonate was added to the residue obtained by evaporation under reduced pressure.
Then, extract the organic layer with chloroform, wash it with water, and
It was dried with magnesium acid. The solvent was distilled off under reduced pressure to obtain
Crystallization was performed by adding isopropyl ether to the obtained residue.
After that, by recrystallizing with isopropyl alcohol
5,6-dihydro-3- (2- (4-phenylpiperazyl
N-1-yl) ethyl) -1,2,4-triazolo
0.2 g of [4,3-d] [1,4] benzoxazepine
I got Melting point 197-199 [deg.] C. Example 42 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 4- (2-methoxyphenyl) piperazi
0.4g, potassium carbonate 1g, dimethylformamide
20 ml was added, and the mixture was heated with stirring at 70 ° C. for 2 to 3 hours. Anti
After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was washed with potassium carbonate.
An aqueous solution of um was added, and the organic layer was extracted with chloroform,
After washing with water, it was dried over anhydrous magnesium sulfate. Then decrease
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography.
Chromatography (chloroform: methanol = 20:
By separating and purifying in 1), 5,6-dihydro-3
-(2- (4- (2-methoxyphenyl) piperazine-
1-yl) ethyl) -1,2,4-triazolo [4,3
0.2 g of -d] [1,4] benzoxazepine was obtained.
Melting point 120-121 ° C Example 43 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Ter 0.7 g, 4-benzylpiperazine 0.5 g, carbonic acid
Add 1 g of potassium to 20 ml of dimethylformamide,
The mixture was heated and stirred at 70 ° C for 2 to 3 hours. After completion of the reaction,
An aqueous solution of potassium carbonate was added to the residue obtained by evaporation under reduced pressure.
Then, extract the organic layer with chloroform, wash it with water, and
It was dried with magnesium acid. Next, the solvent is distilled off under reduced pressure.
And crystallize by adding isopropyl ether to the obtained residue.
Then, in isopropyl alcohol-methanol solution
5,6-dihydro-3- (2-
(4-benzylpiperazin-1-yl) ethyl) -1,
2,4-triazolo [4,3-d] [1,4] benzoo
0.4 g of xazepine was obtained. Melting point 149-150 ° C Example 44 Methanesulfonic acid.2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 1-phenyl-1,3,8-triazas
Pyro [4,5] decan-4-one 0.5 g, potassium carbonate
1g of dimethylformamide to 20ml of dimethylformamide,
The mixture was heated and stirred for 2-3 hours. After the reaction is completed, the solvent is removed under reduced pressure.
An aqueous solution of potassium carbonate was added to the residue obtained by evaporation, and
Extract the organic layer with Loform, wash with water, and then use anhydrous magnesium sulfate.
Dried with sium. Next, the solvent was distilled off under reduced pressure to obtain
The residue thus obtained was crystallized by adding isopropyl ether.
After that, reconstitute with isopropyl alcohol-methanol solution
By crystallization, 5,6-dihydro-3- (2- (4-
Oxo-1-phenyl-1,3,8-triazaspiro
[4,5] Decan-8-yl) ethyl) -1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepi
Thus, 0.48 g of hemihydrate was obtained. Melting point 149-15
0 ° C. Example 45 Methanesulfonic acid.2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.6 g, 4- (4-fluorophenyl) piperazi
Dimethylform containing 0.4 g of potassium carbonate and 1.0 g of potassium carbonate
20 ml of the muamide solution was heated and stirred at 70 ° C for 2 to 3 hours.
Was. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was charcoalized.
Aqueous potassium acid solution was added, and the organic layer was extracted with chloroform.
The product was taken out, washed with water and dried over anhydrous magnesium sulfate. Next
Then, the solvent was distilled off under reduced pressure, and the resulting residue was washed with isopropyl.
After crystallization by adding ether, isopropyl alcohol
3- (2-
(4- (4-fluorophenyl) piperazine-1-i
Ru) ethyl) -5,6-dihydro-1,2,4-tria
Zolo [4,3-d] [1,4] benzoxazepine 0.
4 g were obtained. Melting point 149-150 [deg.] C. Example 46 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Ter 0.7 g, 1- (piperidin-4-yl) -1,3
-Dihydrobenzimidazol-2-one 0.4 g, charcoal
Add 1 g of potassium acid to 20 ml of dimethylformamide.
Then, the mixture was heated and stirred at 70 ° C. for 2 to 3 hours. After the reaction is complete, melt
The medium was evaporated under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue.
In addition, the organic layer was extracted with chloroform, washed with water and then dried.
It was dried over magnesium sulfate. Next, the solvent is distilled off under reduced pressure.
Then, 1N hydrogen chloride-isopropyl acetate was added to the obtained residue.
After adding 0.7 ml of lucol for crystallization, methanol was added.
By recrystallizing in 3- (2- (4- (2-
So-1,3-dihydrobenzimidazol-1-yl)
Piperidin-1-yl) ethyl) -5,6-dihydro-
1,2,4-triazolo [4,3-d] [1,4] ben
0.17 g of zoxazepine dihydrochloride was obtained. Melting point 26
0-262 ° C Example 47 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Ter 0.7 g, 4-phenylpiperidine 0.3 g, carbonic acid
Add 1 g of potassium to 20 ml of dimethylformamide,
The mixture was heated and stirred at 70 ° C for 2 to 3 hours. After completion of the reaction,
An aqueous solution of potassium carbonate was added to the residue obtained by evaporation under reduced pressure.
Then, extract the organic layer with chloroform, wash it with water, and
It was dried with magnesium acid. Next, the solvent is distilled off under reduced pressure.
And crystallize by adding isopropyl ether to the obtained residue.
And recrystallize with isopropyl alcohol
From 5,6-dihydro-3- (2- (4-phenylperylene)
Zin-1-yl) ethyl) -1,2,4-triazolo
0.3 g of [4,3-d] [1,4] benzoxazepine
I got Melting point 193-195 [deg.] C. Example 48 Methanesulfonic acid 2- (5,6) obtained in Example 36
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepin-3-yl) ethyl s
Tell 0.7 g, 4- (2,3-dichlorophenyl) pipe
0.45 g of radine and 1 g of potassium carbonate are added to dimethylform
Add to 20 ml of amide and heat with stirring at 70 ° C for 2-3 hours.
Was. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was charcoalized.
Aqueous potassium acid solution was added, and the organic layer was extracted with chloroform.
The product was taken out, washed with water and dried over anhydrous magnesium sulfate. Next
Then, the solvent was distilled off under reduced pressure, and the resulting residue was washed with isopropyl.
Crystallize by adding ether and recrystallize with toluene
As a result, 3- (2- (4- (2,3-dichlorophenyl)
Le) Piperazin-1-yl) ethyl) -5,6-dihydride
B-1,2,4-triazolo [4,3-d] [1,4]
0.07 g of benzoxazepine was obtained. Melting point 234-2
35 ° C. Example 49 2,3-Dihydro-7-ethyi obtained in Raw Material Synthesis Example 51
Lu-5-methylthio-1,2,4-triazolo [4,3
-D] [1,4] benzoxazepine 0.8 g, 1-
(2- (4-chlorophenyl) ethyl) piperidine-4
-1.1 g of carbohydrazide and 50 ml of n-butanol
In addition, the mixture was heated and stirred at reflux temperature for 2 days. After the reaction,
The solvent was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column.
Chromatography (chloroform: methanol = 2)
3- (1- (2-
(4-Chlorophenyl) ethyl) piperidine-4-i
) -5,6-Dihydro-10-ethyl-1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepi
0.34 g was obtained. Melting point 177 to 178 [deg.] C. Example 50 2,3-Dihydro-7-metho obtained in Raw Material Synthesis Example 52
Xy-5-methylthio-1,2,4-triazolo [4,
3-d] [1,4] benzoxazepine 0.8 g, 1-
(2- (4-chlorophenyl) ethyl) piperidine-4
-1.1 g of carbohydrazide in 1,3-dimethyl-2-
In addition to 30 ml of imidazolidinone, at 220-230 ℃
The mixture was heated and stirred for 6 hours. After completion of the reaction, treat the reaction solution with water
The organic layer was extracted with ethyl acetate, washed with water, and then anhydrous sulfuric acid.
It was dried with magnesium. The solvent was distilled off under reduced pressure to obtain
The resulting residue is subjected to silica gel column chromatography (chromatography).
Separate and purify with Rhoform: Methanol = 20: 1)
With 3- (1- (2- (4-chlorophenyl) ethyl)
Ru) piperidin-4-yl) -5,6-dihydro-10
-Methoxy-1,2,4-triazolo [4,3-d]
0.2 g of [1,4] benzoxazepine was obtained. Melting point 1
68 ° C. Example 51 8-Chloro-4,5-dihydride obtained in Raw Material Synthesis Example 56
Lo-1-methylthio-3H-2-benzazepine and
1- (2-phenylethyl) piperidine-4-carbohi
A similar reaction and treatment as in Example 11 was carried out using dolazide.
By doing so, 10-chloro-3- (1- (2-phen
Nylethyl) piperidin-4-yl) -6,7-dihydr
Ro-5H-1,2,4-triazolo [3,4-a]
[2] Benzazepine is obtained. Example 52 8-Bromo-4,5-dihydride obtained in Raw Material Synthesis Example 59
Lo-1-methylthio-3H-2-benzazepine and
1- (2-phenylethyl) piperidine-4-carbohi
A similar reaction and treatment as in Example 11 was carried out using dolazide.
By carrying out 10-bromo-6,7-dihydro-3
-(1- (2-phenylethyl) piperidine-4-i
) -5H-1,2,4-triazolo [3,4-a]
[2] Benzazepine is obtained. Example 53 2,3-Dihydro-5-methyi obtained in Raw Material Synthesis Example 44
Ruthio-1,4-benzoxazepine and 1- (2-
(4-Nitrophenyl) ethyl) piperidine-4-cal
Reaction and treatment similar to Example 11 using bohydrazide
5,6-dihydro-3- (1-
(2- (4-nitrophenyl) ethyl) piperidine-4
-Yl) -1,2,4-triazolo [4,3-d]
[1,4] benzoxazepine is obtained. Example 54 2,3-Dihydro-5-methyi obtained in Raw Material Synthesis Example 44
Ruthio-1,4-benzoxazepine and 1- (2-
(4-Fluorophenyl) ethyl) piperidine-4-ca
Reaction similar to Example 11 using rubohydrazide and
By performing the processing, 3- (1- (2- (4-fluor
Rophenyl) ethyl) piperidin-4-yl) -5,6
-Dihydro-1,2,4-triazolo [4,3-d]
[1,4] benzoxazepine is obtained. Example 55 2,3-Dihydro-5-methyi obtained in Raw Material Synthesis Example 44
Ruthio-1,4-benzoxazepine and (4-ben
Zyllhomopiperazin-1-yl) methylcarbohydrazide
The same reaction and treatment as in Example 11 using
With, 3- (4-benzylhomopiperazine-1-y
Ru) methyl-5,6-dihydro-1,2,4-triazo
[4,3-d] [1,4] benzoxazepine was obtained.
It is. Example 56 2,3-Dihydro-7,8-obtained in Raw Material Synthesis Example 53
Dimethoxy-5-methylthio-1,4-benzoxase
Pin and 1- (2- (4-chlorophenyl) ethyl)
Example of raw material synthesis using piperidine-4-carbohydrazide
By performing the same reaction and treatment as in 11,
(1- (2- (4-chlorophenyl) ethyl) piperidi
N-4-yl) -5,6-dihydro-9,10-dimeth
Xy-1,2,4-triazolo [4,3-d] [1,
4] Benzoxazepine is obtained. Example 57 2,3-Dihydro-5-methyi obtained in Raw Material Synthesis Example 44
Ruthio-1,4-benzoxazepine and 1- (2-
(4-Methylaminophenyl) ethyl) piperidine-4
-A reaction similar to that in Example 11 using carbohydrazide
And treatment to give 5,6-dihydro-3-
(1- (2- (4-methylaminophenyl) ethyl) pi
Peridin-4-yl) -1,2,4-triazolo [4
3-d] [1,4] benzoxazepine is obtained. Example 58 2,3-Dihydro-5-methyi obtained in Raw Material Synthesis Example 54
Le-5-methylthio-1,4-benzoxazepine and
And 1- (2- (4-chlorophenyl) ethyl) piperidi
Same as in Synthesis Example 11 using starting material 4-carbohydrazide
By carrying out such reaction and treatment, 3- (1- (2
-(4-Chlorophenyl) ethyl) piperidine-4-i
) -5,6-Dihydro-10-methyl-1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepi
Is obtained. Example 59 2,3-Dihydro-7-meth obtained in Raw Material Synthesis Example 55
Xy-5-methylthio-1,4-benzothiazepine and
And 1- (2- (4-chlorophenyl) ethyl) piperidi
Same as in Raw Material Synthesis Example 15 using N-4-carbohydrazide.
By carrying out such reaction and treatment, 3- (1- (2
-(4-Chlorophenyl) ethyl) piperidine-4-i
) -5,6-Dihydro-10-methoxy-1,2,4
-Triazolo [4,3-d] [1,4] benzothiazepi
Is obtained. Example 60 7-Bromo-2,3-dihydride obtained in Raw Material Synthesis Example 60
Lo-5-methylthio-1,4-benzothiazepine and
1- (2- (4-bromophenyl) ethyl) piperidine
Similar to Raw Material Synthesis Example 11 using 4-carbohydrazide
By performing various reactions and treatments, 10-bromo-3
-(1- (2- (4-bromophenyl) ethyl) piperi
Zin-4-yl) -5,6-dihydro-1,2,4-to
Riazolo [4,3-d] [1,4] benzothiazepine
can get. Example 61 5-Methylthio-1,4-be obtained in Raw Material Synthesis Example 61
Nzothiazepine and 1- (2- (4-chlorophenyl)
Ru) ethyl) piperidine-4-carbohydrazide
To perform the same reaction and treatment as in Raw Material Synthesis Example 11.
From 3- (1- (2- (4-chlorophenyl) ethyl)
Le) piperidin-4-yl) -1,2,4-triazolo
To obtain [4,3-d] [1,4] benzothiazepine
You. Example 62 1-Benzyl-2,3-dihi obtained in Raw Material Synthesis Example 62
Doro-5-methylthio-1,4-benzodiazepine and
And 1- (2-phenylethyl) piperidine-4-carbo
Using hydrazide, the same reaction as in Raw Material Synthesis Example 11 and
By performing the treatment, 7-benzyl-5,6-dihydride
Ro-3- (1- (2-phenylethyl) piperidine-4
-Yl) -1,2,4-triazolo [4,3-d]
The [1,4] benzodiazepine is obtained. Example 63 2,3-Dihydro-1-methyi obtained in Raw Material Synthesis Example 63
Le-5-methylthio-1,4-benzodiazepine and
And 1- (2-phenylethyl) piperidine-4-carbo
Using hydrazide, the same reaction as in Raw Material Synthesis Example 11 and
By performing the treatment, 5,6-dihydro-7-methyl
-3- (1- (2-phenylethyl) piperidine-4-
Yl) -1,2,4-triazolo [4,3-d] [1,
4] Benzodiazepine is obtained. Example 64 7-Chloro-3,4-dihydride obtained in Raw Material Synthesis Example 58
Ro-1-methylthioisoquinoline and 2- (4- (3
-Chlorophenyl) piperazin-1-yl) ethyl calc
Reaction and treatment similar to Example 11 using bohydrazide
9-chloro-3- (2- (4-
(3-Chlorophenyl) piperazin-1-yl) eth
) -5,6-Dihydro-1,2,4-triazolo
[4,3-a] isoquinoline is obtained. Example 65 The 5,6-dihydro-3- (piperidyi obtained in Example 1
N-4-yl) -1,2,4-triazolo [4,3-
d] [1,4] benzoxazepine, 1,4-benzodi
Oxan-2-yl) methyl p-toluenesulfone
By a commonly used alkylation method using
(1- (1,4-benzodioxan-2-yl) methyl
Piperidin-4-yl) -5,6-dihydro-1,2,
4-triazolo [4,3-d] [1,4] benzoxa
Zepin is obtained. Example 66 The 5,6-dihydro-3- (piperidi obtained in Example 1
N-4-yl) -1,2,4-triazolo [4,3-
d] [1,4] benzoxazepine and 6-acetyl
-3- (2-chloroethyl) -2-ethyl-4,5,
6,7-Tetrahydrothieno [2,3-c] pyridine
According to the alkylation method usually used, 3- (1-
(2- (6-acetyl-2-ethyl-4,5,6,7-
Tetrahydrothieno [2,3-c] pyridin-3-i
Ru) ethyl) piperidin-4-yl) -5,6-dihydride
B-1,2,4-triazolo [4,3-d] [1,4]
Benzoxazepine is obtained. Example 67 The 3- (1- (2- (4-chlorofluoromethane) obtained in Example 25 was used.
Phenyl) ethyl) piperidin-4-yl) -5,6-di
Hydro-1,2,4-triazolo [4,3-d] [1,
4] Dissolve benzothiazepine in acetic acid solution, and cool under ice-cooling.
3- (1- (2-
(4-Chlorophenyl) ethyl) piperidine-4-i
) -5,6-Dihydro-1,2,4-triazolo
[4,3-d] [1,4] benzothiazepine 7-Oki
Sid is obtained. Example 68 The 3- (1- (2- (4-chlorofluoromethane) obtained in Example 25 was used.
Phenyl) ethyl) piperidin-4-yl) -5,6-di
Hydro-1,2,4-triazolo [4,3-d] [1,
4) Dissolve benzothiazepine in formic acid solution and stir at room temperature
By causing hydrogen peroxide water to act, 3- (1-
(2- (4-chlorophenyl) ethyl) piperidine-4
-Yl) -5,6-dihydro-1,2,4-triazolo
[4,3-d] [1,4] benzothiazepine 7,7-
A dioxide is obtained.

The structural formulas of the compounds mentioned in the above examples are shown in the following [Chemical formula 44] to [Chemical formula 50].

[0116]

Embedded image

[0117]

Embedded image

[0118]

Embedded image

[0119]

Embedded image

[0120]

Embedded image

[0121]

Embedded image

[0122]

Embedded image

In addition to the compounds of the above Examples, the compounds shown in the following [Table 1] to [Table 48] are also included in the present invention.

[0124]

[Table 1]

[0125]

[Table 2]

[0126]

[Table 3]

[0127]

[Table 4]

[0128]

[Table 5]

[0129]

[Table 6]

[0130]

[Table 7]

[0131]

[Table 8]

[0132]

[Table 9]

[0133]

[Table 10]

[0134]

[Table 11]

[0135]

[Table 12]

[0136]

[Table 13]

[0137]

[Table 14]

[0138]

[Table 15]

[0139]

[Table 16]

[0140]

[Table 17]

[0141]

[Table 18]

[0142]

[Table 19]

[0143]

[Table 20]

[0144]

[Table 21]

[0145]

[Table 22]

[0146]

[Table 23]

[0147]

[Table 24]

[0148]

[Table 25]

[0149]

[Table 26]

[0150]

[Table 27]

[0151]

[Table 28]

[0152]

[Table 29]

[0153]

[Table 30]

[0154]

[Table 31]

[0155]

[Table 32]

[0156]

[Table 33]

[0157]

[Table 34]

[0158]

[Table 35]

[0159]

[Table 36]

[0160]

[Table 37]

[0161]

[Table 38]

[0162]

[Table 39]

[0163]

[Table 40]

[0164]

[Table 41]

[0165]

[Table 42]

[0166]

[Table 43]

[0167]

[Table 44]

[0168]

[Table 45]

[0169]

[Table 46]

[0170]

[Table 47]

[0171]

[Table 48]

Formulation Formulation Example 1 The compound of Example 11 (0.5 parts), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were mixed well, and then thoroughly kneaded with the binder prepared from corn starch (2 parts). The kneaded mixture is sieved through 16 mesh and placed in an oven for 5 minutes.
After drying at 0 ° C, it was sieved with 24 mesh. The kneaded powder thus obtained was mixed well with 8 parts of cornstarch, 11 parts of crystalline cellulose and 9 parts of talc, and the mixture was compressed and compressed to give 1
A tablet is obtained containing 0.5 mg of active ingredient per tablet. Formulation Example 2 1.0 mg of the compound of Example 11 and sodium chloride 9.0
mg is dissolved in water for injection, filtered to remove the pyrogen, the filtrate is aseptically transferred to an ampoule, sterilized, and then melt-sealed to obtain an injection containing 1.0 mg of the active ingredient.

The superior pharmacological activity of the compounds of general formula (1) is demonstrated by the series of tests shown below. Experimental Example 1: Affinity for D ₂ receptor; ³ H-spiperone binding Crude synaptic membrane preparation and binding experiments were performed using Crease (I. Cr
eese) et al. [European Journal of Pharmacology, Vol. 46, p. 377 (197).
7)]. Crude synaptic membrane was prepared from cryopreserved rat striatum, and the membrane specimen was reacted with ³ H-spiperone at 37 ° C. for 20 minutes in the presence of the test compound. Immediately after the reaction, Whatman GF / B filter (trade name)
Suction filtration was performed with and the radioactivity on the filter was measured with a liquid scintillation counter. The amount of non-specific binding is 1
It was determined in the presence of 00 μM (±) -sulpiride. The 50% inhibitory concentration (IC ₅₀ ) of the test compound was calculated by nonlinear regression, and the inhibition constant (Ki value) was determined. Experimental Example 2: Preparation of cells expressing D ₄ receptor (1) PCR (polymerase chain rea) of D ₄ receptor cDNA
The human pituitary cDNA [Clonte
ch) company] was used. In addition, the primers are D4S1; 5'-GCCATGGGGAACCGCAGCACCGCGGACGCGGA-3 'D4A1;5'-GCACGGCCACGGCCACGAACCTGTCCACGCT-3' and D4S2; 5'-GTCATGCTGTGCACCGCCTCCATCTTCAAC-3'-D4ACT-3;3'was used.

Amplification by the PCR method is performed in a PCR reaction apparatus.
[Gene Amp PCR System 9600 (Perkin Elmer Si
TAS (PERKIN ELMER CETUS)] at 98 ° C for 2 minutes
Pre-treatment, heat denaturation (98 ° C, 2 min), annealing and
Perform 50 cycles of extension reaction (77 ℃, 5 minutes), then 77 ℃ 1
It was carried out by post-treatment at 0 minutes. Enzyme is thermostable Pf
u DNA polymerase [STRATAGENE]
Company] was used. After the PCR reaction, agarose gel electrophoresis
Approximately 400b amplified by primers D4S1 and D4A1.
About 900b amplified with p. and primers D4S2, D4A2.
Check the DNA band of interest in p. and use QIA quick Gel Extr.
Use action kits (QIAGENE) to
DNA was extracted. DN of about 400b.p. obtained here
A is called D4S and about 900b.p. DNA is called D4L.
You. Also, the D4L band is a bit broader and
The existence of subtypes was suggested. (2) Insertion into cloning vector The DNA fragment (D4S or D4L) extracted from the gel is SureCl.
For one Ligation Kit (Pharmacia)
Cloning vector by performing ligase reaction
-Incorporated into pUC18. Compute with the obtained vector
E. coli JM109 (Toyobo) was transformed. Appeared
Plasmids were extracted from ampicillin resistant colonies and seeded
Digestion with various restriction enzymes_FourReceptor DNA (D4
S or D4L) insertion was confirmed. Then D4S or D4
L-containing pUC18 clone (D4S / pUC18 or D4L / pUC18)
 D4S and D4L D_FourCut off overlapping regions of receptor DNA
Restriction enzyme BstXI to cut and restriction enzyme to cut vector part
After digestion with elemental XbaI, agarose gel electrophoresis was performed. Eye
DNA [D4S (BstXI-XbaI) or D4L (XbaI-BstX
I)] was confirmed and extracted. Obtained D4S (Bst
XI-XbaI) and D4L (XbaI-BstXI) were ligated with ligase
Then, E. coli JM109 was transformed with this vector. Out
Extraction of plasmid from revealed ampicillin resistant colonies
Digested with various restriction enzymes to convert all amino acids.
Do D_FourInsertion of receptor DNA was confirmed. Also this
Two types of D with different molecular weights_FourHas receptor DNA
Vector was confirmed. (3) D_FourDetermination of the total nucleotide sequence of the acceptor DNA AutoRead
 Using Sequence Kit (Pharmacia)
The reaction was carried out by the dideoxy method. Electrophoresis and salt
A.L.F.DNA Sequencer II [Pharmacia
(Pharmacia)]. As a result, the molecular weight
Two different types of D_FourReceptor DNA is located in the third intracellular region.
Two rebounds (D4.2) and five reflows (D4.5)
Was confirmed. The DNA sequences of D4.2 and D4.5
Shown in FIGS. In the figure, HSD4DOP is Nature
(Nature), vol. 350, pp. 160-164 (1991).
D_FourThe nucleotide sequence of the receptor DNA is shown.
The homologous parts of each DNA are shown, and the underlined parts indicate the four types of used
The immer part is shown. The vector obtained here is D4.2 / pU
They are called C18 and D4.5 / pUC18. (4) Preparation of expression vector p4.2 clone containing D4.2 or D4.5 (D4.2 / pUC18
Digested D4.5 / pUC18) with the restriction enzymes HindIII and KpnI and
Purpose of applying each digested fragment to agarose gel electrophoresis
Was separated and extracted. Expression vector pCEP
4 [Invitrogen] also digested with the same enzyme
And then separate and extract D4.2 or D4.5 into the pCEP4 vector.
And transform E. coli JM109 with this vector.
Was. Extraction of plasmid from ampicillin resistant colonies
Digested with various restriction enzymes to obtain D4.2 or D4.5
The insertion and the insertion direction were confirmed. The obtained vector
They are referred to as D4.2 / pCEP4 and D4.5 / pCEP4. (5) D_FourPreparation of cells that stably express the receptor The obtained vector (D4.2 / pCEP4 or D4.5 / pCEP4) was
Transfectam (TRANSFECT)
AM) [IBF Biotechnic]
Human fetal kidney-derived transformant 293 (manufactured by Dainippon
Drug) or monkey kidney-derived cell CV-1 (Dainippon Pharmaceutical) in culture medium
Was added. HYGROMYCIN B [Cal
Biochem (CALBIOCHEM)] to culture in supplemented medium
The introduced cells were selected from (6) Confirmation of transformed cells by RT-PCR method From the obtained transformed cells, RNA Microisolation Spin C was used.
artridge System [GIBCO BRL, trade name Glas
sMax^TM], Each RNA was extracted. ply oligo-dT
And M-MLV reverse transcriptase
 ) Was used to prepare cDNA. Each cDNA obtained was used as a template
Then D_FourThe portion containing the third intracellular region of the receptor DNA is P
It was amplified by the CR method. Perform agarose gel electrophoresis
As a result, the expressed RNAs were D4.2 and D4.5, respectively.
I was sure that. Form containing D4.2 / pCEP4 obtained here
Transformed cells into D4.2 / pCEP4-293 cells and D4.2 / pCEP4
-CV cells and transformed cells containing D4.5 / pCEP4
With D4.5 / pCEP4-293 cells and D4.5 / pCEP4-CV cells
Name. (7) Drug binding test D of the transformed cells obtained_FourConfirm receptor production and properties
For confirmation, prepare the crude membrane fraction (P2 fraction) of each transformed cell.
Made,^ThreeH] Spiperone (Daiichi Pure Chemicals) and various drugs
(Mosapramine hydrochloride, haloperidol, bromperido
Le, clozapine, risperidone, chlorpromazine, la
Cloprid) was added, and the mixture was reacted at 27 ° C. for 2 hours. End of reaction
After that, pass Whatman GF / C glass filter (trade name)
The radioactivity remaining on the filter.
It is measured at the application counter (BECKMAN)
Was. Non-specific binding was due to the presence of 10 μM haloperidol
Asked below. 50% inhibitory concentration of various drugs (IC₅₀) Non
Calculated by linear regression, D _FourOf the receptor [^ThreeH] Spipero
The inhibition constants (Ki values) of various drugs on the binding
Was. Table 1 shows D4.2 / pCEP4-293 cells as transformed cells.
The result when a cell is used is shown.

Table 1 ──────────────────────────────────── Drug Ki (nM) (mean value ± standard deviation) ──────────────────────────────────── Mosapramine hydrochloride 3.3 ± 1.2 Haloperidol 4.0 ± 0.65 Bromperidol 4.1 ± 0.25 Clozapine 26 ± 0.68 Risperidone 11 ± 1.3 Chlorpromazine 34 ± 8.3 Racloprid 3200 ± 440 ───────────── ───────────────────────── D4.2 / pCEP4-293 cells obtained from the above results, D
4.2 / pCEP4-CV cells, D4.5 / pCEP4-293 cells and D
All 4.5 / pCEP4-CV cells expressed a uniform D ₄ receptor, and were able to reproducibly prepare a large amount of D ₄ receptor by subculture. Therefore, the above cell lines were used in the measurement of the pharmacological activity (affinity for D ₄ receptor) of the compounds of the present invention. Experimental Example 3: Affinity for D ₄ receptor; ³ H-spiperone binding D ₄ obtained from D4.2 / pCEP4-293 cells of the above Experimental Example 2
The receptor-expressing cell membrane preparation and ³ H-spiperone were incubated at 27 ° C. for 2 hours in the presence of the test compound. Immediately after the reaction, Whatman GF / B filter (trade name)
Suction filtration was performed with and the radioactivity on the filter was measured with a liquid scintillation counter. The amount of non-specific binding is 1
Determined in the presence of 0 μM haloperidol. 5 of test compounds
The 0% inhibitory concentration (IC ₅₀ ) was calculated by non-linear regression to determine the inhibition constant (Ki value).

The results of Experimental Example 1 and Experimental Example 3 are shown in Table 2. Table 2 ──────────────────────────────────── Receptor binding capacity of test compounds Ki (nM) Example number ──────────────────── D ₂ D ₄ ──────────────────────── ───────────── 12 2700 3.1 18 ＞ 1000 * 0.9 24 ＞ 1000 * 5.6 27 ＞ 1000 * 2.0 ──────────── ───────────────────────── *: From the experiments above the IC ₅₀ value, the compound of the present invention is stronger at the D ₄ receptor than at the D ₂ receptor. It was confirmed to have an affinity. Experimental Example 4: [ ³⁵ S] GTPγS binding test Journal of Neurochemistry (J. Neuroch
em.) C. Chabert described in Vol.63, No.1: 62-65 (1994)
According to these methods, the D ₄ receptor agonist / antagonist of the test substance was identified.

D4.2 / pCEP4-293 cells were treated with 1 mM ED
TA, 3 mM magnesium chloride, 100 mM sodium chloride, 0.1 mM PMSF, 2 μg / ml aprotini
25 mM HE containing n, 10 μg / ml leupeptine
The cells were disrupted in a PES-NaOH buffer (pH 8.0) using a glass-Teflon homogenizer, and the membrane fraction was recovered by centrifugation. Add 1 mM EDTA, 3 mM magnesium chloride, 100 mM sodium chloride, 0.5 mM d
25 mM containing ithiothreitol, 0.01% Lubrol PX
Suspend with HEPES-NaOH buffer (pH 8.0) and GD
P was added so that the final concentration was 10 μM, and the mixture was reacted at 0 ° C. for 10 minutes. Next, the test substance was added and reacted at 37 ° C. for 10 minutes. After completion of the reaction, the agonist dopamine was added to a final concentration of 10 ^-8 to 10 ^-4 M, and [ ³⁵ S] was added.
GTPγS (200,000 dpm / assay) was added and the temperature was 30 at 37 ℃.
Allowed to react for minutes. Then, the reaction suspension was added to Whatman GF.
/ B filter, the filter containing 25 mM magnesium chloride, 100 mM sodium chloride 20
Wash with mM Tris-HCl buffer (pH 8.0), put in a vial, add ACS-II (Amersham) scintillator,
The radiation dose was measured.

As a result, dopamine [ ^35]
S] increases the binding of GTPγS to the membrane, haloperidol, clozapine and the test substance (compound of Example 12).
Antagonized this increasing effect in a concentration-dependent manner. The test substance alone did not increase the binding of [ ³⁵ S] GTPγS to the membrane. From the above, it was suggested that the test substance is an antagonist to the D ₄ receptor, like haloperidol and clozapine.

[0179]

INDUSTRIAL APPLICABILITY The compound of the present invention, an optical isomer or a pharmaceutically acceptable salt thereof is a D ₄ receptor antagonist having a selective and strong blocking action on the D ₄ receptor and, therefore, is effective for schizophrenia. It is a useful antipsychotic drug that is effective not only for positive symptoms such as hallucinations and delusions, which are characteristic of the acute phase, but also for negative symptoms such as apathy, apathy and autism. Further, it is expected as an antipsychotic drug in which side effects such as extrapyramidal symptoms and endocrine abnormalities which are observed when a conventional antipsychotic drug having a D ₂ receptor antagonistic action is administered are reduced. Therefore, the compound of the present invention can be used as a therapeutic agent for diseases such as schizophrenia.

[Brief description of the drawings]

FIG. 1 is a diagram showing a part of the nucleotide sequences of DNAs D4.2 and D4.5.

FIG. 2 is a diagram showing a part of the nucleotide sequences of DNAs D4.2 and D4.5, showing the portion following FIG. 1.

FIG. 3 is a diagram showing a part of the nucleotide sequences of D4.2 and D4.5 DNAs, showing the portion following FIG. 2.

FIG. 4 is a diagram showing a part of the nucleotide sequences of D4.2 and D4.5 DNAs, showing the portion following FIG. 3.

FIG. 5 is a diagram showing a part of the nucleotide sequences of D4.2 and D4.5 DNAs, showing the portion following FIG. 4.

FIG. 6 is a diagram showing a part of the nucleotide sequences of DNAs D4.2 and D4.5, showing the portion following FIG. 5.

FIG. 7 is a diagram showing a part of the nucleotide sequences of D4.2 and D4.5 DNAs, showing the portion following FIG. 6.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/535 A61K 31/535 31/55 AAN 31/55 AAN C07D 498/04 116 C07D 498/04 116 513 / 04 391 513/04 391 // C07M 7:00 (72) Inventor Hiroyuki Ushio 955 Address, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture, Yoshitsumi Pharmaceutical Co., Ltd. 2nd Research Laboratory (72) Inventor Takashi Nimura Fukuoka Prefecture Yoshitomi-cho, Kuchigami-gun, Oita, 955 Address, Second Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd. (72) Inventor, Yoshitaka Ohashi, 3-7-25, Oyada, Iruma City, Saitama Yoshitomi Pharmaceutical Co., Ltd., First Research Laboratory (72) ) Inventor Kazuhiro Yano 3-7-25 Oyata, Iruma City, Saitama Yoshitomi Pharmaceutical Co., Ltd.

Claims (9)

[Claims] 1. A compound of the general formula (1)[Wherein, R¹, R^TwoAre the same or different, hydrogen, halogen
Amine, cyano, nitro, amino, acylamino, carbamo
Yl, alkylcarbamoyl, alkoxycarbonyl,
Acyl, alkylamino, aminoalkyl, alkyl
Minoalkyl, hydroxy, acyloxy, hydroxy
Alkyl, acyloxyalkyl, alkoxy alk
Ru, alkyl, alkenyl, alkynyl, alkoxy,
Alkylthio, alkylsulfinyl or alkyls
Indicates sulfonyl. W is methylene, sulfur atom, SO, SO
_Two, Oxygen atom or NR^Three(Where R ^ThreeIs hydrogen, al
Kill, phenacyl, or optionally substituted aryl
Is alkyl or heteroarylalkyl. )
Is shown. X represents methylene, ethylene or vinylene
You. Y does not exist or has 1 to 8 carbons
Is a straight or branched alkylene chain. Z is -NH
_Two, -NHR^Four(Where R^FourIs alkyl, cycloalk
Group, arylalkyl which may have a substituent, heteroaryl
Reel alkyl or fused heteroarylalkyl,
Or an optionally substituted aryl or heteroaryl
Alternatively, it represents a fused heteroaryl. ), -N (R^Four)
(R^Five) (Where R is^FourIs as defined above. R^FiveIs al
Kill, cycloalkyl, optionally substituted aryl
Alkyl, heteroarylalkyl or fused hetero
Arylalkyl, or optionally substituted aryl
Group, heteroaryl or fused heteroaryl
You. ), Or a cyclic amine of formula (a), a cyclic amine of formula (b)
Amine or cyclic amine of formula (c)(In the formula, the cyclic amine in the formula (a) is an oxygen source in the ring.
May have a child, pyrrolidine, piperidine or
Indicates morpholine. The cyclic amine in formula (b) is piperazi
Or homopiperazine. Cyclic Ami in Formula (c)
The ring may further have an oxygen atom in the ring.
Gin, piperidine, 3,6-dihydro-2H-pyridine
Or morpholine. The bond represented by the solid and dotted lines is
Indicates a single bond or a double bond. A does not exist, or
Is a straight or branched chain alkyl having 1 to 8 carbons
A len chain is shown. B does not exist, or a sulfur atom, an acid
Indicates an elementary atom, carbonyl or hydroxymethyl.
R⁶Is hydrogen, hydroxy, alkyl or alkoxy
Show. R⁷Is hydrogen, aryl which may have a substituent,
Teloaryl or fused heteroaryl, cycloal
An arylalkyl which may have a substituent or a substituent,
Heteroarylalkyl or fused heteroaryl
Indicates a ruquil. ) Shows the group represented by. ] By the table
Condensed triazole compound, its optical isomer or
A pharmaceutically acceptable salt thereof. 2. In the general formula (1), the cyclic amine of the formula (a) of Z is represented by the following formulas (2), (3), (4), (5),
The condensed triazole compound according to claim 1, which is (6) or (7), an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Embedded image 3. The cyclic amine of the formula (b) of Z in the general formula (1) is represented by the following formula (8) or (9).
The condensed triazole compound described above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Embedded image 4. In the general formula (1), the cyclic amine of the formula (c) of Z is represented by the following formula (10), (11) or (12).
The fused triazole compound according to claim 1, which is an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Embedded image 5. In the general formula (1), R ¹ represents hydrogen, halogen, nitro, amino, acyl, alkylamino, alkyl or alkoxy; R ² represents hydrogen, halogen or alkoxy; W is methylene or sulfur. Represents an atom or an oxygen atom; X represents methylene, ethylene or vinylene; Y represents absent or a linear alkylene chain having 1 to 3 carbon chains; Z represents formula (a), (b) Alternatively, the cyclic amine represented by (c) (wherein the cyclic amine in the formula (a) may further have an oxygen atom in the ring and represents pyrrolidine, piperidine or morpholine. In the formula (b), The cyclic amine of formula (3) represents piperazine or homopiperazine.
The cyclic amine therein may further have an oxygen atom in the ring, and is pyrrolidine, piperidine, 3,6-dihydro-2.
Indicates H-pyridine or morpholine. The bond represented by the solid line and the dotted line represents a single bond or a double bond. A is absent or represents a straight chain or branched alkylene chain having 1 to 8 carbon atoms. B is absent or represents a sulfur atom, an oxygen atom, carbonyl or hydroxymethyl. R ⁶ represents hydrogen, hydroxy, alkyl or alkoxy. R ⁷ represents hydrogen, optionally substituted aryl, heteroaryl or fused heteroaryl, cycloalkyl, or optionally substituted arylalkyl, heteroarylalkyl or fused heteroarylalkyl. The condensed triazole compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein 6. In the general formula (1), R ¹ and R ² represent hydrogen; W represents methylene, a sulfur atom or an oxygen atom; X represents methylene, ethylene or vinylene; Y is absent or Or carbon chains 1 to 3
Represents a linear alkylene chain having 1; Z is of the formula (2) or (8) (In the formula, A is absent or represents a linear alkylene chain having 1 to 4 carbon atoms. B is absent or represents carbonyl. R ⁶ represents hydrogen. R ⁷ represents a substituent. Represents a group represented by aryl or heteroaryl which may have); The fused triazole compound according to claim 1, which is an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 7. 3- (1- (2- (4-chlorophenyl))
Ethyl) piperidin-4-yl) -6,7-dihydro-
5H-1,2,4-triazolo [3,4-a] [2] benzazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro- 1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepine, 3- (2- (4- (4-chlorophenyl) piperazine-
1-yl) ethyl) -5,6-dihydro-1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepine, 3- (2- (4- (3-chlorophenyl) piperazine-
1-yl) ethyl) -5,6-dihydro-1,2,4-
Triazolo [4,3-d] [1,4] benzoxazepine, 3- (3- (4- (4-chlorophenyl) piperazine-
1-yl) propyl) -5,6-dihydro-1,2,4
-Triazolo [4,3-d] [1,4] benzoxazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -1,2,4-triazolo [4 , 3
-D] [1,4] benzoxazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4-
Triazolo [4,3-d] [1,4] benzothiazepine, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4 −
Triazolo [4,3-a] isoquinoline, 3- (1- (2- (4-chlorophenyl) ethyl) piperidin-4-yl) -5,6-dihydro-1,2,4-
Triazolo [4,3-d] [1,4] benzothiazepine 7,7-dioxide and 5,6-dihydro-3-
(2- (4-phenylpiperidin-1-yl) ethyl)
The fused triazole compound according to claim 1, which is selected from -1,2,4-triazolo [4,3-d] [1,4] benzoxazepine, or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising the fused triazole compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 9. A medicine comprising the condensed triazole compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof.