JPWO2003011880A1

JPWO2003011880A1 - Glucopyranosyloxybenzylbenzene derivatives, pharmaceutical compositions containing the same, pharmaceutical uses thereof and intermediates for the production thereof

Info

Publication number: JPWO2003011880A1
Application number: JP2003517071A
Authority: JP
Inventors: 伏見　信彦; 信彦伏見; 史顕伊東; 伊佐治　正幸; 正幸伊佐治
Original assignee: Kissei Pharmaceutical Co Ltd
Current assignee: Kissei Pharmaceutical Co Ltd
Priority date: 2001-07-31
Filing date: 2002-07-25
Publication date: 2004-11-18
Also published as: WO2003011880A1

Abstract

本発明は、優れたヒトＳＧＬＴ２活性阻害作用を発現し、糖尿病、糖尿病性合併症、肥満症等の高血糖症に起因する疾患の予防又は治療薬として有用な、一般式（式中のＲ１は水素原子、水酸基、置換可アミノ基、シアノ基、カルバモイル基、置換可低級アルキル基、置換可低級アルコキシ基又は置換可環状アミノ基であり、Ｒ２は水素原子又は低級アルキル基であり、Ｒ３は置換可アリール基、置換可シクロアルキル基、置換可脂肪族複素環基又は置換可芳香族複素環基である）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、それを含有する医薬組成物、及びその医薬用途並びにその製造中間体を提供するものである。The present invention relates to a compound represented by the general formula (R1 in the formula: A hydrogen atom, a hydroxyl group, a substituted amino group, a cyano group, a carbamoyl group, a substituted lower alkyl group, a substituted lower alkoxy group or a substituted cyclic amino group, R2 is a hydrogen atom or a lower alkyl group; A glupyranosyloxybenzylbenzene derivative represented by an aryl group, a substituted cycloalkyl group, a substituted aliphatic heterocyclic group or a substituted aromatic heterocyclic group) or a pharmaceutically acceptable salt thereof Or a prodrug thereof, a pharmaceutical composition containing the same, a pharmaceutical use thereof, and an intermediate for the production thereof.

Description

技術分野
本発明は、医薬品として有用なグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、それを含有する医薬組成物、及びその医薬用途並びにその製造中間体に関するものである。
さらに詳しく述べれば、本発明は、ヒトＳＧＬＴ２活性阻害作用を発現し、糖尿病、糖尿病性合併症、肥満症等の高血糖症に起因する疾患の予防又は治療剤として有用な、一般式

（式中のＲ^１は水素原子、水酸基、アミノ基、モノ又はジ（低級アルキル）アミノ基、シアノ基、カルバモイル基、低級アルキル基、低級アルコキシ基、ヒドロキシ低級アルキル基、ヒドロキシ低級アルコキシ基、低級アルコキシ低級アルキル基、低級アルコキシ低級アルコキシ基、カルバモイル低級アルキル基、低級アルコキシカルボニル低級アルキル基、低級アルコキシカルボニル低級アルコキシ基、カルボキシ低級アルキル基、カルボキシ低級アルコキシ基、結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよく、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族環状アミノ基、または結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基であり、Ｒ^２は水素原子または低級アルキル基であり、Ｒ^３は置換基として低級アルキル基、低級アルコキシ基、ハロゲン原子および水酸基から選択される異種または同種の基を１〜３個有していてもよいアリール基、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい３〜７員環のシクロアルキル基、酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１または２個環内に含み、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族複素環基、または酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１〜４個環内に含み、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５または６員環の芳香族複素環基である）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、それを含有する医薬組成物、及びその医薬用途並びにその製造中間体に関するものである。
背景技術
糖尿病は食生活の変化や運動不足を背景とした生活習慣病の一つである。それ故、糖尿病患者には食事療法や運動療法が実施されているが、充分なコントロールや継続的実施が困難な場合、薬物療法が併用されている。現在、糖尿病治療薬としては、ビグアナイド薬、スルホニルウレア薬やインスリン感受性増強薬などが使用されている。しかしながら、ビグアナイド薬には乳酸アシドーシス、スルホニルウレア薬には低血糖、インスリン感受性増強薬には浮腫などの副作用が認められることがある上、肥満化を促進させることが懸念されている。そのため、このような問題を解消すべく新しい作用機序による糖尿病治療薬の開発が嘱望されている。
近年、腎臓において過剰な糖の再吸収を阻害することで尿糖の排泄を促進させて血糖値を低下させる、新しいタイプの糖尿病治療薬の研究開発が推進されている（Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．，Ｖｏｌ．７９，ｐｐ．１５１０−１５１５（１９８７））。また、腎臓の近位尿細管のＳ１領域にＳＧＬＴ２（ナトリウム依存性グルコース輸送担体２）が存在し、このＳＧＬＴ２が糸球体ろ過された糖の再吸収に主として関与していることが報告されている（Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．，Ｖｏｌ．９３，ｐｐ．３９７−４０４（１９９４））。それ故、ヒトＳＧＬＴ２を阻害することにより腎臓での過剰な糖の再吸収を抑制し、尿から過剰な糖を排泄させて血糖値を正常化することができる。従って、強力なヒトＳＧＬＴ２活性阻害作用を有し、新しい作用機序による糖尿病治療薬の早期開発が待望される。また、このような尿糖排泄促進薬は過剰な血糖を尿から排泄させるため、体内での糖の蓄積が減少することから、肥満症の防止又は軽減効果や利尿効果も期待できる。更には、高血糖症に起因し、糖尿病や肥満症の進展に伴い発症する各種の関連疾患にも有用であると考えられる。
発明の開示
本発明者らは、ヒトＳＧＬＴ２活性阻害作用を有する化合物を見出すべく鋭意検討した結果、前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体が、下記の如く優れたヒトＳＧＬＴ２阻害活性を発現するという知見を得、本発明を成すに至った。
本発明は、ヒトＳＧＬＴ２活性阻害作用を発現し、腎臓での糖の再吸収を抑制し過剰な糖を尿中に排泄させることにより、優れた血糖低下作用を発揮する、上記のグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、それを含有する医薬組成物、及びその医薬用途並びにその製造中間体を提供するものである。
即ち、本発明は、一般式

（式中のＲ^１は水素原子、水酸基、アミノ基、モノ又はジ（低級アルキル）アミノ基、シアノ基、カルバモイル基、低級アルキル基、低級アルコキシ基、ヒドロキシ低級アルキル基、ヒドロキシ低級アルコキシ基、低級アルコキシ低級アルキル基、低級アルコキシ低級アルコキシ基、カルバモイル低級アルキル基、低級アルコキシカルボニル低級アルキル基、低級アルコキシカルボニル低級アルコキシ基、カルボキシ低級アルキル基、カルボキシ低級アルコキシ基、結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよく、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族環状アミノ基、または結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基であり、Ｒ^２は水素原子または低級アルキル基であり、Ｒ^３は置換基として低級アルキル基、低級アルコキシ基、ハロゲン原子および水酸基から選択される異種または同種の基を１〜３個有していてもよいアリール基、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい３〜７員環のシクロアルキル基、酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１または２個環内に含み、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族複素環基、または酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１〜４個環内に含み、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５または６員環の芳香族複素環基である）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグに関するものである。
また、本発明は、前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグを有効成分して含有する医薬組成物、ヒトＳＧＬＴ２活性阻害剤および高血糖症に起因する疾患の予防又は治療剤に関するものである。
本発明は、前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグを有効量投与することからなる、高血糖症に起因する疾患の予防又は治療方法に関するものである。
本発明は、高血糖症に起因する疾患の予防又は治療用の医薬組成物を製造するための、前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグの使用に関するものである。
本発明は、（Ａ）前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、および（Ｂ）インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド１−類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、アルドース還元酵素阻害薬、終末糖化産物生成阻害薬、プロテインキナーゼＣ阻害薬、γ−アミノ酪酸受容体アンタゴニスト、ナトリウムチャンネルアンタゴニスト、転写因子ＮＦ−κＢ阻害薬、脂質過酸化酵素阻害薬、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ阻害薬、インスリン様成長因子−Ｉ、血小板由来成長因子、血小板由来成長因子類縁体、上皮増殖因子、神経成長因子、カルニチン誘導体、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル、スロデキシド、Ｙ−１２８、ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬、フィブラート系化合物、β_３−アドレナリン受容体アゴニスト、アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬、プロブコール、甲状腺ホルモン受容体アゴニスト、コレステロール吸収阻害薬、リパーゼ阻害薬、ミクロソームトリグリセリドトランスファープロテイン阻害薬、リポキシゲナーゼ阻害薬、カルニチンパルミトイルトランスフェラーゼ阻害薬、スクアレン合成酵素阻害薬、低比重リポ蛋白受容体増強薬、ニコチン酸誘導体、胆汁酸吸着薬、ナトリウム共役胆汁酸トランスポーター阻害薬、コレステロールエステル転送タンパク阻害薬、食欲抑制薬、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニスト、利尿薬、カルシウム拮抗薬、血管拡張性降圧薬、交換神経遮断薬、中枢性降圧薬、α_２−アドレナリン受容体アゴニスト、抗血小板薬、尿酸生成阻害薬、尿酸排泄促進薬および尿アルカリ化薬からなる群より選択される少なくとも１種の薬剤を組合わせてなる医薬に関するものである。
本発明は、（Ａ）前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、および（Ｂ）インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、アルドース還元酵素阻害薬、終末糖化産物生成阻害薬、プロテインキナーゼＣ阻害薬、γ−アミノ酪酸受容体アンタゴニスト、ナトリウムチャンネルアンタゴニスト、転写因子ＮＦ−κＢ阻害薬、脂質過酸化酵素阻害薬、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ阻害薬、インスリン様成長因子−Ｉ、血小板由来成長因子、血小板由来成長因子類縁体、上皮増殖因子、神経成長因子、カルニチン誘導体、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル、スロデキシド、Ｙ−１２８、ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬、フィブラート系化合物、β_３−アドレナリン受容体アゴニスト、アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬、プロブコール、甲状腺ホルモン受容体アゴニスト、コレステロール吸収阻害薬、リパーゼ阻害薬、ミクロソームトリグリセリドトランスファープロテイン阻害薬、リポキシゲナーゼ阻害薬、カルニチンパルミトイルトランスフェラーゼ阻害薬、スクアレン合成酵素阻害薬、低比重リポ蛋白受容体増強薬、ニコチン酸誘導体、胆汁酸吸着薬、ナトリウム共役胆汁酸トランスポーター阻害薬、コレステロールエステル転送タンパク阻害薬、食欲抑制薬、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニスト、利尿薬、カルシウム拮抗薬、血管拡張性降圧薬、交換神経遮断薬、中枢性降圧薬、α_２−アドレナリン受容体アゴニスト、抗血小板薬、尿酸生成阻害薬、尿酸排泄促進薬および尿アルカリ化薬からなる群より選択される少なくとも１種の薬剤を有効量投与することからなる、高血糖症に起因する疾患の予防又は治療方法に関するものである。
本発明は、高血糖症に起因する疾患の予防又は治療用の医薬組成物を製造するための、（Ａ）前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ、および（Ｂ）インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、アルドース還元酵素阻害薬、終末糖化産物生成阻害薬、プロテインキナーゼＣ阻害薬、γ−アミノ酪酸受容体アンタゴニスト、ナトリウムチャンネルアンタゴニスト、転写因子ＮＦ−κＢ阻害薬、脂質過酸化酵素阻害薬、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ阻害薬、インスリン様成長因子−Ｉ、血小板由来成長因子、血小板由来成長因子類縁体、上皮増殖因子、神経成長因子、カルニチン誘導体、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル、スロデキシド、Ｙ−１２８、ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬、フィブラート系化合物、β_３−アドレナリン受容体アゴニスト、アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬、プロブコール、甲状腺ホルモン受容体アゴニスト、コレステロール吸収阻害薬、リパーゼ阻害薬、ミクロソームトリグリセリドトランスファープロテイン阻害薬、リポキシゲナーゼ阻害薬、カルニチンパルミトイルトランスフェラーゼ阻害薬、スクアレン合成酵素阻害薬、低比重リポ蛋白受容体増強薬、ニコチン酸誘導体、胆汁酸吸着薬、ナトリウム共役胆汁酸トランスポーター阻害薬、コレステロールエステル転送タンパク阻害薬、食欲抑制薬、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニスト、利尿薬、カルシウム拮抗薬、血管拡張性降圧薬、交換神経遮断薬、中枢性降圧薬、α_２−アドレナリン受容体アゴニスト、抗血小板薬、尿酸生成阻害薬、尿酸排泄促進薬および尿アルカリ化薬からなる群より選択される少なくとも１種の薬剤の使用に関するものである。
更に、本発明は、一般式

（式中のＱは水酸基または２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシルオキシ基であり、Ｒ^１１は水素原子、保護基を有していてもよい水酸基、保護基を有するアミノ基、保護基を有するモノ（低級アルキル）アミノ基、ジ（低級アルキル）アミノ基、シアノ基、カルバモイル基、低級アルキル基、低級アルコキシ基、保護基を有していてもよいヒドロキシ低級アルキル基、保護基を有していてもよいヒドロキシ低級アルコキシ基、低級アルコキシ低級アルキル基、低級アルコキシ低級アルコキシ基、カルバモイル低級アルキル基、低級アルコキシカルボニル低級アルキル基、低級アルコキシカルボニル低級アルコキシ基、カルボキシ低級アルキル基、カルボキシ低級アルコキシ基、結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよく、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族環状アミノ基、または結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基であり、Ｒ^２は水素原子または低級アルキル基であり、Ｒ^１３は置換基として低級アルキル基、低級アルコキシ基、ハロゲン原子および保護基を有していてもよい水酸基から選択される異種または同種の基を１〜３個有していてもよいアリール基、置換基として低級アルキル基、低級アルコキシ基、保護基を有していてもよい水酸基および保護基を有するアミノ基から選択される基を有していてもよい３〜７員環のシクロアルキル基、酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１または２個環内に含み、置換基として低級アルキル基、低級アルコキシ基、保護基を有していてもよい水酸基および保護基を有するアミノ基から選択される基を有していてもよい５または６員環の脂肪族複素環基、または酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１〜４個環内に含み、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５または６員環の芳香族複素環基である）で表されるベンジルフェノール誘導体またはその塩に関するものである。
本発明において、プロドラッグとは、生体内において活性本体である前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体に変換される化合物をいう。前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩のプロドラッグとしては、例えば、一般式

〔式中のＰ^１は水素原子またはプロドラッグを構成する基であり、Ｒ^１０は水素原子、アミノ基、モノ又はジ（低級アルキル）アミノ基、シアノ基、カルバモイル基、低級アルキル基、低級アルコキシ基、低級アルコキシ低級アルキル基、低級アルコキシ低級アルコキシ基、カルバモイル低級アルキル基、低級アルコキシカルボニル低級アルキル基、低級アルコキシカルボニル低級アルコキシ基、カルボキシ低級アルキル基、カルボキシ低級アルコキシ基、結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよく、置換基として低級アルキル基、低級アルコキシ基、水酸基、プロドラッグを構成する基を有する水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族環状アミノ基、または結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基、または一般式Ｐ^２−Ｏ−Ａ^１−（式中のＰ^２は水素原子またはプロドラッグを構成する基であり、Ａ^１は単結合、低級アルキレン基または低級アルキレンオキシ基である）であり、Ｒ^２は水素原子または低級アルキル基であり、Ｒ^３０は置換基として低級アルキル基、低級アルコキシ基、ハロゲン原子、水酸基およびプロドラッグを構成する基を有する水酸基から選択される異種または同種の基を１〜３個有していてもよいアリール基、置換基として低級アルキル基、低級アルコキシ基、水酸基、プロドラッグを構成する基を有する水酸基およびアミノ基から選択される基を有していてもよい３〜７員環のシクロアルキル基、酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１または２個環内に含み、置換基として低級アルキル基、低級アルコキシ基、水酸基、プロドラッグを構成する基を有する水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族複素環基、または酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１〜４個環内に含み、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５または６員環の芳香族複素環基である）で表される、少なくても最低１つプロドラッグを構成する基を有するグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩を挙げることができる。
プロドラッグを構成する基としては、例えば、低級アシル基、低級アルコキシ低級アシル基、低級アルコキシカルボニル低級アシル基、低級アルコキシカルボニル基、低級アルコキシ低級アルコキシカルボニル基等のプロドラッグにおいて通常使用することができる水酸基の保護基を挙げることができる。本発明の化合物の内プロドラッグにおいては、プロドラッグを構成する基は任意の水酸基に位置することができ、また複数でも構わない。
本発明において、低級アルキル基とは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ−ペンチル基、ヘキシル基等の炭素数１〜６の直鎖状または枝分かれ状のアルキル基をいう。低級アルコキシ基とは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ネオペンチルオキシ基、ｔｅｒｔ−ペンチルオキシ基、ヘキシルオキシ基等の炭素数１〜６の直鎖状または枝分かれ状のアルコキシ基をいう。低級アルキレン基とは、メチレン基、エチレン基、トリメチレン基、プロピレン基等の炭素数１〜６の直鎖状または枝分かれ状のアルキレン基をいう。低級アルキレンオキシ基とは、メチレンオキシ基、エチレンオキシ基、プロピレンオキシ基、トリメチレンオキシ基等の炭素数１〜６の直鎖状または枝分かれ状のアルキレンオキシ基をいう。ヒドロキシ低級アルキル基とは、ヒドロキシメチル基、２−ヒドロキシエチル基、１−ヒドロキシエチル基、３−ヒドロキシプロピル基、２−ヒドロキシプロピル基、１−ヒドロキシプロピル基、２−ヒドロキシ−１−メチルエチル基、４−ヒドロキシブチル基、３−ヒドロキシブチル基、２−ヒドロキシブチル基、１−ヒドロキシブチル基、５−ヒドロキシペンチル基、４−ヒドロキシペンチル基、３−ヒドロキシペンチル基、２−ヒドロキシペンチル基、１−ヒドロキシペンチル基、６−ヒドロキシヘキシル基、５−ヒドロキシヘキシル基、４−ヒドロキシヘキシル基、３−ヒドロキシヘキシル基、２−ヒドロキシヘキシル基、１−ヒドロキシヘキシル基等の炭素数１〜６の直鎖状または枝分かれ状のヒドロキシアルキル基をいう。ヒドロキシ低級アルコキシ基とは、２−ヒドロキシエトキシ基、３−ヒドロキシプロポキシ基、２−ヒドロキシプロポキシ基、２−ヒドロキシ−１−メチルエトキシ基、４−ヒドロキシブトキシ基、３−ヒドロキシブトキシ基、２−ヒドロキシブトキシ基、５−ヒドロキシペンチルオキシ基、４−ヒドロキシペンチルオキシ基、３−ヒドロキシペンチルオキシ基、２−ヒドロキシペンチルオキシ基、６−ヒドロキシヘキシルオキシ基、５−ヒドロキシヘキシルオキシ基、４−ヒドロキシヘキシルオキシ基、３−ヒドロキシヘキシルオキシ基、２−ヒドロキシヘキシルオキシ基等の炭素数１〜６の直鎖状または枝分かれ状のヒドロキシアルコキシ基をいう。低級アルコキシ低級アルキル基とは、上記低級アルキル基でＯ−アルキル化された上記ヒドロキシ低級アルキル基をいい、低級アルコキシ低級アルコキシ基とは、上記低級アルキル基でＯ−アルキル化された上記ヒドロキシ低級アルコキシ基をいう。カルバモイル低級アルキル基とは、カルバモイル基で置換された上記低級アルキル基をいう。モノ又はジ（低級アルキル）アミノ基とは、上記低級アルキル基でモノ置換されたアミノ基或いは同一または異なる上記低級アルキル基でジ置換されたアミノ基をいう。低級アルコキシカルボニル基とは、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ−ブトキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基、ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、ネオペンチルオキシカルボニル基、ｔｅｒｔ−ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基、シクロヘキシルオキシカルボニル基等の炭素数２〜７の直鎖状または枝分かれ状、或いは炭素数４〜７の環状のアルコキシカルボニル基をいう。低級アルコキシカルボニル低級アルキル基とは、上記低級アルコキシカルボニル基で置換された上記低級アルキル基をいう。低級アルコキシカルボニル低級アルコキシ基とは、上記低級アルコキシカルボニル基で置換された上記低級アルコキシ基をいう。低級アルコキシ低級アルコキシカルボニル基とは、２−メトキシエトキシカルボニル基等の上記低級アルコキシ基で置換された上記低級アルコキシカルボニル基をいう。カルボキシ低級アルキル基とは、カルボキシ基で置換された上記低級アルキル基をいう。カルボキシ低級アルコキシ基とは、カルボキシ基で置換された上記低級アルコキシ基をいう。アリール基とは、フェニル基、ナフチル基等の１〜３環性の芳香族炭素環基をいう。３〜７員環のシクロアルキル基とは、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等の３〜７員環の脂肪族炭素環基をいう。低級アシル基とは、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基、ヘキサノイル基、シクロヘキシルカルボニル基等の炭素数２〜７の直鎖状または枝分かれ状、或いは炭素数４〜７の環状のアシル基をいう。低級アルコキシ低級アシル基とは、上記低級アルコキシ基で置換された上記低級アシル基をいう。低級アルコキシカルボニル低級アシル基とは、３−（エトキシカルボニル）プロピオニル基等の上記低級アルコキシカルボニル基で置換された上記低級アシル基をいう。酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１または２個環内に含む５または６員環の脂肪族複素環基とは、ピロリジン、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、テトラヒドロフラン、テトラヒドロピラン、オキサゾリジン等の脂肪族複素環から誘導される１価の基をいう。結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよい５または６員環の脂肪族環状アミノ基とは、上述の脂肪族複素環基の中、１−ピロリジニル基、ピラゾリジニル基、ピペリジノ基、ピペラジニル基、モルホリノ基、チオモルホリノ基、３−オキサゾリジニル基等の窒素原子含有の脂肪族複素環から誘導される環状アミノ基をいう。酸素原子、硫黄原子および窒素原子から選択される異種または同種のヘテロ原子を１〜４個環内に含む５または６員環の芳香族複素環基とは、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、ピラゾール、イミダゾール、フラザン、トリアゾール、テトラゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアジン等の芳香族複素環から誘導される１価の基をいう。結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよい５員環の芳香族環状アミノ基とは、上述の芳香族複素環基の中、１−ピロリル基、ピラゾリル基、１−イミダゾリル基、１−トリアゾリル基、１−テトラゾリル基等の窒素原子含有の芳香族複素環から誘導される環状アミノ基をいう。
各種製造中間体における水酸基の保護基とは、上述のプロドラッグにおいて通常使用することができる水酸基の保護基の他、一般的な有機合成反応において用いられる水酸基の保護基をいい、具体的には、ベンジル基、メチル基、メトキシメチル基、アセチル基、ベンゾイル基、ｔｅｒｔ−ブチルジメチルシリル基、２−トリメチルシリルエトキシメチル基等を例示することができる。各種製造中間体におけるアミノ基の保護基とは、ベンジル基、ｐ−メトキシベンジル基、低級アシル基（例えば、アセチル基、フタロイル基）、低級アルコキシカルボニル基（例えば、ｔｅｒｔ−ブトキシカルボニル基、ベンジルオキシカルボニル基）等の一般的な有機合成反応において用いられるアミノ基の保護基をいう。
本発明の化合物において、Ｒ^３としては結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよく、置換基として低級アルキル基、低級アルコキシ基、水酸基およびアミノ基から選択される基を有していてもよい５または６員環の脂肪族環状アミノ基、または結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基が好ましく、結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよく、置換基として低級アルキル基および低級アルコキシ基から選択される異種または同種の基を１〜３個有していてもよい５員環の芳香族環状アミノ基が更に好ましい。結合部位の窒素原子の他に酸素原子、硫黄原子および窒素原子から選択されるヘテロ原子を１個環内に含んでいてもよい５または６員環の脂肪族環状アミノ基としては、１−ピロリジニル基、ピペリジノ基、ピペラジニル基等が好ましく、１−ピロリジニル基が更に好ましい。結合部位の窒素原子の他に更に窒素原子を１〜３個環内に含んでいてもよい５員環の芳香族環状アミノ基としては、１−ピロリル基、ピラゾリル基等が好ましく、ピラゾリル基が更に好ましい。
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体及びそのプロドラッグは、例えば、本発明の下記一般式（ＩＩＩ）で表されるベンジルフェノール誘導体を用いて、以下の方法に従い製造することができる。

（式中のＸ^１はトリクロロアセトイミドイルオキシ基、アセトキシ基、臭素原子、フッ素原子等の脱離基であり、Ｘ^２は臭素原子、塩素原子等の脱離基であり、Ｐ^０はプロドラッグを構成する基であり、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^１１およびＲ^１３は前記と同じ意味をもつ）
工程１
前記一般式（ＩＩＩ）で表されるベンジルフェノール誘導体またはその塩を２，３，４，６−テトラ−Ｏ−アセチル−１−Ｏ−トリクロロアセトイミドイル−α−Ｄ−グルコピラノース、２，３，４，６−テトラ−Ｏ−アセチル−１−Ｏ−トリクロロアセトイミドイル−β−Ｄ−グルコピラノース、１，２，３，４，６−ペンタ−Ｏ−アセチル−β−Ｄ−グルコピラノース、２，３，４，６−テトラ−Ｏ−アセチル−α−Ｄ−グルコピラノシルブロミド、２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシルフルオリド等の前記一般式（ＩＶ）で表される糖供与体を用いて、不活性溶媒中、三フッ化ホウ素−ジエチルエーテル錯体、トリフルオロメタンスルホン酸銀、塩化第二すず、トリフルオロメタンスルホン酸トリメチルシリルなどの活性化剤の存在下、或いはテトラ（ｎ−ブチル）アンモニウムクロリド、ベンジルトリ（ｎ−ブチル）アンモニウムクロリド、ベンジルトリ（ｎ−ブチル）アンモニウムブロミド、テトラ（ｎ−ブチル）アンモニウム硫酸水素塩等の相間移動触媒の存在下または非存在下および水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の塩基の存在下に配糖化させることにより前記一般式（Ｖ）で表される配糖体を製造することができる。用いられる溶媒としては、例えば、塩化メチレン、トルエン、アセトニトリル、ニトロメタン、酢酸エチル、ジエチルエーテル、クロロホルム、水、アセトン、それらの混合溶媒などを挙げることができ、反応温度は通常−３０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分間〜１日間である。尚、置換基Ｒ^１１又は／及びＲ^１３において水酸基やアミノ基の保護基を有する化合物は、上記工程の反応終了後に常法に従い適宜処理して当該保護基を除去して工程２に供しても構わない。
工程２
前記一般式（Ｖ）で表される配糖体をアルカリ加水分解させて水酸基の保護基を除去することにより本発明の化合物（Ｉ）を製造することができる。用いられる溶媒としては、例えば、水、メタノール、エタノール、テトラヒドロフラン、それらの混合溶媒などを挙げることができ、塩基性物質としては、例えば、水酸化ナトリウム、ナトリウムメトキシド、ナトリウムエトキシドなどを使用することができる。処理温度は通常０℃〜還流温度であり、処理時間は使用する原料物質や溶媒、処理温度などにより異なるが、通常３０分間〜６時間である。尚、置換基Ｒ^１１又は／及びＲ^１３において水酸基やアミノ基の保護基を有する場合、当該保護基の種類に応じ、上記処理方法を常法に従い適宜変更して実施することもでき、または上記工程の反応終了後に別途保護基の除去を常法に従い実施することにより所望の化合物（Ｉ）に誘導することができる。
工程３
前記一般式（Ｉ）で表される化合物の水酸基を前記一般式（ＶＩ）で表される保護化試薬を用いて、不活性溶媒中又は無溶媒下、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピコリン、ルチジン、コリジン、キヌクリジン、１，２，２，６，６−ペンタメチルピペリジン、１，４−ジアザビシクロ〔２．２．２〕オクタン等の塩基の存在下にプロドラッグ化した後、必要に応じて、クロマトグラフィー等を用いて所望の化合物を分離するか、或いは常法に従い、反応前に適宜導入した保護基を反応後適宜除去することにより前記一般式（Ｉ）で表される化合物のプロドラッグ（例えば、前記一般式（ＩＡ）のプロドラッグ）を製造することができる。プロドラッグ化の反応に用いられる溶媒としては、例えば、塩化メチレン、アセトニトリル、酢酸エチル、ジイソプロピルエーテル、クロロホルム、テトラヒドロフラン、ジメトキシエタン、１，４−ジオキサン、アセトン、ｔｅｒｔ−ブタノール、それらの混合溶媒などを挙げることができ、反応温度は通常−４０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分間〜２日間である。
また、前記一般式（Ｉ）で表される本発明の化合物の中、下記一般式（Ｉａ）で表される化合物は、例えば、下記一般式（Ｉｂ）で表されるフェノール誘導体を用いて、以下の方法に従い製造することもできる。

（式中のＲ^４は低級アルコキシ基、ヒドロキシ低級アルコキシ基、低級アルコキシ低級アルコキシ基、低級アルコキシカルボニル低級アルコキシ基またはカルボキシ低級アルコキシ基であり、Ｒ^５は低級アルキル基、保護基を有していてもよいヒドロキシ低級アルキル基、低級アルコキシ低級アルキル基または低級アルコキシカルボニル低級アルキル基であり、Ｘ^３は塩素原子、臭素原子、ヨウ素原子、メシルオキシ基、トシルオキシ基等の脱離基であり、Ｒ^２およびＲ^３は前記と同じ意味をもつ）
工程４
前記一般式（Ｉｂ）で表されるフェノール誘導体を、水素化ナトリウム、炭酸カリウム、炭酸セシウム、カリウムｔｅｒｔ−ブトキシド、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム等の塩基性物質の存在下、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリル、それらの混合溶媒等の溶媒中で前記一般式（ＶＩＩ）で表されるアルキル化剤を用いてＯ−アルキル化した後、所望に応じ常法に従い保護基を除去することにより前記一般式（Ｉａ）で表される化合物を製造することができる。反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分間〜１日間である。
尚、前記工程２の原料物質として用いられる前記一般式（Ｖ）で表される本発明の化合物の中、Ｒ^１１が保護基を有するモノ（低級アルキル）アミノ基である化合物は、相当するＲ^１１が保護基を有するアミノ基である化合物と低級アルキルハライド、メシル酸エステル、トシル酸エステル等の適当な低級アルキル基導入試薬とを、水素化ナトリウム、炭酸カリウム等の塩基性物質の存在下、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、それらの混合溶媒等の溶媒中で反応させることにより製造することができる。
前記製造方法において出発物質として用いられる本発明の前記一般式（ＩＩＩ）で表される化合物およびその塩は、例えば、以下の方法に従い製造することができる。

（式中のＭは水素原子または水酸基の保護基であり、ＹおよびＺはどちらか一方がＭｇＢｒ、ＭｇＣｌ、ＭｇＩまたはリチウム原子であり、他方がホルミル基であり、Ｒ^２、Ｒ^１１およびＲ^１３は前記と同じ意味をもつ）
工程Ａ
前記一般式（ＶＩＩＩ）で表されるベンズアルデヒド誘導体と前記一般式（ＩＸ）で表されるグリニャール試薬またはリチウム試薬、若しくは前記一般式（ＶＩＩＩ）で表されるグリニャール試薬またはリチウム試薬と前記一般式（ＩＸ）で表されるベンズアルデヒド誘導体を、不活性溶媒中、縮合させることにより前記一般式（Ｘ）で表される化合物を製造することができる。用いられる溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、それらの混合溶媒などを挙げることができ、反応温度は通常−７８℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分間〜１日間である。
工程Ｂ
前記一般式（Ｘ）で表される化合物を、不活性溶媒中、Ｄｅｓｓ−Ｍａｒｔｉｎ試薬を用いて酸化することにより前記一般式（ＸＩ）で表される化合物を製造することができる。用いられる溶媒としては、例えば、塩化メチレン、クロロホルム、アセトニトリル、それらの混合溶媒などを挙げることができ、反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１時間〜１日間である。
工程Ｃ
前記一般式（ＸＩ）で表される化合物の保護基Ｍを常法に従い除去した後（Ｍが水素原子の場合は不要）、（１）不活性溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ，Ｎ−ジメチルアミノピリジン等の塩基の存在下、クロロギ酸メチルと縮合し、（２）得られた炭酸エステル誘導体を水素化ホウ素ナトリウム等の還元剤を用いて還元することにより、本発明の前記一般式（ＩＩＩ）の化合物を製造することができる。反応（１）において、用いられる溶媒としては、例えば、テトラヒドロフラン、塩化メチレン、アセトニトリル、酢酸エチル、ジエチルエーテル、それらの混合溶媒などを挙げることができ、反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分間〜１日間である。反応（２）において、用いられる溶媒としては、例えば、テトラヒドロフランと水との混合溶媒などを挙げることができ、反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１時間〜１日間である。尚、Ｒ^１１が低級アルコキシカルボニル基である場合は、別途、不活性溶媒中、水素化リチウムアルミニウム等の還元剤を用いてヒドロキシメチル基に還元した後、常法に従い水酸基を保護することにより本発明の前記一般式（ＩＩＩ）の化合物に誘導することができる。還元時に用いられる溶媒としては、例えば、ジエチルエーテル、テトラヒドロフラン、それらの混合溶媒などを挙げることができ、反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分間〜１日間である。また、本発明の前記一般式（ＩＩＩ）の化合物は、常法に従いナトリウム塩、カリウム塩等の塩に変換することができる。
工程Ｄ
前記一般式（Ｘ）で表される化合物を、不活性溶媒中、塩酸等の酸の存在下または非存在下、パラジウム炭素粉末等のパラジウム系触媒を用いて接触還元した後、必要に応じて保護基を常法に従い除去や導入することにより本発明の前記一般式（ＩＩＩ）の化合物を製造することができる。接触還元において用いられる溶媒としては、例えば、メタノール、エタノール、テトラヒドロフラン、酢酸エチル、酢酸、イソプロパノール、それらの混合溶媒などを挙げることができ、反応温度は通常室温〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分間〜１日間である。尚、Ｒ^１１が低級アルコキシカルボニル基である場合は、別途、不活性溶媒中、水素化リチウムアルミニウム等の還元剤を用いてヒドロキシメチル基に還元した後、常法に従い水酸基を保護することにより本発明の前記一般式（ＩＩＩ）の化合物に誘導することができる。還元時に用いられる溶媒としては、例えば、ジエチルエーテル、テトラヒドロフラン、それらの混合溶媒などを挙げることができ、反応温度は通常０℃〜還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分間〜１日間である。また、本発明の前記一般式（ＩＩＩ）の化合物は、常法に従いナトリウム塩、カリウム塩等の塩に変換することができる。
前記製造方法において、前記一般式（ＩＩＩ）、（Ｖ）、（ＶＩＩＩ）、（Ｘ）及び（ＸＩ）で表される化合物の中、Ｒ^１１が保護基を有するアミノ基、保護基を有するモノ（低級アルキル）アミノ基、ジ（低級アルキル）アミノ基、シアノ基、カルバモイル基、保護基を有していてもよいヒドロキシ低級アルキル基、低級アルコキシ低級アルキル基、カルバモイル低級アルキル基、カルボキシ低級アルキル基、低級アルコキシカルボニル低級アルキル基等の置換基である化合物は、置換基として低級アルコキシカルボニル基を有する相当する化合物を用いて、常法に従い適宜変換した後、所望に応じて保護基を導入して、次工程（工程Ａ〜Ｄ、工程１〜２）に供することもできる。
また、前記製造方法において出発物質として用いられる本発明の前記一般式（ＩＩＩ）で表される化合物およびその塩は、以下の方法に従い製造することもできる。

（式中のＸ^４は塩素原子等の脱離基であり、Ｒ^２、Ｒ^１１およびＲ^１３は前記と同じ意味をもつ）
工程Ｅ
前記一般式（ＸＩＩ）で表されるフェノール誘導体を、前記一般式（ＸＩＩＩ）で表されるフェニルメチル誘導体を用いて、無溶媒中、水酸化リチウム等の塩基性物質の存在下にベンジル化することにより前記一般式（ＩＩＩ）で表される化合物を製造することができる。反応温度は通常５０〜２００℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分間〜１日間である。
前記製造方法において得られる本発明の化合物は、慣用の分離手段である分別再結晶法、クロマトグラフィーを用いた精製法、溶媒抽出法、固相抽出法等により単離精製することができる。
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体およびそのプロドラッグは、常法により、その薬理学的に許容される塩とすることができる。このような塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの鉱酸との酸付加塩、ギ酸、酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、プロピオン酸、クエン酸、アジピン酸、オレイン酸、ステアリン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩、２−アミノエタノール、ピペリジン、モルホリン、ピロリジン等の有機アミンとの塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩を挙げることができる。
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体およびそのプロドラッグには、水和物やエタノール等の医薬品として許容される溶媒との溶媒和物も含まれる
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体およびそのプロドラッグのうち、グルコピラノシルオキシ部分を除き不斉炭素原子を有する化合物には、Ｒ配置の化合物とＳ配置の化合物の２種類の光学異性体が存在するが、本発明においてはいずれの光学異性体を使用してもよく、それらの光学異性体の混合物であっても構わない。
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体、その薬理学的に許容される塩及びそれらのプロドラッグは、例えば、下記のヒトＳＧＬＴ２活性阻害作用測定試験において強力なヒトＳＧＬＴ２活性阻害作用を発揮し、優れたヒトＳＧＬＴ２活性阻害作用により血糖降下作用を発揮する。それ故、糖尿病、糖尿病性合併症（例えば、網膜症、神経障害、腎症、潰瘍、大血管症）、肥満症、高インスリン血症、糖代謝異常、高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、アテローム性動脈硬化症、高血圧、うっ血性心不全、浮腫、高尿酸血症、痛風等の高血糖症に起因する疾患の予防または治療薬として極めて有用である。
また、本発明の化合物は、ＳＧＬＴ２活性阻害薬以外の少なくとも１種の薬剤と適宜組み合わせて使用することもできる。本発明の化合物と組み合わせて使用できる薬剤としては、例えば、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン製剤、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール（Ｄ−ｃｈｉｒｏｉｎｏｓｉｔｏｌ）、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、アルドース還元酵素阻害薬、終末糖化産物（ａｄｖａｎｃｅｄｇｌｙｃａｔｉｏｎｅｎｄｐｒｏｄｕｃｔｓ）生成阻害薬、プロテインキナーゼＣ阻害薬、γ−アミノ酪酸受容体アンタゴニスト、ナトリウムチャンネルアンタゴニスト、転写因子ＮＦ−κＢ阻害薬、脂質過酸化酵素阻害薬、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ（Ｎ−ａｃｅｔｙｌａｔｅｄ−α−ｌｉｎｋｅｄ−ａｃｉｄ−ｄｉｐｅｐｔｉｄａｓｅ）阻害薬、インスリン様成長因子−Ｉ、血小板由来成長因子（ＰＤＧＦ）、血小板由来成長因子（ＰＤＧＦ）類縁体（例えば、ＰＤＧＦ−ＡＡ、ＰＤＧＦ−ＢＢ、ＰＤＧＦ−ＡＢ）、上皮増殖因子（ＥＧＦ）、神経成長因子、カルニチン誘導体、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル（ｂｉｍｏｃｌｏｍｏｌ）、スロデキシド（ｓｕｌｏｄｅｘｉｄｅ）、Ｙ−１２８、ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬、フィブラート系化合物、β_３−アドレナリン受容体アゴニスト、アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬、プロブコール、甲状腺ホルモン受容体アゴニスト、コレステロール吸収阻害薬、リパーゼ阻害薬、ミクロソームトリグリセリドトランスファープロテイン阻害薬、リポキシゲナーゼ阻害薬、カルニチンパルミトイルトランスフェラーゼ阻害薬、スクアレン合成酵素阻害薬、低比重リポ蛋白受容体増強薬、ニコチン酸誘導体、胆汁酸吸着薬、ナトリウム共役胆汁酸トランスポーター阻害薬、コレステロールエステル転送タンパク阻害薬、食欲抑制薬、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニスト、利尿薬、カルシウム拮抗薬、血管拡張性降圧薬、交換神経遮断薬、中枢性降圧薬、α_２−アドレナリン受容体アゴニスト、抗血小板薬、尿酸生成阻害薬、尿酸排泄促進薬、尿アルカリ化薬等を挙げることができる。
本発明の化合物と上記の薬剤を１種類又はそれ以上組合わせて使用する場合、本発明は、単一の製剤としての同時投与、別個の製剤としての同一又は異なる投与経路による同時投与、及び別個の製剤としての同一又は異なる投与経路による間隔をずらした投与のいずれの投与形態を含み、本発明の化合物と上記の薬剤を組合わせてなる医薬とは、上記の如く単一製剤としての投与形態や別個の製剤を組み合わせた投与形態を含む。
本発明の化合物は、１種類又はそれ以上の上記薬剤と適宜組合わせて使用することにより、上記疾患の予防又は治療上相加効果以上の有利な効果を得ることができる。または、同様に、単独に使用する場合に比較してその使用量を減少させたり、或いは併用するＳＧＬＴ２活性阻害薬以外の薬剤の副作用を回避又は軽減させることができる。
組合わせて使用される薬剤の具体的な化合物や処置すべき好適な疾患について下記の通り例示するが、本発明の内容はこれらに限定されるものではなく、具体的な化合物においてはそのフリー体、及びその又は他の薬理学的に許容される塩を含む。
インスリン感受性増強薬としては、トログリタゾン、塩酸ピオグリタゾン、マレイン酸ロシグリタゾン、ダルグリタゾンナトリウム、ＧＩ−２６２５７０、イサグリタゾン（ｉｓａｇｌｉｔａｚｏｎｅ）、ＬＧ−１００６４１、ＮＣ−２１００、Ｔ−１７４、ＤＲＦ−２１８９、ＣＬＸ−０９２１、ＣＳ−０１１、ＧＷ−１９２９、シグリタゾン、エングリタゾンナトリウム、ＮＩＰ−２２１等のペルオキシソーム増殖薬活性化受容体γアゴニスト、ＧＷ−９５７８、ＢＭ−１７０７４４等のペルオキシソーム増殖薬活性化受容体αアゴニスト、ＧＷ−４０９５４４、ＫＲＰ−２９７、ＮＮ−６２２、ＣＬＸ−０９４０、ＬＲ−９０、ＳＢ−２１９９９４、ＤＲＦ−４１５８、ＤＲＦ−ＭＤＸ８等のペルオキシソーム増殖薬活性化受容体α／γアゴニスト、ＡＬＲＴ−２６８、ＡＧＮ−４２０４、ＭＸ−６０５４、ＡＧＮ−１９４２０４、ＬＧ−１００７５４、ベクサロテン（ｂｅｘａｒｏｔｅｎｅ）等のレチノイドＸ受容体アゴニスト、及びレグリキサン、ＯＮＯ−５８１６、ＭＢＸ−１０２、ＣＲＥ−１６２５、ＦＫ−６１４、ＣＬＸ−０９０１、ＣＲＥ−１６３３、ＮＮ−２３４４、ＢＭ−１３１２５、ＢＭ−５０１０５０、ＨＱＬ−９７５、ＣＬＸ−０９００、ＭＢＸ−６６８、ＭＢＸ−６７５、Ｓ−１５２６１、ＧＷ−５４４、ＡＺ−２４２、ＬＹ−５１０９２９、ＡＲ−Ｈ０４９０２０、ＧＷ−５０１５１６等のその他のインスリン感受性増強薬が挙げられる。インスリン感受性増強薬は、特には糖尿病、糖尿病性合併症、肥満症、高インスリン血症、糖代謝異常、高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、アテローム性動脈硬化症の処置に好ましく、また抹消におけるインスリン刺激伝達機構の異常を改善することにより、血中グルコースの組織への取り込みを亢進し血糖値を低下させることから、糖尿病、高インスリン血症、糖代謝異常の処置に更に好ましい。
糖吸収阻害薬としては、アカルボース、ボグリボース、ミグリトール、ＣＫＤ−７１１、エミグリテート、ＭＤＬ−２５，６３７、カミグリボース、ＭＤＬ−７３，９４５等のα−グルコシダーゼ阻害薬、ＡＺＭ−１２７等のα−アミラーゼ阻害薬等が挙げられる。糖吸収阻害薬は、特には糖尿病、糖尿病性合併症、肥満症、高インスリン血症、糖代謝異常の処置に好ましく、また食物中に含まれる炭水化物の消化管における酵素消化を阻害し、体内へのグルコースの吸収を遅延または阻害することから、糖尿病、糖代謝異常の処置に更に好ましい。
ビグアナイド薬としては、フェンホルミン、塩酸ブホルミン、塩酸メトホルミン等が挙げられる。ビグアナイド薬は、特には糖尿病、糖尿病性合併症、高インスリン血症、糖代謝異常の処置に好ましく、また肝臓における糖新生抑制作用や組織での嫌気的解糖促進作用あるいは抹消におけるインスリン抵抗性改善作用などにより、血糖値を低下させることから、糖尿病、高インスリン血症、糖代謝異常の処置に更に好ましい。
インスリン分泌促進薬としては、トルブタミド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリブリド（グリベンクラミド）、グリクラジド、１−ブチル−３−メタニリルウレア、カルブタミド、グリボルヌリド、グリピジド、グリキドン、グリソキセピド、グリブチアゾール、グリブゾール、グリヘキサミド、グリミジンナトリウム、グリピナミド、フェンブタミド、トルシクラミド、グリメピリド、ナテグリニド、ミチグリニドカルシウム水和物、レパグリニド等が挙げられる。インスリン分泌促進薬は、特には糖尿病、糖尿病性合併症、糖代謝異常の処置に好ましく、また膵臓β細胞に作用しインスリン分泌を増加させることにより血糖値を低下させることから、糖尿病、糖代謝異常の処置に更に好ましい。
インスリン又はインスリン類縁体としては、ヒトインスリン、動物由来のインスリン、ヒトインスリン類縁体が挙げられる。これらの薬剤は、特には糖尿病、糖尿病性合併症、糖代謝異常の処置に好ましく、糖尿病、糖代謝異常の処置に更に好ましい。
グルカゴン受容体アンタゴニストとしては、ＢＡＹ−２７−９９５５、ＮＮＣ−９２−１６８７等が挙げられ、インスリン受容体キナーゼ刺激薬としては、ＴＥＲ−１７４１１、Ｌ−７８３２８１、ＫＲＸ−６１３等が挙げられ、トリペプチジルペプチダーゼＩＩ阻害薬としては、ＵＣＬ−１３９７等が挙げられ、ジペプチジルペプチダーゼＩＶ阻害薬としては、ＮＶＰ−ＤＰＰ７２８Ａ、ＴＳＬ−２２５、Ｐ−３２／９８等が挙げられ、プロテインチロシンホスファターゼ−１Ｂ阻害薬としては、ＰＴＰ−１１２、ＯＣ−８６８３９、ＰＮＵ−１７７４９６等が挙げられ、グリコゲンホスホリラーゼ阻害薬としては、ＮＮ−４２０１、ＣＰ−３６８２９６等が挙げられ、フルクトース−ビスホスファターゼ阻害薬としては、Ｒ−１３２９１７等が挙げられ、ピルビン酸デヒドロゲナーゼ阻害薬としては、ＡＺＤ−７５４５等が挙げられ、肝糖新生阻害薬としては、ＦＲ−２２５６５９等が挙げられ、グルカゴン様ペプチド−１類縁体としては、エキセンジン−４（ｅｘｅｎｄｉｎ−４）、ＣＪＣ−１１３１等が挙げられ、グルカゴン様ペプチド−１アゴニストとしては、ＡＺＭ−１３４、ＬＹ−３１５９０２が挙げられ、アミリン、アミリン類縁体またはアミリンアゴニストとしては、酢酸プラムリンチド等が挙げられる。これらの薬剤、グルコース−６−ホスファターゼ阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬及びグルカゴン様ペプチド−１は、特には糖尿病、糖尿病性合併症、高インスリン血症、糖代謝異常の処置に好ましく、糖尿病、糖代謝異常の処置に更に好ましい。
アルドース還元酵素阻害薬としては、ガモレン酸アスコルビル、トルレスタット、エパルレスタット、ＡＤＮ−１３８、ＢＡＬ−ＡＲＩ８、ＺＤ−５５２２、ＡＤＮ−３１１、ＧＰ−１４４７、ＩＤＤ−５９８、フィダレスタット、ソルビニール、ポナルレスタット（ｐｏｎａｌｒｅｓｔａｔ）、リサレスタット（ｒｉｓａｒｅｓｔａｔ）、ゼナレスタット（ｚｅｎａｒｅｓｔａｔ）、ミナルレスタット（ｍｉｎａｌｒｅｓｔａｔ）、メトソルビニール、ＡＬ−１５６７、イミレスタット（ｉｍｉｒｅｓｔａｔ）、Ｍ−１６２０９、ＴＡＴ、ＡＤ−５４６７、ゾポルレスタット、ＡＳ−３２０１、ＮＺ−３１４、ＳＧ−２１０、ＪＴＴ−８１１、リンドルレスタット（ｌｉｎｄｏｌｒｅｓｔａｔ）が挙げられる。アルドース還元酵素阻害薬は、糖尿病性合併症組織において認められる持続的高血糖状態におけるポリオール代謝経路の亢進により過剰に蓄積される細胞内ソルビトールをアルドース還元酵素を阻害することにより低下させることから、特には糖尿病性合併症の処理に好ましい。
終末糖化産物生成阻害薬としては、ピリドキサミン、ＯＰＢ−９１９５、ＡＬＴ−９４６、ＡＬＴ−７１１、塩酸ピマゲジン等が挙げられる。終末糖化産物生成阻害薬は、糖尿病状態における持続的高血糖により亢進される終末糖化産物生成を阻害することにより細胞障害を軽減させるため、特には糖尿病性合併症の処置に好ましい。
プロテインキナーゼＣ阻害薬としては、ＬＹ−３３３５３１、ミドスタウリン等が挙げられる。プロテインキナーゼＣ阻害薬は、糖尿病状態における持続的高血糖により認められるプロテインキナーゼＣ活性の亢進を抑制するため、特には糖尿病性合併症の処置に好ましい。
γ−アミノ酪酸受容体アンタゴニストとしては、トピラマート等が挙げられ、ナトリウムチャンネルアンタゴニストとしては、塩酸メキシレチン、オクスカルバゼピン等が挙げられ、転写因子ＮＦ−κＢ阻害薬としては、デクスリポタム（ｄｅｘｌｉｐｏｔａｍ）等が挙げられ、脂質過酸化酵素阻害薬としては、メシル酸チリラザド等が挙げられ、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ阻害薬としては、ＧＰＩ−５６９３等が挙げられ、カルニチン誘導体としては、カルニチン、塩酸レバセカルニン、塩化レボカルニチン、レボカルニチン、ＳＴ−２６１等が挙げられる。これらの薬剤、インスリン様成長因子−Ｉ、血小板由来成長因子、血小板由来成長因子類縁体、上皮増殖因子、神経成長因子、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル、スロデキシド及びＹ−１２８は、特には糖尿病性合併症の処置に好ましい。
ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬としては、セリバスタチンナトリウム、プラバスタチンナトリウム、ロバスタチン（ｌｏｖａｓｔａｔｉｎ）、シンバスタチン、フルバスタチンナトリウム、アトルバスタチンカルシウム水和物、ＳＣ−４５３５５、ＳＱ−３３６００、ＣＰ−８３１０１、ＢＢ−４７６、Ｌ−６６９２６２、Ｓ−２４６８、ＤＭＰ−５６５、Ｕ−２０６８５、ＢＡＹ−ｘ−２６７８、ＢＡＹ−１０−２９８７、ピタバスタチンカルシウム、ロスバスタチンカルシウム、コレストロン（ｃｏｌｅｓｔｏｌｏｎｅ）、ダルバスタチン（ｄａｌｖａｓｔａｔｉｎ）、アシテメート、メバスタチン、クリルバスタチン（ｃｒｉｌｖａｓｔａｔｉｎ）、ＢＭＳ−１８０４３１、ＢＭＹ−２１９５０、グレンバスタチン、カルバスタチン、ＢＭＹ−２２０８９、ベルバスタチン（ｂｅｒｖａｓｔａｔｉｎ）等が挙げられる。ヒドロキシメチルグルタリルコエンザイムＡ還元酵素阻害薬は、特には高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、アテローム性動脈硬化症の処置に好ましく、またヒドロキシメチルグルタリルコエンザイムＡ還元酵素を阻害することにより血中コレステロールを低下させることから、高脂質血症、高コレステロール血症、アテローム性動脈硬化症の処置に更に好ましい。
フィブラート系化合物としては、ベザフィブラート、ベクロブラート、ビニフィブラート、シプロフィブラート、クリノフィブラート、クロフィブラート、クロフィブラートアルミニウム、クロフィブリン酸、エトフィブラート、フェノフィブラート、ゲムフィブロジル、ニコフィブラート、ピリフィブラート、ロニフィブラート、シムフィブラート、テオフィブラート、ＡＨＬ−１５７等が挙げられる。フィブラート系化合物は、特には高インスリン血症、高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、アテローム性動脈硬化症の処置に好ましく、また肝臓におけるリポ蛋白リパーゼの活性化や脂肪酸酸化亢進により血中トリグリセリドを低下させることから、高脂質血症、高トリグリセリド血症、アテローム性動脈硬化症の処置に更に好ましい。
β_３−アドレナリン受容体アゴニストとしては、ＢＲＬ−２８４１０、ＳＲ−５８６１１Ａ、ＩＣＩ−１９８１５７、ＺＤ−２０７９、ＢＭＳ−１９４４４９、ＢＲＬ−３７３４４、ＣＰ−３３１６７９、ＣＰ−１１４２７１、Ｌ−７５０３５５、ＢＭＳ−１８７４１３、ＳＲ−５９０６２Ａ、ＢＭＳ−２１０２８５、ＬＹ−３７７６０４、ＳＷＲ−０３４２ＳＡ、ＡＺ−４０１４０、ＳＢ−２２６５５２、Ｄ−７１１４、ＢＲＬ−３５１３５、ＦＲ−１４９１７５、ＢＲＬ−２６８３０Ａ、ＣＬ−３１６２４３、ＡＪ−９６７７、ＧＷ−４２７３５３、Ｎ−５９８４、ＧＷ−２６９６、ＹＭ１７８等が挙げられる。β_３−アドレナリン受容体アゴニストは、特には肥満症、高インスリン血症、高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常の処置に好ましく、また脂肪におけるβ_３−アドレナリン受容体を刺激し脂肪酸酸化の亢進によりエネルギーを消費させることから、肥満症、高インスリン血症の処置に更に好ましい。
アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬としては、ＮＴＥ−１２２、ＭＣＣ−１４７、ＰＤ−１３２３０１−２、ＤＵＰ−１２９、Ｕ−７３４８２、Ｕ−７６８０７、ＲＰ−７０６７６、Ｐ−０６１３９、ＣＰ−１１３８１８、ＲＰ−７３１６３、ＦＲ−１２９１６９、ＦＹ−０３８、ＥＡＢ−３０９、ＫＹ−４５５、ＬＳ−３１１５、ＦＲ−１４５２３７、Ｔ−２５９１、Ｊ−１０４１２７、Ｒ−７５５、ＦＣＥ−２８６５４、ＹＩＣ−Ｃ８−４３４、アバシミブ（ａｖａｓｉｍｉｂｅ）、ＣＩ−９７６、ＲＰ−６４４７７、Ｆ−１３９４、エルダシミブ（ｅｌｄａｃｉｍｉｂｅ）、ＣＳ−５０５、ＣＬ−２８３５４６、ＹＭ−１７Ｅ、レシミビデ（ｌｅｃｉｍｉｂｉｄｅ）、４４７Ｃ８８、ＹＭ−７５０、Ｅ−５３２４、ＫＷ−３０３３、ＨＬ−００４、エフルシミブ（ｅｆｌｕｃｉｍｉｂｅ）等が挙げられる。アシルコエンザイムＡ：コレステロールアシル基転移酵素阻害薬は、特には高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常の処置に好ましく、またアシルコエンザイムＡ：コレステロールアシル基転移酵素を阻害することにより血中コレステロールを低下させることから、高脂質血症、高コレステロール血症の処置に更に好ましい。
甲状腺ホルモン受容体アゴニストとしては、リオチロニンナトリウム、レボチロキシンナトリウム、ＫＢ−２６１１等が挙げられ、コレステロール吸収阻害薬としては、エゼチミブ、ＳＣＨ−４８４６１等が挙げられ、リパーゼ阻害薬としては、オルリスタット、ＡＴＬ−９６２、ＡＺＭ−１３１、ＲＥＤ−１０３００４等が挙げられ、カルニチンパルミトイルトランスフェラーゼ阻害薬としては、エトモキシル等が挙げられ、スクアレン合成酵素阻害薬としては、ＳＤＺ−２６８−１９８、ＢＭＳ−１８８４９４、Ａ−８７０４９、ＲＰＲ−１０１８２１、ＺＤ−９７２０、ＲＰＲ−１０７３９３、ＥＲ−２７８５６等が挙げられ、ニコチン酸誘導体としては、ニコチン酸、ニコチン酸アミド、ニコモール、ニセリトロール、アシピモクス、ニコランジル等が挙げられ、胆汁酸吸着薬としては、コレスチラミン、コレスチラン、塩酸コレセベラム、ＧＴ−１０２−２７９等が挙げられ、ナトリウム共役胆汁酸トランスポーター阻害薬としては、２６４Ｗ９４、Ｓ−８９２１、ＳＤ−５６１３等が挙げられ、コレステロールエステル転送タンパク阻害薬としては、ＰＮＵ−１０７３６８Ｅ、ＳＣ−７９５、ＪＴＴ−７０５、ＣＰ−５２９４１４等が挙げられる。これらの薬剤、プロブコール、ミクロソームトリグリセリドトランスファープロテイン阻害薬、リポキシゲナーゼ阻害薬及び低比重リポ蛋白受容体増強薬は、特には高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常の処置に好ましい。
食欲抑制薬としては、モノアミン再吸収阻害薬、セロトニン再吸収阻害薬、セロトニン放出刺激薬、セロトニンアゴニスト（特に５ＨＴ_２Ｃ−アゴニスト）、ノルアドレナリン再吸収阻害薬、ノルアドレナリン放出刺激薬、α_１−アドレナリン受容体アゴニスト、β_２−アドレナリン受容体アゴニスト、ドーパミンアゴニスト、カンナビノイド受容体アンタゴニスト、γ−アミノ酪酸受容体アンタゴニスト、Ｈ_３−ヒスタミンアンタゴニスト、Ｌ−ヒスチジン、レプチン、レプチン類縁体、レプチン受容体アゴニスト、メラノコルチン受容体アゴニスト（特にＭＣ３−Ｒアゴニスト、ＭＣ４−Ｒアゴニスト）、α−メラニン細胞刺激ホルモン、コカイン−アンドアンフェタミン−レギュレーテドトランスクリプト、マホガニータンパク、エンテロスタチンアゴニスト、カルシトニン、カルシトニン遺伝子関連ペプチド、ボンベシン、コレシストキニンアゴニスト（特にＣＣＫ−Ａアゴニスト）、コルチコトロピン放出ホルモン、コルチコトロピン放出ホルモン類縁体、コルチコトロピン放出ホルモンアゴニスト、ウロコルチン、ソマトスタチン、ソマトスタチン類縁体、ソマトスタチン受容体アゴニスト、下垂体アデニレートシクラーゼ活性化ペプチド、脳由来神経成長因子、シリアリーニュートロピックファクター、サイロトロピン放出ホルモン、ニューロテンシン、ソーバジン、ニューロペプチドＹアンタゴニスト、オピオイドペプチドアンタゴニスト、ガラニンアンタゴニスト、メラニン−コンセントレイティングホルモン受容体アンタゴニスト、アグーチ関連蛋白阻害薬、オレキシン受容体アンタゴニスト等が挙げられる。具体的には、モノアミン再吸収阻害薬としては、マジンドール等が挙げられ、セロトニン再吸収阻害薬としては、塩酸デクスフェンフルラミン、フェンフルラミン、塩酸シブトラミン、マレイン酸フルボキサミン、塩酸セルトラリン等が挙げられ、セロトニンアゴニストとしては、イノトリプタン、（＋）ノルフェンフルラミン等が挙げられ、ノルアドレナリン再吸収阻害薬としては、ブプロピオン、ＧＷ−３２０６５９等が挙げられ、ノルアドレナリン放出刺激薬としては、ロリプラム、ＹＭ−９９２等が挙げられ、β_２−アドレナリン受容体アゴニストとしては、アンフェタミン、デキストロアンフェタミン、フェンテルミン、ベンズフェタミン、メタアンフェタミン、フェンジメトラジン、フェンメトラジン、ジエチルプロピオン、フェニルプロパノールアミン、クロベンゾレックス等が挙げられ、ドーパミンアゴニストとしては、ＥＲ−２３０、ドプレキシン、メシル酸ブロモクリプチンが挙げられ、カンナビノイド受容体アンタゴニストとしては、リモナバント等が挙げられ、γ−アミノ酪酸受容体アンタゴニストとしては、トピラマート等が挙げられ、Ｈ_３−ヒスタミンアンタゴニストとしてはＧＴ−２３９４等が挙げられ、レプチン、レプチン類縁体またはレプチン受容体アゴニストとしては、ＬＹ−３５５１０１等が挙げられ、コレシストキニンアゴニスト（特にＣＣＫ−Ａアゴニスト）としては、ＳＲ−１４６１３１、ＳＳＲ−１２５１８０、ＢＰ−３．２００、Ａ−７１６２３、ＦＰＬ−１５８４９、ＧＩ−２４８５７３、ＧＷ−７１７８、ＧＩ−１８１７７１、ＧＷ−７８５４、Ａ−７１３７８等が挙げられ、ニューロペプチドＹアンタゴニストとしては、ＳＲ−１２０８１９−Ａ、ＰＤ−１６０１７０、ＮＧＤ−９５−１、ＢＩＢＰ−３２２６、１２２９−Ｕ−９１、ＣＧＰ−７１６８３、ＢＩＢＯ−３３０４、ＣＰ−６７１９０６−０１、Ｊ−１１５８１４等が挙げられる。食欲抑制薬は、特には糖尿病、糖尿病性合併症、肥満症、糖代謝異常、高脂血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、アテローム性動脈硬化症、高血圧、うっ血性心不全、浮腫、高尿酸血症、痛風の処置に好ましく、また中枢の食欲調節系における脳内モノアミンや生理活性ペプチドの作用を促進あるいは阻害することによって食欲を抑制し、摂取エネルギーを減少させることから、肥満症の処置に更に好ましい。
アンジオテンシン変換酵素阻害薬としては、カプトプリル、マレイン酸エナラプリル、アラセプリル、塩酸デラプリル、ラミプリル、リシノプリル、塩酸イミダプリル、塩酸ベナゼプリル、セロナプリル一水和物、シラザプリル、フォシノプリルナトリウム、ペリンドプリルエルブミン、モベルチプリルカルシウム、塩酸キナプリル、塩酸スピラプリル、塩酸テモカプリル、トランドラプリル、ゾフェノプリルカルシウム、塩酸モエキシプリル（ｍｏｅｘｉｐｒｉｌ）、レンチアプリル、等が挙げられる。アンジオテンシン変換酵素阻害薬は、特には糖尿病性合併症、高血圧の処置に好ましい。
中性エンドペプチダーゼ阻害薬としては、オマパトリラート、ＭＤＬ−１００２４０、ファシドトリル（ｆａｓｉｄｏｔｒｉｌ）、サムパトリラート、ＧＷ−６６０５１１Ｘ、ミキサンプリル（ｍｉｘａｎｐｒｉｌ）、ＳＡ−７０６０、Ｅ−４０３０、ＳＬＶ−３０６、エカドトリル等が挙げられる。中性エンドペプチダーゼ阻害薬は、特には糖尿病性合併症、高血圧の処置に好ましい。
アンジオテンシンＩＩ受容体拮抗薬としては、カンデサルタンシレキセチル、カンデサルタンシレキセチル／ヒドロクロロチアジド、ロサルタンカリウム、メシル酸エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、ＥＸＰ−３１７４、Ｌ−１５８８０９、ＥＸＰ−３３１２、オルメサルタン、タソサルタン、ＫＴ−３−６７１、ＧＡ−０１１３、ＲＵ−６４２７６、ＥＭＤ−９０４２３、ＢＲ−９７０１等が挙げられる。アンジオテンシンＩＩ受容体拮抗薬は、特には糖尿病性合併症、高血圧の処置に好ましい。
エンドセリン変換酵素阻害薬としては、ＣＧＳ−３１４４７、ＣＧＳ−３５０６６、ＳＭ−１９７１２等が挙げられ、エンドセリン受容体アンタゴニストとしては、Ｌ−７４９８０５、ＴＢＣ−３２１４、ＢＭＳ−１８２８７４、ＢＱ−６１０、ＴＡ−０２０１、ＳＢ−２１５３５５、ＰＤ−１８０９８８、シタクセンタンナトリウム（ｓｉｔａｘｓｅｎｔａｎ）、ＢＭＳ−１９３８８４、ダルセンタン（ｄａｒｕｓｅｎｔａｎ）、ＴＢＣ−３７１１、ボセンタン、テゾセンタンナトリウム（ｔｅｚｏｓｅｎｔａｎ）、Ｊ−１０４１３２、ＹＭ−５９８、Ｓ−０１３９、ＳＢ−２３４５５１、ＲＰＲ−１１８０３１Ａ、ＡＴＺ−１９９３、ＲＯ−６１−１７９０、ＡＢＴ−５４６、エンラセンタン、ＢＭＳ−２０７９４０等が挙げられる。これらの薬剤は、特には糖尿病性合併症、高血圧の処置に好ましく、高血圧の処置に更に好ましい。
利尿薬としては、クロルタリドン、メトラゾン、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチジド、メチクロチアジド、インダパミド、トリパミド、メフルシド、アゾセミド、エタクリン酸、トラセミド、ピレタニド、フロセミド、ブメタニド、メチクラン、カンレノ酸カリウム、スピロノラクトン、トリアムテレン、アミノフィリン、塩酸シクレタニン、ＬＬＵ−α、ＰＮＵ−８０８７３Ａ、イソソルビド、Ｄ−マンニトール、Ｄ−ソルビトール、フルクトース、グリセリン、アセトゾラミド、メタゾラミド、ＦＲ−１７９５４４、ＯＰＣ−３１２６０、リキシバプタン（ｌｉｘｉｖａｐｔａｎ）、塩酸コニバプタンが挙げられる。利尿薬は、特には糖尿病性合併症、高血圧、うっ血性心不全、浮腫の処置に好ましく、また尿排泄量を増加させることにより血圧を低下させたり、浮腫を改善するため、高血圧、うっ血性心不全、浮腫の処置に更に好ましい。
カルシウム拮抗薬としては、アラニジピン、塩酸エホニジピン、塩酸ニカルジピン、塩酸バルニジピン、塩酸ベニジピン、塩酸マニジピン、シルニジピン、ニソルジピン、ニトレンジピン、ニフェジピン、ニルバジピン、フェロジピン、ベシル酸アムロジピン、プラニジピン、塩酸レルカニジピン、イスラジピン、エルゴジピン、アゼルニジピン、ラシジピン、塩酸バタニジピン、レミルジピン、塩酸ジルチアゼム、マレイン酸クレンチアゼム、塩酸ベラパミール、Ｓ−ベラパミール、塩酸ファスジル、塩酸ベプリジル、塩酸ガロパミル等が挙げられ、血管拡張性降圧薬としては、インダパミド、塩酸トドララジン、塩酸ヒドララジン、カドララジン、ブドララジン等が挙げられ、交換神経遮断薬としては、塩酸アモスラロール、塩酸テラゾシン、塩酸ブナゾシン、塩酸プラゾシン、メシル酸ドキサゾシン、塩酸プロプラノロール、アテノロール、酒石酸メトプロロール、カルベジロール、ニプラジロール、塩酸セリプロロール、ネビボロール、塩酸ベタキソロール、ピンドロール、塩酸タータトロール、塩酸ベバントロール、マレイン酸チモロール、塩酸カルテオロール、フマル酸ビソプロロール、マロン酸ボピンドロール、ニプラジロール、硫酸ペンブトロール、塩酸アセブトロール、塩酸チリソロール、ナドロール、ウラピジル、インドラミン等が挙げられ、中枢性降圧薬としては、レセルピン等が挙げられ、α_２−アドレナリン受容体アゴニストとしては、塩酸クロニジン、メチルドパ、ＣＨＦ−１０３５、酢酸グアナベンズ、塩酸グアンファシン、モクソニジン（ｍｏｘｏｎｉｄｉｎｅ）、ロフェキシジン（ｌｏｆｅｘｉｄｉｎｅ）、塩酸タリペキソール等が挙げられる。これらの薬剤は、特には高血圧の処置に好ましい。
抗血小板薬としては、塩酸チクロピジン、ジピリダモール、シロスタゾール、イコサペント酸エチル、塩酸サルポグレラート、塩酸ジラゼプ、トラピジル、ベラプロストナトリウム、アスピリン等が挙げられる。抗血小板薬は、特にはアテローム性動脈硬化症、うっ血性心不全の処置に好ましい。
尿酸生成阻害薬としては、アロプリノール、オキシプリノール等が挙げられ、尿酸排泄促進薬としては、ベンズブロマロン、プロベネシド等が挙げられ、尿アルカリ化薬としては、炭酸水素ナトリウム、クエン酸カリウム、クエン酸ナトリウム等が挙げられる。これらの薬剤は、特には高尿酸血症、痛風の処置に好ましい。
例えば、ＳＧＬＴ２活性阻害薬以外の薬剤と組合わせて使用する場合、糖尿病の処置においては、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニストおよび食欲抑制薬からなる群より選択される少なくとも１種の薬剤と組合わせるのが好ましく、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体およびアミリンアゴニストからなる群より選択される少なくとも１種の薬剤と組合わせるのが更に好ましく、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬およびインスリン又はインスリン類縁体からなる群より選択される少なくとも１種の薬剤と組合わせるのが最も好ましい。同様に、糖尿病性合併症の処置においては、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、アルドース還元酵素阻害薬、終末糖化産物生成阻害薬、プロテインキナーゼＣ阻害薬、γ−アミノ酪酸受容体アンタゴニスト、ナトリウムチャンネルアンタゴニスト、転写因子ＮＦ−κＢ阻害薬、脂質過酸化酵素阻害薬、Ｎ−アセチル化−α−リンクト−アシッド−ジペプチダーゼ阻害薬、インスリン様成長因子−Ｉ、血小板由来成長因子、血小板由来成長因子類縁体、上皮増殖因子、神経成長因子、カルニチン誘導体、ウリジン、５−ヒドロキシ−１−メチルヒダントイン、ＥＧＢ−７６１、ビモクロモル、スロデキシド、Ｙ−１２８、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬、アンジオテンシンＩＩ受容体拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニストおよび利尿薬からなる群より選択される少なくとも１種の薬剤と組合わせるのが好ましく、アルドース還元酵素阻害薬、アンジオテンシン変換酵素阻害薬、中性エンドペプチダーゼ阻害薬およびアンジオテンシンＩＩ受容体拮抗薬からなる群より選択される少なくとも１種の薬剤と組合わせるのが更に好ましい。また、肥満症の処置においては、インスリン感受性増強薬、糖吸収阻害薬、ビグアナイド薬、インスリン分泌促進薬、インスリン又はインスリン類縁体、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ刺激薬、トリペプチジルペプチダーゼＩＩ阻害薬、ジペプチジルペプチダーゼＩＶ阻害薬、プロテインチロシンホスファターゼ−１Ｂ阻害薬、グリコゲンホスホリラーゼ阻害薬、グルコース−６−ホスファターゼ阻害薬、フルクトース−ビスホスファターゼ阻害薬、ピルビン酸デヒドロゲナーゼ阻害薬、肝糖新生阻害薬、Ｄ−カイロイノシトール、グリコゲン合成酵素キナーゼ−３阻害薬、グルカゴン様ペプチド−１、グルカゴン様ペプチド−１類縁体、グルカゴン様ペプチド−１アゴニスト、アミリン、アミリン類縁体、アミリンアゴニスト、β_３−アドレナリン受容体アゴニストおよび食欲抑制薬からなる群より選択される少なくとも１種の薬剤と組み合わせるのが好ましく、β_３−アドレナリン受容体アゴニストおよび食欲抑制薬からなる群より選択される少なくとも１種の薬剤と組合わせるのが更に好ましい。
本発明の医薬組成物を実際の治療に用いる場合、用法に応じ種々の剤型のものが使用される。このような剤型としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤などを挙げることができ、経口または非経口的に投与される。
これらの医薬組成物は、その剤型に応じ調剤学上使用される手法により適当な賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤などの医薬品添加物と適宜混合または希釈・溶解し、常法に従い調剤することにより製造することができる。また、ＳＧＬＴ２活性阻害薬以外の薬剤と組合わせて使用する場合は、それぞれの活性成分を同時に或いは別個に上記同様に製剤化することにより製造することができる。
本発明の医薬組成物を実際の治療に用いる場合、その有効成分である前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体またはその薬理学的に許容される塩、或いはそのプロドラッグの投与量は、患者の年齢、性別、体重、疾患および治療の程度等により適宜決定されるが、経口投与の場合成人１日あたり概ね０．１〜１０００ｍｇの範囲で、非経口投与の場合は、成人１日あたり概ね０．０１〜３００ｍｇの範囲で、一回または数回に分けて適宜投与することができる。また、ＳＧＬＴ２活性阻害薬以外の薬剤と組合わせて使用する場合、本発明の化合物の投与量は、ＳＧＬＴ２活性阻害薬以外の薬剤の投与量に応じて減量することができる。
実施例
本発明の内容を以下の実施例および試験例でさらに詳細に説明するが、本発明はその内容に限定されるものではない。
実施例１
２−（４−ピラゾール−１−イルベンジル）フェノール
４−フルオロベンズアルデヒド（１．０ｇ）、ピラゾール（０．５５ｇ）および炭酸カリウム（１．２ｇ）のＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）懸濁液を１５０℃で７時間撹拌した。反応混合物を室温に冷却後、水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝６／１〜３／１）にて精製し、４−ピラゾール−１−イルベンズアルデヒド（０．９４ｇ）を得た。２−ベンジルオキシブロモベンゼン（０．９９ｇ）のテトラヒドロフラン（２０ｍＬ）溶液に、−７８℃にてｎ−ブチルリチウム（２．６６ｍｏｌ／Ｌヘキサン溶液、１．２ｍＬ）を加え１０分間撹拌した。反応混合物に４−ピラゾール−１−イルベンズアルデヒド（０．５ｇ）のテトラヒドロフラン（５ｍＬ）溶液を加え、０℃に昇温し、３０分間撹拌した。反応混合物に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。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、（２−ベンジルオキシフェニル）−（４−ピラゾール−１−イルフェニル）−メタノール（０．８４ｇ）を得た。（２−ベンジルオキシフェニル）−（４−ピラゾール−１−イルフェニル）−メタノール（０．８４ｇ）のメタノール（５ｍＬ）溶液に、１０％パラジウム炭素粉末（０．４２ｇ）を加え、水素雰囲気下、室温で２４時間撹拌した。不溶物をろ去し、ろ液の溶媒を留去した。残渣にジエチルエーテルを加え、結晶をろ取し、減圧下乾燥して標記化合物（０．２０ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ ｐｐｍ：
４．０３（２Ｈ，ｓ），４．９１（１Ｈ，ｓ），６．４５（１Ｈ，ｄｄ，Ｊ＝１．８，２．４Ｈｚ），６．７５−６．８５（１Ｈ，ｍ），６．８５−６．９５（１Ｈ，ｍ），７．１０−７．２０（２Ｈ，ｍ），７．２５−７．３５（２Ｈ，ｍ），７．５５−７．６５（２Ｈ，ｍ），７．７１（１Ｈ，ｄｄ，Ｊ＝０．５，１．８Ｈｚ），７．８８（１Ｈ，ｄｄ，Ｊ＝０．５，２．４Ｈｚ）
実施例２
２−（４−ピラゾール−１−イルベンジル）フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド
２−（４−ピラゾール−１−イルベンジル）フェノール（０．１０ｇ）、アセトブロモ−α−Ｄ−グルコース（０．１６ｇ）およびベンジルトリ（ｎ−ブチル）アンモニウムクロリド（０．１２ｇ）の塩化メチレン（５ｍＬ）および水酸化ナトリウム水溶液（５ｍｏｌ／Ｌ、０．３２ｍＬ）混合物を室温で３時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１〜１／１）で精製し、標記化合物（０．０４４ｇ）を得た。
実施例３
２−（４−ピラゾール−１−イルベンジル）フェニル＝β−Ｄ−グルコピラノシド
２−（４−ピラゾール−１−イルベンジル）フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド（０．０４４ｇ）のメタノール（３ｍＬ）溶液にナトリウムメトキシド（２８％メタノール溶液、０．０１５ｍＬ）を加え、室温で１時間撹拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール＝６／１）で精製して標記化合物（０．０２０ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ ｐｐｍ：
３．３０−３．５５（４Ｈ，ｍ），３．６９（１Ｈ，ｄｄ，Ｊ＝５．４，１２．０Ｈｚ），３．８８（１Ｈ，ｄｄ，Ｊ＝２．１，１２．０Ｈｚ），４．０３（１Ｈ，ｄ，Ｊ＝１４．７Ｈｚ），４．１７（１Ｈ，ｄ，Ｊ＝１４．７Ｈｚ），４．９３（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．４５−６．５５（１Ｈ，ｍ），６．８５−７．００（１Ｈ，ｍ），７．１０−７．１５（１Ｈ，ｍ），７．１５−７．２０（２Ｈ，ｍ），７．３５−７．４５（２Ｈ，ｍ），７．５５−７．６５（２Ｈ，ｍ），７．６５−７．７０（１Ｈ，ｍ），８．１０−８．１５（１Ｈ，ｍ）
実施例４
１−〔４−（２−ヒドロキシベンジル）フェニル〕ピペリジン−４−オール
４−フルオロベンズアルデヒド（１．２ｇ）、４−ヒドロキシピペリジン（１．０ｇ）および炭酸カリウム（１．５ｇ）のＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）懸濁液を１５０℃で５時間撹拌した。反応混合物を室温に冷却後、水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣に酢酸エチルおよびジエチルエーテルを加え、結晶をろ取後、乾燥して４−（４−ヒドロキシピペリジン−１−イル）ベンズアルデヒド（０．９４ｇ）を得た。２−ベンジルオキシブロモベンゼン（１．６ｇ）のテトラヒドロフラン（３０ｍＬ）溶液に、−７８℃にてｎ−ブチルリチウム（１．５９ｍｏｌ／Ｌヘキサン溶液、４．０ｍＬ）を加え、１０分間撹拌した。反応混合物に４−（４−ヒドロキシピペリジン−１−イル）ベンズアルデヒド（０．５ｇ）のテトラヒドロフラン（５ｍＬ）溶液を加え、０℃に昇温し、３０分間撹拌した。反応混合物に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。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製し、１−｛４−〔（２−ベンジルオキシフェニル）ヒドロキシメチル〕フェニル｝ピペリジン−４−オール（０．９５ｇ）を得た。１−｛４−〔（２−ベンジルオキシフェニル）ヒドロキシメチル〕フェニル｝ピペリジン−４−オール（０．９５ｇ）のメタノール（１０ｍＬ）溶液に１０％パラジウム炭素粉末（０．１２ｇ）を加え、水素雰囲気下、室温で１５時間撹拌した。不溶物をろ去し、残渣の溶媒を減圧下に留去後、残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール＝１０／１）にて精製し、１−｛４−〔（２−ヒドロキシフェニル）ヒドロキシメチル〕フェニル｝ピペリジン−４−オール（０．２８ｇ）を得た。１−｛４−〔（２−ヒドロキシフェニル）ヒドロキシメチル〕フェニル｝ピペリジン−４−オール（０．２８ｇ）のメタノール（５ｍＬ）溶液に１０％パラジウム炭素粉末（０．２８ｇ）を加え、水素雰囲気下、室温で１５時間撹拌した。不溶物をろ去し、溶媒を減圧下留去して標記化合物（０．２３ｇ）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ ｐｐｍ：
１．３５−１．５０（２Ｈ，ｍ），１．６５−１．８５（２Ｈ，ｍ），２．６５−２．８０（２Ｈ，ｍ），３．３５−３．５０（２Ｈ，ｍ），３．５０−３．６５（１Ｈ，ｍ），３．７３（２Ｈ，ｓ），４．６３（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），６．６０−６．８５（４Ｈ，ｍ），６．９０−７．１０（４Ｈ，ｍ），９．２８（１Ｈ，ｓ）
実施例５
２−〔４−（４−ヒドロキシピペリジン−１−イル）ベンジル〕フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド
１−〔４−（２−ヒドロキシベンジル）フェニル〕ピペリジン−４−オール（０．２３ｇ）、アセトブロモ−α−Ｄ−グルコース（０．３３ｇ）およびベンジルトリ（ｎ−ブチル）アンモニウムクロリド（０．２５ｇ）の塩化メチレン（１０ｍＬ）および水酸化ナトリウム水溶液（５ｍｏｌ／Ｌ、０．６２ｍＬ）混合物を室温で３時間撹拌した。反応混合物をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製し、標記化合物（０．１２ｇ）を得た。
実施例６
２−〔４−（４−ヒドロキシピペリジン−１−イル）ベンジル〕フェニル＝β−Ｄ−グルコピラノシド
２−〔４−（４−ヒドロキシピペリジン−１−イル）ベンジル〕フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド（０．１２ｇ）のメタノール（５ｍＬ）溶液にナトリウムメトキシド（２８％メタノール溶液、０．０７３ｍＬ）を加え、室温で２時間撹拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール＝５／１）で精製して標記化合物（０．０３６ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ ｐｐｍ：
１．５５−１．７０（２Ｈ，ｍ），１．８５−２．００（２Ｈ，ｍ），２．７５−２．８５（２Ｈ，ｍ），３．３０−３．５５（６Ｈ，ｍ），３．６０−３．８０（２Ｈ，ｍ），３．８０−３．９５（２Ｈ，ｍ），４．００（１Ｈ，ｄ，Ｊ＝１４．７Ｈｚ），４．９０（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．８５−６．９５（３Ｈ，ｍ），７．００−７．２０（５Ｈ，ｍ）
実施例７
２−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンジル〕フェノール
４−シアノベンズアルデヒド（３．０ｇ）、アジ化ナトリウム（１．５ｇ）および塩化リチウム（１．５ｇ）の２−メトキシエタノール（２５ｍＬ）懸濁液を７．５時間加熱還流した。反応混合物を室温に冷却した後、氷中に注ぎ、濃塩酸を加えた。結晶をろ取し、水で洗浄後、減圧下乾燥して４−（テトラゾール−５−イル）ベンズアルデヒド（２．９ｇ）を得た。４−（テトラゾール−５−イル）ベンズアルデヒド（２．９ｇ）の１，４−ジオキサン（１５ｍＬ）およびＮ，Ｎ−ジメチルホルムアミド（１５ｍＬ）溶液に０℃で炭酸カリウム（６．８ｇ）を加え、３０分間撹拌した。反応混合物にヨードメタン（３．５ｇ）を加え、室温で２４時間撹拌した後、反応混合物を氷水中に注いだ。析出した結晶をろ取し、水で洗浄し、減圧下乾燥して４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンズアルデヒド（２．７ｇ）を得た。２−ベンジルオキシブロモベンゼン（１．０ｇ）のテトラヒドロフラン（４０ｍＬ）溶液に、−７８℃にてｔｅｒｔ−ブチルリチウム（１．４５ｍｏｌ／Ｌペンタン溶液、２．９ｍＬ）を加え、１０分間撹拌した。反応混合物に４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンズアルデヒド（０．７２ｇ）のテトラヒドロフラン（１０ｍＬ）溶液を加え、０℃に昇温し、３０分間撹拌した。反応混合物に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。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）で精製し、（２−ベンジルオキシフェニル）−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル〕−メタノール（０．９０ｇ）を得た。（２−ベンジルオキシフェニル）−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル〕−メタノール（０．９０ｇ）のメタノール（２０ｍＬ）溶液に１０％パラジウム炭素末（０．５０ｇ）を加え、水素雰囲気下、室温で２４時間撹拌した。不溶物をろ去し、ろ液の溶媒を減圧下留去した。残渣にジエチルエーテルを加え、結晶をろ取後、減圧下乾燥して標記化合物（０．１７ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ ｐｐｍ：
４．０６（２Ｈ，ｓ），４．３９（３Ｈ，ｓ），４．８６（１Ｈ，ｓ），６．７５−６．８５（１Ｈ，ｍ），６．８５−６．９５（１Ｈ，ｍ），７．１０−７．２０（２Ｈ，ｍ），７．３０−７．４０（２Ｈ，ｍ），８．００−８．１０（２Ｈ，ｍ）
実施例８
２−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンジル〕フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド
２−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンジル〕フェノール（０．１０ｇ）、２，３，４，６−テトラ−Ｏ−アセチル−１−Ｏ−トリクロロアセトイミドイル−α−Ｄ−グルコピラノース（０．２２ｇ）の塩化メチレン（５ｍＬ）溶液に三フッ化ホウ素−ジエチルエーテル錯体（０．０７１ｍＬ）を加え、室温で３０分間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１〜１／１）で精製し、標記化合物（０．２１ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ ｐｐｍ：
１．８８（３Ｈ，ｓ），２．０３（３Ｈ，ｓ），２．０５（３Ｈ，ｓ），２．０７（３Ｈ，ｓ），３．８５−３．９５（１Ｈ，ｍ），３．９６（１Ｈ，ｄ，Ｊ＝１５．４Ｈｚ），４．０１（１Ｈ，ｄ，Ｊ＝１５．４Ｈｚ），４．１７（１Ｈ，ｄｄ，Ｊ＝２．６，１２．３Ｈｚ），４．２９（１Ｈ，ｄｄ，Ｊ＝５．８，１２．３Ｈｚ），４．３８（３Ｈ，ｓ），５．１０−５．２５（２Ｈ，ｍ），５．２５−５．４０（２Ｈ，ｍ），６．９５−７．１５（３Ｈ，ｍ），７．１５−７．３０（３Ｈ，ｍ），８．００−８．０５（２Ｈ，ｍ）
実施例９
２−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンジル〕フェニル＝β−Ｄ−グルコピラノシド
２−〔４−（２−メチル−２Ｈ−テトラゾール−５−イル）ベンジル〕フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシド（０．２１ｇ）のメタノール（５ｍＬ）溶液にナトリウムメトキシド（２８％メタノール溶液、０．０６７ｍＬ）を加え、室温で５０分間撹拌した。結晶をろ取し、減圧下乾燥して標記化合物（０．０９７ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ ｐｐｍ：
３．３０−３．５５（４Ｈ，ｍ），３．６９（１Ｈ，ｄｄ，Ｊ＝５．５，１２．１Ｈｚ），３．８８（１Ｈ，ｄｄ，Ｊ＝２．２，１２．１Ｈｚ），４．０５（１Ｈ，ｄ，Ｊ＝１４．８Ｈｚ），４．１９（１Ｈ，ｄ，Ｊ＝１４．８Ｈｚ），４．３９（３Ｈ，ｓ），４．９０−４．９５（１Ｈ，ｍ），６．９０−７．００（１Ｈ，ｍ），７．１０−７．１５（１Ｈ，ｍ），７．１５−７．２０（２Ｈ，ｍ），７．３５−７．４５（２Ｈ，ｍ），７．９０−８．００（２Ｈ，ｍ）
実施例１０
２−（４−フェニルベンジル）フェノール
２−ベンジルオキシブロモベンゼン（０．２９ｇ）のテトラヒドロフラン（１０ｍＬ）溶液に、−７８℃にてｔｅｒｔ−ブチルリチウム（１．４８ｍｏｌ／Ｌペンタン溶液、０．７４ｍＬ）を加え、３０分間撹拌した。反応混合物にビフェニル−４−カルボアルデヒド（０．１８ｇ）のテトラヒドロフラン（２ｍＬ）溶液を加え、０℃に昇温して１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、ジエチルエーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／１）で精製し、（２−ベンジルオキシフェニル）−ビフェニル−４−イルメタノール（０．２６ｇ）を得た。（２−ベンジルオキシフェニル）−ビフェニル−４−イルメタノール（０．２６ｇ）のエタノール（５ｍＬ）および濃塩酸（０．０６ｍＬ）溶液に１０％パラジウム炭素粉末（０．０５２ｇ）を加え、水素雰囲気下、室温で２日間撹拌した。不溶物をろ去し、ろ液の溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／１）で精製し、標記化合物（０．１４ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ ｐｐｍ：
４．０４（２Ｈ，ｓ），４．７３（１Ｈ，ｓ），６．７５−７．８５（１Ｈ，ｍ），６．８５−６．９５（１Ｈ，ｍ），７．１０−７．２０（２Ｈ，ｍ），７．２５−７．３５（３Ｈ，ｍ），７．３５−７．４５（２Ｈ，ｍ），７．４５−７．６０（４Ｈ，ｍ）
実施例１１
２−（４−フェニルベンジル）フェニル＝β−Ｄ−グルコピラノシド
２−（４−フェニルベンジル）フェノール（０．０６３ｇ）、２，３，４，６−テトラ−Ｏ−アセチル−１−Ｏ−トリクロロアセトイミドイル−α−Ｄ−グルコピラノース（０．１３ｇ）の塩化メチレン（３ｍＬ）溶液に、０℃で三フッ化ホウ素−ジエチルエーテル錯体（０．０３４ｍＬ）を加え、３時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、２−（４−フェニルベンジル）フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシドを得た。得られた２−（４−フェニルベンジル）フェニル＝２，３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノシドをメタノール（３ｍＬ）に溶解し、ナトリウムメトキシド（２８％メタノール溶液、０．１９ｍＬ）を加え、室温で１４時間撹拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール＝１０／１）で精製し、標記化合物（０．０２６ｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ ｐｐｍ：
３．３０−３．５５（４Ｈ，ｍ），３．７０（１Ｈ，ｄｄ，Ｊ＝５．２，１２．０Ｈｚ），３．８８（１Ｈ，ｄｄ，Ｊ＝２．０，１２．０Ｈｚ），４．０３（１Ｈ，ｄ，Ｊ＝１４．９Ｈｚ），４．１５（１Ｈ，ｄ，Ｊ＝１４．９Ｈｚ），４．９３（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．９０−７．００（１Ｈ，ｍ），７．０５−７．２０（３Ｈ，ｍ），７．２５−７．３５（３Ｈ，ｍ），７．３５−７．４５（２Ｈ，ｍ），７．４５−７．６０（４Ｈ，ｍ）
試験例１
ヒトＳＧＬＴ２活性阻害作用確認試験
１）ヒトＳＧＬＴ２のクローニングおよび発現ベクターへの組み換え
ヒト小腸由来の総ＲＮＡ（Ｏｒｉｇｅｎｅ）を、オリゴｄＴをプライマーとして逆転写し、ＰＣＲ増幅用ｃＤＮＡライブラリーを作成した。このｃＤＮＡライブラリーを鋳型として、Ｒ．Ｇ．Ｗｅｌｌｓらにより報告されたヒトＳＧＬＴ２（ＡＣＣＥＳＳＩＯＮ：Ｍ９５５４９，Ｍ９５２９９）の２番から２０３９番までの塩基配列をＰＣＲ法により増幅し、ｐｃＤＮＡ３．１（−）（Ｉｎｖｉｔｒｏｇｅｎ）のマルチクローニング部位に挿入した。挿入したＤＮＡの塩基配列は、報告されていた塩基配列と完全に一致していた。
２）ヒトＳＧＬＴ２安定発現株の樹立
ヒトＳＧＬＴ２発現ベクターをＳｃａＩで消化して直鎖状ＤＮＡとした後、ＣＨＯ−Ｋ１細胞にリポフェクション法（ＥｆｆｅｃｔｅｎｅＴｒａｎｓｆｅｃｔｉｏｎＲｅａｇｅｎｔ：ＱＩＡＧＥＮ）にて導入した。１ｍｇ／ｍＬＧ４１８（ＬＩＦＥＴＥＣＮＯＬＯＧＩＥＳ）にてネオマイシン耐性細胞株を得、後述する方法にてメチル−α−Ｄ−グルコピラノシドの取り込み活性を測定した。最も強い取り込み活性を示した株を選択してＣＳ２−５Ｅとし、以後、２００μｇ／ｍＬのＧ４１８存在下で培養した。
３）メチル−α−Ｄ−グルコピラノシド（α−ＭＧ）取り込み阻害活性の測定
９６穴プレートにＣＳ２−５Ｅを３×１０^４個／穴で播種し、２日間培養した後に取り込み実験に供した。取り込み用緩衝液（１４０ｍＭ塩化ナトリウム、２ｍＭ塩化カリウム、１ｍＭ塩化カルシウム、１ｍＭ塩化マグネシウム、１０ｍＭ２−〔４−（２−ヒドロキシエチル）−１−ピペラジニル〕エタンスルホン酸、５ｍＭトリス（ヒドロキシメチル）アミノメタンを含む緩衝液ｐＨ７．４）には、非放射ラベル体（Ｓｉｇｍａ）と^１４Ｃラベル体（ＡｍｅｒｓｈａｍＰｈａｒｍａｃｉａＢｉｏｔｅｃｈ）のα−ＭＧを最終濃度が１ｍＭとなるように混和して添加した。試験化合物はジメチルスルフォキシドに溶解した後、蒸留水にて適宜希釈して１ｍＭα−ＭＧを含む取り込み用緩衝液に添加し、測定用緩衝液とした。対照群用には試験化合物を含まない測定用緩衝液を、基礎取り込み測定用には塩化ナトリウムに替えて１４０ｍＭの塩化コリンを含む基礎取り込み用緩衝液を調製した。培養した細胞の培地を除去し、前処置用緩衝液（α−ＭＧを含まない基礎取り込み用緩衝液）を１穴あたり１８０μＬ加え、３７℃で１０分間静置した。同一操作をもう１度繰り返した後、取り込み用緩衝液を除去し、測定用緩衝液および基礎取り込み用緩衝液を１穴当たり７５μＬずつ加え３７℃で静置した。１時間後に測定用緩衝液を除去し、１穴当たり１８０μＬの洗浄用緩衝液（１０ｍＭ非ラベル体α−ＭＧを含む基礎取り込み用緩衝液）で２回洗浄した。１穴当たり７５μＬの０．２ｍｏｌ／Ｌ水酸化ナトリウムで細胞を溶解し、その液をピコプレート（Ｐａｃｋａｒｄ）に移した。１５０μＬのマイクロシンチ４０（Ｐａｃｋａｒｄ）を加えて混和し、マイクロシンチレーションカウンタートップカウント（Ｐａｃｋａｒｄ）にて放射活性を計測した。対照群の取り込みから基礎取り込み量を差し引いた値を１００％として、試験化合物の各濃度におけるメチル−α−Ｄ−グルコピラノシドの取り込み量を算出した。試験化合物がメチル−α−Ｄ−グルコピラノシドの取り込みを５０％阻害する濃度（ＩＣ_５０値）を、ロジットプロットにより算出した。その結果は表１の通りである。

産業上の利用可能性
本発明の前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体、その薬理学的に許容される塩及びそれらのプロドラッグは、優れたヒトＳＧＬＴ２活性阻害作用を発現し、腎臓での糖の再吸収を抑制し過剰な糖を尿中に排泄させることにより、優れた血糖低下作用を発揮する。本発明により、糖尿病、糖尿病性合併症、肥満症等の高血糖症に起因する疾患の予防または治療薬を提供することができる。また、本発明の前記一般式（ＩＩ）で表される化合物およびそれらの塩は、前記一般式（Ｉ）で表されるグルコピラノシルオキシベンジルベンゼン誘導体、その薬理学的に許容される塩及びそれらのプロドラッグを製造する際の中間体として重要であり、この化合物を経由することにより、当該化合物を容易に製造することができる。Technical field
The present invention relates to a glucopyranosyloxybenzylbenzene derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, a pharmaceutical use thereof, and a production intermediate thereof, which are useful as a pharmaceutical. It is about.
More specifically, the present invention relates to a compound represented by the general formula: which exhibits an inhibitory effect on human SGLT2 activity and is useful as an agent for preventing or treating diseases caused by hyperglycemia such as diabetes, diabetic complications, and obesity.

(R in the formula ¹ Is a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower alkoxy lower alkyl group, a lower Alkoxy lower alkoxy group, carbamoyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonyl lower alkoxy group, carboxy lower alkyl group, carboxy lower alkoxy group, oxygen atom, sulfur atom and nitrogen atom in addition to the nitrogen atom at the bonding site A 5- or 6-membered ring which may contain one hetero atom in the ring, and may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group Aliphatic cyclic amino group, or binding site In addition to the nitrogen atom, it may further contain 1 to 3 nitrogen atoms in the ring, and has 1 to 3 different or similar groups selected from lower alkyl groups and lower alkoxy groups as substituents. A 5-membered aromatic cyclic amino group; ² Is a hydrogen atom or a lower alkyl group; ³ Is a lower alkyl group as a substituent, a lower alkoxy group, an aryl group which may have from 1 to 3 different or similar groups selected from a halogen atom and a hydroxyl group, a lower alkyl group as a substituent, a lower alkoxy group, One or two heterocyclic atoms of the same or different kind selected from a 3- to 7-membered cycloalkyl group which may have a group selected from a hydroxyl group and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom; A 5- or 6-membered aliphatic heterocyclic group which may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group, or an oxygen atom, a sulfur atom and Hetero atoms or hetero atoms of the same kind selected from nitrogen atoms in the ring are contained in one to four rings, and hetero atoms selected from lower alkyl groups and lower alkoxy groups as substituents. Or a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 groups of the same kind) or a pharmacologically acceptable derivative thereof. The present invention relates to a salt or a prodrug thereof, a pharmaceutical composition containing the salt, a pharmaceutical use thereof, and an intermediate for producing the same.
Background art
Diabetes is one of lifestyle-related diseases due to changes in diet and lack of exercise. Therefore, diabetic patients receive diet therapy and exercise therapy, but when sufficient control and continuous administration are difficult, pharmacotherapy is used in combination. Currently, biguanides, sulfonylureas, insulin sensitizers and the like are used as antidiabetic drugs. However, side effects such as lactic acidosis of biguanides, hypoglycemia of sulfonylurea drugs, and edema of insulin sensitivity enhancers may be observed, and there is a concern that they may promote obesity. Therefore, development of a therapeutic agent for diabetes with a new mechanism of action has been demanded in order to solve such problems.
In recent years, research and development of a new type of antidiabetic drug that promotes excretion of urine glucose and lowers blood glucose level by inhibiting reabsorption of excess sugar in the kidney has been promoted (J. Clin. Invest. 79, pp. 1510-1515 (1987)). In addition, SGLT2 (sodium-dependent glucose transporter 2) is present in the S1 region of the proximal tubule of the kidney, and it has been reported that SGLT2 is mainly involved in the reabsorption of glomerularly filtered sugar. (J. Clin. Invest., Vol. 93, pp. 397-404 (1994)). Therefore, by inhibiting human SGLT2, reabsorption of excess sugar in the kidney can be suppressed, and excess sugar can be excreted from urine to normalize blood glucose levels. Therefore, early development of an antidiabetic drug having a strong human SGLT2 activity inhibitory action and a new mechanism of action is expected. In addition, since such a urinary glucose excretion enhancer excretes excess blood glucose from urine, the accumulation of sugar in the body is reduced, so that an effect of preventing or reducing obesity and a diuretic effect can be expected. Furthermore, it is considered to be useful for various related diseases caused by the development of diabetes and obesity due to hyperglycemia.
Disclosure of the invention
The present inventors have conducted intensive studies to find a compound having an inhibitory activity on human SGLT2 activity. As a result, the glucopyranosyloxybenzylbenzene derivative represented by the above general formula (I) was found to have an excellent human SGLT2 inhibitory activity as described below. The present inventors have found that they exhibit an activity, and have accomplished the present invention.
The present invention provides the above glucopyranosyl, which exhibits an inhibitory effect on human SGLT2 activity, suppresses reabsorption of sugar in the kidney, and excretes excess sugar in urine, thereby exhibiting an excellent blood sugar lowering effect. An oxybenzylbenzene derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, a pharmaceutical use thereof, and an intermediate for the production thereof.
That is, the present invention relates to the general formula

(R in the formula ¹ Is a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower alkoxy lower alkyl group, a lower Alkoxy lower alkoxy group, carbamoyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonyl lower alkoxy group, carboxy lower alkyl group, carboxy lower alkoxy group, oxygen atom, sulfur atom and nitrogen atom in addition to the nitrogen atom at the bonding site A 5- or 6-membered ring which may contain one hetero atom in the ring, and may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group Aliphatic cyclic amino group, or binding site In addition to the nitrogen atom, it may further contain 1 to 3 nitrogen atoms in the ring, and has 1 to 3 different or similar groups selected from lower alkyl groups and lower alkoxy groups as substituents. A 5-membered aromatic cyclic amino group; ² Is a hydrogen atom or a lower alkyl group; ³ Is a lower alkyl group as a substituent, a lower alkoxy group, an aryl group which may have from 1 to 3 different or similar groups selected from a halogen atom and a hydroxyl group, a lower alkyl group as a substituent, a lower alkoxy group, One or two heterocyclic atoms of the same or different kind selected from a 3- to 7-membered cycloalkyl group which may have a group selected from a hydroxyl group and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom; A 5- or 6-membered aliphatic heterocyclic group which may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group, or an oxygen atom, a sulfur atom and Hetero atoms or hetero atoms of the same kind selected from nitrogen atoms in the ring are contained in one to four rings, and hetero atoms selected from lower alkyl groups and lower alkoxy groups as substituents. Or a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 groups of the same kind) or a pharmacologically acceptable derivative thereof. It relates to salts or their prodrugs.
Further, the present invention provides a pharmaceutical composition comprising a glucopyranosyloxybenzylbenzene derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient. And a human SGLT2 activity inhibitor and an agent for preventing or treating a disease caused by hyperglycemia.
The present invention relates to hyperglycemia, which comprises administering an effective amount of a glucopyranosyloxybenzylbenzene derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof. The present invention relates to a method for preventing or treating a disease caused by the above.
The present invention relates to a glucopyranosyloxybenzylbenzene derivative represented by the above general formula (I) or a pharmacologically thereof for producing a pharmaceutical composition for preventing or treating a disease caused by hyperglycemia. Pertaining to the use of acceptable salts or their prodrugs.
The present invention relates to (A) a glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitivity enhancer. , Sugar absorption inhibitors, biguanides, insulin secretagogues, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase- 1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 Harmful drug, glucagon-like peptide-1, glucagon-like peptide 1-analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation endproduct formation inhibitor, protein kinase C inhibition Drug, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl Glutaryl coenzy A reductase inhibitors, fibrate compounds, β ₃ -Adrenergic receptor agonist, acyl coenzyme A: cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor Drug, squalene synthase inhibitor, low-density lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor Drug, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calci Arm antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ The present invention relates to a medicament comprising a combination of at least one drug selected from the group consisting of an adrenergic receptor agonist, an antiplatelet drug, a uric acid production inhibitor, a uric acid excretion promoter, and a urinary alkalinizing drug.
The present invention relates to (A) a glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitivity enhancer. , Sugar absorption inhibitors, biguanides, insulin secretagogues, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase- 1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 Harmful drug, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation endproduct formation inhibitor, protein kinase C inhibition Drug, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl Glutaryl coenzy A reductase inhibitors, fibrate compounds, β ₃ -Adrenergic receptor agonist, acyl coenzyme A: cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor Drug, squalene synthase inhibitor, low-density lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor Drug, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calci Arm antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ Caused by hyperglycemia, comprising administering an effective amount of at least one drug selected from the group consisting of an adrenergic receptor agonist, an antiplatelet drug, a uric acid production inhibitor, a uric acid excretion enhancer, and a urinary alkalinizing drug The present invention relates to a method for preventing or treating a disease.
The present invention relates to (A) a glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) or a drug thereof for producing a pharmaceutical composition for preventing or treating a disease caused by hyperglycemia. A physiologically acceptable salt or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretagogue, insulin or an insulin analog, a glucagon receptor antagonist, an insulin receptor Kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor Medicine, liver Neogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reduction Enzyme inhibitor, advanced glycation endproduct formation inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylation-α -Linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin , EGB-761, Bimokuro Le, sulodexide, Y-128, a hydroxymethyl glutaryl coenzyme A reductase inhibitors, fibrate compounds, beta ₃ -Adrenergic receptor agonist, acyl coenzyme A: cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor Drug, squalene synthase inhibitor, low-density lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor Drug, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calci Arm antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ The use of at least one drug selected from the group consisting of adrenergic receptor agonists, antiplatelet drugs, uric acid production inhibitors, uric acid excretion enhancers and urinary alkalinizing drugs.
Further, the present invention provides a compound of the general formula

(Wherein Q is a hydroxyl group or a 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group; ¹¹ Is a hydrogen atom, a hydroxyl group optionally having a protecting group, an amino group having a protecting group, a mono (lower alkyl) amino group having a protecting group, a di (lower alkyl) amino group, a cyano group, a carbamoyl group, and a lower alkyl group. Group, lower alkoxy group, hydroxy lower alkyl group optionally having a protecting group, hydroxy lower alkoxy group optionally having a protecting group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy group, carbamoyl lower alkyl group A lower alkoxycarbonyl-lower alkyl group, a lower alkoxycarbonyl-lower alkoxy group, a carboxy-lower alkyl group, a carboxy-lower alkoxy group, a nitrogen atom at the bonding site and one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom It may be contained in a ring, a lower alkyl group as a substituent, A 5- or 6-membered aliphatic cyclic amino group which may have a group selected from a primary alkoxy group, a hydroxyl group and an amino group, or a nitrogen atom at the bonding site, and 1 to 3 nitrogen atoms A 5-membered aromatic cyclic amino group which may have from 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group as a substituent, R ² Is a hydrogen atom or a lower alkyl group; ^Thirteen Is an aryl group which may have 1 to 3 different or the same kind of groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group which may have a protecting group, A 3- to 7-membered cycloalkyl group optionally having a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group optionally having a protecting group and an amino group having a protecting group, an oxygen atom A heteroalkyl atom or a heteroatom selected from sulfur atoms and nitrogen atoms in a ring, a hydroxyl group and a protecting group which may have a lower alkyl group, a lower alkoxy group and a protecting group as substituents; A 5- or 6-membered aliphatic heterocyclic group which may have a group selected from amino groups having, or a hetero- or hetero-group selected from an oxygen atom, a sulfur atom and a nitrogen atom Or a 5- or 6-membered aromatic ring which may have from 1 to 4 hetero atoms of the same or different kind selected from a lower alkyl group and a lower alkoxy group as a substituent. A benzylphenol derivative or a salt thereof.
In the present invention, a prodrug refers to a compound that is converted in vivo into a glucopyranosyloxybenzylbenzene derivative represented by the general formula (I), which is an active substance. Examples of the prodrugs of the glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof include, for example, a general formula

[P in the formula ¹ Is a hydrogen atom or a group constituting a prodrug; ¹⁰ Is a hydrogen atom, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxy group One heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, in addition to a nitrogen atom at the bonding site, in the ring, a carbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group, a carboxy lower alkoxy group, A 5- or 6-membered aliphatic which may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug, and an amino group as a substituent. Group other than the nitrogen atom A five-membered aromatic ring which may contain 1 to 3 atoms, and may have 1 to 3 hetero or hetero groups selected from lower alkyl groups and lower alkoxy groups as substituents. Aromatic amino group, or the general formula P ² -OA ¹ − (P in the formula ² Is a hydrogen atom or a group constituting a prodrug, ¹ Is a single bond, a lower alkylene group or a lower alkyleneoxy group); ² Is a hydrogen atom or a lower alkyl group; ³⁰ Is a substituted or unsubstituted aryl group which may have from 1 to 3 different or similar groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group having a hydroxyl group and a group constituting a prodrug, A 3- to 7-membered cycloalkyl group which may have a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group, an oxygen atom, sulfur One or two hetero atoms of the same kind or the same kind selected from an atom and a nitrogen atom in a ring, and a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group, A 5- or 6-membered aliphatic heterocyclic group which may have a selected group, or an oxygen atom, a sulfur atom and a nitrogen atom. 5 to 4 heterocyclic or homologous heteroatoms contained in the ring, and optionally 1 to 3 heterologous or homologous groups selected from lower alkyl groups and lower alkoxy groups as substituents or A glucopyranosyloxybenzylbenzene derivative or a pharmacologically acceptable salt thereof having at least one group constituting a prodrug represented by a 6-membered aromatic heterocyclic group). Can be mentioned.
As the group constituting the prodrug, for example, it can be usually used in prodrugs such as a lower acyl group, a lower alkoxy lower acyl group, a lower alkoxycarbonyl lower acyl group, a lower alkoxycarbonyl group, and a lower alkoxy lower alkoxycarbonyl group. A protecting group for a hydroxyl group can be exemplified. In the prodrug of the compound of the present invention, the group constituting the prodrug may be located at an arbitrary hydroxyl group, and may be plural.
In the present invention, a lower alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group. Refers to a linear or branched alkyl group having 1 to 6 carbon atoms such as a group or a hexyl group. Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert -Refers to a linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group and a hexyloxy group. The lower alkylene group refers to a linear or branched alkylene group having 1 to 6 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, and a propylene group. The lower alkyleneoxy group means a linear or branched alkyleneoxy group having 1 to 6 carbon atoms such as a methyleneoxy group, an ethyleneoxy group, a propyleneoxy group, and a trimethyleneoxy group. The hydroxy lower alkyl group is a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, a 1-hydroxypropyl group, a 2-hydroxy-1-methylethyl group , 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 1-hydroxybutyl, 5-hydroxypentyl, 4-hydroxypentyl, 3-hydroxypentyl, 2-hydroxypentyl, 1 Straight chain having 1 to 6 carbon atoms such as -hydroxypentyl group, 6-hydroxyhexyl group, 5-hydroxyhexyl group, 4-hydroxyhexyl group, 3-hydroxyhexyl group, 2-hydroxyhexyl group, 1-hydroxyhexyl group, etc. Or branched hydroxyalkyl group. The hydroxy lower alkoxy group is a 2-hydroxyethoxy group, a 3-hydroxypropoxy group, a 2-hydroxypropoxy group, a 2-hydroxy-1-methylethoxy group, a 4-hydroxybutoxy group, a 3-hydroxybutoxy group, a 2-hydroxy Butoxy, 5-hydroxypentyloxy, 4-hydroxypentyloxy, 3-hydroxypentyloxy, 2-hydroxypentyloxy, 6-hydroxyhexyloxy, 5-hydroxyhexyloxy, 4-hydroxyhexyloxy A straight-chain or branched hydroxyalkoxy group having 1 to 6 carbon atoms, such as a group, 3-hydroxyhexyloxy group, or 2-hydroxyhexyloxy group. The lower alkoxy lower alkyl group refers to the hydroxy lower alkyl group O-alkylated with the lower alkyl group, and the lower alkoxy lower alkoxy group refers to the hydroxy lower alkoxy group O-alkylated with the lower alkyl group. Group. A carbamoyl lower alkyl group refers to the above lower alkyl group substituted with a carbamoyl group. The mono or di (lower alkyl) amino group refers to an amino group monosubstituted with the above lower alkyl group or an amino group disubstituted with the same or different lower alkyl group. A lower alkoxycarbonyl group refers to a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, C 2-7 straight or branched such as isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclohexyloxycarbonyl group, or C 4-7 Refers to a cyclic alkoxycarbonyl group. The lower alkoxycarbonyl lower alkyl group refers to the lower alkyl group substituted with the lower alkoxycarbonyl group. The lower alkoxycarbonyl lower alkoxy group refers to the lower alkoxy group substituted with the lower alkoxycarbonyl group. The lower alkoxy lower alkoxycarbonyl group refers to the lower alkoxycarbonyl group substituted with the lower alkoxy group such as a 2-methoxyethoxycarbonyl group. A carboxy lower alkyl group refers to the above lower alkyl group substituted with a carboxy group. A carboxy lower alkoxy group refers to the above lower alkoxy group substituted with a carboxy group. The aryl group refers to a 1 to 3 cyclic aromatic carbocyclic group such as a phenyl group and a naphthyl group. The 3- to 7-membered cycloalkyl group refers to a 3- to 7-membered aliphatic carbocyclic group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. A lower acyl group is a straight or branched chain having 2 to 7 carbon atoms such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a hexanoyl group, a cyclohexylcarbonyl group, or a cyclic group having 4 to 7 carbon atoms. Means an acyl group. The lower alkoxy lower acyl group refers to the lower acyl group substituted with the lower alkoxy group. The lower alkoxycarbonyl lower acyl group refers to the lower acyl group substituted with the lower alkoxycarbonyl group such as a 3- (ethoxycarbonyl) propionyl group. The 5- or 6-membered aliphatic heterocyclic group containing one or two hetero atoms of the same or different kind selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring is pyrrolidine, pyrazolidine, piperidine, piperazine, morpholine , A monovalent group derived from an aliphatic heterocycle such as thiomorpholine, tetrahydrofuran, tetrahydropyran, oxazolidine and the like. The 5- or 6-membered aliphatic cyclic amino group which may contain one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the nitrogen atom at the bonding site is the above-mentioned aliphatic group. Among the aromatic heterocyclic groups, a 1-pyrrolidinyl group, a pyrazolidinyl group, a piperidino group, a piperazinyl group, a morpholino group, a thiomorpholino group, and a cyclic amino group derived from a nitrogen-containing aliphatic heterocycle such as a 3-oxazolidinyl group. Say. A 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms or hetero atoms of the same kind selected from an oxygen atom, a sulfur atom and a nitrogen atom in a ring includes furan, thiophene, pyrrole, oxazole, iso It refers to a monovalent group derived from an aromatic heterocycle such as oxazole, thiazole, isothiazole, pyrazole, imidazole, furazane, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. The 5-membered aromatic cyclic amino group which may further contain 1 to 3 nitrogen atoms in the ring in addition to the nitrogen atom at the bonding site is a 1-pyrrolyl group in the aromatic heterocyclic groups described above. , Pyrazolyl group, 1-imidazolyl group, 1-triazolyl group, 1-tetrazolyl group and the like.
The hydroxyl-protecting group in various production intermediates refers to a hydroxyl-protecting group used in a general organic synthesis reaction, in addition to the hydroxyl-protecting group that can be usually used in the above-described prodrug, and specifically, Benzyl, methyl, methoxymethyl, acetyl, benzoyl, tert-butyldimethylsilyl, 2-trimethylsilylethoxymethyl, and the like. The amino-protecting group in various production intermediates includes a benzyl group, a p-methoxybenzyl group, a lower acyl group (eg, acetyl group, phthaloyl group), a lower alkoxycarbonyl group (eg, tert-butoxycarbonyl group, benzyloxy group). And a protecting group for an amino group used in a general organic synthesis reaction such as a carbonyl group.
In the compounds of the present invention, R ³ May contain, in the ring, one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the nitrogen atom at the bonding site, and as a substituent, a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group A 5- or 6-membered aliphatic cyclic amino group which may have a group selected from groups, or a nitrogen atom in a bonding site, and may further contain 1 to 3 nitrogen atoms in the ring. And a 5-membered aromatic cyclic amino group which may have 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group as a substituent. May further contain 1 to 3 nitrogen atoms in the ring, and may have 1 to 3 heterogeneous or similar groups selected from lower alkyl groups and lower alkoxy groups as substituents Ring aromatic ring Amino group are more preferable. The 5- or 6-membered aliphatic cyclic amino group which may contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the nitrogen atom in the bonding site is 1-pyrrolidinyl Group, piperidino group, piperazinyl group and the like are preferable, and 1-pyrrolidinyl group is more preferable. As the 5-membered aromatic cyclic amino group which may further contain 1 to 3 nitrogen atoms in the ring in addition to the nitrogen atom at the bonding site, a 1-pyrrolyl group, a pyrazolyl group and the like are preferable, and a pyrazolyl group is preferably More preferred.
The glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) and the prodrug thereof according to the present invention can be obtained, for example, by using a benzylphenol derivative represented by the following general formula (III) of the present invention. Can be produced according to the method described in

(X in the formula ¹ Is a leaving group such as a trichloroacetimidoyloxy group, an acetoxy group, a bromine atom and a fluorine atom; ² Is a leaving group such as a bromine atom and a chlorine atom; ⁰ Is a group constituting a prodrug, and R ¹ , R ² , R ³ , R ¹¹ And R ^Thirteen Has the same meaning as above)
Step 1
The benzylphenol derivative represented by the general formula (III) or a salt thereof is converted to 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose, 2,3 , 4,6-Tetra-O-acetyl-1-O-trichloroacetimidoyl-β-D-glucopyranose, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose, Such as 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl fluoride Using a sugar donor represented by the general formula (IV), boron trifluoride-diethyl ether complex, silver trifluoromethanesulfonate, stannic chloride, and trimethylsilyl trifluoromethanesulfonate in an inert solvent. In the presence of an activator such as tetra (n-butyl) ammonium chloride, benzyltri (n-butyl) ammonium chloride, benzyltri (n-butyl) ammonium bromide, tetra (n-butyl) ammonium hydrogensulfate, etc. Glycosylation in the presence or absence of a phase transfer catalyst and in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., to produce the glycoside represented by the general formula (V) Can be. Examples of the solvent used include methylene chloride, toluene, acetonitrile, nitromethane, ethyl acetate, diethyl ether, chloroform, water, acetone, a mixed solvent thereof and the like, and the reaction temperature is usually -30 ° C to reflux temperature. The reaction time varies depending on the used starting materials, solvent, reaction temperature and the like, but is usually from 10 minutes to 1 day. The substituent R ¹¹ Or / and R ^Thirteen In the above, the compound having a protecting group for a hydroxyl group or an amino group may be subjected to an appropriate treatment according to a conventional method after the completion of the reaction in the above step to remove the protecting group and then subjected to the step 2.
Step 2
The compound (I) of the present invention can be produced by removing the hydroxyl-protecting group by subjecting the glycoside represented by the general formula (V) to alkaline hydrolysis. Examples of the solvent used include water, methanol, ethanol, tetrahydrofuran, a mixed solvent thereof, and the like. Examples of the basic substance include sodium hydroxide, sodium methoxide, and sodium ethoxide. be able to. The treatment temperature is usually from 0 ° C. to reflux temperature, and the treatment time is usually from 30 minutes to 6 hours, depending on the used starting materials, solvent, treatment temperature and the like. The substituent R ¹¹ Or / and R ^Thirteen In the case of having a protecting group for a hydroxyl group or an amino group in the above, depending on the type of the protecting group, the above-mentioned treatment method can be appropriately changed according to a conventional method and carried out. The desired compound (I) can be derived by carrying out according to a conventional method.
Step 3
Pyridine, triethylamine, N, N-diisopropylethylamine in an inert solvent or without solvent using a protecting group represented by the general formula (VI) to form a hydroxyl group of the compound represented by the general formula (I) Prodrugs in the presence of a base such as, picoline, lutidine, collidine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine, 1,4-diazabicyclo [2.2.2] octane, etc. The compound represented by the general formula (I) can be separated by chromatography or the like, or by appropriately removing the protecting group appropriately introduced before the reaction after the reaction according to a conventional method. (For example, a prodrug of the general formula (IA)) can be produced. Examples of the solvent used in the prodrug-forming reaction include, for example, methylene chloride, acetonitrile, ethyl acetate, diisopropyl ether, chloroform, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, acetone, tert-butanol, and a mixed solvent thereof. The reaction temperature is usually from −40 ° C. to the reflux temperature, and the reaction time is usually from 30 minutes to 2 days, varying based on the used starting materials, the solvent and the reaction temperature.
Further, among the compounds of the present invention represented by the general formula (I), the compound represented by the following general formula (Ia) is, for example, a phenol derivative represented by the following general formula (Ib), It can also be produced according to the following method.

(R in the formula ⁴ Is a lower alkoxy group, a hydroxy lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group or a carboxy lower alkoxy group; ⁵ Is a lower alkyl group, a hydroxy lower alkyl group which may have a protecting group, a lower alkoxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group; ³ Is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, a tosyloxy group; ² And R ³ Has the same meaning as above)
Step 4
The phenol derivative represented by the general formula (Ib) is converted into tetrahydrofuran in the presence of a basic substance such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, and sodium hydrogen carbonate. , N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, O-alkylation in a solvent such as a mixed solvent thereof using the alkylating agent represented by the general formula (VII), and then, if desired, a conventional method. The compound represented by the formula (Ia) can be produced by removing the protecting group according to the above. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
In the compound of the present invention represented by the general formula (V) used as a raw material in the step 2, ¹¹ Is a mono (lower alkyl) amino group having a protecting group, ¹¹ Is a compound having an amino group having a protecting group and a suitable lower alkyl group-introducing reagent such as a lower alkyl halide, a mesylate or a tosylate, in the presence of a basic substance such as sodium hydride or potassium carbonate in tetrahydrofuran. , N, N-dimethylformamide, dimethylsulfoxide, a mixed solvent thereof or the like.
The compound represented by the general formula (III) of the present invention and a salt thereof used as a starting material in the production method can be produced, for example, according to the following method.

(Wherein M is a hydrogen atom or a hydroxyl-protecting group, one of Y and Z is MgBr, MgCl, MgI or lithium atom, the other is a formyl group, ² , R ¹¹ And R ^Thirteen Has the same meaning as above)
Step A
The benzaldehyde derivative represented by the general formula (VIII) and the Grignard reagent or lithium reagent represented by the general formula (IX), or the Grignard reagent or lithium reagent represented by the general formula (VIII) and the general formula ( The compound represented by the general formula (X) can be produced by condensing the benzaldehyde derivative represented by the formula (IX) in an inert solvent. As the solvent to be used, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually −78 ° C. to reflux temperature, and the reaction time is the starting material used, the solvent, the reaction temperature and the like. It is usually from 10 minutes to 1 day, though it depends on the method.
Step B
The compound represented by the general formula (XI) can be produced by oxidizing the compound represented by the general formula (X) in an inert solvent using a Dess-Martin reagent. As the solvent used, for example, methylene chloride, chloroform, acetonitrile, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually 0 ° C. to reflux temperature, and the reaction time is the starting material, solvent, and reaction temperature used. Although it depends on the conditions, it is usually 1 hour to 1 day.
Process C
After removing the protecting group M of the compound represented by the general formula (XI) according to a conventional method (unnecessary when M is a hydrogen atom), (1) triethylamine, diisopropylethylamine, N, N- By condensing with methyl chloroformate in the presence of a base such as dimethylaminopyridine, and (2) reducing the resulting carbonate derivative using a reducing agent such as sodium borohydride, the above-mentioned general formula of the present invention ( The compound of III) can be prepared. In the reaction (1), as a solvent used, for example, tetrahydrofuran, methylene chloride, acetonitrile, ethyl acetate, diethyl ether, a mixed solvent thereof and the like can be mentioned, and the reaction temperature is usually 0 ° C to reflux temperature, The reaction time varies depending on the used starting materials, solvent, reaction temperature and the like, but is usually 30 minutes to 1 day. In the reaction (2), examples of the solvent used include a mixed solvent of tetrahydrofuran and water, and the reaction temperature is usually 0 ° C. to reflux temperature, and the reaction time is the starting material and the solvent to be used. Although it depends on the reaction temperature and the like, it is usually 1 hour to 1 day. Note that R ¹¹ When is a lower alkoxycarbonyl group, separately, in an inert solvent, after reducing to a hydroxymethyl group using a reducing agent such as lithium aluminum hydride, protecting the hydroxyl group according to a conventional method, the above general formula of the present invention It can be derived to a compound of formula (III). As the solvent used at the time of reduction, for example, diethyl ether, tetrahydrofuran, a mixed solvent thereof and the like can be illustrated, the reaction temperature is usually 0 ° C. to reflux temperature, and the reaction time is the starting material, solvent and reaction temperature used. The time is usually from 10 minutes to 1 day, depending on the conditions. Further, the compound of the general formula (III) of the present invention can be converted into a salt such as a sodium salt and a potassium salt according to a conventional method.
Process D
After catalytically reducing the compound represented by the general formula (X) in an inert solvent in the presence or absence of an acid such as hydrochloric acid using a palladium-based catalyst such as palladium-carbon powder, if necessary, The compound of the general formula (III) of the present invention can be produced by removing or introducing a protecting group according to a conventional method. Examples of the solvent used in the catalytic reduction include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixed solvent thereof and the like.The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is preferably It is usually 30 minutes to 1 day, depending on the starting material, solvent, reaction temperature, etc. Note that R ¹¹ When is a lower alkoxycarbonyl group, separately, in an inert solvent, after reducing to a hydroxymethyl group using a reducing agent such as lithium aluminum hydride, protecting the hydroxyl group according to a conventional method, the above general formula of the present invention It can be derived to a compound of formula (III). As the solvent used at the time of reduction, for example, diethyl ether, tetrahydrofuran, a mixed solvent thereof and the like can be illustrated, the reaction temperature is usually 0 ° C. to reflux temperature, and the reaction time is the starting material, solvent and reaction temperature used. The time is usually from 10 minutes to 1 day, depending on the conditions. Further, the compound of the general formula (III) of the present invention can be converted into a salt such as a sodium salt and a potassium salt according to a conventional method.
In the production method, among the compounds represented by the general formulas (III), (V), (VIII), (X) and (XI), R ¹¹ Is an amino group having a protecting group, a mono (lower alkyl) amino group having a protecting group, a di (lower alkyl) amino group, a cyano group, a carbamoyl group, a hydroxy lower alkyl group optionally having a protecting group, a lower alkoxy group The compound which is a substituent such as a lower alkyl group, a carbamoyl lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, etc. is appropriately converted according to a conventional method using a corresponding compound having a lower alkoxycarbonyl group as a substituent. After that, a protecting group may be introduced, if desired, and then subjected to the next step (Steps A to D, Steps 1 to 2).
Further, the compound represented by the general formula (III) of the present invention and a salt thereof used as a starting material in the above-mentioned production method can also be produced according to the following method.

(X in the formula ⁴ Is a leaving group such as a chlorine atom; ² , R ¹¹ And R ^Thirteen Has the same meaning as above)
Step E
The phenol derivative represented by the general formula (XII) is benzylated using a phenylmethyl derivative represented by the general formula (XIII) in the absence of a solvent in the presence of a basic substance such as lithium hydroxide. Thereby, the compound represented by the general formula (III) can be produced. The reaction temperature is usually from 50 to 200 ° C., and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
The compound of the present invention obtained in the above production method can be isolated and purified by a conventional separation means such as fractional recrystallization, purification using chromatography, solvent extraction, solid phase extraction, and the like.
The glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) and the prodrug thereof of the present invention can be converted into pharmacologically acceptable salts by a conventional method. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. Sulfonic acid, propionic acid, citric acid, adipic acid, oleic acid, stearic acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc. Examples thereof include acid addition salts with organic acids, salts with organic amines such as 2-aminoethanol, piperidine, morpholine, and pyrrolidine, and salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts.
The glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) and the prodrug thereof of the present invention also include solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
Among the glucopyranosyloxybenzylbenzene derivatives represented by the general formula (I) of the present invention and the prodrugs thereof, compounds having an asymmetric carbon atom except for the glucopyranosyloxy moiety include compounds having an R configuration. There are two types of optical isomers of the compound having the S configuration and the S configuration. In the present invention, any of the optical isomers may be used, or a mixture of these optical isomers may be used.
The glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof and a prodrug thereof can be used, for example, in the following human SGLT2 activity inhibitory activity assay test. It exerts a strong human SGLT2 activity inhibitory action and exerts a hypoglycemic action by an excellent human SGLT2 activity inhibitory action. Therefore, diabetes, diabetic complications (eg, retinopathy, neuropathy, nephropathy, ulcer, macrovascular disease), obesity, hyperinsulinemia, abnormal glucose metabolism, hyperlipidemia, hypercholesterolemia, It is extremely useful as an agent for preventing or treating diseases caused by hyperglycemia such as hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout.
Further, the compound of the present invention can be used in appropriate combination with at least one drug other than the SGLT2 activity inhibitor. Drugs that can be used in combination with the compound of the present invention include, for example, insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl Peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor Drug, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like pep De-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation endproducts generation inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, Transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase (N-acetylated-α-linked-acid-dipeptidase) inhibitor, insulin-like growth factor-I Platelet-derived growth factor (PDGF), platelet-derived growth factor (PDGF) analogs (eg, PDGF-AA, PDGF-BB, PDGF-AB), epidermal growth factor (EGF), nerve growth factor, carnitine Conductor, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, Bimokuromoru (bimoclomol), sulodexide (sulodexide), Y-128, a hydroxymethyl glutaryl coenzyme A reductase inhibitors, fibrate compounds, beta ₃ -Adrenergic receptor agonist, acyl coenzyme A: cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyl transferase inhibitor Drug, squalene synthase inhibitor, low-density lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor Drug, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calci Arm antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ -Adrenergic receptor agonists, antiplatelet agents, uric acid production inhibitors, uric acid excretion enhancers, urinary alkalinizing agents and the like.
When a compound of the present invention and one or more of the above agents are used in combination, the present invention relates to simultaneous administration as a single formulation, simultaneous administration as the same or different administration routes as separate formulations, and separate administration. And the pharmaceutical composition comprising the compound of the present invention and the above-mentioned drug in the form of a single preparation as described above. And dosage forms that combine separate formulations.
When the compound of the present invention is used in combination with one or more of the above-mentioned drugs as appropriate, it is possible to obtain more advantageous effects than additive effects in preventing or treating the above-mentioned diseases. Alternatively, similarly, it is possible to reduce the amount of use compared to the case of using the drug alone, or to avoid or reduce the side effects of drugs other than the SGLT2 activity inhibitor used in combination.
Specific compounds of the drugs used in combination and suitable diseases to be treated are exemplified below, but the present invention is not limited to these, and the specific compounds are free forms. And its or other pharmacologically acceptable salts.
Insulin sensitivity enhancers include troglitazone, pioglitazone hydrochloride, rosiglitazone maleate, dalglitazone sodium, GI-262570, isaglitazone, LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium, peroxisome proliferator-activated receptor gamma agonist such as NIP-221, GW-9578, peroxisome proliferator-activated receptor alpha agonist such as BM-170744, GW- Peroxisome proliferator-activated receptor α / γ such as 409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158, DRF-MDX8 Retinoid X receptor agonists such as gonist, ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754, bexarotene, and reglixan, ONO-5816, MBX-102, CRE-1625, FK -614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242 LY-510929, AR-H049020, GW-501516 and the like. Insulin sensitizers include, in particular, diabetes, diabetic complications, obesity, hyperinsulinemia, dysglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis It is preferable for the treatment of diabetes and improves abnormalities in the insulin stimulatory transmission mechanism in the peripheral region, thereby enhancing the uptake of blood glucose into tissues and lowering the blood glucose level, thus resulting in diabetes, hyperinsulinemia, and abnormal glucose metabolism. More preferred for the treatment of
Examples of sugar absorption inhibitors include α-glucosidase inhibitors such as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25,637, camiglibose, MDL-73,945, and α-amylase inhibitors such as AZM-127. And the like. Glucose absorption inhibitors are particularly preferable for the treatment of diabetes, diabetic complications, obesity, hyperinsulinemia, and abnormal glucose metabolism, and inhibit the enzymatic digestion of carbohydrates contained in food in the gastrointestinal tract. Because it delays or inhibits glucose absorption, it is more preferable for treating diabetes and abnormal glucose metabolism.
Examples of biguanide drugs include phenformin, buformin hydrochloride, metformin hydrochloride and the like. The biguanide drug is particularly suitable for the treatment of diabetes, diabetic complications, hyperinsulinemia, and abnormal glucose metabolism, and also suppresses gluconeogenesis in the liver, promotes anaerobic glycolysis in tissues, or improves insulin resistance in peripheral exclusion. Since it lowers the blood sugar level by its action and the like, it is further preferable for the treatment of diabetes, hyperinsulinemia, and abnormal glucose metabolism.
Insulin secretagogues include tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide, 1-butyl-3-methanilylurea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepide, glybud Examples include thiazole, glybazole, glyhexamide, glymidine sodium, glipinamide, fenbutamide, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repaglinide and the like. Insulin secretagogues are particularly suitable for the treatment of diabetes, diabetic complications, and abnormal glucose metabolism. More preferred for the treatment of
Insulin or insulin analogs include human insulin, animal-derived insulin, and human insulin analogs. These drugs are particularly preferable for the treatment of diabetes, diabetic complications and abnormal glucose metabolism, and more preferable for the treatment of diabetes and abnormal glucose metabolism.
Glucagon receptor antagonists include BAY-27-9955, NNC-92-1687, and the like, and insulin receptor kinase stimulants include TER-17411, L-782811, KRX-613, and the like, tripeptidyl Examples of peptidase II inhibitors include UCL-1397 and the like, examples of dipeptidyl peptidase IV inhibitors include NVP-DPP728A, TSL-225, P-32 / 98 and the like, and examples of protein tyrosine phosphatase-1B inhibitors Include PTP-112, OC-86839, PNU-177496 and the like; glycogen phosphorylase inhibitors include NN-4201 and CP-368296; and fructose-bisphosphatase inhibitors include R-13291 Examples of the pyruvate dehydrogenase inhibitor include AZD-7545 and the like, and examples of the hepatic gluconeogenesis inhibitor include FR-225659 and the like, and the glucagon-like peptide-1 analog includes exendin-4. (Exendin-4), CJC-1131 and the like, and glucagon-like peptide-1 agonists include AZM-134 and LY-315902; amylin, amylin analogs and amylin agonists include pramlintide acetate and the like. Can be These drugs, glucose-6-phosphatase inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor and glucagon-like peptide-1 are particularly useful for diabetes, diabetic complications, hyperinsulinemia, abnormal glucose metabolism. And more preferably for the treatment of diabetes and abnormal glucose metabolism.
Examples of aldose reductase inhibitors include ascorbyl gamolate, tolrestat, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat, sorbinyl, and ponalrestat. ), Risarestat, zenarestat, minarestat, methsolvinyl, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ- 314, SG-210, JTT-811, and lindolestat. Aldose reductase inhibitors reduce intracellular sorbitol, which is excessively accumulated due to enhancement of the polyol metabolic pathway in a persistently hyperglycemic state observed in diabetic complication tissues, by inhibiting aldose reductase, particularly Is preferred for the treatment of diabetic complications.
Examples of the terminal glycation endproduct inhibitor include pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedin hydrochloride and the like. An advanced glycation end product inhibitor is particularly preferable for the treatment of diabetic complications because it reduces cell damage by inhibiting end glycation endogenous production that is promoted by sustained hyperglycemia in a diabetic state.
Examples of protein kinase C inhibitors include LY-333531, midostaurin and the like. A protein kinase C inhibitor is particularly preferable for treating diabetic complications because it suppresses an increase in protein kinase C activity observed due to continuous hyperglycemia in a diabetic condition.
Examples of the γ-aminobutyric acid receptor antagonist include topiramate and the like, examples of the sodium channel antagonist include mexiletine hydrochloride and oxcarbazepine, and examples of the transcription factor NF-κB inhibitor include dexlipotam and the like. Examples of the lipid peroxidase inhibitor include tilirazad mesylate and the like, examples of the N-acetylated-α-linked-acid-dipeptidase inhibitor include GPI-5693 and the like, and examples of the carnitine derivative include , Carnitine, levasecarnin hydrochloride, levocarnitine chloride, levocarnitine, ST-261 and the like. These drugs, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide and Y-128 is particularly preferred for the treatment of diabetic complications.
Hydroxymethylglutaryl coenzyme A reductase inhibitors include cerivastatin sodium, pravastatin sodium, lovastatin, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101, BB- 476, L-669262, S-2468, DMP-565, U-20885, BAY-x-2678, BAY-10-2987, pitavastatin calcium, rosuvastatin calcium, cholestrone, dalvastatin, acitatemate, Mevastatin, crylvastatin, BMS-180431, BMY-21950, Gremba Statins, carvastatin, BMY-22089, bervastatin (bervastatin), and the like. Hydroxymethylglutaryl coenzyme A reductase inhibitors are particularly preferred for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and hydroxymethylglutaryl coenzyme A Since blood cholesterol is reduced by inhibiting reductase, it is more preferable for the treatment of hyperlipidemia, hypercholesterolemia, and atherosclerosis.
Examples of fibrate compounds include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate aluminum, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, ronifibrate, simfibrate, Theofibrate, AHL-157 and the like. Fibrate compounds are particularly preferred for treating hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and activation of lipoprotein lipase in the liver It is further preferable for the treatment of hyperlipidemia, hypertriglyceridemia, and atherosclerosis, because it lowers blood triglycerides due to increased fatty acid oxidation.
β ₃ -As adrenergic receptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413, SR- 59962A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178 and the like. β ₃ Adrenergic receptor agonists are particularly preferred for the treatment of obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, ₃ -It is more preferable for treating obesity and hyperinsulinemia because it stimulates adrenergic receptors and consumes energy by enhancing fatty acid oxidation.
Acyl Coenzyme A: As cholesterol acyltransferase inhibitors, NTE-122, MCC-147, PD-133201-2, DUP-129, U-73482, U-76807, RP-70676, P-06139, CP- 113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8- 434, avasimibe, CI-976, RP-64477, F-1394, eldasimimibe, CS-505, CL-283546, YM-17E, lecimidide, 447C88, YM-750, E-750. 24, KW-3033, HL-004, and the like eflucimibe (eflucimibe) or the like. Acylcoenzyme A: cholesterol acyltransferase inhibitors are particularly preferable for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and lipid metabolism disorder, and also inhibit acylcoenzyme A: cholesterol acyltransferase. By doing so, blood cholesterol is reduced, and thus it is more preferable for the treatment of hyperlipidemia and hypercholesterolemia.
Thyroid hormone receptor agonists include liothyronine sodium, levothyroxine sodium, KB-2611, and the like, cholesterol absorption inhibitors include ezetimibe, SCH-48461, and the like; lipase inhibitors include orlistat, ATL-962, AZM-131, RED-103004, and the like; carnitine palmitoyltransferase inhibitors include etomoxil; and squalene synthase inhibitors include SDZ-268-198, BMS-188494, A- 87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 and the like, and as the nicotinic acid derivative, nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox Nicorandil and the like; bile acid adsorbents include cholestyramine, cholestyrane, colesevelam hydrochloride, GT-102-279, and the like; sodium-conjugated bile acid transporter inhibitors include 264W94, S-8921, and SD- 5613 and the like, and examples of cholesterol ester transfer protein inhibitors include PNU-107368E, SC-795, JTT-705, CP-529414 and the like. These drugs, probucol, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors and low-density lipoprotein receptor enhancers are particularly useful for treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and lipid metabolism disorders. preferable.
Appetite suppressants include monoamine reuptake inhibitors, serotonin reuptake inhibitors, serotonin release stimulants, serotonin agonists (particularly 5HT _2C -Agonists), noradrenaline reuptake inhibitors, noradrenaline release stimulants, α ₁ An adrenergic receptor agonist, β ₂ An adrenergic receptor agonist, a dopamine agonist, a cannabinoid receptor antagonist, a γ-aminobutyric acid receptor antagonist, H ₃ -Histamine antagonist, L-histidine, leptin, leptin analog, leptin receptor agonist, melanocortin receptor agonist (especially MC3-R agonist, MC4-R agonist), α-melanocyte stimulating hormone, cocaine-amphetamine-regulated Transcript, mahogany protein, enterostatin agonist, calcitonin, calcitonin gene-related peptide, bombesin, cholecystokinin agonist (especially CCK-A agonist), corticotropin releasing hormone, corticotropin releasing hormone analog, corticotropin releasing hormone agonist, urocortin, somatostatin, Somatostatin analog, somatostatin receptor agonist, pituitary adenylate cyclase activating peptide Brain-derived nerve growth factor, serially neurotrophic factor, thyrotropin releasing hormone, neurotensin, sorbazine, neuropeptide Y antagonist, opioid peptide antagonist, galanin antagonist, melanin-concentrating hormone receptor antagonist, agouti-related protein inhibitor, orexin Receptor antagonists and the like. Specifically, monoamine reuptake inhibitors include mazindol and the like, and serotonin reuptake inhibitors include dexfenfluramine hydrochloride, fenfluramine, sibutramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride and the like. , Serotonin agonists include inotriptan, (+) norfenfluramine, etc., noradrenaline reuptake inhibitors include bupropion, GW-320659, etc., and noradrenaline release stimulants include rolipram, YM- 992 etc., and β ₂ -Adrenergic receptor agonists include amphetamine, dextroamphetamine, phentermine, benzphetamine, methamphetamine, phendimethrazine, phenmetrazine, diethylpropion, phenylpropanolamine, clobenzolex, etc., and dopamine agonists ER-230, doplexin, and bromocriptine mesylate; cannabinoid receptor antagonists include rimonabant; γ-aminobutyric acid receptor antagonists include topiramate; ₃ -Examples of histamine antagonists include GT-2394, examples of leptin, leptin analogs and leptin receptor agonists include LY-355101, and examples of cholecystokinin agonists (particularly CCK-A agonists) include SR- 146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378, and the like. , SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814 and the like. Appetite suppressants, especially diabetes, diabetic complications, obesity, glucose metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, atherosclerosis, hypertension, congestive Suitable for treatment of heart failure, edema, hyperuricemia, and gout, and because it suppresses appetite by promoting or inhibiting the action of monoamines and bioactive peptides in the brain in the central appetite control system, and reduces energy intake. , More preferred for the treatment of obesity.
Examples of angiotensin converting enzyme inhibitors include captopril, enalapril maleate, alacepril, delapril hydrochloride, ramipril, lisinopril, imidapril hydrochloride, benazepril hydrochloride, seronapril monohydrate, cilazapril, fosinopril sodium, perindopril erbumin, and mobertipril calcium Quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calcium, moexipril hydrochloride, lenticular, and the like. Angiotensin converting enzyme inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
Examples of the neutral endopeptidase inhibitor include omapatrilat, MDL-100240, fasidotril, sampatrilat, GW-660511X, mixampril, SA-7060, E-4030, SLV-306, and ecaditol. No. Neutral endopeptidase inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
Examples of angiotensin II receptor antagonists include candesartan cilexetil, candesartan cilexetil / hydrochlorothiazide, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3313, olmesartan, and tassosartan. KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 and the like. Angiotensin II receptor antagonists are particularly preferred for the treatment of diabetic complications and hypertension.
Examples of endothelin converting enzyme inhibitors include CGS-31447, CGS-35066, SM-19712, and the like, and examples of endothelin receptor antagonists include L-799805, TBC-3214, BMS-182874, BQ-610, and TA-0201. , SB-215355, PD-180988, sitaxsentan sodium (sitaxentan), BMS-193888, darsentan (darusentan), TBC-3711, bosentan, tezosentan sodium (tezosentan), J-104132, YM-598, S-0139. , SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enracentan, BMS-207940 and the like. These drugs are particularly preferred for the treatment of diabetic complications and hypertension, more preferably for the treatment of hypertension.
Diuretics include chlorthalidone, metolazone, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, penflutide, meticlothiazide, indapamide, tripamide, mefluside, azosemide, ethacric acid, tolacemide, piretanide, semitride Methicran, potassium canrenoate, spironolactone, triamterene, aminophylline, cicletanine hydrochloride, LLU-α, PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin, acetozolamide, methazolamide, FR-179544, OPC-31260, Lixibaptan, conivaptan hydrochloride. Diuretics are especially preferred for the treatment of diabetic complications, hypertension, congestive heart failure, edema, and also reduce blood pressure by increasing urine output or improve edema, hypertension, congestive heart failure, More preferred for the treatment of edema.
Examples of calcium antagonists include alanidipine, efonidipine hydrochloride, nicardipine hydrochloride, valnidipine hydrochloride, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besylate, pranidipine, lercanidipine hydrochloride, isradidipine, isradipine, isradipine, eradipine Lacidipine, batanidipine hydrochloride, remildipine, diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridyl hydrochloride, galopamil hydrochloride and the like.Examples of vasodilator antihypertensive drugs include indapamide, todralazine hydrochloride, hydralazine hydrochloride. , Cadralazine, budralazine, etc., and as the sympathomimetic, amosulalol hydrochloride, terazo hydrochloride , Bunazosin hydrochloride, prazosin hydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol hydrochloride, metoprolol tartrate, carvedilol, nipradilol, ceriprolol hydrochloride, nebivolol, betaxolol hydrochloride, pindolol, tartatrol hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride , Bisoprolol fumarate, bopindolol malonate, nipradilol, penbutolol sulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol, urapidil, indolamine, etc., as central antihypertensive drugs, reserpine and the like, α ₂ -Adrenergic receptor agonists include clonidine hydrochloride, methyldopa, CHF-1035, guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine, lolipexin hydrochloride and the like. These agents are particularly preferred for the treatment of hypertension.
Antiplatelet agents include ticlopidine hydrochloride, dipyridamole, cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazep hydrochloride, trapidil, beraprost sodium, aspirin and the like. Antiplatelet drugs are particularly preferred for the treatment of atherosclerosis and congestive heart failure.
Uric acid production inhibitors include allopurinol and oxypurinol; uric acid excretion enhancers include benzbromarone and probenecid; urinary alkalinizing agents include sodium bicarbonate, potassium citrate and citric acid Acid sodium and the like. These drugs are particularly preferable for treating hyperuricemia and gout.
For example, when used in combination with a drug other than an SGLT2 activity inhibitor, in the treatment of diabetes, an insulin sensitizer, a sugar absorption inhibitor, a biguanide drug, an insulin secretagogue, insulin or an insulin analog, a glucagon receptor Antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor Pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, gluca Preferably combined with at least one drug selected from the group consisting of insulin-like peptide-1 agonists, amylin, amylin analogs, amylin agonists and appetite suppressants, insulin sensitivity enhancers, sugar absorption inhibitors, biguanides , Insulin secretagogue, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor Glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 In combination with at least one drug selected from the group consisting of harmful agents, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog and amylin agonist It is most preferred to combine with at least one drug selected from the group consisting of insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues and insulin or insulin analogs. Similarly, in the treatment of diabetic complications, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl Peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor Drug, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin Analogs, amylin agonists, aldose reductase inhibitors, advanced glycation endproducts inhibitors, protein kinase C inhibitors, γ-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-κB inhibitors, lipid peroxidase inhibition Drug, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor Antagonist And at least one drug selected from the group consisting of aldose reductase inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors and angiotensin II receptor antagonists. More preferably, it is combined with at least one drug selected from the following. In the treatment of obesity, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl peptidase II inhibition Drug, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D -Chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analogue, glucagon-like peptide-1 agonist, amylin, amylin analogue, a Phosphorus agonists, β ₃ -Preferably in combination with at least one drug selected from the group consisting of an adrenergic receptor agonist and an appetite suppressant; ₃ -More preferably, it is combined with at least one drug selected from the group consisting of adrenergic receptor agonists and appetite suppressants.
When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Such dosage forms include, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and the like. It is administered orally.
These pharmaceutical compositions are suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, and the like, depending on the method used in pharmacy depending on the dosage form. It can be produced by appropriately mixing or diluting / dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method. When used in combination with a drug other than the SGLT2 activity inhibitor, it can be produced by formulating each active ingredient simultaneously or separately in the same manner as described above.
When the pharmaceutical composition of the present invention is used for actual treatment, its active ingredient is a glucopyranosyloxybenzylbenzene derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The dose of the prodrug is appropriately determined depending on the age, sex, body weight, disease, degree of treatment, and the like of the patient. In the case of oral administration, it is generally in the range of 0.1 to 1000 mg per adult per day. In this case, the dose can be appropriately administered once or several times in the range of approximately 0.01 to 300 mg per adult day. When used in combination with a drug other than the SGLT2 activity inhibitor, the dose of the compound of the present invention can be reduced according to the dose of the drug other than the SGLT2 activity inhibitor.
Example
The content of the present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to the content.
Example 1
2- (4-pyrazol-1-ylbenzyl) phenol
A suspension of 4-fluorobenzaldehyde (1.0 g), pyrazole (0.55 g) and potassium carbonate (1.2 g) in N, N-dimethylformamide (3 mL) was stirred at 150 ° C. for 7 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 6/1 to 3/1) to obtain 4-pyrazol-1-ylbenzaldehyde (0.94 g). To a solution of 2-benzyloxybromobenzene (0.99 g) in tetrahydrofuran (20 mL) was added n-butyllithium (2.66 mol / L hexane solution, 1.2 mL) at -78 ° C, and the mixture was stirred for 10 minutes. A solution of 4-pyrazol-1-ylbenzaldehyde (0.5 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was heated to 0 ° C and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to obtain (2-benzyloxyphenyl)-(4-pyrazol-1-ylphenyl) -methanol (0.84 g). Was. 10% palladium carbon powder (0.42 g) was added to a methanol (5 mL) solution of (2-benzyloxyphenyl)-(4-pyrazol-1-ylphenyl) -methanol (0.84 g), and the mixture was added with a hydrogen atmosphere. Stirred at room temperature for 24 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off. Diethyl ether was added to the residue, and the crystals were collected by filtration and dried under reduced pressure to obtain the title compound (0.20 g).
¹ H-NMR (CDCl ₃ ) Δ ppm:
4.03 (2H, s), 4.91 (1H, s), 6.45 (1H, dd, J = 1.8, 2.4 Hz), 6.75-6.85 (1H, m), 6.85-6.95 (1H, m), 7.10-7.20 (2H, m), 7.25-7.35 (2H, m), 7.55-7.65 (2H, m ), 7.71 (1H, dd, J = 0.5, 1.8 Hz), 7.88 (1H, dd, J = 0.5, 2.4 Hz)
Example 2
2- (4-pyrazol-1-ylbenzyl) phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside
2- (4-pyrazol-1-ylbenzyl) phenol (0.10 g), acetobromo-α-D-glucose (0.16 g) and benzyltri (n-butyl) ammonium chloride (0.12 g) in methylene chloride (5 mL) And a mixture of aqueous sodium hydroxide solution (5 mol / L, 0.32 mL) was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/1) to obtain the title compound (0.044 g).
Example 3
2- (4-pyrazol-1-ylbenzyl) phenyl = β-D-glucopyranoside
To a solution of 2- (4-pyrazol-1-ylbenzyl) phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.044 g) in methanol (3 mL) was added sodium methoxide (28%). (A methanol solution, 0.015 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 6/1) to obtain the title compound (0.020 g).
¹ H-NMR (CD ₃ OD) δ ppm:
3.30-3.55 (4H, m), 3.69 (1H, dd, J = 5.4, 12.0 Hz), 3.88 (1H, dd, J = 2.1, 12.0 Hz) , 4.03 (1H, d, J = 14.7 Hz), 4.17 (1H, d, J = 14.7 Hz), 4.93 (1H, d, J = 7.6 Hz), 6.45− 6.55 (1H, m), 6.85-7.00 (1H, m), 7.10-7.15 (1H, m), 7.15-7.20 (2H, m), 7. 35-7.45 (2H, m), 7.55-7.65 (2H, m), 7.65-7.70 (1H, m), 8.10-8.15 (1H, m)
Example 4
1- [4- (2-hydroxybenzyl) phenyl] piperidin-4-ol
A suspension of 4-fluorobenzaldehyde (1.2 g), 4-hydroxypiperidine (1.0 g) and potassium carbonate (1.5 g) in N, N-dimethylformamide (3 mL) was stirred at 150 ° C. for 5 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, and the crystals were collected by filtration and dried to give 4- (4-hydroxypiperidin-1-yl) benzaldehyde (0.94 g). To a solution of 2-benzyloxybromobenzene (1.6 g) in tetrahydrofuran (30 mL) was added n-butyllithium (1.59 mol / L hexane solution, 4.0 mL) at -78 ° C, and the mixture was stirred for 10 minutes. A solution of 4- (4-hydroxypiperidin-1-yl) benzaldehyde (0.5 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was heated to 0 ° C and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate) to obtain 1- {4-[(2-benzyloxyphenyl) hydroxymethyl] phenyl} piperidin-4-ol (0.95 g). . To a solution of 1- {4-[(2-benzyloxyphenyl) hydroxymethyl] phenyl} piperidin-4-ol (0.95 g) in methanol (10 mL) was added 10% palladium carbon powder (0.12 g), and a hydrogen atmosphere was added. The mixture was stirred at room temperature for 15 hours. The insoluble material was removed by filtration, the solvent of the residue was distilled off under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain 1- {4- [ (2-Hydroxyphenyl) hydroxymethyl] phenyl @ piperidin-4-ol (0.28 g) was obtained. To a solution of 1- {4-[(2-hydroxyphenyl) hydroxymethyl] phenyl} piperidin-4-ol (0.28 g) in methanol (5 mL) was added 10% palladium carbon powder (0.28 g), and the mixture was added under a hydrogen atmosphere. And stirred at room temperature for 15 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (0.23 g).
¹ H-NMR (DMSO-d ₆ ) Δ ppm:
1.35-1.50 (2H, m), 1.65-1.85 (2H, m), 2.65-2.80 (2H, m), 3.35-3.50 (2H, m) ), 3.50-3.65 (1H, m), 3.73 (2H, s), 4.63 (1H, d, J = 4.3 Hz), 6.60-6.85 (4H, m ), 6.90-7.10 (4H, m), 9.28 (1H, s)
Example 5
2- [4- (4-hydroxypiperidin-1-yl) benzyl] phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside
1- [4- (2-hydroxybenzyl) phenyl] piperidin-4-ol (0.23 g), acetobromo-α-D-glucose (0.33 g) and benzyltri (n-butyl) ammonium chloride (0.25 g) A mixture of methylene chloride (10 mL) and an aqueous sodium hydroxide solution (5 mol / L, 0.62 mL) was stirred at room temperature for 3 hours. The reaction mixture was purified by aminopropyl silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2) to obtain the title compound (0.12 g).
Example 6
2- [4- (4-hydroxypiperidin-1-yl) benzyl] phenyl = β-D-glucopyranoside
To a solution of 2- [4- (4-hydroxypiperidin-1-yl) benzyl] phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.12 g) in methanol (5 mL) Sodium methoxide (28% methanol solution, 0.073 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 5/1) to obtain the title compound (0.036 g).
¹ H-NMR (CD ₃ OD) δ ppm:
1.55-1.70 (2H, m), 1.85-2.00 (2H, m), 2.75-2.85 (2H, m), 3.30-3.55 (6H, m ), 3.60-3.80 (2H, m), 3.80-3.95 (2H, m), 4.00 (1H, d, J = 14.7 Hz), 4.90 (1H, d) , J = 7.3 Hz), 6.85-6.95 (3H, m), 7.00-7.20 (5H, m)
Example 7
2- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] phenol
A suspension of 4-cyanobenzaldehyde (3.0 g), sodium azide (1.5 g) and lithium chloride (1.5 g) in 2-methoxyethanol (25 mL) was heated to reflux for 7.5 hours. After the reaction mixture was cooled to room temperature, it was poured into ice and concentrated hydrochloric acid was added. The crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 4- (tetrazol-5-yl) benzaldehyde (2.9 g). To a solution of 4- (tetrazol-5-yl) benzaldehyde (2.9 g) in 1,4-dioxane (15 mL) and N, N-dimethylformamide (15 mL) was added potassium carbonate (6.8 g) at 0 ° C. Stirred for minutes. Iodomethane (3.5 g) was added to the reaction mixture, and after stirring at room temperature for 24 hours, the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 4- (2-methyl-2H-tetrazol-5-yl) benzaldehyde (2.7 g). To a solution of 2-benzyloxybromobenzene (1.0 g) in tetrahydrofuran (40 mL) was added tert-butyllithium (1.45 mol / L pentane solution, 2.9 mL) at -78 ° C, and the mixture was stirred for 10 minutes. A solution of 4- (2-methyl-2H-tetrazol-5-yl) benzaldehyde (0.72 g) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was heated to 0 ° C and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give (2-benzyloxyphenyl)-[4- (2-methyl-2H-tetrazol-5-yl) phenyl]-. Methanol (0.90 g) was obtained. 10% palladium carbon powder (0.50 g) in a solution of (2-benzyloxyphenyl)-[4- (2-methyl-2H-tetrazol-5-yl) phenyl] -methanol (0.90 g) in methanol (20 mL) Was added and stirred at room temperature for 24 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. Diethyl ether was added to the residue, and the crystals were collected by filtration and dried under reduced pressure to obtain the title compound (0.17 g).
¹ H-NMR (CDCl ₃ ) Δ ppm:
4.06 (2H, s), 4.39 (3H, s), 4.86 (1H, s), 6.75-6.85 (1H, m), 6.85-6.95 (1H, m), 7.10-7.20 (2H, m), 7.30-7.40 (2H, m), 8.00-8.10 (2H, m)
Example 8
2- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside
2- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] phenol (0.10 g), 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl- Boron trifluoride-diethyl ether complex (0.071 mL) was added to a methylene chloride (5 mL) solution of α-D-glucopyranose (0.22 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/1) to obtain the title compound (0.21 g).
¹ H-NMR (CDCl ₃ ) Δ ppm:
1.88 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 3.85-3.95 (1H, m), 3 .96 (1H, d, J = 15.4 Hz), 4.01 (1H, d, J = 15.4 Hz), 4.17 (1H, dd, J = 2.6, 12.3 Hz), 4. 29 (1H, dd, J = 5.8, 12.3 Hz), 4.38 (3H, s), 5.10-5.25 (2H, m), 5.25-5.40 (2H, m ), 6.95-7.15 (3H, m), 7.15-7.30 (3H, m), 8.00-8.05 (2H, m)
Example 9
2- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] phenyl = β-D-glucopyranoside
2- [4- (2-methyl-2H-tetrazol-5-yl) benzyl] phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.21 g) in methanol (5 mL) ) Solution was added with sodium methoxide (28% methanol solution, 0.067 mL) and stirred at room temperature for 50 minutes. The crystals were collected by filtration and dried under reduced pressure to obtain the title compound (0.097 g).
¹ H-NMR (CD ₃ OD) δ ppm:
3.30-3.55 (4H, m), 3.69 (1H, dd, J = 5.5, 12.1 Hz), 3.88 (1H, dd, J = 2.2, 12.1 Hz) , 4.05 (1H, d, J = 14.8 Hz), 4.19 (1H, d, J = 14.8 Hz), 4.39 (3H, s), 4.90-4.95 (1H, m), 6.90-7.00 (1H, m), 7.10-7.15 (1H, m), 7.15-7.20 (2H, m), 7.35-7.45 ( 2H, m), 7.90-8.00 (2H, m)
Example 10
2- (4-phenylbenzyl) phenol
To a solution of 2-benzyloxybromobenzene (0.29 g) in tetrahydrofuran (10 mL) was added tert-butyllithium (1.48 mol / L pentane solution, 0.74 mL) at -78 ° C, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of biphenyl-4-carbaldehyde (0.18 g) in tetrahydrofuran (2 mL), and the mixture was heated to 0 ° C and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1) to obtain (2-benzyloxyphenyl) -biphenyl-4-ylmethanol (0.26 g). To a solution of (2-benzyloxyphenyl) -biphenyl-4-ylmethanol (0.26 g) in ethanol (5 mL) and concentrated hydrochloric acid (0.06 mL) was added 10% palladium carbon powder (0.052 g), and the mixture was added under a hydrogen atmosphere. And stirred at room temperature for 2 days. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1) to obtain the title compound (0.14 g).
¹ H-NMR (CDCl ₃ ) Δ ppm:
4.04 (2H, s), 4.73 (1H, s), 6.75-7.85 (1H, m), 6.85-6.95 (1H, m), 7.10-7. 20 (2H, m), 7.25-7.35 (3H, m), 7.35-7.45 (2H, m), 7.45-7.60 (4H, m)
Example 11
2- (4-phenylbenzyl) phenyl = β-D-glucopyranoside
2- (4-phenylbenzyl) phenol (0.063 g), 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose (0.13 g) To a methylene chloride (3 mL) solution was added boron trifluoride-diethyl ether complex (0.034 mL) at 0 ° C., followed by stirring for 3 hours. The reaction mixture was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1), and 2- (4-phenylbenzyl) phenyl = 2,3,4,6-tetra-O-acetyl-β- D-glucopyranoside was obtained. The obtained 2- (4-phenylbenzyl) phenyl = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was dissolved in methanol (3 mL), and sodium methoxide (28% methanol solution, 0.19 mL) and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain the title compound (0.026 g).
¹ H-NMR (CD ₃ OD) δ ppm:
3.30-3.55 (4H, m), 3.70 (1H, dd, J = 5.2, 12.0 Hz), 3.88 (1H, dd, J = 2.0, 12.0 Hz) , 4.03 (1H, d, J = 14.9 Hz), 4.15 (1H, d, J = 14.9 Hz), 4.93 (1H, d, J = 7.6 Hz), 6.90- 7.00 (1H, m), 7.05-7.20 (3H, m), 7.25-7.35 (3H, m), 7.35-7.45 (2H, m), 7. 45-7.60 (4H, m)
Test example 1
Human SGLT2 activity inhibitory activity confirmation test
1) Cloning of human SGLT2 and recombination into an expression vector
Total RNA (Origene) derived from human small intestine was reverse transcribed using oligo dT as a primer to prepare a cDNA library for PCR amplification. Using this cDNA library as a template, R. G. FIG. The nucleotide sequence from No. 2 to No. 2039 of human SGLT2 (ACCESSION: M95549, M95299) reported by Wells et al. Was amplified by PCR and inserted into the multicloning site of pcDNA3.1 (-) (Invitrogen). The nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.
2) Establishment of human SGLT2 stable expression strain
The human SGLT2 expression vector was digested with ScaI to obtain linear DNA, and then introduced into CHO-K1 cells by the lipofection method (Effectene Transfection Reagent: QIAGEN). A neomycin-resistant cell line was obtained with 1 mg / mL G418 (LIFE TECHNOLOGIES), and the uptake activity of methyl-α-D-glucopyranoside was measured by the method described below. The strain showing the strongest uptake activity was selected as CS2-5E, and subsequently cultured in the presence of 200 μg / mL G418.
3) Measurement of methyl-α-D-glucopyranoside (α-MG) uptake inhibitory activity
3 × 10 CS2-5E in 96-well plate ⁴ The seeds were inoculated in each well and cultured for 2 days, and then subjected to an uptake experiment. Buffer for uptake (140 mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, 5 mM tris (hydroxymethyl) aminomethane Buffer (pH 7.4) contains a non-radioactive label (Sigma) ¹⁴ Α-MG of C-labeled body (Amersham Pharmacia Biotech) was mixed and added to a final concentration of 1 mM. The test compound was dissolved in dimethyl sulfoxide, appropriately diluted with distilled water, and added to an uptake buffer containing 1 mM α-MG to prepare a measurement buffer. For the control group, a measurement buffer containing no test compound was prepared, and for the measurement of basal uptake, a buffer for basal uptake containing 140 mM choline chloride was prepared instead of sodium chloride. The culture medium of the cultured cells was removed, and a buffer for pretreatment (a buffer for basal uptake without α-MG) was added at 180 μL per well, and the mixture was allowed to stand at 37 ° C. for 10 minutes. After repeating the same operation once again, the buffer for uptake was removed, and the buffer for measurement and the buffer for basal uptake were added in an amount of 75 μL per well and allowed to stand at 37 ° C. One hour later, the measurement buffer was removed, and the wells were washed twice with 180 μL per well of a washing buffer (a basal buffer containing 10 mM non-labeled α-MG). Cells were lysed with 75 μL per well of 0.2 mol / L sodium hydroxide, and the solution was transferred to a picoplate (Packard). 150 μL of Microscint 40 (Packard) was added and mixed, and the radioactivity was measured using a microscintillation counter TopCount (Packard). The value obtained by subtracting the amount of basal uptake from the uptake of the control group was taken as 100%, and the amount of uptake of methyl-α-D-glucopyranoside at each concentration of the test compound was calculated. The concentration at which the test compound inhibits the uptake of methyl-α-D-glucopyranoside by 50% (IC ₅₀ Value) was calculated by logit plot. Table 1 shows the results.

Industrial applicability
The glucopyranosyloxybenzylbenzene derivative represented by the general formula (I) of the present invention, a pharmaceutically acceptable salt thereof, and a prodrug thereof exhibit excellent human SGLT2 activity inhibitory activity, and By suppressing the reabsorption of sugar in the blood and excreting excess sugar in the urine, thereby exhibiting an excellent blood glucose lowering effect. According to the present invention, it is possible to provide a preventive or therapeutic drug for diseases caused by hyperglycemia such as diabetes, diabetic complications, and obesity. In addition, the compound represented by the general formula (II) and a salt thereof according to the present invention include a glucopyranosyloxybenzylbenzene derivative represented by the general formula (I), and a pharmaceutically acceptable salt thereof. And important as intermediates when producing their prodrugs, and by way of this compound, the compound can be easily produced.

Claims

General formula

(Wherein R ¹ is a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group, a carboxy lower alkoxy group, a nitrogen atom at the bonding site, and an oxygen atom May contain one hetero atom selected from a sulfur atom and a nitrogen atom in the ring, and may have a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group as a substituent. A good 5- or 6-membered aliphatic cyclic amino group, or Or a nitrogen atom at the bonding site may further contain 1 to 3 nitrogen atoms in the ring, and a heterogeneous or similar group selected from a lower alkyl group and a lower alkoxy group may be used as a substituent. R ⁵ is a hydrogen atom or a lower alkyl group, and R ³ is a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group. An aryl group optionally having 1 to 3 groups of the same or different kinds selected from above, and optionally having a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group as a substituent 3 One or two hetero atoms of the same or different kind selected from a cycloalkyl group of 7 to 7 members, an oxygen atom, a sulfur atom and a nitrogen atom in the ring, and a lower alkyl group or a lower alkyl group as a substituent; A 5- or 6-membered aliphatic heterocyclic group which may have a group selected from a oxy group, a hydroxyl group and an amino group, or a heterogeneous or similar heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom In the ring, and a 5- or 6-membered aromatic heterocyclic ring which may have 1 to 3 different or the same kind of groups selected from a lower alkyl group and a lower alkoxy group as a substituent A glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Any ^one of R ¹ and R ³ may contain one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom at the bonding site, and a lower alkyl as a substituent A 5-, 6-membered aliphatic cyclic amino group which may have a group selected from a group, a lower alkoxy group, a hydroxyl group and an amino group, or a nitrogen atom in addition to the nitrogen atom in the bonding site, and A 5-membered aromatic cyclic amino group which may have 1 to 3 hetero- or same-type groups selected from a lower alkyl group and a lower alkoxy group as a substituent which may be contained in the single ring; A certain glucopyranosyloxybenzylbenzene derivative according to claim 1, a pharmacologically acceptable salt thereof, or a prodrug thereof.

General formula

(Wherein R ^1a represents a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group or a carboxy lower alkoxy group, wherein R ² is a hydrogen atom or a lower alkyl group; R ^3a may contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom at the bonding site, and may be a lower alkyl group or a lower alkoxy group as a substituent. Group, hydroxyl group or amino group A 5- or 6-membered aliphatic cyclic amino group which may have a group or a nitrogen atom at the bonding site, and may further contain 1 to 3 nitrogen atoms in the ring. The glucopyra according to claim 2, which is a 5-membered aromatic aromatic amino group which may have 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group. Nosyloxybenzylbenzene derivatives or pharmacologically acceptable salts thereof, or prodrugs thereof.

General formula

(Wherein R ^1a represents a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group or a carboxy lower alkoxy group, wherein R ² is a hydrogen atom or a lower alkyl group; R ³ is an aryl group optionally having 1 to 3 different or the same kind of groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group as a substituent, and a lower alkyl group as a substituent. Group, lower alkoxy group, One or two hetero atoms of the same or different kind selected from a 3- to 7-membered cycloalkyl group which may have a group selected from an acid group and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom; A 5- or 6-membered aliphatic heterocyclic group which is contained in a ring and may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group, or an oxygen atom, a sulfur atom And 1 to 4 heterogeneous or similar heteroatoms selected from a nitrogen atom in the ring, and 1 to 3 heterogeneous or similar groups selected from a lower alkyl group and a lower alkoxy group as a substituent. Or a pharmaceutically acceptable salt thereof, or a glucopyranosyloxybenzylbenzene derivative according to claim 1, which is a 5- or 6-membered aromatic heterocyclic group which may be These prodrugs.

General formula

[In the formula, P ¹ is a hydrogen atom or a group constituting a prodrug, and R ¹⁰ is a hydrogen atom, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group. Group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy group, carbamoyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonyl lower alkoxy group, carboxy lower alkyl group, carboxy lower alkoxy group, other nitrogen atom at the bonding site May contain one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug as a substituent, and 5 or more which may have a group selected from an amino group May further contain 1 to 3 nitrogen atoms in the ring in addition to the 6-membered aliphatic cyclic amino group or the nitrogen atom at the bonding site, and are selected from lower alkyl groups and lower alkoxy groups as substituents. A 5-membered aromatic cyclic amino group which may have 1 to 3 different or similar groups, or a general formula P ² -OA ^1- (wherein P ² is a hydrogen atom or a prodrug A ¹ is a single bond, a lower alkylene group or a lower alkyleneoxy group), R ² is a hydrogen atom or a lower alkyl group, and R ³⁰ is a lower alkyl group or a lower alkyl group as a substituent. An alkoxy group, a halogen atom, an aryl group which may have 1 to 3 different or the same kind of groups selected from a hydroxyl group having a group constituting a hydroxyl group and a prodrug, a lower alkyl group as a substituent, Selected from a 3- to 7-membered cycloalkyl group which may have a group selected from a primary alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom. Having one or two hetero atoms of the same or different kind in the ring, and having a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group. A 5- or 6-membered aliphatic heterocyclic group which may be substituted, or a heterocyclic or heterogeneous heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in 1 to 4 ring (s); Which is a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 heterogeneous or similar groups selected from an alkyl group and a lower alkoxy group). Turkey pyranosyl oxybenzyl benzene derivative or a pharmacologically acceptable salt thereof.

One of R ¹⁰ and R ³⁰ may contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom at the bonding site, and may have a lower alkyl group as a substituent. A 5- or 6-membered aliphatic cyclic amino group which may have a group selected from a group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group, or a nitrogen atom at a bonding site May further contain 1 to 3 nitrogen atoms in the ring, and may have 1 to 3 different or similar groups selected from lower alkyl groups and lower alkoxy groups as substituents. The glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof according to claim 5, which is a 5-membered aromatic cyclic amino group.

General formula

(Wherein P ¹ is a hydrogen atom or a group constituting a prodrug, and R ^10a is a hydrogen atom, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group. group, a lower alkoxy-lower alkyl group, lower alkoxy-lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, lower alkoxycarbonyl lower alkoxy group, carboxy lower alkyl group, a carboxy lower alkoxy group or the formula P ² -O- A ^1- (wherein P ² is a hydrogen atom or a group constituting a prodrug, A ¹ is a single bond, a lower alkylene group or a lower alkyleneoxy group), and R ² is a hydrogen atom or a lower alkyl group. R ^3a is an oxygen atom, a sulfur atom, One heteroatom selected from an atom and a nitrogen atom may be contained in the ring, and the substituent is selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug and an amino group. A 5- or 6-membered aliphatic cyclic amino group which may have a group, or a nitrogen atom at the bonding site, and may further contain 1 to 3 nitrogen atoms in the ring. The glucopyra according to claim 6, which is a 5-membered aromatic aromatic amino group which may have 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group. Nosyloxybenzylbenzene derivatives or pharmacologically acceptable salts thereof.

General formula

(P ¹ is a hydrogen atom or a group constituting a prodrug; R ^10a is a hydrogen atom, an amino group, a mono- or di- (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy group; alkoxy lower alkyl group, lower alkoxy-lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, lower alkoxycarbonyl lower alkoxy group, carboxy lower alkyl group, a carboxy lower alkoxy group or the formula P ² -O-A ¹ - Wherein P ² is a hydrogen atom or a group constituting a prodrug, A ¹ is a single bond, a lower alkylene group or a lower alkyleneoxy group, and R ² is a hydrogen atom or a lower alkyl group. And R ³⁰ are a lower alkyl group or a lower alkoxy group as a substituent An aryl group optionally having 1 to 3 different or similar groups selected from a halogen atom, a hydroxyl group and a hydroxyl group having a group constituting a prodrug, a lower alkyl group, a lower alkoxy group, a hydroxyl group as a substituent A hetero- or homologue selected from a 3- to 7-membered cycloalkyl group optionally having a group selected from a hydroxyl group having a group constituting a prodrug and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom And may have a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group, a hydroxyl group having a group constituting a prodrug, and an amino group as a substituent. A 5- or 6-membered aliphatic heterocyclic group, or a heterocyclic or heterocyclic 1-4 atom selected from oxygen, sulfur and nitrogen Which is a 5- or 6-membered aromatic heterocyclic group which may have 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group as a substituent). A glucopyranosyloxybenzylbenzene derivative according to claim 5, or a pharmacologically acceptable salt thereof.

General formula

(Wherein R ¹ is a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group, a carboxy lower alkoxy group, a nitrogen atom at the bonding site, and an oxygen atom May contain one hetero atom selected from a sulfur atom and a nitrogen atom in the ring, and may have a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group as a substituent. A good 5- or 6-membered aliphatic cyclic amino group, or Or a nitrogen atom at the bonding site may further contain 1 to 3 nitrogen atoms in the ring, and a heterogeneous or similar group selected from a lower alkyl group and a lower alkoxy group may be used as a substituent. R ⁵ is a hydrogen atom or a lower alkyl group, and R ³ is a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group. An aryl group optionally having 1 to 3 groups of the same or different kinds selected from above, and optionally having a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group as a substituent 3 One or two hetero atoms of the same or different kind selected from a cycloalkyl group of 7 to 7 members, an oxygen atom, a sulfur atom and a nitrogen atom in the ring, and a lower alkyl group or a lower alkyl group as a substituent; A 5- or 6-membered aliphatic heterocyclic group which may have a group selected from a oxy group, a hydroxyl group and an amino group, or a heterogeneous or similar heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom In the ring, and may have 1 to 3 hetero or hetero groups of the same or different kind selected from a lower alkyl group and a lower alkoxy group as a substituent. A glucopyranosyloxybenzylbenzene derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

One of R ¹ and R ³ may contain one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom at the bonding site, and a lower alkyl group may be used as a substituent. A 5-, 6-membered aliphatic cyclic amino group which may have a group selected from a group, a lower alkoxy group, a hydroxyl group and an amino group; A 5-membered aromatic cyclic amino group which may have 1 to 3 different or the same kind of groups selected from a lower alkyl group and a lower alkoxy group as a substituent, which may be contained in a single ring; 10. The glucopyranosyloxybenzylbenzene derivative according to claim 9, or a pharmaceutically acceptable salt thereof.

General formula

(Wherein R ^1a represents a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group or a carboxy lower alkoxy group, wherein R ² is a hydrogen atom or a lower alkyl group; R ^3a may contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom at the bonding site, and may be a lower alkyl group or a lower alkoxy group as a substituent. Group, hydroxyl group or amino group A 5- or 6-membered aliphatic cyclic amino group which may have a group or a nitrogen atom at the bonding site, and may further contain 1 to 3 nitrogen atoms in the ring. The glucopyra according to claim 10, which is a 5-membered aromatic aromatic amino group which may have 1 to 3 different or similar groups selected from a lower alkyl group and a lower alkoxy group. Nosyloxybenzylbenzene derivatives or pharmacologically acceptable salts thereof.

General formula

(Wherein R ^1a represents a hydrogen atom, a hydroxyl group, an amino group, a mono or di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower An alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a carbamoyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkyl group or a carboxy lower alkoxy group, wherein R ² is a hydrogen atom or a lower alkyl group; R ³ is an aryl group optionally having 1 to 3 different or the same kind of groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group as a substituent, and a lower alkyl group as a substituent. Group, lower alkoxy group, One or two hetero atoms of the same or different kind selected from a 3- to 7-membered cycloalkyl group which may have a group selected from an acid group and an amino group, an oxygen atom, a sulfur atom and a nitrogen atom; A 5- or 6-membered aliphatic heterocyclic group which may be contained in a ring and may have a substituent selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group, or an oxygen atom or a sulfur atom And 1 to 4 different or similar hetero atoms selected from nitrogen atoms in the ring, and having 1 to 3 different or similar groups selected from lower alkyl groups and lower alkoxy groups as substituents. A glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof according to claim 9, which is a 5- or 6-membered aromatic heterocyclic group which may be substituted.

9. The glucopyranosyloxybenzylbenzene derivative or the pharmaceutically acceptable salt thereof according to claim 5, which has at least one group constituting a prodrug.

The glucopyranosyloxybenzylbenzene according to claim 13, wherein the group constituting the prodrug is a lower acyl group, a lower alkoxy lower acyl group, a lower alkoxycarbonyl lower acyl group, a lower alkoxycarbonyl group or a lower alkoxy lower alkoxycarbonyl group. A derivative or a pharmacologically acceptable salt thereof.

A pharmaceutical composition comprising, as an active ingredient, the glucopyranosyloxybenzylbenzene derivative according to claim 1 or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The pharmaceutical composition according to claim 15, which is a human SGLT2 activity inhibitor.

The pharmaceutical composition according to claim 15 or 16, which is an agent for preventing or treating a disease caused by hyperglycemia.

Diseases caused by hyperglycemia are diabetes, diabetic complications, obesity, hyperinsulinemia, dysglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis 18. The pharmaceutical composition according to claim 17, which is a disease selected from the group consisting of symptom, hypertension, congestive heart failure, edema, hyperuricemia and gout.

19. The pharmaceutical composition according to claim 18, wherein the disease caused by hyperglycemia is diabetes.

19. The pharmaceutical composition according to claim 18, wherein the disease caused by hyperglycemia is a diabetic complication.

19. The pharmaceutical composition according to claim 18, wherein the disease caused by hyperglycemia is obesity.

Prevention or prevention of a disease caused by hyperglycemia, comprising administering an effective amount of the glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof or a prodrug thereof according to any one of claims 1 to 14. Method of treatment.

The glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, for producing a pharmaceutical composition for preventing or treating a disease caused by hyperglycemia, or a salt thereof. Use of prodrugs.

(A) The glucopyranosyloxybenzylbenzene derivative according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide. Drug, insulin secretagogue, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor Drug, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, gluca -Like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation end product formation inhibitor, protein kinase C inhibitor, γ -Aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelets Derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethylglutaryl coenzyme A reductase inhibition Drugs, fibrate compounds, beta ₃ - adrenergic receptor agonists, acyl-coenzyme A: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, Lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthase inhibitors, low-density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid adsorbents, sodium-conjugated bile acid transporter inhibitors, cholesterol ester transfer protein inhibitors, Appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor Antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, antiplatelet agents, uric acid production inhibitor, a uricosuric agent and urine alkalizing A medicament comprising a combination of at least one drug selected from the group consisting of drugs.

The medicament according to claim 24, for preventing or treating a disease caused by hyperglycemia.

The component (B) is an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide drug, an insulin secretagogue, insulin or an insulin analog, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, Peptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol , Glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist And at least one agent selected from the group consisting of appetite suppressants, diseases caused by hyperglycemia is diabetes 25. A medicament according.

The component (B) is an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide drug, an insulin secretagogue, insulin or an insulin analog, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, Peptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol Glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog and amylin agony At least one agent selected from the group consisting of preparative claim 26 A medicament according.

28. The medicament according to claim 27, wherein the component (B) is a drug selected from the group consisting of an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretagogue, and insulin or an insulin analog.

The component (B) is an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide drug, an insulin secretagogue, insulin or an insulin analog, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, Peptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol , Glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist Aldose reductase inhibitor, advanced glycation endproduct formation inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylation -Α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1- Methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist and diuretic From the group At least one drug being-option, a disease caused by hyperglycemia is diabetic complications, claim 25 A medicament according.

30. The component (B) is at least one drug selected from the group consisting of aldose reductase inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors and angiotensin II receptor antagonists. Medicine.

The component (B) is an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretagogue, an insulin analog, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, beta ₃ - address The medicament according to claim 25, which is at least one drug selected from the group consisting of a narin receptor agonist and an appetite suppressant, and wherein the disease caused by hyperglycemia is obesity.

Component (B), beta ₃ - is at least one agent selected from the group consisting of adrenergic receptor agonist and an appetite suppressant agent, claim 31 A medicament according.

Appetite suppressant is monoamine reuptake inhibitor, serotonin reuptake inhibitor, serotonin release stimulant, serotonin agonist, noradrenaline reuptake inhibitor, noradrenaline release stimulant, α ₁ -adrenoceptor agonist, β ₂ -adrenoceptor agonist , Dopamine agonist, cannabinoid receptor antagonist, γ-aminobutyric acid receptor antagonist, H ₃ -histamine antagonist, L-histidine, leptin, leptin analog, leptin receptor agonist, melanocortin receptor agonist, α-melanocyte stimulating hormone, Cocaine-amphetamine-regulated transcript, mahogany protein, enterostatin agonist, calcitonin, calcitonin gene-related peptide, bombesin, kore Stokinin agonist, corticotropin releasing hormone, corticotropin releasing hormone analog, corticotropin releasing hormone agonist, urocortin, somatostatin, somatostatin analog, somatostatin receptor agonist, pituitary adenylate cyclase activating peptide, brain-derived nerve growth factor, serially Selected from the group consisting of neurotropic factor, thyrotropin releasing hormone, neurotensin, sorbazine, neuropeptide Y antagonist, opioid peptide antagonist, galanin antagonist, melanin-concentrating hormone receptor antagonist, agouti-related protein inhibitor and orexin receptor antagonist The medicament according to claim 32, which is a medicament to be administered.

(A) The glucopyranosyloxybenzylbenzene derivative according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide. Drug, insulin secretagogue, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor Drug, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, gluca -Like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation end product formation inhibitor, protein kinase C inhibitor, γ -Aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelets Derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethylglutaryl coenzyme A reductase inhibition Drugs, fibrate compounds, beta ₃ - adrenergic receptor agonists, acyl-coenzyme A: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, Lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthase inhibitors, low-density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid adsorbents, sodium-conjugated bile acid transporter inhibitors, cholesterol ester transfer protein inhibitors, Appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor Antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, antiplatelet agents, uric acid production inhibitor, a uricosuric agent and urine alkalizing A method for preventing or treating a disease caused by hyperglycemia, comprising administering an effective amount of at least one drug selected from the group consisting of drugs.

(A) The glucopyranosyloxybenzylbenzene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, for producing a pharmaceutical composition for preventing or treating a disease caused by hyperglycemia. Or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide, an insulin secretagogue, an insulin or insulin analog, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor , -Chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, terminal Saccharification product formation inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylation-α-linked-acid- Dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, Bimoclomol, Srodeki De, Y-128, a hydroxymethyl glutaryl coenzyme A reductase inhibitors, fibrate compounds, beta ₃ - adrenergic receptor agonists, acyl-coenzyme A: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol Absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low-density lipoprotein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium Conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiote Singh II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, anti Use of at least one drug selected from the group consisting of platelet drugs, uric acid production inhibitors, uric acid excretion enhancers, and urinary alkalinizing drugs.

General formula

(Q in the formula is a hydroxyl group or a 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group, and R ¹¹ may have a hydrogen atom or a protecting group. Having a hydroxyl group, an amino group having a protecting group, a mono (lower alkyl) amino group having a protecting group, a di (lower alkyl) amino group, a cyano group, a carbamoyl group, a lower alkyl group, a lower alkoxy group, and a protecting group. Hydroxy lower alkyl group, hydroxy lower alkoxy group optionally having a protecting group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy group, carbamoyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonyl lower alkoxy group Group, carboxy lower alkyl group, carboxy lower alkoxy group, nitrogen atom May contain one hetero atom selected from a sulfur atom and a nitrogen atom in the ring, and may have a group selected from a lower alkyl group, a lower alkoxy group, a hydroxyl group and an amino group as a substituent. A 5- or 6-membered aliphatic cyclic amino group or a nitrogen atom at the bonding site may further contain 1 to 3 nitrogen atoms in the ring, and the substituent may be a lower alkyl group or a lower alkoxy group. R ⁵ is a hydrogen atom or a lower alkyl group, and R ¹³ is a lower substituent as a substituent. An aryl group optionally having 1 to 3 different or similar groups selected from an alkyl group, a lower alkoxy group, a halogen atom and a hydroxyl group optionally having a protecting group, and a lower alkyl group as a substituent; A 3- to 7-membered cycloalkyl group optionally having a group selected from a kill group, a lower alkoxy group, a hydroxyl group optionally having a protecting group and an amino group having a protecting group, an oxygen atom, sulfur One or two hetero atoms of the same kind or different kinds selected from an atom and a nitrogen atom in the ring, and as a substituent, a lower alkyl group, a lower alkoxy group, a hydroxyl group which may have a protecting group, and a protecting group An aliphatic heterocyclic group having a 5- or 6-membered ring which may have a group selected from an amino group, or 1 to 4 heterogeneous or same heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom A 5- or 6-membered aromatic heterocyclic group which may be contained in the ring and may have from 1 to 3 different or the same kind of groups selected from a lower alkyl group and a lower alkoxy group as a substituent) Expressed Benzyl phenol derivative or a salt thereof that.