JP3776818B2 - Pentacyclic taxane compound and process for producing the same - Google Patents
Pentacyclic taxane compound and process for producing the same Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は経口投与可能な、抗腫瘍活性を有するタキソール誘導体を含有する医薬、特に抗腫瘍剤、及び該タキソール誘導体の製造方法に関する。
【０００２】
【従来の技術】
タキソールは次に示す化学構造式で表される天然物で、西洋イチイの幹等から微量得られる。
【０００３】
【化１５】
タキソールは抗腫瘍活性を有することが知られているが、その作用機作は細胞分裂における微小管の解重合阻害作用に基づくものとされており、従来の抗腫瘍剤とは異なる作用機作を有する抗腫瘍剤としてその臨床応用が期待されている。これまでは、タキソールは天然から極く微量しか得られなかった。しかし、イチイ類の葉等から比較的多量に得ることのできる次式で表されるタキソール前駆体である１０−Ｏ−デアセチルバッカチンIIIを原料に用いて合成したタキソール誘導体が報告されている。
【０００５】
【化１６】
なかでも次式で表される構造を有する化合物（タキソテール、以下、化合物Ａと記す）は、タキソールと同等以上の抗腫瘍活性を有する化合物として注目され、抗腫瘍剤としての開発が進んでいる。
【０００７】
【化１７】
本発明者らは、９位ケトンの還元によって生じる水酸基と１０位水酸基を環状アセタール型に変換した化合物が強い抗腫瘍活性を有することを報告している（特開平9-12578号）。
【０００９】
【発明が解決しようとする課題】
タキソール、タキソテールおよび特開平9-12578号に開示された化合物は抗腫瘍剤として有望なものである。しかしながら、特開平9-12578号に開示された実施例の化合物については毒性が比較的高く、また、これらの化合物の経口投与における有効性は知られていない。患者の投与時負担の軽減、医療経済性の観点等から、経口投与可能な、タキソール誘導体が望まれている。
本発明者は高い抗腫瘍活性を維持しつつ、毒性面も改善され、経口投与に適した高い安全性を確保できるタキソール誘導体を得るべく、種々の研究を行った結果、マウスを用いた抗腫瘍試験等において、経口投与においても有意な抗腫瘍活性を示す次の式
【００１０】
【化１８】
【００１１】
【課題を解決するための手段】
本発明者は代謝による化合物修飾の抑制を目的に、新たなドラッグデザイン研究を行い、１３位側鎖のピリジン環に置換基を導入した化合物が、抗腫瘍活性を維持しつつも、毒性面も改善され、ヒト肝ミクロソームでの代謝を受けにくく、経口投与に適した安全性を確保できることを見出し、本発明を完成した。
すなわち本発明は、次の式で表される化合物、その塩、またはそれらの水和物もしくはそれらの溶媒和物を含有する医薬、更には次の式で表される化合物、その塩、またはそれらの水和物もしくはそれらの溶媒和物を含有する抗腫瘍剤、及びその製造方法を提供するものである。
【００１２】
【化１９】
【００１３】
さらに、本発明は、次の各々に関するものである。
Ｒ2がメトキシ基またはフッ素原子である化合物、その塩、またはそれらの水和物もしくはそれらの溶媒和物；
次式（ＩＩ）で表される化合物、その塩、またはそれらの水和物もしくはそれらの溶媒和物；
【００１４】
【化２０】
上記化合物、その塩、またはそれらの水和物もしくはそれらの溶媒和物を含有する抗腫瘍剤；
次の１）、２）、３）、４）、および５）の工程を含むことを特徴とする次式（Ｉ）
【００１５】
【化２１】
で表される化合物の製造方法；
１）次式（ＩＩＩ）
【００１６】
【化２２】
で表される化合物および次式（ＩＶ）
【００１７】
【化２３】
【００１８】
【化２４】
で表される化合物を反応させて、式（ＶＩ）
【００１９】
【化２５】
２）この化合物のビニル基をアルデヒド基に変換する反応からなる工程、
３）そのアルデヒド基をジメチルアミノメチル基またはモルホリノメチル基に変換する反応からなる工程、および
４）６位炭素と７位炭素との間の結合が二重結合の場合に単結合に変換する反応からなる工程、および
５）Ｒ3が保護基を有する水酸基である場合に該保護基を除去する反応からなる工程；
次式（ＩＩＩ）
【００２０】
【化２６】
で表される化合物が、光学活性体であって次式（ＶＩＩ）
【００２１】
【化２７】
で表される化合物である上記の製造方法；
次式（ＩＩＩ）
【００２２】
【化２８】
で表される化合物がラセミ体である上記の製造方法；
次式（ＩＶ）
【００２３】
【化２９】
【００２４】
【化３０】
次式（ＩＶ）
【００２５】
【化３１】
【００２６】
【化３２】
Ｒ2がメトキシ基またはフッ素原子である上記の製造方法；
次式（ＶＩＩ）
【００２７】
【化３３】
で表される光学活性化合物；
Ｒ2がメトキシ基またはフッ素原子である上記の化合物；
Ｒ3がトリイソプロピルシリロキシ基である上記の化合物；
次式（ＶＩＩＩ）
【００２８】
【化３４】
【００２９】
【化３５】
で表される化合物を反応させて、得られた次式（Ｘ）
【００３０】
【化３６】
で表される化合物に次式（ＸＩ）
【００３１】
【化３７】
で表される化合物を反応させて次式（ＸＩＩ）
【００３２】
【化３８】
で表される化合物を得て、必要に応じてβラクタム環上の３位の水酸基の脱保護反応をさせて、該水酸基に必要に応じて再度保護基を導入する反応をさせて、βラクタム環内の窒素原子の保護基であるＲ4を除去して得られる次式（ＸＩＩＩ）
【００３３】
【化３９】
で表されるラセミ体化合物を光学分割処理し、βラクタム環内の窒素原子にｔ−ブトキシカルボニル基を導入することを特徴とする次式（ＶＩＩ）
【００３４】
【化４０】
で表される光学活性化合物の製造方法；
Ｒ2がメトキシ基またはフッ素原子である上記の製造方法；
Ｒ5がアセチル基である上記の製造方法；
Ｒ4が４−メトキシフェニル基またはビス（４−メトキシフェニル）メチル基である上記の製造方法；
Ｒ3がトリイソプロピルシリロキシ基である上記の製造方法；
次式（ＩＩＩ）
【００３５】
【化４１】
で表されるラセミ体化合物；
Ｒ2がメトキシ基またはフッ素原子である上記の化合物；
Ｒ3がトリイソプロピルシリロキシ基である上記の化合物；
次式（ＶＩＩＩ）
【００３６】
【化４２】
【００３７】
【化４３】
で表される化合物を反応させて、得られた次式（Ｘ）
【００３８】
【化４４】
で表される化合物に次式（ＸＩ）
【００３９】
【化４５】
で表される化合物を反応させて次式（ＸＩＩ）
【００４０】
【化４６】
で表される化合物を得て、必要に応じてβラクタム環上の３位の水酸基の脱保護反応をさせて、該水酸基に必要に応じて再度保護基を導入する反応をさせて、βラクタム環内の窒素原子にｔ−ブトキシカルボニル基を導入することを特徴とする次式（ＩＩＩ）
【００４１】
【化４７】
で表されるラセミ体化合物の製造方法；
Ｒ2がメトキシ基またはフッ素原子である上記の製造方法；
Ｒ5がアセチル基である上記の製造方法；
Ｒ4が４−メトキシフェニル基またはビス（４−メトキシフェニル）メチル基である上記の製造方法；
Ｒ3がトリイソプロピルシリロキシ基である上記の製造方法；
等に関する。
【００４２】
本発明は、次式（Ｉ）で表される化合物（以下、化合物（Ｉ）または本発明の化合物と記す。他の式で表される化合物も同様に記す）、その塩、またはそれらの水和物もしくはそれらの溶媒和物に関する。
【００４３】
【化４８】
化合物（Ｉ）は、下記化合物（ＩＩ）、つまり、(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネートが特に好ましい。
【００４４】
【化４９】
化合物（Ｉ）は、次の１）、２）、３）、４）、および５）の工程から合成することができる。
１）化合物（ＩＩＩ）
【００４６】
【化５０】
【００４７】
【化５１】
【００４８】
【化５２】
２）この化合物（ＶＩ）のビニル基をアルデヒド基に変換する反応からなる工程、
３）そのアルデヒド基をジメチルアミノメチル基またはモルホリノメチル基に変換する反応からなる工程、
４）６位炭素と７位炭素との間の結合が二重結合の場合に単結合に変換する反応からなる工程、および
５）Ｒ3が保護基を有する水酸基である場合に該保護基を除去する反応からなる工程。
【００４９】
化合物（ＩＩＩ）において、Ｒ3は保護基を有していてもよい水酸基を意味する。ここで、β−ラクタム環上の3位のＲ3と4位のピリジル基とはシス配置である。Ｒ3における保護基としては、置換シリル基、ベンジル基、置換ベンジル基、１−エトキシエチル基、ベンジルオキシカルボニル基、２，２，２−トリクロロエトキシカルボニル基等が挙げられる。置換シリル基の置換基としては、アルキル基、アリール基またはアラルキル基等が挙げられ、置換シリル基としてはトリメチルシリル基、イソプロピルジメチルシリル基、第三級ブチルジメチルシリル基、トリベンジルシリル基、第三級ブチルジフェニルシリル基等が挙げられる。置換ベンジル基の置換基としては、ハロゲン原子、アルキル基、アルコキシ基、ニトロ基等が挙げられ、置換ベンジル基としては、パラニトロベンジル、パラメトキシベンジル等が挙げられる。Ｒ3における保護基としては、好ましくはトリイソプロピルシリル基、第三ブチルジメチルシリル基、トリエチルシリル基等のトリアルキルシリル基、および、ベンジル基が挙げられ、特に好ましくはトリイソプロピルシリル基およびベンジル基が挙げられる。
また、化合物（ＩＩＩ）は、ラセミ体でも、光学活性体（ＶＩＩ）であってもよい。
また、化合物（ＩＶ）の部分構造、
【００５０】
【化５３】
化合物（ＶＩＩ）及び化合物（ＩＩＩ）は、次の本発明法により製造される。化合物（ＶＩＩＩ）
【００５１】
【化５４】
【００５２】
【化５５】
【００５３】
【化５６】
【００５４】
【化５７】
【００５５】
【化５８】
【００５６】
【化５９】
【００５７】
【化６０】
また、ラセミ体化合物（ＩＩＩ）は、化合物（ＶＩＩＩ）と化合物（ＩＸ）との反応により化合物（Ｘ）を得、これと化合物（ＸＩ）を反応させて化合物（ＸＩＩ）を得、必要に応じてβラクタム環上の３位の水酸基の脱保護反応をさせて、該水酸基に必要に応じて再度保護基を導入する反応をさせて、βラクタム環内の窒素原子にｔ−ブトキシカルボニル基を導入することにより製造できる。
上記Ｒ2はハロゲン原子または炭素数１〜６のアルコキシ基を意味し、メトキシ基またはフッ素原子が好ましい。
上記Ｒ3は保護基を有することもある水酸基を意味し、トリイソプロピルシリロキシ基が好ましい。
上記Ｒ4は水素原子、水酸基、置換基を有していてもよい炭素数１から６のアルコキシ基、置換基を有していてもよい炭素数１から６のアルカノイル基、置換基を有していてもよい炭素数２から６のアルケノイル基、置換基を有していてもよいアリール基、置換基を有していてもよいアリーロイル基、置換基を有していてもよいアラルキル基、または置換シリル基を意味する。置換シリル基の置換基としては、アルキル基、アリール基またはアラルキル基等が挙げられ、置換シリル基としてはトリメチルシリル基、イソプロピルジメチルシリル基、第三級ブチルジメチルシリル基、トリベンジルシリル基、第三級ブチルジフェニルシリル基等が挙げられる。
置換基を有していてもよいアリール基、置換基を有していてもよいアリーロイル基または置換基を有していてもよいアラルキル基の置換基としては、ハロゲン原子、炭素数１から６のアルキル基、炭素数１から６のハロゲノアルキル基、炭素数１から６のアルコキシ基、ニトロ基、カルバモイル基、およびシアノ基が挙げられる。これらアリール基、アリーロイル基及びアラルキル基は、上記置換基を１または２以上有することができる。
Ｒ4としては置換基を有していてもよいフェニル基または置換基を有していてもよいアラルキル基が好ましい。置換基としては、アルコキシ基が好ましい。中でもＲ4は４−メトキシフェニル基またはビス（４−メトキシフェニル）メチル基が好ましい。
Ｒ5は水酸基の保護基を意味し、アセチル基が好ましい。
Ｑはハロゲン原子を意味し、塩素原子が好ましい。
また、化合物（ＸＩＩＩ）の光学分割処理としては、光学活性カラムによる方法等が挙げられる。
本発明の化合物は特開平9-12578号で報告されている方法に従って合成できる。なお、反応に際しては、必要に応じて置換基を保護基で保護して行うが、脱保護の操作順序は、特に限定されない。例えば、以下の合成法１及び２が例示される。
合成法１
【００５８】
【化６１】
化合物（１）と化合物（２）を塩基の存在下で縮合させて化合物（３）を得る。次いで、水酸基の保護基を除去して化合物（４）に導く。末端オレフィンを四酸化オスミウム触媒下でＮ−メチルモルホリン−Ｎ−オキシド等の酸化剤によりジオールに変換後、過ヨウ素酸ナトリウム等で酸化的に開裂させてアルデヒドとした後、対応するアミンと還元的に反応させて化合物（５）を得ることができる。
合成法２
【００６０】
【化６２】
合成法１と同様に化合物（６）を化合物（２）と縮合させて化合物（７）を得る。次いで、合成法１と同様に末端オレフィン部分を変換して化合物（８）を得ることができる。次いで、６，７位のオレフィンを水素添加により還元して化合物（９）を得た後、最後に水酸基の保護基を除去して化合物（１０）（化合物（５）と同じ）を得ることができる。
原料となる化合物（１）の合成法は特開平９−１２５７８号に記載されている。化合物（６）については特開平９−１２５７８号に記載されている化合物（１０−ａ）から一工程で合成できる。
【００６２】
【化６３】
β−ラクタム化合物（２）の合成は種々の文献（例えば、J. Org. Chem., 61巻，2664-2676頁，1996年またはTetrahedron Letters 39巻，3559-3562頁，1998年、特開平３−８６８６０またはＥＰ０４００９７１Ａ３等）で報告されている方法に準じて合成できる。以下にその一例を示す。
【００６４】
【化６４】
化合物（１１）の合成法は文献（J. Med. Chem., 13巻，1124頁，1970年）で報告されている。化合物（１１）をｐ−アニシジンと脱水縮合させて得たイミン化合物に、アセトキシアセチルクロリドを塩基の存在下反応させると（Staudinger反応として知られている）、化合物（１２）を得ることができる。化合物（１２）をメタノール溶媒中塩基で処理してアセチル基を除去し、続いてイミダゾール存在下トリイソプロピルシリルクロリドを反応させると化合物（１３）を得ることができる。化合物（１３）に硝酸第二セリウムアンモニウムを作用させると化合物（１４）のラセミ体を得ることができる。このラセミ体を光学活性カラムクロマトグラフィーで分割することにより表記立体配置を持つ化合物（１４）を得ることができる。最後に、化合物（１４）にジ-tert-ブチルジカーボネートを作用させることにより化合物（２）を得ることができる。
【００６６】
また、化合物（２）の合成過程において光学分割せず化合物（２）のラセミ体を過剰量用いて化合物（１）または（６）と縮合反応させ、生成したジアステレオマーをシリカゲルカラムクロマトグラフィーで分離させる方法でも所望の立体配置を持つ化合物（３）または（７）を得ることができる。
【００６７】
【化６５】
上記合成法のＲ1、Ｒ2およびＲ3の意味は前記と同じである。略号については、Ｂｏｃは第三ブトキシカルボニル基、Ｍｅはメチル基、Ａｃはアセチル基、Ｂｚはベンゾイル基、ＴＩＰＳはトリイソプロピルシリル基を意味する。
各反応について詳しく説明する。
【００６９】
イミン（Ｘ）の合成
アルデヒド（ＶＩＩＩ）とアミン（ＩＸ）を溶媒中あるいは無溶媒で混合すると、イミン（Ｘ）が生成し水が分離してくる。反応混合物に無水硫酸ナトリウム、塩化カルシウム、モレキュラーシーブス等の脱水剤を加えて濾去することにより、分離した水を除くことができる。水を除く別の方法として、トルエンやベンゼン等、水と共沸混合物を作る溶媒を用い、減圧留去することにより（必要ならば溶媒を加えて再び減圧留去する操作を繰り返す）水を除くことができる。ここで、反応に溶媒を用いるときはトルエン、ベンゼン、塩化メチレン等、またはこれらの混合溶媒が挙げられるが、特に限定されない。反応温度は通常−２０℃から１５０℃もしくは溶媒の沸点までの範囲であるが、好ましくは０℃から１００℃もしくは溶媒の沸点までの範囲である。
【００７０】
βラクタム（ＸＩＩ）の合成
イミン（Ｘ）とトリエチルアミンに代表される三級アミン等の塩基を溶媒に溶解し、室温以下（好ましくは０℃以下）で酸ハライド（ＸＩ）の溶液を加えることで合成できる。この酸ハライド（ＸＩ）溶液は滴下することが好ましい。この反応は、酸ハライドと塩基の反応によりケテンが一旦生成し、これにイミンが反応してシス配置選択的にβラクタム環が構築されると考えられている。また、このβラクタム環構築反応の立体配置については、反応条件やイミンおよび酸ハライドの構造により選択性が変化することが知られている。従って、Ｒ2、Ｒ4、またはＲ5の種類に合わせて反応条件を適切に選択することで目的とするシス配置が選択的に得られる。ここで、反応に用いる溶媒は塩化メチレン、トルエン、ベンゼン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、乾燥したものが好ましい。また、滴下後の反応温度は、通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、−７８℃から室温が好ましい。
【００７１】
３位保護基の入れ替え反応
Ｒ5およびＲ3の種類によって反応条件は異なる。Ｒ5がベンジル基、トリアルキルシリル基等の場合、保護基を入れ替えずに次の工程に進むことも可能である。Ｒ5の脱保護反応は通常の反応条件で行えるが、Ｒ5がアセチル基の場合の例を示す。化合物（ＸＩＩ）を溶媒に溶解し、反応に必要な量の炭酸カリウム等の塩基を加えることにより、Ｒ5が水素原子である化合物を得ることができる。ここで、反応に用いる溶媒はメタノール、テトラヒドロフラン、塩化メチレン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、乾燥したものが好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは０℃から室温までの範囲である。続く水酸基の保護もＲ3の種類により反応条件は異なるが、通常の方法で行うことができる。Ｒ3がトリイソプロピルシリルオキシ基等のトリアルキルシリルオキシ基の場合を示す。原料を溶媒に溶解し、イミダゾール等のアミン型塩基またはその他の塩基（シリル化反応には塩基としてイミダゾールが好ましいことが知られている）とトリイソプロピルシリルクロリド等のトリアルキルシリルクロリドを加えることにより、トリアルキルシリルオキシ化合物を得ることができる。ここで、反応に用いる溶媒は塩化メチレン、ジメチルホルムアミド、テトラヒドロフラン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、乾燥したものが好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは０℃から室温までの範囲である。
【００７２】
Ｎ保護基の脱保護反応
Ｒ4はβラクタム環１位の窒素原子の保護基であり、例えば、４−メトキシフェニル基（アニシル基）、２，４−ジメトキシフェニル基等の置換フェニル基型保護基、２，４−ジメトキシベンジル基、ビス（４−メトキシフェニル）メチル基等のアリール置換メチル基型保護基、または第三ブチルジフェニルシリル基等のトリアルキルシリル基型保護基等を挙げることができる。脱保護の方法はＲ4の種類に応じて通常の手法で行えるが、４−メトキシフェニル基の例を示す。前項で得られたトリアルキルシリルオキシ化合物を溶媒に溶解あるいは懸濁し、硝酸第二セリウムアンモニウム等の酸化剤あるいはその水溶液を加えることにより、化合物（ＸＩＩＩ）を得ることができる。ここで、反応に用いる溶媒については、例えば、水、アセトニトリル、アセトン、テトラヒドロフラン等、またはこれらの混合溶媒が挙げられるが、水と任意の比率で混合可能な有機溶媒もしくは該有機溶媒と水の混合溶媒が好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは−２０℃から室温まで、さらに好ましくは−５℃から５℃の範囲である。
【００７３】
Boc 基の導入反応
化合物（ＸＩＩＩ）を溶媒に溶解し、４−ジメチルアミノピリジン等の塩基の存在下、ジ-tert-ブチルジカーボネートを加えることにより化合物（ＩＩＩ）を得ることができる。ここで、反応に用いる溶媒は塩化メチレン、テトラヒドロフラン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、乾燥したものが好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは０℃から室温までの範囲である。
【００７４】
化合物（ＩＩＩ）と（ＩＶ）の縮合反応
化合物（ＩＩＩ）および（ＩＶ）を溶媒に溶解し、−７８℃から室温にて（以下に示す塩基により好ましい温度は異なるが冷却した方が好ましい）リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、水素化ナトリウム、カリウム第三ブトキシド等の塩基を加える。あるいは、化合物（ＩＩＩ）または（ＩＶ）の一方の溶液に塩基を加えておき、他方の溶液を加えてもよい。これらの操作は水分の少ない条件で行うことが好ましい。その後、混合時の温度で反応させるかあるいは必要に応じて反応温度を室温付近の温度まで上昇させることにより化合物（ＶＩ）を得ることができる。ここで、反応に用いる溶媒は塩化メチレン、テトラヒドロフラン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、乾燥したものが好ましい。
【００７５】
化合物（ＶＩ）から（Ｉ）へ導く反応
化合物（ＶＩ）のビニル基をアルデヒド基に変換する工程：化合物（ＶＩ）をテトラヒドロフラン、アセトン、ブタノール、アセトニトリル、水等、またはこれらの混合溶媒（含水溶媒が好ましい）に溶解し、四酸化オスミウム、オスミウム酸カリウム等のオレフィンをジオールに変換する酸化剤を反応させる、あるいはＮ−メチルモルホリン−Ｎ−オキサイド等の酸化剤の存在下、触媒量の四酸化オスミウム等を加えることにより、オレフィン部分をジオールに変換した化合物を得ることができる。続いて、このジオール化合物をテトラヒドロフラン、メタノール、エタノール、アセトニトリル、水等、またはこれらの混合溶媒（含水溶媒が好ましい）に溶解し、例えばメタ過ヨウ素酸ナトリウム等の１，２−ジオールを酸化的に解裂させる酸化剤を加えることにより、アルデヒド基に変換された化合物を得ることができる。この工程はジオール化反応後、反応液にそのままメタ過ヨウ素酸ナトリウムあるいはその溶液を加えることによりワンポットで行うこともできる。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは室温付近の温度である。
アルデヒド基をジメチルアミノ基あるいはモルホリノ基に変換する工程：上記で得たアルデヒド化合物を溶媒に溶解し、ジメチルアミンもしくはモルホリンのいずれか一方、酢酸等の酸、および水素化シアノホウ素ナトリウムもしくはトリアセトキシ水素化ホウ素ナトリウム等の還元剤を加えることにより、アルデヒド基をジメチルアミノメチル基もしくはモルホリノメチル基に変換することができる。ここで、反応に用いる溶媒はエタノール、テトラヒドロフラン等、またはこれらの混合溶媒が挙げられ、特に限定されないが、反応の終了までに還元剤を反応が完結するのに必要なだけ溶解するものが好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは室温付近の温度である。
式中（Ｖ）で示す部分が二重結合の場合単結合に還元する工程：上記で得たジメチルアミノ化合物またはモルホリノメチル化合物を溶媒に溶解し、パラジウム炭素、白金炭素、ルテニウム炭素等の還元用触媒を加え、水素雰囲気下またはギ酸もしくはギ酸アンモニウム等の水素源存在下で攪拌することにより、二重結合が単結合に還元された化合物を得ることができる。ここで、反応に用いる溶媒は水、メタノール、エタノール等のアルコール類、テトラヒドロフラン、酢酸エチル等またはこれらの混合溶媒が挙げられ、特に限定されないが、極性溶媒が好ましい。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは室温付近の温度である。
Ｒ 3 を除去する工程：Ｒ3の種類により脱保護の条件は異なるが、Ｒ3がトリイソプロピルシリルオキシ基等のトリアルキルシリルオキシ基である例を示す。上記で得た還元体の化合物をテトラヒドロフラン等の溶媒に溶解し、テトラブチルアンモニウムフロリド等の四級アンモニウムのフッ化物を反応させることにより脱保護ができる。反応温度は０℃前後から室温が望ましい。また、ピリジン溶媒中フッ化水素とピリジンの複合体を用いて脱保護する方法もある。ここで、反応に用いる溶媒はテトラヒドロフランが挙げられるが、特に限定されない。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは−５℃から室温までの範囲である。
【００７６】
化合物（ＩＶ）の合成方法
〔Ｃ６−Ｃ７が二重結合の場合〕１０−Ｏ−デアセチルバッカチンIIIを溶媒に溶解し、水素化ホウ素テトラブチルアンモニウム等の還元剤を反応させると９位がβ水酸基に還元された化合物が得られる。この化合物を溶媒に溶解し、カンファースルホン酸、パラトルエンスルホン酸等の強酸性化合物、もしくはこれらの酸のトリエチルアミン等に代表される三級アミン等の塩、または塩化亜鉛等のルイス酸触媒として機能する化合物の存在下、ジエチルアセタールに代表されるアクロレインのアセタールを反応させることにより、化合物（ＩＶ）の７位水酸化体を得ることができる。この化合物を溶媒に溶解し、４−ジメチルアミノピリジン等の塩基の存在下、無水トリフルオロメタンスルホン酸を反応させると脱水反応が進行し、化合物（ＩＶ）を得ることができる。ここで、反応に用いる溶媒は塩化メチレン、ジクロロエタン等またはこれらの混合溶媒が挙げられるが、特に限定されない。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは−５℃から室温までの範囲である。
〔Ｃ６−Ｃ７位が単結合の場合〕１０−Ｏ−デアセチルバッカチンIIIの７位水酸基が水素原子に置換された化合物が知られている。この化合物をテトラヒドロフラン等の溶媒に溶解し、ボラン−テトラヒドロフラン複合体等のボラン複合体あるいはジボラン等と反応させることにより、９位ケトンがβ水酸基に還元された化合物を得ることができる。この化合物を塩化メチレン、ジクロロエタン等の溶媒に溶解し、カンファースルホン酸、パラトルエンスルホン酸等の強酸性化合物あるいはこれら酸のトリエチルアミン等に代表される三級アミン等の塩、あるいは塩化亜鉛等のルイス酸触媒として機能する化合物の存在下、ジエチルアセタールに代表されるアクロレインのアセタールを反応させることにより、化合物（ＩＶ）を得ることができる。反応温度は通常−７８℃から１００℃もしくは溶媒の沸点までの範囲であるが、好ましくは−５℃から室温までの範囲である。
【００７７】
本発明の化合物は遊離体でもよいが、酸付加塩であってもよい。酸付加塩としては、塩酸塩、硫酸塩、硝酸塩、臭化水素塩、ヨウ化水素塩、リン酸塩等の無機酸塩類、あるいは酢酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、乳酸塩等の有機塩類を挙げることができる。更に水和物または溶媒和物であってもよく、溶媒としてはメタノール、エタノール、プロパノール、ブタノール、アセトン、アセトニトリル、ベンゼン、トルエン、テトラヒドロフラン、N,N-ジメチルホルムアミド等が挙げられる。
【００７８】
また、本発明の医薬は、抗腫瘍作用に基づく癌の治療が達成でき、その治療対象としては、肺癌、消化器癌、卵巣癌、子宮癌、乳癌、肝癌、頭頸部癌、血液癌、腎癌、睾丸腫瘍等の各種癌が挙げられる。
本発明の化合物は、静脈内注射、筋肉内注射、皮下注射等の各種注射剤として、あるいは、経口投与、経皮投与等の種々の方法によって投与することができる。これらの投与法の中では、後に述べる効果達成の面から、経口投与が好ましい。経口投与の場合は遊離体や塩の何れでも良い。
本発明の化合物は、非坦癌マウスを用いた試験の結果、腎毒性は認められなかった。
【００７９】
本発明の化合物の経口剤としての適用性はヒト肝ミクロソームを用いたin vitro試験により予測することができる。経口投与では、薬物は胃腸管で溶解し、消化管内および肝臓での代謝を受けた後に血流の循環系に入る。そのため、肝臓における薬物の代謝は薬物の薬効発現に影響をおよぼすと考えられる。特に、本発明の化合物およびその類縁化合物は肝ミクロソーム内の酵素であるCYP3Aにより代謝を受けることが予測されている。そこで、肝ミクロソームを用いたin vitro試験による代謝予測は実際の臨床での使用を考える上で重要である。肝ミクロソームを用いたin vitro試験からの代謝予測値がヒト臨床試験における実測値にほぼ対応することはPharm. Tech. Japan 13 17-39, 1997、J. Pharmacol. Exp. Ther. 283 46-58, 1997等に記載されている。ヒト肝ミクロソームはXenotech LLC社等から入手可能であり、代謝速度の測定は上記文献等を参考におこなえる。
【００８０】
肝ミクロソームにおける薬物代謝速度を測定すると、さらに、その薬物のバイオアベイアビリティを理論値として計算することができる（J. Pharmacol. Exp. Ther. 283 46-58, 1997）。バイオアベイアビリティは全身循環血中に到達する薬物の投与薬物に対する相対的な量とその速度と定義されている（医薬品開発における薬物動態研究 杉山雄一編 p.15 薬事時報社）。経口投与では薬物が循環血に入るまでに、胃腸管での溶解、消化管粘膜の通過、消化管内および肝臓での代謝等の様々な障害が存在する。このため、最終的血中濃度すなわちバイオアベイアビリティの個体間ばらつきの幅は循環血内直接投与に比較して大きくなると考えられる。Hellriegelらは市販されているさまざまな薬物１４９品目についてバイオアベイアビリティ値とその個体間ばらつき（ＣＶ値）を調査し、両者に負の相関があることを報告している（Clin. Pharmacol. Ther. 60 601-607, 1996）。つまり、バイオアベイアビリティの個体間におけるばらつきの幅は、バイオアベイアビリティの値が小さいほど大きくなることが知られている。
【００８１】
抗腫瘍剤の場合、奏効率を上げるために、最大耐量近辺の用量で投与される場合が多く、それに伴って治療域と毒性域は近接し、結果として安全域は狭くなる。したがって、個体間バイオアベイアビリティのばらつきの幅が大きい薬物の抗腫瘍剤としての使用は困難となる。
本発明の化合物はヒト肝ミクロソームにおける代謝速度が低減され、未変化体の理論バイオアベイアビリティ値も向上した。したがって、個体間での未変化体バイオアベイアビリティ値のばらつきの幅が小さいことが予測された。この効果により、有効な薬効発現と安全域を大きくするという安全性の面から、本発明の化合物は経口投与が充分可能である。なお、未変化体のバイオアベイアビリティ値のばらつきの幅を低減するためには、未変化体の理論バイオアベイアビリティ値は０．４以上であることが好ましく、０．７以上であることがさらに好ましい。
さらに、本発明の化合物の経口剤としての適用性はサルを用いたＢＡ試験によっても予測することができる。化合物Ｂは、マウスおよびイヌの肝ミクロソームによる代謝は遅く実際にマウスでの経口吸収性は優れている。一方、サルの肝ミクロソームによる代謝はヒト肝ミクロソームによる場合と同様に早かった。この場合、化合物Ｂについてはサルにおける経口吸収性は低かった。これに対し、本発明の化合物についてはサルの肝ミクロソームによる代謝はヒト、マウスおよびイヌの肝ミクロソームの場合と同様に遅かった。そこで、代謝の抑制による経口吸収改善効果を確認する目的で、サルを用いてバイオアベイラビリティー（ＢＡ）を測定したところ、本発明の化合物は化合物Ｂに比べサルにおける経口吸収が大幅に改善されたことが確認された。
【００８２】
医薬および抗腫瘍剤の製剤の調製方法としては投与法に応じ適当な製剤を選択し、通常用いられている各種製剤の調製方法にて調製できる。本発明の抗腫瘍剤の剤型のうち経口投与用製剤としては、例えば、錠剤、散剤、顆粒剤、カプセル剤等が挙げられる。その剤の形態としては、溶液剤、シロップ剤、エリキシル剤、油性ないし水性の懸濁液等が挙げられる。このうち、カプセル剤、錠剤や溶液剤が好ましい。注射剤の場合は製剤中に安定剤、防腐剤、溶解補助剤等を使用することもできる。これらの補助剤等を含むこともある溶液を凍結乾燥等によって固形製剤として用時調製の製剤として利用できる。
【００８３】
液体製剤としては、溶液、懸濁液、乳液剤等を挙げることができるが、これらの製剤を調製する際、添加剤として懸濁剤、乳化剤等を使用することもできる。
本発明の化合物は哺乳類、特にヒトの癌治療に用いることができ、ヒトに投与する場合、１日あたり１回投与し、適当な間隔で繰り返すのが好ましい。
投与量としては、体表面積１ｍ2につき約０．５ｍｇから５０ｍｇ、好ましくは約１ｍｇから２０ｍｇの範囲で投与するのが好ましい。
【００８４】
【実施例】
次に実施例で詳しく説明する。なお、実施例の記載において、以下の略語を用いることもある。Ｂｏｃは第三ブトキシカルボニル基、Ａｃはアセチル基、Ｂｚはベンゾイル基、ＴＩＰＳはトリイソプロピルシリル基を意味する。
（参考例）
【００８５】
【化６６】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1,13-ジヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン
(1S, 2S, 3R, 4S, 5R, 7S, 8S, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-9,10-[(1R)-2-プロペニリデンジオキシ]-1,7,13-トリヒドロキシタクス-11-エン18 g、4-ジメチルアミノピリジン37.7 g を塩化メチレン360 mlに溶解し、氷冷下トリフルオロメタンスルフォン酸無水物20.7 mlを加え同温で1.5時間攪拌した。反応液を酢酸エチル、飽和炭酸水素ナトリウム水溶液の混液に注ぎ、二層を分離した。水層を酢酸エチルで抽出し、先の有機層とあわせて水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をシリカゲルカラムクロマトグラフィー（クロロホルム：アセトン＝５０：１(v／v)で溶出）を用いて精製し、標記化合物11.5 gを白色物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ :
1.15 (3H, s), 1.52 (3H, s), 1.56 (3H, s), 1.77 (1H, s), 1.90 (3H, s), 2.07 (1H, dd, J=6.8, 15.1 Hz), 2.23 (1H, d, J=9.3 Hz), 2.36 (3H, s), 3.21 (1H, d, J=5.9 Hz), 4.00 (1H, d, J=7.4 Hz), 4.30 (2H, ABq, J=7.8 Hz), 4.79-4.83 (2H, m), 5.25-5.27 (2H, m), 5.48 (1H, d, J=10.3 Hz), 5.60 (1H, d, J=17.1 Hz), 5.70 (1H, dd, J=3.9, 10.2 Hz), 5.96 (1H, d, J=5.9 Hz), 5.98-6.07 (1H, m), 6.13 (1H, d, J=10.2 Hz), 7.49 (2H, t, J=7.3 Hz), 7.61 (1H, t, J=7.3 Hz), 8.16 (2H, d, J=7.3 Hz).
【００８７】
（実施例１）
【００８８】
【化６７】
工程1：(±)-シス-3-アセトキシ-4-(3-フルオロ-2-ピリジル)-1-(4-メトキシフェニル)-2-アゼチジノン
3-フルオロ-2-ホルミルピリジン20 gと4-アニシジン15.6 gをベンゼン100 mlに溶解し、無水硫酸ナトリウム20 gを加え室温で1時間攪拌した。不溶物を濾去し、減圧下濾液を濃縮した。残分を塩化メチレン400 mlに溶解し、-60℃でトリエチルアミン26.5 ml、2-アセトキシアセチルクロリド20.4 mlを加え一晩かけて室温まで昇温した。反応液に水300 mlを加え、二層を分離した。水層をクロロホルムで抽出し、先の有機層とあわせて飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をシリカゲルカラムクロマトグラフィー（酢酸エチルで溶出）を用いて精製し、標記化合物33.2 gを白色物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ :
1.80 (3H, s), 3.74 (3H, s), 5.72 (1H, d, J=5.1 Hz), 6.09 (1H, d, J=5.1 Hz), 6.78-6.82 (2H, m), 7.23-7.29 (2H, m), 7.30-7.33 (1H, m), 7.41-7.46 (1H, m), 8.44-8.46 (1H, m).
【００９０】
工程2：(±)-シス-4-(3-フルオロ-2-ピリジル)-1-(4-メトキシフェニル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
上記工程1で得た化合物18 gをテトラヒドロフラン180 mlとメタノール180 mlの混液に溶解し、炭酸カリウム500 mgを加え室温で1時間攪拌した。反応液に強酸性樹脂を加えて中和後、不溶物を濾去し、減圧下濾液を濃縮した。残分をジメチルホルムアミド180 mlに溶解し、氷冷下イミダゾール5.6 g、トリイソプロピルシリルクロリド17.5 mlを加え、室温で一晩攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。抽出液を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をヘキサンで洗浄して、標記化合物20 gを白色物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.91-1.07 (21H, m), 3.74 (3H, s), 5.38 (1H, d, J=4.9 Hz), 5.50 (1H, d, J=4.9 Hz), 6.78-6.81 (2H, m), 7.23-7.28 (3H, m), 7.34-7.39 (1H, m), 8.41-8.43 (1H, m).
【００９１】
工程3：(3R, 4S)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
上記工程2で得た化合物1.0 gをアセトニトリル50 mlに溶解し、氷冷下硝酸第二セリウムアンモニウム3.7 gの水溶液20 mlを加え、同温で30分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液、飽和亜硫酸ナトリウム水溶液、酢酸エチルを加え、二層を分離した。水層を酢酸エチルで抽出し、先の有機層とあわせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１(v／v)で溶出）を用いて精製し、(±)-シス-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン0.4 gを得た。本化合物を光学活性カラムで分割し、標記化合物0.18 gを白色物質として得た。
1H NMR (400 MHz, CDCl3, TMS) δ :
0.89-1.06 (21H, m), 5.17 (1H, dd, J=1.0, 4.9 Hz), 5.35 (1H, dd, J=1.4, 4.9 Hz), 6.24 (1H, br s), 7.23-7.28 (1H, m), 7.37 (1H, dt, J=1.5, 8.3 Hz), 8.43 (1H, d, J=4.4 Hz).
[α]D 23 + 38 ° (c=0.11, CHCl3).
【００９２】
分割条件
カラム：ダイセル化学工業CHIRALCEL OD (20 mm x 250 mm)
溶媒：ヘキサン：2-プロパノール＝９２：８(v／v)
流速： 10 ml/min
保持時間：10分［(3S, 4R)-体］、14分［(3R, 4S)-体］
【００９３】
工程4：(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
上記工程3で得た化合物0.18 gとジ-tert-ブチルジカーボネート0.17 gをテトラヒドロフラン5 mlに溶解し、4-ジメチルアミノピリジン13 mgを加え室温で1時間攪拌した。減圧下反応液を濃縮し、残分をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１(v／v)で溶出）を用いて精製し、標記化合物0.24 gを油状物質として得た。
1H NMR (400 MHz, CDCl3, TMS) δ :
0.88-1.03 (21H, m), 1.44 (9H, s), 5.27 (1H, d, J=5.8 Hz), 5.46 (1H, d, J=5.8 Hz), 7.24-7.26 (1H, m), 7.38 (1H, t, J=8.8 Hz), 8.42 (1H, d, J=3.9 Hz).
[α]D 18 + 86 ° (c=1.03, CHCl3).
【００９４】
（実施例２）
【００９５】
【化６８】
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
3-フルオロ-2-ホルミルピリジンの代わりに5-メトキシ-2-ホルミルピリジンを使用して、実施例１の工程と同様の操作を行うことにより、標記化合物を油状物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ :
0.88-1.01 (21H, m), 1.43 (9H, s), 3.85 (3H, s), 5.10 (1H, d, J=5.8 Hz), 5.29 (1H, d, J=5.8 Hz), 7.18-7.28 (2H, m), 8.27 (1H, d, J=3 Hz).
【００９７】
（実施例３）
【００９８】
【化６９】
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-クロロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
3-フルオロ-2-ホルミルピリジンの代わりに5-クロロ-2-ホルミルピリジンを使用して、実施例１の工程と同様の操作を行うことにより、標記化合物を油状物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ :
0.88-1.02 (21 H, m), 1.44 (9H, s), 5.12 (1H, d, J=4.9 Hz), 5.31 (1H, d, J=4.9 Hz), 7.29 (1H, d, J=8.3 Hz), 7.68 (1H, dd, J=2.4, 8.3 Hz), 8.54 (1H, d, J=2.4 Hz).
【０１００】
（実施例４）
【化７０】
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
3-フルオロ-2-ホルミルピリジンの代わりに5-フルオロ-2-ホルミルピリジンを使用して、実施例１の工程と同様の操作を行うことにより、標記化合物を油状物質として得た。
1H-NMR (400 MHz, CDCl3, TMS) δ :
0.88-1.01 (21 H, m), 1.44 (9H, s), 5.14 (1H, d, J=4.9 Hz), 5.33 (1H, d, J=4.9 Hz), 7.33-7.45 (2H, m), 8.44 (1H, d, J=2.9 Hz)
【０１０２】
（実施例５）
【０１０３】
【化７１】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-メトキシ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1,13-ジヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン 300 mgを乾燥したテトラヒドロフラン10 mlに溶解し、−60℃でリチウムヘキサメチルジシラジド（1モル−テトラヒドロフラン溶液）0.63 mlを加え25分間攪拌した。同温度で反応液に (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン280 mgのテトラヒドロフラン5 ml 溶液を加え、氷冷下で40分間攪拌した。反応液に飽和塩化アンモニウム水溶液及び酢酸エチルを加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝５：１(v／v)）で精製し、標記化合物540 mgを得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.89-0.95 (21H, m), 1.32 (3H, s), 1.33-1.62 (3H, m), 1.41 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.92-2.32 (3H, m), 2.49 (3H, s), 2.98 (1H, d, J=4.9 Hz), 3.85 (3H, s), 4.20 (1H, d, J=7.4 Hz), 4.22 (1H, d, J=6.8 Hz), 4.32 (1H, d, J=8.3 Hz), 4.95 (1H, s), 5.21 (1H, d, J=5.8 Hz), 5.26-5.29 (2H, m), 5.39-5.47 (3H, m), 5.57 (1H, d, J=17.6 Hz), 5.96-6.02 (2H, m), 6.11 (1H, t-like, J=8.3 Hz), 7.15 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=8.8 Hz), 7.44 (2H, t, J=7.8 Hz), 7.56 (1H, t, J=7.8 Hz), 8.13 (2H, d, J=7.8 Hz), 8.26 (1H, d, J=3.0 Hz).
【０１０５】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-(5-メトキシ-2-ピリジル)プロピオネート
上記工程1で得た化合物530 mgを乾燥したテトラヒドロフラン10 mlに溶解し、氷冷下テトラブチルアンモニウムフルオリド（1モル−テトラヒドロフラン溶液）1.0 mlを加え、同温度で30分間攪拌した。反応液に水および酢酸エチルを加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムを用いて乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１(v／v)）で精製し、標記化合物410 mgを得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.43 (9H, s), 1.50 (3H, s), 1.60-1.91 (3H, m), 1.64 (3H, s), 1.74 (3H, s), 1.91 (1H, s), 2.04-2.16 (2H, m), 2.32-2.37 (1H, m), 2.34 (3H, s), 2.93 (1H, d, J=5.3 Hz), 3.85 (3H, s), 4.18 (1H, d, J=7.3 Hz), 4.22 (1H, d, J=8.3 Hz), 4.33 (1H, d, J=8.3 Hz), 4.79 (1H, br s), 4.85 (1H, br s), 4.92 (1H, br s), 5.23 (1H, d, J=5.8 Hz), 5.29-5.30 (2H, m), 5.46 (1H, d, J=10.3 Hz), 5.58 (1H, d, J=17.1 Hz), 5.90 (1H, d, J=9.7 Hz), 5.96-6.03 (2H, m), 6.09 (1H, t-like, J=8.4 Hz), 7.22 (1H, dd, J=2.4, 8.8 Hz), 7.34 (1H, d, J=8.8 Hz), 7.47 (2H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.13 (2H, d, J=7.8 Hz), 8.22 (1H, d, J=2.4 Hz).
【０１０６】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-(5-メトキシ-2-ピリジル)プロピオネート
上記工程2で得た化合物400 mgをテトラヒドロフラン5 mlに溶解し、アセトン5ml、水5 ml、四酸化オスミウム5.9 mg、およびN-メチルモルホリン-N-オキシド270 mgを加え、室温で4.5 時間攪拌した。反応液に酢酸エチルおよび 10 %チオ硫酸ナトリウム水溶液を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、残渣をテトラヒドロフラン5 mlに溶解し、メタノール5 ml、水 5 mlおよびメタ過ヨウ素酸ナトリウム990 mgを加え、室温で1.5 時間攪拌した。反応液に酢酸エチルおよび水を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエタノール30 mlに溶解し、モルホリン0.2 ml、酢酸 0.13 mlおよび水素化シアノホウ素ナトリウム140 mgを加え、室温で1時間攪拌した。反応液に飽和重曹水、酢酸エチルおよび水を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；クロロホルム：メタノール＝50：1 (v／v)）を用いて精製し、標記化合物220 mgを得た。
融点：160-161℃
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.27 (3H, s), 1.43 (9H, s), 1.48 (3H, s), 1.60 (3H, s), 1.72 (3H, s), 1.78-2.12 (6H, m), 2.31-2.38 (1H, m), 2.34 (3H, s), 2.58-2.68 (4H, m), 2.71 (1H, dd, J=5.4, 13.2 Hz), 2.79 (1H, dd, J=3.9, 13.2 Hz), 2.93 (1H, d,J=5.3 Hz), 3.75 (4H, t, J=4.9 Hz), 3.86 (3H, s), 4.12 (1H, d, J=7.3 Hz),4.21 (1H, d, J=8.3 Hz), 4.33 (1H, d, J=8.3 Hz), 4.76 (1H, br s), 4.85 (1H, br s), 4.92 (1H, s), 5.04 (1H, t, J=4.6 Hz), 5.23 (1H, d, J=6.9 Hz),5.29 (1H, d, J=8.8 Hz), 5.90 (1H, d, J=9.3 Hz), 5.98 (1H, d, J=4.9 Hz),6.08 (1H, t-like, J=8.3 Hz), 7.22 (1H, dd, J=2.9, 8.8 Hz), 7.34 (1H, d,J=8.8 Hz), 7.47 (2H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.13 (2H, d,J=7.8 Hz), 8.22 (1H, d, J=2.9 Hz).
元素分析（C49H65N3O15として）
計算値 : C, 62.87; H, 7.00; N, 4.49
実測値 : C, 62.66; H, 7.08; N, 4.28
【０１０７】
（実施例６）
【０１０８】
【化７２】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-クロロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンの代わりに (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-クロロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンを使用して、実施例５の工程1と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.87-0.94 (21H, m), 1.18-1.69 (2H, m), 1.31 (3H, s), 1.41 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.72-2.05 (2H, m), 2.24-2.34 (2H, m), 2.48 (3H, s), 2.97 (1H, d, J= 5.4 Hz), 4.19-4.23 (2H, m), 4.33 (1H, d, J= 7.8 Hz), 4.95 (1H, s), 5.21 (1H, d, J = 5.8 Hz), 5.27-5.31 (2H, m), 5.42-5.47 (3H, m), 5.58 (1H, d, J = 17.5 Hz), 5.96-6.04 (2H, m), 6.11 (1H, t, J= 8.8 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.57 (1H, t, J = 7.3 Hz), 7.65 (1H, dd, J = 8.3 Hz, 2.5 Hz), 8.13 (2H, d, J = 7.3 Hz), 8.53 (1H, d, J = 2.5 Hz).
【０１１０】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-クロロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程1で得た化合物を原料に用い、実施例５の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:1.26 (3H, s), 1.22-1.65 (2H, m), 1.43 (9H, s), 1.49 (3H, s), 1.64 (3H, s), 1.74 (3H, s), 1.75-2.09 (2H, m), 2.30-2.39 (2H, m), 2.33 (3H, s), 2.94 (1H, d, J= 4.9 Hz), 4.18 (1H, d, J = 5.3 Hz), 4.22 (1H, d, J = 8.3 Hz)4.32 (1H, d, J= 8.3 Hz), 4.61 (1H, br s), 4.92 (2H, m), 5.24 (1H, d, J= 6.3 Hz), 5.30 (1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz), 5.46 (1H,d, J = 10.5 Hz), 5.58 (1H, d, J = 17.5 Hz), 5.87 (1H, d, J = 9.3 Hz), 5.96-6.05 (2H, m), 6.11 (1H, t, J = 7.8 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 7.69 (1H, dd, J = 8.3Hz, 2.4 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.51 (1H, d, J = 2.4 Hz).
【０１１１】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-クロロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程2で得た化合物を原料に用い、実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
融点：146-150℃
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.20-1.72 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.63 (3H, s), 1.73 (3H, s), 1.75-2.03 (2H, m), 2.33 (3H, s), 2.30-2.38 (2H, m), 2.59-2.69 (4H, m), 2.72 (1H, dd, J= 5.4, 13.2 Hz), 2.79 (1H, dd, J=3.9, 13.2Hz), 2.92 (1H, d, J= 4.9 Hz), 3.74 (4H, t, J= 4.9 Hz), 4.12 (1H, d, J= 7.9 Hz), 4.22 (1H, d, J= 8.8 Hz), 4.32 (1H, d, J= 8.8 Hz), 4.59 (1H, br s), 4.91 (2H, m), 5.05 (1H, t, J = 4.4 Hz), 5.24 (1H, d, J = 6.8 Hz), 5.35 (1H, d, J = 9.3 Hz), 5.87 (1H, d, J = 9.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.10 (1H, t, J = 8.0 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 7.69 (1H, dd, J = 8.3 Hz, 2.5 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.50 (1H, d, J = 2.5 Hz).元素分析（C48H62ClN3O14・H2Oとして）
計算値 :C, 60.15; H, 6.73; N, 4.38; Cl, 3.70
実測値 :C, 60.15; H, 6.74; N, 4.20; Cl, 3.63
【０１１２】
（実施例７）
【０１１３】
【化７３】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンの代わりに (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンを使用して、実施例５の工程1と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.87-0.94 (21H, m), 1.20-1.70 (2H, m), 1.31 (3H, s), 1.42 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.75-2.07 (2H, m), 2.26-2.32 (2H, m), 2.49 (3H, s), 2.97 (1H, d, J= 5.4 Hz), 4.19-4.23 (2H, m), 4.33 (1H, d, J= 8 Hz), 4.96 (1H, s), 5.21 (1H, d, J = 5.9 Hz), 5.27-5.32 (2H, m), 5.43-5.49 (3H, m), 5.58 (1H, d, J = 17.5 Hz), 5.96-6.04 (2H, m), 6.12 (1H, t, J= 8 Hz), 7.36-7.47 (4H, m), 7.57 (1H, t, J = 7.3 Hz), 8.13 (2H, d, J = 7.3 Hz), 8.43 (1H, d, J = 2.4 Hz).
【０１１５】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程1で得た化合物を原料に用い、実施例５の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:1.27 (3H, s), 1.20-1.68 (2H, m), 1.44 (9H, s), 1.49 (3H, s), 1.64 (3H, s), 1.74 (3H, s), 1.75-2.05 (2H, m), 2.30-2.39 (2H, m), 2.34 (3H, s), 2.93 (1H, d, J= 4.9 Hz), 4.18 (1H, d, J = 6.8 Hz), 4.23 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J= 8.3 Hz), 4.62 (1H, d, J = 2.5 Hz), 4.90-4.92 (2H, m), 5.24 (1H, d, J = 5.8 Hz), 5.30 (1H, d, J = 6.8 Hz), 5.37 (1H, d, J = 9.3Hz), 5.46 (1H, d, J = 10.2 Hz), 5.58 (1H, d, J = 17 Hz), 5.90 (1H, d, J= 10.2 Hz), 5.96-6.05 (2H, m), 6.10 (1H, t, J = 7.8 Hz), 7.40-7.49 (4H,m), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.41 (1H, s).
【０１１６】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程2で得た化合物を原料に用い、実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
融点：148-152℃
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.20-1.69 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.62 (3H, s), 1.72 (3H, s), 1.75-2.02 (2H, m), 2.33 (3H, s), 2.30-2.39 (2H, m), 2.59-2.69 (4H, m), 2.71 (1H, dd, J= 5.4, 13.2 Hz), 2.79 (1H, dd, J=3.9, 13.2 Hz) 2.92 (1H, d, J= 4.9 Hz), 3.74 (4H, t, J= 4.9 Hz), 4.12 (1H, d, J= 7.3 Hz), 4.22 (1H, d, J= 8.3 Hz), 4.32 (1H, d, J= 8.3 Hz), 4.60 (1H, br s), 4.90-4.92 (2H, m), 5.04 (1H, t, J = 4.9 Hz), 5.24 (1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz), 5.89 (1H, d, J = 9.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.09 (1H, t, J = 8.0 Hz), 7.42-7.49 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.40 (1H, s).
元素分析（C48H62FN3O14・H2Oとして）
計算値 :C, 61.19; H, 6.85; N, 4.46; F, 2.02
実測値 :C, 61.16; H, 6.85; N, 4.36; F, 2.05
【０１１７】
（実施例８）
【０１１８】
【化７４】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-(5-メトキシ-2-ピリジル)プロピオネート
実施例５の工程2で得た化合物を原料に用いて、モルホリンの代わりにジメチルアミン（2モル−メタノール溶液）を使用して実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.43 (9H, s), 1.48 (3H, s), 1.61 (3H, s), 1.73 (3H, s), 1.83-1.97 (3H, m), 2.04-2.12 (2H, m), 2.31-2.38 (2H, m), 2.34 (3H, s), 2.38 (6H, s), 2.64-2.76 (2H, m), 2.93 (1H, d, J=4.9 Hz), 3.85 (3H, s), 4.13 (1H, d, J=7.4 Hz), 4.21 (1H, d, J=8.3 Hz), 4.33 (1H, d, J=8.3 Hz), 4.84 (1H, d, J=2.4 Hz), 4.92 (1H, s), 5.01 (1H, t, J=4.9 Hz), 5.24 (1H, d, J=6.8 Hz), 5.29 (1H, d, J=8.8 Hz), 5.91 (1H, d, J=9.3 Hz), 5.99 (1H, d, J=5.4 Hz), 6.08 (1H, t, J=7.8 Hz), 7.23 (1H, dd, J=3.0, 8.3 Hz), 7.34 (1H, d, J=8.8 Hz), 7.47 (2H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.12 (2H, d, J=7.8 Hz), 8.22 (1H, d, J=3.0 Hz).
【０１２０】
（実施例９）
【０１２１】
【化７５】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
実施例７の工程2で得た化合物を原料に用いて、モルホリンの代わりにジメチルアミン（2モル−メタノール溶液）を使用して実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.20-1.70 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.62 (3H, s), 1.73 (3H, s), 1.75-2.01 (3H, m), 2.33 (3H, s), 2.38 (6H, s), 2.32-2.39 (2H, m), 2.66 (1H, dd, J=5.4, 13.2 Hz), 2.74 (1H, dd, J= 4.0, 13.2 Hz), 2.93 (1H, d, J= 4.9 Hz), 4.12 (1H, d, J= 7.3 Hz), 4.22 (1H, d, J= 8.3 Hz), 4.32 (1H, d, J= 8.3 Hz), 4.90-4.92 (2H, m), 5.02 (1H, t, J = 5.4 Hz), 5.25 (1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 6.8 Hz), 5.90 (1H, d, J = 8.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.09 (1H, t, J = 8.1 Hz), 7.42-7.49 (4H, m), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.41 (1H, s).
【０１２３】
（実施例１０）
【０１２４】
【化７６】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンの代わりに (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンを使用して、実施例５の工程1と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.89-0.93 (21H, m), 1.28 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.66 (3H, s), 1.82 (3H, s), 1.61-1.64 (3H, m), 1.89-1.96 (2H, m), 2.33-2.39 (2H, m), 2.49 (3H, s), 2.98 (1H, d, J=4.8 Hz), 4.21-4.23 (2H, m), 4.36 (1H, d, J=7.8 Hz), 4.96 (2H, br s), 5.20 (1H, d, J=5.9 Hz), 5.27 (1H, d, J=6.8 Hz), 5.46 (1H, d, J=9.8 Hz), 5.58 (1H, d, J=17.1 Hz), 5.61 (1H, d, J=6.8 Hz), 5.96-6.03 (2H, m), 6.08-6.12 (2H, m), 7.25-7.29 (1H, m), 7.40 (1H, t, J=8.3 Hz), 7.47 (2H, t, J=7.8 Hz), 7.59 (1H, t, J=7.8 Hz), 8.16 (2H, d, J=7.8 Hz), 8.39 (1H, d, J=3.4 Hz).
【０１２６】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程1で得た化合物を原料に用い、実施例５の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.30 (3H, s), 1.41 (9H, s), 1.51 (3H, s), 1.65 (3H, s), 1.81 (3H, s), 1.57-1.63 (3H, m), 1.89-1.95 (2H, m), 2.03-2.10 (1H, m), 2.35 (3H, s), 2.43-2.49 (1H, m), 2.95 (1H, d, J=4.9 Hz), 4.20 (1H, d, J=7.4 Hz), 4.23 (1H, d, J=8.8 Hz), 4.33 (1H, d, J=8.3 Hz), 4.68 (1H, d, J=2.5 Hz), 4.92 (1H, s), 5.24 (1H, d, J=6.4 Hz), 5.31 (1H, d, J=6.8 Hz), 5.46 (1H, d, J=9.8 Hz), 5.58 (1H, d, J=17.1 Hz), 5.65 (1H, d, J=8.3 Hz), 5.97-6.05 (2H, m), 6.10 (1H, t, J=8.8 Hz), 6.21 (1H, d, J=8.3 Hz), 7.29-7.32 (1H, m), 7.43-7.49 (3H, m), 7.60 (1H, t, J=7.3 Hz), 8.14 (2H, d, J=7.3 Hz), 8.41 (1H, d, J=4.9 Hz).
【０１２７】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程2で得た化合物を原料に用い、実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.29 (3H, s), 1.40 (9H, s), 1.49 (3H, s), 1.61 (3H, s), 1.79 (3H, s), 1.70-2.03 (5H, m), 2.30-2.44 (2H, m), 2.35 (3H, s), 2.61-2.65 (4H, m), 2.70-2.82 (2H, m), 2.94 (1H, d, J=4.8 Hz), 3.75 (4H, t, J=4.9 Hz), 4.14 (1H, d, J=7.3 Hz), 4.23 (1H, d, J=8.3 Hz), 4.33 (1H, d, J=7.8 Hz), 4.67 (1H, s), 4.92 (1H, s), 5.05 (1H, t, J=4.9 Hz), 5.25 (1H, d, J=7.3 Hz), 5.65 (1H, d, J=7.8 Hz), 5.99 (1H, d, J=5.4 Hz), 6.09 (1H, t, J=7.8 Hz), 6.20 (1H, d, J=8.3 Hz), 7.29-7.33 (1H, m), 7.43-7.49 (3H, m), 7.60 (1H, t, J=7.3 Hz), 8.13 (2H, d, J=7.3 Hz), 8.40 (1H, d, J=4.9 Hz).
【０１２８】
（実施例１１）
【０１２９】
【化７７】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
実施例１０の工程2で得た化合物を原料に用いて、モルホリンの代わりにジメチルアミン（2モル−メタノール溶液）を使用して実施例５の工程3と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.29 (3H, s), 1.41 (9H, s), 1.49 (3H, s), 1.63 (3H, s), 1.79 (3H, s), 1.86-2.08 (5H, m), 2.32-2.38 (2H, m), 2.34 (3H, s), 2.38 (6H, s), 2.66 (1H, dd, J=5.4, 13.6 Hz), 2.75 (1H, dd, J=3.9, 13.6 Hz), 2.94 (1H, d, J=4.9 Hz), 4.14 (1H, d, J=6.9 Hz), 4.23 (1H, d, J=8.3 Hz), 4.33 (1H, d, J=8.3 Hz), 4.68 (1H, d, J=2.9 Hz), 4.92 (1H, s), 5.02 (1H, t, J=4.9 Hz), 5.25 (1H, d, J=6.8 Hz), 5.65 (1H, d, J=8.3 Hz), 6.00 (1H, d, J=4.9 Hz), 6.09 (1H, t, J=7.8 Hz), 6.21 (1H, d, J=8.3 Hz), 7.28-7.33 (1H, m), 7.43-7.49 (3H, m), 7.60 (1H, t, J=7.3 Hz), 8.14 (2H, d, J=7.3 Hz), 8.40 (1H, d, J=4.4 Hz).
【０１３１】
（実施例１２）
【０１３２】
【化７８】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ-3-(5-メトキシ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1,13-ジヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン 300 mgを乾燥したテトラヒドロフラン10 mlに溶解し、−60℃でリチウムヘキサメチルジシラジド（1モル−テトラヒドロフラン溶液）0.63 mlを加え20分間攪拌した。同温で反応液に (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン280 mgのテトラヒドロフラン5 ml 溶液を加え、氷冷下で30分間攪拌した。反応液に飽和塩化アンモニア水および酢酸エチルを加え分液操作し、水層を酢酸エチルで抽出した。有機層をあわせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１(v／v)で溶出）で精製し、標記化合物530 mgを得た。1H-NMR (400 MHz, CDCl3, TMS) δ:
0.87-0.93 (21H, m), 1.29 (3H, s), 1.41 (9H, s), 1.54 (3H, s), 1.69 (3H, s), 1.75 (3H, s), 1.82 (1H, s), 2.29 (1H, dd, J=9.8, 15.1 Hz), 2.40 (1H, dd, J=8.8, 15.1 Hz), 2.53 (3H, s), 3.13 (1H, d, J=5.8 Hz), 3.85 (3H, s), 4.04 (1H, d, J=7.3 Hz), 4.30 (2H, br s), 4.90 (1H, d, J=3.9 Hz), 5.20-5.23 (2H, m), 5.28 (1H, d, J=9.8 Hz), 5.38 (1H, s), 5.47-5.49 (2H, m), 5.60 (1H, d, J=17.0 Hz), 5.71 (1H, dd, J=4.4, 10.2 Hz), 5.96-6.06 (2H, m), 6.09-6.14 (2H, m), 7.16 (1H, dd, J=2.9, 8.3 Hz), 7.31 (1H, d, J=8.3 Hz), 7.47 (2H, t, J=7.8 Hz), 7.58 (1H, t, J=7.8 Hz), 8.14 (2H, d, J=7.8 Hz), 8.26 (1H, d, J=2.9 Hz).
【０１３４】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-メトキシ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
上記工程1で得た化合物520 mgをテトラヒドロフラン 5 mlに溶解し、アセトン 5 ml、水 5 ml、四酸化オスミウム 13 mg、およびN-メチルモルホリン-N-オキシド 300 mgを加え、室温で7.5 時間攪拌した。反応液に酢酸エチルおよび 10 %チオ硫酸ナトリウム水溶液を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をテトラヒドロフラン 5 mlに溶解し、メタノール5 ml、水 5 mlおよびメタ過ヨウ素酸ナトリウム1.1 gを加え、室温で1.5 時間攪拌した。反応液に酢酸エチルおよび水を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエタノール 30 mlに溶解し、氷冷下モルホリン0.22 ml、酢酸 0.15 mlおよび水素化シアノホウ素ナトリウム 160 mgを加え、室温で1時間攪拌した。反応液に飽和重曹水、酢酸エチルおよび水を加え分液操作し、水層を酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：２(v／v)で溶出）を用いて精製し、標記化合物290 mgを得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.87-0.93 (21H, m), 1.28 (3H, s), 1.41 (9H, s), 1.53 (3H, s), 1.55 (3H, s), 1.73 (3H, s), 1.80 (1H, s), 2.26 (1H, dd, J=8.8, 15.1 Hz), 2.39 (1H, dd, J=9.8, 15.1 Hz), 2.53 (3H, s), 2.60-2.68 (4H, m), 2.74 (1H, dd, J=4.9, 13.7 Hz), 2.81 (1H, dd, J=4.9, 13.7 Hz), 3.12 (1H, d, J=5.4 Hz), 3.76 (4H, t, J=4.8 Hz), 3.85 (3H, s), 3.99 (1H, d, J=7.9 Hz), 4.30 (2H, s), 4.89 (1H, d, J=3.9 Hz), 5.02 (1H, t, J=3.9 Hz), 5.14 (1H, d, J=7.3 Hz), 5.27 (1H, d, J=9.8 Hz), 5.37 (1H, d, J=1.5 Hz), 5.47 (1H, d, J=9.8 Hz), 5.69 (1H, dd, J=3.9, 10.5 Hz), 5.94 (1H, d, J=5.3 Hz), 6.07-6.13 (2H, m), 7.16 (1H, dd, J=2.9, 6.3 Hz), 7.30 (1H, d, J=6.3 Hz), 7.47 (2H, t, J=7.8 Hz), 7.58 (1H, t, J=7.8 Hz), 8.15 (2H, d, J=7.8 Hz), 8.26 (1H, d, J=2.9 Hz).
【０１３５】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(5-メトキシ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート上記工程2で得た化合物235 mgをエタノール10 mlに溶解し、5％パラジウム炭素触媒（ウエット）235 mg を加え水素加圧下（4kg/cm2=392kPa）、10時間振盪した。触媒をろ去後、ろ液を濃縮し、標記化合物230 mgを得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.88-0.94 (21H, m), 1.30 (3H, s), 1.42 (9H, s), 1.50 (3H, s), 1.60 (3H, s), 1.79 (3H, s), 1.84-2.30 (7H, m), 2.50 (3H, s), 2.60-2.84 (4H, m), 2.85-2.92 (2H, m), 2.95 (1H, d, J=4.4 Hz), 3.80 (4H, t, J=4.4 Hz), 3.85 (3H, s), 4.17 (1H, d, J=7.3 Hz), 4.19 (1H, d, J=8.7 Hz), 4.33 (1H, d, J=8.3 Hz), 4.96 (1H, s), 5.10 (1H, br s), 5.22-5.28 (2H, m), 5.40 (1H, s), 5.48 (1H, d, J=10.3 Hz), 5.96 (1H, d, J=4.9 Hz), 6.10 (1H, t, J=8.3 Hz), 7.12-7.17 (1H, m), 7.31 (1H, d, J=8.3 Hz), 7.45 (2H, t, J=7.8 Hz), 7.57 (1H, t, J=7.8 Hz), 8.13 (2H, d, J=7.8 Hz), 8.26 (1H, d, J=2.9 Hz)
【０１３６】
工程4：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-(モルホリノ)エチリデンジオキシ]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-(5-メトキシ-2-ピリジル)プロピオネート
上記工程3で得た化合物230 mgを乾燥したテトラヒドロフラン5 mlに溶解し、氷冷下テトラブチルアンモニウムフルオリド（1モル−テトラヒドロフラン溶液）0.43 mlを加え、同温で30分間攪拌した。反応液に飽和食塩水および酢酸エチルを加え分液操作し、水層を酢酸エチルで抽出した。有機層をあわせて飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１(v／v)で溶出）で精製後、含水エタノールより再結晶を行い、標記化合物110 mgを得た。機器データは実施例５の工程3で得た化合物と一致していた。
【０１３７】
（実施例１３）
【０１３８】
【化７９】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンの代わりに (3R, 4S)-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンを使用して、実施例１２の工程1と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.88-0.92 (21H, m), 1.33 (3H, s), 1.38 (9H, s), 1.56 (3H, s), 1.60 (3H, s), 1.76 (3H, s), 2.41-2.45 (2H, m), 2.51 (3H, s), 3.14 (1H, d, J= 5.8 Hz), 4.06 (1H, d, J = 7.8 Hz), 4.33 (2H, s), 4.90 (1H, d, J = 4.4 Hz), 4.94 (1H, d, J = 2.4 Hz), 5.19-5.22 (2H, m), 5.48 (1H, d, J = 10.3 Hz), 5.58-5.64 (2H, m), 5.70 (1H, dd, J = 10.3, 4.4 Hz), 5.96-6.14 (5H, m), 7.26-7.30 (1H, m), 7.41 (1H, t, J = 8.5 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.59(1H, t, J = 7.5 Hz), 8.17 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 4.4 Hz).
【０１４０】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
上記工程1で得た化合物を原料に用い、モルホリンの代わりにジメチルアミン（2モル−メタノール溶液）を使用して実施例１２の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.87-0.92 (21H, m), 1.32 (3H, s), 1.38 (9H, s), 1.55 (3H, s), 1.57 (3H, s), 1.75 (3H, s), 2.39 (6H, s), 2.42-2.45 (2H, m), 2.51 (3H, s), 2.66 (1H, dd, J=5.1, 13.2 Hz), 2.74 (1H, dd, J = 4.2, 13.2 Hz), 3.14 (1H, d, J= 5.8 Hz), 4.01 (1H, d, J = 7.9 Hz), 4.32 (2H, s), 4.90-4.94 (2H, m), 5.00 (1H, t, J = 4.9 Hz), 5.15 (1H, d, J = 7.9 Hz), 5.63 (1H, d, J = 9.8 Hz), 5.69 (1H, dd, J = 9.8, 4.4 Hz), 5.95 (1H, d, J = 5.8 Hz), 6.07-6.13 (3H, m), 7.26-7.28 (1H, m), 7.41 (1H, t, J = 9.2 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.59 (1H, t, J = 7.5 Hz), 8.17 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 4.4 Hz).
【０１４１】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート上記工程2で得た化合物を原料に用い、実施例１２の工程3と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
0.83-0.93 (21H, m), 1.35 (3H, s), 1.38 (9H, s), 1.52 (3H, s), 1.56-2.07 (5H, m), 1.62 (3H, s), 1.81 (3H, s), 2.34-2.43 (2H, m), 2.38 (6H, s), 2.49 (3H, s), 2.66 (1H, dd, J=5.4, 13.2 Hz), 2.74 (1H, dd, J = 3.4, 13.2 Hz), 2.98 (1H, d, J= 5.4 Hz), 4.17 (1H, d, J = 7.3 Hz), 4.22 (1H, d, J=7.8 Hz), 4.36 (1H, d, J=8.3 Hz), 4.96 (2H, s), 5.00 (1H, t, J = 4.8 Hz), 5.22 (1H, d, J = 7.3 Hz), 5.60 (1H, d, J = 8.8 Hz), 5.98 (1H, d, J = 4.9 Hz), 6.08-6.10 (2H, m), 7.26-7.28 (1H, m), 7.40 (1H, t, J = 9.2 Hz), 7.48 (2H, t, J = 7.5 Hz), 7.59 (1H, t, J = 7.5 Hz), 8.16 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 3.9 Hz).
【０１４２】
工程4：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程3で得た化合物を原料に用い、実施例１２の工程4と同様な操作を行うことにより、標記化合物を得た。機器データは実施例１１の工程3で得た化合物と一致していた。
【０１４３】
（実施例１４）
【０１４４】
【化８０】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-(2-プロペニリデンジオキシ)タクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
実施例１３の工程1で得た化合物を原料に用いて、実施例５の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.29 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.60 (3H, s), 1.74 (3H, s), 1.91 (1H, s), 2.35-2.48 (2H, m), 2.41 (3H, s), 3.11 (1H, d, J=5.4 Hz), 3.92 (1H, br s), 4.03 (1H, d, J=7.6 Hz), 4.27 (1H, d, J=8.1 Hz), 4.33 (1H, d, J=8.2 Hz), 4.67 (1H, br s), 4.87 (1H, d, J=4.1 Hz), 5.22-5.25 (2H, m), 5.48 (1H, d, J=10.8 Hz), 5.60 (1H, d, J=17.3 Hz), 5.62-5.64 (1H, m), 5.69 (1H, dd, J=4.1, 10.3 Hz), 5.98-6.13 (4H, m), 6.21 (1H, d, J=8.3 Hz), 7.29-7.33 (1H, m), 7.43-7.50 (3H, m), 7.60 (1H, t, J=7.3 Hz), 8.15 (2H, d, J=7.6 Hz), 8.39 (1H, d, J=4.6 Hz).
【０１４６】
（実施例１５）
【０１４７】
【化８１】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
実施例１３の工程2で得た化合物を原料に用いて、実施例５の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.28 (3H, s), 1.39 (9H, s), 1.52 (3H, s), 1.57 (3H, s), 1.72 (3H, s), 1.86 (1H, s), 2.27-2.46 (2H, m), 2.39 (6H, s), 2.41 (3H, s), 2.69 (1H, dd, J=5.2, 13.2 Hz), 2.79 (1H, dd, J=4.2, 13.2 Hz), 3.11 (1H, d, J=5.9 Hz), 3.98 (1H, d, J=7.6 Hz), 4.28 (1H, d, J=8.1 Hz), 4.33 (1H, d, J=8.3 Hz), 4.66 (1H, d, J=2.5 Hz), 4.87 (1H, d, J=4.1 Hz), 5.02 (1H, dd, J=4.2, 4.8 Hz), 5.17 (1H, d, J=7.8 Hz), 5.62 (1H, d, J=8.5 Hz), 5.68 (1H, dd, J=4.1, 10.3 Hz), 5.96 (1H, m), 6.10 (2H, m), 6.20 (1H, d, J=6.9 Hz), 7.27-7.60 (6H, m), 8.15 (2H, d, J=7.3 Hz), 8.40 (1H, d, J=4.6 Hz).
【０１４９】
（実施例１６）
【０１５０】
【化８２】
工程1：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-(2-プロペニリデンジオキシ)タクス-6,11-ジエン-13-イル (2R, 3S)-2-ベンジルオキシ-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)プロピオネート
(3R, 4S)-1-(tert-ブトキシカルボニル)-4-(5-メトキシ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノンの代わりに (3R, 4S)-3-ベンジルオキシ-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-2-アゼチジノンを使用して、実施例１２の工程1と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.32 (3H, s), 1.39 (9H, s), 1.56 (3H, s), 1.59 (3H, s), 1.77 (3H, s), 1.85 (1H, s), 2.31 (3H, s), 2.39 (2H, m), 3.13 (1H, d, J=6.1 Hz), 4.07 (1H, d, J=7.6 Hz), 4.18 (1H, d, J=12.0 Hz), 4.31 (3H, m), 4.68 (1H, d, J=12.2 Hz), 4.90 (1H, d, J=4.2 Hz), 5.23 (2H, t, J=7.1 Hz), 5.48 (1H, d, J=11.0 Hz), 5.59 (2H, m), 5.70 (1H, dd, J=4.4, 10.5 Hz), 6.02 (1H, m), 6.13 (2H, d, J=10.2 Hz), 6.26 (1H, d, J=9.0 Hz), 6.88 (2H, d, J=7.1 Hz), 7.19 (3H, m), 7.29 (2H, t, J=6.8 Hz), 7.49 (2H, t, J=7.8 Hz), 7.60 (1H, t, J=7.3 Hz), 8.16 (2H, d, J=7.3 Hz), 8.42 (1H, m).
【０１５２】
工程2：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-6,11-ジエン-13-イル (2R, 3S)-2-ベンジルオキシ-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)プロピオネート
上記工程1で得た化合物を原料に用い、モルホリンの代わりにジメチルアミン（2モル−メタノール溶液）を使用して実施例１２の工程2と同様な操作を行うことにより、標記化合物を得た。
1H-NMR (400 MHz, CDCl3, TMS) δ:
1.26 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.57 (3H, s), 1.75 (3H, s), 1.82 (1H, s), 2.31 (3H, s), 2.36-2.39 (2H, m), 2.38 (6H, s), 2.71 (1H, dd, J=5.2, 13.2 Hz), 2.77 (1H, dd, J=4.1, 13.2 Hz), 3.12 (1H, d, J=5.6 Hz), 4.02 (1H, d, J=7.8 Hz), 4.19 (1H, d, J=12.2 Hz), 4.31 (2H, m), 4.36 (1H, d, J=2.9 Hz), 4.68 (1H, d, J=12.7 Hz), 4.88 (1H, d, J=4.1 Hz), 5.01 (1H, t, J=4.7 Hz), 5.16 (1H, d, J=7.8 Hz), 5.60 (1H, d, J=8.8 Hz), 5.69 (1H, dd, J=4.2, 10.3 Hz), 5.93 (1H, d, J=5.6 Hz), 6.11 (2H, m), 6.23 (1H, d, J=9.3 Hz), 6.88 (2H, d, J=6.6 Hz), 7.16-7.31 (5H, m), 7.48 (2H, t, J=7.8 Hz), 7.59 (1H, t, J=7.3 Hz), 8.15 (2H, dd, J=1.5, 7.1 Hz), 8.41 (1H,
d, J=2.9 Hz).
【０１５３】
工程3：(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-9,10-[(1S)-2-(ジメチルアミノ)エチリデンジオキシ]-5,20-エポキシ-1-ヒドロキシタクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-ヒドロキシプロピオネート
上記工程2で得た化合物を原料に用い、実施例１２の工程3と同様な操作を行うことにより、標記化合物を得た。機器データは実施例１１の工程3で得た化合物と一致していた。
【０１５４】
（実施例１７）
【０１５５】
【化８３】
(±)-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン
実施例１の工程３において光学分割を行わずに得られるラセミ体に工程４の操作を行ない、表記化合物を得た。ＮＭＲデータは実施例１の工程４で得た化合物と一致していた。
【０１５７】
（実施例１８）
【０１５８】
【化８４】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-(2-プロペニリデンジオキシ)]タクス-11-エン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1,13-ジヒドロキシ-9,10-[(1S)-(2-プロペニリデンジオキシ)]タクス-11-エン0.56 gを乾燥したテトラヒドロフラン20 mlに溶解し、-60℃でリチウムヘキサメチルジシラジド（1モル−テトラヒドロフラン溶液）1.2 mlを加え20分間攪拌した。同温で反応液に (±)-シス-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン1.1 gのテトラヒドロフラン5 ml 溶液を加え、氷冷下で20分間攪拌した。反応液に飽和塩化アンモニア水および酢酸エチルを加え二層を分離した。水層を酢酸エチルで抽出し、先の有機層とあわせて飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１(v／v)で溶出）で精製し、標記化合物0.9 gを白色物質として得た。機器データは実施例１０の工程１で得た化合物と一致していた。
【０１６０】
（実施例１９）
【０１６１】
【化８５】
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1-ヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン-13-イル (2R, 3S)-3-(tert-ブトキシカルボニルアミノ)-3-(3-フルオロ-2-ピリジル)-2-トリイソプロピルシリロキシプロピオネート
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S)-4-アセトキシ-2-ベンゾイルオキシ-5,20-エポキシ-1,13-ジヒドロキシ-9,10-[(1S)-2-プロペニリデンジオキシ]タクス-6,11-ジエン21 gを乾燥したテトラヒドロフラン400 mlに溶解し、-60℃でリチウムヘキサメチルジシラジド（1モル−テトラヒドロフラン溶液）44.5 mlを加え20分間攪拌した。同温で反応液に (±)-シス-1-(tert-ブトキシカルボニル)-4-(3-フルオロ-2-ピリジル)-3-トリイソプロピルシリロキシ-2-アゼチジノン39 gのテトラヒドロフラン100 ml 溶液を加え、氷冷下で20分間攪拌した。反応液に飽和塩化アンモニア水および酢酸エチルを加え二層を分離した。水層を酢酸エチルで抽出し、先の有機層とあわせて飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残分をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：１(v／v)で溶出）で精製し、標記化合物33 gを白色物質として得た。機器データは実施例１３の工程１で得た化合物と一致していた。
【０１６３】
（試験例１）
マウス（系統名；Balb/c）にマウス繊維肉腫Meth Aを皮下移植し、移植後6,8,10日後（あるいは６日後のみ）に化合物をエタノール、Tween80、５％グルコース（5:5:90(v/v)）の混合溶媒に溶解して静脈内投与した。17日目に解剖し、腫瘍重量、血小板数、腎毒性、を検索した。マウスは各群６匹を使用した。
抗腫瘍効果は、次の式で算出した。
[１−（化合物投与群の腫瘍重量／溶媒投与群の腫瘍重量）]×１００
血小板数は（化合物投与群の血小板数／溶媒投与群の血小板数）×１００で表記した。
腎毒性所見は、解剖時の肉眼的観察で退色等の変化が認められた場合または組織学的検査で腎尿細管細胞・細胞質内の硝子滴物質の沈着等の変化が認められた場合に変化ありと表記した。
【０１６４】
【表１】
（試験例２）
マウス（C57BL/6）にB16メラノーマBL6を皮下移植し、４日後に化合物を投与した。静脈内投与では、化合物Ａはエタノール、Tween80、５％グルコース（5:15:80(v/v)）の混合溶媒に溶解して、実施例１１の化合物は5:5:90(v/v)の同混合溶媒に溶解して投与した。経口投与では、0.5%カルボキシメチルセルロースナトリウム水溶液に懸濁させて投与した。投与後２、３日毎に体重を測定し、移植15日後に解剖して腫瘍重量を測定した。抗腫瘍効果は、次の式で算出した。
[１−（化合物投与群の腫瘍重量／溶媒投与群の腫瘍重量）]×１００
マウスは各群６匹を使用した。
【０１６６】
【表２】
（試験例３）
ヒトミクロソームP４５０における代謝
評価検体をアセトニトリル/水(1:1, v/v)に500 μＭとなるように溶解し、これをヒト肝ミクロソーム（Xenotech LLC社製）および各種補酵素、緩衝液等と混合し、37℃で代謝反応を起こさせた。反応液の組成はリン酸緩衝液（最終濃度、以下同じ、0.076 M）、評価検体（10 μM）、ヒト肝ミクロソーム（1 mg/ml）、グルコース6-リン酸（10 mM）、グルコース6-リン酸脱水素酵素（1 unit/ml）、塩化マグネシウム（4 mM）、ニコチンアミドアデニンジヌクレオチド-リン酸還元型（β-NADPH、1 mM）であり、一つの反応に対して500 μｌを使用した。なお、β-NADPHを除いた反応液を37℃で2分間温めておき、β-NADPH水溶液（50 mM， 10 μl）を添加することで反応を開始した。
反応開始後1, 2および5分後に氷冷したアセトニトリル１mlを添加し反応を停止した。
【０１６８】
なお、反応開始後0分はβ-NADPH水溶液の代わりに水を加えて、直ちにアセトニトリル1 mlを加えて作製した。これらサンプルに内部標準物質を100 μl添加し、反応液を15分間遠心した。上清を高速液体クロマトグラフィー(HPLC)に注入し、評価検体の濃度を測定した。反応開始0分の濃度からの減少量を代謝物の生成量 (nmol/mg protein)とした。代謝物の生成量を反応時間に対してプロットし、最小二乗法で直線回帰を行い、傾きより1分間あたりの代謝物生成量（代謝速度定数：ｋ（nmol/min/mg protein））を算出した。
求められた代謝速度定数ｋ(nmol/min/mg protein）より肝固有クリアランス（CLint ）を以下の式より算出した。
CLint (ml/min/kg体重) =k×[(g肝重量)/(kg体重)]×(45mgのミクロソーム蛋白質)/(g肝重量)
ただし、体重1kgあたりの肝重量は20ｇとした。
さらにCLintよりWell-stirred model（J. Pharmacol. Exp. Ther. 283 46-58, 1997）に従い肝クリアランス(CLh)を算出した。
CLh（ml/min/kg体重） = CLh（ml/min/kg体重）＝Q×CLint/（Q+CLint）
ただし、Qはヒトにおける肝血流量で20 ml/min/kgとした。
CLhより以下の式から代謝物の理論バイオアベイラビリティ（Ｆ）値を算出した。
F =（1−CLh／Q）
さらに、１−Ｆ式により、未変化体の理論バイオアベイアビリティ値を算出した。結果を表３に示した。
【０１６９】
【表３】
本発明の化合物の未変化体の理論Ｆ値は、対照化合物（化合物Ｂ）の未変化体理論Ｆ値０．２７よりも大きな値を示し、これは、バイオアベイアビリティのばらつき幅が抑えられ、ひいては、治療域と毒性域の乖離がより精度良く図れ、経口投与可能なことを示している。
【０１７１】
（試験例４）
化合物Ｂまたは実施例１１の化合物をサルに単回で静脈内または経口投与し、血中濃度推移を測定してＡＵＣ0-( を算出した。ＡＵＣ0-(は投与時を０ｈとした場合の無限時間までの薬物血中濃度の濃度−時間曲線下面積のことを指し、文献記載の方法を用いて算出することができる（薬物速度論入門 山岡清・谷川原祐介共著 ｐ．１１６−１１７ 南江堂）。さらに、静脈内投与時のＡＵＣに対する経口投与時のＡＵＣの割合を経口ＢＡとして算出した。化合物Ｂでは静脈内および経口投与において別個体で１匹ずつのサルを用いて実施し、実施例１１の化合物では静脈内および経口投与で同一個体で４匹ずつのサルで実施しＡＵＣを平均値で求めた。
動物：雌カニクイサル、投与方法（化合物Ｂ）[静脈内] EtOH: Tween 80 : 5% Glucose = 5: 5: 90 ，[経口] 0.1N HCl solution、（実施例１１の化合物）[静脈内] 10%βCyD-SBE7 (pH = 3.5生理食塩水), [経口] 40mM酢酸緩衝液(pH4.0)
【０１７２】
【表４】
【発明の効果】
本発明の化合物は毒性面で改善され、腎毒性は認められなかった。また、本発明の化合物はマウスで経口投与による高い抗腫瘍性効果が認められた。更に、本発明の化合物は未変化体の理論Ｆ値が大きく、これにより、バイオアベイアビリティのばらつき幅が抑えられ、治療域と毒性域の乖離が図られる。本発明の化合物はサルでの優れた経口吸収性を示した。このことにより、本発明の化合物は経口投与可能な抗腫瘍剤として用いることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an orally administrable taxol derivative having antitumor activityContaining a pharmaceutical, particularly an antitumor agent, and the taxol derivativeIt relates to the manufacturing method.
[0002]
[Prior art]
Taxol is a natural product represented by the following chemical structural formula, and is obtained in a trace amount from the trunk of a yew tree.
[0003]
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Taxol is known to have antitumor activity, but its mechanism of action is based on the inhibition of microtubule depolymerization in cell division and has a different mechanism of action from conventional antitumor agents. Its antitumor agent is expected to be clinically applied. Until now, only a very small amount of taxol was obtained from nature. However, taxol derivatives synthesized using 10-O-deacetylbaccatin III, which is a taxol precursor represented by the following formula and can be obtained in relatively large amounts from yew leaves, etc. as raw materials have been reported. .
[0005]
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Among them, a compound having a structure represented by the following formula (Taxotere, hereinafter referred to as Compound A) has been attracting attention as a compound having an antitumor activity equivalent to or higher than that of Taxol, and development as an antitumor agent is progressing.
[0007]
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The present inventors have reported that a compound obtained by converting the hydroxyl group produced by reduction of the 9-position ketone and the 10-position hydroxyl group into a cyclic acetal type has strong antitumor activity (Japanese Patent Laid-Open No. 9-12578).
[0009]
[Problems to be solved by the invention]
Taxol, taxotere and the compounds disclosed in JP-A-9-12578 are promising as antitumor agents. However, the compounds of Examples disclosed in JP-A-9-12578 are relatively highly toxic, and the effectiveness of these compounds in oral administration is not known. Taxol derivatives that can be administered orally are desired from the viewpoint of reducing the burden on patients during administration and medical economics.
The present inventor has conducted various studies to obtain a taxol derivative that maintains high antitumor activity, has improved toxicity, and can ensure high safety suitable for oral administration. The following formula showing significant antitumor activity even in oral administration in tests, etc.
[0010]
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[0011]
[Means for Solving the Problems]
The present inventor conducted a new drug design study for the purpose of suppressing compound modification by metabolism, and the compound in which a substituent was introduced into the pyridine ring of the 13-position side chain maintained antitumor activity, but also had toxic aspects The present invention has been completed by finding that it is improved, is less susceptible to metabolism in human liver microsomes, and can secure safety suitable for oral administration.
That is, the present invention relates to a compound represented by the following formula, a salt thereof, a hydrate thereof, or a solvate thereof.An antitumor agent containing a compound further comprising a compound represented by the following formula, a salt thereof, or a hydrate or a solvate thereof:And a manufacturing method thereof.
[0012]
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[0013]
Furthermore, the present invention relates to each of the following.
R2In which is a methoxy group or a fluorine atom, a salt thereof, or a hydrate or a solvate thereof;
A compound represented by the following formula (II), a salt thereof, a hydrate or a solvate thereof;
[0014]
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An antitumor agent containing the above compound, a salt thereof, or a hydrate or a solvate thereof;
The following formula (I), comprising the following steps 1), 2), 3), 4), and 5)
[0015]
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A process for producing a compound represented by:
1) The following formula (III)
[0016]
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And a compound represented by the following formula (IV)
[0017]
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[0018]
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Is reacted with a compound of formula (VI)
[0019]
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2) a step comprising a reaction of converting the vinyl group of this compound into an aldehyde group,
3) a step comprising a reaction for converting the aldehyde group into a dimethylaminomethyl group or a morpholinomethyl group, and
4) a step comprising a reaction of converting a single bond when the bond between the 6-position carbon and the 7-position carbon is a double bond; and
5) RThreeA step comprising removing the protecting group when is a hydroxyl group having a protecting group;
Formula (III)
[0020]
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Is a compound having the following formula (VII):
[0021]
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Said manufacturing method which is a compound represented by;
Formula (III)
[0022]
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The above production method, wherein the compound represented by the formula:
Formula (IV)
[0023]
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[0024]
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Formula (IV)
[0025]
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[0026]
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R2The above production method wherein is a methoxy group or a fluorine atom;
Formula (VII)
[0027]
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An optically active compound represented by:
R2The above compound wherein is a methoxy group or a fluorine atom;
RThreeA compound as described above wherein is a triisopropylsilyloxy group;
Formula (VIII)
[0028]
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[0029]
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The compound represented by the following formula (X)
[0030]
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The compound represented by the following formula (XI)
[0031]
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The compound represented by the following formula (XII)
[0032]
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And a deprotection reaction of the hydroxyl group at the 3-position on the β-lactam ring, if necessary, and a reaction to introduce a protecting group again to the hydroxyl group, if necessary. R which is a protecting group for the nitrogen atom in the ringFourThe following formula (XIII) obtained by removing
[0033]
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Wherein the racemic compound represented by formula (II) is subjected to optical resolution treatment and a t-butoxycarbonyl group is introduced into the nitrogen atom in the β-lactam ring.
[0034]
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A process for producing an optically active compound represented by:
R2The above production method wherein is a methoxy group or a fluorine atom;
RFiveWherein the production method is acetyl group;
RFourThe above production method wherein is 4-methoxyphenyl group or bis (4-methoxyphenyl) methyl group;
RThreeThe above production method wherein is a triisopropylsilyloxy group;
Formula (III)
[0035]
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A racemic compound represented by:
R2The above compound wherein is a methoxy group or a fluorine atom;
RThreeA compound as described above wherein is a triisopropylsilyloxy group;
Formula (VIII)
[0036]
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[0037]
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The compound represented by the following formula (X)
[0038]
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The compound represented by the following formula (XI)
[0039]
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The compound represented by the following formula (XII)
[0040]
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And a deprotection reaction of the hydroxyl group at the 3-position on the β-lactam ring, if necessary, and a reaction to introduce a protecting group again to the hydroxyl group, if necessary. A t-butoxycarbonyl group is introduced into a nitrogen atom in the ring, and the following formula (III)
[0041]
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A process for producing a racemic compound represented by:
R2The above production method wherein is a methoxy group or a fluorine atom;
RFiveWherein the production method is acetyl group;
RFourThe above production method wherein is 4-methoxyphenyl group or bis (4-methoxyphenyl) methyl group;
RThreeThe above production method wherein is a triisopropylsilyloxy group;
Etc.
[0042]
The present invention is a compound represented by the following formula (I) (hereinafter referred to as compound (I) or a compound of the present invention. The compounds represented by other formulas are also represented in the same manner), a salt thereof, or a water thereof. It relates to a solvate or a solvate thereof.
[0043]
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Compound (I) is compound (II) below: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S ) -2- (Dimethylamino) ethylidenedioxy] -5,20-epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- ( 3-Fluoro-2-pyridyl) -2-hydroxypropionate is particularly preferred.
[0044]
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Compound (I) can be synthesized from the following steps 1), 2), 3), 4), and 5).
1) Compound (III)
[0046]
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[0047]
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[0048]
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2) A step comprising a reaction of converting the vinyl group of this compound (VI) into an aldehyde group,
3) a process comprising a reaction for converting the aldehyde group into a dimethylaminomethyl group or a morpholinomethyl group;
4) a step comprising a reaction of converting a single bond when the bond between the 6-position carbon and the 7-position carbon is a double bond; and
5) RThreeA step comprising a reaction of removing a protecting group when is a hydroxyl group having a protecting group.
[0049]
In compound (III), RThreeMeans a hydroxyl group which may have a protecting group. Where R at the 3-position on the β-lactam ringThreeAnd the 4-position pyridyl group are in cis configuration. RThreeExamples of the protecting group include substituted silyl group, benzyl group, substituted benzyl group, 1-ethoxyethyl group, benzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like. Examples of the substituent of the substituted silyl group include an alkyl group, an aryl group, and an aralkyl group. Examples of the substituted silyl group include a trimethylsilyl group, an isopropyldimethylsilyl group, a tertiary butyldimethylsilyl group, a tribenzylsilyl group, a third group. A class butyl diphenylsilyl group etc. are mentioned. Examples of the substituent for the substituted benzyl group include a halogen atom, an alkyl group, an alkoxy group, and a nitro group. Examples of the substituted benzyl group include paranitrobenzyl and paramethoxybenzyl. RThreeAs the protecting group in, preferably a trialkylsilyl group such as a triisopropylsilyl group, a tert-butyldimethylsilyl group or a triethylsilyl group, or a benzyl group, particularly preferably a triisopropylsilyl group or a benzyl group is mentioned. It is done.
Compound (III) may be a racemate or an optically active substance (VII).
Moreover, the partial structure of compound (IV),
[0050]
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Compound (VII) and compound (III) are produced by the following method of the present invention. Compound (VIII)
[0051]
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[0052]
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[0053]
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[0054]
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[0055]
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[0056]
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[0057]
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In addition, racemic compound (III) is obtained by reacting compound (VIII) with compound (IX) to obtain compound (X), which is reacted with compound (XI) to obtain compound (XII). Then, the hydroxyl group at the 3-position on the β-lactam ring is subjected to deprotection reaction, and a reaction for introducing a protecting group again to the hydroxyl group as necessary is carried out, and a t-butoxycarbonyl group is added to the nitrogen atom in the β-lactam ring. It can manufacture by introducing.
R above2Means a halogen atom or an alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group or a fluorine atom.
R aboveThreeMeans a hydroxyl group which may have a protecting group, and a triisopropylsilyloxy group is preferred.
R aboveFourMay have a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, an optionally substituted alkanoyl group having 1 to 6 carbon atoms, or a substituent. Good C 2-6 alkenoyl group, aryl group optionally having substituent, aryloyl group optionally having substituent, aralkyl group optionally having substituent, or substituted silyl group Means. Examples of the substituent of the substituted silyl group include an alkyl group, an aryl group, and an aralkyl group. Examples of the substituted silyl group include a trimethylsilyl group, an isopropyldimethylsilyl group, a tertiary butyldimethylsilyl group, a tribenzylsilyl group, a third group. A class butyl diphenylsilyl group etc. are mentioned.
As the substituent of the aryl group which may have a substituent, the aryloyl group which may have a substituent or the aralkyl group which may have a substituent, a halogen atom, a carbon number of 1 to 6 Examples thereof include an alkyl group, a halogenoalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, a carbamoyl group, and a cyano group. These aryl group, aryloyl group and aralkyl group can have one or more of the above substituents.
RFourIs preferably a phenyl group which may have a substituent or an aralkyl group which may have a substituent. As the substituent, an alkoxy group is preferable. Above all, RFourIs preferably a 4-methoxyphenyl group or a bis (4-methoxyphenyl) methyl group.
RFiveMeans a protecting group for a hydroxyl group, and an acetyl group is preferred.
Q means a halogen atom, preferably a chlorine atom.
Examples of the optical resolution treatment of compound (XIII) include a method using an optically active column.
The compound of the present invention can be synthesized according to the method reported in JP-A-9-12578. In the reaction, the substituent is protected with a protecting group as necessary, but the deprotection operation order is not particularly limited. For example, the following synthesis methods 1 and 2 are exemplified.
Synthesis method 1
[0058]
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Compound (1) and compound (2) are condensed in the presence of a base to obtain compound (3). Next, the protecting group for the hydroxyl group is removed to lead to the compound (4). The terminal olefin is converted into a diol with an oxidizing agent such as N-methylmorpholine-N-oxide under an osmium tetroxide catalyst, and then oxidatively cleaved with sodium periodate to form an aldehyde, followed by reductive reaction with the corresponding amine. To give compound (5).
Synthesis method 2
[0060]
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In the same manner as in Synthesis Method 1, compound (6) is condensed with compound (2) to obtain compound (7). Next, the terminal olefin moiety can be converted in the same manner as in Synthesis Method 1 to obtain compound (8). Subsequently, the olefins at the 6- and 7-positions are reduced by hydrogenation to obtain a compound (9), and finally a hydroxyl-protecting group is removed to obtain a compound (10) (same as the compound (5)). it can.
A method for synthesizing the starting compound (1) is described in JP-A-9-12578. For the compound (6), the compound (10) described in JP-A-9-12578-A) From one step.
[0062]
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The synthesis of the β-lactam compound (2) has been described in various literatures (for example, J. Org. Chem., 61, 2664-2676, 1996 or Tetrahedron Letters 39, 3559-3562, 1998, JP-A-3 -86860 or EP0400971A3 etc.). An example is shown below.
[0064]
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A method for synthesizing the compound (11) has been reported in the literature (J. Med. Chem., 13, 1124, 1970). Compound (12) can be obtained by reacting an imine compound obtained by dehydrating and condensing compound (11) with p-anisidine in the presence of a base with acetoxyacetyl chloride (known as Staudinger reaction). Compound (13) can be obtained by treating compound (12) with a base in a methanol solvent to remove the acetyl group and subsequently reacting with triisopropylsilyl chloride in the presence of imidazole. When ceric ammonium nitrate is allowed to act on compound (13), a racemate of compound (14) can be obtained. A compound (14) having the indicated configuration can be obtained by resolving this racemate by optically active column chromatography. Finally, compound (2) can be obtained by reacting compound (14) with di-tert-butyl dicarbonate.
[0066]
In addition, the compound (2) is not optically resolved in the process of synthesis, and an excessive amount of the racemate of compound (2) is used for condensation reaction with compound (1) or (6), and the resulting diastereomer is subjected to silica gel column chromatography. The compound (3) or (7) having a desired configuration can also be obtained by the separation method.
[0067]
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R of the above synthesis method1, R2And RThreeMeans the same as above. Regarding the abbreviations, Boc means a tertiary butoxycarbonyl group, Me means a methyl group, Ac means an acetyl group, Bz means a benzoyl group, and TIPS means a triisopropylsilyl group.
Each reaction will be described in detail.
[0069]
Synthesis of imine (X)
When aldehyde (VIII) and amine (IX) are mixed in a solvent or without solvent, imine (X) is produced and water is separated. The separated water can be removed by adding a dehydrating agent such as anhydrous sodium sulfate, calcium chloride, or molecular sieves to the reaction mixture and filtering it off. As another method for removing water, a solvent that forms an azeotrope with water, such as toluene or benzene, is used, and the water is removed by distillation under reduced pressure (repeat the distillation under reduced pressure again if necessary). be able to. Here, when a solvent is used for the reaction, toluene, benzene, methylene chloride, or the like, or a mixed solvent thereof may be used, but it is not particularly limited. The reaction temperature is usually in the range from −20 ° C. to 150 ° C. or the boiling point of the solvent, but preferably in the range from 0 ° C. to 100 ° C. or the boiling point of the solvent.
[0070]
Synthesis of β-lactam (XII)
It can be synthesized by dissolving a base such as tertiary amine represented by imine (X) and triethylamine in a solvent and adding a solution of acid halide (XI) at room temperature or lower (preferably 0 ° C. or lower). This acid halide (XI) solution is preferably added dropwise. In this reaction, it is considered that ketene is once generated by the reaction of an acid halide and a base, and this reacts with an imine to form a β-lactam ring selectively in a cis configuration. Further, it is known that the selectivity of the steric configuration of this β-lactam ring construction reaction varies depending on the reaction conditions and the structures of imine and acid halide. Therefore, R2, RFourOr RFiveThe desired cis configuration can be selectively obtained by appropriately selecting the reaction conditions according to the kind of the above. Here, examples of the solvent used in the reaction include methylene chloride, toluene, benzene, and the like, or a mixed solvent thereof. Although not particularly limited, a dried one is preferable. The reaction temperature after dropping is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, but is preferably −78 ° C. to room temperature.
[0071]
Replacement reaction of 3-position protecting group
RFiveAnd RThreeThe reaction conditions differ depending on the type. RFiveWhen is a benzyl group, a trialkylsilyl group or the like, it is possible to proceed to the next step without replacing the protecting group. RFiveThe deprotection reaction of can be performed under normal reaction conditions, but RFiveAn example in which is an acetyl group is shown. By dissolving compound (XII) in a solvent and adding a base such as potassium carbonate in an amount necessary for the reaction, RFiveA compound in which is a hydrogen atom can be obtained. Here, examples of the solvent used in the reaction include methanol, tetrahydrofuran, methylene chloride, and the like, or a mixed solvent thereof. Although not particularly limited, a dried one is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to room temperature. Subsequent hydroxyl protection is also RThreeAlthough the reaction conditions vary depending on the type, it can be carried out by a usual method. RThreeRepresents a trialkylsilyloxy group such as a triisopropylsilyloxy group. By dissolving the raw material in a solvent and adding an amine-type base such as imidazole or other base (which is known to be preferred as the base for the silylation reaction) and a trialkylsilyl chloride such as triisopropylsilyl chloride A trialkylsilyloxy compound can be obtained. Here, the solvent used in the reaction includes methylene chloride, dimethylformamide, tetrahydrofuran, and the like, or a mixed solvent thereof, and is not particularly limited, but a dried one is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to room temperature.
[0072]
Deprotection reaction of N protecting group
RFourIs a protecting group for the nitrogen atom at the 1-position of the β-lactam ring, for example, a substituted phenyl group-type protecting group such as 4-methoxyphenyl group (anisyl group), 2,4-dimethoxyphenyl group, 2,4-dimethoxybenzyl group, etc. And aryl-substituted methyl group-type protecting groups such as bis (4-methoxyphenyl) methyl group, and trialkylsilyl group-type protecting groups such as tert-butyldiphenylsilyl group. The deprotection method is RFourExamples of 4-methoxyphenyl group are shown below, although it can be performed by a normal method depending on the kind of the compound. The compound (XIII) can be obtained by dissolving or suspending the trialkylsilyloxy compound obtained in the previous item in a solvent and adding an oxidizing agent such as ceric ammonium nitrate or an aqueous solution thereof. Here, examples of the solvent used in the reaction include water, acetonitrile, acetone, tetrahydrofuran, and the like, or a mixed solvent thereof. An organic solvent that can be mixed with water at an arbitrary ratio, or a mixture of the organic solvent and water. A solvent is preferred. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably from −20 ° C. to room temperature, more preferably from −5 ° C. to 5 ° C.
[0073]
Boc Group introduction reaction
Compound (III) can be obtained by dissolving compound (XIII) in a solvent and adding di-tert-butyl dicarbonate in the presence of a base such as 4-dimethylaminopyridine. Here, examples of the solvent used in the reaction include methylene chloride, tetrahydrofuran, and the like, or a mixed solvent thereof. Although not particularly limited, a dried one is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to room temperature.
[0074]
Condensation reaction of compounds (III) and (IV)
Compounds (III) and (IV) are dissolved in a solvent and lithium hexamethyldisilazide, sodium hexamethyldisilazide is preferred at -78 ° C. to room temperature (preferably the temperature varies depending on the base shown below but is preferably cooled). Add a base such as zido, sodium hydride, potassium tert-butoxide. Alternatively, a base may be added to one solution of compound (III) or (IV), and the other solution may be added. These operations are preferably performed under conditions of low moisture. Thereafter, the compound (VI) can be obtained by reacting at the temperature at the time of mixing or, if necessary, raising the reaction temperature to a temperature near room temperature. Here, examples of the solvent used in the reaction include methylene chloride, tetrahydrofuran, and the like, or a mixed solvent thereof. Although not particularly limited, a dried one is preferable.
[0075]
Reaction leading from compound (VI) to (I)
Step of converting vinyl group of compound (VI) into aldehyde group: An oxidizing agent that dissolves compound (VI) in tetrahydrofuran, acetone, butanol, acetonitrile, water, or the like, or a mixed solvent thereof (preferably a water-containing solvent) and converts olefins such as osmium tetroxide and potassium osmate to diol. By reacting or adding a catalytic amount of osmium tetroxide or the like in the presence of an oxidizing agent such as N-methylmorpholine-N-oxide, a compound in which the olefin moiety is converted to a diol can be obtained. Subsequently, this diol compound is dissolved in tetrahydrofuran, methanol, ethanol, acetonitrile, water or the like, or a mixed solvent thereof (preferably a water-containing solvent), and for example, 1,2-diol such as sodium metaperiodate is oxidized oxidatively. By adding an oxidizing agent for cleavage, a compound converted to an aldehyde group can be obtained. This step can also be performed in one pot by adding sodium metaperiodate or a solution thereof as it is to the reaction solution after the diolation reaction. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, but is preferably near room temperature.
Step of converting aldehyde group into dimethylamino group or morpholino group: The aldehyde compound obtained above is dissolved in a solvent, and either dimethylamine or morpholine, an acid such as acetic acid, and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride are added to form an aldehyde. The group can be converted to a dimethylaminomethyl group or a morpholinomethyl group. Here, examples of the solvent used in the reaction include ethanol, tetrahydrofuran, and the like, or a mixed solvent thereof. Although not particularly limited, a solvent that dissolves the reducing agent as much as necessary to complete the reaction by the end of the reaction is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, but is preferably near room temperature.
A step of reducing to a single bond when the moiety represented by (V) in the formula is a double bond: Dissolve the dimethylamino compound or morpholinomethyl compound obtained above in a solvent, add a catalyst for reduction such as palladium carbon, platinum carbon, ruthenium carbon, and stir in a hydrogen atmosphere or in the presence of a hydrogen source such as formic acid or ammonium formate. By doing so, a compound in which the double bond is reduced to a single bond can be obtained. Here, the solvent used in the reaction includes water, alcohols such as methanol and ethanol, tetrahydrofuran, ethyl acetate and the like, or a mixed solvent thereof, and is not particularly limited, but a polar solvent is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, but is preferably near room temperature.
R Three Removing process: RThreeThe deprotection conditions differ depending on the type, but RThreeIs a trialkylsilyloxy group such as a triisopropylsilyloxy group. Deprotection can be achieved by dissolving the reduced compound obtained above in a solvent such as tetrahydrofuran and reacting with a quaternary ammonium fluoride such as tetrabutylammonium fluoride. The reaction temperature is preferably from about 0 ° C. to room temperature. There is also a method of deprotection using a complex of hydrogen fluoride and pyridine in a pyridine solvent. Here, although the solvent used for reaction includes tetrahydrofuran, it is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from −5 ° C. to room temperature.
[0076]
Method for synthesizing compound (IV)
[When C6-C7 is a double bond] Compound in which 9-position is reduced to β-hydroxyl group by dissolving 10-O-deacetylbaccatin III in a solvent and reacting with a reducing agent such as tetrabutylammonium borohydride Is obtained. This compound is dissolved in a solvent and functions as a strongly acidic compound such as camphorsulfonic acid and paratoluenesulfonic acid, or a salt of a tertiary amine such as triethylamine of these acids, or a Lewis acid catalyst such as zinc chloride. By reacting acrolein acetal typified by diethyl acetal in the presence of the compound to be reacted, a 7-position hydroxide of compound (IV) can be obtained. When this compound is dissolved in a solvent and reacted with trifluoromethanesulfonic anhydride in the presence of a base such as 4-dimethylaminopyridine, a dehydration reaction proceeds to obtain compound (IV). Here, examples of the solvent used in the reaction include methylene chloride, dichloroethane, and the like, or a mixed solvent thereof, but are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from −5 ° C. to room temperature.
[When C6-C7 Position is Single Bond] A compound in which the 7-position hydroxyl group of 10-O-deacetylbaccatin III is substituted with a hydrogen atom is known. By dissolving this compound in a solvent such as tetrahydrofuran and reacting with a borane complex such as borane-tetrahydrofuran complex or diborane, a compound in which the 9-position ketone is reduced to a β-hydroxyl group can be obtained. This compound is dissolved in a solvent such as methylene chloride or dichloroethane, and a strongly acidic compound such as camphorsulfonic acid or paratoluenesulfonic acid, or a tertiary amine salt such as triethylamine of these acids, or Lewis such as zinc chloride. Compound (IV) can be obtained by reacting acetal of acrolein represented by diethyl acetal in the presence of a compound that functions as an acid catalyst. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from −5 ° C. to room temperature.
[0077]
The compound of the present invention may be a free form or an acid addition salt. Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrogen bromide, hydrogen iodide, phosphate, acetate, methanesulfonate, benzenesulfonate, toluenesulfonic acid Organic salts such as salt, citrate, maleate, fumarate and lactate can be mentioned. Further, it may be a hydrate or a solvate, and examples of the solvent include methanol, ethanol, propanol, butanol, acetone, acetonitrile, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide and the like.
[0078]
Further, the medicament of the present invention can achieve cancer treatment based on antitumor action, and the treatment targets include lung cancer, digestive cancer, ovarian cancer, uterine cancer, breast cancer, liver cancer, head and neck cancer, blood cancer, kidney Various cancers such as cancer and testicular tumors can be mentioned.
The compound of the present invention can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration and transdermal administration. Among these administration methods, oral administration is preferable from the viewpoint of achieving the effects described later. In the case of oral administration, either a free form or a salt may be used.
The compound of the present invention showed no nephrotoxicity as a result of tests using non-cancerous mice.
[0079]
Applicability of the compound of the present invention as an oral preparation can be predicted by an in vitro test using human liver microsomes. For oral administration, the drug dissolves in the gastrointestinal tract and enters the circulatory system of the bloodstream after undergoing metabolism in the gastrointestinal tract and liver. Therefore, drug metabolism in the liver is thought to affect the drug efficacy. In particular, the compound of the present invention and its related compounds are predicted to undergo metabolism by CYP3A, an enzyme in liver microsomes. Therefore, metabolic prediction by in vitro tests using liver microsomes is important in considering actual clinical use. The predicted metabolic values from in vitro tests using liver microsomes almost correspond to the measured values in human clinical trials. Pharm. Tech. Japan 13 17-39, 1997, J. Pharmacol. Exp. Ther. 283 46-58 , 1997 et al. Human liver microsomes are available from Xenotech LLC, etc., and metabolic rate can be measured with reference to the above-mentioned literature.
[0080]
When the drug metabolic rate in liver microsomes is measured, the bioavailability of the drug can be calculated as a theoretical value (J. Pharmacol. Exp. Ther. 283 46-58, 1997). Bioavailability is defined as the relative amount and rate of a drug that reaches the systemic circulation to the administered drug (Pharmacokinetic Research in Drug Development, Yuichi Sugiyama, p.15 Yakuhojiho). In oral administration, various disorders such as dissolution in the gastrointestinal tract, passage through the gastrointestinal mucosa, metabolism in the gastrointestinal tract and the liver exist before the drug enters the circulating blood. For this reason, it is considered that the range of inter-individual variation in the final blood concentration, that is, bioavailability, is larger than that in direct administration to circulating blood. Hellriegel et al. Investigated the bioavailability value and its inter-individual variation (CV value) for 149 different drugs on the market, and reported that there was a negative correlation between them (Clin. Pharmacol. Ther. 60 601-607, 1996). In other words, it is known that the range of variation in bioavailability among individuals increases as the value of bioavailability decreases.
[0081]
In the case of an antitumor agent, in order to increase the response rate, it is often administered at a dose near the maximum tolerated dose, and accordingly, the therapeutic area and the toxic area are close to each other, and as a result, the safety area is narrowed. Therefore, it becomes difficult to use a drug having a wide range of variation in individual bioavailability as an antitumor agent.
The compound of the present invention has a reduced metabolic rate in human liver microsomes and improved the theoretical bioavailability value of the unchanged form. Therefore, it was predicted that the variation range of the unchanged bioavailability value among individuals was small. Due to this effect, the compound of the present invention can be sufficiently administered orally from the viewpoint of safety, that is, effective drug expression and safety range. In order to reduce the variation range of the bioavailability value of the unchanged substance, the theoretical bioavailability value of the unchanged substance is preferably 0.4 or more, and more preferably 0.7 or more. preferable.
Furthermore, the applicability of the compound of the present invention as an oral preparation can be predicted by a BA test using monkeys. Compound B is slowly metabolized by mouse and dog liver microsomes and is actually excellent in oral absorption in mice. On the other hand, metabolism by monkey liver microsomes was as fast as that by human liver microsomes. In this case, Compound B had low oral absorbability in monkeys. In contrast, the metabolism of monkey liver microsomes for the compounds of the present invention was slow, as was the case for human, mouse and dog liver microsomes. Therefore, when the bioavailability (BA) was measured using monkeys for the purpose of confirming the effect of improving oral absorption by inhibiting metabolism, oral absorption in monkeys of the present invention was significantly improved compared to compound B. It was confirmed.
[0082]
As a method for preparing a pharmaceutical preparation and an antitumor agent, an appropriate preparation can be selected according to the administration method, and it can be prepared by various commonly used preparation methods. Among the dosage forms of the antitumor agent of the present invention, examples of the preparation for oral administration include tablets, powders, granules, capsules and the like. Examples of the form of the agent include solutions, syrups, elixirs, oily or aqueous suspensions, and the like. Of these, capsules, tablets and solutions are preferred. In the case of injections, stabilizers, preservatives, solubilizing agents and the like can also be used in the preparation. A solution that may contain these adjuvants and the like can be used as a preparation prepared at the time of use as a solid preparation by lyophilization or the like.
[0083]
Examples of liquid preparations include solutions, suspensions, emulsions, and the like. When these preparations are prepared, suspending agents, emulsifiers, and the like can be used as additives.
The compounds of the present invention can be used for the treatment of cancer in mammals, particularly humans, and when administered to humans, it is preferable to administer once per day and repeat at appropriate intervals.
As a dosage, body surface area 1m2It is preferred to administer in the range of about 0.5 mg to 50 mg per dose, preferably about 1 mg to 20 mg.
[0084]
【Example】
Next, the embodiment will be described in detail. In the description of the examples, the following abbreviations may be used. Boc means tertiary butoxycarbonyl group, Ac means acetyl group, Bz means benzoyl group, and TIPS means triisopropylsilyl group.
(Reference example)
[0085]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-[(1S)- 2-propenylidenedioxy] tax-6,11-diene
(1S, 2S, 3R, 4S, 5R, 7S, 8S, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-9,10-[(1R) -2-propeni Redenedioxy] -1,7,13-trihydroxytax-11-ene (18 g) and 4-dimethylaminopyridine (37.7 g) were dissolved in methylene chloride (360 ml), and trifluoromethanesulfonic anhydride (20.7 ml) was added under ice cooling. The mixture was stirred at the same temperature for 1.5 hours. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, 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 (eluted with chloroform: acetone = 50: 1 (v / v)) to obtain 11.5 g of the title compound as a white substance.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.15 (3H, s), 1.52 (3H, s), 1.56 (3H, s), 1.77 (1H, s), 1.90 (3H, s), 2.07 (1H, dd, J = 6.8, 15.1 Hz), 2.23 (1H, d, J = 9.3 Hz), 2.36 (3H, s), 3.21 (1H, d, J = 5.9 Hz), 4.00 (1H, d, J = 7.4 Hz), 4.30 (2H, ABq, J = 7.8 Hz), 4.79-4.83 (2H, m), 5.25-5.27 (2H, m), 5.48 (1H, d, J = 10.3 Hz), 5.60 (1H, d, J = 17.1 Hz), 5.70 (1H, dd, J = 3.9, 10.2 Hz), 5.96 (1H, d, J = 5.9 Hz), 5.98-6.07 (1H, m), 6.13 (1H, d, J = 10.2 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.61 (1H, t, J = 7.3 Hz), 8.16 (2H, d, J = 7.3 Hz).
[0087]
(Example 1)
[0088]
Embedded image
Step 1: (±) -cis-3-acetoxy-4- (3-fluoro-2-pyridyl) -1- (4-methoxyphenyl) -2-azetidinone
20 g of 3-fluoro-2-formylpyridine and 15.6 g of 4-anisidine were dissolved in 100 ml of benzene, 20 g of anhydrous sodium sulfate was added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 400 ml of methylene chloride, 26.5 ml of triethylamine and 20.4 ml of 2-acetoxyacetyl chloride were added at −60 ° C. and the temperature was raised to room temperature overnight. 300 ml of water was added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with chloroform, combined with the previous organic layer, washed successively with saturated aqueous sodium hydrogen carbonate solution 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 (eluted with ethyl acetate) to obtain 33.2 g of the title compound as a white substance.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.80 (3H, s), 3.74 (3H, s), 5.72 (1H, d, J = 5.1 Hz), 6.09 (1H, d, J = 5.1 Hz), 6.78-6.82 (2H, m), 7.23-7.29 (2H, m), 7.30-7.33 (1H, m), 7.41-7.46 (1H, m), 8.44-8.46 (1H, m).
[0090]
Step 2: (±) -cis-4- (3-fluoro-2-pyridyl) -1- (4-methoxyphenyl) -3-triisopropylsilyloxy-2-azetidinone
18 g of the compound obtained in the above step 1 was dissolved in a mixed solution of 180 ml of tetrahydrofuran and 180 ml of methanol, 500 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with a strongly acidic resin, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 180 ml of dimethylformamide, 5.6 g of imidazole and 17.5 ml of triisopropylsilyl chloride were added under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with hexane to obtain 20 g of the title compound as a white substance.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.91-1.07 (21H, m), 3.74 (3H, s), 5.38 (1H, d, J = 4.9 Hz), 5.50 (1H, d, J = 4.9 Hz), 6.78-6.81 (2H, m), 7.23 -7.28 (3H, m), 7.34-7.39 (1H, m), 8.41-8.43 (1H, m).
[0091]
Step 3: (3R, 4S) -4- (3-Fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
1.0 g of the compound obtained in the above step 2 was dissolved in 50 ml of acetonitrile, 20 ml of an aqueous solution of 3.7 g of ceric ammonium nitrate was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium sulfite solution and ethyl acetate were added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (eluted with hexane: ethyl acetate = 2: 1 (v / v)) to give (±) -cis-4- (3-fluoro -2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone 0.4 g was obtained. This compound was separated by an optically active column to give the title compound (0.18 g) as a white substance.
1H NMR (400 MHz, CDClThree, TMS) δ:
0.89-1.06 (21H, m), 5.17 (1H, dd, J = 1.0, 4.9 Hz), 5.35 (1H, dd, J = 1.4, 4.9 Hz), 6.24 (1H, br s), 7.23-7.28 (1H , m), 7.37 (1H, dt, J = 1.5, 8.3 Hz), 8.43 (1H, d, J = 4.4 Hz).
[α]D twenty three + 38 ° (c = 0.11, CHClThree).
[0092]
Split condition
Column: Daicel Chemical Industries CHIRALCEL OD (20 mm x 250 mm)
Solvent: Hexane: 2-propanol = 92: 8 (v / v)
Flow rate: 10 ml / min
Retention time: 10 minutes [(3S, 4R) -body], 14 minutes [(3R, 4S) -body]
[0093]
Step 4: (3R, 4S) -1- (tert-butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
0.18 g of the compound obtained in the above Step 3 and 0.17 g of di-tert-butyl dicarbonate were dissolved in 5 ml of tetrahydrofuran, 13 mg of 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 5: 1 (v / v)) to obtain 0.24 g of the title compound as an oily substance.
1H NMR (400 MHz, CDClThree, TMS) δ:
0.88-1.03 (21H, m), 1.44 (9H, s), 5.27 (1H, d, J = 5.8 Hz), 5.46 (1H, d, J = 5.8 Hz), 7.24-7.26 (1H, m), 7.38 (1H, t, J = 8.8 Hz), 8.42 (1H, d, J = 3.9 Hz).
[α]D 18 + 86 ° (c = 1.03, CHClThree).
[0094]
(Example 2)
[0095]
Embedded image
(3R, 4S) -1- (tert-Butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
The title compound was obtained as an oily product by conducting the same operation as in Example 1 except that 5-methoxy-2-formylpyridine was used instead of 3-fluoro-2-formylpyridine.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.88-1.01 (21H, m), 1.43 (9H, s), 3.85 (3H, s), 5.10 (1H, d, J = 5.8 Hz), 5.29 (1H, d, J = 5.8 Hz), 7.18-7.28 (2H, m), 8.27 (1H, d, J = 3 Hz).
[0097]
(Example 3)
[0098]
Embedded image
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-chloro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
The title compound was obtained as an oily substance by performing the same operation as in Example 1 except that 5-chloro-2-formylpyridine was used instead of 3-fluoro-2-formylpyridine.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.88-1.02 (21 H, m), 1.44 (9H, s), 5.12 (1H, d, J = 4.9 Hz), 5.31 (1H, d, J = 4.9 Hz), 7.29 (1H, d, J = 8.3 Hz), 7.68 (1H, dd, J = 2.4, 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
[0100]
(Example 4)
Embedded image
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
The title compound was obtained as an oily product by conducting the same operation as in Example 1 except that 5-fluoro-2-formylpyridine was used instead of 3-fluoro-2-formylpyridine.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.88-1.01 (21 H, m), 1.44 (9H, s), 5.14 (1H, d, J = 4.9 Hz), 5.33 (1H, d, J = 4.9 Hz), 7.33-7.45 (2H, m), 8.44 (1H, d, J = 2.9 Hz)
[0102]
(Example 5)
[0103]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-methoxy-2-pyridyl) -2-triisopropyl Silyloxypropionate
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-[(1S)- 2-Propenylidenedioxy] tax-11-ene (300 mg) was dissolved in 10 ml of dry tetrahydrofuran, 0.63 ml of lithium hexamethyldisilazide (1 mol-tetrahydrofuran solution) was added at −60 ° C., and the mixture was stirred for 25 minutes. . (3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone 280 mg in tetrahydrofuran 5 ml at the same temperature And stirred for 40 minutes under ice cooling. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 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 (developing solvent; hexane: ethyl acetate = 5: 1 (v / v)) to obtain 540 mg of the title compound.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.89-0.95 (21H, m), 1.32 (3H, s), 1.33-1.62 (3H, m), 1.41 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.92-2.32 (3H, m), 2.49 (3H, s), 2.98 (1H, d, J = 4.9 Hz), 3.85 (3H, s), 4.20 (1H, d, J = 7.4 Hz), 4.22 (1H, d, J = 6.8 Hz), 4.32 (1H, d, J = 8.3 Hz), 4.95 (1H, s), 5.21 (1H, d, J = 5.8 Hz), 5.26-5.29 (2H, m ), 5.39-5.47 (3H, m), 5.57 (1H, d, J = 17.6 Hz), 5.96-6.02 (2H, m), 6.11 (1H, t-like, J = 8.3 Hz), 7.15 (1H, dd, J = 2.4, 8.8 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.44 (2H, t, J = 7.8 Hz), 7.56 (1H, t, J = 7.8 Hz), 8.13 (2H, d, J = 7.8 Hz), 8.26 (1H, d, J = 3.0 Hz).
[0105]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- (5-methoxy-2-pyridyl) propionate
530 mg of the compound obtained in the above step 1 was dissolved in 10 ml of dry tetrahydrofuran, 1.0 ml of tetrabutylammonium fluoride (1 mol-tetrahydrofuran solution) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution and the liquids were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate 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 (developing solvent; hexane: ethyl acetate = 1: 1 (v / v)) to obtain 410 mg of the title compound.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.43 (9H, s), 1.50 (3H, s), 1.60-1.91 (3H, m), 1.64 (3H, s), 1.74 (3H, s), 1.91 (1H, s) , 2.04-2.16 (2H, m), 2.32-2.37 (1H, m), 2.34 (3H, s), 2.93 (1H, d, J = 5.3 Hz), 3.85 (3H, s), 4.18 (1H, d , J = 7.3 Hz), 4.22 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.79 (1H, br s), 4.85 (1H, br s), 4.92 (1H , br s), 5.23 (1H, d, J = 5.8 Hz), 5.29-5.30 (2H, m), 5.46 (1H, d, J = 10.3 Hz), 5.58 (1H, d, J = 17.1 Hz), 5.90 (1H, d, J = 9.7 Hz), 5.96-6.03 (2H, m), 6.09 (1H, t-like, J = 8.4 Hz), 7.22 (1H, dd, J = 2.4, 8.8 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.47 (2H, t, J = 7.8 Hz), 7.60 (1H, t, J = 7.8 Hz), 8.13 (2H, d, J = 7.8 Hz), 8.22 (1H , d, J = 2.4 Hz).
[0106]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- (5-methoxy-2-pyridyl) Propionate
400 mg of the compound obtained in the above step 2 was dissolved in 5 ml of tetrahydrofuran, 5 ml of acetone, 5 ml of water, 5.9 mg of osmium tetroxide, and 270 mg of N-methylmorpholine-N-oxide were added, and the mixture was stirred at room temperature for 4.5 hours. . Ethyl acetate and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was subjected to liquid separation. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in 5 ml of tetrahydrofuran, 5 ml of methanol, 5 ml of water and 990 mg of sodium metaperiodate were added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution, and liquid separation was performed, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 30 ml of ethanol, 0.2 ml of morpholine, 0.13 ml of acetic acid and 140 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate, ethyl acetate and water were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 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 (developing solvent; chloroform: methanol = 50: 1 (v / v)) to obtain 220 mg of the title compound.
Melting point: 160-161 ° C
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.27 (3H, s), 1.43 (9H, s), 1.48 (3H, s), 1.60 (3H, s), 1.72 (3H, s), 1.78-2.12 (6H, m), 2.31-2.38 (1H, m), 2.34 (3H, s), 2.58-2.68 (4H, m), 2.71 (1H, dd, J = 5.4, 13.2 Hz), 2.79 (1H, dd, J = 3.9, 13.2 Hz), 2.93 (1H , d, J = 5.3 Hz), 3.75 (4H, t, J = 4.9 Hz), 3.86 (3H, s), 4.12 (1H, d, J=7.3 Hz), 4.21 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.76 (1H, br s), 4.85 (1H, br s), 4.92 (1H, s) , 5.04 (1H, t, J = 4.6 Hz), 5.23 (1H, d, J = 6.9 Hz), 5.29 (1H, d, J = 8.8 Hz), 5.90 (1H, d, J = 9.3 Hz), 5.98 (1H, d, J = 4.9 Hz), 6.08 (1H, t-like, J = 8.3 Hz), 7.22 (1H, dd, J = 2.9, 8.8 Hz), 7.34 (1H, d, J = 8.8 Hz) , 7.47 (2H, t, J = 7.8 Hz), 7.60 (1H, t, J = 7.8 Hz), 8.13 (2H, d, J = 7.8 Hz), 8.22 (1H, d, J = 2.9 Hz).
Elemental analysis (C49H65NThreeO15As)
Calculated values: C, 62.87; H, 7.00; N, 4.49
Actual value: C, 62.66; H, 7.08; N, 4.28
[0107]
(Example 6)
[0108]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-chloro-2-pyridyl) -2-triisopropyl Silyloxypropionate
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone instead of (3R, 4S) -1- (tert -Butoxycarbonyl) -4- (5-chloro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone, and using the same procedure as in Step 1 of Example 5, the title compound was obtained. Obtained.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.87-0.94 (21H, m), 1.18-1.69 (2H, m), 1.31 (3H, s), 1.41 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.72-2.05 (2H, m), 2.24-2.34 (2H, m), 2.48 (3H, s), 2.97 (1H, d, J = 5.4 Hz), 4.19-4.23 (2H, m), 4.33 (1H, d, J = 7.8 Hz), 4.95 (1H, s), 5.21 (1H, d, J = 5.8 Hz), 5.27-5.31 (2H, m), 5.42-5.47 (3H, m), 5.58 ( 1H, d, J = 17.5 Hz), 5.96-6.04 (2H, m), 6.11 (1H, t, J = 8.8 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.57 (1H, t, J = 7.3 Hz), 7.65 (1H, dd, J = 8.3 Hz, 2.5 Hz), 8.13 (2H, d, J = 7.3 Hz), 8.53 (1H, d, J = 2.5 Hz).
[0110]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-2-propenylidenedioxy]Tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-chloro-2-pyridyl) -2-hydroxypropionate
The title compound was obtained in the same manner as in Step 2 of Example 5 using the compound obtained in Step 1 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ: 1.26 (3H, s), 1.22-1.65 (2H, m), 1.43 (9H, s), 1.49 (3H, s), 1.64 (3H, s), 1.74 (3H, s), 1.75 -2.09 (2H, m), 2.30-2.39 (2H, m), 2.33 (3H, s), 2.94 (1H, d, J = 4.9 Hz), 4.18 (1H, d, J = 5.3 Hz), 4.22 ( 1H, d, J = 8.3 Hz) 4.32 (1H, d, J = 8.3 Hz), 4.61 (1H, br s), 4.92 (2H, m), 5.24 (1H, d, J = 6.3 Hz), 5.30 ( 1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz), 5.46 (1H, d, J = 10.5 Hz), 5.58 (1H, d, J = 17.5 Hz), 5.87 (1H, d, J = 9.3 Hz), 5.96-6.05 (2H, m), 6.11 (1H, t, J = 7.8 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 7.69 (1H, dd, J = 8.3Hz, 2.4 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.51 (1H, d, J = 2.4 Hz).
[0111]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-chloro-2-pyridyl) -2-hydroxy Propionate
The title compound was obtained by the same procedures as in Step 3 of Example 5 using the compound obtained in the above Step 2 as a raw material.
Melting point: 146-150 ° C
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.20-1.72 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.63 (3H, s), 1.73 (3H, s), 1.75-2.03 (2H, m), 2.33 (3H, s), 2.30-2.38 (2H, m), 2.59-2.69 (4H, m), 2.72 (1H, dd, J = 5.4, 13.2 Hz), 2.79 (1H, dd, J = 3.9, 13.2Hz), 2.92 (1H, d, J = 4.9 Hz), 3.74 (4H, t, J = 4.9 Hz), 4.12 (1H, d, J = 7.9 Hz), 4.22 (1H, d, J = 8.8 Hz), 4.32 (1H, d, J = 8.8 Hz), 4.59 (1H, br s), 4.91 (2H, m), 5.05 (1H, t, J = 4.4 Hz), 5.24 (1H, d, J = 6.8 Hz), 5.35 (1H, d, J = 9.3 Hz), 5.87 (1H, d, J = 9.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.10 (1H, t, J = 8.0 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 7.69 (1H, dd, J = 8.3 Hz) 2.5 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.50 (1H, d, J = 2.5 Hz). Elemental analysis (C48H62ClNThreeO14・ H2As O)
Calculated values: C, 60.15; H, 6.73; N, 4.38; Cl, 3.70
Found: C, 60.15; H, 6.74; N, 4.20; Cl, 3.63
[0112]
(Example 7)
[0113]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-fluoro-2-pyridyl) -2-triisopropyl Silyloxypropionate
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone instead of (3R, 4S) -1- (tert -Butoxycarbonyl) -4- (5-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone, and using the same procedure as in Step 1 of Example 5, the title compound was obtained. Obtained.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.87-0.94 (21H, m), 1.20-1.70 (2H, m), 1.31 (3H, s), 1.42 (9H, s), 1.52 (3H, s), 1.65 (3H, s), 1.82 (3H, s), 1.75-2.07 (2H, m), 2.26-2.32 (2H, m), 2.49 (3H, s), 2.97 (1H, d, J = 5.4 Hz), 4.19-4.23 (2H, m), 4.33 (1H, d, J = 8 Hz), 4.96 (1H, s), 5.21 (1H, d, J = 5.9 Hz), 5.27-5.32 (2H, m), 5.43-5.49 (3H, m), 5.58 ( 1H, d, J = 17.5 Hz), 5.96-6.04 (2H, m), 6.12 (1H, t, J = 8 Hz), 7.36-7.47 (4H, m), 7.57 (1H, t, J = 7.3 Hz ), 8.13 (2H, d, J = 7.3 Hz), 8.43 (1H, d, J = 2.4 Hz).
[0115]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-fluoro-2-pyridyl) -2-hydroxypro Pionate
The title compound was obtained in the same manner as in Step 2 of Example 5 using the compound obtained in Step 1 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ: 1.27 (3H, s), 1.20-1.68 (2H, m), 1.44 (9H, s), 1.49 (3H, s), 1.64 (3H, s), 1.74 (3H, s), 1.75 -2.05 (2H, m), 2.30-2.39 (2H, m), 2.34 (3H, s), 2.93 (1H, d, J = 4.9 Hz), 4.18 (1H, d, J = 6.8 Hz), 4.23 ( (1H, d, J = 8.3 Hz),4.33 (1H, d, J = 8.3 Hz), 4.62 (1H, d, J = 2.5 Hz), 4.90-4.92 (2H, m), 5.24 (1H, d, J = 5.8 Hz), 5.30 (1H, d , J = 6.8 Hz), 5.37 (1H, d, J = 9.3 Hz), 5.46 (1H, d, J = 10.2 Hz), 5.58 (1H, d, J = 17 Hz), 5.90 (1H, d, J = 10.2 Hz), 5.96-6.05 (2H, m), 6.10 (1H, t, J = 7.8 Hz), 7.40-7.49 (4H, m), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H , d, J = 7.3 Hz), 8.41 (1H, s).
[0116]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-fluoro-2-pyridyl) -2-hydroxy Propionate
The title compound was obtained by the same procedures as in Step 3 of Example 5 using the compound obtained in the above Step 2 as a raw material.
Melting point: 148-152 ° C
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.20-1.69 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.62 (3H, s), 1.72 (3H, s), 1.75-2.02 (2H, m), 2.33 (3H, s), 2.30-2.39 (2H, m), 2.59-2.69 (4H, m), 2.71 (1H, dd, J = 5.4, 13.2 Hz), 2.79 (1H, dd, J = 3.9, 13.2 Hz) 2.92 (1H, d, J = 4.9 Hz), 3.74 (4H, t, J = 4.9 Hz), 4.12 (1H, d, J = 7.3 Hz), 4.22 (1H, d, J = 8.3 Hz), 4.32 (1H, d, J = 8.3 Hz), 4.60 (1H, br s), 4.90-4.92 (2H, m), 5.04 (1H, t, J = 4.9 Hz), 5.24 (1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz), 5.89 (1H, d, J = 9.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.09 (1H, t, J = 8.0 Hz), 7.42-7.49 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.40 (1H, s).
Elemental analysis (C48H62FNThreeO14・ H2As O)
Calculated values: C, 61.19; H, 6.85; N, 4.46; F, 2.02
Found: C, 61.16; H, 6.85; N, 4.36; F, 2.05
[0117]
(Example 8)
[0118]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy] -5 , 20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- (5-methoxy-2-pyridyl) propionate
Using the compound obtained in Step 2 of Example 5 as a raw material and using dimethylamine (2 mol-methanol solution) in place of morpholine, the same operation as in Step 3 of Example 5 was carried out to give the title compound Got.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.43 (9H, s), 1.48 (3H, s), 1.61 (3H, s), 1.73 (3H, s), 1.83-1.97 (3H, m), 2.04-2.12 (2H, m), 2.31-2.38 (2H, m), 2.34 (3H, s), 2.38 (6H, s), 2.64-2.76 (2H, m), 2.93 (1H, d, J = 4.9 Hz), 3.85 (3H , s), 4.13 (1H, d, J = 7.4 Hz), 4.21 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.84 (1H, d, J = 2.4 Hz) ), 4.92 (1H, s), 5.01 (1H, t, J = 4.9 Hz), 5.24 (1H, d, J = 6.8 Hz), 5.29 (1H, d, J = 8.8 Hz), 5.91 (1H, d , J = 9.3 Hz), 5.99 (1H, d, J = 5.4 Hz), 6.08 (1H, t, J = 7.8 Hz), 7.23 (1H, dd, J = 3.0, 8.3 Hz), 7.34 (1H, d , J = 8.8 Hz), 7.47 (2H, t, J = 7.8 Hz), 7.60 (1H, t, J = 7.8 Hz), 8.12 (2H, d, J = 7.8 Hz), 8.22 (1H, d, J = 3.0 Hz).
[0120]
Example 9
[0121]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy] -5 , 20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-fluoro-2-pyridyl) -2-hydroxypropio Nate
Using the compound obtained in Step 2 of Example 7 as a raw material and using dimethylamine (2 mol-methanol solution) instead of morpholine, the same operation as in Step 3 of Example 5 was carried out to give the title compound Got.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.20-1.70 (2H, m), 1.43 (9H, s), 1.48 (3H, s), 1.62 (3H, s), 1.73 (3H, s), 1.75-2.01 (3H, m), 2.33 (3H, s), 2.38 (6H, s), 2.32-2.39 (2H, m), 2.66 (1H, dd, J = 5.4, 13.2 Hz), 2.74 (1H, dd, J = 4.0, 13.2 Hz), 2.93 (1H, d, J = 4.9 Hz), 4.12 (1H, d, J = 7.3 Hz), 4.22 (1H, d, J = 8.3 Hz), 4.32 (1H, d, J = 8.3 Hz) ), 4.90-4.92 (2H, m), 5.02 (1H, t, J = 5.4 Hz), 5.25 (1H, d, J = 6.8 Hz), 5.36 (1H, d, J = 6.8 Hz), 5.90 (1H , d, J = 8.8 Hz), 5.99 (1H, d, J = 4.9 Hz), 6.09 (1H, t, J = 8.1 Hz), 7.42-7.49 (4H, m), 7.60 (1H, t, J = 7.3 Hz), 8.12 (2H, d, J = 7.3 Hz), 8.41 (1H, s).
[0123]
(Example 10)
[0124]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-triisopropyl Silyloxypropionate
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone instead of (3R, 4S) -1- (tert -Butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone, and using the same procedure as in Step 1 of Example 5, the title compound was obtained. Obtained.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.89-0.93 (21H, m), 1.28 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.66 (3H, s), 1.82 (3H, s), 1.61-1.64 (3H, m), 1.89-1.96 (2H, m), 2.33-2.39 (2H, m), 2.49 (3H, s), 2.98 (1H, d, J = 4.8 Hz), 4.21-4.23 (2H, m), 4.36 (1H, d, J = 7.8 Hz), 4.96 (2H, br s), 5.20 (1H, d, J = 5.9 Hz), 5.27 (1H, d, J = 6.8 Hz), 5.46 (1H, d, J = 9.8 Hz), 5.58 (1H, d, J = 17.1 Hz), 5.61 (1H, d, J = 6.8 Hz), 5.96-6.03 (2H, m), 6.08-6.12 (2H, m), 7.25-7.29 (1H, m), 7.40 (1H, t, J = 8.3 Hz), 7.47 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 8.16 (2H, d, J = 7.8 Hz), 8.39 (1H, d, J = 3.4 Hz).
[0126]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-hydroxypro Pionate
The title compound was obtained in the same manner as in Step 2 of Example 5 using the compound obtained in Step 1 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.30 (3H, s), 1.41 (9H, s), 1.51 (3H, s), 1.65 (3H, s), 1.81 (3H, s), 1.57-1.63 (3H, m), 1.89-1.95 (2H, m), 2.03-2.10 (1H, m), 2.35 (3H, s), 2.43-2.49 (1H, m), 2.95 (1H, d, J = 4.9 Hz), 4.20 (1H, d, J = 7.4 Hz ), 4.23 (1H, d, J = 8.8 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.68 (1H, d, J = 2.5 Hz), 4.92 (1H, s), 5.24 (1H, d , J = 6.4 Hz), 5.31 (1H, d, J = 6.8 Hz), 5.46 (1H, d, J = 9.8 Hz), 5.58 (1H, d, J = 17.1 Hz), 5.65 (1H, d, J = 8.3 Hz), 5.97-6.05 (2H, m), 6.10 (1H, t, J = 8.8 Hz), 6.21 (1H, d, J = 8.3 Hz), 7.29-7.32 (1H, m), 7.43-7.49 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 8.14 (2H, d, J = 7.3 Hz), 8.41 (1H, d, J = 4.9 Hz).
[0127]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-hydroxy Propionate
The title compound was obtained by the same procedures as in Step 3 of Example 5 using the compound obtained in the above Step 2 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.29 (3H, s), 1.40 (9H, s), 1.49 (3H, s), 1.61 (3H, s), 1.79 (3H, s), 1.70-2.03 (5H, m), 2.30-2.44 (2H, m), 2.35 (3H, s), 2.61-2.65 (4H, m), 2.70-2.82 (2H, m), 2.94 (1H, d, J = 4.8 Hz), 3.75 (4H, t, J = 4.9 Hz ), 4.14 (1H, d, J = 7.3 Hz), 4.23 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J = 7.8 Hz), 4.67 (1H, s), 4.92 (1H, s ), 5.05 (1H, t, J = 4.9 Hz), 5.25 (1H, d, J = 7.3 Hz), 5.65 (1H, d, J = 7.8 Hz), 5.99 (1H, d, J = 5.4 Hz), 6.09 (1H, t, J = 7.8 Hz), 6.20 (1H, d, J = 8.3 Hz), 7.29-7.33 (1H, m), 7.43-7.49 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 8.13 (2H, d, J = 7.3 Hz), 8.40 (1H, d, J = 4.9 Hz).
[0128]
(Example 11)
[0129]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy] -5 , 20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-hydroxypropio Nate
Using the compound obtained in Step 2 of Example 10 as a raw material and using dimethylamine (2 mol-methanol solution) in place of morpholine, the same operation as in Step 3 of Example 5 was carried out to give the title compound Got.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.29 (3H, s), 1.41 (9H, s), 1.49 (3H, s), 1.63 (3H, s), 1.79 (3H, s), 1.86-2.08 (5H, m), 2.32-2.38 (2H, m), 2.34 (3H, s), 2.38 (6H, s), 2.66 (1H, dd, J = 5.4, 13.6 Hz), 2.75 (1H, dd, J = 3.9, 13.6 Hz), 2.94 (1H, d , J = 4.9 Hz), 4.14 (1H, d, J = 6.9 Hz), 4.23 (1H, d, J = 8.3 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.68 (1H, d, J = 2.9 Hz), 4.92 (1H, s), 5.02 (1H, t, J = 4.9 Hz), 5.25 (1H, d, J = 6.8 Hz), 5.65 (1H, d, J = 8.3 Hz), 6.00 ( 1H, d, J = 4.9 Hz), 6.09 (1H, t, J = 7.8 Hz), 6.21 (1H, d, J = 8.3 Hz), 7.28-7.33 (1H, m), 7.43-7.49 (3H, m ), 7.60 (1H, t, J = 7.3 Hz), 8.14 (2H, d, J = 7.3 Hz), 8.40 (1H, d, J = 4.4 Hz).
[0131]
Example 12
[0132]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino-3- (5-methoxy-2-pyridyl) -2-tri Isopropylsilyloxypropionate
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-[(1S)- 2-Propenylidenedioxy] tax-6,11-diene 300 mg was dissolved in 10 ml of dry tetrahydrofuran, and lithium hexamethyldisilazide (1 mol-tetrahydrofuran solution) 0.63 ml was added at -60 ° C for 20 minutes. Stir. (3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone 280 mg in tetrahydrofuran 5 ml at the same temperature And stirred for 30 minutes under ice-cooling. Saturated aqueous ammonia chloride and ethyl acetate were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 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 (eluted with hexane: ethyl acetate = 5: 1 (v / v)) to obtain 530 mg of the title compound.1H-NMR (400 MHz, CDClThree, TMS) δ:
0.87-0.93 (21H, m), 1.29 (3H, s), 1.41 (9H, s), 1.54 (3H, s), 1.69 (3H, s), 1.75 (3H, s), 1.82 (1H, s) , 2.29 (1H, dd, J = 9.8, 15.1 Hz), 2.40 (1H, dd, J = 8.8, 15.1 Hz), 2.53 (3H, s), 3.13 (1H, d, J = 5.8 Hz), 3.85 ( 3H, s), 4.04 (1H, d, J = 7.3 Hz), 4.30 (2H, br s), 4.90 (1H, d, J = 3.9 Hz), 5.20-5.23 (2H, m), 5.28 (1H, d, J = 9.8 Hz), 5.38 (1H, s), 5.47-5.49 (2H, m), 5.60 (1H, d, J = 17.0 Hz), 5.71 (1H, dd, J = 4.4, 10.2 Hz), 5.96-6.06 (2H, m), 6.09-6.14 (2H, m), 7.16 (1H, dd, J = 2.9, 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 7.47 (2H, t, J = 7.8 Hz), 7.58 (1H, t, J = 7.8 Hz), 8.14 (2H, d, J = 7.8 Hz), 8.26 (1H, d, J = 2.9 Hz).
[0134]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-methoxy-2-pyridyl) -2 -Triisopropylsiloxypropionate
Dissolve 520 mg of the compound obtained in Step 1 above in 5 ml of tetrahydrofuran, add 5 ml of acetone, 5 ml of water, 13 mg of osmium tetroxide, and 300 mg of N-methylmorpholine-N-oxide, and stir at room temperature for 7.5 hours. did. Ethyl acetate and a 10% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was subjected to liquid separation. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in 5 ml of tetrahydrofuran, 5 ml of methanol, 5 ml of water and 1.1 g of sodium metaperiodate were added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution, and liquid separation was performed, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 30 ml of ethanol, 0.22 ml of morpholine, 0.15 ml of acetic acid and 160 mg of sodium cyanoborohydride were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate, ethyl acetate and water were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 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 (eluted with hexane: ethyl acetate = 3: 2 (v / v)) to obtain 290 mg of the title compound.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.87-0.93 (21H, m), 1.28 (3H, s), 1.41 (9H, s), 1.53 (3H, s), 1.55 (3H, s), 1.73 (3H, s), 1.80 (1H, s) , 2.26 (1H, dd, J = 8.8, 15.1 Hz), 2.39 (1H, dd, J = 9.8, 15.1 Hz), 2.53 (3H, s), 2.60-2.68 (4H, m), 2.74 (1H, dd , J = 4.9, 13.7 Hz), 2.81 (1H, dd, J = 4.9, 13.7 Hz), 3.12 (1H, d, J = 5.4 Hz), 3.76 (4H, t, J = 4.8 Hz), 3.85 (3H , s), 3.99 (1H, d, J = 7.9 Hz), 4.30 (2H, s), 4.89 (1H, d, J = 3.9 Hz), 5.02 (1H, t, J = 3.9 Hz), 5.14 (1H , d, J = 7.3 Hz), 5.27 (1H, d, J = 9.8 Hz), 5.37 (1H, d, J = 1.5 Hz), 5.47 (1H, d, J = 9.8 Hz), 5.69 (1H, dd , J = 3.9, 10.5 Hz), 5.94 (1H, d, J = 5.3 Hz), 6.07-6.13 (2H, m), 7.16 (1H, dd, J = 2.9, 6.3 Hz), 7.30 (1H, d, J = 6.3 Hz), 7.47 (2H, t, J = 7.8 Hz), 7.58 (1H, t, J = 7.8 Hz), 8.15 (2H, d, J = 7.8 Hz), 8.26 (1H, d, J = 2.9 Hz).
[0135]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (5-methoxy-2-pyridyl) -2-tri Isopropylsiloxypropionate Dissolve 235 mg of the compound obtained in step 2 above in 10 ml of ethanol, add 235 mg of 5% palladium on carbon catalyst (wet) and add hydrogen under pressure (4 kg / cm2= 392 kPa) and shaken for 10 hours. After removing the catalyst by filtration, the filtrate was concentrated to obtain 230 mg of the title compound.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.88-0.94 (21H, m), 1.30 (3H, s), 1.42 (9H, s), 1.50 (3H, s), 1.60 (3H, s), 1.79 (3H, s), 1.84-2.30 (7H, m), 2.50 (3H, s), 2.60-2.84 (4H, m), 2.85-2.92 (2H, m), 2.95 (1H, d, J = 4.4 Hz), 3.80 (4H, t, J = 4.4 Hz ), 3.85 (3H, s), 4.17 (1H, d, J = 7.3 Hz), 4.19 (1H, d, J = 8.7 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.96 (1H, s ), 5.10 (1H, br s), 5.22-5.28 (2H, m), 5.40 (1H, s), 5.48 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 4.9 Hz), 6.10 (1H, t, J = 8.3 Hz), 7.12-7.17 (1H, m), 7.31 (1H, d, J = 8.3 Hz), 7.45 (2H, t, J = 7.8 Hz), 7.57 (1H, t , J = 7.8 Hz), 8.13 (2H, d, J = 7.8 Hz), 8.26 (1H, d, J = 2.9 Hz)
[0136]
Step 4: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- (morpholino) ethylidenedioxy] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- (5-methoxy-2-pyridyl) Propionate
230 mg of the compound obtained in the above Step 3 was dissolved in 5 ml of dried tetrahydrofuran, 0.43 ml of tetrabutylammonium fluoride (1 mol-tetrahydrofuran solution) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated brine and ethyl acetate were added to the reaction solution, and the liquids were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 50: 1 (v / v)) and recrystallized from aqueous ethanol to obtain 110 mg of the title compound. The instrument data was consistent with the compound obtained in Step 3 of Example 5.
[0137]
(Example 13)
[0138]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2-propenylidenedioxy] tax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino-3- (3-fluoro-2-pyridyl) -2-tri Isopropylsilyloxypropionate
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone instead of (3R, 4S) -1- (tert -Butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone, and using the same procedure as in Step 1 of Example 12, the title compound was obtained. Obtained.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.88-0.92 (21H, m), 1.33 (3H, s), 1.38 (9H, s), 1.56 (3H, s), 1.60 (3H, s), 1.76 (3H, s), 2.41-2.45 (2H, m), 2.51 (3H, s), 3.14 (1H, d, J = 5.8 Hz), 4.06 (1H, d, J = 7.8 Hz), 4.33 (2H, s), 4.90 (1H, d, J = 4.4 Hz), 4.94 (1H, d, J = 2.4 Hz), 5.19-5.22 (2H, m), 5.48 (1H, d, J = 10.3 Hz), 5.58-5.64 (2H, m), 5.70 (1H, dd , J = 10.3, 4.4 Hz), 5.96-6.14 (5H, m), 7.26-7.30 (1H, m), 7.41 (1H, t, J = 8.5 Hz), 7.49 (2H, t, J = 7.5 Hz) , 7.59 (1H, t, J = 7.5 Hz), 8.17 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 4.4 Hz).
[0140]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy ] -5,20-Epoxy-1-hydroxytax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl)- 2-Triisopropylsilyloxypropionate
The title compound was obtained by performing the same operation as in Step 2 of Example 12 using the compound obtained in Step 1 above as a raw material and using dimethylamine (2 mol-methanol solution) instead of morpholine.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.87-0.92 (21H, m), 1.32 (3H, s), 1.38 (9H, s), 1.55 (3H, s), 1.57 (3H, s), 1.75 (3H, s), 2.39 (6H, s) , 2.42-2.45 (2H, m), 2.51 (3H, s), 2.66 (1H, dd, J = 5.1, 13.2 Hz), 2.74 (1H, dd, J = 4.2, 13.2 Hz), 3.14 (1H, d , J = 5.8 Hz), 4.01 (1H, d, J = 7.9 Hz), 4.32 (2H, s), 4.90-4.94 (2H, m), 5.00 (1H, t, J = 4.9 Hz), 5.15 (1H , d, J = 7.9 Hz), 5.63 (1H, d, J = 9.8 Hz), 5.69 (1H, dd, J = 9.8, 4.4 Hz), 5.95 (1H, d, J = 5.8 Hz), 6.07-6.13 (3H, m), 7.26-7.28 (1H, m), 7.41 (1H, t, J = 9.2 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.59 (1H, t, J = 7.5 Hz) , 8.17 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 4.4 Hz).
[0141]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy ] -5,20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2- Triisopropylsilyloxypropionate Using the compound obtained in Step 2 above as a starting material, the title compound was obtained in the same manner as in Step 3 of Example 12.
1H-NMR (400 MHz, CDClThree, TMS) δ:
0.83-0.93 (21H, m), 1.35 (3H, s), 1.38 (9H, s), 1.52 (3H, s), 1.56-2.07 (5H, m), 1.62 (3H, s), 1.81 (3H, s), 2.34-2.43 (2H, m), 2.38 (6H, s), 2.49 (3H, s), 2.66 (1H, dd, J = 5.4, 13.2 Hz), 2.74 (1H, dd, J = 3.4, 13.2 Hz), 2.98 (1H, d, J = 5.4 Hz), 4.17 (1H, d, J = 7.3 Hz), 4.22 (1H, d, J = 7.8 Hz), 4.36 (1H, d, J = 8.3 Hz) ), 4.96 (2H, s), 5.00 (1H, t, J = 4.8 Hz), 5.22 (1H, d, J = 7.3 Hz), 5.60 (1H, d, J = 8.8 Hz), 5.98 (1H, d , J = 4.9 Hz), 6.08-6.10 (2H, m), 7.26-7.28 (1H, m), 7.40 (1H, t, J = 9.2 Hz), 7.48 (2H, t, J = 7.5 Hz), 7.59 (1H, t, J = 7.5 Hz), 8.16 (2H, d, J = 7.5 Hz), 8.40 (1H, d, J = 3.9 Hz).
[0142]
Step 4: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy ] -5,20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2- Hydroxypropionate
The title compound was obtained by the same procedures as in Step 12 of Example 12 using the compound obtained in the above Step 3 as a raw material. The instrument data was consistent with the compound obtained in Step 3 of Example 11.
[0143]
(Example 14)
[0144]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10- (2-propenylidene Oxy) tax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-hydroxypropionate
The title compound was obtained by the same procedures as in Step 2 of Example 5 using the compound obtained in Step 1 of Example 13 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.29 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.60 (3H, s), 1.74 (3H, s), 1.91 (1H, s), 2.35-2.48 (2H, m) , 2.41 (3H, s), 3.11 (1H, d, J = 5.4 Hz), 3.92 (1H, br s), 4.03 (1H, d, J = 7.6 Hz), 4.27 (1H, d, J = 8.1 Hz) ), 4.33 (1H, d, J = 8.2 Hz), 4.67 (1H, br s), 4.87 (1H, d, J = 4.1 Hz), 5.22-5.25 (2H, m), 5.48 (1H, d, J = 10.8 Hz), 5.60 (1H, d, J = 17.3 Hz), 5.62-5.64 (1H, m), 5.69 (1H, dd, J = 4.1, 10.3 Hz), 5.98-6.13 (4H, m), 6.21 (1H, d, J = 8.3 Hz), 7.29-7.33 (1H, m), 7.43-7.50 (3H, m), 7.60 (1H, t, J = 7.3 Hz), 8.15 (2H, d, J = 7.6 Hz), 8.39 (1H, d, J = 4.6 Hz).
[0146]
(Example 15)
[0147]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy] -5 , 20-Epoxy-1-hydroxytax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-hydroxy Propionate
The title compound was obtained by the same procedures as in Step 2 of Example 5 using the compound obtained in Step 2 of Example 13 as a raw material.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.28 (3H, s), 1.39 (9H, s), 1.52 (3H, s), 1.57 (3H, s), 1.72 (3H, s), 1.86 (1H, s), 2.27-2.46 (2H, m) , 2.39 (6H, s), 2.41 (3H, s), 2.69 (1H, dd, J = 5.2, 13.2 Hz), 2.79 (1H, dd, J = 4.2, 13.2 Hz), 3.11 (1H, d, J = 5.9 Hz), 3.98 (1H, d, J = 7.6 Hz), 4.28 (1H, d, J = 8.1 Hz), 4.33 (1H, d, J = 8.3 Hz), 4.66 (1H, d, J = 2.5 Hz), 4.87 (1H, d, J = 4.1 Hz), 5.02 (1H, dd, J = 4.2, 4.8 Hz), 5.17 (1H, d, J = 7.8 Hz), 5.62 (1H, d, J = 8.5 Hz), 5.68 (1H, dd, J = 4.1, 10.3 Hz), 5.96 (1H, m), 6.10 (2H, m), 6.20 (1H, d, J = 6.9 Hz), 7.27-7.60 (6H, m ), 8.15 (2H, d, J = 7.3 Hz), 8.40 (1H, d, J = 4.6 Hz).
[0149]
(Example 16)
[0150]
Embedded image
Step 1: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10- (2-pro (Penylidenedioxy) tax-6,11-dien-13-yl (2R, 3S) -2-benzyloxy-3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) propionate
(3R, 4S) -1- (tert-butoxycarbonyl) -4- (5-methoxy-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone instead of (3R, 4S) -3-benzyloxy The title compound was obtained by the same procedures as in Step 1 of Example 12 using -1- (tert-butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -2-azetidinone. .
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.32 (3H, s), 1.39 (9H, s), 1.56 (3H, s), 1.59 (3H, s), 1.77 (3H, s), 1.85 (1H, s), 2.31 (3H, s), 2.39 (2H, m), 3.13 (1H, d, J = 6.1 Hz), 4.07 (1H, d, J = 7.6 Hz), 4.18 (1H, d, J = 12.0 Hz), 4.31 (3H, m), 4.68 (1H, d, J = 12.2 Hz), 4.90 (1H, d, J = 4.2 Hz), 5.23 (2H, t, J = 7.1 Hz), 5.48 (1H, d, J = 11.0 Hz), 5.59 (2H , m), 5.70 (1H, dd, J = 4.4, 10.5 Hz), 6.02 (1H, m), 6.13 (2H, d, J = 10.2 Hz), 6.26 (1H, d, J = 9.0 Hz), 6.88 (2H, d, J = 7.1 Hz), 7.19 (3H, m), 7.29 (2H, t, J = 6.8 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.60 (1H, t, J = 7.3 Hz), 8.16 (2H, d, J = 7.3 Hz), 8.42 (1H, m).
[0152]
Step 2: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy ] -5,20-Epoxy-1-hydroxytax-6,11-dien-13-yl (2R, 3S) -2-benzyloxy-3- (tert-butoxycarbonylamino) -3- (3-fluoro- 2-Pyridyl) propionate
The title compound was obtained by performing the same operation as in Step 2 of Example 12 using the compound obtained in Step 1 above as a raw material and using dimethylamine (2 mol-methanol solution) instead of morpholine.
1H-NMR (400 MHz, CDClThree, TMS) δ:
1.26 (3H, s), 1.39 (9H, s), 1.54 (3H, s), 1.57 (3H, s), 1.75 (3H, s), 1.82 (1H, s), 2.31 (3H, s), 2.36 -2.39 (2H, m), 2.38 (6H, s), 2.71 (1H, dd, J = 5.2, 13.2 Hz), 2.77 (1H, dd, J = 4.1, 13.2 Hz), 3.12 (1H, d, J = 5.6 Hz), 4.02 (1H, d, J = 7.8 Hz), 4.19 (1H, d, J = 12.2 Hz), 4.31 (2H, m), 4.36 (1H, d, J = 2.9 Hz), 4.68 ( 1H, d, J = 12.7 Hz), 4.88 (1H, d, J = 4.1 Hz), 5.01 (1H, t, J = 4.7 Hz), 5.16 (1H, d, J = 7.8 Hz), 5.60 (1H, d, J = 8.8 Hz), 5.69 (1H, dd, J = 4.2, 10.3 Hz), 5.93 (1H, d, J = 5.6 Hz), 6.11 (2H, m), 6.23 (1H, d, J = 9.3 Hz), 6.88 (2H, d, J = 6.6 Hz), 7.16-7.31 (5H, m), 7.48 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.3 Hz), 8.15 ( 2H, dd, J = 1.5, 7.1 Hz), 8.41 (1H,
d, J = 2.9 Hz).
[0153]
Step 3: (1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-9,10-[(1S) -2- (dimethylamino) ethylidenedioxy ] -5,20-Epoxy-1-hydroxytax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2- Hydroxypropionate
The title compound was obtained by the same procedures as in Step 3 of Example 12 using the compound obtained in Step 2 as a raw material. The instrument data was consistent with the compound obtained in Step 3 of Example 11.
[0154]
(Example 17)
[0155]
Embedded image
(±) -1- (tert-butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone
The racemate obtained without performing optical resolution in Step 3 of Example 1 was subjected to Step 4 to give the title compound. The NMR data was consistent with the compound obtained in Step 4 of Example 1.
[0157]
(Example 18)
[0158]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S)-(2 -Propenylidenedioxy)] tax-11-en-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-triisopropylsilyl Roxypropionate
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-[(1S)- (2-propenylidenedioxy)] tax-11-ene (0.56 g) was dissolved in dry tetrahydrofuran (20 ml), and lithium hexamethyldisilazide (1 mol-tetrahydrofuran solution) (1.2 ml) was added at -60 ° C. for 20 minutes. Stir. To the reaction solution at the same temperature, (±) -cis-1- (tert-butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone 1.1 g in tetrahydrofuran 5 ml solution And stirred for 20 minutes under ice-cooling. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, washed successively with saturated aqueous sodium hydrogen carbonate solution 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 (eluted with hexane: ethyl acetate = 5: 1 (v / v)) to obtain 0.9 g of the title compound as a white substance. The instrument data was consistent with the compound obtained in Step 1 of Example 10.
[0160]
(Example 19)
[0161]
Embedded image
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9,10-[(1S) -2- Propenylidenedioxy] tax-6,11-dien-13-yl (2R, 3S) -3- (tert-butoxycarbonylamino) -3- (3-fluoro-2-pyridyl) -2-triisopropylsilyl Roxypropionate
(1S, 2S, 3R, 4S, 5R, 8R, 9S, 10R, 13S) -4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,13-dihydroxy-9,10-[(1S)- 2-Propenylidenedioxy] tax-6,11-diene (21 g) was dissolved in 400 ml of dry tetrahydrofuran, and 44.5 ml of lithium hexamethyldisilazide (1 mol-tetrahydrofuran solution) was added at -60 ° C for 20 minutes. Stir. (±) -cis-1- (tert-butoxycarbonyl) -4- (3-fluoro-2-pyridyl) -3-triisopropylsilyloxy-2-azetidinone 39 g in tetrahydrofuran 100 ml solution at the same temperature And stirred for 20 minutes under ice-cooling. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, combined with the previous organic layer, washed successively with saturated aqueous sodium hydrogen carbonate solution 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 (eluted with hexane: ethyl acetate = 7: 1 (v / v)) to obtain 33 g of the title compound as a white substance. The instrument data was consistent with the compound obtained in Step 1 of Example 13.
[0163]
(Test Example 1)
Mouse fibrosarcoma Meth A was transplanted subcutaneously into mice (strain name: Balb / c), and the compound was added with ethanol, Tween80, 5% glucose (5: 5: 90) 6,8,10 days after transplantation (or only after 6 days). (v / v)) was dissolved in a mixed solvent and administered intravenously. On day 17, the patient was dissected and searched for tumor weight, platelet count, and nephrotoxicity. Six mice were used for each group.
The antitumor effect was calculated by the following formula.
[1- (tumor weight of compound administration group / tumor weight of solvent administration group)] × 100
The number of platelets was expressed as (number of platelets in compound administration group / number of platelets in solvent administration group) × 100.
Nephrotoxicity changes when changes such as fading are observed by macroscopic observation at the time of dissection or when changes in the deposition of hyaline material in renal tubular cells and cytoplasm are observed by histological examination It was written as “Yes”.
[0164]
[Table 1]
(Test Example 2)
Mice (C57BL / 6) were subcutaneously implanted with B16 melanoma BL6, and the compound was administered 4 days later. For intravenous administration, Compound A is dissolved in a mixed solvent of ethanol, Tween 80, 5% glucose (5:15:80 (v / v)), and the compound of Example 11 is 5: 5: 90 (v / v ) And dissolved in the same mixed solvent. For oral administration, it was suspended in 0.5% sodium carboxymethylcellulose aqueous solution. Body weight was measured every two or three days after administration, and the tumor weight was measured by dissection 15 days after transplantation. The antitumor effect was calculated by the following formula.
[1- (tumor weight of compound administration group / tumor weight of solvent administration group)] × 100
Six mice were used for each group.
[0166]
[Table 2]
(Test Example 3)
Metabolism in human microsome P450
The sample to be evaluated is dissolved in acetonitrile / water (1: 1, v / v) to a concentration of 500 μM, and this is mixed with human liver microsomes (Xenotech LLC), various coenzymes, buffers, etc. at 37 ° C. Caused a metabolic reaction. The composition of the reaction solution was phosphate buffer (final concentration, the same below, 0.076 M), evaluation sample (10 μM), human liver microsome (1 mg / ml), glucose 6-phosphate (10 mM), glucose 6- Phosphate dehydrogenase (1 unit / ml), magnesium chloride (4 mM), nicotinamide adenine dinucleotide-phosphate reduced form (β-NADPH, 1 mM), 500 μl used for one reaction did. The reaction solution from which β-NADPH was removed was warmed at 37 ° C. for 2 minutes, and the reaction was started by adding a β-NADPH aqueous solution (50 mM, 10 μl).
1, 2 and 5 minutes after the start of the reaction, 1 ml of ice-cooled acetonitrile was added to stop the reaction.
[0168]
In addition, 0 minutes after the start of the reaction was prepared by adding water instead of β-NADPH aqueous solution and immediately adding 1 ml of acetonitrile. 100 μl of an internal standard substance was added to these samples, and the reaction solution was centrifuged for 15 minutes. The supernatant was injected into high performance liquid chromatography (HPLC), and the concentration of the test sample was measured. The amount of decrease from the concentration at 0 minutes after the start of the reaction was defined as the amount of metabolite produced (nmol / mg protein). The amount of metabolite produced is plotted against the reaction time, linear regression is performed using the least squares method, and the amount of metabolite produced per minute (metabolic rate constant: k (nmol / min / mg protein)) is calculated from the slope. did.
From the calculated metabolic rate constant k (nmol / min / mg protein), liver specific clearance (CLint) was calculated from the following equation.
CLint (ml / min / kg body weight) = k × [(g liver weight) / (kg body weight)] × (45 mg microsomal protein) / (g liver weight)
However, the liver weight per kg body weight was 20 g.
Furthermore, liver clearance (CLh) was calculated from CLint according to the Well-stirred model (J. Pharmacol. Exp. Ther. 283 46-58, 1997).
CLh (ml / min / kg body weight) = CLh (ml / min / kg body weight) = Q x CLint / (Q + CLint)
However, Q is 20 ml / min / kg as hepatic blood flow in humans.
The theoretical bioavailability (F) value of the metabolite was calculated from the following formula from CLh.
F = (1-CLh / Q)
Furthermore, the theoretical bioavailability value of the unchanged substance was calculated by the 1-F formula. The results are shown in Table 3.
[0169]
[Table 3]
The theoretical F value of the unchanged form of the compound of the present invention is larger than the unchanged form theoretical F value of 0.27 of the control compound (Compound B), which suppresses the variation range of bioavailability, As a result, the difference between the therapeutic range and the toxic range can be achieved with higher accuracy, indicating that oral administration is possible.
[0171]
(Test Example 4)
Compound B or the compound of Example 11 was administered intravenously or orally to monkeys once, and blood concentration transitions were measured to determine AUC.0-(Calculated. AUC0-(Indicates the area under the concentration-time curve of drug blood concentration up to infinite time when the administration time is 0 h, and can be calculated using the method described in the literature (Introduction to Pharmacokinetics Kiyoshi Yamaoka, Tanigawara Yusuke, p. 116-117 Nanedou) Furthermore, the ratio of AUC at the time of oral administration to AUC at the time of intravenous administration was calculated as oral BA.Compound BIn the intravenous and oral administrations, one monkey was used as a separate body, and in the compound of Example 11, the same individual was administered intravenously and orally in four monkeys, and the AUC was obtained as an average value. It was.
Animal: female cynomolgus monkey, administration method (compound B) [intravenous] EtOH: Tween 80: 5% Glucose = 5: 5: 90, [oral] 0.1N HCl solution, (compound of Example 11) [intravenous] 10 % βCyD-SBE7 (pH = 3.5 saline), [Oral] 40 mM acetate buffer (pH 4.0)
[0172]
[Table 4]
【The invention's effect】
The compound of the present invention was improved in toxicity, and no nephrotoxicity was observed. In addition, the compound of the present invention was found to have a high antitumor effect by oral administration in mice. Furthermore, the compound of the present invention has a large theoretical F value of the unchanged form, thereby suppressing the variation range of bioavailability and achieving a difference between the therapeutic range and the toxic range. The compounds of the present invention showed excellent oral absorption in monkeys. Thus, the compound of the present invention can be used as an orally administrable antitumor agent.
Claims (11)
で表される化合物の製造方法。
１）次式（ＩＩＩ）
で表される化合物および次式（ＩＶ）
で表される化合物を反応させて、式（ＶＩ）
２）この化合物のビニル基をアルデヒド基に変換する反応からなる工程、
３）そのアルデヒド基をジメチルアミノメチル基またはモルホリノメチル基に変換する反応からなる工程、
４）６位炭素と７位炭素との間の結合が二重結合の場合に単結合に変換する反応からなる工程、および
５）Ｒ3が保護基を有する水酸基である場合に該保護基を除去する反応からなる工程。The following formula (I), comprising the following steps 1), 2), 3), 4), and 5)
The manufacturing method of the compound represented by these.
1) The following formula (III)
And a compound represented by the following formula (IV)
Is reacted with a compound of formula (VI)
2) a step comprising a reaction of converting the vinyl group of this compound into an aldehyde group,
3) a process comprising a reaction for converting the aldehyde group into a dimethylaminomethyl group or a morpholinomethyl group;
4) a step comprising a reaction for converting to a single bond when the bond between the 6-position carbon and the 7-position carbon is a double bond, and 5) when R 3 is a hydroxyl group having a protecting group, A process consisting of a reaction to be removed.
で表される化合物が、光学活性体であって次式（ＶＩＩ）
で表される化合物であることを特徴とする請求項６に記載の製造方法。Formula (III)
Is a compound having the following formula (VII):
The production method according to claim 6 , wherein the compound is represented by the formula:
で表される化合物がラセミ体であることを特徴とする請求項６に記載の製造方法。Formula (III)
The production method according to claim 6 , wherein the compound represented by the formula is a racemate.
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