JP2015013901A - 治療的使用のための新規7−デアザプリンヌクレオシド - Google Patents
治療的使用のための新規7−デアザプリンヌクレオシド Download PDFInfo
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- JP2015013901A JP2015013901A JP2014213410A JP2014213410A JP2015013901A JP 2015013901 A JP2015013901 A JP 2015013901A JP 2014213410 A JP2014213410 A JP 2014213410A JP 2014213410 A JP2014213410 A JP 2014213410A JP 2015013901 A JP2015013901 A JP 2015013901A
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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Abstract
【解決手段】本発明は、式Iの化合物[式中、R1、R2およびR3は、明細書に定義されている意味を有する]およびその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物、ならびにそのような化合物を含む組成物、およびそのような化合物および/または組成物を使用する治療法を提供する。本発明は、さらに、式(I)の化合物またはその塩を調製するのに有用な、本明細書に開示されている合成法および合成中間体を提供する。
【選択図】なし
Description
本発明は、新規抗増殖性化合物およびその治療的使用に関する。
本発明は抗癌化合物を提供する。従って、1つの態様において、本発明は、本発明の式Iの化合物:
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2は、アリール、ヘテロアリールまたはアルキニルであり、該アリールは、アルコキシ、アルキルチオまたはハロゲンから成る群から選択される1個または2個の置換基で任意に置換されており;
R3は、水素またはアルキルである]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物を提供する。
本明細書の解釈上、以下の定義が適用され、適切な場合に、単数形で使用されている用語は複数形も包含し、逆もまた同様である。
Publishing Company,Easton,Pa.,(1985)に見出すことができ、これは参照により本明細書に組み入れられる。
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2は、アリール、ヘテロアリールまたはアルキニルであり、該アリールは、アルコキシ、アルキルチオまたはハロゲンから成る群から選択される1個または2個の置換基で任意に置換されており;
R3は、水素またはアルキルである]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物を提供する。
− 医薬として使用するための本発明化合物;
− 腫瘍/癌細胞における細胞増殖を阻害するか、または腫瘍/癌細胞における細胞周期進行を減速する医薬を調製するための、本発明化合物の使用;
− 細胞増殖疾患または症状を処置する医薬を調製するための、本発明の化合物の使用;
− in vitroおよびin vivoの両方において腫瘍/癌成長を阻害する医薬を調製するための、本発明化合物の使用;
− 新生物疾患を処置する医薬を調製するための、本発明化合物の使用;
− 腫瘍または癌を処置する医薬を調製するための、本発明の化合物の使用。
Shaughnessy水性条件下に行なわれる7−ヨードツベリシジン1(スキーム1、表1){調製については、Seela,F.;Ming,X.Tetrahedron 2007,63,9850−9861参照}と対応するアリールおよびヘタリールボロン酸とのSuzuki−Miyauraクロスカップリング反応は、所望の7−置換−7−デアザアデノシン2a−nを生じた。
本発明の組成物は、本明細書に記載されている化合物の塩、特に、例えば、Na+、Li+、K+、Ca+2およびMg+2を含有する薬学的に許容されうる非毒性塩を任意に含む。そのような塩は、適切なカチオン、例えば、アルカリおよびアルカリ土類金属イオンまたはアンモニウムおよび第四級アミノイオンと、酸アニオン部分、典型的にはカルボン酸との組合せによって誘導される塩を包含しうる。水溶性塩が所望される場合、一価塩が好ましい。いくつかの塩は、式Iの化合物を精製するための、または他の塩を調製するための、中間体として有用でありうる。
本発明の化合物は、通常慣例に従って選択される従来の担体および賦形剤と共に配合される。錠剤は、賦形剤、滑剤、充填剤、結合剤等を含有する。水性処方物は、滅菌形態で調製され、経口投与以外による送達を意図する場合は、一般に等張性である。全ての処方物は、Handbook of Pharmaceutical Excipients(1986)に規定されているような賦形剤を任意に含有する。賦形剤は、アスコルビン酸および他の酸化防止剤、キレート化剤、例えばEDTA、炭水化物、例えば、デキストリン、ヒドロキシアルキルセルロース、ヒドロキシアルキルメチルセルロース、ステアリン酸等を包含する。処方物のpHは、約3〜約11であるが、通常は約7〜10である。
1つ以上の本発明化合物(本明細書において活性成分と称される)は、処置される症状に適した任意の経路によって投与される。好適な経路は、下記を包含する:経口、直腸、経鼻、局所(口腔内および舌下を包含する)、膣および非経口(皮下、筋肉内、静脈内、皮内、脊髄内および硬膜外を包含する)等。好ましい経路は、例えば、レシピエントの症状によって変化しうるものと理解される。本発明化合物の利点は、それらが経口的に生物学的利用可能であり、経口的に投与できることである。
本発明の活性成分は、他の活性成分との組合せて使用される。そのような組合せは、処置される症状、成分の交差反応性、および組合せの薬剤特性に基づいて選択される。例えば、癌を処置する場合、本発明の組成物を他の化学療法剤と組み合わせることができる。第二化学療法剤は、1つ以上の癌形態に対して生物活性を有する任意の好適な化合物であり得る。
(1)ウリジンヌクレオシドの類似体、チミジンヌクレオシドの類似体、ならびにウリジンおよびチミジンヌクレオシドの類似体。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:5−フルオロデオキシウリジン(フロキシウリジン、FUDR);5−フルオロウラシル(5−FU);5−FUのプロドラッグ(例えば、カペシタビン、5’−デオキシ−5−フルオロウリジン、フトラフール、フルシトシン);ブロモデオキシウリジン;およびヨードデオキシウリジン(iododexoyuridine)。
(2)フルオロピリミジンの調節剤。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:ロイコボリン(leurovorin)、メトトレキサートおよび他のフォレート;レバミゾール;アシビシン;ホスホンアセチル−L−アスパラギン酸(PALA);ブレキナール;5−エチニルウラシル;およびウラシル。
(3)シチジン類似体およびシチジンヌクレオシド類似体。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:シタラビン(Ara−C、シトシンアラビノシド);ゲムシタビン(2’,2’−ジフルオロデオキシシチジン);および5−アザシチジン。
(4)プリン類似体およびプリンヌクレオシド類似体。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:6−チオグアニン;6−メルカプトプリン;アザチオプリン;アデノシンアラビノシド(Ara−A);2’,2’−ジフルオロデオキシグアノシン;デオキシコホルマイシン(ペントスタチン);クラドリビン(2−クロロデオキシアデノシン);および、アデノシンデアミナーゼの阻害剤。
(5)抗葉酸剤。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:メトトレキサート;アミノプテリン;トリメトレキサート;エダトレキサート;N10−プロパルギル−5,8−ジデアザ葉酸(CB3717);ZD1694、5,8−ジデアザイソ葉酸(IAHQ);5,10−ジデアザテトラヒドロ葉酸(DDATHF);5−デアザ葉酸(FPGSの有効基質):PT523(Nアルファ−(4−アミノ−4−デオキシプテロイル)−Nデルタ−ヘミフタロイル−L−オルニチン):10−エチル−10−デアザアミノプテリン(DDATHF、ロマトレキソール);ピリトレキシム;10−EDAM;ZD1694;GW1843;PDX(10−プロパルギル−10−デアザアミノプテリン);多標的フォレート(即ち、LY231514、ペメトレキセド(permetrexed));チミジレートシンターゼ(TS)の任意の葉酸ベース阻害剤;ジヒドロフォレートレダクターゼ(DHFR)の任意の葉酸ベース阻害剤;グリシンアミドリボヌクレオチドトランスホルミラーゼ(GARTF)の任意の葉酸ベース阻害剤;ホリルポリグルタメートシンテターゼ(FPGS)の任意の阻害剤;および、GARホルミルトランスフェラーゼ(AICARトランスホルミラーゼ)の任意の葉酸ベース阻害剤。
(6)他の抗代謝剤。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、ヒドロキシ尿素およびポリアミンを包含する。
(7)S期特異性ラジオトキシン(デオキシチミジン類似体)。これらの化合物は、DNA合成を受けている全ての細胞のS期において作用する。該化合物は、S期の間に、染色体DNAに組み込まれる。これらの化合物は、例えば、下記を包含する:[125I]−ヨードデオキシウリジン;[123I]−ヨードデオキシウリジン;[124I]−ヨードデオキシウリジン;[80mBr]−ヨードデオキシウリジン;[131I]−ヨードデオキシウリジン;および、[211At]−アスタチン−デオキシウリジン。
(8)デオキシヌクレオシド/デオキシヌクレオチド代謝に関わる酵素の阻害剤。これらの化合物は、腫瘍細胞およびおそらくは新生血管内皮細胞のS期において、作用する。これらの化合物は、例えば、下記を包含する:チミジレートシンターゼ(TS)の阻害剤;ジヒドロフォレートレダクターゼ(DHFR)の阻害剤;グリシンアミドリボヌクレオチドトランスホルミラーゼ(GARTF)の阻害剤;ホリルポリグルタメートシンテターゼ(FPGS)の阻害剤;GARホルミルトランスフェラーゼ(AICARトランスホルミラーゼ)の阻害剤;DNAポリメラーゼの阻害剤(DNA Pol;例えばアフィドコリン);リボヌクレオチドレダクターゼ(RNR)の阻害剤;チミジンキナーゼ(TK)の阻害剤;および、トポイソメラーゼI酵素の阻害剤(例えば、カンプトテシン、イリノテカン[CPT−11、カンプトサール(camptosar)]、トポテカン、NX−211[ラルトテカン(lurtotecan)]、ルビテカン(rubitecan)等)。
(9)DNA連鎖停止ヌクレオシド類似体。これらの化合物は、S期細胞に特異的に作用し、S期の間に染色体DNAに組み込まれ、成長DNA鎖を停止させる。これらの化合物は、例えば、下記を包含する:アシクロビル;アバカビル;バラシクロビル;ジドブジン(AZT);ジダノシン(ddI、ジデオキシシチジン);ザルシタビン(ddC);スタブジン(D4T);ラミブジン(3TC);任意の2’3’−ジデオキシヌクレオシド類似体;および、DNA合成を停止させる任意の2’3’−ジデオキシヌクレオシド類似体。これらの化合物は、例えば、下記を包含する:細胞周期のG1期、G1/S境界、またはS期を通して、進行を調節する成長因子受容体チロシンキナーゼの阻害剤(例えば、EGF受容体、HER−2neu/c−erbB2受容体、PDGF受容体等;[例えば、トラスツスマブ、イレッサ、エルビタックス、タルセバ]);非受容体チロシンキナーゼの阻害剤(例えば、チロシンキナーゼのc−srcファミリー;[例えば、グリベック(Gleevec)]);細胞周期のG1期、G1/S境界またはS期を通して進行を調節するセリン−スレオニンキナーゼの阻害剤(例えば、G1サイクリン依存性キナーゼ、G1/Sサイクリン依存性キナーゼ、およびSサイクリン依存性キナーゼ[例えば、CDK2、CDK4、CDK5、CDK6];有糸分裂活性化キナーゼ;MAPキナーゼシグナル伝達経路);G1期、G1/S境界またはS期サイクリンの阻害剤[例えば、サイクリンD1、D2、D3、E、およびA]);細胞周期のG1期、G1/S境界またはS期において、細胞周期進行を正に制御するG−タンパク質およびcGMPホスホジエステラーゼの阻害剤;最初期応答転写因子の誘発を阻害する薬剤(例えば、N末端c−junキナーゼ、c−myc);および、「ネガティブ」細胞周期調節分子を分解するプロテオソームを阻害する薬剤(例えば、p53、p27/Kip1;[例えば、ボルテゾミブ])。
(10)サイトカイン、成長因子、抗血管新生因子、および細胞周期のG1期またはG1/S境界において細胞周期進行を阻害する他のタンパク質。これらの化合物は、腫瘍細胞、およびある場合には新生血管内皮細胞における、細胞周期のG1、G1/SまたはS期において作用する。これらの化合物は、例えば、インターフェロン;インターロイキン;ソマトスタチンおよびソマトスタチン類似体を包含し(オクトレオチド、サンドスタチンLAR);多くの抗血管新生因子は、細胞周期のG1またはG1/S期において、内皮細胞の細胞増殖を阻害する。
(11)細胞周期のG2/M境界またはM期における細胞周期進行を阻害する薬剤および化合物。これらの化合物は、腫瘍細胞、およびある場合には新生血管内皮細胞における、細胞周期のG2/M境界またはM期において、作用する。これらの化合物は、例えば、下記を包含する:(a)微小管標的薬剤−タキサン(例えば、タキソール、タキソテール、エポチロン、ならびに他のタキサンおよび誘導体);(b)微小管標的薬剤−ビンカアルカロイド(例えば、ビンブラスチン、ビンクリスチン、ビンデシン;ビンフルニン、ビノレルビン、ビンゾリジン、ノカダゾール、およびコルチシン);(c)微小管標的薬剤−その他(例えば、エストラムスチン、CP−248およびCP−461);(d)細胞周期のG2/M境界またはM期を通して進行を調節するセリン−スレオニンキナーゼの阻害剤(例えば、G2/Mサイクリン依存性キナーゼの阻害剤(例えば、CDC2);M期サイクリンの阻害剤(例えば、サイクリンB)および、細胞周期のG2/M境界またはM期において細胞周期進行をブロックするか、妨害するか、またはそれ以外の方法で干渉する任意の薬剤)。
(12)放射線療法および/または診断に有用な放射性医薬品。好適な種類の放射性同位体は、「オージェプロセス」または「オージェカスケード」として公知の核壊変プロセスによって崩壊する。オージェ放出同位体は、二重鎖DNAを効果的に開裂する短時間作用電子を発生させる。好適なオージェ放出放射性核種は、例えば、125−ヨウ素、123−ヨウ素および80m−臭素を包含する。好適な対応するハロゲン化ピリミジンおよびプリンヌクレオシドは、例えば、下記を包含する:5−125ヨード−2’−デオキシウリジン、5−123ヨード−2’−デオキシウリジン、5−80mブロモ−2’−デオキシウリジンおよび8−80mブロモ−2’−グアニジン。
多くの成長因子およびサイトカインは、悪性細胞を刺激して、細胞周期における特定点をトラバースさせる能力を有する。例えば、G−CSFまたはGM−CSFは、急性骨髄性白血病における白血病芽細胞を刺激して、G1/S境界をトラバースさせうる。これは、細胞周期特異性薬剤、例えばシタラビンへの細胞の感受性を増加させる。同様の方法が、固形腫瘍に対して、EGFおよび細胞毒性薬剤を使用して試験されている。成長因子に応答するために、細胞は、細胞周期の特定の段階、例えばG1/S境界になければならない。任意の所定時に、芽細胞のサブセットのみがG1/Sにあるので、成長因子の継続的存在が有益でありうる。このように、成長因子は、細胞周期特異的に作用する。同様の論理を、好中球減少症、貧血症および血小板減少症を処置するために使用される造血成長因子の使用に適用できる。
いくつかの治療的成長因子/サイトカインは、細胞周期の特定の段階において、癌細胞および/または新生血管細胞の細胞増殖を阻害することができる。例えば、インターフェロン、ソマトスタチン、オクトレオチドおよびその類似体、トロンボスポンジンおよびトロポニン−Iは、細胞がS期に入る速度を減少させることによって、新生血管内皮細胞増殖を阻害する。従って、任意の1つ以上のこれらの物質を、本発明に使用することができる。
本明細書に記載されている化合物の生体内代謝生成物も本発明の範囲に含まれる。そのような生成物は、例えば、主に酵素的過程によって、投与された化合物の酸化、還元、加水分解、アミド化、エステル化、リン酸化等により生じうる。従って、本発明は、本発明の化合物を、その代謝生成物をもたらすのに充分な時間にわたって哺乳動物に接触させることを含む過程によって生じる化合物を包含する。そのような生成物は、典型的には、下記のように同定される:放射標識した(例えば、C14またはH3)本発明化合物を調製し、それを、生体外培養細胞に、または非経口的に、検出可能投与量(例えば、約0.5mg/kgより多い)で、動物、例えば、ラット、マウス、モルモット、サルまたはヒトに投与し、代謝が起こるのに充分な時間(典型的には、約30秒〜30時間)を与え、その変換生成物を、尿、血液または他の生物学的試料から分離する。これらの生成物は標識されているので容易に分離される(その他は、代謝産物中に生存しているエピトープに結合することができる抗体を使用することによって分離される)。代謝産物構造は、従来法、例えばMSまたはNMR分析によって、決定される。一般に、代謝産物の分析は、当業者に周知の従来の薬剤代謝試験と同様の方法で行なわれる。変換生成物は、それ以外の方法で生体内に見出されない限り、変換生成物がそれら自身のみで抗癌活性を有していなくても、本発明化合物の治療的投与に関する診断アッセイに有用である。
このアッセイは、細胞関連タンパク質の比色検出による、細胞量測定の定量化に基づく。該アッセイは、トリクロロ酢酸(TCA)によって組織培養皿に固定された細胞のタンパク質成分に結合するスルホローダミンB(SRB)の能力に依存する。SRBは、弱酸性条件下に塩基性アミノ酸残基に結合し、塩基性条件下に解離する2個のスルホン酸基を有する明るいピンク色のアミノキサンテン染料である。SRBの結合は化学量論的であるので、染色細胞から抽出される染料の量は、細胞量に正比例する。
1. 細胞系を、表1に記載されている培地に維持する。サブコンフルエント細胞をトリプシン処理し、それらを計数し、表1に記載されている細胞数に従って細胞濃度を調整する。
2. 細胞を、150μLの培地において、96穴皿に分配する。その皿を、加湿CO2インキュベーターにおいて37℃で一晩インキュベートする。
3. 1皿の各細胞系をTCAで固定する。その皿を軽くはたくことによって、皿から培地を捨て、100μLの冷たい10%(vol/vol)TCAを各穴に添加する。その皿を4度の冷蔵庫で1時間インキュベートする。その皿を軽くはたくことによって、皿からTCAを捨てる。水道水が入っている洗面器で皿を4回濯ぐ。皿を室温で保存する。これらの皿は、第0日における細胞数を表す。
4. 96穴皿において5倍系列希釈溶液を作製することによって、種々の濃度の試験化合物を含有する1組の培地溶液を調製する。1穴につき50μLの希釈化合物を添加する。未処置細胞、ならびにドキソルビシン、ツベルシジン、クロファラビンおよび/またはゲムシタビンで処置した細胞を有する対照を含める。
5. 皿を37℃で5日間インキュベートする。
6. さらをTCAで固定する。その皿を軽くはたくことによって、皿から培地を捨て、100μLの冷たい10%(vol/vol)TCAを各穴に添加する。その皿を4度の冷蔵庫で1時間インキュベートする。その皿を軽くはたくことによって、皿からTCAを捨てる。水道水を含有する洗面器で皿を4回濯ぐ。
7. 皿を、ペーパータオル上で下向きにして叩くことによって過剰の水を除去する。皿を室温で風乾する。
8. 第0日および第5日に、TCAで固定した皿の各穴に、1%(vol/vol)酢酸中の100μLの0.057%SRB溶液を添加する。室温で30分間静置する。
9. 皿を軽くはたいて、SRBを捨てる。皿を、1%(vol/vol)酢酸で4回濯ぐ。
10. より速い乾燥を促進するために、皿を37℃のインキュベーターで保存する。
11. 皿が完全に乾燥したら、200μLの10mMトリス塩基溶液(pH10.5)を各穴に添加する。SRBを可溶化するために、室温で30分間静置する。
12. マイクロプレートリーダーで500nmにおいてODを測定する。
13. 次の式を使用して、細胞成長阻害のパーセンテージを計算する:
対照細胞成長の%=100×(OD試料−平均OD第0日)/(OD負の対照−平均OD第0日)。
この試験は、典型的には、血液腫瘍に由来し、懸濁液中で成長する細胞系を使用して行なわれる。そのような細胞系の例は、試験化合物の細胞増殖抑制活性の測定に使用されるヒトMT−4 T−リンパ細胞系である。MT−4細胞を、NIH AIDS Research and Reference Reagents Programから得、10%FBSおよび抗生物質を補足したRPMI−1640培地に維持した。細胞を懸濁液中で週に2回継代培養し、500,000細胞/mL未満の密度に維持した。CC50測定のために、細胞を、20μLの培地において2,000細胞/穴で384穴皿に播種した。化合物を、培地において系列希釈し、最終アッセイ容積である40μL/穴になるように3回で添加した。皿を試験化合物と共に5日間インキュベートした。インキュベーションの終わりに、細胞生存度を、40μLのCellTiter Glo試薬の添加、次にルミネッセンスの読み出しによって測定した。
AcOEt エチルアセテート
Boc tert−ブトキシカルボニル
bd 幅の広い二重線
bs 幅の広い一重線
Bu ブチル
Bz ベンゾイル
calcd 計算値
cat. 触媒
d 二重線
dd 二重線の二重線
ddd 二重線の二重線の二重線
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
dt 三重線の二重線
Et エチル
EDTA エチレンジアミン四酢酸
FAB 高速原子衝撃
gem ジェミナル
HPFC 高性能フラッシュクロマトグラフィー
HR 高分解
i 〜によって
iPr イソプロピル
IR 赤外分光
m 多重線
m メタ
Me メチル
MeCN アセトニトリル
MeOH メタノール
MeONa ナトリウムメトキシド
MS 質量分析
v 波数
naphth ナフタレニル
NMR 核磁気共鳴
o オルト
p パラ
Ph フェニル
PPh3 トリフェニルホスフィン
Py ピリジル
pyrr ピロリル
q 四重線
rel. 比較
RT 室温
s 一重線
sat. 飽和
sol. 溶液
t 三重線
TBS tert−ブチルジメチルシリル
td 二重線の三重線
THF テトラヒドロフラン
TFA トリフルオロ酢酸
TPPTS ナトリウムトリフェニルホスフィントリスルホネート
Tr トリチル、トリフェニルメチル
vic ビシナル
本発明を、以下の非限定的実施例によって例示する。
一般的方法:融点はKoflerブロック上で測定した。旋光度は25℃で測定し、[α]D 20値は10−1deg cm2g−1で示す。NMRスペクトルは、1Hについて400MHzおよび13C原子核について100.6MHz、1Hについて500MHzおよび13Cについて125.8MHz、または1Hについて600MHzおよび13Cについて151MHzにおいて、CDCl3(TMSを内部標準として使用した)、MeOH−d4(残留溶媒シグナルを基準とした)、またはDMSO−d6(残留溶媒シグナルを基準とした)中で測定した。化学シフトはppm(δ−スケール)で示し、結合定数(J)はHzで示す。全てのNMRシグナルの完全な帰属は、H,H−COSY、H,H−ROESY、H,C−HSQCおよびH,C−HMBC実験の組合せを使用して行なった。質量スペクトルは、FAB(Xeによるイオン化、加速電圧8kV、グリセロール+チオグリセロールマトリックス)またはESI(エレクトロスプレー)を使用して測定した。逆相でのクロマトグラフィーは、Biotage SP1装置、HPFCシステム(このシステムは固体支持体としてKP−C18−HS、25+M、35−70mm、90Åまたは40+Mを備える)で行なった。
1H NMR(600MHz,DMSO−d6):3.53(ddd,1H,Jgem=11.9,J5´b,OH=6.1,J5´b,4´=3.9,H−5´b);3.63(ddd,1H,Jgem=11.9,J5´a,OH=5.2,J5´a,4´=3.4,H−5´a);3.90(ddd,1H,J4´,5´=3.9,3.4,J4´,3´=3.5,H−4´);4.10(bm,1H,H−3´);4.46(bm,1H,H−2´);5.16(d,1H,JOH,3´=3.5,OH−3´);5.22(dd,1H,JOH,5´=6.1,5.2,OH−5´);5.36(d,1H,JOH,2´=4.8,OH−2´);6.12(d,1H,J1´,2´=6.3,H−1´);7.37(m,1H,H−p−Ph);7.47(m,2H,H−o−Ph);7.49(m,2H,H−m−Ph);7.54(s,1H,H−6);8.15(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):61.93(CH2−5´);70.89(CH−3´);74.05(CH−2´);85.38(CH−4´);87.27(CH−1´);100.73(C−4a);116.57(C−5);121.41(CH−6);127.20(CH−p−Ph);128.70(CH−o−Ph);129.28(CH−m−Ph);134.71(C−i−Ph);151.10(C−7a);151.95(CH−2);157.57(C−4). ).
IR(KBr):3479,3391,1623,1585,1566,1538,1489,1466,1445,1296,1216,1182,1157,1147,1119,1083,1047,1028,1000,798,762,705,615,503.
MS(FAB):m/z 343(M+H)、365(M+Na)。HRMS(FAB):C17H19N4O4[M+H]:計算値:343.1406;実測値:343.1409。分析:C17H18N4O4・0.8H2O:計算値:C,57.23;H,5.54;N,15.70;実測値:C,57.44;H,5.27;N,15.43。
収率36%。融点121℃。[α]20 D−21.2(c 0.304、MeOH)。
1H NMR(600MHz,DMSO−d6):3.53(ddd,1H,Jgem=11.9,J5´b,OH=6.3,J5´b,4´=3.8,H−5´b);3.62(ddd,1H,Jgem=11.9,J5´a,OH=4.8,J5´a,4´=3.8,H−5´a);3.80(s,3H,CH3O);3.90(td,1H,J4´,5´=3.8,J4´,3´=3.1,H−4´);4.09(ddd,1H,J3´,2´=5.1,J3,OH=4.7,J3´,4´=3.1,H−3´);4.45(ddd,1H,J2´,OH=6.5,J2´,1´=6.3,J2´,3´=5.1,H−2´);5.14(d,1H,JOH,3´=4.7,OH−3´);5.22(dd,1H,JOH,5´=6.3,4.8,OH−5´); 5.33(d,1H,JOH,2´=6.5,OH−2´);6.10(d,1H,J1´,2´=6.3,H−1´);7.05(m,2H,H−m−C6H4OMe);7.38(m,2H,H−o−C6H4OMe);7.45(s,1H,H−6);8.13(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):55.44(CH3O);61.94(CH2−5´);70.90(CH−3´);74.01(CH−2´);85.34(CH−4´) ; 87.24(CH−1´);100.96(C−4a);114.70(CH−m−C6H4OMe);116.20(C−5);120.81(CH−6);126.85(C−i−C6H4OMe);129.97(CH−o−C6H4OMe);150.88(C−7a);151.86(CH−2);157.59(C−4);158.68(C−p−C6H4OMe). IR(KBr):3470,3391,2836,1630,1620,1586,1565,1540,1506,1466,1442,1421,1292,1246,1216,1175,1147,1117,1109,1083,1055,1030,838,796,706,637.
MS(FAB):m/z 373(M+H),395(M+Na)。HRMS(FAB):C18H21N4O5[M+H]:計算値:373.1512;実測値:373.1498;C18H20NaN4O5[M+Na]:計算値:395.1331;実測値:395.1327。分析:C18H20N4O5・0.95H2O:計算値:C,55.51;H,5.67;N,14.38;実測値:C,55.59;H,5.44;N,14.04。
1H NMR(500MHz,DMSO−d6):2.52(s,3H,CH3S);3.53(ddd,1H,Jgem=12.0,J5´b,OH=6.3,J5´,4´=3.9,H−5´b);3.63(ddd,1H,Jgem=12.0,J5´a,OH=5.1,J5´a,4´=3.8,H−5´a);3.90(ddd,1H,J4´,5´=3.9,3.8,J4´,3´=3.1,H−4´);4.10(ddd,1H,J3´,2´=5.1,J3,OH=4.8,J3´,4´=3.1,H−3´);4.45(ddd,1H,J2´,OH=6.5,J2´,1´=6.2,J2´,3´=5.1,H−2´);5.12(d,1H,JOH,3´=4.8,OH−3´);5.20(dd,1H,JOH,5´=6.3,5.1,OH−5´);5.32(d,1H,JOH,2´=6.5,OH−2´);6.11(d,1H,J1´,2´=6.2,H−1´);6.16(bs,2H,NH2);7.37(m,2H,H−m−C6H4SMe);7.41(m,2H,H−o−C6H4SMe);7.52(s,1H,H−6);8.14(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):14.98(CH3S);61.88(CH2−5´);70.83(CH−3´);73.99(CH−2´);85.32(CH−4´);87.24(CH−1´);100.67(C−4a);116.01(C−5);121.25(CH−6);126.72(CH−m−C6H4SMe);129.12(CH−o−C6H4SMe);131.15(C−i−C6H4SMe);136.90(C−p−C6H4SMe);151.07(C−7a);151.90(CH−2);157.55(C−4).
IR(KBr):3476,3440,3343,3318,3200,3123,2693,1630,1584,1570,1549,1534,1492,1465,1430,1402,1298,1269,1212,1177,1147,1124,1096,1080,1054,1016,967,832,796,716,690.
MS(FAB):m/z 389(M+H)。HRMS(FAB):C18H21N4O4S[M+H]:計算値:389.1284;実測値:389.1282。分析:C18H20N4O4S:計算値:C,55.66;H,5.19;N,14.42.;実測値:C,55.28;H,5.25;N,14.16。
1H NMR(500MHz,DMSO−d6,T=353 K):3.57(bddd,1H,Jgem=12.0,J5´b,OH=5.1,J5´,4´=3.8,H−5´b);3.67(bdt,1H,Jgem=12.0,J5´a,OH=J5´a,4´=4.0,H−5´a);3.96(ddd,1H,J4´,5´=4.0,3.8,J4´,3´=3.1,H−4´);4.17(bm,1H,H−3´);4.54(bm,1H,H−2´);4.88(bs,1H,OH−3´);4.95(bdd,1H,JOH,5´=5.1,4.8,OH−5´);5.13(bs,1H,OH−2´);5.43(bs,2H,NH2);6.19(d,1H,J1´,2´=5.9,H−1´);7.49−7.53(m,3H,H−6および H−2,7−naphth);7.56(ddd,1H,J6,5=8.1,J6,7=6.9,J6,8=1.1,H−6−naphth);7.61(dd,1H,J3,4=8.2,J3,2=7.1,H−3−naphth);7.81(bd,1H,J8,7=8.4,H−8−naphth);7.99(bd,1H,J4,3=8.2,H−4−naphth);8.01(bd,1H,J5,6=8.1,H−5−naphth);8.18(s,1H,H−2). 13C NMR(151MHz,DMSO−d6,T=353 K):61.66(CH2−5´);70.53(CH−3´);73.90(CH−2´);85.06(CH−4´);87.75(CH−1´);102.65(C−4a);113.04(C−5);122.03(CH−6);125.38(CH−3−naphth);125.46(CH−8−naphth);125.99(CH−6−naphth);126.38(CH−7−naphth);127.82(CH−4−naphth);128.05(CH−2−naphth);128.10(CH−5−naphth);131.55(C−1−naphth);132.10(C−8a−naphth);133.41(C−4a−naphth);150.43(C−7a);151.66(CH−2);157.09(C−4). IR(KBr):3478,3436,3392,3240,3057,1632,1621,1585,1569,1535,1506,1469,1398,1296,1257,1108,1081,1046,1016,946,849,805,797,790,779,740.
MS(FAB):m/z 393(M+H)。HRMS(FAB):C21H21N4O4[M+H]:計算値:393.1563;実測値:393.1564。分析:計算値:C21H20N4O4・0.8H2O:C,62.00;H,5.35;N,13.77;実測値:C,62.25;H,5.21;N,13.52。
1H NMR(500MHz,DMSO−d6):3.55(ddd,1H,Jgem=11.7,J5´b,OH=6.2,J5´,4´=3.5,H−5´b);3.65(ddd,1H,Jgem=11.7,J5´a,OH=5.1,J5´a,4´=3.5,H−5´a);3.92(q,1H,J4´,5´=J4´,3´=3.5,H−4´);4.13(ddd,1H,J3´,2´=5.2,J3,OH=4.7,J3´,4´=3.5,H−3´);4.49(ddd,1H,J2´,OH=6.5,J2´,1´=6.2,J2´,3´=5.2,H−2´);5.15(d,1H,JOH,3´=4.7,OH−3´);5.22(dd,1H,JOH,5´=6.2,5.1,OH−5´);5.36(d,1H,JOH,2´=6.5,OH−2´);6.15(d,1H,J1´,2´=6.2,H−1´);6.20(bs,2H,NH2);7.53(td,1H,J6,5=J6,7=8.2,J6,8=1.4,H−6−naphth);7.56(td,1H,J7,6=J7,8=8.2,J7,6=1.4,H−7−naphth);7.65(dd,1H,J3,4=8.6,J3,1=1.7,H−3−naphth);7.66(s,1H,H−6);7.97−8.00(m,3H,H−1,5,8−naphth);8.03(d,1H,J4,3=8.6,H−4−naphth);8.17(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):61.86(CH2−5´);70.77(CH−3´);74.00(CH−2´);85.29(CH−4´);87.32(CH−1´);100.83(C−4a);116.50(C−5);121.66(CH−6);126.06(CH−6−naphth);126.70(CH−7−naphth);126.79(CH−1−naphth);127.13(CH−3−naphth);127.79および127.95(CH−5,8−naphth);128.63(CH−4−naphth);132.00および132.10(C−1,4a−naphth);133.40(C−8a−naphth);151.20(C−7a);151.90(CH−2);157.57(C−4). IR(KBr):3475,3438,3392,3240,3054,1630,1621,1584,1566,1538,1505,1469,1376,1295,1145,1119,1085,1047,1020,861,824,796,768,750,624,478.
MS(FAB):m/z 393(M+H)。HRMS(FAB):C21H21N4O4[M+H]:計算値:393.1563;実測値:393.1571。分析:C21H20N4O4・0.65H2O:計算値:C,62.41;H,5.31;N,13.86;実測値:C,62.58;H,5.18;N,13.64。
1H NMR(500MHz,DMSO−d6):3.55および3.65(2 × dd,2H,Jgem=11.9,J5´,4´=3.9,H−5´);3.91(td,1H,J4´,5´=3.9,J4´,3´=3.4,H−4´);4.11(dd,1H,J3´,2´=5.2,J3´,4´=3.4,H−3´);4.41(dd,1H,J2´,1´=6.1,J2´,3´=5.2,H−2´);5.00−5.50(bs,2H,OH−2´,3´,5´);6.09(d,1H,J1´,2´=6.1,H−1´);6.61(dd,1H,J4,3=3.3,J4,5=1.9,H−4−フリル);6.67(dd,1H,J3,4=3.3,J3,5=0.8,H−3−フリル);6.88(bs,2H,NH2);7.78(dd,1H,J5,4=1.9,J5,3=0.8,H−5−フリル);7.83(s,1H,H−6);8.13(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):61.81(CH2−5´);70.67(CH−3´);74.00(CH−2´);85.33(CH−4´);87.27(CH−1´);99.55(C−4a);105.50(CH−3−フリル);106.34(C−5);112.09(CH−4−フリル);120.70(CH−6);142.16(CH−5−フリル);148.77(C−2−フリル);151.04(C−7a);152.26(CH−2);157.45(C−4).
IR(KBr):3468,3391,3252,1631,1577,1562,1532,1497,1456,1299,1145,1121,1083,1049,1015,892,794,550.
MS(FAB):m/z 333(M+H),355(M+Na)。HRMS(FAB):C15H17N4O5[M+H]:計算値:333.1199;実測値:333.1202。分析:C15H16N4O5・1.05H2O:計算値:C,51.30;H,5.19;N,15.95;実測値:C,51.64;H,5.01;N,15.63。
1H NMR(500MHz,DMSO−d6):3.54(ddd,1H,Jgem=12.0,J5´b,OH=6.2,J5´,4´=3.8,H−5´b);3.63(ddd,1H,Jgem=12.0,J5´a,OH=5.0,J5´a,4´=3.8,H−5´a);3.91(td,1H,J4´,5´=3.8,J4´,3´=2.9,H−4´);4.09(ddd,1H,J3´,2´=5.0,J3,OH=4.7,J3´,4´=2.9,H−3´);4.43(ddd,1H,J2´,OH=6.4,J2´,1´=6.3,J2´,3´=5.0,H−2´);5.13(d,1H,JOH,3´=4.7,OH−3´);5.20(dd,1H,JOH,5´=6.2,5.0,OH−5´);5.34(d,1H,JOH,2´=6.4,OH−2´);6.10(d,1H,J1´,2´=6.3,H−1´);6.32(bs,2H,NH2);7.15(dd,1H,J3,4=3.5,J3,5=1.2,H−3−チエニル);7.18(dd,1H,J4,5=5.1,J4,3=3.5,H−4−チエニル);7.57(dd,1H,J5,4=5.1,J5,3=1.2,H−5−チエニル);7.62(s,1H,H−6);8.15(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):61.79(CH2−5´);70.78(CH−3´);74.06(CH−2´);85.40(CH−4´);87.17(CH−1´);100.84(C−4a);108.65(C−5);122.26(CH−6);126.06(CH−5−チエニル);126.58(CH−3−チエニル);128.49(CH−4−チエニル);135.72(C−2−チエニル);150.82(C−7a);152.22(CH−2);157.49(C−4). IR(KBr):3509,3395,3322,3220,3102,1620,1590,1576,1555,1508,1460,1434,1349,1300,1236,1144,1119,1102,1086,1063,1042,1038,852,832,793,703,562,453.
MS(FAB):m/z 349(M+H)。HRMS(FAB):C15H17N4O4S[M+H]:計算値:349.0971;実測値:349.0965。分析:C15H16N4O4S:計算値:C,51.71;H,4.63;N,16.08;実測値:C,51.33;H,4.48;N,15.75。
1H NMR(600MHz,DMSO−d6):3.53(ddd,1H,Jgem=12.0,J5´b,OH=6.2,J5´,4´=3.8,H−5´b);3.62(ddd,1H,Jgem=12.0,J5´a,OH=4.8,J5´a,4´=3.9,H−5´a);3.89(ddd,1H,J4´,5´=3.9,3.8,J4´,3´=3.1,H−4´);4.04(bddd,1H,J3´,OH=3.8,J3´,2´=3.6,J3´,4´=3.1,H−3´);4.42(bddd,1H,J2´,1´=6.3,J2´,OH=5.1,J2´,3´=3.6,H−2´);5.14(bd,1H,JOH,3´=3.8,OH−3´);5.21(dd,1H,JOH,5´=6.2,4.8,OH−5´);5.33(bd,1H,JOH,2´=5.1,OH−2´);6.08(d,1H,J1´,2´=6.3,H−1´);6.27(bs,2H,NH2);6.70(dd,1H,J4,5=1.8,J4,2=0.9,H−4−フリル);7.50(s,1H,H−6);7.81(dd,1H,J5,4=1.8,J5,2=1.6,H−5−フリル);7.83(dd,1H,J2,5=1.6,J2,4=0.9,H−2−フリル);8.12(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):61.92(CH2−5´);70.84(CH−3´);73.96(CH−2´);85.31(CH−4´);87.14(CH−1´);101.22(C−4a);106.44(C−5);111.75(CH−4−フリル);118.77(C−3−フリル);121.17(CH−6);139.86(CH−2−フリル);144.41(CH−5−フリル);150.92(C−7a);151.97(CH−2);157.70(C−4). IR(KBr):3512,3394,3296,3252,1623,1582,1561,1504,1457,1364,1306,1286,1245,1152,1121,1109,1067,1038,1021,972,873,793,777.
MS(FAB):m/z 333(M+H)。HRMS(FAB):C15H17N4O5[M+H]:計算値:333.1199;実測値:333.1204。分析:C15H16N4O5:計算値:C,54.21;H,4.85;N,16.86;実測値:C,53.82;H,4.85;N,16.49。
1H NMR(600MHz,DMSO−d6):3.53(ddd,1H,Jgem=12.0,J5´b,OH=6.1,J5´,4´=3.8,H−5´b);3.62(ddd,1H,Jgem=12.0,J5´a,OH=4.9,J5´a,4´=3.9,H−5´a);3.90(ddd,1H,J4´,5´=3.9,3.8,J4´,3´=3.0,H−4´);4.09(bddd,1H,J3´,2´=4.2,J3,OH=3.2,J3´,4´=3.0,H−3´);4.43(bddd,1H,J2´,1´=6.3,J2´,OH=5.1,J2´,3´=4.2,H−2´);5.14(bd,1H,JOH,3´=3.2,OH−3´);5.21(dd,1H,JOH,5´=6.1,4.9,OH−5´);5.34(bd,1H,JOH,2´=5.1,OH−2´);6.09(d,1H,J1´,2´=6.3,H−1´);6.21(bs,2H,NH2);7.27(dd,1H,J4,5=4.9,J4,2=1.3,H−4−チエニル);7.52(dd,1H,J2,5=2.9,J2,4=1.3,H−2−チエニル);7.55(s,1H,H−6);7.72(dd,1H,J5,4=5.1,J5,2=2.9,H−5−チエニル);8.13(s,1H,H−2). 13C
NMR(151MHz,DMSO−d6):61.90(CH2−5´);70.84(CH−3´);74.00(CH−2´);85.32(CH−4´);87.17(CH−1´);101.00(C−4a);111.19(C−5);121.29(CH−6);122.24(CH−2−チエニル);127.62(CH−5−チエニル);128.71(CH−4−チエニル);134.94(C−3−チエニル);150.79(C−7a);151.96(CH−2);157.62(C−4). IR(KBr):3509,3396,3338,3240,3106,1621,1593,1576,1553,1509,1460,1422,1351,1299,1214,1144,1121,1101,1080,1061,1036,856,796,775,713,562,456.
MS(FAB):m/z 349(M+H)。HRMS(FAB):C15H17N4O4S[M+H]:計算値:349.0971;実測値:349.0962。分析:C15H16N4O4S:計算値:C,51.71;H,4.63;N,16.08;実測値:C,51.51;H,4.63;N,15.76。
1H NMR(500MHz,DMSO−d6):3.57(ddd,1H,Jgem=12.0,J5´b,OH=6.1,J5´,4´=3.9,H−5´b);3.67(ddd,1H,Jgem=12.0,J5´a,OH=5.1,J5´a,4´=3.9,H−5´a);3.93(td,1H,J4´,5´=3.9,J4´,3´=3.3,H−4´);4.13(ddd,1H,J3´,2´=5.1,J3,OH=4.9,J3´,4´=3.3,H−3´);4.46(ddd,1H,J2´,OH=6.3,J2´,1´=6.1,J2´,3´=5.1,H−2´);5.17(d,1H,JOH,3´=4.9,OH−3´);5.23(dd,1H,JOH,5´=6.1,5.1,OH−5´);5.40(d,1H,JOH,2´=6.3,OH−2´);6.14(d,1H,J1´,2´=6.1,H−1´);7.00(bs,2H,NH2);7.13(d,1H,J3,7=1.0,H−3−ベンゾフリル);7.28(td,1H,J5,4=J5,6=7.3,J5,7=1.5,H−5−ベンゾフリル);7.30(td,1H,J6,5=J6,7=7.3,J6,4=1.7,H−6−ベンゾフリル);7.62−7.69(m,2H,H−4,7−ベンゾフリル);8.11(s,1H,H−6);8.18(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):61.79(CH2−5´);70.70(CH−3´);74.12(CH−2´);85.46(CH−4´);87.35(CH−1´);99.62(C−4a);101.83(CH−3−ベンゾフリル);105.72(C−5);111.30(CH−7−ベンゾフリル);120.84(CH−4−ベンゾフリル);122.94(CH−6);123.69(CH−5−ベンゾフリル);124.07(CH−6−ベンゾフリル);129.02(C−3a−ベンゾフリル);151.29(C−2−ベンゾフリル);151.35(C−7a);152.52(CH−2);153.99(C−7a−ベンゾフリル);157.52(C−4). IR(KBr):3498,3473,3462,3379,3328,3234,3197,3118,2700,1639,1628,1614,1576,1558,1525,1483,1474,1456,1303,1262,1186,1145,1127,1108,1085,1056,1010,884,806,792,785,746.
MS(ESI):m/z 383(M+H)。HRMS(ESI):C19H19N4O5[M+H]:計算値:383.1350;実測値:383.1348。分析:C19H18N4O5・0.6H2O:計算値:C,58.04;H,4.92;N,14.25;実測値:C,57.78;H,4.56;N,14.16。
1H NMR(500.0MHz,DMSO−d6):3.54(ddd,1H,Jgem=11.9,J5´b,OH=6.2,J5´b,4´=3.9,H−5´b);3.62(dd,1H,Jgem=11.9,J5´a,OH=5.0,J5´a,4´=3.9,H−5´a);3.90(td,1H,J4´,5´=3.9,J4´,3´=3.1,H−4´);4.09(ddd,1H, J3´,2´=5.1,J3´,OH=4.8,J3´,4´=3.1,H−3´);4.41(ddd,1H,J2´,OH=6.5,J2´,1´=6.3,J2´,3´=5.1,H−2´);5.17(d,1H,JOH,3´=4.8,OH−3´);5.20(dd,1H,JOH,5´=6.2,5.0,OH−5´);5.33(d,1H,JOH,2´=6.5,OH−5´);6.09(d,1H,J1´,2´=6.3,H−1´);6.13(ddd,1H,J3,4=3.3,J3,NH=2.4,J3,5=1.5,H−3−pyrr);6.16(ddd,1H,J4,3=3.3,J4,5=2.7,J4,NH=2.4,H−4−pyrr);6.32(bs,2H,NH2);6.85(td,1H,J5,4=J5,NH=2.7,J5,3=1.5,H−5−pyrr);7.43(s,1H,H−6);8.12(s,1H,H−2);11.14(bs,1H,NH−pyrr).
13C NMR(125.7MHz,DMSO−d6):62.00(CH2−5´);70.92(CH−3´);74.11(CH−2´);85.30(CH−4´);87.20(CH−1´);101.09(C−4a);107.34(CH−3−pyrr);108.68(C−5);109.06(CH−4−pyrr);118.77(CH−5−pyrr);120.55(CH−6);124.69(C−2−pyrr);150.35(C−7a);151.98(CH−2);157.62(C−4).MS(ESI):m/z 332(M+H),354(M+Na)。HRMS(ESI):C15H18N5O4[M+H]:計算値:332.1353;実測値:332.1354。分析:C15H17N5O4・1/3H2O:計算値:C,53.41;H,5.28;N,20.76;実測値:C,53.32;H,5.16;N,20.57。
1H NMR(500.0MHz,DMSO−d6):3.52(ddd,1H,Jgem=12.0,J5´b,OH=6.3,J5´b,4´=3.8,H−5´b);3.61(dd,1H,Jgem=12.0,J5´a,OH=4.9,J5´a,4´=3.8,H−5´a);3.88(td,1H,J4´,5´=3.8,J4´,3´=3.0,H−4´);4.08(ddd,1H, J3´,2´=5.1,J3´,OH=4.7,J3´,4´=3.0,H−3´);4.43(ddd,1H,J2´,OH=6.5,J2´,1´=6.4,J2´,3´=5.1,H−2´);5.11(d,1H,JOH,3´=4.7,OH−3´);5.24(dd,1H,JOH,5´=6.3,4.9,OH−5´);5.30(d,1H,JOH,2´=6.5,OH−5´);6.06(d,1H,J1´,2´=6.4,H−1´);6.18(td,1H,J4,5=J4,NH=2.6,J4,2=1.6,H−4−pyrr);6.26(bs,2H,NH2);6.88(dt,1H,J2,NH=2.6,J2,4=J2,5=1.6,H−2−pyrr);6.90(td,1H,J5,4=J5,NH=2.6,J5,2=1.6,H−5−pyrr);7.27(s,1H,H−6);8.08(s,1H,H−2);11.03(bs,1H,NH−pyrr). 13C NMR(125.7MHz,DMSO−d6):62.00(CH2−5´);70.94(CH−3´);73.89(CH−2´);85.23(CH−4´);87.12(CH−1´);101.65(C−4a);108.29(CH−4−pyrr);111.17(C−5);115.87(C−3−pyrr);116.44(CH−2−pyrr);119.33(CH−2−pyrr);119.65(CH−6);150.42(C−7a);151.62(CH−2);157.77(C−4).
MS(ESI):m/z 332(M+H),354(M+Na)。HRMS(ESI):C15H18N5O4[M+H]:計算値:332.1353;実測値:332.1354。分析:C15H17N5O4・0.8H2O:計算値:C,52.11;H,5.42;N,20.26;実測値:C,52.32;H,5.32;N,20.03。
1H NMR(500MHz,DMSO−d6+DCl):3.53および3.61(2
× dd,2 × 1H,Jgem=11.9,J5´,4´=3.8,H−5´);3.93(td,1H,J4´,5´=3.8,J4´,3´=3.3,H−4´);4.10(dd,1H,J3´,2´=4.9,J3´,4´=3.3,H−3´);4.35(dd,1H,J2´,1´=6.1,J2´,3´=4.9,H−2´);6.15(d,1H,J1´,2´=6.1,H−1´);7.85(s,1H,H−6);8.09(s,2H,H−3,5−ピラゾール);8.52(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6+DCl):61.52(CH2−5´);70.72(CH−3´);74.83(CH−2´);85.97(CH−4´);87.14(CH−1´);99.99(C−4a);109.14(C−4−ピラゾール);112.19(C−5);124.02(CH−6);133.06(CH−3,5−ピラゾール);142.88(CH−2);148.10(C−7a);151.41(C−4). IR(KBr):3468,3338,3239,3200,3115,1740,1629,1583,1559,1523,1469,1306,1123,1076,1044,1024,796.
MS(ESI):m/z 333(M+H),355(M+Na)。HRMS(ESI):C14H17N6O4[M+H]:計算値:333.1306;実測値:333.1304。
1H NMR(500MHz,DMSO−d6):3.55(ddd,1H,Jgem=12.1,J5´b,OH=6.4,J5´b,4´=4.1,H−5´b);3.66(ddd,1H,Jgem=12.1,J5´a,OH=5.0,J5´a,4´=3.9,H−5´a);3.90(ddd,1H,J4´,5´=4.1,3.9,J4´,3´=3.2,H−4´);4.11(ddd,1H,J3´,2´=5.2,J3´,2´=4.8,J3´,4´=3.2,H−3´);4.44(ddd,1H,J2´,OH=6.4,J2´,1´=6.3,J2´,3´=5.2,H−2´);6.04(d,1H,J1´,2´=6.1,H−1´);6.66(dd,1H,J4,5=2.4,J4,NH=1.9,H−4−ピラゾール);7.25(bs,1H,NHaHb);7.81(dd,1H,J5,4=2.4,J5,NH=1.5,H−5−ピラゾール);7.86(s,1H,H−6);8.04(s,1H,H−2);9.24(bs,1H,NHaHb);12.88(bs,1H,NH). 13C NMR(125.7MHz,DMSO−d6):61.98(CH2−5´);70.76(CH−3´);73.75(CH−2´);85.27(CH−4´);87.32(CH−1´);100.36(C−4a);101.91(CH−4−ピラゾール);109.76(C−5);120.64(CH−6);130.20(CH−5−ピラゾール);146.26(C−3−ピラゾール);151.02(C−7a);152.44(CH−2);158.47(C−4). IR(KBr):3411,3290,3136,2665,1633,1597,1576,1550,1474,1301,1138,1109,1082,1050,1019,934,798,765,651.
MS(ESI):m/z 333(M+H),355(M+Na)。HRMS(ESI):C14H17N6O4[M+H]:計算値:333.1306;実測値:333.1306。分析:C14H16N6O4・1.85H2O:計算値:C,45.99;H,5.43;N,22.98;実測値:C,46.22;H,5.44;N,22.68。
1H NMR(400.0MHz,DMSO−d6):0.24(s,9H,CH3−TMS);3.54(ddd,1H,Jgem=12.0,J5´b,OH=6.2,J5´b,4´=3.8,H−5´b);3.63(dd,1H,Jgem=12.0,J5´a,OH=5.0,J5´a,4´=3.8,H−5´a);3.90(td,1H,J4´,5´=3.8,J4´,3´=3.2,H−4´);4.08(ddd,1H,J3´,2´=5.0,J3´,OH=4.8,J3´,4´=3.2,H−3´);4.36(ddd,1H,J2´,OH=6.3,J2´,1´=6.0,J2´,3´=5.0,H−2´);5.15(d,1H,JOH,3´=4.7,OH−3´);5.20(dd,1H,JOH,5´=6.2,5.0,OH−5´);5.35(d,1H,JOH,2´=6.3,OH−5´);6.02(d,1H,J1´,2´=6.0,H−1´);6.64(bs,2H,NH2);7.84(s,1H,H−6);8.13(s,1H,H−2). 13C NMR(100.6MHz,DMSO−d6):−0.19(CH3−TMS);61.47(CH2−5´);70.45(CH−3´);74.06(CH−2´);85.26(CH−4´);87.23(CH−1´);94.60(C−5);96.78(−C≡CTMS);99.14(−C≡CTMS);102.41(C−4a);127.38(CH−6);149.48(C−7a);152.82(CH−2);157.58(C−4).
MS(ESI):m/z 363(M+H),385(M+Na)。HRMS(ESI):C16H23N4O4Si[M+H]:計算値:363.1483;実測値:363.1484。分析:C16H22N4O4Si:計算値:C,53.02;H,6.12;N,15.46;実測値:C,52.91;H,6.11;N,15.30。
1H NMR(500.0MHz,DMSO−d6):3.53(ddd,1H,Jgem=12.0,J5´b,OH=6.2,J5´b,4´=3.8,H−5´b);3.63(dd,1H,Jgem=12.0,J5´a,OH=5.0,J5´a,4´=3.8,H−5´a);3.89(td,1H,J4´,5´=3.8,J4´,3´=3.2,H−4´);4.07(ddd,1H,J3´,2´=5.0,J3´,OH=4.8,J3´,4´=3.2,H−3´);4.29(s,1H,HC≡C−);4.37(ddd,1H,J2´,OH=6.3,J2´,1´=6.1,J2´,3´=5.0,H−2´);5.16(d,1H,JOH,3´=4.8,OH−3´);5.23(dd,1H,JOH,5´=6.2,5.0,OH−5´);5.38(d,1H,JOH,2´=6.3,OH−5´);6.01(d,1H,J1´,2´=6.1,H−1´);6.70(bs,2H,NH2);7.83(s,1H,H−6);8.12(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):61.73(CH2−5´);70.74(CH−3´);74.21(CH−2´);77.52(−C≡CH);83.37(−C≡CH);85.51(CH−4´);87.42(CH−1´);94.17(C−5);102.65(C−4a);127.74(CH−6);149.73(C−7a);153.04(CH−2);157.78(C−4).
MS(ESI):m/z 291(M+H),313(M+Na)。HRMS(ESI):C13H15N4O4[M+H]:計算値:291.1088;実測値:291.1088。分析:C13H14N4O4:計算値:C,53.79;H,4.86;N,18.91;実測値:C,53.34;H,4.95;N,18.97。
1H NMR(499.8MHz,DMSO−d6,t=60 °C):3.58(dd,1H,Jgem=11.9,J5´b,4´=4.2,H−5´b);3.68(dd,1H,Jgem=11.9,J5´a,4´=3.9,H−5´a);3.93(ddd,1H,J4´,5´=4.2,3.9,J4´,3´=3.6,H−4´);4.15(dd,1H,J3´,2´=5.3,J3´,4´=3.6,H−3´);4.45(dd,1H,J2´,1´=6.0,J2´,3´=5.3,H−2´);4.93,5.04および5.17(3 × bs,3 × 1H,OH−2´,3´,5´);6.08(d,1H,J1´,2´=6.0,H−1´);7.85(bs,2H,NH2);7.91(s,1H,H−6);8.09(s,1H,H−2);8.23(s,1H,H−5−トリアゾール). 13C NMR(125,7MHz,DMSO−d6,t=60 °C):61.83(CH2−5´);70.54(CH−3´);73.72(CH−2´);85.15(CH−4´);87.41(CH−1´);100.16(C−4a);105.83(C−5);120.80(CH−6);126.16(CH−5−トリアゾール);141.51(C−4−トリアゾール);151.04(C−7a);152.35(CH−2);158.04(C−4).
MS(ESI):m/z 334(M+H),356(M+Na)。HRMS(ESI):C13H16N7O4[M+H]:計算値:334.1258;実測値:334.1258。分析:C13H15N7O4:計算値:C,46.85;H,4.54;N,29.42;実測値:C,47.12;H,4.82;N,27.96。
1H NMR(500.0MHz,CDCl3):−0.28,−0.08,0.096,0.098,0.17および0.18(6 × s,6 × 3H,CH3Si);0.77,0.93および0.99(3 × s,3 × 9H,(CH3)C);3.77(dd,1H,Jgem=11.4,J5´b,4´=2.3,H−5´b);3.95(dd,1H,Jgem=11.4,J5´a,4´=3.0,H−5´a);4.08(td,1H,J4´,5´=3.0,2.3,J4´,3´=3.0,H−4´);4.22(dd,1H,J3´,2´=4.5,J3´,4´=3.0,H−3´);4.39(dd,1H,J2´,1´=5.6,J2´,3´=4.5,H−2´);5.70(bs,2H,NH2);6.26(d,1H,J1´,2´=5.6,H−1´);7.52(s,1H,H−6);8.26(s,1H,H−2). 13C NMR(125.7MHz,CDCl3):−5.33,−5.31,−5.26,−4.76,−4.75および−4.41(CH3Si);17.84,18.10および18.60(C(CH3)3);25.65,25.84および26.17((CH3)3C);50.20(C−5);62.94(CH2−5´);72.43(CH−3´);76.78(CH−2´);85.46(CH−4´);87.48(CH−1´);104.26(C−4a);126.62(CH−6);150.66(C−7a);152.19(CH−2);156.74(C−4).
MS(ESI):m/z 735(M+H),757(M+Na)。
1H NMR(500.0MHz,CDCl3):−0.36,−0.10,0.11,0.13,0.17および0.18(6 × s,6 × 3H,CH3Si);0.74,0.95および0.99(3 × s,3 × 9H,(CH3)C);3.79(dd,1H,Jgem=11.4,J5´b,4´=2.7,H−5´b);3.96(dd,1H,Jgem=11.4,J5´a,4´=3.2,H−5´a);4.11(ddd,1H,J4´,5´=3.9,2.7,J4´,3´=1.8,H−4´);4.23(dd,1H,J3´,2´=4.7,J3´,4´=1.8,H−3´);4.55(dd,1H,J2´,1´=6.9,J2´,3´=4.7,H−2´);5.96(bs,1H,NHaHb);6.31(d,1H,J1´,2´=6.9,H−1´);7.21(d,1H,J5,4=3.4,H−5−チアゾリル);7.72(d,1H,J4,5=3.4,H−4−チアゾリル);7.74(s,1H,H−6);8.26(s,1H,H−2);9.79(bs,1H,NHaHb). 13C NMR(125.7MHz,CDCl3):−5.35,−5.33,−5.19,−4.65,−4.61および−4.47(CH3Si);17.82,18.13および18.57(C(CH3)3);25.61,25.86および26.15((CH3)3C);63.37(CH2−5´);73.03(CH−3´);76.26(CH−2´);86.28(CH−4´);87.01(CH−1´);100.52(C−4a);112.19(C−5);116.76(CH−5−チアゾリル);122.24(CH−6);141.71(CH−4−チアゾリル);151.57(C−7a);151.94(CH−2);157.52(C−4);163.53(C−2−チアゾリル).
MS(ESI):m/z 692(M+H),714(M+Na)。HRMS(ESI):C32H58N5O4SSi3[M+H]:計算値:692.3512;実測値:692.3512。
1H NMR(600.1MHz,DMSO−d6):3.61(dd,1H,Jgem=12.0,J5´b,4´=3.6,H−5´b);3.72(dd,1H,Jgem=12.0,J5´a,4´=3.9,H−5´a);3.97(td,1H,J4´,5´=3.9,3.6,J4´,3´=3.9,H−4´);4.16(dd,1H,J3´,2´=4.9,J3´,4´=3.9,H−3´);4.41(dd,1H,J2´,1´=5.6,J2´,3´=4.9,H−2´);6.14(d,1H,J1´,2´=5.6,H−1´);7.80(d,1H,J5,4=3.3,H−5−チアゾリル);7.91(d,1H,J4,5=3.3,H−4−チアゾリル);8.48(s,1H,H−2);8.62(s,1H,H−6);8.99および10.88(2 × bs,2H,NH2). 13C NMR(150.9MHz,DMSO−d6):61.12(CH2−5´);70.19(CH−3´);74.78(CH−2´);85.80(CH−4´);87.63(CH−1´);99.39(C−4a);113.09(C−5);120.13(CH−5−チアゾリル);125.34(CH−6);142.09(CH−4−チアゾリル);145.00(CH−2);148.55(C−7a);152.47(C−4);162.07(C−2−チアゾリル).
MS(ESI):m/z 350(M+H),372(M+Na)。HRMS(ESI):C14H16N5O4S[M+H]:計算値:350.0918;実測値:350.0918。分析:C14H15N5O4S・1/2H2O・CH3OH:計算値:C,46.15;H,5.16;N,17.94;実測値:C,46.41;H,4.96;N,17.67。
1H NMR(500.0MHz,DMSO−d6):3.53(ddd,1H,Jgem=12.0,J5´b,OH=6.5,J5´b,4´=4.2,H−5´b);3.64(dd,1H,Jgem=12.0,J5´a,OH=4.8,J5´a,4´=4.2,H−5´a);3.89(td,1H,J4´,5´=4.2,J4´,3´=3.4,H−4´);4.09(ddd,1H,J3´,2´=5.0,J3´,OH=4.8,J3´,4´=3.4,H−3´);4.41(ddd,1H,J2´,OH=6.5,J2´,1´=6.3,J2´,3´=5.0,H−2´);5.14(d,1H,JOH,3´=4.8,OH−3´);5.30(dd,1H,JOH,5´=6.5,4.8,OH−5´);5.34(d,1H,JOH,2´=6.5,OH−5´);6.03(d,1H,J1´,2´=6.3,H−1´);7.14(bs,1H,NHaHb);7.50(d,1H,J5,NH=2.0,J5,2=0.8,H−5−イミダゾール);7.68(s,1H,H−6);7.81(d,1H,J2,5=0.8,H−2−イミダゾール);8.01(s,1H,H−2);9.99(bs,1H,NHaHb);12.31(bs,1H,NH−イミダゾール). 13C NMR(125.7MHz,DMSO−d6):62.11(CH2−5´);70.87(CH−3´);73.76(CH−2´);85.23(CH−4´);87.30(CH−1´);100.77(C−4a);110.84(C−5);111.81(CH−5−イミダゾール);117.90(CH−6);134.95(CH−2−イミダゾール);135.10(C−4−イミダゾール);150.56(C−7a);152.08(CH−2);158.59(C−4).
MS(ESI):m/z 333(M+H),355(M+Na)。HRMS(ESI):C14H17N6O4[M+H]:計算値:333.1306;実測値:333.1306。分析:C14H16N6O4:計算値:C,50.60;H,4.85;N,25.29;実測値:C,50.55;H,5.01;N,24.28。
MS(ESI):m/z 333(M+H),355(M+Na)。HRMS(ESI):C14H17N6O4[M+H]:計算値:333.1306;実測値:333.1306。分析:C14H16N6O4・1.85H2O・0.55CH3OH:計算値:C,45.60;H,5.76;N,21.93;実測値:C,45.67;H,5.66;N,21.86。
1H NMR(500MHz,CDCl3):1.59(s,3H,CH3);4.72(td,1H,J4´,3´=J4´,5´b=5.8,J4´,5´a=3.4,H−4´);4.85(dd,1H,Jgem=12.2,J5´b,4´=5.8,H−5´b);4.95(dd,1H,Jgem=12.2,J5´a,4´=3.4,H−5´a);6.03(d,1H,J3´,4´=5.8,H−3´);6.95(s,1H,H−1´);7.34,7.46および7.47(3 × m,3 × 2H,H−m−Bz);7.54,7.59および7.61(3 × m,3 × 1H,H−p−Bz);7.69(s,1H,H−6);7.96,8.10および8.11(3 × m,3 × 2H,H−o−Bz);8.75(s,1H,H−2). 13C NMR(125.7MHz,CDCl3):17.92(CH3);52.68(C−5);63.33(CH2−5´);75.55(CH−3´);80.04(CH−4´);84.93(C−2´);88.95(CH−1´);117.71(C−4a);128.49,128.54および128.63(CH−m−Bz);128.65,129.50および129.61(C−i−Bz);129.78,129.83および129.92(CH−o−Bz);132.66(CH−6);133.38,133.66,133.72(CH−p−Bz);150.68(C−7a);151.17(CH−2);153.15(C−4);165.09,165.33および166.32(CO). IR(CHCl3):3092,3066,3034,1727,1602,1587,1577,1538,1504,1493,1451,1444,1339,1316,1269,1248,1178,1162,1141,1116,1070,1027,1002,952,943,843,822,725,712,686,617,600.
MS(FAB):m/z 738(M+H)。HRMS(FAB):C33H26ClIN3O7[M+H]:計算値:738.0504;実測値:738.0491。分析:C33H25ClIN3O7:計算値:C,53.71;H,3.41;N,5.69;実測値:C,53.91;H,3.29;N,5.38。
1H NMR(600MHz,DMSO−d6):0.67(s,3H,CH3);3.65(ddd,1H,Jgem=12.1,J5´b,OH=4.8,J5´b,4´=2.7,H−5´b);3.81(ddd,1H,Jgem=12.1,J5´a,OH=4.8,J5´a,4´=2.0,H−5´a);3.79(ddd,1H,J4´,3´=9.1,J4´,5´=2.7,2.0,H−4´);3.93(bd,1H,J3´,4´=9.1,H−3´);5.14(s,1H,OH−2´);5.16(bs,1H,OH−3´);5.22(t,1H,JOH,5´=4.8,OH−5´);6.10(s,1H,H−1´);6.67(bs,2H,NH2);7.82(s,1H,H−6);8.10(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):19.89(CH3);51.68(C−5);59.46(CH2−5´);71.76(CH−3´);78.87(C−2´);82.39(CH−4´);90.71(CH−1´);103.11(C−4a);126.81(CH−6);149.88(C−7a);152.23(CH−2);157.43(C−4). IR(KBr):3474,3429,3392,3366,1631,1582,1553,1504,1440,1343,1295,1147,1128,1070,1045,789.
MS(FAB):m/z 407(M+H)。HRMS(FAB):C12H16IN4O4[M+H]:計算値:407.0216;実測値:407.0225。分析:C12H15IN4O4:計算値:C,35.48;H,3.72;N,13.79;実測値:C,35.37;H,3.72;N,13.39。
1H NMR(600MHz,DMSO−d6):0.75(s,3H,CH3);3.65(bdd,1H,Jgem=12.2,J5´b,4´=2.9,H−5´b);3.82(bdd,1H,Jgem=12.2,J5´a,4´=2.1,H−5´a);3.86(ddd,1H,J4´,3´=9.1,J4´,5´=2.9,2.1,H−4´);4.02(d,1H,J3´,4´=9.1,H−3´);5.15(bs,3H,OH−2´,3´,5´);6.10(bs,2H,NH2);6.23(s,1H,H−1´);7.36(m,1H,H−p−Ph);7.44−7.50(m,4H,H−o,m−Ph);7.70(s,1H,H−6);8.16(s,1H,H−2).
13C NMR(151MHz,DMSO−d6):20.00(CH3);59.60(CH2−5´);72.01(CH−3´);78.88(C−2´);82.39(CH−4´);90.51(CH−1´);100.09(C−4a);116.41(C−5);120.75(CH−6);127.05(CH−p−Ph);128.64(CH−o−Ph);129.23(CH−m−Ph);134.89(C−i−Ph);150.67(C−7a);151.94(CH−2);157.49(C−4).
IR(KBr):3480,3431,3400,1631,1622,1585,1566,1537,1489,1464,1445,1299,1178,1123,1073,1058,1029,799,763,705,550.
MS(FAB):m/z 357(M+H)。HRMS(FAB):C18H21N4O4[M+H]:計算値:357.1563;実測値:357.1557。分析:C18H20N4O4・1.6H2O:計算値:C,56.13;H,6.07;N,14.54;実測値:C,56.52;H,5.74;N,14.14。
1H NMR(600MHz,DMSO−d6):0.74(s,3H,CH3);3.64(bdd,1H,Jgem=12.21,J5´b,4´=2.9,H−5´b);3.80(s,3H,CH3O);3.81(bdd,1H,Jgem=12.1,J5´a,4´=2.1,H−5´a);3.85(ddd,1H,J4´,3´=9.1,J4´,5´=2.9,2.1,H−4´);4.01(d,1H,J3´,4´=9.1,H−3´);5.13(bs,3H,OH−2´,3´,5´);6.08(bs,2H,NH2);6.22(s,1H,H−1´);7.04(m,2H,H−m−C6H4OMe);7.36(m,2H,H−o−C6H4OMe);7.60(s,1H,H−6);8.14(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):19.99(CH3);55.39(CH3O);59.61(CH2−5´);72.03(CH−3´);78.87(C−2´);82.34(CH−4´);90.47(CH−1´);100.31(C−4a);114.65(CH−m−C6H4OMe);116.06(C−5);120.14(CH−6);127.04(C−i−C6H4OMe);129.91(CH−o−C6H4OMe);150.45(C−7a);151.85(CH−2);157.51(C−4);158.58(C−p−C6H4OMe). IR(KBr):3435,2836,1631,1622,1586,1565,1539,1506,1464,1419,1293,1247,1174,1110,1072,1033,839,798,791,712,550.MS(FAB):m/z 387(M+H)。HRMS(FAB):C19H23N4O5[M+H]:計算値:387.1668;実測値:387.1665。分析:C19H22N4O5・1.6H2O:計算値:C,54.96;H,6.12;N,13.49;実測値:C,55.30;H,5.91;N,13.18。
1H NMR(500MHz,DMSO−d6,T=353 K):0.90(s,3H,CH3);3.67(dd,1H,Jgem=12.2,J5´b,4´=3.5,H−5´b);3.83(dd,1H,Jgem=12.2,J5´a,4´=2.3,H−5´a);3.91(ddd,1H,J4´,3´=8.9,J4´,5´=3.5,2.3,H−4´);4.04(d,1H,J3´,4´=8.9,H−3´);4.89(bs,3H,OH−2´,3´,5´);5.39(bs,2H,NH2);6.34(s,1H,H−1´);7.500(ddd,1H,J7,8=8.3,J7,6=6.9,J7,5=1.3,H−7−naphth);7.502(dd,1H,J2,3=6.9,J2,4=1.3,H−2−naphth);7.56(ddd,1H,J6,5=8.1,J6,7=6.9,J6,8=1.3,H−6−naphth);7.60(dd,1H,J3,4=8.3,J3,2=6.9,H−3−naphth);7.63(s,1H,H−6);7.75(dddd,1H,J8,7=8.3,J8,6=1.3,J8,4=1.0,J8,5=0.8,H−8−naphth);7.98(ddd,1H,J4,3=8.3,J4,2=1.3,J4,8=1.0,H−4−naphth);8.01(ddd,1H,J5,6=8.1,J5,7=1.3,J5,8=0.8,H−5−naphth);8.19(s,1H,H−2). 13C NMR(151MHz,DMSO−d6,T=353 K):19.73(CH3);59.70(CH2−5´);72.30(CH−3´);78.69(C−2´);82.28(CH−4´);90.64(CH−1´);102.10(C−4a);113.02(C−5);121.50(CH−6);125.27(CH−8−naphth);125.38(CH−3−naphth);125.98(CH−6−naphth);126.42(CH−7−naphth);127.82(CH−4−naphth);128.12(CH−2,5−naphth);131.63(C−1−naphth);132.13(C−8a−naphth);133.39(C−4a−naphth);150.05(C−7a);151.61(CH−2);156.96(C−4). IR(KBr):3478,3438,3395,3058,2973,1620,1583,1578,1568,1533,1507,1468,1398,1377,1298,1256,1178,1143,1117,1071,1050,1035,1018,852,799,786,780,740.
MS(ESI):m/z 407(M+H),429(M+Na)。HRMS(ESI):C22H23N4O4[M+H]:計算値:407.1714;実測値:407.1704。分析:C22H22N4O4・1.5H2O:計算値:C,60.96;H,5.81;N,12.93;実測値:C,61.30;H,5.72;N,13.28。
1H NMR(500MHz,DMSO−d6):0.79(s,3H,CH3);3.66(ddd,1H,Jgem=12.6,J5´b,OH=5.0,J5´b,4´=2.9,H−5´b);3.84(ddd,1H,Jgem=12.6,J5´a,OH=5.0,J5´a,4´=2.1,H−5´a);3.88(ddd,1H,J4´,3´=9.1,J4´,5´=2.9,2.1,H−4´);4.06(bdd,1H,J3´,4´=9.1,J3´,OH=4.6,H−3´);5.11−5.17(bm,3H,OH−2´,3´,5´);6.19(bs,2H,NH2);6.27(s,1H,H−1´); 7.52(m,1H,H−6−naphth);7.55(m,1H,H−7−naphth);7.62(dd,1H,J3,4=8.5,J3,1=1.8,H−3−naphth);7.81(s,1H,H−6);7.94−7.97(m,3H,H−1,5,8−naphth);8.01(d,1H,J4,3=8.5,H−4−naphth);8.18(s,1H,H−2). 13C NMR(125.7MHz,DMSO−d6):20.03(CH3);59.66(CH2−5´);72.08(CH−3´);78.90(C−2´);82.41(CH−4´);90.57(CH−1´);100.24(C−4a);116.45(C−5);121.14(CH−6);126.10(CH−6−naphth);126.76(CH−7−naphth);126.82(CH−1−naphth);127.23(CH−3−naphth);127.87および128.02(CH−5,8−naphth);128.70(CH−4−naphth);132.00(C−4a−naphth);132.35(C−1−naphth);133.46(C−8a−naphth);150.82(C−7a);152.02(CH−2);157.61(C−4). IR(KBr):3506,3481,3452,3402,3325,3242,3210,3110,3052,2973,1645,1624,1605,1587,1567,1535,1503,1469,1378,1298,1274,1142,1128,1116,1075,1057,1050,1019,897,860,821,796,767,750,478.
MS(ESI):m/z 407(M+H),429(M+Na)。HRMS(ESI):C22H23N4O4[M+H]:計算値:407.1714;実測値:407.1715。分析:C22H22N4O4・1.3H2O:実測値:C,61.47;H,5.77;N,13.03;実測値:C,61.83;H,5.51;N,12.65。
1H NMR(600MHz,DMSO−d6):0.72(s,3H,CH3);3.68および3.85(2 × bd,2H,Jgem=12.0,H−5´);3.87(ddd,1H,J4´,3´=9.1,J4´,5´=2.9,2.0,H−4´);4.00(bd,1H,J3´,4´=9.1,H−3´);5.16(bs,2H,OH−2´,3´);5.25(bs,1H,OH−5´);6.19(s,1H,H−1´);6.58(dd,1H,J3,4=3.3,J3,5=0.8,H−3−フリル);6.60(dd,1H,J4,3=3.3,J4,5=1.9,H−4−フリル);6.90(bs,2H,NH2);7.78(dd,1H,J5,4=1.9,J5,3=0.8,H−5−フリル);8.01(s,1H,H−6);8.14(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):19.91(CH3);59.66(CH2−5´);71.92(CH−3´);78.85(C−2´);82.48(CH−4´);90.60(CH−1´);99.03(C−4a);105.22(CH−3−フリル);106.10(C−5);112.13(CH−4−フリル);120.07(CH−6);142.17(CH−5−フリル);148.98(C−2−フリル);150.60(C−7a);152.35(CH−2);157.46(C−4). IR(KBr):3474,3385,3351,3245,3200,1630,1575,1560,1531,1497,1472,1455,1379,1299,1124,1072,1049,1016,893,795,594.
MS(ESI):m/z 347(M+H),369(M+Na)。HRMS(ESI):C16H19N4O5[M+H]:計算値:347.1355;実測値:347.1347。分析:C16H18N4O5・0.7H2O:計算値:C,53.54;H,5.45;N,15.61;実測値:C,53.86;H,5.48;N,15.22。
1H NMR(600MHz,DMSO−d6):0.73(s,3H,CH3);3.65(dd,1H,Jgem=12.3,J5´b,4´=2.9,H−5´b);3.83(dd,1H,Jgem=12.3,J5´a,4´=2.1,H−5´a);3.86(ddd,1H,J4´,3´=9.1,J4´,5´=2.9,2.1,H−4´);4.00(bd,1H,J3´,4´=9.1,H−3´);5.20(bs,3H,OH−2´,3´,5´);6.19(s,1H,H−1´);6.30(bs,2H,NH2);7.13(dd,1H,J3,4=3.5,J3,5=1.2,H−3−チエニル);7.16(dd,1H,J4,5=5.2,J4,3=3.5,H−4−チエニル);7.55(dd,1H,J5,4=5.2,J5,3=1.1,H−2−チエニル);7.82(s,1H,H−6);8.16(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):19.96(CH3);59.37(CH2−5´);71.76(CH−3´);78.88(C−2´);82.38(CH−4´);90.53(CH−1´);100.27(C−4a);108.51(C−5);121.64(CH−6);125.93(CH−5−チエニル);126.42(CH−3−チエニル);128.53(CH−4−チエニル);136.04(C−2−チエニル);150.40(C−7a);152.26(CH−2);157.47(C−4). IR(KBr):3471,3380,3350,3235,3195,1622,1591,1575,1549,1507,1460,1430,1372,1349,1296,1228,1122,1071,1050,850,796,707,559.
MS(ESI):m/z 363(M+H),385(M+Na)。HRMS(ESI):C16H19N4O4S[M+H]:計算値:363.1127;実測値:363.1121。分析:C16H18N4O4S・0.95H2O:計算値:C,50.64;H,5.28;N,14.76;実測値:C,51.03;H,5.06;N,14.40。
1H NMR(600MHz,DMSO−d6):0.72(s,3H,CH3);3.65(dd,1H,Jgem=12.2,J5´b,4´=3.0,H−5´b);3.82(dd,1H,Jgem=12.2,J5´a,4´=2.1,H−5´a);3.85(ddd,1H,J4´,3´=9.1,J4´,5´=3.0,2.1,H−4´);3.99(d,1H,J3´,4´=9.1,H−3´);5.16(bs,3H,OH−2´,3´,5´);6.19(s,1H,H−1´);6.25(bs,2H,NH2);6.66(dd,1H,J4,5=1.7,J4,2=0.8,H−4−フリル);7.65(s,1H,H−6);7.79(t,1H,J5,2=J5,4=1.7,H−5−フリル);7.80(dd,1H,J2,5=1.7,J2,4=0.8,H−2−フリル);8.13(s,1H,H−2). 13C NMR(151MHz,DMSO−d6):19.99(CH3);59.74(CH2−5´);72.08(CH−3´);78.87(C−2´);82.41(CH−4´);90.56(CH−1´);100.67(C−4a);106.27(C−5);111.78(CH−4−フリル);119.00(C−3−フリル);120.61(CH−6);139.79(CH−2−フリル);144.43(CH−5−フリル);150.52(C−7a);152.03(CH−2);157.68(C−4). IR(KBr):3478,3337,3243,3208,3150,1623,1583,1561,1534,1498,1455,1378,1357,1350,1300,1159,1120,1071,1056,1026,874,793,602.
MS(ESI):m/z 347(M+H)。HRMS(ESI):C16H19N4O5[M+H]:計算値:347.1350;実測値:347.1349。分析:C16H18N4O5・1.7H2O:計算値:C,50.98;H,5.72;N,14.86;実測値:C,51.30;H,5.33;N,14.46。
1H NMR(600MHz,DMSO−d6):0.74(s,3H,CH3);3.65(ddd,1H,Jgem=12.1,J5´b,OH=4.8,J5´b,4´=2.9,H−5´b);3.82(ddd,1H,Jgem=12.1,J5´a,OH=4.8,J5´a,4´=2.1,H−5´a);3.85(ddd,1H,J4´,3´=9.0,J4´,5´=2.9,2.1,H−4´);4.00(dd,1H,J3´,4´=9.0,J3´,OH=7.1,H−3´);5.12(d,1H,JOH,3´=7.1,OH−3´);5.13(s,1H,OH−2´);5.16(t,1H,JOH,5´=4.8,OH−5´);6.20(s,1H,H−1´);6.20(bs,2H,NH2);7.24(dd,1H,J4,5=4.9,J4,2=1.4,H−4−チエニル);7.49(dd,1H,J2,5=2.9,J2,4=1.4,H−2−チエニル);7.698(dd,1H,J5,4=4.9,J5,2=2.9,H−5−チエニル);7.70(s,1H,H−6);8.14(s,1H,H−2).
13C NMR(151MHz,DMSO−d6):20.01(CH3);59.67(CH2−5´);72.04(CH−3´);78.89(C−2´);82.41(CH−4´);90.55(CH−1´);100.44(C−4a);111.08(C−5);120.73(CH−6);122.11(CH−2−チエニル);127.66(CH−5−チエニル);128.72(CH−4−チエニル);135.16(C−3−チエニル);150.38(C−7a);151.96(CH−2);157.57(C−4). IR(KBr):3475,3351,3240,3200,3120,3107,1621,1594,1575,1549,1510,1465,1409,1378,1346,1297,1139,1123,1072,1045,861,788.
MS(ESI):m/z 363(M+H),385(M+Na)。HRMS(ESI):C16H19N4O4S[M+H]:計算値:363.1122;実測値:363.1122。分析:C16H18N4O4S ・1.1H2O:計算値:C,50.28;H,5.33;N,14.66;実測値:C,50.42;H,5.20;N,14.45。
1H NMR(500MHz,DMSO−d6):0.76(s,3H,CH3);3.72(ddd,1H,Jgem=12.5,J5´b,OH=5.0,J5´b,4´=2.9,H−5´b);3.88(ddd,1H,Jgem=12.5,J5´a,OH=5.0,J5´a,4´=2.0,H−5´a);3.90(ddd,1H,J4´,3´=9.2,J4´,5´=2.9,2.0,H−4´);4.04(dd,1H,J3´,4´=9.2,J3´,OH=7.0,H−3´);5.17(d,1H,JOH,3´=7.0,OH−3´);5.19(s,1H,OH−2´);5.28(t,1H,JOH,5´=5.0,OH−5´);6.23(s,1H,H−1´);6.98(bs,2H,NH2);7.04(d,1H,J3,7=1.0,H−3−ベンゾフリル);7.27(td,1H,J5,4=J5,6=7.3,J5,7=1.4,H−5−ベンゾフリル);7.29(td,1H,J6,5=J6,7=7.3,J6,4=1.7,H−6−ベンゾフリル);7.61−7.67(m,2H,H−4,7−ベンゾフリル);8.19(s,1H,H−2);8.26(s,1H,H−6). 13C NMR(125.7MHz,DMSO−d6):19.96(CH3);59.72(CH2−5´);71.97(CH−3´);78.91(C−2´);82.59(CH−4´);90.74(CH−1´);99.19(C−4a);101.58(CH−3−ベンゾフリル);105.47(C−5);111.30(CH−7−ベンゾフリル);120.81(CH−4−ベンゾフリル);122.32(CH−6);123.73(CH−5−ベンゾフリル);124.08(CH−6−ベンゾフリル);129.01(C−3a−ベンゾフリル);150.94(C−7a);151.45(C−2−ベンゾフリル);152.58(CH−2);154.00(C−7a−ベンゾフリル);157.50(C−4).
MS(ESI、ネガティブモード):m/z 395(M−H)。HRMS(ESI、ネガティブモード):C20H19N4O5:[M−H]:計算値:395.1350;実測値:395.1358。分析:C20H20N4O5・1/3H2O:計算値:C,59.70;H,5.18;N,13.92;実測値:C,59.98;H,5.13;N,13.46。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.15(ddd,1H,Jgem=11.6,JH,P=4.9,J5´b,4´=3.3,H−5´b);4.24(ddd,1H,Jgem=11.6,JH,P=6.6,J5´a,4´=3.2,H−5´a);4.34(m,1H,J4´,5´=3.3,3.2,J4´,3´=2.9,JH,P=2.1,H−4´);4.54(ddd,1H,J3´,2´=5.3,J3´,4´=2.9,JH,P=0.4,H−3´);4.65(dd,1H,J2´,1´=6.7,J2´,3´=5.3,H−2´);6.21(d,1H,J1´2´=6.7,H−1´);7.71(s,1H,H−8);8.09(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):55.01(C−7);68.18(d,JC,P=6,CH2−5´);73.21(CH−3´);76.51(CH−2´);86.33(d,JC,P=9,CH−4´);88.50(CH−1´);106.76(C−4a);129.78(CH−6);152.52(C−7a);154.17(CH−2);159.72(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−20.78(t,J=19.5,P−);−9.66(d,J=19.5,P−);−7.00(d,J=19.5,P−).
MS(ESI):m/z 699(M+H),721(M+Na)。MS(ESI、ネガティブモード):m/z 631(M−3Na+2H),653(M−2Na+H),675(M−Na)。HRMS(ESI、ネガティブモード)−:C11H14IN4NaO13P3[M−2Na+H]:計算値:652.8713;実測値:652.8731。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.14(ddd,1H,Jgem=11.6,JH,P=4.7,J5´b,4´=3.5,H−5´b);4.25(ddd,1H,Jgem=11.6,JH,P=6.5,J5´a,4´=3.3,H−5´a);4.35(m,1H,J4´,5´=3.5,3.3,J4´,3´=2.9,JH,P=1.7,H−4´);4.57(dd,1H,J3´,2´=5.4,J3´,4´=2.9,H−3´);4.73(dd,1H,J2´,1´=6.9,J2´,3´=5.4,H−2´);6.30(d,1H,J1´2´=6.9,H−1´);7.45(m,1H,H−p−Ph);7.49−7.56(m,4H,H−o,m−Ph);7.57(s,1H,H−6);8.16(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.22(d,JC,P=5,CH2−5´);73.26(CH−3´);76.24(CH−2´);86.31(d,JC,P=9,CH−4´);88.34(CH−1´);103.75(C−4a);121.56(C−5);122.86(CH−6);130.41(CH−p−Ph);131.59および131.94(CH−o,m−Ph);136.10(C−i−Ph);153.15(C−7a);153.67(CH−2);159.61(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−21.32(dd,J=19.3,19.0,P−);−10.45(d,J=19.3,P−);−6.98(d,J=19.0,P−).
MS(ESI、ネガティブモード):m/z 581(M−3Na+2H),603(M−2Na+H),625(M−Na)。HRMS(ESI、ネガティブモード)−:C17H20N4O13P3[M−3Na+2H]:計算値:581.0240;実測値:581.0253。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.13(dt,1H,Jgem=11.4,JH,P=J5´b,4´=4.2,H−5´b);4.25(ddd,1H,Jgem=11.4,JH,P=6.5,J5´a,4´=3.3,H−5´a);4.35(bddd,1H,J4´,5´=4.2,3.3,J4´,3´=2.7,H−4´);4.58(dd,1H,J3´,2´=5.4,J3´,4´=2.7,H−3´);4.72(dd,1H,J2´,1´=6.9,J2´,3´=5.4,H−2´);6.31(d,1H,J1´2´=6.9,H−1´);7.24(m,2H,H−m−C6H4F);7.53(m,2H,H−o−C6H4F);7.56(s,1H,H−6);8.17(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.19(d,JC,P=6,CH2−5´);73.26(CH−3´);76.21(CH−2´);86.34(d,JC,P=9,CH−4´);88.26(CH−1´);103.93(C−4a);118.57(d,JC,F=22,CH−m−C6H4F);120.54(C−5);122.83(CH−6);132.26(d,JC,F=3,C−i−C6H4F);133.44(d,JC,F=8,CH−o−C6H4F);153.24(C−7a);154.16(CH−2);159.98(C−4);164.95(d,JC,F=244,C−p−C6H4F). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−21.04(dd,J=18.9,18.4,P−);−10.39(d,J=18.9,P−);−6.12(d,J=18.4,P−).
MS(ESI、ネガティブモード):m/z 621(M−2Na+H),643(M−Na)。HRMS(ESI、ネガティブモード):C17H17FN4Na2O13P3[M−Na]:計算値:642.9779;実測値:642.9789。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.19(ddd,1H,Jgem=11.7,JH,P=4.7,J5´b,4´=3.2,H−5´b);4.28(ddd,1H,Jgem=11.7,JH,P=6.2,J5´a,4´=2.8,H−5´a);4.36(ddd,1H,J4´,5´=3.2,2.8,J4´,3´=2.9,H−4´);4.59(dd,1H,J3´,2´=5.2,J3´,4´=2.9,H−3´);4.71(dd,1H,J2´,1´=6.6,J2´,3´=5.2,H−2´);6.25(d,1H,J1´2´=6.6,H−1´);6.57(dd,1H,J4,3=3.4,J4,5=1.9,H−4−フリル);6.75(dd,1H,J3,4=3.4,J3,5=0.7,H−3−フリル);7.57(dd,1H,J5,4=1.9,J5,3=0.7,H−5−フリル);7.84(s,1H,H−6);8.08(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.14(d,JC,P=5,CH2−5´);73.28(CH−3´);76.60(CH−2´);86.40(d,JC,P=9,CH−4´);88.60(CH−1´);102.45(C−4a);108.95(CH−3−フリル);111.18(C−5);114.80(CH−4−フリル);122.05(CH−6);144.63(CH−5−フリル);150.34(C−2−フリル);152.81(C−7a);153.46(CH−2);159.28(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−21.09(dd,J=19.2,18.7,P−);−10.43(d,J=19.2,P−);−6.25(d,J=18.7,P−).
MS(ESI、ネガティブモード):m/z 593(M−2Na+H),615(M−Na)。HRMS(ESI、ネガティブモード):C15H17N4NaO14P3[M−2Na+H]:計算値:592.9846;実測値:592.9868;C15H16N4Na2O14P3[M−Na]:計算値:614.9666;実測値:614.9686;C15H14N4Na4O14P3[M−2H+Na]:計算値:658.9310;実測値:658.9321。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.14(ddd,1H,Jgem=11.7,JH,P=4.9,J5´b,4´=3.6,H−5´b);4.28(ddd,1H,Jgem=11.7,JH,P=6.9,J5´a,4´=3.6,H−5´a);4.35(td,1H,J4´,5´=3.6,J4´,3´=2.7,H−4´);4.58(dd,1H,J3´,2´=5.3,J3´,4´=2.7,H−3´);4.73(dd,1H,J2´,1´=7.1,J2´,3´=5.3,H−2´);6.30(d,1H,J1´2´=7.1,H−1´);7.21(dd,1H,J4,5=5.0,J4,3=3.5,H−4−チエニル);7.22(dd,1H,J3,4=3.5,J3,5=1.4,H−3−チエニル);7.51(dd,1H,J5,4=5.0,J5,3=1.4,H−5−チエニル);7.64(s,1H,H−6);8.18(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.20(d,JC,P=5,CH2−5´);73.22(CH−3´);76.21(CH−2´);86.40(d,JC,P=9,CH−4´);88.28(CH−1´);104.13(C−4a);113.58(C−5);123.93(CH−6);129.26(CH−5−チエニル);130.14(CH−3−チエニル);130.95(CH−4−チエニル);137.11(C−2−チエニル);153.14(C−7a);154.52(CH−2);160.04(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−21.12(bdd,J=20.5,19.4,P−);−10.41(d,J=19.4,P−);−6.23(d,J=20.5,P−).
MS(ESI、ネガティブモード):m/z 609(M−2Na+H),631(M−Na)。HRMS(ESI、ネガティブモード):C15H17N4NaO13P3S[M−2Na+H]:計算値:608.9618;実測値:608.9637。
1H NMR(600MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.14(ddd,1H,Jgem=11.2,JH,P=4.9,J5´b,4´=2.9,H−5´b);4.25(ddd,1H,Jgem=11.2,JH,P=6.4,J5´a,4´=3.1,H−5´a);4.35(ddd,1H,J4´,5´=3.2,2.9,J4´,3´=2.4,H−4´);4.57(dd,1H,J3´,2´=5.4,J3´,4´=2.4,H−3´);4.73(dd,1H,J2´,1´=6.9,J2´,3´=5.4,H−2´);6.29(d,1H,J1´2´=6.9,H−1´);6.73(dd,1H,J4,5=1.9,J4,2=0.9,H−4−フリル);7.58(s,1H,H−6);7.65(dd,1H,J5,4=1.9,J5,2=1.6,H−5−フリル);7.75(dd,1H,J2,5=1.6,J2,4=0.9,H−2−フリル);8.16(s,1H,H−2). 13C NMR(151MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.22(d,JC,P=5,CH2−5´);73.32(CH−3´);76.22(CH−2´);86.35(d,JC,P=9,CH−4´);88.24(CH−1´);104.39(C−4a);111.40(C−5);114.18(CH−4−フリル);120.38(C−3−フリル);122.84(CH−6);143.14(CH−2−フリル);147.03(CH−5−フリル);153.22(C−7a);154.35(CH−2);160.22(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−20.54(bdd,J=17.8,15.0,P−);−10.35(d,J=17.8,P−);−5.66(d,J=15.0,P−).
MS(ESI、ネガティブモード):m/z 593(M−2Na+H),615(M−Na)。HRMS(ESI、ネガティブモード):C15H16N4Na2O14P3[M−Na]:計算値:614.9666;実測値:614.9678。
1H NMR(500MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=3.75ppm):4.14(ddd,1H,Jgem=11.6,JH,P=4.8,J5´b,4´=3.5,H−5´b);4.25(ddd,1H,Jgem=11.6,JH,P=6.6,J5´a,4´=3.2,H−5´a);4.35(ddd,1H,J4´,5´=3.5,3.2,J4´,3´=2.7,H−4´);4.58(dd,1H,J3´,2´=5.3,J3´,4´=2.7,H−3´);4.74(dd,1H,J2´,1´=7.0,J2´,3´=5.3,H−2´);6.30(d,1H,J1´2´=7.0,H−1´);7.33(dd,1H,J4,5=5.0,J4,2=1.4,H−4−チエニル);7.52(dd,1H,J2,5=3.0,J2,4=1.4,H−2−チエニル);7.607(s,1H,H−6);7.610(dd,1H,J5,4=5.0,J5,2=3.0,H−5−チエニル);8.17(s,1H,H−2). 13C NMR(125.7MHz,D2O+リン酸緩衝液,pH=7.1,基準ジオキサン=69.3ppm):68.20(d,JC,P=5,CH2−5´);73.30(CH−3´);76.24(CH−2´);86.38(d,JC,P=9,CH−4´);88.28(CH−1´);104.09(C−4a);116.08(C−5);122.81(CH−6);125.88(CH−2−チエニル);130.18(CH−5−チエニル);131.28(CH−4−チエニル);136.31(C−3−チエニル);153.09(C−7a);154.20(CH−2);160.06(C−4). 31P(1H dec.) NMR(202.4MHz,D2O+リン酸緩衝液,pH=7.1,基準H3PO4=0ppm):−21.14(bdd,J=21.0,19.3,P−);−10.39(d,J=19.3,P−);−6.45(d,J=21.0,P−).
MS(ESI、ネガティブモード):m/z 609(M−2Na+H),631(M−Na)。HRMS(ESI、ネガティブモード):C15H17N4NaO13P3S[M−2Na+H]:計算値:608.9618;実測値:608.9635。
1H NMR(500MHz,D2O,基準ジオキサン=3.75ppm):3.97(dt,1H,Jgem=11.4,JH,P=J5´b,4´=4.0,H−5´b);4.00(ddd,1H,Jgem=11.4,JH,P=5.3,J5´a,4´=3.7,H−5´a);4.30(m,1H,J4´,5´=4.0,3.7,J4´,3´=3.0,JH,P=1.0,H−4´);4.44(dd,1H,J3´,2´=5.4,J3´,4´=3.0,H−3´);4.63(dd,1H,J2´,1´=6.7,J2´,3´=5.4,H−2´);6.20(d,1H,J1´,2´=6.7,H−1´);7.70(s,1H,H−6);8.08(s,1H,H−2). 13C
NMR(125.7MHz,D2O,基準ジオキサン=69.3ppm):54.97(C−5);66.81(d,JC,P=5,CH2−5´);73.50(CH−3´);76.59(CH−2´);86.74(d,JC,P=9,CH−4´);88.52(CH−1´);106.71(C−4a);129.72(CH−6);152.45(C−7a);154.24(CH−2);159.74(C−4). 31P(1H dec.) NMR(202.4MHz,D2O,基準H3PO4=0ppm):3.24.
MS(ESI、ネガティブモード):m/z 471(M−Na)。HRMS(ESI、ネガティブモード):C11H13N4IO7P:[M−Na]:計算値:470.9561;実測値:470.9576。
1H NMR(500MHz,D2O,基準ジオキサン=3.75ppm):3.91(dt,1H,Jgem=11.4,JH,P=J5´b,4´=4.4,H−5´b);3.95(ddd,1H,Jgem=11.4,JH,P=5.6,J5´a,4´=4.2,H−5´a);4.30(ddd,1H,J4´,5´=4.4,4.2,J4´,3´=2.7,H−4´);4.46(dd,1H,J3´,2´=5.4,J3´,4´=2.7,H−3´);4.75(dd,1H,J2´,1´=7.1,J2´,3´=5.4,H−2´);6.31(d,1H,J1´2´=7.1,H−1´);7.46(m,1H,H−p−Ph);7.54(m,2H,H−m−Ph);7.56(m,2H,H−o−Ph);7.58(s,1H,H−6);8.18(s,1H,H−2). 13C NMR(125.7MHz,D2O,基準ジオキサン=69.3ppm):66.53(d,JC,P=5,CH2−5´);73.61(CH−3´);76.15(CH−2´);86.94(d,JC,P=9,CH−4´);88.22(CH−1´);103.97(C−4a);121.38(C−5);122.79(CH−6);130.44(CH−p−Ph);131.72(CH−o−Ph);131.91(CH−m−Ph);136.31(C−i−Ph);153.35(C−7a);154.40(CH−2);160.15(C−4). 31P(1H dec.) NMR(202.4MHz,D2O,基準H3PO4=0ppm):4.64.
MS(ESI):m/z 445(M+H),467(M+Na)。HRMS(ESI):C17H19N4NaO7P:[M+H]:計算値:445.0884;実測値:445.0880。
1H NMR(500MHz,D2O,基準ジオキサン=3.75ppm):3.90(dt,1H,Jgem=11.4,JH,P=J5´b,4´=4.1,H−5´b);3.94(ddd,1H,Jgem=11.4,JH,P=5.6,J5´a,4´=4.1,H−5´a);4.30(tdd,1H,J4´,5´=4.1,J4´,3´=2.7,JH,P=1.1,H−4´);4.46(dd,1H,J3´,2´=5.4,J3´,4´=2.7,H−3´);4.74(dd,1H,J2´,1´=7.2,J2´,3´=5.4,H−2´);6.30(d,1H,J1´2´=7.2,H−1´);7.25(m,2H,H−m−C6H4F);7.54(m,2H,H−o−C6H4F);7.57(s,1H,H−6);8.18(s,1H,H−2). 13C NMR(125.7MHz,D2O,基準ジオキサン=69.3ppm):66.52(d,JC,P=4,CH2−5´);73.61(CH−3´);76.17(CH−2´);86.97(d,JC,P=9,CH−4´);88.20(CH−1´);104.07(C−4a);118.55(d,JC,F=22,CH−m−C6H4F);120.44(C−5);122.89(CH−6);132.35(d,JC,F=3,C−i−C6H4F);133.55(d,JC,F=8,CH−o−C6H4F);153.31(C−7a);154.45(CH−2);160.18(C−4);165.00(d,JC,F=245,C−p−C6H4F). 31P(1H dec.)
NMR(202.4MHz,D2O,基準H3PO4=0ppm):4.65.
MS(ESI、ネガティブモード):m/z 439(M−Na),461(M−H)。HRMS(ESI、ネガティブモード):C17H17FN4O7P[M−Na]:計算値:439.0813;実測値:439.0828;C17H16FN4NaO7P[M−H]:計算値:461.0633;実測値:461.0647。
1H NMR(500MHz,D2O,基準ジオキサン=3.75ppm):3.94(ddd,1H,Jgem=11.4,JH,P=4.0,J5´b,4´=2.6,H−5´b);3.98(ddd,1H,Jgem=11.4,JH,P=5.2,J5´a,4´=3.7,H−5´a);4.31(m,1H,J4´,5´=3.7,2.6,J4´,3´=2.9,JH,P=1.1,H−4´);4.47(dd,1H,J3´,2´=5.3,J3´,4´=2.9,H−3´);4.73(dd,1H,J2´,1´=6.9,J2´,3´=5.3,H−2´);6.28(d,1H,J1´2´=6.9,H−1´);6.61(dd,1H,J4,3=3.3,J4,5=1.9,H−4−フリル);6.78(dd,1H,J3,4=3.3,J3,5=0.7,H−3−フリル);7.63(dd,1H,J5,4=1.9,J5,3=0.7,H−5−フリル);7.87(s,1H,H−6);8.14(s,1H,H−2). 13C NMR(125.7MHz,D2O,基準ジオキサン=69.3ppm):66.52(d,JC,P=5,CH2−5´);73.65(CH−3´);76.41(CH−2´);87.09(d,JC,P=9,CH−4´);88.38(CH−1´);102.81(C−4a);109.23(CH−3−フリル);111.01(C−5);114.78(CH−4−フリル);122.30(CH−6);144.85(CH−5−フリル);150.56(C−2−フリル);153.34(C−7a);154.57(CH−2);160.08(C−4). 31P(1H dec.) NMR(202.4MHz,D2O,基準H3PO4=0ppm):4.37.
MS(ESI、ネガティブモード):m/z 411(M−Na),433(M−H)。HRMS(ESI、ネガティブモード):C15H16N4O8P[M−Na]:計算値:411.0700;実測値:411.0702。
MS(ESI、ネガティブモード):m/z 427(M−Na),449(M−H)。HRMS(ESI、ネガティブモード):C15H16SN4O7P[M−Na]:計算値:427.0472;実測値:427.0473。
1H NMR(500MHz,D2O,基準ジオキサン=3.75ppm):3.91(dt,1H,Jgem=11.3,JH,P=J5´b,4´=4.1,H−5´b);3.95(ddd,1H,Jgem=11.3,JH,P=5.2,J5´a,4´=4.1,H−5´a);4.30(td,1H,J4´,5´=4.1,J4´,3´=2.7,H−4´);4.46(dd,1H,J3´,2´=5.6,J3´,4´=2.7,H−3´);4.73(dd,1H,J2´,1´=7.0,J2´,3´=5.6,H−2´);6.28(d,1H,J1´2´=7.0,H−1´);6.73(dd,1H,J4,5=1.8,J4,2=0.9,H−4−フリル);7.60(s,1H,H−6);7.66(dd,1H,J5,4=1.8,J5,2=1.6,H−5−フリル);7.75(dd,1H,J2,5=1.6,J2,4=0.9,H−2−フリル);8.17(s,1H,H−2). 13C NMR(151MHz,D2O,基準ジオキサン=69.3ppm):66.51(d,JC,P=4,CH2−5´);73.66(CH−3´);76.19(CH−2´);87.04(d,JC,P=9,CH−4´);88.14(CH−1´);104.48(C−4a);111.30(C−5);114.25(CH−4−フリル);120.37(C−3−フリル);122.96(CH−6);143.22(CH−2−フリル);147.02(CH−5−フリル);153.24(C−7a);154.46(CH−2);160.30(C−4). 31P(1H dec.) NMR(202.4MHz,D2O,基準H3PO4=0ppm):4.55.
MS(ESI、ネガティブモード):m/z 411(M−Na),433(M−H)。HRMS(ESI、ネガティブモード):C15H16N4O8P[M−Na]:計算値:411.0700;実測値:411.0706;C15H15N4O8PNa[M−H]:計算値:433.0520;実測値:411.0526。
1H NMR(600MHz,D2O,基準ジオキサン=3.75ppm):3.91(dt,1H,Jgem=11.4,JH,P=J5´b,4´=4.1,H−5´b);3.95(ddd,1H,Jgem=11.4,JH,P=5.5,J5´a,4´=4.0,H−5´a);4.30(m,1H,J4´,5´=4.1,4.0,J4´,3´=2.7,JH,P=1.2,H−4´);4.46(dd,1H,J3´,2´=5.4,J3´,4´=2.7,H−3´);4.74(dd,1H,J2´,1´=7.1,J2´,3´=5.4,H−2´);6.29(d,1H,J1´2´=7.1,H−1´);7.32(dd,1H,J4,5=4.9,J4,2=1.4,H−4−チエニル);7.51(dd,1H,J2,5=2.9,J2,4=1.4,H−2−チエニル);7.608(dd,1H,J5,4=4.9,J5,2=2.9,H−5−チエニル);7.612(s,1H,H−6);8.16(s,1H,H−2). 13C NMR(151MHz,D2O,基準ジオキサン=69.3ppm):66.55(d,JC,P=5,CH2−5´);73.66(CH−3´);76.21(CH−2´);87.00(d,JC,P=9,CH−4´);88.18(CH−1´);104.18(C−4a);115.99(C−5);122.83(CH−6);125.98(CH−2−チエニル);130.186(CH−5−チエニル);131.33(CH−4−チエニル);136.34(C−3−チエニル);153.11(C−7a);154.39(CH−2);160.19(C−4). 31P(1H dec.) NMR(202.4MHz,D2O,基準H3PO4=0ppm):4.46.
MS(ESI、ネガティブモード):m/z 427(M−Na),449(M−H)。HRMS(ESI、ネガティブモード):C15H16SN4O7P:[M−Na]:計算値:427.0472;実測値:427.0474;C15H15SN4O7PNa:[M−H]:計算値:449.0291;実測値:449.0295。
本発明は、例えば、以下を提供する:
(項目1)
式Iの化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2は、アリール、ヘテロアリールまたはアルキニルであり、該アリールは、アルコキシ、アルキルチオまたはハロゲンから成る群から選択される1個または2個の置換基で任意に置換されており;
R3は、水素またはアルキルである]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目2)
式(I)の化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2は、アルコキシ、アルキルチオまたはハロゲンから成る群から選択される1個の置換基で任意に置換されているアリールであり;
R3は水素である]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目3)
R1は水素であり;R2は、(C1−C4)アルコキシ、(C1−C4)アルキルチオまたはハロゲンから成る群から選択される1個の置換基で任意に置換されているフェニルであり;R3は水素である、項目2に記載の化合物、またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目4)
式(I)の化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2は、アルコキシ、アルキルチオまたはハロゲンから成る群から選択される1個の置換基で任意に置換されているアリールであり;
R3はアルキルである]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目5)
R1は水素であり;R2は、(C1−C4)アルコキシ、(C1−C4)アルキルチオまたはハロゲンから成る群から選択される1個の置換基で任意に置換されているフェニルであり;R3は(C1−C4)アルキルである、項目4に記載の化合物、またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目6)
式(I)の化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2はヘテロアリールであり;
R3は水素であり;
但し、R2は、1,3−オキサゾール−2−イル、フラン−2−イル、1,2,4−トリアジン−3−イル、5,6−ジメチル−1,2,4−トリアジン−3−イル、5,6−ジフェニル−1,2,4−トリアジン−3−イル、1,2,4−オキサジアゾール−3−イル、4H−1,2,4−トリアゾール−3−イル、5−チオキソ−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル、4,5−ジヒドロ−1H−イミダゾール−2−イル、4−フェニルチアゾール−2−イル、1H−テトラゾール−5−イル、1,4,5,6−テトラヒドロピリミジン−2−イル、または9−オキソ−9H−インデノ[1,2−e][1,2,4]トリアジン−3−イルでないものとする]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目7)
項目6に記載の化合物[ここで、R1は水素であり;R2は(5−7)員ヘテロアリールであり;R3は水素であり;但し、R2は、1,3−オキサゾール−2−イル、フラン−2−イル、1,2,4−トリアジン−3−イル、5,6−ジメチル−1,2,4−トリアジン−3−イル、5,6−ジフェニル−1,2,4−トリアジン−3−イル、1,2,4−オキサジアゾール−3−イル、4H−1,2,4−トリアゾール−3−イル、5−チオキソ−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル、4,5−ジヒドロ−1H−イミダゾール−2−イル、4−フェニルチアゾール−2−イル、1H−テトラゾール−5−イル、1,4,5,6−テトラヒドロピリミジン−2−イル、または9−オキソ−9H−インデノ[1,2−e][1,2,4]トリアジン−3−イルでないものとする]、またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目8)
式(I)の化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2はヘテロアリールであり;
R3はアルキルであり;
但し、R2は、1,3−オキサゾール−2−イル、フラン−2−イル、1,2,4−トリアジン−3−イル、5,6−ジメチル−1,2,4−トリアジン−3−イル、5,6−ジフェニル−1,2,4−トリアジン−3−イル、1,2,4−オキサジアゾール−3−イル、4H−1,2,4−トリアゾール−3−イル、5−チオキソ−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル、4,5−ジヒドロ−1H−イミダゾール−2−イル、4−フェニルチアゾール−2−イル、1H−テトラゾール−5−イル、1,4,5,6−テトラヒドロピリミジン−2−イル、または9−オキソ−9H−インデノ[1,2−e][1,2,4]トリアジン−3−イルでないものとする]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目9)
項目8に記載の化合物[ここで、R1は水素であり;R2は(5−7)員ヘテロアリールであり;R3は(C1−C4)アルキルであり;但し、R2は、1,3−オキサゾール−2−イル、フラン−2−イル、1,2,4−トリアジン−3−イル、5,6−ジメチル−1,2,4−トリアジン−3−イル、5,6−ジフェニル−1,2,4−トリアジン−3−イル、1,2,4−オキサジアゾール−3−イル、4H−1,2,4−トリアゾール−3−イル、5−チオキソ−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル、4,5−ジヒドロ−1H−イミダゾール−2−イル、4−フェニルチアゾール−2−イル、1H−テトラゾール−5−イル、1,4,5,6−テトラヒドロピリミジン−2−イル、または9−オキソ−9H−インデノ[1,2−e][1,2,4]トリアジン−3−イルでないものとする]、またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目10)
式(I)の化合物:
[式中、
R1は、水素、モノ−、ジ−またはトリ−ホスフェートであり;
R2はアルキニルであり;
R3は水素である]
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目11)
R1およびR3は水素であり;R2はエチニルである、項目10に記載の化合物、またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目12)
下記の化合物から選択される項目1に記載の化合物:
またはその薬学的に許容されうる塩、またはその光学異性体、または光学異性体の混合物。
(項目13)
治療有効量の項目1〜12のいずれか1つに記載の化合物を被験体に投与することを含む、該被験体における腫瘍/癌成長を阻害する方法。
(項目14)
治療有効量の項目1〜12のいずれか1つに記載の化合物を被験体に投与することを含む、該被験体における腫瘍/癌細胞の細胞増殖を阻害する方法。
(項目15)
治療有効量の項目1〜12のいずれか1つに記載の化合物を被験体に投与することを含む、該被験体における細胞増殖疾患を処置する方法。
(項目16)
治療有効量の項目1〜12のいずれか1つに記載の化合物を被験体に投与することを含む、該被験体における新生物疾患を処置する方法。
(項目17)
治療有効量の項目1〜12のいずれか1つに記載の化合物を被験体に投与することを含む、該被験体における腫瘍または癌を処置する方法。
(項目18)
治療有効量の項目1〜12のいずれか1つに記載の化合物、および1つ以上の薬学的に許容されうる担体を含む医薬組成物。
(項目19)
治療有効量の項目1〜12のいずれか1つに記載の化合物;およびアントラサイクリン、DNAインターカレーター、アルキル化剤、ホルモン剤、LHRHアゴニストおよびアンタゴニスト、アロマターゼ阻害剤、抗アンドロゲン剤、化学予防剤、細胞周期化学予防剤、抗新生物剤、抗有糸分裂剤、植物アルカロイド、トポイソメラーゼI阻害剤、トポイソメラーゼII阻害剤、プロテオソーム阻害剤、ヌクレオシド類似体、サイトカイン、成長因子、抗血管新生因子から成る群から選択される第二治療剤;および1つ以上の薬学的に許容されうる担体;を含む医薬組成物。
(項目20)
被験体における腫瘍/癌成長を阻害する医薬を調製するための、項目1〜12のいずれか1つに記載の化合物の使用。
(項目21)
被験体における腫瘍/癌細胞の細胞増殖を阻害する医薬を調製するための、項目1〜12のいずれか1つに記載の化合物の使用。
(項目22)
被験体における細胞増殖疾患を処置する医薬を調製するための、項目1〜12のいずれか1つに記載の化合物の使用。
(項目23)
被験体における新生物疾患を処置する医薬を調製するための、項目1〜12のいずれか1つに記載の化合物の使用。
(項目24)
被験体における腫瘍または癌を処置する医薬を調製するための、項目1〜12のいずれか1つに記載の化合物の使用。
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