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WO2017060400A1 - Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées à des dysfonctions mitochondriales - Google Patents

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

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Publication number
WO2017060400A1
WO2017060400A1 PCT/EP2016/073955 EP2016073955W WO2017060400A1 WO 2017060400 A1 WO2017060400 A1 WO 2017060400A1 EP 2016073955 W EP2016073955 W EP 2016073955W WO 2017060400 A1 WO2017060400 A1 WO 2017060400A1
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complex
deficiency
derived
mitochondrial
acid
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PCT/EP2016/073955
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Steven Moss
Eskil Elmer
Magnus Joakim HANSSON
Karl Henrik Johannes EHINGER
Karl Michael KARLSSON
Sarah PIEL
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Neurovive Pharmaceutical Ab
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • 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

Definitions

  • the present invention provides novel cell-permeable carboxylic acid-based metabolites 5 involved in cellular metabolism such as pyruvate and Kreb's cycle (TCA) intermediates
  • the invention also provides novel cell-permeable carboxylic acid-based metabolites functioning as enzymatic or electron transport inhibitors such
  • the present invention relates to novel compounds as such and to the
  • 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
  • membrane some of them being glutarate, fumarate, malonate, malate, citrate,
  • cell-permeable carboxylic acid-based metabolites can be used to increase cellular metabolic function by enhancing ATP- production in mitochondria or the glycolytic pathway.
  • a cell-permeable carboxylic acid-based metabolite can be used to inhibit activity of mitochondrial
  • 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.
  • 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. producing more ATP than normally, or in restoring defects in glycolytic pathway or the mitochondrial respiratory system.
  • 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. In recent years many papers have been published describing mitochondrial
  • 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.
  • 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.
  • 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. Enhancement of energy production is e.g. relevant in subjects suffering from a mitochondrial defect, disorder or disease. Mitochondrial diseases result from
  • ischemia reperfusion injury can be related to aberrant or over-activity of mitochondrial enzymes or electron transport of the respiratory chain. This aberrant activity can cause release of harmful oxidative molecules that can damage the mitochondria itself and its host cell.
  • Symptoms of a mitochondrial disease may include loss of motor control, muscle weakness and pain, seizures, visual/hearing problems, cardiac diseases, liver diseases, gastrointestinal disorders, swallowing difficulties and more.
  • a mitochondrial disease may be inherited or may be due to spontaneous mutations, which lead to altered functions of the proteins or RNA molecules normally residing in the mitochondria. Also many mitochondrial disorders can be secondary to other diseases or conditions such as, but not limited to, ischemia, ischemia-reperfusion injury, diabetes, cancer, intoxication.
  • a mitochondrial deficiency such as a Complex I, II, III or IV deficiency of the respiratory chain or an enzyme deficiency of metabolic pathways such as the glycolysis and/or TCA cycle.
  • some conditions such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • A is selected from -SR, -OR and NHR, and R is
  • R' is selected from the formula (II) to (IX) below:
  • B is C-
  • R', R" and R'" are independently different or identical and is selected from formula (VII- VIII) below:
  • R- ⁇ 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-alkyl, N-acyl, N-alkyl, Xacyl, - CH 2 Xalkyl, -CH 2 X-acyl, F, -CH 2 COOH, -CH 2 C0 2 alkyl,
  • 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, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
  • X 7 is selected from R-i , -NR-
  • R 9 is selected from H, Me, Et or 0 2 CCH 2 CH 2 COXR;
  • R-io is selected from -Oacyl, -NHalkyl,- NHacyl, or 0 2 CCH 2 CH 2 COX 6 R ⁇ ;8
  • 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;
  • R13 and R14 or R13 and R15 may bridge to form a cyclic system to form cycloalkyl, heterocycloalkyl, lactone or lactams.
  • R f , R g and R h are independently different or identical and are selected from Xacyl, - CH 2 Xalkyl, -CH 2 X-acyl and R 9 , alkyl is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acyl is selected from formyl, acetyl, propionyl, isopropionyl, buturyl, tert-butyryl, pentanoyl, benzoyl, succinyl. acyl and/or alkyl may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula
  • Z is selected from -CH(OH)-CH 2 (OH) and n is 0 eg derived from glyceric acid); or Z is absent or -CH 2 - and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively) and A is -SR.
  • Compounds of the invention of particular interest are those compounds, A is SR, and B is OH or B is SR'", or in case of Formula (IA) B is Me.
  • A is SR and B is OH.
  • Compounds of the invention of particular interest are those compounds, wherein A is SR, B is OH or B is SR, where R is
  • At least one of R-i and R 3 is -H, such that formula II is:
  • a compound according to formula (I) may be any compound according to formula (I).
  • A is selected from -SR, -OR and NHR, and R is
  • B is selected from -O-R', -NHR", -SR'" or -OH;
  • R', R" and R'" are independently different or identical and is selected from one or the formulas below:
  • Ri and R 3 are independently different or identical and are selected from H, Me, Et, propyl, O-Me, O-Et, O-propyl,
  • X is selected from O, NH, S, p is an integer and is 1 , R 6 is selected from H, Me, Et,
  • R 3 X 7 is selected from R-i, -NR-
  • 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, wherein alkyl and acyl are as defined herein before.
  • A is selected from -SR, -OR and NHR, and R is
  • R', R" and R'" are independently different or identical and is selected from one or the formulas below:
  • X is selected from O, NH, S, p is an integer and is 1 ,
  • R 6 is selected from H, Me, Et,
  • R-I3, Ri 4 and Ri 5 are independently different or identical and are selected from H, Me, Et, -COOH.
  • Z is as defined herein before.
  • R 20 is H, Me, Et, iPr, nPr, nBu, sBu, iBu or tBu
  • R 22 is Et, iPr, nPr, nBu, sBu, iBu or tBu
  • R 25 is H, Me, Et, or iPr
  • R 26 is H, Me, Et, or iPr
  • R25 and R 2 6 may both be H, or R 25 is H and R 2 6 is Me or Et, or R 25 is Me or Et and R 2 6 is Me or Et
  • R2 0, R 2 i , and R22 are as defined in claim 1 .
  • R 20 is Me, Et, iPr, nPr, nBu, sBu, iBu or tBu
  • R 23 is R 20 or H
  • R 22 is Et, iPr, nPr, nBu, sBu, iBu or tBu
  • 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 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.
  • a symmetrical starting material is selected.
  • the compound selected is succinic acid or succinyl chloride.
  • the starting material selected is asymmetric. That includes “acid-protected acid”,” acid-activated acid”, and “protected acid-activated acid”. Preferably this includes malonic acid mono-benzyl ester, malonic acid mono-tert butyl ester, .
  • 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.
  • succinic acid 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 (VII) may be made by reacting an activated carboxylic acid with a compound of formula XIV, optionally in the presence of an activating species.
  • formula 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 N,N- 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.
  • a solvent such as dichloromethane, acetone, THF, acetonitrile or N,N- dimethylformamide
  • 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 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 80 °C.
  • the reaction may be performed with optional additives such as sodium iodide or tetraalkyl ammonium halides (e.g. tetrabutyl ammonium iodide).
  • 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
  • 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 compounds of the invention can be used to enhance or restore energy production in mitochondria.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related conditions by inhibiting activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds can be used in medicine or in cosmetics.
  • the compounds can be used in the prevention or treatment of disorders or diseases having a component relating to mitochondrial dysfunction and/or to a component of energy (ATP) deficiency.
  • ATP energy
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • Enhancement of energy production is e.g. relevant in subjects suffering from a mitochondrial defect, disorder or disease.
  • Mitochondrial diseases result from
  • Certain conditions such as ischemia reperfusion injury can be related to aberrant or over-activity of mitochondrial enzymes or electron transport of the respiratory chain. This aberrant activity can cause release of harmful oxidative molecules that can damage the mitochondria itself and its host cell.
  • a mitochondrial deficiency such as a Complex I, II, III or IV deficiency of the respiratory chain or an enzyme deficiency of metabolic pathways such as the glycolysis and/or TCA cycle.
  • some conditions such as ischemia reperfusion injury, can be caused by excess activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds are contemplated to show improved properties for treatment of these and related diseases, including better cell permeability, longer plasma half-life, reduced toxicity, increased energy release to mitochondria, and improved formulation (due to improved properties including increased solubility).
  • the compounds are also orally bioavailable, which allows for easier administration.
  • the advantageous properties of the compound of the invention may include one or more of the following:
  • the present invention provides the compound of the invention for use as a
  • 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 but not limited to, Leigh Syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers), which comprises administering to a subject in need thereof an effective amount of the compound of the invention.
  • mitochondrial complex I related disorders such as but not limited to, Leigh Syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers)
  • the present invention also provides the use of the compound of the invention for the manufacture of a medicament for the treatment of drug-induced lactic acidosis.
  • a compound of the invention may also be useful in any condition where extra energy production would potentially be beneficial such as, but not limited to, prolonged surgery and intensive care.
  • the compounds of the invention are useful in the prevention or treatment of mitochondria-related conditions, such as ischemia reperfusion injury, by inhibiting activity of mitochondrial enzymes or electron transport by the respiratory chain.
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • novel compounds wherein Z is -CH 2 -, 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 are organelles in eukaryotic cells, popularly referred to as the
  • ATP adenosine triphosphate
  • biochemical processes include the citric acid cycle (the tricarboxylic acid cycle, or Kreb's cycle), which generates reduced nicotinamide adenine dinucleotide (NADH) 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.
  • NADH nicotinamide adenine dinucleotide
  • NAD + oxidized nicotinamide adenine dinucleotide
  • FADH2 reduced 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, Complex V (which is not directly associated with Complexes I, II, III and IV) uses the energy stored by the
  • the citric acid cycle and oxidative phosphorylation are preceded by glycolysis, in which a molecule of glucose is broken down into two molecules of pyruvate, with net generation of two molecules of ATP per molecule of glucose.
  • the pyruvate molecules then enter the mitochondria, where they are completely oxidized to C0 2 and H 2 0 via oxidative phosphorylation (the overall process is known as aerobic respiration).
  • the complete oxidation of the two pyruvate molecules to carbon dioxide and water yields about at least 28-29 molecules of ATP, in addition to the 2 molecules of ATP generated by transforming glucose into two pyruvate molecules. If oxygen is not available, the pyruvate molecule does not enter the mitochondria, but rather is converted to lactate, in the process of anaerobic respiration.
  • the overall net yield per molecule of glucose is thus approximately at least 30-31 ATP molecules. ATP is used to power, directly or indirectly, almost every other biochemical reaction in the cell. Thus, the extra (approximately) at least 28 or 29 molecules of ATP contributed by oxidative phosphorylation during aerobic respiration are critical to the proper functioning of the cell. Lack of oxygen prevents aerobic respiration and will result in eventual death of almost all aerobic organisms; a few organisms, such as yeast, are able to survive using either aerobic or anaerobic respiration. When cells in an organism are temporarily deprived of oxygen, anaerobic respiration is utilized until oxygen again becomes available or the cell dies. The pyruvate generated during glycolysis is converted to lactate during anaerobic respiration. The build-up of lactic acid is believed to be responsible for muscle fatigue during intense periods of activity, when oxygen cannot be supplied to the muscle cells. When oxygen again becomes available, the lactate is converted back into pyruvate for use in oxidative phosphorylation.
  • Mitochondrial dysfunction contributes to various disease states. Some mitochondrial diseases are due to mutations or deletions in the mitochondrial genome 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.
  • 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.
  • 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
  • Carnitine Deficiency includes: Guanidinoaceteate Methyltransferase Deficiency (GAMT Deficiency), L-Arginine:Glycine Amidinotransferase Deficiency (AGAT Deficiency), and SLC6A8-Related Creatine Transporter Deficiency (SLC6A8 Deficiency).
  • NADH dehydrogenase NADH-CoQ reductase
  • MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike Episodes
  • Mitochondrial Encephalopathy includes: Encephalomyopathy,
  • MNGIE Myoneurogastointestinal Disorder and Encephalopathy
  • NARP Neuroopathy, Ataxia, and Retinitis Pigmentosa
  • SCHAD Short Chain L-3-Hydroxyacyl-CoA Dehydrogenase
  • Deficiency also referred to as 3-Hydroxy Acyl CoA Dehydrogenase Deficiency HADH
  • VLCAD Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
  • SIRS Systemic inflammation response syndrome
  • 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.
  • 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.
  • 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
  • KSS KSS is a slowly progressive multi-system
  • Degeneration of the retina usually causes difficulty seeing in dimly lit environments.
  • Patients with KSS may also have such problems as deafness, dementia, kidney dysfunction, and muscle weakness. Endocrine abnormalities including growth retardation, short stature, or diabetes may also be evident.
  • KSS is a rare disorder. It is usually caused by a single large deletion (loss) of genetic material within the DNA of the mitochondria (mtDNA), rather than in the DNA of the cell nucleus. These deletions, of which there are over 150 species, typically arise spontaneously. Less frequently, the mutation is transmitted by the mother.
  • Treatments are based on the types of symptoms and organs involved, and may include: Coenzyme Q10, insulin for diabetes, cardiac drugs, and a cardiac pacemaker which may be life-saving. Surgical intervention for drooping eyelids may be considered but should be undertaken by specialists in ophthalmic surgical centers. KSS is slowly progressive and the prognosis varies depending on severity. Death is common in the third or fourth decade and may be due to organ system failures.
  • Leigh Disease or Syndrome Subjectacute Necrotizing Encephalomyelopathy: Symptoms: Seizures, hypotonia, fatigue, nystagmus, poor reflexes, eating and swallowing difficulties, breathing problems, poor motor function, ataxia.
  • Leigh's Disease is a progressive neurometabolic disorder with a general onset in infancy or childhood, often after a viral infection, but can also occur in teens and adults. It is characterized on MRI by visible necrotizing (dead or dying tissue) lesions on the brain, particularly in the midbrain and brainstem.
  • the child often appears normal at birth but typically begins displaying symptoms within a few months to two years of age, although the timing may be much earlier or later.
  • Initial symptoms can include the loss of basic skills such as sucking, head control, walking and talking. These may be accompanied by other problems such as irritability, loss of appetite, vomiting and seizures. There may be periods of sharp decline or temporary restoration of some functions.
  • the child may also have heart, kidney, vision, and breathing complications.
  • PDHC pyruvate dehydrogenase
  • 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.
  • DCA dichloroacetate
  • Leigh's Disease The prognosis for Leigh's Disease is poor. Depending on the defect, individuals typically live anywhere from a few years to the mid-teens. Those diagnosed with Leighlike 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.
  • MELAS - Mitochondrial Myopathy muscle weakness
  • Encephalopathy brain and central nervous system disease
  • Lactic Acidosis build-up of a product from anaerobic respiration
  • 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, 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.
  • MERRF dichloroacetate
  • menadione menadione
  • the prognosis for MELAS is poor.
  • the age of death is between 10 to 35 years, although some patients may live longer. Death may come as a result of general body wasting due to progressive dementia and muscle weakness, or complications from other affected organs such as heart or kidneys.
  • MERRF is a progressive multi-system syndrome usually beginning in childhood, but onset may occur in adulthood. The rate of progression varies widely. Onset and extent of symptoms can differ among affected siblings.
  • MERRF The classic features of MERRF include:
  • Ragged-red fibers a characteristic microscopic abnormality observed in muscle biopsy of patients with MERRF and other mitochondrial disorders
  • Additional symptoms may include: hearing loss, lactic acidosis (elevated lactic acid level in the blood), short stature, exercise intolerance, dementia, cardiac defects, eye abnormalities, and speech impairment.
  • MERRF mitochondrial DNA mutation
  • A8344G mitochondrial DNA mutations
  • MERRF mitochondrial DNA mutations
  • a mother will transmit her MERRF mutation to all of her offspring, some may never display symptoms.
  • 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:
  • 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.
  • 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
  • mitochondrial dysfunction 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.
  • compositions comprising a compound of the invention
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention together with one or more pharmaceutically acceptable diluents or carriers.
  • the compound of the invention or a formulation thereof may be administered by any conventional method for example but without limitation it may be administered parenterally, orally, topically (including buccal, sublingual or transdermal), via a medical device (e.g. a stent), by inhalation or via injection (subcutaneous or intramuscular).
  • a medical device e.g. a stent
  • the treatment may consist of a single dose or a plurality of doses over a period of time.
  • the treatment may be by administration once daily, twice daily, three times daily, four times daily etc.
  • the treatment may also be by continuous administration such as e.g. administration intravenous by drop.
  • the compound of the invention Whilst it is possible for the compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Examples of suitable carriers are described in more detail below.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compound of the invention will normally be administered intravenously, orally or by any parenteral route, in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • the route of administration the route of administration.
  • compositions may be administered at varying doses.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • the compound of the invention can also be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • 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.
  • administration may also contain excipients e.g. ⁇ , ⁇ -dimethylacetamide, dispersants e.g. polysorbate 80, surfactants, and solubilisers, e.g. polyethylene glycol, Phosal 50 PG (which consists of phosphatidylcholine, soya-fatty acids, ethanol,
  • the formulations according to present invention may also be in the form of emulsions, wherein a compound according to Formula (I) may be present in an aqueous oil emulsion.
  • the oil may be any oil-like substance such as e.g. soy bean oil or safflower oil, medium chain triglyceride (MCT-oil) such as e.g. coconut oil, palm oil etc or combinations thereof.
  • Tablets may contain excipients such as microcrystalline cellulose, lactose (e.g. lactose monohydrate or lactose anyhydrous), sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, butylated hydroxytoluene (E321 ), crospovidone, hypromellose, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium, and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), 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.
  • lactose e.g. lactose monohydrate or lactose anyhydrous
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerine, 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 gelatine and glycerine, 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.
  • a cream or ointment 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.
  • the compositions are preferably applied as a topical ointment or cream.
  • the active agent When formulated in an ointment, the active agent may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, 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. 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.
  • 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 an 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 R 10 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 R8 is H, R9 is Me and R10 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 malonic acid.
  • A is SR with R being formula (VII) and B is OH and Z is -CH 2 -, X 5 is C0 2 H and R-, is Et: o o U o o
  • 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
  • Vitamins e.g. Tocopherols, Tocotrienols and Trolox (Vitamin E), Ascorbate (C), Thiamine (B1 ), Riboflavin (B2), Nicotinamide (B3), Menadione (K3),
  • any of the compounds as disclosed herein may be administered together with any other compounds such as e.g. sodium bicarbonate (as a bolus (e.g. 1 mEq/kg) followed by a continuous infusion.) as a concomitant medication to the compounds as disclosed herein.
  • any other compounds such as e.g. sodium bicarbonate (as a bolus (e.g. 1 mEq/kg) followed by a continuous infusion.) as a concomitant medication to the compounds as disclosed herein.
  • the present invention also relates to the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects.
  • the compounds according to the invention are used in the prevention or treatment of a mitochondrial- related drug-induced side effects at or up-stream of Complex I, or expressed otherwise, the invention provides according to the invention for the prevention or treatment of drug-induced direct inhibition of Complex I or of any drug-induced effect that limits the supply of NADH to Complex I (such as, but not limited to, effects on Krebs cycle, glycolysis, beta-oxidation, pyruvate metabolism and even drugs that effects the transport or levels of glucose or other complex I related substrates).
  • Mitochondrial toxicity induced by drugs may be a part of the desired therapeutic effect (e.g. mitochondrial toxicity induced by cancer drugs), but in most case mitochondrial toxicity induced by drugs is an unwanted effect. Mitochondrial toxicity can markedly increase glycolysis to compensate for cellular loss of mitochondrial ATP formation by oxidative phosphorylation. This can result in increased lactate plasma levels, which if excessive results in lactic acidosis, which can be lethal. Type A lactic acidosis is primarily associated with tissue hypoxia, whereas type B aerobic lactic acidosis is associated with drugs, toxin or systemic disorders such as liver diseases, diabetes, cancer and inborn errors of metabolism (e.g. mitochondrial genetic defects).
  • the present invention provides compounds for use in the prevention or treatment of lactic acidosis and of mitochondrial-related drug-induced side effects.
  • novel cell-permeable carboxylic acid-based metabolites are used in the prevention or treatment of a mitochondrial-related drug-induced side effects at or 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).
  • 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) or Formula (1A) and a drug substance that may induce a mitochondrial-related side-effect, in particular a side-effect that is caused by direct or indirect impairment of Complex I by the drug substance.
  • a mitochondrial-related side-effect in particular a side-effect that is caused by direct or indirect impairment of Complex I by the drug substance.
  • Such combination can be used as prophylactic prevention of a mitochondrial-related side-effect or, in case the side-effect appears, in alleviating and/or treating the mitochondrial-related side effect.
  • compounds as described below will be effective in treatment or prevention of drug-induced side-effects, in particular in side-effects related to direct or indirect inhibition of Complex I.
  • Drug substances that are known to give rise in Complex I defects, malfunction or impairment and/or are known to have lactic acidosis as side-effect are:
  • Analgesics including acetaminophen, capsaicin
  • Antianginals including amiodarone, perhexiline
  • Antibiotics including linezolid, trovafloxacin, gentamycin
  • Anticancer drugs including quinones including mitomycin C, adriamycin
  • Anti-convulsant drugs including valproic acid
  • Anti-diabetics including metformin, phenformin, butylbiguanide, troglitazone and rosiglitazone, pioglitazone
  • Anti-Hepatitis B including fialuridine
  • Anti-Parkinson including tolcapone
  • Anti-tuberculosis including isoniazid
  • Fibrates including clofibrate, ciprofibrate, simvastatin Hypnotics including Propofol
  • DMARD Immunosupressive disease-modifying antirheumatic drug
  • Neuroleptics including antipsycotic neuroleptics like chlorpromazine, fluphenazine and haloperidol
  • NRTI Nucleotide reverse Transcriptase Inhibitors
  • efavirenz including efavirenz, tenofovir, emtricitabine, zidovudine, lamivudine, rilpivirine, abacavir, didanosine
  • NSAIDs including nimesulfide, mefenamic acid, sulindac
  • lactic acidosis drugs that are known to have lactic acidosis as side-effects
  • beta2-agonists epinephrine
  • theophylline or other herbicides.
  • Alcohols and cocaine can also result in lactic acidosis.
  • the compounds of the invention also may be effective in the treatment or prevention of lactic acidosis even if it is not related to a Complex I defect. Combination of drugs and compounds of the invention
  • the present invention also relates to a combination of a drug substance and a compound of the invention for use in the treatment and/or prevention of a drug-induced side-effect selected from lactic acidosis and side-effect related to a Complex I defect, inhibition or malfunction, wherein
  • 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.
  • 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.
  • the potential use of compounds of the invention capable of entering cells and deliver a metabolite 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.
  • the 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 i) a first container comprising a drug substance, which has a potential drug-induced side-effect selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction, and
  • a second container comprising a compound of the invention, which has the potential for prevention or alleviation of the side effects induced or inducible by the drug substance, wherein the side-effects are selected from lactic acidosis and side-effects related to a Complex I defect, inhibition or malfunction.
  • the 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.
  • 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 ef 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
  • neuropathic pain 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.
  • suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ⁇ , ⁇ '- 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 2n +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.
  • 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.
  • ⁇ 1 ⁇ 0 alkoxy in the present context designates a group -0-C- ⁇ 6 alkyl used alone or in combination, wherein C r w 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 (1 - piperazine, 2-piperazine, 3-piperazine, 4-piperazine, 5-piperazine, 6-piperazine), morpholine (2-morpholine, 3-morpholine, 4-morpholine, 5-morpholine, 6-morpholine), thi
  • 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 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-triazin
  • 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 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
  • 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.
  • the time course of plasma concentration over time can be used to calculate the absolute bioavailability of the compound as a percentage using standard models. An example of a typical protocol is described below.
  • mice or rats are dosed with 1 or 3 mg/kg of the compound of the invention i.v. or 1 , 5 or 10 mg/kg of the compound of the invention p.o..
  • Blood samples are taken at 5 min, 15 min, 1 h, 4 h and 24 h intervals, and the concentration of the compound of the invention in the sample is determined via LCMS-MS.
  • the time- course of plasma or whole blood concentrations can then be used to derive key parameters such as the area under the plasma or blood concentration-time curve (AUC - which is directly proportional to the total amount of unchanged drug that reaches the systemic circulation), the maximum (peak) plasma or blood drug concentration, the time at which maximum plasma or blood drug concentration occurs (peak time), additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half-life, total body clearance, steady-state volume of distribution and F%. 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.
  • AUC - area under the plasma or blood concentration-time curve
  • additional factors which are used in the accurate determination of bioavailability include: the compound's terminal half-life, total body clearance, steady-state volume of distribution and F%.
  • Measurement of mitochondrial respiration are performed in a high-resolution oxygraph (Oxygraph- 2k, Oroboros Instruments, Innsbruck, Austria) at a constant temperature of 37°C.
  • Isolated human platelets containing live mitochondria are suspended in a 2 ml_ glass chamber at a concentration sufficient to yield oxygen consumption in the medium of ⁇ 10 pmol 0 2 S "1 ml.- 1 .
  • High-resolution respirometry - B 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
  • 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.
  • motoneuron death in vitro a new model for amyotrophic lateral sclerosis. Journal of neurochemistry 74, 1 158-1 165 (2000).
  • 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 obligation 10 pmol 02 s-1 ml_-1.
  • 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.
  • Citric acid (5 g) was dissolved in benzaldehyde and P205 added. The reaction was heated to 80 °C for one hour before standard reaction work up and product NV-214-a being isolated by recrystalisation in petroleum ether and ethyl acetate. NV-214-a was then dissolved in CHCI3 and POCI3 and ⁇ , ⁇ -dimethylanilane added. The reaction was heated under reflux for 10 minutes before standard reaction work up. The resultant solid was washed with CHCI 3 . This product (NV-214-b) was dissolved in THF/water (1 :1 ) and cooled to 0 °C. KHC0 3 and NV-187 (see example 1 ) were added and the reaction stirred on ice for 1 hour.
  • N-(2-mercapto-2-methylpropyl)acetamide was made as in example 1 . Pyruvic acid (300 mg) was dissolved in acetonitrile and HOBT and DCC added. N-(2-mercapto-2- methylpropyl)acetamide (1 .2 equivalents) was added and the reaction was stirred overnight and the product isolated by standard reaction work up and purified by preparative TLC.
  • Acetoacetic acid polyphosphate ester NV-220 N-(2-mercapto-2-methylpropyl)acetamide was made as in example 1 .
  • Tert-butyl acetoacetate (2.0 g) was dissolved in DCM and cooled to 5 °C. TFA was added and the reaction allowed to warm to room temperature and stirred for 2 hours. The solvent was then removed in vacuo and the resultant product used in the next step directly.
  • the product 300 mg was dissolved in CHCI 3 and THF (1 :1 ) and N-(2-mercapto-2- methylpropyl)acetamide (1 .2 equivalents) and polyphosphate ester was added.
  • NV-216-2-a was dissolved in DMF and cooled to 5 °C.
  • HBTU and DIPEA were added along with NV- 187 (see example 1 ).
  • the reaction was allowed to warm to room temperature. After 2 hours the reaction was worked up by standard conditions and the target NV-216-b isolated by preparative TLC.
  • the title compound was then made by dissolving NV-216- b in iPrOH and suspending 10% Pd/C catalyst. This was then subjected to a hydrogen atmosphere for 3 hours before filtration and removal of solvent in vacuo. The title compound was then purified by preparative HPLC.
  • NV-221-a was added and the reaction allowed to warm to room temperature. After 2 hours the reaction was acidified with phosphoric acid and extracted into ethyl acetate. The solvent was removed and the material used in the next step with no further purification by dissolving in DMF and cooling to 5 °C.
  • HBTU, DIPEA and NV-187 were added and the reaction allowed to warm to room temperature.
  • NV-822 was isolated by preparative HPLC.
  • NV822 was dissolved in THF and treated with 2 N HCL at room temperature. After 3 hours the reaction was worked up under standard conditions and NV221 purified by preparative HPLC.
  • NV809 (example 4) is dissolved in CH 2 CI 2 at room temperature. Dess-Martin periodinane (1 .1 . eq) is added and the solution stirred overnight. The reaction is quenched by washing with saturated aqueous Na 2 S0 3 and NaHC0 3 . The organics are passed through celite and are removed in vacuo. The target product is purified by preparative HPLC.
  • Example 10 cis-Aconitic anhydride is dissolved in toluene and NV187 (example 1 ) is added the mixture is heated under reflux overnight before the reaction is worked u. The target compound is then purified by preparative HPLC.
  • NV- 263-b (1.7 g, 4.0 mmol) was dissolved in CH 2 CI 2 (50 mL), then DCC (1.7 g, 8.0 mmol) and HOBt (0.50 g. 4.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h and then diethylamine (0.80 g, 8.0 mmol) was added, then the mixture was stirred at room temperature overnight.
  • NV-263-c 400 mg, 0.800 mmol was dissolved in CH 2 CI 2 (10 mL) at 0 °C then TFA (1 mL) and / ' -Pr 3 SiH (253 mg, 1.60 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours. The solvent was removed in vacuo and NV-263-d isolated by preparative HPLC.
  • NV-265-b (3.50 g, 10.9 mmol) was dissolved in THF (30 mL) then NaH (0.500 g, 13.0 mmol, 60% in oil) was added in portions at 0°C and reaction mixture was stirred 1 hour. Then a solution of NV-265-a (2.1 g, 10.9 mmol) in THF (5 mL) was added dropwise. The resulting mixture was warmed to room temperature over 2 hours. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo and NV-265-c isolated by column
  • NV-267-b NV-267 lodomethane (1 .02 g, 7.16 mmol) was added to a suspension of NV-263-b (example 1 1 , 2.0 g, 4.77 mmol) and K 2 C0 3 (1 .32 g, 9.55 mmol) in DMF (20 ml). The reaction mixture was stirred at room temperature overnight then diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with water then brine and dried over sodium sulfate and filtered. The solvent was evaporated in vacuo and NV-267-a isolated by column chromatography.
  • DL-2-aminopropan-1 -ol (10.0 g, 133 mmol) was dissolved in aqueous NaOH (1 N, 666 ml.) then carbon disulfide (50.6 g, 666 mmol) was added. The reaction mixture was refluxed overnight before being concentrated under reduced pressure to 300 ml_. The resulting suspension was cooled under ice-water bath for 1 hour with stirring. The precipitate NV-343-a was filtered, washed with water, then collected and the solvent removed in vacuo. NV-343-a (12.0 g, 90 mmol) in concentrated HCI (600 ml.) was refluxed for 3 days.
  • NV-343-b was collected and dried in vacuo.
  • NV-343-b (8.1 g, 63 mmol) was dissolved in H 2 0 (162 ml.) in an ice-water bath then KOH (3.56 g, 63 mmol) was added in portions. NaHC0 3 (16.0 g, 190 mmol) was added, then acetic anhydride (16.2 g, 159 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane twice.
  • NV- 343-c was isolated by column chromatography. NaOH (3.7 g, 92 mmol) was added in portions to a suspension of NV-343-c (7.7 g, 44 mmol) in H 2 0 (1 10 ml.) in an ice-water bath. The reaction mixture was stirred at room temperature for 3 hours then acidified to pH 3 with 2N HCI and extracted with dichloromethane 3 times. The combined organic layers were dried over sodium sulfate then the solvent was removed in vacuo to give NV-343-d.
  • N-acetyl-cysteine (100.0 g, 613 mmol) was dissolved in DMF (600 ml.) then
  • NV-344-b was extracted with ethyl acetate twice. The combined organic layers were washed with water, brine, dried over sodium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give NV-344-b.
  • TFA (480 ml.) was added to a solution of NV-344-b (240 g, 554 mmol) and triethylsilane (128.7 g, 1 107 mmol) in dichloromethane (2.4 L) at 0 °C and the reaction mixture allowed to stirred at room temperature overnight. The solvent was removed in vacuo and NV-344-c was isolated by column chromatography.
  • Polyphosphate ester (3.0 g) was added to a suspension of NV-344-c (500 mg, 2.6
  • NV-343-d (example 16, 200 mg, 1 .5 mmol) was dissolved in diethyl ether (3 mL) then malonyl dichloride (635 mg, 4.5 mmol) was added in portions under nitrogen. The mixture was stirred at room temperature for 2 hours before the solvent was removed in vacuo and the title compound isolated by preparative HPLC.
  • NV-267-b NV-266 NV-267-b (example 14, 210 mg, 1 .1 mmol) was dissolved in diethyl ether (3 mL) then malonyl dichloride (77 mg, 0.55 mmol) was added dropwise under nitrogen. The mixture was stirred at room temperature overnight before the solvent was evaporated in vacuo and NV-266 isolated by preparative HPLC.
  • NV-338 1-Amino-2-methyl-2-propanethiol (2.00 g, 14.1 mmol) and acetic anhydride (4.30 g, 42.4 mmol) were dissolved in water (15 mL) then aqueous KOH (8 M, to maintain pH 8) was added dropwise. The mixture was then neutralized by adding 2M HCI and stirred for 1 hour at room temperature. The solution was cooled with an ice bath then solid KOH (2.80 g, 49.4 mmol) was added slowly and the mixture was stirred for 50 minutes at room temperature. The mixture was saturated with NaCI and neutralized with 6M HCI, then extracted with CH 2 CI 2 twice.
  • NV-344-c (example 17, 382 mg, 2.0 mmol) was dissolved in diethyl ether (6 mL) then was malonyl dichloride (141 mg, 1.0 mmol) added dropwise under nitrogen. The mixture was stirred at room temperature for 2 hours before the solvent was removed in vacuo and NV-345 was isolated by preparative HPLC.
  • Propionic anhydride (1 1 .7 g, 89.7 mmol) and aqueous KOH (8 M, to maintain pH8) were added dropwise to a stirred solution of 2-aminoethanethiol (3.40 g, 30.0 mmol) dissolved in water (24 mL).
  • the mixture was stirred for 1 hour at room temperature and neutralized by adding 2M HCI.
  • the solution was cooled with an ice bath and solid KOH (6.00 g, 105 mmol) was added slowly.
  • the mixture was stirred for 50 minutes at room temperature then saturated with NaCI and neutralized with 6M HCI.
  • the mixture was extracted with CH 2 CI 2 (4 30 mL).
  • NV-273-a The combined CH 2 CI 2 extracts were dried (Na 2 S0 4 ) then the solvent was removed in vacuo to give NV-273-a.
  • Fumaroyl dichloride (1034 mg, 6.76 mmol) was dissolved in DCM (15 mL) then a solution of NV-273-a (900 mg, 6.76 mmol) in DCM (5 mL) was added dropwise under nitrogen and the mixture stirred at room temperature overnight. The solvent was evaporated in vacuo and the title compound isolated by preparative HPLC.
  • N-acetyl-cysteine (350 mg, 2.14 mmol) was dissolved in DCM (15 mL) then a solution of fumaroyl dichloride (984 mg, 6.43 mmol) in DCM (5 mL) was added dropwise at -78 °C under nitrogen. Pyridine (339 mg, 4.29 mmol) was added and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with 2 mL of water before the solvent was evaporated in vacuo and the title compound isolated by preparative HPLC.
  • NV-344-a (example 17, 3.3 g, 8.1 mmol) and diethylamine (3.0 g, 40.7 mmol) were dissolved in DMF (20 ml) then HATU (6.2 g, 16.3 mmol) was added under ice-water bath and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with water, brine, dried over sodium sulfate. The solvent was evaporated in vacuo and NV-272-a isolated by column chromatography.
  • a and B are independently different or identical and are selected from -O-R', -NHR", - SR'" or -OH, with the proviso that both A and B cannot be H, R', R" and R'" are independently different or identical and selected from the formula (MB) to (IXB) below: O
  • Ri H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, 0-alkyl, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl, CH 2 X-acyl, F, CH 2 COOH, CH 2 C0 2 alkyl or any of the below formulas (a)-(f)
  • Ri H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyl, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl, CH 2 X-acyl, F, CH 2 COOH.
  • R 2 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 ,
  • R 3 R-i, i.e. is the same or different groups as mentioned under Ri
  • 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, 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 formula (IIB), formula (IIBI) or formula (VIIIB)
  • X 5 may also be CONR-
  • R 9 H, Me, Et or 0 2 CCH 2 CH 2 COXR;
  • R- ⁇ 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, benzoylor formula (MB),
  • Rf , Rg and Rh are independently 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.
  • R', R" and R'" are independently different or identical and selected from the formula (MB), (VB), (VIIB) or VIIIB) below:
  • At least one of Ri and R 3 is -H, such that formula II is:
  • p is 1 or 2
  • p is 1
  • X 5 is -H such that formula (VIIB) 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.
  • A is selected from -SR, -OR and NHR, and wherein R is
  • R' is selected from the formula (I IC) to (IXC) below:
  • R' is selected from the formula (IIC), (VC), to (IXC) below:
  • R', R" and R'" are independently different or identical and is selected from formula (IVC-VIIIC) below:
  • Ri H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, O-acyl, O-alkyI, N-acyl, N-alkyl, Xacyl, -acyl, F, CH 2 COOH, CH 2 C0 2 alkyl or any of formulae (a)-(f)
  • R 2 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 ,
  • R 3 R-i, i.e. may be the same or a different group as defined under R-i ,
  • 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 (IIC), formula (NIC) or formula (VI 11 C)
  • X 5 may also be CONR-
  • R 9 H, Me, Et or O2CCH2CH2COXR8
  • R10 Oacyl, NHalkyl, NHacyl, or O2CCH2CH2COX6R8
  • R 8 H, alkyl, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (IIC), formula (NIC) or formula (VI 11 C)
  • R f , R g and R h are independently selected from Xacyl, -CH 2 Xalkyl, -CH 2 X-acyl and R 9 alkyl is e.g. Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl and acyl is e.g. formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl and the likes and wherein the acyls and alkyls may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula
  • At least one of R-i and R 3 is -H, such that formula II is:
  • p is 1 or 2, preferably p is 1 and X 5 is -H such that formula (VI I C) is
  • At least one of R f , R g , R h is -H or alkyl, with alkyl as defined herein.
  • R- ⁇ and X 5 is as defined herein.
  • X 5 is -H.
  • R 6 , X 5 and R-i are as defined herein.
  • X 5 is -H.
  • X 5 is -H.
  • A is selected from -SR, -OR and NHR and R is
  • R' is selected from the formula (II) to (IX) below:
  • 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, O-alkyI, N-acyl, N-alkyl, Xacyl, CH 2 Xalkyl, CH 2 X-acyl, F, CH 2 COOH, CH 2 C0 2 alkyl or any of the below formulae -(f)
  • R 2 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 ,
  • R 3 R-i , i.e. different or identical with the groups mentioned under R-i ,
  • 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 9 H, Me, Et or 0 2 CCH 2 CH 2 COXR 8
  • R-io Oacyl, NHalkyl, NHacyl, or O2CCH2CH2CO X 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 , R g and R h are independently selected from Xacyl, -CH 2 Xalkyl, -CH 2 X-acyl and R 9 alkyl is e.g. Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl and
  • acyl is e.g. formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl and the likes and wherein the acyls or alkyls may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula
  • X4 is selected from -COOH
  • a compound according to embodiment 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.
  • X 5 and Ri is as defined in claim 1 and wherein X 5 is preferably -H
  • X 5 , R-i and R 6 is as defined in embodiment 1 and wherein X 5 is preferably -H.
  • a compound according to any of embodiments 1-10, for use in cosmetics 13.
  • a compound according for use according to embodiment 1 1 wherein the medical use is prevention or treatment of drug-induced mitochondrial side-effects.
  • a compound for use according to embodiment 14, 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 embodiment 13, wherein diseases of mitochondrial dysfunction involve e.g. mitochondrial deficiency such as a Complex I, II, III or IV deficiency or an enzyme deficiency like e.g. pyruvate dehydrogenase deficiency.
  • mitochondrial deficiency such as a Complex I, II, III or IV deficiency or an enzyme deficiency like e.g. pyruvate dehydrogenase deficiency.
  • CCDS Cerebral Creatine Deficiency Syndromes
  • GAT Deficiency L-Arginine:Glycine Amidinotransferase Deficiency
  • 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), C
  • LCAD Long-Chain Acyl-CoA Dehydrogenase Deficiency
  • LCHAD Leigh Disease or Syndrome
  • LHON Leber's hereditary optic neuropathy
  • MCAD Medium-Chain Acyl-CoA
  • 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)
  • 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 embodiments 1 - 10 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 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).
  • the drug substance is used for treatment of a disease for which the drug substance is indicated, and
  • the compound prodrug 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 embodiments 1 -10, 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
  • 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.
  • a second container comprising a compound according to any of embodiments 1 -10, 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 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 embodiments 1 -10 to the subject. 31 .
  • the drug substance is an anti-diabetic substance.
  • A is selected from -SR, -OR and NHR, and R is
  • B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is C C 4 alkyl, branched or straight, preferably B is Me; and R' is selected from the formula (II) to (IX) below:
  • R', R" and R'" are independently different or identical and is selected from formula (IV- 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-alkyl, N-acyl, N-alkyl, Xacyl,
  • B is selected from -O-R', -NHR", -SR'" or -OH; and R' is selected from the formula (II) to (IX) below: 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, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
  • X 7 is selected from R-i , -NR-
  • Rio is selected from Oacyl, NHalkyl, NHacyl, or 0 2 CCH 2 CH 2 COX 6 R8
  • X 6 is selected from O, NR 8 , NR 6 R 8 , wherein R 6 and R 8 are independently different or identical and are 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 R 12 are independently different or identical and are selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, propionyl, benzoyl, -CH 2 Xalkyl, - CH 2 Xacyl, where X is 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, CHzXalkyl; Substituents on R 13 and R 14 or R 13 and R 15 may bridge to form a cyclic system,
  • R f , R g and R h are independently different or identical and are selected from Xacyl, - CH 2 Xalkyl, -CH 2 X-acyl and R 9 , alkyl is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acyl is selected from formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl, acyl and/or alkyl may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula
  • A is selected from -SR, -OR and NHR, and R is
  • B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is C C 4 alkyl, branched or straight, preferably B is Me; and R' is selected from the formula (II) to (IX) below:
  • R', R" and R'" are independently different or identical and is selected from formula (IV- 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, 0-alkyl, N-acyl, N-alkyl, Xacyl,
  • 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 ,
  • R 6 is selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, acyl, propionyl, benzoyl, or formula (II), or formula (VIII)
  • X 7 is selected from R-i , -NR-
  • R 9 is selected from H, Me, Et or O2CCH2CH2COXR 8
  • R-io is selected from Oacyl, NHalkyl, NHacyl, or 0 2 CCH 2 CH 2 COX 6 R 8
  • X 6 is selected from O, NR 8 , NR 6 R 8 , wherein R 6 and R 8 are independently different or identical and are 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),
  • R11 and R12 are independently different or identical and are selected from H, Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl, acetyl, propionyl, benzoyl, -CH 2 Xalkyl, - CH 2 Xacyl, where X is 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;
  • R13 and R14 or R13 and R15 may bridge to form a cyclic system
  • R f , R g and R h are independently different or identical and are selected from Xacyl, - CH 2 Xalkyl, -CH 2 X-acyl and R 9
  • alkyl is selected from Me, Et, propyl, i-propyl, butyl, iso-butyl, t-butyl
  • acyl is selected from formyl, acetyl, propionyl, isopropionyl, byturyl, tert-butyryl, pentanoyl, benzoyl, acyl and/or alkyl may be optionally substituted, and when the dotted bond between A and B is present, the compound according to formula
  • Z is selected from -CH(OH)-CH 2 (OH) and n is 0 (eg derived from glyceric acid); or Z is absent or -CH 2 - and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively);
  • A is selected from -SR, -OR and NHR, and R is
  • B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is C C 4 alkyl, branched or straight, preferably B is Me; and
  • R', R" and R'" are independently different or identical and is selected from one or the formulas below:
  • R- ⁇ and R 3 are independently different or identical and are selected from H, Me, Et, propyl, O-Me, O-Et, O-propyl, when Ri is Me, Et, propyl, butyl, pentyl, hexyl, heptyl, or succinyl, then X 5 , R 15 , R 14 and R 13 cannot all be H;
  • R 6 is selected from H, Me, Et,
  • X 7 is selected from R-i, -NR-
  • Z is selected from -CH(OH)-CH 2 (OH) and n is 0 eg derived from glyceric acid); or Z is absent or -CH 2 - and n is 1 and B is an alkyl group (eg derived from pyruvic acid or acetoacetic acid, respectively);
  • A is selected from -SR, -OR and NHR, and R is
  • B is selected from -O-R', -NHR", -SR'" or -OH, or in case of Formula (IA) B is C C 4 alkyl, branched or straight, preferably B is Me; and
  • R', R" and R'" are independently different or identical and is selected from one or the formulas below:
  • R- ⁇ and R 3 are independently different or identical and are selected from H, Me, Et, propyl, O-Me, O-Et, O-propyl, when Ri is Me, Et, propyl, butyl, pentyl, hexyl, heptyl, or succinyl, then X 5 , R 15 , R 14 and R 13 cannot all be H;
  • R 6 is selected from H, Me, Et,
  • X 7 is selected from R-i, -NR-
  • 20. A compound according for use according to item19, wherein the medical use is prevention or treatment of drug-induced mitochondrial side-effects.
  • 21 . A compound for use according to item 20, 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 20, 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
  • 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)
  • LHON Leber's hereditary optic neuropathy
  • MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
  • MERRF myoclonic epilepsy with ragged red fibers
  • a composition comprising a compound of Formula (I) as defined according any of items 1-16 and one or more pharmaceutically or cosmetically acceptable excipients.
  • 26. A method of treating a subject suffering from diseases of mitochondrial dysfunction or disease related to mitochondrial dysfunction as defined in any of items 23-24, the method comprising administering to the subject an efficient amount of a composition as defined in item 25.
  • 27. A method according to item 26 wherein the composition is administered
  • 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.
  • 31 . A compound according to any of items 1 -16 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). 32.
  • the drug substance is used for treatment of a disease for which the drug substance is indicated, and
  • 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 1-16, 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 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 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.
  • a second container comprising a compound according to any of items 1-16, 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 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 1-16 to the subject.
  • 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-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.
  • the method comprises administering an effective amount of a compound according to any of items 1 -16 to the subject before, during or after treatment with said drug substance.
  • the drug substance is an anti-diabetic substance.

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Abstract

La présente invention concerne de nouveaux métabolites à base d'acide carboxylique perméables aux cellules et des précurseurs de ceux-ci perméables aux cellules visant à augmenter la production d'ATP dans les mitochondries. La majeure partie de l'ATP produit et utilisé dans la cellule eucaryote provient de la phosphorylation oxydative mitochondriale, un processus où des électrons à haute énergie sont fournis par le cycle de Krebs. Tous les intermédiaires du cycle de Krebs ne sont pas facilement perméables à la membrane cellulaire. L'utilisation des nouveaux métabolites à base d'acide carboxylique perméables aux cellules devrait permettre le passage sur la membrane cellulaire et, par conséquent, les métabolites à base d'acide carboxylique perméables aux cellules selon l'invention peuvent être utilisés pour augmenter la production d'ATP mitochondrial.
PCT/EP2016/073955 2015-10-07 2016-10-07 Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées à des dysfonctions mitochondriales WO2017060400A1 (fr)

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