JP2015513521A - Heterocyclic compounds - Google Patents

Abstract

General formula (1): [wherein, m, l and n each represent an integer of 1 to 2, and X represents —O— or —CH 2 —. R1 represents hydrogen; a lower alkyl group; a hydroxy lower alkyl group; or a protecting group or a tri-lower alkylsilyloxy lower alkyl group. R2 and R3 are the same or different and each independently represents hydrogen or a lower alkyl group; or R2 and R3 are bonded to form a cycloC3-C8 alkyl group. R4 represents an aromatic ring group or a heterocyclic group. One or more arbitrary substituents may be present on the above aromatic ring or heterocyclic group. ] The pharmaceutical which consists of a heterocyclic compound represented by these, or its salt. [Selection figure] None

Description

  The present invention relates to a novel heterocyclic compound.

Three monoamines, known as serotonin, norepinephrine and dopamine, function as neurotransmitters in vivo, so drugs that have reuptake inhibitory action of these monoamines can treat diseases related to the central or peripheral nervous system. Widely used as a medicine.
To date, many of the drugs used to treat depression are those that selectively inhibit norepinephrine or serotonin reuptake. Such drugs include, for example, selective serotonin uptake inhibitors (SSRI, third agents) typified by imipramine (first generation antidepressant), maprotiline (second generation antidepressant), and fluoxetine. Generation antidepressants), serotonin and / or norepinephrine reuptake inhibitors (SNRI, fourth generation antidepressants) represented by venlafaxine (Non-patent Document 1).

  However, all of these drugs require a long period of 3 weeks or more until a therapeutic effect is exhibited, and cannot exhibit a sufficient therapeutic effect for depression patients of about 30% (non- Patent Document 2).

Miura Sadanori, Clinical Psychopharmacology, 2000, 3: 311-318 Phil Skolnick, European Journal of Pharmacology, 1999, 375: 31-40

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a drug that has a broad therapeutic spectrum as compared with known antidepressants and can exhibit a sufficient therapeutic effect in a short period of time.

  As a result of intensive studies to solve the above problems, the present inventors have found that a heterocyclic compound represented by the following general formula (1) can be used for the production of a desired drug. The present invention has been completed based on such findings.

［式中、ｍ、ｌおよびｎは各々１ないし２の整数を示し、Ｘは、−Ｏ−又は−ＣＨ_２−を示す。
Ｒ^１は、水素；低級アルキル基；ヒドロキシ低級アルキル基；又は保護基又はトリ低級アルキルシリルオキシ低級アルキル基を示す。
Ｒ^２およびＲ^３は、同一又は異なってそれぞれ、独立して、水素又は低級アルキル基；又はＲ^２とＲ^３が結合してシクロＣ３−Ｃ８アルキル基を形成する基を示す。
Ｒ^４は、芳香族環基又は複素環基を示す。
上記、芳香族環又は複素環基上に、１個以上の任意の置換基を有していてもよい。]
で表される複素環化合物またはその塩からなる医薬。
項２．
Ｒ^４が、下記で示されるいずれかの基を示す、項１に記載の一般式（１）で表される複素環化合物またはその塩からなる医薬：
（１） フェニル基
（２） インドリル基
（３） ベンゾチエニル基
（４） ナフチル基
（５） ベンゾフリル基
（６） キノリル基
（７） イソキノリル基
（８） ピリジル基
（９） チエニル基
（１０） ジヒドロベンゾオキサジニル基
（１１） ジヒドロベンゾジオキシニル基
（１２） ジヒドロキノリル基
（１３） クロマニル基
（１４） キノキサリニル基
（１５） ジヒドロインデニル基
（１６） ジヒドロベンゾフリル基
（１７） ベンゾジオキソリル基
（１８） インダゾリル基
（１９） ベンゾチアゾリル基
（２０） インドリニル基
（２１） チエノピリジル基、
（２２） テトラヒドロベンゾアゼピニル基
（２３） テトラヒドロベンゾジアゼピニル基
（２４） ジヒドロベンゾジオキセピニル基
（２５） フルオレニル基
（２６） ピリダジニル基
（２７） テトラヒドロキノリル基
（２８） カルバゾリル基
（２９） フェナントリル基
（３０） ジヒドロアセナフチレニル基
（３１） ピロロピリジル基
（３２） アントリル基
（３３） ベンゾジオキシニル基
（３４） ピロリジニル基
（３５） ピラゾリル基
（３６） オキサジアゾリル基
（３７） ピリミジニル基
（３８） テトラヒドロナフチル基
（３９） ジヒドロキナゾリニル基
（４０） ベンゾオキサゾリル基
（４１） チアゾリル基
（４２） キナゾリニル基
（４３） フタラジニル基
（４４） ピラジニル基
（４５） クロメニル基
上記、芳香族環又は複素環上に、下記（１−１）〜（１−４３）から選ばれた置換基を１個以上有していてもよい：
（１−１） ハロゲン原子
（１−２） 低級アルキル基
（１−３） 低級アルカノイル基
（１−４） ハロゲン置換低級アルキル基
（１−５） ハロゲン置換低級アルコキシ基
（１−６） シアノ基
（１−７） 低級アルコキシ基
（１−８） 低級アルキルチオ基
（１−９） イミダゾリル基
（１−１０）トリ低級アルキルシリル基
（１−１１）低級アルキル基を有していてもよいオキサジアゾリル基
（１−１２）オキソ基を有していてもよいピロリジニル基
（１−１３）低級アルコキシ基を有していてもよいフェニル基
（１−１４）低級アルキルアミノ低級アルキル基
（１−１５）オキソ基
（１−１６）低級アルキル基を有していてもよいピラゾリル基
（１−１７）チエニル基
（１−１８）フリル基
（１−１９）低級アルキル基を有していてもよいチアゾリル基
（１−２０）低級アルキルアミノ基
（１−２１）低級アルキル基を有していてもよいピリミジル基
（１−２２）フェニル低級アルケニル基
（１−２３）ハロゲン原子を有していてもよいフェノキシ基
（１−２４）フェノキシ低級アルキル基
（１−２５）ピロリジニル低級アルコキシ基
（１−２６）低級アルキルスルファモイル基
（１−２７）低級アルキル基を有していてもよいピリダジニルオキシ基
（１−２８）フェニル低級アルキル基
（１−２９）低級アルキルアミノ低級アルコキシ基
（１−３０）イミダゾリル低級アルキル基
（１−３１）フェニル低級アルコキシ基
（１−３２）ヒドロキシ基
（１−３３）低級アルコキシカルボニル基
（１−３４）ヒドロキシ低級アルキル基
（１−３５）オキサゾリル基
（１−３６）ピペリジル基
（１−３７）ピロリル基
（１−３８）モルホリニル低級アルキル基
（１−３９）低級アルキル基を有していてもよいピペラジニル低級アルキル基
（１−４０）ピペリジル低級アルキル基
（１−４１）ピロリジニル低級アルキル基
（１−４２）モルホリニル基
（１−４３）低級アルキル基を有していてもよいピペラジニル基。
項３．
Ｒ^４が、下記で示されるいずれかの基を示す、項２に記載の一般式（１）で表される複素環化合物またはその塩からなる医薬：
（１） フェニル基
（２） インドリル基
（３） ベンゾチエニル基
（４） ナフチル基
（５） ベンゾフリル基
（６） キノリル基
（７） イソキノリル基
（８） ピリジル基
（９） チエニル基
（１０） ジヒドロベンゾオキサジニル基
（１１） ジヒドロベンゾジオキシニル基
（１２） ジヒドロキノリル基
（１３） クロマニル基
（１４） キノキサリニル基
（１５） ジヒドロインデニル基
（１６） ジヒドロベンゾフリル基
（１７） ベンゾジオキソリル基
（１８） インダゾリル基
（１９） ベンゾチアゾリル基
（２０） インドリニル基
（２１） チエノピリジル基、
（２２） テトラヒドロベンゾアゼピニル基
（２３） テトラヒドロベンゾジアゼピニル基
（２４） ジヒドロベンゾジオキセピニル基
（２５） フルオレニル基
（２６） ピリダジニル基
（２７） テトラヒドロキノリル基
（２８） カルバゾリル基
（２９） フェナントリル基
（３０） ジヒドロアセナフチレニル基
（３１） ピロロピリジル基
（３２） アントリル基
（３３） ベンゾジオキシニル基
（３４） ピロリジニル基
（３５） ピラゾリル基
（３６） オキサジアゾリル基
（３７） ピリミジニル基
（３８） テトラヒドロナフチル基
（３９） ジヒドロキナゾリニル基
（４０） ベンゾオキサゾリル基
（４１） チアゾリル基
（４２） キナゾリニル基
（４３） フタラジニル基
（４４） ピラジニル基
（４５） クロメニル基
上記、芳香族環又は複素環上に、下記（１−１）〜（１−４３）から選ばれた置換基を１〜４個有していてもよい：
（１−１） ハロゲン原子
（１−２） 低級アルキル基
（１−３） 低級アルカノイル基
（１−４） ハロゲン置換低級アルキル基
（１−５） ハロゲン置換低級アルコキシ基
（１−６） シアノ基
（１−７） 低級アルコキシ基
（１−８） 低級アルキルチオ基
（１−９） イミダゾリル基
（１−１０）トリ低級アルキルシリル基
（１−１１）低級アルキル基を１個有していてもよいオキサジアゾリル基
（１−１２）オキソ基を１個有していてもよいピロリジニル基
（１−１３）低級アルコキシ基を１個有していてもよいフェニル基
（１−１４）低級アルキルアミノ低級アルキル基
（１−１５）オキソ基
（１−１６）低級アルキル基を１個有していてもよいピラゾリル基
（１−１７）チエニル基
（１−１８）フリル基
（１−１９）低級アルキル基を１個有していてもよいチアゾリル基
（１−２０）低級アルキルアミノ基
（１−２１）低級アルキル基を１個有していてもよいピリミジル基
（１−２２）フェニル低級アルケニル基
（１−２３）ハロゲン原子を１個有していてもよいフェノキシ基
（１−２４）フェノキシ低級アルキル基
（１−２５）ピロリジニル低級アルコキシ基
（１−２６）低級アルキルスルファモイル基
（１−２７）低級アルキル基を１個有していてもよいピリダジニルオキシ基
（１−２８）フェニル低級アルキル基
（１−２９）低級アルキルアミノ低級アルコキシ基
（１−３０）イミダゾリル低級アルキル基
（１−３１）フェニル低級アルコキシ基
（１−３２）ヒドロキシ基
（１−３３）低級アルコキシカルボニル基
（１−３４）ヒドロキシ低級アルキル基
（１−３５）オキサゾリル基
（１−３６）ピペリジル基
（１−３７）ピロリル基
（１−３８）モルホリニル低級アルキル基
（１−３９）低級アルキル基を１個有していてもよいピペラジニル低級アルキル基
（１−４０）ピペリジル低級アルキル基
（１−４１）ピロリジニル低級アルキル基
（１−４２）モルホリニル基
（１−４３）低級アルキル基を１個有していてもよいピペラジニル基。
項４．
ｍが２、l及びｎが各々１の整数を示し、Ｘが、−ＣＨ_２−を示す；
Ｒ^１が、水素；低級アルキル基；ヒドロキシ低級アルキル基；ベンジル基又はトリ低級アルキルシリルオキシ低級アルキル基を示す；ならびに
Ｒ^４が下記で示されるいずれかの基を示す、項３に記載の一般式（１）で表される複素環化合物またはその塩からなる医薬：
（１） フェニル基
（２） インドリル基
（４） ナフチル基
（５） ベンゾフリル基
（３１） ピロロピリジル基
上記、芳香族環又は複素環上に、下記から選ばれた置換基を１〜４個有していてもよい：
（１−１） ハロゲン原子
（１−２） 低級アルキル基
（１−３） 低級アルカノイル基
（１−４） ハロゲン置換低級アルキル基
（１−５） ハロゲン置換低級アルコキシ基
（１−６） シアノ基
（１−７） 低級アルコキシ基
（１−８） 低級アルキルチオ基
（１−９） イミダゾリル基
（１−１０）トリ低級アルキルシリル基
（１−１１）低級アルキル基を１個有していてもよいオキサジアゾリル基
（１−１２）オキソ基を１個有していてもよいピロリジニル基
（１−１３）低級アルコキシ基を１個有していてもよいフェニル基
（１−１４）低級アルキルアミノ低級アルキル基
（１−１５）オキソ基
（１−１６）低級アルキル基を１個有していてもよいピラゾリル基
（１−１７）チエニル基
（１−１８）フリル基
（１−１９）低級アルキル基を１個有していてもよいチアゾリル基
（１−２０）低級アルキルアミノ基
（１−２１）低級アルキル基を１個有していてもよいピリミジル基
（１−２２）フェニル低級アルケニル基
（１−２３）ハロゲン原子を１個有していてもよいフェノキシ基
（１−２４）フェノキシ低級アルキル基
（１−２５）ピロリジニル低級アルコキシ基
（１−２６）低級アルキルスルファモイル基
（１−２７）低級アルキル基を１個有していてもよいピリダジニルオキシ基
（１−２８）フェニル低級アルキル基
（１−２９）低級アルキルアミノ低級アルコキシ基
（１−３０）イミダゾリル低級アルキル基
（１−３１）フェニル低級アルコキシ基
（１−３２）ヒドロキシ基
（１−３４）ヒドロキシ低級アルキル基
（１−３５）オキサゾリル基
（１−３６）ピペリジル基
（１−３７）ピロリル基
（１−３８）モルホリニル低級アルキル基
（１−３９）低級アルキル基を有していてもよいピペラジニル低級アルキル基
（１−４０）ピペリジル低級アルキル基
（１−４１）ピロリジニル低級アルキル基
（１−４２）モルホリニル基
（１−４３）低級アルキル基を１個有していてもよいピペラジニル基。
項５．
Ｒ^１が水素を示す；
Ｒ^２およびＲ^３が、同一又は異なってそれぞれ、独立して、低級アルキル基を示す；又はＲ^２とＲ^３が結合してシクロＣ３−Ｃ８アルキル基を形成する基を示す；および
Ｒ^４が下記で示されるいずれかの基を示す、項４に記載の一般式（１）で表される複素環化合物またはその塩からなる医薬：
（１） フェニル基
（２） インドリル基
（４） ナフチル基
（５） ベンゾフリル基
（３１） ピロロピリジル基
上記、芳香族環又は複素環上に、下記から選ばれた置換基を１〜２個有していてもよい：
（１−１） ハロゲン原子
（１−２） 低級アルキル基
（１−５） ハロゲン置換低級アルコキシ基
（１−６） シアノ基
（１−７） 低級アルコキシ基。
項６．
以下の群から選ばれる項５に記載の一般式（１）で表される複素環化合物またはその塩からなる医薬：
（４ａＳ，８ａＲ）−１−（４−クロロフェニル）−３，３−ジメチルデカヒドロキノキサリン、
２−クロロ−４−（（４ａＳ，８ａＳ）−３，３−ジメチルオクタヒドロキノキサリン−１（２Ｈ）−イル）ベンゾニトリル、
（４ａＳ，８ａＲ）−１−（３−クロロ−４−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン、
（４ａＳ，８ａＲ）−１−（７−フルオロベンゾフラン−４−イル）−３，３−ジメチルデカヒドロキノキサリン、
５−（（４ａＲ，８ａＳ）−３，３−ジメチルオクタヒドロキノキサリン−１（２Ｈ）−イル）−１−メチル−１Ｈ−インドール−２−カルボニトリル、
（４ａ’Ｒ，８ａ’Ｓ）−４’−（７−メトキシベンゾフラン−４−イル）オクタヒドロ−１’Ｈ−スピロ［シクロブタン−１，２’−キノキサリン］、
（４ａＳ，８ａＲ）−１−（６，７−ジフルオロベンゾフラン−４−イル）−３，３−ジメチルデカヒドロキノキサリン、
５−（（４ａＳ，８ａＳ）−３，３−ジメチルオクタヒドロキノキサリン−１（２Ｈ）−イル）−１Ｈ−インドール−２−カルボニトリル、
（４ａＳ，８ａＲ）−１−（７−クロロ−２，３−ジヒドロ−１Ｈ−インデン−４−イル）−３，３−ジメチルデカヒドロキノキサリン、
６−（（４ａＳ，８ａＳ）−３，３−ジメチルオクタヒドロキノキサリン−ジメチルデカヒドロキノキサリン−１（２Ｈ）−イル）−２−ナフトニトリル、
（４ａＳ，８ａＳ）−３，３−ジメチル−１−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）デカヒドロキノキサリン及び
（４ａＳ，８ａＳ）−１−（４−（ジフルオロメトキシ）−３−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン。
項７．
有効成分として項１に記載の一般式（１）で表される複素環化合物又はその塩、及び薬理的に許容される担体を含有する医薬組成物。
項８．
項１に記載の一般式（１）で表される複素環化合物又はその塩を有効成分として含有する、セロトニン、ノルエピネフリン又はドパミンの神経伝達の低下に伴う障害の予防及び／又は治療剤。
項９．
障害が、うつ病；適応障害による抑うつ症状；適応障害による不安、各種疾患に伴う不安、全般性不安障害、恐怖症、強迫性障害、パニック障害、心的外傷後ストレス障害、急性ストレス障害、心気症、解離性健忘症、回避性人格障害、身体醜形障害、摂食障害、肥満症、化学物質依存症、疼痛、線維筋痛症、アルツハイマー病、記憶障害、パーキンソン病、むずむず脚症候群、内分泌障害、血管痙攣、小脳性運動失調、胃腸管障害、統合失調症の陰性症候群、月経前症候群、緊張性尿失禁、トウレット症候群、注意欠陥多動性障害（ＡＤＨＤ）、自閉症、アスペルガー症候群、衝動性調節障害、抜毛癖、盗癖、ギャンブル依存症、群発頭痛、片頭痛、慢性発作性片頭痛、慢性疲労、早発射精、男性インポテンス、ナルコレプシー、原発性過眠症、脱力発作、睡眠時無呼吸症候群及び頭痛からなる群から選ばれる障害である項８に記載の予防及び／又は治療剤。
項１０．
うつ病が、大うつ病性障害；双極Ｉ型障害；双極ＩＩ型障害；混合状態；気分変調性障害；ラピッド・サイクラー；非定型うつ病；季節性感情障害；産後うつ病；軽症うつ病；反復性短期うつ病性障害；難治性うつ病・慢性うつ病；重複うつ病；アルコール誘発性気分障害；混合性不安抑うつ障害；クッシング症候群、甲状腺機能低下症、副甲状腺機能亢進症、アジソン病、無月経・乳汁分泌症候群、パーキンソン病、アルツハイマー病、脳血管性認知症、脳梗塞、脳出血、くも膜下出血、糖尿病、ウィルス感染症、多発性硬化症、慢性疲労症候群、冠動脈疾患、疼痛、癌等の種々の身体疾患に伴ううつ病；中年期のうつ病；老年期うつ病；小児・思春期のうつ病及びインターフェロン等の薬物誘発性うつ病からなる群から選ばれるうつ病である項９記載の予防及び／又は治療剤。
項１１．
各種疾患に伴う不安が、頭部外傷、脳の感染症、内耳障害、心不全、不整脈、副腎機能亢進症、甲状腺機能亢進症、喘息及び慢性閉塞性肺疾からなる群から選ばれる不安である項９に記載の予防及び／又は治療剤。
項１２．
疼痛が、慢性疼痛、心因性疼痛、神経因性疼痛、幻肢痛、帯状疱疹後神経痛、外傷性頸部症候群、脊髄損傷痛、三叉神経痛及び糖尿病性神経障害からなる群から選ばれる疼痛である項９に記載の予防及び／又は治療剤。
項１３．
下記の化合物からなる群から選択される複素環化合物又はその塩：

項１４．
下記の化合物からなる群から選択される複素環化合物又はその塩：

項１５．
項１３又は１４の複素環化合物またはその塩からなる医薬。
項１６．
有効成分として項１３又は１４の複素環化合物又はその塩、及び薬理的に許容される担体を含有する医薬組成物。
項１７．
項１３又は１４に記載の一般式（１）で表される複素環化合物又はその塩を有効成分として含有する、セロトニン、ノルエピネフリン又はドパミンの神経伝達の低下に伴う障害の予防及び／又は治療剤。
項１８．
障害が、うつ病；適応障害による抑うつ症状；適応障害による不安、各種疾患に伴う不安、全般性不安障害、恐怖症、強迫性障害、パニック障害、心的外傷後ストレス障害、急性ストレス障害、心気症、解離性健忘症、回避性人格障害、身体醜形障害、摂食障害、肥満症、化学物質依存症、疼痛、線維筋痛症、アルツハイマー病、記憶障害、パーキンソン病、むずむず脚症候群、内分泌障害、血管痙攣、小脳性運動失調、胃腸管障害、統合失調症の陰性症候群、月経前症候群、緊張性尿失禁、トウレット症候群、注意欠陥多動性障害（ＡＤＨＤ）、自閉症、アスペルガー症候群、衝動性調節障害、抜毛癖、盗癖、ギャンブル依存症、群発頭痛、片頭痛、慢性発作性片頭痛、慢性疲労、早発射精、男性インポテンス、ナルコレプシー、原発性過眠症、脱力発作、睡眠時無呼吸症候群及び頭痛からなる群から選ばれる障害である項１６に記載の予防及び／又は治療剤。
項１９．
うつ病が、大うつ病性障害；双極Ｉ型障害；双極ＩＩ型障害；混合状態；気分変調性障害；ラピッド・サイクラー；非定型うつ病；季節性感情障害；産後うつ病；軽症うつ病；反復性短期うつ病性障害；難治性うつ病・慢性うつ病；重複うつ病；アルコール誘発性気分障害；混合性不安抑うつ障害；クッシング症候群、甲状腺機能低下症、副甲状腺機能亢進症、アジソン病、無月経・乳汁分泌症候群、パーキンソン病、アルツハイマー病、脳血管性認知症、脳梗塞、脳出血、くも膜下出血、糖尿病、ウィルス感染症、多発性硬化症、慢性疲労症候群、冠動脈疾患、疼痛、癌等の種々の身体疾患に伴ううつ病；中年期のうつ病；老年期うつ病；小児・思春期のうつ病及びインターフェロン等の薬物誘発性うつ病からなる群から選ばれるうつ病である項１８記載の予防及び／又は治療剤。
項２０．
各種疾患に伴う不安が、頭部外傷、脳の感染症、内耳障害、心不全、不整脈、副腎機能亢進症、甲状腺機能亢進症、喘息及び慢性閉塞性肺疾からなる群から選ばれる不安である項１８に記載の予防及び／又は治療剤。
項２１．
疼痛が、慢性疼痛、心因性疼痛、神経因性疼痛、幻肢痛、帯状疱疹後神経痛、外傷性頸部症候群、脊髄損傷痛、三叉神経痛及び糖尿病性神経障害からなる群から選ばれる疼痛である項１８に記載の予防及び／又は治療剤。 The present invention provides a pharmaceutical comprising the heterocyclic compound or salt thereof shown in the following items 1 to 21, a pharmaceutical composition containing the compound or use of the compound, a method for treating or preventing a disease, or a method for producing the compound. .
Item 1.
General formula (1):

[Wherein, m, l and n each represent an integer of 1 to 2, and X represents —O— or —CH ₂ —.
R ¹ represents hydrogen; a lower alkyl group; a hydroxy lower alkyl group; or a protective group or a tri-lower alkylsilyloxy lower alkyl group.
R ² and R ³ are the same or different and each independently represents hydrogen or a lower alkyl group; or R ² and R ³ are combined to form a cycloC3-C8 alkyl group.
R ⁴ represents an aromatic ring group or a heterocyclic group.
One or more arbitrary substituents may be present on the above aromatic ring or heterocyclic group. ]
Or a salt thereof.
Item 2.
The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of claim | item 1 whose R < ⁴ > shows either group shown below:
(1) phenyl group (2) indolyl group (3) benzothienyl group (4) naphthyl group (5) benzofuryl group (6) quinolyl group (7) isoquinolyl group (8) pyridyl group (9) thienyl group (10) dihydro Benzoxazinyl group (11) dihydrobenzodioxinyl group (12) dihydroquinolyl group (13) chromanyl group (14) quinoxalinyl group (15) dihydroindenyl group (16) dihydrobenzofuryl group (17) benzodi Oxolyl group (18) indazolyl group (19) benzothiazolyl group (20) indolinyl group (21) thienopyridyl group,
(22) Tetrahydrobenzoazepinyl group (23) Tetrahydrobenzodiazepinyl group (24) Dihydrobenzodioxepinyl group (25) Fluorenyl group (26) Pyridazinyl group (27) Tetrahydroquinolyl group (28) Carbazolyl group (29) Phenanthryl group (30) Dihydroacenaphthylenyl group (31) Pyrrolopyridyl group (32) Anthryl group (33) Benzodioxinyl group (34) Pyrrolidinyl group (35) Pyrazolyl group (36) Oxadiazolyl group (37) Pyrimidinyl group (38) tetrahydronaphthyl group (39) dihydroquinazolinyl group (40) benzoxazolyl group (41) thiazolyl group (42) quinazolinyl group (43) phthalazinyl group (44) pyrazinyl group (45) chromenyl group On an aromatic or heterocyclic ring May have one or more substituents selected from the following (1-1) to (1-43):
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) Oxadiazolyl group optionally having lower alkyl group (1-12) pyrrolidinyl group optionally having oxo group (1-13) phenyl group optionally having lower alkoxy group (1-14) lower alkylamino lower alkyl group (1-15) oxo The group (1-16) may have a lower alkyl group Pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) optionally have lower alkyl group Ryl group (1-20) Lower alkylamino group (1-21) Pyrimidyl group optionally having lower alkyl group (1-22) Phenyl lower alkenyl group (1-23) Halogen atom A good phenoxy group (1-24) a phenoxy lower alkyl group (1-25) a pyrrolidinyl lower alkoxy group (1-26) a lower alkylsulfamoyl group (1-27) an optionally substituted pyridazini Ruoxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower alkoxy group (1-32) hydroxy group (1 -33) Lower alkoxycarbonyl group (1-34) hydroxy lower alkyl group (1-35) oxazolyl group (1-36) piperidyl (1-37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group optionally having lower alkyl group (1-40) piperidyl lower alkyl group (1-41) pyrrolidinyl Lower alkyl group (1-42) Morpholinyl group (1-43) Piperazinyl group optionally having lower alkyl group.
Item 3.
The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of claim | item 2 whose R < ⁴ > shows either group shown below:
(1) phenyl group (2) indolyl group (3) benzothienyl group (4) naphthyl group (5) benzofuryl group (6) quinolyl group (7) isoquinolyl group (8) pyridyl group (9) thienyl group (10) dihydro Benzoxazinyl group (11) dihydrobenzodioxinyl group (12) dihydroquinolyl group (13) chromanyl group (14) quinoxalinyl group (15) dihydroindenyl group (16) dihydrobenzofuryl group (17) benzodi Oxolyl group (18) indazolyl group (19) benzothiazolyl group (20) indolinyl group (21) thienopyridyl group,
(22) Tetrahydrobenzoazepinyl group (23) Tetrahydrobenzodiazepinyl group (24) Dihydrobenzodioxepinyl group (25) Fluorenyl group (26) Pyridazinyl group (27) Tetrahydroquinolyl group (28) Carbazolyl group (29) Phenanthryl group (30) Dihydroacenaphthylenyl group (31) Pyrrolopyridyl group (32) Anthryl group (33) Benzodioxinyl group (34) Pyrrolidinyl group (35) Pyrazolyl group (36) Oxadiazolyl group (37) Pyrimidinyl group (38) tetrahydronaphthyl group (39) dihydroquinazolinyl group (40) benzoxazolyl group (41) thiazolyl group (42) quinazolinyl group (43) phthalazinyl group (44) pyrazinyl group (45) chromenyl group On an aromatic or heterocyclic ring May have 1 to 4 substituents selected from the following (1-1) to (1-43):
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) may have one lower alkyl group A pyrrolidinyl group (1-13) which may have one oxadiazolyl group (1-12) oxo group (1-13) a phenyl group which may have one lower alkoxy group (1-14) a lower alkylamino lower alkyl group (1-15) oxo group (1-16) pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) lower alkyl group optionally having one lower alkyl group 1 Pieces A thiazolyl group (1-20) lower alkylamino group (1-21) a pyrimidyl group (1-22) phenyl lower alkenyl group (1-23) halogen optionally having one lower alkyl group A phenoxy group (1-24) phenoxy lower alkyl group (1-25) pyrrolidinyl lower alkoxy group (1-26) lower alkylsulfamoyl group (1-27) lower alkyl group which may have one atom; Pyridazinyloxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower optionally having one Alkoxy group (1-32) hydroxy group (1-33) lower alkoxycarbonyl group (1-34) hydroxy lower alkyl group (1-35) Zolyl group (1-36) piperidyl group (1-37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group optionally having one lower alkyl group (1-40 ) Piperidyl lower alkyl group (1-41) pyrrolidinyl lower alkyl group (1-42) morpholinyl group (1-43) piperazinyl group optionally having one lower alkyl group.
Item 4.
m represents 2, l and n each represents an integer of 1, and X represents —CH ₂ —;
Item ^4. The general term according to Item 3, wherein R ¹ represents hydrogen; lower alkyl group; hydroxy lower alkyl group; benzyl group or tri-lower alkylsilyloxy lower alkyl group; and R ⁴ represents any group shown below. A medicament comprising a heterocyclic compound represented by the formula (1) or a salt thereof:
(1) Phenyl group (2) Indolyl group (4) Naphthyl group (5) Benzofuryl group (31) Pyrrolopyridyl group On the above aromatic ring or heterocyclic ring, it has 1 to 4 substituents selected from the following: May be:
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) may have one lower alkyl group A pyrrolidinyl group (1-13) which may have one oxadiazolyl group (1-12) oxo group (1-13) a phenyl group which may have one lower alkoxy group (1-14) a lower alkylamino lower alkyl group (1-15) oxo group (1-16) pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) lower alkyl group optionally having one lower alkyl group 1 Pieces A thiazolyl group (1-20) lower alkylamino group (1-21) a pyrimidyl group (1-22) phenyl lower alkenyl group (1-23) halogen optionally having one lower alkyl group A phenoxy group (1-24) phenoxy lower alkyl group (1-25) pyrrolidinyl lower alkoxy group (1-26) lower alkylsulfamoyl group (1-27) lower alkyl group which may have one atom; Pyridazinyloxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower optionally having one Alkoxy group (1-32) hydroxy group (1-34) hydroxy lower alkyl group (1-35) oxazolyl group (1-36) piperidyl group (1 37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group (1-40) piperidyl lower alkyl group (1-41) pyrrolidinyl lower alkyl group optionally having lower alkyl group (1-42) A morpholinyl group (1-43) a piperazinyl group optionally having one lower alkyl group.
Item 5.
R ¹ represents hydrogen;
R ² and R ³ are the same or different and each independently represents a lower alkyl group; or R ² and R ³ are combined to form a cycloC3-C8 alkyl group; and R ⁴ is The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of claim | item 4 which shows either group shown below:
(1) Phenyl group (2) Indolyl group (4) Naphtyl group (5) Benzofuryl group (31) Pyrrolopyridyl group On the above aromatic ring or heterocyclic ring, it has 1 to 2 substituents selected from the following: May be:
(1-1) Halogen atom (1-2) Lower alkyl group (1-5) Halogen-substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group.
Item 6.
The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of claim | item 5 selected from the following groups:
(4aS, 8aR) -1- (4-chlorophenyl) -3,3-dimethyldecahydroquinoxaline,
2-chloro-4-((4aS, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) benzonitrile,
(4aS, 8aR) -1- (3-chloro-4-fluorophenyl) -3,3-dimethyldecahydroquinoxaline,
(4aS, 8aR) -1- (7-fluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline,
5-((4aR, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) -1-methyl-1H-indole-2-carbonitrile,
(4a′R, 8a ′S) -4 ′-(7-methoxybenzofuran-4-yl) octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]
(4aS, 8aR) -1- (6,7-difluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline,
5-((4aS, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) -1H-indole-2-carbonitrile,
(4aS, 8aR) -1- (7-chloro-2,3-dihydro-1H-inden-4-yl) -3,3-dimethyldecahydroquinoxaline,
6-((4aS, 8aS) -3,3-dimethyloctahydroquinoxaline-dimethyldecahydroquinoxalin-1 (2H) -yl) -2-naphthonitrile,
(4aS, 8aS) -3,3-dimethyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline and (4aS, 8aS) -1- (4- (difluoromethoxy) -3-Fluorophenyl) -3,3-dimethyldecahydroquinoxaline.
Item 7.
A pharmaceutical composition comprising the heterocyclic compound represented by the general formula (1) according to item 1 or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
Item 8.
A prophylactic and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the heterocyclic compound represented by general formula (1) according to item 1 or a salt thereof as an active ingredient.
Item 9.
Disorder is depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder; anxiety associated with various diseases; generalized anxiety disorder; phobia; obsessive-compulsive disorder; panic disorder; Temperament, dissociative amnesia, avoidance personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory disorder, Parkinson's disease, restless leg syndrome, Endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal disorders, schizophrenia negative syndrome, premenstrual syndrome, stress urinary incontinence, Toulette syndrome, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome Impulsive dysregulation, hair loss, stealing, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hyperactivity Diseases, cataplexy, prevention and / or therapeutic agent according to claim 8, which is a disorder selected from the group consisting of sleep apnea syndrome and headache.
Item 10.
Depression is major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood dysfunction disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; Recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, Amenorrhea / lactation syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc. Depression selected from the group consisting of depression associated with various body diseases; middle-aged depression; geriatric depression; childhood / pubertal depression and drug-induced depression such as interferon Prevention and / or therapeutic agent to claim 9, wherein that.
Item 11.
The anxiety associated with various diseases is anxiety selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, adrenal hyperfunction, hyperthyroidism, asthma and chronic obstructive pulmonary disease 9. The preventive and / or therapeutic agent according to 9.
Item 12.
Pain selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic neck syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy Item 10. The prophylactic and / or therapeutic agent according to Item 9.
Item 13.
A heterocyclic compound selected from the group consisting of the following compounds or a salt thereof:

Item 14.
A heterocyclic compound selected from the group consisting of the following compounds or a salt thereof:

Item 15.
Item 15. A pharmaceutical comprising the heterocyclic compound of Item 13 or 14 or a salt thereof.
Item 16.
Item 15. A pharmaceutical composition comprising the heterocyclic compound of item 13 or 14 or a salt thereof as an active ingredient, and a pharmacologically acceptable carrier.
Item 17.
Item 15. A prophylactic and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the heterocyclic compound represented by the general formula (1) according to item 13 or 14 or a salt thereof as an active ingredient.
Item 18.
Disorder is depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder; anxiety associated with various diseases; generalized anxiety disorder; phobia; obsessive-compulsive disorder; panic disorder; Temperament, dissociative amnesia, avoidance personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory disorder, Parkinson's disease, restless leg syndrome, Endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal disorders, schizophrenia negative syndrome, premenstrual syndrome, stress urinary incontinence, Toulette syndrome, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome Impulsive dysregulation, hair loss, stealing, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hyperactivity Diseases, cataplexy, prevention and / or therapeutic agent according to claim 16, which is a disorder selected from the group consisting of sleep apnea syndrome and headache.
Item 19.
Depression is major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood dysfunction disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; Recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, Amenorrhea / lactation syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc. Depression selected from the group consisting of depression associated with various body diseases; middle-aged depression; geriatric depression; childhood / pubertal depression and drug-induced depression such as interferon Prevention and / or therapeutic agent to claim 18, wherein that.
Item 20.
The anxiety associated with various diseases is anxiety selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, adrenal hyperfunction, hyperthyroidism, asthma and chronic obstructive pulmonary disease 18. The preventive and / or therapeutic agent according to 18.
Item 21.
Pain selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic neck syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy Item 19. The prophylactic and / or therapeutic agent according to Item 18.

Specific examples of the groups shown in the general formula are as follows.
The term “lower” means a group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms) unless otherwise specified.

  Examples of the heterocyclic group include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom. More preferred heterocyclic groups are the following heterocyclic groups:

  Unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycles containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxides thereof , Pyrimidinyl group, pyrazinyl group, pyridazinyl group, triazolyl group (for example, 4H-1,2,4-triazolyl group, 1H-1,2,3-triazolyl group, 2H-1,2,3-triazolyl group, etc.), Tetrazolyl group (for example, 1H-tetrazolyl group, 2H-tetrazolyl group, etc.), dihydrotriazinyl group (for example, 4,5-dihydro-1,2,4-triazinyl group, 2,5-dihydro-1,2, 4-triazinyl group etc.) etc. are mentioned. Preferably, an imidazolyl group, a pyridazinyl group, a pyridyl group, a pyrazinyl group, a pyrimidyl group, a pyrazolyl group, and the like can be given.

  Saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 4 nitrogen atoms, such as azetidinyl group, pyrrolidinyl group, imidazolidinyl group, piperidinyl group, pyrazolidinyl group, piperazinyl group and the like It is done. Preferably, a pyrrolidinyl group is mentioned.

  Partially saturated or unsaturated condensed 7 to 12 membered heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl group, dihydroindolyl group (for example, 2,3-dihydroindolyl group, etc.) , Isoindolyl group, indolizinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group (for example, 3,4-dihydro-1H-isoquinolyl group, etc.), tetrahydroquinolyl group, tetrahydroisoquinolyl group (for example, 1,2,3,4-tetrahydro-1H-isoquinolyl group, 5,6,7,8-tetrahydroisoquinolyl group, etc.), carbostyryl group, dihydrocarbostyryl group (for example, 3,4-dihydrocarbostyril) Group), indazolyl group, benzotriazolyl group, tetrazolopyridyl group, tetrazolopyridazinyl group (example) E.g., tetrazolo [1,5-b] pyridazinyl group), dihydrotriazolopyridazinyl group, imidazopyridyl group (e.g. imidazo [1,2-a] pyridyl group, etc.), naphthyridinyl group, cinnolinyl group, quinoxalinyl Group, pyrazolopyridyl group (for example, pyrazolo [2,3-a] pyridyl group, etc.), pyrrolopyridyl group, carbazolyl group, indolinyl group, tetrahydrobenzodiazepinyl group, tetrahydrobenzoazepinyl group, quinazolinyl group, dihydroquina A zolinyl group, a phthalazinyl group, etc. are mentioned. Preferably, quinolyl, isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl, tetrahydroquinolyl, carbazolyl, indolinyl, quinazolinyl, phthalazinyl, tetrahydrobenzodiazepinyl or tetrahydrobenzoazepinyl Groups and the like.

  An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 2 oxygen atoms, such as a furyl group.

  Partially saturated or unsaturated condensed 7 to 12 membered heterocyclic group containing 1 to 3 oxygen atoms, such as benzofuryl group, dihydrobenzofuryl group (for example, 2,3-dihydrobenzo [b] furyl) Group), chromanyl group, benzodioxanyl group (for example, 1,4-benzodioxanyl group, etc.), dihydrobenzoxazinyl group (for example, 2,3-dihydrobenzo-1,4-oxazinyl group, etc.) ), Benzodioxolyl group (for example, benzo [1,3] dioxolyl group, etc.), benzodioxinyl group, dihydrobenzodioxinyl group, dihydrobenzodioxepinyl group and the like. A benzofuryl group, a benzodioxinyl group, a benzodioxolyl group, a dihydrobenzofuryl group, a dihydrobenzodioxinyl group, a dihydrobenzodioxepinyl group, a chromenyl group, or a chromanyl group is preferable.

  An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as an oxazolyl group, an isoxazolyl group, an oxadiazolyl group (for example, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, etc.). Preferably, an oxazolyl and an oxadiazolyl group are mentioned.

  A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as a morpholinyl group.

  Partially saturated or unsaturated condensed 7 to 12 membered heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl group, benzoxadiazolyl group, benzisoxa Examples include zolyl group, furopyridyl group (for example, furo [2,3-b] pyridyl group, furo [3,2-c] pyridyl group), dihydrobenzoxazinyl group and the like. Preferably, a benzoxazolyl group and a dihydrobenzoxazinyl group are mentioned.

  Unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, 1,2-thiazolyl, thiazolinyl Group, thiadiazolyl group (for example, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,2,3-thiadiazolyl group, etc.) and the like. Preferably, a thiazolyl group is mentioned.

  A saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a thiazolidinyl group.

  Examples thereof include an unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocycle containing one sulfur atom, such as a thienyl group.

  An unsaturated condensed 7 to 12 membered heterocyclic group containing 1 to 3 sulfur atoms, for example, a benzothienyl group (for example, benzo [b] thienyl group and the like) and the like can be mentioned.

  A partially saturated or unsaturated condensed 7 to 12 membered heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a benzothiazolyl group, a benzothiadiazolyl group, a thienopyridyl group ( For example, thieno [2,3-b] pyridyl group, thieno [2,3-c] pyridyl group, thieno [3,2-c] pyridyl group, etc.), imidazothiazolyl group (for example, imidazo [2,1 -B] thiazolyl group), dihydroimidazothiazolyl group (for example, 2,3-dihydroimidazo [2,1-b] thiazolyl group, etc.), thienopyrazinyl group (for example, thieno [2,3-b] pyrazinyl group) Etc.). Preferably, a thienopyridyl group or a benzothiazolyl group is used.

  Here, the heterocyclic group may be substituted with one or more appropriate substituents.

Examples of the aromatic ring group include a C _6-14 aryl group. Preferable examples of the aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like. Of these, phenyl, naphthyl, anthryl, phenanthryl, and the like are preferable. The aryl group may be partially saturated. Examples of the partially saturated aryl group include dihydroindenyl, fluorenyl, dihydroacenaphthylenyl, tetrahydronaphthyl and the like. Here, the heterocyclic group may be substituted with one or more appropriate substituents.

Examples of the saturated hydrocarbon group include a lower alkyl group and a cyclo C3-C8 alkyl group.

  Examples of the unsaturated hydrocarbon group include a lower alkenyl group, a lower alkynyl group, and a phenyl group.

  The characteristic group includes a group (an atom or atomic group other than hydrogen) directly bonded to the parent structure with a bond other than a carbon-carbon bond, and —C≡N and> C═X (X═O, S, Se, (Te, NH, NR) is a general term. Examples of the characteristic group include a carboxy group, a carbamoyl group, a cyano group, a hydroxy group, and an amino group.

  As an arbitrary substituent, the heterocyclic group mentioned above, a saturated hydrocarbon group, an unsaturated hydrocarbon group, a characteristic group, etc. are mentioned. Preferably, the substituents (1-1) to (1-43) described in item 2 above are used.

  As the lower alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) can be exemplified unless otherwise specified. 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.

  As the lower alkoxy group, a linear or branched alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) can be exemplified unless otherwise specified. More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, 1-ethylpropoxy, isopentyloxy, neopentyloxy, n -Hexyloxy, 1,2,2-trimethylpropoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, isohexyloxy, 3-methylpentyloxy group and the like are included.

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

  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 unless otherwise specified. 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 group or the like.

  Examples of the halogen-substituted lower alkoxy group include the above-described lower alkoxy groups substituted with 1 to 7, preferably 1 to 3, halogen atoms unless otherwise specified. More specifically, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro Ethoxy, pentafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropent Shi, 6,6,6 to trifluoroacetic hexyloxy, 6-chloro-hexyloxy include perfluorohexyl group and the like.

  The cyclo C3-C8 alkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group and the like unless otherwise specified.

  As the lower alkanoyl group, a straight chain or branched alkanoyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) can be exemplified unless otherwise specified. More specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group and the like are included.

  As the lower alkylthio group, a thio group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) can be exemplified unless otherwise specified. More specifically, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, 1-ethylpropylthio, isopentylthio, neopentylthio, n-hexylthio, 1,2,2-trimethylpropylthio, 3,3-dimethylbutylthio, 2-ethylbutylthio, isohexylthio, 3-methylpentylthio group and the like are included.

  Examples of the lower alkenyl group include a straight chain or branched alkenyl group having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms) having 1 to 3 double bonds unless otherwise specified. , Including both trans and cis forms. 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-yl, 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.

  As the hydroxy lower alkyl group, unless otherwise specified, the above exemplified lower alkyl group having 1 to 5, preferably 1 to 3 hydroxy groups (preferably having 1 to 6 carbon atoms (more preferably having 1 to 6 carbon atoms). 4) linear or branched alkyl groups). More specifically, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 1-hydroxyethyl, 2-hydroxypropyl, 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 groups and the like are included.

  As the lower alkylamino group, unless otherwise specified, the above-described lower alkyl group (preferably a straight chain having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms)). Or an amino group having 1 to 2 branched alkyl groups). More specifically, methylamino, dimethylamino, diethylamino, diisopropylamino groups and the like are included.

  As the lower alkyl sulfamoyl, unless otherwise specified, the above-described lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms)) is used. And a sulfamoyl group having 1 to 2 chain or branched alkyl groups). More specifically, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, ethylmethylsulfamoyl groups and the like are included.

  Examples of the tri-lower alkylsilyl group include triisopropylsilyl, tert-butyldimethylsilyl, trimethylsilyl, n-butylethylmethylsilyl, tert-butyldipropylsilyl, n-pentyldiethylsilyl, n-hexyl n-propylmethylsilyl. Examples thereof include a silyl group in which three linear or branched alkyl groups having 1 to 6 carbon atoms such as a group are substituted.

  As the tri (lower alkyl) silyloxy lower alkyl group, unless otherwise specified, the lower alkyl moiety is a straight chain having the lower alkyl group exemplified above (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms), or A tri (lower alkyl) silyloxy lower alkyl group which is a branched alkyl group). More specifically, trimethylsilyloxymethyl, 1- (or 2-) trimethylsilyloxyethyl, 1- (or 2- or 3-) trimethylsilyloxypropyl, triethylsilyloxymethyl, 1- (or 2-) triethylsilyloxy Ethyl, 1- (or 2- or 3-) triethylsilyloxypropyl, triisopropylsilyloxymethyl, 1- (or 2-) triisopropylsilyloxyethyl, 1- (or 2- or 3-) triisopropylsilyloxy A propyl group and the like are included.

  Unless otherwise specified, the phenoxy lower alkyl group is the above-described lower alkyl group having 1 to 3, preferably 1 phenoxy group (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms, More preferred examples include straight-chain or branched alkyl groups having 1 to 3 carbon atoms. More specifically, phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 2-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl, 2 -Methyl-3-phenoxypropyl, 1,1-dimethyl-2-phenoxyethyl and the like.

  As the phenyl lower alkoxy group, unless otherwise specified, the above exemplified lower alkoxy group having 1 to 3 phenyl groups, preferably 1 (preferably having 1 to 6 carbon atoms (preferably having 1 to 4 carbon atoms). And more preferably, a straight-chain or branched alkoxy group having 1 to 3 carbon atoms). More specifically, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenyl Ethoxy, 2-methyl-3-phenylpropoxy groups and the like are included.

  As the phenyl lower alkenyl group, unless otherwise specified, the lower alkenyl group exemplified above having 1 to 3 phenyl groups, preferably 1 (preferably having 2 to 6 carbon atoms (more preferably having 2 to 2 carbon atoms). (4) linear or branched alkenyl groups). More specific examples include styryl, 3-phenyl-2-propenyl (common name: cinnamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl- 3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl, 6-phenyl-1,3,5-hexatri An enyl group and the like are included.

  As the lower alkylamino lower alkyl group, a lower alkyl group having 1 to 2 lower alkylamino groups as exemplified above can be exemplified unless otherwise specified. More specifically, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, 1- (or 2-) dimethylaminoethyl, 1- (or 2- or 3-) dimethylaminopropyl, diisopropylaminomethyl, 1- ( Or 2-) diethylaminoethyl, bis (dimethylamino) methyl group and the like.

  Examples of the lower alkylamino lower alkoxy group include lower alkoxy groups having 1 to 2 lower alkylamino groups as exemplified above, unless otherwise specified. More specifically, methylaminomethoxy, ethylaminomethoxy, dimethylaminomethoxy, 1- (or 2-) dimethylaminoethoxy, 1- (or 2- or 3-) dimethylaminopropoxy, diisopropylaminomethoxy, 1- ( Or 2-) diethylaminoethoxy, bis (dimethylamino) methoxy group and the like.

  Examples of the dihydrobenzodioxinyl group include 2,3-dihydrobenzo [b] [1,4] dioxinyl, 3,4-dihydrobenzo [c] [1,2] dioxinyl group, and 2,4-dihydrobenzo [d. ] [1,3] dioxinyl and the like.

  As the imidazolyl lower alkyl group, a linear or branched lower alkyl group having 1 to 3 and preferably 1 imidazolyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). A chain alkyl group). More specifically, 1- (or 2- or 4- or 5-) imidazolylmethyl, 1- (or 2-) {1- (or 2- or 4- or 5-) imidazolyl} ethyl, 1- ( Or 2- or 3-) {1- (or 2- or 4- or 5-) imidazolyl} propyl group.

  Examples of the dihydroindenyl group include a (1-, 2-, 4-, or 5-)-1,2-dihydroindenyl group.

  As the dihydroquinolyl group, 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,4-dihydroquinolyl, 4a, 8a-dihydroquinolyl, 5,6-dihydroquinolyl, 7,8 -Dihydroquinolyl, 5,8-dihydroquinolyl group and the like are included.

  Examples of the fluorenyl group include 1H-fluorenyl, 2H-fluorenyl, 3H-fluorenyl, 4aH-fluorenyl, 5H-fluorenyl, 6H-fluorenyl, 7H-fluorenyl, 8H-fluorenyl, 8aH-fluorenyl, 9H-fluorenyl group and the like.

  Examples of the dihydrobenzofuryl group include a 2,3-dihydro- (2-, 3-, 4-, 5-, 6-, or 7-) benzofuryl group.

  The dihydrobenzooxazinyl group includes (2-, 3-, 4-, 5-, 6-, 7-, or 8-) 3,4-dihydro-2H-benzo [b] [1.4] oxazinyl. , (1-, 2-, 4-, 5-, 6-, 7-, or 8-) 2,4-dihydro-1H-benzo [d] [1.3] oxazinyl group and the like.

  Examples of the tetrahydrobenzodiazepinyl group include (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5-tetrahydro-1H- Benzo [b] [1.4] diazepinyl, (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5-tetrahydro- A 1H-benzo [e] [1.4] diazepinyl group and the like can be mentioned.

  Examples of tetrahydrobenzodiazepinyl groups include (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5-tetrahydro- 1H-benzo [b] [1.4] diazepinyl, (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-) 2,3,4,5- Tetrahydro-1H-benzo [e] [1.4] diazepinyl group and the like are included.

  Examples of the dihydrobenzodioxepinyl group include 3,4-dihydro-2H-1,5-benzodioxepinyl, 4,5-dihydro-3H-1,2-benzodioxepinyl, 3,5- Dihydro-2H-1,4-benzodioxepinyl and the like are included.

  The pyrrolidinyl group which may have an oxo group includes a pyrrolidinyl group which may have 1 to 2 (preferably 1) oxo groups unless otherwise specified. More specifically, (1-, 2-, or 3-) pyrrolidinyl, (2- or 3-) oxo-1-pyrrolidinyl, (3-, 4-, or 5-) oxo-2-pyrrolidinyl, ( 2-, 4-, or 5-) oxo-3-pyrrolidinyl groups are included.

  As the oxadiazolyl group which may have a lower alkyl group, unless otherwise specified, an oxadiazolyl group which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above is mentioned. it can. More specifically, 5-methyl-1,3,4-oxadiazolyl, 5-ethyl-1,3,4-oxadiazolyl, 5-propyl-1,3,4-oxadiazolyl, 5-butyl-1,3,3 4-oxadiazolyl, 5-pentyl-1,3,4-oxadiazolyl, 5-hexyl-1,3,4-oxadiazolyl group and the like are included.

  Examples of the pyrazolyl group which may have a lower alkyl group include, unless otherwise specified, the pyrazolyl group which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above. it can. More specifically, 1-methyl-1H-pyrazolyl, 1-ethyl-1H-pyrazolyl, 1-propyl-1H-pyrazolyl, 1-isopropyl-1H-pyrazolyl, 1-butyl-1H-pyrazolyl, 1-tert- A butyl-1H-pyrazolyl, 1,3-dimethyl-1H-pyrazolyl group and the like are included.

  As the thiazolyl group which may have a lower alkyl group, unless otherwise specified, a thiazolyl group which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above is mentioned. it can. More specifically, 2-methylthiazolyl, 2-ethylthiazolyl, 2-propylthiazolyl, 2-isopropylthiazolyl, 2-butylthiazolyl, 2-tertbutylthiazolyl, 2,5-dimethylthiazolyl group and the like are included. .

  As the pyrimidyl group which may have a lower alkyl group, unless otherwise specified, a pyrimidyl group which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above is mentioned. it can. More specifically, 2-methyltipyrimidyl, 2-ethylpyrimidyl, 2-propylpyrimidyl, 2-isopropylpyrimidyl, 2-butylpyrimidyl, 2-tertbutylpyrimidyl, 2,4-dimethylpyrimidyl group, etc. Is included.

  As the pyridazinyl group which may have a lower alkyl group, unless otherwise specified, a pyridazinyl group which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above is mentioned. it can. More specifically, 3-methyltipyridazinyl, 3-ethylpyridazinyl, 3-propylpyridazinyl, 3-isopropylpyridazinyl, 3-butylpyridazinyl, 3-tertpyridazinyl 3,4-dimethylpyridazinyl group and the like.

  As the pyridazinyloxy group which may have a lower alkyl group, unless otherwise specified, pyridazinyl which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above is Mention may be made of substituted oxy groups. More specifically, 6-methylpyridazinyl-3-yloxy, 4-methylpyridazinyl-3-yloxy and the like are included.

  As the pyrrolidinyl lower alkoxy group, unless otherwise specified, the above-exemplified lower alkoxy group having 1 to 3, preferably 1 pyrrolidinyl group (preferably having 1 to 6 carbon atoms (more preferably, having 1 carbon atom). -4, and more preferably a linear or branched alkoxy group having 1 to 3 carbon atoms). Specific examples thereof include (1-, 2- or 3-) pyrrolidinylmethoxy, 2-[(1-, 2- or 3-) pyrrolidinyl] ethoxy, 1-[(1-, 2- or 3- ) Pyrrolidinyl] ethoxy, 3-[(1-, 2- or 3-) pyrrolidinyl] propoxy, 4-[(1-, 2- or 3-) pyrrolidinyl] butoxy, 5-[(1-, 2- or 3) -) Pyrrolidinyl] pentyloxy, 6-[(1-, 2- or 3-) pyrrolidinyl] hexyloxy, 1,1-dimethyl-2-[(1-, 2- or 3-) pyrrolidinyl] ethoxy, 2- A methyl-3-[(1-, 2- or 3-) pyrrolidinyl] propoxy group and the like are included.

  Protecting groups include substituted or unsubstituted lower alkanoyl (eg formyl, acetyl, propionyl, trifluoroacetyl, etc.), phthaloyl, lower alkoxycarbonyl (eg, tertiary butoxycarbonyl, tertiary amyloxycarbonyl, etc.), substituted or unsubstituted. Substituted aralkyloxycarbonyl (eg benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl (eg benzenesulfonyl, tosyl etc.), nitrophenylsulfenyl, aralkyl (eg Common protecting groups such as trityl, benzyl, etc.] and lower alkylsilyl groups [eg triisopropylsilyl, etc.].

  As the phenyl lower alkyl group, unless otherwise specified, the above exemplified lower alkyl group having 1 to 3, preferably 1 phenyl group (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms)). Straight chain or branched chain alkyl group). More specifically, benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl group and the like can be mentioned.

  Examples of the morpholinyl lower alkyl group include the lower alkyl groups exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) morpholyl groups. it can. More specifically, 2-morpholinylmethyl, 3-morpholinylmethyl, 4-morpholinylmethyl, 2- (2-morpholinyl) ethyl, 2- (3-morpholinyl) ethyl, 2- (4- Morpholinyl) ethyl, 1- (2-morpholinyl) ethyl, 1- (3-morpholinyl) ethyl, 1- (4-morpholinyl) ethyl, 3- (2-morpholinyl) propyl, 3- (3-morpholinyl) propyl, 3 -(4-morpholinyl) propyl, 4- (2-morpholinyl) butyl, 4- (3-morpholinyl) butyl, 4- (4-morpholinyl) butyl, 5- (2-morpholinyl) pentyl, 5- (3-morpholinyl) ) Pentyl, 5- (4-morpholinyl) pentyl, 6- (2-morpholinyl) hexyl, 6- (3-morpholinyl) hexyl, 6- (4-morpholinyl) L) hexyl, 3-methyl-3- (2-morpholinyl) propyl, 3-methyl-3- (3-morpholinyl) propyl, 3-methyl-3- (4-morpholinyl) propyl, 1,1-dimethyl-2 -(2-morpholinyl) ethyl, 1,1-dimethyl-2- (3-morpholinyl) ethyl, 1,1-dimethyl-2- (4-morpholinyl) ethyl group and the like are included.

  Examples of the pyrrolidinyl lower alkyl group include the lower alkyl groups exemplified above having 1 to 3 (preferably 1) pyrrolidinyl groups. More specifically, (1-, 2- or 3-) pyrrolidinylmethyl, 2-[(1-, 2- or 3-) pyrrolidinyl] ethyl, 1-[(1-, 2- or 3- ) Pyrrolidinyl] ethyl, 3-[(1-, 2- or 3-) pyrrolidinyl] propyl, 4-[(1-, 2- or 3-) pyrrolidinyl] butyl, 5-[(1-, 2- or 3) -) Pyrrolidinyl] pentyl, 6-[(1-, 2- or 3-) pyrrolidinyl] hexyl, 1,1-dimethyl-2-[(1-, 2- or 3-) pyrrolidinyl] ethyl, 2-methyl- 3-[(1-, 2- or 3-) pyrrolidinyl] propyl group and the like can be mentioned.

  Examples of the piperidyl lower alkyl group include the lower alkyl groups exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) piperidyl groups. it can. More specifically, for example, (1-, 2-, 3- or 4-) piperidylmethyl, 2-[(1-, 2-, 3- or 4-) piperidyl] ethyl, 1-[(1- 2-, 3- or 4-) piperidyl] ethyl, 3-[(1-, 2-, 3- or 4-) piperidyl] propyl, 4-[(1-, 2-, 3- or 4-) Piperidyl] butyl, 1,1-dimethyl-2-[(1-, 2-, 3- or 4-) piperidyl] ethyl, 5-[(1-, 2-, 3- or 4-) piperidyl] pentyl, 6-[(1-, 2-, 3- or 4-) piperidyl] hexyl, 1-[(1-, 2-, 3- or 4-) piperidyl] isopropyl, 2-methyl-3-[(1- , 2-, 3- or 4-) piperidyl] propyl group and the like.

  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 piperazinyl group which may have a lower alkyl group include piperazinyl groups which may have 1-2 (preferably 1) of the lower alkyl groups exemplified above, unless otherwise specified. it can. More specifically, 2-methylpiperazinyl, 4-methylpiperazinyl, 2-ethylpiperazinyl, 2-propylpiperazinyl, 2-isopropylpiperazinyl, 2-butylpiperazinyl, 2- tertbutylpiperazinyl, 2,4-dimethylpiperazinyl group and the like are included.

  As the piperazinyl lower alkyl group optionally having a lower alkyl group, unless otherwise specified, the piperazinyl lower alkyl group optionally having 1-2 (preferably 1) of the lower alkyl groups exemplified above Can be mentioned. More specifically, 1- (4-methylpiperazinyl) methyl, 1- (2-methylpiperazinyl) methyl, 2- (1-methylpiperazinyl) ethyl, 3- (1-methylpiperazinyl) ) Propyl, 4- (1-methylpiperazinyl) butyl and the like.

  Examples of the phenyl group which may have a lower alkoxy group include a phenyl group which may have 1-2 (preferably 1) of the lower alkoxy groups exemplified above, unless otherwise specified. it can. More specifically, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropylphenyl, 4-butoxyphenyl, 4-tertbutoxyphenyl and the like are included. As a phenoxy group which may have a halogen atom, a phenoxy group which may have 1 to 4 (preferably 1) of the above exemplified halogen atoms can be exemplified unless otherwise specified. More specifically, 4-fluorophenoxy, 3,4-difluorophenoxy, 3,4,5-trifluorophenoxy, 3-chloro-4,5-difluorophenoxy and the like are included.

  Examples of the tetrahydroquinolyl group include 1,2,3,4-tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 4a, 5,8,8a-tetrahydroquinolyl, 3,4,4a. , 8a-tetrahydroquinolyl, 4a, 5,8,8a-tetrahydroquinolyl, 4a, 5,6,7-tetrahydroquinolyl and the like.

Examples of the dihydroacenaphthylenyl group include 1,2-dihydroacenaphthylenyl, 2a ¹ , 3-dihydroacenaphthylenyl, 5,6-dihydroacenaphthylenyl, and 3,7-dihydroacenaphthyl. Renyl, 2a ¹ , 6-dihydroacenaphthylenyl, 1,2a ¹ -dihydroacenaphthylenyl, 6,8a-dihydroacenaphthylenyl and the like can be mentioned. More preferably, a 1,2-dihydroacenaphthylenyl group is mentioned.

  Examples of the tetrahydronaphthyl group include 1,2,3,4-tetrahydronaphthyl, 1,2,3,5-tetrahydronaphthyl, 5,6,7,8-tetrahydronaphthyl, 2,3,7,8-tetrahydro. And naphthyl.

  Examples of the dihydroquinazolinyl group include 1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl, 4a, 5-dihydroquinazolinyl, 5,6-dihydroquinazolinyl, 6,7- Examples include dihydroquinazolinyl, 7,8-dihydroquinazolinyl, 8,8a-dihydroquinazolinyl, 4a, 8a-dihydroquinazolinyl and the like.

  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.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ、ｌ、ｍ及びｎは前記と同じであり、Ｘ_１は、脱離基を示す。］ Reaction Formula-1

[Wherein, R ¹ , R ² , R ³ , R ⁴ , X, l, m and n are the same as defined above, and X ₁ represents a leaving group. ]

In the general formula (3), examples of the leaving group represented by X ₁ include a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, a trihalomethanesulfonyloxy group, a sulfonio group, and toluenesulfoxy. Examples include groups. A preferable leaving group in this reaction includes a halogen atom.

Examples of the halogen atom represented by X ₁ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

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

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. Mention may be made of phenylsulfonyloxy, naphthylsulfonyloxy groups and the like which may have 1 to 3 groups selected from the group consisting of alkoxy groups, nitro groups and halogen atoms. Specific examples of the phenylsulfonyloxy group which may have a 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, β-naphthylmethylsulfonyloxy groups and the like.

Specific examples of the perhaloalkanesulfonyloxy group represented by X ₁ include a trifluoromethanesulfonyloxy group.

Specific examples of the sulfonio group represented by X ₁ include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di (2-cyanoethyl) sulfonio, di (2-nitroethyl) sulfonio, and di- (aminoethyl). Sulfonio, di (2-methylaminoethyl) sulfonio, di- (2-dimethylaminoethyl) sulfonio, di- (2-hydroxyethyl) sulfonio, di- (3-hydroxypropyl) sulfonio, di- (2-methoxyethyl) ) Sulfonio, di- (2-carbamoylethyl) sulfonio, di- (2-carbamoylethyl) sulfonio, di- (2-carboxyethyl) sulfonio, di- (2-methoxycarbonylethyl) sulfonio or diphenylsulfonio group Can be mentioned.

  The compound represented by the general formula (2) and the compound represented by the general formula (3) are reacted in a solvent-free or inert solvent in the presence or absence of a basic compound and in the presence of a palladium catalyst. Compound (1) can be produced.

  Examples of the inert solvent include water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; Lower alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone and methyl ethyl ketone; polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile be able to. These inert solvents are used individually by 1 type or in mixture of 2 or more types.

  Although it does not specifically limit as a palladium compound used in this reaction, For example, tetravalent palladium catalysts, such as sodium hexachloro palladium (IV) acid tetrahydrate and potassium hexachloro palladium (IV); II), palladium (II) bromide, palladium (II) acetate, palladium acetylacetonate (II), dichlorobis (benzonitrile) palladium (II), dichlorobis (acetonitrile) palladium (II), dichlorobis (triphenylphosphine) palladium (II), dichlorotetraamminepalladium (II), dichloro (cycloocta-1,5-diene) palladium (II), palladium trifluoroacetate (II), 1,1′-bis (diphenylphosphino) ferrocene Divalent palladium catalysts such as olopalladium (II) -dichloromethane complex; tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) dipalladium chloroform complex (0), tetrakis (triphenylphosphine) palladium ( And 0) palladium catalysts such as 0). These palladium compounds are used individually by 1 type or in mixture of 2 or more types.

  In this reaction, the amount of the palladium catalyst used is not particularly limited, but is usually in the range of 0.000001 to 20 mol in terms of palladium with respect to 1 mol of the compound of the general formula (2). The more preferable usage-amount of a palladium compound is the range of 0.0001-5 mol in conversion of palladium with respect to 1 mol of compounds of General formula (2).

  This reaction proceeds advantageously in the presence of an appropriate ligand. Examples of the ligand of the palladium catalyst include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tri-o-tolylphosphine, bis (diphenylphosphino) ferrocene, triphenylphosphine, Tri-t-butylphosphine, tri-cyclohexylphosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (XANTPHOS), or the like can be used. These ligands are used alone or in combination of two or more.

  Further, in the present invention, the tertiary phosphines may be added after adjusting to a complex form in advance. Examples of the complex include tri-t-butylphosphonium tetrafluoroborate and tri-t-butylphosphonium tetraphenylborate.

  The usage ratio of the palladium catalyst and the ligand is not particularly limited. The amount of the ligand used is about 0.1 to 100 mol, preferably about 0.5 to 15 mol, per 1 mol of the palladium catalyst.

  As the basic compound, known inorganic bases and organic bases can be widely used.

  Examples of the inorganic base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; hydrogen carbonate Alkali metal hydrogen carbonates such as lithium, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metals such as sodium and potassium; Phosphate salts such as sodium phosphate and potassium phosphate; Amides such as sodium amide; Sodium hydride and hydrogenated Examples thereof include alkali metal hydrides such as potassium.

  Examples of organic bases include alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide; 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. And amines such as 4.0] undecene-7 (DBU) and 1,4-diazabicyclo [2.2.2] octane (DABCO).

  These basic compounds are used individually by 1 type or in mixture of 2 or more types. More preferably, the basic compound used in this reaction includes sodium carbonate, potassium carbonate, cesium carbonate, alkali metal carbonates such as lithium carbonate, sodium t-butoxide and the like.

  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 usage 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 set to at least equimolar, preferably equimolar to 5-fold molar, with respect to the former. .

  This reaction can be performed under normal pressure, under an inert gas atmosphere such as nitrogen or argon, or under pressure.

  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. It can also be achieved by heating at 100 to 200 ° C. for 5 minutes to 1 hour using a microwave reactor.

  After completion of the reaction, the desired compound can be obtained by treatment according to a conventional method.

  The compound represented by the general formula (2) used as a starting material in the above reaction formula-1 is produced from a known compound by, for example, the methods shown in the following reaction formula-3 and reaction formula-4. In addition, about the compound shown by General formula (3), it is a well-known well-known compound or a compound easily manufactured by a well-known method.

［式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ、ｌ、ｍ及びｎは前記と同じであり、Ｒ^１ａは、保護基を示す。］ Reaction formula-2

[Wherein, R ² , R ³ , R ⁴ , X, l, m and n are the same as described above, and R ^1a represents a protecting group. ]

Examples of the protecting group include the protecting groups shown above.
The compound represented by the general formula (1b) can be produced by subjecting the compound represented by the general formula (1a) to a protecting group elimination reaction.

  Conventional methods such as hydrolysis and hydrogenolysis can be applied to the elimination reaction of the protecting group.

  This reaction is usually performed in a conventional solvent that does not adversely influence the reaction. Examples of the solvent include water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme. Ether solvents such as methyl acetate and ethyl acetate; Aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone; Halogenation such as methylene chloride and ethylene chloride Hydrocarbon solvents; or other organic solvents.

(I) Hydrolysis:

  The hydrolysis is preferably carried out in the presence of a base or acid (including a Lewis acid).

  As the base, known inorganic bases and organic bases can be widely used. Suitable inorganic bases include, for example, alkali metals (for example, sodium, potassium, etc.), alkaline earth metals (for example, magnesium, calcium, etc.), their hydroxides, carbonates or bicarbonates. Suitable organic bases include, for example, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo [4,3,0] non-5-ene and the like.

  As the acid, known organic acids and inorganic acids can be widely used. Suitable organic acids include, for example, fatty acids such as formic acid, acetic acid, and propionic acid; trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid. Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and the like. Examples of the Lewis acid include boron trifluoride ether complex, boron tribromide, aluminum chloride, ferric chloride and the like.

  When trihaloacetic acid or Lewis acid is used as the acid, it is preferably carried out in the presence of a cation scavenger (for example, anisole or phenol).

  The amount of the base or acid used is not particularly limited as long as it is an amount necessary for hydrolysis.

  The reaction temperature is generally 0 to 120 ° C, preferably room temperature to 100 ° C, more preferably room temperature to 80 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 12 hours, more preferably 1 to 8 hours.

(Ii) Hydrocracking:
For hydrocracking, known hydrocracking methods can be widely applied. Examples of such hydrocracking methods include chemical reduction and catalytic reduction.

  Suitable reducing agents used for chemical reduction are hydrides (eg hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or metals (eg tin, zinc, iron etc.) ) Or a metal compound (eg, chromium chloride, chromium acetate, etc.) and an organic acid or inorganic acid (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) is there.

  Suitable catalysts used for catalytic reduction are platinum catalysts (eg, platinum plate, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg, sponge palladium, palladium black, palladium oxide). , Palladium carbon, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney cobalt, etc.), iron catalyst (eg, reduced iron, etc.) Etc.

  In addition, when said acid used for chemical reduction is a liquid, they can also be used as a solvent.

  The amount of the reducing agent used for the chemical reduction and the amount of the catalyst used for the catalytic reduction is not particularly limited, and may be a normal amount.

  The present invention can be carried out under normal pressure, under an inert gas atmosphere such as nitrogen or argon, or under pressure.

  The reaction temperature is generally 0 to 120 ° C, preferably room temperature to 100 ° C, more preferably room temperature to 80 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.

  After completion of the reaction, the desired compound (1b) can be obtained by treatment according to a conventional method.

  Furthermore, the deprotection reaction of the protecting group is not limited to the above reaction conditions. W. Green, P.M. G. M.M. Wuts' "Protective Groups in Organic Synthesis", 4th edition, John Wiley &Sons; New York, 1991, P.M. The reaction described in 309 can also be applied to this reaction step.

  The compound represented by the general formula (2) is a novel compound, and as described above, is a compound useful as an intermediate of the compound represented by the compound (1).

  The compound of General formula (2) is manufactured according to the method of following Reaction Formula-3, following Reaction Formula-4, or following Reaction Formula-5, for example.

  Hereinafter, each reaction formula will be described.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、ｌ、ｍ及びｎは前記と同様］ Reaction formula-3

[Wherein R ¹ , R ² , R ³ , X, l, m and n are the same as above]

Reaction formula-3
The compound represented by the general formula (2a) is a compound represented by the general formula (6) by a cyclization reaction between the compound represented by the general formula (4) and the compound represented by the general formula (5). After formation (step A), it is manufactured by reduction (step B).

Process A
The compound represented by the general formula (2a) is obtained by combining the compound represented by the general formula (4) and the compound represented by the general formula (5) in a solvent-free or inert solvent in the presence of a base or non- It can be carried out in the presence.

  Examples of the inert solvent include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl 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-dimethylformimide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile.

  As the basic compound, known compounds can be widely used. For example, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate Alkali metal carbonates such as sodium, potassium, etc .; inorganic bases such as sodium amide, sodium hydride and potassium hydride, and alkali metals such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide Alcoholates; triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazacyclo [ .3.0] Nonene-5 (DBN), 1,8 diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) and other organic bases Can be mentioned.

  These basic compounds are used alone or in combination of two or more.

  The usage-amount of a basic compound is 0.5-10 times mole normally with respect to the compound of General formula (4), Preferably it is 0.5-6 times mole.

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

  The use ratio of the compound of general formula (4) and the compound of general formula (5) in the above reaction formula is usually at least 0.5 times mol, preferably about 0.5 to 5 times mol of the latter with respect to the former. Good.

  The present invention can be carried out under normal pressure, under an inert gas atmosphere such as nitrogen or argon, or under pressure.

  The above reaction is usually performed under a temperature condition of 0 ° C to 200 ° C, preferably room temperature to 150 ° C, and is generally completed in about 1 to 30 hours.

  In the first step, the compound of the general formula (4) and the compound of the general formula (6) used as starting materials are known compounds that are easily available or are easily produced by known methods. A compound.

Process B
The compound represented by the general formula (2a) can be produced by subjecting the compound represented by the general formula (6) to a reduction reaction in a solvent-free or inert solvent.

  Examples of such a reduction method include chemical reduction and catalytic reduction.

  Examples of the inert solvent include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl 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-dimethylformimide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile.

  Suitable reducing agents used for chemical reduction are hydrides (eg, hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, borohydride, sodium borohydride, sodium cyanoborohydride, etc.) or metals (eg, tin, Zinc, iron, etc.) or metal compounds (eg, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) In combination.

  Suitable catalysts used for catalytic reduction are platinum catalysts (eg, platinum plate, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg, sponge palladium, palladium black, palladium oxide). , Palladium carbon, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney cobalt, etc.), iron catalyst (eg, reduced iron, etc.) Etc.

  In addition, when said acid used for chemical reduction is a liquid, they can also be used as a solvent.

  The amount of the reducing agent used for the chemical reduction and the amount of the catalyst used for the catalytic reduction is not particularly limited, and may be a normal amount.

  The present invention can be carried out under normal pressure, under an inert gas atmosphere such as nitrogen or argon, or under pressure.

  The reaction temperature is generally 0 to 120 ° C, preferably room temperature to 100 ° C, more preferably room temperature to 80 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours, more preferably 30 minutes to 4 hours.

  After completion of the reaction, the desired compound (2a) can be obtained by treatment according to a conventional method.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、ｌ、ｍ及びｎは前記と同様］ Reaction formula-4

[Wherein R ¹ , R ² , R ³ , X, l, m and n are the same as above]

  The compound represented by the general formula (2b) is obtained by converting the compound represented by the general formula (8) by the cyclization reaction between the compound represented by the general formula (4) and the compound represented by the general formula (7). After formation (step C), it is manufactured by reduction (step D). The reaction conditions are the same as the reaction formula-3.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、ｌ、ｍ、ｎ及びＸは前記と同じであり、Ｙ及びＺは同一又は異なって、それぞれ独立して脱離基を示す。］ Reaction formula-5

[Wherein R ¹ , R ² , R ³ , R ⁴ , l, m, n and X are the same as described above, and Y and Z are the same or different and each independently represent a leaving group. ]

  In the general formula (9), examples of the leaving group represented by Y and Z include the leaving groups shown above.

Process E
The compound represented by the general formula (2) can be produced by subjecting the compound represented by the general formula (4) and the compound represented by the general formula (9) to a cyclization reaction. The cyclization reaction is usually performed in the presence or absence of a basic compound.

  This reaction is usually performed in a conventional solvent that does not adversely influence the reaction. Examples of the solvent include water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme. Ether solvents such as methyl acetate and ethyl acetate; Aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone; Halogenation such as methylene chloride and ethylene chloride Hydrocarbon solvents; or other organic solvents.

In this reaction, a transition metal catalyst and a ligand may be used. Examples of transition catalysts include ruthenium chloride, dichlorotristriphenylphosphine ruthenium, dibromotristriphenylphosphine ruthenium, dihydridotetrakistriphenylphosphine ruthenium, (η ⁴ -cyclooctadiene) (η ⁶ -cyclooctatriene) ruthenium, dichlorotri Carbonyl ruthenium dimer, dodecacarbonyl triruthenium, (η ⁵ -pentamethylcyclopentadienyl) chloro (η ⁴ -cyclooctatriene) ruthenium, palladium acetate, palladium chloride, dichlorobistriphenylphosphine palladium, tetrakistriphenylphosphine palladium, bis Dibenzylideneacetone palladium, rhodium chloride, chlorotristriphenylphosphine rhodium, hydridocarbonyl tristri Phenylphosphine rhodium, hydridotristriphenylphosphine rhodium, di-μ-chlorotetracarbonyl dirhodium, chlorocarbonylbistriphenylphosphine iridium, (η ⁵ -pentamethylcyclopentadienyl) dichloroiridium dimer, nickel tetrakistriphenylphosphine, di Examples include cobalt octacarbonyl, (η ⁵ -cyclopentadienyl) dicarbonylcobalt, and the like.

  Examples of the ligand include trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tri-i-propylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tri (o-tolyl). ) Monodentate phosphine ligand represented by phosphine, 1,2-bisdiphenylphosphinoethane, 1,3-bisdiphenylphosphinopropane, 1,4-bisdiphenylphosphinobutane, 1,2-diethylphosphino Examples thereof include bidentate phosphine ligands represented by ethane, triethyl phosphite, tributyl phosphite, triphenyl phosphite, and phosphite ligands represented by tri (o-tolyl) phosphite.

  This reaction may be performed in the presence of a base. As the base, known inorganic bases and organic bases can be widely used. Examples of the inorganic base include alkali metals (for example, sodium, potassium, etc.), alkali hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide) Sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (eg, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, etc.) ), Alkali metal hydrides (for example, sodium hydride, potassium hydride, etc.). Examples of the organic base include trialkylamine (for example, trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5 -Diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undeca-7 -En (DBU) etc. are mentioned. Moreover, when these bases are liquid, they can also be used as a solvent. These bases are used individually by 1 type or in mixture of 2 or more types. The amount of the base to be used is generally 0.1 to 10 mol, preferably 0.1 to 3 mol, per 1 mol of compound (7).

  In addition, the above reaction can also be performed under mixing with an oxidizing agent and a reducing agent.

  Examples of the oxidizing agent include manganese dioxide, chromic acid, lead tetraacetate, silver oxide, copper oxide, halogen acid, dimethyl sulfoxide (Swern oxidation), organic peracid, oxygen, and the like, and examples include a method using electrode oxidation. It is done.

  Examples of the reducing agent include borohydride reagents such as sodium borohydride, aluminum hydride reagents such as lithium aluminum hydride, and the like.

  The ratio of the compound (9) and the compound (12) used in the above reaction formula is usually at least 1 mol, preferably about 1 to 5 mol, with respect to 1 mol of the latter.

  The present invention can be carried out under normal pressure, under an inert gas atmosphere such as nitrogen or argon, or under pressure.

  The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. Preferably, the reaction is performed at room temperature to 100 ° C. for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

  After completion of the reaction, the desired compound (2) can be obtained by treatment according to a conventional method.

  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; formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, apple Examples thereof include salts of organic acids such as acid salts, citrate salts, tartrate salts, carbonate salts, picrate salts, methanesulfonate salts, ethanesulfonate salts, p-toluenesulfonate salts, and glutamate salts.

  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.

  Various isomers can be isolated by conventional methods utilizing the difference in physicochemical properties between isomers. For example, racemates can be converted into sterically pure isomers by a general optical resolution method [for example, a method for optical resolution by diastereomeric salts with general optically active acids (tartaric acid, etc.)]. Can do. The mixture of diastereomers can be separated by, for example, fractional crystallization or chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

The present invention also provides the same isotope as the compound represented by the general formula (1) except that one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Also includes body labeled compounds. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F, ³⁶ Cl, respectively. Oxygen, sulfur, fluorine, and chlorine isotopes. Specific isotope-labeled compounds of the invention containing the above isotopes and / or other isotopes of other atoms, for example, compounds incorporating radioactive isotopes such as ³ H and ¹⁴ C, Useful in drug tissue distribution assays and / or matrix tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (ie, ² H) provides certain therapeutic benefits resulting from improved metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. I can expect that. The isotope-labeled compounds of the present invention are generally obtained by substituting non-isotopically labeled reagents with readily available isotope-labeled reagents by the methods disclosed in the above reaction schemes and / or examples below. Can be prepared.

  A medical preparation containing the compound of the present invention as an active ingredient will be described.

  The above-mentioned medical preparation is prepared by formulating the compound of the present invention in the form of a normal medical preparation, and is usually used as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, and a lubricant. Etc. and are prepared using diluents and / or excipients.

  Such a medical preparation can be selected from various forms according to the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules. Suppositories, suppositories, injections (solutions, suspensions, etc.) and the like.

  A wide variety of known carriers can be used as the carrier used for molding into tablets. For example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and the like can be used. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, white sugar, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors, Class Absorption accelerators such as monium base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol And the like.

  Furthermore, the tablets can be coated with a normal coating material as necessary, and can be, for example, sugar coatings, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  As a carrier used for forming into a pill form, a known carrier can be widely used. For example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, Arabic Examples thereof include binders such as rubber powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.

  As the carrier used for molding into a suppository, a wide variety of known ones can be used. For example, polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like. Can be mentioned.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. As the diluent used for forming these liquids, emulsions and suspensions, known ones can be widely used, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxy Isostearyl alcohol, polyoxyethylene sorbetane fatty acid esters and the like. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizer, buffer, soothing agent, etc. If necessary, colorants, preservatives, fragrances, flavors, sweeteners, and / or other pharmaceuticals may be included.

  The amount of the compound of the present invention contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range. Usually, the compound of the present invention is contained in an amount of about 1 to 70% by weight in the medical preparation. preferable.

  There is no restriction | limiting in particular as the administration method of the medical formulation which concerns on this invention, It administers by the method according to various formulation forms, a patient's age, sex, a disease state, and other conditions. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of injections, they are administered alone or mixed with normal fluids such as glucose and amino acids, and administered intravenously, or as needed, intramuscularly, intradermally, subcutaneously or intraperitoneally. Can be administered. In the case of a suppository, it is administered intrarectally.

  The dosage of the above-mentioned medical preparation may be appropriately selected according to usage, patient age, sex, disease level, and other conditions, and is usually about 0.001 to 100 mg per 1 kg body weight per day, preferably Is administered in an amount of about 0.001 to 50 mg divided into 1 to several times.

  Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage exceeding the above range may be necessary.

  The heterocyclic compound of the present invention has a reuptake inhibitory action of one, two or three monoamines (serotonin, norepinephrine, dopamine).

  The heterocyclic compound of the present invention is incorporated in an in vitro test for any one of the three types of monoamines, or any two, or all of the monoamines, as compared with existing compounds having monoamine uptake inhibition activity. The inhibitory activity or the uptake inhibitory activity in the Ex vivo test is remarkably strong. In addition, in the microdialysis study, the heterocyclic compound of the present invention is one or three of the three types of monoamines as compared with existing compounds having monoamine uptake inhibitory activity. Or significantly increased activity against all monoamine increases.

  The heterocyclic compound of the present invention has a broad therapeutic spectrum compared to known antidepressants.

  The heterocyclic compound of the present invention exhibits a sufficient therapeutic effect even when administered for a short period of time.

  The heterocyclic compound of the present invention has excellent bioavailability, weak metabolic enzyme inhibitory activity in the liver, few side effects, and excellent safety.

  The heterocyclic compound of the present invention is excellent in brain migration.

  The heterocyclic compound of the present invention also exhibits strong activity in the mouse forced swimming test used for screening for depression. In addition, the heterocyclic compound of the present invention expresses a strong activity in the rat forced swimming test used for screening for depression. In addition, the heterocyclic compound of the present invention expresses a strong activity in a reserpine-induced hypothermia test used for screening for depression.

  The heterocyclic compound of the present invention expresses strong activity in the mouse marble filling behavior test and the fear conditioning stress model, which are anxiety or stress disease models.

  Since the heterocyclic compound of the present invention has an action of inhibiting reuptake of one, two or three monoamines (serotonin, norepinephrine, dopamine), it is associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine. It is effective in the treatment of various disorders.

  Such disorders include hypertension, depression (eg, major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood modulation disorder; rapid cycler; atypical depression; seasonal feelings Disorders; postpartum depression; mild depression; recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing syndrome, hypothyroidism , Hyperparathyroidism, Addison's disease, amenorrhea / milk secretion syndrome, Parkinson's disease, Alzheimer's disease, cerebral hemorrhage, diabetes, chronic fatigue syndrome, depression associated with various body diseases such as cancer; middle-aged depression; Geriatric depression; childhood / pubertal depression; drug-induced depression such as interferon; depression associated with adaptation disorder; anxiety due to adaptation disorder; anxiety associated with various diseases [eg neuropathy (head Wounds, brain infections and inner ear disorders); cardiovascular disorders (heart failure, arrhythmia); endocrine disorders (adrenal hyperactivity, hyperthyroidism); respiratory disorders (asthma, chronic obstructive pulmonary disease)], generality Anxiety disorder, fear (eg, agoraphobia, social phobia and simple phobia), post-traumatic stress syndrome, acute stress syndrome, avoidance personality disorder, body deformity disorder, premature ejaculation, eating disorder (eg Anorexia and anorexia), obesity, chemical dependence (eg, addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive Sexual disorder, panic disorder, memory disorder (eg dementia, amnestic disorder and age-related cognitive decline (ARCD)), Parkinson's disease (eg Parkinson's disease) Dementia, neuroleptic-induced parkinsonism and late-onset dyskinesia), endocrine disorders (eg, hyperprolactinemia), vasospasm (especially in the cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (motor and secretion) ), Negative syndrome of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, tension urinary incontinence, Toulette syndrome, hair loss, stealing, male impotence, attention deficit hyperactivity disorder (ADHD), chronic seizure This includes sexual migraine, chronic fatigue, weakness, sleep apnea syndrome and headache (related to vascular disorders).

光学活性体

Hereinafter, the present invention will be further clarified with reference examples, examples and pharmacological tests. The chemical structures of the racemate and optically active substance are expressed as follows, for example.
Racemic body

Optically active substance

の製造
シス−シクロペンタン−１，２−ジアミン（９．８８ｇ，９８．６ｍｍｏｌ）の水（１００ｍＬ）溶液に、９０％アセトンシアンヒドリン（９．７９ｇ，１０４ｍｍｏｌ）を室温下加え、１６時間還流下攪拌した。反応混合物から溶媒を減圧除去し、エタノール共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール＝１／１０）で精製し、白色粉末のシス−３，３−ジメチルオクタヒドロシクロペンタピラジン−２−オンを得た（５．００ｇ，３０％）。
¹H-NMR（CDCl₃）δppm : 1.20（1 H，brs)，1.34（3 H，s)，1.39(3 H，s)，1.40-2.20（6 H，m)，3.50-3.70（2 H，m)，5.89（1 H，brs). [Reference Example 1] cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one

To a solution of cis-cyclopentane-1,2-diamine (9.88 g, 98.6 mmol) in water (100 mL), 90% acetone cyanohydrin (9.79 g, 104 mmol) was added at room temperature and refluxed for 16 hours. Stirred under. The solvent was removed from the reaction mixture under reduced pressure and azeotroped with ethanol. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol = 1/10) to obtain cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one as a white powder (5.00 g, 30%).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.20 (1 H, brs), 1.34 (3 H, s), 1.39 (3 H, s), 1.40-2.20 (6 H, m), 3.50-3.70 (2 H , M), 5.89 (1 H, brs).

  The compounds of Reference Examples 2 to 12 below were produced in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR（CDCl₃）δppm : 1.26-1.55（9 H，m)，1.75-2.00（4 H，m)，2.85-3.02（1 H，m)，3.05-3.20（1 H，m)，6.02（1 H，brs). [Reference Example 2] trans-3,3-dimethyloctahydrocyclopentapyrazin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.26-1.55 (9 H, m), 1.75-2.00 (4 H, m), 2.85-3.02 (1 H, m), 3.05-3.20 (1 H, m), 6.02 (1 H, brs).

¹H-NMR（CDCl₃）δppm : 1.37（3H，s)，1.40（3H，s)，1.50-1.85（1H，br)，3.73-4.10（6H，m)，6.02-6.22（1H，br). [Reference Example 3] Cis-3,3-dimethylhexahydrofuro [3,4-b] pyrazin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.37 (3H, s), 1.40 (3H, s), 1.50-1.85 (1H, br), 3.73-4.10 (6H, m), 6.02-6.22 (1H, br) .

¹H-NMR（CDCl₃）δppm : 1.38-1.43（1H，br)，1.44（3H，s)，1.47（3H，s)，3.38-3.52（1H，m)，3.52-3.65（3H，m)，4.00-4.14（2H，m)，6.28-6.45（1H，br). [Reference Example 4] trans-3,3-dimethylhexahydrofuro [3,4-b] pyrazin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.38-1.43 (1H, br), 1.44 (3H, s), 1.47 (3H, s), 3.38-3.52 (1H, m), 3.52-3.65 (3H, m) , 4.00-4.14 (2H, m), 6.28-6.45 (1H, br).

¹H-NMR（CDCl₃）δppm : 1.14-1.43（6H，m)，1.38（3H，s)，1.42（3H，s)，1.69（1H，brs)，1.74-1.84（2H，m)，2.57-2.65（1H，m)，2.96-3.04（1H，m)，5.61（1H，s) [Reference Example 5] (4aS, 8aS) -3,3-dimethyloctahydroquinoxalin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.14-1.43 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.69 (1H, brs), 1.74-1.84 (2H, m), 2.57 -2.65 (1H, m), 2.96-3.04 (1H, m), 5.61 (1H, s)

¹H-NMR（CDCl₃）δppm : 1.14-1.43（6H，m)，1.38（3H，s)，1.42（3H，s)，1.63（1H，brs)，1.73-1.83（2H，m)，2.57-2.66（1H，m)，2.95-3.04（1H，m)，5.55（1H，s) [Reference Example 6] (4aR, 8aR) -3,3-dimethyloctahydroquinoxalin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.14-1.43 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.63 (1H, brs), 1.73-1.83 (2H, m), 2.57 -2.66 (1H, m), 2.95-3.04 (1H, m), 5.55 (1H, s)

¹H-NMR（CDCl₃）δppm : 0.92（3H，t，J = 7.5 Hz)，0.93（3H，t，J = 7.3 Hz)，1.13-1.49（7H，m)，1.60-1.99（6H，m)，2.55-2.60（1H，m)，2.91-3.00（1H，m)，5.69（1H，brs) [Reference Example 7] trans-3,3-diethyloctahydroquinoxalin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 0.92 (3H, t, J = 7.5 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.13-1.49 (7H, m), 1.60-1.99 (6H, m ), 2.55-2.60 (1H, m), 2.91-3.00 (1H, m), 5.69 (1H, brs)

¹H-NMR（CDCl₃）δppm : 1.14-1.46（4H，m)，1.70-2.17（9H，m)，2.43-2.52（1H，m)，2.55-2.66（1H，m)，2.78-2.88（1H，m)，2.97-3.06（1H，m)，5.65（1H，brs) [Reference Example 8] trans-octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline] -3′-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.14-1.46 (4H, m), 1.70-2.17 (9H, m), 2.43-2.52 (1H, m), 2.55-2.66 (1H, m), 2.78-2.88 ( 1H, m), 2.97-3.06 (1H, m), 5.65 (1H, brs)

¹H-NMR（CDCl₃）δppm : 1.1-1.3（ 1H，m )，1.35-2.15（ 12H，m )，2.5-2.6（ 1H，m )，2.75-2.85（ 1H，m )，3.15-3.3（ 2H，m )，5.65（ 1H，br ). [Reference Example 9] Cis-octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline] -3′-one

¹ H-NMR (CDCl ₃ ) δppm: 1.1-1.3 (1H, m), 1.35-2.15 (12H, m), 2.5-2.6 (1H, m), 2.75-2.85 (1H, m), 3.15-3.3 ( 2H, m), 5.65 (1H, br).

¹H-NMR（CDCl₃）δppm : 1.18-1.88（18H，m)，2.03-2.13（1H，m)，2.47-2.58（1H，m)，2.92-3.00（1H，m)，5.59（1H，s) [Reference Example 10] trans-octahydro-1′H-spiro [cyclohexane-1,2′-quinoxaline] -3′-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.18-1.88 (18H, m), 2.03-2.13 (1H, m), 2.47-2.58 (1H, m), 2.92-3.00 (1H, m), 5.59 (1H, s)

¹H-NMR（CDCl₃）δppm : 1.12-2.00（16 H，m)，2.03-2.20（1H，m)，3.35-3.55（2H,m )，5.88（brs). [Reference Example 11] Cis-3,3-dimethyldecahydrocycloheptapyrazin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.12-2.00 (16 H, m), 2.03-2.20 (1 H, m), 3.35-3.55 (2 H, m), 5.88 (brs).

¹H-NMR（CDCl₃）δppm : 1.35（3H，s)，1.39（3H，s)，1.42-1.90（11H，m)，2.73-2.85（1H，m)，3.13-3.26（1H，m)，5.51（1H，brs). [Reference Example 12] trans-3,3-dimethyldecahydrocycloheptapyrazin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.35 (3H, s), 1.39 (3H, s), 1.42-1.90 (11H, m), 2.73-2.85 (1H, m), 3.13-3.26 (1H, m) , 5.51 (1H, brs).

の製造
シス−シクロペンタン−１，２−ジアミン（１９．７ｇ，１９７ｍｍｏｌ），３−メチル−２−ブテン酸（１９．７ｇ，１９７ｍｍｏｌ）のトルエン（２００ｍＬ）懸濁液を、ディーンスターク装置を用いて共沸条件下２４時間還流攪拌した。反応混合物を室温まで冷却した後、減圧濃縮し、析出晶を濾取した。得られた結晶をエーテルで洗浄した後、乾燥することにより、淡褐色粉末のシス−４，４−ジメチルオクタヒドロシクロペンタ［ｂ］［１，４］ジアゼピン−２−オンを得た（８．６０ｇ，２４％）。
¹H-NMR（CDCl₃）δppm : 1.10-1.56（10 H，m)，1.65-1.80（1 H，m)，2.02-2.30（3 H，m)，2.60（1 H，d，J = 12.8 Hz)，3.18-3.37（1 H，m)，3.68-3.85（1 H，m)，5.73（1H，brs)。 [Reference Example 13] Cis-4,4-dimethyloctahydrocyclopenta [b] [1,4] diazepin-2-one

Preparation of a suspension of cis-cyclopentane-1,2-diamine (19.7 g, 197 mmol) and 3-methyl-2-butenoic acid (19.7 g, 197 mmol) in toluene (200 mL) using a Dean-Stark apparatus The mixture was stirred under reflux for 24 hours under azeotropic conditions. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ether and then dried to obtain cis-4,4-dimethyloctahydrocyclopenta [b] [1,4] diazepin-2-one as a light brown powder (8. 60 g, 24%).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.10-1.56 (10 H, m), 1.65-1.80 (1 H, m), 2.02-2.30 (3 H, m), 2.60 (1 H, d, J = 12.8 Hz), 3.18-3.37 (1 H, m), 3.68-3.85 (1 H, m), 5.73 (1 H, brs).

  The compounds of Reference Examples 14 and 15 below were produced in the same manner as in Reference Example 13 using appropriate starting materials.

¹H-NMR（CDCl₃）δppm : 1.00-1.45（11H，m)，1.63-1.83（3H，m)，1.83-2.00（1H，m)，2.31-2.43（1H，m)，2.65-2.81（2H，m)，3.00-3.16（1H，m)，5.54-5.90（1H，br). [Reference Example 14] (5aS, 9aS) -4,4-dimethyldecahydro [b] [1,4] diazepin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.45 (11H, m), 1.63-1.83 (3H, m), 1.83-2.00 (1H, m), 2.31-2.43 (1H, m), 2.65-2.81 ( 2H, m), 3.00-3.16 (1H, m), 5.54-5.90 (1H, br).

¹H-NMR（CDCl₃）δppm : 1.02-1.36（11H，m)，1.64-1.83（3H，m)，1.83-1.97（1H，m)，2.37（1H，dd，J = 2.4，13.9 Hz)，2.66-2.81（2H，m)，3.01-3.15（1H，m)，5.75-5.92（1H，brs). [Reference Example 15] (5aR, 9aR) -4,4-dimethyldecahydro [b] [1,4] diazepin-2-one

¹ H-NMR (CDCl ₃ ) δ ppm: 1.02-1.36 (11H, m), 1.64-1.83 (3H, m), 1.83-1.97 (1H, m), 2.37 (1H, dd, J = 2.4, 13.9 Hz) , 2.66-2.81 (2H, m), 3.01-3.15 (1H, m), 5.75-5.92 (1H, brs).

の製造
シス−３，３−ジメチルオクタヒドロシクロペンタピラジン−２−オン（２．００ｇ，１１．９ｍｍｏｌ）の無水ジオキサン（４０ｍＬ）溶解を室温で攪拌下、水素化リチウムアルミニウム（５４１ｍｇ，１４．３ｍｍｏｌ）を加え、徐々に昇温し、還流下１０分間攪拌した。反応混合物を氷温まで冷却後、水素ガスが発生しなくなるまで硫酸ナトリウム・十水和物を少量ずつ加え、その後室温で１時間攪拌した。不溶物をセライト濾過し、濾液を濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／１０）で精製し淡黄色油状のシス−２，２−ジメチルオクタヒドロ−１Ｈ−シクロペンタ［ｂ］ピラジンを得た（１．６７ｇ，９１％）。
¹H-NMR（CDCl₃）δppm :1.04（3 H，s)，1.16（3 H，s)，1.28-2.02（8 H，m)，2.37（1 H，d，J = 12.9 Hz)，2.70（1 H，d，J = 12.9 Hz)，3.00-3.15（1 H，m)，3.15-3.32（1 H，m)。 [Reference Example 16] Cis-2,2-dimethyloctahydro-1H-cyclopenta [b] pyrazine

Preparation of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol) dissolved in anhydrous dioxane (40 mL) at room temperature with stirring, lithium aluminum hydride (541 mg, 14.3 mmol) The mixture was gradually warmed and stirred for 10 minutes under reflux. After the reaction mixture was cooled to ice temperature, sodium sulfate decahydrate was added little by little until hydrogen gas was not generated, and then stirred at room temperature for 1 hour. The insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate / hexane = 1/10) to obtain cis-2,2-dimethyloctahydro-1H-cyclopenta [b] pyrazine as a pale yellow oil (1 .67 g, 91%).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.04 (3 H, s), 1.16 (3 H, s), 1.28-2.02 (8 H, m), 2.37 (1 H, d, J = 12.9 Hz), 2.70 (1 H, d, J = 12.9 Hz), 3.00-3.15 (1 H, m), 3.15-3.32 (1 H, m).

  The compounds of Reference Examples 17 to 34 below were produced in the same manner as in Reference Example 16 using appropriate starting materials.

¹H-NMR（CDCl₃）δppm : 1.08（3H，s)，1.19-1.92（11H，m)，2.15-2.30（1H，m)，2.55-2.74（2H，m)，2.77（1H，d，J = 12.2 Hz). [Reference Example 17] trans-2,2-dimethyloctahydro-1H-cyclopenta [b] pyrazine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.08 (3H, s), 1.19-1.92 (11H, m), 2.15-2.30 (1H, m), 2.55-2.74 (2H, m), 2.77 (1H, d, J = 12.2 Hz).

¹H-NMR（CDCl₃）δppm : 1.11（3H，s)，1.14（3H，s)，1.14-1.45（6H，m)，1.55-1.68（1H，m)，1.67-1.77（1H，m)，1.97-2.12（2H，m)，2.68-2.80（1H，m)，2.98-3.11（2H，m)，3.16-3.28（1H，m). [Reference Example 18] Cis-2,2-dimethyldecahydrocyclopenta [b] [1,4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.11 (3H, s), 1.14 (3H, s), 1.14-1.45 (6H, m), 1.55-1.68 (1H, m), 1.67-1.77 (1H, m) , 1.97-2.12 (2H, m), 2.68-2.80 (1H, m), 2.98-3.11 (2H, m), 3.16-3.28 (1H, m).

¹H-NMR（CDCl₃）δppm : 1.08（3H，s)，1.18（3H，s)，1.40-1.80（2H，br)，2.41（1H，d，J = 13.2 Hz)，2.69（1H，d，J = 13.2 Hz)，3.33-3.43（1H，m)，3.43-3.55（1H，m)，3.63-3.72（1H，m)，3.75-3.96（3H，m). [Reference Example 19] Cis-2,2-dimethyloctahydrofuro [3,4-b] pyrazine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.08 (3H, s), 1.18 (3H, s), 1.40-1.80 (2H, br), 2.41 (1H, d, J = 13.2 Hz), 2.69 (1H, d , J = 13.2 Hz), 3.33-3.43 (1H, m), 3.43-3.55 (1H, m), 3.63-3.72 (1H, m), 3.75-3.96 (3H, m).

¹H-NMR（CDCl₃）δppm : 1.13（3H，s)，1.30（3H，s)，1.44-1.65（2H，m)，2.64-2.78（2H，m)，2.83（1H，d，J = 12.2 Hz)，3.11-3.22（1H，m)，3.46（1H，dd，J = 7.3，10.5 Hz)，3.55（1H，dd，J = 7.4，10.5 Hz)，3.94（1H，t，J = 7.1 Hz)，4.00（1H，t，J = 7.2 Hz). [Reference Example 20] trans-2,2-dimethyloctahydrofuro [3,4-b] pyrazine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.13 (3H, s), 1.30 (3H, s), 1.44-1.65 (2H, m), 2.64-2.78 (2H, m), 2.83 (1H, d, J = 12.2 Hz), 3.11-3.22 (1H, m), 3.46 (1H, dd, J = 7.3, 10.5 Hz), 3.55 (1H, dd, J = 7.4, 10.5 Hz), 3.94 (1H, t, J = 7.1 Hz), 4.00 (1H, t, J = 7.2 Hz).

¹H-NMR（CDCl₃）δppm : 1.08（3H，s)，1.13（3H，s)，1.18-1.84（12H，m)，2.65-2.93（3H，m)，3.14-3.22（1H，m). [Reference Example 21] Cis-2,2-dimethyldecahydro-1H-benzo [b] [1,4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.08 (3H, s), 1.13 (3H, s), 1.18-1.84 (12H, m), 2.65-2.93 (3H, m), 3.14-3.22 (1H, m) .

¹H-NMR（CDCl₃）δppm : 1.00-1.35（11H，m)，1.50-1.85（7H，m)，2.20-2.31（1H，m)，2.31-2.43（1H,m )，2.79-2.90（1H，m)，2.90-3.04（1H，m). [Reference Example 22] (5aS, 9aS) -2,2-dimethyldecahydro-1H-benzo [b] [1,4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H, m), 2.31-2.43 (1H, m), 2.79-2.90 ( 1H, m), 2.90-3.04 (1H, m).

¹H-NMR（CDCl₃）δppm : 1.00-1.35（11H，m)，1.50-1.85（7H，m)，2.20-2.31（1H，m)，2.31-2.43（1H,m )，2.79-2.90（1H，m)，2.90-3.04（1H，m). [Reference Example 23] (5aR, 9aR) -2,2-dimethyldecahydro-1H-benzo [b] [1,4] diazepine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H, m), 2.31-2.43 (1H, m), 2.79-2.90 ( 1H, m), 2.90-3.04 (1H, m).

¹H-NMR（CDCl₃）δppm : 1.06（3H，s)，1.19（3H，s)，1.20-1.40（5H，m)，1.53-1.60（3H，m)，1.70-1.77（1H，m)，1.92-2.15（1H，m)，2.36（1H，d，J = 12.7 Hz)，2.66-2.72（1H，m)，2.72（1H，d，J = 12.7 Hz)，3.16-3.28（1H，m). [Reference Example 24] Cis-2,2-dimethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 1.06 (3H, s), 1.19 (3H, s), 1.20-1.40 (5H, m), 1.53-1.60 (3H, m), 1.70-1.77 (1H, m) , 1.92-2.15 (1H, m), 2.36 (1H, d, J = 12.7 Hz), 2.66-2.72 (1H, m), 2.72 (1H, d, J = 12.7 Hz), 3.16-3.28 (1H, m ).

¹H-NMR（CDCl₃）δppm : 1.05（3H，s)，1.08-1.74（10H，m), 1.23（3H，s)，2.02-2.12（1H，m)，2.40-2.50（1H，m)，2.60（1H，d，J = 12.1 Hz)，2.73（1H，d，J = 12.1 Hz). [Reference Example 25] trans-2,2-dimethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 1.05 (3H, s), 1.08-1.74 (10H, m), 1.23 (3H, s), 2.02-2.12 (1H, m), 2.40-2.50 (1H, m) , 2.60 (1H, d, J = 12.1 Hz), 2.73 (1H, d, J = 12.1 Hz).

¹H-NMR（CDCl₃）δppm : 1.01-1.43（6H，m)，1.05（3H，s)，1.23（3H，s)，1.58-1.63（1H，m)，1.68-1.74（3H，m)，2.03-2.19（1H，m)，2.40-2.49（1H，m)，2.60（1H，d，J = 12.1 Hz)，2.73（1H，d，J = 12.1 Hz). [Reference Example 26] (4aS, 8aS) -2,2-dimethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 1.01-1.43 (6H, m), 1.05 (3H, s), 1.23 (3H, s), 1.58-1.63 (1H, m), 1.68-1.74 (3H, m) , 2.03-2.19 (1H, m), 2.40-2.49 (1H, m), 2.60 (1H, d, J = 12.1 Hz), 2.73 (1H, d, J = 12.1 Hz).

¹H-NMR（CDCl₃）δppm : 1.05（3H，s)，1.09-1.56（6H，m)，1.23（3H，s)，1.58-1.63（1H，m)，1.66-1.75（3H，m)，2.03-2.12（1H，m)，2.41-2.50（1H，m)，2.61（1H，d，J = 12.1 Hz)，2.75（1H，d，J = 12.1 Hz). [Reference Example 27] (4aR, 8aR) -2,2-dimethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 1.05 (3H, s), 1.09-1.56 (6H, m), 1.23 (3H, s), 1.58-1.63 (1H, m), 1.66-1.75 (3H, m) , 2.03-2.12 (1H, m), 2.41-2.50 (1H, m), 2.61 (1H, d, J = 12.1 Hz), 2.75 (1H, d, J = 12.1 Hz).

¹H-NMR（CDCl₃）δppm : 0.79（3H，t，J = 7.5 Hz)，0.81（3H，t，J = 7.5 Hz)，0.86-1.02（1H，m)，1.08-1.40（8H，m)，1.47-1.60（2H，m)，1.67-1.87（3H，m)，2.06-2.15（1H，m)，2.33-2.42（1H，m)，2.57（1H，d，J = 12.1 Hz)，2.81（1H，d，J = 12.1 Hz). [Reference Example 28] trans-2,2-diethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 0.79 (3H, t, J = 7.5 Hz), 0.81 (3H, t, J = 7.5 Hz), 0.86-1.02 (1H, m), 1.08-1.40 (8H, m ), 1.47-1.60 (2H, m), 1.67-1.87 (3H, m), 2.06-2.15 (1H, m), 2.33-2.42 (1H, m), 2.57 (1H, d, J = 12.1 Hz), 2.81 (1H, d, J = 12.1 Hz).

[Reference Example 29] trans-octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

[Reference Example 30] Cis-octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

¹H-NMR（CDCl₃）δppm : 1.10-1.97（18H，m)，2.10-2.21（1H，m)，2.29-2.38（1H，m)，2.71（1H，d，J = 12.2 Hz)，2.76（1H，d，J = 12.2 Hz). [Reference Example 31] trans-octahydro-1′H-spiro [cyclopentane-1,2′-quinoxaline]

¹ H-NMR (CDCl ₃ ) δppm: 1.10-1.97 (18H, m), 2.10-2.21 (1H, m), 2.29-2.38 (1H, m), 2.71 (1H, d, J = 12.2 Hz), 2.76 (1H, d, J = 12.2 Hz).

¹H-NMR（CDCl₃）δppm : 1.12-1.76（20H，m)，2.12-2.20（1H，m)，2.44-2.53（1H，m)，2.55（1H，d，J = 12.2 Hz)，2.98（1H，d，J = 12.2 Hz). [Reference Example 32] trans-octahydro-1′H-spiro [cyclohexane-1,2′-quinoxaline]

¹ H-NMR (CDCl ₃ ) δppm: 1.12-1.76 (20H, m), 2.12-2.20 (1H, m), 2.44-2.53 (1H, m), 2.55 (1H, d, J = 12.2 Hz), 2.98 (1H, d, J = 12.2 Hz).

¹H-NMR（CDCl₃）δppm : 1.00-2.02（18H，m)，2.42（1H，d，J = 12.4 Hz)，2.58（1H，d，J = 12.4 Hz)，2.75-2.86（1H，m)，3.13-3.25（1H，m). [Reference Example 33] Cis-2,2-dimethyldecahydro-1H-cyclohepta [b] pyrazine

¹ H-NMR (CDCl ₃ ) δppm: 1.00-2.02 (18H, m), 2.42 (1H, d, J = 12.4 Hz), 2.58 (1H, d, J = 12.4 Hz), 2.75-2.86 (1H, m ), 3.13-3.25 (1H, m).

¹H-NMR（CDCl₃）δppm : 1.05（3H，s)，1.21（3H，s)，1.23-1.80（12H，m)，2.09-2.20（1H，m)，2.46-2.60（2H，m)，2.68（1H，d，J = 11.8 Hz). [Reference Example 34] trans-2,2-dimethyldecahydro-1H-cyclohepta [b] pyrazine

¹ H-NMR (CDCl ₃ ) δ ppm: 1.05 (3H, s), 1.21 (3H, s), 1.23-1.80 (12H, m), 2.09-2.20 (1H, m), 2.46-2.60 (2H, m) , 2.68 (1H, d, J = 11.8 Hz).

の製造
トランス−シクロヘキサン−１，２−ジアミン（２．００ｇ，１７．５ｍｍｏｌ）、（±）−１，２−ブタンジオール（１．６９ｍＬ，１８．４ｍｍｏｌ）の水（２０ｍＬ）溶液を、室温攪拌下にジクロロ（ペンタメチルシクロペンタジエニル）イリジウム（ＩＩＩ）ダイマー（７０ｍｇ，０．０９０ｍｍｏｌ）、炭酸水素ナトリウム（７３ｍｇ，０．８７ｍｍｏｌ）を加え、脱気及びアルゴン置換を３回繰り返した後、還流下で２４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール）で精製し、黄色固体の（２Ｒ^＊，４ａＳ＊，８ａＳ＊）−２−エチルデカヒドロキノキサリンを得た（２．０３ｇ，収率６９％）。
¹H-NMR（CDCl₃）δppm : 0.92（3H，t，J = 7.5 Hz)，1.10-1.60（7H，m)，1.64-1.83（5H，m)，2.16-2.31（2H，m)，2.44（1H，dd，J = 11.5，10.4 Hz)，2.58-2.67（1H，m)，3.02（1H，dd，J = 11.5，2.7 Hz). [Reference Example 35] (2RS, 4aSR, 8aSR) -2-ethyldecahydroquinoxaline

A solution of trans-cyclohexane-1,2-diamine (2.00 g, 17.5 mmol), (±) -1,2-butanediol (1.69 mL, 18.4 mmol) in water (20 mL) was stirred at room temperature. Dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (70 mg, 0.090 mmol) and sodium hydrogen carbonate (73 mg, 0.87 mmol) were added below, and after degassing and argon substitution were repeated three times, the mixture was refluxed. Stir for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (methylene chloride / methanol) to obtain (2R ^* , 4aS *, 8aS *)-2-ethyldecahydroquinoxaline as a yellow solid. (2.03 g, 69% yield).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.92 (3H, t, J = 7.5 Hz), 1.10-1.60 (7H, m), 1.64-1.83 (5H, m), 2.16-2.31 (2H, m), 2.44 (1H, dd, J = 11.5, 10.4 Hz), 2.58-2.67 (1H, m), 3.02 (1H, dd, J = 11.5, 2.7 Hz).

の製造
（１Ｓ，２Ｓ）−シクロヘキサン−１，２−ジアミン（３．４３ｇ，３０．０ｍｍｏｌ）のメタノール（３００ｍＬ）溶液を室温攪拌下に、ベンズアルデヒド（３．０５ｍＬ，３０．０ｍｍｏｌ）を加え、同温下で一夜攪拌した。反応混合物を０℃に冷却し、水素化ホウ素ナトリウム（２．２７ｇ，６０．０ｍｍｏｌ）を加え、０℃で２時間攪拌した。反応混合物に水（３０ｍＬ）を加え、生成物を塩化メチレン（５０ｍＬ）で２回抽出した。有機層を合わせて、硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、淡黄色油状の（１Ｓ，２Ｓ）−Ｎ−ベンジルシクロヘキサン−１，２−ジアミン（ｃａｓ ｎｏ． ２０７４５０−１１−１）を得た（２．９５ｇ，収率４８％）。 [Reference Example 36] (4aS, 8aS) -1-benzyldecahydroquinoxaline

Preparation of (1S, 2S) -cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) in methanol (300 mL) was stirred at room temperature and benzaldehyde (3.05 mL, 30.0 mmol) was added. Stir overnight at warm temperature. The reaction mixture was cooled to 0 ° C., sodium borohydride (2.27 g, 60.0 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr. Water (30 mL) was added to the reaction mixture and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate / hexane) to give (1S, 2S) -N-benzylcyclohexane-1,2-diamine (cas no. 207450-11-1) as a pale yellow oil. ) Was obtained (2.95 g, yield 48%).

The obtained (1S, 2S) -N-benzylcyclohexane-1,2-diamine (2.90 g, 14.2 mmol) was dissolved in methylene chloride (284 nL) and stirred under ice-cooling in a nitrogen atmosphere. % Sodium hydride (1.99 g, 49.7 mmol) was added. After 5 minutes, (2-bromoethyl) diphenylsulfonium trifluoromethanesulfonate (6.92 g, 15.6 mmol) was added to the reaction mixture under ice-cooling and stirring overnight at room temperature. A saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture little by little, and then the product was extracted twice with methylene chloride (100 mL). The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate / hexane) to obtain (4aS, 8aS) -1-benzyldecahydroquinoxaline as a light brown solid (2.28 g, 70%).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.05-1.4 (4H, m), 1.50 (1H, br), 1.6-1.9 (4H, m), 2.05-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m), 2.8-2.95 (2H, m), 3.14 (1H, d, J = 13.4Hz), 4.11 (1H, d, J = 13.4Hz), 7.15-7.4 (5H, m).

  The compounds of Reference Examples 37 to 39 below were produced in the same manner as in Reference Example 37 using appropriate starting materials.

¹H-NMR（CDCl₃）δppm : 1.05-1.4（ 4H，m )，1.50（ 1H，br )，1.6-1.9（ 4H，m )，2.05-2.2（ 1H，m )，2.2-2.3（ 1H，m )，2.4-2.5（ 1H，m )，2.65-2.75（ 1H，m )，2.8-2.95（ 2H，m )，3.13（ 1H，d，J = 13.4Hz )，4.11（ 1H，d，J = 13.4Hz )，7.15-7.4（ 5H，m ). [Reference Example 37] (4aS, 8aS) -1-benzyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δ ppm: 1.05-1.4 (4H, m), 1.50 (1H, br), 1.6-1.9 (4H, m), 2.05-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m), 2.8-2.95 (2H, m), 3.13 (1H, d, J = 13.4Hz), 4.11 (1H, d, J = 13.4Hz), 7.15-7.4 (5H, m).

¹H-NMR（CDCl₃）δppm : 1.05-1.15（ 1H，m )，1.2-1.75（ 19H，m )，1.75-1.85（ 1H，m )，1.85-2.2（ 1H，m )，3.70（ 1H，br )，4.83（ 1H，br ). [Reference Example 38] Cis-decahydroquinoxaline-1-carboxylic acid tert-butyl ester

¹ H-NMR (CDCl ₃ ) δppm: 1.05-1.15 (1H, m), 1.2-1.75 (19H, m), 1.75-1.85 (1H, m), 1.85-2.2 (1H, m), 3.70 (1H, br), 4.83 (1H, br).

¹H-NMR（CDCl₃）δppm : 1.0-2.0（ 10H，m )，2.2-2.4（ 1H，m )，2.45-2.7（ 2H，m )，2.75-3.1（ 2H，m )，3.63（ 2H，br )，7.05-7.45（ 5H，m ). [Reference Example 39] Cis-1-benzyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.0-2.0 (10H, m), 2.2-2.4 (1H, m), 2.45-2.7 (2H, m), 2.75-3.1 (2H, m), 3.63 (2H, br), 7.05-7.45 (5H, m).

の製造及び [Reference Example 40] (4aR, 8aS) -2,2-dimethyldecahydroquinoxaline

Manufacturing and

の製造。
シス−２，２−ジメチルデカヒドロキノキサリン（１３．７ｇ，８１．４ｍｍｏｌ）のエタノール（１４０ｍＬ）溶液を室温攪拌下に、（−）−ジベンゾイル−Ｌ−酒石酸一水和物（１３．８ｇ，３６．７ｍｍｏｌ）のエタノール（１４０ｍＬ）を加えた。反応混合物を、還流下３０分間攪拌し、室温まで冷却した後、白色の析出晶を濾取した。得られた結晶を、エタノール（２０ｍＬ）で洗浄後、乾燥することにより白色固体＜１＞を得た（１３．１ｇ）。固体＜１＞を得た際の濾液及び洗浄液を、減圧濃縮した。得られた残渣をエタノール（１００ｍＬ）に溶解し、室温で攪拌下に、（＋）−ジベンゾイル−Ｄ−酒石酸（１３．１ｇ，３６．６ｍｍｏｌ）のエタノール（１３０ｍＬ）溶液を加え、析出晶を濾取した。得られた結晶をエタノール（２０ｍＬ）で洗浄後、乾燥することにより淡褐色固体＜２＞を得た（１６．６ｇ）。 [Reference Example 41] (4aS, 8aR) -2,2-dimethyldecahydroquinoxaline

Manufacturing of.
A solution of cis-2,2-dimethyldecahydroquinoxaline (13.7 g, 81.4 mmol) in ethanol (140 mL) was stirred at room temperature, and (-)-dibenzoyl-L-tartaric acid monohydrate (13.8 g, 36 0.7 mmol) of ethanol (140 mL) was added. The reaction mixture was stirred under reflux for 30 minutes and cooled to room temperature, and white precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol (20 mL) and dried to give a white solid <1> (13.1 g). The filtrate and washing liquid obtained when the solid <1> was obtained were concentrated under reduced pressure. The obtained residue was dissolved in ethanol (100 mL), and a solution of (+)-dibenzoyl-D-tartaric acid (13.1 g, 36.6 mmol) in ethanol (130 mL) was added with stirring at room temperature. I took it. The obtained crystals were washed with ethanol (20 mL) and dried to give a light brown solid <2> (16.6 g).

After stirring a suspension of solid <1> in methanol (130 mL) and water (10 mL) for 30 minutes under reflux, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were washed with methanol (10 mL) and then dried to obtain (4aR, 8aS) -2,2-dimethyldecahydroquinoxaline dibenzoyl-L-tartrate as a white solid (11.4 g, 21.6 mmol). (The absolute configuration of cis-2.2-dimethyldecahydroquinoxaline was determined by X-ray crystallographic analysis of a white solid). This solid was dissolved in 1N aqueous sodium hydroxide solution (44 mL), and the product was extracted three times with ether (100 mL) and three times with methylene chloride (100 mL). The extracted organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give (4aR, 8aS) -2,2-dimethyldecahydroquinoxaline as a white solid (3.44 g, yield 25%).
¹ H-NMR (CDCl ₃ ) δppm: 1.06 (3H, s), 1.20 (3H, s), 1.2-1.4 (4H, m), 1.45-1.95 (5H, m), 1.95-2.15 (1H, m) , 2.36 (1H, d, J = 12.7Hz), 2.65-2.75 (2H, m), 3.15-3.25 (1H, m).

A suspension of solid <2> in methanol (130 mL) and water (10 mL) was stirred under reflux for 1 hour, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were washed with methanol (10 mL) and dried to obtain white solid (4aS, 8aR) -2,2-dimethyldecahydroquinoxaline dibenzoyl-D-tartrate (16.0 g, 30.4 mmol). . This solid was dissolved in 1N aqueous sodium hydroxide solution (65 mL), and the product was extracted three times with methylene chloride (100 mL). The extracted organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give (4aS, 8aR) -2,2-dimethyldecahydroquinoxaline as a light brown solid (4.63 g, yield 34%).
¹ H-NMR (CDCl ₃ ) δppm: 1.06 (3H, s), 1.19 (3H, s), 1.2-1.45 (5H, m), 1.45-1.65 (3H, m), 1.65-1.8 (1H, m) , 1.95-2.15 (1H, m), 2.36 (1H, d, J = 12.7Hz), 2.6-2.8 (2H, m), 3.15-3.25 (1H, m).

  The compounds of Reference Examples 42 to 45 below were produced in the same manner as Reference Examples 40 and 41 using appropriate starting materials.

[Reference Example 42] (4a′R, 8a ′S) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

[Reference Example 43] (4a ′S, 8a′R) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

¹H-NMR（CDCl₃）δppm : 1.0-1.25（ 1H，m )，1.25-1.65（ 5H，m )，1.65-2.05（ 3H，m )，2.2-2.4（ 1H，m )，2.45-2.7（ 2H，m )，2.75-3.1（ 3H，m )，3.63（ 2H，br )，7.15-7.4（ 5H，m ). [Reference Example 44] (4aR, 8aS) -1-benzyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.0-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H, m), 2.2-2.4 (1H, m), 2.45-2.7 ( 2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br), 7.15-7.4 (5H, m).

¹H-NMR（CDCl₃）δppm : 1.05-1.25（ 1H，m )，1.25-1.65（ 5H，m )，1.65-2.05（ 3H，m )，2.2-2.4（ 1H，m )，2.5-2.7（ 2H，m )，2.75-3.1（ 3H，m )，3.63（ 2H，br )，7.15-7.4（ 5H，m ). [Reference Example 45] (4aS, 8aR) -1-benzyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.05-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H, m), 2.2-2.4 (1H, m), 2.5-2.7 ( 2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br), 7.15-7.4 (5H, m).

の製造
トランス−シクロヘキサン−１，２−ジアミン（３．００ｇ，２６．３ｍｍｏｌ）をエタノール（１５ｍｌ）に希釈し、氷冷下、ブロモ酢酸エチル（６．１２ｍＬ，５５．２ｍｍｏｌ）を滴下して加え、その後室温にて終夜撹拌した。 [Reference Example 46] (Trans-3-oxodecahydroquinoxalin-1-yl) acetic acid ethyl ester

Trans-cyclohexane-1,2-diamine (3.00 g, 26.3 mmol) was diluted in ethanol (15 ml), and ethyl bromoacetate (6.12 mL, 55.2 mmol) was added dropwise under ice cooling. And then stirred at room temperature overnight.

Water was added to the reaction mixture and stirred, and the product was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methylene chloride / methanol) to obtain (trans-3-oxodecahydroquinoxalin-1-yl) acetic acid ethyl ester as an orange granular solid ( 2.35 g, yield 74.4%)
¹ H-NMR (CDCl ₃ ) δppm: 1.13-1.41 (4H, m), 1.28 (3H, t, J = 7.1 Hz), 1.72-1.97 (4H, m), 2.59-2.67 (1H, m), 3.06 -3.13 (1H, m), 3.35 (1H, d, J = 17.4 Hz), 3.48 (1H, d, J = 16.8 Hz), 3.52 (1H, d, J = 17.4 Hz), 3.60 (1H, d, J = 16.8 Hz), 4.17 (2H, q, J = 7.1 Hz), 6.79 (1H, brs).

の製造
水素化リチウムアルミニウム（１．００ｇ，２６．４ｍｍｏｌ）を脱水ジオキサン（４０ｍｌ）に懸濁し、撹拌しながら（トランス−３−オキソデカヒドロキノキサリン−１−イル）酢酸 エチルエステル（２．３５ｇ，９．７８ｍｍｏｌ）の脱水ジオキサン（１０ｍｌ）溶液を室温で滴下して加え、その後１０分間還流撹拌した。反応混合物を氷冷し、ガスが発生しなくなるまで硫酸ナトリウム・十水和物を少しずつ加えた。これをセライト濾過し、塩化メチレンで洗浄後、濾液を減圧濃縮し、褐色油状物の２−（トランス−デカヒドロキノキサリン−１−イル）エタノールを得た（１．７４ｇ，収率９７％）。
¹H-NMR（CDCl₃）δppm : 0.95-1.11（1H，m), 1.15-1.44（3H，m)，1.68-1.80（5H，m),1.85-1.94（1H，m)，2.05-2.44（4H，m)，2.87-2.97（3H，m)，3.04-3.16（1H，m)，3.46-3.54（1H，m)，3.60-3.69（1H，m). [Reference Example 47] 2- (Trans-decahydroquinoxalin-1-yl) ethanol

Lithium aluminum hydride (1.00 g, 26.4 mmol) was suspended in dehydrated dioxane (40 ml) and stirred (trans-3-oxodecahydroquinoxalin-1-yl) acetic acid ethyl ester (2.35 g, 9.78 mmol) of dehydrated dioxane (10 ml) was added dropwise at room temperature, and then the mixture was stirred at reflux for 10 minutes. The reaction mixture was ice-cooled, and sodium sulfate decahydrate was added little by little until no gas was generated. This was filtered through Celite, washed with methylene chloride, and the filtrate was concentrated under reduced pressure to give 2- (trans-decahydroquinoxalin-1-yl) ethanol as a brown oil (1.74 g, yield 97%).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.95-1.11 (1H, m), 1.15-1.44 (3H, m), 1.68-1.80 (5H, m), 1.85-1.94 (1H, m), 2.05-2.44 ( 4H, m), 2.87-2.97 (3H, m), 3.04-3.16 (1H, m), 3.46-3.54 (1H, m), 3.60-3.69 (1H, m).

の製造
２−（トランス−デカヒドロキノキサリン−１−イル）エタノール（１．７４ｇ，９．４４ｍｍｏｌ）の塩化メチレン（４０ｍＬ）溶液を、氷冷攪拌下にトリエチルアミン（４．６１ｍＬ，３３．０ｍＬ）、次いでｔｅｒｔ−ブチルジメチルシリルクロライド（４．２７ｇ，２８．３ｍｍｏｌ）を加え、室温で一夜攪拌した。反応混合物に水（１００ｍＬ）を加え反応を停止し、生成物を塩化メチレン（１００ｍＬ）で抽出した。有機層を水で２回、飽和食塩水で１回洗浄した後、硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルカラムクロマト精製（塩化メチレン／メタノール）することにより、淡褐色油状物のトランス−１−［２−（ｔｅｒｔ−ブチルジメチルシリルオキシ）エチル］デカヒドロキノキサリンを得た（２．００ｇ，収率７１％）。
¹H-NMR（CDCl₃）δppm : 0.06（6H，s），0.89（9H，s），0.98-1.36（4H，m），1.65-1.79（4H，m）,1.85-1.95（1H，m），2.08-2.14（1H，m），2.24-2.39（1H，m），2.45-2.61（2H，m），2.79-3.03（4H，m），3.62-3.80（2H，m）. [Reference Example 48] trans-1- [2- (tert-butyldimethylsilyloxy) ethyl] decahydroquinoxaline

Preparation of 2- (trans-decahydroquinoxalin-1-yl) ethanol (1.74 g, 9.44 mmol) in methylene chloride (40 mL) was stirred under ice-cooling and triethylamine (4.61 mL, 33.0 mL), Subsequently, tert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) was added, and the mixture was stirred overnight at room temperature. Water (100 mL) was added to the reaction mixture to stop the reaction, and the product was extracted with methylene chloride (100 mL). The organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol) to obtain trans-1- [2- (tert-butyldimethylsilyloxy) ethyl] decahydroquinoxaline as a light brown oil (2. 00 g, 71% yield).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.06 (6H, s), 0.89 (9H, s), 0.98-1.36 (4H, m), 1.65-1.79 (4H, m), 1.85-1.95 (1H, m) , 2.08-2.14 (1H, m), 2.24-2.39 (1H, m), 2.45-2.61 (2H, m), 2.79-3.03 (4H, m), 3.62-3.80 (2H, m).

The compounds of Reference Examples 50 and 51 below were produced in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm : 0.99-1.38 (4H, m), 1.55-1.78 (5H, m), 1.78-1.94 (3H, m), 2.21-2.33 (2H, m), 2.48-2.59 (1H, m), 2.63 (1H, brs), 2.76-2.87 (1H, m), 7.36 (1H, s). [Reference Example 50] (4a ′S, 8a ′S) -Octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline] -3′-one

¹ H-NMR (CDCl ₃ ) δppm: 0.99-1.38 (4H, m), 1.55-1.78 (5H, m), 1.78-1.94 (3H, m), 2.21-2.33 (2H, m), 2.48-2.59 ( 1H, m), 2.63 (1H, brs), 2.76-2.87 (1H, m), 7.36 (1H, s).

¹H-NMR (CDCl₃) δppm : 0.97-1.36 (4H, m), 1.55-1.77 (5H, m), 1.77-1.92 (3H, m), 2.20-2.32 (2H, m), 2.47-2.57 (1H, m), 2.63 (1H, brs), 2.76-2.86 (1H, m), 7.36 (1H, s). [Reference Example 51] (4a′R, 8a′R) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline] -3′one

¹ H-NMR (CDCl ₃ ) δppm: 0.97-1.36 (4H, m), 1.55-1.77 (5H, m), 1.77-1.92 (3H, m), 2.20-2.32 (2H, m), 2.47-2.57 ( 1H, m), 2.63 (1H, brs), 2.76-2.86 (1H, m), 7.36 (1H, s).

  The compounds of Reference Examples 52 and 53 below were produced in the same manner as in Reference Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm : 1.05-1.90 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, dd, J = 1.5, 12.2 Hz), 3.01 (1H, d, J = 12.2 Hz). [Reference Example 52] (4a ′S, 8a ′S) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

¹ H-NMR (CDCl ₃ ) δppm: 1.05-1.90 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, dd, J = 1.5, 12.2 Hz), 3.01 (1H, d, J = 12.2 Hz).

絶対立体配置



¹H-NMR (CDCl₃) δppm : 1.05-1.91 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, d, J = 12.2 Hz), 3.01 (1H, d, J = 12.2 Hz). [Reference Example 53] (4aR, 8a′R) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

Absolute configuration



¹ H-NMR (CDCl ₃ ) δppm: 1.05-1.91 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, d, J = 12.2 Hz), 3.01 (1H, d, J = 12.2 Hz ).

の製造
（４ａＲ，８ａＳ）−１−ベンジルデカヒドロキノキサリン（１．６３ｇ，７．０８ｍｍｏｌ）のＭｅＯＨ（１６ｍｌ）溶液にジ−ｔｅｒｔ−ブチルジカルボネート（１．７０ｇ，７．７９ｍｍｏｌ）を加え、室温で２時間攪拌した。溶媒を留去した後、残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、無色油状の（４ａＳ，８ａＲ）−ｔｅｒｔ−ブチル４−ベンジルデカヒドロキノキサリン−１−カルボキシレートを得た（２．３８ｇ，収率：定量的）。
¹H-NMR (CDCl₃) δppm : 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.66 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.50-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21-7.36 (5H, m). [Reference Example 54] (4aS, 8aR) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate

Preparation of (4aR, 8aS) -1-benzyldecahydroquinoxaline (1.63 g, 7.08 mmol) in MeOH (16 ml) was added di-tert-butyl dicarbonate (1.70 g, 7.79 mmol) at room temperature. For 2 hours. After the solvent was distilled off, the residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain colorless oily (4aS, 8aR) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate. (2.38 g, yield: quantitative).
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.66 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.50-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21-7.36 (5H, m ).

  The compound of Reference Example 55 below was produced in the same manner as in Reference Example 54 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm : 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.65 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.51-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21-7.36 (5H, m). [Reference Example 55] (4aR, 8aS) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate

¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.65 (1H, brs), 2.86 (1H, d, J = 13.2 Hz), 3.03 (1H, brs), 3.51-4.10 (2H, br), 4.16 (1H, d, J = 13.2 Hz), 7.21-7.36 (5H, m ).

の製法
（４ａＳ，８ａＲ）−ｔｅｒｔ−ブチル４−ベンジルデカヒドロキノキサリン−１−カルボキシレート（２．４ｇ，７．２６ｍｍｏｌ）のＥｔＯＨ（２５ｍｌ）溶液にＰｅａｒｌｍａｎ’ｓＣａｔａｌｙｓｔ（０．２４ｇ）を加えた。この懸濁液を、水素雰囲気下、室温で１時間攪拌した。触媒をセライトろ過し、ＥｔＯＨで洗浄後、ろ液を減圧濃縮し、無色油状の（４ａＳ，８ａＲ）−ｔｅｒｔ−ブチルデカヒドロキノキサリン−１−カルボキシレートを得た（１．６７ｇ，収率：９６％）。
¹H-NMR (CDCl₃) δppm : 1.16-1.53 (14H, m), 1.53-1.82 (3H, m), 1.83-2.00 (1H, m), 2.68-2.83 (1H, m), 2.85-3.10 (3H, m), 3.65-4.06 (2H, m). [Reference Example 56] (4aS, 8aR) -tert-butyldecahydroquinoxaline-1-carboxylate

(4aS, 8aR) -Pearlman's Catalyst (0.24 g) was added to a solution of (4aS, 8aR) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.4 g, 7.26 mmol) in EtOH (25 ml). This suspension was stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was filtered through Celite, washed with EtOH, and the filtrate was concentrated under reduced pressure to obtain colorless oily (4aS, 8aR) -tert-butyldecahydroquinoxaline-1-carboxylate (1.67 g, yield: 96). %).
¹ H-NMR (CDCl ₃ ) δppm: 1.16-1.53 (14H, m), 1.53-1.82 (3H, m), 1.83-2.00 (1H, m), 2.68-2.83 (1H, m), 2.85-3.10 ( 3H, m), 3.65-4.06 (2H, m).

  The compound of Reference Example 57 below was produced in the same manner as in Reference Example 56 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm : 1.18-1.55 (14H, m), 1.55-1.82 (3H, m), 1.85-2.00 (1H, m), 2.68-2.82 (1H, m), 2.85-3.10 (3H, m), 3.65-4.04 (2H, m). [Reference Example 57] (4aR, 8aS) -tert-butyldecahydroquinoxaline-1-carboxylate

¹ H-NMR (CDCl ₃ ) δppm: 1.18-1.55 (14H, m), 1.55-1.82 (3H, m), 1.85-2.00 (1H, m), 2.68-2.82 (1H, m), 2.85-3.10 ( 3H, m), 3.65-4.04 (2H, m).

の製法
ｃｉｓ ｔｅｒｔ−ブチルデカヒドロキノキサリン−１−カルボキシレート（２４０ｍｇ，０．９９９ｍｍｏｌ），１−ブロモ−４−ｃｈｌｏｒｏベンゼン（２１１ｍｇ，１．１０ｍｍｏｌ），Ｐｄ（ＯＡｃ）_２（１１．２ｍｇ，０．０４９９ｍｍｏｌ），ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（１４．５ｍｇ，０．０５００ｍｍｏｌ），ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（４ｍｌ）懸濁液を窒素雰囲気下、５時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ４加え攪拌した。不溶物をセライトろ過し、セライト層をＡｃＯＥｔ（５ｍｌ×２）で洗浄後、ろ液を減圧濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、白色固体を得た（８７ｍｇ，収率：２５％）。
¹H-NMR (CDCl₃) δppm : 1.10-1.40 (4H, m), 1.40-1.52 (10H, m), 1.63-1.71 (1H, m), 1.73-1.82 (1H, m), 2.15-2.28 (1H, m), 2.74 (1H, dt, J = 3.6, 11.8 Hz), 2.90-2.97 (1H, m), 3.05-3.11 (1H, m), 3.27 (1H, dt, J = 3.4, 12.6 Hz), 3.77-3.86 (1H, m), 4.01-4.10 (1H, m), 7.08-7.13 (2H, m), 7.25-7.30 (2H, m). [Reference Example 58] cis tert-butyl 4- (4-chlorophenyl) decahydroquinoxaline-1-carboxylate

Cis tert-Butyldecahydroquinoxaline-1-carboxylate (240 mg, 0.999 mmol), 1-bromo-4-chlorobenzene (211 mg, 1.10 mmol), Pd (OAc) ₂ (11.2 mg, 0. 1) 0499 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (14.5 mg, 0.0500 mmol) and NaOt-Bu (135 mg, 1.40 mmol) in toluene (4 ml) was stirred under reflux for 5 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, and MgSO4 was further added and stirred. The insoluble material was filtered through Celite, and the Celite layer was washed with AcOEt (5 ml × 2), and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (87 mg, yield: 25%).
¹ H-NMR (CDCl ₃ ) δppm: 1.10-1.40 (4H, m), 1.40-1.52 (10H, m), 1.63-1.71 (1H, m), 1.73-1.82 (1H, m), 2.15-2.28 ( 1H, m), 2.74 (1H, dt, J = 3.6, 11.8 Hz), 2.90-2.97 (1H, m), 3.05-3.11 (1H, m), 3.27 (1H, dt, J = 3.4, 12.6 Hz) , 3.77-3.86 (1H, m), 4.01-4.10 (1H, m), 7.08-7.13 (2H, m), 7.25-7.30 (2H, m).

  The compounds of Reference Examples 59 to 63 below were produced in the same manner as in Reference Example 35 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm :1.12-1.58 (6H, m), 1.62-1.78 (4H, m), 2.20-2.29 (2H, m), 2.82-3.02 (4H, m). [Reference Example 59] (4aS, 8aS) -Decahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.12-1.58 (6H, m), 1.62-1.78 (4H, m), 2.20-2.29 (2H, m), 2.82-3.02 (4H, m).

¹H-NMR (CDCl₃) δppm :1.14-1.27 (2H,m ), 1.27-1.57(4H, m), 1.62-1.79 (4H, m), 2.19-2.30(2H, m), 2.83-3.03(4H, m). [Reference Example 60] (4aR, 8aR) -decahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.14-1.27 (2H, m), 1.27-1.57 (4H, m), 1.62-1.79 (4H, m), 2.19-2.30 (2H, m), 2.83-3.03 ( 4H, m).

¹H-NMR (CDCl₃) δppm :1.02 (3H, d, J = 6.3 Hz), 1.11-1.51 (6H, m), 1.62-1.79 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J = 10.2, 11.7 Hz), 2.81-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz). [Reference Example 61] (2R, 4aS, 8aS) -2-methyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.02 (3H, d, J = 6.3 Hz), 1.11-1.51 (6H, m), 1.62-1.79 (4H, m), 2.14-2.22 (1H, m), 2.24 -2.33 (1H, m), 2.44 (1H, dd, J = 10.2, 11.7 Hz), 2.81-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz).

¹H-NMR (CDCl₃) δppm : 1.02 (3H, d, J = 6.3 Hz), 1.10-1.49 (6H, m), 1.62-1.80 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J = 10.3, 11.7 Hz), 2.80-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz). [Reference Example 62] (2S, 4aR, 8aR) -2-methyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 1.02 (3H, d, J = 6.3 Hz), 1.10-1.49 (6H, m), 1.62-1.80 (4H, m), 2.14-2.22 (1H, m), 2.24 -2.33 (1H, m), 2.44 (1H, dd, J = 10.3, 11.7 Hz), 2.80-2.91 (1H, m), 2.94 (1H, dd, J = 2.9, 11.7 Hz).

¹H-NMR (CDCl₃) δppm : 0.92 ( 3H, t, J = 7.5 Hz ), 1.1-1.55 ( 8H, m ), 1.6-1.8 ( 4H, m ), 2.14-2.32 ( 2H, m ), 2.39-2.5 ( 1H, m ), 2.57-2.68 ( 1H, m ), 3.01 ( 1H, dd, J = 2.6, 11.6 Hz ). [Reference Example 63] (2R, 4aS, 8aS) -2-ethyldecahydroquinoxaline

¹ H-NMR (CDCl ₃ ) δppm: 0.92 (3H, t, J = 7.5 Hz), 1.1-1.55 (8H, m), 1.6-1.8 (4H, m), 2.14-2.32 (2H, m), 2.39 -2.5 (1H, m), 2.57-2.68 (1H, m), 3.01 (1H, dd, J = 2.6, 11.6 Hz).

の製造
（４ａＳ，８ａＲ）−２，２−ジメチルデカヒドロキノキサリン（３３７ｍｇ，２．００ｍｍｏｌ）、６−ブロモ−１−（トリイソプロピルシリル）−１Ｈ−インドール（８４６ｍｇ，２．４０ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（２６９ｍｇ，２．８０ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２２．５ｍｇ，０．０９０２ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２９．１ｍｇ，０．１０１ｍｍｏｌ）のトルエン（８ｍＬ）懸濁液を、窒素雰囲気下で還流下に５時間攪拌した。反応混合物を室温に冷却した後、水（０．５ｍＬ）及び酢酸エチル（１０ｍＬ）を加え攪拌した後、硫酸マグネシウムを加えた。不溶物をセライト濾過した後、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）することにより、無色不定形の（４ａＲ，８ａＳ）−３，３−ジメチル−１−（１−（トリイソプロピルシリル）−１Ｈ−インドール−６−イル）デカヒドロキノキサリンを得た（０．７５ｇ，収率８５％）。
¹H-NMR（CDCl₃）δppm : 1.1-1.2（ 18H，m )，1.21（ 3H，s )，1.29（ 3H，s )，1.3-1.55（ 5H，m )，1.55-1.8（ 7H，m )，2.79（ 1H，d，J = 11.6Hz )，2.91（ 1H，d，J = 11.6Hz )，3.45-3.6（ 2H，m )，6.49（ 1H，dd，J = 0.7，3.2Hz )，6.82（ 1H，dd，J = 2.0，8.6Hz )，6.93（ 1H，s )，7.08（ 1H，d，J = 3.2Hz )，7.45（ 1H，d，J = 8.6Hz ). Example 1 (4aR, 8aS) -3,3-dimethyl-1- (1- (triisopropylsilyl) -1H-indol-6-yl) decahydroquinoxaline

(4aS, 8aR) -2,2-dimethyldecahydroquinoxaline (337 mg, 2.00 mmol), 6-bromo-1- (triisopropylsilyl) -1H-indole (846 mg, 2.40 mmol), sodium tert- Suspension of butoxide (269 mg, 2.80 mmol), palladium (II) acetate (22.5 mg, 0.0902 mmol) and tri-tert-butylphosphine tetrafluoroborate (29.1 mg, 0.101 mmol) in toluene (8 mL) The solution was stirred at reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, water (0.5 mL) and ethyl acetate (10 mL) were added and stirred, and magnesium sulfate was added. The insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give colorless amorphous (4aR, 8aS) -3,3-dimethyl-1- (1- (triisopropylsilyl)- 1H-Indol-6-yl) decahydroquinoxaline was obtained (0.75 g, yield 85%).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.1-1.2 (18H, m), 1.21 (3H, s), 1.29 (3H, s), 1.3-1.55 (5H, m), 1.55-1.8 (7H, m) , 2.79 (1H, d, J = 11.6Hz), 2.91 (1H, d, J = 11.6Hz), 3.45-3.6 (2H, m), 6.49 (1H, dd, J = 0.7, 3.2Hz), 6.82 ( 1H, dd, J = 2.0, 8.6Hz), 6.93 (1H, s), 7.08 (1H, d, J = 3.2Hz), 7.45 (1H, d, J = 8.6Hz).

の製造
（４ａＲ，８ａＳ）−３，３−ジメチル−１−（１−（トリイソプロピルシリル）−１Ｈ−インドール−６−イル）デカヒドロキノキサリン（０．７５０ｇ，１．７１ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液を室温で攪拌下に、フッ化テトラ−ｎ−ブチルアンモニウム（１Ｍ ｉｎ ＴＨＦ）（３．４１ｍＬ，３．４１ｍｏｌ）を加え、室温で１時間攪拌した。反応混合物から溶媒を減圧留去し、得られた残渣をＮＨ−シリカゲルカラムクロマト（酢酸エチル／ヘキサン）で精製し、白色固体を得た。得られた固体をジイソプロピルエーテル／ヘキサンで再結晶を行い、（４ａＲ，８ａＳ）−１−（１Ｈ−インドール−６−イル）−３，３−ジメチルデカヒドロキノキサリンを得た（３０５ｍｇ，収率６３％）。
¹H-NMR（CDCl₃）δppm : 1.0-1.55（ 11H，m )，1.55-1.85（ 4H，m )，2.79（ 1H，d，J = 11.6Hz )，2.94（ 1H，d，J = 11.6Hz )，3.45-3.55（ 1H，m )，3.6-3.75（ 1H，m )，6.35-6.5（ 1H，m )，6.79（ 1H，s )，6.86（ 1H，dd，J = 2.1，8.7Hz )，7.03（ 1H，dd，J = 2.7，2.7Hz )，7.47（ 1H，d，J = 8.6Hz )，7.92（ 1H，br ). Example 2 (4aR, 8aS) -1- (1H-Indol-6-yl) -3,3-dimethyldecahydroquinoxaline

Preparation of (4aR, 8aS) -3,3-dimethyl-1- (1- (triisopropylsilyl) -1H-indol-6-yl) decahydroquinoxaline (0.750 g, 1.71 mmol) in tetrahydrofuran (15 mL) While stirring the solution at room temperature, tetra-n-butylammonium fluoride (1M in THF) (3.41 mL, 3.41 mol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate / hexane) to obtain a white solid. The obtained solid was recrystallized from diisopropyl ether / hexane to obtain (4aR, 8aS) -1- (1H-indol-6-yl) -3,3-dimethyldecahydroquinoxaline (305 mg, yield 63). %).
¹ H-NMR (CDCl ₃ ) δppm: 1.0-1.55 (11H, m), 1.55-1.85 (4H, m), 2.79 (1H, d, J = 11.6Hz), 2.94 (1H, d, J = 11.6Hz ), 3.45-3.55 (1H, m), 3.6-3.75 (1H, m), 6.35-6.5 (1H, m), 6.79 (1H, s), 6.86 (1H, dd, J = 2.1, 8.7Hz), 7.03 (1H, dd, J = 2.7, 2.7Hz), 7.47 (1H, d, J = 8.6Hz), 7.92 (1H, br).

の製造
（４ａＳ，８ａＳ）−１−ベンジル−４−（４−クロロフェニル）デカヒドロキノキサリン（０．６５０ｇ，１．９１ｍｍｏｌ）の塩化メチレン（６．５ｍＬ）溶液を氷冷攪拌下、クロロギ酸 １−クロロエチル（２２９μＬ，２．１０ｍｍｏｌ）を加えた。室温で１５時間攪拌した後、反応混合物を減圧濃縮した。得られた残渣をメタノール（６．５ｍＬ）に溶解し、これを還流下１時間攪拌した。反応混合物から溶媒を留去し、得られた残渣にアセトン（５ｍＬ）を加えて攪拌し、析出晶を濾取した。得られた結晶をアセトン（１ｍＬ）で洗浄後、乾燥し白色粉末の（４ａＳ，８ａＳ）−１−（４−クロロフェニル）デカヒドロキノキサリンを得た（２５３ｍｇ，収率５３％）。
¹H-NMR（ DMSO-d₆ ）δppm : 0.85-1.05（ 1H，m )，1.1-1.4（ 2H，m )，1.4-1.65（ 3H，m )，1.65-1.8（ 1H，m )，1.9-2.05（ 1H，m )，2.8-3.05（ 2H，m )，3.05-3.2（ 3H，m )，3.2-3.5（ 1H，m )，7.1-7.2（ 2H，m )，7.35-7.45（ 2H，m )，9.2-9.65（ 2H，m ). Example 3 (4aS, 8aS) -1- (4-chlorophenyl) decahydroquinoxaline

Preparation of (4aS, 8aS) -1-benzyl-4- (4-chlorophenyl) decahydroquinoxaline (0.650 g, 1.91 mmol) in methylene chloride (6.5 mL) under ice-cooling and stirring with chloroformate 1- Chloroethyl (229 μL, 2.10 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (6.5 mL), and this was stirred under reflux for 1 hour. The solvent was distilled off from the reaction mixture, acetone (5 mL) was added to the resulting residue and stirred, and the precipitated crystals were collected by filtration. The obtained crystals were washed with acetone (1 mL) and dried to give (4aS, 8aS) -1- (4-chlorophenyl) decahydroquinoxaline (253 mg, 53% yield) as a white powder.
¹ H-NMR (DMSO-d ₆ ) δppm: 0.85-1.05 (1H, m), 1.1-1.4 (2H, m), 1.4-1.65 (3H, m), 1.65-1.8 (1H, m), 1.9- 2.05 (1H, m), 2.8-3.05 (2H, m), 3.05-3.2 (3H, m), 3.2-3.5 (1H, m), 7.1-7.2 (2H, m), 7.35-7.45 (2H, m ), 9.2-9.65 (2H, m).

の製造
シス−１−（ベンゾ［ｂ］チオフェン−５−イル）−３，３−ジメチルデカヒドロキノキサリン（２９８ｍｇ，０．９９２ｍｍｏｌ）のメタノール（１０ｍＬ）溶液を室温攪拌下に、３７％ホルムアルデヒド水溶液（０．８１ｍＬ，９．９ｍｍｏｌ）を加えた。３０分後、反応溶液にシアノ水素化ホウ素ナトリウム（３１１ｍｇ，４．９６ｍｍｏｌ）、酢酸（０．３０ｍＬ）を室温で加え、一夜攪拌した。反応混合物から溶媒を減圧留去の後、飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で２回抽出した。有機層を水で２回、飽和食塩水で１回洗浄した後、硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルカラムクロマト精製（塩化メチレン：メタノール＝１０：１）し褐色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、４Ｎ−塩酸／酢酸エチル（０．６ｍＬ）を加え析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末のシス−４−（ベンゾ［ｂ］チオフェン−５−イル）−１，２，２−トリメチルデカヒドロキノキサリン 塩酸塩を得た（２５８ｍｇ，収率７４％）。
¹H-NMR（CDCl₃）δppm : 1.17-1.34（1H，m)，1.37-1.74（2H，m)，1.47（3H，s)，1.87-2.04（1H，m)，1.90（3H，s)，2.20-2.30（1H，m)，2.39-2.54（1H，m)，2.64-2.88（2H，m)，2.75（3H，d，J = 4.9 Hz)，3.12（1H，d，J = 13.2 Hz)，3.69-3.74（1H，m)，3.85-3.93（1H，m)，3.87（1H，d，J = 13.2 Hz)，7.01（1H，dd，J = 8.8，2.3 Hz)，7.21-7.32（2H，m)，7.44（1H，d，J = 5.4 Hz)，7.75（1H，d，J = 8.8 Hz)，11.20（1H，brs). [Example 4] Cis-4- (benzo [b] thiophen-5-yl) -1,2,2-trimethyldecahydroquinoxaline hydrochloride

A solution of cis-1- (benzo [b] thiophen-5-yl) -3,3-dimethyldecahydroquinoxaline (298 mg, 0.992 mmol) in methanol (10 mL) was stirred at room temperature with a 37% aqueous formaldehyde solution ( 0.81 mL, 9.9 mmol) was added. After 30 minutes, sodium cyanoborohydride (311 mg, 4.96 mmol) and acetic acid (0.30 mL) were added to the reaction solution at room temperature and stirred overnight. After evaporating the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give a brown oil. 4N-hydrochloric acid / ethyl acetate (0.6 mL) was added to the obtained oily ethanol solution while stirring at room temperature, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to obtain cis-4- (benzo [b] thiophen-5-yl) -1,2,2-trimethyldecahydroquinoxaline hydrochloride as white powder. (258 mg, 74% yield).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.17-1.34 (1H, m), 1.37-1.74 (2H, m), 1.47 (3H, s), 1.87-2.04 (1H, m), 1.90 (3H, s) , 2.20-2.30 (1H, m), 2.39-2.54 (1H, m), 2.64-2.88 (2H, m), 2.75 (3H, d, J = 4.9 Hz), 3.12 (1H, d, J = 13.2 Hz ), 3.69-3.74 (1H, m), 3.85-3.93 (1H, m), 3.87 (1H, d, J = 13.2 Hz), 7.01 (1H, dd, J = 8.8, 2.3 Hz), 7.21-7.32 ( 2H, m), 7.44 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 8.8 Hz), 11.20 (1H, brs).

の製造
トランス−１−（２−（ｔｅｒｔ−ブチルジメチルシリルオキシ）エチル）−４−（ナフタレン−２−イル）デカヒドロキノキサリン（８２０ｍｇ，１．９３ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液を室温で攪拌下にフッ化テトラ−ｎ−ブチルアンモニウム（１Ｍ ｉｎ ＴＨＦ）（２．１ｍＬ，２．１ｍｍｏｌ）を加え、一夜攪拌した。反応混合物に酢酸エチルを加え、水で２回、飽和食塩水で１回洗浄した後、硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルカラムクロマト精製（塩化メチレン：メタノール＝１０：１）し無色不定形固体（５３４ｍｇ）を得た。得られた固体の内３１９ｍｇをエタノールに溶解し、室温攪拌下に、４Ｎ−塩酸／酢酸エチル（１．０ｍＬ）を加え析出晶を濾取した。得られた結晶を、酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の２−（トランス−４−（ナフタレン−２−イル）デカヒドロキノキサリン−１−イル）エタノール２塩酸塩を得た（３６５ｍｇ，収率４９％）。
¹H-NMR（CDCl₃）δppm : 1.23-1.76（4H，m)，1.86-2.08（3H，m)，2.43-2.48（1H，m)，3.18-3.25（1H，m)，3.72-3.77（2H，m)，3.93-3.98（1H，m)，3.93-4.78（1H，br)，4.08-4.20（2H，m)，4.39-4.55（1H，m)，4.57-4.78（2H，m)，4.97-5.06（1H，m)，7.61-7.68（3H，m)，7.81-8.07（3H，m)，8.17-8.69（1H，br)，12.73（1H，brs)，14.91（1H，brs). Example 5 2- (trans-4- (naphthalen-2-yl) decahydroquinoxalin-1-yl) ethanol dihydrochloride

A solution of trans-1- (2- (tert-butyldimethylsilyloxy) ethyl) -4- (naphthalen-2-yl) decahydroquinoxaline (820 mg, 1.93 mmol) in THF (10 mL) was stirred at room temperature. Was added tetra-n-butylammonium fluoride (1M in THF) (2.1 mL, 2.1 mmol) and stirred overnight. Ethyl acetate was added to the reaction mixture, washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to obtain a colorless amorphous solid (534 mg). 319 mg of the obtained solid was dissolved in ethanol, 4N hydrochloric acid / ethyl acetate (1.0 mL) was added with stirring at room temperature, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to obtain 2- (trans-4- (naphthalen-2-yl) decahydroquinoxalin-1-yl) ethanol dihydrochloride as white powder. (365 mg, 49% yield).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.23-1.76 (4H, m), 1.86-2.08 (3H, m), 2.43-2.48 (1H, m), 3.18-3.25 (1H, m), 3.72-3.77 ( 2H, m), 3.93-3.98 (1H, m), 3.93-4.78 (1H, br), 4.08-4.20 (2H, m), 4.39-4.55 (1H, m), 4.57-4.78 (2H, m), 4.97-5.06 (1H, m), 7.61-7.68 (3H, m), 7.81-8.07 (3H, m), 8.17-8.69 (1H, br), 12.73 (1H, brs), 14.91 (1H, brs).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（１６８ｍｇ，０．９９８ｍｍｏｌ）、４−ブロモ−７−フルオロベンゾフラン（２５８ｍｇ、１．２０ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１１．２ｍｇ，０．０４９９ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（１４．５ｍｇ，０．０５００ｍｍｏｌ、ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（４ｍｌ）懸濁液を窒素雰囲気下、４時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ４を加え攪拌した。不溶物をろ過し、ＡｃＯＥｔ（５ｍＬ×２）で洗浄後、ろ液を減圧濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、無色油状物を得た（１６７ｍｇ）。この油状物をヘキサン（１ｍＬ）から結晶化し、白色粉末の（４ａＳ，８ａＲ）−１−（７−フルオロベンゾフラン−４−イル）−３，３−ジメチルデカヒドロキノキサリンを得た（１０７ｍｇ，収率：３５％）。
¹H-NMR ( CDCl₃ ) δppm : 1.0-1.45 ( 11H, m ), 1.6-1.8 ( 3H, m ), 1.8-1.95 ( 1H, m ), 2.70 ( 1H, d, J = 11.3Hz ), 3.04 ( 1H, d, J = 11.3Hz ), 3.50 ( 1H, ddd, J = 3.8, 3.8, 12.1Hz ), 3.55-3.65 ( 1H, m ), 6.47 ( 1H, dd, J = 3.4, 8.6Hz ), 6.84 ( 1H, dd, J = 2.5, 2.5Hz ), 6.89 ( 1H, dd, J = 8.6, 10.4Hz ), 7.60 ( 1H, d, J = 2.2Hz ). Example 77 (4aS, 8aR) -1- (7-Fluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-fluorobenzofuran (258 mg, 1.20 mmol), Pd (OAc) ₂ (11.2 mg, 0.0499 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (14.5 mg, 0.0500 mmol, NaOt-Bu (135 mg, 1.40 mmol) in toluene (4 ml) was stirred under reflux for 4 hours under a nitrogen atmosphere. (0.5 mL) and AcOEt (10 mL) were added and stirred, and MgSO4 was further added and stirred.The insoluble matter was filtered off, washed with AcOEt (5 mL × 2), and the filtrate was concentrated under reduced pressure. Purification by basic silica gel column chromatography (Hex-AcOEt) afforded a colorless oil (167 mg), which was crystallized from hexane (1 mL), and obtained as a white powder of (4aS, 8aR) -1- ( 7-Fluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline was obtained (107 mg, yield: 35%).
¹ H-NMR (CDCl ₃ ) δppm: 1.0-1.45 (11H, m), 1.6-1.8 (3H, m), 1.8-1.95 (1H, m), 2.70 (1H, d, J = 11.3 Hz), 3.04 (1H, d, J = 11.3Hz), 3.50 (1H, ddd, J = 3.8, 3.8, 12.1 Hz), 3.55-3.65 (1H, m), 6.47 (1H, dd, J = 3.4, 8.6 Hz), 6.84 (1H, dd, J = 2.5, 2.5Hz), 6.89 (1H, dd, J = 8.6, 10.4Hz), 7.60 (1H, d, J = 2.2Hz).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２５２ｍｇ，１．５０ｍｍｏｌ）、１−ブロモ−４−クロロベンゼン（３４５ｍｇ、１．８０ｍｍｏｌ、Ｐｄ（ＯＡｃ）_２（１６．８ｍｇ，０．０７４８ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（２１．８ｍｇ，０．０７５１ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（２０２ｍｇ，２．１０ｍｍｏｌ）のトルエン（１０ｍｌ）懸濁液を窒素雰囲気下、５時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）を加えて攪拌し、さらにＭｇＳＯ_４を加え攪拌した後、不溶物をセライトろ過した。ろ液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製した。得られた油状物を１Ｎ−ＨＣｌ−ＥｔＯＨ（３ｍＬ）に溶解し、溶媒を減圧留去した。析出晶をエタノール／アセトンから再結晶し、白色粉末の（４ａＳ，８ａＲ）−１−（４−クロロフェニル）−３，３−ジメチルデカヒドロキノキサリン塩酸塩を得た（２６２ｍｇ，収率：５５％）。
¹H-NMR ( DMSO-d₆ ) δppm : 1.2-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-2.1 ( 5H, m ), 2.93 ( 1H, d, J = 13.6Hz ), 3.40 ( 1H, d, J = 13.8Hz ), 3.65-3.85 ( 1H, m ), 3.9-4.1 ( 1H, m ), 6.8-7.05 ( 2H, m ), 7.1-7.35 ( 2H, m ), 8.14 ( 1H, br ), 9.77 ( 1H, br ). [Example 106] (4aS, 8aR) -1- (4-chlorophenyl) -3,3-dimethyldecahydroquinoxaline hydrochloride

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol), 1-bromo-4-chlorobenzene (345 mg, 1.80 mmol, Pd (OAc) ₂ (16.8 mg, 0. 0748 mmol), t-Bu ₃ P.HBF ₄ (21.8 mg, 0.0751 mmol), NaOt-Bu (202 mg, 2.10 mmol) in toluene (10 ml) was stirred under reflux for 5 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, and further MgSO ₄ was added and stirred, and the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt). Dissolved in Cl-EtOH (3 mL), the solvent was distilled off under reduced pressure, and the precipitated crystals were recrystallized from ethanol / acetone to give (4aS, 8aR) -1- (4-chlorophenyl) -3,3-dimethyl as a white powder. Decahydroquinoxaline hydrochloride was obtained (262 mg, yield: 55%).
¹ H-NMR (DMSO-d ₆ ) δppm: 1.2-1.45 (6H, m), 1.51 (3H, s), 1.6-2.1 (5H, m), 2.93 (1H, d, J = 13.6 Hz), 3.40 (1H, d, J = 13.8Hz), 3.65-3.85 (1H, m), 3.9-4.1 (1H, m), 6.8-7.05 (2H, m), 7.1-7.35 (2H, m), 8.14 (1H , br), 9.77 (1H, br).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（１６８ｍｇ，０．９９８ｍｍｏｌ）、４−ブロモ−２−クロロ−１−フルオロベンゼン（２５１ｍｇ，１．２０ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１１．２ｍｇ，０．０５００ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（１４．５ｍｇ，０．０５００ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（１０ｍｌ）懸濁液を窒素雰囲気下、５時間還流し攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ_４を加え攪拌した後、不溶物をろ過した。ろ液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製した。得られた油状物を１Ｎ−ＨＣｌ−ＥｔＯＨ（３ｍＬ）に溶解し、エタノールを減圧留去した。析出晶をエタノール／アセトンから再結晶し、白色粉末の（４ａＳ，８ａＲ）−１−（３−クロロ−４−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン塩酸塩を得た（１５３ｍｇ，収率：４６％）
¹H-NMR ( DMSO-d₆ ) δppm : 1.15-1.45 ( 6H, m ), 1.51 ( 3H, s ), 1.6-1.9 ( 4H, m ), 1.9-2.05 ( 1H, s ), 2.01 ( 1H, d, J = 8.2Hz ), 3.3-3.45 ( 1H, m ), 3.65-3.8 ( 1H, m ), 3.95-4.1 ( 1H, m ), 6.85-7.0 ( 1H, m ), 7.12 ( 1H, dd, J = 3.0, 6.2Hz ), 7.25 ( 1H, dd, J = 9.1, 9.1Hz ), 8.13 ( 1H, br ), 9.86 ( 1H, br ). [Example 112] (4aS, 8aR) -1- (3-Chloro-4-fluorophenyl) -3,3-dimethyldecahydroquinoxaline hydrochloride

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-2-chloro-1-fluorobenzene (251 mg, 1.20 mmol), Pd (OAc) ₂ ( 11.2 mg, 0.0500 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (14.5 mg, 0.0500 mmol) and NaOt-Bu (135 mg, 1.40 mmol) in toluene (10 ml) was refluxed and stirred for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, MgSO ₄ was further added and stirred, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (Hex-AcOEt). The obtained oil was dissolved in 1N-HCl-EtOH (3 mL), and ethanol was distilled off under reduced pressure. The precipitated crystal was recrystallized from ethanol / acetone to obtain (4aS, 8aR) -1- (3-chloro-4-fluorophenyl) -3,3-dimethyldecahydroquinoxaline hydrochloride (153 mg, yield) as white powder. (Rate: 46%)
¹ H-NMR (DMSO-d ₆ ) δppm: 1.15-1.45 (6H, m), 1.51 (3H, s), 1.6-1.9 (4H, m), 1.9-2.05 (1H, s), 2.01 (1H, d, J = 8.2Hz), 3.3-3.45 (1H, m), 3.65-3.8 (1H, m), 3.95-4.1 (1H, m), 6.85-7.0 (1H, m), 7.12 (1H, dd, J = 3.0, 6.2Hz), 7.25 (1H, dd, J = 9.1, 9.1Hz), 8.13 (1H, br), 9.86 (1H, br).

の製造
（４ａＳ，８ａＲ）−２，２−ジメチルデカヒドロキノキサリン（１６８ｍｇ，０．９９８ｍｍｏｌ）、５−ブロモ−１−メチル−１Ｈ−インドール−２−カルボニトリル（２５９ｍｇ，１．１０ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１１．２ｍｇ，０．０４９９ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（１４．５ｍｇ，０．０５００ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（４ｍＬ）懸濁液を窒素雰囲気下、４時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ４を加え攪拌した。不溶物をセライトろ過し、ＣＨ_２Ｃｌ_２：ＭｅＯＨ（３：１）（５ｍＬ×２）で洗浄後、ろ液を減圧濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、無色油状物を得た。この油状物をヘキサン（１ｍＬ）から結晶化し、淡黄色粉末の５−（（４ａＲ，８ａＳ）−３，３−ジメチルデカヒドロキノキサリン−１−イル）−１−メチル−１Ｈ−インドール−２−カルボニトリル
を得た（１４８ｍｇ，収率：４６％）。
¹H-NMR ( CDCl₃ ) δppm : 0.7-2.3 ( 15H, m ), 2.7-3.2 ( 2H, m ), 3.5-3.8 ( 2H, m ), 3.85 ( 3H, s ), 6.95-7.05 ( 2H, m ), 7.15-7.3 ( 2H, m ). Example 150 5-((4aR, 8aS) -3,3-dimethyldecahydroquinoxalin-1-yl) -1-methyl-1H-indole-2-carbonitrile

(4aS, 8aR) -2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 5-bromo-1-methyl-1H-indole-2-carbonitrile (259 mg, 1.10 mmol), Pd ( OAc) ₂ (11.2 mg, 0.0499 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (14.5 mg, 0.0500 mmol) and NaOt-Bu (135 mg, 1.40 mmol) in toluene (4 mL) was stirred under reflux for 4 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, and MgSO4 was further added and stirred. The insoluble material was filtered through Celite, washed with CH ₂ Cl ₂ : MeOH (3: 1) (5 mL × 2), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to give a colorless oil. This oil was crystallized from hexane (1 mL) to give 5-((4aR, 8aS) -3,3-dimethyldecahydroquinoxalin-1-yl) -1-methyl-1H-indole-2-carbohydrate as a pale yellow powder. The nitrile was obtained (148 mg, yield: 46%).
¹ H-NMR (CDCl ₃ ) δppm: 0.7-2.3 (15H, m), 2.7-3.2 (2H, m), 3.5-3.8 (2H, m), 3.85 (3H, s), 6.95-7.05 (2H, m), 7.15-7.3 (2H, m).

の製造
（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（４００ｍｇ，２．３８ｍｍｏｌ）、４−ブロモ−２−クロロベンゾニトリル（６６９ｍｇ，３．０９ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（５３ｍｇ，０．２４ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（７０ｍｇ，０．２４ｍｍｏｌ）、ｔ−ＢｕＯＮａ（３２０ｍｇ，３．３３ｍｍｏｌ）のトルエン（１０ｍＬ）懸濁液を窒素雰囲気下、５時間還流攪拌した。反応液を冷却後、不溶物をセライトろ過し、ろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）で精製し、オレンジ色のアモルファス固体を得た。このアモルファス固体を酢酸エチル（５ｍＬ）に溶解し、４Ｎ−ＨＣｌ／ＡｃＯＥｔ（０．６ｍＬ）を加え、析出した結晶をろ取、減圧乾燥し、ｐａｌｅｏｒａｎｇｅｐｏｗｄｅｒの（４ａＳ，８ａＳ）−１−（３−クロロ−４−シアノフェニル）−３，３−ジメチルデカヒドロキノキサリン塩酸塩を得た（３０４ｍｇｍ，４８％）。
¹H-NMR ( CDCl₃ ) δppm :1.05-1.20 (1H, m), 1.23-1.44 (2H, m), 1.54-2.10 (4H, m), 1.63 (3H, s), 1.68 (3H, s), 2.35-2.40 (1H, m), 2.89 (1H, d, J = 12.7 Hz), 3.19 (2H, br), 3.34 (1H, d, J = 12.7 Hz), 7.06 (1H, dd, J = 8.4, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br) [Example 237] (4aS, 8aS) -1- (3-Chloro-4-cyanophenyl) -3,3-dimethyldecahydroquinoxaline hydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (400 mg, 2.38 mmol), 4-bromo-2-chlorobenzonitrile (669 mg, 3.09 mmol), Pd (OAc) ₂ (53 mg, 0 .24mmol), _t-Bu 3 P. A suspension of HBF ₄ (70 mg, 0.24 mmol) and t-BuONa (320 mg, 3.33 mmol) in toluene (10 mL) was stirred at reflux under a nitrogen atmosphere for 5 hours. After cooling the reaction solution, the insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH) to obtain an orange amorphous solid. This amorphous solid was dissolved in ethyl acetate (5 mL), 4N-HCl / AcOEt (0.6 mL) was added, and the precipitated crystals were collected by filtration, dried under reduced pressure, and (4aS, 8aS) -1- (3- Chloro-4-cyanophenyl) -3,3-dimethyldecahydroquinoxaline hydrochloride was obtained (304 mgm, 48%).
¹ H-NMR (CDCl ₃ ) δppm: 1.05-1.20 (1H, m), 1.23-1.44 (2H, m), 1.54-2.10 (4H, m), 1.63 (3H, s), 1.68 (3H, s) , 2.35-2.40 (1H, m), 2.89 (1H, d, J = 12.7 Hz), 3.19 (2H, br), 3.34 (1H, d, J = 12.7 Hz), 7.06 (1H, dd, J = 8.4 , 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br)

の製造
（４ａ’Ｒ，８ａ’Ｓ）−オクタヒドロ−１’Ｈ−スピロ［シクロブタン−１，２’−キノキサリン］（１８０ｍｇ，０．９９８ｍｍｏｌ）、４−ブロモ−７−メトキシベンゾフラン（２５０ｍｇ，１．１０ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１１．２ｍｇ，０．０４９９ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（１４．５ｍｇ，０．０５００ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（４ｍＬ）懸濁液を窒素雰囲気下、４時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ４を加え攪拌した。不溶物をろ過し、ＡｃＯＥｔ（５ｍＬ×２）で洗浄後、ろ液を減圧濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、無色アモルファス固体を得た。この固体をヘキサン（１ｍＬ）から結晶化し、白色粉末の（４ａ’Ｒ，８ａ’Ｓ）−４’−（７−メトキシベンゾフラン−４−イル）オクタヒドロ−１’Ｈ−スピロ［シクロブタン−１，２’−キノキサリン］を得た（１０７ｍｇ，収率：３５％）。
¹H-NMR ( CDCl₃ ) δppm : 0.95-1.1 ( 2H, m ), 1.3-1.4 ( 1H, m ), 1,4-2.1 ( 11H, m ), 2.25-2.4 ( 1H, m ), 3.01 ( 1H, d, J = 11.0Hz ), 3.17 ( 1H, d, J = 11.1Hz ), 3.40 ( 1H, br ), 3.45-3.5 ( 1H, m ), 3.97 ( 3H, s ), 6.58 ( 1H, d, J = 8.4Hz ), 6.70 ( 1H, d, J = 8.4Hz ), 6.80 ( 1H, d, J = 2.1Hz ), 7.58 ( 1H, d, J = 2.1Hz ). Example 579 (4a′R, 8a ′S) -4 ′-(7-methoxybenzofuran-4-yl) octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]

(4a′R, 8a ′S) -octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline] (180 mg, 0.998 mmol), 4-bromo-7-methoxybenzofuran (250 mg, 1. 10 mmol), Pd (OAc) ₂ (11.2 mg, 0.0499 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (14.5 mg, 0.0500 mmol) and NaOt-Bu (135 mg, 1.40 mmol) in toluene (4 mL) was stirred under reflux for 4 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, and MgSO4 was further added and stirred. The insoluble material was filtered off, washed with AcOEt (5 mL × 2), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless amorphous solid. This solid was crystallized from hexane (1 mL) and (4a′R, 8a ′S) -4 ′-(7-methoxybenzofuran-4-yl) octahydro-1′H-spiro [cyclobutane-1,2] in the form of a white powder. '-Quinoxaline] was obtained (107 mg, yield: 35%).
¹ H-NMR (CDCl ₃ ) δppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1,4-2.1 (11H, m), 2.25-2.4 (1H, m), 3.01 ( 1H, d, J = 11.0Hz), 3.17 (1H, d, J = 11.1Hz), 3.40 (1H, br), 3.45-3.5 (1H, m), 3.97 (3H, s), 6.58 (1H, d , J = 8.4Hz), 6.70 (1H, d, J = 8.4Hz), 6.80 (1H, d, J = 2.1Hz), 7.58 (1H, d, J = 2.1Hz).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２５２ｍｇ，１．５０ｍｍｏｌ）、４−ブロモ−６，７−ジフルオロベンゾフラン（３８４ｍｇ，１．６５ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１６．８ｍｇ，０．０７４８ｍｍｏｌ）、ｔ−Ｂｕ_３Ｐ．ＨＢＦ_４（２１．８ｍｇ，０．０７５１ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（２０２ｍｇ，２．１０ｍｍｏｌ）のトルエン（６ｍＬ）懸濁液を窒素雰囲気下、３時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ_４を加え攪拌した後、不溶物をセライトろ過した。ろ液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、微黄色油状物を得た（１９３ｍｇ）。この油状物をエタノール（２ｍＬ）に溶解し、１Ｎ−ＨＣｌ−ＥｔＯＨ（１．２ｍＬ）を加え、攪拌した。析出した結晶をろ取、酢酸エチルで洗浄後、減圧乾燥し、白色粉末の（４ａＳ，８ａＲ）−１−（６，７−ジフルオロベンゾフラン−４−イル）−３，３−ジメチルデカヒドロキノキサリン塩酸塩を得た（１６７ｍｇ，収率：３１％）。
¹H-NMR ( DMSO-d₆ ) δppm : 1.01-1.17 ( 2H, m ), 1.34-1.44 ( 1H, m ), 1.48 ( 3H, s ), 1.52 ( 3H, s ), 1.59-2.07 ( 5H, m ), 3.00 ( 1H, d, J = 13.0Hz ), 3.28 ( 1H, d, J = 13.2Hz ), 3.75-3.9 ( 1H, m ), 4.0-4.15 ( 1H, m ), 6.83 ( 1H, dd, J = 5.9, 13.5Hz ), 7.36 ( 1H ,dd, J = 2.6, 2.6Hz ), 8.0-8.2 ( 2H, m ), 9.7-9.9 ( 1H, m ). Example 580 (4aS, 8aR) -1- (6,7-difluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline hydrochloride

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol), 4-bromo-6,7-difluorobenzofuran (384 mg, 1.65 mmol), Pd (OAc) ₂ (16. 8 mg, 0.0748 mmol), t-Bu ₃ P.I. A suspension of HBF ₄ (21.8 mg, 0.0751 mmol) and NaOt-Bu (202 mg, 2.10 mmol) in toluene (6 mL) was stirred under reflux for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (0.5 mL), and stirred with AcOEt (10 mL), was added and stirred further over MgSO _4, the insolubles were filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a slightly yellow oil (193 mg). This oil was dissolved in ethanol (2 mL), 1N-HCl-EtOH (1.2 mL) was added, and the mixture was stirred. The precipitated crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to give (4aS, 8aR) -1- (6,7-difluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline hydrochloride as a white powder. The salt was obtained (167 mg, yield: 31%).
¹ H-NMR (DMSO-d ₆ ) δppm: 1.01-1.17 (2H, m), 1.34-1.44 (1H, m), 1.48 (3H, s), 1.52 (3H, s), 1.59-2.07 (5H, m), 3.00 (1H, d, J = 13.0 Hz), 3.28 (1H, d, J = 13.2 Hz), 3.75-3.9 (1H, m), 4.0-4.15 (1H, m), 6.83 (1H, dd , J = 5.9, 13.5Hz), 7.36 (1H, dd, J = 2.6, 2.6Hz), 8.0-8.2 (2H, m), 9.7-9.9 (1H, m).

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、５−ブロモ−１−（トリイソプロピルシリル）−１Ｈ−インドール−２−カルボニトリル（４９３ｍｇ，１．３１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１３．３ｍｇ，０．０５９４ｍｍｏｌ）、ｔＢｕ_３Ｐ．ＨＢＦ_４（１７．２ｍｇ，０．０５９４ｍｍｏｌ）、ｔ−ＢｕＯＮａ（１３７ｍｇ，１．４３ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を窒素雰囲気下、１００℃で４時間攪拌した。不溶物をセライトろ過し、ろ液を濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ）し、白色アモルファス固形物の（４ａＳ，８ａＳ）−１−（２−シアノ−１−（トリイソプロピルシリル）−１Ｈ−インドール−５−イル）３，３−ジメチルデカヒドロキノキサリンを得た（４３０ｍｇ，７８％）。
¹H-NMR (CDCl₃) δppm : 0.75-1.38 (26H, m), 1.41 (3H, s), 1.54-1.77 (4H, m), 2.01 (1H, sextet, J = 7.5 Hz), 2.25-2.32 (1H, m), 2.65 (1H, d, J = 11.2 Hz), 2.75-2.85 (2H, m), 7.11 (1H, dd, J = 2.0, 9.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.33 (1H, d, J = 0.5 Hz), 7.50 (1H, d, J = 9.1 Hz). Example 581 (4aS, 8aS) -1- (2-cyano-1- (triisopropylsilyl) -1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-1- (triisopropylsilyl) -1H-indole-2-carbonitrile (493 mg, 1.31 mmol), Pd (OAc) ₂ (13.3 mg, 0.0594 mmol), tBu ₃ P.I. A suspension of HBF ₄ (17.2 mg, 0.0594 mmol) and t-BuONa (137 mg, 1.43 mmol) in toluene (5 mL) was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt / Hexane), and (4aS, 8aS) -1- (2-cyano-1- (triisopropylsilyl) -1H-indole- was obtained as a white amorphous solid. 5-yl) 3,3-dimethyldecahydroquinoxaline was obtained (430 mg, 78%).
¹ H-NMR (CDCl ₃ ) δppm: 0.75-1.38 (26H, m), 1.41 (3H, s), 1.54-1.77 (4H, m), 2.01 (1H, sextet, J = 7.5 Hz), 2.25-2.32 (1H, m), 2.65 (1H, d, J = 11.2 Hz), 2.75-2.85 (2H, m), 7.11 (1H, dd, J = 2.0, 9.1 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.33 (1H, d, J = 0.5 Hz), 7.50 (1H, d, J = 9.1 Hz).

の製造
（４ａＳ，８ａＳ）−１−（２−シアノ−１−（トリイソプロピルシリル）−１Ｈ−インドール−５−イル）３，３−ジメチルデカヒドロキノキサリン（１７０ｍｇ，０．３６６ｍｍｏｌ）の脱水テトラヒドロフラン（５ｍＬ）溶液にテトラブチルアンモニウムフルオライド（１Ｍ−ＴＨＦ溶液，０．７３ｍＬ，０．７３ｍｍｏｌ）を室温で加え、反応液を室温で１時間攪拌した。反応液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／１０→１／１）し、溶媒を減圧除去した。得られた残渣を酢酸エチル／ｎ−ヘキサンから再結晶し白色粉末の（４ａＳ，８ａＳ）−１−（２−シアノ−１Ｈ−インドール−５−イル）３，３−ジメチルデカヒドロキノキサリンを得た（３０ｍｇ，収率：２７％）。
¹H-NMR (DMSO-d₆) δppm : 0.82-1.00 (4H, m), 1.18-1.34 (6H, m), 1.42-1.67 (5H, m), 2.19-2.27 (1H, m), 2.55 (1H, d, J = 10.9 Hz), 2.59-2.69 (2H, m), 7.11 (1H, dd, J = 1.8, 8.8 Hz), 7.26 (1H, d, J = 0.8 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.36 (1J, d, J = 8.8 Hz). [Example 582] (4aS, 8aS) -1- (2-Cyano-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline

Preparation of (4aS, 8aS) -1- (2-cyano-1- (triisopropylsilyl) -1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (170 mg, 0.366 mmol) in dehydrated tetrahydrofuran (170 mg, 0.366 mmol) 5 mL) solution was added tetrabutylammonium fluoride (1M-THF solution, 0.73 mL, 0.73 mmol) at room temperature, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (AcOEt / Hexane = 1/10 → 1/1), and the solvent was removed under reduced pressure. The obtained residue was recrystallized from ethyl acetate / n-hexane to obtain (4aS, 8aS) -1- (2-cyano-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline as a white powder. (30 mg, yield: 27%).
¹ H-NMR (DMSO-d ₆ ) δppm: 0.82-1.00 (4H, m), 1.18-1.34 (6H, m), 1.42-1.67 (5H, m), 2.19-2.27 (1H, m), 2.55 ( 1H, d, J = 10.9 Hz), 2.59-2.69 (2H, m), 7.11 (1H, dd, J = 1.8, 8.8 Hz), 7.26 (1H, d, J = 0.8 Hz), 7.32 (1H, d , J = 1.8 Hz), 7.36 (1J, d, J = 8.8 Hz).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（１６８ｍｇ，０．９９８ｍｍｏｌ）、４−ブロモ−７−クロロ−２，３−ジヒドロ−１Ｈ−インデン（２５５ｍｇ，１．１０ｍｍｏｌ）、ＮａＯｔ−Ｂｕ（１３５ｍｇ，１．４０ｍｍｏｌ）のトルエン（４ｍＬ）懸濁液に、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（２５．６ｍｇ，０．０５０１ｍｍｏｌ）のトルエン（１ｍＬ）溶液を加え、窒素雰囲気下、４時間還流下攪拌した。反応液を室温まで冷却後、水（０．５ｍＬ）、ＡｃＯＥｔ（１０ｍＬ）加えて攪拌し、さらにＭｇＳＯ４を加え攪拌した。不溶物をセライトろ過し、ＡｃＯＥｔ（５ｍＬ×２）で洗浄後、ろ液を減圧濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（Ｈｅｘ−ＡｃＯＥｔ）にて精製し、白色固体を得た（１６７ｍｇ）。この固体をエタノール／水から再結晶を行い、白色粉末の（４ａＳ，８ａＲ）−１−（７−クロロ−２，３−ジヒドロ−１Ｈ−インデン−４−イル）−３，３−ジメチルデカヒドロキノキサリンを得た（１３６ｍｇ，収率：４３％）。 Example 583 (4aS, 8aR) -1- (7-chloro-2,3-dihydro-1H-inden-4-yl) -3,3-dimethyldecahydroquinoxaline

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-chloro-2,3-dihydro-1H-indene (255 mg, 1.10 mmol), NaOt To a suspension of -Bu (135 mg, 1.40 mmol) in toluene (4 mL) was added a solution of bis (tri-tert-butylphosphine) palladium (25.6 mg, 0.0501 mmol) in toluene (1 mL), and under a nitrogen atmosphere. The mixture was stirred for 4 hours under reflux. After cooling the reaction solution to room temperature, water (0.5 mL) and AcOEt (10 mL) were added and stirred, and MgSO4 was further added and stirred. The insoluble material was filtered through Celite, washed with AcOEt (5 mL × 2), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (167 mg). This solid was recrystallized from ethanol / water to give (4aS, 8aR) -1- (7-chloro-2,3-dihydro-1H-inden-4-yl) -3,3-dimethyldecahydro as white powder. Quinoxaline was obtained (136 mg, yield: 43%).

の製造
（４ａＲ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、６−ブロモ−２−ナフトニトリル（３０３ｍｇ，１．３１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１３．３ｍｇ，０．０５９４ｍｍｏｌ）、ｔＢｕ_３Ｐ．ＨＢＦ_４（１７．２ｍｇ，０．０５９４ｍｍｏｌ）、ｔ−ＢｕＯＮａ（１３７ｍｇ，１．４３ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を１００℃で４時間攪拌した。不溶物をセライトろ過し、ろ液を濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ）し、溶媒を減圧除去した。得られた残渣を酢酸エチル溶液とし、これに１Ｎ−塩酸−エタノールを加え、析出晶をロ取した。得られた結晶を減圧乾燥し白色粉末の（４ａＳ，８ａＳ）−１−（６−シアノナフタレン−２−イル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩を得た（３０３ｍｇ，収率：６５％）。
¹H-NMR (DMSO-d₆) δppm : 1.10-1.50 (6H, m), 1.56-1.90 (7H, m), 2.00-2.14 (1H, m), 3.08-3.45 (4H, m), 4.65-5.33 (1H, br), 7.45 (1H, dd, J = 2.0, 8.9 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.73 (1H, dd, J = 1.6, 8.6 Hz), 8.00 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, s), 9.10-9.28 (1H, br), 9.60-9.78 (1H, br). Example 584 (4aS, 8aS) -1- (6-cyanonaphthalen-2-yl) -3,3-dimethyldecahydroquinoxaline

(4aR, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 6-bromo-2-naphthonitrile (303 mg, 1.31 mmol), Pd (OAc) ₂ (13.3 mg, 0.0594 mmol), tBu ₃ P.I. A suspension of HBF ₄ (17.2 mg, 0.0594 mmol) and t-BuONa (137 mg, 1.43 mmol) in toluene (5 mL) was stirred at 100 ° C. for 4 hours. The insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt / Hexane), and the solvent was removed under reduced pressure. The obtained residue was made into an ethyl acetate solution, 1N hydrochloric acid-ethanol was added thereto, and the precipitated crystals were collected. The obtained crystals were dried under reduced pressure to obtain (4aS, 8aS) -1- (6-cyanonaphthalen-2-yl) -3,3-dimethyldecahydroquinoxaline dihydrochloride as a white powder (303 mg, yield: 65%).
¹ H-NMR (DMSO-d ₆ ) δppm: 1.10-1.50 (6H, m), 1.56-1.90 (7H, m), 2.00-2.14 (1H, m), 3.08-3.45 (4H, m), 4.65- 5.33 (1H, br), 7.45 (1H, dd, J = 2.0, 8.9 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.73 (1H, dd, J = 1.6, 8.6 Hz), 8.00 (1H , d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, s), 9.10-9.28 (1H, br), 9.60-9.78 (1H, br).

の製造
（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−１−（トリイソプロピルシリル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（４６２ｍｇ，１．３１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１３．３ｍｇ，０．０５９４ｍｍｏｌ）、ｔＢｕ_３Ｐ．ＨＢＦ_４（１７．２ｍｇ，０．０５９４ｍｍｏｌ）、ｔ−ＢｕＯＮａ（１３７ｍｇ，１．４３ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を窒素雰囲気下、１００℃で４時間攪拌した。不溶物をセライトろ過し、ろ液を濃縮した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ）し、白色アモルファス固形物の（４ａＳ，８ａＳ）−３，３−ジメチル−１−（１−（トリイソプロピルシリル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）デカヒドロキノキサリンを得た（４３９ｍｇ，８４％）。
¹H-NMR (CDCl₃) δppm : 0.95-1.20 (22H, m), 1.36-1.45 (3H, m), 1.52 (3H, s), 1.65-1.92 (7H, m), 2.11-2.20 (1H, m), 2.57-2.67 (2H, m), 2.83-2.95 (1H, m), 3.26- (1H, d, J = 11.7 Hz), 6.55 (1H, d, J = 3.5 Hz), 6.63 (1H, d, J = 5.3 Hz), 7.18 (1H, d, J = 3.5 Hz), 8.12 (1H, d, J = 5.3 Hz). Example 585 (4aS, 8aS) -3,3-dimethyl-1- (1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridine (462 mg, 1.31 mmol), Pd (OAc) ₂ (13.3 mg, 0.0594 mmol), tBu ₃ P.I. A suspension of HBF ₄ (17.2 mg, 0.0594 mmol) and t-BuONa (137 mg, 1.43 mmol) in toluene (5 mL) was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt / Hexane), and (4aS, 8aS) -3,3-dimethyl-1- (1- (triisopropylsilyl) -1H- was obtained as a white amorphous solid. Pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline was obtained (439 mg, 84%).
¹ H-NMR (CDCl ₃ ) δppm: 0.95-1.20 (22H, m), 1.36-1.45 (3H, m), 1.52 (3H, s), 1.65-1.92 (7H, m), 2.11-2.20 (1H, m), 2.57-2.67 (2H, m), 2.83-2.95 (1H, m), 3.26- (1H, d, J = 11.7 Hz), 6.55 (1H, d, J = 3.5 Hz), 6.63 (1H, d, J = 5.3 Hz), 7.18 (1H, d, J = 3.5 Hz), 8.12 (1H, d, J = 5.3 Hz).

の製造
（４ａＳ，８ａＳ）−３，３−ジメチル−１−（１−（トリイソプロピルシリル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）デカヒドロキノキサリン（４３０ｍｇ，０．９７６ｎｎｏｌ）の脱水テトラヒドロフラン（５ｍＬ）溶液に、フッ化テトラブチルアンモニウム（１Ｍ−ＴＨＦ溶液，１．９５ｍＬ，１．９５ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を減圧濃縮し、得られた残渣を塩基性シリカゲルカラムクロマトで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／１０→１／１）し、油状の生成物（３７０ｍｇ，１．３０ｍｍｏｌ）を得た。この油状物をエタノール（５ｍＬ）に溶解し、フマル酸（１５１ｍｇ）のエタノール（５ｍＬ）溶液を加え、エタノールを減圧除去した。得られた個体を、エタノール／酢酸エチルから再結晶し、白色粉末の（４ａＳ，８ａＳ）−３，３−ジメチル−１−（１Ｈ−ピロロ［２，３−ｂ］ピリジン−４−イル）デカヒドロキノキサリンフマル酸塩を得た（２４６ｍｇ，収率：６３％）。
¹H-NMR (DMSO-d₆) δppm : 0.94-1.09 (1H, m), 1.20 (3H, s), 1.26-1.55 (7H, m), 1.68-1.78 (1H, m), 1.85-2.04 (2H, m), 2.81-2.93 (1H, m), 2.95-3.23 (3H, m), 6.36-6.42 (1H, m), 6.49 (2H, s), 6.71 (1H, d, J = 5.2 Hz), 7.32-7.38 (1H, m), 8.09 (1H, d, J = 5.2 Hz), 8.50-11.20 (1H, br), 11.59 (1H, s). Example 586 (4aS, 8aS) -3,3-dimethyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline fumarate

(4aS, 8aS) -3,3-Dimethyl-1- (1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline (430 mg, 0.976 nnol) ) In anhydrous tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1M-THF solution, 1.95 mL, 1.95 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (AcOEt / Hexane = 1/10 → 1/1) to obtain an oily product (370 mg, 1.30 mmol). This oil was dissolved in ethanol (5 mL), a solution of fumaric acid (151 mg) in ethanol (5 mL) was added, and ethanol was removed under reduced pressure. The obtained solid was recrystallized from ethanol / ethyl acetate to give (4aS, 8aS) -3,3-dimethyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) deca in the form of a white powder. Hydroquinoxaline fumarate was obtained (246 mg, yield: 63%).
¹ H-NMR (DMSO-d ₆ ) δppm: 0.94-1.09 (1H, m), 1.20 (3H, s), 1.26-1.55 (7H, m), 1.68-1.78 (1H, m), 1.85-2.04 ( 2H, m), 2.81-2.93 (1H, m), 2.95-3.23 (3H, m), 6.36-6.42 (1H, m), 6.49 (2H, s), 6.71 (1H, d, J = 5.2 Hz) , 7.32-7.38 (1H, m), 8.09 (1H, d, J = 5.2 Hz), 8.50-11.20 (1H, br), 11.59 (1H, s).

の製造
（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−１−ジフルオロメトキシ−２−フルオロベンゼン（３１５ｍｇ，１．３１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１３．３ｍｇ，０．０５９４ｍｍｏｌ）、ｔＢｕ_３Ｐ．ＨＢＦ_４（１７．２ｍｇ，０．０５９４ｍｍｏｌ）、ｔ−ＢｕＯＮａ（１３７ｍｇ，１．４３ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を１００℃で４時間攪拌した。不溶物をセライトろ過し、ろ液を濃縮した。得られた残渣を塩基性−シリカゲルカラムクロマトで精製（ＡｃＯＥｔ／Ｈｅｘａｎｅ）し、溶媒を減圧除去した。得られた残渣を酢酸エチル溶液とし、これに１Ｎ−塩酸−エタノールを加え、析出晶をろ取した。得られた結晶を減圧乾燥し白色粉末の（４ａＳ，８ａＳ）−１−（４−ジフルオロメトキシ−３−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩を得た（３０３ｍｇ，収率：６５％）。
¹H-NMR (DMSO-d₆) δppm :1.01-1.39 (6H, m), 1.49-1.67 (6H, m), 1.67-1.77 (1H, m), 1.96-2.05 (1H, m), 2.81-2.95 (2H, m), 3.02 (1H, d, J = 12.5 Hz), 3.10-3.23 (1H, m), 6.96-7.01 (1H, m), 7.02 (0.25H, s), 7.17 (1H, dd, J = 2.5, 12.1 Hz), 7.20 (0.5H, s), 7.33 (1H, t, J = 8.9 Hz), 7.39 (0.25H, s), 9.04-9.21 (1H, m), 9.70-9.85 (1H, m).
［実施例１６７７］（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−４−トリフルオロメチルフェニル）デカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−２−クロロ−１−トリフルオロメチルベンゼン（３７０ｍｇ，１．４３ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−４−トリフルオロメチルフェニル）デカヒドロキノキサリン２塩酸塩（３４８ｍｇ，収率７０％）を得た。
［実施例１６８０］（４ａＳ，８ａＳ）−１−エチニルフェニル−３，３−ジメチルデカヒドロキノキサリン シュウ酸塩

（４ａＳ，８ａＳ）−３，３−ジメチル−１−（４−トリメチルシリルエチニルフェニル）−デカヒドロキノキサリン（３２０ｍｇ，０．９４０ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）懸濁液を、室温攪拌下に１Ｎ−テトラブチルアンモニウムフルオライド／テトラヒドロフラン溶液（１．８８ｍＬ）を加え、一夜攪拌した。反応混合物を減圧濃縮して得られた残渣を、ＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下にシュウ酸（８４．６ｍｇ）のエタノール（５ｍｌ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−エチニルフェニル−３，３−ジメチルデカヒドロキノキサリン シュウ酸塩（１８７ｍｇ，収率５５％）を得た。
［実施例１６８７］（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−４−シクロプロポキシフェニル）デカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−２−クロロ−１−シクロプロポキシベンゼン（３２４ｍｇ，１．３１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−４−シクロプロポキシフェニル）デカヒドロキノキサリン２塩酸塩（３３４ｍｇ，収率６９％）を得た。
［実施例１６９３］（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−５−フルオロ−４−メトキシフェニル）デカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、５−ブロモ−１−クロロ−３−フルオロ−２−メトキシベンゼン（３４２ｍｇ，１．４３ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−３，３−ジメチル−１−（３−クロロ−５−フルオロ−４−メトキシフェニル）デカヒドロキノキサリン２塩酸塩（３２０ｍｇ，収率６７％）を得た。
［実施例１６９５］（４ａＳ，８ａＳ）−１−（４−ジフルオロメトキシ−３−ジフルオロメチルフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−１−ジフルオロメトキシ−２−ジフルオロメチルベンゼン（３５７ｍｇ，１．３１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−（４−ジフルオロメトキシ−３−ジフルオロメチルフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩（２８１ｍｇ，収率５４％）を得た。
［実施例１６９６］（４ａＳ，８ａＳ）−１−（３−クロロ−４−ジフルオロメトキシ−５−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、５−ブロモ−１−クロロ−２−ジフルオロメトキシ−３−フルオロベンゼン（３６０ｍｇ，１．３１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−（３−クロロ−４−ジフルオロメトキシ−５−フルオロフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩（１２０ｍｇ，収率２３％）を得た。
［実施例１６９７］（４ａＳ，８ａＳ）−１−（４−（１，１−ジフルオロエトキシ）フェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、１−ブロモ−４−（１，１−ジフルオロエトキシ）ベンゼン（３１０ｍｇ，１．３１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−（４−（１，１−ジフルオロエトキシ）フェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩（３４２ｍｇ，収率７２％）を得た。
［実施例１６９８］（４ａＳ，８ａＳ）−１−（３−クロロ−４−トリフルオロメトキシフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−２−クロロ−１−トリフルオロメトキシベンゼン（３９３ｍｇ，１．４３ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−（３−クロロ−４−トリフルオロメトキシフェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩（３０８ｍｇ，収率５９％）を得た。
［実施例１７３１］（４ａＳ，８ａＳ）−１−（４−ジフルオロメトキシ−３−（ジフルオロメチル）フェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩

（４ａＳ，８ａＳ）−２，２−ジメチルデカヒドロキノキサリン（２００ｍｇ，１．１９ｍｍｏｌ）、４−ブロモ−１−ジフルオロメトキシ−２−ジフルオロメチルベンゼン（３５７ｍｇ，１．３１ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１３７ｍｇ，１．４３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（２１．３ｍｇ，０．０９５１ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（２７．６ｍｇ，０．０９５１ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下に、１Ｎ−塩酸／エタノール（５．０ｍＬ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（４ａＳ，８ａＳ）−１−（４−ジフルオロメトキシ−３−（ジフルオロメチル）フェニル）−３，３−ジメチルデカヒドロキノキサリン２塩酸塩（２８１ｍｇ，収率５４％）を得た。
［実施例１７４０］（３Ｒ，４ａＳ，８ａＳ）−１−（３−クロロ−４−ジフルオロメトキシ−５−フルオロフェニル）−３−メチルデカヒドロキノキサリン シュウ酸塩

（２Ｒ，４ａＳ，８ａＳ）−２−メチルデカヒドロキノキサリン（３００ｍｇ，１．９４ｍｍｏｌ）、５−ブロモ−１−クロロ−２−ジフルオロメトキシ−３−フルオロベンゼン（５８９ｍｇ，２．１４ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（２２４ｍｇ，２．３３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（４３．７ｍｇ，０．１９４ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（５６．４ｍｇ，０．１９４ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下にシュウ酸（６１ｍｇ）のエタノール（５ｍｌ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（３Ｒ，４ａＳ，８ａＳ）−１−（３−クロロ−４−ジフルオロメトキシ−５−フルオロフェニル）−３−メチルデカヒドロキノキサリン シュウ酸塩（５２ｍｇ，収率６％）を得た。
［実施例１７４１］（３Ｒ，４ａＳ，８ａＳ）−１−（３−フルオロ−４−ジフルオロメトキシフェニル）−３−メチルデカヒドロキノキサリン シュウ酸塩

（２Ｒ，４ａＳ，８ａＳ）−２−メチルデカヒドロキノキサリン（３００ｍｇ，１．９４ｍｍｏｌ）、４−ブロモ−２−フルオロ−１−トリフルオロメトキシベンゼン（５５４ｍｇ，２．１４ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（２２４ｍｇ，２．３３ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（４３．７ｍｇ，０．１９４ｍｍｏｌ）及びトリ−ｔｅｒｔ−ブチルホスフィン・テトラフルオロボレート（５６．４ｍｇ，０．１９４ｍｍｏｌ）のトルエン（５ｍＬ）懸濁液を、窒素雰囲気下に１００℃で４時間攪拌した。反応混合物を室温に冷却した後、不溶物をセライト濾過し、濾液を減圧濃縮した。得られた残渣をＮＨ−シリカゲルカラムクロマト精製（ｎ−ヘキサン：酢酸エチル）して淡黄色油状物を得た。得られた油状物のエタノール溶液を室温攪拌下にシュウ酸（６７ｍｇ）のエタノール（５ｍｌ）を加えよく攪拌した後、この混合溶液を減圧濃縮した。得られた油状物に適量のエタノール／酢酸エチルを加え、析出晶を濾取した。得られた結晶を酢酸エチルで洗浄した後、減圧下乾燥し、白色粉末の（３Ｒ，４ａＳ，８ａＳ）−１−（３−フルオロ−４−ジフルオロメトキシフェニル）−３−メチルデカヒドロキノキサリン シュウ酸塩（２４０ｍｇ，収率２９％）を得た。 Example 587 (4aS, 8aS) -1- (4- (difluoromethoxy) -3-fluorophenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1-difluoromethoxy-2-fluorobenzene (315 mg, 1.31 mmol), Pd (OAc) ₂ (13.3 mg, 0.0594 mmol), tBu ₃ P.I. A suspension of HBF ₄ (17.2 mg, 0.0594 mmol) and t-BuONa (137 mg, 1.43 mmol) in toluene (5 mL) was stirred at 100 ° C. for 4 hours. The insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by basic-silica gel column chromatography (AcOEt / Hexane), and the solvent was removed under reduced pressure. The obtained residue was made into an ethyl acetate solution, 1N-hydrochloric acid-ethanol was added thereto, and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain white powder of (4aS, 8aS) -1- (4-difluoromethoxy-3-fluorophenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride (303 mg, yield). : 65%).
¹ H-NMR (DMSO-d ₆ ) δppm: 1.01-1.39 (6H, m), 1.49-1.67 (6H, m), 1.67-1.77 (1H, m), 1.96-2.05 (1H, m), 2.81- 2.95 (2H, m), 3.02 (1H, d, J = 12.5 Hz), 3.10-3.23 (1H, m), 6.96-7.01 (1H, m), 7.02 (0.25H, s), 7.17 (1H, dd , J = 2.5, 12.1 Hz), 7.20 (0.5H, s), 7.33 (1H, t, J = 8.9 Hz), 7.39 (0.25H, s), 9.04-9.21 (1H, m), 9.70-9.85 ( 1H, m).
Example 1677 (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-4-trifluoromethylphenyl) decahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-2-chloro-1-trifluoromethylbenzene (370 mg, 1.43 mmol), sodium tert-butoxide (137 mg) , 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-4-trifluoromethylphenyl) decahydroquinoxaline 2 as white powder. The hydrochloride (348 mg, 70% yield) was obtained.
Example 1680 (4aS, 8aS) -1-ethynylphenyl-3,3-dimethyldecahydroquinoxaline oxalate

A suspension of (4aS, 8aS) -3,3-dimethyl-1- (4-trimethylsilylethynylphenyl) -decahydroquinoxaline (320 mg, 0.940 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature with 1N-tetrabutyl. Ammonium fluoride / tetrahydrofuran solution (1.88 mL) was added and stirred overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to obtain a pale yellow oil. Ethanol (5 ml) of oxalic acid (84.6 mg) was added to the ethanol solution of the obtained oily substance at room temperature and stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1-ethynylphenyl-3,3-dimethyldecahydroquinoxaline oxalate (187 mg, yield 55%) as a white powder. Got.
Example 1687 (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-4-cyclopropoxyphenyl) decahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-2-chloro-1-cyclopropoxybenzene (324 mg, 1.31 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under an atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate, dried under reduced pressure, and (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-4-cyclopropoxyphenyl) decahydroquinoxaline dihydrochloride as white powder The salt (334 mg, 69% yield) was obtained.
Example 1693 (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-5-fluoro-4-methoxyphenyl) decahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-1-chloro-3-fluoro-2-methoxybenzene (342 mg, 1.43 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) Was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -3,3-dimethyl-1- (3-chloro-5-fluoro-4-methoxyphenyl) decahydro as a white powder. Quinoxaline dihydrochloride (320 mg, 67% yield) was obtained.
Example 1695 (4aS, 8aS) -1- (4-Difluoromethoxy-3-difluoromethylphenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1-difluoromethoxy-2-difluoromethylbenzene (357 mg, 1.31 mmol), sodium tert-butoxide (137 mg) , 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1- (4-difluoromethoxy-3-difluoromethylphenyl) -3,3-dimethyldecahydroquinoxaline 2 as white powder. The hydrochloride (281 mg, 54% yield) was obtained.
Example 1696 (4aS, 8aS) -1- (3-Chloro-4-difluoromethoxy-5-fluorophenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-1-chloro-2-difluoromethoxy-3-fluorobenzene (360 mg, 1.31 mmol), sodium tert- Suspension of butoxide (137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The solution was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1- (3-chloro-4-difluoromethoxy-5-fluorophenyl) -3,3-dimethyldeca as white powder. Hydroquinoxaline dihydrochloride (120 mg, 23% yield) was obtained.
Example 1697 (4aS, 8aS) -1- (4- (1,1-difluoroethoxy) phenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 1-bromo-4- (1,1-difluoroethoxy) benzene (310 mg, 1.31 mmol), sodium tert-butoxide ( 137 mg, 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1- (4- (1,1-difluoroethoxy) phenyl) -3,3-dimethyldecahydroquinoxaline as a white powder. Dihydrochloride (342 mg, 72% yield) was obtained.
Example 1698 (4aS, 8aS) -1- (3-Chloro-4-trifluoromethoxyphenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-2-chloro-1-trifluoromethoxybenzene (393 mg, 1.43 mmol), sodium tert-butoxide (137 mg) , 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1- (3-chloro-4-trifluoromethoxyphenyl) -3,3-dimethyldecahydroquinoxaline 2 as white powder. The hydrochloride (308 mg, 59% yield) was obtained.
Example 1731 (4aS, 8aS) -1- (4-difluoromethoxy-3- (difluoromethyl) phenyl) -3,3-dimethyldecahydroquinoxaline dihydrochloride

(4aS, 8aS) -2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1-difluoromethoxy-2-difluoromethylbenzene (357 mg, 1.31 mmol), sodium tert-butoxide (137 mg) , 1.43 mmol), palladium (II) acetate (21.3 mg, 0.0951 mmol) and tri-tert-butylphosphine tetrafluoroborate (27.6 mg, 0.0951 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. 1N-hydrochloric acid / ethanol (5.0 mL) was added to the ethanol solution of the obtained oily substance at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (4aS, 8aS) -1- (4-difluoromethoxy-3- (difluoromethyl) phenyl) -3,3-dimethyldecahydro as white powder. Quinoxaline dihydrochloride (281 mg, yield 54%) was obtained.
Example 1740 (3R, 4aS, 8aS) -1- (3-chloro-4-difluoromethoxy-5-fluorophenyl) -3-methyldecahydroquinoxaline oxalate

(2R, 4aS, 8aS) -2-methyldecahydroquinoxaline (300 mg, 1.94 mmol), 5-bromo-1-chloro-2-difluoromethoxy-3-fluorobenzene (589 mg, 2.14 mmol), sodium tert- Suspension of butoxide (224 mg, 2.33 mmol), palladium (II) acetate (43.7 mg, 0.194 mmol) and tri-tert-butylphosphine tetrafluoroborate (56.4 mg, 0.194 mmol) in toluene (5 mL) The solution was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. Ethanol (5 ml) of oxalic acid (61 mg) was added to the obtained ethanol solution of the oily substance with stirring at room temperature, and the mixture was stirred well, and then this mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (3R, 4aS, 8aS) -1- (3-chloro-4-difluoromethoxy-5-fluorophenyl) -3-methyldeca in the form of a white powder. Hydroquinoxaline oxalate (52 mg, 6% yield) was obtained.
[Example 1741] (3R, 4aS, 8aS) -1- (3-Fluoro-4-difluoromethoxyphenyl) -3-methyldecahydroquinoxaline oxalate

(2R, 4aS, 8aS) -2-methyldecahydroquinoxaline (300 mg, 1.94 mmol), 4-bromo-2-fluoro-1-trifluoromethoxybenzene (554 mg, 2.14 mmol), sodium tert-butoxide (224 mg) , 2.33 mmol), palladium (II) acetate (43.7 mg, 0.194 mmol) and tri-tert-butylphosphine tetrafluoroborate (56.4 mg, 0.194 mmol) in toluene (5 mL) The mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane: ethyl acetate) to give a pale yellow oil. Ethanol (5 ml) of oxalic acid (67 mg) was added to the obtained ethanol solution of the oily substance while stirring at room temperature, and the mixture was stirred well, and then the mixed solution was concentrated under reduced pressure. An appropriate amount of ethanol / ethyl acetate was added to the obtained oil, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried under reduced pressure to give (3R, 4aS, 8aS) -1- (3-fluoro-4-difluoromethoxyphenyl) -3-methyldecahydroquinoxaline oxalic acid as white powder The salt (240 mg, 29% yield) was obtained.

Examples 6 to 76, 78 to 105, 107 to 111, 113 to 149, 151 to 236, 238 to 578, 238 to 578, and 588 to 1656 shown in the following table were used in the same manner as in the above examples using the corresponding appropriate starting materials. 1657 to 1676, 1678 to 1679, 1681 to 1686, 1688 to 1692, 1694, 1699 to 1730, 1732 to 1739, and 1742 to 1750. In these tables, for example, the crystalline form, m. p. A compound having physical properties such as (melting point), salt, ¹ H-NMR and MS (mass spectrum) was produced.

Pharmacological test 1
Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of Test Compounds by Rat Brain Synaptosomes Male Wistar rats were decapitated, the brain was removed, and the frontal cortex was excised. The separated frontal cortex was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

  Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

  That is, a solvent, unlabeled 5-HT and serially diluted test compound were added to each well, and a synaptosomal fraction of one-tenth of the final volume was added to each well, followed by preincubation at 37 ° C. for 10 minutes, followed by tritium labeling. A 5-HT solution (final concentration 8 nM) was added to start the uptake reaction at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (non-specific uptake value) when unlabeled 5-HT (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 60.

Pharmacological test 2
Measurement of Norepinephrine (NE) Uptake Inhibitory Activity of Test Compound by Rat Brain Synaptosome Male Wistar rats were decapitated, the brain was removed, and the hippocampus was cut out. The separated hippocampus was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

  Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

  That is, a solvent, unlabeled NE and serially diluted test compound were added to each well, and a synaptosome fraction of one-tenth of the final volume was added to each well, followed by preincubation at 37 ° C. for 10 minutes, and then tritium-labeled NE solution. (Final concentration 12 nM) was added and the uptake reaction was started at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (nonspecific uptake value) when unlabeled NE (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 61.

Pharmacological test 3
Measurement of Dopamine (DA) Uptake Inhibitory Activity of Test Compounds by Rat Brain Synaptosomes Male Wistar rats were decapitated, the brain was removed, and the striatum was excised. The separated striatum was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

  Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

  That is, a solvent, unlabeled DA and serially diluted test compound were added to each well, and a synaptosomal fraction of 1/10 of the final volume was added to each well. After preincubation at 37 ° C. for 10 minutes, a tritium-labeled DA solution ( The final concentration 2 nM) was added to start the uptake reaction at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (non-specific uptake value) when unlabeled DA (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 62.

Pharmacological test 4
Forced swimming test This test was performed according to the method of Porsalt et al. (Porsolt, RD, et al., Behavioral despair in mice: A primary screening test for antidepressants. Archp. 29p. ).

  The test compound was suspended in 5% gum arabic / physiological saline solution (w / v) and orally administered to male ICR (ICR) mice (CLEA Japan (JCL), 5-6 weeks old). One hour later, the mouse was placed in a water tank with a water depth of 9.5 cm and a water temperature of 21 to 25 ° C., and a swimming trial was conducted immediately after that for 6 minutes. Then, the time during which the mouse did not move during the last 4 minutes (immobility time) was measured. For measurement and analysis of immobility time, a Scannet MV-20AQ (SCANET MV-20 AQ) system manufactured by Melquest was used.

  In this experiment, animals treated with test compounds showed a reduction in immobility time. From this it is clear that the test compound is useful as an antidepressant.

Search dynamics test 1
CYP2D6 contribution rate calculation test Human liver microsome solution containing test compound (final concentration 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 1.5 mg / mL human liver microsome, test compound 0 Metabolic reaction was initiated by adding and mixing quinidine solution (final concentration 0.001 mmol / L) and NADH / NADPH solution (final concentration 1 mmol / L), which are specific inhibitors of CYP2D6, to .001 mmol / L) . Moreover, an acetonitrile solution of spiperone (5 ng / mL) was prepared as an internal standard substance solution, and this was used as a reaction stop solution.
In other words, 2.5 μL of quinidine acetonitrile solution (or acetonitrile as a control) was added to and mixed with 222.5 μL of human liver microsome solution in ice water, 22.5 μL of which was collected and added to 500 μL of reaction stop solution. As a result, a sample was obtained at 0 minutes after the reaction. Thereafter, preincubation was performed at 37 ° C. for 5 minutes, and 22.5 μL of NADH / NADPH solution was added and mixed to initiate metabolic reaction. Incubation was performed at 37 ° C., and 25 μL of the reaction solution was taken 10 minutes, 30 minutes, and 60 minutes after the start of the reaction, and added to and mixed with 500 μL of the reaction stop solution to stop the reaction. The mixed solution was centrifuged (6130 g, 10 minutes, 4 ° C.), and the obtained supernatant was used as a sample for LC-MS / MS measurement.
The ratio of these peak areas ([peak area of test compound] / [peak area of internal standard substance]) was calculated using the test compound and spiperone as measurement targets. The slope of the straight line obtained from each incubation time and the decay (logarithmic value) of the peak area ratio of the test compound was compared in the presence of control and quinidine. ([Control slope]-[Slope in the presence of quinidine]) / [Control Slope] × 100, the contribution ratio (%) of CYP2D6 to the test compound was calculated.

Search dynamic test 2
CYP inhibition test Human liver microsome solution containing 3 CYP-specific substrates (final concentration 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 0.1 mg / mL human liver microsome, 0.005 mmol / L diclofenac (CYP2C9), 0.01 mmol / L bufuralol (CYP2D6), 0.005 mmol / L midazolam (CYP3A4)), test compound solution (final concentration 0.001 mmol / L) and NADH / NADPH solution ( The metabolic reaction was initiated by adding and mixing the final concentration (1 mmol / L). In addition, as an internal standard solution, stable isotopes of metabolites (50 ng / mL [13C6] diclofenac hydroxide, 5 ng / mL [2H9] bufuralol hydroxide, 5 ng / mL [13C6] midazolam hydroxide (both A stable isotope)) acetonitrile solution was prepared and used as a reaction stop solution.
That is, add and mix 2 μL of test compound acetonitrile solution (or acetonitrile as a control) to 178 μL of human liver microsome solution in ice water, preincubate at 37 ° C. for 1 minute, and then add 20 μL of NADH / NADPH solution. The metabolic reaction was started by mixing. After incubation at 37 ° C. for 10 minutes, 50 μL of the reaction solution was collected and added to and mixed with 500 μL of a reaction stop solution to stop the reaction. The mixed solution was centrifuged (6130 g, 10 minutes, 4 ° C.), and the obtained supernatant was used as a sample for LC-MS / MS measurement.
The peak area ratio ([peak area of metabolite] / [peak area of the corresponding stable isotope]) was calculated using the metabolite and the stable isotope of the metabolite as the measurement target. By comparing the peak area ratio when each test compound solution was added with that of the control, (1- [peak area ratio when adding each test compound solution] / [peak area ratio of control]) × 100 CYP molecular species inhibition rate (%) was calculated.

Test results for CYP2D6 revealed that the compounds of the present invention have excellent metabolic stability. In addition, the compounds shown in the table below showed a% inhibition rate of 60% or less with respect to CYP2D6.

Claims (21)

General formula (1):

[Wherein, m, l and n each represent an integer of 1 to 2, and X represents —O— or —CH ₂ —.
R ¹ represents hydrogen; a lower alkyl group; a hydroxy lower alkyl group; or a protective group or a tri-lower alkylsilyloxy lower alkyl group.
R ² and R ³ are the same or different and each independently represents hydrogen or a lower alkyl group; or R ² and R ³ are combined to form a cycloC3-C8 alkyl group.
R ⁴ represents an aromatic ring group or a heterocyclic group.
One or more arbitrary substituents may be present on the above aromatic ring or heterocyclic group. ]
Or a salt thereof. The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of Claim 1 whose R < ⁴ > shows either group shown below:
(1) phenyl group (2) indolyl group (3) benzothienyl group (4) naphthyl group (5) benzofuryl group (6) quinolyl group (7) isoquinolyl group (8) pyridyl group (9) thienyl group (10) dihydro Benzoxazinyl group (11) dihydrobenzodioxinyl group (12) dihydroquinolyl group (13) chromanyl group (14) quinoxalinyl group (15) dihydroindenyl group (16) dihydrobenzofuryl group (17) benzodi Oxolyl group (18) indazolyl group (19) benzothiazolyl group (20) indolinyl group (21) thienopyridyl group,
(22) Tetrahydrobenzoazepinyl group (23) Tetrahydrobenzodiazepinyl group (24) Dihydrobenzodioxepinyl group (25) Fluorenyl group (26) Pyridazinyl group (27) Tetrahydroquinolyl group (28) Carbazolyl group (29) Phenanthryl group (30) Dihydroacenaphthylenyl group (31) Pyrrolopyridyl group (32) Anthryl group (33) Benzodioxinyl group (34) Pyrrolidinyl group (35) Pyrazolyl group (36) Oxadiazolyl group (37) Pyrimidinyl group (38) tetrahydronaphthyl group (39) dihydroquinazolinyl group (40) benzoxazolyl group (41) thiazolyl group (42) quinazolinyl group (43) phthalazinyl group (44) pyrazinyl group (45) chromenyl group On an aromatic or heterocyclic ring May have one or more substituents selected from the following (1-1) to (1-43):
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) Oxadiazolyl group optionally having lower alkyl group (1-12) pyrrolidinyl group optionally having oxo group (1-13) phenyl group optionally having lower alkoxy group (1-14) lower alkylamino lower alkyl group (1-15) oxo The group (1-16) may have a lower alkyl group Pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) optionally have lower alkyl group Ryl group (1-20) Lower alkylamino group (1-21) Pyrimidyl group optionally having lower alkyl group (1-22) Phenyl lower alkenyl group (1-23) Halogen atom A good phenoxy group (1-24) a phenoxy lower alkyl group (1-25) a pyrrolidinyl lower alkoxy group (1-26) a lower alkylsulfamoyl group (1-27) an optionally substituted pyridazini Ruoxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower alkoxy group (1-32) hydroxy group (1 -33) Lower alkoxycarbonyl group (1-34) hydroxy lower alkyl group (1-35) oxazolyl group (1-36) piperidyl (1-37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group optionally having lower alkyl group (1-40) piperidyl lower alkyl group (1-41) pyrrolidinyl Lower alkyl group (1-42) Morpholinyl group (1-43) Piperazinyl group optionally having lower alkyl group. The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of Claim 2 whose R < ⁴ > shows either group shown below:
(1) phenyl group (2) indolyl group (3) benzothienyl group (4) naphthyl group (5) benzofuryl group (6) quinolyl group (7) isoquinolyl group (8) pyridyl group (9) thienyl group (10) dihydro Benzoxazinyl group (11) dihydrobenzodioxinyl group (12) dihydroquinolyl group (13) chromanyl group (14) quinoxalinyl group (15) dihydroindenyl group (16) dihydrobenzofuryl group (17) benzodi Oxolyl group (18) indazolyl group (19) benzothiazolyl group (20) indolinyl group (21) thienopyridyl group,
(22) Tetrahydrobenzoazepinyl group (23) Tetrahydrobenzodiazepinyl group (24) Dihydrobenzodioxepinyl group (25) Fluorenyl group (26) Pyridazinyl group (27) Tetrahydroquinolyl group (28) Carbazolyl group (29) Phenanthryl group (30) Dihydroacenaphthylenyl group (31) Pyrrolopyridyl group (32) Anthryl group (33) Benzodioxinyl group (34) Pyrrolidinyl group (35) Pyrazolyl group (36) Oxadiazolyl group (37) Pyrimidinyl group (38) tetrahydronaphthyl group (39) dihydroquinazolinyl group (40) benzoxazolyl group (41) thiazolyl group (42) quinazolinyl group (43) phthalazinyl group (44) pyrazinyl group (45) chromenyl group On an aromatic or heterocyclic ring May have 1 to 4 substituents selected from the following (1-1) to (1-43):
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) may have one lower alkyl group A pyrrolidinyl group (1-13) which may have one oxadiazolyl group (1-12) oxo group (1-13) a phenyl group which may have one lower alkoxy group (1-14) a lower alkylamino lower alkyl group (1-15) oxo group (1-16) pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) lower alkyl group optionally having one lower alkyl group 1 Pieces A thiazolyl group (1-20) lower alkylamino group (1-21) a pyrimidyl group (1-22) phenyl lower alkenyl group (1-23) halogen optionally having one lower alkyl group A phenoxy group (1-24) phenoxy lower alkyl group (1-25) pyrrolidinyl lower alkoxy group (1-26) lower alkylsulfamoyl group (1-27) lower alkyl group which may have one atom; Pyridazinyloxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower optionally having one Alkoxy group (1-32) hydroxy group (1-33) lower alkoxycarbonyl group (1-34) hydroxy lower alkyl group (1-35) Zolyl group (1-36) piperidyl group (1-37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group optionally having one lower alkyl group (1-40 ) Piperidyl lower alkyl group (1-41) pyrrolidinyl lower alkyl group (1-42) morpholinyl group (1-43) piperazinyl group optionally having one lower alkyl group. m represents 2, l and n each represents an integer of 1, and X represents —CH ₂ —;
4. R ¹ represents hydrogen; lower alkyl group; hydroxy lower alkyl group; benzyl group or tri-lower alkylsilyloxy lower alkyl group; and R ⁴ represents any of the groups shown below. A medicament comprising a heterocyclic compound represented by the general formula (1) or a salt thereof:
(1) Phenyl group (2) Indolyl group (4) Naphthyl group (5) Benzofuryl group (31) Pyrrolopyridyl group On the above aromatic ring or heterocyclic ring, it has 1 to 4 substituents selected from the following: May be:
(1-1) Halogen atom (1-2) Lower alkyl group (1-3) Lower alkanoyl group (1-4) Halogen substituted lower alkyl group (1-5) Halogen substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group (1-8) Lower alkylthio group (1-9) Imidazolyl group (1-10) Tri-lower alkylsilyl group (1-11) may have one lower alkyl group A pyrrolidinyl group (1-13) which may have one oxadiazolyl group (1-12) oxo group (1-13) a phenyl group which may have one lower alkoxy group (1-14) a lower alkylamino lower alkyl group (1-15) oxo group (1-16) pyrazolyl group (1-17) thienyl group (1-18) furyl group (1-19) lower alkyl group optionally having one lower alkyl group 1 Pieces A thiazolyl group (1-20) lower alkylamino group (1-21) a pyrimidyl group (1-22) phenyl lower alkenyl group (1-23) halogen optionally having one lower alkyl group A phenoxy group (1-24) phenoxy lower alkyl group (1-25) pyrrolidinyl lower alkoxy group (1-26) lower alkylsulfamoyl group (1-27) lower alkyl group which may have one atom; Pyridazinyloxy group (1-28) phenyl lower alkyl group (1-29) lower alkylamino lower alkoxy group (1-30) imidazolyl lower alkyl group (1-31) phenyl lower optionally having one Alkoxy group (1-32) hydroxy group (1-34) hydroxy lower alkyl group (1-35) oxazolyl group (1-36) piperidyl group (1 37) pyrrolyl group (1-38) morpholinyl lower alkyl group (1-39) piperazinyl lower alkyl group (1-40) piperidyl lower alkyl group (1-41) pyrrolidinyl lower alkyl group optionally having lower alkyl group (1-42) A morpholinyl group (1-43) a piperazinyl group optionally having one lower alkyl group. R ¹ represents hydrogen;
R ² and R ³ are the same or different and each independently represents a lower alkyl group; or R ² and R ³ are combined to form a cycloC3-C8 alkyl group; and R ⁴ is The pharmaceutical which consists of a heterocyclic compound or its salt represented by General formula (1) of Claim 4 which shows either group shown below:
(1) Phenyl group (2) Indolyl group (4) Naphtyl group (5) Benzofuryl group (31) Pyrrolopyridyl group On the above aromatic ring or heterocyclic ring, it has 1 to 2 substituents selected from the following: May be:
(1-1) Halogen atom (1-2) Lower alkyl group (1-5) Halogen-substituted lower alkoxy group (1-6) Cyano group (1-7) Lower alkoxy group. A pharmaceutical comprising the heterocyclic compound represented by the general formula (1) according to claim 5 or a salt thereof selected from the following group:
(4aS, 8aR) -1- (4-chlorophenyl) -3,3-dimethyldecahydroquinoxaline,
2-chloro-4-((4aS, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) benzonitrile,
(4aS, 8aR) -1- (3-chloro-4-fluorophenyl) -3,3-dimethyldecahydroquinoxaline,
(4aS, 8aR) -1- (7-fluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline,
5-((4aR, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) -1-methyl-1H-indole-2-carbonitrile,
(4a′R, 8a ′S) -4 ′-(7-methoxybenzofuran-4-yl) octahydro-1′H-spiro [cyclobutane-1,2′-quinoxaline]
(4aS, 8aR) -1- (6,7-difluorobenzofuran-4-yl) -3,3-dimethyldecahydroquinoxaline,
5-((4aS, 8aS) -3,3-dimethyloctahydroquinoxalin-1 (2H) -yl) -1H-indole-2-carbonitrile,
(4aS, 8aR) -1- (7-chloro-2,3-dihydro-1H-inden-4-yl) -3,3-dimethyldecahydroquinoxaline,
6-((4aS, 8aS) -3,3-dimethyloctahydroquinoxaline-dimethyldecahydroquinoxalin-1 (2H) -yl) -2-naphthonitrile,
(4aS, 8aS) -3,3-dimethyl-1- (1H-pyrrolo [2,3-b] pyridin-4-yl) decahydroquinoxaline and (4aS, 8aS) -1- (4- (difluoromethoxy) -3-Fluorophenyl) -3,3-dimethyldecahydroquinoxaline.   A pharmaceutical composition comprising the heterocyclic compound represented by the general formula (1) according to claim 1 or a salt thereof as an active ingredient, and a pharmacologically acceptable carrier.   A prophylactic and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the heterocyclic compound represented by the general formula (1) according to claim 1 or a salt thereof as an active ingredient.   Disorder is depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, heart Temperament, dissociative amnesia, avoidance personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory disorder, Parkinson's disease, restless leg syndrome, Endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal disorders, schizophrenia negative syndrome, premenstrual syndrome, stress urinary incontinence, Toulette syndrome, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome Impulsive dysregulation, hair loss, stealing, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hyperactivity Diseases, cataplexy, prevention and / or therapeutic agent according to claim 8 which is a disorder selected from the group consisting of sleep apnea syndrome and headache.   Depression is major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood dysfunction disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; Recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, Amenorrhea / lactation syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc. Depression selected from the group consisting of depression associated with various body diseases; middle-aged depression; geriatric depression; childhood / pubertal depression and drug-induced depression such as interferon Prevention and / or therapeutic agent according to claim 9, wherein that.   Anxiety associated with various diseases is anxiety selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease Item 10. The prophylactic and / or therapeutic agent according to Item 9.   Pain selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic neck syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy The prophylactic and / or therapeutic agent according to claim 9. A heterocyclic compound selected from the group consisting of the following compounds or a salt thereof:

A heterocyclic compound selected from the group consisting of the following compounds or a salt thereof:

  A medicament comprising the heterocyclic compound or a salt thereof according to claim 13 or 14.   The pharmaceutical composition containing the heterocyclic compound or its salt of Claim 13 or 14 as an active ingredient, and a pharmacologically acceptable carrier.   A preventive and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the heterocyclic compound represented by the general formula (1) according to claim 13 or 14 or a salt thereof as an active ingredient. .   Disorder is depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, heart Temperament, dissociative amnesia, avoidance personality disorder, body dysmorphic disorder, eating disorder, obesity, chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory disorder, Parkinson's disease, restless leg syndrome, Endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal disorders, schizophrenia negative syndrome, premenstrual syndrome, stress urinary incontinence, Toulette syndrome, attention deficit hyperactivity disorder (ADHD), autism, Asperger syndrome Impulsive dysregulation, hair loss, stealing, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hyperactivity Diseases, cataplexy, prevention and / or therapeutic agent according to claim 16 which is a disorder selected from the group consisting of sleep apnea syndrome and headache.   Depression is major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood dysfunction disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; Recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, Amenorrhea / lactation syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc. Depression selected from the group consisting of depression associated with various body diseases; middle-aged depression; geriatric depression; childhood / pubertal depression and drug-induced depression such as interferon Prevention and / or therapeutic agent according to claim 18, wherein that.   Anxiety associated with various diseases is anxiety selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease Item 19. The preventive and / or therapeutic agent according to Item 18.   Pain selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic neck syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy The prophylactic and / or therapeutic agent according to claim 18.