JPWO2010035727A1 - 新規ピロリノン誘導体およびそれを含有する医薬組成物 - Google Patents
新規ピロリノン誘導体およびそれを含有する医薬組成物 Download PDFInfo
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- 0 C**c(cccc1)c1N1CC1 Chemical compound C**c(cccc1)c1N1CC1 0.000 description 2
- NVUIDYCJJZAUMQ-UHFFFAOYSA-N CC(C)(C)c1n[nH]c(C2=O)c1C(c(cccc1)c1OCC(O)=O)N2c(cc1)ccc1-c1c[s]cc1 Chemical compound CC(C)(C)c1n[nH]c(C2=O)c1C(c(cccc1)c1OCC(O)=O)N2c(cc1)ccc1-c1c[s]cc1 NVUIDYCJJZAUMQ-UHFFFAOYSA-N 0.000 description 1
- MFGUOHWZYCTWRK-VDHJMRPNSA-N C[C@H]([C@H](C)N(C(c1c2[nH]nc1C(C)(C)C)c1ccccc1OCC(OC)=O)C2=O)[C@@H](CS)C(C)C=C Chemical compound C[C@H]([C@H](C)N(C(c1c2[nH]nc1C(C)(C)C)c1ccccc1OCC(OC)=O)C2=O)[C@@H](CS)C(C)C=C MFGUOHWZYCTWRK-VDHJMRPNSA-N 0.000 description 1
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Abstract
新規なＰ２Ｘ３および／またはＰ２Ｘ２／３受容体アンタゴニストを提供する。式（Ｉ）：（式中、Ｚ１は、保護されていてもよいヒドロキシ等；Ｚ２は、−Ｃ（＝Ｏ）−等； Ｚ３ａおよびＺ３ｂは、一緒になって＝Ｏもしくは＝Ｓ等；ｔは、０〜４の整数；Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル等；ｍおよびｎは、それぞれ独立して、０〜２の整数；ｋは、０または１の整数；環Ａは、芳香族炭素環またはヘテロ環等；Ｂは、芳香族炭素環ジイルまたはヘテロ環ジイル等；Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル等；Ｒ２は、置換もしくは非置換のアルキル等；Ｒ３は、置換もしくは非置換のアルキル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基等）で示される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を提供する。
Description
本発明は、Ｐ２Ｘ受容体、特にＰ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患または状態を治療するのに有用な化合物、および該化合物を含有する医薬組成物に関する。
ＡＴＰ（アデノシン３リン酸）は細胞内におけるエネルギー源やリン酸化基質として知られている一方、細胞外における情報伝達物質としても働く。ＡＴＰは細胞の損傷、炎症、侵害刺激、血中酸素濃度の低下など様々な刺激により細胞外へ放出されるほか、一次感覚神経終末から他の神経伝達物質とともに細胞外へ放出されることが知られている。細胞外へ放出されたＡＴＰはＡＴＰ受容体を介して各種の細胞外情報伝達を行う（非特許文献６、非特許文献７）。
ＡＴＰ受容体はイオンチャネル型のＰ２ＸファミリーとＧタンパク質共役型のＰ２Ｙファミリーに大別される。Ｐ２Ｘ受容体ファミリーには７種類のサブタイプが報告されており、ホモ３量体または他のＰ２Ｘサブタイプとのヘテロ３量体を形成して非選択的カチオンチャネルとして機能する（非特許文献８）。
ＡＴＰが痛みを引き起こすことは既に知られており、さらにＰ２Ｘ３のノックアウトやノックダウン技術を用いた研究により、Ｐ２Ｘ３受容体は慢性疼痛の伝達に関与していることが示された。Ｐ２Ｘ３受容体は末梢感覚神経特異的に発現し、ホモ複合体またはＰ２Ｘ２とのヘテロ複合体（Ｐ２Ｘ２／３）を形成する。（非特許文献１）
その後、Ｐ２Ｘ３およびＰ２Ｘ２／３受容体に特異的なアンタゴニストとしてＡ−３１７４９１と称する化合物が報告された。Ａ−３１７４９１は、次式
で示されるトリ置換−Ｎ−［（１Ｓ）−１，２，３，４−テトラヒドロ−１−タフタレニル］ベンズアミド誘導体であり（特許文献１）、Ｐ２Ｘ３およびＰ２Ｘ２／３受容体に対してアンタゴニスト活性を示し、ラットの神経障害性疼痛モデル、および炎症性疼痛モデルにおいて鎮痛作用を示したことが報告されている（非特許文献９）。このことは、Ｐ２Ｘ３またはＰ２Ｘ２／３受容体を介して痛覚が伝達されること、そしてＰ２Ｘ３またはＰ２Ｘ２／３受容体アンタゴニストが鎮痛薬として有用であることを示している。また、特許文献２〜７にもＰ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用を示す化合物が記載されている。
で示されるトリ置換−Ｎ−［（１Ｓ）−１，２，３，４−テトラヒドロ−１−タフタレニル］ベンズアミド誘導体であり（特許文献１）、Ｐ２Ｘ３およびＰ２Ｘ２／３受容体に対してアンタゴニスト活性を示し、ラットの神経障害性疼痛モデル、および炎症性疼痛モデルにおいて鎮痛作用を示したことが報告されている（非特許文献９）。このことは、Ｐ２Ｘ３またはＰ２Ｘ２／３受容体を介して痛覚が伝達されること、そしてＰ２Ｘ３またはＰ２Ｘ２／３受容体アンタゴニストが鎮痛薬として有用であることを示している。また、特許文献２〜７にもＰ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用を示す化合物が記載されている。
さらに、Ｐ２Ｘ３ノックアウトマウスが顕著な膀胱反射低下を示すことが近年報告されており（非特許文献２）、Ｐ２Ｘ３拮抗薬が膀胱過活動に起因する疾患の治療においても有用であることを示唆している。
非特許文献１２には、本発明化合物と類似の構造を有する化合物が記載されているが、
鎮痛作用およびＰ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用については記載されていない。また、非特許文献３、４、１０および１１には、本発明化合物と類似の構造を有し、鎮痛活性を示す化合物が記載されているが、Ｐ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用については記載されていない。
鎮痛作用およびＰ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用については記載されていない。また、非特許文献３、４、１０および１１には、本発明化合物と類似の構造を有し、鎮痛活性を示す化合物が記載されているが、Ｐ２Ｘ３またはＰ２Ｘ２／３受容体拮抗作用については記載されていない。
本発明は、新規なＰ２Ｘ３および／またはＰ２Ｘ２／３受容体アンタゴニストを提供する。
本発明者らは、上記目的を達成するために鋭意研究を重ねた結果、Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体に特異的に結合し、拮抗作用を示す新規化合物を見出し、以下に記載する発明を完成した。
（１）式（Ｉ）：
（式中、
Ｚ１は、保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２は、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−もしくは−Ｓ（Ｏ）ｖ−であるか、または
（式中、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素または低級アルキル；
Ｒ６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニル；
ｐは、０〜２の整数）を形成し；
ｖは、０〜２の整数；
Ｚ３ａおよびＺ３ｂは、それぞれ独立して、水素、置換もしくは非置換の低級アルキルであるか、または、一緒になって、＝Ｏもしくは＝Ｓを形成し；
ｔは、０〜４の整数；
Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
ｍおよびｎは、それぞれ独立して、０〜２の整数；
ｋは、０または１の整数；
環Ａは、シクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環；
Ｂは、シクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
Ｒ２は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルコキシ、置換もしくは非置換のアリールオキシ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
Ｒ３は、置換もしくは非置換のアルキル、置換もしくは非置換のアルコキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、カルボキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
である）で示される化合物（ただし、
（ｉ）環Ａがチアジアゾールであり、ｋが０であり、かつ、Ｒ１ａがメチルチオである化合物；
（ｉｉ）環Ａがベンゾチオフェンであり、ｋが０であり、Ｒ１ａがメチルスルホニルであり、かつ、Ｒ２が置換もしくは非置換のフリルまたは置換もしくは非置換のフェニルである化合物；
（ｉｉｉ）環Ａがチアゾールまたは７Ｈ−プリンであり、かつ、Ｒ２が置換もしくは非置換のフリルである化合物；
（ｉｖ）Ｒ３が式:
で示される基であり、ｔが１〜２の整数であり、かつ、環Ａがフランまたはベンゼンである化合物；
（ｖ）Ｒ２がｔ−ブチルまたは４−メチルオキシフェニルである化合物；
（ｖｉ）Ｒ２が置換もしくは非置換のアルキルであり（ただし、置換もしくは非置換のｉ−プロピルおよび置換もしくは非置換のｉ−ブチルを除く）、Ｒ３が置換もしくは非置換の炭素環または置換もしくは非置換のヘテロ環であり、かつ、ｋが０である化合物；
（ｖｉｉ）Ｒ２が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、かつ、Ｒ３がペンタン−３−イルである化合物；ならびに
（ｖｉｉｉ）以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（２）
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基であるか、または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基である、上記（１）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（２’）式（Ｉ）：
（式中、
Ｚ１は、保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２は、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−もしくは−Ｓ（Ｏ）ｖ−であるか、または
（式中、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素または低級アルキル；
Ｒ６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニル；
ｐは、０〜２の整数）を形成し；
ｖは、０〜２の整数；
Ｚ３ａおよびＺ３ｂは、それぞれ独立して、水素、置換もしくは非置換の低級アルキルであるか、または、一緒になって、＝Ｏもしくは＝Ｓを形成し；
ｔは、０〜４の整数；
Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
ｍおよびｎは、それぞれ独立して、０〜２の整数；
ｋは、０または１の整数；
環Ａは、シクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環；
Ｂは、シクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
Ｒ２は、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基；
Ｒ３は、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基であるか、または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基；
である）で示される化合物（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（３）Ｚ３ａおよびＺ３ｂが、一緒になって、＝Ｏである、上記（２）または（２’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（４）ｔが、０である、上記（２）、（２’）または（３）に記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（５）Ｚ２が、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−または−Ｓ（Ｏ）２−である、上記（２）〜（４）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（６）Ｚ２が、−Ｃ（＝Ｏ）−である、上記（２）〜（５）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（７）式：
（式中、Ｚ１、Ｚ２およびＲ２は上記（１）と同意義。）
で示される基が、
式：
（式中、Ｒ２、Ｒ５ａ、Ｒ５ｂ、Ｒ６およびｐは上記（１）と同意義。）である、上記（２）〜（６）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（８）式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、上記（１）と同意義。）で示される基が
式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、上記（１）と同意義。）で示される基である、上記（２）〜（７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（９）式（Ｉ）：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ１ａ、Ｒ１ｂ、Ｒ２、Ｒ３、Ｒ４ａ、Ｒ４ｂ、環Ａ、Ｂ、ｈ、ｍ、ｎ、ｔは、上記（１）と同意義。）が、
式（Ｉ’）：
（式中、
Ｚ１’は保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２’はＯもしくはＳであるか、または
（Ｒ５ａ’およびＲ５ｂ’はそれぞれ独立して水素または低級アルキルであり、Ｒ６’は水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニルであり、ｐ’は０〜２の整数である）を形成し、
ｔ’は０〜４の整数であり、
Ｒ４ａ’およびＲ４ｂ’は、それぞれ独立して水素または低級アルキルであり、
ｍ’およびｎ’はそれぞれ独立して０〜２の整数であり、
環Ａ’はシクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環であり、
Ｂ’はシクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり、
ｎ’が０のとき、Ｂ’はメチルチオ、トリフルオロメチルチオまたは−Ｃ（Ｒ７ａ’）＝Ｎ−Ｏ−Ｒ７ｂ’であってもよく、
Ｒ１ａ’およびＲ１ｂ’は、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロであり、
Ｒ２’およびＲ３’はそれぞれ独立して置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ７ａ’およびＲ７ｂ’はそれぞれ独立して水素または置換もしくは非置換の低級アルキルである）で示される化合物（ただし、環Ａ’がチアジアゾールであり、Ｂ’がメチルチオである化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１０）
Ｒ３’式
（式中、環Ｃ’は置換もしくは非置換の芳香族炭素環または置換もしくは非置換の芳香族ヘテロ環であり、Ｙ’は−Ｏ−、−Ｓ−または−ＮＲ９’−であり、Ｒ９’は水素または低級アルキルであり、Ｚ’はヒドロキシ、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換の低級アルキルスルフィニル、置換もしくは非置換のスルファモイルまたはシアノであり、
Ｒ８ａ’およびＲ８ｂ’は、それぞれ独立して、水素または置換もしくは非置換の低級アルキルであり、
ｓ’は１〜４の整数である）で示される、上記（９）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１１）
Ｙ’が−Ｏ−である、上記（９）または（１０）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１２）
ｔ’が０である上記（９）〜（１１）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１３）
であり、ｔ’およびｐ’が０であり、
Ｒ２が式
（式中、Ｒ１０ａ’およびＲ１０ｂ’は、それぞれ独立して、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロ環式基であるか、
またはＲ１０ａ’とＲ１０ｂ’は隣接する炭素原子と一緒なって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族ヘテロ環を形成してもよく、
Ｒ１０ｃ’は水素、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ１１ａ’およびＲ１１ｂ’は、それぞれ独立して、水素、低級アルキルであるか、または一緒になって＝Ｏであってもよく、
ｒ’は０〜４の整数である）で示される基である
上記（９）〜（１２）のいずれかに記載の化合物（ただし、Ｒ１０ａ’、Ｒ１０ｂ’およびＲ１０ｃ’がすべてメチルである化合物並びに以下に示される化合物：
を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１４）
Ｒ１０ａ’およびＲ１０ｂ’が低級アルキルであって、Ｒ１０ｃ’がカルボキシ、ヒドロキシアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換の低級アルキルカルバモイルである、上記（１３）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１５）
Ｚ１’が保護されていてもよいヒドロキシであり、Ｚ２’がＯであり、Ｒ２’が式
（式中、Ｒ１０ａ’およびＲ１０ｂ’は、それぞれ独立して、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロ環式基であるか、
またはＲ１０ａ’とＲ１０ｂ’は隣接する炭素原子と一緒なって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族ヘテロ環を形成してもよく、
Ｒ１０ｃ’は水素、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ１１ａ’およびＲ１１ｂ’は、それぞれ独立して、水素または低級アルキルであってもよく、
ｒ’は０〜４の整数である）で示される基である、
上記（１０）〜（１２）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１６）
Ｚ１’が保護されていてもよいヒドロキシであり、Ｚ２’がＯであり、Ｒ２’が式
（式中、環Ｄ’は置換もしくは非置換の芳香族炭素環または置換もしくは非置換の芳香族ヘテロ環であり、Ｖ’は−Ｃ（＝Ｏ）−、−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−Ｏ−、−ＮＲ１３’−Ｃ（＝Ｏ）−ＮＲ１３’−、−ＮＲ１３’−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＲ１３’−、−Ｏ−、−Ｓ−または−ＮＲ１３’−であり、Ｒ１３’は水素または低級アルキルであり、Ｗ’はヒドロキシ、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換の低級アルキルスルフィニル、置換もしくは非置換のスルファモイルまたはシアノであり、
Ｒ１２ａ’およびＲ１２ｂ’は、それぞれ独立して水素または置換もしくは非置換の低級アルキルであり、
ｕ’は１〜４の整数である）で示される基である、上記（１０）〜（１２）のいずれかに記載の化合物（ただし、以下に示される化合物：
を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１７）
ｔ’が０である上記（１５）または（１６）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１８）
上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１９）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である上記（１）〜（１７）または（２’）のいずれかに記載の医薬組成物。
（２０）
上記（１）〜（１７）または（２’）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の予防または治療方法。
（２１）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療および／または予防のための、上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
（２２）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療薬および／または予防薬の製造のための、上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
（１）式（Ｉ）：
（式中、
Ｚ１は、保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２は、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−もしくは−Ｓ（Ｏ）ｖ−であるか、または
（式中、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素または低級アルキル；
Ｒ６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニル；
ｐは、０〜２の整数）を形成し；
ｖは、０〜２の整数；
Ｚ３ａおよびＺ３ｂは、それぞれ独立して、水素、置換もしくは非置換の低級アルキルであるか、または、一緒になって、＝Ｏもしくは＝Ｓを形成し；
ｔは、０〜４の整数；
Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
ｍおよびｎは、それぞれ独立して、０〜２の整数；
ｋは、０または１の整数；
環Ａは、シクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環；
Ｂは、シクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
Ｒ２は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルコキシ、置換もしくは非置換のアリールオキシ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
Ｒ３は、置換もしくは非置換のアルキル、置換もしくは非置換のアルコキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、カルボキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
である）で示される化合物（ただし、
（ｉ）環Ａがチアジアゾールであり、ｋが０であり、かつ、Ｒ１ａがメチルチオである化合物；
（ｉｉ）環Ａがベンゾチオフェンであり、ｋが０であり、Ｒ１ａがメチルスルホニルであり、かつ、Ｒ２が置換もしくは非置換のフリルまたは置換もしくは非置換のフェニルである化合物；
（ｉｉｉ）環Ａがチアゾールまたは７Ｈ−プリンであり、かつ、Ｒ２が置換もしくは非置換のフリルである化合物；
（ｉｖ）Ｒ３が式:
で示される基であり、ｔが１〜２の整数であり、かつ、環Ａがフランまたはベンゼンである化合物；
（ｖ）Ｒ２がｔ−ブチルまたは４−メチルオキシフェニルである化合物；
（ｖｉ）Ｒ２が置換もしくは非置換のアルキルであり（ただし、置換もしくは非置換のｉ−プロピルおよび置換もしくは非置換のｉ−ブチルを除く）、Ｒ３が置換もしくは非置換の炭素環または置換もしくは非置換のヘテロ環であり、かつ、ｋが０である化合物；
（ｖｉｉ）Ｒ２が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、かつ、Ｒ３がペンタン−３−イルである化合物；ならびに
（ｖｉｉｉ）以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（２）
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基であるか、または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基である、上記（１）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（２’）式（Ｉ）：
（式中、
Ｚ１は、保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２は、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−もしくは−Ｓ（Ｏ）ｖ−であるか、または
（式中、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素または低級アルキル；
Ｒ６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニル；
ｐは、０〜２の整数）を形成し；
ｖは、０〜２の整数；
Ｚ３ａおよびＺ３ｂは、それぞれ独立して、水素、置換もしくは非置換の低級アルキルであるか、または、一緒になって、＝Ｏもしくは＝Ｓを形成し；
ｔは、０〜４の整数；
Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
ｍおよびｎは、それぞれ独立して、０〜２の整数；
ｋは、０または１の整数；
環Ａは、シクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環；
Ｂは、シクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
Ｒ２は、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基；
Ｒ３は、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基であるか、または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基；
である）で示される化合物（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（３）Ｚ３ａおよびＺ３ｂが、一緒になって、＝Ｏである、上記（２）または（２’）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（４）ｔが、０である、上記（２）、（２’）または（３）に記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（５）Ｚ２が、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−または−Ｓ（Ｏ）２−である、上記（２）〜（４）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（６）Ｚ２が、−Ｃ（＝Ｏ）−である、上記（２）〜（５）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（７）式：
（式中、Ｚ１、Ｚ２およびＲ２は上記（１）と同意義。）
で示される基が、
式：
（式中、Ｒ２、Ｒ５ａ、Ｒ５ｂ、Ｒ６およびｐは上記（１）と同意義。）である、上記（２）〜（６）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（８）式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、上記（１）と同意義。）で示される基が
式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、上記（１）と同意義。）で示される基である、上記（２）〜（７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（９）式（Ｉ）：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ１ａ、Ｒ１ｂ、Ｒ２、Ｒ３、Ｒ４ａ、Ｒ４ｂ、環Ａ、Ｂ、ｈ、ｍ、ｎ、ｔは、上記（１）と同意義。）が、
式（Ｉ’）：
（式中、
Ｚ１’は保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２’はＯもしくはＳであるか、または
（Ｒ５ａ’およびＲ５ｂ’はそれぞれ独立して水素または低級アルキルであり、Ｒ６’は水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニルであり、ｐ’は０〜２の整数である）を形成し、
ｔ’は０〜４の整数であり、
Ｒ４ａ’およびＲ４ｂ’は、それぞれ独立して水素または低級アルキルであり、
ｍ’およびｎ’はそれぞれ独立して０〜２の整数であり、
環Ａ’はシクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環であり、
Ｂ’はシクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり、
ｎ’が０のとき、Ｂ’はメチルチオ、トリフルオロメチルチオまたは−Ｃ（Ｒ７ａ’）＝Ｎ−Ｏ−Ｒ７ｂ’であってもよく、
Ｒ１ａ’およびＲ１ｂ’は、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロであり、
Ｒ２’およびＲ３’はそれぞれ独立して置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ７ａ’およびＲ７ｂ’はそれぞれ独立して水素または置換もしくは非置換の低級アルキルである）で示される化合物（ただし、環Ａ’がチアジアゾールであり、Ｂ’がメチルチオである化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１０）
Ｒ３’式
（式中、環Ｃ’は置換もしくは非置換の芳香族炭素環または置換もしくは非置換の芳香族ヘテロ環であり、Ｙ’は−Ｏ−、−Ｓ−または−ＮＲ９’−であり、Ｒ９’は水素または低級アルキルであり、Ｚ’はヒドロキシ、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換の低級アルキルスルフィニル、置換もしくは非置換のスルファモイルまたはシアノであり、
Ｒ８ａ’およびＲ８ｂ’は、それぞれ独立して、水素または置換もしくは非置換の低級アルキルであり、
ｓ’は１〜４の整数である）で示される、上記（９）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１１）
Ｙ’が−Ｏ−である、上記（９）または（１０）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１２）
ｔ’が０である上記（９）〜（１１）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１３）
であり、ｔ’およびｐ’が０であり、
Ｒ２が式
（式中、Ｒ１０ａ’およびＲ１０ｂ’は、それぞれ独立して、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロ環式基であるか、
またはＲ１０ａ’とＲ１０ｂ’は隣接する炭素原子と一緒なって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族ヘテロ環を形成してもよく、
Ｒ１０ｃ’は水素、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ１１ａ’およびＲ１１ｂ’は、それぞれ独立して、水素、低級アルキルであるか、または一緒になって＝Ｏであってもよく、
ｒ’は０〜４の整数である）で示される基である
上記（９）〜（１２）のいずれかに記載の化合物（ただし、Ｒ１０ａ’、Ｒ１０ｂ’およびＲ１０ｃ’がすべてメチルである化合物並びに以下に示される化合物：
を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１４）
Ｒ１０ａ’およびＲ１０ｂ’が低級アルキルであって、Ｒ１０ｃ’がカルボキシ、ヒドロキシアルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換の低級アルキルカルバモイルである、上記（１３）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１５）
Ｚ１’が保護されていてもよいヒドロキシであり、Ｚ２’がＯであり、Ｒ２’が式
（式中、Ｒ１０ａ’およびＲ１０ｂ’は、それぞれ独立して、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロ環式基であるか、
またはＲ１０ａ’とＲ１０ｂ’は隣接する炭素原子と一緒なって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族ヘテロ環を形成してもよく、
Ｒ１０ｃ’は水素、ヒドロキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、カルボキシ、置換もしくは非置換の低級アルキルカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、
Ｒ１１ａ’およびＲ１１ｂ’は、それぞれ独立して、水素または低級アルキルであってもよく、
ｒ’は０〜４の整数である）で示される基である、
上記（１０）〜（１２）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１６）
Ｚ１’が保護されていてもよいヒドロキシであり、Ｚ２’がＯであり、Ｒ２’が式
（式中、環Ｄ’は置換もしくは非置換の芳香族炭素環または置換もしくは非置換の芳香族ヘテロ環であり、Ｖ’は−Ｃ（＝Ｏ）−、−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−Ｏ−、−ＮＲ１３’−Ｃ（＝Ｏ）−ＮＲ１３’−、−ＮＲ１３’−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＲ１３’−、−Ｏ−、−Ｓ−または−ＮＲ１３’−であり、Ｒ１３’は水素または低級アルキルであり、Ｗ’はヒドロキシ、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換の低級アルキルスルフィニル、置換もしくは非置換のスルファモイルまたはシアノであり、
Ｒ１２ａ’およびＲ１２ｂ’は、それぞれ独立して水素または置換もしくは非置換の低級アルキルであり、
ｕ’は１〜４の整数である）で示される基である、上記（１０）〜（１２）のいずれかに記載の化合物（ただし、以下に示される化合物：
を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１７）
ｔ’が０である上記（１５）または（１６）記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１８）
上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１９）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である上記（１）〜（１７）または（２’）のいずれかに記載の医薬組成物。
（２０）
上記（１）〜（１７）または（２’）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の予防または治療方法。
（２１）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療および／または予防のための、上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
（２２）
Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療薬および／または予防薬の製造のための、上記（１）〜（１７）または（２’）のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
本明細書中で用いる用語を以下に説明する。各用語は、特に記載しない限り以下の意味を有する。
「アルキル」とは、炭素数１〜１０、好ましくは炭素数１〜８、さらに好ましくは炭素数１〜６の直鎖または分枝鎖の１価の炭化水素基を包含する。例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、イソペンチル、ｎｅｏ−ペンチル、ｎ−ヘキシル、イソヘキシル、ｎ−へプチル、イソヘプチル、ｎ−オクチル、イソオクチル、ｎ−ノニル、ｎ−デシル等が挙げられる。
Ｒ２における、「アルキル」としては、ｉ−プロピル、ｉ−ブチル等が好ましい。
Ｒ２における、「アルキル」としては、ｉ−プロピル、ｉ−ブチル等が好ましい。
「低級アルキル」とは、炭素数１〜６、好ましくは炭素数１〜３の直鎖または分枝鎖の１価の炭化水素基を包含する。例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、イソペンチル、ｎｅｏ−ペンチル、ｎ−ヘキシル、イソヘキシル等が挙げられる。
Ｒ１ａにおける、「低級アルキル」としては、炭素数１〜４のアルキル、例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｔｅｒｔ−ブチル等が好ましい。
Ｒ１ｂにおける、「低級アルキル」としては、炭素数１〜３のアルキル、例えば、メチル、エチル等が好ましい。
Ｙにおける、「低級アルキル」としては、炭素数１〜３のアルキル、例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル等が好ましい。
Ｒ１ａにおける、「低級アルキル」としては、炭素数１〜４のアルキル、例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｔｅｒｔ−ブチル等が好ましい。
Ｒ１ｂにおける、「低級アルキル」としては、炭素数１〜３のアルキル、例えば、メチル、エチル等が好ましい。
Ｙにおける、「低級アルキル」としては、炭素数１〜３のアルキル、例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル等が好ましい。
「アシル」とは、Ｒ−ＣＯ−（例えば、Ｒは水素、前記「低級アルキル」または後述の「低級アルケニル」、「アリール」、「ヘテロ環式基」、「シクロアルキル」もしくは「シクロアルケニル」である）で示される基を包含する。
Ｒ１ａにおける、「アシル」としては、炭素数１〜３のアルキルカルボニル、例えば、アセチル等が好ましい。
Ｒ１ａにおける、「アシル」としては、炭素数１〜３のアルキルカルボニル、例えば、アセチル等が好ましい。
「シクロアルカン」とは、炭素数が３〜１０の単環式または多環式飽和炭素環を包含する。単環式シクロアルカンとしては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン等が挙げられる。多環式シクロアルカンとしては、ノルボルナン、テトラヒドロナフタレン等が挙げられる。
環Ａにおける、「シクロアルカン」としては、炭素数が３〜６の単環式シクロアルカン、例えば、シクロへキサン等が好ましい。
環Ａにおける、「シクロアルカン」としては、炭素数が３〜６の単環式シクロアルカン、例えば、シクロへキサン等が好ましい。
「シクロアルキル」とは、上記「シクロアルカン」から導かれる１価の基を包含する。単環式シクロアルキルとしては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。多環式シクロアルキルとしては、ノルボルニル、テトラヒドロナフタレン−５−イル、テトラヒドロナフタレン−６−イル等が挙げられる。
Ｒ２における、「シクロアルキル」としては、炭素数が３〜６の単環式シクロアルキル、例えば、シクロペンチル、シクロヘキシル等が好ましい。
Ｒ２における、「シクロアルキル」としては、炭素数が３〜６の単環式シクロアルキル、例えば、シクロペンチル、シクロヘキシル等が好ましい。
「シクロアルカンジイル」とは、上記「シクロアルカン」から導かれる２価の基を包含する。単環式シクロアルカンジイルとしては、例えば、シクロプロパンジイル、シクロブタンジイル、シクロペンタンジイル、シクロヘキサンジイル、シクロヘプタンジイル、シクロオクタンジイル、シクロノナンジイル、シクロデカンジイル等が挙げられる。多環式シクロアルカンジイルとしては、ノルボルナンジイル等が挙げられる。
Ｂにおける、「シクロアルカンジイル」としては、炭素数が３〜６の単環式シクロアルカンジイル、例えば、シクロペンタンジイル、シクロへキサンジイル等が好ましい。
Ｂにおける、「シクロアルカンジイル」としては、炭素数が３〜６の単環式シクロアルカンジイル、例えば、シクロペンタンジイル、シクロへキサンジイル等が好ましい。
「シクロアルケン」とは、少なくとも１つの炭素−炭素二重結合を含む炭素数３〜１０の非芳香族単環または多環式環を包含する。単環式シクロアルケンとしては、シクロペンテン、シクロヘキセン等が挙げられる。多環式シクロアルケンとしてはノルボルネン、インデン等が挙げられる。
「シクロアルケニル」とは、上記「シクロアルケン」から導かれる１価の基を包含する。単環式シクロアルケニルとしては、シクロペンテニル、シクロヘキセニル等が挙げられる。多環式シクロアルケニルとしてはノルボルネニル、インデン−１−イル、インデン−２−イル、インデン−３−イル等が挙げられる。
「シクロアルケンジイル」とは、上記「シクロアルケン」から導かれる２価の基を包含する。単環式シクロアルケンジイルとしては、シクロペンテンジイル、シクロヘキセンジイル等が挙げられる。多環式シクロアルケンジイルとしてはノルボルネンジイル等が挙げられる。
Ｂにおける、「シクロアルケンジイル」としては、炭素数が３〜６の単環式シクロアルケンジイル、例えば、シクロペンテンジイル、シクロへキセンジイル等が好ましい。
Ｂにおける、「シクロアルケンジイル」としては、炭素数が３〜６の単環式シクロアルケンジイル、例えば、シクロペンテンジイル、シクロへキセンジイル等が好ましい。
「芳香族炭素環」とは、単環または縮合環の芳香族炭化水素環を包含する。例えば、ベンゼン環、ナフタレン環、アントラセン環、フェナントレン環等が挙げられる。
環Ａにおける、「芳香族炭素環」としては、ベンゼン環が好ましい。
環Ａにおける、「芳香族炭素環」としては、ベンゼン環が好ましい。
「アリール」とは、上記「芳香族炭素環」から導かれる１価の基を意味する。例えば、フェニル、１−ナフチル、２−ナフチル、アントリル、フェナントリル等が挙げられる。
Ｒ３における、「アリール」としては、フェニルが好ましい。
Ｒ３における、「アリール」としては、フェニルが好ましい。
「芳香族炭素環ジイル」とは、上記「芳香族炭素環」から導かれる２価の基を包含する。例えば、１，２−フェニレン、１，３−フェニレン、１，４−フェニレン、１，２−ナフチレン等が挙げられる。
Ｂにおける、「芳香族炭素環ジイル」としては、１，２−フェニレン、１，３−フェニレン、１，４−フェニレン等が好ましい。さらに好ましくは、１，４−フェニレンが挙げられる。
Ｂにおける、「芳香族炭素環ジイル」としては、１，２−フェニレン、１，３−フェニレン、１，４−フェニレン等が好ましい。さらに好ましくは、１，４−フェニレンが挙げられる。
「ヘテロ環」とは、環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員環、
それらが２個以上縮合した環、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員環が１以上の上記「芳香族炭素環」、上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環から誘導される、芳香族または非芳香族の単環または縮合環を包含する。例えば、ピロリン、ピロリジン、イミダゾール、ピラゾール、ピペリジン、ピペラジン、モルホリン、チオモルホン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール等の非芳香族ヘテロ環、
例えば、ピロール、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、テトラゾール、トリアジン、ピリダジン、ピリミジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の単環の芳香族ヘテロ環、
インドール、イソインドール、インダゾール、インドリジン、インドリン、イソインドリン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンゾピラン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾール、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の縮合したヘテロ環が挙げられる。
環Ａにおける、「ヘテロ環」としては、ピペリジン、チオフェン、フラン、ピリジン、ベンゾチオフェン、ベンゾチアゾール、ベンゾオキサゾール等が好ましい。
それらが２個以上縮合した環、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員環が１以上の上記「芳香族炭素環」、上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環から誘導される、芳香族または非芳香族の単環または縮合環を包含する。例えば、ピロリン、ピロリジン、イミダゾール、ピラゾール、ピペリジン、ピペラジン、モルホリン、チオモルホン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール等の非芳香族ヘテロ環、
例えば、ピロール、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、テトラゾール、トリアジン、ピリダジン、ピリミジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の単環の芳香族ヘテロ環、
インドール、イソインドール、インダゾール、インドリジン、インドリン、イソインドリン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンゾピラン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾール、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の縮合したヘテロ環が挙げられる。
環Ａにおける、「ヘテロ環」としては、ピペリジン、チオフェン、フラン、ピリジン、ベンゾチオフェン、ベンゾチアゾール、ベンゾオキサゾール等が好ましい。
「ヘテロ環式基」とは、上記「ヘテロ環」から導かれる１価の基を包含する。例えば、ピロリニル、ピロリジノ、ピロリジニル、イミダゾリニル、イミダゾリジニル、ピラゾリニル、ピラゾリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、テトラヒドロピラニル、ジヒドロピリジル、ジヒドロピリダジニル、ジヒドロピラジニル、ジオキサニル、オキサチオラニル、チアニル、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等の非芳香族ヘテロ環式基、
ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の単環の芳香族ヘテロ環式基、
インドリル、イソインドリル、インダゾリル、インドリジニル、インドリニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンゾピラニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル、ベンゾジオキサニル、テトラヒドロキノリン、テトラヒドロベンゾチエニル等の縮合ヘテロ環式基が挙げられる。
Ｙにおける、「ヘテロ環式基」としては、ピペリジノ、モルホリノ等が好ましい。
ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の単環の芳香族ヘテロ環式基、
インドリル、イソインドリル、インダゾリル、インドリジニル、インドリニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンゾピラニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル、ベンゾジオキサニル、テトラヒドロキノリン、テトラヒドロベンゾチエニル等の縮合ヘテロ環式基が挙げられる。
Ｙにおける、「ヘテロ環式基」としては、ピペリジノ、モルホリノ等が好ましい。
「ヘテロ環式ジイル」とは、上記「ヘテロ環」から導かれる２価の基を包含する。例えば、ピロリンジイル、ピロリジンジイル、イミダゾールジイル、イミダゾリジンジイル、ピラゾリンジイル、ピラゾリジンジイル、ピペリジンジイル、ピペラジンジイル、モルホリンジイル、チオモルホリンジイル、テトラヒドロピランジイル、ジヒドロピリジンジイル、ジヒドロピリダジンジイル、ジヒドロピラジンジイル、ジオキサンジル、オキサチオランジイル、チアンジイル、テトラヒドロフランジイル、テトラヒドロピランジイル、テトラヒドロチアゾールジイル、テトラヒドロイソチアゾールジイル等の非芳香族ヘテロ環式ジイル、
ピロールジイル、ピラジンジイル、ピラゾールジイル、テトラゾールジイル、フランジイル、チオフェンジイル、ピリジンジイル、イミダゾールジイル、トリアゾールジイル、テトラゾールジイル、トリアジンジイル、ピリダジンジイル、ピリミジンジイル、ピラジンジイル、イソキサゾールジイル、チアゾールジイル、イソチアゾールジイル、チアジアゾールジイル、オキサゾールジイル、オキサジアゾールジイル等の単環の芳香族ヘテロ環ジイル、
インドールジイル、イソインドールジイル、インダゾールジイル、インドリジンジイル、インドリンジイル、イソインドリンジイル、キノリンジイル、イソキノリンジイル、シンノリンジイル、フタラジンジイル、キナゾリンジイル、ナフチリジンジイル、キノキサリンジイル、プリンジイル、プテリジンジイル、ベンゾピランジイル、ベンズイミダゾールジイル、ベンズイソオキサゾールジイル、ベンズオキサゾールジイル、ベンズオキサジアゾールジイル、ベンゾイソチアゾールジイル、ベンゾチアゾールジイル、ベンゾチアジアゾールジイル、ベンゾフランジイル、イソベンゾフランジイル、ベンゾチオフェンジイル、ベンゾトリアゾールジイル、イミダゾピリジンジイル、トリアゾロピリジンジイル、イミダゾチアゾールジイル、ピラジノピリダジンジイル、ベンズイミダゾリンジイル、ベンゾジオキサンジイル、テトラヒドロキノリンジイル、テトラヒドロベンゾチオフェンジイル等の縮合ヘテロ環ジイルが挙げられる。
Ｂにおける、「ヘテロ環式ジイル」としては、ピロールジイル、ピラジンジイル、ピラゾールジイル、テトラゾールジイル、フランジイル、チオフェンジイル、ピリジンジイル、イミダゾールジイル、トリアゾールジイル、テトラゾールジイル、トリアジンジイル、ピリダジンジイル、ピリミジンジイル、ピラジンジイル、イソキサゾールジイル、チアゾールジイル、イソチアゾールジイル、チアジアゾールジイル、オキサゾールジイル、オキサジアゾールジイル等が好ましい。
さらに好ましくは、ジヒドロチアゾールジイル、ピロリジンジイル、チアゾールジイル、チオフェンジイル、ピロールジイル、フランジイル、イソキサゾールジイル、チアジアゾールジイル等が挙げられる。
ピロールジイル、ピラジンジイル、ピラゾールジイル、テトラゾールジイル、フランジイル、チオフェンジイル、ピリジンジイル、イミダゾールジイル、トリアゾールジイル、テトラゾールジイル、トリアジンジイル、ピリダジンジイル、ピリミジンジイル、ピラジンジイル、イソキサゾールジイル、チアゾールジイル、イソチアゾールジイル、チアジアゾールジイル、オキサゾールジイル、オキサジアゾールジイル等の単環の芳香族ヘテロ環ジイル、
インドールジイル、イソインドールジイル、インダゾールジイル、インドリジンジイル、インドリンジイル、イソインドリンジイル、キノリンジイル、イソキノリンジイル、シンノリンジイル、フタラジンジイル、キナゾリンジイル、ナフチリジンジイル、キノキサリンジイル、プリンジイル、プテリジンジイル、ベンゾピランジイル、ベンズイミダゾールジイル、ベンズイソオキサゾールジイル、ベンズオキサゾールジイル、ベンズオキサジアゾールジイル、ベンゾイソチアゾールジイル、ベンゾチアゾールジイル、ベンゾチアジアゾールジイル、ベンゾフランジイル、イソベンゾフランジイル、ベンゾチオフェンジイル、ベンゾトリアゾールジイル、イミダゾピリジンジイル、トリアゾロピリジンジイル、イミダゾチアゾールジイル、ピラジノピリダジンジイル、ベンズイミダゾリンジイル、ベンゾジオキサンジイル、テトラヒドロキノリンジイル、テトラヒドロベンゾチオフェンジイル等の縮合ヘテロ環ジイルが挙げられる。
Ｂにおける、「ヘテロ環式ジイル」としては、ピロールジイル、ピラジンジイル、ピラゾールジイル、テトラゾールジイル、フランジイル、チオフェンジイル、ピリジンジイル、イミダゾールジイル、トリアゾールジイル、テトラゾールジイル、トリアジンジイル、ピリダジンジイル、ピリミジンジイル、ピラジンジイル、イソキサゾールジイル、チアゾールジイル、イソチアゾールジイル、チアジアゾールジイル、オキサゾールジイル、オキサジアゾールジイル等が好ましい。
さらに好ましくは、ジヒドロチアゾールジイル、ピロリジンジイル、チアゾールジイル、チオフェンジイル、ピロールジイル、フランジイル、イソキサゾールジイル、チアジアゾールジイル等が挙げられる。
「非芳香族炭素環」とは、上記「シクロアルカン」、「シクロアルケン」、上記「シクロアルカン」に上記「芳香族炭素環」が縮合した環、および上記「シクロアルケン」に上記「芳香族炭素環」が縮合した環を包含する。縮合環としては、インデン等が挙げられる。
「芳香族ヘテロ環」とは、上記「ヘテロ環」のうち、芳香環であるものを包含する。
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香環、
それらが２個以上縮合した芳香環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環を包含する。
例えば、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、トリアジン、ピリダジン、ピリミジン、ピラジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の単環の芳香族ヘテロ環、
インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾリン等の縮合ヘテロ芳香環が挙げられる。
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香環、
それらが２個以上縮合した芳香環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環を包含する。
例えば、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、トリアジン、ピリダジン、ピリミジン、ピラジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の単環の芳香族ヘテロ環、
インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾリン等の縮合ヘテロ芳香環が挙げられる。
「ヘテロアリール」とは、上記「芳香族ヘテロ環」から導かれる１価の基を包含する。環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香環式基、
それらが２個以上縮合した芳香環式基、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環式基を包含する。
例えば、ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の単環の芳香族ヘテロ環式基、
インドリル、イソインドリル、インダゾリル、インドリジニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル等の縮合ヘテロ芳香環式基が挙げられる。
それらが２個以上縮合した芳香環式基、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員芳香環が１以上の上記「芳香族炭素環」と縮合した芳香環式基を包含する。
例えば、ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の単環の芳香族ヘテロ環式基、
インドリル、イソインドリル、インダゾリル、インドリジニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル等の縮合ヘテロ芳香環式基が挙げられる。
「非芳香族ヘテロ環」とは、上記「ヘテロ環」のうち、非芳香環であるものを包含する。
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の非芳香族環、
それらが２個以上縮合した非芳香族環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香族環が１以上の上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の非芳香族複素環が１以上の上記「芳香族炭素環」または「非芳香族炭素環」と縮合した環を包含する。例えば、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、チオモルホリン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジヒドロピラジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾリン、テトラヒドロイソチアゾリン等の非芳香族ヘテロ環、
インドリン、イソインドリン、ベンゾピラン、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の非芳香族縮合ヘテロ芳香環が挙げられる。
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の非芳香族環、
それらが２個以上縮合した非芳香族環、
環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の芳香族環が１以上の上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環、
または環内に窒素原子、酸素原子、及び／又は硫黄原子を少なくとも１個有する５〜７員の非芳香族複素環が１以上の上記「芳香族炭素環」または「非芳香族炭素環」と縮合した環を包含する。例えば、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、チオモルホリン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジヒドロピラジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾリン、テトラヒドロイソチアゾリン等の非芳香族ヘテロ環、
インドリン、イソインドリン、ベンゾピラン、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の非芳香族縮合ヘテロ芳香環が挙げられる。
「ハロゲン」とはフッ素、塩素、臭素およびヨウ素を意味する。
「低級アルコキシ」とはＲＯ−で示される基を包含する。例えば、Ｒが前記低級アルキルと同意義である、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ−ブトキシ、ｔｅｒｔ−ブトキシ、ペントキシ、イソペントキシ、ネオペントキシ、ヘキソキシ等の低級アルコキシが挙げられる。
Ｙにおける、「低級アルコキシ」としては、炭素数が１〜４のアルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ等が好ましい。
Ｙにおける、「低級アルコキシ」としては、炭素数が１〜４のアルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ等が好ましい。
「低級アルキルチオ」とは、ＲＳ−で示される基を包含する。例えば、Ｒが前記低級アルキルと同意義である、メチルチオ、エチルチオ、プロピルチオ、ｉ−プロピルチオ、ブチルチオ、イソブチルチオ、ｓｅｃ−ブチルチオ、ｔｅｒｔ−ブチルチオ、ペンチルチオ、イソペンチルチオ、ネオペンチルチオ、ヘキシルチオ等の低級アルキルチオが挙げられる。
Ｒ１ａにおける「低級アルキルチオ」としては、炭素数が１〜４のアルキルチオ、例えば、メチルチオが好ましい。
Ｒ１ａにおける「低級アルキルチオ」としては、炭素数が１〜４のアルキルチオ、例えば、メチルチオが好ましい。
「低級アルコキシカルボニル」とは、Ｒ−Ｏ−Ｃ（＝Ｏ）−で示される基を包含する。例えば、Ｒが前記低級アルキルと同意義である、メチルオキシカルボニル、エチルオキシカルボニル、ｎ−プロピルオキシカルボニル、ｉ−プロピルオキシカルボニル、ｎ−ブチルオキシカルボニル、ｔｅｒｔ−ブチルオキシカルボニル、ｎ−ペンチルオキシカルボニル等の低級アルコキシカルボニルが挙げられる。
Ｒ１ａ、Ｒ３およびＹにおける、「低級アルコキシカルボニル」としては、炭素数が１〜４のアルコキシカルボニル、例えば、メチルオキシカルボニル、エチルオキシカルボニル等が好ましい。
Ｒ１ａ、Ｒ３およびＹにおける、「低級アルコキシカルボニル」としては、炭素数が１〜４のアルコキシカルボニル、例えば、メチルオキシカルボニル、エチルオキシカルボニル等が好ましい。
「低級アルキルカルバモイル」としては、例えばメチルカルバモイル、エチルカルバモイル、ｎ−プロピルカルバモイル、ｉ−プロピルカルバモイル、ｎ−ブチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル基等のアルキル部分の炭素数が１〜６のモノ又はジ低級アルキルカルバモイル基が挙げられる。
Ｒ１ａにおける、「低級アルキルカルバモイル」としては、炭素数が１〜４のアルコキシカルバモイル、例えば、メチルカルバモイル、ジメチルカルバモイル等が好ましい。
Ｒ１ａにおける、「低級アルキルカルバモイル」としては、炭素数が１〜４のアルコキシカルバモイル、例えば、メチルカルバモイル、ジメチルカルバモイル等が好ましい。
「チオカルバモイル」とは、−Ｃ（＝Ｓ）−ＮＲＸＲＹ（例えば、ＲＸおよびＲＹは、それぞれ独立して、水素、前記「アルキル」もしくは「アルケニル」、または後述の「アリール」、「ヘテロアリール」、「非芳香族炭素環基」、「非芳香族複素環基」「アリールアルキル」もしくは「ヘテロアリールアルキル」である。これらは、それぞれ独立して、ヒドロキシ、カルボキシ、前記または後述の、「アルキル」、「アルケニル」、「アルキニル」、「ハロゲン」、「アルキルオキシ」、「アルケニルオキシ」、「アルキニルオキシ」、「アルキルチオ」、「カルバモイル」、「アルキルオキシカルボニル」、「アリールオキシカルボニル」等で置換されていてもよい）で示される基を包含する。
「スルフィニル」とは、−Ｓ（＝Ｏ）−Ｒ（Ｒは、前記「アルキル」もしくは「アルケニル」、または後述の「アリール」、「ヘテロアリール」、「非芳香族炭素環基」、「非芳香族複素環基」「アリールアルキル」もしくは「ヘテロアリールアルキル」である。これらは、それぞれ独立して、ヒドロキシ、カルボキシ、前記または後述の、「アルキル」、「アルケニル」、「アルキニル」、「ハロゲン」、「アルキルオキシ」、「アルケニルオキシ」、「アルキニルオキシ」、「アルキルチオ」、「カルバモイル」、「アルキルオキシカルボニル」、「アリールオキシカルボニル」等で置換されていてもよい）で示される基を包含する。
Ｒ１ａおよびＹにおける、「スルフィニル」としては、炭素数が１〜４のアルキルスルフェニル、例えば、メチルスルフィニル等が好ましい。
Ｒ１ａおよびＹにおける、「スルフィニル」としては、炭素数が１〜４のアルキルスルフェニル、例えば、メチルスルフィニル等が好ましい。
「スルホニル」とは、−Ｓ（＝Ｏ）２−Ｒ（Ｒは、前記「アルキル」もしくは「アルケニル」、または後述の「アリール」、「ヘテロアリール」、「非芳香族炭素環基」、「非芳香族複素環基」「アリールアルキル」もしくは「ヘテロアリールアルキル」である。これらは、それぞれ独立して、ヒドロキシ、カルボキシ、前記または後述の、「アルキル」、「アルケニル」、「アルキニル」、「ハロゲン」、「アルキルオキシ」、「アルケニルオキシ」、「アルキニルオキシ」、「アルキルチオ」、「カルバモイル」、「アルキルオキシカルボニル」、「アリールオキシカルボニル」等で置換されていてもよい）で示される基を包含する。
Ｒ１ａおよびＹにおける、「スルホニル」としては、炭素数が１〜４のアルキルスルホニル、例えば、メチルスルホニル等が好ましい。
Ｒ１ａおよびＹにおける、「スルホニル」としては、炭素数が１〜４のアルキルスルホニル、例えば、メチルスルホニル等が好ましい。
「スルファモイル」とは、−Ｓ（＝Ｏ）２−ＮＲＸＲＹ（例えば、ＲＸおよびＲＹは、それぞれ独立して、水素、前記「アルキル」もしくは「アルケニル」、または後述の「アリール」、「ヘテロアリール」、「非芳香族炭素環基」、「非芳香族複素環基」「アリールアルキル」もしくは「ヘテロアリールアルキル」である。これらは、それぞれ独立して、ヒドロキシ、カルボキシ、前記または後述の、「アルキル」、「アルケニル」、「アルキニル」、「ハロゲン」、「アルキルオキシ」、「アルケニルオキシ」、「アルキニルオキシ」、「アルキルチオ」、「カルバモイル」、「アルキルオキシカルボニル」、「アリールオキシカルボニル」等で置換されていてもよい）で示される基を包含する。
「置換低級アルキル」、「置換ｔｅｒｔ−ブチル」、「置換ｉ−プロピル」、「置換低級アルケニル」、「置換低級アルキニル」、「置換低級アルコキシ」、「置換低級アルキルチオ」、「置換低級アルコキシカルボニル」、「置換低級アルキルカルバモイル」の置換基としては、以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない：
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、アラルキルオキシ（例えば、ベンジルオキシ）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、低級アルキルチオ（例えば、メチルチオ等）、低級アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、カルバモイル、低級アルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル等）、スルファモイル、低級アルキルスルファモイル、アシル（例えば、ホルミル、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルフォ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミド、トリ低級アルキルシリル（トリメチルシリル等）、およびオキソ。
Ｒ１ａおよびＲ１ｂにおける、「置換低級アルキル」の置換基としては、ヒドロキシ、ハロゲン、ニトロ、シアノ、ハロ低級アルコキシ、低級アルケニルオキシ等が好ましい。さらに好ましくは、ヒドロキシ、低級アルコキシ等が挙げられる。
Ｒ１ａおよびＲ１ｂにおける、「置換低級アルコキシ」および「置換低級アルキルチオ」の置換基としては、ハロゲン、ヒドロキシ等が好ましい。
Ｙにおける、「置換低級アルキル」の置換基としては、ヒドロキシ、ハロゲン、シアノ、カルボキシ、カルバモイル、低級アルコキシ、ハロ低級アルコキシ、低級アルキルカルバモイル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルオキシカルボニルメチルオキシ等が好ましい。
さらに好ましくは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、カルバモイル、低級アルコキシ、低級アルキルカルバモイル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルオキシカルボニルメチルオキシ等が挙げられる。
Ｙにおける、「置換低級アルコキシ」および「置換低級アルキルチオ」の置換基としては、ハロゲン、カルボキシ、シアノ、ヒドロキシ、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシ、ハロ低級アルコキシ、低級アルケニルオキシ、低級アルコキシカルボニル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルスルフィニル、低級アルキルスルホニル、カルバモイル、低級アルキルカルバモイル、アミノで置換されたカルバモイル、ヒドロキシで置換されたカルバモイル、低級アルキルスルフィニル、低級アルキルスルホニル、シクロアルキル、ヘテロ環式基等が好ましい。
さらに好ましくは、ハロゲン、カルボキシ、シアノ、カルバモイル、低級アルキルカルバモイル、ヒドロキシで置換されたイミノ、低級アルコキシ、アミノ、低級アルキルアミノ、低級アルコキシカルボニル、低級アルキルスルフィニル、テトラゾリル等が挙げられる。
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、アラルキルオキシ（例えば、ベンジルオキシ）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、低級アルキルチオ（例えば、メチルチオ等）、低級アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、カルバモイル、低級アルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル等）、スルファモイル、低級アルキルスルファモイル、アシル（例えば、ホルミル、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルフォ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミド、トリ低級アルキルシリル（トリメチルシリル等）、およびオキソ。
Ｒ１ａおよびＲ１ｂにおける、「置換低級アルキル」の置換基としては、ヒドロキシ、ハロゲン、ニトロ、シアノ、ハロ低級アルコキシ、低級アルケニルオキシ等が好ましい。さらに好ましくは、ヒドロキシ、低級アルコキシ等が挙げられる。
Ｒ１ａおよびＲ１ｂにおける、「置換低級アルコキシ」および「置換低級アルキルチオ」の置換基としては、ハロゲン、ヒドロキシ等が好ましい。
Ｙにおける、「置換低級アルキル」の置換基としては、ヒドロキシ、ハロゲン、シアノ、カルボキシ、カルバモイル、低級アルコキシ、ハロ低級アルコキシ、低級アルキルカルバモイル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルオキシカルボニルメチルオキシ等が好ましい。
さらに好ましくは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、カルバモイル、低級アルコキシ、低級アルキルカルバモイル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルオキシカルボニルメチルオキシ等が挙げられる。
Ｙにおける、「置換低級アルコキシ」および「置換低級アルキルチオ」の置換基としては、ハロゲン、カルボキシ、シアノ、ヒドロキシ、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシ、ハロ低級アルコキシ、低級アルケニルオキシ、低級アルコキシカルボニル、アミノ、低級アルキルアミノ、低級アルキルスルホニルで置換されたアミノ、低級アルキルスルフィニル、低級アルキルスルホニル、カルバモイル、低級アルキルカルバモイル、アミノで置換されたカルバモイル、ヒドロキシで置換されたカルバモイル、低級アルキルスルフィニル、低級アルキルスルホニル、シクロアルキル、ヘテロ環式基等が好ましい。
さらに好ましくは、ハロゲン、カルボキシ、シアノ、カルバモイル、低級アルキルカルバモイル、ヒドロキシで置換されたイミノ、低級アルコキシ、アミノ、低級アルキルアミノ、低級アルコキシカルボニル、低級アルキルスルフィニル、テトラゾリル等が挙げられる。
「置換アシル」の置換基は、上記「置換低級アルキル」の置換基と同様である。特に、アシル（Ｒ−Ｃ（＝Ｏ）−）のＲが「アリール」、「ヘテロ環式基」、「シクロアルキル」または「シクロアルケニル」である場合、それぞれの環は低級アルキル（例えば、メチル、エチル、ｉ−プロピル、ｔｅｒｔ−ブチル等）、ハロ低級アルキル（例えば、ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３等）、低級アルケニル、低級アルキニル（例えば、エチニル）等を置換基としていてもよい。
「置換カルバモイル」、「置換チオカルバモイル」および「置換スルファモイル」の置換基は、以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない：
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、低級アルキル（例えば、メチル）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、アリール（例えば、フェニル等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナトおよびアシル（例えば、ホルミル、アセチル等）。
Ｒ１ａおよびＲ１ｂにおける、「置換カルバモイル」、「置換チオカルバモイル」および「置換スルファモイル」の置換基としては、低級アルキル、低級アルケニル、低級アルキニル、アミノ、低級アルキルアミノ、アシルアミノ、ヒドロキシアミノ等が好ましい。
さらに好ましくは、低級アルキル、低級アルキルアミノ等が挙げられる。
Ｙにおける、「置換カルバモイル」の置換基としては、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシで置換された低級アルキル、シアノで置換された低級アルキル、低級アルケニル、低級アルキニル、低級アルキルアミノ、アシルアミノ等が好ましい。
さらに好ましくは、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシで置換された低級アルキル、シアノで置換された低級アルキル、低級アルキルアミノ等が挙げられる。
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、低級アルキル（例えば、メチル）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、アリール（例えば、フェニル等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナトおよびアシル（例えば、ホルミル、アセチル等）。
Ｒ１ａおよびＲ１ｂにおける、「置換カルバモイル」、「置換チオカルバモイル」および「置換スルファモイル」の置換基としては、低級アルキル、低級アルケニル、低級アルキニル、アミノ、低級アルキルアミノ、アシルアミノ、ヒドロキシアミノ等が好ましい。
さらに好ましくは、低級アルキル、低級アルキルアミノ等が挙げられる。
Ｙにおける、「置換カルバモイル」の置換基としては、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシで置換された低級アルキル、シアノで置換された低級アルキル、低級アルケニル、低級アルキニル、低級アルキルアミノ、アシルアミノ等が好ましい。
さらに好ましくは、低級アルキル、ヒドロキシで置換された低級アルキル、低級アルコキシで置換された低級アルキル、シアノで置換された低級アルキル、低級アルキルアミノ等が挙げられる。
「置換アミノ」の置換基としては、以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない：
ヒドロキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルキル（例えば、ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３等）、ヒドロキシ低級アルキル（例えば、ヒドロキシエチル、−Ｃ（ＣＨ３）２ＣＨ２ＯＨ等）ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、低級アルキル（例えば、メチル、エチル、ｉ−プロピル、ｔｅｒｔ−ブチル等）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルキルオキシカルボニル（ｔｅｒｔ−ブチルオキシカルボニル等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、シアノおよびアシル（例えば、ホルミル、アセチル等）
Ｒ１ａおよびＲ１ｂにおける「置換アミノ」の置換基としては、低級アルキル、低級アルケニル、低級アルキニル、ハロ低級アルキル、ヒドロキシ低級アルキル、低級アルコキシ、ハロ低級アルコキシ、低級アルケニルオキシ、アシル等が好ましい。
さらに好ましくは、低級アルキル、アシル等が挙げられる。
Ｙにおける、「置換アミノ」の置換基としては、低級アルキル、アセチル、低級アルキルオキシカルボニル、カルバモイル、低級アルキルスルホニル等が好ましい。
ヒドロキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルキル（例えば、ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３等）、ヒドロキシ低級アルキル（例えば、ヒドロキシエチル、−Ｃ（ＣＨ３）２ＣＨ２ＯＨ等）ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、低級アルキル（例えば、メチル、エチル、ｉ−プロピル、ｔｅｒｔ−ブチル等）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルキルオキシカルボニル（ｔｅｒｔ−ブチルオキシカルボニル等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、シアノおよびアシル（例えば、ホルミル、アセチル等）
Ｒ１ａおよびＲ１ｂにおける「置換アミノ」の置換基としては、低級アルキル、低級アルケニル、低級アルキニル、ハロ低級アルキル、ヒドロキシ低級アルキル、低級アルコキシ、ハロ低級アルコキシ、低級アルケニルオキシ、アシル等が好ましい。
さらに好ましくは、低級アルキル、アシル等が挙げられる。
Ｙにおける、「置換アミノ」の置換基としては、低級アルキル、アセチル、低級アルキルオキシカルボニル、カルバモイル、低級アルキルスルホニル等が好ましい。
「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換ヘテロ環式基」、「置換ヘテロアリール」、「置換フェニル」、「置換ピリジル」の置換基としては以下からなる群から選択される１個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない：
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルキル（例えば、ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３等）、ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、低級アルキル（例えば、メチル、エチル、ｉ−プロピル、ｔｅｒｔ−ブチル等）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、アラルキルオキシ（例えば、ベンジルオキシ等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、低級アルキルチオ（例えば、メチルチオ等）、低級アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、置換もしくは非置換のカルバモイル（例えば、カルバモイル、Ｎ−メチル−Ｎ−メトキシカルバモイル等）、置換もしくは非置換の低級アルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ヒドロキシエチルカルバモイル、トリフルオロメチルカルバモイル、トリフルオロエチルカルバモイル等）、スルファモイル、低級アルキルスルファモイル、アシル（例えば、ホルミル、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミドおよびオキソ。
「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換ヘテロ環式基」、「置換ヘテロアリール」、「置換フェニル」、「置換ピリジル」の置換基としては、
ハロゲン、低級アルキル、ハロ低級アルキル、低級アルコキシ、ハロ低級アルコキシ等が好ましい。
ヒドロキシ、カルボキシ、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、ハロ低級アルキル（例えば、ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３等）、ハロ低級アルコキシ（例えば、ＣＦ３Ｏ）、低級アルキル（例えば、メチル、エチル、ｉ−プロピル、ｔｅｒｔ−ブチル等）、低級アルケニル（例えば、ビニル）、低級アルキニル（例えば、エチニル）、シクロアルキル（例えば、シクロプロピル）、シクロアルケニル（例えば、シクロプロペニル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等）、低級アルケニルオキシ（例えば、ビニルオキシ、アリルオキシ等）、低級アルコキシカルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等）、ニトロ、ニトロソ、アミノ、低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等）、アシルアミノ（例えば、アセチルアミノ、ベンゾイルアミノ等）、アラルキルアミノ（例えば、ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、低級アルキルイミノ（例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等）、低級アルコキシイミノ（例えば、メトキシイミノ、エトキシイミノ等）、アシルイミノ（例えば、アセチルイミノ、ベンゾイルイミノ等）、アジド、アリール（例えば、フェニル等）、アラルキル（例えば、ベンジル等）、アラルキルオキシ（例えば、ベンジルオキシ等）、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、低級アルキルチオ（例えば、メチルチオ等）、低級アルキルスルホニル（例えば、メタンスルホニル、エタンスルホニル）、置換もしくは非置換のカルバモイル（例えば、カルバモイル、Ｎ−メチル−Ｎ−メトキシカルバモイル等）、置換もしくは非置換の低級アルキルカルバモイル（例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ヒドロキシエチルカルバモイル、トリフルオロメチルカルバモイル、トリフルオロエチルカルバモイル等）、スルファモイル、低級アルキルスルファモイル、アシル（例えば、ホルミル、アセチル等）、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミドおよびオキソ。
「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換ヘテロ環式基」、「置換ヘテロアリール」、「置換フェニル」、「置換ピリジル」の置換基としては、
ハロゲン、低級アルキル、ハロ低級アルキル、低級アルコキシ、ハロ低級アルコキシ等が好ましい。
ここでハロ低級アルキル、ハロ低級アルコキシのハロゲン部分は上記「ハロゲン」と同義である。
「ハロ低級アルキル」、「低級アルキルアミノ」、「低級アルキルイミノ」、「低級アルキルスルホニル」、「低級アルキルスルファモイル」、「低級アルキルカルバモイル」、「アラルキル」および「アラルキルアミノ」の「アルキル」または「低級アルキル」部分は上記「低級アルキル」と同義である。
「ハロ低級アルコキシ」および「低級アルコキシイミノ」の「低級アルコキシ」部分は上記「低級アルコキシ」と同義である。
「低級アルケニル」とは、任意の位置に１以上の二重結合を有する炭素数２〜６、好ましくは炭素数２〜３の直鎖または分枝状のアルケニルを包含する。具体的にはビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル等が挙げられる。
低級アルケニルオキシの低級アルケニル部分は、上記「低級アルケニル」と同義である。
「低級アルキニル」とは、炭素数２〜６、好ましくは炭素数２〜３の直鎖状または分枝状のアルキニルを包含し、具体的には、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル等が挙げられる。これらは任意の位置に１以上の三重結合を有しており、さらに二重結合を有していてもよい。
「アラルキル」とは、上記「低級アルキル」に上記「アリール」が置換した基を包含する。具体的には、ベンジル、フェネチル等が挙げられる。
「アラルキルアミノ」および「アラルキル」のアリール部分は上記「アリール」と同義である。
「アラルキルアミノ」および「アラルキル」のアリール部分は上記「アリール」と同義である。
「アシル」、「アシルアミノ」および「アシルイミノ」の「アシル」部分は上記「アシル」と同義である。
「保護されていてもよいヒドロキシ」および「保護されていてもよいメルカプト」における保護基は当分野において周知であり、例えば、エーテルおよび置換エーテル形成基（例えばメチル、メトキシメチル、ｔ−ブトキシメチル、１−エトキシエチルおよびベンジル等）；シリルエーテル形成基（例えばトリメチルシリル、トリエチルシリル、ｔｅｒｔ−ブチルジメチルシリルおよびメチル−ジイソプロピルシリル等）；エステル形成基（例えばホルメート、アセテートおよびトリクロロアセテート等）；カルボネート基（例えばメチルカルボネート、２，２，２−トリクロロエチルカルボネート、およびｐ−ニトロフェニルカルボネート等）；スルホニル形成基（メタンスルホニル、ｐ−トルエンスルホニル）等が挙げられる。
「保護されていてもよいヒドロキシ」および「保護されていてもよいメルカプト」における保護基としては、エーテルおよび置換エーテル形成基等が好ましい。特に、置換エーテル形成基等が好ましい。
「保護されていてもよいヒドロキシ」および「保護されていてもよいメルカプト」における保護基としては、エーテルおよび置換エーテル形成基等が好ましい。特に、置換エーテル形成基等が好ましい。
さらに、式（Ｉ）の化合物の一つ以上の水素、炭素または他の原子は、水素、炭素または他の原子の同位体で置換され得る。式（Ｉ）の化合物は、式（Ｉ）の化合物のすべての放射性標識体を包含する。式（Ｉ）の化合物のそのような「放射性標識化」、「放射性標識体」などは、それぞれが本発明に包含され、代謝薬物動態研究ならびに結合アッセイにおける研究および／または診断ツールとして有用である。また、医薬品としても有用である。
本発明の式（Ｉ）の化合物に組み込まれ得る同位体の例としては、それぞれ２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、および３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、および塩素が包含される。本発明の放射性標識化合物は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）のトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）の特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばPd/Cの存在下、塩基の存在または非存在下で、式（Ｉ）の化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含してもよい。他のトリチウム標識化合物を調製するための適切な方法としては、文書Isotopes in the PhysIcal and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987年)を参照にできる。１４Ｃ−標識化合物は、14C炭素を有する原料を用いることによって調製できる。
本発明の式（Ｉ）の化合物に組み込まれ得る同位体の例としては、それぞれ２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、および３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、および塩素が包含される。本発明の放射性標識化合物は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）のトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）の特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばPd/Cの存在下、塩基の存在または非存在下で、式（Ｉ）の化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含してもよい。他のトリチウム標識化合物を調製するための適切な方法としては、文書Isotopes in the PhysIcal and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987年)を参照にできる。１４Ｃ−標識化合物は、14C炭素を有する原料を用いることによって調製できる。
本発明化合物（Ｉ’）において、好ましい態様は以下の通りである。各記号は上記記載と同意義である。
Ｚ１’としては、ヒドロキシが挙げられる。
Ｚ２’としては、Ｏが挙げられる。
が挙げられる。
環Ａ’としては、芳香族炭素環またはヘテロ環が挙げられる。
例えば、環Ａ’としては、芳香族炭素環または芳香族ヘテロ環が挙げられる。
例えば、環Ａ’としては、ベンゼン環またはピリジン環が挙げられる。
Ｒ２’としては、置換もしくは非置換のアリールまたは置換もしくは非置換の芳香族ヘテロ環式基（例えば、チエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のフェニルが挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のピリジルが挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のｔｅｒｔ−ブチルが挙げられる。
Ｒ３’としては、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のフェニルが挙げられる。
例えば、Ｒ３’としては、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ３’としては、式：
が挙げられる。
環Ｄ’としては、ベンゼン環またはピリジン環が挙げられる。
Ｖ’が−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−Ｏ−、−ＮＲ１３’−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＲ１３’−が挙げられる。
Ｒ４ａ’およびＲ４ｂ’としては、それぞれ独立して、水素または低級アルキルが挙げられる。
例えば、Ｒ４ａ’およびＲ４ｂ’としては、水素が挙げられる。
ｔ’としては、０が挙げられる。
ｍ’としては、０〜２の整数が挙げられる。
例えば、ｍ’としては、１または２の整数が挙げられる。
例えば、ｍ’としては、０が挙げられる。
Ｒ１ａ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のフェニル、置換もしくは非置換の芳香族ヘテロ環式基（例えばチエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のフェニル、置換もしくは非置換の芳香族ヘテロ環式基（例えばチエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
Ｒ１ｂ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ｂ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニルが挙げられる。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
Ｚ１’としては、ヒドロキシが挙げられる。
Ｚ２’としては、Ｏが挙げられる。
が挙げられる。
環Ａ’としては、芳香族炭素環またはヘテロ環が挙げられる。
例えば、環Ａ’としては、芳香族炭素環または芳香族ヘテロ環が挙げられる。
例えば、環Ａ’としては、ベンゼン環またはピリジン環が挙げられる。
Ｒ２’としては、置換もしくは非置換のアリールまたは置換もしくは非置換の芳香族ヘテロ環式基（例えば、チエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のフェニルが挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のピリジルが挙げられる。
例えば、Ｒ２’としては、置換もしくは非置換のｔｅｒｔ−ブチルが挙げられる。
Ｒ３’としては、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のフェニルが挙げられる。
例えば、Ｒ３’としては、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ３’としては、式：
が挙げられる。
環Ｄ’としては、ベンゼン環またはピリジン環が挙げられる。
Ｖ’が−Ｏ−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−Ｏ−、−ＮＲ１３’−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）−ＮＲ１３’−が挙げられる。
Ｒ４ａ’およびＲ４ｂ’としては、それぞれ独立して、水素または低級アルキルが挙げられる。
例えば、Ｒ４ａ’およびＲ４ｂ’としては、水素が挙げられる。
ｔ’としては、０が挙げられる。
ｍ’としては、０〜２の整数が挙げられる。
例えば、ｍ’としては、１または２の整数が挙げられる。
例えば、ｍ’としては、０が挙げられる。
Ｒ１ａ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のフェニル、置換もしくは非置換の芳香族ヘテロ環式基（例えばチエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ａ’としては、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のフェニル、置換もしくは非置換の芳香族ヘテロ環式基（例えばチエニル、ピリジル、イミダゾリル、ピリミジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、ピラゾリル、オキサジアゾリル等）が挙げられる。
Ｒ１ｂ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｒ１ｂ’としては、ハロゲン、置換もしくは非置換の低級アルキル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニルが挙げられる。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
本発明化合物（Ｉ’）において、好ましい態様は以下の通りである。
Ｚ２はＯであり、
ｔが０であり、
Ｒ２’が置換もしくは非置換のｔｅｒｔ−ブチル、置換もしくは非置換のｉ−プロピルであり、
Ｒ３’が式
である化合物。
Ｚ２’はＯであり、
ｔ’が０であり、
Ｒ２が
であり、
Ｒ３’が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基である化合物。
であり、
ｔ’が０であり、
Ｒ２’が置換もしくは非置換のｔｅｒｔ−ブチル、置換もしくは非置換のｉ−プロピルであり、
Ｒ３’が式
である化合物。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
Ｚ２はＯであり、
ｔが０であり、
Ｒ２’が置換もしくは非置換のｔｅｒｔ−ブチル、置換もしくは非置換のｉ−プロピルであり、
Ｒ３’が式
Ｚ２’はＯであり、
ｔ’が０であり、
Ｒ２が
Ｒ３’が置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基である化合物。
であり、
ｔ’が０であり、
Ｒ２’が置換もしくは非置換のｔｅｒｔ−ブチル、置換もしくは非置換のｉ−プロピルであり、
Ｒ３’が式
である化合物。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
本発明化合物（Ｉ）において、好ましい態様は以下の通りである。各記号は上記記載と同意義である。
Ｒ２としては、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基が挙げられる。
例えば、Ｒ２としては、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基が挙げられる。
Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
Ｙとしては、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｙとしては、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニルまたは置換スルホニルが挙げられる。
例えば、Ｙとしては、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニルまたは置換スルホニルが挙げられる。
Ｒ１４としては、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロが挙げられる。
例えば、Ｒ１４としては、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロが挙げられる。
ｒとしては、０〜２の整数が挙げられる。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
Ｒ２としては、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基が挙げられる。
例えば、Ｒ２としては、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基が挙げられる。
Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
例えば、Ｒ３としては、式：
で示される基が挙げられる。
Ｙとしては、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基が挙げられる。
例えば、Ｙとしては、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニルまたは置換スルホニルが挙げられる。
例えば、Ｙとしては、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニルまたは置換スルホニルが挙げられる。
Ｒ１４としては、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロが挙げられる。
例えば、Ｒ１４としては、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロが挙げられる。
ｒとしては、０〜２の整数が挙げられる。
さらに、上記で示した各置換基の選択肢の全ての組み合わせで示される化合物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ａ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）；
で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。。
（ａ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）；
で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｂ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、シアノ、カルボキシ、置換スルフィニル、置換スルホニル、置換もしくは非置換のヘテロ環式基；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｂ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換もしくは非置換のアルコキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、シアノ、カルボキシ、置換スルフィニル、置換スルホニル、置換もしくは非置換のヘテロ環式基；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｃ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；
ｒは０）で示される基である化合物。（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｃ）Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；
ｒは０）で示される基である化合物。（ただし、以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｄ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；
ｒは０）で示される基；
ｔが０；
ｋが０または１の整数；
ｍが０または１の整数；
ｎが０または１の整数；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｄ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基；
ｒは０）で示される基；
ｔが０；
ｋが０または１の整数；
ｍが０または１の整数；
ｎが０または１の整数；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｅ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
環Ａが、ベンゼンまたはピリジン；
Ｂが、芳香族炭素環ジイルまたは芳香族へテロ環ジイル；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、または置換もしくは非置換のアミノ；
ｒは０）で示される基；
ｔが０；
ｋが１の整数；
ｍが０または１の整数；
ｎが０または１の整数；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、または置換もしくは非置換の低級アルキルチオ）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｆ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
環Ａが、ベンゼンまたはピリジン；
Ｂが、芳香族炭素環ジイルまたは芳香族へテロ環ジイル；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換低級アルコキシ、置換低級アルキルチオ、または置換アミノ；
ｒは０）で示される基；
ｔが０；
ｋが１；
ｍが０または１；
ｎが０または１；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、または置換もしくは非置換の低級アルキルチオ）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｇ）上記の（ａ）〜（ｆ）において、
Ｙが、置換基群Ａ（置換基群Ａ：ヒドロキシ、カルバモイル、低級アルキルカルバモイル、ヒドロキシで置換されたイミノ、低級アルコキシ、アミノ、低級アルキルアミノ、低級アルコキシカルボニル、低級アルキルスルフィニルおよび低級アルキルスルホニル）から選択される１個またはそれ以上の置換基で置換された低級アルコキシである化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｈ）上記の（ａ）〜（ｇ）において、
式：
で示される基が
式：
（式中の各置換基は、上記（ａ）〜（ｅ）の定義と同意義）
で示される基である化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物の一般的合成方法を以下に示す。これら合成に用いる出発物質および反応試薬はいずれも、商業的に入手可能であるか、または商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。
（ｅ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
環Ａが、ベンゼンまたはピリジン；
Ｂが、芳香族炭素環ジイルまたは芳香族へテロ環ジイル；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、または置換もしくは非置換のアミノ；
ｒは０）で示される基；
ｔが０；
ｋが１の整数；
ｍが０または１の整数；
ｎが０または１の整数；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、または置換もしくは非置換の低級アルキルチオ）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物（Ｉ）において、さらに好ましい態様は以下の通りである。
（ｆ）Ｚ１が、ヒドロキシ；
Ｚ２が−Ｃ（＝Ｏ）−；
Ｚ３ａおよびＺ３ｂが、一緒になって＝Ｏ；
環Ａが、ベンゼンまたはピリジン；
Ｂが、芳香族炭素環ジイルまたは芳香族へテロ環ジイル；
Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜１の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、置換低級アルコキシ、置換低級アルキルチオ、または置換アミノ；
ｒは０）で示される基；
ｔが０；
ｋが１；
ｍが０または１；
ｎが０または１；
Ｒ１ａおよびＲ１ｂが、それぞれ独立して、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、または置換もしくは非置換の低級アルキルチオ）で示される基である化合物（ただし、以下の式：
で示される化合物を除く）、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｇ）上記の（ａ）〜（ｆ）において、
Ｙが、置換基群Ａ（置換基群Ａ：ヒドロキシ、カルバモイル、低級アルキルカルバモイル、ヒドロキシで置換されたイミノ、低級アルコキシ、アミノ、低級アルキルアミノ、低級アルコキシカルボニル、低級アルキルスルフィニルおよび低級アルキルスルホニル）から選択される１個またはそれ以上の置換基で置換された低級アルコキシである化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｈ）上記の（ａ）〜（ｇ）において、
式：
で示される基が
式：
（式中の各置換基は、上記（ａ）〜（ｅ）の定義と同意義）
で示される基である化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
本発明化合物の一般的合成方法を以下に示す。これら合成に用いる出発物質および反応試薬はいずれも、商業的に入手可能であるか、または商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。
本発明の化合物（Ｉ）（すなわち、一般式（Ｉ）で表される化合物。以下、他の式で表される化合物についても同様に略記することがある。）は、例えば、以下に示す合成ルートによって製造することができる。
［ルート１］
［式中、Ｒ１３は置換もしくは非置換の低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉａ）で示される本発明化合物は、化合物（ＩＩ）、化合物（ＩＩＩ）および化合物（ＩＶ）を酸の存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
［ルート１］
［式中、Ｒ１３は置換もしくは非置換の低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉａ）で示される本発明化合物は、化合物（ＩＩ）、化合物（ＩＩＩ）および化合物（ＩＶ）を酸の存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＩＩＩ）および化合物（ＩＶ）は、化合物（ＩＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる酸としては、酢酸、パラトルエンスルホン酸、塩酸などが挙げられる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１６０℃、好ましくは２０〜１２０℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉａ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート２］
［式中の記号は前記と同意義である］
即ち、一般式（Ｉａ）で示される本発明化合物は、化合物（ＩＩ）および化合物（Ｖ）を酸存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
［式中の記号は前記と同意義である］
即ち、一般式（Ｉａ）で示される本発明化合物は、化合物（ＩＩ）および化合物（Ｖ）を酸存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（Ｖ）は、化合物（ＩＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる酸としては、酢酸、パラトルエンスルホン酸、塩酸などが挙げられる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１６０℃、好ましくは２０〜１２０℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉａ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート３］
［式中、ＬおよびＱは一方がジヒドロキシボラン、ジ低級アルキルボランまたはジ低級アルコキシボランを示し、他方はハロゲンまたは−ＯＳＯ２（ＣｉＦ２ｉ＋１）（ｉは１〜４の整数）を示し、他の記号は前記と同意義である。］
［式中、ＬおよびＱは一方がジヒドロキシボラン、ジ低級アルキルボランまたはジ低級アルコキシボランを示し、他方はハロゲンまたは−ＯＳＯ２（ＣｉＦ２ｉ＋１）（ｉは１〜４の整数）を示し、他の記号は前記と同意義である。］
即ち、一般式（Ｉｂ）で示される本発明化合物は、鈴木カップリング反応を用いて、化合物（ＶＩ）および化合物（ＶＩＩ）をパラジウム触媒および塩基存在下、適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＶＩＩ）は、化合物（ＶＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用することができる塩基としては、例えば、金属水酸化物（例、水酸化ナトリウム、水酸化カリウム、リン酸三カリウムなど）、金属水素化物（例、水素化ナトリウム、水素化リチウムなど）、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなど）などが挙げられ、化合物（ＶＩ）に対して１当量またはそれ以上、好ましくは１〜５当量使用することができる。
使用することができるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）、ジクロロビストリフェニルホスフィンパラジウム（ＩＩ）またはテトラキス（トリフェニルホスフィン）パラジウム（ＩＩ）などが挙げられ、化合物（ＶＩ）に対して０．００１当量またはそれ以上、好ましくは０．０１〜１当量使用することができる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、ジメトキシエタンなど）、Ｎ，Ｎ−ジメチルホルムアミド、水およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１８０℃、場合によってはマイクロウェーブ照射化、好ましくは２０〜１２０℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉｂ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート４］
［式中、ＬおよびＭは一方がトリアルキルスズ（例、−ＳｎＢｕ３など）を示し、他方はハロゲンまたは−ＯＳＯ２（ＣｉＦ２ｉ＋１）（ｉは１〜４の整数）を示し、他の記号は前記と同意義である。］
即ち、一般式（Ｉｂ）で示される本発明化合物は、スティルカップリング反応を用いて、化合物（ＶＩ）および化合物（ＶＩＩＩ）を触媒存在下、適当な溶媒中で反応させることにより製造することができる。
即ち、一般式（Ｉｂ）で示される本発明化合物は、スティルカップリング反応を用いて、化合物（ＶＩ）および化合物（ＶＩＩＩ）を触媒存在下、適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＶＩＩＩ）は、化合物（ＶＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用することができる触媒としては、例えば、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）、ジクロロビストリフェニルホスフィンパラジウム（ＩＩ）またはテトラキス（トリフェニルホスフィン）パラジウム（ＩＩ）などが挙げられ、化合物（ＶＩ）に対して０．００１当量またはそれ以上、好ましくは０．０１〜１当量使用することができる。必要に応じて、触媒の２倍モルのホスフィン配位子、例えばトリ−ｔｅｒｔ−ブチルホスフィン、２−（ジ−ｔｅｒｔ−ブチルホスフィノ）ビフェニル、２−（ジ−シクロヘキシルホスフィノ）ビフェニル、トリフェニルホスフィン、トリス−（２−フリル）ホスフィンなどを加えることができる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、ジメトキシエタンなど）、Ｎ，Ｎ−ジメチルホルムアミドおよびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１８０℃、場合によってはマイクロウェーブ照射下、好ましくは２０〜１２０℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉｂ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート５］
［式中の記号は前記と同意義である］
即ち、一般式（Ｘ）で示される本発明化合物は、化合物（ＩＸ）を酸化剤存在下、適当な溶媒中で反応させることにより製造することができる。
［式中の記号は前記と同意義である］
即ち、一般式（Ｘ）で示される本発明化合物は、化合物（ＩＸ）を酸化剤存在下、適当な溶媒中で反応させることにより製造することができる。
使用することができる酸化剤としては、例えば、二酸化マンガン、２−ヨウドキシ安息香酸などが挙げられ、化合物（ＩＸ）に対して１当量またはそれ以上、好ましくは１〜１．５当量使用することができる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、ハロゲン化炭化水素類（例、ジクロロメタン、１，２−ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジオキサンなど）、ケトン類（例、アセトン、メチルエチルケトンなど）、ニトリル類（例、アセトニトリルなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１５０℃、好ましくは２０〜１００℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
化合物（ＩＸ）は粗製物として、あるいは常法（例、カラムクロマトグラフィー、再結晶など）により精製して次工程で使用することができる。
［ルート５（続き）］
［式中、ｉは０〜３の整数であり、Ｘ１およびＸ２はそれぞれ独立して、ＮＲ１４、ＯまたはＳであり、Ｒ１４は水素または低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｃ）で示される本発明化合物は、化合物（Ｘ）および化合物（ＸＩ）を酸存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
［式中、ｉは０〜３の整数であり、Ｘ１およびＸ２はそれぞれ独立して、ＮＲ１４、ＯまたはＳであり、Ｒ１４は水素または低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｃ）で示される本発明化合物は、化合物（Ｘ）および化合物（ＸＩ）を酸存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＸＩ）は、化合物（Ｘ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる酸としては、パラトルエンスルホン酸、硫酸、パラトルエンスルホン酸ピリジニウム塩などが挙げられる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１７０℃、好ましくは２０〜１５０℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉｃ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート６］
［式中の記号は前記と同意義である］
即ち、一般式（Ｉｄ）で示される本発明化合物は、化合物（Ｘ）と化合物（ＸＩＩ）またはその塩を適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＩ）およびその塩は、化合物（Ｘ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
［式中の記号は前記と同意義である］
即ち、一般式（Ｉｄ）で示される本発明化合物は、化合物（Ｘ）と化合物（ＸＩＩ）またはその塩を適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＩ）およびその塩は、化合物（Ｘ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
化合物（ＸＩＩ）の塩としては、例えば、塩酸塩、硫酸塩などの鉱酸塩などが挙げられる。該塩を使用する場合は、塩基で中和して反応させる。
使用することができる塩基としては、例えば、酢酸ナトリウム、アミン類（ピリジンなど）などが挙げられ、その使用量は化合物（ＸＩ）の塩に対して１〜３当量、好ましくは１〜２当量である。
使用できる溶媒としては、例えば、炭化水素類（例、ベンゼン、トルエン、キシレンなど）、ハロゲン化炭化水素類（例、クロロホルム、１，２−ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジオキサンなど）、アルコール類（例、メタノール、エタノール、ｎ−プロパノール、イソプロパノールなど）、水およびそれらの混合溶媒などが挙げられる。
反応温度は、０〜１５０℃、好ましくは２０〜１２０℃である。
反応時間は、通常、１０分〜２４時間程度である。
得られた所望の化合物（Ｉｄ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート７］
［式中、Ｈａｌはハロゲンであり、Ｒ９はヒドロキシの保護基であり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｅ）で示される本発明化合物は、化合物（Ｉａ）と化合物（ＸＩＩＩ）を塩基存在下、適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＩ）は、化合物（Ｉａ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
［式中、Ｈａｌはハロゲンであり、Ｒ９はヒドロキシの保護基であり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｅ）で示される本発明化合物は、化合物（Ｉａ）と化合物（ＸＩＩＩ）を塩基存在下、適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＩ）は、化合物（Ｉａ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
使用することができる塩基としては、例えば、水素化ナトリウム、ナトリウムメトキシド、アミン類（トリエチルアミン、ピリジンなど）などが挙げられ、その使用量は化合物（Ｉａ）に対して１〜３当量、好ましくは１〜２当量である。
使用できる溶媒としては、例えば、炭化水素類（例、ベンゼン、トルエン、キシレンなど）、ハロゲン化炭化水素類（例、クロロホルム、１，２−ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジオキサンなど）、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシドおよびそれらの混合溶媒などが挙げられる。
反応温度は、−２０〜１５０℃、好ましくは０〜１２０℃である。
反応時間は、通常、１０分〜２４時間程度である。
得られた所望の化合物（Ｉｅ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート８］
［式中の記号は前記と同意義である］
即ち、一般式（Ｉｈ）で示される本発明化合物は、化合物（Ｉａ）と化合物（ＸＩＶ）を適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＶ）は、化合物（Ｉａ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
［式中の記号は前記と同意義である］
即ち、一般式（Ｉｈ）で示される本発明化合物は、化合物（Ｉａ）と化合物（ＸＩＶ）を適当な溶媒中で反応させることにより製造することができる。化合物（ＸＩＶ）は、化合物（Ｉａ）に対して１〜４当量、好ましくは１〜２．５当量使用する。
使用できる溶媒としては、例えば、酢酸、炭化水素類（例、ベンゼン、トルエン、キシレンなど）、エーテル類（例、テトラヒドロフラン、ジオキサンなど）、アルコール類（例、メタノール、エタノール、ｎ−プロパノール、イソプロパノールなど）およびそれらの混合溶媒などが挙げられる。
反応温度は、０〜１５０℃、好ましくは５０〜１３０℃である。
反応時間は、通常、１０分〜２４時間程度である。
得られた所望の化合物（Ｉｈ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
［ルート９］
［式中の記号は前記と同意義である］
化合物（Ｉｉ）および光学分割剤（ＸＶ）（例、（Ｒ）または（Ｓ）−メチル２−ヒドロキシ−２−フェニルアセテート）を適当な溶媒中で、縮合剤（例、アゾジカルボン酸イソプロピル）と反応させ、得られた混合物を常法（例えば、カラムクロマトグラフィー、再結晶など）により精製して所望の立体配置を有するジアステレオマー体を単離することができる。得られたジアステレオマー体を脱保護反応（例えば、水素添加反応，塩化リチウムなど）に付すことで目的のエナンチオマーを製造できる。光学分割剤は、化合物（Ｉｉ）に対して１〜４等量、好ましくは１〜２．５等量使用する。
［式中の記号は前記と同意義である］
化合物（Ｉｉ）および光学分割剤（ＸＶ）（例、（Ｒ）または（Ｓ）−メチル２−ヒドロキシ−２−フェニルアセテート）を適当な溶媒中で、縮合剤（例、アゾジカルボン酸イソプロピル）と反応させ、得られた混合物を常法（例えば、カラムクロマトグラフィー、再結晶など）により精製して所望の立体配置を有するジアステレオマー体を単離することができる。得られたジアステレオマー体を脱保護反応（例えば、水素添加反応，塩化リチウムなど）に付すことで目的のエナンチオマーを製造できる。光学分割剤は、化合物（Ｉｉ）に対して１〜４等量、好ましくは１〜２．５等量使用する。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサン、1,3-ジメチル-2-イミダゾリジノンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）アミド類（例、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン）およびそれらの混合溶媒などが挙げられる。
反応温度は、−１０〜１５０℃、好ましくは０〜８０℃である。反応時間は化合物により異なるが、１０分〜４８時間反応させればよい。
［ルート１０］
［式中、Ｒ１4およびＲ１５は、それぞれ独立して置換もしくは非置換の低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｊ）で示される本発明化合物は、化合物（ＩＩＩ）、化合物（ＩＶ）および化合物（ＸＩＸ）を酸の存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
化合物（ＸＩＸ）は，化合物（ＸＶＩＩ）および化合物（ＸＶＩＩＩ）を塩基の存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＸＶＩＩ）は、化合物（ＸＶＩＩＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる塩基としては、水素化ナトリウム，ナトリウムメトキシド，ｔ−ブトキシカリウムなどが挙げられる。
使用できる溶媒としては、アルコール類（例，メタノール，エタノールなど），芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１５０℃、好ましくは２０〜１００℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（ＸＩＸ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶，減圧蒸留など）により精製することができる。
［式中、Ｒ１4およびＲ１５は、それぞれ独立して置換もしくは非置換の低級アルキルであり、その他の記号は前記と同意義である］
即ち、一般式（Ｉｊ）で示される本発明化合物は、化合物（ＩＩＩ）、化合物（ＩＶ）および化合物（ＸＩＸ）を酸の存在下、あるいは非存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
化合物（ＸＩＸ）は，化合物（ＸＶＩＩ）および化合物（ＸＶＩＩＩ）を塩基の存在下、無溶媒または適当な溶媒中で反応させることにより製造することができる。
本反応において、化合物（ＸＶＩＩ）は、化合物（ＸＶＩＩＩ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる塩基としては、水素化ナトリウム，ナトリウムメトキシド，ｔ−ブトキシカリウムなどが挙げられる。
使用できる溶媒としては、アルコール類（例，メタノール，エタノールなど），芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１５０℃、好ましくは２０〜１００℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（ＸＩＸ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶，減圧蒸留など）により精製することができる。
本反応において、化合物（ＩＩＩ）および化合物（ＩＶ）は、化合物（ＸＩＸ）に対して１当量またはそれ以上、好ましくは１〜３当量使用することができる。
使用できる酸としては、酢酸、パラトルエンスルホン酸、塩酸などが挙げられる。
使用できる溶媒としては、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサンなど）およびそれらの混合溶媒などが挙げられる。
反応温度は−１０〜１５０℃、好ましくは２０〜１００℃である。反応時間は化合物により異なるが１０分〜８０時間反応させればよい。
得られた所望の化合物（Ｉａ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製することができる。
本発明化合物は、製薬的に許容し得る酸または塩基との塩、例えば塩酸、硫酸、硝酸、リン酸、フッ化水素酸、臭化水素酸等の無機酸との塩、ギ酸、酢酸、シュウ酸、コハク酸、マレイン酸、酒石酸、乳酸、クエン酸、フマール酸等の有機酸との塩、アンモニウム、トリメチルアンモニウム、トリエチルアンモニウム等の有機塩基の塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩を形成し得る。
さらに、本発明化合物または上記の製薬的に許容し得る塩は、その溶媒和物（好ましくは水和物）の溶媒和物とすることもできる。溶媒和物としては有機溶媒および／または水との溶媒和物が挙げられる。溶媒和物を形成するときは、任意の数の溶媒分子と配位していてもよい。
本発明化合物（Ｉ）は特定の異性体に限定するものではなく、全ての可能な異性体やラセミ体を含むものである。例えば、下記の通り、互変異性体を含有する。
本発明の化合物は、特定の立体配置を有する単離されたエナンチオマー、又はそれらエナンチオマーの混合物のいずれでもよい。例えば、本発明の化合物はピロリジノン環の５位において特定の立体配置を有する単離されたエナンチオマーまたはそのようなエナンチオマーの混合物であり得る。特定の立体配置を有するエナンチオマーは、例えば、結晶化、酵素反応、クロマトグラフィー、ジアステレオマー塩等の当分野で慣用の技術を用いて当業者が容易に単離することができる。
上記一般式（１）で表される本発明化合物は、Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体に対する拮抗作用を有し、Ｐ２Ｘ３および／またはＰ２Ｘ２／３が関与する疾患の治療剤として有用である。Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体は疼痛および泌尿器系疾患に関与すると考えられており（Ｎａｔｕｒｅ ４０７， ２６， １０１１−１０１５ （２０００）， Ｎａｔｕｒｅ， Ｖｏｌ．４０７， Ｎｏ．２６， １０１５−１０１７ （２０００）、非特許文献１、非特許文献２等）、例えば、関節リウマチに伴う痛み、変形性関節症に伴う痛み、頭痛、偏頭痛、口腔顔面痛、歯痛、舌痛症、顎関節症に伴う痛み、三叉神経痛、肩痛、椎間板ヘルニアに伴う痛み、変形性頚椎症に伴う痛み、脊柱管狭窄症に伴う痛み、胸郭出口症候群に伴う痛み、腕神経叢引き抜き症候群に伴う痛み、肩手症候群、むち打ち症に伴う痛み、胸痛、腹痛、疝痛、胆石症に伴う痛み、膵炎に伴う痛み、尿路結石症、過敏性腸症候群に伴う痛み、腰背部痛、坐骨神経痛、骨折に伴う痛み、骨粗鬆症に伴う痛み、関節痛、通風に伴う痛み、馬尾症候群に伴う痛み、強直性脊椎炎症に伴う痛み、筋肉痛、有痛性痙攣、筋筋膜痛症候群、線維筋痛症候群、閉塞性動脈硬化症に伴う痛み、バージャー病に伴う痛み、レイノー現象に伴う痛み、帯状疱疹に伴う痛み、カウザルギー、絞扼性神経障害に伴う痛み、手根管症候群に伴う痛み、糖尿病に伴う痛み、ギランバレー症候群に伴う痛み、ハンセン病に伴う痛み、薬物療法に伴う痛み、放射線療法に伴う痛み、脊髄損傷に伴う痛み、脊髄空洞症に伴う痛み、脳卒中に伴う痛み、視床痛、求心路遮断痛、交感神経依存性疼痛、ＡＢＣ症候群、多発性硬化症、皮膚疾患に伴う痛み、癌性疼痛、術後痛、外傷に伴う痛み、壊疽に伴う痛み、身体表現性障害に伴う痛み、身体化障害に伴う痛み、鬱病に伴う痛み、パーキンソン病に伴う痛み、膝関節痛、関節炎に伴う痛み、生理痛、中間痛、陣痛等の神経障害性疼痛、炎症性疼痛、侵害受容性疼痛、心因性疼痛、及び過活動膀胱、尿失禁、頻尿、尿意逼迫（ｕｒｉｎａｒｙ ｕｒｇｅｎｃｙ）、膀胱萎縮、前立腺肥大、前立腺炎、前立腺痛、利尿筋反射亢進（ｄｅｔｒｕｓｏｒ ｈｙｐｅｒｒｅｆｌｅｓｘｉａ）、排尿障害、神経性頻尿、慢性前立腺炎、慢性膀胱炎等の治療、症状の緩和または予防に有効である。
本発明の化合物は、ＡＴＰ受容体、特にＰ２Ｘ３受容体に対して親和性が高く、サブタイプ選択性および他の受容体に対する選択性が高いため、副作用（たとえば運動機能への影響など）が軽減された医薬となり得る。また本発明の化合物は、安定性が高い、経口吸収性が高い、溶解度が高い、良好なバイオアベイラビリティーを示す、クリアランスが低い、半減期が長い、薬効持続性が高い、および／または肝酵素阻害活性が低い等の利点も有する。
さらなる態様において、本発明は、有効量の本発明化合物と製薬的に許容し得る担体とを組み合わせて含有してなる医薬組成物を提供する。
本発明化合物を医薬として用いる場合、例えば賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤、界面活性剤等、当分野において周知の製薬的に許容し得る担体を用い、常法に従って医薬組成物を製造することができる。
本発明に係る医薬組成物を、ヒトを含む哺乳動物の治療に投与する場合、投与単位剤形は治療目的と投与経路に応じて適宜選択することができる。具体的には錠剤、被覆錠剤、散剤、顆粒剤、カプセル剤、液剤、丸剤、懸濁剤、乳剤等の経口剤、および注射剤、坐剤、軟膏、貼付剤、エアゾール剤等の非経口剤が挙げられる。これら投与単位剤形は、当分野で周知の方法により製剤化される。
上記製剤中に含有されるべき本発明化合物の量は、剤型、投与経路、投与計画等によって適宜変更することができる。
本発明に係る医薬組成物の投与方法は、製剤の剤形、患者の年齢、性別、体重、症状の程度およびその他の条件等に応じて適宜決定され、経口、皮下、経皮、直腸、鼻内、口腔等の種々の経路から選択することができる。
本発明の医薬組成物に含有される本発明化合物の用量は、選択した投与経路、患者の年齢、性別、体重、疾患の状態、投与される本発明化合物の種類、その他の条件等に応じて適宜選択されるが、成人に経口投与する場合、通常０．０５〜１０００ｍｇ／ｋｇ／日であり、好ましくは０．１〜１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５〜１００ｍｇ／ｋｇ／日であり、好ましくは０．０１〜１ｍｇ／ｋｇ／日の範囲内である。これら本発明の医薬組成物は１日に１回または複数回に分けて投与することができる。
本発明化合物の好ましい態様は、以下の式（ａ）〜（ｆ）において、以下の基を有するものである。
（上記表中、Ａｃはアセチル、Ｍｓはメシル、Ｍｅはメチル、Ｅｔはエチル、Ｐｒはプロピル、ｉＰｒはｉ−プロピル、ｎＢｕはｎ−ブチル、ｔＢｕはｔｅｒｔ−ブチル、ｃＰｒはシクロプロピル、ｃＢｕはシクロブチル、ｃＰｅｎｔはシクロペンチル、ｃＨｅｘはシクロヘキシル、Ｐｈはフェニルを示す）
Ｒ１、Ｒ２、Ｚ、ＸおよびＹの組み合わせが（Ｒ１，Ｒ２，Ｚ，Ｘ，Ｙ）が以下である化合物。
(R1,R2,Z,X,Y)=(R1A,R2A,ZA,XA,YA),(R1B,R2A,ZA,XA,YA),(R1C,R2A,ZA,XA,YA),(R1D,R2A,ZA,XA,YA),(R1E,R2A,ZA,XA,YA),(R1F,R2A,ZA,XA,YA),(R1G,R2A,ZA,XA,YA),(R1H,R2A,ZA,XA,YA),(R1I,R2A,ZA,XA,YA),(R1J,R2A,ZA,XA,YA),(R1K,R2A,ZA,XA,YA),(R1L,R2A,ZA,XA,YA),(R1M,R2A,ZA,XA,YA),(R1N,R2A,ZA,XA,YA),(R1O,R2A,ZA,XA,YA),(R1P,R2A,ZA,XA,YA),(R1Q,R2A,ZA,XA,YA),(R1A,R2B,ZA,XA,YA),(R1B,R2B,ZA,XA,YA),(R1C,R2B,ZA,XA,YA),(R1D,R2B,ZA,XA,YA),(R1E,R2B,ZA,XA,YA),(R1F,R2B,ZA,XA,YA),(R1G,R2B,ZA,XA,YA),(R1H,R2B,ZA,XA,YA),(R1I,R2B,ZA,XA,YA),(R1J,R2B,ZA,XA,YA),(R1K,R2B,ZA,XA,YA),(R1L,R2B,ZA,XA,YA),(R1M,R2B,ZA,XA,YA),(R1N,R2B,ZA,XA,YA),(R1O,R2B,ZA,XA,YA),(R1P,R2B,ZA,XA,YA),(R1Q,R2B,ZA,XA,YA),(R1A,R2C,ZA,XA,YA),(R1B,R2C,ZA,XA,YA),(R1C,R2C,ZA,XA,YA),(R1D,R2C,ZA,XA,YA),(R1E,R2C,ZA,XA,YA),(R1F,R2C,ZA,XA,YA),(R1G,R2C,ZA,XA,YA),(R1H,R2C,ZA,XA,YA),(R1I,R2C,ZA,XA,YA),(R1J,R2C,ZA,XA,YA),(R1K,R2C,ZA,XA,YA),(R1L,R2C,ZA,XA,YA),(R1M,R2C,ZA,XA,YA),(R1N,R2C,ZA,XA,YA),(R1O,R2C,ZA,XA,YA),(R1P,R2C,ZA,XA,YA),(R1Q,R2C,ZA,XA,YA),(R1A,R2D,ZA,XA,YA),(R1B,R2D,ZA,XA,YA),(R1C,R2D,ZA,XA,YA),(R1D,R2D,ZA,XA,YA),(R1E,R2D,ZA,XA,YA),(R1F,R2D,ZA,XA,YA),(R1G,R2D,ZA,XA,YA),(R1H,R2D,ZA,XA,YA),(R1I,R2D,ZA,XA,YA),(R1J,R2D,ZA,XA,YA),(R1K,R2D,ZA,XA,YA),(R1L,R2D,ZA,XA,YA),(R1M,R2D,ZA,XA,YA),(R1N,R2D,ZA,XA,YA),(R1O,R2D,ZA,XA,YA),(R1P,R2D,ZA,XA,YA),(R1Q,R2D,ZA,XA,YA),(R1A,R2E,ZA,XA,YA),(R1B,R2E,ZA,XA,YA),(R1C,R2E,ZA,XA,YA),(R1D,R2E,ZA,XA,YA),(R1E,R2E,ZA,XA,YA),(R1F,R2E,ZA,XA,YA),(R1G,R2E,ZA,XA,YA),(R1H,R2E,ZA,XA,YA),(R1I,R2E,ZA,XA,YA),(R1J,R2E,ZA,XA,YA),(R1K,R2E,ZA,XA,YA),(R1L,R2E,ZA,XA,YA),(R1M,R2E,ZA,XA,YA),(R1N,R2E,ZA,XA,YA),(R1O,R2E,ZA,XA,YA),(R1P,R2E,ZA,XA,YA),(R1Q,R2E,ZA,XA,YA),(R1A,R2F,ZA,XA,YA),(R1B,R2F,ZA,XA,YA),(R1C,R2F,ZA,XA,YA),(R1D,R2F,ZA,XA,YA),(R1E,R2F,ZA,XA,YA),(R1F,R2F,ZA,XA,YA),(R1G,R2F,ZA,XA,YA),(R1H,R2F,ZA,XA,YA),(R1I,R2F,ZA,XA,YA),(R1J,R2F,ZA,XA,YA),(R1K,R2F,ZA,XA,YA),(R1L,R2F,ZA,XA,YA),(R1M,R2F,ZA,XA,YA),(R1N,R2F,ZA,XA,YA),(R1O,R2F,ZA,XA,YA),(R1P,R2F,ZA,XA,YA),(R1Q,R2F,ZA,XA,YA),(R1A,R2G,ZA,XA,YA),(R1B,R2G,ZA,XA,YA),(R1C,R2G,ZA,XA,YA),(R1D,R2G,ZA,XA,YA),(R1E,R2G,ZA,XA,YA),(R1F,R2G,ZA,XA,YA),(R1G,R2G,ZA,XA,YA),(R1H,R2G,ZA,XA,YA),(R1I,R2G,ZA,XA,YA),(R1J,R2G,ZA,XA,YA),(R1K,R2G,ZA,XA,YA),(R1L,R2G,ZA,XA,YA),(R1M,R2G,ZA,XA,YA),(R1N,R2G,ZA,XA,YA),(R1O,R2G,ZA,XA,YA),(R1P,R2G,ZA,XA,YA),(R1Q,R2G,ZA,XA,YA),(R1A,R2H,ZA,XA,YA),(R1B,R2H,ZA,XA,YA),(R1C,R2H,ZA,XA,YA),(R1D,R2H,ZA,XA,YA),(R1E,R2H,ZA,XA,YA),(R1F,R2H,ZA,XA,YA),(R1G,R2H,ZA,XA,YA),(R1H,R2H,ZA,XA,YA),(R1I,R2H,ZA,XA,YA),(R1J,R2H,ZA,XA,YA),(R1K,R2H,ZA,XA,YA),(R1L,R2H,ZA,XA,YA),(R1M,R2H,ZA,XA,YA),(R1N,R2H,ZA,XA,YA),(R1O,R2H,ZA,XA,YA),(R1P,R2H,ZA,XA,YA),(R1Q,R2H,ZA,XA,YA),(R1A,R2I,ZA,XA,YA),(R1B,R2I,ZA,XA,YA),(R1C,R2I,ZA,XA,YA),(R1D,R2I,ZA,XA,YA),(R1E,R2I,ZA,XA,YA),(R1F,R2I,ZA,XA,YA),(R1G,R2I,ZA,XA,YA),(R1H,R2I,ZA,XA,YA),(R1I,R2I,ZA,XA,YA),(R1J,R2I,ZA,XA,YA),(R1K,R2I,ZA,XA,YA),(R1L,R2I,ZA,XA,YA),(R1M,R2I,ZA,XA,YA),(R1N,R2I,ZA,XA,YA),(R1O,R2I,ZA,XA,YA),(R1P,R2I,ZA,XA,YA),(R1Q,R2I,ZA,XA,YA),(R1A,R2J,ZA,XA,YA),(R1B,R2J,ZA,XA,YA),(R1C,R2J,ZA,XA,YA),(R1D,R2J,ZA,XA,YA),(R1E,R2J,ZA,XA,YA),(R1F,R2J,ZA,XA,YA),(R1G,R2J,ZA,XA,YA),(R1H,R2J,ZA,XA,YA),(R1I,R2J,ZA,XA,YA),(R1J,R2J,ZA,XA,YA),(R1K,R2J,ZA,XA,YA),(R1L,R2J,ZA,XA,YA),(R1M,R2J,ZA,XA,YA),(R1N,R2J,ZA,XA,YA),(R1O,R2J,ZA,XA,YA),(R1P,R2J,ZA,XA,YA),(R1Q,R2J,ZA,XA,YA),(R1A,R2K,ZA,XA,YA),(R1B,R2K,ZA,XA,YA),(R1C,R2K,ZA,XA,YA),(R1D,R2K,ZA,XA,YA),(R1E,R2K,ZA,XA,YA),(R1F,R2K,ZA,XA,YA),(R1G,R2K,ZA,XA,YA),(R1H,R2K,ZA,XA,YA),(R1I,R2K,ZA,XA,YA),(R1J,R2K,ZA,XA,YA),(R1K,R2K,ZA,XA,YA),(R1L,R2K,ZA,XA,YA),(R1M,R2K,ZA,XA,YA),(R1N,R2K,ZA,XA,YA),(R1O,R2K,ZA,XA,YA),(R1P,R2K,ZA,XA,YA),(R1Q,R2K,ZA,XA,YA),(R1A,R2L,ZA,XA,YA),(R1B,R2L,ZA,XA,YA),(R1C,R2L,ZA,XA,YA),(R1D,R2L,ZA,XA,YA),(R1E,R2L,ZA,XA,YA),(R1F,R2L,ZA,XA,YA),(R1G,R2L,ZA,XA,YA),(R1H,R2L,ZA,XA,YA),(R1I,R2L,ZA,XA,YA),(R1J,R2L,ZA,XA,YA),(R1K,R2L,ZA,XA,YA),(R1L,R2L,ZA,XA,YA),(R1M,R2L,ZA,XA,YA),(R1N,R2L,ZA,XA,YA),(R1O,R2L,ZA,XA,YA),(R1P,R2L,ZA,XA,YA),(R1Q,R2L,ZA,XA,YA),(R1A,R2M,ZA,XA,YA),(R1B,R2M,ZA,XA,YA),(R1C,R2M,ZA,XA,YA),(R1D,R2M,ZA,XA,YA),(R1E,R2M,ZA,XA,YA),(R1F,R2M,ZA,XA,YA),(R1G,R2M,ZA,XA,YA),(R1H,R2M,ZA,XA,YA),(R1I,R2M,ZA,XA,YA),(R1J,R2M,ZA,XA,YA),(R1K,R2M,ZA,XA,YA),(R1L,R2M,ZA,XA,YA),(R1M,R2M,ZA,XA,YA),(R1N,R2M,ZA,XA,YA),(R1O,R2M,ZA,XA,YA),(R1P,R2M,ZA,XA,YA),(R1Q,R2M,ZA,XA,YA),(R1A,R2N,ZA,XA,YA),(R1B,R2N,ZA,XA,YA),(R1C,R2N,ZA,XA,YA),(R1D,R2N,ZA,XA,YA),(R1E,R2N,ZA,XA,YA),(R1F,R2N,ZA,XA,YA),(R1G,R2N,ZA,XA,YA),(R1H,R2N,ZA,XA,YA),(R1I,R2N,ZA,XA,YA),(R1J,R2N,ZA,XA,YA),(R1K,R2N,ZA,XA,YA),(R1L,R2N,ZA,XA,YA),(R1M,R2N,ZA,XA,YA),(R1N,R2N,ZA,XA,YA),(R1O,R2N,ZA,XA,YA),(R1P,R2N,ZA,XA,YA),(R1Q,R2N,ZA,XA,YA),(R1A,R2O,ZA,XA,YA),(R1B,R2O,ZA,XA,YA),(R1C,R2O,ZA,XA,YA),(R1D,R2O,ZA,XA,YA),(R1E,R2O,ZA,XA,YA),(R1F,R2O,ZA,XA,YA),(R1G,R2O,ZA,XA,YA),(R1H,R2O,ZA,XA,YA),(R1I,R2O,ZA,XA,YA),(R1J,R2O,ZA,XA,YA),(R1K,R2O,ZA,XA,YA),(R1L,R2O,ZA,XA,YA),(R1M,R2O,ZA,XA,YA),(R1N,R2O,ZA,XA,YA),(R1O,R2O,ZA,XA,YA),(R1P,R2O,ZA,XA,YA),(R1Q,R2O,ZA,XA,YA),(R1A,R2P,ZA,XA,YA),(R1B,R2P,ZA,XA,YA),(R1C,R2P,ZA,XA,YA),(R1D,R2P,ZA,XA,YA),(R1E,R2P,ZA,XA,YA),(R1F,R2P,ZA,XA,YA),(R1G,R2P,ZA,XA,YA),(R1H,R2P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,XB,YB),(R1A,R2P,ZU,XB,YB),(R1B,R2P,ZU,XB,YB),(R1C,R2P,ZU,XB,YB),(R1D,R2P,ZU,XB,YB),(R1E,R2P,ZU,XB,YB),(R1F,R2P,ZU,XB,YB),(R1G,R2P,ZU,XB,YB),(R1H,R2P,ZU,XB,YB),(R1I,R2P,ZU,XB,YB),(R1J,R2P,ZU,XB,YB),(R1K,R2P,ZU,XB,YB),(R1L,R2P,ZU,XB,YB),(R1M,
R2P,ZU,XB,YB),(R1N,R2P,ZU,XB,YB),(R1O,R2P,ZU,XB,YB),(R1P,R2P,ZU,XB,YB),(R1Q,R2P,ZU,XB,YB),(R1A,R2Q,ZU,XB,YB),(R1B,R2Q,ZU,XB,YB),(R1C,R2Q,ZU,XB,YB),(R1D,R2Q,ZU,XB,YB),(R1E,R2Q,ZU,XB,YB),(R1F,R2Q,ZU,XB,YB),(R1G,R2Q,ZU,XB,YB),(R1H,R2Q,ZU,XB,YB),(R1I,R2Q,ZU,XB,YB),(R1J,R2Q,ZU,XB,YB),(R1K,R2Q,ZU,XB,YB),(R1L,R2Q,ZU,XB,YB),(R1M,R2Q,ZU,XB,YB),(R1N,R2Q,ZU,XB,YB),(R1O,R2Q,ZU,XB,YB),(R1P,R2Q,ZU,XB,YB)および(R1Q,R2Q,ZU,XB,YB)。
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,XB,YB),(R1A,R2P,ZU,XB,YB),(R1B,R2P,ZU,XB,YB),(R1C,R2P,ZU,XB,YB),(R1D,R2P,ZU,XB,YB),(R1E,R2P,ZU,XB,YB),(R1F,R2P,ZU,XB,YB),(R1G,R2P,ZU,XB,YB),(R1H,R2P,ZU,XB,YB),(R1I,R2P,ZU,XB,YB),(R1J,R2P,ZU,XB,YB),(R1K,R2P,ZU,XB,YB),(R1L,R2P,ZU,XB,YB),(R1M,
R2P,ZU,XB,YB),(R1N,R2P,ZU,XB,YB),(R1O,R2P,ZU,XB,YB),(R1P,R2P,ZU,XB,YB),(R1Q,R2P,ZU,XB,YB),(R1A,R2Q,ZU,XB,YB),(R1B,R2Q,ZU,XB,YB),(R1C,R2Q,ZU,XB,YB),(R1D,R2Q,ZU,XB,YB),(R1E,R2Q,ZU,XB,YB),(R1F,R2Q,ZU,XB,YB),(R1G,R2Q,ZU,XB,YB),(R1H,R2Q,ZU,XB,YB),(R1I,R2Q,ZU,XB,YB),(R1J,R2Q,ZU,XB,YB),(R1K,R2Q,ZU,XB,YB),(R1L,R2Q,ZU,XB,YB),(R1M,R2Q,ZU,XB,YB),(R1N,R2Q,ZU,XB,YB),(R1O,R2Q,ZU,XB,YB),(R1P,R2Q,ZU,XB,YB)および(R1Q,R2Q,ZU,XB,YB)。
本発明化合物の好ましい態様は、以下の式（ａ’）〜（ｆ’）において、以下の基を有するものである。
Ｒａ、Ｒｂ、ＸおよびＺの組み合わせが（Ｒａ，Ｒｂ，Ｘ，Ｚ）が以下である化合物。
(Ra,Rb,X,Z)=(Ra1,Rb1,X1,Z1),(Ra1,Rb1,X1,Z2),(Ra1,Rb1,X1,Z3),(Ra1,Rb1,X1,Z4),(Ra1,Rb1,X1,Z5),(Ra1,Rb1,X1,Z6),(Ra1,Rb1,X1,Z7),(Ra1,Rb1,X1,Z8),(Ra1,Rb1,X1,Z9),(Ra1,Rb1,X1,Z10),(Ra1,Rb1,X1,Z11),(Ra1,Rb1,X1,Z12),(Ra1,Rb1,X1,Z13),(Ra1,Rb1,X1,Z14),(Ra1,Rb1,X1,Z15),(Ra1,Rb1,X1,Z16),(Ra1,Rb1,X1,Z17),(Ra1,Rb1,X1,Z18),(Ra1,Rb1,X1,Z19),(Ra1,Rb1,X1,Z20),(Ra1,Rb1,X1,Z21),(Ra1,Rb1,X1,Z22),(Ra1,Rb1,X1,Z23),(Ra1,Rb1,X1,Z24),(Ra1,Rb1,X1,Z25),(Ra1,Rb1,X1,Z26),(Ra1,Rb1,X1,Z27),(Ra1,Rb1,X1,Z28),(Ra1,Rb1,X1,Z29),(Ra1,Rb1,X1,Z30),(Ra1,Rb1,X1,Z31),(Ra1,Rb1,X1,Z32),(Ra1,Rb1,X1,Z33),(Ra1,Rb1,X1,Z34),(Ra1,Rb1,X1,Z35),(Ra1,Rb1,X1,Z36),(Ra1,Rb1,X1,Z37),(Ra1,Rb1,X1,Z38),(Ra1,Rb1,X1,Z39),(Ra1,Rb1,X2,Z1),(Ra1,Rb1,X2,Z2),(Ra1,Rb1,X2,Z3),(Ra1,Rb1,X2,Z4),(Ra1,Rb1,X2,Z5),(Ra1,Rb1,X2,Z6),(Ra1,Rb1,X2,Z7),(Ra1,Rb1,X2,Z8),(Ra1,Rb1,X2,Z9),(Ra1,Rb1,X2,Z10),(Ra1,Rb1,X2,Z11),(Ra1,Rb1,X2,Z12),(Ra1,Rb1,X2,Z13),(Ra1,Rb1,X2,Z14),(Ra1,Rb1,X2,Z15),(Ra1,Rb1,X2,Z16),(Ra1,Rb1,X2,Z17),(Ra1,Rb1,X2,Z18),(Ra1,Rb1,X2,Z19),(Ra1,Rb1,X2,Z20),(Ra1,Rb1,X2,Z21),(Ra1,Rb1,X2,Z22),(Ra1,Rb1,X2,Z23),(Ra1,Rb1,X2,Z24),(Ra1,Rb1,X2,Z25),(Ra1,Rb1,X2,Z26),(Ra1,Rb1,X2,Z27),(Ra1,Rb1,X2,Z28),(Ra1,Rb1,X2,Z29),(Ra1,Rb1,X2,Z30),(Ra1,Rb1,X2,Z31),(Ra1,Rb1,X2,Z32),(Ra1,Rb1,X2,Z33),(Ra1,Rb1,X2,Z34),(Ra1,Rb1,X2,Z35),(Ra1,Rb1,X2,Z36),(Ra1,Rb1,X2,Z37),(Ra1,Rb1,X2,Z38),(Ra1,Rb1,X2,Z39),(Ra1,Rb2,X1,Z1),(Ra1,Rb2,X1,Z2),(Ra1,Rb2,X1,Z3),(Ra1,Rb2,X1,Z4),(Ra1,Rb2,X1,Z5),(Ra1,Rb2,X1,Z6),(Ra1,Rb2,X1,Z7),(Ra1,Rb2,X1,Z8),(Ra1,Rb2,X1,Z9),(Ra1,Rb2,X1,Z10),(Ra1,Rb2,X1,Z11),(Ra1,Rb2,X1,Z12),(Ra1,Rb2,X1,Z13),(Ra1,Rb2,X1,Z14),(Ra1,Rb2,X1,Z15),(Ra1,Rb2,X1,Z16),(Ra1,Rb2,X1,Z17),(Ra1,Rb2,X1,Z18),(Ra1,Rb2,X1,Z19),(Ra1,Rb2,X1,Z20),(Ra1,Rb2,X1,Z21),(Ra1,Rb2,X1,Z22),(Ra1,Rb2,X1,Z23),(Ra1,Rb2,X1,Z24),(Ra1,Rb2,X1,Z25),(Ra1,Rb2,X1,Z26),(Ra1,Rb2,X1,Z27),(Ra1,Rb2,X1,Z28),(Ra1,Rb2,X1,Z29),(Ra1,Rb2,X1,Z30),(Ra1,Rb2,X1,Z31),(Ra1,Rb2,X1,Z32),(Ra1,Rb2,X1,Z33),(Ra1,Rb2,X1,Z34),(Ra1,Rb2,X1,Z35),(Ra1,Rb2,X1,Z36),(Ra1,Rb2,X1,Z37),(Ra1,Rb2,X1,Z38),(Ra1,Rb2,X1,Z39),(Ra1,Rb2,X2,Z1),(Ra1,Rb2,X2,Z2),(Ra1,Rb2,X2,Z3),(Ra1,Rb2,X2,Z4),(Ra1,Rb2,X2,Z5),(Ra1,Rb2,X2,Z6),(Ra1,Rb2,X2,Z7),(Ra1,Rb2,X2,Z8),(Ra1,Rb2,X2,Z9),(Ra1,Rb2,X2,Z10),(Ra1,Rb2,X2,Z11),(Ra1,Rb2,X2,Z12),(Ra1,Rb2,X2,Z13),(Ra1,Rb2,X2,Z14),(Ra1,Rb2,X2,Z15),(Ra1,Rb2,X2,Z16),(Ra1,Rb2,X2,Z17),(Ra1,Rb2,X2,Z18),(Ra1,Rb2,X2,Z19),(Ra1,Rb2,X2,Z20),(Ra1,Rb2,X2,Z21),(Ra1,Rb2,X2,Z22),(Ra1,Rb2,X2,Z23),(Ra1,Rb2,X2,Z24),(Ra1,Rb2,X2,Z25),(Ra1,Rb2,X2,Z26),(Ra1,Rb2,X2,Z27),(Ra1,Rb2,X2,Z28),(Ra1,Rb2,X2,Z29),(Ra1,Rb2,X2,Z30),(Ra1,Rb2,X2,Z31),(Ra1,Rb2,X2,Z32),(Ra1,Rb2,X2,Z33),(Ra1,Rb2,X2,Z34),(Ra1,Rb2,X2,Z35),(Ra1,Rb2,X2,Z36),(Ra1,Rb2,X2,Z37),(Ra1,Rb2,X2,Z38),(Ra1,Rb2,X2,Z39),(Ra1,Rb3,X1,Z1),(Ra1,Rb3,X1,Z2),(Ra1,Rb3,X1,Z3),(Ra1,Rb3,X1,Z4),(Ra1,Rb3,X1,Z5),(Ra1,Rb3,X1,Z6),(Ra1,Rb3,X1,Z7),(Ra1,Rb3,X1,Z8),(Ra1,Rb3,X1,Z9),(Ra1,Rb3,X1,Z10),(Ra1,Rb3,X1,Z11),(Ra1,Rb3,X1,Z12),(Ra1,Rb3,X1,Z13),(Ra1,Rb3,X1,Z14),(Ra1,Rb3,X1,Z15),(Ra1,Rb3,X1,Z16),(Ra1,Rb3,X1,Z17),(Ra1,Rb3,X1,Z18),(Ra1,Rb3,X1,Z19),(Ra1,Rb3,X1,Z20),(Ra1,Rb3,X1,Z21),(Ra1,Rb3,X1,Z22),(Ra1,Rb3,X1,Z23),(Ra1,Rb3,X1,Z24),(Ra1,Rb3,X1,Z25),(Ra1,Rb3,X1,Z26),(Ra1,Rb3,X1,Z27),(Ra1,Rb3,X1,Z28),(Ra1,Rb3,X1,Z29),(Ra1,Rb3,X1,Z30),(Ra1,Rb3,X1,Z31),(Ra1,Rb3,X1,Z32),(Ra1,Rb3,X1,Z33),(Ra1,Rb3,X1,Z34),(Ra1,Rb3,X1,Z35),(Ra1,Rb3,X1,Z36),(Ra1,Rb3,X1,Z37),(Ra1,Rb3,X1,Z38),(Ra1,Rb3,X1,Z39),(Ra1,Rb3,X2,Z1),(Ra1,Rb3,X2,Z2),(Ra1,Rb3,X2,Z3),(Ra1,Rb3,X2,Z4),(Ra1,Rb3,X2,Z5),(Ra1,Rb3,X2,Z6),(Ra1,Rb3,X2,Z7),(Ra1,Rb3,X2,Z8),(Ra1,Rb3,X2,Z9),(Ra1,Rb3,X2,Z10),(Ra1,Rb3,X2,Z11),(Ra1,Rb3,X2,Z12),(Ra1,Rb3,X2,Z13),(Ra1,Rb3,X2,Z14),(Ra1,Rb3,X2,Z15),(Ra1,Rb3,X2,Z16),(Ra1,Rb3,X2,Z17),(Ra1,Rb3,X2,Z18),(Ra1,Rb3,X2,Z19),(Ra1,Rb3,X2,Z20),(Ra1,Rb3,X2,Z21),(Ra1,Rb3,X2,Z22),(Ra1,Rb3,X2,Z23),(Ra1,Rb3,X2,Z24),(Ra1,Rb3,X2,Z25),(Ra1,Rb3,X2,Z26),(Ra1,Rb3,X2,Z27),(Ra1,Rb3,X2,Z28),(Ra1,Rb3,X2,Z29),(Ra1,Rb3,X2,Z30),(Ra1,Rb3,X2,Z31),(Ra1,Rb3,X2,Z32),(Ra1,Rb3,X2,Z33),(Ra1,Rb3,X2,Z34),(Ra1,Rb3,X2,Z35),(Ra1,Rb3,X2,Z36),(Ra1,Rb3,X2,Z37),(Ra1,Rb3,X2,Z38),(Ra1,Rb3,X2,Z39),(Ra1,Rb4,X1,Z1),(Ra1,Rb4,X1,Z2),(Ra1,Rb4,X1,Z3),(Ra1,Rb4,X1,Z4),(Ra1,Rb4,X1,Z5),(Ra1,Rb4,X1,Z6),(Ra1,Rb4,X1,Z7),(Ra1,Rb4,X1,Z8),(Ra1,Rb4,X1,Z9),(Ra1,Rb4,X1,Z10),(Ra1,Rb4,X1,Z11),(Ra1,Rb4,X1,Z12),(Ra1,Rb4,X1,Z13),(Ra1,Rb4,X1,Z14),(Ra1,Rb4,X1,Z15),(Ra1,Rb4,X1,Z16),(Ra1,Rb4,X1,Z17),(Ra1,Rb4,X1,Z18),(Ra1,Rb4,X1,Z19),(Ra1,Rb4,X1,Z20),(Ra1,Rb4,X1,Z21),(Ra1,Rb4,X1,Z22),(Ra1,Rb4,X1,Z23),(Ra1,Rb4,X1,Z24),(Ra1,Rb4,X1,Z25),(Ra1,Rb4,X1,Z26),(Ra1,Rb4,X1,Z27),(Ra1,Rb4,X1,Z28),(Ra1,Rb4,X1,Z29),(Ra1,Rb4,X1,Z30),(Ra1,Rb4,X1,Z31),(Ra1,Rb4,X1,Z32),(Ra1,Rb4,X1,Z33),(Ra1,Rb4,X1,Z34),(Ra1,Rb4,X1,Z35),(Ra1,Rb4,X1,Z36),(Ra1,Rb4,X1,Z37),(Ra1,Rb4,X1,Z38),(Ra1,Rb4,X1,Z39),(Ra1,Rb4,X2,Z1),(Ra1,Rb4,X2,Z2),(Ra1,Rb4,X2,Z3),(Ra1,Rb4,X2,Z4),(Ra1,Rb4,X2,Z5),(Ra1,Rb4,X2,Z6),(Ra1,Rb4,X2,Z7),(Ra1,Rb4,X2,Z8),(Ra1,Rb4,X2,Z9),(Ra1,Rb4,X2,Z10),(Ra1,Rb4,X2,Z11),(Ra1,Rb4,X2,Z12),(Ra1,Rb4,X2,Z13),(Ra1,Rb4,X2,Z14),(Ra1,Rb4,X2,Z15),(Ra1,Rb4,X2,Z16),(Ra1,Rb4,X2,Z17),(Ra1,Rb4,X2,Z18),(Ra1,Rb4,X2,Z19),(Ra1,Rb4,X2,Z20),(Ra1,Rb4,X2,Z21),(Ra1,Rb4,X2,Z22),(Ra1,Rb4,X2,Z23),(Ra1,Rb4,X2,Z24),(Ra1,Rb4,X2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38),(Ra15,Rb7,X1,Z39),(Ra15,Rb7,X2,Z1),(Ra15,Rb7,X2,Z2),(Ra15,Rb7,X2,Z3),(Ra15,Rb7,X2,Z4),(Ra15,Rb7,X2,Z5),(Ra15,Rb7,X2,Z6),(Ra15,Rb7,X2,Z7),(Ra15,Rb7,X2,Z8),(Ra15,Rb7,X2,Z9),(Ra15,Rb7,X2,Z10),(Ra15,Rb7,X2,Z11),(Ra15,Rb7,X2,Z12),(Ra15,Rb7,X2,Z13),(Ra15,Rb7,X2,Z14),(Ra15,Rb7,X2,Z15),(Ra15,Rb7,X2,Z16),(Ra15,Rb7,X2,Z17),(Ra15,Rb7,X2,Z18),(Ra15,Rb7,X2,Z19),(Ra15,Rb7,X2,Z20),(Ra15,Rb7,X2,Z21),(Ra15,Rb7,X2,Z22),(Ra15,Rb7,X2,Z23),(Ra15,Rb7,X2,Z24),(Ra15,Rb7,X2,Z25),(Ra15,Rb7,X2,Z26),(Ra15,Rb7,X2,Z27),(Ra15,Rb7,X2,Z28),(Ra15,Rb7,X2,Z29),(Ra15,Rb7,X2,Z30),(Ra15,Rb7,X2,Z31),(Ra15,Rb7,X2,Z32),(Ra15,Rb7,X2,Z33),(Ra15,Rb7,X2,Z34),(Ra15,Rb7,X2,Z35),(Ra15,Rb7,X2,Z36),(Ra15,Rb7,X2,Z37),(Ra15,Rb7,X2,Z38),(Ra15,Rb7,X2,Z39),(Ra15,Rb8,X1,Z1),(Ra15,Rb8,X1,Z2),(Ra15,Rb8,X1,Z3),(Ra15,Rb8,X1,Z4),(Ra15,Rb8,X1,Z5),(Ra15,Rb8,X1,Z6),(Ra15,Rb8,X1,Z7),(Ra15,Rb8,X1,Z8),(Ra15,Rb8,X1,Z9),(Ra15,Rb8,X1,Z10),(Ra15,Rb8,X1,Z11),(Ra15,Rb8,X1,Z12),(Ra15,Rb8,X1,Z13),(Ra15,Rb8,X1,Z14),(Ra15,Rb8,X1,Z15),(Ra15,Rb8,X1,Z16),(Ra15,Rb8,X1,Z17),(Ra15,Rb8,X1,Z18),(Ra15,Rb8,X1,Z19),(Ra15,Rb8,X1,Z20),(Ra15,Rb8,X1,Z21),(Ra15,Rb8,X1,Z22),(Ra15,Rb8,X1,Z23),(Ra15,Rb8,X1,Z24),(Ra15,Rb8,X1,Z25),(Ra15,Rb8,X1,Z26),(Ra15,Rb8,X1,Z27),(Ra15,Rb8,X1,Z28),(Ra15,Rb8,X1,Z29),(Ra15,Rb8,X1,Z30),(Ra15,Rb8,X1,Z31),(Ra15,Rb8,X1,Z32),(Ra15,Rb8,X1,Z33),(Ra15,Rb8,X1,Z34),(Ra15,Rb8,X1,Z35),(Ra15,Rb8,X1,Z36),(Ra15,Rb8,X1,Z37),(Ra15,Rb8,X1,Z38),(Ra15,Rb8,X1,Z39),(Ra15,Rb8,X2,Z1),(Ra15,Rb8,X2,Z2),(Ra15,Rb8,X2,Z3),(Ra15,Rb8,X2,Z4),(Ra15,Rb8,X2,Z5),(Ra15,Rb8,X2,Z6),(Ra15,Rb8,X2,Z7),(Ra15,Rb8,X2,Z8),(Ra15,Rb8,X2,Z9),(Ra15,Rb8,X2,Z10),(Ra15,Rb8,X2,Z11),(Ra15,Rb8,X2,Z12),(Ra15,Rb8,X2,Z13),(Ra15,Rb8,X2,Z14),(Ra15,Rb8,X2,Z15),(Ra15,Rb8,X2,Z16),(Ra15,Rb8,X2,Z17),(Ra15,Rb8,X2,Z18),(Ra15,Rb8,X2,Z19),(Ra15,Rb8,X2,Z20),(Ra15,Rb8,X2,Z21),(Ra15,Rb8,X2,Z22),(Ra15,Rb8,X2,Z23),(Ra15,Rb8,X2,Z24),(Ra15,Rb8,X2,Z25),(Ra15,Rb8,X2,Z26),(Ra15,Rb8,X2,Z27),(Ra15,Rb8,X2,Z28),(Ra15,Rb8,X2,Z29),(Ra15,Rb8,X2,Z30),(Ra15,Rb8,X2,Z31),(Ra15,Rb8,X2,Z32),(Ra15,Rb8,X2,Z33),(Ra15,Rb8,X2,Z34),(Ra15,Rb8,X2,Z35),(Ra15,Rb8,X2,Z36),(Ra15,Rb8,X2,Z37),(Ra15,Rb8,X2,Z38),および(Ra15,Rb8,X2,Z39)
(Ra,Rb,X,Z)=(Ra1,Rb1,X1,Z1),(Ra1,Rb1,X1,Z2),(Ra1,Rb1,X1,Z3),(Ra1,Rb1,X1,Z4),(Ra1,Rb1,X1,Z5),(Ra1,Rb1,X1,Z6),(Ra1,Rb1,X1,Z7),(Ra1,Rb1,X1,Z8),(Ra1,Rb1,X1,Z9),(Ra1,Rb1,X1,Z10),(Ra1,Rb1,X1,Z11),(Ra1,Rb1,X1,Z12),(Ra1,Rb1,X1,Z13),(Ra1,Rb1,X1,Z14),(Ra1,Rb1,X1,Z15),(Ra1,Rb1,X1,Z16),(Ra1,Rb1,X1,Z17),(Ra1,Rb1,X1,Z18),(Ra1,Rb1,X1,Z19),(Ra1,Rb1,X1,Z20),(Ra1,Rb1,X1,Z21),(Ra1,Rb1,X1,Z22),(Ra1,Rb1,X1,Z23),(Ra1,Rb1,X1,Z24),(Ra1,Rb1,X1,Z25),(Ra1,Rb1,X1,Z26),(Ra1,Rb1,X1,Z27),(Ra1,Rb1,X1,Z28),(Ra1,Rb1,X1,Z29),(Ra1,Rb1,X1,Z30),(Ra1,Rb1,X1,Z31),(Ra1,Rb1,X1,Z32),(Ra1,Rb1,X1,Z33),(Ra1,Rb1,X1,Z34),(Ra1,Rb1,X1,Z35),(Ra1,Rb1,X1,Z36),(Ra1,Rb1,X1,Z37),(Ra1,Rb1,X1,Z38),(Ra1,Rb1,X1,Z39),(Ra1,Rb1,X2,Z1),(Ra1,Rb1,X2,Z2),(Ra1,Rb1,X2,Z3),(Ra1,Rb1,X2,Z4),(Ra1,Rb1,X2,Z5),(Ra1,Rb1,X2,Z6),(Ra1,Rb1,X2,Z7),(Ra1,Rb1,X2,Z8),(Ra1,Rb1,X2,Z9),(Ra1,Rb1,X2,Z10),(Ra1,Rb1,X2,Z11),(Ra1,Rb1,X2,Z12),(Ra1,Rb1,X2,Z13),(Ra1,Rb1,X2,Z14),(Ra1,Rb1,X2,Z15),(Ra1,Rb1,X2,Z16),(Ra1,Rb1,X2,Z17),(Ra1,Rb1,X2,Z18),(Ra1,Rb1,X2,Z19),(Ra1,Rb1,X2,Z20),(Ra1,Rb1,X2,Z21),(Ra1,Rb1,X2,Z22),(Ra1,Rb1,X2,Z23),(Ra1,Rb1,X2,Z24),(Ra1,Rb1,X2,Z25),(Ra1,Rb1,X2,Z26),(Ra1,Rb1,X2,Z27),(Ra1,Rb1,X2,Z28),(Ra1,Rb1,X2,Z29),(Ra1,Rb1,X2,Z30),(Ra1,Rb1,X2,Z31),(Ra1,Rb1,X2,Z32),(Ra1,Rb1,X2,Z33),(Ra1,Rb1,X2,Z34),(Ra1,Rb1,X2,Z35),(Ra1,Rb1,X2,Z36),(Ra1,Rb1,X2,Z37),(Ra1,Rb1,X2,Z38),(Ra1,Rb1,X2,Z39),(Ra1,Rb2,X1,Z1),(Ra1,Rb2,X1,Z2),(Ra1,Rb2,X1,Z3),(Ra1,Rb2,X1,Z4),(Ra1,Rb2,X1,Z5),(Ra1,Rb2,X1,Z6),(Ra1,Rb2,X1,Z7),(Ra1,Rb2,X1,Z8),(Ra1,Rb2,X1,Z9),(Ra1,Rb2,X1,Z10),(Ra1,Rb2,X1,Z11),(Ra1,Rb2,X1,Z12),(Ra1,Rb2,X1,Z13),(Ra1,Rb2,X1,Z14),(Ra1,Rb2,X1,Z15),(Ra1,Rb2,X1,Z16),(Ra1,Rb2,X1,Z17),(Ra1,Rb2,X1,Z18),(Ra1,Rb2,X1,Z19),(Ra1,Rb2,X1,Z20),(Ra1,Rb2,X1,Z21),(Ra1,Rb2,X1,Z22),(Ra1,Rb2,X1,Z23),(Ra1,Rb2,X1,Z24),(Ra1,Rb2,X1,Z25),(Ra1,Rb2,X1,Z26),(Ra1,Rb2,X1,Z27),(Ra1,Rb2,X1,Z28),(Ra1,Rb2,X1,Z29),(Ra1,Rb2,X1,Z30),(Ra1,Rb2,X1,Z31),(Ra1,Rb2,X1,Z32),(Ra1,Rb2,X1,Z33),(Ra1,Rb2,X1,Z34),(Ra1,Rb2,X1,Z35),(Ra1,Rb2,X1,Z36),(Ra1,Rb2,X1,Z37),(Ra1,Rb2,X1,Z38),(Ra1,Rb2,X1,Z39),(Ra1,Rb2,X2,Z1),(Ra1,Rb2,X2,Z2),(Ra1,Rb2,X2,Z3),(Ra1,Rb2,X2,Z4),(Ra1,Rb2,X2,Z5),(Ra1,Rb2,X2,Z6),(Ra1,Rb2,X2,Z7),(Ra1,Rb2,X2,Z8),(Ra1,Rb2,X2,Z9),(Ra1,Rb2,X2,Z10),(Ra1,Rb2,X2,Z11),(Ra1,Rb2,X2,Z12),(Ra1,Rb2,X2,Z13),(Ra1,Rb2,X2,Z14),(Ra1,Rb2,X2,Z15),(Ra1,Rb2,X2,Z16),(Ra1,Rb2,X2,Z17),(Ra1,Rb2,X2,Z18),(Ra1,Rb2,X2,Z19),(Ra1,Rb2,X2,Z20),(Ra1,Rb2,X2,Z21),(Ra1,Rb2,X2,Z22),(Ra1,Rb2,X2,Z23),(Ra1,Rb2,X2,Z24),(Ra1,Rb2,X2,Z25),(Ra1,Rb2,X2,Z26),(Ra1,Rb2,X2,Z27),(Ra1,Rb2,X2,Z28),(Ra1,Rb2,X2,Z29),(Ra1,Rb2,X2,Z30),(Ra1,Rb2,X2,Z31),(Ra1,Rb2,X2,Z32),(Ra1,Rb2,X2,Z33),(Ra1,Rb2,X2,Z34),(Ra1,Rb2,X2,Z35),(Ra1,Rb2,X2,Z36),(Ra1,Rb2,X2,Z37),(Ra1,Rb2,X2,Z38),(Ra1,Rb2,X2,Z39),(Ra1,Rb3,X1,Z1),(Ra1,Rb3,X1,Z2),(Ra1,Rb3,X1,Z3),(Ra1,Rb3,X1,Z4),(Ra1,Rb3,X1,Z5),(Ra1,Rb3,X1,Z6),(Ra1,Rb3,X1,Z7),(Ra1,Rb3,X1,Z8),(Ra1,Rb3,X1,Z9),(Ra1,Rb3,X1,Z10),(Ra1,Rb3,X1,Z11),(Ra1,Rb3,X1,Z12),(Ra1,Rb3,X1,Z13),(Ra1,Rb3,X1,Z14),(Ra1,Rb3,X1,Z15),(Ra1,Rb3,X1,Z16),(Ra1,Rb3,X1,Z17),(Ra1,Rb3,X1,Z18),(Ra1,Rb3,X1,Z19),(Ra1,Rb3,X1,Z20),(Ra1,Rb3,X1,Z21),(Ra1,Rb3,X1,Z22),(Ra1,Rb3,X1,Z23),(Ra1,Rb3,X1,Z24),(Ra1,Rb3,X1,Z25),(Ra1,Rb3,X1,Z26),(Ra1,Rb3,X1,Z27),(Ra1,Rb3,X1,Z28),(Ra1,Rb3,X1,Z29),(Ra1,Rb3,X1,Z30),(Ra1,Rb3,X1,Z31),(Ra1,Rb3,X1,Z32),(Ra1,Rb3,X1,Z33),(Ra1,Rb3,X1,Z34),(Ra1,Rb3,X1,Z35),(Ra1,Rb3,X1,Z36),(Ra1,Rb3,X1,Z37),(Ra1,Rb3,X1,Z38),(Ra1,Rb3,X1,Z39),(Ra1,Rb3,X2,Z1),(Ra1,Rb3,X2,Z2),(Ra1,Rb3,X2,Z3),(Ra1,Rb3,X2,Z4),(Ra1,Rb3,X2,Z5),(Ra1,Rb3,X2,Z6),(Ra1,Rb3,X2,Z7),(Ra1,Rb3,X2,Z8),(Ra1,Rb3,X2,Z9),(Ra1,Rb3,X2,Z10),(Ra1,Rb3,X2,Z11),(Ra1,Rb3,X2,Z12),(Ra1,Rb3,X2,Z13),(Ra1,Rb3,X2,Z14),(Ra1,Rb3,X2,Z15),(Ra1,Rb3,X2,Z16),(Ra1,Rb3,X2,Z17),(Ra1,Rb3,X2,Z18),(Ra1,Rb3,X2,Z19),(Ra1,Rb3,X2,Z20),(Ra1,Rb3,X2,Z21),(Ra1,Rb3,X2,Z22),(Ra1,Rb3,X2,Z23),(Ra1,Rb3,X2,Z24),(Ra1,Rb3,X2,Z25),(Ra1,Rb3,X2,Z26),(Ra1,Rb3,X2,Z27),(Ra1,Rb3,X2,Z28),(Ra1,Rb3,X2,Z29),(Ra1,Rb3,X2,Z30),(Ra1,Rb3,X2,Z31),(Ra1,Rb3,X2,Z32),(Ra1,Rb3,X2,Z33),(Ra1,Rb3,X2,Z34),(Ra1,Rb3,X2,Z35),(Ra1,Rb3,X2,Z36),(Ra1,Rb3,X2,Z37),(Ra1,Rb3,X2,Z38),(Ra1,Rb3,X2,Z39),(Ra1,Rb4,X1,Z1),(Ra1,Rb4,X1,Z2),(Ra1,Rb4,X1,Z3),(Ra1,Rb4,X1,Z4),(Ra1,Rb4,X1,Z5),(Ra1,Rb4,X1,Z6),(Ra1,Rb4,X1,Z7),(Ra1,Rb4,X1,Z8),(Ra1,Rb4,X1,Z9),(Ra1,Rb4,X1,Z10),(Ra1,Rb4,X1,Z11),(Ra1,Rb4,X1,Z12),(Ra1,Rb4,X1,Z13),(Ra1,Rb4,X1,Z14),(Ra1,Rb4,X1,Z15),(Ra1,Rb4,X1,Z16),(Ra1,Rb4,X1,Z17),(Ra1,Rb4,X1,Z18),(Ra1,Rb4,X1,Z19),(Ra1,Rb4,X1,Z20),(Ra1,Rb4,X1,Z21),(Ra1,Rb4,X1,Z22),(Ra1,Rb4,X1,Z23),(Ra1,Rb4,X1,Z24),(Ra1,Rb4,X1,Z25),(Ra1,Rb4,X1,Z26),(Ra1,Rb4,X1,Z27),(Ra1,Rb4,X1,Z28),(Ra1,Rb4,X1,Z29),(Ra1,Rb4,X1,Z30),(Ra1,Rb4,X1,Z31),(Ra1,Rb4,X1,Z32),(Ra1,Rb4,X1,Z33),(Ra1,Rb4,X1,Z34),(Ra1,Rb4,X1,Z35),(Ra1,Rb4,X1,Z36),(Ra1,Rb4,X1,Z37),(Ra1,Rb4,X1,Z38),(Ra1,Rb4,X1,Z39),(Ra1,Rb4,X2,Z1),(Ra1,Rb4,X2,Z2),(Ra1,Rb4,X2,Z3),(Ra1,Rb4,X2,Z4),(Ra1,Rb4,X2,Z5),(Ra1,Rb4,X2,Z6),(Ra1,Rb4,X2,Z7),(Ra1,Rb4,X2,Z8),(Ra1,Rb4,X2,Z9),(Ra1,Rb4,X2,Z10),(Ra1,Rb4,X2,Z11),(Ra1,Rb4,X2,Z12),(Ra1,Rb4,X2,Z13),(Ra1,Rb4,X2,Z14),(Ra1,Rb4,X2,Z15),(Ra1,Rb4,X2,Z16),(Ra1,Rb4,X2,Z17),(Ra1,Rb4,X2,Z18),(Ra1,Rb4,X2,Z19),(Ra1,Rb4,X2,Z20),(Ra1,Rb4,X2,Z21),(Ra1,Rb4,X2,Z22),(Ra1,Rb4,X2,Z23),(Ra1,Rb4,X2,Z24),(Ra1,Rb4,X2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38),(Ra15,Rb7,X1,Z39),(Ra15,Rb7,X2,Z1),(Ra15,Rb7,X2,Z2),(Ra15,Rb7,X2,Z3),(Ra15,Rb7,X2,Z4),(Ra15,Rb7,X2,Z5),(Ra15,Rb7,X2,Z6),(Ra15,Rb7,X2,Z7),(Ra15,Rb7,X2,Z8),(Ra15,Rb7,X2,Z9),(Ra15,Rb7,X2,Z10),(Ra15,Rb7,X2,Z11),(Ra15,Rb7,X2,Z12),(Ra15,Rb7,X2,Z13),(Ra15,Rb7,X2,Z14),(Ra15,Rb7,X2,Z15),(Ra15,Rb7,X2,Z16),(Ra15,Rb7,X2,Z17),(Ra15,Rb7,X2,Z18),(Ra15,Rb7,X2,Z19),(Ra15,Rb7,X2,Z20),(Ra15,Rb7,X2,Z21),(Ra15,Rb7,X2,Z22),(Ra15,Rb7,X2,Z23),(Ra15,Rb7,X2,Z24),(Ra15,Rb7,X2,Z25),(Ra15,Rb7,X2,Z26),(Ra15,Rb7,X2,Z27),(Ra15,Rb7,X2,Z28),(Ra15,Rb7,X2,Z29),(Ra15,Rb7,X2,Z30),(Ra15,Rb7,X2,Z31),(Ra15,Rb7,X2,Z32),(Ra15,Rb7,X2,Z33),(Ra15,Rb7,X2,Z34),(Ra15,Rb7,X2,Z35),(Ra15,Rb7,X2,Z36),(Ra15,Rb7,X2,Z37),(Ra15,Rb7,X2,Z38),(Ra15,Rb7,X2,Z39),(Ra15,Rb8,X1,Z1),(Ra15,Rb8,X1,Z2),(Ra15,Rb8,X1,Z3),(Ra15,Rb8,X1,Z4),(Ra15,Rb8,X1,Z5),(Ra15,Rb8,X1,Z6),(Ra15,Rb8,X1,Z7),(Ra15,Rb8,X1,Z8),(Ra15,Rb8,X1,Z9),(Ra15,Rb8,X1,Z10),(Ra15,Rb8,X1,Z11),(Ra15,Rb8,X1,Z12),(Ra15,Rb8,X1,Z13),(Ra15,Rb8,X1,Z14),(Ra15,Rb8,X1,Z15),(Ra15,Rb8,X1,Z16),(Ra15,Rb8,X1,Z17),(Ra15,Rb8,X1,Z18),(Ra15,Rb8,X1,Z19),(Ra15,Rb8,X1,Z20),(Ra15,Rb8,X1,Z21),(Ra15,Rb8,X1,Z22),(Ra15,Rb8,X1,Z23),(Ra15,Rb8,X1,Z24),(Ra15,Rb8,X1,Z25),(Ra15,Rb8,X1,Z26),(Ra15,Rb8,X1,Z27),(Ra15,Rb8,X1,Z28),(Ra15,Rb8,X1,Z29),(Ra15,Rb8,X1,Z30),(Ra15,Rb8,X1,Z31),(Ra15,Rb8,X1,Z32),(Ra15,Rb8,X1,Z33),(Ra15,Rb8,X1,Z34),(Ra15,Rb8,X1,Z35),(Ra15,Rb8,X1,Z36),(Ra15,Rb8,X1,Z37),(Ra15,Rb8,X1,Z38),(Ra15,Rb8,X1,Z39),(Ra15,Rb8,X2,Z1),(Ra15,Rb8,X2,Z2),(Ra15,Rb8,X2,Z3),(Ra15,Rb8,X2,Z4),(Ra15,Rb8,X2,Z5),(Ra15,Rb8,X2,Z6),(Ra15,Rb8,X2,Z7),(Ra15,Rb8,X2,Z8),(Ra15,Rb8,X2,Z9),(Ra15,Rb8,X2,Z10),(Ra15,Rb8,X2,Z11),(Ra15,Rb8,X2,Z12),(Ra15,Rb8,X2,Z13),(Ra15,Rb8,X2,Z14),(Ra15,Rb8,X2,Z15),(Ra15,Rb8,X2,Z16),(Ra15,Rb8,X2,Z17),(Ra15,Rb8,X2,Z18),(Ra15,Rb8,X2,Z19),(Ra15,Rb8,X2,Z20),(Ra15,Rb8,X2,Z21),(Ra15,Rb8,X2,Z22),(Ra15,Rb8,X2,Z23),(Ra15,Rb8,X2,Z24),(Ra15,Rb8,X2,Z25),(Ra15,Rb8,X2,Z26),(Ra15,Rb8,X2,Z27),(Ra15,Rb8,X2,Z28),(Ra15,Rb8,X2,Z29),(Ra15,Rb8,X2,Z30),(Ra15,Rb8,X2,Z31),(Ra15,Rb8,X2,Z32),(Ra15,Rb8,X2,Z33),(Ra15,Rb8,X2,Z34),(Ra15,Rb8,X2,Z35),(Ra15,Rb8,X2,Z36),(Ra15,Rb8,X2,Z37),(Ra15,Rb8,X2,Z38),および(Ra15,Rb8,X2,Z39)
以下に実施例を示し、本発明を具体的に説明するが、本発明はこれらに限定されるものではない。なお、各略号は以下に示す意味を有する。
Ｍｅ：メチル
Ｅｔ：エチル
Ｂｕ：ブチル
Ａｃ：アセチル
ＴＭＳ：テトラメチルシラン
ＴＭＳ-Ｃｌ：トリメチルシリルクロライド
ＤＭＳＯ：ジメチルスルホキシド
ＤＭＦ：ジメチルホルムアミド
ＴＨＦ：テトラヒドロフラン
ｒｔ：室温
Ｍｅ：メチル
Ｅｔ：エチル
Ｂｕ：ブチル
Ａｃ：アセチル
ＴＭＳ：テトラメチルシラン
ＴＭＳ-Ｃｌ：トリメチルシリルクロライド
ＤＭＳＯ：ジメチルスルホキシド
ＤＭＦ：ジメチルホルムアミド
ＴＨＦ：テトラヒドロフラン
ｒｔ：室温
実施例１
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オンの製造
エチル トリメチルアセトピルベート(0.40 g, 2 mmol)，4-チオフェン-3-イルアニリン(0.35 g, 2 mmol)、2-(メトキシカルボニルメチルオキシ)ベンズアルデヒド(0.39, 2 mmol)、酢酸 (0.057 mL, 1 mmol)およびジオキサン(4 mL)の混合液を加熱還流下で一夜攪拌した。反応後、飽和炭酸水素ナトリウム水と飽和食塩水を反応液に加え、酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製し、得られた目的物を酢酸エチルとジイソプロピルエーテルで粉末化させ、4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.42 g, 収率: 41％）を淡褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.10 (9H, s), 3.78 (3H, s), 4.50-4.90 (2H, m), 6.00-6.45 (1H, m), 6.60-7.11 (11H, m).
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オンの製造
エチル トリメチルアセトピルベート(0.40 g, 2 mmol)，4-チオフェン-3-イルアニリン(0.35 g, 2 mmol)、2-(メトキシカルボニルメチルオキシ)ベンズアルデヒド(0.39, 2 mmol)、酢酸 (0.057 mL, 1 mmol)およびジオキサン(4 mL)の混合液を加熱還流下で一夜攪拌した。反応後、飽和炭酸水素ナトリウム水と飽和食塩水を反応液に加え、酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製し、得られた目的物を酢酸エチルとジイソプロピルエーテルで粉末化させ、4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.42 g, 収率: 41％）を淡褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.10 (9H, s), 3.78 (3H, s), 4.50-4.90 (2H, m), 6.00-6.45 (1H, m), 6.60-7.11 (11H, m).
実施例２
5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.172 g, 0.34 mmol)、ＴＨＦ(1.72 mL)およびメタノール(1.72 mL)の混合液に、1mol/L 水酸化リチウム水溶液(1.02 mL)を加え、室温で1時間攪拌した。反応後、2mol/L 塩酸(0.52 mL)と水(14 mL)を反応液に加え、析出した目的物をろ取した。得られた目的物を酢酸エチルに溶解させ、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.137 g, 収率: 82％）を淡橙色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.10 (9H, s), 4.85 (2H, s), 6.46 (1H, brs), 6.76-7.75 (11H, m).
5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.172 g, 0.34 mmol)、ＴＨＦ(1.72 mL)およびメタノール(1.72 mL)の混合液に、1mol/L 水酸化リチウム水溶液(1.02 mL)を加え、室温で1時間攪拌した。反応後、2mol/L 塩酸(0.52 mL)と水(14 mL)を反応液に加え、析出した目的物をろ取した。得られた目的物を酢酸エチルに溶解させ、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.137 g, 収率: 82％）を淡橙色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.10 (9H, s), 4.85 (2H, s), 6.46 (1H, brs), 6.76-7.75 (11H, m).
実施例３
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.207 g, 0.41 mmol)、ヒドラジン1水和物(0.022 mL, 0.45 mmol)および酢酸(3.1 mL)の混合液を、95℃で1時間攪拌した。反応後、飽和炭酸水素ナトリウム水を反応液に加え、クロロホルムで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.191 g, 収率: 93％）を淡褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.05 (9H, s), 3.78 (3H, s), 4.94 (2H, s), 6.70-7.77 (12H, m), 13.4 (1H, brs).
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシカルボニルメチルオキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.207 g, 0.41 mmol)、ヒドラジン1水和物(0.022 mL, 0.45 mmol)および酢酸(3.1 mL)の混合液を、95℃で1時間攪拌した。反応後、飽和炭酸水素ナトリウム水を反応液に加え、クロロホルムで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.191 g, 収率: 93％）を淡褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.05 (9H, s), 3.78 (3H, s), 4.94 (2H, s), 6.70-7.77 (12H, m), 13.4 (1H, brs).
実施例４
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-ヒドロキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.124 g, 0.25 mmol)、ＴＨＦ(1.24 mL)およびメタノール(1.24 mL)の混合液に、1mol/L 水酸化リチウム水溶液(0.74 mL)を加え、室温で1.5時間攪拌した。反応後、2mol/L 塩酸(0.38 mL)と水(10 mL)を反応液に加え、析出した目的物をろ取した。得られた目的物を酢酸エチルに溶解させ、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.104 g, 収率: 87％）を微褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.05 (9H, s), 4.78 (2H, s), 6.70-7.80 (12H, m), 13.33 (1H, brs).
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-ヒドロキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-t-ブチル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシカルボニルメチルオキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.124 g, 0.25 mmol)、ＴＨＦ(1.24 mL)およびメタノール(1.24 mL)の混合液に、1mol/L 水酸化リチウム水溶液(0.74 mL)を加え、室温で1.5時間攪拌した。反応後、2mol/L 塩酸(0.38 mL)と水(10 mL)を反応液に加え、析出した目的物をろ取した。得られた目的物を酢酸エチルに溶解させ、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をエチルエーテルとジイソプロピルエーテルで粉末化させ、5-(2-ヒドロキシカルボニルメチルオキシフェニル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.104 g, 収率: 87％）を微褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.05 (9H, s), 4.78 (2H, s), 6.70-7.80 (12H, m), 13.33 (1H, brs).
実施例５
1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オンの製造
1-(6-ブロモ-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.10 g, 0.22 mmol)、フラン-3-イルボロン酸(0.038 g, 0.34 mmol)、リン酸三カリウム(0.14 mg, 0.67 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.018 g, 0.022 mmol)を加え、加熱還流下で４時間攪拌した。反応後、飽和塩化アンモニウム水溶液を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.045 g, 収率: 46％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (9H, s), 3.79 (3H, brs), 6.24 (1H, brs), 6.86 (1H, m), 6.96 (1H, m), 7.64-7.95 (4H, m), 8.23 (1H, s), 8.71 (1H, s), 12.31 (1H, brs).
1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オンの製造
1-(6-ブロモ-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.10 g, 0.22 mmol)、フラン-3-イルボロン酸(0.038 g, 0.34 mmol)、リン酸三カリウム(0.14 mg, 0.67 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.018 g, 0.022 mmol)を加え、加熱還流下で４時間攪拌した。反応後、飽和塩化アンモニウム水溶液を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.045 g, 収率: 46％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (9H, s), 3.79 (3H, brs), 6.24 (1H, brs), 6.86 (1H, m), 6.96 (1H, m), 7.64-7.95 (4H, m), 8.23 (1H, s), 8.71 (1H, s), 12.31 (1H, brs).
実施例６
3-t-ブチル-5-(6-チオフェン-2-イル-3-ピリジル)-4-(2-メトキシ-3-ピリジル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
5-(6-ブロモ-3-ピリジル)-3-t-ブチル-4-(2-メトキシ-3-ピリジル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.10 g, 0.23 mmol)、チオフェン-2-イルボロン酸(0.043 g, 0.34 mmol)、リン酸三カリウム(0.14 mg, 0.67 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.018 g, 0.022 mmol)を加え、加熱還流下で３時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.089 g, 収率: 88％）を無色固体して得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.07 (9H, s), 3.97 (3.55) (3H, s), 6.56-7.28 (4H, m), 7.58 (1H, d, J=5.0), 7.69 (1H, d, J=3.7), 7.87-8.10 (3H, m), 8.64 (1H, s), 13.36 (1H, m).
3-t-ブチル-5-(6-チオフェン-2-イル-3-ピリジル)-4-(2-メトキシ-3-ピリジル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
5-(6-ブロモ-3-ピリジル)-3-t-ブチル-4-(2-メトキシ-3-ピリジル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.10 g, 0.23 mmol)、チオフェン-2-イルボロン酸(0.043 g, 0.34 mmol)、リン酸三カリウム(0.14 mg, 0.67 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.018 g, 0.022 mmol)を加え、加熱還流下で３時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、1-(6-フラン-3-イル-3-ピリジル)-4-(2,2-ジメチルプロピオニル)-3-ヒドロキシ-1-5-(2-メトキシ-3-ピリジル)-1,5-ジヒドロピロール-2-オン(0.089 g, 収率: 88％）を無色固体して得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.07 (9H, s), 3.97 (3.55) (3H, s), 6.56-7.28 (4H, m), 7.58 (1H, d, J=5.0), 7.69 (1H, d, J=3.7), 7.87-8.10 (3H, m), 8.64 (1H, s), 13.36 (1H, m).
実施例７
3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
メチル 5,5-ジメチル-2,4-ジオキソ-6-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサノエート (4.29 g, 15 mmol)、4-ブロモアニリン(2.58 g, 15 mmol)、2-メトキシベンズアルデヒド (1.812 mL, 15 mmol)、酢酸 (0.343 mL, 6 mmol)およびジオキサン (15 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製した。得られた目的物を、酢酸エチルとn-ヘキサンで粉末化させ、1-(4-ブロモフェニル)-4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(2.69 g, 収率: 33％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.08 (3H, s), 1.13 (3H, s), 1.20-1.40 (6H, m), 3.50-3.90 (7H, m), 4.37 (1H, m), 6.31 (1H, brs), 6.70-7.44 (8H, m), 12.23 (1H, brs).
1-(4-ブロモフェニル)-4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(1.51 g, 2.77 mmol)、ヒドラジン水和物(0.204 mL, 4.16 mmol)および酢酸(3 mL)の混合液を、95℃で2時間攪拌した。反応後、飽和炭酸水素ナトリウム水 (150 mL)を反応液に加え、酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を酢酸エチルで粉末化させ、5-(4-ブロモフェニル)-3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(1.02 g, 収率: 81％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.88 (3H, s), 1.00 (3H, s), 3.11 (2H, m), 3.87 (3H, s), 4.73 (1H, brs), 6.30-7.50 (9H, m), 13.21 (1H, m).
5-(4-ブロモフェニル)-3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.15 g, 0.33 mmol)、チオフェン-3-イルボロン酸(0.063.g, 0.49 mmol)、リン酸三カリウム(0.21 mg, 0.99 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を、窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.027 mg, 0.033 mmol)を加え、加熱還流下で5時間攪拌した。反応後、反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製した。得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.038 g, 収率: 25％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.91 (3H, s), 1.04 (3H, s), 3.25 (2H, m), 3.91 (3H, s), 4.74 (1H, s), 6.33-7.78 (9H, m), 13.21 (1H, m)
3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
メチル 5,5-ジメチル-2,4-ジオキソ-6-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサノエート (4.29 g, 15 mmol)、4-ブロモアニリン(2.58 g, 15 mmol)、2-メトキシベンズアルデヒド (1.812 mL, 15 mmol)、酢酸 (0.343 mL, 6 mmol)およびジオキサン (15 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製した。得られた目的物を、酢酸エチルとn-ヘキサンで粉末化させ、1-(4-ブロモフェニル)-4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(2.69 g, 収率: 33％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.08 (3H, s), 1.13 (3H, s), 1.20-1.40 (6H, m), 3.50-3.90 (7H, m), 4.37 (1H, m), 6.31 (1H, brs), 6.70-7.44 (8H, m), 12.23 (1H, brs).
1-(4-ブロモフェニル)-4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(1.51 g, 2.77 mmol)、ヒドラジン水和物(0.204 mL, 4.16 mmol)および酢酸(3 mL)の混合液を、95℃で2時間攪拌した。反応後、飽和炭酸水素ナトリウム水 (150 mL)を反応液に加え、酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を酢酸エチルで粉末化させ、5-(4-ブロモフェニル)-3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(1.02 g, 収率: 81％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.88 (3H, s), 1.00 (3H, s), 3.11 (2H, m), 3.87 (3H, s), 4.73 (1H, brs), 6.30-7.50 (9H, m), 13.21 (1H, m).
5-(4-ブロモフェニル)-3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.15 g, 0.33 mmol)、チオフェン-3-イルボロン酸(0.063.g, 0.49 mmol)、リン酸三カリウム(0.21 mg, 0.99 mmol)、エチレングリコールジメチルエーテル(3 mL)および水(0.6 mL）の混合液を、窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ) ジクロロメタン付加体(0.027 mg, 0.033 mmol)を加え、加熱還流下で5時間攪拌した。反応後、反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製した。得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.038 g, 収率: 25％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.91 (3H, s), 1.04 (3H, s), 3.25 (2H, m), 3.91 (3H, s), 4.74 (1H, s), 6.33-7.78 (9H, m), 13.21 (1H, m)
実施例８
3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシ-3-ピリジル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
メチル 5,5-ジメチル-2,4-ジオキソ-6-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサノエート (0.29 mg, 1.0 mmol)、4-(3-チエニル)アニリン(0.18 g, 1.0 mmol)、2-メトキシニコチンアルデヒド (0.14 g, 1.0 mmol)、酢酸 (0.043 mL, 0.75 mmol)およびジオキサン (2 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製し、4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.30 g, 収率: 55％）を淡黄色固体として得た。
4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.30 g, 0.55 mmol)、メタノール (3 mL)およびクロロホルム(3 mL)の混合液に、p-トルエンスルホン酸水和物(0.158 g, 0.8mmol)を加えて室温で3時間攪拌した。反応後、飽和炭酸水素ナトリウム水と飽和食塩水を反応液に加え、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。
得られた4-(2,2-ジメチル-3-ヒドロキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.233 g）の粗製物に酢酸(2 mL)とヒドラジン水和物(0.074 mL, 1.5 mmol)を加え、50℃で1時間攪拌した。反応後、飽和炭酸水素ナトリウム水を反応液に加え、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を酢酸エチルで粉末化させ、3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシ-3-ピリジル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.061 g, 収率: 26％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.95 (3H, s), 1.06 (3H, s), 3.23 (2H, m), 4.06 (2H, s), 4.78 (1H, brs), 6.43-8.10 (10H, m), 13.40 (1H, m).
3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシ-3-ピリジル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
メチル 5,5-ジメチル-2,4-ジオキソ-6-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキサノエート (0.29 mg, 1.0 mmol)、4-(3-チエニル)アニリン(0.18 g, 1.0 mmol)、2-メトキシニコチンアルデヒド (0.14 g, 1.0 mmol)、酢酸 (0.043 mL, 0.75 mmol)およびジオキサン (2 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製し、4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.30 g, 収率: 55％）を淡黄色固体として得た。
4-(2,2-ジメチル-3-テトラヒドロ-2H-ピラン-2-イルオキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.30 g, 0.55 mmol)、メタノール (3 mL)およびクロロホルム(3 mL)の混合液に、p-トルエンスルホン酸水和物(0.158 g, 0.8mmol)を加えて室温で3時間攪拌した。反応後、飽和炭酸水素ナトリウム水と飽和食塩水を反応液に加え、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。
得られた4-(2,2-ジメチル-3-ヒドロキシプロピオニル)-3-ヒドロキシ-5-(2-メトキシ-3-ピリジル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.233 g）の粗製物に酢酸(2 mL)とヒドラジン水和物(0.074 mL, 1.5 mmol)を加え、50℃で1時間攪拌した。反応後、飽和炭酸水素ナトリウム水を反応液に加え、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を酢酸エチルで粉末化させ、3-(1-ヒドロキシメチル-1-メチルエチル)-4-(2-メトキシ-3-ピリジル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.061 g, 収率: 26％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.95 (3H, s), 1.06 (3H, s), 3.23 (2H, m), 4.06 (2H, s), 4.78 (1H, brs), 6.43-8.10 (10H, m), 13.40 (1H, m).
実施例９
3-(1,1-ジヒドロキシメチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-ヒドロキシ-2-ヒドロキシメチル-2-メチルプロピオン酸(6.71 g, 50mmol)、ジメトキシプロパン(7.99 mL, 65mmol)およびアセトン(50 mL)の混合液に、p-トルエンスルホン酸水和物(0.048 g, 0.25mmol)を加えて室温で2.5時間攪拌した。反応後、炭酸水素ナトリウム(0.1 g)を反応液に加え、室温で5分間攪拌後、減圧濃縮して得られた残渣に水を加え、エチルエーテルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮し、2,2,5-トリメチル-1,3-ジオキサン-5-カルボン酸(7.87 g, 収率: 90％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.20 (3H, s), 1.43 (3H, s), 1.46 (3H, s), 3.70 (2H, d, J=11.7), 4.16 (2H, d, J=11.7).
2,2,5-トリメチル-1,3-ジオキサン-5-カルボン酸(1.0 g, 5.74 mmol)およびＤＭＦ(10 mL)の混合液に、窒素ガス雰囲気下で、N,O-ジメチルヒドロキシルアミン塩酸塩(0.84 g, 8.6 mmol)、1-ヒドロキシベンゾトリアゾール水和物(1.32 g, 8.6 mmol)、塩酸1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(1.651 g, 8.61 mmol)およびトリエチルアミン(2.39 mL, 17.2 mmol)を加え、室温で３時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、N-メトキシ-N,2,2,5-テトラメチル-1,3-ジオキサン-5-カルボン酸アミド(1.08 g, 収率: 86％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.38 (3H, s), 1.41 (3H, s), 1.42 (3H, s), 3.18 (3H, s), 3.69 (3H, s), 3.76 (2H, d, J=11.7), 4.19 (2H, d, J=11.7).
N-メトキシ-N,2,2,5-テトラメチル-1,3-ジオキサン-5-カルボン酸アミド (1.07 g, 4.92 mmol)およびTHF (10 mL)の混合液に、窒素ガス雰囲気下で 3mol/L メチルマグネシウムブロミドTHF溶液 (2.46 mL, 7.4 mmol)を０℃で徐々に加え、０℃で4時間攪拌した。反応後、飽和塩化アンモニウム水溶液を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、1-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)エタノン(0.76 g, 収率: 90％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.03 (3H, s), 1.37 (3H, d, J=0.5), 1.45 (3H, d, J=0.5), 2.28 (3H, s), 3.68 (2H, d, J=12.2), 4.16 (2H, d, J=12.2).
1-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)エタノン(0.76g, 4.4 mmol) とTHF (7.6 mL)の混合液に、窒素ガス雰囲気下で水素化ナトリウム (0.16 g, 6.6 mmol)を加え、室温で0.5時間攪拌した。、その反応液にシュウ酸ジメチル (0.78 g, 6.6 mmol)を加え、加熱還流下で２時間攪拌した。反応後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、メチル 2,4-ジオキソ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)ブタノエート(1.0 g, 収率: 88％）を無色油状物として得た。
メチル 2,4-ジオキソ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)ブタノエート (0.26 mg, 1.0 mmol)、4-(3-チエニル)アニリン(0.18 g, 1.0 mmol)、2-メトキチベンズアルデヒド (0.12 mL, 1.0 mmol)、酢酸 (0.023 mL, 0.40 mmol)およびジオキサン (2 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、減圧濃縮した。得られた残渣にジイソプロピルエーテルを加え、氷冷した。析出した目的物をろ取し，3-ヒドロキシ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)カルボニル-5-(2-メトキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.29g, 収率: 56％）を微黄色固体として得た。
1H-NMR (δ ppm TMS / CDCl3): 0.99 (3H, s), 1.12 (3H, s), 1.40 (3H, s), 3.63-3.76 (2H, m), 3.89 (3H, brs), 4.20-4.37 (2H, m), 6.50-7.58 (12H, m), 9.00 (1H, brs).
3-ヒドロキシ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)カルボニル-5-(2-メトキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.15 g, 0.3 mmol)、ヒドラジン水和物(0.07 mL, 1.4 mmol)および酢酸(1 mL)の混合液を加熱還流下で一夜攪拌した。反応液を減圧濃縮後、得られた残渣に2mol/L 塩酸/メタノール溶液 (2.89 mL, 5.8 mmol)を加え、加熱還流下で６時間攪拌した。反応液を減圧濃縮後、飽和炭酸水素ナトリウム水を加え、クロロホルムで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製した。得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、3-(1,1-ジヒドロキシメチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.105 g, 収率: 77％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.95 (3H, s), 3.91 (2H, m), 4.57 (2H, m), 6.29-7.78 (12H, m), 12.97 (1H, m).
3-(1,1-ジヒドロキシメチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-ヒドロキシ-2-ヒドロキシメチル-2-メチルプロピオン酸(6.71 g, 50mmol)、ジメトキシプロパン(7.99 mL, 65mmol)およびアセトン(50 mL)の混合液に、p-トルエンスルホン酸水和物(0.048 g, 0.25mmol)を加えて室温で2.5時間攪拌した。反応後、炭酸水素ナトリウム(0.1 g)を反応液に加え、室温で5分間攪拌後、減圧濃縮して得られた残渣に水を加え、エチルエーテルで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮し、2,2,5-トリメチル-1,3-ジオキサン-5-カルボン酸(7.87 g, 収率: 90％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.20 (3H, s), 1.43 (3H, s), 1.46 (3H, s), 3.70 (2H, d, J=11.7), 4.16 (2H, d, J=11.7).
2,2,5-トリメチル-1,3-ジオキサン-5-カルボン酸(1.0 g, 5.74 mmol)およびＤＭＦ(10 mL)の混合液に、窒素ガス雰囲気下で、N,O-ジメチルヒドロキシルアミン塩酸塩(0.84 g, 8.6 mmol)、1-ヒドロキシベンゾトリアゾール水和物(1.32 g, 8.6 mmol)、塩酸1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(1.651 g, 8.61 mmol)およびトリエチルアミン(2.39 mL, 17.2 mmol)を加え、室温で３時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、N-メトキシ-N,2,2,5-テトラメチル-1,3-ジオキサン-5-カルボン酸アミド(1.08 g, 収率: 86％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.38 (3H, s), 1.41 (3H, s), 1.42 (3H, s), 3.18 (3H, s), 3.69 (3H, s), 3.76 (2H, d, J=11.7), 4.19 (2H, d, J=11.7).
N-メトキシ-N,2,2,5-テトラメチル-1,3-ジオキサン-5-カルボン酸アミド (1.07 g, 4.92 mmol)およびTHF (10 mL)の混合液に、窒素ガス雰囲気下で 3mol/L メチルマグネシウムブロミドTHF溶液 (2.46 mL, 7.4 mmol)を０℃で徐々に加え、０℃で4時間攪拌した。反応後、飽和塩化アンモニウム水溶液を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、1-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)エタノン(0.76 g, 収率: 90％）を無色油状物として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.03 (3H, s), 1.37 (3H, d, J=0.5), 1.45 (3H, d, J=0.5), 2.28 (3H, s), 3.68 (2H, d, J=12.2), 4.16 (2H, d, J=12.2).
1-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)エタノン(0.76g, 4.4 mmol) とTHF (7.6 mL)の混合液に、窒素ガス雰囲気下で水素化ナトリウム (0.16 g, 6.6 mmol)を加え、室温で0.5時間攪拌した。、その反応液にシュウ酸ジメチル (0.78 g, 6.6 mmol)を加え、加熱還流下で２時間攪拌した。反応後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、メチル 2,4-ジオキソ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)ブタノエート(1.0 g, 収率: 88％）を無色油状物として得た。
メチル 2,4-ジオキソ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)ブタノエート (0.26 mg, 1.0 mmol)、4-(3-チエニル)アニリン(0.18 g, 1.0 mmol)、2-メトキチベンズアルデヒド (0.12 mL, 1.0 mmol)、酢酸 (0.023 mL, 0.40 mmol)およびジオキサン (2 ml)の混合液を、加熱還流下で一夜攪拌した。反応後、減圧濃縮した。得られた残渣にジイソプロピルエーテルを加え、氷冷した。析出した目的物をろ取し，3-ヒドロキシ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)カルボニル-5-(2-メトキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.29g, 収率: 56％）を微黄色固体として得た。
1H-NMR (δ ppm TMS / CDCl3): 0.99 (3H, s), 1.12 (3H, s), 1.40 (3H, s), 3.63-3.76 (2H, m), 3.89 (3H, brs), 4.20-4.37 (2H, m), 6.50-7.58 (12H, m), 9.00 (1H, brs).
3-ヒドロキシ-4-(2,2,5-トリメチル-1,3-ジオキサン-5-イル)カルボニル-5-(2-メトキシフェニル)-1-(4-チオフェン-3-イルフェニル)-1,5-ジヒドロピロール-2-オン(0.15 g, 0.3 mmol)、ヒドラジン水和物(0.07 mL, 1.4 mmol)および酢酸(1 mL)の混合液を加熱還流下で一夜攪拌した。反応液を減圧濃縮後、得られた残渣に2mol/L 塩酸/メタノール溶液 (2.89 mL, 5.8 mmol)を加え、加熱還流下で６時間攪拌した。反応液を減圧濃縮後、飽和炭酸水素ナトリウム水を加え、クロロホルムで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム）で精製した。得られた目的物を酢酸エチルとn-ヘキサンで粉末化させ、3-(1,1-ジヒドロキシメチルエチル)-4-(2-メトキシフェニル)-5-(4-チオフェン-3-イルフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.105 g, 収率: 77％）を無色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 0.95 (3H, s), 3.91 (2H, m), 4.57 (2H, m), 6.29-7.78 (12H, m), 12.97 (1H, m).
実施例１０
3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
過ヨウ素酸(0.32 mg, 1.4 mmol)のアセトニトリル (15 mL)溶液に、3-(1-ヒドロキシメチル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.206 g, 0.463 mmol)のジクロロメタン溶液(15 mL)およびクロロクロム酸ピリジニウム(0.01 g, 0.046 mmol)を加え、室温で４時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣にジクロロメタンを加え、析出した目的物をろ取し、3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.11g, 収率: 49％）を微黄色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.19 (3H, s), 1.30 (3H, s), 3.91 (3H, brs), 6.40-7.19 (6H, m), 7.66-7.80 (4H, m), 8.94 (1H, d, J=1.7), 12.50 (1H, brs), 13.55 (1H, brs).
3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
過ヨウ素酸(0.32 mg, 1.4 mmol)のアセトニトリル (15 mL)溶液に、3-(1-ヒドロキシメチル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.206 g, 0.463 mmol)のジクロロメタン溶液(15 mL)およびクロロクロム酸ピリジニウム(0.01 g, 0.046 mmol)を加え、室温で４時間攪拌した。反応後、水を反応液に加え、酢酸エチルで抽出した。抽出液を飽和食塩水で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣にジクロロメタンを加え、析出した目的物をろ取し、3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.11g, 収率: 49％）を微黄色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.19 (3H, s), 1.30 (3H, s), 3.91 (3H, brs), 6.40-7.19 (6H, m), 7.66-7.80 (4H, m), 8.94 (1H, d, J=1.7), 12.50 (1H, brs), 13.55 (1H, brs).
実施例１１
5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-3-[1-(N-メチルカルバモイル)-1-メチルエチル]-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.05 g, 0.11 mmol)およびＤＭＦ(2 mL)の混合液に、メチルアミン塩酸塩(0.013 g, 0.19 mmol)、1-ヒドロキシベンゾトリアゾール(0.039 g, 0.29 mmol)、4-ジメチルアミノピリジン(0.005 g, 0.04 mmol)、塩酸 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(0.058 g, 0.3 mmol)およびトリエチルアミン(0.040 mL, 0.29 mmol)を加えて室温で2時間攪拌した。反応後、水(2 mL)を反応液に加えて氷冷下でしばらく攪拌した。析出した目的物をろ取後、シリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-3-[1-(N-メチルカルバモイル)-1-メチルエチル]-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.036 g, 収率: 40％）を微褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 1.12 (3H, s), 1.29 (3H, s), 2.43 (3H, brs), 3.91 (3H, brs), 6.63-7.20 (7H, m), 7.67-7.82 (4H, m), 8.95 (1H, d, J=1.7), 13.43 (1H, brs).
5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-3-[1-(N-メチルカルバモイル)-1-メチルエチル]-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オンの製造
3-(1-ヒドロキシカルボニル-1-メチルエチル)-5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.05 g, 0.11 mmol)およびＤＭＦ(2 mL)の混合液に、メチルアミン塩酸塩(0.013 g, 0.19 mmol)、1-ヒドロキシベンゾトリアゾール(0.039 g, 0.29 mmol)、4-ジメチルアミノピリジン(0.005 g, 0.04 mmol)、塩酸 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(0.058 g, 0.3 mmol)およびトリエチルアミン(0.040 mL, 0.29 mmol)を加えて室温で2時間攪拌した。反応後、水(2 mL)を反応液に加えて氷冷下でしばらく攪拌した。析出した目的物をろ取後、シリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン）で精製し、5-(4-イソオキサゾリル-3-イルフェニル)-4-(2-メトキシフェニル)-3-[1-(N-メチルカルバモイル)-1-メチルエチル]-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン(0.036 g, 収率: 40％）を微褐色固体として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 1.12 (3H, s), 1.29 (3H, s), 2.43 (3H, brs), 3.91 (3H, brs), 6.63-7.20 (7H, m), 7.67-7.82 (4H, m), 8.95 (1H, d, J=1.7), 13.43 (1H, brs).
実施例１２
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(2.15 g, 5 mmol)，(R)-メチル 2-ヒドロキシ-2-フェニルアセテート(1.00 g, 6.0 mmol)，トリフェニルホスフィン(1.44 g, 5.5 mmol)およびジオキサン(15 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(1.29 g, 5.5 mmol)を１分間にわたって加えて、室温で６時間攪拌した．反応液に水(200 mL)を加え、酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を再結晶（酢酸エチル／n-ヘキサン)し，ジアステレオマー体(0.80 g, 収率: 28％）を淡黄色結晶として得た。
得られたジアステレオマー体(0.59 g, 1 mmol)，塩化リチウム(0.127 g, 3 mmol)および1,3-ジメチル-2-イミダゾリジノン(3 mL)の混合液を、80℃で６時間攪拌した。反応液に水(200 mL)と1mol/L 塩酸 (3 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られた目的物を再結晶（酢酸エチル／n-ヘキサン)し，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.40 g, 収率: 93％）を淡黄色結晶として得た。
[α]D: -142.2±3.6°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.88 (3H, d, J=6.9), 0.91 (3H, d, J=6.9), 3.33 (1H, sept, J=6.9), 3.81 (3H, brs), 6.23 (1H, brs), 6.75-7.15 (4H, m), 7.45-7.53 (4H, m), 12.00 (1H, brs).
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(2.15 g, 5 mmol)，(R)-メチル 2-ヒドロキシ-2-フェニルアセテート(1.00 g, 6.0 mmol)，トリフェニルホスフィン(1.44 g, 5.5 mmol)およびジオキサン(15 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(1.29 g, 5.5 mmol)を１分間にわたって加えて、室温で６時間攪拌した．反応液に水(200 mL)を加え、酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を再結晶（酢酸エチル／n-ヘキサン)し，ジアステレオマー体(0.80 g, 収率: 28％）を淡黄色結晶として得た。
得られたジアステレオマー体(0.59 g, 1 mmol)，塩化リチウム(0.127 g, 3 mmol)および1,3-ジメチル-2-イミダゾリジノン(3 mL)の混合液を、80℃で６時間攪拌した。反応液に水(200 mL)と1mol/L 塩酸 (3 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られた目的物を再結晶（酢酸エチル／n-ヘキサン)し，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.40 g, 収率: 93％）を淡黄色結晶として得た。
[α]D: -142.2±3.6°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.88 (3H, d, J=6.9), 0.91 (3H, d, J=6.9), 3.33 (1H, sept, J=6.9), 3.81 (3H, brs), 6.23 (1H, brs), 6.75-7.15 (4H, m), 7.45-7.53 (4H, m), 12.00 (1H, brs).
実施例１３
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.10 g, 0.23 mmol)，3-チオフェンボロン酸(0.045 g, 0.35 mmol)，リン酸三カリウム(0.148 g, 0.7 mmol)，エチレングリコールジメチルエーテル(3 mL)および水 (3 mL) の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II) ジクロロメタン付加体 (0.019 g, 0.023 mmol)を加え，還流下で３時間攪拌した。反応液に水(50 mL) 加え、ジクロロメタン (50 mL)で抽出した。抽出液を飽和食塩水(50 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物を酢酸エチル／n-ヘキサンで粉末化させ，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン (0.029 g, 収率: 29％）を淡褐色粉末として得た。
[α]D: -57.4±1.9°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.89 (3H, d, J=6.9), 0.92 (3H, d, J=6.9), 3.34 (1H, sept, J=6.9), 3.87 (3H, brs), 6.32 (1H, brs), 6.75-7.15 (5H, m), 7.51 (1H, d, J=1.1), 7.58-7.63 (4H, m), 7.81 (1H, m), 12.00 (1H, brs).
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.10 g, 0.23 mmol)，3-チオフェンボロン酸(0.045 g, 0.35 mmol)，リン酸三カリウム(0.148 g, 0.7 mmol)，エチレングリコールジメチルエーテル(3 mL)および水 (3 mL) の混合液を窒素置換した後に、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II) ジクロロメタン付加体 (0.019 g, 0.023 mmol)を加え，還流下で３時間攪拌した。反応液に水(50 mL) 加え、ジクロロメタン (50 mL)で抽出した。抽出液を飽和食塩水(50 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物を酢酸エチル／n-ヘキサンで粉末化させ，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン (0.029 g, 収率: 29％）を淡褐色粉末として得た。
[α]D: -57.4±1.9°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.89 (3H, d, J=6.9), 0.92 (3H, d, J=6.9), 3.34 (1H, sept, J=6.9), 3.87 (3H, brs), 6.32 (1H, brs), 6.75-7.15 (5H, m), 7.51 (1H, d, J=1.1), 7.58-7.63 (4H, m), 7.81 (1H, m), 12.00 (1H, brs).
実施例１４
3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-1,4,5,6-テトラヒドロ-1H-ピロロ[3,4-c]ピラゾールの製造
3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン (0.72 g, 1.65 mmol)およびジオキサン(40 mL)の混合液に、リチウムアルミニウムハライド (0.19 g, 5 mmol) を加え，加熱還流下で2時間攪拌した。反応液を氷水(100 mL)と2mol/L塩酸 (10 mL) の混合液に加え、クロロホルム(100 mL)で抽出した。抽出液を飽和食塩水(100 mL)で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物をエーテルで粉末化させ，3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-1,4,5,6-テトラヒドロ-1H-ピロロ[3,4-c]ピラゾール (0.029 g, 収率: 29％）を淡褐色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 0.86 (3H, d, J=7.0 ), 0.97 (3H, d, J=7.0), 2.78 (1H, sept, J=7.0), 3.94 (3H, s), 4.42 (1H, d, J=12.6), 4.77 (1H, d, J=12.6), 6.11 (1H, d, J=2.0), 6.55-7.53 (11H, m), 12.32 (1H, s).
3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-1,4,5,6-テトラヒドロ-1H-ピロロ[3,4-c]ピラゾールの製造
3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-4,5-ジヒドロ-1H-ピロロ[3,4-c]ピラゾール-6-オン (0.72 g, 1.65 mmol)およびジオキサン(40 mL)の混合液に、リチウムアルミニウムハライド (0.19 g, 5 mmol) を加え，加熱還流下で2時間攪拌した。反応液を氷水(100 mL)と2mol/L塩酸 (10 mL) の混合液に加え、クロロホルム(100 mL)で抽出した。抽出液を飽和食塩水(100 mL)で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物をエーテルで粉末化させ，3-ｉ−プロピル-5-(4-チオフェン-3-イルフェニル)-4-(2-メトキシフェニル)-1,4,5,6-テトラヒドロ-1H-ピロロ[3,4-c]ピラゾール (0.029 g, 収率: 29％）を淡褐色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 0.86 (3H, d, J=7.0 ), 0.97 (3H, d, J=7.0), 2.78 (1H, sept, J=7.0), 3.94 (3H, s), 4.42 (1H, d, J=12.6), 4.77 (1H, d, J=12.6), 6.11 (1H, d, J=2.0), 6.55-7.53 (11H, m), 12.32 (1H, s).
実施例１５
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシエトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシメチルフェニル)-1,5-ジヒドロピロール-2-オン(11.0 g, 23.7 mmol)，(R)-メチル 2-ヒドロキシ-2-フェニルアセテート(4.73 g, 28.5 mmol)，トリフェニルホスフィン(7.47 g, 28.5 mmol)およびＴＨＦ(150 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(6.67 g, 28.5 mmol)を２分間にわたって加えて室温で一夜攪拌した．反応液に水(200 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を酢酸エチル／n-ヘキサンで再結晶し，ジアステレオマーＡ(4.98 g, 収率: 34％）を淡黄色結晶として得た。
1H-NMR (δ ppm TMS / CDCl3) 0.85 (3H, d, J=7.0 ), 1.15 (3H, d, J=7.0), 3.49 (1H, sept, J=7.0), 3.57 (3H, brs), 3.73 (3H, s), 5.25 (2H, brs), 6.40-6.80 (2H, m), 7.05-7.63 (16H, m).
ジアステレオマーＡ(4.0 g, 6.5 mmol) の酢酸エチル(33 mL)溶液に2mol/l 塩酸／メタノール溶液(32.7 mL)を加え，60℃で1時間攪拌した．反応液に水(200 mL)を加え、酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を酢酸エチル／n-ヘキサンで粉末化させ，ジアステレオマーＢ(2.93 g, 収率: 79％）を黄色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3) 0.90 (3H, d, J=6.9), 1.24 (3H, d, J=6.9), 3.52 (1H, sept, J=6.9), 3.75 (3H, s), 6.22 (1H, s), 6.68-6.75 (2H, m), 6.97-7.56 (15H, m), 7.95 (1H, s).
ジアステレオマーＢ(2.65 g, 4.7 mmol)，2-メトキシエタノール(0.71 g, 9.3 mmol)，トリフェニルホスフィン(1.84 g, 7.0 mmol)およびＴＨＦ(50 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(1.64 g, 7.0 mmol)を２分間にわたって加え、室温で一夜攪拌した．反応液に水(200 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製し、ジアステレオマーＣ(2.44 g, 収率: 84％）を黄色アモルファスとして得た。
得られたジアステレオマーＣ(2.25 g, 3.6 mmol)，塩化リチウム(0.46 g, 10.8 mmol)と1,3-ジメチル-2-イミダゾリジノン(45 mL)の混合液を、100℃で16時間攪拌した．反応液に水(200 mL)と2mol/L塩酸 (15 mL) を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物を酢酸エチル／n-ヘキサンで粉末化させ，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシエトキシフェニル)-1,5-ジヒドロピロール-2-オン (1.01 g, 収率: 59％）を淡黄色粉末として得た。
[α]D: -39.3±1.6°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.89 (3H, d, J=7.0), 0.93 (3H, d, J=7.0), 3.44 (3H, s), 3.57 (2H, brs), 3.83 (3H, s), 4.15 (1H, m), 4.29 (1H, m), 6.01 (1H, s), 6.38 (1H, s), 6.63-7.13 (4H, m), 7.40-7.76 (7H, m), 7.78 (1H, m), 12.5 (1H, brs)
(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシエトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-ブロモフェニル)-5-(2-メトキシメチルフェニル)-1,5-ジヒドロピロール-2-オン(11.0 g, 23.7 mmol)，(R)-メチル 2-ヒドロキシ-2-フェニルアセテート(4.73 g, 28.5 mmol)，トリフェニルホスフィン(7.47 g, 28.5 mmol)およびＴＨＦ(150 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(6.67 g, 28.5 mmol)を２分間にわたって加えて室温で一夜攪拌した．反応液に水(200 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を酢酸エチル／n-ヘキサンで再結晶し，ジアステレオマーＡ(4.98 g, 収率: 34％）を淡黄色結晶として得た。
1H-NMR (δ ppm TMS / CDCl3) 0.85 (3H, d, J=7.0 ), 1.15 (3H, d, J=7.0), 3.49 (1H, sept, J=7.0), 3.57 (3H, brs), 3.73 (3H, s), 5.25 (2H, brs), 6.40-6.80 (2H, m), 7.05-7.63 (16H, m).
ジアステレオマーＡ(4.0 g, 6.5 mmol) の酢酸エチル(33 mL)溶液に2mol/l 塩酸／メタノール溶液(32.7 mL)を加え，60℃で1時間攪拌した．反応液に水(200 mL)を加え、酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製した。得られたジアステレオマー混合物を酢酸エチル／n-ヘキサンで粉末化させ，ジアステレオマーＢ(2.93 g, 収率: 79％）を黄色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3) 0.90 (3H, d, J=6.9), 1.24 (3H, d, J=6.9), 3.52 (1H, sept, J=6.9), 3.75 (3H, s), 6.22 (1H, s), 6.68-6.75 (2H, m), 6.97-7.56 (15H, m), 7.95 (1H, s).
ジアステレオマーＢ(2.65 g, 4.7 mmol)，2-メトキシエタノール(0.71 g, 9.3 mmol)，トリフェニルホスフィン(1.84 g, 7.0 mmol)およびＴＨＦ(50 mL)の混合液に、室温下でアゾジカルボン酸ジメトキシエチル(1.64 g, 7.0 mmol)を２分間にわたって加え、室温で一夜攪拌した．反応液に水(200 mL)を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製し、ジアステレオマーＣ(2.44 g, 収率: 84％）を黄色アモルファスとして得た。
得られたジアステレオマーＣ(2.25 g, 3.6 mmol)，塩化リチウム(0.46 g, 10.8 mmol)と1,3-ジメチル-2-イミダゾリジノン(45 mL)の混合液を、100℃で16時間攪拌した．反応液に水(200 mL)と2mol/L塩酸 (15 mL) を加え、トルエン(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム)で精製した。得られた目的物を酢酸エチル／n-ヘキサンで粉末化させ，(-)-4-(2-メチルプロピオニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシエトキシフェニル)-1,5-ジヒドロピロール-2-オン (1.01 g, 収率: 59％）を淡黄色粉末として得た。
[α]D: -39.3±1.6°.(in CHCl3), 1H-NMR (δ ppm TMS / DMSO-d6) 0.89 (3H, d, J=7.0), 0.93 (3H, d, J=7.0), 3.44 (3H, s), 3.57 (2H, brs), 3.83 (3H, s), 4.15 (1H, m), 4.29 (1H, m), 6.01 (1H, s), 6.38 (1H, s), 6.63-7.13 (4H, m), 7.40-7.76 (7H, m), 7.78 (1H, m), 12.5 (1H, brs)
実施例１６
4-(ｉ−プロピルスルホニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
ｉ−プロピルメチルスルホン(5.17 g, 42.3 mmol)とＴＨＦ(20 mL)の混合液に、室温下で28%ナトリウムメトキシドメタノール溶液(8.58 g, 44.5 mmol)を加えた後に，シュウ酸メチル(5.0 g, 42.3 mmol)を室温で徐々に加え，室温で一夜攪拌した．反応液に氷水(200 mL)を加え、2mol/L 塩酸でpH3以下に調整し，酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製し，メチル 3-(ｉ−プロピルスルホニル)-2-オキソプロパノエート(2.7 g, 収率: 28％）を無色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 1.26 (6H, d, J=6.7), 3.46 (1H, sept, J=6.7), 3.81 (3H, s), 4.74 (2H, s).
メチル 3-(ｉ−プロピルスルホニル)-2-オキソプロパノエート(0.23 g, 1 mmol)，4-チオフェン-3-イルアニリン(0.18 g, 1 mmol)、2-メトキシベンズアルデヒド(0.14, 1 mmol)、酢酸 (0.023 mL, 0.4 mmol)とトルエン(3 mL)の混合液を，加熱還流下で一夜攪拌した．反応後，室温まで冷却し，エーテルを加え、析出した目的物をろ取した。得られた目的物をエーテル／n-ヘキサン溶液で洗浄し、4-(ｉ−プロピルスルホニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.37 g, 収率: 79％）を淡褐色固体として得た．
1H-NMR (δ ppm TMS / DMSO-d6):0.97-1.15 (6H, m), 3.62 (3.87) (3H, s), 6.13 (6.50) (1H, s), 6.82-7.27 (3H, m), 7.48-7.81 (8H, m), 12.20 (1H, brs).
4-(ｉ−プロピルスルホニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オンの製造
ｉ−プロピルメチルスルホン(5.17 g, 42.3 mmol)とＴＨＦ(20 mL)の混合液に、室温下で28%ナトリウムメトキシドメタノール溶液(8.58 g, 44.5 mmol)を加えた後に，シュウ酸メチル(5.0 g, 42.3 mmol)を室温で徐々に加え，室温で一夜攪拌した．反応液に氷水(200 mL)を加え、2mol/L 塩酸でpH3以下に調整し，酢酸エチル(200 mL)で抽出した。抽出液を飽和食塩水(200 mL)で水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／n-ヘキサン)で精製し，メチル 3-(ｉ−プロピルスルホニル)-2-オキソプロパノエート(2.7 g, 収率: 28％）を無色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6) 1.26 (6H, d, J=6.7), 3.46 (1H, sept, J=6.7), 3.81 (3H, s), 4.74 (2H, s).
メチル 3-(ｉ−プロピルスルホニル)-2-オキソプロパノエート(0.23 g, 1 mmol)，4-チオフェン-3-イルアニリン(0.18 g, 1 mmol)、2-メトキシベンズアルデヒド(0.14, 1 mmol)、酢酸 (0.023 mL, 0.4 mmol)とトルエン(3 mL)の混合液を，加熱還流下で一夜攪拌した．反応後，室温まで冷却し，エーテルを加え、析出した目的物をろ取した。得られた目的物をエーテル／n-ヘキサン溶液で洗浄し、4-(ｉ−プロピルスルホニル)-3-ヒドロキシ-1-(4-チオフェン-3-イルフェニル)-5-(2-メトキシフェニル)-1,5-ジヒドロピロール-2-オン(0.37 g, 収率: 79％）を淡褐色固体として得た．
1H-NMR (δ ppm TMS / DMSO-d6):0.97-1.15 (6H, m), 3.62 (3.87) (3H, s), 6.13 (6.50) (1H, s), 6.82-7.27 (3H, m), 7.48-7.81 (8H, m), 12.20 (1H, brs).
上記合成ルート、一般的製造法および実施例に記載の方法に準じて以下の化合物を得た。構造および物性を以下に示す。
（化合物の同定方法）
本発明の化合物のＬＣ／ＭＳデータは、以下の２つの条件（メソッド１〜３）のいずれかで測定し、保持時間および［Ｍ＋Ｈ］＋を示した。
（化合物の同定方法）
本発明の化合物のＬＣ／ＭＳデータは、以下の２つの条件（メソッド１〜３）のいずれかで測定し、保持時間および［Ｍ＋Ｈ］＋を示した。
（メソッド１）
カラム：Ｘｂｒｉｄｇｅ Ｃ１８（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：３ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％−１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。
（メソッド２）
カラム：Ｓｈｉｍ−ｐａｃｋ ＸＲ−ＯＤＳ （２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ） （Ｓｈｉｍａｄｚｕ）
流速：１．６ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％−１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。
（メソッド３）
カラム：Ｇｅｍｉｎｉ−ＮＸ （５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：３ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有メタノール溶液
グラジェント：３．５分間で５％−１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
カラム：Ｘｂｒｉｄｇｅ Ｃ１８（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：３ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％−１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。
（メソッド２）
カラム：Ｓｈｉｍ−ｐａｃｋ ＸＲ−ＯＤＳ （２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ） （Ｓｈｉｍａｄｚｕ）
流速：１．６ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％−１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。
（メソッド３）
カラム：Ｇｅｍｉｎｉ−ＮＸ （５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
流速：３ ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有メタノール溶液
グラジェント：３．５分間で５％−１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
試験例
ヒトＰ２Ｘ3受容体遺伝子（ＧｅｎＢａｎｋ登録配列Ｙ０７６８３）をＣ６ＢＵ−１細胞に導入した安定発現細胞株をＰＤＬコート９６穴マイクロプレートに１穴当たり８０００個になるように播種し、培地（８．３％ウシ胎児血清、８．３％ウマ血清、１％抗生物質抗真菌剤混合溶液を含むＤＭＥＭ)中で、３７℃、５％二酸化炭素下で１日間培養した。培地をＦｌｕｏ−３−ＡＭ ４μＭを含む添加液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭ ＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、１０％ＢＳＡ、０．０８％プルロニックＦ−１２７、ｐＨ７．５）に置換し、３７℃、５％二酸化炭素下で１時間インキュベーションした。洗浄用緩衝液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭ ＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、ｐＨ７．５）により洗浄し、１穴当たり４０μｌの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムＦＤＳＳ ３０００（浜松ホトニクス社）に設置した。ＦＤＳＳ ３０００による蛍光強度の測定を開始し、希釈用緩衝液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭ ＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭ ＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、０．１％プルロニックＦ−１２７、ｐＨ７．５）により異なる濃度になるように希釈した被検化合物ＤＭＳＯ溶液を１穴当たり４０μｌずつＦＤＳＳ ３０００に内蔵された自動分注装置で分注した。５分後、希釈用緩衝液で希釈した４０ｎＭ ＡＴＰ溶液５０μｌをＦＤＳＳ ３０００に内蔵された自動分注装置で分注し、その後３分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ＡＴＰ溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。被検化合物を含まない場合の比最大蛍光強度の値を阻害０％、ＡＴＰの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害１００％とし、阻害５０％となる濃度（ＩＣ50）を算出して被検化合物の阻害活性を評価した。比最大蛍光強度の算出はＦＤＳＳ ソフトウェア（浜松ホトニクス社）を用いて行った。ＩＣ50の算出はマイクロソフト・エクセル（Microsoft社）およびＸＬｆｉｔ（idbs社）のソフトウェアを用いて行った。
ヒトＰ２Ｘ3受容体遺伝子（ＧｅｎＢａｎｋ登録配列Ｙ０７６８３）をＣ６ＢＵ−１細胞に導入した安定発現細胞株をＰＤＬコート９６穴マイクロプレートに１穴当たり８０００個になるように播種し、培地（８．３％ウシ胎児血清、８．３％ウマ血清、１％抗生物質抗真菌剤混合溶液を含むＤＭＥＭ)中で、３７℃、５％二酸化炭素下で１日間培養した。培地をＦｌｕｏ−３−ＡＭ ４μＭを含む添加液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭ ＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、１０％ＢＳＡ、０．０８％プルロニックＦ−１２７、ｐＨ７．５）に置換し、３７℃、５％二酸化炭素下で１時間インキュベーションした。洗浄用緩衝液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭ ＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、ｐＨ７．５）により洗浄し、１穴当たり４０μｌの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムＦＤＳＳ ３０００（浜松ホトニクス社）に設置した。ＦＤＳＳ ３０００による蛍光強度の測定を開始し、希釈用緩衝液（２０ｍＭ ＨＥＰＥＳ、１３７ｍＭ ＮａＣｌ、２．７ｍＭ ＫＣｌ、０．９ｍＭ ＭｇＣｌ2、５．０ｍＭ ＣａＣｌ2、５．６ｍＭ Ｄ−グルコース、２．５ｍＭ プロベネシド、０．１％プルロニックＦ−１２７、ｐＨ７．５）により異なる濃度になるように希釈した被検化合物ＤＭＳＯ溶液を１穴当たり４０μｌずつＦＤＳＳ ３０００に内蔵された自動分注装置で分注した。５分後、希釈用緩衝液で希釈した４０ｎＭ ＡＴＰ溶液５０μｌをＦＤＳＳ ３０００に内蔵された自動分注装置で分注し、その後３分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ＡＴＰ溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。被検化合物を含まない場合の比最大蛍光強度の値を阻害０％、ＡＴＰの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害１００％とし、阻害５０％となる濃度（ＩＣ50）を算出して被検化合物の阻害活性を評価した。比最大蛍光強度の算出はＦＤＳＳ ソフトウェア（浜松ホトニクス社）を用いて行った。ＩＣ50の算出はマイクロソフト・エクセル（Microsoft社）およびＸＬｆｉｔ（idbs社）のソフトウェアを用いて行った。
本発明化合物の試験結果を以下の表に示す。
本発明の化合物はＰ２Ｘ3受容体に対する阻害活性を示した。また、本発明の化合物はＰ２Ｘ3サブタイプに作用するため、同じくＰ２Ｘ2サブタイプを含んで構成されるＰ２Ｘ2/3受容体に対しても阻害活性を示すと考えられる。
（ＣＹＰ３Ａ４蛍光ＭＢＩ試験）
ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による化合物のＣＹＰ３Ａ４阻害の増強を調べる試験であり、酵素に大腸菌発現ＣＹＰ３Ａ４を用いて、７-ベンジルオキシトリフルオロメチルクマリン（ＢＦＣ）がＣＹＰ３Ａ４酵素により脱ベンジル化し、蛍光を発する代謝物７-ハイドロキシトリフルオロメチルクマリン（ＨＦＣ）を生成する反応を指標として行う。
ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による化合物のＣＹＰ３Ａ４阻害の増強を調べる試験であり、酵素に大腸菌発現ＣＹＰ３Ａ４を用いて、７-ベンジルオキシトリフルオロメチルクマリン（ＢＦＣ）がＣＹＰ３Ａ４酵素により脱ベンジル化し、蛍光を発する代謝物７-ハイドロキシトリフルオロメチルクマリン（ＨＦＣ）を生成する反応を指標として行う。
反応条件は以下のとおり：基質、５.６μｍｏｌ／Ｌ ７−ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ，反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；被検薬物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。
９６穴プレートにプレ反応液としてＫ−Ｐｉ緩衝液（ｐＨ７．４）中に酵素、被検薬物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ−Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５mol/L Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ−Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７−ＨＦＣの蛍光値を測定する。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ）
薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、被検薬物溶液を加えたそれぞれの濃度での残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。ＩＣ５０値の差が５μＭ以上の場合を（＋）とし、３μＭ以下の場合を（−）とする。
（ＣＹＰ阻害試験）
市販のプールドヒト肝ミクロソームを用いて、ヒト主要CYP5分子種(CYP1A2、2C9、2C19、2D6、3A4)の典型的基質代謝反応として7-エトキシレゾルフィンのO-脱エチル化(CYP1A2)、トルブタミドのメチル−水酸化(CYP2C9)、メフェニトインの４’−水酸化(CYP2C19)、 デキストロメトルファンのO脱メチル化(CYP2D6)、テルフェナジンの水酸化(CYP3A4)を指標とし、それぞれの代謝物生成量が被検化合物によって阻害される程度を評価する。
市販のプールドヒト肝ミクロソームを用いて、ヒト主要CYP5分子種(CYP1A2、2C9、2C19、2D6、3A4)の典型的基質代謝反応として7-エトキシレゾルフィンのO-脱エチル化(CYP1A2)、トルブタミドのメチル−水酸化(CYP2C9)、メフェニトインの４’−水酸化(CYP2C19)、 デキストロメトルファンのO脱メチル化(CYP2D6)、テルフェナジンの水酸化(CYP3A4)を指標とし、それぞれの代謝物生成量が被検化合物によって阻害される程度を評価する。
反応条件は以下のとおり：基質、0.5 μｍｏｌ／Ｌ エトキシレゾルフィン(CYP1A2)、100 μｍｏｌ／Ｌ トルブタミド(CYP2C9)、50 μｍｏｌ／Ｌ S-メフェニトイン(CYP2C19)、5μｍｏｌ／Ｌ デキストロメトルファン(CYP2D6)、1 μｍｏｌ／Ｌ テルフェナジン(CYP3A4)；反応時間、15分；反応温度、37℃；酵素、プールドヒト肝ミクロソーム 0.2mg タンパク質/mL；被検薬物濃度、1、5、10、20 μｍｏｌ／Ｌ(４点)。
96穴プレートに反応溶液として、50mM Hepes 緩衝液中に各5種の基質、ヒト肝ミクロソーム、被検薬物を上記組成で加え、補酵素であるNADPHを添加して、指標とする代謝反応を開始し、37℃、15分間反応した後、メタノール/アセトニトリル=1/1（v/v）溶液を添加することで反応を停止する。3000rpm、15分間の遠心操作後、遠心上清中のレゾルフィン(CYP1A2代謝物)を蛍光マルチラベルカウンタで、トルブタミド水酸化体 (CYP2C9代謝物)、メフェニトイン４’水酸化体(CYP2C19代謝物)、デキストロルファン(CYP2D6代謝物)、テルフェナジンアルコール体(CYP3A4代謝物)をLC/MS/MSで定量する。
薬物を溶解した溶媒であるDMSOのみを反応系に添加したものをコントロール(100%)とし、被検薬物溶液を加えたそれぞれの濃度での残存活性(%)を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。
（ＦＡＴ試験）
凍結保存しているネズミチフス菌（Salmonella typhimurium TA98株、TA100株）20μLを10 mL液体栄養培地（2.5% Oxoid nutrient broth No.2）に接種し37℃にて10 時間、振盪前培養する。TA98株は9mLの菌液を遠心（2000×g、10 分間）して培養液を除去し、9mLのMicro F緩衝液(K2HPO4：3.5 g/L、 KH2PO4：1 g/L、 (NH4)2SO4：1g/L、 クエン酸三ナトリウム二水和物：0.25 g/L、 MgSO4・7H20：0.1g/L)に菌を懸濁し、110 mLのExposure培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、 グルコース：8 mg/mLを含むMicroF緩衝液)に添加し、TA100株は3.16mL菌液に対しExposure培地120mLに添加し試験菌液を調製する。被験物質DMSO溶液（最高用量50mg/mLから2倍公比で8段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50 μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、 TA100株に対しては0.25 μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミド DMSO溶液、 代謝活性化条件ではTA98株に対して40μg/mLの2-アミノアントラセンDMSO溶液、 TA100株に対しては20 μg/mLの2-アミノアントラセンDMSO溶液それぞれ12 μL と試験菌液588μL（代謝活性化条件では試験菌液498 μLとS9 mix 90 μLの混合液）を混和し、37℃にて90分間、振盪培養した。被験物質を暴露した菌液460 μLを、Indicator培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、グルコース：8 mg/mL、ブロモクレゾールパープル：37.5 μg/mLを含むMicroF緩衝液)2300μLに混和し50 μLずつマイクロプレート48ウェル/用量に分注し、37℃にて 3日間、 静置培養する。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。
凍結保存しているネズミチフス菌（Salmonella typhimurium TA98株、TA100株）20μLを10 mL液体栄養培地（2.5% Oxoid nutrient broth No.2）に接種し37℃にて10 時間、振盪前培養する。TA98株は9mLの菌液を遠心（2000×g、10 分間）して培養液を除去し、9mLのMicro F緩衝液(K2HPO4：3.5 g/L、 KH2PO4：1 g/L、 (NH4)2SO4：1g/L、 クエン酸三ナトリウム二水和物：0.25 g/L、 MgSO4・7H20：0.1g/L)に菌を懸濁し、110 mLのExposure培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、 グルコース：8 mg/mLを含むMicroF緩衝液)に添加し、TA100株は3.16mL菌液に対しExposure培地120mLに添加し試験菌液を調製する。被験物質DMSO溶液（最高用量50mg/mLから2倍公比で8段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50 μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、 TA100株に対しては0.25 μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミド DMSO溶液、 代謝活性化条件ではTA98株に対して40μg/mLの2-アミノアントラセンDMSO溶液、 TA100株に対しては20 μg/mLの2-アミノアントラセンDMSO溶液それぞれ12 μL と試験菌液588μL（代謝活性化条件では試験菌液498 μLとS9 mix 90 μLの混合液）を混和し、37℃にて90分間、振盪培養した。被験物質を暴露した菌液460 μLを、Indicator培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、グルコース：8 mg/mL、ブロモクレゾールパープル：37.5 μg/mLを含むMicroF緩衝液)2300μLに混和し50 μLずつマイクロプレート48ウェル/用量に分注し、37℃にて 3日間、 静置培養する。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。
（溶解性試験）
化合物の溶解度は、1%DMSO添加条件下で決定する。DMSOにて10mM化合物溶液を調製し、化合物溶液6 μLをpH 6.8 人工腸液（0.2 mol/L リン酸二水素カリウム試液 250 mL に 0.2 mol/L NaOH 試液 118 mL、水を加えて 1000 mL とする） 594μLに添加する。25℃で16時間静置させた後、混液を吸引濾過する。濾液をメタノール/水= 1/1にて2倍希釈し、絶対検量線法によりHPLCまたはLC/MS/MSを用いてろ液中濃度を測定する。
化合物の溶解度は、1%DMSO添加条件下で決定する。DMSOにて10mM化合物溶液を調製し、化合物溶液6 μLをpH 6.8 人工腸液（0.2 mol/L リン酸二水素カリウム試液 250 mL に 0.2 mol/L NaOH 試液 118 mL、水を加えて 1000 mL とする） 594μLに添加する。25℃で16時間静置させた後、混液を吸引濾過する。濾液をメタノール/水= 1/1にて2倍希釈し、絶対検量線法によりHPLCまたはLC/MS/MSを用いてろ液中濃度を測定する。
（代謝安定性試験）
市販のプールドヒト肝ミクロソームを用いて、対象化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、肝で代謝される程度を評価する。
市販のプールドヒト肝ミクロソームを用いて、対象化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、肝で代謝される程度を評価する。
ヒト肝ミクロソーム0.5mg タンパク質/mLを含む0.2mLの緩衝液（50mｍｏｌ／Ｌ tris-HCl pH7.4、 150ｍｍｏｌ／Ｌ 塩化カリウム、 10 ｍｍｏｌ／Ｌ 塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ NADPH存在下で37℃、0分あるいは30分間反応させる（酸化的反応）。反応後、メタノール/アセトニトリル=1/1（v/v）溶液の100μＬに反応液50 μLを添加、混合し、3000rpmで15分間遠心する。その遠心上清中の試験化合物をLC/MS/MSにて定量し、反応後の試験化合物の残存量を0分反応時の化合物量を100%として計算する。なお、加水分解反応はNADPH非存在下で、グルクロン酸抱合反応はNADPHに換えて5mM UDP-グルクロン酸の存在下で反応を行い、以後同じ操作を実施する。
（ｈＥＲＧ試験）
心電図QT間隔延長のリスク評価を目的として、human ether-a-go-go related gene (hERG) チャンネルを発現させたHEK293細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流K+電流 (IKr) への作用を検討する。
全自動パッチクランプシステム (PatchXpress 7000A, Axon Instruments Inc.) を用い、ホールセルパッチクランプ法により、細胞を-80 mVの膜電位に保持した後、+50 mVの脱分極刺激を2秒間、さらに-50 mVの再分極刺激を2秒間与えた際に誘発されるIKrを記録する。発生する電流が安定した後、被検物質を目的の濃度で溶解させた細胞外液 (NaCl: 137 mmol/L、 KCl: 4 mmol/L、 CaCl2・2H2O: 1.8 mmol/L、 MgCl2・6H2O: 1 mmol/L、 グルコース: 10 mmol/L、 HEPES（4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、４−（２−ヒドロキシエチル）−１−ピペラジンエタンスルホン酸）: 10 mmol/L、 pH = 7.4) を室温条件下で、10分間細胞に適用させる。得られるIKrから、解析ソフト (DataXpress ver. 1、 Molecular Devices Corporation) を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、被検物質適用前の最大テール電流に対する阻害率を算出し、媒体適用群 (0.1 % ジメチルスルホキシド溶液) と比較して、被検物質のIKrへの影響を評価する。
心電図QT間隔延長のリスク評価を目的として、human ether-a-go-go related gene (hERG) チャンネルを発現させたHEK293細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流K+電流 (IKr) への作用を検討する。
全自動パッチクランプシステム (PatchXpress 7000A, Axon Instruments Inc.) を用い、ホールセルパッチクランプ法により、細胞を-80 mVの膜電位に保持した後、+50 mVの脱分極刺激を2秒間、さらに-50 mVの再分極刺激を2秒間与えた際に誘発されるIKrを記録する。発生する電流が安定した後、被検物質を目的の濃度で溶解させた細胞外液 (NaCl: 137 mmol/L、 KCl: 4 mmol/L、 CaCl2・2H2O: 1.8 mmol/L、 MgCl2・6H2O: 1 mmol/L、 グルコース: 10 mmol/L、 HEPES（4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、４−（２−ヒドロキシエチル）−１−ピペラジンエタンスルホン酸）: 10 mmol/L、 pH = 7.4) を室温条件下で、10分間細胞に適用させる。得られるIKrから、解析ソフト (DataXpress ver. 1、 Molecular Devices Corporation) を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、被検物質適用前の最大テール電流に対する阻害率を算出し、媒体適用群 (0.1 % ジメチルスルホキシド溶液) と比較して、被検物質のIKrへの影響を評価する。
（ＢＡ試験）
経口吸収性の検討実験材料と方法
（１）使用動物：６週齢の雄性Crl:CD(SD) ラットを日本チャールス・リバーより購入し、１週間の予備飼育の後、投与の３日以上前に頸静脈カニュレーションを施し、８週齢で実験に使用する。
（２）飼育条件：ラットは、飼育環境として温度は２０−２６℃、湿度は３０−７０％に設定され、照明は８：００〜２０：００点灯、２０：００〜８：００消灯のサイクルに設定している。予備飼育中、実験期間中は固形飼料（CRF-1、日本チャールス・リバー）および滅菌水道水を自由摂取させる。
（３）個体およびケージの識別：ラットの尾または背中に油性インクで個体番号を記し識別を行う。ケージには試験責任者名、入荷日、系統、性別、供給元を記したラベルを付け、予備飼育中は５匹／ケージで飼育する。実験開始後は１匹／ケージで飼育する。
（４）投与量、群分けの設定：経口投与、静脈内投与の投与量により、以下のように群を設定する。
経口投与 １ｍｇ／ｋｇ（ｎ＝２）
静脈内投与 ０.５ｍｇ／ｋｇ（ｎ＝２）
（５）投与液の調製：経口投与媒体として、０.５％メチルセルロース（４００ｃP）を用い懸濁液を調整する。静脈内投与媒体として、N，N-ジメチルアセトアミド／プロピレングリコール（＝１／１）を用い、可溶化溶液を調整する。
（６）投与方法：経口投与は、５ｍL／ｋｇの割合で経口ゾンデにより強制的に胃内に投与する。静脈内投与は、１ｍL／ｋｇの割合で注射針を付けたシリンジにより尾静脈から投与する。
（７）評価項目：採血は頸静脈カニューレからの採血とし、血漿中薬物濃度をＬＣ/ＭＳ/ＭＳを用いて測定する。
（８）統計解析：血漿中濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣからバイオアベイラビリティ（ＢＡ）を算出する。
経口吸収性の検討実験材料と方法
（１）使用動物：６週齢の雄性Crl:CD(SD) ラットを日本チャールス・リバーより購入し、１週間の予備飼育の後、投与の３日以上前に頸静脈カニュレーションを施し、８週齢で実験に使用する。
（２）飼育条件：ラットは、飼育環境として温度は２０−２６℃、湿度は３０−７０％に設定され、照明は８：００〜２０：００点灯、２０：００〜８：００消灯のサイクルに設定している。予備飼育中、実験期間中は固形飼料（CRF-1、日本チャールス・リバー）および滅菌水道水を自由摂取させる。
（３）個体およびケージの識別：ラットの尾または背中に油性インクで個体番号を記し識別を行う。ケージには試験責任者名、入荷日、系統、性別、供給元を記したラベルを付け、予備飼育中は５匹／ケージで飼育する。実験開始後は１匹／ケージで飼育する。
（４）投与量、群分けの設定：経口投与、静脈内投与の投与量により、以下のように群を設定する。
経口投与 １ｍｇ／ｋｇ（ｎ＝２）
静脈内投与 ０.５ｍｇ／ｋｇ（ｎ＝２）
（５）投与液の調製：経口投与媒体として、０.５％メチルセルロース（４００ｃP）を用い懸濁液を調整する。静脈内投与媒体として、N，N-ジメチルアセトアミド／プロピレングリコール（＝１／１）を用い、可溶化溶液を調整する。
（６）投与方法：経口投与は、５ｍL／ｋｇの割合で経口ゾンデにより強制的に胃内に投与する。静脈内投与は、１ｍL／ｋｇの割合で注射針を付けたシリンジにより尾静脈から投与する。
（７）評価項目：採血は頸静脈カニューレからの採血とし、血漿中薬物濃度をＬＣ/ＭＳ/ＭＳを用いて測定する。
（８）統計解析：血漿中濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣからバイオアベイラビリティ（ＢＡ）を算出する。
製剤例１
以下の成分を含有する顆粒剤を製造する。
成分 式（Ｉ）で示される化合物 10 mg
乳糖 700 mg
コーンスターチ 274 mg
HPC-L 16 mg
式（Ｉ）で示される化合物と乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末にHPC-L（低粘度ヒドロキシプロピルセルロース）水溶液を添加し、練合、造粒（押し出し造粒 孔径0.5〜1mm）、乾燥工程する。得られた乾燥顆粒を振動ふるい（12/60メッシュ）で櫛過し顆粒剤を得る。
以下の成分を含有する顆粒剤を製造する。
成分 式（Ｉ）で示される化合物 10 mg
乳糖 700 mg
コーンスターチ 274 mg
HPC-L 16 mg
式（Ｉ）で示される化合物と乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらをV型混合機にて混合する。混合末にHPC-L（低粘度ヒドロキシプロピルセルロース）水溶液を添加し、練合、造粒（押し出し造粒 孔径0.5〜1mm）、乾燥工程する。得られた乾燥顆粒を振動ふるい（12/60メッシュ）で櫛過し顆粒剤を得る。
製剤例２
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分 式（Ｉ）で示される化合物 15 mg
乳糖 90 mg
コーンスターチ 42 mg
HPC-L 3 mg
式（Ｉ）で示される化合物、乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらを混合し、混合末にHPC-L溶液を添加して練合、造粒、乾燥する。得られた乾燥顆粒を整粒後、その150mgを4号硬ゼラチンカプセルに充填する。
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分 式（Ｉ）で示される化合物 15 mg
乳糖 90 mg
コーンスターチ 42 mg
HPC-L 3 mg
式（Ｉ）で示される化合物、乳糖を60メッシュのふるいに通す。コーンスターチを120メッシュのふるいに通す。これらを混合し、混合末にHPC-L溶液を添加して練合、造粒、乾燥する。得られた乾燥顆粒を整粒後、その150mgを4号硬ゼラチンカプセルに充填する。
製剤例３
以下の成分を含有する錠剤を製造する。
成分 式（Ｉ）で示される化合物 10 mg
乳糖 90 mg
微結晶セルロース 30 mg
CMC-Na 15 mg
ステアリン酸マグネシウム 5 mg
式（Ｉ）で示される化合物、乳糖、微結晶セルロース、CMC-Na（カルボキシメチルセルロース ナトリウム塩）を60メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウム混合し、製錠用混合末を得る。本混合末を直打し、150mgの錠剤を得る。
以下の成分を含有する錠剤を製造する。
成分 式（Ｉ）で示される化合物 10 mg
乳糖 90 mg
微結晶セルロース 30 mg
CMC-Na 15 mg
ステアリン酸マグネシウム 5 mg
式（Ｉ）で示される化合物、乳糖、微結晶セルロース、CMC-Na（カルボキシメチルセルロース ナトリウム塩）を60メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウム混合し、製錠用混合末を得る。本混合末を直打し、150mgの錠剤を得る。
製剤例４
以下の成分を加温混合後、滅菌して注射剤とする。
成分 式（Ｉ）で示される化合物 3 mg
非イオン界面活性剤 15 mg
注射用精製水 1 ml
以下の成分を加温混合後、滅菌して注射剤とする。
成分 式（Ｉ）で示される化合物 3 mg
非イオン界面活性剤 15 mg
注射用精製水 1 ml
製剤例５
以下の成分を含有するハップ剤を製造する。
成分 式（Ｉ）で示される化合物 50 mg
水性基剤（5%エタノール/5%ブチレングリコール/90%精製水）950mg
グリセリン
カオリン
ポリビニルアルコール水溶液
水性基剤に式（Ｉ）で示される化合物を添加し、超音波を15分ほど照射した後、十分に攪拌し、溶液とする。グリセリン5部、カオリン1部、ポリビニルアルコール水溶液5部を均一に混合し、調製した溶液1部を添加する。これをさらに混合してペースト状物とし、不織布上に塗布してポリエステルフィルムで覆い、ハップ剤とする。
以下の成分を含有するハップ剤を製造する。
成分 式（Ｉ）で示される化合物 50 mg
水性基剤（5%エタノール/5%ブチレングリコール/90%精製水）950mg
グリセリン
カオリン
ポリビニルアルコール水溶液
水性基剤に式（Ｉ）で示される化合物を添加し、超音波を15分ほど照射した後、十分に攪拌し、溶液とする。グリセリン5部、カオリン1部、ポリビニルアルコール水溶液5部を均一に混合し、調製した溶液1部を添加する。これをさらに混合してペースト状物とし、不織布上に塗布してポリエステルフィルムで覆い、ハップ剤とする。
本発明の化合物は、Ｐ２Ｘ3および／またはＰ２Ｘ2/3受容体に対する拮抗作用を有し、Ｐ２Ｘ3および／またはＰ２Ｘ2/3受容体が関与する疾患または状態、例えば慢性疼痛、過活動膀胱に対して有用である。
Claims (13)
- 式（Ｉ）：
（式中、
Ｚ１は、保護されていてもよいヒドロキシまたは保護されていてもよいメルカプトであり；
Ｚ２は、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−もしくは−Ｓ（Ｏ）ｖ−であるか、または
（Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素または低級アルキル；
Ｒ６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換のアシルまたは置換もしくは非置換の低級アルコキシカルボニル；
ｐは、０〜２の整数）を形成し；
ｖは、０〜２の整数；
Ｚ３ａおよびＺ３ｂは、それぞれ独立して、水素、置換もしくは非置換の低級アルキルであるか、または、一緒になって、＝Ｏもしくは＝Ｓを形成し；
ｔは、０〜４の整数；
Ｒ４ａおよびＲ４ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
ｍおよびｎは、それぞれ独立して、０〜２の整数；
ｋは、０または１の整数；
環Ａは、シクロアルカン、シクロアルケン、芳香族炭素環またはヘテロ環；
Ｂは、シクロアルカンジイル、シクロアルケンジイル、芳香族炭素環ジイルまたはヘテロ環ジイルであり；
Ｒ１ａおよびＲ１ｂは、それぞれ独立して、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニル、置換もしくは非置換のスルファモイル、シアノ、ニトロまたは−Ｃ（Ｒ７ａ）＝Ｎ−Ｏ−Ｒ７ｂ；
Ｒ７ａおよびＲ７ｂは、それぞれ独立して、水素または置換もしくは非置換の低級アルキル；
Ｒ２は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルコキシ、置換もしくは非置換のアリールオキシ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
Ｒ３は、置換もしくは非置換のアルキル、置換もしくは非置換のアルコキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、カルボキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基；
である）で示される化合物（ただし、
（ｉ）環Ａがチアジアゾールであり、ｋが０であり、かつ、Ｒ１ａがメチルチオである化合物；
（ｉｉ）環Ａがベンゾチオフェンであり、ｋが０であり、Ｒ１ａがメチルスルホニルであり、かつ、Ｒ２が置換もしくは非置換のフリルまたは置換もしくは非置換のフェニルである化合物；
（ｉｉｉ）環Ａがチアゾールまたは７Ｈ−プリンであり、かつ、Ｒ２が置換もしくは非置換のフリルである化合物；
（ｉｖ）Ｒ３が式:
で示される基であり、ｔが１〜２の整数であり、かつ、環Ａがフランまたはベンゼンである化合物；
（ｖ）Ｒ２がｔ−ブチルまたは４−メチルオキシフェニルである化合物；
（ｖｉ）Ｒ２が置換もしくは非置換のアルキルであり（ただし、置換もしくは非置換のｉ−プロピルおよび置換もしくは非置換のｉ−ブチルを除く）、Ｒ３が置換もしくは非置換の炭素環または置換もしくは非置換のヘテロ環であり、かつ、ｋが０である化合物；
（ｖｉｉ）Ｒ２が置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロ環式基であり、かつ、Ｒ３がペンタン−３−イルである化合物；ならびに
（ｖｉｉｉ）以下の式：
で示される化合物を除く）もしくはその製薬上許容される塩またはそれらの溶媒和物。 - Ｒ２が、式：
（式中、Ｍｅはメチル、ｑは０〜４の整数）で示される基；
Ｒ３が、式：
（式中、Ｙは、ヒドロキシ、ハロゲン、シアノ、カルボキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のチオカルバモイル、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換の低級アルキルスルファモイル、置換もしくは非置換のアミノ、置換スルフィニル、置換スルホニルまたは置換もしくは非置換のヘテロ環式基であるか、または、ＹおよびＲ１４が、隣接する炭素原子に結合して、置換もしくは非置換のヘテロ環式基を形成してもよく；
Ｒ１４は、ハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルコキシ、置換もしくは非置換の低級アルキルチオ、置換もしくは非置換のアシル、カルボキシ、置換もしくは非置換の低級アルコキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、シアノまたはニトロ；
ｒは、０〜２の整数）で示される基である、請求項１記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- Ｚ３ａおよびＺ３ｂが、一緒になって、＝Ｏである、請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- ｔが、０である、請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- Ｚ２が、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｓ）−または−Ｓ（Ｏ）２−である、請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- Ｚ２が、−Ｃ（＝Ｏ）−である、請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- 式：
（式中、Ｚ１、Ｚ２およびＲ２は、請求項１と同意義。）
で示される基が、
式：
（式中、Ｒ２、Ｒ５ａ、Ｒ５ｂ、Ｒ６およびｐは請求項１と同意義。）
である、請求項２記載に記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- 式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、請求項１と同意義。）
で示される基が
式：
（式中、Ｚ１、Ｚ２、Ｚ３ａ、Ｚ３ｂ、Ｒ２およびＲ３は、請求項１と同意義。）で示される基である、請求項２記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物。
- 請求項１〜８のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
- Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である請求項１〜８記載の医薬組成物。
- 請求項１〜８記載のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の予防または治療方法。
- Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療および／または予防のための、請求項１〜８のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
- Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体が関与する疾患の治療薬および／または予防薬の製造のための、請求項１〜８のいずれかに記載の化合物、もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。
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| KR20090096890A (ko) | 2008-03-10 | 2009-09-15 | 전남대학교산학협력단 | 대장균에서 조류인플루엔자 바이러스의 뉴라미니다제 ｎ1을발현하기 위한 벡터 및 방법, 이의 사용방법, 및뉴라미니다제 저해제 |
| FR2929851B1 (fr) | 2008-04-09 | 2012-11-30 | Centre Nat Rech Scient | Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules |
-
2009
- 2009-09-24 EP EP09816142A patent/EP2336109A4/en not_active Withdrawn
- 2009-09-24 WO PCT/JP2009/066473 patent/WO2010035727A1/ja active Application Filing
- 2009-09-24 US US13/121,072 patent/US8575197B2/en not_active Expired - Fee Related
- 2009-09-24 TW TW098132205A patent/TW201016702A/zh unknown
- 2009-09-24 JP JP2010530843A patent/JP5637562B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US8575197B2 (en) | 2013-11-05 |
| US20110183939A1 (en) | 2011-07-28 |
| EP2336109A4 (en) | 2012-05-02 |
| WO2010035727A1 (ja) | 2010-04-01 |
| TW201016702A (en) | 2010-05-01 |
| JP5637562B2 (ja) | 2014-12-10 |
| EP2336109A1 (en) | 2011-06-22 |
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