JPH0543582A - Thiophene condensation compound and its use - Google Patents

Abstract

PURPOSE:To obtain the new title compound having selectively high affinity to serotonin 1A receptor and useful as anxiolytics, antipsychotics and therapeutic agent for cardiovascular disease. CONSTITUTION:A compound expressed by formula I [one of E<1> to E<3> is S and other two are C-R<1> or C-R<2> (R<1> and R<2> are H, halogen, nitro, etc.); D is CH2 or S(O)m (m is 0-2); Q is alkylene; T is primary to tertiary amino; A and B are carbonyl, thiocarbonyl, etc.; n is 2 or 3 when either one of A and B do not exist and the other is carbonyl, etc., and n is 1 or 2 in the other case] or pharmaceutically permissible acid addition salt thereof such as 2- bromo-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]5,6,7,8tetrahydro-4H -thieno[3,2- C]azepin-4-one. The compound is obtained by e.g. reacting a compound expressed by the formula X-Q-T (X is cyano, nitro, etc.) with a compound expressed by formula II in a solvent in the presence of a deacidifying agent at 20-150 deg.C for 30min to 30hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiophene-condensed compound or a pharmaceutically acceptable acid addition salt thereof, which is useful as a medicine for central nervous system and circulatory system, its pharmaceutical use and its synthetic intermediate.

[0002]

PRIOR ART Benzodiazepine compounds are widely used as anxiolytic agents. Although these compounds show an excellent anxiolytic effect, on the other hand, since they also have side effects such as muscle relaxant action, sedative action, and addiction, patients suffering from anxiety such as psychosomatic disorder during daily activities (usually daytime
There is a problem such as being cautious in its use. In recent years, in order to develop an anxiolytic drug that selectively acts on anxiety, a compound having a non-benzodiazepine structure has been developed. The representative compound is buspirone, which, unlike conventional benzodiazepine compounds, does not bind to the benzodiazepine receptor, has a high affinity for the serotonin 1A receptor, and is a serotonin 1A.
It is known to exert an anxiolytic effect via receptors. These compounds have excellent characteristics such as high safety, no habit, and no possibility of abuse, and are expected as new anxiolytic drugs. On the other hand, there are also problems to be solved, such as the time required for the onset of action and the side effect of extrapyramidal system. In addition, currently known antipsychotic drugs are effective against symptoms commonly referred to as positive symptoms such as hallucinations and delusions and psychomotor agitation, but are mostly effective against negative symptoms such as apathy, inactivity and cognitive impairment. Not shown. In addition, extrapyramidal symptoms such as acute dystonia, akathisia, and Parkinson's symptoms seen at the beginning of drug administration and delayed dyskinesia seen during long-term administration are unavoidable side effects in antipsychotic drug treatment, and are here today. There is a limit to the antipsychotic treatment drug of the above, and development of an antipsychotic drug effective for negative symptoms and having reduced side effects is awaited. From this point of view, there is a demand for the development of a new antipsychotic drug having a high selectivity for serotonin receptors though it is mediated by serotonin receptors and dopamine receptors. In addition, recently, it has been pointed out that the serotonin 1A receptor is associated with a hypotensive action. 8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT), which has a high affinity for the serotonin 1A receptor, is the medulla oblong serotonin 1A.
It is known to lower blood pressure via receptors. Against this background, the development of a drug having a high affinity for the serotonin 1A receptor as an antihypertensive agent is under way. Although they are mediated by sympathetic nerves, they are expected to be useful antihypertensive agents because they do not cause repulsion, inhibition of salivary secretion, or no sympathetic tone (no tachycardia, rather bradycardic). As these agents, JP-A-60-104
No. 063 discloses a piperazine derivative showing a hypotensive action by a central action mechanism.

[0003]

[Means for Solving the Problems] The present inventors have found that a compound which exerts an anxiolytic effect stronger and more selectively than conventional compounds by selectively acting on the serotonin 1A receptor, and has no side effect. For the purpose of providing the information, we have diligently studied. The present inventors have also conducted research to find compounds that show high affinity selectively for serotonin receptors and dopamine receptors, especially serotonin receptors, and are useful as antipsychotic agents. In addition, serotonin 1
Studies were conducted to find excellent antihypertensive agents that do not cause tachycardia through the A receptor.

As a result, the present inventors have found a novel thiophene-condensed compound which meets the above-mentioned object, and completed the present invention. Therefore, the present invention provides a thiophene condensed compound useful as an excellent anxiolytic drug, antipsychotic drug or antihypertensive drug, and a novel synthetic intermediate thereof.

The present invention has the general formula (I)

[Chemical 13] And a pharmaceutically acceptable acid addition salt thereof. In the formula, E ¹ , E ² , E ³
One of them is a sulfur atom, and the other two are C-
R ¹ and C-R ² are shown. R ¹ and R ² are the same or different and are hydrogen, halogen, nitro, amino, cyano, hydroxyl group,
Formyl, alkyl, alkoxy, haloalkyl, arylalkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl , Arylsulfonyl, hydroxysulfonyl, halosulfonyl, sulfamoyl, substituted sulfamoyl, carboxyl, acylamino, alkoxycarbonyl, carbamoyl, substituted carbamoyl or substituted amino. D is-
CH ₂ - or -S (O) _m - indicates the (m is 0, 1 or 2). Q represents straight chain alkylene or branched chain alkylene. T represents primary amino, secondary amino or tertiary amino. A and B are the same or different and each represents a carbonyl group or a thiocarbonyl group,
A, no one there is B, then the other or show a carbonyl group or a thiocarbonyl group, or A is -CH ₂ - is, B represents a carbonyl group or a thiocarbonyl group.
n represents 2 or 3 when one of A and B does not exist and the other is a carbonyl group or a thiocarbonyl group, and represents 1 or 2 in other cases. In the above definition, the (hetero) aromatic ring and the heterocycle may have 1 to 3 substituents.

The present invention also has the general formula

[Chemical 14] Also provided are thiophene condensed compounds represented by:
In the formula, X is represented by a hydroxyl group, a reactive atom or group derived from a hydroxyl group (halogen, methanesulfonyloxy, paratoluenesulfonyloxy, etc.), and a formula —CO—R ³ (R ³ represents hydrogen or alkyl). Group, a cyano group, a carbamoyl group or a nitro group, and other symbols are as defined above. In addition, in the present specification, the compound represented by the general formula (II) is subdivided into groups of five compounds from the general formula (II-a) to the general formula (II-e) as follows. Compound of general formula (II-a): X represents a hydroxyl group or a reactive atom or group derived from a hydroxyl group. Formula (II-b) a compound: X has the formula -CO-R ³ (R ³
Represents hydrogen or alkyl). Compound of general formula (II-c): X represents a cyano group. Compound of general formula (II-d): X represents a carbamoyl group. Compound of general formula (II-e): X represents a nitro group. Further, the present invention provides a general formula

[Chemical 15] A thiophene-fused compound represented by the formula (wherein each symbol has the same meaning as defined above) is also provided. The compounds of general formula (II) and general formula (IV) are synthetic intermediates of the compound of general formula (I).

In each symbol in the above general formula and in the present specification, halogen is chlorine, bromine, fluorine and iodine, and alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl. , Hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like, and alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,
Pentyloxy, hexyloxy, heptyloxy, octyloxy and the like, and haloalkyl is a halogen-substituted alkyl such as bromomethyl, chloromethyl, trifluoromethyl, 2-bromoethyl, 2-chloroethyl, difluoromethyl, 2,2 -Difluoroethyl, 2,2,2-trifluoroethyl, 3-bromopropyl, 3-chloropropyl, 4-fluorobutyl and the like, and arylalkyl is, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3 -Phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, 4-naphthylbutyl, diphenylmethyl, bis (4-fluorophenyl)
Methyl and the like and acyl represent, for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, alkanoyl such as hexanoyl and octanoyl, aroyl such as benzoyl and naphthoyl and heteroarylcarbonyl such as nicotinoyl, thenoyl and furoyl. Alkoxyalkyl is, for example, methoxymethyl, 1- or 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 1-, 2-, 3- or 4-methoxybutyl, ethoxymethyl, 1- or 2-. Ethoxyethyl, 1,2- or 3-ethoxypropyl, 1
Acyloxyalkyl such as-, 2-, 3- or 4-ethoxybutyl is, for example, acetoxymethyl, propionyloxymethyl, 1- or 2-acetoxyethyl, 1- or 2-propionyloxyethyl, 1
-, 2- or 3-acetoxypropyl, 1-, 2- or 3-propionyloxypropyl, benzoyloxymethyl, 1- or 2-benzoyloxyethyl, 1
-, 2- or 3-benzoyloxypropyl, 1-,
2-, 3- or 4-benzoyloxybutyl and the like,
Hydroxyalkyl is, for example, hydroxymethyl,
1- or 2-hydroxyethyl, 1-, 2- or 3
-Hydroxypropyl, 1-, 2-, 3- or 4-hydroxybutyl and the like, and acyloxyalkanoyl means, for example, acetoxyacetyl, acetoxypropionyl, acetoxybutyryl, benzoyloxyacetyl, benzoyloxypropionyl, benzoyloxybutyryl and the like. , And alkoxyalkanoyl are, for example, methoxyacetyl, ethoxyacetyl, propoxyacetyl, butoxyacetyl, methoxypropionyl, ethoxypropionyl, propoxypropionyl, butoxypropionyl, and the like, hydroxyalkanoyl is
For example, hydroxyacetyl, hydroxypropionyl, hydroxybutyryl, etc., aryloxyalkanoyl, for example, phenoxyacetyl, phenoxypropionyl, phenoxybutyryl, etc., and haloalkanoyl, for example, bromoacetyl, chloroacetyl, bromopropionyl, chloropropionyl, It shows bromobutyryl, chlorobutyryl and the like. Alkylthio means, for example, methylthio, ethylthio, propylthio,
Isopropylthio, butylthio, isobutylthio, third
Alkylsulfonyl, such as secondary butylthio, is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
Isobutylsulfonyl, tertiary butylsulfonyl, etc., and halosulfonyl include, for example, chlorosulfonyl,
Substituted sulfamoyl such as bromosulfonyl, iodosulfonyl and the like are, for example, dimethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, dibutylsulfamoyl, piperidinosulfonyl, morpholinosulfonyl and the like, and alkylsulfinyl is methyl. Sulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc., arylthio is phenylthio, naphthylthio, etc., arylsulfinyl is phenylsulfinyl, naphthylsulfinyl, etc., arylsulfonyl is phenylsulfonyl,
Naphthylsulfonyl and the like, acylamino is acetylamino, propionylamino, butyrylamino, benzoylamino and the like, and alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, etc., substituted carbamoyl is dimethylcarbamoyl, diethylcarbamoyl, piperidinocarbonyl, etc., substituted amino is methylamino,
Dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, N-methyl-N-benzylamino, piperidino and the like are linear alkylenes.
For example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, decamethylene, etc. are substituted with at least one alkyl group, preferably 1 to 4 alkyl groups. Alkylene such as propylene, 1-methyltrimethylene, 3-methyltrimethylene, 1-methyltetramethylene, 4-methyltetramethylene, 1,4-dimethyltetramethylene, 6-methylhexamethylene, 4,4-dimethyltetramethylene. Indicates methylene and the like.

In the general formula (I), T represents a primary amino of --NH _2, a secondary amino represented by --NHRa or a tertiary amino represented by --N (Rb) (Rc). Here, as Ra, alkyl (as defined above), cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), arylalkyl (as defined above), heteroarylalkyl (may be hydrogenated, For example, pyridylmethyl, furylmethyl, thienylmethyl, (1,4-benzodioxan-2-yl) methyl and the like) are shown. Rb, R
c is the same or different and is alkyl (synonymous with the above), cycloalkyl (synonymous with the above), arylalkyl (synonymous with the above) heteroarylalkyl (synonymous with the above) and the like, and examples thereof include dialkylamino (dimethylamino). , Diethylamino, dipropylamino, diisopropylamino, dibutylamino, dihexylamino, dioctylamino, etc.), N-alkyl-N-cycloalkylamino (N-methyl-N-cyclopropylamino, N
-Methyl-N-cyclohexylamino, N-methyl-N
-Cyclopentylamino, N-ethyl-N-cyclopropylamino, N-ethyl-N-cyclopentylamino,
N-ethyl-N-cyclohexylamino, N-propyl-N-cyclopropylamino, N-propyl-N-cyclohexylamino, N-butyl-N-cyclohexylamino, etc.), N-alkyl-N-arylalkylamino (N -Methyl-N-benzylamino, N-methyl-N
-(2-phenylethyl) amino, N-methyl-N-
(3-phenylpropyl) amino, N-ethyl-N-benzylamino, N-ethyl-N- (2-phenylethyl) amino, N-propyl-N-benzylamino, N-
Propyl-N- (2-phenylethyl) amino, N-butyl-N-benzylamino, N-butyl-N- (2-phenylethyl) amino, etc., having a substituent on the aromatic ring. , N-alkyl-N-heteroarylalkylamino (N-methyl-N-pyridylmethylamino, N-methyl-N-thienylmethylamino, N-
Methyl-N-furylmethylamino, N-ethyl-N-pyridylmethylamino, N-ethyl-N-thienylmethylamino, N-ethyl-N-furylmethylamino, N-methyl-N- (1,4-benzo Dioxan-2-ylmethyl) amino and the like). Alternatively, Rb and Rc are combined with the adjacent nitrogen atom to form the formula:

[Chemical 16] It is also possible to form the cyclic amino represented by
In the formula, q represents an integer of 1 to 4, and Z represents methylene, an oxygen atom, a sulfur atom or N—R ⁵ . The substituent V is hydrogen, hydroxyl group, amino, carbamoyl, mono- or di-substituted amino (methylamino, dimethylamino, ethylamino, diethylamino, anilino, N-acetylanilino, N-propionylanilino, pyrrolidinylamino. Etc.), cyclic amino (pyrrolidinyl, piperidino, hexamethyleneimino, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, 4-substituted piperazinyl,
4-substituted homopiperazinyl etc.), acyl (as defined above), aryl (phenyl, naphthyl etc.), arylalkyl (as defined above), arylalkylamino (benzylamino, phenylethylamino, naphthylmethylamino, naphthylethylamino) Etc.), alkyl (as defined above), alkoxy (as defined above), hydroxyalkyl (as defined above), alkoxycarbonyl (as defined above), heteroaryl (pyridyl, thienyl, furyl,
Pyrimidinyl, 1,2-benzisothiazol-3-yl, 1,2-benzisoxazol-3-yl, benzothiophen-3- or 4-yl, benzofuran-3
Or 4-yl, quinolyl, isoquinolyl, benzoxazol-2-yl, pyrazinyl, pyridazinyl, imidazolyl, thieno [3,2-c] pyridin-4-yl,
Furo [3,2-c] pyridin-4-yl, 2-oxo-
1-benzimidazolyl, 2-thioxo-1-benzimidazolyl, 2,4-dioxohexahydropyrimidin-1-yl, hydantoin-1-yl, etc., phenoxyalkyl (phenoxymethyl, 2-phenoxyethyl, 3-phenoxy) Propyl), anilinoalkyl (anilinomethyl, 2-anilinoethyl, 3-anilinopropyl, etc.), alkylaminoalkyl (N-methylaminomethyl, N, N-dimethylaminomethyl, N, N
-Diethylaminomethyl, 2- (N-methylamino) ethyl, 2- (N, N-dimethylamino) ethyl, etc.),
Alkanoylaminoalkyl (N-acetylaminomethyl, N-propionylaminomethyl, N-butyrylaminomethyl, 2- (N-acetylamino) ethyl, etc.),
Bisarylmethylene (bis (4-fluorophenyl)
Methylene, bis (4-chlorophenyl) methylene, etc.)
Etc., and V can be the same or different and 1 to 4 can be substituted. Hydrogen as R ⁵ in the N-R ^5, alkyl (as defined above), cyanoalkyl (cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl etc.), hydroxyalkyl (as defined above),
Aryl (as defined above), arylalkyl (as defined above), alkoxycarbonyl (as defined above), diarylalkyl (diphenylmethyl, bis (4-fluorophenyl) methyl, 2,2-diphenylethyl, 2,2-
Bis (4-fluorophenyl) ethyl etc.), heteroaryl (as defined above), heteroarylalkyl (as defined above), cycloalkyl (as defined above), cycloalkylalkyl (cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl) , Cycloheptylmethyl, etc.), acyl (as defined above), cinnamyl, adamantanemethyl and the like. The cyclic amino of formula (1) may contain a carbonyl group in the ring and may be further fused with aryl or heteroaryl, which are benzene, naphthalene, furan, thiophene, pyridine,
A fused cyclic amino with quinoline, for example, 1,
2,3,4-tetrahydroisoquinolin-2-yl, phthalimide and the like can be mentioned. The ring Am of the formula (2) has an amide bond in the ring and further has an oxygen atom, a sulfur atom, carbonyl and / or N—R ⁶ (R ⁶ represents hydrogen, alkyl or phenyl). Good. Examples of the ring Am having an amide bond in the ring include thiazolidinone, imidazolidinone, pyrazolidinone and pyrrolidinone. Ring Am can also be further fused with a 5 to 7 membered saturated or unsaturated ring, such as 2-oxo-1,2,3,5,6,7,8,8a-.
Octahydroimidazo [1,2-a] pyridine-3-spiro-4′-piperidino and the like can be mentioned. In the above definition, the (hetero) aromatic ring or heterocycle may have 1 to 3 substituents (halogen, nitro, amino, cyano, haloalkyl, hydroxyl group, alkyl, alkoxy, alkenyl, etc.) Good.

The pharmaceutically acceptable acid addition salts of the compound of the general formula (I) are hydrochloride, hydrobromide, phosphate, sulfate, p-toluenesulfonate, benzenesulfonate, It includes salts such as methanesulfonate, citrate, lactate, maleate, fumarate, tartrate, oxalate and the like. The present invention also includes hydrates and solvates of the compounds of general formula (I). The general formulas (I) and (II-
When the compounds a) to (II-e) have asymmetric carbon atoms, they can be obtained in the form of a racemic mixture or optical isomers, and when they have at least two asymmetric atoms, As a diastereomer or a mixture thereof. The invention also includes mixtures and individual isomers thereof. The present invention also includes stereoisomers.

Preferred compounds of the present invention have the general formula (I)
In, T is -NHRa (Ra is optionally hydrogenated and represents a heteroarylalkyl which may have 1 to 3 substituents) or T is -N (Rb) (R
c) [In the formula, Rb and Rc are the same or different and each represents alkyl, arylalkyl or heteroarylalkyl, or Rb and Rc are bonded to each other to form a compound having an adjacent nitrogen atom;

[Chemical 17] It is also possible to form the cyclic amino represented by
In the formula, q represents an integer of 1 to 4, Z is methylene or N
-R ⁵ (R ⁵ is aryl, diaryl alkyl, heteroaryl, heteroarylalkyl or acyl) shows a. V of the substituent is hydrogen, hydroxyl group, carbamoyl, cyclic amino, aryl, arylalkylamino, heteroaryl or bisarylmethylene, and 1 to 4 of the same or different can be substituted. The cyclic amino of the formula (1) may contain a carbonyl group in the ring and may be further condensed with aryl or heteroaryl. The ring Am of the formula (2) has an amide bond in the ring, and may further have a sulfur atom and / or N—R ⁶ (R ⁶ represents phenyl). Ring Am can also be fused with a 5 to 7 membered saturated or unsaturated ring. In the above definition, the aromatic ring or heterocyclic ring may have 1 to 3 substituents. ] It is a compound which is. The preferred definition of T is the formula

[Chemical 18] [In the formula, Z represents NR ⁵ (R ⁵ represents pyrimidinyl which may have a substituent), the substituent V is hydrogen, and q is 2
Indicates. ] The cyclic amino represented by

[Chemical 19] (In the formula, R ^{3 ′} represents hydrogen, halogen, nitro, amino, cyano, hydroxyl group, alkyl, alkoxy or haloalkyl.). A preferred definition of E ¹ , E ² and E ³ is that E ¹ is C—R ¹ and E ² is C—R ² , E ^3.
Is a sulfur atom, and R ¹ and R ² have the same meanings as described above, but preferably the same or different, hydrogen, halogen, nitro, amino, cyano, hydroxyl group, formyl, alkyl, alkoxy, haloalkyl, aryl. Alkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl,
It represents alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl or haloalkyl.
A preferred definition of A, B and n is when A and B are carbonyl and n is 1 or 2, or one of A and B is absent and the other is carbonyl and n is 2 or 3. More preferably, one of A and B is absent, the other is carbonyl, and n is 2. The preferred definition of Q is
It is a straight chain or branched alkylene having 1 to 10 carbon atoms, and more preferably alkylene having 1 to 8 carbon atoms. More preferred definitions of D -CH ₂ - and the like.

The present invention also has the general formula

[Chemical 20] (In the formula, R ¹ and R ² are the same or different and are hydrogen, halogen, nitro, amino, cyano, hydroxyl group, formyl, alkyl, alkoxy, haloalkyl, aralkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, Alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl or haloalkanoyl, R ^{3 ′}
Is as described above, and when A and B are both carbonyl groups, or when one of A and B is absent and the other is a carbonyl group, and n ′ is a carbonyl group. 2 or 3, otherwise 3 or 4 is shown, and Q is a straight-chain alkylene having 1 to 10 carbon atoms or a branched alkylene. And a pharmaceutically acceptable acid addition salt thereof.
Further, the present invention provides a general formula

[Chemical 21] (In the formula, R ¹ , R ² and R ^{3 ′} are as described above,
t represents an integer of 1 to 8, A and B do not exist or represent a carbonyl group, but when A is absent, B is a carbonyl group, and when A is a carbonyl group, B is absent. And a pharmaceutically acceptable acid addition salt thereof. Furthermore, the present invention also provides that T is a formula

[Chemical formula 22] [In the formula, Z is methylene or NR ⁵ (R ⁵ is aryl, diarylalkyl, heteroaryl other than pyrimidinyl, heteroarylalkyl or acyl)
Indicates. The substituent V is hydrogen, hydroxyl group, carbamoyl, cyclic amino, aryl, arylalkylamino, heteroaryl or bisarylmethylene, and 1 to 4 of them can be substituted. q indicates 2. In the above definition, the aromatic ring or heterocyclic ring may have 1 to 3 substituents. ] The compound of general formula (I) which is this, or its pharmaceutically acceptable acid addition salt is also provided.

Preferred compounds of general formula (I) are:
2-Bromo-5- [4- (4- (2-pyrimidinyl)-
1-Piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-methyl-5- [4- (4- (2- Pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-
Tetrahydro-4H-thieno [3,2-c] azepine-
4-one, 2-ethyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl-5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-acetyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl-5,6,6.
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2- (1-hydroxyethyl) -5
-[4- (4- (2-Pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-
Thieno [3,2-c] azepin-4-one, 5- [4-
(4- (1,2-benzisothiazol-3-yl)-
1-Piperazinyl) butyl] -2-methyl-5,6
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 5- [4-[(1,4-benzodioxan-2-yl) methylamino] butyl] -2-methyl- 5,6,7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2,3-dihydro-4- [4- (4- (2-pyrimidinyl) -1-pipet Lazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, 7-bromo-2,3-dihydro-4- [4- (4- (2-pyrimidinyl)- 1-Piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, 7-acetyl-2,3-dihydro-4- [4- (4- (2 -Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, - ethyl 2,3-dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4
Thiazepin-5 (4H) -one, 4- [4- (4-
(1,2-Benzisothiazol-3-yl) -1-piperazinyl) butyl] -2,3-dihydrothieno [3,3
2-f] -1,4-thiazepin-5 (4H) -one, 5
-[4- [4- (bis (4-fluorophenyl) methyl) -1-piperazinyl] butyl] -2-methyl-5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] azepin-4-one, 2-methyl-5- [4- (4
-(2-Pyrimidinyl) -1-piperazinyl) butyl]
-5,6,7,8-tetrahydro-4H-thieno [3,3
2-c] azepine-4,6-dione, 7-methyl-4-
[4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -2,3-dihydro-4H-thieno [3,3
2-f] [1,4] thiazepine-3,5-dione, 5-
[4- (4- (3-trifluoromethylphenyl) -1
-Piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 5- [4- (4- (2,3-dimethylphenyl)) −
1-Piperazinyl) butyl] -2-methyl-5,6
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 5- [4- (4- (2-methoxyphenyl) -1-piperazinyl) butyl] -2-methyl-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] Azepin-4-one, 2,3-dihydro-4-
[4- (4- (2-Methoxyphenyl) -1-piperazinyl) butyl] -7-methylthieno [3,2-f]-
1,4-thiazepin-5 (4H) -one and 4- [4
-(4- (Bis (4-fluorophenyl) methylene) piperidino) butyl] -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5 (4H)
-On and so on.

More preferred compounds of general formula (I) are 2-bromo-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-.
Tetrahydro-4H-thieno [3,2-c] azepine-
4-one, 2-methyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,
8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-ethyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6 ，
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-acetyl-5- [4- (4-
(2-Pyrimidinyl) -1-piperazinyl) butyl-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] azepin-4-one, 2- (1-hydroxyethyl) -5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-tetrahydro -4H-thieno [3,2-c] azepin-4-one,
2,3-Dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinylbutyl] thieno [3,2-f]
-1,4-thiazepin-5 (4H) -one, 7-bromo-2,3-dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] thieno [3. 2-
f] -1,4-thiazepin-5 (4H) -one, 7-acetyl-2,3-dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] thieno [ 3,2-f] -1,4-thiazepin-5 (4H) -one, 7-ethyl-2,3-dihydro-4- [4- (4-
(2-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepine-5 (4H)
-One, 2-methyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepine-4,6-dione and 7-methyl-4- [4- (4-
(2-Pyrimidinyl) -1-piperazinyl) butyl]-
2,3-dihydro-4H-thieno [3,2-f] [1,
4] Thiazepine-3,5-dione and the like.

As a preferred intermediate of the present invention, in the general formulas (II) and (IV), E ¹ is C—R ¹ , E
^A compound in which ² is C—R ² and E ³ is a sulfur atom, that is, a compound represented by the general formula

[Chemical formula 23] (In the formula, each symbol is represented by the general formula (II) or the general formula (IV)
As defined in. ). The present invention relates to a pharmaceutical composition comprising a thiophene-fused compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical additive, particularly an anxiolytic drug, an antipsychotic drug or a cardiovascular disease therapeutic drug. I will provide a.

The synthetic method of the compound of the present invention is as follows. Method (1) The compound of the general formula (I) is a compound of the general formula (II-a) and a compound represented by the general formula HT (III) (wherein T is as defined above) or an acid thereof. Obtained by reacting with an addition salt. The reaction is carried out in a suitable solvent such as methanol, ethanol, propanol, benzene, toluene, dimethylformamide, tetrahydrofuran, acetonitrile,
In the presence of a suitable deoxidizing agent (potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, sodium acetate, potassium acetate, etc.) in a solvent that does not inhibit the reaction such as acetone, at 20 to 150 ° C. for 30 minutes The reaction proceeds for 30 hours. In addition,
When X in the general formula (II-a) is a hydroxyl group, the reaction is carried out in a suitable solvent, for example, a solvent that does not inhibit the reaction such as dimethylformamide and benzene, in an aminophosphonium reagent (N, N-methylphenylaminotriphenylphosphonium iodide). Etc.), the reaction proceeds at 20 to 150 ° C. for 30 minutes to 5 hours. Method (2) The compound represented by the general formula (I) is a compound represented by the compound represented by the general formula (IV) and a compound represented by the general formula X-Q-T (V) (wherein each symbol has the same meaning as described above), or a compound thereof. Obtained by reacting with an acid addition salt. The reaction proceeds under the same conditions as in method (1). Method (3) The compound of general formula (I) can be obtained by reductive amination of the compound of general formula (II-b) with the compound of general formula (III). The reaction is carried out in an appropriate solvent, for example, an alcohol solvent such as methanol, ethanol, propanol, etc., in the presence of an appropriate reducing agent (sodium borohydride, sodium cyanoborohydride, etc.) at 0 ° C. to the boiling point of the solvent for 1 hour. It proceeds by reacting for 24 hours.

Among the compounds of general formula (I), for example, general formula (I ')

[Chemical formula 24] (In the formula, each symbol has the same meaning as described above.) In the compound represented by the formula, R ² is acyl and the compound in which R ² is a group derived from acyl can be synthesized by the following method. Method (4) In the general formula (I ′), the compound in which R ² is acyl has the general formula (VI)

[Chemical 25] (Wherein each symbol has the same meaning as defined above) and the general formula (VII) R ⁴ COOH (VII) (In the formula, R ⁴ represents alkyl, aryl, haloalkyl, pyridyl, thienyl or furyl. )). The reaction is
The reaction is carried out at 10 ° C to 150 ° C in a suitable solvent, for example, a solvent which does not inhibit the reaction such as benzene or toluene, or in the presence of a dehydrating agent (polyphosphoric acid, phosphorus pentoxide, etc.). Method (5) In the general formula (I ′), the compound in which R ² is acyl is the compound of the general formula (VI) and the general formula R ⁴ COZ (VIII) (wherein Z represents halogen and R ⁴ is It has the same meaning as above.) And a compound represented by The reaction is carried out in a suitable solvent such as benzene,
Toluene, chloroform, dichloromethane, dichloroethane, etc., in a solvent that does not inhibit the reaction, in the presence of a suitable Lewis acid (tin chloride, iron chloride, aluminum chloride, zinc chloride, etc.), at -10 ° C to 100 ° C for 30 minutes to 5 minutes. Done in time.

Method (6) The compound of the general formula (I ') in which R ² is alkyl, aralkyl or 1-hydroxyalkyl has the general formula (IX)

[Chemical formula 26] (In the formula, R ⁵ represents alkyl, aralkyl or aryl, and the other symbols have the same meanings as described above.) And the like, or by catalytic reduction in the presence of a suitable catalyst (platinum dioxide, palladium, rhodium, etc.). The reaction proceeds in a suitable solvent (methanol, ethanol, propanol, butanol, acetic acid, etc.) at −10 ° C. to 150 ° C. to give the compound represented by the general formula (X):

[Chemical 27] (In the formula, Y represents —CHOH— or —CH ₂ —, and other symbols have the same meanings as described above.) Can be obtained. Method (7) In the general formula (I ′), the compound of the general formula (XI) in which R ² is acyloxyalkanoyl is

[Chemical 28] (In the formula, p represents an integer of 1 to 4, and other symbols have the same meanings as described above.) And a compound represented by the general formula (VI)
It is obtained by reacting a metal salt of the compound of I) (sodium, potassium, lithium, etc.). The reaction is carried out in a suitable solvent such as chloroform, methylene chloride, benzene, toluene and dimethylformamide at room temperature to 150 ° C. for 1 hour to 20 ° C.
Proceeding by keeping for a while, the general formula (XII)

[Chemical 29] (Wherein each symbol has the same meaning as defined above). Method (8) In the general formula (I ′), the compound in which R ² is alkoxyalkanoyl or aryloxyalkanoyl is
By reacting a compound of the general formula (XI) with a metal salt of an alcohol (sodium, potassium, lithium, etc.) represented by the general formula R ⁶ OH (XIII), wherein R ⁶ represents alkyl or aryl. can get. The reaction is carried out in a suitable solvent such as tetrahydrofuran,
It proceeds by keeping it at room temperature to 150 ° C. for 1 to 20 hours in a solvent which does not inhibit the reaction such as benzene, toluene and dimethylformamide, and then proceeds to the general formula (XIV)

[Chemical 30] (Wherein each symbol has the same meaning as defined above).

Method (9) In the general formula (I '), the compound in which R ² is hydroxyalkanoyl can be obtained by hydrolyzing the compound of the general formula (XII). The reaction is carried out in a suitable solvent such as methanol, ethanol, propanol, butanol,
In a solvent that does not inhibit the reaction such as water, acid such as hydrochloric acid,
-1 in the presence of an aqueous solution of sulfuric acid, phosphoric acid, nitric acid or the like, or an alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate,
The reaction proceeds from 0 ° C to 150 ° C for 1 to 20 hours, and proceeds according to the general formula (XV)

[Chemical 31] (Wherein each symbol has the same meaning as defined above). Method (10) In the general formula (I ′), R ² is acyloxyalkyl,
The compound which is an alkoxyalkyl has the general formula (XVI) obtained by the method (6).

[Chemical 32] (Wherein R ⁷ represents alkyl and other symbols have the same meanings as defined above) and the general formula R ⁸ Z (XVII) (in the formula, R ⁸ represents acyl or alkyl, and Z represents It has the same meaning as above.) And is obtained by reacting a compound represented by The reaction is carried out in a suitable solvent such as methanol, ethanol, propanol, butanol,
N, N-dimethylformamide, tetrahydrofuran,
A deoxidizing agent such as sodium hydride, sodium amide, in a solvent that does not inhibit the reaction such as benzene and toluene.
1 to room temperature in the presence of sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, etc.
It proceeds by reacting at 50 ° C for 1 to 20 hours to give a compound of the general formula (XVIII)

[Chemical 33] (Wherein each symbol has the same meaning as defined above). Method (11) In the general formula (I ′), R ² is hydroxysulfonyl,
The compound which is halosulfonyl can be obtained by reacting the compound of general formula (VI) with sulfuric acid or halosulfonic acid. The reaction proceeds at −10 ° C. to 100 ° C. in the absence of a solvent or a suitable solvent such as benzene or toluene, which does not interfere with the reaction of the general formula (XIX)

[Chemical 34] (In the formula, W represents a hydroxyl group or halogen, and other symbols have the same meanings as described above.). Method (12) In the general formula (I ′), compounds in which R ² is sulfamoyl or substituted sulfamoyl include a compound of the general formula (XIX) and a compound of the general formula HN (R ¹⁰ ) (R ¹¹ ) (XX) (wherein R ¹⁰ and R ¹¹ are the same or different and each is represented by hydrogen, alkyl, arylalkyl or aryl). The reaction is carried out in a suitable solvent such as benzene, toluene,
In the presence of a deoxidizing agent such as sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide or sodium hydroxide in a solvent that does not inhibit the reaction such as N, N-dimethylformamide or tetrahydrofuran, The reaction proceeds at 10 ° C to 150 ° C for 1 to 20 hours, and the reaction proceeds to the general formula (XXI)

[Chemical 35] (Wherein each symbol has the same meaning as defined above). The above methods (4) to (12) are carried out by the general formula (I) other than the general formula (I ′) (wherein E ¹ = C—R ¹ , E
² = sulfur ^{atom, E 3 = C-R 2} ; also applicable to or E ¹ = sulfur ^{atom, E 2 = C-R 1} , E 3 = C-R 2) in compounds.

Method (13) In the general formula (I), the compound in which T is an amino group (—NH ₂ ) is a compound of the general formula (Ia) obtained by the above method.

[Chemical 36] (Wherein each symbol has the same meaning as defined above), a compound that does not inhibit the reaction (such as methanol)
Medium, in the presence of hydrazine hydrate, kept at 20 to 150 ° C. for 1 to 20 hours. The method (14) the general formula (I), solvates T is an amino group (-NH _2), the general formula (II-c) or a compound of general formula (II-e), the reaction is not inhibited ( Lower alcohols such as methanol, ethanol, propanol, water, acetic acid,
Tetrahydrofuran, dioxane, etc.) in the presence of a nickel catalyst such as Raney nickel at 0 ° C. to the boiling point of the solvent for 1 to 24 hours. Method (15) In the general formula (I), the compound in which T is an amino group (—NH ₂ ) is prepared by reacting the compound of the general formula (II-d) with bromine and water in a solvent (such as water) that does not inhibit the reaction. It can be obtained by reacting at 0 to 100 ° C. for 1 to 24 hours in the presence of sodium oxide or potassium hydroxide.

The general formula (II-
The compound of a) is a novel compound and can be synthesized by the following method. Method (16) The compound of the general formula (II-a) is a compound of the general formula (IV) and a compound of the general formula X ¹ -Q-X ² (XXII) [wherein, X ¹ and X ² are derived from a hydroxyl group or a hydroxyl group. Reactive atom or group (halogen, methanesulfonyloxy, paratoluenesulfonyloxy, etc.) but not at the same time a hydroxyl group. Q has the same meaning as above. ]
It is obtained by reacting with a compound represented by The reaction is carried out in an appropriate solvent (for example, methanol, ethanol, propanol, N, N-dimethylformamide, benzene, toluene, tetrahydrofuran, acetonitrile, etc.) which does not interfere with the reaction with an appropriate base (sodium methoxide, sodium ethoxide, potassium). t-butoxide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc.) at -20 ° C to 15 ° C.
Proceed for 30 minutes to 5 hours at 0 ° C. Further, the compound of the general formula (II-b), which is the synthetic intermediate of the present invention, is also a novel compound and can be synthesized by the following method. The method (17) In formula (II-b) a compound of the general compound of formula (IV) and the general formula ^{X 3 -Q-COR 4 (XXIII} ) ( wherein, X ³ is chlorine, bromine, iodine, methanesulfonyloxy , A leaving group such as paratoluenesulfonyloxy, etc., and other symbols are as defined above.), But the carbonyl group is preferably a method known from organic chemistry. Can be obtained in good yield by removing the protecting group after the reaction is completed. The reaction is a suitable solvent,
For example, N, N-dimethylformamide, methanol,
A suitable base (sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium hydride, sodium hydroxide, etc.) in a solvent that does not inhibit the reaction such as ethanol, propanol, butanol, tetrahydrofuran, benzene, toluene and acetonitrile. , Potassium hydroxide, potassium carbonate, sodium carbonate, etc.) at −20 ° C. to 150 ° C. for 30 minutes to 5 hours. The synthetic intermediate of the general formula (II-a) is subjected to the same reaction as in the above methods (4) to (12), whereby R ² is acyl, alkyl, aralkyl, 1-hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl. , Aryloxyalkanoyl, hydroxyalkanoyl, acyloxyalkanoyl, alkoxyalkyl, hydroxysulfonyl, halosulfonyl,
Synthetic intermediates of general formula (II-a) that are sulfamoyl or substituted sulfamoyl can be synthesized. Further, regarding the synthetic intermediate of the general formula (II-b),
The methods of (4) to (12) can be applied.

The general formula (II-
The compounds c), (II-d) and (II-e) are also novel compounds and can be synthesized by the following method. The method (18) compounds of general formula (II-c) is represented by the compounds of the general formula (IV) and the general formula ^{X 3 -Q-CN (XXIV)} ( wherein each symbol is as defined above.) It is obtained by reacting with a compound. The reaction is carried out in a suitable solvent such as dimethylformamide, methanol,
A suitable base (sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, in a solvent that does not inhibit the reaction such as ethanol, propanol, tetrahydrofuran, benzene, toluene, acetonitrile).
Sodium hydroxide, potassium hydroxide, sodium carbonate,
(Eg, potassium carbonate) at -20 ° C to 150 ° C for 30 minutes to 5 hours. The method (19) compounds of general formula (II-d) compounds of general formula (IV) and the general formula ^{(XXV) X 3 -Q-CONH} 2 (XXV) ( wherein each symbol is as defined above. ) Is obtained by reacting with a compound represented by Reaction is a method
Proceed under the same conditions as (18). The method (29) compounds of general formula (II-e) Compounds of general formula (IV) and the general formula ^{(XXVI) X 3 -Q-NO} 2 (XXVI) ( wherein each symbol is as defined above. ) Is obtained by reacting with a compound represented by The reaction proceeds under the same conditions as in method (18). Method (21) In the general formula (I), a compound in which both A and B are carbonyl groups can be synthesized by, for example, the general formula (XXVII)

[Chemical 37] (Wherein each symbol has the same meaning as defined above) and a compound represented by the general formula H ₂ NQT (XXVIII) (wherein each symbol has the same meaning as described above). Is obtained by subjecting the compound to a dehydration reaction. Reaction is a suitable solvent that does not interfere with the reaction (acetic anhydride, toluene, benzene, chloroform, methylene chloride, pyridine, methanol, ethanol, isopropyl alcohol, dimethylformamide, tetrahydrofuran, etc.)
30 minutes to 1 at boiling point from 20 ° C with or without solvent
It progresses in 0 hours.

Method (22) The compound of the general formula (XXVII) is a novel compound, for example, the general formula (XXIX)

[Chemical 38] (In the formula, each symbol has the same meaning as described above.) A compound represented by the general formula (XXX) obtained by reacting a compound represented by the formula (Ozone) with ozone.

[Chemical Formula 39] (Wherein each symbol has the same meaning as defined above), a compound represented by a dehydrating agent (phosphorus pentoxide, dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, acid anhydride, acid halide, benzenesulfonyl chloride, etc.) is used. It is obtained by closing the ring with. The reaction of the compound of the general formula (XXIX) with ozone proceeds in a suitable solvent, for example, a solvent which does not inhibit the reaction such as methanol, ethanol, propanol or tetrahydrofuran at -20 ° C to 150 ° C for 30 minutes to 10 hours. The reaction between the compound of the general formula (XXX) and the dehydrating agent is solvent-free or a suitable solvent (ether, dichloromethane,
Tetrahydrofuran, etc.) at 10 to 150 ° C for 3
It progresses from 0 minutes to 10 hours. Method (23) The compound of the general formula (XXVII) can be prepared, for example, by the general formula (XXXI)

[Chemical 40] (In the formula, each symbol has the same meaning as above.) A compound represented by the general formula (XXXII) is obtained by introducing a formyl group by a Vilsmeier reaction or the like.

[Chemical 41] (In the formula, each symbol has the same meaning as above.) The formyl group of the compound represented by the formula is oxidized by a method known in organic chemistry to obtain the general formula (XXX). It can also be obtained by processing.

In the compound of the general formula (IV), D is S
A compound which is (O) _m and A is a single bond and B is a carbonyl group or A is a carbonyl and B is a single bond is also a novel compound and can be synthesized, for example, by the following methods (24) and (25). Method (24) General formula (XXXIII)

[Chemical 42] (In the formula, each symbol has the same meaning as described above.) A method of subjecting the compound represented by Schmidt rearrangement. The reaction is carried out in a suitable solvent such as chloroform,
Sodium azide in the presence of a suitable acid (trifluoroacetic acid, polyphosphoric acid, sulfuric acid, etc.) in a solvent that does not inhibit the reaction of methylene chloride, toluene, benzene, etc., or in the absence of a solvent, at 0 to 150 ° C. for 30 minutes to 10 hours. The reaction proceeds. Method (25) General formula (XXXIV)

[Chemical 43] (In the formula, R ¹³ is hydrogen, alkyl, methanesulfonyl group,
It represents a paratoluenesulfonyl group and the other symbols have the same meanings as described above. ) Beckmann rearrangement of the compound represented by The reaction is carried out in a suitable solvent such as benzene, toluene, N, N-dimethylformamide, diethyl ether or the like which does not interfere with the reaction or in the absence of a suitable acid (polyphosphoric acid, sulfuric acid, phosphoric acid, phosphorus oxychloride, pentachloromethane, In the presence of phosphorus chloride, phosphorus pentoxide, etc.) at 0 to 150 ° C. for 30 minutes to 10 minutes.
It proceeds by reacting for a time. Method (26) The compound of the general formula (Ia) used in the method (13) is the compound of the general formula (IV) and the general formula (XXXV).

[Chemical 44] (In the formula, each symbol has the same meaning as described above.) The compound can be obtained by reacting with a compound represented by the formula. The reaction proceeds under the same conditions as in method (18). Method (27) Among the compounds of general formula (I), the compounds in which A and / or B is a thiocarbonyl group can be prepared by reacting a compound of general formula (I) in which they are carbonyl groups with a thionation reagent. can get. Thionation reagents include phosphorus pentasulfide, Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetan-2,4
-Disulfide] and the like. The reaction is usually carried out in a solvent inert to the reaction (pyridine, dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, chloroform, dioxane or the like, or a mixed solvent thereof),
Proceed at 30-100 ° C. Method (28) In the general formula (I), R ¹ and R ² , or R ¹ or R ² is an acylamino compound, and the compound in which they are amino can be acylated by a synthetically known method. Can be synthesized by. Further, in the general formula (I), R ¹ and R ² , or a compound in which R ¹ or R ² is acyl is reacted with hydroxylamine to perform Beckmann rearrangement of the oxime, or in the general formula (I) It can also be synthesized by a Schmidt rearrangement method of a compound in which R ¹ and R ² , or R ¹ or R ² is acyl. The method for synthesizing an oxime is a compound of the general formula (I) in which R ¹ and R ² , or R ¹ or R ² is acyl, and hydroxylamine hydrochloride are treated with a base such as potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, or hydroxide. In the presence of potassium, triethylamine, etc., a suitable solvent,
For example, in a solvent that does not inhibit the reaction such as benzene, toluene, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran, methanol, ethanol,
The process proceeds from room temperature to the reflux temperature of the solvent. The Beckmann rearrangement reaction is carried out by treating the above oxime in polyphosphoric acid at 60 ° C to 120 ° C.
It proceeds by reacting at ℃. The Schmidt rearrangement reaction is carried out by using R ¹ and R ² or R in the general formula (I).
It proceeds by reacting a compound in which ¹ or R ² is acyl with sodium azide in polyphosphoric acid or sulfuric acid at 0 ° C to 100 ° C.

Method (29) The compound of the general formula (I) has the general formula

[Chemical 45] (Wherein R ¹⁴ represents alkyl, X ⁴ represents halogen, and other symbols have the same meanings as defined above), and the compound represented by the general formula (III) Be done. The reaction is carried out in a suitable solvent such as methanol, ethanol, benzene, toluene,
The reaction proceeds in a solvent that does not inhibit the reaction, such as dimethylformamide and 1,3-dimethyl-2-imidazolidinone, at 50 to 150 ° C. for 1 to 10 hours. Method (30) The compound of the general formula (XXXVI) includes a compound of the general formula (I) in which T is a tertiary amino and a compound of the general formula R ¹⁴ X ⁴ (XXXVII) (wherein each symbol has the same meaning as described above). .) And a compound represented by The reaction is carried out in a suitable solvent such as benzene, toluene, acetone, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran, methanol, ethanol, acetonitrile or the like which does not inhibit the reaction at -20 ° C.
To the solvent reflux temperature for 10 minutes to 5 hours. Method (31) The compound of the general formula (I) in which T is —NH ₂ and the general formula R ¹⁵ X ³ (XXXVIII) (wherein, R ¹⁵ represents alkyl or arylalkyl, X
³ has the same meaning as above. By reacting a compound represented by), T is -NHR ¹⁵ and -N
A compound of the general formula (I) is obtained which is (R ¹⁵ ) (R ¹⁵ ), where R ¹⁵ is as defined above. The reaction is carried out with a suitable solvent,
For example, in a solvent that does not inhibit the reaction such as methanol, ethanol, propanol, dimethylformamide, tetrahydrofuran, benzene, and toluene, a suitable deoxidizing agent (triethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, In the presence of potassium hydroxide, etc., the reaction proceeds from 0 ° C. to around the boiling point of the solvent. Further, a compound of the general formula (I) in which T is —NHR ¹⁵ and a general formula R ¹⁶ X ³ (XXXIX) (wherein, R ¹⁶ represents alkyl or arylalkyl, X
³ has the same meaning as above. ) Is reacted with a compound represented by the formula (1) to give T-N (R ¹⁵ ) (R ¹⁶ ).
(R ¹⁵ and R ¹⁶ have the same meanings as defined above)
The compound of The reaction proceeds under the same conditions as above. Method (32) A compound of the general formula (I) in which T is —NH ₂ and the general formula

[Chemical 46] [Wherein, i and j are 1 to 3 respectively, J is an oxygen atom,
A sulfur atom, CH—R ¹⁷ or N—R ¹⁷ (R ¹⁷ represents hydrogen, alkyl, arylalkyl or heteroaryl), and X ³ has the same meaning as described above. ] By reacting a compound represented by

[Chemical 47] (In the formula, each symbol has the same meaning as defined above.) A compound of the general formula (I) is obtained. The reaction is carried out in a suitable solvent such as methanol, ethanol, propanol,
Presence of a suitable deoxidizing agent (triethylamine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.) in a solvent that does not interfere with the reaction such as dimethylformamide, tetrahydrofuran, benzene, and toluene. The reaction proceeds from 0 ° C to around the boiling point of the solvent.

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 obtained product is a racemate, it can be resolved into a desired optically active substance, for example, by fractional recrystallization with an optically active acid or by passing through a column packed with an optically active carrier. The 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. In addition, stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

[0025]

The excellent pharmacological activity of the compound of the general formula (I) is proved by the series of tests shown below. Experimental Example 1 Affinity for Serotonin 1A Receptor ³ H-8-Hydroxy-2-dipropylaminotetralin ( ³ H-8-OH-DPAT) Binding Experiment The crude synaptic membrane preparation and binding experiment were performed by the method of Hall et al. [Journal of Neurochemistry (Jour
nal of Neurochemistry) 44, 1685, 198.
5 years]. 4 frozen rat hippocampus
0 volumes of ice-cold 50 mM Tris-HCl buffer (pH
7.4), and the mixture was centrifuged at 500 xg at 0 ° C for 10 minutes. Further, the supernatant was centrifuged at 40,000 × g at 0 ° C. for 20 minutes, the obtained precipitate was suspended in 40 times the amount of the above buffer solution, and reacted at 37 ° C. for 10 minutes. 40,0 after completion of reaction
Centrifuge at 00 xg for 20 minutes at 0 ° C,
It was washed by repeating the operation of suspension-centrifugation in twice the amount of the above buffer solution twice. The finally obtained precipitation was ice-cooled 6
It was suspended in a 50 mM Tris-hydrochloric acid buffer solution (pH 7.4) containing 0 mM amount of 1 mM manganese chloride and used as a crude synaptic membrane sample. To 900 μl of the membrane sample, 50 μl of tritiated 8-OH-DPAT solution and 50 μl of the test compound solution or its solvent, which were prepared so as to have a final concentration of 0.2 nM, were added and reacted at 37 ° C. for 10 minutes. After completion of the reaction, 5 ml of ice-cooled 50 mM Tris-hydrochloric acid buffer solution (pH 7.4)
, And immediately suction-filter with Whatman GF / B filter, and filter with 2 ml of the same buffer solution.
I washed it twice. Radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding 10 ^-5 M
It was determined in the presence of serotonin (5-HT). The 50% inhibitory concentration (IC ₅₀ ) of the test compound was graphically determined, and the inhibition constant (Ki value) was determined. The results are shown in Table A. Experimental Example 2 Affinity for serotonin 2 receptor; ³ H-
Ketanserin binding experiments The preparation of crude synaptic membranes and binding experiments were carried out by the method of Leysen et al. [Molecular Phar
(Macology) Volume 21, p. 301, 1981]. Cryopreserved rat cerebral cortex was homogenized with a 30-fold amount of ice-cooled 0.32M sucrose solution and centrifuged at 1,000 × g at 0 ° C. for 10 minutes. 4 supernatants
Centrifugation was carried out at 0,000 xg for 20 minutes at 0 ° C, and the obtained precipitate was mixed with 30 volumes of ice-cold 50 mM Tris-HCl buffer (pH
It was homogenized to 7.7) and incubated at 37 ° C for 10 minutes. It was centrifuged again at 40,000 × g at 0 ° C. for 20 minutes, and the obtained precipitate was homogenized in 100 times the amount of the above buffer solution and used as a crude synaptic membrane solution. Prepared in 900 μl of synaptic membrane solution to a final concentration of 0.2 nM
50 μl of ³ H-ketanserin solution and 50 μl of the test compound solution or its solvent were added, and the mixture was reacted at 37 ° C. for 20 minutes. Immediately after the reaction, Whatman G
After suction filtration with an F / B filter, the filter was washed 3 times with 5 ml of the above buffer solution. Radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding was determined in the presence of 10 μM mianserin. The 50% inhibitory concentration (IC ₅₀ ) of the test compound was graphically determined, and the inhibition constant (Ki value) was determined. The results are shown in Table A. Experimental Example 3 Affinity for dopamine 2 receptor; ³ H-
Spiperone Coupling Crude synapse membrane preparation and binding experiments are performed by the method of I. Creese et al. [European Journal of Pharmacol., 46, 377, 197].
7 years]. Cryopreserved rat striatum was 100 times ice-cooled in 50 mM Tris-HCl buffer (p
H7.7) and homogenize at 500 xg at 0 ° C for 10
Centrifuged. Supernatant at 50,000 xg at 0 ° C for 15
Centrifugation was performed, the obtained precipitate was homogenized in 100 times the amount of the above-mentioned buffer, and the mixture was centrifuged again at 50,000 xg for 15 minutes at 0 ° C. The obtained precipitate was homogenized in 150 volumes of 50 mM Tris-hydrochloric acid buffer (pH 7.1) containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 0.1% ascorbic acid and 10 μM purgerin. 10 at 37 ° C
After a minute reaction, it was used as a crude synaptic membrane fluid. To 900 μl of synaptic membrane solution, 50 μl of ³ H-spiperone solution and 50 μl of test compound solution or its solvent, which were prepared to a final concentration of 0.2 nM, were added, and the mixture was added at 20 ° C. at 37 ° C.
It was made to react for minutes. Whatman (Wh
After suction filtration with an atman) GF / B filter, the filter was washed 3 times with 5 ml of the above buffer solution. Radioactivity on the filter was measured with a liquid scintillation counter. The amount of non-specific binding was 100 μM (±) -sulpiride (Sulpirid
e) Determined in the presence. 50% inhibitory concentration of test compound (IC
₅₀ ) was determined graphically and the inhibition constant (Ki value) was determined. The results are shown in Table A. Table A ────────────────────────────────── Test compound Example number Ki (nM) of receptor binding force ) ─────────────────────── 5-HT _1A 5HT ₂ D ₂ ────────────────── ──────────────── 11 0.89 900.0 100.0 13 (maleate) 1.6 1400.0 190.0 15 (hydrochloride) 2.1 1500.0 140.0 46 1.3 990.0 78.0 103 5.2 1800.0 1800.0 107 1.5 990.0 120.0 117 4.1 1800.0 270.0 121 1.4 1100.0 150.0 155 0.81 2100.0 170.0 163 0.15 1200.0 6.2 ───────────────────────────────────

Experimental Example 4: Anti-anxiety activity (Vogel type conflict test) The experiment was carried out according to the method of Vogel et al.
In the test, Wistar rats that had been dewatered 72 hours before the start of the test were used. The test equipment is made of plastic and has a light room (38 × 38 × 20 cm) and a dark room (10 × 10 × 20c).
m), with a stainless steel water supply nozzle attached to the outer center, so that the water supply nozzle (3 cm in length) was located 10 cm above the grid floor. A doricometer circuit (Nihon Kohden) was connected to the water supply nozzle, and the number of times of drinking water was measured. Place the rat in the device and
Electric shock (0.2-0.
3 mA, 0.3 seconds). The number of shocks received for 3 minutes after the rat received the first electric shock was recorded. The test compound was orally administered 1 hour before the test. Control group (0.
5% MC treatment group), the number of drinking water in the test compound treatment group was statistically significant (One-way ANOVA test; P <0.0).
5) The amount at which a significant increase was observed was determined as the minimum effective dose (MED). The results are shown in Table B. Table B ─────────────────────────── Anxiolytic effect of test compounds Example number MED (mg / kg, po) ─── ──────────────────────── 13 (maleate) 1.0 15 (hydrochloride) 2.5 46 ≦ 1.0 117 5.0 155 2.5 163 2.5 ──── ─────────────────────── Experimental Example 5: Toxicity test The compound of the present invention was orally administered to male ddY mice (1000
mg / kg) or intraperitoneal administration (300 mg / kg)
However, when observed for 5 days, no deaths were observed in any of them. From the results of various pharmacological tests, the compound (I) of the present invention shows that serotonin 1A (5-HT _1A ), serotonin 2
It is clear that it has a high affinity for the (5-HT ₂ ) and dopamine 2 (D ₂ ) receptors. Among the compounds of the present invention, the compound having a selective high affinity for 5-HT _1A receptor is useful as an excellent anxiolytic drug with few extrapyramidal side effects. Further, compounds having a strong affinity not only for D ₂ receptors but also for 5-HT _1A and 5-HT ₂ receptors can be used for positive symptoms such as hallucinatory delusions, psychomotor excitement, and apathy, apathy, cognitive impairment, etc. It is effective against negative symptoms and is useful as an antipsychotic drug with reduced extrapyramidal side effects. Furthermore, the compound of the present invention is 5
Since it lowers blood pressure and heart rate through the HT _1A receptor, it can be used as a therapeutic agent for circulatory disorders such as antihypertensive agents without sympathetic tone. In addition, the general formula (II),
The compound of (IV) is useful as a synthetic intermediate thereof. When the compound of the general formula (I) of the present invention is used as a medicine, a therapeutically effective amount of the compound is mixed with an appropriate pharmacologically acceptable excipient, carrier, diluent or the like additive,
It can be administered in the form of tablets, capsules, granules, syrups, injections, suppositories or powders. In the case of oral administration, for example, the dose is usually about 5 to 500 mg per day for an adult, and this can be administered once or in several divided doses.

Formulation Example of Pharmaceutical Composition A tablet containing 10 mg of the compound (I) of the present invention can be prepared by the following formulation. Compound (I) 10.0 mg Lactose 58.5 mg Corn starch 25.0 mg Crystalline cellulose 20.0 mg Polyvinylpyrrolidone K-30 2.0 mg Talc 4.0 mg Magnesium stearate 0.5 mg 120.0 mg Compound (I) is ground with an atomizer. To obtain fine powder having an average particle diameter of 10 μm or less. After thoroughly mixing the compound (I), lactose, corn starch and crystalline cellulose in a kneader, a polyvinylpyrrolidone paste solution is added and kneaded. Granulate the kneaded product through a 200-mesh sieve, and
Dry in a hot air dryer at 0 ° C until the water content becomes 3-4%,
After passing through a 24 mesh sieve, talc and magnesium stearate are mixed and then mixed by a rotary tabletting machine.
Tablets are made using a flat punch with a diameter of 8 mm.

[0028]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto. Example 1 5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] To a solution of 10 g of azepin-4-one in 120 ml of dimethylformamide, while stirring under ice cooling, potassium t-
Add 8.7 g of butoxide and stir at room temperature for 2 hours.
Then, the mixture was ice-cooled again and 4-bromo-1-chlorobutane 9.0 was added.
ml is added, and the mixture is further reacted at room temperature for 4 hours. After completion of the reaction, the reaction solution is poured into ice water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 5 as a pale yellow oily substance was obtained from the fraction eluted with chloroform.
-(4-chlorobutyl) -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one 1
0.0 g is obtained. Example 2 5,6,7,8-Tetrahydro-4H-thieno [3,2
-B] To a solution of 7.4 g of azepin-4-one in 70 ml of dimethylformamide, while stirring under ice cooling, potassium t-
Add 6.5 g of butoxide and stir at room temperature for 2 hours.
After that, it was ice-cooled again and 4-bromo-1-chlorobutane 6.6 was used.
g, and the mixture is further reacted at room temperature for 4 hours. After completion of the reaction, the reaction solution is poured into ice water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 4 as a pale yellow oily substance was obtained from the fraction eluted with chloroform.
9.5 g of-(4-chlorobutyl) -4,6,7,8-tetrahydro-5H-thieno [3,2-b] azepin-5-one are obtained. By carrying out the same reaction and treatment as in the above-mentioned Examples, for example, the following compounds are obtained. Example 3 5- (4-chlorobutyl) -2-methyl-5,6,7,
8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one Example 4 4- (4-chlorobutyl) -2-methyl-4,6,7,
8-Tetrahydro-5H-thieno [3,2-b] azepin-5-one Example 5 5- (4-chlorobutyl) -5,6,7,8-tetrahydro-4H-thieno [3,2-c] A solution of 2.1 g of bromine in 5 ml of acetic acid was added dropwise to a solution of 3.0 g of azepin-4-one in 20 ml of acetic acid over 10 minutes. After that, after reacting at room temperature for 3 hours,
The reaction solution is poured into ice water, extracted with chloroform, washed with water, and dried over magnesium sulfate. Then, it was concentrated under reduced pressure to give 2-bromo-5- (4-chlorobutyl) -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one4. 0 g is obtained. This product was used in the next reaction without purification.

By carrying out the same reaction and treatment as in the above-mentioned examples, for example, the following compounds are obtained. Example 6 2-Bromo-4- (4-chlorobutyl) -4,6,7,
8-Tetrahydro-5H-thieno [3,2-b] azepin-5-one Example 7 To a suspension of 2.8 g of aluminum chloride in 20 ml of dichloromethane was added acetyl chloride 1.7 g under ice cooling, and the mixture was kept at the same temperature. And stir for 10 minutes, then 5- (4-chlorobutyl)-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] Azepin-4-one 1.8 g of dichloromethane 5
Add ml solution. After that, react at room temperature for 5 hours and pour into ice water. Extract with chloroform, wash with water, dry over magnesium sulfate, and concentrate under reduced pressure. When the obtained crystals were recrystallized from a mixed solvent of ethyl acetate and isopropyl ether, white crystals of 2-acetyl-5- (4-chlorobutyl) -5,6,7,8-tetrahydro-4H-thieno [3,3] were obtained. 2-c] azepin-4-one is obtained. Melting point 64-65 ° C. By carrying out the same reaction and treatment as in the above-mentioned Examples, for example, the following compounds are obtained. Example 8 2-Acetyl-4- (4-chlorobutyl) -4,6
7,8-Tetrahydro-5H-thieno [3,2-b] azepin-5-one Example 9 5- (4-chlorobutyl) -5,6,7,8-tetrahydro-4H-thieno [3,2- c] Azepin-4-one 3.0 g of toluene-dimethylformamide (1: 1)
In a 50 ml solution, N- (2-pyrimidinyl) piperazine.
Dihydrochloride (3.0 g), potassium carbonate (3.2 g) and potassium iodide (2.0 g) are added, and the mixture is reacted at 90 ° C to 100 ° C for 6 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water and dried over magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The obtained residue was dissolved in ethanol, 1.0 g of fumaric acid was added to form fumaric acid salt, which was collected by filtration and recrystallized from ethanol to give a melting point of 188.
5- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -5,6 as white crystals at 190 ° C
3.1 g of 7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one fumarate are obtained.
By carrying out the same reaction and treatment as in the above-mentioned Examples, for example, the following compounds are obtained. Example 10 4- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -4,6,7,8-tetrahydro-5H
-Thieno [3,2-b] azepin-5-one fumarate, mp 164-166 ° C Example 11 2-Bromo-5- {4- [4- (2-pyrimidinyl)-
1-piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one fumarate, mp 174-176 ° C Example 12 2-Bromo-4 -{4- [4- (2-pyrimidinyl)-
1-piperazinyl] butyl} -4,6,7,8-tetrahydro-5H-thieno [3,2-b] azepin-5-one fumarate, mp 169-172 ° C Example 13 2-Acetyl-5 -{4- [4- (2-pyrimidinyl)
-1-Piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On, melting point 103-106 ° C, melting point of fumarate 16
6-169 ° C, melting point of maleate salt 161-163 ° C,
Hydrochloride salt melting point 205-210 ° C Example 14 2-Acetyl-4- {4- [4- (2-pyrimidinyl)
-1-Piperazinyl] butyl} -4,6,7,8-tetrahydro-5H-thieno [3,2-b] azepine-5-
On fumarate, melting point 159-162 ° C Example 15 2-Methyl-5- {4- [4- (2-pyrimidinyl)-
1-piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, melting point 86-88 ° C, fumarate 168-1.
72 ° C., melting point of hydrochloride 197 to 198 ° C. Example 16 2-Methyl-5- {6- [4- (2-pyrimidinyl)-
1-Piperazinyl] hexyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On-maleate, melting point 108-110 ° C Example 17 2-Acetyl-4- {4- [4- (2-pyrimidinyl).
-1-Piperazinyl] butyl} -4,6,7,8-tetrahydro-5H-thieno [3,2-b] azepine-5-
2.7 ml of triethylsilane was added to 35 ml of trifluoroacetic acid (3.5 g), and the reaction was carried out at room temperature for 20 hours. After completion of the reaction, the reaction solution is poured into water, made alkaline with potassium carbonate, extracted with ethyl acetate, washed with water and dried. After concentration under reduced pressure, the residue was dissolved in acetone and fumaric acid was added to 1.5.
g is added and, after forming the fumarate, it is collected by filtration. When recrystallized from ethanol, 2-ethyl-4- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -4,6,7,8-as white crystals having a melting point of 156 to 158 ° C.
Tetrahydro-5H-thieno [3,2-b] azepine-
2.0 g of 5-one fumarate is obtained.

By carrying out the same reaction and treatment as in the above-mentioned examples, the compounds shown in Tables 1 and 2 are obtained.

[Table 1]

[Table 2]

Example 42 When propionyl chloride was used in place of acetyl chloride in Example 7 and the same reaction and treatment were carried out, the melting point was 9
5- (4-chlorobutyl) as white crystals at 1 to 92 ° C
-5,6,7,8-tetrahydro-2-propionyl-
4H-thieno [3,2-c] azepin-4-one is obtained. By performing the same reaction and treatment as in Example 9, for example, the following compound is obtained. Example 43 2-Methyl-4- {4- [4- (2-pyrimidinyl)-
1-piperazinyl] butyl} -4,6,7,8-tetrahydro-5H-thieno [3,2-b] azepin-5-one oxalate, mp 155-156 ° C. Example 44 2-Methyl-5 -{3- [4- (2-pyrimidinyl)-
1-Piperazinyl] propyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On dihydrochloride, melting point 226-227 ° C Example 45 2-propionyl-5- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -5,6,7,8-
Tetrahydro-4H-thieno [3,2-c] azepine-
4-one, melting point 109-111 ° C. Example 46 2-Acetyl-4- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -4,6 of Example 17.
Instead of 7,8-tetrahydro-5H-thieno [3,2-b] azepin-5-one, 2-acetyl-5- {4-
Similar reactions and treatments were performed using [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one. Melting point 151-154 ° C
As white crystals of 2-ethyl-5- {4- [4- (2
-Pyrimidinyl) -1-piperazinyl] butyl} -5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] Azepin-4-one fumarate is obtained. Example 47 2-Acetyl-4- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -4,6 of Example 17
Instead of 7,8-tetrahydro-5H-thieno [3,2-b] azepin-5-one, 2-propionyl-5-
{4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-
By performing the same reaction and treatment using thieno [3,2-c] azepin-4-one, a melting point of 123-1
As white crystals at 25 ° C., 2-propyl-5- {4-
[4- (2-Pyrimidinyl) -1-piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one fumarate is obtained.

The following compounds are obtained in the same manner as in the above examples. Example 48 2-Methyl-5- {4- [4- (2-pyrimidinyl)-
1-Piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, melting point 86-88 ° C. Hydrochloride, melting point 197-198 ° C Example 49 4- {3- [4- (2-pyrimidinyl) -1-piperazinyl] propyl} -4,6,7,8-tetrahydro-5
H-thieno [3,2-b] azepin-5-one oxalate, mp 171-173 ° C Example 50 5- {4- [4- (2-pyrimidinyl) -1-piperazinyl] pentyl} -5 , 6,7,8-Tetrahydro-4
H-thieno [3,2-c] azepin-4-one fumarate, mp 174-176 ° C Example 51 5- (4-chlorobutyl) -2-methyl-5,6,7,
To a solution of 4.2 g of 8-tetrahydro-4H-thieno [3,2-c] azepin-4-one in 50 ml of toluene-dimethylformamide (1: 1), 4- [bis (4-fluorophenyl) methylene] piperidine 4 was added. 0.8 g, potassium carbonate 4.6 g, and potassium iodide 2.5 g are added, and 90 ° C-
React at 100 ° C. for 6 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water and dried over magnesium sulfate, and ethyl acetate is distilled off under reduced pressure. The obtained residue was dissolved in ethanol, 1.0 g of fumaric acid was added to form fumaric acid salt, which was collected by filtration and recrystallized from ethanol to give white crystals with a melting point of 203 to 204 ° C.
-{4- [4- [bis (4-fluorophenyl) methylene] piperidino] butyl} -2-methyl-5,6,7,
1.4 g of 8-tetrahydro-4H-thieno [3,2-c] azepin-4-one fumarate are obtained. By carrying out the same reaction and treatment as in the above-mentioned Examples, for example, the following compounds are obtained. Example 52 4- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} -4,6,7,8-tetrahydro-
5H-thieno [3,2-b] azepin-5-one base,
Melting point 212-214 ° C (decomposition) Example 53 2-Methyl-5- [4-morpholinobutyl] -5,6.
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one hydrochloride, mp 235-236 ° C Example 54 5- {4- [4- (4-fluorobenzoyl) piperidino] butyl} 2-Methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one hydrochloride, mp 238-241 ° C Example 55 5- {4- [4- ( 1,3-dihydro-2-oxo-2
H-benzimidazol-1-yl) piperidino] butyl} -2-methyl-5,6,7,8-tetrahydro-4
H-thieno [3,2-c] azepin-4-one hydrochloride,
Melting point 259-261 ° C

Example 56 2-Methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one A solution of 5.0 g of dimethylformamide in 70 ml of dimethylformamide was stirred under ice cooling. t-
4.4 g of potassium butoxy potassium is added, and the mixture is stirred at room temperature for 1 hour. After stirring, the mixture was ice-cooled again, and bromoacetaldehyde (2
After dropwise adding 7.1 g of -bromo-1,1-diethoxyethane), the reaction solution is stirred at 60 ° C for 5 hours. After the reaction, the reaction solution is poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried with magnesium sulfate. The oil obtained by concentration under reduced pressure was subjected to silica gel chromatography, and 5- (2,2-diethoxyethyl) -2-methyl-5,6,7 as a pale yellow oil was obtained from the fraction eluted with chloroform. 2.5 g of 8,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one are obtained. 5
-(2,2-diethoxyethyl) -2-methyl-5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] 10 ml of 10% aqueous hydrochloric acid was added to 30 ml of a tetrahydrofuran solution containing 2.1 g of azepin-4-one, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 5- (2-formylethyl) -2-methyl-5,6,7,8-tetrahydro-4.
H-thieno [3,2-c] azepin-4-one 1.39
get g. 5- (2-formylethyl) -2-methyl-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] Azepin-4-one 1.39 g of ethanol 20
To the ml solution, 2.4 g of 4- [bis (4-fluorophenyl) methylene] piperidine is added, 0.39 g of sodium cyanotrihydroborate is added, and the mixture is stirred at room temperature for 2.5 hours. After the reaction, the reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give an orange oil. This was subjected to silica gel chromatography, the fraction eluted with chloroform was concentrated under reduced pressure, the obtained residue was dissolved in ethanol, hydrochloric acid-dissolved ethanol was added to form a hydrochloride salt, which was then collected by filtration and recovered from methanol. When crystallized, melting point 228-
5- [2- [4- [bis (4
-Fluorophenyl) methylene] piperidino] ethyl]
-2-Methyl-5,6,7,8-tetrahydro-4H-
Thieno [3,2-c] azepin-4-one hydrochloride was obtained. Example 57 5- [4- [4- [bis [4- (fluorophenyl) methyl] -1-piperazinyl] butyl] -2-methyl-5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] Azepin-4-one dimaleate 1/4 hydrate, melting point 131-132 ° C. Example 58 5- [4- [4- (5-chlorobenzoxazole-2
-Yl) -1-piperazinyl] butyl] -2-methyl-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] Azepin-4-one maleate, melting point 161
˜162 ° C. Example 59 5- {6- [4- (3-chlorophenyl) -1-piperazinyl] hexyl} -2-methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c ] Azepine-4
-One maleate, melting point 149-150 [deg.] C. Example 60 5- {4- [4- (1,2-benzisothiazole-3]
-Yl) -1-piperazinyl] butyl} -2-methyl-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] Azepin-4-one hydrochloride, melting point 231-233
C. Example 61 5- {4- [4- (3-trifluoromethylphenyl)
-1-Piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On-fumarate, melting point 179-182 ° C. Example 62 5- {2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl} -5,6,7,8-tetrahydro-
4H-thieno [3,2-c] azepin-4-one hydrochloride, mp 231-233 ° C Example 63 5- {4- [4- (2,3-dimethylphenyl) -1-
Piperazinyl] butyl} -2-methyl-5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepin-4-one hydrochloride, melting point 243-247 ° C Example 64 5- {4- [4- (2-methoxyphenyl) -1-piperazinyl] butyl}. 2-Methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4
-One hydrochloride / hydrate, melting point 207-209 ° C

Similarly, the compounds shown in Tables 3 to 5 are obtained.

[Table 3]

[Table 4]

[Table 5]

Example 93 300 g of polyphosphoric acid was heated to 70 ° C. and stirred for 5, 6
-Dihydro-4H-thieno [2,3-b] thiopyran-
19.5 g of 4-one 4-oxime are added portionwise over 20 minutes. Then, after reacting at 80 ° C. for 2.5 hours, the reaction solution is added to ice water, extracted with chloroform, washed with water, and dried with magnesium sulfate. After concentrating chloroform under reduced pressure, the obtained crude crystals were recrystallized from ethanol to give 2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5 as white crystals having a melting point of 195 to 196 ° C.
10 g of (4H) -one are obtained. Example 94 5,6-Dihydro-4H-thieno [2,3-b] thiopyran-4-one used in Example 93 5,6-Dihydro-2-methyl-4H-1 eno instead of 4-oxime By performing the same reaction and treatment with [2,3-b] thiopyran-4-one 4-oxime, 2,3-dihydro- as white crystals having a melting point of 155 to 156 ° C is obtained.
7-Methylthieno [3,2-f] -1,4-thiazepin-5 (4H) -one is obtained. Example 95 The crude product obtained by the reaction of Example 94 except for the compound of the above Example 94 was purified to give 3,4-dihydro-white crystals having a melting point of 208 to 210 ° C.
7-Methylthieno [2,3-b] [1,4] thiazepin-2 (1H) -one is obtained. Example 96 2,3-Dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one 4.9 g of a solution of 4.9 g of N, N-dimethylformamide in ice-cooled solution with stirring t −
Add 3.6 g of butoxypotassium and react at room temperature for 1 hour. After that, 1-bromo-4-chlorobutane 5.4 g
Is added, and after reacting for 5 hours, water is added to the reaction solution. Extract with ethyl acetate, wash with water, dry over magnesium sulfate and evaporate the solvent. The obtained residue was subjected to silica gel column chromatography, and chloroform-methanol (99.
8: 0.2) from the fraction eluted with the mixed solvent, to give 4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5 as a pale yellow oil.
6.9 g of (4H) -one are obtained. Example 97 2,3-dihydrothieno [3,2-used in Example 96
f] -1,4-thiazepin-5 (4H) -one instead of 2,3-dihydro-7-methylthieno [3,2-f]
A similar reaction and treatment with -1,4-thiazepin-5 (4H) -one gave 4- (4-chlorobutyl).
-2,3-Dihydro-7-methylthieno [3,2-f]
-1,4-thiazepin-5 (4H) -one is obtained. Example 98 2,3-Dihydrothieno [3,2-used in Example 96
f] -1,4-thiazepin-5 (4H) -one instead of 3,4-dihydro-7-methylthieno [2,3-b]
The same reaction and treatment with [1,4] thiazepin-2 (1H) -one gives 1- (4-chlorobutyl).
-3,4-Dihydro-7-methylthieno [2,3-b]
[1,4] thiazepin-2 (1H) -one is obtained. Example 99 To a suspension of 13 g of aluminum chloride in 150 ml of methylene chloride was added 4.6 ml of acetyl chloride under ice cooling, and the mixture was stirred for 15 minutes. Later, 4- (4-chlorobutyl) -2,3
A solution of 9.0 g of dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one in 20 ml of methylene chloride was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with chloroform. After washing with water and drying over magnesium sulfate, the solvent was distilled off and the obtained crystals were recrystallized from ethyl acetate to give a melting point of 13
7-acetyl-4- (4
-Chlorobutyl) -2,3-dihydrothieno [3,2-
f] -1,4-thiazepin-5 (4H) -one 6.9 g
Is obtained. Example 100 4- (4-Chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one A solution of 3.0 g of acetic acid in 60 ml was heated to 60 ° C. , 1.5 ml of bromine is added with stirring. After reacting for 20 minutes at the same temperature,
The reaction solution is poured into ice water and extracted with chloroform.
After washing with water and drying over magnesium sulfate, the solvent was distilled off and the obtained crystals were recrystallized from ethanol to give 7-bromo-4- (4-
Chlorobutyl) -2,3-dihydrothieno [3,2-
f] -1,4-thiazepin-5 (4H) -one 2.0 g
Is obtained.

Example 101 2,3-Dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one A solution of 8.0 g of N, N-dimethylformamide in 160 ml was stirred under ice cooling. While t
-Add 6.3 g of butoxypotassium and react at room temperature for 1 hour. After that, the mixture was ice-cooled again, 8.4 ml of bromoacetaldehyde diethyl acetal was added, and after the reaction was continued at room temperature for 5 hours, water was added to the reaction solution. Extract with ethyl acetate, wash with water, dry over magnesium sulfate and evaporate the solvent. The obtained residue was subjected to silica gel column chromatography, and as a pale yellow oily substance, 4 from the fraction eluted with a mixed solvent of chloroform-methanol (99.8: 0.2).
-(2,2-Diethoxyethyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5 (4H)
-6.9 g of on are obtained. 4 obtained in this way
-(2,2-Diethoxyethyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5 (4H)
1-on-6.7 g of tetrahydrofuran in 150 ml of solution
20 ml of 0% hydrochloric acid was added, and the mixture was left at room temperature for 20 hours. The reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. When the solvent was distilled off, 4.4 g of 2,3,4,5-tetrahydro-5-oxothieno [3,2-f] -1,4-thiazepine-4-acetaldehyde was obtained as a pale yellow oily substance. Example 102 4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one 3.4 g of 100% formic acid in 30% hydrogen peroxide 2. 9 ml
Is added and reacted at room temperature for 3 hours. After that, the reaction solution is about 3
% Sodium bisulfite aqueous solution and then extracted with chloroform. After washing with water, dry with magnesium sulfate,
When the solvent was distilled off, 4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f]-was obtained as a pale yellow oily substance.
3.5 g of 1,4-thiazepin-5 (4H) -one 1,1-dioxide are obtained. Example 103 4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one 4.4 g N, N-dimethylformamide-toluene mixed solvent To 100 ml of (1: 1), 5.2 g of N- (2-pyrimidinyl) piperazine and 4.4 g of potassium carbonate were added, and the mixture was reacted at 80 ° C. for 5 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent was evaporated, the obtained residue was subjected to silica gel column chromatography, the oily substance obtained from the fraction eluted from a mixed solvent of chloroform-methanol (95: 5) was dissolved in ethanol, and fumaric acid was added. Form a salt. The precipitated crystals were recrystallized from ethanol to give white crystals with a melting point of 205 to 210 ° C.
-Dihydro-4- {4- [4- (2-pyrimidinyl)-
1-piperazinyl] butyl} thieno [3,2-f]-
2.5 g of 1,4-thiazepin-5 (4H) -one fumarate is obtained. Example 104 When N- (2-pyrimidinyl) piperazine used in Example 103 was replaced with N- (3-trifluoromethylphenyl) piperazine and the same reaction and treatment were carried out, white with a melting point of 205 to 206 ° C. was obtained. 4- {4-as crystals
[4- (3-trifluoromethylphenyl) -1-piperazinyl] butyl} -2,3-dihydrothieno [3,2
-F] -1,4-thiazepin-5 (4H) -one fumarate is obtained. Example 105 Using N- (2-methoxyphenyl) piperazine instead of N- (2-pyrimidinyl) piperazine used in Example 103 and performing similar reaction and treatment, and using hydrochloric acid instead of fumaric acid, 2,3-dihydro-4- {4- [4- (2
-Methoxyphenyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5 (4H)
-On, hydrochloride, hemihydrate is obtained.

Example 106 Instead of N- (2-pyrimidinyl) piperazine used in Example 103, N- (1,2-benzisothiazole-
A similar reaction and treatment was performed using 3-yl) piperazine, and when hydrochloric acid was used instead of fumaric acid, the melting point was 2
4- {4- [4- as white crystals at 31-233 ° C
(1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl} -2,3-dihydrothieno [3,3
2-f] -1,4-thiazepin-5 (4H) -one.hydrochloride is obtained. Example 107 7-Bromo-4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5
(4H) -one 2.0 g of N, N-dimethylformamide-toluene mixed solvent (1: 1) 40 ml, N- (2-pyrimidinyl) piperazine dihydrochloride 1.9 g, potassium carbonate 3.0 g, iodide Add 1.3g of potassium, 80 ℃
React for 5 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent is distilled off, the obtained residue is dissolved in ethanol, and fumaric acid is added to form a salt. When the precipitated crystals are recrystallized from ethanol, the melting point is 169 to 170 ° C.
7-Bromo-2,3-dihydro-4- as white crystals of
{4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one fumarate hemihydrate 2.
5 g are obtained. Example 108 4- (4-chlorobutyl) -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5
(4H) -one 2.0 g of N, N-dimethylformamide-toluene mixed solvent (1: 1) in 30 ml of N- (2-methoxyphenyl) piperazine hydrochloride 2.2 g, potassium carbonate 3.0 g, potassium iodide Add 0.5g, 80 ℃
React for 3 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent is distilled off, the obtained residue is dissolved in ethanol, and then oxalic acid is added to form a salt. The precipitated crystals were recrystallized from methanol to give 2,3-dihydro-4- {4- [4- [4] as white crystals with a melting point of 128-130 ° C.
(2-Methoxyphenyl) -1-piperazinyl] butyl} -7-methylthieno [3,2-f] -1,4-thiazepin-5 (4H) -one oxalate monohydrate 2.
5 g are obtained. Example 109 A similar reaction and treatment was performed using N- [bis (4-fluorophenyl) methyl] piperazine instead of N- (2-methoxyphenyl) piperazine used in Example 108, and replacing oxalic acid with With maleic acid,
4- {4- [4 as white crystals having a melting point of 165 to 166 ° C.
-(Bis (4-fluorophenyl) methyl) -1-piperazinyl] butyl} -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5 (4H)
-On dimaleate 1/4 hydrate is obtained. Example 110 N- (2-Methoxyphenyl) piperazine used in Example 108 was replaced with N- (diphenylmethyl) piperazine to carry out the same reaction and treatment, and maleic acid was used instead of oxalic acid. Melting point 166-168 ° C
2,3-dihydro-7-methyl-4- as white crystals of
This gives {4- [4- (diphenylmethyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one.2 maleate. Example 111 When N- (3-trifluoromethylphenyl) piperazine was used in place of N- (2-methoxyphenyl) piperazine used in Example 108 and the same reaction and treatment were carried out, the melting point was 135-137 ° C. 4- {4 as white crystals
-[4- (3-Trifluoromethylphenyl) -1-piperazinyl] butyl} -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5 (4
H) -one oxalate is obtained. Example 112 When N- (2-pyrimidinyl) piperazine was used in place of N- (2-methoxyphenyl) piperazine used in Example 108 and the same reaction and treatment were carried out, and fumaric acid was used instead of oxalic acid. , 3,3-dihydro-7-methyl-4- as white crystals, mp 196-198 ° C.
This gives {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one fumarate. Example 113 N- (hexadecyl) piperazine used in place of N- (2-methoxyphenyl) piperazine used in Example 108 was subjected to the same reaction and treatment, and hydrochloric acid was used instead of oxalic acid to give a melting point of 157. 4- [4- (4-hexadecyl) -1-piperazinyl] butyl-2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-as white crystals at ˜159 ° C. (decomposition) 5 (4H)
-On dihydrochloride hemihydrate is obtained. Example 114 A similar reaction and treatment were carried out using N- (5-chloro-1,3-benzoxazol-2-yl) piperazine instead of N- (2-methoxyphenyl) piperazine used in Example 108. , Maleic acid was used instead of oxalic acid, the white crystals with a melting point of 188 to 189 ° C.
{4- [4- (5-chloro-1,3-benzoxazol-2-yl) -1-piperazinyl] butyl} -2,3
-Dihydro-7-methylthieno [3,2-f] -1,4
-Thiazepin-5 (4H) -one maleate is obtained. Example 115 N-[(4-chlorophenyl) phenylmethyl] piperazine was used in place of N- (2-methoxyphenyl) piperazine used in Example 108, and the same reaction and treatment were carried out, and maleic acid was used instead of oxalic acid. When an acid is used, 4- [4- (4-
((4-chlorophenyl) phenylmethyl) -1-piperazinyl) butyl] -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5 (4H)
An on-maleate is obtained.

Example 116 4- (6-chlorohexyl) -2,3-dihydro-7-
Methylthieno [3,2-f] -1,4-thiazepine-5
(4H) -one 2.0 g N, N-dimethylformamide-toluene mixed solvent (1: 1) 30 ml N- (2-pyrimidinyl) piperazine dihydrochloride 3.1 g, potassium carbonate 3.0 g, iodide Add 0.5g of potassium, 80 ℃
React for 3 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent is distilled off, the obtained residue is dissolved in ethanol, and then oxalic acid is added to form a salt. The precipitated crystals were recrystallized from methanol to give 2,3-dihydro-7-methyl-4- as white crystals having a melting point of 161 to 162 ° C.
{6- [4- (2-Pyrimidinyl) -1-piperazinyl] hexyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one oxalate monohydrate 1. Three
g is obtained. Example 117 7-Acetyl-4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5
(4H) -one 6.8 g N, N-dimethylformamide-toluene mixed solvent (1: 1) 80 ml N- (2-pyrimidinyl) piperazine dihydrochloride 5.3 g, potassium carbonate 6.2 g, iodide Add 3.6g of potassium, 80 ℃
React for 8 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent was distilled off, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 7-acetyl-2,3-dihydro-4- {4 as white crystals having a melting point of 118 to 120 ° C.
-[4- (2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5
9.4 g of (4H) -one are obtained. Example 118 2,3-dihydro-7-methyl-4- {4- [4- (2
-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one in a solution of 3.9 g of acetic acid in 60 ml of sodium metaperiodate while stirring at room temperature. 10 ml of an aqueous solution of 2.5 g is added and the reaction is carried out for 2.5 hours. After that, the reaction solution was poured into ice water,
It is made alkaline with potassium carbonate and extracted with chloroform. After washing with water, it was dried over magnesium sulfate and the solvent was distilled off. The obtained residue is dissolved in isopropyl alcohol and hydrochloric acid is added to form a salt. When the precipitated crystals are recrystallized with ethanol, the melting point is 250 to 252 ° C (decomposition).
2,3-dihydro-7-methyl-4- as white crystals of
2.7 g of {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepin-5 (4H) -one 1-oxide hydrochloride are obtained. . Example 119 7-acetyl-2,3-dihydro-4- {4- [4-
(2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5 (4H)
1.0 g of 30% hydrogen peroxide is added to a solution of 2.0 g of acetic acid in 20 ml of acetic acid and reacted at room temperature for 20 hours. After that, the reaction solution is poured into an aqueous solution of about 3% sodium hydrogen sulfite and extracted with chloroform. After washing with water, it was dried over magnesium sulfate and the solvent was distilled off. The resulting crude crystals were recrystallized from ethanol to give 7-acetyl-2,3-dihydro-4- {4- [4- [4] as white crystals having a melting point of 103 to 106 ° C.
(2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5 (4H)
1.5 g of -one 1-oxide are obtained. Example 120 4- (4-chlorobutyl) -2,3-dihydrothieno [3,2-f] -1,4-thiazepin-5 (4H) -one 1,1-dioxide 4.1 g of N, N-dimethyl. Formamide-toluene mixed solvent (1: 1) in 80 ml of N-
(2-pyrimidinyl) piperazine dihydrochloride 3.2 g,
3.8 g of potassium carbonate and 2.3 g of potassium iodide are added, and the mixture is reacted at 90 ° C. for 3 hours. After that, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. The solvent was distilled off, the obtained residue was subjected to silica gel column chromatography, and the crystals obtained from the fraction eluted from the mixed solvent of chloroform-methanol (95: 5) were recrystallized from ethanol to give a melting point of 161 to 16
2,3-dihydro-4- {4- as white crystals at 3 ° C
[4- (2-Pyrimidinyl) -1-piperazinyl] butyl} -thieno [3,2-f] -1,4-thiazepine-5
3.0 g of (4H) -one 1,1-dioxide are obtained. Example 121 7-acetyl-2,3-dihydro-4- {4- [4-
(2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5 (4H)
2.9 ml of triethylsilane was added to a solution of 3.5 g of trione-acetate in 35 ml of trifluoroacetic acid and reacted at room temperature for 20 hours.
The reaction solution is added to water and made alkaline with potassium carbonate.
After extraction with chloroform, the extract is washed with water and dried over magnesium sulfate. The solvent is distilled off, the resulting residue is dissolved in ethanol, and hydrochloric acid is added to give the hydrochloride. The precipitated crystals were recrystallized from ethanol to give 7-ethyl-2,3-dihydro-4- {4 as white crystals with a melting point of 207 to 209 ° C.
-[4- (2-Pyrimidinyl) -1-piperazinyl] butyl} thieno [3,2-f] -1,4-thiazepine-5
2.0 g of (4H) -one hydrochloride.3 / 2 hydrate are obtained. Example 122 4- {2- [4- [bis (4-fluorophenyl) methylene] piperidino] ethyl} -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-5 (4H)- On-fumaric acid salt, melting point 205-207 ° C. Example 123 4- {4- [4- (bis (4-fluorophenyl) methylene] piperidino] butyl} -2,3-dihydro-7-
Methylthieno [3,2-f] -1,4-thiazepine-5
(4H) -one maleate monohydrate, melting point 96-
98 ° C. Example 124 4- {4- [4- (4-fluorobenzoyl) piperidino] butyl} -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepine-5 (4H ) -One fumarate, mp 184-185 ° C. Example 125 2,3-dihydro-7-methyl-4- (4-morpholinobutyl) thieno [3,2-f] -1,4-thiazepine-
5 (4H) -maleate, mp 196-197
C. Example 126 2,3-dihydro-4- {4- [N- (2- (3,4-
Dimethoxyphenyl) ethyl) -N-methylamino] butyl} -7-methylthieno [3,2-f] -1,4-thiazepin-5 (4H) -one fumarate, melting point 15
1 to 153 ° C. Example 127 2,3-dihydro-7-methyl-4- (4-piperidinobutyl) thieno [3,2-f] -1,4-thiazepine-
5 (4H) -on maleate, melting point 158-159
C. Example 128 4,5,6,7-tetrahydro-7- {4- [4- (2
-Pyrimidinyl) -1-piperazinyl] butyl} -8H
-Thieno [2,3-c] azepin-8-one maleate, melting point 164-167 ° C.

Thereafter, the compounds shown in Tables 6 and 7 are similarly obtained.

[Table 6]

[Table 7]

Similarly, the following compounds can be synthesized. Example 153 2,3-dihydro-7-methyl-4- [4- (2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo [1,2-a] pyridine -3-spiro-4 ^'-
Piperidino) butyl] thieno [3,2-f] -1,4-
Thiazepin-5 (4H) -one maleate hydrate, melting point 210-211 ° C Example 154 2-Methyl-5- {4- [4- (2-pyridyl) -1-
Piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one.
3/2 maleate, melting point 167-169 [deg.] C. Example 155 2- (1-hydroxyethyl) -5- {4- [4- (2
-Pyrimidinyl) -1-piperazinyl] butyl} -5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] Azepin-4-one maleate, melting point 159-
160 ° C. Example 156 4- {3- [4- (bis (4-fluorophenyl) methyl-1-piperazinyl] propyl} -2,3-dihydro-7-methylthieno [3,2-f] -1. , 4-thiazepin-5 (4H) -one, melting point 100-102 ° C. Example 157 4- (4-aminobutyl) -2,3-dihydro-7-methylthieno [3,2-f] -1,4- Thiazepine-5
(4H) -one hydrochloride, 1/4 hydrate, melting point 171-
172 ° C. Example 158 4- [4- (1,2,3,4-tetrahydro-6,7-
Dimethoxy-2-isoquinolyl) butyl] -2,3-dihydro-7-methylthieno [3,2-f] -1,4-thiazepin-5 (4H) -one maleate 1/4 hydrate, Melting point 153-154 [deg.] C. Example 159 4- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl} -2,3-dihydro-7-methylthieno [3,2-f] -1,4 -Thiazepine-5 (4
H) -one dihydrochloride hemihydrate, melting point 203-2
05 [deg.] C. Example 160 5- {4- [4- (bis (4-fluorophenyl) methyl) -1-piperazinyl] butyl} -5,6,7,8-
Tetrahydro-4H-thieno [3,2-c] azepine-
4-one-2-maleate, melting point 125-126 ° C. Example 161 2-methyl-5- {4- [4- (2-pyrimidinyl)-.
1-Piperazinyl] butyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-thione.hydrochloride.3 / 2 hydrate, melting point 235 [deg.] C. 162 7-methyl-4- {4- [4- (2-pyrimidinyl)-
1-Piperazinyl] butyl} -2,3-dihydrothieno [3,2-f] -1,4-thiazepine-3 (4H) -one fumarate, mp 190-192 ° C Example 163 5- { 4-[(1,4-benzodioxan-2-yl)
Methylamino] butyl} -2-methyl-5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepin-4-one hydrochloride, melting point 189-192 ° C.

Example 164 6,7,8,9-Tetrahydrothieno [3,2-b] azocin-5 (4H) -one 2.0 g of a solution of 2.0 g of dimethylformamide in 20 ml of dimethylformamide under ice-cooling.
g, and after stirring for 1 hour at the same temperature, 2.0 g of 1-bromo-4-chlorobutane is added. After that, the reaction is allowed to proceed at room temperature for 5 hours, the reaction solution is poured into water and extracted with ethyl acetate.
After washing with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue obtained by distilling off the solvent was chromatographed on silica gel. (4-chlorobutyl) -6,7,8,9
-Tetrahydrothieno [3,2-b] azocine-5 (4
2.8 g of H) -one are obtained. Example 165 Instead of 6,7,8,9-tetrahydrothieno [3,2-b] azocin-5 (4H) -one used in Example 164, 6,7,8,9-tetrahydrothieno [3,3]. 2-
c] Azocin-4 (5H) -one followed by similar reaction and treatment yields 4- (4-chlorobutyl) -6,6.
7,8,9-Tetrahydrothieno [3,2-c] azocin-4 (5H) -one is obtained. Example 166 4- (4-chlorobutyl) -6,7,8,9-tetrahydrothieno [3,2-b] azocin-5 (4H) -one 2.8 g dimethylformamide (20 ml) -toluene (20 ml) 2.6 g of 2-pyrimidinyl-1-piperazine dihydrochloride, 4.3 g of potassium carbonate and 1.7 g of potassium iodide are sequentially added to the above solution, and the mixture is reacted at 80 ° C. for 3 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water and dried. The crystals obtained by concentrating ethyl acetate under reduced pressure were recrystallized from ethyl acetate to give a melting point of 108-1.
6,7,8,9-Tetrahydro-4- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} thieno [3,2-b] azocine-as white powder crystals at 12 ° C.
1.2 g of 5 (4H) -one are obtained. Example 167 4- (4-chlorobutyl) -6 used in Example 166
Instead of 7,8,9-tetrahydrothieno [3,2-b] azocin-5 (4H) -one, 4- (4-chlorobutyl) -6,7,8,9-tetrahydrothieno [3,2-
c] Azocin-4 (5H) -one was used for the same reaction and treatment, the resulting pale yellow oily substance was dissolved in ethanol, and isopropyl alcohol-hydrochloric acid was added to precipitate crystals which were recrystallized from ethanol. Then, the melting point 217-
6,7,8,9 as white powder crystals at 222 ℃ (decomposition)
-Tetrahydro-5- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} thieno [3,2-
c] Azocin-4 (5H) -one hydrochloride.hemihydrate is obtained. Example 168 2-Acetyl-5,6,7,8-tetrahydro-5-
{4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} -4H-thieno [3,2-c] azepine-
4-on maleate 6.0 g ethanol 100 m
Hydroxylamine hydrochloride 0.92 g with stirring
And 4.0 g of sodium hydrogen carbonate are added, and the mixture is heated under reflux for 5 hours. After cooling, the reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The crystals obtained by washing with water and drying and then distilling off chloroform were recrystallized from a mixed solvent of ethanol-isopropyl ether to give 5,6,7,8-tetrahydro-2-white crystals having a melting point of 144 to 146 ° C. (1- (hydroxyimino) ethyl)
This gives 4.95 g of -5- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} -4H-thieno [3,2-c] azepin-4-one. Example 169 5,6,7,8-Tetrahydro-2- (1- (hydroxyimino) ethyl) -5- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} -4H- 115% of 2.4 g of thieno [3,2-c] azepin-4-one
Into 30 g of polyphosphoric acid at 70 ° C. with stirring. After reacting for 3 hours at the same temperature, it is poured into ice water and made alkaline with potassium carbonate. The precipitated crystals are collected by filtration, dried and subjected to silica gel chromatography. The crystals obtained from the fraction eluted with chloroform-methanol (95: 5) are recrystallized from ethyl acetate to give a melting point of 158-161 ° C. As white crystals, 2-acetylamino-5,6,7,8
0.65 g of tetrahydro-5- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} -4H-thieno [3,2-c] azepin-4-one are obtained. Example 170 5- {4-((1,4-benzodioxan-2-ylmethyl) amino) butyl} -2-methyl-5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepin-4-one. Hydrochloride 1.0g To a suspension of ethanol 15 ml, formalin 0.4ml was added, and then with stirring, sodium cyanoborohydride 0.3g Is added at room temperature.
After reacting for 2 hours at the same temperature, the reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. After washing with water and drying, chloroform was distilled off to obtain an oily substance, which was dissolved in ethyl acetate, and crystals precipitated by adding isopropyl alcohol-hydrochloride were recrystallized from a mixed solvent of isopropyl alcohol-ethyl acetate. 193-195 ° C
As white crystals of 5- [4- (N- (1,4-benzodioxan-2-ylmethyl) -N-methylamino) butyl] -2-methyl-5,6,7,8-tetrahydro-4
0.7 g of H-thieno [3,2-c] azepin-4-one.hydrochloride.1 / 4 hydrate is obtained. Example 171 5,6,7,8-Tetrahydro-2-methyl-4H-thieno [3,2-c] azepin-4-one A solution of 5.0 g of dimethylformamide in 70 ml of t-butoxycarlium was cooled with ice. After adding 6.8 g, the mixture is stirred at room temperature for 1 hour. Then, 4.4 g of dimethylaminoethyl chloride / hydrochloride was added, and the mixture was reacted at 60 ° C. for 5 hours. After cooling
Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing with water, drying, and concentration under reduced pressure, the oily substance obtained is dissolved in ethyl acetate, isopropyl alcohol-hydrochloric acid is added, and the precipitated crystals are recrystallized from a mixed solvent of ethanol-ethyl acetate to give a melting point of 229 to 231 ° C. As white crystals of
(2-Dimethylaminoethyl) -2-methyl-5,6,
4.0 g of 7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one.hydrochloride are obtained. Example 172 5- (2-Dimethylaminoethyl) -2-methyl-5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] To a solution of 0.9 g of azepin-4-one in 30 ml of acetone, 0.4 ml of methyl iodide is added at room temperature. After 30 minutes, the precipitated crystals were collected by filtration and washed with acetone to give N- {2-> as white crystals having a melting point of 237 to 239 ° C.
1.1 g of (5,6,7,8-tetrahydro-2-methyl-4-oxo-4H-thieno [3,2-c] azepin-5-yl) ethyl} -N, N-dimethylammonium iodide was obtained. can get.

Example 173 N- {2- (5,6,7,8-tetrahydro-2-methyl-4-oxo-4H-thieno [3,2-c] azepin-5-yl) ethyl} -N , 2-Dimethylammonium iodide 0.5 g in 1,3-dimethyl-2-imidazolidinone 20 ml suspension (2-pyrimidinyl) -1
-Add 0.52 g of piperazine and react at 130 ° C for 4 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water and dried. After the ethyl acetate was distilled off, the residue was subjected to silica gel column chromatography, and the crystals obtained from the fraction eluted with chloroform-ethanol (97: 3) were recrystallized from a mixed solvent of ethyl acetate-isopropyl ether to give a melting point of 137. 2 as light brown crystals at ~ 139 ° C
-Methyl-5- {2- (4- (2-pyrimidinyl) -1
0.2 g of -piperazinyl) ethyl} -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one are obtained. Example 174 5- (4-chlorobutyl) -5,6,7,8-tetrahydro-2-methyl-4H-thieno [3,2-c] azepin-4-one 5.0 g of acetic acid 60 ml solution at 60 ° C. At this point, 1.9 ml of bromine is added and stirred for 20 minutes. After cooling, saturated aqueous sodium thiosulfate solution is added to the reaction solution, and the mixture is neutralized with potassium carbonate. This aqueous solution was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to give crude crystals, which were recrystallized from a mixed solvent of isopropyl alcohol and hexane to give pale yellow crystals with a melting point of 78 to 80 ° C. -Bromo-5- (4-chlorobutyl) -5,6,7,8-tetrahydro-2-methyl-4H-thieno [3,2-c]
2.3 g of azepin-4-one are obtained. Example 175 3-Bromo-5- (4-chlorobutyl) -5,6,7,
8-Tetrahydro-2-methyl-4H-thieno [3,2
-C] Azepin-4-one 2.2 g of dimethylformamide-toluene (1: 1) solution (50 ml) in (2-pyrimidinyl) -1-piperazine dihydrochloride 1.6 g, potassium carbonate 1.9 g, iodinated 1.2 g of potassium was added sequentially to obtain 80
React at ~ 90 ° C for 3 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, isopropyl alcohol-hydrochloride was added, and the precipitated crystals were recrystallized from a mixed solvent of isopropyl alcohol-acetone to give 3-bromo- as white powder crystals having a melting point of 209 to 213 ° C.
5- {4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl} -5,6,7,8-tetrahydro-2-
1.2 g of methyl-4H-thieno [3,2-c] azepin-4-one.hydrochloride hemihydrate are obtained. Example 176 4- (4-chlorobutyl) -2,3-dihydro-7-methylthieno [3,2-f] [1,4] thiazepine-5
(4H) -one 3.0 g of dimethylformamide 30 m
2.3 g of potassium phthalimide was added to the 1 l solution,
React at 80 ° C. for 6 hours. After cooling, the reaction solution is poured into water, extracted with ethyl acetate, washed with water and dried. Crude crystals obtained by distilling off ethyl acetate were recrystallized from methanol to give white powder crystals with a melting point of 120 to 121 ° C.
(4-phthalimidobutyl) -2,3-dihydro-7-
Methylthieno [3,2-f] [1,4] thiazepine-5
4.6 g of (4H) -one hydrate are obtained. Example 177 7-methyl-4- (4-phthalimidobutyl) -2,3
-Dihydrothieno [3,2-f] [1,4] thiazepin-5 (4H) -one 4.0 g ethanol 40 ml suspension was added with hydrazine hydrate 1.5 ml and heated to reflux for 5 hours. After cooling, the precipitated crystals were filtered off, and the residue obtained by concentrating the mother liquor was subjected to silica gel column chromatography. An oily substance obtained from the fraction eluted with chloroform-methanol (10: 1) was used in a conventional manner. When recrystallized from methanol as a hydrochloride salt, 4- (4-aminobutyl) -7-methyl-2,3-as white powder crystals having a melting point of 171 to 172 ° C
Dihydrothieno [3,2-f] [1,4] thiazepine-
0.62 g of 5 (4H) -one hydrochloride 1/4 hydrate is obtained.

Example 178 5- [4- (4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino) butyl] -2-methyl-5,6,7,8 -Tetrahydro-4H-thieno [3,2-c] azepin-4-one.hydrochloride, melting point 23
8-241 ° C. Example 179 5- [6- (4-bis (4-fluorophenyl) methyl-1-piperazinyl) hexyl] -2-methyl-5.
6,7,8-Tetrahydro-4H-thieno [3,2-
c] Azepin-4-one dimaleate hemihydrate, melting point 106-108 ° C Example 180 4- [3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl ] -2,3-Dihydro-7-
Methylthieno [3,2-f] [1,4] thiazepine-5
(4H) -one, melting point 144-145 ° C. Example 181 4- [4- (4- (4-chlorophenyl) -4-hydroxypiperidino) butyl] -2,3-dihydro-7-methylthieno [3. 2-f] [1,4] thiazepine-5
(4H) -one hydrochloride, melting point 254-255 ° C Example 182 3-acetyl-2-methyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5. 6,
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one dioxalate, mp 158-159
C. Example 183 1,3-Dimethyl-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -4,6,7,8-
Tetrahydro-5H-thieno [3,4-b] azepine-
5-one hydrochloride, melting point 232-234 ° C. Example 184 2-Methyl-5,6,7,8-tetrahydro-5- [4
Methyl-(4- (2-pyrimidinyl) -1-piperazinyl) butyl] -4-oxo-4H-thieno [3,2-c] azepine-3-carboxylate Example 185 2-Methyl-5- [ 4- (4- (2-pyrimidinyl)-
1-Piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4,6
-Dione Example 186 2-Methyl-5- [4- (4- (5-fluoro-2-pyrimidinyl) -1-piperazinyl) butyl] -5,6.
7,8-Tetrahydro-4H-thieno [3,2-c] azepine-4,6-dione Example 187 7-Methyl-4- [4- (4- (2-pyrimidinyl)-
1-Piperazinyl) butyl] -2,3-dihydro-4H
-Thieno [3,2-f] [1,4] thiazepine-3,5
-Dione Example 188 4- [4- (4- (5-fluoro-2-pyrimidinyl)
-1-Piperazinyl) butyl] -2,3-dihydro-7
-Methyl-4H-thieno [3,2-f] [1,4] thiazepin-3,5-one

Thereafter, the compounds shown in Tables 8 to 31 are similarly obtained.

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[0045]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[0046]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/55 ABU 7252-4C C07D 513/04 391 8415-4C // (C07D 495/04 223: 00 6701-4C 333: 00) 7729-4C (C07D 495/04 225: 00 6701-4C 333: 00) 7729-4C (C07D 513/04 281: 00 8314-4C 333: 00) 7729-4C (C07D 513 / 04 285: 00 8314-4C 333: 00) 7729-4C (31) Priority claim number Japanese Patent Application No. 3-13684 (32) Priority Day Hei 3 (1991) January 11 (33) Priority claim country Japan (JP) (31) Priority claim number Japanese Patent Application No. 3-75657 (32) Priority date 3 (1991) March 14 (33) Country of priority claim Japan (JP) (72) Inventor Shuzo Takehara Oita Prefecture 684 Shimomiyanaga, Nakatsu-shi

Claims (19)

[Claims] 1. A general formula: A thiophene condensed compound represented by: or a pharmaceutically acceptable acid addition salt thereof. In the formula, ^one of E ¹ , E ² , and E ³ represents a sulfur atom, and the other two are C—R ¹ and C—R, respectively.
² is shown. R ¹ and R ² are the same or different and are hydrogen, halogen, nitro, amino, cyano, hydroxyl group, formyl, alkyl, alkoxy, haloalkyl, arylalkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl,
Alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
It represents arylthio, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, halosulfonyl, sulfamoyl, substituted sulfamoyl, carboxyl, acylamino, alkoxycarbonyl, carbamoyl, substituted carbamoyl or substituted amino. D is -CH ₂ - shows a (m is 0, 1 or 2) - or -S (O) _m. Q represents straight chain alkylene or branched chain alkylene. T represents primary amino, secondary amino or tertiary amino. A and B are the same or different and each independently represent a carbonyl group or a thiocarbonyl group, or one of A and B does not exist and the other represents a carbonyl group or a thiocarbonyl group, or A is -CH _2- . , B represents a carbonyl group or a thiocarbonyl group. n represents 2 or 3 when one of A and B does not exist and the other is a carbonyl group or a thiocarbonyl group, and represents 1 or 2 in other cases. In the above definition, the (hetero) aromatic ring and the heterocycle may have 1 to 3 substituents. 2. T is --NH₂First-class ami represented by
No, -NHRa (In the formula, Ra is alkyl, cycloalkyl
And arylalkyl or heteroarylalkyl
Show. ) A secondary amino or -N (Rb)
(Rc) [wherein Rb and Rc are the same or different and
Kill, cycloalkyl, arylalkyl or hetero
Represents an arylalkyl, or Rb and Rc are bonded to each other.
With the adjacent nitrogen atom, the formula:It is also possible to form the cyclic amino represented by
In the formula, q represents an integer of 1 to 4, Z is methylene, oxygen source
Child, sulfur atom or NR^Five(R^FiveIs hydrogen, alkyl,
Cyanoalkyl, hydroxyalkyl, aryl, ant
Alkyl, alkoxycarbonyl, diarylar
Kill, heteroaryl, heteroarylalkyl, shik
Low alkyl, cycloalkyl alkyl, acyl, cinna
Indicates mill or adamantane methyl. ) Is shown. Replacement
The group V is hydrogen, hydroxyl group, amino, carbamoyl, mono or
Or di-substituted amino, cyclic amino, acyl, aryl, a
Reel alkyl, arylalkylamino, alkyl,
Alkoxy, hydroxyalkyl, alkoxycarbony
Ru, heteroaryl, phenoxyalkyl, anilinoa
Rualkyl, alkylaminoalkyl, alkanoylamino
Alkyl or bisarylmethylene, which are the same or
Alternatively, 1-4 different groups can be substituted. Formula (1)
The cyclic amino of can include a carbonyl group in the ring,
Further condensed with aryl or heteroaryl
Good. The ring A of the formula (2) has an amide bond in the ring, and
Oxygen atom, sulfur atom, carbonyl and / or N-
R⁶(R ⁶Represents hydrogen, alkyl or phenyl. )
May have. Ring A is a 5- to 7-membered saturated or
Can also be fused with an unsaturated ring. ] Represented by
The compound according to claim 1, which is a tertiary amino acid, or a pharmaceutical thereof.
Acceptable acid addition salts. In the above definition, (hetero) aromatic
The group ring and the hetero ring have 1 to 3 substituents.
Good. 3. T is —NHRa (Ra represents heteroarylalkyl which may have 1 to 3 substituents)
The compound according to claim 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. 4. T is -N (Rb) (Rc) [in the formula, R
b, Rc are the same or different and represent alkyl, arylalkyl or optionally reduced heteroarylalkyl, or Rb, Rc are linked together with the adjacent nitrogen atom to form the formula: It is also possible to form the cyclic amino represented by
In the formula, q represents an integer of 1 to 4, Z is methylene or N
-R ⁵ (R ⁵ represents aryl, diarylalkyl, heteroaryl, heteroarylalkyl or acyl) is shown. The substituent V is hydrogen, hydroxyl group, carbamoyl, cyclic amino, aryl, arylalkylamino,
Heteroaryl or bisarylmethylene, wherein
1 to 4 which are the same or different can be substituted. The cyclic amino of the formula (1) may contain a carbonyl group in the ring and may be further condensed with aryl or heteroaryl. The ring Am of the formula (2) has an amide bond in the ring, and may further have a sulfur atom and / or N—R ⁶ (R ⁶ represents phenyl). Ring Am can also be fused with a 5 to 7 membered saturated or unsaturated ring. ] The compound or its pharmaceutically acceptable acid addition salt according to claim 1 or 2, which is a tertiary amino represented by In the above definition, the (hetero) aromatic ring and the heterocycle may have 1 to 3 substituents. 5. T is of the formula: [In the formula, Z represents NR ⁵ (R ⁵ represents pyrimidinyl which may have a substituent), the substituent V is hydrogen, and q is 2
Indicates. ] The compound of Claim 1 or 2 which is cyclic amino, or its pharmaceutically acceptable acid addition salt. 6. A general formula: (Wherein R ³ represents hydrogen, halogen, nitro, amino, cyano, hydroxyl group, alkyl, alkoxy or haloalkyl, and each other symbol is as defined in claim 1 or 2.) The compound according to 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. 7. A general formula: (In the formula, R ¹ and R ² are the same or different and are hydrogen, halogen, nitro, amino, cyano, hydroxyl group, formyl, alkyl, alkoxy, haloalkyl, aralkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, Alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl or haloalkanoyl, R ^{3 ′}
Is as described in claim 6, A and B are both carbonyl groups, or one of A and B is absent and the other is a carbonyl group, and n ′ is a carbonyl group. When it shows 2 or 3, at the other time, it shows 3 or 4, and Q shows C1-C10 linear alkylene or branched alkylene. 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable acid addition salt thereof represented by 8. A general formula: (Wherein R ¹ and R ² are as defined in claim 7,
^{3 'are} as described in claim 6, t is an integer of 1-8, but A and B represents absent or carbonyl group, B when A is absent is a carbonyl group, A B is absent when is a carbonyl group. 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable acid addition salt thereof represented by 9. T is of the formula: [In the formula, Z represents methylene or NR ⁵ (R ⁵ represents aryl, diarylalkyl, heteroaryl other than pyrimidinyl, heteroarylalkyl or acyl). Substituent V is hydrogen, hydroxyl group, carbamoyl, cyclic amino, aryl, arylalkylamino,
Heteroaryl or bisarylmethylene, which is 1
~ 4 can be replaced. q indicates 2. In the above definition, the aromatic ring or heterocyclic ring may have 1 to 3 substituents. ] The compound according to claim 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. 10. 2-Bromo-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6.
7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-methyl-5- [4- (4- (2
-Pyrimidinyl) -1-piperazinyl) butyl] -5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] azepin-4-one, 2-ethyl-5- [4- (4
-(2-Pyrimidinyl) -1-piperazinyl) butyl]
-5,6,7,8-tetrahydro-4H-thieno [3,3
2-c] azepin-4-one, 2-acetyl-5- [4
-(4- (2-Pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2- (1- Hydroxyethyl) -5- [4- (4- (2-pyrimidinyl))
-1-Piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On, 5- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl] -2-methyl-5,6,7,8-tetrahydro-4H-thieno [3 , 2-c] azepin-4-one, 5- [4-
[(1,4-Benzodioxan-2-yl) methylamino] butyl] -2-methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2 , 3-Dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2
-F] -1,4-thiazepin-5 (4H) -one, 7-
Bromo-2,3-dihydro-4- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, 7-acetyl-2,3-dihydro-4- [4- (4
-(2-Pyrimidinyl) -1-piperazinyl) butyl]
Thieno [3,2-f] -1,4-thiazepine-5 (4
H) -one, 7-ethyl-2,3-dihydro-4- [4
-(4- (2-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepine-5
(4H) -one, 4- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) butyl] -2,3-dihydrothieno [3,2-f] -1, Four
-Thiazepin-5 (4H) -one, 5- [4- [4-
(Bis (4-fluorophenyl) methyl) -1-piperazinyl] butyl] -2-methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine-4-
On, 2-methyl-5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-
Tetrahydro-4H-thieno [3,2-c] azepine-
4,6-dione, 7-methyl-4- [4- (4- (2-
Pyrimidinyl) -1-piperazinyl) butyl] -2,3
-Dihydro-4H-thieno [3,2-f] [1,4] thiazepine-3,5-dione, 5- [4- (4- (3-trifluoromethylphenyl) -1-piperazinyl) butyl]- 5,6,7,8-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 5- [4- (4-
(2,3-Dimethylphenyl) -1-piperazinyl) butyl] -2-methyl-5,6,7,8-tetrahydro-
4H-thieno [3,2-c] azepin-4-one, 5-
[4- (4- (2-methoxyphenyl) -1-piperazinyl) butyl] -2-methyl-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2,3-Dihydro-4- [4- (4- (2-methoxyphenyl) -1-piperazinyl) butyl] -7-methylthieno [3,2-f] -1,4-thiazepine-5 (4
H) -one and 4- [4- (4- (bis (4-fluorophenyl) methylene) piperidino) butyl] -2,3
-Dihydro-7-methylthieno [3,2-f] -1,4
-Thiazepin-5 (4H) -one.
A compound as described above or a pharmaceutically acceptable acid addition salt thereof. 11. 2-Bromo-5- [4- (4- (2-
Pyrimidinyl) -1-piperazinyl) butyl] -5,
6,7,8-Tetrahydro-4H-thieno [3,2-
c] azepin-4-one, 2-methyl-5- [4- (4
-(2-Pyrimidinyl) -1-piperazinyl) butyl]
-5,6,7,8-tetrahydro-4H-thieno [3,3
2-c] azepin-4-one, 2-ethyl-5- [4-
(4- (2-Pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2-acetyl-5
-[4- (4- (2-Pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8-tetrahydro-4H-
Thieno [3,2-c] azepin-4-one, 2- (1-
Hydroxyethyl) -5- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -5,6,7,8
-Tetrahydro-4H-thieno [3,2-c] azepin-4-one, 2,3-dihydro-4- [4- (4- (2
-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, 7-bromo-2,3-dihydro-4- [4- (4-
(2-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepine-5 (4H)
-One, 7-acetyl-2,3-dihydro-4- [4-
(4- (2-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepine-5
(4H) -one, 7-ethyl-2,3-dihydro-4-
[4- (4- (2-Pyrimidinyl) -1-piperazinyl) butyl] thieno [3,2-f] -1,4-thiazepin-5 (4H) -one, 2-methyl-5- [4- ( 4-
(2-Pyrimidinyl) -1-piperazinyl) butyl]-
5,6,7,8-Tetrahydro-4H-thieno [3,2
-C] azepine-4,6-dione and 7-methyl-4
-[4- (4- (2-Pyrimidinyl) -1-piperazinyl) butyl] -2,3-dihydro-4H-thieno [3,
The compound according to claim 1, which is selected from 2-f] [1,4] thiazepine-3,5-dione, or a pharmaceutically acceptable acid addition salt thereof. 12. A general formula: A thiophene condensed compound represented by: In the formula, X represents a hydroxyl group, a reactive atom or group derived from a hydroxyl group, a group represented by the formula —CO—R ³ (R ³ represents hydrogen or alkyl), a cyano group, a carbamoyl group or a nitro group. , Other symbols are as described in claim 1. 13. A general formula: The compound of claim 12 represented by: Each symbol is as described in claims 1 and 12. 14. A general formula: A thiophene condensed compound represented by: Each symbol is as described in claim 1. 15. A general formula: 15. The compound of claim 14 represented by: Each symbol is as described in claim 1. 16. A pharmaceutical composition comprising the thiophene condensed compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical additive. 17. An anxiolytic drug containing the thiophene condensed compound according to claim 1. 18. An antipsychotic drug containing the thiophene condensed compound according to claim 1. 19. A therapeutic agent for cardiovascular disease, which comprises the thiophene condensed compound according to claim 1.