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WO2012170773A1 - Traitement adjuvant au traitement des maladies mitochondriales avec des quinones et des naphtoquinones - Google Patents

Traitement adjuvant au traitement des maladies mitochondriales avec des quinones et des naphtoquinones Download PDF

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Publication number
WO2012170773A1
WO2012170773A1 PCT/US2012/041486 US2012041486W WO2012170773A1 WO 2012170773 A1 WO2012170773 A1 WO 2012170773A1 US 2012041486 W US2012041486 W US 2012041486W WO 2012170773 A1 WO2012170773 A1 WO 2012170773A1
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formula
vitamin
quinone
alkyl
quinones
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Viktoria Kheifets
Adam L. BARNES
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Edison Phamaceuticals Inc
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Edison Phamaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin

Definitions

  • the present invention relates to an adjunctive therapy for the treatment of mitochondrial disorders comprising the administration of an effective amount of one or more quinones and one or more naphthoquinones to a patient in need therof.
  • the present invention also relates to an adjunctive therapy for the treatment of
  • naphthoquinones or their reduced form naphthohydroquinones to a patient in need therof.
  • Mitochondria are organelles in eukaryotic cells, popularly referred to as the "powerhouse” of the cell.
  • the molecule adenosine triphosphate (ATP) functions as an energy “currency” or energy carrier in the cell, and eukaryotic cells derive the majority of their ATP from biochemical processes carried out by mitochondria.
  • citric acid cycle the tricarboxylic acid cycle, or Kreb's cycle
  • NADH + H + reduced nicotinamide adenine dinucleotide
  • NAD + oxidized nicotinamide adenine dinucleotide
  • OXPHOS oxidative phosphorylation
  • the citric acid cycle also reduces flavin adenine dinucleotide, or FAD, to FADH 2 ; FADH 2 also participates in oxidative phosphorylation.
  • Mitochondria also play an active role in survival and death signaling and cellular calcium homeostasis. Defects in mitochondrial function are associated with mitochondrial dysfunction and numerous neurodegenerative diseases affecting oxidative metabolism and impairing energy production.
  • Mitochondrial disorders are caused by mutations in mitochondrial genes, in nuclear genes encoding for subunits of the respiratory chain complexes or in genes coding for proteins involved in the nuclear-mitochondrial communication.
  • the respiratory chain is located in the inner mitochondrial membrane and consists of five multimeric protein complexes: Complex I (approximately 46 subunits), Complex II (approximately 4 subunits), Complex III (approximately 11 subunits), Complex IV (approximately 13 subunits) and Complex V (approximately 16 units).
  • the respiratory chain also requires two small electron carriers, ubiquinone (coenzyme Q10) and cytochrome c. ATP synthesis involves two coordinated processes.
  • First electrons (actually hydrogen ions derived from NADH and FADH 2 in intermediary metabolism) are transported horizontally from complexes I and II to coenzyme Q to Complex III to cytochrome c to Complex IV, and ultimately to the final electron acceptor, molecular oxygen, thereby producing water.
  • protons are pumped "vertically" across the mitochondrial inner membrane (i.e. from the matrix to the inter membrane space) by complexes I, II, III and IV.
  • ATP is generated by the influx of these protons back into the mitochondrial matrix through complex V (ATP synthetase) (Di Mauro, S., Mitochondrial Medicine, (2006) 7-9.)
  • V ATP synthetase
  • the energy released as these electrons traverse the complexes is used to generate a proton gradient across the inner membrane of the mitochondrion, which creates an electrochemical potential across the inner membrane.
  • Complex I NADH dehydrogenase, also called NADH:ubiquinone oxidoreductase
  • NADH dehydrogenase also called NADH:ubiquinone oxidoreductase
  • Q ubiquinone
  • QH 2 ubiquinone
  • Complex I moves four protons (H + ) across the membrane, producing a proton gradient.
  • Complex I is one of the main sites at which premature electron leakage to oxygen occurs, thus being one of the main sites of production of a harmful free radical called superoxide.
  • Complex II succinate dehydrogenase
  • Q quinone pool
  • FAD quinone pool
  • Complex II consists of four protein subunits: SDHA, SDHB, SDHC, and SDHD.
  • Other electron donors e.g., fatty acids and glycerol 3-phosphate
  • FAD glycerol 3-phosphate
  • Complex III removes two electrons from QH 2 and transfers them to two molecules of cytochrome c, a water-soluble electron carrier located within the inter-membrane space. At the same time, it moves two protons across the membrane, producing a proton gradient (in total 4 protons: 2 protons are translocated and 2 protons are released from ubiquinol).
  • Complex III may leak electrons to oxygen resulting in the formation of superoxide, a highly-toxic species, which is thought to contribute to the pathology of a number of diseases, including aging.
  • LHON Leber's Hereditary Optic Neuropathy
  • Dominant Optic Atrophy also known as autosomal dominant optic atrophy, Kjer type; Kjer optic atrophy; or Kjer's autosomal dominant optic atrophy, is characterized by a slow progressive bilateral loss of central vision starting in childhood and progressing in adult life. Vision loss in DOA is due to optic nerve fiber loss from mitochondrial dysfunction. Dominant optic atrophy is associated with mutation of the OPA1 gene. Six other chromosomal genes are described as causing optic atrophy: OPA2 (obscure), OPA3 (dominant), OPA4 (dominant), OPA5
  • DOA results in significant visual impairment with about half of all affected individuals failing the driving standards, and 13-46% being registered as legally blind.
  • the predominant color defect in DOA is dyschromatopsia involving both the blue-yellow and the red-green axes.
  • Patients with DOA experience diffuse atrophy of the retinal ganglion cell layer, loss of myelin and fibrillary gliosis along the anterior visual pathways extending to the lateral geniculate body.
  • Another syndrome resulting from a respiratory chain disorder is mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS).
  • the disease can manifest itself in infants, children, or young adults. Strokes, accompanied by vomiting and seizures, are one of the most serious symptoms; it is postulated that the metabolic impairment of mitochondria in certain areas of the brain is responsible for cell death and neurological lesions, rather than the impairment of blood flow as occurs in ischemic stroke. Other severe complications, including neurological symptoms, are often present, and elevated levels of lactic acid in the blood occur.
  • Another syndrome resulting from a respiratory chain disorder is
  • Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome one of a group of rare muscular disorders that are called mitochondrial
  • Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that releases energy -mitochondria. This can cause a dysfunction of the brain and muscles
  • MERRF syndrome myoclonic seizures that are usually sudden, brief, jerking, spasms that can affect the limbs or the entire body. Impairment of the ability to coordinate movements (ataxia), as well as an abnormal accumulation of lactic acid in the blood (lactic acidosis) may also be present in affected individuals. Difficulty speaking (dysarthria), optic atrophy, short stature, hearing loss, dementia, and involuntary jerking of the eyes (nystagmus) may also occur.
  • Another syndrome resulting from a respiratory chain disorder is Pearson syndrome, characterized by symptoms associated with bone marrow and pancreas dysfunction. It is caused by single mitochondrial DNA deletions. Those who survive infancy usually develop Kearns-Sayre syndrome.
  • Another syndrome resulting from a respiratory chain disorder is Co- Enzyme Q10 Deficiency, the symptoms of which include encephalomyopathy, mental retardation, exercise intolerance, ragged-red fibers, and recurrent myoglobin in the urine.
  • Another syndrome resulting from a respiratory chain disorder is Complex I Deficiency or NADH dehydrogenase NADH-CoQ reductase deficiency, the symptoms of which are classified by three major forms: (1) fatal infantile multisystem disorder, characterized by developmental delay, muscle weakness, heart disease, congenital lactic acidosis, and respiratory failure; (2) myopathy beginning in childhood or in adult life, manifesting as exercise intolerance or weakness; and (3) mitochondrial encephalomyopathy (including MELAS), which may begin in childhood or adult life and consists of variable combinations of symptoms and signs, including ophthalmoplegia, seizures, dementia, ataxia, hearing loss, pigmentary retinopathy, sensory neuropathy, and uncontrollable movements.
  • MELAS mitochondrial encephalomyopathy
  • Deficiency or succinate dehydrogenase deficiency the symptoms of which include encephalomyopathy and various manifestations, including failure to thrive, developmental delay, hypotonia, lethargy, respiratory failure, ataxia, myoclonus and lactic acidosis.
  • Ubiquinone-cytochrome c oxidoreductase deficiency symptoms of which are categorized in four major forms: (1) fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophic posturing, seizures, and coma; (2) encephalomyopathies of later onset (childhood to adult life): various combinations of weakness, short stature, ataxia, dementia, hearing loss, sensory neuropathy, pigmentary retinopathy, and pyramidal signs; (3) myopathy, with exercise intolerance evolving into fixed weakness; and (4) infantile histiocytoid cardiomyopathy.
  • encephalomyopathy which is typically normal for the first 6 to 12 months of life and then show developmental regression, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal signs, respiratory problems and frequent seizures; and
  • myopathy Two main variants: (a) fatal infantile myopathy: may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems; and (b) benign infantile myopathy: may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory problems, but (if the child survives) followed by spontaneous improvement.
  • Another syndrome resulting from a respiratory chain disorder is
  • Another syndrome resulting from a respiratory chain disorder is CPEO or Chronic Progressive External Ophthalmoplegia syndrome which includes symptoms such as visual myopathy, retinitis pigmentosa, or dysfunction of the central nervous system.
  • KSS Kearns-Sayre syndrome
  • CSF cerebrospinal fluid
  • KSS may affect many organ systems.
  • myopathy dystonia, endocrine abnormalities (e.g., diabetes, growth retardation or short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis.
  • endocrine abnormalities e.g., diabetes, growth retardation or short stature, and hypoparathyroidism
  • bilateral sensorineural deafness e.g., dementia, cataracts, and proximal renal tubular acidosis.
  • KSS may affect many organ systems.
  • Frataxin is believed to be important for the assembly of iron- sulfur clusters in mitochondrial respiratory-chain complexes; it may play a role in iron transport; it may play a role in iron storage; it may stimulate oxidative phosphorylation; and it may have anti-oxidant function (see Sturm, B. et al., J. Biol. Chem. (2005) 280:6701). Frataxin itself, however, does not appear to be incorporated into any of mitochondrial complexes I-V. Estimates of the prevalence of FRDA in the United States range from 1 in every 22,000-29,000 people (see World-Wide-Web address
  • MitoQ has also been proposed for treating FRDA (see U.S. Patent Application Publication No. 2005/0043553).
  • the compound idebenone has also been proposed for treatment of FRDA.
  • Preliminary testing has been done in humans, to see if idebenone could be a safe and effective treatment for Friedreich's ataxia (Tonon, C. et al., Expert Opin. Pharmacother. 2008, 9 (13): 2327-37).
  • a one-year test on eight patients idebenone reduced the rate of deterioration of cardiac function in patients with Friedreich's ataxia, but did not halt the progression of ataxia (Buyse, G. et al., Neurology 2003, 60 (10): 1679-81.)
  • overlap syndromes combine the clinical features of different typical mitochondrial syndromes.
  • One such syndrome characterized by clinical features of both myoclonus epilepsy ragged-red fibers (MERRF) and Kearns-Sayre syndrome (KSS), and due to a mitochondrial DNA (mtDNA) mutation at nucleotide 3255 (G3255A) of the t RNA Leu(UUR) gene has been described by Nishigaki, Y et al., Neuromuscular Disorders (2003) 13:334-340.
  • This particular overlap syndrome manifests sensorineural deafness, atypical pigmentary retinopathy, myoclonus epilepsy, ptosis, ophthalmoparesis, migraine headaches, hypothyroidism, and testosterone insufficiency.
  • Leigh syndrome is a rare inherited neurometabolic disorder characterized by degeneration of the central nervous system. Leigh syndrome can be maternally inherited due to mutation in mitochondria DNA (mtDNA) genes (Clafaloni, E. et al., Journal of Pediatrics 1993, 12(3) 419-422), sex-linked due to pyruvate
  • Leigh syndrome can be caused by mutations in mitochondrial DNA or by deficiencies of pyruvate dehydrogenase. Symptoms of Leigh syndrome usually begin between the ages of 3 months to 2 years and progress rapidly. In most children, the first signs may be poor sucking ability and loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures.
  • COX cytochrome c oxidase
  • Mitochondrial DNA encodes the three subunits containing the catalytic core and the electron-transfer functions, while nuclear DNA encodes the other 10 subunits involved in the regulation and assembly of the enzyme.
  • a disease termed "Leigh-like syndrome” is also recognized, which is characterized by neurologic abnormalities atypical for but suggestive of Leigh syndrome (Finsterer, J., “Leigh and Leigh-like syndrome in children and adults," Pediatr. Neurol. 2008; 39:223-235). The incidence of Leigh syndrome is estimated at 1 in 40,000 live births (Finsterer, J. ibid.) and is the most common mitochondrial disease of infancy.
  • SURF1 Mutation in the complex IV assembly genes, particularly SURF1, is an important cause of isolated COX deficiency that results in Leigh syndrome.
  • the SURF1 gene is located on chromosome 9q34 in a highly conserved cluster of housekeeping genes and is ubiquitously expressed.
  • the SURF1 protein is required to correct assembly of complex IV but it is not a constituent of this enzyme.
  • SURF1 is a chaperone responsible for the incorporation of heme A into nascent complex IV subunits during early steps of complex IV formation (Stiburek. L. et al., Biochemical Journal 2003, 392, 625-632 and Barrientos, A.
  • the present invention is based on the discovery disclosed herein that adjunctive administration of one or more quinones of Formula f x or their reduced form of Formula I red and one or more naphthoquinones of Formula If x or their reduced form of Formula II red can be used for the treatment of disorders due to mitochondrial defects or malfunctions in a person in need therof.
  • the adjunctive administration of one or more compounds of Formula I ox or I red and one or more compounds of Formula If x or II red can also be used for the treatment of impaired oxidative metabolism and energy production resulting from a mitochondrial defect or deficiency in a person in need therof.
  • the present invention also provides a method for treatment of mitochondrial dysfunctions comprising administration of one or more compounds of Formula I ox or I red and one or more compounds of Formula II ox or II red wherein the amount of one or more compounds of Formula I ox or I red and one or more compounds of Formula II ox or II red are selected to produce a synergistic effect.
  • the present invention also provides a method for treatment of mitochondrial disorder comprising administration of one or more compounds of Formula I ox or I red and one or more compounds of Formula II ox or II red wherein the amount of one or more compounds of Formula I ox or I red and one or more compounds of Formula II ox or II red are selected to produce an additive effect.
  • the invention embraces adjunctive administration of one or more quinones of Formula I ox or their reduced form of Formula I red and one or more naphthoquinones of Formula II ox or their reduced form of Formula II red , wherein Formulas I ox and I red
  • R 1 is selected from the group consisting of
  • the bond indicated by a dashed line can be double or single
  • R 11 , R 12 and R 1 1 3 J are independently of each other hydrogen; -(Ci-C 6 )alkyl; or
  • Y is hydrogen; -OR 14 , -CN or -COOR 15 ;
  • R 14 and R 15 are independently of each other selected from hydrogen, -(Ci-C 6 )alkyl, and -(C Ce ⁇ aloalkyl;
  • n is 0-12, with the proviso that when n is an integer from 2 to 12, each unit can be the same or different;
  • n 1-12, with the proviso that when m is an integer from 2 to 12, each unit can be the same or different;
  • v 1-10;
  • w 1-5;
  • z is 1-3, with the proviso that when z is an integer of 2 to 3, w is optionally variable from 1-5 in each occurrence of the group;
  • R is selected from the group consisting of
  • the bond indicated by a dashed line can be double or single
  • R 22 are independently of each other hydrogen; -(C 1 -C 6 )alkyl;
  • R 23 is independently of each other hydrogen; -(Ci-C 6 )alkyl; -OH; or -0(Ci-C 6 )alkyl; p is 0-12, with the proviso that when p is an integer from 2 to 12, each unit can be the same or different; and
  • q is 1-12, with the proviso that when q is an integer from 2 to 12, each unit can be the same or different;
  • the one or more quinones of Formula I ox is selected from alpha tocopherol quinone, beta tocopherol quinone, gamma-tocopherol quinone, delta tocopherol quinone, alpha tocotrienol quinone, beta tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, ubiquinone and idebenone.
  • the one or more quinones of Formula I red is selected from alpha tocopherol hydroquinone, beta-tocopherol hydroquinone, gamma- tocopherol hydroquinone, delta-tocopherol hydroquinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, delta-tocotrienol hydroquinone and ubiquinol.
  • the invention embraces adjunctive administration of one or more quinones of Formula I and one or more naphthoquinones of Formula II, wherein Formula I is:
  • R 1 is selected from the group consisting of
  • the bond indicated by a dashed line can be double or single
  • R 11 , R 12 and R 13 are independently of each other hydrogen; -(Ci-C 6 )alkyl; or
  • Y is hydrogen; -OR 14 , -CN or -COOR 15 ;
  • R 14 and R 15 are independently of each other selected from hydrogen, -(C 1 -C6)alkyl, and -(CrC ⁇ haloalkyl;
  • n is 0-12, with the proviso that when n is an integer from 2 to 12, each unit can be the same or different;
  • n 1-12, with the proviso that when m is an integer from 2 to 12, each unit can be the same or different;
  • z is 1-3, with the proviso that when z is an integer of 2 to 3, w is optionally variable from 1-5 in each occurrence of the group;
  • R is selected from the group consisting of
  • the bond indicated by a dashed line can be double or single
  • R 22 are independently of each other hydrogen; -(C 1 -C 6 )alkyl;
  • R 23 is independently of each other hydrogen; -(Ci-C 6 )alkyl; -OH; or -0(Ci-C 6 )alkyl; p is 0-12, with the proviso that when p is an integer from 2 to 12, each unit can be the same or different; and
  • q is 1-12, with the proviso that when q is an integer from 2 to 12, each unit can be the same or different;
  • the one or more quinones of Formula I are selected from one or more quinones of Formula la: where,
  • R 1 is selected from the group consisting of
  • the bond indicated by a dashed line can be double or single
  • R 11 , R 12 and R 13 are independently of each other hydrogen; -(C 1 -C 6 )alkyl; or
  • Y is hydrogen; -OR 14 , -CN or -COOR 15 ;
  • R 14 and R 15 are independently of each other selected from hydrogen, -(Ci-C6)alkyl, and -(Ci-C 6 )haloalkyl;
  • w is 1-5; and z is 1-3, with the proviso that when z is an integer of 2 to 3, w is optionally variable from 1-5 in each occurrence of the group;
  • the one or more quinones of Formula I are selected from one or more quinones of Formula la:
  • R 1 is selected from the group consisting of :
  • the bond indicated by a dashed line can be double or single
  • R 11 , R 12 and R 1 1 3 J are independently of each other hydrogen; -(C 1 -C 6 )alkyl; or
  • n is 0-12, with the proviso that when n is an integer from 2 to 12, each unit can be the same or different;
  • the one or more quinones of Formula la are selected from quinones wherein R 1 is -(CH 2 )o-i9-CH 3 .
  • the one or more quinones of Formula la are selected from quinones wherein R 1 is -(CH 2 )o-i9-CH 2 -OH.
  • the one or more quinones of Formula la are selected from quinones wherein R 1 is -((CH 2 ) 2 -CH(CH 3 ))i- 2 o-CH 3 .
  • the one or more quinones of Formula la are selected from quinones wherein R 1 is:
  • n is 0-12, wherein when n is 2-12, each unit can be the same or different.
  • the quinone of Formula la is selected from quinones wherein R 11 and R 12 are independently selected from hydrogen, -(Cr
  • the quinone of Formula la is selected from quinones wherein R 11 and R 12 are
  • R 13 is methyl
  • the quinone of Formula la is selected from quinones wherein R 11 and R 12 are independently of each other -0(Ci-C6)alkyl; and
  • R 13 is hydrogen or -(C 1 -C6)alkyl.
  • the quinone of Formula la is selected from quinones wherein R 11 and R 12 are methoxy; and R 13 is hydrogen or methyl.
  • the quinone of Formula la is selected from quinones wherein R 11 , R 12 and R 13 are independently selected from hydrogen and - (C 1 -C6)alkyl. In other embodiments, the quinone of Formula la is selected from quinones wherein R 11 , R 12 and R 13 are independently selected from hydrogen or methyl.
  • the quinone of Formula la is selected from quinones wherein R 11 , R 12 and R 13 are independently of each other -(C 1 -C6)alkyl. In other embodiments, the quinone of Formula la is selected from quinones wherein R 11 , R 12 and R 13 are methyl.
  • the quinone of Formula la is selected from quinones wherein R 11 , R 12 and R 13 are hydrogen.
  • the quinone of Formula la is selected from quinones wherein the bond indicated by a dashed line is a double bond. In some embodiments, the quinone of Formula la is selected from quinones wherein the bond indicated by a dashed line is a single bond.
  • the quinone of Formula la is selected from quinones wherein n is the integer 0. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer one. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer two. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer three. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer four. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer five. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer six.
  • the quinone of Formula la is selected from quinones wherein n is the integer seven. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer eight. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer nine. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer ten. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer eleven. In other embodiments, the quinone of Formula la is selected from quinones wherein n is the integer twelve.
  • the quinone of Formula la is Idebenone. In other embodiments, the quinone of Formula la is ubiquinone or CoQIO. In other embodiments, the quinone of Formula la is CoQ2. In other embodiments, the quinone of Formula la is CoQ4. In some embodiments the quinone of Formula la is 2,3,5- trimethyl-6-nonylcyclohexa-2,5-diene- 1 ,4-dione.
  • the one or more quinones of Formula I are selected from quinones of Formula lb:
  • R 1 is: the * indicates the point of attachment to R 1 ;
  • the bond indicated by a dashed line can be double or single
  • R 11 , R 12 and R 1 1 3 J are independently of each other hydrogen; -(Ci-C6)alkyl; or
  • n 1-12, with the proviso that when m is an integer from 2 to 12, each unit can be the same or different;
  • the quinone of Formula lb is selected from
  • quinone of Formula lb is selected from quinones wherein R and R are
  • the quinone of Formula lb is selected from
  • R is hydrogen or -(C 1 -C6)alkyl.
  • the quinone of Formula lb is hydrogen or -(C 1 -C6)alkyl.
  • R is selected from quinones wherein R and R are methoxy; and R is hydrogen or methyl.
  • the quinone of Formula lb is selected from
  • quinones wherein R , R and R are independently selected from hydrogen and - (C 1 -C6)alkyl.
  • the quinone of Formula lb is selected from
  • the quinone of Formula lb is selected from
  • the quinone of Formula lb is selected from quinones wherein R 11 , R 12 and R 13 are methyl.
  • the quinone of Formula lb is selected from
  • the quinone of Formula lb is selected from quinones wherein the bond indicated by a dashed line is a double bond. In some embodiments, the quinone of Formula lb is selected from quinones wherein the bond indicated by a dashed line is a single bond.
  • the quinone of Formula lb is selected from quinones wherein m is the integer 0. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer one. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer two. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer three. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer four. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer five.
  • the quinone of Formula lb is selected from quinones wherein m is the integer six. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer seven. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer eight. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer nine. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer ten. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer eleven. In other embodiments, the quinone of Formula lb is selected from quinones wherein m is the integer twelve.
  • the quinone of Formula lb is selected from one or more tocopherol quinones. In other embodiments, the quinone of Formula lb is alpha-tocopherol quinone. In other embodiments, the quinone of Formula lb is beta- tocopherol quinone. In other embodiments, the quinone of Formula lb is gamma- tocopherol quinone. In other embodiments, the quinone of Formula lb is delta- tocopherol quinone.
  • the quinone of Formula lb is selected from one or more tocotrienol quinones. In other embodiments, the quinone of Formula lb is alpha- tocotrienol quinone. In other embodiments, the quinone of Formula lb is beta- tocotrienol quinone. In other embodiments, the quinone of Formula lb is gamma- tocotrienol quinone. In other embodiments, the quinone of Formula lb is delta- tocotrienol quinone.
  • the one or more naphthoquinone of Formula II are selected from naphthoquinones of Formula Ila:
  • R is independently selected from the group consisting of :
  • the bond indicated by a dashed line can be double or single
  • R 21 and R 2"2 are independently of each other hydrogen; -(Ci-C 6 )alkyl; or - (Xd-Q alkyl;
  • R 23 is independently of each other hydrogen; -(C 1 -C 6 )alkyl; -OH; or -0(C 1 -C 6 )alkyl; and
  • p is 0-12, with the proviso that when p is an integer from 2 to 12, each unit can be the same or different;
  • the one or more naphthoquinones of Formula Ila are selected from naphthoquinones wherein R is -(CH 2 )o-i9-CH 3 .
  • the one or more naphthoquinones of Formula Ila are selected from naphthoquinones wherein R is -((CH 2 ) 2 -CH(CH )) 1 _ 20 -CH .
  • the one or more naphthoquinones of Formula Ila are selected from naphthoquinones wherein R is
  • each unit can be the same or different.
  • the one or more naphthoquinones of Formula Ila are selected from naphthoquinones wherein R is p is 0-12, with the proviso that when p is an integer from 2 to 12, each unit can be the same or different and the bond represented by a dashed line is a single bond in every unit.
  • the one or more naphthoquinones of Formula Ila is selected from naphthoquinones wherein R is
  • p is 0-12, with the proviso that when p is an integer from 2 to 12, each unit can be the same or different and the bond represented by a dashed line is a double bond in every unit.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen, -(C 1 -C 6 )alkyl and -0(C 1 -C 6 )alkyl; and R 23 is -(C 1 -C 6 )alkyl.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and
  • R 22 are independently selected from hydrogen, methyl and methoxy; and R 23 is methyl.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen,
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen, methyl and methoxy; and R 23 is hydroxy.
  • the naphthoquinone of Formula Ila is selected from quinones wherein R 21 and R 12 are independently of each other -0(C 1 -C 6 )alkyl; and
  • R 23 is hydrogen or -(C 1 -C 6 )alkyl.
  • Formula Ila is selected from quinones wherein R 21 and R 22 are methoxy; and R 23 is hydrogen or methyl.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 , R 22 and R 23 are independently selected from hydrogen and -(C 1 -C 6 )alkyl. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 , R 22 and R 23 are independently selected from hydrogen or methyl. [0076] In some embodiments, the naphthoquinone of Formula Ila is selected from quinones wherein R 21 , R 22 and R 23 are independently of each other -(C 1 -C6)alkyl. In other embodiments, the naphthoquinone of Formula Ila is selected from quinones wherein R 21 , R 22 and R 23 are methyl.
  • the naphthoquinone of Formula Ila is selected from quinones wherein R 21 , R 22 and R 23 are hydrogen.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer 0. In other embodiments, the
  • naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer one. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer two. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer three. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer four. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer five.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer six. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer seven. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer eight. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer nine. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer ten.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer eleven. In other embodiments, the naphthoquinone of Formula Ila is selected from naphthoquinones wherein p is the integer twelve.
  • the naphthoquinone is selected from one or more naphthoquinones of Formula Ila wherein said naphthoquinones are selected from the group of Vitamin Kl, Vitamin K2 and mixtures therof.
  • the naphthoquinone is selected from a naphthoquinone of Formula Ila where R 21 and R 22 are hydrogen, R 23 is methyl, p is 3 and the bond indicated with a dashed line is a single bond in every unit, said naphthoquinone being Vitamin Kl also known as phylloquinone, phytonadione, or phytomenadione .
  • the naphthoquinone of Formula Ila is a Vitamin Kl also known as phylloquinone, phytonadione, or phytomenadione .
  • the naphthoquinone of Formula Ila is selected from vitamin MK-2: (2-(3,7-dimethylocta- 2,6-dien-l-yl)-3-methylnaphthalene-l,4-dione); vitamin MK-3: (2-methyl-3-(3,7,l l- trimethyldodeca-2,6,10-trien-l-yl)naphthalene-l,4-dione); vitamin MK-4: (2-methyl- 3-[3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl]naphthoquinone); vitamin MK-5: (2-methyl-3-(3,7,l l,15,19-pentamethylicosa-2,6,10,14,18-pentaen-
  • the naphthoquinone of Formula Ila is selected from vitamin MK-2, vitamin MK-3, vitamin MK-4, vitamin MK-5, vitamin MK-6, and vitamin MK-7.
  • the naphthoquinone of Formula Ila is vitamin MK2.
  • the naphthoquinone of Formula Ila is vitamin MK-4.
  • the naphthoquinone of Formula Ila is vitamin MK7.
  • the naphthoquinone of Formula Ila is administered as a fermented soy bean food known as natto.
  • the one or more naphthoquinones of Formula II are selected from naphthoquinones of Formula lib:
  • R is independently selected from:
  • the bond indicated by a dashed line can be double or single
  • R 21 and R 2"2 are independently of each other hydrogen; -(C 1 -C 6 )alkyl; or - (Xd-QDalkyl;
  • R 21 and R 2"2 are independently of each other hydrogen; -(C 1 -C 6 )alkyl; -OH; or
  • q is 1-12, with the proviso that when q is an integer from 2 to 12, each unit can be the same or different;
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen, -(C 1 -C 6 )alkyl and -0(C 1 -C 6 )alkyl; and R 23 is -(C 1 -C 6 )alkyl.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein R 21 and
  • R 22 are independently selected from hydrogen, methyl and methoxy and R 23 is methyl.
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen,
  • the naphthoquinone of Formula Ila is selected from naphthoquinones wherein R 21 and R 22 are independently selected from hydrogen, methyl and methoxy; and R 23 is hydroxy.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 and R 12 are independently of each other -0(C 1 -C 6 )alkyl; and R 23 is hydrogen or -(C 1 -C6)alkyl.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 and R 12 are independently of each other -0(C 1 -C 6 )alkyl; and R 23 is hydrogen or -(C 1 -C6)alkyl.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 and R 12 are independently of each other -0(C 1 -C 6 )alkyl; and R 23 is hydrogen or -(C 1 -C6)alkyl.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 and R 12 are independently of each other -0(C 1 -C 6 )alkyl; and R 23 is hydrogen or
  • Formula lib is selected from quinones wherein R 21 and R 22 are methoxy; and R 23 is hydrogen or methyl.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein R 21 , R 22 and R 23 are independently selected from hydrogen and -(C 1 -C6)alkyl. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein R 21 , R 22 and R 23 are independently selected from hydrogen or methyl.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 , R 22 and R 23 are independently of each other -(C 1 -C6)alkyl. In other embodiments, the naphthoquinone of Formula lib is selected from quinones wherein R 21 , R 22 and R 23 are methyl.
  • the naphthoquinone of Formula lib is selected from quinones wherein R 21 , R 22 and R 23 are hydrogen.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein the bond indicated by a dashed line is a double bond. In some embodiments, the naphthoquinone of Formula lib is selected from
  • naphthoquinones wherein the bond indicated by a dashed line is a single bond.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer 0. In other embodiments, the
  • naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer one. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer two. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer three. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer four. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer five.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer six. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer seven. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer eight. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer nine. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer ten.
  • the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer eleven. In other embodiments, the naphthoquinone of Formula lib is selected from naphthoquinones wherein q is the integer twelve.
  • the naphthoquinone of Formula lib is selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien-l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6, 10, 14-trien- 1 -yl)-3,6,7-trimethylnaphthalene- 1 ,4-dione.
  • the adjunctive therapy comprises one or more tocopherol quinones and Vitamin K.
  • the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin K.
  • the adjunctive therapy comprises beta-tocopherol quinone and Vitamin K.
  • the adjunctive therapy comprises gamma-tocopherol quinone and Vitamin K.
  • the adjunctive therapy comprises delta-tocopherol quinone and Vitamin K.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin K.
  • the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises beta-tocopherol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises gamma- tocopherol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin K.
  • the adjunctive therapy comprises alpha-tocotrienol quinone and Vitamin K.
  • the adjunctive therapy comprises beta-tocotrienol quinone and Vitamin K.
  • the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin K.
  • the adjunctive therapy comprises delta-tocotrienol quinone and Vitamin K.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin K.
  • the adjunctive therapy comprises alpha-tocotrienol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises beta-tocotrienol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises gamma- tocotrienol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises delta-tocotrienol hydroquinone and Vitamin K.
  • the adjunctive therapy comprises one or more tocopherol quinones and Vitamin Kl.
  • the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin Kl.
  • the adjunctive therapy comprises beta-tocopherol quinone and Vitamin Kl.
  • the adjunctive therapy comprises gamma-tocopherol quinone and Vitamin Kl.
  • the adjunctive therapy comprises delta- tocopherol quinone and Vitamin Kl.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin Kl.
  • the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises beta-tocopherol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises gamma- tocopherol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin Kl.
  • the adjunctive therapy comprises alpha-tocotrienol quinone and Vitamin Kl.
  • the adjunctive therapy comprises beta-tocotrienol quinone and Vitamin Kl.
  • the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin Kl.
  • the adjunctive therapy comprises delta- tocotrienol quinone and Vitamin Kl.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin Kl.
  • the adjunctive therapy comprises alpha-tocotrienol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises beta-tocotrienol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises gamma- tocotrienol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises delta-tocotrienol hydroquinone and Vitamin Kl.
  • the adjunctive therapy comprises one or more tocopherol quinones and Vitamin K2. In some embodiments the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises beta-tocopherol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises gamma-tocopherol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises delta-tocopherol quinone and Vitamin K2.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin K2. In some embodiments the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises beta-tocopherol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises gamma- tocopherol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin K2.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin K2. In some embodiments the adjunctive therapy comprises alpha-tocotrienol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises beta-tocotrienol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin K2. In some embodiments the adjunctive therapy comprises delta- tocotrienol quinone and Vitamin K2.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin K2. In some embodiments the adjunctive therapy comprises alpha-tocotrienol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises beta-tocotrienol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises gamma- tocotrienol hydroquinone and Vitamin K2. In some embodiments the adjunctive therapy comprises delta-tocotrienol hydroquinone and Vitamin K2.
  • the adjunctive therapy comprises one or more tocopherol quinones and Vitamin MK4. In some embodiments the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises beta-tocopherol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises gamma-tocopherol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises delta- tocopherol quinone and Vitamin MK4.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin MK4. In some embodiments the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises beta-tocopherol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises gamma- tocopherol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin MK4.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin MK4. In some embodiments the adjunctive therapy comprises alpha-tocotrienol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises beta-tocotrienol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises delta- tocotrienol quinone and Vitamin MK4.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin MK4. In some embodiments the adjunctive therapy comprises alpha-tocotrienol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises beta-tocotrienol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises gamma- tocotrienol hydroquinone and Vitamin MK4. In some embodiments the adjunctive therapy comprises delta-tocotrienol hydroquinone and Vitamin MK4.
  • the adjunctive therapy comprises one or more tocopherol quinones and a Vitamin MK7. In some embodiments the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin MK7. In some
  • the adjunctive therapy comprises beta-tocopherol quinone and Vitamin MK7. In some embodiments the adjunctive therapy comprises gamma- tocopherol quinone and Vitamin MK7. In some embodiments the adjunctive therapy comprises delta-tocopherol quinone and Vitamin MK7.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin MK7.
  • the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises beta-tocopherol hydroquinone and Vitamin MK4.
  • the adjunctive therapy comprises gamma- tocopherol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises one or more tocopherol quinones and Vitamin K2 administered as natto.
  • the adjunctive therapy comprises alpha-tocopherol quinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises beta- tocopherol quinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises gamma-tocopherol quinone and Vitamin K2
  • adjunctive therapy comprises delta- tocopherol quinone and Vitamin K2 administered as natto.
  • the adjunctive therapy comprises one or more tocopherol hydroquinones and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises alpha-tocopherol hydroquinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises beta- tocopherol hydroquinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises gamma-tocopherol
  • adjunctive therapy comprises delta-tocopherol hydroquinone and Vitamin K2 administered as natto.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin MK7.
  • the adjunctive therapy comprises alpha- tocotrienol quinone and Vitamin MK7.
  • the adjunctive therapy comprises beta- tocotrienol quinone and Vitamin MK7.
  • the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin MK7.
  • the adjunctive therapy comprises delta- tocotrienol quinone and Vitamin MK7.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin MK7.
  • the adjunctive therapy comprises alpha- tocotrienol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises beta-tocotrienol hydroquinone and Vitamin MK4.
  • the adjunctive therapy comprises gamma- tocotrienol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises delta- tocotrienol hydroquinone and Vitamin MK7.
  • the adjunctive therapy comprises one or more tocotrienol quinones and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises alpha-tocotrienol quinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises beta- tocotrienol quinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises gamma-tocotrienol quinone and Vitamin K2
  • adjunctive therapy comprises delta- tocotrienol quinone and Vitamin K2 administered as natto.
  • the adjunctive therapy comprises one or more tocotrienol hydroquinones and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises alpha-tocotrienol hydroquinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises beta- tocotrienol hydroquinone and Vitamin K2 administered as natto. In some embodiments the adjunctive therapy comprises gamma-tocotrienol
  • adjunctive therapy comprises delta-tocotrienol hydroquinone and Vitamin K2 administered as natto.
  • the adjunctive therapy comprises one or more tocopherol quinones and a compound of Formula lib selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4- dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-
  • the adjunctive therapy comprises alpha-tocopherol quinone and a compound of Formula lib selected from 2- (3-hydroxy-3,7, 11, 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- l,4-dione; 2-(3 -hydroxy- 3,7,11,15 - tetramethylhexadeca- 6,10,14-trien- 1 - yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10,14- trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2- (3-hydroxy-3,7, 11, 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- l,4-dione; 2-(3
  • the adjunctive therapy comprises beta-tocopherol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien- l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6,10,14-trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione;
  • the adjunctive therapy comprises gamma-tocopherol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien- l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6,10,14-trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-d
  • the adjunctive therapy comprises delta-tocopherol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien-l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6, 10, 14-trien- 1 -yl)-3,6,7-trimethylnaphthalene- 1 ,4-dione.
  • Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione;
  • the adjunctive therapy comprises one or more tocotrienol quinones and a compound of Formula lib selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4- dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione;
  • the adjunctive therapy comprises alpha-tocotrienol quinone and a compound of Formula lib selected from 2- (3-hydroxy-3,7, 11, 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- l,4-dione; 2-(3 -hydroxy- 3,7,11,15 - tetramethylhexadeca- 6,10,14-trien- 1 - yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10,14- trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2- (3-hydroxy-3,7, 11, 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- l,4-dione; 2-(3
  • the adjunctive therapy comprises beta-tocotrienol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien- l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6,10,14-trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione
  • the adjunctive therapy comprises gamma-tocotrienol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-
  • the adjunctive therapy comprises delta-tocotrienol quinone and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione;
  • the adjunctive therapy comprises idebenone and Vitamin K.
  • the adjunctive therapy comprises idebenone and Vitamin Kl.
  • the adjunctive therapy comprises idebenone and Vitamin K2.
  • the adjunctive therapy comprises idebenone and Vitamin MK4.
  • the adjunctive therapy comprises idebenone and Vitamin MK7.
  • the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin K. In other embodiments, the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin Kl. In other words, the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin Kl. In other embodiments,
  • the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin K2. In other embodiments, the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin MK4. In other embodiments, the adjunctive therapy comprises Coenzyme Q10 or dihydro-CoQIO, and Vitamin MK7.
  • the adjunctive therapy comprises Coenzyme Q2 or dihydro-CoQ2, and Vitamin K. In other embodiments, the adjunctive therapy comprises Coenzyme Q2 or dihydro-CoQ2, and Vitamin Kl. In other embodiments, the adjunctive therapy comprises Coenzyme Q2 or dihydro-CoQ2, and Vitamin K2. In other embodiments, the adjunctive therapy comprises Coenzyme Q2 or dihydro- CoQ2, and Vitamin MK4. In other embodiments, the adjunctive therapy comprises Coenzyme Q2 or dihydro-CoQ2, and Vitamin MK7.
  • the adjunctive therapy comprises Coenzyme Q4 or dihydro-CoQ4, and Vitamin K. In other embodiments, the adjunctive therapy comprises Coenzyme Q4 or dihydro-CoQ4, and Vitamin Kl. In other embodiments, the adjunctive therapy comprises Coenzyme Q4 or dihydro-CoQ4 and Vitamin K2. In other embodiments, the adjunctive therapy comprises Coenzyme Q4 or dihydro- CoQ4, and Vitamin MK4. In other embodiments, the adjunctive therapy comprises Coenzyme Q4 or dihydro-CoQ4, and Vitamin MK7.
  • the adjunctive therapy comprises 2,3,5-trimethyl-6- (12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone and Vitamin K. In other embodiments, the adjunctive therapy comprises 2,3,5-trimethyl-6-(12- hydroxy-5,10- dodecadiynyl)-l,4-benzoquinone and Vitamin Kl. In other embodiments, the adjunctive therapy comprises 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4- benzoquinone and Vitamin K2.
  • the adjunctive therapy comprises 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone and Vitamin MK4. In other embodiments, the adjunctive therapy comprises 2,3,5- trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone and Vitamin MK7.
  • the adjunctive therapy comprises administration of one or more compounds of Formula f x or I red and one or more compounds of Formula II ox or If ed by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical composition.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, one or more compounds of Formula I ox or f ed and one or more compounds of Formula II ox or If ed .
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of Formula I ox and a compound of Formula II ox .
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a tocopherol quinone or tocotrienol quinone and a Vitamin K.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutical composition comprising a
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a tocopherol quinone or a tocotrienol hydroquinone and a naphthohydroquinone of Vitamin K.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, idebenone and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQIO or dihydro- CoQlO, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQ2 or dihydro-CoQ2, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQ4 or dihydro-CoQ4, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone. and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, alpha-tocopherol quinone or alpha-tocotrienol quinone, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, beta-tocopherol quinone or beta-tocotrienol quinone, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, gamma-tocopherol quinone or gamma-tocotrienol quinone, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, delta- tocopherol quinone or delta- tocotrienol quinone, and Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, alpha-tocopherol hydroquinone or alpha-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, beta-tocopherol hydroquinone or beta-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, gamma-tocopherol hydroquinone or gamma-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, delta-tocopherol hydroquinone or delta-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin Kl.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, idebenone and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQIO or dihydro- CoQlO, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQ2 or dihydro-CoQ2, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, CoQ4 or dihydro-CoQ4, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, alpha-tocopherol quinone or alpha-tocotrienol quinone, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, beta-tocopherol quinone or beta-tocotrienol quinone, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, gamma-tocopherol quinone or gamma-tocotrienol quinone, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, delta-tocopherol quinone or delta-tocotrienol quinone, and Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, alpha-tocopherol hydroquinone or alpha-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, beta-tocopherol hydroquinone or beta-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, gamma-tocopherol hydroquinone or gamma-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier, delta-tocopherol hydroquinone or delta-tocotrienol hydroquinone, and a naphthohydroquinone of Vitamin K2.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more a compounds of Formula la, and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of Formula Ila.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a tocopherol quinone or a tocotrienol quinone; and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien- l-yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca- 6,10,14-trien-l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7, 11,15- tetra
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and alpha-tocotrienol quinone or alpha-tocotrienol quinone; and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2- (3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3-methylnaphthalene- l,4-dione; 2-(3 -hydroxy- 3,7,11,15 - tetramethylhexadeca- 6,10,14-trien- 1 - yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10,14- trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-dione.
  • Formula lib selected from 2- (3-hydroxy-3,7,l l,15-
  • the co- therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and beta-tocopherol quinone or beta-tocotrienol quinone; and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene-l,4-dione.
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable
  • composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene-l,4-dione.
  • a pharmaceutically acceptable carrier selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and delta-tocopherol quinone or delta-tocotrienol quinone and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien- l-yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca- 6,10,14-trien-l-yl)naphthalene-l,4-dione; and 2-(3-hydroxy-3,7, 11,15- tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7-trimethylnaphthalene- 1 ,4-dione.
  • Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhe
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a tocopherol hydroquinone or a tocotrienol hydroquinone and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-diol; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien-l-yl)naphthalene-l,4-diol; and 2-(3-hydroxy-3,7,l 1,15-tetramethylhexadeca- 6,10,14-trien-l-yl)-3,6,7-trimethylnaphthalene-l,4-diol.
  • the co-therapy comprises a pharmaceutical composition comprising
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and beta-tocopherol hydroquinone or beta-tocotrienol hydroquinone and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- 1 ,4-diol; 2-(3-hydroxy- 3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien-l-yl)naphthalene-l,4-diol; and 2-(3- hydroxy-3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene-l,4-diol.
  • Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- t
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and gamma-tocopherol hydroquinone or gamma-tocotrienol hydroquinone and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- 1 ,4-diol; 2-(3-hydroxy- 3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien-l-yl)naphthalene-l,4-diol; and 2-(3- hydroxy-3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene-l,4-diol.
  • Formula lib selected from 2-(3-hydroxy-3,7,
  • the co-therapy comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier and delta-tocopherol hydroquinone or delta-tocotrienol hydroquinone and another pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula lib selected from 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- l-yl)-3-methylnaphthalene- 1 ,4-diol; 2-(3-hydroxy- 3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien-l-yl)naphthalene-l,4-diol; and 2-(3- hydroxy-3,7,1 l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene- 1 ,4-diol.
  • Formula lib selected from 2-(3-hydroxy-3,7,l 1,15-
  • the invention provides a composition comprising one or more compounds of Formula f x or I red , and one or more compounds of Formula If x or II red and a pharmaceutically acceptable carrier.
  • the invention provides a composition comprising a tocopherol quinone or a tocotrienol quinone, vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a composition comprising a tocopherol hydroquinone or a tocotrienol hydroquinone, naphthohydroquinone of vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising one or more compounds of Formula I ox or I red , and one or more compounds of Formula II ox or II red and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising idebenone, vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising CoQIO or dihydro-CoQIO, vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising CoQ2 or dihydro-CoQ2, vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising CoQ4 or dihydro-CoQ4, vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising idebenone, vitamin K and a
  • the invention provides a pharmaceutical composition comprising a tocopherol quinone or a tocotrienol quinone, vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising a tocopherol hydroquinone or a tocotrienol hydroquinone, naphthohydroquinone of vitamin K and a pharmaceutically acceptable carrier.
  • the composition is for the treatment of mitochondrial diseases.
  • the compositions comprise a quinone of Formula I ox or I red , a naphthoquinones of Formula II ox or II red and a pharmaceutically acceptable carrier in amounts wherein the quinone and the naphthoquinone exhibit a synergistic effect.
  • the invention provides a pharmaceutical composition comprising one or more compounds of Formula I ox or I red , and one or more compounds of Formula If x or II red and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising idebenone, vitamin Kl and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising CoQIO or dihydro-CoQIO, vitamin Kl and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising CoQ2 or dihydro-CoQ2, vitamin Kl and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising CoQ4 or dihydro-CoQ4, vitamin Kl and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, vitamin Kl and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising idebenone, vitamin Kl and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a pharmaceutical composition comprising a tocopherol quinone or a tocotrienol quinone, vitamin Kl and a pharmaceutically acceptable carrier. In some
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a tocopherol hydroquinone or a tocotrienol hydroquinone, naphthohydroquinone of vitamin Kl and a pharmaceutically acceptable carrier.
  • the composition is for the treatment of mitochondrial diseases.
  • the compositions comprise a quinone of Formula I ox or I red , a naphthoquinone of Formula II ox or II red and a pharmaceutically acceptable carrier in amounts wherein the quinone and the naphthoquinone exhibit a synergistic effect.
  • the invention provides a pharmaceutical composition comprising one or more compounds of Formula I ox or I red , and one or more compounds of Formula II ox or II red and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising idebenone, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising CoQIO or dihydro-CoQIO, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising CoQ2 or dihydro-CoQ2, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising CoQ4 or dihydro-CoQ4, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising idebenone, vitamin K2 and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising a tocopherol quinone or a tocotrienol quinone, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a tocopherol hydroquinone or a tocotrienol hydroquinone, naphthohydroquinone of vitamin K2 and a pharmaceutically acceptable carrier.
  • the composition is for the treatment of mitochondrial diseases.
  • the compositions comprise a quinone of Formula I ox or I red , a naphthoquinone of Formula If x or II red and a pharmaceutically acceptable carrier in amounts wherein the quinone and the naphthoquinone exhibit a synergistic effect.
  • the invention provides a process for making a pharmaceutical composition comprising mixing one or more compounds of Formula I ox or I red , one or more one or more compounds of Formula II ox or II red and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing idebenone, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing CoQIO or dihydro-CoQIO, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing CoQ2 or dihydro-CoQ2, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing CoQ4 or dihydro-CoQ4, a vitamin K and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a process for making a pharmaceutical composition comprising mixing 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)- 1,4-benzoquinone, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing a tocopherol quinone selected from alpha-tocopherol quinone, beta-tocopherol quinone, delta-tocopherol quinone, and gamma-tocopherol quinone or mixtures therof, a vitamin K and a pharmaceutically acceptable carrier.
  • a tocopherol quinone selected from alpha-tocopherol quinone, beta-tocopherol quinone, delta-tocopherol quinone, and gamma-tocopherol quinone or mixtures therof, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing a tocotrienol quinone selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, delta-tocotrienol quinone, and gamma-tocotrienol quinone or mixtures therof, a vitamin K and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing alpha-tocopherol quinone or alpha-tocotrienol quinone, vitamin Kl and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing alpha-tocopherol quinone or alpha-tocotrienol quinone, vitamin K2 and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing alpha-tocopherol quinone or alpha-tocotrienol quinone, vitamin MK2 and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a process for making a pharmaceutical composition comprising mixing alpha-tocopherol quinone or alpha-tocotrienol quinone, vitamin MK4 and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a process for making a pharmaceutical composition comprising mixing alpha-tocopherol quinone or alpha-tocotrienol quinone, vitamin MK7 and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing a compound of Formula lb, a compound of Formula lib and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising mixing a quinone selected from alpha-tocopherol quinone, beta-tocopherol quinone, delta-tocopherol quinone, gamma-tocopherol quinone, alpha-tocotrienol quinone, beta-tocotrienol quinone, delta-tocotrienol quinone, and gamma-tocotrienol quinone or mixtures therof, a compound of Formula lib selected from 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3- methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-t
  • the invention provides methods of treating
  • mitochondrial disorders with a therapeutically effective amount of one or more compounds of Formula I ox or I red , and one or more compounds of Formula If x or II red , wherein the amount of compound of Formula I ox or I red and the amount of compound of Formula II ox or II red are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of idebenone, and one or more compounds of Vitamin K, wherein the amount of idebenone and the amount of Vitamin K are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of CoQIO or dihydro- CoQlO, and one or more compounds of Vitamin K, wherein the amount of CoQIO or dihydro-CoQIO and the amount of Vitamin K are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of 2,3,5-trimethyl-6- (12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, and one or more compounds of Vitamin K, wherein the amount of 2,3,5-trimethyl-6-(12- hydroxy-5,10- dodecadiynyl)-l,4-benzoquinone and the amount of Vitamin K are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of one or more tocopherol quinones or tocotrienol quinones, and one or more compounds of Vitamin K, wherein the amount of tocopherol quinone(s) or tocotrienol quinone(s) and the amount of Vitamin K are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of idebenone, and Vitamin Kl, wherein the amount of idebenone and the amount of Vitamin Kl are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of CoQIO or dihydro- CoQIO, and Vitamin Kl, wherein the amount of CoQIO or dihydro-CoQIO and the amount of Vitamin Kl are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of 2,3,5-trimethyl-6- (12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, and Vitamin Kl, wherein the amount of 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone and the amount of Vitamin Kl are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocopherol quinone and of Vitamin Kl, wherein the amount of alpha-tocopherol quinone and the amount of Vitamin Kl are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocopherol quinone and of Vitamin K2, wherein the amount of alpha-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocopherol quinone and of Vitamin MK4, wherein the amount of alpha-tocopherol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect. In some embodiments, the invention provides methods of treating mitochondrial disorders with a
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocopherol quinone and of a compound selected from 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4- dione; 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of idebenone, and one or more compounds of Vitamin K2, wherein the amount of idebenone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of CoQIO or dihydro- CoQlO, and one or more compounds of Vitamin K2, wherein the amount of CoQIO or dihydro-CoQIO and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of 2,3,5-trimethyl-6- (12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone, and one or more compounds of Vitamin K2, wherein the amount of 2,3,5-trimethyl-6-(12- hydroxy-5,10- dodecadiynyl)-l,4-benzoquinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocotrienol quinone and the amount of one or more compounds of Vitamin K2, wherein the amount of alpha-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocotrienol quinone and of Vitamin K2, wherein the amount of alpha-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha- tocotrienol quinone and of Vitamin MK4, wherein the amount of alpha-tocotrienol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocotrienol quinone and of Vitamin MK7, wherein the amount of alpha-tocotrienol quinone and the amount of Vitamin MK7 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of alpha-tocotrienol quinone and of a compound selected from 2- (3 -hydroxy- 3, 7,11, 15-tetramethylhexadeca-6, 10,14- trien- 1 -yl) -3 -methylnaphthalene- l,4-dione; 2-(3 -hydroxy- 3,7,11,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4-dione; and 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7-trimethylnaphthalene- 1 ,4- dione, wherein the amount of alpha-tocotrienol quinone and the amount of 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14- trien-
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocopherol quinone and of Vitamin K2, wherein the amount of beta-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocopherol quinone and of Vitamin K2, wherein the amount of beta-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocopherol quinone and of Vitamin MK4, wherein the amount of beta-tocopherol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect. In some embodiments, the invention provides methods of treating mitochondrial disorders with a
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocopherol quinone and of a compound selected from 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4- dione; 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-l,4
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocotrienol quinone and of Vitamin K2, wherein the amount of beta-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocotrienol quinone and of Vitamin K2, wherein the amount of beta-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocotrienol quinone and of Vitamin MK4, wherein the amount of beta-tocotrienol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect. In some embodiments, the invention provides methods of treating mitochondrial disorders with a
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of beta-tocotrienol quinone and of a compound selected from 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4- dione; 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of Vitamin Kl, wherein the amount of gamma-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of Vitamin K2, wherein the amount of gamma-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of Vitamin K2, wherein the amount of gamma-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of Vitamin MK4, wherein the amount of gamma-tocopherol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of Vitamin MK7, wherein the amount of gamma-tocotpherol quinone and the amount of Vitamin MK7 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocopherol quinone and of a compound selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4- dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-l,4-dione, wherein the amount of gamma- tocotrienol quinone and the amount of 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of Vitamin K2, wherein the amount of gamma-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of Vitamin K2, wherein the amount of gamma-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of Vitamin K2, wherein the amount of gamma-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of Vitamin MK4, wherein the amount of gamma-tocotrienol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of Vitamin MK7, wherein the amount of gamma-tocotrienol quinone and the amount of Vitamin MK7 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of gamma-tocotrienol quinone and of a compound selected from 2-(3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2- (3-hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1 ,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3,6,7- trimethylnaphthalene-l,4-dione, wherein the amount of gamma-tocotrienol quinone and the amount of 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocopherol quinone and of Vitamin K2, wherein the amount of delta-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocopherol quinone and of Vitamin K2, wherein the amount of delta-tocopherol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocopherol quinone and of Vitamin MK4, wherein the amount of delta-tocopherol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta- tocopherol quinone and of Vitamin MK7, wherein the amount of delta-tocopherol quinone and the amount of Vitamin MK7 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocopherol quinone and of a compound selected from 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4- dione; 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-l,4-dione, wherein the amount of delta-tocotrienol quinone and the amount of 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocotrienol quinone and of Vitamin K2, wherein the amount of delta-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocotrienol quinone and of Vitamin K2, wherein the amount of delta-tocotrienol quinone and the amount of Vitamin K2 are selected to produce an additive or synergistic effect.
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocotrienol quinone and of Vitamin MK4, wherein the amount of delta-tocotrienol quinone and the amount of Vitamin MK4 are selected to produce an additive or synergistic effect. In some embodiments, the invention provides methods of treating mitochondrial disorders with a
  • the invention provides methods of treating mitochondrial disorders with a therapeutically effective amount of delta-tocotrienol quinone and of a compound selected from 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4- dione; 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)naphthalene- 1,4-dione; and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6,10,14-trien-l-yl)-3,6,7- trimethylnaphthalene-
  • the mitochondrial disorder is caused by mutations in mitochondrial genes.
  • the mitochondrial disorder is caused by mutations in nuclear genes encoding for subunits of the respiratory chain complexes.
  • the mitochondrial disorder is caused by mutations in genes coding for proteins involved in the nuclear-mitochondrial communication.
  • the mitochondrial disorder is caused by mutations in mitochondrial genes.
  • mitochondrial disorder is caused by defects in cytochrome c oxidase (COX) or complex IV.
  • the mitochondrial disorder is caused by the inability of heme A to be incorporated into nascent complex IV subunits.
  • the invention provides methods of treating mitochondrial disorders selected from the group consisting of inherited mitochondrial diseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy,
  • Lactacidosis, and Stroke Lactacidosis, and Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); Optic Dominant Atrophy (DOA); Leigh syndrome or Leigh-like syndrome; SURF1; Kearns-Sayre syndrome (KSS); Friedreich's Ataxia (FRDA); overlap syndromes such as KSS/MERFF, other myopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis; neurodegenerative diseases; Parkinson's Disease; Alzheimer's Disease; Amyotrophic Lateral Sclerosis (ALS); motor neuron diseases; other neurological diseases; epilepsy; genetic diseases; Huntington's disease (HD); mood disorders; schizophrenia; bipolar disorder; age-associated diseases; cerebral vascular accidents, macular degeneration; diabetes; and cancer, in a person in need therof.
  • LHON Hereditary Optic Neuropathy
  • DOA Optic Dominant Atrophy
  • KSS Kearns-Sayre syndrome
  • the mitochondrial disorder is a mitochondrial respiratory chain disorder.
  • the mitochondrial respiratory chain disorder is a respiratory protein chain disorder.
  • the disorder is CoQjo deficiency.
  • the mitochondrial disorder is selected from the group consisting of inherited mitochondrial diseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, and Stroke (MELAS);
  • LHON Leber's Hereditary Optic Neuropathy
  • DOA Optic Dominant Atrophy
  • SURF1 Kearns-Sayre syndrome
  • KSS Kearns-Sayre syndrome
  • FRDA Friedreich's Ataxia
  • the mitochondrial disorder is Friedreich's Ataxia (FRDA).
  • the mitochondrial disorder is Leber' s Hereditary Optic Neuropathy (LHON).
  • the mitochondrial disorder is Optic Dominant Atrophy (DOA).
  • the mitochondrial disorder is
  • the mitochondrial disorder is Kearns-Sayre syndrome (KSS).
  • the mitochondrial disorder is Myoclonic Epilepsy with Ragged Red Fibers (MERRF).
  • the disorder is an overlap syndrome.
  • the disorder is an overlap syndrome such as KSS/MERFF.
  • the disorder is Parkinson's disease.
  • the disorder is Huntington's disease (HD). In another embodiment of the invention including any of the foregoing embodiments, the disorder is amyotrophic lateral sclerosis (ALS). In yet another embodiment of the invention including any of the foregoing embodiments, the disorders are cerebral vascular accidents, such as stroke. In yet another embodiment of the invention, including any of the foregoing embodiments, the mitochondrial disorder is Leigh syndrome. In yet another embodiment of the invention, including any of the foregoing embodiments, the mitochondrial disorder is Leigh-like syndrome. In another embodiment of the invention, including any of the foregoing embodiments, the mitochondrial disorder is SURF1.
  • the invention relates to the treatment of a patient suffering from a mitochondrial disorder has one or more symptoms selected from the group consisting of: one or more lesions in the central nervous system; one or more lesions in the brain; one or more lesions in the basal ganglia; one or more lesions in the thalamus; one or more lesions in the brain stem; one or more lesions in the dentate nuclei; one or more lesions in the optic nerves; one or more lesions in the spinal cord; degeneration of the central nervous system; degeneration of the brain; degeneration of the basal ganglia; degeneration of the thalamus; degeneration of the brain stem;
  • the individual suffering from a mitochondrial disorder has one or more symptoms selected from the group consisting of ataxia, difficulty in walking, poor balance, inability to climb steps, inability to sit without assistance; inability to independently stand with support; inability to turn while sitting; inability to scoot or slide while sitting; inability to move extremities purposefully; inability to perform fine motor tasks; difficulty in sleeping; disrupted sleep patterns; gastrointestinal problems; impaired hand-eye coordination, impaired hearing and difficulty in breathing.
  • the individual suffering from a mitochondrial disorder has one or more symptoms selected from the group consisting of speech problems; difficulty in speaking in complete sentences; difficulty in enunciating; difficulty in counting aloud; poor voice and word association; cognitive difficulties, and difficulty in responding to verbal communication appropriately.
  • the invention relates to the treatment of a patient suffering from Leigh syndrome or Leigh-like syndrome, such as an individual suffering from SURF1, has one or more symptoms selected from the group consisting of: one or more lesions in the central nervous system; one or more lesions in the brain; one or more lesions in the basal ganglia; one or more lesions in the thalamus; one or more lesions in the brain stem; one or more lesions in the dentate nuclei; one or more lesions in the optic nerves; one or more lesions in the spinal cord; degeneration of the central nervous system; degeneration of the brain; degeneration of the basal ganglia; degeneration of the thalamus; degeneration of the brain stem; degeneration of the dentate nuclei; degeneration of the optic nerves; hearing loss, degeneration of the spinal cord; progressive neurological deterioration; psychomotor retardation; mental retardation; tremors; spasms; myoclonic spasms; seizures; hypotonia; weakness
  • the individual suffering from Leigh syndrome or Leigh-like syndrome such as an individual suffering from SURF1
  • the individual suffering from Leigh syndrome or Leigh-like syndrome such as an individual suffering from SURF1
  • the individual suffering from a mitochondrial disorder has been diagnosed with FRDA and has one or more symptoms selected from the group consisting of ataxia, difficulty in walking, poor balance, inability to climb steps, inability to sit without assistance; inability to independently stand with support;
  • the individual suffering from a mitochondrial disorder has been diagnosed with FRDA and has one or more symptoms selected from the group consisting of speech problems; difficulty in speaking in complete sentences; and difficulty in enunciating.
  • the individual suffering from a mitochondrial disorder has been diagnosed with LHON and has one or more symptoms selected from the group loss of visual acuity; loss of central vision; impairment of central vision;
  • the individual suffering from a mitochondrial disorder has been diagnosed with LHON and has one or more symptoms selected from the group loss of visual acuity; loss of central vision; impairment of central vision;
  • Also included in the present invention is the use of one or more tocopherol quinones or tocotrienol quinones, particularly tocotrienol quinone, and one or more naphthoquinone quinones, particularly a vitamin K in the preparation of a medicament for treating a mitochondrial disorder in a person in need therof.
  • the present invention relates to an adjunctive therapy for the treatment of mitochondrial disorders comprising the administration of an effective amount of one or more quinone compounds of Formula f x or their reduced hydroquinone form of Formula I red and one or more naphthoquinone compounds of Formula II ox or their reduced naphthohydroquinone form of Formula II red to a patient in need therof.
  • tocopherol quinones contemplated for use in the adjunctive therapy for the treatment include alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone.
  • the tocopherol quinones with the naturally occurring tocopherol configuration are used in one embodiment of the invention, but other stereoisomers and/or mixtures of stereoisomers in any ratio, such as racemic mixtures, can also be used in the invention.
  • tocotrienol quinones contemplated for use in the adjunctive therapy for the treatment include alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, and delta-tocotrienol quinone.
  • the tocotrienol quinones with the naturally occurring tocotrienol configuration are used in one embodiment of the invention, but other stereoisomers and/or mixtures of stereoisomers in any ratio, such as racemic mixtures, can also be used in the invention.
  • Tocopherol quinones and tocotrienol quinones can be used in their oxidized form, or can be used in their reduced hydroquinone form.
  • the quinone (cyclohexadienedione) form and hydroquinone (benzenediol) form are readily interconverted with appropriate reagents.
  • the quinone can be treated in a biphasic mixture of an ethereal solvent with a basic aqueous solution of Na 2 S 2 0 4 (Vogel, A.I. et al. Vogel' s Textbook of Practical Organic Chemistry, 5 th Edition, Prentice Hall: New York, 1996; Section 9.6.14 Quinones, "Reduction to the Hydroquinone").
  • hydroquinone form can be oxidized to the quinone form with oxidizing agents such as eerie ammonium nitrate (CAN) or ferric chloride.
  • oxidizing agents such as eerie ammonium nitrate (CAN) or ferric chloride.
  • CAN eerie ammonium nitrate
  • ferric chloride ferric chloride
  • stereoisomers of the compounds also includes all stereoisomers of the compounds, including diastereomers and enantiomers, and mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures.
  • stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.
  • the compounds can be administered in prodrug form.
  • Prodrugs are derivatives of the compounds, which are themselves relatively inactive but which convert into the active compound when introduced into the subject in which they are used by a chemical or biological process in vivo, such as an enzymatic conversion.
  • Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds disclosed herein and esters of compounds disclosed herein. Further discussion of suitable prodrugs is provided in H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological
  • the naphthoquinones contemplated for adjunctive therapy in the treatment of mitochondrial disorders are selected from one or more compounds having Vitamin K activity.
  • the naphthoquinones contemplated for adjunctive therapy in the treatment of mitochondrial disorders are selected from one or more compounds having Vitamin Kl activity.
  • the naphthoquinones contemplated for adjunctive therapy in the treatment of mitochondrial disorders are selected from one or more compounds having Vitamin K2 activity.
  • the naphthoquinones contemplated for adjunctive therapy in the treatment of mitochondrial disorders are selected from 2-(3-hydroxy-3,7, 11,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)-3-methylnaphthalene- 1 ,4-dione; 2-(3- hydroxy-3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4-dione and 2-(3-hydroxy-3,7,l l,15-tetramethylhexadeca-6, 10, 14-trien- l-yl)-3, 6,7- trimethylnaphthalene- 1 ,4-dione.
  • “synergy” or “synergistic effect” when used in connection with a description of the efficacy of a combination of agents is meant any measured effect of the combination which is greater than the value predicted from a sum of the effects of the individual agents. (Greco, W.R. et al., Pharmacol. Rev. 1995, 47:331-385).
  • subject or patient
  • animal an animal, preferably a mammal, for example a human, who is object of treatment, observation or
  • Treating" a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disease or one or more symptoms of the disease, or to retard the progression of the disease or of one or more symptoms of the disease, or to reduce the severity of the disease or of one or more symptoms of the disease. "Suppression" of a disease with the
  • compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disease, or to suppress the manifestation of adverse symptoms of the disease.
  • treatment and suppression is that treatment occurs after adverse symptoms of the disease are manifest in a subject, while suppression occurs before adverse symptoms of the disease are manifest in a subject. Suppression may be partial, substantially total, or total.
  • mitochondria diseases are due to genetic mutations
  • genetic screening can be used to identify patients at risk of the disease.
  • disorders such as Leigh syndrome and SURF1
  • deficiencies in cytochrome c oxidase can arise from mutations in Complex IV of the mitochondrial respiratory chain.
  • the compounds disclosed herein can be administered to, and the methods of the invention disclosed herein can be used to treat, asymptomatic patients with mutations in the mitochondrial respiratory chain, such as in Complex IV, who are at risk of developing the clinical symptoms of the disease, in order to suppress the appearance of any adverse symptoms or lessen the severity of symptoms that may occur.
  • compounds disclosed herein can be administered to, and the methods of the invention disclosed herein can be used to treat, asymptomatic patients with defects in
  • cytochrome c oxidase who are at risk of developing the clinical symptoms of the disease, in order to suppress the appearance of any adverse symptoms or lessen the severity of symptoms that may occur.
  • the compounds disclosed herein can be administered to, and the methods of the invention disclosed herein can be used to treat, symptomatic patients with mutations in Complex IV in order to treat the disease.
  • “Therapeutic use” of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disease, as defined above.
  • the term "therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • a "therapeutically effective amount" of a compound when administered to a subject is sufficient to reduce or eliminate either a disease or one or more symptoms of a disease, or to retard the progression of a disease or of one or more symptoms of a disease, or to reduce the severity of a disease or of one or more symptoms of a disease, or to suppress the clinical manifestation of a disease, or to suppress the manifestation of adverse symptoms of a disease.
  • a therapeutically effective amount can be given in one or more administrations.
  • alkyl refers to saturated aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • “Straight-chain alkyl” or “linear alkyl” group refers to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
  • alkyl groups are (Ci-C 6 )alkyl which include groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and any other alkyl group containing between one and five carbon atoms, where the (Ci-C 6 )alkyl groups can be attached via any valence on the (C C 6 ) alkyl groups.
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein.
  • alkoxy groups are (C 1 -C6)alkoxy which include groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, cyclo-propoxy, n-butoxy, tert-butoxy, sec- butoxy, cyclo-butoxy, n-pentoxy, cyclo-pentoxy, n-hexoxy, cyclo-hexoxy, 1,2- dimethylbutoxy, and the like.
  • (CrC ⁇ haloalkyl) refers to any (C 1 -C 6 )alkyl having at least one halogen substituent, the halogen can be attached via any valence on the (Ci-C6)alkyl group.
  • One subset of (Ci-C 6 )haloalk l is -CF 3 , -CCD, -CBr3 and -CD.
  • Another subset is the subset with exactly one halogen substituent.
  • Another subset is the subset with exactly two halogen substituents.
  • the present invention is directed to co-therapy comprising administration of one or more compounds of Formula I ox or I red and one or more compounds of Formula If x or II red
  • "therapeutically effective amount” shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response; and in particular embodiments the combined effect elicits a synergistic response.
  • the therapeutically effective amount of co-therapy comprising administration of a quinone and a naphthoquinone would be the amount of quinone and the amount of naphthoquinone that when taken together or sequentially have a combined effect that is therapeutically effective.
  • the amount of the quinone and the amount of naphthoquinone individually may or may not be therapeutically effective.
  • the term "co-therapy” or “adjunctive therapy” shall mean treatment of a subject in need thereof, with administration of one or more compounds of Formula I ox or I red and one or more compounds of Formula If x or II red , wherein the compounds are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation.
  • the number of dosages administered for each compound may be the same or different.
  • the compounds may be administered via the same or different routes of administration.
  • the compounds may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the compounds of the present invention can be readily prepared by a variety of methods known in the art. Certain quinones of Formula I ox or their reduced hydroquinone form of Formula I red and their preparation have been described in the literature, for example in co-assigned US applications Nos. 11/445,582, 11/521,887 and 11/710,042.
  • Vitamins Kl, K2 and K3 are commercially available for example from Sigma- Aldrich (St. Louis, MO). Additional syntheses of Vitamin K analogues have been described in Weichet J. et ah, Collection of Czechoslovak Chemical Communications (1964) 29, 197-205.
  • Natural or synthetic sources of vitamin K which can be used according to the present invention include the following: phylloquinone from natural sources such as vegetable extracts, fats and oils, synthetic phylloquinone, synthetic vitamin K 3 (menadione), different forms of vitamin K 2 such as synthetic MK-2. MK-3, MK-4, MK-5, MK-6, MK-7, MK-8, MK-9, MK-10, MK-11, MK-12 and MK-13, natto (food prepared from fermented soy-bean, rich in Vitamin K2), and other fermented foods or dairy products rich in Vitamin Kl and/or Vitamin K2.
  • biomarkers can be used to monitor the efficacy of compounds in treatment of mitochondrial disorders. These biomarkers include, but are not limited to, lactic acid (lactate) levels, either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; pyruvic acid (pyruvate) levels, either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;
  • lactate/pyruvate ratios either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; phosphocreatine levels, NADH (NADH +H + ) or NADPH
  • NADPH+H + NAD or NADP levels
  • ATP anaerobic threshold
  • Blood lactate/pyruvate ratio is, therefore, widely used as a noninvasive test for detection of mitochondrial cytopathies and toxic mitochondrial myopathies.
  • Total concentration levels of lactate and total concentration levels of pyruvate that are elevated above the normal range are also observed in Leigh syndrome, and those elevated total concentrations can serve as additional biomarkers in addition to the elevated lactate/pyruvate ratio.
  • Another biomarker which can be monitored is CoQ 10 concentration.
  • Biomarkers and techniques for measurement of biomarkers that can be used to monitor the efficacy of treatment include, but are not limited to:
  • Magnetic resonance spectroscopy Brain lactate measurement and quantification directly reflect cellular electron balance and indirectly reflect energy production. Magnetic resonance spectroscopy can be used to assess metabolic parameters of the brain with a focus on lactate, i.e., central nervous system (CNS) concentration of lactate and lactate/pyruvate ratio. MRS has been used to measure lactate using proton MRS (1H-MRS) (Kaufmann, DC et al, Neurology 2004, 62(8): 1297-302). Phosphorous MRS (3 IP-MRS) has been used to demonstrate low levels of cortical phosphocreatine (PCr) (Matthews, PM et al, Ann. Neurol.
  • CNS central nervous system
  • MRS Magnetic Resonance Spectroscopy
  • Another procedure that may be used is brain imaging with single photon emission computed tomography (SPECT, or less commonly, SPET), a nuclear medicine tomographic imaging technique using gamma rays.
  • SPECT single photon emission computed tomography
  • SPET nuclear medicine tomographic imaging technique using gamma rays.
  • This procedure allows brain blood flow to be assessed with a nuclear gamma camera by revealing the relative blood flow in different parts of the brain.
  • One such technique uses 99m Tc- HMPAO (hexamethylpropylene amine oxime) as the gamma-emitting tracer used in this imaging.
  • Lactic acid (lactate) levels Brain lactate measurement and quantification directly reflect cellular electron balance and indirectly reflect energy production. Lactate levels can be measured by taking samples of appropriate bodily fluids such as whole blood, plasma, or cerebrospinal fluid. Using magnetic resonance, lactate levels can be measured in virtually any volume of the body desired, such as the brain.
  • Whole blood, plasma, and cerebrospinal fluid lactate levels can be measured by commercially available equipment such as the YSI 2300 STAT Plus Glucose & Lactate Analyzer (YSI Life Sciences, Ohio).
  • NAD, NADP, NADH and NADPH levels Measurement of NAD, NADP, NADH (NADH +H + ) or NADPH (NADPH+H + ) can be measured by a variety of fluorescent, enzymatic, or electrochemical techniques, e.g., the electrochemical assay described in US Patent Publication No. US 2005/0067303.
  • VC02 can also be readily measured, and the ratio of VC02 to V02 under the same conditions (VC02/V02, either resting or at maximal exercise intensity) provides the respiratory quotient (RQ).
  • RQ respiratory quotient
  • Other oxygen metabolism deficiencies include deficit in peripheral oxygen extraction (A-V02 difference) and an enhanced oxygen delivery (hyperkinetic circulation) (Taivassalo, T. et al., Brain 2003, 126(Pt 2):413-23 ). This can be demonstrated by a lack of exercise induced deoxygenation of venous blood with direct AV balance measurements (Taivassalo, T. et al., Ann. Neurol.
  • Cytochrome c parameters such as oxidized cytochrome c levels (Cyt C ox ), reduced cytochrome c levels (Cyt C re( j), and the ratio of oxidized cytochrome c/reduced cytochrome c ratio (Cyt C ox )/(Cyt C red ), can be measured by in vivo near infrared spectroscopy. See, e.g., Rolfe, P., "In vivo near- infrared spectroscopy," Ann. Rev.
  • Exercise intolerance is defined as "the reduced ability to perform activities that involve dynamic movement of large skeletal muscles because of symptoms of dyspnea or fatigue" (Pina, I et al.,
  • Exercise intolerance is often accompanied by myoglobinuria, due to breakdown of muscle tissue and subsequent excretion of muscle myoglobin in the urine.
  • Various measures of exercise intolerance can be used, such as time spent walking or running on a treadmill before exhaustion, time spent on an exercise bicycle (stationary bicycle) before exhaustion, and similar tests.
  • Acetoacetate/3-hydroxybutyrate (acetoacetate ⁇ -hydroxybutyrate) ratio Changes in the redox state of liver mitochondria can be investigated by measuring the arterial ketone body ratio (acetoacetate/3-hydroxybutyrate: AKBR) (Ueda, Y. et al., J. Cardiol. 1997, 29(2):95-102).
  • 8-hydroxy-2 '-deoxyguanosine (8-OHdG) Urinary excretion of 8- hydroxy-2'-deoxyguanosine (8-OHdG) often has been used as a biomarker to assess the extent of repair of ROS-induced DNA damage in both clinical and occupational settings (Erhola, M. et al, FEBS Lett.
  • Blood ketone body ratios including lactate: pyruvate, and beta-hydroxy butyrate:acetoacetate reflect electron balance. Alterations in these ratios can be used to assess systemic metabolic function. Increased blood lactate, increased blood pyruvate, increased blood alanine, and blood pH (to check for metabolic acidosis) can also be monitored.
  • Mitochondrial diseases are frequently characterized by altered heart function.
  • 12-lead ECG can be employed to measure QT/QTc.
  • Transthoracic echocardiography can be used to assess dynamic cardiac function.
  • brainstem auditory evoked response BAER
  • SEP or SSEP somatosensory-evoked potentials
  • PSG polysomnography
  • Urine analysis can be performed on the patient, and can include measurement of the following organic acids: lactic acid, pyruvic acid, succinic acid, fumaric acid, 2-ketoglutaric acid, methyl malonic acid, 3-oh butyric acid, acetoacetic acid, 2-keto-3-methylvaleric acid, 2-keto-isocaproic acid, 2-keto-isovaleric acid, ethylmalonic acid, adipic acid, suberic acid, sebacic acid, 4-OH-phenylacetic acid, 4-OH-phenyllactic acid, 4-OH- phenylpyruvic acid, succinylacetone, and creatinine.
  • organic acids lactic acid, pyruvic acid, succinic acid, fumaric acid, 2-ketoglutaric acid, methyl malonic acid, 3-oh butyric acid, acetoacetic acid, 2-keto-3-methylvaleric acid, 2-keto-isocaproic acid, 2-keto-isovaleric acid, e
  • Urine analysis performed on the patient can also include measurement of the following amino acids: proline, glutamine, threonine, serine, glutamic acid, arginine, glycine, alanine, histidine, lysine, valine, asparagine, methionine, phenylalanine, isoleucine, leucine, tyrosine, hydroxyproline, creatinine, aspartic acid, cysteine, ornithine, citrulline, homocysteine, and taurine.
  • proline proline
  • glutamine threonine
  • serine glutamic acid
  • arginine glycine
  • alanine histidine
  • lysine valine
  • asparagine methionine
  • phenylalanine isoleucine
  • leucine leucine
  • tyrosine hydroxyproline
  • creatinine aspartic acid
  • cysteine ornithine
  • citrulline homocy
  • the compounds may be co-administered simultaneously, sequentially, separately or in a single pharmaceutical composition.
  • the number of dosages of each compound given per day may not necessarily be the same, e.g. where one compound may have a greater duration of activity, and will therefore, be administered less frequently.
  • the dosage forms of administration of each compound may not necessarily be the same, e.g. where one compound may be administered in a solid, oral form and another may be administered intravenously or subcutaneously.
  • Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, physical activity, time of administration and concomitant diseases, will result in the need to adjust dosages and/or regimens.
  • quinones and naphthoquinones may be administered by any suitable means, as would be apparent to one skilled in the art.
  • Examples of daily dosages which can be used are an effective amount within the dosage range of about 0.1 mg/kg to about 300 mg/kg body weight, or within about 0.1 mg/kg to about 100 mg/kg body weight, or within about 0.1 mg/kg to about 80 mg/kg body weight, or within about 0.1 mg/kg to about 50 mg/kg body weight, or within about 0.1 mg/kg to about 30 mg/kg body weight, or within about 0.1 mg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 80 mg/kg body weight, or within about 1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 80 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200
  • Quinones and naphthoquinones may be administered in any suitable form that will provide sufficient plasma and/or central nervous system levels of the compounds.
  • the compounds can be administered enterally, orally, parenterally, sublingually, by inhalation (e.g. as mists or sprays), rectally, or topically in unit dosage formulations containing conventional nontoxic pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles as desired.
  • suitable modes of administration include oral, subcutaneous, transdermal, transmucosal,
  • iontophoretic intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue.
  • spinal and epidural administration, or administration to cerebral ventricles can be used.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous injection, intraarterial injection, intramuscular injection, intrasternal injection, or infusion techniques.
  • the compounds are mixed with pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles appropriate for the desired route of administration. [0222] In some embodiments, particularly those for the treatment of
  • the compounds may also be administered by an ocular route, and the excipient will be an "ophthalmically acceptable" vehicle.
  • an "ophthalmically acceptable” component refers to a component which will not cause any significant ocular damage or ocular discomfort at the intended concentration and over the time of intended use. Solubilizers and stabilizers are deemed to be non-reactive.
  • ophthalmically acceptable vehicle refers to any substance or combination of substances which are non-reactive with the compounds and suitable for administration to a patient.
  • Suitable vehicles may be non-aqueous liquid media including the physiologically acceptable oils such as silicone oil, USP mineral oil, white oil, poly(ethylene-glycol), a polyethoxylated castor oil and vegetable oils, for example corn oil, peanut oil, or the like.
  • Other suitable vehicles may be aqueous or oil-in-water solutions suitable for topical application to the patient's eyes. These vehicles may be preferred based on ease of formulation, as well as a patient's ability to easily administer such formulations by means of instilling one to two drops of the solutions in the affected eyes.
  • the formulations may also be suspensions, viscous or semi- viscous gels, or other types of solid or semi-solid formulations, and fat bases, such as natural wax e.g. white bees wax, carnauba wax, wool wax (wool fat), purified lanolin, anhydrous lanolin; petroleum wax e.g. solid paraffin, microcrystalline wax;
  • hydrocarbons e.g. liquid paraffin, white petrolatum, yellow petrolatum; or
  • formulations may be applied by use of the hands or an applicator such as a wipe, a contact lens, a dropper or a spray.
  • an applicator such as a wipe, a contact lens, a dropper or a spray.
  • the compounds may be administered by the oral route.
  • Oral administration is advantageous due to its ease of implementation and patient (or caretaker) compliance.
  • Introduction of medicine via feeding tube, feeding syringe, or gastrostomy can be employed in order to accomplish enteric
  • the active compound (and, if present, other co-administered agents) can be enterally administered in sesame oil, or any other pharmaceutically acceptable carrier suitable for formulation for administration via feeding tube, feeding syringe, or gastrostomy.
  • the compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, gums, jellies, gelatin confections, soft gels, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms.
  • the compounds can also be administered in liposome formulations.
  • the compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in propylene glycol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or di- glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. Alternatively, the compound may also be administered in neat form if suitable.
  • the compounds for use in the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound for use in the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq (1976).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form can vary depending upon the patient to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that 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, body area, body mass index (BMI), general health, sex, and diet of the patient; the time of administration and route of administration used; the rate of excretion; drug combination, if any, used; and the progression, and severity of the disease in the patient undergoing therapy.
  • the pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, cerebrospinal fluid, brain tissues, spinal cord tissues, other tissues, other organs, or other targeted region of the body.
  • Compounds for use in the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
  • antioxidants or molecules involved in the antioxidant pathway such as alpha-tocopherol, selenium, or small molecule glutathione peroxidase mimetics.
  • antioxidants differ in their potency, i.e. the concentration at which they are able to rescue BSO-stressed FRDA fibroblasts.
  • MEM a medium enriched in amino acids and vitamins, catalog no. 1- 31F24-I
  • M199 Medium 199 with Earle's Balanced Salts, without phenol red
  • Fetal Calf Serum was obtained from PAA Laboratories.
  • Basic fibroblast growth factor and epidermal growth factor were purchased from PeproTech.
  • Penicillin-streptomycin-glutamine mix, L-buthionine (S,R)-sulfoximine, Vitamin Kl, Vitamin K2 and insulin from bovine pancreas were purchased from Sigma.
  • Idebenone was obtained from Chemo Iberica.
  • Calcein AM was purchased from Molecular Probes.
  • Cell culture medium was made by combining 125 ml M199 EBS, 50 ml Fetal Calf Serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, 10 ⁇ g/ml insulin, 10 ng/ml EGF, and 10 ng/ml bFGF; MEM EBS was added to make the volume up to 500 ml.
  • a 10 mM BSO solution was prepared by dissolving 444 mg BSO in 200 ml of medium (Invitrogen, Carlsbad, Ca.) with subsequent filter-sterilization. During the course of the experiments, this solution was stored at +4°C.
  • the cells were obtained from the Coriell Cell Repositories (Camden, NJ; repository number GM04078) and grown in 10 cm tissue culture plates. Every third day, they were split at a 1:3 ratio.
  • test samples were supplied in 1.5 ml glass vials.
  • the compounds were diluted with DMSO, ethanol or PBS to result in a 5 mM stock solution. Once dissolved, they were stored at -20°C.
  • Test samples were screened according to the following protocol:
  • a culture with FRDA fibroblasts was started from a 1 ml vial with approximately 500,000 cells stored in liquid nitrogen. Cells were propagated in 10 cm cell culture dishes by splitting every third day in a ratio of 1:3 until nine plates were available. Once confluent, fibroblasts were harvested. For 54 micro titer plates (96 well-MTP) a total of 14.3 million cells (passage eight) were re-suspended in 480 ml medium, corresponding to 100 ⁇ medium with 3,000 cells/well. The remaining cells were distributed in 10 cm cell culture plates (500,000 cells/plate) for propagation. The plates were incubated overnight at 37°C in an atmosphere with 95% humidity and 5% C02 to allow attachment of the cells to the culture plate.
  • MTP medium (243 ⁇ ) is added to a well of the microtiter plate.
  • the test compounds were unfrozen, and 7.5 ⁇ of a 5 mM stock solution was dissolved in the well containing 243 ⁇ medium, resulting in a 150 ⁇ master solution.
  • Serial dilutions from the master solution were made. The period between the single dilution steps was kept as short as possible (generally less than 1 second).
  • fluorescence excitation/emission wavelengths of 485 nm and 525 nm, respectively
  • Gemini fluorescence reader Data was imported into Microsoft Excel (EXCEL is a registered trademark of Microsoft Corporation for a spreadsheet program) and used to calculate the EC50 concentration for each compound and each combination of compounds.
  • Table 2 shows the changes to the ECso's of certain quinones when combined with Vitamin K2. They exhibit a synergistic effect.
  • Table 3 shows the synergism effected to the ECso's of Vitamin Kl
  • Vitamin K2 when combined with 10 nM alpha-tocotrienol quinone or with 10 nM 2,3,5-trimethyl-6-(12- hydroxy-5,10-dodecadiynyl)-l,4-benzoquinone in the assay with fibroblasts of FRDA patients.
  • Table 4 shows the synergism effected to the ECso's of Vitamin Kl and Vitamin K2 when combined with a non active concentration of 10 nM alpha- tocotrienol quinone in the assay with fibroblasts of Huntington's patients.
  • a screen is performed to identify compounds effective for the amelioration of ASD. Test samples, and solvent controls are tested for their ability to rescue ASD fibroblasts stressed by addition of L-buthionine-(S,R)-sulfoximine (BSO).
  • BSO L-buthionine-(S,R)-sulfoximine
  • MEM a medium enriched in amino acids and vitamins, catalog no. Gibco 11965
  • Fetal Calf Serum a medium enriched in amino acids and vitamins, catalog no. Gibco 11965
  • Basic fibroblast growth factor and epidermal growth factor are purchased from PeproTech.
  • Penicillin- streptomycin-glutamine mix, L-buthionine (S,R)-sulfoximine, and insulin from bovine pancreas are purchased from Sigma.
  • Calcein AM is purchased from Molecular Probes.
  • Cell culture medium is made by combining 75 ml Fetal Calf Serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, 10 ng/ml EGF, and 10 ng/ml bFGF; MEM EBS is added to make the volume up to 500 ml.
  • a 10 mM BSO solution is prepared by dissolving 444 mg BSO in 200 ml of medium with subsequent filter- sterilization. During the course of the experiments, this solution is stored at +4°C.
  • the cells obtained from Dr. J.M. Shoffner, Medical Neurogenetics, Atlanta, Ga. are grown in 10 cm tissue culture plates. Every week, they are split at a 1:3 ratio.
  • the samples are supplied in 1.5 ml glass vials.
  • Alpha- Tocotrienol quinone, EPO and different combinations of both alpha tocotrienol and EPO are diluted with DMSO, ethanol or PBS to result in a 5 mM stock solution. Once dissolved, they are stored at -20°C.
  • a culture with ASD fibroblasts is started from a 1 ml vial with
  • MTP medium (243 ⁇ ) is added to a well of the microtiter plate.
  • the test compounds are unfrozen, and 7.5 ⁇ of a 5 mM stock solution is dissolved in the well containing 243 ⁇ medium, resulting in a 150 ⁇ master solution.
  • Serial dilutions from the master solution are made. The period between the single dilution steps is kept as short as possible (generally less than 1 second).
  • Plates are kept overnight in the cell culture incubator. The next day, 10 1 of a 10 mM BSO solution are added to the wells, resulting in a 1 mM final BSO concentration. Forty-eight hours later, three plates are examined under a phase- contrast microscope to verify that the cells in the 0% control (wells El-Hl) are clearly dead. The medium from all plates is discarded, and the remaining liquid is removed by gently tapping the plate inversed onto a paper towel.
  • MEM a medium enriched in amino acids and vitamins, catalog no. 1- 31F24-I
  • M199 Medium 199 with Earle's Balanced Salts, without phenol red
  • Fetal Calf Serum was obtained from PAA Laboratories.
  • Basic fibroblast growth factor and epidermal growth factor were purchased from PeproTech.
  • Penicillin-streptomycin-glutamine mix, L- buthionine (S,R)-sulfoximine, and insulin from bovine pancreas were purchased from Sigma.
  • Calcein AM was purchased from Molecular Probes.
  • Cell culture medium was made by combining 125 mL M199 EBS, 50 ml Fetal Calf Serum, 100 U/mL penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, 10 ⁇ g/mL insulin, 10 ng/mL EGF, and 10 ng/mL bFGF.
  • MEM EBS was added to make the volume up to 500 mL.
  • a 10 mM BSO solution was prepared by dissolving 444 mg BSO in 200 mL of medium with subsequent filter- sterilization. During the course of the experiments, this solution was stored at +4°C.
  • the cells were obtained from the SURF-1 patient and grown in 10 cm tissue culture plates. Every third day, they were split at a 1:3 ratio.
  • test samples are supplied in 1.5 mL glass vials.
  • the individual quinones and naphthoquinones compounds of the invention as well as combinations thereof are are diluted with DMSO, ethanol or PBS to result in a 5 mM stock solution. Once dissolved, they were stored at -20 °C.
  • Test samples are screened according to the following protocol: A culture with FRDA fibroblasts is started from a 1 mL vial with approximately 500,000 cells stored in liquid nitrogen. Cells are propagated in 10 cm cell culture dishes by splitting every third day in a ratio of 1:3 until nine plates were available. Once confluent, fibroblasts are harvested.
  • MTP medium (243 ⁇ ) is added to a well of the microtiter plate.
  • the test compounds are unfrozen, and 7.5 ⁇ ⁇ of a 5 mM stock solution is dissolved in the well containing 243 ⁇ ⁇ medium, resulting in a 150 ⁇ master solution.
  • Serial dilutions from the master solution are made. The period between the single dilution steps is kept as short as possible (generally less than 1 second).
  • Plates are kept overnight in the cell culture incubator. The next day, 10 ⁇ ⁇ of a 10 mM BSO solution are added to the wells, resulting in a 1 mM final BSO concentration. Forty-eight hours later, three plates are examined under a phase- contrast microscope to verify that the cells in the 0% control (wells El-Hl) were clearly dead. The medium from all plates is discarded, and the remaining liquid is removed by gently tapping the plate inversed onto a paper towel.
  • the solvents DMSO, ethanol, PBS
  • DMSO, ethanol, PBS neither have a detrimental effect on the viability of non-BSO treated cells nor do they have a beneficial influence on BSO- treated fibroblasts even at the highest concentration tested (1%).
  • the compounds show no auto-fluorescence.
  • the viability of non-BSO treated fibroblasts is set as 100%, and the viability of the BSO- and compound-treated cells is calculated as relative to this value.

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Abstract

Cette invention concerne un traitement adjuvant au traitement des maladies mitochondriales consistant à administrer une quantité efficace d'une ou de plusieurs quinones et d'une ou de plusieurs naphtoquinones chez un patient. L'invention concerne également un traitement adjuvant au traitement des maladies mitochondriales consistant à administrer une quantité efficace d'une ou de plusieurs quinones ou leurs hydroquinones de forme réduite et d'une ou de plusieurs naphtoquinones ou leurs naphtohydroquinones de forme réduite chez un patient.
PCT/US2012/041486 2011-06-08 2012-06-08 Traitement adjuvant au traitement des maladies mitochondriales avec des quinones et des naphtoquinones Ceased WO2012170773A1 (fr)

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