WO2017060422A1 - Protected carboxylic acid-based metabolites for the treatment of mitochondrial disorders - Google Patents

Protected carboxylic acid-based metabolites for the treatment of mitochondrial disorders Download PDF

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WO2017060422A1
WO2017060422A1 PCT/EP2016/073992 EP2016073992W WO2017060422A1 WO 2017060422 A1 WO2017060422 A1 WO 2017060422A1 EP 2016073992 W EP2016073992 W EP 2016073992W WO 2017060422 A1 WO2017060422 A1 WO 2017060422A1
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complex
deficiency
formula
mitochondrial
derived
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PCT/EP2016/073992
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French (fr)
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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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom

Definitions

  • the present invention provides 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.
  • 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. Some of the compounds disclosed herein may be already known and is hereby disclaimed; thus the invention relates to the compounds as such provided that they are novel. The invention relates to the compounds disclosed herein for use in medicine, notably in the treatment of mitochondrial-related diseases or disorders. Other uses of the compounds appear from the description herein.
  • ATP adenosine triphosphate
  • mitochondrial genome while others may be caused by impairment of the mitochondrial respiratory system or other kind of damage of the mitochondrial function. Further, some conditions, such as ischemia reperfusion injury, can be caused by excess activity of
  • mitochondrial enzymes or electron transport by the respiratory chain At present there almost no available treatment that can counteract or cure mitochondrial diseases.
  • 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. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.
  • 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 and B are independently different or the same and are selected from -OR, -OR', -NHR", or -OH; wherein R is or in those cases, where the compound is according to Formula (IA), then B is C-
  • R' is selected from the formula (II), (V) or (IX) below:
  • R', R" and R'" are independently different or identical and are selected from formula (VII-VIII) below:
  • Ri and R 3 are independently different or identical and are selected from H, Me, Et, propyl, i- propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyI, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl,
  • X is selected from O, NH, NR 6 , S,
  • R 2 is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(0)CH 3 , C(0)CH 2 C(0)CH 3 , C(0)CH 2 CH(OH)CH 3 , p is an integer and is 1 or 2,
  • R 6 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
  • R 9 is selected from H, Me, Et or O2CCH2CH2COXR;
  • R-io is selected from Oacyl, NHalkyl, NHacyl, or O2CCH2CH2CO X 6 R 8 ,
  • X 6 is O or NR 8 , and R 8 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, succinyl, or formula (II), or formula (VIII),
  • R-i -i and R 12 are independently the same or different and are selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, succinyl, acyl, - CH 2 Xalkyl, -CH 2 Xacyl, where X is selected from O, NR 6 or S,
  • R-I4 and R 15 are independently different or identical and are selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, -COOH, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl
  • R f , Rg and Rh are independently selected from Xacyl, -CH 2 Xalkyl, -CH 2 X-acyl and R 9 , alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl, and acyl is selected from formyl, acetyl, propionyl, butyryl pentanoyl, benzoyl, succinyl and the like, R 2 o and R 2 i are independently different or identical and are selected from H, lower alkyl, i.e. C C 4 alkyl or R 20 and R 2 i together may form a C 4 -C 7 cyclo
  • R 20 and R 21 may be
  • acyls and alkyls may be optionally substituted.
  • A is selected from -O-R, wherein R is
  • R B is selected from -O-R', -NHR", -SR'" or -OH; wherein R' is selected from the formula (II), (V) or (IX) above, R', R" and R'" are independently different or identical and are selected from formula (VII) or (VIII) above, or in those cases, where the compound is according to Formula (IA), then R is C-
  • At least one of Ri and R 3 is -H, such that formula II is:
  • p is 1 , preferably 1 , and X 5 is -H such that formula (VII) is
  • At least one of R f , R g , R h is -H or alkyl, with alkyl as defined herein.
  • Compounds of the invention of particular interest are those compounds wherein A is -OR.
  • Compounds of particular interest are those compounds, wherein A is -OR, and B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is Me; wherein R' is selected from the formula (II), (V) or (IX) as described above, and R, R', R" and R'" being as described above.
  • Other compounds of particular interest are those compounds, wherein A is -OR, and B is -OR', wherein R' is selected from -H, formula (VII) or formula (VIII) as defined above.
  • Compounds of the invention of particular interest are those compounds wherein A is -OR and B is -OH.
  • Compounds of the invention of particular interest are those compounds wherein A is -OR and B is -OH, and Ri or R 3 is nds of particular interest are those compounds, wherein R-i or R 3 is
  • a compound of particular interest is given by Formula (IB) or a pharmaceutically acceptable salt thereof, wherein Z is as defined herein before, and
  • a and B are independently different or the same and are selected from or -OH, -OR, or -OR', and A and B cannot both be -OH, wherein Ri, R 2 , R3, R and R' are as defined herein.
  • A is C-
  • R 2 may be C C 4 alkyl. As seen from the examples herein a suitable R 2 group is Me.
  • a and B are independently different or the same and are selected from
  • Rx and Ry according to the invention are only present when the compound of Formula (I) can be drawn as
  • 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.
  • Protecting groups include but are not limited to benzyl and tert-butyl. Other protecting groups for carbonyls and their removal are detailed in 'Greene's Protective Groups in Organic
  • Activating groups includes but is not limited to mixed anhydrides and acyl chlorides.
  • a symmetrical starting material is selected.
  • a symmetrical starting material e.g. a dicarboxylic acid
  • the mono-substituted compound purified out of the reaction mixture.
  • asymmetric starting material is selected, preferable succinic acid, and less derivatising starting material is employed.
  • Hal represents a halogen (e.g. F, CI, Br or I) and R1 , R2 and R3 are as defined in formula (II).
  • the reaction may conveniently be carried out in a solvent such as dichloromethane, acetone, acetonitrile or ⁇ , ⁇ -dimethylformamide with a suitable base such as triethylamine, diisopropylethylamine or caesium carbonate at a temperature, for example, in the range from - 10°C to 80°C, particularly at room temperature.
  • the reaction may be performed with optional additives such as sodium iodide or tetraalkyl ammonium halides (e.g.
  • Compounds of formula (I) that contain formula (V) may be by various routes. Where R 9 and R 10 are both H they can be prepared by reaction of a compound of starting material 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 (V). Compounds of formula (I) that contain formula (V) may also be made by making a suitable ortho enol ester and subjecting that to ozonolysis (see Stetter and Reske, Chem. Ber. 103, 639-642 (1970)).
  • XIV wherein X 5 and R-i are as defined in formula (VII) and X 7 is Hal (CI, F, Br) or mixed anhydride.
  • X 7 CI.
  • the reaction may conveniently be carried out in a solvent such as dichloromethane, acetone, THF, acetonitrile or ⁇ , ⁇ -dimethylformamide, with a suitable base such as triethylamine, diisopropylethylamine or caesium carbonate with at a temperature, for example, in the range from -10°C to 80°C, particularly at room temperature.
  • Compounds of formula (I) that contain formula (VIII) may be made by reacting an activated carboxylic acid with a compound of formula XIV, optionally in the presence of an activating species
  • Hal represents a halogen (e.g. F, CI, Br or I) and R-n , R 12 and R c and R d are as defined in formula (VIII).
  • the reaction may conveniently be carried out in a solvent such as
  • 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
  • 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 Hydrolysis
  • 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.
  • 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.
  • Diseases of the mitochondria appear most often in organs that are very energy demanding such as retina, the cochlea, the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system. 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.
  • mitochondrial disorders can be secondary to other diseases or conditions such as, but not limited to, ischemia, ischemia-reperfusion injury, diabetes, cancer, intoxication.
  • Many diseases have been found to involve 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.
  • 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 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-l-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-l-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.
  • the present invention also provides the use of the compound of the invention for the
  • 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 prodrug/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 "powerhouse" of the cell.
  • One of their primary functions is oxidative phosphorylation.
  • the molecule adenosine triphosphate (ATP) functions as an energy “currency” or energy carrier in the cell, and eukaryotic cells derive the majority of their ATP from biochemical processes carried out by mitochondria.
  • biochemical processes include the citric acid cycle (the tricarboxylic acid cycle, or Kreb's cycle), which generates reduced nicotinamide adenine dinucleotide (NADH) from oxidized nicotinamide adenine dinucleotide (NAD + ) and reduced flavin adenine
  • FADH2 oxidized flavin adenine dinucleotide
  • FAD flavin adenine dinucleotide
  • the electrons released by oxidation of NADH 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 a prosthetic group in the enzyme complex succinate dehydrogenase (complex II)
  • 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
  • oxidative phosphorylation the overall process is known as aerobic 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.
  • 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.
  • 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.
  • 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 or nuclear. If a threshold proportion of mitochondria in the cell are 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 condition, 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.
  • мидл ⁇ онентs 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:
  • 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
  • MCAD Medium-Chain Acyl-CoA Dehydrogenase Deficiency
  • MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike Episodes
  • MERRF Myoclonic Epilepsy and Ragged-Red Fiber Disease
  • Mitochondrial Encephalopathy includes: Encephalomyopathy, Encephalomyelopathy
  • MNGIE Myoneurogastointestinal Disorder and Encephalopathy
  • NARP Neuroopathy, Ataxia, and Retinitis Pigmentosa
  • SCHAD Short Chain L-3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficiency, also referred to as 3-Hydroxy Acyl CoA Dehydrogenase Deficiency HADH
  • VLCAD Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
  • Complex I deficiency Inside the mitochondrion is a group of proteins that carry electrons along four chain reactions (Complexes l-IV), resulting in energy production. This chain is known as the Electron Transport Chain. A fifth group (Complex V) churns out the ATP. Together, the electron transport chain and the ATP synthase form the respiratory chain and the whole process is known as oxidative phosphorylation or OXPHOS.
  • Complex I the first step in this chain, is the most common site for mitochondrial abnormalities, representing as much as one third of the respiratory chain deficiencies.
  • 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 stroke-like 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
  • Myopathy muscle disease
  • Mitochondrial encephalomyopathy brain and muscle disease
  • 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. Most cases of Complex I deficiency result from autosomal recessive inheritance (combination of defective nuclear genes from both the mother and the father). Less frequently, the disorder is maternally inherited or sporadic and the genetic defect is in the mitochondrial DNA.
  • 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.
  • Complex III Deficiency 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.
  • 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. Possible lactic acidosis. iii) Myopathy, with exercise intolerance evolving into fixed weakness. Ragged-red fibers are common. Possible lactic acidosis. iv) Infantile histiocytoid cardiomyopathy.
  • 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.
  • Benign infantile myopathy may begin soon after birth and accompanied by
  • hypotonia weakness, lactic acidosis, ragged-red fibers, respiratory problems, but (if the child survives) followed by spontaneous improvement.
  • KSS Kerns-Sayre Syndrome: KSS is a slowly progressive multi-system mitochondrial disease that often begins with drooping of the eyelids (ptosis). Other eye muscles eventually become involved, resulting in paralysis of eye movement. Degeneration of the retina usually causes difficulty seeing in dimly lit environments.
  • KSS is characterized by three main features: • typical onset before age 20 although may occur in infancy or adulthood
  • 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. As with all mitochondrial diseases, there is no cure for KSS.
  • 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.
  • Leigh Disease or Syndrome Subjective Necrotizing Encephalomyelopathy: Symptoms:
  • 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 I, II, 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.
  • 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 progression, ragged-red fibers.
  • 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.
  • the patient appears normal during infancy, although short stature is common. Less common are early infancy symptoms that may include developmental delay, learning disabilities or attention-deficit disorder. Exercise intolerance, limb weakness, hearing loss, and diabetes may also precede the occurrence of the stroke-like episodes.
  • Stroke-like episodes 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 combinations of loss of motor skills (speech, movement, and eating), impaired sensation (vision loss and loss of body sensations), and mental impairment (dementia).
  • 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.
  • MERRF 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.
  • 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.
  • Therapies may include coenzyme Q10, L-carnitine, and various vitamins, often in a "cocktail" combination.
  • 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.
  • FRDA cardiodegenerative disorder caused by decreased levels of the protein frataxin. Frataxin is important for the assembly of iron-sulfur clusters in mitochondrial respiratory-chain complexes.
  • FRDA mitochondrial respiratory-chain complexes.
  • the disease causes the progressive loss of voluntary motor coordination (ataxia) and cardiac complications. Symptoms typically begin in childhood, and the disease progressively worsens as the patient grows older; patients eventually become wheelchair-bound due to motor disabilities.
  • neurodegenerative disorders associated with aging like Parkinson's, Alzheimer's, and
  • 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 route.
  • 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).
  • 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.
  • 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.
  • compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of
  • 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
  • Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a
  • 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, mono/diglycerides, propylene glycol and ascorbyl palmitate).
  • 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.
  • MCT-oil medium chain triglyceride
  • 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), hydroxy-propylcellulose (HPC), macrogol 8000, sucrose, gelatin and acacia. Additionally, 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.
  • 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 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.
  • 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.
  • 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.
  • suitable formulations and how to prepare it see eg Remington's Pharmaceutical Sciences 18 Ed. or later).
  • suitable administration route and dosage see eg Remington's Pharmaceutical Sciences 18 Ed. or later.
  • 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.
  • R', R" or R'" is a compound of formula (II)
  • the acyl group including R 2 may be cleaved by a suitable enzyme, preferably an esterase. This liberates a hydroxymethyl ester, an aminomethyl ester or a thiolmethyl ester which could spontaneous covert to a carbonyl, imine or thiocarbonyl group and a free carboxylic acid.
  • a suitable enzyme preferably an esterase.
  • R', R" or R'" is a compound of formula (V)
  • the substituent on group Rio may be removed by the action of a suitable enzyme or via chemical hydrolysis in vivo.
  • A is OR' with R' being formula (V) and B is H and Z is -CH 2 -, X is O and R 8 is H, R 9 is Me and R 10 is O-acetyl.
  • R', R" or R'" is a compound of formula (VII) the group may be removed by the action of a suitable enzyme or via chemical hydrolysis in vivo to liberate succinic acid.
  • A is SR'" with R'" being formula (VII) and B is H and Z is -CH 2 -, X 5 is C0 2 H and Ri is Et:
  • 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). Many known drug substances negatively influence mitochondrial respiration (e.g.
  • 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 up-stream 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). It is contemplated that the compounds according to the invention also can be used in industrial applications, e.g.
  • 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.
  • 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-tuberculosis including isoniazid
  • Fibrates including clofibrate, ciprofibrate, simvastatin
  • Local anaesthetics including bupivacaine, diclofenac, indomethacin, and lidocaine
  • Muscle relaxant including dantrolene 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.
  • 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 Complex I defect, inhibition or malfunction, wherein i) 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 administered before the compound of the invention or vice versa.
  • different administration routes e.g. drug substance via oral administration and compound of the invention by parenteral or mucosal administration
  • the drug substance may be administered essentially at the same time or the drug substance may be administered before the compound of the invention or vice versa.
  • the invention also provides a kit comprising
  • 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 invention also relates to a method for treating a subject suffering from a drug-induced 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, 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 carboxylic acid-based metabolites” and “cell permeable precursors of metabolites” are used interchangeably and refer to compounds of formula (I) or formula (IA).
  • 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 et al, 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 pseudo-obstruction), 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.
  • Other 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, ⁇ , ⁇ '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.
  • alkyl refers to any straight or branched chain composed of only sp3 carbon atoms, fully saturated with hydrogen atoms such as e.g. -C n H 2 n+i for straight chain alkyls, wherein n can be in the range of 1 and 10 such as e.g. methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl.
  • the alkyl as used herein may be further substituted.
  • cycloalkyl refers to a cyclic/ring structured carbon chains having the general formula of -C n H 2n -i where n is between 3-10, such as e.g. cyclopropyl, cyclobytyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, bicycle[3.2.1]octyl, spiro[4,5]decyl, norpinyl, norbonyl, norcapryl, adamantly and the like.
  • alkene refers to a straight or branched chain composed of carbon and hydrogen atoms wherein at least two carbon atoms are connected by a double bond such as e.g. C 2- io alkenyl unsaturated hydrocarbon chain having from two to ten carbon atoms and at least one double bond.
  • C 2- 6 alkenyl groups include, but are not limited to, vinyl, 1-propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
  • Cno alkoxy in the present context designates a group -0-C-i- 6 alkyl used alone or in combination, wherein Cno alkyl is as defined above.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • branched alkoxy are iso- propoxy, sec-butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • C 3 - 7 heterocycloalkyl denotes a radical of a totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle.
  • heterocycles include, but are not limited to, pyrrolidine (1 -pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 4-pyrrolidine, 5- pyrrolidine), pyrazolidine (1 -pyrazolidine, 2-pyrazolidine, 3-pyrazolidine, 4-pyrazolidine, 5- pyrazolidine), imidazolidine (1-imidazolidine, 2-imidazolidine, 3-imidazolidine, 4-imidazolidine, 5- imidazolidine), thiazolidine (2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine (1 -piperidine, 2-piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine
  • C-i.-ioalkyl-Cs.-iocycloalkyl refers to a cycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • C 1-10 alkyl-C 3-7 heterocycloalkyl refers to a heterocycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated below.
  • heteroaryl as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected among nitrogen, oxygen and sulphur, such as furyl, thienyl, pyrrolyl, and is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
  • aryl and heteroaryl refers to an aryl, which can be optionally unsubstituted or mono-, di- or tri substituted, or a heteroaryl, which can be optionally
  • aryl and “heteroaryl” include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, thiophenyl (1 -thienyl, 2-thienyl), furyl (1-furyl, 2-furyl), furanyl, thiophenyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyrany
  • Non-limiting examples of partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • 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, C 1-6 alkoxy, cyano, amino, nitro, C 1-6 alkylamino, C 2-6 alkenylamino, di-C 1-6 alkylamino, C 1-6 acylamino, di-C 1-6 acylamino, C 1-6 aryl, C 1-6 arylamino, C 1-6 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 by
  • the oxygen atom can be replaced with sulphur to make groups such as thio (SH) and thio-alkyl (S-alkyl).
  • Optional substituents therefore include 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.
  • a person of skill in the art will be able to determine the pharmacokinetics and bioavailability of the compound of the invention using in vivo and in vitro methods known to a person of skill in the art, including but not limited to those described below and in Gallant-Haidner et al, 2000 and
  • 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
  • AUC - concentration-time curve
  • peak time time at which maximum plasma or blood drug concentration occurs
  • 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%. These parameters are then analysed by non-compartmental or compartmental methods to give a calculated percentage bioavailability, for an example of this type of method see Gallant- Haidner et al, 2000 and Trepanier et al, 1998, and references therein.
  • 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
  • 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_-
  • Real-time respirometric measurements were performed using high-resolution oxygraphs (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria).
  • the experimental conditions during the measurements were the following: 37°C, 2 ml. active chamber volume and 750 rpm stirrer speed. Chamber concentrations of 0 2 were kept between 200-50 ⁇ with reoxygenation of the chamber during the experiments as appropriate 1 .
  • DatLab software version 4 and 5 were used (Oroboros Instruments, Innsbruck, Austria). Settings, daily calibration and instrumental background corrections were conducted according to the manufacturer's instructions.
  • 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_. Evaluation of compounds
  • 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 ⁇ g/mL 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.
  • the compounds according to the invention are evaluated in specialized protocols.
  • mitochondrial function in intact cells or intact fibers is native or repressed with respiratory inhibitors acting on specific Krebs cycle hydrogenases or electron transport complexes.
  • Drug candidates are compared with endogenous (non cell-permeable) substrates/inhibitors before and after permeabilization of the plasma membrane to evaluate bioenergetic enhancement or inhibition.
  • a and B are independently different or identical and are selected from -O-R', -NHR", -SR'" or - OH, with the provisio that both A and B cannot be H,
  • R', R" and R'" are independently different or identical and selected from the formula (II) to (IX) below:
  • R', R" and R'" are independently different or identical and selected from the formula (V), (VII), (IX) below:
  • R 3 are or any of the below formulas (a)-(f)
  • R 2 o and R 2 i are independently different or identical and are selected from H, lower alkyl, i.e. C C 4 alkyl or R 20 and R 2 i together may form a C 4 -C 7 cycloalkyi or an aromatic group, both of which may optionally be substituted with halogen, hydroxyl or a lower alkyl, or R 20 and R 21 may be
  • X is selected from O, NH, NR 6 , S,
  • R 2 is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, -C(0)CH 3 , - C(0)CH 2 C(0)CH 3 , -C(0)CH 2 CH(OH)CH 3 ,
  • n is an integer and is selected from 1 , 2, 3 or 4,
  • p is an integer and is selected from 1 or 2
  • R' 3 H, Me, Et, F
  • R 4 H, Me, Et, i-Pr
  • R 5 acetyl, propionyl, benzoyl, benzylcarbonyl
  • R' 2 H.HX 3 , acyl, acetyl, propionyl, benzoyl, benzylcarbonyl
  • R 6 is formula (III)
  • R 9 is selected from H, Me, Et or O2CCH2CH2COXR;
  • R-io is selected from Oacyl, NHalkyl, NHacyl, or 0 2 CCH 2 CH 2 COX 6 R 8
  • X 6 is O or NR 8
  • R 8 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl or formula (II),
  • R-i -i and R 12 are independently different or the same and is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, acyl, -CH 2 Xalkyl, - CH 2 Xacyl, where X is selected from O, NR 6 or S,
  • R c and R d are independently CH 2 Xalkyl, CH 2 Xacyl, where X is selected from O, NR 6 or S,
  • R f , R g and R h are independently different or the same and are selected from Xacyl, -CH 2 Xalkyl, -CH 2 X-acyl and R 9 , wherein alkyl is e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl and acyl is e.g.
  • the dotted bond between A and B denotes an optional bond to form a cyclic structure of formula (I) and with the proviso that when such a cyclic bond is present, the compound according to formula (I) is selected from
  • R x and R y are independently selected from R-i, R 2 , R 6 or R', R" or R'" with the proviso that R x and R y cannot both be -H.
  • At least one of Ri and R 3 is -H, such that formula II is:
  • p is 1 or 2, preferably 1
  • X 5 is -H such that formula (VII) is
  • At least one of R f , R g , R h is -H or alkyl, with alkyl as defined herein.
  • at least one of Rf, Rg, Rh is -CH 2 Xacyl, with acyl as defined herein.
  • R is and where B is selected from -O-R', -NHR", -SR'" or -OH; wherein R' is selected from the formula (II) to (IX) below:
  • Rh (IX) wherein R', R" and R'" are independently different or identical and is selected from formula (IV- VIII) below:
  • Ri H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, 0-alkyl, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl,
  • R 2 Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(0)CH 3 , C(0)CH 2 C(0)CH 3 ,
  • n 1 -4
  • R' 3 H, Me, Et, F
  • R 4 H, Me, Et, i-Pr
  • R 5 acetyl, propionyl, benzoyl, benzylcarbonyl
  • R' 2 H.HX 3 , acyl, acetyl, propionyl, benzoyl, benzylcarbonyl
  • R 6 H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), formula (III) or formula (VIII)
  • R 9 H, Me, Et or 0 2 CCH 2 CH 2 COXR 8
  • R-io Oacyl, NHalkyl, NHacyl, or 0 2 CCH 2 CH 2 COX 6 R 8
  • R 8 H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), formula (III) or formula (VIII)
  • R f , Rg and Rh are independently selected from Xacyl, -CH 2 Xalkyl, -CH 2 X-acyl and R 9 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl and acyl is selected from formyl, acetyl, propionyl, butyryl pentanoyi, benzoyl, succinyl and the like, and wherein the acyls or al
  • a compound according to item 1 wherein formula (IX) is such that at least one of R f , R g , R h is -H or alkyl, with alkyl as defined herein.
  • a and B are independently selected from -OH or -O-R'
  • a and B are independently selected from
  • a and B are independently selected from or -OH and where A and B cannot both be -OH
  • a compound according to any of item 1 -9 for use in cosmetics 12.
  • a compound according to any of items item 1-9 for use in the treatment of or prevention of metabolic diseases, or in the treatment of diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction, treating or suppressing of mitochondrial disorders, stimulation of mitochondrial energy production, 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.
  • a compound for use according to item 13, wherein the prevention or drug -induced mitochondrial side-effects relates to drug interaction with Complex I, such as e.g. metformin- Complex I interaction.
  • a compound according to item 13, wherein diseases of mitochondrial dysfunction involves e.g. mitochondrial deficiency such as a Complex I, II, III or IV deficiency or an enzyme deficiency like e.g. pyruvate dehydrogenase deficiency
  • MERRF Myoclonic Epilepsy and Ragged-Red Fiber Disease
  • Mitochondrial Recessive Ataxia Syndrome Mitochondrial Cytopathy
  • Mitochondrial DNA Depletion Mitochondrial Encephalopathy including: Encephalomyopathy and Encephalomyelopathy, Mitochondrial Myopathy, MNGIE (Myoneurogastointestinal Disorder and Encephalopathy, NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa), Neurodegenerative disorders associated with Parkinson's, Alzheimer's or Huntington's disease, Pearson
  • LHON Leber's hereditary optic neuropathy
  • MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
  • MERRF myoclonic epilepsy with ragged red fibers
  • composition comprising a compound of Formula (I) as defined according any of items 1 -9 and one or more pharmaceutically or cosmetically acceptable excipients.
  • composition is 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
  • injection subcutaneous or intramuscular
  • composition is administered as a single dose or a plurality of doses over a period of time, such as e.g. one daily, twice daily or 3-5 times daily as needed.
  • a period of time such as e.g. one daily, twice daily or 3-5 times daily as needed.
  • 23. A compound according to any of items 1 -9 for use in the treatment or prevention of lactic acidosis.
  • the compound 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.
  • a composition comprising a drug substance and a compound according to any of items 1-9, wherein the drug substance has a potential drug-induced side-effect selected from i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other Complex-l-related substrates).
  • a potential drug-induced side-effect selected from i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would encompass any drug effect that limits the supply of NADH to Complex I, e.
  • a kit comprising
  • a first container comprising a drug substance, which has a potential drug-induced side-effect selected i) from lactic acidosis, ii) and side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic
  • a second container comprising a compound according to any of items 1 -9, 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 i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or 5 malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates).
  • the method comprises administering an effective amount of a compound according to any of items 1-9 to the subject.
  • 25 effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic
  • the method comprises administering an effective amount of a compound according to any of 30 items 1-9 to the subject before, during or after treatment with said drug substance.
  • metformin A compound according to any of items 1 -9, for use in the treatment of absolute or relative cellular energy deficiency.

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Abstract

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

Description

PROTECTED CARBOXYLIC ACID-BASED METABOLITES FOR THE
TREATMENT OF MITOCHONDRIAL DISORDERS
Field of the invention
The present invention provides 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. 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. Not all 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). The provision of the novel carboxylic acid-based metabolites is envisaged to allow passage over the cellular membrane and thus these cell-permeable carboxylic acid-based metabolites can be used to increase cellular metabolic function by enhancing ATP-production in mitochondria or the glycolytic pathway. In some cases, 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)).
Moreover, 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. Notably, 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. producing more ATP than normally, or in restoring defects in glycolytic pathway or the mitochondrial respiratory system. In some cases, 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.
Background of the invention
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. Some of the compounds disclosed herein may be already known and is hereby disclaimed; thus the invention relates to the compounds as such provided that they are novel. The invention relates to the compounds disclosed herein for use in medicine, notably in the treatment of mitochondrial-related diseases or disorders. Other uses of the compounds appear from the description herein.
In recent years many papers have been published describing mitochondrial contributions to a variety of diseases. Some diseases may be caused by mutations or deletions in the
mitochondrial genome, while others may be caused by impairment of the mitochondrial respiratory system or other kind of damage of the mitochondrial function. Further, some conditions, such as ischemia reperfusion injury, can be caused by excess activity of
mitochondrial enzymes or electron transport by the respiratory chain. At present there almost no available treatment that can counteract or cure mitochondrial diseases.
In view of the recognized importance of adjusting, maintaining or restoring a normal mitochondrial function or of enhancing the cell's energy production (ATP), there is a need to develop compounds which have the following properties: Cell permeability of the compound, the ability to liberate intracellular one or more carboxylic acid-based metabolites or a precursor thereof, low toxicity of the compound and released products, and physicochemical properties consistent with administration to a patient.
Description of the invention
Compounds according to the present invention can be used to enhance energy production in mitochondria. Notably 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. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.
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.
Many diseases have been found to involve 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. Further, some conditions, such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain. No curative treatments are available. The only treatments available are such that can alleviate the symptoms and delay the progression of the disease.
Accordingly, the findings by the present inventors and described herein are very important as they can adjust, maintain or restore normal mitochondrial function or enhance the cell's energy production (ATP).
Disclosed herein is a protected carboxylic acid-based metabolite of Formula (I) or Formula (IA)
Figure imgf000005_0001
(IA)
or a pharmaceutically acceptable salt thereof, wherein the dotted bond between A and B denotes an optional bond so as to form a ring closed structure, and wherein when the formula is Formula (I), Z is selected from -CH2- (eg derived from malonic acid), -CH2- CH2-CH2 (eg derived from glutaric acid), -CH=CH2- (eg derived from fumaric acid), -CH2- CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid),
CH2C(OH)(COOH)-CH2- (eg derived from citric acid), -C(0)-CH2-CH2- (eg derived from alpha- ketoglutaric acid), -CH2-CH2-C(0)- (eg derived from alpha-ketoglutaric acid), -CH2-C(COC(OH)- C(COOH)-CHOH)=CH- (eg derived from aconitic acid), -CH=C(COOH)-CH2- (eg derived from aconitic acid), -CH(OH)-CH(COOH)-CH2- (eg derived from isocitric acid), -CH2-CH(COOH)- CH(OH)- (eg derived from isocitric acid), -CH2-CH(COOH)-C(=0)- (eg derived from
oxalosuccinic acid), -C(=0)-CH(COOH)-CH2- (eg derived from oxalosuccinic acid), -C(=0)-CH2- (eg derived from oxaloacetatic acid), -CH2-C(=0)- (eg derived from oxaloacetic acid); or when the formula is Formula (IA), Z is selected from -CH(OH)-CH2(OH) and n is 0 eg derived from glyceric acid); or Z is absent or -CH2- and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively);
A and B are independently different or the same and are selected from -OR, -OR', -NHR", or -OH; wherein R is
Figure imgf000005_0002
or in those cases, where the compound is according to Formula (IA), then B is C-|-C4- alkyl, branched or straight, preferably R is Me;
R' is selected from the formula (II), (V) or (IX) below:
Figure imgf000006_0001
and both A and B are not -OH,
R', R" and R'" are independently different or identical and are selected from formula (VII-VIII) below:
Figure imgf000006_0002
Ri and R3 are independently different or identical and are selected from H, Me, Et, propyl, i- propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyI, N-acyl, N-alkyl, Xacyl, CH2Xalkyl,
CH2CH2CH2OC(=0)CH2CH2COX6R8 or
Figure imgf000006_0003
X is selected from O, NH, NR6, S,
R2 is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(0)CH3, C(0)CH2C(0)CH3, C(0)CH2CH(OH)CH3, p is an integer and is 1 or 2,
R6 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
X5 is selected from -H, -COOH, -C(=0)XR6,CONR1R3 or one of the formulas
Figure imgf000007_0001
R9 is selected from H, Me, Et or O2CCH2CH2COXR;
R-io is selected from Oacyl, NHalkyl, NHacyl, or O2CCH2CH2CO X6R8,
X6 is O or NR8, and R8 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, succinyl, or formula (II), or formula (VIII),
R-i -i and R12 are independently the same or different and are selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, succinyl, acyl, - CH2Xalkyl, -CH2Xacyl, where X is selected from O, NR6 or S,
Ri3> R-I4 and R15 are independently different or identical and are selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, -COOH, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, CH2Xalkyl
Rc and Rd are independently CH2Xalkyl, CH2Xacyl, where X = O, NR6 or S, and alkyl is e.g. H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, and acyl is e.g. formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl, succinyl, or the like,
Rf , Rg and Rh are independently selected from Xacyl, -CH2Xalkyl, -CH2X-acyl and R9, alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl, and acyl is selected from formyl, acetyl, propionyl, butyryl pentanoyl, benzoyl, succinyl and the like, R2o and R2i are independently different or identical and are selected from H, lower alkyl, i.e. C C4 alkyl or R20 and R2i together may form a C4-C7 cycloalkyl or an aromatic group, both of which may optionally be substituted with halogen, hydroxyl or a lower alkyl, or
R20 and R21 may be
Figure imgf000008_0001
CH2X-acyl, F, CH2COOH, CH2C02alkyl, and when there is a cyclic bond present between A and B the compound is
Figure imgf000008_0002
and acyls and alkyls may be optionally substituted.
The compounds of formula (I) (and any pharmaceutically acceptable salts thereof) are referred to hereinafter as "compound of the invention", "compounds of the invention" or as "compounds of the invention". As mentioned hereinbefore, the invention also relates to the compounds for use in medicine.
More s ntion is given by Formula (I) or Formula (IA)
Figure imgf000008_0003
("A)
or a pharmaceutically acceptable salt thereof, where the dotted bond denotes an optional bond between A and B to form a ring closed structure, and wherein when the formula is Formula (I), Z is selected from -CH2- (eg derived from malonic acid), -CH2- CH2-CH2 (eg derived from glutaric acid), -CH=CH2- (eg derived from fumaric acid), -CH2- CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid),
CH2C(OH)(COOH)-CH2- (eg derived from citric acid), -C(0)-CH2-CH2- (eg derived from alpha- ketoglutaric acid), -CH2-CH2-C(0)- (eg derived from alpha-ketoglutaric acid), -CH2-C(COC(OH)- C(COOH)-CHOH)=CH- (eg derived from aconitic acid), -CH=C(COOH)-CH2- (eg derived from aconitic acid), -CH(OH)-CH(COOH)-CH2- (eg derived from isocitric acid), -CH2-CH(COOH)- CH(OH)- (eg derived from isocitric acid), -CH2-CH(COOH)-C(=0)- (eg derived from
oxalosuccinic acid), -C(=0)-CH(COOH)-CH2- (eg derived from oxalosuccinic acid), -C(=0)-CH2- (eg derived from oxaloacetatic acid), -CH2-C(=0)- (eg derived from oxaloacetic acid); or when the formula is Formula (IA), Z is selected from -CH(OH)-CH2(OH) and n is 0 eg derived from glyceric acid); or Z is absent or -CH2- and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively);
A is selected from -O-R, wherein R is
Figure imgf000009_0001
B is selected from -O-R', -NHR", -SR'" or -OH; wherein R' is selected from the formula (II), (V) or (IX) above, R', R" and R'" are independently different or identical and are selected from formula (VII) or (VIII) above, or in those cases, where the compound is according to Formula (IA), then R is C-|-C4- alkyl, branched or straight, preferably R is Me.
Preferably, and with respect to formula (II), at least one of Ri and R3 is -H, such that formula II is:
Figure imgf000009_0002
Preferably, and with respect to formula (VII), p is 1 , preferably 1 , and X5 is -H such that formula (VII) is
Figure imgf000010_0001
Preferably, and with respect to formula (IX), at least one of Rf, Rg, Rh is -H or alkyl, with alkyl as defined herein. Moreover, it is also preferable with respect to Formula (IX) that at least one of Rf, Rg, Rh is -CH2Xacyl, with acyl as defined herein.
In all the compounds described herein a preferred Z is is selected from -CH2- (eg derived from malonic acid), -CH=CH2- (eg derived from fumaric acid), -CH2-CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid); or Z is absent, n is 1 and B is an alkyl group (eg derived from pyruvic acid and corresponding to Figure (IA)). More preferred are compounds, where Z is -CH2- (eg derived from malonic acid).
Compounds of the invention of particular interest are those compounds wherein A is -OR. Compounds of particular interest are those compounds, wherein A is -OR, and B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is Me; wherein R' is selected from the formula (II), (V) or (IX) as described above, and R, R', R" and R'" being as described above. Other compounds of particular interest are those compounds, wherein A is -OR, and B is -OR', wherein R' is selected from -H, formula (VII) or formula (VIII) as defined above.
Compounds of the invention of particular interest are those compounds wherein A is -OR and B is -OH.
Compounds of the invention of particular interest are those compounds wherein A is -OR and B is -OH, and ^ or R3 is CH2CH2CH2OC(=0)CH2CH2COX6R8.
Compounds of the invention of particular interest are those compounds wherein A is -OR and B is -OH, and Ri or R3 is
Figure imgf000011_0001
nds of particular interest are those compounds, wherein R-i or R3 is
Figure imgf000011_0002
or wherein Ri or R3 is CH2CH2CH20C(=0)CH2CH2COX6R;
A compound of particular interest is given by Formula (IB)
Figure imgf000011_0003
or a pharmaceutically acceptable salt thereof, wherein Z is as defined herein before, and
A and B are independently different or the same and are selected from
Figure imgf000011_0004
or -OH, -OR, or -OR', and A and B cannot both be -OH, wherein Ri, R2, R3, R and R' are as defined herein.
Compounds of particular interest are given by Formula (IA) as above, and wherein R' is formula (VII) or (VIII).
Further compounds of particular interest are those of formula (IA), wherein
A is C-|-C4OX6R8 , or wherein
Figure imgf000012_0001
Figure imgf000012_0002
or -CH2CH2CH2OC(=0)CH2CH2COX6R8.
When A is
Figure imgf000012_0003
R2 may be C C4 alkyl. As seen from the examples herein a suitable R2 group is Me.
In yet a further aspect of the invention the compound according to Formula (I) is
Figure imgf000012_0004
or a pharmaceutically acceptable salt thereof, wherein Z is as defined herein before, and
A and B are independently different or the same and are selected from
Figure imgf000013_0001
-OH, and A and B cannot both be -OH.
As is apparent to a person skilled in the art, the compound of Formula (I), wherein the optional bond connecting the oxygen atoms with Rx and Ry, is primarily intended to mean that the compound of Formula (I) is
Figure imgf000013_0002
y
As a consequence of the above, Rx and Ry according to the invention are only present when the compound of Formula (I) can be drawn as
Figure imgf000013_0003
Interesting compounds are eg
O O
Z^O Z^A e.g. R also drawn as R
Specific compounds according to the invention are
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000015_0001
General Chemistry Methods
The skilled person will recognise that the compounds of the invention may be prepared, in known manner, in a variety of ways. The routes below are merely illustrative of some methods that can be employed for the synthesis of compounds of formula (I).
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. For the dicarboxylic acid-based metabolite then a suitable mono-protected carboxylic acid-based metabolite or a mono-activated carboxylic acid- based metabolite a may be used as a starting material.
Protecting groups include but are not limited to benzyl and tert-butyl. Other protecting groups for carbonyls and their removal are detailed in 'Greene's Protective Groups in Organic
Synthesis' (Wuts and Greene, Wiley, 2006). Protecting groups may be removed by methods known to one skilled in the art including hydrogenation in the presence of a heterogenous catalyst for benzyl esters and treatment with organic or mineral acids, preferably trifluoroacetic acid or dilute HCI, for tert-butyl esters.
Activating groups includes but is not limited to mixed anhydrides and acyl chlorides.
Thus, were compounds of formula (I) are symmetrical then a symmetrical starting material is selected. Either a symmetrical dicarboxylic acid is selected or a di-activated carboxylic acid is selected. Preferably this includes malonic acid mono-benzyl ester, malonic acid mono-tert butyl ester, .Alternatively to make an asymmetric compound of formula (I) then a symmetrical starting material (e.g. a dicarboxylic acid) is used and the mono-substituted compound purified out of the reaction mixture.
Alternatively for an asymmetric compound of formula (I) a symmetric starting material is selected, preferable succinic acid, and less derivatising starting material is employed.
The following general methods are not exhaustive and it will be apparent to one skilled in the art that other methods may be used to generate compounds of the invention. The methods may be used together or separately.
Compounds of formula (I) that contain formula (II) may be made by reacting a carboxylic acid with a suitable alkyl halide (formula (X)). E.g.
Figure imgf000016_0001
formula X wherein Hal represents a halogen (e.g. F, CI, Br or I) and R1 , R2 and R3 are as defined in formula (II). The reaction may conveniently be carried out in a solvent such as dichloromethane, acetone, acetonitrile or Ν,Ν-dimethylformamide with a suitable base such as triethylamine, diisopropylethylamine or caesium carbonate at a temperature, for example, in the range from - 10°C to 80°C, particularly at room temperature. The reaction may be performed with optional additives such as sodium iodide or tetraalkyl ammonium halides (e.g. tetrabutyl ammonium iodide). Compounds of formula X are either commercially available or may be conveniently prepared by literature methods such as those outlined in Journal of the American Chemical Society, 43, 660- 7; 1921 or Journal of medicinal chemistry (1992), 35(4), 687-94.
Compounds of formula (I) that contain formula (V) may be by various routes. Where R9 and R10 are both H they can be prepared by reaction of a compound of starting material 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 (V). Compounds of formula (I) that contain formula (V) may also be made by making a suitable ortho enol ester and subjecting that to ozonolysis (see Stetter and Reske, Chem. Ber. 103, 639-642 (1970)).
Compounds of formula (I) that contain formula (VII) may be made by reacting an activated carboxylic acid with a compound of formula XIV, optionally in the presence of an activating
Figure imgf000017_0001
formula XIV wherein X5 and R-i are as defined in formula (VII) and X7 is Hal (CI, F, Br) or mixed anhydride. Preferably X7 = CI. The reaction may conveniently be carried out in a solvent such as dichloromethane, acetone, THF, acetonitrile or Ν,Ν-dimethylformamide, with a suitable base such as triethylamine, diisopropylethylamine or caesium carbonate with at a temperature, for example, in the range from -10°C to 80°C, particularly at room temperature.
Compounds of formula (I) that contain formula (VIII) may be made by reacting an activated carboxylic acid with a compound of formula XIV, optionally in the presence of an activating species
Figure imgf000017_0002
wherein Hal represents a halogen (e.g. F, CI, Br or I) and R-n , R12 and Rc and Rd are as defined in formula (VIII). The reaction may conveniently be carried out in a solvent such as
dichloromethane, acetone, acetonitrile or Ν,Ν-dimethylformamide with a suitable base such as triethylamine, diisopropylethylamine or caesium carbonate at a temperature, for example, in the range from -10°C to 80°C, particularly at 80 °C. The reaction may be performed with optional additives such as sodium iodide or tetraalkyl ammonium halides (e.g. tetrabutyl ammonium iodide). Compounds of formula X are either commercially available or may be conveniently prepared by literature methods whereby an amine is reacted with an acyl chloride.
Compounds of formula (I) that contain formula (IX) may be made by combining the methods describe above and by other methods known to one skilled in the art.
General use of the compounds of the invention
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. Moreover, it is envisaged that the compounds of the invention may be beneficial in treatment of male infertility.
It is envisaged that 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. 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. As an example and merely to illustrate the idea behind this concept the below compound shown below yields 2 moles of acetic acid, 1 mole of malonic acid and 2 moles of formaldehyde Hydrolysis
► 2AcOH + malonic acid + 2 Glucose
Figure imgf000019_0001
The compounds of the invention can be used to enhance or restore energy production in mitochondria. In some cases, 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.
Notably 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. 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. Diseases of the mitochondria appear most often in organs that are very energy demanding such as retina, the cochlea, the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system. 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. Many diseases have been found to involve 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. Further, some conditions, such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain.
No curative treatments are available. The only treatments available are such that can alleviate the symptoms and delay the progression of the disease.
Accordingly, the findings by the present inventors and described herein are very important as they can adjust, maintain or restore normal mitochondrial function or enhance the cell's energy production (ATP).
In addition, 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). In some cases, the compounds are also orally bioavailable, which allows for easier administration.
Thus the advantageous properties of the compound of the invention may include one or more of the following:
-Increased cell permeability
-Longer half-life in plasma
-Reduced toxicity
-Increased energy release to mitochondria
-Improved formulation
-Increased solubility
-Increased oral bioavailability The present invention provides the compound of the invention for use as a pharmaceutical, in particular in the treatment of cellular energy (ATP)-deficiency.
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-l-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. 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.
In some cases, 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.
Especially regarding the novel compounds, wherein Z is -CH2-, i.e. derived from malonic acid, 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 prodrug/derivative of malonate capable of permeating the cell membrane and releasing malonate inside the cell is an advantage.
Mitochondria
Mitochondria are organelles in eukaryotic cells, popularly referred to as the "powerhouse" of the cell. One of their primary functions is oxidative phosphorylation. The molecule adenosine triphosphate (ATP) functions as an energy "currency" or energy carrier in the cell, and eukaryotic cells derive the majority of their ATP from biochemical processes carried out by mitochondria. These biochemical processes include the citric acid cycle (the tricarboxylic acid cycle, or Kreb's cycle), which generates reduced nicotinamide adenine dinucleotide (NADH) 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 and FADH2 is oxidized back to NAD<+> and FAD.
The electrons released by oxidation of NADH 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 a prosthetic group in the enzyme complex succinate dehydrogenase (complex II) 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, Complex V (which is not directly associated with Complexes I, II, III and IV) uses the energy stored by the electrochemical gradient to convert ADP into ATP. 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 C02 and H20 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 or nuclear. If a threshold proportion of mitochondria in the cell are 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.
Use of the compounds of the invention
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.
In particular, the compounds of the invention can be used in medicine, notably in the treatment or prevention of a mitochondria-related condition, 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.
Compounds of the invention for use in mitochondrial related disorders or diseases The compounds according to the invention may be used in the prevention or treatment a mitochondria-related disease selected from the following:
• Adrenoleukodystrophy (ALD)
• Alpers Disease (Progressive Infantile Poliodystrophy)
• Adrenoleukodystrophy (ALD)
• Amyotrophic lateral sclerosis (ALS)
• Autism
• Barth syndrome (Lethal Infantile Cardiomyopathy)
• Beta-oxidation Defects
• Bioenergetic metabolism deficency
• Carnitine-Acyl-Carnitine Deficiency
• Carnitine Deficiency
• Creatine Deficiency Syndromes (Cerebral Creatine Deficiency Syndromes (CCDS) includes: Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency), L- Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency), and SLC6A8- Related Creatine Transporter Deficiency (SLC6A8 Deficiency).
• Co-Enzyme Q10 Deficiency
• Complex I Deficiency (NADH dehydrogenase (NADH-CoQ reductase) deficiency)
• Complex II Deficiency (Succinate dehydrogenase deficiency)
• Complex III Deficiency (Ubiquinone-cytochrome c oxidoreductase deficiency)
• Complex IV Deficiency/COX Deficiency (Cytochrome c oxidase deficiency is caused by a defect in Complex IV of the respiratory chain)
• Complex V Deficiency (ATP synthase deficiency)
• COX Deficiency
• CPEO (Chronic Progressive External Ophthalmoplegia Syndrome)
• CPT I Deficiency
• CPT II Deficiency
• Friedreich's ataxia (FRDA or FA)
• Glutaric Aciduria Type II
• KSS (Kearns-Sayre Syndrome)
• Lactic Acidosis
• LCAD (Long-Chain Acyl-CoA Dehydrogenase Deficiency)
. LCHAD
• Leigh Disease or Syndrome (Subacute Necrotizing Encephalomyelopathy)
• LHON (Leber's hereditary optic neuropathy)
• Luft Disease
• MCAD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency) • MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike Episodes)
• MERRF (Myoclonic Epilepsy and Ragged-Red Fiber Disease)
• MIRAS (Mitochondrial Recessive Ataxia Syndrome)
• Mitochondrial Cytopathy
· Mitochondrial DNA Depletion
• Mitochondrial Encephalopathy includes: Encephalomyopathy, Encephalomyelopathy
• Mitochondrial Myopathy
• MNGIE (Myoneurogastointestinal Disorder and Encephalopathy)
• NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa)
· Neurodegenerative disorders associated with Parkinson's, Alzheimer's or Huntington's disease
• Pearson Syndrome
• Pyruvate Carboxylase Deficiency
• Pyruvate Dehydrogenase Deficiency
· POLG Mutations
• Respiratory Chain Deficiencies
• SCAD (Short-Chain Acyl-CoA Dehydrogenase Deficiency)
• SCHAD ( Short Chain L-3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficiency, also referred to as 3-Hydroxy Acyl CoA Dehydrogenase Deficiency HADH
· VLCAD (Very Long-Chain Acyl-CoA Dehydrogenase Deficiency)
• Diabetes
• Acute starvation
• Endotoxemia
• Sepsis
· Systemic inflammation response syndrome (SIRS)
• Multiple organ failure
With reference to information from the web-page of United Mitochondrial Disease Foundation (www.umdf.org), some of the above-mentioned diseases are discussed in more details in the following:
Complex I deficiency: Inside the mitochondrion is a group of proteins that carry electrons along four chain reactions (Complexes l-IV), resulting in energy production. This chain is known as the Electron Transport Chain. A fifth group (Complex V) churns out the ATP. Together, the electron transport chain and the ATP synthase form the respiratory chain and the whole process is known as oxidative phosphorylation or OXPHOS. Complex I, the first step in this chain, is the most common site for mitochondrial abnormalities, representing as much as one third of the respiratory chain deficiencies. Often presenting at birth or in early childhood, 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). MELAS stands for (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and 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.
There are three major forms of Complex I deficiency:
i) Fatal infantile multisystem disorder - characterized by poor muscle tone, developmental delay, heart disease, lactic acidosis, and respiratory failure. ii) Myopathy (muscle disease) - starting in childhood or adulthood, and characterized by weakness or exercise intolerance. iii) 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. Most cases of Complex I deficiency result from autosomal recessive inheritance (combination of defective nuclear genes from both the mother and the father). Less frequently, the disorder is maternally inherited or sporadic and the genetic defect is in the mitochondrial DNA.
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. Complex III Deficiency: 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. Possible lactic acidosis. iii) Myopathy, with exercise intolerance evolving into fixed weakness. Ragged-red fibers are common. Possible lactic acidosis. iv) Infantile histiocytoid cardiomyopathy.
Complex IV Deficiency / COX Deficiency: The symptoms include two major forms:
1 . 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
2. Myopathy: Two main variants:
1 . Fatal infantile myopathy: may begin soon after birth and accompanied by
hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems.
2. Benign infantile myopathy: may begin soon after birth and accompanied by
hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory problems, but (if the child survives) followed by spontaneous improvement.
KSS (Kearns-Sayre Syndrome): KSS is a slowly progressive multi-system mitochondrial disease that often begins with drooping of the eyelids (ptosis). Other eye muscles eventually become involved, resulting in paralysis of eye movement. Degeneration of the retina usually causes difficulty seeing in dimly lit environments.
KSS is characterized by three main features: • typical onset before age 20 although may occur in infancy or adulthood
• paralysis of specific eye muscles (called chronic progressive external ophthalmoplegia - CPEO)
• degeneration of the retina causing abnormal accumulation of pigmented (colored)
material (pigmentary retinopathy).
In addition, one or more of the following conditions is present:
• block of electrical signals in the heart (cardiac conduction defects)
• elevated cerebrospinal fluid protein
· incoordination of movements (ataxia).
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. As with all mitochondrial diseases, there is no cure for KSS.
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. Leigh Disease or Syndrome (Subacute Necrotizing Encephalomyelopathy): Symptoms:
Seizures, hypotonia, fatigue, nystagmus, poor reflexes, eating and swallowing difficulties, breathing problems, poor motor function, ataxia.
Causes: Pyruvate Dehydrogenase Deficiency, Complex I Deficiency, Complex II Deficiency, Complex IV/COX Deficiency, NARP. 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.
There is more than one defect that causes Leigh's Disease. These include a pyruvate dehydrogenase (PDHC) deficiency, and respiratory chain enzyme defects - Complexes I, II, 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.
There is no cure for Leigh's Disease. Treatments generally involve variations of vitamin and supplement therapies, often in a "cocktail" combination, and are only partially effective. Various resource sites include the possible usage of: thiamine, coenzyme Q10, riboflavin, biotin, creatine, succinate, and idebenone. Experimental drugs, such as dichloroacetate (DCA) are also being tried in some clinics. In some cases, a special diet may be ordered and must be monitored by a dietitian knowledgeable in metabolic disorders.
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 progression, ragged-red fibers.
Cause: Mitochondrial DNA point mutations: A3243G (most common)
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 developmental delay, learning disabilities or attention-deficit disorder. Exercise intolerance, limb weakness, hearing loss, and diabetes may also precede the occurrence of the stroke-like episodes.
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 combinations of loss of motor skills (speech, movement, and eating), impaired sensation (vision loss and loss of body sensations), and mental impairment (dementia). 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.
There is no cure or specific treatment for MELAS. Although clinical trials have not proven their efficacy, general treatments may include such metabolic therapies as: CoQ10, creatine, phylloquinone, and other vitamins and supplements. Drugs such as seizure medications and insulin may be required for additional symptom management. Some patients with muscle dysfunction may benefit from moderate supervised exercise. In select cases, other therapies that may be prescribed include dichloroacetate (DCA) and menadione, though these are not routinely used due to their potential for having harmful side effects.
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. The classic features of MERRF include:
• Myoclonus (brief, sudden, twitching muscle spasms) - the most characteristic symptom
• Epileptic seizures
• Ataxia (impaired coordination)
• 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. Although a few cases of MERRF are sporadic, most cases are maternally inherited due to a mutation within the mitochondria. The most common MERRF mutation is A8344G, which accounted for over 80% of the cases. Four other mitochondrial DNA mutations have been reported to cause MERRF. While a mother will transmit her MERRF mutation to all of her offspring, some may never display symptoms.
As with all mitochondrial disorders, there is no cure for MERRF. Therapies may include coenzyme Q10, L-carnitine, and various vitamins, often in a "cocktail" combination.
Management of seizures usually requires anticonvulsant drugs. Medications for control of other symptoms may also be necessary.
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:
1 . 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. 3. Hepatopathy: Enlarged liver and intractable liver failure, myopathy. Severe lactic acidosis. Death is typical within the first year. Friedreich's ataxia
Friedreich's ataxia (FRDA or FA) an autosomal recessive neurodegenerative and
cardiodegenerative disorder caused by decreased levels of the protein frataxin. Frataxin is important for the assembly of iron-sulfur clusters in mitochondrial respiratory-chain complexes. Estimates of the prevalence of FRDA in the United States range from 1 in every 22,000-29,000 people (see www.nlm.nih.gov/medlineplus/ency/article/00141 1.htm) to 1 in 50,000 people. The disease causes the progressive loss of voluntary motor coordination (ataxia) and cardiac complications. Symptoms typically begin in childhood, and the disease progressively worsens as the patient grows older; patients eventually become wheelchair-bound due to motor disabilities.
In addition to congenital disorders involving inherited defective mitochondria, acquired mitochondrial dysfunction has been suggested to contribute to diseases, particularly
neurodegenerative disorders associated with aging like Parkinson's, Alzheimer's, and
Huntington's Diseases. The incidence of somatic mutations in mitochondrial DNA rises exponentially with age; diminished respiratory chain activity is found universally in aging people. Mitochondrial dysfunction is also implicated in excitotoxicity, neuronal injury, cerebral vascular accidents such as that associated with seizures, stroke and ischemia. Pharmaceutical compositions comprising a compound of the invention
The present invention also provides 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). 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.
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. Depending upon the disorder and patient to be treated, as well as the route of administration, 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.
For example, 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.
Formulations in accordance with the present invention suitable for oral 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 non-aqueous 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. Ν,Ν-dimethylacetamide, dispersants e.g. polysorbate 80, surfactants, and solubilisers, e.g. polyethylene glycol, Phosal 50 PG (which consists of phosphatidylcholine, soya-fatty acids, ethanol, mono/diglycerides, propylene glycol and ascorbyl palmitate). 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), hydroxy-propylcellulose (HPC), macrogol 8000, sucrose, gelatin and acacia. Additionally, 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. For aqueous suspensions and/or elixirs, 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.
Pharmaceutical 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. Thus, 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. As an illustration only, 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.
Pharmaceutical 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. For example, the active agent may be delivered from the patch by iontophoresis.
For applications to external tissues, for example the mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active agent may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active agent may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
For parenteral administration, 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. The active ingredient, depending on the vehicle and concentration used, can be either colloidal, suspended or dissolved in the vehicle. In preparing solutions the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance the stability, 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.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above 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.
It will be recognized by one of skill in the art that 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.
All % values mentioned herein are % w/w unless the context requires otherwise.
Compounds of the invention all may be transformed in a biological matrix to liberate eg malonic acid, canonical forms of the same. They may do so as follows. Where R', R" or R'" is a compound of formula (II) the acyl group including R2 may be cleaved by a suitable enzyme, preferably an esterase. This liberates a hydroxymethyl ester, an aminomethyl ester or a thiolmethyl ester which could spontaneous covert to a carbonyl, imine or thiocarbonyl group and a free carboxylic acid. By way of example in formula (I) where A is OR' with R' being formula (II) and B is H and Z is -CH2-.
Figure imgf000037_0001
J
Ri„ R¾ ( o o
OH
X
Where R', R" or R'" is a compound of formula (V) the substituent on group Rio may be removed by the action of a suitable enzyme or via chemical hydrolysis in vivo. By way of example in formula (I) where A is OR' with R' being formula (V) and B is H and Z is -CH2-, X is O and R8 is H, R9 is Me and R10 is O-acetyl.
Figure imgf000037_0002
O O HOAZAOH + AcOH
Where R', R" or R'" is a compound of formula (VII) the group may be removed by the action of a suitable enzyme or via chemical hydrolysis in vivo to liberate succinic acid. By way of example in formula (I) where A is SR'" with R'" being formula (VII) and B is H and Z is -CH2-, X5 is C02H and Ri is Et:
Figure imgf000038_0001
Other aspects of the invention
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:
· Quinone derivatives, e.g. Ubiquinone, Idebenone, MitoQ
• Vitamins e.g. Tocopherols, Tocotrienols and Trolox (Vitamin E), Ascorbate (C), Thiamine (B1 ), Riboflavin (B2), Nicotinamide (B3), Menadione (K3),
• Antioxidants in addition to vitamins e.g. TPP-compounds (MitoQ), Sk-compounds,
Epicatechin, Catechin, Lipoic acid, Uric acid, Melatonin
· Dichloroacetate
• Methylene blue
• L-arginine
• Szeto-Schiller peptides
• Creatine
· Benzodiazepines
• Modulators of PGC-1 a
• Ketogenic diet
One other aspect of the invention is that 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.
Lactic acidosis or drug-induced side-effects due to impairment of mitochondrial oxidative phosphorylation
The present invention also relates to the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects. In particular 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). Many known drug substances negatively influence mitochondrial respiration (e.g.
antipsychotics, local anaesthetics and anti-diabetics) and, accordingly, there is a need to identify or develop means that either can be used to circumvent or alleviate the negative mitochondrial effects induced by the use of such a drug substance. The present invention provides compounds for use in the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects. In particular the novel cell- permeable carboxylic acid-based metabolites 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 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). It is contemplated that 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. 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.
It is contemplated that 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
Antihistamines
Anti-Parkinson including tolcapone
Anti-psycotics Risperidone,
Anti-schizoprenia zotepine, clozapine
Antiseptics, quaternary ammonium compounds (QAC)
Anti-tuberculosis including isoniazid
Fibrates including clofibrate, ciprofibrate, simvastatin
Hypnotics including Propofol
Immunosupressive disease-modifying antirheumatic drug (DMARD) Leflunomide
Local anaesthetics including bupivacaine, diclofenac, indomethacin, and lidocaine
Muscle relaxant including dantrolene Neuroleptics including antipsycotic neuroleptics like chlorpromazine, fluphenazine and haloperidol
NRTI (Nucleotide reverse Transcriptase Inhibitors) including efavirenz, tenofovir, emtricitabine, zidovudine, lamivudine, rilpivirine, abacavir, didanosine
NSAIDs including nimesulfide, mefenamic acid, sulindac
Barbituric acids.
Other drug substances that are known to have lactic acidosis as side-effects include beta2- agonists, epinephrine, theophylline or other herbicides. Alcohols and cocaine can also result in lactic acidosis.
Moreover, it is contemplated that 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 Complex I defect, inhibition or malfunction, wherein i) the drug substance is used for treatment of a disease for which the drug substance is indicated, and
ii) 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
i) a 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.
The composition may be in the form of two separate packages:
A first package containing the drug substance or a composition comprising the drug substance and
a second package containing the compound of the invention or a composition comprising the compound of the invention. The composition may also be a single composition comprising both the drug substance and the compound of the invention.
In the event that the composition comprises two separate packages, 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 administered before the compound of the invention or vice versa.
Kits
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
ii) 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.
Method for treatment/prevention of side-effects
The invention also relates to a method for treating a subject suffering from a drug-induced 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, 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.
Definitions
The articles "a" and "an" are used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
As used herein the terms "cell permeable carboxylic acid-based metabolites", "compound(s) of the invention", "cell-permeable carboxylic acid-based metabolites" and "cell permeable precursors of metabolites" are used interchangeably and refer to compounds of formula (I) or formula (IA).
As used herein, the term "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 et al, 1998, Gallant-Haidner et al, 2000).
As used herein 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). As described herein, an excess of lactate in a subject is often an indication of a negative effect on aerobic respiration including Complex I.
As used herein the term "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 pseudo-obstruction), 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.
As used herein the term "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. Other 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. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, Ν,Ν'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.
As used herein the term "alkyl" refers to any straight or branched chain composed of only sp3 carbon atoms, fully saturated with hydrogen atoms such as e.g. -CnH2n+i for straight chain alkyls, wherein n can be in the range of 1 and 10 such as e.g. methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl. The alkyl as used herein may be further substituted.
As used herein the term "cycloalkyl" refers to a cyclic/ring structured carbon chains having the general formula of -CnH2n-i where n is between 3-10, such as e.g. cyclopropyl, cyclobytyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, bicycle[3.2.1]octyl, spiro[4,5]decyl, norpinyl, norbonyl, norcapryl, adamantly and the like.
As used herein, the term "alkene" refers to a straight or branched chain composed of carbon and hydrogen atoms wherein at least two carbon atoms are connected by a double bond such as e.g. C2-io alkenyl unsaturated hydrocarbon chain having from two to ten carbon atoms and at least one double bond. C2-6 alkenyl groups include, but are not limited to, vinyl, 1-propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
The term "Cno alkoxy" in the present context designates a group -0-C-i-6 alkyl used alone or in combination, wherein Cno alkyl is as defined above. Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are iso- propoxy, sec-butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. The term "C3-7 heterocycloalkyl" as used herein denotes a radical of a totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle. Examples of heterocycles include, but are not limited to, pyrrolidine (1 -pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 4-pyrrolidine, 5- pyrrolidine), pyrazolidine (1 -pyrazolidine, 2-pyrazolidine, 3-pyrazolidine, 4-pyrazolidine, 5- pyrazolidine), imidazolidine (1-imidazolidine, 2-imidazolidine, 3-imidazolidine, 4-imidazolidine, 5- imidazolidine), thiazolidine (2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine (1 -piperidine, 2-piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine (1-piperazine, 2-piperazine, 3-piperazine, 4-piperazine, 5-piperazine, 6-piperazine), morpholine (2-morpholine, 3-morpholine, 4-morpholine, 5-morpholine, 6-morpholine), thiomorpholine (2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine, 5-thiomorpholine, 6- thiomorpholine), 1 ,2-oxathiolane (3-(1 ,2-oxathiolane), 4-(1 ,2-oxathiolane), 5-(1 ,2- oxathiolane)), 1 ,3-dioxolane (2-(1 ,3-dioxolane), 3-(1 ,3-dioxolane), 4-(1 ,3-dioxolane)), tetrahydropyrane (2- tetrahydropyrane, 3- tetrahydropyrane, 4- tetrahydropyrane, 5- tetrahydropyrane, 6- tetrahydropyrane), hexahydropyradizine, (1 -(hexahydropyradizine), 2- (hexahydropyradizine), 3-(hexahydropyradizine), 4-(hexahydropyradizine), 5- (hexahydropyradizine), 6-(hexahydropyradizine)).
The term "C-i.-ioalkyl-Cs.-iocycloalkyl" as used herein refers to a cycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "C1-10 alkyl-C3-7 heterocycloalkyl" as used herein refers to a heterocycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated below. The term "heteroaryl" as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected among nitrogen, oxygen and sulphur, such as furyl, thienyl, pyrrolyl, and is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
The terms "aryl" and "heteroaryl" as used herein refers to an aryl, which can be optionally unsubstituted or mono-, di- or tri substituted, or a heteroaryl, which can be optionally
unsubstituted or mono-, di- or tri substituted. Examples of "aryl" and "heteroaryl" include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, thiophenyl (1 -thienyl, 2-thienyl), furyl (1-furyl, 2-furyl), furanyl, thiophenyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridazinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, phteridinyl, azepinyl, diazepinyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), 5-thiophene-2-yl-2H-pyrazol-3-yl, imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3-triazol-1 -yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5- oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), quinolyl (2-quinolyl, 3-quinolyl, 4- quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3- benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4- (2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3- benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7- benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3- dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro- benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl)), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1- indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl, (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6- benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1 -benzoxazolyl, 2- benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5- benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1 -carbazolyl, 2-carbazolyl, 3- carbazolyl, 4-carbazolyl). Non-limiting examples of partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
As used herein the term "acyl" refers to a carbonyl group -C(=0) R wherein the R group is any of the above defined groups. Specific examples are formyl, acetyl, propionyl, butyryl, pentanoyi, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, benzoyl and the likes.
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'.
Examples of suitable substituents for "substituted" and "optionally substituted" moieties include halo (fluoro, chloro, bromo or iodo), C1-6 alkyl, C3-6 cycloalkyl, hydroxy, C1-6 alkoxy, cyano, amino, nitro, C1-6 alkylamino, C2-6 alkenylamino, di-C1-6 alkylamino, C1-6 acylamino, di-C1-6 acylamino, C1-6 aryl, C1-6 arylamino, C1-6 aroylamino, benzylamino, C1-6 arylamido, carboxy, C1-6 alkoxycarbonyl or (C1-6 aryl)(C1-10 alkoxy)carbonyl, carbamoyl, mono-C1-6 carbamoyl, di-C1-6 carbamoyl or any of the above in which a hydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, Ci-2 alkoxy, amino, nitro, carbamoyl, carboxy or Ci-2 alkoxycarbonyl. In groups containing an oxygen atom such as hydroxy and alkoxy, the oxygen atom can be replaced with sulphur to make groups such as thio (SH) and thio-alkyl (S-alkyl). Optional substituents therefore include groups such as S-methyl. In thio-alkyl groups, 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. Thus an alkyl group with a carbonyl (C=0) instead of a CH2 can be considered a substituted alkyl group.
Substituted groups thus include for example CFH2, CF2H, CF3, CH2NH2, CH2OH, CH2CN, CH2SCH3, CH2OCH3, OMe, OEt, Me, Et, -OCH20-, C02Me, C(0)Me, /-Pr, SCF3, S02Me, NMe2, CONH2, CONMe2 etc. In the case of aryl groups, the substitutions may be in the form of rings from adjacent carbon atoms in the aryl ring, for example cyclic acetals such as 0-CH2-0. Experimental
General Biology Methods
A person of skill in the art will be able to determine the pharmacokinetics and bioavailability of the compound of the invention using in vivo and in vitro methods known to a person of skill in the art, including but not limited to those described below and in Gallant-Haidner et al, 2000 and
Trepanier et al, 1998 and references therein. The 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. Alternatively, 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.
In order to measure bioavailability in vivo, 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. 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.
For example, 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%. These parameters are then analysed by non-compartmental or compartmental methods to give a calculated percentage bioavailability, for an example of this type of method see Gallant- Haidner et al, 2000 and Trepanier et al, 1998, and references therein. 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
High resolution Respirometry- A - general method
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 02 s_1 ml_-
1
High-resolution respirometry - B
Real-time respirometric measurements were performed using high-resolution oxygraphs (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria). The experimental conditions during the measurements were the following: 37°C, 2 ml. active chamber volume and 750 rpm stirrer speed. Chamber concentrations of 02 were kept between 200-50 μΜ with reoxygenation of the chamber during the experiments as appropriate 1. For data recording, DatLab software version 4 and 5 were used (Oroboros Instruments, Innsbruck, Austria). Settings, daily calibration and instrumental background corrections were conducted according to the manufacturer's instructions. Respiratory measurements were performed in a buffer containing 0.5 mM EGTA, 3 mM MgCI2, 60 mM K-lactobionate, 20 mM Taurine, 10 mM KH2P04, 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 200x106 cells per ml_. Evaluation of compounds
One typical evaluation protocol in intact cells are utilized.
(1) Assay for inhibition of mitochondrial energy producing function in cells through
competitive inhibition of complex II.
Cells are placed in a buffer containing 1 10 mM sucrose, HEPES 20 mM, taurine 20 mM, K- lactobionate 60 mM, MgCI2 3 mM, KH2P04 10 mM, EGTA 0.5 mM, BSA 1 g/l, pH 7.1 . After baseline respiration with endogenous substrates is established complex I is inhibited with Rotenone 2 μΜ and complex ll-supported respiration is induced by addition of the cell- permeable succinate prodrug SEL 241 500 μΜ. Treatments (Malonate, Dimethyl malonate, NV161 or vehicle (DMSO)) are titrated in increasing concentrations to reach cumulative concentration ranges of 10 μΜ to 5 mM final concentration. After the respiration stabilized the experiment is terminated by addition of Antimycin at final concentration 1 μg/mL and any residual non-mitochondrial oxygen consumption is measured. SEL241
Figure imgf000050_0001
Data analysis
Statistical analysis was performed using Graph Pad PRISM software (GraphPad Software version 6.00, La Jolla, California, USA). All respiratory data are expressed as mean ± SEM and are presented as % of control. Standard non-linear curve fitting was applied to calculate half maximal inhibitory concentration (IC50) values.
Properties of desired compound in respiration assays
The ideal compound inhibits complex-ll-supported respiration in the described protocol in intact cells at low concentration. The 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. After inhibition of respiration with mitochondrial toxins at or downstream of complex III, respiration should be halted.
Desired properties of compounds:
• Maximum inhibition reached at low drug concentration (micromolar range)
· IC50 concentration at least 10 times lower than that achieved with Malonate and Dimethyl Malonate'
Compounds ineffectively permeable to the cellular membrane and/or non-efficacious as complex II inhibitors are identified in the assay as:
· Showing < 20 % inhibition of complex ll-supported respiration at 500 μΜ final dose
1 . Sjovall, F., et al. Mitochondrial respiration in human viable platelets-methodology and influence of gender, age and storage. Mitochondrion 13, 7-14 (2013).
2. Pesta, D. & Gnaiger, E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810, 25- 58 (2012).
3. Kaal, E.C., et al. Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis. Journal of neurochemistry 74, 1 158-1 165 (2000). 4. Chouchani, E.T., et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431-435 (2014).
The efficacy of the compounds of the invention may be tested using one or more of the methods described below:
I. Assays for evaluating enhancement and inhibition of mitochondrial energy producing function in intact cells High resolution Respirometry
Measurement of mitochondrial respiration is performed in a high-resolution oxygraph
(Oxygraph- 2k, Oroboros Instruments, Innsbruck, Austria) at a constant temperature of 37°C. Isolated human platelets, white blood cells, fibroblasts, human heart muscle fibers or other cell types 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 02 s-1 mL-1.
The compounds according to the invention are evaluated in specialized protocols. In the assay, mitochondrial function in intact cells or intact fibers is native or repressed with respiratory inhibitors acting on specific Krebs cycle hydrogenases or electron transport complexes. Drug candidates are compared with endogenous (non cell-permeable) substrates/inhibitors before and after permeabilization of the plasma membrane to evaluate bioenergetic enhancement or inhibition.
Materials & Methods
Materials
Unless otherwise indicated, all reagents used in the examples below are obtained from commercial sources.
Example 1
Figure imgf000051_0001
A solution of 3-chloropropyl-1-ol (8.00 g, 73.7 mmol) and PCC (23.8 g, 1 10.5 mmol) in CH2CI2 (200 ml.) is stirred for at room temperature. The mixture is then diluted with ether, and is filtered through a pad of celite and neutral alumina. The black gum is triturated in ether. The filtrate is concentrated to give 3-chloropropanal which is used in next step without further purification.
Figure imgf000052_0001
To a mixture of ZnCI2 (120 mg, 0.9 mmol) and acetyl chloride (3.50 g, 44.1 mmol) at -5 °C under nitrogen is added dropwise a solution of 3-chloropropanal in CH2CI2. The mixture is stirred at -5 °C for 1 hour and at room temperature for 1 hour. The mixture is diluted with water and is extracted with CH2CI2 twice. The combined CH2CI2 extracts are washed with water, dried (Na2S04) and concentrated to yield 1 ,3-dichloroproyl acetate which is used for next step without further purification.
Figure imgf000052_0002
To a solution of 1 ,3-dichloropropyl acetate and malonic acid monobenzyl ester in CH3CN (15 ml.) is added K2C03 (0.98 g, 7.08 mmol) and Nal (0.09 g, 0.59 mmol). The resulting mixture is stirred at 75 °C overnight. The mixture is diluted with water and extracted with EtOAc twice. The combined organic extracts are dried (Na2S04) and concentrated. The residue is purified by silica gel column chromatography.
O
o o o o o o o o
BnO^^^^O^^^O^^^OBn HO ^ O ^ O ^ OH
A mixture of the result of the previous step and Pd/C (10%, 200 mg) in EtOH (20 ml.) is stirred at room temperature under hydrogen atmosphere (balloon) for 3 hours. The reaction mixture is filtered and concentrated under reduced pressure to yield the target compound.
Example 2
Figure imgf000052_0003
To a mixture of ZnCI2 (26.0 mg, 0.190 mmol) and acetyl bromide (1.15 g, 9.40 mmol) at -5 °C under nitrogen, is added dropwise a solution of 4-chloropropanal (1.0 g, 9.4 mmol) in CH2CI2 (1.5 ml_). The mixture is stirred at -5 °C for 1 hour and at room temperature for 1 hour. The mixture is diluted with water and extracted with CH2CI2 twice. The combined CH2CI2 extracts are washed with water, dried (Na2S04) and concentrated under reduced pressure to yield 1 -bromo- 4-chloropropyl acetate which is used for next step without further purification.
Figure imgf000053_0001
To a solution of 1-bromo-4-chlorobutyl acetate and malonic acid monobenzyl ester in CH3CN (15 ml.) is added K2C03. The mixture is stirred at room temperature overnight. The mixture is diluted with water and extracted with EtOAc twice. The combined organic extracts are dried (Na2S04) and concentrated. The residue is purified by silica gel column chromatography (to yield 1 -acetoxy-3-chlororopyl benzyl malonate.
Figure imgf000053_0002
To a solution of 1-acetoxy-3-chlororopyl benzyl malonate and O-phthalimide) in DMFis added K2C03 (522 mg, 3.80 mmol). The mixture is stirred at 80 °C overnight. The mixture is diluted with water and extracted with EtOAc twice. The combined organic extracts are dried (Na2S04) and concentrated. The residue is purified by silica gel column chromatography to give 1- acetoxy-3-(1 ,3-dioxoisoindolin-2-yl)propyl benzyl malonate.
Figure imgf000053_0003
A mixture of 1-acetoxy-3-(1 ,3-dioxoisoindolin-2-yl)propyl benzyl malonate and Pd/C in EtOH (20 ml.) is stirred at room temperature under hydrogen atmosphere (balloon) for 4 hours. The reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC to yield 3-(1 -acetoxy-3-(1 ,3-dioxoisoindolin-2-yl)propoxy)-3-oxopropanoic acid.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps. General description of the class of compounds to which the compounds according to the invention belong and specific embodiments In accordance with the above, the present invention provides novel analogues, defined by formula (I) below,
Figure imgf000054_0001
y
or a pharmaceutically acceptable salt thereof, where the dotted bond between A and B denotes an optional bond so as to form a ring closed structure, and wherein
Z is as defined herein before,
A and B are independently different or identical and are selected from -O-R', -NHR", -SR'" or - OH, with the provisio that both A and B cannot be H,
R', R" and R'" are independently different or identical and selected from the formula (II) to (IX) below:
Figure imgf000054_0002
Figure imgf000055_0001
Preferably R', R" and R'" are independently different or identical and selected from the formula (V), (VII), (IX) below:
Figure imgf000055_0002
O (VIII)
Figure imgf000055_0003
Ri and R3 are independently selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O- cyl, N-alkyl, Xacyl, CH2Xalkyl, CH2CH2CH2OC(=0)CH2CH2COX6R8 or
Figure imgf000055_0004
alternatively, and R3 are or any of the below formulas (a)-(f)
Figure imgf000056_0001
R2o and R2i are independently different or identical and are selected from H, lower alkyl, i.e. C C4 alkyl or R20 and R2i together may form a C4-C7 cycloalkyi or an aromatic group, both of which may optionally be substituted with halogen, hydroxyl or a lower alkyl, or R20 and R21 may be
Figure imgf000056_0002
CH2X-acyl, F, CH2COOH, CH2C02alkyl,
X is selected from O, NH, NR6, S,
R2 is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, -C(0)CH3, - C(0)CH2C(0)CH3, -C(0)CH2CH(OH)CH3,
Figure imgf000056_0003
n is an integer and is selected from 1 , 2, 3 or 4,
p is an integer and is selected from 1 or 2,
X2 = OR5, NR-|R'2
R'3 = H, Me, Et, F
R4 = H, Me, Et, i-Pr
R5 = acetyl, propionyl, benzoyl, benzylcarbonyl
R'2 = H.HX3, acyl, acetyl, propionyl, benzoyl, benzylcarbonyl
X3 = F, CI, Br and I R6 is selected from H, or alkyl such as e.g. Me, Et, n-propyl, i-propyl, butyl, iso-butyl, t-butyl, or acetyl, such as e.g. acyl, propionyl, benzoyl, or CONR^, or formula (II), or formula (VIII);
alternatively R6 is formula (III)
X5 is selected from -H, -COOH, -C(=0)XR6,
Figure imgf000057_0001
R9 is selected from H, Me, Et or O2CCH2CH2COXR;
R-io is selected from Oacyl, NHalkyl, NHacyl, or 02CCH2CH2COX6R8
X6 is O or NR8
R8 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl or formula (II),
R-i -i and R12 are independently different or the same and is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, acyl, -CH2Xalkyl, - CH2Xacyl, where X is selected from O, NR6 or S,
Rc and Rd are independently CH2Xalkyl, CH2Xacyl, where X is selected from O, NR6 or S,
Rf , Rg and Rh are independently different or the same and are selected from Xacyl, -CH2Xalkyl, -CH2X-acyl and R9 , wherein alkyl is e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl and acyl is e.g. formyl, acetyl, propionyl, butyryl pentanoyi, benzoyl and the like and wherein the acyls and alkyls may be optionally substituted, the dotted bond between A and B denotes an optional bond to form a cyclic structure of formula (I) and with the proviso that when such a cyclic bond is present, the compound according to formula (I) is selected from
Figure imgf000058_0001
wherein X4 is selected from -COOH, -C(=0)XR6,
Figure imgf000058_0002
and wherein Rx and Ry are independently selected from R-i, R2, R6 or R', R" or R'" with the proviso that Rx and Ry cannot both be -H.
Preferably, and with respect to formula (II), at least one of Ri and R3 is -H, such that formula II is:
Figure imgf000058_0003
Preferably, and with respect to formula (VII), p is 1 or 2, preferably 1 , and X5 is -H such that formula (VII) is
Figure imgf000058_0004
Preferably, and with respect to formula (IX), at least one of Rf, Rg, Rh is -H or alkyl, with alkyl as defined herein. Moreover, it is also preferable with respect to Formula (IX) that at least one of Rf, Rg, Rh is -CH2Xacyl, with acyl as defined herein.
Specific embodiments are
1 . A compound according to Formula (I), wherein the compound is
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof, where the dotted bond denotes doptional bond between A and B to form a cyclic structure, wherein Z is as defined herein before, wherein A is
-O-R, and wherein R is
Figure imgf000059_0002
and where B is selected from -O-R', -NHR", -SR'" or -OH; wherein R' is selected from the formula (II) to (IX) below:
Figure imgf000059_0003
Rf
Rh (IX) wherein R', R" and R'" are independently different or identical and is selected from formula (IV- VIII) below:
Figure imgf000060_0001
Ri = H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, 0-alkyl, N-acyl, N-alkyl, Xacyl, CH2Xalkyl,
CH2X-acyl, F, CH2COOH, CH2C02alkyl or any of the below formulae (a)-(f)
Figure imgf000060_0002
X = 0, NH, NR6, S
R2 = Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(0)CH3, C(0)CH2C(0)CH3,
C(0)CH2CH(OH)CH3,
X, = CR'3R'3, NR4
n = 1 -4,
p = 1 -2
X2 = OR5, NR-|R'2
R'3 = H, Me, Et, F
R4 = H, Me, Et, i-Pr
R5 = acetyl, propionyl, benzoyl, benzylcarbonyl
R'2 = H.HX3, acyl, acetyl, propionyl, benzoyl, benzylcarbonyl
X3 = F, CI, Br and I
R6 = H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), formula (III) or formula (VIII)
X5 =-H, -COOH, -C(=0)XR6,
Figure imgf000061_0001
R9 = H, Me, Et or 02CCH2CH2COXR8
R-io = Oacyl, NHalkyl, NHacyl, or 02CCH2CH2COX6R8
X6 = O, NR8
R8 = H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), formula (III) or formula (VIII)
Rii and R12 are independently H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, acyl, -CH2Xalkyl, -CH2Xacyl, where X = O, NR6 or S
Rc and Rd are independently CH2Xalkyl, CH2Xacyl, where X = O, NR6 or S, wherein alkyl is e.g. H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl and wherein acyl is e.g. formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyi, benzoyl and the like, wherein Rf , Rg and Rh are independently selected from Xacyl, -CH2Xalkyl, -CH2X-acyl and R9 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl and acyl is selected from formyl, acetyl, propionyl, butyryl pentanoyi, benzoyl, succinyl and the like, and wherein the acyls or alkyls may be optionally substituted, with the proviso that when there is a cyclic bond present between A and B the compound is
or
Figure imgf000061_0002
2. A compound according to item 1 , wherein formula (II) is such that at least one of R1 and R3 is -H such that formula II is:
O H
R2
(II) 3. A compound according to item 1 , wherein formula (III) is such that R4 is -H and formula (III) is
Figure imgf000062_0001
4. A compound according to item 1 , wherein formula (VII) is such that , p=2 and X5 is -H and formula (VII) is
Figure imgf000062_0002
5. A compound according to item 1 , wherein formula (IX) is such that at least one of Rf, Rg, Rh is -H or alkyl, with alkyl as defined herein.
6. A compound according to item 1 or item 5, wherein formula (IX) is such that at least one of Rf, Rg, Rh is -CH2Xacyl, with acyl as defined herein. 7. A compound according to any of items 1 -6, wherein formula (ID) is
O O
X Z X B (ID) or a pharmaceutically acceptable salt thereof, wherein Z is as defined herein before, and
wherein A and B are independently selected from -OH or -O-R'
where R' is
Figure imgf000062_0003
and where A and B cannot both be -OH 8. A compound according to any of items 1-6, wherein the compound according to Formula (ID) is
O O
or a pharmaceutically acceptable salt thereof. wherein Z is as defined herein before and
wherein A and B are independently selected from
Figure imgf000063_0001
-OH and where A and B cannot both be -OH
9. A compound according to any of items 1-6, wherein the compound is
O O
A ZA or a pharmaceutically acceptable salt thereof, wherein Z is as defined herein before, and
wherein A and B are independently selected from
Figure imgf000063_0002
or -OH and where A and B cannot both be -OH
10. A compound according to any of items 1 -9 for use in medicine
1 1. A compound according to any of item 1 -9, for use in cosmetics 12. A compound according to any of items item 1-9 for use in the treatment of or prevention of metabolic diseases, or in the treatment of diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction, treating or suppressing of mitochondrial disorders, stimulation of mitochondrial energy production, 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. 13. A compound according for use according to item 12, wherein the medical use is prevention or treatment of drug-induced mitochondrial side-effects.
14. A compound for use according to item 13, wherein the prevention or drug -induced mitochondrial side-effects relates to drug interaction with Complex I, such as e.g. metformin- Complex I interaction.
15. A compound according to item 13, wherein diseases of mitochondrial dysfunction involves e.g. mitochondrial deficiency such as a Complex I, II, III or IV deficiency or an enzyme deficiency like e.g. pyruvate dehydrogenase deficiency
16. A compound for use according to any of items 12-15, wherein the diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction are selected from Alpers Disease (Progressive Infantile Poliodystrophy, Amyotrophic lateral sclerosis (ALS), Autism, Barth syndrome (Lethal Infantile Cardiomyopathy), Beta-oxidation Defects, Bioenergetic metabolism deficiency, Carnitine-Acyl-Carnitine Deficiency, Carnitine Deficiency, Creatine Deficiency Syndromes (Cerebral Creatine Deficiency Syndromes (CCDS) includes: Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency), L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency), and SLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency), Co-Enzyme Q10 Deficiency Complex I Deficiency (NADH dehydrogenase (NADH- CoQ reductase deficiency), Complex II Deficiency (Succinate dehydrogenase deficiency), Complex III Deficiency (Ubiquinone-cytochrome c oxidoreductase deficiency), Complex IV Deficiency/COX Deficiency (Cytochrome c oxidase deficiency is caused by a defect in Complex IV of the respiratory chain), Complex V Deficiency (ATP synthase deficiency), COX Deficiency, CPEO (Chronic Progressive External Ophthalmoplegia Syndrome), CPT I Deficiency, CPT II Deficiency, Friedreich's ataxia (FRDA or FA), Glutaric Aciduria Type II, KSS (Kearns-Sayre Syndrome), Lactic Acidosis, LCAD (Long-Chain Acyl-CoA Dehydrogenase Deficiency), LCHAD, Leigh Disease or Syndrome (Subacute Necrotizing Encephalomyelopathy), LHON (Leber's hereditary optic neuropathy), Luft Disease, MCAD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency), MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike
Episodes), MERRF (Myoclonic Epilepsy and Ragged-Red Fiber Disease), MIRAS
(Mitochondrial Recessive Ataxia Syndrome), Mitochondrial Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy including: Encephalomyopathy and Encephalomyelopathy, Mitochondrial Myopathy, MNGIE (Myoneurogastointestinal Disorder and Encephalopathy, NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa), Neurodegenerative disorders associated with Parkinson's, Alzheimer's or Huntington's disease, Pearson
Syndrome, Pyruvate Carboxylase Deficiency, Pyruvate Dehydrogenase Deficiency, POLG Mutations, Respiratory Chain Deficiencies, SCAD (Short-Chain Acyl-CoA Dehydrogenase Deficiency), SCHAD, VLCAD (Very Long-Chain Acyl-CoA Dehydrogenase Deficiency).
17. A compound for use according to item 16, wherein the mitochondrial dysfunction or disease related to mitochondrial dysfunction is attributed to complex I dysfunction and selected from 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).
18. A composition comprising a compound of Formula (I) as defined according any of items 1 -9 and one or more pharmaceutically or cosmetically acceptable excipients.
19. A method of treating a subject suffering from diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction as defined in any of items 16-17, the method comprising administering to the subject an efficient amount of a composition as defined in item 18.
20. A method according to item 19 wherein the composition is 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)
22. A method according to any of items 19-20, wherein the composition is administered as a single dose or a plurality of doses over a period of time, such as e.g. one daily, twice daily or 3-5 times daily as needed. 23. A compound according to any of items 1 -9 for use in the treatment or prevention of lactic acidosis.
24. A compound according to any of items 1 -9 for use in the treatment or prevention of a drug- induced side-effect selected from lactic acidosis and side-effects related to Complex I defect, inhibition or malfunction. 25. A compound according to any of items 1 -9 for use in the treatment or prevention of a drug- induced side-effect selected from lactic acidosis and side-effects related to defect, inhibition or mal-function in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 drugs that affect the levels of glucose or other Complex l-related substrates).
26. A combination of a drug substance and a compound according to any of items 1-9 for use in the treatment and/or prevention of a drug-induced side-effect selected from i) lactic acidosis, ii) and side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 drugs that affect the levels of glucose or other Complex-l-related substrates)., wherein i) the drug substance is used for treatment of a disease for which the drug substance is indicated, and
ii) the compound 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.
27. A composition comprising a drug substance and a compound according to any of items 1-9, wherein the drug substance has a potential drug-induced side-effect selected from i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other Complex-l-related substrates).
28. A kit comprising
i) a first container comprising a drug substance, which has a potential drug-induced side-effect selected i) from lactic acidosis, ii) and side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic
metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates), and ii) a second container comprising a compound according to any of items 1 -9, 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 i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or 5 malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates).
10 29. A method for treating a subject suffering from a drug-induced side-effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would encompass any drug effect that limits the supply of NADH to Complex I, e.g. effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism
15 and even drugs that affect the levels of glucose or other substrates)., the method comprises administering an effective amount of a compound according to any of items 1-9 to the subject.
30. A method for preventing or alleviating a drug-induced side-effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side-
20 effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates), in a subject, who is suffering from a disease that is treated with a drug substance, which potentially induce a side-
25 effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic
metabolism upstream of Complex I, such as in dehydrogenases of Kreb's cycle, pyruvate dehydrogenase and fatty acid metabolism,
the method comprises administering an effective amount of a compound according to any of 30 items 1-9 to the subject before, during or after treatment with said drug substance.
31. A method according to any one of items 29-30, wherein the drug substance is an antidiabetic substance.
35 32. A method according to any one of items 29-31 , wherein the anti-diabetic substance is
metformin. 33. A compound according to any of items 1 -9, for use in the treatment of absolute or relative cellular energy deficiency.

Claims

Claims
1 . A compound according to Formula (I) or Formula (IA)
Figure imgf000069_0001
(IA)
or a pharmaceutically acceptable salt thereof, wherein the dotted bond between A and B denotes an optional bond so as to form a ring closed structure, and wherein when the formula is Formula (I), Z is selected from -CH2- (eg derived from malonic acid), -CH2- CH2-CH2 (eg derived from glutaric acid), -CH=CH2- (eg derived from fumaric acid), -CH2- CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid),
CH2C(OH)(COOH)-CH2- (eg derived from citric acid), -C(0)-CH2-CH2- (eg derived from alpha- ketoglutaric acid), -CH2-CH2-C(0)- (eg derived from alpha-ketoglutaric acid), -CH2-C(COC(OH)- C(COOH)-CHOH)=CH- (eg derived from aconitic acid), -CH=C(COOH)-CH2- (eg derived from aconitic acid), -CH(OH)-CH(COOH)-CH2- (eg derived from isocitric acid), -CH2-CH(COOH)- CH(OH)- (eg derived from isocitric acid), -CH2-CH(COOH)-C(=0)- (eg derived from
oxalosuccinic acid), -C(=0)-CH(COOH)-CH2- (eg derived from oxalosuccinic acid), -C(=0)-CH2- (eg derived from oxaloacetatic acid), -CH2-C(=0)- (eg derived from oxaloacetic acid); or when the formula is Formula (IA), Z is selected from -CH(OH)-CH2(OH) and n is 0 eg derived from glyceric acid); or Z is absent or -CH2- and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively);
A and B are independently different or the same and are selected from -OR, -O-R', -NHR", - SR'" or -OH, or in case of Formula (IA) B is C-|-C4 alkyl, branched or straight, preferably B is Me; both A and B are not -OH, wherein R is
Figure imgf000069_0002
R' is selected from the formula (II), (V) or (IX) below:
Figure imgf000069_0003
Figure imgf000070_0001
R', R" and R'" are independently different or identical and is selected from formula (VII-VIII) below:
Figure imgf000070_0002
Ri and R3 are independently different or identical and are selected from H, Me, Et, propyl, i- propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyI, N-acyl, N-alkyl, Xacyl, CH2Xalkyl,
0)CH2CH2COX6R8 or
Figure imgf000070_0003
X is selected from O, NH, NR6, S,
R2 is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, C(0)CH3, C(0)CH2C(0)CH3, C(0)CH2CH(OH)CH3, p is an integer and is 1 or 2, R6 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
X5 is selected from -H, -COOH, -C(=0)XR6,CONR1R3 or one of the formulas
Figure imgf000071_0001
R9 is selected from H, Me, Et or O2CCH2CH2COXR8,
R10 is selected from Oacyl, NHalkyl, NHacyl, or O2CCH2CH2CO X6R8,
X6 is O or NR8, and R8 is selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII),
R-n and R12 are independently the same or different and are selected from H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, acyl, -CH2Xalkyl, - CH2Xacyl, where X is selected from O, NR6 or S,
Ri3> R-I4 and R15 are independently different or identical and are selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, -COOH, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, CH2Xalkyl
Rc and Rd are independently CH2Xalkyl, CH2Xacyl, where X = O, NR6 or S, and alkyl is e.g. H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, and acyl is e.g. formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl or the like, Rf , Rg and Rh are independently selected from Xacyl, -CH2Xalkyl, -CH2X-acyl and R9, alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, neopentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl or decyl, and acyl is selected from formyl, acetyl, propionyl, butyryl pentanoyl, benzoyl and the like,
R20 and R2i are independently different or identical and are selected from H, lower alkyl, i.e. C C4 alkyl or R20 and R2i together may form a C4-C7 cycloalkyl or an aromatic group, both of which may optionally be substituted with halogen, hydroxyl or a lower alkyl, or R2o and R2i may be
Figure imgf000072_0001
CH2X-acyl, F, CH2COOH, CH2C02alkyl, and when there is a cyclic bond present between A and B the compound
Figure imgf000072_0002
and acyls and alkyls may be optionally substituted
2. A compound according to claim 1 , wherein A is -selected from -O-R, wherein R is
Figure imgf000072_0003
B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is CrC4 alkyl, branched or straight, preferably B is Me; wherein R' is selected from the formula (II), (V) or (IX) above, R', R" and R'" are independently different or identical and are selected from formula (VII) or (VIII) above.
3. A compound according to claim 1 or 2, wherein A is -OR.
4. A compound according to any of the preceding claims, wherein A is -OR, and B is selected from -OR', -NHR", -SR'" or -OH; or in case of Formula (IA) B is Me; and R', R', R" and R'" being as described above.
5. A compound according to any of the preceding claims, wherein A is selected from -O-R, wherein R is
Figure imgf000073_0001
and R-i or R3 is CH2CH2CH20C(=0)CH2CH2COX6R8, and B is -OR' or -OH; or in case of Formula (IA) B is ME..
6. A compound according to any of claims 1 -4, wherein A is -OR, and B is -OH or -OR', or in case of Formula (IA) B is Me; and wherein R' is selected from formula (VII) or formula (VIII) as defined above.
7. A compound according to any of claims 1 -4, wherein A is selected from -O-R, wherein R is
Figure imgf000073_0002
and B is -OR' or -OH; or in case of Formula (IA) B is Me;.
8. A compound according to any of the preceding claims, wherein Z is selected from -CH2- (eg derived from malonic acid), -CH=CH2- (eg derived from fumaric acid), -CH2-CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid); or Z is absent, n is 1 and B is an alkyl group (eg derived from pyruvic acid)..
9. A compound according to any of the preceding claims, wherein A is -OR and B is -OH or in case of Formula (IA) B is Me.
10. A compound according to any of the preceding claims, wherein A is -OR and R is formula (II):
Figure imgf000074_0001
. A compound according to any of the preceding claims, wherein formula (VII)
Figure imgf000074_0002
12. A compound according to any of the preceding claims, wherein at least one of Rf, Rg, Rh in formula (IX) is -H or alkyl, with alkyl as defined herein. according to any of the preceding claims, wherein A is -OR and R-i or R3 is
Figure imgf000074_0003
or Ri or R3 is CH2CH2OC(=0)CH2CH2COX6R8.
14. A compound according to any of the preceding claims, wherein Z is selected from -CH2- (eg derived from malonic acid), -CH=CH2- (eg derived from fumaric acid), -CH2-CH(OH)- (eg derived from malic acid), -CH(OH)-CH2- (eg derived from malic acid); or Z is absent, and n is 1 and B is an alkyl group (eg derived from pyruvic acid).
15. A compound according to any of the preceding claim, wherein Z is -CH2- (eg derived from malonic acid).
16. A compound according to any of claims 1-15 for use in medicine
17. A compound according to any of claim 1-15, for use in cosmetics.
18. A compound according to any of claims claim 1 -15 for use in the treatment of or prevention of metabolic diseases, or in the treatment of diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction, treating or suppressing of mitochondrial disorders, stimulation of mitochondrial energy production, 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.
19. A compound according for use according to claim 18, wherein the medical use is prevention or treatment of drug-induced mitochondrial side-effects.
20. A compound for use according to claim 19, wherein the prevention or drug -induced mitochondrial side-effects relates to drug interaction with Complex I, such as e.g. metformin- Complex I interaction.
21. A compound according to claim 19, wherein diseases of mitochondrial dysfunction involves e.g. mitochondrial deficiency such as a Complex I, II, III or IV deficiency or an enzyme deficiency like e.g. pyruvate dehydrogenase deficiency
22. A compound for use according to any of claims 18-21 , wherein the diseases of
mitochondrial dysfunction or disease related to mitochondrial dysfunction are selected from Alpers Disease (Progressive Infantile Poliodystrophy, Amyotrophic lateral sclerosis (ALS), Autism, Barth syndrome (Lethal Infantile Cardiomyopathy), Beta-oxidation Defects, Bioenergetic metabolism deficiency, Carnitine-Acyl-Carnitine Deficiency, Carnitine Deficiency, Creatine Deficiency Syndromes (Cerebral Creatine Deficiency Syndromes (CCDS) includes:
Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency), L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency), and SLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency), Co-Enzyme Q10 Deficiency Complex I Deficiency (NADH dehydrogenase (NADH-CoQ reductase deficiency), Complex II Deficiency (Succinate dehydrogenase deficiency), Complex III Deficiency (Ubiquinone-cytochrome c oxidoreductase deficiency), Complex IV Deficiency/COX Deficiency (Cytochrome c oxidase deficiency is caused by a defect in Complex IV of the respiratory chain), Complex V Deficiency (ATP synthase deficiency), COX Deficiency, CPEO (Chronic Progressive External Ophthalmoplegia
Syndrome), CPT I Deficiency, CPT II Deficiency, Friedreich's ataxia (FRDA or FA), Glutaric Aciduria Type II, KSS (Kearns-Sayre Syndrome), Lactic Acidosis, LCAD (Long-Chain Acyl-CoA Dehydrogenase Deficiency), LCHAD, Leigh Disease or Syndrome (Subacute Necrotizing Encephalomyelopathy), LHON (Leber's hereditary optic neuropathy), Luft Disease, MCAD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency), MELAS (Mitochondrial
Encephalomyopathy Lactic Acidosis and Strokelike Episodes), MERRF (Myoclonic Epilepsy and Ragged-Red Fiber Disease), MIRAS (Mitochondrial Recessive Ataxia Syndrome), Mitochondrial 5 Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy including:
Encephalomyopathy and Encephalomyelopathy, Mitochondrial Myopathy, MNGIE
(Myoneurogastointestinal Disorder and Encephalopathy, NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa), Neurodegenerative disorders associated with Parkinson's, Alzheimer's or Huntington's disease, Pearson Syndrome, Pyruvate Carboxylase Deficiency, Pyruvate
10 Dehydrogenase Deficiency, POLG Mutations, Respiratory Chain Deficiencies, SCAD (Short- Chain Acyl-CoA Dehydrogenase Deficiency), SCHAD, VLCAD (Very Long-Chain Acyl-CoA Dehydrogenase Deficiency).
23. A compound for use according to claim 22, wherein the mitochondrial dysfunction or 15 disease related to mitochondrial dysfunction is attributed to complex I dysfunction and selected from 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).
20 24. A composition comprising a compound of Formula (I) as defined according any of claims 1 - 15 and one or more pharmaceutically or cosmetically acceptable excipients.
25. A method of treating a subject suffering from diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction as defined in any of claims 22-23, the method
25 comprising administering to the subject an efficient amount of a composition as defined in claim 24.
26. A method according to claim 25 wherein the composition is administered parenterally, orally, topically (including buccal, sublingual or transdermal), via a medical device (e.g. a stent), by
30 inhalation or via injection (subcutaneous or intramuscular)
27. A method according to any of claims 25-26, wherein the composition is administered as a single dose or a plurality of doses over a period of time, such as e.g. one daily, twice daily or 3-5 times daily as needed.
35
28. A compound according to any of claims 1-15 for use in the treatment or prevention of lactic acidosis.
29. A compound according to any of claims 1-15 for use in the treatment or prevention of a drug-induced side-effect selected from lactic acidosis and side-effects related to Complex I defect, inhibition or malfunction.
30. A compound according to any of claims 1-15 for use in the treatment or prevention of a drug-induced side-effect selected from lactic acidosis and side-effects related to defect, inhibition or mal-function in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 drugs that affect the levels of glucose or other Complex l-related substrates).
31. A combination of a drug substance and a compound according to any of claims 1 -15 for use in the treatment and/or prevention of a drug-induced side-effect selected from i) lactic acidosis, ii) and side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 drugs that affect the levels of glucose or other Complex-l-related substrates)., wherein i) the drug substance is used for treatment of a disease for which the drug substance is indicated, and
ii) the compound 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.
32. A composition comprising a drug substance and a compound according to any of claims 1- 15, wherein the drug substance has a potential drug-induced side-effect selected from i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other Complex-l-related substrates).
33. A kit comprising
i) a first container comprising a drug substance, which has a potential drug-induced side-effect selected i) from lactic acidosis, ii) and side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates), and
5
ii) a second container comprising a compound according to any of claims 1-15, 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 i) lactic acidosis, ii) side-effects related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or 10 malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates).
15 34. A method for treating a subject suffering from a drug-induced side-effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side- effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would encompass any drug effect that limits the supply of NADH to Complex I, e.g. effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism
20 and even drugs that affect the levels of glucose or other substrates)., the method comprises administering an effective amount of a compound according to any of claims 1 -15 to the subject.
35. A method for preventing or alleviating a drug-induced side-effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side-
25 effects related to defect, inhibition or malfunction in aerobic metabolism upstream of complex I (indirect inhibition of Complex I, which would 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 affect the levels of glucose or other substrates), in a subject, who is suffering from a disease that is treated with a drug substance, which potentially induce a side-
30 effect selected from i) lactic acidosis, ii) side-effect related to a Complex I defect, inhibition or malfunction, and iii) side-effects related to defect, inhibition or malfunction in aerobic
metabolism upstream of Complex I, such as in dehydrogenases of Kreb's cycle, pyruvate dehydrogenase and fatty acid metabolism,
35 the method comprises administering an effective amount of a compound according to any of claims 1-15 to the subject before, during or after treatment with said drug substance.
36. A method according to any one of claims 34-35, wherein the drug substance is an antidiabetic substance.
37. A method according to any one of claims 34-36, wherein the anti-diabetic substance is metformin.
38. A compound according to any of claims 1-15, for use in the treatment of absolute or relative cellular energy deficiency.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029114A1 (en) * 1996-12-30 1998-07-09 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
WO2001024793A1 (en) * 1999-10-07 2001-04-12 Xanthus Life Sciences, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion
EP1561748A1 (en) * 2002-10-18 2005-08-10 Meiji Seika Kaisha Ltd. Malonic acid monoesters and process for producing the same
WO2014031844A1 (en) * 2012-08-22 2014-02-27 Xenoport, Inc. Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
WO2014053857A1 (en) * 2012-10-05 2014-04-10 Mitopharm Ltd Protected succinates for enhancing mitochondrial atp-production
WO2015155230A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Prodrugs of succinic acid for increasing atp production
WO2015155231A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Novel cell-permeable succinate compounds
WO2015155238A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Succinate prodrugs for use in the treatment of lactic acidosis or drug-induced side-effects due to complex i-related impairment of mitochondrial oxidative phosphorylation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029114A1 (en) * 1996-12-30 1998-07-09 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
WO2001024793A1 (en) * 1999-10-07 2001-04-12 Xanthus Life Sciences, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion
EP1561748A1 (en) * 2002-10-18 2005-08-10 Meiji Seika Kaisha Ltd. Malonic acid monoesters and process for producing the same
WO2014031844A1 (en) * 2012-08-22 2014-02-27 Xenoport, Inc. Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
WO2014053857A1 (en) * 2012-10-05 2014-04-10 Mitopharm Ltd Protected succinates for enhancing mitochondrial atp-production
WO2015155230A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Prodrugs of succinic acid for increasing atp production
WO2015155231A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Novel cell-permeable succinate compounds
WO2015155238A1 (en) * 2014-04-08 2015-10-15 Neurovive Pharmaceutical Ab Succinate prodrugs for use in the treatment of lactic acidosis or drug-induced side-effects due to complex i-related impairment of mitochondrial oxidative phosphorylation

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
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; 1 January 2013 (2013-01-01), 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 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
STETTER; RESKE, CHEM. BER., vol. 103, 1970, pages 639 - 642
WUTS; GREENE: "Greene's Protective Groups in Organic Synthesis", 2006, WILEY

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