JP6072938B2 - チエノピリジン化合物の混合ジスルフィド結合体およびその使用 - Google Patents
チエノピリジン化合物の混合ジスルフィド結合体およびその使用 Download PDFInfo
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- JP6072938B2 JP6072938B2 JP2015552723A JP2015552723A JP6072938B2 JP 6072938 B2 JP6072938 B2 JP 6072938B2 JP 2015552723 A JP2015552723 A JP 2015552723A JP 2015552723 A JP2015552723 A JP 2015552723A JP 6072938 B2 JP6072938 B2 JP 6072938B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
本発明は、国立衛生研究所により授与されたAA020090およびCA016954の下で、政府支援によりなされた。米国政府は、本発明においてある特定の権利を有する。
本発明は、医薬品化学の分野に含まれる。特に、本発明は、チエノピリジン化合物の混合ジスルフィド結合体、ならびに心血管疾患の治療、改善、および予防のための治療剤としてのそれらの使用に関する。
チエノピリジニル化合物は、心臓発作および脳卒中を予防するために、抗血小板剤として広く使用されている。このカテゴリーにおいて、クロピドグレル(プラビックス)、チクロピジン(チクリド)およびプラスグレル(エフィエント)が、3つの一般的に使用されるプロドラッグである。これらの薬剤は、多型シトクロム(P450)媒介酸化的生体内活性化を必要とする。そのような酸化的生体内活性化は、遅い治療効果の開始、ならびに好中球減少症および血栓性血小板減少性紫斑病を含むいくつかの副作用をもたらす。
クロピドグレル(プラビックス)、チクロピジン(チクリド)およびプラスグレル(エフィエント)は、心臓発作および脳卒中を防止するための抗血小板剤として広く使用されるチエノピリジニル化合物のクラスに属する。しかしながら、応答の欠如、毒性および過度の出血を含むいくつかの重大な欠点が、これらの薬剤に関連している。これらの欠点は、それらが全て多型シトクロムP450酵素(P450)による酸化的生体内活性化を必要とするプロドラッグであるという事実に密接に関連している。
図1は、クロピドグレルの活性代謝物(AM)の形成に対するチオール還元剤の効果を示すグラフである。AMは、0.2mg/mlのHLM、0.1mMの2−オキソクロピドグレル、NADPH再生系、およびチオール還元剤を含有する0.1mlの50mM KP緩衝液(pH7.4)中で生成された。チオール還元剤の濃度は1mMであったが、但しCPT、DFTおよびNPTはそれぞれ0.3mMであった。5単位のG6PDの添加により反応を開始させ、37℃で20分間インキュベートした。次いで、活性代謝物を、材料および方法の項に記載のようにMP誘導体として定量した。報告された率は、3回の別個の測定にわたり平均化した。チオール化合物に関する略語は、表1に記載されている。
「チエノピリジン化合物」という用語は、本明細書において使用される場合、その抗血小板活性のために使用されるADP受容体/P2Y12阻害剤のクラスを指す。その例は、クロピドグレル(プラビックス)、チクロピジン(チクリド)、およびプラスグレル(エフィエント)を含むが、これらに限定されない。
チエノピリジニル抗血小板剤は、3つの臨床的に使用される薬物、クロピドグレル(プラビックス)、チクロピジン(チクリド)、およびプラスグレル(エフィエント)を含む。クロピドグレル(プラビックス)、チクロピジン(チクリド)、およびプラスグレル(エフィエント)の化学構造およびIUPAC名は、以下の通りである:
以下の実施例は、本発明の化合物、組成物、および方法の例示であり、限定するものではない。臨床治療において通常遭遇し、また当業者に明らかである様々な条件およびパラメータの他の好適な修正および適合は、本発明の精神および範囲内にある。
本実施例は、クロピドグレルおよびチクロピジンの混合ジスルフィド結合体の合成を説明する。
本実施例は、混合ジスルフィド結合体化合物からの活性代謝物の生成を説明する。結合体Clop−CPT
本実施例は、本発明のチエノピリジン化合物の混合ジスルフィド結合体による血小板凝集の阻害を説明する。
本実施例は、実施例5〜9のための材料および方法を説明する。
本実施例は、クロピドグレルの活性代謝物(AM)の形成に対するチオール還元剤の効果を説明する。チオール還元剤の効果を検査するために、各種チオール還元剤の存在下でのAMの形成のための定常状態の速度を決定した。代謝反応物中に存在するチオール還元剤の濃度は、CPT、DPTおよびNPTを除いて1mMであった。その代わりに、これらの3種類のチオール還元剤の濃度は、それらの低いKm値のために0.3mMであった。図1に示されるように、AMは、3種類のチオール還元剤を除く全ての存在下で形成される。AMの形成のための最高速度は、人体中の内因性還元剤であるGSHの存在下で観察された。具体的には、1mMのGSHの存在下、AMは、167pモルAM/分/mg HLMの速度で生成される。同様に、L−システインは、AMの生成においてGSHの約84%活性である。以前に観察されたように(例えば、Zhang H, et al., (2012) Mol Pharmacol 82:302−309を参照されたい)、ごく低レベルのAMが1mMのNACの存在下で形成された。速度は、1mMのGSHの存在下で観察されるもののわずか約7%である。CPT、DFT、およびNPTの存在下ではAMは観察されなかった。AMの形成速度は、全体的にGSH>CYS>CG>GC>CYA>BME>NAC>CPTまたはDFTまたはNPTの順で減少した。この広範な速度は、AMの形成におけるチオール還元剤の重要な役割を強調している。
本実施例は、クロピドグレルの混合ジスルフィド結合体の分析を説明する。AMの形成は、存在するチオール還元剤により大きく影響された。本実施例において、混合ジスルフィド結合体の形成に対するチオール還元剤の効果を検査した。これは、CPT、DFT、およびNPTの存在下で形成された任意のAMの不足の原因を理解するために特に重要である。AMに関して観察されたものとは著しく対照的に、混合ジスルフィド結合体は、検査された全てのチオール還元剤の存在下で形成された。親イオンMH+のm/zおよびこれらの混合ジスルフィド結合体の保持時間は表1に要約され、4つの選択された混合ジスルフィド結合体の抽出イオンクロマトグラム(EIC)は図2に示される。観察された親イオンMH+は、これらの結合体の理論値とよく一致している。β−メルカプトエタノール(BME)の存在下では、4つの結合体のピークは、m/z 432で観察され、8.9から9.72分で溶出した(図2A)。これらの4つのAMピークは、以前に報告されたように(例えばPereillo JM, et al. (2002) Drug Metab Dispos 30(11):1288−1295を参照されたい)、クロピドグレルの複数の立体異性体の形成に起因し得る。2つの主要な結合体ピークが、CPTおよびNPTの存在下で観察された(それぞれ図2Cおよび図4D)。しかしながら、DFTの存在下では、m/z 482の1つの優勢な結合体ピークが15.8分で観察された(図2B)。CPT、NPTおよびDFT結合体の形成のKm値は、それぞれ23、51および30μMと決定されたが、これは、以前に報告されたGSHの300μMのKmより大幅に低い(例えば、Zhang H, et al., (2012) Mol Pharmacol 82:302−309を参照されたい)。
本実施例は、GSHによるクロピドグレルの混合ジスルフィド結合体の還元の反応速度を説明する。様々な混合ジスルフィド結合体とGSHとの間のチオール−ジスルフィド交換反応の反応速度を決定したが、その結果を図5に示す。結合体のGSHおよび細胞質ゾルとのインキュベーションは、混合ジスルフィド結合体の量における時間依存性の減少をもたらした(図5A)。反応速度データを単一指数関数にフィッティングすると、BME、PT、NAC、DFTおよびNPTの混合ジスルフィド結合体の損失に対して、それぞれ0.07、0.79、0.43、1.65および0.13分−1の一次速度定数が得られた。これらの反応速度は、過剰のGSH(1mM)による擬似1次条件下で決定されたため、これらの速度定数は、それぞれ1.2、13、7.2、28および2.2M−1s−1の2次速度定数に等しい。データはまた、GSHに対するこれらの結合体の可変の反応性を実証した。DFTおよびCPT結合体は、BME結合体よりもそれぞれ10倍から20倍反応性が高い。例えば、40分間のインキュベーション後であってもBME結合体の約50%がまだ残っていたようであり、これは、例えば、この結合体のためのチオール−ジスルフィド交換が平衡に達したことを示している。
本実施例は、クロピドグレルの混合ジスルフィド結合体からの活性代謝物H4の形成を説明する。スキーム2に示されるように、活性代謝物は、2つのキラル中心(C7およびC4)ならびに1つの二重結合(C3−C16)を含有する。したがって、ラセミ2−オキソクロピドグレルの代謝は、潜在的に8つまでの立体異性体を生成し得る。しかしながら、歴史的にH1、H2、H3およびH4と呼ばれるジアステレオマーの4つのみが、従来の逆相C18カラムで分離され得、一方他の4つの立体異性体は、鏡像異性体として共溶出する。H4は、人間における抗血小板活性を担い、H4の二重結合は、シス配置にあることが確立されている(例えば、Pereillo JM, et al., (2002) Drug Metab Dispos 30(11):1288−1295;Savi P, et al., (2000) Thromb Haemost 84(5):891−896;Tuffal G, et al., (2011) Thromb Haemost 105(4):696−705を参照されたい)。これらの結合体の治療可能性を評価するために、H4が混合ジスルフィド結合体において形成されるかどうかを検査したが、その結果を図6に示す。
本実施例は、CPTおよびNPTの混合ジスルフィド結合体の抗血小板活性を説明する。概念の実証として、2つの混合ジスルフィド結合体、CPTおよびNPT結合体の抗血小板活性を、いくつかの理由から検査した。第一に、両方の結合体は、いかなるAMの形成もなしに生成され得る、これにより抗血小板活性アッセイ中にAMからのいかなる干渉も排除される。第二に、両方の結合体は、比較的速い速度でGSHとチオールを交換し、これによりAMの電位減衰が回避される。第三に、2つの結合体の還元は、ヒトにおける抗血小板活性を担うものとして知られているH4異性体を生成する。生体外抗血小板活性アッセイの結果を、図7に示す。凝集のパーセンテージは、血液源、PRP調製物等の環境因子に起因する任意の変化を補償するために、PRPのものに対して正規化した。示されるように、3つの対照試料は、血小板凝集の阻害を示さなかった。第1の対照は、遊離GSHが1mMの濃度では血小板凝集に影響を与えないことを示し(GSH、図7)、第2の対照は、2−オキソクロピドグレルおよび関連不純物等の反応混合物中に存在する非代謝物成分が、血小板凝集を阻害しないことを示した(−G6PD、図7)。クロピドグレルは、非酵素的酸化により副生成物に分解し得ることが知られている(例えば、Mohan A, et al., (2008) J Pharm Biomed Anal 47(1):183−189;Fayed AS, et al., (2009) J Pharm Biomed Anal 49(2):193−200を参照されたい)。これらの副生成物は、血小板凝集に対していかなる阻害効果も有さないようである。第3の対照Iにおいて、任意のチオール還元剤の非存在下での反応混合物からの代謝物も、血小板凝集に対する影響を有さないことが実証された。しかしながら、GSHを含有する反応混合物から調製された試料中の血小板凝集の約60%の阻害が観察された(AM、図7)。1mMのGSHの存在下での2−オキソクロピドグレルの代謝は、図1に示されるようにAMを生成するため、これは予期されるものである。CPTおよびNPT結合体とのPRPのインキュベーションは、血小板凝集を阻害しなかったが、これは、結合体自体は抗血小板活性を有さないことを示している(CPT&NPT、図7)。著しく対照的に、1mMのGSHで処理されたCPTおよびNPT結合体とのPRPのインキュベーションは、それぞれ約50および70%血小板凝集を大きく阻害した。この阻害活性は、GSHにより結合体から放出されたAMから生じる可能性が最も高い。これらの結果は、クロピドグレルの結合体が、抗血小板活性を有さないことを実証しており、またAMのみが血小板凝集の阻害を担うことを確証した。さらに、これらの結果は、多型P450による生体内活性化を必要とせずにAMを提供することが可能であることを実証している。GSH、CPT+GSH、およびNPT+GSH試料において観察された凝集のパーセンテージの変化は、AMの濃度の変化に起因する可能性が最も高いことが指摘されるのが注目に値する。これらの試料中のAMの濃度は、1〜4μMの範囲内であると推定された。
本実施例は、クロピドログレルの混合ジスルフィド結合体のインビボ抗血小板活性を説明する。クロピドグレルの混合ジスルフィド結合体の抗血小板活性は、雄のニュージーランド(NZ)白ウサギにおいて、静脈内注射により決定した。混合ジスルフィド結合体は、以下の技術を使用して生合成した。
組換えシトクロムP450 2C19(CYP2C19)および他の必須成分を含有する再構成系において、クロピドグレルの混合ジスルフィド結合体を合成した。CYP2C19は、再構成系において、各チオール化合物の存在下で2−オキソクロピドグレルを混合ジスルフィド結合体に変換した。スキーム5は、clopNPTと呼ばれる、クロピドグレルと3−ニトロピリジン−2−チオールとの間の混合ジスルフィド結合体の生合成を示す。
クロピドグレルの混合ジスルフィド結合体の抗血小板活性を、雄のNZ白ウサギ(1.2〜1.25kg)を使用して決定した。
本明細書において言及される特許文献および科学論文のそれぞれの開示全体は、全ての目的において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な特徴から逸脱することなく、他の特定の形態で具現化され得る。したがって、前述の実施形態は、全ての点において、本明細書に記載の本発明を限定するのものではなく、例示的とみ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、特許請求の範囲の均等性の意味および範囲内となる全ての変更が含まれることが意図される。
Claims (19)
- 請求項1に記載の化合物と、薬学的に許容される担体とを含むことを特徴とする、医薬組成物。
- 静脈内投与用に構成されることを特徴とする、請求項4に記載の医薬組成物。
- 患者における心血管疾患を治療、改善または予防するための医薬品の製造における、請求項1に記載された化合物の使用。
- 投与が経口投与および静脈内投与からなる群から選択されることを特徴とする、請求項6に記載の使用。
- 前記心血管疾患は、冠動脈疾患、末梢血管疾患、アテローム血栓症、および脳血管疾患からなる群から選択されることを特徴とする、請求項6に記載の使用。
- 前記化合物は、血小板の凝集を低減することを特徴とする、請求項6に記載の使用。
- 前記血小板の凝集の前記低減は、P2Y12受容体への不可逆的結合を介して生じることを特徴とする、請求項9に記載の使用。
- 前記血小板の凝集の前記低減は、ADP受容体の遮断を介して生じることを特徴とする、請求項9に記載の使用。
- 前記化合物は、P450による生体内活性化を必要とせずに内因性グルタチオンの存在下で活性チエノピリジン代謝物を生成することができることを特徴とする、請求項9に記載の使用。
- HMG−CoA還元酵素阻害剤、ACE阻害剤、カルシウムチャネルブロッカー、血小板凝集阻害剤、多価不飽和脂肪酸、フィブリン酸誘導体、胆汁酸封鎖剤、酸化防止剤、血栓溶解剤、および抗狭心症薬からなる群から選択される少なくとも1つの薬剤の同時投与をさらに含むことを特徴とする、請求項9に記載の使用。
- 患者における血管上の血小板の凝集を治療、改善または予防するための医薬品の製造における、請求項1に記載された化合物の使用。
- 投与が経口投与および静脈内投与からなる群から選択されることを特徴とする、請求項14に記載の使用。
- 前記血小板の前記凝集の治療、改善または予防は、P2Y12受容体への不可逆的結合を介して生じることを特徴とする、請求項14に記載の使用。
- 前記血小板の前記凝集の前記治療、改善または予防は、ADP受容体の遮断を介して生じることを特徴とする、請求項14に記載の使用。
- 前記化合物は、P450による生体内活性化を必要とせずに内因性グルタチオンの存在下で活性チエノピリジン代謝物を生成することができることを特徴とする、請求項14に記載の使用。
- HMG−CoA還元酵素阻害剤、ACE阻害剤、カルシウムチャネルブロッカー、血小板凝集阻害剤、多価不飽和脂肪酸、フィブリン酸誘導体、胆汁酸封鎖剤、酸化防止剤、血栓溶解剤、および抗狭心症薬からなる群から選択される少なくとも1つの薬剤の同時投与をさらに含むことを特徴とする、請求項14に記載の使用。
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|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |