JP2022524756A - 置換された二環式および四環式キノン類および関連する使用方法 - Google Patents
置換された二環式および四環式キノン類および関連する使用方法 Download PDFInfo
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Abstract
Description
本発明は、国立衛生研究所より授与されたCA188252に基づく政府支援によりなされた。米国政府は、本発明において一定の権利を有する。
本発明は、医薬化学の分野に属する。特に、本発明は、例えば活性酸素種の誘導を通した抗増殖活性を有する二環式および四環式キノン骨格を有する低分子化合物に関する。本発明はさらに、癌(例えば、膵癌、白血病、非小細胞肺癌、結腸癌、中枢神経系癌、黒色腫、卵巣癌、乳癌、腎癌、および前立腺癌)を治療するためのこれらの化合物を製造するためのプロセス、使用するための方法に関する。
癌は、ヨーロッパおよび北米における死亡原因の第2位である。手術、放射線、化学療法および免疫療法は、様々な癌を治療する際の主要なアプローチである。過去10年間に著しい進歩がみられたが、ほとんどの癌では依然として治癒率は非常に低い。したがって、これらの破壊的な疾患を有する患者の生存を高めるために、新規治療薬が緊急に必要とされている。癌細胞は、複数のシグナル伝達経路およびネットワークを変化させる進化の過程で、多数の突然変異を蓄積する。したがって、複数の標的を有する、複数の薬物の組み合わせまたは単一の化合物の組み合わせは、単剤薬物と比較して優れた活性を示す傾向がある。試験された様々な種類の低分子薬物の中で、キノン含有化合物は、処理された細胞における酸素消費速度が有意に増加することに起因して、非常に有望であった。キノンは、それらの酸化還元、金属キレート化、および、場合によってはマイケル付加による求核試薬に対する反応性のために、様々な経路を阻害することができる。キノン部分を含む24を超える薬物が、FDAによって承認されているか、または腫瘍学だけでなく他の疾患についても臨床研究中である。たとえば、ドキソルビシンおよびその数十の類似体、ミトキサントロン、ならびにマイトマイシンCは、キノン基を含む、多数の癌に対してFDAが承認し使用される化学療法剤の最も一般的なものの一部である。
癌細胞における変異レドックスホメオスタシスは、腫瘍に干渉する新たな機会を提供する。活性酸素種(ROS)は、ミトコンドリア呼吸による天然副産物であり、細胞シグナル伝達におけるセカンドメッセンジャーとして重要な役割を果たす。腫瘍細胞において、抗酸化酵素は、内在性ROSのレベル上昇の結果として、しばしば活性である。変異レドックスホメオスタシスは、腫瘍において、誘導された酸化ストレスに対して腫瘍をより感受性にし、その抗酸化適応能を制圧し、ROS媒介細胞の死を誘発する。
図1:NCI60細胞株における化合物1の成長阻害(%コントロール)。
本明細書中で使用される場合、用語「抗癌剤」は、(例えば哺乳動物において、例えばヒトにおいて)癌などの過剰増殖性疾患の治療に使用される、任意の治療薬(例えば、化学療法化合物および/または分子治療化合物)、アンチセンス療法、放射線療法または外科的介入を指す。
改善された代謝安定性、溶解性、および薬物動態特性を有する、二環式および四環式キノン骨格を有する合成された種々の新規な低分子を開発する過程で、実験が行われた。実際に、実施例IIIに記載されるように、本発明の種々の化合物は、種々の癌細胞株の成長を阻害することが示された(表2、3、4および5;図1、2、3、4および5を参照のこと)。
以下の実施例は、本発明の化合物、組成物および方法を例示するものであり、限定するものではない。臨床治療において通常直面し、当業者に明らかである種々の条件およびパラメータの他の適切な改変および適応は、本発明の精神および範囲の内である。
この実施例は、本発明の化合物を得るための種々の合成方法を記載する。
一般的な方法。試薬および無水溶媒は、さらに精製することなく使用し、市販の供給源から購入した。反応の進行は、Silicycle(SiliaPlate、厚さ200μm、F254)からのアルミニウム裏打ちプレコートシリカプレート上での薄層クロマトグラフィー(TLC)を使用して、UV吸光度によってモニターした。フラッシュクロマトグラフィーを使用する精製は、Silicycleシリカゲル(SiliaFlash F60、40~63μm、230~400メッシュ、PN R10030B)を使用して行った。比率が少ない化合物は、10gおよび25gのUltra-SNAPカートリッジカラム(25μM球形シリカ)を装備したBiotage Isoleraクロマトグラフィーシステムを使用して、精製した。1H NMRスペクトルは、Varian(300または400MHz)装置を使用して、得た。スペクトルデータは、以下の略語を用いて報告される:s=一重線、d=二重線、t=三重線、q=四重線、m=多重線、dd=二重線の二重線、および、結合定数はHzにて報告され、続いて積分される。島津LCMS20-20システムを利用して、HPLCトレースを生成し、質量分析データを得、純度を評価した。このシステムには、PDA UV検出器、およびKinetex 2.6μm、XB-C18 100Å、75mm×4.6mmカラムが備え付けられ、室温で使用された。HPLC勾配法を、0.01%ギ酸を含むH2O中、MeCNを1%から90%へ、0.50mL/分の流速で20分間にわたって、利用した。最終化合物の純度(≧95%)は、記載したカラムおよび方法を用いて、254nmで評価した。逆相予備精製は、島津LC-20モジュラーHPLCシステムで行った。このシステムはPDA検出器、およびKinetex 5μm XB-C18 100Å、150mm×21.2mmカラムを利用した。精製方法は、0.02%トリフルオロ酢酸を含むH2O中、MeCNが1%から90%への27分間の勾配を使用した。
細胞毒性の評価は、紫色ホルマザン生成物を生じる生存細胞によるMTT色素の減少に基づいた。紫色ホルマザン生成物は、540nmで分光光度法を用いて測定することができる。180マイクロリットルの癌細胞を、3,500~4,000細胞/ウェルで96ウェルプレートに播種し、指示された治療の前に37℃で一晩インキュベートした。72時間後、20μlのMTT溶液(3mg/ml)を添加し、再び3時間インキュベートした。媒体を除去し、150μLのDMSO中でホルマザン結晶を可溶化した後、吸光度を570nmで測定した。細胞成長阻害の割合は、1-[(A-B)/(C-B)]×100%として表した(A、BおよびCはそれぞれ、実験細胞、ブランク細胞およびコントロール細胞からの吸光度値であった)。
上記手順によって調製した、式I、式IIおよび式IIIの化合物の1HNMRデータ、LC/MSデータおよび純度を、以下にまとめる:
実施例1:7-クロロ-6-((2,6-ジフルオロ-4-(4-メチルピペラジン-1-イル)フェニル)アミノ)キノリン-5,8-ジオン(1)。一般的なプロトコルBに従う。エタノール(2mL)中の2,6-ジフルオロ-4-(4-メチルピペラジン-1-イル)アニリン(22.7mg、0.1mmol)、6,7-ジクロロキノリン-5,8-ジオン(22.7mg、0.1mmol)、および塩化セリウム(III)七水和物(41mg、0.11mmol)の溶液を65℃にて3時間、撹拌した。7-クロロ-6-((2,6-ジフルオロ-4-(4-メチルピペラジン-1-イル)フェニル)アミノ)キノリン-5,8-ジオンを暗紫色固体(28.8mg、収率69%)として回収した。1H NMR(300MHz,メタノール-d4) δ 9.01(s,1H),8.55(d,J=7.7Hz,1H),7.89(s,1H),6.75(d,J=10.8Hz,2H),3.97(s,2H),3.64(s,2H),3.35(d,J=11.5Hz,4H),3.00(s,3H)。LCMS(ESI) 419.00[M+H]+。254nmにおけるHPLC純度、100%。
代表的な化合物を、国立癌研究所で、60個の癌細胞(NCI60)のパネルにおいて試験した。成長阻害を表2、表3、表4、表5、および図1、図2、図3、図4、図5に示す。
本明細書で参照される特許文献および科学論文それぞれの開示全体が、すべての目的のために、参照により組み込まれる。
本発明は、その精神または本質的特性から逸脱することなく、他の特定の形態内で実施されてもよい。したがって、前述の実施形態は、本明細書で説明される本発明を限定するのではなく、すべての点で例示的であると見なされるべきである。したがって、本発明の範囲は、前述の説明によってではなく、添付の特許請求の範囲によって示され、特許請求の範囲の同等の意味および範囲内に入るすべての変形が、その中に包含されることが意図される。
Claims (31)
- 式I、IIもしくはIIIに包含される化合物:
薬学的に許容可能なその塩、溶媒和物、および/またはプロドラッグを含む、化合物であって;式中:
R1は、水素、または任意に置換されたアルキル、またはハロゲンからなる群から選択され;
R2は、アルキル、任意に置換されたC4~C8シクロアルキル、任意に置換されたC4~C8ヘテロアルキル、任意に置換されたC4~C8ヘテロシクロアルキル、任意に置換されたC5~C6アリール、および任意に置換されたC4~C6ヘテロアリールからなる群から選択され;
R3a、R3b、R3c、またはR3dは、水素、ハロゲン、メチル、メトキシ、トリフルオロメチル、ヒドロキシルまたはシアノからなる群から選択され;
R4は、アルキルまたはヘテロアルキルからなる群から選択され;
Aは、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールを含み;
Xは、水素、ハロゲン、アミノ、ヘテロシクロアルキル、またはヒドロキシルからなる群から選択される、化合物。 - R1は、水素、ハロ、アルキル、ヘテロアルキル、任意に置換されたC6~C14アリール、および任意に置換された5~14員ヘテロアリールからなる群から選択される、請求項1~8のいずれか1項に記載の化合物。
- 前記化合物は、表1に列挙される化合物から選択される、請求項1に記載の化合物。
- 表1に列挙される化合物から選択される化合物。
- 請求項1~15のいずれか1項に記載の化合物を含む薬学的組成物。
- 患者における過剰増殖性疾患を治療、改善、または予防する方法であって、前記患者に治療有効量の請求項19に記載の薬学的組成物を投与することを含む、方法。
- 前記過剰増殖性疾患は癌である、請求項20に記載の方法。
- 前記癌は、乳癌、前立腺癌、リンパ腫、皮膚癌、結腸癌、黒色腫、悪性黒色腫、卵巣癌、脳癌、原発性脳癌腫、頭頸部癌、神経膠腫、膠芽細胞腫、肝癌、膀胱癌、非小細胞肺癌、頭頸部癌腫、乳癌腫、卵巣癌腫、肺癌腫、小細胞肺癌腫、ウィルムス腫瘍、子宮頸癌腫、精巣癌腫、膀胱癌腫、膵癌腫、胃癌腫、結腸癌腫、前立腺癌腫、泌尿生殖器癌腫、甲状腺癌腫、食道癌腫、骨髄腫、多発性骨髄腫、副腎癌腫、腎細胞癌腫、子宮内膜癌腫、副腎皮質癌腫、悪性膵インスリノーマ、悪性カルチノイド癌腫、絨毛癌腫、菌状息肉腫、悪性高カルシウム血症、子宮頸部過形成、白血病、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、慢性骨髄性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、ヘアリー細胞白血病、神経芽細胞腫、横紋筋肉腫、カポジ肉腫、真性赤血球増加症、本態性血小板血症、ホジキン病、非ホジキンリンパ腫、軟部組織肉腫、骨原性肉腫、原発性マクログロブリン血症、および網膜芽細胞腫から選択される、請求項21に記載の方法。
- 前記患者はヒト患者である、請求項20に記載の方法。
- 前記患者に1つ以上の抗癌剤を投与することをさらに含む、請求項20に記載の方法。
- 前記抗癌剤は化学療法剤である、請求項24に記載の方法。
- 前記抗癌剤は放射線療法である、請求項24に記載の方法。
- 請求項1~15に記載の化合物のいずれか、および過剰増殖性疾患を有する患者に前記化合物を投与するための説明書を含む、キット。
- 前記過剰増殖性疾患は癌である、請求項27に記載のキット。
- 前記癌は、乳癌、前立腺癌、リンパ腫、皮膚癌、結腸癌、黒色腫、悪性黒色腫、卵巣癌、脳癌、原発性脳癌腫、頭頸部癌、神経膠腫、膠芽細胞腫、肝癌、膀胱癌、非小細胞肺癌、頭頸部癌腫、乳癌腫、卵巣癌腫、肺癌腫、小細胞肺癌腫、ウィルムス腫瘍、子宮頸癌腫、精巣癌腫、膀胱癌腫、膵癌腫、胃癌腫、結腸癌腫、前立腺癌腫、泌尿生殖器癌腫、甲状腺癌腫、食道癌腫、骨髄腫、多発性骨髄腫、副腎癌腫、腎細胞癌腫、子宮内膜癌腫、副腎皮質癌腫、悪性膵インスリノーマ、悪性カルチノイド癌腫、絨毛癌腫、菌状息肉腫、悪性高カルシウム血症、子宮頸部過形成、白血病、急性リンパ性白血病、慢性リンパ性白血病、急性骨髄性白血病、慢性骨髄性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、ヘアリー細胞白血病、神経芽細胞腫、横紋筋肉腫、カポジ肉腫、真性赤血球増加症、本態性血小板血症、ホジキン病、非ホジキンリンパ腫、軟部組織肉腫、骨原性肉腫、原発性マクログロブリン血症、および網膜芽細胞腫から選択される、請求項28に記載のキット。
- 1つ以上の抗癌剤をさらに含む、請求項27に記載のキット。
- 前記化合物は、1つ以上の抗癌剤と共に投与される、請求項30に記載のキット。
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