WO2012022467A2 - Nouveaux dérivés de benzoquinone et utilisation de ces dérivés en tant que modulateurs de la fonction mitochondriale - Google Patents

Nouveaux dérivés de benzoquinone et utilisation de ces dérivés en tant que modulateurs de la fonction mitochondriale Download PDF

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WO2012022467A2
WO2012022467A2 PCT/EP2011/004122 EP2011004122W WO2012022467A2 WO 2012022467 A2 WO2012022467 A2 WO 2012022467A2 EP 2011004122 W EP2011004122 W EP 2011004122W WO 2012022467 A2 WO2012022467 A2 WO 2012022467A2
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WO2012022467A3 (fr
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Achim Feurer
Barbara Hoffmann-Enger
Holger Deppe
Michael Soeberdt
Nuri Gueven
Roman Haefeli
Fabrice Heitz
Michael Erb
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Santhera Pharmaceuticals (Schweiz) Ag
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Priority to EP11746182.2A priority Critical patent/EP2606022A2/fr
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Publication of WO2012022467A3 publication Critical patent/WO2012022467A3/fr

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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
    • C07C225/26—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel benzoquinone derivatives.
  • the compounds are efficient as modulators of mitochondrial function and as such are useful for the treatment of pathological conditions where mitochondrial function is impaired.
  • Mitochondria sometimes described as "cellular power plants” because they generate most of the cell's supply of adenosine triphosphate (ATP), are essential to eukaryotic life.
  • mitochondria are also involved in a range of other processes, such as signalling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth.
  • Mitochondria have been implicated in several human diseases, including mitochondrial disorders and cardiac dysfunction and may play a role in the aging process.
  • Mitochondrial disorders are often present as neurological disorders, but can also occur as myopathy, diabetes, multiple endocrinopathy, or a variety of other systemic manifestations. These disorders can be caused by mutations of the mitochondrial DNA, by mutations of nuclear genes directly coding for oxidative phosphorylation enzymes and by defects in nuclear genes that are generally important for mitochondrial function. Environmental influences may also interact with hereditary predispositions and cause mitochondrial diseases. For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease.
  • mitochondrial dysfunction Numerous other pathologies involving mitochondrial dysfunction include schizophrenia, bipolar disorder, autosomal dominant optic atrophy, epilepsy, stroke and autism (Jou et al. Chang Gung Med J. 2009; 32(4):370-9), dementia, Alzheimer's, Parkinson's and Huntington's disease (Yang et al. DNA Repair (Amst). 2008; 7(7): 1110-20), cardiovascular disease (Puddu et al. J Biomed Sci. 2009; 16:112), malignancies (Singh & Kulawiec; Methods Mol Biol. 2009; 471 :291-303), retinitis pigmentosa, metabolic syndrome, anorexia, obesity and diabetes mellitus (Burchell et al. Expert Opin Ther Targets 2010; 14(4):369-85; Pieczenik & Neustadt Exp Mol Pathol. 2007; 83(1):84-92).
  • Multiple sclerosis is the most common non-traumatic neurological disease in young adults, with a prevalence of 1:1000 in Northern Europe and North-America (Compston A Int MS J .2003. 10:29-31).
  • the disease course is generally episodic; exacerbations are followed by periods of remission which are characterized by focal infiltration of leukocytes and demyelination in the white matter.
  • the disease becomes more progressive, where demyelination of the grey matter and axonal degeneration in the white matter become more prominent (Hafler DA J. Clin. Invest. 2004; 113:788-794).
  • Available therapies are mainly immunomodulatory, which are effective in reducing the number of relapses. Disease progression, however, remains unchanged by these therapies (Filippini G et al. Lancet 2003; 361 :545-552.), demonstrating the need for novel therapeutic strategies oriented towards neuroprotection.
  • WO-A-2006130775 describes an attempt to treat or suppress mitochondrial diseases by modulating energy biomarkers such as lactic acid levels, levels of NAD, NADP, NADH and NADPH, and cytochrome C parameters.
  • energy biomarkers such as lactic acid levels, levels of NAD, NADP, NADH and NADPH, and cytochrome C parameters.
  • the compounds disclosed in the application have been tested for their ability to rescue human dermal fibroblasts from FRDA patients from oxidative stress. However, the data are not represented in the application.
  • the present invention relates to benzoquinone derivatives of structural formula (I)
  • R , R 2 , R 3 and R 4 are defined as described below.
  • the benzoquinone derivatives of structural formula (I) are effective as modulators of mitochondrial function and as such are useful for the treatment of pathological conditions where mitochondrial function is impaired. It has been found that the compounds of formula (I) are useful in the treatment of mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome, C0QIO deficiency, or mitochondrial complex deficiencies or neurodegenerative diseases such as Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Strok
  • the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
  • the present invention relates to benzoquinone derivatives which are capable to modulate mitochondrial function.
  • R 1 is a substituent represented by formula (II) Y 1 (X 1 ) a R 5
  • X 1 is -O- or -NR 6 -, wherein R 6 is H or linear or branched d. 6 alkyl;
  • R 5 is selected from the group consisting of
  • a linear or branched C 1-6 alkyl which is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, NH 2 or CN, a 6-10 membered monocylic or bicyclic aryl group, optionally fused with a 5-6 membered heterocyclic or heteroaromatic group, the heterocyclic or heteroaryl group having 1 to 2 heteroatoms in the ring independently selected from N, O or S,
  • a 3-10 membered monocylic, bicylic or tricyclic cycloalkyl group wherein each aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of halogen, hydroxy, linear or branched Ci-6 alkyl, linear or branched halo-Ci. 6 alkyl, Ci_ 6 alkoxy, -C(0)NH 2 , - NHC(0)C 1-6 alkyl, 5-6 membered heteroaryl having in the ring 1 to 3 heteroatoms independently selected from N, O or S,
  • X 1 and R 5 together form a 4-7 membered monocyclic heterocyclic group having 1 or 2 heteroatoms in the ring independently selected from N or S and wherein the heterocycle is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, a hydroxyl group and a Ci -6 alkoxy group;
  • Y 1 is a linear C 8 .i 2 alkylene group or a linear C 8 -12 alkenylene group
  • a is an integer of 0 or 1 ;
  • R 2 is a Ci-6 linear or branched alkyl group
  • R 3 is a Ci-e alkoxy group
  • R 4 is a C 1-6 alkoxy group
  • R 5 is not a 2H-pyrane group
  • R 1 is a substituent represented by formula (III)
  • R 7 and R 8 independently from each other are hydrogen, linear or branched d. 6 alkyl or halogen;
  • R 9 and R 10 independently from each other are hydrogen, linear or branched C 2 . 6 alkenyl or linear or branched C 2- 6 alkinyl;
  • R 9 and R 10 together are -(CH 2 ) X - wherein x is an integer of 2 to 6;
  • Y 2 is a linear C 5 . 9 alkylene group or a linear C 5 . 9 alkenylene group
  • R 2 is a linear or branched C 1-6 alkyl group
  • R 3 is a Ci- 6 alkoxy group
  • R 4 is a Ci -6 alkoxy group
  • R 1 is a substituent represented by formula (IV)
  • each alkyl, aryl, heteroaromatic, heterocyclic and cycloalkyi group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy and Ci -6 alkoxy;
  • 4- 7 membered ring having in the ring 0 to 2 additional heteroatoms independently selected from N, O or S, wherein the ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxyl and C ⁇ alkoxy group;
  • Y 3 is a linear C 6 . 10 alkylene group or a linear C 6-10 alkenylene group
  • R 2 is a linear or branched 0 1-6 alkyl group
  • R 3 is a group
  • R 4 is a Ci. 6 alkoxy group
  • R 1 is hydrogen
  • R 2 is a substituent represented by X 2 -R 13
  • X 2 is selected from the group consisting of -O- and -NR 14 -, wherein R 14 is hydrogen or a d-e alkyl group, and
  • R 13 is a C4-12 alkyl group, C4- 12 alkenyl group, -(CH 2 )nCH 2 OH or -C 2 -1 0 alkenylene-CH 2 OH,
  • n is an integer of 1 to 10
  • X 2 -R 13 represents a piperidino group substituted in the 4-position with a C 2 -7 alkenylene-CH 2 OH group, a -(CH 2 ) m CH 2 OH group wherein m is an integer of 1 to 7, a -C(0)-NH-C 2 - 6 alkenylene-CH 2 OH group or a -C(0)-NH-(CH 2 ) p CH 2 OH group wherein p is an integer of 1 to 6;
  • R 3 is hydrogen; and R 4 is OR 15 ,
  • R 15 is a hydrogen atom or a d. 2 alkyl group
  • R 13 and R 15 independently represent a linear -C 2 - 7 alkenylene-CH 2 OH group or a -(CH 2 ) m CH 2 0H group wherein m is an integer of 1 to 7;
  • Y 4 is a linear C 8 -i 2 alkylene group or a linear C 8 -i 2 alkenylene group
  • R 2 is a linear or branched C 1 .6 alkyl group
  • R 3 is a Ci-e alkoxy group
  • R 4 is a Ci. 6 alkoxy group
  • Y 5 is a linear C 8 .i 2 alkylene group or a linear C 8 -i 2 alkenylene group;
  • R 2 is a linear or branched d-ealkyl group;
  • R 3 is a hydroxy group or a Ci. 6 alkoxy group
  • R 4 is a Ci-ealkoxy group
  • Y 6 is a linear C 6 -io alkylene group or a linear C 6 -io alkenylene group
  • R 2 is a linear or branched Ci. 6 alkyl group
  • R 3 is a d. 6 alkoxy group; and R 4 is a Ci. 6 alkoxy group.
  • R 1 has the formula (II);
  • a 1 ;
  • X 1 is an oxygen atom
  • R 5 is selected from the group consisting of a 6 membered heteroaryl group having 1 to 2 nitrogen atom(s) in the ring and a phenyl group wherein the heteroaryl and the phenyl group are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, linear or branched C 1-6 alkyl, linear or branched halo On alkyl, C 1-6 alkoxy, -C(0)NH 2 , alkyl, 5-6 membered heteroaryl having in the ring 1 to 3 heteroatoms independently selected from N, O or S, and hydroxy.
  • R 1 has the formula (II);
  • a 1 ;
  • X 1 is a nitrogen atom (i.e., -NR 6 -);
  • R 5 is selected from the group consisting of
  • heteroaryl group, the phenyl group and the adamantly group are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, linear or branched Ci -6 alkyl, linear or branched halo Ci -6 alkyl, d. 6 alkoxy, -C(0)NH 2 , -NHCiO ⁇ -e alkyl, 5-6 membered heteroaryl having in the ring 1 to 3 heteroatoms independently selected from N, O or S, and hydroxy or
  • X 1 and R 5 together form a 4-7 membered monocyclic heterocyclic group having 1 or 2 heteroatoms in the ring independently selected from N or S and whereby the heterocycle is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, a hydroxyl group and a Ci. 6 alkoxy group.
  • R 1 has the formula (II);
  • a 0;
  • R 5 is a 5-10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaryl group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, linear or branched 0 1-6 alkyl, linear or branched halo C 1-6 alkyl, d -6 alkoxy, - C(0)NH 2 , -NHC(0)Ci-6 alkyl, 5-6 membered heteroaryl having in the ring 1 to 3 heteroatoms independently selected from N, O or S, and hydroxy.
  • R 1 is hydrogen
  • R 2 is X 2 -R 13 wherein X 2 is -NR 14 wherein R 4 is hydrogen or a d-e alkyl group, and R 13 is a linear C 4-12 alkyl group, or -(CH 2 ) n CH 2 OH wherein n is an integer of 1 to 10, or
  • X 2 -R 13 represents a piperidino group substituted in the 4-position with a - (CH 2 ) m CH 2 OH group wherein m is an integer of 1 to 7 or a -C(0)-NH-(CH 2 ) p CH 2 OH group wherein p is an integer of 1 to 6;
  • R 3 is hydrogen
  • R 4 is -O-R 15 wherein R 15 is hydrogen or C -2 alkyl.
  • R 1 is represented by formula (II).
  • R has the formula (II);
  • X 1 is -O- or -NR 6 -, wherein R 6 is H or linear or branched Ci -6 alkyl;
  • R 5 is selected from the group consisting of
  • a linear or branched d -6 alkyl which is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, NH 2 or CN, a 6-10 membered monocylic or bicyclic aryl group, optionally fused with a 5-6 membered heterocyclic or heteroaromatic group, the heterocyclic or heteroaryl group having 1 to 2 heteroatoms in the ring independently selected from N, O or S,
  • X 1 and R 5 together form a 4-7 membered monocyclic heterocyclic group having 1 or 2 heteroatoms in the ring independently selected from N or S and wherein the heterocycle is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, a hydroxyl group and a Ci. 6 alkoxy group;
  • Y 1 is a linear C 8- 12 alkylene group or a linear C 8 .12 alkenylene group
  • a is an integer of 0 or 1 ;
  • R 2 is a C 1-6 linear or branched alkyl group;
  • R 3 is a d-ealkoxy group
  • R 4 is a group
  • R 5 is not a 2H-pyrane group.
  • R 1 has the formula (II);
  • R 5 is not a linear or branched Ci. 6 alkyl which is substituted with one substituent OH, or a phenyl or C 3 . 7 cylcoalkyl, wherein the phenyl or C 3 . 7 cylcoalkyl is substituted with one substituent OH or with one substituent C 1-4 alkoxy.
  • Y 1 is a linear C 8 -i 2 alkylene group or a linear C 8 -i 2 alkenylene group. In a preferred embodiment in combination with any of the above or below embodiments, Y 1 represents a linear C 8 . 12 alkylene group, more preferably a linear C 10 alkylene group.
  • index a represents an integer selected from the values 0 and 1.
  • the index a assumes the value 0. If a is 0, it is preferred that R 5 represents a 5-10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 heteroatoms in the ring(s) independently selected from N, O or S, wherein the monocyclic heteroaryl group and one or both rings of the bicylic heteroaryl group is unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of halogen, linear or branched C 1 .6 alkyl, linear or branched halo-Ci -6 alkyl, C1.6 alkoxy, -C(0)NH 2 , -NHC(0)Ci.
  • R 5 is a 9-10 membered, more preferably a 9 membered bicyclic heteroaryi group having 1 to 4 heteroatoms in the ring(s) independently selected from N, O or S, wherein the heteroaryi group is unsubstituted or substituted with 1 to 3 Ci -6 alkyl groups.
  • the index a assumes the value 1.
  • X 1 represents -O- or -NR 6 - wherein R 6 is H or linear or branched C 1-6 alkyl, more preferably H or CH 3 .
  • X 1 is - 0-
  • R 5 is a 5-10 membered monocyclic or bicyclic heteroaryi group having 1 to 4 heteroatoms in the ring(s) independently selected from N, O or S, wherein the monocyclic heteroaryi group and one or both rings of the bicylic heteroaryi group is unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of halogen, hydroxy, linear or branched d-e alkyl, linear or branched halo-Ci. 6 alky Ci. 6 alkoxy, -C(0)NH 2 , - NHCiOJCi-e alkyl, 5-6 membered heteroaryi having in the ring 1 to 3 heteroatoms independently selected from N, O or S.
  • X 1 is -0-
  • R 5 is a 6-10 membered monocyclic or bicyclic aryl group which may be optionally fused with a 5-6 membered heterocylic or heteroaromatic group, wherein the heterocyclic or heteroaromatic group have 1 to 2 heteroatoms in the ring independently selected from N, O or S.
  • the aryl, the heterocyclic and the heteroaryi group are unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of halogen, hydroxy, linear or branched C1.6 alkyl, linear or branched halo-C 1-6 alkyl, C ⁇ alkoxy, -C(0)NH 2 , - ⁇ (0)0 1-6 alkyl, 5-6 membered heteroaryi having in the ring 1 to 3 heteroatoms independently selected from N, O or S. More preferably, R 5 is a phenyl group which is unsubstituted or substituted with 1 to 3 substituents independently selected from - C(0)NH 2 , halogen, -NHC(0)Ci.
  • 5-6 membered heteroaryi having in the ring 1 to 3 heteroatoms independently selected from N, O or S. More preferably said 5-6 membered heteroaryi group is a 5 membered heteroaryi group having in the ring 1 to 3, preferably 2 to 3 nitrogen atoms.
  • R 5 is preferably a 6-10 membered monocylic or bicyclic aryl group, optionally fused with a 5-6 membered heterocyclic or heteroaromatic group, the heterocyclic or heteroaromatic group having 1 to 2 heteroatoms in the ring independently selected from N, O or S; or a 5-10 membered monocyclic or bicyclic heteroaromatic group having 1 to 4 heteroatoms independently selected from N, O or; or a 5-7 membered monocyclic heterocyclic group having 1 to 4 heteroatoms in the ring independently selected from N, O or S, or a 3-10 membered monocylic, bicylic or tricyclic cycloalkyi group, wherein each aryl, heteroaryl, heterocyclyl and cycloalkyi is unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of hal
  • X 1 is -NR 6 -
  • R 5 is preferably a 5-10 membered monocyclic or bicyclic heteroaromatic group having 1 to 4 heteroatoms in the ring(s) independently selected from N, O or S, wherein the monocyclic heteroaryl group and one or both rings of the bicylic heteroaromatic group is unsubstituted or substituted with 1 to 5 substituents independently from each other selected from the group consisting of halogen, hydroxy, linear or branched C 1-6 alkyl, linear or branched halo-C -6 alkyl, Ci-6 alkoxy, -C(0)NH 2 , -NHCiOJC ⁇ alkyl, 5-6 membered heteroaryl having in the ring 1 to 3 heteroatoms independently selected from N, O or S.
  • R 1 is represented by formula (III).
  • R 1 has the formula (III);
  • R 2 when R 2 is methyl, R 3 is methoxy, R 4 is methoxy, Y 2 is a linear C 5 . 9 alkylene group, R 7 is hydrogen and R 8 is hydrogen,
  • Y 2 is a linear C 5-9 alkylene group or a linear C 5 . 9 alkenylene group.
  • Y 1 represents a linear C5-9 alkylene group, more preferably a linear C 7 alkylene group.
  • R 7 and R 8 both represent hydrogen
  • R 9 represents hydrogen
  • R 10 represents a C 2 -6 alkinyl group, more preferably a C 2 alkinyl group, or R 9 and R 10 together form a -CH 2 -CH 2 - bridge.
  • R 1 is represented by formula (IV).
  • Y 3 is a linear C 6- i 0 alkylene group or a linear C 6- io alkenylene group. In a preferred embodiment in combination with any of the above or below embodiments, Y 3 represents a linear C 6 -io alkylene group, more preferably a linear C 8 alkylene group.
  • R 1 and R 2 independently from each other represent hydrogen, linear or branched C1.6 alkyl, a 4-10 membered monocylic heterocyclic group having 1 to 4 heteroatoms in the ring independently selected from N, O or S, wherein each alkyl and heterocyclic group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, hydroxy and C 1 -6 alkoxy, or R 1 and R 12 together with the nitrogen atom to which they are attached form a 4-7 membered ring having in the ring 0 to 2 additional heteroatoms independently selected from N, O or S, wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C1.6 alkoxy group.
  • one of R 1 and R 1 represents a hydrogen and the other represents a linear or branched C 1 -6 alkyl, a 4-10 membered monocylic heterocyclic group having 1 to 4 heteroatoms in the ring independently selected from N, O or S, wherein each alkyl and heterocyclic group is unsubstituted or substituted with 1 to 5 substituents as defined above, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 4-7 membered ring having in the ring 0 to 2 additional heteroatoms independently selected from N, O or S, wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and Ci.
  • R 1 and R 3 represent hydrogen
  • R 2 represents X -R 13 , wherein X 2 and R 13 are defined as above
  • R 4 represents OR 15 , wherein R 15 is defined as above.
  • X 2 represents -NR 14 - wherein R 14 is defined as above.
  • R 13 represents a C 4- i 2 alkyl group or -(CH 2 ) n CH 2 OH wherein n is an integer of 1 to 10.
  • X 2 and R 3 combine to represent a piperidino group substituted in the 4-position with a - (CH 2 ) m CH 2 OH group wherein m is an integer of 1 to 7 or a -C(0)-NH-(CH 2 ) p CH 2 OH group wherein p is an integer of 1 to 6;
  • Y 4 is preferably a C 8 alkylene group.
  • Alkyl is a straight chain or branched alkyl having preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl.
  • Alkenyl is a straight chain or branched alkyl having preferably 2, 3, 4, 5, 6 carbon atoms and which contains at least one carbon-carbon double bond, preferably one or two double bonds, most preferably one double bound.
  • Preferred examples of a C 2 - 6 alkenyl group are ethenyl, prop-
  • More preferred examples of an alkenyl group are ethenyl and prop-1-enyl.
  • the alkenyl group is exclusively a linear alkenyl group.
  • preferred examples of an alkenyl group have 5 to 12 carbon atoms and at least one double bond up to three double bonds depending on the length of the carbon chain. Generally, the double bonds occur in an isolated or a conjugated order.
  • Alkinyl is a straight chain or branched alkyl having preferably 2, 3, 4, 5, or 6 carbon atoms and which contains at least one carbon-carbon triple bond, preferably one or two triple bonds, most preferably one triple bond.
  • Preferred examples of a C 2 -6 alkinyl group are ethinyl, prop-1-inyl, prop-2-inyl, n-but-1-inyl, n-but-2-inyl, n-but-3-inyl, n-pent-1-inyl, n-pent-2-inyl, n-pent-3-inyl, n- pent-4-inyl, n-pent-1 ,3-inyl, isopent-1-inyl, neopent-1-inyl, n-hex-1-inyl, n-hex-2-inyl, n-hex-3-inyl, n-hex-4-inyl, n-hex-5-
  • alkyl alkenyl and alkinyl equally apply to the groups alkylene, alkenylene and alkinylene used throughout the invention.
  • Cycloalkyl is one, two or three alkyl rings having preferably 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms at the most.
  • Preferred monocyclic examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, more preferably cyclopropyl and cyclopentyl.
  • Preferred bicyclic examples include decalinyl.
  • Preferred tricyclic examples include adamantyl.
  • Heteroaryl is an aromatic moiety having in the ring at least one heteroatom independently selected from O, N or S.
  • the heteroaryl group may be monocylic or bicyclic.
  • Heteroaryl is preferably selected from thienyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4- triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl 1 ,2,5-oxadiazolyl 1 ,3,4-oxadiazolyl indazolyl, quinolinyl, isquinolinyl, cinnolinyl, quinoxalin
  • Heterocyclyl is a saturated or partially unsaturated ring containing at least one heteroatom independently selected from O, N or S.
  • Preferred examples include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, 1 ,4-dioxanyl, more preferred examples include piperidinyl, piperazinyl and pyrrolidinyl.
  • Aryl is either a phenyl or a naphthalin group.
  • Halogen is a halogen atom selected from F, CI, Br and I, preferably from F, CI and Br. Salts
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, furnaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, parnoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic acid and the like.
  • the compounds of formula (I) are preferably formulated into a dosage form prior to administration. Accordingly the present invention also includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a suitable pharmaceutical carrier.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • Suitable administration routes include oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the administration route is oral.
  • the administration route is topical ocular. In another preferred embodiment in combination with any of the above or below embodiments, the administration route is an intraocular injection.
  • the administration route is an intraocular depot implant.
  • 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. All methods include the step of bringing into association a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") 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 into the desired formulation.
  • Formulations of 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.
  • the active ingredient may further be presented 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.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, 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 binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding 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. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds of the present invention may be formulated for parenteral administration by injection, e.g. as intraocular, intraveneous, subcutaneous, intramuscular, or intraarterial injection.
  • the injection may be administered by bolus injection or continuous infusion.
  • the injection may be administered
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example intraocular or subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Compounds of the present invention may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the amount of compound of formula (I) will generally be in the range of 0.001 to 10% weight/volume (%w/v). Preferred concentrations range from 0.1 to 5 %w/v.
  • Topical administration to the eye is given one to six times per day.
  • a typical formulation contains 0.1 - 5 % of compound of formula (I), 0.5 %w/v hydroxypropylmethylcellulose (HMPC), 0.8 %w/v sodium chloride, 0.28 %w/v sodium phosphate, 0.01 %w/v edetate disodium, 0.01 %w/v benzalkonium chloride. The pH is adjusted to 7.2 - 7.4. Purified water is added q.s.
  • Gels for topical or transdermal administration of compounds of the subject invention may comprise a mixture of volatile solvents, nonvolatile solvents, and water.
  • the volatile solvent component of the buffered solvent system may preferably include lower (CVCe) alkyl alcohols, lower alkyl glycols and lower glycol polymers. More preferably, the volatile solvent is ethanol.
  • the volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates.
  • the nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used.
  • the nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system.
  • the amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the non-volatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess will result in a lack of bioavailability due to poor release of drug from solvent mixture.
  • the buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; preferably, water is used.
  • Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or nonaqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil, wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatine and glycerin or sucrose and acacia.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder such as lactose or starch.
  • the powder composition may be presented in unit form, in for example, capsules, cartridges, gelatine or blister packs from which the powder may be with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited or an appropriate fraction thereof, of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of the present invention may be administered via any route discussed above at a dose range for adult humans which is generally from 0.01 mg/kg/day to 60 mg/kg/day, more preferably from 0.01 mg/kg/day to 30 mg/kg day, most preferably from 0.01 mg/kg/day to 15 mg/kg/day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds of the subject invention can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated.
  • the route of administration may vary depending on the condition and its severity.
  • the compounds according to formula (I) are for use in the treatment of a mitochondrial disease, a neurodegenerative disease, a neuromuscular disease, psychiatric disorders, metabolic disorders, cancer, or immune dysfunction.
  • the compounds according to formula (I) are for use in the treatment of a mitochondrial disease.
  • the compounds of the present invention are modulators of mitochondrial function and as such are useful for the treatment of pathological conditions where mitochondrial function is impaired.
  • Mitochondria are e.g. critical for ocular function as they represent the major source of a cell's supply of energy and play an important role in cell differentiation and survival. Furthermore, the eye is one of the tissues with the highest energy consuption in the body (REF).
  • Ocular mitochondrial dysfunction can occur as a result of inherited mitochondrial syndromes and mutations, such as Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (DOA, mutations in OPA1) dominant optic atrophy with cataracts (mutations in OPA3), vitelliform macular dystrophy (VD), Jensen syndrome, optic atrophy of Leigh and Leigh-like syndrome, maculopathy of neuropathy-ataxia-retinitis-pigmentosa (NARP), retinopathy of mitochondrial- encephalomyopathy-lactic-acidosis-stroke (MELAS), chronic progressive external ophthalmoplegia (CPEO) and optic atrophy caused by mutations in the ND3 subunit of complex 1 (MTND3), which are also associated with migraine and encephalopathy.
  • LHON Leber's hereditary optic neuropathy
  • DOA dominant optic atrophy
  • OPA1 dominant optic atrophy with cataracts
  • VD vitelliform macular dystrophy
  • VD
  • mitochondrial haplogroups Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM. Arch Ophthalmol. 2007 Sep; 125(9): 1235-40
  • certain mitochondrial gene variants were implicated in an elevated risk of developing ophtalmological pathologies (Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A. Proc Natl Acad Sci U S A.
  • mitochondrial dysfunction whether inherited or aquired is considered one of the main molecular pathologies involved in the initiation of ocular disorders (such as macular degeneration, glaucoma, retinopathy and cataracts) (reviewed by Jarrett SG, Lewin AS, Boulton ME. Ophthalmic Res. 2010;44(3): 179-90; Brennan LA, Kantorow M. Exp Eye Res. 2009 Feb;88(2): 195-203).
  • AMD age-related macular degeneration
  • VD inherited macular degeneration
  • AMD a medical condition which results in a loss of vision in the center of the visual field (the macula) because of damage to the retina.
  • Glaucoma is a disease in which the optic nerve is damaged, leading to progressive, irreversible loss of vision, which is often, but not always, associated with increased pressure of the fluid in the eye.
  • the nerve damage involves loss of retinal ganglion cells in a characteristic pattern.
  • Raised intraocular pressure is a significant risk factor for developing glaucoma. Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss, which can progress to blindness.
  • Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye.
  • spontaneous forms can be induced by drugs, toxins and radiation (ionizing and ultra violet).
  • retinopathies are ocular manifestations of systemic diseases such as diabetes, hypertension, sickle cell disease or ciliopathy such as Bardet-Biedl syndrome. Similar to macular degeneration and glaucoma, mitochondrial involvement in retinopathy has been well described (reviewed by Jarrett SG, Lewin AS, Boulton ME. Ophthalmic Res.
  • a cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light.
  • the gradual yellowing and opacification of the lens may reduce the perception of blue colours.
  • Cataracts typically progress slowly to cause vision loss and are potentially blinding if untreated.
  • the condition usually affects both the eyes, but similar to the pathology of LHON and VD, one eye is almost always affected earlier than the other.
  • mitochondrial involvement in cataract formation is clearly described.
  • cataract formation is directly associated with some mitochondrial disorders such as dominant optic atrophy with cataracts, autosomal dominant progressive external ophthalmoplegia (PEOA3), PEOA2, mitochondrial myopathy caused by mutations of COX II or various others genes, Sengers syndrome, as well as mutations of mitochondrial genes such as mitochondrial tRNA-Ser (MTTS2), GFER, OPA3 but also large mitochondrial deletions.
  • mitochondrial disorders such as dominant optic atrophy with cataracts, autosomal dominant progressive external ophthalmoplegia (PEOA3), PEOA2, mitochondrial myopathy caused by mutations of COX II or various others genes, Sengers syndrome, as well as mutations of mitochondrial genes such as mitochondrial tRNA-Ser (MTTS2), GFER, OPA3 but also large mitochondrial deletions.
  • Optic disc drusen or optic nerve head drusen (ONHD) are globules of mucoproteins and mucopolysaccharides that progressively calcify in the optic disc. They are thought to be the remnants of the axonal transport system of degenerated retinal ganglion cells. ODD have also been referred to as congenitally elevated or anomalous discs, pseudopapilledema, pseudoneuritis, buried disc drusen, and disc hyaline bodies. They are associated with vision loss of varying degree occasionally resulting in blindness. Mitochondrial impairment due to Ca 2+ overload has been suggested in the process of drusen formation (Tso MO. Ophthalmology.
  • haplotype J mitochondrial haplotype J
  • haplotype H was associated with significantly lower risk
  • Chrysostomou et al. (Chrysostomou V, Trounce IA, Crowston JG. Ophthalmic Res. 2010;44(3): 173-8) suggested that mitochondrial dysfunction, inherited or as a cause or consequence of injury, renders ocular cells (in particular retinal ganglion cells) sensitive to degeneration.
  • Therapeutic approaches that target mitochondria should therefore provide a general means of protecting lens and retinal ganglion cells from degeneration, regardless of the etiology of the disease.
  • a further indication which can be allocated as mitochondrial disease is autosomal dominant optic atrophy (DOA).
  • DOA autosomal dominant optic atrophy
  • Pathogenic OPA1 mutations cause autosomal dominant optic atrophy, a condition characterized by the preferential loss of retinal ganglion cells and progressive optic nerve degeneration.
  • OPA1 was demonstrated to control both mitochondrial fusion and cristae morphology.
  • OPA1 loss-of-function studies have shown that OPA1 also regulates apoptosis induction (Liesa M et al. Physiol Rev. 2009; 89:799-845). Although it is expressed in all the tissues assayed, OPA1 shows a specific tissue expression pattern, with the highest expression in the retina, brain, testis, liver, heart, skeletal muscle, and pancreas.
  • Loss of OPA1 causes a marked reduction in mitochondrial membrane potential and a reduction in basal respiration and incapacity to enhance oxygen consumption in the presence of the uncoupler 2,4-dinitrophenol.
  • Human fibroblasts from patients with certain OPA1 mutations (that cause autosomal dominant optic atrophy or ADOA), in addition to decreased rates of mitochondrial fusion, also show impaired ATP synthesis driven by complex I substrates. Due to their ability to enhance ATP synthesis the compounds of the present invention are useful in the treatment of DOA.
  • the compounds of the present invention are suitable for use in the treatment of ophthalmological mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), and ophtalmological disorders displaying mitochondrial dysfunction such as macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD).
  • LHON Leber's hereditary optic neuropathy
  • DOA autosomal dominant optic atrophy
  • ODD optic disc drusen
  • the compounds of the present invention are also suitable for use in the treatment of genetic neurodegenerative mitochondrial diseases with an ophthalmological component among the various symptoms such as MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms), MERFF (myoclonic epilepsy with ragged red fibers), MNGIE (myoneurogenic gastrointestinal encephalomyopathy), Kearns-Sayre syndrome, CoQ10 deficiency, or mitochondrial complex deficiencies (i.e. complex I, II, III, IV, V deficiency, and CPEO).
  • MELAS mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms
  • MERFF myoclonic epilepsy with ragged red fibers
  • MNGIE myoneurogenic gastrointestinal encephalomyopathy
  • Kearns-Sayre syndrome i.e. complex I, II, III, IV, V deficiency, and CPEO.
  • the following diseases are designated as a "mitochondrial disease”: Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome, CoQ.10 deficiency, and mitochondrial complex deficiencies (1-5, CPEO).
  • LHON Leber's hereditary optic neuropathy
  • DOA autosomal dominant optic atrophy
  • macular degeneration glaucoma
  • ODD optic disc drusen
  • mitochondrial myopathy encephalomyopathy
  • lactic acidosis lactic acidosis
  • MELAS myoclonic epilepsy with ragged red fibers
  • the compounds according to formula (I) are modulators of mitochondrial disorders and are thus useful in the treatment of mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome, CoQ10 deficiency, or mitochondrial complex deficiencies.
  • mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (ME
  • the compounds according to formula (I) are for use in the treatment of a mitochondrial disease selected from Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome, CoQ10 deficiency, or mitochondrial complex deficiencies (1-5, CPEO).
  • a mitochondrial disease selected from Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms
  • the compounds according to formula (I) are for use in the treatment of a mitochondrial disease selected from Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), or mitochondrial complex deficiencies (1-5, CPEO).
  • a mitochondrial disease selected from Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma, mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), or mitochondrial complex deficiencies (1-5, CPEO).
  • the compounds according to formula (I) are for use in the treatment of a Leber's hereditary optic neuropathy (LHON).
  • LHON Leber's hereditary optic neuropathy
  • the compounds according to formula (I) are for use in the treatment of autosomal dominant optic atrophy (DOA). In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of macular degeneration.
  • DOA autosomal dominant optic atrophy
  • the compounds according to formula (I) are for use in the treatment of glaucoma.
  • the compounds according to formula (I) are for use in the treatment of retinopathy.
  • the compounds according to formula (I) are for use in the treatment of cataract.
  • the compounds according to formula (I) are for use in the treatment of optic disc drusen (ODD).
  • the compounds according to formula (I) are for use in the treatment of mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS).
  • the compounds according to formula (I) are for use in the treatment of myoclonic epilepsy with ragged red fibers (MERRF).
  • the compounds according to formula (I) are for use in the treatment of myoneurogenic gastrointestinal encephalomyopathy (MNGIE).
  • MNGIE myoneurogenic gastrointestinal encephalomyopathy
  • the compounds according to formula (I) are for use in the treatment of Keams-Sayre syndrome.
  • the compounds according to formula (I) are for use in the treatment of CoQ10 deficiency. In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of mitochondrial complex deficiencies (1 -5, CPEO).
  • the compounds according to formula (I) are for use in the treatment of a neurodegenerative disease.
  • the compounds of formula (I) can further be used to treat neurodegenerative diseases such as FRDA, ALS, Parkinson's disease, Alzheimer's disease, Huntington's disease, Stroke/Reperfusion Injury, or Dementia. Also associated with mitochondrial dysfunction are neuromuscular diseases such as DMD, BMD, LGMD, XLDCM, PKAN, SMA, Kugelberg- Welander disease, or Werdnig-Hoffmann disease which accordingly are also be treatable by using the compounds of formula (I).
  • neurodegenerative diseases such as FRDA, ALS, Parkinson's disease, Alzheimer's disease, Huntington's disease, Stroke/Reperfusion Injury, or Dementia.
  • neuromuscular diseases such as DMD, BMD, LGMD, XLDCM, PKAN, SMA, Kugelberg- Welander disease, or Werdnig-Hoffmann disease which accordingly are also be treatable by using the compounds of formula (I).
  • the compounds according to formula (I) are for use in the treatment of a neurodegenerative disease selected from Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke/reperfusion injury, or dementia.
  • FRDA Friedreich's ataxia
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease Alzheimer's disease
  • Huntington's disease Huntington's disease
  • stroke/reperfusion injury or dementia.
  • the compounds according to formula (I) are for use in the treatment of Friedreich's ataxia (FRDA).
  • FRDA Friedreich's ataxia
  • the compounds according to formula (I) are for use in the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the compounds according to formula (I) are for use in the treatment of Parkinson's disease.
  • the compounds according to formula (I) are for use in the treatment of Alzheimer's disease.
  • the compounds according to formula (I) are for use in the treatment of Huntington's disease. In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of stroke/reperfusion injury.
  • the compounds according to formula (I) are for use in the treatment of dementia.
  • the compounds according to formula (I) are for use in the treatment of a neuromuscular disease.
  • the compounds according to formula (I) are for use in the treatment of a neuromuscular disease selected from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Limb- Girdle muscular dystrophy (LGMD), X-linked dilated cardiomyopathy (XLDCM), Pantothenate kinase-associated neurodegeneration (PKAN), spinal muscular atrophy (SMA), multiple sclerosis and primary progressive multiple sclerosis (PP-MS), Kugelberg-Welander disease, and Werdnig- Hoffmann disease.
  • a neuromuscular disease selected from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Limb- Girdle muscular dystrophy (LGMD), X-linked dilated cardiomyopathy (XLDCM), Pantothenate kinase-associated neurodegeneration (PKAN), spinal muscular atrophy (SMA), multiple sclerosis and primary progressive multiple sclerosis (PP-MS), Kugelberg-Welander disease, and Werdnig- Hoffmann disease
  • the compounds according to formula (I) are for use in the treatment of Duchenne muscular dystrophy (DMD).
  • DMD Duchenne muscular dystrophy
  • the compounds according to formula (I) are for use in the treatment of Becker muscular dystrophy (BMD).
  • the compounds according to formula (I) are for use in the treatment of Limb-Girdle muscular dystrophy (LGMD).
  • LGMD Limb-Girdle muscular dystrophy
  • the compounds according to formula (I) are for use in the treatment of X-linked dilated cardiomyopathy (XLDCM). In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of Pantothenate kinase- associated neurodegeneration (PKAN).
  • XLDCM X-linked dilated cardiomyopathy
  • PKAN Pantothenate kinase- associated neurodegeneration
  • the compounds according to formula (I) are for use in the treatment of spinal muscular atrophy (SMA).
  • the compounds according to formula (I) are for use in the treatment of multiple sclerosis.
  • the compounds according to formula (I) are for use in the treatment of primary progressive multiple sclerosis (PP-MS).
  • PP-MS primary progressive multiple sclerosis
  • the compounds according to formula (I) are for use in the treatment of Kugelberg-Welander disease.
  • the compounds according to formula (I) are for use in the treatment of Werdnig-Hoffmann disease.
  • RR-MS relapsing-remitting form of the disease
  • PP-MS primary progressive MS
  • PP-MS Primary progressive MS
  • RR-MS patients differ from RR-MS patients in several important characteristics: They tend to be older at the time of disease onset (mean 40 vs. 30 years); males and females tend to be affected equally; clinically there is a high prevalence of cortico-spinal dysfunction characterized by progressive weakness and spasticity; patients have more prominent involvement of the spinal cord and generally lower amount of distinct white matter lesions (i.e. plaques) in the brain and less evidence for brain inflammatory activity and, most importantly, PP-MS patients do not respond to immunomodulatory therapies with proven efficacy in RR-MS. Both new imaging modalities and pathological data suggest that in PP-MS, CNS pathology is more diffuse and occurs to some extent independently of focal lesions.
  • the compounds according to formula (I) are for use in the treatment of psychiatric disorders.
  • the compounds according to formula (I) are for use in the treatment of a psychiatric disorder selected from schizophrenia, major depressive disorder, bipolar disorder, or epilepsy.
  • the compounds according to formula (I) are for use in the treatment of schizophrenia. In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of major depressive disorder.
  • the compounds according to formula (I) are for use in the treatment of bipolar disorder.
  • the compounds according to formula (I) are for use in the treatment of epilepsy.
  • mitochondrial dysfunction has also been intimately linked to epilepsy [reviewed by Waldbaum S, Patel M Epilepsy Res. 2009 Oct 20 and Kudin AP, Zsurka G, Elger CE, Kunz WS Exp Neurol. 2009 Aug;218(2):326-32]. Therefore, the compounds of formula (I) are useful in the treatment of schizophrenia, major depressive disorder, bipolar disorder and epilepsy.
  • the compounds according to formula (I) are for use in the treatment of metabolic disorders.
  • the compounds according to formula (I) are for use in the treatment of a metabolic disorder selected from ageing-related physical decline, obesity, overweight, type II diabetes, or metabolic syndrome. In a preferred embodiment in combination with any of the above or below embodiments, the compounds according to formula (I) are for use in the treatment of ageing-related physical decline.
  • the compounds according to formula (I) are for use in the treatment of obesity.
  • the compounds according to formula (I) are for use in the treatment of overweight.
  • the compounds according to formula (I) are for use in the treatment of type II diabetes.
  • the compounds according to formula (I) are for use in the treatment of metabolic syndrome.
  • the compounds of the present invention show a beneficial effect in diabetes type II, obesity and metabolic syndrome.
  • the compounds according to formula (I) are for use in the treatment of cancer.
  • White modulators of mitochondrial function have been suggested as anti-cancer agents mainly via an apoptosis-inducing function, recent data also links the metastatic potential of tumours directly to mitochondrial DNA and mitochondrial radical production [reviewed by Ishikawa K, Koshikawa N, Takenaga K, Nakada K, Hayashi J Mitochondrion. 2008; 8(4): 339-44]. Therefore, modulating mitochondria in this context could not only be employed as anti-cancer strategy but also to prevent metastasis of malignancies which makes the compounds according to formula (I) useful as cancer therapeutics.
  • the compounds according to formula (I) are for use in the treatment of immune dysfunction.
  • the compounds according to formula (I) are for use in the treatment of an immune dysfunction selected from arthritis, psoriasis or rheumatoid arthritis.
  • the compounds according to formula (I) are for use in the treatment of arthritis.
  • the compounds according to formula (I) are for use in the treatment of psoriasis.
  • the compounds according to formula (I) are for use in the treatment of rheumatoid arthritis.
  • Altered mitochondrial metabolism is also linked to multiple dysfunctions of the immune system.
  • reduced expression of mitochondrial respiratory chain genes was observed [Ishikawa S, Mima T, Aoki C, Yoshio- Hoshino N, Adachi Y, Imagawa T, Mori M, Tomiita M, Iwata N, Murata T, Miyoshi M, Takei S, Aihara Y, Yokota S, Matsubara K, Nishimoto N Ann Rheum Dis. 2009;68(2):264-72].
  • Oxidative stress and mitochondrial pathology has been reported to be associated with sepsis [Victor VM, Espulgues JV, Hernandez-Mijares A, Rocha M Infect Disord Drug Targets. 2009;9(4):376-89]. Furthermore, targeting mitochondrial function has been suggested as treatment strategy for several autoimmune disorders such as arthritis and psoriasis [J.J. Bednarski, R.E. Warner, T. Rao, F. Leonetti, R. Yung, B.C. Richardson, K.J. Johnson, J.A. Ellman, A.W. Opipari Jr., and G.D.
  • idebenone can be reacted with optionally substituted alcohols in the presence of two reagents such as PPh 3 and DEAD in an appropriate solvent such as THF to form the corresponding ether.
  • R in Reaction Scheme 1 is defined based on the corresponding moiety in the compounds of Examples 1 to 24.
  • idebenone can be reacted with a reagent such as Dess Martin reagent in an appropriate solvent such as DCM.
  • a reagent such as Dess Martin reagent in an appropriate solvent such as DCM.
  • the corresponding aldehyde can be reductively aminated.
  • Reaction with an optionally substituted amine in the presence of a reagent like sodium cyano borohydride in appropriate solvents such as MeOH and AcOH yields the target compounds.
  • R1 and R2 in Reaction Scheme 2 are defined like the corresponding moieties in the compounds of Examples 25 to 34.
  • a benzoquinone aldehyde can be reduced with a Grignard reagent in a solvent such as THF to give the corresponding substituted benzoquinone alcohol.
  • a hydroquinone methyl ester may be subjected to a Grignard reaction to yield the corresponding alcohol.
  • R in Reaction Scheme 3 is defined as in the corresponding moieties of Examples 35 and 36.
  • a benzoquinone methyl ester is subjected to a Kulinkovich reaction as shown in Reaction Scheme 4.
  • the benzoquinone methyl ester is reacted with Grignard reagent Et-MgBr in the presence of Ti(OiPr) 4 in a solvent such as THF to yield the desired compound.
  • a hydroquinone may be oxidised with a salt such as NO(S0 3 K) 2 in an aqueous solvent such as acetone and in the presence of a base such as KOH.
  • Reaction Scheme 5 is defined applicable to the preparation of all compounds wherein the oxidation of a hydroquinone is required.
  • R in Reaction Scheme 5 defines each possible moiety attached to the quinone as defined within the claims.
  • the compounds of the present invention were analyzed by analytical LC-MS. The conditions are summarized below.
  • Examples 25 to 33 which were synthesized according to general procedure (II) are: 2,3-Dimethoxy-5-methyl-6-[10-(2H-tetrazol-5-ylamino)-decyl]-[1 ,4]benzoquinone (25)
  • intermediate 35a (200 mg) was dissolved in dry THF (6 ml) and the solution was cooled to -10°C.
  • titanium (IV) isopropoxide (1.6 g) was added drop wise at -30°C to a 3M ethyl magnesium bromide solution in ether (4.6 ml) and THF (2 ml).
  • Intermediate 36b (0.84 g) dissolved in THF (2.5 ml) was added dropwise at -30°C and the reaction mixture was stirred for 15 min, and was monitored by LCMS.
  • Titanium (IV) isopropoxide (1.6 g), a 3M ethyl magnesium bromide solution in ether (4.6 ml) and THF (1 ml) were added and the reaction mixture was stirred for 15 min. at -30°C.
  • the solution was hydrolyzed at 0°C with a saturated ammonium chloride solution and extracted with ethyl acetate (20 ml). After phase separation, the aqueous layer was extracted again with ethyl acetate (2 x 20 ml). The combined organic layer was washed with brine (25 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure.
  • the crude product was purified by flash chromatography (AcOEt- cyclohexane).
  • the pH was adjusted to 8 by adding a 1% aqueous solution of potassium hydroxyde and acetone (1.5 ml) was added.
  • the reaction mixture was monitored by LCMS.
  • the reaction mixture was stirred for 14h at room temperature to obtain a complete conversion.
  • a 1 M aqueous hydrochloride solution (10 ml) was added and the aqueous layer was extracted with ethyl acetate (3x10ml).
  • the combined organic layer was dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure.
  • the crude product was purified with preparative HPLC-MS.
  • the reaction mixture was monitored by LCMS.
  • the reaction mixture was stirred for 14h at room temperature to obtain a complete conversion.
  • a 0.5M aqueous hydrochloride solution (300 ml) was added and the aqueous layer was extracted with ethyl acetate (4x200ml).
  • the combined organic layer was dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure.
  • the crude product was purified by flash-chromatography (AcOEt-cyclohexane).
  • intermediate 37a (6 g) was dissolved in dry THF (300 ml) and the solution was cooled to -60°C.
  • a 2M solution of LDA in THF (31 ml) and iodomethane (6 ml) were added and the reaction mixture was stirred for 1 h.
  • the reaction mixture was poured onto a saturated solution of ammonium chloride (300 ml) at 0°C. After phase separation, the aqueous layer was extracted with ethyl acetate (3x200 ml). The combined organic layer was washed with brine (200 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure.
  • the crude product was purified by flash-chromatography (AcOEt-cyclohexane).
  • intermediate 37b (201 mg) was dissolved in dry THF (5 ml) and lithium aluminium hydride (40 mg) was added at 0°C. The reaction mixture was stirred at this temperature for 15 min. and for 1 h at room temperature. The solution was diluted with ethyl acetate (30 ml) and washed with a saturated ammonium chloride solution (30 ml). The aqueous layer was extracted with ethyl acetate (25 ml). The combined organic layer was washed with brine (30 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure. The crude product was dissolved in toluene and silver carbonate (64 mg) was added. The reaction mixture was stirred for 2h and filtrated over Celite. The solvent was removed under reduced pressure and the crude product was purified with preparative HPLC-MS.
  • intermediate 37b (1 g) was dissolved in dry THF (60 ml) and the solution was cooled to -60°C.
  • the reaction mixture was poured onto a saturated ammonium chloride solution (50 ml) at 0°C. After phase separation, the aqueous layer was extracted with ethyl acetate (3x50 ml). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure.
  • the crude product was purified by flash-chromatography (AcOEt-cyclohexane).
  • intermediate 38a (103 mg) was dissolved in dry THF (4 ml) and lithium aluminium hydride (15 mg) was added at 0°C. The reaction mixture was stirred at this temperature for 15 min. The solution was diluted with ethyl acetate (15 ml) and washed with a saturated solution of ammonium chloride (15 ml). The aqueous layer was extracted with ethyl acetate (15 ml). The combined organic layer was washed with brine (15 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure. The crude product was dissolved in toluene (3 ml) and silver carbonate (36 mg) was added. The reaction mixture was stirred for 2h and filtrated over Celite. The solvent was removed under reduced pressure and the crude product was purified with preparative HPLC-MS.
  • intermediate 37a (600 mg) was dissolved in dry THF (10 ml) and the solution was cooled to -78°C.
  • a 2M solution of LDA in THF (3.3 ml) was added and the reaction mixture was stirred for 15 min. Then the solution was warmed up to -10°C and stirred for 30 min.
  • the reaction mixture was again cooled to -78°C and N-fluorodibenzenesulfonimide (2.0 g) was added.
  • the reaction mixture was stirred for 10 min. at -78°C for 14h at room temperature.
  • the solution was diluted with ethyl acetate (120 ml) and washed with a saturated solution of ammonium chloride (100 ml).
  • intermediate 39a (86 mg) was dissolved in dry THF (3.5 ml) and lithium aluminium hydride (25 mg) was added at 0°C. The reaction mixture was stirred at this temperature for 15 min. and 1 h at room temperature. The solution was diluted with ethyl acetate (15 ml) and washed with a saturated ammonium chloride solution (10 ml). The aqueous layer was extracted with ethyl acetate (15 ml). The combined organic layer was washed with brine (20 ml), dried over sodium sulfate, filtrated, and volatiles were removed under reduced pressure. The crude product was purified with preparative HPLC-MS.
  • Jones reagent was prepared by dissolving 670 mg of Cr0 3 in 1.25 ml dist. water. To this solution was added 0.58 ml of cone. H 2 S0 4 while cooling in an ice bath. After 5 min, the precipitating salts were brought into solution by dropwise addition of 0.15 ml of water.
  • Fmoc-Rink amide resin 200-400 mesh (PepChem, PC-01-0501) (273 mg, 0.21 mmol) was treated with a solution of 20% piperidine in DMF (3 ml) for 30 min. Excess of the reagent was removed by filtration. The resin was successively washed with DMF (3 x 3 ml), MeOH (3 x 3 ml) and DMF (3 x 3 ml) and treated with a solution of product from intermediate 59b (224 mg, 0.41 mmol) activated with DIC (65 ⁇ , 0.42 mmol) and HOBt monohydrate (64 mg, 0.42 mmol) in DMF (2.5 ml) overnight.
  • the resin was washed with DMF (3 x 3 ml). DMF (2.5 ml) was added followed by acetic anhydride (99 ⁇ , 1.05 mmol). The mixture was reacted for 1 h. Excess of the reagent was removed by filtration. The resin-bound intermediate was successively washed with DMF (3 x 3 ml), MeOH (3x3 ml), THF (3x3 ml), DCM (3x3 ml) and diethyl ether (3x3 ml). The resin was dried under reduced pressure.
  • Tritylchlorid-polystyrol resin 100-200 mesh (PepChem, PC-01-0011) (250 mg, 0.363 mmol) was treated with a solution of intermediate 59b (594 mg, 1.089 mmol) in dry DCM (2 ml) overnight. Excess of the reagent was removed by filtration. The resin-bound intermediate was successively washed with DMF (3x5 ml), MeOH (3x5 ml), THF (3x5 ml), DCM (3x5 ml) and diethyl ether (3x5 ml). The resin was dried under reduced pressure.
  • the product was purified by column chromatography.
  • Comparative Compound A is a synthetic derivative to the natural occurring CoQ10.
  • Comparative Compound C is a synthetic derivative to the natural occurring CoQ10.
  • Comparative Compound D is a synthetic derivative to Comparative Compound E.
  • Comparative Compound E Comparative Compound E is Idebenone which is first described in the specification of Japanese Patent Examined Publication No. 3134/1987 filed by Takeda Chemical Industries, Ltd.
  • Comparative Compound F is disclosed in WO-A-2006130775.
  • Mitochondria generate most of the cell's supply of adenosine triphosphate (ATP) which is used as a source of the chemical energy.
  • mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth.
  • the amount of mitochondria per cell varies widely and is also subject to modifications in response to physiological stimuli.
  • Mitochondria replicate independently of nuclear replication in response to low energy conditions via an AMPK driven pathway. Their degradation occurs via a specialized autophagy pathway called mitophagy. This pathway can serve multiple goals: first it is essential for maintaining mitochondrial homeostasis, but more importantly it can also be used to reduce mitochondrial mass. Under conditions of impaired mitochondrial function this is an essential, protective mechanism to prevent excessive buildup of radicals that would otherwise damage cellular integrity.
  • MitoTracker® is used to quantify the number of mitochondria in live cells. After passive diffusion into mitochondria, MitoTracker® Green FM reacts with thiols on proteins and forms a fluorescent conjugate. The method was performed as instructed by the manufacturer. Briefly, fibroblast cells seeded in a 96-well plate at a density of 10 4 cells per well are allowed to grow for 24 h. Cells were treated with 10 ⁇ compounds in growth medium for 72 h. Then, cells are washed with 100 ⁇ Hank's BSS. A working dye solution of MitoTracker® Green FM is prepared by diluting MitoTracker® Green FM stock solution 20000-fold in Hank's BSS.
  • a volume of 100 ⁇ /well of dye solution is added and plates are incubated for 15 min in the cell culture incubator. After washing twice with 50 ⁇ PBS, a volume of 50 ⁇ PBS is added and fluorescence is measured immediately (MitoTracker® Green FM: excitation: 490 nm; emission: 520 nm). After obtaining the MitoTracker signal, cells are fixed with PFA for 10 minutes at RT, wasched with 3x 100 ul PBS and nuclear DNA stained with DAPI solution (O.l Mg/ml DAPI in PBS) for 10 minutes at RT. After 3 additional washes with PBS, DAPI fluorescence is aquired (excitation: 350 nm); emission: 450 nm). Mitotracker signals are normalized to amount of nuclear DNA (equiv. of cell number).
  • Mitochondrial mass is a measure of the amount of mitochondria in cells. As a result of multiple studies, it is now generally accepted that upregulation of mitochondrial mass is beneficial to retain sufficient energy (ATP) levels in disorders where mitochondrial function is impaired. As can be taken from Table 8, while the comparison compound B slightly reduces mitochondrial mass, the compounds of the present invention significantly enhance mitochondrial mass.
  • Mitochondrial membrane potential is an important parameter of mitochondrial function used as an indicator of cell health. It is generated through proton pumps that are fuelled by the electrons donated from the citric acid cycle in form of NADH. These electrons are transferred between complexes I, II and III of the respiratory chain through coenzyme Q10.
  • the membrane potential is used in healthy cells to provide the electrochemical energy to drive mitochondrial ATP production. Under certain conditions however, high ⁇ can be the source of significant radical production by mitochondria.
  • the loss of mitochondrial membrane potential is a hallmark of apoptosis.
  • the mitochondrial permeability transition is an important step in the induction of cellular apoptosis. During this process, the electrochemical gradient across the mitochondrial membrane collapses and is accompanied by the release of cytochrome c into the cytoplasm.
  • the mitochondrial membrane potential is the H+-gradient over the inner mitochondrial membrane that is used for ATP production.
  • the compounds of the present invention significantly enhanced the mitochondrial membrane potential.
  • This assay investigates cytotoxicity which is defined as the cell-killing property of a chemical compound, independent from the mechanisms of cell death.
  • the HepG2 hepatoblastoma cell line is one of the most common human cell lines for hepatotoxicity studies. Even though the cells lack a part of the metabolizing enzymes present in fresh hepatocytes, they have been shown to be a useful tool for studying the toxicity of hepatotoxins.
  • This assay measures metabolic activity of living cells using the WST-1 cell proliferation reagent (Roche Diagnostics). The tetrazolium salt WST-1 is cleaved to water soluble formazan by cellular enzymes. An expansion in the number of viable cells results in an increase in the overall activity of mitochondrial dehydrogenases in the sample.
  • This augmentation in enzyme activity leads to an increase in the amount of formazan dye formed, which directly correlates to the number of metabolically active cells in the culture.
  • the formazan dye produced by metabolically active cells is directly quantified in a scanning multiwell spectrophotometer by measuring the absorbance of the formazan dye solution between 420 and 480 nm. Healthy HepG2 cells, when maintained in culture, continuously divide and multiply over time. A toxic chemical, regardless of site and mechanism of action, will interfere with this process and result in the reduction of the growth rate reflected in the cell number.
  • Hep-G2 cells are seeded into a 96-well microplate and maintained in culture for 24 hours. They are then exposed to the test compound over a range of eight concentrations. After 24 hours exposure, the cells are incubated in presence of reagent WST-1 for 30 min before measuring the absorbance of the formazan dye formed. Cytotoxicity is expressed as a concentration dependent reduction of the conversion formazan dye formation due to a decrease in cell proliferation as compared to untreated cells.
  • the TC 50 Total Concentration 50%
  • the TC 50 % values were calculated using the following formula:
  • Comparative compounds A and J are clearly associated with some level of in vitro toxicity, which can be interpreted as an indicator of expected hepatho-toxic liabilities in vivo, while compounds of the present invention clearly demonstrate no toxicity in the dose range evaluated.
  • Kinetic solubility determines the concentration above which a compound starts to precipitate and demonstrate turbidity (i.e. the solubility limit). Turbidity is measured using optical density.
  • Comparative Compounds F and G are practically insoluble in aqueous solutions which negatively affects the development of oral formulations
  • Comparative Compound I is already soluble enough to show oral bioavailability.
  • Table 11 the compounds of the present invention clearly demonstrate significantly improved solubility characteristics compared to the comparative compounds.
  • NAD7NADH ratio The balance between the oxidized and reduced forms of nicotinamide adenine dinucleotide is called the NAD7NADH ratio, which is an important component of what is called the redox state (RS), a measurement that reflects both the metabolic activities and the health of cells.
  • RS redox state
  • the effects of the NAD7NADH ratio are complex, controlling the activity of several key enzymes, including glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase.
  • estimates of the NAD7NADH ratio are typically around 700, thus it favours for oxidative reactions.
  • the NADP7NADPH ratio is normally about 0.005, so NADPH is the dominant form of this coenzyme.
  • Resazurin (7-Hydroxy-3 - -phenoxazin-3-one 10-oxide) is a blue dye used mainly as an oxidation-reduction indicator in the resazurin test for bacteria. It is also used as an indicator for cell viability in mammalian cell cultures. Blue colored Resazurin is reduced to the pink colored, fluorescent compound Resorufin in the presence of live cells. Resazurin has been used to quantify mitochondrial activity since it is considered to act as an intermediate electron acceptor in the electron transport chain between the final reduction of oxygen and cytochrome oxidase.
  • the cellular redox state is tightly controlled; therefore small changes can have big impacts.
  • the compounds of the invention have a similar or better effect than the comparative compounds, sometimes at even much lower concentrations. More signal in this assay reflects higher NADH levels and therefore better viability.
  • Electrons donated from the citric acid cycle in form of NADH are transferred between complexes I, II and III of the respiratory chain.
  • mitochondrial membrane potential is generated through proton pumps in the mitochondrial inner membrane.
  • This electrochemical gradient across the inner mitochondrial membrane is used in healthy cells to provide the energy to drive mitochondrial ATP production. Consequently, cellular ATP levels are a good indicator of mitochondrial function.
  • this mode of ATP production is impaired and alternative modes of ATP production are utilized that can be associated with toxic byproducts (i.e. lactic acidosis due to increased anaerobic glycolysis).
  • Immortalized lymphoblastoid cells BC1 LCL were used to characterize the effect of compounds on ATP levels under different glucose levels by an ATP dependent luciferase reaction. Briefly, cells were seeded in a 24-well plate at a density of 5 * 10 5 cells/ml with 1 ml per well in two different media containing 25 mM or no glucose, respectively. Both media were supplemented with 10% fetal bovine serum, 1% Pen/Strep, 200 mM L-glutamine.
  • Cells were treated with 0.1 % (v/v) of compounds (10 mM in DMSO; final concentration: 10 ⁇ ) and incubated for 72 h at 37 °C, 5% C0 2 , and 90% rH. The number of cells was counted and after brief washing in PBS and collecting through centrifugation (5 min; 200 x g) the cells were lysed in a volume of 0.5 ml lysis solution (4 mM EDTA, 0.2% Triton X-100) for 15 min on ice and 10 ⁇ of lysate was added into a white 96 well plate. In parallel, ATP standards (concentrations: 0, 1 , 2, 4, 6, 8, and 12 ⁇ in PBS) were also added into the 96 well plate.
  • the reaction was started by addition of 100 ⁇ reaction mix (300 ⁇ D-Luciferin, 5 ⁇ g/ml firefly luciferase, 75 ⁇ DTT, 25 mM HEPES, 6.25 mM MgCI 2 , 625 ⁇ EDTA and 1 mg/ml BSA) and the luminescence signal was quantified in a multimode plate reader (Tecan M1000 plate reader; luminescence integration time: 100 ms). The concentration of cellular ATP normalized to cell number is calculated for each well and triplicate measurements are averaged. The ATP levels are given in Table 13.
  • Lipid peroxidation is a well defined mechanism of cellular damage in both animals and plants that occurs during aging and in some disease states. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which methylene-CH2- groups possess especially reactive hydrogens. If not terminated fast enough, lipid peroxidation damages cellular membranes, affect membrane fluidity and also mitochondrial function. In addition, end products of lipid peroxidation may be mutagenic and carcinogenic. For instance, the reactive end product of lipid peroxidation, malondialdehyde, directly causes DNA damage.
  • BODIPY® (4,4-difluoro-3a,4adiaza- s-indacene) fluorophore is an effective tracer of lipid trafficking, as well as being useful general- purpose membrane probes.
  • BODIPY 581/591-C11 can be used to measure antioxidant activity in lipid environments by exploiting its loss of fluorescence upon interaction with peroxyl radicals.
  • Primary human fibroblasts C4 (GM04545, Coriell) (passage ⁇ 12) were seeded at a concentration of 2000 cells/ well into black 96 well plates and incubated for 72 hours in DMEM in the presence of 10 ⁇ test compound or DMSO only.
  • 0.1 ml freshly prepared dye solution (HBSS, containing BODIPY dye 1 :1000 from stock solution) was added and cells were returned to the incubator for 30 min. After 2 brief washes with 0.1 ml warmed PBS fluorescence was measured in 50 ⁇ PBS. Fluorescence for 4 individual areas per well were individually quantified at two wavelengths (Ex,: 490, Enri!: 600; Ex 2 : 490, Em 2 : 530, bandwith 10nm, 50 flashes, 400Hz frequency, 20 ps integration time).
  • Altered mitochondrial function can lead to cellular damage via lipid peroxidation. Altering mitochondrial function through small molecules therefore also has the inherent risk of producing lipid peroxidation as observed for Comparative Compound A. In this context, all compounds that leave basal lipid peroxidation levels unchanged (at 100%) or even reduce them ( ⁇ 100%) do not show any inherent toxic liability or are even beneficial in the context of elevated levels of lipid peroxidation in a state of disease.
  • the compounds of present invention significantly reduce basal levels of lipid peroxidation while the comparative compounds increase basal levels significantly.
  • CI I Complex II
  • succinate dehydrogenase which catalyzes the conversion from succinate to fumarate.
  • FAD succinate dehydrogenase
  • FADH 2 Ackrell 2000
  • SURFE2R SSM sensors were coated with inner mitochondrial membranes according to the standard protocols. Briefly, sensors were filled with 50 ⁇ _ of SensorPrep A solution and incubated for 10-15 min. Afterwards the solution was removed, sensor were rinsed with deionized water three times dried in a stream of nitrogen gas and incubated for 15 min at room temperature to get rid of remaining solvents. 1.5 ⁇ _ of SensorPrep B1 solution were applied to the sensor and immediately covered with 50 ⁇ _ of the buffer (150 mM Na-gluconate, 30 mM Hepes pH 7.2/NMG, 10 mM MgCI2, 12.5 mM NaPi pH7.2, freshly added 0.2 mM DTT). Incubate the sensor for 15-60 min at 4°C.
  • the buffer 150 mM Na-gluconate, 30 mM Hepes pH 7.2/NMG, 10 mM MgCI2, 12.5 mM NaPi pH7.2, freshly added 0.2 mM DTT.
  • the biosensors were thawed immediately before the experiment and measured with the SURFE2R Workstation 50 or 500 devices.
  • the CII-CIII activity was studied by rapid exchange of a "non-activating" solution for an "activating" solution containing the 3 ⁇ oxidized cytochrome c. 2 s of non-activating buffer was followed by 1 s of activating buffer and then again 1 s non- activating buffer. Afterwards the sensor was rinsed 3 times with 1 mL non-activating buffer. A further activation with cytochrome c was performed after an incubation time of -11 min. Both buffers contained 1 mM succinate and 350 mg/L BSA to enhance the solubility of the test compounds.
  • Cll-lll For the activity of Cll-lll, the peak current (current amplitude) was evaluated.
  • the performed measurements of Cll-lll activities consisted of two parts. First the activity of Cll-lll was recorded in the absence of compound (instead 0.01% DMSO) for about 50 min to obtain a constant CII-CIII activity (constant peak current amplitudes). Afterwards, a test compound ( ⁇ 4 ⁇ ) was supplied to the non-activating and the activating solutions and the Cll-lll activity was recorded for further -50 min (110 min in total). For each sensor, all peak currents were normalized to the mean of the activities after 24, 36 and 48 min.
  • n (t 0-110) 2.
  • the CII- CIII activity was recorded for additional -50 min (up to 160 min in total).
  • a longer integration time just indicates that the compound is in principle capable of triggering higher complex II activities but in a cell free setting unable to quickly insert itself into the membrane via diffusion to affect complex ll-lll.
  • maximal concentrations in the membrane are reached at different speeds. This is an artefact of a cell free system where you rely on diffusion. In vivo, these compounds are likely transported in a coordinated fashion via lipid carrier, so this difference will not be seen.
  • Mitochondrial disorders are characterized by impaired mitochondrial function, which is usually displayed as lower mitochondrial synthesis of ATP. This energy crisis is seen as a major contributor for cellular impairment and ultimately cell death. Thus, improving the abberant energy status that is associated with impaired mitochondrial function is necessary to normalize cellular and tissue function.
  • Rat myoblast cells (L6) were seeded at a density of 5 * 10 3 cells per well in a 96-well plate and incubated for 24 hours in DMEM with 0.3 g/l glucose, 2% FBS and Penicillin-Streptomycin- Glutamine. Cells were treated with 1 ⁇ quinones in presence or absence of rotenone (1 ⁇ ), for 60 minutes in DMEM without glucose before ATP levels were quantified using luminescence from the ATP-dependent enzymatic oxidation of luciferin by luciferase. Cells were lysed in a volume of 200 ⁇ (4 mM EDTA, 0.2% Triton X-100) for five minutes.
  • ATP measurement buffer 25 mM HEPES pH 7.25, 300 ⁇ D-luciferin, 5 pg/ml firefly luciferase, 75 ⁇ DTT, 6.25 mM MgCI 2 , 625 ⁇ EDTA and 1 mg/ml BSA
  • Luminescence was quantified immediately using a multimode plate reader (Tecan M1000, Tecan iControl 1.6 software; Tecan Austria GmbH, Grodig, Austria).
  • ATP levels were standardized to protein levels using BCA assay (ThermoScientific, Rockford, IL, USA) and changes were calculated as percentage relative to levels of DMSO-treated control cells.
  • ATP rescue is defined as the percentage of quinone-induced increase in ATP levels in presence of rotenone relative to the ATP reduction by rotenone alone.
  • Altered mitochondrial function can lead to depleted cellular ATP levels.
  • altering mitochondrial function by small molecules of the current invention but not by Comparative Compound B alows the rescue of cellular energy status as observed here.
  • all compounds that counteract the lowered ATP levels associated with mitochondrial dysfunction can be seen as beneficial for the function and survival of the affected cells.
  • the compounds of present invention significantly rescue ATP levels under conditions of impaired mitochondrial function while the comparative compound B has no effect at all.

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Abstract

L'invention concerne de nouveaux dérivés de benzoquinone. Ces composés sont efficaces en tant que modulateurs de la fonction mitochondriale et sont utiles dans le traitement d'états pathologiques caractérisés par une fonction mitochondriale altérée.
PCT/EP2011/004122 2010-08-16 2011-08-16 Nouveaux dérivés de benzoquinone et utilisation de ces dérivés en tant que modulateurs de la fonction mitochondriale WO2012022467A2 (fr)

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EP2718255A1 (fr) * 2011-05-26 2014-04-16 Indiana University Research and Technology Corporation Composés quinones pour traitement de maladies à médiation par ape1
WO2014059158A1 (fr) * 2012-10-10 2014-04-17 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For An On Behalf Of Arizona State University Agents d'extinction de radicaux multifonctionnels
WO2014063923A1 (fr) * 2012-10-23 2014-05-01 Nicox S.A. Composés donneurs d'oxyde nitrique à base de quinone pour une utilisation ophtalmique
WO2015017589A1 (fr) * 2013-07-31 2015-02-05 Novartis Ag Dérivés de pyridazine 1,4-disubstitués et leur utilisation pour le traitement de pathologies liées à une déficience en smn
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JP2019504018A (ja) * 2015-12-17 2019-02-14 バイオエレクトロン テクノロジー コーポレイション 酸化ストレス障害を処置するためのフルオロアルキル、フルオロアルコキシ、フェノキシ、ヘテロアリールオキシ、アルコキシ、およびアミノ１，４−ベンゾキノン誘導体
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WO2020131282A1 (fr) * 2018-12-18 2020-06-25 Stealth Biotherapeutics Corp. Peptides ciblant les mitochondries
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WO2021067836A1 (fr) * 2019-10-04 2021-04-08 Stealth Biotherapeutics Corp Analogues chinone, hydrochinone et naphtochinone de vatiquinone pour le traitement de maladies à troubles mitochondriaux
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS623134B2 (fr) 1975-04-30 1987-01-23 Takeda Chemical Industries Ltd
WO2006130775A2 (fr) 2005-06-01 2006-12-07 Edison Pharmaceuticals, Inc. Produits therapeutiques actifs en reduction-oxydation destines au traitement de maladies mitochondriales et d'autres etats ainsi que la modulation de bio-marqueurs d'energie

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5919930B2 (ja) * 1974-05-02 1984-05-09 武田薬品工業株式会社 キノン酸誘導体の製造法
US3974187A (en) * 1975-02-28 1976-08-10 Wan Yieh Ping Synthetic analogs having the activity of naturally occurring forms of coenzyme Q
DE3680023D1 (de) * 1985-04-08 1991-08-08 Takeda Chemical Industries Ltd Benzochinonderivate, ihre herstellung und verwendung.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS623134B2 (fr) 1975-04-30 1987-01-23 Takeda Chemical Industries Ltd
WO2006130775A2 (fr) 2005-06-01 2006-12-07 Edison Pharmaceuticals, Inc. Produits therapeutiques actifs en reduction-oxydation destines au traitement de maladies mitochondriales et d'autres etats ainsi que la modulation de bio-marqueurs d'energie

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
ARNOULT D, CARNEIRO L, TATTOLI I, GIRARDIN SE, SEMIN IMMUNOL., vol. 21, no. 4, 2009, pages 223 - 32
BEN-SHACHAR D., J NEURAL TRANSM., vol. 116, no. 11, 2009, pages 1383 - 96
BRENNAN LA, KANTOROW M., EXP EYE RES., vol. 88, no. 2, February 2009 (2009-02-01), pages 195 - 203
BRUSS ET AL., AM J PHYSIOL ENDOCRINOL METAB, vol. 298, 2010, pages E108 - 16
BUGGER H, ABEL ED., CLIN SCI, vol. 114, no. 3, February 2008 (2008-02-01), pages 195 - 210
BURCHELL ET AL., EXPERT OPIN THER TARGETS, vol. 14, no. 4, 2010, pages 369 - 85
CHODACZEK G, BACSI A, DHARAJIYA N, SUR S, HAZRA TK, BOLDOGH I., MOL IMMUNOL., vol. 46, no. 13, 2009, pages 2505 - 14
CHRYSOSTOMOU V, TROUNCE IA, CROWSTON JG., OPHTHALMIC RES., vol. 44, no. 3, 2010, pages 173 - 8
CHUGANI DC, SUNDRAM BS, BEHEN M, LEE ML, MOORE GJ, PROG NEUROPSYCHOPHARMACOL BIOL PSYCHIATRY, vol. 23, no. 4, 1999, pages 635 - 41
COMPSTON A, INT MS J ., vol. 10, 2003, pages 29 - 31
DUTTA, R. ET AL., ANN. NEUROL., vol. 59, 2006, pages 478 - 489
FEHER J, KOVACS I, ARTICO M, CAVALLOTTI C, PAPALE A, BALACCO GABRIELI C., NEUROBIOL AGING., vol. 27, no. 7, July 2006 (2006-07-01), pages 983 - 937
FEHER J, PAPALE A, MANNINO G, GUALDI L, BALACCO GABRIELI C, OPHTHALMOLOGICA, vol. 217, no. 5, September 2003 (2003-09-01), pages 351 - 7
FILIPPINI G ET AL., LANCET, vol. 361, 2003, pages 545 - 552
FRIEDERICH M, HANSELL P, PALM F, CURR DIABETES REV., vol. 5, no. 2, May 2009 (2009-05-01), pages 120 - 44
GUO Y, JOHNSON EC, CEPURNA WO, DYCK J, DOSER T, MORRISON JC., INVEST OPHTHALMOL VIS SCI., 4 November 2010 (2010-11-04)
HAFLER DA, J. CLIN. INVEST., vol. 113, 2004, pages 788 - 794
ISHIKAWA K, KOSHIKAWA N, TAKENAGA K, NAKADA K, HAYASHI J, MITOCHONDRION, vol. 8, no. 4, 2008, pages 339 - 44
ISHIKAWA S, MIMA T, AOKI C, YOSHIO-HOSHINO N, ADACHI Y, IMAGAWA T, MORI M, TOMIITA M, IWATA N, MURATA T, ANN RHEUM DIS., vol. 68, no. 2, 2009, pages 264 - 72
J.J. BEDNARSKI, R.E. WARNER, T. RAO, F. LEONETTI, R. YUNG, B.C. RICHARDSON, K.J. JOHNSON, J.A. ELLMAN, A.W. OPIPARI JR., G.D. GLIC, ARTHRITIS & RHEUMATISM, vol. 48, 2003, pages 757
JARRETT SG, LEWIN AS, BOULTON ME., OPHTHALMIC RES., vol. 44, no. 3, 2010, pages 179 - 90
JONES MM, MANWARING N, WANG JJ, ROCHTCHINA E, MITCHELL P, SUE CM., ARCH OPHTHALMOL., vol. 125, no. 9, September 2007 (2007-09-01), pages 1235 - 40
JOU ET AL., CHANG GUNG MED J., vol. 32, no. 4, 2009, pages 370 - 9
JU WK, KIM KY, DUONG-POLK KX, LINDSEY JD, ELLISMAN MH, WEINREB RN.: "Increased optic atrophy type 1 expression protects retinal ganglion cells in a mouse model of glaucoma", MOL VIS., vol. 16, 15 July 2010 (2010-07-15), pages 1331 - 42
KANDA A, CHEN W, OTHMAN M, BRANHAM KE, BROOKS M, KHANNA R, HE S, LYONS R, ABECASIS GR, SWAROOP A., PROC NATL ACAD SCI U S A., vol. 104, no. 41, 9 October 2007 (2007-10-09), pages 16227 - 32
KUDIN AP, ZSURKA G, EIGER CE, KUNZ WS, EXP NEUROL., vol. 218, no. 2, August 2009 (2009-08-01), pages 326 - 32
LEE S, VAN BERGEN NJ, KONG GY, CHRYSOSTOMOU V, WAUGH HS, O'NEILL EC, CROWSTON JG, TROUNCE IA., EXP EYE RES., 4 August 2010 (2010-08-04)
LIESA M ET AL., PHYSIOL REV., vol. 89, 2009, pages 799 - 845
OLSEN NK ET AL., ACTA NEUROL. SCAND., vol. 91, 1995, pages 326 - 329
PIECZENIK, NEUSTADT, EXP MOL PATHOL., vol. 83, no. 1, 2007, pages 84 - 92
PUDDU ET AL., J BIOMED SCI, vol. 16, 2009, pages 112
REGENOLD WT ET AL., J. NEUROL. SCI., vol. 275, 2008, pages 106 - 112
REZIN GT, AMBONI G, ZUGNO AI, QUEVEDO J, STRECK EL, NEUROCHEM RES., vol. 34, no. 6, June 2009 (2009-06-01), pages 1021 - 9
SEYAMA K ET AL., ACTA NEUROL. SCAND., vol. 80, 1989, pages 561 - 568
SHAO L, MARTIN MV, WATSON SJ, SCHATZBERG A, AKIL H, MYERS RM, JONES EG, BUNNEY WE, VAWTER MP, ANN MED., vol. 40, no. 4, 2008, pages 281 - 95
SINGH, KULAWIEC, METHODS MOL BIOL., vol. 471, 2009, pages 291 - 303
TSO MO., OPHTHALMOLOGY, vol. 88, no. 10, October 1981 (1981-10-01), pages 1066 - 80
VICTOR VM, ESPULGUES JV, HERNANDEZ-MIJARES A, ROCHA M, INFECT DISORD DRUG TARGETS., vol. 9, no. 4, 2009, pages 376 - 89
WALDBAUM S, PATEL M, EPILEPSY RES., 20 October 2009 (2009-10-20)
YANG ET AL., DNA REPAIR, vol. 7, no. 7, 2008, pages 1110 - 20
YAO JK, REDDY RD, VAN KAMMEN DP, CNS DRUGS, vol. 15, no. 4, 2001, pages 287 - 310

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