JP4315393B2 - Heterocyclic compounds - Google Patents

Description

  The present invention relates to a novel heterocyclic compound.

In order to develop a broad therapeutic spectrum for drugs, the etiology of bipolar disorder, mood disorders and emotional disorders including schizophrenia is heterogeneous.
It is desirable to have a plurality of pharmacological actions.

  Patent Document 1 discloses a general formula.

[Wherein, A ′ represents — (CH ₂ ) _m CH ₂ —, — (CH ₂ ) _m O—, or the like. m shows the integer of 1-4. R ^A represents a hydrogen atom, a C _1-4 alkyl group which may be substituted with 1 to 3 fluorine atoms, or the like. ]
It is disclosed that the carbostyril derivative represented by the formula has a D ₂ receptor antagonistic action and a serotonin 2A (5-HT _2A ) receptor antagonistic action, and is effective in the treatment of schizophrenia and other central nervous diseases. Has been.

However, in Patent Document 1, the carbostyril derivative described in the document has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action, an α ₁ receptor antagonist action, and a serotonin uptake inhibitory action. However, there is no disclosure regarding the point of having a wide therapeutic spectrum.

  Patent Document 2 discloses certain [1,8] naphthyridin-2-one derivatives.

However, also in Patent Document 2, the [1,8] naphthyridin-2-one derivative described in the above document has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action, an α ₁ receptor antagonist action. In addition, there is no disclosure of the fact that it has both serotonin uptake inhibitory action and a broad therapeutic spectrum.
WO2004 / 026864A1 WO2005 / 019215A1

  An object of the present invention is to provide an antipsychotic drug having a broader therapeutic spectrum, fewer side effects, and excellent tolerability and safety compared to known typical antipsychotic drugs and atypical antipsychotic drugs. And

As a result of intensive studies in order to solve the above-mentioned problems, the present inventors have conducted a dopamine D ₂ receptor partial agonist action (D ₂ receptor partial agonist action), a serotonin 5-HT _2A receptor antagonist action (5- HT _2A receptor antagonistic action) and adrenaline α ₁ receptor antagonistic action (α ₁ receptor antagonistic action), and in addition to these actions, serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) The compound was successfully synthesized. The present invention has been completed based on such findings.

  The present invention provides a heterocyclic compound or a salt thereof and a production method thereof shown in the following section.

［式中、

で示される環Ｑは、

を示す。
（式中、

は、−ＮＨ−ＣＨ_２−、−Ｎ＝ＣＨ−、−ＣＨ_２−ＮＨ−、または、−ＣＨ＝Ｎ−を示す。
Ｚ及びＹを含む複素環骨格の３位及び４位に示される

の炭素間結合は、一重結合または二重結合を示す。）
環Ｑ上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、アリール基、アリール低級アルキル基、アリール低級アルコキシ基、アリールカルボニル基、低級アルケニルオキシ基、低級アルカノイル基、シクロアルキル基、シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、窒素原子を１または２個有する３から８員の飽和複素単環低級アルキル基、オキソ基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が少なくとも１つ置換していてもよい。
Ｒ_２は、水素または低級アルキル基を示す。
Ａは、−Ｏ−Ａ_１−（式中、Ａ_１は、ヒドロキシ基が置換していてもよいアルキレン基（該アルキレン基には１個の酸素原子が含まれていてもよい）または低級アルケニレン基を示す。）または低級アルキレン基を示す。
但し、Ａが低級アルキレン基を示す場合、環Ｑは、

及び

からなる群から選択される二環式複素環基を示す。二環式複素環基中の点線を含む炭素間結合は、一重結合または二重結合を示す。］
で表される複素環化合物またはその塩；
項２．
環Ｑが、 Item 1.
General formula (1)

[Where:

The ring Q represented by

Indicates.
(Where

Represents —NH—CH ₂ —, —N═CH—, —CH ₂ —NH—, or —CH═N—.
Shown at the 3- and 4-positions of the heterocyclic skeleton containing Z and Y

The carbon-carbon bond represents a single bond or a double bond. )
On ring Q, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl group, lower alkenyl Oxy group, lower alkanoyl group, cycloalkyl group, cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group optionally An amino group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group optionally having a lower alkyl group, a thienyl group, a 3- to 8-membered saturated heteromonocyclic lower alkyl group having 1 or 2 nitrogen atoms, From the group consisting of an oxo group and a lower alkanoyloxy group Barre substituents may be substituted with at least one.
R ₂ represents hydrogen or a lower alkyl group.
A represents —O—A ₁ — (wherein A ₁ represents an alkylene group which may be substituted with a hydroxy group (the alkylene group may contain one oxygen atom) or lower alkenylene. Group) or a lower alkylene group.
Provided that when A represents a lower alkylene group, ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of: A carbon-carbon bond including a dotted line in the bicyclic heterocyclic group represents a single bond or a double bond. ]
A heterocyclic compound represented by the formula:
Item 2.
Ring Q is

及び

からなる群から選択される二環式複素環基を示す。（上記二環式複素環骨格の３位及び４位に示される点線を含む炭素間結合は、一重結合または二重結合を示す。二環式複素環上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、フェニル基、フェニル低級アルキル基、ナフチル低級アルキル基、フェニル低級アルコキシ基、ナフチル低級アルコキシ基、ベンゾイル基、低級アルケニルオキシ基、低級アルカノイル基、Ｃ３−Ｃ８シクロアルキル基、Ｃ３−Ｃ８シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、窒素原子を１または２個有する５から６員の飽和複素単環低級アルキル基、及び低級アルカノイルオキシ基からなる群から選ばれた置換基が１〜４個置換していてもよい）を示し、
Ａが、−Ｏ−Ａ_１−（式中、Ａ_１は、ヒドロキシ基が置換していてもよいＣ１−Ｃ６アルキレン基（該アルキレン基には１個の酸素原子が含まれていてもよい）を示す
項１に記載の複素環化合物またはその塩；
項３．
環Ｑが、

as well as

A bicyclic heterocyclic group selected from the group consisting of: (The carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the bicyclic heterocyclic ring, a lower alkyl group, a lower alkenyl group , Lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower Alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group Amino group, nitro group, hydroxy lower alkyl group, lower alkyl group A substituent selected from the group consisting of an amino lower alkyl group, a thienyl group, a 5- to 6-membered saturated heteromonocyclic lower alkyl group having 1 or 2 nitrogen atoms, and a lower alkanoyloxy group, which may have 1-4 may be substituted),
A is —O—A ₁ — (wherein A ₁ is a C1-C6 alkylene group optionally substituted with a hydroxy group (the alkylene group may contain one oxygen atom)) The heterocyclic compound or its salt of claim | item 1 which shows these;
Item 3.
Ring Q is

及び

からなる群から選択される二環式複素環基（ここで、二環式複素環基上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、フェニル基、フェニル低級アルキル基、ナフチル低級アルキル基、フェニル低級アルコキシ基、ナフチル低級アルコキシ基、ベンゾイル基、低級アルケニルオキシ基、低級アルカノイル基、Ｃ３−Ｃ８シクロアルキル基、Ｃ３−Ｃ８シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、フェニル基、チエニル基、ピロリジニル低級アルキル基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が１〜３個置換していてもよい）を示し、
Ａが、−Ｏ−Ａ_１−（式中、Ａ_１は、ヒドロキシ基が置換していてもよいＣ１−Ｃ６アルキレン基（該アルキレン基には１個の酸素原子が含まれていてもよい）を示す
項２に記載の複素環化合物またはその塩；
項４．
環Ｑが

as well as

A bicyclic heterocyclic group selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogen-substituted lower alkyl group. Group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower group An alkyl group, a halogen, a carbamoyl group optionally having a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, a lower alkyl group; Amino lower alkyl group which may have a phenyl group Thienyl group, a pyrrolidinyl lower alkyl group and a substituent selected from the group consisting of a lower alkanoyloxy group represents may) be in 1-3 substituents,
A is —O—A ₁ — (wherein A ₁ is a C1-C6 alkylene group optionally substituted with a hydroxy group (the alkylene group may contain one oxygen atom)) The heterocyclic compound or its salt of claim | item 2 which shows these;
Item 4.
Ring Q is

及び

からなる群から選択される二環式基（ここで、環Ｑ上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、フェニル基、フェニル低級アルキル基、ナフチル低級アルキル基、フェニル低級アルコキシ基、ナフチル低級アルコキシ基、ベンゾイル基、低級アルケニルオキシ基、低級アルカノイル基、Ｃ３−Ｃ８シクロアルキル基、Ｃ３−Ｃ８シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、ピロリジニル低級アルキル基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が１〜３個置換していてもよい）を示す
項２に記載の複素環化合物またはその塩；
項５．
環Ｑが、

as well as

A bicyclic group selected from the group consisting of (wherein the ring Q is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogen-substituted lower alkyl group, a phenyl group, a phenyl group, Lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, lower A carbamoyl group optionally having an alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, a lower alkyl group Good amino lower alkyl group, thienyl group, pyrrolidinyl low Heterocyclic compound according to item 2 represents an alkyl group and a substituent selected from the group consisting of lower alkanoyloxy group may be one to three substituents) or a salt thereof;
Item 5.
Ring Q is

及び

からなる群から選択される二環式基（上記二環式複素環骨格の３位及び４位に示される点線を含む炭素間結合は、一重結合または二重結合を示す。上記二環式複素環骨格上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、フェニル基、フェニル低級アルキル基、ナフチル低級アルキル基、フェニル低級アルコキシ基、ナフチル低級アルコキシ基、ベンゾイル基、低級アルケニルオキシ基、低級アルカノイル基、Ｃ３−Ｃ８シクロアルキル基、Ｃ３−Ｃ８シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、ピロリジニル低級アルキル基、オキソ基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が１〜４個置換していてもよい。）を示し、
Ａが低級アルキレン基を示す
項１に記載の複素環化合物またはその塩；
項６．
環Ｑが、

as well as

A bicyclic group selected from the group consisting of (the carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the ring skeleton, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl A lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl lower alkyl group, a halogen, a carbamoyl group optionally having a lower alkyl group, a carboxy group, A lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, 1 to 4 substituents selected from the group consisting of a droxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group, an oxo group and a lower alkanoyloxy group You may have)
Item 2. The heterocyclic compound or a salt thereof according to Item 1, wherein A represents a lower alkylene group;
Item 6.
Ring Q is

及び

からなる群から選択される上記二環式複素環基（上記二環式複素環骨格の３位及び４位に示される点線を含む炭素間結合は、一重結合または二重結合を示す。上記二環式複素環骨格上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、フェニル基、フェニル低級アルキル基、ナフチル低級アルキル基、フェニル低級アルコキシ基、ナフチル低級アルコキシ基、ベンゾイル基、低級アルケニルオキシ基、低級アルカノイル基、Ｃ３−Ｃ８シクロアルキル基、Ｃ３−Ｃ８シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、ピロリジニル低級アルキル基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が１〜３個置換していてもよい。）を示す項５に記載の複素環化合物またはその塩；
項７．
（１）７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−１Ｈ−キノリン−２−オン、
（２）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−１Ｈ−キノリン−２−オン、
（３）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−３，４−ジヒドロ−１Ｈ−キノリン−２−オン、
（４）７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−３，４−ジヒドロ−１Ｈ−キノリン−２−オン、
（５）７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−１−メチル−３，４−ジヒドロ−１Ｈ−キノリン−２−オンおよび
（６）６−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−３，４−ジヒドロ−１Ｈ−キノリン−２−オンからなる群から選ばれた項３に記載の複素環化合物又はその塩；
項８．
（１）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−３，４−ジヒドロ−２Ｈ−イソキノリン−１−オン、
（２）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−２−メチル−３，４−ジヒドロ−２Ｈ−イソキノリン−１−オン、
（３）７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−２−メチル−３，４−ジヒドロ−２Ｈ−イソキノリン−１−オン、
（４）７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−３，４−ジヒドロ−２Ｈ−イソキノリン−１−オン、
（５）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−２Ｈ−イソキノリン−１−オンおよび
（６）７−［３−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）プロポキシ］−２−メチル−２Ｈ−イソキノリン−１−オンからなる群から選ばれた項４に記載の複素環化合物またはその塩；
項９．
一般式（１）

as well as

The bicyclic heterocyclic group selected from the group consisting of (the carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the cyclic heterocyclic skeleton, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy A carbamoyl group optionally having a group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, lower alkyl group, A carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, 1 to 3 substituents selected from the group consisting of a tro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group and a lower alkanoyloxy group The heterocyclic compound or a salt thereof according to Item 5, wherein
Item 7.
(1) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one,
(2) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1H-quinolin-2-one,
(3) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one,
(4) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one,
(5) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1-methyl-3,4-dihydro-1H-quinolin-2-one and (6 Item 3 selected from the group consisting of 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one Or a heterocyclic compound thereof as described in
Item 8.
(1) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one,
(2) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(3) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(4) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-2H-isoquinolin-1-one,
(5) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one and (6) 7- [3- (4-benzo [B] The heterocyclic compound or the salt thereof according to item 4, selected from the group consisting of thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one;
Item 9.
General formula (1)

［式中、

で示される環Ｑは、

を示す。
（式中、

は、−ＮＨ−ＣＨ_２−、−Ｎ＝ＣＨ−、−ＣＨ_２−ＮＨ−、または、−ＣＨ＝Ｎ−を示す。
Ｚ及びＹを含む複素環骨格の３位及び４位に示される

の炭素間結合は、一重結合または二重結合を示す。）
（ここで、環Ｑ上には、低級アルキル基、低級アルケニル基、低級アルキニル基、ヒドロキシ基、低級アルコキシ基、ハロゲン置換低級アルキル基、アリール基、アリール低級アルキル基、アリール低級アルコキシ基、アリールカルボニル基、低級アルケニルオキシ基、低級アルカノイル基、シクロアルキル基、シクロアルキル低級アルキル基、ハロゲン、低級アルキル基を有していてもよいカルバモイル基、カルボキシ基、低級アルコキシカルボニル基、低級アルカノイル基を有していてもよいアミノ基、ニトロ基、ヒドロキシ低級アルキル基、低級アルキル基を有していてもよいアミノ低級アルキル基、チエニル基、窒素原子を１または２個有する３から８員の飽和複素単環低級アルキル基、オキソ基及び低級アルカノイルオキシ基からなる群から選ばれた置換基が少なくとも１つ置換していてもよい。
Ｒ_２は、水素または低級アルキル基を示す。
Ａは、−Ｏ−Ａ_１−（式中、Ａ_１は、ヒドロキシ基が置換していてもよいアルキレン基（該アルキレン基には１個の酸素原子が含まれていてもよい。）または低級アルケニレン基を示す。）または低級アルキレン基を示す。
但し、Ａが低級アルキレン基を示す場合、環Ｑは、

及び

からなる群から選択される二環式複素環基を示す。二環式複素環基中の点線を含む炭素間結合は、一重結合または二重結合を示す。］
で表される複素環化合物またはその塩の製造方法であって、
一般式

［式中、環Ｑ及びＡは前記に同じ。Ｘ_１は、ハロゲン原子又はハロゲン原子と同様の置換反応を起こす基を示す。］
で表される化合物またはその塩と、
一般式

［式中、Ｒ_２は前記に同じ。］
で表される化合物またはその塩とを反応させる方法。

[Where:

The ring Q represented by

Indicates.
(Where

Represents —NH—CH ₂ —, —N═CH—, —CH ₂ —NH—, or —CH═N—.
Shown at the 3- and 4-positions of the heterocyclic skeleton containing Z and Y

The carbon-carbon bond represents a single bond or a double bond. )
(Here, on ring Q, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl Group, lower alkenyloxy group, lower alkanoyl group, cycloalkyl group, cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group An amino group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group optionally having a lower alkyl group, a thienyl group, a 3- to 8-membered saturated heteromonocyclic ring having 1 or 2 nitrogen atoms From lower alkyl group, oxo group and lower alkanoyloxy group That substituent selected from the group may be substituted with at least one.
R ₂ represents hydrogen or a lower alkyl group.
A represents —O—A ₁ — (wherein A ₁ represents an alkylene group which may be substituted with a hydroxy group (the alkylene group may contain one oxygen atom) or lower group. Represents an alkenylene group) or a lower alkylene group.
Provided that when A represents a lower alkylene group, ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of: A carbon-carbon bond including a dotted line in the bicyclic heterocyclic group represents a single bond or a double bond. ]
A method for producing a heterocyclic compound represented by the formula:
General formula

[Wherein, rings Q and A are the same as defined above. X ₁ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
A compound represented by the formula:
General formula

[Wherein R ₂ is the same as defined above. ]
The compound or its salt represented by these is made to react.

  Specific examples of the groups shown in the general formula are as follows.

  Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms. More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2 , 2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl group and the like.

  Examples of the lower alkenyl group include linear or branched alkenyl groups having 1 to 2 carbon atoms and having 2 to 3 carbon atoms, and include both trans and cis isomers. More specifically, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-ynyl, 2-hexenyl, 1- Hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl group and the like are included.

  Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms. More specifically, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl group and the like are included.

  As a lower alkoxy group, a C1-C6 linear or branched alkoxy group can be mentioned. More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, iso Hexyloxy, 3-methylpentyloxy groups and the like are included.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the halogen-substituted lower alkyl group include the above-described lower alkyl groups substituted with 1 to 7, more preferably 1 to 3, halogen atoms. More specifically, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl , Pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5 , 5-trifluoropentyl, 5-chloropentyl, 6, , Hexyl 6-trifluoromethyl, 6-chloro hexyl, perfluorohexyl and the like.

  Examples of the aryl group include phenyl, biphenyl, naphthyl and the like, and the lower alkyl group exemplified above as a substituent on the phenyl ring or naphthalene ring (preferably a linear or branched chain having 1 to 6 carbon atoms). -Like alkyl group), 1 to 3 groups selected from the group consisting of the above-described lower alkoxy groups (preferably linear or branched alkoxy groups having 1 to 6 carbon atoms), nitro groups and halogen atoms. Optional phenyl, biphenyl, naphthyl groups and the like are included. Specific examples of the aryl group include phenyl, 2- (or 3- or 4-) methylphenyl, 2- (or 3- or 4-) nitrophenyl, 2- (or 3- or 4-) methoxyphenyl, 2 Examples include-(or 3- or 4-) chlorophenyl, biphenyl, α-naphthyl, β-naphthyl group and the like.

  Examples of the aryl lower alkyl group include the lower alkyl groups exemplified above having 1 to 3, preferably 1 aryl groups as exemplified above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms). be able to. Specific examples of the aryl lower alkyl group include benzyl, 2- (or 3- or 4-) methylbenzyl, 2- (or 3- or 4-) nitrobenzyl, 2- (or 3- or 4-) methoxybenzyl. 2- (or 3- or 4-) chlorobenzyl, 1- (or 2-) phenylethyl, 1-methyl-1-phenylethyl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethyl- 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl groups and the like are included.

  Examples of the aryl lower alkoxy group include the above exemplified lower alkoxy group (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms) having 1 to 3, preferably 1 of the above exemplified aryl groups. be able to. Specific examples of the aryl lower alkoxy group include benzyloxy, 2- (or 3- or 4-) methylbenzyloxy, 2- (or 3- or 4-) nitrobenzyloxy, 2- (or 3- or 4- or ) Methoxybenzyloxy, 2- (or 3- or 4-) chlorobenzyloxy, 1- (or 2-) phenylethoxy, 1-methyl-1-phenylethoxy, 1,1-dimethyl-2-phenylethoxy, 1 , 1-dimethyl-3-phenylpropoxy, α-naphthylmethoxy, β-naphthylmethoxy and the like.

  Examples of the aryl moiety of the arylcarbonyl group include the aryl groups exemplified above. Specific examples of the arylcarbonyl group include benzoyl, 2- (or 3- or 4-) methylbenzoyl, 2- (or 3- or 4-) nitrobenzoyl, 2- (or 3- or 4-) methoxybenzoyl, 2- (or 3- or 4-) chlorobenzoyl, α-naphthoyl, β-naphthoyl groups and the like are included.

  As the lower alkenyloxy group, a lower alkenyloxy group whose lower alkenyl moiety is as exemplified above (preferably a C2-C6 linear or branched alkenyloxy group having 1 to 3 double bonds) Can be mentioned. More specifically, vinyloxy, 1-propenyloxy, 1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy, 2-propenyloxy, 2-butenyloxy, 1-butenyloxy, 3-butenyloxy, 2 -Pentenyloxy, 1-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 1,3-butadienyloxy, 1,3-pentadienyloxy, 2-penten-4-ynyloxy, 2-hexenyloxy, 1-hexenyloxy, 5-hexenyloxy, 3-hexenyloxy, 4-hexenyloxy, 3,3-dimethyl-1-propenyloxy, 2-ethyl-1-propenyloxy, 1,3,5-hexatrienyloxy 1,3-hexadienyloxy, 1,4-hexadienyloxy group, etc. It is.

  Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms. More specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group and the like are included.

  Examples of the cycloalkyl group include cyclo C3-C8 alkyl groups having 3 to 8 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

  As the cycloalkyl lower alkyl group, the above exemplified cycloalkyl group (preferably a cyclo C3-C8 alkyl group having 3 to 8 carbon atoms) having 1 to 3, preferably 1, the above exemplified lower alkyl group. (Preferably a linear or branched alkyl group having 1 to 6 carbon atoms). More specifically, cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl group and the like are included.

  The carbamoyl group which may have a lower alkyl group may have 1-2 lower alkyl groups (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) exemplified above. Mention may be made of good carbamoyl groups. More specifically, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl group and the like can be mentioned.

  As the lower alkoxycarbonyl group, the lower alkoxy moiety is as exemplified above, and preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms can be mentioned. More specifically, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group and the like are included.

  Examples of the amino group having a lower alkanoyl group include the above-exemplified lower alkanoyl group (preferably an amino group which may have one linear or branched alkanoyl group having 1 to 6 carbon atoms). Specific examples include amino, N-formylamino, and N-acetylamino.

  Examples of the hydroxy lower alkyl group include those exemplified lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) having 1 to 5, preferably 1 to 3 hydroxy groups. Can do. More specifically, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2 -Hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, perhydroxyhexyl group, etc. included.

  The amino lower alkyl group optionally having a lower alkyl group has 1 to 2 lower alkyl groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) exemplified above. The lower alkyl group illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 5, preferably 1, amino group may be exemplified. More specific examples of the amino lower alkyl group which may have such a lower alkyl group include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5- Aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, N, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, N-methylamino Methyl, 2- (N-methylamino) ethyl, 1-methyl-2- (N, N-dimethylamino) ethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl 2- (N, N-diisopropylamino) ethyl, 3- (N, N-dimethylamino) propyl, 3- (N, N-diethylamino) propyl group and the like.

  Examples of the 3- to 8-membered saturated heterocyclic monocyclic group having 1 or 2 nitrogen atoms include azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl group, and the like. 5- to 6-membered saturated heterocyclic monocyclic groups having 1 or 2 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl and piperazinyl groups.

  Examples of the 3- to 8-membered saturated monocyclic lower alkyl group having 1 or 2 nitrogen atoms include 3- to 8-membered (more preferably 5 to 6-membered) saturated heterocycles having 1 or 2 nitrogen atoms as exemplified above. Examples thereof include the lower alkyl groups exemplified above having 1 to 2 (preferably 1) monocyclic groups (preferably linear or branched alkyl groups having 1 to 6 carbon atoms). More specifically, [(1-, 2- or 3-) azetidinyl] methyl, [(1-, 2- or 3-) pyrrolidinyl] methyl, [(1-, 2- or 4-) imidazolidinyl] methyl , [(1-, 3- or 4-) pyrazolidinyl] methyl, [(1-, 2-, 3- or 4-) piperidyl] methyl, [(2-, 3- or 4-) morpholinyl] methyl, 2 -[(1-, 2- or 3-) pyrrolidinyl] ethyl, 1-[(1-, 2- or 3-) pyrrolidinyl] ethyl, 3-[(1-, 2- or 3-) piperidyl] propyl, 4-[(1-, 2- or 3-) pyrrolidinyl] butyl, 5-[(1-, 2- or 3-) piperidyl] pentyl and the like are included.

  As a lower alkanoyloxy group, a C1-C6 linear or branched alkanoyloxy group can be mentioned. More specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy groups and the like are included.

  Examples of the alkylene group (the alkylene group may contain one oxygen atom) include, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyltetramethylene, 2,2-dimethyltrimethyl. Methylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethoxyethylene, methoxymethylene, 1-ethoxyethylene, 2-methoxyethylene, 2-propoxyethylene, 3-isopropoxy Trimethylene, 4-butoxytetramethylene, 5-pentyloxypentamethylene, 6-hexyloxyhexamethylene, 1,1-dimethyl-2-methoxyethylene, 2-methyl-3-ethoxytrimethylene, 3-methoxytrimethylene group 1-12 carbon atoms such as (preferred Or a linear or branched alkylene group of 1 to 6) (the alkylene group may contain one oxygen atom).

Examples of the alkylene group which may be substituted with a hydroxy group (the alkylene group may contain one oxygen atom) include, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyl Tetramethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethoxyethylene (—CH ₂ CH ₂ OCH ₂ CH ₂ —), methoxy Methylene (—CH ₂ OCH ₂ —), 1-ethoxyethylene (—CH ₂ CH ₂ OCH (CH ₃ ) —), 2-methoxyethylene (—CH ₂ OCH ₂ CH ₂ —), 2-propoxyethylene (—CH _{2 CH 2 CH 2 OCH 2 CH} 2 -), 3- isopropoxyphenyl trimethylene (-CH ( _{CH 3) CH 2 OCH 2 CH} 2 CH 2 -), 4- butoxy tetramethylene _{(-CH 2 CH 2 CH 2 CH} 2 OCH 2 CH 2 CH 2 CH 2 -), 5- pentyloxy pentamethylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ —), 6-hexyloxyhexamethylene (—CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), 1,1- dimethyl-2-methoxy ethylene _{(-CH 2 OCH 2 C (CH} 3) 2 -), 2- methyl-3-ethoxy-trimethylene _{(-CH 2 CH 2 OCH 2 CH} ( _{CH 3) CH 2 -),} 3- methoxy-trimethylene _{(-CH 2 OCH 2 CH 2 CH} 2 -), hydroxymethylene, 1-hydroxy Styrene, 2-hydroxy-trimethylene, 2-hydroxymethyl-trimethylene, 3-tetramethylene, 3-pentamethylene, 4-hexamethylene, 2- (2-hydroxyethoxy) ethylene _{(-CH (OH) CH 2 OCH} 2 CH ₂ CH ₂ -), hydroxy-methoxy-methylene _{(-CH (OH) OCH 2 -} ), 1- (2- hydroxyethoxy) ethylene _{(-CH (OH) CH 2 OCH} (CH 3) -), 4- (4- hydroxybutoxy) tetramethylene _{(-CH (OH) CH 2 CH} 2 CH 2 OCH 2 CH 2 CH 2 CH 2 -), 5- (5- hydroxypentyl oxy) pentamethylene _{(-CH (OH) CH 2 CH} 2 CH _{2 CH 2 OCH 2 CH 2 CH} 2 CH 2 CH 2 -), 6- (6- hydroxyhexyloxy) hex Styrene _{(-CH (OH) CH 2 CH} 2 CH 2 CH 2 CH 2 OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), 2,3- dihydroxy-trimethylene, 2,3,4-trihydroxy-pentamethylene , 3- (2,3-dihydroxypropoxy) trimethylene (—CH (OH) CH (OH) CH ₂ OCH ₂ CH ₂ CH ₂ —) group etc. may be substituted with 1 to 3 hydroxy groups Examples thereof include 1 to 12 (preferably 1 to 6) linear or branched alkylene groups (the alkylene group may contain one oxygen atom).

  Examples of the lower alkenylene group include vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-pentene-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4 -Double bonds such as -hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene group Examples thereof include 1 to 3 linear or branched alkenylene groups having 2 to 6 carbon atoms.

  Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyltetramethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, and pentane. C1-C6 linear or branched alkylene groups, such as a methylene and a hexamethylene group, can be mentioned.

The heterocyclic compound represented by the general formula (1) can be produced by various methods. For example, the heterocyclic compound can be produced by a method represented by the following reaction formula.
[Reaction Formula-1]

[Wherein, ring Q, A, R ₂ and X ₁ are the same as above. ]
In the general formula (2), the halogen atom represented by X ₁ is the same as described above.

  Examples of the group that causes a substitution reaction similar to a halogen atom include a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, and the like.

Specific examples of the lower alkanesulfonyloxy group represented by X ₁ include methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy, n- Examples include pentanesulfonyloxy and linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms in the n-hexanesulfonyloxy group.

Examples of the arylsulfonyloxy group represented by X ₁ include a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched chain group having 1 to 6 carbon atoms as a substituent on the phenyl ring. Examples thereof include phenylsulfonyloxy and naphthylsulfonyloxy groups, which may have 1 to 3 groups selected from the group consisting of an alkoxy group, a nitro group and a halogen atom. Specific examples of the phenylsulfonyloxy group that may have the above substituent include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, Examples include 2-nitrophenylsulfonyloxy and 3-chlorophenylsulfonyloxy groups. Specific examples of the naphthylsulfonyloxy group include an α-naphthylsulfonyloxy group and a β-naphthylsulfonyloxy group.

Examples of the aralkylsulfonyloxy group represented by X ₁ include a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched chain group having 1 to 6 carbon atoms as a substituent on the phenyl ring. A linear or branched alkanesulfonyloxy group or naphthyl group having 1 to 6 carbon atoms substituted with a phenyl group that may have 1 to 3 groups selected from the group consisting of an alkoxy group, a nitro group and a halogen atom And a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms and the like substituted. Specific examples of the alkanesulfonyloxy group substituted with the phenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- Examples thereof include nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy group and the like. Specific examples of the alkanesulfonyloxy group substituted with the naphthyl group include α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy groups.

  The reaction of the compound represented by the general formula (2) and the compound represented by the general formula (3) is performed in the absence or presence of a basic compound in a solvent-free or inert solvent.

  Examples of the inert solvent include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol. Ketones such as acetone and methyl ethyl ketone; polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile.

  As the basic compound, known compounds can be widely used. For example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide; sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate Alkali metal carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metals such as sodium and potassium; inorganic bases such as sodium amide, sodium hydride and potassium hydride; and Alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine Trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1, An organic base such as 4-diazabicyclo [2.2.2] octane (DABCO) can be mentioned.

  These basic compounds are used individually by 1 type or in mixture of 2 or more types.

  The usage-amount of a basic compound is 0.5-10 times mole normally with respect to the compound of General formula (2), Preferably it is 0.5-6 times mole.

  The above reaction can be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide as a reaction accelerator if necessary.

  The use ratio of the compound of the general formula (2) and the compound of the general formula (3) in the above reaction formula-1 is usually at least 0.5 times mol, preferably about 0.5 to 5 times mol of the latter with respect to the former. And it is sufficient.

The above reaction is usually performed at room temperature to 200 ° C, preferably room temperature to 150 ° C, and is generally completed in about 1 to 30 hours.
[Reaction Formula-2]

[Wherein, ring Q, R ₂ and A ₁ are the same as described above. X ₂ represents a hydroxyl group, a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
The reaction between the compound represented by the general formula (4) and the compound represented by the general formula (5a) is a reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction formula-1. The reaction is carried out under the same reaction conditions.

In the case of the compound (4) in which X ₂ represents a hydroxyl group, the reaction of the compound (4) and the compound (5a) can also be performed in a suitable solvent in the presence of a condensing agent.

  Specific examples of the solvent used here include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether and diisopropyl. Ethers such as ether, tetrahydrofuran and dimethoxyethane; esters such as methyl acetate, ethyl acetate and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve Aprotic polar solvents such as acetonitrile, pyridine, acetone, DMF, DMSO, hexamethylphosphoric triamide, or a mixed solvent thereof.

  Examples of the condensing agent include a mixture of azocarboxylates such as diethyl azodicarboxylate and a phosphorus compound such as triphenylphosphine.

  The amount of the condensing agent to be used is usually at least equimolar amount, preferably equimolar to 2-fold molar amount relative to compound (4).

  The amount of compound (5a) to be used is generally at least equimolar amount, preferably equimolar to 2-fold molar amount relative to compound (4).

This reaction normally proceeds suitably at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 1 to 10 hours.
[Reaction Formula-3]

[Wherein R ₂ is the same as defined above. X ₃ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. A ₂ represents a lower alkylene group.
Ring Q1 is

as well as

A bicyclic heterocyclic group selected from the group consisting of: A carbon-carbon bond including a dotted line in the bicyclic heterocyclic group represents a single bond or a double bond.
Here, on ring Q1, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, lower alkenyloxy group, lower alkanoyl group, Cycloalkyl group, cycloalkyl (lower) alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, amino group optionally having lower alkanoyl group, nitro group , A hydroxy lower alkyl group, an amino lower alkyl group having a lower alkyl group, a thienyl group, a 3- to 8-membered saturated heteromonocyclic lower alkyl group having 1 or 2 nitrogen atoms, and an oxo group At least one group may be substituted. ]
The reaction between the compound represented by the general formula (6) and the compound represented by the general formula (5b) is a reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction formula-1. The reaction is carried out under the same reaction conditions.

The compound of the general formula (2) used as the starting material is, for example, according to the method shown in the following reaction formula-4, and the compound represented by the general formula (5) is, for example, in accordance with the method shown in the following reaction formula-5. , Each manufactured.
[Reaction Formula-4]

[Wherein, ring Q, A ₁ , X ₁ and X ₃ are the same as above. ]
The reaction between the compound represented by the general formula (4) and the compound represented by the general formula (8) is performed by reacting the compound represented by the general formula (4) and the compound represented by the general formula (5a) in the reaction formula-2. The reaction is carried out under the same reaction conditions.
[Reaction Formula-5]

[Wherein, R ₂ , A and X ₂ are the same as above. X ₄ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
The reaction between the compound represented by the general formula (3) and the compound represented by the general formula (9) is performed by reacting the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction formula-1. The reaction is carried out under the same reaction conditions. The compound of general formula (3) and the compound of general formula (9) are both known compounds that are easily available.

  In compound (1), a compound having a hydroxyl group on ring Q is produced by treating compound (1) having a methoxy group on ring Q in the presence of an acid in a suitable solvent or without solvent. .

  Here, examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Halogenated hydrocarbons such as: fatty acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile, pyridine, DMF, DMSO, hexamethylphosphoric triamide or a mixed solvent thereof Can be mentioned.

  Examples of the acid include mineral acids such as hydrobromic acid, hydrochloric acid and concentrated sulfuric acid, fatty acids such as formic acid and acetic acid, organic acids such as p-toluenesulfonic acid, aluminum chloride, zinc chloride, iron chloride, tin chloride, Examples thereof include Lewis acids such as boron fluoride and boron tribromide, iodides such as sodium iodide and potassium iodide, and mixtures of the above Lewis acids and iodides.

  Such an acid is usually used in an amount of 0.1 to 15 times by mole, preferably 0.5 to 10 times by mole, relative to the compound (1). When the reaction is carried out in the absence of a solvent, the acid is usually used in a large excess.

  This reaction is usually performed at 0 to 150 ° C., preferably about 0 to 100 ° C., and is generally completed in about 0.5 to 75 hours.

  The starting compound used in each of the above reaction formulas may be a suitable salt, and the target compound obtained in each reaction may form a suitable salt. Suitable salts thereof include suitable salts of the compound (1) exemplified below.

  Suitable salts of the compound (1) are pharmacologically acceptable salts such as alkali metal salts (for example, sodium salts and potassium salts), alkaline earth metal salts (for example, calcium salts and magnesium salts). Metal salts such as ammonium salts, alkali metal carbonates (eg, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (eg, lithium hydrogen carbonate, sodium bicarbonate, potassium hydrogen carbonate, etc.), alkalis Salts of inorganic bases such as metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); eg, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N-ethyldiisopropyl) Amines), pyridine, quinoline, piperidine, imidazole, picoline Dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (eg, N-methylmorpholine), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [ 5.4.0] Salts of organic bases such as undecene-7 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO); hydrochlorides, hydrobromides, hydroiodides , Inorganic acid salts such as sulfate, nitrate, phosphate; formic acid, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malic acid Examples thereof include salts of organic acids such as salts, citrates, tartrates, carbonates, picrates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, and glutamates.

  In addition, compounds in a form in which a solvate (eg, hydrate, ethanolate, etc.) is added to the raw materials and target compounds shown in each reaction formula are also included in each general formula. Preferred solvates include hydrates.

  Each target compound obtained in each of the above reaction formulas is obtained by cooling the reaction mixture, for example, separating the crude reaction product by an isolation operation such as filtration, concentration, extraction, etc., and performing column chromatography, recrystallization, etc. It can be isolated and purified from the reaction mixture by ordinary purification procedures.

  The compound represented by the general formula (1) of the present invention naturally includes isomers such as geometric isomers, stereoisomers, and optical isomers.

  The compound of the general formula (1) and a salt thereof are used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).

  In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, absorption accelerators such as quaternary ammonium base, sodium lauryl sulfate, glyce Emissions, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  When forming into the form of a pill, those conventionally known in this field can be widely used as the carrier. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar. Can be used.

  In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.

  Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.

  In this case, a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.

  The amount of the compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70% by weight in the preparation composition. , Preferably about 1 to 30% by weight.

  The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, disease degree, and the like. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal fluid such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally.

  The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, gender and other conditions, the degree of the disease, etc. It should be about 10 mg. In addition, the active ingredient compound is desirably contained in the dosage unit form in a range of about 1 to 200 mg.

The compound of the present invention has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action and a serotonin uptake inhibitory action (or a serotonin reuptake inhibitory action).

D ₂ receptor partial agonist action suppresses this when dopamine (DA) -acting neurotransmission is enhanced, while promoting it when DA-acting neurotransmission is reduced. It has a function to stabilize DA neurotransmission to a normal state (dopamine system stabilizer, dopamine system stabilizer). By this function, without causing any side effects, excellent clinical improvement action, such as positive and negative symptom improvement action, cognitive impairment improvement action, depressive symptom improvement, on symptoms based on DA neurotransmission abnormality (up and down) (Miyako: Psychiatry, 46, 855-864 (2004), Tetsuro Kikuchi and Satoshi Hirose: Brain Science, 25, 579-583 (2004) and Harrison) , TS and Perry, CM: Drugs 64: 1715-1736, 2004).

The 5-HT _2A receptor antagonistic action reduces the extrapyramidal side effects and exhibits an excellent clinical effect, and is effective for improving negative symptoms, cognitive impairment, depressive symptoms, insomnia, etc. ( Jun Ishigoka and Ken Inada: Clinical Psychopharmacology, Vol. 4, pp. 1653-1664 (2001), Mitsuaki Murasaki: Clinical Psychopharmacology, Vol. 1, pp. 5-22 (1998), Pullar, IA et al., : Eur. J. Pharmacol., 407: _39-46, 2000 and Meltzer, HY et al .: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

  The serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) is effective, for example, in the improvement of depressive symptoms (Murazaki Mitsukuni: Clinical Psychopharmacology, Vol. 1, pp. 5-22 (1998)).

  The compounds of the present invention are all excellent in these three actions, or one or two of these actions are remarkably excellent.

Further, some of the compounds of the present invention have an α ₁ receptor antagonistic action in addition to the above action. α ₁ receptor antagonistic action is effective in improving the positive symptoms of schizophrenia (see Svensson, TH: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

  Therefore, the compounds of the present invention have a broad therapeutic spectrum for schizophrenia and other central nervous diseases and have excellent clinical effects.

  Accordingly, the compounds of the present invention can be used to treat schizophrenia, refractory, refractory or chronic schizophrenia, ataxic emotional disorders, psychotic disorders, mood disorders, bipolar disorders (eg, bipolar type I disorder and bipolar II Type disorders), depression, intrinsic depression, major depression, melancholic and treatment-resistant depression, mood modulation disorders, mood circulation disorders, anxiety disorders (eg, panic attacks, panic disorders, agoraphobia, social phobia) Obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatic expression disorder (eg hysteria, somatization disorder, conversion disorder, pain disorder, psychosis), falseness Disorders, dissociative disorders, sexual disorders (eg, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction), eating disorders (eg, anorexia nervosa, bulimia nervosa, etc.), Sleep disorders, adaptation disorders, substance-related disorders (E.g. alcohol abuse, addiction and drug addiction, stimulant addiction, narcotic addiction, etc.), annoyance (disappearance, anhedonia, e.g. iatrogenic annoysia, annoyance due to psychological and mental causes, Anxiety associated with depression, anxiety associated with schizophrenia), delirium, cognitive impairment, Alzheimer's disease, Parkinson's disease, cognitive impairment associated with other neurodegenerative diseases, neurodegeneration of Alzheimer's disease, Parkinson's disease and related disorders Cognitive impairment due to disease, cognitive impairment of schizophrenia, treatment resistance, refractory or cognitive impairment due to chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autistic disorder (Autism), Toulette disorder, tic disorder, attention deficit / hyperactivity disorder, behavioral disorder, Down's syndrome, etc. are extremely effective in improving various disorders of the central nervous system.

  Furthermore, the compound of the present invention has few side effects and is excellent in terms of tolerability and safety.

  Hereinafter, the present invention will be further clarified with reference examples, examples, pharmacological test examples and formulation examples.

Reference example 1
Synthesis of 7- (4-chlorobutoxy) -1H-quinolin-2-one To a suspension of 7-hydroxy-1H-quinolin-2-one 30 g in methanol (250 ml), 14.7 g of potassium hydroxide was added, and 50 After stirring at 0 ° C. to make a solution, 65 ml of 1-bromo-4-chlorobutane was added, and the mixture was heated to reflux for 8 hours. After cooling to room temperature, the precipitated crystals were collected by filtration. Purification by silica gel column chromatography (dichloromethane: methanol = 100: 3) gave 29.6 g of 7- (4-chlorobutoxy) -1H-quinolin-2-one as a white powder.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.15 (4H, m), 3.60-3.70 (2H, m), 4.10 (2H, t, J = 5.6 Hz), 6.56 (1H, dd, J = 9.0 Hz, 3.8 Hz), 6.81 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.85 (1H, d, J = 2.3 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.75 (1H, d, J = 9.4 Hz), 12.54 (1H, brs).

Reference example 2
Synthesis of 7- (4-chlorobutoxy) -4-methyl-1H-quinolin-2-one In the same manner as in Reference Example 1, synthesis was performed from 7-hydroxy-4-methyl-1H-quinolin-2-one.
White powder
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.80-2.00 (4H, m), 2.37 (3H, s), 3.72 (2H, t, J = 6.0 Hz), 4.05 (2H, t, J = 6.0 Hz) ), 6.20 (1H, s), 6.75-6.90 (2H, m), 7.60 (1H, d, J = 8.5 Hz), 11.42 (1H, brs).

Reference example 3
Synthesis of 7-methoxy-3-methyl-1H-quinolin-2-one To a solution of 13 g of 7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde in trifluoroacetic acid (300 ml), ice-cooled. Then, 30.7 ml of triethylsilane was added and stirred overnight at room temperature. The reaction solution was poured into ice water, extracted with dichloromethane, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain 11.1 g of 7-methoxy-3-methyl-1H-quinolin-2-one as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.02 (3H, s), 3.77 (3H, s), 6.70-6.80 (2H, m), 7.45 (1H, d, J = 8.4 Hz), 7.64 ( 1H, s), 11.56 (1H, brs).

Reference example 4
Synthesis of 7-hydroxy-3-methyl-1H-quinolin-2-one 7-Methoxy-3-methyl-1H-quinolin-2-one 2.12 g of a 47% hydrobromic acid (60 ml) suspension Heated to reflux for 6 hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals are dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.7 g of brown powdery 7-hydroxy-3-methyl-1H-quinolin-2-one. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.99 (3H, s), 6.57 (1H, dd, J = 8.5 Hz, 2.5 Hz), 6.65 (1H, d, J = 2.5 Hz), 7.34 (1H, d , J = 8.5 Hz), 7.58 (1H, s), 9.90 (1H, s), 11.48 (1H, brs).

Reference Example 5
Synthesis of 7- (3-chloropropoxy) -3-methyl-1H-quinolin-2-one In the same manner as in Reference Example 1, from 7-hydroxy-3-methyl-1H-quinolin-2-one to 1-bromo White powdery 7- (3-chloropropoxy) -3-methyl-1H-quinolin-2-one was synthesized using -3-chloropropane.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.05 (3H, s), 2.15-2.25 (2H, m), 3.81 (2H, t, J = 6.5 Hz), 4.11 (2H, t, J = 6.0 Hz) ), 6.75-6.85 (2H, m), 7.48 (1H, d, J = 8.5 Hz), 7.67 (1H, s), 11.59 (1H, brs).

Reference Example 6
Synthesis of 7- (4-chlorobutoxy) -3-methyl-1H-quinolin-2-one In the same manner as in Reference Example 1, from 7-hydroxy-3-methyl-1H-quinolin-2-one to 1-bromo White powdery 7- (4-chlorobutoxy) -3-methyl-1H-quinolin-2-one was synthesized using -4-chlorobutane.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.80-1.95 (4H, m), 2.04 (3H, s), 3.72 (2H, t, J = 6.0 Hz), 4.03 (2H, t, J = 6.0 Hz) ), 6.75-6.80 (2H, m), 7.47 (1H, d, J = 8.5 Hz), 7.66 (1H, s), 11.58 (1H, brs).

Reference Example 7
Synthesis of 1- (4-chlorobutyl) -1H-quinolin-2-one To a solution of 1.0 g of 1H-quinolin-2-one in dimethylformamide (20 ml) was added sodium hydride (60% oily) under stirring with ice cooling. After adding 30 g and stirring at room temperature for 0.5 hour, 1.6 ml of 1-bromo-4-chlorobutane was added and stirred at room temperature for 14 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 1.02 g of colorless oily 1- (4-chlorobutyl) -1H-quinolin-2-one.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.85 to 2.00 (4H, m), 3.60 to 3.65 (2H, m), 4.35 (2H, t, J = 7.0 Hz), 6.70 (1H, d, J = 9.5 Hz), 7.23 (1H, dd, J = 8.6 Hz, 7.5 Hz), 7.38 (1H, d, J = 8.9 Hz), 7.54-7.62 (2H, m), 7.68 (1H, d, J = 9.5 Hz).

Reference Example 8
Synthesis of 1- (5-chloropentyl) -1H-quinolin-2-one In the same manner as in Reference Example 7, colorless oily oil was obtained from 1H-quinolin-2-one using 1-bromo-5-chloropentane. 1- (5-Chloropentyl) -1H-quinolin-2-one was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.55-1.70 (2H, m), 1.75-1.95 (4H, m), 3.56 (2H, t, J = 6.6 Hz), 4.31 (2H, t, J = 7.8 Hz), 6.70 (1H, d, J = 9.5 Hz), 7.23 (1H, dd, J = 7.3 Hz, 7.3 Hz), 7.35 (1H, d, J = 8.9 Hz), 7.54-7.60 (2 H, m), 7.67 (1 H, d, J = 9.4 Hz).

Reference Example 9
Synthesis of 7- (4-chloro- (Z) -2-butenyloxy) -3,4-dihydro-1H-quinolin-2-one 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one A mixture consisting of 0 g, potassium carbonate 1.7 g, cis-1,4-dichloro-2-butene 3.2 ml, dimethylformamide 50 ml was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give 7- (4-chloro- (Z) -2-butenyloxy) -3,4-dihydro-1H as a white powder. -Quinolin-2-one (1.3 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.62 (2H, t, J = 6.3 Hz), 2.90 (2H, t, J = 6.3 Hz), 4.16 (2H, d, J = 6.3 Hz), 4.62 (2H , D, J = 4.6 Hz), 5.86-5.90 (2H, m), 6.31 (1H, d, J = 2.5 Hz), 6.54 (1H, dd, J = 8. 3 Hz, 2.5 Hz), 7.06 (1 H, d, J = 8.3 Hz), 7.56 (1 H, brs).

Reference Example 10
Synthesis of 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy) butyric acid methyl ester To a solution of 5 g of 4-chloro-2-methylbutyric acid methyl ester in acetonitrile (70 ml), 4.98 g of sodium iodide was added and heated to reflux for 3 hours. Water was added to the reaction solution, extracted with dichloromethane, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was added to a mixture consisting of 4.33 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 6.0 g of potassium carbonate and dimethylformamide (90 ml) and stirred at 80 ° C. for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 3) to give 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy) butyric acid as a yellow oil. Methyl ester 6.0 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.23 (3H, d, J = 7.1 Hz), 1.75-1.90 (1H, m), 2.10-2.25 (1H, m), 2.55-2.65 (2H) M), 2.72 (1H, q, J = 7.0 Hz), 2.80-2.90 (2H, m), 3.68 (3H, s), 3.95 (2H, t, J = 6.2 Hz), 6.33 (1H, d, J = 2.3 Hz), 6.49 (1H, dd, J = 8.3 Hz, 2.21 Hz), 7.02 (1H, d, J = 8.3 Hz), 8.41 (1H, brs).

Reference Example 11
Synthesis of 7- (4-hydroxy-3-methylbutoxy) -3,4-dihydro-1H-quinolin-2-one To a suspension of 1.6 g of lithium aluminum hydride in tetrahydrofuran (200 ml) under ice-cooling and stirring, 6 g of 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy) butyric acid methyl ester was added dropwise and stirred at the same temperature for 2 hours. Under ice-cooling and stirring, a saturated aqueous solution of Rochelle salt was added, extracted with diethyl ether, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to give 7- (4-hydroxy-3-methylbutoxy) -3,4-dihydro-1H-quinolin-2-one 2 as a yellow oil. .8 g was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
0.99 (3H, d, J = 6.5 Hz), 1.60-2.05 (3H, m), 2.60-2.65 (2H, m), 2.85-2.95 (2H M), 3.55 (2H, t, J = 5.3 Hz), 3.95-4.10 (2H, m), 6.38 (1H, d, J = 2.5 Hz), 6.53. (1H, dd, J = 8.3 Hz, 2.4 Hz), 7.04 (1H, d, J = 8.3 Hz), 8.59 (1H, brs).

Reference Example 12
Synthesis of methanesulfonic acid 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy) butyl ester 7- (4-hydroxy-3-methylbutoxy) -3,4- Methanesulfonyl chloride (1.0 ml) was added to a solution of 2.8 g of dihydro-1H-quinolin-2-one and 2.4 ml of triethylamine in dichloromethane (80 ml) under ice-cooling and stirring at room temperature overnight. Water was added to the reaction solution, extracted with dichloromethane, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to give 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinoline-7) methanesulfonate as a green powder. -Iloxy) butyl ester (2.8 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.07 (3H, d, J = 6.8 Hz), 1.60-1.80 (1H, m), 1.90-2.00 (1H, m), 2.15-2.25 (1H M), 2.50-2.65 (2H, m), 2.90 (2H, t, J = 7.3 Hz), 3.95-4.10 (2H, m), 4.10-4 .20 (2H, m), 6.33 (1H, d, J = 2.5 Hz), 6.51 (1H, dd, J = 8.3 Hz, 2.5 Hz), 7.05 (1H, d, J = 8.3 Hz), 8.16 (1H, brs).

Reference Example 13
Synthesis of 7- (4-bromo- (E) -2-butenyloxy) -3,4-dihydro-1H-quinolin-2-one In the same manner as in Reference Example 7, 7-hydroxy-3,4-dihydro- 7- (4-Bromo- (E) -2-butenyloxy) -3,4-dihydro-1H- in the form of white powder using trans-1,4-dibromo-2-butene from 1H-quinolin-2-one Quinolin-2-one was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.61 (2H, t, J = 7.5 Hz), 2.89 (2H, t, J = 7.5 Hz), 3.98 (2H, d, J = 7.0 Hz), 4.51 (2H , D, J = 4.8 Hz), 5.90-6.10 (2H, m), 6.43 (1H, d, J = 2.1 Hz), 6.51 (1H, dd, J = 8. 2 Hz, 2.1 Hz), 7.03 (1 H, d, J = 8.2 Hz), 9.35 (1 H, brs).

Reference Example 14
Synthesis of 7- (4-chlorobutoxy) -4-methyl-3,4-dihydro-1H-quinolin-2-one 7-methoxy-4-methyl-3,4-dihydro-1H-quinolin-2-one 0 Boron tribromide (1M dichloromethane solution, 6.2 ml) was added to a solution of .54 g of dichloromethane (5 ml) under ice-cooling, and 0.23 g of precipitated crude crystals were collected by filtration. To a solution of crude crystals in acetonitrile (2.5 ml) -water (2.5 ml) were added 0.2 g of potassium carbonate and 0.45 ml of 1-bromo-4-chlorobutane, and the mixture was heated to reflux for 6 hours. Water was poured into the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to give 7- (4-chlorobutoxy) -4-methyl-3,4-dihydro-1H-quinolin-2-one as a white powder. 0.29 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.28 (3H, d, J = 7.0 Hz), 1.85-2.05 (4H, m), 2.35-2.45 (1H, m), 2.65-2.75 (1H M), 3.00-3.15 (1H, m), 3.62 (2H, t, J = 6.0 Hz), 3.97 (2H, t, J = 6.0 Hz), 6.32. (1H, d, J = 2.5 Hz), 6.55 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.08 (1H, d, J = 8.5 Hz), 7.96 ( 1H, brs).

Reference Example 15
Synthesis of 7- [2- (2-chloroethoxy) ethoxy] -3,4-dihydro-1H-quinolin-2-one 7-hydroxy-3,4-dihydro-1H-quinolin-2-one 7.0 g, A mixture consisting of 7.1 g of potassium carbonate, 30 ml of bis-2-chloroethyl ether and 400 ml of acetonitrile was heated to reflux for 2 days. Water was poured into the reaction solution, extracted with dichloromethane, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to give 7- [2- (2-chloroethoxy) ethoxy] -3,4-dihydro-1H-quinoline-2- in the form of a white powder. 8.3 g of ON was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.61 (2H, t, J = 7.4 Hz), 2.90 (2H, t, J = 7.4 Hz), 3.66 (2H, t, J = 5.8 Hz), 3.74-3 .88 (4H, m), 4.11 (2H, t, J = 4.7 Hz), 6.36 (1H, d, J = 2.2 Hz), 6.54 (1H, dd, J = 8. 3 Hz, 2.2 Hz), 7.05 (1H, d, J = 8.3 Hz), 8.01 (1H, m).

Reference Example 16
Synthesis of 6- (3-chloropropoxy) -3,4-dihydro-1H-quinolin-2-one In the same manner as in Reference Example 9, 6-hydroxy-3,4-dihydro-1H-quinolin-2-one 1-bromo-3-chloropropane was used to synthesize 6- (3-chloropropoxy) -3,4-dihydro-1H-quinolin-2-one in the form of a white powder.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.15-2.35 (2H, m), 2.55-2.65 (2H, m), 2.90-3.00 (2H, m), 3.50-3.80 (2H, m ), 4.00-4.10 (2H, m), 6.73 (3H, brs), 8.68 (1H, brs).

Reference Example 17
Synthesis of 6- (4-bromobutoxy) -3,4-dihydro-1H-quinolin-2-one In the same manner as in Reference Example 9, 6-hydroxy-3,4-dihydro-1H-quinolin-2-one Thus, 6- (4-bromobutoxy) -3,4-dihydro-1H-quinolin-2-one in the form of a white powder was synthesized using 1,4-dibromobutane.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 2.30-2.45 (2H, m), 2.75-2.85 (2H, m ), 3.58 (2H, t, J = 6.5 Hz), 3.91 (2H, t, J = 6.5 Hz), 6.70-6.80 (3H, m), 9.88 (1H) , Brs).

Reference Example 18
Synthesis of 1- (5-chloropentyl) -3,4-dihydro-1H-quinolin-2-one In the same manner as in Reference Example 7, from 1,4-dihydro-1H-quinolin-2-one to 1-bromo A colorless oily 1- (5-chloropentyl) -3,4-dihydro-1H-quinolin-2-one was synthesized using -5-chloropentane.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.45-1.60 (2H, m), 1.60-1.75 (2H, m), 1.75-1.90 (2H, m), 2.60-2.70 (2H, m ), 2.85-2.95 (2H, m), 3.54 (2H, d, J = 6.6 Hz), 3.59 (2H, d, J = 7.7 Hz), 6.76-7 .04 (2H, m), 7.15-7.29 (2H, m).

Reference Example 19
Synthesis of 2- (5-chloropentyl) -3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 7, from 3,4-dihydro-2H-isoquinolin-1-one to 1-bromo Brown oily 2- (5-chloropentyl) -3,4-dihydro-2H-isoquinolin-1-one was synthesized using -5-chloropentane.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.50-2.00 (6H, m), 2.99 (2H, t, J = 6.6 Hz), 3.52-3.60 (6H, m), 7.17 (1H, d, J = 7.3 Hz), 7.31-7.44 (2H, m), 8.07 (1H, dd, J = 1.3 Hz, 7.5 Hz).

Reference Example 20
Synthesis of 7- (3-chloropropoxy) -3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 9, 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one 1-Bromo-3-chloropropane was used to synthesize 7- (3-chloropropoxy) -3,4-dihydro-2H-isoquinolin-1-one as a brown oil.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.20-2.40 (2H, m), 2.90-3.00 (2H, m), 3.50-3.80 (4H, m), 4.15-4.20 (4H, m ), 6.48 (1H, brs), 7.01 (1H, dd, J = 4.0 Hz, 1.5 Hz), 7.13 (1H, d, J = 4.0 Hz), 7.59 (1H , D, J = 1.4 Hz).

Reference Example 21
Synthesis of 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 4, 7-methoxy-2-methyl-3,4-dihydro-2H-isoquinoline- Brown powdery 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one was synthesized from 1-one.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.84 (2H, t, J = 6.5 Hz), 3.01 (3H, s), 3.47 (2H, t, J = 6.6 Hz), 6.85 (1H, dd, J = 8 .1 Hz, 2.5 Hz), 7.08 (1 H, d, J = 8.1 Hz), 7.29 (1 H, d, J = 2.5 Hz), 9.49 (1 H, s).

Reference Example 22
Synthesis of 7- (4-chlorobutoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 9, 7-hydroxy-2-methyl-3,4-dihydro Using 1-bromo-4-chlorobutane from -2H-isoquinolin-1-one, 7- (4-chlorobutoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one as a brown oil Synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.90-2.00 (4H, m), 2.93 (2H, t, J = 6.8 Hz), 3.15 (3H, s), 3.45-3.65 (4H, m), 4.04 (2H, t, J = 5.8 Hz), 6.95 (1H, dd, J = 8.3 Hz, 2.5 Hz), 7.07 (1H, d, J = 8.3 Hz), 7 .59 (1H, d, J = 2.5 Hz).

Reference Example 23
Synthesis of 7- (4-chlorobutoxy) -3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 9, 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one 1-Bromo-4-chlorobutane was used to synthesize 7- (4-chlorobutoxy) -3,4-dihydro-2H-isoquinolin-1-one in the form of a white powder.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.93-2.00 (4H, m), 2.88-2.96 (2H, m), 3.51-3.58 (2H, m), 3.62 (2H, t, J = 6) .2 Hz), 4.05 (2 H, t, J = 5.7 Hz), 6.25 (1 H, s), 7.00 (1 H, dd, J = 8.3 Hz, 2.7 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 2.7 Hz).

Reference Example 24
Synthesis of 2- (4-chlorobutyl) -2H-isoquinolin-1-one In the same manner as in Reference Example 7, 1-bromo-4-chlorobutane was used from 2H-isoquinolin-1-one to give yellow oil 2- (4-Chlorobutyl) -2H-isoquinolin-1-one was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.80-2.00 (4H, m), 3.59 (2H, t, J = 6.3 Hz), 4.05 (2H, t, J = 7.0 Hz), 6.51 (1H, d , J = 7.4 Hz), 7.05 (1H, d, J = 7.4 Hz), 7.46-7.52 (2H, m), 7.63 (1H, m), 8.42 (1H , D, J = 8.1 Hz).

Reference Example 25
Synthesis of 7- (3-chloropropoxy) -2H-isoquinolin-1-one In the same manner as in Reference Example 9, using 1-bromo-3-chloropropane from 7-hydroxy-2H-isoquinolin-1-one, White powdery 7- (3-chloropropoxy) -2H-isoquinolin-1-one was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.30 (2H, quint, J = 6.1 Hz), 3.78 (2H, t, J = 6.4 Hz), 4.28 (2H, t, J = 5.9 Hz), 6.54 (1H , D, J = 7.1 Hz), 7.06 (1H, d, J = 6.6 Hz), 7.29 (1H, dd, J = 8.7 Hz, 2.7 Hz), 7.51 (1H, d, J = 8.7 Hz), 7.82 (1H, d, J = 2.7 Hz), 10.64 (1H, s).

Reference Example 26
Synthesis of 7- (3-chloropropoxy) -2-ethyl-2H-isoquinolin-1-one Iodinated from 7- (3-chloropropoxy) -2H-isoquinolin-1-one in the same manner as in Reference Example 7. A colorless oily 7- (3-chloropropoxy) -2-ethyl-2H-isoquinolin-1-one was synthesized using ethyl.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.38 (3H, t, J = 7.2 Hz), 2.29 (2H, quint, J = 6.1 Hz), 3.76 (2H, t, J = 6.4 Hz), 4.07 (2H , Q, J = 7.2 Hz), 4.25 (2H, d, J = 5.8 Hz), 6.48 (1H, d, J = 7.3 Hz), 6.98 (1H, d, J = 7.3 Hz), 7.23 (1H, dd, J = 8.7 Hz, 2.7 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.85 (1H, d, J = 2) .6 Hz).

Reference Example 27
Synthesis of 2- (4-chlorobutyl) -7-methoxy-2H-isoquinolin-1-one In the same manner as in Reference Example 7, 1-bromo-4-chlorobutane was obtained from 7-methoxy-2H-isoquinolin-1-one. Used to synthesize colorless oily 2- (4-chlorobutyl) -7-methoxy-2H-isoquinolin-1-one.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.64-2.00 (4H, m), 3.59 (2H, t, J = 6.3 Hz), 3.93 (3H, s), 4.06 (2H, t, J = 6.9 Hz) ), 6.49 (1H, d, J = 7.3 Hz), 6.96 (1H, d, J = 7.3 Hz), 7.25 (1H, dd, J = 8.6 Hz, 2.7 Hz) 7.45 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 2.7 Hz).

Reference Example 28
Synthesis of 6- (3-chloropropoxy) -2H-isoquinolin-1-one In the same manner as in Reference Example 9, 1-bromo-3-chloropropane was used to lightly prepare 6-hydroxy-2H-isoquinolin-1-one. Yellow powdery 6- (3-chloropropoxy) -2H-isoquinolin-1-one was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.30 (2H, quint, J = 6.0 Hz), 3.78 (2H, t, J = 6.2 Hz), 4.24 (2H, t, J = 5.9 Hz), 6.46 (1H , D, J = 7.2 Hz), 6.93 (1H, d, J = 2.4 Hz), 7.05-7.12 (2H, m), 8.33 (1H, d, J = 8. 9 Hz), 10.33 (1 H, s).

Reference Example 29
Synthesis of 7- (3-chloropropoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one In the same manner as in Reference Example 7, 7-hydroxy-2-methyl-3,4-dihydro 7- (3-Chloropropoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one in the form of a brown powder using 1-bromo-3-chloropropane from -2H-isoquinolin-1-one Was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.15-2.35 (2H, m), 2.85-3.00 (2H, m), 3.15 (3H, s), 3.50-3.80 (4H, m), 4. 10-4.20 (2H, m), 6.96 (1H, dd, J = 8.3 Hz, 2.7 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.62 (1H , D, J = 2.7 Hz).

Reference Example 30
Synthesis of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride 14.4 g of 4-bromobenzo [b] thiophene, 29.8 g of anhydrous piperazine, 9.3 g of sodium t-butoxide, (R)-(+)- A mixture consisting of 0.65 g of 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 0.63 g of tris (dibenzylideneacetone) dipalladium (0) and 250 ml of toluene was placed under a nitrogen atmosphere. Heated to reflux for 1 hour. Water was poured into the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia = 100: 10: 1) to obtain 9.5 g of 1-benzo [b] thiophen-4-yl-piperazine as a yellow oil.

To a methanol solution of 9.5 g of 1-benzo [b] thiophen-4-yl-piperazine was added 3.7 ml of concentrated hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain colorless needle crystal 1-benzo [b] thiophen-4-yl-piperazine hydrochloride.
Melting point: 276-280 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
3.25-3.35 (8H, m), 6.94 (1H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.73 (1H, d, J = 5.5 Hz), 9.35 (2H, brs) .

Example 1
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one 7- (4-Chlorobutoxy) -1H-quinoline-2 -On 9. g, A mixture of 10 g of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 3). Recrystallization from ethanol gave 13.6 g of 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one as a white powder. .
Melting point 183.5-184.5 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44 (2H, t, J = 7 Hz), 2.5-2.8 (4H, m ), 2.9-3.2 (4H, m), 4.06 (2H, t, J = 6.5 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.75-6. .85 (2H, m), 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5. 5 Hz), 7.55 (1 H, d, J = 9.5 Hz), 7.61 (1 H, d, J = 8 Hz), 7.69 (1 H, d, J = 5.5 Hz), 7.80 ( 1H, d, J = 9.5 Hz), 11.59 (1H, bs).

Example 2
Synthesis of 3- [2- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) ethoxy] -1H-quinolin-2-one In the same manner as in Example 1, 3- (2- Synthesized from bromoethoxy) -1H-quinolin-2-one.
White powder (chloroform)
Melting point: 201.9-204.5 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
2.90-2.95 (4H, m), 3.10 (2H, t, J = 5.9 Hz), 3.23-3.27 (4H, m), 4.30 (2H, t, J = 5.9 Hz), 6.90 (1H, d, J = 7.7 Hz), 7.08 (1H, s), 7.15-7.32 (2H, m), 7.37-7.41. (4H, m), 7.47-7.49 (1H, m), 7.55 (1H, d, J = 8.1 Hz), 11.33 (1H, br).

Example 3
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -4-methyl-1H-quinolin-2-one According to a method similar to that in Example 1, Synthesized from-(3-chloropropoxy) -4-methyl-1H-quinolin-2-one.
Fine brown powder (ethyl acetate)
Melting point 202-208 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.95-2.0 (2H, m), 2.37 (3H, s), 2.55 (2H, t, J = 7 Hz), 2.6-2.7 (4H, m), 3. 05-3.2 (4H, m), 4.09 (2H, t, J = 6.5 Hz), 6.21 (1H, bs), 6.8-6.85 (2H, m), 6. 90 (1H, d, J = 7.5 Hz), 7.28 (1 H, dd, J = 8 Hz, 8 Hz), 7.41 (1H, d, J = 5.5 Hz), 7.6-7.7 (2H, m), 7.69 (1H, d, J = 5.5 Hz), 11.41 (1H, bs).

Example 4
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -4-methyl-1H-quinolin-2-one In the same manner as in Example 1, It was synthesized from-(4-chlorobutoxy) -4-methyl-1H-quinolin-2-one.
White powder (ethyl acetate)
Melting point 164-168 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.6-1.7 (2H, m), 1.75-1.85 (2H, m), 2.37 (3H, s), 2.44 (2H, t, J = 7 Hz), 2. 55-2.7 (4H, m), 3.0-3.2 (4H, m), 4.0-4.15 (2H, m), 6.20 (1H, bs), 6.8- 6.85 (2H, m), 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5) .5Hz), 7.6-7.7 (2H, m), 7.69 (1H, d, J = 5.5 Hz), 11.42 (1H, bs).

Example 5
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3-methyl-1H-quinolin-2-one According to the same procedure as in Example 1, It was synthesized from-(3-chloropropoxy) -3-methyl-1H-quinolin-2-one.
White powder (ethyl acetate)
Melting point 185-187 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.9-2.0 (2H, m), 2.04 (3H, s), 2.55 (2H, t, J = 7 Hz), 2.6-2.75 (4H, m), 3. 0-3.2 (4H, m), 4.07 (2H, t, J = 6.5 Hz), 6.75-6.85 (2H, m), 6.90 (1H, d, J = 7) .5 Hz), 7.28 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.48 (1H, d, J = 8.5 Hz), 7 .61 (1H, d, J = 8 Hz), 7.65-7.7 (2H, m), 11.57 (1H, bs).

Example 6
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3-methyl-1H-quinolin-2-one In the same manner as in Example 1, It was synthesized from-(4-chlorobutoxy) -3-methyl-1H-quinolin-2-one.
White powder (ethyl acetate)
Melting point 197-199 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.6-1.7 (2H, m), 1.75-1.9 (2H, m), 2.04 (3H, s), 2.44 (2H, t, J = 7 Hz), 2. 55-2.7 (4H, m), 3.0-3.15 (4H, m), 4.04 (2H, t, J = 6.5 Hz), 6.75-6.85 (2H, m ), 6.88 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.65-7.75 (2H, m), 11.59 (1H, bs).

Example 7
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1H-quinolin-2-one In the same manner as in Example 1, 7- (3- Synthesized from chloropropoxy) -1H-quinolin-2-one.
White powder (ethyl acetate-diethyl ether)
Melting point 204-207 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.97 (2H, t, J = 6.8 Hz), 2.50-2.60 (2H, m), 2.60-2.65 (4H, m), 3.05-3.10 (4H M), 4.08 (2H, t, J = 6.4 Hz), 6.29 (1H, d, J = 9.5 Hz), 6.75-6.85 (2H, m), 6.90. (1H, d, J = 7.7 Hz), 7.25-7.30 (1H, m), 7.40 (1H, d, J = 5.6 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.60-7.65 (1 H, m), 7.69 (1 H, d, J = 5.5 Hz), 7.80 (1 H, d, J = 9.5 Hz), 11. 57 (1H, s).

Example 8
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -1H-quinolin-2-one hydrochloride After synthesizing from (4-chlorobutyl) -1H-quinolin-2-one to make an ethanol solution, 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration to give white powder 1- [4- (4- Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -1H-quinolin-2-one hydrochloride was obtained.
Melting point 282.0 ° C (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.60-2.00 (4H, m), 3.10-3.40 (6H, m), 3.50-3.60 (4H, m), 4.31 (2H, t, J = 7 .4 Hz), 6.63 (1 H, d, J = 9.4 Hz), 6.96 (1 H, d, J = 7.6 Hz), 7.24-7.35 (2 H, m), 7.48. (1H, d, J = 5.4 Hz), 7.59-7.78 (5H, m), 7.93 (1H, d, J = 9.5 Hz), 10.00-10.20 (1H, m).

Example 9
Synthesis of 1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) pentyl] -1H-quinolin-2-one hydrochloride In the same manner as in Example 1, 1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) pentyl] -1H-quinolin-2-one from (5-chloropentyl) -1H-quinolin-2-one After synthesizing and preparing an ethanol solution, 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration to give 1- [5- (4-benzo [b] thiophen-4-yl-piperazine-1 as white powder. -Yl) pentyl] -1H-quinolin-2-one hydrochloride was obtained.
Melting point 225.0-227.0 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.35-1.50 (2H, m), 1.60-1.80 (4H, m), 3.10-3.30 (6H, m), 3.50-3.60 (4H, m) ), 4.27 (2H, t, J = 7.4 Hz), 6.61 (1H, d, J = 9.5 Hz), 6.96 (1H, d, J = 7.5 Hz), 7.20. -7.34 (2H, m), 7.47 (1H, d, J = 5.5 Hz), 7.61-7.77 (5H, m), 7.91 (1H, d, J = 9. 5 Hz), 10.30-10.50 (1 H, m).

Example 10
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one In the same manner as in Example 1. , 7- (3-chloropropoxy) -3,4-dihydro-1H-quinolin-2-one.
White powder (methanol)
Melting point 163-165 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.8-2.0 (2H, m), 2.41 (2H, t, J = 7.5 Hz), 2.45-2.6 (2H, m), 2.6-2.7 (4H M), 2.78 (2H, t, J = 7.5 Hz), 2.95-3.2 (4H, m), 3.97 (2H, t, J = 6.3 Hz), 6.46. (1H, d, J = 2.3 Hz), 6.50 (1H, dd, J = 2.4 Hz, 8.2 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.04 ( 1H, d, J = 8.2 Hz), 7.27 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.40 (1H, d, J = 5.6 Hz), 7.61 (1H , D, J = 8.0 Hz), 7.69 (1H, d, J = 5.5 Hz), 9.97 (1H, bs).

Example 11
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one In the same manner as in Example 1. , 7- (4-chlorobutoxy) -3,4-dihydro-1H-quinolin-2-one.
White powder (methanol)
Melting point 147-148 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.55-1.65 (2H, m), 1.65-1.8 (2H, m), 2.35-2.5 (4H, m), 2.55-2.7 (4H, m) ), 2.78 (2H, t, J = 7.5 Hz), 3.0-3.15 (4H, m), 3.93 (2H, t, J = 6.4 Hz), 6.44 (1H) , D, J = 2.5 Hz), 6.49 (1H, dd, J = 2.5 Hz, 8.3 Hz), 6.89 (1H, d, J = 7.5 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.27 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.35-7.45 (1H, m), 7.61 (1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 5.6 Hz), 9.97 (1H, bs).

Example 12
Synthesis of 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one hydrochloride synthesized in Example 11 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one in ethanol solution of 1N hydrochloric acid The precipitated crystals were collected by filtration and recrystallized from 90% aqueous ethanol to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) as fine brown needles. ) Butoxy] -3,4-dihydro-1H-quinolin-2-one hydrochloride was obtained.
Melting point 237-239 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.75-1.85 (2H, m), 1.85-2.0 (2H, m), 2.42 (2H, t, J = 7.5 Hz), 2.79 (2H, t, J = 7.5 Hz), 3.15-3.5 (6 H, m), 3.5-3.7 (4 H, m), 3.96 (2 H, t, J = 6 Hz), 6.46 (1 H) , D, J = 2.5 Hz), 6.5-6.55 (1H, m), 6.97 (1H, d, J = 7.5 Hz), 7.07 (1H, d, J = 8. 5 Hz), 7.32 (1 H, dd, J = 8 Hz, 8 Hz), 7.50 (1 H, d, J = 5.5 Hz), 7.71 (1 H, d, J = 8 Hz), 7.77 ( 1H, d, J = 5.5 Hz), 10.03 (1H, s), 10.65 (1H, br).

Example 13
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl)-(Z) -2-butenyloxy] -3,4-dihydro-1H-quinolin-2-one Synthesized from 7- (4-chloro- (Z) -2-butenyloxy) -3,4-dihydro-1H-quinolin-2-one by the same method as in Example 1.
White powder (methanol)
Melting point 68-70 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.42 (2H, t, J = 7.5 Hz), 2.64 (4H, br), 2.79 (2H, t, J = 7.5 Hz), 2.9-3.25 (6H, m ), 4.61 (2H, d, J = 3 Hz), 5.65-5.9 (2H, m), 6.48 (1H, d, J = 2.5 Hz), 6.54 (1H, dd) , J = 2.5, 8.5 Hz), 6.89 (1H, d, J = 7.5 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.27 (1H, dd, J = 8 Hz, 8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5 Hz), 10.01 (1H, bs).

Example 14
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) -3-methylbutoxy] -3,4-dihydro-1H-quinolin-2-one hydrochloride In the same manner as in Example 1, methanesulfonic acid 2-methyl-4- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy) butyl ester was converted to 7- [4- (4-benzo [ b] Thiophen-4-yl-piperazin-1-yl) -3-methylbutoxy] -3,4-dihydro-1H-quinolin-2-one was synthesized into a methanol solution, and then a 0.5N hydrochloric acid methanol solution. And the precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) -3 as a slightly yellow powder. -Methylbut Xyl] -3,4-dihydro-1H-quinolin-2-one hydrochloride was obtained.
Melting point 217-219 (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.12 (3H, d, J = 6.5 Hz), 1.55-1.7 (1H, m), 1.9-2.05 (1H, m), 2.2-2.3 (1H M), 2.41 (2H, t, J = 7.5 Hz), 2.79 (2H, t, J = 7.5 Hz), 3.05 to 3.15 (1H, m), 3.15. -3.25 (1H, m), 3.25-3.45 (4H, m), 3.45-3.55 (2H, m), 3.55-3.7 (2H, m), 3 .9-4.1 (2H, m), 6.49 (1H, d, J = 2.5 Hz), 6.54 (1H, dd, J = 2.5 Hz, 8.5 Hz), 6.97 ( 1H, d, J = 7.5 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 8 Hz, 8 Hz), 7.49 (1H, d, J = 5.5 Hz), 7.70 (1H, d, J = 8 Hz) , 7.77 (1H, d, J = 5.5Hz), 10.03 (1H, bs), 10.66 (1H, br).

Example 15
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl)-(E) -2-butenyloxy] -3,4-dihydro-1H-quinolin-2-one Synthesized from 7- (4-bromo- (E) -2-butenyloxy) -3,4-dihydro-1H-quinolin-2-one in the same manner as in Example 1.
White powder (dichloromethane-diisopropyl ether)
Melting point: 147.8-149.7 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
2.61 (2H, t, J = 7.5 Hz), 2.65-2.75 (4H, m), 2.90 (2H, t, J = 7.5 Hz), 3.1-3.2 (6H, m), 4.52 (2H, d, J = 4.3 Hz), 5.9-6.0 (2H, m), 6.31 (1H, d, J = 2.3 Hz), 6 .55 (1H, dd, J = 8.3 Hz, 2.3 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.05 (1H, d, J = 8.3 Hz), 7. 27 (1H, m), 7.37-7.41 (2H, m), 7.53-7.60 (2H, m).

Example 16
Synthesis of 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -4-methyl-3,4-dihydro-1H-quinolin-2-one Example 1 It was synthesized from 7- (4-chlorobutoxy) -4-methyl-3,4-dihydro-1H-quinolin-2-one by the same method.
White powder (methanol)
Melting point 112-115 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.14 (3H, d, J = 7 Hz), 1.55-1.7 (2H, m), 1.7-1.8 (2H, m), 2.19 (1H, dd, J = 7) , 16 Hz), 2.43 (2H, t, J = 7 Hz), 2.5-2.7 (5H, m), 2.9-3.0 (1H, m), 3.0-3.1. (4H, m), 3.94 (2H, t, J = 6.5 Hz), 6.45 (1H, d, J = 2.5 Hz), 6.53 (1H, dd, J = 2.5, 8.5 Hz), 6.89 (1 H, d, J = 7.5 Hz), 7.07 (1 H, d, J = 8.5 Hz), 7.27 (1 H, dd, J = 8 Hz, 8 Hz), 7.39 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 5.5 Hz), 9.98 (1H, bs) ).

Example 17
Synthesis of 7- {2- [2- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) ethoxy] ethoxy} -3,4-dihydro-1H-quinolin-2-one dihydrochloride In the same manner as in Example 1, from 7- [2- (2-chloroethoxy) ethoxy] -3,4-dihydro-1H-quinolin-2-one to 7- {2- [2- (4-benzo [ b] Thiophen-4-yl-piperazin-1-yl) ethoxy] ethoxy} -3,4-dihydro-1H-quinolin-2-one was synthesized into an ethanol solution, and then a 1N hydrochloric acid ethanol solution was added. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl alcohol-diisopropyl ether to give white powder 7- {2- [2- (4-benzo [b] thiophen-4-yl-piperazin-1-yl]. D Carboxymethyl] was obtained ethoxy} -3,4-dihydro -1H- quinolin-2-one dihydrochloride.
Melting point 172.3-177.2 ° C.
¹ H-NMR (CDCl ₃ ) δ ppm:
2.53 (2H, t, J = 7.5 Hz), 2.80 (2H, t, J = 7.5 Hz), 3.40 (2H, m), 3.54-3.59 (2H, m ), 3.79-3.94 (6H, m), 4.16-4.30 (6H, m), 6.50-6.53 (2H, m), 7.01 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 8 Hz, 8 Hz), 7.53-7.62 (2H, m), 7.82 (1H, d, J = 8.0 Hz), 7 .91 (1H, m), 8.02 (1H, brs), 13.31 (1H, brs).

Example 18
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride -[4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one 0.40 g of dimethylformamide (5 ml) and tetrahydrofuran To the (5 ml) solution, 48 mg of sodium hydride (60% oily) was added under ice-cooling and stirred at room temperature for 1 hour, and then 0.07 ml of methyl iodide was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: methanol = 30: 1). The solvent was distilled off under reduced pressure, 0.5N hydrochloric acid ethanol solution was added to the residual ethanol solution, and the precipitated crystals were collected by filtration to give 7- [4- (4-benzo [b] thiophene as a slightly yellow powder. 0.15 g of -4-yl-piperazin-1-yl) butoxy] -1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride was obtained.
Melting point 275.6-277.6 ° C.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.70-1.94 (4H, m), 2.48-2.52 (2H, m), 2.77 (2H, t, J = 7.2 Hz), 3.15-3.30 (9H) , M), 3.52-3.63 (4H, m), 4.03 (2H, t, J = 6.0 Hz), 6.58-6.63 (2H, m), 6.96 (1H , D, J = 7.5 Hz), 7.11 (1H, d, J = 8.1 Hz), 7.31 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.48 (1H, d, J = 5.5 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.61 (1H, br).

Example 19
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one hydrochloride as in Example 1 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl from 6- (3-chloropropoxy) -3,4-dihydro-1H-quinolin-2-one ) Propoxy] -3,4-dihydro-1H-quinolin-2-one was synthesized into a methanol solution, 0.5N hydrochloric acid methanol solution was added, and the precipitated crystals were collected by filtration, and ethyl acetate-diethyl ether Recrystallization from a mixed solvent gave 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinoline-2- as a white powder. On-hydrochloride Obtained.
Melting point 231-234 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.20-2.30 (2H, m), 2.35-2.45 (2H, m), 2.83 (2H, t, J = 7.5 Hz), 3.20-3.70 (10H M), 4.02 (2H, t, J = 5.9 Hz), 6.70-6.85 (3H, m), 6.96 (1H, d, J = 7.6 Hz), 7.31 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.48 (1H, d, J = 5.6 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.76 ( 1H, d, J = 5.5 Hz), 9.93 (1H, brs), 10.90 (1H, brs).

Example 20
Synthesis of 6- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one In the same manner as in Example 1. , 6- (4-Bromobutoxy) -3,4-dihydro-1H-quinolin-2-one.
White powder (ethyl acetate-diethyl ether)
Melting point 175-178 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.65-1.90 (4H, m), 2.52 (2H, t, J = 7.3 Hz), 2.55-2.65 (2H, m), 2.65-2.75 (4H M), 2.94 (2H, t, J = 7.5 Hz), 3.15-3.25 (4H, m), 3.90-4.00 (2H, m), 6.65-6. .75 (3H, m), 6.89 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.27 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.35- 7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 8.02 (1H, brs).

Example 21
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -3,4-dihydro-1H-quinolin-2-one hydrochloride As in Example 1 1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) from 1- (4-chlorobutyl) -3,4-dihydro-1H-quinolin-2-one Butyl] -3,4-dihydro-1H-quinolin-2-one was synthesized into an ethanol solution, 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration to give a white powder of 1- [4 -(4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -3,4-dihydro-1H-quinolin-2-one hydrochloride was obtained.
Melting point 257.0-259.0 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.60-1.80 (4H, m), 2.54 (2H, t, J = 8.3 Hz), 2.87 (2H, t, J = 7.9 Hz), 3.10-3.30 (6H, m), 3.50-3.60 (4H, m), 3.95 (2H, t, J = 7.0 Hz), 6.94-7.04 (2H, m), 7.14 −7.35 (4H, m), 7.48 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.6 Hz), 10.00-10.20 (1 H, m).

Example 22
Synthesis of 1- [5- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) pentyl] -3,4-dihydro-1H-quinolin-2-one hydrochloride as in Example 1 1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl from 1- (5-chloropentyl) -3,4-dihydro-1H-quinolin-2-one ) Pentyl] -3,4-dihydro-1H-quinolin-2-one was synthesized into an ethanol solution, and then a 1N hydrochloric acid ethanol solution was added. 5- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) pentyl] -3,4-dihydro-1H-quinolin-2-one hydrochloride was obtained.
Melting point: 242.0-244.0 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.30-1.45 (2H, m), 1.50-1.65 (2H, m), 1.70-1.85 (2H, m), 2.53 (2H, t, J = 8) .2 Hz), 2.85 (2H, t, J = 8.0 Hz), 3.10-3.30 (6H, m), 3.50-3.60 (4H, m), 3.91 (2H , T, J = 7.3 Hz), 6.94-7.03 (2H, m), 7.13-7.34 (4H, m), 7.47 (1H, d, J = 5.6 Hz) 7.69 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.5 Hz), 10.30-10.50 (1H, m).

Example 23
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -3,4-dihydro-2H-isoquinolin-1-one hydrochloride as in Example 1 By 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) from 2- (4-chlorobutyl) -3,4-dihydro-2H-isoquinolin-1-one Butyl] -3,4-dihydro-2H-isoquinolin-1-one was synthesized into an ethanol solution, and then a 1N hydrochloric acid ethanol solution was added. Crystallized white powder of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -3,4-dihydro-2H-isoquinolin-1-one hydrochloride Got.
Melting point 257.5-265.5 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.6-1.9 (4H, m), 2.98-3.60 (16H, m), 6.98 (1H, d, J = 7.7 Hz), 7.30-7.38 (3H M), 7.46-7.51 (2H, m), 7.71 (1H, d, J = 8.2 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.89. (1H, d, J = 7.7 Hz), 10.10 (1H, brs).

Example 24
Synthesis of 2- [5- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) pentyl] -3,4-dihydro-2H-isoquinolin-1-one By the same method as in Example 1 , 2- (5-chloropentyl) -3,4-dihydro-2H-isoquinolin-1-one.
White powder (ethyl acetate-diisopropyl ether)
Melting point 91.8-93.3 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.32-1.37 (2H, m), 1.56-1.64 (4H, m), 2.38 (2H, t, J = 7.6 Hz), 2.62 (4H, m), 2.92 (2H, t, J = 6.5 Hz), 3.09-3.11 (4H, m), 3.47-3.55 (4H, m), 6.81 (1H, d, J = 7.5 Hz), 7.08-7.11 (2H, m), 7.17-7.35 (4H, m), 7.47 (1 H, d, J = 8.0 Hz), 8.01 (1H, dd, J = 7.5 Hz, 1.4 Hz).

Example 25
Synthesis of 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one By a method similar to that in Example 1. , 6- (3-chloropropoxy) -3,4-dihydro-2H-isoquinolin-1-one.
White powder (ethyl acetate-diethyl ether)
Melting point 203-205 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
2.00-2.10 (2H, m), 2.60-2.70 (2H, m), 2.74 (4H, brs), 2.96 (2H, t, J = 6.5 Hz), 3.20 (4H, brs), 3.50-3.60 (2H, m), 4.11 (2H, t, J = 6.3 Hz), 6.09 (1H, brs), 6.73 ( 1H, s), 6.85-6.95 (2H, m), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 8.6 Hz).

Example 26
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one Example 18 and In a similar manner, methyl iodide is obtained from 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one. And synthesized.
White powder (ethyl acetate-diethyl ether)
Melting point 110-113 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
2.05 (2H, t, J = 6.9 Hz), 2.65 (2H, t, J = 7.3 Hz), 2.74 (4H, brs), 2.97 (2H, t, J = 6) .7 Hz), 3.14 (3 H, s), 3.21 (4 H, brs), 3.54 (2 H, t, J = 6.7 Hz), 4.11 (2 H, t, J = 6.4 Hz) ), 6.68 (1H, s), 6.86 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.91 (1H, d, J = 7.7 Hz), 7.25-7 .30 (1H, m), 7.40 (1H, d, J = 5.5 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 7. 9 Hz), 8.03 (1H, d, J = 8.6 Hz).

Example 27
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-3,4-dihydro-2H-isoquinolin-1-one Example 18 and In a similar manner, ethyl iodide is obtained from 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one. And synthesized.
White powder (ethyl acetate-diethyl ether)
Melting point 128-131 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.21 (3H, t, J = 7.2 Hz), 2.05 (2H, t, J = 6.9 Hz), 2.65 (2H, t, J = 7.3 Hz), 2.74 (4H , Brs), 2.96 (2H, t, J = 6.6 Hz), 3.21 (4H, brs), 3.54 (2H, t, J = 6.7 Hz), 3.62 (2H, q , J = 7.2 Hz), 4.11 (2H, t, J = 6.3 Hz), 6.68 (1H, d, J = 1.7 Hz), 6.86 (1H, dd, J = 2. 3 Hz, 8.2 Hz), 6.91 (1 H, d, J = 7.7 Hz), 7.25-7.30 (1 H, m), 7.40 (1 H, d, J = 5.5 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 7.8 Hz), 8.03 (1H, d, J = 8.6 Hz).

Example 28
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one By a method similar to that of Example 1. , 7- (3-chloropropoxy) -3,4-dihydro-2H-isoquinolin-1-one.
White powder (ethyl acetate-diethyl ether)
Melting point 176-179 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
2.00-2.10 (2H, m), 2.64 (2H, t, J = 7.3 Hz), 2.73 (4H, brs), 2.94 (2H, t, J = 6.6 Hz) ), 3.20 (4H, brs), 3.50-3.60 (2H, m), 4.12 (2H, t, J = 6.3 Hz), 5.92 (1H, brs), 6. 90 (1H, d, J = 7.7 Hz), 7.03 (1H, dd, J = 2.8 Hz, 8.3 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.25 −7.30 (1H, m), 7.39 (1H, d, J = 5.5 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.62 (1H, d, J = 2.7 Hz).

Example 29
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one Example 18 and In the same manner, methyl iodide was obtained from 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one. And synthesized.
White powder (ethanol)
Melting point 115-117 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.10 (2H, m), 2.64 (2H, t, J = 7.3 Hz), 2.70-2.80 (4H, m), 2.94 (2H, t, J = 6.7 Hz), 3.10-3.25 (4H, m), 3.16 (3H, s), 2.54 (2H, t, J = 6.7 Hz), 4.11 (2H, t) , J = 6.5 Hz), 6.90 (1H, d, J = 7.0 Hz), 6.98 (1H, dd, J = 2.7 Hz, 8.3 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.28 (1 H, dd, J = 7.9 Hz, 7.9 Hz), 7.35-7.45 (2 H, m), 7.55 (1 H, d, J = 8) .1 Hz), 7.63 (1H, d, J = 2.6 Hz).

Example 30
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one hydrochloride After [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one was made into an ethanol solution, A 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give white powder 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) Propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one hydrochloride was obtained.
Melting point 229-233 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.20-2.30 (2H, m), 2.89 (2H, t, J = 6.7 Hz), 3.01 (3H, s), 3.21 (2H, t, J = 6.9 Hz) ), 3.30-3.60 (8H, m), 3.60-3.70 (2H, m), 4.11 (2H, t, J = 6.0 Hz), 6.97 (1H, d) , J = 7.7 Hz), 7.06 (1H, dd, J = 2.8 Hz, 8.3 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.31 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.41 (1H, d, J = 2.7 Hz), 7.49 (1H, d, J = 5.5 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.5 Hz), 10.70 (1H, brs).

Example 31
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-3,4-dihydro-2H-isoquinolin-1-one dihydrochloride From 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one in the same manner as in Example 18 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-3,4-dihydro-2H-isoquinolin-1-one using ethyl iodide After synthesizing and making a methanol solution, a 0.5N hydrochloric acid methanol solution was added, and the precipitated crystals were collected by filtration and recrystallized from a methanol-ethyl acetate mixed solvent to give 7- [3- (4- Benzo [b] thio Fen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-3,4-dihydro-2H-isoquinolin-1-one dihydrochloride was obtained.
Melting point 210-213 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.09 (3H, t, J = 7.1 Hz), 2.20-2.30 (2H, m), 2.87 (2H, t, J = 6.5 Hz), 3.20-3.70 (14H, m), 4.11 (2H, t, J = 5.9 Hz), 6.96 (1H, d, J = 7.7 Hz), 7.00-7.10 (1H, m), 7 .22 (1H, d, J = 8.3 Hz), 7.25-7.35 (1H, m), 7.41 (1H, d, J = 2.7 Hz), 7.48 (1H, d, J = 5.5 Hz), 7.69 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 5.5 Hz), 11.08 (1H, brs).

Example 32
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one hydrochloride In the same manner as in Example 1, from 7- (4-chlorobutoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one to 7- [4- (4-benzo [b] thiophene-4 -Yl-piperazin-1-yl) butoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one was synthesized into a methanol solution, followed by addition of a 0.5N hydrochloric acid methanol solution to precipitate. The crystals are filtered and recrystallized from a methanol-ethyl acetate mixed solvent to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -2 as a white powder. -Methyl-3,4 -Dihydro-2H-isoquinolin-1-one hydrochloride was obtained.
Melting point 213-218 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.70-2.00 (4H, m), 2.88 (2H, t, J = 6.6 Hz), 3.01 (3H, s), 3.10-3.70 (12H, m), 4.03 (2H, t, J = 5.8 Hz), 6.95 (1H, d, J = 7.5 Hz), 7.04 (1H, dd, J = 2.8 Hz, 8.5 Hz), 7 .20 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.39 (1H, d, J = 2.7 Hz), 7. 48 (1H, d, J = 5.7 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.71 (1H, brs) ).

Example 33
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-2H-isoquinolin-1-one hydrochloride as in Example 1 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl from 7- (4-chlorobutoxy) -3,4-dihydro-2H-isoquinolin-1-one ) Butoxy] -3,4-dihydro-2H-isoquinolin-1-one to make an ethyl acetate solution, 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate. To obtain 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-2H-isoquinolin-1-one hydrochloride as a white powder It was.
Melting point 223.8-226.8 ° C.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.81-1.93 (4H, m), 2.83 (2H, t, J = 6.5 Hz), 3.16-3.32 (8H, m), 3.43-3.64 (4H M), 4.06 (2H, t, J = 5.9 Hz), 6.97 (1H, d, J = 7.6 Hz), 7.07 (1H, dd, J = 8.3 Hz, 2.). 7 Hz), 7.24 (1 H, d, J = 7.7 Hz), 7.32 (1 H, dd, J = 7.9 Hz, 7.9 Hz), 7.39 (1 H, d, J = 2.7 Hz) ), 7.50 (1H, d, J = 5.6 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.95 (1H, s), 10.62 (1H, s).

Example 34
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2H-isoquinolin-1-one In the same manner as in Example 1, 2- (4- (Chlorobutyl) -2H-isoquinolin-1-one.
Light brown powder (ethyl acetate-diisopropyl ether)
Melting point 141.1-142.7 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.62 (2H, m), 1.87 (2H, m), 2.50 (2H, t, J = 7.4 Hz), 2.66-2.71 (4H, m), 3.16- 3.19 (4H, m), 4.06 (2H, t, J = 7.2 Hz), 6.50 (1H, d, J = 7.3 Hz), 6.89 (1H, d, J = 7) .7 Hz), 7.08 (1 H, d, J = 7.3 Hz), 7.24-7.65 (7 H, m), 8.44 (1 H, d, J = 7.9 Hz).

Example 35
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one According to a method similar to that in Example 1, 7- (3- (Chloropropoxy) -2H-isoquinolin-1-one.
White powder (ethyl acetate)
Melting point 220.1-222.5 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.99 (2H, quint, J = 6.6 Hz), 2.57 (2H, t, J = 7.0 Hz), 2.66 (4H, brs), 3.09 (4H, brs), 4. 16 (2H, t, J = 6.3 Hz), 6.52 (1H, d, J = 7.1 Hz), 6.90 (1H, d, J = 7.4 Hz), 7.04 (1H, dd) , J = 6.9 Hz, 6.9 Hz), 7.26 (1H, d, J = 7.9 Hz), 7.33 (1H, dd, J = 8.8 Hz, 2.8 Hz), 7.41 ( 1H, d, J = 5.5 Hz), 7.59-7.63 (3H, m), 7.69 (1H, d, J = 5.5 Hz), 11.21 (1H, d, J = 4) .9 Hz).

Example 36
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one hydrochloride The same method as in Example 18 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one using methyl iodide to produce 7- [3- (4 -Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one was synthesized into an ethyl acetate solution, and then added with a 1N hydrochloric acid ethanol solution to precipitate. The crystals are filtered and recrystallized from ethyl acetate to give 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H as a white powder. -Isoquino Phosphorus-1-one hydrochloride was obtained.
Melting point 227.6-230.2 ° C.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.31 (2H, quint, J = 7.0 Hz), 3.20-3.40 (6H, m), 3.52 (3H, s), 3.54-3.70 (4H, m), 4.23 (2H, t, J = 5.8 Hz), 6.60 (1H, d, J = 7.3 Hz), 6.99 (1H, d, J = 7.7 Hz), 7.30-7 .38 (3H, m), 7.51 (1H, d, J = 5.6 Hz), 7.63-7.73 (3H, m), 7.78 (1H, d, J = 5.5 Hz) , 10.88 (1H, s).

Example 37
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-2H-isoquinolin-1-one hydrochloride The same method as in Example 1 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy]-from 7- (3-chloropropoxy) -2-ethyl-2H-isoquinolin-1-one 2-Ethyl-2H-isoquinolin-1-one was synthesized to make an ethyl acetate solution, and then a 1N hydrochloric acid ethanol solution was added. -[3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-ethyl-2H-isoquinolin-1-one hydrochloride was obtained.
Melting point 229.9-231.2 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.25 (3H, t, J = 7.1 Hz), 2.29 (2H, brs), 3.14-3.49 (6H, m), 3.56-3.72 (4H, m), 4.00 (2H, q, J = 7.2 Hz), 4.23 (2H, t, J = 5.9 Hz), 6.62 (1H, d, J = 7.3 Hz), 6.99 (1H , D, J = 7.6 Hz), 7.27-7.39 (3H, m), 7.51 (1H, d, J = 5.6 Hz), 7.62-7.73 (3H, m) 7.78 (1H, d, J = 5.5 Hz), 10.38 (1H, s).

Example 38
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7-methoxy-2H-isoquinolin-1-one hydrochloride The same method as in Example 1 To 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7 from 2- (4-chlorobutyl) -7-methoxy-2H-isoquinolin-1-one -Methoxy-2H-isoquinolin-1-one was synthesized into an ethyl acetate solution, 1N hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate. [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7-methoxy-2H-isoquinolin-1-one hydrochloride was obtained.
Melting point 243.5-245.6 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.78 (4H, brs), 3.10-3.28 (6H, m), 3.56 (4H, t, J = 9.6 Hz), 3.87 (3H, s), 4.04 ( 2H, t, J = 5.3 Hz), 6.64 (1H, d, J = 7.3 Hz), 6.96 (1H, d, J = 7.6 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.34 (1H, dd, J = 8.6 Hz, 2.9 Hz), 7.41 (1H, d, J = 7.3 Hz), 7.49 (1H, d, J = 5.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.69 (1H, dd, J = 8.0 Hz, 8.0 Hz), 7.77 (1H, d, J = 5) .5 Hz), 10.60 (1 H, s).

Example 39
Synthesis of 2- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7-hydroxy-2H-isoquinolin-1-one hydrobromide 2- [4 -(4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7-methoxy-2H-isoquinolin-1-one (0.16 g) in dichloromethane (50 ml) was stirred with ice cooling. Then, boron tribromide (2M dichloromethane solution, 1.0 ml) was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction solution and stirred at room temperature for 0.5 hour. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -7-hydroxy-2H as a white powder. -Isoquinolin-1-one hydrobromide (0.13 g) was obtained.
Melting point 273.6-275.7 ° C.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.75 (4H, brs), 3.08 (2H, t, J = 11.1 Hz), 3.16-3.28 (4H, m), 3.59 (2H, t, J = 10.5 Hz) ), 4.01 (2H, brs), 6.58 (1H, d, J = 7.3 Hz), 6.97 (1H, d, J = 7.5 Hz), 7.19 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7.29-7.36 (2 H, m), 7.49-7.65 (3 H, m), 7.71 (1 H, d, J = 8.0 Hz) 7.78 (1H, d, J = 5.5 Hz), 9.50 (1H, brs), 9.95 (1H, s).

Example 40
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one In the same manner as in Example 1, 6-chloropropoxy- Synthesized from 2H-isoquinolin-1-one.
White powder (ethyl acetate)
Melting point 228.8-230.7 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.98 (2H, quint, J = 6.7 Hz), 2.56 (2H, t, J = 7.0 Hz), 2.65 (4H, brs), 3.09 (4H, brs), 4. 17 (2H, t, J = 6.3 Hz), 6.47 (1H, d, J = 7.1 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.05 (1H, dd) , J = 8.8 Hz, 2.4 Hz), 7.10-7.15 (2H, m), 7.28 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 5.5 Hz), 7.62 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J = 5.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 11.03 (1H, s).

Example 41
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one hydrochloride The same method as in Example 18 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one with methyl iodide using 6- [3- (4 -Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one was made into an ethyl acetate solution, and then a 1N hydrochloric acid ethanol solution was added. The precipitated crystals were collected by filtration, recrystallized from ethyl acetate, and white powder of 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl- 2H-Isochi Norin-1-one hydrochloride was obtained. Melting point 241.4-244.8 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.31 (2H, t, J = 7.6 Hz), 3.46 (3H, s), 3.19-3.70 (10H, m), 4.24 (2H, t, J = 5.9 Hz) ), 6.54 (1H, d, J = 7.4 Hz), 6.99 (1H, d, J = 7.6 Hz), 7.10 (1H, dd, J = 8.8 Hz, 2.4 Hz) 7.15 (1H, d, J = 2.3 Hz), 7.33 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.45 (1H, d, J = 7.1 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 5.5 Hz), 8.14 (1H , D, J = 8.8 Hz), 10.86 (1H, s).

Example 42
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one hydrochloride 7- [4- (4-Benzo [b 1N aqueous hydrochloric acid was added to a methanol and dichloromethane solution of thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one, and the solvent was distilled off under reduced pressure. The residue was recrystallized from 70% ethanol to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one hydrochloride as a white powder Salt was obtained.
238-241 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.80-2.00 (4H, m), 3.20-3.45 (6H, m), 3.50-3.60 (4H, m), 4.06 (2H, t, J = 5 .6 Hz), 6.28 (1 H, d, J = 9.5 Hz), 6.75-6.85 (2 H, m), 6.95 (1 H, d, J = 7.5 Hz), 7.30. (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.47 (1H, d, J = 5.7 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.68 ( 1H, d, J = 8.1 Hz), 7.70-7.85 (2H, m), 10.92 (1H, brs), 11.61 (1H, brs).

Example 43
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one sulfate 7- [4- (4-Benzo [b Diluted sulfuric acid was added to a methanol and dichloromethane solution of thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one, and the solvent was distilled off under reduced pressure. The residue was recrystallized from 60% ethanol to give white powder 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one sulfuric acid Salt was obtained.
Melting point: 248-251 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.80-1.95 (4H, m), 2.50-4.00 (10H, m), 4.00-4.10 (2H, m), 6.30 (1H, d, J = 8 .2 Hz), 6.75-6.85 (2 H, m), 6.97 (1 H, d, J = 7.6 Hz), 7.31 (1 H, dd, J = 7.8 Hz, 7.8 Hz) , 7.49 (1H, d, J = 5.6 Hz), 7.55-7.60 (1H, m), 7.70 (1H, d, J = 8.0 Hz), 7.75-7. 85 (2H, m), 9.25-9.75 (1H, br), 11.62 (1H, brs).

Example 44
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one maleate 7- [4- (4-Benzo [ b] Thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one in methanol and dichloromethane solution was added maleic acid methanol solution, and the solvent was distilled off under reduced pressure. The residue was recrystallized from 80% ethanol to give white powder 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one malein The acid salt was obtained.
Melting point 181.6-182.8 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.87 (2H, brs), 3.26-3.47 (10H, m), 4.10 (2H, s), 6.07 (2H, s), 6.33 (1H, d, J = 9.5 Hz), 6.82-6.84 (2 H, m), 6.99 (1 H, d, J = 7.6 Hz), 7.33 (1 H, d, J = 7.8 Hz), 7. 51 (1H, d, J = 5.5 Hz), 7.59 (1H, d, J = 9.3 Hz), 7.70-7.85 (3H, m), 11.65 (1H, s).

Example 45
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one fumarate 7- [4- (4-Benzo [ b] Thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one was added to a methanol and dichloromethane solution, fumaric acid was added, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one fumarate as a white powder. Got.
Melting point 209-211 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.60-1.90 (4H, m), 2.47-2.50 (2H, m), 2.60-2.75 (4H, m), 3.00-3.15 (4H, m ), 4.05 (2H, t, J = 6.3 Hz), 6.28 (1H, d, J = 9.4 Hz), 6.60 (2H, s), 6.76-6.82 (2H) M), 6.88 (1H, d, J = 7.4 Hz), 7.26 (1H, dd, J = 7.9 Hz, 7.8 Hz), 7.39 (1H, d, J = 5. 9 Hz), 7.54 (1 H, d, J = 9.4 Hz), 7.61 (1 H, d, J = 8.0 Hz), 7.69 (1 H, d, J = 5.5 Hz), 7. 79 (1H, d, J = 9.5 Hz), 11.58 (1H, brs).

Example 46
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one citrate 7- [4- (4-Benzo [4- b] Thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one in methanol and dichloromethane was added citric acid, and the solvent was distilled off under reduced pressure. The residue was recrystallized from 50% ethanol to give 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one citrate as a white powder. The acid salt was obtained.
Melting point 183-185 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.50-2.00 (4H, m), 2.58 (2H, s), 2.62 (2H, s), 2.75-2.85 (2H, m), 2.95-3. 05 (4H, m), 3.10-3.20 (4H, m), 4.05 (2H, t, J = 5.3 Hz), 6.28 (1H, d, J = 9.4 Hz), 6.75-6.85 (2H, m), 6.90 (1H, d, J = 7.6 Hz), 7.27 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 9.3 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 5.5 Hz), 7.79 (1H, d, J = 9.5 Hz), 11.59 (1H, brs).

Example 47
Synthesis of 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one p-toluenesulfonate 7- [4- (4 P-Toluenesulfonic acid monohydrate was added to a solution of benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one in methanol and dichloromethane, and the solvent was removed under reduced pressure. Was distilled off. The residue was recrystallized from methanol to give white powder 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one p-toluene The sulfonate was obtained.
Melting point: 121.0-125.0 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.73-2.00 (4H, m), 2.28 (3H, s), 3.07 (2H, J = 11.0 Hz), 3.23-3.43 (4H, m), 3. 62 (4H, t, J = 15.0 Hz), 4.09 (2H, t, J = 7.1 Hz), 6.31 (1H, dd, J = 9.5 Hz, 2.3 Hz), 6.80 (1H, s), 6.84 (1H, d, J = 2.3 Hz), 6.98 (1H, d, J = 7.5 Hz), 7.11 (2H, d, J = 8.0 Hz) 7.33 (1H, dd, J = 7.5 Hz, 7.5 Hz), 7.46-7.52 (3H, m), 7.58 (1H, d, J = 9.5 Hz), 7. 72 (1H, d, J = 7.5 Hz), 7.78 (1H, d, J = 11.3 Hz), 7.81 (1H, d, J = 9.5 Hz), 9.31-9.49 (1H, m), 11.5 -11.63 (1H, m).

Example 48
Synthesis of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one sulfate -[3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one in ethanol and dichloromethane solution; Dilute sulfuric acid was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from 85% ethanol to give 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro in the form of a white powder. -2H-isoquinolin-1-one sulfate was obtained.
Melting point 222-224 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.10-2.30 (2H, m), 2.91 (2H, t, J = 6.6 Hz), 3.03 (3H, s), 3.05 to 4.00 (12H, m), 4.13 (2H, t, J = 5.9 Hz), 6.99 (1H, d, J = 7.5 Hz), 7.09 (1H, dd, J = 2.7 Hz, 8.3 Hz), 7 .24 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.44 (1H, d, J = 2.7 Hz), 7. 51 (1H, d, J = 5.5 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.78 (1H, d, J = 5.5 Hz), 9.00-10.05 (1H, br).

Example 49
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one fumarate 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one in ethanol solution Acid was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from 70% ethanol to give 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4- as a pale yellow powder. Dihydro-2H-isoquinolin-1-one fumarate was obtained.
Melting point 149-151 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.85 to 2.00 (2H, m), 2.58 (2H, t, J = 7.2 Hz), 2.65-2.75 (4H, m), 2.88 (2H, t, J = 6.7 Hz), 3.01 (3H, s), 3.05 to 3.15 (4 H, m), 3.50 (2 H, t, J = 6.7 Hz), 4.05 (2 H, t) , J = 6.3 Hz), 6.60 (2H, s), 6.89 (1H, d, J = 7.6 Hz), 7.03 (1H, dd, J = 8.3 Hz, 2.7 Hz) , 7.19 (1H, d, J = 8.3 Hz), 7.27 (1H, dd, J = 7.9 Hz, 7.8 Hz), 7.38 (1H, d, J = 3.0 Hz), 7.40 (1H, d, J = 5.9 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 5.5 Hz).

Example 50
Of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one difumarate Synthesis 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one in ethanol solution Fumaric acid was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from 90% ethanol to give white prism crystals 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4- Dihydro-2H-isoquinolin-1-one difumarate was obtained.
Melting point 188-189 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.85-2.00 (2H, m), 2.60 (2H, t, J = 7.0 Hz), 2.65-2.75 (4H, m), 2.88 (2H, t, J = 6.6 Hz), 3.01 (3H, s), 3.00-3.10 (4H, m), 3.50 (2H, t, J = 6.7 Hz), 4.05 (2H, t) , J = 6.4 Hz), 6.61 (4H, s), 6.90 (1H, d, J = 7.5 Hz), 7.04 (1H, dd, J = 8.2 Hz, 2.8 Hz) 7.19 (1H, d, J = 8.4 Hz), 7.27 (1 H, dd, J = 7.9 Hz, 7.8 Hz), 7.38 (1H, d, J = 3.0 Hz), 7.40 (1H, d, J = 6.2 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 5.5 Hz).

Example 51
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one maleate 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one in methanol and dichloromethane solution Then, a maleic acid methanol solution was added, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and ethyl acetate to give 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4- as white powder. Dihydro-2H-isoquinolin-1-one maleate was obtained.
Melting point 134.6-135.5 ° C.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.17 (2H, brs), 2.91 (2H, t, J = 6.7 Hz), 3.03 (3H, s), 3.33 (10H, brs), 3.52 (2H, t, J = 6.7 Hz), 4.12 (2H, t, J = 5.9 Hz), 6.04 (2H, s), 6.99 (1H, d, J = 7.6 Hz), 7.07 ( 1H, dd, J = 8.3 Hz, 2.6 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7 .43 (1H, d, J = 2.6 Hz), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 7.9 Hz), 7.77 (1H, d, J = 5.5 Hz).

Example 52
7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one p-toluenesulfonic acid Synthesis of salt 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one with methanol P-Toluenesulfonic acid monohydrate was added to the dichloromethane solution, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol and ethyl acetate to give 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4- as white powder. Dihydro-2H-isoquinolin-1-one p-toluenesulfonate was obtained.
Melting point 173.0-175.5 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.00-2.33 (2H, m), 2.28 (3H, s), 2.91 (2H, t, J = 6.6 Hz), 3.02 (3H, s), 3.00- 3.16 (2H, m), 3.29-3.80 (10H, m), 4.12 (2H, t, J = 5.5 Hz), 6.99 (1H, d, J = 7.9 Hz) ), 7.06 (1H, d, J = 2.5 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.33 (1H, dd, J = 8.0 Hz, 8.0 Hz), 7.44 (1H, d, J = 2.5 Hz), 7.48 (1H, d, J = 7.9 Hz), 7.51 ( 1H, d, J = 5.5 Hz), 7.72 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 5.5 Hz), 9.39-9.58 (1H , M)
Example 53
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one Example 1 It was synthesized from 7- (3-chloropropoxy) -2-methyl-3,4-dihydro-2H-isoquinolin-1-one by the same method.
White powder (ethanol)
Melting point 115-117 ° C
¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.10 (2H, m), 2.64 (2H, t, J = 7.3 Hz), 2.70-2.80 (4H, m), 2.94 (2H, t, J = 6.7 Hz), 3.10-3.25 (4H, m), 3.16 (3H, s), 2.54 (2H, t, J = 6.7 Hz), 4.11 (2H, t) , J = 6.5 Hz), 6.90 (1H, d, J = 7.0 Hz), 6.98 (1H, dd, J = 2.7 Hz, 8.3 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.28 (1 H, dd, J = 7.9 Hz, 7.9 Hz), 7.35-7.45 (2 H, m), 7.55 (1 H, d, J = 8) .1 Hz), 7.63 (1H, d, J = 2.6 Hz).

Example 54
Of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one methanesulfonate Synthesis 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one was added to an ethanol solution of methanesulfonic acid, and the solvent was removed under reduced pressure. Was distilled off. The residue was recrystallized from 80% ethanol to give pale yellow prisms of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4 -Dihydro-2H-isoquinolin-1-one methanesulfonate was obtained.
Melting point 147-149 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.10-2.25 (2H, m), 2.29 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.02 (3H, s), 3.05- 3.15 (2H, m), 3.40-3.50 (4H, m), 3.51 (2H, t, J = 6.7 Hz), 3.55-3.70 (4H, m), 4.12 (2H, t, J = 6.0 Hz), 6.98 (1H, d, J = 7.6 Hz), 7.06 (1H, dd, J = 8.3 Hz, 2.7 Hz), 7 .23 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 7.9 Hz, 7.8 Hz), 7.43 (1H, d, J = 2.7 Hz), 7. 50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 9.40-9.60 (1H, m).

Reference Example 31
Synthesis of 4-benzo [b] thiophen-4-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester In the same manner as in Reference Example 30, 3-methylpiperazine-1-carboxylic acid tert-butyl ester and Synthesized from 4-bromobenzo [b] thiophene.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.85-1.95 (3H, m), 1.50 (9H, s), 2.8-2.9 (1H, m), 3.15-3 .35 (2H, m), 3.4-3.5 (1H, m), 3.5-3.65 (1H, m), 3.65-3.7 (1H, m), 3.7 -3.9 (1H, m), 6.98 (1H, d, J = 7.5 Hz), 7.29 (1H, dd, J = 8 Hz, 8 Hz), 7.38 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 8 Hz).

Reference Example 32
Synthesis of 1-benzo [b] thiophen-4-yl-2-methylpiperazine dihydrochloride 4-benzo [b] thiophen-4-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester 1.22 g ( 3.7 mmol) in dichloromethane (12 ml) was added 6 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 5% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure. Concentrated hydrochloric acid (0.6 ml) and methanol (10 ml) were added to the residue, and the mixture was concentrated under reduced pressure. The residue was crystallized from acetonitrile to obtain 0.98 g of 1-benzo [b] thiophen-4-yl-2-methylpiperazine dihydrochloride as a fine brown powder.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.92 (3H, d, J = 6.5 Hz), 2.8-3.6 (6H, m), 3.6-4.0 (1H, m), 5.3-6.8 (1H, m), 7.20 (1H, br), 7.38 (1H, dd, J = 8 Hz, 8 Hz), 7.5-8.0 (3H, m), 9.4-10. 1 (2H, m).

Reference Example 33
Synthesis of 1-benzo [b] thiophen-4-yl-3-methylpiperazine dihydrochloride Synthesis was performed from 2-methylpiperazine and 4-bromobenzo [b] thiophene in the same manner as in Reference Example 30.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, d, J = 6.5 Hz), 2.85-2.95 (1H, m), 3.05-3.15 (1H, m), 3.2-3.6 (6H, m), 6.97 (1H, d, J = 7.5 Hz), 7.31 (1H, dd, J = 8 Hz, 8 Hz), 7.54 ( 1H, d, J = 5.5 Hz), 7.69 (1H, d, J = 8 Hz), 7.75 (1H, d, J = 5.5 Hz), 9.2-9.3 (1H, m ), 9.64 (1H, br).

Reference Example 34
Synthesis of ethyl 3- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) propionate 5.05 g (19.8 mmol) of 1-benzo [b] thiophen-4-ylpiperazine hydrochloride was added to water. Extracted with dichloromethane in addition to aqueous sodium oxide. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol, 2.44 ml (21.8 mmol) of ethyl acrylate was added, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, isopropyl ether was added to the residue, the precipitated insoluble matter was collected by filtration, washed with isopropyl ether and dried to give white powder of 3- (4-benzo [b] thiophene-4. -Ylpiperazin-1-yl) ethyl propionate (5.26 g) was obtained.

Reference Example 35
Synthesis of 3- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) propan-1-ol ethyl 3- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) propionate To a solution (55 ml) of 5.26 g (16.5 mmol) in tetrahydrofuran (THF) was added 1.18 g (24.8 mmol) of lithium aluminum hydride under ice cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction solution, 1.2 ml of water, 1.2 ml of 15% aqueous sodium hydroxide solution and 3.6 ml of water were added in this order, and the mixture was stirred at room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2 → ethyl acetate). Concentration to dryness under reduced pressure gave 0.23 g of 3- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) propan-1-ol as a white powder.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.75-1.85 (2H, m), 2.74 (2H, t, J = 5.8 Hz), 2.75-2.85 (4H, m) 3.15-3.25 (4H, m), 3.85 (2H, t, J = 5.3 Hz), 5.19 (1H, brs), 6.88 (1H, d, J = 7. 6 Hz), 7.27 (1 H, dd, J = 7.9 Hz, 7.8 Hz), 7.39 (2 H, s), 7.56 (1 H, d, J = 8.0 Hz).

Reference Example 36
Synthesis of 4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl acetate 1.0 g (3.9 mmol) of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride Suspended in 20 ml of formamide (DMF), 1.3 g (9.4 mmol) of potassium carbonate and 0.7 ml (4.8 mmol) of 4-bromobutyl acetate were added and stirred at 80 ° C. for 6 hours. The mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1). Concentration under reduced pressure gave 0.72 g of 4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl acetate as a pale yellow oil.

Reference Example 37
Synthesis of 4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butan-1-ol Acetic acid 4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl ester To 7.76 g (23.3 mmol) of a 90% methanol solution (150 ml), 3.87 g (28 mmol) of potassium carbonate was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 → 1: 1). Concentration under reduced pressure afforded 6.65 g of colorless oil 4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butan-1-ol.

Reference Example 38
Synthesis of 1-benzo [b] thiophen-4-yl-4- (3-chloropropyl) piperazine 3- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) propan-1-ol 56 g (12.9 mmol) was suspended in 30 ml of dichloromethane, 30 ml of carbon tetrachloride and 4.06 g (15.5 mmol) of triphenylphosphine were added, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, methanol and dichloromethane were added to the reaction solution to make a homogeneous solution. 30 g of silica gel was added and the solvent was distilled off under reduced pressure. The residue was loaded on a silica gel column (300 g) and eluted with a mixed solvent of n-hexane and ethyl acetate (2: 1). Concentration under reduced pressure yielded 2.36 g of 1-benzo [b] thiophen-4-yl-4- (3-chloropropyl) piperazine as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.95-2.10 (2H, m), 2.60 (2H, t, J = 7.2 Hz), 2.65-2.75 (4H, m) 3.15-3.25 (4H, m), 3.65 (2H, t, J = 6.6 Hz), 6.89 (1H, dd, J = 7.6 Hz, 0.7 Hz), 7. 27 (1H, dd, J = 7.9 Hz, 7.8 Hz), 7.38 (1H, d, J = 5.6 Hz), 7.41 (1H, d, J = 5.7 Hz), 7.55 (1H, d, J = 8.0 Hz).

Example 55
Synthesis of 4- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] quinoline hydrochloride 4-Chloroquinoline 230 mg (1.58 mmol), 3- (4-Benzo [ b] 310 mg (1.05 mmol) of thiophen-4-ylpiperazin-1-yl) propan-1-ol and 220 mg (1.6 mmol) of potassium carbonate were added to 10 ml of DMF and stirred at 80 ° C. for 5 hours. The mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated under reduced pressure, and the residue was dissolved in 3 ml of ethanol. The insoluble matter produced by adding 1 ml of 1N-hydrochloric ethanol solution was collected by filtration and dried to give 4- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy as a pale yellow powder. ] 360 mg (yield 78%) of quinoline hydrochloride was obtained.
Melting point: 240-242 ° C.

Example 56
Synthesis of 3- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] isoquinoline hydrochloride 3-hydroxyisoquinoline 170 mg (1.17 mmol), 1-benzo [b] thiophene 290 mg (1.0 mmol) of -4-yl-4- (3-chloropropyl) piperazine and 200 mg (1.45 mmol) of potassium carbonate were added to 8 ml of DMF and stirred at 80 ° C. for 7 hours. The mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 9: 1). The purified product was concentrated under reduced pressure, and the residue was dissolved in 2 ml of ethanol. Insoluble matter formed by adding 0.5 ml of 1N-hydrochloric ethanol solution was collected by filtration and dried to give 3- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) as a white powder. Propoxy] isoquinoline hydrochloride 160 mg (yield 37%) was obtained.
Melting point: 227-229 ° C.

Example 57
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -6-methoxy-3,4-dihydroisoquinoline dihydrochloride 7-Hydroxy-6-methoxy- A THF solution of 80 mg (0.45 mmol) of 3,4-dihydroisoquinoline and 83 mg (0.3 mmol) of 3- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) propan-1-ol ( 1 ml) was added PS-triphenylphosphine (3 mmol / g) 110 mg and azodicarboxylate dibenzyl 70 mg (0.3 mmol) and stirred at 50 ° C. for 3 hours. The mixture was cooled to room temperature and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure, and the residue was dissolved in 2-propanol. 1N-hydrochloric acid ethanol solution was added, isopropyl ether was added, and the resulting crystals were collected by filtration, dried, and dried as a pale yellow powder of 7- [3- (4-benzo [b] thiophen-4-yl-piperazine-1- Yl) propoxy] -6-methoxy-3,4-dihydroisoquinoline dihydrochloride (26 mg, 17% yield).
Melting point: 211.0-213.0 ° C.

Example 58
Synthesis of 1-acetyl-7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1,2,3,4-tetrahydroquinoline hydrochloride 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1,2,3,4-tetrahydroquinoline 0.49 g (1.2 mmol) in dichloromethane (10 ml) was cooled with ice. Then, 0.34 ml (3.6 mmol) of acetic anhydride and 0.34 ml (4.3 mmol) of pyridine were added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue for liquid separation. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. 0.63 ml of 1N-hydrochloric acid ethanol solution was added, and the resulting crystals were collected by filtration, dried and dried as a white powder of 1-acetyl-7- [3- (4-benzo [b] thiophen-4-yl-piperazine-1 -Il) propoxy] -1,2,3,4-tetrahydroquinoline hydrochloride 0.27 g (yield 52%) was obtained.
Melting point: 123.2-124.3 ° C.

Example 59
Synthesis of 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1,2,3,4-tetrahydroquinoline hydrochloride 6- [3- (4-Benzo [B] Thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one in a THF solution (40 ml) of lithium hydride (1.6 ml, 3.8 mmol) 160 mg (4.2 mmol) of aluminum was added and heated to reflux for 1 hour. The reaction mixture was ice-cooled, 0.16 ml of water, 0.16 ml of 15% aqueous sodium hydroxide solution and 0.5 ml of water were added in this order, and the mixture was stirred and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure to obtain 1.4 g of an amorphous solid. 0.6 g of the obtained amorphous solid was dissolved in 15 ml of ethyl acetate. 1.45 ml of 1N-hydrochloric ethanol solution was added, and the produced crystals were collected by filtration and dried to give 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy as a white powder. ] -1,2,3,4-tetrahydroquinoline hydrochloride 0.55 g (obtained).
Melting point: 123.2-124.3 ° C.

Example 60
Synthesis of 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1,2,3,4-tetrahydroisoquinoline 0.25 g (0.6 mmol) in methanol solution (20 ml) 37% 0.15 ml (1.8 mmol) of an aqueous formaldehyde solution, 0.76 g (1.8 mmol) of MP-cyanoborohydride (2.41 mmol / g) and a catalytic amount of acetic acid were added and stirred overnight at room temperature. The resin was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane: methanol = 20: 1). The purified product was concentrated under reduced pressure, and the residue (175 mg) was dissolved in 5 ml of ethyl acetate. 0.42 ml of 1N-hydrochloric ethanol solution was added, and the resulting crystals were collected by filtration, dried and dried as white powder of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy. ] 103 mg (yield 37%) of 2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride was obtained.
Melting point: 260.1-262.8 ° C.

Example 61
4- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid methylamide Synthesis of dihydrochloride 4- [3- (4-Benzo [b ] 0.28 g of thiophen-4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid ethyl ester was added to 10 ml of 40% methylamine methanol solution and stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 11: 1). The purified product was concentrated under reduced pressure, and the residue (166 mg) was dissolved in ethyl acetate. 0.7 ml of 1N-hydrochloric ethanol solution was added, and the resulting crystals were collected by filtration and dried to give 4- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy as a white powder. ] 0.17 g (yield 54%) of -quinoline-2-carboxylic acid methylamide dihydrochloride was obtained.
Melting point: 224.0 ° C. (decomposition).

Example 62
Synthesis of 4- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid hydrochloride 4- [3- (4-Benzo [b] thiophene To a methanol solution (7 ml) of 1.5 g of -4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid ethyl ester, 3 ml of 4N-lithium hydroxide aqueous solution was added and stirred overnight at room temperature. 10 ml of water and 3 ml of 4N-lithium hydroxide aqueous solution were added and stirred at 50 ° C. for 11 hours. The reaction mixture was ice-cooled, 6 ml of 6N hydrochloric acid was added and stirred, and the resulting crystals were collected by filtration. After washing with water and drying, 1.43 g of 4- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid hydrochloride as a white powder (98 %).
Melting point: 235.0 ° C.

Example 63
Synthesis of 4- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -quinoline-2-carboxamide 4- [3- (4-Benzo [b] thiophene-4- (Il-piperazin-1-yl) propoxy] -quinoline-2-carboxylic acid 0.53 g (1.2 mmol) in acetonitrile (10 ml) was ice-cooled, triethylamine 0.25 ml (1.8 mmol) and chloroform 0.19 ml (1.4 mmol) of isobutyl acid was added and stirred at 0 ° C. for 3 hours. To this, 0.15 ml of 28% aqueous ammonia solution was added and stirred at room temperature for 5 minutes. Ethyl acetate was added to the reaction solution, washed with water, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 3: 1). The purified product was concentrated under reduced pressure, and the residue (0.2 g) was recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 4- [3- (4-benzo [b] thiophen-4-yl-piperazine as a white powder. -1-yl) propoxy] -quinoline-2-carboxamide 79 mg (yield 16%) was obtained.
Melting point: 153.0-154.5 ° C.

The following compounds can be produced in the same manner as in the above Reference Examples or Examples using appropriate starting materials. In the following table, for example, the crystalline form, m. p. A compound having physical properties such as (melting point), salt, ¹ H-NMR, MS (mass spectrum) was actually produced.

Pharmacological test 1
1) Dopamine D ₂ receptor binding experiment
Kohler et al. (Kohler C, Hall H, Ogren SO and Gawell L. Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem. Pharmacol., 1985; 34: 2251-2259).

Wistar male rats were decapitated, the brain was immediately removed, and the striatum was removed. Homogenize in a 50 mM tris (hydroxymethyl) aminomethane (Tris) -hydrochloric acid buffer solution (pH: 7.4) 50 times the tissue weight using a homogenizer with a high-speed rotating blade, 4 ° C., 48,000 × g. And centrifuged for 10 minutes. The obtained sediment was suspended again in the above buffer of 50 times the tissue weight, incubated at 37 ° C. for 10 minutes, and then centrifuged under the above conditions. The obtained sediment is suspended in 50 mM Tris-HCl buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , pH: 7.4) 25 times the tissue weight, and these are bound as a membrane specimen. The sample was stored frozen at -85 ° C until used in the experiment.

Binding experiments consisted of 40 μl membrane specimen, 20 μl [ ³ H] -Raclopride (final concentration 1-2 nM), 20 μl test drug and 50 mM Tris-HCl buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , pH 7.4) with a total volume of 200 μl (final dimethyl sulfoxide concentration 1%). The reaction was carried out at room temperature for 1 hour, and was terminated by suction filtration through a glass fiber filter plate using a cell harvester. The glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Nonspecific binding was defined as radioactivity in the presence of 10 μM (+)-butaclamol hydrochloride.

IC ₅₀ values were calculated from concentration-dependent reactions using a non-linear analysis program. Ki values were calculated from IC ₅₀ values using the Cheng-Prussoff equation. The results are shown in the following table.

2) Serotonin 5-HT _2A receptor binding experiment
Leysen JE et al. (Leysen JE, Niemegeers CJE, Van Nueten JM, and Laduron PM. [3H] Ketanserin (R 41 468), a selective 3H-ligand for serotonin 2 receptor binding sites. Mol. Pharmacol., 1982; 21 : 301-314).

  Wistar male rats were decapitated, the brain was immediately removed, and the frontal cortex was removed. The tissue was homogenized with a Teflon (registered trademark) glass homogenizer in 0.25 M sucrose of 10 times the tissue weight, and centrifuged at 4 ° C. and 1,000 × g for 10 minutes. The obtained supernatant was transferred to another centrifuge tube, and the sediment was suspended in 0.25M sucrose, which is 5 times the tissue weight, and centrifuged under the above conditions. The obtained supernatant was combined with the previously obtained supernatant and adjusted to a volume 40 times the tissue weight with 50 mM Tris-HCl buffer (pH: 7.4), and 10 minutes at 4 ° C. and 35,000 × g. Centrifuged. The obtained sediment was suspended again in the buffer solution 40 times the tissue weight and centrifuged under the above conditions. The obtained sediment was suspended in the above buffer solution having an amount 20 times the weight of the tissue, and these were frozen and stored at −85 ° C. until used as a membrane specimen for binding experiments.

The binding experiment was performed with a membrane sample of 40 μl, [ ³ H] -ketanserin 20 μl (final concentration 1-3 nM), a test drug 20 μl, and 50 mM Tris-HCl buffer (pH: 7.4) in a total volume of 200 μl (final) Dimethyl sulfoxide concentration 1%). The reaction was performed at 37 ° C. for 20 minutes and terminated by suction filtration through a glass fiber filter plate using a cell harvester.

  The glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM spiperone was defined as nonspecific binding.

IC ₅₀ values were calculated from concentration-dependent reactions using a non-linear analysis program. Ki values were calculated from IC ₅₀ values using the Cheng-Prussoff equation. The results are shown in the following table.

3) Adrenaline α ₁ receptor binding experiment
Grob G et al. (Grob G, Hanft G, and Kolassa N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for a1-adrenoceptor binding sites Naunyn-Schmiedeberg's Arch Pharmacol, 1987; 336: 597-601).

  Wistar male rats were decapitated, the brain was immediately removed, and the cerebral cortex was removed. Homogenize in 20 mM tissue weight of 50 mM Tris-HCl buffer (100 mM NaCl, 2 mM ethylenediaminetetraacetate disodium dihydrogen, pH: 7.4) using a homogenizer with a high speed rotary blade, 4 ° C., 80 Centrifugation was performed at 1,000,000 g for 20 minutes. The obtained sediment was suspended in the above buffer solution having a volume 20 times the tissue weight, incubated at 37 ° C. for 10 minutes, and then centrifuged under the above conditions. The obtained sediment was suspended again in the above buffer solution having a volume 20 times the tissue weight, and centrifuged under the above conditions. The obtained precipitate was suspended in 50 mM Tris-HCl buffer (containing 1 mM ethylenediaminetetraacetic acid dihydrogen dihydrogen, pH: 7.4), which was 20 times the tissue weight, and these were used as membrane specimens for binding experiments— It was stored frozen at 85 ° C.

Binding experiments were performed with 40 μl of membrane preparation, 20 μl of [ ³ H] -prazosin (final concentration 0.2-0.5 nM), 20 μl of the test drug and 50 mM Tris-HCl buffer (containing 1 mM EDTA, pH: 7.4). The volume was 200 μl (final dimethyl sulfoxide concentration 1%). The reaction was carried out at 30 ° C. for 45 minutes and terminated by suction filtration through a glass fiber filter plate using a cell harvester.

  The glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM phentolamine hydrochloride was defined as nonspecific binding.

IC ₅₀ values were calculated from concentration-dependent reactions using a non-linear analysis program. Ki values were calculated from IC ₅₀ values using the Cheng-Prussoff equation.

Pharmacological test 2
Partial agonist against dopamine D ₂ receptors with dopamine D ₂ receptor-expressing cells (partial agonistic)
By quantifying the cyclic AMP production inhibitory action of the measurement compound in dopamine D ₂ receptor-expressing cells induced by forskolin to induce cyclic adenosine 3 ′, 5′-monophosphate (cyclic AMP) production, dopamine It was evaluated partial agonist against D ₂ receptors.

Human dopamine D ₂ receptor-expressing Chinese hamster ovary / DHFR (−) cells in medium (Iscob modified Dulbecco medium (IMDM medium), 10% fetal calf serum, 50 IU / ml penicillin, 50 μg / ml streptomycin, 200 μg / ml geneticin, 0.1 mM sodium hypoxanthine, 16 μM thymidine) at 37 ° C. and 5% carbon dioxide gas. 10 ⁴ cells / well of cells were seeded in a 96-well microplate coated with poly-L-lysine and cultured under the same conditions for 2 days. Each well was washed with 100 μl of washing solution (IMDM medium, 0.1 mM hypoxanthine sodium, 16 μM thymidine), and 50 μl of test compound-added medium (IMDM medium, 0.1% sodium ascorbate, 0.1 mM hypopoxine) in which 3 μM of the test compound was dissolved. (Xanthine sodium, 16 μM thymidine). After standing at 37 ° C. and 5% carbon dioxide for 20 minutes, 100 μl of test compound-added forskolin-stimulated medium in which 3 μM of the same test compound was dissolved (IMDM medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine, 10 μM forskolin, 500 μM 3-isobutyl-1-methylxanthine), and allowed to stand at 37 ° C. under 5% carbon dioxide for 10 minutes. After removing the medium, 200 μl of Lysis 1B aqueous solution (Amersham Biosciences cyclic AMP biotrack enzyme immunoassay system attached reagent) was dispensed and shaken for about 10 minutes. The aqueous solution in each well was used as a measurement sample. Using the enzyme immunoassay system, a cyclic AMP amount was measured on a measurement sample diluted 4-fold. The inhibition rate of each test compound was calculated with the amount of cyclic AMP in a well to which no test compound was added as 100%. In this experimental system, dopamine used as a control drug suppressed the amount of cyclic AMP to about 10% as the maximum activity.

In the above test, it was confirmed that the test compound has a partial agonistic property to the dopamine D ₂ receptor.

Since the test compound has a partial agonistic property to the dopamine D ₂ receptor, it can stabilize dopamine neurotransmission to a normal state in a schizophrenic patient, and as a result, without causing side effects, For example, clinical improvement effects such as positive and negative symptom improvement effects and cognitive impairment improvement effects can be exhibited.

Pharmacological test 3
Wistar rats (male, 6-7 weeks old, Nippon SLC Co., Ltd.) were used as test animals for suppressing the apomorphine-induced stereotyped behavior using rats . The test compound was suspended in 5% gum arabic / (saline or water) using an agate mortar and diluted with the same solution as necessary.

  The test animals were fasted overnight from the previous day. Each test compound was orally administered (5 ml / kg), and 0.7 mg / kg apomorphine was subcutaneously administered 1 hour later (1 ml / kg). At 20, 30, and 40 minutes after administration of apomorphine, the same behavior was observed for 1 minute each.

The normal behavior of each animal was scored under the following conditions, and the three scores were totaled to evaluate the anti-apomorphine action. In each group, 6 test animals were used.
0: No difference in observation from rats administered with physiological saline 1: Exploratory behavior is continuously performed, but sniffing is performed only intermittently 2: Sniffing is performed continuously, exploration State where action is performed only occasionally 3: State where sniffing operation is continuously performed, but a biting operation and a tongue licking operation are performed only intermittently. In addition, the spontaneous exercise amount at this time is very small.
4: State in which continuous biting operation and tongue licking operation are performed. At this time, no exploratory behavior is observed.

  All non-clinical statistical analysis systems were used for statistical processing. When the significance value was lower than 0.05, it was determined that there was a significant difference. The difference in score between the solvent administration group and each test compound administration group was analyzed using Wilcoxon rank sum test or Steel test. In addition, linear regression analysis was used to calculate the 50% effective dose (95% confidence interval).

In the above test, the test compound because it showed inhibitory effect on apomorphine-induced stereotyped behavior, the test compound was determined to have a D ₂ receptor antagonism.

Pharmacological test 4
As a test animal for inhibitory effect on (±) D-2,5-dimethoxy-4-iodoamphetamine (DOI) -induced swinging behavior using rats, Wistar rats (male, 6-7 weeks old, Japan SLC Co., Ltd.) Was used. The test compound was suspended in 5% gum arabic / (saline or water) using an agate mortar and diluted with the same solution as necessary.

  The test animals were fasted overnight from the previous day. Each test compound was orally administered (5 ml / kg), 1 hour later, 5.0 mg / kg DOI was subcutaneously administered (1 ml / kg), and the number of swing motions induced during the next 10 minutes was counted. It was. In each group, 6 test animals were used.

  All non-clinical statistical analysis systems were used for statistical processing. When the significance value was lower than 0.05, it was considered significant. The difference in the number of swings between the solvent administration group and each test compound administration group was analyzed using t-test or Dunnett's test. In addition, linear regression analysis was used to calculate the 50% effective dose (95% confidence interval).

In the said test, since the test compound showed the inhibitory action with respect to DOI induced swing behavior, it was confirmed that the test compound has a serotonin 5HT _2A receptor antagonistic action.

Pharmacological test 5
Wistar rats (male, 6-7 weeks old, Nippon SLC Co., Ltd.) were used as test animals for inducing stiffness (catalepsy) in rats. The test compound was suspended in 5% gum arabic / (saline or water) using an agate mortar and diluted with the same solution as necessary.

  The test animals were fasted overnight from the previous day. Each test compound was orally administered (5 ml / kg), and catalepsy and ptosis were observed 1, 2, 4, 6 and 8 hours later. In each group, 6 test animals were used.

  A rat's hand is placed on the edge of a steel box (width: 6.5 cm, depth: 4.0 cm, height: 7.2 cm) (unnatural posture), and the posture is maintained for more than 30 seconds. Were determined to be positive for catalepsy. Observation was performed three times at each time point, and if it was positive even once, it was determined that the individual had caused catalepsy.

  As a result of the above test, it was confirmed that the catalepsy-inducing action of the test compound was different from the apomorphine-induced stereotyped action-inhibiting action, so that the concern about the occurrence of extrapyramidal side effects in the clinic was low.

Pharmacological test 6
Measurement of compound serotonin (5-HT) uptake inhibitory activity by rat brain synaptosomes Male Wistar rats are decapitated, the brain is removed, the frontal cortex is separated, and this is divided into 20 times the weight of 0.32 molar (M) shoal. The solution was placed in a sugar solution and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g for 10 minutes at 4 ° C., the supernatant was further centrifuged at 20000 g for 20 minutes at 4 ° C., and the pellet was incubated with incubation buffer (10 milli (m) M glucose, 145 mM sodium chloride, 4.5 mM potassium chloride). , 1.2 mM magnesium chloride, 1.5 mM calcium chloride in 20 mM Hepes buffer (pH 7.4)) was used as a crude synaptosome fraction. The uptake reaction was carried out using a 96-well round bottom plate with a volume of 200 microliters (l), and during the reaction, incubation protein was added with pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml). Used in addition. The 100% uptake value is taken as the uptake activity when only the compound solvent is added, and the 0% uptake value (non-specific uptake value) is taken as the uptake activity when unlabeled 5-HT (final concentration 10 μM) is added. Each hole was prepared. A hole was prepared in which the evaluation compound was diluted so that the final concentration was 300 nM. The synaptosome fraction was added to each hole at one-tenth the final volume and preincubated for 10 minutes at 37 ° C., and then the tritium-labeled 5-HT solution (final concentration 8 nM) was added to start the uptake reaction at 37 ° C. The uptake time is 10 minutes, the reaction is terminated by suction filtration through a 96-hole glass fiber filter paper plate, the filter paper is washed with cold physiological saline, and then thoroughly dried, and then microcinch 0 (Perkin Elmer) is added. The residual radioactivity on the filter was measured. The inhibitory activity of each compound was calculated from the radioactivity at uptake of 100% and 0% and the radioactivity of each compound.

Formulation Example 100 g of the compound of the present invention, 40 g of Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate were mixed and polished, and tableted with a sugar coated R10 mm kine.

  The obtained tablets were coated with a film coating agent consisting of 10 g of TC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil, and an appropriate amount of ethanol. A film coating tablet having the above composition was produced.

Claims (9)

General formula (1)

[Where:

The ring Q represented by

Indicates.
(Where

Represents —NH—CH ₂ —, —N═CH—, —CH ₂ —NH—, or —CH═N—.
Shown at the 3- and 4-positions of the heterocyclic skeleton containing Z and Y

The carbon-carbon bond represents a single bond or a double bond. )
On ring Q, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl group, lower alkenyl Oxy group, lower alkanoyl group, cycloalkyl group, cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group optionally An amino group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group optionally having a lower alkyl group, a thienyl group, a 3- to 8-membered saturated heteromonocyclic lower alkyl group having 1 or 2 nitrogen atoms, From the group consisting of an oxo group and a lower alkanoyloxy group Barre substituents may be substituted with at least one.
R ₂ represents hydrogen or a lower alkyl group.
A represents —O—A ₁ — (wherein A ₁ represents an alkylene group which may be substituted with a hydroxy group (the alkylene group may contain one oxygen atom) or lower alkenylene. Group) or a lower alkylene group.
Provided that when A represents a lower alkylene group, ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of: A carbon-carbon bond including a dotted line in the bicyclic heterocyclic group represents a single bond or a double bond. ]
Or a salt thereof. Ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of: (The carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the bicyclic heterocyclic ring, a lower alkyl group, a lower alkenyl group , Lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower Alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group Amino group, nitro group, hydroxy lower alkyl group, lower alkyl group A substituent selected from the group consisting of an amino lower alkyl group, a thienyl group, a 5- to 6-membered saturated heteromonocyclic lower alkyl group having 1 or 2 nitrogen atoms, and a lower alkanoyloxy group, which may have 1-4 may be substituted),
A is —O—A ₁ — (wherein A ₁ is a C1-C6 alkylene group optionally substituted with a hydroxy group (the alkylene group may contain one oxygen atom)) The heterocyclic compound or its salt of Claim 1 which shows these. Ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogen-substituted lower alkyl group. Group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower group An alkyl group, a halogen, a carbamoyl group optionally having a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, a lower alkyl group; Amino lower alkyl group which may have a phenyl group Thienyl group, a pyrrolidinyl lower alkyl group and a substituent selected from the group consisting of a lower alkanoyloxy group represents may) be in 1-3 substituents,
A is —O—A ₁ — (wherein A ₁ is a C1-C6 alkylene group optionally substituted with a hydroxy group (the alkylene group may contain one oxygen atom)) The heterocyclic compound or its salt of Claim 2 which shows these. Ring Q is

as well as

A bicyclic group selected from the group consisting of (wherein the ring Q is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogen-substituted lower alkyl group, a phenyl group, a phenyl group, Lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, lower A carbamoyl group optionally having an alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, a lower alkyl group Good amino lower alkyl group, thienyl group, pyrrolidinyl low Heterocyclic compound or salt thereof according to claim 2 represents an alkyl group and a substituent selected from the group consisting of lower alkanoyloxy group may be one to three substituents). Ring Q is

as well as

A bicyclic group selected from the group consisting of (the carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the ring skeleton, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy group, naphthyl A lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl lower alkyl group, a halogen, a carbamoyl group optionally having a lower alkyl group, a carboxy group, A lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, a nitro group, 1 to 4 substituents selected from the group consisting of a droxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group, an oxo group and a lower alkanoyloxy group You may have)
The heterocyclic compound or a salt thereof according to claim 1, wherein A represents a lower alkylene group. Ring Q is

as well as

The bicyclic heterocyclic group selected from the group consisting of (the carbon-carbon bond including the dotted lines shown at the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond. On the cyclic heterocyclic skeleton, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, phenyl group, phenyl lower alkyl group, naphthyl lower alkyl group, phenyl lower alkoxy A carbamoyl group optionally having a group, naphthyl lower alkoxy group, benzoyl group, lower alkenyloxy group, lower alkanoyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkyl lower alkyl group, halogen, lower alkyl group, A carboxy group, a lower alkoxycarbonyl group, an amino group optionally having a lower alkanoyl group, 1 to 3 substituents selected from the group consisting of a tro group, a hydroxy lower alkyl group, an amino lower alkyl group optionally having a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group, and a lower alkanoyloxy group are substituted. The heterocyclic compound or a salt thereof according to claim 5, wherein (1) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1H-quinolin-2-one,
(2) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -1H-quinolin-2-one,
(3) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one,
(4) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-1H-quinolin-2-one,
(5) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -1-methyl-3,4-dihydro-1H-quinolin-2-one and (6 ) 6- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-1H-quinolin-2-one 4. The heterocyclic compound or a salt thereof according to 3. (1) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -3,4-dihydro-2H-isoquinolin-1-one,
(2) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(3) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -2-methyl-3,4-dihydro-2H-isoquinolin-1-one,
(4) 7- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butoxy] -3,4-dihydro-2H-isoquinolin-1-one,
(5) 7- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2H-isoquinolin-1-one and (6) 7- [3- (4-benzo [B] The heterocyclic compound or a salt thereof according to claim 4, selected from the group consisting of [b] thiophen-4-yl-piperazin-1-yl) propoxy] -2-methyl-2H-isoquinolin-1-one. General formula (1)

[Where:

The ring Q represented by

Indicates.
(Where

Represents —NH—CH ₂ —, —N═CH—, —CH ₂ —NH—, or —CH═N—.
Shown at the 3- and 4-positions of the heterocyclic skeleton containing Z and Y

The carbon-carbon bond represents a single bond or a double bond. )
(Here, on ring Q, lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogen-substituted lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl Group, lower alkenyloxy group, lower alkanoyl group, cycloalkyl group, cycloalkyl lower alkyl group, halogen, carbamoyl group optionally having lower alkyl group, carboxy group, lower alkoxycarbonyl group, lower alkanoyl group An amino group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group optionally having a lower alkyl group, a thienyl group, a 3- to 8-membered saturated heteromonocyclic ring having 1 or 2 nitrogen atoms From lower alkyl group, oxo group and lower alkanoyloxy group That substituent selected from the group may be substituted with at least one.
R ₂ represents hydrogen or a lower alkyl group.
A represents —O—A ₁ — (wherein A ₁ represents an alkylene group which may be substituted with a hydroxy group (the alkylene group may contain one oxygen atom) or lower group. Represents an alkenylene group) or a lower alkylene group.
Provided that when A represents a lower alkylene group, ring Q is

as well as

A bicyclic heterocyclic group selected from the group consisting of: A carbon-carbon bond including a dotted line in the bicyclic heterocyclic group represents a single bond or a double bond. ]
A method for producing a heterocyclic compound represented by the formula:
General formula

[Wherein, rings Q and A are the same as defined above. X ₁ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
A compound represented by the formula:
General formula

[Wherein R ₂ is the same as defined above. ]
The compound or its salt represented by these is made to react.