JP4011780B2 - Dihydroquinoline derivatives - Google Patents
Dihydroquinoline derivatives Download PDFInfo
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- JP4011780B2 JP4011780B2 JP05940699A JP5940699A JP4011780B2 JP 4011780 B2 JP4011780 B2 JP 4011780B2 JP 05940699 A JP05940699 A JP 05940699A JP 5940699 A JP5940699 A JP 5940699A JP 4011780 B2 JP4011780 B2 JP 4011780B2
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- 0 COc1cc(C(N(CC2)CCS2(*)C(C(N(*)c2cc(*)c(*)cc22)=O)=C2[O-])=O)cc(*)c1OC Chemical compound COc1cc(C(N(CC2)CCS2(*)C(C(N(*)c2cc(*)c(*)cc22)=O)=C2[O-])=O)cc(*)c1OC 0.000 description 2
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Description
【０００１】
【発明の属する技術分野】
本発明は医薬有途を有する新規なジヒドロキノリン誘導体及びその薬理学的に許容しうる塩に関する、当該化合物は優れた鎮痛作用を有し、医薬として有用である。
【０００２】
【従来の技術】
本発明のジヒドロキノリン誘導体は、文献未載の新規化合物である。本発明者らは、従来より、医薬品として価値ある薬理活性を有する化合物の研究、開発を進めてきており、その過程で先に血糖降下作用を有し血糖降下剤として糖尿病の治療及び予防に有効な一連のジヒドロキノリン化合物の合成に成功し、該化合物に係る発明を特許出願した（特願平９―２５５６５８号公報参照）。
【０００３】
【発明が解決しようとする課題】
本発明は医薬品、特に鎮痛作用を有し医薬として有用な新規化合物を提供することを目的とする。
【０００４】
【課題を解決するための手段】
引き続く研究の結果、本発明者らは、上記公知化合物と共通するジヒドロキノリン骨格を有するが、特にその３位置換基において明確に区別される他の一連の新規なジヒドロキノリン誘導体の合成に成功すると共に、之等の新規な誘導体が上記先の化合物の有する血糖降下作用とは本質的に異なり、しかも該作用からは予測できない鎮痛作用を有することを見出し、ここに上記課題に合致する本発明を完成するに至った。
【０００５】
すなわち、本発明は、（１）一般式
【化２】
【０００６】
（２） 請求項１の一般式において、Ｒ１ 、Ｒ２ 、Ｒ３ 及びＲ４ はそれぞれ水素原子、アルコキシ基又はハロゲン原子を、Ｒ５ は水素原子又はアルキル基を、Ｒ６ 及びＲ７ はそれぞれ基−Ａ−Ｏ−Ｒ８ （式中、Ａはアルキレン基を、Ｒ８ はアルコキシ基３個を有するベンゾイル基又はアルコキシ基３個を有するベンジル基を示す）を示すか、Ｒ６ がアルキル基でＲ７ が基−Ａ−Ｚ−Ｒ９ （式中、Ａは前記に同じ。Ｚは−Ｏ−、−ＮＨ−又は−Ｎ（アルキル基）−を、Ｒ９ は▲１▼アルカノイル基、▲２▼フェニル基、▲３▼ベンゼン環上にアルコキシ基１〜３個を有することのあるベンジル基、▲４▼ベンゼン環上にアルコキシ基３個を有することのあるシンナモイル基又は▲５▼置換基としてアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基を示す）を示すか、或いはＲ６及びＲ７ は互いに結合してそれらが結合する硫黄原子と共に、４位が▲１▼２−フロイル基、▲２▼アルコキシ基の１〜３個を有するベンゾイル基若しくは▲３▼ベンゼン環上にアルコキシ基３個を有することのあるシンナモイル基で置換されたテトラヒドロ−４Ｈ−１，４−チアジン環を形成してもよい請求項１のジヒドロキノリン誘導体。
【０００７】
（３） Ｒ１ 及びＲ４ がそれぞれ水素原子である請求項２に記載のジヒドロキノリン誘導体。
（４） Ｒ２ 及びＲ３ がそれぞれ水素原子又はアルコキシ基であるか、或いは一方が水素原子で他方がハロゲン原子である請求項３に記載のジヒドロキノリン誘導体。
（５） Ｒ６ がアルキル基でＲ７ が基−Ａ−Ｚ−Ｒ９ （式中、Ａ、Ｚ及びＲ９ は前記に同じ。）である請求項４に記載のジヒドロキノリン誘導体。
（６） Ｚがエチレン基で、Ｒ９ がフェニル基、ベンゼン環上にアルコキシ基３個を有するシンナモイル基又はアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基である請求項５に記載のジヒドロキノリン誘導体。
【０００８】
（７） Ｒ２ 、Ｒ３ 及びＲ５ がそれぞれ水素原子で、Ｒ６ がメチル基で、Ｒ７ が２−（２−アセトキシベンゾイルオキシ）エチル基、２−（２−アセトキシベンゾイルアミノ）エチル基、２−（２−メトキシベンゾイルオキシ）エチル基、２−フェノキシエチル基及び２−（３，４，５−トリメトキシシンナモイルオキシ）エチル基からなる群より選ばれる基である請求項６に記載のジヒドロキノリン誘導体。
（８） 請求項１記載のジヒドロキノリン誘導体又はその薬理学的に許容される塩及び製剤学的に許容される担体を含有する医薬組成物。
請求項１記載のジヒドロキノリン誘導体又はその薬理学的に許容される塩を有効成分として含有する鎮痛剤。
【０００９】
〔置換基の定義〕
アルキル基としては、炭素数１〜６のものが好ましく、炭素数１〜４のものがより好ましく、具体的には例えばメチル、エチル、プロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル基等の直鎖又は分枝鎖状アルキル基が好ましい。
【００１０】
アルコキシ基としては、炭素数１〜６のものが好ましく、炭素数１〜４のものがより好ましく、具体的には例えばメトキシ、エトキシ、プロポキシ、ブトキシ、ペンチルオキシ、ヘキシルオキシ基等が挙げられる。アルキルチオ基としては炭素数１〜６のものが好ましく、炭素数１〜４のものがより好ましく、具体的には例えばメチルチオ、エチルチオ、イソプロピルチオ、ｎ−ブチルチオ等が挙げられる。
【００１１】
ハロゲン原子としては、フッ素、塩素、臭素及びヨウ素原子が挙げられる。
アルキレン基としては、炭素数１〜６のものが好ましく、炭素数１〜４のものがより好ましく、具体的には例えばメチレン、エチレン、エチリデン、トリメチレン、プロピリデン、テトラメチレン、ペンタメチレン、ヘキサメチレン基等が挙げられる。
【００１２】
アルカノイル基としては、炭素数２〜７のものが好ましく、炭素数２〜５のものがより好ましく、具体的には例えばアセチル、プロピオニル、ブチリル、イソブチリル、バレリル、ピバロイル、ヘキサノイル、ヘプタノイル基等が挙げられる。
アルカノイルオキシ基としては、炭素数２〜７のものが好ましく、炭素数２〜５のものがより好ましく、具体的には例えばアセトキシ、プロピオニルオキシ、ブチリルオキシ、イソブチリルオキシ、バレリルオキシ、ピバロイルオキシ、ヘキサノイルオキシ、ヘプタノイルオキシ基等が挙げられる。
【００１３】
アルコキシ基１〜３個を有するベンジル基としては、好ましくは例えば、２，３，４−トリメトキシベンジル、２，３，５−トリメトキシベンジル、２，３，６−トリメトキシベンジル、２，４，５−トリメトキシベンジル、２，４，６−トリメトキシベンジル、３，４，５−トリメトキシベンジル、３，４，５−トリエトキシベンジル、３，４，５−トリプロポキシベンジル、３，４，５−トリブトキシベンジル、３，４，５−トリペンチルオキシベンジル、３，４，５−トリヘキシルオキシベンジル、３，５−ジ−ｔ−ブトキシ−４−メトキシベンジル基等が挙げられる。
【００１４】
アルコキシ基３個を有するベンゾイル基としては、具体的には例えば、２，３，４−トリメトキシベンゾイル、２，３，５−トリメトキシベンゾイル、２，３，６−トリメトキシベンゾイル、２，４，５−トリメトキシベンゾイル、２，４，６−トリメトキシベンゾイル、３，４，５−トリメトキシベンゾイル、３，４，５−トリエトキシベンゾイル、３，４，５−トリプロポキシベンゾイル、３，４，５−トリブトキシベンゾイル、３，４，５−トリペンチルオキシベンゾイル、３，４，５−トリヘキシルオキシベンゾイル、３，５−ジ−ｔ−ブトキシ−４−メトキシベンゾイル基等が挙げられる。
【００１５】
アルコキシ基の１〜３個を有するベンゾイル基としては、具体的には例えば、上記アルコキシ基３個を有するベンゾイル基に加え、２−メトキシベンゾイル、３−メトキシベンゾイル、４−メトキシベンゾイル、４−エトキシベンゾイル、４−プロポキシベンゾイル、４−ブトキシベンゾイル、４−ペンチルオキシベンゾイル、２，３−ジメトキシベンゾイル、２，４−ジメトキシベンゾイル、２，５−ジメトキシベンゾイル、２，６−ジメトキシベンゾイル、３，４−ジメトキシベンゾイル、３，５−ジメトキシベンゾイル基等が挙げられる。
【００１６】
置換基としてアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基としては、具体的には例えば、上記アルコキシ基の１〜３個を有するベンゾイル基に加え、２−アセトキシベンゾイル、３−アセトキシベンゾイル、４−アセトキシベンゾイル、２−プロピオニルオキシベンゾイル、２−ブチリルオキシベンゾイル、２−イソブチリルオキシベンゾイル、２−バレリルオキシベンゾイル、２−ピバロイルオキシベンゾイル、２−ヘキサノイルオキシベンゾイル、２−ヘプタノイルオキシベンゾイル基等が挙げられる。
【００１７】
ベンゼン環上にアルコキシ基３個を有することのあるシンナモイル基としては、具体的には例えば、シンナモイル基に加え、２，３，４−トリメトキシシンナモイル、２，３，５−トリメトキシシンナモイル、２，３，６−トリメトキシシンナモイル、２，４，５−トリメトキシシンナモイル、２，４，６−トリメトキシシンナモイル、３，４，５−トリメトキシシンナモイル、３，４，５−トリエトキシシンナモイル、３，４，５−トリプロポキシシンナモイル、３，４，５−トリブトキシシンナモイル、３，４，５−トリペンチルオキシシンナモイル、３，４，５−トリヘキシルオキシシンナモイル、３，５−ジ−ｔ−ブトキシ−４−メトキシシンナモイル基等が挙げられる。
【００１８】
芳香環カルボニル基又は芳香環アルキレン基における芳香環は例えばフェニル基、ナフチル基等の同素環基、例えばチエニル、フリル、チアジニル等のＮ，Ｓ又は／及びＯを同一又は異なって１〜３個含有する５〜７員の複素環基が挙げられる。従って芳香環カルボニル基としては具体的には上記したベンゾイル基、フロイル基、チエニルカルボニル基が挙げられる。又、芳香環アルケニレンカルボニル基の具体例としては上記したシンナモイル基、スチリルアセチル、４−フェニルクロトノイル基等が挙げられる。
【００１９】
アシル基としては、具体的には上記したアルカノイル基以外に、具体的にはメチルスルホニル基、エチルスルホニル基等のアルキルスルホニル基、上記した芳香環カルボニル基、芳香環スルホニル基（芳香環は上記と同意義）、ジアルキルホスホリル基（アルキル基は前記と同意義）等が挙げられる。
【００２０】
アラルキル基は、例えばベンジル基、ナフチルメチル基等で例示されるが、芳香環基−アルキレン基（芳香環基とアルキレン基は上記と同意義）で示される。なお、更に付言すれば、例えば上記の芳香環並びにアシル基等上記の置換基は、例えば、上記したアルキル基、アルコキシ基、アルキルチオ基、ハロゲン原子以外にも、例えば、アミノ基、グニジル基等の塩基性置換分、例えばスルホ基、カルボキシル基などの酸性置換分、例えばニトロ基、水酸基等のその他の置換分など通常の医薬成分に汎用される置換分を更に１〜３個程度有していてもよい。一般式（１）で表されるジヒドロキノリン誘導体の薬理学的に許容される塩としては例えば、塩酸、リン酸、硫酸等の酸性物質との塩、例えば、ナトリウム、カリウム等の塩基性物質との塩が挙げられる。以下本願明細書においては、ジヒドロキノリン誘導体にはその薬理学的に許容される塩も含むものとする。
【００２１】
本発明に係わる前記一般式（１）で表されるジヒドロキノリン誘導体は、鎮痛作用を有しており、鎮痛剤として、特に神経因性疼痛（特に末梢神経における疼痛）の緩和のための鎮痛剤として有用である。また、本発明化合物は、従来の鎮痛剤有効成分に見られる如き依存性、習慣性、幻覚等の副作用を示さないかあるいは著しく軽減されている特徴を有しており、之等の点でも鎮痛剤として特に有効である。
本発明化合物は、自体公知の方法を含む種々の方法により製造することができる。その例を以下に反応工程式を挙げて説明する。
【００２２】
【化３】
上記反応工程式において、化合物（２）から化合物（３）を経て本発明化合物（１）を合成する反応は、自体公知の方法に従って行われてよく、例えば特開平９―２５５６５８号公報に記載の方法に準じて行うことができる。
【００２３】
即ち、まず公知の化合物（２）を、アルカリの存在下に、ヨードベンゼンジアセテートと反応させることにより、化合物（３）を得る。該反応においては、溶媒として水を好適に使用でき、アルカリとしては炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等を使用できる。上記アルカリ及びヨードベンゼンジアセテートの使用量は、それぞれ原料化合物を基準として等モル量〜少過剰量とするのが好ましい。反応は０℃〜室温付近の温度で約１〜１０時間を要して行われる。
【００２４】
次に、上記で得られる化合物（３）は、これをチオエーテル誘導体（４）と反応させることにより、化合物（１）に変換できる。該反応は、メタノール、エタノール、トリフルオロエタノール等のアルコールを溶媒として用い、p−トルエンスルホン酸、酢酸等の酸触媒を適量添加して行うことができる。チオエーテル誘導体（４）の使用量は、化合物（３）に対して１〜１０倍モル量程度とするのがよく、反応は室温〜溶媒の還流温度にて１０分〜２４時間程度で完了する。
上記のごとくして得られる本発明化合物（１）は、下記に示す共鳴構造をとると考えられ、従って、それらのいずれの構造式でも表し得る。これらはいずれも本発明化合物（１）の範囲内である。
【００２５】
【化４】
【００２６】
【化５】
【００２７】
【化６】
【００２８】
【化７】
【００２９】
上記反応工程式−２〜４において、化合物（５）と化合物（６）、化合物（７）と化合物（８）並びに化合物（９）と化合物（１０）との反応は、それぞれ同様の反応条件で行い得る。
即ち、各化合物を、ピリジン、ルチジン、コリジン、トリエチルアミン、Ｎ，Ｎ−ジメチルアニリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン等のアミン系溶媒中、０℃〜５０℃程度の温度にて約１〜５０時間反応するか、或いはＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ−ジメチルアセトアミド（ＤＭＡ）、ジメチルスルホキシド（ＤＭＳＯ）等の不活性溶媒中、水素化ナトリウム、水素化カリウム、ナトリウムアミド、ナトリウムメトキシド等の塩基１〜過剰当量の存在下、０℃〜５０℃程度の温度にて約２０分〜５時間反応することにより行われる。
尚、化合物（６）の使用割合は、化合物（５）に対して２〜過剰モル量、化合物（８）並びに化合物（１０）の使用割合は、それぞれ化合物（７）並びに化合物（９）対してほぼ等モル量〜過剰モル量とするのが好ましい。
【００３０】
上記反応工程式に示した各工程における目的化合物は、通常の分離手段により容易に単離精製できる。該手段としては、例えば吸着クロマトグラフィー、プレパラィブ薄層クロマトグラフィー、再結晶、溶媒抽出等を例示できる。
【００３１】
本発明化合物の一部には、硫黄原子及び／又は炭素原子を不斉中心とする光学異性体が存在するものがあり、本発明は光学活性体であるＲ体及びＳ体並びにラセミ体のいずれをも包含する。上記光学活性体は、慣用の方法、例えば公知の光学分割剤を使用する方法等で分離することができる。
また、本発明化合物のうち、例えばベンゼン環上にアルコキシ基３個を有することのあるシンナモイル基を置換基として有するものは、二重結合による幾何異性体が存在し、本発明はＥ体及びＺ体並びにそれらの混合物のいずれをも包含する。上記異性体は、通常の分離手段により分離することができる。
【００３２】
本発明化合物（１）は、これを適当な無毒性製剤担体と共に用いて、一般的な医薬製剤の形態として使用される。上記製剤担体としては、製剤の使用形態に応じて通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤等の希釈剤あるいは賦形剤等が挙げられ、これは得られる製剤の投与単位形態に応じて適宜選択使用される。
本発明化合物（１）が使用される医薬製剤の投与単位形態としては、各種の形態が治療目的に応じて選択でき、その代表的なものとしては、錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤（液剤、懸濁剤）、軟膏剤等が挙げられる。又、これらの各種製剤は自体公知の手段に従って徐放性製剤としてもよい。
【００３３】
錠剤の形態に成形するに際しては、上記製剤担体として例えば乳糖、白糖、塩化ナトリウム、ぶどう糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸、燐酸カリウム等の賦形剤；水、エタノール、プロパノール、単シロップ、ぶどう糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン糖の結合剤；カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、乾燥デンプン、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム等の崩壊剤；ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド等の界面活性剤；白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤；第４級アンモニウム塩基; ラウリル硫酸ナトリウム等の吸収促進剤；グリセリン、デンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤等が使用可能である。
【００３４】
さらに錠剤は必要に応じて通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包剤、腸溶被錠、フィルムコーティング錠剤あるいは二重錠、二重錠とすることができる。
丸剤の形態に成形するに際しては、製剤担体として例えばぶどう糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤；アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤；ラミナラン、カンテン等の崩壊剤等が使用可能である。
【００３５】
坐剤の形態に成形するに際しては、製剤担体として例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等が使用可能である。
カプセル剤は常法に従って、通常、本発明化合物（１）を上記で例示した各種の製剤担体と混合して硬質ゼラチンカプセル、軟質カプセル等に充填して調整される。
【００３６】
液剤、乳剤、懸濁剤等の注射剤として調整する場合、これらは殺菌され且つ血液と等張であるのが好ましい。注射剤の調整に際しては、希釈剤として例えば水、エチルアルコール、マクロゴール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等が使用可能である。なお、この場合、等張性の溶液を調整するのに十分な量の食塩、ぶどう糖、グリセリン等を含有させてもよく、また通常の溶解補助剤、緩衝材、無痛化剤等を添加してもよい。
【００３７】
さらに、上記医薬製剤中には、必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有させることができる。
ペースト、クリーム、ゲル等の軟膏剤の形態に調整するに際しては、希釈剤として例えば白色ワセリン、パラフィン、グリセリン、セルロース誘導体、プリエチレングリコール、シリコン、ベントナイト等が使用可能である。
上記医薬製剤中に含有されるべき本発明化合物（１）の量は、特に制限されず、広範囲より適宜選択されるが、通常、医薬製剤中に約１〜８５重量％程度含有させるのがよい。
【００３８】
上記医薬製剤の投与方法は特に制限がなく、製剤形態、患者の年齢、性別その他の条件、疾患の程度等に応じて適宜決定される。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤は経口投与され、注射は単独またはぶどう糖、アミノ酸等の通常の補液と混合して静脈内投与され、さらに必要に応じて単独で筋肉内、皮内、皮下もしくは腹腔内投与され、坐剤は直腸内投与される。
上記医薬製剤の投与量は、その用法、患者の年齢、性別その他の条件、疾患の程度等に応じて適宜決定されるが、通常、本発明化合物（１）の１日当たりの投与量が体重１ｋｇあたり約０．５〜２０ｍｇ、好ましくは１〜１０ｍｇ程度とするのがよい。また、上記医薬製剤は１日１〜４回に分けて投与することができる。
なお、本発明化合物（１）は所望により他の医薬成分、例えば他の鎮痛剤と併用することもできる。
【発明の実施の形態】
次に本発明の参考例、実施例、薬理試験例および製剤例を示して、本発明を具体的に説明するが本発明はこれらに限定されるべきものではない。
【００３９】
【実施例】
以下に、本発明化合物の製造例を実施例として挙げる。また本発明化合物の製造のための原料化合物（中間体）の製造例を参考例としてあげる。
更に、本発明化合物を用いた薬理試験例及び製剤例を挙げる。
各実施例で得られた化合物は、その構造、融点及び １Ｈ−ＮＭＲスペクトルデータを同定資料として記載する。
尚、下記参考例及び実施例における １Ｈ−ＮＭＲスペクトルは、内部基準としてＴＭＳ（テトラメチルシラン）を用いて測定し、測定溶媒は、特に明示しない限り、ＤＭＳＯ（ジメチルスルホキシド）−ｄ６を用いた。
【００４０】
〔参考例１〕 ビス［２−（３，４，５−トリメトキシベンジルオキシ）エチル］スルフィドの製造
６０％水素化ナトリウム５．４ｇをＤＭＦ７０ｍｌに懸濁させ、そこにビス（２−ヒドロキシエチル）スルフィド７．５ｇ及び３，４，５−トリメトキシベンジルクロリド３０．４ｇを０℃で順次加え、室温で１時間攪拌した。反応液に水を加えて希釈し、酢酸エチル２００ｍｌで抽出した。有機層を集めて水及び飽和食塩水で順次洗浄し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出液…酢酸エチル：ｎ−ヘキサン＝１：３）で精製して、標記化合物の油状物２７．８ｇを得た。
【００４１】
〔参考例２〕 ビス［２−（３，４，５−トリメトキシベンゾイルオキシ）エチル］スルフィドの製造
ビス（２−ヒドロキシエチル）スルフィド及び３，４，５−トリメトキシベンゾイルクロリドを用い、上記参考例１と同様にして、標記化合物を得た。
【００４２】
〔参考例３〕 ［２−（３，４，５−トリメトキシベンジルオキシ）エチル］メチルスルフィドの製造
２−（メチルチオ）エタノール及び３，４，５−トリメトキシベンジルクロリドを用い、上記参考例１と同様にして、標記化合物を得た。
【００４３】
〔参考例４〜１５〕
２−（メチルチオ）エタノール、２−（メチルチオ）エチルアミン又はＮ−［２−（メチルチオ）エチル］−Ｎ−メチルアミン並びに適当な塩化物を用い、参考例３と同様にして、下記(4)〜(15)の各化合物を製造した。
（４） ［２−（２−アセトキシベンゾイルオキシ）エチル］メチルスルフィド
（５） （２−シンナモイルオキシエチル）メチルスルフィド
（６） ［２−（３，４，５−トリメトキシシンナモイルオキシ）エチル］メチルスルフィド
（７） [２−（３，４，５−トリメトキシベンゾイルオキシ）エチル］メチルスルフィド
（８） ［２−（２−メトキシベンゾイルオキシ）エチル］メチルスルフィド
（９） (２−フェノキシエチル）メチルスルフィド
【００４４】
（１０）（２−アセトキシエチル）メチルスルフィド
（１１）［２−（Ｎ−アセチルアミノ）エチル］メチルスルフィド
（１２）［２−［Ｎ−（３，４，５−トリメトキシベンゾイル）アミノ］エチル］メチルスルフィド
（１３）［２−［Ｎ−（２−アセトキシベンゾイル）アミノ］エチル］メチルスルフィド
（１４）［２−［Ｎ−メチル−Ｎ−（３，４，５−トリメトキシベンゾイル）アミノ］エチル］メチルスルフィド
（１５）［２−［Ｎ−（３，４，５−トリメトキシシンナモイル）アミノ］エチル］メチルスルフィド
【００４５】
〔参考例１６〕 ４−（３，４，５−トリメトキシベンゾイル）テトラヒドロ−４Ｈ−１，４−チアジンの製造
テトラヒドロ−４Ｈ−１，４−チアジン１０．３ｇをピリジン５０ｍｌに溶かし、そこに３，４，５−トリメトキシベンゾイルクロリド２３．１ｇを０℃で加え、室温で２４時間攪拌した。反応液に水を加えて希釈し、酢酸エチル２００ｍｌで２回抽出した。有機層を集めて２Ｎ水酸化ナトリウム水溶液、３Ｎ塩酸及び飽和食塩水で順次洗浄し、減圧濃縮した。残渣を酢酸エチル−ｎ−ヘキサンより再結晶して、標記化合物２４．０ｇ（融点： ９８〜 １００℃）を得た。
【００４６】
〔参考例１７〜１９〕
テトラヒドロ−４Ｈ−１，４−チアジン並びに３，４−ジメトキシベンゾイルクロリド、３，４，５−トリメトキシシンナモイルクロリド又は２−フロイルクロリドを用い、参考例１６と同様にして、下記(17)〜(19)の各化合物を製造した。
（１７) ４−（３，４−ジメトキシベンゾイル）テトラヒドロ−４Ｈ−１，４−チアジン
（１８） ４−（３，４，５−トリメトキシシンナモイル）テトラヒドロ−４Ｈ−１，４−チアジン
（１９） ４−（２−フロイル）テトラヒドロ−４Ｈ−１，４−チアジン
【００４７】
〔参考例２０〕 ７−クロロ−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラートの製造
８．３ｇの炭酸ナトリウムを水４００ｍｌに溶解し、この水溶液に１４．５ｇの７−クロロ−４−ヒドロキシ−２−オキソ−１，２−ジヒドロキノリンを溶かし、更に室温下、ヨードベンゼンジアセテート２４．０ｇを加え、室温で３時間攪拌した。反応終了後、析出した結晶を濾取し、メタノールで洗浄した後、６０℃で５時間減圧乾燥して目的化合物の結晶２８．１ｇ（融点：１６３〜１６５℃）を得た。
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
7.12(1H,d,J=7.4), 7.17-7.29(2H,m), 7.36-7.61(4H,m), 7.80-7.99(3H,m), 10.80(1H,s)
【００４８】
〔参考例２１〜２６〕
参考例２０と同様にして、下記（２１）〜（２２）の各化合物を製造した。
（２１） ２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
融点：２４４〜２４６℃
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
7.01(1H,dd,J=6.9,7.4), 7.17(1H,d,J=8.4), 7.32-7.50(4H,m), 7.81(2H,d,J=7.4), 7.89(1H,d,J=6.9), 10.63(1H,s)
【００４９】
（２２） ６−クロロ−１−メチル−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
融点：１０４〜１０６℃
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.48(3H,s), 7.33-7.58(5H,m), 7.83(2H,d,J=7.9), 7.92(1H,d,J=3.0)
更に同様にして、下記（２３）〜（２６）の各化合物を製造した。これらの化合物は、粗生成物のまま中間体として本発明化合物の製造に用いた。
【００５０】
（２３） ６−クロロ−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
（２４） １−メチル−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
（２５） ６，７−ジメトキシ−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
（２６） ６，７−ジメトキシ−１−メチル−２−オキソ−３−フェニルヨードニウム−１，２−ジヒドロキノリン−４−オラート
【００５１】
〔実施例１〕 ２−オキソ−３−［４−（３，４，５−トリメトキシベンゾイル）−１，４−チオキサニウム］−１，２−ジヒドロキノリン−４−オラートの製造
上記参考例２１で得られた化合物２．２ｇ、上記参考例１６で得られた化合物２．０ｇ及びｐ−トルエンスルホン酸１００ｍｇをトリフルオロエタノール２０ｍｌに溶かし、６０℃で３０分攪拌した。反応終了後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出液…メタノール：クロロホルム＝１：１０）で精製し、得られた結晶をジエチルエーテルで洗浄して、目的化合物の結晶２．５ｇを得た。以下の化学構造式中のＭｅはメチル基を表す。
【００５２】
【化８】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.10-3.33(2H,m), 3.41-3.69(2H,m), 3.71(3H,s), 3.84(6H,s), 4.41-4.61(4H,m), 6.81(2H,s), 7.03(1H,dd,J=7.2,7.9)、7.13(1H,d,J=8.2), 7.41(1H,dd,J=7.2,8.2), 7.84(1H,d,J=7.9), 10.55(1H,s)
【００５３】
〔実施例２〜４２〕
上記各参考例の化合物を原料に用い、実施例１と同様にして、下記の各化合物を製造した。
〔実施例２〕
【化９】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15-3.24(2H,m), 3.41-3.67(2H,m), 3.80(3H,s), 3.81(3H,s), 4.35-4.60(4H,m), 7.00-7.09(4H,m), 7.12(1H,d,J=7.9), 7.41(1H,dd,J=6.9,7.9), 7.84(1H,d,J=6.4), 10.53(1H,s)
【００５４】
〔実施例３〕
【化１０】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.20-3.32(2H,m), 3.45-3.75(2H,m), 4.45-4.65(2H,m), 4.71-4.88(2H,m), 6.69(1H,dd,J=1.5,3.5), 7.02(1H,dd,J=6.9,7.9), 7.12(1H,d,J=7.9), 7.17(1H,d,J=3.5), 7.42(1H,dd,J=6.9,7.9), 7.81(1H,d,J=6.9), 7.91(1H,d,J=1.5), 10.52(1H,s)
【００５５】
〔実施例４〕
【化１１】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.20-3.31(2H,m), 3.44(3H,s), 3.45-3.76(2H,m), 4.47-4.64(2H,m), 4.73-4.87(2H,m), 6.69(1H,dd,J=1.0,3.5), 7.14(1H,dd,J=6.9,8.4), 7.17(1H,d,J=3.5), 7.33(1H,d,J=8.4), 7.55(1H,dd,J=6.9,8.4), 7.92(1H,d,J=1.0), 7.97(1H,d,J=8.4)
【００５６】
〔実施例５〕
【化１２】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.14-3.27(2H,m), 3.45(3H,s), 3.46-3.69(2H,m), 3.81(3H,s), 3.82(3H,s), 4.37-4.61(4H,m), 7.05(2H,s), 7.10(1H,s), 7.15(1H,dd,J=7.4,7.4), 7.33(1H,d,J=8.4), 7.57(1H,dd,J=7.4,8.4), 7.99(1H,d,J=7.4)
【００５７】
〔実施例６〕
【化１３】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.11-3.27(2H,m), 3.45(3H,s), 3.46-3.68(2H,m), 3.70(3H,s), 3.84(6H,s), 4.41-4.60(4H,m), 6.82(2H,s), 7.15(1H,dd,J=7.9,7.9), 7.33(1H,d,J=8.4), 7.57(1H,dd,J=7.9,8.4), 7.98(1H,d,J=7.9)
【００５８】
〔実施例７〕
【化１４】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15-3.27(2H,m), 3.45-3.70(2H,m), 3.73(3H,s), 3.77(3H,s), 4.49-4.64(2H,m), 4.74-4.85(2H,m), 6.68-6.70(2H,m), 7.16(1H,d,J=3.5), 7.25(1H,s), 7.91(1H,d,J=1.7), 10.27(1H,s)
【００５９】
〔実施例８〕
【化１５】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.07-3.21(2H,m), 3.51-3.68(2H,m), 3.70(3H,s), 3.74(3H,s), 3.77(3H,s), 3.83(6H,s), 4.40-4.61(4H,m), 6.68(1H,s), 6.81(2H,s), 7.27(1H,s), 10.30(1H,s)
【００６０】
〔実施例９〕
【化１６】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.09-3.21(2H,m), 3.41-3.65(2H,m), 3.45(3H,s), 3.77(3H,s), 3.80(3H,s), 3.81(3H,s), 4.41-4.69(4H,m), 6.68(1H,s), 7.05(2H,s), 7.08(1H,s), 7.28(1H,s), 10.29(1H,s)
【００６１】
〔実施例１０〕
【化１７】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.20-3.31(2H,m), 3.43(3H,s), 3.51-3.73(2H,m), 4.45-4.57(2H,m), 4.73-4.84(2H,m), 6.69(1H,dd,J=2.0,3.5), 7.17(1H,d,J=3.5), 7.36(1H,d,J=8.9), 7.58(1H,dd,J=3.0,8.9), 7.88(1H,d,J=3.0), 7.91(1H,d,J=2.0)
【００６２】
〔実施例１１〕
【化１８】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15-3.29(2H,m), 3.44(3H,s), 3.45-3.70(2H,m), 3.71(3H,s), 3.83(6H,s), 4.37-4.55(4H,m), 6.80(2H,s), 7.37(1H,d,J=8.9), 7.59(1H,dd,J=2.6,8.9), 7.90(1H,d,J=2.6)
【００６３】
〔実施例１２〕
【化１９】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.18-3.28(2H,m), 3.44(3H,s), 3.45-3.69(2H,m)m 3.81(3H,s), 3.82(3H,s), 4.40-4.55(4H,m), 7.03-7.10(3H,m), 7.37(1H,d,J=8.9), 7.59(1H,dd,J=2.8,8.9), 7.90(1H,d,J=2.8)
【００６４】
〔実施例１３〕
【化２０】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.20-3.33(2H,m), 3.45(3H,s), 3.46-3.71(2H,m), 3.76(3H,s), 3.89(3H,s), 4.49-4.65(2H,m), 4.73-4.84(2H,m), 6.69(1H,dd,J=1.8,3.5), 6.79(1H,s), 7.16(1H,d,J=3.5), 7.42(1H,s), 7.91(1H,d,J=1.8)
【００６５】
〔実施例１４〕
【化２１】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.09-3.25(2H,m), 3.46(3H,s), 3.71(3H,s), 3.77(3H,s), 3.84(6H,s), 3.89(3H,s), 4.43-4.95(4H,m), 6.80(1H,s), 6.83(2H,s), 7.44(1H,s)
【００６６】
〔実施例１５〕
【化２２】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.11-3.24(2H,m), 3.45(3H,s), 3.46-3.65(2H,m), 3.78(3H,s), 3.80(3H,s), 3.82(3H,s), 3.89(3H,s), 4.46-4.59(4H,m), 6.80(1H,s), 7.05(2H,s), 7.09(1H,s), 7.44(1H,s)
【００６７】
〔実施例１６〕
【化２３】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.27(3H,s), 3.33(3H,s), 3.71-3.85(1H,m), 4.28-4.48(2H,m), 4.53-4.65(1H,m), 7.01(1H,dd,J=6.9,7.9), 7.10(1H,d,J=7.9), 7.15-7.25(2H,m), 7.39(1H,dd,J=6.9,8.4), 7.63(1H,dd,J=6.9,7.9), 7.83(1H,d,J=7.9), 7.90(1H,d,J=7.9), 10.47(1H,s)
【００６８】
〔実施例１７〕
【化２４】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.27(3H,s), 3.17(3H,s), 3.71-3.84(1H,m), 4.30-4.47(2H,m), 4.52-4.67(1H,m), 7.03(1H,d,J=8.4), 7.13(1H,s), 7.18-7.27(2H,m), 7.66(1H,dd,J=7.6,7.9), 7.79(1H,d,J=8.4), 7.90(1H,d,J=7.9), 10.59(1H,s)
【００６９】
〔実施例１８〕
【化２５】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.26(3H,s), 3.17(3H,s), 3.38(3H,s), 3.71-3.84(1H,m), 4.31-4.49(2H,m), 4.52-4.66(1H,m), 7.09-7.24(3H,m), 7.30(1H,d,J=8.2), 7.50-7.79(2H,m), 7.85(1H,d,J=8.2), 7.96(1H,d,J=7.9)
【００７０】
〔実施例１９〕
【化２６】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.26(3H,s), 3.40-3.69(2H,m), 3.70(3H,s), 3.83(6H,s), 3.84-3.95(2H,m), 7.01(1H,dd,J=7.9,8.2), 7.11(1H,d,J=7.7), 7.19(2H,s), 7.38(1H,dd,J=7.7,8.2), 7.82(1H,d,J=9.9), 8.68(1H,brs), 10.46(1H,s)
【００７１】
〔実施例２０〕
【化２７】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.26(3H,s), 3.17(3H,s), 3.70-3.85(1H,m), 4.30-4.48(2H,m), 4.53-4.68(1H,m), 7.12(1H,d,J=8.7), 7.13-7.23(2H,m), 7.45(1H,d,J=8.7), 7.65(1H,dd,J=7.7,7.9), 7.72(1H,s), 7.89(1H,d,J=7.7), 10.63(1H,s)
【００７２】
〔実施例２１〕
【化２８】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15(3H,s), 3.73(3H,s), 3.74-3.81(1H,m), 3.82(6H,s), 4.20-4.33(1H,m), 4.35-4.49(1H,m), 4.70-4.80(1H,m), 6.98(1H,dd,J=6.9,7.7), 7.05(1H,d,J=7.7), 7.25(2H,s), 7.38(1H,dd,J=7.7,8.2), 7.78(1H,d,J=7.7), 10.40(1H,s)
【００７３】
〔実施例２２〕
【化２９】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.91(3H,s), 3.14(3H,s), 3.40-3.80(6H,m), 3.80(6H,s), 4.10-4.35(1H,m), 6.75(2H,s), 7.00(1H,dd,J=7.2,7.9), 7.10(1H,d,J=8.2), 7.39(1H,dd,J=6.9,8.2), 7.83(1H,d,J=9.9), 10.45(1H,s)
【００７４】
〔実施例２３〕
【化３０】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.90(3H,s), 3.13(3H,s), 3.41-3.75(6H,m), 3.80(6H,s), 4.10-4.31(1H,m), 6.74(2H,s), 7.03(1H,d,J=8.7), 7.14(1H,s), 7.81(1H,d,J=8.7), 10.57(1H,s)
【００７５】
〔実施例２４〕
【化３１】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.16(3H,s), 3.72-3.86(1H,m), 4.25-4.46(2H,m), 4.48-4.59(1H,m), 6.49(1H,d,J=16.1),7.00(1H,dd,J=6.9,7.9), 7.32-7.50(4H,m), 7.53-7.67(3H,m), 7.82(1H,d,J=7.9), 10.46(1H,s)
【００７６】
〔実施例２５〕
【化３２】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.25(3H,s), 3.15(3H,s), 3.35-3.60(2H,m), 3.73-3.95(2H,m), 7.01(1H,dd,J=7.2,7.9), 7.11(1H,d,J=7.9), 7.18(1H,d,J=8.2), 7.32(1H,dd,J=7.6,7.6), 7.38(1H,dd,J=7.6,8.2), 7.51(1H,dd,J=7.9,7.9), 7.64(1H,d,J=7.6), 7.82(1H,d,J=7.2), 8.54(1H,brs), 10.46(1H,s)
【００７７】
〔実施例２６〕
【化３３】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
2.27(3H,s), 3.15(3H,s), 3.74(3H,s), 3.77(3H,s), 3.78-3.99(1H,m), 4.23-4.47(2H,m), 4.52-4.65(1H,m), 6.67(1H,s), 7.17-7.30(3H,m), 7.66(1H,dd,J=7.7,7.9), 7.93(1H,d,J=7.9), 10.25(1H,s)
【００７８】
〔実施例２７〕
【化３４】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.16(3H,s), 3.81(3H,s), 3.82-3.95(1H,m), 4.25-4.42(2H,m), 4.50-4.65(1H,m), 6.89(1H,dd,J=7.4,7.6), 7.02(1H,dd,J=7.6,7.9), 7.03-7.18(2H,m), 7.38(1H,dd,J=7.2,7.6), 7.49(1H,dd,J=7.4,7.6), 7.69(1H,d,J=7.6), 7.82(1H,d,J=7.9), 10.47(1H,s)
【００７９】
〔実施例２８〕
【化３５】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15(3H,s), 3.82-3.97(1H,s), 4.02-4.17(1H,s), 4.27-4.40(2H,s), 6.85-7.03(4H,m), 7.10(1H,d,J=7.9), 7.20-7.30(2H,m), 7.39(1H,dd,J=6.9,7.9), 7.81(1H,d,J=7.9), 10.44(1H,s)
【００８０】
〔実施例２９〕
【化３６】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.16(3H,s), 3.82-3.95(1H,m), 4.05-4.15(1H,m), 4.28-4.40(2H,m), 6.88-6.99(3H,m), 7.03(1H,d,J=8.4), 7.14(1H,s), 7.20-7.31(2H,m), 7.79(1H,d,J=8.4), 10.57(1H,s)
【００８１】
〔実施例３０〕
【化３７】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.09(3H,s), 3.49-3.60(1H,m), 3.62(3H,s), 3.63-3.76(2H,m), 3.77(6H,s), 4.11-4.20(1H,m), 4.38(2H,s), 6.66(2H,s), 7.02(1H,dd,J=6.4,7.9), 7.11(1H,d,J=7.9), 7.38(1H,dd,J=6.4,7.9), 7.82(1H,d,J=6.4), 10.43(1H,s)
【００８２】
〔実施例３１〕
【化３８】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15(3H,s), 3.70(3H,s), 3.82(6H,s), 3.83-3.99(1H,m), 4.20-4.38(2H,m), 4.50-4.60(1H,m), 6.57(1H,d,J=16.1), 6.95-7.10(4H,m), 7.37(1H,dd,J=6.9,7.9), 7.60(1H,d,J=16.1), 7.81(1H,d,J=7.9), 10.44(1H,s)
【００８３】
〔実施例３２〕
【化３９】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.71(6H,s), 3.76(12H,s), 3.77-3.95(2H,m), 4.27-4.40(2H,m), 4.45-4.60(2H,m), 4.70-4.85(2H,m), 6.95(1H,dd,J=6.9,7.9), 7.01(1H,d,J=7.9), 7.20(4H,s), 7.35(1H,dd,J=6.9,7.9), 7.72(1H,d,J=7.9), 10.34(1H,s)
【００８４】
〔実施例３３〕
【化４０】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.50-3.61(2H,m), 3.62(6H,s), 3.63-3.73(4H,m), 3.74(12H,s), 4.15-4.25(1H,m), 4.38(4H,s), 6.64(4H,s), 7.01(1H,dd,J=6.9,7.9), 7.12(1H,d,J=7.7), 7.39(1H,dd,J=6.9,7.7), 7.83(1H,d,J=7.9), 10.43(1H,s)
【００８５】
〔実施例３４〕
【化４１】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.08(3H,s), 3.50-3.61(1H,m), 3.62(3H,s), 3.63-3.73(2H,m), 3.74(3H,s), 3.77(3H,s), 3.78(6H,s), 4.11-4.20(1H,m), 4.38(2H,s), 6.66(2H,s), 6.68(1H,s), 7.28(1H,s), 10.22(1H,s)
【００８６】
〔実施例３５〕
【化４２】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.15-3.30(2H,m), 3.69(3H,s), 3.70-3.83(2H,m), 3.84(6H,s), 4.35-4.60(2H,m), 4.76-4.96(2H,m), 7.02(1H,dd,J=7.4,8.2), 7.10-7.15(3H,m), 7.29(1H,d,J=15.1), 7.40(1H,dd,J=7.9,8.2), 7.57(1H,d,J=15.1), 7.81(1H,d,J=7.4), 10.50(1H,s)
【００８７】
〔実施例３６〕
【化４３】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.10(3H,s), 3.50-3.61(1H,m), 3.62(3H,s), 3.63-3.76(2H,m), 3.77(6H,s), 4.10-4.20(1H,m), 4.37(2H,s), 6.65(2H,s), 7.13(1H,d,J=8.9), 7.45(1H,d,J=8.9), 7.75(1H,s), 10.60(1H,s)
【００８８】
〔実施例３７〕
【化４４】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.09(3H,s), 3.49-3.61(1H,m), 3.62(3H,s), 3.63-3.76(2H,m), 3.77(6H,s), 4.10-4.20(1H,m), 4.38(2H,s), 6.65(2H,s), 7.04(1H,d,J=8.4), 7.14(1H,s), 7.81(1H,d,J=8.4), 10.56(1H,s)
【００８９】
〔実施例３８〕
【化４５】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.09(3H,s), 3.40(3H,s), 3.41-3.60(1H,m), 3.61(3H,s), 3.62-3.75(2H,m), 3.77(6H,s), 4.10-4.20(1H,m), 4.37(2H,s), 6.65(2H,s), 7.12(1H,dd,J=7.4,7.7), 7.30(1H,d,J=8.7), 7.54(1H,dd,J=7.4,8.7), 7.97(1H,d,J=7.7)
【００９０】
〔実施例３９〕
【化４６】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.20-3.33(2H,m), 3.43(3H,s), 3.70(3H,s), 3.71-3.83(2H,m), 3.84(6H,s), 4.35-4.60(2H,m), 4.80-4.98(2H,m), 7.10-7.17(3H,m), 7.23-7.35(2H,m), 7.51-7.62(2H,m), 7.96(1H,d,J=7.7)
【００９１】
〔実施例４０〕
【化４７】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.14(3H,s), 3.32-3.45(1H,m), 3.46-3.63(1H,m), 3.68(3H,s), 3.69-3.80(2H,m), 3.81(6H,s), 6.57(1H,d,J=15.8), 6.91(2H,s), 7.00(1H,dd,J=6.9,7.7), 7.10(1H,d,J=7.9), 7.33-7.43(2H,m), 7.82(1H,d,J=7.7), 8.37(1H,brs), 10.45(1H,s)
【００９２】
〔実施例４１〕
【化４８】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
1.96(3H,s), 3.13(3H,s), 3.75-3.80(1H,m), 4.10-4.23(2H,m), 4.25-4.40(1H,m), 7.01(1H,dd,J=6.9,7.9), 7.10(1H,d,J=7.9), 7.40(1H,dd,J=6.9,7.9), 7.82(1H,d,J=7.9), 10.45(1H,s)
【００９３】
〔実施例４２〕
【化４９】
１Ｈ−ＮＭＲ（δ：ｐｐｍ）〔ＤＭＳＯ−ｄ６〕：
3.11(3H,s), 3.18-3.38(2H,m), 3.65-3.85(2H,m), 7.01(1H,dd,J=6.9,7.9), 7.11(1H,d,J=7.9), 7.40(1H,dd,J=6.9,7.9), 7.82(1H,d,J=7.9), 8.15(1H,brs), 10.45(1H,s)
【００９４】
〔薬理試験例〕
６週齢ウィスター系雄性ラット１群７匹を用い、まず各ラットの左後肢足蹠の疼痛閾値を圧刺激鎮痛効果測定装置（ユニコム社製）を用いて、ランダール・セリット法〔Randall,L.O. and Sellitto, J.J., Arch. Int. Pharmacodyn., 111,409(1957)〕に準じて測定した。得られた値を「前値」とする。
上記前置の測定１時間後に、実験群には、更に本発明化合物の５％アラビアゴム懸濁液を、対照群には５％アラビアゴム懸濁液（本発明化合物を含まない）を、それぞれ１０ｍｌ／ｋｇの割合で、投与量が１０ｍｇ／ｋｇとなるように経口投与し、更にその１時間後にサブスタンスＰの生理食塩水溶液（２５んｇ／０．１ｍｌ）を、各ラットの左後肢足蹠皮下に注射した。
つぎにサブスタンスＰ注射の所定時間後に、各群ラットの左後肢足蹠の疼痛閾値を上記と同様にして測定して、これを「後値」とした。
各群の測定値（後値）と前値より、疼痛閾値回復率（％）を、次式に従って算出した。
疼痛閾値回復率（％）＝〔（実験群平均後値）−（対照群平均後値）〕／〔（対照群平均前値）−（対照群平均後値）〕× １００
得られた結果（最大の回復率）を下記表１に示す。
【００９５】
【表１】
〔製剤例１〕 錠剤の調整
実施例１６で得た化合物のそれぞれ５ｍｇを含有する経口使用のための１０００錠を次の処方により調整した。
実施例１６で得た本発明化合物 ５ｇ
乳糖（日本薬局方） ５０ｇ
コーンスターチ（日本薬局方） ２５ｇ
結晶セルロース（日本薬局方） ２５ｇ
メチルセルロース（日本薬局方） １．５ｇ
ステアリン酸マグネシウム（日本薬局方） １ｇ
即ち、実施例１６で得た本発明化合物、乳糖、コーンスターチ及び結晶セルロースを充分混合し、混合物をメチルセルロースの５％水溶液で顆粒化し、２００メッシュの篩に通して注意深く乾燥した。乾燥した顆粒を２００メッシュの篩に通し、ステアリン酸マグネシウムと混合して錠剤にプレス成形した。
【００９７】
〔製剤例２〕 カプセル剤の調整
実施例２８で得た化合物のそれぞれ１０ｍｇを含有する経口使用のための１０００個の２片硬質ゼラチンカプセルを次の処方により調整した。
実施例２８で得た本発明化合物 １０ｇ
乳糖（日本薬局方） ８０ｇ
澱粉（日本薬局方） ３０ｇ
滑石（日本薬局方） ５ｇ
ステアリン酸マグネシウム（日本薬局方） １ｇ
即ち、上記各成分を細かく粉末にし、均一な混合物となるように充分に攪拌した後、所望の寸法を有する経口投与用カプセルに充填した。
【００９８】
〔製剤例３〕 注射剤の調整
実施例１６で得た化合物を含む非経口投与に適した殺菌された水溶液を、下記処方により調整した。
実施例１６で得た本発明化合物 １ｇ
ポリエチレングリコール（日本薬局方）（分子量：４０００） ０．９ｇ
塩化ナトリウム（日本薬局方） ０．９ｇ
ポリオキシエチレンソルビタンモノオレエート（日本薬局方） ０．４ｇ
メタ重亜硫酸ナトリウム（日本薬局方） ０．１ｇ
メチル−パラベン（日本薬局方） ０．１８ｇ
プロピル−パラベン（日本薬局方） ０．０２ｇ
注射用蒸留水 １００ｍｌ
即ち、上記パラベン類、メタ重亜硫酸ナトリウム及び塩化ナトリウムを攪拌しながら８０℃で上記の約半量の蒸留水に溶解し、得られた溶液を４０℃まで冷却し、これに実施例１６で得た本発明化合物及びポリオキシエチレンソルビタンモノオレエートを溶解させた。次に得られた溶液に注射用蒸留水を加えて最終容量に調整し、適当なフィルターペーパーを用いて滅菌濾過して注射剤を調整した。
【発明の効果】
本発明が提供する上記一般式（１）で示される新規ジヒドロキノリン誘導体は特に神経因性疼痛に対する優れた鎮痛作用を有し、毒性および副作用が顕著に軽減された医薬として有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel dihydroquinoline derivative and a pharmacologically acceptable salt thereof having a medicinal purpose, and the compound has an excellent analgesic action and is useful as a medicine.
[0002]
[Prior art]
The dihydroquinoline derivative of the present invention is a novel compound not described in any literature. The inventors of the present invention have been researching and developing compounds having valuable pharmacological activity as pharmaceuticals. In the process, they have a hypoglycemic action and are effective in the treatment and prevention of diabetes. Has succeeded in synthesizing a series of dihydroquinoline compounds and has applied for a patent for an invention relating to the compounds (see Japanese Patent Application No. 9-255658).
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel compound useful as a medicine, particularly a medicine having analgesic action.
[0004]
[Means for Solving the Problems]
As a result of subsequent studies, the present inventors have succeeded in synthesizing a series of other novel dihydroquinoline derivatives having a dihydroquinoline skeleton in common with the above-mentioned known compounds but particularly clearly distinguished at the 3-position substituent. In addition, the present inventors have found that these novel derivatives have an analgesic action that is essentially different from the hypoglycemic action of the above-mentioned compounds and that cannot be predicted from the action, and the present invention that meets the above-mentioned problems It came to be completed.
[0005]
That is, the present invention comprises (1) the general formula
[0006]
(2) In the general formula of claim 1, R 1 , R 2 , R 3 and R 4 Are a hydrogen atom, an alkoxy group or a halogen atom, R 5 is a hydrogen atom or an alkyl group, R 6 and R 7, respectively. Are each a group -A-O-R 8 (In the formula, A represents an alkylene group, R 8 Represents a benzoyl group having 3 alkoxy groups or a benzyl group having 3 alkoxy groups), or R 6 is an alkyl group and R 7 Is a group -A-Z-R 9 (In the formula, A is the same as described above. Z represents —O—, —NH— or —N (alkyl group) —, R 9 May have (1) alkanoyl group, (2) phenyl group, (3) benzyl group which may have 1 to 3 alkoxy groups on the benzene ring, and (4) may have 3 alkoxy groups on the benzene ring. A cinnamoyl group or (5) a benzoyl group having 1 to 3 alkanoyloxy groups or alkoxy groups as substituents), or R 6 and R 7 Are bonded to each other and together with the sulfur atom to which they are bonded, the 4-position is (1) 2-furoyl group, (2) benzoyl group having 1 to 3 of alkoxy groups, or (3) three alkoxy groups on the benzene ring A dihydroquinoline derivative according to claim 1, which may form a tetrahydro-4H-1,4-thiazine ring substituted with a cinnamoyl group which may have
[0007]
(3) R 1 And R 4 The dihydroquinoline derivative according to claim 2, wherein each is a hydrogen atom.
(4) R 2 And R 3 Is a hydrogen atom or an alkoxy group, respectively, or one is a hydrogen atom and the other is a halogen atom, The dihydroquinoline derivative of Claim 3.
(5) R 7 R 6 is an alkyl group Is a group -A-Z-R 9 (Wherein A, Z and R 9 Is the same as above. The dihydroquinoline derivative according to claim 4, wherein
(6) Z is an ethylene group, R 9 6. The dihydroquinoline derivative according to claim 5, wherein is a phenyl group, a cinnamoyl group having 3 alkoxy groups on the benzene ring, or a benzoyl group having 1 to 3 alkanoyloxy groups or alkoxy groups.
[0008]
(7) R 2 , R 3 And R 5 Are each a hydrogen atom and R 6 Is a methyl group and R 7 Are 2- (2-acetoxybenzoyloxy) ethyl group, 2- (2-acetoxybenzoylamino) ethyl group, 2- (2-methoxybenzoyloxy) ethyl group, 2-phenoxyethyl group and 2- (3,4, The dihydroquinoline derivative according to claim 6, which is a group selected from the group consisting of 5-trimethoxycinnamoyloxy) ethyl group.
(8) A pharmaceutical composition comprising the dihydroquinoline derivative according to claim 1 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.
An analgesic comprising the dihydroquinoline derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
[0009]
(Definition of substituents)
As the alkyl group, those having 1 to 6 carbon atoms are preferable, those having 1 to 4 carbon atoms are more preferable, and specifically, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl groups, etc. The linear or branched alkyl group is preferable.
[0010]
As the alkoxy group, those having 1 to 6 carbon atoms are preferable, those having 1 to 4 carbon atoms are more preferable, and specific examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups and the like. The alkylthio group preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and specific examples include methylthio, ethylthio, isopropylthio, n-butylthio and the like.
[0011]
Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.
As the alkylene group, those having 1 to 6 carbon atoms are preferred, those having 1 to 4 carbon atoms are more preferred, and specifically, for example, methylene, ethylene, ethylidene, trimethylene, propylidene, tetramethylene, pentamethylene, hexamethylene groups. Etc.
[0012]
As the alkanoyl group, those having 2 to 7 carbon atoms are preferable, those having 2 to 5 carbon atoms are more preferable, and specific examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl groups and the like. It is done.
The alkanoyloxy group is preferably one having 2 to 7 carbon atoms, more preferably one having 2 to 5 carbon atoms, specifically, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pivaloyloxy, hexanoyl Examples include oxy and heptanoyloxy groups.
[0013]
The benzyl group having 1 to 3 alkoxy groups is preferably 2,3,4-trimethoxybenzyl, 2,3,5-trimethoxybenzyl, 2,3,6-trimethoxybenzyl, 2,4, for example. , 5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3,4,5-trimethoxybenzyl, 3,4,5-triethoxybenzyl, 3,4,5-tripropoxybenzyl, 3,4 , 5-tributoxybenzyl, 3,4,5-tripentyloxybenzyl, 3,4,5-trihexyloxybenzyl, 3,5-di-t-butoxy-4-methoxybenzyl group, and the like.
[0014]
Specific examples of the benzoyl group having three alkoxy groups include 2,3,4-trimethoxybenzoyl, 2,3,5-trimethoxybenzoyl, 2,3,6-trimethoxybenzoyl, and 2,4. , 5-trimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 3,4,5-triethoxybenzoyl, 3,4,5-tripropoxybenzoyl, 3,4 , 5-tributoxybenzoyl, 3,4,5-tripentyloxybenzoyl, 3,4,5-trihexyloxybenzoyl, 3,5-di-t-butoxy-4-methoxybenzoyl group and the like.
[0015]
Specific examples of the benzoyl group having 1 to 3 alkoxy groups include 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 4-ethoxy in addition to the above-mentioned benzoyl group having 3 alkoxy groups. Benzoyl, 4-propoxybenzoyl, 4-butoxybenzoyl, 4-pentyloxybenzoyl, 2,3-dimethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 3,4- Examples include dimethoxybenzoyl and 3,5-dimethoxybenzoyl groups.
[0016]
Specific examples of the benzoyl group having 1 to 3 alkanoyloxy groups or alkoxy groups as a substituent include, for example, 2-acetoxybenzoyl, 3-acetoxy in addition to the benzoyl group having 1 to 3 alkoxy groups. Benzoyl, 4-acetoxybenzoyl, 2-propionyloxybenzoyl, 2-butyryloxybenzoyl, 2-isobutyryloxybenzoyl, 2-valeryloxybenzoyl, 2-pivaloyloxybenzoyl, 2-hexanoyloxybenzoyl, Examples include 2-heptanoyloxybenzoyl group.
[0017]
Specific examples of the cinnamoyl group that may have three alkoxy groups on the benzene ring include, for example, 2,3,4-trimethoxycinnamoyl and 2,3,5-trimethoxycinnamoyl in addition to the cinnamoyl group. 2,3,6-trimethoxycinnamoyl, 2,4,5-trimethoxycinnamoyl, 2,4,6-trimethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 3,4,5 -Triethoxycinnamoyl, 3,4,5-tripropoxycinnamoyl, 3,4,5-tributoxycinnamoyl, 3,4,5-tripentyloxycinnamoyl, 3,4,5-trihexyloxycinna And moyl, 3,5-di-t-butoxy-4-methoxycinnamoyl group, and the like.
[0018]
The aromatic ring in the aromatic ring carbonyl group or aromatic ring alkylene group is 1 to 3 of the same or different N, S or / and O such as phenyl, naphthyl and the like, for example, thienyl, furyl, thiazinyl and the like. Examples thereof include 5- to 7-membered heterocyclic groups. Therefore, specific examples of the aromatic carbonyl group include the benzoyl group, furoyl group, and thienylcarbonyl group described above. Specific examples of the aromatic ring alkenylenecarbonyl group include the cinnamoyl group, styrylacetyl, 4-phenylcrotonoyl group described above.
[0019]
Specific examples of the acyl group include, in addition to the above-described alkanoyl group, specifically, an alkylsulfonyl group such as a methylsulfonyl group and an ethylsulfonyl group, an aromatic ring carbonyl group, an aromatic ring sulfonyl group (the aromatic ring is as described above) And the like), dialkylphosphoryl groups (alkyl groups are as defined above) and the like.
[0020]
The aralkyl group is exemplified by, for example, a benzyl group, a naphthylmethyl group and the like, and is represented by an aromatic ring group-alkylene group (the aromatic ring group and the alkylene group are as defined above). In addition, for example, the above-mentioned substituents such as the above-mentioned aromatic ring and acyl group include, for example, amino groups, gnidyl groups, etc. in addition to the above-described alkyl groups, alkoxy groups, alkylthio groups, halogen atoms, etc. It has about 1 to 3 additional substituents that are commonly used in normal pharmaceutical ingredients such as basic substituents, such as acidic substituents such as sulfo groups and carboxyl groups, and other substituents such as nitro groups and hydroxyl groups. Also good. Examples of the pharmacologically acceptable salt of the dihydroquinoline derivative represented by the general formula (1) include salts with acidic substances such as hydrochloric acid, phosphoric acid and sulfuric acid, for example, basic substances such as sodium and potassium Of the salt. Hereinafter, in the present specification, the dihydroquinoline derivative includes a pharmacologically acceptable salt thereof.
[0021]
The dihydroquinoline derivative represented by the general formula (1) according to the present invention has an analgesic action, and as an analgesic, in particular, an analgesic for alleviating neuropathic pain (particularly pain in peripheral nerves). Useful as. In addition, the compound of the present invention has the characteristics that it does not exhibit or is significantly reduced in side effects such as dependence, habituality, hallucination, and the like as found in conventional active ingredients for analgesics. It is particularly effective as an agent.
The compound of the present invention can be produced by various methods including a method known per se. Examples thereof will be described below with reference to reaction process formulas.
[0022]
[Chemical 3]
In the above reaction process formula, the reaction for synthesizing the compound (1) of the present invention from the compound (2) through the compound (3) may be carried out according to a method known per se, for example, as described in JP-A-9-255658 It can be carried out according to the method.
[0023]
That is, first, a known compound (2) is reacted with iodobenzene diacetate in the presence of an alkali to obtain a compound (3). In the reaction, water can be suitably used as a solvent, and sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or the like can be used as an alkali. The amounts of the alkali and iodobenzene diacetate used are preferably equimolar amounts to small excess amounts based on the raw material compounds. The reaction is carried out at a temperature between 0 ° C. and room temperature, taking about 1 to 10 hours.
[0024]
Next, the compound (3) obtained above can be converted into the compound (1) by reacting it with the thioether derivative (4). The reaction can be performed using an alcohol such as methanol, ethanol or trifluoroethanol as a solvent and adding an appropriate amount of an acid catalyst such as p-toluenesulfonic acid or acetic acid. The amount of the thioether derivative (4) used is preferably about 1 to 10 times the molar amount of the compound (3), and the reaction is completed in about 10 minutes to 24 hours at room temperature to the reflux temperature of the solvent.
The compound (1) of the present invention obtained as described above is considered to have the resonance structure shown below, and can therefore be represented by any structural formula thereof. These are all within the scope of the compound (1) of the present invention.
[0025]
[Formula 4]
[0026]
[Chemical formula 5]
[0027]
[Chemical 6]
[0028]
[Chemical 7]
[0029]
In the above reaction process formulas -2 to 4, the reaction between the compound (5) and the compound (6), the compound (7) and the compound (8), and the compound (9) and the compound (10) is carried out under the same reaction conditions. Can be done.
That is, each compound is about about 0 ° C. to 50 ° C. in an amine solvent such as pyridine, lutidine, collidine, triethylamine, N, N-dimethylaniline, 4- (N, N-dimethylamino) pyridine. React for 1 to 50 hours, or in an inert solvent such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), sodium hydride, potassium hydride, sodium The reaction is carried out by reacting at a temperature of about 0 ° C. to 50 ° C. for about 20 minutes to 5 hours in the presence of 1 to excess equivalent of a base such as amide or sodium methoxide.
In addition, the use ratio of the compound (6) is 2 to excess molar amount with respect to the compound (5), and the use ratios of the compound (8) and the compound (10) are relative to the compound (7) and the compound (9), respectively. It is preferable that the amount be approximately equimolar to excess molar.
[0030]
The target compound in each step shown in the above reaction process formula can be easily isolated and purified by ordinary separation means. Examples of the means include adsorption chromatography, preparative thin layer chromatography, recrystallization, solvent extraction and the like.
[0031]
Some of the compounds of the present invention have optical isomers having a sulfur atom and / or a carbon atom as an asymmetric center, and the present invention includes any of R-form, S-form and racemic form which are optically active forms. Is also included. The optically active substance can be separated by a conventional method such as a method using a known optical resolution agent.
Among the compounds of the present invention, those having, for example, a cinnamoyl group having 3 alkoxy groups on the benzene ring as a substituent have geometric isomers due to double bonds. The body as well as mixtures thereof. The isomers can be separated by ordinary separation means.
[0032]
The compound (1) of the present invention is used in the form of a general pharmaceutical preparation by using it together with a suitable non-toxic preparation carrier. Examples of the preparation carrier include fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and other diluents or excipients that are usually used according to the form of use of the preparation. These are appropriately selected and used depending on the dosage unit form of the resulting preparation.
As the dosage unit form of the pharmaceutical preparation in which the compound (1) of the present invention is used, various forms can be selected according to the therapeutic purpose, and representative examples thereof include tablets, pills, powders, liquids, suspensions. Agents, emulsions, granules, capsules, suppositories, injections (solutions, suspensions), ointments and the like. These various preparations may be sustained-release preparations according to means known per se.
[0033]
In the case of forming into a tablet form, examples of the above-mentioned preparation carrier include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate; water, ethanol, Propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone sugar binder; carboxymethylcellulose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, dried starch, sodium alginate Disintegrating agents such as Kanteng powder, laminaran powder, sodium bicarbonate, calcium carbonate; polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, Surfactants such as monoglyceride, disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; quaternary ammonium bases; absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; Adsorbents such as lactose, kaolin, bentonite and colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can be used.
[0034]
Furthermore, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin encapsulating agents, enteric-coated tablets, film-coated tablets, double tablets, double tablets.
In the case of forming into a pill form, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and the like as a formulation carrier; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; Disintegrants such as laminaran and agar can be used.
[0035]
In molding into a suppository, for example, polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like can be used as a pharmaceutical carrier.
Capsules are usually prepared by mixing the compound (1) of the present invention with the various preparation carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
[0036]
When preparing as injections such as solutions, emulsions, suspensions, etc., these are preferably sterilized and isotonic with blood. In preparing the injection, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used as diluents. In this case, a sufficient amount of sodium chloride, glucose, glycerin, etc. may be added to adjust the isotonic solution, and usual solubilizing agents, buffer materials, soothing agents, etc. may be added. Also good.
[0037]
Furthermore, in the above-mentioned pharmaceutical preparations, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, etc. and other pharmaceuticals can be contained as necessary.
When adjusting to the form of an ointment such as paste, cream, gel, etc., white petrolatum, paraffin, glycerin, cellulose derivatives, preethylene glycol, silicon, bentonite and the like can be used as a diluent.
The amount of the compound (1) of the present invention to be contained in the pharmaceutical preparation is not particularly limited and is appropriately selected from a wide range, but it is usually preferable to contain about 1 to 85% by weight in the pharmaceutical preparation. .
[0038]
The administration method of the pharmaceutical preparation is not particularly limited, and is appropriately determined depending on the preparation form, patient age, sex and other conditions, the degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, capsules are administered orally, and injections are administered alone or mixed intravenously with normal fluids such as glucose and amino acids, and if necessary It is administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally, and suppositories are administered rectal.
The dosage of the above pharmaceutical preparation is appropriately determined according to its usage, the patient's age, sex and other conditions, the degree of disease, etc. Usually, the daily dosage of the compound (1) of the present invention is 1 kg body weight. About 0.5 to 20 mg per unit, preferably about 1 to 10 mg. Moreover, the said pharmaceutical formulation can be administered in 1 to 4 times a day.
In addition, this invention compound (1) can also be used together with another pharmaceutical ingredient, for example, another analgesic, if desired.
DETAILED DESCRIPTION OF THE INVENTION
Next, reference examples, examples, pharmacological test examples and formulation examples of the present invention will be shown to specifically explain the present invention, but the present invention should not be limited to these.
[0039]
【Example】
The production examples of the compounds of the present invention are listed below as examples. In addition, a production example of a raw material compound (intermediate) for producing the compound of the present invention is given as a reference example.
Furthermore, examples of pharmacological tests and preparations using the compounds of the present invention are given.
The compound obtained in each example has its structure, melting point and 1 H-NMR spectrum data is described as identification data.
In the following Reference Examples and Examples, 1 H-NMR spectra were measured using TMS (tetramethylsilane) as an internal reference, and DMSO (dimethyl sulfoxide) -d 6 was used as a measurement solvent unless otherwise specified. It was.
[0040]
[Reference Example 1] Preparation of bis [2- (3,4,5-trimethoxybenzyloxy) ethyl] sulfide 5.4 g of 60% sodium hydride was suspended in 70 ml of DMF, and bis (2-hydroxyethyl) was added thereto. 7.5 g of sulfide and 30.4 g of 3,4,5-trimethoxybenzyl chloride were sequentially added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with 200 ml of ethyl acetate. The organic layer was collected, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 3) to obtain 27.8 g of the title compound as an oil.
[0041]
[Reference Example 2] Preparation of bis [2- (3,4,5-trimethoxybenzoyloxy) ethyl] sulfide Using bis (2-hydroxyethyl) sulfide and 3,4,5-trimethoxybenzoyl chloride, the above reference In the same manner as in Example 1, the title compound was obtained.
[0042]
[Reference Example 3] Preparation of [2- (3,4,5-trimethoxybenzyloxy) ethyl] methyl sulfide The above Reference Example 1 was carried out using 2- (methylthio) ethanol and 3,4,5-trimethoxybenzyl chloride. In the same manner as above, the title compound was obtained.
[0043]
[Reference Examples 4 to 15]
Using 2- (methylthio) ethanol, 2- (methylthio) ethylamine or N- [2- (methylthio) ethyl] -N-methylamine and an appropriate chloride, in the same manner as in Reference Example 3, the following (4) to (4) to Each compound of (15) was produced.
(4) [2- (2-acetoxybenzoyloxy) ethyl] methyl sulfide (5) (2-cinnamoyloxyethyl) methyl sulfide (6) [2- (3,4,5-trimethoxycinnamoyloxy) ethyl ] Methyl sulfide (7) [2- (3,4,5-trimethoxybenzoyloxy) ethyl] methyl sulfide (8) [2- (2-methoxybenzoyloxy) ethyl] methyl sulfide (9) (2-phenoxyethyl) ) Methyl sulfide [0044]
(10) (2-acetoxyethyl) methyl sulfide (11) [2- (N-acetylamino) ethyl] methyl sulfide (12) [2- [N- (3,4,5-trimethoxybenzoyl) amino] ethyl ] Methyl sulfide (13) [2- [N- (2-acetoxybenzoyl) amino] ethyl] methyl sulfide (14) [2- [N-methyl-N- (3,4,5-trimethoxybenzoyl) amino] Ethyl] methyl sulfide (15) [2- [N- (3,4,5-trimethoxycinnamoyl) amino] ethyl] methyl sulfide
[Reference Example 16] Preparation of 4- (3,4,5-trimethoxybenzoyl) tetrahydro-4H-1,4-thiazine 10.3 g of tetrahydro-4H-1,4-thiazine was dissolved in 50 ml of pyridine, and 3 , 4,5-Trimethoxybenzoyl chloride 23.1g was added at 0 degreeC, and it stirred at room temperature for 24 hours. The reaction solution was diluted with water and extracted twice with 200 ml of ethyl acetate. The organic layer was collected, washed successively with 2N aqueous sodium hydroxide, 3N hydrochloric acid and saturated brine, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain 24.0 g (melting point: 98 to 100 ° C.) of the title compound.
[0046]
[Reference Examples 17 to 19]
Using tetrahydro-4H-1,4-thiazine and 3,4-dimethoxybenzoyl chloride, 3,4,5-trimethoxycinnamoyl chloride or 2-furoyl chloride, in the same manner as in Reference Example 16, the following (17) Each compound of (19) was produced.
(17) 4- (3,4-Dimethoxybenzoyl) tetrahydro-4H-1,4-thiazine (18) 4- (3,4,5-trimethoxycinnamoyl) tetrahydro-4H-1,4-thiazine (19 ) 4- (2-Furoyl) tetrahydro-4H-1,4-thiazine
Reference Example 20 Preparation of 7-chloro-2-oxo-3-phenyliodonium-1,2-dihydroquinolin-4-olate 8.3 g of sodium carbonate was dissolved in 400 ml of water, and 14.5 g of this aqueous solution was dissolved in this aqueous solution. 7-Chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline was dissolved, and 24.0 g of iodobenzene diacetate was further added at room temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the precipitated crystals were collected by filtration, washed with methanol, and dried under reduced pressure at 60 ° C. for 5 hours to obtain 28.1 g (melting point: 163 to 165 ° C.) of the target compound.
1 H-NMR (δ: ppm ) [DMSO-d 6]:
7.12 (1H, d, J = 7.4), 7.17-7.29 (2H, m), 7.36-7.61 (4H, m), 7.80-7.99 (3H, m), 10.80 (1H, s)
[0048]
[Reference Examples 21-26]
In the same manner as in Reference Example 20, the following compounds (21) to (22) were produced.
(21) 2-Oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate Melting point: 244-246 ° C
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
7.01 (1H, dd, J = 6.9,7.4), 7.17 (1H, d, J = 8.4), 7.32-7.50 (4H, m), 7.81 (2H, d, J = 7.4), 7.89 (1H, d, J = 6.9), 10.63 (1H, s)
[0049]
(22) 6-chloro-1-methyl-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate Melting point: 104-106 ° C
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.48 (3H, s), 7.33-7.58 (5H, m), 7.83 (2H, d, J = 7.9), 7.92 (1H, d, J = 3.0)
Further, in the same manner, the following compounds (23) to (26) were produced. These compounds were used as intermediates in the production of the compounds of the present invention as crude products.
[0050]
(23) 6-chloro-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate (24) 1-methyl-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4 -Olate (25) 6,7-dimethoxy-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate (26) 6,7-dimethoxy-1-methyl-2-oxo-3-phenyl Iodonium-1,2-dihydroquinoline-4-olate
Example 1 Preparation of 2-oxo-3- [4- (3,4,5-trimethoxybenzoyl) -1,4-thioxonium] -1,2-dihydroquinolin-4-olate In Reference Example 21 above 2.2 g of the compound obtained, 2.0 g of the compound obtained in Reference Example 16 and 100 mg of p-toluenesulfonic acid were dissolved in 20 ml of trifluoroethanol and stirred at 60 ° C. for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol: chloroform = 1: 10). The obtained crystals were washed with diethyl ether to obtain 2.5 g of the target compound as crystals. Obtained. Me in the following chemical structural formulas represents a methyl group.
[0052]
[Chemical 8]
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.10-3.33 (2H, m), 3.41-3.69 (2H, m), 3.71 (3H, s), 3.84 (6H, s), 4.41-4.61 (4H, m), 6.81 (2H, s), 7.03 ( 1H, dd, J = 7.2,7.9), 7.13 (1H, d, J = 8.2), 7.41 (1H, dd, J = 7.2,8.2), 7.84 (1H, d, J = 7.9), 10.55 (1H, s)
[0053]
[Examples 2 to 42]
The following compounds were prepared in the same manner as in Example 1 using the compounds of the above Reference Examples as raw materials.
[Example 2]
[Chemical 9]
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15-3.24 (2H, m), 3.41-3.67 (2H, m), 3.80 (3H, s), 3.81 (3H, s), 4.35-4.60 (4H, m), 7.00-7.09 (4H, m), 7.12 (1H, d, J = 7.9), 7.41 (1H, dd, J = 6.9,7.9), 7.84 (1H, d, J = 6.4), 10.53 (1H, s)
[0054]
Example 3
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.20-3.32 (2H, m), 3.45-3.75 (2H, m), 4.45-4.65 (2H, m), 4.71-4.88 (2H, m), 6.69 (1H, dd, J = 1.5,3.5), 7.02 (1H, dd, J = 6.9,7.9), 7.12 (1H, d, J = 7.9), 7.17 (1H, d, J = 3.5), 7.42 (1H, dd, J = 6.9,7.9), 7.81 (1H , d, J = 6.9), 7.91 (1H, d, J = 1.5), 10.52 (1H, s)
[0055]
Example 4
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.20-3.31 (2H, m), 3.44 (3H, s), 3.45-3.76 (2H, m), 4.47-4.64 (2H, m), 4.73-4.87 (2H, m), 6.69 (1H, dd, J = 1.0,3.5), 7.14 (1H, dd, J = 6.9,8.4), 7.17 (1H, d, J = 3.5), 7.33 (1H, d, J = 8.4), 7.55 (1H, dd, J = 6.9 , 8.4), 7.92 (1H, d, J = 1.0), 7.97 (1H, d, J = 8.4)
[0056]
Example 5
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.14-3.27 (2H, m), 3.45 (3H, s), 3.46-3.69 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.37-4.61 (4H, m), 7.05 ( 2H, s), 7.10 (1H, s), 7.15 (1H, dd, J = 7.4,7.4), 7.33 (1H, d, J = 8.4), 7.57 (1H, dd, J = 7.4,8.4), 7.99 (1H, d, J = 7.4)
[0057]
Example 6
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.11-3.27 (2H, m), 3.45 (3H, s), 3.46-3.68 (2H, m), 3.70 (3H, s), 3.84 (6H, s), 4.41-4.60 (4H, m), 6.82 ( 2H, s), 7.15 (1H, dd, J = 7.9,7.9), 7.33 (1H, d, J = 8.4), 7.57 (1H, dd, J = 7.9,8.4), 7.98 (1H, d, J = 7.9)
[0058]
Example 7
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15-3.27 (2H, m), 3.45-3.70 (2H, m), 3.73 (3H, s), 3.77 (3H, s), 4.49-4.64 (2H, m), 4.74-4.85 (2H, m), 6.68-6.70 (2H, m), 7.16 (1H, d, J = 3.5), 7.25 (1H, s), 7.91 (1H, d, J = 1.7), 10.27 (1H, s)
[0059]
Example 8
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.07-3.21 (2H, m), 3.51-3.68 (2H, m), 3.70 (3H, s), 3.74 (3H, s), 3.77 (3H, s), 3.83 (6H, s), 4.40-4.61 ( 4H, m), 6.68 (1H, s), 6.81 (2H, s), 7.27 (1H, s), 10.30 (1H, s)
[0060]
Example 9
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.09-3.21 (2H, m), 3.41-3.65 (2H, m), 3.45 (3H, s), 3.77 (3H, s), 3.80 (3H, s), 3.81 (3H, s), 4.41-4.69 ( 4H, m), 6.68 (1H, s), 7.05 (2H, s), 7.08 (1H, s), 7.28 (1H, s), 10.29 (1H, s)
[0061]
Example 10
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.20-3.31 (2H, m), 3.43 (3H, s), 3.51-3.73 (2H, m), 4.45-4.57 (2H, m), 4.73-4.84 (2H, m), 6.69 (1H, dd, J = 2.0,3.5), 7.17 (1H, d, J = 3.5), 7.36 (1H, d, J = 8.9), 7.58 (1H, dd, J = 3.0,8.9), 7.88 (1H, d, J = 3.0 ), 7.91 (1H, d, J = 2.0)
[0062]
Example 11
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15-3.29 (2H, m), 3.44 (3H, s), 3.45-3.70 (2H, m), 3.71 (3H, s), 3.83 (6H, s), 4.37-4.55 (4H, m), 6.80 ( 2H, s), 7.37 (1H, d, J = 8.9), 7.59 (1H, dd, J = 2.6,8.9), 7.90 (1H, d, J = 2.6)
[0063]
Example 12
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.18-3.28 (2H, m), 3.44 (3H, s), 3.45-3.69 (2H, m) m 3.81 (3H, s), 3.82 (3H, s), 4.40-4.55 (4H, m), 7.03- 7.10 (3H, m), 7.37 (1H, d, J = 8.9), 7.59 (1H, dd, J = 2.8,8.9), 7.90 (1H, d, J = 2.8)
[0064]
Example 13
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.20-3.33 (2H, m), 3.45 (3H, s), 3.46-3.71 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.49-4.65 (2H, m), 4.73- 4.84 (2H, m), 6.69 (1H, dd, J = 1.8,3.5), 6.79 (1H, s), 7.16 (1H, d, J = 3.5), 7.42 (1H, s), 7.91 (1H, d , J = 1.8)
[0065]
Example 14
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.09-3.25 (2H, m), 3.46 (3H, s), 3.71 (3H, s), 3.77 (3H, s), 3.84 (6H, s), 3.89 (3H, s), 4.43-4.95 (4H, m), 6.80 (1H, s), 6.83 (2H, s), 7.44 (1H, s)
[0066]
Example 15
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.11-3.24 (2H, m), 3.45 (3H, s), 3.46-3.65 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 3.89 (3H, s), 4.46-4.59 (4H, m), 6.80 (1H, s), 7.05 (2H, s), 7.09 (1H, s), 7.44 (1H, s)
[0067]
Example 16
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.27 (3H, s), 3.33 (3H, s), 3.71-3.85 (1H, m), 4.28-4.48 (2H, m), 4.53-4.65 (1H, m), 7.01 (1H, dd, J = 6.9 , 7.9), 7.10 (1H, d, J = 7.9), 7.15-7.25 (2H, m), 7.39 (1H, dd, J = 6.9,8.4), 7.63 (1H, dd, J = 6.9,7.9), 7.83 (1H, d, J = 7.9), 7.90 (1H, d, J = 7.9), 10.47 (1H, s)
[0068]
Example 17
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.27 (3H, s), 3.17 (3H, s), 3.71-3.84 (1H, m), 4.30-4.47 (2H, m), 4.52-4.67 (1H, m), 7.03 (1H, d, J = 8.4 ), 7.13 (1H, s), 7.18-7.27 (2H, m), 7.66 (1H, dd, J = 7.6,7.9), 7.79 (1H, d, J = 8.4), 7.90 (1H, d, J = 7.9), 10.59 (1H, s)
[0069]
Example 18
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.26 (3H, s), 3.17 (3H, s), 3.38 (3H, s), 3.71-3.84 (1H, m), 4.31-4.49 (2H, m), 4.52-4.66 (1H, m), 7.09- 7.24 (3H, m), 7.30 (1H, d, J = 8.2), 7.50-7.79 (2H, m), 7.85 (1H, d, J = 8.2), 7.96 (1H, d, J = 7.9)
[0070]
Example 19
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.26 (3H, s), 3.40-3.69 (2H, m), 3.70 (3H, s), 3.83 (6H, s), 3.84-3.95 (2H, m), 7.01 (1H, dd, J = 7.9,8.2 ), 7.11 (1H, d, J = 7.7), 7.19 (2H, s), 7.38 (1H, dd, J = 7.7,8.2), 7.82 (1H, d, J = 9.9), 8.68 (1H, brs) , 10.46 (1H, s)
[0071]
Example 20
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.26 (3H, s), 3.17 (3H, s), 3.70-3.85 (1H, m), 4.30-4.48 (2H, m), 4.53-4.68 (1H, m), 7.12 (1H, d, J = 8.7 ), 7.13-7.23 (2H, m), 7.45 (1H, d, J = 8.7), 7.65 (1H, dd, J = 7.7,7.9), 7.72 (1H, s), 7.89 (1H, d, J = 7.7), 10.63 (1H, s)
[0072]
Example 21
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15 (3H, s), 3.73 (3H, s), 3.74-3.81 (1H, m), 3.82 (6H, s), 4.20-4.33 (1H, m), 4.35-4.49 (1H, m), 4.70- 4.80 (1H, m), 6.98 (1H, dd, J = 6.9,7.7), 7.05 (1H, d, J = 7.7), 7.25 (2H, s), 7.38 (1H, dd, J = 7.7,8.2) , 7.78 (1H, d, J = 7.7), 10.40 (1H, s)
[0073]
[Example 22]
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.91 (3H, s), 3.14 (3H, s), 3.40-3.80 (6H, m), 3.80 (6H, s), 4.10-4.35 (1H, m), 6.75 (2H, s), 7.00 (1H, dd, J = 7.2,7.9), 7.10 (1H, d, J = 8.2), 7.39 (1H, dd, J = 6.9,8.2), 7.83 (1H, d, J = 9.9), 10.45 (1H, s)
[0074]
Example 23
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.90 (3H, s), 3.13 (3H, s), 3.41-3.75 (6H, m), 3.80 (6H, s), 4.10-4.31 (1H, m), 6.74 (2H, s), 7.03 (1H, d, J = 8.7), 7.14 (1H, s), 7.81 (1H, d, J = 8.7), 10.57 (1H, s)
[0075]
Example 24
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.16 (3H, s), 3.72-3.86 (1H, m), 4.25-4.46 (2H, m), 4.48-4.59 (1H, m), 6.49 (1H, d, J = 16.1), 7.00 (1H, dd , J = 6.9,7.9), 7.32-7.50 (4H, m), 7.53-7.67 (3H, m), 7.82 (1H, d, J = 7.9), 10.46 (1H, s)
[0076]
Example 25
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.25 (3H, s), 3.15 (3H, s), 3.35-3.60 (2H, m), 3.73-3.95 (2H, m), 7.01 (1H, dd, J = 7.2,7.9), 7.11 (1H, d , J = 7.9), 7.18 (1H, d, J = 8.2), 7.32 (1H, dd, J = 7.6,7.6), 7.38 (1H, dd, J = 7.6,8.2), 7.51 (1H, dd, J = 7.9,7.9), 7.64 (1H, d, J = 7.6), 7.82 (1H, d, J = 7.2), 8.54 (1H, brs), 10.46 (1H, s)
[0077]
Example 26
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
2.27 (3H, s), 3.15 (3H, s), 3.74 (3H, s), 3.77 (3H, s), 3.78-3.99 (1H, m), 4.23-4.47 (2H, m), 4.52-4.65 ( 1H, m), 6.67 (1H, s), 7.17-7.30 (3H, m), 7.66 (1H, dd, J = 7.7,7.9), 7.93 (1H, d, J = 7.9), 10.25 (1H, s )
[0078]
Example 27
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.16 (3H, s), 3.81 (3H, s), 3.82-3.95 (1H, m), 4.25-4.42 (2H, m), 4.50-4.65 (1H, m), 6.89 (1H, dd, J = 7.4 , 7.6), 7.02 (1H, dd, J = 7.6,7.9), 7.03-7.18 (2H, m), 7.38 (1H, dd, J = 7.2,7.6), 7.49 (1H, dd, J = 7.4,7.6 ), 7.69 (1H, d, J = 7.6), 7.82 (1H, d, J = 7.9), 10.47 (1H, s)
[0079]
Example 28
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15 (3H, s), 3.82-3.97 (1H, s), 4.02-4.17 (1H, s), 4.27-4.40 (2H, s), 6.85-7.03 (4H, m), 7.10 (1H, d, J = 7.9), 7.20-7.30 (2H, m), 7.39 (1H, dd, J = 6.9,7.9), 7.81 (1H, d, J = 7.9), 10.44 (1H, s)
[0080]
Example 29
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.16 (3H, s), 3.82-3.95 (1H, m), 4.05-4.15 (1H, m), 4.28-4.40 (2H, m), 6.88-6.99 (3H, m), 7.03 (1H, d, J = 8.4), 7.14 (1H, s), 7.20-7.31 (2H, m), 7.79 (1H, d, J = 8.4), 10.57 (1H, s)
[0081]
Example 30
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.09 (3H, s), 3.49-3.60 (1H, m), 3.62 (3H, s), 3.63-3.76 (2H, m), 3.77 (6H, s), 4.11-4.20 (1H, m), 4.38 ( 2H, s), 6.66 (2H, s), 7.02 (1H, dd, J = 6.4,7.9), 7.11 (1H, d, J = 7.9), 7.38 (1H, dd, J = 6.4,7.9), 7.82 (1H, d, J = 6.4), 10.43 (1H, s)
[0082]
Example 31
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15 (3H, s), 3.70 (3H, s), 3.82 (6H, s), 3.83-3.99 (1H, m), 4.20-4.38 (2H, m), 4.50-4.60 (1H, m), 6.57 ( 1H, d, J = 16.1), 6.95-7.10 (4H, m), 7.37 (1H, dd, J = 6.9,7.9), 7.60 (1H, d, J = 16.1), 7.81 (1H, d, J = 7.9), 10.44 (1H, s)
[0083]
[Example 32]
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.71 (6H, s), 3.76 (12H, s), 3.77-3.95 (2H, m), 4.27-4.40 (2H, m), 4.45-4.60 (2H, m), 4.70-4.85 (2H, m), 6.95 (1H, dd, J = 6.9,7.9), 7.01 (1H, d, J = 7.9), 7.20 (4H, s), 7.35 (1H, dd, J = 6.9,7.9), 7.72 (1H, d, J = 7.9), 10.34 (1H, s)
[0084]
Example 33
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.50-3.61 (2H, m), 3.62 (6H, s), 3.63-3.73 (4H, m), 3.74 (12H, s), 4.15-4.25 (1H, m), 4.38 (4H, s), 6.64 ( 4H, s), 7.01 (1H, dd, J = 6.9,7.9), 7.12 (1H, d, J = 7.7), 7.39 (1H, dd, J = 6.9,7.7), 7.83 (1H, d, J = 7.9), 10.43 (1H, s)
[0085]
Example 34
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.08 (3H, s), 3.50-3.61 (1H, m), 3.62 (3H, s), 3.63-3.73 (2H, m), 3.74 (3H, s), 3.77 (3H, s), 3.78 (6H, s), 4.11-4.20 (1H, m), 4.38 (2H, s), 6.66 (2H, s), 6.68 (1H, s), 7.28 (1H, s), 10.22 (1H, s)
[0086]
Example 35
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.15-3.30 (2H, m), 3.69 (3H, s), 3.70-3.83 (2H, m), 3.84 (6H, s), 4.35-4.60 (2H, m), 4.76-4.96 (2H, m), 7.02 (1H, dd, J = 7.4,8.2), 7.10-7.15 (3H, m), 7.29 (1H, d, J = 15.1), 7.40 (1H, dd, J = 7.9,8.2), 7.57 (1H, d, J = 15.1), 7.81 (1H, d, J = 7.4), 10.50 (1H, s)
[0087]
Example 36
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.10 (3H, s), 3.50-3.61 (1H, m), 3.62 (3H, s), 3.63-3.76 (2H, m), 3.77 (6H, s), 4.10-4.20 (1H, m), 4.37 ( 2H, s), 6.65 (2H, s), 7.13 (1H, d, J = 8.9), 7.45 (1H, d, J = 8.9), 7.75 (1H, s), 10.60 (1H, s)
[0088]
Example 37
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.09 (3H, s), 3.49-3.61 (1H, m), 3.62 (3H, s), 3.63-3.76 (2H, m), 3.77 (6H, s), 4.10-4.20 (1H, m), 4.38 ( 2H, s), 6.65 (2H, s), 7.04 (1H, d, J = 8.4), 7.14 (1H, s), 7.81 (1H, d, J = 8.4), 10.56 (1H, s)
[0089]
Example 38
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.09 (3H, s), 3.40 (3H, s), 3.41-3.60 (1H, m), 3.61 (3H, s), 3.62-3.75 (2H, m), 3.77 (6H, s), 4.10-4.20 ( 1H, m), 4.37 (2H, s), 6.65 (2H, s), 7.12 (1H, dd, J = 7.4,7.7), 7.30 (1H, d, J = 8.7), 7.54 (1H, dd, J = 7.4,8.7), 7.97 (1H, d, J = 7.7)
[0090]
Example 39
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.20-3.33 (2H, m), 3.43 (3H, s), 3.70 (3H, s), 3.71-3.83 (2H, m), 3.84 (6H, s), 4.35-4.60 (2H, m), 4.80- 4.98 (2H, m), 7.10-7.17 (3H, m), 7.23-7.35 (2H, m), 7.51-7.62 (2H, m), 7.96 (1H, d, J = 7.7)
[0091]
Example 40
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.14 (3H, s), 3.32-3.45 (1H, m), 3.46-3.63 (1H, m), 3.68 (3H, s), 3.69-3.80 (2H, m), 3.81 (6H, s), 6.57 ( 1H, d, J = 15.8), 6.91 (2H, s), 7.00 (1H, dd, J = 6.9,7.7), 7.10 (1H, d, J = 7.9), 7.33-7.43 (2H, m), 7.82 (1H, d, J = 7.7), 8.37 (1H, brs), 10.45 (1H, s)
[0092]
Example 41
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
1.96 (3H, s), 3.13 (3H, s), 3.75-3.80 (1H, m), 4.10-4.23 (2H, m), 4.25-4.40 (1H, m), 7.01 (1H, dd, J = 6.9 , 7.9), 7.10 (1H, d, J = 7.9), 7.40 (1H, dd, J = 6.9,7.9), 7.82 (1H, d, J = 7.9), 10.45 (1H, s)
[0093]
Example 42
Embedded image
1 H-NMR (δ: ppm) [DMSO-d 6 ]:
3.11 (3H, s), 3.18-3.38 (2H, m), 3.65-3.85 (2H, m), 7.01 (1H, dd, J = 6.9,7.9), 7.11 (1H, d, J = 7.9), 7.40 (1H, dd, J = 6.9,7.9), 7.82 (1H, d, J = 7.9), 8.15 (1H, brs), 10.45 (1H, s)
[0094]
[Pharmacological test example]
7 groups of 6-week-old male Wistar rats were used, and the pain threshold of the left hind paw of each rat was first determined using a pressure-stimulated analgesic effect measuring device (Unicom), and the Randall, Cerit method [Randall, LO and Sellitto, JJ, Arch. Int. Pharmacodyn., 111, 409 (1957)]. The obtained value is defined as “previous value”.
One hour after the above measurement, the experimental group further contained a 5% gum arabic suspension of the compound of the present invention, and the control group contained a 5% gum arabic suspension (without the compound of the present invention). Oral administration was carried out at a rate of 10 ml / kg so that the dose would be 10 mg / kg. One hour later, a physiological saline solution of substance P (25 g / 0.1 ml) was added to each rat's left hind footpad. It was injected subcutaneously.
Next, after a predetermined time after substance P injection, the pain threshold value of the left hind footpad of each group of rats was measured in the same manner as described above, and this was set as the “after value”.
From the measured value (after value) and the previous value of each group, the pain threshold recovery rate (%) was calculated according to the following formula.
Pain threshold recovery rate (%) = [(average value after experimental group) − (average value after control group)] / [(average value before control group) − (average value after control group)] × 100
The obtained results (maximum recovery rate) are shown in Table 1 below.
[0095]
[Table 1]
[Preparation Example 1] Preparation of Tablets 1000 tablets for oral use each containing 5 mg of the compound obtained in Example 16 were prepared according to the following formulation.
5 g of the compound of the present invention obtained in Example 16
Lactose (Japanese Pharmacopoeia) 50g
Corn starch (Japanese Pharmacopoeia) 25g
Crystalline cellulose (Japanese Pharmacopoeia) 25g
Methylcellulose (Japanese Pharmacopoeia) 1.5g
Magnesium stearate (Japanese Pharmacopoeia) 1g
That is, the compound of the present invention obtained in Example 16, lactose, corn starch and crystalline cellulose were thoroughly mixed, and the mixture was granulated with a 5% aqueous solution of methylcellulose and carefully dried through a 200 mesh sieve. The dried granules were passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.
[0097]
[Preparation Example 2] Preparation of Capsules 1000 two-piece hard gelatin capsules for oral use each containing 10 mg of the compound obtained in Example 28 were prepared according to the following formulation.
10 g of the compound of the present invention obtained in Example 28
Lactose (Japanese Pharmacopoeia) 80g
Starch (Japanese Pharmacopoeia) 30g
Talc (Japanese Pharmacopoeia) 5g
Magnesium stearate (Japanese Pharmacopoeia) 1g
That is, each of the above components was finely powdered and sufficiently stirred so as to form a uniform mixture, and then filled into capsules for oral administration having desired dimensions.
[0098]
[Preparation Example 3] Preparation of injection A sterilized aqueous solution suitable for parenteral administration containing the compound obtained in Example 16 was prepared according to the following formulation.
1 g of the compound of the present invention obtained in Example 16
Polyethylene glycol (Japanese Pharmacopoeia) (Molecular weight: 4000) 0.9g
Sodium chloride (Japanese Pharmacopoeia) 0.9g
Polyoxyethylene sorbitan monooleate (Japanese Pharmacopoeia) 0.4g
Sodium metabisulfite (Japanese Pharmacopoeia) 0.1g
Methyl-paraben (Japanese Pharmacopoeia) 0.18g
Propyl-paraben (Japanese Pharmacopoeia) 0.02g
100ml distilled water for injection
That is, the above parabens, sodium metabisulfite and sodium chloride were dissolved in about half of the above distilled water at 80 ° C. with stirring, and the resulting solution was cooled to 40 ° C., which was obtained in Example 16. The compound of the present invention and polyoxyethylene sorbitan monooleate were dissolved. Next, distilled water for injection was added to the resulting solution to adjust the final volume, and sterile injection was performed using an appropriate filter paper to prepare an injection.
【The invention's effect】
The novel dihydroquinoline derivative represented by the above general formula (1) provided by the present invention has an excellent analgesic action particularly against neuropathic pain, and is useful as a medicament with significantly reduced toxicity and side effects.
Claims (9)
Ｚが−Ｏ−であり、Ｒ９がフェニル基、又はアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基であるか、
Ｚが−ＮＨ−であり、Ｒ ９ がベンゼン環上にアルコキシ基３個を有するシンナモイル基、又はアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基であるか、
Ｚが−Ｎ（アルキル基）−であり、Ｒ ９ がアルカノイルオキシ基若しくはアルコキシ基の１〜３個を有するベンゾイル基である、
請求項５に記載のジヒドロキノリン誘導体。 A is an ethylene group ,
Z is -O-, and either R 9 is phenyl, also a benzoyl group having 1-3 alkanoyloxy group or alkoxy group,
Z is —NH— and R 9 is a cinnamoyl group having 3 alkoxy groups on the benzene ring, or a benzoyl group having 1 to 3 alkanoyloxy groups or alkoxy groups,
Z is —N (alkyl group) —, and R 9 is a benzoyl group having 1 to 3 alkanoyloxy groups or alkoxy groups,
The dihydroquinoline derivative according to claim 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05940699A JP4011780B2 (en) | 1999-03-05 | 1999-03-05 | Dihydroquinoline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP05940699A JP4011780B2 (en) | 1999-03-05 | 1999-03-05 | Dihydroquinoline derivatives |
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| JP2000256324A JP2000256324A (en) | 2000-09-19 |
| JP4011780B2 true JP4011780B2 (en) | 2007-11-21 |
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