JP2018188474A - 重水素化されたcftr増強物質 - Google Patents
重水素化されたcftr増強物質 Download PDFInfo
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- JP2018188474A JP2018188474A JP2018152302A JP2018152302A JP2018188474A JP 2018188474 A JP2018188474 A JP 2018188474A JP 2018152302 A JP2018152302 A JP 2018152302A JP 2018152302 A JP2018152302 A JP 2018152302A JP 2018188474 A JP2018188474 A JP 2018188474A
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- compound
- deuterium
- mmol
- acid
- pharmaceutically acceptable
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- 239000006187 pill Substances 0.000 description 1
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Abstract
Description
(1)式Iの化合物またはその薬学的に許容される塩:
式中、
X1、X2、X3、X4、X5、X6、およびX7はそれぞれ独立に水素または重水素であり;
Y1、Y2、Y3、Y4、Y5、およびY6はそれぞれ独立にCH3またはCD3であり;
Y1、Y2、Y3、Y4、Y5、およびY6がいずれもCH3の場合、X1、X2、X3、X4、X5、X6、およびX7のうち少なくとも一つは重水素である;
(2)X1、X2、X3、およびX4が同一である、(1)記載の化合物;
(3)X6およびX7が同一である、(2)記載の化合物;
(4)Y1、Y2、およびY3が同一である、(2)または(3)記載の化合物;
(5)Y4、Y5、およびY6が同一である、(2)〜(4)のいずれか一項記載の化合物;
(6)X6およびX7が同一である、(2)〜(5)のいずれか一項記載の化合物;
(7)X5が重水素である、(1)〜(6)のいずれか一項記載の化合物;
(8)C(Y1)(Y2)(Y3)およびC(Y4)(Y5)(Y6)の少なくとも一方がC(CD3)3である、(1)〜(7)のいずれか一項記載の化合物;
(9)Y1、Y2、およびY3がCD3である、(1)〜(8)のいずれか一項記載の化合物;
(10)Y4、Y5、およびY6がCD3である、(1)〜(9)のいずれか一項記載の化合物;
(11)上記の任意の態様において重水素と指定されていない原子がいずれも、その天然同位体存在度で存在する、(1)〜(10)のいずれか一項記載の化合物;
(12)式Iの化合物が下記の表
に記載の化合物のいずれか一つまたはその薬学的に許容される塩であり、重水素と指定されていない原子がいずれも、その天然同位体存在度で存在する、(1)記載の化合物;
(13)式Iの化合物が下記の表
に記載の化合物のいずれか一つまたはその薬学的に許容される塩であり、重水素と指定されていない原子がいずれも、その天然同位体存在度で存在する、(1)記載の化合物;
(14)式Iの化合物が下記の表
に記載の化合物のいずれか一つまたはその薬学的に許容される塩であり、重水素と指定されていない原子がいずれも、その天然同位体存在度で存在する、(1)記載の化合物;
(15)(1)〜(14)のいずれか一項記載の化合物またはその薬学的に許容される塩、および薬学的に許容される担体を含む、薬学的組成物;
(16)(15)記載の薬学的組成物または(1)〜(14)のいずれか一項記載の化合物を対象に投与する工程を含む、対象における嚢胞性線維症を治療する方法。
用語「治療する」は、疾患(例えば、本明細書に記載される疾患または障害)の発症または進行を減少させる、抑制する、弱める、少なくする、阻止する、または安定させること、疾患の重篤度を小さくすること、または、疾患と関連する症状を改善することを意味する。
本発明は、式Iの化合物:
またはその薬学的に許容される塩を提供し、式中、
X1、X2、X3、X4、X5、X6、およびX7はそれぞれ独立に水素または重水素であり;
Y1、Y2、Y3、Y4、Y5、およびY6はそれぞれ独立にCH3またはCD3であり;
Y1、Y2、Y3、Y4、Y5、およびY6がいずれもCH3の場合、X1、X2、X3、X4、X5、X6、およびX7のうち少なくとも一つは重水素である。
スキーム2:
スキーム4a:
スキーム4b:
スキーム4c:
スキーム4d:
本発明はまた、有効量の式I(例えば、本明細書中の式のいずれをも含む)の化合物またはその化合物の薬学的に許容される塩;および薬学的に許容される担体を含む、薬学的組成物を提供する。製剤の他の成分と適合性であり、かつ、薬学的に許容される担体の場合は、医薬において使用される量ではそのレシピエントに有害でないという意味で、担体は「許容される」。
別の態様において、本発明は、感染した細胞内のCFTRの活性を増強する方法であって、そのような細胞を本明細書の式Iの化合物またはその薬学的に許容される塩と接触させる工程を含む方法を提供する。
下記スキーム5に概説するとおり、化合物110を調製した。
スキーム5. 化合物110の調製
*7.10 ppmにおける1H NMRシグナルは、アリールの二つの重水素化位置のうちの一つにおける重水素の組み込みが約80%であることを示す。7.20 ppmおよび1.37 ppmにシグナルが無いことは、残りの重水素化位置における組み込みレベルが高い(>95%)ことを示す。
下記スキーム6に概説するとおり、化合物125を調製した。
スキーム6. 化合物125の調製
*7.09 ppmにおける1H NMRシグナルは、二つのアリール位のうちの一つにおける重水素の組み込みが約70%であることを示す。
下記スキーム7に概説するとおり、化合物106を調製した。
スキーム7. 化合物106の調製
下記スキーム5に概説するとおり、化合物105を調製した。
スキーム8. 化合物105の調製
(6.76 ppmのピークは、2位、4位、および6位の水素原子に相当する。従って、0.14という積分値は、得られた物質のこれらの位置における重水素の組み込みが〜95%であることを示す。)
(積分値が0.5Hである6.67 ppmのピークは、反応を行う過程で2位において約50%Dまで同位体が減少したことを示す。1.28 ppmおよび1.17 ppmのピークは、t-ブチル基の水素含有量を示す。従って、0.18および0.21という積分値は、いずれの位置においても約98%のDの組み込みを示す。)
(1.32 ppmおよび1.30 ppmのピークは、t-ブチル基の水素含有量を示す。従って、0.20および0.18という積分値は、いずれの位置においても約98%のDの組み込みを示す。)MS(ESI)411.4[(M+H)+]。
SUPERSOMES(商標)アッセイ。DMSO中、試験化合物(化合物110およびイバカフトル)の7.5 mMの原液を調製した。7.5 mMの原液をアセトニトリル(ACN)で50 mMに希釈した。ヒトCYP3A4 supersomes(商標)(1000 pmol/mL、BD Gentest(商標)Products and Servicesより購入)は、3 mM MgCl2を含むpH7.4の0.1 Mリン酸カリウム緩衝液中で62.5 pmol/mLに希釈した。希釈したsupersomesをポリプロピレン製の96穴プレートのウェルにトリプリケートで加えた。50 mMの試験化合物を10 mLずつsupersomesに分注し、この混合物を予め10分間温めた。予め温めておいたNADPH溶液を加えることにより反応を開始させた。最終的な反応物の体積は0.5 mLであり、3 mM MgCl2を含むpH7.4の0.1 Mリン酸カリウム緩衝液中に50 pmol/mLのCYP3A4 supersomes(商標)、1.0 mMの試験化合物、および2 mMのNADPHを含んでいた。反応混合物を37℃でインキュベートし、0、5、10、20、および30分の時点で50 mLずつ抜き取り、内部標準と共に氷冷ACN 50 mLを含む96穴プレートに加え、反応を停止させた。プレートを4℃で20分間保存した後、まずプレートのウェルに100 mLの水を加え、次に沈殿したタンパク質のペレット形成の為の遠心分離を行った。上清を別の96穴プレートに移し、Applied Bio-systems API 4000質量分析計を用いたLC-MS/MSにより親化合物の残量を分析した。
インビトロt1/2=0.693/k、k=−[親化合物の残量%(ln)対インキュベーション時間の直線回帰の傾き]
SUPERSOMES(商標)アッセイ。DMSO中、試験化合物(化合物105、106、およびイバカフトル)の7.5 mMの原液を調製した。7.5 mMの原液をアセトニトリル(ACN)で50 mMに希釈した。ヒトCYP3A4 supersomes(商標)(1000 pmol/mL、BD Gentest(商標)Products and Servicesより購入)は3 mM MgCl2を含むpH7.4の0.1 Mリン酸カリウム緩衝液中で62.5 pmol/mLに希釈した。希釈したsupersomesをポリプロピレン製の96穴プレートのウェルにトリプリケートで加えた。50 mMの試験化合物を10 mLずつsupersomesに分注し、この混合物を予め10分間温めた。予め温めておいたNADPH溶液を加えることにより反応を開始させた。最終的な反応物の体積は0.5 mLであり、3 mM MgCl2を含むpH7.4の0.1 Mリン酸カリウム緩衝液中に50 pmol/mLのCYP3A4 supersomes(商標)、1.0 mMの試験化合物、および2 mMのNADPHを含んでいた。反応混合物を37℃でインキュベートし、0、5、10、20、および30分の時点で50mLずつ抜き取り、内部標準と共に氷冷ACN 50 mLを含む96穴プレートに加え、反応を停止させた。プレートを4℃で20分間保存した後、まずプレートのウェルに100 mLの水を加え、次に沈殿したタンパク質のペレット形成の為の遠心分離を行った。上清を別の96穴プレートに移し、Applied Bio-systems API 4000質量分析計を用いたLC-MS/MSにより親化合物の残量を分析した。
インビトロt1/2=0.693/k、k=−[親化合物の残量%(ln)対インキュベーション時間の直線回帰の傾き]
イバカフトル、化合物105、および化合物106を別々にラットに経口経管栄養(PO)として投与した。化合物はそれぞれ三匹のラットに10 mg/kgの用量で投与された(N=ラット3匹/化合物;合計9匹のラットを実験に使用)。化合物はそれぞれ濃度が2 mg/mLとなるよう100% PEG400中で調合された。血液サンプルは各ラットより投与後15分および30分、ならびに1、2、4、6、8、12、24、48および72時間の時点で回収した。血液サンプルを遠心分離し、血漿を得た。血漿サンプルを用いて、LC-MS/MSにより各時点での投与化合物の濃度を分析した。各化合物の定量化の限度は1 ng/mLであった。
Claims (16)
- X1、X2、X3、およびX4が同一である、請求項1記載の化合物。
- X6およびX7が同一である、請求項2記載の化合物。
- Y1、Y2、およびY3が同一である、請求項2または3記載の化合物。
- Y4、Y5、およびY6が同一である、請求項2〜4のいずれか一項記載の化合物。
- X6およびX7が同一である、請求項2〜5のいずれか一項記載の化合物。
- X5が重水素である、前記請求項のいずれか一項記載の化合物。
- C(Y1)(Y2)(Y3)およびC(Y4)(Y5)(Y6)の少なくとも一方がC(CD3)3である、前記請求項のいずれか一項記載の化合物。
- Y1、Y2、およびY3がCD3である、前記請求項のいずれか一項記載の化合物。
- Y4、Y5、およびY6がCD3である、前記請求項のいずれか一項記載の化合物。
- 上記の任意の態様において重水素と指定されていない原子がいずれも、その天然同位体存在度で存在する、前記請求項のいずれか一項記載の化合物。
- 前記請求項のいずれか一項記載の化合物またはその薬学的に許容される塩、および薬学的に許容される担体を含む、薬学的組成物。
- 請求項15記載の薬学的組成物または請求項1〜14のいずれか一項記載の化合物を対象に投与する工程を含む、対象における嚢胞性線維症を治療する方法。
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