Novel Cell-Permeable Succinate Compounds

摘要

The present invention provides novel cell-permeable succinates and cell permeable precursors of succinateaimed at increasing ATP-production in mitochondria. The main part of ATP produced and utilized in the eukaryotic cell originates from mitochondrial oxidative phosphorylation, a process to which high-energy electrons are provided by the Kreb's cycle. Not all Kreb's cycle intermediates are readily permeable to the cellular membrane, one of them being succinate. The provision of the novel cell permeable succinates is envisaged to allow passage over the cellular membrane and thus the cell permeable succinates can be used to enhance mitochondrial ATP-output.

主权项

1: A compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein the dotted bond between A and B denotes an optional bond so as to form a ring closed structure, and wherein Z is —CH2—CH2— or >CH(CH3), A is selected from the group consisting of —SR, —OR and NHR, and R is B is selected from the group consisting of —O—R′, —NHR″, —SR′″ and —OH; and R′ is selected from: R′, R″ and R′″ are independently different or identical and are selected from: R1 and R3 are independently different or identical and are selected from the group consisting of H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, CH2Xalkyl, CH2X-acyl, F, CH2COOH, and CH2CO2alkyl, X is selected from the group consisting of O, NH, NR6, and S, R2 is selected from the group consisting of Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(O)CH3, C(O)CH2C(O)CH3, and C(O)CH2CH(OH)CH3, p is an integer and is 1 or 2 R6 is selected from the group consisting of H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, formula (II), and formula (VIII), X5 is selected from the group consisting of —H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, —COOH, —C(═O)XR6,and CONR1R3,
X7 is R1 or —NR1R3, R9 is selected from the group consisting of H, Me, Et and O2CCH2CH2COXR8, R10 is selected from the group consisting of Oacyl, NHalkyl, NHacyl, and O2CCH2CH2COX6R8, X6 is selected from the group consisting of O, NR8, and NR6R8, wherein R6 and R8 are independently different or identical and are selected from the group consisting of H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, formula (II), and formula (VIII), R11 and R12 are independently different or identical and are selected from the group consisting of H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, propionyl, benzoyl, —CH2Xalkyl, and —CH2Xacyl, where X is O, NR6 or S, Rc and Rd are independently different or identical and are CH2Xalkyl or CH2Xacyl, where X═O, NR6 or S, R13, R14 and R15 are independently different or identical and are selected from the group consisting of H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, —COOH, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, and CH2Xalkyl; Substituents on R13 and R14 or R13 and R15 may bridge to form a cyclic system, Rf, Rg and Rh are independently different or identical and are selected from the group consisting of Xacyl, —CH2Xalkyl, —CH2X-acyl and R9, alkyl is selected from the group consisting of Me, Et, propyl, i-propyl, butyl, iso-butyl, and t-butyl, acyl is selected from the group consisting of formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, and benzoyl, acyl and/or alkyl may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula (I) is wherein X4 is selected from the group consisting of —COOH, —C(═O)XR6, with the proviso that the compound is not