JP2009527501A - S1p受容体アゴニストとしてのフェニル−シクロアルキル誘導体およびフェニル−複素環誘導体 - Google Patents
S1p受容体アゴニストとしてのフェニル−シクロアルキル誘導体およびフェニル−複素環誘導体 Download PDFInfo
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- JP2009527501A JP2009527501A JP2008555537A JP2008555537A JP2009527501A JP 2009527501 A JP2009527501 A JP 2009527501A JP 2008555537 A JP2008555537 A JP 2008555537A JP 2008555537 A JP2008555537 A JP 2008555537A JP 2009527501 A JP2009527501 A JP 2009527501A
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
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- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
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- 238000011200 topical administration Methods 0.000 description 1
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- 230000008733 trauma Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
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Abstract
【化27】
【選択図】図1
Description
本出願は2006年2月21日出願の仮出願No. 60/775,309の優先権を主張し、その開示は参照によってその全容が組み込まれる。
本発明はNational Institutes of Healthによって授与されたGrant No. R01 GM067958において米国政府支援の下で行われた。米国政府は本発明についての一定の権利を有する。
それにより、各サブユニットはエフェクタータンパク質と結合できるようになる。エフェクタータンパク質は、細胞応答をもたらす二次メッセンジャーを活性化する。最終的に、Gタンパク質のGTPはGDPに加水分解され、Gタンパク質のサブユニットは相互に再結合し、その後受容体と再結合する。増幅は一般的なGPCR経路において重要な役割を果たす。一つのリガンドの一つの受容体への結合は、多くのGタンパク質の活性化につながり、そのGタンパク質の各々は、増幅された細胞応答をもたらす多くのエフェクタータンパク質と結合することができる。
環基、もしくはヘテロアリール基のいずれかは、1、2、3、もしくは4個の置換基で随意に置換され、ここで置換基は独立にオキソ基(=O)、イミノ基(=NRd)、(C1-C10)アルキル基、(C1-C10)アルコキシ基、もしくはC6-アリール基であり、あるいはR2アルキル基の炭素原子の一つ以上は、過酸化物の酸素ではない酸素(non-peroxide oxygen)、硫黄、もしくはNRcで独立に置換することができる。R3のアルキル基は、1もしくは2個のヒドロキシ基で随意に置換され、RcおよびRdは独立に水素もしくは(C1-C10)アルキル基である。本発明は、構造式Iもしくは構造式IIの化合物の薬学的に許容可能な塩もしくはエステルを含む。
などの外傷や切断(例えば幻肢痛)を含み得る。神経因性疼痛は、例えばビンクリスチンやパクリタキセル(TAXOLTM)などの薬物治療の副作用によって起こる可能性があり、あるいは1型糖尿病や2型糖尿病、帯状疱疹、HIV-1感染などの疾病病変の一部として起こる可能性がある。通常は、神経因性疼痛はアスピリンなどの鎮静剤や非ステロイド性抗炎症薬には反応しない。
、置換基、および範囲に対して下記に列挙した特定の好ましい値は一例に過ぎず、ラジカルと置換基の規定範囲内のその他の値もしくはその他の規定値を除外するものではない。
ト、ホスホロジチオエート、ホスホロセレノエート、ホスホロジセレノエート、ホスホロアニロチオエート、ホスホロアニリデート、ホスホラミデート、ボロノホスフェートなどを含み、例えば水素、NH4、Na、Kなどの付随する対イオンを、こうした対イオンが存在する場合に含む。
ン酸塩、α-ケトグルタル酸塩、および、α-グリセロリン酸塩)である。塩酸塩、硫酸塩、硝酸塩、重炭酸塩、炭酸塩を含む無機塩も形成され得る。
を含む。有用な液体担体は、水、アルコール、もしくはグリコール、もしくは水‐アルコール/グリコール混合物を含み、その中に本発明の化合物が、随意に非毒性の界面活性剤を用いて、効果的なレベルで溶解もしくは分散することができる。香料および追加の抗菌剤などのアジュバントを、所定の使用のために特性を最適化するために付加することができる。得られる液体組成物は、吸収パッドから適用することができ、包帯およびその他の包帯剤に浸透させるために使用することができ、あるいは、ポンプタイプもしくはエアロゾルスプレーを用いて患部上にスプレーすることができる。
酢酸パラジウム(II)(0.23g、0.1eq)および塩化アンチモン(III)(0.23g、0.1eq)を、2-シクロペンテン-1-オン(2)(0.82g、10mmol)、酢酸ナトリウム(1.6g、20mmol)および4-シアノフェニルボロン酸(1)(1.46g、10mmol)を含む80mLの酢酸溶液に窒素下で加える。反応混合物を24時間25℃で攪拌し、黒色沈殿物をろ別する。ろ液を250mLのブラインで希釈し50mLの塩化メチレンで2回抽出する。有機相を飽和重炭酸塩溶液と30分攪拌し、ブラインで洗浄し、硫酸マグネシウム上で脱水する。溶媒を除去し、化合物Aを得るためにクロマトグラフィーで処理を行う。
酢酸パラジウム(II)(0.23g、0.1eq)および塩化アンチモン(III)(0.23g、0.1eq)を、2-シクロペンテン-1-オン(2)(0.82g、10mmol)、酢酸ナトリウム(1.6g、20mmol)および4-tert-ブチルジメチルシリルオキシフェニルボロン酸(4)(2.54g、10mmol)を含む80mLの酢酸溶液に窒素下で加える。反応混合物を24時間25℃で攪拌し、黒色沈殿物をろ別する。ろ液を250mLのブラインで希釈し50mLの塩化メチレンで2回抽出する。有機相を飽和重炭酸塩溶液と30分攪拌し、ブラインで洗浄し、硫酸マグネシウム上で脱水する。溶媒を除去し、3-(4'-ヒドロキシフェニル)シクロペンタノンを得るためにクロマトグラフィーで処理を行う。
化合物A(1.0mmol)を95%エタノール(1.5mL)に溶解する。トリエチルアミン(2.3mmol)およびヒドロキシルアミン塩酸塩(2.2mmol)を加えて、反応混合物を3時間約75℃に加熱する。反応の進行はTLCでモニターできる。一般に、約3時間後に、出発物質のニトリルは残存しない。その溶液を、スラリーになるまで濃縮した後、水もしくは有機溶媒から(the solution is concentrated to a slurry and from water, or an organic solvent)。固体をろ別し、冷水で洗浄し、真空圧乾燥することにより粗生成物が得られる。粗生成物は、さらに精製を行わずに次のステップで使用することができる。
4-イソブチル安息香酸(3)(0.150mmol)を乾燥した塩化メチレン(4mL)に溶かした溶液に、(ベンゾトリアゾール-1-イルオキシ)トリピロリジノホスホニウムヘキサフルオロリン酸(PyBOP)(0.150mmol)およびジイソプロピルエチルアミン(0.150mmol)を加え、その後、アルドキシミノフェニル誘導体(化合物B)(0.150mmol)を加える。反応物を室温で約12〜16時間攪拌する。混合物をジエチルエーテル(15mL)で希釈し、塩化アンモニウム飽和水溶液(2×5mL)およびブライン(5mL)で洗浄し、真空で濃縮する。カラムクロマトグラフィーによって、化合物Cを精製する。
スキーム1に概要を示した手順によって合成されたシクロペンタノン中間体を、国際出願WO 2006/088944 A1の37〜39ページに記載された3ステップの手順によって、1-アミノ-1-ヒドロキシメチル-3-(4'-置換フェニル)シクロペンタン(化合物VIII〜XIII)に変換することができる。この手順は、図3に化合物VIIIの合成について図説されている。IX〜XIIIを合成するためのシクロペンタノン前駆体は、同様の方法で変換することができる。
シクロペンタノン中間体(11.8mmol)、シアン化ナトリウム(0.15g、23.5mmol)および塩化アンモニウム(1.25g、23.5mmol)を20mLのアンモニア水溶液に加える。混合物を一晩、激しく振とうする。終了後、反応混合物を10mLの塩化メチレンで2回抽出する。有機相を硫酸マグネシウム上で乾燥し、濃縮するとアミノニトリルDが得られる。粗生成物
は、さらに精製することなく、次のステップで使用する(J. Med. Chem, 1986, 29, 1988-1995を参照)。
ステップ1で得られた粗生成物(〜11.2mmol)および50mL濃塩酸を、アルゴン雰囲気下もしくは窒素雰囲気下で約70℃に加熱し、一晩攪拌する。得られた水溶液を蒸発乾固する。水10mLを加え、再度、乾燥する。この過程を2回繰り返す。粗生成物を冷水とアセトンで洗浄すると、化合物Eが得られる。
ステップ2で得られた生成物(0.20mmol)および水素化ホウ素ナトリウム(27mg、0.6mmol)を3mLのテトラヒドロフランに溶解する。その溶液を約0℃まで冷却した後、1mLのテトラヒドロフランに溶かした51mg(0.2mmol)のヨウ素を1滴ずつ加える。容器に冷却管を取り付け、反応混合物をアルゴン下で5時間還流する。過剰の水素化ホウ素ナトリウムをメタノールでクエンチする。溶媒を真空で蒸発させて除去した後で、2mLの水および5mLの塩化メチレンを混合物に加え、約1時間攪拌する。有機相を回収し、水相を塩化メチレンで2回抽出する。有機相を混合し、脱水し、濃縮すると粗生成物が得られる。カラムクロマトグラフィーによってさらに精製すると、精製された化合物が得られる。
アルコールVIII〜XIIIは、以下の手順により対応するリン酸エステルに変換することができる。1mLの85%リン酸水溶液を0.5gの五酸化リンにゆっくりと加え、窒素下で1時間、100℃に加熱する。さらに0.5gの五酸化リンおよび30mgのアルコールVIII(もしくはIX〜XIII)を混合物に加え、反応物をさらに5時間加熱する。室温まで冷却した後、10mLの氷冷水を反応混合物に加える。生成物を沈殿物として回収する。生成物を回収し、水で洗浄し、その後、真空乾燥する。
組み換えスフィンゴシンキナーゼタイプ2(SPHK2)は、関連プラスミドDNAをHEK293T細胞もしくはCHO K1細胞に導入することによって、マウスもしくはヒトの組み換え酵素の発現を強制することによって調製される。60時間後、細胞を採取し、破壊された非ミクロソーム(例えば溶解性の)画分が保持される。組み換え酵素を含む破壊細胞の上澄みを、試験化合物(FTY720、AA151、VIIIおよびXVIII)(5〜50μM)とγ-32P-ATPと混合し、37℃で0.5〜2.0時間インキュベートする。反応混合物中の脂質を有機溶媒に抽出し、順相薄層クロマトグラフィーで示す。放射性標識したバンドをオートラジオグラフィーで検出し、プレートから擦り取ってシンチレーション計数で定量化する。試験化合物は約50μMの濃度であった。インキュベーション時間は約20分であった。
このアッセイは、単独でのGタンパク質共役受容体(GPCR)のアゴニスト活性を説明す
る。このアッセイは、それぞれのタンパク質をコードする四つのプラスミドDNAを細胞に導入することによって、HEK293T細胞における、組み換えGPCR(例えばS1P1-5受容体)、およびヘテロ三量体Gタンパク質の三つのサブユニット(典型的にはα-i2、β-1、もしくはγ-2)の各々の発現を同時に強制する。導入から約60時間後、細胞を採取し、破壊し、核を除去する。粗ミクロソームを残留物から精製する。ミクロソーム上の受容体-Gタンパク質複合体のアゴニスト(例えばS1P)刺激は、用量依存的なやり方でα-サブユニット上のGTPからGDPへの交換をもたらす。GTP結合α-サブユニットは、GDPに加水分解されない放射性核種(硫黄35)標識ホスホチオネート(phosphothionate)である、GTPアナログ(GTPγS-35)を用いて検出される。Gタンパク質が付着したミクロソームはろ過によって回収され、結合したGTPγS-35が液体シンチレーションカウンターで定量化される。アッセイは相対効力(relative potency:EC50値)と最大効価(maximum effect:有効性、Emax)を与える。アンタゴニスト活性は、一定量のアンタゴニストの存在下で、アゴニストの用量‐反応曲線の右方向のシフトとして検出される。アンタゴニストが競合的に作用する場合、受容体/アンタゴニストの対の親和性(Ki)を決定できる。アッセイは、Davis, M.D., J.J. Clemens, T.L. Macdonald and K.R. Lynch (2005) "S1P Analogs as Receptor Antagonists" Journal of Biological Chemistry, vol. 280, pp.9833-9841に記載されているように実施した。
化合物(例えば一級アルコール試験化合物)を2%ヒドロキシプロピルβ-シクロデキストリンに溶解し、体重あたり0.01、1.0および10 mg/kgの投与量で強制経口投与によってマウス群に導入する。例えば24時間、48時間もしくは96時間などの間隔をあけた後、マウスを軽度麻酔して、ca. 0.1 mlの血液を眼窩静脈叢(orbital sinus)から採取する。リンパ球の数(マイクロリットルの血液あたり1000のオーダーで;通常は4-11)を、Hemavet blood analyzerを用いて測定した。
マウスに試験化合物(静脈内、3 mg/kg)、もしくは溶媒(2%ヒドロキシプロピルβ-シクロデキストリン)を投与し、投与1時間後に心拍数を測定した。心拍数は、ECGenieTMシステムを用いて、非拘束状態の意識のある動物で記録した。
Claims (26)
- 構造式Iあるいは構造式IIの化合物または薬学的に許容されるそれらの塩もしくはエステルであって、
R1は、水素、ハロ基、(C1-C10)アルキル基、(C1-C10)ハロアルキル基、もしくは、(C1-C10)アルコキシ基で;
R2は構造式III、IV、VもしくはVIを持つ基であって、
さらにここで、R1のアルキル基は1、2、3、もしくは4個の置換基で随意に置換され、置換基は独立にアリール基、(C1-C10)アルコキシ基もしくはシアノ基であり;R2のアル
キル基、アルケニル基、アルキニル基、シクロアルキル基、アリール基、複素環基、もしくはヘテロアリール基は、1、2、3、もしくは4個の置換基で随意に置換され、置換基は独立にオキソ基(=O)、イミノ基(=NRd)、(C1-C10)アルキル基、(C1-C10)アルコキシ基、もしくはC6-アリール基であるか、または、R2アルキル基の1つ以上の炭素原子は、独立に、過酸化物ではない酸素、硫黄、もしくは、NRcで置換され;R3のアルキル基は1個もしくは2個のヒドロキシル基で随意に置換され;Rdは水素もしくは(C1-C10)アルキル基である。 - R1は、水素、フッ素、塩素、臭素、トリフルオロメチル基、メトキシ基、(C1-C6)アルキル基、(C1-C6)ハロアルキル基、または、アルコキシ基、シアノ基、もしくは、アリール基で置換された(C1-C6)アルキル基
であることを特徴とする請求項1に記載の化合物。 - R1は、水素、トリフルオロメチル基、もしくは、-CH2CF3であることを特徴とする請求項2に記載の化合物。
- R1は、ベンジル基、フェニルエチル基、もしくは、メチルベンジル基であることを特徴とする請求項2に記載の化合物。
- R2は、
- R2が
- R2が
- R2が
- R2が
- R2が
- R2が構造式IVの構造
- R2が
- X1、Y1、および、Z1の各々がCもしくはCH2であることを特徴とする請求項1〜12のいずれか一項の化合物。
- R3が水素、メチル基、ヒドロキシメチル基、エチル基、ヒドロキシエチル基、プロピル基、もしくはイソプロピル基であることを特徴とする請求項1〜13のいずれか一項に記載の化合物。
- R3が水素、メチル基、ヒドロキシメチル基、エチル基、もしくは、ヒドロキシエチル基、であることを特徴とする請求項14に記載の化合物。
-
-
- 哺乳類における病態もしくは症状の予防もしくは処置のための方法であり、スフィンゴシン-1-リン酸受容体の活性が関係し、かつそのような活性のアゴニズムが要求され、前記哺乳類に請求項1〜17のいずれか一項に記載の化合物の有効量を投与するステップを含むことを特徴とする方法。
- 前記病態が自己免疫疾患であることを特徴とする請求項18に記載の方法。
- 前記自己免疫疾患が、ブドウ膜炎、I型糖尿病、関節リウマチ、炎症性腸疾患、もしくは多発性硬化症であることを特徴とする請求項19に記載の方法。
- 前記自己免疫疾患が多発性硬化症であることを特徴とする請求項20に記載の方法。
- 前記病態がリンパ球トラフィッキングの変化であることを特徴とする請求項21に記載の方法。
- 前記処置がリンパ球トラフィッキングの変化であることを特徴とする請求項22に記載の方法。
- リンパ球トラフィッキングが同種移植片生着の延長をもたらすことを特徴とする請求項23に記載の方法。
- 前記同種移植片が移植用であることを特徴とする請求項24に記載の方法。
- 哺乳類における病態もしくは症状の予防もしくは処置のための方法であって、S1Pリアーゼ活性が関与し、かつ前記S1Pリアーゼの阻害が要求され、前記哺乳類に請求項1〜17のいずれか一項に記載の化合物の有効量を投与するステップを含むことを特徴とする方法。
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