WO2017060418A1 - Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées aux mitochondries - Google Patents

Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées aux mitochondries Download PDF

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WO2017060418A1
WO2017060418A1 PCT/EP2016/073985 EP2016073985W WO2017060418A1 WO 2017060418 A1 WO2017060418 A1 WO 2017060418A1 EP 2016073985 W EP2016073985 W EP 2016073985W WO 2017060418 A1 WO2017060418 A1 WO 2017060418A1
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formula
acid
independently
derived
optionally substituted
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PCT/EP2016/073985
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Steven Moss
Eskil Elmér
Magnus Joakim HANSSON
Karl Henrik Johannes EHINGER
Karl Michael KARLSSON
Sarah PIEL
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Neurovive Pharmaceutical Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/38—Malonic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms

Definitions

  • the present invention provides cell-permeable carboxylic acid-based metabolites involved in cellular metabolism such as pyruvate and Kreb's cycle (TCA)
  • the invention also provides novel cell-permeable carboxylic acid-based metabolites functioning as enzymatic or electron transport inhibitors such as malonate.
  • the present invention relates to novel compounds as such and to the compounds for use in medicine, notably in the treatment of a mitochondria-related disease or disorder.
  • the compounds may also be used as cosmetics.
  • 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.
  • carboxylic acid-based metabolites are readily permeable to the cellular membrane, some of them being glutarate, fumarate, malonate, malate, citrate, acetoacetate, glycerate, pyruvate, alpha-ketoglutarate, aconitate, isocitrate, oxalosuccinate, oxaloacetate (in the following commonly denoted carboxylic acid-based metabolites; please note that this definition does not encompass succinate).
  • a cell-permeable carboxylic acid-based metabolite can be used to inhibit activity of mitochondrial enzymes or electron transport by the respiratory chain, such as a cell-permeable precursor of malonate, which is an inhibitor of succinate dehydrogenase (complex II of the electron transport chain). Inhibition of complex II has, in animal studies, been shown to be useful in eg. ischemia-reperfusion injury (Chouchani, E.T., et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431-435 (2014)).
  • present invention also provides cell permeable carboxylic acid-based metabolites or equivalents to carboxylic acid-based metabolites which in addition to being cell permeable and releasing the carboxylic acid-based metabolite in the cytosol are also potentially able to provide additional energy to the organism by the hydrolytic products resulting from either chemical or enzymatic hydrolysis of the carboxylic acid-based metabolites.
  • the present invention also provides methods for preparing compounds of the invention that have improved properties for use in medicine and/or in cosmetics.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related disorders, in maintaining or enhancing cellular metabolic status, normal mitochondrial function, enhancing mitochondrial function, i.e.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related conditions, such as ischemia reperfusion injury, by inhibiting activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • Mitochondria are organelles in eukaryotic cells. They generate most of the cell's supply of adenosine triphosphate (ATP), which is used as an energy source. Thus, mitochondria are indispensable for energy production, for the survival of eukaryotic cells and for correct cellular function. In addition to supplying energy, mitochondria are involved in a number of other processes such as cell signalling, cellular differentiation, cell death as well as the control of the cell cycle and cell growth. In particular, mitochondria are crucial regulators of cell apoptosis and they also play a major role in multiple forms of non-apoptotic cell death such as necrosis.
  • ATP adenosine triphosphate
  • a compound of the invention is given by Formula (I) or Formula (IA)
  • R 3 and R 4 are independently H, optionally substituted C-
  • R 4 is H
  • R 5 is OCOR a , OCOOR b , OCONR c R d , S0 2 R e , OPO(OR f )(OR g ), CONR c R d or is linked to R 3 by a group of formula COO(CR'R")0 to form a ring, where R' and R" are independently H, optionally substituted Ci-C 3 alkyl, or are linked together to form a ring; where
  • R a is optionally substituted methyl, ethyl or cycloalkyl
  • R b is optionally substituted C C 3 alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms;
  • R e is optionally substituted alkyl;
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • R 3 and/or R 4 can be methyl or ethyl.
  • R 3 can be methoxy or ethoxy.
  • R-i can be methyl.
  • R 5 can be an optionally substituted alkyl ester providing the alkyl ester does not contain a further succinate (OCOCH 2 CH 2 COO) moiety.
  • R 5 can be OCOR a where R a is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 .
  • the compound can be where Ri and R 5 are linked together to form a ring and the ring comprises one or more acetal groups.
  • Compounds may include those according to formula (III)
  • R 3 and R 4 are independently H, optionally substituted C-
  • the compound can be of type according to formula (I) or formula (IA) wherein R- ⁇ is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Rc and Rd can be methyl or ethyl.
  • the compound can be of type according to formula (I) or formula (IA) where R-i is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 4 is H or optionally substituted C-
  • Ci-C 3 alkyl independently H, optionally substituted Ci-C 3 alkyl, or are linked together to form a ring.
  • the compound may be a compound according to formula (Va) where formula (Va) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • R 4 is H
  • R 5 is OCOR a , OCOOR b , OCONR c R d , S0 2 R e , OPO(OR f )(OR g ), CONR c R d or is linked to R 3 by a group of formula COO(CR'R")0 to form a ring, where R' and R" are independently H, optionally substituted C-
  • R a is optionally substituted methyl, ethyl or cycloalkyl
  • R b is optionally substituted C C 3 alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms;
  • R e is optionally substituted alkyl;
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • the compound may be selected from
  • the compound may be a compound according to formula XII where formula XII is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Compounds as described herein can be used in medicine or in cosmetics, or in the manufacture of a composition for such use.
  • the medicament can be used in the treatment of metabolic diseases, or in the treatment of diseases of mitochondrial dysfunction, treating or suppressing of mitochondrial disorders.
  • the compounds may be used in the stimulation of mitochondrial energy production.
  • the compounds may be used in the treatment of cancer and following hypoxia, ischemia, stroke, myocardial infarction, acute angina, an acute kidney injury, coronary occlusion and atrial fibrillation, or to avoid or counteract reperfusion injuries.
  • Figure 1 Inhibition of mitochondrial complex ll-supported respiration in intact human platelets.
  • Cells 200 « 10 6 /ml were incubated with 2 ⁇ of the respiratory complex I inhibitor Rotenone and 500 ⁇ of the cell-permeable succinate prodrug compound SEL 241 to establish complex ll-supported respiration and subsequently were titrated with increasing, cumulative doses of either Malonate (M), Dimethyl malonate (DM) or the cell-permeable malonate derivative NV161 .
  • Rates of complex ll-supported respiration are expressed as % of control and are presented as mean ⁇ SEM. Standard non-linear curve fitting was applied to obtain half maximal inhibitory concentration (IC 5 o) values.
  • Compounds according to the present invention can be used to enhance energy production in mitochondria.
  • the compounds can be used in medicine, medical research or in cosmetics.
  • the compounds can be used in the prevention or treatment of disorders or diseases having a component relating to mitochondrial dysfunction or aberrant activity.
  • Enhancement of energy production is e.g. relevant in subjects suffering from a mitochondrial defect, disorder or disease.
  • Mitochondrial diseases result from dysfunction of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondria fail, less and less energy is generated within the cell and cell injury or even cell death will follow. If this process is repeated throughout the body the life of the subject in whom this is happening is severely compromised.
  • Certain conditions, such as ischemia reperfusion injury can be related to aberrant or over-activity of mitochondrial enzymes or electron transport of the respiratory chain. This aberrant activity can cause release of harmful oxidative molecules that can damage the mitochondria itself and its host cell.
  • a mitochondrial deficiency such as a Complex I, II, III or IV deficiency of the respiratory chain or an enzyme deficiency of metabolic pathways such as the glycolysis and/or TCA cycle.
  • some conditions such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • Ri and R 2 can be the same, or R-i can be a different formula (II) such that both acids of the molecule, if present, are protected in the form of different moieties where Ri and R 2 are different.
  • R-i can be alkyl.
  • R-i can be methyl.
  • Ri can be ethyl.
  • Both Ri and R 2 can be different versions of formula (II) such that each end of the molecule is provided with a different moiety.
  • R 3 and/or R 4 can be methyl or ethyl.
  • R 3 can be H.
  • R 3 can be C-
  • R 4 can be H.
  • R 3 and R 4 can be different at each end of the molecule.
  • R 3 and R 4 can be linked together to form a ring.
  • R 3 and R 5 can be linked together to form a ring.
  • the ring may be an all carbon ring, or may contain additional heteroatoms.
  • the R 3 -R 5 ring may contain one or more OCR'R'O linkages where R' and R" are independently H, optionally substituted C-
  • the compounds may be of formula (I) or (IA) where A is -OR-i and R-i is H or a pharmaceutically acceptable salt, or an optionally substituted alkyl group or a group of formula (II) and B is -OR 2 and R 2 is
  • R 5 is linked to R-i to form a ring or R 5 is selected from OCOR a , OCOOR b , OCONR c R d ,S0 2 R e , OPO(OR f )(OR g ) or CON R c R d
  • R a is optionally substituted alkyl
  • R b is optionally substituted alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms
  • R e is optionally substituted alkyl
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • R 5 can be an optionally substituted alkyl ester.
  • R 5 can be an optionally substituted alkyl ester with the exception of butyl ester where R 5 is OCOCH 2 CH 2 CH 3 .
  • R 5 can be OCOR a where R a is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 .
  • Exemplary compounds may be of formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • Ra is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 and R x is H or a pharmaceutically acceptable salt or alkyl or an optionally substituted alkyl or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C1-C3 alkyl, or are linked together to form a ring and where R 5 is selected from OCOR a , OCOOR b ,
  • R a is optionally substituted alkyl
  • R b is optionally substituted alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms
  • R e is optionally substituted alkyl
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • Exemplary compounds can be where R-i and R 5 are linked together to form a ring and the ring comprises one or more acetal groups.
  • Compounds may include those according to formula (III)
  • R 3 and R 4 are independently H, optionally substituted C-
  • R 3 and/or R 4 can be methyl or ethyl.
  • R 3 can be H .
  • R 4 can be H . If n is greater than 1 , each of the R 3 and R 4 groups can be different at each acetal moiety.
  • R 3 and R 4 can be linked together to form a ring.
  • the ring may be an all carbon ring, or may contain additional heteroatoms.
  • Exemplary compounds can be of type according to formula (I) or formula (IA),
  • a and B are as herein defined before, and wherein Ri is H or an optionally substituted alkyl group or a group of formula (I I) and R 2 is independently a group according to formula (I I) where formula (I I) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • R b can be alkyl.
  • R b can be methyl or ethyl.
  • Exemplary compounds may be of formula where R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can be of type according to formula (I) or formula (IA) and A and B being as defined herein before, and wherein R-i is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 3 is linked together with R 5 by a group of formula COO(CR'R")0 to form a ring, where R' and R" are independently H, optionally substituted C-
  • R 4 is H or optionally substituted C-
  • R 5 is linked to R 3 by a group of formula COO(CR'R")0 to form a ring, where R' and R" are independently H, optionally substituted C-
  • Exemplary compounds may be of formula
  • R 3 is linked together with Rb to form a ring
  • R 4 is H, optionally substituted C C 3 alkyl
  • R b is linked to R 3 ;
  • R x is H or a pharmaceutically acceptable salt or alkyl or optionally substituted alkyl or a group of formula (II) where formula (II) is
  • R 3 is H, optionally substituted C-
  • R 4 is H, optionally substituted C-
  • R 5 is selected from OCOR a , OCOOR b , COOR b , OCONR c R d , S0 2 R e , OPO(OR f )(OR g ) or CONR c R d or R 5 is linked to R 3 to form a ring containing one or more OCR'R'O linkages where R' and R" are independently H, optionally substituted C-
  • R a is optionally substituted alkyl or optionally substituted cycloalkyl
  • R b is optionally substituted alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms;
  • R e is optionally substituted alkyl
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • R 3 and R 5 can be linked by a group to form a ring containing one or more OCR'R'O linkages where R' and R" are independently H, optionally substituted C-
  • R 3 and R 5 can be linked by a group of formula COO(CR'R")0 to form a ring.
  • the ring can comprise a moiety of formula (V) where formula (V) is
  • R 4 is H or optionally substituted C-
  • R' and R" can each be methyl.
  • One or both ends of the succinate may contain the ring as shown above. Where both ends of the succinate contain the ring, the compound may be a compound according to formula (Va) where formula (Va) is
  • Exemplary compounds can be of type according to formula (i) or (IA), wherein A and B are as defined herein before, and wherein Ri is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds may be of formula where R 3 and R 4 are independently H, optionally substituted C-
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds may be of formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • R c and R d are independently H, alkyl, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms
  • R x is H or a pharmaceutically acceptable salt or alkyl or optionally substituted alkyl or a group of formula (II) where formula (II) is where R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can be of type according to formula (I) or formula (IA),
  • R-i is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted Ci-C 3 alkyl, or are linked together to form a ring and R 5 is S0 2 R e where R e is optionally substituted alkyl.
  • Exemplary compounds may be of formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • R e is alkyl, cycloalkyi, optionally substituted alkyl or an amino or substituted amino group
  • R x is H or a pharmaceutically acceptable salt or alkyl or optionally substituted alkyl or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can be of type according to formula (I) or formula (IA), wherein A and B are as defined herein before, and wherein Ri is H or an optionally substituted alkyl group or a group of formula (II) and R 2 is independently a group according to formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds may be of formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • R f and R g are independently, H, a pharmaceutically acceptable salt, methyl, ethyl, propyl or are linked together to form a ring
  • R x is H or a pharmaceutically acceptable salt or alkyl or optionally substituted alkyl or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • R a is optionally substituted alkyl
  • R b is optionally substituted alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms
  • R e is optionally substituted alkyl
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • Exemplary examples include compounds of formula (I) where one or both ends of the compound is protected with a moiety selected from:
  • R 3 is H, methyl or ethyl and Ra is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 .
  • the other end of the molecule can be H or a pharmaceutically acceptable salt or optionally substituted alkyl group or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary examples include compounds of formula (I) where one of the ends of the compound is protected with a moiety selected from:
  • R 3 is H, methyl or ethyl and R c and R d are independently H, CH 3 , or CH 2 CH 3
  • the other end of the molecule can be H or a pharmaceutically acceptable salt or optionally substituted alkyl group or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can include those of formula O O R 7 O
  • R 7 is H, methyl or ethyl
  • R 6 is H or methyl
  • R x is H or a pharmaceutically acceptable salt or alkyi or optionally substituted alkyi or a group of formula (II) where formula (II) is
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can include those of formula
  • each R 7 is independently H, methyl or ethyl and each R 6 is independently H or methyl.
  • Exemplary compounds can include compounds where two moieties are linked together via an acetal linkage.
  • Exemplary compounds can include those of formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • R 4 is H
  • R 5 is OCOR a , OCOOR b , OCONR c R d , S0 2 R e , OPO(OR f )(OR g ), CONR c R d or is linked to R 3 by a group of formula COO(CR'R")0 to form a ring, where R' and R" are independently H, optionally substituted C-
  • R a is optionally substituted C C 3 alkyl or cycloalkyl
  • R b is optionally substituted C C 3 alkyl
  • R c and R d are independently H, optionally substituted alkyl or are linked together to form a ring which may contain one or more further heteroatoms;
  • R e is optionally substituted alkyl;
  • R f and R g are independently, H, methyl, ethyl or are linked together to form a ring.
  • Exemplary compounds can include those of formula XV
  • each R 7 is independently H, methyl or ethyl and each R 6 is independently H or methyl.
  • Z may independently be the same or different.
  • the compound may be selected from or The compound may be a compound according to formula
  • R 3 and R 4 are independently H, optionally substituted C-
  • Exemplary compounds can include those of formula XIII
  • the exemplary compounds may be according to formula XIII
  • each R 6 and R 8 is H and wherein each R 7 is independently H or methyl.
  • the exemplary compounds may be according to formula (XIII)
  • R 9 is a moiety selected from;
  • R 4 is H or optionally substituted C1-C 3 alkyl and R' and R" are
  • R 4 is H
  • R 3 is H or optionally substituted C-
  • R 5 is OCOR a , where R a is optionally substituted methyl, ethyl or cycloalkyi or forms part of a succinate CH2CH2CO2- moiety;
  • R-io is a moiety selected from:
  • R 4 is H or optionally substituted C-
  • R 4 is H
  • R 3 is H or optionally substituted C-
  • R 5 is OCOR a , where R a is optionally substituted methyl, ethyl or cycloalkyl.
  • Compounds of the invention may include a compound having one or more of the acid carboxyl groups protected by the following groups:
  • Compounds of the invention may be made by starting with a suitable carboxylic acid-based metabolite such as malonic acid, fumaric acid, malic acid, glutamic acid, alpha-ketoglutaric acid, acetoacetic acid, citric acid, iso-citric acid, glyceric acid, pyruvic acid, aconitic acid, iso-citric acid, oxalosuccinic acid or oxaloacetic acid.
  • a suitable mono-protected carboxylic acid-based metabolite or a mono-activated carboxylic acid-based metabolite a may be used as a starting material.
  • the present invention further provides a process for the preparation of a compound of formula (I) which comprises reacting a carboxylic acid-based metabolite as listed above with compound of formula (VI)
  • Hal represents a halogen (e.g. F, CI, Br or I) and R 3 , R 4 and R 5 are as defined in formula (I).
  • reaction of a carboxylic acid-based metabolite and the compound for formula (VI) may conveniently be carried out in a solvent such as dichloromethane, acetone, acetonitrile or /V,/V-dimethylformamide with a suitable base such as triethylamine, di/sopropylethylamine or caesium carbonate at a temperature, for example, in the range from -10°C to 80°C, particularly at room temperature.
  • a suitable base such as triethylamine, di/sopropylethylamine or caesium carbonate
  • the reaction may be performed with optional additives such as sodium iodide or tetraalkyl ammonium halides (e.g. tetrabutyl ammonium iodide).
  • the compound of formula (I) may be prepared by reacting a group of formula (VII)
  • PG-i is a protecting group such as ferf-butyl, benzyl or 4-methoxybenzyl, with a group of formula (VI) under the conditions outlined above followed by deprotection of the protecting group under appropriate conditions such as trifluoroacetic acid or hydrochloric acid in a solvent such as dichloromethane or by hydrogenation (aryl groups) with a catalyst such as palladium on carbon in a solvent such as ethyl acetate, followed by reaction of the resulting compound with a different group of formula (VI) under the conditions outlined above to react with the deprotected carboxylate.
  • a protecting group such as ferf-butyl, benzyl or 4-methoxybenzyl
  • the compound of formula (I) may be prepared by reacting a group of formula (VIII)
  • Protected double carboxylic acid-based metabolite compounds may conveniently be prepared by reaction of a group of formula (IX) 0 0 0 0 0
  • Compounds of formula (IX) may be conveniently prepared by reaction of a compound of formula (VII) with dichloromethane in a suitable solvent such as dichloromethane with a suitable additive such as tetrabutylhydrogensulfate. The resulting bis-ester may be subsequently hydrolysed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid in a solvent such as dichloromethane to afford compounds of formula (IX).
  • the disclosures herein include any pharmaceutically acceptable salts. Where compounds are isomers, all chiral forms and racemates are included. The disclosures include all solvates, hydrates and crystal forms.
  • the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers.
  • the invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared.
  • any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein.
  • the salt should be seen as being a pharmaceutically acceptable salt.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium or organic bases such as ammonium, ethanolamine, ⁇ , ⁇ -dialkylethanolamines or morpholine salts.
  • acid addition salts include acid addition salts formed with acetic, 2,2- dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene- 2-sulfonic, naphthalene-1 ,5-disulfonic and p-toluenesulfonic), ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • o oxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic
  • lactic e.g. (+)-L-lactic and ( ⁇ )-DL-lactic
  • lactobionic maleic, malic (e.g.
  • salts are salts derived from mineral acids such as
  • hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • solvates of the compounds and their salts are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • a non-toxic pharmaceutically acceptable solvent referred to below as the solvating solvent.
  • solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide.
  • Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent.
  • Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
  • TGE thermogravimetric analysis
  • DSC differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • the solvates can be stoichiometric or non-stoichiometric solvates.
  • Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.
  • solvates and the methods used to make and characterise them see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.
  • Compounds as described herein can be used in medicine, medical research or in cosmetics, or in the manufacture of a composition for such use.
  • the medicament can be used in in any situation where an adjusted, enhanced or restored
  • mitochondrial function is desired, such as in the treatment of metabolic diseases, or in the treatment of diseases or conditions of mitochondrial dysfunction, treating or suppressing of mitochondrial disorders.
  • the compounds may be used in the stimulation of mitochondrial energy production and in the restoration of drug-induced mitochondrial dysfunction such as e.g. sensineural hearing loss or tinnitus (side effect of certain antitbiotics due to mito-toxicity) or lactic acidosis.
  • the compounds may be used in the treatment of cancer, diabetes, acute starvation, endotoxemia, sepsis, systemic inflammatory response syndrome, multiple organ dysfunction syndrome and following hypoxia, ischemia, stroke, myocardial infarction, acute angina, an acute kidney injury, coronary occlusion and atrial fibrillation, or to avoid or counteract reperfusion injuries.
  • the compounds of the invention may be beneficial in treatment of male infertility.
  • the compounds of the invention will provide novel cell- permeable carboxylic acid-based metabolites involved in cellular metabolism such as pyruvate and Kreb's cycle (TCA) intermediates and other substances and cell permeable precursors of these substances aimed at increasing cellular metabolic function by enhancing ATP-production in mitochondria or the glycolytic pathway.
  • TCA Kreb's cycle
  • the invention also provides novel cell-permeable carboxylic acid-based metabolites functioning as enzymatic or electron transport inhibitors such as malonate. It is envisaged that following entry into the cell, enzymatic or chemical hydrolysis will liberate a carboxylic acid-based metabolite along with other energy-providing materials, such as acetate.
  • the below compound shown below yields 2 moles of acetic acid, 1 mole of malonic acid and 2 moles of formaldehyde
  • the compounds of the invention can be used to enhance or restore energy production in mitochondria.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related conditions by inhibiting activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds can be used in medicine or in cosmetics.
  • the compounds can be used in the prevention or treatment of disorders or diseases having a component relating to mitochondrial dysfunction and/or to a component of energy (ATP) deficiency.
  • ATP energy
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • Enhancement of energy production is e.g. relevant in subjects suffering from a mitochondrial defect, disorder or disease.
  • Mitochondrial diseases result from dysfunction of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondrial function decreases, the energy generated within the cell reduces and cell injury or cell death will follow. If this process is repeated throughout the body the life of the subject is severely compromised.
  • Certain conditions, such as ischemia reperfusion injury can be related to aberrant or over-activity of mitochondrial enzymes or electron transport of the respiratory chain. This aberrant activity can cause release of harmful oxidative molecules that can damage the mitochondria itself and its host cell.
  • Symptoms of a mitochondrial disease may include loss of motor control, muscle weakness and pain, seizures, visual/hearing problems, cardiac diseases, liver diseases, gastrointestinal disorders, swallowing difficulties and more.
  • a mitochondrial disease may be inherited or may be due to spontaneous mutations, which lead to altered functions of the proteins or RNA molecules normally residing in the mitochondria. Also many mitochondrial disorders can be secondary to other diseases or conditions such as, but not limited to, ischemia, ischemia-reperfusion injury, diabetes, cancer, intoxication.
  • a mitochondrial deficiency such as a Complex I, II, III or IV deficiency of the respiratory chain or an enzyme deficiency of metabolic pathways such as the glycolysis and/or TCA cycle.
  • some conditions such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds of the invention are contemplated to show improved properties for treatment of these and related diseases, including better cell permeability, longer plasma half-life, reduced toxicity, increased energy release to mitochondria, and improved formulation (due to improved properties including increased solubility).
  • the compounds are also orally bioavailable, which allows for easier administration.
  • the advantageous properties of the compound of the invention may include one or more of the following:
  • the present invention provides the compound of the invention for use as a pharmaceutical, in particular in the treatment of cellular energy (ATP)-deficiency.
  • ATP cellular energy
  • a compound of the invention may be used in the treatment of complex I impairment, either dysfunction of the complex itself or any condition or disease that limits the supply of NADH to Complex I, e.g. dysfunction of Krebs cycle, glycolysis, beta- oxidation, pyruvate metabolism and even transport of glucose or other Complex-I- related substrates).
  • complex I impairment either dysfunction of the complex itself or any condition or disease that limits the supply of NADH to Complex I, e.g. dysfunction of Krebs cycle, glycolysis, beta- oxidation, pyruvate metabolism and even transport of glucose or other Complex-I- related substrates).
  • the present invention also provides a method of treatment of mitochondrial complex I related disorders such as e.g., but not limited to, Leigh Syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers), which comprises administering to a subject in need thereof an effective amount of the compound of the invention.
  • mitochondrial complex I related disorders such as e.g., but not limited to, Leigh Syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers)
  • the present invention also provides the use of the compound of the invention for the manufacture of a medicament for the treatment of drug-induced lactic acidosis.
  • a compound of the invention may also be useful in any condition where extra energy production would potentially be beneficial such as, but not limited to, prolonged surgery and intensive care.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related conditions, such as ischemia reperfusion injury, by inhibiting activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • the usefulness of such compounds relate to the fact that malonate is a competitive inhibitor of succinate binding to succinate/dehydrogenase/complex II of the mitochondria. Malonate is not in itself able to permeate the cell membrane and, accordingly, a prod rug/derivative of malonate capable of permeating the cell membrane and releasing malonate inside the cell is an advantage.
  • Mitochondria are organelles in eukaryotic cells, popularly referred to as the
  • ATP adenosine triphosphate
  • biochemical processes include the citric acid cycle (the tricarboxylic acid cycle, or Kreb's cycle), which generates reduced nicotinamide adenine dinucleotide (NADH + H ⁇ +> ) from oxidized nicotinamide adenine dinucleotide (NAD ⁇ +> ) and reduced flavin adenine dinucleotide (FADH2) from oxidized flavin adenine dinucleotide (FAD), as well as oxidative phosphorylation, during which NADH + H ⁇ +> and FADH2 is oxidized back to NAD ⁇ +> and FAD.
  • citric acid cycle the tricarboxylic acid cycle, or Kreb's cycle
  • NADH + H ⁇ +> oxidized nicotinamide adenine dinucleotide
  • FADH2 reduced flavin adenine dinucleotide
  • FAD flavin adenine dinucleotide
  • the electrons released by oxidation of NADH + H ⁇ +> are shuttled down a series of protein complexes (Complex I, Complex II, Complex III, and Complex IV) known as the respiratory chain.
  • the oxidation of succinate occurs at Complex II (succinate dehydrogenase complex) and FAD is part of the complex.
  • the respiratory complexes are embedded in the inner membrane of the mitochondrion.
  • Complex IV at the end of the chain, transfers the electrons to oxygen, which is reduced to water.
  • the energy released as these electrons traverse the complexes is used to generate a proton gradient across the inner membrane of the mitochondrion, which creates an electrochemical potential across the inner membrane.
  • Another protein complex which is not directly associated with Complexes I, II, III and IV
  • the citric acid cycle and oxidative phosphorylation are preceded by glycolysis, in which a molecule of glucose is broken down into two molecules of pyruvate, with net generation of two molecules of ATP per molecule of glucose.
  • the pyruvate molecules then enter the mitochondria, where they are completely oxidized to C0 2 and H 2 0 via oxidative phosphorylation (the overall process is known as aerobic respiration).
  • the complete oxidation of the two pyruvate molecules to carbon dioxide and water yields about at least 28-29 molecules of ATP, in addition to the 2 molecules of ATP generated by transforming glucose into two pyruvate molecules. If oxygen is not available, the pyruvate molecule does not enter the mitochondria, but rather is converted to lactate, in the process of anaerobic respiration.
  • the overall net yield per molecule of glucose is thus approximately at least 30-31 ATP molecules. ATP is used to power, directly or indirectly, almost every other biochemical reaction in the cell. Thus, the extra (approximately) at least 28 or 29 molecules of ATP contributed by oxidative phosphorylation during aerobic respiration are critical to the proper functioning of the cell. Lack of oxygen prevents aerobic respiration and will result in eventual death of almost all aerobic organisms; a few organisms, such as yeast, are able to survive using either aerobic or anaerobic respiration. When cells in an organism are temporarily deprived of oxygen, anaerobic respiration is utilized until oxygen again becomes available or the cell dies. The pyruvate generated during glycolysis is converted to lactate during anaerobic respiration. The build-up of lactic acid is believed to be responsible for muscle fatigue during intense periods of activity, when oxygen cannot be supplied to the muscle cells. When oxygen again becomes available, the lactate is converted back into pyruvate for use in oxidative phosphorylation.
  • Mitochondrial dysfunction contributes to various disease states. Some mitochondrial diseases are due to mutations or deletions in the mitochondrial genome. If a threshold proportion of mitochondria in the cell is defective, and if a threshold proportion of such cells within a tissue have defective mitochondria, symptoms of tissue or organ dysfunction can result. Practically any tissue can be affected, and a large variety of symptoms may be present, depending on the extent to which different tissues are involved. Also many mitochondrial disorders can be secondary to other diseases or conditions such as, but not limited to, ischemia, ischemia- reperfusion injury, diabetes, cancer, intoxication.
  • the compounds of the invention may be used in any situation where an adjusted, enhanced or restored mitochondrial function is desired. Examples are e.g. in all clinical conditions where there is a potential benefit of increased mitochondrial ATP- production or a restoration of mitochondrial function, such as in the restoration of drug-induced mitochondrial dysfunction or lactic acidosis and the treatment of cancer, diabetes, acute starvation, endotoxemia, sepsis, reduced hearing visual acuity, systemic inflammatory response syndrome and multiple organ dysfunction syndrome.
  • the compounds may also be useful following hypoxia, ischemia, stroke, myocardial infarction, acute angina, an acute kidney injury, coronary occlusion, atrial fibrillation and in the prevention or limitations of reperfusion injuries.
  • the compounds of the invention can be used in medicine, notably in the treatment or prevention of a mitochondria-related disease or disorder or in cosmetics.
  • Dysfunction of mitochondria is also described in relation to renal tubular acidosis; motor neuron diseases; other neurological diseases such as adrenoleukodystrophy (ALD) and its adult form adrenomyeloneuropathy (AMN); epilepsy; genetic diseases; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; age- associated diseases; cerebral vascular accidents, macular degeneration; diabetes; and cancer.
  • ALD adrenoleukodystrophy
  • AMD adult form adrenomyeloneuropathy
  • epilepsy genetic diseases; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; age- associated diseases; cerebral vascular accidents, macular degeneration; diabetes; and cancer.
  • Compounds of the invention for use in mitochondrial related disorders or diseases may be used in the prevention or treatment a mitochondria-related disease selected from the following:
  • ALD Adrenoleukodystrophy
  • ALS Amyotrophic lateral sclerosis
  • Creatine Deficiency Syndromes includes: Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency), L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency), and SLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency).
  • NADH dehydrogenase NADH-CoQ reductase
  • MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike Episodes
  • MERRF Myoclonic Epilepsy and Ragged-Red Fiber Disease
  • MIRAS Mitochondrial Recessive Ataxia Syndrome
  • Mitochondrial Encephalopathy includes: Encephalomyopathy,
  • MNGIE Myoneurogastointestinal Disorder and Encephalopathy
  • NARP Neuroopathy, Ataxia, and Retinitis Pigmentosa
  • VLCAD Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
  • Complex I deficiency is usually a progressive neurodegenerative disorder and is responsible for a variety of clinical symptoms, particularly in organs and tissues that require high energy levels, such as brain, heart, liver, and skeletal muscles.
  • a number of specific mitochondrial disorders have been associated with Complex I deficiency including: Leber's hereditary optic neuropathy (LHON), MELAS, MERRF, and Leigh Syndrome (LS).
  • LHON Leber's hereditary optic neuropathy
  • MELAS stands for (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes)
  • MERRF stand for myoclonic epilepsy with ragged red fibers.
  • LHON is characterized by blindness which occurs on average between 27 and 34 years of age; blindness can develop in both eyes simultaneously, or sequentially (one eye will develop blindness, followed by the other eye two months later on average). Other symptoms may also occur, such as cardiac abnormalities and neurological complications.
  • Fatal infantile multisystem disorder - characterized by poor muscle tone, developmental delay, heart disease, lactic acidosis, and respiratory failure.
  • Myopathy muscle disease
  • Mitochondrial encephalomyopathy (brain and muscle disease) - beginning in childhood or adulthood and involving variable symptom combinations which may include: eye muscle paralysis, pigmentary retinopathy (retinal color changes with loss of vision), hearing loss, sensory neuropathy (nerve damage involving the sense organs), seizures, dementia, ataxia (abnormal muscle coordination), and involuntary movements.
  • This form of Complex I deficiency may cause Leigh Syndrome and MELAS.
  • Treatment As with all mitochondrial diseases, there is presently no cure for Complex I deficiency.
  • a variety of treatments which may or may not be effective, can include such metabolic therapies as: riboflavin, thiamine, biotin, co-enzyme Q10, carnitine, and ketogenic diet.
  • therapies for the infantile multisystem form have been unsuccessful.
  • the clinical course and prognosis for Complex I patients is highly variable and may depend on the specific genetic defect, age of onset, organs involved, and other factors.
  • the symptoms include four major forms: i) Fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophic posturing, seizures, and coma. Ragged-red fibers in muscle tissue are common. ii) Encephalomyopathies of later onset (childhood to adult life): various combinations of weakness, short stature, ataxia, dementia, hearing loss, sensory neuropathy, pigmentary retinopathy, and pyramidal signs. Ragged-red fibers are common.
  • Encephalomyopathy Typically normal for the first 6 to 12 months of life and then show developmental regression, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal signs, and respiratory problems. Frequent seizures. May cause Leigh Syndrome
  • Fatal infantile myopathy may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems.
  • KSS Kearns-Sayre Syndrome
  • Patients with KSS may also have such problems as deafness, dementia, kidney dysfunction, and muscle weakness. Endocrine abnormalities including growth retardation, short stature, or diabetes may also be evident.
  • KSS is a rare disorder. It is usually caused by a single large deletion (loss) of genetic material within the DNA of the mitochondria (mtDNA), rather than in the DNA of the cell nucleus. These deletions, of which there are over 150 species, typically arise spontaneously. Less frequently, the mutation is transmitted by the mother.
  • Treatments are based on the types of symptoms and organs involved, and may include: Coenzyme Q10, insulin for diabetes, cardiac drugs, and a cardiac pacemaker which may be life-saving. Surgical intervention for drooping eyelids may be considered but should be undertaken by specialists in ophthalmic surgical centers. KSS is slowly progressive and the prognosis varies depending on severity. Death is common in the third or fourth decade and may be due to organ system failures.
  • Symptoms Seizures, hypotonia, fatigue, nystagmus, poor reflexes, eating and swallowing difficulties, breathing problems, poor motor function, ataxia.
  • Leigh's Disease is a progressive neurometabolic disorder with a general onset in infancy or childhood, often after a viral infection, but can also occur in teens and adults. It is characterized on MRI by visible necrotizing (dead or dying tissue) lesions on the brain, particularly in the midbrain and brainstem.
  • the child often appears normal at birth but typically begins displaying symptoms within a few months to two years of age, although the timing may be much earlier or later.
  • Initial symptoms can include the loss of basic skills such as sucking, head control, walking and talking. These may be accompanied by other problems such as irritability, loss of appetite, vomiting and seizures. There may be periods of sharp decline or temporary restoration of some functions. Eventually, the child may also have heart, kidney, vision, and breathing complications.
  • PDHC pyruvate dehydrogenase
  • respiratory chain enzyme defects - Complexes ⁇ , ⁇ , IV, and V Depending on the defect, the mode of inheritance may be X-linked dominant (defect on the X chromosome and disease usually occurs in males only), autosomal recessive (inherited from genes from both mother and father), and maternal (from mother only). There may also be spontaneous cases which are not inherited at all.
  • Leigh's Disease The prognosis for Leigh's Disease is poor. Depending on the defect, individuals typically live anywhere from a few years to the mid-teens. Those diagnosed with Leigh-like syndrome or who did not display symptoms until adulthood tend to live longer.
  • MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like
  • Episodes Symptoms: Short statue, seizures, stroke-like episodes with focused neurological deficits, recurrent headaches, cognitive regression, disease
  • MELAS Mitochondrial Myopathy (muscle weakness), Encephalopathy (brain and central nervous system disease), Lactic Acidosis (build-up of a product from anaerobic respiration), and Stroke-like episodes (partial paralysis, partial vision loss, or other neurological abnormalities).
  • MELAS is a progressive neurodegenerative disorder with typical onset between the ages of 2 and 15, although it may occur in infancy or as late as adulthood. Initial symptoms may include stroke-like episodes, seizures, migraine headaches, and recurrent vomiting. Usually, the patient appears normal during infancy, although short stature is common. Less common are early infancy symptoms that may include
  • Stroke-like episodes often accompanied by seizures, are the hallmark symptom of MELAS and cause partial paralysis, loss of vision, and focal neurological defects. The gradual cumulative effects of these episodes often result in variable
  • MELAS patients may also suffer additional symptoms including: muscle weakness, peripheral nerve dysfunction, diabetes, hearing loss, cardiac and kidney problems, and digestive abnormalities. Lactic acid usually accumulates at high levels in the blood, cerebrospinal fluid, or both. MELAS is maternally inherited due to a defect in the DNA within mitochondria. There are at least 17 different mutations that can cause MELAS. By far the most prevalent is the A3243G mutation, which is responsible for about 80% of the cases.
  • the prognosis for MELAS is poor. Typically, the age of death is between 10 to 35 years, although some patients may live longer. Death may come as a result of general body wasting due to progressive dementia and muscle weakness, or complications from other affected organs such as heart or kidneys.
  • MERRF is a progressive multi-system syndrome usually beginning in childhood, but onset may occur in adulthood. The rate of progression varies widely. Onset and extent of symptoms can differ among affected siblings.
  • MERRF The classic features of MERRF include:
  • Ragged-red fibers a characteristic microscopic abnormality observed in muscle biopsy of patients with MERRF and other mitochondrial disorders
  • Additional symptoms may include: hearing loss, lactic acidosis (elevated lactic acid level in the blood), short stature, exercise intolerance, dementia, cardiac defects, eye abnormalities, and speech impairment.
  • MERRF mitochondrial disorders
  • therapies may include coenzyme Q10, L-carnitine, and various vitamins, often in a "cocktail" combination. Management of seizures usually requires anticonvulsant drugs.
  • the prognosis for MERRF varies widely depending on age of onset, type and severity of symptoms, organs involved, and other factors.
  • Mitochondrial DNA Depletion The symptoms include three major forms:
  • Congenital myopathy Neonatal weakness, hypotonia requiring assisted ventilation, possible renal dysfunction. Severe lactic acidosis. Prominent ragged-red fibers. Death due to respiratory failure usually occurs prior to one year of age. 2. Infantile myopathy: Following normal early development until one year old, weakness appears and worsens rapidly, causing respiratory failure and death typically within a few years.
  • Hepatopathy Enlarged liver and intractable liver failure, myopathy. Severe lactic acidosis. Death is typical within the first year.
  • FRDA Friedreich's ataxia
  • Frataxin is important for the assembly of iron-sulfur clusters in mitochondrial respiratory-chain complexes.
  • compositions comprising a compound of the invention
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention together with one or more pharmaceutically acceptable diluents or carriers.
  • the compound of the invention or a formulation thereof may be administered by any conventional method for example but without limitation it may be administered parenterally, orally, topically (including buccal, sublingual or transdermal), via a medical device (e.g. a stent), by inhalation or via injection (subcutaneous or intramuscular).
  • a medical device e.g. a stent
  • the treatment may consist of a single dose or a plurality of doses over a period of time.
  • the treatment may be by administration once daily, twice daily, three times daily, four times daily etc.
  • the treatment may also be by continuous administration such as e.g. administration intravenous by drop.
  • the compound of the invention Whilst it is possible for the compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Examples of suitable carriers are described in more detail below.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compound of the invention will normally be administered intravenously, orally or by any parenteral route, in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • the compound of the invention can also be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Solutions or suspensions of the compound of the invention suitable for oral administration may also contain excipients e.g. ⁇ , ⁇ -dimethylacetamide, dispersants e.g. polysorbate 80, surfactants, and solubilisers, e.g. polyethylene glycol, Phosal 50 PG (which consists of phosphatidylcholine, soya-fatty acids, ethanol,
  • the formulations according to present invention may also be in the form of emulsions, wherein a compound according to Formula (I) may be present in an aqueous oil emulsion.
  • the oil may be any oil-like substance such as e.g. soy bean oil or safflower oil, medium chain triglyceride (MCT-oil) such as e.g. coconut oil, palm oil etc or combinations thereof.
  • Tablets may contain excipients such as microcrystalline cellulose, lactose (e.g.
  • lactose monohydrate or lactose anyhydrous sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, butylated hydroxytoluene (E321 ), crospovidone, hypromellose, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium, and certain complex silicates, and granulation binders such as polyvinylpyrrolidone,
  • hydroxypropylmethylcellulose HPMC
  • HPC hydroxy-propylcellulose
  • macrogol 8000 sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils, transdermal devices, dusting powders, and the like.
  • These compositions may be prepared via conventional methods containing the active agent.
  • they may also comprise compatible conventional carriers and additives, such as preservatives, solvents to assist drug penetration, emollient in creams or ointments and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1 % up to about 98% of the
  • composition More usually they will form up to about 80% of the composition.
  • a cream or ointment is prepared by mixing sufficient quantities of hydrophilic material and water, containing from about 5-10% by weight of the compound, in sufficient quantities to produce a cream or ointment having the desired consistency.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active agent may be delivered from the patch by iontophoresis.
  • compositions are preferably applied as a topical ointment or cream.
  • the active agent When formulated in an ointment, the active agent may be employed with either a paraffinic or a water-miscible ointment base.
  • the active agent may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, for example but without limitation water, alcohols, polyols, glycerine and vegetable oils, water being preferred.
  • a sterile vehicle for example but without limitation water, alcohols, polyols, glycerine and vegetable oils, water being preferred.
  • the active ingredient depending on the vehicle and concentration used, can be either colloidal, suspended or dissolved in the vehicle.
  • the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • Parenteral suspensions are prepared in substantially the same manner as solutions, except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a person skilled in the art will know how to choose a suitable formulation and how to prepare it (see eg Remington's Pharmaceutical Sciences 18 Ed. or later). A person skilled in the art will also know how to choose a suitable administration route and dosage.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and condition of the particular subject being treated, and that a physician will ultimately determine appropriate dosages to be used. This dosage may be repeated as often as appropriate. If side effects develop the amount and/or frequency of the dosage can be altered or reduced, in accordance with normal clinical practice.
  • the present invention also provides a combination (for example for the treatment of mitochondrial dysfunction) of a compound of formula (I) or formula (IA) or a pharmaceutically acceptable form thereof as hereinbefore defined and one or more agents independently selected from:
  • Vitamins e.g. Tocopherols, Tocotrienols and Trolox (Vitamin E), Ascorbate (C), Thiamine (B1 ), Riboflavin (B2), Nicotinamide (B3), Menadione (K3),
  • any of the compounds as disclosed herein may be administered together with any other compounds such as e.g. sodium bicarbonate (as a bolus (e.g. 1 mEq/kg) followed by a continuous infusion.) as a concomitant medication to the compounds as disclosed herein.
  • any other compounds such as e.g. sodium bicarbonate (as a bolus (e.g. 1 mEq/kg) followed by a continuous infusion.) as a concomitant medication to the compounds as disclosed herein.
  • the present invention also relates to the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects.
  • the compounds according to the invention are used in the prevention or treatment of a mitochondrial-related drug-induced side effects at or up-stream of Complex I, or expressed otherwise, the invention provides according to the invention for the prevention or treatment of drug-induced direct inhibition of Complex I or of any drug- induced effect that limits the supply of NADH to Complex I (such as, but not limited to, effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism and even drugs that effects the transport or levels of glucose or other complex I related substrates).
  • Mitochondrial toxicity induced by drugs may be a part of the desired therapeutic effect (e.g. mitochondrial toxicity induced by cancer drugs), but in most case mitochondrial toxicity induced by drugs is an unwanted effect. Mitochondrial toxicity can markedly increase glycolysis to compensate for cellular loss of mitochondrial ATP formation by oxidative phosphorylation. This can result in increased lactate plasma levels, which if excessive results in lactic acidosis, which can be lethal. Type A lactic acidosis is primarily associated with tissue hypoxia, whereas type B aerobic lactic acidosis is associated with drugs, toxin or systemic disorders such as liver diseases, diabetes, cancer and inborn errors of metabolism (e.g. mitochondrial genetic defects).
  • the present invention provides compounds for use in the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects.
  • novel cell-permeable carboxylic acid-based metabolites are used in the prevention or treatment of a mitochondrial-related drug-induced side effects at or upstream of Complex I, or expressed otherwise, the invention provides cell-permeable carboxylic acid-based metabolites for the prevention or treatment of drug-induced direct inhibition of Complex I or of any drug-induced effect that limits the supply of NADH to Complex I (such as, but not limited to, effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism and even drugs that effects the transport or levels of glucose or other Complex I related substrates).
  • the compounds according to the invention also can be used in industrial applications, e.g. in vitro to reduce or inhibit formation of lactate or to increase the ATP-availability of commercial or industrial cell lines. Examples include the use in cell culture, in organ preservation, etc.
  • the compounds according to the invention are used in the treatment or prevention of drug-induced mitochondrial-related side-effects or to increase or restore cellular levels of energy (ATP), in the treatment. Especially, they are used in the treatment or prevention of direct or indirect drug-induced Complex I mitochondrial-related side- effects. In particular, they are used in the treatment or prevention of lactic acidosis, such as lactic acidosis induced by a drug substance.
  • the invention also relates to a combination of a compound of Formula (I) and a drug substance that may induce a mitochondrial-related side-effect, in particular a side- effect that is caused by direct or indirect impairment of Complex I by the drug substance.
  • a mitochondrial-related side-effect in particular a side- effect that is caused by direct or indirect impairment of Complex I by the drug substance.
  • Such combination can be used as prophylactic prevention of a mitochondrial-related side-effect or, in case the side-effect appears, in alleviating and/or treating the mitochondrial-related side effect.
  • compounds as described below will be effective in treatment or prevention of drug-induced side-effects, in particular in side-effects related to direct or indirect inhibition of Complex I.
  • Drug substances that are known to give rise in Complex I defects, malfunction or impariment and/or are known to have lactic acidosis as side-effect are:
  • Analgesics including acetaminophen, capsaicin
  • Antianginals including amiodarone, perhexiline
  • Antibiotics including linezolid, trovafloxacin, gentamycin
  • Anticancer drugs including quinones including mitomycin C, adriamycin
  • Anti-convulsant drugs including valproic acid
  • Anti-diabetics including metformin, phenformin, butylbiguanide, troglitazone and rosiglitazone, pioglitazone
  • Anti-Hepatitis B including fialuridine
  • Anti-Parkinson including tolcapone Anti-psycotics Risperidone
  • Anti-tuberculosis including isoniazid
  • Fibrates including clofibrate, ciprofibrate, simvastatin
  • DMARD Immunosupressive disease-modifying antirheumatic drug
  • Neuroleptics including antipsycotic neuroleptics like chlorpromazine, fluphenazine and haloperidol
  • NRTI Nucleotide reverse Transcriptase Inhibitors
  • efavirenz including efavirenz, tenofovir, emtricitabine, zidovudine, lamivudine, rilpivirine, abacavir, didanosine
  • NSAIDs including nimesulfide, mefenamic acid, sulindac
  • lactic acidosis drugs that are known to have lactic acidosis as side-effects
  • beta2-agonists epinephrine
  • theophylline or other herbicides.
  • Alcohols and cocaine can also result in lactic acidosis.
  • the compounds of the invention also may be effective in the treatment or prevention of lactic acidosis even if it is not related to a Complex I defect. Combination of drugs and compounds of the invention
  • the present invention also relates to a combination of a drug substance and a compound of the invention for use in the treatment and/or prevention of a drug- induced side-effect selected from lactic acidosis and side-effect related to a
  • the drug substance is used for treatment of a disease for which the drug substance is indicated, and
  • the compound of the invention is used for prevention or alleviation of the side effects induced or inducible by the drug substance, wherein the side-effects are selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction. Any combination of such a drug substance with any compound of the invention is within the scope of the present invention. Accordingly, based on the disclosure herein a person skilled in the art will understand that the gist of the invention is the findings of the valuable properties of compounds of the invention to avoid or reduce the side-effects described herein. Thus, the potential use of compounds of the invention capable of entering cells and deliver a TCA-substance and possibly other active moeties in combination with any drug substance that has or potentially have the side-effects described herein is evident from the present disclosure.
  • the invention further relates to
  • composition comprising a drug substance and a compound of the invention, wherein the drug substance has a potential drug-induced side-effect selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction, ii) a composition as described above under i), wherein the compound of the invention is used for prevention or alleviation of side effects induced or inducible by the drug substance, wherein the side-effects are selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction.
  • composition may be in the form of two separate packages:
  • composition may also be a single composition comprising both the drug substance and the compound of the invention.
  • the drug substance and the compound of the invention may be administered by different administration routes (e.g. drug substance via oral administration and compound of the invention by parenteral or mucosal administration) and/or they may be administered essentially at the same time or the drug substance may be
  • the invention also provides a kit comprising i) a first container comprising a drug substance, which has a potential drug-induced side-effect selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction, and
  • a second container comprising a compound of the invention, which has the potential for prevention or alleviation of the side effects induced or inducible by the drug substance, wherein the side-effects are selected from lactic acidosis and side- effects related to a Complex I defect, inhibition or malfunction.
  • the method comprises administering an effective amount of a compound of the invention to the subject, and to a method for preventing or alleviating a drug-induced side-effect selected from lactic acidosis and side-effect related to a Complex I defect, inhibition or malfunction in a subject, who is suffering from a disease that is treated with a drug substance, which potentially induce a side-effect selected from lactic acidosis and side-effect related to a Complex I defect, inhibition or malfunction, the method comprises administering an effective amount of a compound of the invention to the subject before, during or after treatment with said drug substance.
  • analogue means one analogue or more than one analogue.
  • cell permeable carboxylic acid-based metabolites As used herein the terms “cell permeable carboxylic acid-based metabolites”, “compound(s) of the invention”, “cell-permeable metabolite derivatives” and “cell permeable precursors of metabolites” are used interchangeably and refer to compounds of formula (I) or formula (lA).
  • bioavailability refers to the degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of biological activity after administration. This property is dependent upon a number of factors including the solubility of the compound, rate of absorption in the gut, the extent of protein binding and metabolism etc. Various tests for bioavailability that would be familiar to a person of skill in the art are described herein (see also Trepanier ef a/. 1998, Gallant-Haidner et al, 2000).
  • the terms "impairment”, inhibition”, “defect” used in relation to Complex I of the respiratory chain is intended to denote that a given drug substance have negative effect on Complex I or on mitochondrial metabolism upstream of Complex I, which could encompass any drug effect that limits the supply of NADH to Complex I, e.g. effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism and even drugs that effect the transport or levels of glucose or other complex l-related substrates).
  • an excess of lactate in a subject is often an indication of a negative effect on aerobic respiration including Complex I.
  • side-effect used in relation to the function of Complex I of the respiratory chain may be a side-effect relating to lactic acidosis or it may be a side-effect relating to idiosyncratic drug organ toxicity e.g. hepatotoxicity, neurotoxicity, cardiotoxicity, renal toxicity and muscle toxicity encompassing, but not limited to, e.g. ophthalmoplegia, myopathy, sensorineural hearing impairment, seizures, stroke, stroke-like events, ataxia, ptosis, cognitive impairment, altered states of consciousness, neuropathic pain, polyneuropathy, neuropathic
  • gastrointestinal problems gastroesophageal reflux, constipation, bowel pseudoobstruction
  • proximal renal tubular dysfunction cardiac conduction defects (heart blocks)
  • cardiomyopathy hypoglycemia, gluconeogenic defects
  • nonalcoholic liver failure optic neuropathy, visual loss, diabetes and exocrine pancreatic failure
  • fatigue respiratory problems including intermittent air hunger.
  • drug-induced in relation to the term “side-effect” is to be understood in a broad sense. Thus, not only does it include drug substances, but also other substances that may lead to unwanted presence of lactate. Examples are herbicides, toxic mushrooms, berries etc.
  • the pharmaceutically acceptable salts of the compound of the invention include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene- 2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
  • Amino means NH 2 .
  • Amino includes substituted amino.
  • Substituted amino means NHR or NR 2 R 3 where R 2 and R 3 are independent substituents or where NR 2 R 3 forms an optionally substituted 4 to 7 membered non-aromatic heterocyclic ring optionally containing a second heteroatom ring member selected from O, N and S and oxidised forms thereof.
  • Exemplary substituted amino groups include NMe 2 , NEt 2 , piperidinyl, piperazinyl, morpholino, N-cyclohexyl, where the rings may be further substituted.
  • Alkyl means an aliphatic hydrocarbon group.
  • the alkyl group may be straight or branched or cyclic. "Branched” means that at least one carbon branch point is present in the group. Thus, for example, ferf-butyl and isopropyl are both branched groups.
  • the alkyl group may be a lower alkyl group.
  • “Lower alkyl” means an alkyl group, straight or branched, having 1 to about 6 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, / ' -propyl, n-butyl, f-butyl, s- butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3- heptyl, 4-heptyl, 2-methyl-but-1-yl, 2-methyl-but-3-yl, 2-methyl-pent-1-yl, 2-methyl- pent-3-yl.
  • alkyl group may be optionally substituted, e.g. as exemplified below.
  • alkyl also includes aliphatic hydrocarbon groups such as alkenyl, and alkylidene and cycloalkyl, cycloalkylidene, heterocycloalkyl and
  • Alkenyl means an unsaturated aliphatic hydrocarbon group.
  • the unsaturation may include one or more double bond, one or more triple bond or any combination thereof.
  • the alkenyl group may be straight or branched. "Branched" means that at least one carbon branch point is present in the group. Any double bond may, independently of any other double bond in the group, be in either the (E) or the (Z) configuration.
  • the alkenyl group may be a lower alkenyl group.
  • “Lower alkenyl” means an alkenyl group, straight or branched, having 2 to 6 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include ethenyl, n-propenyl, / ' -propenyl, but-1-en-1-yl, but- 2-en-1 -yl, but-3-en-1-yl, pent-1-en-1 -yl, pent-2-en-1 -yl, pent-3-en-1 -yl, pent-4-en-1- yl, pent-1 -en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pent-2-en-3-yl, pentadien-1-yl, pentadien-2-yl, pentadien-3-yl.
  • alkenyl group may be optionally substituted, e.g. as exemplified below.
  • Alkenyl includes cyano.
  • Alkylidene means any alkyl or alkenyl group linked to the remainder of the molecule via a double bond.
  • alkyl and alkenyl groups apply with appropriate modification also to alkylidene groups.
  • Cycloalkyl means a cyclic non-aromatic hydrocarbon group.
  • the cycloalkyl group may include non-aromatic unsaturation.
  • the cycloalkyl group may have 3 to 6 carbon atoms, e.g. 3, 4, 5 or 6 carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl.
  • the cycloalkyi group may be optionally substituted, as defined below, e.g. as exemplified below.
  • Exemplary substituted cycloalkyi groups include mono- or poly- alkyl-substituted cycloalkyi groups such as 1 -methylcyclopropyl, 1-methylcyclobutyl,
  • Cydoalkylidene means any cycloalkyi group linked to the remainder of the molecule via a double bond.
  • the definitions and illustrations provided herein for cycloalkyi groups apply with appropriate modification also to cydoalkylidene groups.
  • Heterocycloalkyl group means a non-aromatic cyclic group which contains one or more heteroatoms in the ring.
  • the heterocycloalkyl group may contain O, N or S atoms.
  • the heterocycloalkyl group may be fully saturated or partially unsaturated.
  • the heterocycloalkyl group is typically monocyclic or bicyclic, and more usually is monocyclic.
  • heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5- dihydro-1 H-maleimido, dioxolanyl, 2-imidazolinyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, pyrrolidinonyl, 2-pyrrolinyl, 3-pyrrolinyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g.
  • Heterocycloalkylidene means any heterocycloalkyl group linked to the remainder of the molecule via a double bond.
  • the definitions and illustrations provided herein for heterocycloalkyl groups apply with appropriate modification also to
  • Optionally substituted as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different.
  • Optionally substituted alkyl' includes both 'alkyl' and 'substituted alkyl'.
  • substituents for "substituted” and “optionally substituted” moieties include halo (fluoro, chloro, bromo or iodo), C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy, Ci -6 alkoxy, cyano, amino, nitro, Ci -6 alkylamino, C 2-6 alkenylamino, di-Ci -6 alkylamino, Ci -6 acylamino, di-Ci -6 acylamino, Ci -6 aryl, Ci -6 arylamino, Ci -6 aroylamino, benzylamino, C 1-6 arylamido, carboxy, C 1-6 alkoxycarbonyl or (C 1-6 aryl)(C 1-10 alkoxy)carbonyl, carbamoyl, mono-C 1-6 carbamoyl, di-C 1-6 carbamoyl or any of the above in which a hydrocarbyl moiety is itself substituted
  • the oxygen atom can be replaced with sulphur to make groups such as thio (SH) and thio-alkyl (S- alkyl).
  • Optional substituents therefore includes groups such as S-methyl.
  • the sulphur atom may be further oxidised to make a sulfoxide or sulfone, and thus optional substituents therefore includes groups such as S(0)-alkyl and S(0) 2 -alkyl. Substitution may take the form of double bonds, and may include heteroatoms.
  • Substituted groups thus include for example CFH 2 , CF 2 H, CF 3 , CH 2 NH 2 , CH 2 OH, CH 2 CN, CH 2 SCH 3 , CH 2 OCH 3 , OMe, OEt, Me, Et, -OCH 2 0-, C0 2 Me, C(0)Me, /-Pr, SCF 3 , S0 2 Me, NMe 2 , CONH 2 , CONMe 2 etc.
  • the substitutions may be in the form of rings from adjacent carbon atoms in the aryl ring, for example cyclic acetals such as 0-CH 2 -0.
  • bioavailability of a compound is determined by a number of factors, (e.g. water solubility, cell membrane permeability, the extent of protein binding and metabolism and stability) each of which may be determined by in vitro tests as described in the examples herein, it will be appreciated by a person of skill in the art that an improvement in one or more of these factors will lead to an improvement in the bioavailability of a compound.
  • factors e.g. water solubility, cell membrane permeability, the extent of protein binding and metabolism and stability
  • the bioavailability of the compound of the invention may be measured using in vivo methods as described in more detail below, or in the examples herein.
  • a compound may be administered to a test animal (e.g. mouse or rat) both intraperitoneally (i.p.) or intravenously (i.v.) and orally (p.o.) and blood samples are taken at regular intervals to examine how the plasma concentration of the drug varies over time.
  • a test animal e.g. mouse or rat
  • intraperitoneally i.p.
  • intravenously i.v.
  • orally p.o.
  • blood samples are taken at regular intervals to examine how the plasma concentration of the drug varies over time.
  • the time course of plasma concentration over time can be used to calculate the absolute bioavailability of the compound as a percentage using standard models.
  • An example of a typical protocol is described below.
  • mice or rats are dosed with 1 or 3 mg/kg of the compound of the invention i.v. or 1 , 5 or 10 mg/kg of the compound of the invention p.o..
  • Blood samples are taken at 5 min, 15 min, 1 h, 4 h and 24 h intervals, and the
  • concentration of the compound of the invention in the sample is determined via
  • LCMS-MS The time-course of plasma or whole blood concentrations can then be used to derive key parameters such as the area under the plasma or blood concentration-time curve (AUC - which is directly proportional to the total amount of unchanged drug that reaches the systemic circulation), the maximum (peak) plasma or blood drug concentration, the time at which maximum plasma or blood drug concentration occurs (peak time), additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half-life, total body clearance, steady-state volume of distribution and F%.
  • AUC - area under the plasma or blood concentration-time curve
  • additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half-life, total body clearance, steady-state volume of distribution and F%.
  • the efficacy of the compound of the invention may be tested using one or more of the methods described below: I. Assays for evaluating inhibition of mitochondrial energy producing function in intact cells
  • Measurement of mitochondrial respiration are performed in a high-resolution oxygraph (Oxygraph- 2k, Oroboros Instruments, Innsbruck, Austria) at a constant temperature of 37°C. Isolated human platelets containing live mitochondria are suspended in a 2 ml. glass chamber at a concentration sufficient to yield oxygen consumption in the medium of ⁇ 10 pmol 0 2 s _1 mL 1 . High-resolution respirometry - B
  • Respiratory measurements were performed in a buffer containing 0.5 mM EGTA, 3 mM MgCI 2 , 60 mM K-lactobionate, 20 mM Taurine, 10 mM KH 2 P0 4 , 20 mM HEPES, 1 10 mM sucrose and 1 g/L bovine serum albumin (MiR05), pH 7.1 . Respiratory values were corrected for the oxygen solubility factor of the media (0.92) 2 . All measurements were performed at a platelet concentration of 200x10 6 cells per mL.
  • Cells are placed in a buffer containing 1 10 mM sucrose, HEPES 20 mM, taurine 20 mM, K-lactobionate 60 mM, MgCI 2 3 mM, KH 2 P0 4 10 mM, EGTA 0.5 mM, BSA 1 g/l, pH 7.1.
  • a buffer containing 1 10 mM sucrose, HEPES 20 mM, taurine 20 mM, K-lactobionate 60 mM, MgCI 2 3 mM, KH 2 P0 4 10 mM, EGTA 0.5 mM, BSA 1 g/l, pH 7.1.
  • Treatments are titrated in increasing concentrations to reach cumulative concentration ranges of 10 ⁇ to 5 mM final concentration. After the respiration stabilized the experiment is terminated by addition of Antimycin at final concentration 1 ⁇ / ⁇ . and any residual non- mitochondrial oxygen consumption is measured.
  • the ideal compound inhibits complex-ll-supported respiration in the described protocol in intact cells at low concentration.
  • concentration to reach maximal inhibitory effect should be in the micromolar range to distinguish it from Malonate and Dimethyl malonate as they have been shown to induce inhibition in the millimolar range 3A .
  • respiration should be halted.
  • NV161 inhibited complex ll-supported respiration at much lower concentrations than Malonate and Dimethyl malonate: NV161 decreased complex ll-supported respiration to a level of 64% of control at 10 ⁇ . Malonate and Dimethyl malonate did not decrease complex ll-supported respiration at the same dose.

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Abstract

La présente invention concerne de nouveaux métabolites à base d'acide carboxylique perméables aux cellules et des précurseurs de ceux-ci perméables aux cellules visant à augmenter la production d'ATP dans les mitochondries et par conséquent, destinés à être utilisés en médecine. La majeure partie de l'ATP produit et utilisé dans la cellule eucaryote provient de la phosphorylation oxydative mitochondriale, un processus où des électrons à haute énergie sont fournis par le cycle de Krebs. Tous les intermédiaires du cycle de Krebs ne sont pas facilement perméables à la membrane cellulaire, l'un d'entre eux étant le malonate. L'utilisation des nouveaux métabolites à base d'acide carboxylique perméables aux cellules devrait permettre le passage sur la membrane cellulaire et, par conséquent, les métabolites perméables aux cellules peuvent être utilisés pour augmenter la production d'ATP mitochondrial.
PCT/EP2016/073985 2015-10-07 2016-10-07 Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées aux mitochondries WO2017060418A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341493A (zh) * 2020-10-21 2021-02-09 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用
WO2022228223A1 (fr) * 2021-04-26 2022-11-03 重庆理工大学 Mitochondries modifiées et leur procédé de préparation

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029114A1 (fr) * 1996-12-30 1998-07-09 Bar-Ilan University Oxyalkylesters contenant de l'acide tricarboxylique et leurs utilisations
WO2001024793A1 (fr) * 1999-10-07 2001-04-12 Xanthus Life Sciences, Inc. Composition a base d"ester pyruvate et procede d"utilisation pour la reanimation suite a un accident ischemique cerebral ou a une reperfusion
WO2005066173A2 (fr) * 2004-01-08 2005-07-21 Glaxo Group Limited Nouveaux procedes
EP1561748A1 (fr) * 2002-10-18 2005-08-10 Meiji Seika Kaisha Ltd. Monoesters d'acide malonique et procede de fabrication correspondant
WO2014031844A1 (fr) * 2012-08-22 2014-02-27 Xenoport, Inc. Méthodes d'administration du monométhyl fumarate et des promédicaments associés présentant des effets secondaires réduits
WO2014053857A1 (fr) * 2012-10-05 2014-04-10 Mitopharm Ltd Succinates protégés pour accroître la production mitochondriale d'atp
WO2015155231A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Nouveaux composés de succinate perméables à travers les cellules
WO2015155238A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Promédicaments à base de succinate destinés à être utilisés dans le traitement de l'acidose lactique ou d'effets secondaires induits par un médicament dus à une déficience liée au complexe i de la phosphorylation oxydative mitochondriale
WO2015155230A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Promédicaments d'acide succinique pour augmenter la production d'atp

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029114A1 (fr) * 1996-12-30 1998-07-09 Bar-Ilan University Oxyalkylesters contenant de l'acide tricarboxylique et leurs utilisations
WO2001024793A1 (fr) * 1999-10-07 2001-04-12 Xanthus Life Sciences, Inc. Composition a base d"ester pyruvate et procede d"utilisation pour la reanimation suite a un accident ischemique cerebral ou a une reperfusion
EP1561748A1 (fr) * 2002-10-18 2005-08-10 Meiji Seika Kaisha Ltd. Monoesters d'acide malonique et procede de fabrication correspondant
WO2005066173A2 (fr) * 2004-01-08 2005-07-21 Glaxo Group Limited Nouveaux procedes
WO2014031844A1 (fr) * 2012-08-22 2014-02-27 Xenoport, Inc. Méthodes d'administration du monométhyl fumarate et des promédicaments associés présentant des effets secondaires réduits
WO2014053857A1 (fr) * 2012-10-05 2014-04-10 Mitopharm Ltd Succinates protégés pour accroître la production mitochondriale d'atp
WO2015155231A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Nouveaux composés de succinate perméables à travers les cellules
WO2015155238A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Promédicaments à base de succinate destinés à être utilisés dans le traitement de l'acidose lactique ou d'effets secondaires induits par un médicament dus à une déficience liée au complexe i de la phosphorylation oxydative mitochondriale
WO2015155230A1 (fr) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Promédicaments d'acide succinique pour augmenter la production d'atp

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BRYN ET AL.: "Solid-State Chemistry of Drugs", 1999, SSCI
CHOUCHANI, E.T. ET AL.: "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS", NATURE, vol. 515, 2014, pages 431 - 435, XP055205795, DOI: doi:10.1038/nature13909
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BAO, XIUCONG ET AL: "A Chemical Probe for Lysine Malonylation", XP002752058, retrieved from STN Database accession no. 2013:459828 *
JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 4, 1992, pages 687 - 94
JOURNAL OF ORGANIC CHEMISTRY, vol. 72, no. 19, 2007, pages 7253 - 7259
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 43, 1921, pages 660 - 7
KAAL, E.C. ET AL.: "Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis", JOURNAL OF NEUROCHEMISTRY, vol. 74, 2000, pages 1158 - 1165
PESTA, D.; GNAIGER, E.: "High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle", METHODS MOL BIOL, vol. 810, 2012, pages 25 - 58
SJOVALL, F. ET AL.: "Mitochondrial respiration in human viable platelets-methodology and influence of gender, age and storage", MITOCHONDRION, vol. 13, 2013, pages 7 - 14, XP028969159, DOI: doi:10.1016/j.mito.2012.11.001

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341493A (zh) * 2020-10-21 2021-02-09 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用
CN112341493B (zh) * 2020-10-21 2023-08-15 重庆医药高等专科学校附属第一医院(重庆市职业病防治院重庆市第六人民医院重庆市中毒控制中心) 一种基于三苯基膦修饰的线粒体靶向褪黑素及其制备方法和应用
WO2022228223A1 (fr) * 2021-04-26 2022-11-03 重庆理工大学 Mitochondries modifiées et leur procédé de préparation

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