Cell-permeable succinate compounds
AssigneeAbliva AB
InventorsEskil Elmer, Magnus Joakim Hansson, Karl Henrik Johannes Ehinger, Steven Moss
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Abstract
The present invention provides novel cell-permeable succinates and cell permeable precursors of succinate aimed 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.
Claims19
A method for treating a disease selected from the group consisting of metabolic diseases, diseases of mitochondrial dysfunction, diseases related to mitochondrial dysfunction, and mitochondrial disorders, or treating drug-induced mitochondrial side-effects, said method comprising administering to a subject a compound of Formula (IA)
- or a pharmaceutically acceptable salt thereof, wherein
- Z is —CH2—CH2—,
- A is —SR, wherein R is
- B is selected from the group consisting of —O—R′, —SR′″ and —OH;
- wherein R′ is selected from the group consisting of:
- R′″ is selected from the group consisting of:
- 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, 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,
- 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, NRs, 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, Re 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, where X=O, NR6 or S;
- 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, where X=O, NR6 or S,
- 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, butyryl, tert-butyryl, pentanoyl, and benzoyl,
- acyl and/or alkyl may be optionally substituted.
Dependencies are inferred from the claim text.