JP6830460B2 - ルキソリチニブの重水素化誘導体 - Google Patents
ルキソリチニブの重水素化誘導体 Download PDFInfo
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- JP6830460B2 JP6830460B2 JP2018128417A JP2018128417A JP6830460B2 JP 6830460 B2 JP6830460 B2 JP 6830460B2 JP 2018128417 A JP2018128417 A JP 2018128417A JP 2018128417 A JP2018128417 A JP 2018128417A JP 6830460 B2 JP6830460 B2 JP 6830460B2
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Images
Description
現在の多くの薬剤は、それらの広範な使用を妨げるかまたは特定の適応におけるそれらの使用を制限する、乏しい吸収、分配、代謝および/または排出(ADME)特性の欠点を持つ。また、乏しいADME特性は、臨床試験における薬物候補の不足が主な原因となっている。特定のADME特性を向上するいくつかの場合において製剤化技術およびプロドラッグ戦略を使用することができるが、これらのアプローチはしばしば、多くの薬物および薬物候補について存在する根元的なADME課題の取り組みに失敗している。このような課題の1つは、そうでなければ疾患の治療に非常に有効な、多くの薬物が体内からあまりに早く除去されるという迅速な代謝である。迅速な薬物クリアランスの可能な解決法は、薬物の充分に高い血漿レベルを達成するための頻繁なまたは高頻度の投薬である。しかしながら、このことにより、投与計画による乏しい患者コンプライアンス、投薬が多くなるにつれてより激しくなる副作用および治療のコストの増加などの多くの潜在的な治療課題がもたらされる。また、迅速に代謝された薬物は、患者を望ましくない毒性または反応性の代謝産物に曝露させ得る。
〔1〕式I:
Y6、Y7およびY8は、それぞれ水素であり、該化合物は、以下の表:
重水素であるとは指定されない任意の原子がその天然の同位体存在度で存在する、化合物またはその薬学的に許容され得る塩、
〔2〕式I:
Y6、Y7およびY8は、それぞれ重水素であり、該化合物は、以下の表:
重水素であるとは指定されない任意の原子がその天然の同位体存在度で存在する、化合物またはその薬学的に許容され得る塩、
〔3〕前記〔1〕記載の化合物および薬学的に許容され得る担体を含む、医薬組成物、
〔4〕前記〔2〕記載の化合物および薬学的に許容され得る担体を含む、医薬組成物、
〔5〕化合物127,
〔6〕レナリドマイド、パノビノスタット、カペシタビン、エキセメスタンおよびそれらの組み合わせから選択される治療剤をさらに含む、前記[3]、[4]または〔5〕記載の組成物、
〔7〕 前記〔1〕もしくは〔2〕記載の化合物、またはそれらの薬学的に許容され得る塩を含む、細胞におけるJAK1またはJAK2の1つ以上の活性を阻害するための医薬組成物、
〔8〕化合物127:
〔9〕骨髄線維症、膵臓癌、前立腺癌、乳癌、白血病、非ホジキンリンパ腫、多発性骨髄腫、乾癬またはそれらの組み合わせを治療するための、前記〔3〕〜〔5〕いずれかに記載の医薬組成物、
〔10〕骨髄線維症が、原発性骨髄線維症、真性赤血球増加症後骨髄線維症、本態性血小板血症後骨髄線維症、本態性血小板血症またはそれらの組み合わせである、前記〔9〕記載の医薬組成物、
〔11〕前記〔3〕〜〔5〕いずれか記載の医薬組成物ならびにレナリドマイド、パノビノスタット、カペシタビン、エキセメスタンおよびそれらの組み合わせから選択される治療剤を含む、骨髄線維症、膵臓癌、前立腺癌、乳癌、白血病、非ホジキンリンパ腫、多発性骨髄腫、乾癬またはそれらの組み合わせを治療するための組み合わせ医薬
に関する。
本発明は、新規のヘテロアリール置換ピロロ[2,3-d]ピリミジンおよびその薬学的に許容され得る塩に関する。本発明はまた、本発明の化合物を含む組成物、ならびにサブタイプ1および2(JAK1/JAK2)について選択性を有するヤーヌス関連キナーゼのインヒビターの投与により有利に治療される疾患および状態の治療方法におけるかかる組成物の使用を提供する。
定義
用語「治療」は、疾患(例えば本明細書に示される疾患または障害)の発症もしくは進行の減少、抑制、減退、縮小、拘束もしくは安定化、疾患の重症度の低下、または該疾患に関連する症状の改善を意味する。
一態様において、本発明の式A:
Y1は、水素および重水素から選択され;
各Y2は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y2は同じものであるとし;
各Y3は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y3は同じものであるとし;
Y4は、水素および重水素から選択され;
各Y5は、同じであり、水素および重水素から選択され;
Y6、Y7、Y8、Y9およびY10は、それぞれ独立して水素および重水素から選択され;
ただし、Y1が水素であり、各Y2および各Y3が水素であり、Y4が水素であり、Y6、Y7、Y8、Y9およびY10のそれぞれが水素である場合、各Y5は重水素である)
の化合物、またはその薬学的に許容され得る塩を提供する。
Y1は水素および重水素から選択され;
各Y2は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y2は同じものであるとし;
各Y3は独立して、水素および重水素から選択されるが、ただし、共通の炭素に結合する各Y3は同じものであるとし;
Y4は水素および重水素から選択され;
各Y5は同じものであり、水素および重水素から選択され;
Y6、Y7およびY8は、それぞれ独立して水素および重水素から選択され;
ただし、Y1が水素であり、各Y2および各Y3が水素であり、Y4が水素であり、Y6、Y7およびY8のそれぞれが水素である場合、各Y5は重水素である)
の化合物、またはその薬学的に許容され得る塩を提供する。
式Iまたは式Aの化合物は、US特許第7,598,257号およびOrganic Letters, 2009, 11(9): 1999-2009に示される合成と類似の様式で、適切に重水素化された開始物質を使用して調製され得る。
本発明はまた、式Iもしくは式A(たとえは本明細書中の式のいずれかを含む)の化合物または前記化合物の薬学的に許容され得る塩の有効量、ならびに薬学的に許容され得る担体を含む発熱源非含有医薬組成物を提供する。担体(1つまたは複数)は、製剤の他の成分と適合性であるという意味において「許容可能」であり、薬学的に許容され得る担体の場合、医薬において使用される量でそのレシピエントに対して有害でない。
別の態様において、本発明は、細胞と、1つ以上の式Iもしくは式Aの化合物またはそれらの薬学的に許容され得る塩を接触させる工程を含む、細胞におけるヤーヌス関連キナーゼ(JAK)JAK1およびJAK2の1つ以上を阻害する方法を提供する。
実施例1. (R)-3-(4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル)-3-(2,2,5,5-d4-シクロペンチル)プロパンニトリル(化合物107)の合成。
スキーム3. 化合物107の調製
スキーム4.化合物103の調製
スキーム5. 化合物127の調製
ヒトCYP3A4 SupersomesTM中の化合物103、107および127の代謝安定性の評価
SUPERSOMESTMアッセイ。試験化合物、化合物103、107、127およびルキソリチニブの10mMのストック溶液をDMSO中に調製した。10mMのストック溶液をアセトニトリル(ACN)中15.6μMに希釈した。ヒトCYP3A4 supersomesTM(1000pmol/mL、BD GentestTMProducts and Servicesから購入)を、3mM MgCl2を含む0.1Mリン酸カリウムバッファー、pH7.4中で62.5pmol/mLに希釈した。希釈したsupersomesを、96ウェルポリプロピレンプレートのウェルに3ヶ所添加した。10μLアリコートの15.6μM試験化合物をsupersomesに添加し、混合物を10分間予備的に温めた。予め温めたNADPH溶液を添加して反応を開始した。最終反応容量は0.5mLであり、50pmol/mL CYP3A4 supersomesTM、0.25μM試験化合物、および0.1Mリン酸カリウムバッファー、pH7.4中の2mM NADPHおよび3mM MgCl2を含んだ。反応混合物を37℃でインキュベートし、50μLのアリコートを0、5、10、20および30分で取出し、内部標準を有する50μLの氷冷ACNを含んだ96ウェルプレートに添加して反応を停止した。プレートを4℃で20分間保存し、その後100mLの水をプレートのウェルに添加し、次いで沈殿したタンパク質をペレットになるまで遠心分離した。上清を別の96ウェルプレートに移し、Applied Bio-systems API 4000質量分析器を使用して、LC-MS/MSにより親の残存物の量について分析した。
インビトロt1/2=0.693/k、式中k=-[%親残留物の直線回帰(ln)の傾斜 対 インキュベーション時間]。
ミクロソームアッセイ:ヒト肝臓ミクロソーム(20mg/mL)はXenotech, LLC (Lenexa, KS)から入手する。β-ニコチンアミドアデニンリン酸ジヌクレオチド、還元型(NADPH)、塩化マグネシウム(MgCl2)およびジメチルスルホキシド(DMSO)はSigma-Aldrichから購入する。
インビトロt1/2=0.693/k
k=-[%親残留物の直線回帰(ln)の傾斜 対 インキュベーション時間]
Claims (16)
- JAK1またはJAK2の1つ以上を阻害するための医薬の製造における式I:
(式中、
Y1は水素であり;
各Y2は独立して、水素および重水素から選択され、ただし、共通の炭素に結合する各Y2は同じであり;
各Y3は独立して、水素および重水素から選択され、ただし、共通の炭素に結合する各Y3は同じであり;
Y4は水素および重水素から選択され;
各Y5は同じであり、水素および重水素から選択され;
Y6、Y7およびY8は、それぞれ独立して水素および重水素から選択され;
ただし、
各Y2が重水素である、または
各Y3が重水素である、または
各Y2および各Y3が重水素である、
のいずれかであり、「重水素」と特に指定された位置は、少なくとも52.5%の重水素の組み込みを有する)
で表される化合物またはその薬学的に許容され得る塩の使用。 - 各Y2は水素である、請求項1記載の使用。
- 各Y3は水素である、請求項1記載の使用。
- 各Y5は水素である、請求項1〜3いずれか記載の使用。
- 各Y7およびY8は水素である、請求項1〜4いずれか記載の使用。
- Y6は水素である、請求項1〜5いずれか記載の使用。
- Y4は水素である、請求項1〜6いずれか記載の使用。
- 重水素であるとは指定されない任意の原子がその天然の同位体存在度で存在する、請求項1〜7、10または11いずれか1項記載の使用。
- 重水素と特に指定された位置は、少なくとも95%の重水素の組み込みを有する、請求項1〜12いずれか記載の使用。
- 重水素と特に指定された位置は、少なくとも97%の重水素の組み込みを有する、請求項1〜12いずれか記載の使用。
- 該医薬が、薬学的に許容され得る担体を含む、請求項1〜14いずれか記載の使用。
- 該医薬が、レナリドミド、パノビノスタット、カペシタビン、エキセメスタンおよびそれらの組み合わせから選択される治療剤と組み合わせて使用される、請求項1〜15いずれか記載の使用。
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