JP6892457B2 - 3−デスオキシ誘導体およびその医薬組成物 - Google Patents
3−デスオキシ誘導体およびその医薬組成物 Download PDFInfo
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- JP6892457B2 JP6892457B2 JP2018547355A JP2018547355A JP6892457B2 JP 6892457 B2 JP6892457 B2 JP 6892457B2 JP 2018547355 A JP2018547355 A JP 2018547355A JP 2018547355 A JP2018547355 A JP 2018547355A JP 6892457 B2 JP6892457 B2 JP 6892457B2
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Description
特定の実施形態では、例えば、以下が提供される:
(項目1)
以下の構造の化合物:
またはその薬学的に許容できる塩もしくはアミノ酸抱合体。
(項目2)
項目1に記載の化合物の遊離酸。
(項目3)
項目1に記載の化合物の薬学的に許容できる塩。
(項目4)
前記アミノ酸がグリシンまたはサルコシンである、項目1に記載の化合物のアミノ酸抱合体。
(項目5)
項目1に記載の化合物および薬学的に許容できる担体または賦形剤を含む医薬組成物。
(項目6)
FXRにより活性化される疾患または病態を治療または予防する方法であって、それを必要とする対象に、有効量の項目1に記載の化合物を投与することを含み、FXRにより活性化される前記疾患または病態が、心血管疾患、慢性肝疾患、脂質疾患、胃腸疾患、腎疾患、代謝疾患、がん、および神経疾患から選択される方法。
「医薬組成物」とは、対象への投与に好適な形態の本発明の化合物を含有する製剤である。一実施形態では、医薬組成物は、バルクまたは単位剤形である。投与を容易にし、投与量を均一にするために、組成物を単位剤形に製剤化することが有利であり得る。本明細書で使用される単位剤形とは、処置されることになる対象への単位投与量として適した、物理的に個別の単位を指し、各単位は、必要な医薬担体と共同して所望の治療効果を生じるように計算された所定量の活性な試薬を含有する。単位剤形の仕様は、活性な試薬に独自の特徴、達成されるべき特定の治療効果、および各個体を処置するための活性剤などの調合に関する当技術分野に固有の制限によって決定され、これらに直接的に依存する。
本発明の化合物は、ヒトを含む哺乳動物などの対象の療法に有用である。特に、本発明の化合物は、対象の疾患または病態を処置または予防する方法であって、それを必要とする対象に、本発明の化合物、またはその薬学的に許容される塩、もしくはアミノ酸抱合体の有効量を投与するステップを含む方法において有用である。一実施形態では、疾患または病態はFXRにより活性化される(例えば、FXRが、疾患または病態の開始または進行において役割を担う)。一実施形態では、疾患または病態は、心血管疾患、慢性肝疾患、脂質障害、胃腸疾患、腎疾患、代謝性疾患、がんおよび神経系疾患から選択される。
肝線維症の現行療法は主として、病因の除去、例えば過剰な鉄の除去(例えばヘモクロマトーシスの場合)、ウイルス量の低減(例えば慢性ウイルス性肝炎の場合)、または毒素への曝露の排除または低減(例えば、アルコール性肝疾患の場合)に向けられている。コルチコステロイドおよびコルヒチンなどの抗炎症薬も、肝線維症に至ることがある炎症の処置に使用されることが知られている。当技術分野において公知のとおり、肝線維症は、通常、生検材料の組織学的検査に基づいて、臨床的に5段階の重症度(S0、S1、S2、S3およびS4)に分類することができる。S0は線維症を示さず、S4は肝硬変を示す。肝線維症の重症度を病期分類するための様々な基準が存在するが、一般に、初期段階の線維症は、肝臓の一門脈(帯域)における、不連続な限局領域の瘢痕化によって特定され、後期段階の線維症は、架橋線維症(肝臓の各帯域にわたる瘢痕化)によって特定される。
実施例1.化合物1の合成
化合物1を、スキーム1に記載の手順に従って、7α,11β−ジヒドロキシ−6α−エチル−5β−コラン−24−酸(A1)を出発材料として調製した。A1は、当技術分野において公知である方法により調製した。例えば、A1は、PCT公報国際公開第2014/184271号パンフレットに記載の手順により調製できる。
A1(0.46mmol)およびp−TSA(0.046mmol)のMeOH(5mL)溶液を一晩反応させた。溶媒を減圧下で除去し、残渣を酢酸エチル(10mL)に溶解させ、NaHCO3の飽和溶液により中性pHになるまで洗浄した。水相をEtOAcで抽出し、合わせた有機層をブラインで洗浄し、無水Na2SO4で乾燥させ、真空下で濃縮した。粗製物をトルエン(6.5mL)に溶解させ、フェティゾン試薬と共に18時間還流した。混合物をセライトパッドで濾過し、濾液を真空下で濃縮して、さらに精製せずに次の工程に使用した。
1H−NMR(400MHz,CDCl3):δ 0.87−0.95(9H,m,CH3−18,CH3−21,CH3−26),1.23(3H,s,CH3−19),3.0(1H,t,J=14.2Hz,CH−4),3.65(3H,s,COOCH3),3.87(1H,s,CH−7),4.32(1H,s,CH−11).
メチル7α,11β−ジヒドロキシ−6α−エチル−3−オキソ−5β−コラン−24−オエート(A2)(150mg)を、NaOHのメタノール溶液と共に一晩撹拌した。溶媒を減圧下で蒸発させ、残渣を水に溶解させ、Et2Oで洗浄した。水相をHCl 3NでpH 1に酸性化し、CHCl3で抽出し、回収した有機層をH2O、ブラインで洗浄し、無水Na2SO4で乾燥させ、真空下で濃縮した。粗製物を、石油エーテルと酢酸エチルの混合物を溶離溶媒系として使用してシリカゲルのフラッシュクロマトグラフィーにより精製した。7α,11β−ジヒドロキシ−6α−エチル−3−オキソ−5β−コラン−24−酸(0.21mmol)のエチレングリコール(2mL)中の懸濁液を、KOH(0.518mmol)およびNH2NH2・H2O(2.07mmol)と共に30時間還流した。混合物を室温に冷却し、H2Oで希釈し、Et2O(3×5mL)で洗浄した。HCl 3NによるpH 1への酸性化の後、水相をEtOAcで抽出し、回収した有機層をH2O、ブラインで洗浄し、無水Na2SO4で乾燥させ、減圧下で濃縮した。粗製物を、H2O−MeOHを溶離溶媒系として使用して逆相C18フラッシュクロマトグラフィーにより精製し、このように7α,11β−ジヒドロキシ−6α−エチル−5β−コラン−24−酸(1)を白色の固体として得た。
1H−NMR(400MHz,CD3OD):δ 0.87−0.92(6H,m,CH3−18,CH3−25),1.00(3H,d,J=6.4Hz,CH3−21),1.14(3H,s,CH3−19),3.73(1H,s,CH−7),4.19(1H,s,CH−11).13C−NMR(100.6MHz,CD3OD):12.1,14.7,19.0,23.2,23.5,24.7,25.5,28.6,29.0,29.1,34.1,36.3,37.5,37.8,38.3,38.5,38.8,42.8(x2),50.1,51.5,52.3,58.1,69.3,71.8,183.6.
一般に、化合物の薬物候補としての見込みは、当技術分野において公知の種々のアッセイを使用して評価することができる。例えば、FXRのin vitro検証では、その活性および選択性はAlphaScreen(生化学アッセイ)を使用して評価することができ、遺伝子発現はRT−PCR(FXR標的遺伝子)を使用して評価することができ、細胞毒性(例えばHepG2)は、ATP含量、LDH放出およびカスパーゼ−3活性化を使用して評価することができる。TGR5のin vitro検証では、その活性および選択性は、HTR−FRET(細胞ベースアッセイ)を使用して評価することができ、遺伝子発現は、RT−PCR(TGR5標的遺伝子(すなわちcFOS))を使用して評価することができ、細胞毒性(例えばHepG2)は、ATP含量、LDH放出およびカスパーゼ−3活性化を使用して評価することができる。以下の化合物を、下記の実施例において対照として使用した。
核内で、リガンドが結合した核内受容体(NR)は、基底転写機構と直接相互作用することにより、または活性化補助因子と呼ばれる架橋因子と接触することにより、転写の開始を調節する(Onate,et al.,Science,1995,270,1354−1357;Wang,et al.,J Biol Chem,1998,273,30847−30850;およびZhu,et al.,Gene Expr,1996,6,185−195)。NRの、その活性化補助因子とのリガンド依存性の相互作用は、受容体のリガンド結合ドメイン(LBD)に位置する活性化機能2(activation function 2:AF−2)と、活性化補助因子に位置する核内受容体ボックス(NRボックス)の間で発生する(Nolte,et al.,Nature,1998,395,137−143)。NRボックス中に存在するLXXLLペプチド配列は、様々なタンパク質のAF−2領域との相互作用を容易にするシグネチャーモチーフとなることが、複数の証拠によって実証されている(Heery,et al.,Nature,1997,387,733−736;およびTorchia,et al.,Nature,1997,387,677−684)。
AlphaScreenアッセイを利用して、代謝経路に関与する以下の核内受容体に対する化合物1の選択性を評価できる:LXRα、LXRβ、PXR、CAR、PPARα、PPARδ、PPARγ、RAR、RARα、VDR、TR、PR、RXRα、GR、およびER。
化合物1がFXR標的遺伝子を調節する能力を評価するために、定量的RT−PCRアッセイを行う(図1を参照)。本発明の化合物が内在性FXR遺伝子ネットワークを調整することができるかどうかを判定するのに適切な細胞株として、HepG2細胞を選択する。本発明の化合物がFXR標的遺伝子を誘導する能力は、1μΜの比較化合物および本発明の化合物で終夜処理した細胞から全RNAを単離することによって査定される。化合物Aは強力なFXR選択的アゴニストとして確立しており、化合物Bは強力な二重FXR/TGR5アゴニストとして確立している。
化合物1のin vitro細胞毒性を評価するために、2つの異なるアッセイ法を使用する。これらのアッセイは、ATP値を測定することによって細胞生存率を評価し、LDH放出を測定することによって細胞毒性を評価する。アデノシン三リン酸(ATP)ヌクレオチドは、あらゆる細胞内で補酵素として使用される多官能性分子であり、ミトコンドリアのDNAの不可欠部分であるため、基本的分子レベルでのエネルギー源である(Kangas,et al.,Medical Biology,1984,62,338−343;Crouch,et al.,J Immunol.Methods,1993,160,81−88;およびPetty,et al.,J Biolumin.Chemilumin.1995,10,29−34)。それは、細胞内エネルギー移動に関して、「分子単位の通貨」と呼ばれている。これは代謝におけるATPの重要な役割を確言するものであり、ATP含量の低下は、細胞傷害が現れる最初の段階である(Storer,et al.,Mutation Research,1996,368,59−101;およびCree and Andreotti,Toxicology In−Vitro,1997,11,553−556)。細胞生存率を、試験化合物の暴露時間および濃度に関連した細胞内ATPの測定値として決定する(Sussman,Promega Cell Notes,Issue 3,2002)。
化合物1の薬物・薬物相互作用の可能性を評価するために、主要な6種のCYP450アイソフォーム(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4)を調査する(Obach,et al.,J Pharmacol.Exp.Ther,2006,316,336−348)。
イオンチャネル機能を判定するために、Predictor(商標)hERG蛍光偏光アッセイは、試験化合物がhERGチャネルを遮断する傾向の初期判断に有効な方法となるため、これを使用する(Dorn,et al.J Biomol.Screen,2005,10,339−347)。このアッセイは、hERGカリウムチャネル活性が、永久にトランスフェクトした細胞中で静止膜電位をもたらすという仮定に基づいており、このため、hERGチャネルを遮断すると、細胞膜の脱分極が起こるはずとなる。このアッセイは、パッチクランプ電気生理学試験と正確に相関するデータを生成することによって、潜在的なhERGチャネル遮断剤を特定するように設計される。Predictor(商標)アッセイの結果は、パッチクランプ法から得られたものと高い相関性を示す(Dorn,et al.J Biomol Screen,2005,10,339−347)。
Pgp ATPアーゼ活性に対する化合物1の影響を、製造者の標準的なプロトコルに従ってPgp−Glo(商標)アッセイで(Technical Bulletin;Pgp−GloTM Assay Systems Instructions for Use of Products V3591 and V3601;2015年11月改定)検討した。
水溶性、臨界ミセル濃度、表面張力、およびLogPAなどの化合物1の生理化学的性質を、当技術分野において公知である方法を利用して決定した。データを表9に与える。
目的および原理:化合物の構造修飾は、その肝臓取り込み、肝臓輸送、ならびに分泌および腸内吸収に影響を与える。したがって、静脈内または十二指腸投与後の胆汁分泌とその代謝の知識は、追加の試験の候補選択における要点である。腸内吸収の様式および効率を評価するため、化合物1を、静脈内(大腿部注入)と経口(十二指腸注入)の両方で、同じ投与量で投与し、その胆汁分泌速度を胆汁瘻ラットモデルで評価する。胆汁産生に対する胆汁分泌促進作用も評価する。静脈内と十二指腸投与の間の時間に対する胆汁分泌の曲線下面積(AUC)の差はその腸内吸収を説明し(account of)、そのバイオアベイラビリティについての情報を与える。さらに、肝臓代謝と腸代謝もきわめて異なっている可能性があり、したがって、化合物1の胆汁分泌ならびにその主な(腸の)および肝臓の代謝物を決定する。
胆汁瘻ラットモデルを、University of Bologna Lab facilitiesで開発する。化合物1を、約1μmol/kg/分(1時間注入)の投与量で、ラットの群に十二指腸注入(id)により投与する。ラットは、注入の前またはその間の異なる時点で胆汁試料を回収するための胆汁瘻を有する。十二指腸注入実験のために、ラット(250±10g)を処置する。胆汁試料を15分ごとに4時間回収する。さらに、3匹の対照ラットを、同じ時間およびサンプリングの条件下で食塩水により処置する(十二指腸対照ラット)。
大腿部注入実験のために、ラットを、約lμmol/分/kgの化合物1により処置する。大腿部注入は、約75分の定常状態後に開始し、約60分間継続する。胆汁試料を約15分ごとに4時間回収する。さらに、ラットを、同じ時間およびサンプリングの条件下で食塩水により処置する(大腿部対照ラット)。
Claims (9)
- 請求項1に記載の化合物の遊離酸。
- 請求項1に記載の化合物の薬学的に許容できる塩。
- 請求項1に記載の化合物および薬学的に許容できる担体または賦形剤を含む医薬組成物。
- FXRにより活性化される疾患または病態を治療または予防するための組成物であって、有効量の請求項1に記載の化合物を含み、前記組成物は、それを必要とする対象に投与されることを特徴とし、FXRにより活性化される前記疾患または病態が、心血管疾患、慢性肝疾患、脂質疾患、胃腸疾患、腎疾患、代謝疾患、がん、および神経疾患から選択される組成物。
- 前記疾患が慢性肝疾患である、請求項5に記載の組成物。
- 前記慢性肝疾患が、原発性胆汁性肝硬変(PBC)(原発性胆汁性胆管炎(PBC)としても知られる)、脳腱黄色腫症(CTX)、原発性硬化性胆管炎(PSC)、薬物性胆汁うっ滞、妊娠性肝内胆汁うっ滞、非経口栄養関連胆汁うっ滞(PNAC)、細菌過剰増殖または敗血症関連胆汁うっ滞、自己免疫性肝炎、慢性ウイルス性肝炎、アルコール性肝疾患、非アルコール性脂肪性肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、肝臓移植関連移植片対宿主病、生体ドナー移植肝再生、先天性肝線維症、総胆管結石症、肉芽腫性肝疾患、肝内または肝外悪性病変、シェーグレン症候群、サルコイドーシス、ウィルソン病、ゴーシェ病、ヘモクロマトーシスおよびα1−アンチトリプシン欠損症から選択される、請求項6に記載の組成物。
- 前記慢性肝疾患が、NAFLDである、請求項7に記載の組成物。
- 前記慢性肝疾患が、NASHである、請求項7に記載の組成物。
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