NEW CELL-PERMEABLE SUCCINATE COMPOUNDS

Abstract

The present invention relates to novel cell-permeable succinates and cell-permeable precursors of succinate for increasing ATP production in mitochondria. Most of the ATP produced and used in eukaryotic cells originates from mitochondrial oxidative phosphorylation, a process to which the Krebs cycle provides high-energy electrons. Not all Krebs cycle intermediates are readily permeable to the cell membrane, succinate being one such intermediate. The provision of novel cell-permeable succinates is intended to enable passage across the cell membrane, and thus the cell-permeable succinates can be used to enhance mitochondrial ATP output.

Description

cellular and thus cell-permeable succinates can be used to enhance mitochondrial ATP output.

Claims

DEMANDS 1. Compound according to the invention represented by formula (I) or a pharmaceutically acceptable salt thereof, a formula in which the The 5-line dash between A and B represents an optional link to form a closed cyclic structure, and in which Z is chosen from -CH2-CH2- and >CH(CH3), A is chosen from -SR, -OR and NHR, and R is 10 B is chosen from -O-R', -NHR", -SR'" and -OH; and R' is chosen from formulas (II) to (IX) below: R', R" and R'" are independently identical or different and are chosen from the formulas (IV-VIII) below: RI and R3 are independently identical or different and are chosen from H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, O-acyl, O-alkyl, N-acyl, N-alkyl, X-acyl, CH2X-alkyl, CH2X-acyl, F, CH2COH, CH2CO2-alkyl, X is chosen from O, NH, NR6, s, R2 is chosen from Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, C(O)CH3, C(O)CH2C(O)CH3, C(O)CH2CH(OH)CH3, P is an integer and is equal to 1 or 2. R6 is chosen from H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, acyl, propionyl, benzoyl, formula (II), and formula (VIII), X5 is chosen from -H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, -COOH, -C(=O)XR6, CONRIR3 or meets the formula X7 is chosen from RI, -NRIR3, R9 is chosen from H, Me, Et and 02CCH2CH2C0XR8, RIO is chosen from O-acyl, NH-alkyl, NH-acyl, and O2CCH2CH2COX6R8. X6 is chosen from O, NR8, NR6R8, where R6 and R8 are independently identical or different and are chosen from H, alkyl, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, acyl, propionyl, benzoyl, formula (II), and formula (VIII), R11 and RI 2 are independently identical or different and are chosen from H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, propionyl, benzoyl, -CH2X-alkyl, -CH2X-acyl, where X is O, NR6 or s, Rc and Rd are independently identical or different and are chosen from CH2X-alkyl, CH2X-acyl, where X = O, NR6 or s, RI 3, RI 4 and are independently identical or different and are chosen from H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, -COOH, o-acyl, o-alkyl, N-acyl, N-alkyl, x-acyl, CH2X-alkyl, The substituents on R13 and R14 or R13 and can be bridged to form a cyclic system, Rf, Rg and Rh are independently identical or different and are chosen from X-acyl, -CH2X-alkyl, -CH2X-acyl and R9, the alkyl is chosen from Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, the acyl is chosen from formyl, acetyl, propionyl, isopropionyl, butyryl, tert-butyryl, pentanoyl, benzoyl. The acyl and / or alkyl groups may optionally be substituted, and when the line of dashes between A and B is present, the compound of formula (I) is when X4 is chosen from -COOH, -C(=O)XR6, 2. Compound according to claim 1, of formula (IA) or a pharmaceutically acceptable salt thereof, formula in which Zest -CH2-CH2-, A is chosen from -SR, -OR and NHR, and R is B is chosen from -O-R', -NHR'", -SR'", and -OH; and R', R" and R'" are independently identical or different and are chosen from the formulas below: RI and R3 are independently identical or different and are chosen from H, Me, Et, propyl, O-Me, O-Et, O-propyl, X is chosen from O, NH, s. P is an integer and its value is... R6 is chosen from H, Me, Et, X5 is chosen from -H, Me, Et, -COOH, -C(=O)XR6, CONRIR3, X7 is chosen from RI, -NRIR3, RI 3, RI 4 and are independently identical or different and are chosen from H, Me, Et, propyl, isopropyl, butyl, isobutyl, tert-butyl, -COOH, O-acyl, O- alkyl, N-acyl, N-alkyl, X-acyl, CH2X-alkyl, where the alkyl and acyl are as defined above.

3. Compound according to claim 1 or 2, of formula (IA) or a pharmaceutically acceptable salt thereof, formula in which Zest -CH2-CH2-, A is chosen from -SR, -OR and NHR, and R is B is chosen from -O-R', -NHR'", -SR'", and -OH; and R', R" and R'" are independently identical or different and are chosen from the formulas below: RI and R3 are independently identical or different and are chosen from H, Me, Et, propyl, O-Me, O-Et, O-propyl, X is chosen from O, NH, s. P is an integer and its value is... R6 is chosen from H, Me, Et, X5 is chosen from -H, Me, Et, -COOH, -C(=O)OR6, CONRIR3, X7 is chosen from RI, -NRIR3, R13, R14 and are independently identical or different and are chosen from H, Me, Et, -COOH.

4. Compose according to any one of the preceding claims, wherein Z is -CH2CH2- and A is -SR.

5. Compound according to any one of the preceding claims, wherein Z is -CH2CH2-, A is -SR, and B is OH or SR'".

6. A compound according to any one of the preceding claims, wherein Z is -CH2CH2-, A is -SR, B is OH or -SR'", where R'" is 7. A compound according to any one of the preceding claims, wherein Z is -CH2CH2- and A is SR and B is OH.

8. A compound according to any one of claims 1 to 3, wherein Z is -CH2CH2-, A is NR, B is OH and R is and X is S.

9. Compose according to any one of the preceding claims, wherein R and / or R'" are and P = 1 and X5 is -H so that formula (VII) is 10. Compose according to any one of claims 1 to 8, wherein R and / or R'" are and P = 1 and X5 is C0XR6 so that formula (VII) is 11. Composed according to any one of claims 1 to 8, wherein R and / or R'" are and P = 1 and X5 is CONRIR3 so that formula (VII) is 12. Compose according to any one of the preceding claims, which compose is chosen from:

13. Compose according to any one of the claims there 12, for use in medicine.

14. Composed according to any one of the claims there 12, for use in cosmetics. 10 15. Composition comprising a compound of formula (I) as defined according to any one of the claims there 12 and one or more excipients acceptable from a pharmaceutical or cosmetic point of view.