JP2005343791A - Medicinal composition for treating digestive tract disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicinal composition for treating a disease accompanying an organic change in the digestive tract. <P>SOLUTION: This medicinal composition comprises a calcium channel antagonist represented by the formula or an analogue thereof. The composition is used for treatment of diseases accompanying the organic change in the digestive tract. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

【０００８】
〔式中、環Ｇ、Ｊ、Ｋはそれぞれベンゼン環または含窒素芳香環を表す。Ｒ¹〜Ｒ⁸は同一でも異なっていてもよく、ハロゲン原子又は水素原子を表し、Ｒ⁹〜Ｒ¹³は同一でも異なっていてもよく、水素原子、ハロゲン原子、シアノ基、ヒドロキシ基、低級アルキル基、低級アルコキシ基、アミノ基又は低級アルキルアミノ基及びそれらの低級アシル体、低級ジアルキルアミノ基、環状アルキルアミノ基を表すか、又はＲ⁹とＲ¹⁰、若しくはＲ¹⁰とＲ¹¹は一緒になって−Ｏ（ＣＨ₂）ｎＯ−基（ｎは１、２又は３）を表す。ＡはＣＨ₂、ＣＨＯＨ、ＣＯ、又はＯのいずれか、ＢはＣＨ₂、ＣＨＯＨ又はＣＯのいずれか、又はＡ−ＢがＣＨ＝ＣＨを表し、ＤはＣＨ₂、ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂のいずれか、或いはＢ−ＤがＣＨ₂を表す。ＸとＺはお互いに結合してＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂のいずれかを表し、そのときにＹは水素原子を表す。或いは、ＹとＺはお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂−ＣＨ₂のいずれかを表し、そのときにＸは水素原子を表す。ＸとＺ、及びＹとＺがいずれもお互いに結合しないときＸとＹは水素原子を表し、Ｚは低級アルキル基を表す。
但し、Ｒ⁹〜Ｒ¹³のいずれかが式[Ｅ]で表される環状アミノ基である場合、Ｒ¹〜Ｒ⁸はハロゲン原子又は水素原子のいずれでもよいが、Ｒ⁹〜Ｒ¹³のいずれもが式[Ｅ]で表される環状アミノ基でない場合には、Ｒ¹〜Ｒ⁸のいずれか１つないし２つがハロゲン原子であり他は水素原子を表すものとする。
【０００９】
【化１１】

【００１０】
〔式中、ｎ、ｍは１又は２を表し、Ｗは炭素原子、低級アルキル基で置換されていてもよい窒素原子、酸素原子、硫黄原子を表す。〕
【００１１】
(II) 以下の一般式〔2〕で表される５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕チアゼピン誘導体、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物；
【００１２】
【化１２】

【００１３】
（式中、
ｋ、ｍ及びｎはそれぞれ１、２又は３であり、
ｐは０、１又は２であり、
Ｘは、Ｏ、Ｓ又は連結基であるが、ＸがＯ又はＳのときｎは２又は３であり、
Ｒ¹は、Ｈ又はＣ₁−Ｃ₄アルキルであり、及び
Ｒ²は、
【００１４】
【化１３】

【００１５】
（式中、Ｒ³及びＲ⁴はそれぞれ独立してＨ、Ｃ₁−Ｃ₄アルキル、Ｃ₁−Ｃ₄アルコキシ、-ＯＨ、-Ｎ(Ｃ₁−Ｃ₄アルキル)₂、ハロ又は-ＣＦ₃である。）であるか、
【００１６】
【化１４】

【００１７】
（式中、ｑは、１、２又は３であり、
Ｘ¹及びＸ²はそれぞれ独立してＯ及び-ＣＨ₂-から選択される）であるか、又は
（c）ピリジニル、ピリダジニル、ピリミジニル、ピラジニル又はチエニル基であり、ここで該基は、Ｃ₁−Ｃ₄アルキル及びＣ₁−Ｃ₄アルコキシから独立して選ばれる２以下の置換基で置換されていてもよい。）
【００１８】
(III) 以下の一般式〔3〕で表される５−（２−ピロジニルメチル）−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン誘導体、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物；
【００１９】
【化１５】

【００２０】
〔式中、Ｒ¹及びＲ²は同一でも異なっていてもよく、水素原子、ハロゲン原子、シアノ基、ヒドロキシ基又は低級アルコキシ基を表すか、又はＲ¹及びＲ²は一緒になって−Ｏ（ＣＨ₂)_nＯ−基（ｎは１、２又は３）を表し、Ｒ³は水素原子又はヒドロキシ基を表し、Ｒ⁴及びＲ⁵は同一又は異なってもよく、水素原子又はヒドロキシ基を表し、若しくは一緒になって＝Ｏを表す。〕
【００２１】
(IV) 以下の一般式〔4〕で表される５−アルキル−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン誘導体、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物；及び
【００２２】
【化１６】

【００２３】
〔式中、Ｒ¹〜Ｒ⁵は同一でも異なっていてもよく、水素原子、低級アルコキシ基、アミノ基又はアルキルアミノ基を表すが、いずれか１つ以上はアミノ基又はアルキルアミノ基を表し、Ｒ⁶及びＲ⁷は同一でも異なっていてもよく、水素原子又はヒドロキシ基を表し、若しくは一緒になって＝Ｏを表し、Ｙ¹はメチレン、イオウ原子又はヒドロキシメチンを表す。〕
(V) 以下の一般式〔5〕で表される５−アルキル−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン誘導体、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物。
【００２４】
【化１７】

【００２５】
〔式中、Ｒ¹〜Ｒ⁵は同一でも異なっていてもよく、水素原子、ハロゲン原子、シアノ基、ヒドロキシ基、低級アルキル基、低級アルコキシ基、アミノ基又は低級アルキルアミノ基を表すか、又はＲ¹とＲ²、Ｒ²とＲ³、Ｒ³とＲ⁴、若しくはＲ⁴とＲ⁵は一緒になって−Ｏ（ＣＨ₂)ｎＯ−基（ｎは１、２又は３）を表し、Ｒ⁶は水素又は低級アルキル基を表し、Ｙはメチレン、酸素原子、イオウ原子、又はアルキルアミノ基を表し、ＡはＣＨ₂、ＣＨＯＨ、ＣＯ又はＯのいずれかを表し、ＢはＣＨ₂、ＣＨＯＨ又はＣＯのいずれかを表し、又はＡ−ＢがＣＨ＝ＣＨを表し、ＤはＣＨ₂、ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂のいずれか、或いはＢ−ＤがＣＨ₂を表す。〕
本発明において、カルシウムチャネル拮抗薬が、上記一般式[I]で表される５，１１−ジヒドロアリール〔ｂ，ｅ〕〔１，４〕オキサゼピン誘導体、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物であるのが好ましい。
【００２６】
本発明において、カルシウムチャネル拮抗薬が、以下の式で表される化合物、その立体異性体、薬理学的に許容されるその塩、それらの水和物又は溶媒和物であるのが特に好ましい。
【００２７】
【化１８】

【００２８】
上記一般式〔Ｉ〕における環Ｇ，Ｊ，Ｋの含窒素芳香環としては６員環化合物が望ましく、例えばピリジン環、ピリミジン環、ピラジン環、ピリダジン環があげられる。但し、環Ｇ，Ｊにおいて、オキサゼピン環上に芳香環窒素原子が存在する事はなく、また、Ｒ¹〜Ｒ⁸のいずれかがハロゲン原子である場合、そのハロゲン原子は芳香環窒素原子には結合しない。また環Ｋにおいて芳香環窒素原子は、Ａとは結合せず、窒素原子上に置換基を持たない。
【００２９】
上記一般式〔Ｉ〕における環Ｇ，Ｊ，Ｋについては、(i)環Ｇ、Ｊがいずれもベンゼン環である場合、(ii)環Ｇ、Ｊのいずれか一方がピリジン環であり、他方がベンゼン環である場合、(iii)環Ｋがベンゼン環である上記(i)又は(ii)の場合、(iv)環Ｋがピリジン環、ピリミジン環、ピラジン環、ピリダジン環のいずれかである上記(i)又は(ii)の場合、又は(v)環Ｇ、Ｊ及びＫがいずれもベンゼン環である場合が好ましい。一般式[ＸＶ]及び[ＸＶＩ]においても同様である。
【００３０】
上記一般式におけるＲ¹〜Ｒ⁸のハロゲン原子としては、フッ素原子、塩素原子、臭素原子等をあげることが出来るが、好ましくはフッ素原子又は塩素原子である。Ｒ¹〜Ｒ⁸のうち、Ｒ²、Ｒ³、Ｒ⁶、Ｒ⁷のいずれか１つがフッ素原子又は塩素原子であり、他が水素原子であることがより好ましい。Ｒ⁹〜Ｒ¹³のハロゲン原子としては、フッ素原子、塩素原子等、臭素原子等、低級アルキル基としては、メチル基、エチル基、プロピル基等の炭素数１〜５の低級アルキル基、低級アルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基等の炭素数１〜５の低級アルコキシ基、低級アルキルアミノ基としては、モノメチルアミノ基、モノエチルアミノ基、モノプロピルアミノ基等の炭素数１〜５の低級アルキルアミノ基が挙げられる。アミノ基及びこれらの低級アルキルアミノ基の低級アシル体としてはホルミルアミノ基、アセチルアミノ基、プロピオニルアミノ基、ホルミルメチルアミノ基、ホルミルエチルアミノ基、ホルミルプロピルアミノ基、アセチルメチルアミノ基、アセチルエチルアミノ基、アセチルプロピルアミノ基、プロピオニルメチルアミノ基、プロピオニルエチルアミノ基、プロピオニルプロピルアミノ基等、炭素数１〜３の脂肪酸アシル体が挙げられる。ジアルキルアミノ基としては、ジメチルアミノ基、ジエチルアミノ基、メチルエチルアミノ基等の炭素数の合計が２〜７の低級アルキルアミノ基、環状アルキルアミノ基としてはアゼチジノ基、ピロリジノ基、ピペリジノ基、ホモピペリジノ基、ピペラジノ基、モルフォリノ基等の４から７員環アミノ基、−Ｏ（ＣＨ₂）ｎＯ−基としては、メチレンジオキシ基、エチレンジオキシ基、プロピレンジオキシ基を挙げることができる。これらのうち、ハロゲン原子としては、フッ素原子、塩素原子が好ましく、低級アルキル基としては、炭素数１〜３の低級アルキル基が好ましい。低級アルコキシ基としては、炭素数１〜３の低級アルコキシ基が好ましい。又、モノアルキルアミノ基としては炭素数１〜３の低級アルキルアミノ基が好ましく、ジアルキルアミノ基としては、アルキル基の炭素数の合計が２〜６のものが好ましい。環状アルキルアミノ基としては環の員数が４から６のものが好ましい。アミノ基又はこれらの低級アルキルアミノ基の低級アシル体のアシル基としてはホルミル基ないしアセチル基が好ましい。ここでＲ⁹〜Ｒ¹³が同時に水素原子とならないのが好ましい。
【００３１】
上記一般式[Ｉ]においては、以下のものが好ましく、一般式[ＸＶ]及び[ＸＶＩ]においても同様である。
(i)ＸとＺがお互いに結合してＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂を表し、Ｙが水素原子、
(ii)ＹとＺがお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂ −ＣＨ₂−ＣＨ₂を表し、Ｘが水素原子、
(iii)ＸとＹが水素原子であり、Ｚが低級アルキル基、
(iv)Ｒ¹⁰、Ｒ¹¹のうちいずれか一つ、或いは双方がメトキシ基であるか、或いはＲ¹⁰とＲ¹¹が一緒になってメチレンジオキシ基を表し、Ｒ⁹及びＲ¹²、Ｒ¹³が水素原子、
【００３２】
(v)Ｒ¹¹がメトキシ基であり、Ｒ⁹、Ｒ¹⁰及びＲ¹²、Ｒ¹³が水素原子、
(vi)Ｒ¹⁰、Ｒ¹¹のいずれか１つがアミノ基又は低級アルキルアミノ基及びそれらの低級アシル体、低級ジアルキルアミノ基、或いは環状アルキルアミノ基であり、他が水素原子,
(vii)Ｒ¹〜Ｒ⁸のいずれもが水素原子、
(viii)Ｒ¹〜Ｒ⁸のいずれか１つがフッ素原子又は塩素原子であり、他が水素原子、
【００３３】
(ix)Ｒ²、Ｒ³、Ｒ⁶、Ｒ⁷のいずれか１つがフッ素原子又は塩素原子であり、他が水素原子、
(x)Ａ、Ｂ−Ｄの双方がＣＨ₂、
(xi)Ｘの結合した炭素原子の絶対配置がＲ体、
(xii)Ｘの結合した炭素原子の絶対配置がＳ体、
(xiii)Ｙの結合した炭素原子の絶対配置がＲ体、
(xiv)Ｙの結合した炭素原子の絶対配置がＳ体。
【００３４】
式[Ｅ]で表される環状アミノ基としては、アゼチジノ基、ピロリジノ基、ピペリジノ基等の窒素原子を１つ含む環状アミノ基、ピペラジノ基、モルフォリノ基など更に窒素原子や酸素原子などのヘテロ原子を含む環状アミノ基をあげることが出来るが、好ましくはピロリジノ基及びモルフォリノ基である。Ｒ⁹〜Ｒ¹³のうち、Ｒ¹⁰、Ｒ¹¹のいずれか１つが環状アミノ基であり、他が水素原子であることがより好ましい。
【００３５】
Ａ−Ｂ−ＤはＣＨ₂−ＣＨ₂、ＣＯ−ＣＨ₂、ＣＨＯＨ−ＣＨ₂、ＣＨＯＨ−ＣＨ₂−ＣＨ₂、ＣＨ₂−ＣＨＯＨ−ＣＨ₂、ＣＨ＝ＣＨ−ＣＨ₂、ＣＯ−ＣＨ₂−ＣＨ₂、Ｏ−ＣＨ₂、ＣＨ₂−ＣＯ−ＣＨ₂、又はＣＨ₂−ＣＨ₂−ＣＨ₂のいずれかが好ましい。
本発明では、これらのうち、好ましい化合物は、例えば下記の式〔II〕で表される化合物である。但し、式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄは式〔I〕と同じものを表し、ｒは１または２を表す。
【００３６】
【化１９】

【００３７】
〔II〕で表される化合物としては、例えば、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−アミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−アミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−メチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−メチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−フロロフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−フロロフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−アセチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−アセチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−アミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−アミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−メチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−メチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−フロロフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−フロロフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−アセチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−アセチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−ピぺリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−ピぺリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン及びそれらのハロゲン置換位置異性体、薬理学的に許容されるこれらの塩又は水和物、溶媒和物が挙げられる。
【００３８】
なお本発明で用いることのできる化合物〔II〕は、１個又はそれ以上の不斉炭素原子を有しており、光学異性体が存在し得る。これらの光学異性体、それらの任意の混合物あるいはラセミ体は本発明の化合物に包含される。このうち、ジヒドロジベンゾオキサゼピン環にメチレンを介して結合したピロリジン環ないしピペリジン環の２位の立体配置がＲ体であることが好ましい。
また他に好ましい化合物は、例えば下記の式〔III〕で表される化合物である。
【００３９】
【化２０】

【００４０】
但し、式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄは式〔I〕と同じものを表し、ｒは１または２を表す。式〔III〕で表される化合物としては、例えば、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−メトキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−アミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−アミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−メチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−メチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−フロロフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−フロロフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（４−アセチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−［１−（３−アセチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−メトキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−アミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−アミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−メチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−メチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−フロロフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−フロロフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（４−アセチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−［１−（３−アセチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−ピペリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−ピペリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（４−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−［１−（３−モルフォリノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン及びそれらのハロゲン置換位置異性体、薬理学的に許容されるこれらの塩又は水和物、溶媒和物が挙げられる。
【００４１】
なお本発明で用いることのできる化合物〔III〕は、１個又はそれ以上の不斉炭素原子を有しており、光学異性体が存在し得る。これらの光学異性体、それらの任意の混合物あるいはラセミ体は本発明の化合物に包含される。このうち、ジヒドロジベンゾオキサゼピン環に結合したピロリジン環ないしピペリジン環の２位の立体配置がＲ体であることが好ましい。
また他に好ましい化合物は、例えば下記の式〔IV〕で表される化合物である。但し、式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄは式〔I〕と同じものを表し、Ｒ¹⁴は炭素数１〜３の低級アルキル基を表す。
【００４２】
【化２１】

【００４３】
式〔IV〕で表される化合物としては、例えば、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−メトキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−メトキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３，４−メチレンジオキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−アミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−アミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−メチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−メチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−ジメチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−ジメチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−ピロリジノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−ピロリジノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−モルフォリノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−モルフォリノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−フロロフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−フロロフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−アセチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、２−フルオロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−アセチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−メトキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−メトキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３，４−メチレンジオキシフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−アミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−アミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−メチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−メチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−ジメチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−ジメチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−ピロリジノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−ピロリジノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−モルフォリノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−モルフォリノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−フロロフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−フロロフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（４−アセチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、３−クロロ−５，１１−ジヒドロ−５−｛２−［Ｎ−（３−アセチルアミノフェネチル）−Ｎ−メチル］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（４−ピロリジノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（３−ピロリジノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（４−ピペリジノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（３−ピぺリジノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（４−モルフォリノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン、５，１１−ジヒドロ−５−｛２−［Ｎ−メチル−Ｎ−（３−モルフォリノフェネチル）］アミノエチル｝ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン及びそれらのハロゲン置換位置異性体、薬理学的に許容されるこれらの塩又は水和物、溶媒和物が挙げられる。
【００４４】
本発明では、(i)Ｒ⁹〜Ｒ¹³のいずれか１つが式[Ｅ]で表される環状アミノ基であり、他が水素原子であり、Ｒ¹〜Ｒ⁸のいずれもが水素原子である式[Ｉ]の誘導体、(ii)Ｒ⁹〜Ｒ¹³のいずれか１つが式[Ｅ]で表される環状アミノ基であり、他が水素原子であり、Ｒ¹〜Ｒ⁸の１つ又は２つがフッ素原子又は塩素原子であり、他が水素原子である式[Ｉ]の誘導体、(iii) Ｒ⁹〜Ｒ¹³のいずれもが式[Ｅ]で表される環状アミノ基以外の基を表し、Ｒ¹〜Ｒ⁸の１つ又は２つがフッ素原子又は塩素原子であり、他が水素原子である式[Ｉ]の誘導体が好ましい。
【００４５】
上記一般式〔ＸＶ〕及び〔ＸＶＩ〕においては、(i)Ｒ¹〜Ｒ⁸は同一でも異なっていてもよく、フッ素原子、塩素原子又は水素原子を表し、Ｌ₁−Ｌ₂がＣＨ₂又はＣＨ₂−ＣＨ₂を表し、ＹとＺはお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂−ＣＨ₂を表すか、及び/又は(ii)Ｒ⁹〜Ｒ¹³は同一でも異なっていてもよく、水素原子、アミノ基又は低級アルキルアミノ基及びそれらの低級アシル体、低級ジアルキルアミノ基、環状アルキルアミノ基を表すのが好ましい。
【００４６】
具体的には、（Ｒ）−｛〔２−（３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン〕−１−イル｝−２−（４−ジメチルアミノフェニル）エタノン、（Ｒ）−１−〔（４−ジメチルアミノフェニル）アセチル〕ピロリジン−２−カルボン酸〔２−（２−ブロモ−４−クロロベンジルオキシ）フェニル〕アミド、（Ｒ）−｛（２−（２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン］−１−イル｝−２−（４−ピロリジノフェニル）エタノン、（Ｒ）−１−〔（４−ピロリジノフェニル）アセチル〕ピロリジン−２−カルボン酸〔２−（２−ブロモ−５−フルオロベンジルオキシ）フェニル〕アミド、これらの立体異性体及び塩が好ましい。
【００４７】
本発明で用いることのできる化合物〔Ｉ〕の薬理学的に許容される塩としては、例えば、塩酸塩、臭化水素塩、硫酸塩、リン酸塩等の鉱酸塩（無機塩）や酢酸塩、乳酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、アスパラギン酸塩、メタンスルホン酸塩等の有機酸塩を挙げることができる。
本発明で用いることのできる化合物〔Ｉ〕のうち式〔II〕で表される化合物は、例えば、例えば、国際特許第９７３３８８５Ａ１号に開示されている方法に従い、下記の方法(反応式１)によって製造できる。
【００４８】
【化２２】

【００４９】
〔式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄは式〔Ｉ〕と同じであり、ｒは１または２を表し、Ｗは塩素原子、臭素原子、ヨウ素原子などのハロゲン原子を表す。〕
化合物〔V〕を、溶媒中塩基の存在下、上記一般式〔VI]で表される化合物と反応させることにより、本発明で用いることのできる化合物〔II〕を製造することができる。上記反応における反応溶媒としては、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等のアミド類、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２−ジメトキシエタン等のエーテル類、アセトニトリル、トルエン、キシレン、ベンゼン等が好適に使用できる。前記塩基としては、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、ｎ−ブチルリチウム、ナトリウムメトキシド、カリウムｔ−ブトキシドなどを挙げることができる。反応温度は、通常０℃〜１５０℃、好適には室温〜１００℃の範囲で行われる。反応時間は、反応温度あるいは溶媒の種類によって異なるが、通常１〜５０時間である。化合物〔VI〕及び塩基の使用量は、化合物〔V〕の使用量に対して、それぞれ0.5〜5モル当量、好ましくは0.8〜2モル当量である。
なお、前記反応の原料に用いた化合物〔V〕は、公知の方法 [J. Med. Chem., 7, 609 (1964)] により製造できる。
【００５０】
また、上記一般式〔VI〕で表されるハロゲン化物は、ヨーロッパ特許第０４０４３５９Ａ１号に開示されている方法に準じて、プロリン、ホモプロリンを原料として、これらを還元して得られるアルコールをＮ−アルキル化し、次いで水酸基をメタンスルホニルクロリド、トシルクロリド等を用いてハロゲン化する事により、環拡大を伴って製造することが出来る。
又、本発明で用いることのできる化合物〔II〕は、国際特許第９９１２９２５Ａ１号に開示されている方法に従い、下記の方法（反応式２）によっても製造できる。
【００５１】
【化２３】

【００５２】
〔式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄは前記と同じであり、ｒは１または２を表し、Ｖ及びＶ'は塩素原子、臭素原子、ヨウ素原子、トシルオキシ基、メシルオキシ基などの脱離基を表し、Ｕはｔ−ブチルオキシカルボニル基、ベンジルオキシカルボニル基、トシル基などアミノ基の保護基を表す。〕
化合物〔V〕を、塩基存在下、上記一般式〔VII〕で表されるＮ−ｔ−ブトキシカルボニル−２−ピペリジルメチルトシレート等を滴下して反応させ、一般式〔VIII〕の化合物を調製し、ついで脱保護して一般式〔IX〕の化合物を得、これに一般式〔X〕の化合物を塩基存在下で反応させることにより、本発明で用いることのできる化合物〔II〕を製造することができる。〔V〕から〔VIII〕及び、〔IX〕から〔II〕への反応溶媒、塩基としては、上記反応式１におけるのと同じものを使用することができる。
【００５３】
本発明で用いることのできる化合物〔Ｉ〕のうち式〔III〕で表される化合物は、例えば、国際特許第００４０５７０Ａ１号に開示されている方法に従い、下記の方法(反応式３)によって製造できる。
【００５４】
【化２４】

【００５５】
〔式中、芳香環K、Ｒ⁹〜Ｒ¹³、Ａ、Ｂ、Ｄ、Ｖ及びｒは反応式２と同じものを表す。〕
【００５６】
化合物〔V〕を、溶媒中塩基の存在下、上記一般式〔XI〕で表される化合物と反応させることにより、本発明で用いることのできる化合物〔III〕を製造することができる。上記反応における反応溶媒としては、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等のアミド類、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２−ジメトキシエタン等のエーテル類、アセトニトリル、トルエン、キシレン、ベンゼン等が好適に使用できる。前記塩基としては、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、ｎ−ブチルリチウム、ナトリウムメトキシド、カリウムｔ−ブトキシドなどを挙げることができる。反応温度は、通常０℃〜１５０℃、好適には室温〜１００℃の範囲で行われる。反応時間は、反応温度あるいは溶媒の種類によって異なるが、通常１〜５０時間である。化合物〔XI〕及び塩基の使用量は、化合物〔V〕の使用量に対して、それぞれ0.5〜10モル当量、好ましくは0.8〜5モル当量である。
【００５７】
尚、上記一般式〔XI〕で表される化合物は、３−ヒドロキシピロリジン、３−ヒドロキシピペリジンをＮ−アルキル化した後に、オキシ塩化リン、塩化チオニル、トシルクロリド、メタンスルフォニルクロリド等を作用させることにより得ることができる。
本発明で用いることのできる化合物〔Ｉ〕のうち式〔IV〕で表される化合物は、例えば、例えば、国際特許第００４０５７０Ａ１号に開示されている方法に従い、下記の方法(反応式４)によって製造できる。
【００５８】
【化２５】

【００５９】
〔式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄ及びＶは前記と同じであり、Ｒ¹⁴は低級アルキル基を表す。〕
【００６０】
すなわち、化合物〔V〕を上記一般式〔XII〕で表される化合物に導き、一般式〔XIII〕の化合物と塩基存在下、反応させる。ここで本反応における反応溶媒としては、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等のアミド類、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２−ジメトキシエタン等のエーテル類、アセトニトリル、トルエン、キシレン、ベンゼン等が好適に使用できる。前記塩基としては、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、水素化カリウム、リチウムジイソプロピルアミド、ｎ−ブチルリチウム、ナトリウムメトキシド、カリウムｔ−ブトキシドなどを挙げることができる。反応温度は、通常０℃〜１５０℃、好適には室温〜１００℃の範囲で行われる。反応時間は、反応温度あるいは溶媒の種類によって異なるが、通常１〜５０時間である。塩基の使用量は、化合物〔XII〕に対して、等モル以上、好ましくは１〜５倍モルであり、化合物〔XII〕と〔XIII〕の量比は０．５〜２倍モル、好ましくは０．７倍から１．５倍である。
【００６１】
或いは、化合物〔V〕を上記一般式〔XIV〕で表される化合物に導き、ついで化合物〔X〕と塩基存在下、縮合させて本発明で用いることのできる化合物〔IV〕を製造することができる。縮合反応における反応溶媒、塩基としては上記反応と同一の物を用いることができ、反応温度、反応時間に関しても同様である。塩基の使用量は、化合物〔XIV〕に対して、等モル以上、好ましくは１〜５倍モルであり、化合物〔XIV〕と〔X〕の量比は０．５〜２倍モル、好ましくは０．７倍から１．５倍である。
【００６２】
化合物〔XII〕は化合物〔V〕をα−ハロ酢酸エステルでアルキル化した後に還元してアルコールとし、更にその水酸基を脱離基に変換するか、或いは水酸基を保護した２−ハロエタノールによって化合物〔V〕をアルキル化し、脱保護後にその水酸基を脱離基に変換する等、既知の方法を組み合わせることにより容易の製造できる。また、化合物〔XIII〕は国際特許第００４０５７０Ａ１号に開示されているように、対応するハロゲン化物による１級アミンのアルキル化反応、対応するアルデヒドによる１級アミンの還元アルキル化反応、対応するカルボン酸によりアミンをアシル化した後に還元する等、種々の公知の方法により容易に製造できる。
【００６３】
化合物〔XIV〕は国際特許第００４０５７０Ａ１号に開示されているように、化合物〔V〕をハロ酢酸エステルでアルキル化した後に、アミド化して還元する等、種々の公知の方法により容易に製造できる。
又、上に示した以外に、本発明で用いることのできる化合物〔I〕のうち式〔II〕または式〔IV〕で表される化合物は、国際特許第０１１７９８０Ａ１号に記載の方法と類似の方法により、下記式〔XVI〕および式〔XV〕で表される化合物を経由して製造できる。即ち式〔II〕で表される化合物を式〔II-1〕、式〔IV〕で表される化合物を式〔IV-1〕で表記すると、これらは反応式５に従い、式〔XVI〕で表される化合物を分子内アリール化して式〔XV〕で表される化合物へと導き、続いてこれを還元することで、それぞれに対応する中間体から得られる。
【００６４】
【化２６】

【００６５】
〔式中、芳香環Ｇ、Ｊ、K、Ｒ¹〜Ｒ¹⁴、Ｌ₁、Ｌ₂は式〔XV〕と同じであり、ｒは１または２を表し、ＹとＺはお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂−ＣＨ₂を表すか、又はＹとＺはお互いに結合しないときＹは水素原子を表し、Ｚは低級アルキル基を表す。〕
【００６６】
ここで本還元反応における反応溶媒としては、例えば、ジエチルエーテル、ジオキサン、テトラヒドロフラン、１，２−ジメトキシエタン等のエーテル類があげられる。又、溶媒には、ベンゼン、トルエン、キシレン等が０〜５０％含まれていてもよい。還元試剤としては、例えば、ジボラン、ボランアンモニア錯体、ボラン−ｔｅｒｔ−ブチルアミン錯体、ボラン−Ｎ，Ｎ−ジエチルアニリン錯体、ボラン−Ｎ，Ｎ−ジイソプロピルエチルアミン錯体、ボランジメチルアミン錯体、ボラン−４−（ジメチルアミノ）ピリジン錯体、ボランジフェニルホスフィン錯体、ボラン−４−エチルモルホリン錯体、ボラン−２，６−ルチジン錯体、ボラン−４−メチルモルホリン錯体、ボランジメチルスルフィド錯体、ボランモルホリン錯体、ボラン−１，４−オキサチアン錯体、ボラン−４−フェニルモルホリン錯体、ボランピリジン錯体、ボランテトラヒドロフラン錯体、ボラントリブチルホスフィン錯体、ボラントリエチルアミン錯体、ボラントリメチルアミン錯体、ボラントリフェニルホスフィン錯体等のボラン化合物、水素化アルミニウムリチウムや、水素化ホウ素ナトリウム、水素化ホウ素リチウム等の金属水素化物ないしこれらのアルキル、アルコキシないしアシル置換体が挙げられる。若しくはこれらの金属水素化物に酸などを加えることにより反応容器内に還元試剤を調製してもよい。ここで用いられる酸類としては、例えば、塩酸、硫酸、メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸、カンファースルホン酸、酢酸、トリフルオロ酢酸などのブレンステッド酸、三フッ化ホウ素、三塩化ホウ素、三塩化アルミニウムなどのルイス酸およびその錯体などがあげられる。これらの還元試剤のうち、例えば、ジボラン、ボランテトラヒドロフラン錯体などを使用する方法、若しくは水素化ホウ素ナトリウムにメタンスルホン酸、三フッ化ホウ素およびその錯体などを加えることにより反応容器内に還元試剤を調製する方法が好適に使用できる。反応温度は、溶媒の沸点にもよるが、通常５℃〜１００℃、好適には３０℃〜６０℃の範囲で行なわれる。反応時間は、還元試剤の種類、反応温度あるいは溶媒の種類によって異なるが、通常４〜７０時間である。還元試剤の使用量は、還元試剤の種類によっても異なるが、発生しうるヒドリドの量が４倍モル以上、好ましくは７倍モル以上である。反応で得られた化合物〔II-1〕ないし化合物〔IV-1〕は、シリカゲルカラムクロマトグラフィーないし晶析などにより精製することができる。又、化合物〔II-1〕ないし化合物〔IV-1〕は、適当な酸との塩の形態で晶析を行ない、取得してもよい。ここで適当な酸との塩とは、例えば、塩酸塩、臭化水素塩、硫酸塩、リン酸塩、硝酸塩等の鉱酸塩（無機塩）や酢酸塩、乳酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、アスパラギン酸塩、メタンスルホン酸塩等の有機酸塩を挙げることができる。
【００６７】
前記還元反応の原料に用いた化合物〔XV〕は、化合物〔XVI〕を塩基存在下、金属触媒により分子内アリール化することにより製造できる。ここで本反応における反応溶媒としては、例えば、ベンゼン及びその置換体、ピリジン及びその置換体、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドンなどのアミド類などがあげられる。これらの反応溶媒のうち、例えば、トルエン、ピリジン、ピコリン、Ｎ−メチルピロリドンなどが好適に使用できる。前記塩基としては、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなどの炭酸塩類、ナトリウムメトキシド、ナトリウムｔ−ブトキシド、カリウムｔ−ブトキシドなどの金属アルコキシド類、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリンなどのアミン類があげられる。これらの塩基のうち、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどが好適に使用できる。前記金属触媒としては、例えば、銅、塩化銅（Ｉ）、臭化銅（Ｉ）、ヨウ化銅（Ｉ）などの銅触媒、パラジウム、塩化パラジウム、酢酸パラジウム及びテトラキス（トリフェニルホスフィン）パラジウムなどのパラジウム触媒ないしその錯体、ないし白金および塩化白金などの白金触媒及びその錯体などがあげられる。これらの金属触媒のうち、例えば、銅、臭化銅（Ｉ）などが好適に使用できる。これらの金属触媒は又、反応容器内に調製してもよい。反応温度は、溶媒の沸点にもよるが、通常室温〜２００℃、好適には１００℃〜１５０℃の範囲で行なわれる。反応時間は、前記塩基や金属触媒の種類、反応温度あるいは溶媒の種類によって異なるが、通常８〜２００時間である。前記塩基の使用量は、その種類によっても異なるが、通常１倍モル〜１０倍モル、好ましくは１倍モル〜４倍モルである。前記金属触媒の使用量は、その種類によっても異なるが、通常０．００１倍モル〜１倍モル、好ましくは０．００５倍モル〜０．２倍モルである。反応で得られた化合物〔XV〕は、反応液から抽出、シリカゲルカラムクロマトグラフィーないし晶析などにより精製し、次の反応に用いることができるが、そのまま次の反応に用いることもできる。ここで本化合物〔XV〕は、又、適当な酸との塩の形態で取得してもよい。ここで適当な酸との塩とは、例えば、塩酸塩、臭化水素塩、硫酸塩、リン酸塩、硝酸塩等の鉱酸塩（無機塩）や酢酸塩、乳酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、アスパラギン酸塩、メタンスルホン酸塩等の有機酸塩を挙げることができる。
【００６８】
前記分子内アリール化反応の原料に用いた化合物〔XVI〕は、下記の方法（反応式６）によって製造できる。
【００６９】
【化２７】

【００７０】
〔式中、芳香環G、J、K、Ｒ¹〜Ｒ¹³、Ｌ₁、Ｌ₂は式〔XVI〕と同じであり、ＹとＺはお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂−ＣＨ₂を表すか、又はＹとＺはお互いに結合しないときＹは水素原子を表し、Ｚは低級アルキル基を表す。〕
【００７１】
すなわち化合物〔XVI〕は、化合物〔XVII〕と化合物〔XVIII〕を縮合することによって製造できる。ここで縮合反応とは、例えば、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミドないしＮ−ジメチルアミノプロピル−Ｎ’−エチルカルボジイミドおよびその塩などを用いるアミド化反応、化合物〔XVIII〕を酸無水物としたのちに縮合させる酸無水物法、および化合物〔XVIII〕の酸塩化物ないし酸臭化物を経由する方法などの既知の方法から選択できる。反応で得られた化合物〔XVI〕は、反応液から抽出、シリカゲルカラムクロマトグラフィーないし晶析などにより精製し、次の反応に用いることができるが、そのまま次の反応に用いることもできる。ここで本化合物〔XVI〕は、又、適当な酸との塩の形態で取得してもよい。ここで適当な酸との塩とは、例えば、塩酸塩、臭化水素塩、硫酸塩、リン酸塩、硝酸塩等の鉱酸塩（無機塩）や酢酸塩、乳酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、アスパラギン酸塩、メタンスルホン酸塩等の有機酸塩を挙げることができる。
【００７２】
前記反応式６の原料に用いた化合物〔XVII〕は、公知の方法［J. Med. Chem., 7, 609 (1964)］により製造できる。
化合物〔XVIII〕は下記の方法（反応式７）によって製造できる。
【００７３】
【化２８】

【００７４】
〔式中、芳香環K、Ｒ⁹〜Ｒ¹³、Ｌ₁、Ｌ₂は前記と同じであり、ＹとＺはお互いに結合してＣＨ₂−ＣＨ₂−ＣＨ₂又はＣＨ₂−ＣＨ₂−ＣＨ₂−ＣＨ₂を表すか、又はＹとＺはお互いに結合しないときＹは水素原子を表し、Ｚは低級アルキル基を表す。〕
【００７５】
すなわち化合物〔XVIII〕は、化合物〔XIX〕と化合物〔XX〕を縮合することによって製造できる。ここで縮合反応とは、例えば、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミドないしＮ−ジメチルアミノプロピル−Ｎ’−エチルカルボジイミドおよびその塩などを用いるアミド化反応、化合物〔XIX〕を酸無水物としたのちに縮合させる酸無水物法、および化合物〔XIX〕の酸塩化物ないし酸臭化物を経由する方法などの既知の方法から選択できる。反応で得られた化合物〔XVIII〕は、反応液を抽出、シリカゲルカラムクロマトグラフィーないし晶析などにより精製し、次の反応に用いることができるが、そのまま次の反応に用いることもできる。化合物〔XVIII〕は、又、化合物〔XX〕のカルボン酸部分を適当な保護基で保護し、化合物〔XIX〕との上記同様の縮合反応の後に脱保護を行なうことによって製造してもよい。ここで適当な保護基とは、例えば、メチル、エチル、ｎ−プロピル、ｉｓｏ−プロピル、ｎ−ブチル、ｉｓｏ−ブチル、ｔｅｒｔ−ブチル、ないしその置換体とのエステル、トリメチルシリル、トリエチルシリル、ｔｅｒｔ−ブチルジメチルシリル等とのシリルエステルなどが挙げられる。
【００７６】
又、本発明で用いることのできる化合物〔I〕のうち式〔III〕で表される化合物は、下記の方法（反応式８）によっても製造できる。
【００７７】
【化２９】

【００７８】
〔式中、芳香環G、J、K、Ｒ¹〜Ｒ¹³、Ａ、Ｂ、Ｄ、Ｖ及びｒは前記と同じである。〕
【００７９】
すなわち化合物〔III〕は、化合物〔XXI〕を塩基存在下、金属触媒により分子内アリール化することによっても製造できる。ここで本反応における反応溶媒としては、例えば、ベンゼン及びその置換体、ピリジン及びその置換体、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドンなどのアミド類などがあげられる。前記塩基としては、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなどの炭酸塩類、ナトリウムメトキシド、ナトリウムｔ−ブトキシド、カリウムｔ−ブトキシドなどの金属アルコキシド類、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリンなどのアミン類があげられる。前記金属触媒としては、例えば、銅、塩化銅（Ｉ）、臭化銅（Ｉ）、ヨウ化銅（Ｉ）などの銅触媒、パラジウム、塩化パラジウム、酢酸パラジウム及びテトラキス（トリフェニルホスフィン）パラジウムなどのパラジウム触媒ないしその錯体、ないし白金および塩化白金などの白金触媒及びその錯体などがあげられる。これらの金属触媒は又、反応容器内に調製してもよい。反応温度は、溶媒の沸点にもよるが、通常室温〜２００℃、好適には８０℃〜１６０℃の範囲で行なわれる。反応時間は、前記塩基や金属触媒の種類、反応温度あるいは溶媒の種類によって異なるが、通常５〜１５０時間である。前記塩基の使用量は、その種類によっても異なるが、通常１倍モル〜２０倍モル、好ましくは１．５倍モル〜８倍モルである。前記金属触媒の使用量は、その種類によっても異なるが、通常０．００１倍モル〜１倍モル、好ましくは０．００５倍モル〜０．３倍モルである。反応で得られた化合物〔III〕は、反応液から抽出、シリカゲルカラムクロマトグラフィー、高速液体クロマトグラフィーないし晶析などにより精製することができる。又、本発明で用いることのできる化合物〔III〕は、適当な酸との塩の形態で晶析を行ない、取得してもよい。ここで適当な酸との塩とは、例えば、塩酸塩、臭化水素塩、硫酸塩、リン酸塩、硝酸塩等の鉱酸塩（無機塩）や酢酸塩、乳酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、アスパラギン酸塩、メタンスルホン酸塩等の有機酸塩を挙げることができる。
【００８０】
前記分子内アリール化反応の原料に用いた化合物〔XXI〕は、化合物〔XVII〕のアミノ基を、化合物〔XI〕によりアルキル化することによって製造できる。ここでアルキル化反応とは、例えば、塩基存在下でのアルキル化反応が挙げられる。すなわち化合物〔XVII〕と化合物〔XI〕を、塩基存在下、適当な溶媒中にて反応させることにより製造できる。前記塩基としては、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウムなどの炭酸塩類、ナトリウムメトキシド、ナトリウムｔ−ブトキシド、カリウムｔ−ブトキシドなどの金属アルコキシド類、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリンなどのアミン類があげられる。反応で得られた化合物〔XXI〕は、反応液から抽出、シリカゲルカラムクロマトグラフィーなどにより精製し、次の反応に用いることができるが、そのまま次の反応に用いることもできる。
【００８１】
本発明で用いることのできる化合物を医薬製剤又は医薬組成物として用いる場合、医薬上許容され得る賦形剤、担体、希釈剤等の製剤補助剤を適宜混合し、常法により錠剤、カプセル剤、顆粒剤、細粒剤、粉末剤、丸剤、シロップ剤、懸濁剤、乳剤、軟膏剤、坐剤又は注射剤等の形態で、経口又は非経口で投与することができる。本発明では、活性成分としての本発明の化合物と、医薬上許容され得る担体及び／又は希釈剤とを含有する医薬製剤又は医薬組成物が好ましい。ここで、担体及び希釈剤としては、グルコース、スクロース、ラクトース、タルク、シリカ、セルロース、メチルセルロース、スターチ、ゼラチン、エチレングリコール、ポリエチレングリコール、グリセリン、エタノール、水や油脂などがあげられる。
【００８２】
また、本発明の医薬組成物の投与量及び投与回数は、病気の種類、患者の年齢、体重等に応じて適宜選択することができる。例えば、本発明の医薬組成物を、胃潰瘍、十二指腸潰瘍、逆流性食道炎、潰瘍性大腸炎又はクローン病等の消化管の器質的変化を伴う疾患の治療剤として経口投与する場合は、成人に対し１日約０．１〜１０００ｍｇを１回〜数回に分けて投与すればよい。
【００８３】
本発明におけるカルシウムチャネル結合化合物をスクリーニングする方法は、
(a) 標識化した一般式［I］で表される５，１１−ジヒドロジアリール［ｂ，ｅ］［１，４］オキサゼピン誘導体の、結腸又は回腸の膜標本への結合量を測定すること、
(b) 試験化合物の存在下、標識化した一般式［I］で表される５，１１−ジヒドロジアリール［ｂ，ｅ］［１，４］オキサゼピン誘導体の、結腸又は回腸の膜標本への結合量を測定すること、及び
(c) 工程(a)で得られる結果と工程(b)で得られる結果とを比較すること、
を含む。
【００８４】
工程(a)
本発明において、一般式［I］で表される５，１１−ジヒドロジアリール［ｂ，ｅ］［１，４］オキサゼピン誘導体を標識化する方法としては、例えば該誘導体中の水素原子を³Ｈで置換する方法や、該誘導体中の炭素原子を¹⁴Ｃで置換する方法があげられ、特に制限なく使用することができる。
膜標本の調製は、例えば以下のようにして行うことができる。すなわち、まず結腸及び回腸の縦走筋を細切し、氷冷したTris緩衝液に懸濁させる。その後、該懸濁液をホモジナイズする。次いで、得られた均質化溶液を遠心分離し、得られた上清を再度遠心分離する。最後に、得られた沈査をTris緩衝液に再懸濁することにより、膜標本を調製することができる。
このようにして得られた膜標本に、例えばTris緩衝液中でインキュベートすることにより該標識化誘導体を結合させることができる。本発明において使用する一般式［I］で表される化合物は、大動脈と比べて結腸及び回腸に高い親和性を有し、さらに結腸及び回腸において、既存のカルシウムチャネル拮抗薬の結合部位とは異なる結合部位を有することから、本発明の方法を使用することにより、腸管に選択的に作用するカルシウムチャネル結合化合物をスクリーニングすることができる。
ここで、標識化誘導体は、受容体の全結合部位に結合するのに充分な量で使用するのが好ましい。次いで、ガラス繊維濾紙等を用いて吸引濾過することにより反応を中止させ、濾紙をTris緩衝液等で洗浄する。得られた濾液中の標識化誘導体の量を、例えば液体シンチレーションカウンターを用いて放射活性β線量(dpm)を測定することにより、結腸又は回腸の膜標本への結合量を測定することができる。
【００８５】
工程(b)
試験化合物の存在下、該標識化誘導体を膜標本に結合させることにより、該試験化合物が該標識化誘導体の膜標本への結合を阻害するかを測定することができる。試験化合物は、標識化誘導体と一緒に膜標本に接触させてもよいし、標識化誘導体を膜標本に結合させた後に導入することもできる。試験化合物は、標識化誘導体ど同じ量で使用するのが望ましい。試験化合物と標識化誘導体とを膜標本に結合させた後の処理は、工程（a）に記載したのと同じように行うことができる。
【００８６】
工程(c)
工程(a)において得られた標識化誘導体の膜標本への総結合量から、工程(b)において得られた試験化合物により結合が阻害された標識化誘導体の量を減ずることにより、試験化合物がカルシウムチャネル結合能を有するか測定することができる。
本発明において、受容体リガンドとして、５，１１−ジヒドロジアリール［ｂ，ｅ］［１，４］オキサゼピン誘導体を使用することにより、低濃度でも、具体的には１〜２０ｎＭでも、効率よくカルシウムチャネル結合化合物をスクリーニングすることができる。
【００８７】
【参考例】
次に、本発明に記載される化合物の製造方法を、参考例としてさらに詳細に説明するが、本発明はこれら参考例に何ら限定されるものではない。
【００８８】
〔参考例１〕
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、６０％水素化ナトリウム（４４ｍｇ、１．１ｍｍｏｌ）をヘキサンで洗浄し、ジメチルスルホキシド（５ｍｌ）に懸濁して室温で３０分間撹拌した後、３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（０．２２ｇ，１．０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で更に３０分間撹拌した後、この溶液に（Ｒ）−３−クロロ−１−（４−メトキシフェネチル）ピペリジン（０．２５ｇ、１．０ｍｍｏｌ、国際特許第９７３３８８５Ａ１号記載の方法により調製）のジメチルスルホキシド（２ｍｌ）溶液を滴下して、５０℃で６時間攪拌した。反応液を飽和食塩水と酢酸エチルに分配した。有機層を乾燥後、溶媒を減圧留去し、得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（７：３）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−〔１−（４−メトキシフェネチル）ピペリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（０．３０ｇ、７０％）。
ＥＳＩ／Ｍａｓｓ：４３３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.90(4H, m), 2.27(1H, m), 2.50-2.60(1H, m), 2.70-2.82(3H, m), 2.98-3.10(1H, m), 3.18-3.24(1H, m), 3.35(1H, dd, J=9.3, 12.9Hz), 3.82(3H, s), 4.02(1H, dd, J=3.60, 13.2Hz), 5.20(1H, d, J=12.0Hz), 5.27(1H, d, J=12.0Hz), 6.70-6.95(6H, m), 6.98-7.05(1H, m), 7.15-7.30(4H, m)
【００８９】
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−〔１−（４−メトキシフェネチル）ピペリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−〔１−（４−メトキシフェネチル）ピペリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（３００ｍｇ, ０．７ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液に４Ｍ塩化水素／ジオキサン０．３ｍｌを加え、３０分撹拌した後、溶媒を減圧留去した。得られた残留物をヘキサン、酢酸エチルの混合溶媒を用いて固化させ、析出した固体を濾別することにより表記化合物を褐色固体として得た（２５７ｍｇ、７９％）。
ＥＳＩ／Ｍａｓｓ：４３３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.90-2.06(1H, m), 2.06-2.30(3H, m), 2.74-2.86(1H, m), 2.90-3.20(2H, m), 3.25-3.40(1H, m), 3.42-3.68(2H, m), 3.80(3H, s), 3.85-4.00(1H, m), 4.24(1H, dd, J=7.8, 14.1Hz), 4.62(1H, dd, J=5.7, 14.1Hz), 5.12(1H, d, J=12.3Hz), 5.32(1H, d, J=12.3Hz), 6.72-7.03(8H, m), 7.12(2H, d, J=8.4Hz), 7.18-7.25(1H, m)
【００９０】
〔参考例２〕
（Ｒ）−８−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに８−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例１と同様の操作により、（Ｒ）−８−フルオロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色固体。収率１９％。
ＥＳＩ／Ｍａｓｓ：４３３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.58-1.88(4H, m), 2.22-2.30(1H, m), 2.48-2.58(1H, m), 2.68-2.82(3H, m), 2.99-3.08(1H, m), 3.21-3.36,2H, m), 3.81(3H,s), 4.00-4.05(1H, m), 5.20(1H, d, J=13.0Hz), 5.34(1H, d, J=13.0Hz), 6.47-6.50(2H, m), 6.79-6.93(3H, m),7.02-7.18(4H, m), 7.26-7.34(2H, m)
【００９１】
これを参考例１と同様に４Ｍ塩酸／ジオキサンで処理し、表記化合物を褐色固体として得た。収率８１％。
ＥＳＩ／Ｍａｓｓ： ４３３ [M＋Ｈ⁺]
ＮＭＲ(CDCl３) δ：1.90-2.32(4H, m), 2.75-2.88(1H, m), 2.94-3.23(2H, m), 3.28-3.60(3H, m), 3.81(3H,s), 3.91-4.00(1H, m), 4.14-4.30(1H, m), 4.58-4.73(1H, m), 5.17(1H, d, J=13.0Hz), 5.34(1H, d, J=13.0Hz), 6.50-6.60(2H, m), 6.81-7.00(3H, m), 7.08-7.39(6H, m)
【００９２】
〔参考例３〕
（Ｒ）−２−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに２−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例１と同様の操作により、（Ｒ）−２−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色固体。収率４４％。
ＥＳＩ／Ｍａｓｓ： ４４９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.87(4H, m), 2.20-2.28(1H, m), 2048-2.56(1H, m), 2.67-2.82(3H, m), 2.93-3.06(1H, m), 3.16-3.23(1H, m), 3.34(1H, dd, J=10.3, 14.7Hz), 3.81(3H, s), 4.04(1H, dd, J=4.0, 14.7Hz), 5.15(1H, d, J=13.0Hz), 5.25(1H, J=13.0Hz), 6.75-6.89(5H, m), 6.97-7.04(2H, m), 7.10-7.16(2H, m), 7.22-7.30(2H, m)
【００９３】
これを参考例１と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た。収率９０％。
ＥＳＩ／Ｍａｓｓ： ４４９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.92-2.28(4H, m), 2.72-2.88(1H, m), 2.93-3.13(2H, m), 3.26-3.38(1H, m), 3.43-3.6.(2H, m), 3.81(3H, s), 3.83-3.98(1H, m), 4.20-4.35(1H, m), 4.61-4.74(1H, m), 5.11(1H, d, J=14.0Hz), 5.27(1H, d, J=14.0Hz), 6.87-6.92(5H, m), 7.01-7.16(3H, m), 7.22-7.30(3H, m)
【００９４】
〔参考例４〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例１と同様の操作により、（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−メトキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色固体。収率５５％。
ＥＳＩ／Ｍａｓｓ： ４４９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.90(4H, m), 2.22-2.30(1H, m), 2.52-2.62(1H, m), 2.68-2.82(3H, m), 2.97-3.07(1H, m), 3.16-3.22(1H, m), 3.35(1H, dd, J=10.3, 14.7Hz), 3.81(3H, s), 4.03(1H, dd, J=4.0, 14.7Hz), 5.20(1H, d, J=13.7Hz), 5.23(1H, d, J=13.7Hz), 6.75-6.90(5H, m), 6.96-7.02(2H, m), 7.10-7.20(4H, m)
【００９５】
これを参考例１と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た。収率８６％。
ＥＳＩ／Ｍａｓｓ：４４９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.92-2.03(1H, m), 2.10-2.30(3H, m), 2.75-2.84(1H,m), 2.96-3.12(2H,m), 3.24-3.34(1H,m), 3.44-3.60(2H,m）,3.81(1H,s）3.87-3.981H,m）, 4.24(1H,dd,J=8.7,15.3Hz), 4.62(1H,dd,J=6.3,15.3Hz), 5.12(1H,d, J=14.0Hz), 5.35(1H,d,J=14.0Hz), 6.83-6.96(3H,m), 6.84(2H,d,J=9.3Hz), 7.01-7.19(4H,m), 7.12(2H,d,J=9.3Hz)
【００９６】
〔参考例５〕
（Ｒ）−７−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
（Ｒ）−３−クロロ−１−（３，４−メチレンジオキシフェネチル）ピぺリジン
アセトニトリル（５０ｍｌ）中に、（Ｒ）−２−ヒドロキシメチルピロリジン、（５０５ｍｇ、５．００ｍｍｏｌ）、３，４−メチレンジオキシフェネチルメシレート（１．３４ｇ、５．５０ｍｍｏｌ）、炭酸ナトリウム（５８５ｍｇ，５．５０ｍｍｏｌ）、ヨウ化ナトリウム（５０ｍｇ，０．３３ｍｍｏｌ）を加え、９０℃で１３．５時間加熱還流した後、減圧下に溶媒を留去し、残留物を酢酸エチルと飽和重曹水に分配した。有機層を水洗し、硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をジクロロメタン２５ｍｌに溶解し、氷冷下で撹拌しながら、ジイソプロピルエチルアミン７１２ｍｇ（５．５ｍｍｏｌ）、およびメタンスルホニルクロリド６３０ｍｇ（５．５ｍｍｏｌ）を加え、氷冷下で１時間、更に室温下で２時間撹拌した。反応液をジクロロメタンと飽和重曹水に分配した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液としてヘキサンと酢酸エチル（１５：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−クロロ−１−（３，４−メチレンジオキシフェネチル）ピペリジンが淡黄色油状物質として得られた（１．０２ｇ、７６％）。
ＮＭＲ(CDCl３) δ：1.55-1.68(3H, m), 1.75-1.87(1H, m), 2.12-2.20(2H, m), 2.55-2.64(2H, m), 2.69-2.78(3H, m), 3.08-3.18(1H, m), 3.98-4.06(1H, m), 5.93(2H, s), 6.63-6.75(3H, m)
【００９７】
（Ｒ）−７−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、６０％水素化ナトリウム（４８ｍｇ、１．２ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（８ｍｌ）に懸濁し、室温で３０分間撹拌した後、７−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２３２ｍｇ，１ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で３０分間撹拌した後、この溶液に（Ｒ）−３−クロロ−１−（３，４−メチレンジオキシフェネチル）ピペリジン（３０８ｍｇ、１．１５ｍｍｏｌ）のジメチルスルホキシド（３ｍｌ）溶液を滴下して、５０℃で４時間攪拌した。反応液を飽和重曹水と酢酸エチルに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液としてヘキサンと酢酸エチル（１０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−７−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色固体として得られた（３６２ｍｇ、７８％）。
ＥＳＩ／Ｍａｓｓ：４６３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.84(4H, m), 2.20-2.30(1H, m), 2.49-2.59(1H, m), 2.65-2.78(3H, m), 2.95-3.05(1H,m), 3.13-3.21(1H,m), 3.34(1H, dd, J=10.3, 13.0Hz), 4.00(1H, dd, J=3.3, 13.0Hz), 5.15(1H, d, J=13.0Hz), 5.23(1H, d, J=13.0Hz), 5.95(2H,s), 6.63-6.78(5H, m), 6.96(1H, s), 7.02-7.13(2H, m), 7.26-7.37(2H,m)
【００９８】
（Ｒ）−７−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン塩酸塩
（Ｒ）−７−クロロ−５，１１−ジヒドロ−５−［１−（３，４−メチレンジオキシフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（０．６３ｇ）のジクロロメタン（５ｍｌ）溶液に２Ｍ塩化水素／ジエチルエーテル３．０ｍｌを加え、２時間撹拌した後、溶媒を減圧留去した。得られた残留物をヘキサン中で撹拌して表記化合物を淡褐色固体として得た（３４８ｍｇ、８９％）。
ＥＳＩ／Ｍａｓｓ：４６３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.92-2.33(4H, m), 2.74-3.16(3H, m), 3.24-3.37(1H, m), 3.44-3.58(2H, m), 3.88-3.98(1H, m), 4.15-4.28(1H, m), 4.60-4.72(1H, m), 5.19(1H, d, J=14.0Hz), 5.27(1H, d, J=14.0Hz), 5.98(2H, s), 6.64-6.77(5H, m), 6.80-6.88(1H, m), 6.98(1H, s), 7.09-7.20(2H, m), 7.28-7.38(2H, m)
【００９９】
〔参考例６〕
（Ｒ）−１−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−２−ヒドロキシメチル−１−（４−ジメチルアミノフェネチル）ピロリジン
アセトニトリル（５０ｍｌ）中に、D−プロリノール（２．０２ｇ、２０．０ｍｍｏｌ）、４−ジメチルアミノフェネチルメシレート、（５．３５ｇ、２２．０ｍｍｏｌ）、炭酸ナトリウム（２．６５ｇ、２５．０ｍｍｏｌ）、ヨウ化ナトリウム（３００ｍｇ，２．０ｍｍｏｌ）を加え、９０℃で１３．５時間加熱還流した後、室温まで冷却し、ろ過した。ろ液を減圧下で濃縮乾固し、残留物を酢酸エチルと飽和重曹水に分配した。有機層に１M塩酸を加え、水層のｐHを１に保ち、目的物を水層に抽出した。水層に４M水酸化ナトリウムを加え、水層のｐHを１４とし、生成する沈殿を酢酸エチルで抽出した。抽出液を硫酸マグネシウムで乾燥後、溶媒を減圧下に留去すると、（Ｒ）−２−ヒドロキシメチル−１−（４−ジメチルアミノフェネチル）ピロリジンが淡黄色油状物質として得られた（４．９１ｇ、９９％）。
ＮＭＲ(CDCl３) δ：1.69-1.90(4H, m), 2.29-2.38(1H, m), 2.45-2.54(1H, m), 2.56-2.64(1H, m), 2.66-2.74(2H, m), 2.88-2.94(1H, m), 2.91(6H, ms), 3.23-3.30(1H, m), 3.31(1H, dd, J=2.7, 12.0Hz), 3.58(1H, dd, J=4.0, 12.0Hz), 6.70(2H, d, J=9.7Hz), 7.07(2H, d, J=9.7Hz)
【０１００】
（Ｒ）−３−クロロ−１−（４−ジメチルアミノフェネチル）ピぺリジン
（Ｒ）−２−ヒドロキシメチル−１−（４−ジメチルアミノフェネチル）ピロリジン（４．９１ｇ、１９．８ｍｍｏｌ）をジクロロメタン６０ｍｌに溶解し、氷冷下で撹拌しながら、ジイソプロピルエチルアミン３．１１ｇ（２４．４ｍｍｏｌ）、およびメタンスルホニルクロリド２．７５ｇ（２４．０ｍｍｏｌ）を加え、氷冷下で１時間、更に室温下で２時間撹拌した。反応液をジクロロメタンと飽和重曹水に分配し、有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液としてヘキサンと酢酸エチル（９：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−クロロ−１−（４−ジメチルアミノフェネチル）ピぺリジンが淡黄色固体として得られた（３．０３ｇ、５７％）。
ＮＭＲ(CDCl３) δ：1.50-1.68(3H, m), 1.76-1.88(1H, m), 2.09-2.20(2H, m), 2.55-2.62(2H, m), 2.66-2.73(2H, m), 2.75-2.84(1H, m), 2.91(6H, s), 3.08-3.17(1H, m), 3.98-4.08(1H, m), 6.69(2H, d, J=9.7Hz), 7.06(2H, d, J=9.7Hz)
【０１０１】
（Ｒ）−１−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、６０％水素化ナトリウム（３５ｍｇ、０．８８ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（５ｍｌ）に懸濁し、室温で３０分間撹拌した後、１−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（０．１７ｇ，０．８０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で３０分間撹拌した後、この溶液に（Ｒ）−３−クロロ−１−（４−ジメチルアミノフェネチル）ピペリジン（０．１８ｇ、０．８０ｍｍｏｌ）のジメチルスルホキシド（２ｍｌ）溶液を滴下して、５０℃で６時間攪拌した。反応液を飽和食塩水と酢酸エチルに分配し、有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（６：４）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−１−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピペリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（０．２３ｇ、６４％）。
ＥＳＩ／Ｍａｓｓ：４４６［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.90(4H, m), 2.20-2.30(1H, m), 2.48-2.55(1H, m), 2.70-2.80(3H, m), 2.94(6H, s), 2.98-3.08(1H, m), 3.16-3.25(1H, m), 3.38(1H, dd, J=9.3, 13.0Hz), 4.10(1H, dd, J=3.60, 13.0Hz), 5.35(1H, d, J=12.0Hz), 5.42(1H, d, J=12.0Hz), 6.70-6.78(3H, m), 6.80-6.90(4H, m), 7.00-7.15(3H, m), 7.18-7.28(1H, m)
【０１０２】
（Ｒ）−１−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−１−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２２８ｍｇ, ０．５ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液に４Ｍ塩化水素／ジオキサン０．５ｍｌを加え、３０分撹拌した後、溶媒を減圧留去した。得られた残留物をヘキサン、酢酸エチルの混合溶媒を用いて固化させ、析出した固体を濾別して表記化合物を褐色固体として得た（１７０ｍｇ、６４％）。
ＥＳＩ／Ｍａｓｓ：４４６［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.92-2.30(3H, m), 2.78-2.90(1H, m), 2.91-3.16(3H, m), 3.16(6H, s), 3.38-3.50(2H, m), 3.62-3.75(1H, m), 3.82-3.95(1H, m), 4.28(1H, dd, J=6.3, 14.7Hz), 4.77(1H, dd, J=6.0, 14.7Hz), 5.24(2H, s), 6.76(1H, t, J=8.1Hz), 6.90-7.12(5H, m), 7.21-7.30(1H, m), 7.37(2H, d, J=8.4Hz) , 7.71(2H, d, J=8.4Hz)
【０１０３】
〔参考例７〕
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
１−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例６と同様の操作により、（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（０．２４ｇ、５３％）。
ＥＳＩ／Ｍａｓｓ：４４６［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.60-1.90(4H, m), 2.22-2.32(1H, m), 2.50-2.60(1H, m), 2.70-2.82(3H, m), 2.94(6H, s), 2.98-3.08(1H, m), 3.15-3.25(1H, m), 3.34(1H, dd, J=9.3, 13.0Hz), 4.05(1H, dd, J=3.60, 13.0Hz), 5.20(1H, d, J=12.0Hz), 5.26(1H, d, J=12.0Hz), 6.68-6.90(7H, m), 6.97-7.04(1H, m), 7.08-7.15(2H, m), 7.20-7.25(1H, m)
【０１０４】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を淡褐色固体として得た（１００％）。
ＥＳＩ／Ｍａｓｓ：４４６［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(3H, m), 2.80-3.00(1H, m), 3.00-3.25(9H, m), 3.42-3.60(2H, m), 3.60-3.75(1H, m), 3.85-3.98(1H, m), 4.19-4.28(1H, m), 4.58-4.68(1H, m), 5.11(1H, d, J=12.6Hz), 5.35(1H, d, J=12.6Hz), 6.76(1H, t, J=8.1Hz), 6.80-7.08(5H, m), 7.20(1H, dd, J=6.3, 8.1Hz), 7.43(2H, d, J=6.9Hz), 7.75(2H, d, J=6.9Hz)
【０１０５】
〔参考例８〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
１−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例６と同様の操作により、（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンオキサゼピンを得た。淡黄色油状物質。収率６７％。
ＥＳＩ／Ｍａｓｓ：４６２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.50-1.91(4H, m), 2.23-2.32(1H, m), 2.51-2.60(1H, m), 2.65-2.83(3H, m), 2.93(6H, s), 2.97-3.07(1H, m), 3.15-3.23(1H, m), 3.34(1H, dd, J=10.3, 14.3Hz), 4.06(1H, dd, J=4.0, 14.3Hz), 5.22(2H, s), 6.72(2H, d, J=10.0Hz), 6.75-6.85(3H, m), 6.98-7.01(2H, m), 7.09-7.19(2H, m), 7.11(2H, d, J=10.0Hz)
【０１０６】
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンオキサゼピン（３０６ｍｇ，０．６６２ｍｍｏｌ）を酢酸エチルとエタノール（２：１）の混合溶媒６．０ｍｌに溶解し、２Ｍ塩化水素／エーテル（０．７３ｍｌ，１．４６ｍｍｏｌ）を添加した後、酢酸エチル２．０ｍｌを加えて室温で攪拌した。２日間、室温に静置した後、ろ過・乾燥して表記化合物を白色結晶として得た（９６％）。
ＥＳＩ／Ｍａｓｓ：４６２[M+H⁺]
ＮＭＲ(CDCl３) δ：2.02-2.28(4H, m), 2.80-2.90(1H, m), 2.98-3.24(2H, m), 3.17(6H, s), 3.44-3.56(2H, m), 3.59-3.69(1H, m), 3.88-3.98(1H, m), 4.23(1H, dd, J=7.7, 15.7Hz), 4.64(1H, dd, J=6.3, 15.7Hz), 5.11(1H, d, J=14.0Hz), 5.33(1H, d, J=14.0Hz), 6.85-6.97(3H, m), 7.02-7.07(2H, m), 7.12-7.18(2H, m), 7.41(2H, d, J=9.3Hz), 7.75(2H, d, J=9.3Hz)
【０１０７】
〔参考例９〕
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
４−ピロリジノフェネチルアルコール
乾燥した酢酸パラジウム（２７０ｍｇ、１．２０ｍｍｏｌ）、２−（ジ−ｔ−ブチルフォスフィノ）ビフェニル（７２０ｍｇ、２．４０ｍｍｏｌ）、ｔ−ブトキシナトリウム（１４．４２ｇ、１５０ｍｍｏｌ）に２−（４−ブロモフェネトキシ）テトラヒドロ−２H−ピラン（２８．０１ｇ、９８．３９ｍｍｏｌ）のトルエン（１００ｍｌ）溶液とピロリジン（９．９３ｍｌ、１１９ｍｍｏｌ）を加え、７０℃で１２時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、生成物を有機層から１Ｍ塩酸で抽出した。水層を水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を乾燥し、４−ピロリジノフェネチルアルコールを淡黄色固体として得た。（１６．４１ｇ、８７％）
ＮＭＲ(CDCl３) δ：1.97-2.01(4H, m), 2.77(2H, t, J=7.3Hz), 3.24-3.29(4H, m), 3.79(2H, q, J=6.7Hz), 6.53(2H, d, J=9.3Hz), 7.03(2H, d, J=9.35Hz)
【０１０８】
４−ピロリジノフェネチルメシレート
４−ピロリジノフェネチルアルコール（１６．４１ｇ、８５．９ｍｍｏｌ）をジクロロメタン（１５０ｍｌ）に溶解し、０℃でジイソプロピルエチルアミン（１９．０ｍｌ、１０８ｍｍｏｌ）とメタンスルフォニルクロリド（８．４０ｍｌ、１０８ｍｍｏｌ）を加えて一晩攪拌した。反応溶液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（７：３）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、４−ピロリジノフェネチルメシレートが白色固体として得られた（２１．１４ｇ、８０％）。
ＥＳＩ／Ｍａｓｓ：２７０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.98-2.01(4H, m), 2.84(3H, s), 2.95(2H, t, J=8.0Hz), 3.24-3.28(4H, m), 4.46(2H, t, J=8.0Hz), 6.52(2H, d, J=9.3Hz), 7.07(2H, d, J=9.3Hz)
【０１０９】
（Ｒ）−２−ヒドロキシメチル−１−（４−ピロリジノフェネチル）ピロリジン
アセトニトリル（１５０ｍｌ）中に、Ｄ−プロリノール、（２．７２ｇ、２５．０ｍｍｏｌ）、４−ピロリジノフェネチルメシレート、（６．０６ｇ、２２．５ｍｍｏｌ）、炭酸カリウム（３．４５ｇ、２５．０ｍｍｏｌ）を加え、９０℃で３．５時間加熱還流した後、室温まで冷却し、ろ過した。ろ液を減圧下で濃縮乾固し、残留物を酢酸エチルと飽和重曹水に分配した。有機層に１M塩酸を加え、水層のｐHを１に保ち、目的物を水層に抽出した。水層に４M水酸化ナトリウムを加え、水層のｐHを１４にし、生成した沈殿を酢酸エチルで抽出した。抽出液を硫酸マグネシウムで乾燥後、溶媒を減圧下に留去すると、（Ｒ）−２−ヒドロキシメチル−１−（４−ピロリジノフェネチル）ピロリジンが淡黄色油状物質として得られた（４．９６ｇ、８５％）。
ＮＭＲ(CDCl３) δ：1.70-1.91(4H, m), 1.95-2.04(4H, m), 2.26-2.36(1H, m), 2.42-2.56(1H, m), 2.57-2.77(4H, m), 2.87-2.96(1H, m), 3.18-3.27(4H, m), 3.28(1H, dd, J=2.7, 12.0Hz), 3.57(1H, dd, J=4.0, 12.0Hz), 6.51(2H, d, J=9.3Hz), 7.05(2H, d, J=9.7Hz)
【０１１０】
（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピぺリジン
（Ｒ）−２−ヒドロキシメチル−１−（４−ピロリジノフェネチル）ピロリジン（４．９６ｇ、１９．１ｍｍｏｌ）をジクロロメタン７０ｍｌに溶解し、氷冷下で撹拌しながら、ジイソプロピルエチルアミン３．２１ｇ（２４．８ｍｍｏｌ）、およびメタンスルホニルクロリド２．８４ｇ（２４．８ｍｍｏｌ）を加え、氷冷下で１時間、更に室温下で２時間撹拌した。反応液をジクロロメタンと飽和重曹水に分配した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液としてヘキサンと酢酸エチル（３：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピぺリジンが淡黄色固体として得られた（３．２３ｇ、６１％）。
ＥＳＩ／Ｍａｓｓ：２９３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.50-1.70(3H, m), 1.78-1.87(1H, m), 1.96-2.01(4H, m), 2.10-2.20(2H, m), 2.54-2.61(2H, m), 2.65-2.72(2H, m), 2.75-2.85(1H, m), 3.10-3.17(1H, m), 3.23-3.28(4H, m), 3.96-4.06(1H, m), 6.51(2H, d, J=9.7Hz), 7.05(2H, d, J=9.7Hz)
【０１１１】
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、６０％水素化ナトリウム（３４８ｍｇ、８．７ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（５０ｍl）に懸濁し、室温で３０分間撹拌した。これに２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（１．７０ｇ、７．９０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で更に３０分間撹拌した後、この溶液に（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピペリジン（２．６４ｇ、９．０２ｍｍｏｌ）のジメチルスルホキシド（２５ｍl）溶液を滴下して、５０℃で３時間攪拌した。反応液を飽和重曹水と酢酸エチルに分配し、有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液として最初にヘキサンと酢酸エチル（６：１）を用い、次いでヘキサンと酢酸エチル（１：１）に変えて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物質として得られた（２．２９ｇ、６８％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.59-1.86(4H,m), 1.96-2.02(4H,m), 2.21-2.29(1H,m), 2.46-2.55(1H,m), 2.60-2.78(3H,m), 2.97-3.06(1H,m), 3.19-3.31(6H,m), 4.08(1H,dd,3.7,14.3Hz), 5.16(1H,m), 5.30(1H,d,J=13.0Hz), 6.54(2H,d,J=9.0Hz), 6.75-6.85(3H,m), 6.95-7.09(4H,m), 6.99(2H,d,J=9.0Hz)
【０１１２】
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２．２９ｇ）のジクロロメタン（３０ｍｌ）溶液に２Ｍ塩化水素／ジエチルエーテル２０ｍｌを加え、２時間撹拌した後、溶媒を減圧留去した。得られた残留物をヘキサン中で撹拌して固化させて濾別し、表記化合物を淡褐色固体として得た（２．１７ｇ、８１％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.36(8H, m), 2.84-2.96(1H, m), 3.03-3.27(3H, m), 3.40-3.72(6H, m), 3.82-3.93(1H, m), 4.21(1H, dd, J=8.7, 15.7Hz), 4.63(1H, dd, J=6.3, 15.7Hz), 5.13(1H, d, J=14.0Hz), 5.33(1H, d, J=14.0Hz), 6.81-7.03(6H, m), 7.11-7.14(1H, m), 7.37(2H, d, J=9.0Hz), 7.60(2H, d, J=9.0Hz)
【０１１３】
〔参考例１０〕
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピペリジンを使用して、参考例６と同様の操作により（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．１９ｇ、５０％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.55-1.90(4H, m), 1.95-2.06(4H, m), 2.20-2.32(1H, m), 2.48-2.60(1H, m), 2.70-2.82(3H, m), 2.95-3.10(1H, m), 3.18-3.40(6H, m), 4.06(1H, m), 5.20(1H, d, J=12.0Hz), 5.26(1H, d, J=12.0Hz), 6.54(2H, d, J=8.7Hz), 6.68-6.85(5H, m), 6.95-7.03(1H, m), 7.08(2H, d, J=8.7Hz), 7.20-7.30(1H, m)
【０１１４】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を淡褐色固体として得た（９０％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(4H, m), 2.34(4H, m), 2.82-2.95(1H, m), 3.00-3.24(2H, m), 3.39-3.78(7H, m), 3.82-3.95(1H, m), 4.21(1H, dd, J=7.2, 14.1Hz), 4.62(1H, dd, J=5.7, 14.1Hz), 5.11(1H, d, J=12.6Hz), 5.34(1H, d, J=12.6Hz), 6.76(1H, t, J=8.1Hz), 6.80-7.05(5H, m), 7.19(1H, t, J=8.1Hz), 7.37(2H, d, J=8.4Hz), 7.64(2H, d, J=8.4Hz)
【０１１５】
〔参考例１１〕
（Ｒ）−７−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
７−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピペリジンを使用して、参考例６と同様の操作により（Ｒ）−７−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．１９ｇ、５１％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.58-1.90(4H, m), 1.95-2.06(4H, m), 2.20-2.32(1H, m), 2.48-2.60(1H, m), 2.68-2.82(3H, m), 2.98-3.08(1H, m), 3.18-3.40(6H, m), 4.05(1H, dd, J=5.8, 13.2Hz), 5.14(1H, d, J=12.0Hz), 5.31(1H, d, J=12.0Hz), 6.45-6.58(3H, m), 6.68-6.78(2H, m), 7.02-7.13(4H, m), 7.28-7.35(2H, m)
【０１１６】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た（９８％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(4H, m), 2.34(4H, m), 2.78-2.92(1H, m), 2.94-3.25(2H, m), 3.40-3.76(7H, m), 3.83-3.94(1H, m), 4.23(1H, dd, J=7.2, 14.4Hz), 4.66(1H, dd, J=6.0, 14.4Hz), 5.13(1H, d, J=12.9Hz), 5.24(1H, d, J=12.9Hz), 6.58-6.63(1H, m), 6.72-6.82(2H, m), 7.05-7.25(4H, m), 7.35(2H, d, J=8.4Hz), 7.60(2H, d, J=8.4Hz)
【０１１７】
〔参考例１２〕
（Ｒ）−８−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
８−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピペリジンを使用して、参考例６と同様の操作により（Ｒ）−８−フルオロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．１３ｇ、３２％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.58-1.90(4H, m), 1.95-2.06(4H, m), 2.18-2.34(1H, m), 2.45-2.58(1H, m), 2.65-2.80(3H, m), 2.95-3.10(1H, m), 3.14-3.38(6H, m), 4.05-4.14(1H, m), 5.21(1H, d, J=11.7Hz), 5.35(1H, d, J=11.7Hz), 6.48-6.58(4H, m), 6.88-6.95(1H, m), 7.02-7.12(4H, m), 7.24-7.35(2H, m)
【０１１８】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た（９８％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(4H, m), 2.35(4H, m), 2.78-2.94(1H, m), 2.95-3.10(1H, m), 3.10-3.25(1H, m), 3.40-3.80(7H, m), 3.80-3.95(1H, m), 4.19(1H, dd, J=7.8, 14.1Hz), 4.64(1H, dd, J=4.2, 14.1Hz), 5.16(1H, d, J=12.3Hz), 5.44(1H, d, J=12.3Hz), 6.50-6.61(2H, m), 6.88-7.00(1H, m), 7.05-7.18(2H, m), 7.30-7.41(4H, m), 7.64(2H, d, J=7.8Hz)
【０１１９】
〔参考例１３〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−クロロ−１−（４−ピロリジノフェネチル）ピペリジンを使用して、参考例６と同様の操作により（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．１８ｇ、６８％）。
ＥＳＩ／Ｍａｓｓ：４８８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.50-1.90(4H, m), 1.95-2.06(4H, m), 2.20-2.34(1H, m), 2.50-2.62(1H, m), 2.65-2.82(3H, m), 2.90-3.10(1H, m), 3.16-3.40(6H, m), 4.05-4.14(1H, m), 5.22(2H, s), 6.54(2H, d, J=8.7Hz), 6.75-6.88(3H, m), 6.96-7.04(2H, d, J=8.7Hz), 7.05-7.14(3H, m), 7.18(1H, d, J=8.4Hz)
【０１２０】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た（９１％）。
ＥＳＩ／Ｍａｓｓ：４８８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(4H, m), 2.34(4H, m), 2.78-2.92(1H, m), 2.92-3.25(2H, m), 3.40-3.81(7H, m), 3.83-3.99(1H, m), 4.21(1H, dd, J=6.9, 14.1Hz), 4.63(1H, dd, J=6.3, 14.1Hz), 5.10(1H, d, J=12.9Hz), 5.36(1H, d, J=12.9Hz), 6.85-7.06(5H, m), 7.15(2H, t, J=8.1Hz), 7.35(2H, d, J=8.7Hz), 7.62(2H, d, J=8.7Hz)
【０１２１】
〔参考例１４〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
３−ピロリジノフェネチルアルコール
乾燥した酢酸パラジウム（５８ｍｇ、０．２６ｍｍｏｌ）、２−（ジ−ｔ−ブチルフォスフィノ）ビフェニル（１３６ｍｇ、０．４６ｍｍｏｌ）、ｔ−ブトキシナトリウム（３．２３ｇ、３３．６ｍｍｏｌ）に２−（３−ブロモフェネトキシ）テトラヒドロ−２H−ピラン（６．２７ｇ、２１．９ｍｍｏｌ）のトルエン（１５ｍｌ）溶液とピロリジン（２．２ｍｌ、２６．４ｍｍｏｌ）を加え、７０℃で１２時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、生成物を有機層から１Ｍ塩酸で抽出した。水層を水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を乾燥し、３−ピロリジノフェネチルアルコールを淡黄色固体として定量的に得た。
ＮＭＲ(CDCl３) δ：1.98-2.02(4H, m), 2.82(2H, t, J=7.0Hz), 3.26-3.30(4H, m), 3.86(2H, q, J=7.0Hz), 6.42-6.54(3H, m), 7.17(1H, t, J=8.3Hz)
【０１２２】
３−ピロリジノフェネチルメシレート
３−ピロリジノフェネチルアルコールをジクロロメタン（２０ｍｌ）に溶解し、０℃でトリエチルアミン（３．７ｍｌ、２６．７ｍｍｏｌ）とメタンスルフォニルクロリド（１．９ｍｌ、２４．５ｍｍｏｌ）を加えて一晩攪拌した。反応溶液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（７：３）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、３−ピロリジニノフェネチルメシレートが白色固体として得られた（５．１３ｇ、８７％）。
ＥＳＩ／Ｍａｓｓ：２７０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.98-2.03(4H, m), 2.86(3H, s), 2.98(2H, t, J=7.3Hz), 3.25-3.30(4H, m), 4.43(2H, t, J=7.3Hz), 6.40-6.53(3H, m), 7.16(1H, t, J=8.7Hz)
【０１２３】
（Ｒ）−３−クロロ−１−（３−ピロリジノフェネチル）ピペリジン
４−ピロリジノフェネチルメシラートの代わりに３−ピロリジノフェネチルメシラートを用いて、参考例１３と同様の方法により、合成した。収率５０％。
ＥＳＩ／Ｍａｓｓ：２９３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.55-1.70(2H, m), 1.78-1.88(2H, m), 1.95-2.03(4H, m), 2.10-2.22(2H, m), 2.30(1H, t, J=10.5Hz), 2.60-2.67(2H, m), 2.67-2.82(2H, m), 3.16(1H, m), 3.22-3.30(4H, m), 4.02(1H, m), 6.40(2H, m), 6.49(1H, d, J=7,5Hz), 7.13(1H, t, J=7.5Hz)
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−クロロ−１−（３−ピロリジノフェネチル）ピペリジンを使用して、参考例６と同様の操作により（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．２１ｇ、４５％）。
ＥＳＩ／Ｍａｓｓ：４８８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.50-1.90(4H, m), 1.95-2.06(4H, m), 2.24-2.34(1H, m), 2.55-2.70(1H, m), 2.70-2.88(3H, m), 3.02-3.15(1H, m), 3.16-3.40(6H, m), 4.02-4.14(1H, m), 5.23(2H, s), 6.40-6.58(3H, m), 6.75-6.88(3H, m), 6.96-7.04(2H, m), 7.10-7.20(3H, m)
【０１２４】
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を褐色固体として得た（８８％）。
ＥＳＩ／Ｍａｓｓ：４８８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.95-2.30(4H, m), 2.32(4H, m), 2.77-2.90(1H, m), 3.00-3.30(2H, m), 3.38-3.78(7H, m), 3.80-3.92(1H, m), 4.21(1H, dd, J=6.6, 14.1Hz), 4.64(1H, dd, J=5.7, 14.1Hz), 5.10(1H, d, J=12.9Hz), 5.33(1H, d, J=12.9Hz), 6.82-7.08(5H, m), 7.14(2H, t, J=8.4Hz), 7.20-7.30(1H, m), 7.38-7.53(2H, m), 7.60-7.70(1H, m)
【０１２５】
〔参考例１５〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−モルホリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
４−モルホリノフェネチルアルコール
乾燥した酢酸パラジウム（３２．３ｍｇ、０．１４ｍｍｏｌ）、２−（ジ−ｔ−ブチルフォスフィノ）ビフェニル（８６．０ｍｇ、０．２９ｍｍｏｌ）、ｔ−ブトキシナトリウム（１．７３ｇ、１８ｍｍｏｌ）に２−（４−ブロモフェネトキシ）テトラヒドロ−２H−ピラン（３．４２ｇ、１２．０ｍｍｏｌ）のトルエン（９．０ｍｌ）溶液とモルホリン（１．２２ｇ、１４ｍｍｏｌ）を加え、７０℃で１６時間攪拌した。反応液に水を加えて酢酸エチルで抽出し、生成物を有機層から１Ｍ塩酸で抽出した。水層を水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を乾燥し４−モルホリノフェネチルアルコールを淡黄色固体として得た（２．３５ｇ、９５％）。
ＮＭＲ(CDCl３) δ：2.80(2H, t, J=8.7Hz), 3.13(4H, t, J=6.8), 3.78-3.88(6H. m), 6.88(2H, d, J=11.7Hz), 7.14(2H, d, J=11.7Hz)
【０１２６】
４−モルホリノフェネチルメシレート
４−モルホリノフェネチルアルコール（２．３５ｇ、１１．３ｍｍｏｌ）をジクロロメタン（２０ｍｌ）に溶解し、０℃でジイソプロピルエチルアミン（２．６０ｍｌ、１４．８ｍｍｏｌ）とメタンスルフォニルクロリド（１．１１ｍｌ、１４．８ｍｍｏｌ）を加えて４時間攪拌した。反応溶液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶出液として最初にヘキサンと酢酸エチル（３：１）を用い、次いで同溶媒（１：１）に変えて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、４−モルホリノフェネチルメシレートが白色固体として得られた（２．６０ｇ、８１％）。
ＮＭＲ(CDCl３) δ：2.86(3H, s), 2.98(2H, t, J=9.3Hz), 3.14(4H, m), 3.86(4H, m), 4.38(2H, t, J=9.3Hz), 6.87(2H, d, J=11.7Hz), 7.14(2H, d, J=11.7Hz)
【０１２７】
（Ｒ）−３−クロロ−１−（４−モルホリノフェネチル）ピペリジン
アセトニトリル（２０ｍｌ）に４−モルホリノフェネチルメシレート（０．４３ｇ、１．５１ｍｍｏｌ）とＤ−プロリノール（０．１７ｇ、１．６６ｍｍｏｌ）、炭酸カリウム（０．４０ｇ、２．８９ｍｍｏｌ）を加え、７０℃で一夜攪拌した。冷却後ろ過し、ろ液を減圧下で蒸発乾固去し、得られた残留物を水と酢酸エチルに分配した。目的物を酢酸エチル層から１Ｍ塩酸で抽出し、水層を中和してから再び酢酸エチルで抽出した。有機層を乾燥後、減圧下に溶媒を留去すると、（Ｒ）−２−ヒドロキシメチル−１−（４−モルホリノフェネチル）ピロリジンが淡黄色固体として得られた（０．４４ｇ、１．５ｍｍｏｌ、１００％）。これをジクロロメタン（１０ｍｌ）に溶解し、０℃でトリエチルアミン（０．２９ｍｌ、２．１ｍｍｏｌ）とメタンスルホニルクロリド（０．１５ｍｌ、１．９ｍｍｏｌ）を加え、室温で１時間攪拌した。反応溶液を５％炭酸水素ナトリウム溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（１：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−クロロ−１−（４−モルホリノフェネチル）ピペリジンが白色固体として得られた（０．３０ｇ、６４％）。
ＥＳＩ／Ｍａｓｓ：３０９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.50-1.86(4H, m), 2.10-2.20(2H, m), 2.28(1H, t, J=7.8Hz), 2.55-2.64(2H, m), 2.65-2.80(3H, m), 3.10-3.18(4H, m), 3.80-3.88(4H, m), 3.96-4.04(1H, m), 6.82-6.88(2H, m), 7.10-7.20(2H, m)
【０１２８】
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−モルホリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−３−クロロ−１−（４−モルホリノフェネチル）ピペリジンと３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例６と同様の操作により、（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−モルホリノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色油状物質。収率４６％。
ＥＳＩ／Ｍａｓｓ：５０４［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ： 1.60-1.95(4H, m), 2.22-2.31(1H, m), 2.52-2.61(1H, m), 2.69-2.80(3H, m), 2.98-3.07(1H, m), 3.01-3.19(1H, m), 3.15(4H, t, J=5.3Hz), 3.35(1H, dd, J=10,3 , 14.7Hz), 3.87(4H, t, J=5.3Hz), 4.03(1H, dd, J=4.0, 14.7Hz), 5.21(1H, d, J=13.3Hz), 5.23(1H, d, J=13.3Hz), 6.76-6.90(3H, m), 6.88(2H, d, J=9.7Hz), 6.97-7.01(2H, m), 7.09-7.19(2H, m), 7.14(2H, d, J=9.7Hz)
【０１２９】
これを参考例６と同様に４Ｍ塩化水素／ジオキサンで処理し、表記化合物を淡褐色固体として得た。収率９６％。
ＥＳＩ／Ｍａｓｓ：５０４［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.98-2.33(4H, m), 2.83-3.30(4H, m), 3.38-3.70(6H, m), 3.87-3.98(1H, m), 4.15-4.42(5H, m), 4.60-4.70(1H, m), 5.12(1H, d, J=14.0Hz), 5.39(1H, d, J=14.0Hz), 6.84-6.93 (3H, m), 7.04-7.19(4H, m), 7.43(2H, s), 7.78(2H, s)
【０１３０】
〔参考例１６〕
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、６０％水素化ナトリウム（１００ｍｇ、２．５ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（８ｍｌ）に懸濁した。室温で３０分間撹拌した後、２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（５３８ｍｇ、２．５ｍｍｏｌ）を加え、室温で３０分間、さらに５０℃で４０分間攪拌した。この溶液に（Ｓ）−１−（４−ジメチルアミノフェネチル）−３−メタンスルフォニルオキシピロリジン（３１２ｍｇ、１．０ｍｍｏｌ、国際特許第００４０５７０Ａ１号記載の方法により調製）のジメチルスルホキシド（３ｍｌ）溶液を滴下して、５０℃で１３時間攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液として最初にヘキサンと酢酸エチル（３：１）を用い、ついでヘキサンと酢酸エチル（１：１）に変えて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（１４０ｍｇ、３２％）。
ＥＳＩ／Ｍａｓｓ：４３２［Ｍ＋Ｈ⁺]
ＮＭＲ(CDCl３) δ： 1.74-1.84(1H, m), 2.22-2.34(1H, m), 2.37-2.47(1H, m), 2.48-2.71(5H, m), 2.75-2.85(1H, m), 2.90(6H, s), 3.18(1H, dd, J=7.7, 10.7Hz), 4.60-4.70(1H, m), 5.25-5.40(2H, bs), 6.37-6.49(3H, m), 6.72-6.87(5H, m), 6.95-7.24(3H, m),
【０１３１】
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（１４０ｍｇ）のジクロロメタン（５ｍｌ）溶液に４Ｍ塩化水素／酢酸エチル１．０ｍｌを加え、１時間撹拌した後、溶媒を減圧留去し、残留物をヘキサン中で撹拌して固化させ、濾別により表記化合物を淡黄色固体として得た（１４５ｍｇ、９０％）。
ＥＳＩ／Ｍａｓｓ：４３２［Ｍ＋Ｈ⁺]
ＮＭＲ(CD３OD) δ： 1.90-2.08(1H, m), 2.10-2.30(1H, m), 2.38-2.53(1H, m), 2.60-2.73(1H, m), 3.14(2H, t, J=8.0Hz), 3.26(6H, s), 3.49(2H, t, J=8.0Hz), 3.60-3.82(2H, m), 4.03-4.14(1H, m), 4.95-5.03(1H, m), 5.06-5.15(1H, m), 6.73-6.92(3H, m), 7.03-7.26(4H, m), 7.47-7.59(4H, m)
【０１３２】
〔参考例１７〕
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例１６と同様の操作により、（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色固体。収率４０％。
ＥＳＩ／Ｍａｓｓ：４３２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.73-1.84(1H, m), 2.21-2.30(1H, m), 2.41-2.48(1H, m), 2.50-2.71(5H, m), 2.75-2.82(1H, m), 2.90(6H, s), 3.18(1H, dd, J=7.7, 10.7Hz), 5.28(1H, d, J=12.0Hz), 5.40(1H, d, J=12.0Hz), 6.48-6.54(1H, m), 6.63-6.72(4H, m), 7.01-7.12(4H, m), 7.25-7.34(2H, m)
【０１３３】
これを参考例１６と同様に４Ｍ塩化水素／酢酸エチルで処理し、表記化合物を淡褐色固体として得た。収率９２％。
ＥＳＩ／Ｍａｓｓ：４３２［Ｍ＋Ｈ⁺］
ＮＭＲ(CD３OD) δ： 1.90-2.07(1H, m), 2.14-2.27(1H, m), 2.42-2.52(1H, m), 2.63-2.77(1H, m), 3.15(2H, t, J=9.0Hz), 3.26(6H, s), 3.49(2H, t, J=9.0Hz), 3.64-3.82(2H, m), 4.07-4.16(1H, m), 4.97-5.06(1H, m), 5.10-5.18(1H, m), 6.72-6.94(4H, m), 7.00-7.09(2H, m), 7.43-7.65(5H, m)
【０１３４】
〔参考例１８〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを用いて参考例１６と同様の操作により、（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（４−ジメチルアミノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを得た。淡黄色油状物質。収率３９％。
ＥＳＩ／Ｍａｓｓ：４４８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.74-1.84(1H, m), 2.22-2.34(1H, m), 2.37-2.47(1H, m), 2.48-2.71(5H, m), 2.75-2.85(1H, m), 2.90(6H, s), 3.18(1H, dd, J=7.7, 10.7Hz), 4.60-4.70(1H, m), 5.25-5.40(2H, bs), 6.68(2H, d, J=9.7Hz), 6.71-6.88(4H, m), 6.92-7.10(3H, m) 7.04(2H, d, J=9.7Hz)
【０１３５】
これを参考例１６と同様に４Ｍ塩化水素／酢酸エチルで処理し、表記化合物を褐色固体として得た。収率９０％。
ＥＳＩ／Ｍａｓｓ：４４８［Ｍ＋Ｈ⁺］
ＮＭＲ(CD３OD) δ： 1.86-2.08(1H, m), 2.10-2.27(1H, m), 2.40-2.53(1H, m), 2.60-2.74(1H, m), 3.12(2H, t, J=9.0Hz), 3.27(6H, s), 3.50(2H, t, J=9.0Hz), 3.64-3.84(2H, m), 4.06-4.16(1H, m), 5.00-5.08(1H, m), 5.10-5.19(1H, m), 6.73-7.07(4H, m), 7.17-7.42(3H, m), 7.47-7.67(4H, m)
【０１３６】
〔参考例１９〕
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｓ）−３−メタンスルフォニルオキシ−１−（３−ピロリジノフェネチル）ピロリジン
３−ピロリジノフェネチルメシラート（１．８０ｇ、４．００ｍｍｏｌ）、（Ｓ）−３−ピロリジノール塩酸塩（０．５０ｇ，４．０５ｍｍｏｌ）、炭酸カリウム（１．７０ｇ，１２．３ｍｍｏｌ）をアセトニトリル（２０ｍｌ）に加え、１００℃で１２時間攪拌した。アセトニトリルを減圧留去した後、水と酢酸エチルに分配した。酢酸エチル層から１Ｍ塩酸で目的物を抽出し、水層を中和してから再び酢酸エチルで抽出した。有機層を乾燥後、減圧下に溶媒を留去すると、（Ｓ）−３−ヒドロキシ−１−（３−ピロリジノフェネチル）ピロリジンが淡黄色固体として定量的に得られた。これをジクロロメタン（１０ｍｌ）に溶解し、０℃でトリエチルアミン（０．７６ｍｌ、５．４９ｍｍｏｌ）とメタンスルホニルクロリド（０．３９ｍｌ、５．０３ｍｍｏｌ）を加えて一晩攪拌した。反応溶液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、クロロホルムとメタノール（９５：５）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−メタンスルフォニルオキシ−１−（３−ピロリジノフェネチル）ピロリジンが淡黄色油状物として得られた（１．３０ｇ、９６％）。
ＥＳＩ／Ｍａｓｓ：３３９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.99(4H, m), 2.03-2.15(1H, m), 2.25-2.38(1H, m), 2.44-2.54(1H, m), 2.70-2.80(4H, m), 2.80-3.02(3H, m), 3.02(3H, s), 3.23-3.30(4H, m), 5.23(1H, m), 6.42(2H, m), 6.50(1H, d, J=7.5Hz), 7.14(1H, t, J=7.5Hz)
【０１３７】
（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンアルゴン気流下、６０％水素化ナトリウム（８８ｍｇ、２．２ｍｍｏｌ）をヘキサンで洗浄して、ジメチルスルホキシド（１０ｍｌ）に懸濁し、室温で３０分間撹拌した後、３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（０．４３ｇ，２．０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で更に３０分間撹拌した後、この溶液に（Ｓ）−３−メタンスルフォニルオキシ−１−（３−ピロリジノフェネチル）ピロリジン（０．３４ｇ、１．０ｍｍｏｌ）のジメチルスルホキシド（４ｍｌ）溶液を滴下して、７０℃で２時間攪拌した。反応液を飽和食塩水と酢酸エチルに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（１：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−３−フルオロ−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（０．１９ｇ、４２％）。
ＥＳＩ／Ｍａｓｓ：４５８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.68-1.84(1H, m), 1.90-1.99(4H, m), 2.22-2.36(1H, m), 2.40-2.48(1H, m), 2.50-2.76(5H, m), 2.76-2.86(1H, m), 3.16-3.28(5H, m), 4.64(1H, m), 5.36(2H, m), 6.37-6.49(3H, m), 6.72-6.87(5H, m), 6.95(1H, d, J=6.6Hz), 7.12-7.28(1H, t, J=7.5Hz), 7.28(1H, d, J=6.6Hz)
【０１３８】
これを参考例１６と同様に４Ｍ塩化水素／酢酸エチルで処理し、表記化合物を褐色固体として得た（６９％）。
ＮＭＲ(CD３OD) δ：1.90-2.08(1H, m), 2.10-2.30(5H, m), 2.35-2.55(1H, m), 2.60-2.78 (2H, m), 3.12(2H, t, J=8.1Hz), 3.30-3.48(1H, m), 3.53(1H, t, J=8.1Hz), 3.60-3.83(6H, m), 4.95-5.15(2H, m), 6.70-7.10(6H, m), 7.25-7.53(5H, m)
【０１３９】
〔参考例２０〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジン−１−イルフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンと（Ｒ）−３−メチルスルホニル−１−（３−ピロリジン−１−イルフェネチル）ピロリジンを使用して、参考例１９と同様の操作により（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−［１−（３−ピロリジン−１−イルフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンを淡黄色油状物として得た（０．２０ｇ、４３％）。
ＥＳＩ／Ｍａｓｓ：４７４［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.63-1.80(1H, m), 1.92-2.00(4H, m), 2.22-2.36(1H, m), 2.40-2.48(1H, m), 2.52-2.75(5H, m), 2.75-2.86(1H, m), 3.15-3.30 (5H, m), 4.60-4.70(1H, m), 5.38(2H, brs), 6.37-6.49(3H, m), 6.72-6.80(3H, m), 6.95(1H, dd, J=1.8, 7.8Hz), 7.04-7.14(3H, m), 7.24(1H, d, J=7.8Hz)
【０１４０】
これを参考例１６と同様に４Ｍ塩化水素／酢酸エチルで処理し、表記化合物を褐色固体として得た（９３％）。
ＥＳＩ／Ｍａｓｓ：４７４［Ｍ＋Ｈ⁺］
ＮＭＲ(CD３OD) δ：1.90-2.10(1H, m), 2.13-2.32(5H, m), 2.37-2.55(1H, m), 2.60-2.78 (2H, m), 3.10(2H, t, J=7.8Hz), 3.30-3.45(1H, m), 3.53(1H, t, J=7.8Hz), 3.58-3.81(5H, m), 4.00-4.12(1H, m), 4.95-5.18(2H, m), 6.70-7.10(4H, m), 7.16-7.50(7H, m)
【０１４１】
〔参考例２１〕
（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アセトニトリル（２０ｍｌ）中に、（Ｒ）−５，１１−ジヒドロ−５−（２−ピロリジルメチル）ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２４０ｍｇ、０．８５ｍｍｏｌ、国際特許第９９１２９２５Ａ１号記載の方法により調製）、３−ピロリジノフェネチルメシレート（２５３ｍｇ、０．９４ｍｍｏｌ）、炭酸ナトリウム（１０６ｍｇ、１．０ｍｍｏｌ）、ヨウ化ナトリウム（１０ｍｇ、０．０７ｍｍｏｌ）を加え、９０℃で６．５時間加熱還流した後、減圧下に溶媒を留去し、残留物を酢酸エチルと飽和重曹水に分配した。有機層を水洗し、硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液として最初にヘキサンと酢酸エチル（１５：１）を用い、次いでヘキサンと酢酸エチル（２：１）に変えて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物質として得られた（２０８ｍｇ、５４％）。
ＥＳＩ／Ｍａｓｓ：４５４［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.65-1.88(4H, m), 1.99-2.05(4H, m), 2.23-2.32(1H, m), 2.55-2.64(1H, m), 2.71-2.84(3H, m), 3.06-3.16(1H, m), 3.19-3.24(1H, m), 3.28-3.32(4H, m), 3.37(1H, dd, J=11.0, 14.3Hz), 4.15(1H, dd, J=4.0, 14.3Hz), 5.22(1H, d, J=13.0Hz), 5.34(1H, d, J=13.0Hz), 6.44-6.55(3H, m), 6.75-6.83(3H, m), 7.00-7.20(4H, m), 7.26-7.32(2H, m)
【０１４２】
（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−２−イルメチル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２０８ｍｇ）のジクロロメタン（２ｍｌ）溶液に２Ｍ塩化水素／ジエチルエーテル２．０ｍｌを加え、２時間撹拌した後、溶媒を減圧留去した。得られた残留物をヘキサン中で撹拌して固化させ、濾別することにより表記化合物を淡褐色固体として得た（２２０ｍｇ、９１％）。
ＥＳＩ／Ｍａｓｓ：４５４［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.90-2.42(8H, m), 2.98-3.30(3H, m), 3.40-3.90(8H, m), 4.18-4.35(1H, m), 4.62-4.76(1H, m), 5.14(1H, d, J=13.0Hz), 5.30(1H, d, J=13.0Hz), 6.78-6.94(3H, m), 6.97-7.16(3H, m), 7.20-7.40(4H, m), 7.45(1H, s), 7.59(1H, s)
【０１４３】
〔参考例２２〕
（Ｒ）−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｓ）−３−ヒドロキシ−１−（４−ピロリジノフェネチル）ピロリジン
アセトニトリル（２００ｍｌ）に４−ピロリジノフェネチルメシレート（１３．４５ｇ、５０．０ｍｍｏｌ）と（Ｓ）−３−ピロリジノール塩酸塩（５．５６ｇ、４５．０ｍｍｏｌ）、炭酸カリウム（１８．６３ｇ、１３５ｍｍｏｌ）を加え、９０℃で３時間攪拌した。冷却後ろ過し、ろ液を減圧下で蒸発乾固去し、得られた残留物を水と酢酸エチルに分配した。酢酸エチル層から１Ｍ塩酸で目的物を抽出し、水層を中和してから再び酢酸エチルで抽出した。有機層を乾燥後、減圧下に溶媒を留去すると、（Ｓ）−３−ヒドロキシ−１−（４−ピロリジノフェネチル）ピロリジンが淡黄色固体として得られた（６．３０ｇ、５２％）。
ＮＭＲ(CDCl３) δ：1.74-1.84(1H, m), 1.96-2.04(4H, m), 2.15-2.25(1H, m), 2.34-2.43(1H, m), 2.55-2.63(1H, m), 2.65-2.80(5H, m), 2.92-3.03(1H, m), 3.23-3.28(4H, m), 4.33-4.40(1H, m), 6.51(2H, d, J=9.3Hz), 7.06(2H, d, J=9.3Hz)
【０１４４】
（Ｓ）−３−メタンスルフォニルオキシ−１−（４−ピロリジノフェネチル）ピロリジン
（Ｓ）−３−ヒドロキシ−１−（４−ピロリジノフェネチル）ピロリジン（６．３０ｇ、２３．４ｍｍｏｌ）をジクロロメタン１００ｍｌに溶解し、０℃でジイソプロピルエチルアミン（５．２８ｍｌ、３０．０ｍｍｏｌ）とメタンスルフォニルクロリド（２．３４ｍｌ、３０．０ｍｍｏｌ）を加えて４時間撹拌した。反応液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ジクロロメタンとメタノール（１０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｓ）−３−メタンスルフォニルオキシ−１−（４−ピロリジノフェネチル）ピロリジンが淡黄色油状物として得られた（７．５０ｇ、４９％）。
ＥＳＩ／Ｍａｓｓ：３３９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.96-2.00(4H, m), 2.04-2.16(1H, m), 2.27-2.38(1H, m), 2.44-2.52(1H, m), 2.65-2.74(4H, m), 2.82-2.98(3H, m), 3.02(3H, s), 3.23-3.28(4H, m), 5.19-5.27(1H, m), 6.50(2H, d, J=9.3Hz), 7.05(2H, d, J=9.3Hz)
【０１４５】
（Ｒ）−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
アルゴン気流下、６０％水素化ナトリウム（１３２ｍｇ、３．３ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（１０ｍｌ）に懸濁し、室温で３０分間撹拌した後、５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（６００ｍｇ、３．０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で３０分間撹拌した後、この溶液に（Ｓ）−３−メタンスルフォニルオキシ−１−（４−ピロリジノフェネチル）ピロリジン（３４０ｍｇ、１．０ｍｍｏｌ）のジメチルスルホキシド（５ｍｌ）溶液を滴下して、５０℃で４２時間攪拌した。反応液を飽和食塩水と酢酸エチルに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（３：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（１４２ｍｇ、３２％）。
ＮＭＲ(CDCl３) δ：1.72-1.84(1H, m), 1.96-2.04(4H, m), 2.22-2.41(2H, m), 2.49-2.71(5H, m), 2.80-2.89(1H, m), 3.22-3.27(5H, m), 4.67-4.74(1H, m), 5.30-5.50(2H, b), 6.48(2H, d, J=9.7Hz), 6.72-6.82(3H, m), 6.95-7.13(3H, m), 7.02(2H, d, J=9.7Hz), 7.26-7.33(2H, m)
【０１４６】
これを参考例２１と同様に２Ｍ塩化水素／ジエチルエーテルで処理し、表記化合物を褐色固体として得た（８３％）。
ＥＳＩ／Ｍａｓｓ：４４０［Ｍ＋Ｈ⁺］
ＮＭＲ(CD３OD) δ：1.90-2.08(1H, m), 2.10-2.30(5H, m), 2.35-2.55(1H, m), 2.60-2.78 (2H, m), 3.08(2H, t, J=10.0Hz), 3.23-3.38(1H, m), 3.47(1H, t, J=10.0Hz), 3.60-3.83(5H, m), 4.02-4.11(1H, m), 4.99-5.08(1H, m), 5.10-5.18(1H, m), 6.72-7.04(4H, m), 7.15-7.24(2H, m), 7.36-7.44(6H, m)
【０１４７】
〔参考例２３〕
（Ｒ）−５，１１−ジヒドロ−５−［１−（３−ピロリジノフェネチル）ピロリジン−３−イル］ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｓ）−３−ヒドロキシ−１−（３−ピロリジノフェネチル）ピロリジン
アセトニトリル（２０ｍｌ）に参考例２１で合成した３−ピロリジノフェネチルメシレート（１．８０ｇ、４．００ｍｍｏｌ）と（Ｓ）−３−ピロリジノール塩酸塩（０．５０ｇ、４．０５ｍｍｏｌ）、炭酸カリウム（１．７０ｇ、１２．３ｍｍｏｌ）を加え、１００℃で１２時間攪拌した。アセトニトリルを減圧下で留去した後、水と酢酸エチルに分配した。酢酸エチル層から目的物を１Ｍ塩酸で抽出し、中和してから再び酢酸エチルで抽出した。有機層を乾燥後、減圧下に溶媒を留去すると、（Ｓ）−３−ヒドロキシ−１−（３−ピロリジノフェネチル）ピロリジンが淡黄色固体として得られた（１．０４ｇ、１００％）。
ＮＭＲ(CDCl３) δ：1.68-1.80(1H, m), 1.91-2.02(4H, m), 2.13-2.25(1H, m), 2.30-2.40(1H, m), 2.55-2.63(1H, m), 2.67-2.80(5H, m), 2.89-2.98(1H, m), 3.15-3.25(4H, m), 4.28-4.39(1H, m), 6.39-6.42(2H, m), 6.50(1H, d, J=8.0Hz), 7.13(1H, t, J=8.0Hz)
【０１４８】
（Ｓ）−３−メタンスルフォニルオキシ−１−（３−ピロリジノフェネチル）ピロリジン
（Ｓ）−３−ヒドロキシ−１−（３−ピロリジノフェネチル）ピロリジン（１．０４ｇ，４．００ｍｍｏｌ）をジクロロメタン（１０ｍｌ）に溶解し、０℃でトリエチルアミン（０．７６ｍｌ、５．４９ｍｍｏｌ）とメタンスルホニルクロライド（０．３９ｍｌ、５．０３ｍｍｏｌ）を加えて一晩攪拌した。反応溶液を５％炭酸水素ナトリウム水溶液とジクロロメタンに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、クロロホルムとメタノール（９５：５）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｓ）−３−メタンスルフォニルオキシ−１−（３−ピロリジノフェネチル）ピロリジンが淡黄色油状物として得られた（１．３０ｇ、９６％）。
ＥＳＩ／Ｍａｓｓ：３３９［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.96-2.02(4H, m), 2.03-2.15(1H, m), 2.25-2.38(1H, m), 2.44-2.54(1H, m), 2.70-2.80(4H, m), 2.80-3.02(3H, m), 3.02(3H, s), 3.23-3.30(4H, m), 5.20-5.28(1H, m), 6.42(2H, m), 6.50(1H, d, J=7.5Hz), 7.14(1H, t, J=7.5Hz)
【０１４９】
（Ｒ）−５，１１−ジヒドロ−５−〔１−（３−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
アルゴン気流下、６０％水素化ナトリウム（１３２ｍｇ、３．３ｍｍｏｌ）をヘキサンで洗浄した後、ジメチルスルホキシド（１０ｍｌ）に懸濁し、室温で３０分間撹拌した後、５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（６００ｍｇ、３．０ｍｍｏｌ）を加え、室温で３０分間攪拌した。５０℃で３０分間撹拌した後、この溶液に（Ｓ）−３−メタンスルフォニルオキシ−１−（４−ピロリジノフェネチル）ピロリジン（３４０ｍｇ、１．０ｍｍｏｌ）のジメチルスルホキシド（５ｍｌ）溶液を滴下して、５０℃で４２時間攪拌した。反応液を飽和食塩水と酢酸エチルに分配した。有機層を乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、ヘキサンと酢酸エチル（３：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、（Ｒ）−５，１１−ジヒドロ−５−〔１−（３−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物として得られた（２２５ｍｇ、５１％）。
ＥＳＩ／Ｍａｓｓ：４４０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.74-1.84(1H, m), 1.95-2.00(4H, m), 2.23-2.34(1H, m), 2.34-2.43(1H, m), 2.49-2.57(1H, m), 2.61-2.76(5H, m), 2.81-2.88(1H, m), 3.23-3.29(4H, m), 4.67-4.76(1H, m), 5.30-5.50(2H, bs), 6.34-6.48(3H, m), 6.71-6.85(3H, m), 6.94-6.97(1H, m), 7.04-7.16(3H, m), 7.25-7.32(2H, m)
【０１５０】
これを参考例２１と同様に２Ｍ塩化水素／ジエチルエーテルで処理し、表記化合物を褐色固体として得た（７８％）。
ＥＳＩ／Ｍａｓｓ：４４０［Ｍ＋Ｈ⁺］
ＮＭＲ(CD３OD) δ：1.90-2.08(1H, m), 2.10-2.30(5H, m), 2.35-2.55(1H, m), 2.60-2.78 (1H, m), 3.10(2H, t, J=10.0Hz), 3.25-3.40(1H, m), 3.25(2H, t, J=10.0Hz), 3.60-3.80(5H, m), 4.03-4.12(1H, m), 4.99-5.09(1H, m), 5.11-5.19(1H, m), 6.70-7.04(5H, m), 7.14-7.47(7H, m)
【０１５１】
〔参考例２４〕
５，１１−ジヒドロ−５−〔２−〔Ｎ−メチル−Ｎ−（３−ピロリジノフェネチル）アミノ〕エチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
アセトニトリル（２０ｍｌ）中に、５，１１−ジヒドロ−５−〔２−（Ｎ−メチルアミノ）エチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（２５４ｍｇ、１．００ｍｍｏｌ、国際特許第００４０５７０Ａ１号記載の方法により調製）、３−ピロリジノフェネチルメシレート（２９６ｍｇ、１．１０ｍｍｏｌ）、炭酸ナトリウム（１３８ｍｇ、１．３０ｍｍｏｌ）、ヨウ化ナトリウム（２０ｍｇ、０．１３ｍｍｏｌ）を加え、９０℃で６．５時間加熱還流した後、減圧下に溶媒を留去し、残留物を酢酸エチルと飽和重曹水に分配した。有機層を水洗し、硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、溶離液として最初にヘキサンと酢酸エチル（１０：１）を用い、次いでヘキサンと酢酸エチル（３：１）に変えて溶出した。適当なフラクションを集め、減圧下に溶媒を留去すると、５，１１−ジヒドロ−５−〔２−〔Ｎ−メチル−Ｎ−（３−ピロリジノフェネチル）アミノ〕エチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンが淡黄色油状物質として得られた（３３１ｍｇ、７８％）。
ＥＳＩ／Ｍａｓｓ：４２８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：1.96-2.00(4H, m), 2.32(3H, s), 2.61(4H, s), 2.66(2H, t, J=8.0Hz), 3.23-3.27(4H, m), 3.90(2H, t, J=8.0Hz), 5.29(2H, s), 6.32-6.44(3H, m), 6.77-6.84(3H, m), 7.00-7.14(4H, m), 7.25-7.32(2H, m)
【０１５２】
これを参考例２１と同様に２Ｍ塩化水素／ジエチルエーテルで処理し、表記化合物を褐色固体として得た（８１％）。
ＥＳＩ／Ｍａｓｓ：４２８［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl３) δ：2.28-2.40(4H, m), 2.85(3H, d, J=4.3Hz), 3.10-3.48(6H, m), 3.55-3.74(4H, m), 4.23-4.35(1H, m), 4.40-4.52(1H, m), 5.23(1H, d, J=14.3Hz), 5.25(1H, d, J=14.3Hz), 6.82-6.93(3H, m), 7.06-7.11(2H, m), 7.18(1H, d, J=8.7Hz), 7.24-7.44(4H, m), 7.53(1H, d, J=8.7Hz), 7.78(1H, m)
【０１５３】
〔参考例２５〕
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩 （＝参考例８の化合物）
（Ｒ）−Ｎ−〔（４−ジメチルアミノフェニル）アセチル〕−Ｄ−プロリンメチルエステル
（４−ジメチルアミノフェニル）酢酸（７．４ｇ、４１．３ｍｍｏｌ）、Ｄ−プロリンメチルエステル塩酸塩（７．１９ｇ、４３．４ｍｍｏｌ）の塩化メチレン（１５０ｍｌ）溶液に、１−ヒドロキシベンゾトリアゾール一水和物（６．１ｇ、４５．４ｍｍｏｌ）、およびＮ−ジメチルアミノプロピル−Ｎ’−エチルカルボジイミド塩酸塩（８．７ｇ、４５．４ｍｍｏｌ）を加えた。この混合物を室温にて６時間攪拌したのち、トリエチルアミン（６．３ｍｌ、４５．４ｍｍｏｌ）を加えた。これを室温にて一晩攪拌し、反応液を水（２００ｍｌ）、５％重曹水（２００ｍｌ）、水（２００ｍｌ）にて逐次洗浄した。溶媒を減圧下に留去して得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（１０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を褐色油状物として取得した（１１．０ｇ、８３％）。
ＥＳＩ／Ｍａｓｓ：２９１［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.82-2.26(4H, m), 2.82-2.98(6H, m), 3.40-3.76(2H, m), 3.60(3H, s), 3.73(2H, s), 4.41-4.52(1H, m), 6.64-6.74(2H, m), 7.07-7.19(2H, m)
【０１５４】
（Ｒ）−Ｎ−〔（４−ジメチルアミノフェニル）アセチル〕−Ｄ−プロリン
（Ｒ）−Ｎ−〔（４−ジメチルアミノフェニル）アセチル〕−Ｄ−プロリンメチルエステル（１．０ｇ、３．４ｍｍｏｌ）をテトラヒドロフラン（１０ｍｌ）に溶解させ、水（１０ｍｌ）および１Ｍ水酸化ナトリウム水溶液（３．７ｍｌ、３．７ｍｍｏｌ）を加えた。室温にて一晩攪拌したのち、飽和塩化アンモニウム水溶液（１５ｍｌ）を加え、１Ｍ塩酸にてｐＨを４付近に調整した。この混合物を減圧下に溶媒を留去した後、アセトンを加えて混合した。濾過を行なって濾液を取得し、減圧下にて溶媒を留去し、乾燥することで標題化合物を黄色固体として取得した（０．９１ｇ、９６％）。
ＥＳＩ／Ｍａｓｓ：２７７［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.80-2.28(3H, m), 2.45-2.58(1H, m), 2.95(6H, s), 3.42-3.70(2H, m), 3.65(2H, s), 4.60-4.68(1H, m), 6.72-6.83(2H, m), 7.08-7.19(2H, m)
【０１５５】
（Ｒ）−１−〔（４−ジメチルアミノフェニル）アセチル〕ピロリジン−２−カルボン酸 〔２−（２−ブロモ−４−クロロベンジルオキシ）フェニル〕アミド（Ｒ）−Ｎ−〔（４−ジメチルアミノフェニル）アセチル〕−Ｄ−プロリン（８．５６ｇ、３１．０ｍｍｏｌ）にトルエン（１１１ｍｌ）、Ｎ−メチルモルホリン（３．８５ｍｌ、３５．０ｍｍｏｌ）を加えた。氷浴下でここにクロロギ酸エチル（３．２６ｍｌ、３４．１ｍｍｏｌ）を加え、２時間攪拌した。ここに、２−（２−ブロモ−４−クロロベンジルオキシ）アニリン塩酸塩（１０．８ｇ、３１．０ｍｍｏｌ）、およびＮ−メチルモルホリン（４．０９ｍｌ、３７．２ｍｍｏｌ）を加え、室温にて一晩攪拌した。反応液に水（４０ｍｌ）を加え、有機層を水（４０ｍｌ）にて洗浄したのち、硫酸ナトリウムにて乾燥し、減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（３０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を黄色固体として取得した（１６．３ｇ、９２％）。
ＥＳＩ／Ｍａｓｓ：５７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.80-1.94(1.2H, m), 1.96-2.06(0.8H, m), 2.08-2.36(1.2H, m), 2.51-2.59(0.8H, m), 2.79 and 2.92(total 6.0H, each s), 3.45-3.75(4H, m), 4.53-4.59(0.2H, m), 4.81-4.87(0.8H, m), 4.94-5.13(0.3H, m), 5.13(1.7H, s), 6.47-6.69(2.0H, m), 6.84-7.14(5.1H, m), 7.19-7.26(0.9H, m), 7.51-7.68(1.9H, m), 8.26(0.1H, br s), 8.35-8.42(1.0H, m), 9.53(1H, br s)
【０１５６】
（Ｒ）−｛〔２−（３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン〕−１−イル｝−２−（４−ジメチルアミノフェニル）エタノン
（Ｒ）−１−〔（４−ジメチルアミノフェニル）アセチル〕ピロリジン−２−カルボン酸 〔２−（２−ブロモ−４−クロロベンジルオキシ）フェニル〕アミド（１．７３ｇ、３．０３ｍｍｏｌ）に炭酸カリウム（１．２７ｇ、９．１９ｍｍｏｌ）、臭化銅（Ｉ）（２４．１ｍｇ、０．１６８ｍｍｏｌ）、４−ピコリン（８．６５ｍｌ）を加えた。これを１４５℃にて２０時間加熱した後に、濾過して濾液を取得し、減圧下にて溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（２０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を褐色固体として取得した（０．９７ｇ、６６％）。
ＥＳＩ／Ｍａｓｓ：４９０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.52-2.34(4H, m), 2.92 and 2.96(total 6.0H, each s), 3.44-3.77(4.1H, m), 4.34-4.41(0.2H, m), 4.65-4.72(0.4H, m), 4.77-4.91(1.1H, m), 5.08-5.15(0.2H, m), 5.50-5.67(0.3H, m), 6.34-6.41(0.7H, m), 6.65-7.03(4.0H, m), 7.06-7.50(6.5H, m), 7.59(0.2H, br s), 7.91-7.96(0.2H, m), 8.11(0.1H, br s)
【０１５７】
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
（Ｒ）−｛〔２−（３−クロロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン〕−１−イル｝−２−（４−ジメチルアミノフェニル）エタノン（０．９７ｇ、１．９８ｍｍｏｌ）をテトラヒドロフラン（１９．４ｍｌ）に溶解させ、水素化ホウ素ナトリウム（０．３９ｇ、１０．４ｍｍｏｌ）を加えた後、氷浴下にて三フッ化ホウ素テトラヒドロフラン錯体（１．６９ｍｌ、１３．９ｍｍｏｌ）を加えた。反応液を３７℃に４２時間加熱したのち、水素化ホウ素ナトリウム（０．０５６ｇ、１．５ｍｍｏｌ）と三フッ化ホウ素テトラヒドロフラン錯体（０．２４ｍｌ、１．９９ｍｍｏｌ）を加えた。反応液を３７℃に２４時間加熱したのち、氷浴下にて１．５Ｍ水酸化ナトリウム水溶液（１６ｍｌ、２４ｍｍｏｌ）を加えた。反応液を６０℃に１２時間加熱したのち、トルエン（２０ｍｌ）と水（１０ｍｌ）に分配させた。有機層を取得し、減圧下にテトラヒドロフランを留去し、水（１０ｍｌ）にて洗浄した後、減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（１０：１）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を褐色固体として取得した（０．６７ｇ、７４％）。
ＥＳＩ／Ｍａｓｓ：４６２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.59-1.90(4H, m), 2.22-2.31(1H, m), 2.50-2.59(1H, m), 2.66-2.84(3H, m), 2.93(6H, s), 2.97-3.06(1H, m), 3.16-3.24(1H, m), 3.34(1H, dd, J=13.0, 9.4Hz), 4.07(1H, dd, J=13.0, 3.7Hz), 5.22(2H, s), 6.70-6.75(2H, m), 6.75-6.86(3H, m), 6.97-7.02(2H, m), 7.08-7.14(3H, m), 7.17(1H, d, J=7.9Hz)
【０１５８】
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−３−クロロ−５，１１−ジヒドロ−５−〔１−（４−ジメチルアミノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（１０．６ｇ、２２．９ｍｍｏｌ）を２−プロパノール（１００ｍｌ）に溶解させ、４Ｍ塩化水素／２−プロパノール（２２．９ｍｌ）を加えた。減圧下に溶媒を留去し、得られた残留物に４Ｍ塩化水素／２−プロパノール（１１．５ｍｌ）を加えた。減圧下に溶媒を留去し、標題化合物を薄黄色固体として取得した（１２．９ｇ、１００％）。
ＥＳＩ／Ｍａｓｓ：４６２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 2.00-2.21(2H, m), 2.21-2.34(2H, m), 2.86-2.98(1H, m), 3.03-3.15(1H, m), 3.19(6H, s), 3.15-3.30(1H, m), 3.47-3.70(3H, m), 3.90-4.00(1H, m), 4.24(1H, dd, J=14.0, 7.2Hz), 4.65(1H, dd, J=14.0, 6.0Hz), 5.12(1H, d, J=12.7Hz), 5.40(1H, d, 12.7Hz), 6.87(1H, dd, J=7.8, 1.9Hz), 6.89-7.00(2H, m), 7.03-7.09(2H, m), 7.14(1H, d, J=1.9Hz), 7.18(1H, d, J=8.0Hz), 7.45(2H, d, J=8.4Hz), 7.79(2H, d, J=8.6Hz)
【０１５９】
〔参考例２６〕
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（４−ピロリジノフェニル）酢酸 （＝参考例９の化合物）
酢酸パラジウム（２２．３ｍｇ、０．１０ｍｍｏｌ）、（２−ビフェニル）−ジ−ｔｅｒｔ−ブチルホスフィン（５９．８ｍｇ、０．２０ｍｍｏｌ）、ナトリウム−ｔｅｒｔ−ブトキシド（２．４０ｇ、２５．０ｍｍｏｌ）にトルエン（１０ｍｌ）を加え、（４−ブロモフェニル）酢酸（２．１５ｇ、１０．０ｍｍｏｌ）およびピロリジン（１．１０ｍｌ、１３．２ｍｍｏｌ）を加えた。この混合物を７０℃にて４６時間加熱したのち、水（２０ｍｌ）を加えた。水層のｐＨを２以下にしたのちにトルエンにて洗浄し、水層のｐＨを４〜５に調整した。氷浴にてしばらく攪拌したのちに濾過し、標題化合物を淡黄色固体として取得した（１．１ｇ、５４％）。
ＥＳＩ／Ｍａｓｓ：２０６［Ｍ＋Ｈ⁺］
ＮＭＲ(DMSO−d6)δ： 1.90-1.95(4H, m), 3.15-3.20(4H, m), 3.38(2H, s), 6.47(2H, d, J=8.4Hz), 7.03(2H, d, J=8.4Hz)
【０１６０】
（Ｒ）−Ｎ−〔（４−ピロリジノフェニル）アセチル〕−Ｄ−プロリンメチルエステル
（４−ピロリジノフェニル）酢酸（２．０５ｇ、１０．０ｍｍｏｌ）、Ｄ−プロリンメチルエステル塩酸塩（１．６６ｇ、１０．０ｍｍｏｌ）に塩化メチレン（２０ｍｌ）を加え、トリエチルアミン（１．５５ｍｌ、１１．１ｍｍｏｌ）、およびＮ−ジメチルアミノプロピル−Ｎ’−エチルカルボジイミド塩酸塩（２．１１ｇ、１１．０ｍｍｏｌ）を加えた。この混合物を室温にて４時間攪拌したのち、反応液を水（１０ｍｌ）、水（５ｍｌ）、５％クエン酸水溶液（５ｍｌ）、５％重曹水（５ｍｌ）にて逐次洗浄した。硫酸マグネシウムにて乾燥後、溶媒を減圧下に留去し、標題化合物を淡赤色固体として取得した（３．０６ｇ、９６％）。
ＮＭＲ(CDCl₃)δ： 1.85-2.15(8H, m), 3.23-3.28(4H, m), 3.31-3.68(4H, m), 3.68-3.75(3H, m), 4.40-4.53(1H, m), 6.45-6.54(2H, m), 7.05-7.14(2H, m)
【０１６１】
（Ｒ）−Ｎ−〔（４−ピロリジノフェニル）アセチル〕−Ｄ−プロリン
（Ｒ）−Ｎ−〔（４−ピロリジノフェニル）アセチル〕−Ｄ−プロリンメチルエステル（３０．１ｇ、９４．２ｍｍｏｌ）をテトラヒドロフラン（１５０ｍｌ）に溶解させ、水（１３４ｍｌ）および６Ｍ水酸化ナトリウム水溶液（１６．５ｍｌ、９９．２ｍｍｏｌ）を加えた。室温にて４時間攪拌したのち、６Ｍ塩酸（１６．６ｍｌ、９９．７ｍｍｏｌ）を加えた。この混合物のうち、テトラヒドロフランを減圧下に留去した後、冷蔵庫にて一晩静置した。これを濾過し、減圧下に乾燥することで標題化合物を淡紫色固体として取得した（２３．４ｇ、８２％）。
ＥＳＩ／Ｍａｓｓ：３０３［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.85-2.05(7H, m), 2.45-2.55(1H, m), 3.23-3.29(4H, m), 3.45-3.70(4H, m), 4.60-4.64(1H, m), 6.48-6.55(2H, m), 7.07-7.11(2H, m)
【０１６２】
（Ｒ）−１−〔（４−ピロリジノフェニル）アセチル〕ピロリジン−２−カルボン酸 〔２−（２−ブロモ−５−フルオロベンジルオキシ）フェニル〕アミド （Ｒ）−Ｎ−〔（４−ピロリジノフェニル）アセチル〕−Ｄ−プロリン（２．９０ｇ、９．５９ｍｍｏｌ）にトルエン（３７．８ｍｌ）、Ｎ−メチルモルホリン（１．１０ｇ、１０．８ｍｍｏｌ）を加えた。氷浴下でクロロギ酸エチル（１．１４ｇ、１０．５ｍｍｏｌ）を加え、２時間攪拌した。ここに、２−（２−ブロモ−５−フルオロベンジルオキシ）アニリン塩酸塩（３．１９ｇ、９．５９ｍｍｏｌ）、およびＮ−メチルモルホリン（１．１６ｇ、１１．５ｍｍｏｌ）を加え、１６時間かけて室温に昇温した。ここに水（３０ｍｌ）、クエン酸（１．６１ｇ）、トルエン（１０ｍｌ）を加えて分配させ、有機層を水（１０ｍｌ）、水（１０ｍｌ）、６．７％重曹水（１０ｍｌ）、６．７％重曹水（１０ｍｌ）、水（１０ｍｌ）、水（１０ｍｌ）にて逐次洗浄した。硫酸ナトリウムにて乾燥し、減圧下に溶媒を留去して、標題化合物を薄黄色固体として取得した（５．１３ｇ、９３％）。
ＥＳＩ／Ｍａｓｓ：５８０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.77-2.20(7H, m), 2.48-2.57(1H, m), 3.14-3.25(4H, m), 3.42-3.67(4H, m), 4.80-4.88(1H, m), 5.11(2H, s), 6.29-6.46(2H, m), 6.80-7.10(6H, m), 7.43-7.61(2H, m), 8.26-8.39(1H, m), 9.57(1H, s)
【０１６３】
（Ｒ）−｛〔２−（２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン〕−１−イル｝−２−（４−ピロリジノフェニル）エタノン
（Ｒ）−１−〔（４−ピロリジノフェニル）アセチル〕ピロリジン−２−カルボン酸 〔２−（２−ブロモ−５−フルオロベンジルオキシ）フェニル〕アミド（５．０ｇ、８．６１ｍｍｏｌ）に炭酸カリウム（３．５８ｇ、２５．９ｍｍｏｌ）、臭化銅（Ｉ）（６３．５ｍｇ、０．４４３ｍｍｏｌ）、４−ピコリン（２５ｍｌ）を加えた。これを１４５℃にて２１時間加熱した後に、濾過を行なって濾液を取得し、減圧下に溶媒を留去した。この混合物をトルエンと９．５％クエン酸水溶液に分配させ、有機層を９．５％クエン酸水溶液にて２回洗浄した。硫酸ナトリウムにて乾燥し、減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（９７：３）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を紫色固体として取得した（４．１６ｇ、９７％）。
ＥＳＩ／Ｍａｓｓ：５００［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.60-2.40(8H, m), 3.14-3.35(4H, m), 3.39-3.75(4H, m), 4.29-5.68(3H, m), 6.32-6.60(3H, m), 6.77-8.11(8H, m)
【０１６４】
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
（Ｒ）−｛〔２−（２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン−５−カルボニル）ピロリジン〕−１−イル｝−２−（４−ピロリジノフェニル）エタノン（３．７９ｇ、７．５９ｍｍｏｌ）をテトラヒドロフラン（４８ｍｌ）に溶解させ、水素化ホウ素ナトリウム（１．５２ｇ、４０．２ｍｍｏｌ）を加えた後、氷浴下にて三フッ化ホウ素テトラヒドロフラン錯体（７．３８ｇ、４９．５ｍｍｏｌ）を加えた。反応液を３７℃に６６時間加熱したのち、氷浴下にて１．５Ｍ水酸化ナトリウム水溶液（４８ｍｌ、７５ｍｍｏｌ）を加えた。反応液を６０℃に１３時間加熱したのち、トルエン（３０ｍｌ）を加えた。有機層を取得し、減圧下に溶媒を留去して２１．０ｇとし、トルエン（１２ｍｌ）を加えた。これを水（１０ｍｌ）にて２回洗浄し、減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーに付し、塩化メチレンとメタノール（９７：３）を用いて溶出した。適当なフラクションを集め、減圧下に溶媒を留去し、標題化合物を紫色固体として取得した（２．９５ｇ、８２％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.59-1.90(4H, m), 1.90-2.10(4H, m), 2.18-2.30(1H, m), 2.42-2.58(1H, m), 2.62-2.83(3H, m), 2.92-3.08(1H, m), 3.12-3.38(6H, m), 4.08(1H, dd, J=12.8, 3.0Hz), 5.16(1H, d, J=11.8Hz), 5.30(1H, d, J=11.8Hz), 6.54(2H, d, J=8.5Hz), 6.72-6.86(3H, m), 6.93-7.12(6H, m)
【０１６５】
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン・２塩酸塩
（Ｒ）−２−フルオロ−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−２−イルメチル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン（１２．０４ｇ、２５．５ｍｍｏｌ）を２−プロパノール（２５０ｍｌ）に溶解させ、４Ｍ塩化水素／２−プロパノール（１７．０ｍｌ）を加えた後、室温にて０．５時間攪拌した。減圧下に溶媒を留去した。得られた残留物に、２−プロパノール（約５０ｍL）を加え、減圧下に溶媒を留去することを４回繰り返し、標題化合物を薄赤色固体として取得した（１４．８９ｇ、１００％）。
ＥＳＩ／Ｍａｓｓ：４７２［Ｍ＋Ｈ⁺］
ＮＭＲ(DMSO−d6)δ： 1.76-2.19(8H, m), 2.89-3.25(4H, m), 3.33-3.54(5H, m), 3.54-3.67(2H, m), 4.10(1H, dd, J=13.6, 7.5Hz), 4.39(1H, dd, J=13.6, 6.5Hz), 5.18(1H, d, J=12.0Hz), 5.44(1H, d, J=12.1Hz), 6.72-6.78(1H, m), 6.83-6.90(2H, m), 6.96-7.27(6H, m), 7.31-7.38(2H, m)
【０１６６】
〔参考例２７〕
（Ｒ）−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン （＝参考例２２の化合物）
（Ｒ）−Ｎ−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕−２−（２−ブロモベンジルオキシ）アニリン
アルゴン気流下、２−（２−ブロモベンジルオキシ）アニリン（１．１５ｇ、４．１３ｍｍｏｌ）に（Ｓ）−３−メタンスルフォニルオキシ−１−（４−ピロリジノフェネチル）ピロリジン（０．３０ｇ、０．８９ｍｍｏｌ）を加え、アセトニトリル（５０ｍｌ）に溶解させた。ここに炭酸カリウム（１．６２ｇ、１１．７ｍｍｏｌ）を加え、８５時間還流させた。その後アセトニトリル（１５ｍｌ）を加え、さらに４８時間還流させた。反応液をセライトにて濾過して濾液を取得し、減圧下に溶媒を留去して、標題化合物を褐色油状の混合物として取得した（１．４０ｇ）。
ＥＳＩ／Ｍａｓｓ：５２０［Ｍ＋Ｈ⁺］
【０１６７】
（Ｒ）−５，１１−ジヒドロ−５−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕ジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピン
アルゴン気流下、（Ｒ）−Ｎ−〔１−（４−ピロリジノフェネチル）ピロリジン−３−イル〕−２−（２−ブロモベンジルオキシ）アニリン（１．４０ｇ、混合物として）に炭酸カリウム（１．７１ｇ、１２．４ｍｍｏｌ）、臭化銅（Ｉ）（５３ｍｇ、０．３７ｍｍｏｌ）およびトルエン（３０ｍｌ）を加えた。反応液を加熱下に５３時間還流させ、臭化銅（Ｉ）（６０ｍｇ、０．４２ｍｍｏｌ）を加えた。反応液を加熱下にさらに５０時間還流させ、さらにトルエン（１０ｍｌ）、炭酸カリウム（１．０４ｇ、７．５２ｍｍｏｌ）および臭化銅（Ｉ）（４２ｍｇ、０．２９ｍｍｏｌ）を加えた。さらに反応液を加熱下に４８時間還流させた後、セライトにて濾過し、濾液に水を加えた。有機層を取得し、硫酸ナトリウムにて乾燥させ、減圧下に溶媒を留去した。得られた残留物（１．１２ｇ）のうち１８７ｍｇを高速液体クロマトグラフィーに付し、アセトニトリルと水（２０：８０から７０：３０までのグラジエント）を用いて溶出した。適当なフラクションを集め、塩化メチレンと飽和重曹水に分配させた。有機層を硫酸ナトリウムにて乾燥させたのち、減圧下に溶媒を留去した。得られた残留物を薄層シリカゲルクロマトグラフィーに付し、ヘキサンと酢酸エチル（１：５）を用いて展開した。適当な部位のシリカゲルを集め、塩化メチレンとメタノール（３：１）の混合溶媒にて溶出した。溶出液を集め、減圧下に溶媒を留去し、標題化合物を白色固体として取得した（２５．５ｍｇ、２工程収率３９％）。
ＥＳＩ／Ｍａｓｓ：４４０［Ｍ＋Ｈ⁺］
ＮＭＲ(CDCl₃)δ： 1.72-1.84(1H, m), 1.92-2.05(4H, m), 2.24-2.49(2H, m), 2.49-2.77(5H, m), 2.82-2.94(1H, m), 3.18-3.36(5H, m), 4.68-4.79(1H, m), 5.19-5.62(2H, m), 6.48(2H, d, J=8.4Hz), 6.70-6.85(3H, m), 6.95(1H, dd, J=7.8, 1.6Hz), 7.02(2H, d, J=8.6Hz), 7.03-7.14(2H, m), 7.25-7.35(2H, m)
【０１６８】
参考例１と同様の方法により、３−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに表１に示した化合物［V］を、（Ｒ）−３−クロロ−１−（４−メトキシフェネチル）ピペリジンの代わりに表１に示した化合物［VI］を用いることにより、表１に示した化合物［II］を調製することが出来る。
【０１６９】
【表１】

【０１７０】
〔参考例２９〕
参考例１６と同様の方法により、２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに表２に示した化合物［V］を、（Ｓ）−１−（４−ジメチルアミノフェネチル）−３−メタンスルフォニルオキシピロリジンの代わりに表２に示した化合物［XI］を用いることにより、表２に示した化合物［III］を調製することが出来る。
【０１７１】
【表２】

【０１７２】
〔参考例３０〕
参考例２４と同様の方法により、２−フルオロ−５，１１−ジヒドロジベンゾ〔ｂ，ｅ〕〔１，４〕オキサゼピンの代わりに表３に示した化合物［V］を、３−ピロリジノフェネチルメシレートの代わりに表３に示した化合物［X］を用いることにより、表３に示した化合物［IV］を調製することが出来る。
【０１７３】
【表３】

【０１７４】
＜製剤例＞
以下に製剤例を記載する。
〔製剤例１〕
下記混合物を常法に従って混合し、打錠することにより、１錠当り主薬５０mgを含有する錠剤を得た。
参考例８の化合物 ５０mg
乳糖 ２００mg
結晶セルロース ４０mg
ステアリン酸マグネシウム ５mg
【０１７５】
〔製剤例２〕
下記混合物を常法に従って造粒し、顆粒剤とした。
参考例８の化合物 ５０mg
乳糖 ９０mg
トウモロコシ澱粉 ６０mg
タルク ３０mg
ステアリン酸マグネシウム １０mg
【０１７６】
【実施例】
平滑筋膜表本の調製：
Wistar系ラット（8〜12週齢、オス）の結腸、回腸または大動脈の縦走筋を細切し、氷冷したTris緩衝液に懸濁、テフロン（登録商標）ホモゲナイザー及びポリトロンを用いてホモゲナイズした。これを遠心分離し、上清を冷却超遠心分離機により遠心分離した。ここで得られた沈査をTris緩衝液で再懸濁させ、結合実験に使用した。タンパク定量はウシ血清アルブミンを標準液として、Protein Assay Kit（Bio-Rad）を用いて行なった。
【０１７７】
結合実験：
受容体リガンドとして[³H]参考例８の化合物を、Ca拮抗薬として参考例８の化合物、verapamil, diltiazem, 及びnicardipineを用いた。
膜標本, Tris緩衝液または各Ca拮抗薬、標識リガンドをインキュベートした後、ガラス繊維濾紙（Whatman GF/C）で吸引濾過することにより反応を中止させた。濾紙はTris緩衝液で洗浄後、液体シンチレーションカウンターで放射活性β線量（dpm）を測定した。[³H] 参考例８の化合物の特異的結合量は、受容体リガンドの総結合量から、10μMの参考例８の化合物を添加した時に得られた非特異的結合量を差し引いた値として求めた。実験は全てn=4で行なった。解離定数（Kd値）、最大結合数（Bmax）及び各Ca拮抗薬による50％結合阻害濃度（IC₅₀）は、解析ソフトGraphPad Prism（登録商標）を用いて算出した。結果を表４に示す。
【０１７８】
【表４】

【０１７９】
[³H]参考例８の化合物は、大動脈に比べて結腸、回腸で高い親和性を示し、各組織における[³H]参考例８の化合物の結合に対する阻害能は、参考例８の化合物＞＞verapami＞diltiazem＞nicardipineの順であった。
[³H]参考例８の化合物の各組織への結合は、用いた4種のCa拮抗薬の中で、参考例８の化合物によって最も低濃度で阻害されたことから、既存のよく知られているdihydropyridine結合サイト、diltiazem結合サイト、verapamil結合サイトとは別の参考例８の化合物特有の結合サイトが存在することが示唆された。
【発明の効果】
本発明により、副作用を示さずに、消化管の器質的変化を伴う疾患を治療することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition having a calcium channel antagonism and useful for the treatment of diseases accompanied by organic changes in the gastrointestinal tract.
[0002]
[Prior art]
For example, EP 0404359A1 discloses that 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivatives are useful as calcium channel antagonists with selectivity for the gastrointestinal tract. Yes. Also, Quinn et al. (Quinn, P. et al.), Brit. J. Pharmacol., 1994, 112 (Suppl.), Abst. 573P and Wallis et al. (Wallis, RM et al.), Brit. J. Pharmacol., 1994, 112 (Suppl.), Abst. 574P includes (S) -5-[[1- (4-methoxyphenyl) ethyl] pyrrolidin-2-ylmethyl] -5,11-dihydrodibenzo [b , E] [1,4] thiazepine maleate has the same effect. However, one of the drawbacks is that these compounds are not sufficiently active and selective for the gastrointestinal tract and have an anticholinergic action that contributes to side effects such as dry mouth and mydriasis. In addition, International Patent Nos. 9733885A1 and 9912925A1 disclose 5- (2-pyrrolidinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivatives as ameliorating agents for gastrointestinal motility. ing. Furthermore, International Patent No. 0040570A1 discloses a 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative as an agent for improving gastrointestinal dysfunction. However, these compounds have not yet been sufficiently active and selective for the gastrointestinal tract, and have not been used as drugs.
[0003]
On the other hand, reports that calcium channel antagonists can suppress 5-lipoxygenase in patients with active ulcerative colitis and can be expected to have therapeutic effects (Alimentary Pharmacology & Therapeutics 6 (2): 163-168, 1992) There is a report (Japanese Journal of Pharmacology 78 (4): 435-441, 1998) that improves gastric protection and ulcer in a hydrochloric acid-ethanol gastric mucosal disorder model.
[0004]
[Problems to be solved by the invention]
An object of this invention is to provide the outstanding pharmaceutical composition for treating the disease accompanying the organic change of a digestive tract.
[Means for Solving the Problems]
The present invention provides a pharmaceutical composition for treating a disease associated with an organic change in the gastrointestinal tract, comprising a calcium channel antagonist.
The present invention is also a method of screening for calcium channel binding compounds comprising:
(a) measuring the amount of the labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen;
(b) Binding of a labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen in the presence of a test compound Measuring the amount, and
(c) comparing the result obtained in step (a) with the result obtained in step (b);
A method comprising the steps of:
The present invention also provides the use of a calcium antagonist to prepare a pharmaceutical composition for treating a disease associated with an organic change in the gastrointestinal tract.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
As a “calcium channel antagonist” which is an active ingredient of the present invention, a drug that acts on calcium channels existing in skeletal muscle, myocardium, vascular smooth muscle, brain, endocrine and kidney and inhibits inflow of calcium is used. Can do. In particular, a calcium channel antagonist having intestinal selectivity is preferable.
[0006]
Examples of the “calcium channel antagonist” used in the present invention include compounds represented by the following (I) to (V) or pharmaceutically acceptable salts thereof.
(I) 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivatives represented by the following general formula [I], stereoisomers, pharmacologically acceptable salts thereof, Hydrates or solvates;
[0007]
[Chemical Formula 10]

[0008]
[Wherein, rings G, J and K each represent a benzene ring or a nitrogen-containing aromatic ring. R ¹ ~ R ⁸ May be the same or different and each represents a halogen atom or a hydrogen atom, R ⁹ ~ R ¹³ May be the same or different, and may be a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group, and their lower acyl, lower dialkylamino group, cyclic alkyl Represents an amino group or R ⁹ And R ^Ten Or R ^Ten And R ¹¹ Together -O (CH ₂ ) Represents an nO- group (n is 1, 2 or 3). A is CH ₂ , CHOH, CO, or O, B is CH ₂ , CHOH or CO, or AB represents CH = CH, D is CH ₂ , CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ Or BD is CH ₂ Represents. X and Z are bonded to each other and CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ In this case, Y represents a hydrogen atom. Alternatively, Y and Z are bonded together and CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ In which case X represents a hydrogen atom. When X and Z, and Y and Z are not bonded to each other, X and Y represent a hydrogen atom, and Z represents a lower alkyl group.
However, R ⁹ ~ R ¹³ When any of the above is a cyclic amino group represented by the formula [E], R ¹ ~ R ⁸ May be either a halogen atom or a hydrogen atom, but R ⁹ ~ R ¹³ In the case where none of these is a cyclic amino group represented by the formula [E], R ¹ ~ R ⁸ Any one or two of these are halogen atoms, and the others represent hydrogen atoms.
[0009]
Embedded image

[0010]
[Wherein, n and m represent 1 or 2, and W represents a nitrogen atom, an oxygen atom or a sulfur atom which may be substituted with a carbon atom or a lower alkyl group. ]
[0011]
(II) 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivative represented by the following general formula [2], its stereoisomer, pharmacologically acceptable salt thereof, Hydrates or solvates;
[0012]
Embedded image

[0013]
(Where
k, m and n are 1, 2 or 3, respectively.
p is 0, 1 or 2;
X is O, S or a linking group, but when X is O or S, n is 2 or 3,
R ¹ Is H or C ₁ -C _Four Is alkyl, and
R ² Is
[0014]
Embedded image

[0015]
(Wherein R ^Three And R ^Four Are independently H, C ₁ -C _Four Alkyl, C ₁ -C _Four Alkoxy, —OH, —N (C ₁ -C _Four Alkyl) ₂ , Halo or -CF _Three It is. ) Or
[0016]
Embedded image

[0017]
(Wherein q is 1, 2 or 3,
X ¹ And X ² Are independently O and -CH. ₂ -Selected from) or
(C) a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or thienyl group, wherein the group is C ₁ -C _Four Alkyl and C ₁ -C _Four It may be substituted with 2 or less substituents independently selected from alkoxy. )
[0018]
(III) 5- (2-pyrrolidinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [3], its stereoisomer, pharmacologically Acceptable salts, hydrates or solvates thereof;
[0019]
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[0020]
[In the formula, R ¹ And R ² May be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group or a lower alkoxy group, or R ¹ And R ² Together -O (CH ₂ ) _n O-group (n is 1, 2 or 3), R ^Three Represents a hydrogen atom or a hydroxy group, R ^Four And R ^Five May be the same or different and each represents a hydrogen atom or a hydroxy group, or together represents ═O. ]
[0021]
(IV) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivatives represented by the following general formula [4], their stereoisomers, pharmacologically acceptable Salts, hydrates or solvates thereof; and
[0022]
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[0023]
[In the formula, R ¹ ~ R ^Five May be the same or different and each represents a hydrogen atom, a lower alkoxy group, an amino group or an alkylamino group, but at least one represents an amino group or an alkylamino group, and R ⁶ And R ⁷ May be the same or different and each represents a hydrogen atom or a hydroxy group, or together represents ═O, Y ¹ Represents methylene, sulfur atom or hydroxymethine. ]
(V) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [5], its stereoisomer, pharmacologically acceptable Salts, hydrates or solvates thereof.
[0024]
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[0025]
[In the formula, R ¹ ~ R ^Five May be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group, or R ¹ And R ² , R ² And R ^Three , R ^Three And R ^Four Or R ^Four And R ^Five Together -O (CH ₂ ) represents an nO-group (n is 1, 2 or 3) and R ⁶ Represents hydrogen or a lower alkyl group, Y represents a methylene, oxygen atom, sulfur atom, or alkylamino group, and A represents CH ₂ , CHOH, CO or O, and B is CH ₂ , CHOH or CO, or AB represents CH = CH and D is CH ₂ , CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ Or BD is CH ₂ Represents. ]
In the present invention, the calcium channel antagonist is a 5,11-dihydroaryl [b, e] [1,4] oxazepine derivative represented by the above general formula [I], its stereoisomer, pharmacologically acceptable. And their salts, hydrates or solvates thereof.
[0026]
In the present invention, the calcium channel antagonist is particularly preferably a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.
[0027]
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[0028]
The nitrogen-containing aromatic ring of rings G, J and K in the general formula [I] is preferably a 6-membered ring compound, and examples thereof include a pyridine ring, a pyrimidine ring, a pyrazine ring and a pyridazine ring. However, in rings G and J, there is no aromatic ring nitrogen atom on the oxazepine ring, and R ¹ ~ R ⁸ When any of these is a halogen atom, the halogen atom is not bonded to an aromatic ring nitrogen atom. In ring K, the aromatic ring nitrogen atom is not bonded to A and has no substituent on the nitrogen atom.
[0029]
Regarding the rings G, J and K in the above general formula [I], (i) when both rings G and J are benzene rings, (ii) either one of rings G and J is a pyridine ring, and the other Is a benzene ring, (iii) in the case of (i) or (ii) above in which ring K is a benzene ring, (iv) ring K is any one of a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring. In the case of (i) or (ii) above, or (v) the case where rings G, J and K are all benzene rings is preferred. The same applies to the general formulas [XV] and [XVI].
[0030]
R in the above general formula ¹ ~ R ⁸ Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom, and a fluorine atom or a chlorine atom is preferable. R ¹ ~ R ⁸ Of which, R ² , R ^Three , R ⁶ , R ⁷ It is more preferable that any one of is a fluorine atom or a chlorine atom and the other is a hydrogen atom. R ⁹ ~ R ¹³ As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, etc., a lower alkyl group as a lower alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, and a propyl group, and a lower alkoxy group as a methoxy group A lower alkylamino group having 1 to 5 carbon atoms such as a group, an ethoxy group, or a propoxy group, and a lower alkylamino group having 1 to 5 carbon atoms such as a monomethylamino group, a monoethylamino group, or a monopropylamino group Groups. The amino group and lower acyl forms of these lower alkylamino groups include formylamino, acetylamino, propionylamino, formylmethylamino, formylethylamino, formylpropylamino, acetylmethylamino, acetylethylamino Groups, acetylpropylamino groups, propionylmethylamino groups, propionylethylamino groups, propionylpropylamino groups and the like, and fatty acid acyls having 1 to 3 carbon atoms. The dialkylamino group is a lower alkylamino group having 2 to 7 carbon atoms in total such as a dimethylamino group, a diethylamino group, or a methylethylamino group, and the cyclic alkylamino group is an azetidino group, a pyrrolidino group, a piperidino group, or a homopiperidino group , Piperazino group, morpholino group, etc., 4-7 membered amino group, -O (CH ₂ ) Examples of the nO- group include a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group. Among these, as a halogen atom, a fluorine atom and a chlorine atom are preferable, and as a lower alkyl group, a C1-C3 lower alkyl group is preferable. As a lower alkoxy group, a C1-C3 lower alkoxy group is preferable. The monoalkylamino group is preferably a lower alkylamino group having 1 to 3 carbon atoms, and the dialkylamino group is preferably one having a total of 2 to 6 carbon atoms in the alkyl group. The cyclic alkylamino group preferably has 4 to 6 ring members. The acyl group of the amino group or the lower acyl form of these lower alkylamino groups is preferably a formyl group or an acetyl group. Where R ⁹ ~ R ¹³ Are preferably not simultaneously hydrogen atoms.
[0031]
In the general formula [I], the following are preferable, and the same applies to the general formulas [XV] and [XVI].
(i) X and Z are bonded to each other and CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ Y is a hydrogen atom,
(ii) Y and Z are bonded to each other and CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ X is a hydrogen atom,
(iii) X and Y are hydrogen atoms, Z is a lower alkyl group,
(iv) R ^Ten , R ¹¹ One or both of them are methoxy groups, or R ^Ten And R ¹¹ Together represent a methylenedioxy group, R ⁹ And R ¹² , R ¹³ Is a hydrogen atom,
[0032]
(v) R ¹¹ Is a methoxy group and R ⁹ , R ^Ten And R ¹² , R ¹³ Is a hydrogen atom,
(vi) R ^Ten , R ¹¹ Any one of these is an amino group or a lower alkylamino group and a lower acyl form thereof, a lower dialkylamino group, or a cyclic alkylamino group, and the other is a hydrogen atom,
(vii) R ¹ ~ R ⁸ Are both hydrogen atoms,
(viii) R ¹ ~ R ⁸ Any one of is a fluorine atom or a chlorine atom, the other is a hydrogen atom,
[0033]
(ix) R ² , R ^Three , R ⁶ , R ⁷ Any one of is a fluorine atom or a chlorine atom, the other is a hydrogen atom,
(x) Both A and BD are CH ₂ ,
(xi) the absolute configuration of the carbon atom to which X is bonded is R-form,
(xii) the absolute configuration of the carbon atom to which X is bonded is S-form,
(xiii) the absolute configuration of the carbon atom to which Y is bonded is R,
(xiv) The absolute configuration of the carbon atom to which Y is bonded is S.
[0034]
The cyclic amino group represented by the formula [E] includes a cyclic amino group containing one nitrogen atom such as an azetidino group, a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, and a hetero atom such as a nitrogen atom or an oxygen atom. And a pyrrolidino group and a morpholino group are preferable. R ⁹ ~ R ¹³ Of which, R ^Ten , R ¹¹ It is more preferable that any one of these is a cyclic amino group and the other is a hydrogen atom.
[0035]
A-BD is CH ₂ -CH ₂ , CO-CH ₂ , CHOH-CH ₂ , CHOH-CH ₂ -CH ₂ , CH ₂ -CHOH-CH ₂ , CH = CH-CH ₂ , CO-CH ₂ -CH ₂ , O-CH ₂ , CH ₂ -CO-CH ₂ Or CH ₂ -CH ₂ -CH ₂ Either of these is preferable.
In the present invention, among these, preferred compounds are, for example, compounds represented by the following formula [II]. However, in the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B and D are the same as those in formula [I], and r represents 1 or 2.
[0036]
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[0037]
Examples of the compound represented by [II] include 2-fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4 ] Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 -Dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [ 1- (4-aminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-amino Enethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [B, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-methylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4 Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 11-dihydro-5- [1- (3-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-phenyl Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5 -[1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-morpholino Phenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [B, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-fluorophenethyl) pyrrolidin-2-ylmethyl] dibe Zo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-fluorophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4 Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 11-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-Methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-methoxyphene) Til) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidine-2- Ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-aminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1 , 4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-aminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5 , 11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihi Dro-5- [1- (3-methylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4 -Dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-dimethylaminophenethyl) pyrrolidine-2- Ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1, ] Oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5 11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-Fluorophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-fluorophenethyl) pyrrolidine-2- Ylmethyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidin-2-yl Methyl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine, 5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5 -[1- (3-Pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (4-piperidinophenethyl) Pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (3-piperidinophenethyl) pyrrolidin-2-ylmethyl] di Benzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 5,11-Dihydro-5- [1- (3-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepines and their halogen substituted positional isomers, pharmacologically acceptable These salts, hydrates, and solvates.
[0038]
The compound [II] that can be used in the present invention has one or more asymmetric carbon atoms, and optical isomers can exist. These optical isomers, arbitrary mixtures thereof or racemates are included in the compounds of the present invention. Of these, the steric configuration at the 2-position of the pyrrolidine ring or piperidine ring bonded to the dihydrodibenzoxazepine ring via methylene is preferably R.
Another preferred compound is, for example, a compound represented by the following formula [III].
[0039]
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[0040]
However, in the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B and D are the same as those in formula [I], and r represents 1 or 2. Examples of the compound represented by the formula [III] include 2-fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1, 4] Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5, 11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5 [1- (4-Aminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-aminophenethyl) pyrrolidine 3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e ] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-methylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2 -Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro- 5- [1- (3-Dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-pyrrole) Nophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [B, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4 Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5 11-dihydro-5- [1- (4-fluorophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-Fluorophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidine-3 -Yl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro -5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5 [1- (3,4-Methylenedioxyphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4- Aminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-aminophenethyl) pyrrolidin-3-yl] dibenzo [B, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-methylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4 Oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-methylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5 11-di Dro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3 -Dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidine-3- Yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [ 1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro − 5,11-dihydro-5- [1- (3-morpholinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [ 1- (4-Fluorophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-fluorophenethyl) pyrrolidine- 3-yl] dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (4-acetylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e ] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- [1- (3-acetylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5 , 1 -Dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (3-pyrrolidino Phenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (4-piperidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (3-piperidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11 -Dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- [1- (3-morpholino Phenethyl) Roridin-3-yl] dibenzo [b, e] [1,4] oxazepine and their halogen-substituted regioisomers, pharmacologically acceptable salts thereof or hydrates which are include solvates.
[0041]
The compound [III] that can be used in the present invention has one or more asymmetric carbon atoms, and optical isomers may exist. These optical isomers, arbitrary mixtures thereof or racemates are included in the compounds of the present invention. Among these, the configuration at the 2-position of the pyrrolidine ring or piperidine ring bonded to the dihydrodibenzoxazepine ring is preferably an R form.
Another preferred compound is, for example, a compound represented by the following formula [IV]. However, in the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B and D represent the same as in formula [I], R ¹⁴ Represents a lower alkyl group having 1 to 3 carbon atoms.
[0042]
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[0043]
Examples of the compound represented by the formula [IV] include 2-fluoro-5,11-dihydro-5- {2- [N- (4-methoxyphenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-methoxyphenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1, 4] Oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3,4-methylenedioxyphenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4 ] Oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-aminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2- Fluoro-5,11-dihydride -5- {2- [N- (3-aminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2 -[N- (4-Methylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-Methylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-dimethyl) Aminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-dimethylaminophenethyl)- N-methyl] amino Ethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-pyrrolidinophenethyl) -N-methyl] aminoethyl} dibenzo [ b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-pyrrolidinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (4-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4 ] Oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2 -Fluoro-5,1 -Dihydro-5- {2- [N- (4-fluorophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5 {2- [N- (3-Fluorophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N -(4-Acetylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11-dihydro-5- {2- [N- (3- Acetylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-methoxyphenethyl)- N-methyl] amino Til} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-methoxyphenethyl) -N-methyl] aminoethyl} dibenzo [b , E] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3,4-methylenedioxyphenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-aminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1, 4] Oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-aminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3 -Chloro-5,11-dihydro-5 -{2- [N- (4-methylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-methylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- ( 4-dimethylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-dimethylamino) Phenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-pyrrolidinophenethyl) -N -Methyl] aminoethyl} Benzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-pyrrolidinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1 , 4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-morpholinophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine 3-chloro-5,11-dihydro-5- {2- [N- (4-fluorophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro- 5,11-dihydro-5- {2 [N- (3-Fluorophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (4 -Acetylaminophenethyl) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 3-chloro-5,11-dihydro-5- {2- [N- (3-acetylaminophenethyl) ) -N-methyl] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl-N- (4-pyrrolidinophenethyl)] aminoethyl } Dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl-N- (3-pyrrolidinophenethyl)] aminoethyl} dibenzo [b, e] [ 1,4] oxazepine 5,11-dihydro-5- {2- [N-methyl-N- (4-piperidinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro- 5- {2- [N-methyl-N- (3-piperidinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [ N-methyl-N- (4-morpholinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine, 5,11-dihydro-5- {2- [N-methyl-N- (3 -Morpholinophenethyl)] aminoethyl} dibenzo [b, e] [1,4] oxazepine and their halogen-substituted positional isomers, pharmaceutically acceptable salts or hydrates, solvates thereof It is done.
[0044]
In the present invention, (i) R ⁹ ~ R ¹³ Any one of is a cyclic amino group represented by the formula [E], the other is a hydrogen atom, and R ¹ ~ R ⁸ A derivative of formula [I], each of which is a hydrogen atom, (ii) R ⁹ ~ R ¹³ Any one of is a cyclic amino group represented by the formula [E], the other is a hydrogen atom, and R ¹ ~ R ⁸ A derivative of the formula [I] wherein one or two of them are a fluorine atom or a chlorine atom and the other is a hydrogen atom, (iii) R ⁹ ~ R ¹³ Each represents a group other than the cyclic amino group represented by the formula [E], and R ¹ ~ R ⁸ A derivative of the formula [I], in which one or two of them are a fluorine atom or a chlorine atom and the other is a hydrogen atom, is preferred.
[0045]
In the general formulas [XV] and [XVI], (i) R ¹ ~ R ⁸ May be the same or different and each represents a fluorine atom, a chlorine atom or a hydrogen atom; ₁ -L ₂ Is CH ₂ Or CH ₂ -CH ₂ Y and Z are bonded to each other to form CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ And / or (ii) R ⁹ ~ R ¹³ May be the same or different, and preferably represents a hydrogen atom, an amino group or a lower alkylamino group and a lower acyl form thereof, a lower dialkylamino group or a cyclic alkylamino group.
[0046]
Specifically, (R)-{[2- (3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-dimethylaminophenyl) ethanone, (R) -1-[(4-dimethylaminophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-bromo-4-chlorobenzyloxy) phenyl] amide, ( R)-{(2- (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-pyrrolidinophenyl) ) Ethanone, (R) -1-[(4-pyrrolidinophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-bromo-5-fluorobenzyloxy) phenyl] amide, stereoisomers thereof Fine salt is preferred.
[0047]
Examples of the pharmacologically acceptable salt of the compound [I] that can be used in the present invention include mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, and acetic acid. Examples thereof include organic acid salts such as salts, lactate, fumarate, maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.
Among the compounds [I] that can be used in the present invention, the compound represented by the formula [II] is obtained by the following method (Scheme 1) according to, for example, the method disclosed in International Patent No. 9733885A1. Can be manufactured.
[0048]
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[0049]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B and D are the same as those in formula [I], r represents 1 or 2, and W represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. ]
Compound [II] that can be used in the present invention can be produced by reacting compound [V] with a compound represented by the above general formula [VI] in the presence of a base in a solvent. As the reaction solvent in the above reaction, amides such as dimethyl sulfoxide and N, N-dimethylformamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, acetonitrile, toluene, xylene, benzene and the like are preferable. Can be used for Examples of the base include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyl lithium, sodium methoxide, potassium t-butoxide and the like. The reaction temperature is usually 0 ° C to 150 ° C, preferably room temperature to 100 ° C. The reaction time varies depending on the reaction temperature or the type of solvent, but is usually 1 to 50 hours. The usage-amount of compound [VI] and a base is 0.5-5 molar equivalent with respect to the usage-amount of compound [V], respectively, Preferably it is 0.8-2 molar equivalent.
The compound [V] used as a starting material for the reaction can be produced by a known method [J. Med. Chem., 7, 609 (1964)].
[0050]
In addition, the halide represented by the above general formula [VI] is prepared by converting alcohol obtained by reducing these from N-alkyl, using proline and homoproline as raw materials according to the method disclosed in European Patent No. 0404359A1. Then, the hydroxyl group is halogenated using methanesulfonyl chloride, tosyl chloride, or the like, whereby it can be produced with ring expansion.
Compound [II] that can be used in the present invention can also be produced by the following method (Scheme 2) according to the method disclosed in International Patent No. 9912925A1.
[0051]
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[0052]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B and D are as defined above, r represents 1 or 2, V and V ′ represent a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a tosyloxy group, a mesyloxy group, and U represents Represents an amino-protecting group such as t-butyloxycarbonyl group, benzyloxycarbonyl group, and tosyl group. ]
In the presence of a base, compound [V] is reacted dropwise with Nt-butoxycarbonyl-2-piperidylmethyl tosylate represented by the above general formula [VII] to prepare a compound of general formula [VIII] And then deprotecting to obtain a compound of the general formula [IX], which is reacted with a compound of the general formula [X] in the presence of a base to produce a compound [II] that can be used in the present invention. be able to. As the reaction solvent and base from [V] to [VIII] and from [IX] to [II], the same ones as in the above reaction scheme 1 can be used.
[0053]
Among the compounds [I] that can be used in the present invention, the compound represented by the formula [III] can be produced by, for example, the following method (Scheme 3) according to the method disclosed in International Patent No. 0040570A1. .
[0054]
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[0055]
[In the formula, aromatic rings K, R ⁹ ~ R ¹³ , A, B, D, V and r are the same as those in Reaction Scheme 2. ]
[0056]
Compound [III] that can be used in the present invention can be produced by reacting compound [V] with a compound represented by the above general formula [XI] in the presence of a base in a solvent. As the reaction solvent in the above reaction, amides such as dimethyl sulfoxide and N, N-dimethylformamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, acetonitrile, toluene, xylene, benzene and the like are preferable. Can be used for Examples of the base include sodium hydride, potassium hydride, lithium diisopropylamide, n-butyl lithium, sodium methoxide, potassium t-butoxide and the like. The reaction temperature is usually 0 ° C to 150 ° C, preferably room temperature to 100 ° C. The reaction time varies depending on the reaction temperature or the type of solvent, but is usually 1 to 50 hours. The usage-amount of compound [XI] and a base is 0.5-10 molar equivalent with respect to the usage-amount of compound [V], respectively, Preferably it is 0.8-5 molar equivalent.
[0057]
In addition, the compound represented by the above general formula [XI] can be reacted with phosphorus oxychloride, thionyl chloride, tosyl chloride, methanesulfonyl chloride, etc. after N-alkylation of 3-hydroxypyrrolidine and 3-hydroxypiperidine. Can be obtained.
Among the compounds [I] that can be used in the present invention, the compound represented by the formula [IV] is obtained by the following method (Scheme 4), for example, according to the method disclosed in International Patent No. 0040570A1. Can be manufactured.
[0058]
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[0059]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B, D and V are the same as above, R ¹⁴ Represents a lower alkyl group. ]
[0060]
That is, the compound [V] is led to the compound represented by the above general formula [XII] and reacted with the compound of the general formula [XIII] in the presence of a base. Here, as a reaction solvent in this reaction, amides such as dimethyl sulfoxide and N, N-dimethylformamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, acetonitrile, toluene, xylene, benzene and the like Can be suitably used. Examples of the base include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyl lithium, sodium methoxide, potassium t-butoxide and the like. The reaction temperature is usually 0 ° C to 150 ° C, preferably room temperature to 100 ° C. The reaction time varies depending on the reaction temperature or the type of solvent, but is usually 1 to 50 hours. The amount of the base used is equimolar or more with respect to compound [XII], preferably 1 to 5 times mol, and the amount ratio of compound [XII] and [XIII] is 0.5 to 2 times mol, preferably It is 0.7 times to 1.5 times.
[0061]
Alternatively, the compound [V] can be converted into the compound represented by the above general formula [XIV] and then condensed with the compound [X] in the presence of a base to produce the compound [IV] that can be used in the present invention. it can. As the reaction solvent and base in the condensation reaction, the same ones as in the above reaction can be used, and the reaction temperature and reaction time are the same. The amount of the base used is equimolar or more, preferably 1 to 5 times moles relative to compound [XIV], and the amount ratio of compound [XIV] and [X] is 0.5 to 2 times moles, preferably It is 0.7 times to 1.5 times.
[0062]
Compound [XII] is obtained by alkylating compound [V] with α-haloacetic acid ester and reducing it to alcohol, and further converting the hydroxyl group to a leaving group, or 2-haloethanol protecting the hydroxyl group. V] can be alkylated, and after deprotection, the hydroxyl group can be converted to a leaving group. Further, as disclosed in International Patent No. 0040570A1, compound [XIII] is an alkylation reaction of a primary amine with a corresponding halide, a reductive alkylation reaction of a primary amine with a corresponding aldehyde, a corresponding carboxylic acid It can be easily produced by various known methods such as reduction of the amine after acylation.
[0063]
As disclosed in International Patent No. 0040570A1, compound [XIV] can be easily produced by various known methods such as alkylation of compound [V] with a haloacetate ester followed by amidation and reduction.
Besides the compounds shown above, among the compounds [I] that can be used in the present invention, the compound represented by the formula [II] or [IV] is similar to the method described in International Patent No. 0117980A1. Depending on the method, it can be produced via a compound represented by the following formula [XVI] and formula [XV]. That is, when the compound represented by the formula [II] is represented by the formula [II-1] and the compound represented by the formula [IV] is represented by the formula [IV-1], these are represented by the formula [XVI] according to the reaction formula 5. Intramolecular arylation of the represented compounds leads to compounds represented by the formula [XV], which are subsequently reduced to obtain the corresponding intermediates.
[0064]
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[0065]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹⁴ , L ₁ , L ₂ Is the same as in formula [XV], r represents 1 or 2, and Y and Z are bonded to each other to form CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ Or Y and Z are not bonded to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]
[0066]
Here, examples of the reaction solvent in the reduction reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane. The solvent may contain 0 to 50% of benzene, toluene, xylene and the like. Examples of the reducing agent include diborane, borane ammonia complex, borane-tert-butylamine complex, borane-N, N-diethylaniline complex, borane-N, N-diisopropylethylamine complex, borane dimethylamine complex, borane-4- ( Dimethylamino) pyridine complex, borane diphenylphosphine complex, borane-4-ethylmorpholine complex, borane-2,6-lutidine complex, borane-4-methylmorpholine complex, borane dimethylsulfide complex, boranemorpholine complex, borane-1,4 -Oxathiane complex, borane-4-phenylmorpholine complex, borane pyridine complex, borane tetrahydrofuran complex, borane tributyl phosphine complex, borane triethylamine complex, borane trimethylamine complex, borane triphenyl phosphite Borane compounds such complexes, hydride or lithium aluminum, sodium borohydride, metal hydrides or of alkyl, such as lithium borohydride, alkoxy or acyl-substituted products thereof. Alternatively, a reducing agent may be prepared in the reaction vessel by adding an acid or the like to these metal hydrides. Examples of acids used here include Bronsted acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid, boron trifluoride, and boron trichloride. And Lewis acids such as aluminum trichloride and complexes thereof. Of these reducing agents, for example, a method using diborane, borane tetrahydrofuran complex, or the like, or by adding methanesulfonic acid, boron trifluoride and its complex to sodium borohydride, a reducing agent is prepared in the reaction vessel. This method can be preferably used. While the reaction temperature depends on the boiling point of the solvent, it is usually 5 ° C to 100 ° C, preferably 30 ° C to 60 ° C. The reaction time varies depending on the type of reducing agent, the reaction temperature, or the type of solvent, but is usually 4 to 70 hours. The amount of reducing agent used varies depending on the type of reducing agent, but the amount of hydride that can be generated is 4 times mol or more, preferably 7 times mol or more. The compound [II-1] to [IV-1] obtained by the reaction can be purified by silica gel column chromatography or crystallization. Compound [II-1] to [IV-1] may be obtained by crystallization in the form of a salt with an appropriate acid. Examples of suitable salts with acids include mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, maleate. And organic acid salts such as acid salts, malates, tartrate, citrate, oxalate, aspartate, methanesulfonate, and the like.
[0067]
Compound [XV] used as a raw material for the reduction reaction can be produced by intramolecular arylation of compound [XVI] with a metal catalyst in the presence of a base. Examples of the reaction solvent in this reaction include benzene and its substituted products, pyridine and its substituted products, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone. . Of these reaction solvents, for example, toluene, pyridine, picoline, N-methylpyrrolidone and the like can be suitably used. Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, metal alkoxides such as sodium methoxide, sodium t-butoxide, potassium t-butoxide, trimethylamine, triethylamine, diisopropyl Examples include amines such as ethylamine and N-methylmorpholine. Among these bases, for example, sodium carbonate, potassium carbonate, cesium carbonate and the like can be preferably used. Examples of the metal catalyst include copper catalysts such as copper, copper (I) chloride, copper (I) bromide, and copper (I) iodide, palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine) palladium. Palladium catalysts or complexes thereof, platinum catalysts such as platinum and platinum chloride, and complexes thereof. Among these metal catalysts, for example, copper and copper (I) bromide can be suitably used. These metal catalysts may also be prepared in a reaction vessel. The reaction temperature varies depending on the boiling point of the solvent, but is usually room temperature to 200 ° C, preferably 100 ° C to 150 ° C. The reaction time varies depending on the type of the base or metal catalyst, the reaction temperature, or the type of solvent, but is usually 8 to 200 hours. Although the usage-amount of the said base changes also with the kind, it is 1 time mole-10 times mole normally, Preferably it is 1 time mole-4 times mole. Although the usage-amount of the said metal catalyst changes also with the kind, it is 0.001 times mol-1 times mol normally, Preferably it is 0.005 times mol-0.2 times mol. The compound [XV] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography or crystallization and used for the next reaction, but can also be used for the next reaction as it is. Here, the present compound [XV] may also be obtained in the form of a salt with an appropriate acid. Examples of suitable salts with acids include mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, maleate. And organic acid salts such as acid salts, malates, tartrate, citrate, oxalate, aspartate, methanesulfonate, and the like.
[0068]
The compound [XVI] used as a raw material for the intramolecular arylation reaction can be produced by the following method (Scheme 6).
[0069]
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[0070]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , L ₁ , L ₂ Is the same as in formula [XVI], Y and Z are bonded to each other to form CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ Or Y and Z are not bonded to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]
[0071]
That is, compound [XVI] can be produced by condensing compound [XVII] and compound [XVIII]. Here, the condensation reaction means, for example, an amidation reaction using N, N′-dicyclohexylcarbodiimide or N-dimethylaminopropyl-N′-ethylcarbodiimide or a salt thereof, and the like after compound [XVIII] is converted to an acid anhydride. It can be selected from known methods such as an acid anhydride method for condensation and a method via an acid chloride or acid bromide of compound [XVIII]. The compound [XVI] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography or crystallization and used for the next reaction, but can also be used for the next reaction as it is. Here, the present compound [XVI] may also be obtained in the form of a salt with an appropriate acid. Examples of suitable salts with acids include mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, maleate. And organic acid salts such as acid salts, malates, tartrate, citrate, oxalate, aspartate, methanesulfonate, and the like.
[0072]
Compound [XVII] used as the starting material of Reaction Scheme 6 can be produced by a known method [J. Med. Chem., 7, 609 (1964)].
Compound [XVIII] can be produced by the following method (Scheme 7).
[0073]
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[0074]
[In the formula, aromatic rings K, R ⁹ ~ R ¹³ , L ₁ , L ₂ Is the same as above, and Y and Z are bonded to each other to form CH ₂ -CH ₂ -CH ₂ Or CH ₂ -CH ₂ -CH ₂ -CH ₂ Or Y and Z are not bonded to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]
[0075]
That is, compound [XVIII] can be produced by condensing compound [XIX] and compound [XX]. Here, the condensation reaction means, for example, an amidation reaction using N, N′-dicyclohexylcarbodiimide or N-dimethylaminopropyl-N′-ethylcarbodiimide and a salt thereof, and the like after compound [XIX] is converted to an acid anhydride. It can be selected from known methods such as an acid anhydride method for condensation and a method via an acid chloride or acid bromide of compound [XIX]. The compound [XVIII] obtained by the reaction can be used for the next reaction after extracting the reaction solution and purifying it by silica gel column chromatography or crystallization, but can also be used for the next reaction as it is. Compound [XVIII] may also be produced by protecting the carboxylic acid moiety of compound [XX] with an appropriate protecting group and performing deprotection after the same condensation reaction as described above with compound [XIX]. Suitable protecting groups here include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or esters thereof with their substituents, trimethylsilyl, triethylsilyl, tert- Examples thereof include silyl esters with butyldimethylsilyl and the like.
[0076]
Of the compounds [I] that can be used in the present invention, the compound represented by the formula [III] can also be produced by the following method (reaction formula 8).
[0077]
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[0078]
[In the formula, aromatic rings G, J, K, R ¹ ~ R ¹³ , A, B, D, V and r are the same as described above. ]
[0079]
That is, compound [III] can also be produced by intramolecular arylation of compound [XXI] with a metal catalyst in the presence of a base. Examples of the reaction solvent in this reaction include benzene and its substituted products, pyridine and its substituted products, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone. . Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, metal alkoxides such as sodium methoxide, sodium t-butoxide, potassium t-butoxide, trimethylamine, triethylamine, diisopropyl Examples include amines such as ethylamine and N-methylmorpholine. Examples of the metal catalyst include copper catalysts such as copper, copper (I) chloride, copper (I) bromide, and copper (I) iodide, palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine) palladium. Palladium catalysts or complexes thereof, platinum catalysts such as platinum and platinum chloride, and complexes thereof. These metal catalysts may also be prepared in a reaction vessel. While the reaction temperature depends on the boiling point of the solvent, it is usually carried out in the range of room temperature to 200 ° C, preferably 80 ° C to 160 ° C. The reaction time varies depending on the type of the base or metal catalyst, the reaction temperature or the type of solvent, but is usually 5 to 150 hours. Although the usage-amount of the said base changes also with the kind, it is 1 times mole-20 times mole normally, Preferably it is 1.5 times mole-8 times mole. Although the usage-amount of the said metal catalyst changes also with the kind, it is 0.001 times mol-1 times mol normally, Preferably it is 0.005 times mol-0.3 times mol. Compound [III] obtained by the reaction can be purified by extraction from the reaction solution, silica gel column chromatography, high performance liquid chromatography or crystallization. The compound [III] that can be used in the present invention may be obtained by crystallization in the form of a salt with an appropriate acid. Examples of suitable salts with acids include mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, maleate. And organic acid salts such as acid salts, malates, tartrate, citrate, oxalate, aspartate, methanesulfonate, and the like.
[0080]
The compound [XXI] used as the raw material for the intramolecular arylation reaction can be produced by alkylating the amino group of the compound [XVII] with the compound [XI]. Examples of the alkylation reaction include an alkylation reaction in the presence of a base. That is, it can be produced by reacting compound [XVII] and compound [XI] in a suitable solvent in the presence of a base. Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, metal alkoxides such as sodium methoxide, sodium t-butoxide, potassium t-butoxide, trimethylamine, triethylamine, diisopropyl Examples include amines such as ethylamine and N-methylmorpholine. The compound [XXI] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography, etc. and used in the next reaction, but can also be used in the next reaction as it is.
[0081]
When the compound that can be used in the present invention is used as a pharmaceutical preparation or pharmaceutical composition, pharmaceutically acceptable excipients, carriers, diluents and other formulation adjuvants are appropriately mixed, and tablets, capsules, It can be administered orally or parenterally in the form of granules, fine granules, powders, pills, syrups, suspensions, emulsions, ointments, suppositories or injections. In this invention, the pharmaceutical formulation or pharmaceutical composition containing the compound of this invention as an active ingredient, and a pharmaceutically acceptable carrier and / or diluent is preferable. Here, examples of the carrier and diluent include glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and fats and oils.
[0082]
Moreover, the dosage and the frequency | count of administration of the pharmaceutical composition of this invention can be suitably selected according to the kind of disease, a patient's age, a body weight, etc. For example, when the pharmaceutical composition of the present invention is orally administered as a therapeutic agent for diseases associated with gastrointestinal organic changes such as gastric ulcer, duodenal ulcer, reflux esophagitis, ulcerative colitis or Crohn's disease, On the other hand, about 0.1 to 1000 mg per day may be administered once to several times.
[0083]
The method of screening for a calcium channel binding compound in the present invention comprises:
(a) measuring the amount of the labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen;
(b) Binding of a labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen in the presence of a test compound Measuring the amount, and
(c) comparing the result obtained in step (a) with the result obtained in step (b);
including.
[0084]
Step (a)
In the present invention, as a method for labeling the 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I], for example, a hydrogen atom in the derivative is ^Three A method of substituting with H, or a carbon atom in the derivative ¹⁴ There is a method of substituting with C, and it can be used without particular limitation.
The membrane specimen can be prepared as follows, for example. That is, first, the longitudinal muscles of the colon and ileum are minced and suspended in ice-cooled Tris buffer. Thereafter, the suspension is homogenized. The resulting homogenized solution is then centrifuged and the resulting supernatant is centrifuged again. Finally, membrane specimens can be prepared by resuspending the resulting precipitate in Tris buffer.
The labeled derivative can be bound to the membrane specimen thus obtained by, for example, incubation in a Tris buffer. The compound represented by the general formula [I] used in the present invention has a higher affinity for the colon and ileum than the aorta, and is different from the binding site of an existing calcium channel antagonist in the colon and ileum. Since it has a binding site, a calcium channel binding compound that selectively acts on the intestinal tract can be screened by using the method of the present invention.
Here, the labeled derivative is preferably used in an amount sufficient to bind to the entire binding site of the receptor. Next, the reaction is stopped by suction filtration using glass fiber filter paper or the like, and the filter paper is washed with Tris buffer or the like. By measuring the amount of the labeled derivative in the obtained filtrate, for example, the radioactive β dose (dpm) using a liquid scintillation counter, the amount of binding to the membrane specimen of the colon or ileum can be measured.
[0085]
Step (b)
By binding the labeled derivative to the membrane specimen in the presence of the test compound, it can be determined whether the test compound inhibits the binding of the labeled derivative to the membrane specimen. The test compound can be brought into contact with the membrane specimen together with the labeled derivative, or can be introduced after the labeled derivative is bound to the membrane specimen. The test compound is preferably used in the same amount as the labeled derivative. The treatment after the test compound and the labeled derivative are bound to the membrane specimen can be performed in the same manner as described in the step (a).
[0086]
Step (c)
By subtracting the amount of labeled derivative whose binding was inhibited by the test compound obtained in step (b) from the total amount of labeled derivative obtained in step (a) to the membrane specimen, It can be measured whether it has calcium channel binding ability.
In the present invention, by using a 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative as a receptor ligand, a calcium channel can be efficiently used even at a low concentration, specifically 1 to 20 nM. Binding compounds can be screened.
[0087]
[Reference example]
Next, although the manufacturing method of the compound described in this invention is demonstrated in detail as a reference example, this invention is not limited to these reference examples at all.
[0088]
[Reference Example 1]
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, 60% sodium hydride (44 mg, 1.1 mmol) was washed with hexane, suspended in dimethyl sulfoxide (5 ml) and stirred at room temperature for 30 minutes, and then 3-fluoro-5,11-dihydrodibenzo [ b, e] [1,4] oxazepine (0.22 g, 1.0 mmol) was added and stirred at room temperature for 30 minutes. After stirring for an additional 30 minutes at 50 ° C., (R) -3-chloro-1- (4-methoxyphenethyl) piperidine (0.25 g, 1.0 mmol, prepared by the method described in International Patent No. 9733885A1) was added to this solution. Of dimethyl sulfoxide (2 ml) was added dropwise and stirred at 50 ° C. for 6 hours. The reaction solution was partitioned between saturated brine and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluting with hexane and ethyl acetate (7: 3). The appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -3-fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) piperidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow oil (0.30 g, 70%).
ESI / Mass: 433 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.90 (4H, m), 2.27 (1H, m), 2.50-2.60 (1H, m), 2.70-2.82 (3H, m), 2.98-3.10 (1H, m), 3.18 -3.24 (1H, m), 3.35 (1H, dd, J = 9.3, 12.9Hz), 3.82 (3H, s), 4.02 (1H, dd, J = 3.60, 13.2Hz), 5.20 (1H, d, J = 12.0Hz), 5.27 (1H, d, J = 12.0Hz), 6.70-6.95 (6H, m), 6.98-7.05 (1H, m), 7.15-7.30 (4H, m)
[0089]
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) piperidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) piperidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (300 mg, 0.7 mmol) To a dichloromethane (5 ml) solution of 4M hydrogen chloride / dioxane 0.3 ml was added and stirred for 30 minutes, and then the solvent was distilled off under reduced pressure. The obtained residue was solidified using a mixed solvent of hexane and ethyl acetate, and the precipitated solid was filtered off to obtain the title compound as a brown solid (257 mg, 79%).
ESI / Mass: 433 [M + H ⁺ ]
NMR (CDCl3) δ: 1.90-2.06 (1H, m), 2.06-2.30 (3H, m), 2.74-2.86 (1H, m), 2.90-3.20 (2H, m), 3.25-3.40 (1H, m) , 3.42-3.68 (2H, m), 3.80 (3H, s), 3.85-4.00 (1H, m), 4.24 (1H, dd, J = 7.8, 14.1Hz), 4.62 (1H, dd, J = 5.7, 14.1Hz), 5.12 (1H, d, J = 12.3Hz), 5.32 (1H, d, J = 12.3Hz), 6.72-7.03 (8H, m), 7.12 (2H, d, J = 8.4Hz), 7.18 -7.25 (1H, m)
[0090]
[Reference Example 2]
(R) -8-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
Reference example using 8-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (R) -8-Fluoro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine Got. Pale yellow solid. Yield 19%.
ESI / Mass: 433 [M + H ⁺ ]
NMR (CDCl3) δ: 1.58-1.88 (4H, m), 2.22-2.30 (1H, m), 2.48-2.58 (1H, m), 2.68-2.82 (3H, m), 2.99-3.08 (1H, m) , 3.21-3.36,2H, m), 3.81 (3H, s), 4.00-4.05 (1H, m), 5.20 (1H, d, J = 13.0Hz), 5.34 (1H, d, J = 13.0Hz), 6.47-6.50 (2H, m), 6.79-6.93 (3H, m), 7.02-7.18 (4H, m), 7.26-7.34 (2H, m)
[0091]
This was treated with 4M hydrochloric acid / dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. Yield 81%.
ESI / Mass: 433 [M + H ⁺ ]
NMR (CDCl3) δ: 1.90-2.32 (4H, m), 2.75-2.88 (1H, m), 2.94-3.23 (2H, m), 3.28-3.60 (3H, m), 3.81 (3H, s), 3.91 -4.00 (1H, m), 4.14-4.30 (1H, m), 4.58-4.73 (1H, m), 5.17 (1H, d, J = 13.0Hz), 5.34 (1H, d, J = 13.0Hz), 6.50-6.60 (2H, m), 6.81-7.00 (3H, m), 7.08-7.39 (6H, m)
[0092]
[Reference Example 3]
(R) -2-Chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
Reference example using 2-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine 1 to give (R) -2-chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine Got. Pale yellow solid. Yield 44%.
ESI / Mass: 449 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.87 (4H, m), 2.20-2.28 (1H, m), 2048-2.56 (1H, m), 2.67-2.82 (3H, m), 2.93-3.06 (1H, m) , 3.16-3.23 (1H, m), 3.34 (1H, dd, J = 10.3, 14.7Hz), 3.81 (3H, s), 4.04 (1H, dd, J = 4.0, 14.7Hz), 5.15 (1H, d , J = 13.0Hz), 5.25 (1H, J = 13.0Hz), 6.75-6.89 (5H, m), 6.97-7.04 (2H, m), 7.10-7.16 (2H, m), 7.22-7.30 (2H, m)
[0093]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. Yield 90%.
ESI / Mass: 449 [M + H ⁺ ]
NMR (CDCl3) δ: 1.92-2.28 (4H, m), 2.72-2.88 (1H, m), 2.93-3.13 (2H, m), 3.26-3.38 (1H, m), 3.43-3.6. (2H, m ), 3.81 (3H, s), 3.83-3.98 (1H, m), 4.20-4.35 (1H, m), 4.61-4.74 (1H, m), 5.11 (1H, d, J = 14.0Hz), 5.27 ( 1H, d, J = 14.0Hz), 6.87-6.92 (5H, m), 7.01-7.16 (3H, m), 7.22-7.30 (3H, m)
[0094]
[Reference Example 4]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
Reference example using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine 1 to give (R) -3-chloro-5,11-dihydro-5- [1- (4-methoxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine Got. Pale yellow solid. Yield 55%.
ESI / Mass: 449 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.90 (4H, m), 2.22-2.30 (1H, m), 2.52-2.62 (1H, m), 2.68-2.82 (3H, m), 2.97-3.07 (1H, m) , 3.16-3.22 (1H, m), 3.35 (1H, dd, J = 10.3, 14.7Hz), 3.81 (3H, s), 4.03 (1H, dd, J = 4.0, 14.7Hz), 5.20 (1H, d , J = 13.7Hz), 5.23 (1H, d, J = 13.7Hz), 6.75-6.90 (5H, m), 6.96-7.02 (2H, m), 7.10-7.20 (4H, m)
[0095]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 1 to obtain the title compound as a brown solid. Yield 86%.
ESI / Mass: 449 [M + H ⁺ ]
NMR (CDCl3) δ: 1.92-2.03 (1H, m), 2.10-2.30 (3H, m), 2.75-2.84 (1H, m), 2.96-3.12 (2H, m), 3.24-3.34 (1H, m) , 3.44-3.60 (2H, m), 3.81 (1H, s) 3.87-3.981H, m), 4.24 (1H, dd, J = 8.7,15.3Hz), 4.62 (1H, dd, J = 6.3,15.3Hz ), 5.12 (1H, d, J = 14.0Hz), 5.35 (1H, d, J = 14.0Hz), 6.83-6.96 (3H, m), 6.84 (2H, d, J = 9.3Hz), 7.01-7.19 (4H, m), 7.12 (2H, d, J = 9.3Hz)
[0096]
[Reference Example 5]
(R) -7-Chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
(R) -3-Chloro-1- (3,4-methylenedioxyphenethyl) piperidine
In acetonitrile (50 ml), (R) -2-hydroxymethylpyrrolidine, (505 mg, 5.00 mmol), 3,4-methylenedioxyphenethyl mesylate (1.34 g, 5.50 mmol), sodium carbonate (585 mg, 5.50 mmol) and sodium iodide (50 mg, 0.33 mmol) were added, and the mixture was heated to reflux at 90 ° C. for 13.5 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. did. The organic layer was washed with water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 25 ml of dichloromethane, and while stirring under ice-cooling, 712 mg (5.5 mmol) of diisopropylethylamine and 630 mg (5.5 mmol) of methanesulfonyl chloride were added, and further for 1 hour under ice-cooling. Stir at room temperature for 2 hours. The reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (15: 1) as an eluent. Appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -3-chloro-1- (3,4-methylenedioxyphenethyl) piperidine as a pale yellow oil (1.02 g, 76%).
NMR (CDCl3) δ: 1.55-1.68 (3H, m), 1.75-1.87 (1H, m), 2.12-2.20 (2H, m), 2.55-2.64 (2H, m), 2.69-2.78 (3H, m) , 3.08-3.18 (1H, m), 3.98-4.06 (1H, m), 5.93 (2H, s), 6.63-6.75 (3H, m)
[0097]
(R) -7-Chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, 60% sodium hydride (48 mg, 1.2 mmol) was washed with hexane, suspended in dimethyl sulfoxide (8 ml), stirred at room temperature for 30 minutes, and then 7-chloro-5,11-dihydrodibenzo. [B, e] [1,4] oxazepine (232 mg, 1 mmol) was added and stirred at room temperature for 30 minutes. After stirring at 50 ° C. for 30 minutes, a solution of (R) -3-chloro-1- (3,4-methylenedioxyphenethyl) piperidine (308 mg, 1.15 mmol) in dimethyl sulfoxide (3 ml) was added dropwise to this solution. And stirred at 50 ° C. for 4 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (10: 1) as an eluent. The appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -7-chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] Dibenzo [b, e] [1,4] oxazepine was obtained as a pale yellow solid (362 mg, 78%).
ESI / Mass: 463 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.84 (4H, m), 2.20-2.30 (1H, m), 2.49-2.59 (1H, m), 2.65-2.78 (3H, m), 2.95-3.05 (1H, m) , 3.13-3.21 (1H, m), 3.34 (1H, dd, J = 10.3, 13.0Hz), 4.00 (1H, dd, J = 3.3, 13.0Hz), 5.15 (1H, d, J = 13.0Hz), 5.23 (1H, d, J = 13.0Hz), 5.95 (2H, s), 6.63-6.78 (5H, m), 6.96 (1H, s), 7.02-7.13 (2H, m), 7.26-7.37 (2H, m)
[0098]
(R) -7-Chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine hydrochloride
(R) -7-Chloro-5,11-dihydro-5- [1- (3,4-methylenedioxyphenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (0. 63 g) in dichloromethane (5 ml) was added 2 M hydrogen chloride / diethyl ether (3.0 ml) and stirred for 2 hours, and then the solvent was distilled off under reduced pressure. The resulting residue was stirred in hexanes to give the title compound as a light brown solid (348 mg, 89%).
ESI / Mass: 463 [M + H ⁺ ]
NMR (CDCl3) δ: 1.92-2.33 (4H, m), 2.74-3.16 (3H, m), 3.24-3.37 (1H, m), 3.44-3.58 (2H, m), 3.88-3.98 (1H, m) , 4.15-4.28 (1H, m), 4.60-4.72 (1H, m), 5.19 (1H, d, J = 14.0Hz), 5.27 (1H, d, J = 14.0Hz), 5.98 (2H, s), 6.64-6.77 (5H, m), 6.80-6.88 (1H, m), 6.98 (1H, s), 7.09-7.20 (2H, m), 7.28-7.38 (2H, m)
[0099]
[Reference Example 6]
(R) -1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -2-Hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine
D-prolinol (2.02 g, 20.0 mmol), 4-dimethylaminophenethyl mesylate, (5.35 g, 22.0 mmol), sodium carbonate (2.65 g, 25.0 mmol) in acetonitrile (50 ml) , Sodium iodide (300 mg, 2.0 mmol) was added, and the mixture was heated to reflux at 90 ° C. for 13.5 hours, cooled to room temperature, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 1M hydrochloric acid was added to the organic layer, the pH of the aqueous layer was kept at 1, and the target product was extracted into the aqueous layer. 4M sodium hydroxide was added to the aqueous layer to adjust the pH of the aqueous layer to 14, and the resulting precipitate was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (R) -2-hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine as a pale yellow oily substance (4.91 g). 99%).
NMR (CDCl3) δ: 1.69-1.90 (4H, m), 2.29-2.38 (1H, m), 2.45-2.54 (1H, m), 2.56-2.64 (1H, m), 2.66-2.74 (2H, m) , 2.88-2.94 (1H, m), 2.91 (6H, ms), 3.23-3.30 (1H, m), 3.31 (1H, dd, J = 2.7, 12.0Hz), 3.58 (1H, dd, J = 4.0, 12.0Hz), 6.70 (2H, d, J = 9.7Hz), 7.07 (2H, d, J = 9.7Hz)
[0100]
(R) -3-Chloro-1- (4-dimethylaminophenethyl) piperidine
(R) -2-Hydroxymethyl-1- (4-dimethylaminophenethyl) pyrrolidine (4.91 g, 19.8 mmol) was dissolved in 60 ml of dichloromethane, and 3.11 g (24 of diisopropylethylamine was stirred with stirring under ice cooling. .4 mmol) and 2.75 g (24.0 mmol) of methanesulfonyl chloride were added, and the mixture was stirred for 1 hour under ice-cooling and further for 2 hours at room temperature. The reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (9: 1) as an eluent. The appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -3-chloro-1- (4-dimethylaminophenethyl) piperidine as a pale yellow solid (3.03 g, 57% ).
NMR (CDCl3) δ: 1.50-1.68 (3H, m), 1.76-1.88 (1H, m), 2.09-2.20 (2H, m), 2.55-2.62 (2H, m), 2.66-2.73 (2H, m) , 2.75-2.84 (1H, m), 2.91 (6H, s), 3.08-3.17 (1H, m), 3.98-4.08 (1H, m), 6.69 (2H, d, J = 9.7Hz), 7.06 (2H , d, J = 9.7Hz)
[0101]
(R) -1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, 60% sodium hydride (35 mg, 0.88 mmol) was washed with hexane, suspended in dimethyl sulfoxide (5 ml), stirred at room temperature for 30 minutes, and then 1-fluoro-5,11-dihydrodibenzo. [B, e] [1,4] oxazepine (0.17 g, 0.80 mmol) was added and stirred at room temperature for 30 minutes. After stirring at 50 ° C. for 30 minutes, a solution of (R) -3-chloro-1- (4-dimethylaminophenethyl) piperidine (0.18 g, 0.80 mmol) in dimethyl sulfoxide (2 ml) was added dropwise to this solution. And stirred at 50 ° C. for 6 hours. The reaction solution was partitioned between saturated brine and ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (6: 4). Appropriate fractions were collected and the solvent was distilled off under reduced pressure to give (R) -1-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) piperidin-2-ylmethyl] dibenzo [b , E] [1,4] oxazepine was obtained as a pale yellow oil (0.23 g, 64%).
ESI / Mass: 446 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.90 (4H, m), 2.20-2.30 (1H, m), 2.48-2.55 (1H, m), 2.70-2.80 (3H, m), 2.94 (6H, s), 2.98 -3.08 (1H, m), 3.16-3.25 (1H, m), 3.38 (1H, dd, J = 9.3, 13.0Hz), 4.10 (1H, dd, J = 3.60, 13.0Hz), 5.35 (1H, d , J = 12.0Hz), 5.42 (1H, d, J = 12.0Hz), 6.70-6.78 (3H, m), 6.80-6.90 (4H, m), 7.00-7.15 (3H, m), 7.18-7.28 ( 1H, m)
[0102]
(R) -1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -1-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (228 mg, 0.5 mmol) ) In dichloromethane (5 ml) was added 4M hydrogen chloride / dioxane 0.5 ml and stirred for 30 minutes, and then the solvent was distilled off under reduced pressure. The obtained residue was solidified using a mixed solvent of hexane and ethyl acetate, and the precipitated solid was separated by filtration to obtain the title compound as a brown solid (170 mg, 64%).
ESI / Mass: 446 [M + H ⁺ ]
NMR (CDCl3) δ: 1.92-2.30 (3H, m), 2.78-2.90 (1H, m), 2.91-3.16 (3H, m), 3.16 (6H, s), 3.38-3.50 (2H, m), 3.62 -3.75 (1H, m), 3.82-3.95 (1H, m), 4.28 (1H, dd, J = 6.3, 14.7Hz), 4.77 (1H, dd, J = 6.0, 14.7Hz), 5.24 (2H, s ), 6.76 (1H, t, J = 8.1Hz), 6.90-7.12 (5H, m), 7.21-7.30 (1H, m), 7.37 (2H, d, J = 8.4Hz), 7.71 (2H, d, (J = 8.4Hz)
[0103]
[Reference Example 7]
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Reference example using 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 1-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine 6 to give (R) -3-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] Oxazepine was obtained as a pale yellow oil (0.24 g, 53%).
ESI / Mass: 446 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.90 (4H, m), 2.22-2.32 (1H, m), 2.50-2.60 (1H, m), 2.70-2.82 (3H, m), 2.94 (6H, s), 2.98 -3.08 (1H, m), 3.15-3.25 (1H, m), 3.34 (1H, dd, J = 9.3, 13.0Hz), 4.05 (1H, dd, J = 3.60, 13.0Hz), 5.20 (1H, d , J = 12.0Hz), 5.26 (1H, d, J = 12.0Hz), 6.68-6.90 (7H, m), 6.97-7.04 (1H, m), 7.08-7.15 (2H, m), 7.20-7.25 ( 1H, m)
[0104]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a light brown solid (100%).
ESI / Mass: 446 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (3H, m), 2.80-3.00 (1H, m), 3.00-3.25 (9H, m), 3.42-3.60 (2H, m), 3.60-3.75 (1H, m) , 3.85-3.98 (1H, m), 4.19-4.28 (1H, m), 4.58-4.68 (1H, m), 5.11 (1H, d, J = 12.6Hz), 5.35 (1H, d, J = 12.6Hz ), 6.76 (1H, t, J = 8.1Hz), 6.80-7.08 (5H, m), 7.20 (1H, dd, J = 6.3, 8.1Hz), 7.43 (2H, d, J = 6.9Hz), 7.75 (2H, d, J = 6.9Hz)
[0105]
[Reference Example 8]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Reference example using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 1-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine 6 to give (R) -3-chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] Oxazepine oxazepine was obtained. Pale yellow oily substance. Yield 67%.
ESI / Mass: 462 [M + H ⁺ ]
NMR (CDCl3) δ: 1.50-1.91 (4H, m), 2.23-2.32 (1H, m), 2.51-2.60 (1H, m), 2.65-2.83 (3H, m), 2.93 (6H, s), 2.97 -3.07 (1H, m), 3.15-3.23 (1H, m), 3.34 (1H, dd, J = 10.3, 14.3Hz), 4.06 (1H, dd, J = 4.0, 14.3Hz), 5.22 (2H, s ), 6.72 (2H, d, J = 10.0Hz), 6.75-6.85 (3H, m), 6.98-7.01 (2H, m), 7.09-7.19 (2H, m), 7.11 (2H, d, J = 10.0 Hz)
[0106]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine oxazepine ( 306 mg, 0.662 mmol) is dissolved in 6.0 ml of a mixed solvent of ethyl acetate and ethanol (2: 1), 2M hydrogen chloride / ether (0.73 ml, 1.46 mmol) is added, and then 2.0 ml of ethyl acetate. And stirred at room temperature. After standing at room temperature for 2 days, the product was filtered and dried to obtain the title compound as white crystals (96%).
ESI / Mass: 462 [M + H ⁺ ]
NMR (CDCl3) δ: 2.02-2.28 (4H, m), 2.80-2.90 (1H, m), 2.98-3.24 (2H, m), 3.17 (6H, s), 3.44-3.56 (2H, m), 3.59 -3.69 (1H, m), 3.88-3.98 (1H, m), 4.23 (1H, dd, J = 7.7, 15.7Hz), 4.64 (1H, dd, J = 6.3, 15.7Hz), 5.11 (1H, d , J = 14.0Hz), 5.33 (1H, d, J = 14.0Hz), 6.85-6.97 (3H, m), 7.02-7.07 (2H, m), 7.12-7.18 (2H, m), 7.41 (2H, d, J = 9.3Hz), 7.75 (2H, d, J = 9.3Hz)
[0107]
[Reference Example 9]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
4-pyrrolidinophenethyl alcohol
Dried palladium acetate (270 mg, 1.20 mmol), 2- (di-t-butylphosphino) biphenyl (720 mg, 2.40 mmol), t-butoxy sodium (14.42 g, 150 mmol) to 2- (4-bromo A solution of phenetoxy) tetrahydro-2H-pyran (28.01 g, 98.39 mmol) in toluene (100 ml) and pyrrolidine (9.93 ml, 119 mmol) were added, and the mixture was stirred at 70 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The product was extracted from the organic layer with 1M hydrochloric acid. The aqueous layer was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried to give 4-pyrrolidinophenethyl alcohol as a pale yellow solid. (16.41g, 87%)
NMR (CDCl3) δ: 1.97-2.01 (4H, m), 2.77 (2H, t, J = 7.3Hz), 3.24-3.29 (4H, m), 3.79 (2H, q, J = 6.7Hz), 6.53 ( 2H, d, J = 9.3Hz), 7.03 (2H, d, J = 9.35Hz)
[0108]
4-pyrrolidinophenethyl mesylate
4-Pyrrolidinophenethyl alcohol (16.41 g, 85.9 mmol) was dissolved in dichloromethane (150 ml), and diisopropylethylamine (19.0 ml, 108 mmol) and methanesulfonyl chloride (8.40 ml, 108 mmol) were added at 0 ° C. Stir overnight. The reaction solution was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). Appropriate fractions were collected and the solvent was removed under reduced pressure to give 4-pyrrolidinophenethyl mesylate as a white solid (21.14 g, 80%).
ESI / Mass: 270 [M + H ⁺ ]
NMR (CDCl3) δ: 1.98-2.01 (4H, m), 2.84 (3H, s), 2.95 (2H, t, J = 8.0 Hz), 3.24-3.28 (4H, m), 4.46 (2H, t, J = 8.0Hz), 6.52 (2H, d, J = 9.3Hz), 7.07 (2H, d, J = 9.3Hz)
[0109]
(R) -2-Hydroxymethyl-1- (4-pyrrolidinophenethyl) pyrrolidine
D-prolinol, (2.72 g, 25.0 mmol), 4-pyrrolidinophenethyl mesylate, (6.06 g, 22.5 mmol), potassium carbonate (3.45 g, 25.0 mmol) in acetonitrile (150 ml). ) And heated to reflux at 90 ° C. for 3.5 hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 1M hydrochloric acid was added to the organic layer, the pH of the aqueous layer was kept at 1, and the target product was extracted into the aqueous layer. 4M sodium hydroxide was added to the aqueous layer to adjust the pH of the aqueous layer to 14, and the resulting precipitate was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (R) -2-hydroxymethyl-1- (4-pyrrolidinophenethyl) pyrrolidine as a pale yellow oily substance (4.96 g). 85%).
NMR (CDCl3) δ: 1.70-1.91 (4H, m), 1.95-2.04 (4H, m), 2.26-2.36 (1H, m), 2.42-2.56 (1H, m), 2.57-2.77 (4H, m) , 2.87-2.96 (1H, m), 3.18-3.27 (4H, m), 3.28 (1H, dd, J = 2.7, 12.0Hz), 3.57 (1H, dd, J = 4.0, 12.0Hz), 6.51 (2H , d, J = 9.3Hz), 7.05 (2H, d, J = 9.7Hz)
[0110]
(R) -3-Chloro-1- (4-pyrrolidinophenethyl) piperidine
(R) -2-Hydroxymethyl-1- (4-pyrrolidinophenethyl) pyrrolidine (4.96 g, 19.1 mmol) was dissolved in 70 ml of dichloromethane, and stirred under ice-cooling, 3.21 g (24 .8 mmol) and 2.84 g (24.8 mmol) of methanesulfonyl chloride were added, and the mixture was stirred for 1 hour under ice cooling and further for 2 hours at room temperature. The reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1) as an eluent. Appropriate fractions were collected and the solvent was removed under reduced pressure to yield (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine as a pale yellow solid (3.23 g, 61% ).
ESI / Mass: 293 [M + H ⁺ ]
NMR (CDCl3) δ: 1.50-1.70 (3H, m), 1.78-1.87 (1H, m), 1.96-2.01 (4H, m), 2.10-2.20 (2H, m), 2.54-2.61 (2H, m) , 2.65-2.72 (2H, m), 2.75-2.85 (1H, m), 3.10-3.17 (1H, m), 3.23-3.28 (4H, m), 3.96-4.06 (1H, m), 6.51 (2H, d, J = 9.7Hz), 7.05 (2H, d, J = 9.7Hz)
[0111]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, 60% sodium hydride (348 mg, 8.7 mmol) was washed with hexane, suspended in dimethyl sulfoxide (50 ml), and stirred at room temperature for 30 minutes. To this was added 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (1.70 g, 7.90 mmol), and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C. for another 30 minutes, a solution of (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine (2.64 g, 9.02 mmol) in dimethyl sulfoxide (25 ml) was added dropwise to this solution. And stirred at 50 ° C. for 3 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. First, hexane and ethyl acetate (6: 1) were used as an eluent, and then the hexane and ethyl acetate (1: 1) were used for elution. The appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -2-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b , E] [1,4] oxazepine was obtained as a pale yellow oil (2.29 g, 68%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.59-1.86 (4H, m), 1.96-2.02 (4H, m), 2.21-2.29 (1H, m), 2.46-2.55 (1H, m), 2.60-2.78 (3H, m) , 2.97-3.06 (1H, m), 3.19-3.31 (6H, m), 4.08 (1H, dd, 3.7,14.3Hz), 5.16 (1H, m), 5.30 (1H, d, J = 13.0Hz), 6.54 (2H, d, J = 9.0Hz), 6.75-6.85 (3H, m), 6.95-7.09 (4H, m), 6.99 (2H, d, J = 9.0Hz)
[0112]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (2.29 g) 20 ml of 2M hydrogen chloride / diethyl ether was added to a dichloromethane (30 ml) solution and stirred for 2 hours, and then the solvent was distilled off under reduced pressure. The resulting residue was stirred in hexane to solidify and filtered to give the title compound as a light brown solid (2.17 g, 81%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.36 (8H, m), 2.84-2.96 (1H, m), 3.03-3.27 (3H, m), 3.40-3.72 (6H, m), 3.82-3.93 (1H, m) , 4.21 (1H, dd, J = 8.7, 15.7Hz), 4.63 (1H, dd, J = 6.3, 15.7Hz), 5.13 (1H, d, J = 14.0Hz), 5.33 (1H, d, J = 14.0 Hz), 6.81-7.03 (6H, m), 7.11-7.14 (1H, m), 7.37 (2H, d, J = 9.0Hz), 7.60 (2H, d, J = 9.0Hz)
[0113]
[Reference Example 10]
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Similar to Reference Example 6 using 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine (R) -3-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was pale yellow Obtained as an oil (0.19 g, 50%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.55-1.90 (4H, m), 1.95-2.06 (4H, m), 2.20-2.32 (1H, m), 2.48-2.60 (1H, m), 2.70-2.82 (3H, m) , 2.95-3.10 (1H, m), 3.18-3.40 (6H, m), 4.06 (1H, m), 5.20 (1H, d, J = 12.0Hz), 5.26 (1H, d, J = 12.0Hz), 6.54 (2H, d, J = 8.7Hz), 6.68-6.85 (5H, m), 6.95-7.03 (1H, m), 7.08 (2H, d, J = 8.7Hz), 7.20-7.30 (1H, m)
[0114]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a light brown solid (90%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (4H, m), 2.34 (4H, m), 2.82-2.95 (1H, m), 3.00-3.24 (2H, m), 3.39-3.78 (7H, m), 3.82 -3.95 (1H, m), 4.21 (1H, dd, J = 7.2, 14.1Hz), 4.62 (1H, dd, J = 5.7, 14.1Hz), 5.11 (1H, d, J = 12.6Hz), 5.34 ( 1H, d, J = 12.6Hz), 6.76 (1H, t, J = 8.1Hz), 6.80-7.05 (5H, m), 7.19 (1H, t, J = 8.1Hz), 7.37 (2H, d, J = 8.4Hz), 7.64 (2H, d, J = 8.4Hz)
[0115]
[Reference Example 11]
(R) -7-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Similar to Reference Example 6 using 7-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine (R) -7-fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine is pale yellow Obtained as an oil (0.19 g, 51%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.58-1.90 (4H, m), 1.95-2.06 (4H, m), 2.20-2.32 (1H, m), 2.48-2.60 (1H, m), 2.68-2.82 (3H, m) , 2.98-3.08 (1H, m), 3.18-3.40 (6H, m), 4.05 (1H, dd, J = 5.8, 13.2Hz), 5.14 (1H, d, J = 12.0Hz), 5.31 (1H, d , J = 12.0Hz), 6.45-6.58 (3H, m), 6.68-6.78 (2H, m), 7.02-7.13 (4H, m), 7.28-7.35 (2H, m)
[0116]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (98%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (4H, m), 2.34 (4H, m), 2.78-2.92 (1H, m), 2.94-3.25 (2H, m), 3.40-3.76 (7H, m), 3.83 -3.94 (1H, m), 4.23 (1H, dd, J = 7.2, 14.4Hz), 4.66 (1H, dd, J = 6.0, 14.4Hz), 5.13 (1H, d, J = 12.9Hz), 5.24 ( 1H, d, J = 12.9Hz), 6.58-6.63 (1H, m), 6.72-6.82 (2H, m), 7.05-7.25 (4H, m), 7.35 (2H, d, J = 8.4Hz), 7.60 (2H, d, J = 8.4Hz)
[0117]
[Reference Example 12]
(R) -8-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Similar to Reference Example 6 using 8-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine (R) -8-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was pale yellow Obtained as an oil (0.13 g, 32%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.58-1.90 (4H, m), 1.95-2.06 (4H, m), 2.18-2.34 (1H, m), 2.45-2.58 (1H, m), 2.65-2.80 (3H, m) , 2.95-3.10 (1H, m), 3.14-3.38 (6H, m), 4.05-4.14 (1H, m), 5.21 (1H, d, J = 11.7Hz), 5.35 (1H, d, J = 11.7Hz ), 6.48-6.58 (4H, m), 6.88-6.95 (1H, m), 7.02-7.12 (4H, m), 7.24-7.35 (2H, m)
[0118]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (98%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (4H, m), 2.35 (4H, m), 2.78-2.94 (1H, m), 2.95-3.10 (1H, m), 3.10-3.25 (1H, m), 3.40 -3.80 (7H, m), 3.80-3.95 (1H, m), 4.19 (1H, dd, J = 7.8, 14.1Hz), 4.64 (1H, dd, J = 4.2, 14.1Hz), 5.16 (1H, d , J = 12.3Hz), 5.44 (1H, d, J = 12.3Hz), 6.50-6.61 (2H, m), 6.88-7.00 (1H, m), 7.05-7.18 (2H, m), 7.30-7.41 ( 4H, m), 7.64 (2H, d, J = 7.8Hz)
[0119]
[Reference Example 13]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Similar to Reference Example 6 using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-chloro-1- (4-pyrrolidinophenethyl) piperidine (R) -3-chloro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was pale yellow Obtained as an oil (0.18 g, 68%).
ESI / Mass: 488 [M + H ⁺ ]
NMR (CDCl3) δ: 1.50-1.90 (4H, m), 1.95-2.06 (4H, m), 2.20-2.34 (1H, m), 2.50-2.62 (1H, m), 2.65-2.82 (3H, m) , 2.90-3.10 (1H, m), 3.16-3.40 (6H, m), 4.05-4.14 (1H, m), 5.22 (2H, s), 6.54 (2H, d, J = 8.7Hz), 6.75-6.88 (3H, m), 6.96-7.04 (2H, d, J = 8.7Hz), 7.05-7.14 (3H, m), 7.18 (1H, d, J = 8.4Hz)
[0120]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (91%).
ESI / Mass: 488 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (4H, m), 2.34 (4H, m), 2.78-2.92 (1H, m), 2.92-3.25 (2H, m), 3.40-3.81 (7H, m), 3.83 -3.99 (1H, m), 4.21 (1H, dd, J = 6.9, 14.1Hz), 4.63 (1H, dd, J = 6.3, 14.1Hz), 5.10 (1H, d, J = 12.9Hz), 5.36 ( 1H, d, J = 12.9Hz), 6.85-7.06 (5H, m), 7.15 (2H, t, J = 8.1Hz), 7.35 (2H, d, J = 8.7Hz), 7.62 (2H, d, J = 8.7Hz)
[0121]
[Reference Example 14]
(R) -3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
3-pyrrolidinophenethyl alcohol
Dry palladium acetate (58 mg, 0.26 mmol), 2- (di-t-butylphosphino) biphenyl (136 mg, 0.46 mmol), t-butoxy sodium (3.23 g, 33.6 mmol) in 2- (3 -Bromophenoxy) tetrahydro-2H-pyran (6.27 g, 21.9 mmol) in toluene (15 ml) and pyrrolidine (2.2 ml, 26.4 mmol) were added and stirred at 70 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The product was extracted from the organic layer with 1M hydrochloric acid. The aqueous layer was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried, and 3-pyrrolidinophenethyl alcohol was quantitatively obtained as a pale yellow solid.
NMR (CDCl3) δ: 1.98-2.02 (4H, m), 2.82 (2H, t, J = 7.0Hz), 3.26-3.30 (4H, m), 3.86 (2H, q, J = 7.0Hz), 6.42- 6.54 (3H, m), 7.17 (1H, t, J = 8.3Hz)
[0122]
3-pyrrolidinophenethyl mesylate
3-Pyrrolidinophenethyl alcohol was dissolved in dichloromethane (20 ml), triethylamine (3.7 ml, 26.7 mmol) and methanesulfonyl chloride (1.9 ml, 24.5 mmol) were added at 0 ° C. and stirred overnight. The reaction solution was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). Appropriate fractions were collected and the solvent was removed under reduced pressure to give 3-pyrrolidininophenethyl mesylate as a white solid (5.13 g, 87%).
ESI / Mass: 270 [M + H ⁺ ]
NMR (CDCl3) δ: 1.98-2.03 (4H, m), 2.86 (3H, s), 2.98 (2H, t, J = 7.3Hz), 3.25-3.30 (4H, m), 4.43 (2H, t, J = 7.3Hz), 6.40-6.53 (3H, m), 7.16 (1H, t, J = 8.7Hz)
[0123]
(R) -3-Chloro-1- (3-pyrrolidinophenethyl) piperidine
The compound was synthesized in the same manner as in Reference Example 13 using 3-pyrrolidinophenethyl mesylate instead of 4-pyrrolidinophenethyl mesylate. Yield 50%.
ESI / Mass: 293 [M + H ⁺ ]
NMR (CDCl3) δ: 1.55-1.70 (2H, m), 1.78-1.88 (2H, m), 1.95-2.03 (4H, m), 2.10-2.22 (2H, m), 2.30 (1H, t, J = 10.5Hz), 2.60-2.67 (2H, m), 2.67-2.82 (2H, m), 3.16 (1H, m), 3.22-3.30 (4H, m), 4.02 (1H, m), 6.40 (2H, m ), 6.49 (1H, d, J = 7,5Hz), 7.13 (1H, t, J = 7.5Hz)
(R) -3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
Similar to Reference Example 6 using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-chloro-1- (3-pyrrolidinophenethyl) piperidine (R) -3-chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was pale yellow Obtained as an oil (0.21 g, 45%).
ESI / Mass: 488 [M + H ⁺ ]
NMR (CDCl3) δ: 1.50-1.90 (4H, m), 1.95-2.06 (4H, m), 2.24-2.34 (1H, m), 2.55-2.70 (1H, m), 2.70-2.88 (3H, m) , 3.02-3.15 (1H, m), 3.16-3.40 (6H, m), 4.02-4.14 (1H, m), 5.23 (2H, s), 6.40-6.58 (3H, m), 6.75-6.88 (3H, m), 6.96-7.04 (2H, m), 7.10-7.20 (3H, m)
[0124]
(R) -3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a brown solid (88%).
ESI / Mass: 488 [M + H ⁺ ]
NMR (CDCl3) δ: 1.95-2.30 (4H, m), 2.32 (4H, m), 2.77-2.90 (1H, m), 3.00-3.30 (2H, m), 3.38-3.78 (7H, m), 3.80 -3.92 (1H, m), 4.21 (1H, dd, J = 6.6, 14.1Hz), 4.64 (1H, dd, J = 5.7, 14.1Hz), 5.10 (1H, d, J = 12.9Hz), 5.33 ( 1H, d, J = 12.9Hz), 6.82-7.08 (5H, m), 7.14 (2H, t, J = 8.4Hz), 7.20-7.30 (1H, m), 7.38-7.53 (2H, m), 7.60 -7.70 (1H, m)
[0125]
[Reference Example 15]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
4-morpholinophenethyl alcohol
To dry palladium acetate (32.3 mg, 0.14 mmol), 2- (di-t-butylphosphino) biphenyl (86.0 mg, 0.29 mmol), sodium t-butoxy (1.73 g, 18 mmol) A toluene (9.0 ml) solution of (4-bromophenetoxy) tetrahydro-2H-pyran (3.42 g, 12.0 mmol) and morpholine (1.22 g, 14 mmol) were added, and the mixture was stirred at 70 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The product was extracted from the organic layer with 1M hydrochloric acid. The aqueous layer was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried to give 4-morpholinophenethyl alcohol as a pale yellow solid (2.35 g, 95%).
NMR (CDCl3) δ: 2.80 (2H, t, J = 8.7Hz), 3.13 (4H, t, J = 6.8), 3.78-3.88 (6H. M), 6.88 (2H, d, J = 11.7Hz), 7.14 (2H, d, J = 11.7Hz)
[0126]
4-morpholinophenethyl mesylate
4-morpholinophenethyl alcohol (2.35 g, 11.3 mmol) was dissolved in dichloromethane (20 ml) and diisopropylethylamine (2.60 ml, 14.8 mmol) and methanesulfonyl chloride (1.11 ml, 14.8 mmol) at 0 ° C. And stirred for 4 hours. The reaction solution was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane and ethyl acetate (3: 1) were first used as an eluent, and then the eluent was changed to the same solvent (1: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give 4-morpholinophenethyl mesylate as a white solid (2.60 g, 81%).
NMR (CDCl3) δ: 2.86 (3H, s), 2.98 (2H, t, J = 9.3Hz), 3.14 (4H, m), 3.86 (4H, m), 4.38 (2H, t, J = 9.3Hz) , 6.87 (2H, d, J = 11.7Hz), 7.14 (2H, d, J = 11.7Hz)
[0127]
(R) -3-Chloro-1- (4-morpholinophenethyl) piperidine
4-morpholinophenethyl mesylate (0.43 g, 1.51 mmol), D-prolinol (0.17 g, 1.66 mmol), potassium carbonate (0.40 g, 2.89 mmol) were added to acetonitrile (20 ml), and 70 Stir overnight at ° C. After cooling, the mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain (R) -2-hydroxymethyl-1- (4-morpholinophenethyl) pyrrolidine as a pale yellow solid (0.44 g, 1.5 mmol, 100%). This was dissolved in dichloromethane (10 ml), triethylamine (0.29 ml, 2.1 mmol) and methanesulfonyl chloride (0.15 ml, 1.9 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was partitioned between 5% sodium bicarbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane and ethyl acetate (1: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to yield (R) -3-chloro-1- (4-morpholinophenethyl) piperidine as a white solid (0.30 g, 64%).
ESI / Mass: 309 [M + H ⁺ ]
NMR (CDCl3) δ: 1.50-1.86 (4H, m), 2.10-2.20 (2H, m), 2.28 (1H, t, J = 7.8Hz), 2.55-2.64 (2H, m), 2.65-2.80 (3H , m), 3.10-3.18 (4H, m), 3.80-3.88 (4H, m), 3.96-4.04 (1H, m), 6.82-6.88 (2H, m), 7.10-7.20 (2H, m)
[0128]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -3-Chloro-1- (4-morpholinophenethyl) piperidine and 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine were used in the same manner as in Reference Example 6. , (R) -3-chloro-5,11-dihydro-5- [1- (4-morpholinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine was obtained. Pale yellow oily substance. Yield 46%.
ESI / Mass: 504 [M + H ⁺ ]
NMR (CDCl3) δ: 1.60-1.95 (4H, m), 2.22-2.31 (1H, m), 2.52-2.61 (1H, m), 2.69-2.80 (3H, m), 2.98-3.07 (1H, m) , 3.01-3.19 (1H, m), 3.15 (4H, t, J = 5.3Hz), 3.35 (1H, dd, J = 10,3, 14.7Hz), 3.87 (4H, t, J = 5.3Hz), 4.03 (1H, dd, J = 4.0, 14.7Hz), 5.21 (1H, d, J = 13.3Hz), 5.23 (1H, d, J = 13.3Hz), 6.76-6.90 (3H, m), 6.88 (2H , d, J = 9.7Hz), 6.97-7.01 (2H, m), 7.09-7.19 (2H, m), 7.14 (2H, d, J = 9.7Hz)
[0129]
This was treated with 4M hydrogen chloride / dioxane in the same manner as in Reference Example 6 to obtain the title compound as a light brown solid. Yield 96%.
ESI / Mass: 504 [M + H ⁺ ]
NMR (CDCl3) δ: 1.98-2.33 (4H, m), 2.83-3.30 (4H, m), 3.38-3.70 (6H, m), 3.87-3.98 (1H, m), 4.15-4.42 (5H, m) , 4.60-4.70 (1H, m), 5.12 (1H, d, J = 14.0Hz), 5.39 (1H, d, J = 14.0Hz), 6.84-6.93 (3H, m), 7.04-7.19 (4H, m ), 7.43 (2H, s), 7.78 (2H, s)
[0130]
[Reference Example 16]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, 60% sodium hydride (100 mg, 2.5 mmol) was washed with hexane, and then suspended in dimethyl sulfoxide (8 ml). After stirring for 30 minutes at room temperature, 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (538 mg, 2.5 mmol) was added, 30 minutes at room temperature, and 40 minutes at 50 ° C. Stir. A solution of (S) -1- (4-dimethylaminophenethyl) -3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mmol, prepared by the method described in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml) was added dropwise to this solution. And stirred at 50 ° C. for 13 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. First, hexane and ethyl acetate (3: 1) were used as eluents, and then the hexane and ethyl acetate (1: 1) were used for elution. Appropriate fractions were collected and the solvent was evaporated under reduced pressure to give (R) -2-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b , E] [1,4] oxazepine was obtained as a pale yellow oil (140 mg, 32%).
ESI / Mass: 432 [M + H ⁺ ]
NMR (CDCl3) δ: 1.74-1.84 (1H, m), 2.22-2.34 (1H, m), 2.37-2.47 (1H, m), 2.48-2.71 (5H, m), 2.75-2.85 (1H, m) , 2.90 (6H, s), 3.18 (1H, dd, J = 7.7, 10.7Hz), 4.60-4.70 (1H, m), 5.25-5.40 (2H, bs), 6.37-6.49 (3H, m), 6.72 -6.87 (5H, m), 6.95-7.24 (3H, m),
[0131]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine (140 mg) in dichloromethane ( 5 ml) After adding 1.0 M of 4M hydrogen chloride / ethyl acetate to the solution and stirring for 1 hour, the solvent was distilled off under reduced pressure, the residue was stirred to solidify in hexane, and the title compound was separated by filtration to give a pale yellow solid. As (145 mg, 90%).
ESI / Mass: 432 [M + H ⁺ ]
NMR (CD3OD) δ: 1.90-2.08 (1H, m), 2.10-2.30 (1H, m), 2.38-2.53 (1H, m), 2.60-2.73 (1H, m), 3.14 (2H, t, J = 8.0Hz), 3.26 (6H, s), 3.49 (2H, t, J = 8.0Hz), 3.60-3.82 (2H, m), 4.03-4.14 (1H, m), 4.95-5.03 (1H, m), 5.06-5.15 (1H, m), 6.73-6.92 (3H, m), 7.03-7.26 (4H, m), 7.47-7.59 (4H, m)
[0132]
[Reference Example 17]
(R) -3-Fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Reference example using 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine In the same manner as in No. 16, (R) -3-fluoro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] Oxazepine was obtained. Pale yellow solid. Yield 40%.
ESI / Mass: 432 [M + H ⁺ ]
NMR (CDCl3) δ: 1.73-1.84 (1H, m), 2.21-2.30 (1H, m), 2.41-2.48 (1H, m), 2.50-2.71 (5H, m), 2.75-2.82 (1H, m) , 2.90 (6H, s), 3.18 (1H, dd, J = 7.7, 10.7Hz), 5.28 (1H, d, J = 12.0Hz), 5.40 (1H, d, J = 12.0Hz), 6.48-6.54 ( 1H, m), 6.63-6.72 (4H, m), 7.01-7.12 (4H, m), 7.25-7.34 (2H, m)
[0133]
This was treated with 4M hydrogen chloride / ethyl acetate as in Reference Example 16 to give the title compound as a light brown solid. Yield 92%.
ESI / Mass: 432 [M + H ⁺ ]
NMR (CD3OD) δ: 1.90-2.07 (1H, m), 2.14-2.27 (1H, m), 2.42-2.52 (1H, m), 2.63-2.77 (1H, m), 3.15 (2H, t, J = 9.0Hz), 3.26 (6H, s), 3.49 (2H, t, J = 9.0Hz), 3.64-3.82 (2H, m), 4.07-4.16 (1H, m), 4.97-5.06 (1H, m), 5.10-5.18 (1H, m), 6.72-6.94 (4H, m), 7.00-7.09 (2H, m), 7.43-7.65 (5H, m)
[0134]
[Reference Example 18]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Reference example using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine (R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] Oxazepine was obtained. Pale yellow oily substance. Yield 39%.
ESI / Mass: 448 [M + H ⁺ ]
NMR (CDCl3) δ: 1.74-1.84 (1H, m), 2.22-2.34 (1H, m), 2.37-2.47 (1H, m), 2.48-2.71 (5H, m), 2.75-2.85 (1H, m) , 2.90 (6H, s), 3.18 (1H, dd, J = 7.7, 10.7Hz), 4.60-4.70 (1H, m), 5.25-5.40 (2H, bs), 6.68 (2H, d, J = 9.7Hz ), 6.71-6.88 (4H, m), 6.92-7.10 (3H, m) 7.04 (2H, d, J = 9.7Hz)
[0135]
This was treated with 4M hydrogen chloride / ethyl acetate as in Reference Example 16 to give the title compound as a brown solid. Yield 90%.
ESI / Mass: 448 [M + H ⁺ ]
NMR (CD3OD) δ: 1.86-2.08 (1H, m), 2.10-2.27 (1H, m), 2.40-2.53 (1H, m), 2.60-2.74 (1H, m), 3.12 (2H, t, J = 9.0Hz), 3.27 (6H, s), 3.50 (2H, t, J = 9.0Hz), 3.64-3.84 (2H, m), 4.06-4.16 (1H, m), 5.00-5.08 (1H, m), 5.10-5.19 (1H, m), 6.73-7.07 (4H, m), 7.17-7.42 (3H, m), 7.47-7.67 (4H, m)
[0136]
[Reference Example 19]
(R) -3-Fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(S) -3-Methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine
3-pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol), (S) -3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol), potassium carbonate (1.70 g, 12.3 mmol) in acetonitrile ( 20 ml) and stirred at 100 ° C. for 12 hours. Acetonitrile was distilled off under reduced pressure and then partitioned between water and ethyl acetate. The target product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to quantitatively obtain (S) -3-hydroxy-1- (3-pyrrolidinophenethyl) pyrrolidine as a pale yellow solid. This was dissolved in dichloromethane (10 ml), triethylamine (0.76 ml, 5.49 mmol) and methanesulfonyl chloride (0.39 ml, 5.03 mmol) were added at 0 ° C. and stirred overnight. The reaction solution was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform and methanol (95: 5). Appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -3-methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine as a pale yellow oil (1.30 g, 96 %).
ESI / Mass: 339 [M + H ⁺ ]
NMR (CDCl3) δ: 1.99 (4H, m), 2.03-2.15 (1H, m), 2.25-2.38 (1H, m), 2.44-2.54 (1H, m), 2.70-2.80 (4H, m), 2.80 -3.02 (3H, m), 3.02 (3H, s), 3.23-3.30 (4H, m), 5.23 (1H, m), 6.42 (2H, m), 6.50 (1H, d, J = 7.5Hz), 7.14 (1H, t, J = 7.5Hz)
[0137]
(R) -3-fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine under an argon stream, 60% sodium hydride (88 mg, 2.2 mmol) was washed with hexane, suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then 3-fluoro-5,11-dihydrodibenzo [b, e ] [1,4] Oxazepine (0.43 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 50 ° C. for another 30 minutes, a solution of (S) -3-methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine (0.34 g, 1.0 mmol) in dimethyl sulfoxide (4 ml) was added to this solution. The solution was added dropwise and stirred at 70 ° C. for 2 hours. The reaction solution was partitioned between saturated brine and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane and ethyl acetate (1: 1). The appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -3-fluoro-5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b , E] [1,4] oxazepine was obtained as a pale yellow oil (0.19 g, 42%).
ESI / Mass: 458 [M + H ⁺ ]
NMR (CDCl3) δ: 1.68-1.84 (1H, m), 1.90-1.99 (4H, m), 2.22-2.36 (1H, m), 2.40-2.48 (1H, m), 2.50-2.76 (5H, m) , 2.76-2.86 (1H, m), 3.16-3.28 (5H, m), 4.64 (1H, m), 5.36 (2H, m), 6.37-6.49 (3H, m), 6.72-6.87 (5H, m) , 6.95 (1H, d, J = 6.6Hz), 7.12-7.28 (1H, t, J = 7.5Hz), 7.28 (1H, d, J = 6.6Hz)
[0138]
This was treated with 4M hydrogen chloride / ethyl acetate in the same manner as in Reference Example 16 to obtain the title compound as a brown solid (69%).
NMR (CD3OD) δ: 1.90-2.08 (1H, m), 2.10-2.30 (5H, m), 2.35-2.55 (1H, m), 2.60-2.78 (2H, m), 3.12 (2H, t, J = 8.1Hz), 3.30-3.48 (1H, m), 3.53 (1H, t, J = 8.1Hz), 3.60-3.83 (6H, m), 4.95-5.15 (2H, m), 6.70-7.10 (6H, m ), 7.25-7.53 (5H, m)
[0139]
[Reference Example 20]
(R) -3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidin-1-ylphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride salt
Using 3-chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine and (R) -3-methylsulfonyl-1- (3-pyrrolidin-1-ylphenethyl) pyrrolidine for reference (R) -3-Chloro-5,11-dihydro-5- [1- (3-pyrrolidin-1-ylphenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1 , 4] Oxazepine was obtained as a pale yellow oil (0.20 g, 43%).
ESI / Mass: 474 [M + H ⁺ ]
NMR (CDCl3) δ: 1.63-1.80 (1H, m), 1.92-2.00 (4H, m), 2.22-2.36 (1H, m), 2.40-2.48 (1H, m), 2.52-2.75 (5H, m) , 2.75-2.86 (1H, m), 3.15-3.30 (5H, m), 4.60-4.70 (1H, m), 5.38 (2H, brs), 6.37-6.49 (3H, m), 6.72-6.80 (3H, m), 6.95 (1H, dd, J = 1.8, 7.8Hz), 7.04-7.14 (3H, m), 7.24 (1H, d, J = 7.8Hz)
[0140]
This was treated with 4M hydrogen chloride / ethyl acetate in the same manner as in Reference Example 16 to give the title compound as a brown solid (93%).
ESI / Mass: 474 [M + H ⁺ ]
NMR (CD3OD) δ: 1.90-2.10 (1H, m), 2.13-2.32 (5H, m), 2.37-2.55 (1H, m), 2.60-2.78 (2H, m), 3.10 (2H, t, J = 7.8Hz), 3.30-3.45 (1H, m), 3.53 (1H, t, J = 7.8Hz), 3.58-3.81 (5H, m), 4.00-4.12 (1H, m), 4.95-5.18 (2H, m ), 6.70-7.10 (4H, m), 7.16-7.50 (7H, m)
[0141]
[Reference Example 21]
(R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
(R) -5,11-dihydro-5- (2-pyrrolidylmethyl) dibenzo [b, e] [1,4] oxazepine (240 mg, 0.85 mmol, International Patent No. 9912925A1) in acetonitrile (20 ml) Prepared by the method described), 3-pyrrolidinophenethyl mesylate (253 mg, 0.94 mmol), sodium carbonate (106 mg, 1.0 mmol), sodium iodide (10 mg, 0.07 mmol) was added, and 6. After heating to reflux for 5 hours, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. First, hexane and ethyl acetate (15: 1) were used as an eluent, and then the hexane and ethyl acetate (2: 1) were used for elution. Appropriate fractions were collected and the solvent was removed under reduced pressure to yield (R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (208 mg, 54%).
ESI / Mass: 454 [M + H ⁺ ]
NMR (CDCl3) δ: 1.65-1.88 (4H, m), 1.99-2.05 (4H, m), 2.23-2.32 (1H, m), 2.55-2.64 (1H, m), 2.71-2.84 (3H, m) , 3.06-3.16 (1H, m), 3.19-3.24 (1H, m), 3.28-3.32 (4H, m), 3.37 (1H, dd, J = 11.0, 14.3Hz), 4.15 (1H, dd, J = 4.0, 14.3Hz), 5.22 (1H, d, J = 13.0Hz), 5.34 (1H, d, J = 13.0Hz), 6.44-6.55 (3H, m), 6.75-6.83 (3H, m), 7.00- 7.20 (4H, m), 7.26-7.32 (2H, m)
[0142]
(R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride (R) -5 11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (208 mg) in dichloromethane (2 ml) in 2M hydrogen chloride / diethyl ether After adding 2.0 ml and stirring for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was solidified by stirring in hexane, and filtered to obtain the title compound as a light brown solid (220 mg, 91%).
ESI / Mass: 454 [M + H ⁺ ]
NMR (CDCl3) δ: 1.90-2.42 (8H, m), 2.98-3.30 (3H, m), 3.40-3.90 (8H, m), 4.18-4.35 (1H, m), 4.62-4.76 (1H, m) , 5.14 (1H, d, J = 13.0Hz), 5.30 (1H, d, J = 13.0Hz), 6.78-6.94 (3H, m), 6.97-7.16 (3H, m), 7.20-7.40 (4H, m ), 7.45 (1H, s), 7.59 (1H, s)
[0143]
[Reference Example 22]
(R) -5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(S) -3-Hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine
4-pyrrolidinophenethyl mesylate (13.45 g, 50.0 mmol), (S) -3-pyrrolidinol hydrochloride (5.56 g, 45.0 mmol), potassium carbonate (18.63 g, 135 mmol) in acetonitrile (200 ml) And stirred at 90 ° C. for 3 hours. After cooling, the mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The target product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain (S) -3-hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine as a pale yellow solid (6.30 g, 52%).
NMR (CDCl3) δ: 1.74-1.84 (1H, m), 1.96-2.04 (4H, m), 2.15-2.25 (1H, m), 2.34-2.43 (1H, m), 2.55-2.63 (1H, m) , 2.65-2.80 (5H, m), 2.92-3.03 (1H, m), 3.23-3.28 (4H, m), 4.33-4.40 (1H, m), 6.51 (2H, d, J = 9.3Hz), 7.06 (2H, d, J = 9.3Hz)
[0144]
(S) -3-Methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine
(S) -3-Hydroxy-1- (4-pyrrolidinophenethyl) pyrrolidine (6.30 g, 23.4 mmol) was dissolved in 100 ml of dichloromethane, and diisopropylethylamine (5.28 ml, 30.0 mmol) and methane were dissolved at 0 ° C. Sulphonyl chloride (2.34 ml, 30.0 mmol) was added and stirred for 4 hours. The reaction was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with dichloromethane and methanol (10: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give (S) -3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine as a pale yellow oil (7.50 g, 49 %).
ESI / Mass: 339 [M + H ⁺ ]
NMR (CDCl3) δ: 1.96-2.00 (4H, m), 2.04-2.16 (1H, m), 2.27-2.38 (1H, m), 2.44-2.52 (1H, m), 2.65-2.74 (4H, m) , 2.82-2.98 (3H, m), 3.02 (3H, s), 3.23-3.28 (4H, m), 5.19-5.27 (1H, m), 6.50 (2H, d, J = 9.3Hz), 7.05 (2H , d, J = 9.3Hz)
[0145]
(R) -5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Under an argon stream, 60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane, suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then 5,11-dihydrodibenzo [b, e ] [1,4] Oxazepine (600 mg, 3.0 mmol) was added and stirred at room temperature for 30 minutes. After stirring at 50 ° C. for 30 minutes, a solution of (S) -3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to this solution. And stirred at 50 ° C. for 42 hours. The reaction solution was partitioned between saturated brine and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (142 mg, 32%).
NMR (CDCl3) δ: 1.72-1.84 (1H, m), 1.96-2.04 (4H, m), 2.22-2.41 (2H, m), 2.49-2.71 (5H, m), 2.80-2.89 (1H, m) , 3.22-3.27 (5H, m), 4.67-4.74 (1H, m), 5.30-5.50 (2H, b), 6.48 (2H, d, J = 9.7Hz), 6.72-6.82 (3H, m), 6.95 -7.13 (3H, m), 7.02 (2H, d, J = 9.7Hz), 7.26-7.33 (2H, m)
[0146]
This was treated with 2M hydrogen chloride / diethyl ether in the same manner as in Reference Example 21 to give the title compound as a brown solid (83%).
ESI / Mass: 440 [M + H ⁺ ]
NMR (CD3OD) δ: 1.90-2.08 (1H, m), 2.10-2.30 (5H, m), 2.35-2.55 (1H, m), 2.60-2.78 (2H, m), 3.08 (2H, t, J = 10.0Hz), 3.23-3.38 (1H, m), 3.47 (1H, t, J = 10.0Hz), 3.60-3.83 (5H, m), 4.02-4.11 (1H, m), 4.99-5.08 (1H, m ), 5.10-5.18 (1H, m), 6.72-7.04 (4H, m), 7.15-7.24 (2H, m), 7.36-7.44 (6H, m)
[0147]
[Reference Example 23]
(R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(S) -3-Hydroxy-1- (3-pyrrolidinophenethyl) pyrrolidine
3-pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol) and (S) -3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol) synthesized in Reference Example 21 in acetonitrile (20 ml), potassium carbonate ( 1.70 g, 12.3 mmol) was added and the mixture was stirred at 100 ° C. for 12 hours. Acetonitrile was distilled off under reduced pressure and then partitioned between water and ethyl acetate. The desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, neutralized, and extracted again with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain (S) -3-hydroxy-1- (3-pyrrolidinophenethyl) pyrrolidine as a pale yellow solid (1.04 g, 100%).
NMR (CDCl3) δ: 1.68-1.80 (1H, m), 1.91-2.02 (4H, m), 2.13-2.25 (1H, m), 2.30-2.40 (1H, m), 2.55-2.63 (1H, m) , 2.67-2.80 (5H, m), 2.89-2.98 (1H, m), 3.15-3.25 (4H, m), 4.28-4.39 (1H, m), 6.39-6.42 (2H, m), 6.50 (1H, d, J = 8.0Hz), 7.13 (1H, t, J = 8.0Hz)
[0148]
(S) -3-Methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine
(S) -3-Hydroxy-1- (3-pyrrolidinophenethyl) pyrrolidine (1.04 g, 4.00 mmol) was dissolved in dichloromethane (10 ml) and triethylamine (0.76 ml, 5.49 mmol) was dissolved at 0 ° C. Methanesulfonyl chloride (0.39 ml, 5.03 mmol) was added and stirred overnight. The reaction solution was partitioned between 5% aqueous sodium bicarbonate and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with chloroform and methanol (95: 5). Appropriate fractions were collected and the solvent was removed under reduced pressure to give (S) -3-methanesulfonyloxy-1- (3-pyrrolidinophenethyl) pyrrolidine as a pale yellow oil (1.30 g, 96 %).
ESI / Mass: 339 [M + H ⁺ ]
NMR (CDCl3) δ: 1.96-2.02 (4H, m), 2.03-2.15 (1H, m), 2.25-2.38 (1H, m), 2.44-2.54 (1H, m), 2.70-2.80 (4H, m) , 2.80-3.02 (3H, m), 3.02 (3H, s), 3.23-3.30 (4H, m), 5.20-5.28 (1H, m), 6.42 (2H, m), 6.50 (1H, d, J = 7.5Hz), 7.14 (1H, t, J = 7.5Hz)
[0149]
(R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
Under an argon stream, 60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane, suspended in dimethyl sulfoxide (10 ml), stirred at room temperature for 30 minutes, and then 5,11-dihydrodibenzo [b, e ] [1,4] Oxazepine (600 mg, 3.0 mmol) was added and stirred at room temperature for 30 minutes. After stirring at 50 ° C. for 30 minutes, a solution of (S) -3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to this solution. And stirred at 50 ° C. for 42 hours. The reaction solution was partitioned between saturated brine and ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (3: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give (R) -5,11-dihydro-5- [1- (3-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [ 1,4] oxazepine was obtained as a pale yellow oil (225 mg, 51%).
ESI / Mass: 440 [M + H ⁺ ]
NMR (CDCl3) δ: 1.74-1.84 (1H, m), 1.95-2.00 (4H, m), 2.23-2.34 (1H, m), 2.34-2.43 (1H, m), 2.49-2.57 (1H, m) , 2.61-2.76 (5H, m), 2.81-2.88 (1H, m), 3.23-3.29 (4H, m), 4.67-4.76 (1H, m), 5.30-5.50 (2H, bs), 6.34-6.48 ( 3H, m), 6.71-6.85 (3H, m), 6.94-6.97 (1H, m), 7.04-7.16 (3H, m), 7.25-7.32 (2H, m)
[0150]
This was treated with 2M hydrogen chloride / diethyl ether in the same manner as in Reference Example 21 to give the title compound as a brown solid (78%).
ESI / Mass: 440 [M + H ⁺ ]
NMR (CD3OD) δ: 1.90-2.08 (1H, m), 2.10-2.30 (5H, m), 2.35-2.55 (1H, m), 2.60-2.78 (1H, m), 3.10 (2H, t, J = 10.0Hz), 3.25-3.40 (1H, m), 3.25 (2H, t, J = 10.0Hz), 3.60-3.80 (5H, m), 4.03-4.12 (1H, m), 4.99-5.09 (1H, m ), 5.11-5.19 (1H, m), 6.70-7.04 (5H, m), 7.14-7.47 (7H, m)
[0151]
[Reference Example 24]
5,11-Dihydro-5- [2- [N-methyl-N- (3-pyrrolidinophenethyl) amino] ethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
5,11-dihydro-5- [2- (N-methylamino) ethyl] dibenzo [b, e] [1,4] oxazepine (254 mg, 1.00 mmol, International Patent No. 0040570A1) in acetonitrile (20 ml) Prepared), 3-pyrrolidinophenethyl mesylate (296 mg, 1.10 mmol), sodium carbonate (138 mg, 1.30 mmol), sodium iodide (20 mg, 0.13 mmol) were added and 6. After heating to reflux for 5 hours, the solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane and ethyl acetate (10: 1) were first used as an eluent, and then changed to hexane and ethyl acetate (3: 1) for elution. Appropriate fractions were collected and the solvent was distilled off under reduced pressure to give 5,11-dihydro-5- [2- [N-methyl-N- (3-pyrrolidinophenethyl) amino] ethyl] dibenzo [b, e]. [1,4] oxazepine was obtained as a pale yellow oil (331 mg, 78%).
ESI / Mass: 428 [M + H ⁺ ]
NMR (CDCl3) δ: 1.96-2.00 (4H, m), 2.32 (3H, s), 2.61 (4H, s), 2.66 (2H, t, J = 8.0 Hz), 3.23-3.27 (4H, m), 3.90 (2H, t, J = 8.0Hz), 5.29 (2H, s), 6.32-6.44 (3H, m), 6.77-6.84 (3H, m), 7.00-7.14 (4H, m), 7.25-7.32 ( 2H, m)
[0152]
This was treated with 2M hydrogen chloride / diethyl ether in the same manner as in Reference Example 21 to give the title compound as a brown solid (81%).
ESI / Mass: 428 [M + H ⁺ ]
NMR (CDCl3) δ: 2.28-2.40 (4H, m), 2.85 (3H, d, J = 4.3Hz), 3.10-3.48 (6H, m), 3.55-3.74 (4H, m), 4.23-4.35 (1H , m), 4.40-4.52 (1H, m), 5.23 (1H, d, J = 14.3Hz), 5.25 (1H, d, J = 14.3Hz), 6.82-6.93 (3H, m), 7.06-7.11 ( 2H, m), 7.18 (1H, d, J = 8.7Hz), 7.24-7.44 (4H, m), 7.53 (1H, d, J = 8.7Hz), 7.78 (1H, m)
[0153]
[Reference Example 25]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride (= Compound of Reference Example 8)
(R) -N-[(4-Dimethylaminophenyl) acetyl] -D-proline methyl ester
To a solution of (4-dimethylaminophenyl) acetic acid (7.4 g, 41.3 mmol) and D-proline methyl ester hydrochloride (7.19 g, 43.4 mmol) in methylene chloride (150 ml) was added 1-hydroxybenzotriazole monohydrate. The Japanese product (6.1 g, 45.4 mmol) and N-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (8.7 g, 45.4 mmol) were added. After the mixture was stirred at room temperature for 6 hours, triethylamine (6.3 ml, 45.4 mmol) was added. This was stirred overnight at room temperature, and the reaction solution was washed successively with water (200 ml), 5% aqueous sodium bicarbonate (200 ml), and water (200 ml). The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, and eluted with methylene chloride and methanol (10: 1). The appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a brown oil (11.0 g, 83%).
ESI / Mass: 291 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.82-2.26 (4H, m), 2.82-2.98 (6H, m), 3.40-3.76 (2H, m), 3.60 (3H, s), 3.73 (2H, s), 4.41-4.52 (1H, m), 6.64-6.74 (2H, m), 7.07-7.19 (2H, m)
[0154]
(R) -N-[(4-Dimethylaminophenyl) acetyl] -D-proline
(R) -N-[(4-dimethylaminophenyl) acetyl] -D-proline methyl ester (1.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (10 ml), and water (10 ml) and 1M aqueous sodium hydroxide solution were dissolved. (3.7 ml, 3.7 mmol) was added. After stirring overnight at room temperature, a saturated aqueous ammonium chloride solution (15 ml) was added, and the pH was adjusted to around 4 with 1M hydrochloric acid. After the solvent was distilled off from this mixture under reduced pressure, acetone was added and mixed. Filtration was performed to obtain a filtrate, and the solvent was distilled off under reduced pressure, followed by drying to obtain the title compound as a yellow solid (0.91 g, 96%).
ESI / Mass: 277 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.80-2.28 (3H, m), 2.45-2.58 (1H, m), 2.95 (6H, s), 3.42-3.70 (2H, m), 3.65 (2H, s), 4.60-4.68 (1H, m), 6.72-6.83 (2H, m), 7.08-7.19 (2H, m)
[0155]
(R) -1-[(4-Dimethylaminophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-bromo-4-chlorobenzyloxy) phenyl] amide (R) -N-[(4-dimethyl Toluene (111 ml) and N-methylmorpholine (3.85 ml, 35.0 mmol) were added to aminophenyl) acetyl] -D-proline (8.56 g, 31.0 mmol). In an ice bath, ethyl chloroformate (3.26 ml, 34.1 mmol) was added thereto and stirred for 2 hours. To this, 2- (2-bromo-4-chlorobenzyloxy) aniline hydrochloride (10.8 g, 31.0 mmol) and N-methylmorpholine (4.09 ml, 37.2 mmol) were added, and the mixture was added at room temperature. Stir overnight. Water (40 ml) was added to the reaction solution, and the organic layer was washed with water (40 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride and methanol (30: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a yellow solid (16.3 g, 92%).
ESI / Mass: 572 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.80-1.94 (1.2H, m), 1.96-2.06 (0.8H, m), 2.08-2.36 (1.2H, m), 2.51-2.59 (0.8H, m), 2.79 and 2.92 (total 6.0H , each s), 3.45-3.75 (4H, m), 4.53-4.59 (0.2H, m), 4.81-4.87 (0.8H, m), 4.94-5.13 (0.3H, m), 5.13 (1.7H, s ), 6.47-6.69 (2.0H, m), 6.84-7.14 (5.1H, m), 7.19-7.26 (0.9H, m), 7.51-7.68 (1.9H, m), 8.26 (0.1H, br s) , 8.35-8.42 (1.0H, m), 9.53 (1H, br s)
[0156]
(R)-{[2- (3-Chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-dimethylamino Phenyl) ethanone
(R) -1-[(4-Dimethylaminophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-bromo-4-chlorobenzyloxy) phenyl] amide (1.73 g, 3.03 mmol) and carbonic acid Potassium (1.27 g, 9.19 mmol), copper (I) bromide (24.1 mg, 0.168 mmol), 4-picoline (8.65 ml) were added. After heating this at 145 degreeC for 20 hours, it filtered and the filtrate was acquired and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride and methanol (20: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a brown solid (0.97 g, 66%).
ESI / Mass: 490 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.52-2.34 (4H, m), 2.92 and 2.96 (total 6.0H, each s), 3.44-3.77 (4.1H, m), 4.34-4.41 (0.2H, m), 4.65-4.72 (0.4H , m), 4.77-4.91 (1.1H, m), 5.08-5.15 (0.2H, m), 5.50-5.67 (0.3H, m), 6.34-6.41 (0.7H, m), 6.65-7.03 (4.0H , m), 7.06-7.50 (6.5H, m), 7.59 (0.2H, br s), 7.91-7.96 (0.2H, m), 8.11 (0.1H, br s)
[0157]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
(R)-{[2- (3-Chloro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-dimethylamino Phenyl) ethanone (0.97 g, 1.98 mmol) was dissolved in tetrahydrofuran (19.4 ml), sodium borohydride (0.39 g, 10.4 mmol) was added, and boron trifluoride was added in an ice bath. Tetrahydrofuran complex (1.69 ml, 13.9 mmol) was added. After the reaction solution was heated to 37 ° C. for 42 hours, sodium borohydride (0.056 g, 1.5 mmol) and boron trifluoride tetrahydrofuran complex (0.24 ml, 1.99 mmol) were added. The reaction solution was heated to 37 ° C. for 24 hours, and 1.5 M aqueous sodium hydroxide solution (16 ml, 24 mmol) was added in an ice bath. The reaction was heated to 60 ° C. for 12 hours and then partitioned between toluene (20 ml) and water (10 ml). The organic layer was obtained, and tetrahydrofuran was distilled off under reduced pressure. After washing with water (10 ml), the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with methylene chloride and methanol (10: 1). Appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a brown solid (0.67 g, 74%).
ESI / Mass: 462 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.59-1.90 (4H, m), 2.22-2.31 (1H, m), 2.50-2.59 (1H, m), 2.66-2.84 (3H, m), 2.93 (6H, s), 2.97-3.06 ( 1H, m), 3.16-3.24 (1H, m), 3.34 (1H, dd, J = 13.0, 9.4Hz), 4.07 (1H, dd, J = 13.0, 3.7Hz), 5.22 (2H, s), 6.70 -6.75 (2H, m), 6.75-6.86 (3H, m), 6.97-7.02 (2H, m), 7.08-7.14 (3H, m), 7.17 (1H, d, J = 7.9Hz)
[0158]
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -3-Chloro-5,11-dihydro-5- [1- (4-dimethylaminophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (10.6 g, 22 0.9 mmol) was dissolved in 2-propanol (100 ml) and 4M hydrogen chloride / 2-propanol (22.9 ml) was added. The solvent was distilled off under reduced pressure, and 4M hydrogen chloride / 2-propanol (11.5 ml) was added to the obtained residue. The solvent was removed under reduced pressure to obtain the title compound as a pale yellow solid (12.9 g, 100%).
ESI / Mass: 462 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 2.00-2.21 (2H, m), 2.21-2.34 (2H, m), 2.86-2.98 (1H, m), 3.03-3.15 (1H, m), 3.19 (6H, s), 3.15-3.30 ( 1H, m), 3.47-3.70 (3H, m), 3.90-4.00 (1H, m), 4.24 (1H, dd, J = 14.0, 7.2Hz), 4.65 (1H, dd, J = 14.0, 6.0Hz) , 5.12 (1H, d, J = 12.7Hz), 5.40 (1H, d, 12.7Hz), 6.87 (1H, dd, J = 7.8, 1.9Hz), 6.89-7.00 (2H, m), 7.03-7.09 ( 2H, m), 7.14 (1H, d, J = 1.9Hz), 7.18 (1H, d, J = 8.0Hz), 7.45 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.6 Hz)
[0159]
[Reference Example 26]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(4-Pyrrolidinophenyl) acetic acid (= compound of Reference Example 9)
Toluene in palladium acetate (22.3 mg, 0.10 mmol), (2-biphenyl) -di-tert-butylphosphine (59.8 mg, 0.20 mmol), sodium-tert-butoxide (2.40 g, 25.0 mmol) (10 ml) was added and (4-bromophenyl) acetic acid (2.15 g, 10.0 mmol) and pyrrolidine (1.10 ml, 13.2 mmol) were added. The mixture was heated at 70 ° C. for 46 hours, after which water (20 ml) was added. After adjusting the pH of the aqueous layer to 2 or less, it was washed with toluene, and the pH of the aqueous layer was adjusted to 4-5. After stirring for a while in an ice bath, the mixture was filtered to obtain the title compound as a pale yellow solid (1.1 g, 54%).
ESI / Mass: 206 [M + H ⁺ ]
NMR (DMSO-d6) δ: 1.90-1.95 (4H, m), 3.15-3.20 (4H, m), 3.38 (2H, s), 6.47 (2H, d, J = 8.4Hz), 7.03 (2H, d , J = 8.4Hz)
[0160]
(R) -N-[(4-pyrrolidinophenyl) acetyl] -D-proline methyl ester
Methylene chloride (20 ml) was added to (4-pyrrolidinophenyl) acetic acid (2.05 g, 10.0 mmol) and D-proline methyl ester hydrochloride (1.66 g, 10.0 mmol), and triethylamine (1.55 ml, 11 0.1 mmol), and N-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.11 g, 11.0 mmol). After the mixture was stirred at room temperature for 4 hours, the reaction solution was washed successively with water (10 ml), water (5 ml), 5% aqueous citric acid solution (5 ml), and 5% aqueous sodium bicarbonate (5 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a pale red solid (3.06 g, 96%).
NMR (CDCl _Three ) δ: 1.85-2.15 (8H, m), 3.23-3.28 (4H, m), 3.31-3.68 (4H, m), 3.68-3.75 (3H, m), 4.40-4.53 (1H, m), 6.45- 6.54 (2H, m), 7.05-7.14 (2H, m)
[0161]
(R) -N-[(4-pyrrolidinophenyl) acetyl] -D-proline
(R) -N-[(4-pyrrolidinophenyl) acetyl] -D-proline methyl ester (30.1 g, 94.2 mmol) was dissolved in tetrahydrofuran (150 ml), and water (134 ml) and 6M aqueous sodium hydroxide solution were dissolved. (16.5 ml, 99.2 mmol) was added. After stirring at room temperature for 4 hours, 6M hydrochloric acid (16.6 ml, 99.7 mmol) was added. Tetrahydrofuran was distilled off from the mixture under reduced pressure, and then allowed to stand overnight in a refrigerator. This was filtered and dried under reduced pressure to give the title compound as a pale purple solid (23.4 g, 82%).
ESI / Mass: 303 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.85-2.05 (7H, m), 2.45-2.55 (1H, m), 3.23-3.29 (4H, m), 3.45-3.70 (4H, m), 4.60-4.64 (1H, m), 6.48- 6.55 (2H, m), 7.07-7.11 (2H, m)
[0162]
(R) -1-[(4-Pyrrolidinophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-Bromo-5-fluorobenzyloxy) phenyl] amide (R) -N-[(4-Pyrrolyl Toluene (37.8 ml) and N-methylmorpholine (1.10 g, 10.8 mmol) were added to dinophenyl) acetyl] -D-proline (2.90 g, 9.59 mmol). In an ice bath, ethyl chloroformate (1.14 g, 10.5 mmol) was added and stirred for 2 hours. To this, 2- (2-bromo-5-fluorobenzyloxy) aniline hydrochloride (3.19 g, 9.59 mmol) and N-methylmorpholine (1.16 g, 11.5 mmol) were added, over 16 hours. The temperature was raised to room temperature. Water (30 ml), citric acid (1.61 g) and toluene (10 ml) were added thereto for partitioning, and the organic layer was divided into water (10 ml), water (10 ml), 6.7% aqueous sodium bicarbonate (10 ml), and 6. The mixture was washed successively with 7% aqueous sodium bicarbonate (10 ml), water (10 ml), and water (10 ml). Drying over sodium sulfate and evaporation of the solvent under reduced pressure gave the title compound as a pale yellow solid (5.13 g, 93%).
ESI / Mass: 580 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.77-2.20 (7H, m), 2.48-2.57 (1H, m), 3.14-3.25 (4H, m), 3.42-3.67 (4H, m), 4.80-4.88 (1H, m), 5.11 ( 2H, s), 6.29-6.46 (2H, m), 6.80-7.10 (6H, m), 7.43-7.61 (2H, m), 8.26-8.39 (1H, m), 9.57 (1H, s)
[0163]
(R)-{[2- (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-pyrrolidino Phenyl) ethanone
(R) -1-[(4-Pyrrolidinophenyl) acetyl] pyrrolidine-2-carboxylic acid [2- (2-bromo-5-fluorobenzyloxy) phenyl] amide (5.0 g, 8.61 mmol) and carbonic acid Potassium (3.58 g, 25.9 mmol), copper (I) bromide (63.5 mg, 0.443 mmol), 4-picoline (25 ml) were added. After heating this at 145 ° C. for 21 hours, filtration was performed to obtain a filtrate, and the solvent was distilled off under reduced pressure. The mixture was partitioned between toluene and 9.5% aqueous citric acid, and the organic layer was washed twice with 9.5% aqueous citric acid. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride and methanol (97: 3). Appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a purple solid (4.16 g, 97%).
ESI / Mass: 500 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.60-2.40 (8H, m), 3.14-3.35 (4H, m), 3.39-3.75 (4H, m), 4.29-5.68 (3H, m), 6.32-6.60 (3H, m), 6.77- 8.11 (8H, m)
[0164]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine
(R)-{[2- (2-Fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine-5-carbonyl) pyrrolidin] -1-yl} -2- (4-pyrrolidino Phenyl) ethanone (3.79 g, 7.59 mmol) was dissolved in tetrahydrofuran (48 ml), sodium borohydride (1.52 g, 40.2 mmol) was added, and boron trifluoride tetrahydrofuran complex was added in an ice bath. (7.38 g, 49.5 mmol) was added. After the reaction solution was heated to 37 ° C. for 66 hours, 1.5 M aqueous sodium hydroxide solution (48 ml, 75 mmol) was added in an ice bath. The reaction solution was heated to 60 ° C. for 13 hours, and then toluene (30 ml) was added. The organic layer was obtained, the solvent was distilled off under reduced pressure to 21.0 g, and toluene (12 ml) was added. This was washed twice with water (10 ml), and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with methylene chloride and methanol (97: 3). Appropriate fractions were collected and the solvent was removed under reduced pressure to give the title compound as a purple solid (2.95 g, 82%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.59-1.90 (4H, m), 1.90-2.10 (4H, m), 2.18-2.30 (1H, m), 2.42-2.58 (1H, m), 2.62-2.83 (3H, m), 2.92- 3.08 (1H, m), 3.12-3.38 (6H, m), 4.08 (1H, dd, J = 12.8, 3.0Hz), 5.16 (1H, d, J = 11.8Hz), 5.30 (1H, d, J = 11.8Hz), 6.54 (2H, d, J = 8.5Hz), 6.72-6.86 (3H, m), 6.93-7.12 (6H, m)
[0165]
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine dihydrochloride
(R) -2-Fluoro-5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine (12.04 g, 25 0.5 mmol) was dissolved in 2-propanol (250 ml), 4M hydrogen chloride / 2-propanol (17.0 ml) was added, and the mixture was stirred at room temperature for 0.5 hour. The solvent was distilled off under reduced pressure. To the obtained residue, 2-propanol (about 50 mL) was added and the solvent was distilled off under reduced pressure four times to obtain the title compound as a pale red solid (14.89 g, 100%).
ESI / Mass: 472 [M + H ⁺ ]
NMR (DMSO-d6) δ: 1.76-2.19 (8H, m), 2.89-3.25 (4H, m), 3.33-3.54 (5H, m), 3.54-3.67 (2H, m), 4.10 (1H, dd, J = 13.6, 7.5Hz), 4.39 (1H, dd, J = 13.6, 6.5Hz), 5.18 (1H, d, J = 12.0Hz), 5.44 (1H, d, J = 12.1Hz), 6.72-6.78 ( 1H, m), 6.83-6.90 (2H, m), 6.96-7.27 (6H, m), 7.31-7.38 (2H, m)
[0166]
[Reference Example 27]
(R) -5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine (= compound of Reference Example 22)
(R) -N- [1- (4-Pyrrolidinophenethyl) pyrrolidin-3-yl] -2- (2-bromobenzyloxy) aniline
Under an argon stream, 2- (2-bromobenzyloxy) aniline (1.15 g, 4.13 mmol) and (S) -3-methanesulfonyloxy-1- (4-pyrrolidinophenethyl) pyrrolidine (0.30 g, 0 .89 mmol) was added and dissolved in acetonitrile (50 ml). To this was added potassium carbonate (1.62 g, 11.7 mmol), and the mixture was refluxed for 85 hours. Acetonitrile (15 ml) was then added and refluxed for a further 48 hours. The reaction solution was filtered through Celite to obtain a filtrate, and the solvent was distilled off under reduced pressure to obtain the title compound as a brown oily mixture (1.40 g).
ESI / Mass: 520 [M + H ⁺ ]
[0167]
(R) -5,11-dihydro-5- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] dibenzo [b, e] [1,4] oxazepine
Under an argon stream, potassium carbonate (1) was added to (R) -N- [1- (4-pyrrolidinophenethyl) pyrrolidin-3-yl] -2- (2-bromobenzyloxy) aniline (1.40 g, as a mixture). 0.71 g, 12.4 mmol), copper (I) bromide (53 mg, 0.37 mmol) and toluene (30 ml) were added. The reaction was refluxed with heating for 53 hours and copper (I) bromide (60 mg, 0.42 mmol) was added. The reaction was refluxed for an additional 50 hours with heating, and more toluene (10 ml), potassium carbonate (1.04 g, 7.52 mmol) and copper (I) bromide (42 mg, 0.29 mmol) were added. The reaction mixture was further refluxed for 48 hours under heating, filtered through celite, and water was added to the filtrate. The organic layer was obtained, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 187 mg of the obtained residue (1.12 g) was subjected to high performance liquid chromatography and eluted with acetonitrile and water (gradient from 20:80 to 70:30). Appropriate fractions were collected and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to thin layer silica gel chromatography and developed using hexane and ethyl acetate (1: 5). Silica gel at an appropriate site was collected and eluted with a mixed solvent of methylene chloride and methanol (3: 1). The eluate was collected and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (25.5 mg, 2 step yield 39%).
ESI / Mass: 440 [M + H ⁺ ]
NMR (CDCl _Three ) δ: 1.72-1.84 (1H, m), 1.92-2.05 (4H, m), 2.24-2.49 (2H, m), 2.49-2.77 (5H, m), 2.82-2.94 (1H, m), 3.18- 3.36 (5H, m), 4.68-4.79 (1H, m), 5.19-5.62 (2H, m), 6.48 (2H, d, J = 8.4Hz), 6.70-6.85 (3H, m), 6.95 (1H, dd, J = 7.8, 1.6Hz), 7.02 (2H, d, J = 8.6Hz), 7.03-7.14 (2H, m), 7.25-7.35 (2H, m)
[0168]
In the same manner as in Reference Example 1, instead of 3-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, the compound [V] shown in Table 1 was converted to (R) -3- By using the compound [VI] shown in Table 1 instead of chloro-1- (4-methoxyphenethyl) piperidine, the compound [II] shown in Table 1 can be prepared.
[0169]
[Table 1]

[0170]
[Reference Example 29]
In the same manner as in Reference Example 16, instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, the compound [V] shown in Table 2 was converted into (S) -1- By using the compound [XI] shown in Table 2 instead of (4-dimethylaminophenethyl) -3-methanesulfonyloxypyrrolidine, the compound [III] shown in Table 2 can be prepared.
[0171]
[Table 2]

[0172]
[Reference Example 30]
In the same manner as in Reference Example 24, instead of 2-fluoro-5,11-dihydrodibenzo [b, e] [1,4] oxazepine, compound [V] shown in Table 3 was converted to 3-pyrrolidinophenethylmesi. The compound [IV] shown in Table 3 can be prepared by using the compound [X] shown in Table 3 instead of the rate.
[0173]
[Table 3]

[0174]
<Formulation example>
Formulation examples are described below.
[Formulation Example 1]
The following mixture was mixed according to a conventional method and tableted to obtain tablets containing 50 mg of the active ingredient per tablet.
50 mg of the compound of Reference Example 8
Lactose 200mg
Crystalline cellulose 40mg
Magnesium stearate 5mg
[0175]
[Formulation Example 2]
The following mixture was granulated according to a conventional method to obtain granules.
50 mg of the compound of Reference Example 8
Lactose 90mg
Corn starch 60mg
Talc 30mg
Magnesium stearate 10mg
[0176]
【Example】
Preparation of smooth fascia surface:
Wistar rats (8-12 weeks old, male) were cut into colon, ileum or aorta longitudinal muscles, suspended in ice-cold Tris buffer, and homogenized using a Teflon (registered trademark) homogenizer and polytron. This was centrifuged, and the supernatant was centrifuged with a cooled ultracentrifuge. The precipitate obtained here was resuspended in Tris buffer and used for binding experiments. Protein quantification was performed using Protein Assay Kit (Bio-Rad) with bovine serum albumin as a standard solution.
[0177]
Binding experiment:
As a receptor ligand [ ^Three H] The compound of Reference Example 8, the compound of Reference Example 8, verapamil, diltiazem, and nicardipine were used as the Ca antagonist.
After incubating the membrane specimen, Tris buffer, each Ca antagonist, and the labeled ligand, the reaction was stopped by suction filtration with glass fiber filter paper (Whatman GF / C). The filter paper was washed with a Tris buffer, and the radioactive β dose (dpm) was measured with a liquid scintillation counter. [ ^Three H] The specific binding amount of the compound of Reference Example 8 was determined by subtracting the nonspecific binding amount obtained when 10 μM of the compound of Reference Example 8 was added from the total binding amount of the receptor ligand. All experiments were performed at n = 4. Dissociation constant (Kd value), maximum binding number (Bmax) and 50% binding inhibition concentration (IC by each Ca antagonist) ₅₀ ) Was calculated using analysis software GraphPad Prism (registered trademark). The results are shown in Table 4.
[0178]
[Table 4]

[0179]
[ ^Three H] The compound of Reference Example 8 shows higher affinity in the colon and ileum than in the aorta, and [[ ^Three H] The ability to inhibit the binding of the compound of Reference Example 8 was in the order of the compound of Reference Example 8 >>verapami>diltiazem> nicardipine.
[ ^Three H] Since the compound of Reference Example 8 bound to each tissue was inhibited by the compound of Reference Example 8 at the lowest concentration among the four types of Ca antagonists used, it is well known in the art. It was suggested that there exists a binding site specific to the compound of Reference Example 8 different from the dihydropyridine binding site, diltiazem binding site, and verapamil binding site.
【The invention's effect】
According to the present invention, it is possible to treat a disease accompanied by an organic change in the digestive tract without showing side effects.

Claims (8)

  A pharmaceutical composition for treating a disease associated with an organic change in the digestive tract, comprising a calcium channel antagonist.   The pharmaceutical composition according to claim 1, wherein the disease accompanied by organic changes in the gastrointestinal tract is gastric ulcer, duodenal ulcer, reflux esophagitis, ulcerative colitis or Crohn's disease.   The pharmaceutical composition according to claim 1, wherein the calcium channel antagonist has intestinal selectivity. The pharmaceutical composition according to claim 1, wherein the calcium channel antagonist is selected from the following group.
(I) 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivatives represented by the following general formula [I], stereoisomers, pharmacologically acceptable salts thereof, Hydrates or solvates;

[Wherein, rings G, J and K each represent a benzene ring or a nitrogen-containing aromatic ring. R ^{1 to} R ⁸ may be the same or different and each represents a halogen atom or a hydrogen atom; R ^{9 to} R ¹³ may be the same or different; and a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, or a lower alkyl Represents a group, a lower alkoxy group, an amino group or a lower alkylamino group and a lower acyl form thereof, a lower dialkylamino group, a cyclic alkylamino group, or R ⁹ and R ¹⁰ , or R ¹⁰ and R ¹¹ together. Te represents an -O (CH ₂₎ nO- group (n is 1, 2 or 3). A is any of CH ₂ , CHOH, CO, or O, B is any of CH ₂ , CHOH, or CO, or AB represents CH═CH, D is CH ₂ , CH ₂ —CH ₂ or CH Either _2- CH ₂ -CH ₂ or BD represents CH ₂ . X and Z are bonded to each other to represent either CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ , and then Y represents a hydrogen atom. Alternatively, Y and Z are bonded to each other to represent either CH ₂ —CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ —CH ₂ , where X represents a hydrogen atom. When X and Z, and Y and Z are not bonded to each other, X and Y represent a hydrogen atom, and Z represents a lower alkyl group.
However, when any of R ^{9 to} R ¹³ is a cyclic amino group represented by the formula [E], R ^{1 to} R ⁸ may be either a halogen atom or a hydrogen atom, but any of R ^{9 to} R ¹³ When is not a cyclic amino group represented by the formula [E], any one or two of R ^{1 to} R ⁸ are halogen atoms, and the others represent hydrogen atoms.

[Wherein, n and m represent 1 or 2, and W represents a nitrogen atom, an oxygen atom or a sulfur atom which may be substituted with a carbon atom or a lower alkyl group. ]
(II) 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivative represented by the following general formula [2], its stereoisomer, pharmacologically acceptable salt thereof, Hydrates or solvates;

(Where
k, m and n are 1, 2 or 3, respectively.
p is 0, 1 or 2;
X is O, S or a linking group, but when X is O or S, n is 2 or 3,
R ¹ is H or C ₁ -C ₄ alkyl, and R ² is

Wherein R ³ and R ⁴ are each independently H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —OH, —N (C ₁ -C ₄ alkyl) ₂ , halo or —CF ₃ Or)

(Wherein q is 1, 2 or 3,
X ¹ and X ² are each independently selected from O and —CH ₂ —) or (c) a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or thienyl group, wherein the group is C ₁ -C ₄ alkyl and C ₁ -C ₄ 2 following substituents independently selected from alkoxy may be substituted. )
(III) 5- (2-pyrrolidinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [3], its stereoisomer, pharmacologically Acceptable salts, hydrates or solvates thereof;

[Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group or a lower alkoxy group, or R ¹ and R ² together represent —O (CH ₂ ) _n O— group (n is 1, 2 or 3), R ³ represents a hydrogen atom or a hydroxy group, R ⁴ and R ⁵ may be the same or different, and each represents a hydrogen atom or a hydroxy group. Together or together represents = 0. ]
(IV) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivatives represented by the following general formula [4], their stereoisomers, pharmacologically acceptable Salts, hydrates or solvates thereof; and

[Wherein, R ^{1 to} R ⁵ may be the same or different and each represents a hydrogen atom, a lower alkoxy group, an amino group or an alkylamino group, and at least one of them represents an amino group or an alkylamino group; R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom or a hydroxy group, or together, represents ═O, and Y ¹ represents a methylene, sulfur atom or hydroxymethine. ]
(V) 5-alkyl-5,11-dihydrodibenzo [b, e] [1,4] oxazepine derivative represented by the following general formula [5], its stereoisomer, pharmacologically acceptable Salts, hydrates or solvates thereof.

[Wherein R ^{1 to} R ⁵ may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group, or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , or R ⁴ and R ⁵ together represent an —O (CH ₂ ) nO— group (n is 1, 2 or 3); R ⁶ represents hydrogen or a lower alkyl group, Y represents a methylene, oxygen atom, sulfur atom or alkylamino group, A represents any of CH ₂ , CHOH, CO or O, and B represents CH ₂ , CHOH. Or CO, or AB represents CH═CH, D represents CH ₂ , CH ₂ —CH ₂ or CH ₂ —CH ₂ —CH ₂ , or BD represents CH ₂ . Represent. ]   The calcium channel antagonist is a 5,11-dihydroaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] according to claim 4, its stereoisomer, pharmacologically acceptable. The pharmaceutical composition according to claim 4, which is a salt thereof, a hydrate or a solvate thereof. The pharmaceutical composition according to claim 1, wherein the calcium channel antagonist is a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, a hydrate or a solvate thereof.

A method for screening a calcium channel binding compound comprising:
(a) measuring the amount of the labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen;
(b) Binding of a labeled 5,11-dihydrodiaryl [b, e] [1,4] oxazepine derivative represented by the general formula [I] to a colonic or ileal membrane specimen in the presence of a test compound Measuring the amount, and
(c) comparing the result obtained in step (a) with the result obtained in step (b);
Including said method.   Use of a calcium antagonist for the preparation of a pharmaceutical composition for the treatment of diseases associated with organic changes in the gastrointestinal tract.