ES2805081T3 - Derivatives of 4- (p-quinonyl) -2-hydroxybutanamide for the treatment of mitochondrial diseases - Google Patents

Abstract

A compound selected from the group consisting of: - 2-5 hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide and - its hydroquinone form thereof or a salt, a stereoisomer or a mixture of stereoisomers thereof.

Description

DESCRIPTION

Derivatives of 4- (p-quinonyl) -2-hydroxybutanamide for the treatment of mitochondrial diseases

Technical field

The application describes compounds and compositions useful for the treatment, prevention or suppression of diseases, developmental delay and symptoms related to mitochondrial disorders, such as Friedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-Sayre syndrome, mitochondrial myopathy, encephalopathy. , lactacidosis, and stroke and cerebrovascular accidents, and to modulate energy biomarkers in a subject. The compounds and compositions of the present invention are administered to a subject for the purpose of compensating for mitochondrial dysfunction and improving mitochondrial functions. Compositions and compounds useful in treating other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's and Parkinson's are also described.

Background

Mitochondria are organelles in eukaryotic cells, popularly referred to as the "powerhouse" of the cell. One of its main functions is oxidative phosphorylation. Molecular adenosine triphosphate (ATP) functions as an "energy" reserve or energy support in the cell, and eukaryotic cells obtain most of their ATP from the biochemical processes performed by the mitochondria. These biochemical processes include the citric acid cycle (the tricarboxylic acid cycle or Krebs cycle), which generates the reduced niconamide adenine dinucleotide (NADH H +) from oxidized niconamide adenine dinucleotide (NAD +), and oxidative phosphorylation, during which NADH H + is oxidized back to NAD +. (The citric acid cycle also reduces flavin adenine dinucleotide or FAD to FADH ² ; FADH ^{2 is} also involved in oxidative phosphorylation.)

Electrons released by the oxidation of NADH H + are released under a series of protein complexes (Complex I, Complex II, Complex III, and Complex IV) known as the respiratory chain. These complexes are incorporated into the inner membrane of the mitochondria. Complex IV, at the end of the chain, transfers the electrons to oxygen, which is reduced to water. The energy released as these electrons pass through the complexes is used to generate a proton gradient across the inner membrane of the mitochondrion, creating an electrochemical potential across the inner membrane. Another protein complex, Complex V (not directly associated with Complexes I, II, III, and IV) uses the energy stored by the electrochemical gradient to convert ADP to ATP.

The citric acid cycle and oxidative phosphorylation are preceded by glycolysis, in which one molecule of glucose is broken down into two molecules of pyruvate, with a net generation of two molecules of ATP per molecule of glucose. The pyruvate molecules then enter the mitochondria, where they are fully oxidized to CO ² and H ² O through oxidative phosphorylation (the whole process is known as aerobic respiration). The complete oxidation of the two pyruvate molecules to carbon dioxide and water produces approximately 28-29 ATP molecules, in addition to the 2 ATP molecules generated by the transformation of glucose into two pyruvate molecules. If oxygen is not available, the pyruvate molecule does not enter the mitochondria, but is converted to lactate, in the process of anaerobic respiration.

The total net yield per glucose molecule in that way is roughly at least 30-31 ATP molecules. ATP is used to energize, directly or indirectly, almost every different biochemical reaction in the cell. Thus, the supplement (approximately) of at least 28 or 29 ATP molecules contributed by oxidative phosphorylation during aerobic respiration is critical for the proper functioning of the cell. The lack of oxygen prevents aerobic respiration and will result in the eventual death of almost all aerobic organisms; a few organisms, such as yeast, have the ability to survive with either aerobic or anaerobic respiration.

When cells in an organism are temporarily deprived of oxygen, anaerobic respiration is used until the cell becomes viable again or dies. Pyruvate generated during glycolysis is converted to lactate during anaerobic respiration. The accumulation of lactic acid is thought to be responsible for muscle fatigue during intense periods of activity, when oxygen cannot be provided to the muscle cells. When oxygen becomes viable again, lactate is converted back to pyruvate for use in oxidative phosphorylation.

Mitochondrial dysfunction contributes to several disease states. Some mitochondrial diseases are due to mutations or deletions in the mitochondrial genome. If a threshold proportion of mitochondria in the cell is defective, and if a threshold proportion of such cells within a tissue have a defective mitochondrion, it can result in symptoms of tissue or organ dysfunction. Virtually any tissue can be affected, and a wide variety of symptoms can be present, depending on the degree to which different tissues are involved.

One disease is Friedreich's ataxia (FRDA, or FA). Friedreich's ataxia is an autosomal recessive neurodegenerative and cardiodegenerative disorder caused by decreased levels of the protein frataxin. Frataxin is important for the assembly of iron-sulfide groups in mitochondrial respiratory chain complexes. The prevalence of FRDA in the United States of America is estimated to range from 1 in every 22,000-29,000 people (see www.nlm.nih.gov/medlineplus/ency/article/001411.htm) to 1 in 50,000 people (see www .umc-cares.org / health_info / ADAM / Articles / 001411.asp). The disease causes progressive loss of voluntary motor coordination (ataxia) and cardiac complications. Symptoms usually begin in childhood, and the disease progressively worsens as the patient grows older; patients eventually become wheelchair bound due to motor disabilities.

Another disease linked to mitochondrial dysfunction is Leber's Hereditary Optic Neuropathy (LHON). The disease is characterized by blindness that occurs on average between 27 and 34 years of age; blindness can develop in both eyes simultaneously or sequentially (one eye will develop blindness, followed by the other eye two months later on average). Other symptoms can also occur, such as heart abnormalities and neurological complications.

Another devastating syndrome that results from mitochondrial defects is mitochondrial myopathy, encephalopathy, lactacidosis and stroke (MELAS). The disease can manifest itself in infants, children, or young adults. Strokes, accompanied by vomiting and stroke, are one of the most serious symptoms; It has been postulated that the metabolic disability of mitochondria in certain areas of the brain is responsible for cell death and neurological damage, rather than the inability of blood flow as occurs in an ischemic stroke. Other severe complications, including neurological symptoms, are frequently present, and elevated levels of lactic acid are present in the blood.

Another mitochondrial disease is Kearns-Sayre Syndrome (KSS). KSS is characterized by a triad of characteristics including: (1) typical onset in people younger than 20 years; (2) chronic, progressive, external ophthalmoplegia; and (3) pigmentary degeneration of the retina. In addition, KSS can include cardiac conduction defects, cerebellar ataxia, and increased levels of cerebrospinal fluid protein (CSF) (eg,> 100 mg / dl). Additional features associated with KSS may include myopathy, dystonia, endocrine abnormalities (eg, diabetes, growth retardation or short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis. Thus, KSS can affect many organ systems.

CoEnzyme Q10 deficiency is a disorder of the respiratory chain, with syndromes such as myopathy with exercise intolerance and recurrent myoglobin in the urine manifested by ataxia, seizures or mental retardation and leading to renal failure (Di Mauro et al., (2005 ) Neuromusc. Disord., 15: 311-315), childhood-onset cerebellar ataxia and cerebellar atrophy (Masumeci et al., (2001) Neurology 56: 849-855 and Lamperti et al., (2003) 60: 1206 : 1208); and nephrosis-associated infantile encephalomyopathy. Biochemical measurement of muscle homogenates from patients with CoQ10 deficiency showed that the activity of respiratory chain complexes I and II III was seriously decreased, while complex IV (COX) was moderately decreased (Gempel et al., (2007) Brain , 130 (8): 2037-2044).

Complex I deficiency or NADH-CoQ reductase deficiency of NADH dehydrogenase is a respiratory chain disorder, with symptoms classified by three main forms: (1) fatal childhood multisystemic disorder, characterized by developmental delay, muscle weakness, disease cardiac, congenital lactic acidosis, and respiratory failure; (2) onset of myopathy in childhood or in adult life, manifested 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, pigmentary retinopathy, sensory neuropathy, and involuntary movements.

Complex II deficiency or succinate dehydrogenase deficiency is a respiratory chain disorder with symptoms that include encephalomyopathy and various manifestations, including growth deficiency, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia, myoclonus, and lactic acidosis.

Complex III deficiency or Ubiquinone-cytochrome C oxidoreductase deficiency is a respiratory chain disorder with symptoms categorized into four main forms: (1) fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophic establishment, seizures, and coma; (2) later onset encephalomyopathies (childhood to adulthood): various combinations of weakness, short stature, ataxia, dementia, sensory neuropathy, pigmentary retinopathy, and pyramidal signs; (3) myopathy, with exercise intolerance that develops into fixed weakness; and (4) infantile histiocytoid cardiomyopathy.

Complex IV Deficiency or Cytochrome C oxidase deficiency is a respiratory chain disorder with symptoms categorized in two main ways: (1) encephalomyopathy, which is normally normal for the first 6 to 12 months of life and then regresses in the development, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal signs, respiratory problems and frequent seizures; and (2) myopathy with two main variants: (a) fatal Infantile myopathy that may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, irregular red fibers, respiratory failure, and kidney problems: and (b) myopathy benign infantile that may start soon after birth and is accompanied by hypotonia, weakness, lactic acidosis, irregular red fibers, respiratory problems, but (if the child survives) it is followed by spontaneous improvement.

Complex V deficiency or ATP synthase deficiency is a respiratory chain disorder that includes symptoms such as slow, progressive myopathy.

CPEO or Chronic Progressive External Ophthalmoplegia Syndrome is a respiratory chain disorder that includes symptoms such as myopathy pigmentosa, visual retinitis or dysfunction of the central nervous system.

In addition to congenital disorders involving inherited defective mitochondria, acquired mitochondrial dysfunction contributes to diseases, particularly aging-associated neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. The incidence of somatic mutations in mitochondrial DNA increases exponentially with age; decreased respiratory chain activity is universally found in aging people. Mitochondrial dysfunction is also implicated in excitoxic, neuronal injury, cerebrovascular accidents such as that associated with seizures, stroke, and ischemia.

The above diseases appear to be caused by defects in complex I of the respiratory chain. Electron transfer from complex I to the rest of the respiratory chain is measured by the compound coenzyme Q (also known as ubiquinone). The oxidized coenzyme Q (CoQox or ubiquinone) is reduced by complex I to a reduced coenzyme Q (CoQred (CoQred or ubiquinol). The reduced coenzyme Q then transfers its electrons to complex III of the respiratory chain (which jumps over complex II ) in which it is re-oxidized to CoQox (ubiquinone) .The CoQox can then participate in additional iterations of electron transfer.

Very few treatments are available for patients suffering from these diseases. Recently, the compound idebenone has been proposed for the treatment of Friedreich's ataxia. While the clinical effects of idebenone have been relatively modest, the complications of mitochondrial disease can be so severe that even marginally useful therapies are preferable to cycles without disease treatment. Another compound, MitoQ, has been proposed to treat mitochondrial disorders (see US Patent No. 7,179,928); clinical results for MitoQ have not yet been reported. Administration of coenzyme Q10 (CoQ10) and vitamin supplements have shown only transient beneficial effects in individual cases of KSS.

Mitochondrial dysfunction has also been implicated in several different diseases. Recent studies have suggested that as many as 20 percent of autism patients have markers for mitochondrial disease (Shoffner, J. the 60th Annual American Academy of Neurology meeting in Chicago, April 12-19, (2008); Poling, JS et al . /. child Neurol. 2008, 21 (2) 170-2; and Rossignol et al., Am. J. Biochem. & Biotech. (2008) 4, 208-217). Some cases of autism have been associated with several different organic conditions, including bioenergetic deficiency of metabolism suggested by the detection of high levels of lactate in some patients (Coleman M. et al., Autism and Lactic Acidosis, J. Autism Dev Disord. , (1985) 15: 1-8; Laszlo et al. Serum serotonin, lactate and pyruvate levels in infantile autistic children, Clin. Chim. Acta (1994) 229: 205-207; and Chugani et al., Evidence of altered energy metabolism in autistic children, Progr. Neuropsychopharmacol Biol Psychiat., (1999) 23: 635-641); and nuclear magnetic resonance imaging as well as positron emission tomography scan in which abnormalities in brain metabolism were documented. Although the mechanism of hyperlactacidemia remains unknown, a likely possibility involves dysfunction of mitochondrial oxidative phosphorylation in neuronal cells. A small subset of autistic patients diagnosed with deficiencies in complex I or III of the respiratory chain has been reported in the literature (see Oliveira, G., Developmental Medicine & Child Neurology (2005) 47 185-189; and Filipek, PA et al. ., Journal of Autism and Developmental Disorders (2004) 34: 615-623). However, in many of the cases of autism where there is some evidence of mitochondrial dysfunction, there is an absence of classic features associated with a mitochondrial disease, such as mitochondrial pathology on muscle biopsy (See Rossignol, DA et al., Am J Biochem. & Biotech, (2008) 4 (2) 208-217).

Recently, Hayashi et al. (Science Express, published online April 3, 2008: DOI: 10,1126 / science.1156906, and Ishikawa et al., Science (May 2, 2008) 320 (5876) 661-664) indicated that the mutations Mitochondrial DNA can contribute to tumor progression by increasing the metastatic potential of tumor cells.

EP 1454627 discloses compounds comprising a quinone moiety linked to a dipeptide which are said to be useful in the treatment of mitochondrial disorders. WO 2007/100652 discloses compounds comprising a quinone moiety that is useful in the treatment or suppression of mitochondrial diseases.

The ability to adjust biological energy production has application beyond the diseases described above. The other disorders can result in suboptimal levels of energy biomarkers (sometimes also referred to as indicators of energy function), such as ATP levels. Treatments for these disorders are also a necessity, with the purpose of modulating one or more energy biomarkers to improve the health of the patient. In other applications, it may be desirable to modulate certain energy biomarkers far from their normal values in an individual who is not suffering from a disease. For example, if an individual is experiencing an extremely strenuous task, it may be desirable to increase the ATP level in that individual.

Accordingly, compounds for treating mitochondrial disease and / or adjusting biological energy production have a wide range of practical uses.

Disclosure of the invention

In one embodiment, compounds of formula I-S are described herein:

in which R is selected from the group consisting of:

wherein the * indicates the point of attachment of R to the rest of the molecule;

R1, R2, and R3 are independently selected from hydrogen, C ¹ -C ⁶ alkyl and O-C ¹ -C ⁶ alkyl;

R4 is -C ¹ -C ⁶ alkyl;

R5 and R6 are independently selected from hydrogen, hydroxy, alkoxy, alkyl-C ¹ -C ⁴⁰ alkyl , C ¹ -C ^{40-alkynyl-C 1} -C ⁴⁰ and aryl; wherein the alkyl, alkenyl, alkynyl or aryl groups may be optionally substituted with

-Or 10, -S (O) ^0-2 R10, -CN, -F, -Cl, -Br, -I, -NR10R10 ', oxo, cycloalkyl-CrC6, aryl, aryl-alkyl-CrC6, heteroaryl, heterocyclyl , -C (O) -R11, -C (O) -C ^{0 -C 6} -aryl alkyl, -C (O) -O-R11, -C (O) -O-C ⁰ -C ^{6 alkyl} -aryl, -C (O) -N-R11R11 ', -C (O) -N-alkyl-C ⁰ -C ⁶ -aryl, -NC (O) -R11, -NC (O) -C ^{1 alkyl} -C ⁶ -aryl; wherein the substituents on the aryl ring, heteroaryl and heterocyclyl may be further substituted with alkyl-C ¹ -C ⁶ haloalkyl-C ¹ -C ⁶ alkyl, oxo, hydroxy, alkoxy-C ¹ -C ⁶ -alkyl, -C (O) -C ^{1 -C 6} alkyl and -C (O) -O-C ¹ -C ⁶ alkyl; and wherein one of the carbons of the alkyl, alkenyl or alkynyl groups may be substituted with a heteroatom selected from O, N or; or

R5 and R6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one or more additional, such as one, two or three, N, O or S atoms and optionally substituted with oxo, -OR10, -SR10, -CN, -F, -Cl, -Br, -I, -NR10R10 ', alkyl-C ¹ -C ⁶ haloalkyl-C ¹ -C ^6; hydroxy-C ¹ -C ⁶ alkyl, -C (O) -H, C (O) -C ^{1 -C 6} alkyl, -C (O) -aryl, -C (O) -OH or -C ( O) -O-C ¹ -C ⁶ alkyl; or

R5 and R6 together with the nitrogen atom to which they are attached form a disubstituted N, N'-piperazine in which the nitrogen substitution at position 4 is a group identical to the substitution at position 1 forming a compound of the formula I-Saa or I-Sbb, where R1, R2, R3, and R4 are as defined above:

R10 and R10 'are independently selected from the alkyl aryl-C group consisting of H, alkyl-C ¹ -C ⁶ haloalkyl-C ¹ -C ⁶ alkyl, aryl, ¹ -C ⁶ -alkyl, heteroaryl, heterocyclyl, -C ( O) -H, -C (O) -C ¹ -C ⁶ alkyl, -C (O) -aryl and -C (O) -C ^{1 -C 6} -aryl alkyl;

R11 and R11 'are selected from hydrogen and C ¹ -C ⁶ alkyl; Y

M and M 'are independently selected from hydrogen, -C (O) -R12, -C (O) -alkenyl-Ci-C6, -C (O) -alkynyl-C ¹ -Ca, -C (O) -aryl ; -C (O) -heteroaryl, -C (O) O-R12, -C (O) NR12R12, -SO ² OR ^12, -SO ² -alkyl-Cr Ca, -SO ² -haloalkyl-C ¹ -C 6; -SO ² -aryl, -SO ² -NR12R12, -P (O) (OR12) (OR12), and mono or di C - linked peptide, wherein R12 is hydrogen or-C ¹ -Ca optionally substituted with -OH, -NH ² , -NH (C ¹ -C ⁴ alkyl), -N (C ¹ -C ⁴ alkyl) ² , -C (O) -OH, -C (O) -O-alkyl or halogen;

provided that the compound is not N- (a-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,4, tetrahydropyrimidin-5-yl) -2-hydroxy-2-methyl- 4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dieni) butanamide or N- (a-amino-3-methyl-2,4-dioxo-1-phenyl-1,2, 3,4-tetrahydropyrimidin-5-yl) -4- (2,5-dihydroxy-3,4, α-trimethylphenyl) -2-hydroxy-2-methylbutanamide;

and all salts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, solvates and hydrates thereof.

In another embodiment, a method of treating or suppressing a mitochondrial disorder is described herein, which modulates one or more energy biomarkers, normalizes one or more energy biomarkers, or improves one or more energy biomarkers, by administering a therapeutically effective amount or effective amount of one or more compounds of formula IS as described above.

In one embodiment, compounds of formula I are described herein:

in which R is selected from the group consisting of:

where * indicates the point of attachment of R to the rest of the molecule;

R1, R2, and R3 are independently selected from hydrogen and C ¹ -alkyl-Ca;

R4 is alkyl-C ¹ -Ca;

R5 and Ra are independently selected from hydrogen, hydroxy, alkoxy, alkyl-C ¹ -C ^40, alkenyl-C ¹ -C ⁴⁰ alkynyl-C ¹ -C ⁴⁰ and aryl; wherein the alkyl, alkenyl, alkynyl or aryl groups may be optionally substituted with

-OR10, -S (O) or ^-2 R10, -CN, -F, -Cl, -Br, -I, -NR10R10 ', oxo, C ³ -cycloalkyl -Ca, aryl, aryl-C ¹ -alkyl - Ca, heteroaryl, heterocyclyl, -C (O) -R11, -C (O) -C ⁰ -alkyl -Ca-aryl, -C (O) -O-R11, -C (O) -O-alkyl-C ⁰ -Ca-aryl, -C (O) -N-R11R11 ', -C (O) -N-alkyl-C ⁰ -Ca-aryl, -NC (O) -R11, -NC (O) -alkyl- C ⁰ -Ca-aryl; wherein the substituents on the aryl ring, heteroaryl and heterocyclyl may be further substituted with alkyl-C ¹ -Ca haloalkyl-C ¹ -Ca, oxo, hydroxy, alkoxy-C ¹ -Ca, -C (O) -C -C ¹ -Ca and -C (O) -O-C ¹ -Caalkyl and wherein one of the carbons of the alkyl, alkenyl or alkynyl groups may be substituted with a heteroatom selected from -O-, -N - or; or R5 and Ra together with the atom to which they are attached form a 3-8 membered saturated or unsaturated ring, optionally incorporating one or more, such as one, two or three additional and optionally substituted N, O or S atoms oxo, -OR10, -SR10, -CN, -F, -Cl, -Br, -I, -NR10R10 ', alkyl-C ¹ -Ca haloalkyl-C ¹ -Ca; hydroxy-C ¹ -alkyl -Ca, -C (O) -H, -C (O) -C ¹ -Ca alkyl, -C (O) -aryl, -C (O) -OH or -C (O ) -O-C ¹ -alkyl -Ca; or

R5 and Ra together with the nitrogen atom to which they are attached form a disubstituted W, W-piperazine in which the nitrogen substitution at position 4 is an identical group to the substitution at position 1 forming a compound of formula Iaa or Ibb, where R1, R2, R3 and R4 are as defined above:

to

R10 and R10 'are independently selected from the group consisting of H, Ci-C6 alkyl, Ci-C6 haloalkyl, aryl, aryl-C ¹ -C ⁶ alkyl, heteroaryl, heterocyclyl, -C (O) -H , -C (O) -alkyl-C ¹ -C ⁶ -alkyl, -C (O) -aryl and -C (O) -alkyl-C ¹ -Caarilo;

R11 and R11 'are selected from hydrogen and C ¹ -C ⁶ alkyl; Y

M and M 'are independently selected from hydrogen, -C (O) -R12, -C (O) -alkenyl-C ¹ -C ⁶ , -C (O) -alkynyl-C ¹ -Ca, -C (O) -aryl; -C (O) -heteroaryl, -C (O) O-R12, -C (O) NR12R12, -SO ² OR ^12, -SO ² -alkyl-Cr Ca, -SO ² -halo-alkyl-C ¹ - C ⁶ ; -SO ² -aryl, -S- ² -NR12R12, -P (O) (0r 12) (OR12), and mono or di-peptide linked to C, in which R12 is hydrogen or-C ¹ -Ca optionally substituted with -Oh, -NH ² , -NH (C ¹ -C ⁴ alkyl), -N (C ¹ -C ⁴ alkyl) ² , -C (O) -OH, -C (O) -O-alkyl -C ¹ -C ⁴ or halogen;

provided that the compound is not W- (a-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl) -2-hydroxy-2 -methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide or A / - (a-amino-3-methyl-2,4-dioxo-1-phenyl- 1,2,3,4-tetrahydropyrimidin-5-yl) -4- (2,5-dihydroxy-3,4, α-trimethylphenyl) -2-hydroxy-2-methylbutanamide;

and all salts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, solvates and hydrates thereof.

The present invention provides a compound selected from the group consisting of:

• 2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide and

• its hydroquinone form of it;

or a salt, a stereoisomer or a mixture of stereoisomers thereof.

The present invention also provides a pharmaceutical composition comprising a compound of the invention, together with a pharmaceutically acceptable excipient, carrier or vehicle.

In another embodiment, the invention encompasses a compound or composition of the invention for use in a method of treating or suppressing a mitochondrial disorder that modulates one or more energy biomarkers, normalizes one or more energy biomarkers, or enhances one. or more energy biomarkers, administering a therapeutically effective amount or effective amount of the compound or composition.

Compounds of formula I selected from among:

2-hydroxy-N-isopropyl-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2- (3-hydroxy-3-methyl-4-oxo-4- (piperidin-1-yl) butyl) -3,5, α-trimethylcyclohexa-2,5-diene-1,4-dione;

2- (4- (azepan-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5, α-trimethylcyclohexa-2,5-diene-1,4-dione;

W-hexyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W-tert-butyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W, W, 2-trimethyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W-ethyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W-benzyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-2-methyl-N-propyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W- (cyclopropylmethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-2-methyl-N-phenethyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (3-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N-isopentyl-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W-cyclopropyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2- (3-hydroxy-4- (4-hydroxypiperidin-1-yl) -3-methyl-4-oxobutyl) -3,5, α-trimethylcyclohexa-2,5-diene-1,4-dione;

2-hydroxy-N-isobutyl-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

W-ethyl-2-hydroxy-W, 2-dimethyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (4-hydroxybutyl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (5-hydroxypentyl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (2-methoxyethyl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-N- (1-hydroxypropan-2-yl) -2-methyl-4- (2,4,5-trimethyl-3, α-dioxocyclohexa-1,4-dienyl) butanamide;

(R) -2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxoidohexa-1,4-dienyl) butanamide;

(S) -2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide;

methyl 2- (2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamido) acetate;

W- (3- (1H-m¡dazoM-¡l) prop¡l) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6 -dioxoddohexa-1,4-dieml) butanamide;

2-hydroxy-N- (2- (2-hydroxyethoxy) ethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide;

2-h¡drox¡-2-met¡lN- (p¡r¡d¡n-2-¡lmet¡l) -4- (2,4,5-tr¡met¡l-3,6-d Oxo-dohexa-1,4-dimethyl) butanamide;

2-hydrox¡-2-met¡lN- (2- (p¡r¡d¡n-2-¡l) eth¡l) -4- (2,4,5-trimethyl-3, 6-dioxoddohexa-1,4-dieml) butanamide;

2-hydrox¡-2-methylN- (3- (2-oxop¡rrol¡d¡n-1-yl) prop¡l) -4- (2,4,5-tr¡met¡l -3,6-dioxoxydohexa-1,4-dimenyl) butanamide;

2-hydroxy-N- (2-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa- 1,4-dimethyl) butanamide;

2-hydrox¡-N- (6-hydrox¡hexyl) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-dioxoxydohexa- 1,4-dimethyl) butanamide;

2- (3-hydrox¡-3-methyl-4- (4-methylpiperaz¡n-1-¡l) -4-oxobut¡l) -3,5,6-tr¡met¡ lcdohexa-2,5-diene-1,4-dine;

2- (4- (4-bendlp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3,5,6-trimethylddohexa- 2,5-diene-1,4-dione;

2-hydrox¡-2-methylN - ((tetrahydrofuran-2-yl) methyl) -4- (2,4,5-tr¡met¡l-3,6-d¡oxoc Dohexa-1,4-d¡en¡l) butanam¡da;

2-hydrox¡-2-methyl-N- (3-morpholmopropyl) -4- (2,4,5-tr¡methyl-3,6-dioxoxydohexa-1,4- d¡en¡l) butanam¡da;

2-hydroxy-N-methoxy-N, 2-dimethyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa-1,4-d En¡l) butanam¡da;

2-h¡drox¡-W, A / -b¡s (2-h¡drox¡et¡l) -2-methyl-4- (2,4,5-trimethyl-3,6- dioxoddohexa-1,4-dieml) butanamide;

W- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-d Oxoddohexa-1,4-dieml) butanamide;

2-hydroxy-N- (4-hydroxyphenethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa- 1,4-dimethyl) butanamide;

N- (3- (dimethyl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6- dioxoxydohexa-1,4-dimenyl) butanamide;

6,6 '- (4,4' - (p¡peraz¡n-1,4-d¡¡l) b¡s (3-hydrox¡-3-methyl-4-oxobutane-4,1- d¡¡l)) b¡s (2,3,5-tr¡melc¡dohexa-2,5-diene-1,4-dine);

W-but¡l-2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanam¡ gives;

2-h¡drox¡-N- (2-h¡drox¡et¡l) -W, 2-d¡met¡l-4- (2,4,5-trimethyl-3,6-d¡ oxoddohexa-1,4-diml) butanamide;

W, Wd¡et¡l-2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

2- (2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-dioxoxydohexa-1,4-d¡en¡l) butanam Do) tert-butyl ethylcarbamate;

2-h¡drox¡-2-met¡lN- (p¡r¡d¡n-4-¡lmet¡l) -4- (2,4,5-trimethyl-3,6-d¡oxoddohexa -1,4-d¡eml) butanamida;

2-h¡drox¡-2-met¡lN- (p¡r¡d¡n-3-ylmeth¡l) -4- (2,4,5-tr¡met¡l-3,6-d¡ oxoxydohexa-1,4-dienel) butanamide;

2-hydroxy-2-methylN- (3- (methylsulfonyl) propyl) -4- (2,4,5-trimethyl-3,6-dioxoxydohexa -1,4-d¡en¡l) butanamida;

2- (2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa-1,4-d¡en¡l) acid butanamido) acetic;

2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6-trimethyl lddohexa-2,5-diene-1,4-dione;

2- (4- (4-fluorop¡per¡per¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡met¡ lcdohexa-2,5-diene-1,4-dine;

2- (4- (4,4-d¡fluorop¡per¡per¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6- trimethyl dohexa-2,5-diene-1,4-dine;

2- (3-hydroxy-3-methyl-4-oxo-4- (piperaz¡n-1-¡l) but¡l) -3,5,6-tr¡melc¡dohexa -2,5-diene-1,4-dione;

4- (2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa-1,4-dimenyl) butane L) tert-butyl piperazin-1-carboxylate; 2- (4- (4-benzo¡lp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methyldohexa-2,5-diene-1,4-dione;

(R) -2-hydroxy-2-methyl-4- (2,4,5-tr¡metal-3,6-dioxoxydohexa-1,4-d¡en¡l ) butanamida;

(S) -2-hydroxy-2-methyl-4- (2,4,5-tr¡methyl-3,6-dioxoxydohexa-1,4-d¡en¡l ) butanamida;

2- (3-h¡drox¡-4- (4-¡soprop¡lp¡peraz¡n-1-¡l) -3-methyl-4-oxobut¡l) -3,5,6-tr Methyldohexa-2,5-diene-1,4-dione;

2- (4- (4- (c¡dopropanecarbon¡l) piperaz¡n-1-yl) -3-hydrox¡-3-methyl-4-oxobut¡l) -3.5, 6-trimethyl dohexa-2,5-diene-1,4-dione;

(R) -2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6- trimethyl dohexa-2,5-diene-1,4-dine;

(S) -2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6- trimethyl dohexa-2,5-diene-1,4-dine;

(R) -2- (3-h¡drox¡-4- (4-h¡drox¡p¡per¡d¡n-1-¡l) -3-methyl-4-oxobut¡l) - 3,5,6-trimethylddohexa-2,5-diene-1,4-diene;

(S) -2- (3-h¡drox¡-4- (4-h¡drox¡p¡per¡per¡l) -3-methyl-4-oxobut¡l) -3, 5,6-trimethyl-dohexa-2,5-diene-1,4-dine;

W- (2-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

W- (3-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

W- (4-fluoropheneti) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

W- (2-dorofeneth¡l) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

W- (3-dorofenet¡l) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

W- (4-dorofenet¡l) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡ eml) butanamida;

2-hydroxy-N- (4-methoxyphenyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxydohexa-1, 4-day) butanamida;

W- (4-fluorofeml) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (4-dorofeml) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (2-fluorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (3-fluorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (4-fluorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡metal-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (2-dorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (3-dorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

W- (4-dorobendl) -2-hydrox¡-2-methyl-4- (2,4,5-trimethyl-3,6-d¡oxoddohexa-1,4-d¡eml) butanamida;

and all salts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites, solvates and hydrates thereof.

In other embodiments, including any of the above embodiments, 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); Leber's hereditary optic neuropathy (LHON); Leigh's disease; Kearns-Sayre syndrome (KSS); Friedreich's ataxia (FA); other myopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis; neurodegenerative diseases; Parkinson's disease; Alzheimer disease; Amyotrophic lateral sclerosis (ALS); motor neuron diseases; other neurological diseases; epilepsy; genetic diseases; Huntington's disease; mood disorders; schizophrenia; Bipolar disorder; age-related diseases; cerebrovascular accidents, macular degeneration; diabetes; and cancer.

In another embodiment, including any of the above embodiments, the mitochondrial disorder is a mitochondrial respiratory chain disorder. In a particular embodiment, the mitochondrial respiratory chain disorder is a disorder of the respiratory protein chain. In another particular embodiment, the disorder is CoQ10 deficiency.

In another embodiment, including any of the above embodiments, the mitochondrial disorder is selected from the group consisting of inherited mitochondrial diseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRf, for its acronym in English); Mitochondrial myopathy, encephalopathy, Lactacidosis and stroke (MELAS); Leber's hereditary optic neuropathy (LHON); Leigh's disease; Kearns-Sayre syndrome (KSS); Friedreich's ataxia (FA).

In another embodiment of the invention, including any of the above embodiments, the mitochondrial disorder is Friedreich's ataxia (FA). In another embodiment of the invention, the mitochondrial disorder is Leber's hereditary optic neuropathy (LHON). In another embodiment of the invention, including any of the above embodiments, the mitochondrial disorder is mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS). In another embodiment of the invention, including any of the above embodiments, the mitochondrial disorder is Kearns-Sayre syndrome (KSS). In another embodiment of the invention, the mitochondrial disorder is Myoclonic Epilepsy with Broken Red Fibers (MERRF). In another embodiment of the invention, including any of the above embodiments, the disorder is Parkinson's disease. In another embodiment of the invention, including any of the above embodiments, the disorder is Huntington's disease. In another embodiment of the invention that includes any of the above embodiments, the disorder is amyotrophic lateral sclerosis (ALS). In yet another embodiment of the invention including any of the above embodiments, the disorders are cerebrovascular accidents, such as stroke.

The compounds described herein can be administered to subjects suffering from a mitochondrial disorder to modulate one or more of several energy biomarkers, including, but not limited to, lactic acid (lactate) levels, in whole blood, plasma, fluid cerebrospinal or cerebral ventricular fluid; levels of pyruvic acid (pyruvate), in all blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; lactate / pyruvate ratios, in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; phosphocreatine levels, levels of NADH (NADH H +) or NADPH (NADPH + H +); levels of NAD or NADP; ATP levels; reduced levels of coenzyme Q (CoQred); oxidized coenzyme Q (CoQox) levels; total coenzyme Q (CoQtot) levels; oxidized cytochrome C levels; reduced cytochrome C levels; ratio of oxidized cytochrome C / reduced cytochrome C; acetoacetate levels; beta-hydroxy butyrate levels; acetoacetate / beta-hydroxy butyrate ratio; 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels; levels of reactive oxygen species; oxygen consumption (VO2), carbon dioxide output (VCO2), respiratory quotient (VCO2 / VO2), and to modulate exercise intolerance (or conversely, modulate exercise tolerance) and modulate the anaerobic threshold. Energy biomarkers can be measured in all blood, plasma, cerebrospinal fluid, cerebroventricular fluid, arterial blood, venous blood, or any other body fluid, body gas, or other biological sample useful for such measurement. In one embodiment, the levels are modulated to a value within about 2 standard deviations of the value in a healthy subject. In another embodiment, the levels are modulated to a value within about 1 standard deviation of the value in a healthy subject. In another embodiment, the levels in a subject are changed by at least about 10% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 20% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 30% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 40% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 50% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 75% above or below the level in the subject prior to modulation. In another embodiment, the levels are changed by at least about 100% above or at least about 90% below the level in the subject prior to modulation.

The compounds described herein can be administered to treat subjects suffering from the pervasive developmental disorders selected from Autistic Disorder, Asperger's Disorder, Childhood Disintegrative Disorder (CDD), Rett's Disorder, and pervasive developmental disorders no (PDD-NOS). In another embodiment, the disorder is Austistic disorder.

In another embodiment, including any of the foregoing embodiments, the subject or subjects in whom a method of treating or suppressing a mitochondrial disorder is performed, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or improves one or more energy biomarkers is selected / selected from the group consisting of subjects experiencing vigorous or prolonged physical activity; subjects with chronic energy problems; subjects with chronic respiratory problems; pregnant women; pregnant women in labor; newly born; premature newborns; subjects exposed to extreme environments; subjects exposed to hot environments; subjects exposed to cold environments; subjects exposed to environments with lower than average oxygen content; subjects exposed to environments with higher than average carbon dioxide content; subjects exposed to environments with higher than average levels of air pollution; airline travelers; flight attendants; subjects at high altitudes; subjects who live in cities with lower than average air quality; subjects who work in confined environments where air quality degrades; subjects with lung diseases; subjects with lower than average lung capacity; tubercular patients; patients with lung cancer; patients with emphysema; cystic fibrosis patients; subjects recovering from surgery; subjects recovering from illness; subjects of the third age; elderly subjects experiencing decreased energy; subjects suffering from chronic fatigue; subjects suffering from chronic fatigue syndrome; subjects experiencing acute trauma; subjects in concussion; subjects requiring acute oxygen administration; subjects requiring chronic oxygen administration; or other subjects with acute, chronic or prolonged energy demands that can benefit from the improvement of energy biomarkers.

In another embodiment, the invention encompasses one or more of the compounds of the invention, in combination with a pharmaceutically acceptable excipient, carrier, or vehicle.

In another embodiment, the invention encompasses a compound or composition of the invention in the manufacture of a medicament for use in therapy of a mitochondrial disease.

For all compounds and methods described above, the quinone form can also be used in its reduced form (hydroquinone) when desired. Likewise, the hydroquinone form can also be used in its oxidized form (quinone) when desired.

Modes of carrying out the invention

The invention encompasses compounds useful in treating or suppressing mitochondrial disorders. Such compounds can be used for the modulation of energy biomarkers. Redox active therapeutics for the treatment or suppression of mitochondrial diseases and associated aspects of the invention are described in more detail herein.

"Subject", "individual," or "patient" means an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.

"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, to reduce or eliminate the disease or one or more symptoms. of the disease, or slow the progression of the disease or one or more symptoms of the disease, or reduce the severity of the disease or 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, to suppress the clinical manifestation of the disease, or to suppress the manifestation of adverse symptoms of the disease. The distinction between treatment and suppression is that treatment occurs after the adverse symptoms of the disease are manifested in a subject, whereas suppression occurs before the adverse symptoms of the disease are manifested in a subject. The deletion can be partial, substantially total or total. Because many of the mitochondrial disorders are inherited, genetic research can be used to identify patients at risk for the disease. The compounds and methods of the invention can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disease, to suppress the appearance of any adverse symptoms. "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. An "effective amount" of a compound is an amount of the compound sufficient to modulate, normalize, or enhance one or more biomarkers of energy (modulation, normalization, and enhancement are defined below). "A therapeutically effective amount" of a compound is an amount of the compound, which, when administered to a subject, is sufficient to reduce or eliminate a disease or one or more symptoms of a disease, or to slow 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. An "effective amount" of a compound comprises a therapeutically effective amount, as well as an amount effective to modulate, normalize or enhance one or more biomarkers of energy in a subject.

"Modulation" of or for "modulating," an energy biomarker means changing the level of the energy biomarker toward a desired value or changing the level of the energy biomarker in a desired direction (eg, increase or decrease). Modulation may include, but is not limited to, standardization and enhancement as defined below.

"Normalization" of or to "normalize," an energy biomarker is defined as changing the level of the energy biomarker from a pathological value towards a normal value, where the normal value of the energy biomarker may be 1) the level of the energy biomarker in a healthy person or subject, or 2) a level of the energy biomarker that alleviates one or more undesirable symptoms in the person or subject. That is, normalizing an energy biomarker that is depressed in a disease state means increasing the level of the energy biomarker towards the normal (healthy) value or towards a value that alleviates an undesirable symptom; to normalize an energy biomarker that rises in a disease state means to decrease the energy biomarker level toward the normal (healthy) value or toward a value that alleviates an undesirable symptom.

"Enhancement" of or to "enhance," energy biomarkers means intentionally changing the level of one or more energy biomarkers away from the normal value or value prior to enhancement, to achieve a beneficial or desired effect. For example, in a situation where significant energy demands are placed on a subject, it may be desirable to increase the ATP level in that subject to a level above the normal ATP level in that subject. Enhancement may also be of beneficial effect in a subject suffering from a disease or pathology such as mitochondrial disease, in which normalization of an energy biomarker may not achieve the optimal result for the subject; in such cases, enhancement of one or more energy biomarkers may be beneficial, eg, higher than normal levels of ATP or lower than normal levels of lactic acid (lactate) may be beneficial to such a subject.

To "modulate, normalize, or enhance coenzyme Q of the energy biomarker" means to modulate, normalize, or enhance the variant or variants of coenzyme Q that is predominant in the species of interest. For example, the predominant variant of coenzyme Q in humans is coenzyme Q10. If a species or subject has more than one coenzyme Q variant present in significant amounts (in this case, present in amounts that, when modulated, normalized, or enhanced, may have a beneficial effect on the species or subject), modulate, normalize or "improving coenzyme Q" can refer to modulating, normalizing or improving any or all of the variants of coenzyme Q present in the species or subject.

While the compounds described herein can occur and can be used as the neutral compound (no salt), the description is intended to encompass all salts of the compounds described herein, as well as methods of using such salts of compounds. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts that can be administered as drugs or pharmaceuticals to humans and / or animals and that, during administration, retain at least some biological activity of the free compound (neutral compound or compound without salt). The desired salt of a basic compound can be prepared by methods known to those skilled in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid. , cinnamic acid, mandelic acid, sulfonic acids and salicylic acid. Salts of the basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those skilled in the art by treating the compound with a base. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine W, W-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. Additional salts particularly useful for pharmaceutical preparations are described in Berge SM et al., "Pharmaceutical salts," J. Pharm. Sci. 1977 Jan; 66 (1): 1-19.

The invention also includes all stereoisomers of the compounds, including diastereomers and enantiomers. The invention also includes mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly stated in a structure, the structure is intended to comprise all possible stereoisomers of the depicted compound. If the stereochemistry is explicitly stated for a portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to comprise all possible stereoisomers for the portion or portions where the stereochemistry is not explicitly stated.

For the purpose of the invention, the compounds of formula I, and the rest of the compounds described herein, generically or specifically, which include derivatives in which one or more hydrogen atoms have been replaced by an isotope of hydrogen, for example by deuterium.

The compounds can be administered in the form of a prodrug. Prodrugs are derivatives of compounds, which are themselves relatively inactive but which become the active compound when introduced into the subject, in which they are used by an in vivo chemical or biological process, such as enzymatic conversion. Suitable prodrug formulations include, but are not limited to, conjugated peptides of the compounds of the invention and esters of the compounds of the inventions. In addition, 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 RL Juliano (ed.), Biological Approaches to the Controlled Delivery of Drugs (Annals of the New York Academy of Sciences, v. 507), New York: New York Academy of Sciences, 1987; and in EB Roche (ed.), Design of Biopharmaceutical Properties Through Prodrugs and Analogs (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), Washington: The Academy, 1977.

The metabolites of the compounds are also encompassed by the invention.

"Alkyl-C-i-Ca" is intended to encompass a hydrocarbon of 1 to 6 carbon atoms, saturated, branched, cyclic, or a combination thereof. Examples of "Ci-Ca alkyl" are methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl in which the point of attachment of the pentyl group to the rest of the molecule can be at any location on the pentyl, cyclopentyl, hexyl fragment where the point of attachment of the hexyl group to the rest of the molecule can be at any location on the hexyl fragment, and cyclohexyl.

"Halogen" or "halo" indicates fluorine, chlorine, bromine and iodine.

"Haloalkyl-Ci-Ca" is intended to encompass any alkyl-Ci-C6 substituent having at least one halogen substituent; halogen can be attached via any valence on the C ¹ -C ⁶ alkyl group. Some examples of C ¹ -C ⁶ haloalkyl are -CF ³ , -CCh, -CHF ² , -CHCh, -CHBr ² , -CH ² F, -CH ² CL

The term "aryl" is intended to encompass a C6-20 aromatic cyclic hydrocarbon group having a single ring (eg, phenyl) or multiple fused (fused) rings (eg, naphthyl or anthryl).

The term "Friedreich's ataxia" is intended to encompass other ataxias, and is also sometimes referred to as hereditary ataxia, familial ataxia, or Friedreich tabes.

The terms "heterocycle", "heterocyclic", "heterocycle", and "heterocyclyl" are intended to encompass a monovalent, saturated or partially unsaturated carbocyclic radical, having one or more rings incorporating one, two, three, or four heteroatoms within the ring ( chosen from nitrogen, oxygen, and / or sulfur). Examples of heterocycles include morpholine, piperidine, piperazine, thiazolidine, pyrazolidine, pyrazoline, imidazolidine, pyrrolidine, tetrahydropyran, tetrahydrofuran, quinuclidine, and the like.

The term "heteroaryl" is intended to encompass a monovalent, aromatic carbocyclic radical having one or more rings incorporating one, two, three or four heteroatoms within the ring (chosen from nitrogen, oxygen and / or sulfur). Examples of heteroaryl include pyridine, pyrazine, imidazoline, thiazole, isothiazole, pyrazine, triazine, pyrimidine, pyridazine, pyrazole, thiophene, pyrrole, pyran, furan, indole, quinoline, quinazoline, benzimidazole, benzothiophene, benzofriazole, benzoxazole, benzothiophene, benzofriazole, benzoxazole, benzothiophene, benzofriazole, benzoxazole, imidazo-pyridines, pyrazolo-pyridines, pyrazolo-pyrazine, acridine, carbazole, and the like.

The terms "Parkinson's", (also referred to as "Parkinsonism" "Parkinsonian syndrome") ("PD") are intended to include not only Parkinson's disease but also drug-induced Parkinsonism and post-encephalitic Parkinsonism. Parkinson's disease is also known as shaking paralysis or trembling paralysis. It is characterized by tremor, muscle stiffness, and loss of postural reflexes. The disease generally progresses slowly with intervals of 10 to 20 years that elapse before symptoms cause disability. Due to its mimicry of the effects of Parkinson's disease, treatment of animals with methamphetamine or MPTP has been used to generate models for Parkinson's disease. These animal models have been used to evaluate the efficacy of various therapies for Parkinson's disease.

Diseases susceptible to treatment or suppression with the compounds and methods of the invention

Various diseases are believed to be caused or aggravated by mitochondrial disorders and impaired energy processing, and can be treated or suppressed using the compounds and methods of the invention. Such diseases include, but are not limited to, inherited mitochondrial diseases, such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial myopathy, encephalopathy, Lactacidosis and stroke (MELAS); Leber's hereditary optic neuropathy (LHON, also referred to as Leber's disease, Atropia Leber's Optic (LOA) or Leber's Optic Neuropathy (LON)); Leigh's disease or Leigh's syndrome; Kearns-Sayre syndrome (KSS); Friedreich's ataxia (FA); other myopathies (including cardiomyopathy; and encephalomyopathy) and renal tubular acidosis; neurodegenerative diseases; Parkinson's disease; Alzheimer disease; Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease); motor neuron diseases; other neurological diseases; epilepsy; genetic diseases; Huntington's disease (which is also a neurological disease); mood disorders such as schizophrenia and bipolar disorder; cerebrovascular accidents, age-associated diseases, particularly diseases for which CoQ10 has been proposed for treatment, macular degeneration; diabetes; and cancer. Mitochondrial dysfunction is also implicated in excilotoxic neuronal injury, such as that associated with seizures, stroke, and ischemia. Mitochondrial dysfunction is also implicated in certain patients suffering from the selected pervasive developmental disorders of Autistic Disorder, Asperger's Disorder, Childhood Disintegrative Disorder (CDD), Rett's Disorder, and Pervasive Developmental Disorder Not Specified (PDD-NOS), and those disorders can also be treated or suppressed using the compounds and methods of the invention.

Clinical assessment of mitochondrial dysfunction and efficacy of therapy

Several easily measurable clinical markers are used to assess the metabolic status of patients with mitochondrial disorders. These markers can also be used as indicators of the efficacy of a given therapy, as the level of a marker moves from the pathological value to the healthy value. These clinical markers include, but are not limited to, one or more of the previously discussed energy biomarkers, such as lactic acid (lactate) levels, in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; levels of pyruvic acid (pyruvate), in all blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; lactate / pyruvate ratios, in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; levels of phosphocreatine, NADH (NADH + H +) or levels of NADPH (NADPH + H +); levels of NAD or NADP; ATP levels; anaerobic threshold; reduced coenzyme Q levels (CoQred); levels of oxidized coenzyme Q (CoQox); total coenzyme Q levels (CoQtot); levels of oxidized cytochrome C; reduced cytochrome C levels; ratio of oxidized cytochrome C / reduced cytochrome C; acetoacetate levels, p-hydroxy butyrate levels, acetoacetate / p-hydroxy butyrate ratio, 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels; levels of reactive oxygen species; and levels of oxygen consumption (VO2), levels of carbon dioxide output (VCO2), and respiratory ratio (VCO2 / VO2). Several of these clinical markers are routinely measured in exercise physiology laboratories, and provide appropriate values for a subject's metabolic status. In one embodiment of the invention, the level of one or more energy biomarkers in a patient suffering from a mitochondrial disease, such as Friedreich's ataxia, Leber's hereditary optic neuropathy, MELAS, or KSS, is improved to within two standard deviations. of the average level in a healthy subject. In another embodiment of the invention, the level of one or more of these energy biomarkers in a patient suffering from a mitochondrial disease, such as Friedreich's ataxia, Leber's hereditary optic neuropathy, MELAS, or KSS is improved within one standard deviation. of the average level in a healthy subject. Exercise intolerance can also be used as an indicator of the efficacy of a given therapy, where an improvement in exercise tolerance (ie, a decrease in exercise intolerance) indicates efficacy of a given therapy.

Several metabolic biomarkers have already been used to assess the efficacy of CoQ10, and these metabolic biomarkers can be monitored as energy biomarkers for use in the methods of the present invention. Pyruvate, a product of anaerobic glucose metabolism, is eliminated by reduction to lactic acid in an anaerobic configuration or by oxidative metabolism, which is dependent on a functional mitochondrial respiratory chain. Respiratory chain dysfunction can lead to inadequate elimination of lactate and pyruvate from the circulation, and elevated lactate / pyruvate ratios are seen in mitochondrial cytopathies (see Scriver, The metabolic and molecular bases of inherited disease, 7th ed., New York: McGraw-Hill, Health Professions Division, 1995; and Munnich et al., J. Inherit. Metab. Dis. 15 (4): 448-55 (1992)). Lactate / pyruvate ratio in the blood (Chariot et al., Arch. Pathol. Lab. Med. 118 (7): 695-7 (1994)) is therefore widely used as a non-invasive test for the detection of mitochondrial cytopathies (see again Scriver CR, The metabolic and molecular bases of inherited disease, 7th ed., New York: McGraw-Hill, Health Professions Division, 1995; and Munnich et al., J. Inherit. Metab. Dis. 15 (4): 448-55 (1992)) and toxic mitochondrial myopathies (Chariot et al., Arthritis Rheum. 37 (4): 583-6 (1994)). Changes in the redox status of the liver mitochondria can be investigated by measuring the arterial proportion of the ketone body (acetoacetate / 3-hydroxybutyrate: AKBR) (Ueda et al., J. Cardiol. 29 (2): 95-102 ( 1997)). Urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) has frequently been used as a biomarker to assess the degree of repair of ROS-induced DNA damage in clinical and occupational settings (Erhola et al., FEBS Lett .

409 (2): 287-91 (1997); Honda et al., Leuk. Res. 24 (6): 461-8 (2000); Pilger et al., Free Radic. Res. 35 (3): 273-80 (2001); Kim et al. Environ Health Perspect 112 (6): 666-71 (2004)).

Magnetic resonance spectroscopy (ERM) has been useful in the diagnosis of mitochondrial cytopathy demonstrating elevations in cerebrospinal fluid (CSF) and cortical white matter lactate using the proton MRS (ERM 1H) (Kaufmann et al., Neurology 62 (8 ): 1297-302 (2004)). Phosphorous MRS (31P-MRS) has been used to demonstrate low levels of cortical phosphocreatine (PCr) (Matthews et al., Ann. Neurol. 29 (4): 435-8 (1991)), and a delay in the kinetics of recovery of PCr after exercise in skeletal muscle (Matthews et al., Ann. Neurol. 29 (4): 435-8 (1991); Barbiroli et al., J. Neurol. 242 (7): 472-7 ( 1995); Fabrizi et al., J. Neurol. Sci. 137 (l): 20-7 (nineteen ninety six)). A low PCr skeletal muscle has also been confirmed in patients with mitochondrial cytopathy by direct biochemical measurements.

The exercise test is particularly helpful as an evaluation and diagnostic tool in mitochondrial myopathies. One of the typical features of mitochondrial myopathies is a reduction in maximal whole body oxygen consumption (VO2max) (Taivassalo et al., Brain 126 (Pt 2): 413-23 (2003)). Given that VO2max is determined by cardiac output (Qc) and the difference in peripheral oxygen extraction (arterial venous total oxygen content), some mitochondrial cytopathies affect cardiac function where release can be altered; however, most mitochondrial myopathies show a characteristic deficit in peripheral oxygen extraction (AV O2 difference) and improved oxygen delivery (hyperkinetic circulation) (Taivassalo et al., Brain 126 (Pt 2): 413-23 (2003)). This can be demonstrated by a lack of venous blood-induced exercise deoxygenation with direct AV balance measurements (Taivassalo et al., Ann. Neurol. 51 (l): 38-44 (2002)) and non-invasively by spectroscopy. near infrared (Lynch et al., Muscle Nerve 25 (5): 664-73 (2002); van Beekvelt et al., Ann. Neurol. 46 (4): 667-70 (1999)).

Several of these energy biomarkers are discussed in more detail as follows. It should be emphasized that, while certain energy biomarkers are discussed and listed herein, the invention is not limited to modulating, normalizing, or enhancing only these listed energy biomarkers.

Lactic acid ( lactate) levels: Mitochondrial dysfunction usually results in abnormal lactic acid levels, as pyruvate levels increase and pyruvate is converted to lactate to maintain the ability for glycolysis. Mitochondrial dysfunction can also result in abnormal levels of NADH + H +, NADPH + H +, NAD, or NADP, since reduced niconamide adenine dinucleotides are not efficiently processed by the respiratory chain. Lactate levels can be measured by taking appropriate body fluid samples such as whole blood, plasma, or cerebrospinal fluid. Using MRI, lactate levels can be measured in virtually any desired body volume, such as the brain.

Measurement of cerebral lactic acidosis using magnetic resonance imaging in MELAS patients is described in Kaufmann et al., Neurology 62 (8): 1297 (2004). The values of lactic acid levels in the lateral ventricles of the brain are presented for two mutations resulting in MELAS, A3243G and A8344G. Whole blood, plasma, and cerebrospinal fluid lactate levels can be measured by commercially available equipment such as the YSI STAT plus 2300 Lactate and Glucose Analyzer (YSI Life Sciences, Ohio).

Levels of NAD, NADP, NADH and NADPH: The measurement of NAD, NADP, NADH (NADH H +) or NADPH (NADPH + H +) can be measured by various fluorescent, enzymatic or electrochemical techniques, for example, the electrochemical analysis described in US 2005/0067303.

Oxygen consumption ( vO2 or VO2), carbon dioxide production ( vCO2 or VCO2), and respiratory quotient ( VCO2 / VO2): vO ^{2 is} usually measured while resting (resting vO2) or at maximum exercise intensity (vO ² max). Optimally, both values will be measured. However, for severely disabled patients, measuring vO ² max can be impractical. Measurement of both forms of vO ² is easily accomplished using standard equipment from various vendors, for example Korr Medical Technologies, Inc. (Salt Lake City, Utah). VCO2 can also be easily measured, and the ratio of VCO2 to VO2 under the same conditions (VCO2 / VO2), whether at rest or at maximum exercise intensity) provides the respiratory quotient (RQ).

Oxidized Cytochrome C, Reduced Cytochrome C, and ratio of Oxidized Cytochrome C to Reduced Cytochrome C: Cytochrome C parameters, such as levels of oxidized cytochrome C (Cit Cox), reduced levels of cytochrome C (Cit Cred), and the ratio of oxidized cytochrome C / reduced cytochrome C (Cit Cox) / (Cit Cred), can be measured by near infrared spectroscopy in vivo. See, for example, Rolfe, P., "In vivo near-infrared spectroscopy," Annu. Rev. Biomed. In. 2: 715-54 (2000) and Strangman et al., "Non-invasive neuroimaging using nearinfrared light". Psychyatry 52: 679-93 (2002).

Exercise tolerance / exercise intolerance: Exercise intolerance is defined as "the reduced ability to perform activities involving the dynamic movement of large skeletal muscles due to symptoms of dyspnea or fatigue" (Piña et al., Circulation 107: 1210 ( 2003)). Exercise intolerance is frequently accompanied by myoglobinuria, due to disruption of muscle tissue and subsequent excretion of myoglobin from muscle in urine. Various measures of exercise intolerance can be used, such as time spent walking or running in a routine before exhaustion, time spent on an exercise bike (stationary bike) before exhaustion, and the like. Treatment with the compounds or methods of the invention may result in approximately 10% or greater improvement in exercise tolerance (eg, approximately 10% or greater increase in time to exhaustion, eg, 10 to 11 minutes. minutes), approximately 20% or greater improvement in exercise tolerance, approximately 30% or greater improvement in exercise tolerance, approximately 40% or greater improvement in exercise tolerance, approximately 50% or greater improvement in exercise tolerance, about 75% or a greater improvement in exercise tolerance, or approximately 100% or greater improvement in exercise tolerance. While exercise tolerance is not, strictly speaking, an energy biomarker, for the purposes of the invention, modulation, normalization, or enhancement of energy biomarkers includes modulation, normalization, or enhancement of exercise tolerance.

Similarly, tests for normal and abnormal values of pyruvic acid (pyruvate) levels, lactate / pyruvate ratio, ATP levels, anaerobic threshold, reduced coenzyme Q (CoQred) levels, oxidized coenzyme Q (CoQox ), total coenzyme Q levels (CoQtot), oxidized cytochrome C levels, reduced cytochrome C levels, oxidized cytochrome C / reduced cytochrome C ratio, acetoacetate levels, p-hydroxy butyrate levels, acetoacetate / p- ratio Hydroxy butyrate, levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), and levels of reactive oxygen species are known in the prior art and can be used to evaluate the efficacy of the compounds and methods of the invention. (For the purposes of the invention, modulation, normalization, or enhancement of energy biomarkers includes modulation, normalization, or enhancement of the anaerobic threshold.)

Table 1, below, illustrates the effect that the various dysfunctions can have on biochemistry and energy biomarkers. It also indicates the physical effect (such as symptom of disease or other effect of dysfunction) normally associated with a given dysfunction. It should be noted that any of the energy biomarkers listed in the table, in addition to the energy biomarkers listed elsewhere, can also be modulated, enhanced or normalized by the compounds and methods of the invention. RQ = respiratory quotient; BMR = basal metabolic rate; HR (CO) = heart rate (cardiac output); T = body temperature (preferably measured as core temperature); AT = anaerobic threshold; pH = pH of the blood (venous and / or arterial).

Table 1

Treatment of a subject afflicted with a disease in accordance with the methods of the invention may result in inducing a reduction or alleviation of symptoms in the subject, for example, paralyzing the progress of the disorder.

Partial or complete suppression of mitochondrial disease can result in hyposensitization of the severity of one or more symptoms that the subject would otherwise experience. For example, partial suppression of MELAS could result in a reduction in the number of stroke-like or seizure-like episodes experienced.

Some or any combination of energy biomarkers described herein provide conveniently measurable reference values by which the effectiveness of treatment or suppression therapy is measured. Additionally, other energy biomarkers are known to those of skill in the art and can be monitored to assess the efficacy of anti-disease treatment or therapy.

Use of compounds for the modulation of energy biomarkers.

In addition to monitoring energy biomarkers to assess the status of mitochondrial disease treatment or suppression, the compounds of the invention can be used in subjects or patients to modulate one or more energy biomarkers. Modulation of energy biomarkers can be done to normalize energy biomarkers in a subject or to enhance energy biomarkers in a subject.

Normalization of one or more energy biomarkers is defined as the restoration of the level of one or more of such energy biomarkers to normal or near normal levels in a subject whose levels of one or more energy biomarkers show pathological differences in levels. normal (in this case, in a healthy subject), or changing the levels of one or more energy biomarkers to alleviate pathological symptoms in a subject. Depending on the nature of the energy biomarker, such levels can show measured values either above or below a normal value. For example, a pathological lactate level is normally higher than the lactate level in a normal (in this case, healthy) person, and a decrease in the level may be desirable. A pathological ATP level is normally less than the ATP level in a normal (in this case, healthy) person, and an increase in the ATP level may be desirable. Accordingly, the normalization of energy biomarkers may involve restoring the level of energy biomarkers to within at least two standard deviations from normal in a subject, more preferably within about one standard deviation to normal in a subject, a within approximately at least one mean standard deviation of normal, or within approximately one quarter standard deviation of normal.

Enhancement of the level of one or more energy biomarkers is defined as changing existing levels of one or more energy biomarkers in a subject to a level at which it provides beneficial or desirable effects for the subject. For example, a person experiencing strenuous exertion or prolonged vigorous physical activity, such as climbing a mountain, could benefit from increased ATP levels or decreased lactate levels. As described above, the normalization of energy biomarkers may not reach the optimal state for a subject with mitochondrial disease, and such subjects may also benefit from the enhancement of energy biomarkers. Examples of subjects who could benefit from increased levels of one or more energy biomarkers include, but are not limited to, subjects who experience prolonged or strenuous physical activity, subjects with chronic energy problems, or subjects with chronic respiratory problems. Such subjects include, but are not limited to, pregnant women, particularly pregnant women in labor, newborns, particularly premature newborns, subjects exposed to extreme environments, such as hot environments (temperatures that routinely exceed approximately 85-86 degrees Fahrenheit or about 30 degrees Celsius for about 4 hours daily or more), cold environments (temperatures that are routinely below 32 degrees Fahrenheit or about 0 degrees Celsius for about 4 hours or more daily), or environments with lower than average oxygen content, with higher than average carbon dioxide content, or higher than average polluted air levels (air travelers, flight attendants, subjects exposed to high altitudes, subjects living in cities with less than average air quality, subjects who work in closed environments in which the quality has degraded d of air); subjects with lung diseases or below average lung capacity, such as tuberculosis patient, lung cancer patients, emphysema patients, and cystic fibrosis patients, subjects recovering from surgery or illness; elderly subjects, including elderly experiencing energy decay; subjects suffering from chronic fatigue, including chronic fatigue syndrome, subjects experiencing acute trauma, subjects in shock; subjects requiring acute oxygen administration, subjects requiring chronic oxygen administration; or other subjects with acute, chronic energy demands, or at the moment who would benefit from the enhancement of energy biomarkers.

Therefore, when an increase in the level of one or more energy biomarkers is beneficial to a subject, the enhancement of one or more energy biomarkers may involve increasing the level of the respective energy biomarker or biomarkers up to about less than a quarter of the standard deviation above normal, approximately at least one-half standard deviation above normal, approximately at least one standard deviation above normal, or approximately at least two standard deviations above normal. Alternatively, the level of one or more energy biomarkers can be increased by about at least 10% above the subject's level of one or more respective energy biomarkers prior to enhancement, by about at least 20% above the level. the subject's level of one or more energy biomarkers prior to enhancement, by about at least 30% above the subject's level of one or more energy biomarkers prior to enhancement, by about at least 40% above the subject's level of one or more energy biomarkers prior to enhancement, by about at least 50 % above the subject's level of one or more energy biomarkers prior to enhancement, by approximately at least 75% above the subject's level of one or more energy biomarkers prior to enhancement enhancement, or by about at least 100% above the subject's level of one or more energy biomarkers prior to enhancement.

When a decrease in a level of one or more energy biomarkers is desired to improve one or more energy biomarkers, the level of one or more energy biomarkers can be decreased by an amount of about at least one-quarter standard deviation of normal in a subject, decreased by approximately at least one-half standard deviation from normal in a subject, decreased by approximately at least one standard deviation from normal in a subject, or decreased by approximately at least two standard deviations than normal in a subject. Alternatively, the level of the one or more energy biomarkers can be decreased by about at least 10% below the subject's level of the one or more respective energy biomarkers prior to enhancement, by about at least 20% below the level of the subject of one or more respective energy biomarkers prior to enhancement, by about at least 30% below the subject's level of one or more respective energy biomarkers prior to enhancement, by approximately at least 40% below the level of the subject of one or more respective energy biomarkers prior to enhancement, by about at least 50% below the subject's level of one or more respective energy biomarkers prior to enhancement, by approximately at least 75% below the level of the subject of one or more respective energy biomarkers prior to enhancement, or by about at least 90% below level that of the subject of one or more respective energy biomarkers prior to enhancement.

Use of compounds in research applications, experimental systems and tests

The compounds of the invention can also be used in research applications. They can be used in in vitro, in vivo or ex vivo experiments to modulate one or more energy biomarkers in an experimental system. Such experimental systems can be cell samples, tissue samples, cell components, or mixtures of cell components, partial organs, whole organs, or organisms. Any one or more of the compounds of the invention can be used in experimental systems or research applications. Such research applications may include, but are not limited to, use as assay reagents, elucidation of biochemical pathways, or evaluation of the effects of other agents on the metabolic status of the experimental system in the presence / absence of one or more compounds of the invention.

Additionally, the compounds of the invention can be used in biochemical tests or assays. Such tests may include incubation of one or more compounds of the invention with a tissue or cell sample from a subject to assess a potential response of the subject (or the response of a specific subset of subjects) to the administration of one or more compounds, or to determine which compound of the invention produces the optimal effect in a specific subject or subgroup of subjects. A test or assay would involve 1) obtaining a cell sample or tissue sample from a subject in which the modulation of one or more energy biomarkers can be assayed; 2) administering one or more compounds of the invention to the cell sample or tissue sample; and 3) determining the amount of modulation of one or more energy biomarkers after administration of one or more compounds, compared to the status of the energy biomarker prior to administration of one or more compounds. Another test or assay would involve 1) obtaining a cell sample or tissue sample from a subject in which modulation of one or more energy biomarkers can be assayed; 2) administering at least two compounds of the invention to the cell sample or tissue sample; and 3) determine the amount of modulation of one or more energy biomarkers after administration of at least two compounds, compared to the status of the energy biomarker prior to administration of the at least compounds, and 4) select a compound for use in treatment, suppression, or modulation based on the amount of modulation determined in step 3).

Pharmaceutical formulations

The compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable carriers. Pharmaceutically acceptable excipients, carriers, and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, calcium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-p-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th Edition (2003). and 21st edition (2005).

A pharmaceutical composition may comprise a unit dose formulation, wherein the unit dose is a dose sufficient to have a therapeutic or suppressive effect or an amount effective to modulate, normalize or improve an energy biomarker. The unit dose may be sufficient for a single dose to have a therapeutic or suppressive effect or an amount effective to modulate, normalize, or enhance an energy biomarker. Alternatively, the unit dose can be a dose administered periodically in a cycle of treatment or suppression of a disorder, or modulate, normalize or enhance an energy biomarker.

The pharmaceutical compositions containing the compounds of the invention can be in any form appropriate to the intended method of administration, including, for example, a solution, a suspension or an emulsion. Liquid supports are normally used to prepare solutions, suspensions and emulsions. Liquid supports contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent (s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid support may contain other appropriate pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Appropriate organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention can also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.

Timed or controlled release delivery systems can be used, such as a controlled diffusion matrix system or an erodible system, as described for example in: Lee, "Diffusion-Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible Systems", pp. 199-224, in "Treatise on Controlled Drug Delivery", A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix can be, for example, a biodegradable material that can spontaneously degrade in situ and in vivo, for example, by hydrolysis or enzymatic cleavage, by proteases. The delivery system can be, for example, a polymer or copolymer of natural or synthetic origin, for example in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly (phosphoesters), polyamides, polyurethanes, poly (imidocarbonates) and poly (phosphonates).

The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation, (for example, as sprays or sprays), rectally, or topically in unit dose formulations containing non-pharmaceutically acceptable carriers, adjuvants and vehicles. conventional toxins as desired. For example, appropriate modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (eg, nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. They can be used for delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles. Topical administration can also involve the use of transdermal administration such as patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Administration is the preferred route of administration, and preferred formulations are formulations suitable for oral administration. The compounds described for use herein can be administered in solid form, in aerosol form, or in the form of tablets, pills, powder mixtures, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, premixes. nutritional, and in other appropriate ways. The compounds can be administered in liposomal formulations. The compounds can also be administered as prodrugs, in which 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, eg, sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid find use in the preparation of injectables.

Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, for example lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents. Tablets and pills can be further prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art. Such compositions may also comprise adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. It is also known in the art that 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 lipid that can be metabolized and is pharmaceutically acceptable with the ability to form liposomes can be used. The present compositions in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phosphatidyl phospholipids and cholines (lecithins), both natural and synthetic. Methods for forming 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 can be combined with the carrier materials to produce a single dose form will vary depending on the host to which the active ingredient is administered and the particular mode of administration. It should be understood, however, that the specific dose level for any particular patient will depend on several factors including the activity of the specific compound employed, age, body weight, body area, muscle mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progress, and severity of the particular disease under therapy. The selected pharmaceutical unit dose is usually manufactured and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other target regions of the body. The therapeutically effective amount or effective amount for a given situation can be readily determined by routine experimentation and is within the ability and judgment of one of ordinary skill in the art.

Examples of the doses that can be used are an effective amount within the dose range of about 0.1 mg / kg to about 300 mg / kg of body weight, or within about 1.0 mg / kg to about 100 mg / kg of body weight, or within about 1.0 mg / kg to about 50 mg / kg of body weight, or within about 1.0 mg / kg to about 30 mg / kg of body weight, or within about 1.0 mg / kg to about 10 mg / kg of body weight, or within about 10 mg / kg to about 100 mg / kg of body weight, or within about 50 mg / kg to about 150 mg / kg of body weight, or within about 100 mg / kg to about 200 mg / kg of body weight, or within about 150 mg / kg to about 250 mg / kg of body weight, or within about 200 mg / kg to about 300 mg / kg of body weight, or within about 250 mg / kg up to about 300 mg / kg of body weight. The compounds of the present invention can be administered in a single daily dose or the total daily dose can be administered in divided doses two, three or four times a day.

While the compounds of the invention can be administered with the active pharmaceutical agent alone, they can be used in combination with one or more of the other agents used in the treatment or suppression of disorders. Representative agents useful in combination with the compounds of the invention for the treatment or suppression of mitochondrial diseases include, but are not limited to, Coenzyme Q, vitamin E, idebenone, MitoQ, vitamins, and antioxidant compounds.

When additional active agents are used in combination with the compounds of the present invention, the additional active agents can generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) manual 53rd Edition ( 1999), or as therapeutically useful amounts that would be known to one of ordinary skill in the art.

The compounds of the invention and the other therapeutically active agents can be administered in the highest or lowest recommended clinical dose. The dosage levels of the active compounds in the compositions of the invention can be varied to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. When administered in combination with other therapeutic agents, the therapeutic agents can be formulated as separate compositions that are provided at the same time or at different times, or the therapeutic agents can be provided as a single composition.

The invention will be further understood by the following non-limiting examples.

In general, the nomenclature used in this Application was generated with the help of the ChemOffice naming computer package. RTM. version 11.0 suite of programs by CambridgeSoft Corp (Cambridge, Mass.).

Preparation of the compounds of the invention

The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions occur (in this case, reaction temperatures, times, mole ratios of reagents, solvents, pressures, etc.), other process conditions may also be used unless otherwise indicated. contrary. Optimal reaction conditions can vary with the particular reagents or solvent used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

In addition, the compounds of this invention will normally contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as the pure stereoisomers, in this case as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents.

Protocol A

Synthesis of 6-hydroxy-2,5,7.8-tetramethylchroman-1-carboxamides.

6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1 equivalent) is dissolved in 0.2M THF and the pale yellow solution was treated under stirring with carbonyldiimidazole (CDI) (1, 1 equiv.). The reaction is allowed to stir for one hour and amine solution (1.1 equivalents 0.2M in THF) is added over one hour and the reaction is stirred overnight. The solution was concentrated, dissolved in ^{0.04 M CH 2} Ch and washed sequentially with half volumes of 0.5 M HCl, ^{1.0 M NaHCO 3} , saturated NaCl, the organic phase was dried over Na ² SO ⁴ and he concentrated. Flash chromatography produced the desired 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide derivative.

Protocol B

Oxidation of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxamides.

A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1.0 equivalents.) In 3 ml of AcCN (0.28 M) and a drop of water was cooled to 0 ° C. A solution of ceric ammonium nitrate (CAN) (2.2 equivalents) in water (0.5 M) cooled to 0 ° C was added dropwise over 2-3 minutes. The solution was immediately treated with 10 ml of EtOAc and the phases were separated. The organic phase was washed 3 times with 5 ml of H ² O and the combined aqueous phases were re-extracted 3 times with 5 ml of EtOAc. The combined organics were washed with 10 ml of saturated NaCl and dried over Na ² SO ⁴ . Flash chromatography yielded the desired 2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide derivative.

In the examples, the compounds of the claimed invention are marked with an asterisk.

Example 1

N-tert-But¡l-2-h¡drox¡-2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanamida.

Following the amide coupling procedure described in Protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 355 mg of CDI (2.20 mmol ) and 160 mg of t-butylamine (2.20 mmol) of CDI produced 125.1 mg of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a solid white crystalline.

1H NMR (400 MHz, CDCla) 86.40 (bs, 1H), 4.51 (s, 1H), 2.60 (m, 2H), 2.26 (m, 1H), 2.19 (s, 3H), 2.16 (S, 3H), 2.10 (s, 3H), 1.88 (m, 1H), 1.47 (s, 3H), 1.26 (m, 9H).

Oxidation as described in protocol B, using 95 mg (0.311 mmol) of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 358 mg of CAN (0.653 mmol) yielded 92.2 mg of N-tert-butyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a solid of yellow color.

1H NMR (400 MHz, CDCla) 86.61 (bs, 1H), 3.45 (s, 1H), 2.55 (m, 1H), 2.39 (m, 1H), 2.04-1, 91 (m, 10H), 1.56 (m, 1H), 1.37 (m, 12H).

Example 2

2-Hydroxy-MA / .2-trimethyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide

Following the amide coupling procedure described in Protocol A, 504 mg of acid 6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid (2.01 mmol), 361 mg of CDI (2.23 mmol) and 1.1 ml of a 2.0 M solution of N, N- Dimethylamine in THF (2.2 mmol) yielded 412 mg of 6-hydroxy-N, N, 2,5,7,8-hexamethylchroman-2-carboxamide as an amorphous powder.

1H NMR (400MHz, CDCh) 84.31 (s, 1H), 3.26 (s, 3H), 2.85 (S, 3H), 2.80-2.41 (m, 3H), 2, 16 (s, 6H), 2.08 (s, 3H), 1.70-1.60 (m, 4H).

Oxidation as described in protocol B, using 138.6 mg (0.50 mmol) of 6-hydroxy-N, N, 2,5,7,8-hexamethylchroman-2-carboxamide and 560 mg of CAN (1 0.02 mmol) produced 139.9 mg of 2-hydroxy-N, N, 2-trimethyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow oil.

1H NMR (400MHz, CDCh) 85.07 (s, 1H), 2.23 (bs, 3H), 3.07 (bs, 3H), 2.51 (m, 1H), 2.33 (m, 1H), 2.02 (m, 3H), 1.99-1.94 (m, 7H), 1.69 (m, 1H), 1.47 (s, 3H).

Example 3

N-Benc¡l-2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1,4-d¡en¡l) butanamida.

Following the amide coupling procedure described in Protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 362 mg of CDI (2.23 mmol ) and 235 mg of benzylamine (2.20 mmol) yielded 507 mg of N-benzyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a brown oil.

1H NMR (400MHz, CDCla) 87.22 (m, 3H), 7.00 (m, 2H), 6.76 (rt, 1H), 4.81 (s, 1H), 4.50 (m, 1H), 4.35 (m, 1H), 2.62 (m, 2H), 2.45 (m, 1H), 2.16 (s, 3H), 2.11 (S, 6H), 1, 92 (m, 1H), 1.58 (s, 3H).

Oxidation as described in protocol B, using 130 mg (0.383 mmol) of N-benzyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 441 mg of CAN (0.805 mmol) yielded 119 , 7 mg of N-benzyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow foam.

1H NMR (400 MHz, CDCh) 87.26 (m, 6H), 4.42 (m, 2H), 3.57 (s, 1H), 2.56 (m, 1H), 2.36 (m, 1H), 2.04-1.93 (m, 10H), 1.59 (m, 1H), 1.42 (s, 3H).

Example 4

N-Et¡l-2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡ gives.

Following the amide coupling procedure described in protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 356 mg of CDI (2.20 mmol ) and 1.1 ml of a 2.0 solution of ethylamine in methanol (2.2 mmol) produced 334 mg of N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.

1H NMR (400 MHz, CDCh) 86.44 (bs, 1H), 4.40 (s, 1H), 3.24 (m, 2H), 2.57 (m, 2H), 2.31 (m, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 1.89 (m, 1H), 1.49 (s, 3H), 1.07 (t, 3H).

Oxidation as described in protocol B, using 100 mg (0.360 mmol) of N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 415 mg of CAN (0.757 mmol) yielded 96 2 mg of N-ethyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide in the form of a yellow oil.

1H NMR (400 MHz, CDCh) 86.87 (bs, 1H), 3.64 (s, 1H), 3.29 (m, 2H), 2.56 (m, 1H), 2.38 (m, 1H), 2.10-1.97 (m, 10H), 1.59 (m, 1H), 1.39 (s, 3H), 1.15 (t, 3H).

Example 5

2-Hydroxy-2-methyl-N-propyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dimethyl) butanamide.

Following the amide coupling procedure described in protocol A, 502.3 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 358 mg of CDI (2, 21 mmol) and 130 mg of propylamine (2.20 mmol) produced 371 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide as an off-white syrup.

1H NMR (400 MHz, CDCh) 86.50 (brs, 1H), 4.85 (brs, 1H), 3.18 (q, 2H), 2.62 (m, 2H), 2.37 (m, 1H), 2.18 (s, 6H), 2.09 (s, 3H), 1.91 (m, 1H), 1.50 (s, 3H), 1.42 (m, 2H), 0, 80 (t, 3H).

Oxidation as described in protocol B, using 90.6 mg (0.311 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide and 374.9 mg of CAN (0.684 mmol) produced 2-hydroxy-2-methyl-N-propyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow powder.

1H NMR (400 MHz, CDCh) 86.89 (rt, 1H), 3.61 (s, 1H), 2.21 (q, 2H), 2.56 (m, 1H), 2.36 (m, 1H), 2.02 (m, 10H), 1.56 (m, 3H), 1.40 (m, 3H), 0.92 (t, 3H).

Example 6

N- (Cyclopropylmethyl) -2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡ en¡l) butanam¡da.

Following the amide coupling procedure described in Protocol A, 502 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 356 mg of CDI (2.20 mmol ) and 158 mg of cyclopropylmethylamine (2.22 mmol) produced 445 mg of N- (cyclopropylmethyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a pale colorless oil.

1H NMR (400MHz, CDCh) 86.53 (bs, 1H), 4.39 (s, 1H), 3.05 (m, 2H), 2.57 (m, 2H), 2.31 (m, 2H), 2.17 (s, 6H), 2.08 (s, 3H), 1.90 (m, 1H), 1.50 (m, 3H), 0.86 (m, 1H), 0, 40 (m, 2H), 0.070 (m, 2H).

Oxidation as described in protocol B, using 76.7 mg (0.253 mmol) of N- (cyclopropylmethyl) -6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxamide and 435 mg of CAN (0.794 mmol) yielded 71 , 4 of N- (cyclopropylmethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow powder.

1H NMR (400 MHz, CDCla) 86.93 (rt, 1H), 3.46 (s, 1H), 3.13 (t, 2H), 2.58 (m, 1H), 2.42 (m, 1H), 2.05-1.84 (m, 10H), 1.60 (m, 1H), 1.42 (s, 3H), 0.97 (m, 1H), 0.51 (m, 2H ), 0.22 (m, 2H).

Example 7

2-H¡drox¡-N-¡sopent¡l-2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1,4-d¡en¡l ) butanamida.

Following the amide coupling procedure described in Protocol A, 492 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (0.97 mmol), 370 mg of CDI (2.28 mmol ) and 192 mg of 3-methylbutamine (2.20 mmol) produced 375 mg of 6-hydroxy-N-isopentyl-2,5,7,8-tetramethylchroman-2-carboxamide as white crystals.

Oxidation as described in protocol B, using 101 mg CAN (0.316 mmol) 6-hydroxy-N-isopentyl-2.5.7.8-tetramethylchroman-2-carboxamide and 380 mg CAN (0.694 mmol) yielded 101.2 mg of 2-hydroxy-N-isopentyl-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow oil.

1H NMR (400 MHz, CDCh) 86.85 (rt, 1H), 3.65 (s, 1H), 3.65 (q, 2H), 2.55 (m, 1H), 2.35 (m, 1H), 2.02-1.95 (m, 10H), 1.59 (m, 2H), 1.43-1.37 (m, 5H), 0.89 (d, 6H).

Example 8

2-Hydroxy-2-methyl-N-phenethyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dimethyl) butanamide.

Following the amide coupling procedure described in protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 356 mg of CDI (2.20 mmol ) and 226 mg of phenethylamine produced 440 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-phenethylchroman-2-carboxamide as a light pale brown oil.

1H NMR (400 MHz, CDCh) 87.21 (m, 3H), 7.05 (m, 2H), 6.46 (rt, 1H), 4.29 (s, 1H), 3.52 (m, 2H), 2.78-2.57 (m, 3H), 2.48 (m, 1H), 2.33 (dt, 1H), 2.16 (s, 3H), 2.09 (s, 3H ), 1.98 (s, 3H), 1.82 (m, 1H), 1.47 (s, 3H).

Oxidation as described in protocol B, using 102 mg (0.287 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-phenethylchroman-2-carboxamide and 355 mg of CAN (0.647 mmol) produced 95 , 8 mg of 2-hydroxy-2-methyl-N-phenethyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow oil.

1H NMR (400 MHz, CDCh) 87.29 (m, 2H), 7.20 (m, 3H), 6.88 (rt, 1H), 3.54 (m, 2H), 3.32 (s, 1H), 2.84 (t, 2H), 2.48 (m, 1H), 2.29 (m, 1H), 2.02-1.94 (m, 10H), 1.54 (m, 1H ), 1.36 (s, 3H).

Example 9

2-Hydrox¡-N- (3-hydrox¡prop¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da.

Following the amide coupling procedure described in Protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg of CDI (2.20 mmol ) and 165 mg of 3-aminopropanol (2.20 mmol) produced 297 mg of 6-hydroxy-N- (hydroxypropyl) -2,5,7,8-tetramethylchroman-2-carboxamide as a white amorphous solid .

1H NMR (400 MHz, CDCh) 86.78 (rt, 1H), 4.88 (brs, 1H), 3.50-3.31 (m, 5H), 2.66-2.49 (m, 2H ), 2.33 (m, 1H), 2.17 (s, 6H), 2.09 (s, 3H), 1.88 (m, 1H), 1.66-1.51 (m, 5H) .

Oxidation as described in protocol B, using 56.7 mg (0.184 mmol) of 6-hydroxy-N- (3-hydroxypropyl) -2,5,7,8-tetramethylchroman-2-carboxamide and 222 mg of CAN (0.406 mmol) produced 49.7 mg of 2-hydroxy-N- (3-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow solid.

1H NMR (400 MHz, CDCh) 87.19 (rt, 1H), 3.65 (q, 2H), 3.58 (bs, 1H), 3.43 (m, 2H), 2.56 (m, 1H), 2.41 (m, 1H), 2.05-1.99 (m, 10H), 1.73 (quintet, 2H), 1.61 (m, 1H), 1.42 (s, 3H ).

Example 10

NC¡cloprop¡l-2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡ gives.

Following the amide coupling procedure described in Protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg of CDI (2.20 mmol ) and 126 mg of cyclopropylamine (2.20 mmol) yielded 227 mg of N-cyclopropyl-6-hydroxy-N-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown oil.

1H NMR (400MHz, CDCh) 86.50 (brs, 1H), 4.32 (brs, 1H), 2.68-2.58 (m, 3H), 2.32 (m, 1H), 2, 17 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 1.87 (m, 1H), 1.48 (s, 3H), 0.75 (m, 2H ), 0.38 (m, 2H).

Oxidation as described in protocol B, using 100 mg (0.346 mmol) of N-cyclopropyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 417 mg of CAN (0.762 mmol) yielded 40 mg of N-cyclopropyl-2-hydroxy-2-methyl-4- (dioxocyclohexa-1,2,4,5-trimethyl-3,6-, 4-dienyl) butanamide as a yellow oil.

1H NMR (400 MHz, CDCh) 86.86 (bs, 1H), 3.45 (s, 1H), 2.74 (m, 1H), 2.54 (m, 1H), 2.38 (m, 1H), 2.02-1.98 (m, 9H), 1.77 (d, 1H), 1.58 (m, 1H), 1.39 (s, 3H), 0.79 (q, 2H ), 0.53 (m, 2H).

Example 11

2-H¡drox¡-N-¡sobut¡l-2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1,4-d¡en¡l ) butanamida.

Following the amide coupling procedure described in protocol A, 510 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.04 mmol), 357 mg of CDI (2.20 mmol ) and 161 mg of isobutylamine (2.2 mmol) yielded 467 mg of 6-hydroxy-N-isobutyl-2,5,7,8-tetramethylchroman-2-carboxylic acid as an off-white solid.

1H NMR (400 MHz, CDCla) 86.49 (bs, 1H), 4.29 (s, 1H), 3.09 (m, 1H), 3.00 (m, 1H), 2.59 (m, 2H), 2.36 (dt, 1H), 2.10 (s, 6H), 2.09 (s, 3H), 1.88 (m, 1H), 1.65 (m, 1H), 1, 52 (s, 3H), 0.76 (dd, 6H).

Oxidation as described in protocol B, using 84 mg (0.278 mmol) of 6-hydroxy-N-isobutyl-2,5,7,8-tetramethylchroman-2-carboxamide and 335 mg of CAN (0.612 mmol) produced 78 mg of 2-hydroxy-N-isobutyl-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow-orange oil.

1H NMR (400MHz, CDCh) 86.94 (t, 1H), 3.55 (s, 1H), 3.09 (m, 2H), 2.58 (m, 1H), 2.89 (m, 1H), 2.07-1.94 (m, 10H), 1.79 (m, 1H), 1.58 (m, 1H), 1.41 (s, 3H), 0.88 (d, 6H ).

Example 12

2- (3-H¡drox¡-4- (4-hydrox¡p¡per¡n-1-¡l) -3-methyl-4-oxobut¡l) -3.5.6- trimethylclohexa-2.5-diene-1.4-dine.

Following the amide coupling procedure described in Protocol A, 500 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 370 mg of CDI (2.28 mmol ) and 222 mg of 4-hydroxypiperidine (2.20 mmol) produced 222 mg of a (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) (4-hydroxypiperidin-1-yl) methanone as of a white foam.

1H NMR (400 MHz, CDCh) 84.56-4.31 (da, 1H), 4.27 (bs, 1H), 4.08 (bs, 1H), 3.85 (m, 1H), 3, 56-3.46 (ma, 1H), 3.08 (bs, 1H), 3.77 (m, 1H), 2.57 (n, 2H), 2.15 (s, 6H), 2.08 (m, 3H), 1.82 (brs, 2H), 1.69 (m, 1H), 1.58 (brs, 6H).

Oxidation as described in protocol B, using 100 mg (0.302 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) (4-hydroxypiperidin-1-yl) methanone and 364 mg of CAN (0.664 mmol) produced 95 mg of a yellow syrup.

1H NMR (400 MHz, CDCh) 84.00 (m, 4H), 3.45 (m, 3H), 2.53-2.42 (m, 1H), 2.05-1.92 (m, 10H ), 1.71 (m, 1H), 1.56 (m, 3H), 1.49 (s, 3H).

Example 13

N-eth¡l-2-hydrox¡-N2-d¡met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanamida.

Following the amide coupling procedure described in protocol A, 499 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 360 mg of CDI (2.22 mmol ) and 130 mg of N-methyl ethyalmine (2.2 mmol) produced N-ethyl-6-hydroxy-N, 2,5,7,8-pentamethylchroman-2-carboxamide as a clear oil.

1H NMR (400 MHz, CDCh) 84.30 (bs, 1H), 3.82 (B, m, 2H), 3.44 (A, m, 1H), 3.20 (A, s, 3H), 3.08 (A, m, 1H), 2.82 (B, s, 3H), 2.75 (m, 1H), 2.66-2.52 (m, 2H), 2.16 (s, 6H), 2.08 (s, 3H), 1.70-1.58 (m, 4H), 1.03 (A + B, dt, 3H). two rotomers in the 60:40 mixture, A and B.

Oxidation as described in protocol B, using 78 mg (0.268 mmol) of N-ethyl-6-hydroxy-N, 2,5,7,8-pentamethylchroman-2-carboxamide and 323 mg (0.590 mmol) yielded 76 mg of N-ethyl-2-hydroxy-N, 2-dimethyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow oil.

1H NMR (400 MHz, CDCh) 85.12 (bs, 1H), 3.61 (bs, 1H), 3.40 (bs, 1H), 3.21 (s, 3H), 2.98 (bs, 1H), 2.51 (td, 1H), 2.35 (brs, 1H), 2.02 (s, 3H), 1.97 (s, 6H), 1.67 (td, 1H), 1, 46 (s, 3H), 1.80 (ma, 3H).

Example 14

2- (3-Hydrox¡-3-methyl-4- (4-met¡lp¡peraz¡n-1-¡l) -4-oxobut¡l) -3.5.6-tr¡met¡ cyclohexa-2.5-diene-1.4-dine.

Following the amida coupling procedure described in protocol A. 502 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid (2.01 mmol ). 354 mg of CDI (2.18 mmol) and 220 mg of N-methylp¡prazole (2.2 mmol) produced 557 mg of (6-hydrox¡-2.5.7.8-tetramethylchroman-2-¡l) (4-methylp¡peraz¡n-1-¡l) methanone in the form of a light oil.

1H NMR (400 MHz. CDCh) 84.02 (brs. 2H). 3.56 (d a.2H). 2.78 (m. 1H). 2.55 (m. 2H). 2.35 (bs 4H). 2.24 (s. 3H).

2.16 (s. 3H). 2.13 (s. 3H). 2.08 (s. 3H). 1.72 (m. 1H). 1.58 (2.3H).

Oxidation as described in protocol B. using 122 mg (0.368 mmol) of (6-hydrox¡-2.5.7.8-tetramethlchoman-2-¡l ) (4-methylp¡peraz¡n-1-¡l) methanone and 444 mg CAN (0.811 mmol) produced 2- (3-hydrox¡-3-methyl-4- (4-met ¡Lp¡peraz¡n-1-¡l) -4-oxobut¡l) -3.5.6-tr¡met¡lc¡clohexa-2.5-diene-1.4-d¡one in the form of an oil orange.

67.9 mg.

1H NMR (400 MHz. CDCh) 84.91 (brs. 1H). 3.77 (m br. 4H). 2.58-2.30 (m. 8H). 2.04-1.76 (m. 10H). 1.71 (m. 1H).

1.48 (s. 3H).

Example 15

2- (4- (4-Benc¡lp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3.5.6-tr¡met¡ cyclohexa-2.5-diene-1.4-dine.

Following the amida coupling procedure described in protocol A. 506 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid co (2.02 mmol). 365 mg of CDI (2.25 mmol) and 386 mg of 1-benzylp¡perazine (2.2 mmol) produced 568 mg of (4-benzylp¡peraz¡n-1-¡l) (6-h¡ drox-2.5.7.8-tetramethylchroman-2-l) methanone in the form of a white powder.

1H NMR (400MHz. CDCla) 87.30 (m. 5H). 5.18 (bs 1H). 4.06 (br. 2H). 3.66 (bs 1H). 3.47 (dd. 2H). 2.78 (m. 1H).

2.58 (m. 2H). 2.39 (m. 5H). 2.18 (s. 3H). 2.14 (s. 3H). 2.08 (s. 3H). 1.74 (m. 1H). 1.60 (s. 3H).

Oxidation as described in protocol B. using 98 mg (0.242 mmol) of (4-benzylp¡peraz¡n-1-¡l) (6-h ¡Drox¡-2.5.7.8- tetramethylchroman-2-¡l) methanone and 291 mg (0.531 mmol) produced 76 mg of 2- (4- (4-benz¡lp¡peraz¡n-1-¡l) -3-h¡drox¡-3-met¡l-4-oxobut¡l) -3.5.6-tr¡met¡lc¡clohexa-2.5-d¡eno-1.4-d¡one in the form of an ace¡ yellow color tea.

1H NMR (400MHz. CDCh) 87.21 (m. 5H). 4.94 (s. 1H). 3.70 (bs 2H). 3.63 (bs 2H). 3.98 (dd. 2H). 2.49-2.31 (m.

6H). 1.96 (s. 3H). 1.91 (s. 6H). 1.84 (m. 1H). 1.61 (m. 1H). 1.30 (s. 3H). APCI-MS M ++ H 425 m / z.

Example 16 (according to the invention)

2-Hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡da. *

Following the amida coupling procedure described in protocol A. 498 mg of 6-hydrox¡-2.5.7.8-tetramethylchroman-2-carboxylic acid¡ co (1.99 mmol). 367 mg of CDI (2.26 mmol) and 1.4 ml of NH ³ in MeOH (9.8 mmol) produced 187 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxamide as a solid. white color.

Oxidation as described in protocol B. using 186 mg (0.747 mmol) of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxamide and 907 mg of CAN (1.65 mmol) produced 157 mg of 2-hydrox¡-2-methyl-4- (2.4.5-tr¡metal-3.6-d¡oxoc¡clohexa-1.4-d ¡En¡l) butanam¡da in the form of a yellow solid.

1H NMR (400 MHz. CDCh) 82.71 (ddd. 1H). 2.39 (ddd.1H). 2.01 (s. 3H). 1.99 (s. 6H). 1.85 (ddd. 1H). 1.58 (m. 1H).

1.38 (s. 3H).

Example 17

2-H¡drox¡-N- (4-h¡drox¡but¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 507 mg of 6-hydrox¡-2.5.7.8-tetramethylchroman-2-carboxylic acid¡ co (2.03 mmol). 356 mg of CDI (2.20 mmol) and 196 mg of 4-am¡nobutanol (2.20 mmol) produced 488 mg of 6-hydrox¡-N- (4-hydrox¡but¡l) -2.5.7.8- tetramethylchroman-2-carboxamide as a white powder.

1H NMR (400 MHz. CDCh) 87.22 (t br 1H). 3.41 (t. 2H). 3.25 (m. 1H). 3.12 (m. 1H). 2.61 (dt. 1H). 2.50 (m. 1H). 2.32 (dt. 1H). 2.16 (s. 3H). 2.14 (s. 3H). 2.05 (s. 3H). 1.75 (m. 1H). 1.47 (s. 3H). 1.41 (m. 2H). 1.28 (m. 2H).

Oxidation as described in protocol B. using 100 mg (0.311 mmol) of 6-hydrox¡-N- (4-hydrox¡but¡l) -2.5.7.8- tetramethylchroman-2-carboxamide and 375 mg (0.685 mmol) produced 2-hydroxy-N- (4-hydroxy-butyl) -2-methyl-4 - (2.4.5-tr¡met¡l-3.6-dioxoc¡clohexa-1.4-d¡en¡l) butanamida in the form of a yellow solid.

1H NMR (400 MHz. CDCh) 87.12 (t. 1H). 3.97 (s. 1H). 3.67 (t. 2H). 3.29 (q. 2H). 2.81 (bs 1H). 3.56 (td. 1H). 2.34 (td. 1H). 2.02-1.92 (m. 10H). 1.61 (m. 5H). 1.39 (s. 3H).

Example 18

2-H¡drox¡-N-5-h¡drox¡pent¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d En¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 497 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid (1.98 mmol ). 370 mg of CDI (2.28 mmol) and 239 mg of 5-am¡nopentanol (2.2 mmol) produced 468 mg of 6-hydrox¡-N- (5-hydrox¡pent¡l) -2.5.7.8- tetramethylchroman-2-carboxamide as a pale brown solid.

1H NMR (400 MHz. CDCh) 87.16 (t br. 1H). 3.42 (t. 2H). 3.07 (m. 1H). 2.60 (dt. 1H). 2.50 (m. 1H). 2.36 (m. 1H). 2.18 (s. 3H). 2.16 (s. 3H). 2.06 (2.3H). 1.78 (m. 1H). 1.49 (s. 3H). 1.37 (m. 4H). 1.09 (m. 2H).

Oxidation as described in protocol B. using 96 mg (0.286 mmol) of 6-hydrox¡-N- (5-hydrox¡pent¡l) -2.5.7.8-tetramethylchroman-2-carboxamide and 345 mg of CAN (0.629 mmol) produced 92.8 mg of 2-hydroxy-N- (5-hydroxypentyl) -2- methyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dienil) butanamide in the form of a yellow oil.

1H NMR (400 MHz. CDCh) 86.96 (t. 1H). 3.83 (bs 1H). 3.65 (t. 2H). 3.26 (q. 2H). 2.65 (td. 1H). 2.35 (m. 1H). 2.24 (bs. 1H). 2.02-1.93 (m. 10H). 1.57 (m. 5H). 1.43 (m. 5H).

Example 19

2-H¡drox¡-N- (1-h¡drox¡propan-2-¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa -1.4-d¡en¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 500 mg of 6-hydrox¡-2.5.7.8-tetramethylchroman-2-carboxylic acid¡ co (2.00 mmol). 365 mg of CDI (2.25 mmol) and 165 mg of 2-amino-1-propanol (2.2 mmol) produced 488 mg of 6-hydrox¡-N- (1-hydrox¡propan-2-¡ l) -2.5.7.8-tetramethylchroman-2-carboxamide in the form of a pale brown foam.

1H NMR (400 MHz. CDCla) 87.31 (t. 0.4H). 7.21 (t. 0.6H). 3.97 (bs 1.5H). 3.83 (bs 0.4H). 3.56 (bs 0.6H. 3.53 3.44 (m. 1H). 3.67 (bs. 0.4H). 3.16 (m. 1H). 2.58 (m. 1H). 2.36 (m. 1H). 2.03-1.90 ( m.10H) 1.61 (m.1H) 1.424 (s.

1.4H). 1,416 (s. 1.6H). 1.21 (d. 3H).

Oxidation as described in protocol B. using 102.2 mg (0.329 mmol) of 6-hydroxy-N- (1-hydroxypropan-2- ¡L) -2.5.7.8-tetramethylchroman-2-carboxamide and 397 mg CAN (2.45 mmol) produced 98.5 mg of 2-hydrox¡-N- (1-hydrox¡propan-2- ¡L) -2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡da in the form of a yellow foam ¡Llo.

Example 20

2-Hydrox¡-N- (2-hydrox¡et¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da

6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid (5.00 g 19.98 mmol) in 150 ml THF was treated with 3.65 g of CDI (22.5 mmol) and the exothermic reaction It was left to stir for 1 h at room temperature. Ethanolamine (1.35 g. 22.10 mmol) in 50 ml of THF was added over 1 h and the solution was stirred overnight. The reaction was concentrated. It was dissolved in 375 ml of CH ² Ch and washed with 250 ml of 0.1 M HCl. 250 ml of ^{0.5 M NaHCO 3} 2 times with 100 ml of saturated NaCl and dried over Na ² SO ⁴ . The acidic aqueous phase was extracted 3 times with 100 ml of CH ² Ch and washed with 50 ml of saturated NaCl and dried over Na ² SO ⁴ . The combined organics were concentrated and purified by flash chromatography yielding 2.88 g of 6-hydroxy-N- (2-hydroxy-ethyl) -2.5. 7.8-tetramethylchroman-2-carboxamide in the form of an off-white solid that is not purified.

1H NMR (400 MHz. CDCh) 86.88 (brs. 1H). 4.35 (t. 2H). 3.62 (m. 2H). 3.39 (m. 2H). 2.60 (m. 2H). 2.50 (t. 2H). 2.34 (m. 1H). 2.27 (m. 1H). 2.18 (s. 6H). 2.09 (s. 3H). 1.90 (m. 1H). 1.53 (s. 3H).

6-hydroxy-N- (2-hydroxy-ethyl) -2.5.7.8-tetramethylchroman-2-carboxamide (2.38 g, 8.11 mmol) was dissolved in 150 ml of AcCN. it was cooled to 0 ° C and treated with 9.75 g of CAN (17.84 mmol) in 30 ml of H ² O for 20 minutes. Then EtOAc (150 ml) and H ² O (20 ml) were added. the phases were separated and the organic phase was washed 21 x 20 ml of H ² O. The aqueous phase was re-extracted 4 x 50 ml of EtOAc and the combined organics were washed with saturated NaCl. dried over Na ² SO ⁴ and concentrated to give a yellow powder. Flash chromatography produced 1.68 g of 2-hydrox¡-N- (2-hydrox¡et¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6 -d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡da in the form of a yellow solid.

1H NMR (400MHz. D6-Ace) 87.55 (brs. 1H). 4.62 (s. 1H). 3.99 (t. 1H). 3.62 (q. 2H). 3.34 (m. 2H). 2.69 (td. 1H). 2.36 (td. 1H). 1.98 (s. 9H). 1.89 (m. 1H). 1.60 (m. 1H). 1.37 (s. 3H).

Example 21

2-Hydrox¡-N- (2-methox¡et¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡ en¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 499 mg of 6-hydrox¡-2.5.7.8-tetramethylchroman-2-carboxylic acid¡ co (2.00 mmol). 370 mg of CDI (2.28 mmol) 165.2 mg of 2-methoxy ethylamine (2.20 mmol) produced 6-hydroxy-N- (2-methoxy ethyl) -2.5.7.8-tetramethyl Chroman-2-carboxamide as a white crystalline solid.

Oxidation as described in protocol B, 101 mg (0.329 mmol) of 2-methoxyethylamine (2.20 mmol) 6-hydroxy-N- (2-methoxyethyl) -2,5,7,8-tetramethylchroman-2- carboxamide and 396 mg of CAN (0.724 mmol) produced 6-hydroxy-N- (2-methoxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide as a yellow crystalline solid. 1H NMR (400 MHz, CDCh) 87.14 (bs, 1H), 3.53 (s, 1H), 3.46 (m, 4H), 3.35 (s, 3H), 2.58 (td, 1H), 2.37 (td, 1H), 2.05 1.94 (m, 10H), 1.60 (m, 1H) 1.41 (s, 3H).

Example 22

2-2-H¡drox¡-2-met¡l-4 - ((2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1,4-d¡en¡l) butanedin ) methyl acetate.

Following the amide coupling procedure described in protocol A, 499 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), and 361 mg of CDI (2.23 mmol) were dissolved in THF. Glycine methyl ester hydrochloride (263.7 mg, 2.1 mmol) dissolved in 10 ml of THF, 5 ml of CH ² Ch, 100 µl of Et ³ N and 2.5 ml of MeOH was added over 1 h. Developed as described in protocol A, it produced 471.3 mg of methyl 2- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido) acetate

1H NMR (400 MHz, CDCh) 87.02 (bs, 1H), 4.10 (dd, 1H), 3.92 (dd, 1H), 3.72 (s, 3H), 2.61 (m, 2H), 2.35 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H), 1.91 (m, 1H), 1, 53 (s, 3H).

Oxidation as described in protocol B, using 110 mg (0.344 mmol) of methyl 2- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido) acetate and 415 mg (0.757 mmol) produced 94.0 mg of methyl 2- (2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamido) acetate as a powder of yellow color. 1H NMR (400 MHz, CDCla) 87.41 (t, 1H), 4.05 (cd, 2H), 3.74 (s, 3H), 3.62 (bs, 1H), 2.62 (td, 1H), 2.43 (m, 1H), 2.04 (m, 1H), 1.99 (s, 6H), 1.97 (s, 3H), 1.61 (m, 1H), 1, 43 (s, 3H).

Example 23

N- (3- (1H-imidazol-1-yl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide.

A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 ml of THF was treated with 358 mg of CDI and stirred for 1.25 h. room temperature. To this light yellow solution a solution of 278 mg of 1- (3-aminopropyl) imidazole in 10 ml of THF was added over 1 hr. The solution was stirred overnight at room temperature, concentrated to give a pale brown oil, dissolved in 70 ml of CH ² Cl ² , washed 1 time with 50 ml of saturated NaCl and dried over Na ² SO ⁴ . The organic phases were concentrated and flash chromatographed to yield 524 mg of A / - (3- (1H-imidazol-1-¡l) prop¡l) -6-hydrox¡-2.5, 7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.

1H NMR (400MHz, CDCh) 8 7.22 (s, 1H), 7.02 (s, 1H), 6.58 (s, 1H), 6.41 (t, 1H), 3.71 (quintet , 1H), 3.58 (quintet, 1H), 3.37 (sextet, 1H), 3.02 (sextet, 1H), 2.34 (dt, 1H), 2.54 (m, 1H), 2 , 44 (m, 1H), 2.20 (s, 6H), 2.08 (s, 3H), 1.93 (m, 1H), 1.83 (m, 2H), 1.54 (s, 3H).

To a solution of W- (3- (1H-imidazol-1-yl) propyl) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (100.7 mg, 0.282 mmol) in 6 ml of AcCN and 6 ml of CH ² Ch, cooled to 0 ° C, a cooled solution of CAN (340 mg, 0.620 mmol) in 2 ml of H ² O was added dropwise over 5 minutes. The reaction was immediately treated with 5 ml of EtOAc and washed 3 times with 3 ml of H ² O. The aqueous phase was basified with 6 ml of ^{saturated NaHCO 3} solution and extracted 6 times with 3 ml of EtOAc. The combined organics were dried over Na ² SO ⁴ and concentrated to give a yellow oil. Flash chromatography yielded 98.1 mg, of N- (3- (1H-imidazol-1-yl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6- dioxocyclohexa-1,4-dienyl) butanamide as a yellow solid. 1H NMR (400 MHz, CDCh) 87.56 (s, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 4.02 (t, 2H), 3.60 (sa, 1H), 3.29 (m, 2H), 2.60 (td, 1H), 2.37 (td, 1H), 2.07-1.92 (m, 12H), 1.63 (m, 1H ), 1.41 (s, 3H)

Example 24

(R) -2-h¡drox¡-N- (2-h¡drox¡et¡l) -2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡ clohexa-1,4-d¡en¡l) butanamida.

Following the amide coupling procedure described in Protocol A, 1.846 g of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (7.37 mmol), 1.315 g of CDI (8.11 mmol ) and 991 mg of ethanolamine (16.22 mmol) yielded 1.765 g of (R) -6-hydroxy-N- (2-hydroxyethyl) -2,5,7,8-tetramethylchroman-2-carboxamide as a solid waxy white.

1H NMR (400MHz, CDCh) 86.88 (bs, 1H), 3.63 (td, 2H), 3.39 (m, 2H), 2.70-2.54 (m, 2H), 2, 35 (dt, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 1.90 (m, 1H), 1.53 (s, 3H).

The oxidation as described in protocol B, using 1.49 g (5.11 mmol) of the precursor (R) -6-hydroxy-N- (2-hydroxyethyl) -2,5,7,8-tetramethylchroman-2 -carboxamide and 6.16 g of CAN (11.2 mmol) produced 1.46 g of (R) -2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5 -trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide as a yellow waxy solid.

1H NMR (400MHz, CDCh) 8 7.14 (bs, 1H), 3.78 (t, 2H), 3.48 (m, 2H), 2.59 (m, 1H), 2.39 (m , 1H), 2.04-1.94 (m, 10H), 1.64 (m, 1H), 1.43 (s, 3H).

Example 25

2-Hydrox¡-N- (2- (2-hydrox¡ethox¡) eth¡l) -2-methyl-4- (2.4.5-tr¡methyl-3.6-d¡oxoc¡ clohexa-1,4-d¡en¡l) butanamida.

Following the amyda coupling procedure described in protocol A, 501 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2 acid carboxylic (2.0 mmol), 360 mg of CDI (2.23 mmol) and 231 mg of 2 (2-aminoethoxy) ethanol (2.19 mmol) produced 557 mg of 6-hydroxy -N- (2- (2-hydroxyethoxy) ethyl) -2,5,7,8-tetramethylchroman-2-carboxamide in the form of a white amorphous solid.

1H NMR (400 MHz, CDCh) 86.83 (brs, 1H), 3.63 (t, 2H), 3.53-3.36 (m, 6H), 2.60 (m, 2H), 2, 35 (dt, 1H), 2.18 (s, 6H), 2.09 (s, 3H), 1.88 (m, 1H), 1.52 (s, 3H).

Oxidation as described in protocol B, using 98.1 mg (0.305 mmol) of 6-Nhydrox, -N- (2- (2-hydrox Ethoxy) ethyl) -2,5,7,8-tetramethylchroman-2-carboxamide and 368 mg (0.671 mmol) of CAN produced 2-hydroxy-N- (2 (2- hydroxyethoxy) ethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1,4-d¡en L) butanamida in the form of a yellow oil.

1H NMR (400MHz, CDCh) 81H 7.26 (t, 1H), 3.82 (bs, 1H), 3.74 (m, 2H), 3.60 (m, 4H), 3.50 (m , 2H), 2.90 (bs, 1H), 2.57 (td, 1H), 2.38 (m, 1H), 2.03-1.93 (m, 10H), 1.61 (m, 1H), 1.41 (s, 3H).

Example 26

2-H¡drox¡-2-met¡lN- (2- (p¡r¡d¡n-2-¡l) et¡l) -4- (2.4.5-tr¡met¡l-3.6- d¡oxoc¡clohexa-1,4-d¡en¡l) butanam¡da.

Following the amyda coupling procedure described in protocol A, 499 mg of 6-hydroxy-2,5,7,8-tetramethyl acid lchroman-2-carboxylic (1.99 mmol), 370 mg of CDI (2.28 mmol) and 324 mg of 2-pcollamine (3.0 mmol), produced 579 mg of 6- hydrox¡-2,5,7,8-tetrameth¡lN- (p¡r¡d¡n-2-¡lmeth¡l) chroman-2-carboxam¡da as a white solid .

1H NMR (400 MHz, CDCla) 88.48 (d, 1H), 7.68 (bs, 1H), 7.58 (td, 1H), 7.15 (m, 1H), 7.02 (d, 1H), 4.53 (m, 2H), 4.32 (s, 1H), 2.63 (m, 2H), 2.39 (dt, 1H), 2.25 (s, 3H), 2, 17 (s, 3H), 2.09 (s, 3H), 1.93 (m, 1H), 1.56 (s, 3H).

A solution of 6-hydrox¡-2,5,7,8-tetrameth¡lN- (p¡r¡d¡n-2-¡lmeth¡l) chroman-2-carboxamide (104 mg 0.307 mmol) in 4 ml of AcCN was cooled to 0 ° C and CAN (370 mg in 2 ml of H ² O) was added followed by 8 ml of EtOAc, 4 ml of NaHCO3 1.0 M and 250 mg K ² CO ³ . The emulsion was extracted 5 times with 4 ml of EtOAc and the combined organics were washed 2 times with 4 ml of saturated NaCl, dried over Na ² SO ⁴ and concentrated to give a colored oil. yellow it. Flash chromatography produced 2-hydrox¡-2-methylN- (p¡r¡d¡n-2-¡lmet¡l) -4- (2,4,5-tr¡met¡l -3,6-dioxoxyclohexa-1,4-d¡en¡l) butanamida.

1H NMR (400 MHz, CDCh) 88.51 (d, 1H), 8.02 (t, 1H), 7.65 (td, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 4.55 (m, 2H), 4.39 (bs, 1H), 2.63 (m, 1H), 2.34 (m, 1H), 1.99 (m, 1H), 1, 96 (s, 3H), 1.93 (s, 6H), 1.66 (m, 1H), 1.46 (s, 3H).

Example 27

2-H¡drox¡-2-met¡lN- (2- (p¡r¡d¡n-2-¡l) et¡l) -4- (2.4.5-tr¡met¡l-3.6- d¡oxoc¡clohexa-1,4-d¡en¡l) butanam¡da.

A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.0 mmol) in 10 ml of THF was treated with 356 mg CDI (2.2 mmol). After 1 hr, 366 mg of 2- (2-methylamnoethyl) p¡r¡d¡na (3.0 mmol) in 10 ml of THF was added over 1 hr and stirred overnight. The solution was concentrated, dissolved in 70 ml of CH ² Ch, extracted once with NaHCO ³ 1.0 M. Then, the aqueous phase was extracted again 2 times with 25 ml of CH ² Ch and the combined organics were washed 2 times with 25 ml of saturated NaCl and dried over Na ² SO ⁴ . The solution was concentrated and purified by flash chromatography to give 6-hydroxy-2,5,7,8-tetramethylN- (2- (p¡r¡d¡n -2-l) ethyl) chroman-2-carboxamide.

1H NMR (400 MHz, CDCh) 88.43 (d, 1H), 7.52 (t, 1H), 7.12 (m, 2H), 6.98 (d, 1H), 4.27 (s, 1H), 3.69 (q, 2H), 2.92 (m, 2H), 2.34 (dt, 1H), 2.52 (m, 1H), 2.32 (m, 1H), 2, 15 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.84 (m, 1H), 1.46 (s, 3H).

6-hydrox¡-2,5,7,8-tetramethylN- (2- (p¡r¡d¡n-2-¡l) eth¡l) chroman-2- was dissolved carboxamide (97.7 mg, 0.276 mmol) in 3 ml of AcCN and 2 ml of CH ² Ch and cooled to 0 ° C before treatment with 332.5 mg of CAN (0.606 mmol) in 2 ml of H ² O. The reaction was stopped by adding 5 ml of EtOAc and 4 ml of ^{1.0 M NaHCO 3} followed by the extraction of aqueous phase 3 times with 5 ml of EtOAc. The combined organics were re-extracted 3 times with 3 ml of saturated NaCl, dried over Na ² SO ^4, and concentrated. Flash chromatography yielded 85.8 mg of 2-hydrox¡-2-methylN- (2 (p¡r¡d¡n-2-¡l) eth¡l) -4- (2, 4,5-trimethyl-3,6-dioxoxyclohexa-1,4-dienil) butanamide in the form of a yellow oil.

1H NMR (400 MHz, CDCh) 88.53 (d, 1H), 7.65 (t, 1H), 7.48 (rt, 1H), 7.21 (m, 2H), 3.71 (q, 2H), 3.04 (t, 2H), 2.52 (m, 1H), 2.34 (m, 1H), 2.00-1.89 (m, 10H), 1.58 (m, 1H ), 1.37 (s, 3H).

Example 28

(S) -2-h¡drox¡-N- (2-h¡drox¡et¡l) -2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡ clohexa-1,4-d¡en¡l) butanamida.

Following the amida coupling procedure described in protocol A. 5.06 g of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid (20.2 mmol ). 3.68 g of CDI (22.7 mmol) and 2.44 g (39.52 mmol) ethanolamine yielded 4.576 g of (S) -6-hydroxy-N- (2-hydroxy ethyl) -2.5. 7.8-tetramethylchroman-2-carboxamide as a white powder.

1H NMR (400 MHz. CDCh) 86.88 (s. 1H). 3.64 (t. 2H). 3.39 (m. 2H). 2.62 (m. 2H). 2.35 (dt 1H). 2.18 (s. 6H). 2.10 (s.

3H). 1.90 (m. 1H). 1.53 (s. 3H).

Oxidation as described in protocol B. using 3.50 g (11.93 mmol) of (S) -6-hydrox¡ -N- (2-hydrox¡ ethyl) -2.5.7.8- tetramethylchroman-2-carboxamide and 13.73 g of CAN (25.06 mmol) produced 3.341 g of (S) -2-hydrox, -N- (2-hydrox ¡Eth¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanamida in the form of a solid yellow color. 1H NMR (400 MHz. CDCh) 87.24 (t. 1H). 3.75 (t. 2H). 3.47 (m. 2H). 3.29 (s. 2H). 2.58 (td. 1H). 2.35 (td. 1H). 2.00 1.94 (m. 10H). 1.61 (td. 1H). 1.42 (s. 3H).

Example 29

2-H¡drox¡-2-met¡lN- (3- (2-oxop¡rrol¡d¡n-1-¡l) prop¡l) -4- (2.4.5-tr¡met¡l- 3.6-dioxocyclohexa-1.4-d¡en¡l) butanamida.

Following the amida coupling procedure described in protocol A. 499 mg of 6-hydrox¡-2.5.7.8-tetramethylchroman-2-carboxylic acid¡ co (2.00 mmol). 357 mg of CDI (2.2 mmol) and 569 mg of 1- (3-am¡nopropyl) p¡rrol¡d¡n-2-one (4.0 mmol) produced 598 mg of 6-hydrox¡-2.5 .7.8-tetramethylN- (3- (2-oxopyrrol¡d¡n-1-¡l) prop¡l) chroman-2-carboxamide as a white powder.

1H NMR (400MHz. CDCla) 87.02 (t. 1H). 3.31 (m. 2H). 3.24 (m. 1H). 3.11 (m. 2H). 2.59 (m. 2H). 2.37 (m. 3H). 2.24 (s. 3H). 2.17 (s. 3H). 2.08 (s. 3H). 2.01 (m. 2H). 1.87 (m. 1H). 1.61 (m. 4H). 1.51 (s. 3H).

Oxidation as described in protocol B. using 113.2 mg (0.302 mmol) of 6-hydroxy-2.5.7.8-tetramethylN- (3- (2 -oxop¡rrol¡d¡n-1-¡l) prop¡l) chroman-2-carboxam¡da and 364.6 mg of CAN (0.665 mmol) produced 118 mg of 2-hydrox¡-2-methyl - (3- (2-oxop¡rrol¡d¡n-1-¡l) prop¡l) -4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡ en¡l) butanam¡da in the form of a yellow oil.

1H NMR (400 MHz. CDCh) 8 7.52 (t br. 1H). 3.41 (quintuplet. 4H). 3.26 (m. 2H). 2.58 (td. 1H). 2.42 (m. 3H). 2.09 1.88 (m. 12H). 1.75 (m. 2H). 1.66 (m. 1H). 1.44 (s. 3H).

Example 30

2-Hydrox¡-N- (2-hydrox¡prop¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 4.98 g of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid co (19.9 mmol). 3.99 g of CDI (24.6 mmol) and 3.01 g of 3-amino-2-propanol (39.9 mmol) produced 5.15 g of 6-hydroxy-N- (2-hydroxypropyl) - 2.5.7.8-tetramethylchroman-2-carboxamide as a white powder.

1H NMR (400MHz. CDCh) 86.83 (brs. 1H). 3.8 (m.1H). 3.39 (m. 1H). 3.11 (m. 1H). 2.62 (m. 2H). 2.38 (dt 1H). 2.19 (s. 6H). 2.09 (s. 3H). 1.88 (m. 1H). 1.53 (s. 3H). 1.07 (dd. 3H).

Oxidation as described in protocol B. using 505 mg (1.64 mmol) of 6-hydroxy-N- (2-hydroxypropyl) -2.5.7.8- tetramethylchroman-2-carboxamide and 1.99 mg of CAN (3.62 mmol) produced 496 mg of 2-hydroxy-N- (2-hydroxypropyl) -2- methyl-4-2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡da) in the form of a yellow oil.

1H NMR (400 MHz. CDCh) 8 7.21 (t. 0.5H). 7.07 (t. 0.5H). 3.98 (m. 1H). 3.52 (m. 1H). 3.15 (m. 1H). 2.61 (m. 1H).

2.42 (m. 1H). 2.04-1.91 (m. 10H). 1.63 (m. 1H). 1.42 (s. 1H). 1.24 (m. 3H).

Example 31

2-H¡drox¡-N- (6-h¡drox¡hex¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da.

Following the amida coupling procedure described in protocol A. 500 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2-carboxylic acid ¡Co (2.0 mmol). 356 mg of CDI (2.2 mmol) and 468 mg of 6-amino-1-hexanol (4.0 mmol) produced 161 mg of 6-hydrox¡-N- (6-hydrox¡hex¡l) 2.5 .7.8-tetramethylchroman-2-carboxamide as a white solid.

1H NMR (400MHz. CDCh) 86.35 (t. 1H). 3.56 (t. 2H). 3.53 (sextet. 1H). 3.05 (sextet. 1H). 2.58 (m. 2H). 2.42 (sd.

1 HOUR). 2.19 (s. 6H). 2.09 (s. 3H). 1.83 (m. 1H). 1.53 (s. 3H). 1.53-1.29 (m. 5H). 1.20 (m. 2H). 0.99 (m. 2H).

Oxidation as described in protocol B. using 64.2 mg (0.183 mmol) of 6-hydrox¡ -N- (6-hydrox¡hex¡l) -2.5.7.8- tetramethylchroman-2-carboxamide and 230 mg of CAN (0.419 mmol) produced 40 mg of 2-hydroxy-N- (6-hydroxy hexyl) -2- methyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dienil) butanamide in the form of a yellow oil.

1H NMR (400 MHz, CDCI ³ ) 56.86 (t, 1H), 3.64 (t, 2H), 3.28 (q, 2H), 2.54 (m, 1H), 2.39 (m , 1H), 2.04-1.99 (m, 10H), 1.55 (m, 7H), 1.38 (m, 5H).

Example 32

2-Hydrox¡-N-6-hydrox¡hex¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1,4 -d¡en¡l) butanam¡da.

Following the amyda coupling procedure described in protocol A, 496 mg of 6-hydroxy-2,5,7,8-tetramethylchroman-2 acid carboxylic (1.98 mmol), 376 mg of CDI (2.32 mmol) and 404 mg of tetrahydrofuranlamine (4.0 mmol) produced 408.0 mg of 6-hydroxy- 2,5,7,8-tetramethylN - ((tetrahydrofuran-2-¡l) methyl) chroman-2-carboxamide crude that was oxidized following protocol B, with 335 mg CAN (0.612 mmol) to produce 74.7 mg of 2-hydroxy-2-methylN - ((tetrahydrofuran-2-¡l) methyl) -4- ( 2,4,5-trimethyl-3,6-dioxoxyclohexa-1,4-dienil) butanamide in the form of a yellow oil.

1H NMR (400 MHz, CDCh) 7.16 (m, 1H), 3.98 (m, 1H), 3.87 (m, 1H), 3.76 (q, 1H), 3.56 (m , 1H), 3.3 (d, 1H), 3.20 (m, 1H), 2.59 (m, 1H), 2.40 (m, 1H), 1.99 (m, 10H), 1 , 89 (q, 2H), 1.56 (m, 2H), 1.42 (s, 3H).

Example 33

2-Hydrox¡-2-met¡lN- (3-morphol¡noprop¡l) -4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡ l) butanamida.

To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (511 mg, 2.1 mmol) in 10 ml of THF was added They produced 356 mg of CDI and were stirred for 2 h. 3-Morpholin-propylamine (438 µL, 432 mg, 3.0 mmol) in 10 mL of THF was added dropwise and stirred overnight. The reaction was concentrated, dissolved in 70 ml of CH ² Ch, the organics were washed once with 50 ml of the saturated NaCl solution, dried over Na ² SO ⁴ and concentrated to give a brown oil. Flash chromatography produced 6-hydroxy-2,5,7,8-tetramethylN- (3-morpholnopropyl) chroman-2-carboxamide as a colored solid. pale brown.

1H NMR (400 MHz, CDCla) 56.57 (bs, 1H), 4.38 (bs, 1H), 3.68 (bs, 4H), 3.64 (m, 1H), 3.21 (m, 1H), 1.57 (m, 2H), 2.42-2.30 (m, 5H), 2.19 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H ), 1.84 (m, 1H), 1.61 (m, 4H), 1.52 (s, 3H). LRMS, APCI, (M ++ 1) 377.

To a 100 mg (0.266 mmol) solution of 6-hydroxy-2,5,7,8-tetramethylN- (3-morpholnopropyl) chroman-2-carboxamide at 5 ml of AcCN and a drop of H ² O at 0 ° C, a solution of 320.3 mg of CAN (0.584 mmol) in 3 ml of H ² O was added dropwise to it. It was treated with 5 ml of EtOAc and 5 ml of saturated NaCl followed by ~ 1 g of NaHCO ³ and 1 h of flask shaking. Then, the suspension was extracted 3 times with 5 ml of the isopropyl alcohol: isopropyl acetate 4: 1 solution and the combined organics were dried over Na ² SO ⁴ , were concentrated to give a yellow oil and flash chromatography was performed to yield 16 mg of 2-hydroxy-2-methylN- (3-morpholnopropyl). ) -4- (2,4,5-tr¡metal-3,6-dioxoxyclohexa-1,4-d¡en¡l) butanamide in the form of a yellow oil Dark it.

1H NMR (400MHz, CDCh) 57.75 (t, 1H), 3.74 (m, 4H), 3.36 (m, 2H), 2.53 (m, 4H), 2.40 (dt, 1H), 2.00 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3), 1.95 (m, 1H), 1.75 (m, 2H), 1, 58 (m, 1H), 1.39 (s, 3H).

13C NMR (100 MHz, CDCh) 5 187.6, 187.4, 175.5, 143.3, 140.95, 140.91, 140.2, 75.1, 66.5, 57.6, 53 , 6, 38.9, 38.6, 27.1, 25.0, 21.1, 12.4, 21.2, 12.0.

Example 34

2-Hydrox¡ -N-methox¡-N2-d¡met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanam gives.

To a solution of 5.47 g of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (21.9 mmol) in 170 ml of THF 3.92 g of CDI (24.2 mmol) were added and the mixture was stirred for 1.25 h at room temperature. To this, a solution of 2.14 g of N hydrochloride, Odemethylhydroxylamine (21.97 mmol) and 8.2 g of N were added dropwise. , N- d¡¡soprop¡let¡lam¡na in 50 ml of CH ² Cl ² for 1 h. The reaction was stirred overnight and concentrated, 250 mL of CH ² Ch was added and washed sequentially with 100 mL of 0.625 M HCl, 100 mL of ^{1.0 M NaHCO 3,} and 100 mL of Saturated NaCl. The organics were dried over Na ² SO ⁴ , concentrated and purified by flash chromatography yielding 4.43 g of 6 hydroxy-N-methoxy-N, 2.5 , 7,8-pentamethylchroman-2-carboxamide in the form of an off-white crystalline solid.

13 C NMR (100 MHz, CDCh) 53.63 (s, 3H), 3.31 (s, 3H), 2.74-2.55 (m, 3H), 2.18 (s, 3H), 2, 16 (s, 3H), 2.08 (s, 3H), 1.73 (m, 1H), 1.59 (s, 3H).

Oxidation as described in protocol B, using 155 mg (0.528 mmol) of 6-hydroxy-N-methoxy-N, 2,5,7, 8-pentamethylchroman-2-carboxamide and 637 mg of CAN (1.16 mmol) produced 119.4 mg of 2-hydroxy-N-methoxy-N, 2-di-methyl- 4-2,4,5-trimethyl-3,6-di-oxo-cyclohexa-1,4-di-en-l) butanamide as a yellow solid.

13C NMR (100 MHz, CDCh) 53.80 (s, 3H), 3.25 (s, 3H), 2.55 (dt, 1H), 2.37 (dt, 1H), 2.03 (s, 3H), 1.99 (m, 7H), 1.68 (dt, 1H), 1.48 (s, 3H).

Example 35

2-H¡drox¡-MN-b¡s (2-h¡drox¡et¡l) -2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa -1.4-d¡en¡l) butanam¡da.

To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 ml of THF was added 356 mg CDI (2.20 mmol). After stirring for 1.5 h. A solution of diethanolamine (231 mg, 2.2 mmol) in 10 ml of THF was added over 1 h and the reaction was stirred overnight. The reaction was concentrated. It was dissolved in 70 ml of CH ² Ch and washed sequentially with 50 ml of 0.62 M HCl. 50 ml of ^{1.0 M NaHCO 3.} 50 ml of saturated NaCl and dried over Na ² SO ⁴ . The combined aqueous phases were extracted 3 times with 50 ml of isopropyl alcohol / isopropyl acetate 3: 1, dried and concentrated to give a brown oil. Flash chromatography produced 63 mg of 6-hydrox¡-W, Ñ-b¡s (2-hydrox¡et¡l) -2.5.7.8-tetramethylchroman-2-carboxamide in the form of a yellow oil color.

1H NMR (400 MHz. CDCh) 84.35 (s. 1H). 4.11 (m. 1H). 3.91 (br. 1H). 3.81-3.65 (m br. 4H). 3.51 (bs 2H). 2.71-2.57 (m. 4H). 2.16 (s. 6H). 2.09 (s. 3H). 1.74 (m. 1H).

The oxidation as described in protocol B. using 68.4 mg (0.203 mmol) of the precursor 6-hydrox¡ -W, Wb¡s (2-hydrox¡ et¡l) -2.5.7.8-tetramethylchroman-2-carboxam¡da and 244 mg of CAN (0.446 mmol) producing 18.4 mg of 2-h¡drox¡-W, Wb¡s (2-h¡ drox¡et¡l) -2-met¡l-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4-d¡en¡l) butanamide in the form of an ace Yellow tea (25.7%).

1H NMR (400MHz. CDCla) 84.0-3.5 (m. 8H). 2.56 (td. 1H). 2.42 (td. 1H). 2.04 (s. 3H). 2.00 (s. 3H). 1.98 (s. 3H). 1.67 (m. 1H). 1.51 (s. 3H).

Example 36

N- (4-H¡drox¡fenet¡l) -2-h¡drox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc¡clohexa-1.4- d¡en¡l) butanam¡da.

Following the amyda coupling procedure described in protocol A. 500 mg of 6-hydroxy-2.5.7.8-tetramethylchroman-2- acid carboxylic (2.0 mmol). 356 mg of CDI (2.2 mmol) and 548 mg of t¡ramina (4.0 mmol) produced 537.8 mg of 6-hydrox¡-N- (4-hydrox¡fenet¡l) -2.5.7.8- tetramethylchroman-2-carboxamide as a brown solid.

1H NMR (400MHz. D6-DMSO) 89.16 (s. 1H). 7.51 (s. 1H). 7.17 (t.1H). 6.84 (d. 2H). 6.60 (d. 2H). 3.24 (q. 2H). 2.50 (m). 2.37 (m. 1H). 2.14 (m. 1H). 2.10 (s. 3H). 2.01 (s. 3H). 1.99 (s. 3H). 1.69 (m. 1H). 1.32 (s. 3H).

Oxidation as described in protocol B. using 100 mg of 6-hydrox¡-N- (4-hydrox¡fenet¡l) -2.5.7.8 -tetramethylchroman-2-carboxam¡da (0.271 mmol) and 325 mg of CAN (0.595 mmol) produced 15 mg of N- (4-hydrox¡fenet¡l) -2-hydrox¡-2- methyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dienil) butanamide in the form of a yellow solid. 1H NMR (400 MHz. CDCh) 87.75 (t. 1H). 7.00 (d. 2H). 6.63 (d. 2H). 3.34 (m. 2H). 2.68 (t. 2H). 2.54 (m. 1H). 2.12 (m.

1 HOUR). 1.93 (s. 6H). 1.90 (s. 3H). 1.78 (td. 1H). 1.48 (m. 1H). 1.28 (s. 3H).

Example 37

N- (2- (D¡met¡lam¡no) eth¡l) -2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc Clohexa-1.4-d¡en¡l) butanam¡da

Following the amida coupling procedure described in protocol A. 1.03 g of 6-hydroxy acid-2.5.7.8-tetramethylchroman-2- carboxylic (4.11 mmol). 0.712 g of CDI (4.39 mmol) and 704 mg of W, Wd¡met¡let¡lend¡am¡na (7.99 mmol) produced 1 g of N- (2- (d¡met¡lam¡no) et¡l ) -6-hydroxy-2.5.7.8-tetramethylchoman-2-carboxamide in the form of a white crystalline solid.

1H NMR (400 MHz. CDCh) 87.10 (bs 1H). 4.28 (bs 1H). 3.22 (m. 2H). 2.60 (m. 2H). 2.33 (m. 2H). 2.23 (m. 6H).

2.09 (s. 9H). 1.89 (m. 1H). 1.52 (s. 3H).

Oxidation as described in protocol B. uses 150 mg of N- (2 (dimetholamine) -etio) -6-hydrox -2.5.7.8-tetramethylchroman-2-carboxamide (0.468 mmol) and 564 mg of CAN (1.03 mmol) with exceptions as observed. The aqueous phase was basified with NaHCO ³ (s). It was extracted with EtOAc and the combined organics were dried over Na ² SO ⁴ . were concentrated and subjected to flash chromatography yielding 131 mg (83%) of N- (2- (dimethylamine) -ethl) -2-hydrox¡-2 -metal-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-dienil) butanamida in the form of a yellow solid.

1H NMR (400 MHz. CDCh) 87.62 (t. 1H). 3.48 (q. 2H). 2.63 (m. 3H). 2.37 (s. 6H). 2.30 (td. 1H). 1.96 (m. 10H). 1.57 (m. 1H). 1.41 (s. 3H).

Example 38

N- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2.4.5-trimethyl-3.6) hydrochloride -d¡oxoc¡clohexa-1.4-d¡en¡l) butanam¡da.

A solution of 22.8 mg of starting quinone in 2 ml of MeOH was treated with 20 µl of 4.0 M HCl in dixane solution. After five minutes. the yellow solution was concentrated. It was again dissolved in 0.2 ml of MeOH and triturated in a large excess of Et ² O. It was concentrated after one hour and ^{freshly prepared Et 2} O was added. After 72 h the reaction was filtered and a yellow solid of N- (2- (dimethylamine) ethyl) hydrochloride was collected. 2-hydroxy-2-methyl-4- (2.4.5-trimethyl-3.6-dioxoxyclohexa-1.4-di-ene) butanamide (15.6 mg).

1H NMR (400 MHz, CDCI ³ ) 59.09 (s, 1H), 5.02 (m, 1H), 4.85 (m, 1H), 4.59 (t, J = 5.6 Hz, 2H ), 4.09 (s, ^6H), 3.94 (td, 1H), 3.67 (td, 1H), 3.26 (s, 3H), 3.23 (s, ^6H), 3 .07 (td, 1H), 2.91 (td, 1H), 2.64 (s, 3H).

Example 39

N- (2- (D¡methylam¡no) eth¡l) -2-hydrox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d mesylate Oxocyclohexa-1,4-dimethyl) butanamide.

N- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimet) was dissolved ¡L-3,6-dioxoc¡clohexa-1,4-d¡en¡l) butanamida in 1 ml of CH ² Cl ² and 5.2 ml of methanesulfonic acid were added pure to the stirred yellow solution. The solution was concentrated, dissolved in CH ² Cl ² and triturated from Et ² O to give 20 mg of N- (2- (dimethylamine) et ¡L) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-l, 4-d¡en¡ l) butanamide in the form of a hydroscopic yellow solid. 1H NMR (400 MHz, CDCh) 57.9 (t, 1H), 3.87 (m, 1H), 3.56 (m, 1H), 3.32 (m, 1H), 2.96 (s, 3H), 2.95 (s, 3H), 2.80 (s, 3H), 2.65 (td, 1H).

Example 40

N- (3- (dimethyl) prop¡l) -2-h¡rox¡-2-methyl-4- (2.4.5-tr¡met¡l-3.6-d¡oxoc Clohexa-1,4-d¡en¡l) butanam¡da.

N- (3- (dimethyl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3 , 6-d¡oxoc¡clohexa-1,4-d¡en¡l) butanam¡da following the procedure of example 37 but substituting W, Wd¡met¡let¡lenod¡ amine with N ¹ N ¹ -d¡methylpropane-1,3-diamine.

1H NMR (400 MHz, CDCla) 57.2 (t, 1H), 3.36 (m, 1H), 3.2-3.3 (m, 3H), 2.93 (s, ⁶ H), 2 , 6 (m, 1H), 2.35 (m, 1H), 2.06 (m, 2H), 2.00 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H), 1.82 (td, 1H), 1.62 (td, 1H), 1.43 (s, 3H).

Example 41

6.6 '- (4.4' - (p¡peraz¡n-1.4-d¡¡l) b¡s (3-hydrox¡-3-methyl-4-oxobutane-4.1-d¡¡l)) b¡s (2.3.5-tr¡melc¡clohexa-2.5-diene-1.4-d¡one).

A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.0 g, 20 mmol), pyridine ( 50 ml) and acetic anhydride (43 ml) was stirred for 5 h. Water was added and the mixture was extracted into t-butyl methyl ether (MTBE) (2x 100 ml) and the combined organics were washed with water ( ² x ^{2 0 0} ml), a copper sulfate solution ( ² x ^{2 0 0} ml) and anally brine (2x 50 ml). The organic phase was collected, dried over sodium sulfate and decolorized using activated charcoal and concentrated to give a light green foam. The crude material was redissolved in CH ² Ch (50 ml) and dimethylformamide (2 drops) was added dropwise followed by oxalyl chloride ( 1.9 ml). Immediate gas evolution was observed. The mixture was stirred open to air for 2 h and the solvent was removed to give 2- (chlorocarbonyl) -2,5,7,8-tetramethylchroman-6-i acetate. (3.9 g, 13 mmol), which was used without additional purification.

2- (Chlorocarbonyl) -2,5,7,8-tetramethylchroman-6-lo acetate (3.9 g, 13 mmol) in CH2Cl2 (25 mL) was treated with di-isopropyl Letlamine (IDEA) (5.0 ml) followed by perazine (0.48 g, 5.6 mmol). The reaction mixture was heated to reflux briefly itself during the addition of peppermint. The reaction was allowed to cool to room temperature and stirred for 16 h. The mixture was then poured into MTBE (100 ml), the organic phase was extracted and washed with a saturated ammonium chloride solution (3x 50 ml) then dried over sodium sulfate. or. The solvent was extracted to provide 2,2 'diacetate - (p¡peraz¡n-1,4-d¡lb¡s (oxomethyl)) b¡s (2,5, 7,8-tetramethyl-3,4,5,8-tetrahydro-2H-chromene-6,2-d¡¡l) (3.7 g, 5.8 mmol) as a solid whitish amorphous color, which was used directly without additional purification.

To a 2,2 'diacetate solution - (p¡peraz¡n-1,4-d¡¡lb¡s (oxomethyl)) b¡s (2,5,7,8- tetramethyl-3,4,5,8-tetrahydro-2H-chromene-6,2-dl) (2.36 g), THF (25 ml) and MeOH (10 ml) were added ¡Or k Oh (1.04 g as a solution in 10 ml of MeOH). The reaction mixture was stirred at room temperature for 16 h, after which time it was completely dissolved. To the reaction mixture under stirring, CAN (9.16 g, 16.7 mmol) was then added as a solution in water (50 ml). After 1 h, add water (50 ml) was added, which caused the formation of a beige colored cap. The supernatant was decanted and extracted with MTBE. The solvent was removed in vacuo to give a crude yellow product, which was purified by flash chromatography, eluting with EtOAc / hexane (30% to 100%) to provide 6 , 6 '- (4,4' - (p¡peraz¡n-1,4-d¡¡l) b¡s (3-hydrox¡-3-methyl-4-oxobutane-4.1 -d¡¡l)) b¡s (2,3,5-tr¡melc¡clohexa-2,5-diene-1,4-d¡one) in the form of an amorphous solid of hard yellow color.

1H NMR (400 MHz, CDCls) 55.50 (bs, 2H), 3.95 (bs, 4H), 2.50 to 3.28 (m, ^6H), 2.50 to 2.40 (m, 4H), 2.02 to 1.90 (m, 18H), 1.75 (m, 2H), 1.59 (m, 2H), 1.36 (s, ^6H).

Example 42

2- (3-Hydrox¡-3-methyl-4-oxo-4- (p¡per¡d¡n-1-¡l) but¡l) -3.5.6-tr¡met¡lc Clohexa-2.5-diene-1.4-dine.

6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.005 g, 4.00 mmol) was treated in 22 ml of THF with 722.8 mg of CDI (4.4 mmol) and stirred for 2 h at room temperature. The light yellow solution was then treated with 450 μl of pyridine (381 mg, 4.47 mmol) in 22 ml of THF in 1-2 ml portions for 2 h . The reaction was stirred overnight at room temperature. The reaction was concentrated and the residue dissolved in 100 ml of CH ² CI ² and washed sequentially with 50 ml of 0.25 M HCl, 50 ml of ^{1.0 M NaHCO 3} , 50 ml of saturated NaCl and dried with Na ² SO ⁴ . The organic phase was concentrated. Flash chromatography yielded 992 mg of ( ^6- hydroxy-2,5,7,8-tetramethylchroman-2-yl) (piperidin-1-yl) methanone as an off-white solid.

1H NMR (400MHz, CDCh) ⁸ 4.42 (s, 1H), 3.95-3.83 (ma, 2H), 3.46 (br, 2H), 2.77 (m, 1H), 2 , 63-2.52 (m, 2H), 2.16 (s, 3H), 2.15 (s, 3H), 2.08 (S, 3H), 1.70 (m, 1H), 1, 58-1.48 (m, 2H), 1.45-1.36 (brs, 2H).

A solution of 319 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) (piperidin-1-yl) methanone (1.02 mmol) in 5 ml of MTBE that was treated with 1.077 g of F eC ^ ⁶ H ² O in ⁶ mL of H ² O. The reaction mixture rapidly returned to black which faded to a yellow color during the course of the reaction. 2 ml of MTBE were added and stirred vigorously for 3 h at room temperature. The reaction was stopped with 10 ml of H ² O and 10 ml of MTBE, the phases were separated, and the organics were washed with H ² O until colorless. The combined aqueous phases were extracted 2 times with 10 ml of MTBE and the combined organics were washed with saturated NaCl and dried over Na ² SO ⁴ . Flash chromatography yielded 335 mg of 2- (3-hydroxy-3-methyl-4-oxo-4- (piperidin-1-yl) butyl) -3,5,6-trimethylcyclohexa-2,5-diene-1, 4-dione in the form of a dark yellow oil.

1H NMR (400 MHz, CDCh) ⁸ 5.14 (s, 1H), 3.65-3.45 (ma, 4H), 2.48 (td, 1H), 2.36 (dt, 1H), 1 , 97 (s, 3H), 1.94 (s, ^6H), 1.88 (m, 1H), 1.68 to 1.57 (m, 7H), 1.42 (s, 3H).

13C NMR (100 MHz, CDCla) ⁸ 187.4, 187.1, 173.4, 143.4, 140.6, 140.5, 140.1, 73.3, 38.9, 26.2, 25 , 9, 24.3, 21.3, 12.3, 12.2, 11.8.

Example 43

N-Hexl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide.

6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.0 g, 19.99 mmol) was dissolved in pyridine (18 ml) and added in one portion Ac ² O (10 ml) . The exothermic reaction was heated to 40 ° C, allowed to cool to room temperature, and stirred overnight. The crude reaction mixture was quenched with 100 mL of H ² O, stirred for 1 hr followed by an additional 100 mL of H ² O and 1 h of stirring. A fine white precipitate of 6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was formed and filtration (4.544 g) was collected.

The crude 6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was dissolved in 30 ml of CH ² Ch, 2 drops of DMF were added followed by the slow addition of 1.5 ml of chloride of oxalyl. The gas evolved for 1 h and the solution was stirred overnight at room temperature. The reaction mixture was concentrated separately into five equal aliquots of 2- (chlorocarbonyl) -2,5,7,8-tetramethylchroman-6-yl acetate.

To one of the above aliquots of 2- (chlorocarbonyl) -2,5,7,8-tetramethylchroman-6-yl acetate in 10 ml of CH ² Ch was added 1.0 ml of diisopropylethylamine followed by 315 mg of 1 -hexylamine and stirred overnight. The reaction mixture was poured into 1.0M citric acid and 50 ml of EtOAc was added. The organic phase was separated and purified by flash chromatography to provide 781 mg of 2- (hexylcarbamoyl) -2,5,7,8-tetramethylchroman- ^6- yl acetate, as a clear syrup. MS (m / z): M + 376.3

Crude 2- (hexylcarbamoyl) -2,5,7,8-tetramethylchroman-6-yl acetate (187 mg, 0.25 mmol) in 1.25 ml MeOH was treated with 33.7 mg (0.625 mmol) NaOMe and left stirring overnight. The stirred brown solution was diluted with water (10 ml), neutralized with 2.5M HCl (1.5 ml) and 10 ml of EtOAc was added. The phases were separated and the organics were dried over Na ² SO ⁴ and concentrated. Flash chromatography provided 90 mg of A / -hexyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide.

1H NMR (400MHz, CDCh) ⁸ 6.46 (t, 1H), 4.76 (s, 1H), 3.20 (m, 2H), 2.58 (m, 3H), 2.18 (s , ⁶ H), 2.09 (s, 3H), 1.88 (m, 1H), 1.51 (s, 3H), 1.38 (m, 2H), 1.25 to 1.11 (m , ⁶ H), 0.85 (t, 3H).

A solution of 75 mg of N-hexyl-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (0.225 mmol) in 2 ml MTBE was treated with 2.0 ml of 0.5 MF eC ^ ⁶ H ² O and stirred vigorously for 24 h. The solution was treated with 5 ml of H ² O and 10 ml of MTBE, the phases were separated and the organics were rinsed 2 x 5 ml of H ² O, 2 x 5 ml of saturated NaCl. The combined organics were dried over Na ² SO ⁴ and concentrated. Flash chromatography produced W-hexyl-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as an orange-brown oil which was re-chromatographed to yield 31 mg of an oil of bright yellow color.

1H NMR (400 MHz, CDCh) ⁸ 6.82 (t, 1H), 3.48 (s, 1H), 3.22 (q, 2H), 2.55 (m, 1H), 2.36 (m , 1H), 2.04-1.96 (m, 10H), 1.61-1.46 (m, 3H), 1.38 (s, 3H), 1.33-1.22 (m, ⁶ H), 0.84 (t, 3H).

Biological Examples

Example A

Detection compounds of the invention in human dermal fibroblast from Friedreich's ataxia patients

An initial screening was performed to identify effective compounds for ameliorating redox disorders. Test samples, 4 reference compounds (idebenone, decilubiquinone, Trolox, and atocopherol acetate), and solvent controls were evaluated for their ability to save FRDA fibroblasts. stressed by the addition of L-butionine- (S, R) -sulfoximine (BSO), as described in Jauslin et al, Hum. Mol. Genet. 11 (24): 3055 (2002), Jauslin et al, FASEB J. 17: 1972-4 (2003), and International Patent Application WO 2004/003565. Human dermal fibroblasts from Friedreich's Ataxia patients have been shown to be hypersensitive to inhibition of de novo synthesis of glutathione (GSH) with L-butionine- (S, R) -sulfoximine (BSO), a specific inhibitor of GSH synthetase (Jauslin et al., Hum. Mol. Genet. 11 (24): 3055 (2002)). This specific BSO-mediated cell death can be prevented by the administration of antioxidants or molecules involved in the antioxidant pathway, such as α-tocopherol, selenium, or small molecules that resemble glutathione peroxidase. However, antioxidants differ in their potencies, in this case the concentration at which they have the ability to salvage FRDA fibroblasts stressed by BSO.

MEM (a medium enriched in amino acids and vitamins, catalog no. 1-31F24-I) and Medium 199 (M199, catalog no. 1-21F22-I) with Earle's Balanced Salts, without phenol red, were purchased at Bioconcept. Fetal Calf Serum was obtained from PAA Laboratories. The basic fibroblast growth factor and epidermal growth factor were purchased from Pepro Tech. A mixture of penicillin-Streptomycin-glutamine, L-butionine (S, R) -sulfoximine acetate, (+) - a-tocopherol, decylubiquinone, and bovine pancreas insulin were purchased from Sigma. Trolox (6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) was obtained from Fluka. Ibedona was obtained from Chemo Iberica. Calcein AM was purchased from Molecular Probes. The cell culture medium was made by combining 125 ml of M199 EBS, 50 ml of Fetal Calf Serum, 100 U / ml of penicillin, 100 | jg / ml of streptomycin, 2mM of glutamine, 10 jg / ml insulin, 10 ng / ml of EGF, and 10 ng / ml of bFGF; MEM EBS was added to make a volume of up to 500 ml. A 10 mM solution of BSO was prepared by dissolving 444 mg of BSO in 200 ml of medium with subsequent filter sterilization. During the course of the experiments, this solution was stored at 4 ° C. Cells were obtained from Coriell Cell Stores (Camden, NJ; warehouse number GM04078) and grown in 10 cm tissue culture plates. Every third day, they were divided in a 1: 3 ratio.

The test samples were supplied in 1.5 ml glass bottles. Compounds were diluted with DMSO, ethanol, or PBS to result in a 5 nM stock solution. Once dissolved, they were stored at -20 ° C. The reference antioxidants (ibedone, decylubiquinione, α-tocopherol acetate and trolox) were dissolved in DMSO.

The samples were screened according to the following protocol:

FRDA fibroblast culture was started from a 1 ml flask with approximately 500,000 cells stored in liquid nitrogen. The cells were propagated in 10 cm cell culture dishes by division every other day in a ratio of 1: 3 until nine plates were available. Once confluent, the fibroblasts were harvested. For the microtiter plates (96-well MTP) a total of 14.3 million cells (passage eight) were resuspended in 480 ml of medium, corresponding to 100 µl of medium with 3000 cells / well. The remaining cells were distributed into 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% CO ² to allow coupling of the cells to the culture plate.

MTP medium (243 µl) was added to one well of the microtiter plate. The test compounds were thawed, and 7.5 µl of a 5 mM stock solution was dissolved in the well containing 243 µl of medium, resulting in a 150 jM master solution. Serial dilutions of the master solution were made. The period between single dilution steps was kept as short as possible (generally less than 1 second).

The plates were kept overnight in the cell culture incubator. The next day, 10 µl of a 10 mM BSO solution was added to the wells, resulting in a final 1 mM BSO concentration. Forty-eight hours later, three plates were examined under a phase contrast microscope to verify that the cells in the 0% control (wells E1-H1) were clearly dead. The medium from all plates was discarded, and the remaining liquid was removed by gently tilting the plate by inverting it on a paper towel.

Then, 100 µl of PBS containing 1.2 µM Calcein AM was added to each well. The plates were incubated for 50-70 minutes at room temperature. After that time the PBS was discarded, the plate was gently tilted on a paper towel and the fluorescence (excitation / emission wavelengths of 485 nm and 525 nm, respectively) was read on a Gemini fluorescence reader. The data was imported into Microsoft Excel (Excel is a Microsoft Corporation trademark for a spreadsheet program) and used to calculate the EC ⁵⁰ concentration for each compound.

The compounds were tested three times, in this case, the experiment was performed three times, the number of passages of the cells increasing by one time each repetition.

The solvents (DMSO, ethanol, PBS) did not have a detrimental effect on the viability of cells not treated with BSO nor did they have a beneficial influence on fibroblasts treated with BSO even at the highest concentrations tested (1%). Not one of the compounds showed auto fluorescence. The viability of fibroblasts not treated with BSO was set as 100%, and the viability of cells treated with BSO and compound was calculated as relative to this value.

The following Table 2 summarizes the EC ⁵⁰ for the four control compounds.

Certain compounds such as:

2-hydroxy-W- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (3-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2- (3-hydroxy-4- (4-hydroxypiperidin-1-yl) -3-methyl-4-oxobutyl) -3,5,6-trimethylddohexa-2,5-diene-1,4-dione;

2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide *;

2-hydroxy-W- (4-hydroxybutyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (5-hydroxypentyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (1-hydroxypropan-2-yl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide; (R) -2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

(S) -2-hydroxy-N- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide;

W- (3- (1H-imidazol-1-yl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (2- (2-hydroxyethoxy) ethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (2-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2- (3-hydrox¡-3-methyl-4- (4-methylp¡peraz¡n-1-¡l) -4-oxobut¡l) -3,5,6-tr¡ methyldohexa-2,5-diene-1,4-dione;

2- (4- (4-benzylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcidohexa-2,5-diene-1,4-dione;

2-hydroxy-2-methyl-W- (3-morpholinopropyl) -4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W, A / -bis (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2- (dimethylamino) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (4-hydroxyphenethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

6,6 '- (4,4' - (piperazine-1,4-diyl) bis (3-hydroxy-3-methyl-4-oxobutane-4,1-diyl)) bis (2,3,5-trimethylcidohexa -2,5-diene-1,4-dione);

W- (3- (dimethylamino) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2- (4- (4-acetylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcidohexa-2,5-diene-1,4-dione;

2- (3-hydroxy-3-methyl-4-oxo-4- (piperazin-1-yl) butyl) -3,5,6-trimethylcidohexa-2,5-diene-1,4-dione;

(R) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide *;

(S) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide *;

(R) -2- (4- (4-acetylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4- dione;

(S) -2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3.5, 6-trimethyldohexa-2,5-diene-1,4-dione;

(R) -2- (3-hydroxy-4- (4-hydroxypiperidin-1-yl) -3-methyl-4-oxobutyl) -3,5,6-trimethylddohexa-2,5-diene-1,4- dione;

(S) -2- (3-hydroxy-4- (4-hydroxypiperidin-1-yl) -3-methyl-4-oxobutyl) -3,5,6-trimethylcidohexa-2,5-diene-1,4- dione;

W- (2-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2-chlorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-chlorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (4-methoxyphenyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-fluorophenyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorophenyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

exhibited protection against FRDA with an EC ⁵⁰ of less than about 100 nM.

Example B

Detection compounds in fibroblasts from Huntington's patients

Compounds were tested using the screen as described in Example A, but replacing the FRDA cells with Huntington cells obtained from Coriell's cell repositories (Camden, NJ; repository number GM 04281). The compounds were tested for their ability to rescue human skin fibroblasts from Huntington's patients from oxidative stress.

Certain compounds such as:

2-hydroxy-W- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (3-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide *;

2-hydroxy-W- (4-hydroxybutyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (5-hydroxypentyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (1-hydroxypropan-2-yl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

(R) -2-hydroxy-A / - (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

(S) -2-hydroxy-A / - (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3- (1H-imidazoM-yl) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (2- (2-hydroxyethoxy) ethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-2-methyl-W- (3- (2-oxopyrrolidin-1-yl) propyl) -4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (2-hydroxypropyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2- (3-hydroxy-3-methyl-4- (4-methylpiperazin-1-yl) -4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2- (4- (4-benzylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-hydroxy-2-methyl-W- (3-morpholinopropyl) -4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W, A / -bis (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2- (dimethylamino) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (4-hydroxyphenethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

6,6 '- (4,4' - (piperazine-1,4-diyl) bis (3-hydroxy-3-methyl-4-oxobutane-4,1-diyl)) bis (2,3,5-trimethylcyclohexa -2,5-diene-1,4-dione);

W- (3- (dimethylamino) propyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2- (4- (4-acetylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

(R) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide *;

(S) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide *;

(R) -2- (4- (4-acetylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4- dione;

(S) -2- (4- (4-acetylpiperazin-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4- dione;

W- (4-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-chlorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

2-hydroxy-W- (4-methoxyphenyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-fluorophenyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorophenyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (2-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (3-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W- (4-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

it exhibited protection against Huntington with an EC ⁵⁰ of less than about 100 nM.

Example C

Detection compounds in fibroblasts from Leber's hereditary optic neuropathy patients

The compounds were protected as described in Example A, but replacing the FRDA cells with Leber Hereditary Optic Neuropathy (LHON) cells obtained from Coriell's Cell Deposits (Camden, NJ; deposit number GM03858). The compounds were tested for their ability to rescue human skin fibroblasts of LHON patients from oxidative stress.

Certain compounds such as:

• 2-hydroxy-W- (2-hydroxyethyl) -2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

• 2- (3-hydroxy-3-methyl-4-oxo-4- (piperidin-1-yl) butyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

• 2- (4- (azepan-1-yl) -3-hydroxy-3-methyl-4-oxobutyl) -3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

• W-hexyl-2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;

W-benc¡l-2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d¡ en¡l) butanamida;

2-hydrox¡-W- (3-hydrox¡prop¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

2-hydrox¡-W-¡sopent¡l-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d En¡l) butanam¡da;

2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-dioxoxyclohexa-1,4-d¡en¡l) butanam¡ gives*;

2-h¡drox¡-W- (4-h¡drox¡but¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

2-h¡drox¡-W- (5-h¡drox¡pent¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

2-hydrox¡-W- (1-hydrox¡propan-2-¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d Oxocyclohexa-1,4-dimethyl) butanamide;

2-hydrox¡-W- (2- (2-hydrox¡ethox¡) eth¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3, 6-dioxocyclohexa-1,4-dimenyl) butanamide;

2-hydrox¡-W- (2-hydrox¡prop¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

2- (4- (4-benzylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methylcyclohexa-2,5-diene-1,4-dine;

W- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6 -dioxoxyclohexa-1,4-dienl) butanamida;

2-h¡drox¡-W- (4-h¡drox¡fenet¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

6,6 '- (4,4' - (p¡peraz¡n-1,4-d¡¡l) b¡s (3-hydrox¡-3-methyl-4-oxobutane-4, 1-d¡¡l)) b¡s (2,3,5-tr¡melc¡dohexa-2,5-diene-1,4-dione);

2-h¡drox¡-2-met¡lW- (p¡r¡d¡n-4-¡lmet¡l) -4- (2,4,5-tr¡met¡l-3,6-d Oxocyclohexa-1,4-dimethyl) butanamide;

2-h¡drox¡-2-met¡lW- (p¡r¡d¡n-3-¡lmet¡l) -4- (2,4,5-tnmet¡l-3,6-d¡oxoc Clohexa-1,4-dimethyl) butanamide;

2-hydrox¡-2-methylW- (3- (meth¡lsulfon¡l) prop¡l) -4- (2,4,5-tr¡mel-3,6-d¡oxoc Clohexa-1,4-dimethyl) butanamide;

2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methylcyclohexa-2,5-diene-1,4-dine;

2- (4- (4,4-d¡fluorop¡per¡d¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3.5, 6-trimethylclohexa-2,5-dimene-1,4-dione;

2- (4- (4-benzo¡lp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methylcyclohexa-2,5-diene-1,4-dine;

(R) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-dioxoxyclohexa-1,4-d¡en¡ l) butanamida *;

(S) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d¡en¡ l) butanamida *;

(R) -2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3.5, 6-trimethylclohexa-2,5-dimene-1,4-dione;

(S) -2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3.5, 6-trimethylclohexa-2,5-dimene-1,4-dione;

(R) -2- (3-h¡drox¡-4- (4-h¡drox¡p¡per¡d¡n-1-¡l) -3-methyl-4-oxobut¡l) - 3,5,6-trimethylcyclohexa-2,5-diene-1,4-dine;

(S) -2- (3-h¡drox¡-4- (4-h¡drox¡p¡per¡d¡n-1-¡l) -3-methyl-4-oxobut¡l) - 3,5,6-trimethylcyclohexa-2,5-diene-1,4-dine;

W- (2-fluorophenethyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (3-fluorophenethyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (4-fluorophenethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (3-chlorophenethyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡metal-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (4-chlorophenethyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡metal-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (4-fluorophenil) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (4-chlorophenyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (2-fluorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (3-fluorobenzl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (4-fluorobenzl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (2-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (3-chlorobenzyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (4-chlorobenz¡l) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡metal-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

exhibited protection against LHON with an EC ⁵⁰ of less than about 100 mm

Example D

Detection compounds in fibroplasts of Parknson's disease patients

The compounds were protected as described in Example A, but replacing the FRDA cells with Parknson's disease (PD) cells obtained from the cell's depots. Cor¡ell (Camden, NJ; warehouse number AG20439). The compounds were tested for their ability to rescue human dermal fibroblasts from patients of Parkinson's disease from oxidative stress.

Certain compounds such as:

2-hydrox¡-W-¡soprop¡l-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d En¡l) butanam¡da;

2-h¡drox¡-W- (2-h¡drox¡et¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

2-h¡drox¡-W- (5-h¡drox¡pent¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

(R) -2-hydrox¡-A / - (2-hydrox¡et¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6 -dioxoxyclohexa-1,4-dienl) butanamida;

(S) -2-hydrox¡-A / - (2-hydrox¡et¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6 -dioxoxyclohexa-1,4-dienl) butanamida;

W- (3- (1H-m¡dazol-1-¡l) prop¡l) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l -3,6-dioxoxyclohexa-1,4-dien-l) butanamide;

2-hydrox¡-W- (2- (2-hydrox¡ethox¡) eth¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3, 6-dioxocyclohexa-1,4-dimenyl) butanamide;

2- (4- (4-benzylp¡peraz¡n-1-¡l) -3-hydrox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methylcyclohexa-2,5-diene-1,4-dine;

W- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6 -dioxoxyclohexa-1,4-dienl) butanamida;

2-h¡drox¡-W- (4-h¡drox¡fenet¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

• W- (3- (dimethyl) prop¡l) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3, 6-dioxocyclohexa-1,4-dimenyl) butanamide;

exhibited protection against PD with an EC ⁵⁰ of less than about 100 nM

Example E

Detection Compounds in Fibroblasts of CoQ10 Deficient Patients

Compounds were tested using protection similar to that described in Example A, but replacing FRDA cells with cells obtained from def patients. CoQ10 patients harboring a CoQ2 mutation. The compounds were tested for their ability to rescue human dermal fibroblasts from CoQ10-deficient patients from oxidative stress.

2-h¡drox¡-W- (2-h¡drox¡et¡l) -2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡ clohexa-1,4-dimethyl) butanamide;

W-hex¡l-2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d¡ en¡l) butanamida;

2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-dioxoxyclohexa-1,4-d¡en¡l) butanam¡ gives*;

W- (2- (dimethyl) ethyl) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6 -dioxoxyclohexa-1,4-dienl) butanamida;

2-h¡drox¡-2-met¡lW- (p¡r¡d¡n-3-¡lmet¡l) -4- (2,4,5-tr¡met¡l-3,6-d Oxocyclohexa-1,4-dimethyl) butanamide;

2- (4- (4-acetylp¡peraz¡n-1-¡l) -3-h¡drox¡-3-methyl-4-oxobut¡l) -3,5,6-tr¡ methylcyclohexa-2,5-diene-1,4-dine;

2- (3-hydrox¡-3-methyl-4-oxo-4- (piperaz¡n-1-¡l) but¡l) -3,5,6-tr¡met¡lc Clohexa-2,5-diene-1,4-dione;

4- (2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-dioxoc¡clohexa-1,4-d¡en¡l tert-butylo) butano / l) piperazin-1-carboxylate; (S) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡met¡l-3,6-d¡oxoc¡clohexa-1,4-d¡en¡ l) butanamida *;

W- (2-chlorophenethyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

W- (4-fluorophenil) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxoxyclohexa-1, 4-day) butanamida;

W- (4-chlorophenyl) -2-hydrox¡-2-methyl-4- (2,4,5-tr¡methyl-3,6-d¡oxoc¡clohexa-1, 4-day) butanamida;

It exhibited protection against CoQ10 deficiency with an EC ⁵⁰ of less than about 100 nM.

Example F

Detection compounds in human dermal fibroblasts from autistic patients

A detection was performed to identify compounds effective for the improvement of ASD. The test samples, and solvent controls were tested for their ability to rescue ASD fibroblasts stressed by the addition of L-butyonyna- (S, R) -sulfox¡m ¡Na (BSO).

MEM (a rich medium in amino acids and vitamins, Gbco catalog no. 11965) and Fetal Calf Serum were obtained from Introgen. The basic fibroblast growth factor and epidermal growth factor were purchased from PeproTech. The mixture of pen¡c¡l¡na-streptomyna-glutamine, L-but¡on¡na (S, R) -sulfox¡m¡na, and insul¡na of bovine pancreas they were acquired from Sigma. Calcein AM was purchased from Molecular Probes. The cell culture medium (ATP) was prepared by combining 75 ml of Fetal Goat Serum, 100 U / ml of penny, 100 | jg / ml streptomycin, 2 mM glutamine, 10 ng / ml EGF and 10 ng / ml bFGF; MEM EBS was added to form a volume of 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, the solution was stored at 4 ° C. The cells were obtained from Dr. J.M. Shoffner, Medcal Neurogenetics, Atlanta, Ga. were grown on 10 cm tissue culture plates. Each week, they were entertained in a 1: 3 ratio. The samples were drawn into 1.5 ml glass bottles. Compounds were diluted with DMSO, ethane, or PBS to result in a 5 nM stock solution. Once dissolved, they were stored at -20 ° C.

The samples were screened according to the following protocol:

An ASD fibroblast culture was obtained from a 1 ml flask with approximately 500,000 cells stored in liquid nitrogen. The cells were propagated in 10 cm per day cell culture dishes each week in a ratio of 1: 3 until nine plates were available. Once confluent, the fibroblasts were harvested. For 54 micro-titer plates (96-well MTP), a total of 14.3 million cells (passage eight) were resuspended in 480 ml of medium, corresponding to or at 100 µl of medium with 3000 cells / well. The remaining cells were spread into 10 cm cell culture plates (500,000 cells / plate) for propagation. The plates were incubated overnight at 37 ° C in an atmosphere of 95% humidity and 5% CO ² to allow coupling of the cells to the culture plate.

The MTP medium (243 µl) was added to a well of the microtiter plate. The test compounds were thawed, and 7.5 µl of a 5 mM stock solution was dissolved in the well containing 243 µl of media, resulting in a 150 µM master solution. Serial dluctions of the master solution were performed. The period between single-ductile steps was kept as short as possible (generally less than 1 second).

The plates were kept overnight in the cell culture incubator. The next day, 10 jl were added of a 10 mM BSO solution to the wells, resulting in a final 1 mM BSO concentration. Forty-eight hours later, three plates were examined under a phase contrast microscope to verify that the cells in the 0% control (wells E1-H1) were clearly dead. The medium from all plates was discarded, and the remaining liquid was removed by gently tilting the plate by inverting it on a paper towel.

Then, 100 µl of PBS containing 1.2 pM Calcein AM was added to each well. The plates were incubated for 50-70 minutes at room temperature. After that time the PBS was discarded, the plate was gently tilted onto a paper towel and the fluorescence (excitation / emission wavelengths of 485 nm and 525 nm, respectively) was read on a Gemini fluorescence reader. The data was imported into Microsoft Excel (Excel is a Microsoft Corporation trademark for a spreadsheet program) and used to calculate the EC ⁵⁰ concentration for each compound.

The compounds were tested three times, in this case, the experiment was performed three times, the passage number of the cells increasing by one time each repetition.

The solvents (DMSO, ethanol, PBS) did not have a detrimental effect on the viability of cells not treated with BSO nor did they have a beneficial influence on fibroblasts treated with BSO even at the highest concentrations tested (1%). Not one of the compounds showed auto fluorescence. The viability of fibroblasts not treated with BSO was set as 100%, and the viability of cells treated with BSO and compound was calculated as relative to this value.

Compounds are considered to be active if they exhibit protection against ASD with an EC ⁵⁰ of less than 300 nM. One compound was evaluated using the above protocol and showed an activity of 50 nM.

Claims (15)

1. A compound selected from the group consisting of: • 2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocidohexa-1,4-dienyl) butanamide and • its hydroquinone form of it or a salt, a stereoisomer or a mixture of stereoisomers thereof. 2. The compound of claim 1, wherein the compound is selected from the group selected from the group consisting of: • (R) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide and • its hydroquinone form of it or a salt of it. 3. The compound of claim 1, wherein the compound is selected from the group consisting of: • (S) -2-hydroxy-2-methyl-4- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide and • its hydroquinone form of it or a salt of it. 4. The compound of any one of claims 1-3, wherein the compound is not a salt thereof. 5. The compound of any one of claims 1-4 wherein the compound is in its hydroquinone form. 6. A pharmaceutical composition comprising a compound as defined in any one of claims 1-5, together with a pharmaceutically acceptable excipient, carrier or vehicle. 7. A compound as claimed in any one of claims 1-5 or a composition as claimed in claim 6 for use in 1) treatment or suppression of a mitochondrial disorder, 2) modulation of one or more biomarkers of energy, 3) normalization of one or more energy biomarkers, or 4) enhancement of one or more energy biomarkers, which comprises administering to a subject a therapeutically effective amount or an effective amount of the compound or composition. A compound as claimed in any one of claims 1-5 or a composition as claimed in claim 6 for use in the treatment or suppression of mitochondrial disorder, comprising administering a therapeutically effective amount of the compound or composition, where 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); Leber's hereditary optic neuropathy (LHON); Leigh's disease; Kearns-Sayre syndrome (KSS); Friedreich's ataxia (FA); other myopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis; neurodegenerative diseases; Parkinson's disease; Alzheimer disease; amyotrophic lateral sclerosis (ALS); motor neuron diseases; other neurological diseases; epilepsy; genetic diseases; Huntington's disease; mood disorders; schizophrenia; Bipolar disorder; age-related diseases; cerebrovascular accidents; macular degeneration; diabetes; Cancer; coenzyme Q-10 deficiency; Complex I deficiency or NADH-CoQ reductase dehydrogenase deficiency; Complex II deficiency or succinate dehydrogenase deficiency; Complex III deficiency or ubiquinone-cytochrome C oxidoreductase deficiency; Complex IV deficiency or cytochrome C oxidase deficiency; Complex V deficiency or ATP synthase deficiency; Chronic progressive external ophthalmoplegia syndrome and ischemia. 9. The compound or composition as claimed in claim 7, for use in the treatment or suppression of a mitochondrial disorder, wherein the mitochondrial disorder is Alzheimer's disease. 10. The compound or composition as claimed in claim 7, for use in the treatment or suppression of a mitochondrial disorder, wherein the mitochondrial disorder is Parkinson's disease. The compound or composition as claimed in claim 7, for use in the treatment or suppression of a mitochondrial disorder, wherein the mitochondrial disorder is ALS. 12. The compound or composition as claimed in claim 7, for use in the treatment or suppression of a mitochondrial disorder, wherein the mitochondrial disorder is Huntington's disease. The compound or composition as claimed in any one of claims 7 to 12, for use in the treatment of mitochondrial disorder. A compound as claimed in any one of claims 1 to 5 or a composition as claimed in claim 6 for use in treating a subject suffering from a pervasive developmental disorder, comprising administering an amount therapeutically effective compound or composition to the subject, wherein Pervasive Developmental Disorder is selected from the group consisting of Autistic Disorder, Asperger's Disorder, Childhood Disintegrative Disorder (CDD), Rett's Disorder, or Rett's Syndrome, and Pervasive Disorder development not otherwise specified (PDD-NOS). 15. The compound or composition as claimed in claim 14, for use in treating a pervasive developmental disorder, Rett disorder or Rett syndrome.