MULTIFUNCTIONAL NITROXIDE DERIVATIVES AND USES THEREOF

摘要

Multifunctional nitroxide derivatives comprising a potassium channel opener and a reactive oxygen species (ROS) degradation catalyst that can act as an anti-oxidant, as well as pharmaceutical compositions comprising them are provided. The multifunctional compounds and pharmaceutical compositions are useful for treatment of diseases, disorders or conditions associated with oxidative stress or endothelial dysfunction.

主权项

1. A compound of the formula I: or an enantiomer, wastereomer, racemate, or a pharmaceutically acceptable salt or solvate thereof; wherein A is a moiety of the formula II linked through its terminal —NH group to any carbon atom of the pyridine ring: X is —(CR2R2)n—; R1 is absent or 1 to 4 substituents each independently selected from the group consisting of halogen, —CN, —OH, —NO2, —N(R6)2, —OCF3, —CF3, —OR6, —COR6, —COOR6, —CON(R6)2, —OCOOR6, —OCON(R6)2, —(C1-C8)alkyl, —(C1-C8)alkylene-COOR6, —SR6, —SO2R6, —SO2N(R6)2, and —S(═O)R6, wherein said —(C1-C8)alkyl and —(C1-C8)alkylene-COOR6 may optionally be substituted with —OH, —OR3, —OCF3, —CF3, —COR3, —COOR3, —OCOOR3, —OCON(R3)2, —(C1-C8)alkylene-COOR3, —CN, —NH2, —NO2, —SH, —SR3, —(C1-C8)alkyl, —O—(C1-C8)alkyl, —N(R3)2, —CON(R3)2, —SO2R3, or —S(═O)R3, or two adjacent R1 groups and the carbon atoms to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, (C6-C10)aryl, or 6- to 10-membered heteroaryl; R2 each independently is selected from the group consisting of H, halogen, —OCF3, —CF3, —OR7, —COR3, —COOR3, —OCOOR7, —OCON(R7)2, —(C1-C8)alkylene-COOR7, —CN, —NO2, —SH, —SR3, —(C1-C8)alkyl, —N(R7)2, —CON(R7)2, —SO2R7, SO2N(R7)2, and —S(═O)R7; R3 each independently is selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, and (C2-C8)alkynyl; R4 is selected from the group consisting of H, —COOR3, —(C1-C8)alkylene-COOR7, —CN, —(C1-C8)alkyl, and —CON(R7)2; R5 is selected from the group consisting of H, —OH, —O—(C1-C8)alkyl, —CO—(C1-C8)alkyl, —COO—(C1-C8)alkyl, —CN, and —NH2; R6 each independently is selected from the group consisting of H, (C1-C8)alkyl, (C3-C10)cycloalkyl, 4-12-membered heterocyclyl, (C6-C14)aryl, and —(C1-C8)alkylene-NH2; R7 each independently is selected from the group consisting of H, (C1-C8)alkyl, —(C1-C8)alkylene-NH2, (C3-C10)cyclo alkyl, 4-12-membered heterocyclyl, and (C6-C14)aryl, each of which other than H may optionally be substituted with —OR6, —COR6, —COOR6, —OCOOR6, —OCON(R6)2, —(C1-C8)alkylene-COOR6, —CN, —NO2; —SR6, —(C1-C8)alkyl, —N(R6)2, —CON(R6)2, —SO2R6, or —S(═O)R6; and n is an integer of 1 or 2.