JP4302207B2 - Aryloxyaniline derivatives - Google Patents

Description

【０００８】
［式中、Ａｒ¹及びＡｒ²は同一若しくは異なって、置換若しくは非置換のフェニル基、置換若しくは非置換のピリジル基又はナフチル基を示し、Ｒ¹は水素原子、置換若しくは非置換の炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基、置換若しくは非置換のフェニル基又は式−ＮＲ²(Ｒ³)（式中、Ｒ²及びＲ³は同一若しくは異なって水素原子又は炭素数１〜１０のアルキル基を示すか、隣接する窒素原子と一緒になって４〜１０員環の環状アミノ基を示す基を示す。）で表される基を示し、Ｘ¹は水素原子、炭素数１〜５のアルキル基、炭素数１〜５のアルコキシ基、フェノキシ基、ハロゲン原子、トリフルオロメチル基、カルバモイル基又はアミノスルホニル基を示し、Ｙ¹は分岐鎖を有するか有さない炭素数１〜６のアルキレン基又は単結合を示す。］で表されるアリールオキシアニリン誘導体又はその医薬上許容される塩である。
【０００９】
本発明において、置換フェニル基とは、炭素数１〜１０のアルキル基、「ハロゲン原子、水酸基、炭素数１〜１０のアルカノイルオキシ基、カルボキシル基又はアルコキシカルボニル基」で置換された炭素数１〜１０のアルキル基、炭素数２〜１０のアルケニル基、炭素数１〜１０のアルコキシ基、炭素数１〜１０のアルキルチオ基、式−Ｏ−Ｚ−Ｒ⁴（式中、Ｚは分岐鎖を有するか有さない炭素数１〜１０のアルキレン基を示し、Ｒ⁴はアミノ基、炭素数１〜７のアルキル基の１若しくは２個で置換されたアミノ基、炭素数２〜７の環状アミノ基、水酸基、カルボキシル基又はアルコキシカルボニル基を示す。）で表される基、炭素数２〜１０のアルカノイル基若しくはそのケタール体、ホルミル基若しくはそのアセタール体、カルボキシル基、炭素数２〜１０のアルコキシカルボニル基、カルバモイル基、窒素原子が炭素数１〜１０のアルキル基の１若しくは２個で置換されたカルバモイル基、アミノスルホニル基、窒素原子が炭素数１〜１０のアルキル基の１若しくは２個で置換されたアミノスルホニル基、ハロゲン原子及びニトロ基から任意に選択された基の１〜３個で置換されたフェニル基であり、例えば２−メチルフェニル基、２−プロピルフェニル基、２−イソプロピルフェニル基、２−シクロペンチルフェニル基、２−(１−ヒドロキシエチル)フェニル基、２−カルボキシメチルフェニル基、２−メトキシカルボニルフェニル基、２−ビニルフェニル基、２−メトキシフェニル基、３−メトキシフェニル基、４−メトキシフェニル基、２−エトキシフェニル基、２−ヘキシルオキシフェニル基、２−イソプロポキシフェニル基、２−シクロペントキシフェニル基、２,５−ジメトキシフェニル基、２,４,６−トリメトキシフェニル基、４−メチルチオフェニル基、２−イソプロピルチオフェニル基、４−シクロヘキシルチオフェニル基、２−(２−ジメチルアミノエトキシ)フェニル基、２−(２−ヒドロキシエトキシ)フェニル基、２−カルボキシメトキシフェニル基、２−メトキシカルボニルメトキシフェニル基、２−アセチルフェニル基、２−(２−メチル−１,３−ジオキソラン−２−イル)フェニル基、２−ホルミルフェニル基、２−(１,３−ジオキソラン−２−イル)フェニル基、２−カルボキシルフェニル基、２−(Ｎ−メチルアミノカルボニル)フェニル基、２−(Ｎ,Ｎ−ジメチルアミノカルボニル)フェニル基、２−アミノカルボニルフェニル基、２−アミノスルホニルフェニル基、４−アミノスルホニルフェニル基、２−メチルアミノスルホニルフェニル基、２−ジメチルアミノスルホニルフェニル基、２−フルオロフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、２−クロロフェニル基、３−クロロフェニル基、４−クロロフェニル基、２−ブロモフェニル基、３−ブロモフェニル基、４−ブロモフェニル基、２,４−ジフルオロフェニル基、２−ニトロフェニル基、２−アミノフェニル基、２−ピロリジノフェニル基、４−ジメチルアミノフェニル基などである。置換ピリジル基とは、炭素数１〜１０の直鎖状又は分岐鎖状アルコキシ基で置換されたピリジル基を示し、例えば２−メトキシ−３−ピリジル基、３−メトキシ−２−ピリジル基、４−メトキシ−３−ピリジル基などである。炭素数１〜１０のアルキル基とは、直鎖状、分岐鎖状又は環状のアルキル基を示し、例えばメチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ブチル基、イソブチル基、シクロブチル基、シクロプロピルメチル基、ペンチル基、イソペンチル基、シクロペンチル基、シクロブチルメチル基、１−エチルプロピル基、ヘキシル基、イソヘキシル基、シクロヘキシル基、シクロペンチルメチル基、１−エチルブチル基、ヘプチル基、イソヘプチル基、シクロヘキシルメチル基、オクチル基、ノニル基、デシル基などである。炭素数１〜１０の置換アルキル基とは「水酸基、アルカノイルオキシ基、アルカノイル基、アルコキシ基、ハロゲン原子、アジド基、アミノ基、カルボキシル基」で置換されたアルキル基を示し、例えばヒドロキシメチル基、アセチルオキシメチル基、メトキシメチル基、クロロメチル基、トリフルオロメチル基、アジドメチル基、アミノメチル基、ジメチルアミノメチル基、ピロリジノメチル基などである。炭素数１〜１０のアルコキシ基とは直鎖状、分岐鎖状又は環状のアルコキシ基を示し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、シクロプロピルメトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ヘキシルオキシ基、ヘプチルオキシ基、オクチルオキシ基、ノニルオキシ基、デシルオキシ基などである。Ｒ²及びＲ³で示される炭素数１〜１０のアルキル基とは、直鎖状、分岐鎖状又は環状のアルキル基を示し、従ってＲ²及びＲ³が炭素数１〜１０のアルキル基の場合の式−ＮＲ²(Ｒ³)で表される基とは、例えばメチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ブチルアミノ基、イソブチルアミノ基、シクロプロピルメチルアミノ基、ペンチルアミノ基、イソペンチルアミノ基、シクロペンチルアミノ基、シクロブチルメチルアミノ基、１−エチルプロピルアミノ基、ヘキシルアミノ基、イソヘキシルアミノ基、シクロヘキシルアミノ基、シクロペンチルメチルアミノ基、１−エチルブチルアミノ基、ヘプチルアミノ基、イソヘプチルアミノ基、シクロヘキシルメチルアミノ基、オクチルアミノ基、ノニルアミノ基、デシルアミノ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジブチルアミノ基、ジペンチルアミノ基、ジヘキシルアミノ基、Ｎ−メチルエチルアミノ基、Ｎ−メチルプロピルアミノ基、Ｎ−メチルブチルアミノ基、Ｎ−メチルペンチルアミノ基、Ｎ−メチルヘキシルアミノ基、Ｎ−エチルプロピルアミノ基、Ｎ−エチルブチルアミノ基、Ｎ−エチルペンチルアミノ基などである。また、式−ＮＲ²(Ｒ³)で表される４〜１０員環の環状アミノ基とは、窒素原子又は酸素原子を含むこともある環状アミノ基を示し、例えばピロリジノ基、ピペリジノ基、ピペラジノ基、Ｎ−メチルピペラジノ基、モルホリノ基などである。Ｘ¹で示される炭素数１〜５のアルキル基とは「直鎖状、分岐鎖状又は環状」のアルキル基を示し、例えばメチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ブチル基、イソブチル基、シクロブチル基、シクロプロピルメチル基などであり、また、炭素数１〜５のアルコキシ基とは「直鎖状、分岐鎖状又は環状」のアルコキシ基を示し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、シクロプロピルメトキシ基などである。Ｙ¹で示される分岐鎖を有するか有さない炭素数１〜６のアルキレン基とは、例えばメチレン基、エチレン基、プロピレン基、メチルメチレン基、ジメチルメチレン基などである。ハロゲン原子とはフッ素原子、塩素原子、臭素原子又はヨウ素原子を示す。
【００１０】
また、本発明における医薬上許容される塩とは、例えば硫酸、塩酸、燐酸などの鉱酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との塩、ナトリウムイオン、カリウムイオン、カルシウムイオンなどの金属イオンとの塩、ジエタノールアミンなど有機塩基との塩、アンモニウム塩などである。
【００１１】
【発明の実施の形態】
式［Ｉ］の化合物は、以下の一般的製造法１〜６によって製造することができる（以下の反応式中、Ａｒ¹、Ａｒ²、Ｒ¹、Ｘ¹及びＹ¹は前記と同様であり、Ｙ²は単結合又は炭素数１〜３のアルキル基で置換若しくは非置換の炭素数１〜５のアルキレン基を示し、Ｒ⁵は炭素数１〜３のアルキル基又は水素原子を示し、Ｘ²は炭素数１〜１０のアシルオキシ基、塩素原子、臭素原子、水酸基又は炭素数１〜５のアルコキシ基を示し、Ｘ³は塩素原子、臭素原子又はヨウ素原子を示す。）
［一般的製造法１］
【００１２】
【化３】

【００１３】
酸触媒の存在下又は非存在下不活性溶媒中アニリン誘導体（１）とカルボニル誘導体（２）を反応後還元するか、あるいは酸触媒の存在下又は非存在下不活性溶媒中アニリン誘導体（１）とカルボニル誘導体（２）の混合物を還元することによって化合物（３）を得ることができる。化合物（３）をＮ−カルボニル化剤と塩基の存在下又は非存在下不活性溶媒中反応することによって本発明化合物（４）を得ることができる。また、これらＮ−カルボニル化剤としてホスゲンを化合物（３）に反応し、クロロカルボニル誘導体とした後、塩基の存在下又は非存在下アルコール類又はアミン類と反応することによっても本発明化合物（４）を得ることができる。
【００１４】
ここで酸触媒とは、例えば塩化水素、臭化水素などのハロゲン化水素、例えば塩酸、硫酸などの無機酸、例えば酢酸、トシル酸などの有機酸、例えばＰＰＴＳ、ピペリジン・塩酸塩である。
【００１５】
還元は、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化シアノホウ素ナトリウムなどのホウ素系還元剤、水素化リチウムアルミニウムなどのアルミニウム系還元剤を用いるか、又はパラジウム、二酸化白金、ラネーニッケルなどを触媒に用いた水素添加によって行われる。Ｎ−カルボニル化剤とは、例えばアシルハライド、有機酸無水物、アルコキシカルボニルハライド、カルバモイルハライド、シアン酸（反応液中、シアン酸カリウムと酢酸より生成）、イソシアネートなどである。塩基とはトリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどの有機アミン類、炭酸カリウム、水酸化ナトリウム、水素化ナトリウム、金属ナトリウムなどの無機塩基類である。不活性溶媒とは、例えばメタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、例えばクロロホルム、ジクロロメタンなどのハロゲン化炭化水素系溶媒、アセトニトリル、水又はこれらの混合溶媒などである。
【００１６】
［一般的製造法２］
【００１７】
【化４】

【００１８】
化合物（３）のＲ²が水素原子である化合物（７）は、アニリン誘導体（１）と化合物（５）で示されるカルボン酸無水物、アシルハライド、カルボン酸又はカルボン酸エステルと塩基の存在下又は非存在下不活性溶媒中反応しアミド化合物（６）とし、これを不活性溶媒中還元剤と反応することによっても合成できる。
【００１９】
［一般的製造法３］
【００２０】
【化５】

【００２１】
アニリン誘導体（１）をＮ−カルボニル化剤と塩基の存在下又は非存在下不活性溶媒中反応し化合物（８）とした後、ハロゲン化物（９）と塩基の存在下、必要に応じ相関移動触媒、銅粉、ハロゲン化第一銅などを用い、不活性溶媒中反応し本発明化合物（１０）を得ることができる。また、これらＮ−カルボニル化剤としてホスゲンを化合物（１）に反応し、クロロカルボニル誘導体とした後、塩基の存在下アルコール類又はアミン類と反応することによっても化合物（８）を得ることができる。
【００２２】
ここでＮ−カルボニル化剤とは、例えばアシルハライド、有機酸無水物、アルコキシカルボニルハライド、カルバモイルハライド、シアン酸（反応液中、シアン酸カリウムと酢酸より生成）又はイソシアネートなどである。塩基とはトリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどの有機アミン類、炭酸カリウム、水酸化ナトリウム、水素化ナトリウム、金属ナトリウムなどの無機塩基類、カリウムｔ−ブトキシド、ナトリウムエトキシドなどのアルコラート類などである。相間移動触媒とはベンジルトリエチルアンモニウムブロミドなどの四級アンモニウム塩、１８−クラウン−６エーテルなどのクラウンエーテル類などである。不活性溶媒とは、例えばメタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、アセトンなどのケトン系溶媒、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミド、ニトロベンゼン、水又はこれらの混合溶媒などである。
【００２３】
［一般的製造法４］
Ａｒ¹、Ａｒ²の一方又は両方にニトロ基を含む場合、このニトロ基は水素添加又は金属還元によりアミノ基に変換できる。このアミノ基は塩基の存在下、相間移動触媒を必要に応じ用い不活性溶媒中ハロゲン化化合物と反応し、炭素数１〜１０の直鎖状、分岐鎖状又は環状アルキル基で置換されたアミノ基に変換される。
【００２４】
ここで水素添加とはパラジウム、二酸化白金、ラネーニッケルなどを触媒に用いた水素添加を示し、金属還元とはスズ、塩化第一スズなどの二価のスズ塩、鉄、塩化第一鉄などの二価の鉄塩、亜鉛などの金属又は金属塩を通常用いる酸性、中性又は塩基性条件の還元を示す。塩基とはトリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどの有機アミン類、炭酸カリウム、水酸化ナトリウム、水素化ナトリウム、金属ナトリウムなどの無機塩基類、カリウムｔ−ブトキシド、ナトリウムエトキシドなどのアルコラート類などである。相関移動触媒とはベンジルトリエチルアンモニウムブロミドなどの四級アンモニウム塩、１８−クラウン−６エーテルなどのクラウンエーテル類などである。不活性溶媒とは、例えばメタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミド、水又はこれらの混合溶媒などである。
【００２５】
［一般的製造法５］
Ａｒ¹、Ａｒ²の一方又は両方にアシルオキシ基を含む場合、このアシルオキシ基は酸性又は塩基性条件下加水分解することによって水酸基に変換できる。この水酸基は塩基の存在下、相関移動触媒を必要に応じ用い不活性溶媒中ハロゲン化化合物と反応し、炭素数１〜１０の直鎖状又は分岐鎖状アルコキシ基、置換又は無置換のアミノ基で置換された炭素数１〜１０の直鎖状又は分岐鎖状アルコキシ基、カルボキシル基又はアルコキシカルボニル基で置換された炭素数１〜１０のアルコキシ基に変換される。
【００２６】
ここで酸性又は塩基性条件下とは塩酸、硫酸など無機酸、又は水酸化ナトリウム、水酸化カリウムなどの無機塩基を、メタノール、エタノールなどのアルコール類、テトラヒドロフラン、ジオキサンなどのエーテル類、アセトンなどのケトン類、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミド、水又はこれらの混合溶媒中用いることを示す。塩基とはトリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどの有機アミン類、炭酸カリウム、水酸化ナトリウム、水素化ナトリウム、金属ナトリウムなどの無機塩基類、カリウムｔ−ブトキシド、ナトリウムエトキシドなどのアルコラート類などである。相間移動触媒とはベンジルトリエチルアンモニウムブロミドなどの四級アンモニウム塩、１８−クラウン−６エーテルなどのクラウンエーテル類などである。不活性溶媒とは、例えばメタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミド、水又はこれらの混合溶媒などである。
【００２７】
［一般的製造法６］
Ａｒ¹、Ａｒ²の一方又は両方にアルコキシカルボニル基を含む場合、このアルコキシカルボニル基は通常のエステルの加水分解条件によってカルボキシル基に変換される。更にカルボキシル基はエステル化により炭素数１〜１０のアルコキシカルボニル基、アミド化により炭素数１〜１０の１級又は２級アルキルアミノカルボニル基、アミノカルボニル基に変換される。
【００２８】
ここで、加水分解条件とは例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウムなどの塩基、又は例えば塩酸、硫酸などの無機酸を、例えばメタノール、エタノールなどのアルコール系溶媒、例えばアセトンなどのケトン系溶媒などの不活性溶媒中反応することを示す。エステル化とは塩素原子、臭素原子又はヨウ素原子で置換されたアルキル化合物又はジアルキル硫酸を、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウムなどの無機塩基、例えばナトリウムメトキシド、カリウムｔ−ブトキシドなどのアルコラート類、例えばトリエチルアミン、ジイソプロピルエチルアミンなどの有機塩基とともに反応するか、又はアルコールを例えば塩化水素、硫酸などの酸とともに反応すること示す。アミド化とはカルボキシル基を塩化チオニル、トリフェニルホスフィン−四塩化炭素などにより酸ハライドに変換後、対応するアミン誘導体と反応するか、例えば混合酸無水物法、ジシクロヘキシルカルボジイミド法等の通常用いるアミド化を示す。
【００２９】
［一般的製造法７］
Ａｒ¹、Ａｒ²の一方又は両方にホルミル基又はアシル基を含む場合、このホルミル基又はアシル基のカルボニル基はウィティッヒ試薬と反応しアルケニル基に変換される。更にアルケニル基は還元することによってアルキル基に変換される。
【００３０】
ここで、ウィティッヒ試薬とは炭素数１〜９のアルキル基を有するトリフェニルアルキルホスホニウムハライド又はジエチルアルキルホスホネートなどを示し、例えばメタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、塩化メチレン、クロロホルムなどのハロゲン化炭化水素類、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミドなどの不活性溶媒中、水素化ナトリウム、カリウムｔ−ブトキシド、ナトリウムエトキシド、ｎ−ブチルリチウムなどの塩基と、必要に応じベンジルトリエチルアンモニウムブロミドなどの四級アンモニウム塩、１８−クラウン−６エーテルなどのクラウンエーテル類等の相関移動触媒と伴に用いる。還元とはパラジウム、二酸化白金、ラネーニッケルなどを触媒に用いた水素添加を示す。
【００３１】
［一般的製造法８］
Ａｒ¹、Ａｒ²の一方又は両方にホルミル基又はアシル基を含む場合、このホルミル基又はアシル基のカルボニル基はグリニャール試薬と反応し２級又は３級アルコール体に変換される。更に２級アルコール体は各種酸化剤によって酸化することによってアシル基に変換される。
【００３２】
ここで、グリニャール試薬とは炭素数１〜９のアルキル又はアルケニルマグネシウムハライドを示し、例えばメチルマグネシウムブロミド、エチルマグネシウムブロミドなどを示す。各種酸化剤とは塩化オギザリル−ジメチルスルホキシドを用いたスワン酸化、クロム系酸化剤、二酸化マンガン等の金属酸化剤を示す。
【００３３】
本発明の化合物を医薬として用いるためには、本発明の化合物を常用の増量剤、結合剤、崩壊剤、ｐＨ調節剤、溶解剤などを添加し、常用の製剤技術によって錠剤、丸剤、カプセル剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、注射剤などに調製することができる。
【００３４】
本発明の化合物は、成人の患者に対して０.１〜５００ｍｇ／日を１日１回又は数回に分けて経口又は非経口で投与することができる。この投与量は疾患の種類、患者の年齢、体重、症状により適宜増減することができる。
【００３５】
【発明の効果】
本発明により、ＭＤＲに高い親和性を有する薬物が提供された。従ってこれらは、不安及びその関連疾患、うつ病、てんかん、睡眠障害、認知学習障害、精神分裂病などの中枢性疾患、筋硬直に伴う運動障害、摂食障害、循環障害、薬物依存症、癌、脂質代謝障害、脳梗塞、ＡＩＤＳ、アルツハイマー病並びにハンチントン舞踏病の治療剤及び予防剤として有用である。
【００３６】
【実施例】
以下に実施例及び試験例を示し本発明を具体的に説明する。
実施例１
Ｎ−アセチル−Ｎ−（２−イソプロポキシベンジル）−２−フェノキシアニリンの合成
（１）２−イソプロポキシベンズアルデヒド１.６４ｇをメタノール１０ｍｌに溶解し、２−アミノジフェニルエーテル１.８５ｇを加え、室温で３０分間撹拌後、氷水にて冷却した。この冷却した反応溶液に水素化ホウ素ナトリウム１.５０ｇを少量ずつ加え、氷冷下３０分間、続いて室温にて３０分間撹拌した。反応溶液に酢酸水溶液（酢酸１.５ｍｌ−水３０ｍｌ）を滴下し、１０分間室温で撹拌後酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：２５）にて精製し、油状のＮ−（２−イソプロポキシベンジル）−２−フェノキシアニリン２.６５ｇを得た。
【００３７】
（２）Ｎ−（２−イソプロポキシベンジル）−２−フェノキシアニリン２.６５ｇ及びトリエチルアミン１.５ｍｌをテトラヒドロフラン３０ｍｌに溶解し、この溶液に塩化アセチル０.８ｍｌを撹拌下滴下し、３０分間撹拌した。反応混合物を水に注ぎ、酢酸エチルにて抽出し、０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、油状のＮ−アセチル−Ｎ−（２−イソプロポキシベンジル）−２−フェノキシアニリン２.９２ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００３８】
実施例２
Ｎ−アセチル−Ｎ−（２,４−ジメトキシベンジル）−２−フェノキシアニリンの合成
（１）２−アミノジフェニルエーテル３.７０ｇと２,４−ジメトキシベンズアルデヒド３.７０ｇをメタノール６０ｍｌに溶解し、これに酸化白金７０ｍｇを加え、水素気流下室温で一夜撹拌した。反応混合物にクロロホルム３０ｍｌを加え、析出物を溶解後触媒を濾別した。濾液は減圧下濃縮し、残渣をメタノールより再結晶し、Ｎ−（２,４−ジメトキシベンジル）−２−フェノキシアニリン５.０６ｇを得た。
【００３９】
（２）Ｎ−（２,４−ジメトキシベンジル）−２−フェノキシアニリン１.００ｇのピリジン１.１８ｇの溶液に、無水酢酸０.７６ｇを加え、室温で１日撹拌した。反応混合物を水に注ぎ、酢酸エチルにて抽出し、０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、油状のＮ−アセチル−Ｎ−（２,４−ジメトキシベンジル）−２−フェノキシアニリン１.０９ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４０】
実施例３
Ｎ−アセチル−Ｎ−（２−クロロベンジル）−２−フェノキシアニリンの合成（１）２−フェノキシアニリン２８.５ｇとトリエチルアミン２５.８ｍｌの塩化メチレン２５０ｍｌの溶液に、塩化アセチル１１.５ｍｌを氷冷下滴下した。室温で１.５時間撹拌後、反応混合物を減圧下濃縮し、残渣を水に注ぎ、酢酸エチルにて抽出した。抽出液を０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、Ｎ−アセチル−２−フェノキシアニリン３３.７ｇを得た。
【００４１】
（２）水素化ナトリウム（６０％ in oil）４００ｍｇのジメチルホルムアミド３０ｍｌの懸濁溶液にＮ−アセチル−２−フェノキシアニリン２.００ｇを室温で加え、更に室温で３０分間撹拌した。この溶液に２−クロロベンジルクロリド１.６４ｇを室温で撹拌下滴下し、３０分間撹拌後、反応混合物に氷水を加え、エーテルにて抽出した。抽出液を０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、油状のＮ−アセチル−Ｎ−（２−クロロベンジル）−２−フェノキシアニリン２.９２ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４２】
実施例４
Ｎ−アミノカルボニル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリンの合成
実施例１の（１）と同様に合成したＮ−（２−メトキシベンジル）−２−フェノキシアニリン１.５４ｇを酢酸２０ｍｌに溶解し、この溶液にシアン酸カリウム水溶液（シアン酸カリウム１.２３ｇ−水１０ｍｌ）を滴下後、室温で２.５時間撹拌した。反応混合物を水に注ぎ、酢酸エチルにて抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、油状のＮ−アミノカルボニル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.６９ｇを得た。
【００４３】
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４４】
実施例５
Ｎ−（２−メトキシベンジル）−Ｎ−（Ｎ−メチルアミノカルボニル）−２−フェノキシアニリンの合成
トリホスゲン７５１ｍｇの塩化メチレン溶液１４ｍｌに、Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン２.０３ｇとジイソプロピルエチルアミン１.０３ｇの塩化メチレン２５ｍｌの溶液を撹拌下滴下し、室温で５分間撹拌した。この溶液に撹拌下、過剰量のメチルアミンをふきこみ、室温で５分間撹拌後、減圧下濃縮した。反応混合物を酢酸エチルに注ぎ、５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、析出した結晶を酢酸エチルにて再結晶し、Ｎ−（２−メトキシベンジル）−Ｎ−（Ｎ−メチルアミノカルボニル）−２−フェノキシアニリン２.０２ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４５】
実施例６
Ｎ−（２,５−ジメトキシベンジル）−Ｎ−（Ｎ−メチルアミノカルボニル）−２−フェノキシアニリンの合成
酢酸３.４３ｍｌとトリエチルアミン８.３６ｍｌのベンゼン９０ｍｌの溶液にジフェニルホスホリルアジド１２.９ｍｌを加え、２時間加熱還流した。この反応液に実施例２の（１）と同様にして合成したＮ−（２,５−ジメトキシベンジル）−２−フェノキシアニリン２.０１ｇを加え、６時間加熱還流した。反応混合物を水中に注ぎ有機相を分取し、５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：２）にて精製し、ジエチルエーテルにて再結晶し、Ｎ−（２,５−ジメトキシベンジル）−Ｎ−（Ｎ−メチルアミノカルボニル）−２−フェノキシアニリン１.２０ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４６】
実施例７
Ｎ−（２−メトキシベンジル）−Ｎ−メトキシカルボニル−２−フェノキシアニリンの合成
（１）トリホスゲン７７５ｍｇの塩化メチレン溶液１４ｍｌに、Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン２.１６ｇとジイソプロピルエチルアミン１.１０ｇを溶解した塩化メチレン２５ｍｌを撹拌下ゆっくり滴下し、室温で１５分間撹拌した。反応混合物を減圧下濃縮し、酢酸エチルに注ぎ、５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：１５）にて精製し、Ｎ−クロロカルボニル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン２.５７ｇを得た。
【００４７】
（２）ナトリウムメトキシド２２６ｍｇのテトラヒドロフラン溶液５ｍｌに氷冷下、テトラヒドロフラン５ｍｌに溶解したＮ−クロロカルボニル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.２２ｇを撹拌下滴下し、室温で２０分間撹拌した。反応混合物を減圧下濃縮後、水に注ぎ、酢酸エチルにて抽出し、５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：６）にて精製後、酢酸エチルより再結晶し、Ｎ−（２−メトキシベンジル）−Ｎ−メトキシカルボニル−２−フェノキシアニリン１.１８ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００４８】
実施例８
Ｎ−アミノアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリンの合成
（１）実施例１と同様に合成したＮ−クロロアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.５１ｇとアジ化ナトリウム７７０ｍｇのジメチルホルムアミド溶液１０ｍｌを室温で一晩撹拌した。反応混合物を水に注いだ後、酢酸エチルにて抽出した。抽出液を５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、油状のＮ−アジドアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.５５ｇを得た。
【００４９】
（２）Ｎ−アジドアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン６４７ｍｇをメタノール７ｍｌに溶解し、酸化白金２０ｍｇを加え、水素雰囲気下室温にて一晩撹拌した。反応混合物をセライトにて濾過し、減圧下濃縮後、シリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：６）にて精製後、酢酸エチル−イソプロピルエーテルにて再結晶し、Ｎ−アミノアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン０.２４ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００５０】
実施例９
Ｎ−ヒドロキシアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリンの合成
（１）Ｎ−クロロアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.０１ｇ、酢酸ナトリウム１.３０ｇ、及び臭化テトラ−ｎ−ブチルアンモニウム１７０ｍｇをベンゼン１０ｍｌ中８０℃で５時間撹拌した。反応混合物を酢酸エチルに注いだ後、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、油状のＮ−アセトキシアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン１.０３ｇを得た。
【００５１】
（２）Ｎ−アセトキシアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン５２５ｍｇをメタノール６ｍｌに溶解し、炭酸カリウム５３７ｍｇを加え、５０℃で７時間撹拌後、反応混合物を水に注ぎ、酢酸エチルにて抽出した。抽出液を５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、室温で放置後、結晶性のＮ−ヒドロキシアセチル−Ｎ−（２−メトキシベンジル）−２−フェノキシアニリン４５０ｍｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００５２】
実施例１０
Ｎ−アセチル−Ｎ−（２−ピロリジノベンジル）−２−フェノキシアニリン一塩酸塩の合成
（１）実施例３と同様に合成したＮ−アセチル−Ｎ−（２−ニトロベンジル）−２−フェノキシアニリン８.００ｇをメタノール８０ｍｌに溶解し、二酸化白金６６ｍｇを加え、水素雰囲気下室温にて一夜撹拌した。反応混合物にクロロホルム４０ｍｌを加え析出物を溶解後、触媒を濾別した。濾液は減圧下濃縮し、残渣をメタノールにて再結晶し、Ｎ−アセチル−Ｎ−（２−アミノベンジル）−２−フェノキシアニリン６.８８ｇを得た。
【００５３】
（２）Ｎ−アセチル−Ｎ−（２−アミノベンジル）−２−フェノキシアニリン１.００ｇ、１、４−ジブロモブタン６８０ｍｇ、炭酸カリウム１.０３ｇ、及びヨウ化カリウム５０ｍｇをＮ,Ｎ−ジメチルホルムアミド溶液１０ｍｌ中７０℃で３日間撹拌した。反応混合物を水に注ぎ、酢酸エチルにて抽出し、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製した。得られた生成物をエーテル５ｍｌに溶解し、４規定塩化水素−酢酸エチル溶液を０.９ｍｌ加えたのち、溶液を濃縮し、酢酸エチル−エーテルにて再結晶し、Ｎ−アセチル−Ｎ−（２−ピロリジノベンジル）−２−フェノキシアニリン１塩酸塩０.４９ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００５４】
実施例１１
Ｎ−アセチル−Ｎ−（２−カルボキシメトキシベンジル）−２−フェノキシアニリンの合成
（１）２−アセトキシベンズアルデヒド１.７４ｇと２−フェノキシアニリン１.８５ｇをメタノール３０ｍｌに溶解し、室温で１時間撹拌後、水素化ホウ素ナトリウムを３.００ｇ加え、同温で３０分間撹拌した。反応溶液に酢酸水溶液（酢酸３.０ｍｌ−水６０ｍｌ）を滴下し、１０分間室温で撹拌後酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮した。残渣とトリエチルアミン４ｍｌの塩化メチレン溶液５０ｍｌを０℃に冷却し、塩化アセチル２.００ｍｌを撹拌下滴下し、室温で２０分間撹拌した後、反応混合物を水に注ぎ、酢酸エチルにて抽出した。抽出液を０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、粗のＮ−アセチル−Ｎ−（２−アセチルオキシベンジル）−２−フェノキシアニリンを得た。
【００５５】
これをメタノール溶液４０ｍｌに溶解し、５％水酸化カリウム水溶液１４ｍｌを加え、室温で１時間撹拌した。反応混合物を減圧下濃縮し、水に注いだ後、酢酸エチルにて抽出し、抽出液を５％塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をジイソプロピルエーテルにて結晶化し、Ｎ−アセチル−Ｎ−（２−ヒドロキシベンジル）−２−フェノキシアニリン１.８６ｇを得た。
【００５６】
（２）Ｎ−アセチル−Ｎ−（２−ヒドロキシベンジル）−２−フェノキシアニリン６６６ｍｇのＮ,Ｎ−ジメチルホルムアミド１０ｍｌの溶液に６０％ＮａＨ／オイル８０ｍｇを加え、室温で３０分間攪拌した。これにブロモ酢酸メチル０.３ｍｌを加え、室温で３０分間攪拌した。反応液を０.５規定塩酸に注ぎ、酢酸エチルにて抽出し、０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濾過後、濾液を減圧下濃縮し、粗のＮ−アセチル−Ｎ−（２−メトキシカルボニルメトキシベンジル）−２−フェノキシアニリンを得た。
【００５７】
これをメタノール１０ｍｌに溶解し、５％水酸化カリウム水溶液５ｍｌを加え、室温で１時間攪拌した。反応液に２規定塩酸を加え酸性とし、酢酸エチルにて抽出し、抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をジイソプロピルエーテルにて結晶化し、Ｎ−アセチル−Ｎ−（２−カルボキシメトキシベンジル）−２−フェノキシアニリン７４５ｍｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００５８】
実施例１２
Ｎ−アセチル−Ｎ−（２−プロピルベンジル）−２−フェノキシアニリンの合成
（１）実施例３と同様に合成したＮ−アセチル−Ｎ−（２−（１,３−ジオキソラン−２−イル）ベンジル）−２−フェノキシアニリン２.８１ｇをアセトン４０ｍｌに溶解し、ｐ−トルエンスルホン酸１水和物０.１０ｇを加え、室温で６時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、減圧下アセトンを濃縮後、残渣を酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、乾燥後放置し、室温放置により結晶性のＮ−アセチル−Ｎ−（２−ホルミルベンジル）−２−フェノキシアニリン２.１２ｇを結晶として得た。
【００５９】
（２）窒素気流下、エチルトリフェニルホスホニウムブロミド４.３４ｇのテトラヒドロフラン２０ｍｌの懸濁溶液に、反応液温を−１５〜−１０℃に保ちつつ１.６３Ｍ ｎ−ブチルリチウム／ヘキサン溶液６.６３ｍｌを滴下した。反応液をゆっくり室温まで昇温し、室温で２０分間撹拌後、Ｎ−アセチル−Ｎ−（２−ホルミルベンジル）−２−フェノキシアニリン１.０１ｇのテトラヒドロフラン１０ｍｌの溶液を滴下し、更に１時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、油状のＮ−アセチル−Ｎ−（２−（プロペン−１−イル）ベンジル）−２−フェノキシアニリン８５９ｍｇを約３：２の幾何異性体の混合物として得た。
【００６０】
（３）Ｎ−アセチル−Ｎ−（２−（プロペン−１−イル）ベンジル）−２−フェノキシアニリン（約３：２の幾何異性体の混合物）７５７ｍｇをエタノール７ｍｌに溶解し、酸化白金１５ｍｇを加え、水素雰囲気下室温で３時間撹拌した。反応液中の触媒を濾別し、減圧下濃縮後、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、油状のＮ−アセチル−Ｎ−（２−プロピルベンジル）−２−フェノキシアニリン６４７ｍｇを得た。本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００６１】
実施例１３
Ｎ−アセチル−Ｎ−（２−アセチルベンジル）−２−フェノキシアニリンの合成
（１）氷冷した１Ｍメチルマグネシウムクロライド／テトラヒドロフラン溶液５.２５ｍｌのテトラヒドロフラン１５ｍｌの希釈溶液に、Ｎ−アセチル−Ｎ−（２−ホルミルベンジル）−２−フェノキシアニリン１.２０ｇのテトラヒドロフラン７ｍｌの溶液を滴下し、更に室温で１時間攪拌した。反応液を再び氷冷し、これに飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：１）にて精製し、油状のＮ−アセチル−Ｎ−（２−（１−ヒドロキシエチル）ベンジル）−２−フェノキシアニリン１.１９ｇを得た。
【００６２】
（２）塩化オギザリル０.２２ｍｌのジクロロメタン１３.５ｍｌの溶液をドライアイス−アセトンにて−７０℃以下に冷却し、これにジメチルスルホキシド０.２４ｍｌのジクロロメタン０.９ｍｌの溶液を滴下し、更に１０分間攪拌した。これにＮ−アセチル−Ｎ−（２−（１−ヒドロキシエチル）ベンジル）−２−フェノキシアニリン０.４８ｇのジクロロメタン４.５ｍｌの溶液を滴下し、反応液温を−４５℃まで徐々に上げ、同温で更に１時間攪拌した。この反応液にトリエチルアミン１.３４ｍｌを−４０℃以下で滴下し、０℃で更に２０分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：１）にて精製し、酢酸エチル−ヘキサンにて再結晶し、Ｎ−アセチル−Ｎ−（２−アセチルベンジル）−２−フェノキシアニリン０.４１ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００６３】
実施例１４
Ｎ−アセチル−Ｎ−（２−ジメチルアミノカルボニルベンジル）−２−フェノキシアニリンの合成
（１）実施例２と同様に合成したＮ−アセチル−Ｎ−（２−メトキシカルボニルベンジル）−２−フェノキシアニリン２.２６ｇをメタノール２３ｍｌと２規定水酸化カリウム水溶液３.６ｍｌの混合溶液に加え、６０℃で１時間攪拌した。反応混合物を減圧下濃縮し、残渣に水を加え、２規定塩酸にて酸性とした後、酢酸エチルにて抽出し、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：１）にて精製し、油状のＮ−アセチル−Ｎ−（２−カルボキシベンジル）−２−フェノキシアニリン２.０１ｇを得た。
【００６４】
（２）Ｎ−アセチル−Ｎ−（２−カルボキシベンジル）−２−フェノキシアニリン０.５０ｇをテトラヒドロフラン１０ｍｌとヘキサメチルホスホルアミド０.１ｍｌの混合溶媒に溶解し、塩化チオニル０.２ｍｌを加え、室温で３時間攪拌した。反応混合物を濃縮し、残渣をテトラヒドロフラン１０ｍｌに溶解し、５０％ジメチルアミン水溶液２ｍｌを攪拌下滴下した。反応混合物を水中に注ぎ、酢酸エチルにて抽出し、１規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：３）にて精製し、油状のＮ−アセチル−Ｎ−（２−ジメチルアミノカルボニルベンジル）−２−フェノキシアニリン０.４９ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００６５】
実施例１５
Ｎ−アセチル−Ｎ−（２−エトキシカルボニルベンジル）−２−フェノキシアニリンの合成
Ｎ−アセチル−Ｎ−（２−カルボキシベンジル）−２−フェノキシアニリン０.５０ｇ、無水炭酸カリウム０.２０ｇ及びジエチル硫酸０.２２ｍｌをＮ,Ｎ−ジメチルホルムアミド１０ｍｌ中３時間室温で攪拌した。反応混合物を水中に注ぎ、酢酸エチルにて抽出し、１規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：７）にて精製し、油状のＮ−アセチル−Ｎ−（２−エトキシカルボニルベンジル）−２−フェノキシアニリン０.５０ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００６６】
実施例１６
Ｎ−アセチル−Ｎ−（２−メトキシフェニル）−２−フェノキシアニリンの合成
Ｎ−アセチル−２−フェノキシアニリン２.２７ｇ、２−ヨードアニソール１.３ｍｌ、炭酸カリウム１.３８ｇ、銅粉１３３ｍｇ及び臭化銅２００ｍｇをニトロベンゼン２０ｍｌ中８時間加熱環流した。反応液を室温に冷却後、酢酸エチルを加え、不溶物を濾別した。濾液を０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：４）にて精製し、油状のＮ−アセチル−Ｎ−（２−メトキシフェニル）−２−フェノキシアニリン６６０ｍｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００６７】
実施例１７
Ｎ−アセチル−Ｎ−（２−（２−メトキシフェニル）エチル）−２−フェノキシアニリンの合成
（１）２−メトキシフェニル酢酸４.９８ｇとＮ,Ｎ−ジメチルホルムアミド０.５ｍｌをトルエン３０ｍｌに溶解し、塩化チオニル４ｍｌを加え、７０℃で１時間撹拌後、減圧下濃縮した。残渣を塩化メチレン２０ｍｌに溶解し、これを氷冷した２−フェノキシアニリン５.５５ｇとトリエチルアミン４.６ｍｌの塩化メチレン３０ｍｌの溶液に撹拌下滴下し、更に室温で１時間撹拌した。反応液を減圧下濃縮し、氷水を加え、酢酸エチルにて抽出し、０.５規定塩酸、飽和炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、減圧下溶媒を濃縮した。
【００６８】
残渣をテトラヒドロフラン４０ｍｌに溶解し、これを水素化リチウムアルミニウム１.７０ｇのテトラヒドロフラン４０ｍｌの懸濁液に滴下し、３０分間加熱環流した。反応混合物を氷水で冷却し、飽和硫酸ナトリウム水溶液を撹拌下滴下した。反応液中の不溶物を無水硫酸マグネシウムプレートを通して濾別後、濾液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（展開溶媒：酢酸エチル−ヘキサン＝１：１０）にて精製し、油状のＮ−（２−（２−メトキシフェニル）エチル）−２−フェノキシアニリン８.２３ｇを得た。
【００６９】
（２）Ｎ−（２−（２−メトキシフェニル）エチル）−２−フェノキシアニリン３.１９ｇを用い実施例１の（２）と同様に反応、後処理後、ヘキサンにて結晶化し、Ｎ−アセチル−Ｎ−（２−（２−メトキシフェニル）エチル）−２−フェノキシアニリン２.９５ｇを得た。
本化合物及び同様にして得た化合物の構造と物性データを表１及び表２に示した。
【００７０】
【表１】

【００７１】
【表２】

【００７２】
【表３】

【００７３】
【表４】

【００７４】
【表５】

【００７５】
【表６】

【００７６】
【表７】

【００７７】
【表８】

【００７８】
【表９】

【００７９】
【表１０】

【００８０】
【表１１】

【００８１】
【表１２】

【００８２】
【表１３】

【００８３】
【表１４】

【００８４】
【表１５】

【００８５】
【表１６】

【００８６】
【表１７】

【００８７】
【表１８】

【００８８】
【表１９】

【００８９】
【表２０】

【００９０】
【表２１】

【００９１】
【表２２】

【００９２】
【表２３】

【００９３】
【表２４】

【００９４】
試験例［ＭＤＲ受容体結合実験］
受容体標品としてラット大脳皮質から調製した粗ミトコンドリア画分を用いた。
【００９５】
［³Ｈ］標識リガンドとして［³Ｈ］ＰＫ１１１９５を用いた。
［³Ｈ］標識リガンドを用いた結合実験は、Journal of Pharmacology and Experimental Therapeutics, 262, 971(1992年）に記載された以下の方法で行った。
【００９６】
受容体標品の調製：ラット大脳皮質をテフロンホモジナイザーを用い、湿重量の１０倍容量の０.３２Ｍスクロースを含む１０ｍＭヘペス緩衝液（ｐＨ７.４）でホモジナイズした。ホモジネートを９００×ｇで１０分間遠心分離し、得られた上清を９、０００×ｇで１０分間遠心分離した。沈渣をヘペス緩衝液に、タンパク質濃度１ｍｇ／ｍｌになるように懸濁し、１２、０００×ｇで１０分間遠心分離した。得られた沈渣を５０ｍＭヘペス緩衝液（ｐＨ７.４）に懸濁し、粗ミトコンドリア画分とした。
【００９７】
ＭＤＲ結合実験：ミトコンドリア標品（１.０ｍｇタンパク質／ｍｌ）、［³Ｈ］ＰＫ１１１９５（２ｎＭ）及び被験薬を、４℃で９０分間反応させた。
【００９８】
反応終了後、０.３％ポリエチレンイミン処理したガラスフィルター（ＧＦ／Ｂ）に吸引濾過し、濾紙の放射能を液体シンチレーションスペクトロメーターにて測定した。
１０μＭＰＫ１１１９５存在下で反応させた時の結合を、［³Ｈ］ＰＫ１１１９５の非特異結合とし、総結合と非特異結合との差を特異的結合とした。一定濃度の［³Ｈ］ＰＫ１１１９５（２ｎＭ）と濃度を変えた被験薬を上記の条件で反応させることで抑制曲線を得、この抑制曲線から［³Ｈ］ＰＫ１１１９５結合を５０％抑制する被験薬の濃度（ＩＣ₅₀）を求め、結果を表３に示した。
【００９９】
【表２５】

【０１００】
【表２６】

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a medicine, and more particularly, to a medicine having high affinity for MDR.
[0002]
[Prior art]
Currently, the benzodiazepine (BZ) receptor is GABA _A Central Benzodiazepine Receptor (CBR) present on the receptor / ion channel complex, and Mitochondrial DBI Receptor (MDR, DBI; Neuroazecol Binding Inhibitor: Neuropharmacol., 30, 1425) present in the central nervous system (glia cells) and adrenal glands. -1433, 1991) (Clin. Neuropharmacol., 16, 401-417, 1993).
[0003]
MDR agonists are indirectly GABA via endogenous neurosteroids. _A Useful for symptoms (compulsive disorder, panic disorder) that are not satisfactory with conventional BZs due to its action on the Ion / ion channel complex and manifesting anxiolytic effects, and excess observed in BZs It may reduce side effects such as sedation or mental dependence. In addition, the ligand of MDR is indirectly GABA _A Through the receptor, it may be a therapeutic drug for sleep disorders, epilepsy, movement disorders associated with muscle rigidity, eating disorders, circulatory disorders, cognitive learning disorders, and drug addiction (Progress in Neurobiology, 38,379-395 1992; ibit, 49, 73-97, 1996, J. Neurochem. 58, 1589-1601; Neuropharmacol. 30, 1435-1440, 1991)). Furthermore, ligands of MDR are cancer (Biochimica et BIOphysica Acta, 1241, 453-470, 1995), lipid metabolism disorders (Eur. J. Pharmacol., 294, 601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075). -1079, 1996), cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstracts of the fifth international conference on AIDS, P458, 1989), Alzheimer's disease (Alzhemer Dis. Assoc. Disotd., 2,331-336,1988) and Huntington's disease (Brain Res., 248,396-401, 1982).
WO9533715, JP61040249, JP57208295, etc. have been reported as phenoxyaniline derivatives. However, these have not been reported on derivatives in which the substituent on the nitrogen atom of aniline is a hydrogen atom or an alkyl group and the carbonyl group is a substituent. Furthermore, the use of said patent is PGI, an anti-inflammatory drug based on its action on the arachidonic acid system ₂ It is an anti-arteriosclerotic drug and a thermosensitive recording material based on increased production, and there is no description of an anxiolytic action based on affinity for MDR or affinity for MDR.
[0004]
[Problems to be solved by the invention]
An object of the present invention is anxiety and related diseases that are effective for symptoms for which satisfactory therapeutic effects cannot be obtained with conventional BZs and that do not exhibit side effects such as excessive sedation or mental dependence, which are observed with BZs. Another object of the present invention is to provide a drug having high affinity for MDR, which exhibits therapeutic and preventive effects on central diseases such as depression and epilepsy. Furthermore, sleep disorders, movement disorders associated with muscle stiffness, eating disorders, circulatory disorders, cognitive learning disorders, drug addiction, cancer, lipid metabolism disorders, schizophrenia, cerebral infarction, AIDS, Alzheimer's disease, Huntington's chorea, etc. To provide therapeutic drugs.
[0005]
[Means for Solving the Problems]
As a result of intensive studies on the aryloxyaniline derivatives, the present inventors have found a novel aryloxyaniline derivative exhibiting high affinity for MDR and completed the present invention.
[0006]
The present invention will be described below.
The present invention provides compounds of formula [I]
[0007]
[Chemical formula 2]

[0008]
[Wherein Ar ¹ And Ar ² Are the same or different and each represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or a naphthyl group; ¹ Is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group, or the formula —NR ² (R ^Three ) (Where R ² And R ^Three Are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or a group that represents a 4- to 10-membered cyclic amino group together with an adjacent nitrogen atom. X represents a group represented by ¹ Represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoromethyl group, a carbamoyl group or an aminosulfonyl group; ¹ Represents a C1-C6 alkylene group with or without a branched chain or a single bond. Or an pharmaceutically acceptable salt thereof.
[0009]
In the present invention, the substituted phenyl group is an alkyl group having 1 to 10 carbon atoms, “a halogen atom, a hydroxyl group, an alkanoyloxy group having 1 to 10 carbon atoms, a carboxyl group, or an alkoxycarbonyl group” substituted with 1 to 1 carbon atoms. 10 alkyl groups, alkenyl groups having 2 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, alkylthio groups having 1 to 10 carbon atoms, formula -O-Z-R ^Four (In the formula, Z represents a C 1-10 alkylene group having or not having a branched chain, and R ^Four Represents an amino group, an amino group substituted with 1 or 2 alkyl groups having 1 to 7 carbon atoms, a cyclic amino group having 2 to 7 carbon atoms, a hydroxyl group, a carboxyl group, or an alkoxycarbonyl group. ), A alkanoyl group having 2 to 10 carbon atoms or a ketal body thereof, a formyl group or an acetal body thereof, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, and a nitrogen atom having 1 to A carbamoyl group substituted with 1 or 2 of 10 alkyl groups, an aminosulfonyl group, an aminosulfonyl group substituted with 1 or 2 of an alkyl group having 1 to 10 carbon atoms, a halogen atom and a nitro group A phenyl group substituted with 1 to 3 of arbitrarily selected groups, for example, 2-methylphenyl group, 2-propylphenyl group, 2-isopropylphenyl group, 2-cyclopentylphenyl group, 2- (1- Hydroxyethyl) phenyl group, 2-carboxymethylphenyl group, 2-methoxycarbonylphenyl group, 2- Nylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 2-hexyloxyphenyl group, 2-isopropoxyphenyl group, 2-cyclopentoxyphenyl group, 2 , 5-dimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 4-methylthiophenyl group, 2-isopropylthiophenyl group, 4-cyclohexylthiophenyl group, 2- (2-dimethylaminoethoxy) phenyl group, 2- (2-hydroxyethoxy) phenyl group, 2-carboxymethoxyphenyl group, 2-methoxycarbonylmethoxyphenyl group, 2-acetylphenyl group, 2- (2-methyl-1,3-dioxolan-2-yl) phenyl Group, 2-formylphenyl group, 2- (1,3-dioxolan-2-yl) phenyl 2-carboxylphenyl group, 2- (N-methylaminocarbonyl) phenyl group, 2- (N, N-dimethylaminocarbonyl) phenyl group, 2-aminocarbonylphenyl group, 2-aminosulfonylphenyl group, 4-amino Sulfonylphenyl group, 2-methylaminosulfonylphenyl group, 2-dimethylaminosulfonylphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4- Chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,4-difluorophenyl group, 2-nitrophenyl group, 2-aminophenyl group, 2-pyrrolidinophenyl group, 4- A dimethylaminophenyl group and the like. The substituted pyridyl group refers to a pyridyl group substituted with a linear or branched alkoxy group having 1 to 10 carbon atoms, such as a 2-methoxy-3-pyridyl group, a 3-methoxy-2-pyridyl group, 4 -Methoxy-3-pyridyl group and the like. A C1-C10 alkyl group shows a linear, branched or cyclic alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, cyclobutyl. Group, cyclopropylmethyl group, pentyl group, isopentyl group, cyclopentyl group, cyclobutylmethyl group, 1-ethylpropyl group, hexyl group, isohexyl group, cyclohexyl group, cyclopentylmethyl group, 1-ethylbutyl group, heptyl group, isoheptyl group Cyclohexylmethyl group, octyl group, nonyl group, decyl group and the like. The substituted alkyl group having 1 to 10 carbon atoms refers to an alkyl group substituted with “a hydroxyl group, an alkanoyloxy group, an alkanoyl group, an alkoxy group, a halogen atom, an azide group, an amino group, and a carboxyl group”. An acetyloxymethyl group, a methoxymethyl group, a chloromethyl group, a trifluoromethyl group, an azidomethyl group, an aminomethyl group, a dimethylaminomethyl group, a pyrrolidinomethyl group, and the like. The alkoxy group having 1 to 10 carbon atoms represents a linear, branched or cyclic alkoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a cyclopropylmethoxy group, A pentyloxy group, an isopentyloxy group, a hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group, and the like. R ² And R ^Three The alkyl group having 1 to 10 carbon atoms represented by the above formula represents a linear, branched or cyclic alkyl group, and therefore R ² And R ^Three Where-is an alkyl group having 1 to 10 carbon atoms ² (R ^Three Group represented by, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, cyclopropylmethylamino group, pentylamino group, isopentylamino group, cyclopentyl Amino group, cyclobutylmethylamino group, 1-ethylpropylamino group, hexylamino group, isohexylamino group, cyclohexylamino group, cyclopentylmethylamino group, 1-ethylbutylamino group, heptylamino group, isoheptylamino group, Cyclohexylmethylamino group, octylamino group, nonylamino group, decylamino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, N-methylethylamino group, N- A methylpropylamino group, an N-methylbutylamino group, an N-methylpentylamino group, an N-methylhexylamino group, an N-ethylpropylamino group, an N-ethylbutylamino group, an N-ethylpentylamino group, and the like. And the formula -NR ² (R ^Three ) Represents a cyclic amino group that may contain a nitrogen atom or an oxygen atom, such as a pyrrolidino group, piperidino group, piperazino group, N-methylpiperazino group, morpholino group. Etc. X ¹ The alkyl group having 1 to 5 carbon atoms represented by represents a linear, branched or cyclic alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, An isobutyl group, a cyclobutyl group, a cyclopropylmethyl group, and the like, and an alkoxy group having 1 to 5 carbon atoms represents a "linear, branched or cyclic" alkoxy group, such as a methoxy group, an ethoxy group, A propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a cyclopropylmethoxy group, and the like. Y ¹ Examples of the alkylene group having 1 to 6 carbon atoms, which may or may not have a branched chain, include a methylene group, an ethylene group, a propylene group, a methylmethylene group, and a dimethylmethylene group. The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0010]
Further, the pharmaceutically acceptable salt in the present invention is, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid. And salts with organic acids such as sodium ions, potassium ions and calcium ions, salts with organic bases such as diethanolamine, and ammonium salts.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The compound of the formula [I] can be produced by the following general production methods 1 to 6 (in the following reaction formula, Ar ¹ , Ar ² , R ¹ , X ¹ And Y ¹ Is the same as above, Y ² Is a single bond or a C1-C5 alkylene group substituted or unsubstituted by a C1-C3 alkyl group, R ^Five Represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom, and X ² Represents an acyloxy group having 1 to 10 carbon atoms, a chlorine atom, a bromine atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms; ^Three Represents a chlorine atom, a bromine atom or an iodine atom. )
[General production method 1]
[0012]
[Chemical 3]

[0013]
Reduction of aniline derivative (1) and carbonyl derivative (2) in an inert solvent in the presence or absence of an acid catalyst after the reaction, or aniline derivative (1) in an inert solvent in the presence or absence of an acid catalyst Compound (3) can be obtained by reducing a mixture of carbonyl derivative (2) and carbonyl derivative (2). The compound (4) of the present invention can be obtained by reacting the compound (3) with an N-carbonylating agent in the presence or absence of a base in an inert solvent. In addition, after reacting phosgene with the compound (3) as an N-carbonylating agent to form a chlorocarbonyl derivative, the compound of the present invention (4) is reacted with alcohols or amines in the presence or absence of a base. ) Can be obtained.
[0014]
Examples of the acid catalyst include hydrogen halides such as hydrogen chloride and hydrogen bromide, inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and tosylic acid, such as PPTS, and piperidine / hydrochloride.
[0015]
For the reduction, for example, a boron-based reducing agent such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, an aluminum-based reducing agent such as lithium aluminum hydride, or a catalyst of palladium, platinum dioxide, Raney nickel, etc. By hydrogenation used in Examples of the N-carbonylating agent include acyl halides, organic acid anhydrides, alkoxycarbonyl halides, carbamoyl halides, cyanic acid (generated from potassium cyanate and acetic acid in the reaction solution), isocyanate, and the like. The base is an organic amine such as triethylamine, diisopropylethylamine or pyridine, or an inorganic base such as potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium. Inert solvents include, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as chloroform and dichloromethane, acetonitrile, water, or a mixture thereof. Such as a solvent.
[0016]
[General production method 2]
[0017]
[Formula 4]

[0018]
R of compound (3) ² Compound (7) in which is a hydrogen atom is an inert solvent in the presence or absence of a carboxylic acid anhydride, acyl halide, carboxylic acid or carboxylic acid ester represented by aniline derivative (1) and compound (5) and a base. It can also be synthesized by reacting in the middle to obtain an amide compound (6), which is reacted with a reducing agent in an inert solvent.
[0019]
[General production method 3]
[0020]
[Chemical formula 5]

[0021]
The aniline derivative (1) is reacted with an N-carbonylating agent in the presence or absence of a base in an inert solvent to give a compound (8), and then, in the presence of a halide (9) and a base, correlation transfer is performed as necessary. This invention compound (10) can be obtained by reacting in an inert solvent using a catalyst, copper powder, cuprous halide and the like. In addition, after reacting phosgene with the compound (1) as the N-carbonylating agent to form a chlorocarbonyl derivative, the compound (8) can also be obtained by reacting with alcohols or amines in the presence of a base. .
[0022]
Examples of the N-carbonylating agent include acyl halides, organic acid anhydrides, alkoxycarbonyl halides, carbamoyl halides, cyanic acid (generated from potassium cyanate and acetic acid in the reaction solution), and isocyanate. Examples of the base include organic amines such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and sodium metal, alcoholates such as potassium t-butoxide and sodium ethoxide. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide and crown ethers such as 18-crown-6 ether. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, ketone solvents such as acetone, acetonitrile N, N-dimethylformamide, nitrobenzene, water or a mixed solvent thereof.
[0023]
[General production method 4]
Ar ¹ , Ar ² When one or both of them contain a nitro group, this nitro group can be converted to an amino group by hydrogenation or metal reduction. This amino group reacts with a halogenated compound in an inert solvent using a phase transfer catalyst as necessary in the presence of a base, and is substituted with a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. Converted to the base.
[0024]
Here, hydrogenation refers to hydrogenation using palladium, platinum dioxide, Raney nickel, etc. as a catalyst, and metal reduction refers to divalent tin salts such as tin and stannous chloride, iron and ferrous chloride A reduction under acidic, neutral or basic conditions, usually using a metal or metal salt such as a valent iron salt or zinc. Examples of the base include organic amines such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and sodium metal, alcoholates such as potassium t-butoxide and sodium ethoxide. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide and crown ethers such as 18-crown-6 ether. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, acetonitrile, N, N-dimethylformamide. , Water or a mixed solvent thereof.
[0025]
[General production method 5]
Ar ¹ , Ar ² When one or both of them contain an acyloxy group, the acyloxy group can be converted to a hydroxyl group by hydrolysis under acidic or basic conditions. This hydroxyl group reacts with a halogenated compound in an inert solvent using a phase transfer catalyst as necessary in the presence of a base, to obtain a linear or branched alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted amino group. It is converted into an alkoxy group having 1 to 10 carbon atoms substituted with a linear or branched alkoxy group having 1 to 10 carbon atoms, a carboxyl group or an alkoxycarbonyl group.
[0026]
Here, acidic or basic conditions include inorganic acids such as hydrochloric acid and sulfuric acid, or inorganic bases such as sodium hydroxide and potassium hydroxide, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetone and the like. It shows use in ketones, acetonitrile, N, N-dimethylformamide, water or a mixed solvent thereof. Examples of the base include organic amines such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as potassium carbonate, sodium hydroxide, sodium hydride and sodium metal, alcoholates such as potassium t-butoxide and sodium ethoxide. Examples of the phase transfer catalyst include quaternary ammonium salts such as benzyltriethylammonium bromide and crown ethers such as 18-crown-6 ether. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene and benzene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, acetonitrile, N, N-dimethylformamide. , Water or a mixed solvent thereof.
[0027]
[General production method 6]
Ar ¹ , Ar ² When one or both of them contain an alkoxycarbonyl group, this alkoxycarbonyl group is converted into a carboxyl group by the usual ester hydrolysis conditions. Further, the carboxyl group is converted into an alkoxycarbonyl group having 1 to 10 carbon atoms by esterification, and a primary or secondary alkylaminocarbonyl group or aminocarbonyl group having 1 to 10 carbon atoms by amidation.
[0028]
Here, the hydrolysis conditions are, for example, bases such as sodium hydroxide, potassium hydroxide and sodium carbonate, or inorganic acids such as hydrochloric acid and sulfuric acid, alcohol solvents such as methanol and ethanol, ketone systems such as acetone and the like. It shows reacting in an inert solvent such as a solvent. Esterification refers to converting an alkyl compound or dialkyl sulfuric acid substituted with a chlorine atom, bromine atom or iodine atom into an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, such as sodium methoxide. Reaction with alcoholates such as potassium t-butoxide, organic bases such as triethylamine, diisopropylethylamine, or alcohols with acids such as hydrogen chloride, sulfuric acid. Amidation refers to conversion of a carboxyl group to an acid halide with thionyl chloride, triphenylphosphine-carbon tetrachloride, etc., and then reacting with the corresponding amine derivative, or a conventional amidation such as mixed acid anhydride method, dicyclohexylcarbodiimide method, etc. Indicates.
[0029]
[General production method 7]
Ar ¹ , Ar ² When one or both of them contain a formyl group or an acyl group, the carbonyl group of the formyl group or acyl group reacts with a Wittig reagent and is converted to an alkenyl group. Furthermore, the alkenyl group is converted to an alkyl group by reduction.
[0030]
Here, the Wittig reagent refers to triphenylalkylphosphonium halide or diethylalkylphosphonate having an alkyl group having 1 to 9 carbon atoms, such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, toluene, benzene and the like. Hydrocarbons, halogenated hydrocarbons such as methylene chloride, chloroform, etc., in inert solvents such as acetonitrile, N, N-dimethylformamide, sodium hydride, potassium t-butoxide, sodium ethoxide, n-butyllithium, etc. Used with a base and a phase transfer catalyst such as a quaternary ammonium salt such as benzyltriethylammonium bromide or a crown ether such as 18-crown-6 ether, if necessary. Reduction means hydrogenation using palladium, platinum dioxide, Raney nickel or the like as a catalyst.
[0031]
[General production method 8]
Ar ¹ , Ar ² When one or both of them contain a formyl group or an acyl group, the carbonyl group of the formyl group or acyl group reacts with a Grignard reagent to be converted into a secondary or tertiary alcohol form. Further, the secondary alcohol is converted to an acyl group by being oxidized with various oxidizing agents.
[0032]
Here, the Grignard reagent represents an alkyl or alkenyl magnesium halide having 1 to 9 carbon atoms, such as methyl magnesium bromide, ethyl magnesium bromide, and the like. Various oxidizing agents refer to metal oxidizing agents such as swan oxidation using oxalyl chloride-dimethyl sulfoxide, chromium-based oxidizing agents, and manganese dioxide.
[0033]
In order to use the compound of the present invention as a medicine, the compound of the present invention is added with usual bulking agents, binders, disintegrants, pH adjusters, solubilizers, etc., and tablets, pills, capsules are added by conventional formulation techniques. Preparations, granules, powders, solutions, emulsions, suspensions, injections and the like.
[0034]
The compound of the present invention can be orally or parenterally administered to an adult patient at a dose of 0.1 to 500 mg / day once or several times a day. This dose can be appropriately increased or decreased depending on the type of disease, the age, weight and symptoms of the patient.
[0035]
【The invention's effect】
According to the present invention, a drug having high affinity for MDR is provided. Therefore, these are central diseases such as anxiety and related diseases, depression, epilepsy, sleep disorders, cognitive learning disorders, schizophrenia, movement disorders associated with muscle rigidity, eating disorders, circulatory disorders, drug dependence, cancer It is useful as a therapeutic and prophylactic agent for lipid metabolism disorders, cerebral infarction, AIDS, Alzheimer's disease and Huntington's chorea.
[0036]
【Example】
The present invention will be specifically described below with reference to examples and test examples.
Example 1
Synthesis of N-acetyl-N- (2-isopropoxybenzyl) -2-phenoxyaniline
(1) 1.64 g of 2-isopropoxybenzaldehyde was dissolved in 10 ml of methanol, 1.85 g of 2-aminodiphenyl ether was added, and the mixture was stirred at room temperature for 30 minutes and then cooled with ice water. To this cooled reaction solution, 1.50 g of sodium borohydride was added little by little, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 30 minutes. An aqueous acetic acid solution (1.5 ml of acetic acid-30 ml of water) was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes at room temperature and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 25) to give oily N- (2-isopropoxybenzyl) -2-phenoxy. 2.65 g of aniline was obtained.
[0037]
(2) 2.65 g of N- (2-isopropoxybenzyl) -2-phenoxyaniline and 1.5 ml of triethylamine were dissolved in 30 ml of tetrahydrofuran, and 0.8 ml of acetyl chloride was added dropwise to this solution with stirring, followed by stirring for 30 minutes. . The reaction mixture was poured into water, extracted with ethyl acetate, washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-isopropoxybenzyl). 2.92 g of -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0038]
Example 2
Synthesis of N-acetyl-N- (2,4-dimethoxybenzyl) -2-phenoxyaniline
(1) 3.70 g of 2-aminodiphenyl ether and 3.70 g of 2,4-dimethoxybenzaldehyde were dissolved in 60 ml of methanol, 70 mg of platinum oxide was added thereto, and the mixture was stirred overnight at room temperature under a hydrogen stream. 30 ml of chloroform was added to the reaction mixture, and after dissolving the precipitate, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 5.06 g of N- (2,4-dimethoxybenzyl) -2-phenoxyaniline.
[0039]
(2) 0.76 g of acetic anhydride was added to a solution of 1.18 g of pyridine in 1.00 g of N- (2,4-dimethoxybenzyl) -2-phenoxyaniline, and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-acetyl-N- (2,4- 1.09 g of dimethoxybenzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0040]
Example 3
Synthesis of N-acetyl-N- (2-chlorobenzyl) -2-phenoxyaniline (1) In a solution of 28.5 g of 2-phenoxyaniline and 25.8 ml of triethylamine in 250 ml of methylene chloride, 11.5 ml of acetyl chloride was ice-cooled. Added dropwise. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The extract was washed successively with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to obtain 33.7 g of N-acetyl-2-phenoxyaniline.
[0041]
(2) 2.00 g of N-acetyl-2-phenoxyaniline was added to a suspension of 400 mg of sodium hydride (60% in oil) in 30 ml of dimethylformamide at room temperature, and the mixture was further stirred at room temperature for 30 minutes. To this solution, 1.64 g of 2-chlorobenzyl chloride was added dropwise at room temperature with stirring. After stirring for 30 minutes, ice water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-chlorobenzyl). ) -2-phenoxyaniline 2.92 g was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0042]
Example 4
Synthesis of N-aminocarbonyl-N- (2-methoxybenzyl) -2-phenoxyaniline
1.54 g of N- (2-methoxybenzyl) -2-phenoxyaniline synthesized in the same manner as in (1) of Example 1 was dissolved in 20 ml of acetic acid, and an aqueous potassium cyanate solution (1.23 g of potassium cyanate- Water (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-aminocarbonyl-N- (2-methoxy). 1.69 g of (benzyl) -2-phenoxyaniline was obtained.
[0043]
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0044]
Example 5
Synthesis of N- (2-methoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline
A solution of 2.03 g of N- (2-methoxybenzyl) -2-phenoxyaniline and 25 ml of methylene chloride in 1.03 g of diisopropylethylamine was added dropwise to 14 ml of a methylene chloride solution of 751 mg of triphosgene with stirring, and the mixture was stirred at room temperature for 5 minutes. This solution was stirred with an excess amount of methylamine, stirred at room temperature for 5 minutes, and concentrated under reduced pressure. The reaction mixture was poured into ethyl acetate, washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate to give N- (2-methoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline 2 0.02 g was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0045]
Example 6
Synthesis of N- (2,5-dimethoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline
Diphenylphosphoryl azide (12.9 ml) was added to a solution of acetic acid (3.43 ml) and triethylamine (8.36 ml) in benzene (90 ml), and the mixture was heated to reflux for 2 hours. To this reaction solution, 2.01 g of N- (2,5-dimethoxybenzyl) -2-phenoxyaniline synthesized in the same manner as in (1) of Example 2 was added, and the mixture was heated to reflux for 6 hours. The reaction mixture was poured into water, the organic phase was separated, washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 2), recrystallized from diethyl ether, and N- (2, 1.20 g of 5-dimethoxybenzyl) -N- (N-methylaminocarbonyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0046]
Example 7
Synthesis of N- (2-methoxybenzyl) -N-methoxycarbonyl-2-phenoxyaniline
(1) To 14 ml of methylene chloride solution of 775 mg of triphosgene, 25 ml of methylene chloride in which 2.16 g of N- (2-methoxybenzyl) -2-phenoxyaniline and 1.10 g of diisopropylethylamine were dissolved was slowly added dropwise with stirring. Stir for minutes. The reaction mixture was concentrated under reduced pressure, poured into ethyl acetate, washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 15), and N-chlorocarbonyl-N- (2-methoxybenzyl). There were obtained 2.57 g of -2-phenoxyaniline.
[0047]
(2) 1.22 g of N-chlorocarbonyl-N- (2-methoxybenzyl) -2-phenoxyaniline dissolved in 5 ml of tetrahydrofuran was added dropwise to 5 ml of a tetrahydrofuran solution of 226 mg of sodium methoxide under ice-cooling at room temperature. Stir for 20 minutes. The reaction mixture was concentrated under reduced pressure, poured into water, extracted with ethyl acetate, washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 6), recrystallized from ethyl acetate, and N- (2-methoxybenzyl). 1.18 g of -N-methoxycarbonyl-2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0048]
Example 8
Synthesis of N-aminoacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline
(1) 1.51 g of N-chloroacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline synthesized in the same manner as in Example 1 and 10 ml of a dimethylformamide solution of 770 mg of sodium azide were stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-azidoacetyl-N- (2-methoxy). 1.55 g of (benzyl) -2-phenoxyaniline was obtained.
[0049]
(2) N-azidoacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline (647 mg) was dissolved in methanol (7 ml), platinum oxide (20 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, concentrated under reduced pressure, purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 6), recrystallized from ethyl acetate-isopropyl ether, and N-aminoacetyl. 0.24 g of -N- (2-methoxybenzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0050]
Example 9
Synthesis of N-hydroxyacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline
(1) 1.01 g of N-chloroacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline, 1.30 g of sodium acetate, and 170 mg of tetra-n-butylammonium bromide in 10 ml of benzene at 80 ° C. for 5 hours Stir. The reaction mixture was poured into ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-acetoxyacetyl-N- (2-methoxy). 1.03 g of (benzyl) -2-phenoxyaniline was obtained.
[0051]
(2) 525 mg of N-acetoxyacetyl-N- (2-methoxybenzyl) -2-phenoxyaniline was dissolved in 6 ml of methanol, 537 mg of potassium carbonate was added, and after stirring at 50 ° C. for 7 hours, the reaction mixture was poured into water, Extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3), allowed to stand at room temperature, and then crystalline N-hydroxyacetyl- 450 mg of N- (2-methoxybenzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0052]
Example 10
Synthesis of N-acetyl-N- (2-pyrrolidinobenzyl) -2-phenoxyaniline monohydrochloride
(1) 8.00 g of N-acetyl-N- (2-nitrobenzyl) -2-phenoxyaniline synthesized in the same manner as in Example 3 was dissolved in 80 ml of methanol, and 66 mg of platinum dioxide was added at room temperature under a hydrogen atmosphere. Stir overnight. After adding 40 ml of chloroform to the reaction mixture to dissolve the precipitate, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 6.88 g of N-acetyl-N- (2-aminobenzyl) -2-phenoxyaniline.
[0053]
(2) N-acetyl-N- (2-aminobenzyl) -2-phenoxyaniline 1.00 g, 1,4-dibromobutane 680 mg, potassium carbonate 1.03 g, and potassium iodide 50 mg were added to N, N-dimethylformamide. The solution was stirred at 70 ° C. in 10 ml for 3 days. The reaction mixture was poured into water, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3). The obtained product was dissolved in 5 ml of ether, 0.9 ml of 4N hydrogen chloride-ethyl acetate solution was added, the solution was concentrated, recrystallized with ethyl acetate-ether, and N-acetyl-N- ( 0.49 g of 2-pyrrolidinobenzyl) -2-phenoxyaniline monohydrochloride was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0054]
Example 11
Synthesis of N-acetyl-N- (2-carboxymethoxybenzyl) -2-phenoxyaniline
(1) 1.74 g of 2-acetoxybenzaldehyde and 1.85 g of 2-phenoxyaniline were dissolved in 30 ml of methanol, stirred for 1 hour at room temperature, added with 3.00 g of sodium borohydride, and stirred at the same temperature for 30 minutes. An aqueous acetic acid solution (3.0 ml of acetic acid-60 ml of water) was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes at room temperature and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure. The residue and 50 ml of a methylene chloride solution of 4 ml of triethylamine were cooled to 0 ° C., and 2.00 ml of acetyl chloride was added dropwise with stirring. After stirring for 20 minutes at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure to obtain crude N-acetyl-N- (2-acetyloxybenzyl) -2-phenoxyaniline.
[0055]
This was dissolved in 40 ml of methanol solution, 14 ml of 5% aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into water and extracted with ethyl acetate. The extract was washed successively with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was crystallized with diisopropyl ether to obtain 1.86 g of N-acetyl-N- (2-hydroxybenzyl) -2-phenoxyaniline.
[0056]
(2) To a solution of 666 mg of N-acetyl-N- (2-hydroxybenzyl) -2-phenoxyaniline in 10 ml of N, N-dimethylformamide was added 60 mg of NaH / oil 80 mg, and the mixture was stirred at room temperature for 30 minutes. To this, 0.3 ml of methyl bromoacetate was added and stirred at room temperature for 30 minutes. The reaction mixture is poured into 0.5N hydrochloric acid, extracted with ethyl acetate, washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous sodium sulfate, filtered, and filtrate. Was concentrated under reduced pressure to obtain crude N-acetyl-N- (2-methoxycarbonylmethoxybenzyl) -2-phenoxyaniline.
[0057]
This was dissolved in 10 ml of methanol, 5 ml of 5% aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 2N hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was concentrated under reduced pressure, and the residue was crystallized with diisopropyl ether to obtain 745 mg of N-acetyl-N- (2-carboxymethoxybenzyl) -2-phenoxyaniline.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0058]
Example 12
Synthesis of N-acetyl-N- (2-propylbenzyl) -2-phenoxyaniline
(1) N-acetyl-N- (2- (1,3-dioxolan-2-yl) benzyl) -2-phenoxyaniline synthesized in the same manner as in Example 3 was dissolved in 40 ml of acetone, and p- Toluenesulfonic acid monohydrate (0.10 g) was added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and acetone was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3), dried and allowed to stand at room temperature to give crystalline N-acetyl- 2.12 g of N- (2-formylbenzyl) -2-phenoxyaniline was obtained as crystals.
[0059]
(2) Under a nitrogen stream, a suspension solution of 4.34 g of ethyltriphenylphosphonium bromide in 20 ml of tetrahydrofuran was added to a 1.63 M n-butyllithium / hexane solution 6.63 ml while keeping the reaction solution temperature at -15 to -10 ° C. Was dripped. The reaction solution was slowly warmed to room temperature and stirred at room temperature for 20 minutes, and then a solution of N-acetyl-N- (2-formylbenzyl) -2-phenoxyaniline (1.01 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture was further stirred for 1 hour. did. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure, and 859 mg of oily N-acetyl-N- (2- (propen-1-yl) benzyl) -2-phenoxyaniline was dissolved in about 3: 2 geometric isomer. Obtained as a mixture.
[0060]
(3) 757 mg of N-acetyl-N- (2- (propen-1-yl) benzyl) -2-phenoxyaniline (a mixture of about 3: 2 geometric isomers) was dissolved in 7 ml of ethanol, and 15 mg of platinum oxide was dissolved. In addition, the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst in the reaction solution was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-propyl). 647 mg of (benzyl) -2-phenoxyaniline was obtained. Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0061]
Example 13
Synthesis of N-acetyl-N- (2-acetylbenzyl) -2-phenoxyaniline
(1) An ice-cooled 1M methylmagnesium chloride / tetrahydrofuran solution 5.25 ml of tetrahydrofuran 15 ml diluted solution of N-acetyl-N- (2-formylbenzyl) -2-phenoxyaniline 1.20 g of tetrahydrofuran 7 ml The solution was added dropwise and further stirred at room temperature for 1 hour. The reaction solution was ice-cooled again, a saturated aqueous ammonium chloride solution was added thereto, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1) to give oily N-acetyl-N- (2- (1 1.19 g of -hydroxyethyl) benzyl) -2-phenoxyaniline were obtained.
[0062]
(2) A solution of 0.22 ml of oxalyl chloride in 13.5 ml of dichloromethane was cooled to −70 ° C. or lower with dry ice-acetone, and a solution of 0.24 ml of dimethyl sulfoxide in 0.9 ml of dichloromethane was added dropwise to the solution. Stir for minutes. To this was added dropwise a solution of 0.48 g of N-acetyl-N- (2- (1-hydroxyethyl) benzyl) -2-phenoxyaniline in 4.5 ml of dichloromethane, and the temperature of the reaction solution was gradually raised to -45 ° C. The mixture was further stirred at the same temperature for 1 hour. To this reaction solution, 1.34 ml of triethylamine was added dropwise at -40 ° C or lower, and the mixture was further stirred at 0 ° C for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1), recrystallized from ethyl acetate-hexane, and N-acetyl. 0.41 g of -N- (2-acetylbenzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0063]
Example 14
Synthesis of N-acetyl-N- (2-dimethylaminocarbonylbenzyl) -2-phenoxyaniline
(1) 2.26 g of N-acetyl-N- (2-methoxycarbonylbenzyl) -2-phenoxyaniline synthesized in the same manner as in Example 2 was added to a mixed solution of 23 ml of methanol and 3.6 ml of 2N aqueous potassium hydroxide solution. And stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 1) to give oily N-acetyl-N- (2-carboxybenzyl). ) -2-phenoxyaniline (2.01 g) was obtained.
[0064]
(2) N-acetyl-N- (2-carboxybenzyl) -2-phenoxyaniline (0.50 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and hexamethylphosphoramide (0.1 ml), and thionyl chloride (0.2 ml) was added. Stir at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 50% dimethylamine aqueous solution was added dropwise with stirring. The reaction mixture was poured into water, extracted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to give oily N-acetyl-N- (2-dimethylamino). 0.49 g of carbonylbenzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0065]
Example 15
Synthesis of N-acetyl-N- (2-ethoxycarbonylbenzyl) -2-phenoxyaniline
0.50 g of N-acetyl-N- (2-carboxybenzyl) -2-phenoxyaniline, 0.20 g of anhydrous potassium carbonate and 0.22 ml of diethyl sulfate were stirred in 10 ml of N, N-dimethylformamide for 3 hours at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 7) to give oily N-acetyl-N- (2-ethoxycarbonyl). 0.50 g of (benzyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0066]
Example 16
Synthesis of N-acetyl-N- (2-methoxyphenyl) -2-phenoxyaniline
2.27 g of N-acetyl-2-phenoxyaniline, 1.3 ml of 2-iodoanisole, 1.38 g of potassium carbonate, 133 mg of copper powder and 200 mg of copper bromide were heated to reflux in 20 ml of nitrobenzene for 8 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, and insoluble material was filtered off. The filtrate was washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 4) to give oily N-acetyl-N- (2-methoxyphenyl)- 660 mg of 2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0067]
Example 17
Synthesis of N-acetyl-N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline
(1) 4.98 g of 2-methoxyphenylacetic acid and 0.5 ml of N, N-dimethylformamide were dissolved in 30 ml of toluene, 4 ml of thionyl chloride was added, and the mixture was stirred at 70 ° C. for 1 hour and concentrated under reduced pressure. The residue was dissolved in 20 ml of methylene chloride, which was added dropwise to a solution of 5.55 g of 2-phenoxyaniline and 4.6 ml of triethylamine in 30 ml of methylene chloride with stirring, and further stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate, washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated under reduced pressure.
[0068]
The residue was dissolved in 40 ml of tetrahydrofuran, and this was added dropwise to a suspension of 1.70 g of lithium aluminum hydride in 40 ml of tetrahydrofuran and heated to reflux for 30 minutes. The reaction mixture was cooled with ice water, and a saturated aqueous sodium sulfate solution was added dropwise with stirring. The insoluble material in the reaction solution was filtered off through an anhydrous magnesium sulfate plate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate-hexane = 1: 10) to give oily N- There were obtained 8.23 g of (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline.
[0069]
(2) Using N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline (3.19 g), reacting in the same manner as in (2) of Example 1, after-treatment, crystallizing with hexane, N- 2.95 g of acetyl-N- (2- (2-methoxyphenyl) ethyl) -2-phenoxyaniline was obtained.
Tables 1 and 2 show the structures and physical property data of this compound and the compounds obtained in the same manner.
[0070]
[Table 1]

[0071]
[Table 2]

[0072]
[Table 3]

[0073]
[Table 4]

[0074]
[Table 5]

[0075]
[Table 6]

[0076]
[Table 7]

[0077]
[Table 8]

[0078]
[Table 9]

[0079]
[Table 10]

[0080]
[Table 11]

[0081]
[Table 12]

[0082]
[Table 13]

[0083]
[Table 14]

[0084]
[Table 15]

[0085]
[Table 16]

[0086]
[Table 17]

[0087]
[Table 18]

[0088]
[Table 19]

[0089]
[Table 20]

[0090]
[Table 21]

[0091]
[Table 22]

[0092]
[Table 23]

[0093]
[Table 24]

[0094]
Test example [MDR receptor binding experiment]
A crude mitochondrial fraction prepared from rat cerebral cortex was used as a receptor preparation.
[0095]
[ ^Three H] As a labeled ligand [ ^Three H] PK11195 was used.
[ ^Three Binding experiments using H] -labeled ligand were performed by the following method described in Journal of Pharmacology and Experimental Therapeutics, 262, 971 (1992).
[0096]
Preparation of receptor preparation: Rat cerebral cortex was homogenized using a Teflon homogenizer with 10 mM hepes buffer (pH 7.4) containing 0.32 M sucrose in a volume 10 times wet weight. The homogenate was centrifuged at 900 × g for 10 minutes, and the resulting supernatant was centrifuged at 9,000 × g for 10 minutes. The sediment was suspended in Hepes buffer so that the protein concentration became 1 mg / ml, and centrifuged at 12,000 × g for 10 minutes. The obtained sediment was suspended in 50 mM Hepes buffer (pH 7.4) to obtain a crude mitochondrial fraction.
[0097]
MDR binding experiment: mitochondrial preparation (1.0 mg protein / ml), [ ^Three H] PK11195 (2 nM) and the test drug were reacted at 4 ° C. for 90 minutes.
[0098]
After completion of the reaction, the solution was suction filtered through a glass filter (GF / B) treated with 0.3% polyethyleneimine, and the radioactivity of the filter paper was measured with a liquid scintillation spectrometer.
Binding when reacted in the presence of 10 μMPK11195, ^Three H] PK11195 was defined as nonspecific binding, and the difference between total binding and nonspecific binding was defined as specific binding. [Concentration of [ ^Three H] PK11195 (2 nM) and a test drug with different concentrations were reacted under the above conditions to obtain an inhibition curve. From this inhibition curve, [ ^Three H] concentration of test drug that inhibits PK11195 binding by 50% (IC ₅₀ ) And the results are shown in Table 3.
[0099]
[Table 25]

[0100]
[Table 26]

Claims (3)

formula

[Wherein Ar ¹ and Ar ² are the same or different and each represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or a naphthyl group, and R ¹ represents a hydrogen atom, a substituted or unsubstituted carbon number of 1 10 alkyl group, an alkoxy group having 1 to 10 carbon atoms, in substituted or unsubstituted phenyl group, or the formula -NR ² (R ³⁾ (wherein, R ² and R ³ is a hydrogen atom or a carbon atoms the same or different 1 represents an alkyl group of 1 to 10 or represents a group of 4 to 10-membered cyclic amino group together with an adjacent nitrogen atom.), X ¹ represents a hydrogen atom, carbon An alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoromethyl group, a carbamoyl group or an aminosulfonyl group, and Y ¹ having a branched chain or not. 1-6 al A xylene group or a single bond is shown. Or a pharmaceutically acceptable salt thereof, wherein the substituted phenyl group is substituted with an alkyl group having 1 to 10 carbon atoms, “halogen atom, hydroxyl group, carboxyl group or alkoxycarbonyl group” An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, a formula —O—Z—R ⁴ (wherein Z is An alkylene group having 1 to 10 carbon atoms having or not having a branched chain, wherein R ⁴ is an amino group, an amino group substituted with 1 or 2 of an alkyl group having 1 to 7 carbon atoms, or an alkyl group having 2 to 7 carbon atoms; A cyclic amino group, a hydroxyl group, a carboxyl group or an alkoxycarbonyl group.), A alkanoyl group having 2 to 10 carbon atoms or a ketal form thereof, a formyl group or an acetate thereof. Body, carboxyl group, alkoxycarbonyl group having 2 to 10 carbon atoms, carbamoyl group, carbamoyl group in which the nitrogen atom is substituted with 1 or 2 alkyl groups having 1 to 10 carbon atoms, aminosulfonyl group, nitrogen atom having carbon number 1 to 10 alkyl groups substituted with 1 or 2 aminosulfonyl groups, halogen groups and phenyl groups substituted with 1 to 3 groups arbitrarily selected from a nitro group, and the substituted pyridyl group is carbon It is a pyridyl group substituted with 1 to 3 alkoxy groups of 1 to 10.   A medicament comprising the aryloxyaniline derivative according to claim 1 or a pharmaceutically acceptable salt thereof.   A ligand of MDR comprising the aryloxyaniline derivative or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.