JP6958979B2 - ミトコンドリア疾患を治療する新規化合物 - Google Patents
ミトコンドリア疾患を治療する新規化合物 Download PDFInfo
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- JP6958979B2 JP6958979B2 JP2019232983A JP2019232983A JP6958979B2 JP 6958979 B2 JP6958979 B2 JP 6958979B2 JP 2019232983 A JP2019232983 A JP 2019232983A JP 2019232983 A JP2019232983 A JP 2019232983A JP 6958979 B2 JP6958979 B2 JP 6958979B2
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Description
Lは、炭素、窒素及び酸素から選択される1〜10個の任意選択で置換されている主鎖原子を含む、アミド窒素原子と遠位窒素原子(N*)の間にあるリンカーであり、
R1及びR2は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルからそれぞれ独立して選択され、又はR1及びR2は、一緒に結合し、それによってアミド窒素原子と遠位窒素原子の間に第2のリンカーを形成し、又はR1は、環状構造におけるリンカーLの主鎖原子と結合し、及び/若しくはR2は、環状構造におけるリンカーLの主鎖原子と結合し、
R3は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルから選択され、ここでアルキル若しくはアルケニル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、又はR3は、遠位窒素原子がイミン部分の一部であるとき、不在であり、
遠位窒素原子がカチオン性形態である(すなわち、化合物が塩形態である)場合、R4は、水素(H)又はC1〜C6アルキルから選択され、ここでアルキル部分は、1個又は複数のハロゲン原子又は(ハロ)アルコキシ部分で置換されていてもよく、Xは、アニオン、好ましくは薬学的に許容されるアニオンであり、或いは
遠位窒素原子が中性形態である場合、R4及びXは不在である。
L=L1であり、R1−R2=L1であり、R3=Hである、
L=L1であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L2であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L3であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L4であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L5であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L6であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L3であり、R1=Hであり、R2=Meであり、R3=Meである、
L=L1であり、R1=Hであり、R2=Meであり、R3=Meである、
L=L7であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L8であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L9であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L10であり、R1−R1’=L1であり、R2=Hであり、R3=不在である、
L=L11であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L12であり、R1=Hであり、R2=Hであり、R3=不在である、
L=L13であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L14であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L15であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L11であり、R1=Hであり、R2=Meであり、R3=Meである、
L=L16であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L17であり、R1=Hであり、R2=Hであり、R3=Hである、
L=L16であり、R1=Hであり、R2=Meであり、R3=Meである、
L=L18であり、R1=Hであり、R2−R2’=L3であり、R3=Hである、
L=L19であり、R1=Hであり、R2−R2’=L3であり、R3=Hである、
L=L20であり、R1=Hであり、R2=Hであり、R5−R5’=L3であり、R3=不在である、
L=L21であり、R1=Hであり、R2−R2’=L1であり、R3=Hである、
L=L22であり、R1−R1’=L1であり、R2=Hであり、R3=Hである、
L=L23であり、R1−R1’=L1であり、R2=Hであり、R3=Hである、
L=L24であり、R1−R1’=L3であり、R2=Hであり、R3=Hである、
L=L25であり、R1−R1’=L3であり、R2=Hであり、R3=不在である、
L=L26であり、R1=Hであり、R2=Hであり、R5−R5’=L1であり、R3=Hである、
L=L19であり、R1=Hであり、R2−R2’=L3であり、R3=Meである、
L=L19であり、R1=Hであり、R2−R2’=L1であり、R3=Hである、又は
L=L21であり、R1=Hであり、R2−R2’=L1であり、R3=Meである、
ものである。
Lは、炭素、窒素及び酸素から選択される1〜10個の任意選択で置換されている主鎖原子を含む、アミド窒素原子と遠位窒素原子(N*)の間にあるリンカーであり、
R1及びR2は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルからそれぞれ独立して選択され、又はR1及びR2は、一緒に結合し、それによってアミド窒素原子と遠位窒素原子の間に第2のリンカーを形成し、又はR1は、環状構造におけるリンカーLの主鎖原子と結合し、及び/若しくはR2は、環状構造におけるリンカーLの主鎖原子と結合し、
R3は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルから選択され、ここでアルキル若しくはアルケニル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、又はR3は、遠位窒素原子がイミン部分の一部であるとき、不在であり、
遠位窒素原子がカチオン性形態である(すなわち、化合物が塩形態である)場合、R4は、水素(H)又はC1〜C6アルキルから選択され、ここでアルキル部分は、1個又は複数のハロゲン原子又は(ハロ)アルコキシ部分で置換されていてもよく、Xは、アニオン、好ましくは薬学的に許容されるアニオンであり、或いは
遠位窒素原子が中性形態である場合、R4及びXは不在である。
Lは、アミド窒素原子と遠位窒素原子の間にあるリンカーであり、
R1は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルから選択され、又はR1は、環状構造におけるリンカーLの主鎖原子と結合し、
R2はリンカーLの主鎖原子と結合して、ピペリジン環、ピロリジン環、イミダゾリジン環、ピラゾリジン環又はアゼパン環から選択される環状構造を形成し、
R3は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルから選択され、ここでアルキル若しくはアルケニル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、又はR3は、遠位窒素原子がイミン部分の一部であるとき、不在であり、
R4及びXは、不在である。
Lは、アミド窒素原子と遠位窒素原子の間にあるリンカーであり、3〜10個の主鎖原子又は2個の主鎖原子を含み、そのうちの1個は、第2にリンカーを介して遠位窒素原子と接続しており、
R1及びR2は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルからそれぞれ独立して選択され、又はR1及びR2は、一緒に結合し、それによってアミド窒素原子と遠位窒素原子の間に第2のリンカーを形成し、又はR1は、環状構造におけるリンカーLの主鎖原子と結合し、及び/若しくはR2は、環状構造におけるリンカーLの主鎖原子と結合し、
R3は、水素(H)、C1〜C6アルキル若しくはC1〜C6アルケニルから選択され、ここでアルキル若しくはアルケニル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、又はR3は、遠位窒素原子がイミン部分の一部であるとき、不在であり、
R4は、水素(H)又はC1〜C6アルキルから選択され、ここでアルキル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、
Xは、アニオン、好ましくは薬学的に許容されるアニオンである。
化合物Aでは、L=L1であり、R1−R2=L1であり、R3=Hである。
化合物Bでは、L=L1であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Cでは、L=L2であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Dでは、L=L3であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Eでは、L=L4であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Fでは、L=L5であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Gでは、L=L6であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Hでは、L=L3であり、R1=Hであり、R2=Meであり、R3=Meである。
化合物Iでは、L=L1であり、R1=Hであり、R2=Meであり、R3=Meである。
化合物Jでは、L=L7であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Kでは、L=L8であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Lでは、L=L9であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Mでは、L=L10であり、R1−R1’=L1であり、R2=Hであり、R3=不在である。
化合物Nでは、L=L11であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Oでは、L=L12であり、R1=Hであり、R2=Hであり、R3=不在である。
化合物Pでは、L=L13であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Qでは、L=L14であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Rでは、L=L15であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Sでは、L=L11であり、R1=Hであり、R2=Meであり、R3=Meである。
化合物Tでは、L=L16であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Uでは、L=L17であり、R1=Hであり、R2=Hであり、R3=Hである。
化合物Vでは、L=L16であり、R1=Hであり、R2=Meであり、R3=Meである。
化合物Wでは、L=L18であり、R1=Hであり、R2−R2’=L3であり、R3=Hである。
化合物Xでは、L=L19であり、R1=Hであり、R2−R2’=L3であり、R3=Hである。
化合物Yでは、L=L20であり、R1=Hであり、R2=Hであり、R5−R5’=L3であり、R3=不在である。
化合物Zでは、L=L21であり、R1=Hであり、R2−R2’=L1であり、R3=Hである。
化合物AAでは、L=L22であり、R1−R1’=L1であり、R2=Hであり、R3=Hである。
化合物ABでは、L=L23であり、R1−R1’=L1であり、R2=Hであり、R3=Hである。
化合物ACでは、L=L24であり、R1−R1’=L3であり、R2=Hであり、R3=Hである。
化合物ADでは、L=L25であり、R1−R1’=L3であり、R2=Hであり、R3=不在である。
化合物AEでは、L=L26であり、R1=Hであり、R2=Hであり、R5−R5’=L1であり、R3=Hである。
化合物AFでは、L=L19であり、R1=Hであり、R2−R2’=L3であり、R3=Meである。
化合物AGでは、L=L19であり、R1=Hであり、R2−R2’=L1であり、R3=Hである。
化合物AHでは、L=L21であり、R1=Hであり、R2−R2’=L1であり、R3=Meである。
L=−C(iPr)−C(O)−NH−C(4−クロロベンジル)−C(O)−C(O)−であり、R1=Hであり、R2=−CH2−CH3(Et)であり、R3=Hであり、R4=X=不在であり、及び/又は
L=−(CH2)2−NR1−pPh−N=C(チオフェン−2−イル)−であり、R1−R1’=−(CH2)2−(L1)であり、R2=Hであり、R3=Hであり、R4=X=不在であり、pPhは、パラ置換フェニレン環を表し、及び/又は
L=−(CH2)2−(L1)であり、R1=Hであり、R2=Meであり、R3=Meであり、R4=X=不在であり、及び/又は
L=−CH2−Cp(R2)−(CpH)2−であり、R1=Hであり、R2−R2’=−(CpH)2−であり、R3=R4=X=不在であり、Cpが遠位窒素原子と一緒になっている全ての場合に、ピリジン環を構成し、及び/又は
L=−CH2−Cp(R2)−CpH−であり、R1=Hであり、R2−R2’=−(CpH)3−であり、R3=R4=X=不在であり、Cpが遠位窒素原子と一緒になっている全ての場合に、ピリジン環を構成し、及び/又は
L=−CH2−Cp(R2)−であり、R1=Hであり、R2−R2’=−(CpH)4−であり、R3=R4=X=不在であり、Cpが遠位窒素原子と一緒になっている全ての場合に、ピリジン環を構成し、及び/又は
L=−(CH2)3−(L3)であり、R1=Hであり、R2=Meであり、R3=Meであり、R4=X=不在であり、及び/又は
L=−(CH2)2−(L1)であり、R1−R2=−(CH2)2−(L1)であり、R3=Meであり、R4=X=不在であり、及び/又は
L=−(CH2)2−(L1)であり、R1−R2=−(CH2)2−(L1)であり、R3=Hであり、R4=X=不在であり、及び/又は
L=−(CH2)2−Cp(R2)−であり、R1=Hであり、R2−R2’=−(CpH)4−であり、R3=R4=X=不在であり、Cpが遠位窒素原子と一緒になっている全ての場合に、ピリジン環を構成し、及び/又は
L=−(CH2)3−Ni(R2)−CiH−であり、R1=Hであり、R2−R2’=−(CiH)2−であり、R3=R4=X=不在であり、CiがNi及び遠位窒素原子と一緒になっている全ての場合に、イミダゾール環を構成し、及び/又は
L=−(CH2)2−(L1)であり、R1−R2=−(CH2)2−(L1)であり、R3=iPrあり、R4=X=不在であり、及び/又は
L=−C(R5)=C(R5)−であり、R1=Hであり、R2=Hであり、R3=Hであり、R4=X=不在であり、R5−R5=−C(O)−N(Me)−C(O)−N(Ph)−であり、リンカーR5−R5は、C(O)部分を介して、アミド窒素原子に隣接する炭素原子に結合し、N(Ph)部分を介して、遠位窒素原子に隣接する炭素原子に結合し、及び/又は
L=−(CH2)2−(L1)であり、R1=Hであり、R2=Meであり、R3=Meであり、R4=Hであり、X=Clであり、及び/又は
L=−(CH2)2−(L1)であり、R1=Hであり、R2=Meであり、R3=Meであり、R4=Hであり、X=MeSO3である。
本発明の化合物の合成は、一般構造(II)の閉鎖クロマン誘導体を最初に調製することによって実施した。これらの本発明の化合物の閉鎖形態誘導体は、上付き文字IIによって示されている。例えば、上記に定義されている化合物Tの閉鎖形態は、化合物TIIと参照される。一般構造(II)の化合物は、国際公開第2014/011047号に従って調製されている。
方法:酸化ストレス誘導性細胞死に対して患者の細胞を保護する化合物の能力を評価するため、複合体I欠損患者から誘導された、ストレスを受けた一次ヒト線維芽細胞を使用して、アッセイを確立した。ミトコンドリア疾患を有する患者の線維芽細胞における固有の酸化ストレスを利用して、それらの酸化負荷を、グルタチオン合成の阻害剤であるL−ブチオニン−(S,R)−スルホキシイミン(BSO)により細胞グルタチオンを枯渇させることによって、更に増加させた。その結果、健康な個体の線維芽細胞は完全な生存率を保持しているが、患者の線維芽細胞は、BSO侵襲(200μM)の48時間以内に完全な細胞死を示した(図1)。
方法:CM−H2DCFDAは、反応性酸素種(ROS)の細胞透過性レポーター分子であり、細胞内エストラーゼによる酢酸塩基の除去後に、非蛍光膜非透過性CM−H2DCFに変換される。ROSにより酸化されると、CM−H2DCFは、蛍光CM−DCFに変換される。多種多様なROSが、CM−H2DCF酸化の原因でありうることが広く受け入れられており、細胞酸化レベルの適切なレポーターになっている。平均細胞CM−DCF蛍光強度は、細胞ROSレベルの間接的な尺度であると考慮される。
方法:HEt(ヒドロエチジン)は、非蛍光化合物であり、細胞に自由に侵入することができる。これはスーパーオキシドにより酸化されて蛍光産物のE+及び2OHE+になり、負荷電細胞区画(すなわち、核及びミトコンドリア)に蓄積する。したがってE+及び2OHE+蛍光は、細胞内のスーパーオキシド産生の尺度として考慮される。
Claims (21)
- 一般構造(I)の化合物:
[式中、
Lは、
−CH2−CH2−NH−C(O)−CH2− (L2)、
−CH2−CH2−NH−C(NH2)= (L4)、
−CH2−CH2−NH−C(O)−CH2−NH−C(NH2)= (L5)、
−CH2−CH2−CH2−NH−C(NH2)= (L6)、
−CH2−CH2−NH−C(Me)= (L7)、
−CH2−CH2−NH−C(O)−CH2−NH−C(Me)= (L8)、
−CH2−CH2−CH2−NH−C(Me)= (L9)、
−CH2−CH2−NR1’−C(NH2)= (L10)、
−CH(CO2H)−CH2−CH2−CH2− (L11)、
−CH(CO2H)−CH2−CH2−CH2−NH−C(NH2)= (L12)、
−CH(CO2H)−CH2− (L13)、
−CH(CO2H)−CH2−CH2− (L14)、
−CH(CO2H)−CH2−CH2−CH2−CH2− (L15)、
−CH2−CH2−CH2−CH2− (L16)、
−CH2−CH2−CH2−CH2−CH2− (L17)、
−CHR2’−C(O)− (L18)、
−CHR2’−CH2− (L19)、
−CHR5−CH2−NR5’−C(Me)= (L20)、
−CHR2’−CH2−CH2− (L21)、
−CH2−CH2−CHR1’− (L22)、
−CH2−CH2−CHR1’−NH−C(O)−C(Me)− (L23)、
−CH2−CHR1’− (L24)、
−CH2−CHR1’−NH−C(Me)= (L25)、又は
−CHR5−CH2−CH2−CHR5’− (L26)
から選択されるリンカーであり、
R1及びR2は、H、C1〜C6アルキル若しくはC2〜C6アルケニルからそれぞれ独立して選択され、又はR1は、4員〜10員環状構造におけるR1’と結合し、及び/若しくはR2は、4員〜10員環状構造におけるR2’と結合し、R 1’ は、4員〜10員環状構造におけるR1と結合し、R2’は、4員〜10員環状構造におけるR2と結合し、
R3は、H、C1〜C6アルキル若しくはC2〜C6アルケニルから選択され、前記アルキル若しくはアルケニル部分は、1個若しくは複数のハロゲン原子若しくは(ハロ)アルコキシ部分で置換されていてもよく、又はR3は、リンカーLが遠位窒素原子とリンカーの隣接主鎖原子との間に配置されている少なくとも1つの二重結合を含むとき、若しくはR2が遠位窒素原子とR2の隣接原子との間に配置されている少なくとも1つの二重結合を含むとき、不在であり、
R4及びXは不在であり、
R5は、4員〜10員環状構造におけるR5’と結合する]。 - R2が、4員〜10員飽和環状構造におけるR2’と結合している、請求項1に記載の化合物。
- R2が、ピペリジン環におけるR2’と結合している、請求項1又は2に記載の化合物。
- L=−CH(CO2H)−(CH2)3−であり、R1=R2=R3=Hである、
L=−(CH2)4−であり、R1=Hであり、R2=R3=Meである、
L=−CHR2’CH2−であり、R1=R3=Hであり、R2−R2’=−(CH2)3−である、又は
L=−CHR5(CH2)2CHR5’−であり、R1=R2=R3=Hであり、R5−R5’=−(CH2)2−である、
請求項1〜3のいずれか一項に記載の化合物。 - 請求項1〜5のいずれか一項に記載の化合物と生理学的に許容される担体とを含む、医薬組成物。
- 請求項1〜5のいずれか一項に記載の化合物と生理学的に許容される担体とを含む、美容組成物。
- ミトコンドリア形態、OXPHOS酵素の発現及びROSレベルのうちの少なくとも1つの調節に使用される薬剤であって、前記薬剤は請求項1〜5のいずれか一項に記載の化合物を含む、薬剤。
- 増加したROSレベルに関連する病理、状態又は障害に関連する症状を治療、予防又は抑制することに使用される薬剤であって、前記薬剤は請求項1〜5のいずれか一項に記載の化合物を含む、薬剤。
- 増加したスーパーオキシドレベルに関連する病理、状態又は障害に関連する症状を治療、予防又は抑制することに使用される薬剤であって、前記薬剤は請求項1〜5のいずれか一項に記載の化合物を含む、薬剤。
- 前記増加したROSレベルに関連する病理、状態又は障害が、パーキンソン病、アルツハイマー病、てんかん、認知症、喘息、筋萎縮性側索硬化症、先天性代謝異常、全身性硬化症、アテローム性動脈硬化症、骨関節炎、関節リウマチ、生体異物毒性、虚血後再灌流傷害、高血圧症、肺高血圧症、肺水腫、腸疾患、子宮内膜症、糖尿病、糖尿病誘発性心機能不全、糖尿病性腎症、がん、胎児性横紋筋肉腫、先天性筋ジストロフィー、ジストロフィン異常症、副腎白質ジストロフィー、ミトコンドリア障害及びミトコンドリア機能不全関連状態からなる群から選択される、請求項9に記載の薬剤。
- 前記ミトコンドリア障害が、ミオクローヌスてんかん、赤色ぼろ線維を伴うミオクローヌスてんかん(MERRF)、レーベル遺伝性視神経症(LHON)、神経性薄弱運動失調網膜色素変性症(NARP)、ミトコンドリア脳筋症乳酸アシドーシス脳卒中(MELAS)、リー症候群、リー様症候群、優性視神経萎縮症(DOA)、カーンズセイヤー症候群(KSS)、母系遺伝性糖尿病及び難聴(MIDD)、アルパースフッテンロッハー症候群、運動失調ニューロパチースペクトラム、慢性進行性外眼筋麻痺(CPEO)、ピアソン症候群、ミトコンドリア神経胃腸脳症(MNGIE)、Sengers症候群、3−メチルグルタコン酸尿症、感音難聴、脳症及び神経放射線学知見のリー様症候群(MEGDEL)、筋疾患、ミトコンドリア筋疾患、心筋症、脳筋症、SURF1(複合体IVのsurfeitタンパク質欠損に起因するCOX欠損リー症候群)、並びに単独のOXPHOS欠損、又はピルビン酸酸化及びATP+PCr産生速度の妨害を含む現在まで未解決な遺伝子欠陥と組み合わされたOXPHOS欠損からなる群から選択される障害であり、前記ミトコンドリア機能不全に関連する状態が、フリートライヒ運動失調症(FRDA)、尿細管性アシドーシス、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、ハンチントン病、広汎性発達障害、聴力損失、難聴、先天性筋ジストロフィー、ジストロフィン異常症、糖尿病、老化、及びミトコンドリア機能を妨げる薬物有害作用からなる群から選択される状態である、請求項11に記載の薬剤。
- 測定可能な臨床マーカーが、本発明の化合物の使用による療法の有効性を評価するために使用される、請求項8〜12のいずれか一項に記載の薬剤。
- 前記臨床マーカーが、全血、血漿、脳脊髄液又は脳室液中の乳酸(乳酸塩)レベル;全血、血漿、脳脊髄液又は脳室液中のピルビン酸(ピルビン酸塩)レベル;全血、血漿、脳脊髄液又は脳室液中の乳酸塩/ピルビン酸塩の比;全血、血漿、又は脳脊髄液中のアミノ酸、特にアラニン、シトルリン及びプロリン、体液中の有機酸、血清及び骨格筋中のFGF21、ホスホクレアチンレベル、NADH(NADH+H+)又はNADPH(NADPH+H+)レベル;NAD又はNADPレベル;ATPレベル;無酸素性作業閾値;還元補酵素Q(CoQred)レベル;酸化補酵素Q(CoQox)レベル;総補酵素Q(CoQtot)レベル;酸化チトクロムCレベル;還元チトクロムCレベル;酸化チトクロムC/還元チトクロムCの比;アセト酢酸塩レベル、ベータ−ヒドロキシ酪酸塩レベル、アセト酢酸塩/ベータヒドロキシ酪酸塩の比、8−ヒドロキシ−2’−デオキシグアノシン(8−OHdG)レベル;反応性酸化種のレベル;並びに酸素消費(VO2)レベル、二酸化炭素排出量(VCO2)レベル及び呼吸商(VCO2/VO2)からなる群から選択される1つ又は複数のマーカーである、請求項13に記載の薬剤。
- 対象において皮膚の更なる老化を治療する又は遅延させるための美容組成物であって、請求項1〜5のいずれか一項に記載の化合物を含む、美容組成物。
- 細胞において反応性酸素種を捕捉するエキソビボの方法であって、前記細胞を、請求項1〜5のいずれか一項に記載の化合物に曝露するステップを含む、方法。
- 前記細胞が、体細胞、配偶子、生殖母細胞又は未分化幹細胞である、請求項16に記載の方法。
- 前記体細胞が、前記細胞を少なくとも1つの再プログラム化因子に曝露することによって、誘導多能性幹細胞(iPSC)に更に再プログラム化される、請求項17に記載の方法。
- 前記再プログラム化因子が、Oct4、Sox2、KLF4、c−Myc、Lin28、Nanog、Glis1、Sall4、Esrrb及びNr5a2のうちの少なくとも1つである、請求項18に記載の方法。
- 前記体細胞が、線維芽細胞、神経(前駆)細胞、肝細胞、B細胞、腎細胞、筋細胞、副腎細胞、ケラチン生成細胞、メラニン形成細胞、上皮細胞又は末梢血由来細胞である、請求項17〜19のいずれか一項に記載の方法。
- 前記末梢血由来細胞が、内皮前駆細胞(L−EPC)又は臍帯血由来細胞型(CD34+)である、請求項20に記載の方法。
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EP2600857A4 (en) | 2010-08-06 | 2014-06-11 | Edison Pharmaceuticals Inc | TREATMENT OF OCHONDRIAL DISEASES WITH NAPHTHOCHINONES |
SG190472A1 (en) * | 2011-11-25 | 2013-06-28 | Creative Tech Ltd | A speaker apparatus suitable for use with a computer |
EP2872497B2 (en) * | 2012-07-12 | 2019-10-09 | Khondrion Ip B.V. | Chromanyl derivatives for treating mitochondrial disease |
CA2912871A1 (en) * | 2013-05-31 | 2014-12-04 | Edison Pharmaceuticals, Inc. | Carboxylic acid derivatives for treatment of oxidative stress disorders |
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US10815211B2 (en) | 2020-10-27 |
US11530190B2 (en) | 2022-12-20 |
US20210024484A1 (en) | 2021-01-28 |
JP6639656B2 (ja) | 2020-02-05 |
JP2018531250A (ja) | 2018-10-25 |
JP2020073524A (ja) | 2020-05-14 |
EP3359521A1 (en) | 2018-08-15 |
HK1257665A1 (zh) | 2019-10-25 |
WO2017060432A1 (en) | 2017-04-13 |
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