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JP4409680B2 - Tricyclic fused imidazole derivatives - Google Patents

Tricyclic fused imidazole derivatives Download PDF

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JP4409680B2
JP4409680B2 JP29521499A JP29521499A JP4409680B2 JP 4409680 B2 JP4409680 B2 JP 4409680B2 JP 29521499 A JP29521499 A JP 29521499A JP 29521499 A JP29521499 A JP 29521499A JP 4409680 B2 JP4409680 B2 JP 4409680B2
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JP2001114780A (en
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▲隆▼ 八重樫
裕之 西山
利幸 逸見
誠吾 沢田
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Yakult Honsha Co Ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Description

【０００１】
【産業上の利用分野】
本発明は抗炎症作用を有する新規な三環性縮合イミダゾール誘導体に関する。
【０００２】
【従来技術】
アスピリンやインドメタシンなどの非ステロイド系抗炎症薬（NSAIDs）は、汎用されている薬剤の一つであるが、消化管粘膜障害などの副作用が問題となっている。NSAIDsの副作用は、その主作用であるシクロオキシゲナーゼ（COX）の阻害によるプロスタグランジン（PG）の生合成の低下によるものと考えられている。最近、COXには二つのアイソフォーム、COX-1とCOX-2が存在することが明らかにされた。COX-1は全組織に広く存在し、その生理機能の恒常性維持に寄与し、COX-2は主に炎症部位に誘導されると考えられている。従って、選択的なCOX-2阻害薬は消化管粘膜障害などのない抗炎症薬として期待されることから、従来のNSAIDsよりも有用である。
【０００３】
そのような抗炎症薬は、ジャーナル オブ メディシナル ケミストリー(J. Med. Chem)３７、３８７８（１９９４）、J. Med. Chem., ３８、４５７０（１９９５）、 J. Med. Chem., ４０、１３４７（１９９７）、 J. Med. Chem., ４０、１６１９（１９９７）、 J. Med. Chem., ４０、１６３４（１９９７）、バイオオーガニック & メディシナル ケミストリー レターズ(Bioorganic & Medicinal Chemistry Letters)６、８７（１９９６）及びBioorganic & Medicinal Chemistry Letters., ６、２８２７（１９９６）などに様々な化合物が開示されている。しかしながら、消化管粘膜障害等の副作用の少ない炎症の治療に有効な化合物を得るためには、更に効果的にPGE2などの炎症のメディエーターの産生を抑制する化合物の創製が待望されている。
【０００４】
【発明が解決しようとする課題】
従って、本発明の課題は、シクロオキシゲナーゼ−２に対する阻害作用を有する副作用の少ない物質を提供することにある。
【０００５】
【課題を解決するための手段】
本発明者らは、ある種の三環性縮合イミダゾール誘導体が選択的にCOX-2を阻害することにより、PGE2の産生を著しく抑制することを見い出し、本発明を完成した。
【０００６】
即ち、本発明は、一般式（１）
【化２】

Figure 0004409680
【０００７】
（式中、Ｒ１は、低級アルコキシル基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、アミノスルホニル基、またはハロゲン原子、
Ｒ２は、水素原子、低級アルキル基、低級アルコキシル基、低級アルキルチオ基、トリハロゲノメチル基、低級アルキルスルホニル基、アミノスルホニル基、モノまたはジハロゲン原子、
Ｘ−Ａは、−（CH2）n−、−OCH2−、−ＳCH2−、または−C(R3)=C(R4)−であって、この場合、nは１−３の整数、Ｒ３、Ｒ４は、水素原子、ハロゲン原子であり、
Ｙ−Ｚは、＝C(R5)−Ｎ＝、＝Ｎ−C(R6)＝、または＝C(R5)−C(R6)＝であって、この場合、
Ｒ5 、Ｒ6は、水素原子、ハロゲン原子、低級アルキル基、ヒドロキシメチル基、モノハロゲノメチル基、ジハロゲノメチル基、トリハロゲノメチル基、シアノ基、ニトロ基、ホルミル基、カルボキシル基、低級アルコキシカルボニル基、低級アルコキシメチル基、置換または非置換のアラルキルオキシメチル基、またはアリールオキシメチル基であることを示す）
で表される三環性縮合イミダゾール誘導体に関する。
また、本発明は、上記三環性縮合イミダゾール誘導体を有効成分とするシクロオキシゲナーゼ−２の阻害剤に関する。
さらに本発明は、上記三環性縮合イミダゾール誘導体を有効成分とする医薬に関する。
以下、本発明を詳細に説明する。
【０００８】
【発明の実施の形態】
本発明の三環性縮合イミダゾール誘導体は新規化合物であり、下記の方法で製造することができるが、これらは本発明を制限するものではない。
例えば、式１−１の方法でＲ６が低級アルキル基でＹが窒素原子（Ｎ）である三環性縮合イミダゾール誘導体を製造することができる。
【０００９】
【化３】
Figure 0004409680
式１−１
【００１０】
（式中、Ｒ１、Ｒ２、Ｒ６は、先の定義に同じ。）
【００１１】
化合物Ｉを塩基の存在下Ｒ６が、低級アルキル基であるハロゲン化カルボニル化合物（halo−CH2COR６）と反応させてN-アルキル体（化合物ＩＩ）を得る。例えば、 Ｒ６がメチル基の場合、クロロアセトンが例示される。塩基としては炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属塩、ピリジン、４−Ｎ，Ｎ−ジメチルアミノピリジン（DMAP）、トリエチルアミン、ジイソブチルアミン等の有機塩基類が挙げられる。
【００１２】
溶媒としてはアセトン、テトラヒドロフラン（THF）、ジメトキシエタン、ベンゼン、トルエン、Ｎ，Ｎ-ジメチルホルムアミド（DMF）等を用いることができるが、乾燥アセトン中無水炭酸カリウムの存在下加熱還流することが好ましい。アルカリ金属塩を使用する場合、ベンジルトリエチルアンモニウム塩、テトラブチルアンモニウム塩などの４級アンモニウム塩を添加するのが好ましい。化合物ＩＩを酢酸アンモニウムと酢酸中加熱還流することによりイミダゾール体（化合物ＩＩＩ）とし、次いで、化合物ＩＩＩをハロゲン化することにより、1-位ハロゲノ体（化合物ＩＶ）が得られる。 ハロゲン化は、臭素（Br2）、N−ブロモこはく酸イミド（NBS）、一塩化よう素（ICl）、N−ヨードこはく酸イミド（NCI）を用いることによりブロム体、ヨード体が得られる。溶媒としては酢酸またはアセトニトリルなどが用いられるが、酢酸が好ましい。また、反応は遮光下行うことが望ましい。
【００１３】
最後に、化合物ＩＶとアミノスルホニル基を除く上記で定義したＲ２を有するアリールほう酸類とのSuzukiカップリング反応によりアリール基を導入して本発明化合物Ｖを製造することができる。Suzukiカップリング反応の触媒としてはテトラキストリフェニルホスフィンパラジウム（Pd[PPh3]4）が好ましく、塩基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のアルカリ金属塩、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等の水酸化アルカリ及びこれらの水溶液が挙げられる。溶媒としてはメタノール、エタノール、ベンゼン、トルエン、キシレン等及びこれらの混合溶媒を用い、アルゴンガス雰囲気下で加熱還流することが望ましい。例えば、塩基として２Ｍ 炭酸ナトリウム水溶液を用い、エタノール−トルエンの混合溶媒中でアルゴンガス雰囲気下加熱還流する方法が例示される。
【００１４】
Ｘ−Ａが−(CH2)n−や−O−CH2−で、Ｒ1が低級アルキルチオ基の化合物Ｖの場合、m-クロロ過安息香酸（mCPBA）や過酸化水素等の酸化剤を用いて酸化することにより、低級アルキルスルフィニル体及び低級アルキルスルホニル体を製造することができる。例えば、メチルチオ体を塩化メチレン中1当量のmCPBAで処理してメチルスルフィニル体を、２．２当量用いることによりメチルスルホニル体を製造することができる。
【００１５】
また、Ｘ−Ａがイオウ原子を含みＲ１が低級アルキルスルホニル基の化合物Ｖの場合、Ｒ１が低級アルキルスルホニル基の化合物Ｉを出発物質に用いることが望ましい。
式１−２の方法でＲ６が低級アルキル基を除く上記の定義で表され、Ｙが窒素原子（Ｎ）の場合の三環性縮合イミダゾール誘導体を製造することができる。
【００１６】
【化４】
Figure 0004409680
式１−２
【００１７】
（式中、Ｒ１、Ｒ２、Ｒ６は、先の定義に同じであり、Ｒ７は、水素原子、 ハロゲン原子、Ｒ2基を有するアリール基、Xは、−CH2−、−CH2CH2−、酸素原子、またはイオウ原子を表す。）
【００１８】
化合物ＩをLawesson試薬で処理してチオアミド体（化合物ＶＩ）へと変換し、次いで、塩基の存在下ハロゲン化メチルとの反応でメチルチオ体（化合物ＶＩＩ）を得る。 Lawesson試薬との反応の溶媒としては、THF、塩化メチレン、クロロホルム等が使用できる。Ｓ−メチル化反応は、ハロゲン化メチルとしてよう化メチルや臭化メチルなどを用い、THF、塩化メチレン、クロロホルム、DMF等を溶媒として行うことができる。塩基としては、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム等のアルカリ金属塩、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、n-ブチルリチウム、tert−ブトキシカリウムまたはトリエチルアミンなどの３級アミンが例示できる。
【００１９】
化合物ＶＩＩとアミン（NH2CH2COR７）との反応でアミジン体（化合物ＶＩＩＩ）を得る。アミジノ化反応は、溶媒としてアセトニトリル、THF、塩化メチレン、クロロホルム、DMF等を用いて行うことができる。好ましくは、乾燥したアセトニトリル中加熱還流することが望ましい。アミンとしては、Ｒ７が、上記で定義したＲ２を有するアリール基で表されるアリールカルボニルメチルアミン類、またはそれらの塩を用いる。塩酸塩などの塩を用いる場合、トリエチルアミン等の塩基を共存させることが望ましい。また、Ｒ６が、水素原子すなわちアルデヒド化合物の場合、カルボニル基が通常用いられる保護基で保護されたアルキルアセタール類（NH2CH2CH[Oアルキル]２）が用いられる。例えば、アミノアセトアルデヒドジメチルアセタールが例示される。
【００２０】
Ｒ７が、上記で定義したＲ２を有するアリール基である化合物ＶＩＩＩを酸で処理することにより環化し、Ｒ６が水素原子である三環性縮合イミダゾール誘導体（化合物Ｖ）を製造することができる。環化反応は、無水ｐ−トルエンスルホン酸の存在下に溶媒として乾燥したベンゼン、トルエン、キシレン等を用い、加熱還流下に行われる。また、Ｒ７が、水素原子である化合物ＶＩＩＩ（アルキルアセタール体）を塩酸、臭化水素酸、硫酸等の鉱酸やｐ−トルエンスルホン酸等で処理することにより、例えば、１N塩酸中加熱還流することで環化し、Ｒ６が水素原子である三環性縮合イミダゾール誘導体（化合物ＩＩＩ）を得る。このものを式１−１に示した方法と同様に、１位の選択的ハロゲン化、次いで、アミノスルホン基を除く上記で定義したR2を有するアリールほう酸類とのSuzukiカップリング反応によりＲ６が水素原子である三環性縮合イミダゾール誘導体類（化合物Ｖ）を製造することができる。Ｒ１が低級アルキルチオ基の場合、適当な酸化剤、例えばmCPBAで酸化することによりメチルスルフィニル体及びメチルスルホニル体を製造することができる。
【００２１】
Ｒ６が、低級アルキル基を除く上記で定義した置換基、例えば、ハロゲン原子、ニトロ基、シアノ基、トリフルオロメチル基を有する三環性縮合イミダゾール誘導体（化合物Ｖ）は、 Ｒ６が、水素原子またはそれから誘導されるハロゲン原子、好ましくはブロム原子の化合物Ｖの置換反応で製造することができる。例えば、Ｒ６が水素原子の化合物を反応の溶媒としてアセトニトリルまたは酢酸を用い、NCSまたはNBSと処理することでクロロ体及びブロム体を、無水酢酸中硝酸と加熱することでニトロ体を製造できる。また、ブロム体をDMF中シアン化第一銅と加熱（170℃）することでシアノ体を、Ｎ，Ｎ−ジメチルアセトアミド（DMA）中よう化銅の存在下トリフルオロ酢酸ナトリウムと煮沸還流することでトリフルオロメチル体を製造できる。
【００２２】
式２−１の方法でＺが窒素原子（Ｎ）である三環性縮合イミダゾール誘導体を製造することができる。
【００２３】
【化５】
Figure 0004409680
式２−１
【００２４】
（式中、Ｒ１、Ｒ２、Ｒ５は、先の定義に同じ。）
【００２５】
化合物ＩＸは、ジャーナル オブ ヘテロサイクリック ケミストリー（J. Heterocyclic Chem.）,２０、１６０５（１９８３）及び J. Heterocyclic Chem.,２６、２０５（１９８９）．に開示された方法を参考に製造することができる。すなわち、化合物ＩをDMFを溶媒として用い、カリウムtert-ブトキシドの存在下クロロりん酸ジエチルで処理し、活性なイミダート体とし、この反応液にカリウムtert-ブトキシドの存在下イソシアノ酢酸アルキルエステルを作用させ、Ｒ５が、低級アルコキシカルボニル基である三環性縮合イミダゾール類（化合物ＩＸ）を得る。Ｒ１が、低級アルキルチオ基の場合は、前述のように酸化して低級アルキルスルフィニル基及び低級アルキルスルホニル基へと変換することができる。Ｘがイオウ原子の場合、 Ｒ１が、低級アルキルスルホニル基の化合物Ｉを用いることが望ましい。
【００２６】
次いで、化合物ＩＸをハロゲン化することにより、1-位ハロゲノ体（化合物Ｘ）を得る。 ハロゲン化反応の条件は、化合物ＩＩＩのハロゲン化の場合と同様である。この場合、溶媒としてはアセトニトリルが好ましい。ハロゲン化反応において、Ｘが、−CH2−の場合、デヒドロ体（Ｘ−Ａが−CH=CH−）が得られる。例えば、式２−２（製造例２２）に示す様に、化合物ＩＸbのNBSによるブロム化で、テトラヒドロ体（化合物Ｘa）とデヒドロ体（化合物Ｘｂ）が得られる。反応を遮光下行うことにより化合物Ｘaの生成比は増加する。
【００２７】
最後に、化合物Ｘとアミノスルホニル基を除く上記で定義したR2を有するアリールほう酸類との前述のSuzukiカップリング反応によりアリール基を導入して本発明化合物ＸＩを製造することができる。 Suzukiカップリング反応の条件は、上記式１−１の場合と同様である。反応に依存して、はじめに、Ｒ５が低級アルコキシカルボニル基の化合物、例えば、ＸＩ’が得られる。また、化合物Ｘaと化合物Ｘbは分離が困難であるため、混合物としてSuzukiカップリング反応を行った後分離することにより化合物ＸＩ−１及び化合物ＸＩ−２を得ることができる。化合物ＸＩ−２は、ロジウムを触媒として用い、酢酸を溶媒として還元することにより化合物ＸＩ−１へ変換することができる。
【００２８】
【化６】
Figure 0004409680
式２−２
【００２９】
次いで、式３に示す様に低級アルコキシカルボニル基を通常用いられる反応により変換することで、上記で定義したＲ５を有するＺが窒素原子（Ｎ）である三環性縮合イミダゾール類（化合物ＸＩ）を製造できる。
【００３０】
【化７】
Figure 0004409680
式３
【００３１】
（式中、Ｒ１、Ｒ２、Ｒ５は、先の定義に同じ。）
【００３２】
Ｒ５が、低級アルコキシカルボニル基である化合物ＸＩを、通常用いられる条件で加水分解してカルボキシ体を得る。例えば、塩基として水酸化ナトリウム、水酸化カリウム、水酸化リチウム等の水溶液を用い、メタノール、エタノール等のアルコール類を溶媒として加熱還流することで得られる。カルボキシ体をキノリン中銅粉末と220-225℃で加熱し、脱炭酸することによりＲ５が、水素原子の化合物 を製造できる。Ｒ５が、水素原子の化合物をハロゲン化することによりＲ５にクロル及びブロム原子の導入された化合物を製造できる。ハロゲン化反応は、溶媒としてアセトニトリルまたは酢酸を用い、臭素、塩素、NCSやNBS等のＮ−ハロゲン化こはく酸イミドを用いて行うことができる。Ｘが、−CH2−の場合、例えば実施例４１及び実施例４２で示す様に、化合物ＸＩ−４をアセトニトリル中NCSで処理することにより化合物ＸＩ−５（ジヒドロ−クロル体）、ＸＩ−６（デヒドロ−クロル体）及びＸＩ−７（デヒドロ−ジクロル体）が得られる。
【００３３】
ブロム体をDMF中シアン化第一銅と加熱（１７０−１８０℃）することで、また、DMA中よう化第一銅存在下トリフルオロ酢酸ナトリウムと加熱還流することで、シアノ体及びトリフルオロメチル体を製造できる。
【００３４】
また、低級アルコキシカルボニル体をTHF中水素化リチウムアルミニウムを用いて還元することでヒドロキシメチル体に変換できる。このものを乾燥塩化メチレン中サルファー トリフルオリド ジエチルアミン コンプレクス（DAST）で処理することでモノフルオロメチル体を、また、乾燥クロロホルム中チオニルクロリドで処理することによりクロロメチル体を製造できる。クロロメチル体をDMF中ナトリウムアリールオキシドと反応することでアリールオキシメチル体を製造できる。また、ヒドロキシメチル体をTHFまたはDMF中塩基の存在下低級ハロゲン化アルキル及びハロゲン化アラルキルで処理して低級アルコキシメチル体及びアラルキルオキシメチル体を製造できる。この場合、塩基としては、水素化ナトリウム（NaH）やブチルリチウムなどのアルカリ金属塩が例示される。また、ヒドロキシメチル体は、塩化メチレン中Dess-Martin試薬で処理してホルミル体に変換できる。更に、ホルミル体を無水のメタノール中ピリジン存在下ヒドロキシアミン-O-スルホン酸と煮沸還流することでシアノ体を、また、塩化メチレン中DASTで処理してジフルオロメチル体を製造できる。
【００３５】
Ｒ１またはＲ２がアミノスルホニル基である化合物Ｖあるいは化合物ＸＩは、対応するメチルスルホニル体よりテトラヘドロン レターズ、３５、７２０１（１９９４）に記載された方法を参考にして製造することができる。例えば、実施例８４で示す様に、メチルスルホン体（化合物Ｖ−６５）をTHF中塩化プロピルマグネシウム、トリエチルほう素と反応させた後、酢酸ナトリウム及びヒドロキシルアミン-O-スルホン酸と処理することでアミノスルホニル体（化合物Ｖ−６８）を製造できる。
【００３６】
上記の反応の出発物質である環状ラクタム化合物（化合物Ｉ）は、例えば、下記の式 に示した方法で製造することができる。
【００３７】
【化８】
Figure 0004409680
【００３８】
Ｘ−Ａが−(CH2)2−のジヒドロキノリン類の場合、例えば、メチルチオ体（化合物Ia）は、文献記載（Chem, Pharm, Bull., ３１、７９８（１９８３））の チオール体（Ｓ−２）を塩基の存在下メチル化することで得られる。メチル化剤としてよう化メチル、臭化メチル等を用い、溶媒としてＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、クロロホルム、塩化メチレン、テトラヒドロフラン（ＴＨＦ）等を使用し、塩基として水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ、炭酸水素ナトリウムや炭酸水素カリウム等のアルカリ金属塩またはトリエチルアミンなどの有機塩基を用いることができる。例えば、溶媒としてＤＭＦを使用し、塩基としてトリエチルアミンを用いる方法が例示される。Ｓ−２の製造に際して、文献に記載されたクロロスルホニル体の還元工程は、理由は分からないが文献記載の条件では良好な結果が得られず、酢酸中活性化亜鉛を用いることで中程度の収率で得ることができる（参考例２）。
【００３９】
また、化合物Ｉｂは、ジャーナル オブ オルガニック ケミストリー（J, Org, Chem.,）５５、１７４４（１９９０）及びJ. Heterocyclic Chem., ２５、１２７９（１９８８）に記載された方法に従い、市販のテトラヒドロキノリンをタングステン酸ナトリウムで酸化、ヒドロキシルアミン-O-メチル体とし、酸触媒での転移反応により製造できる。
【００４０】
【化９】
Figure 0004409680
【００４１】
Ｘが−CH2CH2−の出発原料である化合物Icは、米国特許ＰＣＴ／ＵＳ９２／０２２７１及びＥＰ０ ３２５ ９６３ Ａ１に開示されている方法で得られる。しかしながら、理由は分からないが、最初の工程のベンゼン中塩化アルミニウムによる脱メチル化反応及び最終工程のメタンスルホン酸−無水りん酸中のオキシム体のベックマン転移反応の収率は低いものであった。そこで、脱メチル化反応は４７％臭化水素酸中加熱還流することにより、高収率でヒドロキシ体が得られた。また、ベックマン転移反応は、８５％りん酸−無水りん酸中９０℃で加熱するかもしくは、オキシム体をピリジン中塩化トシルで処理し、次いで加熱還流することでＩｃが中程度の収率で得られた。
【００４２】
【化１０】
Figure 0004409680
【００４３】
（式中Ｒ１は、低級アルキルチオ基、低級アルキルスルホン基、またはハロゲン原子を表す。）
【００４４】
Ｘ−Ａが-O-CH2-のベンゾオキサジノン類の場合、５位にＲ１基を有する２−ニトロフェノール類を塩基の存在下ハロゲン化酢酸アルキルエステルを用いてＯ−アルキル化し、次いで、ニトロ基を還元すると同時に環化して製造することができる。 Ｏ−アルキル化反応は、溶媒としてアセトン、ＴＨＦ、ＤＭＦ等が使用でき、塩基としては、炭酸カリウム、炭酸ナトリウム、水素化ナトリウム、tert−ブトキシカリウム等が挙げられる。
【００４５】
Ｒ１が、低級アルキルチオ基である化合物Ｉの場合、５−フルオロ−２−ニトロフェノールを出発原料に用い、溶媒としてＤＭＦ、ＴＨＦ等を使用し、塩基の存在下低級チオアルキコキシドナトリウムを作用させることでフッ素原子をイオウで置換し、次いで前記と同様にして製造できる。例えば、製造例２３に示す様に、ＤＭＦを溶媒として用い、１Ｎ 水酸化ナトリウムの存在下、チオメトキシドナトリウムとの反応でメチルチオ体（化合物Ｉｄ）が製造できる。また、Ｒ１が、低級アルキルチオ基の場合、適当な酸化剤、例えばmCPBAで酸化することによりメチルスルフィニル体及びメチルスルホニル体を製造できる。還元−環化反応は、例えば、溶媒としてメタノール、エタノール等のアルコールを用い、鉄−塩酸、錫−塩酸、及び塩化錫−塩酸等と加熱還流することで行うことができる。
【００４６】
【化１１】
Figure 0004409680
【００４７】
（式中Ｒ１は、低級アルコキシル基、低級アルキルスルホニル基、またはハロゲン原子を表す。）
【００４８】
Ｘ−Ａが-S-CH2-のベンゾチアジノン類の場合、上記の式に従って製造することができる。例えば、Ｒ１基が、ハロゲン原子の化合物は、４位にハロゲン原子を有する２−フルオロニトロベンゼン類を塩基の存在下チオグリコール酸アルキルエステルを用いてフッ素原子をイオウ原子で置換し、次いで、ニトロ基を還元すると同時に環化して製造することができる。チオグリコール酸アルキルエステルの置換反応は、溶媒として、ＴＨＦ、ＤＭＦ等が使用でき、塩基としては、炭酸カリウム、炭酸ナトリウム、水素化ナトリウム、tert−ブトキシカリウム等が挙げられる。また、還元−環化反応の条件は、Ｘが酸素の場合と同様である。例えば、Ｒ１がフッ素原子の化合物Ｉｇの場合、２、４−ジフルオロニトロベンゼンをＤＭＦ中炭酸カリウムの存在下、チオグリコール酸メチルと８０℃で加熱することで５−フルオロ−２−ニトロチオエーテル体へ変換し、次いでエタノール中鉄−塩酸と加熱還流することで製造できる（製造例５１及び製造例５４）。また、Ｒ１が、低級アルキルスルホニル基の場合は、前記の５−フルオロ−２−ニトロチオエーテル体と低級アルキルスルフィン酸ナトリウムをＤＭＦを溶媒として用い、加熱することで低級アルキルスルホニル体へ変換し、次いで前記したように還元と同時に閉環して製造できる。例えば、メチルスルフィン酸ナトリウムを用いることで、化合物Ｉｆ（Ｒ１がCH3SO2）を製造できる（製造例５２及び製造例５３）。
【００４９】
Ｒ１が、低級アルコキシル基の化合物は、２−アミノ−６−アルコキシベンゾチアゾールをアルカリ加水分解し、生成するチオフェノキシド体をハロゲン化酢酸アルキルエステルによりＳ−アルキル化し、次いで酢酸などを添加し酸性条件下で加熱還流し、環化することで製造できる。加水分解反応は、水酸化カリウム水溶液、水酸化ナトリウム水溶液等の水酸化アルカリ中加熱還流する方法が挙げられる。また、ハロゲン化酢酸アルキルエステルとしては塩化酢酸メチル、臭化酢酸エチル、臭化酢酸メチル、よう化酢酸エチル等が例示できる。
【００５０】
本発明に係る三環性縮合イミダゾール誘導体は、シクロオキシゲナーゼ−２に対する強い阻害活性を有しており、選択性の高い抗炎症剤として有用である。
また、使用上問題となるような生理作用は確認されていない。
【００５１】
本発明は、三環性縮合イミダゾール誘導体を有効成分とし薬学的、製剤的に許容される医薬品添加物を含有する薬剤組成物を提供する。有効成分の三環性縮合イミダゾール誘導体は、１日当たり約０．００１ｎｇ〜約１００ｍｇの範囲で投与することが可能であるが、もちろん症状、年齢、疾患の程度、併用する薬剤などに応じ、副作用などを生じないようにその投与量を選択することができるし、投与回数も１日当たり１回からそれ以上の複数回といったように適宜選択することができる。有効成分の三環性縮合イミダゾール誘導体は、製剤に０．０００１％〜５０％の範囲で配合することができるが、必要に応じその量は適宜選択することは可能である。
【００５２】
本発明の薬剤組成物は混合などによって調製され、適宜必要に応じて安定化剤、ｐＨ調節剤、界面活性剤、緩衝剤、香料、防腐剤、基剤、溶剤、希釈剤、充填剤、増量剤、溶解補助剤、可溶化剤、等張化剤、乳化剤、懸濁化剤、分散剤、増粘剤、ゲル化剤、硬化剤、吸収剤、粘着剤、弾性剤、可塑剤、結合剤、崩壊剤、噴射剤、保存剤、抗酸化剤、遮光剤、保湿剤、緩和剤、帯電防止剤、無痛化剤などを単独もしくは組合わせて含有させることができる。安定化剤としては、グリシンなどのアミノ酸あるいはその塩、ブドウ糖、ショ糖などの糖、マンニトール、ソルビトールなどの糖アルコール、オリゴ糖、多糖、アルブミン、ゼラチン、グロブリン、プロタミンなどのタンパク質、ペプチドなどが挙げられる。ｐＨ調節剤としては、塩酸、硫酸、燐酸、炭酸などの無機酸、クエン酸などの有機酸、あるいはそれらの塩が挙げられる。その他、医薬品に配合されて用いることが知られているものから適宜必要に応じ選択して用いることが出来る。 本発明の医薬組成物は、好ましくは塩類（塩化ナトリウム、リン酸塩など）、賦形剤（乳糖、トウモロコシデンプンなど）、軟膏基剤（白色ワセリン、パラフィン、オリーブ油、マクロゴール４００、マクロゴール軟膏など）、溶解剤（注射用蒸留水、アセトン、エーテル、プロピレングリコールなど）、矯味・矯臭・着色剤（単シロップ、ｌ−メントール、ハッカ油、クエン酸など）を配合することができる。
【００５３】
本発明の医薬組成物は、もちろん他の抗炎症剤などの薬剤と併用することも可能である。
【００５４】
本発明の医薬組成物は、経口、局所、経皮、静脈内、筋肉内、皮下、皮内もしくは腹腔内投与に適用し得るが、腫瘍患部への直接投与も可能であり、またある場合には好適でもある。また好ましくはヒトを含む哺乳動物に経口的に、あるいは非経口的（例、腫瘍内、静脈内、筋肉内、皮下、皮内、腹腔内、胸腔内、脊髄腔内、点滴静脈内、注腸、経直腸、点眼や点鼻、皮膚や粘膜への塗布など）に投与することができる。本発明の医薬組成物は、散剤、顆粒剤、錠剤、硬カプセル剤、軟カプセル剤、マイクロカプセル剤、軟膏製剤、硬膏製剤、溶液剤、水剤、油剤、クリーム剤、パスタ剤、パップ剤、リニメント剤、ローション剤、エアゾール剤、スプレー剤、点鼻剤、懸濁剤、乳濁剤、チンキ剤、皮膚用水剤、点眼剤、埋込剤、直腸坐剤、灌注剤、貼付剤、輸液剤、注射剤、注射用液剤などのための粉末剤、凍結乾燥製剤等を任意に選択することができる。
【００５５】
錠剤、カプセル剤などの固体の単位投与形態では、慣用の形態のものでよいが、例えば本発明の三環性縮合イミダゾール誘導体と、トウモロコシデンプン、バレイショデンプン、アルギン酸ナトリウム、カルボキシメチルセルロース（ＣＭＣ）、ゼラチンなどの崩壊剤、デキストリン、アラビアゴム、トラガント、トウモロコシデンプン、白糖、ヒドロキシプロピルセルロース（ＨＰＣ）などの結合剤、ステアリン酸塩（Ａｌ、Ｋ、Ｎａ、Ｃａ、Ｍｇ）などの滑沢剤、乳糖、結晶セルロース、微結晶セルロース、セラックなどの担体と混合され、製剤化されて錠剤、カプセル剤などの固体製剤にされる。非経口投与には、界面活性剤及びその他の薬学的に許容される助剤を加えるか、あるいは加えずに、水、エタノール又は油のような無菌の薬学的に許容される液体中に溶液あるいは懸濁液の形態に製剤化される。製剤に使用される油としては、天然、半合成あるいは合成の油脂類が挙げられ、例えばピーナツ油、トウモロコシ油、大豆油、ごま油などの植物油が挙げられる。一般的には、水、食塩水、デキストロース水溶液、その他関連した糖の溶液、エタノール、プロピレングリコール、ポリエチレングリコールなどのグリコール類が好ましい注射剤用液体担体としてあげられる。
【００５６】
次に、実施例により、本発明を更に詳細に説明するが、これによって本発明の範囲は限定されるものではない。実施例で用いられる略語は、以下に示す意味を表す。
DMF：N,N-ジメチルホルムアミド、 DMA：N,N-ジメチルアセトアミド、NBS：N-ブロモこはく酸イミド、 NCS：N-クロロこはく酸イミド、 NIS：Ｎ-ヨードこはく酸イミド、 TEBAC：塩化 ベンジルトリエチルアンモニウム、 THF：テトラヒドロフラン、 mCPBA：m-クロロ過安息香酸、 Pd(PPh3)4：テトラキストリフェニルホスフィンパラジウム(0)、DAST：サルファー トリフルオリド ジエチルアミン コンプレクス、 NaH：水素化ナトリウム、 DMSO：ジメチルスルフォキシド。
【００５７】
参考例１： 6-クロロスルホニル-3,4-ジヒドロ-2(1H)-キノリノン(化合物S-1)の製造：(Chem. Pharm. Bull., 31, 798(1983))
3,4-ジヒドロ-2(1H)-キノリノン(40.0 g, 0.27 mol)の四塩化炭素(190 ml)溶液に、氷冷化クロロスルホン酸(126 ml)を加え、室温で３時間撹拌した。反応液を氷水に注ぎ析出物を吸引ろ過後、水、エーテルで洗浄、次いで乾燥し、結晶性固体として表題化合物(49.7g, 収率 74%)を得た。1H-NMR(DMSO-d6)δ(ppm) : 2.43(2H, t, J=7Hz, CH2), 2.86(2H, t, J=7Hz, CH 2 ), 6.76〜7.40(3H, m, aromatic-H), 10.05(1H, br, NH). IR(KBr): 3178, 3059, 2908, 1686, 1582, 1484, 1374, 1168, 853 cm-1. EI-MS m/z : 245(M+), 247(M++2).
【００５８】
参考例２： 3,4- ジヒドロ -6- メルカプト -2(1H)- キノリノン ( 化合物 S-2) の製造：(Chem. Pharm. Bull., 31, 798(1983))
化合物S-1(10.0 g, 40.7 mmol)の酢酸(50 ml)溶液に、室温で活性化亜鉛(10.0 g)を加え、1.5時間加熱還流した。反応液に水を加え、氷浴で冷却後、析出物を吸引ろ取した。このものを0.5 N水酸化ナトリウム水溶液(98 ml, 48.9 mmol)に溶解し、不溶物をろ去し、ろ液に6 N塩酸(9.5 ml, 57.0 mmol)を加え、析出する固形物をろ取した。ろ取物を水で洗浄後乾燥し、結晶性固体として表題化合物(2.81 g, 収率 39%)を得た。 1H-NMR(DMSO-d6)δ(ppm) : 2.40(2H, t, J=7Hz, CH2), 2.81(2H, t, J=7Hz, CH2), 5.01 (1H, s, SH), 6.73〜7.10(3H, m, aromatic-H), 9.96 (1H, br, NH). IR(KBr): 3177, 3053, 2935, 2526, 1685, 1491, 1372, 1197, 815 cm-1. EI-MS m/z : 179(M+).
【００５９】
製造例１： 3,4- ジヒドロ -6- メチルチオ -2(1H)- キノリノン ( 化合物Ｉ a) の製造：
化合物S-2(5.20 g, 29.1 mmol)及びトリエチルアミン(3.09 g, 30.5 mmol)のDMF(50 ml)溶液に、氷冷アルゴン気流下、よう化メチル(4.33 g, 30.5 mmol)のDMF(40 ml)溶液を滴下し、２時間撹拌した。反応液にクロロホルムを加え、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、結晶性固体として表題化合物(4.86 g, 収率 87%）を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.46(3H, s, CH3), 2.63(2H, t, J=7Hz, CH2), 2.95 (2H, t, J=7Hz, CH2), 6.71〜7.12(3H, m, aromatic-H), 8.20 (1H, br, NH). IR(KBr): 3177, 3047, 2909, 1711, 1494, 1375, 1198, 812 cm-1. EI-MS m/z : 193(M+).
【００６０】
製造例２： 3,4- ジヒドロ -6- メチルチオ -1-(2- オキソプロピル )-2- キノリノン ( 化合物ＩＩ a) の製造：
化合物Ｉa(6.66 g, 34.5 mmol)、クロロアセトン(12.8 g, 138 mmol)、炭酸カリウム(14.3 g, 104 mmol)、TEBAC (3.93 g, 17.3 mmol)、よう化カリウム(2.86 g, 17.3 mmol)をアセトン(100ml)に加えアルゴン気流下、16時間加熱還流した。反応混合物を減圧下に濃縮乾固し、残留物にクロロホルムを加え、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。次いで減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(ジクロロメタン→クロロホルム)により精製し、結晶性固体として表題化合物(4.57 g, 収率 53%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.22(3H, s, CH3), 2.46(3H, s, CH3), 2.71(2H, t, J=7Hz, CH2), 2.94(2H, t, J=7Hz, CH2), 4.67(2H, s, CH2), 6.55〜7.12(3H, m, aromatic-H). IR(KBr): 3059, 2919, 1724, 1661, 1494, 1369, 1186, 797 cm-1. EI-MS m/z
: 249(M+).
【００６１】
製造例３： 4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物ＩＩＩ a) の製造：
化合物ＩＩa(5.89 g, 23.7 mmol)及び酢酸アンモニウム(18.2 g, 237 mmol)を酢酸(60 ml)に加え、３時間加熱還流した。反応混合物を減圧下に濃縮後、濃縮液に飽和炭酸水素ナトリウム水溶液を加えpH8〜9に調製し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(1%メタノール-クロロホルム)により精製し、結晶性固体として表題化合物(3.58 g, 収率 66%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.32(3H, d, J=1Hz, CH3), 2.50(3H, s, CH3), 3.00(2H, t, J=7Hz, CH2), 3.14 (2H, t, J=7Hz, CH2), 7.07〜7.23(4H, m, aromatic-H). IR(KBr): 2965, 2948, 1527, 1496, 1423, 1310, 1188, 822, 744 cm-1. EI-MS m/z : 230(M+).
【００６２】
製造例４： 4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物ＩＩＩ b) の製造：
化合物ＩＩＩa(0.94 g, 4.09 mmol)の塩化メチレン(15 ml)溶液に、氷冷下mCPBA(純度70%, 2.42 g, 9.82 mmol)の塩化メチレン(20ml)溶液を滴下し、その後、室温で1.5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てpH8〜9に調製し、クロロホルムで抽出した。有機層を水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム→1%メタノール-クロロホルム)により精製し、結晶性固体として表題化合物(0.54 g, 収率 51%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm): 2.31(3H, d, J=1Hz, CH3), 3.08(3H, s, CH3), 3.09〜3.18 (4H, m, CH2 ×2), 7.12 〜7.91 (4H, m, aromatic-H). IR(neat): 2951, 1496, 1399, 1317, 1143, 957 cm-1. EI-MS m/z : 262(M+).
【００６３】
製造例５： 1- ブロモ -4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物ＩＶ a) の製造：
化合物ＩＩＩa(3.58 g, 15.6 mmol)の酢酸(30ml)溶液に、NBS(3.05 g, 17.1 mmol)を加え、室温で１時間撹拌した。反応液を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、７％炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、結晶性固体として表題化合物(2.57 g, 収率 53%）を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.27(3H, s, CH3), 2.51(3H, s, CH3), 2.92〜3.04(4H, m, CH2 ×2), 7.20〜8.03(3H, m, aromatic-H). IR(KBr): 2964, 2901, 1527, 1491, 1410, 1382, 1194, 806 cm-1. EI-MS m/z : 308(M+), 310(M++2).
【００６４】
製造例６： 1- ブロモ -4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物ＩＶ b) の製造：
製造例５と同様の実験操作により、化合物ＩＩＩb(0.29 g, 1.11 mmol)、NBS(0.29 g, 1.62 mmol)及び酢酸(5 ml)から、結晶性固体として表題化合物(0.16 g,収率 42%）を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.30(3H, s, CH3), 3.07〜3.14(7H, m, CH3 & CH2×2), 7.92〜8.32(3H, m, aromatic-H). IR(KBr): 3002, 2910, 1581, 1533, 1488, 1379, 1294, 1143, 971, 784 cm-1. EI-MS m/z : 340(M+), 342(M++2).
【００６５】
製造例７： 4,5- ジヒドロ -1- ヨード -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物ＩＶ c) の製造：
製造例５と同様の実験操作により、化合物ＩＩＩa(1.00 g, 4.35 mmol)、NIS(1.08 g, 4.78 mmol)及び酢酸(10 ml)から、結晶性固体として表題化合物(1.06 g, 収率 68%）を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.35(3H, s, CH3), 2.52 (3H, s, CH3), 2.94〜3.09(4H, m, CH2 ×2), 7.21〜8.12(3H, m, aromatic-H). IR(KBr): 2974, 2901, 1539, 1488, 1412, 1380, 1186, 827 cm-1. EI-MS m/z : 356(M+).
【００６６】
1- アリール -4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン類の一般合成法：
化合物ＩＶaまたは化合物ＩＶc(100-400 mg, 0.32-1.12 mmol)及び各種置換基を有するフェニルほう酸類(1.2当量)をトルエン(3-10 ml)−エタノール(3-10 ml)混液に溶解または懸濁し、2 M炭酸ナトリウム水溶液(4.0当量)とPd(PPh3)4 (5モル％)を加え、アルゴンガス雰囲気下激しく撹拌しながら3.5時間加熱還流した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法により精製して表題化合物類を得た。
【００６７】
実施例１： 4,5- ジヒドロ -2- メチル -7- メチルチオ -1- フェニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 1) ：
化合物ＩＶa及びフェニルほう酸を用い、タール状物質として表題化合物(収率 88%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.23(3H, s, CH3), 2.43(3H, s, CH3), 2.99〜3.03(4H, m, CH2 ×2), 6.48〜7.43(8H, m, aromatic-H). IR(neat): 2951, 1489, 147, 816 cm-1. EI-MS m/z : 306(M+).
【００６８】
実施例２： 4,5- ジヒドロ -1-(3- フルオロフェニル )-2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 2) ：
化合物ＩＶa及び3-フルオロフェニルほう酸を用い、タール状物質として表題化合物(収率 86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.24(3H, s, CH3), 2.44(3H, s, CH3), 2.99〜3.03(4H, m, CH2 ×2), 6.48〜7.40(7H, m, aromatic-H). IR(neat): 2948, 1488, 1432, 1264, 868 cm-1. EI-MS m/z : 324(M+).
実施例３： 1-(3- ブロモフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 3) ：
化合物ＩＶc及び3-ブロモフェニルほう酸を用い、結晶性固体として表題化合物(収率 56%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.26(3H, s, CH3), 2.46(3H, s, CH3), 3.00〜3.11(4H, m, CH2 x 2), 6.49〜7.55(7H, m, aromatic-H). IR(KBr): 2910, 1488, 1413, 1377, 810, 781cm-1. EI-MS m/z : 384(M+), 386(M++2).
【００６９】
実施例４： 4,5- ジヒドロ -1-(3- メトキシフェニル )-2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 4) ：
化合物ＩＶa及び3-メトキシフェニルほう酸を用い、タール状物質として表題化合物(収率 89％)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 2.24(3H, s, CH3), 2.44(3H, s, CH3S), 2.99〜3.03(4H, m, CH2CH2), 3.80(3H, s, CH3O), 6.54(1H, d, J=9Hz, 9-H), 6.83〜6.86(3H, m, 8-H & aromatic-H), 6.91(1H, m, aromatic-H), 7.16(1H, d, J=2Hz, 6-H), 7.32(1H, t, J=8Hz, aromatic-H). EI-MS(m/z) : 336[M+]
【００７０】
実施例５： 4,5- ジヒドロ -1-(4- フルオロフェニル )-2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 5) ：
化合物ＩＶa及び4-フルオロフェニルほう酸を用い、結晶性固体として表題化合物(収率 70%)を得た。mp.101〜102℃。1H-NMR(CDCl3/TMS)δ(ppm): 2.13 (3H, s, CH3), 2.36(3H, s, CH3), 2.90〜2.98(4H, m, CH2×2), 6.38〜7.20(7H, m, aromatic-H). IR(KBr): 2942, 1501, 1412, 1382, 1290, 839, 811 cm-1. EI-MS m/z : 324(M+)。
【００７１】
実施例６： 1-(4- クロロフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 6) ：
化合物ＩＶa及び4-クロロフェニルほう酸を用い、タール状物質として表題化合物(収率 100%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.22(3H, s, CH3), 2.45(3H, s, CH3), 2.97〜3.03(4H, m, CH2 ×2), 6.48〜7.40(7H, m, aromatic-H). IR(neat): 2950, 1488, 1417, 1091, 834 cm-1. EI-MS m/z : 340(M+), 342(M++2)。
【００７２】
実施例７： 4,5- ジヒドロ -2- メチル -1-(4- メチルフェニル )-7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 7) ：
化合物ＩＶa及び4-メチルフェニルほう酸を用い、タール状物質として表題化合物(収率 98%）を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.22 (3H, s, CH3), 2.41(3H, s, CH3), 2.43(3H, s, CH3), 2.96〜3.04(4H, m, CH2×2), 6.52〜7.23(7H, m, aromatic-H). IR(neat): 2922, 1492, 1434, 825 cm-1. EI-MS m/z : 320(M+).
【００７３】
実施例８： 4,5- ジヒドロ -2- メチル -7- メチルチオ -1-(4- トリフルオロメチルフェニル ) イミダゾ [1,2-a] キノリン ( 化合物Ｖ− 8) ：
化合物ＩＶa及び4-トリフルオロメチルフェニルほう酸を用い、タール状物質として表題化合物(収率 96%）を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.26(3H, s, CH3), 2.45 (3H, s, CH3), 3.01〜3.05(4H, m, CH2×2), 6.44〜7.68(7H, m, aromatic-H). IR(neat): 2950, 1490, 1323, 1127, 846 cm-1. EI-MS m/z : 374(M+).
【００７４】
実施例９： 4,5- ジヒドロ -1-(4- メトキシフェニル )-2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 9) ：
化合物ＩＶa及び4-メトキシフェニルほう酸を用い、タール状物質として表題化合物(収率 100%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 2.20(3H, s, CH3), 2.42(3H, s, CH3), 2.96〜3.02(4H, m, CH2 ×2), 3.84(3H, s, CH3), 6.53〜7.20(7H, m, aromatic-H). IR(neat): 2982, 1507, 1488, 1244, 835 cm-1. EI-MS m/z : 336(M+).
【００７５】
実施例１０： 4,5- ジヒドロ -2- メチル -7- メチルチオ -1-(4- メチルチオフェニル ) イミダゾ [1,2-a] キノリン ( 化合物Ｖ− 10) ：
化合物ＩＶa及び4-メチルチオフェニルほう酸を用い、タール状物質として表題化合物(収率 81%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 2.24(3H, s, CH3), 2.45(3H, s, CH3), 2.54(3H, s, CH3), 3.00〜3.07(4H, m, CH2×2), 6.55〜7.30(7H, m, aromatic-H). IR(neat): 2983, 1489, 1417, 1093, 826 cm-1. EI-MS m/z : 352(M+).
【００７６】
実施例１１： 1-(3- クロロ -4- フルオロフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 11) ：
化合物ＩＶa及び3-クロロ-4-フルオロフェニルほう酸を用い、タール状物質として表題化合物(収率 83%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.21(3H, s, CH3), 2.45(3H, s, CH3), 2.99〜3.03 (4H, m, CH2 ×2), 6.47〜7.36(6H, m, aromatic-H). IR(neat): 2947, 1490, 1429, 1258, 824 cm-1. EI-MS m/z : 358(M+), 360(M++2).
【００７７】
1- アリール -4,5- ジヒドロ -2- メチル -7- メチルスルフィニルイミダゾ [1,2-a] キノリン類の一般合成法：
メチルチオ体(化合物Ｖ−2-4、8、9、11)を塩化メチレン(10-50 mg/ml)に溶解し、氷冷下mCPBA (1.0モル)を加え、室温で1.5時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を分取し、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法により精製して表題化合物類を得た。
【００７８】
実施例１２：4,5- ジヒドロ - １−（３ーフルオロフェニル）−２−メチル−７−メチルスルフィニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ−１２）：
化合物Ｖ−２を用いて、結晶性固体として表題化合物(収率80%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.25(3H, s, CH3), 2.73(3H, s, CH3), 3.09〜3.13(4H, m, CH2×2), 6.69〜7.65(7H, m, aromatic-H). IR(KBr): 2906, 1582, 1485, 1417, 1378, 1048, 866 cm-1.EI-MS m/z :340(M+).
【００７９】
実施例１３： 1-(3- ブロモフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルスルフィニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 13) ：
化合物Ｖ−3を用いて、結晶性固体として表題化合物(収率86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.29 (3H, s, CH3), 2.73(3H, s, CH3), 3.14〜3.16(4H, m, CH2×2), 6.71〜7.67(7H, m, aromatic-H). IR(KBr): 2908, 1487, 1417, 1376, 1049, 824 cm-1.EI-MS m/z :401(M+),403(M++2).
【００８０】
実施例１４： 4,5- ジヒドロ -1-(3- メトキシフェニル )-2- メチル -7- メチルスルフィニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 14) ：
化合物Ｖ−４を用いて、タール状物質として表題化合物(収率72%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.25(3H, s, CH3), 2.72(3H, s, CH3SO), 3.06〜3.12(4H, m, CH2CH2), 3.81(3H, s, CH3O), 6.75(1H, d, J=8Hz, 9-H), 6.82〜6.86(2H, m, aromatic-H), 6.95(1H, m, aromatic-H), 7.21(1H, dd, J=2, 8Hz, 8-H), 7.35(1H, t, J=8Hz, aromatic-H), 7.63(1H, d, J=2Hz, 6-H). EI-MS(m/z) : 352[M+]
【００８１】
実施例１５： 4,5- ジヒドロ -2- メチル -7- メチルスルフィニル -1-(4- トリフルオロメチルフェニル ) イミダゾ [1,2-a] キノリン ( 化合物Ｖ− 15) ：
化合物Ｖ−８を用いて、結晶性固体として表題化合物(収率68%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm): 2.34(3H, s, CH3), 2.74(3H, s, CH3), 3.15〜3.26(4H, m, CH2 ×2), 6.68〜7.75(7H, m, aromatic-H). IR(KBr): 2946, 1504, 1379, 1324, 1119, 845 cm-1.EI-MS m/z :390(M+).
【００８２】
実施例１６： 4,5- ジヒドロ -1-(4- メトキシフェニル )-2- メチル -7- メチルスルフィニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 16) ：
化合物Ｖ−９を用いて、結晶性固体として表題化合物(収率 64%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 2.22(3H, s, CH3), 2.71(3H, s, CH3SO), 3.07〜3.11(4H, m, CH2CH2), 3.88(3H, s, CH3O), 6.74(1H, d, J=9Hz, 9-H), 6.97(2H, d, J=8Hz, aromatic-H), 7.18〜7.22(3H, m, 8-H & aromatic-H), 7.62(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 352[M+]
【００８３】
実施例１７： 1-(3- クロロ -4- フルオロフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルスルフィニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 17) ：
化合物Ｖ−11を用いて、結晶性固体として表題化合物(収率68%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm): 2.23(3H, s, CH3), 2.73(3H, s, CH3), 3.07〜3.13(4H, m, CH2 X 2), 6.67〜7.67(6H, m, aromatic-H). IR(KBr): 2909, 1489, 1416, 1362, 1255, 1052, 824 cm-1. EI-MS m/z : 374(M+), 376(M++2).
【００８４】
1- アリール -4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン類の一般合成法：
化合物ＩＶb及び各種置換基を有するフェニルほう酸類を用いて、1-アリール-4,5-ジヒドロ-2-メチル-7-メチルチオイミダゾ[1,2-a]キノリン類の一般合成法と同様に反応、後処理して表題化合物を得た。
また、別法としてメチルチオ体（化合物Ｖ−2-6、8、9、11）を塩化メチレン(10-50 mg/ml)に溶解し、氷冷下mCPBA (2.2モル)を加え、1-アリール-4,5-ジヒドロ-2-メチル-7-メチルスルフィニルイミダゾ[1,2-a]キノリン類の一般合成法と同様に反応、後処理して表題化合物を得た。
【００８５】
実施例１８： 4,5- ジヒドロ -2- メチル -7- メチルスルホニル -1- フェニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 18) ：
化合物ＩＶb及びフェニルほう酸を用いて、アモルファス粉末として表題化合物(収率 92%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm): 2.26(3H, s, CH3), 3.04(3H, s, CH3), 3.12〜3.16(4H, m, CH2 ×2), 6.71〜7.88(8H, m, aromatic-H). IR(KBr): 2951, 1489, 1378, 1307, 1143, 758 cm-1. EI-MS m/z : 338(M+).
【００８６】
実施例１９： 4,5- ジヒドロ -1-(3- フルオロフェニル )-2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 19) ：
化合物Ｖ−2を用いて、 結晶性固体として表題化合物(収率80%)、を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.25(3H, s, CH3), 3.05(3H, s, CH3), 3.09〜3.13(4H, m, CH2×2), 6.73〜7.89(7H, m, aromatic-H). IR(KBr): 2914, 1487, 1424, 1378, 1309, 1143, 758 cm-1.EI-MS m/z :356(M+).
【００８７】
実施例２０： 1-(3- ブロモフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 20) ：
化合物Ｖ−3を用いて、結晶性固体として表題化合物(収率94%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.28(3H, s, CH3), 3.06(3H, s, CH3), 3.14〜3.18(4H, m, CH2×2), 6.74〜7.91(7H, m, aromatic-H). IR(KBr): 2913, 1488, 1420, 1376, 1309, 1145, 758 cm-1.EI-MS m/z :417(M+),419(M++2).
【００８８】
実施例２１： 4,5- ジヒドロ -1-(3- メトキシフェニル )-2- メチル -7- メチルスルホ ニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 21) ：
化合物Ｖ−4を用いて、タール状物質として表題化合物(収率 86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.25(3H, d, J=1Hz, CH3), 3.04(3H, s, CH3SO2), 2.99〜3.13(4H, m, CH2CH2), 3.82(3H, s, CH3O), 6.77(1H, d, J=9Hz, 9-H), 6.83(2H, m, aromatic-H), 6.96(1H, m, aromatic-H), 7.36(1H, t, J=8Hz, aromatic-H), 7.54(1H, dd, J=2, 9Hz, 8-H), 7.86(1H, d, J=2Hz, 6-H). EI-MS(m/z) : 368[M+]
【００８９】
実施例２２： 4,5-ジヒドロ-1-(4-フルオロフェニル)-2-メチル-7-メチルスルホニルイミダゾ[1,2-a]キノリン(化合物Ｖ−22)：
化合物Ｖ−5を用いて、結晶固体として表題化合物(収率 56%）を得た。mp.112〜115℃。1H-NMR(CDCl3/TMS)δ(ppm): 2.25(3H, s, CH3), 3.06(3H, s, CH3), 3.12〜3.19(4H, m, CH2 ×2), 6.71〜7.90(7H, m, aromatic-H). IR(KBr): 2915, 1526, 1454, 1379, 1313, 1145, 840, 758 cm-1. EI-MS m/z : 356(M+).
【００９０】
実施例２３： 1-(4- クロロフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 23) ：
化合物Ｖ−6を用い、 結晶性固体として表題化合物(収率65%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.29(3H, s, CH3), 3.06(3H, s, CH3), 3.21〜3.25(4H, m, CH2 ×2), 6.76〜7.92(7H, m aromatic-H). IR(KBr): 2989, 1488, 1377, 1309, 1145, 759 cm-1.EI-MS m/z :372(M+),374(M++2).
【００９１】
実施例２４： 4,5- ジヒドロ -2- メチル -1-(4- メチルフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 24) ：
化合物ＩＶb及び4-メチルフェニルほう酸を用いて、結晶性固体として表題化合物(収率 100%）を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.24(3H, s, CH3), 2.44(3H, s, CH3), 3.04(3H, s, CH3), 3.10〜3.14(4H, m, CH2 ×2), 6.75〜7.87(7H, m, aromatic-H). IR(KBr): 2910, 1489, 1377, 1309, 1144, 759 cm-1. EI-MS m/z : 352(M+).
【００９２】
実施例２５： 4,5- ジヒドロ -2- メチル -7- メチルスルホニル -1-(4- トリフルオロメチルフェニル ) イミダゾ [1,2-a] キノリン ( 化合物Ｖ− 25) ：
化合物Ｖ−8を用い、結晶性固体として表題化合物(収率78%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.31(3H, s, CH3), 3.06(3H, s, CH3), 3.16〜3.20(4H, m, CH2 ×2), 6.69〜7.93(7H, m, aromatic-H). IR(KBr): 2915, 1504, 1324, 1146, 1115, 846 cm-1.EI-MS m/z :406(M+).
【００９３】
実施例２６： 4,5- ジヒドロ -1-(4- メトキシフェニル )-2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 26) ：
化合物Ｖ−９を用い、 アモルファス粉末として表題化合物(収率 47%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.22(3H, s, CH3), 3.04(3H, s, CH3), 3.09〜3.11(4H, m, CH2×2), 3.88(3H, s, CH3), 6.76〜7.86(7H, m, aromatic-H). IR(KBr): 2909, 1532, 1506, 1378, 1309, 1246, 1145, 835 cm-1.EI-MS m/z :368(M+).
【００９４】
実施例２７： 4,5-ジヒドロ-2-メチル-7-メチルスルホニル-1-(4-メチルチオフェニル)イミダゾ[1,2-a]キノリン(化合物Ｖ−27)：
化合物ＩＶb及び4-メチルチオフェニルほう酸を用い、結晶性固体として表題化合物(収率 93%）を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.31(3H, s, CH3), 2.55(3H, s, CH3), 3.06(3H, s, CH3), 3.14〜3.29(4H, m, CH2×2), 6.84〜7.91(7H, m, aromatic-H). IR(KBr): 2912, 1489, 1376, 1308, 1144, 759 cm-1. EI-MS m/z : 384(M+).
【００９５】
実施例２８： 1-(3- クロロ -4- フルオロフェニル )- 4,5- ジヒドロ -2- メチル -7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 28) ：
化合物Ｖ−11を用い、結晶性固体として表題化合物(収率82%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.22 (3H, s, CH3), 3.06(3H, s, CH3), 3.07〜3.12(4H, m, CH2 ×2), 6.71〜7.90(6H, m, aromatic-H). IR(KBr): 2911, 1490, 1361, 1309, 1145, 759 cm-1. EI-MS m/z : 390(M+), 392(M++2).
【００９６】
製造例８： 3,4- ジヒドロ -6- メトキシ -1-(2- オキソプロピル )-2- キノリノン ( 化合物ＩＩ b) の製造：
3,4-ジヒドロ-6-メトキシ-2(1H)-キノリノンＩb(4.77 g, 26.95 mmol)のアセトン溶液(100 ml)にTEBAC(2.06 g, 10.79 mmol)、炭酸カリウム(5.75 g, 41.60 mmol)、クロロアセトン(3.15 g, 34.04 mmol)を加え、48時間煮沸還流した。製造例２と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製して表題化合物(0.37 g, 収率 6%)を得た。1H-NMR(CDCl3/TMS)δ(ppm): 2.21(3H, s, Me), 2.71(2H, t, J=7Hz, CH2), 2.93(2H, t, J=7Hz, CH2), 3.78(3H, s, OMe), 4.66(2H, s, CH2), 6.56(1H, d, J=8Hz, aromatic-H), 6.76(1H, m, aromatic-H), 7.62(1H, m, aromatic-H). EI-MS(m/z):233(M+).
【００９７】
製造例９： 4,5- ジヒドロ -7- メトキシ -2- メチルイミダゾ [1,2-a] キノリン ( 化合物ＩＩＩ c) の製造：
化合物ＩＩb(110 mg, 0.48 mmol)の酢酸溶液(10 ml)に酢酸アンモニウム(520 mg, 6.75 mmol)を加え、20時間煮沸還流した。製造例３と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相：酢酸エチル:n-ヘキサン=4:1)により精製して表題化合物(90 mg, 収率 88%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):2.26(3H, d, J=1Hz, Me), 2.94〜3.04(4H, m, CH2CH2), 3.81(3H, s, OMe), 6.79〜6.82(2H, m, aromatic-H), 7.02(1H, d, J=1Hz, 1-H), 7.12〜7.17(1H, m, aromatic-H). EI-MS(m/z):214(M+).
【００９８】
製造例１０： 1- ブロモ -4,5- ジヒドロ -7- メトキシ -2- メチルイミダゾ [1,2-a] キノリン ( 化合物ＩＶ d) の製造：
化合物ＩＩＩc(90 mg, 0.42 mmol)の酢酸溶液(10 ml)に、NBS(188 mg, 1.06 mmol)を加え、室温で3時間攪拌した。製造例５と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相;酢酸エチル:n-ヘキサン=4:1)により精製して表題化合物(50 mg, 収率 41%)を得た。 EI-MS(m/z):292(M+), 294(M+2).
【００９９】
実施例２９： 4,5- ジヒドロ -7- メトキシ -2- メチル -1-(4- メチルスルホニルフェニル ) イミダゾ [1,2-a] キノリン ( 化合物Ｖ− 29) の合成：
Pd(PPh3)4 (18 mg, 0.016 mmol)存在下、化合物ＩＶd (50 mg, 0.17 mmol)のエタノール(5 ml)、トルエン(5 ml)混合溶液に2M炭酸ナトリウム水溶液(0.35 ml)及び4-メチルスルホニルフェニルほう酸(41 mg, 0.20 mmol)を加え、激しく撹拌しながら21時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、濾過し、濾液を減圧下濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相;酢酸エチル:n-ヘキサン=4:1)により精製し、表題化合物(20 mg, 収率 32%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):2.29(3H, s, Me), 3.02(4H, s, CH2CH2), 3.14(3H, s, SO2Me), 3.77(3H, s, OMe), 6.42〜6.54(2H, m, aromatic-H), 6.86(1H, d, J=3Hz, aromatic-H), 7.46〜7.49(2H, m, aromatic-H), 7.96〜7.98(2H, m, aromatic-H). EI-MS(m/z):368(M+).
【０１００】
参考例３： 6- ヒドロキシ -1- テトラロン ( 化合物 S-3) の製造：（EP 0325963 A参照）
6-メトキシ-1-テトラロン(50 g, 0.28 mol)を47%臭化水素酸(500ml)に懸濁し、1.5時間煮沸還流した。反応混合物を冷却し、水(500 ml)を加え酢酸エチル(500 ml)で3回抽出した。抽出液を合し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固した。残留物をn-ヘキサン−アセトンから再結晶して淡黄褐色粉末の表題化合物(38.52 g)を得た。ろ液部を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(1% メタノール−クロロホルム)により精製して表題化合物(5.20 g、総収量43.72 g、収率 95 %)を得た。1H-NMR(CDCl3): 2.09(2H, m), 2.61(2H, t, J=7Hz), 2.88(2H, t, J=6Hz), 6.70(1H, d, J=2Hz), 6.78(1H, dd, J=2, 9Hz), 7.01(1H, s), 7.97(1H, d, J=9Hz).
【０１０１】
参考例４： 6- ジメチルチオカルバモイルオキシ -1- テトラロン ( 化合物 S-4) の製 造：（EP 0325963 A参照）
化合物S-3(56.06 g, 0.35 mol)を1 N水酸化カリウム水溶液(346 ml, 0.35 mol)に溶解し、この溶液に氷冷下攪拌しながら塩化ジメチルチオカルバモイル(55.55 g, 0.45 mol)のTHF(200 ml)溶液を1時間で滴下した。滴下後反応混合物を室温で0.5時間攪拌し、酢酸エチル(1.5 リットル)で抽出した。抽出液を飽和食塩水(1.0 リットル)で洗浄し、無水硫酸マグネシウムで乾燥後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1% メタノール−クロロホルム)により精製して黄橙色粘性油状物を得た。この油状物にエーテル(200 ml)を加え、種晶を添加して結晶化し、更にn-へキサン(300 ml)を加えてろ取、減圧下に乾燥して無色固体として表題化合物(77.04 g, 収率 89 %)を得た。1H-NMR(CDCl3): 2.13(2H, m), 2.63(2H, m), 2.95(2H, m), 3.32(3H, s), 3.43(3H, s), 6.94(1H, d, J=2Hz), 6.99(1H, dd, J=2, 9Hz), 8.05(1H, d, J=9Hz).
【０１０２】
参考例５： 6- ジメチルカルバモイルチオ -1- テトラロン ( 化合物 S-5) の製造：（EP 0325963 A参照）
化合物S-4(10.0 g, 0.04 mol)をミネラルオイル(60 ml)に懸濁し、徐々に昇温して約270℃で3時間加熱した。また、同様に11.0 g(0.04 mol)を処理し、合して以下の後処理を行った。反応混合物を徐々に室温に冷却すると茶褐色固体と無色針状晶を含むミネラルオイルの2層に分離した。無色針状晶をろ取し、n-ヘキサンで洗浄後減圧下に乾燥して表題化合物(1.68 g)を得た。茶褐色固体はクロロホルムに溶解し、シリカゲルカラムクロマトグラフ法(クロロホルム)により精製した。n-ヘキサン−エーテルから再結晶して淡黄色固体として表題化合物(16.87g : 総収量18.55 g, 収率 88 %)を得た。 1H-NMR(CDCl3): 2.12(2H, m), 2.63(2H, m), 2.95(2H, m), 3.02(3H, br-s), 3.07(3H, br-s), 7.37〜7.43(2H, m), 7.99(1H, d, J=8Hz).
【０１０３】
参考例６： 6- メチルチオ -1- テトラロン ( 化合物 S-6) の製造：（EP 0325963 A参照）
化合物S-5(19.36g, 0.08 mol)をメタノール(230 ml)に懸濁し、この溶液に水酸化ナトリウム(13.67 g, 0.34 mol)を加え2時間煮沸還流した。反応混合物を氷冷し、攪拌しながらよう化メチル(13.23 g, 0.09 mol)を加え2時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加えクロロホルムで2回抽出した。有機層を合し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をクロロホルムに溶解し、活性炭処理した後減圧下に濃縮乾固し、油状の粗生成物を得た。粗生成物をn-ヘキサン−クロロホルムから結晶化し、淡褐色プリズム晶の表題化合物(11.79 g)を得た。ろ液部を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製して表題化合物(1.37 g: 総収量13.16 g, 収率 88%)を得た。 1H-NMR(CDCl3): 2.10(2H, m), 2.49(3H, s), 2.60(2H, m), 2.90(2H, t, J=6Hz), 7.02(1H, d, J=2Hz), 7.11(1H, dd, J=2, 8Hz), 7.92(1H, d, J=8Hz).
【０１０４】
参考例７： 6- メチルチオ -1- テトラロンオキシム ( 化合物 S-7) の製造：(PCT/US92/02271参照）
水(32 ml)に室温で攪拌しながら酢酸ナトリウム(11.23 g, 0.14 mol)及び塩酸ヒドロキシルアミン(9.51 g, 0.14 mol)を溶解し、この溶液にエタノール(70 ml)及び化合物S-6(13.16 g, 0.07 mol)を加えた。反応混合物を内温75℃まで徐々に昇温し(約40〜50分)、75〜80℃で75分間攪拌した。反応混合物を内温32℃以下に冷却し、氷水(500 ml)中に注ぎ、氷片が溶解後沈殿物をろ取し、吸引乾燥した。ろ取物をエーテルで洗浄、減圧下に乾燥し、淡黄色粉末として表題化合物(14.09 g, 収率 99 %)を得た。1H-NMR(CDCl3): 1.85(2H, m), 2.47(3H, s), 2.71(2H, t, J=6Hz), 2.78(2H, t, J=7Hz), 6.99(1H, d, J=2Hz), 7.06(1H, dd, J=2, 8Hz), 7.78(1H, d, J=8Hz), 8.09(1H, br-s). EI-MS m/z: 207(M+).
【０１０５】
製造例１１： 7- メチルチオ -2,3,4,5- テトラヒドロ -1H-1- ベンズアゼピン -2- オン ( 化合物Ｉ c) の製造：
85 %りん酸(60 ml)に攪拌しながら無水りん酸(100 g)を加え90℃に加熱した。その混合物に化合物S-7(8.58 g, 0.04 mol)を分割して(約30〜40分)加え、4時間攪拌した。反応混合物を室温に冷却し、攪拌しながら氷水中に加え、析出する沈殿物を酢酸エチルで2回抽出した。抽出液を合し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、活性炭処理後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1 %メタノール−クロロホルム)により精製し、淡桃色固体として表題化合物(2.76 g, 収率 32 %)を得た。1H-NMR(CDCl3): 2.20(2H, m), 2.33(2H, m), 2.47(3H, s), 2.76(2H, t, J=7Hz), 6.88(1H, d, J=9Hz), 7.07〜7.13(2H, m), 7.58(1H, br-s). EI-MS m/z: 207(M+).
【０１０６】
化合物Ｉ c の別途製造：
化合物S-7(1.56 g, 7.53 mmol)をピリジン(15 ml)に溶解し、この溶液に塩化p-トルエンスルホニル(1.58 g, 8.28 mmol)を加え、50〜60℃で1時間攪拌した。次いで、反応混合物を10分間煮沸還流し、減圧下に濃縮乾固した。残留物に氷水を加え、酢酸エチルで2回抽出し、抽出液を合し、1 N塩酸及び飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、活性炭で処理し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1 %メタノール−クロロホルム)により精製し、淡黄色固体として表題化合物(648 mg, 収率 42 %)を得た。
【０１０７】
製造例１２： 7- メチルチオ -1-(2- オキソプロピル )-2,3,4,5- テトラヒドロ -1- ベンズアゼピン -2- オン ( 化合物ＩＩ c) の製造：
乾燥アセトン(25 ml)に化合物Ｉc(960 mg, 4.63 mmol)、無水炭酸カリウム(960 mg, 6.95 mmol)及びTEBAC(369 mg, 1.62 mmol)を加え、この混合物にクロロアセトン(1.54 g, 16.67 mmol)を3回に分割して加え、激しく攪拌しながら24時間煮沸還流した。反応混合物から不溶物を濾去し、クロロホルムで洗浄、濾洗液を合し、減圧下に乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製し、黄色粘性油状物として表題化合物(1.10 g, 収率 90 %)を得た。1H-NMR(CDCl3): 2.15(4H, s), 2.17(3H, s), 2.31(2H, t, J=7Hz), 2.45(3H, s), 4.50(2H, s), 6.92(1H, d, J=8Hz), 7.06(1H, d, J=2Hz), 7.09(1H, dd, J=2, 8Hz). EI-MS m/z: 263(M+).
【０１０８】
製造例１３： 2- メチル -8- メチルチオ -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズ アゼピン ( 化合物ＩＩＩ d) の製造：
化合物ＩＩc(1.10 g, 4.18 mmol)を酢酸(20 ml)に溶解し、この溶液に酢酸アンモニウム(3.22 g, 41.80 mmol)を加え、3時間煮沸還流した。製造例３と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(1 %メタノール−クロロホルム)により精製して淡黄褐色固体として表題化合物(730 mg, 収率 72 %)を得た。1H-NMR(CDCl3): 2.29(2H, quintet, J=7Hz), 2.31(3H, d, J=1Hz), 2.57(3H, s), 2.63(2H, t, J=7Hz), 2.76(2H, t, J=7Hz), 6.86(1H, d, J=1Hz), 7.20-7.33(3H, m). EI-MS m/z: 244(M+).
【０１０９】
製造例１４： 1- ブロモ -2- メチル -8- メチルチオ -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズアゼピン ( 化合物ＩＶ e) の製造：
化合物ＩＩＩd(300 mg, 1.23 mmol)を酢酸(6 ml)に溶解し、この溶液にNBS(240 mg, 1.35 mmol)を加え、遮光して室温で1時間攪拌した。製造例５と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製して淡黄色固体として表題化合物(250 mg, 収率 63 %)を得た。1H-NMR(CDCl3): 2.05〜2.13(1H,m), 2.22〜2.61(4H, m), 2.23(3H, s), 2.51(3H, s), 2.85〜2.93(1H, m), 7.17(1H, d, J=2Hz), 7.21(1H, dd, J=2, 9Hz), 7.30 (1H, d, J=9Hz). EI-MS m/z: 322(M+).
【０１１０】
製造例１５： 2- メチル -8- メチルスルホニル -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズアゼピン ( 化合物ＩＩＩ e) の製造：
化合物ＩＩＩd(240 mg, 0.98 mmol)を塩化メチレン(5 ml)に溶解し、この溶液にmCPBA(373 mg[90 %], 2.16 mmol)を加え、室温で1時間攪拌した。反応混合物を塩化メチレンで希釈し、7 %炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製し、無色固体として表題化合物(200 mg, 収率 74 %)を得た。1H-NMR(CDCl3): 2.25(3H, d, J=1Hz), 2.30(2H, m), 2.66〜2.74(4H, m), 3.09(3H, s), 6.86(1H, d, J=1Hz), 7.41(1H, d, J=9Hz), 7.85〜7.95(2H, m). EI-MS m/z: 276(M+).
【０１１１】
製造例１６： 1- ブロモ -2- メチル -8- メチルスルホニル -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズアゼピン ( 化合物ＩＶ f) の製造：
化合物ＩＩＩe(180 mg, 0.65 mmol)を酢酸(5 ml)に溶解し、この溶液にNBS(128 mg, 0.72 mmol)を加え、遮光して室温で1時間攪拌した。製造例５と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製し、無色固体として表題化合物(220 mg, 収率 95 %)を得た。1H-NMR(CDCl3): 2.11〜2.20(1H, m), 2.24(3H, s), 2.29〜2.43(2H, m), 2.53〜2.64(1H, m), 2.71〜2.80(1H, m), 2.91〜3.02(1H, m), 3.12(3H, s), 7.58(1H, d, J=8Hz), 7.93(1H, d, J=2Hz), 7.95 (1H, dd, J=2, 8Hz),). EI-MS m/z: 354(M+).
【０１１２】
実施例３０： 1-(4- メトキシフェニル )-2- メチル -8- メチルチオ -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズアゼピン ( 化合物Ｖ− 30) の合成：
化合物ＩＶe(150 mg, 0.46 mmol)及びp-メトキシフェニルほう酸(85 mg, 0.56 mmol)をトルエン(2 ml)−エタノール(2 ml)混液に溶解し、この溶液に2 M炭酸ナトリウム水溶液(2 ml)及びPd(PPh3)4(37 mg, 0.03 mmol)を加え、アルゴンガス雰囲気下激しく攪拌しながら22時間煮沸還流した。反応混合物を減圧下に乾固し、残留物をクロロホルムに溶解し、7 %炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製し、淡黄色粘性油成物として表題化合物(155 mg, 収率 95 %)を得た。1H-NMR(CDCl3): 2.22(2H, m), 2.26(3H, s), 2.45(3H, s), 2.56(2H, t, J=7Hz), 2.69(2H, t, J=7Hz), 3.78(3H, s), 6.48(1H, d, J=8Hz), 6.80(2H, d, J=9Hz), 6.87(1H, dd, J=2, 8Hz), 6.94 (2H, d, J=9Hz), 7.16(1H, d, J=2Hz). EI-MS m/z: 350(M+).
【０１１３】
実施例３１： 1-(4- メトキシフェニル )-2- メチル -8- メチルスルホニル -4,5,6- トリヒドロイミダゾ [1,2-a] ベンズアゼピン ( 化合物Ｖ− 31) の合成：
化合物Ｖ−３０(155 mg, 0.44 mmol)を塩化メチレン(10 ml)に溶解し、この溶液にmCPBA(196 mg[90 %], 1.02 mmol)を加え、室温で1時間攪拌した。反応混合物を塩化メチレンで希釈し、7 %炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製し、無色アモルファス粉末として表題化合物(170 mg, 収率 96 %)を得た。1H-NMR(CDCl3): 2.10〜2.48(3H, br), 2.27(3H, s), 2.78〜2.87(2H, br-m), 2.90〜3.08(1H, br), 3.07(3H, s), 3.79(3H, s), 6.73(1H, d, J=8Hz), 6.82(2H, d, J=9Hz), 6.93(2H, d, J=9Hz), 7.58(1H, dd, J=2, 8Hz), 7.91(1H, d, J=2Hz). EI-MS m/z: 382(M+).
【０１１４】
化合物Ｖ− 31 別途合成法： 化合物ＩＶf(210 mg, 0.59 mmol)及びp-メトキシフェニルほう酸(108 mg, 0.71 mmol)をトルエン(3 ml)−エタノール(3 ml)混液に溶解し、この溶液に2 M炭酸ナトリウム水溶液(3 ml)及びPd(PPh3)4 (46 mg, 0.04 mmol)を加え、アルゴンガス雰囲気下激しく攪拌しながら3時間煮沸還流した。実施例３０と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(0.5 %メタノール−クロロホルム)により精製して表題化合物(78 mg, 収率 35 %)を得た。
【０１１５】
製造例１７： 3,4- ジヒドロ -6- メチルチオ -2(1H)- キノリンチオン ( 化合物ＶＩ a) の製造：
化合物Ｉa(3.07 g, 15.9 mmol)のTHF溶液(150 ml)にLawesson試薬(3.29 g, 81.4 mmol)を加え、室温で22時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物にエタノールを加え不溶物を濾過、乾燥することにより表題化合物(3.0 g, 収率90%)を得た。EI-MS(m/z):209(M+).
【０１１６】
製造例１８： 3,4- ジヒドロ -2,6- ジメチルチオキノリン ( 化合物ＶＩＩ a) の製造：
氷冷下、化合物ＶＩa(3.0 g, 14.5 mmol)のTHF溶液(150 mmol)に水素化ナトリウム(0.41 g, 17.1 mmol)を加え、15分間攪拌した。次いで、よう化メチル(2.5 g, 17.7 mmol)を加え、室温で18時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(1.84 g, 収率 57%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):2.47(2H, t, J=8Hz, CH2), 2.48(3H, s, Me), 2.51(3H, s, Me), 2.75(2H, t, J=8Hz, CH2), 7.00(1H, m, aromatic-H), 7.12(1H, dd, J=2, 8Hz, aromatic-H),7.18(1H, d, J=8Hz, aromatic-H). EI-MS(m/z):233(M+).
【０１１７】
製造例１９： 3,4- ジヒドロ - 〔 2-(4- メトキシフェニル） -2- オキソエチルアミノ〕 -6- メチルチオキノリン ( 化合物ＶＩＩＩ a) の製造：
トリエチルアミン(0.36 g, 3.56 mmol)存在下、化合物ＶＩＩa(0.76 g, 3.41 mmol)のアセトニトリル溶液(30 ml)に2-アミノ-4'-メトキシアセトフェノン塩酸塩(0.70 g, 3.48 mmol)を加え、24時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物に少量の酢酸エチルを加え、不溶物をろ過、乾燥することで表題化合物(0.88 g, 収率 76%)を得た。1H-NMR(DMSO-d6/TMS)δ(ppm):2.47(3H, s, SMe), 2.92〜3.04(4H, m, CH2CH2), 3.89(3H, s, OMe), 5.21(2H, s, CH2), 7.10〜7.22(5H, m, aromatic-H), 8.04〜8.07(2H, m, aromatic-H), 11.38(1H, br-s, NH). EI-MS(m/z):340(M+).
【０１１８】
実施例３２： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルチオイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 32) の合成：
化合物ＶＩＩＩa(1.71 g, 5.0 mmol)のトルエン溶液(300 ml)に無水p-トルエンスルホン酸(0.44 g, 2.56 mmol)を加え、18時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、表題化合物(1.38 g, 収率 86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):2.46(3H, s, SMe), 2.97〜3.09(4H, m, CH2CH2), 3.86(3H, s, OMe), 6.72(1H, d, J=8Hz, aromatic-H), 6.88〜6.97(4H, m, aromatic-H), 7.19(1H, d, J=2Hz), 7.26〜7.29(2H, m, aromatic-H). EI-MS(m/z):322(M+).
【０１１９】
実施例３３： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 33) の合成：
化合物Ｖ−32(0.59 g, 1.83 mmol)の塩化メチレン溶液(30 ml)にmCPBA(0.79 g, 4.60 mmol)を加え、室温で22時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、表題化合物(0.56 g, 収率 86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):3.06(3H, s, SMe), 3.10〜3.14(4H, m, CH2CH2), 3.87(3H, s, OMe), 6.95〜6.97(2H, m, aromatic-H), 7.02(1H, s, 2-H), 7.24〜7.27(3H, m, aromatic-H), 7.59(1H, dd, J=2, 8Hz, aromatic-H), 7.89(1H, d, J=2Hz, aromatic-H). EI-MS(m/z):354(M+).
【０１２０】
実施例３４： 2- クロロ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 34) の合成：
化合物Ｖ−33(100 mg, 0.29 mmol)の酢酸溶液(5 ml)にNCS(55 mg, 0.41 mmol)を加え、24時間煮沸還流した。反応混合物を氷水中に注ぎ、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(酢酸エチル:n-ヘキサン=4:1)により精製し、アモルファス粉末として表題化合物(40 mg, 収率 36%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):3.05(3H, s, SO2Me), 3.07〜3.15(4H, m, CH2CH2), 3.89(3H, s, OMe), 6.84(1H, d, J=8Hz, aromatic-H), 6.99〜7.01(2H, m, aromatic-H), 7.27〜7.29(2H, m, aromatic-H), 7.58(1H, dd, J=2, 8Hz, aromatic-H), 7.88(1H, d, J=2Hz, aromatic-H). EI-MS(m/z):388(M+).
【０１２１】
実施例３５： 2- ブロモ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 35) の合成：
化合物Ｖ−33(0.56 g, 1.58 mmol)の酢酸溶液(20 ml)にNBS(0.31 g, 1.75 mmol)を加え、室温で24時間攪拌した。反応混合物を氷水に注ぎ、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、表題化合物(0.48 g, 収率 70%)を得た。mp.114〜116℃。1H-NMR(CDCl3/TMS)δ(ppm):3.05(3H, s, SO2Me), 3.08〜3.15(4H, m, CH2CH2), 3.89(3H, s, OMe), 6.80(1H, d, J=8Hz, aromatic-H), 6.98〜7.01(2H, m, aromatic-H), 7.26〜7.29(2H, m, aromatic-H), 7.57(1H, dd, J=2,8Hz, aromatic-H), 7.88(1H, d, J=2Hz, aromatic-H). EI-MS(m/z):432(M+), 434(M+2).
【０１２２】
実施例３６： 2- シアノ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 36) の合成：
化合物Ｖ−35(0.60 g, 1.40 mmol)のDMF溶液(1 ml)にシアン化銅(Ｉ)(0.15 g, 1.67 mmol)を加え、アルゴン雰囲気下170℃で19時間攪拌した。反応混合物を酢酸エチルで希釈し、不溶物をセライトパッドを用いてろ去した。ろ液は飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(5%メタノール/クロロホルム)により精製し、表題化合物(40 mg, 収率 8%)を得た。mp.208〜209.5℃。1H-NMR(CDCl3/TMS)δ(ppm):3.07(3H, s, SO2Me), 3.13〜3.16(4H, m, CH2CH2), 3.90(3H, s, OMe), 6.96(1H, d, J=8Hz, aromatic-H), 7.01〜7.05(2H, m, aromatic-H), 7.34〜7.37(2H, m, aromatic-H), 7.64(1H, dd, J=2, 8Hz, aromatic-H), 7.94(1H, d, J=2Hz, aromatic-H). EI-MS(m/z):379(M+).
【０１２３】
実施例３７： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニル -2- トリフルオロメチルイミダゾ [1,2-a] キノリン ( 化合物Ｖ− 37) の合成：
化合物Ｖ−35(0.48 g, 1.11 mmol)のDMA溶液(15 ml)にトリフルオロ酢酸ナトリウム(0.61 g, 4.51 mmol)及びヨウ化銅(Ｉ)(0.42 g, 2.22 mmol)を加え、18時間煮沸還流した。反応混合物にクロロホルム及び1.5 N塩酸を加えて分液し、水層は再度クロロホルムで抽出した。有機層を合し、不溶物をセライトパッドを用いてろ去した。ろ液は飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(酢酸エチル:n-ヘキサン=4:1)により精製し、表題化合物(0.1 g, 収率21%)を得た。1H-NMR(CDCl3/TMS)δ(ppm):3.05(3H, s, SO2Me), 3.15(4H, s, CH2CH2), 3.89(3H, s, OMe), 6.71(1H, d, J=8Hz, aromatic-H), 6.98〜7.12(2H, m, aromatic-H), 7.25〜7.29(2H, m, aromatic-H), 7.55(1H, dd, J=2, 8Hz, aromatic-H), 7.90(1H, d, J=2Hz, aromatic-H). EI-MS(m/z):422(M+).
【０１２４】
製造例２０： 4,5- ジヒドロ -3- エトキシカルボニル -7- メチルチオイミダゾ [1,5-a] キノリン ( 化合物ＩＸ a) の製造：
化合物Ｉa(7.89g, 40.88mmol)の乾燥DMF(116ml)溶液に、アルゴンガス雰囲気下で氷冷しながらカリウム tert-ブトキシド(5.05g, 44.97mmol)を加え10分間攪拌した。この反応液にクロロりん酸ジエチル(14.11g, 81.76mmol)を加え5分間攪拌後、イソシアノ酢酸エチル(6.94g, 61.32mmol)の乾燥DMF(64ml)溶液及びカリウム tert-ブトキシド(6.88g, 61.32mmol)を加え、17時間反応させた。この間、温度は室温まで上昇させた。氷水に反応混合液を注ぎ析出物をろ取し、クロロホルムに溶解した。クロロホルム溶液を水で洗浄し、無水硫酸ナトリウムで乾燥、減圧下に濃縮し粗表題化合物を得た。このものをシリカゲルカラムクロマトグラフ法(n-ヘキサン : 酢酸エチル＝1 : 1→2 : 3→3 : 7→1 : 4)により精製し、結晶性固体として表題化合物(3.01g, 収率 26%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 1.42(3H, t, J＝7Hz, CH 3 CH2), 2.51(3H, s, CH3S), 2.93(2H, t, J＝7Hz, CH 2 CH2), 3.34(2H, t, J＝7Hz, CH2CH 2 ), 4.40(2H, 8, J＝7Hz, CH3CH 2 ), 7.21(2H, m, 6-H & 8-H), 7.39(1H, d, J＝9Hz, 9-H), 7.98(1H, s, 1-H). EI-MS(m/z) : 288[M+]
【０１２５】
製造例２１： 4,5- ジヒドロ 3- エトキシカルボニル -7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＩＸ b) の製造：
化合物ＩＸa(3.01g, 10.45mmol)の塩化メチレン(75ml)溶液に、氷冷下mCPBA(4.51g, 26.13mmol)の塩化メチレン(75ml)溶液を滴下した。氷冷下2.5時間攪拌した後、反応液を塩化メチレンで希釈し、有機層を飽和炭酸水素ナトリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1%メタノール含有クロロホルム)により精製し、結晶性固体として表題化合物(3.28g, 収率 98%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 1.43(3H, t, J＝7Hz, CH 3CH2), 3.07(2H, t, J＝7Hz, CH 2CH2), 3.10(3H, s, CH3SO2), 3.41(2H, t, J＝7Hz,CH 2CH2), 4.42(2H, 8, J＝7Hz, CH3CH 2), 7.66(1H, d, J＝9Hz, 9-H), 7.95(1H, dd, J＝2, 9Hz, 8-H), 7.96(1H, d, J＝2Hz, 6-H), 8.09(1H, s, 1-H) EI-MS(m/z) : 320[M+]
【０１２６】
製造例２２： 1- ブロモ -4,5- ジヒドロ -3- エトキシカルボニル -7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物Ｘ a) 及び 1- ブロモ -3- エトキシカルボニル -7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物Ｘ b) の製造：
遮光容器中、化合物ＩＸb(1.98g, 6.19mmol)のアセトニトリル(190ml)溶液に、室温でNBS(1.82g, 13.61mmol)を加え、1.5時間加熱還流した。反応液を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、結晶性固体として化合物ＸaとＸbの混合物(2.18g, 1H-NMR比Ｘa: Ｘb＝6 : 1)を得た。これらは分離困難のため、そのまま次の反応に使用した。 化合物Ｘa： 1H-NMR(CDCl3/TMS)δ(ppm) : 1.42(3H, t, J＝7Hz, CH 3H2), 3.02(2H, t, J＝7Hz, CH 2CH2), 3.11(3H, s, CH3SO2), 3.36(2H, t, J＝7Hz, CH2CH 2), 4.42(2H, 8, J＝7Hz, CH3CH2), 7.97(1H, d, J＝2Hz, 6-H), 7.99(1H, dd, J＝2, 9Hz, 8-H), 8.41(1H, d, J＝9Hz, 9-H) EI-MS(m/z) : 398[M+], 400[M++2]
【０１２７】
化合物Ｘb： 1H-NMR(CDCl3/TMS)δ(ppm) : 1.48(3H, t, J＝7Hz, CH3CH2), 3.16(3H, s, CH3SO2), 4.50(2H, 8, J＝7Hz, CH3CH2), 7.47(1H, d, J＝10Hz), 8.19(1H, dd, J＝2, 9Hz, 8-H), 8.28(1H, d, J＝10Hz), 8.39(1H, d, J＝2Hz, 6-H), 9.61(1H, d, J＝9Hz, 9-H) EI-MS(m/z) : 396[M+], 398[M++2]
【０１２８】
実施例３８： 4,5- ジヒドロ -3- エトキシカルボニル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 1) 及び 3- エトキシカルボニル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 2) の合成：
製造例２２で製造した化合物ＸaとＸbの混合物(2.18g)のトルエン(200ml)-エタノール(100ml)溶液に、室温で4-メトキシフェニルほう酸(1.25g, 8.20mmol)、 Pd(PPh3)4 (0.63g, 0.55mmol)及び2M炭酸ナトリウム水溶液(10.9ml, 21.86mmol)を加え、アルゴンガス雰囲気下2.5時間加熱還流した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(5%酢酸エチル含有ジクロロメタン→10%酢酸エチル含有ジクロロメタン)により精製し、結晶性固体として表題化合物ＸＩ−1(2.13g, 収率 81%(2工程))と化合物ＸＩ−2(0.34g, 収率13%(2工程))を各々単離した。化合物ＸＩ−1：mp.196〜198℃, 1H-NMR(CDCl3/TMS)δ(ppm) : 1.42(3H, t,J=7Hz, CH 3CH2), 3.07(2H, t, J＝7Hz, CH 2CH2), 3.08(3H, s, CH3SO2), 3.38(2H, t, J＝7Hz, CH2CH 2), 3.87(3H, s, CH 3O), 4.44(2H, 8, J＝7Hz, CH3CH 2), 6.95(2H, d, J＝9Hz), 7.08(1H, d, J＝9Hz, 9-H), 7.47(2H, d, J＝9Hz), 7.62(1H, dd, J＝2, 9Hz, 8-H), 7.94(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 426[M+]. 化合物ＸＩ−2： mp.244〜246℃, 1H-NMR(CDCl3/TMS)δ(ppm) : 1.47(3H, t, J＝7Hz, CH 3CH2), 3.09(3H, s, CH3SO2), 3.93(3H, s, CH3O), 7.07(2H, d, J＝9Hz), 7.43(1H, d, J＝10Hz), 7.55(2H, d, J＝9Hz), 7.74(1H, d, J＝9Hz, 9-H), 7.79(1H, dd, J＝2, 9Hz, 8-H), 8.32(1H, d, J＝10Hz), 8.33(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 424[M+].
【０１２９】
化合物ＸＩ− 1 の別途合成 ( 化合物ＸＩ− 2 の接触還元 ) ：
化合物ＸＩ―2(0.61 g, 1.44 mmol)の酢酸(60 ml)溶液中に、10% Rh-Al2O3(100 mg)を加え、水素ガス雰囲気下、80℃で2日間攪拌した。反応液を室温まで冷却し、飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出した。クロロホルム層を分取し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(n-ヘキサン：酢酸エチル＝2：3)により精製し、結晶性固体として表題化合物(0.54 g, 収率 89%)を得た。
【０１３０】
実施例３９： 3- カルボキシ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 3) の合成：
化合物ＸＩ−1(1.20 g, 2.82 mmol)のメタノール(250 ml)溶液に、室温で1 N 水酸化ナトリウム(14.1 ml, 14.1 mmol)を加え、20時間加熱還流した。反応液を1 N 塩酸でpH 5〜6に調製し、減圧下に濃縮乾固した。残留物をクロロホルムで抽出し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固し、結晶性固体として表題化合物(1.02 g, 収率91%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.07〜3.11(5H, m, CH3SO2 & CH2), 3.39(2H, t, J＝7Hz, CH2), 3.89(3H, s, CH3O), 6.98(2H, d, J＝9Hz), 7.12(1H, d, J＝9Hz, 9-H), 7.47(2H, d, J＝9Hz), 7.65(1H, dd, J＝2, 9Hz, 8-H), 7.96(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 399[M+]
【０１３１】
実施例４０： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 4) の合成：
化合物ＸＩ−3(0.96 g, 2.41 mmol)のキノリン(3.5 ml)溶液に、室温で銅粉末(168 mg, 2.65 mmol)を加え、220〜225℃で1時間攪拌した。反応液にクロロホルムを加え、不溶物をろ去し、ろ液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(30%酢酸エチル含有ジクロロメタン)により精製し、アモルファス粉末として表題化合物(0.39 g, 収率 46%)を得た。1H-NMR(DMSO-d6)δ(ppm) : 2.90〜3.05(4H, m, CH2×2), 3.21(3H, s, CH3SO2), 3.82(3H, s, CH3O), 6.95(1H, s, 3-H), 7.00(1H, d, J＝9Hz, 9-H), 7.03(2H, d, J＝9Hz), 7.42(2H, d, J＝9Hz), 7.64(1H, dd, J＝2, 9Hz, 8-H), 8.00(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 354[M+]
【０１３２】
実施例４１： 3- クロロ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 5) 及び 3- クロロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 6) の合成：
化合物ＸＩ−4(240 mg, 0.86 mmol)をアセトニトリル(12 ml)に溶解し、NCS(90 mg, 0.68 mmol)を加えて、遮光下45℃で4日間攪拌した。反応液を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水で洗浄、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法により精製し、先に溶出する画分を減圧下に濃縮乾固し、n-ヘキサン−クロロホルムから再結晶して無色針状晶として化合物ＸＩ−6(41 mg, 収率16%)を得た。次いで溶出する画分を減圧下に濃縮乾固し、n-ヘキサン−クロロホルムから再結晶して淡黄色固体として化合物ＸＩ−5(110 mg, 収率42%)を得た。化合物ＸＩ−5： 1H-NMR(CDCl3)δ(ppm) : 2.89〜2.95(2H, m, CH2), 3.01〜3.08(2H, m, CH2), 3.05(3H, s, CH3SO2), 3.85(3H, s, CH3O), 6.93(2H, d, J=9Hz ), 7.10(1H, d, J=9Hz, 9-H), 7.43(2H, d, J=9Hz), 7.59(1H, dd, J=2, 9Hz, 8-H), 7.90(1H, d, J=2Hz, 6-H). EI-DI m/z : 388[M+]. 化合物ＸＩ−6： 1H-NMR(DMSO-d6)δ(ppm) : 3.24(3H, s, CH3SO2), 3.88(3H, s, CH3O), 7.15(2H, d, J=9Hz), 7.46(1H, d, J=10Hz, C4 or C5-H), 7.52-7.63(4H, m), 7.84(1H, dd, J=2, 9Hz, 8-H), 8.44(1H, d, J=2Hz, 6-H). EI-DI m/z : 386[M+].
【０１３３】
実施例４２： 3,5- ジクロロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 7) の合成：
化合物ＸＩ−4(0.13 g, 0.37 mmol)のアセトニトリル(3 ml)溶液に、室温でNCS(86 mg, 0.66 mmol)を加え500Cで7時間攪拌した。反応液にクロロホルムを加え、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、次いで減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(30%n-ヘキサン含有酢酸エチル)により精製し、黄色固体として表題化合物(34mg, 収率 22%)及び化合物ＸＩ−６(17mg, 収率 12%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.11(3H, s, CH3SO2), 3.93(3H, s, CH3O), 7.07(2H, d, J=9Hz, aromatic-H), 7.53(2H, d, J=9Hz, aromatic-H), 7.58(1H, s, 4-H), 7.78(1H, d, J=9Hz, 9-H), 7.82(1H, dd, J=2, 9Hz, 8-H), 8.65(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 420[M+], 422[M++2], 424[M++4].
【０１３４】
実施例４３： 3- ブロモ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 8) の合成：
化合物ＸＩ−4(0.37 g, 1.05 mmol)のアセトニトリル(10 ml)溶液に、室温でNBS(205 mg, 1.15 mmol)を加え50℃で15分間攪拌した。反応液にクロロホルムを加え、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(5% 酢酸エチル含有ジクロロメタン→10% 酢酸エチル含有ジクロロメタン)により精製し、結晶性固体として表題化合物(0.30 g, 収率67%)を得た。mp.250.5〜252℃。1H-NMR(CDCl3/TMS)δ(ppm) : 2.91〜3.09(7H, m, CH3SO2 & CH2×2), 3.87(3H, s, CH3O), 6.95(2H, d, J＝9Hz), 7.11(1H, d, J＝9Hz, 9-H), 7.45(2H, d, J＝9Hz), 7.61(1H, dd, J＝2, 9Hz, 8-H), 7.92(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 432[M+], 434[M++2].
【０１３５】
実施例４４： 3- シアノ -4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 9) の合成：
化合物ＸＩ−8(108 mg, 0.25 mmol)の乾燥DMF(3 ml)溶液に、室温でシアン化銅(Ｉ)(27 mg, 0.30 mmol)を加え、アルゴンガス雰囲気下170℃で18時間攪拌した。反応液を室温まで冷却しエチレンジアミン(0.5 ml)水(3 ml)溶液を加え、よく振り混ぜ銅イオンを除去した。この混液にクロロホルムを加え、水で洗浄、無水硫酸ナトリウムにより乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(5 %酢酸エチル含有ジクロロメタン→10 %酢酸エチル含有ジクロロメタン)により精製し、結晶性固体として表題化合物(33 mg, 収率 35%)を得た。mp.256.2〜259.5℃。1H-NMR(CDCl3/TMS)δ(ppm) : 3.08(3H, s, CH3SO2), 3.11〜3.15(4H, m, CH2CH2), 3.89(3H, s, CH3O), 6.98(2H, d, J＝9Hz), 7.14(1H, d, J＝9Hz, 9-H), 7.45(2H, d, J＝9Hz), 7.66(1H, dd, J＝2, 9Hz, 8-H), 7.96(1H, d, J＝2Hz, 6-H). EI-MS(m/z) : 379[M+].
【０１３６】
実施例４５： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニル -3- トリフルオロメチルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 10) の合成：
化合物ＸＩ−8(0.15 g, 0.35 mmol)のDMA(5 ml)溶液に、室温でトリフルオロ酢酸ナトリウム(189 mg, 1.39 mmol)及びヨウ化銅(Ｉ)(132 mg, 0.69 mmol)を加え、アルゴンガス雰囲気下5.5時間加熱還流した。反応液にクロロホルムを加え、水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(n-ヘキサン : 酢酸エチル＝1 : 1)により精製し、結晶性固体として表題化合物(13 mg, 収率 9%)を得た。mp.278.5〜280℃。1H-NMR(CDCl3/TMS)δ(ppm) : 3.08(3H, s, CH3SO2), 3.08〜3.13(4H, m, CH2×2), 3.88(3H, s, CH3O), 6.96(2H, d, J＝9Hz), 7.12(1H, d, J＝8.5Hz, 9-H), 7.47(2H, d, J＝9Hz), 7.64(1H, dd, J＝2, 9Hz, 8-H), 7.94(1H, d, J＝2Hz, 6-H) EI-MS(m/z) : 422[M+].
【０１３７】
実施例４６： 4,5- ジヒドロ -3- ヒドロキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 11) の合成：
化合物ＸＩ−1(0.26 g, 0.61 mmol)の乾燥THF(7 ml)溶液に、氷冷下水素化リチウムアルミニウム(53 mg, 1.40 mmol)を加え、20分間攪拌した。反応液に過剰の酢酸エチルを加え数分間攪拌した後、不溶物をろ去した。ろ液にクロロホルムを加え、水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1% メタノール含有クロロホルム)により精製し、結晶性固体として表題化合物(0.13 g, 収率 57%)を得た。mp.188.5〜189.5℃。1H-NMR(CDCl3/TMS)δ(ppm) : 2.99(2H, t, J＝4Hz, CH 2CH2), 3.04(2H, t, J＝4Hz, CH2CH 2), 3.07(3H, s, CH3SO2), 3.87(3H, s, CH3O), 4.68(2H, s, CH 2OH), 6.95(2H, d, J＝9Hz), 7.07(1H, d, J＝9Hz), 7.44(2H, d, J＝9Hz), 7.60(1H, dd, J＝2, 9Hz, 8-H), 7.90(1H, d, J＝2.2Hz, 6-H). EI-MS(m/z) : 384[M+].
【０１３８】
実施例４７： 4,5- ジヒドロ -3- フルオロメチル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 12) の合成：
化合物ＸＩ−11(60 mg, 0.16 mmol)の乾燥塩化メチレン(12 ml)溶液に、氷冷下DAST(31 μl, 0.23 mmol)を加え、アルゴン雰囲気下90分間攪拌した。反応液を塩化メチレンにより希釈し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をクロロホルム-n-ヘキサンから再結晶し、結晶性固体として表題化合物(19 mg, 収率 32%)を得た。mp.180〜181℃。1H-NMR(CDCl3/TMS)δ(ppm) : 3.04〜3.08(4H, m, CH2CH2), 3.08(3H, s, CH3SO2), 3.87(3H, s, CH3O), 5.43(2H, d, J＝50Hz, CH2F), 6.96(2H, d, J＝9Hz), 7.11(1H, d, J＝9Hz, 9-H), 7.46(2H, d, J＝9Hz), 7.62(1H, dd, J＝2, 9Hz, 8-H), 7.92(1H, d, J＝2Hz, 6-H). EI-MS(m/z) : 386[M+].
【０１３９】
実施例４８： 4,5- ジヒドロ -3- メトキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 13) の合成：
化合物ＸＩ−11(0.10 g, 0.26 mmol)の乾燥THF(10 ml)溶液に、アルゴンガス雰囲気下室温でNaH(9 mg, 0.39 mmol)、よう化メチル(74 mg, 0.52 mmol)を加え、室温で1.5日間攪拌した。反応液をクロロホルムで希釈し、飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、結晶性固体として表題化合物(63 mg, 収率 61%)を得た。mp.182〜186℃。1H-NMR(CDCl3/TMS)δ(ppm) : 2.98〜3.06(4H, m, CH2 ×2), 3.07(3H, s, CH3SO2), 3.48(3H, s, CH3O), 3.86(3H, s, CH3O), 4.48(2H, s, CH2O), 6.94(2H, d, J=9Hz, aromatic-H), 7.08(1H, d, J=9Hz, 9-H), 7.45(2H, d, J=9Hz, aromatic-H), 7.59(1H, d, J=2, 9Hz, 8-H), 7.90(1H, d, J=2Hz, 6-H). EI-MS(m/z) : 398[M+].
【０１４０】
実施例４９： 4,5- ジヒドロ -3- エトキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 14) の合成：
化合物ＸＩ−11(0.10 g, 0.26 mmol)の乾燥DMF(5 ml)溶液に、アルゴンガス雰囲気下室温でNaH(12 mg, 0.52 mmol)、よう化エチル(122 mg, 0.78 mmol)を加え、室温で1日間攪拌した。実施例４８と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製して結晶性固体として表題化合物(81 mg, 収率 76%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 1.27(3H, t, J=7Hz, OCH2CH 3), 3.00〜3.04(4H, m, CH2CH2), 3.07(3H, s, CH3SO2), 3.66(2H, 8, J=7Hz, OCH 2CH3), 3.86(3H, s, CH3O), 4.53(2H, s, CH2O), 6.93(2H, d, J=9Hz, aromatic-H), 7.06(1H, d, J=9Hz, 9-H), 7.44(2H, d, J=9Hz, aromatic-H), 7.59(1H, dd, J=2, 9Hz, 8-H), 7.90(1H, d, J=2Hz, 6-H). EI-MS(m/z) : 412[M+].
【０１４１】
実施例５０： 4,5-ジヒドロ3-ベンジルオキシメチル-1-(4-メトキシフェニル)-7-メチルスルホニルイミダゾ[1,5-a]キノリン(化合物ＸＩ−15)の合成：
化合物ＸＩ−11(0.10 g, 0.26 mmol)の乾燥THF(10 ml)溶液に、アルゴンガス雰囲気下室温でNaH(8 mg, 0.31 mmol)、臭化ベンジル(67 mg, 0.39 mmol)を加え3時間加熱還流した。実施例４８と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製して結晶性固体として表題化合物(38 mg, 収率 31%)を得た。mp.140〜142℃。1H-NMR(CDCl3/TMS)δ(ppm) : 2.94〜3.02(4H, m, CH2×2), 3.07(3H, s, CH3SO2), 3.87(3H, s, CH3O), 4.59(2H, s, CH 2OCH2), 4.67(2H, s, CH2OCH 2), 6.94(2H, d, J=9Hz, aromatic-H), 7.07(1H, d, J=9Hz, 9-H), 7.34(5H, m, Ph), 7.45(2H, d, J=9Hz, aromatic-H), 7.59(1H, dd, J=2, 9Hz, 8-H), 7.89(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 474[M+].
【０１４２】
実施例５１： 4,5- ジヒドロ -3-(4- メトキシベンジルオキシメチル )-1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 16) の合成：
化合物ＸＩ−11(50 mg, 0.13 mmol)の乾燥DMF(5 ml)溶液に、アルゴンガス雰囲気下室温でNaH(6 mg, 0.26 mmol)、塩化4-メトキシベンジル(41 mg, 0.26 mmol)を加え、室温で2時間攪拌した。実施例４８と同様に後処理し、残留物をシリカゲルカラムクロマトグラフ法(移動相：n-ヘキサン：酢酸エチル＝3：7)により精製して結晶性固体として表題化合物(43 mg, 収率 65%)を得た。mp.154〜156℃。1H-NMR(CDCl3/TMS)δ(ppm) : 2.93〜3.03(4H, m, CH2×2), 3.07(3H, s, CH3SO2), 3.80(3H, s, CH3O), 3.87(3H, s, CH3O), 4.55(2H, s, CH 2OCH2), 4.60(2H, s, CH2OCH 2), 6.88(2H, d, J=8.5Hz, aromatic-H), 6.94(2H, d, J=9Hz, aromatic-H), 7.07(1H, d, J=9Hz, 9-H), 7.32(2H, d, J=9Hz, aromatic-H), 7.45(2H, d, J=9Hz, aromatic-H), 7.59(1H, dd, J=2, 9Hz, 8-H), 7.89(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 505[M++H].
【０１４３】
実施例５２： 4,5- ジヒドロ -3- クロロメチル -1-(4- メトキシフェニル )-7- メチルスルホニルイミダゾ [1,2-a] キノリン ( 化合物ＸＩ− 17) の合成：
化合物ＸＩ−11(0.14 g, 0.37 mmol)のクロロホルム(5 ml)溶液に、室温で塩化チオニル(52 μl, 0.73 mmol) を加え1時間加熱還流した。反応液を室温まで冷却し、これに飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固して表題化合物(0.12 g, 収率 80%)を得た。このものは粗製のまま次の反応に使用した。1H-NMR (CDCl3/TMS)δ(ppm) : 2.99-3.07(4H, m, CH2×2), 3.07(3H, s, CH3SO2), 3.87(3H, s, CH3O), 4.69(2H, s, CH2Cl), 6.95(2H, d, J=9Hz, aromatic-H), 7.10(1H, d, J=9Hz, 9-H), 7.46(2H, d, J=9Hz, aromatic-H), 7.61(1H, dd, J=2, 9Hz, 8-H), 7.92(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 366[M+−36].
【０１４４】
実施例５３： 4,5- ジヒドロ -1-(4- メトキシフェニル )-7- メチルスルホニル -3- フェノキシメチルイミダゾ [1,5-a] キノリン ( 化合物ＸＩ− 18) の合成：
粗製の化合物ＸＩ−17(0.10 g, 0.25 mmol)の乾燥DMF(5 ml)溶液に、アルゴンガス雰囲気下室温でNaH(15 mg, 0.63 mmol)及びフェノール(94 mg, 1.00 mmol)を加え、室温で1晩攪拌した。反応液をクロロホルムで希釈し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(移動相：1回目,クロロホルム、2回目,n-ヘキサン：酢酸エチル＝3：7)で2回精製し、結晶性固体として表題化合物(47 mg, 収率 41%)を得た。mp.206〜209℃。1H-NMR(CDCl3/TMS)δ(ppm) : 3.01〜3.05(4H, m, CH2CH2), 3.07(3H, s, CH3SO2), 3.87(3H, s, CH3O), 5.11(2H, s, CH2O), 6.95(2H, d, J=9Hz, aromatic-H), 6.97(1H, m, aromatic-H), 7.05(2H, m, aromatic-H), 7.10(1H, d, J=9Hz, 9-H), 7.31(2H, m, aromatic-H), 7.47(2H, d, J=9Hz, aromatic-H), 7.60(1H, dd, J=2, 9Hz, 8-H), 7.90(1H, d, J=2Hz, 6-H). EI-DI(m/z) : 460[M+]
【０１４５】
製造例２３： 5- メチルチオ -2- ニトロフェノール ( 化合物 S-8) の製造：
5-フルオロ-2-ニトロフェノール(25.0 g, 0.16mol)をDMF(600 ml)に溶解し、室温で攪拌しながら1 N水酸化ナトリウム(190 ml, 0.19 mol)及びナトリウム チオメトキシド(15% 水溶液、123g, 0.26mol)を加え、9時間攪拌した。反応混合物に酢酸エチル(1000 ml)を加え、１ N塩酸(300 ml)次いで飽和食塩水で洗浄後、酢酸エチル層を分取し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法により精製後n-ヘキサン−クロロホルムから再結晶して黄色結晶性固体として表題化合物(28.6 g, 収率 97%)を得た。1H-NMR(CDCl3): 2.51(3H, s, SCH3), 6.77(1H, dd, J=2, 9Hz, 4-H), 6.84(1H, d, J=2Hz, 6-H), 7.95(1H, d, J=9Hz, 3-H), 10.86(1H, s, OH). MS(EI-DI) m/z: 185[M+].
【０１４６】
製造例２４： (5- メチルチオ -2- ニトロ ) フェノキシ酢酸エチル ( 化合物 S-9) の製造：
化合物 S-8(57.16 g, 0.31 mol)をアセトン(800 ml)に溶解し、炭酸カリウム(51.14 g, 0.37 mol)及びブロモ酢酸エチル(61.85 g, 0.37 mol)を加え、6時間煮沸還流した。反応混合物から不溶物をろ去し、ろ液を減圧下に濃縮乾固して得られる粗生成物をシリカゲルカラムクロマトグラフ法により精製して黄色粘性油状の表題化合物を定量的に得た。1H-NMR(CDCl3): 1.25(3H, t, J=7Hz, CO2CH2CH 3 ), 2.47(3H, s, SCH3), 4.23(2H, q, J=7Hz, CO2CH 2 CH3), 4.72(2H, s, OCH2), 6.74(1H, d, J=2Hz, 6-H), 6.84(1H, dd, J=2, 9Hz, 4-H), 7.85(1H, d, J=9Hz, 3-H). MS(EI-DI) m/z: 271[M+].
【０１４７】
製造例２５： (5- フルオロ -2- ニトロ ) フェノキシ酢酸エチル ( 化合物 S-10) の製造：
5-フルオロ-2-ニトロフェノール(25.0 g, 0.16 mol)をアセトン(500 ml)に溶解し、炭酸カリウム(26.4 g, 0.19 mol)及びブロモ酢酸エチル(31.9 g, 0.19 mol)を加え、15時間煮沸還流した。反応混合物から不溶物をろ去し、ろ液を減圧下に濃縮乾固して得られる粗生成物をシリカゲルカラムクロマトグラフ法により精製して黄色固体の表題化合物を定量的に得た。1H-NMR(CDCl3): 1.27(3H, t, J=7Hz, CO2CH2CH 3 ), 4.25(2H, q, J=7Hz, CO2CH 2 CH3), 4.74(2H, s, OCH2), 6.66(1H, dd, J=2, 10Hz, 6-H), 6.77(1H, ddd, J=2, 7, 9Hz, 4-H), 7.95(1H, dd, J=6, 9Hz, 3-H). MS(EI-DI) m/z: 198[M+-45].
【０１４８】
製造例２６： 7- メチルチオ -2H-1,4- ベンゾオキサジン -3(4H)- オン ( 化合物Ｉ d) の製造：
化合物S-9(83.73 g, 0.31 mol)をエタノール(1500 ml)に溶解し、鉄粉(53.19 g, 0.96 mol)及び濃塩酸(207 ml)を加え、5時間煮沸還流した。反応混合物を減圧下に濃縮し、析出する黄色固体をろ取、ろ取物を水及びエーテルで洗浄し、無色結晶性固体として表題化合物(48.01 g, 収率 80%)を得た。1H-NMR(DMSO-d6): 2.41(3H, s, SCH3), 4.54(2H, s, CH2), 6.80〜6.89(3H, m, 5, 6, 8-H), 10.67(1H, s, NH). MS(EI-DI) m/z: 195[M+].
【０１４９】
製造例２７： 7- フルオロ -2H-1,4- ベンゾオキサジン -3(4H)- オン ( 化合物Ｉ e) の製造：
化合物S-10(37.0 g, 0.15 mol)をエタノール(820 ml)に溶解し、鉄粉(27.5 g)及び濃塩酸(106 ml)を加え、15時間煮沸還流した。反応混合物を冷却後不溶物をろ去し、ろ取物をメタノール−クロロホルム混液で洗浄し、ろ洗液を合して減圧下に濃縮乾固した。残留物を水及びエーテルで洗浄し、無色結晶性固体として表題化合物(22.7 g, 収率 89%)を得た。クロロホルムから再結晶して無色針状晶。 1H-NMR(DMSO-d6): 4.57(2H, s, CH2), 6.75〜6.91(3H, m, 5, 6, 8-H), 10.70(1H, s, NH). MS(EI-DI) m/z: 167[M+].
【０１５０】
製造例２８： 7- メチルチオ -4-(2- オキソプロピル )-2H-1,4- ベンゾオキサジン -3 - オン ( 化合物ＩＩ d) の製造：
化合物Ｉd(19.50 g, 0.10 mol)をアセトン(500ml)に懸濁し、炭酸カリウム(20.70 g, 0.15 mol)、TEBAC(8.00 g, 35.0 mmol)及びクロロアセトン(12.0 g, 0.13 mol)を加え、24時間煮沸還流した。反応混合物から不溶物をろ去し、ろ取物をクロロホルムで洗浄し、ろ洗液を合して減圧下に濃縮乾固した。粘性油状残留物をシリカゲルカラムクロマトグラフ法により精製し、n-ヘキサン−クロロホルムから再結晶して無色針状晶として表題化合物(22.6 g, 収率 90%)を得た。 1H-NMR(CDCl3): 2.23(3H, s, CH3), 2.43(3H, s, SCH3), 4.25(2H, s, CH2), 4.65(2H, s, CH2), 6.51(1H, d, J=8Hz, 5-H), 6.86(1H, dd, J=2, 8Hz, 6-H), 6.92(1H, d, J=2Hz, 8-H). MS(EI-DI) m/z: 251[M+].
【０１５１】
製造例２９： 7- フルオロ -4-(2- オキソプロピル )-2H-1,4- ベンゾオキサジン -3- オン ( 化合物ＩＩ e) の製造：
化合物Ｉe(10.20 g, 61.0 mmol)をアセトン(200 ml)に懸濁し、炭酸カリウム(12.81 g, 92.7 mmol)、TEBAC(4.88 g, 21.4 mmol)及びクロロアセトン(6.78 g, 73.2 mmol)を加え、17時間煮沸還流した。反応混合物から不溶物をろ去し、ろ取物をクロロホルムで洗浄し、ろ洗液を合して減圧下に濃縮乾固した。粘性油状残留物をシリカゲルカラムクロマトグラフ法により精製し、エーテルから再結晶して無色針状晶として表題化合物(11.06 g, 収率 81%)を得た。 1H-NMR(CDCl3): 2.24(3H, s, CH3), 4.65(2H, s, CH2), 4.66(2H, s, CH2), 6.52(1H, dd, J=5, 9Hz, 5-H), 6.68(1H, ddd, J=3, 8, 9Hz, 6-H), 6.75(1H, dd, J=3, 9Hz, 8-H). MS(EI-DI) m/z: 223[M+].
【０１５２】
製造例３０： 7- メチルチオ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＩＩ f) の製造：
化合物ＩＩd(25.0 g, 0.10 mol)を酢酸(430 ml)に溶解し、酢酸アンモニウム(77.10 g, 1.00 mol)を加え、26時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物にクロロホルムを加え、水、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製、n-ヘキサン-エタノールから再結晶して淡黄色固体として表題化合物(17.72 g, 収率 76%) を得た。1H-NMR(CDCl3): 2.30(3H, d, J=1Hz, CH3), 2.47(3H, s, SCH3), 5.25(2H, s, CH2), 6.93(1H, dd, J=2, 8Hz, 8-H), 6.96(1H, d, J=2Hz, 6-H), 7.04(1H, d, J=1Hz, 1-H), 7.12(1H, d, J=8Hz, 9-H). MS(EI-DI) m/z: 232[M+].
【０１５３】
製造例３１： 7- フルオロ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＩＩ g) の製造：
化合物ＩＩe(6.70 g, 30.0 mmol)を酢酸(100 ml)に溶解し、酢酸アンモニウム(23.1 g, 0.30 mol)を加え、43時間煮沸還流した。反応混合物を減圧下に濃縮し、残留物にクロロホルムを加え、１N水酸化ナトリウム及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に濃縮乾固した後残留物をシリカゲルカラムクロマトグラフ法により精製し、n-ヘキサン−クロロホルムから再結晶して無色プリズム晶として表題化合物(5.34 g, 収率 85%)を得た。 1H-NMR(CDCl3): 2.28(3H, d, J=1Hz, CH3), 5.24(2H, s, CH2), 6.75(1H, ddd, J=3, 8, 9Hz, 8-H), 6.80(1H, dd, J=3, 9Hz, 6-H), 7.03(1H, d, J=1Hz, 1-H), 7.15(1H, dd, J=5, 9Hz, 9-H). MS(EI-DI) m/z: 204[M+].
【０１５４】
製造例３２： 1- ブロモ -2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＶ g) の製造：
化合物ＩＩＩf(6.00 g, 25.8 mmol)を酢酸(120 ml)に溶解し、NBS(4.83 g, 27.1 mmol)を加え、室温で2時間攪拌した。反応混合物にクロロホルムを加え、水、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製後n-ヘキサンを用いて結晶化し、黄色粉末として表題化合物(5.76 g, 収率 72%) を得た。1H-NMR(CDCl3): 2.26(3H, s, CH3), 2.48(3H, s, SCH3), 5.12(2H, s, CH2), 6.97(1H, dd, J=2, 9Hz, 8-H), 7.00(1H, d, J=2Hz, 6-H), 8.08(1H, d, J=9Hz, 9-H). MS(EI-DI) m/z: 310[M+], 312[M++2].
【０１５５】
製造例３３： 1- ブロモ -7- フルオロ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＶ h) の製造：
化合物ＩＩＩg(3.06 g, 15.0 mmol)を酢酸(30ml)に溶解し、NBS(2.93 g, 16.5 mmol)を加え、室温で1時間攪拌した。反応混合物にクロロホルムを加え、水、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製後n-ヘキサン−クロロホルムから再結晶し、淡黄色結晶性固体として表題化合物(3.69 g, 収率 87%) を得た。1H-NMR(CDCl3): 2.24(3H, s, CH3), 5.12(2H, s, CH2), 6.82(1H, ddd, J=3, 8, 9Hz, 8-H), 6.86(1H, dd, J=3, 9Hz, 6-H), 8.14(1H, dd, J=5, 9Hz, 9-H). MS(EI-DI) m/z: 282[M+], 284[M++2].
【０１５６】
1- アリール -2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジンの一般合成法：
化合物ＩＶg(500 mg, 1.6 mmol)及び各種置換基を有するフェニルほう酸類(1.9 mmol)をトルエン(5 ml)−エタノール(5 ml)混液に溶解し、2 M炭酸ナトリウム水溶液(5 ml)とPd(PPh3)4(0.1 mmol)を加え、アルゴンガス雰囲気下激しく撹拌しながら3時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法により精製して表題化合物を得た。
【０１５７】
実施例５４： 2- メチル -7- メチルチオ -1- フェニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 38) の合成：
フェニルほう酸を用い、淡黄褐色固体（収率89%）。1H-NMR(CDCl3): 2.23(3H, s, CH3), 2.42(3H, s, SCH3), 5.26(2H, s, CH2), 6.50(1H, d, J=9Hz, 9-H), 6.61(1H, dd, J=2, 9Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.28〜7.34(2H, m, aromatic), 7.43〜7.49(3H, m, aromatic). MS(EI-DI) m/z: 308[M+].
【０１５８】
実施例５５： 1-(3- フルオロフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2, 1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 39) の合成：
3-フルオロフェニルほう酸を用い、黄橙色固体（収率78%）。 1H-NMR(CDCl3): 2.20(3H, s, CH3), 2.42(3H, s, SCH3), 5.18(2H, s, CH2), 6.51(1H, d, J=9Hz, 9-H), 6.64(1H, dd, J=2, 9Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.00〜7.16(3H, m, aromatic), 7.38〜7.45(1H, m, aromatic). MS(EI-DI) m/z: 326[M+].
【０１５９】
実施例５６： 1-(4-フルオロフェニル)-2-メチル-7-メチルチオ-4H-イミダゾ[2,1-c][1,4]ベンゾオキサジン(化合物Ｖ−40)の合成：
4-フルオロフェニルほう酸を用い、淡黄色個体（収率88%）。mp.74〜76℃。1H-NMR(CDCl3): 2.18(3H, s, CH3), 2.42(3H, s, SCH3), 5.21(2H, s, CH2), 6.47(1H, d, J=9Hz, 9-H), 6.63(1H, dd, J=2, 9Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.15(2H, dd, J=9, 9Hz, aromatic), 7.29(2H, dd, J=5, 9Hz, aromatic). MS(EI-DI) m/z: 326[M+].
【０１６０】
実施例５７： 1-(4- クロロフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 41) の合成：
4-クロロフェニルほう酸を用い、淡黄色固体（収率87%）。1H-NMR(CDCl3): 2.19(3H, s, CH3), 2.43(3H, s, SCH3), 5.18(2H, s, CH2), 6.51(1H, d, J=9Hz, 9-H), 6.65(1H, dd, J=2, 9Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.24(2H, d, J=9Hz, aromatic), 7.42(2H, d, J=9Hz, aromatic). MS(EI-DI) m/z: 342[M+].
【０１６１】
実施例５８： 2- メチル -1-(4- メチルフェニル )-7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 42) の合成：
4-メチルフェニルほう酸を用い、淡褐色固体（収率99%）。1H-NMR(CDCl3): 2.21(3H, s, CH3), 2.42(3H, s, SCH3), 2.43(3H, s, CH3), 5.25(2H, s, CH2), 6.55(1H, d, J=9Hz, 9-H), 6.62(1H, dd, J=2, 9Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.19(2H, d, J=8Hz, aromatic), 7.26(2H, d, J=8Hz, aromatic). MS(EI-DI) m/z: 322[M+].
【０１６２】
実施例５９： 2- メチル -7- メチルチオ -1-(4- トリフルオロメチルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 43) の合成：
4-トリフルオロメチルフェニルほう酸を用い、淡黄色固体（収率78%）。 1H-NMR(CDCl3): 2.22(3H, s, CH3), 2.42(3H, s, SCH3), 5.20(2H, s, CH2), 6.47(1H, d, J=9Hz, 9-H), 6.66(1H, dd, J=2, 9Hz, 8-H), 7.00(1H, d, J=2Hz, 6-H), 7.44(2H, d, J=8Hz, aromatic), 7.70(2H, d, J=8Hz, aromatic). MS(EI-DI) m/z: 376[M+].
【０１６３】
実施例６０： 1-(3- メトキシフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 44) の合成：
3-メトキシフェニルほう酸を用い、淡黄褐粘性油成物（収率94%）。1H-NMR(CDCl3): 2.20(3H, s, CH3), 2.42(3H, s, SCH3), 3.79(3H, s, OCH3), 5.20(2H, s, CH2), 6.55(1H, d, J=9Hz, 9-H), 6.63(1H, dd, J=2, 9Hz, 8-H), 6.82〜6.99(4H, m, aromatic), 7.35(1H, dd, J=8, 8Hz, aromatic 5-H). MS(EI-DI) m/z: 338[M+].
【０１６４】
実施例６１： 1-(4- メトキシフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 45) の合成：
4-メトキシフェニルほう酸を用い、黄橙色固体（収率86%）。 1H-NMR(CDCl3): 2.16(3H, s, CH3), 2.41(3H, s, SCH3), 3.86(3H, s, OCH3), 5.13(1H, d, J=14Hz, 4-H), 5.19(1H, J=14Hz, 4-H), 6.54(1H, d, J=9Hz, 9-H), 6.62(1H, dd, J=2, 9Hz, 8-H), 6.96(2H, d, J=9Hz, aromatic), 6.97(1H, d, J=2Hz, 6-H), 7.22(2H, d, J=9Hz, aromatic). MS(EI-DI) m/z: 338[M+].
【０１６５】
実施例６２： 1-(3- クロロ -4- フルオロフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 46) の合成：
3-クロロ-4-フルオロフェニルほう酸を用い、淡黄色固体（収率79%）。 1H-NMR(CDCl3): 2.18(3H, s, CH3), 2.43(3H, s, SCH3), 5.18(2H, s, CH2), 6.48(1H, d, J=9Hz, 9-H), 6.66(1H, dd, J=2, 9Hz, 8-H), 6.99(1H, d, J=2Hz, 6-H), 7.17(1H, ddd, J=2, 5, 8Hz, aromatic 6-H), 7.22(1H,dd, J=9, 9Hz, aromatic 5-H), 7.38(1H, dd, J=2, 7Hz, aromatic 2-H). MS(EI-DI) m/z: 360[M+].
【０１６６】
実施例６３： 1-(3,5- ジクロロフェニル )-2- メチル -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 47) の合成：
3,5-ジクロロフェニルほう酸を用い、無色〜淡黄色固体（収率73%）。1H-NMR(CDCl3): 2.22(3H, s, CH3), 2.44(3H, s, SCH3), 5.21(2H, s, CH2), 6.52(1H, d, J=9Hz, 9-H), 6.70(1H, dd, J=2, 9Hz, 8-H), 7.01(1H, d, J=2Hz, 6-H), 7.20(2H, d, J=2Hz, aromatic 2, 6-H), 7.44(1H, dd, J=2, 2Hz, aromatic 4-H).
MS(EI-DI) m/z: 376[M+].
【０１６７】
1- アリール -2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジンの一般合成法：
メチルチオ体(化合物Ｖ−38-47)を塩化メチレン(50 mg/ml)に溶解し、mCPBA(1.0当量)を加え、室温で0.5時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物を酢酸エチルに溶解し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。酢酸エチル層を分取し、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法により精製して表題化合物を得た。
【０１６８】
実施例６４： 2- メチル -7- メチルスルフィニル -1- フェニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 48) の合成：
化合物Ｖ−38を用い、無色固体（収率88%）。1H-NMR(CDCl3): 2.21(3H, s, CH3), 2.68(3H, s, SOCH3), 5.26(1H, d, J=14Hz, 4-H), 5.30(1H, d, J=14Hz, 4-H), 6.72(1H, d, J=9Hz, 9-H), 7.01(1H, dd, J=2, 9Hz, 8-H), 7.28〜7.34(2H, m, aromatic), 7.39(1H, d, J=2Hz, 6-H), 7.44〜7.50(3H, m, aromatic). MS(EI-DI) m/z: 324[M+].
【０１６９】
実施例６５： 1-(3- フルオロフェニル )-2- メチル -7- メチルスルフィニル -4H- イ ミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 49) の合成：
化合物Ｖ−39を用い、無色固体（収率88%）。1H-NMR(CDCl3): 2.20(3H, s, CH3), 2.70(3H, s, SOCH3), 5.22(1H, d, J=14Hz, 4-H), 5.26(1H, d, J=14Hz, 4-H), 6.73(1H, d, J=9Hz, 9-H), 7.01〜7.13(4H, m, aromatic), 7.40〜7.47(2H, m, aromatic). MS(EI-DI) m/z: 342[M+].
【０１７０】
実施例６６： 1-(4- フルオロフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 50) の合成：
化合物Ｖ−40を用い、無色固体（収率87%）。1H-NMR(CDCl3): 2.16(3H, s, CH3), 2.69(3H, s, SOCH3), 5.20(1H, d, J=14Hz, 4-H), 5.24(1H, d, J=14Hz, 4-H), 6.70(1H, d, J=9Hz, 9-H), 7.01(1H, dd, J=2, 9Hz,8-H), 7.16(2H, dd, J=9, 10Hz), 7.29(2H, dd, J=5, 9Hz), 7.40(1H, d, J=2Hz, 6-H).MS(EI-DI) m/z: 342[M+].
【０１７１】
実施例６７： 1-(4- クロロフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 51) の合成：
化合物Ｖ−41を用い、無色固体（収率96%）。1H-NMR(CDCl3): 2.18(3H, s, CH3), 2.69(3H, s, SOCH3), 5.22(1H, d, J=14Hz, 4-H), 5.25(1H, d, J=14Hz, 4-H), 6.73(1H, d, J=8Hz, 9-H), 7.03(1H, dd, J=2, 8Hz, 8-H), 7.24(2H, d, J=9Hz, aromatic), 7.41(1H, d, J=2Hz, 6-H), 7.44(2H, d, J=9Hz, aromatic). MS(EI-DI) m/z: 358[M+].
【０１７２】
実施例６８： 2- メチル -1-(4- メチルフェニル )-7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 52) の合成：
化合物Ｖ−42を用い、淡黄色粉末（収率89%）。1H-NMR(CDCl3): 2.17(3H, s, CH3), 2.42(3H, s, SOCH3), 2.68(3H, s, CH3), 5.22(1H, d, J=14Hz, 4-H), 5.26(1H, d, J=14Hz, 4-H), 6.76(1H, d, J=9Hz, 9-H), 7.01(1H, dd, J=2, 9Hz, 8-H), 7.18(2H, d, J=8Hz, aromatic), 7.25(2H, d, J=8Hz, aromatic), 7.37(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 338[M+].
【０１７３】
実施例６９： 2- メチル -7- メチルスルフィニル -1-(4- トリフルオロメチルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 53) の合成：
化合物Ｖ−43を用い、無色アモルファス粉末（収率85%）。1H-NMR(CDCl3): 2.20(3H, s, CH3), 2.69(3H, s, SOCH3), 5.20(1H, d, J=14Hz, 4-H), 5.24(1H, d, J=14Hz, 4-H), 6.67(1H, d, J=8Hz, 9-H), 7.03(1H, dd, J=2, 8Hz, 8-H), 7.40〜7.45(3H, m, aromatic), 7.71(2H, d, J=8Hz, aromatic). MS(EI-DI) m/z: 392[M+].
【０１７４】
実施例７０： 1-(3- メトキシフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 54) の合成：
化合物Ｖ−44を用い、無色アモルファス粉末（収率83%）。 1H-NMR(CDCl3): 2.16(3H, s, CH3), 2.66(3H, s, SOCH3), 3.77(3H, s, OCH3), 5.20(2H, s, CH2), 6.75(1H, d, J=9Hz, 9-H), 6.79〜6.88(2H, m), 6.94(1H, m), 6.99(1H, dd, J=2, 9Hz, 8-H), 7.31〜7.38(2H, m). MS(EI-DI) m/z: 354[M+].
【０１７５】
実施例７１： 1-(4- メトキシフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 55) の合成：
化合物Ｖ−45を用い、淡黄色アモルファス粉末（収率79%）。 1H-NMR(CDCl3): 2.51(3H, s, CH3), 2.67(3H, s, SOCH3), 3.85(3H, s, OCH3), 5.19(1H, d, J=14Hz, 4-H), 5.23(1H, d, J=14Hz, 4-H), 6.75(1H, d, J=9Hz, 9-H), 6.96(2H, d, J=9Hz, aromatic), 6.99(1H, dd, J=2, 9Hz, 8-H), 7.20(2H, d, J=9Hz, aromatic), 7.36(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 354[M+].
【０１７６】
実施例７２： 1-(3- クロロ -4- フルオロフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 56) の合成：
化合物Ｖ−46を用い、無色アモルファス粉末（収率96%）。1H-NMR(CDCl3): 2.16(3H, s, CH3), 2.68(3H, s, SOCH3), 5.21(1H, d, J=14Hz, 4-H), 5.22(1H, d, J=14Hz, 4-H), 6.70(1H, d, J=9Hz, 9-H), 7.03(1H, dd, J=2, 9Hz, 8-H), 7.16(1H, ddd, J=2, 5, 9Hz, aromatic 6-H), 7.23(1H, dd, J=9, 9Hz, aromatic 5-H), 7.37(1H, dd, J=2, 7Hz, aromatic 2-H), 7.40(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 376[M+].
【０１７７】
実施例７３： 1-(3,5- ジクロロフェニル )-2- メチル -7- メチルスルフィニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 57) の合成：
化合物Ｖ−47を用い、無色固体（収率78%）。1H-NMR(CDCl3): 2.20(3H, s, CH3), 2.71(3H, s, SOCH3), 5.23(2H, s, CH2), 6.74(1H, d, J=9Hz, 9-H), 7.08(1H, dd, J=2, 9Hz, 8-H), 7.20(2H, d, J=2Hz, aromatic 2, 6-H ), 7.43(1H, d, J=2Hz, 6-H), 7.44(1H,dd, J=2, 2Hz, aromatic 4-H). MS(EI-DI) m/z: 392[M+].
【０１７８】
1- アリール -2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジンの一般合成法：
メチルチオ体(化合物Ｖ−38-47)を塩化メチレン(50 mg/ml)に溶解し、2.4当量のmCPBAを加え、室温で0.5時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物を酢酸エチルに溶解し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。酢酸エチル層を分取し、無水硫酸ナトリウムで乾燥後減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法により精製して表題化合物を得た。
【０１７９】
実施例７４： 2- メチル -7- メチルスルホニル -1- フェニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 58) の合成：
化合物Ｖ−38を用い、淡黄色固体（収率79%）。mp.176〜177℃。1H-NMR(CDCl3): 2.21(3H, s, CH3), 3.01(3H, s, SO2CH3), 5.29(2H, s, CH2), 6.74(1H, d, J=9Hz, 9-H), 7.26〜7.34(3H, m, aromatic), 7.44〜7.52(3H, m, aromatic), 7.65(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 340[M+].
【０１８０】
実施例７５： 1-(3- フルオロフェニル )-2- メチル -7- メチルスルホニル -4H- イミ ダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 59) の合成：
化合物Ｖ−39を用い、淡黄色固体（収率86%）。mp.201〜202℃。1H-NMR(CDCl3): 2.21(3H, s, CH3), 3.02(3H, s, SO2CH3), 5.27(2H, s, CH2), 6.75(1H, d, J=9Hz, 9-H), 7.00〜7.21(3H, m, aromatic), 7.42〜7.49(1H, m, aromatic), 7.35(1H, dd, J=2, 9Hz, 8-H), 7.67(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 358[M+].
【０１８１】
実施例７６： 1-(3- メトキシフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 60) の合成：
化合物Ｖ−44を用い、無色針状晶（収率 76%）。 1H-NMR(CDCl3): 2.19(3H, s, CH3), 3.01(3H, s, SO2CH3), 3.80(3H, s, OCH3), 5.26(2H, s, CH2), 6.78(1H, d, J=9Hz, 9-H), 6.80〜6.90(2H, m, aromatic), 6.97〜7.03(1H, m, aromatic), 7.30〜7.42(2H, m, aromatic), 7.64(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 370[M+].
【０１８２】
実施例７７： 1-(4- フルオロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 61) の合成：
化合物Ｖ−40を用い、無色〜淡黄色固体（収率81%）。mp.224〜226℃。1H-NMR(CDCl3): 2.21(3H, s, CH3), 3.02(3H, s, SO2CH3), 5.33(2H, s, CH2), 6.74(1H, d, J=9Hz, 9-H), 7.20(2H, dd, J=9, 9Hz, aromatic 3, 5-H), 7.30(2H, dd, J=5, 9Hz, aromatic 2, 6-H), 7.35(1H, dd, J=2, 9Hz, 8-H), 7.68(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 358[M+].
【０１８３】
実施例７８： 1-(4- クロロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 62) の合成：
化合物Ｖ−41を用い、淡黄色固体（収率73%）。mp.229〜232℃。1H-NMR(CDCl3): 2.18(3H, s, CH3), 3.02(3H, s, SO2CH3), 5.25(2H, s, CH2), 6.75(1H, d, J=9Hz, 9-H), 7.24(2H, d, J=8Hz, aromatic), 7.35(1H, dd, J=2, 9Hz, 8-H), 7.45(2H, d, J=8Hz, aromatic), 7.66(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 374[M+].
【０１８４】
実施例７９： 2- メチル -1-(4- メチルフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 63) の合成：
化合物Ｖ−42を用い、淡黄色固体（収率55%）。mp.180〜182℃。 1H-NMR(CDCl3): 2.17(3H, s, CH3), 2.43(3H, s, CH3), 3.01(3H, s, SO2CH3), 5.25(2H, s, CH2), 6.77(1H, d, J=9Hz, 9-H), 7.17(2H, d, J=8Hz, aromatic), 7.26(2H, d, J=8Hz, aromatic), 7.31(1H, dd, J=2, 9Hz, 8-H), 7.63(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 354[M+].
【０１８５】
実施例８０： 2- メチル -7- メチルスルホニル -1-(4- トリフルオロメチルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 64) の合成：
化合物Ｖ−43を用い、淡黄色固体（収率98%）。mp.225〜228℃。 1H-NMR(CDCl3): 2.23(3H, s, CH3), 3.03(3H, s, SO2CH3), 5.28(2H, s, CH2), 6.71(1H, d, J=9Hz, 9-H), 7.37(1H, dd, J=2, 9Hz, 8-H), 7.44(2H, d, J=8Hz, aromatic), 7.69(1H, d, J=2Hz, 6-H), 7.74(2H, d, J=8Hz, aromatic). MS(EI-DI) m/z: 408[M+].
【０１８６】
実施例８１： 1-(4- メトキシフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 65) の合成：
化合物Ｖ−45を用い、淡黄色固体（収率82%）。mp.225〜227.5℃。1H-NMR(CDCl3): 2.18(3H, s, CH3), 3.01(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.27(2H, s, CH2), 6.79(1H, d, J=9Hz, 9-H), 6.99(2H, d, J=9Hz, aromatic), 7.22(2H, d, J=9Hz, aromatic), 7.32(1H, dd, J=2, 9Hz, 8-H), 7.64(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 370[M+].
【０１８７】
実施例８２： 1-(3- クロロ -4- フルオロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 66) の合成：
化合物Ｖ−46を用い、無色〜淡黄色固体（収率96%）。 1H-NMR(CDCl3): 2.19(3H, s, CH3), 3.03(3H, s, SO2CH3), 5.26(2H, s, CH2), 6.74(1H, d, J=9Hz, 9-H), 7.18(1H, ddd, J=2, 5, 9Hz, aromatic 6-H), 7.26(1H, dd, J=9, 9Hz, aromatic 5-H), 7.36〜7.41(2H, m, aromotic), 7.67(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 392[M+].
【０１８８】
実施例８３： 1-(3,5- ジクロロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 67) の合成：
化合物Ｖ−47を用い、無色〜淡黄色固体（収率98%）。 1H-NMR(CDCl3): 2.22(3H, s, CH3), 3.04(3H, s, SO2CH3), 5.27(2H, s, CH2), 6.77(1H, d, J=9Hz, 9-H), 7.20(2H, d, J=2Hz, aromatic 2, 6-H), 7.42(1H, dd, J=2, 9Hz, 8-H), 7.43(1H, dd, J=2, 2Hz, aromatic 4-H), 7.69(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 408[M+].
【０１８９】
実施例８４： 7- アミノスルホニル -1-(4- メトキシフェニル )-2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 68) の合成：
化合物Ｖ−65(1.00 g, 2.70 mmol)を無水THF(25 ml)に懸濁し、アルゴンガス雰囲気下に氷冷、攪拌しながら塩化n-プロピルマグネシウム(1.5 ml, 2.97 mmol: 2.0Mエーテル溶液)を加え、室温で1時間攪拌した。反応混合物を再び氷冷し、トリエチルホウ素(4.1 ml, 4.05 mmol: 1.0Mテトラヒドロピラン溶液)を加え、45時間煮沸還流した。反応混合物を氷冷し、攪拌下に酢酸ナトリウム水溶液(2.06 g, 25.10 mmol/3.5 ml)及びヒドロキシルアミン-O-スルホン酸(2.46 g, 21.79 mmol)を加え、室温で4時間攪拌した。反応混合物を酢酸エチルで希釈し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後酢酸エチル層を分取し、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム次いで2%メタノール含有クロロホルム)により精製し、n-ヘキサン−クロロホルムから結晶化して微黄色粉末として表題化合物(40 mg, 4%)を得た。 mp.202〜205℃(dec.). 1H-NMR(DMSO-d6): 2.07(3H, s, 2-CH3), 3.83(3H, s, OCH3), 5.29(2H, s, OCH2), 6.68(1H, d, J=9Hz, 9-H), 7.08(2H, d, J=9Hz), 7.27(1H, dd, J=2, 9Hz, 8-H), 7.28(2H, d, J=9Hz), 7.38(2H, s, SO2NH2), 7.54(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 371[M+].
【０１９０】
実施例８５： 7- フルオロ -2- メチル -1-(4- メチルチオフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 69) の合成：
化合物ＩＶh(500 mg, 1.6 mmol)及び4-メチルチオフェニルほう酸(1.9 mmol)を用い、1-アリール-2-メチル-7-メチルチオ-4H-イミダゾ[2,1-c][1,4]ベンゾオキサジンの一般合成法に従って反応、後処理して淡褐色固体として表題化合物を得た。収率86%。mp.126〜128℃。1H-NMR(CDCl3): 2.16(3H, s, CH3), 2.52(3H, s, SCH3), 5.17(2H, s, CH2), 6.47(1H, ddd, J=3, 8, 9Hz, 8-H), 6.61(1H, dd, J=6, 9Hz, 9-H), 6.81(1H, dd, J=3, 9Hz, 6-H), 7.20(2H, d, J=9Hz), 7.29(2H, d, J=9Hz). MS(EI-DI) m/z: 326[M+].
【０１９１】
実施例８６： 7- フルオロ -2- メチル -1-(4- メチルスルフィニルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 70) の合成：
化合物Ｖ−69を用い、1-アリール-2-メチル-7-メチルスルフィニル-4H-イミダゾ[2,1-c][1,4]ベンゾオキサジンの一般合成法に従って反応、後処理して黄橙色固体として表題化合物を得た。収率85%。1H-NMR(CDCl3): 2.21(3H, s, CH3), 2.81(3H, s, SOCH3), 5.18(2H, s, CH2), 6.45〜6.54(2H, m, 8,9-H), 6.86(1H, dd, J=3, 9Hz, 6-H), 7.47(2H, d, J=9Hz), 7.73(2H, d, J=9Hz). MS(EI-DI) m/z: 342[M+].
【０１９２】
実施例８７： 7- フルオロ -2- メチル -1-(4- メチルスルホニルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 71) の合成：
化合物Ｖ−69を用い、1-アリール-2-メチル-7-メチルスルホニル-4H-イミダゾ[2,1-c][1,4]ベンゾオキサジンの一般合成法に従って反応、後処理して淡黄色固体として表題化合物を得た。収率89%。mp.171〜173℃。1H-NMR(CDCl3): 2.27(3H, s, CH3), 3.14(3H, s, SO2CH3), 5.29(2H, s, CH2), 6.48〜6.60(2H, m, 8, 9-H), 6.90(1H, dd, J=2, 9Hz, 6-H), 7.53(2H, d, J=8Hz, aromatic), 8.04(2H, d, J=8Hz, aromatic). MS(EI-DI) m/z: 358[M+].
【０１９３】
実施例８８： 1-(4- アミノスルホニルフェニル )-7- フルオロ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 72) の合成：
化合物Ｖ−71(990 mg, 2.8 mmol)を無水THF(15 ml)に溶解し、アルゴンガス雰囲気下に氷冷、攪拌しながら塩化n-プロピルマグネシウム(1.5 ml, 3.0 mmol: 2.0 Mエーテル溶液)を加え、室温で0.5時間攪拌した。反応混合物を再び氷冷し、トリエチルホウ素(4.2 ml, 4.2 mmol: 1.0 Mテトラヒドロピラン溶液)を加え、45時間煮沸還流した。反応混合物を氷冷し、攪拌下に酢酸ナトリウム水溶液(2.10 g/3.5 ml)およびヒドロキシルアミン-O-スルホン酸(2.52 g, 22.3 mmol)を加え、室温で4時間攪拌した。実施例８４と同様に後処理、精製し、n-ヘキサン−クロロホルムから再結晶して無色固体として表題化合物(80 mg, 収率 8%)を得た。 1H-NMR(CDCl3): 2.11(3H, s, CH3), 5.26(2H, s, CH2), 6.56(1H, dd, J=5, 9Hz, 9-H), 6.79(1H, ddd, J=3, 9, 9Hz, 8-H), 7.17(1H, dd, J=3, 9Hz, 6-H), 7.47(2H, s, NH2), 7.55(2H, d, J=9Hz, aromatic), 7.91(2H, d, J=9Hz, aromatic). MS(EI-DI) m/z: 359[M+].
【０１９４】
製造例３４： 7- メチルチオ -2H-1,4- ベンゾオキサジン -3(4H)- チオン ( 化合物ＶＩ b) の製造：
化合物Ｉd(15.6 g, 80.0 mmol)を乾燥THF(900 ml)に溶解し、Lawesson試薬(16.20 g, 40.0 mmol)を加え、室温で14時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製し、エタノールから再結晶して無色針状晶として表題化合物(5.22 g, 収率 95%)を得た。1H-NMR(CDCl3): 2.45(3H, s, SCH3), 4.85(2H, s, CH2), 6.78(1H, d, J=8Hz, 5-H), 6.84(1H, dd, J=2, 8Hz, 6-H), 6.87(1H, d, J=2Hz, 8-H), 9.76(1H, br-s, NH).
MS(EI-DI) m/z: 211[M+].
【０１９５】
製造例３５： 7- フルオロ -2H- １ ,4- ベンゾオキサジン -3(4H)- チオン ( 化合物ＶＩ c) の製造：
化合物Ｉe(5.01 g, 30.0 mmol)を乾燥THF(350 ml)に溶解し、Lawesson試薬(6.06 g, 15.0 mmol)を加え、室温で1.5時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製し、エタノールから再結晶して黄色針状晶として表題化合物(14.98 g, 収率 89%)を得た。1H-NMR(CDCl3): 4.86(2H, s, CH2), 6.65〜6.76(2H, m, 6, 8-H), 6.83(1H, dd, J=5, 9Hz, 5-H), 9.90(1H, br, NH). MS(EI-DI) m/z: 183[M+].
【０１９６】
製造例３６： 3, 7- ジメチルチオ -2H-1,4- ベンゾオキサジン ( 化合物ＶＩＩ b) の製造：
化合物ＶＩb(15.6 g, 73.8 mmol)を乾燥THF(160 ml)に溶解し、氷冷下攪拌しながらNaH(2.13 g, 88.6 mmol)を加え0.5時間攪拌し、次いで室温で0.25時間攪した後よう化メチル(21.0 g, 147.7 mmol)を加え、2時間攪拌した。 反応混合物を減圧下に濃縮乾固し、残留物にクロロホルムを加え、水及び飽和食塩水で洗浄した。クロロホルム層を無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製して淡黄色固体として表題化合物(15.03 g, 収率 90%)を得た。1H-NMR(CDCl3): 2.45(3H, s, SCH3), 2.55(3H, s, SCH3), 4.47(2H, s, CH2), 6.75(1H, d, J=2Hz, 8-H), 6.85(1H, dd, J=2, 8Hz, 6-H), 7.20(1H, d, J=8Hz, 5-H). MS(EI-DI) m/z: 225[M+].
【０１９７】
製造例３７： 7- フルオロ -3- メチルチオ -2H-1,4- ベンゾオキサジン ( 化合物 ＶＩＩ c) の製造：
化合物ＶＩc(4.58 g, 25.0 mmol)を乾燥THF(60 ml)に溶解し、氷冷下攪拌しながらNaH(0.72 g, 30.0 mmol)を加え、0.5時間攪拌した。ついで室温で0.25時間攪拌後よう化メチル(7.10 g, 50.0 mmol)を加え、1.5時間攪拌した。製造例３６と同様に後処理、精製して黄色固体として表題化合物(4.62 g, 収率 94%)を得た。1H-NMR(CDCl3): 2.52(3H, s, SCH3), 4.47(2H, s, CH2), 6.59(1H, dd, J=3, 9Hz, 8-H), 6.67(1H, ddd, J=3, 9, 9Hz, 6-H), 7.21(1H, dd, J=6, 9Hz, 5-H).
MS(EI-DI) m/z: 197[M+].
【０１９８】
製造例３８： 3-(2,2- ジメトキシエチルアミノ )-7- メチルチオ -2H-1,4- ベンゾオ キサジン ( 化合物ＶＩＩＩ b) の製造：
化合物VIIb(14.0 g, 62.1 mmol)を乾燥アセトニトリル(70 ml)に溶解し、アミノアセトアルデヒド ジメチルアセタール(13.06 g, 105.1 mmol)を加え、5日間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製して定量的に黄褐色粘性油状物として表題化合物を得た。1H-NMR(CDCl3): 2.40(3H, s, SCH3), 3.38(6H, s, OCH3×2), 3.57(2H, d, J=5Hz, CH2), 4.35(2H, s, CH2), 4.49(1H, t, J=5Hz, CH), 6.76(1H, d, J=2Hz, 8-H), 6.83(1H, dd, J=2, 8Hz, 6-H), 6.99(1H, d, J=8Hz, 5-H). MS(EI-DI) m/z: 282[M+].
【０１９９】
製造例３９： 3-(2,2- ジメトキシエチルアミノ )-7- フルオロ -2H-1,4- ベンゾオキサジン ( 化合物 ＶＩＩＩ c) の製造：
化合物ＶＩＩc(1.97 g, 10.0 mmol)を乾燥アセトニトリル(10 ml)に溶解し、アミノアセトアルデヒド ジメチルアセタール(2.10 g, 20.0 mmol)を加え、3日間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法により精製して定量的に黄色粘性油状物として表題化合物を得た。1H-NMR(CDCl3): 3.42(6H, s, OCH3×2), 3.60(2H, d, J=5Hz, CH2), 4.39(2H, s, CH2), 4.52(1H, t, J=5Hz, CH), 6.58(1H, dd, J=3, 9Hz, 8-H), 6.63(1H, ddd, J=3, 9, 9Hz, 6-H), 7.02(1H, dd, J=6, 9Hz, 5-H). MS(EI-DI) m/z: 254[M+].
【０２００】
製造例４０： 7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物 ＩＩＩ h) の製造：
化合物ＶＩＩＩb(17.0 g, 60.2 mmol)を1 N塩酸 (900 ml)に加え、1.5時間煮沸還流した。反応混合物に氷冷下攪拌しながら2 N水酸化ナトリウム水溶液(500 ml)を加え、クロロホルムで二回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固し、残留物をn-へキサン−クロロホルムから再結晶して無色固体として表題化合物(12.4 g, 収率 94%)を得た。1H-NMR(CDCl3): 2.47(3H, s, SCH3), 5.25(2H, s, CH2), 6.93(1H, dd, J=2, 8Hz, 8-H), 6.97(1H, d, J=2Hz, 6-H), 7.16(1H, d, J=2Hz), 7.18(1H, d, J=8Hz, 9-H), 7.32(1H, d, J=2Hz). MS(EI-DI) m/z: 218[M+].
【０２０１】
製造例４１： 7- フルオロ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＩＩ i) の製造：
化合物ＶＩＩＩc(2.30 g, 9.1 mmol)を1 N塩酸 (120 ml)に加え、1.5時間煮沸還流した。反応混合物に氷冷下攪拌しながら2 N水酸化ナトリウム(65 ml)を加え、クロロホルムで二回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固し、残留物をn-へキサン−クロロホルムから再結晶して無色固体として表題化合物(1.54 g, 収率 90%)を得た。1H-NMR(CDCl3): 5.35(2H, s, CH2), 6.81(1H, ddd, J=3, 8, 9Hz, 8-H), 6.86(1H, dd, J=3, 9Hz, 6-H), 7.26(1H, dd, J=5, 9Hz, 9-H), 7.32(1H, d, J=2Hz), 7.36(1H, d, J=2Hz). MS(EI-DI) m/z: 190 [M+].
【０２０２】
製造例４２： 1- ブロモ -7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＶ i) の製造：
化合物ＩＩＩh(1.00 g, 4.6 mmol)を酢酸(10 ml)に溶解し、水浴中で攪拌しながらNBS(856 mg, 4.8 mmol)を加え、2時間攪拌した。反応混合物を酢酸エチルで希釈し、水、7%炭酸水素ナトリウム水溶液次いで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法により精製して黄色固体として表題化合物(170 mg, 収率 13%)を得た。1H-NMR(CDCl3): 2.48(3H, s, SCH3), 5.12(2H, s, CH2), 6.97(1H, dd, J=2, 9Hz, 8-H), 7.00(1H, d, J=2Hz, 6-H), 7.10(1H, s, 2-H), 8.09(1H, d, J=9Hz, 9-H). MS(EI-DI) m/z: 296 [M+], 298[M++2].
【０２０３】
製造例４３： 1- ブロモ -7- フルオロ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＶ j) の製造：
化合物ＩＩＩi(860 mg, 4.5 mmol)を酢酸(10 ml)に溶解し、水浴中で攪拌しながらNBS(845 mg, 4.8 mmol)を加え、1時間攪拌した。製造例４２と同様に後処理、精製して黄色固体として表題化合物(260 mg, 収率 21%)を得た。 1H-NMR(CDCl3): 5.12(2H, s, CH2), 6.81(1H, ddd, J=3, 8, 9Hz, 8-H), 6.86(1H, dd, J=3, 9Hz, 6-H), 7.09(1H, s, 2-H), 8.15(1H, dd, J=5, 9Hz, 9-H). 13C-NMR(CDCl3): 64.63, 98.53, 106.29(d, J=26Hz), 109.44(d, J=23Hz), 118.30(d, J=9Hz), 121.90, 131.30, 141.43, 148.28(d, J=13Hz), 160.81(d, J=246Hz). MS(EI-DI) m/z: 268 [M+], 270[M++2].
【０２０４】
実施例８９： 1-(4- フルオロフェニル )-7- メチルチオ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 73) の合成：
化合物ＩＶi(140 mg, 0.5 mmol)及び4-フルオロフェニルほう酸(79 mg, 0.6 mmol)をトルエン(1.5 ml)−エタノール(1.5 ml)混液に溶解し、2 M炭酸ナトリウム水溶液(1.5 ml)とPd(PPh3)4(37 mg, 0.03 mmol)を加え、アルゴンガス雰囲気下激しく撹拌しながら3時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法により精製して淡黄色固体として表題化合物(130 mg, 収率 90%)を得た。1H-NMR(CDCl3): 2.43(3H, s, CH3), 5.18(2H, s, CH2), 6.65〜6.69(2H, m), 7.00(1H, m), 7.03(1H, s, 2-H), 7.11(2H, dd, J=9, 9Hz, aromatic 3, 5-H), 7.35(2H, dd, J=5, 9Hz, aromatic 2, 6-H). MS(EI-DI) m/z: 312[M+].
【０２０５】
参考例８： 4-メチルスルホニルフェニルほう酸の製造：
4-メチルチオフェニルほう酸(1.50 g, 8.93 mmol)の水酸化ナトリウム(0.75 g, 18.8 mmol)水溶液(50 ml)に、氷冷下、過マンガン酸カリウム(2.96 g, 18.8 mmol)水溶液(50 ml)を滴下し、室温で1時間攪拌した。エタノール(5〜10 ml)を加え未反応の過マンガン酸塩を分解した後、吸引ろ過により二酸化マンガンの沈殿をろ別した。ろ液に濃塩酸を加え、析出する結晶を吸引ろ過により集め、水から再結晶して表題化合物(1.56 g, 収率 87%)を得た。1H-NMR(DMSO-d6)δ(ppm) : 3.18(3H, s, CH3), 7.86〜7.88(2H, d, J=8Hz), 7.99〜8.01(2H, d, J=8Hz), 8.30(2H, s, OH×2). EI-MS(m/z) : 200(M+).
【０２０６】
製造例４４： 7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＩＩ j) の製造：
化合物ＩＩＩh(5.00 g, 22.9 mmol)を塩化メチレン(50 ml)に溶解し、mCPBA(9.50 g, 55.1 mmol)を加え、室温で40分間攪拌した。反応混合物を塩化メチレンで希釈し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をn-ヘキサン−塩化メチレンから結晶化して無色固体として表題化合物(5.40g, 収率 94%)を得た。mp.223〜226℃(dec.). 1H-NMR(CDCl3): 3.06(3H, s, SO2CH3), 5.35(2H, s, OCH2), 7.23(1H, s,), 7.40(1H, s), 7.44(1H, d, J=9Hz, 8-H), 7.64-7.69(2H, m). MS(EI-DI) m/z: 250[M+].
【０２０７】
製造例４５： 1- ブロモ -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物ＩＶ k) の製造：
化合物ＩＩＩj(5.20 g, 20.78 mmol)をアセトニトリル(520 ml)に懸濁し、NBS(4.07 g, 22.87 mmol)を加えて50℃で2時間加熱攪拌した。反応混合物を減圧下に濃縮乾固し、残留物にクロロホルムを加え、不溶物をろ去し、クロロホルムで洗浄した。ろ洗液を合し、水で洗浄、 有機層を分取し、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5%メタノール含有クロロホルム)により精製し、微黄色固体として表題化合物(3.95 g, 収率 58%)を得た。mp.167〜169℃(dec.). 1H-NMR(CDCl3): 3.07(3H, s, SO2CH3), 5.21(2H, s, OCH2), 7.16(1H, s, 2-H), 7.68〜7.74(2H, m), 8.40(1H, d, J=9Hz, 8-H). MS(EI-DI) m/z: 328[M+], 330[M++2].
【０２０８】
実施例９０： 1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 74) の合成：
化合物ＩＶk(3.95 g, 12.00 mmol)、4-メトキシフェニルほう酸(2.19 g, 14.40 mmol)及びPd(PPh3)4(947 mg, 0.82 mmol)の混合物にトルエン(40 ml)、エタノール(40 ml)及び2 M炭酸ナトリウム水溶液(40 ml)を加え、アルゴンガス雰囲気下で3時間激しく攪拌しながら煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物にクロロホルムを加え、水及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法（クロロホルム−n-ヘキサン混液(3:1)次いで0.5%メタノール含有クロロホルム）により精製し、表題化合物(4.16 g, 収率 97%)を得た（エタノールから再結晶して無色針状結晶）。 mp.193〜195℃.1H-NMR(CDCl3): 3.03(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.27(2H, s, OCH2), 6.97(2H, d, J=9Hz), 6.98(1H, d, J=9Hz, 9-H), 7.05(1H, s, 2-H), 7.28(2H, d, J=9Hz), 7.37(1H, dd, J=2, 9Hz, 8-H), 7.67(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 356[M+].
【０２０９】
実施例９１： 2- クロロ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 75) の合成：
化合物Ｖ−74(100 mg, 0.28 mmol)を酢酸(4 ml)に溶解し、NCS(39 mg, 0.29 mmol)を加え、80℃で2時間攪拌した。反応混合物を酢酸エチルで希釈し、水、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液(4:1)次いで2%メタノール含有クロロホルム)により精製し、無色固体として表題化合物(60 mg, 収率 55%)を得た。 mp.217〜219℃(dec.).1H-NMR(CDCl3): 3.02(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.23(2H, s, OCH2), 6.86(1H, d, J=9Hz, 9-H), 7.01(2H, d, J=9Hz), 7.29(2H, d, J=9Hz), 7.36(1H, dd, J=2, 9Hz, 8-H), 7.66(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 390[M+].
【０２１０】
実施例９２： 2- ブロモ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 76) の合成：
化合物Ｖ−74(600 mg, 1.68 mmol)を酢酸(18 ml)に溶解し、NBS(315 mg, 1.77 mmol)を加え、室温で3時間攪拌した。反応混合物をクロロホルムで希釈し、1 N水酸化ナトリウム水溶液(310 ml)及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をn-ヘキサン−クロロホルムから結晶化して、淡黄色固体として表題化合物(705 mg, 収率 96%)を得た。 mp.243〜244℃(dec.). 1H-NMR(CDCl3): 3.02(3H, s, SO2CH3), 3.88(3H, s, OCH3), 5.24(2H, s, OCH2), 6.83(1H, d, J=9Hz, 9-H), 7.01(2H, d, J=9Hz), 7.29(2H, d, J=9Hz), 7.35(1H, dd, J=2, 9Hz, 8-H), 7.66(1H, d, J=2Hz, 6-H). IR(KBr): 1495, 1420, 1315, 1300cm-1. MS(EI-DI) m/z: 434[M+], 436 [M++2].
【０２１１】
実施例９３： 1-(4- メトキシフェニル )-7- メチルスルホニル -2- トリフルオロメチル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 77) の合成：
化合物Ｖ−76(700 mg, 1.61 mmol)をDMA(14 ml)に溶解し、トリフルオロ酢酸ナトリウム(876 mg, 6.44 mmol)及びよう化銅(I)(590 mg, 3.10 mmol)を加え、5.5時間煮沸還流した。反応混合物にクロロホルム(20 ml)及び1.5 N塩酸(20 ml)を加えて分液し、水層は更にクロロホルムで抽出した。有機層を合し、不溶物をセライトパッドを用いてろ去し、ろ液部を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液(3:2)次いで2%メタノール含有クロロホルム)により精製し、n-ヘキサン−クロロホルムから結晶化して無色固体として表題化合物(200 mg, 収率 29%)を得た。 mp.188〜190℃. 1H-NMR(CDCl3): 3.01(3H, s, SO2CH3), 3.89(3H, s, OCH3), 5.29(2H, s, OCH2), 6.70(1H, d, J=9Hz, 9-H), 7.01(2H, d, J=9Hz), 7.29(2H, d, J=9Hz), 7.33(1H, dd, J=2, 9Hz, 8-H), 7.68(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 424[M+].
【０２１２】
実施例９４： 2- シアノ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 78) の合成：
化合物Ｖ−76(210 mg, 0.48 mmol)をDMF(0.5 ml)に溶解し、シアン化銅(I)(52 mg, 0.58 mmol)を加え、アルゴンガス雰囲気下170℃で2時間攪拌した。反応混合物を酢酸エチルで希釈し、不溶物をセライトパッドを用いてろ去した。ろ液部を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液[3:1])により精製し、n-ヘキサン−クロロホルムから結晶化して無色固体として表題化合物(50 mg, 収率 27%)を得た。 mp.226〜228℃. 1H-NMR(CDCl3): 3.04(3H, s, SO2CH3), 3.89(3H, s, OCH3), 5.26(2H, s, OCH2), 7.00(1H, d, J=9Hz, 9-H), 7.05(2H, d, J=9Hz), 7.37(2H, d, J=9Hz), 7.42(1H, dd, J=2, 9Hz, 8-H), 7.73(1H, d, J=2Hz, 6-H). IR(KBr): 2220, 1500, 1400, 1315, 1300cm-1.MS(EI-DI) m/z: 381[M+].
【０２１３】
実施例９５： 1-(4- メトキシフェニル )-7- メチルスルホニル -2- ニトロ -4H- イミダゾ [2,1-c][1,4] ベンゾオキサジン ( 化合物Ｖ− 79) の合成：
化合物Ｖ−74(200 mg, 0.56 mmol)を無水酢酸(4 ml)に溶解し、硝酸(d=1.52, 48μl, 1.16 mmol)を加え、50℃で2時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液(7:3)次いで5%メタノール含有クロロホルム)により精製し、n-ヘキサン−クロロホルムから結晶化して淡黄色固体として表題化合物(60 mg, 収率 27%)を得た。 mp.250〜252℃(dec.). 1H-NMR(CDCl3): 3.02(3H, s, SO2CH3), 3.90(3H, s, OCH3), 5.29(2H, s, OCH2), 6.72(1H, d, J=9Hz, 9-H), 7.06(2H, d, J=9Hz), 7.36(2H, d, J=9Hz), 7.37(1H, dd, J=2, 9Hz, 8-H), 7.72(1H, d, J=2Hz, 6-H). IR(KBr): 1515, 1395, 1315, 1300cm-1. MS(EI-DI) m/z: 401[M+].
【０２１４】
製造例４６： 3- エトキシカルボニル -7- メチルチオ -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＩＸ c) の製造：
化合物Ｉd(5.50 g, 28.17 mmol)を乾燥DMF(80 ml)に溶解し、アルゴンガス雰囲気下で氷冷しながらカリウムtert-ブトキシド(3.35 g, 29.86 mmol)を加え15分間攪拌した。この反応混合物にクロロりん酸ジエチル(8.75 g, 50.71 mmol)を加え10分間攪拌後、イソシアノ酢酸エチル(4.56 g, 40.28 mmol)の乾燥DMF溶液(40 ml)及びカリウムtert-ブトキシド(4.43 g, 39.45 mmol)を加え15分間攪拌し、次いで室温で22時間攪拌した。氷冷下攪拌しながら反応混合物に酢酸(5.5 ml)を滴下し、これを氷水(1000 ml)に加え酢酸エチルで抽出した。酢酸エチル層を飽和食塩水溶液で洗浄し、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固し、茶褐色固体として粗表題化合物を得た。このものは精製することなく次の反応に使用した。
一部をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、n-ヘキサン−エタノールから結晶化して淡黄色粉末として表題化合物を得た。 mp.162〜164℃.1H-NMR(CDCl3): 1.40(3H, t, J=7Hz, CO2CH2CH 3 ), 2.48(3H, s, SCH3), 4.39(2H, q, J=7Hz, CO2CH 2 CH3), 5.50(2H, s, OCH2), 6.95(1H, dd, J=2, 8Hz, 8-H), 6.98(1H, d, J=2Hz, 6-H), 7.37(1H, d, J=8Hz, 9-H), 8.01(1H, s, 1-H). IR(KBr): 1715, 1595, 1515, 1285, 1165cm-1. MS(EI-DI) m/z: 290[M+].
【０２１５】
製造例４７： 7- メチルスルホニル -2H-1,4- ベンゾオキサジン -3(4H)- オン ( 化合物Ｉ f) の製造：
化合物Ｉd(6.00 g, 30.73 mmol)を塩化メチレン(150 ml)に懸濁し、mCPBA(11.67 g, 67.61 mmol)を加え、室温で2時間攪拌した。析出物を濾取し、塩化メチレンで洗浄後水に懸濁し、攪拌しながら7%炭酸水素ナトリウム水溶液を発泡しなくなるまで加え、不溶物をろ取、水及びエーテルで洗浄、乾燥して無色固体として表題化合物(6.77 g, 収率 97%)を得た。 mp.273〜276℃(dec.). 1H-NMR(DMSO-d6): 3.16(3H, s, SO2CH3), 4.68(2H, s, OCH2), 7.06(1H, d, J=8Hz, 5-H), 7.43(1H, d, J=2Hz, 8-H), 7.49(1H, dd, J=2, 8Hz, 6-H), 11.13(1H, br-s). MS(EI-DI) m/z: 227[M+].
【０２１６】
製造例４８： 3- エトキシカルボニル -7- メチルスルフィニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＩＸ d) の製造：
化合物ＩＸc(100 mg, 0.34 mmol)を酢酸(3 ml)に溶解し、NBS(67 mg, 0.38 mmol)を加え、室温で分30間加熱攪拌した。反応混合物に酢酸エチルを加え、水、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(2→5%メタノール含有クロロホルム)により精製し、無色固体として表題化合物(100 mg, 収率 85%)を得た。 mp.157〜166℃. 1H-NMR(CDCl3): 1.40(3H, t, J=7Hz, CO2CH2CH 3 ), 2.74(3H, s, SOCH3), 4.39(2H, q, J=7Hz, CO2CH 2 CH3), 5.57(2H, s, OCH2), 7.37(1H, dd, J=2, 8Hz, 8-H), 7.41(1H, d, J=2Hz, 6-H), 7.63(1H, d, J=8Hz, 9-H), 8.06(1H, s, 1-H). MS(EI-DI) m/z: 306[M+].
【０２１７】
製造例４９： 3- エトキシカルボニル -7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＩＸ e) の製造：
[A法]粗生の化合物ＩＸc（製造例46）(28.17 mmol)を塩化メチレン(100 ml)に溶解し、氷冷下攪拌しながらmCPBA(10.69 g, 61.95 mmol)を加え、室温で3時間攪拌した。析出物をろ去し(化合物If： 2.20 g)、塩化メチレンで洗浄し、ろ洗液を合して7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(2%メタノール含有クロロホルム)により精製し、n-ヘキサン−エタノールから結晶化して淡黄色固体として表題化合物(4.02 g, 収率 44.3%)を得た。 mp.198〜201℃. 1H-NMR(CDCl3): 1.41(3H, t, J=7Hz, CO2CH2CH 3 ), 3.07(3H, s, SO2CH3), 4.40(2H, q, J=7Hz, CO2CH 2 CH3), 5.60(2H, s, OCH2), 7.61-7.72(3H, m), 8.06(1H, s, 1-H). MS(EI-DI) m/z: 322[M+].
【０２１８】
[B法] 化合物Ｉf(5.00 g, 22.00 mmol)を乾燥DMF(100 ml)に溶解し、アルゴンガス雰囲気下で氷冷しながらカリウムtert-ブトキシド(2.62 g, 23.32 mmol)を加え20分間攪拌した。この反応混合物にクロロりん酸ジエチル(6.83 g, 39.60 mmol)を加え5分間攪拌後、イソシアノ酢酸エチル(3.56 g, 31.46 mmol)の乾燥DMF溶液(50 ml)及びカリウムtert-ブトキシド(3.48 g, 31.02 mmol)を加え15分間攪拌し、次いで室温で20時間攪拌した。反応混合物に酢酸(5 ml)を滴下し、これを氷水(60 ml)に加え1.5時間攪拌した。析出物をセライトパッドを用いて濾取し、水洗後クロロホルム−メタノール混液で溶出した。溶出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後減圧下に濃縮乾固した。濾洗液部は酢酸エチルで抽出し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後減圧下に濃縮乾固し、残留物をクロロホルムで洗浄し、減圧下に乾燥して原料If(720 mg, 14%)を回収した。クロロホルム洗浄液は先の濃縮乾固物と合してシリカゲルカラムクロマトグラフ法(1→2%メタノール含有クロロホルム)により精製し、n-ヘキサン−クロロホルムから結晶化して淡黄色粉末として表題化合物(1.63 g, 収率 23%)を得た。
【０２１９】
[C法] 化合物ＩＸd(80 mg, 0.26 mmol)を塩化メチレン(2 ml)に溶解し、mCPBA(50 mg, 0.29 mmol)を加え、室温で40分間攪拌した。反応混合物を塩化メチレンで希釈し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下に濃縮乾固した。残留物をn-ヘキサン−クロロホルムから結晶化して無色固体として表題化合物(59 mg, 収率 70%)を得た。
【０２２０】
製造例５０： 1- ブロモ -3- エトキシカルボニル -7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物Ｘ c) の製造：
化合物ＩＸe(2.00 g, 6.20 mmol)をアセトニトリル(200 ml)に溶解し、NBS(2.43 g, 13.65 mmol)を加え、攪拌しながら2時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物をクロロホルムに溶解し、7%炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5%メタノール含有クロロホルム)により精製し、淡黄色固体として表題化合物(1.32 g, 収率 53%)を得た。1H-NMR(CDCl3): 1.40(3H, t, J=7Hz, CO2CH2CH 3 ), 3.08(3H, s, SO2CH3), 4.41(2H, q, J=7Hz, CO2CH 2 CH3), 5.49(2H, s, OCH2), 7.70〜7.77(2H, m), 8.50(1H, d, J=9Hz, 9-H). MS(EI-DI) m/z: 400, 402[M+].
【０２２１】
実施例９６： 3- エトキシカルボニル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 19) の合成：
化合物Ｘc(1.32 g, 3.29 mmol)、4-メトキシフェニルほう酸(0.60 g, 3.95 mmol)及びPd(PPh3)4(260 mg, 0.22 mmol)の混合物にトルエン(15 ml)、エタノール(15 ml)及び2M炭酸ナトリウム水溶液(15 ml)を加え、アルゴンガス雰囲気下で3時間激しく攪拌しながら煮沸還流した。反応混合物を冷却し、これにクロロホルム及び水を加えて分液した。クロロホルム層を分取し、飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液(3:1)次いで1%メタノール含有クロロホルム)により精製し、表題化合物(842 mg, 収率 60%)を得た(エタノールから再結晶して無色針状結晶)。 mp.204.5〜206.5℃. 1H-NMR(CDCl3): 1.40(3H, t, J=7Hz, CO2CH2CH 3 ), 3.05(3H, s, SO2CH3), 3.87(3H, s, OCH3), 4.42(2H, q, J=7Hz, CO2CH 2 CH3), 5.54(2H, s, OCH2), 6.97(2H, d, J=9Hz), 7.10(1H, d, J=9Hz, 9-H), 7.39(1H, dd, J=2, 9Hz, 8-H), 7.46(2H, d, J=9Hz), 7.71(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 428[M+].
【０２２２】
実施例９７： 3- カルボキシ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 20) の合成：
化合物ＸＩ−19(300 mg, 0.70 mmol)をメタノール(5 ml)に懸濁し 、1 N水酸化ナトリウム(5 ml, 5.0 mmol)を加え、攪拌しながら1時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水と酢酸を加えクロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固し、残留物をn-ヘキサン−クロロホルムより再結晶して無色固体として表題化合物(266 mg,収率 95%)を得た。 mp.251〜252℃(dec.). 1H-NMR(DMSO-d6): 3.24(3H, s, SO2CH3), 3.84(3H, s, OCH3), 5.55(2H, s, OCH2), 7.40〜7.12(3H, m), 7.47(1H, dd, J=2, 9Hz, 8-H), 7.51(2H, d, J=9Hz), 7.73(1H, d, J=2Hz, 6-H), 12.91(1H, br, CO2H). MS(EI-DI) m/z: 400[M+].
【０２２３】
実施例９８： 1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 21) の合成：
化合物ＸＩ−20(250 mg, 0.62 mmol)と銅粉末(44 mg, 0.69 mmol)の混合物にキノリン(2.5 ml)を加え、220〜225℃で1時間攪拌した。反応混合物に酢酸エチルを加え、不溶物を濾去し、濾液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物を留物をシリカゲルカラムクロマトグラフ法(クロロホルム次いで0.5%メタノール含有クロロホルム)により精製し、エーテル−クロロホルムより結晶化して淡黄色固体として表題化合物(112 mg, 収率 50%)を得た。 mp.137〜144℃. 1H-NMR(CDCl3): 3.04(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.21(2H, s, OCH2), 6.98(2H, d, J=9Hz), 7.08(1H, s, 3-H), 7.17(1H, d, J=9Hz, 9-H), 7.39(1H, dd, J=2, 9Hz, 8-H), 7.46(2H, d, J=9Hz), 7.70(1H, d, J=2Hz, 6-H ). MS(EI-DI) m/z: 356[M+].
【０２２４】
実施例９９： 3- クロロ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 22) の合成：
化合物ＸＩ−21(70 mg, 0.20 mmol)のアセトニトリル(7 ml)溶液にNCS(29 mg, 0.22 mmol)を加え、煮沸還流下に19時間攪拌した。反応混合物を減圧下に乾固し、残留物をクロロホルムに溶解し、水及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1% メタノール含有クロロホルム)により精製し、n-ヘキサン−クロロホルムより結晶化して無色粉末として表題化合物(28 mg, 収率 36%)を得た。 mp.212〜214℃.1H-NMR(CDCl3)δ: 3.04(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.17(2H, s, OCH2), 6.97(2H, d, J=9Hz), 7.15(1H, d, J=9Hz, 9-H), 7.39(1H, dd, J=2, 9Hz, 8-H), 7.44(2H, d, J=9Hz), 7.70(1H, d, J=2Hz, 6-H). EI-MS m/z: 390(M+).
【０２２５】
実施例１００： 3- ブロモ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 23) の合成：
化合物ＸＩ−21(40 mg, 0.11 mmol)をアセトニトリル(4 ml)に溶解し、NBS(30 mg, 0.17 mmol)を加え、50℃で1時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(クロロホルム−n-ヘキサン混液[2:1])により精製し、淡黄色粉末として表題化合物(25 mg, 収率 51%)を得た。 mp.198〜200℃(dec.). 1H-NMR(CDCl3): 3.04(3H, s, SO2CH3), 3.86(3H, s, OCH3), 5.41(2H, s, OCH2), 6.96(2H, d, J=9Hz), 7.14(1H, d, J=9Hz, 9-H), 7.39(1H, dd, J=2, 9Hz, 8-H), 7.43(2H, d, J=9Hz), 7.70(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 434, 436[M+].
【０２２６】
実施例１０１： 1-(4-メトキシフェニル)-7-メチルスルホニル-3-トリフルオロメチル-4H-イミダゾ[5,1-c][1,4]ベンゾオキサジン(化合物ＸＩ−24)の合成：
化合物ＸＩ−23(300 mg, 0.69 mmol)、トリフルオロ酢酸ナトリウム(362 mg, 2.66 mmol)及びよう化銅(I)(240 mg, 1.26 mmol)をDMA(6 ml)に加え、煮沸還流下に6時間攪拌した。反応混合物を減圧下に乾固し、残留物にクロロホルムを加え、不溶物をセライトパッドを用いてろ去した。ろ液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1% メタノール含有クロロホルム)により精製し、粗生の表題化合物(96 mg)を得た。次いで粗生成物を逆相のHPLC法により精製し、目的の画分を合し減圧下に濃縮した。濃縮液に飽和炭酸水素ナトリウム水溶液及び塩化ナトリウムを加え、クロロホルムで3回抽出し、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物を石油エーテル−クロロホルムから再結晶して無色針状晶として表題化合物(62 mg, 収率 21%)を得た。mp 224−226℃. [HPLC操作条件] 装置：Waters Delta Prep 4000、移動相：0.01Mりん酸二水素カリウム−アセトニトリル(1:1)、流速：30 ml/min.、検出器：UV(254 nm)。1H-NMR(CDCl3)δ: 3.05(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.32(2H, d, J=1Hz, OCH2), 6.98(2H, d, J=9Hz), 7.15(1H, d, J=9Hz, 9-H), 7.42(1H, dd, J=2, 9Hz, 8-H), 7.46(2H, d, J=9Hz), 7.73(1H, d, J=2Hz, 6-H). EI-MS m/z: 424(M+).
【０２２７】
実施例１０２： 3- ヒドロキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 25) の合成：
化合物ＸＩ−19(100 mg, 0.23 mmol)をTHF(10 ml)に溶解し、水素化リチウムアルミニウム(20 mg, 0.53 mmol)を加え室温で30分間攪拌した。反応混合物に水を加えて過剰の水素化リチウムアルミニウムを分解し、減圧下に濃縮乾固した。残留物に酢酸エチルと水を加え分液し、両層に不溶の固形物をセライトパッドを用いてろ去し、酢酸エチル層を分取、飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(3%メタノール含有クロロホルム)により精製し、 n-ヘキサン−クロロホルムより結晶化して無色固体として表題化合物(61 mg, 収率 68%)を得た。 mp.204〜207℃(dec.).1H-NMR(CDCl3): 2.29(1H, br, OH), 3.04(3H, s, SO2CH3), 3.86(3H, s, OCH3), 4.70(2H, s, CH 2 OH), 5.26(2H, s, OCH2), 6.97(2H, d, J=9Hz), 7.12(1H, d, J=9Hz, 9-H), 7.37(1H, dd, J=2, 9Hz, 8-H), 7.42(2H, d, J=9Hz), 7.68(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 386[M+].
【０２２８】
実施例１０３： 3- フルオロメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 26) の合成：
化合物ＸＩ−25(60 mg, 0.16 mmol)を乾燥塩化メチレン(12 ml)に懸濁し 、DAST試薬(31μl, 0.24 mmol)を加え室温で30分間攪拌した。反応混合物を塩化メチレンで希釈し、飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(0.5%メタノール含有クロロホルム)により精製し、 n-ヘキサン−クロロホルムより結晶化して無色固体として表題化合物(40 mg, 収率 68%)を得た。 mp.223〜226℃(dec.).1H-NMR(CDCl3): 3.05(3H, s, SO2CH3), 3.87(3H, s, OCH3), 5.27(2H, d, J=1Hz, OCH2), 5.43(2H, d, J=49Hz, CH 2 F), 6.97(2H, d, J=9Hz), 7.14(1H, d, J=9Hz, 9-H), 7.39(1H, dd, J=2, 9Hz, 8-H), 7.44(2H, d, J=9Hz), 7.70(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 388[M+].
【０２２９】
実施例１０４： 3- ホルミル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 27) の合成：
化合物ＸＩ−25(350 mg, 0.91 mmol)の塩化メチレン(100 ml)懸濁溶液に、Dess-Martin Periodinan(580 mg, 1.37 mmol)を加え室温で30分間攪拌した。反応混合物に1 N水酸化ナトリウムを加え分液し、有機層を分取、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、表題化合物(320 mg, 収率92%)を得た。n-ヘキサン-クロロホルムから再結晶して無色固体。 mp.248〜250.5℃.1H-NMR(CDCl3)δ: 3.07(3H, s), 3.91(3H, s), 5.56(2H, s), 7.03(2H, d, J=9Hz), 7.17(1H, d, J=9Hz), 7.43(1H, dd, J=2, 9Hz), 7.49(2H, d, J=9Hz), 7.74(1H, d, J=2Hz), 10.03(1H, s). EI-MS m/z: 384(M+).
【０２３０】
実施例１０５： 3- ジフルオロメチル -1-(4- メトキシフェニル )-7- メチルスルホ ニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 28) の合成：
化合物ＸＩ−27(160 mg, 0.42 mmol)の乾燥塩化メチレン(10 ml)懸濁溶液にDAST試薬(160 μl, 1.25 mmol)を加え、室温で46時間攪拌した。反応混合物を塩化メチレンで希釈し、水洗、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(n-ヘキサン-クロロホルム, 3:2)により精製し、無色固体(n-ヘキサン-クロロホルム)として表題化合物(80 mg, 収率 47%)を得た。 mp.177〜178℃. 1H-NMR(CDCl3)δ: 3.05(3H, s), 3.87(3H, s), 5.34(2H, t, J=2Hz), 6.76(1H, t, J=56Hz), 6.98(2H, d, J=9Hz), 7.14(1H, d, J=9Hz), 7.40(1H, dd, J=2, 9Hz), 7.44(2H, d, J=9Hz), 7.71(1H, d, J=2Hz). EI-MS m/z: 406(M+).
【０２３１】
実施例１０６： 3- シアノ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 29) の合成：
化合物ＸＩ−27(200 mg, 0.52 mmol)及びヒドロキシルアミン-O-スルホン酸(118 mg, 1.04 mmol)の無水メタノール(25 ml)懸濁溶液に無水ピリジン(2.3 ml)を加え、煮沸還流下に4時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物を塩化メチレンに溶解、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、表題化合物(151 mg, 収率 76%)を得た。n-ヘキサン-クロロホルムから再結晶して無色固体。 mp.230〜231℃. 1H-NMR(CDCl3)δ: 3.06(3H, s), 3.88(3H, s), 5.33(2H, s), 7.00(2H, d, J=9Hz), 7.17(1H, d, J=9Hz), 7.41-7.46(3H, m), 7.75(1H, d, J=2Hz). EI-MS m/z: 381(M+).
【０２３２】
実施例１０７： 3- メトキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 30) の合成：
化合物ＸＩ−25(100 mg, 0.26 mmol)の乾燥DMF(3 ml)溶液にNaH(13 mg, 0.52 mmol)を加え、室温で5分間攪拌した後ヨウ化メチル(111 mg, 0.78 mmol)を加えて1時間攪拌した。反応混合物を酢酸エチルで希釈し、水洗、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(1% メタノール含有クロロホルム)により精製し、n-ヘキサン-クロロホルムから再結晶して無色針状晶として表題化合物(44 mg, 収率 42%)を得た。mp.185〜186℃. 1H-NMR(CDCl3)δ: 3.04(3H, s), 3.45(3H, s), 3.86(3H, s), 4.50(2H, s), 5.25(2H, s), 6.96(2H, d, J=9Hz), 7.12(1H, d, J=9Hz), 7.36(1H, dd, J=2, 9Hz), 7.43(2H, d, J=9Hz), 7.68(1H, d, J=2Hz). EI-MS m/z: 400(M+).
【０２３３】
実施例１０８： 3- エトキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 31) の合成：
実施例１０７の合成法に従って、化合物ＸＩ−25(100 mg, 0.26 mmol)とヨウ化エチル(122 mg, 0.78 mmol)より表題化合物(57 mg, 収率 53%)を得た。無色粉末(石油エーテル−クロロホルム). mp.139〜141℃.1H-NMR(CDCl3)δ: 1.25(3H, t, J=7Hz), 3.04(3H, s), 3.62(2H, q, J=7Hz), 3.86(3H, s), 4.55(2H, s), 5.27(2H, s), 6.95(2H, d, J=9Hz), 7.11(1H, d, J=9Hz), 7.36(1H, dd, J=2, 9Hz), 7.42(2H, d, J=9Hz), 7.67(1H, d, J=2Hz). EI-MS m/z: 414(M+).
【０２３４】
実施例１０９： 3- ベンジルオキシメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 32) の合成：
実施例１０７の合成法に従って、化合物ＸＩ−25(130 mg, 0.34 mmol)と臭化ベンジル(174 mg, 1.02 mmol)より表題化合物(62 mg, 収率40%)を得た。無色針状晶(石油エーテル−クロロホルム)。mp.175〜177.5℃。1H-NMR(CDCl3)δ: 3.04(3H, s), 3.86(3H, s), 4.61(2H, s), 4.64(2H, s), 5.22(2H, s), 6.96(2H, d, J=9Hz), 7.11(1H, d, J=9Hz), 7.21〜7.40(6H, m), 7.43(2H, d, J=9Hz), 7.66(1H, d, J=2Hz). EI-MS m/z: 476(M+).
【０２３５】
実施例１１０： 3-(4- メトキシベンジルオキシメチル )-1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 33) の合成：
実施例１０７の合成法に従って、化合物ＸＩ−25(100 mg, 0.26 mmol)と塩化 4-メトキシベンジル(122 mg, 0.78 mmol)より表題化合物(79 mg, 収率 60%)を得た。無色粉末(石油エーテル−クロロホルム). mp.211〜213℃. 1H-NMR(CDCl3)δ: 3.04(3H, s), 3.79(3H, s), 3.86(3H, s), 4.56(2H, s), 4.58(2H, s), 5.21(2H, s), 6.88(2H, d, J=9Hz), 6.96(2H, d, J=9Hz), 7.11(1H, d, J=9Hz), 7.29(2H, d, J=9Hz), 7.36(1H, dd, J=2, 9Hz), 7.43(2H, d, J=9Hz), 7.66(1H, d, J=2Hz). EI-MS m/z: 370(M+−136).
【０２３６】
実施例１１１： 3- クロロメチル -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 34) 及び 1-(4- メトキシフェニル )-7- メチルスルホニル -3- フェノキシメチル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 35) の合成：
化合物ＸＩ−25(150 mg, 0.39 mmol)の乾燥クロロホルム(5 ml)懸濁溶液に、塩化チオニル(93 mg, 0.78 mmol)を加え、煮沸還流下に1時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物を乾燥DMF(4 ml)に溶解し、このものをフェノール(73 mg, 0.78 mmol)の乾燥DMF(2 ml)溶液にNaH(14 mg, 0.59 mmol)を加え、室温で10分間攪拌した混合物に加えた。混合物を室温で20時間攪拌し、酢酸エチルで希釈し、水及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、無色粉末として化合物ＸＩ−35(105 mg, 収率 58%, 石油エーテル-クロロホルムから再結晶)及び無色粉末として化合物ＸＩ−34(27 mg, 収率 17%, 石油エーテル-クロロホルムから再結晶)を得た。 化合物ＸＩ−34： mp.218〜224℃. １H-NMR(CDCl3)δ: 3.05(3H, s), 3.87(3H, s), 4.64(2H, s), 5.26(2H, s), 6.97(2H, d, J=9Hz), 7.13(1H, d, J=9Hz), 7.39(1H, dd, J=2, 9Hz), 7.44(2H, d, J=9Hz), 7.70(1H, d, J=2Hz). 化合物ＸＩ−35： mp.176〜177℃. １H-NMR(CDCl3)δ: 3.04(3H, s), 3.87(3H, s), 5.15(2H, s), 5.28(2H, s), 6.42〜7.22(5H, m), 7.13(1H, d, J=9Hz), 7.27〜7.34(2H, m), 7.37(1H, dd, J=2, 9Hz), 7.45(2H, d, J=9Hz), 7.67(1H, d, J=2Hz). EI-MS m/z: 462(M+).
【０２３７】
実施例１１２： 3- エトキシカルボニル -1-(4- フルオロフェニル )-7- メチルスル ホニル -4H- イミダゾ [5,1-c][1,4] ベンゾオキサジン ( 化合物ＸＩ− 36) の合成：
化合物Ｘc(0.93 g, 2.32 mmol)、4-フルオロフェニルほう酸(0.49 g, 3.48 mmol)及びPd(PPh3)4(266 mg, 0.23 mmol)の混合物にトルエン(10 ml)、エタノール(10 ml)及び2M炭酸ナトリウム水溶液(10 ml)を加え、アルゴンガス雰囲気下で3時間激しく攪拌しながら煮沸還流した。実施例96と同様に後処理及び精製し、表題化合物(798 mg, 収率 81%)を得た。1H-NMR(CDCl3): 1.43(3H, t, J=7Hz, CO2CH2CH 3 ), 3.07(3H, s, SO2CH3), 4.45(2H, q, J=7Hz, CO2CH 2 CH3), 5.57(2H, s, OCH2), 7.06(1H, d, J=9Hz, 9-H), 7.19(2H, m), 7.42(1H, dd, J=2, 9Hz, 8-H), 7.57(2H, m), 7.75(1H, d, J=2Hz, 6-H). MS(EI-DI) m/z: 416[M+].
【０２３８】
製造例５１： (5- フルオロ -2- ニトロ ) チオフェノキシ酢酸メチル ( 化合物 S-11) の製造：
炭酸カリウム(21.71 g, 0.16 mol)存在下、2,4-ジフルオロニトロベンゼン(25 g, 0.16 mol)のDMF溶液（250 ml）にチオグリコール酸メチルエステル(16.68 g, 0.16 mol)を加え、80℃で 30 分間撹拌した。反応混合物を氷水中に注ぎ、酢酸エチルで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム：ヘキサン＝１：１)により精製し、表題化合物(23.05 g, 収率 60%）を得た。1H-NMR(TMS/CDCl3): 3.72(2H, s, CH2), 3.77(3H, s, CH3), 6.96〜6.99 (1H, m), 7.20(1H, dd, J=10, 3Hz), 8.30(1H, dd, J=10, 5Hz). EI-MS m/z :245(M+).
【０２３９】
製造例５２： (5- メチルスルホニル -2- ニトロ ) チオフェノキシ酢酸メチル ( 化合物 S-12) の製造：
化合物S-11(11.94 g, 0.05 mol)のDMF溶液(100 ml)にメタンスルフィン酸ナトリウム(5.85 g, 0.06 mmol)を加え、100℃で 60 分間撹拌した。反応混合物を氷水中に注ぎ、酢酸エチルで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(8.81 g, 収率 60%)を得た。1H-NMR(TMS/CDCl3): 3.11(3H, s, SO2CH3), 3.76(3H, s, CO2CH3), 3.83 (2H, s, CH2), 7.82(1H, dd, J=9, 2Hz), 8.15(1H, d, J=2Hz), 8.36(1H, d, J=9Hz). EI-MS m/z :305(M+).
【０２４０】
製造例５３： 7- メチルスルホニル -2H-1,4- ベンゾチアジン -3(4H)- オン ( 化合物Ｉ g) の製造：
化合物S-12(8.81 g, 28.88 mmol)のエタノール溶液(850 ml)に鉄粉(4.87 g)及び濃塩酸(20 ml)を加え、2時間煮沸還流した。反応混合物を減圧下に濃縮、析出した結晶を濾過し、クロロホルム−ヘキサン混液で洗浄、乾燥し、表題化合物(4.35 g, 収率 62%)を得た。1H-NMR(DMSO-d6): 3.19(3H, s, SO2CH3), 3.57(2H, s, CH2), 7.14 (1H, d, J=9Hz), 7.70(1H, dd, J=2, 9Hz), 7.87(1H, d, J=2Hz), 11.00(1H, br-s, NH). EI-MS m/z :243(M+).
【０２４１】
製造例５４： 7- フルオロ -2H-1,4- ベンゾチアジン -3(4H)- オン ( 化合物Ｉｈ ) の製造：
化合物S-11を用い、製造例５３に従って反応、後処理して表題化合物(収率74%)を得た。1H-NMR(DMSO-d6): 3.48(2H, s, CH2), 6.97 (1H, dd, J=9, 5Hz), 7.04(1H, ddd, J=9, 9, 3Hz), 7.25(1H, dd, J=9, 3Hz), 10.57(1H, br-s, NH). IR(KBr): 1683cm-1. EI-MS m/z : 183(M+).
【０２４２】
製造例５５： 7- メチルスルホニル -4-(2- オキソプロピル )-2H-1,4- ベンゾチアジン -3- オン ( 化合物ＩＩ f) の製造：
化合物Ｉg(1.08 g, 4.68 mmol)のアセトン溶液(100 ml)にTEBAC(0.37 g, 1.87 mmol)、炭酸カリウム(1.00 g, 7.24 mmol)、クロロアセトン(0.49 g, 5.30 mmol)を加え、14時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(0.65 g, 収率 47%)を得た。 mp. 167〜168℃. 1H-NMR(TMS/CDCl3): 2.32(3H, s, COCH3), 3.05(3H, s, SO2CH3), 3.52(2H, s, SCH2), 4.77 (2H, s, CH2CO), 6.84(1H, d, J=9Hz), 7.74(1H, dd, J=9, 2Hz), 7.97(1H, d, J=2Hz). IR(KBr): 1723, 1674, 1322, 1148cm-1. EI-MS m/z : 299(M+).
【０２４３】
製造例５６： 7- フルオロ -4-(2- オキソプロピル )-1,4- ベンゾチアジン -3- オン ( 化合物 ＩＩ g) の製造：
化合物Ｉhを用い、製造例５５に従って反応、後処理して表題化合物(収率65%)を得た。 mp.83〜85℃. 1H-NMR(TMS/CDCl3): 2.27(3H, s, COCH3), 3.48(3H, s, CH2), 4.69(2H, s, CH2CO), 6.69(1H, dd, J=9, 5Hz), 6.88〜6.93(1H, m), 7.12(1H, dd, J=8, 3Hz). IR(KBr): 1723, 1663cm-1. EI-MS m/z : 239(M+).
【０２４４】
製造例５７： 2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＩＩ k) の製造：
化合物ＩＩf(1.04 g, 3.48 mmol)の酢酸溶液(15 ml)に酢酸アンモニウム(2.68 g, 34.77 mmol)を加え、19時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(移動相：酢酸エチル：ヘキサン＝４：１)により精製し、表題化合物(0.94 g, 収率 97%)を得た。mp. 158〜159℃. 1H-NMR(TMS/CDCl3): 2.31(3H, d, J=1Hz, CH3), 3.09(3H, s, SO2CH3), 4.11(2H, s, CH2), 7.12(1H, d, J=1Hz), 7.43(1H, d, J=8Hz), 7.84(1H, dd, J=8, 2Hz), 8.03(1H, d, J=2Hz). IR(KBr): 3337, 1309, 1149cm-1. EI-MS m/z : 280(M+).
【０２４５】
製造例５８： 7- フルオロ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＩＩ l) の製造：
化合物ＩＩgを用い、製造例５７に従って反応、後処理して表題化合物(収率 71%)を得た。 mp. 149〜150℃. 1H-NMR(TMS/CDCl3): 2.29(3H, d, J=1Hz, CH3), 4.05(2H, s, CH2), 6.96〜7.01(1H, m), 7.04(1H, d, J=1Hz), 7.17(1H, dd, J=8, 3Hz),7.24(1H, dd, J=9, 5Hz). IR(KBr):1491,1438cm-1. EI-MS m/z : 220(M+).
【０２４６】
製造例５９： 1-ブロモ-2-メチル-7-メチルスルホニル-4H-イミダゾ[2,1-c][1,4]ベンゾチアジン(化合物ＩＶl)の製造：
化合物ＩＩＩk(0.53 g, 1.89 mmol)の酢酸溶液(10 ml)にNBS（0.34 g, 1.93 mmol）を加え、室温で30 分間撹拌した。反応混合物を氷水中に注ぎ、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：酢酸エチル：ヘキサン＝４：１)により精製し、表題化合物(0.6 g, 収率 89%)を得た。1H-NMR(TMS/CDCl3): 2.29 (3H, s, CH3), 3.11(3H, s, SO2CH3), 4.01(2H, s, CH2), 7.89(1H, dd, J=9, 2Hz), 8.11(1H, d, J=2Hz), 8.19(1H, d, J=9Hz). IR(KBr): 2956, 1398, 1146cm-1. EI-MS m/z : 358(M+), 360(M+2).
【０２４７】
実施例１１３： 2- メチル -7- メチルスルホニル -1- フェニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 80) の合成：
化合物ＩＶl(60 mg, 0.17 mmol)のエタノール(5 ml)、トルエン(5 ml)混合溶液に、２M炭酸ナトリウム水溶液(0.35 ml)、フェニルほう酸(26 mg, 0.21 mmol)及びPd(PPh3)4(20 mg, 0.017 mmol)を加え、3時間煮沸還流した。反応混合物を減圧下濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：酢酸エチル：ヘキサン＝４：１)により精製し、表題化合物(39 mg, 収率 65%)を得た。 mp.190〜192℃. 1H-NMR(TMS/CDCl3):2.29 (3H, s, CH3), 3.06(3H, s, SO2CH3), 4.14(2H, s, CH2), 6.80(1H, d, J=9Hz), 7.19〜7.22(2H, m), 7.44〜7.49(4H, m), 8.09(1H, d, J=2Hz). IR(KBr): 1307, 1151cm-1. EI-MS m/z : 356(M+).
【０２４８】
実施例１１４： 1-(4- フルオロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 81) の合成：
4-フルオロフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率 87%)を得た。 mp.211〜213℃.1H-NMR(TMS/CDCl3): 2.24(3H, s, CH3), 3.07(3H, s, SO2CH3), 4.08(2H, s, CH2), 6.78 (1H, d, J=9Hz), 7.12〜7.21(3H, m), 7.49(2H, dd, J=9, 2Hz), 8.09(1H, d, J=2Hz). IR(KBr): 1309, 1150cm-1. EI-MS m/z : 374(M+).
【０２４９】
実施例１１５： 1-(4- クロロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 82) の合成：
4-クロロフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率88%)を得た。 mp.240〜242℃.1H-NMR(TMS/CDCl3): 2.25(3H, s, CH3), 3.07(3H, s, SO2CH3), 4.07(2H, s, CH2), 6.79(1H, d, J=9Hz), 7.13〜7.15(2H, m), 7.41〜7.43(2H, m), 7.52(1H, dd, J=9, 2Hz), 8.10(1H, d, J=2Hz). IR(KBr): 1311, 1151cm-1. EI-MS m/z : 390(M+), 392(M+2).
【０２５０】
実施例１１６： 2- メチル -1-(4- メチルフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 83) の合成：
4-メチルフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率93%)を得た。 mp. 181〜183℃.1H-NMR(CDCl3): 2.28(3H, s, CH3), 2.43(3H, s, SCH3), 3.06(3H, s, SO2CH3), 4.15(2H, s, CH2), 6.84(1H, d, J=9Hz), 7.08(2H, d, J=8Hz), 7.25(2H, d, J=8Hz), 7.50(1H, dd, J=9, 2Hz), 8.08(1H, d, J=2Hz). IR(KBr):1305,1149cm-1. EI-MS m/z :370(M+).
【０２５１】
実施例１１７： 1-(4- メトキシフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 84) の合成：
4-メトキシフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率72%)を得た。 mp.138〜140℃.1H-NMR(TMS/CDCl3): 2.24(3H, s, CH3), 3.06(3H, s, SO2CH3), 3.87(3H, s, OCH3), 4.08 (2H, s, CH2), 6.84(1H, d, J=9Hz), 6.96(2H, d, J=7Hz), 7.12 (2H, d, J=7Hz), 7.48(1H, dd, J=9, 2Hz), 8.07(1H, d, J=2Hz). IR(KBr): 1310, 1151cm-1. EI-MS m/z : 386(M+).
【０２５２】
実施例１１８： 2- メチル -7- メチルスルホニル -1-(4- メチルチオフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 85) の合成：
4-メチルチオフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率93%)を得た。 mp. 135〜137℃.1H-NMR(TMS/CDCl3): 2.25(3H, s, CH3), 2.54(3H, s, SCH3), 3.07(3H, s, SO2CH3), 4.07(2H, s, CH2), 6.85(1H, d, J=9Hz), 7.09〜7.11(2H, m), 7.26〜7.29(2H, m), 7.50(1H, d, J=9, 2Hz), 8.08(1H, d, J=2Hz). IR(KBr): 1311,1151cm-1. EI-MS m/z : 402(M+).
【０２５３】
実施例１１９： 1-(3, 5- ジクロロフェニル )-2- メチル -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 86) の合成：
3,5-ジクロロフェニルほう酸を用い、実施例１１３と同様に反応、後処理して表題化合物(収率86%)を得た。 mp.226〜228℃.1H-NMR(TMS/CDCl3): 2.27(3H, s, CH3), 3.08(3H, s, SO2CH3), 4.05(2H, s, CH2), 6.79(1H, d, J=9Hz), 7.09(2H, d, J=2Hz), 7.42(1H, t, J=2Hz), 7.58(1H, dd, J=9, 2Hz), 8.12(1H, d, J=2Hz). IR(KBr): 1310, 1149cm-1. EI-MS m/z: 424(M+), 426(M+2).
【０２５４】
製造例６０： 7- メチルスルホニル -2H-1,4- ベンゾチアジン -3(4H)- チオン ( 化合物ＶＩ d) の製造：
化合物Ｉg(4.00 g, 16.5 mmol)のTHF溶液(300 ml)にLawesson試薬(3.33 g, 8.23 mmol)を加え、室温で20時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物にエタノールを加え、不溶物をろ過、乾燥することにより、表題化合物(3.96 g, 収率 93%）を得た。1H-NMR(DMSO-d6)δ(ppm) : 3.19(3H, s, CH3SO2), 3.99(2H, s, CH2), 7.36 (1H, d, J=8Hz), 7.72(1H, dd, J=2, 8Hz), 7.90(1H, d, J=2Hz), 12.80(1H, br-s, NH). EI-MS(m/z) : 259(M+).
【０２５５】
製造例６１： 7- メチルスルホニル -3- メチルチオ -2H-1,4- ベンゾチアジン ( 化合物ＶＩＩ d) の製造：
化合物ＶＩd(3.85 g, 14.9 mmol)のTHF溶液（300 ml）にNaH（0.43 g, 17.8 mmol）を加え、15分間攪拌した。次いで、ヨウ化メチル(4.22 g, 29.7 mmol)を加え、5時間攪拌した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、溶媒を減圧下に留去し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(3.47 g, 収率 86%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.59(3H, s, CH3S), 3.06(3H, s, CH3SO2), 3.28(2H, s, CH2), 7.43(1H, d, J=8Hz), 7.71(1H, dd, J=2, 8Hz), 7.87(1H, d, J=2Hz). EI-MS(m/z)
: 273(M+).
【０２５６】
製造例６２： 3-(2,2- ジメトキシエチルアミノ )-7- メチルスルホニル -2H-1,4- ベンゾチアジン ( 化合物ＶＩＩＩ d) の製造：
化合物ＶＩＩd(3.37 g, 12.3 mmol)のアセトニトリル溶液(150 ml)にアミノアセトアルデヒドジメチルアセタール(3.37 g, 32.1 mmol)を加え、7日間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(3.46 g, 収率 85%）を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.06(3H, s, CH3SO2), 3.12(2H, s, SCH2), 3.44(6H, s, CH3×2), 3.71(2H, t, J=5Hz, CH2), 4.57(1H, t, J=5Hz, CH), 5.09(1H, br-s, NH), 7.21(1H, d, J=8Hz), 7.64(1H, dd, J=2, 8Hz), 7.80(1H, d, J=2Hz). EI-MS(m/z) : 330(M+).
【０２５７】
製造例６３： 7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＩＩ m) の製造：
化合物ＶＩＩＩd(3.03 g, 9.18 mmol)のトルエン溶液(150 ml)にp-トルエンスルホン酸(0.79 g, 4.59 mmol)を加え、2時間煮沸還流した。反応混合物を減圧下に濃縮、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(2.07 g, 収率 85%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.09(3H, s, CH3), 4.12(2H, s, CH2), 7.19 (1H, d, J=2Hz), 7.40(1H, d, J=2Hz), 7.49(1H, d, J=8Hz), 7.86(1H, dd, J=2, 8Hz), 8.05(1H, d, J=2Hz). EI-MS(m/z) : 266(M+).
【０２５８】
製造例６４： 1- ブロモ -7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＶ m) の製造：
化合物ＩＩＩm(50 mg, 0.19 mmol)の酢酸溶液(1.5 ml)にNBS(33 mg, 0.19 mmol)を加え、室温で2時間攪拌した。反応混合物を氷水中に注ぎ、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(12 mg, 収率 19%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.11(3H, s, CH3), 4.02(2H, s, CH2), 7.16(1H, s), 7.90(1H, dd, J=2, 8Hz), 8.13(1H, d, J=2Hz), 8.21(1H, d, J=8Hz). EI-MS(m/z) : 344(M+), 346(M++2).
【０２５９】
製造例６５： 3- 〔 2-(4- メトキシフェニル )-2- オキソエチルアミノ〕 -7- メチルスルホニル -2H-1,4- ベンゾチアジン ( 化合物ＶＩＩＩ e) の製造：
トリエチルアミン(388 mg, 3.84 mmol)存在下、化合物ＶＩＩd(1.00 g, 3.66 mol)のアセトニトリル溶液(15 ml)に2-アミノ-(4-メトキシ)アセトフェノン塩酸塩(738 mg, 3.66 mmol)を加え、4時間煮沸還流した。反応混合物を減圧下に濃縮乾固し、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固した。残留物に少量の酢酸エチルを加え、不溶物をろ過、乾燥することにより、表題化合物(210 mg, 収率 61%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.08(3H, s, SO2CH3), 3.25(2H, s, SCH2), 3.91(3H, s, OCH3), 4.97(2H, d, COCH2), 6.13(1H, br, NH), 7.01(2H, dd, J=2, 6Hz), 7.27(1H, d, J=8Hz), 7.67(1H, dd, J=2, 8Hz), 7.83(1H, d, J=2Hz), 8.05(2H, dd, J=2, 6Hz). EI-MS(m/z) : 390(M+).
【０２６０】
実施例１２０： 1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 87) の合成：
化合物ＶＩＩＩe(360 mg, 0.92 mmol)のトルエン溶液(40 ml)に無水p-トルエンスルホン酸(79 mg, 0.46 mmol)を加え、22時間煮沸還流した。反応混合物を減圧下に濃縮、残留物に水を加え、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：クロロホルム)により精製し、表題化合物(4.35 g, 収率 62%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.08(3H, s, CH3SO2), 3.86(3H, s, CH3O), 4.06(2H, s, CH2), 6.93(2H, d, J=8Hz), 7.00(1H, d, J=8Hz), 7.06(1H, s), 7.18(2H, d, J=8Hz), 7.53(1H, dd, J=2, 8Hz), 8.1(1H, d, J=2Hz). EI-MS(m/z) : 372(M+).
【０２６１】
実施例１２１： 2- ブロモ -1-(4- メトキシフェニル )-7- メチルスルホニル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 88) の合成：
化合物Ｖ−87(15 mg, 0.04 mmol)の酢酸溶液(4 ml)にNBS(8 mg, 0.04 mmol)を加え、室温で4時間攪拌した。反応混合物を氷水中に注ぎ、クロロホルムで抽出した。抽出液は無水硫酸ナトリウムで乾燥し、ろ過し、ろ液を減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(移動相：酢酸エチル：ヘキサン＝４：１)により精製し、表題化合物(0.6 g, 収率 88%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 3.06(3H, s, CH3SO2), 3.88(3H, s, CH3O), 4.03(2H, s, CH2), 6.87(1H, d, J=8Hz), 6.97(2H, d, J=8Hz), 7.21(2H, d, J=8Hz), 7.50(1H, dd, J=2, 8Hz), 8.08(1H, d, J=2Hz). EI-MS(m/z) : 450(M+), 452(M++2).
【０２６２】
製造例６６： 7- メトキシ -2H-1,4- ベンゾチアジン -3(4H)- オン ( 化合物Ｉ i) の製造：
２-アミノ-６-メトキシベンゾチアゾール(10.0 g, 55.50 mmol)の水溶液(100 ml)に室温で水酸化カリウム(54.9 g, 0.83 mmol)を加え、2時間加熱還流した。この溶液を室温に冷却し、酢酸(43.3 g, 0.72 mol)及びブロモ酢酸エチル(13.9 g, 83.20 mmol)を加え1時間加熱還流後、更に酢酸(10.0 g, 0.17 mol)を加え1時間加熱還流した。室温に冷却後、析出物をろ取、エタノールから再結晶して表題化合物(5.20 g, 収率 48%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 3.42(2H, s, CH2), 3.78(3H, s, CH3O), 6.73(1H, dd, J=2, 9Hz), 6.76(1H, d, J=9Hz), 6.87(1H, d, J=2Hz), 7.93(1H, br-s, NH). EI-MS(m/z) : 195(M+).
【０２６３】
製造例６７： 7- メトキシ -4-(2- オキソプロピル )-2H-1,4- ベンゾチアジン -3- オン ( 化合物ＩＩ h) の製造 ：
化合物Ｉi(5.20 g, 26.7 mmol)、クロロアセトン(4.94 g, 53.3 mmol)、炭酸カリウム(5.53 g, 40.0 mmol)及びTEBAC(3.04 g, 13.3 mmol)のアセトン(100 ml)溶液をアルゴン気流下、一晩加熱還流した。反応混合物を減圧下濃縮し、クロロホルムを加え、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥次いで減圧下に濃縮乾固し、残留物をシリカゲルカラムクロマトグラフ法(ジクロロメタン：クロロホルム＝３：２→クロロホルム)により精製し、結晶性固体として表題化合物(4.80 g, 収率 72%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.23(3H, s, CH3CO), 3.47(2H, s, CH2), 3.78(3H, s, CH3O), 4.67(2H, s, NCH2), 6.66〜6.92(3H, m, aromatic-H). EI-MS(m/z) : 251(M+).
【０２６４】
製造例６８： 7- メトキシ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＩＩ n) の製造：
化合物ＩＩh(4.6 g, 18.30 mmol)及び酢酸アンモニウム(14.1 g, 0.18 mol)の酢酸(50 ml)溶液を3時間加熱還流した。反応液を減圧下に濃縮乾固し、7%炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(クロロホルム)により精製し、結晶性固体として表題化合物(3.21 g, 収率 76%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.29(3H, s, CH3), 3.82(3H, s, CH3O), 4.05(2H, s, CH2), 6.82(1H, dd, J＝3, 9Hz), 6.96(1H, d, J=3Hz), 7.03(1H, s), 7.20(1H, d, J=9Hz). EI-MS(m/z) : 232(M+).
【０２６５】
製造例６９： 1- ブロモ -7- メトキシ -2- メチル -4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物ＩＶ n) の製造：
化合物ＩＩＩn(1.98 g, 8.53 mmol)の酢酸(20 ml)溶液に室温でNBS(1.67 g, 11.90 mmol)を加え、室温で2時間攪拌した。反応液を7%炭酸水素ナトリウム水溶液によりpH8〜9に調製し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムにより乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(ジクロロメタン：クロロホルム=３：２)により精製し、結晶性固体として表題化合物(0.68 g, 収率 26%)を得た。1H-NMR(CDCl3/TMS)δ(ppm) : 2.27(3H, s, CH3), 3.84(3H, s, CH3O), 3.97(2H, s, CH2), 6.87(1H, dd, J=3, 9Hz), 7.04(1H, d, J=3Hz), 7.92(1H, d, J=9Hz). EI-MS(m/z) : 310(M+), 312(M++2).
【０２６６】
実施例１２２： 7- メトキシ -2- メチル -1-(4- メチルスルホニルフェニル )-4H- イミダゾ [2,1-c][1,4] ベンゾチアジン ( 化合物Ｖ− 89) の合成：
化合物ＩＶn(150 mg, 0.48 mmol)、4-メチルスルホニルフェニルほう酸（参考例８）(116 mg, 0.58 mmol)、Pd(PPh3)4(56 mg, 0.05 mmol)及び2M炭酸ナトリウム水溶液(0.96 ml, 1.93 mmol)のトルエン(5 ml)-エタノール(5 ml)溶液をアルゴン気流下、3.5時間加熱還流した。反応液を減圧下に濃縮し、クロロホルムを加え、飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥し、減圧下に濃縮乾固した。残留物をシリカゲルカラムクロマトグラフ法(ジクロロメタン：クロロホルム=３：２)により精製し、結晶性固体として表題化合物(159 mg, 収率 90%)を得た。 1H-NMR(CDCl3/TMS)δ(ppm) : 2.29(3H, s, CH3), 3.12(3H, s, CH3SO2), 3.79(3H, s, CH3O), 3.99(2H, s, CH2), 6.47(1H, d, J=9Hz), 6.52(1H, dd, J＝3, 9Hz), 7.05(1H, d, J＝3Hz), 7.40(2H, d, J＝9Hz), 7.96(2H, d, J＝9Hz). IR(KBr) cm-1 : 2917, 1599, 1490, 1310, 1149, 773. EI-MS(m/z) : 386(M+).
【０２６７】
以上の本発明の化合物例を一覧としてまとめたものを表１として示す。
上記実施例で製造した本発明化合物のヒツジ胎盤由来のCOX-2及びヒツジ精嚢由来のCOX-1に対する阻害作用を試験した。なお、以下の試験例における対照化合物のDCF-Na及びSC58635は、ジクロフェナックナトリウム及び4-[5-(4-メチルフェニル)-3-(トリフルオロメチル)-1H-ピラゾール-1-イル]ベンゼンスルホンアミド（セレコキシブ；J. Med. Chem., １９９７、４０、１３４７）である。
【０２６８】
試験例１：COX-2及びCOX-1阻害作用の測定並びに選択性
[酵素・試薬] COX-1(Sheep Seminal Ves., Cayman) 及びCOX-2(Sheep Placenta, Cayman)、アラキドン酸(約90%、Sigma)、エピネフリン(和光純薬)、グルタチオン(還元型、和光純薬)、ヘマチン(Sigma)、Prostaglandin E2 EIA Kit(Cayman)。
【０２６９】
[COX-1及びCOX-2阻害活性の測定] 被験薬溶液の調製：被験薬の反応溶液中での濃度が100μMになる10.7 mMの被験薬原液(DMSO)を調製し、反応溶液中での被験薬の濃度が0.001〜100μMとなるように被験薬原液をDMSOで希釈する。酵素溶液の調製：購入後直ちに200 unitに分注し、凍結保存した。使用時には室温で融解し、分注した酵素に50 mMトリス塩酸緩衝液(pH 8.0)を加えて溶かし、1 mlとし、酵素溶液とする。
【０２７０】
反応溶液の調製：被験薬の2μlに5 mMグルタチオン、5 mMエピネフリン及び1μMヘマチンを含む50 mMトリス塩酸緩衝液(pH 8.0)を200μl添加し、酵素溶液の10μl(2 unit)を添加し、反応溶液とする。
インキュベーション：反応溶液を37℃、30分間のプレインキュベーション後、アラキドン酸のエタノール溶液2μl(反応溶液中最終濃度6.6μM)を添加し、さらに37℃で10分間インキュベーションする。0.2 N塩酸を50μl添加し、氷槽中で反応を停止後、7分間以上氷槽中に静置し、0.2 N水酸化ナトリウムを50μl添加して中和する。PGE 2 産生量の測定：被験薬のCOX-1及びCOX-2阻害活性は、PGE2 EIAキットを用いて反応溶液中のPGE2を発色させ、414 nmでの吸光度を測定し、既知のPGE2濃度を含む標準溶液を同様に発色させ、それらの吸光度より導いた検量線により算出する。各濃度の被験薬の反応を3回繰り返し、その平均値を用いる。被験薬を含まないDMSO溶液を用いて同様の処理を行い、ブランクとする。結果を表２に示す。
【０２７１】
［表１］ 本発明化合物の一覧
【化１２】
Figure 0004409680
【０２７２】
【表１】
Figure 0004409680
【０２７３】
【表２】
Figure 0004409680
【０２７４】
【表３】
Figure 0004409680
【０２７５】
【表４】
Figure 0004409680
【０２７６】
【表５】
Figure 0004409680
【０２７７】
【発明の効果】
COX-2を選択的に阻害することにより炎症に関与するメディエーターであるPGE2の産生抑制活性を有し、消化管粘膜等の副作用のない抗炎症作用が期待される。[0001]
[Industrial application fields]
The present invention relates to a novel tricyclic fused imidazole derivative having anti-inflammatory action.
[0002]
[Prior art]
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin are one of the widely used drugs, but side effects such as gastrointestinal mucosal disorders are problematic. The side effects of NSAIDs are thought to be due to a decrease in prostaglandin (PG) biosynthesis due to inhibition of cyclooxygenase (COX), which is its main action. Recently, it was revealed that COX has two isoforms, COX-1 and COX-2. COX-1 is widely present in all tissues and contributes to maintaining the homeostasis of its physiological function, and COX-2 is thought to be induced mainly at inflammatory sites. Therefore, selective COX-2 inhibitors are expected to be anti-inflammatory drugs without gastrointestinal mucosal damage, and thus are more useful than conventional NSAIDs.
[0003]
Such anti-inflammatory drugs are described in Journal of Medicinal Chemistry (J. Med. Chem) 37, 3878 (1994), J. Med. Chem., 38, 4570 (1995), J. Med. Chem., 40, 1347. (1997), J. Med. Chem., 40, 1619 (1997), J. Med. Chem., 40, 1634 (1997), Bioorganic & Medicinal Chemistry Letters 6, 87 (1996). ) And Bioorganic & Medicinal Chemistry Letters., 6, 2827 (1996), and the like. However, in order to obtain a compound effective for the treatment of inflammation with few side effects such as gastrointestinal mucosal disorder, the creation of a compound that effectively suppresses the production of mediators of inflammation such as PGE2 is awaited.
[0004]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a substance having an inhibitory action on cyclooxygenase-2 and having few side effects.
[0005]
[Means for Solving the Problems]
The present inventors have shown that certain tricyclic fused imidazole derivatives selectively inhibit COX-2, thereby allowing PGE2The present invention has been completed by remarkably suppressing the production of.
[0006]
That is, the present invention relates to the general formula (1)
[Chemical 2]
Figure 0004409680
[0007]
(Wherein R1Is a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aminosulfonyl group, or a halogen atom,
R2Is a hydrogen atom, lower alkyl group, lower alkoxyl group, lower alkylthio group, trihalogenomethyl group, lower alkylsulfonyl group, aminosulfonyl group, mono- or dihalogen atom,
X-A is-(CH2)n-, -OCH2-, -SCH2−, Or −C (RThree) = C (RFour)-, Where n is an integer of 1-3, R3,R4Is a hydrogen atom or a halogen atom,
Y-Z is = C (RFive) -N =, = N-C (R6) = Or = C (RFive) −C (R6) =, And in this case
RFive ,R6Is a hydrogen atom, halogen atom, lower alkyl group, hydroxymethyl group, monohalogenomethyl group, dihalogenomethyl group, trihalogenomethyl group, cyano group, nitro group, formyl group, carboxyl group, lower alkoxycarbonyl group, lower alkoxy A methyl group, a substituted or unsubstituted aralkyloxymethyl group, or an aryloxymethyl group)
It is related with the tricyclic condensed imidazole derivative represented by these.
Moreover, this invention relates to the inhibitor of cyclooxygenase-2 which uses the said tricyclic condensed imidazole derivative as an active ingredient.
Furthermore, this invention relates to the pharmaceutical which uses the said tricyclic fused imidazole derivative as an active ingredient.
Hereinafter, the present invention will be described in detail.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The tricyclic fused imidazole derivative of the present invention is a novel compound and can be produced by the following method, but these do not limit the present invention.
For example, R in the method of Formula 1-16A tricyclic fused imidazole derivative in which is a lower alkyl group and Y is a nitrogen atom (N) can be produced.
[0009]
[Chemical Formula 3]
Figure 0004409680
Formula 1-1
[0010]
(Wherein R1, R2, R6Is the same as the previous definition. )
[0011]
Compound I in the presence of a base R6Are halogenated carbonyl compounds (halo-CH2COR6To obtain an N-alkyl compound (compound II). For example, R6When is a methyl group, chloroacetone is exemplified. Examples of the base include alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, and organic bases such as pyridine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine and diisobutylamine.
[0012]
As the solvent, acetone, tetrahydrofuran (THF), dimethoxyethane, benzene, toluene, N, N-dimethylformamide (DMF), and the like can be used, but it is preferable to heat and reflux in the presence of anhydrous potassium carbonate in dry acetone. When an alkali metal salt is used, it is preferable to add a quaternary ammonium salt such as benzyltriethylammonium salt or tetrabutylammonium salt. The compound II is heated to reflux in ammonium acetate and acetic acid to obtain an imidazole form (compound III), and then the compound III is halogenated to obtain a 1-position halogeno form (compound IV). Halogenation is bromine (Br2), N-bromosuccinimide (NBS), iodine monochloride (ICl), and N-iodosuccinimide (NCI), bromide and iodine. Acetic acid or acetonitrile is used as the solvent, and acetic acid is preferred. In addition, the reaction is desirably performed in the dark.
[0013]
Finally, R as defined above excluding compound IV and the aminosulfonyl group2This invention compound V can be manufactured by introduce | transducing an aryl group by Suzuki coupling reaction with the aryl boric acids which have this. As a catalyst for Suzuki coupling reaction, tetrakistriphenylphosphine palladium (Pd [PPhThree]FourThe base includes alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, alkali hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and aqueous solutions thereof. As the solvent, methanol, ethanol, benzene, toluene, xylene or the like and a mixed solvent thereof are preferably used and heated to reflux in an argon gas atmosphere. For example, a method in which a 2M aqueous sodium carbonate solution is used as a base and heated to reflux in an ethanol-toluene mixed solvent in an argon gas atmosphere is exemplified.
[0014]
X-A is-(CH2)n-Or -O-CH2-, R1In the case of compound V having a lower alkylthio group, a lower alkylsulfinyl compound and a lower alkylsulfonyl compound can be produced by oxidation using an oxidizing agent such as m-chloroperbenzoic acid (mCPBA) or hydrogen peroxide. . For example, a methylsulfonyl compound can be produced by treating a methylthio compound with 1 equivalent of mCPBA in methylene chloride and using 2.2 equivalent of the methylsulfinyl compound.
[0015]
X-A contains a sulfur atom and R1Is a compound V having a lower alkylsulfonyl group, R1It is desirable to use a compound I having a lower alkylsulfonyl group as a starting material.
R in the method of Formula 1-26Is represented by the above definition excluding a lower alkyl group, and a tricyclic fused imidazole derivative in the case where Y is a nitrogen atom (N) can be produced.
[0016]
[Formula 4]
Figure 0004409680
Formula 1-2
[0017]
(Wherein R1, R2, R6Is the same as defined above and R7Is a hydrogen atom, a halogen atom, R2Aryl group having a group, X is -CH2-, -CH2CH2-Represents an oxygen atom or a sulfur atom. )
[0018]
Compound I is treated with Lawesson reagent to convert to thioamide (compound VI), and then reacted with methyl halide in the presence of a base to give methylthio (compound VII). As a solvent for the reaction with Lawesson's reagent, THF, methylene chloride, chloroform and the like can be used. The S-methylation reaction can be carried out using methyl iodide, methyl bromide or the like as the methyl halide and using THF, methylene chloride, chloroform, DMF or the like as a solvent. Examples of the base include alkali metal salts such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and tertiary compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, n-butyl lithium, tert-butoxy potassium, and triethylamine. An amine can be illustrated.
[0019]
Compound VII and amine (NH2CH2COR7) To give an amidine form (compound VIII). The amidinolysis reaction can be performed using acetonitrile, THF, methylene chloride, chloroform, DMF, or the like as a solvent. Preferably, heating to reflux in dry acetonitrile is desirable. As an amine, R7R defined above2Arylcarbonylmethylamines represented by an aryl group having a salt thereof, or a salt thereof is used. When a salt such as hydrochloride is used, it is desirable that a base such as triethylamine coexists. R6Is a hydrogen atom, that is, an aldehyde compound, an alkylacetal (NH having a carbonyl group protected with a commonly used protecting group2CH2CH [O alkyl]2) Is used. For example, aminoacetaldehyde dimethyl acetal is exemplified.
[0020]
R7R defined above2Compound VIII, which is an aryl group having a cyclization, is cyclized by treatment with an acid and R6A tricyclic fused imidazole derivative (compound V) in which is a hydrogen atom can be produced. The cyclization reaction is performed under heating and reflux using benzene, toluene, xylene, etc., dried as a solvent in the presence of anhydrous p-toluenesulfonic acid. R7Is treated with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, etc., for example, by heating to reflux in 1N hydrochloric acid. R6A tricyclic fused imidazole derivative (compound III) in which is hydrogen atom is obtained. Similar to the method shown in Formula 1-1, this was selectively halogenated at the 1-position, and then R as defined above with the exception of the aminosulfone group.2By the coupling reaction of Suzuki with arylboric acids having6Tricyclic fused imidazole derivatives (compound V) in which is a hydrogen atom can be produced. R1When is a lower alkylthio group, a methylsulfinyl compound and a methylsulfonyl compound can be produced by oxidation with a suitable oxidizing agent such as mCPBA.
[0021]
R6Wherein the tricyclic fused imidazole derivative (compound V) having a substituent as defined above excluding a lower alkyl group, for example, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group, is R6Can be produced by a substitution reaction of compound V with a hydrogen atom or a halogen atom derived therefrom, preferably a bromine atom. For example, R6A nitro compound can be produced by heating a chloro compound and a bromine compound with nitric acid in acetic anhydride by treating the compound having a hydrogen atom with NCS or NBS using acetonitrile or acetic acid as a reaction solvent. Also, heating the bromine body with cuprous cyanide in DMF (170 ° C) to boil the cyano body with sodium trifluoroacetate in the presence of copper iodide in N, N-dimethylacetamide (DMA). A trifluoromethyl compound can be produced with
[0022]
A tricyclic fused imidazole derivative in which Z is a nitrogen atom (N) can be produced by the method of Formula 2-1.
[0023]
[Chemical formula 5]
Figure 0004409680
Formula 2-1
[0024]
(Wherein R1, R2, R5Is the same as the previous definition. )
[0025]
Compound IX is described in Journal of Heterocyclic Chem., 20, 1605 (1983) and J. Heterocyclic Chem., 26, 205 (1989). Can be produced with reference to the method disclosed in (1). Specifically, Compound I was treated with diethyl chlorophosphate in the presence of potassium tert-butoxide using DMF as a solvent to form an active imidate, and this reaction solution was allowed to act on isocyanoacetic acid alkyl ester in the presence of potassium tert-butoxide. , R5Gives a tricyclic fused imidazole (compound IX), which is a lower alkoxycarbonyl group. R1However, in the case of a lower alkylthio group, it can be converted to a lower alkylsulfinyl group and a lower alkylsulfonyl group by oxidation as described above. When X is a sulfur atom, R1However, it is desirable to use a compound I having a lower alkylsulfonyl group.
[0026]
Subsequently, the 1-position halogeno body (compound X) is obtained by halogenating compound IX. The conditions for the halogenation reaction are the same as in the halogenation of compound III. In this case, acetonitrile is preferable as the solvent. In the halogenation reaction, X is —CH2In the case of-, a dehydro form (X-A is -CH = CH-) is obtained. For example, as shown in Formula 2-2 (Production Example 22), a tetrahydro form (Compound Xa) and a dehydro form (Compound Xb) are obtained by bromination of Compound IXb with NBS. When the reaction is carried out in the dark, the production ratio of compound Xa increases.
[0027]
Finally, R as defined above excluding compound X and the aminosulfonyl group2This invention compound XI can be manufactured by introduce | transducing an aryl group by the above-mentioned Suzuki coupling reaction with the aryl boric acids which have this. The conditions for the Suzuki coupling reaction are the same as in the case of Formula 1-1. Depending on the reaction, first, R5Is a compound having a lower alkoxycarbonyl group, for example, XI '. In addition, since compound Xa and compound Xb are difficult to separate, compound XI-1 and compound XI-2 can be obtained by separating after performing a Suzuki coupling reaction as a mixture. Compound XI-2 can be converted to compound XI-1 by reducing rhodium as a catalyst and using acetic acid as a solvent.
[0028]
[Chemical 6]
Figure 0004409680
Formula 2-2
[0029]
Then, as shown in Formula 3, the lower alkoxycarbonyl group is converted by a commonly used reaction to thereby define R as defined above.5Tricyclic fused imidazoles (Compound XI) in which Z having a nitrogen atom (N) can be produced.
[0030]
[Chemical 7]
Figure 0004409680
Formula 3
[0031]
(Wherein R1, R2, R5Is the same as the previous definition. )
[0032]
R5Is a lower alkoxycarbonyl group, and is hydrolyzed under conditions usually used to obtain a carboxy form. For example, it can be obtained by using an aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide or the like as a base and heating and refluxing with an alcohol such as methanol or ethanol as a solvent. By heating the carboxy compound with copper powder in quinoline at 220-225 ° C and decarboxylation, R5However, a compound having a hydrogen atom can be produced. R5R can be obtained by halogenating a compound of a hydrogen atom.5A compound having chloro and bromine atoms introduced therein can be produced. The halogenation reaction can be performed using acetonitrile or acetic acid as a solvent and N-halogenated succinimide such as bromine, chlorine, NCS or NBS. X is -CH2In the case of-, for example, as shown in Example 41 and Example 42, compound XI-4 was treated with NCS in acetonitrile to give compound XI-5 (dihydro-chloro form), XI-6 (dehydro-chloro form). And XI-7 (dehydro-dichloro form) are obtained.
[0033]
By heating the bromide with cuprous cyanide in DMF (170-180 ° C.) and heating to reflux with sodium trifluoroacetate in the presence of cuprous iodide in DMA, the cyano compound and trifluoromethyl The body can be manufactured.
[0034]
Moreover, it can convert into a hydroxymethyl body by reducing a lower alkoxycarbonyl body using lithium aluminum hydride in THF. A monofluoromethyl compound can be produced by treating this with sulfur trifluoride diethylamine complex (DAST) in dry methylene chloride, and a chloromethyl compound can be produced by treating with thionyl chloride in dry chloroform. An aryloxymethyl compound can be produced by reacting a chloromethyl compound with sodium aryloxide in DMF. Further, a hydroxymethyl compound can be treated with a lower alkyl halide and a halogenated aralkyl in the presence of a base in THF or DMF to produce a lower alkoxymethyl compound and an aralkyloxymethyl compound. In this case, examples of the base include alkali metal salts such as sodium hydride (NaH) and butyl lithium. The hydroxymethyl compound can be converted to a formyl compound by treatment with a Dess-Martin reagent in methylene chloride. Further, a difluoromethyl compound can be produced by treating a formyl compound with hydroxyamine-O-sulfonic acid in the presence of pyridine in anhydrous methanol by boiling and refluxing and treating with a DAST in methylene chloride.
[0035]
R1Or R2Compound V or Compound XI, wherein is an aminosulfonyl group, can be produced from the corresponding methylsulfonyl compound with reference to the method described in Tetrahedron Letters, 35, 7201 (1994). For example, as shown in Example 84, a methylsulfone compound (compound V-65) was reacted with propylmagnesium chloride and triethylboron in THF and then treated with sodium acetate and hydroxylamine-O-sulfonic acid. An aminosulfonyl compound (Compound V-68) can be produced.
[0036]
  Starting material for the above reactionqualityThe cyclic lactam compound (compound I) can be produced, for example, by the method shown in the following formula.
[0037]
[Chemical 8]
Figure 0004409680
[0038]
X-A is-(CH2)2In the case of -dihydroquinolines, for example, the methylthio form (compound Ia) is obtained by methylating the thiol form (S-2) described in the literature (Chem, Pharm, Bull., 31, 798 (1983)) in the presence of a base. It is obtained by doing. Methyl iodide, methyl bromide, etc. are used as methylating agents, N, N-dimethylformamide (DMF), chloroform, methylene chloride, tetrahydrofuran (THF), etc. are used as solvents, sodium hydroxide, potassium hydroxide as bases Alkali hydroxides such as alkali metal salts such as sodium hydrogen carbonate and potassium hydrogen carbonate, or organic bases such as triethylamine can be used. For example, a method using DMF as a solvent and triethylamine as a base is exemplified. In the production of S-2, the reduction step of the chlorosulfonyl compound described in the literature does not give the reason, but good results cannot be obtained under the conditions described in the literature, and it is moderate by using activated zinc in acetic acid. It can be obtained in a yield (Reference Example 2).
[0039]
In addition, Compound Ib was prepared according to the method described in Journal of Organic Chemistry (J, Org, Chem.) 55, 1744 (1990) and J. Heterocyclic Chem., 25, 1279 (1988). Is oxidized with sodium tungstate to form hydroxylamine-O-methyl compound, which can be produced by an acid-catalyzed transfer reaction.
[0040]
[Chemical 9]
Figure 0004409680
[0041]
X is -CH2CH2Compound Ic which is the starting material of-is obtained by the methods disclosed in US Pat. Nos. PCT / US92 / 02271 and EP0 325 963 A1. However, although the reason is unknown, the yield of the demethylation reaction with aluminum chloride in benzene in the first step and the Beckmann rearrangement reaction of the oxime in methanesulfonic acid-phosphoric anhydride in the first step was low. Therefore, the demethylation reaction was performed under reflux in 47% hydrobromic acid to obtain a hydroxy compound in high yield. In addition, the Beckmann rearrangement reaction can be obtained by heating at 90 ° C. in 85% phosphoric acid-phosphoric anhydride or treating the oxime with tosyl chloride in pyridine and then heating to reflux to obtain Ic in a moderate yield. It was.
[0042]
[Chemical Formula 10]
Figure 0004409680
[0043]
(Where R1Represents a lower alkylthio group, a lower alkylsulfone group, or a halogen atom. )
[0044]
X-A is -O-CH2-In the case of benzoxazinones, R at the 5-position12-Nitrophenols having a group can be prepared by O-alkylation using a halogenated acetic acid alkyl ester in the presence of a base, and then reducing the nitro group simultaneously with cyclization. In the O-alkylation reaction, acetone, THF, DMF or the like can be used as a solvent, and examples of the base include potassium carbonate, sodium carbonate, sodium hydride, tert-butoxypotassium and the like.
[0045]
R1In the case of Compound I, wherein is a lower alkylthio group, 5-fluoro-2-nitrophenol is used as a starting material, DMF, THF, etc. are used as a solvent, and lower thioalkoxide sodium is allowed to act in the presence of a base. The fluorine atom can be replaced with sulfur, and then it can be produced in the same manner as described above. For example, as shown in Production Example 23, a methylthio form (compound Id) can be produced by reaction with sodium thiomethoxide in the presence of 1N sodium hydroxide using DMF as a solvent. R1In the case of a lower alkylthio group, a methylsulfinyl compound and a methylsulfonyl compound can be produced by oxidation with a suitable oxidizing agent such as mCPBA. The reduction-cyclization reaction can be performed, for example, by using an alcohol such as methanol or ethanol as a solvent and heating to reflux with iron-hydrochloric acid, tin-hydrochloric acid, tin chloride-hydrochloric acid, or the like.
[0046]
Embedded image
Figure 0004409680
[0047]
(Where R1Represents a lower alkoxyl group, a lower alkylsulfonyl group, or a halogen atom. )
[0048]
X-A is -S-CH2In the case of -benzothazinones, it can be produced according to the above formula. For example, R1When the group is a halogen atom, a 2-fluoronitrobenzene having a halogen atom at the 4-position is substituted with a sulfur atom using a thioglycolic acid alkyl ester in the presence of a base, and then the nitro group is reduced. It can be produced by cyclization at the same time. In the substitution reaction of thioglycolic acid alkyl ester, THF, DMF or the like can be used as a solvent, and examples of the base include potassium carbonate, sodium carbonate, sodium hydride, tert-butoxypotassium and the like. The conditions for the reduction-cyclization reaction are the same as in the case where X is oxygen. For example, R1Is a fluorine-containing compound Ig, 2,4-difluoronitrobenzene is converted to the 5-fluoro-2-nitrothioether form by heating at 80 ° C. with methyl thioglycolate in the presence of potassium carbonate in DMF, It can be produced by heating to reflux with iron-hydrochloric acid in ethanol (Production Example 51 and Production Example 54). R1Is a lower alkylsulfonyl group, the above 5-fluoro-2-nitrothioether and sodium alkylsulfinate are converted to a lower alkylsulfonyl by heating using DMF as a solvent and then as described above. Can be produced by ring closure simultaneously with reduction. For example, by using sodium methylsulfinate, compound If (R1Is CHThreeSO2) Can be manufactured (Production Example 52 and Production Example 53).
[0049]
R1However, a compound having a lower alkoxyl group is obtained by subjecting 2-amino-6-alkoxybenzothiazole to alkaline hydrolysis, S-alkylating the resulting thiophenoxide with an alkyl halide ester, and then adding acetic acid or the like under acidic conditions. It can manufacture by heating and refluxing with cyclization. Examples of the hydrolysis reaction include heating and refluxing in an alkali hydroxide such as an aqueous potassium hydroxide solution and an aqueous sodium hydroxide solution. Examples of the halogenated acetic acid alkyl ester include methyl chloroacetate, ethyl bromoacetate, methyl bromoacetate, and ethyl iodide acetate.
[0050]
The tricyclic fused imidazole derivative according to the present invention has strong inhibitory activity against cyclooxygenase-2 and is useful as a highly selective anti-inflammatory agent.
In addition, no physiological effects that would cause problems in use have been confirmed.
[0051]
The present invention provides a pharmaceutical composition comprising a pharmaceutically and pharmaceutically acceptable excipient as a tricyclic fused imidazole derivative as an active ingredient. The tricyclic fused imidazole derivative as an active ingredient can be administered in a range of about 0.001 ng to about 100 mg per day. The dose can be selected so as not to occur, and the number of administrations can be appropriately selected from once to multiple times per day. The tricyclic fused imidazole derivative as an active ingredient can be added to the preparation in the range of 0.0001% to 50%, but the amount can be appropriately selected as necessary.
[0052]
The pharmaceutical composition of the present invention is prepared by mixing and the like, and if necessary, a stabilizer, a pH adjuster, a surfactant, a buffer, a fragrance, an antiseptic, a base, a solvent, a diluent, a filler, and an increase. Agent, solubilizer, solubilizer, tonicity agent, emulsifier, suspending agent, dispersant, thickener, gelling agent, curing agent, absorbent, adhesive, elastic agent, plasticizer, binder , Disintegrating agents, propellants, preservatives, antioxidants, light-shielding agents, humectants, relaxation agents, antistatic agents, soothing agents and the like can be contained alone or in combination. Examples of the stabilizer include amino acids such as glycine or salts thereof, sugars such as glucose and sucrose, sugar alcohols such as mannitol and sorbitol, oligosaccharides, polysaccharides, proteins such as albumin, gelatin, globulin, and protamine, peptides, and the like. It is done. Examples of the pH adjuster include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and carbonic acid, organic acids such as citric acid, and salts thereof. In addition, it can be appropriately selected as necessary from those known to be used in pharmaceutical preparations. The pharmaceutical composition of the present invention is preferably a salt (sodium chloride, phosphate, etc.), excipient (lactose, corn starch, etc.), ointment base (white petrolatum, paraffin, olive oil, macrogol 400, macrogol ointment Etc.), solubilizers (distilled water for injection, acetone, ether, propylene glycol, etc.), taste-masking / flavoring / coloring agents (single syrup, l-menthol, mint oil, citric acid, etc.).
[0053]
Of course, the pharmaceutical composition of the present invention can be used in combination with other drugs such as anti-inflammatory agents.
[0054]
The pharmaceutical composition of the present invention can be applied to oral, topical, transdermal, intravenous, intramuscular, subcutaneous, intracutaneous or intraperitoneal administration, but can also be directly administered to a tumor affected part. Is also preferred. Preferably, it is orally or parenterally to mammals including humans (eg, intratumoral, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathoracic, intrathecal, intravenous, intravenous enema) , Transrectal, ophthalmic and nasal, application to skin and mucous membranes, etc.). The pharmaceutical composition of the present invention comprises powders, granules, tablets, hard capsules, soft capsules, microcapsules, ointment preparations, plaster preparations, solutions, liquids, oils, creams, pasta preparations, poultices, Liniment, lotion, aerosol, spray, nasal drop, suspension, emulsion, tincture, skin solution, eye drops, implant, rectal suppository, irrigation, patch, infusion In addition, powders, lyophilized preparations and the like for injections, liquids for injection and the like can be arbitrarily selected.
[0055]
Solid unit dosage forms such as tablets, capsules and the like may be in conventional forms. For example, tricyclic fused imidazole derivatives of the present invention and corn starch, potato starch, sodium alginate, carboxymethylcellulose (CMC), gelatin Disintegrants such as dextrin, gum arabic, tragacanth, corn starch, sucrose, hydroxypropyl cellulose (HPC) and other binders, stearates (Al, K, Na, Ca, Mg) and other lubricants, lactose, It is mixed with a carrier such as crystalline cellulose, microcrystalline cellulose, shellac and the like, and formulated into a solid preparation such as a tablet or capsule. For parenteral administration, a solution or solution in a sterile pharmaceutically acceptable liquid such as water, ethanol or oil, with or without the addition of surfactants and other pharmaceutically acceptable auxiliaries. Formulated in the form of a suspension. Examples of the oil used in the preparation include natural, semi-synthetic or synthetic fats and oils such as peanut oil, corn oil, soybean oil, and sesame oil. In general, water, saline, aqueous dextrose solution, other related sugar solutions, and glycols such as ethanol, propylene glycol and polyethylene glycol are preferable liquid carriers for injections.
[0056]
EXAMPLES Next, although an Example demonstrates this invention further in detail, this does not limit the scope of the present invention. Abbreviations used in the examples represent the following meanings.
DMF: N, N-dimethylformamide, DMA: N, N-dimethylacetamide, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, NIS: N-iodosuccinimide, TEBAC: benzyltriethyl chloride Ammonium, THF: Tetrahydrofuran, mCPBA: m-Chloroperbenzoic acid, Pd (PPhThree)Four: Tetrakis triphenylphosphine palladium (0), DAST: Sulfur trifluoride diethylamine complex, NaH: Sodium hydride, DMSO: Dimethyl sulfoxide.
[0057]
Reference example 1:Preparation of 6-chlorosulfonyl-3,4-dihydro-2 (1H) -quinolinone (Compound S-1):(Chem. Pharm. Bull., 31, 798 (1983))
  Ice-cooled chlorosulfonic acid (126 ml) was added to a solution of 3,4-dihydro-2 (1H) -quinolinone (40.0 g, 0.27 mol) in carbon tetrachloride (190 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, the precipitate was filtered with suction, washed with water and ether, and then dried to obtain the title compound (49.7 g, yield 74%) as a crystalline solid.1H-NMR (DMSO-d6) δ (ppm): 2.43 (2H, t, J = 7Hz, CH2), 2.86 (2H, t, J = 7Hz, CH 2 ), 6.76-7.40 (3H, m, aromatic-H), 10.05 (1H, br, NH) .IR (KBr): 3178, 3059, 2908, 1686, 1582, 1484, 1374, 1168, 853 cm-1EI-MS m / z: 245 (M+), 247 (M++2).
[0058]
Reference example 2:3,4- Dihydro -6- Mercapto -2 (1H)- Quinolinone ( Compound S-2) Manufacturing of:(Chem. Pharm. Bull., 31, 798 (1983))
To a solution of compound S-1 (10.0 g, 40.7 mmol) in acetic acid (50 ml), activated zinc (10.0 g) was added at room temperature, and the mixture was heated to reflux for 1.5 hours. Water was added to the reaction solution, and after cooling in an ice bath, the precipitate was collected by suction filtration. This was dissolved in 0.5 N aqueous sodium hydroxide solution (98 ml, 48.9 mmol), insolubles were removed by filtration, 6 N hydrochloric acid (9.5 ml, 57.0 mmol) was added to the filtrate, and the precipitated solid was collected by filtration. did. The filtered product was washed with water and dried to give the title compound (2.81 g, yield 39%) as a crystalline solid. 1H-NMR (DMSO-d6) δ (ppm): 2.40 (2H, t, J = 7Hz, CH2), 2.81 (2H, t, J = 7Hz, CH2), 5.01 (1H, s, SH), 6.73-7.10 (3H, m, aromatic-H), 9.96 (1H, br, NH) .IR (KBr): 3177, 3053, 2935, 2526, 1685, 1491, 1372, 1197, 815 cm-1EI-MS m / z: 179 (M+).
[0059]
Production Example 1:3,4- Dihydro -6- Methylthio -2 (1H)- Quinolinone ( Compound I a) Manufacturing of:
A solution of compound S-2 (5.20 g, 29.1 mmol) and triethylamine (3.09 g, 30.5 mmol) in DMF (50 ml) was added to a solution of methyl iodide (4.33 g, 30.5 mmol) in DMF (40 ml) under an ice-cooled argon stream. ) The solution was added dropwise and stirred for 2 hours. Chloroform was added to the reaction solution, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure.The residue was purified by silica gel column chromatography (chloroform) to give the title compound (4.86) as a crystalline solid. g, yield 87%).1H-NMR (CDClThree/ TMS) δ (ppm): 2.46 (3H, s, CHThree), 2.63 (2H, t, J = 7Hz, CH2), 2.95 (2H, t, J = 7Hz, CH2), 6.71 ~ 7.12 (3H, m, aromatic-H), 8.20 (1H, br, NH) .IR (KBr): 3177, 3047, 2909, 1711, 1494, 1375, 1198, 812 cm-1EI-MS m / z: 193 (M+).
[0060]
Production Example 2:3,4- Dihydro -6- Methylthio -1- (2- Oxopropyl ) -2- Quinolinone ( Compound II a) Manufacturing of:
Compound Ia (6.66 g, 34.5 mmol), chloroacetone (12.8 g, 138 mmol), potassium carbonate (14.3 g, 104 mmol), TEBAC (3.93 g, 17.3 mmol), potassium iodide (2.86 g, 17.3 mmol) In addition to acetone (100 ml), the mixture was heated to reflux for 16 hours under an argon stream. The reaction mixture was concentrated to dryness under reduced pressure, chloroform was added to the residue, washed with saturated brine, and dried over anhydrous sodium sulfate. Then, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane → chloroform) to obtain the title compound (4.57 g, yield 53%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 2.46 (3H, s, CHThree), 2.71 (2H, t, J = 7Hz, CH2), 2.94 (2H, t, J = 7Hz, CH2), 4.67 (2H, s, CH2), 6.55-7.12 (3H, m, aromatic-H) .IR (KBr): 3059, 2919, 1724, 1661, 1494, 1369, 1186, 797 cm-1EI-MS m / z
: 249 (M+).
[0061]
Production Example 3:4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound III a) Manufacturing of:
Compound IIa (5.89 g, 23.7 mmol) and ammonium acetate (18.2 g, 237 mmol) were added to acetic acid (60 ml), and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated solution to adjust to pH 8-9, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol-chloroform) to give the title compound as a crystalline solid ( 3.58 g, 66% yield).1H-NMR (CDClThree/ TMS) δ (ppm): 2.32 (3H, d, J = 1Hz, CHThree), 2.50 (3H, s, CHThree), 3.00 (2H, t, J = 7Hz, CH2), 3.14 (2H, t, J = 7Hz, CH2), 7.07 ~ 7.23 (4H, m, aromatic-H). IR (KBr): 2965, 2948, 1527, 1496, 1423, 1310, 1188, 822, 744 cm-1EI-MS m / z: 230 (M+).
[0062]
Production Example 4:4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound III b) Manufacturing of:
To a solution of compound IIIa (0.94 g, 4.09 mmol) in methylene chloride (15 ml) was added dropwise a solution of mCPBA (purity 70%, 2.42 g, 9.82 mmol) in methylene chloride (20 ml) under ice cooling, and then 1.5 ml at room temperature. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust to pH 8-9, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform → 1% methanol-chloroform) to give the title compound (0.54 g, yield 51%).1H-NMR (CDClThree/ TMS) δ (ppm): 2.31 (3H, d, J = 1Hz, CHThree), 3.08 (3H, s, CHThree), 3.09 to 3.18 (4H, m, CH2× 2), 7.12 to 7.91 (4H, m, aromatic-H). IR (neat): 2951, 1496, 1399, 1317, 1143, 957 cm-1EI-MS m / z: 262 (M+).
[0063]
Production Example 5:1- Bromo -4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound IV a) Manufacturing of:
NBS (3.05 g, 17.1 mmol) was added to a solution of compound IIIa (3.58 g, 15.6 mmol) in acetic acid (30 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the title compound (2.57 g, yield 53%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.27 (3H, s, CHThree), 2.51 (3H, s, CHThree), 2.92 ~ 3.04 (4H, m, CH2× 2), 7.20〜8.03 (3H, m, aromatic-H). IR (KBr): 2964, 2901, 1527, 1491, 1410, 1382, 1194, 806 cm-1EI-MS m / z: 308 (M+), 310 (M++2).
[0064]
Production Example 6:1- Bromo -4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound IV b) Manufacturing of:
The title compound (0.16 g, yield 42%) was obtained as a crystalline solid from Compound IIIb (0.29 g, 1.11 mmol), NBS (0.29 g, 1.62 mmol) and acetic acid (5 ml) by the same experimental procedure as in Production Example 5. )1H-NMR (CDClThree/ TMS) δ (ppm): 2.30 (3H, s, CHThree), 3.07 ~ 3.14 (7H, m, CHThree & CH2× 2), 7.92-8.32 (3H, m, aromatic-H). IR (KBr): 3002, 2910, 1581, 1533, 1488, 1379, 1294, 1143, 971, 784 cm-1EI-MS m / z: 340 (M+), 342 (M++2).
[0065]
Production Example 7:4,5- Dihydro -1- Iodo -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound IV c) Manufacturing of:
The title compound (1.06 g, yield 68%) was obtained as a crystalline solid from compound IIIa (1.00 g, 4.35 mmol), NIS (1.08 g, 4.78 mmol) and acetic acid (10 ml) by the same experimental procedure as in Production Example 5. )1H-NMR (CDClThree/ TMS) δ (ppm): 2.35 (3H, s, CHThree), 2.52 (3H, s, CHThree), 2.94 to 3.09 (4H, m, CH2× 2), 7.21〜8.12 (3H, m, aromatic-H). IR (KBr): 2974, 2901, 1539, 1488, 1412, 1380, 1186, 827 cm-1EI-MS m / z: 356 (M+).
[0066]
1- Aryl -4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] General synthesis of quinolines:
Compound IVa or Compound IVc (100-400 mg, 0.32-1.12 mmol) and phenylboric acids having various substituents (1.2 equivalents) are dissolved or suspended in a mixture of toluene (3-10 ml) -ethanol (3-10 ml). Turbid, 2 M aqueous sodium carbonate (4.0 eq) and Pd (PPhThree)Four(5 mol%) was added, and the mixture was heated to reflux for 3.5 hours with vigorous stirring under an argon gas atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compounds.
[0067]
Example 1:4,5- Dihydro -2- Methyl -7- Methylthio -1- Phenylimidazo [1,2-a] Quinoline ( Compound V- 1) :
Using compound IVa and phenylboric acid, the title compound (yield 88%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.23 (3H, s, CHThree), 2.43 (3H, s, CHThree), 2.99 to 3.03 (4H, m, CH2× 2), 6.48〜7.43 (8H, m, aromatic-H). IR (neat): 2951, 1489, 147, 816 cm-1EI-MS m / z: 306 (M+).
[0068]
Example 2:4,5- Dihydro -1- (3- Fluorophenyl ) -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 2) :
Using compound IVa and 3-fluorophenyl boric acid, the title compound (yield 86%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.24 (3H, s, CHThree), 2.44 (3H, s, CHThree), 2.99 to 3.03 (4H, m, CH2× 2), 6.48 ~ 7.40 (7H, m, aromatic-H). IR (neat): 2948, 1488, 1432, 1264, 868 cm-1EI-MS m / z: 324 (M+).
Example 3:1- (3- Bromophenyl )-4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 3) :
Using compound IVc and 3-bromophenyl boric acid, the title compound (56% yield) was obtained as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.26 (3H, s, CHThree), 2.46 (3H, s, CHThree), 3.00 to 3.11 (4H, m, CH2x 2), 6.49-7.55 (7H, m, aromatic-H). IR (KBr): 2910, 1488, 1413, 1377, 810, 781cm-1EI-MS m / z: 384 (M+), 386 (M++2).
[0069]
Example 4:4,5- Dihydro -1- (3- Methoxyphenyl ) -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- Four) :
Using compound IVa and 3-methoxyphenyl boric acid, the title compound (yield 89%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.24 (3H, s, CHThree), 2.44 (3H, s, CHThreeS), 2.99 to 3.03 (4H, m, CH2CH2), 3.80 (3H, s, CHThreeO), 6.54 (1H, d, J = 9Hz, 9-H), 6.83 to 6.86 (3H, m, 8-H & aromatic-H), 6.91 (1H, m, aromatic-H), 7.16 (1H, d, J = 2Hz, 6-H), 7.32 (1H, t, J = 8Hz, aromatic-H) .EI-MS (m / z): 336 [M+]
[0070]
Example 5:4,5- Dihydro -1- (4- Fluorophenyl ) -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- Five) :
Using compound IVa and 4-fluorophenylboric acid, the title compound (yield 70%) was obtained as a crystalline solid. mp.101-102 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.13 (3H, s, CHThree), 2.36 (3H, s, CHThree), 2.90-2.98 (4H, m, CH2× 2), 6.38〜7.20 (7H, m, aromatic-H). IR (KBr): 2942, 1501, 1412, 1382, 1290, 839, 811 cm-1EI-MS m / z: 324 (M+).
[0071]
Example 6:1- (4- Chlorophenyl )-4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 6) :
Using compound IVa and 4-chlorophenylboric acid, the title compound (yield 100%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 2.45 (3H, s, CHThree), 2.97 to 3.03 (4H, m, CH2× 2), 6.48 ~ 7.40 (7H, m, aromatic-H). IR (neat): 2950, 1488, 1417, 1091, 834 cm-1EI-MS m / z: 340 (M+), 342 (M++2).
[0072]
Example 7:4,5- Dihydro -2- Methyl -1- (4- Methylphenyl ) -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 7) :
Using compound IVa and 4-methylphenylboric acid, the title compound (yield 98%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 2.41 (3H, s, CHThree), 2.43 (3H, s, CHThree), 2.96 to 3.04 (4H, m, CH2× 2), 6.52 ~ 7.23 (7H, m, aromatic-H). IR (neat): 2922, 1492, 1434, 825 cm-1EI-MS m / z: 320 (M+).
[0073]
Example 8:4,5- Dihydro -2- Methyl -7- Methylthio -1- (4- Trifluoromethylphenyl ) Imidazo [1,2-a] Quinoline ( Compound V- 8) :
Using compound IVa and 4-trifluoromethylphenyl boric acid, the title compound (yield 96%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.26 (3H, s, CHThree), 2.45 (3H, s, CHThree), 3.01 ~ 3.05 (4H, m, CH2× 2), 6.44-7.68 (7H, m, aromatic-H). IR (neat): 2950, 1490, 1323, 1127, 846 cm-1EI-MS m / z: 374 (M+).
[0074]
Example 9:4,5- Dihydro -1- (4- Methoxyphenyl ) -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 9) :
Using compound IVa and 4-methoxyphenyl boric acid, the title compound (yield 100%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.20 (3H, s, CHThree), 2.42 (3H, s, CHThree), 2.96 to 3.02 (4H, m, CH2× 2), 3.84 (3H, s, CHThree), 6.53-7.20 (7H, m, aromatic-H). IR (neat): 2982, 1507, 1488, 1244, 835 cm-1EI-MS m / z: 336 (M+).
[0075]
Example 10:4,5- Dihydro -2- Methyl -7- Methylthio -1- (4- Methylthiophenyl ) Imidazo [1,2-a] Quinoline ( Compound V- Ten) :
Using compound IVa and 4-methylthiophenyl boric acid, the title compound (yield 81%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.24 (3H, s, CHThree), 2.45 (3H, s, CHThree), 2.54 (3H, s, CHThree), 3.00 ~ 3.07 (4H, m, CH2× 2), 6.55 ~ 7.30 (7H, m, aromatic-H). IR (neat): 2983, 1489, 1417, 1093, 826 cm-1EI-MS m / z: 352 (M+).
[0076]
Example 11:1- (3- Chloro -Four- Fluorophenyl )-4,5- Dihydro -2- Methyl -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 11) :
Using compound IVa and 3-chloro-4-fluorophenylboric acid, the title compound (yield 83%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.21 (3H, s, CHThree), 2.45 (3H, s, CHThree), 2.99 to 3.03 (4H, m, CH2× 2), 6.47-7.36 (6H, m, aromatic-H). IR (neat): 2947, 1490, 1429, 1258, 824 cm-1EI-MS m / z: 358 (M+), 360 (M++2).
[0077]
1- Aryl -4,5- Dihydro -2- Methyl -7- Methylsulfinyl imidazo [1,2-a] General synthesis of quinolines:
The methylthio compound (compounds V-2-4, 8, 9, 11) was dissolved in methylene chloride (10-50 mg / ml), mCPBA (1.0 mol) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, and washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compounds.
[0078]
Example 12:4,5- Dihydro - 1- (3-Fluorophenyl) -2-methyl-7-methylsulfinylimidazo [1,2-a] Quinoline ( Compound V-12):
Compound V-2 was used to give the title compound (yield 80%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.25 (3H, s, CHThree), 2.73 (3H, s, CHThree), 3.09 ~ 3.13 (4H, m, CH2× 2), 6.69-7.65 (7H, m, aromatic-H). IR (KBr): 2906, 1582, 1485, 1417, 1378, 1048, 866 cm-1.EI-MS m / z: 340 (M+).
[0079]
Example 13:1- (3- Bromophenyl )-4,5- Dihydro -2- Methyl -7- Methylsulfinyl imidazo [1,2-a] Quinoline ( Compound V- 13) :
Compound V-3 was used to obtain the title compound (yield 86%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.29 (3H, s, CHThree), 2.73 (3H, s, CHThree), 3.14-3.16 (4H, m, CH2× 2), 6.71-7.67 (7H, m, aromatic-H). IR (KBr): 2908, 1487, 1417, 1376, 1049, 824 cm-1.EI-MS m / z: 401 (M+), 403 (M++2).
[0080]
Example 14:4,5- Dihydro -1- (3- Methoxyphenyl ) -2- Methyl -7- Methylsulfinyl imidazo [1,2-a] Quinoline ( Compound V- 14) :
Using compound V-4, the title compound (yield 72%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.25 (3H, s, CHThree), 2.72 (3H, s, CHThreeSO), 3.06 to 3.12 (4H, m, CH2CH2), 3.81 (3H, s, CHThreeO), 6.75 (1H, d, J = 8Hz, 9-H), 6.82 to 6.86 (2H, m, aromatic-H), 6.95 (1H, m, aromatic-H), 7.21 (1H, dd, J = 2, 8Hz, 8-H), 7.35 (1H, t, J = 8Hz, aromatic-H), 7.63 (1H, d, J = 2Hz, 6-H). EI-MS (m / z): 352 [ M+]
[0081]
Example 15:4,5- Dihydro -2- Methyl -7- Methylsulfinyl -1- (4- Trifluoromethylphenyl ) Imidazo [1,2-a] Quinoline ( Compound V- 15) :
Compound V-8 was used to give the title compound (68% yield) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.34 (3H, s, CHThree), 2.74 (3H, s, CHThree), 3.15-3.26 (4H, m, CH2× 2), 6.68-7.75 (7H, m, aromatic-H). IR (KBr): 2946, 1504, 1379, 1324, 1119, 845 cm-1.EI-MS m / z: 390 (M+).
[0082]
Example 16:4,5- Dihydro -1- (4- Methoxyphenyl ) -2- Methyl -7- Methylsulfinyl imidazo [1,2-a] Quinoline ( Compound V- 16) :
Compound V-9 was used to obtain the title compound (yield 64%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 2.71 (3H, s, CHThreeSO), 3.07 to 3.11 (4H, m, CH2CH2), 3.88 (3H, s, CHThreeO), 6.74 (1H, d, J = 9Hz, 9-H), 6.97 (2H, d, J = 8Hz, aromatic-H), 7.18 to 7.22 (3H, m, 8-H & aromatic-H), 7.62 (1H, d, J = 2Hz, 6-H) .EI-DI (m / z): 352 [M+]
[0083]
Example 17:1- (3- Chloro -Four- Fluorophenyl )-4,5- Dihydro -2- Methyl -7- Methylsulfinyl imidazo [1,2-a] Quinoline ( Compound V- 17) :
Compound V-11 was used to give the title compound (68% yield) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.23 (3H, s, CHThree), 2.73 (3H, s, CHThree), 3.07 ~ 3.13 (4H, m, CH2 X2), 6.67-7.67 (6H, m, aromatic-H). IR (KBr): 2909, 1489, 1416, 1362, 1255, 1052, 824 cm-1EI-MS m / z: 374 (M+), 376 (M++2).
[0084]
1- Aryl -4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] General synthesis of quinolines:
Using compound IVb and phenylboric acids having various substituents, the reaction is carried out in the same manner as the general synthesis of 1-aryl-4,5-dihydro-2-methyl-7-methylthioimidazo [1,2-a] quinolines Work up to give the title compound.
Alternatively, the methylthio compound (compounds V-2-6, 8, 9, 11) is dissolved in methylene chloride (10-50 mg / ml), and mCPBA (2.2 mol) is added under ice cooling to give 1-aryl. The title compound was obtained by reaction and post-treatment in the same manner as in the general synthesis of -4,5-dihydro-2-methyl-7-methylsulfinylimidazo [1,2-a] quinolines.
[0085]
Example 18:4,5- Dihydro -2- Methyl -7- Methylsulfonyl -1- Phenylimidazo [1,2-a] Quinoline ( Compound V- 18) :
The title compound (92% yield) was obtained as an amorphous powder using Compound IVb and phenylboric acid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.26 (3H, s, CHThree), 3.04 (3H, s, CHThree), 3.12-3.16 (4H, m, CH2× 2), 6.71〜7.88 (8H, m, aromatic-H). IR (KBr): 2951, 1489, 1378, 1307, 1143, 758 cm-1EI-MS m / z: 338 (M+).
[0086]
Example 19:4,5- Dihydro -1- (3- Fluorophenyl ) -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 19) :
Compound V-2 was used to give the title compound (yield 80%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.25 (3H, s, CHThree), 3.05 (3H, s, CHThree), 3.09 ~ 3.13 (4H, m, CH2× 2), 6.73〜7.89 (7H, m, aromatic-H). IR (KBr): 2914, 1487, 1424, 1378, 1309, 1143, 758 cm-1.EI-MS m / z: 356 (M+).
[0087]
Example 20:1- (3- Bromophenyl )-4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 20) :
Compound V-3 was used to obtain the title compound (yield 94%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.28 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.14-3.18 (4H, m, CH2× 2), 6.74-7.91 (7H, m, aromatic-H). IR (KBr): 2913, 1488, 1420, 1376, 1309, 1145, 758 cm-1.EI-MS m / z: 417 (M+), 419 (M++2).
[0088]
Example 21:4,5- Dihydro -1- (3- Methoxyphenyl ) -2- Methyl -7- Methylsulfo Nilimidazo [1,2-a] Quinoline ( Compound V- twenty one) :
Using compound V-4, the title compound (yield 86%) was obtained as a tar-like substance.1H-NMR (CDClThree/ TMS) δ (ppm): 2.25 (3H, d, J = 1Hz, CHThree), 3.04 (3H, s, CHThreeSO2), 2.99-3.13 (4H, m, CH2CH2), 3.82 (3H, s, CHThreeO), 6.77 (1H, d, J = 9Hz, 9-H), 6.83 (2H, m, aromatic-H), 6.96 (1H, m, aromatic-H), 7.36 (1H, t, J = 8Hz, aromatic-H), 7.54 (1H, dd, J = 2, 9Hz, 8-H), 7.86 (1H, d, J = 2Hz, 6-H). EI-MS (m / z): 368 [M+]
[0089]
Example 22:4,5-dihydro-1- (4-fluorophenyl) -2-methyl-7-methylsulfonylimidazo [1,2-a] quinoline (compound V-22):
  Using compound V-5, the crystalline solidBody andTo give the title compound (yield 56%). mp.112-115 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.25 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.12-3.19 (4H, m, CH2× 2), 6.71〜7.90 (7H, m, aromatic-H). IR (KBr): 2915, 1526, 1454, 1379, 1313, 1145, 840, 758 cm-1EI-MS m / z: 356 (M+).
[0090]
Example 23:1- (4- Chlorophenyl )-4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- twenty three) :
Using Compound V-6, the title compound (yield 65%) was obtained as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.29 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.21 ~ 3.25 (4H, m, CH2× 2), 6.76〜7.92 (7H, m aromatic-H). IR (KBr): 2989, 1488, 1377, 1309, 1145, 759 cm-1.EI-MS m / z: 372 (M+), 374 (M++2).
[0091]
Example 24:4,5- Dihydro -2- Methyl -1- (4- Methylphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- twenty four) :
The title compound (100% yield) was obtained as a crystalline solid using compound IVb and 4-methylphenylboric acid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.24 (3H, s, CHThree), 2.44 (3H, s, CHThree), 3.04 (3H, s, CHThree), 3.10-3.14 (4H, m, CH2× 2), 6.75〜7.87 (7H, m, aromatic-H). IR (KBr): 2910, 1489, 1377, 1309, 1144, 759 cm-1EI-MS m / z: 352 (M+).
[0092]
Example 25:4,5- Dihydro -2- Methyl -7- Methylsulfonyl -1- (4- Trifluoromethylphenyl ) Imidazo [1,2-a] Quinoline ( Compound V- twenty five) :
Using Compound V-8, the title compound (yield 78%) was obtained as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.31 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.16-3.20 (4H, m, CH2× 2), 6.69-7.93 (7H, m, aromatic-H). IR (KBr): 2915, 1504, 1324, 1146, 1115, 846 cm-1.EI-MS m / z: 406 (M+).
[0093]
Example 26:4,5- Dihydro -1- (4- Methoxyphenyl ) -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 26) :
Using Compound V-9, the title compound (yield 47%) was obtained as an amorphous powder.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 3.04 (3H, s, CHThree), 3.09 to 3.11 (4H, m, CH2× 2), 3.88 (3H, s, CHThree), 6.76-7.86 (7H, m, aromatic-H). IR (KBr): 2909, 1532, 1506, 1378, 1309, 1246, 1145, 835 cm-1.EI-MS m / z: 368 (M+).
[0094]
Example 27:4,5-Dihydro-2-methyl-7-methylsulfonyl-1- (4-methylthiophenyl) imidazo [1,2-a] quinoline (compound V-27):
  Using compound IVb and 4-methylthiophenyl boric acid, a crystalline solidBody andTo give the title compound (93% yield).1H-NMR (CDClThree/ TMS) δ (ppm): 2.31 (3H, s, CHThree), 2.55 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.14-3.29 (4H, m, CH2× 2), 6.84〜7.91 (7H, m, aromatic-H). IR (KBr): 2912, 1489, 1376, 1308, 1144, 759 cm-1EI-MS m / z: 384 (M+).
[0095]
Example 28:1- (3- Chloro -Four- Fluorophenyl )-4,5- Dihydro -2- Methyl -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 28) :
Using compound V-11, the title compound (yield 82%) was obtained as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.22 (3H, s, CHThree), 3.06 (3H, s, CHThree), 3.07 to 3.12 (4H, m, CH2× 2), 6.71〜7.90 (6H, m, aromatic-H). IR (KBr): 2911, 1490, 1361, 1309, 1145, 759 cm-1EI-MS m / z: 390 (M+), 392 (M++2).
[0096]
Production Example 8:3,4- Dihydro -6- Methoxy -1- (2- Oxopropyl ) -2- Quinolinone ( Compound II b) Manufacturing of:
3,4-Dihydro-6-methoxy-2 (1H) -quinolinone Ib (4.77 g, 26.95 mmol) in acetone (100 ml) was added to TEBAC (2.06 g, 10.79 mmol), potassium carbonate (5.75 g, 41.60 mmol). Chloroacetone (3.15 g, 34.04 mmol) was added and the mixture was boiled and refluxed for 48 hours. Workup was performed in the same manner as in Production Example 2, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.37 g, yield 6%).1H-NMR (CDClThree/ TMS) δ (ppm): 2.21 (3H, s, Me), 2.71 (2H, t, J = 7Hz, CH2), 2.93 (2H, t, J = 7Hz, CH2), 3.78 (3H, s, OMe), 4.66 (2H, s, CH2), 6.56 (1H, d, J = 8Hz, aromatic-H), 6.76 (1H, m, aromatic-H), 7.62 (1H, m, aromatic-H). EI-MS (m / z): 233 ( M+).
[0097]
Production Example 9:4,5- Dihydro -7- Methoxy -2- Methylimidazo [1,2-a] Quinoline ( Compound III c) Manufacturing of:
Ammonium acetate (520 mg, 6.75 mmol) was added to an acetic acid solution (10 ml) of compound IIb (110 mg, 0.48 mmol), and the mixture was boiled and refluxed for 20 hours. Workup was performed in the same manner as in Production Example 3, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate: n-hexane = 4: 1) to give the title compound (90 mg, yield 88%). It was.1H-NMR (CDClThree/ TMS) δ (ppm): 2.26 (3H, d, J = 1Hz, Me), 2.94 to 3.04 (4H, m, CH2CH2), 3.81 (3H, s, OMe), 6.79-6.82 (2H, m, aromatic-H), 7.02 (1H, d, J = 1Hz, 1-H), 7.12-7.17 (1H, m, aromatic-H ) EI-MS (m / z): 214 (M+).
[0098]
Production Example 10:1- Bromo -4,5- Dihydro -7- Methoxy -2- Methylimidazo [1,2-a] Quinoline ( Compound IV d) Manufacturing of:
NBS (188 mg, 1.06 mmol) was added to an acetic acid solution (10 ml) of compound IIIc (90 mg, 0.42 mmol), and the mixture was stirred at room temperature for 3 hours. Workup was performed in the same manner as in Production Example 5, and the residue was purified by silica gel column chromatography (mobile phase; ethyl acetate: n-hexane = 4: 1) to give the title compound (50 mg, yield 41%). It was. EI-MS (m / z): 292 (M+), 294 (M + 2).
[0099]
Example 29:4,5- Dihydro -7- Methoxy -2- Methyl -1- (4- Methylsulfonylphenyl ) Imidazo [1,2-a] Quinoline ( Compound V- 29) Synthesis of:
Pd (PPhThree)Four (18 mg, 0.016 mmol), compound IVd (50 mg, 0.17 mmol) in ethanol (5 ml) and toluene (5 ml) mixed solution was added 2M aqueous sodium carbonate (0.35 ml) and 4-methylsulfonylphenylborate ( 41 mg, 0.20 mmol) was added, and the mixture was boiled and refluxed for 21 hours with vigorous stirring. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase; ethyl acetate: n-hexane = 4: 1). A compound (20 mg, yield 32%) was obtained.1H-NMR (CDClThree/ TMS) δ (ppm): 2.29 (3H, s, Me), 3.02 (4H, s, CH2CH2), 3.14 (3H, s, SO2Me), 3.77 (3H, s, OMe), 6.42-6.54 (2H, m, aromatic-H), 6.86 (1H, d, J = 3Hz, aromatic-H), 7.46-7.49 (2H, m, aromatic- H), 7.96-7.98 (2H, m, aromatic-H) .EI-MS (m / z): 368 (M+).
[0100]
Reference Example 3:6- Hydroxy -1- Tetralone ( Compound S-3) Manufacturing of:(See EP 0325963 A)
6-Methoxy-1-tetralone (50 g, 0.28 mol) was suspended in 47% hydrobromic acid (500 ml) and boiled under reflux for 1.5 hours. The reaction mixture was cooled, water (500 ml) was added, and the mixture was extracted 3 times with ethyl acetate (500 ml). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from n-hexane-acetone to give the title compound (38.52 g) as a pale tan powder. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol-chloroform) to obtain the title compound (5.20 g, total yield 43.72 g, yield 95%). .1H-NMR (CDClThree): 2.09 (2H, m), 2.61 (2H, t, J = 7Hz), 2.88 (2H, t, J = 6Hz), 6.70 (1H, d, J = 2Hz), 6.78 (1H, dd, J = 2, 9Hz), 7.01 (1H, s), 7.97 (1H, d, J = 9Hz).
[0101]
Reference example 4:6- Dimethylthiocarbamoyloxy -1- Tetralone ( Compound S-4) Made of Structure:(See EP 0325963 A)
Compound S-3 (56.06 g, 0.35 mol) was dissolved in 1 N aqueous potassium hydroxide solution (346 ml, 0.35 mol), and dimethylthiocarbamoyl chloride (55.55 g, 0.45 mol) was added to this solution while stirring under ice-cooling. A THF (200 ml) solution was added dropwise over 1 hour. After the addition, the reaction mixture was stirred at room temperature for 0.5 hour and extracted with ethyl acetate (1.5 liters). The extract was washed with saturated brine (1.0 L), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol-chloroform) to give a yellow orange viscous oil. Ether (200 ml) was added to this oily substance, crystallized by adding seed crystals, and n-hexane (300 ml) was further added, and the mixture was collected by filtration and dried under reduced pressure to give the title compound (77.04 g, Yield 89%) was obtained.1H-NMR (CDClThree): 2.13 (2H, m), 2.63 (2H, m), 2.95 (2H, m), 3.32 (3H, s), 3.43 (3H, s), 6.94 (1H, d, J = 2Hz), 6.99 ( 1H, dd, J = 2, 9Hz), 8.05 (1H, d, J = 9Hz).
[0102]
Reference example 5:6- Dimethylcarbamoylthio -1- Tetralone ( Compound S-5) Manufacturing of:(See EP 0325963 A)
Compound S-4 (10.0 g, 0.04 mol) was suspended in mineral oil (60 ml), heated gradually and heated at about 270 ° C. for 3 hours. Similarly, 11.0 g (0.04 mol) was treated, and the following post-treatment was performed. When the reaction mixture was gradually cooled to room temperature, it was separated into two layers, a brown solid and a mineral oil containing colorless needles. Colorless needle crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give the title compound (1.68 g). The brown solid was dissolved in chloroform and purified by silica gel column chromatography (chloroform). Recrystallization from n-hexane-ether gave the title compound (16.87 g: total yield 18.55 g, yield 88%) as a pale yellow solid.1H-NMR (CDClThree): 2.12 (2H, m), 2.63 (2H, m), 2.95 (2H, m), 3.02 (3H, br-s), 3.07 (3H, br-s), 7.37-7.43 (2H, m), 7.99 (1H, d, J = 8Hz).
[0103]
Reference Example 6:6- Methylthio -1- Tetralone ( Compound S-6) Manufacturing of:(See EP 0325963 A)
Compound S-5 (19.36 g, 0.08 mol) was suspended in methanol (230 ml), sodium hydroxide (13.67 g, 0.34 mol) was added to the solution, and the mixture was boiled and refluxed for 2 hours. The reaction mixture was ice-cooled, methyl iodide (13.23 g, 0.09 mol) was added with stirring, and the mixture was boiled under reflux for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in chloroform, treated with activated carbon, and concentrated to dryness under reduced pressure to obtain an oily crude product. The crude product was crystallized from n-hexane-chloroform to obtain the title compound (11.79 g) as light brown prism crystals. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (1.37 g: total yield 13.16 g, yield 88%).1H-NMR (CDClThree): 2.10 (2H, m), 2.49 (3H, s), 2.60 (2H, m), 2.90 (2H, t, J = 6Hz), 7.02 (1H, d, J = 2Hz), 7.11 (1H, dd , J = 2, 8Hz), 7.92 (1H, d, J = 8Hz).
[0104]
Reference example 7:6- Methylthio -1- Tetralone oxime ( Compound S-7) Manufacturing of:(Refer to PCT / US92 / 02271)
Sodium acetate (11.23 g, 0.14 mol) and hydroxylamine hydrochloride (9.51 g, 0.14 mol) were dissolved in water (32 ml) with stirring at room temperature, and ethanol (70 ml) and compound S-6 (13.16) were dissolved in this solution. g, 0.07 mol) was added. The reaction mixture was gradually warmed to an internal temperature of 75 ° C. (about 40-50 minutes) and stirred at 75-80 ° C. for 75 minutes. The reaction mixture was cooled to an internal temperature of 32 ° C. or lower and poured into ice water (500 ml). After the ice pieces were dissolved, the precipitate was collected by filtration and sucked dry. The filtered product was washed with ether and dried under reduced pressure to give the title compound (14.09 g, yield 99%) as a pale yellow powder.1H-NMR (CDClThree): 1.85 (2H, m), 2.47 (3H, s), 2.71 (2H, t, J = 6Hz), 2.78 (2H, t, J = 7Hz), 6.99 (1H, d, J = 2Hz), 7.06 (1H, dd, J = 2, 8Hz), 7.78 (1H, d, J = 8Hz), 8.09 (1H, br-s) .EI-MS m / z: 207 (M+).
[0105]
Production Example 11:7- Methylthio -2,3,4,5- Tetrahydro -1H-1- Benzazepine -2- on ( Compound I c) Manufacturing of:
Phosphoric anhydride (100 g) was added to 85% phosphoric acid (60 ml) with stirring and heated to 90 ° C. Compound S-7 (8.58 g, 0.04 mol) was added to the mixture in portions (about 30 to 40 minutes) and stirred for 4 hours. The reaction mixture was cooled to room temperature, added to ice water with stirring, and the deposited precipitate was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, treated with activated carbon, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol-chloroform) to obtain the title compound (2.76 g, yield 32%) as a pale pink solid.1H-NMR (CDClThree): 2.20 (2H, m), 2.33 (2H, m), 2.47 (3H, s), 2.76 (2H, t, J = 7Hz), 6.88 (1H, d, J = 9Hz), 7.07 ~ 7.13 (2H , m), 7.58 (1H, br-s) .EI-MS m / z: 207 (M+).
[0106]
Compound I c Separate manufacture of:
Compound S-7 (1.56 g, 7.53 mmol) was dissolved in pyridine (15 ml), p-toluenesulfonyl chloride (1.58 g, 8.28 mmol) was added to this solution, and the mixture was stirred at 50-60 ° C. for 1 hr. The reaction mixture was then boiled and refluxed for 10 minutes and concentrated to dryness under reduced pressure. Ice water was added to the residue, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with 1 N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, treated with activated carbon, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol-chloroform) to give the title compound (648 mg, yield 42%) as a pale yellow solid.
[0107]
Production Example 12:7- Methylthio -1- (2- Oxopropyl ) -2,3,4,5- Tetrahydro -1- Benzazepine -2- on ( Compound II c) Manufacturing of:
Compound Ic (960 mg, 4.63 mmol), anhydrous potassium carbonate (960 mg, 6.95 mmol) and TEBAC (369 mg, 1.62 mmol) were added to dry acetone (25 ml), and chloroacetone (1.54 g, 16.67 mmol) was added to the mixture. ) Was added in 3 portions and boiled under reflux for 24 hours with vigorous stirring. Insolubles were removed from the reaction mixture by filtration, washed with chloroform, combined with the filtrate, and dried under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to give the title compound (1.10 g, yield 90%) as a yellow viscous oil.1H-NMR (CDClThree): 2.15 (4H, s), 2.17 (3H, s), 2.31 (2H, t, J = 7Hz), 2.45 (3H, s), 4.50 (2H, s), 6.92 (1H, d, J = 8Hz ), 7.06 (1H, d, J = 2Hz), 7.09 (1H, dd, J = 2, 8Hz). EI-MS m / z: 263 (M+).
[0108]
Production Example 13:2- Methyl -8- Methylthio -4,5,6- Trihydroimidazo [1,2-a] Benz Azepine ( Compound III d) Manufacturing of:
Compound IIc (1.10 g, 4.18 mmol) was dissolved in acetic acid (20 ml), ammonium acetate (3.22 g, 41.80 mmol) was added to this solution, and the mixture was boiled and refluxed for 3 hours. Work-up was performed in the same manner as in Production Example 3, and the residue was purified by silica gel column chromatography (1% methanol-chloroform) to give the title compound (730 mg, yield 72%) as a pale tan solid.1H-NMR (CDClThree): 2.29 (2H, quintet, J = 7Hz), 2.31 (3H, d, J = 1Hz), 2.57 (3H, s), 2.63 (2H, t, J = 7Hz), 2.76 (2H, t, J = 7Hz), 6.86 (1H, d, J = 1Hz), 7.20-7.33 (3H, m) .EI-MS m / z: 244 (M+).
[0109]
Production Example 14:1- Bromo -2- Methyl -8- Methylthio -4,5,6- Trihydroimidazo [1,2-a] Benzazepine ( Compound IV e) Manufacturing of:
Compound IIId (300 mg, 1.23 mmol) was dissolved in acetic acid (6 ml), NBS (240 mg, 1.35 mmol) was added to this solution, and the mixture was stirred for 1 hour at room temperature, protected from light. Workup was performed in the same manner as in Production Example 5, and the residue was purified by silica gel column chromatography (chloroform) to give the title compound (250 mg, yield 63%) as a pale yellow solid.1H-NMR (CDClThree): 2.05 ~ 2.13 (1H, m), 2.22 ~ 2.61 (4H, m), 2.23 (3H, s), 2.51 (3H, s), 2.85 ~ 2.93 (1H, m), 7.17 (1H, d, J = 2Hz), 7.21 (1H, dd, J = 2, 9Hz), 7.30 (1H, d, J = 9Hz). EI-MS m / z: 322 (M+).
[0110]
Production Example 15:2- Methyl -8- Methylsulfonyl -4,5,6- Trihydroimidazo [1,2-a] Benzazepine ( Compound III e) Manufacturing of:
Compound IIId (240 mg, 0.98 mmol) was dissolved in methylene chloride (5 ml), mCPBA (373 mg [90%], 2.16 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to obtain the title compound (200 mg, yield 74%) as a colorless solid.1H-NMR (CDClThree): 2.25 (3H, d, J = 1Hz), 2.30 (2H, m), 2.66 ~ 2.74 (4H, m), 3.09 (3H, s), 6.86 (1H, d, J = 1Hz), 7.41 (1H , d, J = 9Hz), 7.85-7.95 (2H, m) .EI-MS m / z: 276 (M+).
[0111]
Production Example 16:1- Bromo -2- Methyl -8- Methylsulfonyl -4,5,6- Trihydroimidazo [1,2-a] Benzazepine ( Compound IV f) Manufacturing of:
Compound IIIe (180 mg, 0.65 mmol) was dissolved in acetic acid (5 ml), NBS (128 mg, 0.72 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour while protected from light. Work-up was performed in the same manner as in Production Example 5, and the residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to give the title compound (220 mg, yield 95%) as a colorless solid.1H-NMR (CDClThree): 2.11 ~ 2.20 (1H, m), 2.24 (3H, s), 2.29 ~ 2.43 (2H, m), 2.53 ~ 2.64 (1H, m), 2.71 ~ 2.80 (1H, m), 2.91 ~ 3.02 (1H , m), 3.12 (3H, s), 7.58 (1H, d, J = 8Hz), 7.93 (1H, d, J = 2Hz), 7.95 (1H, dd, J = 2, 8Hz),). EI- MS m / z: 354 (M+).
[0112]
Example 30:1- (4- Methoxyphenyl ) -2- Methyl -8- Methylthio -4,5,6- Trihydroimidazo [1,2-a] Benzazepine ( Compound V- 30) Synthesis of:
Compound IVe (150 mg, 0.46 mmol) and p-methoxyphenylboric acid (85 mg, 0.56 mmol) were dissolved in a toluene (2 ml) -ethanol (2 ml) mixture, and this solution was dissolved in 2 M aqueous sodium carbonate solution (2 ml). ) And Pd (PPhThree)Four(37 mg, 0.03 mmol) was added, and the mixture was boiled and refluxed for 22 hours with vigorous stirring under an argon gas atmosphere. The reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to obtain the title compound (155 mg, yield 95%) as a pale yellow viscous oily product.1H-NMR (CDClThree): 2.22 (2H, m), 2.26 (3H, s), 2.45 (3H, s), 2.56 (2H, t, J = 7Hz), 2.69 (2H, t, J = 7Hz), 3.78 (3H, s ), 6.48 (1H, d, J = 8Hz), 6.80 (2H, d, J = 9Hz), 6.87 (1H, dd, J = 2, 8Hz), 6.94 (2H, d, J = 9Hz), 7.16 ( 1H, d, J = 2Hz) .EI-MS m / z: 350 (M+).
[0113]
Example 31:1- (4- Methoxyphenyl ) -2- Methyl -8- Methylsulfonyl -4,5,6- Trihydroimidazo [1,2-a] Benzazepine ( Compound V- 31) Synthesis of:
Compound V-30 (155 mg, 0.44 mmol) was dissolved in methylene chloride (10 ml), mCPBA (196 mg [90%], 1.02 mmol) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to obtain the title compound (170 mg, yield 96%) as a colorless amorphous powder.1H-NMR (CDClThree): 2.10 ~ 2.48 (3H, br), 2.27 (3H, s), 2.78 ~ 2.87 (2H, br-m), 2.90 ~ 3.08 (1H, br), 3.07 (3H, s), 3.79 (3H, s ), 6.73 (1H, d, J = 8Hz), 6.82 (2H, d, J = 9Hz), 6.93 (2H, d, J = 9Hz), 7.58 (1H, dd, J = 2, 8Hz), 7.91 ( 1H, d, J = 2Hz) .EI-MS m / z: 382 (M+).
[0114]
Compound V- 31 Separate synthesis method: Compound IVf (210 mg, 0.59 mmol) and p-methoxyphenylboric acid (108 mg, 0.71 mmol) were dissolved in a mixture of toluene (3 ml) -ethanol (3 ml), and 2 M aqueous sodium carbonate solution (3 ml) was dissolved in this solution. ) And Pd (PPhThree)Four (46 mg, 0.04 mmol) was added and the mixture was boiled and refluxed for 3 hours with vigorous stirring under an argon gas atmosphere. Workup was performed in the same manner as in Example 30, and the residue was purified by silica gel column chromatography (0.5% methanol-chloroform) to obtain the title compound (78 mg, yield 35%).
[0115]
Production Example 17:3,4- Dihydro -6- Methylthio -2 (1H)- Quinoline Thion ( Compound VI a) Manufacturing of:
Lawesson reagent (3.29 g, 81.4 mmol) was added to a THF solution (150 ml) of compound Ia (3.07 g, 15.9 mmol), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated to dryness under reduced pressure, ethanol was added to the residue, the insoluble material was filtered and dried to give the title compound (3.0 g, yield 90%). EI-MS (m / z): 209 (M+).
[0116]
Production Example 18:3,4- Dihydro -2,6- Dimethylthioquinoline ( Compound VII a) Manufacturing of:
Under ice cooling, sodium hydride (0.41 g, 17.1 mmol) was added to a THF solution (150 mmol) of compound VIa (3.0 g, 14.5 mmol), and the mixture was stirred for 15 minutes. Subsequently, methyl iodide (2.5 g, 17.7 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (1.84 g, yield 57%).1H-NMR (CDClThree/ TMS) δ (ppm): 2.47 (2H, t, J = 8Hz, CH2), 2.48 (3H, s, Me), 2.51 (3H, s, Me), 2.75 (2H, t, J = 8Hz, CH2), 7.00 (1H, m, aromatic-H), 7.12 (1H, dd, J = 2, 8Hz, aromatic-H), 7.18 (1H, d, J = 8Hz, aromatic-H). EI-MS (m / z): 233 (M+).
[0117]
Production Example 19:3,4- Dihydro - [ 2- (4- Methoxyphenyl) -2- Oxoethylamino] -6- Methylthioquinoline ( Compound VIII a) Manufacturing of:
In the presence of triethylamine (0.36 g, 3.56 mmol), 2-amino-4′-methoxyacetophenone hydrochloride (0.70 g, 3.48 mmol) was added to an acetonitrile solution (30 ml) of compound VIIa (0.76 g, 3.41 mmol), and 24 Refluxed at the boil for hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. A small amount of ethyl acetate was added to the residue, and the insoluble material was filtered and dried to obtain the title compound (0.88 g, yield 76%).1H-NMR (DMSO-d6/ TMS) δ (ppm): 2.47 (3H, s, SMe), 2.92 to 3.04 (4H, m, CH2CH2), 3.89 (3H, s, OMe), 5.21 (2H, s, CH2), 7.10-7.22 (5H, m, aromatic-H), 8.04-8.07 (2H, m, aromatic-H), 11.38 (1H, br-s, NH) .EI-MS (m / z): 340 ( M+).
[0118]
Example 32:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylthioimidazo [1,2-a] Quinoline ( Compound V- 32) Synthesis of:
To a toluene solution (300 ml) of compound VIIIa (1.71 g, 5.0 mmol) was added p-toluenesulfonic anhydride (0.44 g, 2.56 mmol), and the mixture was boiled and refluxed for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (1.38 g, yield 86%).1H-NMR (CDClThree/ TMS) δ (ppm): 2.46 (3H, s, SMe), 2.97 to 3.09 (4H, m, CH2CH2), 3.86 (3H, s, OMe), 6.72 (1H, d, J = 8Hz, aromatic-H), 6.88-6.97 (4H, m, aromatic-H), 7.19 (1H, d, J = 2Hz), 7.26-7.29 (2H, m, aromatic-H) .EI-MS (m / z): 322 (M+).
[0119]
Example 33:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 33) Synthesis of:
MCPBA (0.79 g, 4.60 mmol) was added to a methylene chloride solution (30 ml) of compound V-32 (0.59 g, 1.83 mmol), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (0.56 g, yield 86%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.06 (3H, s, SMe), 3.10-3.14 (4H, m, CH2CH2), 3.87 (3H, s, OMe), 6.95-6.97 (2H, m, aromatic-H), 7.02 (1H, s, 2-H), 7.24-7.27 (3H, m, aromatic-H), 7.59 ( 1H, dd, J = 2, 8Hz, aromatic-H), 7.89 (1H, d, J = 2Hz, aromatic-H) .EI-MS (m / z): 354 (M+).
[0120]
Example 34:2- Chloro -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 34) Synthesis of:
NCS (55 mg, 0.41 mmol) was added to an acetic acid solution (5 ml) of compound V-33 (100 mg, 0.29 mmol), and the mixture was boiled and refluxed for 24 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1) to obtain the title compound (40 mg, yield 36%) as an amorphous powder.1H-NMR (CDClThree/ TMS) δ (ppm): 3.05 (3H, s, SO2Me), 3.07 to 3.15 (4H, m, CH2CH2), 3.89 (3H, s, OMe), 6.84 (1H, d, J = 8Hz, aromatic-H), 6.99 to 7.01 (2H, m, aromatic-H), 7.27 to 7.29 (2H, m, aromatic-H ), 7.58 (1H, dd, J = 2, 8Hz, aromatic-H), 7.88 (1H, d, J = 2Hz, aromatic-H). EI-MS (m / z): 388 (M+).
[0121]
Example 35:2- Bromo -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 35) Synthesis of:
NBS (0.31 g, 1.75 mmol) was added to an acetic acid solution (20 ml) of compound V-33 (0.56 g, 1.58 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (0.48 g, yield 70%). mp.114-116 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.05 (3H, s, SO2Me), 3.08 to 3.15 (4H, m, CH2CH2), 3.89 (3H, s, OMe), 6.80 (1H, d, J = 8Hz, aromatic-H), 6.98 to 7.01 (2H, m, aromatic-H), 7.26 to 7.29 (2H, m, aromatic-H ), 7.57 (1H, dd, J = 2,8Hz, aromatic-H), 7.88 (1H, d, J = 2Hz, aromatic-H) .EI-MS (m / z): 432 (M+), 434 (M + 2).
[0122]
Example 36:2- Cyano -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound V- 36) Synthesis of:
Copper (I) cyanide (0.15 g, 1.67 mmol) was added to a DMF solution (1 ml) of compound V-35 (0.60 g, 1.40 mmol), and the mixture was stirred at 170 ° C. for 19 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration using a celite pad. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to obtain the title compound (40 mg, yield 8%). mp.208-209.5 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.07 (3H, s, SO2Me), 3.13-3.16 (4H, m, CH2CH2), 3.90 (3H, s, OMe), 6.96 (1H, d, J = 8Hz, aromatic-H), 7.01 to 7.05 (2H, m, aromatic-H), 7.34 to 7.37 (2H, m, aromatic-H) ), 7.64 (1H, dd, J = 2, 8Hz, aromatic-H), 7.94 (1H, d, J = 2Hz, aromatic-H) .EI-MS (m / z): 379 (M+).
[0123]
Example 37:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -2- Trifluoromethylimidazo [1,2-a] Quinoline ( Compound V- 37) Synthesis of:
To a DMA solution (15 ml) of compound V-35 (0.48 g, 1.11 mmol), sodium trifluoroacetate (0.61 g, 4.51 mmol) and copper (I) iodide (0.42 g, 2.22 mmol) were added and boiled for 18 hours. Refluxed. Chloroform and 1.5 N hydrochloric acid were added to the reaction mixture for liquid separation, and the aqueous layer was extracted again with chloroform. The organic layers were combined and the insoluble material was filtered off using a celite pad. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1) to obtain the title compound (0.1 g, yield 21%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.05 (3H, s, SO2Me), 3.15 (4H, s, CH2CH2), 3.89 (3H, s, OMe), 6.71 (1H, d, J = 8Hz, aromatic-H), 6.98-7.12 (2H, m, aromatic-H), 7.25-7.29 (2H, m, aromatic-H ), 7.55 (1H, dd, J = 2, 8Hz, aromatic-H), 7.90 (1H, d, J = 2Hz, aromatic-H) .EI-MS (m / z): 422 (M+).
[0124]
Production Example 20:4,5- Dihydro -3- Ethoxycarbonyl -7- Methylthioimidazo [1,5-a] Quinoline ( Compound IX a) Manufacturing of:
To a solution of compound Ia (7.89 g, 40.88 mmol) in dry DMF (116 ml) was added potassium tert-butoxide (5.05 g, 44.97 mmol) with ice cooling under an argon gas atmosphere, and the mixture was stirred for 10 minutes. To this reaction solution was added diethyl chlorophosphate (14.11 g, 81.76 mmol) and stirred for 5 minutes. ) Was added and allowed to react for 17 hours. During this time, the temperature was raised to room temperature. The reaction mixture was poured into ice water, and the precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound. This was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → 2: 3 → 3: 7 → 1: 4) to give the title compound (3.01 g, 26% yield) as a crystalline solid. )1H-NMR (CDClThree/ TMS) δ (ppm): 1.42 (3H, t, J = 7Hz, CH Three CH2), 2.51 (3H, s, CHThreeS), 2.93 (2H, t, J = 7Hz, CH 2 CH2), 3.34 (2H, t, J = 7Hz, CH2CH 2 ), 4.40 (2H, 8, J = 7Hz, CHThreeCH 2 ), 7.21 (2H, m, 6-H & 8-H), 7.39 (1H, d, J = 9Hz, 9-H), 7.98 (1H, s, 1-H). EI-MS (m / z ): 288 [M+]
[0125]
Production Example 21:4,5- Dihydro 3- Ethoxycarbonyl -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound IX b) Manufacturing of:
To a solution of compound IXa (3.01 g, 10.45 mmol) in methylene chloride (75 ml) was added dropwise a solution of mCPBA (4.51 g, 26.13 mmol) in methylene chloride (75 ml) under ice cooling. After stirring for 2.5 hours under ice cooling, the reaction solution was diluted with methylene chloride, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol) to obtain the title compound (3.28 g, yield 98%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 1.43 (3H, t, J = 7Hz, CH ThreeCH2), 3.07 (2H, t, J = 7Hz, CH 2CH2), 3.10 (3H, s, CHThreeSO2), 3.41 (2H, t, J = 7Hz,CH 2CH2), 4.42 (2H, 8, J = 7Hz, CHThreeCH 2), 7.66 (1H, d, J = 9Hz, 9-H), 7.95 (1H, dd, J = 2, 9Hz, 8-H), 7.96 (1H, d, J = 2Hz, 6-H), 8.09 (1H, s, 1-H) EI-MS (m / z): 320 [M+]
[0126]
Production Example 22:1- Bromo -4,5- Dihydro -3- Ethoxycarbonyl -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound X a) as well as 1- Bromo -3- Ethoxycarbonyl -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound X b) Manufacturing of:
In a light shielding container, NBS (1.82 g, 13.61 mmol) was added to a solution of compound IXb (1.98 g, 6.19 mmol) in acetonitrile (190 ml) at room temperature, and the mixture was heated to reflux for 1.5 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give a mixture of compounds Xa and Xb (2.18 g,1H-NMR ratio Xa: Xb = 6: 1) was obtained. Since these were difficult to separate, they were used in the next reaction as they were. Compound Xa:1H-NMR (CDClThree/ TMS) δ (ppm): 1.42 (3H, t, J = 7Hz, CH ThreeH2), 3.02 (2H, t, J = 7Hz, CH 2CH2), 3.11 (3H, s, CHThreeSO2), 3.36 (2H, t, J = 7Hz, CH2CH 2), 4.42 (2H, 8, J = 7Hz, CHThreeCH2), 7.97 (1H, d, J = 2Hz, 6-H), 7.99 (1H, dd, J = 2, 9Hz, 8-H), 8.41 (1H, d, J = 9Hz, 9-H) EI- MS (m / z): 398 [M+], 400 [M++2]
[0127]
Compound Xb:1H-NMR (CDClThree/ TMS) δ (ppm): 1.48 (3H, t, J = 7Hz, CHThreeCH2), 3.16 (3H, s, CHThreeSO2), 4.50 (2H, 8, J = 7Hz, CHThreeCH2), 7.47 (1H, d, J = 10Hz), 8.19 (1H, dd, J = 2, 9Hz, 8-H), 8.28 (1H, d, J = 10Hz), 8.39 (1H, d, J = 2Hz , 6-H), 9.61 (1H, d, J = 9Hz, 9-H) EI-MS (m / z): 396 [M+], 398 [M++2]
[0128]
Example 38:4,5- Dihydro -3- Ethoxycarbonyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 1) as well as 3- Ethoxycarbonyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 2) Synthesis of:
To a solution of a mixture of the compounds Xa and Xb produced in Production Example 22 (2.18 g) in toluene (200 ml) -ethanol (100 ml) at room temperature was added 4-methoxyphenylboric acid (1.25 g, 8.20 mmol), Pd (PPhThree)Four (0.63 g, 0.55 mmol) and 2M aqueous sodium carbonate solution (10.9 ml, 21.86 mmol) were added, and the mixture was heated to reflux for 2.5 hours under an argon gas atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane containing 5% ethyl acetate → dichloromethane containing 10% ethyl acetate) to give the title compound XI-1 (2.13 g, yield 81% (2 steps)) as a crystalline solid. Compound XI-2 (0.34 g, yield 13% (2 steps)) was isolated. Compound XI-1: mp.196-198 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 1.42 (3H, t, J = 7Hz, CH ThreeCH2), 3.07 (2H, t, J = 7Hz, CH 2CH2), 3.08 (3H, s, CHThreeSO2), 3.38 (2H, t, J = 7Hz, CH2CH 2), 3.87 (3H, s, CH ThreeO), 4.44 (2H, 8, J = 7Hz, CHThreeCH 2), 6.95 (2H, d, J = 9Hz), 7.08 (1H, d, J = 9Hz, 9-H), 7.47 (2H, d, J = 9Hz), 7.62 (1H, dd, J = 2, 9Hz) , 8-H), 7.94 (1H, d, J = 2Hz, 6-H) EI-MS (m / z): 426 [M+Compound XI-2: mp.244-246 ° C.,1H-NMR (CDClThree/ TMS) δ (ppm): 1.47 (3H, t, J = 7Hz, CH ThreeCH2), 3.09 (3H, s, CHThreeSO2), 3.93 (3H, s, CHThreeO), 7.07 (2H, d, J = 9Hz), 7.43 (1H, d, J = 10Hz), 7.55 (2H, d, J = 9Hz), 7.74 (1H, d, J = 9Hz, 9-H) , 7.79 (1H, dd, J = 2, 9Hz, 8-H), 8.32 (1H, d, J = 10Hz), 8.33 (1H, d, J = 2Hz, 6-H) EI-MS (m / z ): 424 [M+].
[0129]
Compound XI- 1 Separate synthesis of ( Compound XI- 2 Catalytic reduction ) :
In a solution of compound XI-2 (0.61 g, 1.44 mmol) in acetic acid (60 ml), 10% Rh-Al2OThree(100 mg) was added, and the mixture was stirred at 80 ° C. for 2 days under a hydrogen gas atmosphere. The reaction solution was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 3) to give the title compound (0.54 g, yield 89%) as a crystalline solid.
[0130]
Example 39:3- Carboxy -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 3) Synthesis of:
To a solution of compound XI-1 (1.20 g, 2.82 mmol) in methanol (250 ml) was added 1 N sodium hydroxide (14.1 ml, 14.1 mmol) at room temperature, and the mixture was heated to reflux for 20 hours. The reaction solution was adjusted to pH 5-6 with 1 N hydrochloric acid and concentrated to dryness under reduced pressure. The residue was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (1.02 g, yield 91%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 3.07 to 3.11 (5H, m, CHThreeSO2 & CH2), 3.39 (2H, t, J = 7Hz, CH2), 3.89 (3H, s, CHThreeO), 6.98 (2H, d, J = 9Hz), 7.12 (1H, d, J = 9Hz, 9-H), 7.47 (2H, d, J = 9Hz), 7.65 (1H, dd, J = 2, 9Hz, 8-H), 7.96 (1H, d, J = 2Hz, 6-H) EI-MS (m / z): 399 [M+]
[0131]
Example 40:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- Four) Synthesis of:
To a quinoline (3.5 ml) solution of compound XI-3 (0.96 g, 2.41 mmol), copper powder (168 mg, 2.65 mmol) was added at room temperature, followed by stirring at 220 to 225 ° C. for 1 hour. Chloroform was added to the reaction solution, insoluble matter was removed by filtration, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane containing 30% ethyl acetate) to give the title compound (0.39 g, yield 46%) as an amorphous powder.1H-NMR (DMSO-d6) δ (ppm): 2.90 ~ 3.05 (4H, m, CH2× 2), 3.21 (3H, s, CHThreeSO2), 3.82 (3H, s, CHThreeO), 6.95 (1H, s, 3-H), 7.00 (1H, d, J = 9Hz, 9-H), 7.03 (2H, d, J = 9Hz), 7.42 (2H, d, J = 9Hz) , 7.64 (1H, dd, J = 2, 9Hz, 8-H), 8.00 (1H, d, J = 2Hz, 6-H) EI-MS (m / z): 354 [M+]
[0132]
Example 41:3- Chloro -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- Five) as well as 3- Chloro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 6) Synthesis of:
Compound XI-4 (240 mg, 0.86 mmol) was dissolved in acetonitrile (12 ml), NCS (90 mg, 0.68 mmol) was added, and the mixture was stirred at 45 ° C. for 4 days under light shielding. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted earlier was concentrated to dryness under reduced pressure and recrystallized from n-hexane-chloroform to give Compound XI-6 (41 mg, 41 mg, Yield 16%) was obtained. The eluted fraction was then concentrated to dryness under reduced pressure and recrystallized from n-hexane-chloroform to obtain Compound XI-5 (110 mg, yield 42%) as a pale yellow solid. Compound XI-5:1H-NMR (CDClThree) δ (ppm): 2.89 ~ 2.95 (2H, m, CH2), 3.01 ~ 3.08 (2H, m, CH2), 3.05 (3H, s, CHThreeSO2), 3.85 (3H, s, CHThreeO), 6.93 (2H, d, J = 9Hz), 7.10 (1H, d, J = 9Hz, 9-H), 7.43 (2H, d, J = 9Hz), 7.59 (1H, dd, J = 2, 9Hz, 8-H), 7.90 (1H, d, J = 2Hz, 6-H) .EI-DI m / z: 388 [M+Compound XI-6:1H-NMR (DMSO-d6) δ (ppm): 3.24 (3H, s, CHThreeSO2), 3.88 (3H, s, CHThreeO), 7.15 (2H, d, J = 9Hz), 7.46 (1H, d, J = 10Hz, CFour or CFive-H), 7.52-7.63 (4H, m), 7.84 (1H, dd, J = 2, 9Hz, 8-H), 8.44 (1H, d, J = 2Hz, 6-H). EI-DI m / z: 386 [M+].
[0133]
Example 42:3,5- Dichloro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 7) Synthesis of:
To a solution of compound XI-4 (0.13 g, 0.37 mmol) in acetonitrile (3 ml), NCS (86 mg, 0.66 mmol) was added at room temperature.0Stir at C for 7 hours. Chloroform was added to the reaction solution, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate containing 30% n-hexane) to give the title compound (34 mg, yield 22%) and compound XI-6 (17 mg, yield 12%) as a yellow solid. It was.1H-NMR (CDClThree/ TMS) δ (ppm): 3.11 (3H, s, CHThreeSO2), 3.93 (3H, s, CHThreeO), 7.07 (2H, d, J = 9Hz, aromatic-H), 7.53 (2H, d, J = 9Hz, aromatic-H), 7.58 (1H, s, 4-H), 7.78 (1H, d, J = 9Hz, 9-H), 7.82 (1H, dd, J = 2, 9Hz, 8-H), 8.65 (1H, d, J = 2Hz, 6-H). EI-DI (m / z): 420 [M+], 422 [M++2], 424 [M++4].
[0134]
Example 43:3- Bromo -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 8) Synthesis of:
NBS (205 mg, 1.15 mmol) was added to a solution of compound XI-4 (0.37 g, 1.05 mmol) in acetonitrile (10 ml) at room temperature, and the mixture was stirred at 50 ° C. for 15 minutes. Chloroform was added to the reaction solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate-containing dichloromethane → 10% ethyl acetate-containing dichloromethane) to give the title compound (0.30 g, yield 67%) as a crystalline solid. mp.250.5-252 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.91 ~ 3.09 (7H, m, CHThreeSO2 & CH2× 2), 3.87 (3H, s, CHThreeO), 6.95 (2H, d, J = 9Hz), 7.11 (1H, d, J = 9Hz, 9-H), 7.45 (2H, d, J = 9Hz), 7.61 (1H, dd, J = 2, 9Hz, 8-H), 7.92 (1H, d, J = 2Hz, 6-H) EI-MS (m / z): 432 [M+], 434 [M++2].
[0135]
Example 44:3- Cyano -4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 9) Synthesis of:
To a solution of compound XI-8 (108 mg, 0.25 mmol) in dry DMF (3 ml) was added copper (I) cyanide (27 mg, 0.30 mmol) at room temperature, and the mixture was stirred at 170 ° C. for 18 hours under an argon gas atmosphere. . The reaction solution was cooled to room temperature, a solution of ethylenediamine (0.5 ml) and water (3 ml) was added, and the mixture was shaken well to remove copper ions. Chloroform was added to the mixture, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate-containing dichloromethane → 10% ethyl acetate-containing dichloromethane) to give the title compound (33 mg, yield 35%) as a crystalline solid. mp.256.2-259.5 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.08 (3H, s, CHThreeSO2), 3.11 to 3.15 (4H, m, CH2CH2), 3.89 (3H, s, CHThreeO), 6.98 (2H, d, J = 9Hz), 7.14 (1H, d, J = 9Hz, 9-H), 7.45 (2H, d, J = 9Hz), 7.66 (1H, dd, J = 2, 9Hz, 8-H), 7.96 (1H, d, J = 2Hz, 6-H) .EI-MS (m / z): 379 [M+].
[0136]
Example 45:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -3- Trifluoromethylimidazo [1,5-a] Quinoline ( Compound XI- Ten) Synthesis of:
To a solution of compound XI-8 (0.15 g, 0.35 mmol) in DMA (5 ml) at room temperature was added sodium trifluoroacetate (189 mg, 1.39 mmol) and copper (I) iodide (132 mg, 0.69 mmol), The mixture was heated to reflux under an argon gas atmosphere for 5.5 hours. Chloroform was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (13 mg, yield 9%) as a crystalline solid. mp.278.5-280 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.08 (3H, s, CHThreeSO2), 3.08 ~ 3.13 (4H, m, CH2× 2), 3.88 (3H, s, CHThreeO), 6.96 (2H, d, J = 9Hz), 7.12 (1H, d, J = 8.5Hz, 9-H), 7.47 (2H, d, J = 9Hz), 7.64 (1H, dd, J = 2 , 9Hz, 8-H), 7.94 (1H, d, J = 2Hz, 6-H) EI-MS (m / z): 422 [M+].
[0137]
Example 46:4,5- Dihydro -3- Hydroxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 11) Synthesis of:
Lithium aluminum hydride (53 mg, 1.40 mmol) was added to a dry THF (7 ml) solution of compound XI-1 (0.26 g, 0.61 mmol) under ice cooling, and the mixture was stirred for 20 minutes. Excess ethyl acetate was added to the reaction solution, and the mixture was stirred for several minutes. Chloroform was added to the filtrate, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol) to give the title compound (0.13 g, yield 57%) as a crystalline solid. mp.188.5-189.5 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.99 (2H, t, J = 4Hz, CH 2CH2), 3.04 (2H, t, J = 4Hz, CH2CH 2), 3.07 (3H, s, CHThreeSO2), 3.87 (3H, s, CHThreeO), 4.68 (2H, s, CH 2OH), 6.95 (2H, d, J = 9Hz), 7.07 (1H, d, J = 9Hz), 7.44 (2H, d, J = 9Hz), 7.60 (1H, dd, J = 2, 9Hz, 8- H), 7.90 (1H, d, J = 2.2Hz, 6-H) .EI-MS (m / z): 384 [M+].
[0138]
Example 47:4,5- Dihydro -3- Fluoromethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 12) Synthesis of:
To a dry methylene chloride (12 ml) solution of compound XI-11 (60 mg, 0.16 mmol), DAST (31 μl, 0.23 mmol) was added under ice cooling, and the mixture was stirred for 90 minutes under an argon atmosphere. The reaction mixture was diluted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from chloroform-n-hexane to give the title compound (19 mg, yield 32%) as a crystalline solid. mp.180-181 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.04 to 3.08 (4H, m, CH2CH2), 3.08 (3H, s, CHThreeSO2), 3.87 (3H, s, CHThreeO), 5.43 (2H, d, J = 50Hz, CH2F), 6.96 (2H, d, J = 9Hz), 7.11 (1H, d, J = 9Hz, 9-H), 7.46 (2H, d, J = 9Hz), 7.62 (1H, dd, J = 2, 9Hz, 8-H), 7.92 (1H, d, J = 2Hz, 6-H) .EI-MS (m / z): 386 [M+].
[0139]
Example 48:4,5- Dihydro -3- Methoxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 13) Synthesis of:
To a solution of compound XI-11 (0.10 g, 0.26 mmol) in dry THF (10 ml) was added NaH (9 mg, 0.39 mmol) and methyl iodide (74 mg, 0.52 mmol) at room temperature under an argon gas atmosphere. For 1.5 days. The reaction solution was diluted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (63 mg, yield 61%) as a crystalline solid. mp.182-186 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.98 to 3.06 (4H, m, CH2× 2), 3.07 (3H, s, CHThreeSO2), 3.48 (3H, s, CHThreeO), 3.86 (3H, s, CHThreeO), 4.48 (2H, s, CH2O), 6.94 (2H, d, J = 9Hz, aromatic-H), 7.08 (1H, d, J = 9Hz, 9-H), 7.45 (2H, d, J = 9Hz, aromatic-H), 7.59 ( 1H, d, J = 2, 9Hz, 8-H), 7.90 (1H, d, J = 2Hz, 6-H) .EI-MS (m / z): 398 [M+].
[0140]
Example 49:4,5- Dihydro -3- Ethoxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 14) Synthesis of:
To a solution of compound XI-11 (0.10 g, 0.26 mmol) in dry DMF (5 ml) was added NaH (12 mg, 0.52 mmol) and ethyl iodide (122 mg, 0.78 mmol) at room temperature under an argon gas atmosphere. For 1 day. Workup was performed in the same manner as in Example 48, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (81 mg, yield 76%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 1.27 (3H, t, J = 7Hz, OCH2CH Three), 3.00 ~ 3.04 (4H, m, CH2CH2), 3.07 (3H, s, CHThreeSO2), 3.66 (2H, 8, J = 7Hz, OCH 2CHThree), 3.86 (3H, s, CHThreeO), 4.53 (2H, s, CH2O), 6.93 (2H, d, J = 9Hz, aromatic-H), 7.06 (1H, d, J = 9Hz, 9-H), 7.44 (2H, d, J = 9Hz, aromatic-H), 7.59 ( 1H, dd, J = 2, 9Hz, 8-H), 7.90 (1H, d, J = 2Hz, 6-H) .EI-MS (m / z): 412 [M+].
[0141]
Example 50:Synthesis of 4,5-dihydro-3-benzyloxymethyl-1- (4-methoxyphenyl) -7-methylsulfonylimidazo [1,5-a] quinoline (Compound XI-15):
  To a dry THF (10 ml) solution of compound XI-11 (0.10 g, 0.26 mmol), NaH (8 mg, 0.31 mmol) and benzyl bromide (67 mg, 0.39 mmol) were added at room temperature under an argon gas atmosphere for 3 hours. Heated to reflux. Post-treatment was performed in the same manner as in Example 48, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to obtain a crystalline solid.TableThe title compound (38 mg, yield 31%) was obtained. mp.140-142 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.94 to 3.02 (4H, m, CH2× 2), 3.07 (3H, s, CHThreeSO2), 3.87 (3H, s, CHThreeO), 4.59 (2H, s, CH 2OCH2), 4.67 (2H, s, CH2OCH 2), 6.94 (2H, d, J = 9Hz, aromatic-H), 7.07 (1H, d, J = 9Hz, 9-H), 7.34 (5H, m, Ph), 7.45 (2H, d, J = 9Hz , aromatic-H), 7.59 (1H, dd, J = 2, 9Hz, 8-H), 7.89 (1H, d, J = 2Hz, 6-H). EI-DI (m / z): 474 [M+].
[0142]
Example 51:4,5- Dihydro -3- (4- Methoxybenzyloxymethyl ) -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,5-a] Quinoline ( Compound XI- 16) Synthesis of:
To a solution of compound XI-11 (50 mg, 0.13 mmol) in dry DMF (5 ml) was added NaH (6 mg, 0.26 mmol) and 4-methoxybenzyl chloride (41 mg, 0.26 mmol) at room temperature under an argon gas atmosphere. And stirred at room temperature for 2 hours. Workup was performed in the same manner as in Example 48, and the residue was purified by silica gel column chromatography (mobile phase: n-hexane: ethyl acetate = 3: 7) to give the title compound (43 mg, yield 65) as a crystalline solid. %). mp.154-156 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 2.93 to 3.03 (4H, m, CH2× 2), 3.07 (3H, s, CHThreeSO2), 3.80 (3H, s, CHThreeO), 3.87 (3H, s, CHThreeO), 4.55 (2H, s, CH 2OCH2), 4.60 (2H, s, CH2OCH 2), 6.88 (2H, d, J = 8.5Hz, aromatic-H), 6.94 (2H, d, J = 9Hz, aromatic-H), 7.07 (1H, d, J = 9Hz, 9-H), 7.32 ( 2H, d, J = 9Hz, aromatic-H), 7.45 (2H, d, J = 9Hz, aromatic-H), 7.59 (1H, dd, J = 2, 9Hz, 8-H), 7.89 (1H, d , J = 2Hz, 6-H). EI-DI (m / z): 505 [M++ H].
[0143]
Example 52:4,5- Dihydro -3- Chloromethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonylimidazo [1,2-a] Quinoline ( Compound XI- 17) Synthesis of:
To a solution of compound XI-11 (0.14 g, 0.37 mmol) in chloroform (5 ml) was added thionyl chloride (52 μl, 0.73 mmol) at room temperature, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (0.12 g, yield 80%). This was used crude in the next reaction.1H-NMR (CDClThree/ TMS) δ (ppm): 2.99-3.07 (4H, m, CH2× 2), 3.07 (3H, s, CHThreeSO2), 3.87 (3H, s, CHThreeO), 4.69 (2H, s, CH2Cl), 6.95 (2H, d, J = 9Hz, aromatic-H), 7.10 (1H, d, J = 9Hz, 9-H), 7.46 (2H, d, J = 9Hz, aromatic-H), 7.61 ( 1H, dd, J = 2, 9Hz, 8-H), 7.92 (1H, d, J = 2Hz, 6-H) .EI-DI (m / z): 366 [M+−36].
[0144]
Example 53:4,5- Dihydro -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -3- Phenoxymethylimidazo [1,5-a] Quinoline ( Compound XI- 18) Synthesis of:
To a solution of crude compound XI-17 (0.10 g, 0.25 mmol) in dry DMF (5 ml) was added NaH (15 mg, 0.63 mmol) and phenol (94 mg, 1.00 mmol) at room temperature under an argon gas atmosphere. And stirred overnight. The reaction solution was diluted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified twice by silica gel column chromatography (mobile phase: 1st time, chloroform, 2nd time, n-hexane: ethyl acetate = 3: 7), and the title compound (47 mg, yield 41) was obtained as a crystalline solid. %). mp.206-209 ° C.1H-NMR (CDClThree/ TMS) δ (ppm): 3.01 to 3.05 (4H, m, CH2CH2), 3.07 (3H, s, CHThreeSO2), 3.87 (3H, s, CHThreeO), 5.11 (2H, s, CH2O), 6.95 (2H, d, J = 9Hz, aromatic-H), 6.97 (1H, m, aromatic-H), 7.05 (2H, m, aromatic-H), 7.10 (1H, d, J = 9Hz, 9-H), 7.31 (2H, m, aromatic-H), 7.47 (2H, d, J = 9Hz, aromatic-H), 7.60 (1H, dd, J = 2, 9Hz, 8-H), 7.90 ( 1H, d, J = 2Hz, 6-H) .EI-DI (m / z): 460 [M+]
[0145]
Production Example 23:Five- Methylthio -2- Nitrophenol ( Compound S-8) Manufacturing of:
5-Fluoro-2-nitrophenol (25.0 g, 0.16 mol) was dissolved in DMF (600 ml) and stirred at room temperature with 1 N sodium hydroxide (190 ml, 0.19 mol) and sodium thiomethoxide (15% aqueous solution, 123g, 0.26mol) was added and stirred for 9 hours. Ethyl acetate (1000 ml) was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid (300 ml) and then with saturated brine. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from n-hexane-chloroform to obtain the title compound (28.6 g, yield 97%) as a yellow crystalline solid.1H-NMR (CDClThree): 2.51 (3H, s, SCHThree), 6.77 (1H, dd, J = 2, 9Hz, 4-H), 6.84 (1H, d, J = 2Hz, 6-H), 7.95 (1H, d, J = 9Hz, 3-H), 10.86 (1H, s, OH). MS (EI-DI) m / z: 185 [M+].
[0146]
Production Example 24:(Five- Methylthio -2- Nitro ) Phenoxyethyl acetate ( Compound S-9) Manufacturing of:
Compound S-8 (57.16 g, 0.31 mol) was dissolved in acetone (800 ml), potassium carbonate (51.14 g, 0.37 mol) and ethyl bromoacetate (61.85 g, 0.37 mol) were added, and the mixture was refluxed for 6 hours. Insolubles were removed from the reaction mixture by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography to quantitatively obtain the title compound as a yellow viscous oil.1H-NMR (CDClThree): 1.25 (3H, t, J = 7Hz, CO2CH2CH Three ), 2.47 (3H, s, SCHThree), 4.23 (2H, q, J = 7Hz, CO2CH 2 CHThree), 4.72 (2H, s, OCH2), 6.74 (1H, d, J = 2Hz, 6-H), 6.84 (1H, dd, J = 2, 9Hz, 4-H), 7.85 (1H, d, J = 9Hz, 3-H). MS (EI-DI) m / z: 271 [M+].
[0147]
Production Example 25:(Five- Fluoro -2- Nitro ) Phenoxyethyl acetate ( Compound S-10) Manufacturing of:
5-Fluoro-2-nitrophenol (25.0 g, 0.16 mol) is dissolved in acetone (500 ml), and potassium carbonate (26.4 g, 0.19 mol) and ethyl bromoacetate (31.9 g, 0.19 mol) are added for 15 hours. Boiled and refluxed. Insolubles were removed from the reaction mixture by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography to quantitatively obtain the title compound as a yellow solid.1H-NMR (CDClThree): 1.27 (3H, t, J = 7Hz, CO2CH2CH Three ), 4.25 (2H, q, J = 7Hz, CO2CH 2 CHThree), 4.74 (2H, s, OCH2), 6.66 (1H, dd, J = 2, 10Hz, 6-H), 6.77 (1H, ddd, J = 2, 7, 9Hz, 4-H), 7.95 (1H, dd, J = 6, 9Hz, 3-H). MS (EI-DI) m / z: 198 [M+-45].
[0148]
Production Example 26:7- Methylthio -2H-1,4- Benzoxazine -3 (4H)- on ( Compound I d) Manufacturing of:
Compound S-9 (83.73 g, 0.31 mol) was dissolved in ethanol (1500 ml), iron powder (53.19 g, 0.96 mol) and concentrated hydrochloric acid (207 ml) were added, and the mixture was boiled and refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, the precipitated yellow solid was collected by filtration, and the filtered product was washed with water and ether to give the title compound (48.01 g, yield 80%) as a colorless crystalline solid.1H-NMR (DMSO-d6): 2.41 (3H, s, SCHThree), 4.54 (2H, s, CH2), 6.80-6.89 (3H, m, 5, 6, 8-H), 10.67 (1H, s, NH) .MS (EI-DI) m / z: 195 [M+].
[0149]
Production Example 27:7- Fluoro -2H-1,4- Benzoxazine -3 (4H)- on ( Compound I e) Manufacturing of:
Compound S-10 (37.0 g, 0.15 mol) was dissolved in ethanol (820 ml), iron powder (27.5 g) and concentrated hydrochloric acid (106 ml) were added, and the mixture was boiled and refluxed for 15 hours. After cooling the reaction mixture, insolubles were removed by filtration, and the filtered product was washed with a methanol-chloroform mixture, and the filtrate was combined and concentrated to dryness under reduced pressure. The residue was washed with water and ether to give the title compound (22.7 g, yield 89%) as a colorless crystalline solid. Recrystallization from chloroform gave colorless needles.1H-NMR (DMSO-d6): 4.57 (2H, s, CH2), 6.75-6.91 (3H, m, 5, 6, 8-H), 10.70 (1H, s, NH) .MS (EI-DI) m / z: 167 [M+].
[0150]
Production Example 28:7- Methylthio -4- (2- Oxopropyl ) -2H-1,4- Benzoxazine -3 - on ( Compound II d) Manufacturing of:
Compound Id (19.50 g, 0.10 mol) was suspended in acetone (500 ml), potassium carbonate (20.70 g, 0.15 mol), TEBAC (8.00 g, 35.0 mmol) and chloroacetone (12.0 g, 0.13 mol) were added. Refluxed at the boil for hours. Insolubles were removed from the reaction mixture by filtration, and the filtered product was washed with chloroform. The filtrates were combined and concentrated to dryness under reduced pressure. The viscous oily residue was purified by silica gel column chromatography and recrystallized from n-hexane-chloroform to obtain the title compound as colorless needle crystals (22.6 g, yield 90%).1H-NMR (CDClThree): 2.23 (3H, s, CHThree), 2.43 (3H, s, SCHThree), 4.25 (2H, s, CH2), 4.65 (2H, s, CH2), 6.51 (1H, d, J = 8Hz, 5-H), 6.86 (1H, dd, J = 2, 8Hz, 6-H), 6.92 (1H, d, J = 2Hz, 8-H). (EI-DI) m / z: 251 [M+].
[0151]
Production Example 29:7- Fluoro -4- (2- Oxopropyl ) -2H-1,4- Benzoxazine -3- on ( Compound II e) Manufacturing of:
Compound Ie (10.20 g, 61.0 mmol) was suspended in acetone (200 ml), potassium carbonate (12.81 g, 92.7 mmol), TEBAC (4.88 g, 21.4 mmol) and chloroacetone (6.78 g, 73.2 mmol) were added, Boiled and refluxed for 17 hours. Insolubles were removed from the reaction mixture by filtration, and the filtered product was washed with chloroform. The filtrates were combined and concentrated to dryness under reduced pressure. The viscous oily residue was purified by silica gel column chromatography and recrystallized from ether to give the title compound (11.06 g, yield 81%) as colorless needle crystals.1H-NMR (CDClThree): 2.24 (3H, s, CHThree), 4.65 (2H, s, CH2), 4.66 (2H, s, CH2), 6.52 (1H, dd, J = 5, 9Hz, 5-H), 6.68 (1H, ddd, J = 3, 8, 9Hz, 6-H), 6.75 (1H, dd, J = 3, 9Hz, 8-H). MS (EI-DI) m / z: 223 [M+].
[0152]
Production Example 30:7- Methylthio -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound III f) Manufacturing of:
Compound IId (25.0 g, 0.10 mol) was dissolved in acetic acid (430 ml), ammonium acetate (77.10 g, 1.00 mol) was added, and the mixture was boiled and refluxed for 26 hours. The reaction mixture was concentrated to dryness under reduced pressure, chloroform was added to the residue, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography and recrystallized from n-hexane-ethanol to obtain the title compound (17.72 g, yield 76%) as a pale yellow solid.1H-NMR (CDClThree): 2.30 (3H, d, J = 1Hz, CHThree), 2.47 (3H, s, SCHThree), 5.25 (2H, s, CH2), 6.93 (1H, dd, J = 2, 8Hz, 8-H), 6.96 (1H, d, J = 2Hz, 6-H), 7.04 (1H, d, J = 1Hz, 1-H), 7.12 (1H, d, J = 8Hz, 9-H) .MS (EI-DI) m / z: 232 [M+].
[0153]
Production Example 31:7- Fluoro -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound III g) Manufacturing of:
Compound IIe (6.70 g, 30.0 mmol) was dissolved in acetic acid (100 ml), ammonium acetate (23.1 g, 0.30 mol) was added, and the mixture was boiled and refluxed for 43 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, washed with 1N sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate. After concentration to dryness under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from n-hexane-chloroform to give the title compound (5.34 g, yield 85%) as colorless prism crystals.1H-NMR (CDClThree): 2.28 (3H, d, J = 1Hz, CHThree), 5.24 (2H, s, CH2), 6.75 (1H, ddd, J = 3, 8, 9Hz, 8-H), 6.80 (1H, dd, J = 3, 9Hz, 6-H), 7.03 (1H, d, J = 1Hz, 1- H), 7.15 (1H, dd, J = 5, 9Hz, 9-H). MS (EI-DI) m / z: 204 [M+].
[0154]
Production Example 32:1- Bromo -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound IV g) Manufacturing of:
Compound IIIf (6.00 g, 25.8 mmol) was dissolved in acetic acid (120 ml), NBS (4.83 g, 27.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Chloroform was added to the reaction mixture, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography and crystallized using n-hexane to give the title compound (5.76 g, yield 72%) as a yellow powder.1H-NMR (CDClThree): 2.26 (3H, s, CHThree), 2.48 (3H, s, SCHThree), 5.12 (2H, s, CH2), 6.97 (1H, dd, J = 2, 9Hz, 8-H), 7.00 (1H, d, J = 2Hz, 6-H), 8.08 (1H, d, J = 9Hz, 9-H). (EI-DI) m / z: 310 [M+], 312 [M++2].
[0155]
Production Example 33:1- Bromo -7- Fluoro -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound IV h) Manufacturing of:
Compound IIIg (3.06 g, 15.0 mmol) was dissolved in acetic acid (30 ml), NBS (2.93 g, 16.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Chloroform was added to the reaction mixture, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography and recrystallized from n-hexane-chloroform to obtain the title compound (3.69 g, yield 87%) as a pale yellow crystalline solid.1H-NMR (CDClThree): 2.24 (3H, s, CHThree), 5.12 (2H, s, CH2), 6.82 (1H, ddd, J = 3, 8, 9Hz, 8-H), 6.86 (1H, dd, J = 3, 9Hz, 6-H), 8.14 (1H, dd, J = 5, 9Hz, 9-H). MS (EI-DI) m / z: 282 [M+], 284 [M++2].
[0156]
1- Aryl -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] General synthesis of benzoxazine:
Compound IVg (500 mg, 1.6 mmol) and phenylboric acids having various substituents (1.9 mmol) were dissolved in a mixture of toluene (5 ml) -ethanol (5 ml), and 2 M aqueous sodium carbonate solution (5 ml) and Pd (PPhThree)Four(0.1 mmol) was added and the mixture was boiled and refluxed for 3 hours with vigorous stirring under an argon gas atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.
[0157]
Example 54:2- Methyl -7- Methylthio -1- Phenyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 38) Synthesis of:
Pale boric acid was used as a pale tan solid (89% yield).1H-NMR (CDClThree): 2.23 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 5.26 (2H, s, CH2), 6.50 (1H, d, J = 9Hz, 9-H), 6.61 (1H, dd, J = 2, 9Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.28 ~ 7.34 (2H, m, aromatic), 7.43 ~ 7.49 (3H, m, aromatic). MS (EI-DI) m / z: 308 [M+].
[0158]
Example 55:1- (3- Fluorophenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2, 1-c] [1,4] Benzoxazine ( Compound V- 39) Synthesis of:
Yellow-orange solid (yield 78%) using 3-fluorophenyl boric acid.1H-NMR (CDClThree): 2.20 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 5.18 (2H, s, CH2), 6.51 (1H, d, J = 9Hz, 9-H), 6.64 (1H, dd, J = 2, 9Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.00 〜7.16 (3H, m, aromatic), 7.38〜7.45 (1H, m, aromatic). MS (EI-DI) m / z: 326 [M+].
[0159]
Example 56:Synthesis of 1- (4-fluorophenyl) -2-methyl-7-methylthio-4H-imidazo [2,1-c] [1,4] benzoxazine (Compound V-40):
  Using 4-fluorophenyl boric acid, pale yellow solid (88% yield).mp.74-76 ° C.1H-NMR (CDClThree): 2.18 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 5.21 (2H, s, CH2), 6.47 (1H, d, J = 9Hz, 9-H), 6.63 (1H, dd, J = 2, 9Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.15 (2H, dd, J = 9, 9Hz, aromatic), 7.29 (2H, dd, J = 5, 9Hz, aromatic). MS (EI-DI) m / z: 326 [M+].
[0160]
Example 57:1- (4- Chlorophenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 41) Synthesis of:
A pale yellow solid (yield 87%) using 4-chlorophenylboric acid.1H-NMR (CDClThree): 2.19 (3H, s, CHThree), 2.43 (3H, s, SCHThree), 5.18 (2H, s, CH2), 6.51 (1H, d, J = 9Hz, 9-H), 6.65 (1H, dd, J = 2, 9Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.24 (2H, d, J = 9Hz, aromatic), 7.42 (2H, d, J = 9Hz, aromatic). MS (EI-DI) m / z: 342 [M+].
[0161]
Example 58:2- Methyl -1- (4- Methylphenyl ) -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 42) Synthesis of:
A light brown solid (99% yield) using 4-methylphenylboric acid.1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 2.43 (3H, s, CHThree), 5.25 (2H, s, CH2), 6.55 (1H, d, J = 9Hz, 9-H), 6.62 (1H, dd, J = 2, 9Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.19 (2H, d, J = 8Hz, aromatic), 7.26 (2H, d, J = 8Hz, aromatic). MS (EI-DI) m / z: 322 [M+].
[0162]
Example 59:2- Methyl -7- Methylthio -1- (4- Trifluoromethylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 43) Synthesis of:
A pale yellow solid (78% yield) using 4-trifluoromethylphenyl boric acid.1H-NMR (CDClThree): 2.22 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 5.20 (2H, s, CH2), 6.47 (1H, d, J = 9Hz, 9-H), 6.66 (1H, dd, J = 2, 9Hz, 8-H), 7.00 (1H, d, J = 2Hz, 6-H), 7.44 (2H, d, J = 8Hz, aromatic), 7.70 (2H, d, J = 8Hz, aromatic). MS (EI-DI) m / z: 376 [M+].
[0163]
Example 60:1- (3- Methoxyphenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 44) Synthesis of:
Pale yellowish brown oily product (94% yield) using 3-methoxyphenyl boric acid.1H-NMR (CDClThree): 2.20 (3H, s, CHThree), 2.42 (3H, s, SCHThree), 3.79 (3H, s, OCHThree), 5.20 (2H, s, CH2), 6.55 (1H, d, J = 9Hz, 9-H), 6.63 (1H, dd, J = 2, 9Hz, 8-H), 6.82-6.99 (4H, m, aromatic), 7.35 (1H, dd , J = 8, 8Hz, aromatic 5-H). MS (EI-DI) m / z: 338 [M+].
[0164]
Example 61:1- (4- Methoxyphenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 45) Synthesis of:
Yellow-orange solid (yield 86%) using 4-methoxyphenyl boric acid.1H-NMR (CDClThree): 2.16 (3H, s, CHThree), 2.41 (3H, s, SCHThree), 3.86 (3H, s, OCHThree), 5.13 (1H, d, J = 14Hz, 4-H), 5.19 (1H, J = 14Hz, 4-H), 6.54 (1H, d, J = 9Hz, 9-H), 6.62 (1H, dd , J = 2, 9Hz, 8-H), 6.96 (2H, d, J = 9Hz, aromatic), 6.97 (1H, d, J = 2Hz, 6-H), 7.22 (2H, d, J = 9Hz, aromatic). MS (EI-DI) m / z: 338 [M+].
[0165]
Example 62:1- (3- Chloro -Four- Fluorophenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 46) Synthesis of:
Pale yellow solid (yield 79%) using 3-chloro-4-fluorophenyl boric acid.1H-NMR (CDClThree): 2.18 (3H, s, CHThree), 2.43 (3H, s, SCHThree), 5.18 (2H, s, CH2), 6.48 (1H, d, J = 9Hz, 9-H), 6.66 (1H, dd, J = 2, 9Hz, 8-H), 6.99 (1H, d, J = 2Hz, 6-H), 7.17 (1H, dd, J = 2, 5, 8Hz, aromatic 6-H), 7.22 (1H, dd, J = 9, 9Hz, aromatic 5-H), 7.38 (1H, dd, J = 2, 7Hz, aromatic 2-H). MS (EI-DI) m / z: 360 [M+].
[0166]
Example 63:1- (3,5- Dichlorophenyl ) -2- Methyl -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 47) Synthesis of:
Colorless to pale yellow solid (73% yield) using 3,5-dichlorophenyl boric acid.1H-NMR (CDClThree): 2.22 (3H, s, CHThree), 2.44 (3H, s, SCHThree), 5.21 (2H, s, CH2), 6.52 (1H, d, J = 9Hz, 9-H), 6.70 (1H, dd, J = 2, 9Hz, 8-H), 7.01 (1H, d, J = 2Hz, 6-H), 7.20 (2H, d, J = 2Hz, aromatic 2, 6-H), 7.44 (1H, dd, J = 2, 2Hz, aromatic 4-H).
MS (EI-DI) m / z: 376 [M+].
[0167]
1- Aryl -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] General synthesis of benzoxazine:
The methylthio compound (compound V-38-47) was dissolved in methylene chloride (50 mg / ml), mCPBA (1.0 equivalent) was added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, and washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound.
[0168]
Example 64:2- Methyl -7- Methylsulfinyl -1- Phenyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 48) Synthesis of:
Using compound V-38, colorless solid (yield 88%).1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 2.68 (3H, s, SOCHThree), 5.26 (1H, d, J = 14Hz, 4-H), 5.30 (1H, d, J = 14Hz, 4-H), 6.72 (1H, d, J = 9Hz, 9-H), 7.01 (1H , dd, J = 2, 9Hz, 8-H), 7.28-7.34 (2H, m, aromatic), 7.39 (1H, d, J = 2Hz, 6-H), 7.44-7.50 (3H, m, aromatic) MS (EI-DI) m / z: 324 [M+].
[0169]
Example 65:1- (3- Fluorophenyl ) -2- Methyl -7- Methylsulfinyl -4H- I Midazo [2,1-c] [1,4] Benzoxazine ( Compound V- 49) Synthesis of:
Using compound V-39, colorless solid (yield 88%).1H-NMR (CDClThree): 2.20 (3H, s, CHThree), 2.70 (3H, s, SOCHThree), 5.22 (1H, d, J = 14Hz, 4-H), 5.26 (1H, d, J = 14Hz, 4-H), 6.73 (1H, d, J = 9Hz, 9-H), 7.01 to 7.13 (4H, m, aromatic), 7.40-7.47 (2H, m, aromatic). MS (EI-DI) m / z: 342 [M+].
[0170]
Example 66:1- (4- Fluorophenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 50) Synthesis of:
Using compound V-40, colorless solid (yield 87%).1H-NMR (CDClThree): 2.16 (3H, s, CHThree), 2.69 (3H, s, SOCHThree), 5.20 (1H, d, J = 14Hz, 4-H), 5.24 (1H, d, J = 14Hz, 4-H), 6.70 (1H, d, J = 9Hz, 9-H), 7.01 (1H , dd, J = 2, 9Hz, 8-H), 7.16 (2H, dd, J = 9, 10Hz), 7.29 (2H, dd, J = 5, 9Hz), 7.40 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 342 [M+].
[0171]
Example 67:1- (4- Chlorophenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 51) Synthesis of:
Colorless solid (yield 96%) using compound V-41.1H-NMR (CDClThree): 2.18 (3H, s, CHThree), 2.69 (3H, s, SOCHThree), 5.22 (1H, d, J = 14Hz, 4-H), 5.25 (1H, d, J = 14Hz, 4-H), 6.73 (1H, d, J = 8Hz, 9-H), 7.03 (1H , dd, J = 2, 8Hz, 8-H), 7.24 (2H, d, J = 9Hz, aromatic), 7.41 (1H, d, J = 2Hz, 6-H), 7.44 (2H, d, J = 9Hz, aromatic). MS (EI-DI) m / z: 358 [M+].
[0172]
Example 68:2- Methyl -1- (4- Methylphenyl ) -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 52) Synthesis of:
A pale yellow powder (yield 89%) was obtained using compound V-42.1H-NMR (CDClThree): 2.17 (3H, s, CHThree), 2.42 (3H, s, SOCHThree), 2.68 (3H, s, CHThree), 5.22 (1H, d, J = 14Hz, 4-H), 5.26 (1H, d, J = 14Hz, 4-H), 6.76 (1H, d, J = 9Hz, 9-H), 7.01 (1H , dd, J = 2, 9Hz, 8-H), 7.18 (2H, d, J = 8Hz, aromatic), 7.25 (2H, d, J = 8Hz, aromatic), 7.37 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 338 [M+].
[0173]
Example 69:2- Methyl -7- Methylsulfinyl -1- (4- Trifluoromethylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 53) Synthesis of:
Using Compound V-43, colorless amorphous powder (yield 85%).1H-NMR (CDClThree): 2.20 (3H, s, CHThree), 2.69 (3H, s, SOCHThree), 5.20 (1H, d, J = 14Hz, 4-H), 5.24 (1H, d, J = 14Hz, 4-H), 6.67 (1H, d, J = 8Hz, 9-H), 7.03 (1H , dd, J = 2, 8Hz, 8-H), 7.40-7.45 (3H, m, aromatic), 7.71 (2H, d, J = 8Hz, aromatic). MS (EI-DI) m / z: 392 [ M+].
[0174]
Example 70:1- (3- Methoxyphenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 54) Synthesis of:
Using Compound V-44, colorless amorphous powder (yield 83%).1H-NMR (CDClThree): 2.16 (3H, s, CHThree), 2.66 (3H, s, SOCHThree), 3.77 (3H, s, OCHThree), 5.20 (2H, s, CH2), 6.75 (1H, d, J = 9Hz, 9-H), 6.79 ~ 6.88 (2H, m), 6.94 (1H, m), 6.99 (1H, dd, J = 2, 9Hz, 8-H), 7.31 ~ 7.38 (2H, m). MS (EI-DI) m / z: 354 [M+].
[0175]
Example 71:1- (4- Methoxyphenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 55) Synthesis of:
Pale yellow amorphous powder (yield 79%) using compound V-45.1H-NMR (CDClThree): 2.51 (3H, s, CHThree), 2.67 (3H, s, SOCHThree), 3.85 (3H, s, OCHThree), 5.19 (1H, d, J = 14Hz, 4-H), 5.23 (1H, d, J = 14Hz, 4-H), 6.75 (1H, d, J = 9Hz, 9-H), 6.96 (2H , d, J = 9Hz, aromatic), 6.99 (1H, dd, J = 2, 9Hz, 8-H), 7.20 (2H, d, J = 9Hz, aromatic), 7.36 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 354 [M+].
[0176]
Example 72:1- (3- Chloro -Four- Fluorophenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 56) Synthesis of:
Using Compound V-46, colorless amorphous powder (96% yield).1H-NMR (CDClThree): 2.16 (3H, s, CHThree), 2.68 (3H, s, SOCHThree), 5.21 (1H, d, J = 14Hz, 4-H), 5.22 (1H, d, J = 14Hz, 4-H), 6.70 (1H, d, J = 9Hz, 9-H), 7.03 (1H , dd, J = 2, 9Hz, 8-H), 7.16 (1H, ddd, J = 2, 5, 9Hz, aromatic 6-H), 7.23 (1H, dd, J = 9, 9Hz, aromatic 5-H ), 7.37 (1H, dd, J = 2, 7Hz, aromatic 2-H), 7.40 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 376 [M+].
[0177]
Example 73:1- (3,5- Dichlorophenyl ) -2- Methyl -7- Methylsulfinyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 57) Synthesis of:
Using compound V-47, colorless solid (yield 78%).1H-NMR (CDClThree): 2.20 (3H, s, CHThree), 2.71 (3H, s, SOCHThree), 5.23 (2H, s, CH2), 6.74 (1H, d, J = 9Hz, 9-H), 7.08 (1H, dd, J = 2, 9Hz, 8-H), 7.20 (2H, d, J = 2Hz, aromatic 2, 6-H ), 7.43 (1H, d, J = 2Hz, 6-H), 7.44 (1H, dd, J = 2, 2Hz, aromatic 4-H). MS (EI-DI) m / z: 392 [M+].
[0178]
1- Aryl -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] General synthesis of benzoxazine:
The methylthio compound (Compound V-38-47) was dissolved in methylene chloride (50 mg / ml), 2.4 equivalents of mCPBA was added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, and washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound.
[0179]
Example 742- Methyl -7- Methylsulfonyl -1- Phenyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 58) Synthesis of:
Compound V-38 was used as a pale yellow solid (yield 79%). mp.176-177 ° C.1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 3.01 (3H, s, SO2CHThree), 5.29 (2H, s, CH2), 6.74 (1H, d, J = 9Hz, 9-H), 7.26-7.34 (3H, m, aromatic), 7.44-7.52 (3H, m, aromatic), 7.65 (1H, d, J = 2Hz, 6 -H). MS (EI-DI) m / z: 340 [M+].
[0180]
Example 75:1- (3- Fluorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imi Dazo [2,1-c] [1,4] Benzoxazine ( Compound V- 59) Synthesis of:
Using compound V-39, pale yellow solid (yield 86%). mp.201-202 ° C.1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 3.02 (3H, s, SO2CHThree), 5.27 (2H, s, CH2), 6.75 (1H, d, J = 9Hz, 9-H), 7.00 ~ 7.21 (3H, m, aromatic), 7.42 ~ 7.49 (1H, m, aromatic), 7.35 (1H, dd, J = 2, 9Hz , 8-H), 7.67 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 358 [M+].
[0181]
Example 761- (3- Methoxyphenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 60) Synthesis of:
Using compound V-44, colorless needles (yield 76%).1H-NMR (CDClThree): 2.19 (3H, s, CHThree), 3.01 (3H, s, SO2CHThree), 3.80 (3H, s, OCHThree), 5.26 (2H, s, CH2), 6.78 (1H, d, J = 9Hz, 9-H), 6.80-6.90 (2H, m, aromatic), 6.97-7.03 (1H, m, aromatic), 7.30-7.42 (2H, m, aromatic), 7.64 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 370 [M+].
[0182]
Example 771- (4- Fluorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 61) Synthesis of:
Using compound V-40, colorless to pale yellow solid (81% yield). mp.224-226 ° C.1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 3.02 (3H, s, SO2CHThree), 5.33 (2H, s, CH2), 6.74 (1H, d, J = 9Hz, 9-H), 7.20 (2H, dd, J = 9, 9Hz, aromatic 3, 5-H), 7.30 (2H, dd, J = 5, 9Hz, aromatic 2, 6-H), 7.35 (1H, dd, J = 2, 9Hz, 8-H), 7.68 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 358 [M+].
[0183]
Example 78:1- (4- Chlorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 62) Synthesis of:
Using compound V-41, pale yellow solid (73% yield). mp.229-232 ° C.1H-NMR (CDClThree): 2.18 (3H, s, CHThree), 3.02 (3H, s, SO2CHThree), 5.25 (2H, s, CH2), 6.75 (1H, d, J = 9Hz, 9-H), 7.24 (2H, d, J = 8Hz, aromatic), 7.35 (1H, dd, J = 2, 9Hz, 8-H), 7.45 (2H , d, J = 8Hz, aromatic), 7.66 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 374 [M+].
[0184]
Example 792- Methyl -1- (4- Methylphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 63) Synthesis of:
Using compound V-42, pale yellow solid (yield 55%). mp.180-182 ° C.1H-NMR (CDClThree): 2.17 (3H, s, CHThree), 2.43 (3H, s, CHThree), 3.01 (3H, s, SO2CHThree), 5.25 (2H, s, CH2), 6.77 (1H, d, J = 9Hz, 9-H), 7.17 (2H, d, J = 8Hz, aromatic), 7.26 (2H, d, J = 8Hz, aromatic), 7.31 (1H, dd, J = 2, 9Hz, 8-H), 7.63 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 354 [M+].
[0185]
Example 802- Methyl -7- Methylsulfonyl -1- (4- Trifluoromethylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 64) Synthesis of:
Using compound V-43, pale yellow solid (yield 98%). mp.225-228 ° C.1H-NMR (CDClThree): 2.23 (3H, s, CHThree), 3.03 (3H, s, SO2CHThree), 5.28 (2H, s, CH2), 6.71 (1H, d, J = 9Hz, 9-H), 7.37 (1H, dd, J = 2, 9Hz, 8-H), 7.44 (2H, d, J = 8Hz, aromatic), 7.69 (1H , d, J = 2Hz, 6-H), 7.74 (2H, d, J = 8Hz, aromatic). MS (EI-DI) m / z: 408 [M+].
[0186]
Example 81:1- (4- Methoxyphenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 65) Synthesis of:
Using compound V-45, pale yellow solid (yield 82%). mp.225-227.5 ° C.1H-NMR (CDClThree): 2.18 (3H, s, CHThree), 3.01 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.27 (2H, s, CH2), 6.79 (1H, d, J = 9Hz, 9-H), 6.99 (2H, d, J = 9Hz, aromatic), 7.22 (2H, d, J = 9Hz, aromatic), 7.32 (1H, dd, J = 2, 9Hz, 8-H), 7.64 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 370 [M+].
[0187]
Example 82:1- (3- Chloro -Four- Fluorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 66) Synthesis of:
Using compound V-46, a colorless to pale yellow solid (yield 96%).1H-NMR (CDClThree): 2.19 (3H, s, CHThree), 3.03 (3H, s, SO2CHThree), 5.26 (2H, s, CH2), 6.74 (1H, d, J = 9Hz, 9-H), 7.18 (1H, ddd, J = 2, 5, 9Hz, aromatic 6-H), 7.26 (1H, dd, J = 9, 9Hz, aromatic 5-H), 7.36-7.41 (2H, m, aromotic), 7.67 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 392 [M+].
[0188]
Example 83:1- (3,5- Dichlorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 67) Synthesis of:
Colorless to pale yellow solid (98% yield) using compound V-47.1H-NMR (CDClThree): 2.22 (3H, s, CHThree), 3.04 (3H, s, SO2CHThree), 5.27 (2H, s, CH2), 6.77 (1H, d, J = 9Hz, 9-H), 7.20 (2H, d, J = 2Hz, aromatic 2, 6-H), 7.42 (1H, dd, J = 2, 9Hz, 8-H ), 7.43 (1H, dd, J = 2, 2Hz, aromatic 4-H), 7.69 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 408 [M+].
[0189]
Example 84:7- Aminosulfonyl -1- (4- Methoxyphenyl ) -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 68) Synthesis of:
Compound V-65 (1.00 g, 2.70 mmol) is suspended in anhydrous THF (25 ml) and cooled with ice in an argon gas atmosphere with stirring and n-propylmagnesium chloride (1.5 ml, 2.97 mmol: 2.0M ether solution). And stirred at room temperature for 1 hour. The reaction mixture was ice-cooled again, triethylboron (4.1 ml, 4.05 mmol: 1.0 M tetrahydropyran solution) was added, and the mixture was refluxed for 45 hours. The reaction mixture was ice-cooled, aqueous sodium acetate solution (2.06 g, 25.10 mmol / 3.5 ml) and hydroxylamine-O-sulfonic acid (2.46 g, 21.79 mmol) were added with stirring, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform and then 2% methanol-containing chloroform) and crystallized from n-hexane-chloroform to obtain the title compound (40 mg, 4%) as a slightly yellow powder. mp.202-205 ° C (dec.).1H-NMR (DMSO-d6): 2.07 (3H, s, 2-CHThree), 3.83 (3H, s, OCHThree), 5.29 (2H, s, OCH2), 6.68 (1H, d, J = 9Hz, 9-H), 7.08 (2H, d, J = 9Hz), 7.27 (1H, dd, J = 2, 9Hz, 8-H), 7.28 (2H, d , J = 9Hz), 7.38 (2H, s, SO2NH2), 7.54 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 371 [M+].
[0190]
Example 85:7- Fluoro -2- Methyl -1- (4- Methylthiophenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 69) Synthesis of:
Using compound IVh (500 mg, 1.6 mmol) and 4-methylthiophenyl boric acid (1.9 mmol), 1-aryl-2-methyl-7-methylthio-4H-imidazo [2,1-c] [1,4] benzo Reaction and workup according to the general synthesis of oxazines afforded the title compound as a light brown solid. Yield 86%. mp.126-128 ° C.1H-NMR (CDClThree): 2.16 (3H, s, CHThree), 2.52 (3H, s, SCHThree), 5.17 (2H, s, CH2), 6.47 (1H, ddd, J = 3, 8, 9Hz, 8-H), 6.61 (1H, dd, J = 6, 9Hz, 9-H), 6.81 (1H, dd, J = 3, 9Hz, 6-H), 7.20 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz). MS (EI-DI) m / z: 326 [M+].
[0191]
Example 86:7- Fluoro -2- Methyl -1- (4- Methylsulfinylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 70) Synthesis of:
Using compound V-69, reaction according to the general synthesis method of 1-aryl-2-methyl-7-methylsulfinyl-4H-imidazo [2,1-c] [1,4] benzoxazine, after-treatment, yellow orange The title compound was obtained as a solid. Yield 85%.1H-NMR (CDClThree): 2.21 (3H, s, CHThree), 2.81 (3H, s, SOCHThree), 5.18 (2H, s, CH2), 6.45-6.54 (2H, m, 8,9-H), 6.86 (1H, dd, J = 3, 9Hz, 6-H), 7.47 (2H, d, J = 9Hz), 7.73 (2H, d , J = 9Hz). MS (EI-DI) m / z: 342 [M+].
[0192]
Example 87:7- Fluoro -2- Methyl -1- (4- Methylsulfonylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 71) Synthesis of:
Using compound V-69, reaction according to the general synthesis method of 1-aryl-2-methyl-7-methylsulfonyl-4H-imidazo [2,1-c] [1,4] benzoxazine, post-treatment, pale yellow The title compound was obtained as a solid. Yield 89%. mp.171-173 ° C.1H-NMR (CDClThree): 2.27 (3H, s, CHThree), 3.14 (3H, s, SO2CHThree), 5.29 (2H, s, CH2), 6.48-6.60 (2H, m, 8, 9-H), 6.90 (1H, dd, J = 2, 9Hz, 6-H), 7.53 (2H, d, J = 8Hz, aromatic), 8.04 (2H , d, J = 8Hz, aromatic). MS (EI-DI) m / z: 358 [M+].
[0193]
Example 88:1- (4- Aminosulfonylphenyl ) -7- Fluoro -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 72) Synthesis of:
Compound V-71 (990 mg, 2.8 mmol) is dissolved in anhydrous THF (15 ml) and cooled with ice in an argon gas atmosphere with stirring and n-propylmagnesium chloride (1.5 ml, 3.0 mmol: 2.0 M ether solution). And stirred at room temperature for 0.5 hour. The reaction mixture was ice-cooled again, triethylboron (4.2 ml, 4.2 mmol: 1.0 M tetrahydropyran solution) was added, and the mixture was boiled and refluxed for 45 hours. The reaction mixture was ice-cooled, aqueous sodium acetate solution (2.10 g / 3.5 ml) and hydroxylamine-O-sulfonic acid (2.52 g, 22.3 mmol) were added with stirring, and the mixture was stirred at room temperature for 4 hr. Work-up and purification were conducted in the same manner as in Example 84, and recrystallization from n-hexane-chloroform gave the title compound (80 mg, yield 8%) as a colorless solid.1H-NMR (CDClThree): 2.11 (3H, s, CHThree), 5.26 (2H, s, CH2), 6.56 (1H, dd, J = 5, 9Hz, 9-H), 6.79 (1H, ddd, J = 3, 9, 9Hz, 8-H), 7.17 (1H, dd, J = 3, 9Hz, 6-H), 7.47 (2H, s, NH2), 7.55 (2H, d, J = 9Hz, aromatic), 7.91 (2H, d, J = 9Hz, aromatic). MS (EI-DI) m / z: 359 [M+].
[0194]
Production Example 34:7- Methylthio -2H-1,4- Benzoxazine -3 (4H)- Thion ( Compound VI b) Manufacturing of:
Compound Id (15.6 g, 80.0 mmol) was dissolved in dry THF (900 ml), Lawesson reagent (16.20 g, 40.0 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from ethanol to give the title compound (5.22 g, yield 95%) as colorless needle crystals.1H-NMR (CDClThree): 2.45 (3H, s, SCHThree), 4.85 (2H, s, CH2), 6.78 (1H, d, J = 8Hz, 5-H), 6.84 (1H, dd, J = 2, 8Hz, 6-H), 6.87 (1H, d, J = 2Hz, 8-H), 9.76 (1H, br-s, NH).
MS (EI-DI) m / z: 211 [M+].
[0195]
Production Example 35:7- Fluoro -2H- 1 ,Four- Benzoxazine -3 (4H)- Thion ( Compound VI c) Manufacturing of:
Compound Ie (5.01 g, 30.0 mmol) was dissolved in dry THF (350 ml), Lawesson reagent (6.06 g, 15.0 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethanol to give the title compound (14.98 g, yield 89%) as yellow needles.1H-NMR (CDClThree): 4.86 (2H, s, CH2), 6.65 to 6.76 (2H, m, 6, 8-H), 6.83 (1H, dd, J = 5, 9Hz, 5-H), 9.90 (1H, br, NH). MS (EI-DI) m / z: 183 [M+].
[0196]
Production Example 36:3, 7- Dimethylthio -2H-1,4- Benzoxazine ( Compound VII b) Manufacturing of:
Compound VIb (15.6 g, 73.8 mmol) was dissolved in dry THF (160 ml), NaH (2.13 g, 88.6 mmol) was added with stirring under ice-cooling, and the mixture was stirred for 0.5 hours, and then stirred at room temperature for 0.25 hours. Methyl chloride (21.0 g, 147.7 mmol) was added and stirred for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, chloroform was added to the residue, and the mixture was washed with water and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (15.03 g, yield 90%) as a pale yellow solid.1H-NMR (CDClThree): 2.45 (3H, s, SCHThree), 2.55 (3H, s, SCHThree), 4.47 (2H, s, CH2), 6.75 (1H, d, J = 2Hz, 8-H), 6.85 (1H, dd, J = 2, 8Hz, 6-H), 7.20 (1H, d, J = 8Hz, 5-H). (EI-DI) m / z: 225 [M+].
[0197]
Production Example 37:7- Fluoro -3- Methylthio -2H-1,4- Benzoxazine ( Compound VII c) Manufacturing of:
Compound VIc (4.58 g, 25.0 mmol) was dissolved in dry THF (60 ml), and NaH (0.72 g, 30.0 mmol) was added with stirring under ice cooling, followed by stirring for 0.5 hours. Subsequently, methyl iodide (7.10 g, 50.0 mmol) was added after stirring at room temperature for 0.25 hour, and stirred for 1.5 hours. Post-treatment and purification were conducted in the same manner as in Production Example 36 to obtain the title compound (4.62 g, yield 94%) as a yellow solid.1H-NMR (CDClThree): 2.52 (3H, s, SCHThree), 4.47 (2H, s, CH2), 6.59 (1H, dd, J = 3, 9Hz, 8-H), 6.67 (1H, ddd, J = 3, 9, 9Hz, 6-H), 7.21 (1H, dd, J = 6, 9Hz, 5-H).
MS (EI-DI) m / z: 197 [M+].
[0198]
Production Example 38:3- (2,2- Dimethoxyethylamino ) -7- Methylthio -2H-1,4- Benzoo Xazine ( Compound VIII b) Manufacturing of:
Compound VIIb (14.0 g, 62.1 mmol) was dissolved in dry acetonitrile (70 ml), aminoacetaldehyde dimethyl acetal (13.06 g, 105.1 mmol) was added, and the mixture was boiled and refluxed for 5 days. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound quantitatively as a tan viscous oil.1H-NMR (CDClThree): 2.40 (3H, s, SCHThree), 3.38 (6H, s, OCHThree× 2), 3.57 (2H, d, J = 5Hz, CH2), 4.35 (2H, s, CH2), 4.49 (1H, t, J = 5Hz, CH), 6.76 (1H, d, J = 2Hz, 8-H), 6.83 (1H, dd, J = 2, 8Hz, 6-H), 6.99 (1H , d, J = 8Hz, 5-H) .MS (EI-DI) m / z: 282 [M+].
[0199]
Production Example 39:3- (2,2- Dimethoxyethylamino ) -7- Fluoro -2H-1,4- Benzoxazine ( Compound VIII c) Manufacturing of:
Compound VIIc (1.97 g, 10.0 mmol) was dissolved in dry acetonitrile (10 ml), aminoacetaldehyde dimethyl acetal (2.10 g, 20.0 mmol) was added, and the mixture was boiled and refluxed for 3 days. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound quantitatively as a yellow viscous oil.1H-NMR (CDClThree): 3.42 (6H, s, OCHThree× 2), 3.60 (2H, d, J = 5Hz, CH2), 4.39 (2H, s, CH2), 4.52 (1H, t, J = 5Hz, CH), 6.58 (1H, dd, J = 3, 9Hz, 8-H), 6.63 (1H, ddd, J = 3, 9, 9Hz, 6-H) , 7.02 (1H, dd, J = 6, 9Hz, 5-H). MS (EI-DI) m / z: 254 [M+].
[0200]
Production Example 40:7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound III h) Manufacturing of:
Compound VIIIb (17.0 g, 60.2 mmol) was added to 1 N hydrochloric acid (900 ml), and the mixture was boiled and refluxed for 1.5 hours. A 2N aqueous sodium hydroxide solution (500 ml) was added to the reaction mixture with stirring under ice cooling, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was recrystallized from n-hexane-chloroform to give the title compound (12.4 g, yield 94) as a colorless solid. %).1H-NMR (CDClThree): 2.47 (3H, s, SCHThree), 5.25 (2H, s, CH2), 6.93 (1H, dd, J = 2, 8Hz, 8-H), 6.97 (1H, d, J = 2Hz, 6-H), 7.16 (1H, d, J = 2Hz), 7.18 (1H, d , J = 8Hz, 9-H), 7.32 (1H, d, J = 2Hz). MS (EI-DI) m / z: 218 [M+].
[0201]
Production Example 41:7- Fluoro -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound III i) Manufacturing of:
Compound VIIIc (2.30 g, 9.1 mmol) was added to 1 N hydrochloric acid (120 ml), and the mixture was boiled and refluxed for 1.5 hours. 2N sodium hydroxide (65 ml) was added to the reaction mixture with stirring under ice cooling, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was recrystallized from n-hexane-chloroform to give the title compound (1.54 g, yield 90) as a colorless solid. %).1H-NMR (CDClThree): 5.35 (2H, s, CH2), 6.81 (1H, dd, J = 3, 8, 9Hz, 8-H), 6.86 (1H, dd, J = 3, 9Hz, 6-H), 7.26 (1H, dd, J = 5, 9Hz, 9-H), 7.32 (1H, d, J = 2Hz), 7.36 (1H, d, J = 2Hz). MS (EI-DI) m / z: 190 [M+].
[0202]
Production Example 42:1- Bromo -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound IV i) Manufacturing of:
Compound IIIh (1.00 g, 4.6 mmol) was dissolved in acetic acid (10 ml), NBS (856 mg, 4.8 mmol) was added while stirring in a water bath, and the mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (170 mg, yield 13%) as a yellow solid.1H-NMR (CDClThree): 2.48 (3H, s, SCHThree), 5.12 (2H, s, CH2), 6.97 (1H, dd, J = 2, 9Hz, 8-H), 7.00 (1H, d, J = 2Hz, 6-H), 7.10 (1H, s, 2-H), 8.09 (1H, d , J = 9Hz, 9-H). MS (EI-DI) m / z: 296 [M+], 298 [M++2].
[0203]
Production Example 43:1- Bromo -7- Fluoro -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound IV j) Manufacturing of:
Compound IIIi (860 mg, 4.5 mmol) was dissolved in acetic acid (10 ml), NBS (845 mg, 4.8 mmol) was added while stirring in a water bath, and the mixture was stirred for 1 hour. Post-treatment and purification were conducted in the same manner as in Production Example 42 to obtain the title compound (260 mg, yield 21%) as a yellow solid.1H-NMR (CDClThree): 5.12 (2H, s, CH2), 6.81 (1H, ddd, J = 3, 8, 9Hz, 8-H), 6.86 (1H, dd, J = 3, 9Hz, 6-H), 7.09 (1H, s, 2-H), 8.15 (1H, dd, J = 5, 9Hz, 9-H).13C-NMR (CDClThree): 64.63, 98.53, 106.29 (d, J = 26Hz), 109.44 (d, J = 23Hz), 118.30 (d, J = 9Hz), 121.90, 131.30, 141.43, 148.28 (d, J = 13Hz), 160.81 ( d, J = 246Hz) .MS (EI-DI) m / z: 268 [M+], 270 [M++2].
[0204]
Example 89:1- (4- Fluorophenyl ) -7- Methylthio -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 73) Synthesis of:
Compound IVi (140 mg, 0.5 mmol) and 4-fluorophenylboric acid (79 mg, 0.6 mmol) were dissolved in a toluene (1.5 ml) -ethanol (1.5 ml) mixture, and 2 M aqueous sodium carbonate solution (1.5 ml) and Pd (PPhThree)Four(37 mg, 0.03 mmol) was added, and the mixture was boiled and refluxed for 3 hours with vigorous stirring under an argon gas atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (130 mg, yield 90%) as a pale yellow solid.1H-NMR (CDClThree): 2.43 (3H, s, CHThree), 5.18 (2H, s, CH2), 6.65-6.69 (2H, m), 7.00 (1H, m), 7.03 (1H, s, 2-H), 7.11 (2H, dd, J = 9, 9Hz, aromatic 3, 5-H), 7.35 (2H, dd, J = 5, 9Hz, aromatic 2, 6-H). MS (EI-DI) m / z: 312 [M+].
[0205]
Reference Example 8:Production of 4-methylsulfonylphenyl boric acid:
  4-methylthiophenyl borate (1.50 g, 8.93 mmol) in sodium hydroxide (0.75 g, 18.8 mmol) in water (50 ml), ice-cooled potassium permanganate (2.96 g, 18.8 mmol) in water (50 ml) Was added dropwise and stirred at room temperature for 1 hour. Ethanol (5 to 10 ml) was added to decompose the unreacted permanganate, and then the manganese dioxide precipitate was separated by suction filtration. Concentrated hydrochloric acid is added to the filtrate, and the precipitated crystals are removed by suction filtration.RCollected and recrystallized from water to give the title compound (1.56 g, 87% yield).1H-NMR (DMSO-d6) δ (ppm): 3.18 (3H, s, CHThree), 7.86 to 7.88 (2H, d, J = 8Hz), 7.99 to 8.01 (2H, d, J = 8Hz), 8.30 (2H, s, OH × 2) .EI-MS (m / z): 200 ( M+).
[0206]
Production Example 44:7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound III j) Manufacturing of:
Compound IIIh (5.00 g, 22.9 mmol) was dissolved in methylene chloride (50 ml), mCPBA (9.50 g, 55.1 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with methylene chloride, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was crystallized from n-hexane-methylene chloride to give the title compound (5.40 g, yield 94%) as a colorless solid. mp.223-226 ° C (dec.).1H-NMR (CDClThree): 3.06 (3H, s, SO2CHThree), 5.35 (2H, s, OCH2), 7.23 (1H, s,), 7.40 (1H, s), 7.44 (1H, d, J = 9Hz, 8-H), 7.64-7.69 (2H, m). MS (EI-DI) m / z : 250 [M+].
[0207]
Production Example 45:1- Bromo -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound IV k) Manufacturing of:
Compound IIIj (5.20 g, 20.78 mmol) was suspended in acetonitrile (520 ml), NBS (4.07 g, 22.87 mmol) was added, and the mixture was stirred with heating at 50 ° C. for 2 hr. The reaction mixture was concentrated to dryness under reduced pressure, chloroform was added to the residue, insolubles were filtered off, and washed with chloroform. The filtrate was combined and washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-containing chloroform) to give the title compound (3.95 g, yield 58%) as a pale yellow solid. mp.167-169 ° C (dec.).1H-NMR (CDClThree): 3.07 (3H, s, SO2CHThree), 5.21 (2H, s, OCH2), 7.16 (1H, s, 2-H), 7.68-7.74 (2H, m), 8.40 (1H, d, J = 9Hz, 8-H) .MS (EI-DI) m / z: 328 [M+], 330 [M++2].
[0208]
Example 901- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 74) Synthesis of:
Compound IVk (3.95 g, 12.00 mmol), 4-methoxyphenyl boric acid (2.19 g, 14.40 mmol) and Pd (PPhThree)FourToluene (40 ml), ethanol (40 ml) and 2 M aqueous sodium carbonate solution (40 ml) were added to a mixture of (947 mg, 0.82 mmol), and the mixture was boiled and refluxed with vigorous stirring for 3 hours under an argon gas atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, chloroform was added to the residue, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-n-hexane mixture (3: 1) and chloroform containing 0.5% methanol) to obtain the title compound (4.16 g, yield 97%) (recrystallized from ethanol). Colorless needle-like crystals). mp.193-195 ° C.1H-NMR (CDClThree): 3.03 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.27 (2H, s, OCH2), 6.97 (2H, d, J = 9Hz), 6.98 (1H, d, J = 9Hz, 9-H), 7.05 (1H, s, 2-H), 7.28 (2H, d, J = 9Hz), 7.37 (1H, dd, J = 2, 9Hz, 8-H), 7.67 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 356 [M+].
[0209]
Example 91:2- Chloro -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 75) Synthesis of:
Compound V-74 (100 mg, 0.28 mmol) was dissolved in acetic acid (4 ml), NCS (39 mg, 0.29 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-n-hexane mixture (4: 1) and then 2% methanol-containing chloroform) to obtain the title compound (60 mg, yield 55%) as a colorless solid. mp.217-219 ° C (dec.).1H-NMR (CDClThree): 3.02 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.23 (2H, s, OCH2), 6.86 (1H, d, J = 9Hz, 9-H), 7.01 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.36 (1H, dd, J = 2, 9Hz) , 8-H), 7.66 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 390 [M+].
[0210]
Example 92:2- Bromo -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 76) Synthesis of:
Compound V-74 (600 mg, 1.68 mmol) was dissolved in acetic acid (18 ml), NBS (315 mg, 1.77 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform, washed with 1N aqueous sodium hydroxide solution (310 ml) and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was crystallized from n-hexane-chloroform to give the title compound (705 mg, yield 96%) as a pale yellow solid. mp.243-244 ° C (dec.).1H-NMR (CDClThree): 3.02 (3H, s, SO2CHThree), 3.88 (3H, s, OCHThree), 5.24 (2H, s, OCH2), 6.83 (1H, d, J = 9Hz, 9-H), 7.01 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.35 (1H, dd, J = 2, 9Hz) , 8-H), 7.66 (1H, d, J = 2Hz, 6-H). IR (KBr): 1495, 1420, 1315, 1300cm-1MS (EI-DI) m / z: 434 [M+], 436 [M++2].
[0211]
Example 931- (4- Methoxyphenyl ) -7- Methylsulfonyl -2- Trifluoromethyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 77) Synthesis of:
Compound V-76 (700 mg, 1.61 mmol) was dissolved in DMA (14 ml), sodium trifluoroacetate (876 mg, 6.44 mmol) and copper (I) iodide (590 mg, 3.10 mmol) were added, and 5.5. Refluxed at the boil for hours. Chloroform (20 ml) and 1.5 N hydrochloric acid (20 ml) were added to the reaction mixture for liquid separation, and the aqueous layer was further extracted with chloroform. The organic layers were combined, insolubles were filtered off using a celite pad, and the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-n-hexane mixture (3: 2) and then 2% methanol-containing chloroform) and crystallized from n-hexane-chloroform to give the title compound as a colorless solid (200 mg, yield). Rate 29%). mp.188-190 ° C.1H-NMR (CDClThree): 3.01 (3H, s, SO2CHThree), 3.89 (3H, s, OCHThree), 5.29 (2H, s, OCH2), 6.70 (1H, d, J = 9Hz, 9-H), 7.01 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.33 (1H, dd, J = 2, 9Hz) , 8-H), 7.68 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 424 [M+].
[0212]
Example 942- Cyano -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 78) Synthesis of:
Compound V-76 (210 mg, 0.48 mmol) was dissolved in DMF (0.5 ml), copper (I) cyanide (52 mg, 0.58 mmol) was added, and the mixture was stirred at 170 ° C. for 2 hours under an argon gas atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration using a celite pad. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-n-hexane mixture [3: 1]) and crystallized from n-hexane-chloroform to give the title compound (50 mg, 27% yield) as a colorless solid. It was. mp.226-228 ° C.1H-NMR (CDClThree): 3.04 (3H, s, SO2CHThree), 3.89 (3H, s, OCHThree), 5.26 (2H, s, OCH2), 7.00 (1H, d, J = 9Hz, 9-H), 7.05 (2H, d, J = 9Hz), 7.37 (2H, d, J = 9Hz), 7.42 (1H, dd, J = 2, 9Hz) , 8-H), 7.73 (1H, d, J = 2Hz, 6-H). IR (KBr): 2220, 1500, 1400, 1315, 1300cm-1.MS (EI-DI) m / z: 381 [M+].
[0213]
Example 95:1- (4- Methoxyphenyl ) -7- Methylsulfonyl -2- Nitro -4H- Imidazo [2,1-c] [1,4] Benzoxazine ( Compound V- 79) Synthesis of:
Compound V-74 (200 mg, 0.56 mmol) was dissolved in acetic anhydride (4 ml), nitric acid (d = 1.52, 48 μl, 1.16 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-n-hexane mixture (7: 3), then 5% methanol-containing chloroform) and crystallized from n-hexane-chloroform. The title compound (60 mg, 27% yield) was obtained as a pale yellow solid. mp.250-252 ° C (dec.).1H-NMR (CDClThree): 3.02 (3H, s, SO2CHThree), 3.90 (3H, s, OCHThree), 5.29 (2H, s, OCH2), 6.72 (1H, d, J = 9Hz, 9-H), 7.06 (2H, d, J = 9Hz), 7.36 (2H, d, J = 9Hz), 7.37 (1H, dd, J = 2, 9Hz) , 8-H), 7.72 (1H, d, J = 2Hz, 6-H). IR (KBr): 1515, 1395, 1315, 1300cm-1MS (EI-DI) m / z: 401 [M+].
[0214]
Production Example 46:3- Ethoxycarbonyl -7- Methylthio -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound IX c) Manufacturing of:
Compound Id (5.50 g, 28.17 mmol) was dissolved in dry DMF (80 ml), and potassium tert-butoxide (3.35 g, 29.86 mmol) was added with ice cooling under an argon gas atmosphere, followed by stirring for 15 minutes. To this reaction mixture was added diethyl chlorophosphate (8.75 g, 50.71 mmol), and the mixture was stirred for 10 minutes, and then a solution of ethyl isocyanoacetate (4.56 g, 40.28 mmol) in dry DMF (40 ml) and potassium tert-butoxide (4.43 g, 39.45). mmol) was added and stirred for 15 minutes, then at room temperature for 22 hours. Acetic acid (5.5 ml) was added dropwise to the reaction mixture while stirring under ice-cooling, and the mixture was added to ice water (1000 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain the crude title compound as a brown solid. This was used in the next reaction without purification.
A portion was purified by silica gel column chromatography (chloroform) and crystallized from n-hexane-ethanol to give the title compound as a pale yellow powder. mp.162-164 ° C.1H-NMR (CDClThree): 1.40 (3H, t, J = 7Hz, CO2CH2CH Three ), 2.48 (3H, s, SCHThree), 4.39 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.50 (2H, s, OCH2), 6.95 (1H, dd, J = 2, 8Hz, 8-H), 6.98 (1H, d, J = 2Hz, 6-H), 7.37 (1H, d, J = 8Hz, 9-H), 8.01 (1H, s, 1-H). IR (KBr): 1715, 1595, 1515, 1285, 1165cm-1MS (EI-DI) m / z: 290 [M+].
[0215]
Production Example 47:7- Methylsulfonyl -2H-1,4- Benzoxazine -3 (4H)- on ( Compound I f) Manufacturing of:
Compound Id (6.00 g, 30.73 mmol) was suspended in methylene chloride (150 ml), mCPBA (11.67 g, 67.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride and suspended in water, and a 7% aqueous sodium bicarbonate solution was added until stirring until it no longer foamed. The insoluble material was collected by filtration, washed with water and ether, and dried to give a colorless solid. To give the title compound (6.77 g, yield 97%). mp.273-276 ° C (dec.).1H-NMR (DMSO-d6): 3.16 (3H, s, SO2CHThree), 4.68 (2H, s, OCH2), 7.06 (1H, d, J = 8Hz, 5-H), 7.43 (1H, d, J = 2Hz, 8-H), 7.49 (1H, dd, J = 2, 8Hz, 6-H), 11.13 (1H, br-s). MS (EI-DI) m / z: 227 [M+].
[0216]
Production Example 48:3- Ethoxycarbonyl -7- Methylsulfinyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound IX d) Manufacturing of:
Compound IXc (100 mg, 0.34 mmol) was dissolved in acetic acid (3 ml), NBS (67 mg, 0.38 mmol) was added, and the mixture was heated and stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, washed with water, 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (2 → 5% methanol-containing chloroform) to give the title compound (100 mg, yield 85%) as a colorless solid. mp.157-166 ° C.1H-NMR (CDClThree): 1.40 (3H, t, J = 7Hz, CO2CH2CH Three ), 2.74 (3H, s, SOCHThree), 4.39 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.57 (2H, s, OCH2), 7.37 (1H, dd, J = 2, 8Hz, 8-H), 7.41 (1H, d, J = 2Hz, 6-H), 7.63 (1H, d, J = 8Hz, 9-H), 8.06 (1H, s, 1-H) .MS (EI-DI) m / z: 306 [M+].
[0217]
Production Example 49:3- Ethoxycarbonyl -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound IX e) Manufacturing of:
[Method A] Crude compound IXc (Production Example 46) (28.17 mmol) was dissolved in methylene chloride (100 ml), mCPBA (10.69 g, 61.95 mmol) was added with stirring under ice-cooling, and 3 hours at room temperature. Stir. The precipitate was removed by filtration (Compound If: 2.20 g), washed with methylene chloride, and the combined filtrate was washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. Concentrated to dryness. The residue was purified by silica gel column chromatography (2% methanol-containing chloroform) and crystallized from n-hexane-ethanol to give the title compound (4.02 g, yield 44.3%) as a pale yellow solid. mp.198-201 ° C.1H-NMR (CDClThree): 1.41 (3H, t, J = 7Hz, CO2CH2CH Three ), 3.07 (3H, s, SO2CHThree), 4.40 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.60 (2H, s, OCH2), 7.61-7.72 (3H, m), 8.06 (1H, s, 1-H). MS (EI-DI) m / z: 322 [M+].
[0218]
[Method B] Compound If (5.00 g, 22.00 mmol) was dissolved in dry DMF (100 ml), and potassium tert-butoxide (2.62 g, 23.32 mmol) was added with ice cooling under an argon gas atmosphere, followed by stirring for 20 minutes. . To this reaction mixture was added diethyl chlorophosphate (6.83 g, 39.60 mmol), and the mixture was stirred for 5 minutes, and then a solution of ethyl isocyanoacetate (3.56 g, 31.46 mmol) in dry DMF (50 ml) and potassium tert-butoxide (3.48 g, 31.02). mmol) was added and stirred for 15 minutes, then at room temperature for 20 hours. Acetic acid (5 ml) was added dropwise to the reaction mixture, which was added to ice water (60 ml) and stirred for 1.5 hours. The precipitate was collected by filtration using a celite pad, washed with water and eluted with a chloroform-methanol mixture. The eluate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with chloroform and dried under reduced pressure to prepare a raw material If (720 mg , 14%). The chloroform washing solution was combined with the above concentrated dry solid and purified by silica gel column chromatography (chloroform containing 1 → 2% methanol) and crystallized from n-hexane-chloroform to give the title compound (1.63 g, Yield 23%) was obtained.
[0219]
[Method C] Compound IXd (80 mg, 0.26 mmol) was dissolved in methylene chloride (2 ml), mCPBA (50 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with methylene chloride, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was crystallized from n-hexane-chloroform to obtain the title compound (59 mg, yield 70%) as a colorless solid.
[0220]
Production Example 50:1- Bromo -3- Ethoxycarbonyl -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound X c) Manufacturing of:
Compound IXe (2.00 g, 6.20 mmol) was dissolved in acetonitrile (200 ml), NBS (2.43 g, 13.65 mmol) was added, and the mixture was boiled and refluxed for 2 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with 7% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-containing chloroform) to give the title compound (1.32 g, yield 53%) as a pale yellow solid.1H-NMR (CDClThree): 1.40 (3H, t, J = 7Hz, CO2CH2CH Three ), 3.08 (3H, s, SO2CHThree), 4.41 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.49 (2H, s, OCH2), 7.70-7.77 (2H, m), 8.50 (1H, d, J = 9Hz, 9-H) .MS (EI-DI) m / z: 400, 402 [M+].
[0221]
Example 96:3- Ethoxycarbonyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 19) Synthesis of:
Compound Xc (1.32 g, 3.29 mmol), 4-methoxyphenyl boric acid (0.60 g, 3.95 mmol) and Pd (PPhThree)FourTo a mixture of (260 mg, 0.22 mmol), toluene (15 ml), ethanol (15 ml) and 2M aqueous sodium carbonate solution (15 ml) were added, and the mixture was boiled and refluxed with vigorous stirring for 3 hours under an argon gas atmosphere. The reaction mixture was cooled, and chloroform and water were added thereto for liquid separation. The chloroform layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-n-hexane mixture (3: 1) then 1% methanol-containing chloroform) to give the title compound (842 mg, yield 60%) (recrystallized from ethanol). Colorless needles). mp.204.5-206.5 ° C.1H-NMR (CDClThree): 1.40 (3H, t, J = 7Hz, CO2CH2CH Three ), 3.05 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 4.42 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.54 (2H, s, OCH2), 6.97 (2H, d, J = 9Hz), 7.10 (1H, d, J = 9Hz, 9-H), 7.39 (1H, dd, J = 2, 9Hz, 8-H), 7.46 (2H, d , J = 9Hz), 7.71 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 428 [M+].
[0222]
Example 973- Carboxy -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 20) Synthesis of:
Compound XI-19 (300 mg, 0.70 mmol) was suspended in methanol (5 ml), 1 N sodium hydroxide (5 ml, 5.0 mmol) was added, and the mixture was boiled and refluxed for 1 hour with stirring. The reaction mixture was concentrated to dryness under reduced pressure, water and acetic acid were added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure, and the residue was recrystallized from n-hexane-chloroform to obtain the title compound (266 mg, yield 95%) as a colorless solid. mp.251-252 ° C (dec.).1H-NMR (DMSO-d6): 3.24 (3H, s, SO2CHThree), 3.84 (3H, s, OCHThree), 5.55 (2H, s, OCH2), 7.40 ~ 7.12 (3H, m), 7.47 (1H, dd, J = 2, 9Hz, 8-H), 7.51 (2H, d, J = 9Hz), 7.73 (1H, d, J = 2Hz, 6 -H), 12.91 (1H, br, CO2H). MS (EI-DI) m / z: 400 [M+].
[0223]
Example 98:1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- twenty one) Synthesis of:
Quinoline (2.5 ml) was added to a mixture of compound XI-20 (250 mg, 0.62 mmol) and copper powder (44 mg, 0.69 mmol), and the mixture was stirred at 220 to 225 ° C for 1 hour. Ethyl acetate was added to the reaction mixture, the insoluble material was removed by filtration, the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform followed by chloroform containing 0.5% methanol) and crystallized from ether-chloroform to obtain the title compound (112 mg, yield 50%) as a pale yellow solid. mp.137-144 ° C.1H-NMR (CDClThree): 3.04 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.21 (2H, s, OCH2), 6.98 (2H, d, J = 9Hz), 7.08 (1H, s, 3-H), 7.17 (1H, d, J = 9Hz, 9-H), 7.39 (1H, dd, J = 2, 9Hz) , 8-H), 7.46 (2H, d, J = 9Hz), 7.70 (1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 356 [M+].
[0224]
Example 99:3- Chloro -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- twenty two) Synthesis of:
NCS (29 mg, 0.22 mmol) was added to a solution of compound XI-21 (70 mg, 0.20 mmol) in acetonitrile (7 ml), and the mixture was stirred for 19 hours under boiling reflux. The reaction mixture was dried under reduced pressure, the residue was dissolved in chloroform, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol) and crystallized from n-hexane-chloroform to obtain the title compound (28 mg, yield 36%) as a colorless powder. mp.212-214 ° C.1H-NMR (CDClThree) δ: 3.04 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.17 (2H, s, OCH2), 6.97 (2H, d, J = 9Hz), 7.15 (1H, d, J = 9Hz, 9-H), 7.39 (1H, dd, J = 2, 9Hz, 8-H), 7.44 (2H, d , J = 9Hz), 7.70 (1H, d, J = 2Hz, 6-H) .EI-MS m / z: 390 (M+).
[0225]
Example 100:3- Bromo -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- twenty three) Synthesis of:
Compound XI-21 (40 mg, 0.11 mmol) was dissolved in acetonitrile (4 ml), NBS (30 mg, 0.17 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-n-hexane mixture [2: 1]) to give the title compound as a pale yellow powder (25 mg, 51% yield). ) mp.198-200 ° C (dec.).1H-NMR (CDClThree): 3.04 (3H, s, SO2CHThree), 3.86 (3H, s, OCHThree), 5.41 (2H, s, OCH2), 6.96 (2H, d, J = 9Hz), 7.14 (1H, d, J = 9Hz, 9-H), 7.39 (1H, dd, J = 2, 9Hz, 8-H), 7.43 (2H, d , J = 9Hz), 7.70 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 434, 436 [M+].
[0226]
Example 101:Synthesis of 1- (4-methoxyphenyl) -7-methylsulfonyl-3-trifluoromethyl-4H-imidazo [5,1-c] [1,4] benzoxazine (Compound XI-24):
  Compound XI-23 (300 mg, 0.69 mmol), sodium trifluoroacetate (362 mg, 2.66 mmol) and copper (I) iodide (240 mg, 1.26 mmol) were added to DMA (6 ml), and boiled under reflux. Stir for 6 hours. The reaction mixture was dried under reduced pressure, chloroform was added to the residue, and the insoluble material was filtered off using a celite pad. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol)LivingOf the title compound (96 mg). The crude product was then purified by reverse phase HPLC and the desired fractions were combined and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and sodium chloride were added to the concentrate, and the mixture was extracted 3 times with chloroform, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from petroleum ether-chloroform to give the title compound (62 mg, yield 21%) as colorless needle crystals. mp 224-226 ° C. [HPLC operating conditions] Equipment: Waters Delta Prep 4000, mobile phase: 0.01M potassium dihydrogen phosphate-acetonitrile (1: 1), flow rate: 30 ml / min., detector: UV (254 nm).1H-NMR (CDClThree) δ: 3.05 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.32 (2H, d, J = 1Hz, OCH2), 6.98 (2H, d, J = 9Hz), 7.15 (1H, d, J = 9Hz, 9-H), 7.42 (1H, dd, J = 2, 9Hz, 8-H), 7.46 (2H, d , J = 9Hz), 7.73 (1H, d, J = 2Hz, 6-H) .EI-MS m / z: 424 (M+).
[0227]
Example 102:3- Hydroxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- twenty five) Synthesis of:
Compound XI-19 (100 mg, 0.23 mmol) was dissolved in THF (10 ml), lithium aluminum hydride (20 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture to decompose excess lithium aluminum hydride, and the mixture was concentrated to dryness under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is separated, and solids insoluble in both layers are filtered off using a celite pad. The ethyl acetate layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. Concentrated to dryness. The residue was purified by silica gel column chromatography (chloroform containing 3% methanol) and crystallized from n-hexane-chloroform to obtain the title compound (61 mg, yield 68%) as a colorless solid. mp.204-207 ° C (dec.).1H-NMR (CDClThree): 2.29 (1H, br, OH), 3.04 (3H, s, SO2CHThree), 3.86 (3H, s, OCHThree), 4.70 (2H, s, CH 2 OH), 5.26 (2H, s, OCH2), 6.97 (2H, d, J = 9Hz), 7.12 (1H, d, J = 9Hz, 9-H), 7.37 (1H, dd, J = 2, 9Hz, 8-H), 7.42 (2H, d , J = 9Hz), 7.68 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 386 [M+].
[0228]
Example 103:3- Fluoromethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 26) Synthesis of:
Compound XI-25 (60 mg, 0.16 mmol) was suspended in dry methylene chloride (12 ml), DAST reagent (31 μl, 0.24 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0.5% methanol-containing chloroform) and crystallized from n-hexane-chloroform to obtain the title compound (40 mg, yield 68%) as a colorless solid. mp.223-226 ° C (dec.).1H-NMR (CDClThree): 3.05 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 5.27 (2H, d, J = 1Hz, OCH2), 5.43 (2H, d, J = 49Hz, CH 2 F), 6.97 (2H, d, J = 9Hz), 7.14 (1H, d, J = 9Hz, 9-H), 7.39 (1H, dd, J = 2, 9Hz, 8-H), 7.44 (2H, d, J = 9Hz), 7.70 (1H, d, J = 2Hz, 6-H). MS (EI-DI) m / z: 388 [M+].
[0229]
Example 104:3- Formyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 27) Synthesis of:
Dess-Martin Periodinan (580 mg, 1.37 mmol) was added to a suspension of compound XI-25 (350 mg, 0.91 mmol) in methylene chloride (100 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1 N sodium hydroxide, and the mixture was separated. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (320 mg, yield 92%). Recrystallized from n-hexane-chloroform to give a colorless solid. mp.248 ~ 250.5 ° C.1H-NMR (CDClThree) δ: 3.07 (3H, s), 3.91 (3H, s), 5.56 (2H, s), 7.03 (2H, d, J = 9Hz), 7.17 (1H, d, J = 9Hz), 7.43 (1H, dd, J = 2, 9Hz), 7.49 (2H, d, J = 9Hz), 7.74 (1H, d, J = 2Hz), 10.03 (1H, s) .EI-MS m / z: 384 (M+).
[0230]
Example 105:3- Difluoromethyl -1- (4- Methoxyphenyl ) -7- Methylsulfo Nil -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 28) Synthesis of:
DAST reagent (160 μl, 1.25 mmol) was added to a suspension of compound XI-27 (160 mg, 0.42 mmol) in dry methylene chloride (10 ml), and the mixture was stirred at room temperature for 46 hours. The reaction mixture was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane-chloroform, 3: 2) to give the title compound (80 mg, 47% yield) as a colorless solid (n-hexane-chloroform). mp.177-178 ° C.1H-NMR (CDClThree) δ: 3.05 (3H, s), 3.87 (3H, s), 5.34 (2H, t, J = 2Hz), 6.76 (1H, t, J = 56Hz), 6.98 (2H, d, J = 9Hz), 7.14 (1H, d, J = 9Hz), 7.40 (1H, dd, J = 2, 9Hz), 7.44 (2H, d, J = 9Hz), 7.71 (1H, d, J = 2Hz). EI-MS m / z: 406 (M+).
[0231]
Example 106:3- Cyano -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 29) Synthesis of:
Anhydrous pyridine (2.3 ml) was added to a suspension of compound XI-27 (200 mg, 0.52 mmol) and hydroxylamine-O-sulfonic acid (118 mg, 1.04 mmol) in anhydrous methanol (25 ml). Stir for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the title compound (151 mg, yield 76%). Recrystallized from n-hexane-chloroform to give a colorless solid. mp.230-231 ° C.1H-NMR (CDClThree) δ: 3.06 (3H, s), 3.88 (3H, s), 5.33 (2H, s), 7.00 (2H, d, J = 9Hz), 7.17 (1H, d, J = 9Hz), 7.41-7.46 ( 3H, m), 7.75 (1H, d, J = 2Hz) .EI-MS m / z: 381 (M+).
[0232]
Example 107:3- Methoxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 30) Synthesis of:
To a solution of compound XI-25 (100 mg, 0.26 mmol) in dry DMF (3 ml) was added NaH (13 mg, 0.52 mmol), stirred at room temperature for 5 minutes, and then methyl iodide (111 mg, 0.78 mmol) was added. And stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol) and recrystallized from n-hexane-chloroform to obtain the title compound (44 mg, yield 42%) as colorless needle crystals. mp.185-186 ° C.1H-NMR (CDClThree) δ: 3.04 (3H, s), 3.45 (3H, s), 3.86 (3H, s), 4.50 (2H, s), 5.25 (2H, s), 6.96 (2H, d, J = 9Hz), 7.12 (1H, d, J = 9Hz), 7.36 (1H, dd, J = 2, 9Hz), 7.43 (2H, d, J = 9Hz), 7.68 (1H, d, J = 2Hz). EI-MS m / z: 400 (M+).
[0233]
Example 108:3- Ethoxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 31) Synthesis of:
According to the synthesis method of Example 107, the title compound (57 mg, yield 53%) was obtained from Compound XI-25 (100 mg, 0.26 mmol) and ethyl iodide (122 mg, 0.78 mmol). Colorless powder (petroleum ether-chloroform). Mp 139-141 ° C.1H-NMR (CDClThree) δ: 1.25 (3H, t, J = 7Hz), 3.04 (3H, s), 3.62 (2H, q, J = 7Hz), 3.86 (3H, s), 4.55 (2H, s), 5.27 (2H, s), 6.95 (2H, d, J = 9Hz), 7.11 (1H, d, J = 9Hz), 7.36 (1H, dd, J = 2, 9Hz), 7.42 (2H, d, J = 9Hz), 7.67 (1H, d, J = 2Hz). EI-MS m / z: 414 (M+).
[0234]
Example 109:3- Benzyloxymethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 32) Synthesis of:
According to the synthesis method of Example 107, the title compound (62 mg, yield 40%) was obtained from Compound XI-25 (130 mg, 0.34 mmol) and benzyl bromide (174 mg, 1.02 mmol). Colorless needles (petroleum ether-chloroform). mp.175-177.5 ° C.1H-NMR (CDClThree) δ: 3.04 (3H, s), 3.86 (3H, s), 4.61 (2H, s), 4.64 (2H, s), 5.22 (2H, s), 6.96 (2H, d, J = 9Hz), 7.11 (1H, d, J = 9Hz), 7.21 ~ 7.40 (6H, m), 7.43 (2H, d, J = 9Hz), 7.66 (1H, d, J = 2Hz) .EI-MS m / z: 476 ( M+).
[0235]
Example 110:3- (4- Methoxybenzyloxymethyl ) -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 33) Synthesis of:
According to the synthesis method of Example 107, the title compound (79 mg, 60% yield) was obtained from Compound XI-25 (100 mg, 0.26 mmol) and 4-methoxybenzyl chloride (122 mg, 0.78 mmol). Colorless powder (petroleum ether-chloroform). Mp 211-213 ° C.1H-NMR (CDClThree) δ: 3.04 (3H, s), 3.79 (3H, s), 3.86 (3H, s), 4.56 (2H, s), 4.58 (2H, s), 5.21 (2H, s), 6.88 (2H, d , J = 9Hz), 6.96 (2H, d, J = 9Hz), 7.11 (1H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.36 (1H, dd, J = 2, 9Hz ), 7.43 (2H, d, J = 9Hz), 7.66 (1H, d, J = 2Hz) .EI-MS m / z: 370 (M+−136).
[0236]
Example 111:3- Chloromethyl -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 34) as well as 1- (4- Methoxyphenyl ) -7- Methylsulfonyl -3- Phenoxymethyl -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 35) Synthesis of:
Thionyl chloride (93 mg, 0.78 mmol) was added to a dry chloroform (5 ml) suspension of compound XI-25 (150 mg, 0.39 mmol), and the mixture was stirred for 1 hour under boiling reflux. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in dry DMF (4 ml), and this was dissolved in a solution of phenol (73 mg, 0.78 mmol) in dry DMF (2 ml) with NaH (14 mg, 0.59 mmol) and added to the stirred mixture at room temperature for 10 minutes. The mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform), compound XI-35 (105 mg, yield 58%, recrystallized from petroleum ether-chloroform) as a colorless powder and compound XI-34 (27 mg as a colorless powder). , Yield 17%, recrystallized from petroleum ether-chloroform). Compound XI-34: mp.218-224 ° C.1H-NMR (CDClThree) δ: 3.05 (3H, s), 3.87 (3H, s), 4.64 (2H, s), 5.26 (2H, s), 6.97 (2H, d, J = 9Hz), 7.13 (1H, d, J = 9Hz), 7.39 (1H, dd, J = 2, 9Hz), 7.44 (2H, d, J = 9Hz), 7.70 (1H, d, J = 2Hz). Compound XI-35: mp. 176-177 ° C.1H-NMR (CDClThree) δ: 3.04 (3H, s), 3.87 (3H, s), 5.15 (2H, s), 5.28 (2H, s), 6.42 ~ 7.22 (5H, m), 7.13 (1H, d, J = 9Hz) , 7.27-7.34 (2H, m), 7.37 (1H, dd, J = 2, 9Hz), 7.45 (2H, d, J = 9Hz), 7.67 (1H, d, J = 2Hz). EI-MS m / z: 462 (M+).
[0237]
Example 112:3- Ethoxycarbonyl -1- (4- Fluorophenyl ) -7- Methylsul Honil -4H- Imidazo [5,1-c] [1,4] Benzoxazine ( Compound XI- 36) Synthesis of:
Compound Xc (0.93 g, 2.32 mmol), 4-fluorophenyl boric acid (0.49 g, 3.48 mmol) and Pd (PPhThree)FourToluene (10 ml), ethanol (10 ml) and 2M aqueous sodium carbonate solution (10 ml) were added to a mixture of (266 mg, 0.23 mmol), and the mixture was boiled and refluxed with vigorous stirring for 3 hours under an argon gas atmosphere. Post-treatment and purification were conducted in the same manner as in Example 96 to obtain the title compound (798 mg, yield 81%).1H-NMR (CDClThree): 1.43 (3H, t, J = 7Hz, CO2CH2CH Three ), 3.07 (3H, s, SO2CHThree), 4.45 (2H, q, J = 7Hz, CO2CH 2 CHThree), 5.57 (2H, s, OCH2), 7.06 (1H, d, J = 9Hz, 9-H), 7.19 (2H, m), 7.42 (1H, dd, J = 2, 9Hz, 8-H), 7.57 (2H, m), 7.75 ( 1H, d, J = 2Hz, 6-H) .MS (EI-DI) m / z: 416 [M+].
[0238]
Production Example 51:(Five- Fluoro -2- Nitro ) Methyl thiophenoxyacetate ( Compound S-11) Manufacturing of:
Add thioglycolic acid methyl ester (16.68 g, 0.16 mol) to DMF solution (250 ml) of 2,4-difluoronitrobenzene (25 g, 0.16 mol) in the presence of potassium carbonate (21.71 g, 0.16 mol) For 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform: hexane = 1: 1) to give the title compound. (23.05 g, 60% yield) was obtained.1H-NMR (TMS / CDClThree): 3.72 (2H, s, CH2), 3.77 (3H, s, CHThree), 6.96 to 6.99 (1H, m), 7.20 (1H, dd, J = 10, 3Hz), 8.30 (1H, dd, J = 10, 5Hz) .EI-MS m / z: 245 (M+).
[0239]
Production Example 52:(Five- Methylsulfonyl -2- Nitro ) Methyl thiophenoxyacetate ( Compound S-12) Manufacturing of:
Sodium methanesulfinate (5.85 g, 0.06 mmol) was added to a DMF solution (100 ml) of compound S-11 (11.94 g, 0.05 mol), and the mixture was stirred at 100 ° C. for 60 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (8.81 g, yield). 60%) was obtained.1H-NMR (TMS / CDClThree): 3.11 (3H, s, SO2CHThree), 3.76 (3H, s, CO2CHThree), 3.83 (2H, s, CH2), 7.82 (1H, dd, J = 9, 2Hz), 8.15 (1H, d, J = 2Hz), 8.36 (1H, d, J = 9Hz) .EI-MS m / z: 305 (M+).
[0240]
Production Example 53:7- Methylsulfonyl -2H-1,4- Benzothiazine -3 (4H)- on ( Compound I g) Manufacturing of:
Iron powder (4.87 g) and concentrated hydrochloric acid (20 ml) were added to an ethanol solution (850 ml) of compound S-12 (8.81 g, 28.88 mmol), and the mixture was boiled and refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were filtered, washed with a chloroform-hexane mixture and dried to give the title compound (4.35 g, yield 62%).1H-NMR (DMSO-d6): 3.19 (3H, s, SO2CHThree), 3.57 (2H, s, CH2), 7.14 (1H, d, J = 9Hz), 7.70 (1H, dd, J = 2, 9Hz), 7.87 (1H, d, J = 2Hz), 11.00 (1H, br-s, NH) .EI- MS m / z: 243 (M+).
[0241]
Production example54: 7- Fluoro -2H-1,4- Benzothiazine -3 (4H)- on ( Compound Ih ) Manufacturing of:
Using compound S-11, the reaction and post-treatment were carried out according to Production Example 53 to obtain the title compound (yield 74%).1H-NMR (DMSO-d6): 3.48 (2H, s, CH2), 6.97 (1H, dd, J = 9, 5Hz), 7.04 (1H, ddd, J = 9, 9, 3Hz), 7.25 (1H, dd, J = 9, 3Hz), 10.57 (1H, br-s , NH). IR (KBr): 1683cm-1. EI-MS m / z: 183 (M+).
[0242]
Production Example 55:7- Methylsulfonyl -4- (2- Oxopropyl ) -2H-1,4- Benzothiazine -3- on ( Compound II f) Manufacturing of:
TEBAC (0.37 g, 1.87 mmol), potassium carbonate (1.00 g, 7.24 mmol), chloroacetone (0.49 g, 5.30 mmol) were added to an acetone solution (100 ml) of compound Ig (1.08 g, 4.68 mmol) for 14 hours. Boiled and refluxed. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.65 g, yield). 47%). mp. 167-168 ° C.1H-NMR (TMS / CDClThree): 2.32 (3H, s, COCHThree), 3.05 (3H, s, SO2CHThree), 3.52 (2H, s, SCH2), 4.77 (2H, s, CH2CO), 6.84 (1H, d, J = 9Hz), 7.74 (1H, dd, J = 9, 2Hz), 7.97 (1H, d, J = 2Hz). IR (KBr): 1723, 1674, 1322, 1148cm-1EI-MS m / z: 299 (M+).
[0243]
Production Example 56:7- Fluoro -4- (2- Oxopropyl ) -1,4- Benzothiazine -3- on ( Compound II g) Manufacturing of:
The title compound (yield 65%) was obtained by reacting and working up according to Preparation 55 using Compound Ih. mp.83-85 ° C.1H-NMR (TMS / CDClThree): 2.27 (3H, s, COCHThree), 3.48 (3H, s, CH2), 4.69 (2H, s, CH2CO), 6.69 (1H, dd, J = 9, 5Hz), 6.88 to 6.93 (1H, m), 7.12 (1H, dd, J = 8, 3Hz). IR (KBr): 1723, 1663cm-1EI-MS m / z: 239 (M+).
[0244]
Production Example 57:2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound III k) Manufacturing of:
Ammonium acetate (2.68 g, 34.77 mmol) was added to an acetic acid solution (15 ml) of compound IIf (1.04 g, 3.48 mmol), and the mixture was boiled and refluxed for 19 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate: hexane = 4: 1) to obtain the title compound (0.94 g, yield 97%). mp. 158-159 ° C.1H-NMR (TMS / CDClThree): 2.31 (3H, d, J = 1Hz, CHThree), 3.09 (3H, s, SO2CHThree), 4.11 (2H, s, CH2), 7.12 (1H, d, J = 1Hz), 7.43 (1H, d, J = 8Hz), 7.84 (1H, dd, J = 8, 2Hz), 8.03 (1H, d, J = 2Hz). IR ( KBr): 3337, 1309, 1149cm-1EI-MS m / z: 280 (M+).
[0245]
Production Example 58:7- Fluoro -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound III l) Manufacturing of:
The compound IIg was used for the reaction and post-treatment according to Preparation Example 57 to obtain the title compound (yield 71%). mp. 149-150 ° C.1H-NMR (TMS / CDClThree): 2.29 (3H, d, J = 1Hz, CHThree), 4.05 (2H, s, CH2), 6.96 to 7.01 (1H, m), 7.04 (1H, d, J = 1Hz), 7.17 (1H, dd, J = 8, 3Hz), 7.24 (1H, dd, J = 9, 5Hz). IR ( (KBr): 1491,1438cm-1EI-MS m / z: 220 (M+).
[0246]
Production Example 59:Preparation of 1-bromo-2-methyl-7-methylsulfonyl-4H-imidazo [2,1-c] [1,4] benzothiazine (Compound IVl):
  NBS (0.34 g, 1.93 mmol) was added to an acetic acid solution (10 ml) of compound IIIk (0.53 g, 1.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Ice water reaction mixtureDuring ~And extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate: hexane = 4: 1). The compound (0.6 g, yield 89%) was obtained.1H-NMR (TMS / CDClThree): 2.29 (3H, s, CHThree), 3.11 (3H, s, SO2CHThree), 4.01 (2H, s, CH2), 7.89 (1H, dd, J = 9, 2Hz), 8.11 (1H, d, J = 2Hz), 8.19 (1H, d, J = 9Hz). IR (KBr): 2956, 1398, 1146cm-1EI-MS m / z: 358 (M+), 360 (M + 2).
[0247]
Example 113:2- Methyl -7- Methylsulfonyl -1- Phenyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 80) Synthesis of:
To a mixed solution of compound IVl (60 mg, 0.17 mmol) in ethanol (5 ml) and toluene (5 ml), 2M aqueous sodium carbonate solution (0.35 ml), phenylboric acid (26 mg, 0.21 mmol) and Pd (PPhThree)Four(20 mg, 0.017 mmol) was added and the mixture was boiled and refluxed for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate: hexane = 4: 1). The compound (39 mg, yield 65%) was obtained. mp.190-192 ° C.1H-NMR (TMS / CDClThree): 2.29 (3H, s, CHThree), 3.06 (3H, s, SO2CHThree), 4.14 (2H, s, CH2), 6.80 (1H, d, J = 9Hz), 7.19 ~ 7.22 (2H, m), 7.44 ~ 7.49 (4H, m), 8.09 (1H, d, J = 2Hz). IR (KBr): 1307, 1151cm-1EI-MS m / z: 356 (M+).
[0248]
Example 114:1- (4- Fluorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 81) Synthesis of:
Using 4-fluorophenyl boric acid, the reaction and post-treatment were carried out in the same manner as in Example 113 to obtain the title compound (yield 87%). mp. 211-213 ° C.1H-NMR (TMS / CDClThree): 2.24 (3H, s, CHThree), 3.07 (3H, s, SO2CHThree), 4.08 (2H, s, CH2), 6.78 (1H, d, J = 9Hz), 7.12 ~ 7.21 (3H, m), 7.49 (2H, dd, J = 9, 2Hz), 8.09 (1H, d, J = 2Hz). IR (KBr) : 1309, 1150cm-1EI-MS m / z: 374 (M+).
[0249]
Example 115:1- (4- Chlorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 82) Synthesis of:
4-Chlorophenylboric acid was used for reaction and post-treatment in the same manner as in Example 113 to obtain the title compound (yield 88%). mp. 240-242 ° C.1H-NMR (TMS / CDClThree): 2.25 (3H, s, CHThree), 3.07 (3H, s, SO2CHThree), 4.07 (2H, s, CH2), 6.79 (1H, d, J = 9Hz), 7.13-7.15 (2H, m), 7.41-7.43 (2H, m), 7.52 (1H, dd, J = 9, 2Hz), 8.10 (1H, d, J = 2Hz). IR (KBr): 1311, 1151cm-1EI-MS m / z: 390 (M+), 392 (M + 2).
[0250]
Example 116:2- Methyl -1- (4- Methylphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 83) Synthesis of:
Using 4-methylphenylboric acid, the reaction and post-treatment were conducted in the same manner as in Example 113 to obtain the title compound (yield 93%). mp. 181-183 ° C.1H-NMR (CDClThree): 2.28 (3H, s, CHThree), 2.43 (3H, s, SCHThree), 3.06 (3H, s, SO2CHThree), 4.15 (2H, s, CH2), 6.84 (1H, d, J = 9Hz), 7.08 (2H, d, J = 8Hz), 7.25 (2H, d, J = 8Hz), 7.50 (1H, dd, J = 9, 2Hz), 8.08 ( 1H, d, J = 2Hz) .IR (KBr): 1305,1149cm-1EI-MS m / z: 370 (M+).
[0251]
Example 117:1- (4- Methoxyphenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 84) Synthesis of:
Using 4-methoxyphenylboric acid, the reaction and post-treatment were carried out in the same manner as in Example 113 to obtain the title compound (yield 72%). mp.138-140 ° C.1H-NMR (TMS / CDClThree): 2.24 (3H, s, CHThree), 3.06 (3H, s, SO2CHThree), 3.87 (3H, s, OCHThree), 4.08 (2H, s, CH2), 6.84 (1H, d, J = 9Hz), 6.96 (2H, d, J = 7Hz), 7.12 (2H, d, J = 7Hz), 7.48 (1H, dd, J = 9, 2Hz), 8.07 ( 1H, d, J = 2Hz). IR (KBr): 1310, 1151cm-1EI-MS m / z: 386 (M+).
[0252]
Example 118:2- Methyl -7- Methylsulfonyl -1- (4- Methylthiophenyl ) -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 85) Synthesis of:
Using 4-methylthiophenyl boric acid, the reaction and post-treatment were carried out in the same manner as in Example 113 to obtain the title compound (yield 93%). mp. 135-137 ° C.1H-NMR (TMS / CDClThree): 2.25 (3H, s, CHThree), 2.54 (3H, s, SCHThree), 3.07 (3H, s, SO2CHThree), 4.07 (2H, s, CH2), 6.85 (1H, d, J = 9Hz), 7.09 ~ 7.11 (2H, m), 7.26 ~ 7.29 (2H, m), 7.50 (1H, d, J = 9, 2Hz), 8.08 (1H, d, J = 2Hz). IR (KBr): 1311,1151cm-1EI-MS m / z: 402 (M+).
[0253]
Example 119:1- (3, 5- Dichlorophenyl ) -2- Methyl -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 86) Synthesis of:
The reaction and workup were conducted in the same manner as in Example 113 using 3,5-dichlorophenylboric acid to obtain the title compound (yield 86%). mp.226-228 ° C.1H-NMR (TMS / CDClThree): 2.27 (3H, s, CHThree), 3.08 (3H, s, SO2CHThree), 4.05 (2H, s, CH2), 6.79 (1H, d, J = 9Hz), 7.09 (2H, d, J = 2Hz), 7.42 (1H, t, J = 2Hz), 7.58 (1H, dd, J = 9, 2Hz), 8.12 ( 1H, d, J = 2Hz). IR (KBr): 1310, 1149cm-1EI-MS m / z: 424 (M+), 426 (M + 2).
[0254]
Production Example 60:7- Methylsulfonyl -2H-1,4- Benzothiazine -3 (4H)- Thion ( Compound VI d) Manufacturing of:
Lawesson reagent (3.33 g, 8.23 mmol) was added to a THF solution (300 ml) of compound Ig (4.00 g, 16.5 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure, ethanol was added to the residue, the insoluble material was filtered and dried to give the title compound (3.96 g, yield 93%).1H-NMR (DMSO-d6) δ (ppm): 3.19 (3H, s, CHThreeSO2), 3.99 (2H, s, CH2), 7.36 (1H, d, J = 8Hz), 7.72 (1H, dd, J = 2, 8Hz), 7.90 (1H, d, J = 2Hz), 12.80 (1H, br-s, NH). EI- MS (m / z): 259 (M+).
[0255]
Production Example 61:7- Methylsulfonyl -3- Methylthio -2H-1,4- Benzothiazine ( Compound VII d) Manufacturing of:
NaH (0.43 g, 17.8 mmol) was added to a THF solution (300 ml) of compound VId (3.85 g, 14.9 mmol), and the mixture was stirred for 15 minutes. Then, methyl iodide (4.22 g, 29.7 mmol) was added and stirred for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (3.47 g, yield 86%). )1H-NMR (CDClThree/ TMS) δ (ppm): 2.59 (3H, s, CHThreeS), 3.06 (3H, s, CHThreeSO2), 3.28 (2H, s, CH2), 7.43 (1H, d, J = 8Hz), 7.71 (1H, dd, J = 2, 8Hz), 7.87 (1H, d, J = 2Hz). EI-MS (m / z)
: 273 (M+).
[0256]
Production Example 62:3- (2,2- Dimethoxyethylamino ) -7- Methylsulfonyl -2H-1,4- Benzothiazine ( Compound VIII d) Manufacturing of:
Aminoacetaldehyde dimethyl acetal (3.37 g, 32.1 mmol) was added to an acetonitrile solution (150 ml) of compound VIId (3.37 g, 12.3 mmol), and the mixture was boiled and refluxed for 7 days. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (3.46 g, yield). 85%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.06 (3H, s, CHThreeSO2), 3.12 (2H, s, SCH2), 3.44 (6H, s, CHThree× 2), 3.71 (2H, t, J = 5Hz, CH2), 4.57 (1H, t, J = 5Hz, CH), 5.09 (1H, br-s, NH), 7.21 (1H, d, J = 8Hz), 7.64 (1H, dd, J = 2, 8Hz), 7.80 (1H, d, J = 2Hz) .EI-MS (m / z): 330 (M+).
[0257]
Production Example 63:7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound III m) Manufacturing of:
P-Toluenesulfonic acid (0.79 g, 4.59 mmol) was added to a toluene solution (150 ml) of compound VIIId (3.03 g, 9.18 mmol), and the mixture was boiled and refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (2.07 g, yield). 85%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.09 (3H, s, CHThree), 4.12 (2H, s, CH2), 7.19 (1H, d, J = 2Hz), 7.40 (1H, d, J = 2Hz), 7.49 (1H, d, J = 8Hz), 7.86 (1H, dd, J = 2, 8Hz), 8.05 ( 1H, d, J = 2Hz) .EI-MS (m / z): 266 (M+).
[0258]
Production Example 64:1- Bromo -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound IV m) Manufacturing of:
NBS (33 mg, 0.19 mmol) was added to an acetic acid solution (1.5 ml) of compound IIIm (50 mg, 0.19 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (12 mg, yield). 19%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.11 (3H, s, CHThree), 4.02 (2H, s, CH2), 7.16 (1H, s), 7.90 (1H, dd, J = 2, 8Hz), 8.13 (1H, d, J = 2Hz), 8.21 (1H, d, J = 8Hz). EI-MS (m / z): 344 (M+), 346 (M++2).
[0259]
Production Example 65:3- [ 2- (4- Methoxyphenyl ) -2- Oxoethylamino] -7- Methylsulfonyl -2H-1,4- Benzothiazine ( Compound VIII e) Manufacturing of:
In the presence of triethylamine (388 mg, 3.84 mmol), 2-amino- (4-methoxy) acetophenone hydrochloride (738 mg, 3.66 mmol) was added to an acetonitrile solution (15 ml) of compound VIId (1.00 g, 3.66 mol), Boiled and refluxed for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure. A small amount of ethyl acetate was added to the residue, and the insoluble material was filtered and dried to obtain the title compound (210 mg, yield 61%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.08 (3H, s, SO2CHThree), 3.25 (2H, s, SCH2), 3.91 (3H, s, OCHThree), 4.97 (2H, d, COCH2), 6.13 (1H, br, NH), 7.01 (2H, dd, J = 2, 6Hz), 7.27 (1H, d, J = 8Hz), 7.67 (1H, dd, J = 2, 8Hz), 7.83 ( 1H, d, J = 2Hz), 8.05 (2H, dd, J = 2, 6Hz) .EI-MS (m / z): 390 (M+).
[0260]
Example 120:1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 87) Synthesis of:
To a toluene solution (40 ml) of compound VIIIe (360 mg, 0.92 mmol) was added p-toluenesulfonic anhydride (79 mg, 0.46 mmol), and the mixture was boiled and refluxed for 22 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (4.35 g, yield). 62%) was obtained.1H-NMR (CDClThree/ TMS) δ (ppm): 3.08 (3H, s, CHThreeSO2), 3.86 (3H, s, CHThreeO), 4.06 (2H, s, CH2), 6.93 (2H, d, J = 8Hz), 7.00 (1H, d, J = 8Hz), 7.06 (1H, s), 7.18 (2H, d, J = 8Hz), 7.53 (1H, dd, J = 2, 8Hz), 8.1 (1H, d, J = 2Hz) .EI-MS (m / z): 372 (M+).
[0261]
Example 121:2- Bromo -1- (4- Methoxyphenyl ) -7- Methylsulfonyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 88) Synthesis of:
NBS (8 mg, 0.04 mmol) was added to an acetic acid solution (4 ml) of compound V-87 (15 mg, 0.04 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate: hexane = 4: 1). The compound (0.6 g, yield 88%) was obtained.1H-NMR (CDClThree/ TMS) δ (ppm): 3.06 (3H, s, CHThreeSO2), 3.88 (3H, s, CHThreeO), 4.03 (2H, s, CH2), 6.87 (1H, d, J = 8Hz), 6.97 (2H, d, J = 8Hz), 7.21 (2H, d, J = 8Hz), 7.50 (1H, dd, J = 2, 8Hz), 8.08 ( 1H, d, J = 2Hz) .EI-MS (m / z): 450 (M+), 452 (M++2).
[0262]
Production Example 66:7- Methoxy -2H-1,4- Benzothiazine -3 (4H)- on ( Compound I i) Manufacturing of:
To an aqueous solution (100 ml) of 2-amino-6-methoxybenzothiazole (10.0 g, 55.50 mmol) was added potassium hydroxide (54.9 g, 0.83 mmol) at room temperature, and the mixture was heated to reflux for 2 hours. The solution was cooled to room temperature, acetic acid (43.3 g, 0.72 mol) and ethyl bromoacetate (13.9 g, 83.20 mmol) were added, and the mixture was heated under reflux for 1 hour. did. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from ethanol to give the title compound (5.20 g, yield 48%).1H-NMR (CDClThree/ TMS) δ (ppm): 3.42 (2H, s, CH2), 3.78 (3H, s, CHThreeO), 6.73 (1H, dd, J = 2, 9Hz), 6.76 (1H, d, J = 9Hz), 6.87 (1H, d, J = 2Hz), 7.93 (1H, br-s, NH) .EI -MS (m / z): 195 (M+).
[0263]
Production Example 67:7- Methoxy -4- (2- Oxopropyl ) -2H-1,4- Benzothiazine -3- on ( Compound II h) Manufacturing of :
A solution of compound Ii (5.20 g, 26.7 mmol), chloroacetone (4.94 g, 53.3 mmol), potassium carbonate (5.53 g, 40.0 mmol) and TEBAC (3.04 g, 13.3 mmol) in acetone (100 ml) Heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, chloroform was added, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: chloroform = 3: 2 → chloroform). The title compound (4.80 g, yield 72%) was obtained as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.23 (3H, s, CHThreeCO), 3.47 (2H, s, CH2), 3.78 (3H, s, CHThreeO), 4.67 (2H, s, NCH2), 6.66-6.92 (3H, m, aromatic-H) .EI-MS (m / z): 251 (M+).
[0264]
Production Example 68:7- Methoxy -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound III n) Manufacturing of:
A solution of compound IIh (4.6 g, 18.30 mmol) and ammonium acetate (14.1 g, 0.18 mol) in acetic acid (50 ml) was heated to reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, 7% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the title compound (3.21 g, yield 76%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.29 (3H, s, CHThree), 3.82 (3H, s, CHThreeO), 4.05 (2H, s, CH2), 6.82 (1H, dd, J = 3, 9Hz), 6.96 (1H, d, J = 3Hz), 7.03 (1H, s), 7.20 (1H, d, J = 9Hz). EI-MS (m / z): 232 (M+).
[0265]
Production Example 69:1- Bromo -7- Methoxy -2- Methyl -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound IV n) Manufacturing of:
To a solution of compound IIIn (1.98 g, 8.53 mmol) in acetic acid (20 ml), NBS (1.67 g, 11.90 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 8-9 with 7% aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: chloroform = 3: 2) to give the title compound (0.68 g, yield 26%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.27 (3H, s, CHThree), 3.84 (3H, s, CHThreeO), 3.97 (2H, s, CH2), 6.87 (1H, dd, J = 3, 9Hz), 7.04 (1H, d, J = 3Hz), 7.92 (1H, d, J = 9Hz). EI-MS (m / z): 310 (M+), 312 (M++2).
[0266]
Example 122:7- Methoxy -2- Methyl -1- (4- Methylsulfonylphenyl ) -4H- Imidazo [2,1-c] [1,4] Benzothiazine ( Compound V- 89) Synthesis of:
Compound IVn (150 mg, 0.48 mmol), 4-methylsulfonylphenyl boric acid (Reference Example 8) (116 mg, 0.58 mmol), Pd (PPhThree)FourA toluene (5 ml) -ethanol (5 ml) solution of (56 mg, 0.05 mmol) and a 2M aqueous sodium carbonate solution (0.96 ml, 1.93 mmol) was heated to reflux under an argon stream for 3.5 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: chloroform = 3: 2) to give the title compound (159 mg, yield 90%) as a crystalline solid.1H-NMR (CDClThree/ TMS) δ (ppm): 2.29 (3H, s, CHThree), 3.12 (3H, s, CHThreeSO2), 3.79 (3H, s, CHThreeO), 3.99 (2H, s, CH2), 6.47 (1H, d, J = 9Hz), 6.52 (1H, dd, J = 3, 9Hz), 7.05 (1H, d, J = 3Hz), 7.40 (2H, d, J = 9Hz), 7.96 ( 2H, d, J = 9Hz). IR (KBr) cm-1 : 2917, 1599, 1490, 1310, 1149, 773.EI-MS (m / z): 386 (M+).
[0267]
Table 1 shows a summary of the above compound examples of the present invention.
The inhibitory action of the compounds of the present invention produced in the above examples on COX-2 derived from sheep placenta and COX-1 derived from sheep seminal vesicles was tested. Note that DCF-Na and SC58635 as control compounds in the following test examples are diclofenac sodium and 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfone. Amide (celecoxib; J. Med. Chem., 1997, 40, 1347).
[0268]
Test Example 1: Measurement and selectivity of COX-2 and COX-1 inhibitory action
[Enzymes / Reagents] COX-1 (Sheep Seminal Ves., Cayman) and COX-2 (Sheep Placenta, Cayman), arachidonic acid (approximately 90%, Sigma), epinephrine (Wako Pure Chemical Industries), glutathione (reduced, Photopure drugs), hematin (Sigma), Prostaglandin E2 EIA Kit (Cayman).
[0269]
[Measurement of COX-1 and COX-2 inhibitory activity] Preparation of test drug solution: Prepare a 10.7 mM test drug stock solution (DMSO) with a test drug concentration in the reaction solution of 100 μM. The test drug stock solution is diluted with DMSO so that the concentration of the test drug is 0.001 to 100 μM.Preparation of enzyme solution: Immediately after purchase, dispensed into 200 units and stored frozen. When using, melt at room temperature, add 50 mM Tris-HCl buffer (pH 8.0) to the dispensed enzyme, dissolve to make 1 ml, and use this solution as the enzyme solution.
[0270]
Preparation of reaction solution: Add 200 μl of 50 mM Tris-HCl buffer (pH 8.0) containing 5 mM glutathione, 5 mM epinephrine and 1 μM hematin to 2 μl of the test drug, and add 10 μl (2 units) of the enzyme solution to obtain a reaction solution.
incubation: After pre-incubation of the reaction solution at 37 ° C. for 30 minutes, 2 μl of an arachidonic acid ethanol solution (final concentration in the reaction solution of 6.6 μM) is added, and further incubated at 37 ° C. for 10 minutes. Add 50 μl of 0.2 N hydrochloric acid, stop the reaction in an ice bath, leave it in the ice bath for 7 minutes or more, and neutralize it by adding 50 μl of 0.2 N sodium hydroxide.PGE 2 Measurement of production amount:COX-1 and COX-2 inhibitory activity2 PGE in reaction solution using EIA kit2And measure the absorbance at 414 nm to obtain a known PGE2The standard solution containing the concentration is developed in the same manner, and is calculated by a calibration curve derived from the absorbance. Repeat the reaction of the test drug at each concentration 3 times, and use the average value. The same treatment is performed using a DMSO solution not containing the test drug to make a blank. The results are shown in Table 2.
[0271]
[Table 1] List of compounds of the present invention
Embedded image
Figure 0004409680
[0272]
[Table 1]
Figure 0004409680
[0273]
[Table 2]
Figure 0004409680
[0274]
[Table 3]
Figure 0004409680
[0275]
[Table 4]
Figure 0004409680
[0276]
[Table 5]
Figure 0004409680
[0277]
【The invention's effect】
By inhibiting COX-2 selectively, it has the activity of suppressing the production of PGE2, which is a mediator involved in inflammation, and is expected to have an anti-inflammatory effect without side effects such as gastrointestinal mucosa.

Claims (3)

一般式（１）
Figure 0004409680
（式中、Ｒ１は、低級アルコキシル基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、アミノスルホニル基、またはハロゲン原子、
Ｒ２は、水素原子、低級アルキル基、低級アルコキシル基、低級アルキルチオ基、トリハロゲノメチル基、低級アルキルスルホニル基、アミノスルホニル基、モノまたはジハロゲン原子、
Ｘ−Ａは、−（CH2）n−、−OCH2−、−ＳCH2−、または−C(R3)=C(R4)−であって、この場合、nは２−３の整数、Ｒ３、Ｒ４は、水素原子、ハロゲン原子であり、
Ｙ−Ｚは、＝C(R5)−Ｎ＝、または＝Ｎ−C(R6)＝であって、この場合、
Ｒ5、Ｒ6は、水素原子、ハロゲン原子、低級アルキル基、ヒドロキシメチル基、モノハロゲノメチル基、ジハロゲノメチル基、トリハロゲノメチル基、シアノ基、ニトロ基、ホルミル基、カルボキシル基、低級アルコキシカルボニル基、低級アルコキシメチル基、置換または非置換のアラルキルオキシメチル基、またはアリールオキシメチル基であることを示す）
で表される三環性縮合イミダゾール誘導体。General formula (1)
Figure 0004409680
 (Wherein R 1 represents a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aminosulfonyl group, or a halogen atom;
R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a trihalogenomethyl group, a lower alkylsulfonyl group, an aminosulfonyl group, a mono- or dihalogen atom,
X-A is — (CH 2 ) n —, —OCH 2 —, —SCH 2 —, or —C (R 3 ) ═C (R 4 ) —, where n is 2 −3 An integer, R 3 and R 4 are a hydrogen atom or a halogen atom;
YZ is = C (R 5 ) -N = or = N-C (R 6 ) =,
R 5 and R 6 are hydrogen atom, halogen atom, lower alkyl group, hydroxymethyl group, monohalogenomethyl group, dihalogenomethyl group, trihalogenomethyl group, cyano group, nitro group, formyl group, carboxyl group, lower alkoxy A carbonyl group, a lower alkoxymethyl group, a substituted or unsubstituted aralkyloxymethyl group, or an aryloxymethyl group)
A tricyclic fused imidazole derivative represented by: 請求項１記載の三環性縮合イミダゾール誘導体を有効成分とするシクロオキシゲナーゼ−２の阻害剤。  An inhibitor of cyclooxygenase-2 comprising the tricyclic fused imidazole derivative according to claim 1 as an active ingredient. 請求項１記載の三環性縮合イミダゾール誘導体を有効成分とする医薬。  A pharmaceutical comprising the tricyclic fused imidazole derivative according to claim 1 as an active ingredient.
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US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
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