Multifunctional radical quenchers for the treatment of mitochondrial dysfunction

摘要

The present disclosure provides methods for identifying therapeutic agents that are multifunctional radical quenchers. It also provides compounds of formula (I), (II), or (II-A):;
and pharmaceutically acceptable salts thereof, compositions comprising these compounds, and methods of using these compounds in a variety of applications, such as treatment or suppression of diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation.

主权项

1. A compound of formula: wherein X is halogen; R1 is hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, —OR7, —SR7, —NHR7, or —N(R7)2, each optionally substituted with one to four substituents selected from halogen, —CN, —NO2, C1-C6 alkyl, halo(C1-C6 alkyl), —OR8, —NR82, —CO2R8, —CONR82, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, and heterocyclyl, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R9;
where each R7 independently is hydrogen, C1-C6 alkyl, or halo(C1-C6 alkyl);where each R8 independently is hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-C6 alkyl), C3-C8 cycloalkyl(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), or heterocyclyl(C1-C6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R9;where each R9 independently is halogen, —CN, —NO2, —N3, C1-C6 alkyl, halo(C1-C6 alkyl), C1-C6 alkoxy, amino, C1-C6 alkylamino, or diC1-C6alkylamino; R2 is —OH, —O(C1-C6 alkyl), —O(halo C1-C6 alkyl), —NHR11, or —N(R11)2;
where each Ru independently is C4-C20 alkyl, C4-C20 alkenyl, or C4-C20 alkynyl; R3 is hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, or —OR7, each optionally substituted with one to four substituents selected from halogen, —CN, —NO2, C1-C6 alkyl, halo(C1-C6 alkyl), —OR8, —NR82, —CO2R8, —CONR82, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, and heterocyclyl, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R9; R4 and R5 are independently C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl, each optionally substituted with one to four substituents selected from halogen, —CN, —NO2, C1-C6 alkyl, halo(C1-C6 alkyl), —OR8, —NR82, —CO2R8, —CONR82, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, and heterocyclyl, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R9; each R6 is hydrogen, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, or —OR10, wherein each alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from halogen, —CN, —NO2, C1-C6 alkyl, halo(C1-C6 alkyl), —OR8, —NR82, —CO2R8, —CONR82, C3-C8 cycloalkyl optionally substituted with R9, C3-C8 cycloalkenyl optionally substituted with R9, aryl optionally substituted with R9, heteroaryl optionally substituted with R9, and heterocyclyl optionally substituted with R9;
where R10 is C1-C6 alkyl, halo(C1-C6 alkyl), C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-C6 alkyl), C3-C8 cycloalkyl(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), or heterocyclyl(C1-C6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R9.